Thiosemicarbazole (thiacetazone-like) compound with activity against Mycobacterium avium in mice

In vitro screening of thiacetazone derivatives indicated that two derivatives, SRI-286 and SRI-224, inhibited a panel of 25 Mycobacterium avium complex (MAC) isolates at concentrations of 2 micro g/ml or lower. In mice, SRI-224 and thiacetazone had no significant activity against the MAC in livers and spleens, but treatment with SRI-286 resulted in significant reduction of bacterial loads in livers and spleens. A combination of SRI-286 and moxifloxacin was significantly more active than single drug regimens in liver and spleen.     

Initial experience in laparoscopic partial nephrectomy for renal tumor with clamping of renal vessels

PURPOSE: To describe our initial experience with laparoscopic partial nephrectomy (LPN) with clamping of the renal vessels before tumor excision and suturing of the renal parenchyma. PATIENTS AND METHODS: Between July 2001 and April 2002, 19 consecutive patients underwent transperitoneal LPN in our institution, 14 for tumors <4 cm with suspicion of renal-cell cancer and 5 for suspicion of angiomyolipoma at CT with one tumor confirmed histopathologically by percutaneous needle biopsy. We divided these patients into the first 10 cases (Group 1) and the last 9 cases (Group 2). One patient had end-stage renal disease but was not on dialysis; the remaining patients had elective partial nephrectomy. Initially, a ureteral catheter was placed. The partial nephrectomy was performed with clamping of the renal vessels, so that the tumor was excised with cold scissors. Intracorporeal cooling of the kidney was achieved by a ureteral catheter connected to a 4 degrees C solution flowing to the renal pelvis during the whole procedure until the clamps were released. Intracorporeal free-hand suturing was exclusively used to close the collecting system (when opened) and to approximate the renal parenchyma. RESULTS: All procedures were completed laparoscopically. The mean renal warm ischemia time was 28.5+/-7 minutes (range 15-47 minutes). The mean laparoscopic operating time was 125+/-37 minutes (range 90-390 minutes). The mean intraoperative blood loss was 290+/-276 mL (range 25-1200 mL). Two patients required blood transfusion, and four had complications. There was immediate deterioration in renal function (creatinine 1.42+/-0.56 mg/dL), but improvement was seen at 1 month (1.17+/-0.34 mg/dL). There were no statistically significant differences in operative features and outcomes in Groups 1 and 2, but there were improvements in the mean operating time by 30 minutes, the mean intraoperative blood loss by 113 mL without any transfusion, and the mean renal warm ischemia time by 6 minutes. There was only one patient in Group 2 with a complication. The surgical margin was negative for tumor for all patients. Postoperative pathology examination showed renal-cell cancer in 11 patients (pT1), oncocytoma in 3 patients, and angiomyolipoma in 5 patients. The mean tumor grade was 2. The mean tumor size was 25.8+/-11.6 mm with a mean tumor-free margin of 2.6+/-2.4 mm. The median follow-up is 3 months, so oncologic outcome cannot be assessed. CONCLUSION: The technique of LPN can be standardized and should be proposed for small tumors when they are not invading the hilum. Clamping the renal pedicle allows better vision for more accurate tumor excision with a safety margin and hemostatic suturing of the parenchymal defect, resulting in less blood loss and shorter operative time, parameters that improve with experience.     

A comparison of the antimicrobial resistance patterns of gram-positive cocci isolated from community-private and university-affiliated hospitals from Puerto Rico

The antimicrobial resistance patterns of 2,462 selected Gram-positive cocci obtained from three Community-Private Hospitals (CPH) and three University-Affiliated Hospitals (UAH) were evaluated utilizing the institutions' antimicrobial susceptibility reports for the year 2000. The objectives of this study were: 1) to evaluate the in vitro resistance to selected standard antibiotics of Staphylococcus aureus, Enterococcus faecalis, Enterococcus faecium and Streptococcus pneumoniae clinical isolates, and 2) to compare the antimicrobial resistance patterns between community-private (CPH) and university-affiliated hospitals (UAH). Staphylococcus aureus was the most common Gram-positive isolated organism in CPH (63.3%) followed by E. faecalis (31.0%). In UAH, the most prevalent cocci were E. faecalis (51.7%) followed by S. aureus (43.9%). Enterococcus faecium represented 2.3% and 4.4% of CPH and UAH isolates, respectively. Streptococcus pneumoniae represented 3.4% of the total Gram-positive isolates from CPH, no S. pneumoniae was reported in UAH. The antimicrobial susceptibility results showed that for Staphylococcus aureus there was a statistically significant higher resistance to methicillin and thrimethoprim sulfamethoxazole in UAH, while resistance to erythromycin was significantly higher in CPH. There was no difference in the resistance of S. aureus to other antimicrobial agents between hospitals groups. A statistically significant resistant to vancomycin was found between enterococcal isolates from UAH (43%) and CPH (12.7%). High-level aminoglycoside resistance (HLAR) was observed among UAH enterococcal isolates with E. faecium showing a higher resistance than E. faecalis, no data for HLAR in CPH could be obtained. For pneumococci 46% of CPH isolates were resistant to penicillin. In summary, there are important differences in the prevalence and antimicrobial resistance between the Gram-positive bacteria isolated from community and teaching hospitals.     

