Troglitazone increases cytochrome P-450 3A protein and activity in primary cultures of human hepatocytes.

Troglitazone (TRO) is an insulin sensitizer used in the treatment of type II diabetes. TRO is known to increase the activity of cytochrome P-450 (CYP) 3A in vivo. We have investigated the effect of TRO on CYP3A protein content and the activity of CYP3A (as measured by the formation of 6beta-hydroxytestosterone formation) in primary cultures of human hepatocytes in comparison with rifampicin (RIF). Hepatocytes were isolated from four human livers by perfusion with collagenase, plated on collagen-coated plates, and maintained in William's E medium. After 48 h in culture, cells were exposed to RIF (10 microM) or TRO (0-50 microM) twice, each over a period of 24 h, and the activity of CYP3A was measured. TRO increased the activity of CYP3A in a concentration-dependent manner, reaching a maximal response at 5 microM. Pretreatment of the hepatocytes with 10 microM TRO or 10 microM RIF resulted in a 4- to 15-fold increase in the activity of CYP3A. Maximum increase in CYP3A protein was observed at 5 microM TRO. There was a significant correlation (R(2) = 0.89) between the content of immunoreactive CYP3A protein in the hepatocytes and the rate of formation of 6beta-hydroxytestosterone. These results indicate that TRO is a potent inducer of CYP3A and is similar to RIF in inducing CYP3A in human hepatocytes. At concentrations of 25 microM and above, TRO was toxic to the cells, as determined by a decrease in the activity of CYP3A, a reduction in the amount of immunoreactive protein, and changes in the morphology of the cells.     

Std trends in chengalpattu hospital

A retrospective data analysis was carried out to find the trends in frequency and distribution of different STDs at Chengalpattu during 1988-1994. Of the 4549 patients who attended the clinic 3621 (79.6%) were males and 928 (20.4%) were females. The commonest STD was Chancroid (24.4%) in men and Syphillis (29%) in women. Balanoposthitis (11.4%) ranked third among STDs in males. Though the STD attendance showed a declining trend, most diseases showed a constant distribution. The percentage composition of secondary and latent syphillis, Genital Warts, Genital Herpes and the Non-Venereal group showed an increased composition in recent years. Primary syphillis in females showed a definite declining trend. The HIV sero-positive detection rate was 2.06%. Of the 1116 patients screened for HIV antibody, 23 patients were detected sero-positive. Time Series Regression Analysis was used to predict the number of patients who would attend the STD clinic with various STDs in 1995 and 1996 to help in the understanding of the disease load and pattern in future, in resources management and in developing and evaluating preventive measures.     

Bilateral pneumothorax with pneumomediastinum under anaesthesia in a healthy female

A case of bilateral pneumothorax and Pneumomediastinum developing under general anaesthesia without apparent cause is reported. Possible aetiologic factors and mechanisms of the condition are outlined. Clinical signs and the immediate management of pneumothorax and Pneumomediastinum are discussed.     

Phantom limbs and neural plasticity

The study of phantom limbs has received tremendous impetus from recent studies linking changes in cortical topography with perceptual experience. Systematic psychophysical testing and functional imaging studies on patients with phantom limbs provide 2 unique opportunities. First, they allow us to demonstrate neural plasticity in the adult human brain. Second, by tracking perceptual changes (such as referred sensations) and changes in cortical topography in individual patients, we can begin to explore how the activity of sensory maps gives rise to conscious experience. Finally, phantom limbs also allow us to explore intersensory effects and the manner in which the brain constructs and updates a "body image" throughout life.     

Scintigraphic evaluation of colonic transit in two patients with idiopathic chronic constipation

Bowel transit in two women with protracted constipation was evaluated after oral administration of In-111 DTPA in water. Serial abdominal images were obtained for as long as 96 hours to assess transit through the stomach, small bowel, and colon. In both patients, large bowel transit was delayed. A pattern of colonic inertia was observed in one patient, whereas retention in the distal colon was seen in the other patient. Both patients underwent total colectomy with marked symptomatic relief. Colonic transit studies of these patients are presented, and the literature is reviewed.     

Motion capture anisotropy

Two uncorrelated random dot patterns were superimposed and alternated to produce dynamic incoherent noise. When a low spatial frequency sine wave grating was optically superimposed on this noise and moved in step with the alternation of the two frames, the incoherent motion was masked and all the dots were seen to adhere to the grating and to move with it as a single rigid sheet ("Motion Capture"). Over a wide range of displacements subjects could not discriminate uncorrelated noise which was "captured" from correlated noise patterns which moved physically in the same direction as the grating. In fact the motion signal from the low frequency grating was even strong enough to overcome signals from two correlated random dot patterns which moved in the opposite direction. Capture was not as strong if the direction of dot motion was orthogonal to the direction of grating motion. We conclude that in any dynamic visual scene the motion of certain salient features in the image tends to dominate our perceptual experience. The signal from low frequencies masks or inhibits the signal from the high frequencies. Since the latter now have no motion signal of their own they are assumed to move with the low frequencies. Thus, motion capture suggests an important biological role for long-range apparent motion: the process serves to preserve continuity of object identity while at the same time eliminating spurious motion signals that arise from finer image features. In this manner the visual system solves the "correspondence problem" without benefit from either computation or cognition.     

