J Anim Sci, 2000 Feb, 78(2), 267 - 74 Effects of preshipping vs . arrival medication with tilmicosin phosphate and feeding chlortetracycline on health and performance of newly received beef cattle; Duff GC et al.; Our objective was to determine the effects of preshipping (PRE) vs . arrival (ARR) medication with tilmicosin phosphate (MIC; Exp . 1 and 2) and feeding chlortetracycline (CTC; 22 mg/kg of BW from d 5 to 9; Exp . 2) on health and performance of beef calves received in the feedlot . Ninety-six steers (Exp . 1; pay weight 236 kg) and 240 (Exp . 2; average pay weight 188 kg) steer and bull calves were used . For Exp . 1, treatments included no MIC (CON), PRE, and ARR . For Exp . 2, treatments were arranged in a 3x2 factorial . Treatments included CON, PRE, and ARR, either with CTC or without CTC . For Exp . 2, serum concentrations of immunoglobulin (Ig)G and alpha-1-acid glycoprotein (AGP) were determined on samples collected on d 0, 5, 10, and 28 and d 0, 5, and 10, respectively . No MIC x CTC interactions were observed . No differences were noted among MIC or CTC treatments in any of the experiments for ADG, daily DMI, or gain:feed ratio for the overall receiving periods . For Exp . 1, percentage of steers treated for bovine respiratory disease (BRD) was decreased (P<.05) for MIC-treated animals vs CON (71.9, 45.2, and 46.9 for CON, PRE, and ARR, respectively), and the week that calves were treated for BRD differed (P<.10) among treatments . For Exp . 2, the number of calves treated for BRD was decreased (P<.01) for MIC-treated steers vs CON and decreased (P<.05) for ARR vs . PRE (40.0, 18.7, and 7.5% for CON, PRE, and ARR, respectively) . Averaged across days, serum IgG was decreased (P<.05) for MIC-treated steers vs . CON, with no differences noted among treatments for AGP . Results suggest that preshipping medication programs are no more effective than arrival medication programs using tilmicosin phosphate. Chem Pharm Bull (Tokyo), 2000 Jan, 48(1), 60 - 4 Structure-activity relationships of a new antifungal imidazole, AFK-108, and related compounds; Hori K et al.; Fungicidal activity of widely used imidazole antifungal drugs in topical applications is not so strong in spite of their fungistatic activities against dermatophytes and pathogenic yeasts . In order to improve fungicidal activity of imidazole antifungal agents, a series of novel imidazole derivatives having a hydrophobic substituent derived from isoprenoid were synthesized . The efficacy of these compounds was evaluated with respect to direct cell-membrane damaging activity, ergosterol biosynthesis inhibition, minimum growth-inhibitory concentration (MIC) and therapeutic effect for experimental dermatophytosis of guinea pigs . Among the newly synthesized compounds, the geranyl derivative named AFK-108 (2a) showed the highest in vivo fungicidal activity with both cell membrane damaging activity and ergosterol biosynthesis inhibition in vitro. J Antimicrob Chemother, 2000 Mar, 45(3), 363 - 5 Comparative activity of new quinolones against 326 clinical isolates of Stenotrophomonas maltophilia; Weiss K et al.; Stenotrophomonas maltophilia is an important emerging pathogen causing a variety of infections in severely ill patients . This microorganism is inherently resistant to many antibiotics, and only a few therapeutic options are available . The principal aim of this study was to assess the in vitro activity of new quinolones against this pathogen . Three hundred and twenty-six single clinical isolates were tested in this study . The MIC(90) was 16 mg/L for ciprofloxacin, 8 mg/L for levofloxacin and gatifloxacin, 4 mg/L for trovafloxacin, moxifloxacin and sparfloxacin and 2 mg/L for clinafloxacin . At a 2 mg/L concentration, a C(max) lung:MIC ratio of >/=10 can be reached for 95%, 84.3%, 83.1% and 81.5% of isolates, respectively, for clinafloxacin, trovafloxacin, moxifloxacin and sparfloxacin (P < 0 . 001 compared with levofloxacin and ciprofloxacin) . In spite of the rare but serious adverse events associated with the new-generation quinolones, these agents may become very useful in the treatment of certain severe or life-threatening infectious conditions due to S . maltophilia, notably lower respiratory tract infections. J Antimicrob Chemother, 2000 Mar, 45(3), 337 - 42 Pharmacokinetics and burn eschar penetration of intravenous ciprofloxacin in patients with major thermal injuries; Varela JE et al.; Adequate penetration of antibiotics into burn tissue and maintenance of effective serum levels are essential for the treatment of patients sustaining major thermal injuries . The pharmacokinetics and burn eschar penetration of intravenous ciprofloxacin were determined in 12 critically ill patients with burn injuries . Mean age for the 12 patients was 45 +/- 17 (range 25-82 years), total body surface area burned (TBSAB) = 38 +/- 15% and Acute Physiology and Chronic Health Evaluation (APACHE) II score = 8 +/- 6 . Patients received recommended doses of ciprofloxacin, 400 mg q12h iv, for three doses beginning 72 h post-burn . Serum concentrations were measured at t = 0, 0.25, 0.5, 0.75, 1.0, 1.25, 1.5, 2.0, 4.0 and 12.0 h after the first and third doses . Burn eschar biopsies were obtained after the third ciprofloxacin dose . Three of these 12 patients (25%) manifested later signs of clinical sepsis (TBSAB = 61 +/- 6% and APACHE II score = 11 +/- 3) and underwent a second infusion of three doses of intravenous ciprofloxacin, blood sampling and eschar biopsy . Serum and eschar concentrations were determined by high performance liquid chromatography . Serum ciprofloxacin concentrations were comparable to those of normal volunteers (C(max) = 4.0 +/- 1 mg/L and AUC = 11.4 +/- 2 mg.h/L) during the immediate post-burn period after dose 1 (C(max1) = 4.8 +/- 3 mg/L and AUC(0-12) = 12.5 +/- 7 mg . h/L) and dose 3 (C(max3) = 4.9 +/- 2 mg/L and AUC(24-36) = 17.5 +/- 11 mg.h/L) . Mean burn eschar concentration during the 72 h post-burn was significantly lower than that found during clinical sepsis (18 +/- 17 compared with 41.3 +/- 54 microg/g; P < 0.05 by t test) . Similar serum concentrations were achieved in patients with clinical sepsis (C(max1) = 4.2 +/- 0.2 mg/L and AUC(0-12) = 15.0 +/- 3 mg . h/L; C(max3) = 5.0 +/- 1 mg/L and AUC(24-36) = 22.8 +/- 9 mg.h/L) . A positive correlation between burn eschar concentrations and C(max) (r = 0.71, r(2) = 0.51, P = 0.01) was found by linear regression analysis . A C(max)/MIC ratio > 10 (MIC = 0.5 mg/L) and an AUC/MIC ratio > 100 SIT(-1).h (serum inhibitory titre) (MIC = 0.125 mg/L) were achieved . High burn eschar concentrations and serum levels, similar to those found in normal volunteers, can be achieved after intravenous ciprofloxacin infusion in critically ill burns patients. Indian J Med Res, 1999 Dec, 110, 186 - 9 Evaluation of various methods of susceptibility to ofloxacin in strains of Mycobacterium tuberculosis; Sulochana S et al.; A comparison of three methods of susceptibility testing was undertaken on 30 susceptible and 25 resistant strains of Mycobacterium tuberculosis to determine an acceptable in vitro definition of resistance of ofloxacin . The strains were tested by the proportion method on Lowenstein Jensen (L-J) and 7H11 media and also by the BACTEC radiometric method . Using a criterion of 1 per cent or more growth at a concentration of 2 mg/1, there was a 100 per cent agreement with the conventional MIC method by the proportion tests on L-J as well as on 7H11 media . The BACTEC radiometric method, at the same concentration, yielded 98 per cent agreement . Thus, any of these methods could be used depending upon the infrastructure available. J Clin Microbiol, 2000 Mar, 38(3), 971 - 6 Evaluation of a capacitance method for direct antifungal susceptibility testing of yeasts in positive blood cultures; Chang HC et al.; The feasibility of using a capacitance method (CM) for direct antifungal susceptibility testing of yeasts in positive blood cultures was evaluated . The CM used the same test conditions as those recommended by the National Committee for Clinical Laboratory Standards . After direct inoculation of positive culture broths into module wells (Bactometer; bioMerieux, Inc., Hazelwood, Mo.), the end-point determination was made by monitoring the capacitance change in the culture broths with Bactometer . The MIC of amphotericin B was the lowest concentration at which yeast growth was completely inhibited, while the MICs of ketoconazole, flucytosine, and fluconazole were the concentrations at which a >/=80% reduction in capacitance change was observed . The MICs of the four drugs against each blood isolate obtained on subculture plates were also determined by the macrodilution method . For 51 positive blood cultures tested, the percent agreement (+/-2 log(2) dilutions) between the CM and the macrodilution method were as follows: amphotericin B (98%), ketoconazole (92%), flucytosine (84%), and fluconazole (96%) . The CM was further used for breakpoint susceptibility testing of fluconazole (8 and 64 microg/ml) and flucytosine (4 and 32 microg/ml) against yeasts in positive blood cultures . After testing of 74 specimens by the CM, flucytosine and fluconazole produced one (1.4%) major error and two (2.8%) minor errors, respectively . All yeasts that displayed resistance to flucytosine or fluconazole were detected within 24 h after direct inoculation of the positive broths into Bactometer . The CM may be useful for the rapid detection of antifungal resistance in positive blood cultures containing yeasts. Nippon Jibiinkoka Gakkai Kaiho, 2000 Jan, 103(1), 19 - 23 {Identification of bacterial strain at each episode of recurrent acute otitis media}; Suetake M et al.; This study was undertaken to investigate whether each episode of recurrent acute otitis media (rAOM) is caused by the same strain of bacteria or different strains at each episode . Seventy infants less than 3-years of age, having experienced rAOM for a period shorter than 8 weeks, were selected and included in the present study . The total number of AOM episodes experienced by this group was 282 . At each subsequent episode of AOM, otorrhea and nasopharyngeal swabs were taken for bacterial culture and determination of the MIC for antibiotics . When S . pneumoniae was identified, its serotype, and its pbp, ermAM, and mefE genes were also investigated to determine the bacterial species and strains . S . pneumoniae was the most frequently cultured bacteria with 26 penicillin-sensitive S . pneumoniae (PSSP), 65 penicillin-insensitive S . pneumoniae (PISP), and 50 penicillin-resistant S . pneumoniae (PRSP) . H . influenzae was the next most frequently cultured bacteria of which 65 were sensitive to penicillin, 27 were found to be beta-bactamase-negative-ampicillin-resistant (BLNAR) and 17 were found to be beta-bactamase positive . Bacteria cultured from each pair of two successive episodes of AOM were compared as to the identity of the bacteria during the two episodes . In 150 out of 202 pairs (74%), the cultured pathogen was different . In 22 cases in which either PISP or PRSP was the pathogen detected in two consecutive AOM episodes, 15 cases (68%) were found in which the involved strain differed between the two episodes . This study indicates that the pathogen involved in rAOM is likely to differ at each episode of AOM, not only in cases caused by PSSP, but also in those caused by PRSP. Clin Exp Immunol, 2000 Mar, 119(3), 553 - 8 PERB11 (MIC): a polymorphic MHC gene is expressed in skin and single nucleotide polymorphisms are associated with psoriasis; Tay GK et al.; The susceptibility genes for psoriasis remain to be identified . At least one of these must be in the major histocompatibility complex (MHC) to explain associations with alleles at human leucocyte antigen (HLA)-A, -B, -C, -DR, -DQ and C4 . In fact, most of these alleles are components of just two ancestral haplotypes (AHs) designated 13.1 and 57.1 . Although relevant MHC gene(s) could be within a region of at least 4 Mb, most studies have favoured the area near HLA-B and -C . This region contains a large number of non-HLA genes, many of which are duplicated and polymorphic . Members of one such gene family, PERB11.1 and PERB11.2, are expressed in the skin and are encoded in the region between tumour necrosis factor and HLA-B . To investigate the relationship of PERB11.1 alleles to psoriasis, sequence based typing was performed on 97 patients classified according to age of onset and family history . The frequency of the PERB11.1*06 allele is 44% in type I psoriasis but only 7% in controls (Pc = 0.003 by Fisher's exact test, two-tailed) . The major determinant of this association is a single nucleotide polymorphism (SNP) within intron 4 . In normal and affected skin, expression of PERB11 is mainly in the basal layer of the epidermis including ducts and follicles . PERB11 is also present in the upper keratin layers but there is relative deficiency in the intermediate layers . These findings suggest a possible role for PERB11 and other MHC genes in the pathogenesis of psoriasis. Eur J Clin Microbiol Infect Dis, 1999 Dec, 18(12), 866 - 70 Meropenem alone and in combination with vancomycin in experimental meningitis caused by a penicillin-resistant pneumococcal strain; Gerber CM et al.; In a rabbit model of meningitis caused by a pneumococcus highly resistant to penicillin (MIC, 4 microg/ml), meropenem, a broad-spectrum carbapenem, was bactericidal (-0.48+/-0.14 deltalog10 cfu/ml h) and slightly superior to ceftriaxone (-0.34+/-0.23 deltalog10 cfu/ml x h) and vancomycin (-0.39+/-0.19 deltalog10 cfu/ml x h) . Although the combination of vancomycin with ceftriaxone was significantly more active than ceftriaxone alone (-0.55+/-0.19 deltalog10 cfu/ml x h), only an insignificant gain was observed by the addition of vancomycin to meropenem (-0.55+/-0.28 deltalog10 cfu/ml x h). Dtsch Tierarztl Wochenschr, 2000 Jan, 107(1), 23 - 7 Tissue distribution and disposition kinetics of enrofloxacin in healthy and E . coli infected broilers; Soliman GA; Concentrations of enrofloxacin equivalent activity were determined by microbiological assay in the plasma of healthy and E . coli-infected broilers following single intravenous and oral administrations at 10 mg/kg . Tissue distribution and residue-depletion following multiple oral doses (10 mg/kg for 3 successive days) were investigated . Pharmacokinetic variables were determined using compartmental and non-compartmental analytical methods . Plasma enrofloxacin concentrations after intravenous dosing to healthy and infected birds were best described by a two-compartments model . Enrofloxacin concentrations in plasma of infected birds were lower than those of healthy ones . The disposition kinetics of intravenously administered drug in healthy and infected birds were somewhat different . The elimination half-life (t1/2 beta) was 4.75 vs . 