Hua Xi Kou Qiang Yi Xue Za Zhi, 2004 Feb, 22(1), 57 - 8, 61 {The effect of Redix Scutellariae on butyrate of Porphyromonas endodontalis in vitro}; Li JY et al.; OBJECTIVE: To study the effect of Radix Scutellariae on the growth, metabolism of Porphyromonas endodontalis (P.e), as a preparation for studying the mechanism of Radix Scutellariae in treating pulp and periapical diseases . METHODS: P.e was chosen as the experimental bacteria . Radix Scutellariae was extracted by means of reflux with 80% ethanol . The value of MIC of Radix Scutellariae was measured by minute amount serial dilusion test, and the production of butyrate was measured by high liquid chromatograph(HPLC) . RESULTS: Radix Scutellariae could inhibit the growth of P.e, of which the MIC was 100 mg/L . Following the increase in concentration of Radix Scutellariae, the amount of butyrate decreased to (3.527 +/- 0.009) mg/L, (3.048 +/- 0.005) mg/L, (2.490 +/- 0.011) mg/L, (2.209 +/- 0.016) mg/L, respectively (P < 0.05) . CONCLUSION: Radix Scutellariae could inhibit the growth and metabolism of P.e and might be an effective agent in treating pulp and periapical diseases. Int J Antimicrob Agents, 2004 Feb, 23(2), 197 - 9 Validation of commercial dry-form broth microdilution panels and test reproducibility for susceptibility testing of dalbavancin, a new very long-acting glycopeptide; Jones RN et al.; Results from dalbavancin dry-form commercial broth microdilution MIC panels (Sensititre, TREK Diagnostics) were compared with reference frozen-form MIC values to assure the validity and reproducibility of the extended shelf-life product . A collection of 402 organisms from four major organism groups were used in the validation trial and 10 strains for reproducibility replicate tests . A total of 98.6% commercial dalbavancin MIC results were within +/-1 log(2) dilution of reference values (76.2% were identical) and reproducibility trials produced identical MIC results in 88.9-92.2% of dalbavancin MIC comparisons . These dalbavancin MIC results demonstrated the acceptable accuracy of commercially-prepared broth microdilution products for use in subsequent clinical trials. Int J Antimicrob Agents, 2004 Feb, 23(2), 120 - 8 Antibiotic therapy for severe bacterial infections: correlation between the inhibitory quotient and outcome; Spanu T et al.; In severe bacterial infections, treatment failure can occur even when the infecting organism has displayed in vitro susceptibility to the antibiotics used . Several pharmacokinetic-pharmacodynamic parameters show better correlation with therapeutic outcome than susceptibility results . This study was devised to assess the relation between the inhibitory quotient (IQ), i.e., the ratio of achievable antibiotic concentration at the infection site to the minimum inhibitory concentration for the infecting organism, and both clinical and bacteriological outcomes in 290 severe bacterial infections . Multivariate analysis showed that the IQ was a strong predictor of therapeutic outcome ( P< 0.001-0.002): values <4 predicted failure, and those >or=6 cure . This simple parameter could be routinely used to guide effective antibiotic therapy. Int J Pharm, 2004 Apr 1, 273(1-2), 203 - 12 The release of cefazolin and gentamicin from biodegradable PLA/PGA beads; Wang G et al.; Infection has been one of the most common causes of problems and complications after the operation despite the advance in surgical techniques and the availability of newly developed antibiotics . Local antibiotic delivery beads for treatment of various surgical infections had been studied recently especially in osteomyelitis . This current paper used cefazolin sodium and gentamicin sulfate combined with biodegradable polymers (50:50 poly(DL-lactide):co-glycolide) as antibiotic beads for a long-term drug release . To manufacture an antibiotic bead, polylactide-polyglycolide copolymers were mixed with the antibiotics . The mixture was compressed and sintered at 55 degrees C to form beads of different sizes . The beads were placed in 3 ml of phosphate buffered saline and incubated at 37 degrees C . An elution method combined with a bacterial inhibitory test was employed to characterize the release rate of the antibiotics over a 30-day period . The results suggested that the biodegradable beads released high concentrations of antibiotic (well above the minimum inhibitory concentration) in vitro for the period of time needed to treat bone infection; i.e . 2-4 weeks . This provides advantages as a first line choice of long-term antibiotics for patients with osteomyelitis and various infections such as thoracic, abdominal, and pelvic infections, as well as for the prophylaxis of these infections. Electromyogr Clin Neurophysiol, 2004 Jan-Feb, 44(1), 15 - 21 Analysis of knee movements on leg extension machine: an electromyography study of the rectus femoris muscle; Moraes AC et al.; The Rectus Femoris muscle was analyzed by electromyography in 10 female subjects between 19 and 22 years old . Surface electrodes were utilized by placing them at the middle of the muscle . The course of the flexing/extending movements of the knee were analyzed on a Leg Extension Machine . The results showed that the MIC value was greater in the series with loads than in the series without loads . For the Maximum Isometric Contraction (MIC) the value was 144.00 . In the movement executed without load the value was 73.96 . In the first series with the initial 15 Kg load the value was 163.7 and in the last series of the initial load the value was 194.9 . With the 19 Kg load in the first series the value was 182.5 and in the last series the value was 205.1 . In the first series with the 21 Kg load the value was 165.1 and in the last series with the 21 Kg load the value was 23.09 . The values reflecting the need to recruit more muscle fibers to continue executing the movement . The value 23.09 shows the difficulty in proceeding with the movements and can be considered the beginning of a muscular fatigue process in the Rectus Femoris muscle. Jpn J Antibiot, 2003 Dec, 56(6), 705 - 11 {In vitro activity of a new semisynthetic echinocandin, micafungin, against clinical isolates of Candida species isolated in Tenri Hospital}; Komatsu M et al.; We have examined the antifungal activities of the available antifungal agents including micafungin (MCFG), one of the echinocandin antifungal group, against 92 yeast-like fungi isolated at our hospital during a 3-month period from November 2002 to February 2003 . Determination of the antifungal susceptibility was conducted in conformity with the Standards of the Japanese Society for Medical Mycology . The MIC 80% of the antifungal agents against 4 fungi species including C . albicans (55 strains), C . tropicalis (20 strains), C . glabrata (8 strains), C . krusei (5 strains) were as follows; MCFG: 0.03-0.125 microgram/ml, amphotericin-B: 0.125-0.25 microgram/ml, 5-fluorocytosine: 0.125-16 micrograms/ml, itraconazole: 0.25-2 micrograms/ml, fluconazole: 0.5-32 micrograms/ml . The isolation rate of the drug-resistant fungi was 20% for the fluconazole (FLCZ)-resistant C . tropicalis and 33% when including the susceptible dose dependent (S-DD) class . The rate was 5% for FLCZ-resistant strains of C . albicans and 11% when including the S-DD class . However, MCFG was shown to have an excellent antifungal activity against those azole-resistant strains of Candida species . An analysis of the randomly amplified polymorphic DNA pattern (RAPD) was carried out to assess the fingerprinting of the azole-resistant strains . The results demonstrated a common pattern in 3 of the 6 strains of C . tropicalis that showed MIC of > or = 16 micrograms/ml for fluconazole, while all of the 6 strains of C . albicans demonstrated their respective patterns. Jpn J Antibiot, 2003 Dec, 56(6), 691 - 6 {Activity of fosfomycin against Escherichia coli O157:H7--morphological changes and production of Shiga toxins}; Takata T et al.; We examined the effects of fosfomycin (FOM), norfloxacin (NFLX), kanamycin (KM), chloramphenicol (CP), and ampicillin (ABPC) on the morphology of E . coli O157:H7, and the accumulation (cell fraction) and release (medium fraction) of Shiga toxins (Stxs: Stx1 and Stx2) in E . coli O157:H7 three hours after treatment with the antibiotics . For each drug, 16 MIC was used for measurement of the activity at a high drug concentration and 1/4 MIC at a low concentration . At 16 MIC, cell wall synthesis inhibitors, FOM and ABPC, strongly induced lysis of the cell of E . coli KU3342, a strain of E . coli O157:H7 . The release of Stx1 was observed, but there was no accumulation of Stxs . Nucleic acid synthesis inhibitor NFLX and protein synthesis inhibitor KM induced partial lysis and short filamentation of the cell, and the accumulation and release of Stxs were low . No morphological change was observed after treatment with protein synthesis inhibitor CP, but the accumulation and release of Stxs by CP were low . At 1/4 MIC, FOM induced strong lysis of the cell, and the release of Stx1 was observed, but there was no accumulation of Stxs . ABPC and NFLX had weak lytic reaction, but induced filamentation of the cell, and the accumulation and release of Stxs were observed . In particular, NFLX significantly induced accumulation and release of Stx2 . KM and CP had no effect on the morphology of the cells, and the accumulation of Stx1 was not observed, but there was no release of Stxs . The above-mentioned results support the clinical efficacy of FOM in the control of enterohoemorhagic E . coli infections. J Clin Microbiol, 2004 Mar, 42(3), 1260 - 2 Susceptibility pattern and molecular type of species-specific Candida in oropharyngeal lesions of Indian human immunodeficiency virus-positive patients; Lattif AA et al.; A study of oropharyngeal candidiasis (OPC) in Indian human immunodeficiency virus (HIV)/AIDS patients was conducted over a period of 15 months . This study revealed that 75% of the HIV/AIDS patients had OPC . MIC testing revealed that 5% of the Candida isolates were fluconazole resistant . A correlation between CD4(+)-T-cell counts and development of OPC in HIV/AIDS patients was also observed . Molecular typing of C . albicans isolates showed that all were genetically unrelated. J Clin Microbiol, 2004 Mar, 42(3), 1224 - 7 Comparison of the semisolid agar antifungal susceptibility test with the NCCLS M38-P broth microdilution test for screening of filamentous fungi; Kuzucu C et al.; Antifungal susceptibility testing of pathogenic molds is being developed . A simple screening semisolid agar antifungal susceptibility (SAAS) test accurately measures susceptibilities of yeasts . The performance of the SAAS screening test for filamentous fungi was assessed by comparing MICs of four antifungals (amphotericin B {AMB}, AMB lipid complex {ABEL}, itraconazole {ITZ}, and posaconazole {POS}) for 54 clinical mold isolates with the results of the National Committee for Clinical Laboratory Standards (NCCLS) proposed broth microdilution method (M38-P) . The SAAS test utilized inocula stabbed into tubes of 0.5% semisolid heart infusion agar . In both tests MICs were read after incubation at 35 degrees C for 48 h . The isolates tested were Aspergillus fumigatus, Aspergillus niger, Aspergillus flavus, other Aspergillus spp., Fusarium spp., Penicillium sp., Mucor sp., Scedosporium prolificans, Trichophyton sp., and an unidentified dematiaceous mold . Concordance of test results was determined as the percent agreement of MICs +/- 1 dilution . The overall agreement between the tests for each drug was as follows: AMB, 94%; ABEL, 83%; ITZ, 94%; POS, 94% . For the Aspergillus spp., all but one were susceptible to ITZ by SAAS test; all were susceptible to POS (MIC range, 0.25 to 4 micro g/ml) . Three of six non-Aspergillus molds that were resistant to AMB and ABEL by SAAS (MIC >/= 2 micro g/ml) were also resistant by the NCCLS test . The SAAS test compared favorably to the NCCLS broth microdilution test for molds, and most of the clinical isolates tested were susceptible to all four drugs. J Chemother, 2003 Dec, 15(6), 555 - 7 In vitro antifungal activity of sertaconazole against 309 dermatophyte clinical isolates; Carrillo-Munoz AJ et al.; Three hundred and nine strains belonging to 11 species of dermatophyte moulds were tested against sertaconazole following mainly the National Committee for Clinical Laboratory Standards (M38-P) for filamentous fungi . However, several important factors such as the temperature (28 degrees C vs 35 degrees C) and time of incubation (4-10 d vs 21-74 h), have been modified . Sertaconazole was active against all the clinically important dermatophyte moulds involved in human infections tested . Overall geometric mean MIC of sertaconazole was 0.21 microg/ml with a MIC range of 0.01-8 microg/ml . MIC50 and MIC90 were respectively of 0.25 and 1 microg/ml . Sertaconazole was very active against Epidermophyton floccosum, Trichophyton rubrum, Trichophyton tonsurans and Microsporum canis (geometric means 0.08, 0.13, 0.13 and 0.19 microg/ml respectively) . Microsporum audouinii had the lowest susceptibility in the study (geometric mean 0.59 microg/ml) . Considering MIC50 and MIC90 these differences were significantly in favor of the activity of sertaconazole against E . floccosum (0.06 and 0.5 microg/ml respectively). Expert Opin Pharmacother, 2004 Feb, 5(2), 247 - 54 Treating chromoblastomycosis with systemic antifungals; Bonifaz A et al.; Chromoblastomycosis is a subcutaneous mycosis for which there is no treatment of choice but rather, several treatment options, with low cure rates and many relapses . The choice of treatment should consider several conditions, such as the causal agent (the most common one being Fonsecaea pedrosoi ), extension of the lesions, clinical topography and health status of the patient . Most oral and systemic antifungals have been used; the best results have been obtained with itraconazole and terbinafine at high doses, for a mean of 6 - 12 months . In extensive and refractory cases, chemotherapy with