Minimal inhibiting concentration

J Enzyme Inhib Med Chem, 2002 Dec, 17(6), 425 - 9
In vitro activity of a new antifungal azolyl-substituted indole against Aspergillus fumigatus; Pagniez F et al.; A new 2-(alpha-azolylbenzyl)indole derivative exhibited high in vitro activity against 10 strains of Aspergillus fumigatus . This active compound, MT18n, had MIC of 2 microg/mL and is slightly less active than itraconazole and amphotericin B . The mechanism of action of this compound was evaluated through scanning electron microscopy, ergosterol biosynthesis inhibition and phospholipase A2-like activity inhibition studies . Scanning electron microscopy allowed observation of the membrane perturbations caused by MT18n and inference of a critical role of MT18n in membrane synthesis inhibition . Like other azole derivatives MT18n inhibits ergosterol biosynthesis, with a minimal inhibitory concentration of 6 microM . On the other hand, MT18n (10 microM) decreased the secreted phospholipase A2-like activity of Aspergillus fumigatus, an enzyme involved in the invasion process of the host . These results show the high in vitro activity of MT18n against Aspergillus fumigatus and suggest that this compound disturbs the membrane structure via ergosterol biosynthesis inhibition and exhibits phospholipase activity inhibition.

Structure (Camb), 2003 Apr, 11(4), 411 - 22
Symmetry recognizing asymmetry: analysis of the interactions between the C-type lectin-like immunoreceptor NKG2D and MHC class I-like ligands; McFarland BJ et al.; Engagement of diverse protein ligands (MIC-A/B, ULBP, Rae-1, or H60) by NKG2D immunoreceptors mediates elimination of tumorigenic or virally infected cells by natural killer and T cells . Three previous NKG2D-ligand complex structures show the homodimeric receptor interacting with the monomeric ligands in similar 2:1 complexes, with an equivalent surface on each NKG2D monomer binding intimately to a total of six distinct ligand surfaces . Here, the crystal structure of free human NKG2D and in silico and in vitro alanine-scanning mutagenesis analyses of the complex interfaces indicate that NKG2D recognition degeneracy is not explained by a classical induced-fit mechanism . Rather, the divergent ligands appear to utilize different strategies to interact with structurally conserved elements of the consensus NKG2D binding site.

Minerva Anestesiol, 2003 Jan-Feb, 69(1-2), 35 - 56, 56-65
Critical points for sepsis management at the patient bedside; Tulli G; Following an interpretative philosophy, dyna-mic and faithful to the complexity theory, a clinical pathway is outlined close to the reality, at the patient bedside, that is comprehensive of the diagnostic process in its temporal dynamism, of the therapeutic process in its specificity (antibiotic therapy, surgical souce control), in the use of organs supportive therapy (haemodynamic, respiratory, renal, etc.) and in the use of adjunctive and immunomodulatory therapies (APC, AT, etc.) . The importance of the contextual activation of microbiological, immunological and coagulative monitorings is underlined . Through a critical review of the more recent literature, a strict relationship, in sepsis and septic shock, between inflammation and coagulation is described, that allowed the activated protein C (drotrecogin alpha activated) success, in terms of reduction of the absolute and relative mortality . This therapeutic success is contextualized into two other important therapeutic successes, recently obtained in severe sepsis and septic shock, based on the medical evidence, one using low doses of corticosteroids and the other using the early (6 h) goal directed haemodynamic therapy to restore a balance between oxygen delivery and oxygen demand . Once systemic inflammation is complicated by organ failure, there are few options . Treatment with activated protein C lowers the risk of death but is associated with an increased risk of bleeding and is likely to be expensive . The strategies described by the groups of Rivers and Annane offer the opportunity for good therapeutic results, by preventing the progression or even the development of sepsis and its complications: septic shock and multiple organ dysfunction.

Prog Drug Res, 2003, Spec No, 191 - 241
Susceptibility testing of fungi--current status and open questions; Seibold M et al.; The increase of fungal infections and the improvement of therapeutical options demand reliable antifungal susceptibility testing . In vitro susceptibility testing of fungi--in contrast to bacteria--is not yet established as a routine method . The NCCIS (National Committee for Clinical Laboratory Standards) guidelines for susceptibility testing of yeasts (and proposed for hyphomycetes) are most important for standardization . Meanwhile, essential parts of this test procedure are accepted, but it should still be improved . The concept of using only one test medium for all drugs and test organisms is not realized so far . There are also some test situations that prevent the NCCLS standard from being applied . Based on our experience, this article describes the NCCLS methods and their modifications . It places emphasis on lipophilic drugs showing controversies despite standardization . Furthermore, the prediction of MICs on the clinical outcome is discussed . Since there are some pitfalls in testing antifungals, this should be done in experienced laboratories only . The MIC has to be regarded as only one, but an important, factor in the management of fungal diseases . Host-, drug-, and pathogen-specific data should be considered simultaneously.

Int J Antimicrob Agents, 2003 Apr, 21(4), 364 - 91
Comité de l'Antibiogramme de la Société Française de Microbiologie report 2003; Members of the SFM Antibiogram Committee; Following the recommendations of the WHO Expert Committee for Biological Standardization (Technical reports No . 610, 1977), the French Society for Microbiology created an Antibiogram Committee (CA-SFM), with the aim of proposing the standards which define the clinical categories of antibiotic susceptibility (formerly therapeutic categories) . The MIC and zone diameter interpretive standards, as well as the specific recommendations for certain species or certain antibiotic groups, are published in a yearly report.

Immunogenetics, 2003 Mar, 54(12), 850 - 5 Epub 2003 Mar 06.
MICB typing by PCR amplification with sequence specific primers; Gonzalez S et al.; MICB is a member of the MIC (MHC class I chain-related gene) family . Sixteen MICB alleles have been described; however, the functional relevance and population distribution of MICB alleles or their potential association to disease has not yet been evaluated . In this study, we have developed a PCR system using sequence-specific primers (PCR-SSP) that allows unambiguous amplification of all MICB alleles . This approach has been applied to type 100 healthy unrelated individuals from the Spanish population . The extent of polymorphism in this population is lower than that initially expected, and only nine alleles were detected . The alleles MICB01021 (46%), MICB0103101 (13.5%), MICB0104 (13.5%) and MICB0106 (12.5%) were found to be the most frequent alleles . HLA-B and MICA transmembrane polymorphism typing were also performed in this population . Our data showed that MICB is in linkage disequilibrium with MICA and even with HLA-B . Thus, the linkage disequilibrium with MICA and HLA-B suggests that MICB is a potential candidate for those diseases classically associated with HLA class I alleles.

Br J Cancer, 2003 Apr 7, 88(7), 1101 - 4
Quantitative analysis of macrophage inhibitory cytokine-1 (MIC-1) gene expression in human prostatic tissues; Nakamura T et al.; Macrophage inhibitory cytokine-1 (MIC-1) gene is a member of transforming growth factor-beta superfamily and was reported to be highly overexpressed in human prostate cancer using microarray technology . The aim of this study was to evaluate the quantitative expression of MIC-1 in malignant and benign prostate tissues and to associate expression levels with clinicopathological parameters of prostate cancer . Matched (paired) prostatic tissue samples from the cancerous and noncancerous parts of the same prostates were obtained from 66 patients who underwent radical prostatectomy . Quantitative RT-PCR was performed using SYBR Green I on the Roche LightCycler system . Macrophage inhibitory cytokine-1 gene overexpression in cancerous tissues was observed in 88% of cases, compared to noncancerous tissues (P<0.001) . The expression level of MIC-1 in cancerous tissues was significantly higher than in noncancerous tissue (P<0.001) . Higher expression of MIC-1 gene was significantly associated with higher Gleason score (P=0.004) . The expression of the MIC-1 gene in prostate cancer is significantly higher than in noncancerous tissues, especially in more aggressive forms of the disease (Gleason score>5) . This is in contrast to prostate-specific antigen that is downregulated in higher-grade tumours . The upregulation of MIC-1 in prostate cancer and in advanced and more aggressive prostatic tumours suggests that MIC-1 protein should be evaluated as a potential diagnostic and prognostic biomarker.

Acta Pol Pharm, 2002 Nov-Dec, 59(6), 439 - 42
Antimycobacterial activity of some pyrido-1,2-thiazine derivatives; Malinka W et al.; The 3-benzoylpyrido-1,2-thiazine-1,1-dioxides 1 and the related pyrazolopyrido-1,2-thiazine-5,5-dioxides 2 with a 4-arylpiperazin-1-ylpropyl side chained by the nitrogen atom of the thiazine ring were evaluated in vitro against Myobacterium tuberculosis H37Rv . Some of the tested compounds proved to be potent antimycobacterial agents and for the most active of them (1a,b) minimum inhibitory concentrations (MIC = 3.13 and 6.25 microg/ml, respectively) were determined . The correlation between mycobacterium growth inhibition and the lipophilicity (logPcalc.) within the series of derivatives 1 and 2 was studied.

Biophys J, 2003 Apr, 84(4), 2293 - 305
Polyvalent cations as permeant probes of MIC and TRPM7 pores; Kerschbaum HH et al.; Recent studies in Jurkat T cells and in rat basophilic leukemia cells revealed an Mg(2+)-inhibited cation (MIC) channel that has electrophysiological properties similar to TRPM7 Eyring rate model expressed exogenously in mammalian cells . Here we compare the characteristics of several polyvalent cations and Mg(2+) to block monovalent MIC current from the outside . Putrescine, spermidine, spermine, PhTX-343 (a derivative of the naturally occurring polyamine toxin philanthotoxin), and Mg(2+) each blocked in a dose- and voltage-dependent manner, indicating a blocking site within the electric field of the ion channel . Spermine and the relatively bulky PhTX-343 exhibited voltage dependence steeper than that expected for the number of charges on the molecule . Polyamines and Mg(2+) are permeant blockers, as judged by relief of block at strongly negative membrane potentials . Intracellular dialysis with spermine (300 microM) had no effect, indicating an asymmetrical pore . At the single-channel level, spermine and Mg(2+) induced flickery block of 40-pS single channels . I/V characteristics and polyamine block are similar in expressed TRPM7 and in native MIC currents, consistent with the conclusion that native MIC channels are composed of TRPM7 subunits . An Eyring rate model is developed to account for I/V characteristics and block of MIC channels by polyvalent cations from the outside.

Bioorg Med Chem Lett, 2003 Apr 17, 13(8), 1419 - 23
Identification of a broad-spectrum azasordarin with improved pharmacokinetic properties; Serrano-Wu MH et al.; The synthesis and antifungal activity of 5'- and 5'-6'-substituted azasordarin derivatives are described . Modification of the 5'-position led to the discovery of the spirocyclopentyl analogue 7g, which is the first azasordarin to register single-digit MIC values versus Aspergillus spp . Further investigation identified the 5'-i-Pr derivative 7b, which displays superior pharmacokinetic properties compared to other azasordarins.

Diagn Microbiol Infect Dis, 2003 Mar, 45(3), 203 - 6
Minimum fungicidal concentrations of amphotericin B for bloodstream Candida species; Canton E et al.; Minimum fungicidal concentrations (MFCs) of amphotericin B were obtained for 165 bloodstream isolates (104 Candida parapsilosis, 14 C.glabrata, 13 C.tropicalis, 15 C.krusei, and 19 C.albicans) and 36 C.dubliniensis from oropharyngeal infections . Minimum inhibitory concentrations (MICs) were determined by the M27-A microdilution method . MFCs (> or =99.9% killing) were obtained following MIC determination (inoculum size, 10(4) CFU/ml) by seeding the entire volume of all clear wells . The best fungicidal activity was for C . albicans, (MFC90 1 microg/ml) and the lowest for C.parapsilosis, C.tropicalis and C.glabrata (MFC90 16 microg/ml) . Although MFCs were > or =16x MIC for some isolates, including C . glabrata, the overall MFCs were > or =2x MICs . However, major differences between MICs and MFCs were observed for C.parapsilosis and C.dubliniensis (3.8% and 8.9%, respectively, were tolerant: MFC > or =32MIC) . MFCs for C.tropicalis and C . glabrata were > or =2 microg/ml . By this more stringent method we found substantial differences from those previously reported between amphotericin B MIC and MFCs for Candida spp.

J Cataract Refract Surg, 2003 Mar, 29(3), 487 - 91
Penetration of topically applied ciprofloxacin and ofloxacin into the aqueous humor and vitreous; Yalvac IS et al.; PURPOSE: To determine the intraocular penetration of topical drops of 2 antibiotics, ciprofloxacin 0.3% and ofloxacin 0.3%, into the aqueous humor and vitreous and to relate these levels to the miminum inhibitory concentration (MIC(90)) for organisms associated with ocular bacterial infections . SETTING: Department of Ophthalmology, Ankara Hospital, and Department of Pharmacology, Faculty of Medicine, Hacettepe University, Ankara, Turkey . METHODS: This prospective randomized clinical trial comprised 18 patients having cataract surgery, all with an intact corneal epithelium . The patients were randomly assigned to receive topical ciprofloxacin 0.3% (n = 10) or topical ofloxacin 0.3% (n = 8) 1 drop every 15 minutes 5 times and every 30 minutes 3 times before surgery . Aqueous and vitreous samples (if vitreous loss occurred during the cataract surgery) were collected 30 minutes after the administration of the last dose . Drug concentrations were determined by high-performance liquid chromatography (HPLC) fluorescence . RESULTS: All patients had detectable drug concentrations in the aqueous humor and vitreous measurable by HPLC . The mean aqueous humor concentration of ciprofloxacin was 1.13 microg/mL +/- 1.90 (SD) and the mean vitreous concentration, 0.23 +/- 0.06 microg/mL . Topical administration of ciprofloxacin yielded 4.9 times more drug concentration in the anterior chamber than in the vitreous . The mean aqueous concentration of ofloxacin was 2.06 +/- 1.06 microg/mL and the mean vitreous concentration, 0.46 +/- 0.10 microg/mL . Topical administration of ofloxacin yielded 4.7 times more drug concentration in the anterior chamber than in the vitreous . Aqueous humor concentrations of ofloxacin and ciprofloxacin were not statistically significantly different (P =.353) . Intravitreal concentrations of ofloxacin were statistically significantly higher than those of ciprofloxacin (P =.001) . CONCLUSIONS: Topical ofloxacin 0.3% penetrated better than topical ciprofloxacin 0.3% into the anterior chamber and vitreous in noninflamed eyes . Both drugs were above the MIC(90) for most ocular pathogens in the anterior chamber . The mean concentration in the vitreous of topically applied ofloxacin 0.3% was statistically significantly higher than that of ciprofloxacin 0.3%, but it was not sufficiently above the MIC(90) for most ocular pathogens in terms of empirical endopthalmitis therapy.

Vet Dermatol, 2003 Apr, 14(2), 99 - 102
Synergistic inhibition of the growth in vitro of Microsporum canis by miconazole and chlorhexidine; Perrins N et al.; An agar dilution technique was used to assess the minimum inhibitory concentrations (MIC) of miconazole, chlorhexidine and a 1:1 combination of both agents for 10 isolates of Microsporum canis . For nine of 10 of the isolates, a combination of miconazole and chlorhexidine was more effective than either agent alone; fractional inhibitory concentration indices indicated a synergistic effect for five isolates and an additive effect for four . These results illustrate the potent antimycotic effect of miconazole and chlorhexidine against M . canis and are in accordance with previous clinical studies that showed the value of using miconazole and chlorhexidine shampoo in association with oral griseofulvin in the treatment of feline dermatophytosis caused by M . canis.

Kansenshogaku Zasshi, 2003 Feb, 77(2), 83 - 8
{Fundamental studies on legionellosis--the growth with in Acanthamoeba sp . and antibiotics susceptibility of Legionella spp . isolated from soil samples in Japan}; Furuhata K et al.; As part of an epidemiological study of legionellosis, we investigated the growth within Acanthamoeba sp . and antibiotic susceptibility of 62 strains of Legionella spp . isolated from surface soils nationwide in 2001 . 1) All strains tested grew in Acanthamoeba sp., suggesting that the strains were pathogenic . The minimum bacterial number required for the growth in the amoeba was 10(3)-10(8) CFU/ml and there were differences between the strains . 2) Susceptibility to 10 drugs was investigated using the Etest . The MIC90 values of imipenem, as a beta-lactam, and rifampicin, as an antitubercular agent, were 0.047 microgram/ml and 0.064 microgram/ml, respectively, showing high sensitivity . In contrast, sensitivity to minocycline, as a tetracycline, and piperacillin, as a beta-lactam, was low and the MIC90 values were 12 micrograms/ml and 16 micrograms/ml, respectively . Sensitivity to minocycline was particularly low, with a MIC value of 32 micrograms/ml, in two strains . The above findings suggested that all soil-derived strains were pathogenic, and susceptibility of the strains tended to be slightly lower than that of clinical isolates.

Bioorg Med Chem, 2003 Apr 17, 11(8), 1653 - 62
Hydrophobic derivatives of 2-amino-2-deoxy-D-glucitol-6-phosphate: a new type of D-glucosamine-6-phosphate synthase inhibitors with antifungal action; Janiak AM et al.; Several N-acyl and ester derivatives of 2-amino-2-deoxy-D-glucitol-6-phosphate (ADGP) have been synthesised and tested as inhibitors of fungal enzymes involved in early steps of chitin biosynthesis and for antifungal activity . All the tested derivatives were found to be much poorer inhibitors of the enzyme, D-glucosamine-6-phosphate (GlcN-6-P) synthase, than the parent compound but some of them exhibited much better antifungal activity . MIC values for the investigated compounds ranged between 10 mg mL(-1), found for ADGP and 0.3 mg mL(-1) for the most active derivative, namely ADGP dimethyl ester . Increased affinity of ADGP derivatives to the artificial immobilised cell membrane was correlated with their enhanced ability to be taken up by fungal cells by free diffusion . It was found that some of the examined derivatives behaved as 'pro-drugs' and after internalisation were converted into ADGP in the cell-free extract . This conversion was relatively rapid for ADGP esters but very slow for N-acyl derivatives . Results of our studies demonstrate a possibility of design and preparation of GlcN-6-P synthase inhibitors exhibiting antifungal activity.

Am J Health Syst Pharm, 2003 Mar 15, 60(6), 565 - 8
Economic benefit of a meropenem dosage strategy based on pharmacodynamic concepts; Kuti JL et al.; The economic benefit of a meropenem dosage strategy based on pharmacodynamic concepts is described . The pharmacodynamics of novel meropenem dosing regimens were compared with FDA-approved regimens by using Monte Carlo simulation with 5000 subjects . Using the meropenem NCCLS-susceptibility breakpoint of 4 micrograms/mL, the percentage of the dosing interval that drug concentration remained above the minimum inhibitory concentration (%t > MIC) was calculated for each regimen . Probability distributions for half-life and volume of distribution using previously published pharmacokinetic data from healthy volunteers were developed . Cost-minimization analysis was performed from the institution's perspective using both drug acquisition and supply costs . Daily costs for the lower dosage regimens were calculated using 2001 average wholesale prices . The mean %t > MIC for meropenem 500 mg administered every six hours (43.91% {95% confidence interval (CI), 36.77-51.46%}) was similar to that of 1000 mg every eight hours (45.77% {95% CI, 40.06-50.69%}) . The mean %t > MIC for meropenem 1000 mg administered every six hours (61.02% {95% CI, 54.71-67.43%}) was similar to the regimen of 2000 mg every eight hours (57.77% {95% CI, 51.84-63.76%}) . The 500-mg regimen reduced drug costs by $38.64 per day compared with the standard regimen of 1000 mg administered every eight hours . A pharmacodynamically influenced dosage strategy for meropenem resulted in %t > MIC exposure similar to standard regimens and required a lesser amount of the drug, thereby reducing costs without compromising efficacy.

Compr Psychiatry, 2003 Mar-Apr, 44(2), 154 - 61
The Spanish-Language Version of the Diagnostic Interview for DSM-IV personality disorders: development and initial psychometric evaluation of diagnoses and criteria; Grilo CM et al.; We describe the development of the Spanish-Language Version of the Diagnostic Interview for DSM-IV Personality Disorders (S-DIPD-IV) . Initial descriptive (frequency and gender distribution of personality disorders {PDs}) and psychometric findings (inter-rater reliability of diagnoses, internal consistency, and criteria inter-relatedness) are reported based on administration of the S-DIPD-IV to 95 adult monolingual Hispanic patients . The S-DIPD-IV had adequate inter-rater reliability for most PD (mean kappa =.83) . Except for the significantly greater proportion of males diagnosed with antisocial PD, no significant gender differences in the distribution of PD were observed . Within-category inter-relatedness of PD criteria was evaluated by coefficient alpha and mean intercriterion correlations (MIC) . Between-category criteria overlap was evaluated by intercategory mean intercriterion correlations between all pairs of PD (ICMIC) . For PD criteria, alpha ranged .36 to .99 (mean =.75, median =.81), MIC ranged .07 to .95 (mean = .36), and ICMIC ranged.09 to.45 (mean = .24) . Six PD (borderline, antisocial, narcissistic, avoidant, obsessive-compulsive, and depressive) had no instances in which their criteria sets correlated higher with those of other PD than their own . Two PD (histrionic and dependent PD) had some instances of overlap, and four PD (paranoid, schizotypal, schizoid, and passive-aggressive) had pervasive overlap with other PD criteria sets . These findings suggest the utility of the S-DIPD-IV for assessing PD in Spanish-speaking Hispanic outpatients . Our initial findings for this patient group suggest that, except for antisocial PD in males, specific PD diagnoses are not differentially distributed by gender . Moreover, except for cluster A PD, the criteria for specific PD tend to be more highly correlated within than across PD . The S-DIPD-IV appears to have utility to facilitate PD research with Hispanic groups .

Parasitol Res, 2003 Apr, 89(6), 467 - 72 Epub 2003 Jan 10.
The toxicity of praziquantel against Mesocestoides vogae (syn . corti) tetrathyridia can be assessed using a novel in vitro system; Saldana J et al.; We recently standardised Mesocestoides vogae (syn . corti) tetrathyridia cultures in the presence of sodium taurocholate . Parasite clustering and segmentation were observed as taurocholate-dependent effects in biphasic and monophasic media, respectively, and both were inhibited by a specific minimum inhibitory concentration (m.i.c.) of the cestocidal drugs albendazol and praziquantel . In the present study, we analysed the relationship between clustering inhibition and drug toxicity using praziquantel and a mouse experimental infection . In an "in vitro-in vivo" trial, a significant (ANOVA, P<0.05) reduction was observed in the infectivity of tetrathyridia previously cultured with praziquantel m.i.c . (0.06 micro g/ml) for 10 days . In an "in vivo-in vitro" trial, the clustering of tetrathyridia recovered from mice treated with praziquantel was found to be markedly reduced: 22%, compared with 83% cluster-containing wells of parasites from control mice . These results show that the outcome of infection and the suppression of taurocholate-induced clustering provide consistent indications of praziquantel toxicity against M . vogae, an observation confirmed by histological studies . The easily recorded clustering inhibition of M . vogae tetrathyridia in biphasic medium is a potentially useful system for the assessment of drug toxicity against cestode larvae.

Bioorg Med Chem Lett, 2003 Apr 7, 13(7), 1253 - 5
Antimycobacterial pimarane diterpenes from the Fungus Diaporthe sp; Dettrakul S et al.; Two new pimarane diterpenes, diaportheins A (1) and B (2), were isolated from a culture broth of the fungus Diaporthe sp . BCC 6140 . Diaporthein B (2) strongly inhibited the growth of Mycobacterium tuberculosis with the MIC value of 3.1 microg/mL, while diaporthein A (1) showed only mild activity (MIC value of 200 microg/mL).

Cell Mol Biol Lett, 2003, 8(1), 105 - 10
pH-dependent influence of a quaternary ammonium salt and an aminoester on the yeast Saccharomyces cerevisiae ultrastructure; Oblak E et al.; Quaternary ammonium salts inhibited the growth of yeast especially at pH higher (pH 8) than optimal . It was postulated that compounds integrate with the cell membrane and interfere with its functions . The yeast cell ultrastructure investigated under an electron microscope confirms this hypothesis . A relatively high percentage of cells treated at pH 6 with the quaternary ammonium salt of alanine derivative (DMALM-12) at the minimal inhibitory concentration showed an irregularity in the cell shape . No such irregularity was observed in the control . Besides, in the cells treated with the drug, practically no lipid droplets were seen at all . Inside the control cells, electron-dense round bodies were clearly seen and interpreted as vacuoles . These bodies were absent in the cells treated with DMALM-12 . Although the yeast cells growing at pH 8 showed a more or less normal shape, they seemed to have difficulty in budding - no fully developed buds were found in the preparations . Only some convexities of the cell wall were seen that could be the beginning of budding which stopped early after the start . Some changes in the round bodies interpreted as vacuoles were visible: they were less dense and full of granules.

Antimicrob Agents Chemother, 2003 Apr, 47(4), 1447 - 8
In vitro activity of a new antibiotic, NVP-PDF386 (VRC4887), against Chlamydia pneumoniae; Roblin PM et al.; The in vitro activity of NVP-PDF386 (VRC4887), a novel new peptide deformylase inhibitor, and those of levofloxacin and clarithromycin were tested against 21 isolates of Chlamydia pneumoniae . The MIC at which 90% of the isolates were inhibited and the minimal bactericidal concentration at which 90% of the isolates were killed by NVP-PDF386 for all isolates of C . pneumoniae were 0.008 micro g/ml (range, 0.008 to 0.015 micro g/ml) compared to 0.25 and 0.06 micro g/ml for levofloxacin and clarithromycin, respectively.

Antimicrob Agents Chemother, 2003 Apr, 47(4), 1439 - 42
Tissue penetration by ertapenem, a parenteral carbapenem administered once daily, in suction-induced skin blister fluid in healthy young volunteers; Laethem T et al.; The penetration of 1 g of intravenous ertapenem once daily for 3 days in suction-induced skin blisters was evaluated . Ten forearm blisters were formed (n = 12) 12 h prior to the last dose . Concentrations of ertapenem in blister fluid exceeded 4 micro g/ml (the MIC at which 90% of the isolates tested are eliminated) for the entire dosing interval . The area under the concentration-time curve for 0 to 24 h ratio of blister fluid to plasma was 61% (90% confidence interval, 56, 65%) suggesting good blister penetration.

Antimicrob Agents Chemother, 2003 Apr, 47(4), 1416 - 8
In vitro synergy of caspofungin and itraconazole against Aspergillus spp.: MIC versus minimal effective concentration end points; Shalit I et al.; Caspofungin and itraconazole were studied alone and in combination against 31 clinical isolates of Aspergillus spp . according to NCCLS M38-P guidelines . MICs and microscopic minimal effective concentrations (MECs) were recorded, and synergy was calculated by using both end points . Synergy or synergy to additivity was found in 30 of 31 isolates by using MIC end points . With MEC end points no synergy was found and indifference was detected in 26 of 31 strains.

Antimicrob Agents Chemother, 2003 Apr, 47(4), 1275 - 84
Flucytosine-fluconazole cross-resistance in purine-cytosine permease-deficient Candida lusitaniae clinical isolates: indirect evidence of a fluconazole uptake transporter; Noel T et al.; An unusual interaction between flucytosine and fluconazole was observed when a collection of 60 Candida lusitaniae clinical isolates was screened for cross-resistance . Among eight isolates resistant to flucytosine (MIC >/= 128 micro g/ml) and susceptible to fluconazole (0.5 < MIC < 2 micro g/ml), four became flucytosine-fluconazole cross resistant when both antifungals were used simultaneously . Fluconazole resistance occurred only in the presence of high flucytosine concentrations, and the higher the fluconazole concentration used, the greater the flucytosine concentration necessary to trigger the cross-resistance . When the flucytosine- and fluconazole-resistant cells were grown in the presence of fluconazole alone, the cells reversed to fluconazole susceptibility . Genetic analyses of the progeny from crosses between resistant and sensitive isolates showed that resistance to flucytosine was derived from a recessive mutation in a single gene, whereas cross-resistance to fluconazole seemed to vary like a quantitative trait . We further demonstrated that the four clinical isolates were susceptible to 5-fluorouracil and that cytosine deaminase activity was unaffected . Kinetic transport studies with {(14)C}flucytosine showed that flucytosine resistance was due to a defect in the purine-cytosine permease . Our hypothesis was that extracellular flucytosine would subsequently behave as a competitive inhibitor of fluconazole uptake transport . Finally, in vitro selection of spontaneous and induced mutants indicated that such a cross-resistance mechanism could also affect other Candida species, including C . albicans, C . tropicalis, and C . glabrata . This is the first report of a putative fluconazole uptake transporter in Candida species and of a possible resistance mechanism associated with a deficiency in the uptake of this drug.

Drug Dev Ind Pharm, 2003 Feb, 29(2), 215 - 21
Ophthalmic delivery of ciprofloxacin hydrochloride from different polymer formulations: in vitro and in vivo studies; Charoo NA et al.; Reservoir-type ocular inserts were fabricated using sodium alginate containing ciprofloxacin hydrochloride as the core (drug reservoir) that was sandwiched between the Eudragit and/or polyvinylacetate films . Ocular inserts were packaged in aluminium foil and sterilized by gamma radiation . These were tested for sterility as per British Pharmacopoeia (BP) . Ocular inserts were evaluated for in vitro release rate studies, microbial efficacy, in vivo release studies, efficacy against induced bacterial conjunctivitis in rabbit's eyes, concentration in the aqueous humor, and stability studies as per the International Conference on Harmonization (ICH) guidelines . Ocular inserts passed the test for sterility . They showed zero-order release of the drug in the in vitro and in vivo release studies over a period of 120 hr . The drug was found to be active against selected microorganisms as was proved by microbial efficacy studies . A high correlation coefficient was found between in vitro and in vivo release rate studies . Better improvement was observed in artificially induced bacterial conjunctivitis in rabbit's eyes, compared with marketed eye drops and placebo . Drug concentration in the aqueous humor was found above Minimum Inhibitory Concentration (MIC-90) against selected microorganisms . Shelf-life of the product was found to be more than 2 years.

Ir J Med Sci, 2002 Oct-Dec, 171(4), 193 - 6
Combination chemotherapy in the treatment of inoperable non-small cell lung cancer; Rutherford RM et al.; BACKGROUND: Chemotherapy is an established intervention in inoperable non-small cell lung cancer (NSCLC), yet few Irish patients receive this treatment . AIM: To determine survival, toxicity and radiological response following chemotherapy for NSCLC at our institution . METHODS: Retrospective audit of all patients receiving chemotherapy for histologically proven, inoperable NSCLC from January 1997 to December 2000 . RESULTS: There were 80 treatment episodes in 77 patients, mean age 62 years . Forty-eight (60%) patients had locally advanced and 32 (40%) metastatic disease . Mitomycin, Ifosfamide, Carboplatin (MIC) and Paclitaxel/Carboplatin (PC) were the most commonly administered regimens . Median survival for locally advanced and metastatic disease was 13.9 months and 7.1 months respectively . Severe neutropenia and thrombocytopenia were each witnessed after less than 9% of cycles . Eleven (16.7%) patients had radiological response including 4 (6.1%) complete responses . CONCLUSION: Survival for inoperable NSCLC treated with chemotherapy was encouraging and achieved at low toxicity.

AAPS PharmSci . 2002;4(4):E20.
Bioerodible injectable poly(ortho ester) for tetracycline controlled delivery to periodontal pockets: preliminary trial in humans; Schwach-Abdellaoui K et al.; The semisolid consistency of poly(ortho esters) (POEs) containing tetracycline free base allows direct injection in the periodontal pocket and shows sustained and almost constant in vitro release in phosphate buffer, pH 7.4 at 37 degrees C, for up to 14 days . Total polymer degradation concomitant with drug release was obtained . Formulations containing 10% or 20% (wt/wt) tetracycline were evaluated in a panel of 12 patients suffering from severe and recurrent periodontitis . In the first trial including 6 patients, single-rooted teeth and molar teeth with furcations were treated immediately after scaling and root planing . Patients tolerated both formulations well, experienced no pain during application, and showed no signs of irritation or discomfort during the observation period . However, retention of the formulation was minimal in this first study . An improved clinical protocol followed in the second study (stopping bleeding after scaling and root planning) prolonged the retention of the formulations in the inflamed periodontal pockets . For up to 11 days, tetracycline concentrations in the gingival crevicular fluid were higher than the minimum inhibitory concentration of tetracycline against most periodontal pathogens.

Bioorg Med Chem Lett, 2003 Mar 24, 13(6), 1051 - 4
Substituted 4-methylquinolines as a new class of anti-tuberculosis agents; Jain R et al.; We report synthesis and anti-tuberculosis activities of a series of novel ring-substituted quinolines . The most effective compound of the series 3d (MIC=6.25 microg/mL, Mycobacterium tuberculosis H37Rv strain) was synthesized in one step; thus is an attractive lead molecule for anti-tuberculosis drug development . The results of this study represent the discovery of ring-substituted 4-methylquinolines as new class of potential anti-tuberculosis agents.

Arzneimittelforschung, 2003, 53(2), 126 - 32
Suitability of cefotiam and cefuroxime axetil for the perioperative short-term prophylaxis in tonsillectomy patients; Muller R et al.; The efficacy of the perioperative short-term prophylaxis with cefotiam (CAS 66309-69-1) and cefuroxime axetil (CAS 64544-07-6) was analysed by the assessment of the pharmacological kinetics in the serum and the tonsil tissue in 50 patients with recurrent tonsillitis . Twenty-four patients received 1 g cefotiam by the intravenous route 30 min to 4 h before the tonsillectomy, and 26 patients received 250 mg cefuroxime axetil orally 1 to 6 h before the tonsillectomy . Bactericidal serum levels were reached for cefotiam up to 4 h after intravenous application and for cefuroxime axetil up to 3 h after oral application . In the tissue of the tonsil there were proved levels which were definitely above the MIC 90 (MIC = minimum inhibitory concentration) known for the clinically relevant germs for cefotiam after 30 min up to 2 h, for cefuroxime axetil after only 2 h . Considering the distribution areas, the capacity of the protein binding and the microbiological measuring methods, one can expect an efficient antibiotic coverage after an intravenous one-shot bolus injection of 1 g cefotiam from 30 min to 4 h and after oral application of 250 mg cefuroxime axetil on an empty stomach from 1 to 6 h . Because of the short duration of a tonsillectomy and the serum and tonsil tissue kinetics cefotiam and cefuroxime axetil are suitable for the perioperative antibiotic prophylaxis of high-risk patients.

Water Sci Technol, 2003, 47(3), 249 - 53
Antibiotic selective pressure for the maintenance of antibiotic resistant genes in coliform bacteria isolated from the aquatic environment; Park JC et al.; Coliform bacteria isolated from the aquatic environment were investigated for antibiotic susceptibility and detailed structures of class 1 integrons . A high proportion of isolates were found to be resistant to sulfamethoxazole, aminoglycosides, and beta-lactams . The 750 (53.6%) isolates were resistant to one or more of the antibiotics tested out of 1,400 coliform bacteria . Based on the MIC of antibiotics and antibiogram, 150 isolates were selected and further studied for class 1 integrons . The intI1 gene was found in 36 (24.0%) of the 150 isolates . Twelve isolates carried the gene cassettes responsible for antibiotic resistance, while no gene cassettes were found in 24 isolates . Seven different genes, dfrA5, dfrA7, dfrA12, dfrA17, aaA2, aaA5, and aad(3'), were detected in gene cassettes . The dfrA and aad genes located on class 1 integrons were responsible for resistance to trimethoprim and aminoglycosides . The remaining 24 coliform bacteria had the incomplete or non-functional class 1 integrons . These results indicated that antibiotic selective pressures may play an important role to maintain gene cassettes of class 1 integrons and in the absence of sustained antibiotic pressures, such as the aquatic environment, coliform bacteria may carry empty or non-functional class 1 integrons.

Folia Microbiol (Praha), 2002, 47(6), 742 - 6
Fatty acid analysis of Stenotrophomonas maltophilia clinical strains showing different susceptibility to antibiotics at 30 and 37 degrees C; Hejnar P et al.; Isolates of Stenotrophomonas maltophilia species display the feature "temperature-dependent susceptibility" (TDS) to antibiotics . Both 30TDS strains (at least 4 times lower value of minimum inhibitory concentration (MIC) of an antibiotic at 30 than at 37 degrees C) and 37TDS strains (at least 4 times lower value of MIC at 37 than at 30 degrees C) were described . Changes in the distribution of saturated and unsaturated fatty acids (FA) at 30 and 37 degrees C were considered as one of possible causes of the TDS phenomenon . Gas chromatography was used to determine the distribution of individual FA in five 37TDS strains of S . maltophilia (Group I); in five strains with MIC values unaffected by the cultivation temperature (Group II) and in six 30TDS (four strains) or 30/37TDS (two strains) isolates (Group III) . At identical temperatures, no statistically significant differences in the distribution of major FA (iso-15:0, anteiso-15:0, 16:0 and 16:1) were registered between individual groups . Statistically significant (p < 0.05) differences between groups were found in minor FA only (iso-16:0, iso-17:0 and iso-17:1) . Distribution changes of cellular FA at 30 and 37 degrees C can be considered to play only a minor role in the formation of the TDS phenomenon.

J Comb Chem, 2003 Mar-Apr, 5(2), 172 - 87
Combinatorial lead optimization of {1,2}-diamines based on ethambutol as potential antituberculosis preclinical candidates; Lee RE et al.; Despite relatively modest potency, ethambutol (EMB, (S,S)-{N,N-di-2-amino-1-butanol}ethylenediamine) is a mainstay of contemporary chemotherapy for the treatment of tuberculosis . We have developed a solid-phase synthesis of 1,2-diamine analogues of EMB using a novel acylation-reduction sequence that is compatible with high-throughput 96-well format chemistry . Using this procedure, we have synthesized 63 238 diamine analogues in pools of 10 that are suitable for testing . MIC and a target-based reporter assay were used to direct deconvolution of 2796 individual compounds from these mixtures, and the 69 most potent molecules were resynthesized in milligram quantities for hit confirmation . Purification of these individual active diamine analogues allowed the identification of 26 compounds with activity equal to or greater than EMB . Amines which occurred most frequently in active compounds included many with large hydrophobic moieties, suggesting that optimization was perhaps selecting for the isoprenoid binding site of the arabinosyltransferase target of EMB . N-Geranyl-N'-(2-adamantyl)ethane-1,2-diamine (109), the most active of these diamines, displayed a 14-35-fold improvement in activity in vitro against Mycobacterium tuberculosis, as compared to EMB.

Planta Med, 2003 Feb, 69(2), 155 - 7
Coumarins and carbazoles from Clausena excavata exhibited antimycobacterial and antifungal activities; Sunthitikawinsakul A et al.; Four known coumarins, dentatin (1), nor-dentatin (2), clausenidin (3) and xanthoxyletin (5), and six known carbazole derivatives, 3-formylcarbazole (6), mukonal (7), 3-methoxycarbonylcarbazole (8), murrayanine (9), 2-hydroxy-3-formyl-7-methoxycarbazole (10) and clauszoline J (11) were isolated from Clausena excavata . Compounds 1 and 6 were first isolated from the crude chloroform extract of the rhizomes . Compounds 1, 2, 3, 6, 7, 8, 10 and 11 showed antimycobacterial activity at a minimum inhibitory concentration (MIC) of 50, 100, 200, 100, 200, 50, 100 and 100 microg/mL, respectively . O-Methylated clausenidin ( 4), prepared from 3, exhibited antimycobacterial activity at MIC 50 microg/mL . Compounds 6, 7, 8 and 10 showed antifungal activity with IC 50 values of 13.6, 29.3, 9.5 and 2.8 microg/mL, respectively . All compounds demonstrated no cytotoxicity against KB and BC-1 cell lines.

J Clin Microbiol, 2003 Mar, 41(3), 1143 - 6
Proficiency testing program for clinical laboratories performing antifungal susceptibility testing of pathogenic yeast species; Ramani R et al.; Antifungal susceptibility testing is expected to facilitate the selection of adequate therapy for fungal infections . The general availability of antifungal susceptibility testing in clinical laboratories is low, even though a number of standard methods are now available . The objective of the present study was to develop and evaluate a proficiency testing program (PTP) for the antifungal susceptibility testing of pathogenic yeasts in laboratories licensed by the New York State Department of Health . A number of quality control standards, and methods for documenting laboratory performance, were developed in consultation with the laboratory directors . The participating laboratories were provided with five American Type Culture Collection strains of pathogenic yeasts for which the minimum inhibitory concentrations (MICs) of amphotericin B and fluconazole were well defined . A majority of laboratories (14 of 17) used broth microdilution, and these were evenly split between the NCCLS M-27A protocol and the Sensititre YeastOne method . The other three laboratories performed susceptibility testing with Etest . Overall, the levels of agreement between MIC reference ranges and the reported MICs were 85 and 74% for amphotericin B and for fluconazole, respectively . All laboratories except one successfully detected fluconazole resistance in a Candida krusei strain . However, amphotericin B resistance in a Candida lusitaniae strain was not detected by any of the participating labs . It is concluded that a suitably designed PTP could adequately monitor the competence of clinical laboratories performing antifungal susceptibility testing.

J Med Microbiol, 2003 Mar, 52(Pt 3), 239 - 45
Characterization of rifampicin-resistant Mycobacterium tuberculosis in Taiwan; Hwang HY et al.; Sixty-three rifampicin-resistant (Rif(r)) isolates of Mycobacterium tuberculosis from Kaohsiung, Taiwan, were analysed for mutations in the core region (69 bp, codons 511-533) of the rpoB gene . Some 84.1 % (53/63) of the resistant isolates showed mutations in this region, especially in codons 531 (41.5 %), 526 (18.9 %), 516 (15.1 %) and 533 (7.5 %) . Five novel alleles of a total of 16 different types of mutations were identified in Rif(r) isolates . Ten Rif(r) isolates (15.9 %) exhibited no mutations in the core region of rpoB . Also, they did not show mutations in another 365 bp fragment (codons 99-220) of rpoB . The agar proportion method was used to determine the relationship between the degree of rifampicin resistance and alterations in the core region of rpoB . The results revealed that the mean MIC was 92.38 micro g ml(-1) for the 53 isolates with a mutation in the core region, whereas the mean MIC of the other 10 isolates without mutations was only 24.8 micro g ml(-1) . This indicates that the isolates with mutations in the core region had higher levels of resistance than those without mutations in this region . IS6110 restriction fragment length polymorphism (RFLP) was used for typing of 55 Rif(r) M . tuberculosis isolates . Isolates contained two to 19 copies of IS6110, with sizes ranging from 600 to 16 000 bp . The majority (85 %) contained six to 16 copies . No strains lacking IS6110 were found . A total of 54 of 55 RFLP types were defined at the 90 % similarity level . The observation of varied IS6110-associated banding patterns indicates that an outbreak of drug-resistant tuberculosis did not occur in this area.

