Cutaneous necrosis in a young woman.
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Adult↗
Biomedical subjects
B Sinha
Publications and source records attributed to B Sinha.
Staphylococcus aureus induces caspase-independent cell death in human peritoneal mesothelial cells.
Bacterial peritonitis remains a serious complication of peritoneal dialysis. Although Staphylococcus epidermidis is the most common pathogen involved, infections with Staphylococcus aureus lead to severe peritoneal damage and are often associated with a dramatic loss of mesothelial cells. Induction of cell death appears to be involved in peritoneal damage and mesothelial cell loss during bacterial infections. Using cultured human peritoneal mesothelial cells (HMCs), we investigated the ability of different S. epidermidis and S. aureus strains to damage the HMC monolayer and to trigger cell death. We show that only a subgroup of live S. aureus isolates, characterized by an invasive and alpha-hemolysin-producing phenotype, induces cell death. None of the tested S. epidermidis strains, which were not invasive or hemolytic, had a cytotoxic effect. After host cell invasion, S. aureus resided within phagocytic vacuoles, and HMCs were apparently able to degrade staphylococci. However, even after prolonged infection, a high percentage of S. aureus remained alive within HMCs and might be released after host cell death. Cell death induced by S. aureus was accompanied by apoptotic alterations, such as DNA fragmentation, but was independent of endogenous FasL and tumor necrosis factor-alpha death ligand expression. Moreover, caspases were not involved in S. aureus-induced mesothelial cell death. In conclusion, our data indicate that mesothelial cell death might represent a major mechanism of S. aureus-induced damage of the peritoneum during bacterial peritonitis.
Apoptosis↗
Energy cost and cardiorespiratory changes during the practice of Surya Namaskar.
Surya Namaskar (SN), a group of Yogic exercise consists of a set of twelve postures which is practiced by some of the yoga practitioners. The present study was undertaken to observe critically the energy cost and different cardiorespiratory changes during the practice of SN. Twenty-one male volunteers from the Indian Army practiced selected Yogic exercises for six days in a week for three months duration. The Yogic practice schedule consisted of Hatha Yogic Asanas (28 min), Pranayama (10.5 min) and Meditation (5 min). In the Yogic practice schedule 1st they practiced Kapal Bhathi (breathing maneuvers) for 2 min then Yogamudra (yogic postural exercise) for 2 min, after that they took rest until oxygen consumption and heart rate (HR) came to resting value. Subsequently subjects performed SN for 3 min 40 seconds on an average. After three months of training at the beginning of the fourth month subjects performed entire Yogic practice schedule in the laboratory as they practiced during their training session and experiments were carried out. Their pulmonary ventilation, carbondioxide output, Oxygen consumption, HR and other cardiorespiratory parameters were measured during the actual practice of SN. Oxygen consumption was highest in the eighth posture (1.22+/-0.073 1 min(-1)) and lowest in the first posture (0.35+/-0.02 1 min(-1)). Total energy cost throughout the practice of SN was 13.91 kcal and at an average of 3.79 kcal/min. During its practice highest HR was 101+/-13.5 b.p.m. As an aerobic exercise SN seemed to be ideal as it involves both static stretching and slow dynamic component of exercise with optimal stress on the cardiorespiratory system.
Adult↗
Staphylococcus aureus alpha-toxin-induced cell death: predominant necrosis despite apoptotic caspase activation.
Recent data suggest that alpha-toxin, the major hemolysin of Staphylococcus aureus, induces cell death via the classical apoptotic pathway. Here we demonstrate, however, that although zVAD-fmk or overexpression of Bcl-2 completely abrogated caspase activation and internucleosomal DNA fragmentation, they did not significantly affect alpha-toxin-induced death of Jurkat T or MCF-7 breast carcinoma cells. Caspase inhibition had also no effect on alpha-toxin-induced lactate dehydrogenase release and ATP depletion. Furthermore, whereas early assessment of apoptosis induction by CD95 resulted solely in the generation of cells positive for active caspases that were, however, not yet permeable for propidium iodide, a substantial proportion of alpha-toxin-treated cells were positive for both active caspases and PI. Finally, electron microscopy demonstrated that even in the presence of active caspases, alpha-toxin-treated cells displayed a necrotic morphology characterized by cell swelling and cytoplasmic vacuolation. Together, our data suggest that alpha-toxin-induced cell death proceeds even in the presence of activated caspases, at least partially, in a caspase-independent, necrotic-like manner.