oral antifungals may be associated with thermotherapy (local heat and/or cryosurgery) . Limited or early cases may be managed with surgical methods, always associated with oral antifungal agents . It is important to determine the in vitro sensitivity of the major causal agents to the various drugs, by estimating the minimum inhibitory concentration, as well as drug tolerability and drug interactions. J Vet Pharmacol Ther, 2004 Feb, 27(1), 7 - 11 Pharmacokinetics of ceftiofur in red deer (Cervus elaphus); Drew ML et al.; Twelve adult female red deer (Cervus elaphus) were given 250 mg of ceftiofur sodium by intramuscular injection (i.m.) and ballistic implant in a crossover design . Blood samples were taken from an in-dwelling jugular catheter prior to drug administration and at 0.25, 0.5, 1, 2, 4, 8, 12, 24, 36, 48, and 72 h postadministration of the drug . Samples were centrifuged and plasma kept frozen at -70 degrees C until analysis for ceftiofur and active metabolites using an HPLC method . The pharmacokinetics of ceftiofur and metabolites after i.m . dosing and following ballistic implant were quite different . Absorption after i.m . injection was rapid; whereas following ballistic implant there was a lag-time until concentrations were detectable in plasma . The maximum concentration reached in plasma was higher following injection compared with ballistic implant, however the AUC calculated after ballistic implant was almost identical to the mean AUC found after i.m . dosing . The results indicate that i.m . administration of ceftiofur maintains adequate plasma levels for most susceptible bacterial pathogens for at least 12 h; therefore twice daily administration is needed in red deer . Ballistic implants produced plasma concentrations above the MIC for most bacterial pathogens from 4 to 24 h in most animals after administration; however, absorption of the drug was variable and some did not maintain effective concentrations for more than a few hours . Ceftiofur is a useful drug in red deer and twice daily i.m . administration dosing should allow treatment for susceptible bacterial pathogens. Brain Res Mol Brain Res, 2004 Mar 17, 122(1), 71 - 8 N-Acetylaspartate synthase is bimodally expressed in microsomes and mitochondria of brain; Lu ZH et al.; N-Acetylaspartate (NAA) is an abundant amino acid derivative of the central nervous system that is localized primarily in neurons and has found widespread use in clinical NMR spectroscopy (MRS) as a non-invasive indicator of neuronal survival and/or viability . Its function, although still obscure, is thought to reflect its unusual metabolic compartmentalization wherein NAA synthase occurs in the neuron and aspartoacylase, the hydrolytic enzyme that removes the acetyl moiety, occurs in myelin and glia . The NAA synthase enzyme, acetyl-CoA/l-aspartate N-acetyltransferase (ANAT), was previously shown to function in mitochondria (MIT), although other subcellular fractions were apparently not examined . In this study we confirmed its presence in MIT but also found significant activity in rat brain microsomes (MIC) . The reaction mixture, consisting of {(14)C}aspartate plus acetyl-CoA in Na-phosphate buffer (pH 7), gave rise to {(14)C}NAA that was separated and quantified by TLC . Reaction rates were 29.0+/-0.46 and 6.27+/-0.27 nmol/h/mg for MIC and MIT, respectively . K(m) values and pH optima were similar, and both fractions showed modest enhancement of ANAT activity with the detergents Triton CF-54 and CHAPS . Our tentative conclusion is that ANAT is bimodally targeted to MIT and a component of MIC-likely endoplasmic reticulum . ANAT activity increased in both MIC and MIT between 29 and 60 days of age but differed thereafter in that only MIT ANAT showed a decrease after 1 year. Zhonghua Jie He He Hu Xi Za Zhi, 2004 Feb, 27(2), 84 - 8 {A preliminary study on the definition of resistant breakpoints of ofloxacin and levofloxacin for Mycobacterium tuberculosis}; Huang XR et al.; OBJECTIVE: To test the MIC of ofloxacin and levofloxacin (MIC(F) and MIC(V)) in 101 strains of Mycobacterium tuberculosis (M . tb) isolated from patients with active tuberculosis and to analyze the relation between MIC and past history of fluoroquinolones (FQs) administration . And according to the analysis of the therapeutic effect of the regimen including FQs, we want to define the resistant breakpoints of OFLX and LVFX clinically . METHOD: All isolates from sputa or pus obtained from in-patients in our hospital from Jan 1999 to Sept 2000 were tested for MIC and susceptibility . 47 patients with pulmonary tuberculosis received regimens including FQs were observed consecutively . Chi-square test was applied for the statistical analysis . RESULT: (1) The MIC(V) of 96% clinical isolates tested were 2 times lower than MIC(F) . (2) The MIC(F) < 8 microg/ml and MIC(V) < 4 microg/ml were found among 91% and 92% patients without previous FQs administration, while only the MIC(F) > or = 8 microg/ml and MIC(V) > or = 4 microg/ml were found among 54% and 57% for the patients with FQs administration history . (3) If MIC(F) > or = 8 microg/ml and MIC(V) > or = 4 microg/ml were defined as the clinical resistant breakpoints, in susceptible group, the sputum negative conversion rates were 54%, 75% and 82% respectively after receiving the regimens including FQs in 3, 6, and 12 months, while 16%, 32%, and 42% respectively in resistant group, (P < 0.01) . Also, there were significant differences between these two groups for chest X-ray improvements after 12 months' treatment, (P < 0.01) . There were significant differences for sputum conversion rates and chest X-ray improvement between MIC(V) < 4 microg/ml and MIC(V) > or = 4 microg/ml groups (P < 0.01) . CONCLUSIONS: According to the evaluation for the therapeutic effects of regimens including FQs, it is suggested that MIC(F) > or = 8 microg/ml and MIC(V) > or = 4 microg/ml be defined as resistant breakpoints clinically . The emergence of resistance to FQs in patients with tuberculosis can influence the therapeutic effects. Science, 2004 Mar 26, 303(5666), 1990 - 2 Epub 2004 Feb 26. Discovery of a large dust disk around the nearby star AU Microscopii; Kalas P et al.; We present the discovery of a circumstellar dust disk surrounding AU Microscopii (AU Mic, GJ 803, HD 197481) . This young M star at 10 parsec has the same age and origin as beta Pictoris, another nearby star surrounded by a dust disk . The AU Mic disk is detected between 50 astronomical units (AU) and 210 AU radius, a region where dust lifetimes exceed the present stellar age . Thus, AU Mic is the nearest star where we directly observe the solid material required for planet formation . Because 85% of stars are M-type, the AU Mic disk provides new clues on how the majority of planetary systems might form and evolve. Intensive Care Med, 2004 May, 30(5), 989 - 91 Epub 2004 Feb 24. Plasma and lung concentrations of ceftazidime administered in continuous infusion to critically ill patients with severe nosocomial pneumonia; Boselli E et al.; OBJECTIVE: To determine the steady-state plasma and epithelial lining fluid (ELF) concentrations of ceftazidime administered in continuous infusion to critically ill patients with severe nosocomial pneumonia . DESIGN: Prospective, open-label study . SETTING: An intensive care unit and research ward in a university hospital . PATIENTS: A total of 15 adult patients with severe nosocomial bacterial pneumonia on mechanical ventilation were enrolled . INTERVENTIONS: All subjects received a 30 min intravenous infusion of 2 g ceftazidime followed by a continuous infusion of 4 g over 24 h . The concentrations of ceftazidime in plasma and ELF were determined at steady-state after 2 days of therapy by high performance liquid chromatography . MEASUREMENTS AND MAIN RESULTS: The mean +/-SD steady-state plasma and ELF concentrations of 4 g ceftazidime in continuous infusion were 39.6+/-15.2 microg/mL and 8.2+/-4.8 microg/mL, respectively, showing a mean +/-SD percentage penetration of ceftazidime into ELF of 20.6+/-8.9% . CONCLUSION: The administration of 4 g ceftazidime in continuous infusion in critically ill patients with severe nosocomial pneumonia provides concentrations in excess of the minimal inhibitory concentration of many susceptible organisms over the course of therapy both in serum and ELF . However, for some pathogens such as P . aeruginosa, higher doses of ceftazidime should be administered, or another agent should be used in combination. Antimicrob Agents Chemother, 2004 Mar, 48(3), 747 - 52 Antibiotic susceptibility of Tropheryma whipplei in MRC5 cells; Boulos A et al.; Whipple's disease is considered a rare chronic disease with a broad spectrum of clinical manifestations . Several antibiotics have been used for the treatment of this disease, and the current reference treatment was determined empirically on the basis of only a few clinical observations . Patients should be treated for months, and many relapse after antibiotic withdrawal . We report here the first extensive study on the susceptibilities of three reference strains of Tropheryma whipplei to antibiotic in cell culture by using a real-time PCR assay as previously described . We found that doxycycline, macrolides, ketolides, aminoglygosides, penicillin, rifampin, teicoplanin, chloramphenicol, and trimethoprim-sulfamethoxazole were active, with MICs ranging from 0.25 to 2 microg/ml . Vancomycin was somewhat active at an MIC of 10 microg/ml . We found heterogeneity in the susceptibility to imipenem, with one strain being susceptible and the two other strains being resistant . Cephalosporins, colimycine, aztreonam, and fluoroquinolones were not active . We also demonstrated that a combination of doxycycline and hydroxychloroquine was bactericidal . This combination has been shown to be active in the treatment of patients suffering from chronic infections with Coxiella burnetii, a bacterium that is also found intracellularly in acidic vacuoles . We believe, then, that this combination therapy should be further evaluated in clinical trials for the treatment of Whipple's disease. Water Sci Technol, 2004, 49(2), 99 - 105 MIC mitigation in a 100 MW district heating peak load unit; Olesen BH et al.; During inspection of AISI316 stainless steel plate heat exchangers in a district heating peak load unit, localised corrosion attacks along with indications of microbiological activity were found on the boiler side beneath patches of sturdy black deposits . Bacteria and sulphide were detected within black deposits . Thorough investigation of the boiler system revealed several incidents of localised corrosion on low alloy steel along with deposits of organic matter and bacteria primarily in places with stagnant water or places operating at a low flow rate . A relatively large amount of bacteria was detected within the system, primarily in deposits and around corrosion sites . The observations suggested the combination of deposits and bacterial activity, being the major reason for the observed corrosion . Prior to the investigation, the boiler system had operated with cat-/anion-exchanged, de-aerated water for 3 years, during which the water fulfilled strict chemical limits set to minimise corrosion . Based on these findings, the system has been modified in order to minimise the risk of microbiologically influenced corrosion and a monitoring program for fouling and corrosion has been established. Bioorg Med Chem, 2004 Mar 1, 12(5), 1199 - 207 Anti-HIV natural product (+)-calanolide A is active against both drug-susceptible and drug-resistant strains of Mycobacterium tuberculosis; Xu ZQ et al.; Naturally occurring anti-HIV-1 agent (+)-calanolide A was found to be active against all of the strains of Mycobacterium tuberculosis tested, including those resistant to the standard antitubercular drugs . Efficacy evaluations in macrophages revealed that (+)-calanolide A significantly inhibited intracellular replication of M . tuberculosis H37Rv at concentrations below the MIC observed in vitro . Preliminary mechanistic studies indicated that (+)-calanolide A rapidly inhibits RNA and DNA synthesis followed by an inhibition of protein synthesis . Compared with known inhibitors, this scenario is more similar to effects observed with rifampin, an inhibitor of RNA synthesis . Since (+)-calanolide A was active against a rifampin-resistant strain, it is believed that these two agents may involve different targets . (+)-Calanolide A and its related pyranocoumarins are the first class of compounds identified to possess antimycobacterial and antiretroviral activities, representing a new pharmacophore for anti-TB activity. Diagn Microbiol Infect Dis, 2004 Feb, 48(2), 101 - 5 In vitro susceptibilities of rare Candida bloodstream isolates to ravuconazole and three comparative antifungal agents; Pfaller MA et al.; We determined the in vitro susceptibilities of 643 strains of Candida spp., representing 13 species rarely isolated from blood, to ravuconazole as well as three licensed systemic antifungal agents (amphotericin B, fluconazole, and flucytosine) . The organisms included 234 isolates of C . krusei, 102 isolates of C . guilliermondii, 103 isolates of C . lusitaniae, 18 isolates of C . famata, 29 isolates of C . kefyr, 20 isolates of C . pelliculosa, 13 isolates of C . rugosa, 101 isolates of C . dubliniensis, 4 isolates of C . inconspicua, 11 isolates of C . lipolytica, 1 isolate of C . sake, and 2 isolates of C . lambica and 5 isolates of C . zeylanoides . MIC determinations were made by the National Committee for Clinical Laboratory Standards reference broth microdilution method and Etest (amphotericin B) . Ravuconazole demonstrated excellent activity (98% susceptible at MIC < or = 1 microg/mL) against all species with the exception of C . inconspicua (75% {3 of 4}) . By comparison, decreased susceptibility to fluconazole and/or amphotericin B was observed among isolates of C . krusei, C . guilliermondii, C . famata, C . rugosa, C . inconspicua, and C . lambica . These findings illustrate