J Environ Monit, 2003 Feb, 5(1), 100 - 5
Diffusive sampling of methyl isocyanate using 4-nitro-7-piperazinobenzo-2-oxa-1,3-diazole (NBDPZ) as derivatizing agent; Henneken H et al.; A diffusive sampling method for the determination of methyl isocyanate (MIC) in air is introduced . MIC is collected using a glass fiber filter impregnated with 4-nitro-7-piperazinobenzo-2-oxa-1,3-diazole (NBDPZ) . The urea derivative formed is desorbed from the filter with acetonitrile and analyzed by means of high-performance liquid chromatography (HPLC) using fluorescence detection (FLD) with lambdaex = 471 nm and lambdaex = 540 nm . Additionally, a method was developed using tandem mass spectrometric (MS-MS) detection, which was performed as selected reaction monitoring (SRM) on the transition {MIC-NBDPZ + H}+ (m/z 307) to {NBDPZ + H}+ (m/z 250) . The diffusive sampler was tested with MIC concentrations between 1 and 35 microg m(-3) . The sampling periods varied from 15 min to 8 h, and the relative humidity (RH) was set from 20% up to 80% . The sampling rate for all 15 min experiments was determined to be 15.0 mL min(-1) (using HPLC-FLD) with a relative standard deviation of 9.9% for 56 experiments . At 80% RH, only 15 min sampling gave acceptable results . Further experiments revealed that humidity did not affect the MIC derivative but the reagent on the filter prior to and during sampling . The sampling rate for all experiments (including long term sampling) performed at 20% RH was found to be 15.0 mL min(-1) with a relative standard deviation of 6.3% (N = 42) . The limit of quantification was 3 microg m(-3) (LC-MS-MS: 1.3 microg m(-3)) for 15 min sampling periods and 0.2 microg m(-3) (LC-MS-MS: 0.15 microg m(-3)) for 8 h sampling runs applying fluorescence detection.

Diagn Microbiol Infect Dis, 2003 Feb, 45(2), 131 - 5
In vitro activity of voriconazole, itraconazole, caspofungin, anidulafungin (VER002, LY303366) and amphotericin B against aspergillus spp; Serrano Mdel C et al.; Voriconazole, anidulafungin (VER002, LY303366) and caspofungin are promising antifungal agents which provide a good protection against a variety of fungi, including yeasts and filamentous fungi . In this study, we tested the in vitro efficacy of voriconazole, itraconazole, caspofungin, anidulafungin (VER002, LY303366) and amphotericin B, against different species of Aspergillus spp . isolated from clinical specimens, using a microdilution broth method and following the NCCLS guidelines (document M38-P) . We also evaluated the effect that time readings have on MIC results . For caspofungin, we determined the minimun effective concentration (MEC), defined like the lowest concentration of caspofungin causing abnormal hyphal growth . Anidulafungin (VER002, LY303366) was the most active antifungal agent tested with MIC(90) of < or =0,03 mg/L . The activity of voriconazole, and itraconazole very similar with MIC(90) of 0,12 mg/L, 0,12 mg/L respectively . For caspofungin the MEC(90) was of 0,25 mg/L . Amphotericin B was the lest active antifungal agent studied with MIC(90) of 1 mg/L . There were no differences between MIC values at 48 and 72 h . These data demonstrate promising activity of voriconazole, anidulafungin (VER002, LY303366) and caspofungin against Apergillus spp.

Pharm Res, 2003 Jan, 20(1), 117 - 25
Direct formation of nanospheres from amphiphilic beta-cyclodextrin inclusion complexes; Memisoglu E et al.; PURPOSE: The aim of this work was to develop and characterize a highly loaded nanoparticulate system based on amphiphilic beta-cyclodextrins (CDs) to facilitate the parenteral administration of poorly soluble antifungal model drugs bifonazole and clotrimazole . METHODS: Inclusion complexes were characterized with spectroscopic techniques . Particle size distribution of nanospheres were determined by photon correlation spectroscopy (PCS) . Nanospheres were assessed for hemolytic activity . Entrapped and released drug quantities were determined and minimum inhibitory concentration (MIC) values of drugs, amphiphilic beta-CDs, and drug loaded nanospheres were evaluated . RESULTS: 1:1 inclusion complexes of model drugs with amphiphilic beta-CDs gave nanospheres <300 nm (polydispersity index < 0.15) by nanoprecipitation technique without using surfactants . By direct preparation from preformed inclusion complexes, loading was increased 2- to 8-fold depending on CD type and loading technique . Conventionally loaded CD nanospheres displayed immediate release whereas preloaded and highly loaded nanospheres liberated model drugs over a period of 1 h reducing the initial burst effect . MIC values of bifonazole and clotrimazole were lowered significantly when associated to amphiphilic beta-CD nanospheres . CONCLUSION: Amphiphilic beta-CDs form nonsurfactant, highly loaded nanospheres with lower hemolytic activity than that of natural CDs directly from inclusion complexes . They enhanced solubility and subsequently therapeutic efficacy of the model drugs.

Antimicrob Agents Chemother, 2003 Mar, 47(3), 1081 - 7
Use of the microbial growth curve in postantibiotic effect studies of Legionella pneumophila; Smith RP et al.; Using the standard Craig and Gudmundsson method (W . A . Craig and S . Gudmundsson, p . 296-329, in V . Lorian, ed., Antibiotics in Laboratory Medicine, 1996) as a guideline for determination of postantibiotic effects (PAE), we studied a large series of growth curves for two strains of Legionella pneumophila . We found that the intensity of the PAE was best determined by using a statistically fitted line over hours 3 to 9 following antibiotic removal . We further determined the PAE duration by using a series of observations of the assay interval from hours 3 to 24 . We determined that inoculum reduction was not necessarily the only predictor of the PAE but that the PAE was subject to the type and dose of the drug used in the study . In addition, there was a variation between strains . Only levofloxacin at five and ten times the minimum inhibitory concentration (MIC) resulted in a PAE duration of 4 to 10 h for both strains of L . pneumophila tested . Ciprofloxacin at five and ten times the MIC and azithromycin at ten times the MIC caused a PAE for one strain only . No PAE could be demonstrated for either strain with erythromycin or doxycycline . Using the presently described method of measuring PAE for L . pneumophila, we were able to detect differences in PAE which were dependent upon the L . pneumophila strain, the antibiotic tested, and the antibiotic concentration . We suggest the use of mathematically fitted curves for comparison of bacterial growth in order to measure PAE for L . pneumophila.

Antimicrob Agents Chemother, 2003 Mar, 47(3), 997 - 1001
Comparing pharmacokinetics of amoxicillin given twice or three times per day to children older than 3 months with pneumonia; Fonseca W et al.; For children with ambulatory pneumonia, the World Health Organization (WHO) recommends oral amoxicillin (15 mg/kg of body weight/dose) thrice daily (t.i.d.) or oral cotrimoxazole (4 mg of trimethoprim/kg/dose) twice daily (b.i.d.) . The more frequent amoxicillin dosing may lead to compliance problems . To compare the pharmacokinetics and levels of amoxicillin in plasma in the current WHO acute respiratory infection recommendations with the 25-mg/kg/dose b.i.d . regimen, we performed a two-group parallel study of 66 children ages 3 to 59 months with pneumonia . Amoxicillin was given orally at 25 mg/kg/dose b.i.d . or 15 mg/kg/dose t.i.d . Amoxicillin concentrations were determined by high-performance liquid chromatography after the first dose on days 1 and 3 . After the first dose on day 1, the mean area under the concentration-time curve (AUC) for amoxicillin after the 25-mg/kg dose was 54.7 versus 24.9 micro g . h/ml after the 15-mg/kg dose . After the first dose on day 3, the mean AUC was 44.1 versus 28.5 micro g . h/ml . All but two children had plasma amoxicillin concentrations above 0.5 micro g/ml for >50% of the dose interval on both days . Six children on day 1 and five children on day 3 had concentrations above 1.0 micro g/ml for <50% of the dose interval . On day 1, 16 of 27 children in the b.i.d . group and 11 of 26 children in the t.i.d . group had concentrations that were above 2.0 micro g/ml for <50% of the dose interval, and on day 3, 18 of 31 children in the b.i.d . group and 8 of 31 children in the t.i.d . group had concentrations that were above 2.0 micro g/ml for <50% of the dose interval . Amoxicillin b.i.d . is a feasible alternative for t.i.d . dosing . To lengthen the time above the MIC at higher concentration levels, a 30- to 40-mg/kg/dose b.i.d . should be considered instead of the 25 mg/kg/dose used in this study.

Zhongguo Zhong Xi Yi Jie He Za Zhi, 2002 Feb, 22(2), 122 - 5
{Effect of Erigeron breviscapus injection on ventricular and vascular remodeling in spontaneous hypertension rats}; Zhou JZ et al.; OBJECTIVE: To observe the ventricular and vascular remodeling reversal effect of Erigeron breviscapus injection (EBI), a protein kinase C inhibitor, in spontaneous hypertension rats (SHR) . METHODS: Twenty-four SHR were divided into 4 groups, they were treated respectively with EBI, Fosinopril, Enalapril and normal saline 10 mg/kg per day by intraperitoneal injection for 8 weeks . Systolic blood pressure (SBP), ventricular weight index (VWI) and protein kinase C (PKC) activity in myocardial cells were determined, ultrastructural changes of heart and vessel were observed by polaroscope and transmission electron microscope, and the area and content of myocardial interstitial collagen (MIC) were determined by image analyzer system . RESULTS: The left ventricular hypertrophy was regressed to certain degree after EBI, Fosinopril and Enalapril treatment, but no significant change in heart rate and right VWI was found . Fosinopril and Enalapril were superior to EBI in lowering SBP and left VWI, and EBI was more obvious in improving myocardial ultrastructure such as hypertrophy and degeneration . All the 3 drugs could improve the MIC and vascular remodeling, the MIC area, content and collagen volume fraction in the EBI group were lowered after treatment, as compared with those in the control group, but comparison between the three groups showed no significant difference . The 3 drugs could reduce the PKC activity in myocardial cell membrane, and EBI showed the effect more significant than that of the other two (P < 0.05) . CONCLUSION: EBI could reverse the myocardial, interstitial and vascular remodeling, improve the rigidness of cardiac muscle, thus, has protective effect on heart.

Vet Ther, 2002 Winter, 3(4), 409 - 19
Plasma concentrations of enrofloxacin and its active metabolite ciprofloxacin in dogs following single oral administration of enrofloxacin at 7.5, 10, or 20 mg/kg; Boothe DM et al.; Plasma concentrations of enrofloxacin and its active metabolite ciprofloxacin were monitored following oral administration of enrofloxacin at 7.5, 10, and 20 mg/kg to six healthy female bloodhounds using a randomized crossover design . Plasma samples were collected at various times over 24 hours following drug administration . Both the parent drug and its metabolite were detected by high-performance liquid chromatography, and plasma drug concentration-versus-time curves were subjected to noncompartmental pharmacokinetic analysis . Descriptive statistics were determined for each dosage, and comparisons were made among dosage groups for selected pharmacokinetic parameters . Increasing dosages of enrofloxacin resulted in increased plasma concentrations of both enrofloxacin and ciprofloxacin . Maximum concentration (Cmax) was 2.12 +/- 0.59, 2.1 +/- 0.34, and 4.74 +/- 1.05 mcg/ml for enrofloxacin and 1.30 +/- 0.31, 1.30 +/- 0.32, and 1.86 +/- 0.35 mcg/ml for ciprofloxacin when enrofloxacin was given at dosages of 7.5, 10, and 20 mg/kg, respectively . Cmax and area under the curve (AUC) for both enrofloxacin and ciprofloxacin were significantly greater at 20 mg/kg than at 7.5 and 10 mg/kg . Disappearance half-life was similar for all dosages, ranging from 4.6 to 5.2 hours for enrofloxacin and 8.8 to 10.7 hours for ciprofloxacin . Ciprofloxacin contributed up to 42% of the Cmax and up to 55% of the AUC of the total (enrofloxacin plus ciprofloxacin) . For organisms with a minimum inhibitory concentration (MIC) of 0.5 mcg enrofloxacin/ml, an inhibitory quotient (IQ; Cmax:MIC) of 8 or more was achieved in plasma only at 20 mg/kg.

Rev Esp Quimioter, 2002 Sep, 15(3), 268 - 71
{Study of the susceptibility of black yeasts of the Exophiala genus to antifungals using the Sensititre System}; Puerto JL et al.; Black yeasts belong to a group of dematiaceous fungi which are difficult to classify and identify . One of the genera that cause human infection, mainly phaeohyphomycosis, is Exophiala, which includes the species E . berger, E . castellanii, E . dermatitidis, E . jeanselmei, E . lecanii-corni, E . moniliae, E . pisciphila, E . salmonis and E . spinifera . We carried out a susceptibility study of five of these species (E . castellanii, E.dermatitidis, E, jeanselmei, E . lecanii-corni and E . moniliae), isolated from cutaneous exudates, to the usual antimycotic agents . Strains were cultured on Sabouraud agar and potato-dextrose agar . Species identification was made by conidiogenous microscopic observation and the following characteristics: maximum growth temperature, tolerance to cicloheximide and carbohydrate assimilation . Susceptibility to antimycotic agents (amphotericin B, fluconazole, itraconazole, ketoconazole and 5-fluorocytosine) was determined by the Sensititre YeastOne (Aamar Blue) commercial method . Amphotericin B activity was good for the five tested species, although the MIC for E . jeanselmei was high (1 mg/l . MICs for fluconazole were high for all the species, but only E . moniliae and E . lecanii-corni c be considered resistant . Activity of itraconazole, ketoconazole and 5-fluorocytosine was good.

Boll Chim Farm, 2002 Nov-Dec, 141(6), 423 - 7
Formulation studies on modified releasing amoxicillin trihydrate microcapsules; Canefe K et al.; In vitro researches and in vivo animal experiments show that, generally the antibiotic concentration should be above minimum inhibitory concentration for optimal efficiency . There is also direct and indirect evidence from human trials to support this claim . Consequently, a modified-release dosage form of the beta-lactam antibiotics might be therapeutically more efficient than the existing conventional products, which are rapidly absorbed to produce transient peaks in serum drug levels . In our study, Amoxicillin was chosen as the model drug, because it is currently one of the most widely prescribed oral semisynthetic penicillins . By using various types of polymers and different formulations of them, we tried to improve a microparticular system . We succeeded in obtaining optimal production of particulars in the prepared microcapsule form with the solvent evaporation technique . By applying suitable pharmaceutical technological production parameters, the production of the dosage form which releases modified-release form of the model antibiotic is provided . Production processes and availability for the aim is controlled by using the pharmaceutical technological tests, mainly with the methods according to USP XXIV . Consequently compared to the classical Amoxicillin trihydrate dosage forms used in treatment, we managed to form the microcapsule structure containing modified release.

Hua Xi Yi Ke Da Xue Xue Bao, 2002 Apr, 33(2), 253 - 5
{The in vitro study of the effects of 11 kinds of traditional Chinese medicine on the growth and acid production of Actinomyces viscosus}; Xiao Y et al.; OBJECTIVE: To assess the effects of different natural medicines on the growth and acid production of Actinomyces viscosus, thus making preparations for screening an effective agent to mediate the balance of oral microflora . METHODS: Actinomyces viscosus ATCC 19246 was chosen as the experimental bacteria . 11 kinds of traditional Chinese medicine, such as Rhizoma Ligustici Chuanxiong, Sargentodoxa Cuneata and Galla Chinensis were extracted by means of maceration, percolation and reflux extraction . First, the values of MIC of various extracts were measured . Second, the experimental medium containing various extracts was prepared . The concentration of the extracts was lower than the MIC of the medicine, and the initial pH of the medium was 7.4 . Then Actinomyces viscosus was cultured in the medium for 48 h, and finally the rest pH was measured . RESULTS: When the concentration of the medicines was lower than or equal to 8.000 mg/ml, it was found that all kinds of medicine except Radix Notoginseng can inhibit the growth of Actinomyces viscosus effectively, especially Polistes mandarinus and Semen Arecae . Tea polyphenols, Radix Notoginseng, Radix et Rhizoma Rhei, Polistes mandarinus and Sargentodoxa cuneata can inhibit the acid production of Actinomyces viscosus effectively, but Radix Scutellariae, Rhizoma Ligustici Chuanxiong, Semen Arecae, Radix Angelicae Dahuricae, Galla Chinensis and Catechu have no preliminary effect on it . CONCLUSION: Tea polyphenols, Radix et Rhizoma Rhei, Polistes mandarinus and Sargentodoxa cuneata can inhibit the growth and the acid production of Actinomyces viscosus effectively.

Zhong Yao Cai, 1999 Jun, 22(6), 295 - 8
{Chemical constituents of the essential oil from the fruits of Lindera glauca and its antifungal activities}; Yang D et al.; The chemical constituents of the two essential oils extracted from the fruits of Lindera glauca by hydrodistillation and petroleum ether have been studied by means of GC-MS . Among which, 32 kinds of constituents were identified in distilling oil and 22 kinds in solvent oil . The main components in distilling oil were n-carpric acid (25.39%), germacrene A (10.71%), n-dodecanole acid (10.08%), epishyobunol acetate (7.29%) and caryophyllene oxide (5.44%), and in solvent oil were camphene (17.55%), 3,6,6-trimethyl-2-norpinene (16.85%), capric acid, ethyl ester (13.61%), eucalyptol (8.10%), and alpha-cis-ocimene (7.38%), In vitro the distilling oil exhibited more manifest antifungal properties than the solvent oil with MIC between 0.03-0.5 ml/L for pathogenic fungi species and 1.0-1.5 ml/L for moulds . Almost having not contained the sesquiterpenoids and their derivatives in the solvent oil maybe were a reason of poor inhibitory.

Vet J, 2003 Mar, 165(2), 143 - 8
Strategic administration of enrofloxacin in poultry to achieve higher maximal serum concentrations; Sumano LH et al.; To achieve a higher maximal serum concentration (Cs(max)) of enrofloxacin after oral administration of 10mg/kg/day of three commercial preparations of enrofloxacin to chickens, two concentrations of the drug were tested (0.1 and 0.2%), under controlled laboratory conditions . A single oral bolus dose was delivered directly into the proventriculus of each of 240 chickens, which were equally divided into six groups: three received the customary concentration (0.1%), and three received the higher concentration . A quantitative/qualitative microbiological analytical method to determine serum concentrations of enrofloxacin and a software program to obtain pharmacokinetic variables, revealed that time vs . concentration relationships best fitted double peak shape curves, Cs(max1) and Cs(max2) . Statistically significant (P>0.01) increments were obtained when 0.2% enrofloxacin oral solutions from the three different commercial preparations were administered . The increments ranged from 175% to 338% for Cs(max1) and 69% to 342% for Cs(max2) . Optimal bactericidal concentrations of enrofloxacin are usually twice the value of their minimal inhibitory concentration . Although clinical trials are now required, it would appear that increments in the serum concentration of enrofloxacin may reduce to the rate at which bacterial resistance occurs and so increase clinical efficacy without affecting the cost per treatment.

Arch Biochem Biophys, 2003 Feb 15, 410(2), 222 - 9
Isolation, purification, and physicochemical characterization of a D-galactose-binding lectin from seeds of Erythrina speciosa; Konozy EH et al.; A lectin was isolated from the saline extract of Erythrina speciosa seeds by affinity chromatography on lactose-Sepharose . The lectin content was about 265 mg/100g dry flour . E . speciosa seed lectin (EspecL) agglutinated all human RBC types, showing no human blood group specificity; however a slight preference toward the O blood group was evident . The lectin also agglutinated rabbit, sheep, and mouse blood cells and showed no effect on horse erythrocytes . Lactose was the most potent inhibitor of EspecL hemagglutinating activity (minimal inhibitory concentration (MIC)=0.25 mM) followed by N-acetyllactosamine, MIC=0.5mM, and then p-nitrophenyl alpha-galactopyranoside, MIC=2 mM . The lectin was a glycoprotein with a neutral carbohydrate content of 5.5% and had two pI values of 5.8 and 6.1 and E(1%)(1 cm) of 14.5 . The native molecular mass of the lectin detected by hydrodynamic light scattering was 58 kDa and when examined by mass spectroscopy and SDS-PAGE it was found to be composed of two identical subunits of molecular mass of 27.6 kDa . The amino acid composition of the lectin revealed that it was rich in acidic and hydroxyl amino acids, contained a lesser amount of methionine, and totally lacked cysteine . The N-terminal of the lectin shared major similarities with other reported Erythrina lectins . The lectin was a metaloprotein that needed both Ca(2+) and Mn(2+) ions for its activity . Removal of these metals by EDTA rendered the lectin inactive whereas their addition restored the activity . EspecL was acidic pH sensitive and totally lost its activity when incubated with all pH values between pH 3 and pH 6 . Above pH 6 and to pH 9.6 there was no effect on the lectin activity . At 65 degrees C for more than 90 min the lectin was fairly stable; however, when heated at 70 degrees C for 10 min it lost more than 80% of its original activity and was totally inactivated at 80 degrees C for less than 10 min . Fluorescence studies of EspecL indicated that tryptophan residues were present in a highly hydrophobic environment, and binding of lactose to EspecL neither quenched tryptophan fluorescence nor altered lambda(max) position . Treating purified EspecL with NBS an affinity-modifying reagent specific for tryptophan totally inactivated the lectin with total modification of three tryptophan residues . Of these residues only the third modified residue seemed to play a crucial role in the lectin activity . Addition of lactose to the assay medium did not provide protection against NBS modification which indicated that tryptophan might not be directly involved in the binding of haptenic sugar D-galactose . Modification of tyrosine with N-acetylimidazole led to a 50% drop in EspecL activity with concomitant acetylation of six tyrosine residues . The secondary structure of EspecL as studied by circular dichroism was found to be a typical beta-pleated-sheet structure which is comparable to the CD structure of Erythrina corallodendron lectin . Binding of lactose did not alter the EspecL secondary structure as revealed by CD examination.

Zhong Yao Cai, 1999 Aug, 22(8), 414 - 5
{Study on activities of eight kinds of traditional Chinese medicine against urogential Chlamydia trachomatis}; Li J et al.; In order to screen the susceptibilities of urogenital chlamydia trachomatis (CT) to 8 kinds of traditional Chinese medicine by microculture technigue of McCoy cell in Vitro . The results showed that 8 kinds of Chinese medicines all had activities against urogenital CT . Their minimal inhibitory concentrations (MIC) were from 0.49 mg/ml to 15.63 mg/ml . The number and the volume of inclusions were reducing gradually, disappeared finally . These traditional Chinese medicines hadn't any action of cytotoxicity to McCoy cell . The result of this study will be useful for the further study.

Zhong Yao Cai, 1999 Aug, 22(8), 400 - 2
{Chemical composition of essential oil from leaves of litsea cubeba and its antifungal activities}; Wang F et al.; The 24 chemical constituents of the essential oil extracted from the leaves of Litsea cubeba have been identified by means of GC-MS technique . Among which, alpha-cis-ocimene(25.11%), 3,7-dimethyl-1,6-octadien-3-ol(16.85%) and n-transnerolidol (13.89%) were the principal components . In vitro this oil had a manifest antifungal activities with MIC between 0.03-0.4 microliter/ml for utilized pathogenic fungi and 1.0-2.0 microliters/ml for moulds.

J Antimicrob Chemother, 2003 Feb, 51(2), 435 - 8
Antimycobacterial activity of diospyrin derivatives and a structural analogue of diospyrin against Mycobacterium tuberculosis in vitro; Lall N et al.; Three derivatives and one structural analogue of diospyrin were synthesized and investigated for their inhibitory activity against Mycobacterium tuberculosis employing the rapid radiometric method in vitro . A novel aminoacetate derivative was found to be more active than the parent compound, the MICs being 50 and 100 mg/L, respectively, for a drug-susceptible strain, H37Rv, of M . tuberculosis . This derivative also exhibited an MIC of 50 mg/L for a few multidrug-resistant strains of M . tuberculosis . The other two derivatives and the analogue did not show any significant antimycobacterial activity at the highest concentration (100 mg/L) tested.

Environ Toxicol Chem, 2003 Feb, 22(2), 252 - 60
Toxicity of lead in aqueous medium to desulfovibrio desulfuricans G20; Sani RK et al.; The toxicity of Pb(II) to sulfate-reducing bacteria (SRB) was studied using Desulfovibrio desulfuricans G20 in a medium specifically designed to assess metal toxicity . The effects of Pb(II) toxicity were observed in terms of longer lag times, lower specific growth rates, and in some cases no measurable growth . With an increase in medium pH from 6 to 8, Pb(II) toxicity decreased . At all pH values, in the presence of Pb(II) concentrations ranging from 3 to 15 microM, specific growth rates decreased and lag times increased . The minimum inhibiting concentration (MIC) of Pb(II) causing a complete inhibition in growth at pH 6 was 10 microM, as compared to 15 microM at pH 7.2 and 8 . These MIC values are 40 times lower than previously reported for SRB . Results also show that with increases in initial cell protein concentration (inoculum size), soluble Pb(II) removal rates increased and the degree to which Pb(II) caused increased lag times was reduced . In the presence of Pb(II), in all cases in which D . desulfuricans grew (even after a 312-h lag time), the final cell protein concentration was equivalent to that of the Pb-free control . Live/dead staining, based on membrane integrity, indicated that while Pb(II) inhibited growth, Pb(II) did not cause a loss of D . desulfuricans membrane integrity.

Invest Ophthalmol Vis Sci, 2003 Feb, 44(2), 505 - 9
Intraocular ciprofloxacin levels after oral administration in silicone oil-filled eyes; Talwar D et al.; PURPOSE: To evaluate penetration of oral ciprofloxacin in the retro-silicone oil space fluid (RSOF) in silicone oil (SO)-filled eyes . METHODS: One dose of 750 mg ciprofloxacin was given to two groups of five patients with vitrectomized eyes with SO endotamponade, 4 hours (group I) and 8 hours (group II) before SO removal . In 10 vitrectomized eyes with SO endotamponade (group III) and another 10 patients scheduled for vitrectomy for the first time (group IV), two 750-mg doses every 12 hours, with the last dose 12 hours before surgery, were given . Blood samples were taken at the time of collection of RSOF samples in groups I, II, and III and of the vitreous in group IV . All samples were assayed for ciprofloxacin by high-performance liquid chromatography . RESULTS: The mean drug concentration in the RSOF was 0.34 +/- 0.09, 0.37 +/- 0.04, 0.84 +/- 0.29, and 0.44 +/- 0.11 micro g/mL in groups I, II, III, and IV respectively . The mean serum concentration was 1.29 +/- 0.63, 1.08 +/- 0.14, 1.93 +/- 0.84, and 1.34 +/- 0.55 micro g/mL in groups I, II, III, and IV respectively with no statistically significant difference between groups III and IV (P = 0.081) . CONCLUSIONS: Antibiotic levels in the RSOF in SO-filled eyes after oral administration of ciprofloxacin in two 750-mg doses exceeded the minimal inhibitory concentration for 90% of isolates (MIC(90)) for most bacterial species and was higher than levels reached in the vitreous in nonvitrectomized eyes (P = 0.001).

Anticancer Res, 2002 Nov-Dec, 22(6C), 4179 - 81
Turmeric (Curcuma longa) and curcumin inhibit the growth of Helicobacter pylori, a group 1 carcinogen; Mahady GB et al.; BACKGROUND: Curcumin, a polyphenolic chemical constituent derived from turmeric (Curcuma longa), has been shown to prevent gastric and colon cancers in rodents . Many mechanisms have been proposed for the chemopreventative effects, although the effect of curcumin on the growth of Helicobacter pylori has not been reported . H . pylori is a Group 1 carcinogen and is associated with the development of gastric and colon cancer . MATERIALS AND METHODS: A methanol extract of the dried powdered turmeric rhizome and curcumin were tested against 19 strains of H . pylori, including 5 cagA+ strains . RESULTS: Both the methanol extract and curcumin inhibited the growth of all strains of H . pylori in vitro with a minimum inhibitory concentration range of 6.25-50 micrograms/ml . CONCLUSION: These data demonstrate that curcumin inhibits the growth of H . pylori cagA+ strains in vitro, and this may be one of the mechanisms by which curcumin exerts its chemopreventative effects.

Wei Sheng Wu Xue Bao, 2001 Dec, 41(6), 723 - 30
{Preliminary study on citral impaires the Aspergillus flavus membrane}; Luo M et al.; Compared with the normally growing A . flauas, the content as below was determined: the utilization ratio to protein and reducing sugar of hyphostroma poisened by citral, the activity of {Na+, K+}-ATPase capable of decomposition ATP, and the seepagevity ratio of electrolyte . In addition, the shape change in spore was observed via the scanning electron microscope (SEM) and the fast multi-channel micro-spectrophotomer (FMCM) . The result above all suggested facts as following after it's poised by the citral in MIC . The surface of hyphostroma and spore turned into be porous and rough . The pass trace on spore shriveled and closed . The rate of conduct electricity increased by 52.8% . The utilization ratio to protein and reducing sugar respectively decreased 61.5% and 44.3% . The rate of spore's sprout dropped to 61.4% . The molecular structure of membrane was so distinctly changed that it lost the selective permeability . There was inhibition on hyphostroma growth and spore sprout.

Biophys J, 2003 Feb, 84(2 Pt 1), 922 - 7
MIC channels are inhibited by internal divalent cations but not ATP; Kozak JA et al.; TRPM7 channels are nonselective cation channels that possess a functional alpha-kinase domain . It has been proposed that heterologously expressed TRPM7 channels are activated (Runnels et al., 2001) or inhibited (Nadler et al., 2001) by dialyzing the cell with millimolar levels of ATP . The endogenous correlate of TRPM7 has been identified in T-lymphocytes and RBL (rat basophilic leukemia) cells and named MagNuM (for Mg(2+)-nucleotide-inhibited metal) or MIC (for Mg(2+)-inhibited cation) . Here, we report that internal Mg(2+) rather than MgATP inhibits this current . Cytoplasmic MgATP, supplied by dialysis at millimolar concentrations, effectively inhibits only when a weak Mg(2+) chelator is present in the pipette solution . Thus, MgATP acts as a source of Mg(2+) rather than a source of ATP . Using an externally accessible site within the pore of the MIC channel itself as a bioassay, we show that equimolar MgCl(2) and MgATP solutions contain similar amounts of free Mg(2+), explaining the fact that numeric values of Mg(2+) and MgATP concentrations necessary for complete inhibition are the same . Furthermore, we demonstrate that Mg(2+) is not unique in its inhibitory action, as Ba(2+), Sr(2+), Zn(2+), and Mn(2+) can substitute for Mg(2+), causing complete inhibition . We conclude that MIC current inhibition occurs simply by divalent cations.

Trends Immunol, 2003 Feb, 24(2), 82 - 7
HLA-G and MIC expression in tumors and their role in anti-tumor immunity; Seliger B et al.; Non-classical MHC class Ib molecules have attracted growing interest in recent years, especially because they interact with non-T-cell inhibitory or triggering receptors expressed on natural killer (NK) and T cells, suggesting that they have a role in immune recognition . Abnormalities in MHC class Ib expression are frequently found in human tumors of various histologies and might be associated with poor clinical outcome despite the local accumulation of immune competent cells . Available data suggest that the balance between activating and suppressing signals significantly influences the efficacy of the immune response and consequently of tumor progression.

Cancer Genet Cytogenet, 2002 Nov, 139(1), 67 - 70
Malignant peripheral primitive neuroectodermal tumor of the kidney; Vicha A et al.; Ewing family of tumors is a group of highly aggressive neoplasias that occur most commonly in the first two decades of life . These tumors are most frequently localized in bones, less frequently in soft tissues . They usually appear as undifferentiated small round-cell tumors . With current treatment regiments, 5-year disease-free survival rates exceed 60% in patients with a localized disease . Patients with metastatic disease at the time of their first presentation have a poor prognosis . We describe a rare case of visceral primitive neuroectodermal tumor with the involvement of the kidney in a 9-year-old girl . The tumor was studied with immunohistochemistry, cytogenetics, and molecular biology methods . Strong expression of protein MIC(2) by immunochemistry (antibody HBA 71) with subsequent demonstration of a translocation consistent with t(11;22)(q24;q12) using cytogenetic and reverse transcriptase polymerase chain reaction (RT-PCR) confirmed the histopathological diagnosis of peripheral primitive neuroectodermal tumor . We detected minimal residual disease in bone marrow using RT-PCR.

Antimicrob Agents Chemother, 2003 Feb, 47(2), 588 - 93
The antifungal protein from Aspergillus giganteus causes membrane permeabilization; Theis T et al.; We investigated the inhibitory effects of the antifungal protein (AFP) from Aspergillus giganteus on the growth of several filamentous fungi . For this purpose, the MICs of AFP were determined and ranged from 0.1 micro g/ml for Fusarium oxysporum to 200 micro g/ml for Aspergillus nidulans . The antifungal activity of AFP was diminished in the presence of cations . We were able to show that incubation of AFP-sensitive fungi with the protein resulted in membrane permeabilization using an assay based on the uptake of the fluorescent dye SYTOX Green . No permeabilization by AFP could be detected at concentrations below the species-specific MIC . Furthermore, AFP-induced permeabilization could readily be detected after 5 min of incubation . Localization experiments with fluorescein isothiocyanate-labeled AFP and immunofluorescence staining with an AFP-specific antibody supported the observation that the protein interacts with membranes . After treatment of AFP-sensitive fungi with AFP, the protein was localized at the plasma membrane, whereas it was mainly detected inside the cells of AFP-resistant fungi . We conclude from these data that the growth-inhibitory effect of AFP is caused by permeabilization of the fungal membranes.

Antimicrob Agents Chemother, 2003 Feb, 47(2), 524 - 8
Activities of azithromycin and amphotericin B against Naegleria fowleri in vitro and in a mouse model of primary amebic meningoencephalitis; Goswick SM et al.; Inhalation of fresh water containing the free-living ameba Naegleria fowleri may lead to a potentially fatal infection known as primary amebic meningoencephalitis . Amphotericin B is the only agent with established clinical efficacy in the treatment of primary amebic meningoencephalitis in humans, but therapy with this drug is often associated with adverse effects on the kidneys and other organs, and not all persons treated with amphotericin B have survived . We investigated the in vitro activity and in vivo efficacy of newer therapeutic agents in an attempt to identify other useful agents for treating primary amebic meningoencephalitis . Azithromycin has shown in vitro activity against Acanthamoeba spp . and in vivo activity against experimental toxoplasmosis . In our study, the MIC of azithromycin against N . fowleri was 13.4 micro M (10 micro g/ml), which was 123 times greater than the MIC of amphotericin B, which was 0.108 micro M (0.1 micro g/ml) . Azithromycin protected 100% of mice infected with N . fowleri at a dose of 75 mg/kg/day for 5 days, whereas amphotericin B protected only 50% of mice at a dose of 7.5 mg/kg/day for 5 days, and all control mice died during the 28-day observation period . We conclude that azithromycin has both in vitro and in vivo activity versus N . fowleri and may be a useful addition to therapy for primary amebic meningoencephalitis.

Diagn Microbiol Infect Dis, 2002 Dec, 44(4), 359 - 61
In vitro susceptibility of Mycoplasma hominis clinical isolates to tetracyclines, quinolones and macrolides; Samra Z et al.; We tested the in vitro activity of levofloxacin, ciprofloxacin, doxycycline, tetracycline, erythromycin, roxithromycin, clarithromycin and azithromycin against 110 clinical isolates of Mycoplasma hominis . The minimal inhibitory concentrations (MICs) were determined with the Etest . The minimal concentrations at which 90% of the isolates were inhibited (MIC(90)) were 0.064 microg/ml doxycycline and 0.19 microg/ml tetracycline . In 9 isolates (8.1%), the MIC for doxycycline was 4-12 microg/ml . These isolates were also resistant to tetracycline with a MIC of 32-128 microg/ml . No significant difference was found between doxycycline and tetracycline (p = 0.076) . Comparison of the two quinolones revealed that the MIC(90) for levofloxacin was 0.19 microg/ml and for ciprofloxacin, 0.5 microg/ml . A significant difference was found between doxycycline/tetracycline and levofloxacin or ciprofloxacin (p = 0.0001), and between levofloxacin and ciprofloxacin (p = 0.001) . All the isolates were highly resistant to the macrolides with MIC > or = 256 microg/ml . This finding has important implications for cases in which Mycoplasma infection is suspected and culture and/or in vitro susceptibility tests are not available.

Diagn Microbiol Infect Dis, 2002 Dec, 44(4), 347 - 52
Evaluation of BACTEC MGIT 960 PZA medium for susceptibility testing of Mycobacterium tuberculosis to pyrazinamide (PZA): compared with the results of pyrazinamidase assay and Kyokuto PZA test; Aono A et al.; The fully automated BACTEC MGIT 960 PZA medium for susceptibility testing of Mycobacterium tuberculosis to pyrazinamide (PZA) was evaluated using 101 Mycobacterium tuberculosis clinical isolates . The results obtained with the system were compared with those of the pyrazinamidase (PZase) assay and the Kyokuto PZA test based on a broth culture, which is commercially available in Japan . The overall concordance rate was 90.1% (91/101) among the three methods in the initial test . The concordance rates between the BACTEC MGIT 960 PZA medium vs the PZase assay, the BACTEC MGIT 960 PZA medium vs the Kyokuto PZA test, and the PZase assay vs the Kyokuto PZA test were 93.1, 91.1, and 96.0%, respectively . On the repeat test of the 10 strains with discrepant results among the three methods, the concordance rates reached over 97% between each of the two systems . The results of the repeat test were confirmed by MIC testing and sequencing analysis of the pncA gene encoding PZase of M . tuberculosis . The mean turnaround times from incubation for PZA susceptibility testing were almost similar for the two methods based on liquid media, the BACTEC MGIT 960 PZA medium and the Kyokuto PZA test (7.7 and 7.4 days, respectively) . These results indicate that both methods based on liquid media, the fully automated BACTEC MGIT 960 PZA medium and the Kyokuto PZA test for susceptibility testing to PZA, are useful for rapid diagnosis of PZA resistant tuberculosis.

Tissue Antigens, 2002 Dec, 60(6), 526 - 8
A new allele within the transmembrane region of the human MICA gene with seven GCT repeats; Rueda B et al.; Major histocompatibility complex class I chain-related genes (MIC) belong to a multicopy gene family located within the HLA class I region of chromosome 6 . They encode for proteins that have a completely different organization, expression, and products from classical HLA class I gene products . One member of this family is the MICA gene, which is characterized by its high degree of polymorphism, with over 50 MICA alleles described . Moreover, MICA exon 5 presents a microsatellite polymorphism consisting of a variable number of GCT repeats that encode for 4, 5, 6, 9, or 10 alanine residues, and a variant (MICA A5.1) that includes a nucleotide insertion (GCT-->GGCT) . In this study, we report a novel allele in the transmembrane region of the MICA gene consisting of seven GCT repeats found in a family based study of MICA polymorphism in celiac disease.

J Endod, 2003 Jan, 29(1), 44 - 7
Antibiotic susceptibility of bacteria associated with endodontic abscesses; Baumgartner JC et al.; Antibiotics to treat endodontic infections are routinely prescribed based on previously published susceptibility tests . There is increased concern that bacteria have increased resistance to the currently recommended antibiotics . The purpose of this investigation was to perform antibiotic susceptibility tests on a panel of bacteria recently isolated from endodontic infections . The bacteria in this study were aseptically aspirated with a needle from endodontic abscesses, cultivated, and identified at the species level . Each of the 98 species of bacteria was tested for antibiotic susceptibility to a panel of six antibiotics using the Etest . The antibiotics were penicillin V, amoxicillin, amoxicillin + clavulanic acid, clindamycin, metronidazole, and clarithromycin . The percentages of susceptibility for the 98 species were penicillin V: 83/98 (85%), amoxicillin: 89/98 (91%), amoxicillin + clavulanic acid: 98/98 (100%), clindamycin: 94/98 (96%), and metronidazole: 44/98 (45%) . Metronidazole had the greatest amount of bacterial resistance; however, if it is used in combination with penicillin V or amoxicillin, susceptibility of the combination with penicillin V or amoxicillin increased to 93% and 99%, respectively . Clarithromycin seems to have efficacy, but it is still considered an antibiotic under investigation because the minimum inhibitory concentration has not been established.

Hua Xi Kou Qiang Yi Xue Za Zhi, 2000 Jun, 18(3), 143 - 6
{Properties and infiltration arts of machinable infiltration ceramic(MIC)}; Yang H et al.; OBJECTIVE: The purpose of this study is to explore the infiltration arts of MIC and study the effects of different packing density of Al2O3 matrix on the properties of MIC . METHODS: alpha-Al2O3 specimens were fabricated by pouring alpha-Al2O3 slip with different powder/liquid ratios(P/L = 3.5, 7.5, 10.5) into a mold, and subsequently pre-fired at 1160 degrees C for 6 hours to form Al2O3 matrix . The packing density of the matrices were measured . Infiltration concepts were introduced into this study by infiltrating molten mica micro-crystalline glass into the porous Al2O3 matrix at 1160 degrees C for 6 hours to form a continuous interpenetrating composite . The composite then underwent micro-crystallization by nucleating at 550 degrees C for 1 hour and crystallizing at 900 degrees C for 1 hour, which resulted in the MIC . Mechanical properties including three point flexural strength, elastic modulus, Vicker's hardness, indentation fracture toughness and Weibull's modulus of flexural strength were determined . Parameters of machinability(H/KIC)2 of MIC were calculated . XRD and SEM were employed to study its microstructure . RESULTS: The resulted matrices reached packing densities of 63%, 76%, 78% with P/L of 3.5, 7.5 and 10.5 . The MIC attained high strength and good machinability after infiltration . Three-point flexural strength and indentation fracture toughness were 342, 431, 374 MPa and 4.05, 4.14, 5.02 MPa m1/2 for MIC with packing density of 63%, 76%, 78% separately . And parameters of machinability were 5.41, 6.84 and 7.39 respectively . Packing density of Al2O3 matrix significantly influenced the mechanical properties . Maximum properties were obtained with a matrix packing density of 75%(P/L = 7.5), with a Weibull's modulus of flexural strength of 6.8 . Machinability decreased with the increase of P/L ratio . Micro-crystallizing treatment resulted in the formation of evenly distributed mica crystalline in the composite, which contributed to the high strength of this composite material . CONCLUSION: MIC is a new infiltrated ceramic with favorable strength and machinability which can satisfy the prosthodontic requirements as all ceramic crown and bridge materials, it also shows promising outlook for future developments and clinical usage.

Hua Xi Kou Qiang Yi Xue Za Zhi, 1999 Nov, 17(4), 325 - 8
{Investigation of aluminum oxide matrix of the machinable infiltrated ceramic(MIC)}; Yang H et al.; OBJECTIVE: To explore the effects of different powder/liquid ratio during the procedure of aluminum oxide slip preparation on the properties and microstructure of the machinable infiltrated ceramic(MIC) aluminum matrice . METHODS: PI alpha-Al2O3 powder was employed in this study . Aluminum slip with different powder/liquid ratios of 3.5, 4.5, 5.5, 6.5, 7.5, 8.5, 9.5 and 10.5 was prepared separately . Specimens were slip-casted and pre-fired, and whose physical properties were determined and morphology of specimens was examined under scanning electromicroscope . RESULTS: The packing density increased while the linear shrinkage decreased, when the powder/liquid ratio increased . Elevated pre-firing temperature resulted in higher flexural strength of the matrice . The matrice demonstrated porous morphology under electromicroscope, and neck-fusion between Al2O3 particles was observed and increased with elevated prefiring temperature . CONCLUSION: MIC is a kind of easy-manipulated material with high packing density, optimum porosity and lower linear shrinkage, so it may be an ideal aluminum matrix for infiltrated ceramic.

