Evaluation of the antiplatelet effect of generic ticagrelor 90 mg (ticaspan®) alone and in combination with aspirin 75 mg as compared to ticagrelor (innovator): An in vitro study.

Objective: To evaluate an in vitro antiplatelet effect of generic ticagrelor 90 mg (ticaspan) alone and in combination with aspirin 75 mg as compared to the innovator formulation of ticagrelor alone and in combination with aspirin among healthy Indian volunteers. Methods: 18 volunteers were enrolled and platelet viability was tested using lactate dehydrogenase (LDH) assay in six of 18 volunteers. In 12 volunteers, maximum platelet aggregation (MPA) and percentage inhibition of platelet aggregation (PI) were assessed using a platelet aggregometer in six study groups. Results: There was no significant increase in LDH levels when platelets were incubated with an innovator or generic drug alone and in combination with aspirin as compared to the dimethyl sulfoxide [DMSO] group. All five study groups showed a significant reduction in the MPA values compared to the DMSO group (P < 0.01). The extent of decrease in MPA observed with the generic drug was not significantly different from the innovator drug (P = 0.325). Similarly, the MPA observed with the two combination groups did not differ from each other (P = 1.000), but it was significantly different from the MPA observed with aspirin (P = 0.039, each). The PI of platelet aggregation was significantly more in four study groups [generic drug alone; innovator alone; generic drug + aspirin; and innovator drug + aspirin] (P < 0.01) as compared to the aspirin group. Conclusion: The generic ticagrelor and its combination with aspirin demonstrated an antiplatelet effect equivalent to the innovator drug and its combination with aspirin.

The relationship of sinus opacification, olfaction and dupilumab efficacy in patients with CRSwNP.

BACKGROUND: Loss of sense of smell is one of the most burdensome symptoms of chronic rhinosinusitis with nasal polyps (CRSwNP) but its relationship to sinus disease on imaging is unclear. Dupilumab improves sense of smell and radiographic severity of sinus disease in patients with CRSwNP. We investigated the relationship of sinus opacification severity and loci to olfactory impairment and dupilumab efficacy in patients with CRSwNP from the SINUS-24/SINUS-52 (NCT02912468/NCT02898454) studies. METHODS: Sinus opacification was evaluated using the Lund-Mackay computed tomography (LMK-CT) score and sense of smell using patient-reported loss of smell (LoS) score, University of Pennsylvania Smell Identification Test (UPSIT) score and the 22-item Sino-Nasal Outcome Test (SNOT-22) smell/taste item. RESULTS: At baseline, 95% of patients (688/724) had impaired sense of smell and opacification was extensive across all sinuses. Greater olfactory impairment was associated with greater opacification, especially in the ethmoid, sphenoid and frontal sinuses. At Week 24, reductions in LMK-CT total score and ethmoid and sphenoid sinus scores with dupilumab were weakly correlated with improvements in sense of smell assessed by LoS, UPSIT and SNOT-22 smell/taste item. More dupilumab than placebo patients achieved clinically meaningful improvement in LMK-CT total score at Week 24 and Week 52. CONCLUSION: Radiographic disease severity on imaging was associated with smell outcomes in this cohort. Opacification of the ethmoid, sphenoid and frontal sinuses was associated with severe smell loss. These data suggest that dupilumab effects on smell may be partly mediated through reduced sinus inflammation.

Dupilumab reduces systemic corticosteroid use and sinonasal surgery rate in CRSwNP.