3.63 h; mean residence time (MRT) was 6.72 vs 4.90 h; apparent volume of the central compartment (Vc) was 1.11 vs 1.57 l/kg; rate constant for transfer from peripheral to central compartment (k21) was 1.15 vs 1.41 h-1 and total body clearance (ClB) was 0.35 vs 0.53 l/h/kg in healthy and infected birds, respectively . After oral administration, the absorption half-life (t1/2abs) in the infected birds was significantly longer than in healthy birds, while elimination half-life (t1/2el) and MRT were significantly shorter . Bioavailability was higher in infected birds (72.50%) as compared to healthy ones (69.78%) . Enrofloxacin was detected in the tissues of healthy and infected birds after daily oral dosing of 10 mg/kg for 3 days . It was more concentrated in liver, kidney, and breast muscle . The minimal inhibitory concentration (MIC) of enrofloxacin against E . coli was 0.064 microgram/ml . On the basis of maintaining enrofloxacin plasma concentrations over the MIC, a dose of 10 mg/kg given intravenously every 20.14 hrs or orally every 20.86 hrs should provide tissue concentrations effective against E . coli infection in chickens. Laryngorhinootologie, 2000 Jan, 79(1), 30 - 3 {Antibiotic impregnation of cartilage implants: diffusion kinetics of fluoroquinolones}; Tasman AJ et al.; BACKGROUND: Antibiotic impregnation of cartilage implants may reduce the risk of bacterial infection and subsequent absorption . The aim of this study was to investigate the penetration kinetics of two quinolone antibiotics into fresh cartilage and the concentrations in the core of lyophilized cartilage after rehydration . METHODS: Fresh human costal cartilage was impregnated with ofloxacin and ciprofloxacin (2 mg/ml) for 2, 15 and 90 min . Concentrations were measured in 6 levels (0.5 mm each) from the surface to 3 mm beneath the surface with high performance liquid chromatography (HPLC) . Lyophilized human costal cartilage was rehydrated in ofloxacine and ciprofloxacine solutions (2 mg/ml, 0.2 mg/ml and 0.02 mg/ml) for 18 hours and concentrations in the core of the rib segment were measured . RESULTS: Quinolone antibiotics penetrate into cartilage by free diffusion . We found no evidence of significant binding to cartilage . After 2 and 15 min of impregnation, concentrations above the minimal inhibitory concentration (MIC90) for pseudomonas species are found from 0-0.5 mm below the surface of fresh cartilage . After 90 min concentrations above the MIC90 were found 1.0-1.5 mm below surface of the implant . In lyophilized rib grafts which were rehydrated in 1/10 diluted intravenous solutions (0.2 mg/ml), concentrations in the core of the specimen were above MIC90 . Differences between the penetration characteristics of ofloxacine and ciprofloxacine were minor . CONCLUSION: Intraoperative impregnation of cartilage implants with ofloxacin or ciprofloxacin probably offers only short-term protection against bacterial infection . Rehydrated rib grafts, however, contain high quinolone concentrations which may be effective even in infected implant beds for several hours. Br J Ophthalmol, 2000 Mar, 84(3), 300 - 2 Intraocular penetration of vancomycin eye drops after application to the medial canthus with closed lids; Alster Y et al.; AIMS: To investigate the intraocular penetration of vancomycin eye drops and to compare the conventional method of drop instillation to the lower cul de sac with applying drops to the medial canthus with closed lids . METHODS: This prospective randomised trial evaluated 53 eyes of 53 patients who had undergone extracapsular cataract extraction (ECCE) with intraocular lens implantation . Vancomycin (50 mg/ml) eye drops were applied to either the lower cul de sac with open lids (conventional method), or to the medial canthus with the patient in a supine position and with closed lids . After paracentesis performed during ECCE, an aqueous humour sample was taken and vancomycin concentration was measured using the TDX vancomycin assay (fluorescence polarisation immunoassay) . RESULTS: Vancomycin concentration in the anterior chamber were above the minimal inhibitory concentration for Gram positive bacteria in the two methods of drop instillation examined (2.04 (SD 1.9) microg/ml and 1.49 (1.1) microg/ml in the open and closed methods, respectively (p =0.202)) . CONCLUSIONS: Vancomycin (50 mg/ml) reaches therapeutic concentration in the anterior chamber after topical drop application . Comparable concentrations were reached when drops were applied in either the lower cul de sac or to the medial canthus with closed lids . The latter method is proposed as likely to improve patient compliance. J Clin Lab Anal, 2000, 14(2), 59 - 63 Diagnosis of quinolone-resistant Coxiella burnetii strains by PCR-RFLP; Spyridaki I et al.; A total of 12 strains of Coxiella burnetii (8 Greek isolates from acute Q-fever patients, two reference strains-Nine Mile and Q212-and two pefloxacin-resistant laboratory strains) were examined for the presence of point mutations in the quinolone resistance determining region (QRDR) of gyrA gene by direct DNA sequencing of the polymerase chain reaction (PCR)-amplified fragments . The gene sequences of all eight Greek isolates and the two reference strains Nine Mile and Q212 {minimal inhibitory concentration (MIC)</= 4 microg/ml} were identical . Direct DNA sequencing of the in vitro-selected resistant strains (MICs to pefloxacin, 8-32 microg/ml) revealed a transition (G-->A) at the corresponding codon 87 of E . coli . This mutation lead to the substitution of Glu (codon GAG) by Lys (codon AAG ) . Restriction maps of amplified gyrA gene sequences were determined by GCG Wisconsin PACKAGE, and the MnlI restriction enzyme was found to cut only the sensitive strains sequences and not the resistant ones . The present PCR-RFLP analysis has proved to be a simple, rapid, and useful method for the detection of Coxiella burnetii and, at the same time, for the diagnosis of quinolone-resistant Coxiella burnetii strains . Mycoses, 1999, 42(11-12), 641 - 4 In vitro antifungal susceptibility of clinical isolates of Candida spp . from hospitalized patients; de Resende JC et al.; A total of 122 Candida spp . strains, isolated from a group of 100 patients hospitalized in the Santa Casa de Misericordia of Belo Horizonte were assayed for in vitro susceptibility to amphotericin B, fluconazole, itraconazole, ketoconazole and flucytosine using a microbroth technique proposed by the National Committee for Clinical Laboratory Standards . In this study large variations were observed among minimum inhibitory concentration values depending on the species tested . The statistical analysis (Kruskal-Wallis test) showed that itraconazole and flucytosine were the more efficient antifungal drugs for most of species, and amphotericin B and fluconazole were the least efficient. Antimicrob Agents Chemother, 2000 Mar, 44(3), 697 - 704 Pharmacokinetics and pharmacodynamics of lumefantrine (benflumetol) in acute falciparum malaria; Ezzet F et al.; The objective of this study was to conduct a prospective population pharmacokinetic and pharmacodynamic evaluation of lumefantrine during blinded comparisons of artemether-lumefantrine treatment regimens in uncomplicated multidrug-resistant falciparum malaria . Three combination regimens containing an average adult lumefantrine dose of 1,920 mg over 3 days (four doses) (regimen A) or 2,780 mg over 3 or 5 days (six doses) (regimen B or C, respectively) were given to 266 Thai patients . Detailed observations were obtained for 51 hospitalized adults, and sparse data were collected for 215 patients of all ages in a community setting . The population absorption half-life of lumefantrine was 4.5 h . The model-based median (5th and 95th percentiles) peak plasma lumefantrine concentrations were 6.2 (0.25 and 14.8) microgram/ml after regimen A, 9 . 0 (1.1 and 19.8) microgram/ml after regimen B, and 8 (1.4 and 17.4) microgram/ml after regimen C . During acute malaria, there was marked variability in the fraction of drug absorbed by patients (coefficient of variation, 150%) . The fraction increased considerably and variability fell with clinical recovery, largely because food intake was resumed; taking a normal meal close to drug administration increased oral bioavailability by 108% (90% confidence interval, 64 to 164) (P, 0.0001) . The higher-dose regimens (B and C) gave 60 and 100% higher areas under the concentration-time curves (AUC), respectively, and thus longer durations for which plasma lumefantrine concentrations exceeded the putative in vivo MIC of 280 microgram/ml (median for regimen B, 252 h; that for regimen C, 298 h; that for regimen A, 204 h {P, 0.0001}) and higher cure rates . Lumefantrine oral bioavailability is very dependent on food and is consequently poor in acute malaria but improves markedly with recovery . The high cure rates with the two six-dose regimens resulted from increased AUC and increased time at which lumefantrine concentrations were above the in vivo MIC. Antimicrob Agents Chemother, 2000 Mar, 44(3), 528 - 32 pncA mutations as a major mechanism of pyrazinamide resistance in Mycobacterium tuberculosis: spread of a monoresistant strain in Quebec, Canada; Cheng SJ et al.; Pyrazinamide (PZA) is an important first-line tuberculosis drug that is part of the currently used short-course tuberculosis chemotherapy . PZA is a prodrug that has to be converted to the active form pyrazinoic acid by pyrazinamidase (PZase) activity, encoded by the pncA gene of Mycobacterium tuberculosis, and loss of PZase activity is associated with PZA resistance . To further define the genetic basis of PZA resistance and determine the frequency of PZA-resistant strains having pncA mutations, we sequenced the pncA gene from a panel of 59 PZA-resistant clinical isolates from Canada, the United States, and Korea . Two strains that did not contain pncA mutations and had positive PZase turned out to be falsely resistant . Three PZase-negative strains (MIC, >900 microgram of PZA per ml) and one PZase-positive strain (strain 9739) (MIC, >300 microgram of PZA per ml) did not have pncA mutations . The remaining 53 of the 57 PZA-resistant isolates had pncA mutations, confirming that pncA mutation is the major mechanism of PZA resistance . Various new and diverse mutations were found in the pncA gene . Interestingly, 20 PZA-monoresistant strains and 1 multidrug-resistant isolate from Quebec, Canada, all had the same pncA mutation profile, consisting of an 8-nucleotide deletion and an amino acid substitution of Arg140-->Ser . Strain typing indicated that these strains are highly related and share almost identical IS6110 patterns . These data strongly suggest the spread of a PZA-monoresistant strain, which has not previously been described. FEMS Microbiol Lett, 2000 Feb 15, 183(2), 271 - 4 Plasmid curing from an acidophilic bacterium of the genus Acidocella; Ghosh S et al.; Preservation of the acidophilic heterotroph, Acidocella sp . strain GS19h, at 4 degrees C in stab culture eliminated all indigenous plasmids from this bacterium . Growth at 42 degrees C initially caused changes in the plasmid profile followed by total elimination of plasmids after 10 cycles of growth . Concomitant to this loss of all plasmids, the cured derivatives became sensitive to CdSO(4) and ZnSO(4), and the MIC value of the salts dropped from 1 M for each in the case of parental strain to 2 mM and 5 mM, respectively, suggesting plasmid-mediated inheritance of metal resistance in this bacterium . The cured derivatives could not utilise lactose, indicating this metabolic activity to be plasmid-associated in this strain. Pathol Biol (Paris), 1999 Dec, 47(10), 1060 - 4 {Pneumococcus observatory data in the Rhône-Alps region . Results from 1996}; Thierry J et al.; Throughout 1996, 22 hospital-based laboratories in the Rhone-Alpes region of France collected pneumococcal strains and used a standardized protocol to record the following data; patient age and sex; type of specimen; and determination of susceptibility to at least the following antibiotics: oxacillin 1 microgram and 5 micrograms, erythromycin (Ery), tetracycline (Tet), chloramphenicol (Chl), rifampin (Rmp), and loracarbef . For penicillin-nonsusceptible strains (PNSSs), which were identified based on results with oxacillin, MICs for penicillin G, amoxicillin (Amx), and cefotaxime (Ctx) were determined using the E Test, at the study site and agar dilution at the coordinating center . Of the 1153 strains, 65.5% were from adults and 31.8% from children; patient age was unknown in 2.7% of cases . PNSPs (MIC > 0.06 mg/l) contributed 32.9% of strains (I: 23.3%; R: 9.6%) and were more common in children (41.1%) than in adults (28.1%) . The frequency of PNSSs varied across specimen types: 27.9% in blood cultures (305 strains), 15.6% in cerebrospinal fluid (32), 38.7% in protected bronchopulmonary specimens (31), 31.5% in unprotected bronchopulmonary specimens (434), 50.8% in acute otitis media (118), and 34.4% in other specimens (221) . Among PNSSs, nonsusceptibility (I + R) to other antibiotics was variable: Ery, 62.1%; Tet, 41.5%; Chl, 40.4%; Rmp, 1.1% . Corresponding figures for the overall strain population were Ery, 33.3%; Tet, 22.7%; Chl, 22.8%; Rmp, 0.9% . In addition, 56.5% of PNSSs exhibited multiple drug resistance . Resistance to amoxicillin (MIC > 2 mg/l) was demonstrated for only 5 strains . No strains were resistant to loracarbef or cefotaxime . Serotypes of the 379 