Transpl Infect Dis, 2002 Dec, 4(4), 212 - 7
Breakthrough Scedosporium apiospermum (Pseudallescheria boydii) brain abscess during therapy for invasive pulmonary aspergillosis following high-risk allogeneic hematopoietic stem cell transplantation . Scedosporiasis and recent advances in antifungal therapy; Safdar A et al.; Systemic scedosporiasis due to the anamorph or asexual form Scedosporium apiospermum (Pseudallescheria boydii) has become an important cause of opportunistic mycosis, especially in patients undergoing high-risk hematopoietic stem cell transplantation . We report a case of rapidly progressive cerebellar hyalohyphomycosis due to Scedosporium apiospermum in an allogeneic marrow graft recipient receiving treatment for severe graft-versus-host disease . This fatal breakthrough intracranial abscess, due to amphotericin B-resistant (minimum inhibitory concentration > 16 micro g/ml) mold, developed during the course of systemic antifungal therapy given for multicentric pulmonary aspergillosis . Despite treatment with high-dose Abelcet (10 mg/kg daily), free amphotericin B was not detected in postmortem cerebellar tissue . A broad-spectrum triazole-based agent (voriconazole/UK-109, 496--Vfend), and a novel fungal cell wall inhibitor, an echinocandin/pneumocandin analog (caspofungin/MK-0991--Cancidas), which exhibit excellent in vitro activity against most clinical Pseudallescheria boydii-Scedosporium apiospermum isolates, have recently become available in the United States and may provide much needed treatment options for patients at risk.

J Pharm Sci, 2003 Feb, 92(2), 407 - 13
Preparation of in situ-forming ophthalmic gels of ciprofloxacin hydrochloride for the treatment of bacterial conjunctivitis: in vitro and in vivo studies; Charoo NA et al.; Sol-to-gel systems of ciprofloxacin hydrochloride were prepared utilizing the phase transition properties of hydroxy propyl methyl cellulose K 15 M grade (HPMC) and carbopol 934 . The sol-to-gel systems were sterilized by gamma radiation and/or filtration . The sol-to-gel systems were evaluated for rheological characteristics, in vitro release behavior, microbial efficacy, in vivo release behavior, and efficacy against induced bacterial conjunctivitis in rabbits' eyes . Concentration in aqueous humor was determined and stability studies were carried out as per the ICH guidelines . The system passed the test for sterility . The sol-to-gel system exhibited a zero-order drug release pattern over 24 h in in vitro release studies . The drug was active against selected microorganisms in microbial efficacy studies . Better improvement in artificially induced bacterial conjunctivitis in rabbits' eyes was observed in animals treated with the sol-to-gel system compared with marketed eye drops . Drug concentration in aqueous humor was greater than the minimum inhibitory concentration (MIC 90) against selected microorganisms . The shelf-life of the product was >2 years .

Mikrobiologiia, 2002 Nov-Dec, 71(6), 778 - 85
{The production of phenazine antibiotics by the Pseudomonas aureofaciens strain with plasmid-controlled resistance to cobalt and nickel}; Siunova TV et al.; Plasmid pBS501 responsible for the resistance of the wild-type Pseudomonas sp . BS501 (pBS501) to cobalt and nickel ions was conjugatively transferred to the rhizosphere Pseudomonas aureofaciens strain BS1393, which is able to synthesize phenazine antibiotics and to suppress a wide range of phytopathogenic microorganisms . The transconjugant P . aureofaciens BS1393 (pBS501) turned out to be resistant to cobalt and nickel with an MIC of 8 mM . When grown in a synthetic medium with 0.25 mM cobalt, the transconjugant accumulated 6 times more cobalt than the wild-type strain BS501 (pBS501) (1.2 and 0.2 microgram Co/mg protein) . Electron microscopic studies showed that cobalt accumulates on the surface of transconjugant cells in the form of electron-opaque granules . In a culture medium with 2 mM cobalt or nickel, strain BS1393 produced phenazine-1-carboxylic acid in trace amounts . The transconjugant P . aureofaciens BS1393 (pBS501) produced this antibiotic in still smaller amounts . Unlike the parent strain BS1393, the transconjugant P . aureofaciens BS1393 (pBS501) was able to suppress in vitro the growth of the phytopathogenic fungus Gaeumannomyces graminis var . tritici 1818 in a medium containing 0.5 mM cobalt or nickel.

J Infect Chemother, 2002 Dec, 8(4), 374 - 7
Usefulness of a colorimetric method for testing antifungal drug susceptibilities of Aspergillus species to voriconazole; Yamaguchi H et al.; The usefulness of a colorimetric method using Alamar Blue (Alamar Blue method) for susceptibility testing of Aspergillus species to voriconazole and three existing antifungal agents, itraconazole (ITCZ), flucytosine (5-FC), and amphotericin B (AMPH-B), was studied using four ATCC strains of three species, including two strains of A . fumigatus and one each of A . flavus and A . niger . For comparison, the broth microdilution method for antifungal susceptibility testing of filamentous fungi proposed by the National Committee for Clinical Laboratory Standards (NCCLS method M38-P) was also used . Minimum inhibitory concentration (MIC) endpoints were read spectrophotometrically for the Alamar Blue method and visually for the NCCLS method after 46-50 h . Like the NCCLS method, Alamar Blue produced highly reproducible results for all the drugs and strains tested; most MIC values obtained by nine tests were within the range of 2 twofold dilutions for each strain . Voriconazole and ITCZ susceptibility testing with the Alamar Blue method and the NCCLS method yielded comparable results in 94% of the tests, meaning that the endpoints obtained were identical or differed by no more than 2 twofold dilutions . On the other hand, susceptibility testing for 5-FC and AMPH-B yielded scores of 25% and 64%, respectively . Our study suggests the potential value of the Alamar Blue method as a convenient alternative to the NCCLS M38-P method for routine testing of Aspergillus species susceptibility to at least voriconazole and ITCZ.

J Antibiot (Tokyo), 2002 Oct, 55(10), 873 - 80
TPU-0037-A, B, C and D, novel lydicamycin congeners with anti-MRSA activity from Streptomyces platensis TP-A0598; Furumai T et al.; In screening for anti-MRSA antibiotics, novel lydicamycin congeners, TPU-0037-A, B, C and D, were isolated from a culture broth of an actinomycete strain . The producing strain, TP-A0598, was isolated from a seawater sample collected in Toyama Bay, Japan, and identified as Streptomyces platensis based on taxonomic characteristics . TPU-0037-A, B, C and D were purified by HP-20 resin, ODS column chromatographies and preparative HPLC, consecutively, and their structures were determined to be 30-demethyllydicamycin, 14,15-dehydro-8-deoxylydicamycin, 30-demethyl-8-deoxylydicamycin and 8-deoxylydicamycin, respectively, by NMR and MS analyses . The new congeners showed antibiotic activity against gram-positive bacteria including MRSA with the MIC of 1.56 to approximately 12.5 microg/ml.

Microb Drug Resist, 2002 Winter, 8(4), 311 - 9
Emergence of nosocomial candidemia at a teaching hospital in Taiwan from 1981 to 2000: increased susceptibility of Candida species to fluconazole; Hsueh PR et al.; The incidence of nosocomial Candida fungemia increased 36-fold from 1981 (0.8/10,000 discharges) to 2000 (28.8/10,000 discharges) at the National Taiwan University Hospital, a 2000-bed teaching hospital in northern Taiwan . To understand the current status of resistance to available antifungal agents among Candida species causing invasive infections, the in vitro susceptibilities of 222 isolates (collected from July, 1999-June, 2001) were determined . Among all of the Candida species tested, 6% and 7% were resistant to fluconazole and itraconazole, respectively . The MIC90 values of voriconazole and amphotericin B were 0.5 and 1 microg/ml, respectively, although some isolates of C . krusei (amphotericin B and voriconazole MIC, >64 microg/ml) and C . tropicalis and C . glabrata (voriconazole MICs, >64 microg/ml) were less susceptible to voriconazole or amphotericin B . About one-half of the C . glabrata isolates belonged to susceptible dose-dependent (SDD, 36%) or resistant (12%) categories for fluconazole and 96% belonged to SDD (56%) or resistant (40%) category for itraconazole . When compared with fluconazole susceptibility data of blood Candida isolates recovered from patients treated at the same hospital (NTUH) from two different time periods (January, 1994, to June, 1995, and January, 1997, to June, 1999 described in previous reports), the incidence of increased susceptibility of non-krusei Candida isolates to fluconazole was evident . This trend of increasing susceptibility for fluconazole did not correlate to the increasing use of this agent in the hospital . None of the random amplified polymorphic DNA patterns generated by arbitrarily primed PCR using four random oligonucleotide primers for 14 isolates, which exhibited fluconazole MICs of > or = 16 microg/ml, were identical, indicating an absence of clonal dissemination among these isolates in the hospital.

J Clin Microbiol, 2003 Jan, 41(1), 403 - 9
Evaluation of broth microdilution testing parameters and agar diffusion Etest procedure for testing susceptibilities of Aspergillus spp . to caspofungin acetate (MK-0991); Espinel-Ingroff A; The NCCLS M38-A document does not describe guidelines for testing caspofungin acetate (MK-0991) and other echinocandins against molds . This study evaluated the susceptibilities of 200 isolates of Aspergillus fumigatus, A . flavus, A . nidulans, A . niger, and A . terreus to caspofungin (MICs and minimum effective concentrations {MECs}) by using standard RPMI 1640 (RPMI) and antibiotic medium 3 (M3), two inoculum sizes (10(3) and 10(4) CFU/ml), and two MIC determination criteria (complete {MICs-0} and prominent growth inhibition {MICs-2}) at 24 and 48 h . Etest MICs were also determined . In general, caspofungin MIC-2 and MEC pairs were comparable with both media and inocula (geometric mean ranges of MECs and MICs, respectively, with larger inoculum: 0.12 to 0.64 microg/ml and 0.12 to 0.44 microg/ml with RPMI versus 0.04 to 0.51 microg/ml and 0.03 to 0.21 microg/ml with M3); however, MEC results were less influenced by testing conditions than MICs, especially with the larger inoculum . Overall, the agreement between caspofungin Etest MICs and broth dilution values was higher with MECs obtained with M3 (>90%) and the large inoculum than under the other testing conditions . Because RPMI is a more stable and chemically defined medium than M3, the determination at 24 h of the easier visual MECs with RPMI and the inoculum recommended in the M38-A document appears to be a suitable procedure at present for in vitro testing of caspofungin against Aspergillus spp . Future in vitro correlations with in vivo outcome of both microdilution and Etest procedures may detect more-relevant testing conditions.

J Clin Microbiol, 2003 Jan, 41(1), 78 - 83
In vitro activities of voriconazole, posaconazole, and four licensed systemic antifungal agents against Candida species infrequently isolated from blood; Pfaller MA et al.; We determined the in vitro susceptibilities of 314 strains of Candida spp., representing 13 species rarely isolated from blood, to posaconazole and voriconazole as well as four licensed systemic antifungal agents (amphotericin B, flucytosine, fluconazole, and itraconazole) . The organisms included 153 isolates of C . krusei, 67 isolates of C . lusitaniae, 48 isolates of C . guilliermondii, 10 isolates of C . famata, 10 isolates of C . kefyr, 6 isolates of C . pelliculosa, 5 isolates of C . rugosa, 4 isolates of C . lipolytica, 3 isolates of C . dubliniensis, 3 isolates of C . inconspicua, 2 isolates of C . sake, and 1 isolate each of C . lambica, C . norvegensis, and C . zeylanoides . MIC determinations were made by the National Committee for Clinical Laboratory Standards reference broth microdilution method and Etest (amphotericin B) . Resistance to both amphotericin B and fluconazole was observed in strains of C . krusei, C . lusitaniae, C . guilliermondii, C . inconspicua, and C . sake . Resistance to amphotericin B, but not to fluconazole, was also observed among isolates of C . kefyr and C . rugosa . Posaconazole and voriconazole were active (MIC, < or = 1 micro g/ml) against 94 to 100% of these isolates . In contrast to the more common species of Candida causing bloodstream infection, these rare species appear to be less susceptible to the currently licensed systemic antifungal agents, with the exception of voriconazole . Continued surveillance will be necessary to detect the emergence of these species as more prevalent, resistant pathogens . The new triazoles appear to offer acceptable coverage of uncommon Candida sp . bloodstream infections.

Zhongguo Zhong Yao Za Zhi, 2000 May, 25(5), 306 - 8
{Observation of cell ultrastructuse in suppurative otitis media treated with bosneol and application}; Chang SP et al.; OBJECTIVE: To explore the pharmacological action and optimal concentration of borneol in treating suppurative otitis media . METHOD: Aspergillus niger separated from the secretion in external auditory canal of the patient and the fungus strains kept in the laboratory were used to determine the minimum fungus inhibiting concentration (MIC) and minimum fungus killing concentration (MFC) of borne . The change of cell ultrastructure after borneol taking effect was observed under electron microscope . RESULT: Borneol MIC and MFC turned out to be 5% and 10% respectively . The cell wall of Aspergillus niger became thicker and blurred with vacuoles . In the cytoplasm various materials were found deep dyed and agglutinated with many fat drops . The electron density increased and the ridge arrangement was in disorder . Some organelles were destroyed, and many areas of electron blank appeared . Some cells became warped and deformed and lost their original structure . CONCLUSION: Borneol can destroy the structure of fungus cells, make fungus dissolve and dieout and thus features a fungus inhibiting and killing function . The optimal inhibiting concentration is 5% and killing concentration 10%.

Cell Mol Biol Lett, 2002, 7(4), 1121 - 9
Lysosomotropic N,N- dimethyl alpha-aminoacid N-alkyl esters and their quaternary ammonium salts as plasma membrane and mitochondrial ATPases inhibitors; Oblak E et al.; A set of n-alkyl esters of N,N-dimethylglycine (DMG-n) and their methobromides (DMGM-n) was synthesized, and their activities on yeast Saccharomyces cerevisiae were compared . The compounds differ in the number of carbon atoms in the aliphatic chain . Aminoesters with 12 carbon atoms appeared to be most active . Unlike quaternary ammonium salts previously tested, the activities of the compounds were not pH-dependent; the minimal inhibitory concentrations (MIC) were identical at pH 8 and at pH 6 . In contrast to quaternary ammonium salts, aminoesters showed similar effects on respiratory sufficient (rho+) and respiratory deficient (rho0) mutants . When tested on glucose stimulated proton extrusion, aminoesters applied at MIC increased external pH . Aminoesters inhibited the plasma membrane H+-ATPase, whereas they were less inhibitory on the mitochondrial ATPase . In order to further compare the aminoesters and their corresponding quaternary ammonium salts, derivatives of N,N-dimethylalanine (DMAL-n and DMALM-n, respectively) were synthesized . The quaternary ammonium salts appeared to have a higher inhibitory potency than aminoesters, especially at pH 8, and alanine derivatives inhibited growth at a lower concentration than glycine derivatives . Both alanine derivatives of the aminoester and the quaternary ammonium salt inhibited the plasma membrane H+- ATPase at lower concentrations than glycine derivatives, but the alanine aminoester was without a detectable effect on the mitochondrial ATPase.

Int J Antimicrob Agents, 2003 Jan, 21(1), 39 - 48
Parasitological cure of acute and chronic experimental Chagas disease using the long-acting experimental triazole TAK-187 . Activity against drug-resistant Trypanosoma cruzi strains; Urbina JA et al.; We investigated the activity of TAK-187, an experimental antifungal triazole with a long terminal half-life in several experimental animals, against Trypanosoma cruzi . In vitro studies showed that the minimal inhibitory concentration (MIC) against the (extracellular) epimastigote form was 0.3-1 microM, while the corresponding concentration against clinically relevant intracellular amastigotes was 1 nM . At the MIC the endogenous epimastigote C4,14-desmethyl sterols were replaced by di- and tri-methylated sterols, supporting the notion that the primary target of TAK-187 is the parasite's sterol C14alpha demethylase . We investigated the in vivo activity of the compound in a murine model of acute Chagas disease, using T . cruzi strains with different susceptibilities to the drugs currently used clinically (nitrofurans and nitroimidazoles) . It was found that TAK-187 given orally at 20 mg/kg induced complete protection against death and high levels (60-100%) of parasitological cures, independently of the infecting strain and even when administered every other day (e.o.d.), consistent with its long terminal half-life in mice . Other experiments, using longer treatment periods were carried out in both acute and chronic models of the disease and showed that TAK-187 given at 10-20 mg/kg e.o.d . induced 80-100% survival with 80-100% of parasitological cures of survivors in both models . No toxic side effects were observed in any of the experimental protocols . TAK-187 is a potent anti-T . cruzi compound with trypanocidal activity in vivo and should be considered for further studies as a potential specific treatment of human Chagas disease.

Int J Antimicrob Agents, 2003 Jan, 21(1), 27 - 38
In vitro and in vivo activities of ravuconazole on Trypanosoma cruzi, the causative agent of Chagas disease; Urbina JA et al.; Ravuconazole is an experimental triazole derivative with potent and broad-spectrum antifungal activity and a remarkably long half-life in humans . In this work, we investigated the in vitro and in vivo activities of this compound against Trypanosoma cruzi . Ravuconazole showed very potent in vitro anti-T . cruzi activity with minimal inhibitory concentrations (MIC) of 300 and 1 nM against the extracellular epimastigote and intracellular amastigote forms, respectively . As with other azole derivatives, ravuconazole at the MIC led to an essentially complete depletion of the epimastigotes' endogenous C4,14-desmethyl sterols and their replacement by di- and tri-methylated sterols . In murine acute models of acute Chagas disease, it was found that ravuconazole treatment led to high levels of parasitological cures, but only when given twice a day (b.i.d.), consistent with its short terminal half-life in mice (4 h) . Furthermore, it was found that this curative activity was restricted towards nitrofuran/nitroimidazole-susceptible (CL) and partially drug-resistant (Y) strains of T . cruzi, with no curative activity in animals infected with the fully drug-resistant Colombiana strain . No curative activity occurred in a chronic model of the disease . No toxic side effects were observed resulting from treatment with the triazole . Ravuconazole is a very potent and specific anti-T . cruzi agent in vitro but its in vivo activity in mice is limited, probably due to its unfavourable pharmacokinetic properties in this animal model . However, these results do not necessarily rule out the potential utility of ravuconazole in the treatment of human T . cruzi infections.

Pathol Biol (Paris), 2002 Dec, 50(10), 591 - 4
In vitro sensitivity of Mycobacterium xenopi to five antibiotics; Dauendorffer JN et al.; We tested 20 strains of Mycobacterium xenopi (M . xenopi) in order to evaluate their in vitro sensitivity to amikacine, clarithromycine, ethambutol, ofloxacine and rifampicin, by establishing minimal inhibitory concentration (MIC) on agar medium . MICs of amikacine, clarithromycine and ofloxacine are low, so that these antibiotics can be used in the treatment of M . xenopi infections . MICs of ethambutol are higher than seric concentrations . Though, its therapeutic use is due to its in vivo ability to enhance penetration of other antibiotics in mycobacteria . Strain sensitivity to rifampicin seems heterogeneous but the small number of tested strains does not entitle the exclusion of rifampicin from the treatment of M . xenopi infections.

Cornea, 2003 Jan, 22(1), 33 - 6
Activity of voriconazole against corneal isolates of Scedosporium apiospermum; Shah KB et al.; PURPOSE: To determine the in vitro antifungal activity of voriconazole, a new triazole, compared with other polyene and imidazole antifungal agents against corneal isolates of Scedosporium apiospermum . METHODS: Macro-broth dilution susceptibility testing was performed on five isolates of S . apiospermum obtained from patients with keratomycosis to determine the minimal inhibitory concentrations (MICs) for amphotericin B, natamycin, ketoconazole, itraconazole, and voriconazole . The use of oral voriconazole in the management of a patient with posttraumatic S . apiospermum keratitis is described . RESULTS: S . apiospermum is generally resistant to commonly used topical ophthalmic antifungal agents . The MIC of voriconazole was 0.5 microg/mL, a concentration lower than that of other imidazoles . CONCLUSION: Voriconazole has promising activity against and may prove useful in the management of fungal keratitis.

J Agric Food Chem, 2003 Jan 1, 51(1), 95 - 9
Fungichromin: a substance from Streptomyces padanus with inhibitory effects on Rhizoctonia solani; Shih HD et al.; Streptomyces padanus strain PMS-702 is an antagonist of Rhizoctonia solani AG-4, the causal agent of damping-off of cabbage . Treatment of cabbage seeds with the culture filtrate of S . padanus strain PMS-702 was effective in reducing the incidence of damping-off of cabbage . The major active ingredient from the culture filtrate of S . padanus strain PMS-702 was purified by silica gel column chromatography and identified as the polyene macrolide, fungichromin, by NMR and mass spectral data . Bioassay studies showed that fungichromin had a strong antifungal activity against R . solani AG-4, and its minimum inhibitory concentration (over 90% inhibition) was found to be 72 microg/mL . This is the first report of fungichromin from S . padanus as an active ingredient for the control of Rhizoctonia damping-off of cabbage.

Antimicrob Agents Chemother, 2003 Jan, 47(1), 106 - 17
In vitro drug interaction modeling of combinations of azoles with terbinafine against clinical Scedosporium prolificans isolates; Meletiadis J et al.; The in vitro interaction between terbinafine and the azoles voriconazole, miconazole, and itraconazole against five clinical Scedosporium prolificans isolates after 48 and 72 h of incubation was tested by a microdilution checkerboard (eight-by-twelve) technique . The antifungal effects of the drugs alone and in combination on the fungal biomass as well as on the metabolic activity of fungi were measured using a spectrophotometric method and two colorimetric methods, based on the lowest drug concentrations showed 75 and 50% growth inhibition (MIC-1 and MIC-2, respectively) . The nature and the intensity of the interactions were assessed using a nonparametric approach (fractional inhibitory concentration {FIC} index model) and a fully parametric response surface approach (Greco model) of the Loewe additivity (LA) no-interaction theory as well as a nonparametric (Prichard model) and a semiparametric response surface approaches of the Bliss independence (BI) no-interaction theory . Statistically significant synergy was found between each of the three azoles and terbinafine in all cases, although with different intensities . A 27- to 64-fold and 16- to 90-fold reduction of the geometric mean of the azole and terbinafine MICs, respectively, was observed when they were combined, resulting in FIC indices of <1 to 0.02 . Using the MIC-1 higher levels of synergy were obtained, which were more consistent between the two incubation periods than using the MIC-2 . The strongest synergy among the azoles was found with miconazole using the BI-based models and with voriconazole using the LA-based models . The synergistic effects both on fungal growth and metabolic activity were more potent after 72 h of incubation . Fully parametric approaches in combination with the modified colorimetric method might prove useful for testing the in vitro interaction of antifungal drugs against filamentous fungi.

Antimicrob Agents Chemother, 2003 Jan, 47(1), 82 - 6
Clinical Trichophyton rubrum strain exhibiting primary resistance to terbinafine; Mukherjee PK et al.; The in vitro antifungal susceptibilities of six clinical Trichophyton rubrum isolates obtained sequentially from a single onychomycosis patient who failed oral terbinafine therapy (250 mg/day for 24 weeks) were determined by broth microdilution and macrodilution methodologies . Strain relatedness was examined by random amplified polymorphic DNA (RAPD) analyses . Data obtained from both broth micro- and macrodilution assays were in agreement and revealed that the six clinical isolates had greatly reduced susceptibilities to terbinafine . The MICs of terbinafine for these strains were >4 microg/ml, whereas they were <0.0002 microg/ml for the susceptible reference strains . Consistent with these findings, the minimum fungicidal concentrations (MFCs) of terbinafine for all six strains were >128 microg/ml, whereas they were 0.0002 microg/ml for the reference strain . The MIC of terbinafine for the baseline strain (cultured at the initial screening visit and before therapy was started) was already 4,000-fold higher than normal, suggesting that this is a case of primary resistance to terbinafine . The results obtained by the broth macrodilution procedure revealed that the terbinafine MICs and MFCs for sequential isolates apparently increased during the course of therapy . RAPD analyses did not reveal any differences between the isolates . The terbinafine-resistant isolates exhibited normal susceptibilities to clinically available antimycotics including itraconazole, fluconazole, and griseofulvin . However, these isolates were fully cross resistant to several other known squalene epoxidase inhibitors, including naftifine, butenafine, tolnaftate, and tolciclate, suggesting a target-specific mechanism of resistance . This is the first confirmed report of terbinafine resistance in dermatophytes.

Placenta, 2003 Jan, 24(1), 100 - 6
Macrophage inhibitory cytokine-1 in gestational tissues and maternal serum in normal and pre-eclamptic pregnancy; Marjono AB et al.; Macrophage inhibitory cytokine-1 (MIC-1), a divergent member of transforming growth factor-beta superfamily, has been recently shown to be produced by the human placenta with detectable levels in maternal serum . In this study, using immunohistochemistry, we have localized MIC-1 in placenta, decidua and foetal membranes across pregnancy and, using an enzyme-linked immunoassay, measured MIC-1 in maternal serum in normal pregnancy, in association with labour and pre-eclampsia . In the placenta MIC-1 was principally localized to the syncytiotrophoblast while in the foetal membranes MIC-1 was present in the amniotic epithelium, chorionic trophoblasts and adherent decidual cells . There were no differences in MIC-1 staining distribution or intensity in the placentae between women in labour and not in labour, or between healthy and pre-eclamptic pregnancies . MIC-1 staining in the foetal membranes was slightly stronger after a labour and delivery compared to those delivered by elective Caesarean section . MIC-1 levels in the maternal serum increased with advancing gestation but there were no significant differences in maternal serum levels associated with either labour or pre-eclampsia.These observations would be consistent with MIC-1 having roles at the maternal-foetal interface, perhaps in the establishment and/or maintenance of pregnancy . Our data argue against MIC-1 having a significant role in the regulation of labour or in the pathophysiology of pre-eclampsia.

J Antimicrob Chemother, 2003 Jan, 51(1), 45 - 52
In vitro susceptibilities of zygomycetes to conventional and new antifungals; Dannaoui E et al.; In vitro susceptibilities of 36 zygomycete isolates, belonging to six genera, to itraconazole, posaconazole, voriconazole, terbinafine, amphotericin B and 5-fluorocytosine were determined by using a broth microdilution adaptation of the National Committee for Clinical Laboratory Standards M-38P reference method . The influence of incubation time on MIC values, and the performance of a spectrophotometric method for MIC determination in comparison with the visual reference method, were also evaluated . Amphotericin B was active against most of the isolates . All the isolates were highly resistant to 5-fluorocytosine (MICs > 256 mg/L) . Voriconazole was significantly less active than the other drugs with an overall MIC(90) (MIC at which 90% of the isolates were inhibited) of 32 mg/L . In contrast, posaconazole showed good activity (MIC(90) 1 mg/L) . A wide range of MICs, from 0.03 to > or =32 mg/L, was obtained for itraconazole and terbinafine . Differences in susceptibility between and within genera were noted . Rhizopus spp . were significantly less susceptible to itraconazole, posaconazole, terbinafine and amphotericin B than Absidia spp., and less susceptible than Mucor spp . to amphotericin B . Terbinafine appeared to be more active against Rhizopus microsporus than against Rhizopus oryzae (geometric mean MIC of 0.15 and 64 mg/L, respectively) . The activity of the drugs was dependent on the incubation period . A significant increase in MICs was noted between 24 and 48 h of incubation . On the other hand, the two methods used for MIC determination (visual and spectrophotometric readings) showed good agreement . These results suggest that the zygomycetes are a heterogeneous group for antifungal susceptibility . Some of the conventional and new antifungals are effective in vitro; their efficacies in vivo remain to be determined . The spectrophotometric method appears to be a valuable alternative to the visual method for MIC determination for zygomycetes.

Pathol Biol (Paris), 2002 Nov, 50(9), 525 - 9
{Endemic heteroresistant glycopeptide intermediate Staphylcoccus aureus (hGISA) comprising unrelated clonal types and not associated with vancomycin therapy}; Lecaillon E et al.; The detection of methicillin-resistant S . aureus (SA) (MRSA) refractory to glycopeptides is a serious clinical issue . The prevalence of hetero-resistant GISA (hGISA) strains at H . Marechal Joffre, France is reported.858 non-repeat SA were isolated during 1999 . 367 (43%) of these, from 257 patients, were MRSA (mean incidence 11.9/1000 admissions) . All MSRA detected during 1999 were screened for vancomycin (VAN) resistance (BHI+4 mg/l VAN) . Isolates recovered were retested using Etest strips (2 McFarland inoculum on BHI) and population analysis profile/area under the curve (PAP-AUC) analysis with hGISA SA Mu3 as a comparator . 58 selected strains were screened for teicoplanin resistance(TEI) using SFM recommended screen (2 McFarland inoculum on MH+5 mg/L TEI) and MIC (0.5 MF inoculum swabbed on MH agar) methods . 188 (51.3%) grew on VAN screen agar (6.1/1000 admissions) . 58 strains (7.6%) possessed Etest VAN MIC > 8 mg/l all others being VAN < 8 mg/l . Of these 58 isolates, 10 were stably heterogeneously resistant to both VAN and teicoplanin (MIC > 8 mg/l) . PAP-AUC showed 12 strains to have PAP-AUC ratios > 0.95 but < 1.5 (ie . hGISA, not GISA) . All 7 isolates defined as hGISA by both Etest and PAP-AUC comprised 1 PFGE clone (< 3 bands difference).Additionally 2 distinct PFGE types were detected among the other 5 hGISA identified PAP-AUC . The 12 hGISAs, were derived from 12 patients with severe underlying disease . None were on glycopeptide therapy prior to hGISA isolation.This is the first report of endemic hGISA, comprising 3 clonal types . The isolation of hVISA seems not to be associated with patient-specific glycopeptide therapies.

J Pharm Sci, 2003 Jan, 92(1), 142 - 8
Enhanced econazole penetration into human nail by 2-n-nonyl-1,3-dioxolane; Hui X et al.; This study determines the enhancing effects of 2-n-nonyl-1,3-dioxolane on the penetration of econazole, an antifungal drug, into the deeper layers of the human nail where fungal infection resides . Aliquots (10 microL) of Econail lacquer formulation containing 0.45 mg of {(14)C}-econazole with 18% 2-n-nonyl-1,3-dioxolane (test group) or without 2-n-nonyl-1,3-dioxolane (control group) were applied twice daily for 14 days to human nails that had been washed with ethanol before each morning's application . The hydration of the nail sample was well controlled to simulate normal physiological conditions . After 14 days of dosing, the inner ventral section of the nail plate was assayed for absorbed drug content, using a micrometer-controlled drilling and nail powder removal system . The mass balance values of {(14)C}-econazole in this study were 90.8 and 96.4% for the test and control groups, respectively . The weight-normalized econazole content in the ventral/intermediate nail plate center in the test group was 6-fold greater than that in the control (p = 0.008) . The total econazole absorbed into the supporting bed cotton ball in the test group was nearly 200-fold greater than that in the control group (p = 0.008) over the 14-day period . The amount of econazole after dosing in the inner part of the human nail (potential diseased area) was 11.1 +/- 2.6 (SD) microg/mg of nail powder with 2-n-nonyl-1,3-dioxolane in the lacquer and 1.78 +/- 0.32 microg/mg without 2-n-nonyl-1,3-dioxolane (p = 0.008) . The surface nail contained more econazole (p = 0.004), that is, nonabsorbed drug, where 2-n-nonyl-1,3-dioxolane was not part of the dosing solution . Econazole in the support bed under the nail (the total absorbed dose) was 47.5 +/- 22.0 mg in the lacquer with 2-n-nonyl-1,3-dioxolane and 0.2 +/- 0.1 mg in the lacquer without 2-n-nonyl-1,3-dioxolane (p = 0.008) . Moreover the concentration in the deep nail layer in the test group is 14,000 times higher than minimum inhibitory concentration (MIC) believed necessary to inhibit the growth of infecting fungi (Dermatophytes species) . In a subsequent study, {(14)C}-dioxolane did not penetrate the nail well . Therefore, the mechanism of enhancement of econazole penetration is at the formulation/nail interface .

Zhonghua Nei Ke Za Zhi, 2002 Oct, 41(10), 685 - 7
{The morphological, immunophenotypical and cytogenetic characteristics study of blast crisis in chronic myeloid leukemia}; Tang X et al.; OBJECTIVE: To explore the morphological, immunophenotypical and cytogenetic (MIC) characteristics of chronic myeloid leukemia in blast crisis (CML-BC) . METHODS: Marrow cells from 31 CML-BC patients were studied by bone marrow smears with morphological and cytochemical stain analysis . Immunophenotypic analysis was performed by micro blood method and flow cytometry . Cytogenetic analysis was performed using bone marrow cells prepared directly and or after 24 hours culture . RHG banding was used for karyotypic analysis . RESULTS: 23 patients (74.2%) were found to have myeloid blast crisis . 5 cases (16.1%) had a B-lymphoid immunophenotype and 4 of them expressed myeloid associated antigens at the same time . Another 3 cases were classified as acute undifferentiated leukemia (AUL 1 patient) and acute myeloid -lymphoid leukemia (AMLL 2 patients) with B and myeloid markers expression . A significant proportion (67.7%) of blast crisis cases were CD(34) positive . CD(34) was expressed in 80.0% of lymphoid and 65.2% of myeloid BC . Analysis of the relationship between CD(7) and CD(34) expression in blasts of myeloid crisis showed their dual expression in 8/23 (34.8%) of the cases . Cytogenetic analysis indicated that 14/27 (51.9%) of the patients had developed secondary cytogenetic abnormalities in addition to the Ph chromosome . These newly emerging abnormalities included a trisomy 8 in 3 patients, a double Ph chromosome in 3 patients, an iso chromosome 17q in 2 patients, loss of Y chromosome in 1 patent and other complicated translocation in 5 patients . CONCLUSION: Blast crisis of CML is a kind of disease of stem cell . The differentiation of blast cell is blocked in the early stage . The prognosis of such patients is poor . MIC showed its important values in diagnosis, judgement of prognosis and determination of therapeutic protocol of CML-BC.

J Vet Med B Infect Dis Vet Public Health, 2002 Dec, 49(10), 513 - 8
Effects of subminimal inhibitory concentrations of amoxicillin against Actinobacillus pleuropneumoniae; Tanigawa M et al.; The bactericidal effects of amoxicillin at below minimum inhibitory concentration (MIC) against Actinobacillus pleuropneumoniae NB001 were studied in vitro and in vivo . In vivo, the efficacy of amoxicillin on experimentally induced A . pleuropneumoniae infection in disease-free pigs was evaluated . Nine pigs were divided into three groups and all three groups were housed in the same room . Group I pigs were given long-acting amoxicillin injection 22 h prior to A . pleuropneumoniae challenge . Group II pigs were also A . pleuropneumoniae challenged but not given long-acting amoxicillin . Group III pigs were not treated . In vitro, A . pleuropneumoniae growth was suppressed in porcine blood with amoxicillin at below MIC . In vivo, clinical signs of disease were absent or mild in group I during 50 h post-challenge, and serum amoxicillin concentration was already less than MIC from 15 h post-challenge . Infected group II controls were severely affected by the infection, and mortality reached 100% within 50 h post-challenge . All non-treated pigs in group III became infected with NB001 from infected control pigs, and they displayed severe clinical signs of disease within 24 h post-challenge of groups I and II, and died within 50 h post-challenge of groups I and II.

Lett Appl Microbiol, 2003, 36(1), 20 - 4
Preliminary investigations into possible resistance to oxytetracycline in Melissococcus plutonius, a pathogen of honeybee larvae; Waite R et al.; AIMS: To investigate the occurrence of oxytetracycline (OTC) resistance in Melissococcus plutonius, which causes European foulbrood in honeybee colonies . METHODS AND RESULTS: Strains of M . plutonius were isolated from diseased colonies in England and Wales and tested for resistance to OTC . The minimum inhibitory concentration (MIC) of OTC was also determined for selected isolates . No resistance to the antibiotic was found in any isolate and the average MIC was found to be 3.9 microg ml-1 . Melissococcus plutonius was found to be susceptible to both chlortetracycline and tetracycline . CONCLUSIONS: No resistance to OTC was found in M . plutonius . SIGNIFICANCE AND IMPACT OF THE STUDY: This study demonstrated that OTC can continue to be used to treat European foulbrood and that resistance may not explain why some treatments fail.

Farmaco, 2002 Nov, 57(11), 909 - 16
Antimycobacterial activity of 5-arylidene derivatives of hydantoin; Kiec-Kononowicz K et al.; The synthesis of various 5-arylidene-2-thiohydantoins and results of the primary assay in vitro for their antimycobacterial activity is reported . Eight of those compounds exhibited > 90% inhibition of Mycobacterium tuberculosis growth and for them the minimum inhibitory concentrations, cytotoxicity (IC50) and the selectivity index values were determined . The most active structure, (5Z)-5-(1,1'-biphenyl-4-ylmethylene)-2-thioxoimidazolidin-4-one, showed MIC = 0.78 microg/ml . For all compounds log P and log D (pH 6.5) values were calculated.

Symp Ser Soc Appl Microbiol, 2002, (31), 78S - 84S
Antibiotic exposure as a risk factor for emergence of resistance: the influence of concentration; Gould IM et al.; Evolution of antibiotic resistance (AR) is increasingly perceived as a major clinical problem . The use of bactericidal antibiotics may protect against this, to some extent, by eradication of the pathogen, but the borders between cidal and inhibitory activity in the patient are often blurred . In addition, there are clinical reasons why eradication of the pathogen may not always be desirable . Antibiotic dosing schedules are currently driven by the perception that T > MIC and AUIC are the main predictors of outcome for time-dependent and concentration-dependent antibiotics, respectively . In the context of protecting against development of resistance in the pathogen however, peak antibiotic concentration and the concept of mutant prevention concentrations may be more important . The role of post-antibiotic and sub-MIC effects is more conjectural . Considerations of mechanisms of resistance and their relationship to antibiotic dosing schedules will also be highlighted . Lastly, the relevance of all this to the development of resistance in the normal bacterial flora will be discussed.

Boll Chim Farm, 2002 Sep-Oct, 141(5), 394 - 6
Antituberculosis agents . VI . Activity of a new ciprofloxacin derivative against Mycobacterium avium and some drug-resistant strains of Mycobacterium tuberculosis; Foroumadi A et al.; The in vitro antimycobacterial activity of a new quinolone derivative, 1a containing 2-(2-furyl)-2-oxoethyl group at N-4 position of piperazine ring of Ciprofloxacin was tested for efficacy in vitro in TB-infected macrophage model (EC90 = 3.25 micrograms/ml and EC99 > 12.5 micrograms/ml) . The MIC values of 1a were determined against M . tuberculosis strains resistant to Isoniazid (MIC = 1.56 micrograms/ml), Rifampin (MIC = 1.56 micrograms/ml), Ethambutol (MIC = 0.78 microgram/ml), Kanamycin (MIC = 0.78 microgram/ml) and Ciprofloxacin (MIC > 25 micrograms/ml) . Furthermore, the MIC and selectivity index (SI) of 1a were evaluated against M . avium . Also, in this study the minimum bactericidal concentration (MBC) of 1a was determined against M . tuberculosis H37Rv (MBC = 6.25 micrograms/ml) and strain resistant to Rifampim (MBC = 25 micrograms/ml) and Isoniazid (MBC = 25 micrograms/ml).

J Control Release, 2002 Dec 13, 85(1-3), 125 - 34
Controlled release of oxytetracycline in sheep; Sun Y et al.; A novel biodegradable injectable formulation of oxytetracycline (OTC) was administered subcutaneously to sheep at a dose of 40 mg/kg . Blood samples were collected from the jugular vein at predetermined time intervals . The concentration of OTC in plasma was analyzed by an HPLC method . The concentrations of OTC in plasma were maintained at or above 0.5 microg/ml (minimum inhibitory concentration) for approximately 6 days . The pharmacokinetic parameters of OTC in sheep were also determined by monitoring the plasma concentration of OTC after a single intravenous injection of a commercially available OTC formulation at 10 mg/kg body weight . The in vivo release profiles of OTC from the biodegradable injectable formulations in sheep were determined from the plasma concentration time profiles by the deconvolution method using PCDCON software . The in vitro release of OTC from the biodegradable injectable formulation was tested in phosphate buffer (pH 7.4), containing 0.686% w/v of sodium sulfite as antioxidant . The correlation between the in vitro and in vivo release of OTC from the injectable formulation was also evaluated . The results of the in vivo evaluation of the formulation in sheep indicated that a controlled release biodegradable injectable dosage form of OTC for food animals is feasible.

J Periodontal Res, 2002 Dec, 37(6), 433 - 8
Improvement of periodontal status by green tea catechin using a local delivery system: a clinical pilot study; Hirasawa M et al.; The purpose of this study was to determine the usefulness of green tea catechin for the improvement of periodontal disease . The minimum inhibitory concentration (MIC) and bactericidal activity of green tea catechin against black-pigmented, Gram-negative anaerobic rods (BPR) were measured . Hydroxypropylcellulose strips containing green tea catechin as a slow release local delivery system were applied in pockets in patients once a week for 8 weeks . The clinical, enzymatic and microbiological effects of the catechin were determined . Green tea catechin showed a bactericidal effect against Porphyromonas gingivalis and Prevotella spp . in vitro with an MIC of 1.0 mg/ml . In the in vivo experiment, the pocket depth (PD) and the proportion of BPR were markedly decreased in the catechin group with mechanical treatment at week 8 compared with the baseline with significant difference . In contrast, PD and BPR were similar to the baseline and the value at the end of the experimental period in the placebo sites of scaled groups . The peptidase activities in the gingival fluid were maintained at lower levels during the experimental period in the test sites, while it reached 70% of that at baseline in the placebo sites . No morbidity was observed in the placebo and catechin groups without mechanical treatment . Green tea catechin showed a bactericidal effect against BPR and the combined use of mechanical treatment and the application of green tea catechin using a slow release local delivery system was effective in improving periodontal status.

Mycoses, 2002 Dec, 45(11-12), 482 - 7
Mathematical modelling of antifungal action; Giordani R et al.; In this paper a simplified modelling approach indicated that yeast growth was inhibited by an antifungal drug according to an exponential function . In addition, the corresponding inhibition rate followed a hyperbolic function the parameters of which permit us to determine the percentage of maximum inhibition and the minimum inhibitory concentration for 80% . From the equation of a hyperbola it was also possible to calculate an affinity constant Kaff corresponding to the inverse of the concentration of antifungal drugs giving half the maximal inhibition . The affinity constant was demonstrated to be characteristic of the yeast strain and of the antifungal drug employed . Simulation of the mathematical modelling enabled determination of a theoretical inhibition level corresponding to strong concentrations of antifungal drugs which cannot be carried out for technical reasons (precipitates, opacity etc.) . The interest of this mathematical modelling of growth and inhibition to predict the doses of antifungals which can act synergistically is discussed.

Scand J Immunol, 2002 Dec, 56(6), 642 - 4
Neutralization titres and vertical HIV-1 transmission; Bongertz V et al.; Replication of the human immunodeficiency virus type 1 (HIV-1) isolate MN in CEM cells was less neutralized by the plasma from the mothers of infected children (MIC) in comparison with the plasma from the mothers of uninfected children (MUC) . Significantly higher neutralization titres were observed for the sera from MUCs compared with MICs, and only the sera from MUC showed 100% neutralization of the HIV-1 MN strain . We suggest that a simple neutralization assay as described here could be useful in prognostic analyses.