the fact that many of the less common species of Candida exhibit decreased susceptibility to one or more of the established systemically active antifungal agents . Ravuconazole is clearly an "extended-spectrum" triazole with potent in vitro activity against these rare and potentially "emerging" opportunistic pathogens. Boll Chim Farm, 2003 Nov, 142(9), 416 - 9 Synthesis and evaluation of in vitro antimycobacterial activity of some 5-(5-nitro-2-thienyl)-2-(piperazinyl, piperidinyl and morpholinyl)-1,3,4-thiadiazole derivatives; Foroumadi A et al.; A new series of 5-(5-nitro-2-thienyl)-2-(piperazinyl, piperidinyl and morpholinyl)-1,3,4-thiadiazole derivatives(5a-g) have been synthesized and evaluated against Mycobacterium tuberculosis H37Rv as apart of TAACF TB screening program under direction of the US National Institute of Health, NIAID division . Primary screening was conducted at the single concentration, 6.25 mg/ml against Mycobacterium tuberculosis H37Rv (ATCC 27294) in BACTEC 12B medium using a broth microdilution assay, the Microplate Alamar Blue Assay (MABA) . The minimum inhibitory concentration (MIC) determined for compounds demonstrating 90% growth inhibition in the primary screening . The tested compounds showed a varying degree of inhibitory activity (Inhibition = 0-100%) . The most active compounds were 4-methyl and 4-benzoylpiperaxinyl analogues(5b and 5g) with the same MIC value of 3.13 micrograms/ml. J Food Prot, 2004 Feb, 67(2), 391 - 5 The potential application of vanillin in preventing yeast spoilage of soft drinks and fruit juices; Fitzgerald DJ et al.; The preservative effect of vanillin, the major constituent of vanilla beans, was studied in an apple juice and peach-flavored soft drink . Vanillin activity was tested against Saccharomyces cerevisiae and Candida parapsilosis at 8 and 25 degrees C over an 8-week storage period . Initial results in laboratory media indicated minimum inhibitory concentration values of 17 and 9 mM vanillin for the two yeast strains . Concentrations of 20 and 10 mM vanillin, respectively, were required to achieve complete inhibition of both yeast strains inoculated at a level of approximately 10(4) CFU/ml in the apple juice and peach-flavored soft drink over the 8-week storage at 25 degrees C . These effective levels were reduced to 5 and 1 mM, when the storage temperature was reduced to 8 degrees C . A biocidal effect against both yeasts was observed within 96 h to 8 weeks, with vanillin concentrations of 5 to 40 mM depending on the beverage and the storage temperatures used . The increased activity of vanillin in the peach-flavored soft drink (pH 3.1) in comparison to the apple juice (pH 3.5) is probably a result of the lower intrinsic pH of the former; however, variation in vitamin and mineral levels or the presence of other phenolic compounds between the two drinks might also have contributed to the observed differences . Furthermore, the increased activity at the lower temperature could be linked to the combination of the increased membrane fluidity and the membrane-perturbing action of vanillin . We conclude that vanillin has the potential to preserve fruit juices and soft drinks that are low in both lipid and protein content against S . cerevisiae and C . parapsilosis. J Clin Microbiol, 2004 Feb, 42(2), 718 - 21 Multicenter comparison of the Sensititre YeastOne colorimetric antifungal panel with the NCCLS M27-A2 reference method for testing new antifungal agents against clinical isolates of Candida spp; Espinel-Ingroff A et al.; A multicenter (three centers) study compared MICs obtained by the Sensititre YeastOne Colorimetric Antifungal plate to reference microdilution broth (NCCLS M27-A2 document) MICs of three new triazoles (posaconazole, ravuconazole, and voriconazole) and the echinocandin caspofungin acetate for 100 isolates of Candida spp . In addition, amphotericin B and fluconazole were tested as control drugs . Colorimetric MICs of caspofungin and amphotericin B corresponded to the first blue well (no growth), and MICs of the other agents corresponded to the first slightly purple or blue well . Two comparisons of MIC pairs by the two methods were evaluated: 24-h colorimetric MICs were compared to NCCLS MICs at 24 and at 48 h . The interlaboratory reproducibility of YeastOne and reference MICs was also examined . The best performance of the YeastOne plate was with 24-h MICs (overall, 95 to 99% agreement) for all the species and antifungal agents . These results suggest the potential value of the YeastOne plate for use in the clinical laboratory for the four new antifungal agents evaluated. Gynecol Oncol, 2004 Feb, 92(2), 689 - 96 Primary primitive neuroectodermal tumor of the uterus: a report of two cases and review of the literature; Odunsi K et al.; BACKGROUND: Primary primitive neuroectodermal (pPNET) tumors rarely occur in adults, and they very rarely present as primary tumors of the uterus . Only 12 reported cases of pPNET of the uterus have been published in the English literature . We report two additional cases treated at the Roswell Park Cancer Institute, Buffalo, NY, between 1999 and 2002 . CASES: Two postmenopausal patients presenting with abnormal uterine bleeding underwent endometrial biopsy, and subsequently staging laparotomy . The diagnosis of pPNET in both cases was confirmed only by extensive immunohistochemical analysis of the tumors . One patient with disease confined to an endometrial polyp received no adjuvant therapy, while the second patient with extrauterine disease received adjuvant pelvic radiation followed by chemotherapy . CONCLUSIONS: The diagnosis of pPNET of the uterus may be a challenge . Features of diagnostic significance include positive staining with neuron-specific enolase, presence of neurosecretory granules, and positive staining with the MIC-2 gene . Currently, there is no uniformity in the treatment of these cases since the majority of the patients reported to date have had surgery, chemotherapy, and/or radiation therapy. J Med Chem, 2004 Feb 12, 47(4), 1008 - 17 Novel heteroarotinoids as potential antagonists of Mycobacterium bovis BCG; Brown CW et al.; A series of 15 heteroarotinoids has been prepared and evaluated for activity against Mycobacterium bovis BCG with the thiourea-containing isoxyl (7) (0.5 microg/mL) as the standard . 2,2,4-Trimethyl-2H-chromen-7-yl 4-(methoxycarbonyl)benzoate (8) displayed the most significant activity (2.0-4.0 microg/mL) in terms of the lowest concentration (microg/mL) (MIC, minimum inhibitory concentration) required to produce a 99% reduction in the number of colonies on a plate as compared to that system free of the agent at the same dilution of the culture suspension . Ethyl 4-{{N-(2,2,4,4-tetramethylchroman-6-yl)thiocarbamoyl}amino}benzoate (9) and {{(1E,3Z,5E)-1-aza-4-methyl-6-(1,2,2,4-tetramethyl(1,2-dihydroquinolyl))hexa-1,3,5-trienyl}amino}aminomethane-1-thione (10) exhibited activity at 5.0-10.0 and 10.0-20.0 microg/mL, respectively, while the other examples had MIC values of 20 microg/mL or greater . The inhibitory ability of 8 may occur via the inhibition of mycolic acid synthesis in a like manner as found with 7, but this requires further study . The heteroarotinoids are the first examples to exhibit inhibitory ability against the growth of Mycobacterium bovis BCB. J Colloid Interface Sci, 2004 Mar 1, 271(1), 206 - 11 Surface and micellar properties of new nonionic gemini aldonamide-type surfactants; Komorek U et al.; A new group of gemini aldonamide-type surfactants-N,N'-bisalkyl-N,N'-bis{(3-gluconylamide)propyl}ethylenediamines, N,N'-bisdodecyl-N,N'-bis{(3-glucoheptonylamide)propyl}ethylenediamine, and N,N'-bisalkyl-N,N'-bis{(3-lactobionylamide)propyl}ethylenediamines, (alkyl: n-C(8)H(17), n-C(12)H(25)), were synthesized and characterized . The surface properties, such as surface excess concentration, Gamma(cmc), surface area demand per molecule, A(min), efficiency in surface tension reduction, pC(20), the effectiveness of surface tension reduction, gamma(cmc), critical micelle concentration, cmc, and a measure of the tendency of the surfactant to adsorb at the aqueous/air interface relative to its tendency to form micelles in the bulk surfactant solution, cmc/C(20), and standard free energy of micellization, DeltaG(mic)(0), have been obtained by means of surface tension measurements . The standard fluorescence shift technique using PRODAN as a probe provide confirmation of the cmc values by an alternative method . Additionally, the micellar properties for the concentration near above the cmc have been characterized by the aggregation number, N(agg) . The presence of the dimeric segments with the aldonamide hydrophilic units in the surfactant molecule is found to be the source of their unusual physicochemical behavior . They are very efficient at adsorbing at the free surface and at forming micelles in water . Their critical micelle concentration values are remarkably low . They reveal remarkably low A(min) values in relation to conventional nonionic surfactants, which is unexpected from the molecular dimensions for the molecule but which is possible if one assumes some type of multilayer structure or a coherent interfacial film. In Vivo, 2003 Nov-Dec, 17(6), 541 - 4 Extracts of spice and food plants from Thai traditional medicine inhibit the growth of the human carcinogen Helicobacter pylori; Bhamarapravati S et al.; BACKGROUND: Helicobacter pylori (HP) is a gramnegative bacterium and well recognized as being the primary etiological agent responsible for the development of gastritis, dyspepsia, peptic ulcer disease and gastric cancer . In developing countries, a high prevalence of HP infection is associated with an increased incidence of gastric cancer . Thailand, however, while having a high prevalence of HP infections, has a lower than expected gastric cancer rate than other developing countries . It has been suggested that the diet and life style in Thailand may explain this discrepancy . MATERIALS AND METHODS: The in vitro susceptibility of 18 strains of HP to 20 extracts of spice and food plants used in Thai traditional medicine for the treatment of GI disorders was assessed . RESULTS: Methanol extracts of Myristica fragrans (aril) inhibited the growth of all HP strains with minimum inhibitory concentration (MIC) of 12.5 micrograms/ml; extracts from Barringtonia acutangula (leaf) and Kaempferia galanga (rhizome) had an MIC of 25.0 micrograms/ml; Cassia grandis (leaf), Cleome viscosa (leaf), Myristica fragrans (leaf) and Syzygium aromaticum (leaf) had MICs of 50.0 micrograms/ml . Extracts with an MIC of 100.0 micrograms/ml included Pouzolzia pentandra (leaf), Cycas siamensis (leaf), Litsea elliptica (leaf) and Melaleuca quinquenervia (leaf) . CONCLUSION: Plants used in Thai traditional medicine to treat gastrointestinal ailments inhibit the growth of HP . These data indicate that these plants may have chemopreventative activities and thus may partly explain the reduced incidence of gastric cancer in Thailand. Ann Pharmacother, 2004 Mar, 38(3), 414 - 7 Epub 2004 Jan 30. Voriconazole in fungal keratitis caused by Scedosporium apiospermum; Hernandez Prats C et al.; OBJECTIVE: To describe the first case, to the best of our knowledge, of posttraumatic Scedosporium apiospermum (ScA) keratitis successfully treated with systemic and topical voriconazole . CASE SUMMARY: A 19-year-old man was admitted to the hospital with an incisive wound of his left eye and the cornea totally sectioned after trauma with a cutter used in gardening . Initial empirical treatment was followed by systemic and topical voriconazole, and the eye did not have to be enucleated . Five months after the trauma, a penetrating keratoplasty and chamber intraocular lens implantation was performed with a favorable visual outcome . DISCUSSION: ScA keratitis is rare, but it must be suspected if a history of ocular injury with contaminated objects exists . Among the antifungals available to treat ScA keratitis, voriconazole has shown advantages such as the lowest minimum inhibitory concentration and the availability of an oral formulation . CONCLUSIONS: Voriconazole shows promise as an effective alternative to conventional antifungals in the treatment of ScA keratitis . It is available both as oral and intravenous preparations, which is a great advantage in these lengthy infections. J Vasc Res, 2004 Jan-Feb, 41(1), 84 - 90 Epub 2004 Jan 27. Expression of costimulatory molecules (4-1BBL and Fas) and major histocompatibility class I chain-related A (MICA) in aortic tissue with Takayasu's arteritis; Seko Y et al.; To further investigate the immunological mechanisms involved, we analyzed the expression of costimulatory molecules in aortic tissue and their counterpart molecules on infiltrating cells of patients with Takayasu's arteritis . We also examined the expression of major histocompatibility complex (MHC) class I chain-related (MIC) A in aortic tissue, which is known to be induced by external stress, and its counterpart NKG2D receptors on infiltrating cells . Among these costimulatory molecules, strong expression of 4-1BBL and Fas was induced in the aortic tissue, and most of the infiltrating cells expressed 4-1BB and FasL, suggesting these pathways play critical roles in T-cell-mediated vascular injury . We also found that MICA was strongly induced in the aortic tissue and that at least part of the infiltrating cells expressed NKG2D receptors . Some infiltrating cells - but not vascular smooth muscle cells - seemed to have undergone apoptosis . Our findings strongly suggest that 4-1BB/4-1BBL and Fas/FasL pathways play important roles in vascular injury in Takayasu's arteritis . We assume that gammadelta T cells infiltrated aortic tissue recognizing MICA, resulting in the induction of MHC antigens and costimulatory molecules, and then alphabeta T-cells infiltrated recognizing some auto-antigens presented by MHC antigens, leading to chronic inflammation . Int J Radiat Oncol Biol Phys, 2004 Feb 1, 58(2), 528 - 35 18F-FDG positron emission tomography staging and restaging in rectal cancer treated with preoperative chemoradiation; Calvo FA et al.; PURPOSE: To assess the information supplied by FDG-PET in patients with locally advanced rectal cancer both in the initial staging and in the evaluation of tumor changes induced by preoperative chemoradiation (restaging) . METHODS AND MATERIALS: Twenty-five consecutive patients with rectal cancer were included, with tumor stages (c)T(2-4)N(x)M(0), during the period 1997-1999 . We prospectively performed two FDG-PET scans in all patients to assess disease stage (1) at initial diagnosis and (2) presurgically, 4 to 5 weeks after protracted chemoradiation . Protracted chemoradiation was carried out during 5-6 weeks with 45-50 Gy, plus concurrent oral tegafur 1200 mg/day or 5-fluorouracil 500-1000 mg/m(2) administered as a 24-h continuous i.v . infusion on Days 1-4 and 21-25 of the radiotherapy treatment . Tumors were staged with CT in 95% of patients, whereas endorectal ultrasound was used in 90% of patients . Maximum standardized uptake value (SUVmax) was used as the quantitative parameter to estimate the tumor:tissue metabolic ratio . RESULTS: Preoperative chemoradiation significantly decreased the SUVMAX: 5.9 (mean SUVmax at initial staging) vs . 