Amino Acid Chloromethyl Ketones↗
Maternal ante-natal parameters as predictors of persistent postnatal glucose intolerance: a comparative study between Afro-Caribbeans, Asians and Caucasians.
AIMS: To measure the prevalence of persistent glucose intolerance at 6-12 weeks postpartum in various ethnic groups to assess the value of targeted postpartum screening. METHODS: A retrospective study was performed using computerized databases from two large maternity units within one UK region. Both units used the same screening strategy for gestational diabetes mellitus (GDM) and the same postpartum follow-up at 6-12 weeks using a 75-g oral glucose tolerance test (OGTT). A total of 221 women with a diagnosis of GDM/impaired glucose tolerance (IGT) in the index pregnancy in addition to a completed postpartum 75-g OGTT were studied. Of these, 91 were Caucasian, 89 were of Indo-Asian (Asian) origin and 41 were of Afro-Caribbean origin. RESULTS: The study showed that 35% Indo-Asians had persistent postpartum glucose intolerance compared with 7% Caucasians and 5% Afro-Caribbeans (P < 0.003). Insulin requirement during pregnancy and a diagnosis of gestational diabetes prior to 20 weeks of pregnancy were predictive for persistent postpartum glucose intolerance amongst Indo-Asians. CONCLUSIONS: The frequency of postpartum glucose intolerance among Indo-Asian women is significantly greater than among age-matched Caucasian and Afro-Caribbean women. We suggest that all Indo-Asian women with gestational diabetes should undergo postpartum screening for persistent glucose intolerance. However, in non-Asian women selective screening may be more cost effective.
Adult↗
["Problem-based learning--inflammation and transplantation": an integrated, subject-centred course in the clinical section of the medical curriculum at the medical school of the University of Muenster].
Conventional medical curricula present information pertinent to chronic inflammatory diseases, infectious diseases and transplantation, via systematic lectures and courses in medical specialties without any integrated approach. The authors report on a 3-week model course that attempts to provide students with an overview of clinical presentation, diagnostics, and therapy of representative disease entities with particular emphasis on the interdisciplinary approach to these problems in hospital practice. In addition to problem-based learning in small groups, the model course comprises interdisciplinary concept lectures, practical demonstrations of specific diagnostic procedures, and bedside teaching. In the meantime, the course "Problem-Based Learning--Inflammation and Transplantation" has been held twice successfully as a mandatory course in the clinical part of the curriculum at the Muenster Medical School.
Autoimmune Diseases↗
Carcinoma metastasis to unexpected synchronous lymphoproliferative disorder: report of three cases and review of literature.
Metastasis of one cancer to another cancer is rare. This report describes three cases in which low grade non-Hodgkin lymphomas were incidentally detected during the examination of lymph nodes removed as part of treatment of a previously diagnosed malignancy.
Aged↗
Expression of 11beta-hydroxysteroid dehydrogenase type 1 in adipose tissue is not increased in human obesity.
Central obesity is associated with increased morbidity and mortality. Preadipocyte proliferation and differentiation contribute to increases in adipose tissue mass, yet the mechanisms that underlie these processes remain unclear. Patients with glucocorticoid excess develop a reversible form of central obesity, but circulating cortisol levels in idiopathic obesity are invariably normal. We have hypothesized that the enzyme 11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD1), by converting inactive cortisone to active cortisol in adipose tissue, might be an important autocrine regulator of fat mass. Paired omental and sc fat biopsies were obtained from 32 women (median age, 43 yr; range, 28-65; median body mass index, 27.5 kg/m(2); range, 19.7-39.2) undergoing elective abdominal surgery. 11beta-HSD1 activity and mRNA levels were assessed in whole tissue and in isolated preadipocytes and adipocytes using specific enzyme assays and real-time PCR. Preadipocyte proliferation was measured using tritiated thymidine incorporation. Whole adipose tissue 11beta-HSD1 mRNA levels did not differ between omental and sc samples (P = 0.73). In addition, mRNA levels did not correlate with body mass index (omental: r = 0.1; P = 0.6; sc: r = 0.15; P = 0.4). In keeping with earlier studies, 11beta-HSD1 mRNA levels were higher in omental compared with sc preadipocytes. However, in cultured omental preadipocytes, 11beta-HSD1 activity inversely correlated with body mass index (r = -0.47; P = 0.03). In omental preadipocytes, both cortisol and cortisone decreased proliferation (P < 0.05). Inhibition of 11beta-HSD1 with glycyrrhetinic acid partially reversed the cortisone-induced decrease in preadipocyte proliferation (P < 0.05). Enhanced preadipocyte proliferation within omental adipose tissue as a consequence of decreased 11beta-HSD1 mRNA levels and activity may contribute to increases in visceral adipose tissue mass in obese patients.
