Toll-like receptor-mediated NF-kappaB activation: a phylogenetically conserved paradigm in innate immunity.
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Biomedical subjects
Publications and source records attributed to S Ghosh.
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The treatment goal in Crohn's disease is clinical remission, not complete mucosal healing. The incidence of mucosal inflammation in Crohn's disease patients in clinical remission is not known. Whole gut lavage is an objective method of assessing mucosal inflammation. We aimed to assess levels of mucosal inflammatory activity in a group of patients with clinically inactive Crohn's disease. We prospectively assessed 30 patients with inactive Crohn's disease and 28 controls. Inactive disease was defined as Crohn's disease activity index of less than 150. All underwent whole put lavage, with analysis of whole gut lavage fluid IgG, haemoglobin, interleukin-1 beta, interleukin-8 and granulocyte elastase. Serum inflammatory parameters were collected for comparison. Of the 30 patients with Crohn's disease, 10 (33%) had an abnormal immunoglobulin G, 21 (70%) had an elevated interleukin-1 beta 20 (66%) interleukin-8 and 10 (33%) granulocyte elastase in the whole gut lavage fluid. 58% of patients had either 1 or 2 abnormal results. In contrast only 10% had 1 or 2 abnormal serum results. Few abnormalities were present in lavage fluid or serum of the control population. We concluded that ongoing mucosal inflammation is detectable in whole gut lavage fluid of up to 2/3 of Crohn's disease patients in clinical remission.
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Using footwear often becomes troublesome and creates many problems. Most of these problems are associated with the wearing of ill-fitting footwear, as it leads to biomechanical imbalance and ultimately give rise to different foot problems. In the present investigation different foot problems, viz., discomfort, pain and other hazards related to the use of footwear have been evaluated and attempts have been made to study different foot dimensions of men and women that are related to the design of footwear. For the present study different foot dimensions of both right and left feet of the subjects were measured on 300 Bengalee (Indian) subjects having the age range of 20-35 years. The subjects reported that they had got discomfort, pain, blister and corn due to using different footwear. It was noted that the occurrence of these problems in right foot was greater than that in left foot. There was no significant correlation between foot troubles and type of footwear. Results also showed that there was no significant difference in most of the foot dimensions between left foot and right foot. However, significant difference (P < 0.001) in all foot dimensions was observed between male and female subjects. Correlation coefficient among different foot dimensions has also been evaluated and it was noted that foot length was highly correlated with stature and foot volume, particularly in left foot. Footwear should be made according to the foot dimensions of the user population. The database collected from the Bengalee (Indian) population may be a helpful guide for manufacturing different footwear.
Increasing knowledge of the structure and function of the Epidermal Growth Factor Receptor (EGFR) subfamily of tyrosine kinases, and of their role in the initiation and progression of various cancers has led to the search for inhibitors of signaling molecules that may prove to be important in cancer therapy. The complex nature of EGFR biology allows for potential opportunities for EGFR inhibitors in a number of areas of cancer therapy, including proliferative, angiogenic, invasive, and metastatic aspects. Different approaches have been used to target either the extracellular ligand-binding domain of the EGFR or the intracellular tyrosine kinase region that results in interference with its signaling pathways that modulate cancer-promoting responses. Examples of these include a number of monoclonal antibodies, immunotoxins and ligand-binding cytotoxic agents that target the extracellular ligand binding region of EGFR, and small molecule inhibitors that target the intracellular kinase domain and act by interfering with ATP binding to the receptor. During the past 3 years, significant progress has been made towards the identification of new structural classes of small molecule inhibitors that show high potency and specificity towards EGFR. The search for new small molecules that inhibit kinases has included traditional approaches like the testing of natural products, random screening of chemical libraries, the use of classical structure-activity-relationship studies, and the incorporation of structure-based drug design and combinatorial chemistry techniques. There has been a significant improvement in the development of selective EGFR inhibitors with the use of a structure-based design approach employing a homology model of the EGFR kinase domain. Molecular modeling procedures have been used to generate novel molecules that are complementary in shape and electrostatics to the EGFR kinase domain topography. This review focuses on some examples of the successful use of this method.