SARS CoV-2 (Delta Variant) Infection Kinetics and Immunopathogenesis in Domestic Cats

Continued emergence of SARS-CoV-2 variants highlights the critical need for adaptable and translational animal models for acute COVID-19. Limitations to current animal models for SARS CoV-2 (e.g., transgenic mice, non-human primates, ferrets) include subclinical to mild lower respiratory disease, divergence from clinical COVID-19 disease course, and/or the need for host genetic modifications to permit infection. We therefore established a feline model to study COVID-19 disease progression and utilized this model to evaluate infection kinetics and immunopathology of the rapidly circulating Delta variant (B.1.617.2) of SARS-CoV-2. In this study, specific-pathogen-free domestic cats (n = 24) were inoculated intranasally and/or intratracheally with SARS CoV-2 (B.1.617.2). Infected cats developed severe clinical respiratory disease and pulmonary lesions at 4- and 12-days post-infection (dpi), even at 1/10 the dose of previously studied wild-type SARS-CoV-2. Infectious virus was isolated from nasal secretions of delta-variant infected cats in high amounts at multiple timepoints, and viral antigen was co-localized in ACE2-expressing cells of the lungs (pneumocytes, vascular endothelium, peribronchial glandular epithelium) and strongly associated with severe pulmonary inflammation and vasculitis that were more pronounced than in wild-type SARS-CoV-2 infection. RNA sequencing of infected feline lung tissues identified upregulation of multiple gene pathways associated with cytokine receptor interactions, chemokine signaling, and viral protein–cytokine interactions during acute infection with SARS-CoV-2. Weighted correlation network analysis (WGCNA) of differentially expressed genes identified several distinct clusters of dysregulated hub genes that are significantly correlated with both clinical signs and lesions during acute infection. Collectively, the results of these studies help to delineate the role of domestic cats in disease transmission and response to variant emergence, establish a flexible translational model to develop strategies to prevent the spread of SARS-CoV-2, and identify potential targets for downstream therapeutic development.     

Prospective technical validation and assessment of intra-tumour heterogeneity of a low density array hypoxia gene profile in head and neck squamous cell carcinoma

Background and purposeTumour hypoxia is associated with a poor prognosis in head and neck squamous cell carcinoma (HNSCC), however there is no accepted method for assessing hypoxia clinically. We aimed to conduct a technical validation of a hypoxia gene expression signature using the TaqMan Low Density Array (TLDA) platform to investigate if this approach reliably identified hypoxic tumours.Materials and methodsTumour samples (n = 201) from 80 HNSCC patients were collected prospectively from two centres. Fifty-three patients received pimonidazole prior to surgery. TaqMan Low Density Array-Hypoxia Scores (TLDA-HS) were obtained by quantitative real-time PCR (qPCR) using a 25-gene signature and customised TLDA cards. Assay performance was assessed as coefficient of variation (CoV).ResultsThe assay was sensitive with linear reaction efficiencies across a 4log₁₀ range of inputted cDNA (0.001–10 ng/μl). Intra- (CoV = 6.9%) and inter- (CoV = 2.0%) assay reproducibility were excellent. Intra-tumour heterogeneity was lower for TLDA-HS (23.2%) than for pimonidazole (67.2%) or single gene measurements of CA9 (62.2%), VEGFA (45.0%) or HIG2 (39.4%). TLDA-HS in HNSCC cell lines increased with decreasing pO₂. TLDA-HS correlated with Affymetrix U133 Plus 2.0 microarray HS (p < 0.01) and positive pimonidazole scores (p = 0.005).ConclusionsGene expression measurements of hypoxia using a 25-gene signature and TLDA cards are sensitive, reproducible and associated with lower intra-tumour heterogeneity than assaying individual genes or pimonidazole binding. The approach is suitable for further assessment of prognostic and predictive capability in clinical trial material.     

Metabolic Syndrome and Inflammatory Biomarkers: a community-based cross-sectional Study at the Framingham Heart Study

ABSTRACT: BACKGROUND: Prior studies reported conflicting findings on the association between metabolic syndrome and inflammatory biomarkers. We tested the cross-sectional association between metabolic syndrome, its components, and 9 inflammatory markers. METHODS: We measured C-reactive protein, CD40 ligand, interleukin-6, intercellular adhesion molecule-1, monocyte chemoattractant protein-1, osteoprotegerin, P-selectin, tumor necrosis factor-alpha, and tumor necrosis factor receptor-2 in 2570 Framingham Offspring Study participants free of diabetes and cardiovascular disease at exam 7. Metabolic syndrome was defined by criteria of the National Cholesterol Education Program. We performed multivariable linear regressions for each biomarker with metabolic syndrome as the exposure adjusting for age, sex, smoking, aspirin use, and hormone replacement. We subsequently added each component of the metabolic syndrome as a continuous trait to the models, adjusting for age, sex, smoking, aspirin use, hormone replacement, lipid lowering treatment and hypertension therapy. We considered P < 0.05 as statistically significant. RESULTS: Metabolic syndrome was present in 984 participants, and statistically significantly associated with each biomarker (all P<0.0001) except osteoprotegerin. After adjusting for its components, the metabolic syndrome was only associated with P-selectin (beta=0.16, 95% CI (0.05, 0.27)). CONCLUSIONS: Metabolic syndrome was associated with multiple inflammatory biomarkers. However, adjusting for each of its components eliminated the association with most inflammatory markers, except P-selectin. Our results support the hypothesis that the relation between metabolic syndrome and inflammation is largely accounted for by its components.