Mol Biochem Parasitol, 2002 Nov-Dec, 125(1-2), 35 - 45
Squalene synthase as a chemotherapeutic target in Trypanosoma cruzi and Leishmania mexicana; Urbina JA et al.; Trypanosoma cruzi and Leishmania parasites have a strict requirement for specific endogenous sterols (ergosterol and analogs) for survival and growth and cannot use the abundant supply of cholesterol present in their mammalian hosts . Squalene synthase (SQS, E.C . 2.5.1.21) catalyzes the first committed step in sterol biosynthesis and is currently under intense study as a possible target for cholesterol-lowering agents in humans, but it has not been investigated as a target for anti-parasitic chemotherapy . SQS is a membrane-bound enzyme in both T . cruzi epimastigotes and Leishmania mexicana promastigotes with a dual subcellular localization, being almost evenly distributed between glycosomes and mitochondrial/microsomal vesicles . Kinetic studies showed that the parasite enzymes display normal Michaelis-Menten kinetics and the values of the kinetic constants are comparable to those of the mammalian enzyme . We synthesized and purified 3-(biphenyl-4-yl)-3-hydroxyquinuclidine (BPQ-OH), a potent and specific inhibitor of mammalian SQS and found that it is also a powerful non-competitive inhibitor of T . cruzi and L . mexicana SQS, with K(i)'s in the range of 12-62 nM . BPQ-OH induced a dose-dependent reduction of proliferation the extracellular stages of these parasites with minimal growth inhibitory concentrations (MIC) of 10-30 microM . Growth inhibition and cell lysis induced by BPQ-OH in both parasites was associated with complete depletion of endogenous squalene and sterols, consistent with a blockade of de novo sterol synthesis at the level of SQS . BPQ-OH was able to eradicate intracellular T . cruzi amastigotes from Vero cells cultured at 37 degrees C, with a MIC of 30 microM with no deleterious effects on host cells . Taken together, these results support the notion that SQS inhibitors could be developed as selective anti-trypanosomatid agents.

J Org Chem, 2002 Dec 13, 67(25), 8862 - 70
Synthesis and antituberculosis activity of C-phosphonate analogues of decaprenolphosphoarabinose, a key intermediate in the biosynthesis of mycobacterial arabinogalactan and lipoarabinomannan; Centrone CA et al.; The cell wall complex in mycobacteria, including the human pathogen Mycobacterium tuberculosis, is comprised in large part of two polysaccharides that contain a significant number of arabinofuranose residues . Both polysaccharides are assembled by a family of arabinosyltransferases that use decaprenolphosphoarabinose (3) as the donor species . In this paper, we describe the synthesis of a panel of C-phosphonate analogues of 3, which were designed to inhibit these arabinosyltransferases and thus block the biosynthesis of mycobacterial cell wall polysaccharides . A number of routes were explored for the preparation of the targets . The successful approach involved the synthesis of a protected C-phosphonate allyl ester 16, which was then coupled to an alkene via an olefin cross metathesis reaction . Subsequent reduction of the alkene with diimide and deprotection afforded the targets . Screening of these compounds in vitro against Mycobacterium tuberculosis revealed that one of the compounds, 15f, possessed antituberculosis activity, with an MIC value of 3.13 microg/mL.

Acta Pharmacol Sin, 2002 Dec, 23(12), 1121 - 6
Effect of tetrandrine on free intracellular calcium in cultured calf basilar artery smooth muscle cells; Wang B et al.; AIM: To study the effects of tetrandrine (Tet) on extracellular Ca2+ influx and intracellular Ca2+ release in cultured calf basilar artery smooth muscle cells . METHODS: Free intracellular calcium was examined by a system of measurement of AR-CM-MIC, using Fura 2-AM as a fluorescent indicator . RESULTS: In the presence of extracellular Ca2+ 1.3 mmol/L, no significant effect of Tet on resting {Ca2+}i was found . KCl 20, 40, and 60 mmol/L triggered a sustained rise in {Ca2+}i, pretreatment with Tet inhibited the elevation of {Ca2+}i induced by KCl in concentration-dependent manner, Tet at high concentration (100 micromol/L) almost abolished the rise of {Ca2+}i evoked by KCl . Caffeine 10 mmol/L only produced a transient increase of {Ca2+}i, which spontaneously declined back to resting levels . Tet 10-30 micromol/L had no effect on caffeine-induced {Ca2+}i transient peak . Tet at high concentration (100 micromol/L), however, reduced the {Ca2+}i transient peak induced by caffeine . Phenylephrine (PE) 10 mmol/L produced a rapid transient peak and a distinct sustained elevation in {Ca2+}i in the presence of extracellular Ca2+ . In the absence of extracellular Ca2+ containing egtazic acid (EGTA), PE only produced a rapid transient peak in {Ca2+}i . Pretreatment of Tet (10-100 micromol/L) inhibited the sustained elevation in {Ca2+}i induced by PE in a concentration-dependent manner . However, only 100 micromol/L of Tet inhibited the transient peak in {Ca2+}i induced by PE both in the presence of extracellular Ca2+ 1.3 mmol/L and in the absence of extracellular Ca2+ containing EGTA . CONCLUSION: Tet inhibited the Ca2+ influx from the extracellular site via voltage-activated Ca2+ channel and PE-receptor-operated Ca2+ channel . At a high concentration, Tet may inhibit the Ca2+ release from sarcoplasmic reticulum (SR) or refilling of intracellular calcium store in cerebral artery smooth muscle cells.

J Clin Invest, 2002 Dec, 110(11), 1629 - 41
Epimorphin expression in intestinal myofibroblasts induces epithelial morphogenesis; Fritsch C et al.; The formation of the crypt-villus axis during gut ontogeny requires continued reciprocal interactions between the endoderm and mesenchyme . Epimorphin/syntaxin 2 (epimorphin) is a mesenchymal protein expressed in the fetal gastrointestinal tract during villus morphogenesis . To elucidate its role in gut ontogeny, the epimorphin cDNA was transfected, in sense and antisense orientations, into a rat intestinal myofibroblast cell line, MIC 216 . To determine the effects of epimorphin on the epithelium, myofibroblasts were cocultured with the Caco2 cell line . Caco2 cells spread in a simple monolayer over antisense-transfected cells lacking epimorphin . In contrast, sense-transfected myofibroblasts induced Caco2 cells to form compact, round clusters with small lumens . These morphologic differences were preserved in Transwell cocultures in which cell-cell contact was prevented, suggesting that epimorphin's effects were mediated by secreted factor(s) . To determine the effects of epimorphin on crypt-villus axis formation in an in vivo model, rat gut endoderm was combined with epimorphin-transfected myofibroblasts and implanted into the chick intracoelomic cavity . The grafts in which epimorphin was overexpressed revealed multiple well-formed villi with crypt-like units, whereas those in which epimorphin expression was inhibited developed into round cystic structures without crypts or villi . Of several potential secreted morphogens, only the expression of bone morphogenetic protein 4 (Bmp4) was increased in the epimorphin-transfected cells . Incubation with noggin partially blocked the transfected myofibroblasts' effects on Caco2 colony morphology . These results indicate that mesenchymal epimorphin has profound effects on crypt-villus morphogenesis, mediated in part by secreted factor(s) including the Bmp's.

J Chemother, 2002 Oct, 14(5), 465 - 72
Comparison of microdilution and disc diffusion methods in assessing the in vitro activity of fluconazole and Melaleuca alternifolia (tea tree) oil against vaginal Candida isolates; Ergin A et al.; The in vitro activity of fluconazole and Melaleuca alternifolia (tea tree) oil was evaluated against 99 vaginal Candida strains by the broth microdilution and disc diffusion methods . The microdilution method was performed in accordance with NCCLS-M27A guidelines . An investigational method was used for the disc diffusion test . Fluconazole and tea tree oil minimum inhibitory concentrations (MICs) obtained at 48 h tended to increase 1- to 2-fold or remain the same compared to 24 h readings for most of the isolates tested . C . krusei and C . norvegensis had significantly higher MICs and smaller inhibition zones for fluconazole compared to other species . Tea tree oil MICs were found to be similar, in general, for all Candida spp . tested . The geometric mean MIC of tea tree oil for all isolates was 2.2% (range, 0.25-4%) at 24 h and 3.0% (range, 1-8%) at 48 h . Tea tree oil mean inhibition zone diameter was 24 mm (range, 14-42 mm) at 24 h and 15.8 mm (range, 10-35 mm) at 48 h . In vitro activity of tea tree oil against fluconazole-resistant Candida strains was of particular interest . The isolates had similar tea tree oil MICs and inhibition zone diameters regardless of their fluconazole susceptibility profile . Tea tree oil MIC ranges (inhibition zone diameter ranges) were 2-4% (12-21 mm) and 2% (35 mm) at 48 h for C . krusei and C . norvegensis, respectively . These results suggest that tea tree oil MICs of the fluconazole-resistant isolates are comparable to those of fluconazole-susceptible isolates . This in vitro finding is promising for potential use of topical tea tree oil formulations in the treatment of candidiasis due to fluconazole-resistant strains.

Nat Prod Lett, 2002 Dec, 16(6), 419 - 23
Antimycobacterial activity of lipodepsipeptides produced by Pseudomonas syringae pv syringae B359; Buber E et al.; Some lipodepsipeptides produced by Pseudomonas syringae pv . syringae showed strong antimycobacterial activity towards Mycobacterium smegmatis . MIC values found were between 1.5-3.2 microg/ml, which is comparable to some primary drugs for tuberculosis . Among the lipodepsipeptides, Syringomycin E (SRE) appears to be the most potent antimycobacterial agent.

J Antimicrob Chemother, 2002 Dec, 50(6), 895 - 902
Comparative in vitro activity of five cathelicidin-derived synthetic peptides against Leptospira, Borrelia and Treponema pallidum; Sambri V et al.; OBJECTIVE: The minimum inhibitory concentration (MIC) and minimum bactericidal concentration (MBC) of five different cathelicidin-derived synthetic peptides (SMAP-29, LL-37, PG-1, CRAMP and BMAP-28) for Leptospira interrogans, Borrelia spp . and Treponema pallidum subsp . pallidum were investigated in vitro . METHODS: The MIC of individual peptides was defined as the lowest concentration able to inhibit the motility of spirochaetes after 2 h of incubation, as detected by dark-field microscopy . The MBC of individual peptides was defined as the lowest concentration at which no spirochaetes were subcultured either in cathelicidin-free medium (leptospires and borreliae) or in hamsters (T . pallidum) . RESULTS: The MIC values of peptides for leptospires were highly variable, depending on the compound and the strain used . Of the five cathelicidin-derived peptides, SMAP-29 from sheep and BMAP-28 from cattle were the most active against L . interrogans serovars, with MIC values varying between 3 and 51 mg/L, depending on the strains . The MICs of the remaining synthetic peptides ranged between 4.3 and 224 mg/L . The MIC values of synthetic peptides for T . pallidum ranged between 32.3 mg/L for PG-1 and 449.4 mg/L for LL-37 . The MICs of all cathelicidin-derived peptides tested for Borrelia strains ranged between 307 and 449.4 mg/L . The activity of the peptides on the motility of spirochaetes was both dose- and time-dependent . The MBC values of the peptides were the same as the MIC values . CONCLUSION: The results of this study demonstrate that the activity of cathelicidin-derived peptides against spirochaetes is fast and highly variable, depending on the species and the strain.

J Med Chem, 2002 Dec 5, 45(25), 5604 - 6
Synthesis and antimycobacterial activity of pyrazine and quinoxaline derivatives; Seitz LE et al.; A series of pyrazine and quinoxaline derivatives have been synthesized, and their activity against M . tuberculosis (Mtb) and Mycobacterium avium (MAC) are reported . The 4-acetoxybenzyl ester of pyrazinoic acid and 4'-acetoxybenzyl 2-quinoxalinecarboxylate showed excellent activity against Mtb (MIC ranges of less than 1-6.25 microg/mL) but only modest activity against MAC (MICs of 4-32 microg/mL).

Int J Antimicrob Agents, 2002 Dec, 20(6), 464 - 7
In vitro activity of moxifloxacin, levofloxacin, gatifloxacin and linezolid against Mycobacterium tuberculosis; Rodriguez JC et al.; The in vitro activity of moxifloxacin, gatifloxacin, levofloxacin and linezolid was evaluated against 234 strains of Mycobacterium tuberculosis isolated in the Southeast of Spain . All drugs tested showed good activity, with an MIC(90) of less than 1 mg/l, and were active against isociacide and rifampicin resistant strains . Three strains were resistant to isoniazid and to the fluoroquinolones, which suggested the existence of mechanisms of resistance not yet described . These new compounds may prove to be therapeutic alternatives for treatment of multi-resistant tuberculosis and further studies should be done to demonstrate their true usefulness .

J Asian Nat Prod Res, 2002 Dec, 4(4), 243 - 52
Two new and four known polyphenolics obtained as new cell-cycle inhibitors from Rubus aleaefolius Poir; Cui CB et al.; Two new polyphenolics, rubuphenol (1) and sanguiin H-2 ethyl ester (2), were isolated together with ellagic acid (3), ethyl gallate (4), 1,2,3,4,6-penta-O-galloyl-beta-D-glucopyranose (5) and 1,2,3,6-tetra-O-galloyl-beta-D-glucopyranose (6) as new cell-cycle inhibitors from Rubus aleaefolius by bioassay-guided separation procedure and the structures of 1 and 2 were elucidated by spectroscopic method . Compounds 1-6 inhibited the cell cycle progression of tsFT210 cells at the G0/G1 phase with the MIC values of 14.6 microM (1), 22.1 microM (2), 10.3 microM (3), 7.8 microM (4), 7.9 microM (5) and 6.6 microM (6).

J Asian Nat Prod Res, 2002 Dec, 4(4), 233 - 41
Carbazole alkaloids as new cell cycle inhibitor and apoptosis inducers from Clausena dunniana Levl; Cui CB et al.; Carbazole alkaloids, 3-methylcarbazole (1), murrayafoline A (2), girinimbine (3), mahanimbine (4) and bicyclomahanimbine (5), were isolated for the first time from Clausena dunniana Levl . by bioassay-guided separation procedure and were identified by spectroscopic methods . Compounds 1-5 showed growth inhibitory activity (1, IC50 25 microg/ml) on human fibrosarcoma HT-1080 cells and cell cycle M-phase inhibitory (2, MIC 0.78 microg/ml) and apoptosis inducing (2, MIC 1.56 microg/ml; 3, MIC 25 microg/ml; 4, MIC 20 microg/ml; 5, MIC 30 microg/ml) activities on mouse tsFT210 cells, respectively, and 2-5 provided the first examples of carbazole alkaloids as new cell cycle inhibitors and apoptosis inducers.

Plast Reconstr Surg, 2002 Dec, 110(7), 1680 - 7
Wet wound healing; Vranckx JJ et al.; Wound treatment in a flexible transparent chamber attached to the perimeter of the wound and containing a liquid has been extensively tested in preclinical experiments in pigs and found to offer several advantages . It protects the wound; the liquid medium or saline in the chamber provides in vivo tissue culture-like conditions; and antibiotics, analgesics, and various molecules can be delivered to the wound through the chamber . The wound chamber causes no injury to the wound itself or to the surrounding intact skin . Topical delivery of, for instance, antibiotics can provide very high concentrations at the wound site and with a favorable direction of the concentration gradient . A series of 28 wounds in 20 patients were treated with a wound chamber containing saline and antibiotics . Most patients had significant comorbidity and had not responded to conservative or surgical management with debridement and delayed primary closure or skin grafts . Six wounds had foreign bodies present; four of these were joint prostheses . Seven patients were on corticosteroids for rheumatoid arthritis, lupus, or chronic obstructive pulmonary disease, and four patients had diabetes . Most patients were treated with the wound chamber in preparation for a delayed skin graft or flap procedure, but one was treated with a wound chamber until the wound healed . Twenty-five of the wounds (89 percent) healed, and five wounds (18 percent) required additional conservative management after the initial chamber treatment and grafting procedure . Of the three wounds that did not heal, one healed after additional chamber treatment, one had a skin graft that did not take, and one required reamputation at a higher level . Antibiotic delivery was less than one intravenous dose daily, which avoided the potential for systemic absorption to toxic levels . Antibiotics such as vancomycin and gentamicin could be used in concentrations of up to 10,000 times the minimal inhibitory concentration . Forty-eight hours after application, 20 percent or more of the original antibiotic concentration was present in the wound chamber fluid . In conclusion, the wound chamber provides a safe, powerful tool in the treatment of difficult infected wounds.

Immunol Rev, 2002 Oct, 188, 9 - 21
The innate immune response to tumors and its role in the induction of T-cell immunity; Diefenbach A et al.; Recent genetic studies have resurrected the concept that the adaptive and innate immune systems play roles in tumor surveillance . Natural killer (NK) cells recognize many tumor cells but not normal self cells, and they are thought to aid in the elimination of nascent tumors . Two main strategies are employed by NK cells to recognize tumor targets . Many tumor cells down-regulate class I major histocompatibility complex (MHC) molecules, thus releasing the NK cell from the inhibition provided by class I MHC-specific inhibitory receptors ('missing self recognition') . More recently, it has become clear that a stimulatory receptor expressed by NK cells, T cells and macrophages (NKG2D) recognizes ligands (MHC class I chain related {MIC}, H6O, retinoic acid early inducible {Rae1} and UL16 binding proteins {ULBP}) that are up-regulated on tumor cells and virally infected cells but are not expressed well by normal cells . Ectopic expression of these ligands on tumor cells leads to the potent rejection of the tumors in vivo . Importantly, mice that previously rejected the ligand+ tumor cells develop T-cell immunity to the parental (ligand-) tumor cells . The recognition of induced-self ligands as a strategy to recognize abnormal self sets a precedent for a new immune recognition strategy of the innate immune system.

Pathol Int, 2002 Oct, 52(10), 664 - 8
Pleomorphic hyalinizing angiectatic tumor of soft parts: a case report and literature review; Matsumoto K et al.; Pleomorphic hyalinizing angiectatic tumor (PHAT) is a rare, recently recognized neoplasm occurring predominantly in the subcutaneous tissue of the lower limbs of adults . We report a case of PHAT in an 83-year-old woman who presented with a 5.0 x 5.0 x 2.0 cm mass in the soft part of her left thigh . Histologically, the tumor was well circumscribed by a thin fibrous capsule and predominantly composed of fusiform cells with eosinophilic cytoplasm and round-to-oval or pleomorphic nuclei . The tumor cells resembled those of malignant fibrous histiocytoma, but differed from them by less prominent mitotic figures . Immunohistochemically, the tumor cells were diffusely and strongly positive for CD34; partially positive for vimentin and CD99 (MIC-2); and negative for epithelial and non-epithelial markers . Ultrastructurally, the tumor cells had pleomorphic cytoplasm and nucleus . Intermediate-sized cytoplasmic filaments were observed in a few tumor cells, but neurosecretory-type granule-like intracytoplasmic organelles were not seen . These findings suggest that this tumor is derived from stromal fibroblast, such as solitary fibrous tumors or giant cell angiofibroma.

Antimicrob Agents Chemother, 2002 Dec, 46(12), 3997 - 9
In vitro killing effect of moxifloxacin on clinical isolates of Stenotrophomonas maltophilia resistant to trimethoprim-sulfamethoxazole; Giamarellos-Bourboulis EJ et al.; The time-kill effect of moxifloxacin on 20 genetically distinct isolates of Stenotrophomonas maltophilia resistant to trimethoprim-sulfamethoxazole was studied . The majority (80%) were killed by a concentration equivalent to four times the MIC; the MIC induced a transient decrease in bacterial counts at 4 h, followed by regrowth . No effect was detected in four isolates . These results merit further clinical consideration.

Antimicrob Agents Chemother, 2002 Dec, 46(12), 3782 - 9
Ex vivo pharmacodynamics of amoxicillin-clavulanate against beta-lactamase-producing Escherichia coli in a yucatan miniature pig model that mimics human pharmacokinetics; Bronner S et al.; The objective of the present study was to investigate the potential bactericidal activity of amoxicillin-clavulanate against beta-lactamase-producing Escherichia coli strains and to elucidate the extent to which enzyme production affects the activity . Six adult Yucatan miniature pigs received a single intravenous dose of 1.1 g of amoxicillin-clavulanate as an intravenous infusion over 30 min . The pharmacokinetic parameters were determined for the serum samples and compared to the published data for humans (2.2-g intravenous dose) . The parameters were comparable for the two species, and therefore, the miniature pig constitutes a good model for pharmacodynamic study of amoxicillin-clavulanate . Therefore, the model was used in an ex vivo pharmacodynamic study of amoxicillin-clavulanate against four strains of Escherichia coli producing beta-lactamases at different levels . The E . coli strains were cultured with serial dilutions (1:2 to 1:256) of the serum samples from the pharmacokinetic study, and the number of surviving bacteria was determined after 1, 3, and 6 h of exposure . Amoxicillin-clavulanate at concentrations less than the MIC and the minimal bactericidal concentration had marked bactericidal potency against the strain that produced low levels of penicillinase . For high-level or intermediate-level beta-lactamase-producing strains, the existence of a clavulanate concentration threshold of 1.5 to 2 micro g/ml, below which there was no bactericidal activity, was demonstrated . The index of surviving bacteria showed the existence of mixed concentration- and time-dependent actions of amoxicillin (in the presence of clavulanate) which varied as a function of the magnitude of beta-lactamase production by the test strains . This study shows the effectiveness of amoxicillin-clavulanate against low- and intermediate-level penicillinase-producing strains of E . coli . These findings are to be confirmed in a miniature pig experimental infection model.

Antimicrob Agents Chemother, 2002 Dec, 46(12), 3765 - 9
New site of modification of 23S rRNA associated with clarithromycin resistance of Helicobacter pylori clinical isolates; Fontana C et al.; Resistance of Helicobacter pylori to clarithromycin occurs with a prevalence ranging from 0 to 15% . This has an important clinical impact on dual and triple therapies, in which clarithromycin seems to be the better choice to achieve H . pylori eradication . In order to evaluate the possibility of new mechanisms of clarithromycin resistance, a PCR assay that amplified a portion of 23S rRNA from H . pylori isolates was used . Gastric tissue biopsy specimens from 230 consecutive patients were cultured for H . pylori isolation . Eighty-six gastric biopsy specimens yielded H . pylori-positive results, and among these 12 isolates were clarithromycin resistant . The latter were studied to detect mutations in the 23S rRNA gene . Sequence analysis of the 1,143-bp PCR product (portion of the 23S rRNA gene) did not reveal mutation such as that described at position 2142 to 2143 . On the contrary, our findings show, for seven isolates, a T-to-C transition at position 2717 . This mutation conferred a low level of resistance, equivalent to the MIC for the isolates, selected using the E-test as well as using the agar dilution method: 1 micro g/ml . Moreover, T2717C transition is located in a highly conserved region of the 23S RNA associated with functional sites: domain VI . This fact has a strong effect on the secondary structure of the 23S RNA and on its interaction with macrolide . Mutation at position 2717 also generated an HhaI restriction site; therefore, restriction analysis of the PCR product also permits a rapid detection of resistant isolates.

Curr Eye Res, 2002 May, 24(5), 403 - 6
Aqueous humor levels of topically applied levofloxacin in human eyes; Yamada M et al.; PURPOSE: To evaluate transcorneal penetration of topically applied 0.5% levofloxacin into the aqueous humor in human eyes . METHODS: Twenty cataract patients (14 females, 6 males) received 3 drops of 0.5% levofloxacin at 15 min intervals from 90 minutes before the surgery . At the beginning of the cataract surgery, 50 microL of aqueous humor was aspirated from the anterior chamber and stored at -80 degrees C until analysis . The drug concentration of the samples was analyzed using high-performance liquid chromatography . RESULTS: A mean aqueous humor level of levofloxacin was 1.00 +/- 0.48 microg/mL (mean +/- standard deviation, n = 20), ranging from 0.30 microg/mL to 2.32 microg/mL . CONCLUSIONS: The mean concentration of levofloxacin in the aqueous humor was higher than the MIC(90) values against some common pathogens of postoperative endophthalmitis, although a great degree of interpatient variability was present.

Drug Metab Dispos, 2002 Dec, 30(12), 1504 - 11
Effects of olopatadine, a new antiallergic agent, on human liver microsomal cytochrome P450 activities; Kajita J et al.; Olopatadine, a new histamine H(1) receptor-selective antagonist, is a tricyclic drug containing an alkylamino moiety . Some compounds containing a similar alkylamino group form a cytochrome p450 (p450) -iron (II)-nitrosoalkane metabolite complex {metabolic intermediate complex (MIC)}, thereby causing quasi-irreversible inhibition of the p450 . There was concern that olopatadine might also form MICs, therefore, the present investigation was undertaken to explore this possibility . We identified the enzymes catalyzing olopatadine metabolism and investigated the effect of olopatadine on human p450 activities . During incubation with human liver microsomes in the presence of a NADPH-generating system, olopatadine was metabolized to two metabolites, M1 (N-monodemethylolopatadine) and M3 (olopatadine N-oxide) at rates of 0.330 and 2.50 pmol/min/mg protein, respectively . Troleandomycin and ketoconazole, which are both selective inhibitors of CYP3A, significantly reduced M1 formation but specific inhibitors of other p450 isozymes did not decrease M1 formation . Incubation of olopatadine with cDNA-expressed human p450 isozymes confirmed that M1 formation was almost exclusively catalyzed by CYP3A4 . The formation of M3 was enhanced by N-octylamine and was inhibited by thiourea . High specific activity of M3 formation was exhibited by cDNA-expressed flavin-containing monooxygenase (FMO)1 and FMO3 . Olopatadine did not inhibit p450 activities when it was simultaneously incubated with substrates for different p450 isozymes . Also, p450 activities in human liver microsomes were unaffected by pretreatment with olopatadine or M1 . Furthermore, spectral analysis revealed that neither olopatadine nor M1 formed an MIC . Therefore, it is unlikely that olopatadine will cause drug-drug interactions involving p450 isozymes.

Int J Pharm, 2002 Nov 6, 248(1-2), 115 - 22
Effect of chitosan on in vitro release and ocular delivery of ofloxacin from erodible inserts based on poly(ethylene oxide); Di Colo G et al.; The effects of chitosan hydrochloride (CH-HCl) on in vitro release of ofloxacin (OFX) from mucoadhesive erodible ocular inserts and on the relevant ocular pharmacokinetics have been studied both to contribute evidence of the ability of CH-HCl to enhance transcorneal penetration of drugs and to increase the therapeutic efficacy of topically applied OFX . Circular inserts of 6 mm in diameter, 0.8-0.9 mm in thickness and 20 mg in weight, medicated with 0.3 mg drug, were prepared by powder compression . The addition of 10, 20 or 30% medicated CH-HCl microparticles, obtained by spray-drying, to formulations based on poly(ethylene oxide) of MW 900 kDa (PEO 900) or 2000 kDa (PEO 2000) produced changes in the insert microstructure which accelerated both insert erosion and OFX release from inserts . The effect was stronger with higher CH-HCl fractions . Of the CH-HCl-containing formulations based on either PEO 900 or PEO 2000, PEO 900-CH-HCl (9:1 w/w) was more suitable for a prolonged OFX release . Following insertion in the lower conjunctival sac of the rabbit's eye, such an insert produced no substantial increase of AUC(eff) (AUC in the aqueous humour for concentrations >MIC(90%)) with respect to inserts based on plain PEO; however, it produced a concentration peak in the aqueous significantly higher than that produced by any of the CH-HCl-free PEO inserts, and well higher than the MIC(90%) for the more resistant ocular pathogens (7 microg/ml vs . 4 microg/ml) . It has been argued that the increase was due to the ability of CH-HCl to enhance the transcorneal permeability of the drug.

Presse Med, 2002 Oct 19, 31(34), 1596 - 603
{Sinusal penetration of amoxicillin-clavulanic acid . Formulation 1 g./125 mg., twice daily versus formulation 500 mg./125 mg., three times daily}; Jehl F et al.; INTRODUCTION: In order to meet the evolution of pneumococcus resistance to beta-lactam antibiotics, a new formulation of amoxicillin (AMX) and clavulanic acid (CA), with twice as much AMX (1 g/125 mg vs . 500 mg/125 mg) was developed for the treatment of acute pneumonia in patients at risk . This formulation can also be used in the treatment of acute maxillary sinusitis using a 1 g/125 mg regimen twice-daily . OBJECTIVES: Compare the sinusal penetration of AMX and CA (1 g/125 mg twice-daily vs . 500 mg/125 mg three times a day) when administered at both regimens to demonstrate equivalent pharmacokinetic and pharmacodynamic behaviour of the former when compared to the latter . METHODS: Concentrations of AMX and CA were measured in the anterior ethmoid, maxillary, posterior ethmoid sinus and in the middle nasa concha in 62 patients undergoing surgery for nasosinusal polyps . Patients randomised in two groups corresponding to 2 oral regimens, received either 1 g/125 mg twice a day or 500 mg/125 mg three times a day for 4 days . The last dose in both groups was administered 1 h 30, 3, 5 or 8 hrs prior to surgery . Serum samples were taken simultaneously to tissue samples . AMX and CA were measured by high performance liquid chromatography . Exogenous and above all endogenous blood contamination were taken into account with the hematocrit as well as blood and tissue haemoglobin concentrations . Comparisons of tissue concentrations were made for each sampling time, according to values obtained for a specific tissue with both doses on one hand, and on the other to values obtained with a specific dose in different tissues . The calculated pharmacodynamic parameters, which are considered to be predictive for bacteriological and clinical efficacy, result directly from tissue concentrations of AMX . tissue inhibitory quotients (IQtissue = Tissue concentration/MIC) . time above MICs for serum and tissue concentrations (T > MIC) . RESULTS: As regards AMX, whatever the dose, at 1 h 30 and at 3 hrs, tissue concentrations did not differ significantly whatever the tissue studied (from 1.1 to 2.5 micrograms/g) . Conversely, at 5 and 8 hrs, they were greater than after the 1 g/125 mg regimen given twice-daily (0.06-0.7 vs . 0.7-1.8 micrograms/g) . If we consider a given dose, the comparison between the various tissues showed identical concentrations in the four tissues studied at each sampling time, except in two cases with the dose of 500 mg/125 mg 3 times a day . T > MIC for serum and tissue showed higher values than those required for AMX/pneumococcus association (40-50%) with, nevertheless, greater tissue values for the 1 g/125 mg dose given twice-daily when MIC was of 1 microgram/ml (40-52% vs . 50-66%) . The maximum tissue inhibitory quotients were also greater with the twice-daily 1 g/125 mg dose, when calculated with MIC 50 or 90 of S . Pneumoniae, H . influenzae, M . catarrhalis or S . pyogenes . As for CA, concentrations were equivalent for both doses at each sampling time and greater than those required in vitro during respectively 4 and 5 hours for beta-lactamases H . influenzae and M . catarrhalis . DISCUSSION-CONCLUSION: A least an equivalence between both dose regimens was observed, with occasionally a superiority of the twice-daily 1 g/125 mg dose, in terms of pharmacokinetics, tissue penetration and pharmacodynamics for both AMX and CA . This new regimen therefore appears more appropriate for the treatment of acute maxillary sinusitis in adults.

Zhonghua Kou Qiang Yi Xue Za Zhi, 2002 Sep, 37(5), 388 - 90
Extract and identify ingredient from Ligustrum Lucidum Ait and study its effect to periodontal pathogen; Wang Q et al.; OBJECTIVE: To extract the effective ingredient (crystal I) from effective section (saponin) of Ligustrum Lucidum Ait, identify the chemical structure of crystal I, study the effect of crystal I on P . gingivalis, B . forsythus and P . intermedia . METHODS: Isolated crystal I from saponin using the silica gel column chromatograph . Identified crystal I with IR spectra, (1)H-NMR and (13)C-NMR . Measured the minimal inhibitory concentration (MIC) and the minimal bactericidal concentration (MBC) through micro-liquid dilution . Studied the killing curve of ursolic acid on B . forsythus and P . intermedia . RESULTS: The crystal I was identified as ursolic acid; its MIC and MBC to P . gingivalis, B . forsythus and P . intermedia were 0.740 and 0.295 microg/L respectively . The killing curve indicated that 0.800 microg/L ursolic acid could kill P . intermedia and B . forsythus in 3 and 6 hours respectively . CONCLUSION: Ursolic acid has obvious effect to inhibit periodontal pathogen.

Pharm Res, 2002 Oct, 19(10), 1424 - 9
Polyethylene glycol-diacyllipid micelles demonstrate increased acculumation in subcutaneous tumors in mice; Lukyanov AN et al.; PURPOSE: The purpose of this work is to study the potential of micelles prepared from amphiphilic polyethelene glycol/phosphatidylethanolamine (PEG-PE) conjugates as a particulate drug delivery system capable of accumulation in tumors via the enhanced permeability and retention (EPR) effect . METHODS: Micelles were prepared from PEGs of different molecular lengths conjugated with PE . The micelles were characterized by fluorescence-based critical micellization concentration (CMC) measure ments, dynamic light scattering, and HPLC . Blood clearance an tumor accumulation of 111In-labeled micelles were studied in mic with subcutaneously established Lewis lung carcinoma (LLC) and EL4 T lymphoma (EL4) tumors . RESULTS: Various versions of PEG-PE conjugates with PEG blocks ranging from 750 to 5000 Da formed very stable low CMC micelles at all concentrations down to 10(-5) M . The size of the micelles varie between 7 and 35 nm depending on the length of the PEG block . Micelles remained intact after prolonged incubation with the blood serum . Upon intravenous administration into mice, the micelles demonstrated circulation longevity, and they efficiently and selectively accumulated in both subcutaneous Lewis lung carcinoma and EL4 T lymphoma tumors . CONCLUSIONS: PEG-PE conjugates form very stable, long-circulating micelles . These micelles efficiently accumulate in tumors in vivo an may potentially be used as a tumor-specific delivery system for poorly soluble anticancer drugs.

J Infect, 2002 Nov, 45(4), 263 - 7
Postantifungal effect and effects of sub-MIC concentrations on previously treated Candida sp . influence of growth phase; Garcia MT et al.; OBJECTIVES: This study evaluates the influence of growth phase on the postantifungal effect (PAFE) and on the effect of sub-MIC concentrations (1/4x MIC) on Candida sp . in PAFE stage (PAFSE) . METHODS: This stage was induced by pre-treatments of 1.5 h of C . albicans or C . glabrata in their exponential or stationary phase, with 1x, 4x or 8x MIC of four antifungal agents that are fundamental for modern candidiasis therapy . RESULTS: Ketoconazole and fluconazole induced longer PAFSEs on microorganisms in logarithmic growth phase . However, this influence did not exist in the case of PAFSEs induced by AmB and 5-Fc or with the postantifungal effect induced by the four antifungal agents . In any way, significant PAFEs were always observed for Amphotericin B and 5-fluorocytosine (0.8-4.8 and 0.5-3 h, respectively, depending on the treatment dose) . These values were increased (2.3-3.6 and 1.4-3.2 h respectively, depending on the pre-treatment dose) by posterior exposition to 1/4x MIC of the respective antifungal agent . In the case of ketoconazole and fluconazole, both antimycotics were not able to induce significant PAFEs, but posterior treatments to 1/4x MIC of each of the two azoles led in both yeast species to significant PAFSE of up to 2.6 h duration with ketoconazole, and 0.8 h with fluconazole, depending on the pre-treatment concentration . CONCLUSION: The growth phase of microorganisms should be considered in the planning of dosage protocols with azoles, because if the concentration applied is not high enough, the sub-MIC effects could be no significant for fungi in stationary phase of large wounds.Amphotericin B and 5-fluorocytosine induced significant postantifungal effect onCandida sp . This effect was increased by posterior exposition to sub-MIC concentration of the antifungal agents . Ketoconazole and fuconazole were not able to induce significant PAFEs at the concentrations tested, but posterior treatments to sub-MIC concentrations led to significant PAFSE . The growth phase of the culture at the time of its pre-treatment did not influence the length of the PAFE induced in it . However, the effect of the sub-MIC concentrations of Kz or Flu in yeast in PAFE phase was greater on yeast in exponential phase than for cultures in stationary phase.

Bioresour Technol, 2003 Jan, 86(1), 7 - 13
Impact of long-term application of industrial wastewater on the emergence of resistance traits in Azotobacter chroococcum isolated from rhizospheric soil; Aleem A et al.; A total of 57 (36 and 21) Azotobacter chroococcum were isolated from wheat (Triticum aestivum) rhizospheric soil irrigated with industrial wastewater (about a decade) and ground water (uncontaminated) and characterized on the basis of morphological, cultural and biochemical characteristics . Rhizospheric soils were analyzed for metal concentrations by atomic absorption spectrophotometery and the test soil samples were contaminated with Fe, Zn, Cu, Cr, Ni and Pb . All the isolates of A . chroococcum were tested for their resistance against Hg2+, Cd2+, Cu2+, Cr3+, Cr6+, Zn2+, Ni2+ and Pb2+ . Among 36 isolates of Azotobacter from soil irrigated with industrial wastewater, 94.4% were resistant to Pb2+ and Hg2+ and 86.1%, 77.5% and 63.8% were resistant to Zn2+, Cr6+ and Cr3+ respectively . The highest minimum inhibitory concentration of 200 microg/ml for Hg2+ and 1600 microg/ml for other metals were observed against these bacteria from soil . The incidences of metal resistance and MICs of metals for A . chroococcum from wastewater irrigated soil were significantly different to those of uncontaminated soil . All A . chroococcum isolates were tested for their resistance against 11 commonly used antibiotics/drugs . 91.6% were found to be resistant against nitrofurantoin while 86.4% and 80.5% were found to be resistant against polymyxin-B and co-trimoxazole respectively . Agarose gel electrophoresis using the miniprep method for plasmid isolation revealed that these isolates harboured plasmids of molecular weights 58.8 and 64.5 kb using EcoRI and HindIII digests of X DNA and undigested X DNA as standard markers.

J Vet Med B Infect Dis Vet Public Health, 2002 Sep, 49(7), 346 - 8
Anti-microbial susceptibility for east1 + Escherichia coli isolated from diarrheic pigs in Korea; Han DU et al.; The in vitro susceptibilities of 128 isolates of east1 + Escherichia coli from pre-weaned and post-weaned pigs with diarrhoea were tested with nine commonly used anti-microbial agents by an agar dilution minimal inhibitory concentration (MIC) procedure according to National Committee for Clinical Laboratory Standards guidelines . For the isolates from preweaned and post-weaned pigs, most of them were susceptible to low concentrations (MIC90) of tetracycline (4 and 2 microg/ml), ceftiofur (2 and 2 microg/ml), and colistin (4 and 2 microg/ml) . Marked resistance was found in others.

J Chemother, 2002 Aug, 14(4), 342 - 5
Antibiotic susceptibility patterns of Helicobacter pylori strains isolated from northeastern Mexico; Garza-Gonzalez E et al.; There are reports of increased antibiotic resistance rates in Helicobacter pylori strains around the world . The aim of this study was to determine the susceptibility patterns in H . pylori strains isolated in Monterrey, Mexico . We studied 62 strains isolated from the same number of symptomatic adult patients . Metronidazole (Mtz), clarithromycin (Cla), amoxicillin (Amx) and tetracycline (Tet) were tested by the E-test method . We observed that 37.1% of the strains were resistant to Mtz (MIC > or = 8 mg/L), and 8.1% to Cla (MIC > or = 8 mg/L), but we did not observe resistance to Amx (MIC > or = 2 mg/L) or Tet (MIC > or = 4 mg/L) . In northeastern Mexico, the percentage of resistant strains was similar to that observed in developed countries . These results confirm that it is necessary to evaluate the susceptibility patterns of H . pylori strains by geographic area.

Xenobiotica, 2002 Oct, 32(10), 863 - 78
Reversible and irreversible inhibition of CYP3A enzymes by tamoxifen and metabolites; Zhao XJ et al.; 1 . Preliminary studies have identified cytochrome P450 (CYP) 3A4 and CYP1B1 as the human CYPs inhibited by tamoxifen . To quantify the inhibitory potency of tamoxifen and its major metabolites, the metabolism of three substrates of CYP3A, midazolam, diltiazem and testosterone, and 7-ethoxyresorufin as a substrate of CYP1B1 were examined in catalytic assays carried out using human liver microsomes and cDNA-expression systems . 2 . Tamoxifen, N-desmethyltamoxifen, 4-hydroxytamoxifen and 3-hydroxytamoxifen reversibly inhibited midazolam 1'-hydroxylation, diltiazem N-demethylation and testosterone 6beta-hydroxylation with K(i) ranging from 3 to 37 micro M in human liver microsomes . Tamoxifen, N-desmethyltamoxifen, 4-hydroxytamoxifen and 3-hydroxytamoxifen also reversibly inhibited the activity of cDNA-expressed CYP3A4, CYP3A5 and CYP1B1 . 3 . Tamoxifen and N-desmethyltamoxifen exhibited time-dependent inactivation of testosterone 6beta-hydroxylation by cDNA-expressed CYP3A4 (+ cytochrome b5) yielding k(inact) and K(i) of 0.04 min(-1) and 0.2 micro M for tamoxifen and 0.08 min(-1) and 2.6 micro M for N-desmethyltamoxifen . A metabolic intermediate complex (MIC) was also formed by tamoxifen and N-desmethyltamoxifen with CYP3A4 (+ cytochrome b5) and CYP3A4 but not with CYP3A5 or CYP3A7 . Pre-incubation with 4-hydroxytamoxifen and 3-hydroxytamoxifen did not result in any CYP3A inactivation or detectable MIC formation . There was no detectable time-dependent inactivation or MIC formation with tamoxifen or metabolites with CYP1B1 . 4 . These data indicate that tamoxifen and its three major metabolites are effective inhibitors of CYP3A in vitro and that tamoxifen and N-desmethyltamoxifen are effective mechanism-based inhibitors . Thus, caution should be exercised when tamoxifen is coadministered with other CYP3A substrates.

Biophys J, 2002 Nov, 83(5), 2693 - 701
Triton promotes domain formation in lipid raft mixtures; Heerklotz H; Biological membranes are supposed to contain functional domains (lipid rafts) made up in particular of sphingomyelin and cholesterol, glycolipids, and certain proteins . It is often assumed that the application of the detergent Triton at 4 degrees C allows the isolation of these rafts as a detergent-resistant membrane fraction . The current study aims to clarify whether and how Triton changes the domain properties . To this end, temperature-dependent transitions in vesicles of an equimolar mixture of 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine, egg sphingomyelin, and cholesterol were monitored at different Triton concentrations by differential scanning calorimetry and pressure perturbation calorimetry . Transitions initiated by the addition of Triton to the lipid mixture were studied by isothermal titration calorimetry, and the structure was investigated by (31)P-NMR . The results are discussed in terms of liquid-disordered (ld) and -ordered (lo) bilayer and micellar (mic) phases, and the typical sequence encountered with increasing Triton content or decreasing temperature is ld, ld + lo, ld + lo + mic, and lo + mic . That means that addition of Triton may create ordered domains in a homogeneous fluid membrane, which are, in turn, Triton resistant upon subsequent membrane solubilization . Hence, detergent-resistant membranes should not be assumed to resemble biological rafts in size, structure, composition, or even existence . Functional rafts may not be steady phenomena; they might form, grow, cluster or break up, shrink, and vanish according to functional requirements, regulated by rather subtle changes in the activity of membrane disordering or ordering compounds.