BACKGROUND: Chronic rhinosinusitis with nasal polyps (CRSwNP) is a type 2 inflammatory disease with a high symptom burden and poor quality of life. Treatment options include recurrent surgeries and/or frequent systemic corticosteroids (SCS). Dupilumab, a fully human monoclonal antibody, blocks the shared receptor component for interleukin-4 and interleukin-13, key drivers of type 2-mediated inflammation. We report results of pooled analyses from 2 randomised, double-blind, placebo-controlled phase 3 studies (SINUS 24 [NCT02912468]; SINUS-52 [NCT02898454]) to evaluate dupilumab effect versus placebo in adults with CRSwNP with/without SCS use and sinonasal surgery. METHODOLOGY: SINUS-24 patients were randomised 1:1 to subcutaneous dupilumab 300 mg (n=143) or placebo (n=133) every 2 weeks (q2w) for 24 weeks. SINUS-52 patients were randomised 1:1:1 to 52 weeks of subcutaneous dupilumab 300 mg q2w (n=150), 24 weeks q2w followed by 28 weeks of dupilumab 300 mg every 4 weeks (n=145) or 52 weeks of placebo q2w (n=153). RESULTS: Dupilumab reduced the number of patients undergoing sinonasal surgery (82.6%), the need for in-study SCS use (73.9%), and SCS courses (75.3%). Significant improvements were observed with dupilumab vs placebo regardless of prior sinonasal surgery or SCS use in nasal polyp, nasal congestion, Lund-MacKay, and Sinonasal Outcome Test (22-items) scores, and the University of Pennsylvania Smell Identification Test. CONCLUSIONS: Dupilumab demonstrated significant improvements in disease signs and symptoms and reduced the need for sino-nasal surgery and SCS use versus placebo in patients with severe CRSwNP, regardless of SCS use in the previous 2 years, or prior sinonasal surgery.

Over-the-counter medicines: Global perspective and Indian scenario.

Patients often approach a pharmacist instead of visiting a doctor for minor ailments such as cough, cold, allergies, pain, fever, acidity, diarrhea, and skin-related conditions. Purchase of specific medicines over the counter is legally recognized in most countries. 'Over-the-Counter (OTC) Medicines' means drugs which are legally allowed to be sold by pharmacists without need for a prescription. The term does not have a legal definition in India. Technically, drugs are OTC unless they are specifically stated as prescription only drugs. OTC drugs allow faster and cheaper access to healthcare; however, their misuse and adverse health effects cause concerns. This article describes concept of OTC medicines and practices in India against the background of globally prevalent regulations and practices. A recognized category of OTC medicines by law, patient awareness programs, and support of pharmacists and pharmaceutical companies are required to optimize the use of OTC medicines in India.

Chronic hyponatremia and association with osteoporosis among a large racially/ethnically diverse population.

Chronic hyponatremia may contribute to decreased bone density. We studied 341,003 men and women who underwent DXA testing and observed that individuals with chronic hyponatremia (sodium < 135 mEq/L) had an 11% greater likelihood of having osteoporosis. There was a dose-dependent effect with lower sodium and stronger association with osteoporosis. INTRODUCTION: Chronic hyponatremia has been associated with both neurologic deficits and increased risk of gait abnormalities leading to falls and resultant bone fractures. Whether chronic hyponatremia contributes to decreased bone density is uncertain. We evaluated whether chronic, mild hyponatremia based on serial sodium measurements was associated with increased risk of osteoporosis within a large, ethnically diverse population. METHODS: This is a retrospective cohort study between January 1, 1998 and December 31, 2014 within Kaiser Permanente Southern California, an integrated healthcare delivery system. Men and women were aged ≥ 55 years with ≥ 2 serum sodium measurements prior to dual-energy X-ray absorptiometry (DXA) testing. Time-weighted (TW) mean sodium values were calculated by using the proportion of time (weight) elapsed between sodium measurements and defined as < 135 mEq/L. Osteoporosis defined as any T-score value ≤ - 2.5 of lumbar spine, femoral neck, or hip. RESULTS: Among 341,003 individuals with 3,330,903 sodium measurements, 11,539 (3.4%) had chronic hyponatremia and 151,505 (44.4%) had osteoporosis. Chronic hyponatremic individuals had an osteoporosis RR (95% CI) of 1.11 (1.09, 1.13) compared to those with normonatremia. A TW mean sodium increase of 3 mEq/L was associated with a lower risk of osteoporosis [adjusted RR (95% CI) 0.95 (0.93, 0.96)]. A similar association was observed when the arithmetic mean sodium value was used for comparison. CONCLUSIONS: We observed a modest increase in risk for osteoporosis in people with chronic hyponatremia. There was also a graded association between higher TW mean sodium values and lower risk of osteoporosis. Our findings underscore the premise that chronic hyponatremia may lead to adverse physiological effects and responses which deserves better understanding.

