Syntheses of new tetrasubstituted thiophenes as novel anti-inflammatory agents

A series of new tetrasubstituted thiophenes (4a-4i, 5a-5i and 6a-6f) have been synthesized as novel anti-inflammatory agents and were evaluated for their anti-inflammatory activity in carrageenin-induced rat hind paw oedema model at the doses of 10, 20 and 40mg/kg body weight. Among ester series, the best compound 4c showed 71% protection at 10mg/kg, 72% at 20mg/kg, and 76% at 40mg/kg to inflamed paw; while in acid series 5a showed 79% protection at 10mg/kg, 80% at 20mg/kg, and 70% at 40mg/kg, and 5c showed 72% protection at 10mg/kg, 75% at 20mg/kg, and 69% at 40mg/kg, to inflamed paw. In case of oxime series 6a-6f, the anti-inflammatory activities of the candidates were found to be poor as compared to acid and ester series. It was found on the basis of SAR studies of target compounds, that the presence of OCH(3) at R(2) position and H, OCH(3) at R(1) are one of the requirements for eliciting comparable anti-inflammatory activity in both tetrasubstituted thiophenes' ester and acid series. Compounds 4a-4i, 5a-5i were investigated for their analgesic activity in acetic acid induced writhing response model at 10mg/kg dose. Among the ester series compound 4e showed maximum protection of 60%, while 4a, 4b, and 4i exhibited 55%, 45%, and 43% protection, respectively. The result showed that presence of H, Cl at R(1) and OCH(3), CH(3) at R(2) in tetrasubstituted thiophene ester series enhances their analgesic activity. The candidates of acid series 5a-5i showed poor analgesic activity as compared to the standard drug ibuprofen. Compounds 4a-4i, 5a-5i were evaluated for their in vitro antioxidant nitric oxide radical scavenging assay. Among the ester series 4a showed maximum in vitro nitric oxide radical scavenging activity having IC(50) value 30.08microg/ml while in acid series 5a has IC(50) value 25.20microg/ml. The results showed that the presence of R(1)=H, R(2)=OCH(3) and R(1)=R(2)=OCH(3) enhances nitric oxide radical scavenging property in tetrasubstituted thiophenes' acid series.     

The psychosocial experience of women with PCOS--a case control study

Polycystic ovary syndrome (PCOS) is a common endocrine disorder affecting 5-10% of women. It is characterised by androgenisation and anovulation, with sufferers being at increased risk of metabolic problems such as noninsulin dependent diabetes mellitus and dyslipidaemia. An increased risk of cardiovascular disease is speculated. Clinically, sufferers may experience acne, obesity, hirsutism and/or male pattern baldness.     

Eosinophil adhesion under flow conditions activates mechanosensitive signaling pathways in human endothelial cells

Leukocyte transmigration can be affected by shear stress; however, the mechanisms by which shear stress modulates transmigration are unknown. We found that adhesion of eosinophils or an eosinophilic cell line to intereukin 4-stimulated endothelial cells led to a shear-dependent increase in endothelial cell intracellular calcium and increased phosphorylation of extracellular signal-regulated kinase (ERK) 2, but not c-Jun NH2-terminal kinase or p38 mitogen-activated protein kinase. Latex beads coated with antibodies were used to characterize the role of specific endothelial cell surface molecules in initiating signaling under shear conditions. We found that ligation of either vascular cell adhesion molecule-1 or E-selectin, but not major histocompatibility complex class I, induced a shear-dependent increase in ERK2 phosphorylation in cytokine-stimulated endothelial cells. Disassembly of the actin cytoskeleton with latrunculin A prevented ERK2 phosphorylation after adhesion under flow conditions, supporting a role for the cytoskeleton in mechano-sensing. Rapid phosphorylation of focal adhesion kinase and paxillin occurred under identical conditions, suggesting that focal adhesions were also involved in mechanotransduction. Finally, we found that Rho-associated protein kinase and calpain were both critical in the subsequent transendothelial migration of eosinophils under flow conditions. These data suggest that ligation of leukocyte adhesion molecules under flow conditions leads to mechanotransduction in endothelial cells, which can regulate subsequent leukocyte trafficking.     

Real-time ultrasonography in neuromuscular problems in children

Ultrasound imaging of 20 cases of progressive muscular dystrophy and 10 cases of suspected infantile spinal muscular atrophy in children was performed by us, as a double-blind plot study matched against 25 controls. Open muscle biopsy was restricted to the muscular dystrophy group. The ultrasonographic findings were correlated with parameters such as functional disability of muscle and muscle biopsy features in the dystrophy group. It was interesting to observe that the muscle echogram was abnormal in both types of neuromuscular problems, the controls giving a normal muscle echogram. Ultrasonography was helpful in detection of unequivocal changes in our cases with mild clinical disability. It had a close correlation with changes in gross muscle architecture, as seen on muscle biopsy.     

Family-Driven Youth-Guided Practices in Residential Treatment: Findings from a National Survey of Residential Treatment Facilities

Family-driven, youth-guided practices have shaped the development of community-based mental health services for children and youth; however, the extent to which residential treatment providers have adopted these practices is unclear. This study reports the findings from a survey of 293 residential treatment providers conducted to examine the adoption of family-driven, youth-guided care. Residential treatment providers reported several practices consistent with family-driven, youth-guided care, including strength-based individualized treatment planning, collaboration with community-based providers to develop treatment plans, and the provision of various forms of support to families. Thirty percent of providers reported that the youth or family member was the primary decision maker in the development of treatment plans, 20.9% included youth or family members in program oversight, and 88.0% reported that staff had not heard of family-driven, youth-guided principles or required further training to implement them.     

Repeated administration of sulpiride for three weeks produces behavioural and biochemical evidence for cerebral dopamine receptor supersensitivity

Administration of sulpiride (2 × 100 mg/kg i.p.) or haloperidol (5 mg/kg i.p.) to rats for 3 weeks with subsequent withdrawal for 3 or 4 days induced cerebral dopamine receptor supersensitivity. Apomorphine-induced stereotyped behaviour after drug withdrawal was enhanced by pretreatment with either haloperidol or sulpiride both of which increased the number of specific striatal binding sites (B_max) for [³H]spiperone, [³H]N,n-propylnorapomorphine and [³H]sulpiride. Neither drug altered the dissociation constant (K_D) for the ligand binding assays. Striatal dopamine sensitive adenylate cyclase activity was unaltered by such a pretreatment with either haloperidol or sulpiride. The data show that sulpiride, like haloperidol, is capable of inducing behavioural and biochemical supersensitivity of cerebral dopamine receptors.     

Chemical-viral co-carcinogenesis: Requirement for leukemia virus expression in accelerated transformation

The essential role of Rauscher leukemia virus (RLV) multiplication in viral—chemical co-carcinogenesis was investigated by the use of ethidium bromide (EtBr) as an inhibitor of viral complementary DNA (cDNA) integration in the host genome. EtBr inhibited co-carcinogenic transformation when present at the time of RLV inoculation but was ineffective when added to preinfected cells. Inhibitors of protein synthesis, puromycin and cyclohexamide also inhibited co-carcinogenic transformation of chronically infected cells. Purified rat interferon used at a concentration which inhibited 85% of RLV production did not modify the course of co-carcinogenic transformation. The implications of these observations in terms of the possible role of the virus-specific protein(s) in the co-carcinogenic process are discussed.