Recently identified agents that interact with cytoskeletal elements such as tubulin include synthetic spiroketal pyrans (SPIKET) and monotetrahydrofuran compounds (COBRA compounds). SPIKET compounds target the spongistatin binding site of beta-tubulin and COBRA compounds target a unique binding cavity on alpha-tubulin. At nanomolar concentrations, the SPIKET compound SPIKET-P causes tubulin depolymerization and exhibits potent cytotoxic activity against cancer cells. COBRA-1 inhibits GTP-induced tubulin polymerization. Treatment of human breast cancer and brain tumor cells with COBRA-1 caused destruction of microtubule organization and apoptosis. Other studies have identified some promising protein tyrosine kinase inhibitors as anti-cancer agents. These include EGFR inhibitors such as the quinazoline derivative WHI-P97 and the leflunomide metabolite analog LFM-A12. Both LFM-A12 and WHI-P97 inhibit the in vitro invasiveness of EGFR positive human breast cancer cells at micromolar concentrations and induce apoptotic cell death. Dimethoxyquinazoline compounds WHI-P131 and WHI-P154 inhibit tyrosine kinase JAK3 in leukemia cells. Of particular interest is WHI-P131, which inhibits JAK3 but not JAK1, JAK2, SYK, BTK, LYN, or IRK at concentrations as high as 350 microM. Studies of BTK inhibitors showed that the leflunomide metabolite analog LFM-A13 inhibited BTK in leukemia and lymphoma cells. Consistent with the anti-apoptotic function of BTK, treatment of leukemic cells with LFM-A13 enhanced their sensitivity to chemotherapy-induced apoptosis.
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Effect of quercetin was studied on DMBA induced skin carcinogenesis in young adult Swiss albino mice. Quercetin was administered continuously with the diet (2%) for four weeks and chromosomal aberration, a predictor of future cancer risk, studied in the bone marrow cells at different time intervals. Significant reduction of chromosomal aberration was observed in bone marrow after four weeks (P< 0.02). The reduction was first evident after 96 hrs though it was not significant at this stage. Significant decrease occurred from the 21st day onward when quercetin was given in concomitance with 7,12-dimethylbenz[a]anthracene (DMBA) indicating a definite protective effect of quercetin on chromosomal aberration.
Thermophilic (55 degrees C) anaerobic digestion of wastewaters from wet carbonization of Minnesota peat was conducted in a simple, upflow digester at an HRT of one day to provide a methane yield of 0.20 SCM/kg VS added and a BOD5 reduction of 85%. Carbonization of Maine peat conducted for a much longer duration of thermal treatment produced recalcitrant and potentially toxic end products that reduced the biodegradability of wastewaters. Methane fermentation of the Maine-peat wet-carbonization waste was inhibited at an HRT of one day in the single-stage digester. However, two-phase digestion with separate acid-phase fermentation to promote hydrolytic degradation of toxic end products followed by separate methane fermentation at an HRT of 2 days exhibited a methane yield of 0.21 SCM/kg VS added and a BOD5 reduction of 76%. Volatile fatty acids profiles along the depths digesting cultures indicated that single-stage and two-phase digestion could be accomplished at one-half the reactor residence times (one day for single-stage and three days for two-phase) used in this research.
The herb Desmotrichum fimbriatum Bl. (family: Orchidaceae), sold as Jibanti in West Bengal, is used in 'Rasayana therapy' in Ayurveda. Its effect on the modulation of the two antioxidant enzymes peroxidase and catalase has been studied in mice liver during 'cold water swim' (CWS) stress using appropriate controls. The drug, i.e. the aqueous ethanolic extract of the herb (whole plant) was found to increase peroxidase titre in the hepatic cells of normal mice. But in the stressed group, the drug displayed no effect on the peroxidase content, while it elicited an elevation of the catalase content. infinity-Tocoferol was used as the standard drug. These data suggested that the drug can ameliorate the peroxidative damage caused in mice by CWS stress.
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OBJECTIVE: To assess the utility of the hematologic scoring system (HSS) of Rodwell et al for the early detection of neonatal sepsis. DESIGN: Analysis of the peripheral smear findings according to the HSS by a pathologist blinded to the infection status of the neonate. SUBJECTS: One hundred and three high risk neonates having predisposing perinatal factors or clinical suspicion of sepsis. RESULTS: Analysis of the hematologic profiles in the light of the HSS found that an abnormal immature to total neutrophil (1:T) ratio followed by an abnormal immature to mature neutrophil (1:M) ratio were the most sensitive indicators in identifying infants with sepsis. These two criteria along with thrombocytopenia (< 1,50,000/cm3) had a high negative predictive value over 94%. The study also found that the higher the score the greater the certainty of sepsis being present. CONCLUSION: The HSS is simple, quick, cost effective and readily available tool in the early-diagnosis of neonatal sepsis and could provide a guideline to decisions regarding antibiotic therapy.
Administration of aqueous extracts of V. rosea flower and leaf have been found to regulate the blood sugar level in alloxan diabetic male albino rats. V. rosea therapy not only produced blood glucose homeostasis but also reversed changes in carbohydrate, protein, lipid metabolisms and metabolic and pathologic changes that took place in pancreatic islet cells, liver and kidney following a single dose (150 mg/kg body weight) of alloxan monohydrate. B-cell secretory activity resumed near-normalcy as evidenced by near-normal serum insulin concentration and electron-microscopic study proving that V. rosea manifests its beneficial activity through B-cell rejuvenation, regeneration and stimulation.
