Contact angle measurement system with liquid sodium in inert atmosphere.

Liquid sodium is the heat transport medium in fast breeder reactors due to its favorable chemical, physical, and nuclear properties. Wetting of liquid sodium with the material of reactor components is essential for the effective functioning of the reactor. Liquid sodium wetting plays a crucial role, such as in (i) heat transfer and (ii) image reconstruction under sodium ultrasonic scanners. Contact angle is the inverse measure of the wetting of liquids over solid surfaces. A contact angle measurement system was set up in an inert atmosphere glow box to study the wetting behavior of liquid sodium on reactor materials. The contact angle of liquid sodium on nickel surface was measured as a function of temperature, and the results obtained were found to be in good agreement with the literature values. The contact angle of liquid sodium on SS316LN as a function of temperature was measured for the first time using this facility.

Spontaneous nontraumatic subarachnoid hemorrhage without cerebrovascular malformations in a maintenance hemodialysis patient.

Nontraumatic subarachnoid hemorrhage (SAH) in a dialysis patient is an uncommon occurrence and is often associated with high mortality. We report for the first time in India, a case of spontaneous nontraumatic, nonaneurysmal SAH without any cerebrovascular malformation in a maintenance hemodialysis patient, following a session of hemodialysis. The dialysis prescription needs to be modified in these patients, in order to prevent worsening of cerebral edema and progression of hemorrhage. Where available, continuous forms of renal replacement therapies, with regional anticoagulation seem to be the best option for such patients, till neurologic stabilization is achieved.

Extragastrointestinal stromal tumour of the abdominal wall - a case report.

Stromal tumours occurring in areas other than the GastroIntestinal Tract (GIT) are known as Extra GastroIntestinal Stromal Tumours (EGISTs). They usually arise in the mesentery, omentum or retroperitoneum, while EGISTs which occur in the abdominal wall are very rare. Both gastrointestinal stromal tumours (GISTs) and EGISTs are histologically and immunophenotypically similar. We are reporting a case of EGIST, which occurred in the anterior abdominal wall in a twenty five-year-old female patient. The tumour was present in the right loin and imaging studies suggested that it was a desmoid tumour. It was surgically excised by doing an abdominal wall mesh repair. The histological examinations revealed a tumour with spindle cell morphology, with <2 mitoses per 50 High Power Field (HPF) and no necrosis, with tumour free margins. Immunohistochemistry was strongly positive for CD117 and Smooth Muscle Actin (SMA), while it was negative for ß-catenin and S100. The patient is well post operatively and is on close follow up. EGISTs should be considered in the differential diagnosis of mesenchymal tumours which occur in the abdominal wall, inspite of their rarity, as the high risk patients may need Imatinib chemotherapy.

Immediate impact of a diabetes training programme for primary care physicians--an endeavour for national capacity building for diabetes management in India.

AIMS: India faces a huge burden from diabetes. National capacity for management of diabetes has to be strengthened by improving knowledge of physicians treating diabetes, especially in semi urban and rural areas. A training programme was formulated and conducted at national level, as a step towards this goal. METHODS: Physicians from 6 states of India (n=3023, M:F 2311:712), aged 30-55 years, with service of >or=3 years, (government n=1720, private n=1303, semi urban and rural areas (n=1581:1442)) were trained in diabetes care in 5-day workshops between March 2004 to December 2006. Impact of training was assessed by pre- and post-training knowledge scores, feedback on usefulness of training modules, prioritizing activities to be introduced in their practice and methods to be used for raising public awareness on diabetes. RESULTS: The training significantly improved knowledge on treatment, complications, pathophysiology and diagnosis of diabetes (p<0.001). The participants considered information on preventive aspects of diabetes and foot care as highly educative. Patient education and team-training were considered important in diabetes management. Interest was evinced in raising public awareness about the disease. CONCLUSIONS: Well-planned short training programmes are useful in improving knowledge and in creating enthusiasm to improve diabetes care and awareness.

Population based study of quality of diabetes care in southern India.

OBJECTIVES: To analyse and compare the clinical profile and glycaemic outcome in known diabetic cases in South Indian urban and periurban populations. MATERIAL AND METHODS: Details of known type 2 diabetic cases identified in a population survey of diabetes in Chennai city, Kanchipuram town and Periurban Villages (PUV) of Panruti in Tamil Nadu were analyzed (n=524, M:F, 256:268). Glycaemic outcome, prevalence of hypertension, dyslipidaemia and obesity, and treatment details were studied and compared between the areas. RESULTS: Mean age at diagnosis was 45.3 +/- 10.1 years, prevalence of hypertension was 57.4% (32% known), 48% were obese and a larger percentage (63.3%) had abdominal obesity Dyslipidaemia was present in nearly 50%. Abnormalities were more in urban areas than in PUV. Glycaemic target (post prandial glucose < or =160 mg/dl) was met by 28.8% only; better results were seen in PUV. In PUV 46% were not taking any diabetic treatment. As expected, majority of patients in all areas were treated with oral drugs. CONCLUSIONS: This population-based data indicated that the clinical outcome in known diabetic cases was far from satisfactory even in the city, where specialized diabetes care was available.