J Clin Microbiol, 2002 Nov, 40(11), 3999 - 4003
Collaborative evaluation of optimal antifungal susceptibility testing conditions for dermatophytes; Fernandez-Torres B et al.; A multicenter study was conducted to define the most suitable testing conditions for antifungal susceptibility of dermatophytes . Broth microdilution MICs of clotrimazole, itraconazole, and terbinafine were determined in three centers against 60 strains of dermatophytes . The effects of inoculum density (ca . 10(3) and 10(4) CFU/ml), incubation time (3, 7, and 14 days), endpoint criteria for MIC determination (complete {MIC-0} and prominent {MIC-2} growth inhibition), and incubation temperature (28 and 37 degrees C) on intra- and interlaboratory agreement were analyzed . The optimal testing conditions identified were an inoculum of 10(4) CFU/ml, a temperature of incubation of 28 degrees C, an incubation period of 7 days, and MIC-0.

J Clin Microbiol, 2002 Nov, 40(11), 3976 - 9
Multicenter evaluation of ethambutol susceptibility testing of mycobacterium tuberculosis by agar proportion and radiometric methods; Madison B et al.; Reproducibility of ethambutol (EMB) susceptibility test results for Mycobacterium tuberculosis has always been difficult for a variety of reasons, including the narrow range between the critical breakpoint for EMB resistance and the MIC for susceptible strains, borderline results obtained with the BACTEC 460TB method, the presence of microcolonies determined using the agar proportion (AP) method, and a lack of agreement between these two testing methods . To assess the frequency of these problems, M . tuberculosis drug susceptibility data were collected in a multicenter study involving four laboratories . Resistant, borderline, and susceptible isolates were shared among the laboratories to measure interlaboratory test agreement . Half of isolates determined by BACTEC 460TB to be resistant were determined to be susceptible by the AP method . Isolates determined to be resistant to EMB by both BACTEC 460TB and AP methods were almost always resistant to isoniazid . Results from isolates tested by the BACTEC 460TB method with an EMB concentration of 3.75 micro g/ml in addition to the standard 2.5 micro g/ml did not show improved agreement by the AP method . While these results do not indicate that the AP method is more accurate than the BACTEC 460TB method, laboratories should not report EMB monoresistance based on BACTEC 460TB results alone . Monoresistance to EMB should only be reported following confirmation by the AP method . Microcolonies could not be confirmed as resistant by the BACTEC 460TB method or by repeat testing with the AP method and do not appear to be indicative of resistance.

Soc Sci Med, 2002 Dec, 55(12), 2171 - 5
Differences in low-birthweight among documented and undocumented foreign-born and US-born Latinas; Kelaher M et al.; In the USA foreign-born women tend to have fewer low-birthweight births than US-born women from the same ethnicity . This "healthy migrant" effect could be caused by immigration of the fittest or by healthy people being deliberately selected in the immigration process . This study tests these hypotheses by comparing self-reported history of low-birth-weight among foreign-born documented and undocumented Latinas and US-born Latinas . The sample includes 2398 (57.5%) documented foreign-born Latinas, 782 (18.7%) undocumented foreign-born Latinas, and 993 (23.4%) US-born Latinas who initiated prenatal care at MIC-Women's Health Services/MHRA in New York City during 1996-1997 . Only women who reported previous live births were included in the sample . Documented foreign-born Latinas were less likely than US-born Latinas to have low-birth-weight babies taking into account parity, age, risk, and education . There were no significant differences between rates of low-birthweight for undocumented foreign-born Latinas and US-born Latinas, or documented foreign-born Latinas . There was, however, a significant trend for rates of low-birthweight to increase from documented foreign-born to undocumented foreign-born to US-born women . This suggests that both official screening and migration of the fittest play a role in lower rates of low-birthweight among foreign-born Latinas compared to US-born Latinas .

Zhonghua Zhong Liu Za Zhi, 2002 Jul, 24(4), 375 - 7
Acute biphenotypic leukemia in the adults; Shen Y et al.; OBJECTIVE: To study the clinical, biological features and prognosis of acute biphenotypic leukemia (BAL) in the adults . METHODS: Bone marrow specimens of 63 BAL patients were evaluated to prove the diagnosis and the classification by morphologic, cytochemical, immunologic and cytogenetic (MIC) examinations . These patients were treated with protocols suitable for acute myeloid leukemia (AML), or acute lymphoblastic leukemia (ALL), or both . RESULTS: No significant difference in clinical features was observed between BAL, AML or ALL . Morphologically, the subtypes of M(5), M(1) and M(2) were predominant in AML, as L(2) and L(1) were in ALL . Immunologically, coexpression of myeloid and B lineage associated antigens was predominant and CD(34) was hyperexpressed in BAL, which suggested that BAL might originate from malignant transformation of earlier hematopoietic cells . Cytogenetically, Ph chromosome was observed in 25.5% (13/51) of BAL patients . Prognostically, both the treatment response and the overall survival of BAL patients were poor . CONCLUSION: Patients with BAL have unique clinical, biological and prognostic features.

Semin Laparosc Surg, 2002 Sep, 9(3), 180 - 9
Gastroesophageal reflux disease in neurologically impaired children: the role of the gastrostomy tube; Wadie GM et al.; We review our experience with gastrostomy techniques in neurologically impaired (NI) children, with or without a Nissen fundoplication . The records of 130 NI children who had a gastrostomy tube (GT) placed between January 1999 and October 2001 were reviewed . Data collected included: demographics, neurological status, operative time, time to first feed, postoperative stay, analgesic requirements, follow-up, mortality and complication rates . Open GTs were placed using the standard Stamm gastrostomy technique through a midline incision and were combined with a standard open Nissen fundoplication when indicated . Laparoscopic GTs were placed after institution of carbon dioxide pneumoperitoneum using a 2-port technique, a Mic-key G device of appropriate size and anchored to the anterior abdominal wall with 2 "U" stitches . The laparoscopic Nissen fundoplication (LNF) procedures were performed using a 5-port technique . Patients were divided into 4 groups: group I (n = 12) laparoscopic GT alone, group II (n = 44) open GT alone, Group III (n = 44) laparoscopic GT with LNF and Group IV (n = 30) open GT with Nissen fundoplication . Based on their similar characteristics, Groups I and II and Groups III and IV were compared together . Data were analysed using Student's t test, and internal review board approval was obtained . Patients ranged in age between 10 days and 17.7 years (mean 3.64 years) . Their weight was between 1.2 and 63.4 kg (mean 12.8 kg) . The compared groups showed similar characteristics with regard to age, weight, cause of mental impairment, and the reason for placement of the GT . The operative time for group III was significantly longer than that of group IV (P < 0.05) . Time to first feed was significantly shorter for group I when compared to group II . The postoperative analgesic requirements were not statistically different . The overall short- and long-term complication rates were not statistically different when the related groups were compared, however, site-related complications and feeding problems were significantly less in group I compared to group II . Only 1 operative mortality occurred in group III . Follow-up showed less long-term morbidity and fewer complications with the laparoscopic GT compared to the open one as regard to admissions, surgery, and emergency department visits related to GT problems as well as frequency of GT change . Based on our experience, laparoscopic placement of a low-profile GT in NI children appears to be associated with less morbidity, permits earlier enteral nutrition, and has a cosmetic advantage . We believe that the laparoscopic technique should be the procedure of choice for GT placement in these children even when a Nissen fundoplication is deemed necessary .

J Agric Food Chem, 2002 Nov 6, 50(23), 6697 - 703
Zoosporicidal activity of polyflavonoid tannin identified in Lannea coromandelica stem bark against phytopathogenic oomycete Aphanomyces cochlioides; Islam MT et al.; In a survey of nonhost plant secondary metabolites regulating motility and viability of zoospores of the Aphanomyces cochlioides, we found that stem bark extracts of Lannea coromandelica remarkably inhibited motility of zoospores followed by lysis . Bioassay-guided fractionation and chemical characterization of Lannea extracts by MALDI-TOF-MS revealed that the active constituents were angular type polyflavonoid tannins . Commercial polyflavonoid tannins, Quebracho and Mimosa, also showed identical zoosporicidal activity . Against zoospores, the motility-inhibiting and lytic activities were more pronounced in Lannea extracts (MIC 0.1 microg/mL) than in Quebracho (MIC 0.5 microg/mL) and Mimosa (MIC 0.5 microg/mL) . Scanning electron microscopic observation visualized that both Lannea and commercial tannins caused lysis of cell membrane followed by fragmentation of cellular materials . Naturally occurring polyflavonoid tannin merits further study as potential zoospore regulating agent or as lead compound . To the best of our knowledge, this is the first report of zoosporicidal activity of natural polyflavonoid tannins against an oomycete phytopathogen.

Tumori, 2002 Jul-Aug, 88(4), 345 - 6
The first report of extraosseous Ewing's sarcoma in the rectovaginal septum; Petkovic M et al.; AIMS AND BACKGROUND: To report an extremely rare case of Ewing's sarcoma located in the rectovaginal septum . Ewing's sarcoma is a highly malignant neoplasm of bone, which usually occurs during childhood . Common extraosseous localizations of Ewing's sarcoma include the trunk, extremities, uterus, cervix and vagina . METHODS: A 45-year-old woman presented to us with a six-month history of pain in the lower abdomen during intercourse . Pelvic examination was performed and a palpable mass was found . The mass had a size of 9 x 6 cm, a soft tissue consistency, was partially movable and the patient felt the pain during palpation . Examination of the inguinal lymph nodes revealed no signs of inguinal adenopathy . The results of laboratory tests, rectoscopy, chest X-rays, barium enema and bone scan were normal . Computed tomography (CT) showed an inhomogeneous expansive mass in the rectovaginal septum measuring 8.7 x 6.1 cm, without any signs of rectum or bladder invasion . The vascular structures of the pelvis were normal . At laparotomy the process was judged inoperable and only biopsy of the tumor mass was carried out . Histology showed a neoplasm with small, round to oval cells with scarce cytoplasm . Immunohistology with the monoclonal antibody CD99 (MIC-2 gene product, Ewing's sarcoma marker, clone 12E7, DAKO A/S, Glostrup, Denmark) revealed an extraosseous Ewing's sarcoma . The patient was treated with chemotherapy followed by whole-pelvis external beam radiation and intracavitary brachytherapy . RESULTS: A residual mass measuring 3.5 x 2.5 cm was visible on a control CT scan 18 months after treatment; however, the patient was feeling well and refused surgery to remove the residual mass . CONCLUSIONS: To our knowledge this is the first reported case of extraosseous Ewing's sarcoma in the rectovaginal septum.

Bioorg Med Chem Lett, 2002 Nov 18, 12(22), 3275 - 8
Heterocyclic benzazole derivatives with antimycobacterial in vitro activity; Koci J et al.; The series of 2-benzylsulfanyl derivatives of benzoxazole and benzothiazole were synthesized, evaluated for their in vitro antimycobacterial activity against Mycobacterium tuberculosis and non-tuberculous mycobacteria, and the activity expressed as the minimum inhibitory concentration (MIC) in micromol/L . The substances bearing two nitro groups (4e, 4f, 5e, 5f) or a thioamide group (4i, 4j, 5i, 5j) exhibited appreciable activity particularly against non-tuberculous strains . The most active compounds were subjected to the toxicity assay and were evaluated as moderately cytotoxic.

Tissue Antigens, 2002 Aug, 60(2), 164 - 79
High resolution MIC genotyping: design and application to the investigation of inflammatory bowel disease susceptibility; Ahmad T et al.; The highly polymorphic nonclassical MHC class I chain-related (MIC) genes MICA and MICB encode stress inducible glycoproteins expressed on a variety of epithelial cells including intestinal cells . Interaction with the receptor NKG2D is likely to provide an important costimulatory signal for activation and proliferation of NK cells, activated macrophages and CD8 alphabeta and gammadelta T cells . Fifty-four MICA and 17 MICB alleles have been described to date . Although the functional significance of this polymorphism is not known, the high degree of nonconservative substitution, concentration to the putative ligand-binding site and recent observation that different MICA alleles bind to NKG2D with varying affinity has generated much interest . The MIC genes are attractive functional and positional candidate genes for inflammatory bowel disease susceptibility as a consequence of their position in the HLA region and expression on the gastrointestinal epithelium . We developed a robust, high-resolution PCR-SSP genotyping method that can be incorporated into the standard 'Phototyping' system and which effectively identifies 46 of 54 MICA alleles, and all 17 MICB alleles . We applied this system in combination with microsatellite genotyping of the exon 5 variable number of tandem repeats (VNTR) to the investigation of genetic susceptibility to the inflammatory bowel diseases, ulcerative colitis and Crohn's disease . We studied 248 patients with Crohn's disease, 329 with ulcerative colitis and 354 ethnically matched controls . Linkage disequilibrium patterns between HLA-B, MICA and MICB are presented . Analysis by individual allele or by multilocus haplotype failed to identify any significant disease associations.

Biochem J, 2003 Feb 1, 369(Pt 3), 611 - 8
Neighbouring bases in template influence base-pairing of isoguanine; Maciejewska AM et al.; Assuming that the efficiency of the incorporation of 5-methyl-2'-deoxyisocytosine-5' triphosphate (dMiCTP) and dTTP opposite isoguanine (iG) is a measure of the proportion of the keto and enol tautomers of iG in the Thermus aquaticus DNA polymerase active centre, we studied the influence of temperature and iG-neighbouring bases in the template on base-pairing of iG . On the basis of experiments with four sequences (3'-TXT-5', 3'-GXG-5', 3'-CXC-5', 3'-CXT-5', where X=iG) at 37, 50, 65 and 80 degrees C, we found that 3'-neighbours decrease the fraction of the keto tautomer in the order C>G>or=T, whereas temperature apparently does not influence the tautomeric equilibrium of iG . The variability of the ratio of incorporation of dMiCTP versus dTTP (5-20) primarily reflects the variability of K (m) values, since V (max) values are roughly similar, which indicates that the iG.MiC and iG.T pairs fit the polymerase active centre equally well . The altering of the base-pairing of iG by sequence context is discussed in relation to tautomerism and miscoding of this oxidized adenine derivative . A key derivative for preparation oligodeoxynucleotides, O (2)-diphenylcarbamoyl- N (6)-{(dimethylamino)ethylidene}-2'-deoxyisoguanosine, is extremely labile (t (1/2)=3.5 min) in 3% trichloroacetic acid/dichloromethane, i.e . under the conditions of automated DNA synthesis, which results in low yield and length heterogeneity of templates.

Farmaco, 2002 Sep, 57(9), 765 - 9
Antituberculosis agents . V . Synthesis, evaluation of in vitro antituberculosis activity and cytotoxicity of some 2-(5-nitro-2-furyl)-1,3,4-thiadiazole derivatives; Foroumadi A et al.; A new series of 2-(5-nitro-2-furyl)-1,3,4-thiadiazole-2-sulfide, sulfoxide and sulfones were synthesized and evaluated for in vitro antituberculosis activity against Mycobacterium tuberculosis strain H37Rv using the radiometric BACTEC 460-TB methodology . Active compounds were also screened by serial dilution to assess toxicity to a VERO cell line . The results indicate that some compounds exhibited a good antituberculosis activity and the ethylthio analogue (5b) was the most active compound (MIC = 0.78 microg ml(-1)) . Also, the cytotoxic effects indicate that compound 5b was the least toxic compound.

Clin Infect Dis, 2002 Nov 1, 35(9), 1066 - 70 Epub 2002 Oct 10.
Vaginitis due to Candida krusei: epidemiology, clinical aspects, and therapy; Singh S et al.; Twelve women with vaginal Candida krusei infection were evaluated . In vitro antifungal susceptibility testing and molecular typing were performed . Patients infected with C . krusei frequently had refractory vulvovaginal signs and symptoms that were otherwise indistinguishable from vaginitis due to other yeasts . Patients were 32-63 years old and had previously received multiple courses of antimycotic agents, including fluconazole and miconazole . The most active azole in vitro was clotrimazole, with a 90% minimum inhibitory concentration of 0.25 microg/mL . Four of 6 patients treated with boric acid had clinical and mycological cure . Two dominant genotypes of C . krusei were identified via contour-clamped homogenous electrical field analysis . No major genotypic change was observed in successive isolates from the same patient in most cases, suggesting that these refractory cases were relapses . C . krusei is a rare but important cause of refractory vaginitis and is unique because of its intrinsic resistance to fluconazole.

Nature, 2002 Oct 17, 419(6908), 734 - 8
Tumour-derived soluble MIC ligands impair expression of NKG2D and T-cell activation; Groh V et al.; Engagement of the NKG2D receptor by tumour-associated ligands may promote tumour rejection by stimulating innate and adaptive lymphocyte responses . In humans, NKG2D is expressed on most natural killer cells, gammadelta T cells and CD8alphabeta T cells . Ligands of NKG2D include the major histocompatibility complex class I homologues MICA and MICB, which function as signals of cellular stress . These molecules are absent from most cells and tissues but can be induced by viral and bacterial infections and are frequently expressed in epithelial tumours . MIC engagement of NKG2D triggers natural killer cells and costimulates antigen-specific effector T cells . Here we show that binding of MIC induces endocytosis and degradation of NKG2D . Expression of NKG2D is reduced markedly on large numbers of tumour-infiltrating and matched peripheral blood T cells from individuals with cancer . This systemic deficiency is associated with circulating tumour-derived soluble MICA, causing the downregulation of NKG2D and in turn severe impairment of the responsiveness of tumour-antigen-specific effector T cells . This mode of T-cell silencing may promote tumour immune evasion and, by inference, compromise host resistance to infections.

Antimicrob Agents Chemother, 2002 Nov, 46(11), 3518 - 21
In vitro activities of 5-fluorocytosine against 8,803 clinical isolates of Candida spp.: global assessment of primary resistance using National Committee for Clinical Laboratory Standards susceptibility testing methods; Pfaller MA et al.; We determined the in vitro activity of flucytosine (5-fluorocytosine {5FC}) against 8,803 clinical isolates of Candida spp . (18 species) obtained from more than 200 medical centers worldwide between 1992 and 2001 . The MICs were determined by broth microdilution tests performed according to NCCLS guidelines by using RPMI 1640 as the test medium and the following interpretive breakpoints: susceptible (S), < or =4 micro g/ml; intermediate (I), 8 to 16 micro g/ml; resistant (R), > or =32 micro g/ml . 5FC was very active against the 8,803 Candida isolates (MIC(90), 1 micro g/ml), 95% S . A total of 99 to 100% of C . glabrata (MIC(90), 0.12 micro g/ml), C . parapsilosis (MIC(90), 0.25 micro g/ml), C . dubliniensis (MIC(90), 0.12 micro g/ml), C . guilliermondii (MIC(90), 0.5 micro g/ml), and C . kefyr (MIC(90), 1 micro g/ml) were susceptible to 5FC at the NCCLS breakpoint . C . albicans (MIC(90), 1 micro g/ml; 97% S) and C . tropicalis (MIC(90), 1 micro g/ml; 92% S) were only slightly less susceptible . In contrast, C . krusei was the least susceptible species: 5% S; MIC(90), 32 micro g/ml . Primary resistance to 5FC is very uncommon among Candida spp . (95% S, 2% I, and 3% R), with the exception of C . krusei (5% S, 67% I, and 28% R) . The in vitro activity of 5FC, combined with previous data demonstrating a prolonged post-antifungal effect (2.5 to 4 h) and concentration-independent activity (optimized at 4x MIC), suggest that 5FC could be used in lower doses to reduce host toxicity while maintaining antifungal efficacy.

Cell Transplant, 2002, 11(5), 459 - 64
Implantation of BDNF-producing packaging cells into brain; Fukumitsu H et al.; In order to invent a screening system to check in vivo gene function and the efficiency of gene transfer mediated by a retroviral vector system, we established a novel packaging cell, PacC6/A8, that is transplantable to rat brains . The packaging cell is based on the gene of the neuropatogenic retrovirus, A8-V . For expression in the brain, a vector that expresses brain-derived neurotrophic factor (BDNF) tagged by c-Myc-His6 (LxA/bdmh) was constructed . After transfection of LxA/bdmh to PacC6/A8, a cloned cell line, PacC6/A8/bmh, was established . PacC6/A8/bmh cells stably produced pseudotyped retroviruses carrying LxA/bdmh . For a control, a retroviral vector that bears the gene that codes enhanced green fluorescent protein (EGFP) tagged by C-Mic-His6 was also created and used for the establishment of PacC6/A8/gfmh cells that produce pseudotyped retroviruses carrying LxA/gfmh . PacC6/A8/bmh and PacC6/A8/gfmh cells were injected to the brain of newborn rats . A tumor was formed in all the rats injected that did not exhibit any symptoms until 3-4 weeks after the injection . A histological study of the injected rats revealed that the transferred BDNF gene was expressed in the brain of rats injected with PacC6/A8/bmh cells, but not in rats with PacC6/A8/gfmh cells . Interestingly, many activated microglia had migrated into the tumor induced by PacC6/A8/bmh cells, and expressed a high amount of BDNF.

Anat Rec, 2002 Nov 1, 268(3), 252 - 75
Molecular basis of endothelial cell morphogenesis in three-dimensional extracellular matrices; Davis GE et al.; Although many studies have focused on blood vessel development and new blood vessel formation associated with disease processes, the question of how endothelial cells (ECs) assemble into tubes in three dimensions (i.e., EC morphogenesis) remains unanswered . EC morphogenesis is particularly dependent on a signaling axis involving the extracellular matrix (ECM), integrins, and the cytoskeleton, which regulates EC shape changes and signals the pathways necessary for tube formation . Recent studies reveal that genes regulating this matrix-integrin-cytoskeletal (MIC) signaling axis are differentially expressed during EC morphogenesis . The Rho GTPases represent an important class of molecules involved in these events . Cdc42 and Rac1 are required for the process of EC intracellular vacuole formation and coalescence that regulates EC lumen formation in three-dimensional (3D) extracellular matrices, while RhoA appears to stabilize capillary tube networks . Once EC tube networks are established, supporting cells, such as pericytes, are recruited to further stabilize these networks, perhaps by regulating EC basement membrane matrix assembly . Furthermore, we consider recent work showing that EC morphogenesis is balanced by a tendency for newly formed tubes to regress . This morphogenesis-regression balance is controlled by differential gene expression of such molecules as VEGF, angiopoietin-2, and PAI-1, as well as a plasmin- and matrix metalloproteinase-dependent mechanism that induces tube regression through degradation of ECM scaffolds that support EC-lined tubes . It is our hope that this review will stimulate increased interest and effort focused on the basic mechanisms regulating capillary tube formation and regression in 3D extracellular matrices .

Clin Ther, 2002 Sep, 24(9), 1439 - 50
Tear concentrations of levofloxacin following topical administration of a single dose of 0.5% levofloxacin ophthalmic solution in healthy volunteers; Raizman MB et al.; BACKGROUND: Several fluorinated carboxyquinolones are used to treat ocular infectious disease . Levofloxacin, in particular, has demonstrated activity against both gram-negative and gram-positive bacteria . OBJECTIVES: An open-label study was undertaken to assess the pharmacokinetics and ocular bioavailability of levofloxacin in human tears, and to determine the tear concentration of levofloxacin in healthy volunteers, following topical administration of a single-dose of 0.5% levofloxacin ophthalmic solution . METHODS: Volunteers received 1 drop of 0.5% levofloxacin in each eye and were assigned sequentially to 1 of 5 groups for tear sampling . Tear samples were collected on Schirmer test strips at 9 predetermined time points ranging from 5 minutes to 24 hours after administration . Six tear samples were collected at each time point (1 eye each from 6 volunteers), except the 24-hour time point, at which 12 samples were collected (both eyes of 6 volunteers) . No eye had > 1 tear sample taken during the study . Levofloxacin concentrations were measured using reverse-phase high-performance liquid chromatography . RESULTS: Thirty volunteers were enrolled, with 6 assigned to each of the 5 sampling groups . At 5 minutes after administration of a single topical dose of levofloxacin, the mean tear concentration was 49.19 +/- 26.73 microg/mL . The mean peak concentration of levofloxacin in the tear film, 221.06 +/- 256.68 microg/mL, was reached at 15 minutes after administration . At 4 hours after administration, the mean tear concentration of levofloxacin was 17.04 +/- 15.13 microg/mL . At 6 hours after administration, the mean concentration of levofloxacin was 6.57 +/- 5.26 microg/mL . At 24 hours after administration, levofloxacin concentrations > 2 microg/mL were measured in 2 of 6 (33%) subjects . CONCLUSIONS: Levofloxacin concentrations in the tear fluid after a single topical dose (1 drop) reached high levels quickly and remained above the minimum inhibitory concentration for most suspected ophthalmic pathogens (< or = 2 microg/mL) for at least 6 hours in most healthy volunteers, and for up to 24 hours in some volunteers.

J Korean Med Sci, 2002 Oct, 17(5), 599 - 603
Mutations in the 23S rRNA gene of Helicobacter pylori associated with clarithromycin resistance; Kim KS et al.; Among 12 clarithromycin-resistant Helicobacter pylori strains isolated in Guri, Korea, 8 showed an adenine to guanine mutation at position 2143 (formerly A2144G or E . coli 2059) in the 23S rRNA gene by the PCR-restriction fragment length polymorphism (RFLP) method . The remaining 4 strains, digested by neither BsaI nor BbsI, showed a thymine to cytosine mutation at position 2182 (T2182C) by direct sequencing of the PCR products . The T2182C mutants showed a tendency of higher levels of minimum inhibitory concentration to clarithromycin than the A2143G mutants . In conclusion, either the A2143G or the T2182C mutation was present in 100% of clarithromycin-resistant H . pylori isolates examined . The PCR-RFLP technique with restriction enzymes BbsI and BsaI was a rapid and relatively simple method to detect the clarithromycin resistance . But undigested isolates were quite frequent among our isolates (33.3%), the PCR-RFLP method with restriction enzymes BbsI and BsaI should not be used alone, and development of other rapid detection method for clarithromycin resistance is mandatory.

J Biol Chem, 2002 Dec 13, 277(50), 48205 - 9 Epub 2002 Oct 07.
The antibiotic activity of N-pentylpantothenamide results from its conversion to ethyldethia-coenzyme a, a coenzyme a antimetabolite; Strauss E et al.; Pantothenic acid (vitamin B(5)) is the natural precursor of coenzyme A (CoA), an essential cofactor in all organisms . The pantothenic acid antimetabolite N-pentylpantothenamide inhibits the growth of Escherichia coli with a minimum inhibitory concentration of 2 microm . In this study, we examine the mechanism of this inhibition . Using the last five enzymes of the CoA biosynthetic pathway in E . coli we demonstrate that N-pentylpantothenamide does not inhibit the CoA biosynthetic enzymes but instead acts as an alternative substrate, forming the CoA analog ethyldethia-CoA . We show that N-pentylpantothenamide is converted to ethyldethia-CoA 10.5 times faster than CoA is biosynthesized from pantothenic acid, demonstrating that ethyldethia-CoA biosynthesis can effectively compete with CoA biosynthesis in the cell . We conclude that the mechanism of toxicity of N-pentylpantothenamide is most likely due to its biosynthetic conversion to the CoA analog ethyldethia-CoA, which may act as an inhibitor of CoA- and acetyl-CoA-utilizing enzymes.

Proc Natl Acad Sci U S A, 2002 Oct 15, 99(21), 13687 - 92 Epub 2002 Oct 07.
A family of MHC class I-like genes located in the vicinity of the mouse leukocyte receptor complex; Kasahara M et al.; Some members of the major histocompatibility complex (MHC) class I gene family are encoded outside the MHC . Here we describe a family of mouse class I-like genes mapping to the vicinity of the leukocyte receptor complex (LRC) on chromosome 7 . This family, which we call Mill (MHC class I-like located near the LRC), has two members designated Mill1 and Mill2 . Both genes are predicted to encode membrane glycoproteins with domain organization essentially similar to that of MHC class I heavy chains . The following features of Mill are noteworthy . (i) The deduced MILL proteins lack most of the residues known to be involved in the docking of peptides in classical MHC class I molecules . (ii) Among the known members of the class I gene family, MILL1 and MILL2 are related most closely to MICA/MICB encoded in the human MHC . (iii) Unlike all other known members of the class I gene family, Mill1 and Mill2 have an exon between those coding for the signal peptide and the alpha1 domain . (iv) Mill1 has a more restricted expression profile than Mill2 . (v) The gene orthologous to Mill1 or Mill2 apparently is absent in the human . (vi) Mill1 and Mill2 show a limited degree of polymorphism in laboratory mice . The observation that the Mill family is related most closely to the MIC family, together with its apparent absence in the human, suggests its involvement in innate immunity.

J Immunol, 2002 Oct 15, 169(8), 4079 - 83
Cutting edge: murine UL16-binding protein-like transcript 1: a newly described transcript encoding a high-affinity ligand for murine NKG2D; Carayannopoulos LN et al.; Murine NKG2D is known to recognize H60 and five RAE1 variants . The human homologue recognizes both inducible MHC class I chain-related gene and constitutive (UL16-binding protein (ULBP)) ligands . Widely expressed, the latter are thought to mark transformed or infected cells for destruction by NK cells in the context of down-regulated cell surface class I (i.e., the "missing self"-response) . Unlike MIC and ULBP however, mRNA for the murine ligands appears only in very limited contexts in the mature animal . In this study, we describe a NKG2D ligand termed "murine ULBP-like transcript 1 (MULT1) whose mRNA appears to be widely expressed in adult parenchyma . This molecule possesses MHC class I-like alpha1 and alpha2 domains as well as a large cytoplasmic domain . Recombinant MULT1 binds NKG2D with relatively high affinity (K(D) approximately 6 nM) and low k(off) (approximately 0.006s(-1)) . Expression of MULT1 by normally resistant RMA cells results in their susceptibility to lysis by C57BL/6 splenocytes.

Curr Protein Pept Sci, 2001 Sep, 2(3), 245 - 59
Life and death in the placenta: new peptides and genes regulating human syncytiotrophoblast and extravillous cytotrophoblast lineage formation and renewal; Morrish DW et al.; Differential techniques have revealed several novel genes and peptides involved in trophoblast development including PL74/gdf15/MIC-1, a TGFbeta family cytokine that controls apoptosis and differentiation, PL48, a new serine-threonine protein kinase, serum and glucocorticoid-induced kinase, PBK-1, a tunicamycin-responsive gene, a cathepsin D-like gene (DAP-1) and hypoxia- regulated genes HRF-1,2,6,8 and HIF-1alpha, HIF-1beta, and hEPAS-1 . Syncytin, a cell fusion- inducing gene, has been cloned from placenta where it regulates cell fusion . ERV-3 has also been demonstrated to promote cell fusion . These two genes represent the first demonstrated functions of endogenous retroviral sequences in human tissues . Endoglin, PlGF, TGFbeta3, IGF-II, IGFBP-1, and a placental IGFBP protease have found new roles in regulating cytotrophoblast proliferation and invasiveness . A specific placental p105 rasGAP protein has been identified . The homeobox genes DLX4, HB24, MSX2 and MOX2 also likely play a role in development at the epithelial-mesenchymal boundary . Transcription factors such as TEF-5, Hand1, HEB, HASH-2 and two genes represented by ESTs may have regulatory roles in placental development . Evidence suggests that the placenta has an unusual two-cell system for apoptosis regulation in which the cytotrophoblast may direct later apoptotic events in the syncytium, and with syncytialization possibly triggered by the "phosphatidylserine flip" . Thus, the placenta is both a rich source of new growth-regulatory substances, and a model system for originating new paradigms of developmental biology.

Biochemistry, 2002 Oct 15, 41(41), 12450 - 6
Mechanism of regulation of Acanthamoeba myosin-IC by heavy-chain phosphorylation; Ostap EM et al.; The ATPase activity of myosin-Is from lower eukaryotes is activated by phosphorylation by the p21-activated kinase family at the TEDS site on an actin-binding surface-loop . This actin-binding loop is the site of a cardiac myosin-II mutation responsible for some forms of familial hypertrophic cardiomyopathy . To determine the mechanism of myosin-I regulation by heavy-chain phosphorylation (HCP) and to better understand the importance of this loop in the function of all myosin isoforms, we performed a kinetic investigation of the regulatory mechanism of the Acanthamoeba myosin-IC motor domain (MIC(IQ)) . Phosphorylated and dephosphorylated MIC(IQ) show actin-activated ATPase activity; however, HCP increases the ATPase activity >20-fold . HCP does not greatly affect the rate of phosphate release from MIC in the absence of actin, as determined by single turnover experiments . Additionally, HCP does not significantly affect the affinity of myosin for actin in the absence or presence of ATP, the rate of ATP-induced dissociation of actoMIC(IQ), the affinity of ADP, or the rate of ADP release . Sequential-mix single-turnover experiments show that HCP regulates the rate of phosphate release from actin-bound MIC(IQ) . We propose that the TEDS-containing actin-binding loop plays a direct role in regulating phosphate release and the force-generating (A-to-R) transition of myosin-IC.

Microbiology, 2002 Oct, 148(Pt 10), 3101 - 9
Analogues of thiolactomycin: potential drugs with enhanced anti-mycobacterial activity; Douglas JD et al.; Analogues of the antibiotic thiolactomycin (TLM) have been synthesized and have been shown to have enhanced activity against whole cells of Mycobacterium tuberculosis H37Rv and against mycolic acid biosynthesis in cell extracts of Mycobacterium smegmatis . TLM has a methyl-branched butadienyl side chain attached at position 5 on a 'thiolactone' ring, namely 4-hydroxy-3,5-dimethyl-5H-thiophen-2-one . Various combinations of strong bases were explored to create a reactive anion at position 5 on the thiolactone ring which could react with halides to produce 5-substituted derivatives; the best reagent was two equivalents of lithium-bis-(trimethylsilyl)amide in tetrahydrofuran . The analogue with a 5-tetrahydrogeranyl substituent showed the best biological activity with an MIC(90) for M . tuberculosis of 29 micro M and 92% mycolate inhibition in extracts of M . smegmatis, as compared to 125 micro M and 54%, respectively, for TLM; other related C(10) and C(15) isoprenoid derivatives had similar biological activity . These isoprenoid-based derivatives did not inhibit type II fatty acid synthase from M . smegmatis, but compounds with iso-butyl and iso-butenyl side chains did show some inhibitory activity against this enzyme . These short-chain derivatives did not inhibit mycolate synthesis or have significant antibiotic activity . Treatment of the thiolactone with a weaker base, sodium hydride in tetrahydrofuran, gave 3-alkyl-3,5-dimethyl-thiophene-2,4-dione analogues, which had no effect on fatty acid or mycolate synthesis . However, the geranyl derivative had an MIC(99) of 60 micro M for M . tuberculosis, one quarter that (240 micro M) of TLM, demonstrating its excellent antibiotic potential against an unknown cellular target.

Toxicol Lett, 2002 Nov 15, 136(1), 1 - 8
Nifurtimox biotransformation to reactive metabolites or nitrite in liver subcellular fractions and model systems; Montalto de Mecca M et al.; Liver microsomal (mic); nuclei (N) and mitochondria (mit) anaerobically nitroreduce Nifurtimox (Nfx) in the presence of NADPH generating system . Simultaneous formation of small amounts of nitrite was observed in microsomes and nuclei but not in mitochondria . The microsomal nitroreductase activity was enhanced by the presence of flavine-adenine-dinucleotide disodium salt (FAD), was not inhibited by CO and was significantly inhibited by diphenyleneiodonium (DPI) . In the microsomal NADPH-dependent fraction nitrite formation was null in the presence of FAD, DPI and under air and was partially inhibited by pure CO . Pure human cytochrome P450 reductase in the presence of NADPH significantly nitroreduced Nfx and produced small amounts of nitrite . The nitroreductive process was significantly enhanced by FAD but the nitrite formation became null . FAD itself was able to chemically nitroreduce Nfx without production of nitrite . NADPH generating system enhanced the FAD nitroreductive effect and led to small production of nitrite . Formation of reactive metabolites and nitric oxide during Nfx metabolism might contribute to its toxicity.

Int J Gynecol Cancer, 2002 Sep-Oct, 12(5), 485 - 9
The value of loop electrosurgical conization in the treatment of stage IA1 microinvasive carcinoma of the uterine cervix; Bekkers RL et al.; The objective of this study is to assess the value of Loop Electrosurgical Conization (LEC) in the treatment of stage IA1 microinvasive squamous cell carcinoma (MIC) of the uterine cervix . Retrospectively, 82 patients with FIGO stage IA1 MIC, primarily treated with LEC on see and treat basis, were analyzed . After the initial LEC, 16 patients received cytologic and colposcopic follow-up only, 66 patients underwent a second procedure (repeat LEC, Cold Knife Conization (CKC), or hysterectomy), and four patients underwent a third procedure (hysterectomy) . In 63 patients (77%) no residual CIN 3 or MIC was present after the initial LEC . Treatment of residual CIN 3 or MIC was equally effective with a repeat LEC as with CKC . One patient defaulted follow-up and developed a recurrence in the vaginal vault and was treated with a radical hysterectomy . LEC can be used as an alternative for CKC in treatment of patients with stage IA1 MIC . The advantage of LEC is that it can be performed as an outpatient procedure in addition to a diagnostic colposcopy and does not require a major anesthetic . Only a small number of patients will need a more extensive procedure.

Int J Tuberc Lung Dis, 2002 Oct, 6(10), 933 - 5
In vitro activity of thiacetazone on mycobacterial species belonging to the Mycobacterium tuberculosis complex; Abate G et al.; Thiacetazone, despite frequent side-effects, may still be considered for the treatment of new tuberculosis cases when there is a shortage of drugs and for the management of multidrug-resistant tuberculosis . Fifty-four strains of M . tuberculosis complex were characterised based on the minimum inhibitory concentration (MIC) of thiacetazone and the growth pattern in the presence of different concentrations of the drug . The results showed that the MIC of thiacetazone to type II M . africanum strains was significantly higher than for other strains in the study (P < 0.01) . Thiacetazone showed a paradoxical effect on 63% of strains where lower concentrations exhibited a better inhibiting activity than higher concentrations.

Microbiol Immunol, 2002, 46(8), 521 - 5
A novel method using micropig stratum corneum in vitro for the evaluation of anti-Trichophyton mentagrophytes activity; Nakashima T et al.; Antifungal susceptibility testing under conditions close to clinical status is expected to provide more helpful information than that obtained by a conventional microdilution method . For this purpose, we developed a novel method to evaluate anti-Trichophyton mentagrophytes activity of antifungal agents in vitro by using disks of micropig stratum corneum epidermis (SCE) . Basal agar medium containing K2HPO4, MgSO4, CaCl2 and three kinds of antibiotics . Bifonazole (BFZ), lanoconazole (LCZ) or terbinafine (TBF) was added to the basal agar medium to give serially doubling dilutions ranging from 0.0006 to 10 microg/ml . Five-hundred-microl portions of the agar media thus prepared were solidified in wells of flat-bottomed plates . SCE disks (6 mm in diameter) were placed on surfaces of the agar medium and 10(4) conidia of T . mentagrophytes were inoculated on each SCE disk . There was very good correlation between the initial concentration of the antifungal agents added to the basal agar medium (microg/ml) and the concentration of the agents impregnated into the SCE disks (microg/g) (r2>0.99) . The minimum inhibitory concentration (MIC) values of BFZ, LCZ and TBF were respectively 26-, 10- and 78-times higher than those measured by the standard microdilution method . From the correlation between the concentration of the agents in the basal medium and that in the SCE disks, the above MIC values corresponded to the concentrations in SCE disks (microg/g), 832.95 for BFZ, 1.42 for LCZ and 8.87 for TBF . This novel method of antidermatophytic susceptibility testing using SCE would be useful as an in vitro screening of proper antimycotics for topical treatment of dermatophytosis.

J Med Chem, 2002 Oct 10, 45(21), 4669 - 78
Parallel synthesis of potent, pyrazole-based inhibitors of Helicobacter pylori dihydroorotate dehydrogenase; Haque TS et al.; The identification of several potent pyrazole-based inhibitors of bacterial dihydroorotate dehydrogenase (DHODase) via a directed parallel synthetic approach is described below . The initial pyrazole-containing lead compounds were optimized for potency against Helicobacter pylori DHODase . Using three successive focused libraries, inhibitors were rapidly identified with the following characteristics: K(i) < 10 nM against H . pylori DHODase, sub-microg/mL H . pylori minimum inhibitory concentration activity, low molecular weight, and >10 000-fold selectivity over human DHODase.

Planta Med, 2002 Sep, 68(9), 853 - 5
Chabamide, a novel piperine dimer from stems of Piper chaba; Rukachaisirikul T et al.; A novel piperine dimer, named chabamide, was isolated from stems of Piper chaba Hunter and its structure was elucidated on the basis of spectroscopic evidence . Chabamide showed antimalarial activity with an IC(50) value of 2.7 microg/ml and antituberculosis activity with the minimum inhibitory concentration (MIC) of 12.5 microg/ml.

Planta Med, 2002 Sep, 68(9), 780 - 3
Antiviral activity of characterized extracts from echinacea spp . (Heliantheae: Asteraceae) against herpes simplex virus (HSV-I); Binns SE et al.; Extracts of 8 taxa of the genus Echinacea were found to have antiviral activity against Herpes simplex (HSV) virus Type I in vitro when exposed to visible and UV-A light . n-Hexane extracts of roots containing alkenes and amides were more active in general than ethyl acetate extracts containing caffeic acids . The most potent inhibitors of HSV were E . pallida var . sanguinea crude (70 % ethanol) inflorescence extract (MIC = 0.026 mg/mL), cichoric acid (MIC = 0.045 mg/mL) and Echinacea purpurea n-hexane root extract (MIC = 0.12 mg/mL).

Tuberculosis (Edinb), 2002, 82(2-3), 91 - 6
Population pharmacokinetics of ethionamide in patients with tuberculosis; Zhu M et al.; SETTING: Three US referral hospitals . OBJECTIVE: Determine the population pharmacokinetic (PK) parameters of ethionamide (ETA) following multiple oral doses . DESIGN: Fifty-five patients with tuberculosis (TB) participated . Patients received multiple oral doses of ETA as part of their treatment . They also received other anti-tuberculosis medications based upon in vitro susceptibility data . Serum samples were collected over 12 h post-dose, and concentrations were determined using a validated high-performance liquid chromatography (HPLC) assay . Concentration-time data were analyzed using population methods . RESULTS: ETA areas under the concentration-versus-time curve (AUCs) increased linearly with increasing oral doses from 250 to 1000 mg . Compared to the population pattern, delayed absorption was seen at least once in 15% of patients . ETA PK parameter estimates were independent of age, weight, height, gender, and creatinine clearance . TB patients appeared to have larger volumes of distribution (3.22 l/kg) and clearance values (1.88 l/h/kg) compared to previously studied healthy volunteers . This resulted in lower AUC values (3.95 mcg h/ml) in the TB patients . ETA displayed a short elimination half-life (1.94 h) . The effect of different dosing strategies on calculated pharmacodynamic parameters was explored . Simulated doses of 250 mg BID to TID failed to achieve serum concentrations above the MIC . CONCLUSION: ETA PK parameters differed between TB patients and healthy volunteers, possibly due to differences in the completeness of absorption . Doses of at least 500 mg appear to be required to achieve serum concentrations above the typical ETA MIC . Additional research is needed to determine the optimal dosing of ETA.