Dialysis-requiring acute kidney injury among hospitalized adults with documented hepatitis C Virus infection: a nationwide inpatient sample analysis.

Chronic hepatitis C virus (HCV) infection may cause kidney injury, particularly in the setting of cryoglobulinemia or cirrhosis; however, few studies have evaluated the epidemiology of acute kidney injury in patients with HCV. We aimed to describe national temporal trends of incidence and impact of severe acute kidney injury (AKI) requiring renal replacement 'dialysis-requiring AKI' in hospitalized adults with HCV. We extracted our study cohort from the Nationwide Inpatient Sample of the Healthcare Cost and Utilization Project using data from 2004 to 2012. We defined HCV and dialysis-requiring acute kidney injury based on previously validated ICD-9-CM codes. We analysed temporal changes in the proportion of hospitalizations complicated by dialysis-requiring AKI and utilized survey multivariable logistic regression models to estimate its impact on in-hospital mortality. We identified a total of 4,603,718 adult hospitalizations with an associated diagnosis of HCV from 2004 to 2012, of which 51,434 (1.12%) were complicated by dialysis-requiring acute kidney injury. The proportion of hospitalizations complicated by dialysis-requiring acute kidney injury increased significantly from 0.86% in 2004 to 1.28% in 2012. In-hospital mortality was significantly higher in hospitalizations complicated by dialysis-requiring acute kidney injury vs those without (27.38% vs 2.95%; adjusted odds ratio: 2.09; 95% confidence interval: 1.74-2.51). The proportion of HCV hospitalizations complicated by dialysis-requiring acute kidney injury increased significantly between 2004 and 2012. Similar to observations in the general population, dialysis-requiring acute kidney injury was associated with a twofold increase in odds of in-hospital mortality in adults with HCV. These results highlight the burden of acute kidney injury in hospitalized adults with HCV infection.

Projects not initiated by investigators: a retrospective analysis of the queries raised by the institutional ethics committees of a teaching hospital.

BACKGROUND: Some investigators on receiving queries from Institutional Ethics Committee (IEC), either leave the queries unanswered or withdraw their studies. The present study was conducted to assess the queries raised by two IECs after reviewing studies that were not initiated and to identify reasons for the same. Clinical Trials Registry-India (CTRI) website was checked to review approval status of these studies at other sites. MATERIALS AND METHODS: A retrospective analysis of studies (submitted between January 2006 and December 2011) not initiated by investigators on receiving queries from IECs were identified. The nature of of these studies: whether sponsored (pharmaceutical industry (pharma)/government/investigator initiated), single-centre/multi-centric, and queries raised were analyzed. Status of multi-centric trials; not initiated at our site was checked at CTRI. Data was analyzed using descriptive statistics. RESULTS: A total of 219/2075 (11%) studies were not initiated. The proportions in pharma sponsored, investigator initiated, and government sponsored were 33%. 7.4%, and 8%, respectively. Out of a total of 1676 queries, the maximum queries were related to ethics (42%) and the least were administrative (7%). The largest proportion of queries in the pharma studies was ethical (47%), whereas majority were scientific queries (45.5%) for the investigator initiated studies. Twenty-one of the 94 multi-centric studies not initiated at our site were found registered at the CTRI and were ongoing or completed at 2-55 sites. CONCLUSION: Inability of investigators to defend studies due to lack of good clinical research practice (GCP) and research methodology training or unwillingness of sponsors to comply with local IEC requirements could be potential reasons for studies remaining uninitiated. Continued GCP training of investigators and IEC members and development of uniform ethical review standards across IECs are strongly recommended.

Comparison of nifedipine and progesterone for maintenance tocolysis after arrested preterm labour.