Response latencies to visual stimulation and disparity sensitivity in single cells of the awake Macaca mulatta visual cortex

The onset response latencies to dynamic random dot figures (solid figures) and dynamic random dot stereograms were measured in single units recorded from areas V1 and V2 of two awake Macaca mulatta monkeys. We studied 56 cells, 39 from V1 and 17 from V2. In 14 disparity sensitive and 13 disparity unsensitive cells from V1 the median latencies to solid figures were 59.8 and 73.6 ms, respectively, which were statistically different. In 26 disparity sensitive cells from V1 and 17 from V2 the median latencies to stereofigures were 85.6 and 97.9 ms, respectively, which were statistically different. These results indicate that V1 disparity sensitive cells may have shorter integration time than disparity unsensitive cells and that there is a transferring delay for disparity information between areas V1 and V2.     

A validation of the MOS-HIV quality of life measure in HIV-infected patients in Mexico]

OBJECTIVE: To validate the Medical Outcomes Study HIV Health Survey (MOS-HIV) quality of life instrument for its application in clinical research in Mexico. METHODS: The data for this study were collected between April, 2002, and February, 2004. An expert committee combined two Spanish-language translations of the MOS-HIV questionnaire. The new questionnaire's feasibility was assessed in a group of 32 HIV-infected persons by measuring how long they took to complete the questionnaire and the numbers of items they left unanswered. The questionnaire was then applied to a group of 120 HIV-positive patients and to a control group of 102 HIV-negative individuals. The following questionnaire characteristics were evaluated: (1) internal reliability (Cronbach alpha coefficient), (2) discriminant validity (the receiver operating characteristic (ROC) curves derived from the scores of the two groups), and (3) convergent validity (the Spearman correlation coefficients for the scores of the HIV-positive patients on the 11 MOS-HIV dimensions and their scores on the analog visual scale of the European Quality of Life 5-Dimensional format (EQ-5D) questionnaire, a list of symptoms, the viral load, and the CD4 cell count). RESULTS: The mean response time with the questionnaire was 10 minutes and 22 seconds, and the mean number of unanswered items was 0.62. With each of the 11 dimensions of the questionnaire, the Cronbach alpha coefficient was at least 0.75. The mean scores obtained by the two groups were different for 9 of the 11 dimensions, and the 95% confidence intervals of the areas under the ROC curves did not include the value of 0.5 for 8 of the dimensions. The absolute value of the Spearman correlation coefficient was less than 0.3 for the CD4 cell count and for the viral load, and it was greater than 0.3 for each dimension and the scores on the list of symptoms and on the analog visual scale of the EQ-5D questionnaire. CONCLUSIONS: The MOS-HIV measure is valid for use in clinical research among HIV-infected persons in Mexico.     

Effects of diltiazem on human nicotinic acetylcholine and GABA(A) receptors

Effects of the L-type calcium channel antagonist diltiazem on recombinant human GABA(A) receptor (alpha1beta2gamma2s) or on muscle (alpha1beta1deltagamma and alpha1beta1delta(epsilon)) or neuronal (alpha7 and alpha4beta2) nicotinic acetylcholine receptors expressed in Xenopus oocytes were examined using two-electrode voltage-clamp. Diltiazem inhibited the function of both muscle and neuronal nicotinic receptors, but it had no effect on GABA(A) receptors. The extent of functional inhibition of nicotinic receptors depended on the receptor subtype, and the order of inhibition potency by diltiazem was alpha7>alpha4beta2 approximately alpha1beta1deltagamma approximately alpha1beta1delta(epsilon). Inhibition of alpha7 receptor function was non-competitive and voltage-independent, and it occurred at concentrations far lower than those needed to inhibit (never completely) binding of (125)I-alpha-bungarotoxin to heterologously expressed alpha7 receptors in mammalian cells. Pre-incubation in diltiazem before concomitant application with acetylcholine increased inhibition of function and slowed recovery from inhibition. Verapamil, a phenylalkylamine antagonist of L-type Ca(2+) channels also fully inhibited alpha7 receptor function and partially inhibited (125)I-alpha-bungarotoxin binding to alpha7 receptors, but was less potent than diltiazem. Effects on both alpha7 receptor function and (125)I-alpha-bungarotoxin binding by verapamil plus diltiazem suggest separate sites for verapamil and diltiazem on alpha7 receptors. These results provide further evidence that L-type Ca(2+) channel drugs inhibit ligand-gated cationic channels and suggest that caution should be applied when using these compounds to study systems in which L-type Ca(2+) channels and ligand-gated cationic channels co-exist.     

Trisomy of rat chromosome 1 associated with mesothelial cell transformation.