PNSSs were as follows: 23F, 26.6%; 14 (25.6%); 9V (18.2%), 6 (8.7%), 15 (5%), 19 (4.5%). J Mol Biol, 2000 Feb 18, 296(2), 335 - 40 Stabilization of poliovirus by capsid-binding antiviral drugs is due to entropic effects; Tsang SK et al.; When poliovirus attaches to its receptor or is heated in hypotonic buffers, the virion undergoes an irreversible conformational transition from the native 160 S (or N) particle to the 135 S (or A) particle, which is believed to mediate cell entry . The first-order rate constants for the thermally induced transition have been measured as a function of temperature for virus alone and for complexes of the virus with capsid-binding drugs that inhibit the receptor and thermally mediated conversion . Although the drugs have minimum inhibitory concentrations (MIC) that differ by almost three orders of magnitude, the activation energies for the N to A transition for the drug complexes (145 kcal/mol) were indistinguishable from each other or from that of the virus alone . We conclude that the antiviral activity of these drugs derives from a novel mechanism in which drug-binding stabilizes the virions through entropic effects . Farmaco, 1999 Nov-Dec, 54(11-12), 758 - 60 Formulation of a neutral solution of ciprofloxacin upon complexation with aluminum; Allemandi DA et al.; Clear solutions of 0.5 and 1.0% ciprofloxacin (CF) of pH 7.2 were prepared by the addition of aluminum chloride hexahydrate (AlCl3.6H2O) in the molar proportion CF:AlCl3.6H2O (3:1) . Minimum inhibitory concentrations (MIC) of these solutions were the same as an equimolar solution of CF.HCl . Solutions exhibited good physical, chemical and microbiological stability and satisfactorily overcame an ocular irritation test on rabbits. J Antimicrob Chemother, 2000 Feb, 45(2), 247 - 50 Use of meropenem 3 g once daily for outpatient treatment of infective exacerbations of bronchiectasis; Darley ES et al.; Meropenem administered as a single iv 3 g dose once every 24 h was used to treat nine ambulatory patients with infective exacerbations of bronchiectasis . Serum meropenem concentrations were measured before dosing and at 30 min after each 30 min infusion . Mean pre-dose concentrations were <0.1 mg/L and mean post-dose concentrations 93.9 +/- 29.5 mg/L (95% confidence interval (CI) 86 . 2-101.6, n = 59) . A pathogen was cultured from sputum in six patients and eradicated (<100 cfu/g sputum) in all but one by day 6 of therapy . Previous work on animals has shown that a bacteriostatic effect is seen with meropenem when t > MIC is greater than 20-30% of the dose interval . In these nine patients, this could be achieved and was associated with successful outcome for pathogens for which MICs are </= 0.5 mg/L . Therefore, once-a-day meropenem therapy may be a useful option for outpatient treatment for isolates for which MICs are </= 0.5 mg/L. Br J Anaesth, 1999 Sep, 83(3), 405 - 9 Acoustic monitoring of intraoperative neuromuscular block; Dascalu A et al.; Standard methods for accurate intraoperative measurement of neuromuscular block are either expensive or inconvenient and are not used widely . We have evaluated a new method of monitoring neuromuscular block using a low-frequency microphone . The method is based on the phenomenon of low-frequency sound emission by contracting skeletal muscle . Acoustic monitoring (MIC) with an air-coupled microphone was used to evaluate intraoperative neuromuscular block in 25 anaesthetized patients . The MIC recorded the response of the adductor pollicis muscle to supramaximal electrical stimulation of the ulnar nerve with train-of-four stimuli . The ratios of the first response (TI) to control (TC) were used for evaluation . Data obtained from the MIC were compared with simultaneous recordings, from the same hand, of mechanomyography (FDT), electromyography (EMG) and accelerography (ACC) . Throughout the operative procedure, TI/TC ratios of the acoustic method correlated with the three reference devices: FDT, 12 patients, 262 data sets, r = 0.86, bias (%MIC-%FDT) = mean -5.3 (SD 19.6)%; EMG, 18 patients, 490 data sets, r = 0.85, bias (%MIC-%EMG) = -0.39 (20.29)%; and ACC, 13 patients, 328 data sets, r = 0.91, bias (%MIC-%ACC) = -3.0 (15.6)% . We conclude that monitoring intraoperative neuromuscular block by a microphone which transduces low-frequency muscle sounds is clinically feasible. J Clin Microbiol, 2000 Feb, 38(2), 656 - 61 Multisite reproducibility of Etest for susceptibility testing of Mycobacterium abscessus, Mycobacterium chelonae, and Mycobacterium fortuitum; Woods GL et al.; A multicenter study was conducted to assess the inter- and intralaboratory reproducibility of the Etest for susceptibility testing of the rapidly growing mycobacteria . The accuracy also was evaluated by comparing Etest results to those obtained by broth microdilution . Ten isolates (four of the Mycobacterium fortuitum group, three of Mycobacterium abscessus, and three of Mycobacterium chelonae) were tested against amikacin, cefoxitin, ciprofloxacin, clarithromycin, doxycycline, imipenem, and trimethoprim-sulfamethoxazole in each of four laboratories . At each site, isolates were tested three times on each of three separate days (nine testing events per isolate) using common lots of media and Etest strips . Interlaboratory agreement among MICs (i.e., mode +/- 1 twofold dilution) varied for the different drug-isolate combinations and overall was best for trimethoprim-sulfamethoxazole (75% for one isolate and 100% for all others), followed by doxycycline and ciprofloxacin . Interlaboratory agreement based on interpretive category also varied and overall was best for doxycycline (100% for all isolates), followed by trimethoprim-sulfamethoxazole and ciprofloxacin . Interlaboratory reproducibility among MICs was most variable for imipenem, and agreement by interpretive category was lowest for imipenem and amikacin . Modal Etest MICs agreed with those by broth microdilution only for doxycycline and the sulfonamides . For all other drugs, the modal MICs by the two methods differed by more than +/- 1 twofold dilution for one or more isolates . In all cases, the Etest MIC was higher and would have caused reports of false resistance . In summary, the Etest in this evaluation did not perform as well as broth microdilution for susceptibility testing of the rapidly growing mycobacteria . It was problematic for most species and drugs, primarily because of a trailing endpoint and/or high MICs compared to broth . Its use will necessitate further investigation, including determination of the optimal medium and incubation conditions and clarification of endpoint interpretation. J Clin Microbiol, 2000 Feb, 38(2), 489 - 91 Fluorometric assessment of In vitro antidermatophytic activities of antimycotics based on their keratin-penetrating power; Okeke CN et al.; Keratin particles impregnated with amorolfine or clotrimazole in serial doubling dilutions (64 to 0.125 microg/ml) were used to evaluate the activities of these agents against 20 isolates each of Trichophyton mentagrophytes and Trichophyton rubrum in a yeast carbon broth medium incorporating Alamar Blue dye . The proposed MIC with keratin impregnation (MIC(K)) is defined as the lowest concentration of an agent used to impregnate keratin particles that effects a fluorescence-based fungal growth quotient of 0.05 or less . The conventional colorimetric and visual MICs of amorolfine for the dermatophytes, </=0.03 microg/ml for T . mentagrophytes and </=0.063 microg/ml for T . rubrum, were approximately half of those of clotrimazole for the same isolates . The superiority of the MIC(K)s of amorolfine for isolates of T . mentagrophytes (2.0 microg/ml; range, 0.5 to 8.0 microg/ml) and T . rubrum (4.0 microg/ml; range, 2 . 0 to 8.0 microg/ml) over those of clotrimazole (32 microg/ml {range, 8.0 to >64 microg/ml} and 64 microg/ml {range, 16 to >64 microg}, respectively) may indicate the strong in vivo antidermatophytic activity of amorolfine as a topical agent . The new antidermatophytic susceptibility testing procedure has potential clinical utility for the in vitro screening of agents for use in the topical treatment of superficial mycoses. J Nat Prod, 1999 Dec, 62(12), 1678 - 81 Oceanapiside, an antifungal bis-alpha,omega-amino alcohol glycoside from the marine sponge Oceanapia phillipensis; Nicholas GM et al.; The structure of oceanapiside, an antifungal alpha, omega-bis-aminohydroxylipid glycoside from the temperate marine sponge Oceanapia sp., was elucidated by a combination of 2D NMR, chemical degradation/correlation, and MALDI MS-MS spectrometry . Oceanapiside exhibits antifungal activity against Candida glabrata at 10 micrograms/mL (MIC). Med Mycol, 1999 Dec, 37(6), 405 - 9 In vitro susceptibility of chromoblastomycosis and phaeohyphomycosis agents to antifungal drugs; Caligiorne RB et al.; The in vitro susceptibility of chromoblastomycosis and phaeohyphomycosis agents to antifungal drugs was appraised using the reference macrodilution method proposed by the National Committee for Clinical Laboratory Standards (NCCLS) for yeasts modified for filamentous fungi . The antifungal drugs amphotericin B, 5-fluorocytosine, itraconazole and fluconazole were tested against one environmental and 18 clinical isolates . This work amended the macrodilution methods proposed by NCCLS and suggests that a conidial suspension free of hyphae leads to a more reliable assay and provides for better reproducibility . The macrodilution method was performed with 10(4) conidia ml-1 . The MIC values ranged from 1.0 to 16.0 micrograms ml-1 for amphotericin B and 3.12 to 25.0 micrograms ml-1 for 5-fluorocytosine . A MIC range of 0.06 to 1.95 micrograms ml-1 was determined for itraconazole while 2.0 to 64.0 micrograms ml-1 was detected for fluconazole. Indian J Exp Biol, 1999 Mar, 37(3), 305 - 7 Biodegradable dental implants of ciprofloxacin beta-cyclodextrin inclusion complex in the treatment of periodontitis; Nagaraju R et al.; Dental implants of ciprofloxacin beta-cyclodextrin inclusion complex were formulated using poly (epsilon-caprolactone), a biodegradable polymer and evaluated . Clinical evaluation was carried out in ten patients with acute peridontitis . Various clinical parameters, viz . gingival index, plaque score, attachment gain, reduction in pocket depth were evaluated at 10, 20, 30, 40 days of treatment and compared with placebo as control . A significant (P < 0.0001) improvement in the healing of periodontal pockets treated with ciprofloxacin beta-cyclodextrin implant was observed in most of the clinical parameters . Estimation of gingival crevicular fluids (GCF) for the drug content revealed that drug levels above the minimum inhibitory concentration (10.2 micrograms/mg) for many of the periodontal pathogens were maintained throughout the period of study (40 days) . This confirms the clinical efficacy of the dose and the duration of the study . It was found that biodegradable carrier was better accepted than the non-biodegradable carriers reported earlier. Antimicrob Agents Chemother, 2000 Feb, 44(2), 441 - 3 In vitro activity of the new triazole BMS-207147 against Aspergillus species in comparison with itraconazole and amphotericin B; Moore CB et al.; The in vitro activity of BMS-207147 against 80 clinical isolates of Aspergillus was compared with that of itraconazole and amphotericin B, using a validated microtiter method . Geometric mean MICs (in microg/ml) were as follows: 1.71 for BMS-207147, 0.67 for itraconazole, and 0.63 for amphotericin B . The range of concentrations of each drug was 0.125 to >16 microg/ml . Aspergillus fumigatus was significantly more susceptible to BMS-207147 (P < 0 . 05) than A . terreus and A . flavus . No BMS-207147-resistant A . fumigatus isolates were identified, though eight itraconazole-resistant (MIC, >8 microg/ml) isolates were . BMS-207147 is active against Aspergillus spp . at slightly high concentrations compared with itraconazole and amphotericin B. Antimicrob Agents Chemother, 2000 Feb, 44(2), 304 - 10 Antipneumococcal activities of gemifloxacin compared to those of nine other agents; Davies TA et al.; The activities of gemifloxacin compared to those of nine other agents was tested against a range of penicillin-susceptible and -resistant pneumococci by agar dilution, microdilution, time-kill, and post-antibiotic effect (PAE) methods . Against 64 penicillin-susceptible, 68 penicillin-intermediate, and 75 penicillin-resistant pneumococci (all quinolone susceptible), agar dilution MIC(50)s (MICs at which 50% of isolates are inhibited)/MIC(90)s (in micrograms per milliliter) were as follows: gemifloxacin, 0.03/0.06; ciprofloxacin, 1.0/4.0; levofloxacin, 1.0/2 . 0; sparfloxacin, 0.5/1.0; grepafloxacin, 0.125/0.5; trovafloxacin, 0 . 125/0.25; amoxicillin, 0.016/0.06 (penicillin-susceptible isolates), 0.125/1.0 (penicillin-intermediate isolates), and 2.0/4.0 (penicillin-resistant isolates); cefuroxime, 0.03/0.25 (penicillin-susceptible isolates), 0.5/2.0 (penicillin-intermediate isolates), and 8.0/16.0 (penicillin-resistant isolates); azithromycin, 0.125/0.5 (penicillin-susceptible isolates), 0 . 