The aim of our study was to compare the efficacy and safety of nifedipine and progesterone for maintenance tocolysis after arrested preterm labour, in prolonging pregnancy and preventing recurrence of preterm labour. This study was a randomised comparative study conducted on 110 pregnant women with arrested preterm labour, randomised to receive either nifedipine 20 mg Q 8-hourly or progesterone 400 mg daily for maintenance tocolysis. Other than demographic parameters, obstetric parameters like previous history of abortions or preterm deliveries, gestational age, cervical dilatation and effacement, ultrasound measured cervical length at admission, were noted. Outcome measures studied were mean prolongation of pregnancy, mode of delivery, neonatal outcome and side-effects of both the drugs. We found that there was no significant difference in the demographic profile, parity, number of abortions, previous preterm deliveries, gestational age, cervical dilatation and effacement at admission between the two groups. A total of 10% of the patients in the nifedipine group and 61% of the patients in the progesterone group delivered at term (p value 0.000). The mean prolongation of pregnancy in the nifedipine group was 16.63 days and 40.14 days in the progesterone group which was significant (p = 0.000). Neonates in the progesterone group had better birth weight, better Apgar scores at 1 and 5 min, lesser need for ventilation and significantly lesser composite morbidity. Nifedipine was associated significantly with side-effects. We conclude that when compared with nifedipine, progesterone significantly prolongs pregnancy in women with arrested preterm labour with better neonatal outcomes and fewer side-effects.

Xylitol production by Cyberlindnera (Williopsis) saturnus, a tropical mangrove yeast from xylose and corn cob hydrolysate.

AIM: Potential for xylitol production from xylose and corn cob hydrolysate by a tropical mangrove yeast. METHODS AND RESULTS: In the present study, 21 fungi were isolated from detritus-based mangrove wetlands along the Indian west coast. Of these, one yeast isolate had the ability to grow and assimilate xylose producing significant amounts of xylitol (38·63 g l(-1) ). A maximum yield of 0·54 g g(-1) was obtained after 144 h of growth on xylose (150 g l(-1) ) and corn cob hydrolysate (CCH, containing 65 g l(-1) xylose). Using biochemical and molecular methods, the yeast was identified as Cyberlindnera (Williopsis) saturnus. Preliminary characterization of enzymes in the cell-free extract revealed that while xylose reductase (XR) preferred NADPH to NADH as cofactor, xylitol dehydrogenase (XDH) was NAD specific. CONCLUSIONS: Significant amounts of xylitol could be produced on CCH using C. saturnus isolated from tropical mangrove wetlands. The yeast has the potential to assimilate rather than ferment xylose as its XR has a preference for NADPH. SIGNIFICANCE AND IMPACT OF THE STUDY: Microbes offer an economically viable and green approach for production of xylitol, an industrially important compound. A mangrove ecosystem with its battery of lignocellulolytic enzymes is an ideal location for isolating fungi capable of producing xylitol from agroindustrial waste such as CCH.

Assessment of prescribing pattern of drugs and completeness of prescriptions as per the World Health Organization prescribing indicators in various Indian tertiary care centers: A multicentric study by Rational Use of Medicines Centers-Indian Council of Medical Research network under National Virtual Centre Clinical Pharmacology activity.

OBJECTIVE: The rational use of medicines as per the World Health Organization (WHO) should be practiced globally. However, data regarding the completeness of the prescriptions and their rational use is lacking from developing countries like India. Thus, the aim of this study was to assess the prescribing patterns of drugs and completeness of prescriptions as per WHO core drug use and complementary indicators to provide real-life examples for the Indian Council of Medical Research (ICMR) online prescribing skill course for medical graduates. METHODS: Prescriptions of the patients, fulfilling inclusion criteria, attending Outpatient Departments of various specialties of tertiary care hospitals, were collected by thirteen ICMR Rational use of medicines centers located in tertiary care hospitals, throughout India. Prescriptions were evaluated for rational use of medicines according to the WHO guidelines and for appropriateness as per standard treatment guidelines using a common protocol approved by local Ethics committees. RESULTS: Among 4838 prescriptions, an average of about three drugs (3.34) was prescribed to the patients per prescription. Polypharmacy was noted in 83.05% of prescriptions. Generic drugs were prescribed in 47.58% of the prescriptions. Further, antimicrobials were prescribed in 17.63% of the prescriptions and only 4.98% of prescriptions were with injectables. During the prescription evaluation, 38.65% of the prescriptions were incomplete due to multiple omissions such as dose, duration, and formulation. CONCLUSION: Most of the parameters in the present study were out of the range of WHO-recommended prescribing indicators. Therefore, effective intervention program, like training, for the promotion of rational drug use practice was recommended to improve the prescribing pattern of drugs and the quality of prescriptions all over the country.