11-beta-Hydroxysteroid Dehydrogenase Type 1↗
alpha-Toxin is a mediator of Staphylococcus aureus-induced cell death and activates caspases via the intrinsic death pathway independently of death receptor signaling.
Infections with Staphylococcus aureus, a common inducer of septic and toxic shock, often result in tissue damage and death of various cell types. Although S. aureus was suggested to induce apoptosis, the underlying signal transduction pathways remained elusive. We show that caspase activation and DNA fragmentation were induced not only when Jurkat T cells were infected with intact bacteria, but also after treatment with supernatants of various S. aureus strains. We also demonstrate that S. aureus-induced cell death and caspase activation were mediated by alpha-toxin, a major cytotoxin of S. aureus, since both events were abrogated by two different anti-alpha-toxin antibodies and could not be induced with supernatants of an alpha-toxin-deficient S. aureus strain. Furthermore, alpha-toxin-induced caspase activation in CD95-resistant Jurkat sublines lacking CD95, Fas-activated death domain, or caspase-8 but not in cells stably expressing the antiapoptotic protein Bcl-2. Together with our finding that alpha-toxin induces cytochrome c release in intact cells and, interestingly, also from isolated mitochondria in a Bcl-2-controlled manner, our results demonstrate that S. aureus alpha-toxin triggers caspase activation via the intrinsic death pathway independently of death receptors. Hence, our findings clearly define a signaling pathway used in S. aureus-induced cytotoxicity and may provide a molecular rationale for future therapeutic interventions in bacterial infections.
Adaptor Proteins, Signal Transducing↗
Upper gastrointestinal mucosal disease in pediatric Crohn disease and ulcerative colitis: a blinded, controlled study.
BACKGROUND: Upper gastrointestinal endoscopic biopsies often show histologic abnormalities in Crohn disease. Consequently, it has been proposed that routine endoscopy could help to distinguish Crohn disease from ulcerative colitis. Surprisingly, however, recent case reports and an uncontrolled study suggested that similar abnormalities may occur in ulcerative colitis. Therefore, a blinded, controlled study was performed. METHODS: Esophageal, gastric antral, and duodenal biopsies from children with Crohn disease (n = 28) and ulcerative colitis (n = 14) were compared with those from controls undergoing endoscopy for suspected reflux esophagitis (n = 22). Two pathologists, unaware of patient identity and diagnosis, agreed on a consensus report. Severity of inflammation was scored semiquantitatively. Helicobacter pylori colonization was an exclusion criterion. RESULTS: Inflammation was reported as follows: esophagitis: controls 91%; Crohn disease: 72%; ulcerative colitis: 50%; gastritis: controls: 27%; Crohn disease: 92% (P < 0.001); ulcerative colitis: 69%; duodenitis: controls: 9%; Crohn disease: 33%; ulcerative colitis: 23%. In Crohn disease, granulomas were noted in 40% of patients (P = 0.001). Duodenal cryptitis was noted in 26% of patients with Crohn disease but not ulcerative colitis. In one patient with ulcerative colitis, neutrophilic infiltration of gastric glands was seen. Abnormalities seen in Crohn disease and ulcerative colitis included gastroduodenal ulceration (Crohn disease, 7%; ulcerative colitis, 8%), villus atrophy (Crohn disease, 11%; ulcerative colitis, 15%), and increased intraepithelial lymphocytes (Crohn disease, 15%; ulcerative colitis, 31% [P < 0.05]). None of these abnormalities was noted in the controls. CONCLUSION: Although the presence of granulomas can support a diagnosis of Crohn disease, severe inflammation and other abnormalities occur in the proximal gastrointestinal tract in Crohn disease and ulcerative colitis.
Adolescent↗
Aerobic capacity & perceived exertion after practice of Hatha yogic exercises.