125/>128.0 (penicillin-intermediate isolates), and 4.0/>128.0 (penicillin-resistant isolates); and clarithromycin, 0.03/0.06 (penicillin-susceptible isolates), 0.03/32.0 (penicillin-intermediate isolates), and 2.0/>128.0 (penicillin-resistant isolates) . Against 28 strains with ciprofloxacin MICs of >/=8 microg/ml, gemifloxacin had the lowest MICs (0.03 to 1.0 microg/ml; MIC(90), 0.5 microg/ml), compared with MICs ranging between 0.25 and >32.0 microg/ml (MIC(90)s of 4.0 to >32.0 microg/ml) for other quinolones . Resistance in these 28 strains was associated with mutations in parC, gyrA, parE, and/or gyrB or efflux, with some strains having multiple resistance mechanisms . For 12 penicillin-susceptible and -resistant pneumococcal strains (2 quinolone resistant), time-kill results showed that levofloxacin at the MIC, gemifloxacin and sparfloxacin at two times the MIC, and ciprofloxacin, grepafloxacin, and trovafloxacin at four times the MIC were bactericidal for all strains after 24 h . Gemifloxacin was uniformly bactericidal after 24 h at </=0.5 microg/ml . Various degrees of 90 and 99% killing by all quinolones were detected after 3 h . Gemifloxacin and trovafloxacin were both bactericidal at two times the MIC for the two quinolone-resistant pneumococci . Amoxicillin at two times the MIC and cefuroxime at four times the MIC were uniformly bactericidal after 24 h, with some degree of killing at earlier time points . Macrolides gave slower killing against the seven susceptible strains tested, with 99.9% killing of all strains at two to four times the MIC after 24 h . PAEs for five quinolone-susceptible strains were similar (0.3 to 3.0 h) for all quinolones, and significant quinolone PAEs were found for the quinolone-resistant strain. Acta Pol Pharm, 1999 Mar-Apr, 56(2), 121 - 6 Studies on pyrazine derivatives . XXXIII . Synthesis and tuberculostatic activity of 1-{1-(2-pyrazinyl)-ethyl}-4-N-substituted thiosemicarbazide derivatives; Milczarska B et al.; Hydrogenation of 4-N-substituted thiosemicarbazonic acid acetylpyrazine derivatives with NaBH4 in dry ethanol led to seventeen new compounds . The in vitro tuberculostatic activity investigations of the 15 synthesized compound were carried out . MIC few of i.v . compounds were lower than 32 micrograms/cm3. Planta Med, 1999 Dec, 65(8), 732 - 4 Antimycobacterial ergosterol-5,8-endoperoxide from Ajuga remota; Cantrell CL et al.; In a bioassay-guided search for antimycobacterial natural products from higher plants, we have chemically investigated the methanol extract of aerial parts of Ajuga remota Benth . (Labiatae) for its active constituent(s) . Bioactive chromatographic fractions of the crude extract provided the known triterpene ergosterol-5,8-endoperoxide plus the diterpenes clerodin, ajugarin-I, and ajugarin-II, which had been previously isolated from A . remota . This is the first report on the isolation of ergosterol-5,8-endoperoxide from this plant . The above compounds were tested in a radiorespirometric bioassay for activity against Mycobacterium tuberculosis . Ergosterol-5,8-endoperoxide showed a minimum inhibitory concentration (MIC) of 1 microgram/ml, while ergosterol-5,8-endoperoxide acetate, ergosterol, and ergosta-5,7,9(11),22-tetraen-3 beta-ol gave MICs of 8 micrograms/ml, > 128 micrograms/ml, and 128 micrograms/ml, respectively . Clerodin, ajugarin-I, and ajugarin-II were inactive with MICs of > 128 micrograms/ml. J Neurosci, 2000 Dec 1, 20(23), 8597 - 603 Growth/differentiation factor-15/macrophage inhibitory cytokine-1 is a novel trophic factor for midbrain dopaminergic neurons in vivo; Strelau J et al.; Transforming growth factor-betas (TGF-betas) constitute an expanding family of multifunctional cytokines with prominent roles in development, cell proliferation, differentiation, and repair . We have cloned, expressed, and raised antibodies against a distant member of the TGF-betas, growth/differentiation factor-15 (GDF-15) . GDF-15 is identical to macrophage inhibitory cytokine-1 (MIC-1) . GDF-15/MIC-1 mRNA and protein are widely distributed in the developing and adult CNS and peripheral nervous systems, including choroid plexus and CSF . GDF-15/MIC-1 is a potent survival promoting and protective factor for cultured and iron-intoxicated dopaminergic (DAergic) neurons cultured from the embryonic rat midbrain floor . The trophic effect of GDF-15/MIC-1 was not accompanied by an increase in cell proliferation and astroglial maturation, suggesting that GDF-15/MIC-1 probably acts directly on neurons . GDF-15/MIC-1 also protects 6-hydroxydopamine (6-OHDA)-lesioned nigrostriatal DAergic neurons in vivo . Unilateral injections of GDF-15/MIC-1 into the medial forebrain bundle just above the substantia nigra (SN) and into the left ventricle (20 microgram each) immediately before a 6-OHDA injection (8 microgram) prevented 6-OHDA-induced rotational behavior and significantly reduced losses of DAergic neurons in the SN . This protection was evident for at least 1 month . Administration of 5 microgram of GDF-15/MIC-1 in the same paradigm also provided significant neuroprotection . GDF-15/MIC-1 also promoted the serotonergic phenotype of cultured raphe neurons but did not support survival of rat motoneurons . Thus, GDF-15/MIC-1 is a novel neurotrophic factor with prominent effects on DAergic and serotonergic neurons . GDF-15/MIC-1 may therefore have a potential for the treatment of Parkinson's disease and disorders of the serotonergic system. J Antimicrob Chemother, 2000 Jan, 45(1), 85 - 93 Lack of correlation of in vitro amphotericin B susceptibility testing with outcome in a murine model of Aspergillus infection; Johnson EM et al.; Amphotericin B has been the standard therapy for invasive aspergillosis since its introduction in 1957 . It is only moderately effective . Many susceptibility tests have been used but little variation has been noted between strains . We have studied three strains of Aspergillus fumigatusand one of Aspergillus terreusin a neutropenic mouse model of invasive aspergillosis and attempted to correlate the variable efficacy in vivowith MICs generated by over 30 different susceptibility test formats . One strain of A . fumigatus(AF65) and the strain of A . terreus(AT49) were 'resistant' and the remaining two strains of A . fumigatus(AF210 and AF294) were 'susceptible' in vivo . Only AT49 had elevated MICs of amphotericin (MIC 2 mg/L) by 41 of 54 in vitrotesting systems . With each test format, including Etest, there was no distinction between MICs obtained for AF65, AF210 and AF294 (MICs 0.125-64 mg/L depending on the test) . Thus despite extensive efforts we have been unable to correlate susceptible test results with in vivooutcome in A . fumigatusbut we have with A . terreus, with some test formats . This suggests that, at present, amphotericin B susceptibility testing of A . fumigatus is of limited clinical value and further work needs to be done to find testing systems that can identify the 'resistance' documented in vivo. J Antimicrob Chemother, 2000 Jan, 45(1), 77 - 83 Preparation of a clofazimine nanosuspension for intravenous use and evaluation of its therapeutic efficacy in murine Mycobacterium avium infection; Peters K et al.; Clofazimine nanosuspensions were produced by high pressure homogenization and the formulation was optimized for lyophilization . Characterization of the product by photon correlation spectroscopy, laser diffraction and Coulter counter analysis showed that the clofazimine nanosuspensions were suitable for iv injection with a particle size permitting passive targeting to the reticuloendothelial system . Following iv administration to mice of either the nanocrystalline or a control liposomal formulation at a dose of 20 mg clofazimine/kg bodyweight, drug concentrations in livers, spleens and lungs reached comparably high concentrations, well in excess of the MIC for most Mycobacterium avium strains . When C57BL/6 mice were experimentally infected with M . avium strain TMC 724, nanocrystalline clofazimine was as effective as liposomal clofazimine in reducing bacterial loads in the liver, spleen and lungs of infected mice . Nanocrystalline suspensions of poorly soluble drugs such as riminophenazines are easy to prepare and to lyophilize for extended storage and represent a promising new drug formulation for intravenous therapy of mycobacterial infections. J Antimicrob Chemother, 2000 Jan, 45(1), 63 - 8 Evaluation of cefepime alone and in combination with vancomycin against penicillin-resistant pneumococci in the rabbit meningitis model and in vitro; Gerber CM et al.; Cefepime, a broad-spectrum, fourth-generation cephalosporin, showed excellent CSF penetration with levels ranging between 10 and 16 mg/L after two intravenous injections (100 mg/kg) . The bactericidal activity of cefepime (-0.60 +/- 0.28 Deltalog(10) cfu/mL/h) was superior to that of ceftriaxone (-0.34 +/- 0.23 Deltalog(10) cfu/mL/h, P < 0.05) and vancomycin (-0.39 +/- 0.19 Deltalog(10) cfu/mL/h, P < 0.05) in the treatment of rabbits with meningitis caused by an isolate highly resistant to penicillin (MIC of penicillin G: 4 mg/L) . The addition of vancomycin to both cephalosporins did not significantly increase the killing rate compared with monotherapies (P > 0.05) . Similar results were obtained in time-killing experiments in vitro. Clin Pharmacokinet, 1999 Dec, 37(6), 471 - 84 Clinical pharmacokinetics of the prodrug oseltamivir and its active metabolite Ro 64-0802; He G et al.; Oseltamivir is an ethyl ester prodrug of Ro 64-0802, a selective inhibitor of influenza virus neuraminidase . Oral administration of oseltamivir delivers the active antiviral Ro 64-0802 to the bloodstream, and thus all sites of influenza infection (lung, nasal mucosa, middle ear) are accessible . The pharmacokinetic profile of oseltamivir is simple and predictable, and twice daily treatment results in effective antiviral plasma concentrations over the entire administration interval . After oral administration, oseltamivir is readily absorbed from the gastrointestinal tract and extensively converted to the active metabolite . The absolute bioavailability of the active metabolite from orally administered oseltamivir is 80% . The active metabolite is detectable in plasma within 30 minutes and reaches maximal concentrations after 3 to 4 hours . After peak plasma concentrations are attained, the concentration of the active metabolite declines with an apparent half-life of 6 to 10 hours . Oseltamivir is eliminated primarily by conversion to and renal excretion of the active metabolite . Renal clearance of both compounds exceeds glomerular filtration rate, indicating that renal tubular secretion contributes to their elimination via the anionic pathway . Neither compound interacts with cytochrome P450 mixed-function oxidases or glucuronosyltransferases . The pharmacokinetic profile of the active metabolite is linear and dose-proportional, with less than 2-fold accumulation over a dosage range of oseltamivir 50 to 500 mg twice daily . Steady-state plasma concentrations are achieved within 3 days of twice daily administration, and at a dosage of 75mg twice daily the steady-state plasma trough concentrations of active metabolite remain above the minimum inhibitory concentration for all influenza strains tested . Exposure to the active metabolite at steady state is approximately 25% higher in elderly compared with young individuals; however, no dosage adjustment is necessary . In patients with renal impairment, metabolite clearance decreases linearly with creatinine clearance . A dosage reduction to 75mg once daily is recommended for patients with creatinine clearance <30 ml/min (1.8 L/h) . The pharmacokinetics in patients with influenza are qualitatively similar to those in healthy young adults . In vitro and in vivo studies indicate no clinically significant drug interactions . Neither paracetamol (acetaminophen) nor cimetidine altered the pharmacokinetics of Ro 64-0802 . Coadministration of probenecid resulted in a 2.5-fold increase in exposure to Ro 64-0802; however, this competition is unlikely to result in clinically relevant effects . These properties make oseltamivir a suitable candidate for use in the prevention and treatment of influenza. Gynecol Oncol, 2000 Jan, 76(1), 73 - 9 Expression of CD44 in uterine cervical squamous neoplasia: a predictor of microinvasion? Callagy G, O'Grady A, Butler D, Leader M, Kay E. OBJECTIVE: CD44, an integral membrane glycoprotein, may have an important role in early tumorigenesis, specifically, facilitating early tumor progression . Reports of the expression of CD44 in early uterine cervical squamous carcinogenesis are conflicting . We examined the expression of CD44 in microinvasive carcinoma of the cervix (MIC), as yet unreported, and compared it to that in cervical intraepithelial neoplasia (CIN) 1 and CIN 3 to further elucidate its role in early squamous carcinogenesis . METHODS: Seventeen cases of CIN 1, 24 cases of CIN 3, and 20 cases of MIC were stained with antibodies to CD44s, CD44v5, and CD44v6 . Only membranous staining was considered positive . RESULTS: Positive membranous staining (>50% cells) was observed in 97% of cases of CIN 1 using all three antibodies . In CIN 3, positive staining was seen more often with CD44v6 (18/24) and CD44v5 (19/24) than with CD44s (6/24) . Expression of CD44v6 was retained more often in MIC (16/20) compared with CD44s (3/20) and CD44v5 (9/20) . Those cases of CIN 3 and MIC that failed to meet our criteria for positive staining showed either heterogeneous or absent staining . CONCLUSION: There is a qualitative and quantitative reduction in expression of CD44 in MIC and CIN 3 compared with CIN 1 . Down-regulation of CD44 variants may occur later in neoplastic progression than CD44s . This pattern may reflect their important biological function in early progression by cervical cancer cells . Patchy and heterogeneous staining in more advanced lesions limits the usefulness of CD44 and its variants in the assessment of microinvasion . J Clin Microbiol, 2000 Jan, 38(1), 333 - 40 Determination of antifungal MICs by a rapid susceptibility assay; Riesselman MH et al.; A novel microtiter assay for antifungal susceptibility testing was developed . This method has several potential advantages over the M27-A assay of the National Committee for Clinical Laboratory Standards . These include provision of MIC results within 6 to 19 h, graphical display of data, and the availability of objective quantitative endpoints . We refer to the method as the rapid susceptibility assay (RSA) . RSA is based on substrate utilization by fungi in the presence of antifungal drugs . Substrate uptake is determined by a colorimetric method, which can be scored by analysis of data obtained from a microplate reader . Variables evaluated in the development of the RSA included inoculum size, incubation period, and efficacy with different classes of antifungal drugs and different yeast isolates . With the rapidly available and quantitative endpoints of the RSA, correlation of MICs and therapeutic drug doses can be evaluated more successfully than they can be evaluated by existing assays. J Clin Microbiol, 2000 Jan, 38(1), 210 - 4 Detection of clarithromycin-resistant