Antiinflammatory activity of Phyllanthus emblica, Plumbago zeylanica and Cyperus rotundus in acute models of inflammation.

Experimental studies conducted earlier have proved that Phyllanthus emblica (Pe), Plumbago zeylanica (Pz) and Cyperus rotundus (Cr), plants from the medohara group of Ayurveda possess antiatherosclerotic activity. As inflammation is also one of the pathophysiological factors, it was of interest to evaluate whether these drugs exhibit any antiinflammatory activity. Two models of acute inflammation, namely carrageenan induced rat paw edema and acetic acid induced peritonitis in mice were used. In the model of carrageenan induced paw edema Pe, Pz and Cr showed a trend to reduce the edema while the combination of Pe + Pz (PI: 20.64%) showed results comparable to aspirin (23.74%). Whereas in a model of acetic acid induced peritonitis, all the plant drugs i.e. Pe, Pz, Cr and a combination of Pe + Pz showed a significant decrease in the protein content of the peritoneal exudates compared with the disease control group (p < 0.05), however, only Pe + Pz exhibited activity comparable to aspirin.

Mutations in dynamin-related protein result in gross changes in mitochondrial morphology and affect synaptic vesicle recycling at the Drosophila neuromuscular junction.

Mitochondria are the primary source of ATP needed for the steps of the synaptic vesicle cycle. Dynamin-related protein (DRP) is involved in the fission of mitochondria and peroxisomes. To assess the role of mitochondria in synaptic function, we characterized a Drosophila DRP mutant combination that shows an acute temperature-sensitive paralysis. Sequencing of the mutant reveals a single amino acid change in the guanosine triphosphate hydrolysing domain (GTPase domain) of DRP. The synaptic mitochondria in these mutants are remarkably elongated, suggesting a role for DRP in mitochondrial fission in Drosophila. There is a loss of neuronal transmission at restrictive temperatures in electroretinogram (ERG) recordings. Like stress-sensitive B (sesB), a mitochondrial adenosine triphosphate (ATP) translocase mutant we studied earlier for its effects on synaptic vesicle recycling, an allele-specific reduction in the temperature of paralysis of Drosophila synaptic vesicle recycling mutant shibire was seen in the DRP mutant background. These data, in addition to depletion of vesicles observed in electron microscopic sections of photoreceptor synapses at restrictive temperatures, suggest a block in synaptic vesicle recycling due to reduced mitochondrial function.

The IL-1 receptor and Rho directly associate to drive cell activation in inflammation.

IL-1-stimulated mesenchymal cells model molecular mechanisms of inflammation. Binding of IL-1 to the type I IL-1 receptor (IL-1R) clusters a multi-subunit signaling complex at focal adhesion complexes. Since Rho family GTPases coordinately organize actin cytoskeleton and signaling to regulate cell phenotype, we hypothesized that the IL-1R signaling complex contained these G proteins. IL-1 stimulated actin stress fiber formation in serum-starved HeLa cells in a Rho-dependent manner and rapidly activated nucleotide exchange on RhoA. Glutathione S-transferase (GST) fusion proteins, containing either the full-length IL-1R cytosolic domain (GST-IL-1Rcd) or the terminal 68 amino acids of IL-1R required for IL-1-dependent signal transduction, specifically coprecipitated both RhoA and Rac-1, but not p21(ras), from Triton-soluble HeLa cell extracts. In whole cells, a small-molecular-weight G protein coimmunoprecipitated by anti-IL-1R antibody was a substrate for C3 transferase, which specifically ADP-ribosylates Rho GTPases. Constitutively activated RhoA, loaded with [gamma-32P]GTP, directly interacted with GST-IL-1Rcd in a filter-binding assay. The IL-1Rcd-RhoA interaction was functionally important, since a dominant inhibitory mutant of RhoA prevented IL-1Rcd-directed transcriptional activation of the IL-6 gene. Consistent with our previous data demonstrating that IL-1R-associated myelin basic protein (MBP) kinases are necessary for IL-1-directed gene expression, cellular incorporation of C3 transferase inhibited IL-1R-associated MBP kinase activity both in solution and in gel kinase assays. In summary, IL-1 activated RhoA, which was physically associated with IL-1Rcd and necessary for activation of cytosolic nuclear signaling pathways. These findings suggest that IL-1-stimulated, Rho-dependent cytoskeletal reorganization may cluster signaling molecules in specific architectures that are necessary for persistent cell activation in chronic inflammatory disease.