J Ind Microbiol Biotechnol, 2002 Oct, 29(4), 155 - 62
The effect of levofloxacin concentration on the development and maintenance of antibiotic-resistant clones of Escherichia coli in chemostat culture; Fleming GT et al.; A levofloxacin-sensitive strain of Escherichia coli (broth MIC: 0.0625 mg x l(-1)) was grown in carbon-limited chemostat culture for 316 h (D=0.294 h(-1)) . Hyperresistant strains isolated after 58 and 91 generations of culture retained a 16- to 47-fold increase in tolerance to levofloxacin during antibiotic-free serial batch and continuous culture (20 generations, glucose-limited, D=0.2 h(-1)) . Isolates differed from the original strain in their maximum growth rates in the presence and absence of subinhibitory levels of levofloxacin, protein-banding profiles, and resistance to a range of antibiotics . Competition between resistant isolates and the original sensitive strain was studied in glucose-limited chemostat cultures (D=0.2 h(-1)) . At levofloxacin concentrations less than 0.03 mg x l(-1), the sensitive strain outcompeted resistant isolates and displaced them from the culture, whereas the reverse was true at higher concentrations . These results have clinical and environmental implications for those administering levofloxacin.

J Clin Microbiol, 2002 Oct, 40(10), 3841 - 4
Comparison of the Antifungal Susceptibility Testing Subcommittee of the European Committee on Antibiotic Susceptibility Testing proposed standard and the E-test with the NCCLS broth microdilution method for voriconazole and caspofungin susceptibility testing of yeast species; Chryssanthou E et al.; The proposed standard of the Antifungal Susceptibility Testing Subcommittee of the European Committee on Antibiotic Susceptibility Testing (AFST-EUCAST) and the E-test procedures were compared with the NCCLS reference broth microdilution method for voriconazole and caspofungin susceptibility testing of 102 clinical Candida species and Saccharomyces cerevisiae isolates . The voriconazole MIC at which 50% of strains were inhibited (MIC(50)) was < or =0.125 mg/liter for all yeast species except for Candida glabrata and Candida krusei, which yielded MIC(50) values of 0.25 to 1 mg/liter depending on the method . Caspofungin exhibited in vitro activity (MIC(50) of < or =0.125 to 2 mg/liter) against all yeast species except for Candida guilliermondii . The agreements between MICs within +/-2 dilutions obtained by the NCCLS method and the EUCAST standard were 97% for voriconazole and 96% for caspofungin . Intraclass correlation coefficients were statistically significant (P < 0.05) . The agreements between voriconazole MICs provided by the E-test and the NCCLS and between the E-test and the AFST-EUCAST method were 100 and 90%, respectively . Because of lower caspofungin MICs provided by the E-test, the agreement was slightly poorer with the NCCLS method (89%) than with the AFST-EUCAST procedure (94%) . Both the EUCAST and the E-test procedures can be reliable techniques for susceptibility testing of yeasts to voriconazole and caspofungin.

J Clin Microbiol, 2002 Oct, 40(10), 3776 - 81
Optimal testing conditions for determining MICs and minimum fungicidal concentrations of new and established antifungal agents for uncommon molds: NCCLS collaborative study; Espinel-Ingroff A et al.; This collaborative three-center study evaluated NCCLS M38-A document testing conditions and other testing conditions for the antifungal susceptibility testing of 35 isolates of Aspergillus nidulans, A . terreus, Bipolaris hawaiiensis, B . spicifera, Cladophialophora bantiana, Dactylaria constricta, Fusarium solani, Paecilomyces lilacinus, Scedosporium prolificans, Trichoderma longibrachiatum, and Wangiella dermatitidis for itraconazole, three new triazoles (voriconazole, posaconazole, and ravuconazole), and amphotericin B . MICs and minimum fungicidal concentrations (MFCs) were determined in each center by using four media (standard RPMI-1640 {RPMI}, RPMI with 2% dextrose {RPMI-2%}, antibiotic medium 3 {M3}, and M3 with 2% dextrose {M3-2%}) and two criteria of MIC determination (complete growth inhibition {MICs-0} and prominent growth inhibition {MICs-2}) at 24, 48 and 72 h . MFCs were defined as the lowest drug concentrations that yielded <3 colonies (approximately 99 to 99.5% killing activity) . The reproducibility (within three wells) was higher among MICs-0 (93 to 99%) with either RPMI or M3 media than among all MICs-2 (86 to 95%) for the five agents at 48 to 72 h . The agreement for MFCs was lower (86 to 94%) . Based on interlaboratory agreement, the optimal testing conditions were RPMI broth, 48 to 72 h of incubation and 100% growth inhibition (MIC-0); MFCs can be obtained after MIC determination with the above optimal testing parameters . These results warrant consideration for inclusion in the future version of the NCCLS M38 document . However, the role of these in vitro values as predictors of clinical outcome remains to be established in clinical trials.

Pediatr Infect Dis J, 2002 Sep, 21(9), 859 - 65
Pneumococcal serotypes from acute otitis media in rural Kentucky; Block SL et al.; OBJECTIVE: Acute otitis media (AOM) accounts for most infections caused by, but few data are available regarding the incidence of pneumococcal serotypes recovered from children with AOM in the United States . METHODS: Between January 1992 and March 1998, 777 middle ear pathogens from AOM were obtained from 701 patients by tympanocentesis (84.6%) or by culture of otorrhea (15.4%) from spontaneous perforation or draining tubes . The ambulatory patient population was mostly white and cared for by a sole private pediatric practice in rural Kentucky . RESULTS: Penicillin-nonsusceptible (penicillin MIC > or = 0.1 microg/ml) (PNSP) isolates accounted for 18% {6% resistant PNSP (rPNSP) and 12% intermediate resistant PNSP}, and penicillin-susceptible strains accounted for 35% of the pathogens recovered from children with culture-proved AOM . Comparing the frequency of isolates between 1992 and 1993 with those between 1994 and 1998, overall rates of PNSP strains remained remarkably stable (32.2% 37.3%), but intermediate resistant PNSP strains doubled from 14% to 27% ( < 0.01), whereas rPNSP strains fell by one-third . Serotypes 19F (34%), 23F (30%), 6B (26%) and 14 (8%) accounted for nearly all rPNSP isolates . Two cross-reactive serotypes (6A and 19A) not included in the available pneumococcal conjugate vaccine comprised 8.4 and 15% of all serotypes and PNSP serotypes, respectively . Nearly all PNSP strains recovered in children < or =24 months are included in the vaccine serogroups . CONCLUSION: Depending on rates of efficacy and serotype cross-protection, the current pneumococcal conjugate vaccine could potentially protect against most PNSP strains in all ages, particularly in those < or =24 months.

J Med Assoc Thai, 2002 Jul, 85(7), 757 - 64
Clinical and mycological responses to fluconazole and fluconazole MIC in oropharyngeal candidiasis in HIV-infected patients; Bussaratid V et al.; INTRODUCTION: OPC is a common opportunistic infection in HIV-infected patients . Although some patients are asymptomatic, progression of the disease may occur leading to esophageal candidiasis . Fluconazole resistant candidiasis has been reported in several international studies . OBJECTIVES: This study aimed to test the MICs (minimal inhibitory concentrations) to fluconazole of Candida species isolated from mouthwash specimens of 54 HIV positive patients with oral candidiasis . Clinical and mycological responses to fluconazole were also assessed in 16 patients . MATERIAL AND METHOD: This was a prospective study . Mouthwash specimens were cultured on sabouraud dextrose agar twice . Candida species identification was performed and MICs for fluconazole were obtained using NCCLS guidelines . Clinical and mycological responses were assessed on day 14 and 42 in 16 patients who received a 14-day course of fluconazole . RESULTS: 48/54 patients (88.89%) were found to carry pure C . albicans . The other 6 patients (11.11%) had mixed Candida species on cultures . Among these 6 patients, 5 patients had mixed C . albicans and C . glabrata, and 1 patient had C . albicans and C . krusei . Fluconazole MICs of C . albicans, C . glabrata, and C . krusei ranged from 0.125-32 (median=0.250), 4-64 (median=2), and 8 g/L respectively . This study showed that the MICs to fluconazole of oropharyngeal Candida was a good predictor of the therapeutic responses.

Immunogenetics, 2002 Sep, 54(6), 439 - 41 Epub 2002 Jul 16.
High frequency of MIC null haplotype (HLA-B48-MICA-del-MICB*0107 N) in the Angaite Amerindian community in Paraguay; Aida K et al.; We describe a high frequency of the MIC null haplotype, HLA-B48-MICA-del-MICB*0107 N, in the Angaite Amerindian community in Paraguay . Of the 16 unrelated subjects, 9 (56.5%) had this haplotype . The structural analyses revealed this haplotype was similar to the previously reported Asian haplotype in that they had a large-scale deletion including the entire MICA gene and linked to MICB*0107 N and HLA-B*48 . The novel recombination haplotype between this MIC null haplotype and HLA-B15, HLA-B15-MICA-del-MICB*0107 N, was also found in this community.

Antimicrob Agents Chemother, 2002 Oct, 46(10), 3323 - 6
In vitro synergistic interaction between amphotericin B and pentamidine against Scedosporium prolificans; Afeltra J et al.; To develop new approaches for the treatment of invasive infections caused by Scedosporium prolificans, the in vitro interaction between amphotericin B and pentamidine against 30 clinical isolates was evaluated using a checkerboard microdilution method based on the National Committee for Clinical Laboratory Standards M38-P guidelines . The interaction between the drugs was analyzed using fractional inhibitory concentration index (FICI) analysis and response surface modeling . Amphotericin B alone was inactive against all the isolates . The geometric mean MIC for pentamidine was 57 micro g/ml (range, 8 to 256 micro g/ml; MIC at which 50% of the isolates tested were inhibited {MIC(50)}, 64 micro g/ml; MIC(90), 128 micro g/ml) . The combination was synergistic against 28 of 30 isolates (93.3%) by FICI analysis and 30 of 30 (100%) by response surface modeling analysis . Antagonism was not observed.

Antimicrob Agents Chemother, 2002 Oct, 46(10), 3156 - 63
Beta-lactamases in ampicillin-resistant Escherichia coli isolates from foods, humans, and healthy animals; Brinas L et al.; TEM-, SHV-, and OXA-type beta-lactamases were studied by PCR with 124 ampicillin-resistant (AMP(r)) Escherichia coli isolates recovered from foods of animal origin (n = 20) and feces of humans (n = 49) and healthy animals (n = 55) . PCR showed that 103 isolates were positive for TEM and negative for SHV and OXA . Three E . coli isolates showed a positive reaction for OXA, and one showed a positive reaction for SHV . The remaining 17 E . coli isolates were negative for the three enzymes by PCR . Fifty-seven of the 103 bla(TEM) amplicons were sequenced . Different molecular variants of bla(TEM-1) were found in 52 isolates: bla(TEM-1a) (n = 9), bla(TEM-1b) (n = 36), bla(TEM-1c) (n = 6), and bla(TEM-1f) (n = 1) . Four inhibitor-resistant TEM (IRT) beta-lactamase-encoding genes were also detected: bla(TEM-30c) (IRT-2), bla(TEM-34b) (IRT-6), bla(TEM-40b) (IRT-11), and bla(TEM-51a) (IRT-15) . A new bla(TEM) gene, named bla(TEM-95b), which showed a mutation in amino acid 145 (P-->A) was detected . It was found in a food isolate of chicken origin (AMP(r), amoxicillin-clavulanic acid susceptible) . The promoter region in 24 bla(TEM) amplicons was analyzed, and the weak P3 promoter was found in 23 of them (bla(TEM-1) in 20 amplicons and bla(TEM-51a), bla(TEM-30c), and bla(TEM-95b) in 1 amplicon each) . The strong Pa/Pb promoter was found only in the bla(TEM-34b) gene . No extended-spectrum beta-lactamases were detected . Mutations at position -42 or -32 in the ampC gene promoter were demonstrated in 4 of 10 E . coli isolates for which the cefoxitin MIC was >/=16 micro g/ml . Different variants of bla(TEM-1) and IRT bla(TEM) genes were found among the AMP(r) E . coli isolates from foods and the feces of humans and healthy animals, and a new gene, bla(TEM-95b) (P3), was detected.

Res Microbiol, 2002 Jul-Aug, 153(6), 353 - 60
Use of potassium tellurite for testing the survival and viability of Pseudomonas pseudoalcaligenes KF707 in soil microcosms contaminated with polychlorinated biphenyls; Zanaroli G et al.; This study shows that the oxyanion tellurite TeO3(2-) can be used as a tool to detect and quantify the release in soil microcosms of Pseudomonas pseudoalcaligenes KF707, a strain spontaneously resistant to tellurite with a minimal inhibitory concentration (MIC) of 150 microg ml(-1) . KF707 cells which carry the genes for degradation of a wide range of polychlorinated biphenyl congeners (PCBs) were used for inoculation of laboratory microcosms prepared with two different PCB-contaminated soils (Ci/s and Di/s) in the presence or absence of biphenyl as carbon source . In all microcosms supplemented with biphenyl, significant survival of strain KF707 was noted over a time period of 35 days; conversely, in microcosms containing Ci/s soil without biphenyl addition a rapid decrease in KF707 inoculated cells was observed . By comparing the number of inoculated KF707 cells with the number of indigenous bacteria growing on biphenyl (IBGB) of both Ci/s and Di/s microcosms, it could be concluded that the KF707/IBGB ratio is a relevant parameter in determining the fate of the added strain . The efficacy of potassium tellurite as a selective marker to monitor strain KF707 in laboratory microcosms was confirmed by ARDRA analyses of the 16S rDNA, while the isolated indigenous bacteria growing on biphenyl were identified as members of three different species of the genus Pseudomonas . We also report that in microcosms inoculated with KF707 cells in the absence of biphenyl, only low chlorinated biphenyls were degraded.

Pharmacotherapy, 2002 Sep, 22(9), 1077 - 83
Evaluation of four once-daily aminoglycoside dosing nomograms; Wallace AW et al.; STUDY OBJECTIVE: To evaluate the accuracy of four once-daily aminoglycoside dosing nomograms in producing the desired gentamicin peak concentration (Cmax) target of 20 microg/ml in patients with varying degrees of renal function . DESIGN: Retrospective analysis using prospectively collected pharmacokinetic data . SETTING: Rural teaching hospital . PATIENTS: Ninety patients receiving intravenous gentamicin divided into three groups (30 patients each) determined by estimated renal function: group 1, creatinine clearance (Cl(cr),) 60 ml/minute or greater; group 2, Cl(cr) 40-59 ml/minute; group 3, Cl(cr) 20-39 ml/minute . Intervention . Serum gentamicin concentrations were collected for a 2-point (two consecutive infusions and one predose and one postdose concentration sampled during steady state) or 3-point (single infusion and one predose and two postdose concentrations at least 1.5 estimated half-lives apart) pharmacokinetic study for determination of patient-specific pharmacokinetic parameters (elimination rate constant, volume of distribution at steady state, and clearance) after 30-minute infusions of gentamicin 2.8 +/- 1.6 mg/kg . MEASUREMENTS AND RESULTS: The four nomograms evaluated were from Hartford Hospital, Barnes-Jewish Hospital, University of Rochester, and the Sanford Guide . With a pharmacokinetic analysis program and the patient-specific pharmacokinetic parameters, Cmax and minimum concentration (Cmin) were determined with use of the recommended doses and dosing intervals of the four nomograms . Also, the gentamicin dose and interval needed to achieve a Cmax and Cmin of 20 microg/ml and 0.2 microg/ml, respectively, were determined . Dosing was based on total body weight unless that weight was more than 25% of ideal body weight, in which case, an adjusted body weight was used . In general, the recommended dosages and resultant Cmax produced by the nomograms were significantly less (p < 0.05) than the dosage and Cmax actually needed to achieve a Cmax:minimum inhibitory concentration (MIC) ratio of 10 or greater for bacteria with an MIC of 2 microg/ml . CONCLUSION: Once-daily aminoglycoside dosing using the four nomograms resulted in inaccurate dosing, and because of the large variability in human pharmacokinetics, dosing nomograms such as these should be abandoned in favor of individualizing dosages with therapeutic drug monitoring.

Eur J Oral Sci, 2002 Aug, 110(4), 296 - 301
Amine fluoride gel affects the viability and the generation of superoxide anions in human polymorphonuclear leukocytes: an in vitro study; Knoll-Kohler E et al.; Amine hydrofluorides are widely used to prevent caries . As an acidulated gel, they were also studied for their applicability to reduce pathogenic bacteria in periodontal pockets . We assessed the toxicity of this pharmaceutical amine hydrofluoride preparation on human polymorphonuclear leukocytes in vitro by measuring Trypan blue exclusion and the generation of superoxide anions (O2) by the chemotactic peptide N-formyl-L-methionyl-L-leucyl-L-phenylalanine (fMLP) after a 3-min contact with gel . Depending on the experimental conditions, gel dilutions up to 1.3 x 10(4) resulted in an increase in Trypan blue-colored cells and liberation of beta-glucuronidase . Dilutions between 3 x 10(4) and 1 x 10(5) augmented the fMLP-mediated O2- generation, which could be prevented by Ca2+ chelation with BAPTA-AM (1,2'-bis (o-aminophenoxyethane-N.N.N'.N'-tetraacetic acid tetra (acetoxymethyl) ester) and ethyleneglycoltetraacetic acid (EGTA) or inhibition of protein kinase C (PKC) with staurosporine and bisindolylmaleimide I . respectively . Compared with data published on the minimal inhibitory concentration for periodontal pathogenic bacteria, the cytotoxicity of amine hydrofluorides on eukaryotic cells is much greater and thus of consequence for their clinical use.

Hua Xi Kou Qiang Yi Xue Za Zhi, 1998 May, 16(2), 105 - 7
{Research on inhibition of sodium fluoride on five subgingival bacteria in vitro}; Qian W et al.; This in vitro study was aimed at observing inhibition action of fluoride on 5 common periodontal bacteria in subgingival microflora . The liquid media two-fold dilution method was used to determine the minimal inhibition concentration (MIC) of sodium fluoride (NaF) to 9 strains of bacteria representing the main periodontopathic species(P . gingivalis, A . actinomycetemcomitans, P . intermedius) and the periodontal beneficial species (S . sanguis) and 1 strain of S . sorbrinus . The results showed that all the bacteria were inhibited at different concentration of NaF . The MIC values ranged from 128 micrograms/ml for P . gingivalis and A . actinomycetemcomitans, 256 micrograms/ml for S . sorbrinus, 1024 micrograms/ml for P . intermedius to 2048-4096 micrograms/ml for S . sanguis . The results suggest that NaF can also be used as a periodontal anti-bacterium agent and those preparations containing about 1000 micrograms/ml fluoride can be used effectively against the periodontopathic bacteria without disturbing the local ecological balance.

Vet Res Commun, 2002 Jul, 26(5), 371 - 80
Endometrial tissue concentrations of enrofloxacin after intrauterine administration to mares; Fumuso E et al.; Endometritis in mares is a common cause of infertility . Conventional treatments of the disease have mostly been unsuccessful, so new therapeutic alternatives need to be investigated . This study evaluated the uterine disposition and plasma pharmacokinetic behaviour of a commercial formulation of enrofloxacin (EFX) given by the intrauterine (i.u.) route (2.5 mg/kg) in healthy mares . In order to evaluate the uterine inflammatory response, an initial histopathological study assessing polymorphonuclear cell infiltration was carried out in 20 mares over a 14-day period after treatment . In a second study, 6 healthy adult mares were used for the pharmacokinetic study . Samples of uterine tissue and plasma were collected from 0 to 24 h after the i.u . treatment with 5% EFX solution . Samples were analysed by conventional microbiological assay using an EFX-sensitive strain of Escherichia coli (ATCC 25922) . There was a moderate but statistically nonsignificant inflammatory response following i.u . administration of either the formulation or the vehicle alone . Pharmacokinetic analysis of the uterine concentrations of EFX showed a slow and sustained depletion, with EFX remaining at concentrations above the MIC for 24 h after treatment . The area under the concentration-time curve obtained for the uterus suggested that EFX and its metabolites are specifically retained in the uterus, which is the target tissue for bacterial colonization . Neither study provided any evidence of EFX toxicity . In conclusion, these results are encouraging and suggest that EFX may be a useful local treatment in mares with bacterial endometritis.

Pharmacol Res, 2002 Jul, 46(1), 89 - 94
Prognostic factors for the clinical effectiveness of fluconazole in the treatment of oral candidiasis in HIV-1-infected individuals; Koks CH et al.; OBJECTIVE: To identify prognostic factors for the clinical effectiveness of fluconazole in HIV-1-infected patients with oropharyngeal candidiasis.DESIGN AND SETTING: The study was designed as a prospective, open label, non-comparative, dose escalating, single centre trial.PATIENTS AND METHODS: Thirty-four HIV-1-infected patients with oropharyngeal Candida infection were treated with 50 or 100mg fluconazoleday(-1), depending on the clinical manifestation (erythematous or pseudomembranous) . The dose was doubled weekly until clinical cure . The predictive value of potential prognostic factors for the duration of treatment and cumulative fluconazole dose until cure was studied: exposure to fluconazole, previous use of fluconazole, the use of antiretroviral drugs, the CD4(+) cell count, erythematous or pseudomembranous appearance, the minimum inhibitory concentration (MIC) for fluconazole of the isolated Candida strain, and xerostomia.RESULTS: Twenty-eight patients (with 30 episodes of oropharyngeal candidiasis) were evaluated . Twenty-five episodes were cured within 1-week of treatment, the remaining five episodes were cured within 2 weeks . No predictive value for any of the studied factors on the duration of fluconazole treatment or the cumulative fluconazole dose until cure was demonstrated.CONCLUSION: Because of the high susceptibility to fluconazole and the positive clinical outcome, the variation in outcome measurements was too modest to establish a significant relationship between any of the investigated potentially prognostic factors and the cumulative fluconazole dose and the duration of treatment to reach cure . On the other hand it can be concluded, that fluconazole is very effective in patients with advanced HIV infection and low CD4(+) cell counts, even if they are not using antiretroviral agents.

J Antimicrob Chemother, 2002 Sep, 50(3), 407 - 10
Comparative in vitro activity of garenoxacin against Chlamydia spp; Donati M et al.; The in vitro susceptibilities of 33 isolates of Chlamydia trachomatis, Chlamydia pneumoniae and Chlamydia psittaci to a new quinolone drug, garenoxacin (BMS-284756), in comparison with levofloxacin, ciprofloxacin, doxycycline, erythromycin and roxithromycin, were determined . Garenoxacin was the most active of the quinolone drugs tested, with identical MIC and MBC, which ranged from 0.007 to 0.03 mg/L . The MIC and MBC of the other two quinolones tested, levofloxacin and ciprofloxacin, were also identical, ranging from 0.25 to 2 mg/L . The MICs and MBCs of doxycycline, erythromycin and roxithromycin were also determined.

Res Vet Sci, 2002 Oct, 73(2), 125 - 9
Disposition kinetics of enrofloxacin (Baytril 5%) in sheep and goats following intravenous and intramuscular injection using a microbiological assay; Elsheikh HA et al.; The pharmacokinetics of enrofloxacin were determined in Desert sheep and Nubian goats after intravenous and intramuscular administration of Baytril at the dose of 5mgkg(-1) bodyweight . A two compartment open model best represented the intravenous plasma concentration versus time data in both species . Comparisons between the means of the pharmacokinetic parameters obtained after intravenous administration of enrofloxacin (Baytril) revealed a significantly smaller distribution rate constant (lambda(1)) and consequently a shorter half-life time of distribution in sheep (P<0.05) . A larger volume of the central compartment (Vc) was observed in goats (P<0.05) . Similar values were obtained for sheep and goats for the remaining parameters.Plasma concentrations versus time data of enrofloxacin after 5mgkg(-1) intramuscular administration of Baytril in sheep and goats were adequately described by one-compartment open model with first order absorption and elimination . There were no significant differences between sheep and goats in any of the estimated pharmacokinetic parameters.The results indicate that the pharmacokinetics of enrofloxacin did not differ significantly between sheep and goats; similar intravenous and intramuscular dose rates of enrofloxacin should therefore be applicable to both species . Owing to the high variations in MIC (minimal inhibitory concentration) of sensitive veterinary pathogens, it is recommended that enrofloxacin dosage regimens be calculated according to the sensitivity of the individual pathogen, site of infection and clinical response, than by following a preset dosage regimen.

Res Vet Sci, 2002 Oct, 73(2), 105 - 14
The pharmacokinetic-pharmacodynamic approach to a rational dosage regimen for antibiotics; Toutain PL et al.; Pharmacokinetic-pharmacodynamic (PK/PD) surrogate indices (AUIC, AUC/MIC, C(max)/MIC, T>MIC) for measuring antibiotic efficacy are presented and reviewed . As clinical trials are not sufficiently sensitive to establish a dosage regimen which guarantees total bacteriological cure (Pollyanna phenomenon), PK/PD indexes have been proposed from in vitro, ex vivo, and in vivo infection models and subsequently validated in retrospective or prospective human clinical trials . The target value for time-dependent antibiotics (beta-lactams, macrolides) is a time above the MIC (T>MIC) of 50-80% of the dosage interval, while for concentration-dependent antibiotics (quinolones and aminoglycosides), the area under the inhibitory curve (AUIC, or more simply AUC/MIC of about 125h) is the best surrogate indicator of activity . Using the latter drugs, high concentrations achieved early during therapy are desirable to prevent the development of resistance . A C(max)/MIC ratio greater than 10-12 seems to be an appropriate target for aminoglycosides.

Phytother Res, 2002 Aug, 16(5), 445 - 8
Antimycobacterial physalins from Physalis angulata L . (Solanaceae); Januario AH et al.; Crude extracts and fractions from aerial parts of Physalis angulata have been bioassayed for antimycobacterial activity . Fraction A1-29-12 containing physalins B, F and D exhibited a minimum inhibitory concentration value (MIC) against Mycobacterium tuberculosis H(37)Rv strain of 32 microg/mL . Purified physalin B and physalin D were also tested showing MIC values against Mycobacterium tuberculosis H(37)Rv strain of > 128 microg/mL and 32 microg/mL respectively, suggesting that physalin D plays a relevant role in the antimycobacterial activity displayed . Structural elucidation of both physalins D and B was based on detailed (13)C and (1)H NMR spectral analysis with the aid of 2D-correlation spectroscopy ((1)H-(1)H, COSY, HSQC and HMBC) . The assignment of the (13)C chemical shift for physalin D is reported here for the first time .

J Clin Microbiol, 2002 Sep, 40(9), 3204 - 8
Testing conditions for determination of minimum fungicidal concentrations of new and established antifungal agents for Aspergillus spp.: NCCLS collaborative study; Espinel-Ingroff A et al.; Standard conditions are not available for evaluating the minimum fungicidal concentrations (MFCs) of antifungal agents . This multicenter collaborative study investigated the reproducibility in three laboratories of itraconazole, posaconazole, ravuconazole, voriconazole, and amphotericin B MFCs for 15 selected isolates of Aspergillus spp . After MIC determinations for the 15 isolates in each center by the NCCLS M38-A broth microdilution method with four media, standard RPMI 1640 (RPMI), RPMI with 2% dextrose, antibiotic medium 3 (M3), and M3 with 2% dextrose, MFCs were determined for each isolate-medium-drug combination . MFCs were defined as the lowest drug dilutions that yielded <3 colonies (approximately 99 to 99.5% killing activity) . The highest reproducibility (96 to 100%) was for amphotericin B MFCs with the four media . Although reproducibility was more variable and medium dependent for the azoles (91 to 98%), agreement was good to excellent for itraconazole, ravuconazole, and voriconazole MFCs with RPMI and M3 (93 to 98%) . For posaconazole, the agreement was higher with M3 media (91 to 96%) than with RPMI media (91%) . These data extend the refinement of testing guidelines for susceptibility testing of Aspergillus spp . and warrant consideration for introduction into future versions of the M38 document . The role of the MFC under these standardized testing conditions as a predictor of clinical outcome needs to be established in clinical trials.

Appl Environ Microbiol, 2002 Sep, 68(9), 4613 - 22
Isolation of tellurite- and selenite-resistant bacteria from hydrothermal vents of the Juan de Fuca Ridge in the Pacific Ocean; Rathgeber C et al.; Deep-ocean hydrothermal-vent environments are rich in heavy metals and metalloids and present excellent sites for the isolation of metal-resistant microorganisms . Both metalloid-oxide-resistant and metalloid-oxide-reducing bacteria were found . Tellurite- and selenite-reducing strains were isolated in high numbers from ocean water near hydrothermal vents, bacterial films, and sulfide-rich rocks . Growth of these isolates in media containing K(2)TeO(3) or Na(2)SeO(3) resulted in the accumulation of metallic tellurium or selenium . The MIC of K(2)TeO(3) ranged from 1,500 to greater than 2,500 micro g/ml, and the MIC of Na(2)SeO(3) ranged from 6,000 to greater than 7,000 micro g/ml for 10 strains . Phylogenetic analysis of 4 of these 10 strains revealed that they form a branch closely related to members of the genus Pseudoalteromonas, within the gamma-3 subclass of the Proteobacteria . All 10 strains were found to be salt tolerant, pH tolerant, and thermotolerant . The metalloid resistance and morphological, physiological, and phylogenetic characteristics of newly isolated strains are described.

Acta Pol Pharm, 2001 Nov-Dec, 58(6), 439 - 45
Susceptibility to antibiotics and biochemical properties of Desulfovibrio desulfuricans strains; Dzierzewicz Z et al.; Susceptibility to several antibiotics and biochemical properties of intestinal and soil strains of Desulfovibrio desulfuricans bacteria were investigated using the tests: ATB ANA, Sceptor Anaerobic MIC/ID and API ZYM . It was demonstrated that the D . desulfuricans strains were resistant to penicillin, cefoxitin, clindamycin, metronidazole, erythromycin, rifampicin and teicoplanin . The strains initially susceptible to imipenem became resistant to this drug following 72 h incubation with it . Of 25 analyzed antibiotics there was none that after 72 h action on the bacteria was effective in relation to all of the investigated strains . The differences in susceptibility of D . desulfuricans strains to antibiotics were not associated with the strains' biochemical properties.

Boll Chim Farm, 2002 May-Jun, 141(3), 247 - 9
Antituberculosis agents . III . In vitro evaluation of antimycobacterial activity and cytotoxicity of some N-piperazinyl quinolone derivatives; Foroumadi A et al.; A series of N-{2-oxo-2-(4-substitutedphenyl)ethyl}piperazinyl quinolones(1a-e,2a-e and 3a-c) and N-{2-hydroxyimino-2-(4-substitutedphenyl)ethyl}piperazinyl quinolones(1f-j,2f-j and 3d-f) were evaluated for antituberculosis activity against Mycobacterium tuberculosis H37R, using the BACTEC 460 radiometric system and BACTEC 12B medium . Active compounds were also screened by serial dilution to assess toxicity to a VERO cell line . Nine compounds were efficient antimycobacterial agents showing MIC values ranging from 0.78 to 6.25 micrograms/ml . Generally, ciprofloxacin derivatives were more active than norfloxacin and enoxacin derivatives and the oxime analogues were less active than corresponding ketones . The most selective and less toxic compound 1a was tested for efficacy in vitro in TB-infected macrophage model (EC90 = 3.68 micrograms/ml, EC99 = 9.18 micrograms/ml).

Arzneimittelforschung, 2002, 52(7), 565 - 71
Synthesis and antituberculosis activity of cycloalkylidenehydrazide and 4-aza-1-thiaspiro{4.5}decan-3-one derivatives of imidazo{2,1-b}thiazole; Ulusoy N; New N2-cycloalkylidene-(6-phenyl/4-chlorophenylimidazo{2,1-b}thiazol-3-yl) acetic acid hydrazides (2a-h and 3a-b) were synthesized by reacting (6-phenyl/4-chlorophenylimidazo{2,1-b}thiazol-3-yl)acetic acid hydrazides with cyclohexanones or cyclopentanone . Furthermore, 2a-h were refluxed with thioglycolic or thiolactic acid to give 4-{{(6-phenyl/4-chlorophenylimidazo{2,1-b}thiazol-3-yl) acetyl}amino}-4-aza-1-thiaspiro{4.5}decan-3-ones (4a-h and 5a-h) . The structures of the title compounds were established by spectral data (IR, 1H-NMR, 13C-NMR and EIMS (Electron Impact Mass Spectrometry)) and elemental analysis . The synthesized compounds were evaluated for antituberculosis activity against Mycobacterium tuberculosis H37Rv (ATCC 27294) . The compounds exhibited varying degrees of inhibition in the in vitro primary screening that was conducted at a concentration of 6.25 micrograms/ml against M . tuberculosis H37Rv (ATCC 27294) in Bactec 12B medium using the Bactec 460 radiometric system or a broth microdilution assay, the Microplate Alamar Blue Assay (MABA) . Compounds 2f, 2h, 3b, 4a, 4c, 4d, 5a-e and 5h demonstrating at 1-east 90% inhibition in the primary screen were re-tested at lower concentrations against M . tuberculosis H37Rv (ATCC 27294) to determine the actual minimum inhibitory concentration (MIC) using MABA . The most active compounds were found to be 4d and 5c . The structure-activity relationships of the derivatives were investigated.

Br J Cancer, 2002 Aug 27, 87(5), 481 - 90
The case for the introduction of new chemotherapy agents in the treatment of advanced non small cell lung cancer in the wake of the findings of The National Institute of Clinical Excellence (NICE); Waters JS et al.; After years of nihilism towards the use of chemotherapy for non small cell lung cancer in the UK it would appear that we have now reached the point where the use of chemotherapy to relieve symptoms, maintain quality of life, and prolong life, are now accepted for informed patients with good performance status willing to accept short-term toxicities . The use of the new agents vinorelbine, gemcitabine and paclitaxel in combination with cisplatin or carboplatin are all active regimens which offer small but real advantages over standard UK triple therapies (MVP, MIC) in terms of resource use, toxicity profiles and response rates . Overall survival could be increased by as much as 10% at one year on indirect comparisons . The use of docetaxel as second line therapy now offers lung cancer patients a second bite of the cherry, and should overall also prolong survival . It is only in embracing these small gains that we can currently make progress in the treatment of NSCLC.

Kekkaku, 2002 Jul, 77(7), 533 - 5
{A study of INH 0.1 microgram/ml resistant M . tuberculosis strains assessed by BrothMIC MTB-1 method}; Yoshida H et al.; In the antimycobacterial susceptibility test for INH using the egg-based Ogawa media, 3 concentrations (0.1, 1, or 5 micrograms/ml) of INH were used, and 1 microgram/ml was used as a critical concentration for INH resistance . However, it was controversial whether INH 0.1 microgram/ml resistant M . tuberculosis was clinically significant or not . We investigated the MIC values of INH 0.1 microgram/ml resistant strains by using BrothMIC MTB-1 method, and 115 strains of M . tuberculosis confirmed by DNA-prove test were used . The distribution of MIC values of 115 strains determined by Ogawa INH susceptibility test was shown in figure . By BrothMIC MTB-1 method, they were classified into 3 groups; susceptible, low resistant and high resistant groups . The mean MIC value of INH 0.1 microgram/ml resistant M . tuberculosis was estimated to be 4.53 micrograms/ml with its 95% confidence interval 3.21-5.85 micrograms/ml, and they were determined as "resistant" in BrothMIC MTB-1 method . These results supported the idea that patients with INH 0.1 microgram/ml resistant M . tuberculosis strains should be regarded as clinically "resistant".

Eur J Clin Pharmacol, 2002 Aug, 58(5), 339 - 51 Epub 2002 Jul 13.
Population pharmacokinetic and pharmacodynamic modelling of artemisinin and mefloquine enantiomers in patients with falciparum malaria; Svensson US et al.; OBJECTIVES: The aims of this study were to investigate whether artemisinin influences the pharmacokinetics of mefloquine enantiomers or vice versa and to model the antiparasitic effect of these drugs alone and in combination in Plasmodium falciparum malaria patients . METHODS: Forty-two male and female patients were randomised to treatment with either oral artemisinin 500 mg daily for 3 days followed by oral mefloquine 750 mg on day 4, oral artemisinin 500 mg daily for 3 days plus oral mefloquine 750 mg on day 1 or a single 750-mg oral dose of mefloquine . The data was modelled using NONMEM . RESULTS: All patients were successfully treated regardless of treatment . The fastest parasite clearance rates were observed in patients receiving artemisinin together with mefloquine on the first day of treatment . A pharmacodynamic model based on the life cycle of P . falciparum successfully described the efficacy of artemisinin, mefloquine and the combination . The time artemisinin concentration stays above a minimum inhibitory concentration was estimated to 2.97 h (relative standard error 4.7 h) . The two mefloquine enantiomers exhibited different pharmacokinetics, with an oral clearance of 3.51 (7.9) l/h and 0.602 (6.9) l/h for RS-mefloquine and SR-mefloquine, respectively . In patients receiving only artemisinin the first 3 days, artemisinin oral clearance was 6.9-fold higher the last day of treatment compared with the first day . There was no difference in the pharmacokinetics of mefloquine enantiomers when mefloquine was given alone, in combination with artemisinin or after a 3-day regimen of artemisinin . There was a tendency towards, although non-significant, higher artemisinin concentrations when artemisinin was given together with mefloquine compared with when given alone . CONCLUSIONS: No significant pharmacokinetic interactions were observed after co-administration of artemisinin and mefloquine . The P . falciparum malaria pharmacodynamic model successfully described the antimalarial effect of artemisinin, mefloquine and a combination of the two drugs.

Antimicrob Agents Chemother, 2002 Sep, 46(9), 2996 - 3000
16S rRNA mutation-mediated tetracycline resistance in Helicobacter pylori; Gerrits MM et al.; Most Helicobacter pylori strains are susceptible to tetracycline, an antibiotic commonly used for the eradication of H . pylori . However, an increase in incidence of tetracycline resistance in H . pylori has recently been reported . Here the mechanism of tetracycline resistance of the first Dutch tetracycline-resistant (Tet(r)) H . pylori isolate (strain 181) is investigated . Twelve genes were selected from the genome sequences of H . pylori strains 26695 and J99 as potential candidate genes, based on their homology with tetracycline resistance genes in other bacteria . With the exception of the two 16S rRNA genes, none of the other putative tetracycline resistance genes was able to transfer tetracycline resistance . Genetic transformation of the Tet(s) strain 26695 with smaller overlapping PCR fragments of the 16S rRNA genes of strain 181, revealed that a 361-bp fragment that spanned nucleotides 711 to 1071 was sufficient to transfer resistance . Sequence analysis of the 16S rRNA genes of the Tet(r) strain 181, the Tet(s) strain 26695, and four Tet(r) 26695 transformants showed that a single triple-base-pair substitution, AGA(926-928)-->TTC, was present within this 361-bp fragment . This triple-base-pair substitution, present in both copies of the 16S rRNA gene of all our Tet(r) H . pylori transformants, resulted in an increased MIC of tetracycline that was identical to that for the Tet(r) strain 181.

Antimicrob Agents Chemother, 2002 Sep, 46(9), 2804 - 10
Isoniazid-induced transient high-level resistance in Mycobacterium tuberculosis; Viveiros M et al.; An American Type Culture Collection reference strain and eight clinical strains of Mycobacterium tuberculosis, all of which were susceptible to isoniazid (INH) (mean MIC, 0.06 mg/liter) and negative for the Ser315Thr katG mutation, were left in their BACTEC 12B vials (for use with the BACTEC 460-TB method) containing 0.1 mg of INH per liter for periods of up to 28 days after the completion of the antibiotic susceptibility test . Each eventually grew to levels compatible with those of INH-resistant strains . Successive passages in INH-containing BACTEC 12B vials and onto solid media showed that the resistance noted above was maintained . Successive passages of these M . tuberculosis strains in which INH resistance had been induced into BACTEC 12B vials or solid media containing stepwise increases in INH concentrations eventually yielded organisms resistant to 20 mg of INH per liter . Transfer of cells in which INH resistance had been induced to drug-free medium followed by repeated passages in that medium eventually yielded organisms whose susceptibility to INH was identical to that of the original parent strains . The cycle of induced INH resistance could be repeated with these now INH-susceptible cells . The use of M . tuberculosis identification probes and IS6110-based restriction fragment length polymorphism analyses of cultures throughout the induction of INH resistance and the reversal of resistance in drug-free medium eliminated the possibility that the culture was contaminated or that the initial specimen had a mixed type of infection . Induced high-level resistance to INH (20 mg/liter) could be reduced 100-fold with a subinhibitory concentration of reserpine but not with verapamil . These results collectively suggest that high-level resistance to INH can be induced in INH-susceptible M . tuberculosis strains by the induction of a reserpine-sensitive efflux mechanism.

Antimicrob Agents Chemother, 2002 Sep, 46(9), 2765 - 71
Oxidative stress increases susceptibility of Mycobacterium tuberculosis to isoniazid; Bulatovic VM et al.; Isoniazid is a first-line antibiotic used in the treatment of infections caused by Mycobacterium tuberculosis . Isoniazid is a prodrug requiring oxidative activation by the catalase-peroxidase hemoprotein, KatG . Resistance to isoniazid can be obtained by point mutations in the katG gene, with one of the most common being a threonine-for-serine substitution at position 315 (S315T) . The S315T mutation is found in more than 50% of isoniazid-resistant clinical isolates and results in an approximately 200-fold increase in the MIC of isoniazid compared to that for M . tuberculosis H37Rv . In the present study we investigated the hypothesis that superoxide plays a role in KatG-mediated isoniazid activation . Plumbagin and clofazimine, compounds capable of generating superoxide anion, resulted in a lower MIC of isoniazid for M . tuberculosis H37Rv and a strain carrying the S315T mutation . These agents did not cause as great of an increase in isoniazid susceptibility in the mutant strain when the susceptibilities were assessed by using the inhibitory concentration that causes a 50% decrease in growth . These results provide evidence that superoxide can play a role in isoniazid activation . Since clofazimine alone has antitubercular activity, the observation of synergism between clofazimine and isoniazid raises the interesting possibility of using both drugs in combination to treat M . tuberculosis infections.

Lett Appl Microbiol, 2002, 35(3), 203 - 7
Comparative study of in vitro methods used to analyse the activity of propolis extracts with different compositions against species of Candida; Sawaya AC et al.; AIMS: Propolis is known for its activity against micro-organisms and different in vitro assays have been used to evaluate this activity, frequently with contradictory results . METHODS AND RESULTS: Brazilian propolis from the state of Sao Paulo was extracted by maceration using different concentrations of ethanol and water . The resultant extracts were analysed by chromatographic methods . Several microbiological methods were compared to determine which one best evaluated the activity of the propolis extracts against species of Candida, with average minimal inhibitory concentration values between 6 and 12 mg ml(-1) . CONCLUSIONS: Agar dilution in plates showed the clearest results . These were in agreement with the chromatographic analyses, which also identified the active substances . SIGNIFICANCE AND IMPACT OF THE STUDY: Although the active substances identified in this sample are typical of Brazilian propolis, their activity against Candida had not been recognized previously, demonstrating the importance of standardizing the correct combination of microbiological and chromatographic analyses.