helicobacter pylori strains by a preferential homoduplex formation assay; Maeda S et al.; It has been shown that resistance to clarithromycin, a major cause of failure in Helicobacter pylori eradication therapy, is associated with point mutations in the 23S rRNA gene . We sought to apply the preferential homoduplex formation assay (PHFA), a novel technique for the efficient detection of point mutations, to detection of the mutations . PHFA was performed on streptavidin-coated microtiter plates with biotin- and dinitrophenyl-labeled amplicons to detect the wild-type gene or each mutant gene . DNA samples were extracted from gastric juice specimens of 412 patients with H . pylori infection and were applied to the assay . The detection threshold of PHFA was as few as 10 gene copies . The sensitivity of PHFA for the detection of H . pylori infection was higher than those of culture and the rapid urease test . A total of 337 (81.8%) samples had the wild-type gene, 38 (9.2%) had the A2144G mutation, and 37 (9.0%) contained both the wild type and a mutation (A2144G in 30 samples, A2143G in 5 samples, and A2143G plus A2144G in 2 samples) . About half the strains isolated from patients with mixed infection were susceptible by the agar dilution method (MIC, <0.1 mg/liter) . Therefore, PHFA can detect clarithromycin-resistant H . pylori strains, even in patients with mixed infections with the wild type, that are not detectable by the agar dilution method. Cancer Causes Control, 1999 Dec, 10(6), 627 - 36 Cancer patterns of lung, oropharynx and oral cavity cancer in relation to gas exposure at Bhopal; Dikshit RP et al.; BACKGROUND: In Bhopal, India, on 2 December 1984, a chemical disaster caused by a gas leak mostly of methyl isocyanate (MIC) from the Union Carbide Factory led to massive mortality and morbidity of the population . This is the first study to shed light on the cancer experience of the Bhopal population as a result of exposure to a mixture of gases which have highly toxic and potentially carcinogenic properties . To observe the effect of gas exposure, incidence rates of the three most common cancer sites (lung, oropharynx and oral cavity) from 1987 to 1992 among the municipal wards were studied in males . METHODS: Relative risks (RR) using cases from the cancer registry and controls from a tobacco survey were estimated for the gas-affected regions . RESULTS: Based on a descriptive study the relative risks of 1.4, 1.3 and 0.7 for lung, oropharynx and oral cavity cancer, respectively, for gas-affected regions in the year 1992 in comparison to gas-unaffected regions and the year 1987-1990 combined were estimated . In the case-control study the RRs of 0.9, 1.4 and 1.2 for lung, oropharynx (adjusted for smoking) and oral cavity cancer, respectively, (adjusted for tobacco chewing) were estimated as the effect of the gas accident . CONCLUSION: The full potential of excess risk, if any, may not manifest for 15-20 years after the accident. Eur J Pharm Biopharm, 1999 Nov, 48(3), 253 - 8 Pharmacokinetics, bioavailability and absorption of flumequine in the rat; Ruiz-Garcia A et al.; The study demonstrates that the oral extent of bioavailability of flumequine in the rat, relative to the intravenous injection, is complete (0.94 +/- 0.04) and not significantly different from that found by the intraduodenal route (0.95 +/- 0.04) . The rate of oral bioavailability, however, is slow (ka = 1.20 +/- 0.07 h-1; Tmax = 2.0 h), but enough to maintain plasma levels above the minimal inhibitory concentration of the most common pathogens for an extended period of time (about 10 h) . The reason for the oral absorption slowness could be a slow gastric emptying, an adsorption to the gastric mucosae, a precipitation in the gastric medium or any other feature concerning the stomach as the intraduodenal administration is very quick (kid = 38.1 +/- 4.7 h-1; Tmax = 0.05 h) . A possible precipitation of flumequine cannot be discarded as the solubility of flumequine is very low in the pH range of 3 to 6 (mean pH values for rat stomach and rat intestine, respectively; T.T . Kararli, Biopharm . Drug Dispos . 16 (1995) 351-380) . Flumequine was shown to be not substantially excreted in bile (2-3% of the dose) . Surprisingly, plasma levels and AUC values found for animals with interrupted bile flow always surpass those found for animals with enterohepatic circulation . This could be due to experimental model features, which might bias plasmatic flumequine concentrations if the homeostatic equilibrium of the animal is not completely restored due to the volume reduction induced by biliary extraction. Curr Opin Struct Biol, 1999 Dec, 9(6), 745 - 53 MHC superfamily structure and the immune system; Maenaka K et al.; During the past year, a plethora of structural information has provided detailed insights into the interactions between classical MHC class I molecules and their cognate receptors on T cells . Likewise, there have been major advances in our knowledge of the structures and functions of five nonclassical MHC-like molecules: HLA-DM (murine H2-M), HLA-E, HFE, ZAG and MIC-A. Antimicrob Agents Chemother, 2000 Jan, 44(1), 186 - 9 Postantibiotic effects of grepafloxacin compared to those of five other agents against 12 gram-positive and -negative bacteria; Spangler SK et al.; The postantibiotic effect (PAE) (10x the MIC) and the postantibiotic sub-MIC effects (0.125, 0.25, and 0.5x the MIC) were determined for six compounds against 12 strains . Measurable PAEs ranged between 0 and 1.8 h for grepafloxacin, 0 and 2.2 h for ciprofloxacin, 0 and 3 . 1 h for levofloxacin, 0 and 2.2 h for sparfloxacin, 0 and 2.4 h for amoxicillin-clavulanate and 0 and 4.8 h for clarithromycin . Reexposure to subinhibitory concentrations increased the PAEs against some strains. Helicobacter, 1999 Dec, 4(4), 222 - 5 Quadruple therapy is effective for eradicating Helicobacter pylori after failure of triple proton-pump inhibitor-based therapy: a detailed, prospective analysis of 21 consecutive cases; Gomollon F et al.; BACKGROUND: Data regarding the effectiveness of second-line treatment of Helicobacter pylori infection are limited, especially if microbiological studies are considered . METHODS AND PATIENTS: We conducted a prospective, uncontrolled study of a consecutive series of 21 peptic ulcer patients with failure of 1-week lansoprazole, amoxicillin, and clarithromycin . H . pylori status was evaluated by urease test, histology, culture, and urea breath test . Susceptibility to amoxicillin, clarithromycin, and metronidazole was studied by E-test . Cure of infection was defined as negative results from endoscopy-based tests 1 month after treatment and negative results from a urea breath test at 2 months . Treatment consisted of a 1-week combination of lansoprazole (30 mg bid), tetracycline (500 mg qid), metronidazole (500 mg tid), and bismuth subcitrate (120 mg qid) . RESULTS: H . pylori was resistant to metronidazole in three cases, to clarithromycin in three cases, and to both clarithromycin and metroinidazole in an additional three patients . No resistance to amoxicillin was found . Eradication was obtained in 20 cases (95.2% confidence interval {CI}, 76.2-99.9) . The only patient in whom infection was not eradicated harbored a metronidazole-resistant (minimum inhibitory concentration > 32 micrograms/ml) strain . No significant side effects were reported . CONCLUSION: Quadruple therapy obtains a high eradication rate even in patients with clarithromycin- and metronidazole-resistant strains . Further randomized and controlled studies are warranted and are urgently needed. Drugs, 1999, 58 Suppl 2, 29 - 36 Pharmacokinetics and pharmacodynamics of fluoroquinolones; Turnidge J; The fluoroquinolones have moderate to excellent bioavailability, moderate to long elimination half-lives (50 to 98%) and volumes of distribution >1.5 L/kg . There is considerable variation in elimination pattern between fluoroquinolone agents, ranging from predominant renal excretion to extensive hepatic metabolism . Protein binding also varies between agents . Tissue concentrations often exceed plasma concentrations, while concentrations in CSF are modest in the presence of inflammation . Fluoroquinolones show concentration-dependent killing in vitro, and animal models have demonstrated the 24-hour AUC/MIC (area under the concentration-time curve/minimum inhibitory concentration) ratio to be the best predictor of bacterial killing in vivo, with the peak plasma concentration (Cmax)/MIC ratio being important for some bacteria, to prevent the emergence of resistance during treatment . Animal models and human studies with ciprofloxacin, grepafloxacin and levofloxacin show that a 24-hour AUC/MIC ratio of about 100, or a Cmax/MIC ratio of about 10 gives maximum clinical and bacteriological efficacy . These values can be used to predict the efficacy of different agents against different pathogens, and to define pharmacodynamic 'breakpoints'. J Antimicrob Chemother, 1999 Nov, 44(5), 697 - 700 In-vitro activity of voriconazole (UK-109,496), LY303366 and other antifungal agents against oral Candida spp . isolates from HIV-infected patients; Chavez M et al.; In this report we compare the activity of two new antifungal agents, voriconazole (UK-109,496) and LY303366 with the activities of other antifungals including fluconazole, itraconazole, 5-fluorocytosine (5FC) and amphotericin B against 219 oral Candida spp . isolates from HIV-infected patients . We used the broth microdilution method following the guidelines of the NCCLS . The in-vitro activity of voriconazole (UK-109,496) (MIC(90) 0.12 mg/L) and LY303366 (CMI(90) 0.25 mg/L) against clinical isolates of Candida spp . was excellent and comparable with that of amphotericin B (MIC(90) 0.5 mg/L), and better than those of fluconazole (MIC(90) > or = 64 mg/L), itraconazole (MIC(90) 4 mg/L) and 5FC (MIC(90) 1 mg/L). Int J Antimicrob Agents, 1999 Oct, 13(2), 109 - 15 A 1-year study of antibiotic resistance among paediatric pneumococcal isolates in 1995 from four regions of France; Chardon H et al.; The main object of this study was to describe the features of antibiotic resistance in pneumococci from children in four regions of France in 1995 . Despite the high prevalence (40%) of pneumococci with diminished susceptibilty to penicillin (PDSP), resistance to amoxycillin (0.8%) and cefotaxime (0.4%) was rare; 16% of pneumococci were resistant to penicillin G (PRP, MIC > 1 mg/l) . PDSP showed the expected resistance to macrolides (67%) and cotrimoxazole (57%) and were predominantly serotypes 23F, 14, 9 and 6 . This study by the Regional Pneumococcal Observatories confirms the high prevalence and the main characteristics of antibiotic resistance among pneumococci isolated from children . Nevertheless, the resistance to all antibiotics was lower than that found in French multicentre, nationwide surveys, possibly because of differences in the mode of strain collection and geographic origin. J Med Microbiol, 1999 Dec, 48(12), 1087 - 93 In-vivo itraconazole resistance of Aspergillus fumigatus in systemic murine aspergillosis . EBGA Network . European research group on Biotypes and Genotypes of Aspergillus fumigatus; Dannaoui E et al.; An animal model of disseminated aspergillosis was used to test the in-vivo activity of itraconazole against four isolates of Aspergillus fumigatus . Two reference isolates of A . fumigatus known to be resistant to itraconazole in vitro and in vivo were used as control isolates, and two new isolates were tested under the same conditions . For each isolate MICs for itraconazole and amphotericin B were determined by an NCCLS-based method . Mice infected intravenously were treated either with itraconazole 100 mg/ kg/day or amphotericin B 4.5 mg/kg/day for 10 days . Amphotericin B showed good in-vivo activity against all four isolates . For one strain, which had a low in-vitro MIC for itraconazole, in-vivo therapy with itraconazole prolonged the survival of mice and reduced fungal burdens in organs compared with untreated controls . In mice infected with a strain with a high MIC of >16 mg/L, itraconazole neither prolonged survival nor reduced fungal load in organs compared with controls . It is concluded that there is a relationship between MIC and treatment outcome in mice for A . fumigatus infection. Mech Dev, 2000 Jan, 90(1), 29 - 39 lacZ sequences prevent regulated expression of housekeeping genes; Cohen-Tannoudji M et al.; In order to dissect the MHC class I H-2K gene regulatory sequences, we p reviously generated transgenic mice containing various H-2K/lacZ fusion genes . However contrary to transgenes where H-2K sequences were fused to other coding sequences, none of the lacZ fusion transgenes was widely ex pressed like H-2K gene . We now show that this silencing also occurs when lacZ is inserted into a larger H-2K genomic construct including promoter and other regulatory elements . Because the 5'H-2K region contains a CpG island, we suspected that the presence of lacZ coding sequences was inte rfering with the mechanism by which the H-2K promoter region is normally unmethylated and transcriptionally active . Indeed, we show that in high ( >10) copy number transgenic mice, insertion of lacZ sequences in the v icinity of the H-2K promoter results in partial or complete methylation of the H-2K CpG island . However, in low (1-3) copy number transgenic mic e no methylation was observed but the transgene was still silent, sugges ting that the silencing effect of lacZ does not only rely on abnormal CpG methylation . Intriguingly, when the H -2/lacZ construct was introduced via embryonic stem (ES) cells, regulate d transgene expression was observed in several chimaeric embryos derived from independent ES clones, but never in adult chimeras . Combined with t he fact that, despite much effort, it has been very difficult to generat e 'blue' mice, our results highlight the transcription-silencing effect of lacZ sequences when they are associated with regulatory sequences of ubiquitously expressed genes. Mol Biochem Parasitol, 1999 Oct 25, 104(1), 81 - 91 Sterol composition and biosynthesis in Trypanosoma cruzi amastigotes; Liendo