BACKGROUND & OBJECTIVES: Reports on the effect of yogic exercises on aerobic capacity are few. There is also no literature available on the effect of yogic exercise on perceived exertion (PE) after maximal exercise. In this study the effect of training in Hatha yogic exercises on aerobic capacity and PE after maximal exercise was observed. METHODS: Forty men from the Indian army (aged 19-23 yr) were administered maximal exercise on a bicycle ergometer in a graded work load protocol. The oxygen consumption, carbon dioxide output, pulmonary ventilation, respiratory rate, heart rate (HR) etc., at maximal exercise and PE score immediately thereafter were recorded. The subjects were divided into two equal groups. Twelve subjects dropped out during the course of study. One group (yoga, n = 17) practiced Hatha yogic exercises for 1 h every morning (6 days in a week) for six months. The other group (PT, n = 11) underwent conventional physical exercise training during the same period. Both groups participated daily in different games for 1 h in the afternoon. In the 7th month, tests for maximal oxygen consumption (VO2Max) and PE were repeated on both groups of subjects. RESULTS: Absolute value of VO2Max increased significantly (P < 0.05) in the yoga group after 6 months of training. The PE score after maximal exercise decreased significantly (P < 0.001) in the yoga group after 6 months but the PT group showed no change. INTERPRETATION & CONCLUSION: The practice of Hatha yogic exercises along with games helps to improve aerobic capacity like the practice of conventional exercises (PT) along with games. The yoga group performed better than the PT group in terms of lower PE after exhaustive exercise.
Adult↗
A mammalian H+ channel generated through alternative splicing of the NADPH oxidase homolog NOH-1.
Voltage-gated proton (H+) channels are found in many human and animal tissues and play an important role in cellular defense against acidic stress. However, a molecular identification of these unique ion conductances has so far not been achieved. A 191-amino acid protein is described that, upon heterologous expression, has properties indistinguishable from those of native H+ channels. This protein is generated through alternative splicing of messenger RNA derived from the gene NOH-1 (NADPH oxidase homolog 1, where NADPH is the reduced form of nicotinamide adenine dinucleotide phosphate).
Alternative Splicing↗
Is Staphylococcus aureus an intracellular pathogen?
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Adhesins, Bacterial↗
Heterologously expressed Staphylococcus aureus fibronectin-binding proteins are sufficient for invasion of host cells.
Staphylococcus aureus invasion of mammalian cells, including epithelial, endothelial, and fibroblastic cells, critically depends on fibronectin bridging between S. aureus fibronectin-binding proteins (FnBPs) and the host fibronectin receptor integrin alpha(5)beta(1) (B. Sinha et al., Cell. Microbiol. 1:101-117, 1999). However, it is unknown whether this mechanism is sufficient for S. aureus invasion. To address this question, various S. aureus adhesins (FnBPA, FnBPB, and clumping factor [ClfA]) were expressed in Staphylococcus carnosus and Lactococcus lactis subsp. cremoris. Both noninvasive gram-positive microorganisms are genetically distinct from S. aureus, lack any known S. aureus surface protein, and do not bind fibronectin. Transformants of S. carnosus and L. lactis harboring plasmids coding for various S. aureus surface proteins (FnBPA, FnBPB, and ClfA) functionally expressed adhesins (as determined by bacterial clumping in plasma, specific latex agglutination, Western ligand blotting, and binding to immobilized and soluble fibronectin). FnBPA or FnBPB but not of ClfA conferred invasiveness to S. carnosus and L. lactis. Invasion of 293 cells by transformants was comparable to that of strongly invasive S. aureus strain Cowan 1. Binding of soluble and immobilized fibronectin paralleled invasiveness, demonstrating that the amount of accessible surface FnBPs is rate limiting. Thus, S. aureus FnBPs confer invasiveness to noninvasive, apathogenic gram-positive cocci. Furthermore, FnBP-coated polystyrene beads were internalized by 293 cells, demonstrating that FnBPs are sufficient for invasion of host cells without the need for (S. aureus-specific) coreceptors.
Adhesins, Bacterial↗
Fibronectin-binding protein acts as Staphylococcus aureus invasin via fibronectin bridging to integrin alpha5beta1.
The ability of Staphylococcus aureus to invade mammalian cells may explain its capacity to colonize mucosa and to persist in tissues after bacteraemia. To date, the underlying molecular mechanisms of cellular invasion by S. aureus are unknown, despite its high prevalence and difficulties in treatment. Here, we show cellular invasion as a novel function for an S. aureus adhesin, previously implicated solely in attachment. S. aureus, but not S. epidermidis, invaded epithelial 293 cells in a temperature- and F-actin-dependent manner. Formaldehyde-fixed and live bacteria were equally invasive, suggesting that no active bacterial process was involved. All clinical S. aureus isolates analysed, but only a subset of laboratory strains, were invasive. Fibronectin-binding proteins (FnBPs) acted as S. aureus invasins, because: (i) FnBP deletion mutants of invasive laboratory strains lost invasiveness; (ii) expression of FnBPs in noninvasive strains conferred invasiveness; and (iii) the soluble isolated fibronectin-binding domain of FnBP (D1-D4) completely blocked invasion. Integrin alpha5beta1 served as host cell receptor, which interacted with staphylococcal FnBPs through cellular or soluble fibronectin. FnBP-deficient mutants lost invasiveness for epithelial cells, endothelial cells and fibroblasts. Thus, fibronectin-dependent bridging between S. aureus FnBPs and host cell integrin alpha5beta1 is a conserved mechanism for S. aureus invasion of human cells. This may prove useful in developing new therapeutic and vaccine strategies for S. aureus infections.
