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Biomedical subjects

R Malhotra

Publications and source records attributed to R Malhotra.

At least 19 recordsLinked to original sources
PubMed2000

Lung surfactant protein A provides a route of entry for respiratory syncytial virus into host cells.

Lung surfactant protein A (SP-A) has a central role in host defense mediated by the interaction of surface carbohydrates of inhaled pathogens with the lectin domains of SP-A. Respiratory syncytial virus (RSV), the most important viral pathogen of neonates and infants, encodes a highly glycosylated attachment protein, G. Binding studies were performed with G-protein from RSV (human, A2 strain) and human SP-A. The effect of SP-A on the interaction between RSV and host cells was determined by two methods: an infectivity study with monolayers of Hep-2C cells and by interleukin-8 (IL-8) release from buffy coat (BC) cells. SP-A binds to RSV G-protein in a concentration-dependent manner that is inhibitable by both ethylenediamine tetraacetic acid (EDTA) and mannan, indicating that binding is through the carbohydrate recognition domain of the SP-A and a carbohydrate moiety of the G-protein. The level of RSV infection of Hep-2C cells increases with increasing concentrations of SP-A. The amount of IL-8 released by BC cells in the presence of RSV is increased with SP-A concentrations of 2.9 microg/mL or greater. Our results show that SP-A enhances the attachment of RSV and subsequent entry into host cells. The effect of SP-A on viral uptake by epithelial cells and macrophage may determine both innate and adaptive immune responses to RSV.

Bronchoalveolar Lavage Fluid↗
PubMed2000

GLUT-1 reduces hypoxia-induced apoptosis and JNK pathway activation.

Many studies have suggested that enhanced glucose uptake protects cells from hypoxic injury. More recently, it has become clear that hypoxia induces apoptosis as well as necrotic cell death. We have previously shown that hypoxia-induced apoptosis can be prevented by glucose uptake and glycolytic metabolism in cardiac myocytes. To test whether increasing the number of glucose transporters on the plasma membrane of cells could elicit a similar protective response, independent of the levels of extracellular glucose, we overexpressed the facilitative glucose transporter GLUT-1 in a vascular smooth muscle cell line. After 4 h of hypoxia, the percentage of cells that showed morphological changes of apoptosis was 30.5 +/- 2.6% in control cells and only 6.0 +/- 1.1 and 3.9 +/- 0.3% in GLUT-1-overexpressing cells. Similar protection against cell death and apoptosis was seen in GLUT-1-overexpressing cells treated for 6 h with the electron transport inhibitor rotenone. In addition, hypoxia and rotenone stimulated c-Jun-NH(2)-terminal kinase (JNK) activity >10-fold in control cell lines, and this activation was markedly reduced in GLUT-1-overexpressing cell lines. A catalytically inactive mutant of MEKK1, an upstream kinase in the JNK pathway, reduced hypoxia-induced apoptosis by 39%. These findings show that GLUT-1 overexpression prevents hypoxia-induced apoptosis possibly via inhibition of stress-activated protein kinase pathway activation.

Animals↗
PubMed1999

The Galilean satellites.

NASA's Galileo mission to Jupiter and improved Earth-based observing capabilities have allowed major advances in our understanding of Jupiter's moons Io, Europa, Ganymede, and Callisto over the past few years. Particularly exciting findings include the evidence for internal liquid water oceans in Callisto and Europa, detection of a strong intrinsic magnetic field within Ganymede, discovery of high-temperature silicate volcanism on Io, discovery of tenuous oxygen atmospheres at Europa and Ganymede and a tenuous carbon dioxide atmosphere at Callisto, and detection of condensed oxygen on Ganymede. Modeling of landforms seen at resolutions up to 100 times as high as those of Voyager supports the suggestion that tidal heating has played an important role for Io and Europa.

Atmosphere↗
PubMed1999

Mechanical stretch and angiotensin II differentially upregulate the renin-angiotensin system in cardiac myocytes In vitro.

Pressure overload in vivo results in left ventricular hypertrophy and activation of the renin-angiotensin system in the heart. Mechanical stretch of neonatal rat cardiac myocytes in vitro causes secretion of angiotensin II (Ang II), which in turn plays a pivotal role in mechanical stretch-induced hypertrophy. Although in vivo data suggest that the stimulus of hemodynamic overload serves as an important modulator of cardiac renin-angiotensin system (RAS) activity, it is not clear whether observed upregulation of RAS genes is a direct effect of hemodynamic stress or is secondary to neurohumoral effects in response to hemodynamic overload. Moreover, it is unclear whether activation of the local RAS in response to hemodynamic overload predominantly occurs in cardiac myocytes or fibroblasts or both. In the present study, we examined the effect of mechanical stretch on expression of angiotensinogen, renin, angiotensin-converting enzyme (ACE), and Ang II receptor (AT(1A), AT(1B), and AT(2)) genes in neonatal rat cardiac myocytes and cardiac fibroblasts in vitro. The level of expression of angiotensinogen, renin, ACE, and AT(1A) genes was low in unstretched cardiac myocytes, but stretch upregulated expression of these genes at 8 to 24 hours. Stimulation of cardiac myocytes with Ang II also upregulated expression of angiotensinogen, renin, and ACE genes, whereas it downregulated AT(1A) and did not affect AT(1B) gene expression. Although losartan, a specific AT(1) antagonist, completely inhibited Ang II-induced upregulation of angiotensinogen, renin, and ACE genes, as well as stretch-induced upregulation of AT(1A) expression, it did not block upregulation of angiotensinogen, renin, and ACE genes by stretch. Western blot analyses showed increased expression of angiotensinogen and renin protein at 16 to 24 hours of stretch. The ACE-like activity was also significantly elevated at 24 hours after stretch. Radioligand binding assays revealed that stretch significantly upregulated the AT(1) density on cardiac myocytes. Interestingly, stretch of cardiac fibroblasts did not result in any discernible increases in the expression of RAS genes. Our results indicate that mechanical stretch in vitro upregulates both mRNA and protein expression of RAS components specifically in cardiac myocytes. Furthermore, components of the cardiac RAS are independently and differentially regulated by mechanical stretch and Ang II in neonatal rat cardiac myocytes.