A et al.; A detailed analysis of the endogenous sterols present in the clinically relevant intracellular (amastigote) stages of Trypanosoma cruzi, is presented . The parasites were grown in cultured Vero cells in the absence or presence of different sterol biosynthesis inhibitors, including the C14alpha demethylase inhibitor ketoconazole and two inhibitors of delta24(25)-sterol methyl transferase, 20 piperidin-2-yl-5alpha-pregnan-3beta-20-R-diol (22,26-azasterol) and 24-(R,S),25-epiminolanosterol . Amastigotes were isolated and purified from their host cells and neutral lipids were extracted, separated and analyzed by chromatographic and mass spectrometric methods . Control (untreated) amastigotes contained as main endogenous sterols 24-methyl-cholesta-7-en-3beta-ol (ergosta-7-en-3beta-ol) and its 24-ethyl analog, plus smaller amounts of their precursor, ergosta-7,24(28)dien-3beta-ol; these cells also contained cholesterol (up to 80% by weight of total sterols), probably derived from host cells . Amastigotes that proliferated in the presence of 10 nM ketoconazole (minimal inhibitory concentration, MIC) for 24 h had a sharply reduced content of endogenous 4-desmethyl sterols with a concomitant accumulation of 24-methyl-dihydrolanosterol and 24-methylene-dihydrolanosterol . On the other hand, amastigotes incubated during the same period of time with the two inhibitors of 24(25)-SMT at their respective MICs (100-300 nM) accumulated large amounts of C27 sterols whose structure suggested, in the case of 22,26-azasterol, that delta14 sterol reductase was also inhibited . Ketoconazole produced a dose-dependent reduction in the incorporation of {2-(14)C}-acetate into the parasite's endogenous C4-desmethyl sterols with an IC50 of 50 nM, indistinguishable from the value reported previously for the extracellular epimastigote form . Taken together, the results showed that amastigotes have a simpler sterol biosynthetic pathway than that previously described for epimastigotes, lacking both delta5 and delta22 reductases . They also suggest that the 100-fold higher potency of antifungal azoles as antiproliferative agents against amastigotes, when compared with epimastigotes, is most probably due to a smaller pool of endogenous sterols in the intracellular parasites. J Antimicrob Chemother, 1999 Oct, 44(4), 553 - 5 In-vitro susceptibility of Aspergillus spp . isolates to amphotericin B and itraconazole; Dannaoui E et al.; The MICs of amphotericin B and itraconazole for 230 isolates of Aspergillus spp., comprising 156 Aspergillus fumigatus, 20 Aspergillus terreus, 22 Aspergillus flavus, 17 Aspergillus nidulans and 15 Aspergillus niger, were determined by a broth microdilution method with RPMI 1640 medium . No isolate was detected with an MIC of amphotericin B >2 mg/L . Itraconazole MICs >16 mg/L were detected for four Aspergillus fumigatus and one Aspergillus nidulans isolates. J Antimicrob Chemother, 1999 Oct, 44(4), 471 - 6 Cephalosporin clinical concentration-time profile modelling and in-vitro bactericidal effects on Escherichia coli; Cholewka KA et al.; We assessed the cephalosporin concentration-time curve area (AUC), peak concentration, maintained concentration and duration of exposure on in-vitro bactericidal effects on Escherichia coli NCTC 10418, using exposures modelling cephazolin clinical profiles after 1 g and 2 g i.m . injection, equal AUC exposures (288 mg x h/L, 576 mg x h/L; 48 h) and constant exposures to 6, 12 and 24 mg/L . Cephalosporin dosage exposures based on maintenance of concentrations at multiples (6-24 times) of the MIC were not as effective in early or sustained (24 h) bactericidal effect as exposures modelling im injection profiles with equal or lower AUC (P<0.05, ANOVA) . Similar results applied to i.m . comparisons with equal AUC exposures modelling extremes of concentration and time exposures . These results indicate a need for intermittent dosage to produce optimally effective profiles, and raise the possibility that these optimum dosing profiles may allow an extension of minimum interdose intervals beyond 8 h. Antimicrob Agents Chemother, 1999 Dec, 43(12), 3030 - 2 Comparative bacteriostatic and bactericidal activities of cefodizime against Borrelia burgdorferi sensu lato; Murgia R et al.; The MIC and MSC (minimum spirocheticidal concentration) and killing rate for Borrelia burgdorferi, the etiological agent of Lyme disease, were assessed for cefodizime in comparison with ceftriaxone, minocycline, azithromycin, roxithromycin, and ciprofloxacin . The range of cefodizime MICs was greater than those of azithromycin and roxithromycin but comparable to those of ceftriaxone and minocycline . The MSCs were 1 to 2 dilutions higher than the MICs of all of the tested compounds . The killing curves of cefodizime and ceftriaxone showed parallel courses . In conclusion, cefodizime exerted an activity comparable to that of ceftriaxone against B . burgdorferi. Antimicrob Agents Chemother, 1999 Dec, 43(12), 2922 - 4 High-dose isoniazid therapy for isoniazid-resistant murine Mycobacterium tuberculosis infection; Cynamon MH et al.; The use of isoniazid (INH) for the treatment of INH-resistant Mycobacterium tuberculosis infection has been controversial . The purpose of the present studies was to determine if there is a dose response with INH for INH-susceptible M . tuberculosis Erdman (ATCC 35801), and whether high-dose INH (100 mg/kg of body weight) was more effective than standard-dose INH (25 mg/kg) for therapy of tuberculosis infections caused by INH-resistant mutants of M . tuberculosis Erdman . Six-week-old CD-1 mice were infected with approximately 10(7) viable mycobacteria . Early control groups of infected but untreated mice were euthanized by CO(2) inhalation 1 week later when treatment was initiated . INH (25, 50, 75, and 100 mg/kg) was given by gavage 5 days/week for 4 weeks . Late control groups of untreated mice and treated mice were sacrificed 2 days after the last dose of drug . Spleens and right lungs were removed aseptically and homogenized, and viable cell counts were determined by titration on 7H10 agar plates . In the next study, INH at 100 mg/kg was compared to INH at 25 mg/kg against an isogenic mutant of M . tuberculosis Erdman (INH MIC, 2 microg/ml) and the parent strain . This mutant was found to have a mutation in the KatG protein (Phe to Leu at position 183) . In the first study, there was no dose response with increasing doses of INH . In the second study, there was no significant difference between the reduction of viable cell counts for mice treated with INH at 100 mg/kg and that for mice treated with INH at 25 mg/kg (parent or INH-resistant mutant) . These preliminary results suggest that INH may be useful in combination therapy of M . tuberculosis infections caused by low-level INH-resistant organisms (INH MICs, 0.2 to 5 microg/ml) and that higher doses of INH are unlikely to be more efficacious than the standard 300-mg/day dose. Antimicrob Agents Chemother, 1999 Dec, 43(12), 2898 - 903 Activities of poloxamer CRL-1072 against Mycobacterium avium in macrophage culture and in mice; Jagannath C et al.; Earlier studies reported that certain large hydrophobic poloxamer surfactants were able to inhibit the growth of Mycobacterium avium-M . intracellulare complex (MAI) in broth and to produce synergistic enhancement of the activity of rifampin . CRL-1072 was synthesized to have an optimal structure for antimicrobic effects and greater purity . Its MIC for MAI in broth was greater than 100 microg/ml . Surprisingly, its MIC for MAI growing in human U937 monocytoid cells was much lower, 5 microg/ml . A still lower concentration, 0.1 microg/ml, produced synergistic enhancement of the activities of clarithromycin, rifampin, amikacin, streptomycin, and clindamycin, but not isoniazid, against MAI infecting monocytoid cells . Mice tolerated injection of doses of CRL-1072 as high as 125 mg/kg of body weight . Pharmacokinetic analysis revealed that the copolymer had an elimination half-life of 60 h and suggested dosing regimens that might produce therapeutic concentrations in tissue . In a mouse model of acute MAI infection, CRL-1072 significantly enhanced the bactericidal activities of clarithromycin and rifampin when it was administered at 1.0 mg/kg intravenously (i.v.) three times per week . CRL-1072 given i.v . or orally also enhanced the bactericidal activity of clindamycin against MAI. Ann Oncol, 1999, 10 Suppl 5, S25 - 8 Ifosfamide in non-small-cell lung cancer; Rosell R et al.; Ifosfamide has been used in combination with several drugs including cisplatin, giving rise to multiple doublets and triplets including the ifosfamide-cisplatin-mitomycin regimen (Cullen's MIC regimen) that has been commonly used in Europe . However, new combinations are challenging the activity of the old chemotherapy regimens, especially in terms of objective response rate and time to progressive disease, as has been shown in several phase III randomized trials . Among these new combinations, ifosfamide-vinorelbine and ifosfamide-gemcitabine-cisplatin are especially promising . In this paper, several ifosfamide doublets and triplets are reviewed. Vet Rec, 1999 Oct 2, 145(14), 397 - 9 Pharmacokinetics of florfenicol after treatment of pigs with single oral or intramuscular doses or with medicated feed for three days; Voorspoels J et al.; The pharmacokinetics of florfenicol, a structural analogue of thiamphenicol, were studied in six pigs after single oral and intramuscular doses of 15 mg/kg bodyweight, and after feeding them with medicated feed containing 250 mg/kg for three days, a concentration which provided approximately the same dose rate of the drug . The oral doses contained a specially prepared pelleted formulation of the drug . The bioavailability of the drug was similar for the oral and intramuscular doses . Florfenicol was absorbed rapidly from the feed and its concentration in plasma remained between 2 and 6 microg/ml - above the minimum inhibitory concentration values for common pig pathogens - during the three days. J Chromatogr B Biomed Sci Appl, 1999 Oct 29, 734(1), 121 - 7 Determination of cefepime and cefpirome in human serum by high-performance liquid chromatography using an ultrafiltration for antibiotics serum extraction; Breilh D et al.; The aim of this study was to describe a high-performance liquid chromatography (HPLC) assay for the determination of cefepime and cefpirome in human serum without changing chromatographic conditions . The assay consisted to measure cefepime and cefpirome which were unbound to proteins having a molecular mass of 10,000 or more by ultrafiltration followed by HPLC with a Supelcosil ABZ+ column and UV detection at a wavelength of 263 nm . The assay was been found to be linear and has been validated over the concentration range 200 to 0.50 microg/ml for both cefepime and cefpirome, from 200 microl serum, extracted . In future, the assay will support therapeutic drug monitoring for cefepime and cefpirome in neutropenic patients in correlation with microbiological parameters such as MIC90 (minimal inhibitory concentration of antibiotic which kills 90% of the initial bacterial inoculum) and clinical efficacy. Hum Pathol, 1999 Nov, 30(11), 1356 - 60 Absence of EWS/FLI1 fusion in olfactory neuroblastomas indicates these tumors do not belong to the Ewing's sarcoma family; Kumar S et al.; The balanced reciprocal translocation t(11;22)(q24;q12) is a specific molecular marker for the Ewing's sarcoma family of tumors (ESFT) . Based on the detection of this translocation in some olfactory neuroblastomas (ONBs), it has been proposed that ONBs also belong to the ESFT . Others have challenged this hypothesis; however, the rarity of ONBs, as well as the lack of molecular techniques that work reliably on formalin fixed tissue, have precluded the molecular analysis of a significant number of cases . We evaluated the immunophenotypic and molecular features of 17 paranasal small round neuroectodermal tumors using routinely fixed tissue . Probes localizing to 22q12 (EWS) and 11q24 (FLI-1) were used in a standard 2-color fluorescence in situ hybridization (FISH) assay to evaluate EWS/FLI1 fusion on the der(22) . Sixteen tumors were mic-2 negative, whereas 1 tumor was mic-2 positive, compatible with ONB and ESFT, respectively . Thirteen of 15 ONBs could be evaluated by FISH, and all 13 were negative for the EWS/FLI1 fusion . Distinct fusion signals were identified in the single paranasal ESFT . Our findings indicate that ONBs lack the EWS/FLI1 fusion and are unrelated to the ESFT; however, true ESFTs may rarely occur as primary sinonasal tumors. J Clin Microbiol, 1999 Dec, 37(12), 3856 - 9 Detection of fluconazole-resistant Candida strains by a disc diffusion screening test; Sandven P; A commercial disc diffusion test has been evaluated as a screening method for the detection of Candida species with decreased susceptibility to fluconazole . A total of 1,407 Candida strains of different species were tested, and the results were compared with the MIC results . The recently published National Committee for Clinical Laboratory Standards breakpoint criteria have been used . Isolates were classified as susceptible if the MIC for the isolates was </=8 microg/ml, susceptible-dose dependent (S-DD) if the MIC was 16 to 32 microg/ml, and resistant if the MIC was >/=64 microg/ml . All 77 resistant strains and 121 of 122 S-DD strains had fluconazole zone diameters of </=21 mm, and most of the strains (91%) had zone diameters of </=15 mm . It was not possible to distinguish between resistant and S-DD strains by the disc test . Among a total of 1,208 strains found to be susceptible by the microdilution method, 49 (4 . 