Hydatid disease is caused by parasitic tapeworm Echinococcus. The larval stage of this parasite can thrive in many parts of the body, most frequently in the liver. Primary ovarian location is very rare. In our case the patient had bilateral ovarian cysts which on histopathological study was found to be hydatid cysts. Moreover one of the cysts was multilocular which is also unusual.
Foot-and-mouth disease virus (FMDV) type OR(2)/75, grown on BHK 21 clone 13 cell monolayers, was inactivated with formalin. The virus was clarified and was either concentrated with 8% polyethylene glycol 6000 (PEG) or used in its untreated form for the preparation of oil adjuvant vaccines. The oil adjuvants used in this study were Montanide ISA 206 (which renders a water-in-oil-in-water (w/o/w) type of emulsion), Montanide ISA 57 and Montanide ISA 50V (both of which render water-in-oil (w/o) type of emulsions). The vaccines were tested on guinea pigs and calves. The results indicated that vaccines emulsified using Montanide ISA 57 elicited the best protective immune response in the animals, followed by those emulsified with Montanide ISA 50V and Montanide ISA 206. It was also found that vaccines formulated with virus concentrated using 8% polyethylene glycol (PEG) were more immunogenic than the vaccines formulated with the untreated harvest virus.
The reaction of Cp*ReCl4, [Cp*ReCl3]2, or [Cp*ReCl2]2 (Cp* = eta 5-C5Me5) with LiBH4 leads to the formation of 7-skeletal-electron-pair (7-sep) (Cp*ReH2)2(B2H3)2 (1) together with Cp*ReH6. Compound 1 is metastable and eliminates H2 at room temperature to generate 6-sep (Cp*ReH2)2B4H4 (2). The reaction of 2 with BH3.thf produces 7-sep (Cp*Re)2B7H7, a hypoelectronic cluster characterized previously. Heating of 2 with 1 atm of CO leads to 6-sep (Cp*ReCO)(Cp*ReH2)B4H4 (3). Both 2 and 3 have the same bicapped Re2B2 tetrahedral cluster core structure. Monitoring the reaction of 2 with CO at room temperature by NMR reveals the formation of a 7-sep, metastable intermediate, (Cp*ReCO)(Cp*ReH2)(B2H3)2 (4), which converts to 3 on heating. An X-ray structure determination reveals two isomeric forms (4-cis and 4-trans) in the crystallographic asymmetric unit which differ in geometry relative to the disposition of the metal ancillary ligands with respect to the Re-Re bond. The presence of these isomers in solution is corroborated by the solution NMR data and the infrared spectrum. In both isomers, the metallaborane core consists of fused B2Re2 tetrahedra sharing the Re2 fragment. On the basis of similarities in electron count and spectroscopic data, 1 also possesses the same bitetrahedral structure. The reaction of 2 with CO2(CO)8 results in the formal replacement of the four rhenium hydrides with a 4-electron CO2(CO)5 fragment, thereby closing the open face in 2 to produce the 6-sep hypoelectronic cluster (Cp*Re)2CO2(CO)5B4H4 (5). These reaction outcomes are compared and contrasted with those previously observed for 5-sep (Cp*Cr2)2B4H8.
We analysed apoptosis, caspase-1 and -3, and trypsin-like protease activity in the nigrostriatal pathway during 1-methyl-4-phenyl-1,2,3, 6-tetrahydropyridine (MPTP)-induced neurotoxicity. MPTP injected (30 mg/kg, i.p., twice, 16 h apart) mice were sacrificed on 1, 2 and 7 days. DNA extracted from nucleus caudatus putamen (NCP) and substantia nigra (SN) was subjected to agarose gel electrophoresis. Typical apoptotic-like DNA cleavage was absent in SN or NCP after this dose of MPTP. A trypsin-like protease activity was significantly decreased in SN and not in NCP. While caspase-3 activity in the whole brain was increased significantly, caspase-1 activity was unaffected. Striatal dopamine content was decreased to 75% by 7 days. The absence of typical DNA 'ladder' when there was severe striatal dopamine depletion suggests that in vivo MPTP-mediated dopaminergic neurotoxicity may not involve apoptotic cell death, and explains why in mice MPTP-induced dopamine depletion is transient. The region-specific decrease in trypsin-like protease activity and absence of caspase-3 activation in SN signify the importance of trypsin-like protease in the regulation of apoptosis in MPTP-neurotoxicity in mice.
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