High prevalence of cardiometabolic risk factors among young physicians in India.

AIM: To assess the health status of young Indian doctors engaged in clinical practice compared with the general population. MATERIALS AND METHODS: During a continuing medical education programme on diabetes, data from 2499 doctors from urban and semiurban areas, (mean age 39.0 + 9.0 yrs), were collected and was compared with 3278 subjects from general population (mean age 37.0 +/- 8.0 yrs). Prevalence of diabetes, hypertension, obesity, dyslipidaemia, metabolic syndrome, smoking and alcohol consumption were analysed. RESULTS: Doctors had significantly higher (p<0.001) prevalence of all abnormalities except diabetes, compared with the general population (diabetes 13.3 Vs 14.8%, impaired glucose tolerance 10.7 Vs 7.4%, hypertension 35.6% Vs 27.0%, obesity 55.5% Vs 35.8%, metabolic syndrome 29.0% Vs 24.8%). Undetected cases of diabetes and hypertension were similar in both groups. Use of alcohol was more common among doctors. Other illness was less common among doctors (13.2% Vs 21.8%, p < 0.001). CONCLUSIONS: In India, doctors had high prevalence of metabolic disorders showing that they had not taken good care of their health. Doctors need to be motivated to practise good healthcare habits that they advocate to their clients.

Awareness about diabetes and its complications in the general and diabetic population in a city in southern India.

OBJECTIVE: The study was done to find out the levels of awareness on diabetes in urban adult Indian population and to identify factors that influenced the awareness, including presence of diabetes. RESEARCH DESIGN AND METHODS: In population aged > or =20 years (n=3681, M=1769, F=1912), details regarding awareness about diabetes in relation with physical activity, healthy and unhealthy diet, causes, symptoms, prevention, complications and measures to improve health were collected using a questionnaire. A high total score indicated good knowledge. Influence of age, gender, educational status, occupation and presence of diabetic history was analysed. RESULTS: Fifty percent of subjects scored less than 15. Maximum scored was 51/65. The median total score was 16. Total score was significantly lower in women than in men (15.0 versus 17.0, p<0.0001). Educational status was low in women. Higher education (16.0 versus 12.0, p<0.0001) and professional or executive jobs (17.0 versus 15.0, p<0.0001) were significantly associated with better awareness. Age had no influence. Knowledge regarding causes of diabetes, its prevention and the methods to improve health was significantly low among the general population. Diabetic subjects had better knowledge about symptoms of diabetes and the preventive aspects. CONCLUSIONS: The low median score indicated that the awareness was generally poor. The score was low especially in women and subjects with low education. The study highlights the urgent need for strategies to spread awareness about diabetes in the general population. Diabetic subjects also required better education on many aspects.

Application of structure-metabolism relationships in the identification of a selective endothelin A antagonist, BMS-193884, with favourable pharmacokinetic properties.

1. Based on binding affinity, 2'-amino-N-(3,4-dimethyl-5-isoxazolyl)-4'-(2-methylpropyl)[1,1'-biphenyl]-2-sulfonamide (2) was identified as an initial lead in a programme to identify selective endothelin (ET) receptor antagonists. However, the compound was extensively metabolized in preclinical animal species and human in vitro systems due to oxidative biotransformation. 2. To optimize this structural class, the site of metabolism of 2 was determined. This allowed for focussed structure-activity and structure-metabolism studies aimed at finding more metabolically stable analogues that maintained potency. New analogues were screened for their ET binding characteristics and their stability in rat and human liver microsomes. 3. The use of the microsomal stability screen was tested by the determination of the pharmacokinetic parameters of select analogues. A good correlation was found between reduced rates of rat microsomal metabolism and reduced clearance in the rat. 4. N-(3,4-dimethyl-5-isoxazolyl)-4'-(2-oxazolyl)[1,1'-biphenyl]-2-sulfonamide (3) was identified as an analogue with improved in vitro properties and further studies revealed that the compound had improved pharmacokinetic properties. 5. N-[[2'-[[(3,4-dimethyl-5-isoxazolyl)amino]sulfonyl]-4-(2-oxazolyl)[1,1'-biphenyl]-2-yl]methyl]acetamide (4) was subsequently identified as a compound with superior in vitro properties compared with compound 3, but when tested in vivo it had a substantially increased rate of clearance. Further studies demonstrated that the clearance of this closely related structural analogue was not dictated by metabolic processes, but was mediated by transport-mediated direct biliary excretion. 6. The utility of screening for in vitro liver microsomal stability as part of the lead optimization process for compounds with metabolic liabilities was shown. It was also shown that relatively small molecular changes can dramatically change the disposition of closely related analogues and care must be used when screening for a single property.

Biphenylsulfonamide endothelin receptor antagonists. 2. Discovery of 4'-oxazolyl biphenylsulfonamides as a new class of potent, highly selective ET(A) antagonists.