1%) yielded fluconazole zone sizes of </=21 mm and would have been misclassified as resistant or S-DD strains on the basis of the disc test . For the majority (86%) of these 49 strains the fluconazole MIC was 8 microg/ml . The fluconazole disc test is recommended as a simple and reliable screening test for the detection of Candida strains with decreased susceptibility to fluconazole . Fluconazole MICs should be determined for strains found to be resistant by the disc test . The reason for confirmatory testing is twofold: to determine if isolates are resistant or S-DD, since the disc test does not make this distinction, and to identify fluconazole-susceptible strains that are found to be falsely resistant by the fluconazole disc test. Kansenshogaku Zasshi, 1999 Oct, 73(10), 1054 - 63 {Therapeutic effects of antibiotics against enterohemorrhagic Escherichia coli (EHEC) O157:H7 (O157) infection: in vivo analysis using germfree mice}; Sawamura S et al.; Though O157 can cause a life-threatening diseases, the therapeutic protocol using antibiotics for the infection is still controversial . Main reasons for hesitating the uses of antibiotics for the infection is their possibility to enhance the release of verotoxins (VT) . We have recently established the mouse model of O157 infection using germfree mice . Using this animal model of O157 infection, we examined therapeutic efficacy of antibiotics . Fosfomycin (FOM) and norfloxacin (NFLX) were selected for in vivo examination, because of their lower MIC under anaerobic condition (MIC:FOM = 0.78; NFLX = 0.10 microgram/ml) than those of the other antibiotics including kanamycin, doxycycline, minocycline, choramphenicol, cefaclor and ampicilin . When germfree BALB/c mice were orally infected with 1 x 10(5)CFU of O157 (clinically-isolated strain, TI001) at day 0, all mice died at 8 to 9 d after the infection . Oral treatment of the mice with FOM (500 mg/kg/d, twice a day) or NFLX (50 mg/kg/d, twice a day) everyday for 5 days starting at 3 hr after the infection significantly improved the survival rate from 0% to 83.3%, and 100%, respectively . VT could not be detected in the feces of the mice in either groups, suggesting that neither of these antibiotics enhanced the release of VT . Interestingly, when FOM treatment was started at 3, 6, 12 or 24 hr after the infection, the survival rate was 100%, 100%, 0% and 0%, respectively . Thus, in conclusion, FOM and NFLX are both useful as the therapeutic agents for O157 infection . However, the treatment should be started in the early phase after the infection. Proc Natl Acad Sci U S A, 1999 Nov 9, 96(23), 13282 - 7 Molecular dynamics of MHC genesis unraveled by sequence analysis of the 1,796,938-bp HLA class I region; Shiina T et al.; The intensely studied MHC has become the paradigm for understanding the architectural evolution of vertebrate multigene families . The 4-Mb human MHC (also known as the HLA complex) encodes genes critically involved in the immune response, graft rejection, and disease susceptibility . Here we report the continuous 1,796,938-bp genomic sequence of the HLA class I region, linking genes between MICB and HLA-F . A total of 127 genes or potentially coding sequences were recognized within the analyzed sequence, establishing a high gene density of one per every 14.1 kb . The identification of 758 microsatellite provides tools for high-resolution mapping of HLA class I-associated disease genes . Most importantly, we establish that the repeated duplication and subsequent diversification of a minimal building block, MIC-HCGIX-3.8-1-P5-HCGIV-HLA class I-HCGII, engendered the present-day MHC . That the currently nonessential HLA-F and MICE genes have acted as progenitors to today's immune-competent HLA-ABC and MICA/B genes provides experimental evidence for evolution by "birth and death," which has general relevance to our understanding of the evolutionary forces driving vertebrate multigene families. Curr Eye Res, 1999 Dec, 19(6), 461 - 4 The effect of long-term use and inflammation on the ocular penetration of topical ofloxacin; Ozturk F et al.; PURPOSE . To study the penetration of ofloxacin into the aqueous and vitreous humors after long-term topical administration and to investigate the effects of inflammation on drug penetration in rabbits . METHODS . A standardized model of intraocular infection after penetrating injury was achieved in the right eyes of 16 rabbits . The animals were randomly and equally divided into two groups . The intact left eyes of the groups were maintained as the control . Ofloxacin eyedrops (0.3%) were instilled into all eyes at a frequency of 2 drops every hour for 7 hours in the first group and for 14 hours in the second group . Half an hour after the last drop, samples of the aqueous and vitreous humors were taken and ofloxacin concentrations were measured by using HPLC . RESULTS . The mean aqueous humor concentrations of ofloxacin in control eyes after 7 and 14 hours of instillation were: 1.45 +/- 0.93 microg/ml and 2.48 +/- 0.33 microg/ml, respectively; those in infected eyes 2.35 +/- 1 . 84 microg/ml and 3.49 +/- 1.47 microg/ml, respectively . However the differences among the groups were not significant (p > 0.05) . The vitreous ofloxacin concentrations in the control eyes were similar after 7 and 14 hours of instillation (0.23 +/- 0.14 microg/ml, 0.27 +/- 0.10 microg/ml, respectively) . In infected eyes, the mean vitreous ofloxacin concentration after 14 hour of instillation was significantly higher than that in control eyes (p < 0.05; 0.4 +/- 0 . 09 microg/ml, 0.29 +/- 0.11 microg/ml, respectively) . The mean vitreous ofloxacin concentration in infected eyes after 14 hours instillation was not significantly higher than that after 7 hours instillation . CONCLUSIONS . Topical ofloxacin instillation for 7 or 14 hours yields aqueous concentrations above the MIC(90) for common ocular pathogens . Prolonged application and the presence of inflammation increased the penetration of ofloxacin into the vitreous humor. J Colloid Interface Sci, 1999 Dec 1, 220(1), 57 - 62 Effect of Oxypropylene Chain Length on the Surface Properties of Dialkyl Glycerol Ether Nonionic Surfactants; Chlebicki J et al.; In this work, as a continuation of our studies concerning the preparation and surface properties of nonionic surfactants, derivatives of 1,3-dialkoxy-2-propanols and 1,3-dialkoxy(oligooxypropylene)-2-propanols with oligooxypropylene chains have been synthesized and investigated . The surface activity of these compounds has been determined, i.e., critical micelle concentration (CMC), surface excess concentration (Gamma), surface area demand per molecule (A), surface tension at CMC (gamma(CMC)), DeltaG(ads)( degrees ), and DeltaG(mic)( degrees ) . A linear decrease of the log CMC vs number of oxypropylene groups is observed, and based on the Shinoda equation the work of cohesion per oxypropylene group when passing from molecular to micellar state is calculated for 0.43 kT . The equivalent of CH(2) in the aliphatic alcohol group is ca . 2.50 oxypropylene units . Surface properties of these surfactants, i.e., cloud point, wetting ability, contact angle, foam height, and emulsion stability type (O/W), have been determined as well . J Clin Oncol, 1999 Nov, 17(11), 3522 - 30 Gemcitabine and cisplatin versus mitomycin, ifosfamide, and cisplatin in advanced non-small-cell lung cancer: A randomized phase III study of the Italian Lung Cancer Project; Crino L et al.; PURPOSE: To compare gemcitabine and cisplatin (GC) with mitomycin, ifosfamide, and cisplatin (MIC) chemotherapy in patients with stage IIIB (limited to T4 for pleural effusion and N3 for supraclavicular lymph nodes) or stage IV non-small-cell lung cancer (NSCLC) . The end points were the evaluation of quality of life (QoL), response rates, survival, and toxicity . PATIENTS AND METHODS: Three hundred seven patients were randomized to receive either gemcitabine 1,000 mg/m(2) on days 1, 8, and 15 plus cisplatin 100 mg/m(2) on day 2, every 28 days, or mitomycin 6 mg/m(2), ifosfamide 3,000 mg/m(2), and mesna on day 1 plus cisplatin 100 mg/m(2) on day 2, every 28 days . The whole-blood cell count was repeated on day 1 in both arms and weekly in the GC arm before each gemcitabine administration . RESULTS: No major differences in changes in QoL were observed between the two treatment arms . The objective response rate was 38% in the GC arm compared with 26% in the MIC arm (P =.029) . The median survival time was 8.6 months in the GC arm and 9.6 months in the MIC arm (P =.877, log-rank test) . Grade 3 and 4 thrombocytopenia was significantly worse in the GC arm (64% v 28%, P <.001), whereas grade 3 and 4 alopecia was reported more commonly in the MIC arm (39% v 12%, P < . 001) . CONCLUSION: We report an increased response rate without changes in QoL and a similar overall survival, time to progression, and time to treatment failure for the GC when compared with the MIC regimen in the treatment of advanced NSCLC. Biol Pharm Bull, 1999 Oct, 22(10), 1141 - 3 Anti-Helicobacter pylori activity of quinolone alkaloids from Evodiae fructus; Rho TC et al.; A biologically monitored fractionation of methanol extract of the fruit of Evodia rutaecarpa led to the isolation of six quinolone alkaloids, evocarpine (1), 1-methyl-2-{(4Z,7Z)-4,7-tridecadienyl}-4(1H)-quinolone (2), 1-methyl-2-{(6Z,9Z)-6,9-pentadecadienyl}-4(1H)-quinolo ne (3), 1-methyl-2-undecyl-4(1H)-quinolone (4), dihydroevocarpine (5), 1-methyl-2-pentadecyl-4(1H)-quinolone (6) . They showed potent anti-Helicobacter pylori activity with the minimum inhibitory concentration (MIC) value of 10-20 microg/ml . However, they had no effect on Helicobacter pylori urease activity at the concentration of 300 microg/ml. J Nat Prod, 1999 Oct, 62(10), 1353 - 7 In vitro evaluation of antifungal properties of phenylpropanoids and related compounds acting against dermatophytes; Zacchino SA et al.; Thirty-four arylpropanoids and related compounds were evaluated in vitro for antifungal properties . Among them, 22 phenyl-, 4 naphthyl-, and 4 phenanthrylpropanoids; naphthalene; phenanthrene; and 2-chloro-1-hexyl-1-propanone were tested against dermatophytes by the agar dilution method . alpha-Halopropiophenones exhibited a broad spectrum of activities against Microsporum canis, Microsporum gypseum, Trichophyton mentagrophytes, Trichophyton rubrum, and Epidermophyton floccosum, with MIC values between 0.5 and >50 microg/mL . Keto, alcohol, and alpha-haloketo propyl derivatives of naphthalene and phenanthrene also showed very good activity against all dermatophytes tested, clearly showing that in these series, a halogen atom is not necessary for activity . Phenanthryl derivatives were more active (MICs, 3-20 microg/mL) than naphthyl ones (MICs, 3-50 microg/mL) . A structure-activity relationship study was carried out and aided in establishing the structural requirements of arylpropanoids for antifungal activities . Because dermatophytes are a group of fungi that characteristically infect the keratinized areas of the body, these new series of antifungal compounds open the possibility of discovering new topical antifungal drugs for the treatment of dermatomycoses, which are frequently very difficult to eradicate. Antimicrob Agents Chemother, 1999 Nov, 43(11), 2806 - 7 In vitro activities of gemifloxacin (SB 265805, LB20304) against recent clinical isolates of Chlamydia pneumoniae; Roblin PM et al.; We compared the in vitro activity of gemifloxacin, a new quinolone antibiotic, to the activities of levofloxacin, moxifloxacin, trovafloxacin, erythromycin, and doxycycline against 20 isolates of Chlamydia pneumoniae . Gemifloxacin was the most active quinolone tested, with a MIC at which 90% of the isolates are inhibited and a minimal bactericidal concentration at which 90% of strains tested are killed of 0.25 microg/ml, but this activity was less than those of doxycycline and erythromycin. Antimicrob Agents Chemother, 1999 Nov, 43(11), 2600 - 6 Drug tolerance in Mycobacterium tuberculosis; Wallis RS et al.; Although Mycobacterium tuberculosis is eradicated rapidly during therapy in some patients with pulmonary tuberculosis, it can persist for many months in others . This study examined the relationship between mycobacterial drug tolerance (delayed killing in vitro), persistence, and relapse . It was performed with 39 fully drug-susceptible isolates from a prospective trial of standard short-course antituberculous therapy with sputum smear-positive, human immunodeficiency virus-uninfected subjects with pulmonary tuberculosis in Brazil and Uganda . The rate of killing in vitro was determined by monitoring the growth index (GI) in BACTEC 12B medium after addition of drug to established cultures and was measured as the number of days required for 99% sterilization . Drugs differed significantly in bactericidal activity, in the following order from greatest to least, rifampin > isoniazid-ethambutol > ethambutol (P < 0.001) . Isolates from subjects who had relapses (n = 2) or in whom persistence was prolonged (n = 1) were significantly more tolerant of isoniazid-ethambutol and rifampin than isolates from other subjects (P < 0.01) . More generally, the duration of persistence during therapy was predicted by strain tolerance to isoniazid and rifampin (P = 0.012 and 0.026, respectively) . Tolerance to isoniazid-ethambutol and tolerance to rifampin were highly correlated (P < 0.001) . Tolerant isolates did not differ from others with respect to the MIC of isoniazid; the rate of killing of a tolerant isolate by isoniazid-ethambutol was not increased at higher drug concentrations . These observations suggest that tolerance may not be due to drug-specific mechanisms . Tolerance was of the phenotypic type, although increased tolerance appeared to emerge after prolonged drug exposure in vivo . This study suggests that drug tolerance may be an important determinant of the outcome of therapy for tuberculosis. Acta Obstet Gynecol Scand, 1999 Oct, 78(9), 818 - 23 Pathological indications for conservative therapy in treating cervical cancer; Okamoto Y et al.; BACKGROUND: Neodymium-ytlium, argon, gadolinium (Nd-YAG) laser conization was performed in 366 patients with carcinoma in situ (CIS), and 198 with microinvasive carcinoma (MIC), and 29 with early invasive cancer (IC) . The diagnostic accuracy was 72.5% in the CIS group, and 74.6% in the MIC and early IC group . RESULTS: All of the patients who obtained complete excision are now alive and doing well following the conization, with no evidence of recurrence of the disease . Incomplete excision was found in 21.7% of the MIC, 50.0% of the IC with 3 mm or less invasion, 22.2% of the IC with 3.1-4 mm, 60.0% of the IC with 4.1-5 mm invasion, 100% of the IC with 5 mm or more invasion . The residual rate of the MIC and IC with 4 mm or less invasion was 8.5%, lower than 62.5% of the IC with 4.1-5 mm invasion . The cure rate by conization in the patients with IC of 4.0 mm or less was much higher than that in the patients with IC of over 4.1 mm . CONCLUSIONS: These results suggested that the indication of laser conization for early IC was the case within 4 mm invasion, completely excised. Pediatr Infect Dis J, 1999 Oct, 18(10), 882 - 8 Rifapentine pharmacokinetics in adolescents; Marshall JD et al.; OBJECTIVE: Determination of rifapentine pharmacokinetics in healthy adolescent children . DESIGN: Prospective Phase II clinical trial . SETTING: Clinical research center within a university children's hospital . PATIENTS: Twelve subjects ranging in age from 12 to 15 years, male and female . INTERVENTIONS: A single oral dose of rifapentine was administered to healthy adolescent volunteers, 450 mg if <45 kg or 600 mg if > or =45 kg . Blood was collected at serial intervals (0, 2, 3, 4, 5, 6, 8, 12, 18, 24, 48 and 72 h postdose) . Subjects were observed for adverse effects during the period of study . MEASUREMENTS: High pressure liquid chromatography was used to measure the plasma concentration of rifapentine and 25-desacetyl rifapentine in each blood sample . For each subject a plot of mean plasma concentration vs . time data for rifapentine and its metabolite (i.e . 