Effects of low-dose aspirin on in vitro platelet aggregation in the early minutes after ingestion in normal subjects.

Aspirin interferes with platelet aggregation by inhibiting the metabolism of arachidonic acid to thromboxane A2. Although both high- and low-dose aspirin therapies are effective for secondary prophylaxis in patients with atherosclerotic vascular disease, the acute response to low-dose aspirin therapy is controversial. Eighteen volunteer subjects ingested 81, 162, or 324 mg of aspirin in a longitudinal crossover study design. Initial doses were randomly assigned and dosing intervals were separated by 2 weeks. Platelet aggregation in response to 0.9 mM arachidonic acid was measured at baseline, 15, 30, 60, and 90 minutes after ingestion. Thromboxane B2 production was assayed on simultaneously obtained samples after stimulation with arachidonic acid. The median inhibition of aggregation was 97%, 97%, and 97% 15 minutes after ingestion of 81, 162, and 324 mg, respectively. Four subjects had < 20% inhibition 15 minutes after ingesting 81 mg, but all 4 had > 90% inhibition after 30 minutes. Thromboxane B2 production declined by > 93% in all subjects at each dose. There was no difference between doses in inhibition of thromboxane B2 production.

The antibody response to methyl isocyanate: experimental and clinical findings.

As a result of the industrial accident in Bhopal, India (December 1984) in which thousands of people were exposed to methyl isocyanate (MIC), concern was raised for possible long-term health effects. The well-recognized immunologic consequences of exposure to other industrial isocyanates prompted investigation of an antibody response to MIC. Using procedures which had been developed in this laboratory to evaluate isocyanate immunotoxicity, animal studies were undertaken to develop and test reagents which could be used to detect antibodies to MIC in the exposed population. Guinea pigs were injected with MIC in its reactive isocyanate form. Three weeks later, blood was drawn and serum evaluated using ELISA. To detect antibodies, an antigen was prepared by reaction of MIC with guinea pig serum albumin. Antibodies were detected in each of the four animals injected with MIC. Titers achieved were 1:5120 to 1:10,240. Inhibition assays revealed antibody specificity directed toward the MIC hapten. Analogous antigens prepared by reaction of MIC with human serum albumin were used to evaluate sera from individuals exposed in Bhopal to MIC. Antibodies were detected in 12 of 144 exposed persons. Antibodies were specific for MIC, as evidenced by inhibition assays, and belonged to the IgG, IgM and IgE classes. However, titers were generally low and transient and were found in persons having had the highest MIC exposures. Total IgE values of sera were not significantly different from those of control sera obtained from Bombay residents. The results indicate that exposure to methyl isocyanate resulted in production of specific antibodies. However, the low titers observed and the transient nature of the response suggest little health consequence should result form the antibody response.

Sequential respiratory, psychologic, and immunologic studies in relation to methyl isocyanate exposure over two years with model development.