2.4 (mean SUVmax after chemoradiation) with p < 0.001 . Unknown liver metastases were detected by FDG-PET in 2 patients, in 1 of them with the initial staging FDG-PET scan, and with the restaging FDG-PET scan in the other . After an average follow-up of 39 months, the value of SUVmax > or =6 allowed us to discriminate for survival at 3 years: 92% vs . 60% (p = 0.04) . T downstaging (total 62%) was significantly correlated with SUVmax changes: 1.9 vs . 3.3 (p = 0.03) . The degree of rectal cancer response to chemoradiation, established as mic vs . mac categories, was not associated with SUVmax differences (mean values of 2.0 vs . 2.7) . CONCLUSION: Preliminary results observed suggest the potential utility of FDG-PET as a complementary diagnostic procedure in the initial clinical evaluation (8% of unsuspected liver metastases) as well as in the assessment of chemoradiation response (any T downstaged event) of locally advanced rectal cancer . Initial SUVmax might be of prognostic value related to long-term patient outcome. Zhonghua Er Ke Za Zhi, 2003 May, 41(5), 325 - 8 {Analysis of 21 children with acute non-lymphoid leukemia carrying AML1/ETO fusion gene}; Zhao W et al.; OBJECTIVE: It was revealed that t(8; 21) (q22; q22) was one of the most common chromosomal aberrations in acute non-lymphoid leukemia . The translocation was found to be involved in the AML1 gene on the chromosome 21 and the ETO gene on the chromosome 8, and resulted in the formation of AML1/ETO fusion gene on the derivative chromosome 8 . The fusion gene was a transcription factor and played a direct role in the leukemogenesis . The translocation was mainly observed in M(2), accidentally in M(4) and M(1) and rarely in MDS . Here we studied the main clinical data in children with acute non-lymphoid leukemia (ANLL) carrying the AML1/ETO fusion gene . In addition, we discussed the significance of the detection of AML1/ETO fusion gene in the diagnosis and prognosis of children with ANLL . METHODS: The authors investigated 29 patients in our hospital from December 2000 to March 2002 . The patients were divided into two groups . Group A included 21 patients, 14 males and 7 females . They were 3.6 to 14 years old and the median was 9 . Group B included 8 patients, 6 males and 2 females . They were 0.8 to 14 years old and the median was 6 . Diagnosis was made according to FAB and MIC criteria and the expression of AML1/ETO fusion gene was detected with nested RT-PCR . The patients were treated according to DA, DAE or BFM regimen, respectively . The main clinical indexes including age, Hb, white blood count, platelet, blasts in PBC and BM, and time of arrival at complete remission (CR), were compared statistically between the two groups with t test of independent samples . RESULTS: All the 21 patients in group A were found carrying AML1/ETO, and 17 patients (81%) were classified as M(2), the other 4 cases were of M(2) developed from MDS-RAEB-T, M(4Eo), M(5) and eosinophil leukemia, respectively . Eighteen out of 20 patients whose effects could be assessed reached CR, and the CR ratio was 90% . Two patients in group B were of AML-M(1), 3 M(2), 1 M(3), 1 M(4), and 1 M(5), respectively . None of them was found carrying AML1/ETO . Seven cases reached CR and the ratio was 87.5% . There was no significant difference between the two groups in the above clinical indices . CONCLUSIONS: Between the two groups of patients there was no significant difference in the above clinical indices . RT-PCR for the detection of AML1/ETO in children with ANLL was quick, convenient and sensitive, and could be regarded as a useful method for the diagnosis and prognosis of ANLL. Planta Med, 2003 Dec, 69(12), 1147 - 9 Inhibitory effects of manassantin A and B isolated from the roots of Saururus chinensis on PMA-induced ICAM-1 expression; Rho MC et al.; Cell adhesion inhibitors were isolated from the methanol extract of Saururus chinensis roots by bioactivity-guided fractionation . The active compounds were identified as manassantin A ( 1) and B ( 2), dineolignan compounds . Compounds 1 and 2 inhibited PMA-induced ICAM-1/LFA-1-mediated homotypic aggregation of the HL-60 cells without cytotoxicity with MIC values of 1.0 and 5.5 nM, respectively . Even though 1 and 2 did not affect the adhesion of ICAM-1 to LFA-1, these compounds inhibited PMA-induced ICAM-1 expression in HL-60 cells in a dose-dependent fashion . These results suggest that 1 and 2 inhibit cell aggregation through down-regulation of ICAM-1 expression. Planta Med, 2003 Dec, 69(12), 1130 - 5 Antifungal chromans inhibiting the mitochondrial respiratory chain of pea seeds and new xanthones from Calophyllum caledonicum; Hay AE et al.; Two new xanthones, caledonixanthone M 1 and caloxanthone L 2, and one new acid, caledonic acid 6 were isolated from the hexane-soluble extract of the stem bark of Calophyllum caledonicum . In the course of this phytochemical study, seven other known compounds - calothwaitesixanthone, calozeyloxanthone, allanxanthone, isoapetalic acid 3, calolongic acid 4, apetalic acid 5 and isocalolongic acid 7 - were isolated . Their antifungal activity against the growth of the human pathogenic fungus Aspergillus fumigatus was then investigated . The results indicated that the crude extract, calolongic acid 4 and isocalolongic acid 7 exhibited strong inhibitory effects with MIC (80) values of 8, 4, 2 microg/mL, respectively . Besides, calolongic acid 4, its lactone derivative 4a and isocalolongic acid 7 markedly reduced the respiration of pea seed mitochondria. J Clin Pharm Ther, 2004 Feb, 29(1), 65 - 70 Evaluation of once daily tobramycin dosing in critically ill patients through Bayesian simulation; Peris-Marti JF et al.; OBJECTIVE: To evaluate if once-daily dose (ODD) regimens of tobramycin attain pharmacodynamic goals using individualized pharmacokinetic monitoring of critically ill patients with creatinine clearance (Clcr) over 60 mL/min . METHODS: Fifty-one adult critically ill patients treated with intravenous tobramycin with ODD were included in the study . The effect of dosing using the proposed method was compared with a weight-based (7 mg/kg) dosing method . Pharmacokinetics parameters, peak concentration (Cpeak), minimum concentration (Cmin) and the time below the minimum inhibitory concentration (MIC) were estimated using Bayesian analysis . Pharmacodynamic parameters used to evaluate both dosing regimens were Cpeak/MIC ratio and, secondly, time below MIC (T< MIC) . RESULTS: The median dose of tobramycin administrated in our hospital was too low for achieving pharmacodynamic goals . In contrast, the weight-based (7 mg/kg) method produced an adequate Cpeak/MIC ratio but an increase of the dose would not reduce the secondary pharmacodynamic index T<MIC . CONCLUSION: The results from the current study explain why weight-based daily dosing of tobramycin in critically ill patients with Clcr>60 mL/min achieved the Cpeak/MIC target values of 10 . However in critically ill patients with Clcr>80 mL/min, T<MIC is greater than the aminoglycoside post-antibiotic effect, so these patients do not attain the secondary pharmacodynamic index . These data show the need for rapid pharmacokinetic optimization with individualized aminoglycoside dosing . Additional studies are necessary to better define the best tobramycin regimen for critically ill patients. Clin Microbiol Infect, 2004 Mar, 10 Suppl 1, 11 - 23 Twelve years of fluconazole in clinical practice: global trends in species distribution and fluconazole susceptibility of bloodstream isolates of Candida; Pfaller MA et al.; We determined the species distribution and in-vitro susceptibility of 6082 bloodstream infection (BSI) isolates of Candida spp . collected from 250 medical centres in 32 nations over a 10-year period from 1992 through 2001 . The species included 3401 C . albicans, 984 C . glabrata, 796 C . parapsilosis, 585 C . tropicalis, 153 C . krusei, 67 C . lusitaniae, 48 C . guilliermondii, 10 C . famata, 10 C . kefyr, six C . pelliculosa, five C . rugosa, four C . lipolytica, three C . dubliniensis, three C . inconspicua, two C . sake and one isolate each of C . lambica, C . norvegensis and C . zeylanoides . Minimum inhibitory concentration determinations were made using the National Committee for Clinical Laboratory Standards reference broth microdilution method . Variation in the rank order and frequency of the different species of Candida was observed over time and by geographic area . The proportion of BSI due to C . albicans and C . glabrata increased and C . parapsilosis decreased over time in Canada, the USA and Europe . C . glabrata was an infrequent cause of BSI in Latin America and the Asia-Pacific region . Very little variation in fluconazole susceptibility was observed among isolates of C . albicans, C . tropicalis and C . parapsilosis . These species accounted for 78% of all BSI and remained highly susceptible (91-100% susceptible) to fluconazole from 1992 to 2001 irrespective of geographic origin . The prevalence of fluconazole resistance among C . glabrata isolates was variable both over time and among the various countries and regions . Resistance to fluconazole among C . glabrata isolates was greatest in the USA and varied by US census region (range 0-23%) . These observations are generally encouraging relative to the sustained usefulness of fluconazole as a systemically active antifungal agent for the treatment of candida BSI. Org Lett, 2004 Feb 5, 6(3), 337 - 40 Citrafungins A and B, two new fungal metabolite inhibitors of GGTase I with antifungal activity; Singh SB et al.; {structure: see text} Screening of natural products extracts led to the discovery of citrafungins A and B, two new fungal metabolites of the alkylcitrate family that are inhibitors of GGTase I of various pathogenic fungal species with IC(50) values of 2.5-15 microM . These compounds exhibited antifungal activities with MIC values of 0.40-55 microM . The isolation, structure elucidation, relative and absolute stereochemistry, and biological activities of citrafungins are described. Eur J Cardiothorac Surg, 2004 Feb, 25(2), 256 - 60 Pharmacokinetics of intravenous flucloxacillin and amoxicillin in neonatal and infant cardiopulmonary bypass surgery; Adrianzen Vargas MR et al.; OBJECTIVES: To determine the blood and tissue concentrations of flucloxacillin and amoxicillin during cardiopulmonary bypass (CPB) in infants weighing less than 5 kg . METHODS: Eleven patients aged between 3 and 60 days and weighing <5 kg . Intravenous flucloxacillin 30 mg kg(-1) and amoxicillin 30 mg kg(-1) were administered at time of anaesthesia . Blood and muscle samples were collected at four stages of the operation: immediately before commencement of CPB; before cross-clamping; after weaning of CPB; and at the time of skin closure . Concentrations, half-lives (t(1/2)), clearance and volume of distribution were calculated for both antibiotics in serum and tissue . RESULTS: After connection to CPB the mean serum concentration of flucloxacillin decreased by 42.5% from 75.5 to 43.4 mg l(-1) (P=0.003) and that of amoxicillin decreased by 36.2% from 73.3 to 46.7 mg l(-1) (P=0.021) . Serum concentrations of the two antibiotics decreased by a further 16.5 and 14.5% during the remainder of the surgery, but remained >15-fold above the expected minimum inhibitory concentration (MIC) for target pathogens . Muscle concentrations of both antibiotics reached MIC values by the time of the first sample and there was no decrease associated with connection to CPB . Levels remained >8-fold above MIC for target pathogens throughout the procedure . The t(1/2) for flucloxacillin was 2.64(+/-0.23)h and for amoxicillin was 3.16(+/-0.29)h, both of which are more than double the values in normal adults . There was an equivalent reduction in clearance for both antibiotics . CONCLUSIONS: Single doses of flucloxacillin and amoxicillin at 30 mg kg(-1) maintain serum and muscle concentrations well above the MIC throughout cardiac surgery . This is partly due to a prolonged t(1/2) and reduced clearance of both antibiotics in infants. Antimicrob Agents Chemother, 2004 Feb, 48(2), 596 - 601 Multiplex PCR amplimer conformation analysis for rapid detection of gyrA mutations in fluoroquinolone-resistant Mycobacterium tuberculosis clinical isolates; Cheng AF et al.; A new strategy known as multiplex PCR amplimer conformation was developed for detection of mutation in the gyrA gene of 138 clinical isolates of Mycobacterium tuberculosis . The method generated a single-stranded and heteroduplex DNA banding pattern of multiplex PCR amplimers of the region of interest that was extremely sensitive to specific mutations, thus enabling much more sensitive and reliable mutation analysis compared to the standard single-stranded conformation