The synthesis and structure-activity relationship (SAR) studies of a series of 4'-oxazolyl-N-(3,4-dimethyl-5-isoxazolyl)[1, 1'-biphenyl]-2-sulfonamide derivatives as endothelin-A (ET(A)) receptor antagonists are described. The data reveal a remarkable improvement in potency and metabolic stability when the 4'-position of the biphenylsulfonamide is substituted with an oxazole ring. Additional 2'-substitution of an acylaminomethyl group further increased the binding activity and provided one of the first subnanomolar ET(A)-selective antagonists in the biphenylsulfonamide series (17, ET(A) K(i) = 0.2 nM). Among the compounds described, 3 (N-(3,4-dimethyl-5-isoxazolyl)-4'-(2-oxazolyl)[1, 1'-biphenyl]-2-sulfonamide; BMS-193884) had the optimum pharmacological profile and was therefore selected as a clinical candidate for studies in congestive heart failure.

Biphenylsulfonamide endothelin antagonists: structure-activity relationships of a series of mono- and disubstituted analogues and pharmacology of the orally active endothelin antagonist 2'-amino-N- (3,4-dimethyl-5-isoxazolyl)-4'-(2-methylpropyl)[1, 1'-biphenyl]-2-sulfonamide (BMS-187308).

Substitution at the ortho position of N-(3,4-dimethyl-5-isoxazolyl) benzenesulfonamide led to the identification of the biphenylsulfonamides as a novel series of endothelin-A (ETA) selective antagonists. Appropriate substitutions on the pendant phenyl ring led to improved binding as well as functional activity. A hydrophobic group such as isobutyl or isopropoxyl was found to be optimal at the 4'-position. Introduction of an amino group at the 2'-position also led to improved analogues. Combination of the optimal 4'-isobutyl substituent with the 2'-amino function afforded an analogue (20, BMS-187308) with improved ETA binding affinity and functional activity. Compound 20 also has good oral activity in inhibiting the pressor effect caused by an ET-1 infusion in rats. Doses of 10 and 30 micromol/kg iv 20 attenuated the pressor responses due to the administration of exogenous ET-1 to conscious monkeys, indicating that the compound inhibits the in vivo activity of endothelin-1 in nonhuman primates.

Chemistry of the alkali-labile lesion formed from iron(II) bleomycin and d(CGCTTTAAAGCG).

Two sets of products are formed from DNA upon treatment with Fe(II).bleomycin + O2. One set, which is believed to derive from a C-4' hydroperoxy derivative of the DNA deoxyribose moiety, includes the four possible base propenals, as well as DNA oligomers having deoxynucleoside 3'-(phosphoro-2"-O-glycolates) at their 3'-termini. The other set of products consists of free bases and alkali-labile lesions, the latter of which had not previously been characterized structurally. By use of the self-complementary dodecanucleotide d(CGCTTTAAAGCG) having a site modified by Fe-bleomycin three nucleotides from the 5'-end, it has been possible to characterize the alkali-labile product as a C-4' hydroxyapurinic acid. When the bleomycin-treated dodecanucleotide was treated with agents that effected decomposition of the alkali-labile lesion, products of the form CpGpx were obtained, and these proved useful for structural characterization of the alkali-labile lesion. Treatment with alkali produced CpGpx, where x was 2,4-dihydroxycyclopentenone. Alternatively, treatment with hydrazine provided a pyridazine derivative, and aqueous alkylamines led to formation of CpGp itself. The structures of all dinucleotides produced from the alkali-labile lesion were verified by direct comparison with authentic synthetic samples.

Analysis of products formed during bleomycin-mediated DNA degradation.

By the use of DNA, copolymers of defined nucleotide composition, and a synthetic dodecanucleotide having putative bleomycin cleavage sites in proximity to the 5'- and 3'-termini, the products formed concomitant with DNA strand scission have been isolated and subjected to structural identification and quantitation via direct comparison with authentic synthetic samples. The products of DNA strand scission by Fe(II)-bleomycin include oligonucleotides having each of the four possible nucleoside 3'-(phosphoro-2''-O-glycolates) at their 3'-termini, as well as the four possible base propenals. At least for 3-(adenin-9'-yl)propenal and 3-(thymin-1'-yl)propenal, the products formed were exclusively of the trans configuration.

Oxygen transfer from bleomycin-metal complexes.

Both Fe(III) and Cu(II) complexes of bleomycin (BLM), but not N-acetyl BLM . Fe(III), mediated the transfer of oxygen from iodosobenzene to organic substrates. In analogy with results obtained using certain cytochrome P-450 analogs, cis-stilbene was converted cleanly to the respective oxide, while no more than traces of trans-stilbene oxide were formed from trans-stilbene under identical conditions. The possible relevance of these observations to the degradation of DNA by bleomycin was also studied. In both the presence and absence of O2, BLM . Cu(II) . C6H5IO effected DNA degradation, as judged by the release of [3H]thymine from radiolabeled Escherichia coli DNA. These findings provide a valuable new assay system for the study of bleomycin analogs and suggest the possibility that bleomycin may function as an "oxygen transferase" in its degradation of DNA in situ.