25-desacetyl rifapentine) were created . Subsequently model-independent methods were used to determine the pharmacokinetic profiles for each subject . RESULTS: All subjects tolerated rifapentine without adverse effects . The 2-h postdose plasma concentrations of rifapentine (6.59 to 9.05 microg/ml) and 25-desacetyl rifapentine (0.57 to 2.64 microg/ml) far exceeded the MIC of Mycobacterium tuberculosis to rifapentine (approximately 0.12 microg/ml) . The combination of a high Cmax (rifapentine, 9.95 to 18.63 microg/ml; 25-desacetyl rifapentine, 3.73 to 7.46 microg/ml) and lengthy terminal elimination phase t1/2 (rifapentine, 10 to 23 h; 25-desacetyl rifapentine, 14 to 35 h) resulted in potentially effective plasma concentrations of both compounds that persisted for at least 48 h in most subjects . CONCLUSIONS: A well-tolerated oral rifapentine dose produced rapid and sustained plasma drug concentrations in adolescents that should effectively treat infections caused by M . tuberculosis . Rifapentine pharmacokinetics appears to be similar in adolescent and adult populations. Gene, 1999 Sep 3, 237(1), 105 - 11 Characterization of the rat, mouse, and human genes of growth/differentiation factor-15/macrophage inhibiting cytokine-1 (GDF-15/MIC-1); Bottner M et al.; We have isolated the rat, mouse and human genes of a distant member of the TGF-beta superfamily, growth/differentiation factor-15/macrophage inhibiting cytokine-1 (GDF-15/MIC-1) by screening of genomic libraries . All three genes are composed of two exons, and contain one single intron that interrupts the coding sequences at identical positions within the prepro-domain of the corresponding proteins . The predicted proteins contain the structural hallmarks of members of the TGF-beta superfamily, including the seven conserved carboxy-terminal cysteine residues that form the cystine knot . The orthologous molecules show the lowest sequence conservation of all members of the TGF-beta superfamily . RT-PCR reveals an abundant expression of GDF-15/MIC-1 mRNA in numerous embryonic and adult organs and tissues . Promoter analysis of the rat promoter indicates the presence of multiple regulatory elements, including a TATA-like sequence as well as several SP1, AP-1 and AP-2 sites . Deletion analysis suggests that a 350 bp region upstream of the start of the open reading frame appears to be the most important for regulation of transcription. J Clin Endocrinol Metab, 1999 Oct, 84(10), 3701 - 7 Microsatellite polymorphism of the MHC class I chain-related (MIC-A and MIC-B) genes marks the risk for autoimmune Addison's disease; Gambelunghe G et al.; The major histocompatibility complex class I chain-related MIC-A and MIC-B genes are located on chromosome 6 between the histocompatibility leucocyte antigen (HLA)-B and the B-associated transcript genes . The presence of 21-hydroxylase autoantibodies is a sensitive and specific marker of autoimmune Addison's disease . We studied the polymorphism of exon 5 of the MIC-A gene, of intron 1 of the MIC-B gene, and of HLA-DRB1, -DQA1, and -DQB1 genes in 28 autoimmune (21-hydroxylase autoantibody positive) Addison's disease patients and in 75 healthy subjects from central Italy . The MIC-A5.1 allele was significantly more frequent in Addison's disease patients (79%) than in healthy subjects (36%) {odds ratio (OR) = 6.52, corrected P (Pc) = 0.0015}, whereas MIC-A6 was significantly reduced in affected subjects (15% vs . 56%, OR = 0.13, Pc = 0.002) . The A5.1/A5.1 genotype had an OR for autoimmune Addison's disease as high as 18.0 and an absolute risk of 1 per 1131 . In the presence of MIC-A5.1, MICB-CA-25 was significantly increased in Addison's disease patients (25% vs . 4%, OR = 8.0, P = 0.0039, Pc = 0.047) . The MICB-CA-17 allele was absent in Addison's disease patients, but present in more than 25% healthy individuals (OR = 0.10, P = 0.0025, Pc = 0.03) . Among HLA-DR and -DQ haplotypes, only DRB1*03-DQA1*0501-DQB1*0201 (DR3/DQ2) was significantly more frequent in Addison's disease patients than in healthy subjects, but only in the presence of MIC-A5.1 . The frequency of MIC-A5.1 was significantly increased in Addison's disease patients only in the presence of HLA-DR3-DQ2 . Our study demonstrates that susceptibility to autoimmune Addison's disease is linked to the MIC-A microsatellite allele 5.1 and that both MIC-A5.1 and HLA-DR3/DQ2 are necessary to confer increased genetic risk for Addison's disease. Hepatogastroenterology, 1999 Jul-Aug, 46(28), 2363 - 71 A three-day course of intravenous omeprazole plus antibiotics for H . pylori-positive bleeding duodenal ulcer; Sheu BS et al.; BACKGROUND/AIMS: This prospective trial aimed to test the efficacy of 3-day intravenous omeprazole plus antibiotics for Helicobacter pylori (H . pylori) eradication rate, and to see whether individualized response to omeprazole in intragastric pH elevation will alter the success of eradication . METHODOLOGY: One hundred and thirty-eight cases with H . pylori-positive duodenal ulcer bleeding were randomized into four therapy groups: Group 1 (n = 32) received a 3-day course of intravenous omeprazole (80 mg loading then 40 mg q 9 am & 9 pm) plus ampicillin/salbactum (1.5 gm i.v . loading then 750 mg q 9 am, 3 pm, & 9 pm); Group 2 (n = 35) followed protocol as for Group 1 except the antibiotics were metronidazole and erythromycin (both 500 mg i.v . q 9 am, 3 pm, & 9 pm) . Group 3 (n = 31) followed protocol as for Group 1 and further added with erythromycin (both 500 mg i.v . q 9 am, 3 pm, & 9 pm) . Group 4 served as a control group (n = 40) receiving oral dual therapy after leaving the emergency room (omeprazole 20 mg and amoxycillin 1 g bid x 2 weeks) . In each case, three gastric biopsies were done for total histologic density of H . pylori (THPD) (range: 0-15) before, 1 day and 6 weeks after completion of therapy . Except for the control group, the 24-hour ambulatory intragastric pH meter (MIC Inc, Gastrograph Spark III, Swiss) was inserted as possible on the 2nd day of therapy . RESULTS: The 3-day intravenous regimens achieved high clearance rates of H . pylori (Group 1: 93.8%; Group 2: 93.9%; Group 3: 100%) . The eradication rates of H . pylori in Groups 1-4 were 43.8%, 57.1%, 58.1%, and 72.8%, respectively . In Groups 1-3, the H . pylori-eradicated cases had lower pre-treatment THPD than non-eradicated cases (6.01 vs . 9.24, p < 0.001) . Among 72 cases with pH meter insertion, the percentage of intragastric pH > 5.3 during 24-hour was not different among 35 H . pylori non-eradicated and 37 eradicated cases (78.7 vs . 76.7%, p > 0.05) . CONCLUSIONS: The 3-day intravenous regimens may achieve clearance of H . pylori quickly . However, they were not so effective for eradication, especially in cases with higher bacterial loads . The interindividual response to omeprazole in intragastric pH elevation under the study dosage had insignificant variations to alter the success of eradication. Toxicon, 1999 Dec, 37(12), 1803 - 25 A neurophysiological method of rapid detection and analysis of marine algal toxins; Kerr DS et al.; We have examined the effectiveness of the in vitro rat hippocampal slice preparation as a means of rapidly and specifically detecting the marine algal toxins saxitoxin, brevetoxin, and domoic acid and have identified toxin-specific electrophysiological signatures for each . Brevetoxin (PbTX3, 50-200 nM) produced a significant reduction in orthodromic population spike amplitude which was quick to reverse during a 50 min wash-out, while antidromic population spikes and field EPSPs exhibited only slight reductions, and fibre spiof orthodrokes showed no change at all . Domoic acid (100 nM) produced a robust, reversible increase in amplitude mic spikes, and the appearance of multiple spikes (i.e., epileptiform activity) within minutes of toxin wash-in . Other notable features of the domoic acid signature included a significant decrease in amplitude of the field EPSPs, and a complete absence of effect on either antidromic or fibre spikes . Fifty nanomolar saxitoxin (PSP) abolished all responses in all slices . Only antidromic spikes showed any recovery during wash-out . Field EPSP and fiber spike analysis further demonstrated that the preparation is capable of reliably detecting saxitoxin in a linearly responsive fashion at toxin concentrations of 25-200 nM, and tests of naturally contaminated shellfish confirmed the utility of this assay as a screening method for PSP . Our findings suggest that the in vitro hippocampal slice preparation has potential in the detection and analysis of three marine algal toxins important to the shellfish industry. Microbiology, 1999 Sep, 145 ( Pt 9), 2549 - 57 Tellurite-mediated thiol oxidation in Escherichia coli; Turner RJ et al.; The oxyanion of tellurium, tellurite (TeO3(2-)), is toxic to most micro-organisms, particularly gram-negative bacteria . The mechanism of tellurite toxicity is presently unknown . Many heavy metals and oxyanions, including tellurite, interact with reduced thiols (RSH) . To determine if tellurite interaction with RSH groups is involved in the toxicity mechanism, the RSH content of Escherichia coli cultures was assayed . After exposure to tellurite, cells were harvested and lysed in the presence of the RSH-specific reagent 5,5'-dithiobis(2-nitrobenzoic acid) . Upon exposure of tellurite-susceptible cells to TeO3(2-), the RSH content decreased markedly . Resistance to potassium tellurite (Te(r)) in gram-negative bacteria is encoded by plasmids of incompatibility groups IncFI, IncP alpha, IncHI2, IncHI3 and IncHII, as well as the tehAtehB operon from the E . coli chromosome . When cells harbouring a Te(r) determinant were exposed to TeO3(2-), only a small fraction of the RSH content became oxidized . In addition to tellurite-dependent thiol oxidation, the resistance of E . coli mutants affected in proteins involved in disulfide-bond formation (dsb) was investigated . Mutant strains of dsbA and dsbB were found to be hypersensitive to tellurite (MIC 0.008-0.015 microg K2TeO3 ml(-1) compared to wild-type E . coli with MICs of 1-2 microg K2TeO3 ml(-1)) . In contrast, dsbC and dsbD mutants showed no hypersensitivity . The results suggest that hypersensitivity to tellurite is reliant on the presence of an isomerase activity and not the thiol oxidase activity of the Dsb proteins . The results establish that the Te(r) determinants play an important role in maintaining homeostasis of the intracellular reducing environment within gram-negative cells through specific reactions with either TeO3(2-) or thiol:tellurium products. J Nat Prod, 1999 Sep, 62(9), 1341 - 2 New antimycobacterial saponin from Colubrina retusa; ElSohly HN et al.; A new jujubogenin saponin was isolated from the stems of Colubrina retusa and identified as jujubogenin 3-O-alpha-L-arabinofuranosyl (1-->2)-{3-O-(trans)-p-coumaroyl-beta-D-glucopyranosyl (1-->3)}-alpha-L-arabinopyranoside (4) on the basis of chemical and spectroscopic data . The antimycobacterial activity expressed as minimum inhibitory concentration (MIC) for compound 4 was 10 microg/mL. Arthritis Rheum, 1999 Sep, 42(9), 1961 - 6 Association analysis between the MIC-A and HLA-B alleles in Japanese patients with Behçet's disease; Mizuki N et al.; OBJECTIVE: Behcet's disease is known to be strongly associated with HLA-B51 in many different ethnic groups . Recently, by association analysis using refined microsatellite mapping, the critical region for Behcet's disease was identified as a 46-kb segment centromeric to the HLA-B gene . No expressed gene has been detected in this segment to date except the MIC-A (major histocompatibility complex class I chain-related gene A) and HLA-B genes . The present study was undertaken to analyze allelic distribution of the MIC-A gene among Japanese patients with Behcet's disease . METHODS: Ninety-five Japanese patients with Behcet's disease and 116 ethnically matched healthy controls were enrolled in this study . MIC-A genotyping was performed by direct sequencing of polymerase chain reaction products from exons 2, 3, and 4 of the MIC-A gene, using an automated DNA sequencer . RESULTS: The MIC-A009 allele was significantly more frequent in the patient group (69.5%) compared with the healthy controls (31.0%) (relative risk 5.06, corrected P = 0.00000024) . In stratification analysis on the confounding effect of MIC-A009 on HLA-B*51 association and vice versa, Behcet's disease was distinctively associated only with HLA-B*51 . Further, MIC-A009 was found to be strongly associated not only with HLA-B51, but also with HLA-B52, which was not increased in the patient group to any degree . CONCLUSION: These results