polymorphism technique . The genetic profiles of the gyrA gene of the 138 isolates as detected by MPAC were confirmed by nucleotide sequencing and were found to correlate strongly with the in vitro susceptibilities of the mutant strains to six fluoroquinolones (ofloxacin, levofloxacin, sparfloxacin, moxifloxacin, gatifloxacin, and sitafloxacin) . All 32 isolates that contained gyrA mutations exhibited cross-resistance to the six fluoroquinolones (ofloxacin MIC for 90% of strains > 16 mg/liter), although moxifloxacin, gatifloxacin, and sitafloxacin (MIC for 90% of strains </= 4 mg/liter) were apparently more active than ofloxacin, levofloxacin, and sparfloxacin (MIC for 90% of strains >/==" BORDER="0"> 16 mg/liter) . All gyrA mutations were clustered in codons 90, 91, and 94, and aspartic acid 94 was most frequently mutated . Twenty-three isolates without gyrA mutations were also found to exhibit reduced susceptibility to ofloxacin (MIC for 90% of strains = 4 mg/liter), but largely remained susceptible to other drugs (MIC for 90% of strains </= 1 mg/liter) . Another 83 isolates without mutations were fully susceptible to all six fluoroquinolones (ofloxacin MIC for 90% of strains = 1 mg/liter) . In conclusion, high-level phenotypic resistance to fluoroquinolones among M . tuberculosis clinical isolates, which appears to be predominantly due to gyrA mutations, may be readily detected by genotyping techniques such as multiplex PCR amplimer conformation. Br J Ophthalmol, 2004 Feb, 88(2), 218 - 22 An in vitro study on the compatibility and precipitation of a combination of ciprofloxacin and vancomycin in human vitreous; Hui M et al.; AIMS: To investigate the precipitation process of a mixture of vancomycin and ciprofloxacin by equilibrium dialysis and its subsequent effect on the level of available free antibiotics . METHODS: Concentrations of vancomycin and ciprofloxacin in an equilibrium dialysis chamber were measured during the equilibrium process by high performance liquid chromatography and fluorescence polarisation immunoassay . Normal saline (NS), balanced salt solution plus (BSS Plus), and vitreous were used separately as the medium of dialysis . RESULTS: Precipitation of ciprofloxacin occurred on incubation at 37 degrees C . It formed precipitate on its own or when mixed with vancomycin in all the three media of NS, BSS Plus, and vitreous . There was more precipitation at higher initial ciprofloxacin concentrations; at 25.0 mg/l about 75% free drug in BSS Plus was lost after 72 hours . The extent of precipitation was similar in both NS and BSS Plus . In the dialysis chambers, 20 mg/l ciprofloxacin dialysed against 125 mg/l vancomycin was reduced to a concentration about 5.0 mg/l after 168 hours . Precipitation of vancomycin was negligible . Ciprofloxacin precipitated in vitreous at body temperature, irrespective of the presence of vancomycin . Even after precipitation, the resultant concentration of ciprofloxacin was still higher than the MIC(90) of the drug against most Gram negative organisms . CONCLUSIONS: Based on this in vitro study, ciprofloxacin precipitated in vitreous at body temperature, irrespective of the presence of vancomycin or the medium for intravitreal injection . The resultant amount of ciprofloxacin was still higher than the MIC(90) of the drug against most Gram negative organisms after precipitation . The authors suggest ciprofloxacin in place of ceftazidime when used in combination with vancomycin for treatment of infective endophthalmitis. J Antimicrob Chemother, 2004 Feb, 53(2), 305 - 10 Epub 2004 Jan 16. Ceftriaxone acts synergistically with levofloxacin in experimental meningitis and reduces levofloxacin-induced resistance in penicillin-resistant pneumococci; Flatz L et al.; Ceftriaxone acted synergistically with levofloxacin in time-killing assays in vitro over 8 h against two penicillin-resistant pneumococcal strains (WB4 and KR4; MIC of penicillin: 4 mg/L) . Synergy was confirmed with the chequerboard method, showing FIC indices of 0.25 . In the experimental rabbit meningitis model, ceftriaxone (1x 125 mg/kg) was slightly less bactericidal (-0.30 Deltalog(10) cfu/mL(.)h) compared with levofloxacin (-0.45 Deltalog(10) cfu/mL(.)h) against the penicillin-resistant strain WB4 . The combination therapy (levofloxacin and ceftriaxone) was significantly superior (-0.64 Deltalog(10) cfu/mL(.)h) to either monotherapy . In cycling experiments in vitro, the addition of ceftriaxone at a sub-MIC concentration (1/16 MIC) reduced levofloxacin-induced resistance in the two strains KR4 and WB4 . After 12 cycles with levofloxacin monotherapy, the MIC increased 64-fold in both strains versus a 16-fold increase with the combination (levofloxacin + ceftriaxone 1/16 MIC) . In both strains, levofloxacin-induced resistance was confirmed by mutations detected in the genes parC and gyrA, encoding for subunits of topoisomerase IV and gyrase, respectively . The addition of ceftriaxone suppressed mutations in parC but led to a new mutation in parE in both strains. Lancet, 2004 Jan 10, 363(9403), 129 - 30 Serum concentrations of macrophage inhibitory cytokine 1 (MIC 1) as a predictor of miscarriage; Tong S et al.; Macrophage inhibitory cytokine 1 (MIC 1) is thought to have immunomodulatory actions favouring fetal viability . We measured serum concentrations of MIC 1 in asymptomatic women at 6-13 weeks' gestation who subsequently miscarried or who had already miscarried . MIC 1 concentrations in the miscarriage cohort (n=100), were a third of those who had ongoing pregnancies (n=197) . Multiples of the median for miscarriage was 0.32 (95% CI 0.23-0.32) versus 1.00 (0.93-1.06) for ongoing pregnancies; p<0.0001 . Concentrations were just as low 3 weeks before diagnosis as on the day of diagnosis . That MIC 1 serum concentrations seem to be low weeks before miscarriage suggests possible predictive and causative roles, as well as therapeutic potential. Di Yi Jun Yi Da Xue Xue Bao, 2004 Jan, 24(1), 57 - 8 {Experimental study of the effect of Astragalus membranaceus against herpes simplex virus type 1}; Sun Y et al.; OBJECTIVE: To study the inhibitory effects of Astragalus membranaceus on herpes simplex virus type 1(HSV-1) . METHODS: In the 2BS cells infected with HSV-1, the antiviral effect of Astragalus membranaceus decoction was investigated by observing the inhibition of HSV-1-induced cytopathic effect in response to treatment with the decoction . RESULTS: The half inhibition concentration (IC50) and minimal inhibition concentration (MIC) of Astragalus membranaceus were 0.98 and 1.95 g/ml respectively, with the therapeutic index (TI) of 128 . CONCLUSION: Astragalus membranaceus has obvious HSV-1-inhibiting efficacy and low cytotoxicity. Antibiot Khimioter, 2003, 48(8), 3 - 6 {Screening of natural immunosuppressors by their ability to modify steroid synthesis in hepatocytes}; Bibikova MV et al.; In the programme for screening sterol synthesis inhibitors with the use of actinomycetes and fungi 702 strains were tested . The effect of alcohol extracts of the mycelium of fungi and actinomycetes at a dilution of 1/10(3) on sterol synthesis by the Hep G2 hepatome cells was determined by incorporation of 3H acetate into sterols and proteins . Lovastatin (200 pg/ml) was used as the control: the sterol synthesis was decreased by 49 +/- 4% without inhibiting the protein synthesis . A number of the cultures produced compounds inhibiting under the experimental conditions the synthesis of sterols by 70 to 80% with simultaneous inhibition of the protein synthesis at least by 60 to 70% . Three compounds from that group produced by streptomycetes were subjected to a more detailed investigation . The compounds were demonstrated to be active antifungal antibiotics (MIC 0.1-1 mcg/ml) . In a dose of 0.1-1 mcg/ml they showed high immunosuppressive activity in models of lymphocyte transformation in mice, whereas cyclosporin was active in a dose of 1 mcg/ml . Therefore, the model for screening hypolipidemic compounds could be considered useful for screening promising natural immunosuppressors. Arch Ophthalmol, 2004 Jan, 122(1), 42 - 7 Determination of vitreous, aqueous, and plasma concentration of orally administered voriconazole in humans; Hariprasad SM et al.; OBJECTIVE: To investigate the penetration of voriconazole, a new-generation triazole antifungal agent, into the vitreous and aqueous humor after oral administration . METHODS: A prospective, nonrandomized clinical study included 14 patients scheduled for elective pars plana vitrectomy surgery between December 1, 2002, and February 28, 2003, at the Cullen Eye Institute, Houston, Tex . Aqueous, vitreous, and plasma samples were obtained and analyzed from 14 patients after oral administration of two 400-mg doses of voriconazole taken 12 hours apart before surgery . Assays were performed by means of high-performance liquid chromatography . RESULTS: Mean +/- SD voriconazole concentrations in plasma (n = 14), vitreous (n = 14), and aqueous (n = 11) were 2.13 +/- 0.93 microg/mL, 0.81 +/- 0.31 microg/mL, and 1.13 +/- 0.57 microg/mL, respectively . Mean +/- SD sampling times after oral administration of the second voriconazole dose for plasma, vitreous, and aqueous were 2.4 +/- 0.6 hours, 3.0 +/- 0.5 hours, and 2.9 +/- 0.5 hours, respectively . The percentages of plasma voriconazole concentration achieved in the vitreous and aqueous were 38.1% and 53.0%, respectively . Mean vitreous and aqueous minimum inhibitory concentrations for 90% of isolates (MIC(90)) were achieved against a wide spectrum of yeasts and molds, including Aspergillus species and Candida species, along with many other organisms . CONCLUSIONS: Orally administered voriconazole achieves therapeutic aqueous and vitreous levels in the noninflamed human eye, and the activity spectrum appears to appropriately encompass the most frequently encountered mycotic species involved in the various causes of fungal endophthalmitis . Because of its broad spectrum of coverage, low MIC(90) levels for the organisms of concern, good tolerability, and excellent bioavailability with oral administration, it may represent a major advance in the prophylaxis or management of exogenous or endogenous fungal endophthalmitis. Microbiol Res, 2003, 158(4), 271 - 9 Efficiency of procedures for induction and cultivation of Pseudomonas syringae pv . pisi L-form; Elvira-Recuenco M et al.; The L-form of Pseudomonas syringae pv . phaseolicola has been proved to induce resistance to bean halo blight . Various procedures were tested to induce the L-form of Pseudomonas syringae pv . pisi for its potential use as biocontrol agent of pea bacterial blight . Cell-wall deficient cells were induced in a liquid medium with penicillin following a protocol described for P . s . pv . phaseolicola . Cell growth on solid induction medium developed as typical granular and vacuolated structures, and characteristic colonies were observed in the first transfer . However, there was poor growth in subsequent transfers and some reversion to the parental type . To improve the induction procedure, the following new procedures were applied: (1) viability of cells was monitored during induction . The optimum induction time in liquid medium with penicillin was lower for pv . pisi than for pv . phaseolicola . Viability of L-forms in solid induction medium with penicillin was low and decreased in time . (2) the inducer ticarcillin was combined with clavulanic acid, which prevented the reversion to the parental type and (3) a range of concentrations of penicillin and ticarcillin/clavulanic acid was applied by the spiral gradient endpoint method for calculation of minimum inhibitory concentrations (MIC) . Based on the results from these tests an induction method for P . s . pv . pisi L-form is proposed and the relevance of L-form is discussed for practice. Sheng Wu Yi Xue Gong Cheng Xue Za Zhi, 2003 Dec, 20(4), 664 - 7 {Study on infiltration glass for machinable-infiltrated-ceramic and on its colorants}; Yang X et al.; In order to develop tinted infiltration glass and its colorants, which can make the ceramic have good spectrum transmittance, color space, color stability and be suitable for clinical use, we selected the best prescription and confirm the ingredient and content of the colorants . Molten glass was prepared in Al2O3 crucible by heating the components to 1420 degrees C for 2 hours . The refractive index and thermal stability of the glass were investigated . The refractive index of the MIC infiltration glass was 1.5969(587.6 nm, nd) . It was close to the index of aluminous matrix 1.759(546.07 nm, ne), which increased the spectrum transmittance of MIC . The thermal expansion coefficient of the glass was 7.565 microns/m/degree C, which was compatible with the thermal expansion coefficient of aluminous matrix(8.214 microns/m/degree C) . This study proved that the tinted infiltration glass has good color stability, spectrum transmittance, and thermal expansion properties. Infect Dis Clin North Am, 2003 Sep, 17(3), 503 - 28, v Pharmacodynamics and dosing of aminoglycosides; Turnidge J; Aminoglycosides are concentration-dependent killing agents whose pharmacodynamic predictors of efficacy are the area-under-the-curve to minimum inhibitory concentration ratio and the peak to minimum inhibitory concentration ratio . Prospective studies have shown that these agents can be given once-daily or less frequently in most clinical settings, with equal efficacy and possible reduced toxicity . Dosages for different clinical settings have been studied and methods are available to monitor once-daily dosing. Ter Arkh, 2003, 75(11), 42 - 6 {Use of affinity interaction of biologically active substances in practice of public health system}; Pokrovskii VI et al.; AIM: To determine the potentialities of use of affinity interaction of immobilized biologically active substances (bacterial cells or their fragments, toxins, antigens of various chemical nature, immunoglobulins, enzymes, gangliosides, etc.) for medical practice . MATERIALS AND METHODS: Emulsion