Of 113 methyl isocyanate (MIC)-exposed subjects studied initially at Bhopal, India, 79, 56, 68, and 87 were followed with clinical, lung function, radiographic, and immunologic tests at 3, 6, 12, 18, and 24 months. Though our cohort consisted of subjects at all ages showing a varied severity of initial illness, fewer females and young subjects were seen. Initially all had eye problems, but dominant symptoms were exertional dyspnea, cough, chest pain, sputum, and muscle weakness. A large number showed persistent depression mixed with anxiety, with disturbances of personality parameters. The early radiographic changes were lung edema, overinflation, enlarged heart, pleural scars, and consolidation. The persistent changes seen were interstitial deposits. Lung functions showed mainly restrictive changes with small airway obstruction; there was impairment of oxygen exchange. Oxygen exchange improved at 3-6 months, and spirometry improved at 12 months, only to decline later. The expiratory flow rates pertaining to large and medium airway function improved, but those for small airways remained low. There were changes of alveolitis in bronchoalveolar lavage fluid on fiber optic bronchoscopy, and in 11 cases positive MIC-specific antibodies to IgM, IgG, and IgE were demonstrated. On follow up, only 48% of the subjects were clinically stable, while 50% showed fluctuations. Thirty-two percent of the subjects had lung function fluctuations. Detailed sequential behavior over 2-4 years was predicted for dyspnea, forced vital capacity, maximum expiratory flow rate (0.25-0.75), peak expiratory flow rate, VO2, and depression score. A model for clinical behavior explained a total variance of 52.4% by using the factors of cough, PCO2 and X-ray zones in addition to above five parameters. The behavior of the railway colony group (1640 patients) revealed a similar pattern of illness. When this observed pattern of changes was transferred to the affected Bhopal city sections (with an equitable age-sex distribution), our model results were again validated. Thus the picture of MIC-induced disease seems similar despite the differences for age-sex and initial severity of illness in our cohort and in the population of Bhopal city as predicted by our model.

Computer-assisted semen analysis parameters in men with varicocele: is surgery helpful?

OBJECTIVE: To assess sperm characteristics and fertility before and after varicocelectomy using computer-assisted semen analysis (CASA). DESIGN: Preoperative and postoperative sperm parameters of infertile men with varicocele were analyzed statistically and the outcome of pregnancy was determined. SETTING: Department of Infertility Management and Assisted Reproduction, Jaslok Hospital and Research Centre, Bombay. PATIENTS: Semen samples of 49 men with varicocele-related infertility were analyzed using CASA. INTERVENTIONS: Sperm parameters of 26 men who underwent varicocelectomy were evaluated 3, 6, and 9 months postoperatively. Conception, occurring either naturally or therapeutically, was recorded. MAIN OUTCOME MEASURES: Evaluation of improvement of sperm parameters after surgery. RESULTS: Sperm count, motility parameters, curvilinear velocity, straightline velocity, lateral head displacement, and normal morphology were significantly lower in men with varicocele. Postoperatively, there was significant improvement in count, motility, and normal morphology, with a decrease in proportion of acrosome-deficient heads and tapering forms. After varicocelectomy, 46.2% of the men had normal semen parameters, with the overall pregnancy rate being 50%. CONCLUSIONS: Computer-assisted semen analysis provides the potential for accurate quantitative evaluation of semen in men with varicocele. Varicocelectomy results in improvement in semen quality with pregnancy rates of 50%.

Genital tuberculosis--a major pelvic factor causing infertility in Indian women.

OBJECTIVE: To study the effect of tuberculosis, a common infectious disease in the Indian subcontinent, on the female pelvic factor and its subsequent effect on female fertility. DESIGN: Retrospective case studies. SETTING: Department of Infertility Management and Assisted Reproduction, Jaslok Hospital and Research Centre, Bombay, India. PATIENT(S): Three hundred women, between the ages of 25 and 35 years, with tubal factor as a cause of their infertile state. RESULT(S): One hundred seventeen women with a tubal factor were found to have tuberculosis as the cause of tubal blockage. On laparoscopy, 49.5% were found to have simple tubal blockage, 15.3% showed tubo-ovarian masses, and 23.9% had a frozen pelvis. Seventy-five percent complained of menstrual irregularities, thus indicating endometrial involvement; 25.6% of these women underwent an IVF procedure. The pregnancy rate after IVF-ET was 16.6% per transfer. CONCLUSION(S): This study highlights the fact that tuberculosis, a chronic infectious disease, is one of the major etiologic factors of female tubal infertility, especially on the Indian subcontinent.