Hum Immunol, 2002 Sep, 63(9), 783 - 94
High resolution molecular phototyping of MICA and MICB alleles using sequence specific primers; Collins RW et al.; Major histocompatibility complex (MHC) class I chain-related genes, MICA and MICB, are located centromeric to human leukocyte antigen B (HLA-B) on chromosome 6 . In response to stress stimuli, MIC is expressed on epithelial, endothelial and fibroblast cells, but not lymphocytes and has been demonstrated to ligate the natural killer (NK) cell receptor, NKG2D . Nucleotide sequences of MICA and MICB are highly polymorphic and several methods have been established to identify these polymorphisms, including sequence-based typing and sequence-specific oligonucleotide probing . In this study we have developed a high-resolution polymerase chain reaction-sequence-specific primer (PCR-SSP) phototyping scheme that detects all WHO-recognized MICA alleles and all 12 MICB alleles . Our method will also recognize a MICA deletion haplotype and distinguish between MICA alleles with different binding affinities for NKG2D, encoded by a non-synonymous nucleotide substitution in codon 129 . Furthermore, our scheme targets almost 90% of the dimorphic codon positions in exons 2, 3, and 4, which result in non-synonymous amino acid changes . This method can be used to determine MIC allele frequencies within different populations, as well as investigate MIC associations in cohorts of patients with autoimmune and infectious diseases and explore the impact of MIC on the survival of solid organ and stem cell transplants.

Monaldi Arch Chest Dis, 2002 Feb, 57(1), 39 - 43
Clinical use of Levofloxacin in the long-term treatment of drug resistant tuberculosis; Richeldi L et al.; Multidrug-resistant (MDR) tuberculosis (TB) is a form of TB that is resistant to some of the first-line drugs used for the treatment of the disease . It is associated both with a higher incidence of treatment failures and of disease recurrence, as well as with higher mortality than forms of TB sensitive to first-line drugs . Levofloxacin (LFX) represents one of the few second-line drugs recently introduced in the therapeutic regimens for MDR TB . We report our experience concerning in vitro activity and clinical safety of LFX in long term second-line regimens for MDR TB . IN VITRO ACTIVITY ON MYCOBACTERIA: The in vitro activity of ciprofloxacin, ofloxacin and LFX was studied on 28 strains belonging to different species of Mycobacteria . In Dubos medium, LFX inhibited the growth of both library and MDR clinical Mycobacteria strains in a range of 0.25-1 mcg/ml . In International Union Tuberculosis Medium (IUTM) the minimum inhibitory concentrations (MIC) were slightly higher, but LFX activity was not affected by the higher complexity of the medium . CLINICAL EXPERIENCE: Four patients with MDR TB were treated with a second-line regimen comprising oral LFX 500 mg twice daily, for at least 9 months . Two isolates obtained from the patients reported here showed multi resistance to isoniazid and rifampin, one to rifampin and streptomycin and one to isoniazid and ethambutol . During therapy, no significant alteration of either liver function tests, blood tests or any other described side effect of the fluoroquinolone class was observed . The 3 patients with pulmonary MDR TB showed radiologic and clinical improvement . CONCLUSION: We confirm the higher in vitro activity of LFX compared to older fluoroquinolones . Furthermore, in a limited number of MDR TB patients, second-line regimens comprising LFX 500 mg b.i.d . administered in a range of 9-24 months were well tolerated and safe.

Farmaco, 2002 Jul, 57(7), 583 - 7
Synthesis, characterization of novel coupling products and 4-arylhydrazono-2-pyrazoline-5-ones as potential antimycobacterial agents; Kucukguzel SG et al.; Novel coupling products 7a-d and 4-arylhydrazono-2-pyrazoline-5-ones 8a-e were synthesized and evaluated for antimycobacterial activity against Mycobacterium tuberculosis H37Rv and Mycobacterium avium . Compound 7b was found to be the most potent derivatives of the 7a-d series by an MIC value of 6.25 microg/ml.

Rev Inst Med Trop Sao Paulo, 2002 May-Jun, 44(3), 121 - 5
Evaluation of Etest and macrodilution broth method for antifungal susceptibility testing of Candida sp strains isolated from oral cavities of AIDS patients; Silva Mdo R et al.; A comparison of the Etest and the reference broth macrodilution susceptibility test for fluconazole, ketoconazole, itraconazole and amphotericin B was performed with 59 of Candida species isolated from the oral cavities of AIDS patients . The Etest method was performed according to the manufacturer's instructions, and the reference method was performed according to National Committee for Clinical Laboratory Standards document M27-A guidelines . Our data showed that there was a good correlation between the MICs obtained by the Etest and broth dilution methods . When only the MIC results at +/- 2 dilutions for both methods were considered, the agreement rates were 90.4% for itraconazole, ketoconazole and amphotericin B and 84.6% for fluconazole of the C . albicans tested . In contrast, to the reference method, the Etest method classified as susceptible three fluconazole-resistant isolates and one itraconazole-resistant isolate, representing four very major errors . These results indicate that Etest could be considered useful for antifungal sensitivity evaluation of yeasts in clinical laboratories.

J Pharm Pharmacol, 2002 Jul, 54(7), 997 - 1003
Non-specific binding of the experimental anti-cancer drug 5,6-dimethylxanthenone-4-acetic acid (DMXAA) in liver microsomes from various species; Zhou S et al.; Total (added) drug concentrations other than unbound concentrations have been used to estimate the in-vitro enzyme kinetic parameters for 5,6-dimethylxanthenone-4-acetic acid (DMXAA), an experimental anti-cancer drug . This study aimed to investigate the non-specific binding of DMXAA to liver microsomes from variousspecies and to microsomesfrom human lymphoblastoid cells expressing drug-metabolising enzymes, and to examine the effect of the binding on the estimation of enzyme kinetic parameters for DMXAA in-vitro . The separation of unbound DMXAA was conducted by ultrafiltration and DMXAA concentrations were determined by validated HPLC . The results indicated that DMXAA was bound to liver microsomes and lymphoblastoid cell microsomes to a small extent (free fraction in microsomes, f(u(mic)) mostly > 0.85) . Correction forthe unbound DMXAA concentration resulted in slightly lower apparent Michaelis-Menten constant (Km) values, but with the maximal velocity of reaction (Vmax) unchanged, leading to slightly higher unbound Vmax/Km values . These results indicate that the non-specific binding of DMXAA to microsomes is insignificant and has little impact on the enzyme kinetic estimation in-vitro.

J Gastroenterol, 2002, 37(7), 543 - 9
Primitive neuroectodermal tumor of the transverse colonic mesentery defined by the presence of EWS-FLI1 chimeric mRNA in a Japanese woman; Tokudome N et al.; We report a case of primitive neuroectodermal tumor (PNET) arising in the transverse colonic mesentery . A 24-year-old Japanese woman was admitted to Kagoshima City Hospital with complaints of abdominal pain and sensations of abdominal fullness of 5 months' duration . On palpation, a mass the size of an infant's head was noted in the right flank . Abdominal computed tomography (CT) and ultrasonography showed a huge mass that consisted of multiple cystic components . On arteriography, a slight tumor stain appeared, with stretched and displaced tributaries of the right colic and middle colic arteries . Barium swallow examination demonstrated that the ascending colon was shifted to the right and small intestine to the left . We performed an en-bloc resection of the tumor in the transverse colonic mesentery, including the ascending colon, proximal jejunum (20 cm in length), and greater omentum . The resected tumor was 12 x 10 x 7 cm in size, 590g in weight, elastic soft in consistency, and multicystic . Histologically, the specimens showed a sheet-like proliferation of spindle-to-polygonal cells, and focally, the tumor formed rosette structures . Immunohistochemically, the tumor cells were positive for neuron-specific enolase (NSE) and mic-2 . EWS-FLI1 chimeric mRNA was detected by reverse transcriptase-polymerase chain reaction (RT-PCR) . Based on the above findings, we finally diagnosed the tumor as PNET of the colonic mesentery . There has been no recurrence for 20 months after operation . PNET arising in the mesentery is very rare, and we distinguished PNET from other tumors by immunohistochemical examination and by demonstration of the presence of EWS-FLI1 chimeric mRNA in the tumor.

J Clin Endocrinol Metab, 2002 Aug, 87(8), 3578 - 82
Long-term follow-up of prolactinomas: normoprolactinemia after bromocriptine withdrawal; Passos VQ et al.; Bromocriptine (BRC) and other dopamine agonist drugs are the first-choice treatment for prolactinomas . However, the major disadvantage is the need for prolonged therapy . We retrospectively studied 131 patients {62 microprolactinoma (MIC), 69 macroprolactinoma (MAC)}, who achieved serum prolactin (PRL) normalization during BRC use . Twenty-seven percent of them (31% MIC and 69% MAC) underwent previous surgery . Twenty-seven patients (20.6%: 25.8% MIC and 15.9% MAC) persisted with normoprolactinemia after a median time of 44 months of BRC withdrawal . The median time of BRC use was 47 months . There were no statistically significant differences regarding age, gender, BRC initial dose, length of BRC use, tumor size, pregnancy during treatment, previous surgery, or radiotherapy among patients who persisted with normoprolactinemia and those who did not, using both univariate and multivariate analysis . BRC-induced prolactinoma cell alterations are highly controversial; and so, whether the mechanism of PRL normalization after BRC withdrawal is related to BRC use or whether it is attributable to natural history is a matter for debate . A periodic assessment of PRL levels during BRC (and other dopamine-agonist drugs) withdrawal is recommended to avoid the unnecessary maintenance of therapy in a subset of patients with prolactinomas.

Biomedica, 2002 Jun, 22(2), 133 - 40
{Effect of some biocides on non-tuberculous mycobacteria}; Leon CI et al.; The incidence of disease and nosocomial infections produced by non tuberculosis mycobacteria (NTM) has increased in immunocompetent patients, but also and more frequently, in immunosuppressed patients . Several studies have disclosed that mycobacteria are more resistant to biocides than non-sporulating bacteria; in addition, some species are particularly resistant . The biocide action of sodium hypochloride and glutaraldehyde on Mycobacterium aviumintracellulare, Mycobacterium gordonae, Mycobacterium fortuitum and Mycobacterium chelonae was studied, using a modified Kelsey Maurer test . For the different species, both the minimal inhibitory concentration (MIC) and the minimal action time were determined . Effectiveness of sodium hypochloride and glutaraldehyde against the different mycobacterial species varied . The same was true for different isolates of the same species . Sodium hypochloride effective MIC and exposure time (killing of 99.99% of all NTM) were 0.2% and 5 minutes, respectively . In order to achieve 100% killing, 0.5% MIC and 15 minute exposure were needed . In the case of glutaraldehyde, 99.99% of the bacteria were killed with 1% MIC and a 15 minute exposure . An effectiveness of 100% was achieved with a 2% MIC of glutaraldehyde and a 15 minute exposure . Sodium hypochloride and glutaraldehyde are effective biocides for mycobacteria . The first biocide is cheap and effective at low concentrations, but its corrosive and oxidant nature makes it impossible for use in hospitals or with laboratory equipment . Glutaraldehyde (neither corrosive nor oxidant) is a safe alternative for disinfection of this type of equipment . However, it is important to bear in mind that these pathogens may develop resistance to biocides.

Ginekol Pol, 2002 Apr, 73(4), 325 - 30
{An advanced cervical carcinoma coexisting with pregnancy in 19-years old primipara--a case report and review of current literature}; Liro M et al.; In our case report we described an fatal outcome of very young, nineteen years old primipara with advanced, aggressive squamous cervical cancer associated with 20 weeks gestation . Despite of our intentions to abort the pregnancy and started immediate therapy, she decided to delay treatment to allow fetal maturity . After 12 weeks interval, she was readmitted to the hospital with symptoms of intestinal occlusions caused by fast progression of disease . In 33 week of gestation we performed classical caesarean section with Pivercs type III radical hysterectomy . She was delivered of viable female infant weighing 1800 g . Simultaneously, we extended operation of possible cytoreductive surgery . After that, patient received two courses of adjuvant chemotherapy (MIC-scheme) and supplemental external beam radiation . Unfortunately, despite of multidisciplinary, aggressive treatment, she experienced recurrence in pelvic side walls within 6 months of surgery . At last follow-up, she was receiving salvage therapy.

Transplantation, 2002 Jul 27, 74(2), 268 - 77
Identification of the nonclassical HLA molecules, mica, as targets for humoral immunity associated with irreversible rejection of kidney allografts; Sumitran-Holgersson S et al.; BACKGROUND: A substantial portion of kidney allografted patients experience early acute rejection episodes and even irreversible rejections in the early posttransplantation period . The presence of HLA alloantibodies before grafting is associated with early immunological complications, but in many patients rejections and graft loss occur even in the absence of such antibodies . METHODS: In this study, 748 serum samples taken before and at various time points after kidney transplantation from 139 patients were investigated for the presence, frequency, and specificity of kidney microvascular endothelial cell (KMEC)-reactive antibodies using major histocompatability class (MHC) I-related chain A (MICA) transfected cells and flow cytometry, antibody blocking experiments, and Western blotting . The ability of MICA-specific antibodies to fix complement and to induce a prothrombotic phenotype in KMECs was investigated . RESULTS: A polymorphic, 62 kDa nonclassical HLA class I molecule is identified as a new target molecule for reactivity in sera from patients with irreversible rejections . Specific blocking and transfection experiments verified the target molecule as MICA . A significant correlation was established for pre- or posttransplantation MICA humoral immunity and graft loss (P<0.001) . MICA-specific antibody titers increased in the posttransplantation period and were present before any signs of clinical rejection . MICA antibody-containing patient sera induced a prothrombotic phenotype in KMECs . CONCLUSION: The increasing polymorphism detected at the MIC loci combined with the results of this study suggest that typing for the MIC loci and crossmatching for the detection of anti-MIC antibodies before transplantation should be used routinely . A better recipient-donor selection based on a negative crossmatch for both anti-donor HLA and MICA antibodies will decrease early graft rejections and losses.

J Clin Microbiol, 2002 Aug, 40(8), 2876 - 85
Comparison of the Etest and the sensititre colorimetric methods with the NCCLS proposed standard for antifungal susceptibility testing of Aspergillus species; Meletiadis J et al.; The susceptibilities of 25 clinical isolates of Aspergillus fumigatus, A . flavus, A . terreus, A . nidulans, and A . ustus to itraconazole and amphotericin B were determined by an agar diffusion-dilution method (the Etest method) and a colorimetric broth microdilution method (the Sensititre method); and the results were compared with those obtained by the NCCLS proposed standard M-38P method for antifungal susceptibility testing of filamentous fungi . Various MIC endpoints for the three methods were determined visually by four different observers in three blinded experiments, and the reproducibilities among the observers (interobserver agreement) and among the replicates (interexperimental agreement) as well as the levels of agreement between the NCCLS, the Etest, and the Sensititre methods were calculated . High levels of reproducibility (within 1 twofold dilution) were found for the NCCLS method (>95%) with the MIC-0 endpoint (complete inhibition of growth) for both drugs and with the MIC-1 endpoint (slight growth) for itraconazole and for the Sensititre method (>90%) with all MIC endpoints, although for the latter the interexperimental agreement for itraconazole was comparatively lower (83 to 93%) . The Etest method was less reproducible (67 to 87%) for both drugs . Using the recommended MIC endpoints, high levels of agreement (within one twofold dilution) between the NCCLS and the Sensititre methods for all species were found for amphotericin B (>77%) but not for itraconazole (<66%), for which the MICs by the Sensititre method were up to 3 twofold dilutions lower than the corresponding MICs by the NCCLS method . The use of the first blue well as an endpoint for the Sensititre method and 48 h of incubation improved the levels of agreement with the NCCLS method . Low levels of agreement between the NCCLS and the Etest methods using the recommended MIC endpoints were found for most species, especially after 48 h of incubation (<50%), when the MICs obtained by the Etest method were up to 9 twofold dilutions higher than the corresponding MICs obtained by the NCCLS method . Relatively better agreement was found after 24 h, although it was species dependent, with the highest levels of agreement (>82%) found for A . terreus and A . ustus for amphotericin B and A . fumigatus for both drugs . Overall, better agreement was found when MIC-0 was used as the MIC endpoint for the NCCLS method for both drugs and when the MICs by the Etest method were determined after 48 h of incubation for itraconazole and after 24 h of incubation for amphotericin B.

J Clin Microbiol, 2002 Aug, 40(8), 2741 - 5
Conidial viability assay for rapid susceptibility testing of Aspergillus species; Balajee SA et al.; Antifungal susceptibility testing of filamentous fungi has become more important given the recognition of drug-resistant organisms and the availability of therapies other than amphotericin B (AMB) . As current microdilution and E-test methods are limited by a 2 to 3 day incubation time required to obtain results, a more rapid method for susceptibility testing of fungi is needed . We report here a flow cytometric assay that relies on conidial metabolism of the viability dye FUN-1 . Conidia are incubated in media containing increasing concentrations of AMB for 3 h, exposed to FUN-1, and then analyzed by flow cytometry . Relative susceptibility to AMB can be measured both by forward and side scatter characteristics of the conidial population and by mean fluorescence intensity (MFI) of the dye . MIC, calculated as the concentration of AMB to yield 90% reduction in MFI relative to growth controls, was determined for 27 clinical isolates Aspergillus species and correlated well with the standard (i.e., NCCLS) method . The results of these studies illustrate a method by which AMB susceptibility can be rapidly and reproducibly determined by measuring conidial viability.

J Gen Physiol, 2002 Aug, 120(2), 221 - 35
Distinct properties of CRAC and MIC channels in RBL cells; Kozak JA et al.; In rat basophilic leukemia (RBL) cells and Jurkat T cells, Ca(2+) release-activated Ca(2+) (CRAC) channels open in response to passive Ca(2+) store depletion . Inwardly rectifying CRAC channels admit monovalent cations when external divalent ions are removed . Removal of internal Mg(2+) exposes an outwardly rectifying current (Mg(2+)-inhibited cation {MIC}) that also admits monovalent cations when external divalent ions are removed . Here we demonstrate that CRAC and MIC currents are separable by ion selectivity and rectification properties: by kinetics of activation and susceptibility to run-down and by pharmacological sensitivity to external Mg(2+), spermine, and SKF-96365 . Importantly, selective run-down of MIC current allowed CRAC and MIC current to be characterized under identical ionic conditions with low internal Mg(2+) . Removal of internal Mg(2+) induced MIC current despite widely varying Ca(2+) and EGTA levels, suggesting that Ca(2+)-store depletion is not involved in activation of MIC channels . Increasing internal Mg(2+) from submicromolar to millimolar levels decreased MIC currents without affecting rectification but did not alter CRAC current rectification or amplitudes . External Mg(2+) and Cs(+) carried current through MIC but not CRAC channels . SKF-96365 blocked CRAC current reversibly but inhibited MIC current irreversibly . At micromolar concentrations, both spermine and extracellular Mg(2+) blocked monovalent MIC current reversibly but not monovalent CRAC current . The biophysical characteristics of MIC current match well with cloned and expressed TRPM7 channels . Previous results are reevaluated in terms of separate CRAC and MIC channels.

Nippon Ishinkin Gakkai Zasshi, 2002, 43(3), 181 - 7
{Fungicidal activity of liranaftate against Trichophyton rubrum}; Oku Y et al.; The fungicidal activities of thiocarbamate antifungal agent liranaftate were studied by determining the MIC and the MCC against Trichophyton rubrum with the Milliflex -100 Test System and by determining the time-kill curve in comparison to that of six reference agents . Liranaftate and lanoconazole both showed excellent fungistatic activity against the conidia of T . rubrum . For each of these agents, the MIC after 14 days of contact was 0.009 g/ml . The liranaftate-induced decrease in the MCC occurred from 9 days onwards; MCC at 14 days was 0.039 g/ml . The MCC for tolciclate was also reduced from 9 days onwards, but that of amorolfine, lanoconazole, neticonazole, clotrimazole and bifonazole was not lowered up to 14 days . Similar results were obtained when the studies were performed with germinated conidia . The time-kill curves showed that both liranaftate and tolciclate, at concentrations ranging from 2 to 32 times the MICs, achieved a decrease in viable counts to below the detection limit within 7 to 9 days . In experiments with low levels of inoculum, only amorolfine produced a decrease to below the detection level, and that occurred at 14 days; no reduction in viable counts was observed up to 14 days with the four azole agents . Our data suggest that antifungal agents of the thiocarbamate class possess the most potent fungicidal activity against dermatophytes; these are followed in order by morpholine and azole antifungals.

Biotechniques, 2002 Jul, 33(1), 118 - 20, 122, 124 passim
Antibody-based approach to high-volume genotyping for MIC-1 polymorphism; Brown DA et al.; Macrophage inhibitory cytokine-1 (MIC-1) is a divergent member of the TGF-beta superfamily . There are at least two known alleles of MIC-1 that are due to a G-->C point substitution at position 6 of the mature protein, which alters a histidine to an aspartic acid (MIC-1 H and MIC-1 D) . We have determined the phenotype of MIC-1 circulating in serum by exploiting the differences in the affinity of the two monoclonal antibodies to the H and D alleles of MIC-1 . A PCR-RFLP-based method for genotyping MIC-1 is also described . We validate these two assays using DNA sequencing of 19 subjects as the standard . We then used the validated assay to determine the frequency of the two MIC-1 alleles in a population of 261 adult blood donors . Inter-assay and sequencing concordance was 100% . The frequency of the three common MIC-1 genotypes was homozygous (HH), 54%; heterozygous (HD), 39%; and homozygous (DD), 7% . This novel antibody-based assay confidently determines the genotype of MIC-1 . It offers the advantages of an ELISA-ease of automation, high-volume throughput of samples, and ease of use in a routine, clinical laboratory.

J Antibiot (Tokyo), 2002 May, 55(5), 499 - 507
Synthesis and anti-Helicobacter pylori activity of pyloricidin derivatives II . The combination of amino acid residues in the dipeptidic moiety and its effect on the anti-Helicobacter pylori activity; Hasuoka A et al.; The novel natural antibiotics pyloricidin A, B and C, consisting of a common (2S,3R,4R,5S)-5-amino-2,3,4,6-tetrahydroxyhexanoyl-beta-D-phenylalanine moiety and a terminal peptidic moiety (pyloricidin A: L-valine-L-valine-L-leucine; pyloricidin B: L-valine-L-leucine; pyloricidin C: L-leucine), exhibit potent and highly selective anti-Helicobacter pylori activity . In order to develop more potent compounds and to investigate structure activity relationships for the peptidic moiety with regard to the combination of amino acids, a series of derivatives with various dipeptidic moieties were prepared and evaluated for their anti-H . pylori activity . The combination of the two amino acids in the moiety was found to have a significant effect on the activity; the compound with Nva-Abu showed excellent anti-H . pylori activity with an MIC value of 0.013 microg/ml against H . pylori TN2 . In addition, this compound was found to show 60% clearance of H . pylori from infected Mongolian gerbils upon repetitive oral administration (10 mg/kg, b . i . d . for 7 days).

Acta Biochim Pol, 2002, 49(1), 77 - 86
Facilitated diffusion of glucosamine-6-phosphate synthase inhibitors enhances their antifungal activity; Janiak A et al.; N3-(4-Methoxyfumaroyl)-L-2,3-diaminopropanoic acid (FMDP) and 2-amino-2-deoxy-D-glucitol-6-phosphate (ADGP) are strong inhibitors of the essential fungal enzyme, glucosamine-6-phosphate synthase, but their antifungal activity is poor, due to slow penetration of these agents through the cytoplasmic membrane . In the present studies we have exploited the possibility of enhancement of ADGP and FMDP antifungal activity by improving their transport properties . It has been found that membrane-permeabilising polyene macrolides amphotericin B (AMB) and its N-methyl-N-fructosyl methyl ester derivative (MF-AME), at subinhibitory concentrations, facilitate diffusion of ADGP through the fungal cell membrane, thus allowing a decrease of its minimal inhibitory concentration (MIC) . Synergistic effects have been observed for combinations of ADGP with AMB or MF-AME . Fractional inhibitory concentration (FIC) indexes, determined against a number of Candida spp., have been in the 0.18-0.81 range . Weak antifungal synergistic effects have been found for combinations of FMDP with AMB or MF-AME . ADGP can be easily encapsulated into unilamellar lipid vesicles . Liposomal preparations of ADGP demonstrated stronger antifungal activity against some fungal strains than free ADGP.

J Immunol, 2002 Aug 1, 169(3), 1395 - 400
Structural studies of allelic diversity of the MHC class I homolog MIC-B, a stress-inducible ligand for the activating immunoreceptor NKG2D; Holmes MA et al.; MIC-A and MIC-B are distant MHC class I homologs that serve as stress-inducible Ags on epithelial and epithelially derived cells . They are ligands for the widely expressed activating immunoreceptor NKG2D . To define the structural and functional consequences of sequence differences between MIC-A and MIC-B and between alleles of MIC-A and alleles of MIC-B, we determined the crystal structure of one allele of human MIC-B . Comparisons between the two previously reported MIC-A crystal structures and the MIC-B crystal structure show that, as expected, MIC-B is very similar in structure to MIC-A and likely interacts with NKG2D in an analogous manner . The interdomain flexibility observed in the MIC-A structures, a feature unique to MIC proteins among MHC class I proteins and homologs, is also displayed by MIC-B, with an interdomain relationship intermediate between the two examples of MIC-A structures . Mapping sequence variations onto the structures of MIC-A and MIC-B reveals patterns completely distinct from those displayed by classical MHC class I proteins, with a number of substitutions falling on positions likely to affect interactions with NKG2D, but with other positions lying distant from the NKG2D binding sites or buried within the core of the proteins.

J Immunol, 2002 Aug 1, 169(3), 1236 - 40
T cell antigen receptor engagement and specificity in the recognition of stress-inducible MHC class I-related chains by human epithelial gamma delta T cells; Wu J et al.; Human gamma delta T cells with the TCR variable region V(delta)1 occur mainly in epithelia and respond to stress-induced expression of the MHC class I-related chains A and B, which have no function in Ag presentation . MIC function as ligands for NKG2D-DAP10, an activating receptor complex that triggers NK cells, costimulates CD8 alpha beta and V(gamma)9V(delta)2 gamma delta T cells, and is required for stimulation of V(delta)1 gamma delta T cells . It is unresolved, however, whether triggering of V(delta)1 gamma delta TCRs is also mediated by MIC or by unidentified cell surface components . Soluble MICA tetramers were used as a binding reagent to demonstrate specific interactions with various V(delta)1 gamma delta TCRs expressed on transfectants of a T cell line selected for lack of NKG2D . Tetramer binding was restricted to TCRs derived from responder T cell clones classified as reactive against a broad range of MIC-expressing target cells and was abrogated when TCRs were composed of mismatched gamma- and delta-chains . These results and the inability of V(delta)1 gamma delta T cells to respond to target cells expressing the ULBP/N2DL ligands of NKG2D, which are highly divergent from MIC, indicate that MIC delivers both the TCR-dependent signal 1 and the NKG2D-dependent costimulatory signal 2 . This dual function may serve to prevent erroneous gamma delta T cell activation by cross-reactive cell surface determinants.

Am J Med, 2002 Aug 1, 113(2), 120 - 6
The effect of cephalosporin resistance on mortality in adult patients with nonmeningeal systemic pneumococcal infections; Pallares R et al.; PURPOSE:To evaluate the clinical relevance of cephalosporin (ceftriaxone/cefotaxime) resistance among patients with nonmeningeal systemic pneumococcal infection . SUBJECTS AND METHODS: From January 1994 to October 2000, we prospectively studied 522 episodes of nonmeningeal systemic pneumococcal infections (448 pneumonias) in 499 adults who were treated according to hospital guidelines . In vitro antibiotic susceptibility, as the minimum inhibitory concentration (MIC), was determined by microdilution method . The MIC methods and breakpoints (cutoffs) were established by the National Committee for Clinical Laboratory Standards . RESULTS: Of the 522 pneumococcal strains, 413 strains (79%) were susceptible to ceftriaxone/cefotaxime, MIC < or =0.5 microg/mL; 79 (15%) were intermediate, MIC = 1 microg/mL; and 30 (6%) were resistant, MIC = 2 microg/mL . After adjusting for several variables, including pneumococcal serogroups/serotypes, infections due to nonsusceptible (intermediate and resistant) pneumococcal strains were independently associated with prior antibiotic therapy, with an odds ratio of 5.9 (95% confidence interval: 2.6 to 13.6) . Thirty-day mortality among the 185 patients who were treated with ceftriaxone (1 g/d) or cefotaxime (1.5 g every 8 hours) did not differ by cephalosporin susceptibility: 18% (26/148) among those with susceptible organisms, 13% (3/24) with intermediate organisms, and 15% (2/13) in resistant cases (P = 0.81) . CONCLUSION: Ceftriaxone or cefotaxime were effective in treating patients with nonmeningeal systemic pneumococcal infections caused by strains with MIC < or =2 microg/mL . These results support the newly established ceftriaxone/cefotaxime MIC breakpoints (cutoffs) for nonmeningeal pneumococcal infections.

Lancet Infect Dis, 2002 Jul, 2(7), 404 - 15
Treatment of drug-resistant pneumococcal pneumonia; Garau J; The increasing prevalence of resistance to penicillin and other drugs among pneumococci has considerably complicated the empirical treatment of community-acquired pneumonia . Penicillin resistance has become widespread and is a worldwide occurrence . Resistance to other classes of antibiotics traditionally used as alternatives in the treatment of pneumococcal infections has also increased markedly during recent years . In some areas of the USA, Europe, and east Asia a prevalence of macrolide resistance as high as 35% or more has been reported recently . From the clinical standpoint, a growing number of failures following the use of these agents has been described . Resistance to fluoroquinolones remains low but several failures have been reported in different parts of the world . Pharmacokinetic/pharmacodynamic parameters have become essential at the time of making a rational choice and calculation of dosage . Penicillin G remains the mainstay of therapy for the treatment of penicillin-susceptible pneumococcal pneumonia . Penicillin-resistant pneumococcal pneumonia (minimum inhibitory concentration <4 microg/mL) can be safely treated with adequate betalactams at the right dosage . The new fluoroquinolones are very active and effective in pneumococcal pneumonia . Caution should be exercised in the widespread prescription of these drugs if we are to limit the rate of resistance to these agents.

Int J Pediatr Otorhinolaryngol, 2002 Aug 1, 65(1), 1 - 6
OK-432 therapy for lymphatic malformation in 32 patients (28 children); Claesson G et al.; BACKGROUND/PURPOSE: Operating lymphatic malformation (LM) may lead to nerve damage with permanent cosmetic disturbance . Even sclerosants as ethanol and Sotradecol may sometimes harm more than cure . The purpose with this study was to evaluate the effect of a relatively new drug for intralesional injections, OK-432 . METHODS: The diagnosis of LM was made clinically by means of ultrasound and MRT and/or CT . Thirty-two patients (28 children) with LM were consecutively enrolled in the study . Twenty-nine (27 children) had not been treated previously: 17 (15 children) had macrocysts (MAC), four microcysts (MIC) and eight had combined cysts (CC) . Three patients (one child) had got previous treatment without any curative effect . All patients got intralesional injections with OK-432 at intervals according to a previously published protocol (Lakartidningen, 95 (1998) 2074) . RESULTS: No serious adverse effects were seen . The results obtained were excellent in all with macrocysts but in one, who was pretreated with ethanol, where no LM-regression was seen . None of four with MIC-LM required further therapy; for two of them the results were excellent . Of 10 with CC, seven showed excellent results . Only one required surgery . CONCLUSION: OK-432 is effective and is proposed to be the first choice of treatment for LM.

Zhonghua Jie He He Hu Xi Za Zhi, 2002 Jun, 25(6), 333 - 6
{Pharmacodynamics and pharmacokinetics of domestic fixed-dose combination of antituberculosis drugs}; Zhao W et al.; OBJECTIVE To study the pharmacodynamics and pharmacokinetics of domestic fixed-dose of antituberculosis drugs and to evaluate its quality and activity against Mycobacterium tuberculosis both in vitro and in vivo . METHODS The MIC was determined by the tube doubling dilution method, and the effect of the drugs was assessed by half survival time of the mice . A single oral dose of domestic and imported fixed-dose combination of antituberculosis drugs was given to healthy volunteers, and the drug concentration in serum was determined by HPLC . The pharmacokinetic parameters and the relative bioavailability were calculated . RESULTS The MIC of each composition in the compound (INH, RFP, PZA) against Mycobacterium tuberculosis was lower than that of each composition used by single-dose . In a murine tuberculosis model, the antituberculosis activity of this compound drug was superior to that of each agent used alone with the same dose . No significant difference was found as compared to the imported drug, Refater; The major pharmacokinetic parameters of the domestic and the imported drugs, t (1/2), C (max), AUC, and t(max), were not significantly different . Statistical analysis showed the two formulations were bioequivalent . CONCLUSION The three compositions in the combination had synergistic effect, and the domestic and the imported drugs were bioequivalent.

Intensive Care Med, 2002 Jul, 28(7), 936 - 42 Epub 2002 May 30.
Experience with a once-daily dosing program of aminoglycosides in critically ill patients; Buijk SE et al.; BACKGROUND: As aminoglycosides show concentration-dependent killing, once-daily aminoglycoside (ODA) regimens have been instituted . Data on experience with ODA regimens in critically ill patients are limited . OBJECTIVES: 1) To evaluate the ODA-program in critically ill patients; 2) to describe the pharmacokinetics of aminoglycosides (gentamicin and tobramycin); and 3) to assess the incidence of nephrotoxicity associated with an ODA regimen in this specific of group patients . DESIGN: A prospective, descriptive study . SETTING: Eighteen-bed surgical and 12-bed medical intensive care unit in a referral centre . PATIENTS: Eighty-nine critically ill patients with a suspected or confirmed infection for which gentamicin or tobramycin was indicated and a creatinine clearance > 30 ml/min were monitored . One hundred and nine pharmacokinetic profiles were gathered . INTERVENTIONS: A first dose of 7 mg/kg/24 h of gentamicin or tobramycin was given to every patient independent of renal function . Subsequent doses were chosen on the basis of the pharmacokinetic results of the first dose . MEASUREMENTS: Serum samples were collected 1 h and 6 h after start of the aminoglycoside infusion . All samples were assayed by using immunofluorescence . Pharmacokinetic parameters were estimated using a one-compartment model . RESULTS: The volume of distribution of aminoglycosides was significantly higher in critical ill patients with septic shock than in those without . Consequently, the maximum concentration reached was significantly lower in patients with septic shock . In P . aeruginosa infections the mean (SD) estimated Cmax/MIC ratio was 10.3 (3.3) . In n = 17 (49%) of the patients treated > 24 h ( n = 35), a dose adjustment or lengthening of interval was necessary . The recommended dosing interval based on the Hartford Hospital nomogram and one-serum concentration at 6 h was correct in only 62% of all cases . Signs of renal impairment occurred in n = 12 (14%) of the patients; in all survivors renal function recovered completely and no haemofiltration was needed . CONCLUSIONS: An ODA-regimen of 7 mg/kg produced Cmax/MIC ratios > 10 in the majority of critically ill patients in our population . Septic shock and renal dysfunction caused an aberrant pharmacokinetic profile of aminoglycosides in these patients . Therefore, individual therapeutic drug monitoring is warranted . Signs of renal impairment were common in the presence of shock, but appeared to be reversible.

Antimicrob Agents Chemother, 2002 Aug, 46(8), 2554 - 63
Safety, pharmacokinetics, and pharmacodynamics of cyclodextrin itraconazole in pediatric patients with oropharyngeal candidiasis; Groll AH et al.; The safety, pharmacokinetics, and pharmacodynamics of cyclodextrin itraconazole (CD-ITRA) oral suspension were investigated in an open sequential dose escalation study with 26 human immunodeficiency virus (HIV)-infected children and adolescents (5 to 18 years old; mean CD4(+)-cell count, 128/microl) with oropharyngeal candidiasis (OPC) . Patients received CD-ITRA at either 2.5 mg/kg of body weight once a day (QD) or 2.5 mg/kg twice a day (BID) for a total of 15 days . Pharmacokinetic sampling was performed after the first dose and for up to 120 h after the last dose, and antifungal efficacy was evaluated by standardized scoring of the oropharynx . Apart from mild to moderate gastrointestinal disturbances in three patients (11.5%), CD-ITRA was well tolerated . Two patients (7.6%) discontinued treatment prematurely due to study drug-related adverse events . After 15 days of treatment, the peak concentration of drug in plasma (C(max)), the area under the plasma concentration-time curve (AUC) from 0 to 24 h (AUC(0-24)), the concentration in plasma at the end of the dosing interval (predose) (C(min)), and the terminal half-life of itraconazole (ITRA) were (means and standard deviations) 0.604 +/- 0.53 microg/ml, 6.80 +/- 7.4 microg . h/ml, 0.192 +/- 0.06 microg/ml, and 56.48 +/- 44 h, respectively, for the QD regimen and 1.340 +/- 0.75 microg/ml, 23.04 +/- 14.5 microg . h/ml, 0.782 +/- 0.19 microg/ml, and 104.22 +/- 94 h, respectively, for the BID regimen . The mean AUC-based accumulation factors for ITRA on day 15 were 4.14 +/- 0.9 and 3.53 +/- 0.6, respectively . A comparison of the dose-normalized median AUC of the two dosage regimens revealed a trend toward nonlinear drug disposition (P = 0.05) . The mean metabolic ratios (AUC of hydroxyitraconazole/AUC of ITRA) at day 15 were 1.96 +/- 0.1 for the QD regimen and 1.29 +/- 0.2 for the BID regimen, respectively (P < 0.05) . The OPC score (range, 0 to 13) for all 26 patients decreased from a mean of 7.46 +/- 0.8 at baseline to 2.8 +/- 0.7 at the end of therapy (P < 0.001), demonstrating antifungal efficacy in this setting . The relationships among C(max), C(min), AUC(0-12), C(max)/MIC, C(min)/MIC, AUC(0-12)/MIC, time during the dosing interval when the plasma drug concentrations were above the MIC for the infecting isolate, and the residual OPC score at day 15 for the entire study population fit inhibitory effect pharmacodynamic models (r, 0.595 to 0.421; P, <0.01 to <0.05) . All patients with fluconazole-resistant isolates responded to treatment with CD-ITRA; however, there was no clear correlation between the MIC of ITRA and response to therapy . In conclusion, CD-ITRA was well tolerated and efficacious for the treatment of OPC in HIV-infected pediatric patients . Pharmacodynamic modeling revealed significant correlations between plasma drug concentrations and antifungal efficacy . Based on this documented safety and efficacy, a dosage of 2.5 mg/kg BID can be recommended for the treatment of OPC in pediatric patients > or =5 years old.

Antimicrob Agents Chemother, 2002 Aug, 46(8), 2477 - 81
Comparison of visual and spectrophotometric methods of broth microdilution MIC end point determination and evaluation of a sterol quantitation method for in vitro susceptibility testing of fluconazole and itraconazole against trailing and nontrailing Candida isolates; Arthington-Skaggs BA et al.; Visual determination of MIC end points for azole antifungal agents can be complicated by the trailing growth phenomenon . To determine the incidence of trailing growth, we performed testing of in vitro susceptibility to fluconazole and itraconazole using the National Committee for Clinical Laboratory Standards broth microdilution M27-A reference procedure and 944 bloodstream isolates of seven Candida spp., obtained through active population-based surveillance between 1998 and 2000 . Of 429 C . albicans isolates, 78 (18.2%) showed trailing growth at 48 h in tests with fluconazole, and 70 (16.3%) showed trailing in tests with itraconazole . Of 118 C . tropicalis isolates, 70 (59.3%) showed trailing growth in tests with fluconazole, and 35 (29.7%) showed trailing in tests with itraconazole . Trailing growth was not observed with any of the other five Candida spp . tested (C . dubliniensis, C . glabrata, C . krusei, C . lusitaniae, and C . parapsilosis) . To confirm whether or not isolates that showed trailing growth in fluconazole and/or itraconazole were resistant in vitro to these agents, all isolates that showed trailing growth were retested by the sterol quantitation method, which measures cellular ergosterol content rather than growth inhibition after exposure to azoles . By this method, none of the trailing isolates was resistant in vitro to fluconazole or itraconazole . For both agents, a 24-h visual end point or a spectrophotometric end point of 50% reduction in growth relative to the growth control after 24 or 48 h of incubation correlated most closely with the result of sterol quantitation . Our results indicate that MIC results determined by either of these end point rules may be more predictive of in vivo outcome for isolates that give unclear visual end points at 48 h due to trailing growth.

J Chemother, 2002 Jun, 14(3), 246 - 52
Effect of medium composition on static and cidal activity of amphotericin B, itraconazole, voriconazole, posaconazole and terbinafine against Aspergillus fumigatus: a multicenter study; Tortorano AM et al.; The effect of the medium composition on the fungistatic (MIC) and fungicidal (MLC) activity of amphotericin B, itraconazole, voriconazole, posaconazole and terbinafine against four Aspergillus fumigatus strains has been investigated by four European laboratories . MICs were determined by broth microdilution, using RPMI 1640 and Antibiotic Medium 3 (AM3), three times in three independent determinations by the four laboratories . MLCs were determined for the three independent determinations by the four laboratories, subculturing 100 microl from each well showing no visible growth after 48 hours . Except for a 2-dilution difference observed in three cases, no differences were observed between MICs determined on the two media . In contrast, a 3- to 6-dilution discrepancy between the MLCs was observed for the azoles . Endpoints on RPMI were higher than those on AM3 . A 1-2 dilution difference was noted between both the endpoints of amphotericin B and of terbinafine . The highest inter- and intra-laboratory agreements were reached on AM3 . The azoles showed a medium-dependent fungicidal activity.

Am J Vet Res, 2002 Jul, 63(7), 1012 - 7
Pharmacokinetics after intravenous and oral administration of enrofloxacin in sheep; Bermingham EC et al.; OBJECTIVE: To compare pharmacokinetics of enrofloxacin administered IV and in various oral preparations to ewes . ANIMALS: 5 mature Katahdin ewes weighing 42 to 50 kg . PROCEDURE: Ewes received 4 single-dose treatments of enrofloxacin in a nonrandomized crossover design followed by a multiple-dose oral regimen . Single-dose treatments consisted of an IV bolus of enrofloxacin (5 mg/kg), an oral drench (10 mg/kg) made from crushed enrofloxacin tablets, oral administration in feed (10 mg/kg; mixture of crushed enrofloxacin tablets and grain), and another type of oral administration in feed (10 mg/kg; mixture of enrofloxacin solution and grain) . The multiple-dose regimen consisted of feeding a mixture of enrofloxacin solution and grain (10 mg/kg, q 24 h, for 7 days) . Plasma concentrations of enrofloxacin and ciprofloxacin were measured by use of high-performance liquid chromatography . RESULTS: Harmonic mean half-life for oral administration was 14.80, 10.80, and 13.07 hours, respectively, for the oral drench, crushed tablets in grain, and enrofloxacin solution in grain . Oral bioavailability for the oral drench, crushed tablets in grain, and enrofloxacin in grain was 4789, 98.07, and 94.60%, respectively, and median maximum concentration (Cmax) was 1.61, 2.69, and 2.26 microg/ml, respectively . Median Cmax of the multiple-dose regimen was 2.99 microg/ml . CONCLUSIONS AND CLINICAL RELEVANCE: Enrofloxacin administered orally to sheep has a prolonged half-life and high oral bioavailability . Oral administration at 10 mg/kg, q 24 h, was sufficient to achieve a plasma concentration of 8 to 10 times the minimum inhibitory concentration (MIC) of any microorganism with an MIC < or = 0.29 microg/ml.