polymerization of acrylamide monomers in the gaseous nitrogen current was used as a basic method for preparation of solid-phase magnetic immunosorbents (MIC) . A procedure for preparation of siliceous MIC was also applied . The prepared MICs were used a solid phase in enzyme immunoassay and immunofluorescence assay and the recorded data were compared with those of studied conventionally used in practical medicine . RESULTS: The use of MIC made it possible to detect pathogens of particularly dangerous infections in large volumes of the samples contaminated with another microflora . With the proposed MIC, one can stand a good chance of surveying large contingents of the population, of obtaining the quantitative results in shorter periods to establish a diagnosis . With this, the sensitivity and specificity of immunoassays substantially increase . Whether MIC may be used as selective hemosorbents to remove specific antibodies from the blood of patients with rheumatic diseases for therapeutic purposes was studied . CONCLUSION: The findings are indicative of wide potentialities of use of affinity interaction of biologically active substances immobilized on inert carriers with the inserted magnetic material in the laboratory diagnosis of diseases of both infectious and autoimmune nature, which may be widely used in the in- and outpatient settings. Perit Dial Int, 2003 Nov-Dec, 23(6), 574 - 9 Pharmacokinetics of ceftazidime in CAPD-related peritonitis; Booranalertpaisarn V et al.; OBJECTIVE: The aim of this study was to measure and evaluate the appropriateness of the actual concentrations of serum and dialysate ceftazidime in Thai continuous ambulatory peritoneal dialysis (CAPD) patients . DESIGN: Prospective and descriptive study of patients treated following the International Society for Peritoneal Dialysis (ISPD) 2000 recommendation for the empiric therapy of CAPD-related peritonitis . SETTING: Institutional level of clinical care . PATIENTS: CAPD-related peritonitis patients were diagnosed by dialysate effluent white blood cell count of more than 100/mm3 and polymorphonuclear leukocytes of at least 50% . There were 10 patients, all at least 18 years of age, entered; all completed the study . INTERVENTION: In accordance with the ISPD 2000 recommendations, the antibiotic regimen comprised continuous intraperitoneal (i.p.) cefazolin and once-daily i.p . ceftazidime . Cefazolin was administered as loading and continuous maintenance doses of 500 and 125 mg/L dialysate respectively . Ceftazidime (20 mg/kg body weight) was given i.p . once daily . Duration of treatment was 96 hours . MAIN OUTCOME MEASURES: Serum and dialysate effluent samples of the 10 CAPD patients with peritonitis were measured for ceftazidime levels, which were used for the development of pharmacokinetic equations that could predict drug concentrations at any treatment time . RESULTS: Following ceftazidime administration as in the ISPD 2000 recommendation, serum ceftazidime levels were above 8 microg/mL, the minimum inhibitory concentration (MIC) recommended by NCCLS, throughout 24 hours . Dialysate ceftazidime levels were below the MIC for total periods of 4.19 and 6.26 hours in day 1 and day 4 respectively . The clinical response rate to the empiric regimen was 90% . CONCLUSIONS: Once-daily i.p . administration of ceftazidime according to the ISPD 2000 recommendation could not provide adequately therapeutic levels of ceftazidime in dialysate throughout 24 hours . Despite this finding and the poor post-antibiotic property of ceftazidime, the empiric regimen including once-daily i.p . ceftazidime could yield good clinical outcome. Transplant Proc, 2003 Dec, 35(8), 2873 - 7 Beneficial pharmacokinetic interaction between cyclosporine and itraconazole in renal transplant recipients; Florea NR et al.; BACKGROUND: Itraconazole is often given for fungal prophylaxis to renal transplant recipients, who require concomitant cyclosporine in the immediate posttransplant period . We determined the extent of the pharmacokinetic interaction between cyclosporine and itraconazole oral solution in renal transplant recipients and the effect on daily drug costs . METHOD: This was a single-center, open-label, nonrandomized study . Posttransplantation, renal transplant recipients received itraconazole solution 200 mg twice daily and cyclosporine, dosed to achieve target concentrations . Once at steady state, blood samples were collected over 12 hours for pharmacokinetic evaluation of cyclosporine, itraconazole, and hydroxy-itraconazole . Itraconazole was discontinued after approximately a 3-month prophylaxis regimen . Cyclosporine doses were titrated to achieve target concentrations and cyclosporine concentrations were once again determined when steady state was achieved . A noncompartmental analysis was used to analyze cyclosporine pharmacokinetic parameters . The pharmacoeconomic impact was measured based on the percent change in dose of cyclosporine when administered with and without itraconazole . Drug costs were calculated using the average wholesale price . The cost per patient, as well as the average cost, was calculated for the cyclosporine/itraconazole combination, as well as the cyclosporine regimen alone . RESULTS: Eight renal transplant recipients completed the study . All were included for itraconazole analyses and seven for cyclosporine analyses . Mean peak and trough itraconazole levels were 1.64 +/- 0.82 and 1.23 +/- 0.90 microg/mL respectively . Mean peak and trough hydroxy-itraconazole levels were 2.37 +/- 1.55 and 2.20 +/- 1.48 microg/mL, respectively . While on itraconazole, a 48% reduction in the mean total daily dose of cyclosporine was necessary to maintain target concentrations (171 +/- 63.6 versus 329 +/- 103.5 mg, P =.003) . This reduction in cyclosporine dose resulted in a discounted itraconazole daily drug cost of approximately 29.5% . CONCLUSION: Administering itraconazole with cyclosporine allows for a decrease in the cyclosporine dose, thus lowering daily drug costs and providing adequate antifungal coverage with itraconazole and hydroxy-itraconazole trough concentrations above the MIC(90) of Candida and Aspergillus spp. Am J Chin Med, 2003, 31(5), 751 - 61 The evaluation of Chinese herbal medicine effectiveness on periodontal pathogens; Chan Y et al.; The aim of this study was to evaluate the effects of herbal medicines in treating periodontal diseases . Three Chinese herbal composites {Conth Su (CS), Chi Tong Ning (CTN) and Xi Gua Shuang (XGS)}, widely used for prevention and treatment of periodontal diseases, and the major components of these composites were tested for their ability to: (1) alleviate disease progression of experimental periodontitis in hamsters, (2) inhibit bacterial growth, and (3) induce mutations . Our results indicate that in treating experimental periodontitis, there were no significant differences between the animal groups with or without the use of Chinese herbal medicines in terms of the degree of inflammation, alveolar bone resorption, and rate of repair . However, hamsters treated with CS presented earlier regenerative epithelium . CTN demonstrated superior bacterial inhibition ability among all tested herbs (MIC 0.025 g/ml); CS showed good anti-bacterial abilities at a concentration of 0.05 g/ml . It is interesting to note that while both CS and CTN were capable of inhibiting bacterial growth, none of the individual herb components showed comparable bacterial inhibition abilities . None of the tested herbal composites or their components showed signs of inducing cell mutations using the Ames test . These results indicated that traditional Chinese herbal medicines, which have been used to treat periodontal diseases for hundreds of years by Chinese people, can effectively inhibit bacterial growth without causing cell mutation . Further investigation into their possible clinical applications in periodontal therapy is encouraged. J Med Chem, 2004 Jan 1, 47(1), 273 - 6 Antimycobacterial agents . 1 . Thio analogues of purine; Pathak AK et al.; Thio analogues of purine, pyridine, and pyrimidine were prepared based on the initial activity screening of several analogues of these heterocycles against Mycobacterium tuberculosis (Mtb) . Certain 6-thio-substituted purine analogues described herein showed moderate to good inhibitory activity . In particular, two purine analogues 9-(ethylcarboxymethyl)-6-(decylthio)-9H-purine (20) and 9-(ethylcarboxymethyl)-6-(dodecylthio)-9H-purine (21) exhibited MIC values of 1.56 and 0.78 microg/mL respectively against the Mtb H(37)Rv strain . N(9)-Substitution apparently enhances the antimycobacterial activity in the purine series described herein. Antimicrob Agents Chemother, 2004 Jan, 48(1), 344 - 7 Comparison of in vitro activities of ketolides, macrolides, and an azalide against the spirochete Borrelia burgdorferi; Hunfeld KP et al.; Two ketolides, three macrolides, and one azalide were tested in vitro against 17 isolates of the B . burgdorferi s.l . complex . As measured in micrograms per milliliter, activity was highest for cethromycin (MIC at which 90% of the tested isolates were inhibited {MIC(90)}, 0.0019 micro g/ml) and telithromycin (MIC(90), 0.0078 micro g/ml) . Electron-microscope analysis and time-kill studies also supported enhanced effectiveness of both ketolides. Crit Rev Oncol Hematol, 2003 Dec, 48(3), 251 - 61 Microinvasive squamous cell cervical carcinoma; Raspagliesi F et al.; Several histologic tumor-related features are the key factors for further treatment planning in microinvasive cervical cancer (MIC) after conization . To better define the indications for conservative treatment of MIC we conducted a literature review for prognostic factors for MIC and we carried out a prospective observational study evaluating most important pathologic factors and the relationships between tumor and edges of the cone and incidence of recurrences . In our experience seven recurrences were observed . Two distinct groups of patients were identified with a clearance lower or higher of 10 and 8 mm for apical and lateral margin respectively . Depth of infiltration and even lymph-vascular involvement have been confirmed as the most important histologic parameters to be evaluated . Apical and lateral clearance of the tumor are significantly correlated with the recurrence rate . If an adequate lateral border of healthy tissue is present on the specimen, conization may be considered as definitive treatment of MIC. J Antimicrob Chemother, 2004 Feb, 53(2), 185 - 91 Epub 2003 Dec 19. Design and synthesis of antituberculars: preparation and evaluation against Mycobacterium tuberculosis of an isoniazid Schiff base; Hearn MJ et al.; OBJECTIVES: Enzymatic acetylation of the antitubercular isoniazid (INH) by N-acetyltransferase represents a major metabolic pathway for INH in human beings . Acetylation greatly reduces the therapeutic activity of the drug, resulting in underdosing, decreased bioavailability and acquired INH resistance . Chemical modification of INH with a functional group that blocks acetylation, while maintaining strong antimycobacterial action, may improve clinical outcomes and help reduce the rise of INH resistance . The goal of this study was to probe activities, toxicity and bioavailability of an investigational compound prepared by this chemical modification . METHODS: The investigational compound was chosen from a cohort of lipophilic antitubercular INH Schiff bases based on its strong activity in primary assays . The compound was evaluated in vitro, in vivo in mice, in mutagenicity tests and in rats for bioavailability . RESULTS: The INH Schiff base acts against both intracellular and extracellular organisms in vitro, with a wide range between active and cytotoxic concentrations . The material is active against non-tubercular mycobacteria . The INH Schiff base is non-mutagenic in the Ames test and has excellent bioavailability in Sprague-Dawley rats, achieving early peak plasma concentrations approximately three orders of magnitude above its MIC when administered orally . In tuberculosis-infected mice the compound is well tolerated and in a 4 week study provides 3 log cfu reduction in spleens and 4 log cfu reduction in lungs . CONCLUSION: The results demonstrate that investigational compounds in which N-acetylation of INH is blocked by chemical modification can display strong activity, low toxicity and excellent bioavailability, making them suitable for further exploration. Ann N Y Acad Sci, 2003 Nov, 1005, 310 - 3 MIC-A genotypes 4/5.1 and 9/9 are positively associated with type 1 diabetes mellitus in Brazilian population; Tica V et al.; The aim of our study was to evaluate the frequencies of MIC-A alleles and genotypes in Brazilian patients with type 1 diabetes mellitus (T1DM) and healthy controls . MHC class I chain-related gene-A (MIC-A) has been shown to be associated with susceptibility to T1DM in different populations . We analyzed the DNA samples from 86 patients and 201 healthy controls for MIC-A by PCR amplification, and fragment sizes were determined in an ABI prism DNA sequencer . We found increased frequencies of two genotypes, MIC-A 4/5.1 (pc = 0.006; OR, 6.1) and 9/9 (pc = 0.045; OR, 5.75), in our patients (mean diagnosis age, 11.70 years; SD, 8.86; mean age, 20.44 years; SD, 12.17) compared with the controls (median age, 26.41 years; SD, 8.87). J Eur Acad Dermatol Venereol, 2004 Jan, 18(1), 73 - 8 Antifungal activity of Thymus oils and their major compounds; Pina-Vaz C et al.; The increasing recognition and importance of fungal infections, the difficulties encountered in their treatment and the increase in resistance to antifungals have stimulated the search for therapeutic alternatives . Essential oils have been used empirically . The essential oils of Thymus (Thymus vulgaris, T . zygis subspecies zygis and T . mastichina subspecies mastichina) have often been used in folk medicine . The aim of the present study was to evaluate objectively the antifungal activity of Thymus oils according to classical