Adhesins, Bacterial↗
Verapamil prolongs atrial fibrillation by evoking an intense sympathetic neurohumoral effect.
BACKGROUND: Verapamil is an effective drug to slow ventricular rate in atrial fibrillation (AF). Clinically, however, i.v. verapamil enhances AF despite experimental evidence suggesting favorable effects of the drug on AF-induced electrical remodeling of the atria. METHODS AND RESULTS: To clarify this controversy, i.v. verapamil's effects were determined in 41 anesthetized dogs, including 6 after beta-blockade. Intravenous verapamil (0.20 mg/kg, bolus, and 0.20 mg/kg/h, infusion) increased the duration of AF (induced by a single extrastimulus), from 19 +/- 6 to 130 +/- 24 s, P < 0.001, and slowed its ventricular response, from 246 +/- 25 to 110 +/- 15 min-1, P < 0.001. Mean aortic pressure, P = 0.002, and systemic vascular resistance, P < 0.035, decreased, and mean right atrial pressure increased, P < 0.001. Plasma norepinephrine concentration increased by 502 +/- 83 pg/mL, P < 0.001, plasma epinephrine concentration by 804 +/- 206 pg/mL, P = 0.002, and plasma total catecholamine concentration by 1606 +/- 366 pg/mL, P = 0.001. Prolongation of AF was related to an increase in mean right atrial pressure, R = 0.49, P = 0.014, right atrial wall tension, R = 0.45, P = 0.044, and plasma norepinephrine concentration, R = 0.83, P < 0.001, with plasma norepinephrine concentration remaining as an independent predictor of AF lengthening on multivariable analysis. In the presence of beta-blockade, verapamil produced comparable or more exaggerated hemodynamic effects, but it did not promote AF. CONCLUSION: The prolongation of AF by verapamil can be related directly to the intense sympathetic neurohumoral effect that occurs following the drug's administration.
Animals↗
Nitric oxide downregulates tumour necrosis factor in mRNA in RAW 264.7 cells.
Nitric oxide (NO) and tumour necrosis factor (TNF) are essential mediators in a number of biological processes, including the immune response. TNF stimulates NO production via expression of inducible NO synthase (iNOS), with L-arginine being the only substrate. Previously, we demonstrated that, inversely, NO inhibits lipopolysaccharide (LPS)-induced TNF synthesis. We have now investigated whether this reduction of TNF bioactivity is also reflected at the level of TNF mRNA in the murine macrophage cell line RAW 264.7. TNF mRNA was quantified by Northern analysis using an alpha[33P]dCTP-labelled probe. Cells stimulated with 10 microg/ml LPS in the absence of L-arginine, in order to prevent endogenous NO formation, contained more TNF mRNA than cells supplied with 1 mM L-arginine at 14 h and 20 h after stimulation. By contrast, no difference was observed at 4 h. This time course is compatible with the involvement of iNOS. The half-life of TNF mRNA in the presence of NO was roughly half that observed under L-arginine-free conditions (41 min versus 77 min, respectively). L-citrulline (1 mM), which has been shown to be recycled in RAW 264.7 cells to L-arginine, completely restored attenuation of TNF bioactivity and TNF message to control levels obtained with 1 mM L-arginine. Together, these findings suggest that endogenous NO regulates TNF mRNA, mainly by reducing its half-life. In addition, a distinct additional band (approximately 1.4 kb) hybridizing with the TNF probe was consistently observed in non-stimulated cells. This may correspond to TNF mRNA specifically hydrolysed at the AU-rich region, possibly reflecting another control point for TNF expression.
Animals↗
Taming TNF: strategies to restrain this proinflammatory cytokine.
Recent studies have demonstrated the essential role of tumor necrosis factor alpha (TNF-alpha) in rheumatoid arthritis and Crohn's disease. This article discusses agents known to suppress the formation or activity of TNF-alpha, and summarizes clinical studies using anti-TNF-alpha antibodies.
Animals↗