J Antimicrob Chemother, 2002 Jul, 50(1), 119 - 23
In vitro activity of three new triazoles and one echinocandin against Candida bloodstream isolates from cancer patients; Laverdiere M et al.; The in vitro activities of voriconazole, posaconazole, ravuconazole and micafungin were compared with those of fluconazole, itraconazole, ketoconazole, flucytosine and amphotericin B against 164 candidaemia isolates recovered from cancer patients in two Canadian centres . The MIC(50) results for ravuconazole, voriconazole, posaconazole and micafungin were 0.01, 0.03, 0.12 and 0.25 mg/L, respectively . The new antifungal agents showed substantial activity against isolates demonstrating in vitro resistance to fluconazole and itraconazole . These results suggest that the newer antifungal agents possess promising activity against invasive Candida isolates, particularly against those with reduced susceptibility to fluconazole and itraconazole.

J Antimicrob Chemother, 2002 Jul, 50(1), 115 - 7
Susceptibility testing of Aspergillus spp . by means of an automated blood culture system; Rath PM et al.; The BacT/Alert blood culture system was evaluated for the MIC determination of amphotericin B for 27 strains of Aspergillus from five different species . An inoculum of c . 10(8) cfu/mL and an incubation time of 48 h resulted in MICs for 26 of 27 strains that corresponded with published MICs obtained in a microdilution assay . Twelve of 13 strains with MIC(48) values >/=2 mg/L showed growth within 24 h in bottles containing 0.25 mg/L amphotericin B, indicating that results can be obtained the day following inoculation . It is concluded that the BacT/Alert blood culture system can be used for susceptibility testing of Aspergillus spp . with amphotericin B.

J Antimicrob Chemother, 2002 Jul, 50(1), 95 - 100
Antipneumococcal activity of AZD2563, a new oxazolidinone, compared with nine other agents; Peric M et al.; The in vitro activity of AZD2563, a new oxazolidinone, was compared with that of linezolid, vancomycin, quinupristin/dalfopristin, amoxicillin, levofloxacin, penicillin, erythromycin, azithromycin and clindamycin against a range of pneumococci by microdilution and time-kill studies . Against 300 pneumococci (99 penicillin susceptible, 86 penicillin intermediate, 115 penicillin resistant, 185 erythromycin resistant, 35 quinolone resistant), both oxazolidinones remained active against isolates less susceptible to other agents, with MICs ranging between 0.125 and 2 mg/L; AZD2563 MICs were generally one dilution lower than those of linezolid . Both quinupristin/dalfopristin and vancomycin were active against all groups (MIC ranges 0.125-2 and 0.125-0.25 mg/L, respectively) . Apart from 35 isolates with levofloxacin MICs > or= 8 mg/L, levofloxacin MICs were < or =0.25-4 mg/L . MICs of amoxicillin and erythromycin rose with penicillin G MICs; most macrolide-resistant isolates were either penicillin-intermediate or -resistant . Against 16 organisms with differing beta-lactam, macrolide and quinolone MICs, time-kill studies showed that AZD2563 was bactericidal (99.9% killing) at 4 x MIC against nine strains at 24 h, with 90% killing of all 16 strains at 2 x MIC after 12 h . Similar results were obtained with linezolid . Both oxazolidinones were bacteriostatic at the MIC against all 16 strains . Amoxicillin, levofloxacin and vancomycin, at 2 x MIC, were bactericidal against 15 of the 16 strains after 24 h . Quinupristin/dalfopristin yielded the most rapid killing, with bactericidal activity against 13 of 16 strains at the MIC after 3 h and against 15 strains at 2 x MIC after 24 h . Erythromycin was bactericidal against all 10 strains with MICs < or= 8 mg/L at 4 x MIC after 24 h.

J Antimicrob Chemother, 2002 Jul, 50(1), 73 - 7
Penetration of linezolid into bone, fat, muscle and haematoma of patients undergoing routine hip replacement; Lovering AM et al.; Twelve patients undergoing total hip replacement were given 600 mg of linezolid as a 20 min iv infusion along with conventional prophylaxis of 1 g of cefamandole immediately before surgery . Routine total hip arthroplasty was carried out, and at timed intervals during surgery samples of bone, fat, muscle and blood were collected for assay by high-performance liquid chromatography analysis . Samples of the haematoma fluid that formed around the operation site and further blood samples for assay were also collected at timed intervals following the operation . The penetration of linezolid into bone was rapid, with mean concentrations of 9.1 mg/L (95% CI 7.7-10.6 mg/L) achieved at 10 min after the infusion, decreasing to 6.3 mg/L (95% CI 3.9-8.6 mg/L) at 30 min . Correction for the simultaneous blood concentrations gave mean values for bone penetration of 51% at 10 min, 60% at 20 min and 47% at 30 min . Although the penetration of linezolid into fat was also rapid, mean concentrations and degree of penetration were c . 60% of those in bone; at 10 min they were 4.5 mg/L (95% CI 3.0-6.1 mg/L; penetration 27%); at 20 min they were 5.2 mg/L (95% CI 4.0-6.4 mg/L; penetration 37%); and at 30 min, 4.1 mg/L (95% CI 3.3-4.8 mg/L; penetration 31%) . For muscle the corresponding values were 10.4 mg/L (95% CI 8.1-12.7 mg/L; penetration 58%) at 10 min, 13.4 mg/L (95% CI 10.2-16.5 mg/L; penetration 94%) at 20 min and 12.0 mg/L (95% CI 9.2-14.8 mg/L; penetration 93%) at 30 min . Mean concentrations of linezolid in the haematoma fluid drained from around the operation site were 8.2 mg/L at 6-8 h and 5.6 mg/L at 10-12 h after the infusion, and 7.0 mg/L at 2-4 h following a second 600 mg infusion given 12 h post-operatively . We conclude that linezolid exhibits rapid penetration into bone, fat and muscle of patients undergoing hip arthroplasty, to achieve levels in excess of its MIC for susceptible organisms (< or=4 mg/L); therapeutic concentrations were maintained in the haematoma fluid that surrounds the operation site for >16 h.

Endocrinol Metab Clin North Am, 2002 Jun, 31(2), 353 - 68, vi-vii
The genetics of autoimmune polyendocrine syndrome type II; Robles DT et al.; A series of autoimmune disorders, often Addison's disease, type 1 diabetes mellitus, and thyroid autoimmunity, frequently occurs together in patients with the autoimmune polyendocrine syndrome type II (APS-II) . The highest risk HLA genotype for Addison's disease, either as a single disease or in APS-II patients, consists of the genotype DR3/4, DQ2/DQ8 with DRB1*0404 . As many as 30% of patients with Addison's disease have this genotype versus less than 0.5% of controls . An additional and important associated locus within the HLA region is the class I related gene, MIC-A . Patients who develop Addison's disease often have a delayed diagnosis and may die from Addisonian crisis; therefore, improved genetic testing combined with testing for 21-hydroxylase autoantibodies might allow the identification of relatively high-risk populations (greater than 1 in 200 defined genetic risk compared with 1 in 10,000 population risk).

Lancet, 2002 Jun 22, 359(9324), 2159 - 63
Concentration in plasma of macrophage inhibitory cytokine-1 and risk of cardiovascular events in women: a nested case-control study; Brown DA et al.; BACKGROUND: Macrophage inhibitory cytokine-1 (MIC-1) is part of the TGF-beta superfamily . Raised concentrations of MIC-1 in serum arise in several disease states, can be detected in normal individuals, and can partly be genetically determined . We aimed to investigate whether MIC-1 has a role in atherothrombosis . METHODS: We did a prospective, nested, case-control study in 27628 initially healthy women . Of these women, we established baseline concentrations of MIC-1 in 257 who subsequently had myocardial infarction, stroke, or died from a cardiovascular event (cases) and in 257 matched for age and smoking status, who did not report cardiovascular disease during 4-year follow-up (controls) . We also assessed polymorphisms in the MIC-1 gene (MIC-1 H and MIC-1 D) in all 514 women . FINDINGS: MIC-1 concentrations were higher at baseline in women who subsequently had cardiovascular events than in those who did not (618 vs 538 pg/mL, p=0.0002) . Concentrations above the 90th percentile (>856 pg/mL) were associated with a 2.7-fold increase in risk (95% CI 1.6-4.9, p=0.001) . This effect was independent of traditional cardiovascular risk factors and at least additive to that of C-reactive protein . There was no significant association between MIC-1 polymorphism and vascular events . INTERPRETATION: MIC-1 could be a novel target for cardiovascular disease prevention.

Rev Med Chil, 2002 Apr, 130(4), 416 - 23
{Identification and antifungal susceptibility of Candida spp isolated from invasive mycoses . Influence of growth inhibition percentage to determine minimal inhibitory concentration}; Alvarado D et al.; BACKGROUND: An increase in the frequency of resistant strains to antifungal drugs has been detected in the last decade . AIM: To report the minimal inhibitory concentration (MIC) to amphotericin B, fluconazole, ketoconazole and itraconazole . To compare the MIC obtained with 80% and 50% of growth inhibition to the azoles . MATERIAL AND METHODS: Fifty yeast strains isolated between 1998 and 1999, from 17 adults and 33 children with invasive mycosis were studied . Susceptibility was determined by broth microdilution method with RPMI 1640 plus glucose 2% according to the National Committee for Clinical Laboratory Standards (1997) . RESULTS: The most frequently isolated strains were C albicans in 27 cases and C parapsilosis in 12 . All isolates were susceptible to amphotericin B . According to the MICs obtained with 80% of inhibition, 12 strains had MICs considered as resistant to azoles . Five strains were resistant both to fluconazole and itraconazole . Considering MICs obtained with 50% of inhibition, only five strains were found resistant to azoles (p < 0.05) . Using this criterion, only one C glabrata strain was found to be simultaneously resistant to fluconazole and itraconazole . CONCLUSIONS: Similar results in the pattern of susceptibility of Candida spp to azoles, to those reported abroad, are obtained when the MIC is calculated using 50% inhibition.

Diagn Microbiol Infect Dis, 2002 Jun, 43(2), 107 - 11
Comparison of NCCLS microdilution method and Etest in antifungal susceptibility testing of clinical Trichosporon asahii isolates; Arikan S et al.; We investigated the in vitro activity of amphotericin B, fluconazole, and itraconazole against clinical Trichosporon asahii isolates (n = 43) by NCCLS M27A reference microdilution method and explored the correlation between Etest and NCCLS reference method . Microdilution MIC ranges following 48 h of incubation were 1-8, 0.25-16, and 0.06-4 microg/ml for amphotericin B, fluconazole, and itraconazole, respectively . The corresponding Etest MIC ranges were determined as 0.125- > 8, 0.25- > 64, and 0.03-8 microg/ml . Of interest, Etest tended to produce lower amphotericin B MICs and widen the MIC range compared to microdilution . The influence of Etest on fluconazole and itraconazole MICs was in contrary with that observed for amphotericin B . Etest MICs of fluconazole and itraconazole tended to be higher than microdilution MICs . The wider range of amphotericin B MICs obtained by using Etest methodology may facilitate discrimination of isolates with reduced susceptibility to amphotericin B . However, clinical significance of these findings remain yet unknown and determination of MIC breakpoint values is required.

Oncogene, 2002 Jun 20, 21(27), 4212 - 9
Anoxia induces macrophage inhibitory cytokine-1 (MIC-1) in glioblastoma cells independently of p53 and HIF-1; Albertoni M et al.; Human astrocytic brain tumors select for mutations in the p53 tumor suppressor gene early in malignant progression . p53 is activated upon various kinds of cellular stress leading to apoptosis or cell cycle arrest, but is also implicated in complex biological processes such as inhibition of angiogenesis and metastasis . In an effort to shed light on consequences mediated by p53 inactivation in gliomas, we established the Tet-On system for p53 in the LN-Z308 glioblastoma cell line . The macrophage inhibitory cytokine-1 (MIC-1) gene was identified as a most prominent p53 target gene upon gene expression profiling . Oxygen deprivation, an important cellular stress, revealed MIC-1 as an anoxia responsive gene in glioblastoma cell lines . MIC-1 up-regulation by anoxia is mediated through an alternative, p53 and hypoxia inducible factor 1 (HIF-1) independent pathway . Furthermore, ectopic expression of MIC-1 in LN-Z308 cell line completely abolished its inherent tumorigenicity in nude mice, while proliferation in vitro was not affected . In the present experimental model MIC-1 may exert its anti-tumorigenic properties via a paracrine mechanism mediated by host cells in vivo . Taken together, these data suggest that MIC-1 is an important downstream mediator of p53 function, while acting itself as an intercessor of cellular stress signaling and exerting anti-tumorigenic activities.

Carcinogenesis, 2002 Jun, 23(6), 967 - 75
Expression profile of differentially-regulated genes during progression of androgen-independent growth in human prostate cancer cells; Karan D et al.; Because of the heterogeneous nature of prostate cancer, identifying the molecular mechanisms involved during the transition from an androgen-sensitive to an androgen-independent phenotype is very complex . An LNCaP cell model that recapitulates prostate cancer progression, comprising early passage androgen-sensitive (LNCaP-C33) and late passage androgen-independent (LNCaP-C81) phenotypes, would help to provide a better understanding of such molecular events . In this study, we examined the genes expressed by LNCaP-C33 and LNCaP-C81 cells using cDNA microarrays containing 1176 known genes . This analysis demonstrated that 34 genes are up-regulated and eight genes are down-regulated in androgen-independent cells . Northern blot analysis confirmed the differences identified by microarrays on several candidate genes, including c-MYC, c-MYC purine-binding transcription factor (PuF), macrophage migration inhibitory factor (MIF), macrophage inhibitory cytokine-1 (MIC-1), lactate dehydrogenase-A (LDH-A), guanine nucleotide-binding protein Gi, alpha-1 subunit (NBP), cyclin dependent kinase-2 (CDK-2), prostate-specific membrane antigen (PSM), cyclin H (CCNH), 60S ribosomal protein L10 (RPL10), 60S ribosomal protein L32 (RPL32), and 40S ribosomal protein S16 (RPS16) . These differentially-regulated genes are correlated with progression of human prostate cancer and may be of therapeutic relevance as well as an aid in understanding the molecular genetic events involved in the development of this disease's hormone-refractory behavior.

APMIS, 2002 Apr, 110(4), 290 - 8
Conditions influencing the in vitro antifungal activity of lactoferrin combined with antimycotics against clinical isolates of Candida . Impact on the development of buccal preparations of lactoferrin; Kuipers ME et al.; Lactoferrin, an iron-binding glycoprotein, is a potential agent for the treatment of oropharyngeal Candidiasis . The aim of the present study was to test the capability of lactoferrin, combined or not combined with conventional antifungal agents, to inhibit the growth of different Candida species under various experimental conditions to be of guidance in the development of a suitable pharmaceutical formulation containing lactoferrin . The anti-Candida activities of lactoferrin were considerably higher using RPMI instead of SLM as assay medium . They were moreover increased by raising the medium pH from 5.6 to 7.5 . With the 'standard' antifungal agent fluconazole similar results were found as for lactoferrin, but the medium type and pH did not affect MIC values of amphotericin B . The addition of saliva to medium did not reduce the antifungal activities of the individual compounds . Synergistic inhibitory effects on Candida growth were found for combinations of lactoferrin and fluconazole or amphotericin B, irrespective of the medium type and pH, or the addition of saliva . This indicates that for treatment of oral Candidiasis a formulation containing lactoferrin seems appropriate; results may be optimized if the formulation is provided with buffer capacity to attain pH 7.5 in the mucosal fluid . The synergistic effects between lactoferrin and 'standard' antifungals indicate that combinations should be considered in such a formulation.

Tissue Antigens, 2002 Mar, 59(3), 216 - 8
Identification of a new MICA allele, MICA*047; Perez-Rodriguez M et al.; The MHC Class I related (MIC) gene family has been shown to be very polymorphic with 46 different MICA alleles being officially named by the WHO Nomenclature Committee for factors of the HLA system to date . We have identified a novel MICA allele, MICA*047, in a Coya American Indian individual from the Jujuy province of north-western Argentina . The novel MICA*047 allele differs from the MICA*030 allele by a single non-synonymous substitution in exon 2, condon 26 GTA-->GGA, Valine to Glycine1.

Kansenshogaku Zasshi, 2002 May, 76(5), 396 - 9
{A case of abrupt pulmonary infection by Rhizopus microsporus var . rhizopodiformis during treatment for bronchial asthma}; Maniwa K et al.; We presented a case of pulmonary Rhizops microsporus var . rhizopodiformis infection which developed abruptly during treatment of bronchial asthma by systemic corticosteroids . The patient, an 85 year-old-woman, was given systemic steroid therapy for 15 days . She suddenly became febrile two days after the therapy and was coughing up yellow sputum . Chest X-ray film showed multiple nodules with cavities which became worsened rapidly . A specimen of sputum culture gave a growth of Mucoraceae, which was identified to be Rhizopus microsporus var . rhizopodiformis . She was given amphotericin B and miconazole was added on the basis of MIC value of the strain . Although she improved initially, her clinical course showed neutropenia, pseudomembranous enterocolitis, malnutrition, and then died after about six months . Because the diagnosis of pulmonary mucormycosis is difficult and prognosis is poor, further studies for investigating clinical features would be necessary.

Antimicrob Agents Chemother, 2002 Jul, 46(7), 2310 - 2
In vivo activity of posaconazole against Mucor spp . in an immunosuppressed-mouse model; Sun QN et al.; The in vivo activities of posaconazole, itraconazole, and amphotericin B in neutropenic mice with zygomycosis were compared . The in vitro MICs of posaconazole and itraconazole for the strains of Mucor spp . used in this study ranged from 0.125 to 8 microg/ml and 0.25 to 8 microg/ml, respectively . The in vitro MIC range for amphotericin B is 0.125 to 0.25 microg/ml . At twice-daily doses of >or=15 mg/kg of body weight, posaconazole prolonged the survival of the mice and reduced tissue burden.

Antimicrob Agents Chemother, 2002 Jul, 46(7), 2229 - 33
Alterations in penicillin-binding protein 1A confer resistance to beta-lactam antibiotics in Helicobacter pylori; Gerrits MM et al.; Most Helicobacter pylori strains are susceptible to amoxicillin, an important component of combination therapies for H . pylori eradication . The isolation and initial characterization of the first reported stable amoxicillin-resistant clinical H . pylori isolate (the Hardenberg strain) have been published previously, but the underlying resistance mechanism was not described . Here we present evidence that the beta-lactam resistance of the Hardenberg strain results from a single amino acid substitution in HP0597, a penicillin-binding protein 1A (PBP1A) homolog of Escherichia coli . Replacement of the wild-type HP0597 (pbp1A) gene of the amoxicillin-sensitive (Amx(s)) H . pylori strain 1061 by the Hardenberg pbp1A gene resulted in a 100-fold increase in the MIC of amoxicillin . Sequence analysis of pbp1A of the Hardenberg strain, the Amx(s) H . pylori strain 1061, and four amoxicillin-resistant (Amx(r)) 1061 transformants revealed a few amino acid substitutions, of which only a single Ser(414)-->Arg substitution was involved in amoxicillin resistance . Although we cannot exclude that mutations in other genes are required for high-level amoxicillin resistance of the Hardenberg strain, this amino acid substitution in PBP1A resulted in an increased MIC of amoxicillin that was almost identical to that for the original Hardenberg strain.

Scand J Infect Dis, 2002, 34(5), 327 - 30
In vitro susceptibility to quinolones of Francisella tularensis subspecies tularensis; Johansson A et al.; Francisella tularensis is a potent pathogen and a possible bioterrorism agent, for which quinolones offer promising new therapeutic options . There are, however, no data on the susceptibility to quinolones of natural isolates of F . tularensis tularensis, the highly virulent North American subspecies . In the present study, 8 isolates of F . tularensis tularensis, originating from 8 different states of the USA, and 16 US isolates of F . tularensis holarctica were tested . All 24 isolates showed MIC values < or = 0.125 mg/l to 6 different quinolones . Against ciprofloxacin, the predominant quinolone used to date in therapy against subspecies holarctica, MIC values were consistently < or = 0.064 mg/l . Thus quinolones seem to be promising options for the treatment of tularemia, including cases caused by the highly virulent subspecies F . tularensis tularensis.

Int J Tuberc Lung Dis, 2002 Jun, 6(6), 503 - 9
Ofloxacin population pharmacokinetics in patients with tuberculosis; Stambaugh JJ et al.; SETTING: Two tuberculosis hospitals in the United States . OBJECTIVE: To determine the population pharmacokinetic (PK) parameters of ofloxacin following multiple oral doses . DESIGN: A total of 73 patients with tuberculosis (TB) participated in the study . Subjects received multiple doses of ofloxacin as part of their treatment . They also received concurrent medications based on in vitro susceptibility data . Serum samples were collected over 10 h and assayed by a validated high performance liquid chromatography (HPLC) assay . Concentration-time data were analyzed using population methods . RESULTS: Ofloxacin concentrations increased linearly with increasing oral doses . Delayed absorption was seen at least once in 29% of patients . Ofloxacin elimination decreased with declining renal function and increasing age . Higher daily doses were well tolerated, and appeared to maximize the peak concentration to minimal inhibitory concentration ratio (Cmax:MIC) . CONCLUSION: Ofloxacin PK parameters were comparable to those previously published for other patient populations . Higher daily doses may offer pharmacodynamic advantages for the treatment of TB.

Farmaco, 2002 May, 57(5), 355 - 62
Antimycobacterial activity of 5-arylidene aromatic derivatives of hydantoin; Szymanska E et al.; Various 5-(chlorobenzylidene)-2-isoniazido and 5-(chlorobenzylidene)-2-amino substituted derivatives of imidazoline-4-one were synthesized and evaluated in the primary assay for their antimycobacterial activity against Mycobacterium tuberculosis H37Rv . Eight of them exhibited > 90% inhibition in the primary screening at 12.5 microg/ml . For these primarily selected compounds the actual MIC and IC50 values were determined . Two of the isoniazid derivatives, for which MIC < 3.13 microg/ml and SI > 10, were selected for further screening and investigated for efficacy in vitro in a TB-infected macrophage model . The most promising compound, 5-(3-chlorobenzylidene)-2-(isonicotinoylhydrazino)-imidazoline-4-one, with activity in vitro comparable with rifampin (MIC = 0.8 microg/ml . SI > 78) was tested in vivo in the animal tuberculosis model but exhibited insignificant activity . For several compounds the primary screening of antimycobacterial activity against Mycobacterium avium (ATCC 25291) was conducted as well, but none of them demonstrated satisfactory activity.

Med Mycol, 2002 Apr, 40(2), 179 - 83
In vitro susceptibility of Microsporum canis and other dermatophyte isolates from veterinary infections during therapy with terbinafine or griseofulvin; Hofbauer B et al.; We investigated the in vitro activity of terbinafine against fresh veterinary isolates of Microsporum canis and the potential of this organism to develop resistance in vivo during oral therapy . Dermatophyte cultures (n = 300) were obtained from naturally infected cats and dogs undergoing oral therapy with terbinafine or griseofulvin . M . canis comprised 92% of isolates; other species included Microsporum gypseum and Trichophyton mentagrophytes . Minimum inhibitory concentrations (MICs) and minimum fungicidal concentrations (MFCs) of terbinafine and griseofulvin were determined by broth macrodilution assay . Terbinafine was highly active against all three species with MIC90< or =0.03 microg ml(-1), in agreement with published data . However, terbinafine exhibited primary cidal activity against 66% of Microsporum isolates (n = 275) in contrast to the almost complete cidal effect in Trichophyton (n = 18) . Griseofulvin was significantly less active than terbinafine (MIC90 = 4 microg ml(-1)) but had a primary cidal action on about 40% of the isolates . The data were analysed for changes in MIC and MFC during the course of therapy, which could be indicative for development of acquired resistance . Oral treatment of 37 animals with terbinafine for up to 39 weeks caused no increase in MIC or MFC of terbinafine, either in individual patients or in the whole group.

Bioorg Med Chem, 2002 Aug, 10(8), 2795 - 802
Chalcones and flavonoids as anti-tuberculosis agents; Lin YM et al.; A series of flavonoids, chalcones and chalcone-like compounds were evaluated for inhibitory activity against Mycobacterium tuberculosis H37Rv . Among them, eight compounds exhibited >90% inhibition on the growth of the bacteria at a concentration of 12.5 microg/mL . Chalcones 1-(2-hydroxyphenyl)-3-(3-chlorophenyl)-2-propen-1-one (22) and 1-(2-hydroxyphenyl)-3-(3-iodophenyl)-2-propen-1-one (37) demonstrated 90 and 92% inhibition, respectively . Chalcone-like compounds (heterocyclic ring-substituted 2-propen-1-one) 1-(4-fluorophenyl)-3-(pyridin-3-yl)-2-propen-1-one (48), 1-(3-hydroxyphenyl)-3-(phenanthren-9-yl)-2-propen-1-one (49), 1-(pyridin-3-yl)-3-(phenanthen-9-yl)-2-propen-1-one (50) and 1-(furan-2-yl)-3-phenyl-2-propen-1-one (51) exhibited 98, 97, 96 and 96% inhibition, respectively . The actual minimum inhibitory concentrations (MIC), defined as the lowest concentration inhibiting 99% of the inoculum, for 22, 37, 48, 49, 50 and 51 were 20.3, 31.5, 48.3, >35.7, 6.8 and 19.2, respectively . A hydrophobic substituent on one aromatic ring, and a hydrogen-bonding group on the other aromatic ring resulted in increased anti-TB activity of the chalcones and chalcone-like compounds . Flavones and flavanones are more geometrically constrained than the corresponding chalcone analogues . The decreased activity of the flavones with respect to the chalcones may be due to the confinement of the terminal aromatic rings to the same plane.

Bioorg Med Chem, 2002 Aug, 10(8), 2589 - 96
Synthesis of some new 2-substituted-phenyl-1H-benzimidazole-5-carbonitriles and their potent activity against Candida species; Goker H et al.; New 2-substituted-phenyl-1H-benzimidazole-5-carboxylic acids (35, 38), ethyl-5-carboxylate (36), -5-carboxamides (37, 39),-5-carboxaldehyde (42), -5-chloro (40), -5-trifluoromethyl (41), and -5-carbonitriles (44-53, 55-67), -6-carbonitrile (54) were prepared and evaluated in vitro against Candida species . The cyano substituted compounds 53, 57, 58 and 61 exhibited the greatest activity with MIC values of 3.12 microg/mL, values similar to that of fluconazole.

Clin Microbiol Infect, 2002 Apr, 8(4), 240 - 2
In vitro activities of new quinolones against Brucella melitensis isolated in a tertiary-care hospital in Turkey; Kocagoz S et al.; We have evaluated the in vitro activities of seven fluoroquinolones against 69 strains of Brucella melitensis . According to their minimum inhibitory concentration for 90% growth (MIC(90)) values, the most active agent was found to be sparfloxacin (MIC(90) 0.12 mg/L) followed by levofloxacin, ciprofloxacin, ofloxacin (MIC(90) 0.50 mg/L) and grepafloxacin (MIC(90) 1 mg/L), gemifloxacin (MIC(90) 2 mg/L) and gatifloxacin (MIC(90) 4 mg/L).

J Chemother, 1991 Jan, 3 Suppl 1, 66 - 8
Preliminary evaluation of in-vitro antimycobacterial properties of N1-(aryliden)-2-pyridinecarboxyamidrazones; Banfi E et al.; After preliminary in vitro screening of 17 newly synthesized compounds belonging to the chemical class of N1-(aryliden)-2-pyridinecarboxyamidrazones, active against Mycobacterium tuberculosis H37Rv, the minimum inhibitory concentrations (MICs) of the ten most promising agents against three clinical isolates were determined by agar dilution . Compounds 12 and 14 were the most active, each inhibiting strain H37Rv at concentrations of 8 microg/ml and having a MIC of 16 microg/ml against the human isolates . The results obtained in this preliminary study confirmed the interesting antitubercular properties of these newly synthesized compounds and allowed us to carry out our investigations over a large number of isolated clinical strains.

J Chemother, 1991 Jan, 3 Suppl 1, 57 - 61
In vitro activity, beta-lactamase stability and PBP affinity of RU 51,746-2, the active metabolite of the new orally absorbed cephalosporin ester, RU 51807; Boaretti M et al.; The activity of RU 51,746-2 was determined against strains of Escherichia coli producing different types of beta-lactamases or showing alterations of permeability . The production of TEM 1, OXA 2, CARB 3 and PSE 1 beta-lactamases had no influence on susceptibility to the antibiotic, whereas the synthesis of TEM 2, SHV 1 and OXA 1 beta-lactamases increased minimum inhibitory concentrations (MIC) by 2-4 times . Highly resistant to the antibiotic was a strain producing CEP 1 beta-lactamase . E . coli mutans deficient in Omp F but not in Omp C had a decreased susceptibility to RU 51,746-2 . RU 51,746-2 showed a good affinity for high molecular weight penicillin binding proteins (PBPs) of E . coli . PBP 3 was found to be the target for growth inhibition, whereas the additional saturation of PBP 1 and 2 was required for obtaining the best bactericidal activity.

J Chemother, 1991 Jan, 3 Suppl 1, 36 - 8
In-vitro and in-vivo activity of roxithromycin against Chlamydia trachomatis; Furneri PM et al.; The object of study was the evaluation of both the in-vitro and in-vivo activity of roxithromycin against Chlamydia trachomatis . In-vitro activity against C . trachomatis was achieved by means of minimum inhibitory concentration (MIC) determinations and was recorded as 0.05 mg/l . In vivo activity was tested in 15 of 60 women, attending the Planning Clinic, who were positive for C . trachomatis . Microbiological diagnosis of chlamydial infection was achieved by using a monoclonal direct smear test (Biomerieux-C trachomatis direct IF) . All the patients and their partners were treated with 150 mg of roxithromycin twice a day for 15 days . All the patients were requested to avoid unprotected sexual intercourse up to the end of the therapy . The criterion for clinical efficacy was defined as disappearance of clinical signs and the criterion for microbiological efficacy was evidence of eradication of C . trachomatis at the follow-up (mean time: 30 days) . A clinical cure and chlamydial eradication was recorded for all the patients at the end of the treatment and at follow-up . Clinical safety was also satisfactory.

J Chemother, 1991 Jan, 3 Suppl 1, 136 - 40
Immunization of mice with antibiotic treated Escherichia coli; Raponi G et al.; The hypothesis of a different immunogenicity between untreated and antibiotic-treated Escherichia coli was investigated in vivo . Groups of mice were injected weekly for eight weeks with formalin-killed E . coli ATCC 25922 either exposed or not to 0.1 x MIC of aztreonam . A group of mice injected with sterile saline only served as control . IgG production towards whole bacteria was clearly enhanced in the group immunized with antibiotic-treated E . coli as shown in ELISA assays . In the same group, the appearance of additional bands of reactivity in the region of major outer membrane proteins was observed in immunoblot experiments as well as an enhanced protection towards a challenge of 10 x LD50 of live E . coli . These findings seem to support the hypothesis that sub-MICs of antibiotics modify the bacterial surface influencing host-parasite relationships.

Southeast Asian J Trop Med Public Health, 2001 Dec, 32(4), 733 - 8
Partial purification of mitochondrial DNA topoisomerase II from Plasmodium falciparum and its sensitivity to inhibitors; Chavalitshewinkoon-Petmitr P et al.; Mitochondria of Plasmodium falciparum (K1 strain) were isolated by differential centrifugation . Mitochondrial DNA topoisomerase II from P . falciparum was partially purified using fast protein liquid chromatography(FPLC) . Parasite mitochondria contained approximately 8% of DNA topoisomerase II activity compared with its nuclear fraction . The effects of fluoroquinolones, inhibitors of bacterial DNA topoisomerase II or DNA gyrase, against partially purified P . falciparum mitochondrial DNA topoisomerase II were investigated using a decatenation assay . Minimum inhibitory concentrations (MIC) of ofloxacin, ciprofloxacin and norfloxacin were > 1, 10 and 100 mM, compared with that of >0.5 and 10 mM for eukaryotic DNA topoisomerase II inhibitor etoposide (VP-16) and amsacrine, respectively . The results indicate that partially purified mitochondrial DNA topoisomerase II was insensitive to fluoroquinolones and it is suggested that their inhibitory effects on P . falciparum growth may be directed against plastid DNA topoisomerase II.

Przegl Lek, 2001, 58(12), 1076 - 8
{Human histocompatibility HLA system . Considerations in the light of current concepts . VIII . Polymorphism of HLA-related MIC system}; Kedzierska A et al.; The recent advances about a new distinct family of polymorphic genes MIC (PERB11) "mapped" in the region of the major histocompatibility complex of antigens MHC were presented . Some aspects connected with their molecular organisation, degree of polymorphism, expression, and immunogenetical function were discussed . Special attention sacrificed to results of investigations over existence of particular MICA allele association with some diseases . Many relating problems, especially functional MICA and MICB genes are still in interests both clinicians, and immunogenetists.

Indian J Med Res, 2001 Dec, 114, 187 - 91
Comparison of different methods of assessing in vitro resistance of Mycobacterium tuberculosis to rifampicin; Paramasivan CN et al.; BACKGROUND & OBJECTIVES: Definitions of in vitro resistance to rifampicin in strains of Mycobacterium tuberculosis by different methods have not been consistent, leading to variations in the interpretation and validity of results . This study compared three methods of defining in vitro resistance to rifampicin . METHODS: (i) A total of 598 clinical isolates of M . tuberculosis were concurrently compared by the minimal inhibitory concentration (MIC) and the proportion method on Lowenstein-Jensen medium; (ii) 54 strains tested by the MIC method were retested by the proportion method and the BACTEC radiometric method; and (iii) 72 strains which yielded an MIC of 64 mg/l by the MIC method were retested by the same method . RESULTS: Out of 598 cultures tested by the MIC and the proportion methods, identical classification as susceptible or resistant was observed in 99.7 per cent . A 100 per cent agreement was observed when 54 strains were tested by the MIC, proportion and BACTEC radiometric methods . When 72 strains with an MIC of 64 mg/l were retested by the same method, 61 (85%) yielded a lower MIC, 9 (12%) gave the same MIC while 2 (3%) yielded a higher MIC of 128 mg/l, reflecting perhaps the inherent limitations of the variations in the inoculum size . INTERPRETATION & CONCLUSION: All 3 definitions of resistance, viz., an MIC of 128 mg/l, a proportion of 1 per cent or more on 40 mg/l by the proportion method, both on L-J medium and a growth of 1 per cent or more on 2 mg/l by the radiometric method were found to be equally satisfactory.

J Antimicrob Chemother, 2002 Jun, 49(6), 1023 - 6
Resistance of Helicobacter pylori isolated in Israel to metronidazole, clarithromycin, tetracycline, amoxicillin and cefixime; Samra Z et al.; The resistance of Helicobacter pylori isolated in Israel to metronidazole, clarithromycin, tetracycline, amoxicillin and cefixime was tested in 138 isolates, including 28 from treatment failures . No resistance to tetracycline was detected . Resistance to amoxicillin was found in one isolate (MIC = 1.5 mg/L) from an untreated patient, and resistance to cefixime in two isolates from each group (P = 0.18) . Resistance to metronidazole and clarithromycin was much higher in the isolates from treated than from untreated patients: 60.7% and 38.2% for metronidazole (MIC >or= 8 mg/L) (P = 0.03); 46.4% and 8.2% for clarithromycin (MIC >or= 2 mg/L) (P < 0.001) . Therapeutic outcome would benefit from susceptibility testing, especially after treatment failure.

Appl Environ Microbiol, 2002 Jun, 68(6), 2666 - 75
An antifungal protein from the marine bacterium streptomyces sp . Strain AP77 is specific for Pythium porphyrae, a causative agent of red rot disease in Porphyra spp; Woo JH et al.; A novel antifungal protein (SAP) was found in the culture supernatant of a marine bacterium, Streptomyces sp . strain AP77, and was purified . This protein was characterized by chemical, biochemical, and biological analyses . By using gel filtration, the molecular mass of SAP was estimated to be 160 kDa . Structural analysis of SAP by sodium dodecyl sulfate-polyacrylamide gel electrophoresis and matrix-assisted laser desorption ionization-time of flight mass spectrometry suggested that SAP is composed of three heterologous protein subunits of 41.7 kDa (SAP1), 21.7 kDa (SAP2), and 18.7 kDa (SAP3) at a molar ratio of 1:1:5 (or 1:1:6) . N-terminal amino acid sequence analysis and a homology search revealed that SAP1, SAP2, and SAP3 exhibit 64.3, 68.4, and 86.7% similarity to three Streptomyces coelicolor polypeptides, puromycin resistance protein (Pur8), a conserved hypothetical protein, and bacterioferritin, respectively . The MIC of purified SAP against Pythium porphyrae was determined to be 1.6 microg/disk, whereas no inhibitory effect was observed at concentrations up to 100 microg/disk against most of the fungal and bacterial strains tested; the only exception was relatively strong antifungal activity against Pythium ultimum (MIC, 6.3 microg/disk) . In vitro and in vivo toxicity tests demonstrated that SAP showed no toxicity against Porphyra yezoensis cells, human normal dermal fibroblasts, and mice at doses up to 700 microg/ml (for 24 h), 250 microg/ml (for 12 h), and 75 mg/kg (for 35 days), respectively . SAP was labile when it was subjected to a heated-air drying treatment, which is a great advantage in food production procedures . These results indicated that Streptomyces sp . strain AP77 might be useful as a gene source for safe transgenic Porphyra breeding for tolerance to Pythium infection.

J Clin Microbiol, 2002 Jun, 40(6), 2266 - 9
Transient fungemia caused by an amphotericin B-resistant isolate of Candida haemulonii; Rodero L et al.; A bloodstream infection due to Candida haemulonii afflicting a patient with fever and a medical history of megaloblastic anemia is reported . The clinical isolate was misidentified by the API 20C and VITEK identification systems . The results of susceptibility tests showed that the MIC of amphotericin B for C . haemulonii was 4 microg/ml . Additional susceptibility testing procedures based on the use of antibiotic medium 3 and Iso-Sensitest broth were performed, and killing curves were determined . Two collection strains of C . haemulonii were employed as controls . The three isolates exhibited resistance to amphotericin B in vitro regardless of the antifungal susceptibility testing method employed . In addition, the MICs of fluconazole for the three isolates were high . Further studies are needed in order to ascertain whether this species exhibits innate or acquired resistance to amphotericin B and other antifungal agents.

Biol Pharm Bull, 2002 May, 25(5), 669 - 70
In vitro antifungal activity of naphthoquinone derivatives; Sasaki K et al.; In vitro antifungal activities of naphtoquinone-derivatives, which are constituents of Shikon, roots of Lithospermum erythrorhizon, were investigated against several fungal pathogens . When the biological activity of these compounds was tested against fungi, a wide range of sensitivity was recorded . Shikonin was found to have a stronger than fluconazole against yeast-like fungi: four-fold against Candida krusei (minimal inhibitory concentration (MIC); 4 microg/ml) and two-fold (MIC; 4 microg/ml) against Saccharomyces cerevisiae, though it showed the same potency as fluconazole against C . glabrata . Deoxyshikonin also exhibited four-fold stronger activity against C . krusei (MIC; 4 microg/mi) and three-fold (MIC; 2 microg/ml) stronger against S . cerevisiae . Acetylshikonin and beta-hydroxyisovaleryl shikonin showed lower activities against all fungal pathogens except for C . krusei compared with the standard . Against the filamentous fungus, Trichosporon cutaneum, all naphthoquinones were found to have a range of activity with lower potency than standard . This result provides a rational basis for the clinical use of shikon and shows the possibility of its use in medicinal treatment as an anti-inflammatory agent with antifungal activity.

Biochim Biophys Acta, 2002 Jun 7, 1576(1-2), 214 - 8
A novel root-specific gene, MIC-3, with increased expression in nematode-resistant cotton (Gossypium hirsutum L.) after root-knot nematode infection; Zhang XD et al.; A full-length cDNA, MIC-3, has been identified from a lambda ZAPII cDNA library constructed from the mRNA of nematode-resistant cotton (Gossypium hirsutum L.) roots after infection with root-knot nematode (Meloidogyne incognita) . The putative open reading frame of MIC-3 encoded a protein of 141 amino acids with a calculated molecular mass of 15.3 kDa . Seven alternative polyadenylation sites have been identified for the MIC-3 transcripts, and the major transcripts are the longest ones . The MIC-3 gene contains a single intron within its coding region and belongs to a novel, multi-gene family containing up to six members . Expression of MIC-3 is root localized and specifically enhanced in the nematode induced, immature galls of resistant cotton line M-249, suggesting that MIC-3 may play a critical role in the resistance response to root-knot nematode.

Indian J Med Sci, 2001 Dec, 55(12), 655 - 62
Antibiotic combinations in polymicrobic diabetic foot infections; Pathare NA et al.; OBJECTIVE: The aim of this study was to evaluate synergistic potential of antibiotic combinations against pathogenic microorganisms isolated from patients with diabetic foot wounds . RESEARCH DESIGN AND METHODS: 272 diabetic foot patients were studied prospectively over a two-year period . Tissue curettage samples from ulcer base were processed microbiologically to isolate aerobic as well as anaerobic pathogens . {775 isolates} Antibiotic susceptibility testing {MIC/MBC}, from amongst these organisms revealed 75 multiresistant organisms, of which only 69 strains could be further studied to assess synergistic effect of various antibiotic combinations by the microtitre checkerboard assay technique . RESULTS: The checkerboard synergy studies showed that overall, synergy could be demonstrated in 21.74% to 59.57% . Amongst the 14 combinations tested, it was found that four combinations could be of worthwhile clinical significance, namely Amikacin/Piperacillin {AK + PP} {77.50%}; Ampicillin-Sulbactum/Piperacillin {AS + PP} {76.92%}; Ampicillin Sulbactum/Cefoperazone {AS + CP} {74.47%}, and Ofloxacillin/Cefotaxime {OF + CT} {71.43%} . CONCLUSIONS: Amikacin/Piperacillin is a combination that has been proven to be of synergistic potential . This study not only confirms this observation but also showed that Ampitum-Sulbactum in combination with either Piperacillin or Cefoperazone was equally efficacious . Furthermore, it was also observed that Ofloxacillin/Cefotaxime combination could be almost equally useful . The study thus emphasizes that antibiotic combinations which are synergistic can be of great clinical significance in the management of patients with diabetic foot infections.

Hindustan Antibiot Bull, 1999 Feb-Nov, 41(1-4), 22 - 4
In vitro evaluation on inhibitory nature of some Neem formulations against plant pathogenic fungi; Bhonde SB et al.; Different Neem formulations derived from the Neem tree (Azadirachta indica) have been found to be potential fungicides against a broad spectrum of plant pathogenic fungi . Some Neem formulations viz . Achook (0.15% EC), Bioneem (0.03% EC), Nimbecidine (0.03% EC) and Neemark (0.03% EC) were examined against some plant pathogenic fungi such as (Fusarium oxysporum, Alternaria solani, Curvularia lunata, Helminthosporium sp . and Sclerotium rolfsii) . Among these Achook (0.15% EC) was found to be more active in terms of Minimum Inhibition Concentration (MIC) value followed by Bioneem, Neemark and Nimbecidine . Remarkably, although all these formulations are oil based, Neem oil itself did not exhibit any fungicidal activity.

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