bacteriological methodologies - determination of the minimal inhibitory concentration (MIC) and the minimal lethal concentration (MLC) - as well as flow cytometric evaluation . The effect of essential oils upon germ tube formation, an important virulence factor, was also studied . The mechanism of action was studied by flow cytometry, after staining with propidium iodide . The chemical composition of the essential oils was investigated by gas chromatography (GC) and gas chromatography/mass spectroscopy (GC/MS) . The antifungal activity of the major components (carvacrol, thymol, p-cymene and 1,8-cineole) and also possible interactions between them were also investigated . The essential oils of T . vulgaris and T . zygis showed similar antifungal activity, which was greater than T . mastichina . MIC and MLC values were similar for all the compounds tested . At MIC values of the essential oils, propidium iodide rapidly penetrated the majority of the yeast cells, indicating that the fungicidal effect resulted primarily from an extensive lesion of the cell membrane . Concentrations below the MIC values significantly inhibited germ tube formation . This study describes the potent antifungal activity of the essential oils of Thymus on Candida spp., warranting future therapeutical trials on mucocutaneous candidosis. J Appl Microbiol, 2004, 96(1), 201 - 8 Cross-resistance to antibiotics of Escherichia coli adapted to benzalkonium chloride or exposed to stress-inducers; Langsrud S et al.; AIMS: To study the effects of adaptation and stress on the resistance to benzalkonium chloride (BC) and cross-resistance to antibiotics in Escherichia coli . METHODS AND RESULTS: Precultivation of E . coli ATCC 11775 and E . coli DSM 682 in the presence of subinhibitory concentrations of BC or stress inducers (salicylate, chenodeoxycholate and methyl viologen) resulted in higher minimum inhibitory concentration (MIC) of BC and chloramphenicol (CHL) . Adaptation to growth in sixfold of the initial MIC of BC resulted in stable BC resistance and enhanced tolerance to several antibiotics and ethidium bromide (EtBr) . The MIC of CHL increased more than 10-fold for both strains . Enhanced efflux of EtBr in adapted E . coli ATCC 11775 indicated that the observed resistance was due to efflux . Changes in outer membrane protein profiles were detected in the BC-adapted cells . There were no indications of lower membrane permeability to BC . CONCLUSIONS: Induction of stress response or gradual adaptation to BC or CHL results in acquired cross-tolerance between BC and antibiotics in E . coli . Enhanced efflux was one of the observed differences in adapted cells . SIGNIFICANCE AND IMPACT OF THE STUDY: Provided not taking due precautions, extensive use of disinfectants could lead to emergence of antibiotic-resistant isolates. Clin Pharmacokinet, 2003, 42(15), 1411 - 23 Clinical pharmacodynamics of linezolid in seriously ill patients treated in a compassionate use programme; Rayner CR et al.; OBJECTIVE: To characterise the pharmacokinetic-pharmacodynamic relationships for linezolid efficacy . DESIGN AND STUDY POPULATION: Retrospective nonblinded analysis of severely debilitated adult patients with numerous comorbid conditions and complicated infections enrolled under the manufacturer's compassionate use programme . METHODS: Patients received intravenous or oral linezolid 600 mg every 12 hours . Plasma concentrations were obtained and a multicompartmental pharmacokinetic model was fitted . Numerical integration of the fitted functions provided the area under the concentration-time curve over 24 hours (AUC), the ratio of AUC to minimum inhibitory concentration (AUC/MIC) and the percentage of time that plasma concentrations exceeded the MIC (%T>MIC) . MAIN OUTCOME MEASURES: Modelled pharmacodynamic outcomes of efficacy included probabilities of eradication and clinical cure (multifactorial logistic regression, nonparametric tree-based modelling, nonlinear regression) and time to bacterial eradication (Kaplan-Meier and Cox proportional hazards regression) . Factors considered included AUC/MIC, %T>MIC, site of infection, bacterial species and MIC, and other medical conditions.RESULTS: There were 288 cases evaluable by at least one of the efficacy outcomes . Both %T>MIC and AUC/MIC were highly correlated (Spearman r2 = 0.868) . In our analyses, within specific infection sites, the probability of eradication and clinical cure appeared to be related to AUC/MIC (eradication: bacteraemia, skin and skin structure infection {SSSI}, lower respiratory tract infection {LRTI}, bone infection; clinical cure: bacteraemia, LRTI) and %T>MIC (eradication: bacteraemia, SSSI, LRTI; clinical cure: bacteraemia, LRTI) . Time to bacterial eradication for bacteraemias appeared to be related to the AUC, %T>MIC and AUC/MIC . For most sites, AUC/MIC and %T>MIC models performed similarly . CONCLUSIONS: Higher success rates for linezolid may occur at AUC/MIC values of 80-120 for bacteraemia, LRTI and SSSI . Chance of success in bacteraemia, LRTI and SSSI also appear to be higher when concentrations remain above the MIC for the entire dosing interval. Chemotherapy, 2003 Dec, 49(6), 280 - 6 Correlation of meropenem plasma levels with pharmacodynamic requirements in critically ill patients receiving continuous veno-venous hemofiltration; Krueger WA et al.; BACKGROUND: In patients with acute renal failure, the pharmacokinetics of meropenem depend on the operational characteristics of the renal replacement therapy . Dosage recommendations are based on the correlation of plasma levels with pharmacodynamic requirements . METHODS: Eight critically ill patients with acute renal failure were treated by continuous veno-venous hemofiltration with a filtrate flow of 1,600 ml/h and received 500 mg of meropenem every 12 h . Plasma and hemofiltrate concentrations of meropenem at steady state were determined by HPLC . RESULTS: Peak levels in plasma amounted to 39.5 +/- 10.5 mg/l (mean +/- SD) and trough levels were 2.4 +/- 1.5 mg/l . The minimal inhibitory concentration (MIC) for susceptible bacteria (4 mg/l) was covered for 40% of the dosing interval or longer in all patients . The MIC for intermediately susceptible organisms (8 mg/l) was covered for 33% in 6 of the 8 patients . The elimination half-life was prolonged to 3.63 +/- 0.77 h . The sieving coefficient of meropenem was 0.91 +/- 0.10 and the recovery in hemofiltrate amounted to 30.9 +/- 11.5% of the dose . CONCLUSIONS: A dosage of 500 mg twice daily provides appropriate serum levels for the treatment of infections caused by susceptible bacteria . A higher dosage is adequate for infections by intermediately susceptible bacteria or for renal replacement therapies with markedly higher filtrate flow rates . Tuberculosis (Edinb), 2004, 84(1-2), 56 - 62 Susceptibility of Mycobacterium tuberculosis to isoniazid and its derivative, 1-isonicotinyl-2-nonanoyl hydrazine: investigation at cellular level; Mohamad S et al.; In this study, the susceptibility of Mycobacterium tuberculosis to isoniazid (INH) was compared with its derivative, 1-isonicotinyl-2-nonanoyl hydrazine (INH-C9), prepared synthetically . The minimum inhibitory concentration (MIC) of the drugs was determined using the 1% proportion method . INH-C9 was found to lower the MIC of INH from 0.05 to 0.025 microg/ml . Further studies on the effects of INH and INH-C9 on M . tuberculosis were assessed by exposing the cells to the above at the MIC level . M . tuberculosis cells grown on Middlebrook 7H10 agar were harvested at different stages of their growth cycle (initial stage, 24 and 72 h), exposed to the MICs of INH and INH-C9, and stained with acid-fast staining . The observations were made for a week . The cellular morphologies and staining characteristics were examined using a Brightfield microscope . The result indicated cells only at the initial stage of growth were most susceptible to the drugs resulting in the loss of acid-fastness and intact cellular morphology in the majority of cells. Immunity, 2003 Dec, 19(6), 803 - 12 Thermodynamic analysis of degenerate recognition by the NKG2D immunoreceptor: not induced fit but rigid adaptation; McFarland BJ et al.; The homodimeric immunoreceptor NKG2D drives the activation of effector cells following engagement of diverse, conditionally expressed MHC class I-like protein ligands . NKG2D recognition is highly degenerate in that a single surface on receptor monomers binds pairs of distinct surfaces on each structurally divergent ligand, simultaneously accommodating multiple nonconservative ligand allelic or isoform substitutions . In contrast to TCR-pMHC and other NK receptor-ligand interactions, thermodynamic and kinetic analyses of four NKG2D-ligand pairs (MIC-A*001, MIC-B*005, ULBP1, and RAE-1beta) reported here show that the relative enthalpic and entropic terms, heat capacity, association rates, and activation energy barriers are comparable to typical, rigid protein-protein interactions . Rather than "induced-fit" binding, NKG2D degeneracy is achieved using distinct interaction mechanisms at each rigid interface. Angiology, 2003 Nov-Dec, 54(6), 671 - 8 The degree of albuminuria is related to left ventricular hypertrophy in hypertensive diabetics and is associated with abnormal left ventricular filling: a pilot study; Salmasi AM et al.; The association of albuminuria and left ventricular (LV) hypertrophy (LVH) in diabetics aggravates the prognosis . The authors studied the relation between LVH and the degree of albuminuria in diabetics and investigated the relationship of albuminuria to LV filling . A comparison was made between 30 hypertensive diabetics, 10 of whom had microalbuminuria (MIC) and 20 had macroalbuminuria (MAC), and 18 diabetics who were normotensive and normalbuminuric (NOR) . LV mass index (LVMI) and LV ejection fraction (LVEF) were measured during echocardiography . LV filling pattern at rest and at peak standardized isometric exercise (IME) using handgrip was assessed by measuring E/A (peak velocity of the early/atrial filling waves) of the transmitral flow during Doppler and echocardiography . Each patient underwent a stress ECG test . LVMI was higher in MAC (132.3 +/- 55.4) than in MIC (115.6 +/- 32.5) or NOR (90.0 +/- 31.8) (p<0.01) . There were more patients in MAC with LVH (n = 13) and abnormal filling (n = 9 at rest and 16 with IME) than in MIC (LVH = 5, abnormal filling = 1 at rest and 10 during IME) or NOR (LVH = 3, abnormal filling = 1 at rest and 9 during IME) (p < 0.02) . LVMI was not related to LVEF . Although blood pressure was not different between MAC and MIC groups, it was significantly higher than in the NOR group . This study suggests that a high degree of albuminuria in hypertensive diabetics is associated with greater value for LVMI and an increased incidence of LVH independent of blood pressure level or systolic LV function . LVH is associated with abnormal LV filling . The degree of albuminuria may predict LVMI and LVH, which are associated with abnormal LV filling . This association of abnormal LV filling with albuminuria in hypertensive diabetic patients may account for their high risk of cardiovascular events. Anticancer Res, 2003 Sep-Oct, 23(5A), 3699 - 702 Ginger (Zingiber officinale Roscoe) and the gingerols inhibit the growth of Cag A+ strains of Helicobacter pylori; Mahady GB et al.; BACKGROUND: Ginger root (Zingiber officinale) has been used traditionally for the treatment of gastrointestinal ailments such as motion sickness, dyspepsia and hyperemesis gravidarum, and is also reported to have chemopreventative activity in animal models . The gingerols are a group of structurally related polyphenolic compounds isolated from ginger and known to be the active constituents . Since Helicobacter pylori (HP) is the primary etiological agent associated with dyspepsia, peptic ulcer disease and the development of gastric and colon cancer, the anti-HP effects of ginger and its constituents were tested in vitro . MATERIALS AND METHODS: A methanol extract of the dried powdered ginger rhizome, fractions of the extract and the isolated constituents, 6-,8-,10-gingerol and 6-shogoal, were tested against 19 strains of HP, including 5 CagA+ strains . RESULTS: The methanol extract of ginger rhizome inhibited the growth of all 19 strains in vitro with a minimum inhibitory concentration range of 6.25-50 micrograms/ml . One fraction of the crude extract, containing the gingerols, was active and inhibited the growth of all HP strains with an MIC range of 0.78 to 12.5 micrograms/ml and with significant activity against the CagA+ strains . CONCLUSION: These data demonstrate that ginger root extracts containing the gingerols inhibit the growth of H . pylori CagA+ strains in vitro and this activity may contribute to its chemopreventative effects. J Agric Food Chem, 2003 Dec 17, 51(26), 7596 - 9 Antifungal activity of some essential oils; Sridhar SR et al.; Thirteen essential oils recovered by steam distillation from Indian herbs were analyzed for their chemical compositions using GC and GCMS . The antifungal activity against plant and Food mold rot were examined in vitro using poison food technique . The essential oil from cymbopogan exhibited control over all the plant and food mold rot tested . The bioactive compound in the oil and its minimum inhibitory concentration were determined using TLC bioautography. Klin Med (Mosk), 2003, 81(10), 17 - 9 {Daily blood pressure profile in patients with hypertensive encephalopathy}; Mashin VV et al.; The purpose of the study was to study daily variations of blood pressure (BP) in patients with hypertensive encephalopathy (HE) . Daily BP monitoring (DBPM) was made in 100 patients with different stages of HE . In HE, a proportion of patients from a non-dippers group substantially increased . An excessive nocturnal reduction in systolic BP (SBP) was more common . A dippers group was predominant in the controls . The daily index for SBP significantly decreased in patients with stage I HE; that for diastolic BP (DBP) reduced in those with