Identification of specific chromosomal aberrations in transformed mesothelial cells is an important step in elucidating the mechanism of transformation of these cells which are targets for occupational and environmental carcinogens, such as asbestos fibers. Cytogenetic analysis of normal rat mesothelial cell lines revealed that at late passage (p20-p34), trisomy of chromosome 1 was present in greater than 80% of the cells in four spontaneously immortalized lines examined, whereas at early passage (p8-p10), only 15-44% of the cells had trisomy 1. Trisomy of chromosome 1 had increased in the population as a function of passage, suggesting that cells with trisomy 1 had a selective growth advantage under in vitro culture conditions and that this alteration was associated with transformation. A commercially available rat mesothelial cell line (4/4 RM4, ATCC), was also found to have a duplication of a portion of the long arm of chromosome 1. To determine if chromosome 1 alterations have relevance to the transformed phenotype in vivo, a neoplastic cell line was established from a spontaneous rat mesothelioma. At passage 15, trisomy of chromosome 1 was observed in 26% of the metaphases in this line. However, when these cells were injected into nude mice, 99% of the cells from the resulting tumor contained an additional copy of chromosome 1. Therefore, trisomy 1 also conferred a selective growth advantage in vivo and/or was associated with the malignant subpopulation in the tumor derived cell line. These studies suggest that chromosome 1 contains a gene(s) involved in transformation of rat mesothelial cells.     

Stimulation of Canine Gastric Motility by BRL 24924, a New Gastric Prokinetic Agent

We describe the actions and pharmacology of BRL 24924, a new gastric prokinetic agent, in conscious dogs. In Heidenhain pouch preparations, BRL 24924 (0.01–0.16 mg/kg i.v.) is a potent stimulant of interdigestive phasic motility (increases in intraluminal pressure), approximately 50 times more potent than metoclopramide. The stimulatory effect of BRL 24924 (0.025 mg/kg i.v.) was prevented by atropine (0.1 mg/kg s.c.). It was initially unaffected by hexamethonium (5 mg/kg i.v.), but hexamethonium prevented BRL 24924 from causing sustained stimulation of motility. The stimulatory activity of BRL 24924 (0.025 mg/kg i.v.) was unaffected by propranolol (3 mg/kg i.v.) or by phentolamine (1 mg/kg i.v.). The selective 5-hydroxytryptamine₃ receptor antagonist granisetron (BRL 43694; 0.1 or 1.0 mg/kg i.v.) neither mimicked nor prevented the stimulatory actions of BRL 24924. In dogs with a gastric fistula, the gastric emptying of a liquid test meal was accelerated following BRL 24924 (0.1 mg/kg i.v.) but was unaffected by granisetron (0.1 and 1 mg/kg i.v.). We conclude that BRL 24924 is a potent, long-lasting, and effective stimulant of canine gastric motility, which accelerates gastric emptying. The pharmacology of BRL 24924 is discussed in terms of its relationship with myenteric 5-hydroxytryptamine receptors.     

Blood levels and production rate of 17-hydroxypregnenolone in man

A reliable radio-ligand assay has been developed for the measurement of 17-hydroxypregnenolone in human peripheral vein plasma. The mean plasma concentration of 17-hydroxypregnenolone was, in men, 1.9 mmug/ml; and in women, 3.5 mmug/ml. These means were not significantly different from each other, and the levels were the same in the follicular and luteal phases of the menstrual cycle. In women, the adrenal cortex was the source of the 17-hydroxypregnenolone; in men, 40% was produced by the testis. Since the metabolic clearance rate was about 2000 liters/24 hr production rate estimates were 4-7 mg/24 hr.The conversion of blood 17-hydroxypregnenolone to blood 17-hydroxyprogesterone and dehydroepiandrosterone was measured. This varied from 5 to 20%. Thus, in women during the follicular phase, 17-hydroxyprogesterone derived from blood 17-hydroxypregnenolone could be the major fraction of the 17-hydroxyprogesterone production rate. Blood 17-hydroxypregnenolone is a minor precursor of blood dehydroepiandrosterone.     

Clarithromycin-resistant mycobacterium avium is still susceptible to treatment with clarithromycin and is virulent in mice

Resistance to clarithromycin in breakthrough Mycobacterium avium complex (MAC) isolates typically occurs 3 to 4 months after the initiation of monotherapy in bacteremic AIDS patients. It has been suggested that continuation of clarithromycin therapy still results in clinical and microbiological improvement. To study this paradox, C57BL/6 beige mice were infected with a clarithromycin-resistant (MIC, > or =128 microg/ml) strain of MAC 101 (CLA-R MAC 101) and treated with 200 mg of clarithromycin per kg of body weight/day alone or in combination with ethambutol (100 mg/kg/day) for 2 weeks. Mice infected with a clarithromycin-susceptible strain of MAC 101 had bacterial loads reduced by 90% in the liver and 91% in the spleen (P<0.05, compared with the control). Clarithromycin treatment of CLA-R MAC 101 resulted in a 65% reduction of bacterial loads in the liver (P = 0.009) and a 71% reduction in the spleen (P = 0.009), compared with the results for the untreated control. CLA-R MAC 101 and MAC 101 (isogenic strains) had comparable growth rates in murine tissue, ruling out a loss of virulence of CLA-R MAC 101. Strains of MAC currently defined as macrolide resistant may still respond to treatment with an agent such as clarithromycin within infected tissues.