Platelets and platelet inhibitors in acute myocardial infarction.

Platelets and platelet-rich thrombi play a pivotal role in the pathogenesis of acute myocardial infarction. A ruptured atherosclerotic plaque evokes a hemostatic response that is mediated by platelets, its membrane receptors, adhesive ligands, the presence or generation of platelet agonists, and the activation of the coagulation cascade with fibrin generation. The interaction of platelets with the coagulation and the fibrinolytic systems is complex; new and exciting developments, however, in the ability to pharmacologically control platelet responses during thrombolysis in acute myocardial infarction will enhance our understanding of these interactions and will eventually translate into clinical benefit.

Cocaine increases beta-myosin heavy-chain protein expression in cardiac myocytes.

BACKGROUND: As many as 47% of chronic cocaine users develop cardiac ventricular hypertrophy. The presence and degree of cocaine-induced ventricular hypertrophy is not correlated with the use of other substances of abuse such as alcohol or cigarettes. Moreover, this hypertrophy occurs in individuals without sustained increases in arterial blood pressure or heart rate, or increases in the plasma concentration of renin, aldosterone, norepinephrine, or cortisol. Therefore, we investigated whether cocaine, in concentrations commonly found in cocaine users, has any direct effects on the protein content in cardiac ventricular myocytes. We compared the effects of cocaine with norepinephrine, which increases the total protein content, especially beta-myosin heavy-chain contractile protein (beta-MHC), in cardiac ventricular myocytes. METHODS: Experiments were performed on 30-day-old rat ventricular myocytes suspended in culture media and cultured in flasks. In 12 suspension-culture experiments, cocaine or norepinephrine, in doses of 0 (control) or 10(-6) mol/L was added to each culture and the cells were harvested on day 5. In 16 flask-culture experiments, cocaine or norepinephrine was added to each culture on day 7 in doses of 0 (control-vehicle), 10(-7), or 10(-6) mol/L and the cells were harvested on day 10. The total protein content and the myosin protein expression of the myocytes in each culture were determined. Juvenile and adult rat cardiac myosin protein is predominately alpha-myosin heavy-chain protein (alpha-MHC), whereas beta-MHC occurs primarily in fetal rat hearts. RESULTS: In the suspension-culture experiments, cocaine, 10(-6) mol/L, increased the cardiomyocyte total protein concentration by 29% +/- 2% (P <.001) and the beta-MHC expression by 81% +/- 10% (P <.01) in comparison with the control myocytes. Cocaine slightly decreased cardiomyocyte alpha-MHC. Norepinephrine increased the total protein concentration by 21% +/- 3% (P <.001) and the beta-MHC expression by 59% +/- 10% (P <.01), but did not increase alpha-MHC expression. In the flask-culture experiments, cocaine, 10(-6) mol/L, maximally increased the total protein concentration by 28% (P <.001), the protein/cell ratio by 57% +/- 10% (P <.01), and the beta-MHC expression by 85% +/- 8% (P <.01). Cocaine slightly decreased alpha-MHC. Norepinephrine, 10(-6) mol/L, maximally increased the total protein concentration by 35%, the protein/cell ratio by 63% +/- 9% (P <.01), and the expression of beta-MHC by 78% +/- 11% (P <. 01). Norepinephrine did not increase alpha-MHC expression. In 18 separate flask-culture experiments, cocaine, 10(-6) mol/L, was added to the cardiomyocyte cultures after the addition of phentolamine (n = 9), in concentrations of 10(-7) to 10(-5) mol/L, or metoprolol (n = 9), in concentrations of 10(-7) to 10(-5) mol/L. Neither phentolamine nor metoprolol inhibited the cocaine-induced increase in cardiomyocyte total protein content or the expression of beta-MHC. CONCLUSION: Cocaine, similar to norepinephrine, significantly increases the total protein content and the expression of beta-MHC in cardiac ventricular myocytes. In this manner, cocaine may cause cardiac ventricular hypertrophy. This process is not inhibited by alpha- or beta-adrenergic receptor blockade.