stages I-II HE . The morning increase rate (MIC) of BP was studied . MIC of SBP was higher in patients with HE, which was most commonly observed in the non-dippers group . There was a more significant reduction in DBP in combination with high MIC in 10% of the examinees. J Clin Microbiol, 2003 Dec, 41(12), 5729 - 31 Caspofungin activity against clinical isolates of fluconazole-resistant Candida; Pfaller MA et al.; A total of 7,837 clinical isolates of Candida were tested against fluconazole, and 351 resistant (fluconazole MIC >/=64 micro g/ml) isolates were identified (4% of the total tested) . All fluconazole-resistant isolates were inhibited by caspofungin at concentrations that can be exceeded by standard doses (MIC at which 90% of the isolates were inhibited, 1 micro g/ml; 99% of the MICs were </=2 micro g/ml). J Clin Microbiol, 2003 Dec, 41(12), 5683 - 8 New methods to assess susceptibilities of Aspergillus isolates to caspofungin; Imhof A et al.; Echinocandins are a group of antifungal agents that target 1,3-beta-glucan synthase, causing disruption of mold growth at cells compromising tips and branch points . In part because echinocandins do not induce clear growth inhibition end points using broth dilution techniques, methods to test susceptibility have not yet been standardized . We developed a novel susceptibility assay that measures growth of Aspergillus species on solid agar media that contain serial dilutions of caspofungin (agar dilution) . Results of agar dilution testing of multiple isolates were compared to results obtained by broth microdilution (MIC), microscopic evaluation (minimal effective concentration {MEC}), and a new method to measure fungal burden, quantification of secreted hyphal antigen . MICs obtained by the agar dilution method were within 1 dilution of MECs for 85% of the Aspergillus isolates; the highest agreement was observed for isolates of Aspergillus niger (95%), which were particularly susceptible to caspofungin . Agar dilution MICs were also consistent with those obtained by quantifying antigen secretion . MICs obtained by broth microdilution were different than MICs by any other method . Several Aspergillus isolates with decreased susceptibility to caspofungin were identified . Agar dilution is simple and reproducible, and results were consistent with the results of more technically demanding techniques . This method may be appropriate for use in the clinical laboratory. J Immunol, 2003 Dec 15, 171(12), 6891 - 9 Evasion from NK cell immunity by MHC class I chain-related molecules expressing colon adenocarcinoma; Doubrovina ES et al.; Evasion of host immune responses is well documented for viruses and may also occur during tumor immunosurveillance . The mechanisms involve alterations in MHC class I expression, Ag processing and presentation, chemokine and cytokine production, and lymphocyte receptor expression . Epithelial tumors overexpress MHC class I chain-related (MIC) molecules, which are ligands for the activating receptor NKG2D on NK and T cells . We report that NK cells from patients with colorectal cancer lack expression of activating NKG2D and chemokine CXCR1 receptors, both of which are internalized . Serum levels of soluble MIC (sMIC) are elevated and are responsible for down-modulation of NKG2D and CXCR1 . In contrast, high serum levels of CXC ligands, IL-8, and epithelial-neutrophil-activating peptide (ENA-78) do not down-modulate CXCR1 . In vitro, internalization of NKG2D and CXCR1 occurs within 4 and 24 h, respectively, of incubating normal NK cells with sMIC-containing serum . Furthermore, natural cytotoxicity receptor NKp44 and chemokine receptor CCR7 are also down-modulated in IL-2-activated NK cells cocultured in MIC-containing serum-an effect secondary to the down-modulation of NKG2D and not directly caused by physical association with sMIC . The patients' NK cells up-regulate expression of NKG2D, NKp44, CXCR1, and CCR7 when cultured in normal serum or anti-MIC Ab-treated autologous serum . NKG2D(+) but not NKG2D(-) NK cells are tumoricidal in vitro, and in vivo they selectively traffic to the xenografted carcinoma, form immunological synapse with tumor cells, and significantly retard tumor growth in the SCID mice . These results suggest that circulating sMIC in the cancer patients deactivates NK immunity by down-modulating important activating and chemokine receptors. Dermatology, 2003, 207(4), 375 - 80 Evaluation of in vitro resistance in patients with onychomycosis who fail antifungal therapy; Gupta AK et al.; BACKGROUND: With the increased awareness of onychomycosis and the increasing use of antifungals for this indication, it is prudent to be concerned about the possible emergence of resistant strains . There has been substantial work on the development of standardized methods for testing the in vitro resistance of various fungi and yeasts to the currently available antifungal agents . However, relatively little research has been published concerning the resistance of dermatophyte species . OBJECTIVE: We report the results of a retrospective study analyzing the relationship between in vitro and clinical resistance in strains of Trichophyton rubrum cultured from patients with recalcitrant dermatophyte toe onychomycosis . MATERIALS AND METHODS: We analyzed the in vitro resistance of dermatophyte strains obtained from 18 patients with chronic onychomycosis who failed antifungal therapy with itraconazole or terbinafine . Multiple-sequential strains from 11 patients were included in the study . Susceptibility testing of these strains was performed against 4 antifungals, itraconazole, ketoconazole, terbinafine and ciclopirox, using the broth microdilution method as per the NCCLS M27-A guidelines . A record of clinical characteristics that may relate to patient treatment and therapy was maintained . RESULTS: All of the strains were susceptible to 3 of the 4 antifungal agents tested . Although there was no direct correlation between clinical resistance and in vitro resistance, increased minimum inhibitory concentration values for ketoconazole were observed in strains obtained after treatment from 3 of 18 patients evaluated in the study . In all but 1 patient, we were able to identify other factors that may have been responsible for treatment failure . CONCLUSIONS: With the more common use of antifungals to treat various fungal infections, development of increased resistance in the causative organisms remains a possibility . However, factors other than fungal resistance may also be implicated in treatment failure . J Control Release, 2003 Dec 12, 93(3), 341 - 54 Ciprofloxacin implants for bone infection . In vitro-in vivo characterization; Castro C et al.; To elucidate the antibiotic release mechanism from implants composed of calcium phosphates (hydroxyapatite {HAP} and tricalcium phosphate {TCP}), 30 kDa poly(DL-lactide) (PLA-30) and ciprofloxacin (CFX), nine formulations were prepared . In vitro results show that the release rate decreased as compression load and PLA/phosphates ratio increased . In contrast, a slower percent release rate was observed with higher drug loading . Swelling-erosion-disintegration of the implants was observed during the release assays, due to CFX swelling . Two CFX implant formulations were selected for implantation in the femur of rabbits, according to in vitro results . The implant drug loads tested were 10% and 40% of CFX . The in vivo results showed that the antibiotic concentrations achieved throughout the femur were higher for 4 weeks than the minimum inhibitory concentrations (MIC) against the most common of the pathogens that cause osteomyelitis . The CFX-10% implant was considered the best formulation as CFX was totally released within 6 weeks, and therapeutic bone levels were achieved, and the histological and radiographic analyses showed the osteoconductive properties of the materials . All these results showed that CFX release is limited by its solubility, and the erosion-disintegration and bone ingrowth into the implants enhanced the antibiotic release. Cell Biol Int, 2003, 27(12), 997 - 1003 Polarised secretion of cytokines in primary human microvascular endothelial cells is not dependent on N-linked glycosylation; Jurczyluk J et al.; Human microvascular endothelial cells (HMVEC) grow in monolayers on Transwell filters and restrict permeability between the apical and basolateral media . We show that these cell monolayers are capable of sorting labelled endogenous proteins, including chemokines, growth factors and cytokines, to either the apical or basolateral media . IL-8 and GMCSF were secreted predominantly into the apical medium, whereas MIC-1 was secreted into the basolateral medium . This polarity did not correlate with glycosylation, as IL-8 and MIC-1 are both N-glycosylated, but were sorted to opposite sides of the cell . IL-6 is not glycosylated and did not display significant polarity in secretion . Similarly, the polarity of secretion of endogenous glycoproteins was not related to their glycosylation. Mycoses, 2003 Dec, 46(11-12), 506 - 10 Action mechanisms of modern antifungal agents and resulting problems in the management of onychomycosis; Seebacher C; Successful treatment of onychomycosis in the infection site depends not only on achieving the minimal inhibitory concentration (MIC) of the antifungal agent, usually determined on fresh, proliferating fungal strains, but also on the effectivity against fungal spores dormant in nail keratin . Ciclopiroxolamine and terbinafine were investigated for their fungicidal properties against proliferating and dormant dermatophyte strains . While ciclopiroxolamine was 100% effective against Trichophyton mentagrophytes (50 microg ml(-1)) and Microsporum canis (5 microg ml(-1)) both in the proliferative and dormant phase after 5 days of incubation, the same result was achieved under identical test conditions with 0.002 microg ml(-1) terbinafine using T . mentagrophytes as test organism in the proliferative and 2.0 microg ml-1 in the dormant phase . The terbinafine concentrations of 0.52 microg g(-1) measured in the nail are well below 2.0 . This explains the high treatment failure and relapse rates observed under monotherapy of toenail onychomycosis even with modern antifungals . Consequently, combined therapy is recommended, beginning with atraumatic removal of the affected toenails and continuing with an antifungal nail lacquer combined with a systemic antifungal. Vet Surg, 2003 Nov-Dec, 32(6), 559 - 65 Bone gentamicin concentration after intra-articular injection or regional intravenous perfusion in the horse; Werner LA et al.; OBJECTIVE: To compare intra-articular (IA) and bone gentamicin concentrations achieved after intra-articular administration or regional intravenous perfusion (RIP) . STUDY DESIGN: Experimental study . ANIMALS: Twelve healthy adult horses . METHODS: Horses were assigned to 2 treatment groups (n = 6/group): Group 1, 1 g gentamicin administered simultaneously in both left and right metacarpophalangeal joints and group 2, 1 g gentamicin administered simultaneously in both left and right lateral palmar veins . Serum, synovial fluid, and bone biopsy specimens were collected . Gentamicin concentrations were determined by fluorescence polarization immunoassay . Bone, synovial fluid, and serum gentamicin concentrations were compared over time and between groups using 2-way ANOVA . Significance of all tests were evaluated at P <.05 . RESULTS: IA metacarpophalangeal joint administration resulted in higher concentration of gentamicin in synovial fluid than RIP administration . Synovial fluid concentration remained above minimum inhibitory concentration (MIC) for common pathogens for over 24 hours with IA and RIP administration . Bone gentamicin concentration remained above MIC for 8 hours with both methods; there was no significant difference in gentamicin concentration in bone with either method . Neither IA nor RIP administration had a significant effect on serum concentration of gentamicin . CONCLUSIONS: In normal horses, there is no difference in bone gentamicin concentration obtained with IA or RIP administration . CLINICAL RELEVANCE: Based on MIC for common equine pathogens, administration of gentamicin intra-articularly or by regional intravenous perfusion should be useful for treatment of osteomyelitis . Planta Med, 2003 Oct, 69(10), 956 - 9 Pangelin, an antimycobacterial coumarin from Ducrosia anethifolia; Stavri M et al.; The aerial parts of Ducrosia anethifolia afforded the monoterpene glucoside 8-debenzoylpaeoniflorin ( 1) and the prenylated furanocoumarin pangelin {5-{2"( R)-hydroxy-3"-methyl-3"-butenyloxy}furocoumarin} ( 2) . Their structures were determined by extensive 1- and 2-dimensional NMR studies . Compound 2 demonstrated activity against a panel of fast growing mycobacteria, namely Mycobacterium fortuitum, M . aurum, M . phlei and M . smegmatis and minimum inhibitory concentration (MIC) values ranged from 64 - 128 microg/mL . Whilst compounds 1 and 2 have previously been reported as an antihyperglycaemic component from Paeonia lactiflora, and as a constituent of Angelica pancici, respectively, this is the first report of the full (1)H- and (13)C-NMR data for these natural products. Mycoses, 2003 Dec, 46(11-12), 524 - 6 Skin infection caused by Scedosporium apiospermum; Karaarslan A et al.; A woman with a skin infection because of Scedosporium apiospermum, in the interdigital spaces of her feet is presented . The minimum inhibition concentration values (MIC, microg ml(-1)) of this isolated mould for itraconazole, amphotericin B and terbinafine after 48 h were determined as 1, 8 and 16, respectively . The patient was treated successfully with oral terbinafine and topical clotrimazole. Antimicrob Agents Chemother, 2003 Dec, 47(12), 3815 - 24 Antipneumococcal activity of DK-507k, a new quinolone, compared with the activities of 10 other agents; Browne FA et al.; Agar dilution MIC determination was used to compare the activity of DK-507k with those of ciprofloxacin, levofloxacin, gatifl