Angiotensin II↗
PubMed1999

Identification of human complement Factor H as a ligand for L-selectin.

The selectin family of adhesion molecules (E-, P- and L-selectins) is involved in leukocyte recruitment to sites of inflammation and tissue damage. Recently it has been shown that L-selectin is involved not only in leukocyte tethering and rolling, but also plays an important role in leukocyte activation. For example, glycosylation-dependent cell-adhesion molecule 1 (GlyCAM-1), a known ligand for L-selectin, has been shown to enhance beta2-integrin function. GlyCAM-1 is a secreted protein and is present in mouse serum at a concentration of approx. 1.5 microg/ml. There is no obvious GlyCAM-1 homologue in man and, to date, L-selectin ligand(s) from human serum have not been characterized. Therefore we have used L-selectin affinity chromatography, followed by ion-exchange chromatography, to isolate specific ligand(s) for L-selectin. Using this procedure, we have isolated three major glycoproteins of apparent molecular masses 170 kDa, 70kDa and 50 kDa. The 170 kDa protein band was digested with trypsin and peptides were analysed by delayed extraction matrix-assisted laser desorption ionization MS and protein database searching. The 170 kDa protein was identified as the human complement protein Factor H. Human Factor H, isolated by a different method, was shown to bind specifically to L-selectin in the presence of CaCl2, and binding was inhibited by anti-L-selectin antibodies, fucoidan and lipopolysaccharide. Only a part of the purified Factor H preparation bound to immobilized L-selectin. The interaction of Factor H with leukocyte L-selectin was shown to induce the secretion of tumour necrosis factor-alpha (TNF-alpha). Pretreatment of Factor H with sialidase reduced both the binding of L-selectin to Factor H and the Factor H-induced L-selectin-mediated TNF-alpha secretion by leukocytes. Taken together, these results demonstrate that a post-translationally modified form of human plasma Factor H is a potential physiological ligand for L-selectin.

Blood Proteins↗
PubMed1999

Glucose uptake and glycolysis reduce hypoxia-induced apoptosis in cultured neonatal rat cardiac myocytes.

Myocardial ischemia/reperfusion is well recognized as a major cause of apoptotic or necrotic cell death. Neonatal rat cardiac myocytes are intrinsically resistant to hypoxia-induced apoptosis, suggesting a protective role of energy-generating substrates. In the present report, a model of sustained hypoxia of primary cultures of Percoll-enriched neonatal rat cardiac myocytes was used to study specifically the modulatory role of extracellular glucose and other intermediary substrates of energy metabolism (pyruvate, lactate, propionate) as well as glycolytic inhibitors (2-deoxyglucose and iodoacetate) on the induction and maintenance of apoptosis. In the absence of glucose and other substrates, hypoxia (5% CO2 and 95% N2) caused apoptosis in 14% of cardiac myocytes at 3 h and in 22% of cells at 6-8 h of hypoxia, as revealed by sarcolemmal membrane blebbing, nuclear fragmentation, and chromatin condensation (Hoechst staining), terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) staining, and DNA laddering. This was accompanied by translocation of cytochrome c from the mitochondria to the cytosol and cleavage of the death substrate poly(ADP-ribose) polymerase. Cleavage of poly(ADP-ribose) polymerase and DNA laddering were prevented by preincubation with the caspase inhibitors benzyloxycarbonyl-Val-Ala-Asp-fluoromethyl ketone (zVAD-fmk) and benzyloxycarbonyl-Asp-Glu-Val-Asp-fluoromethyl ketone (zDEVD-fmk), indicating activation of caspases in the apoptotic process. The caspase inhibitor zDEVD-fmk also partially inhibited cytochrome c translocation. The presence of as little as 1 mM glucose, but not pyruvate, lactate, or propionate, before hypoxia prevented apoptosis. Inhibiting glycolysis by 2-deoxyglucose or iodoacetate, in the presence of glucose, reversed the protective effect of glucose. This study demonstrates that glycolysis of extracellular glucose, and not other metabolic pathways, protects cardiac myocytes from hypoxic injury and subsequent apoptosis.

Animals↗
PubMed1999

A recombinant trimeric surfactant protein D carbohydrate recognition domain inhibits respiratory syncytial virus infection in vitro and in vivo.

The pulmonary collectin, lung surfactant protein D (SP-D), plays a role in host defense mediated by the interaction of surface carbohydrates of inhaled pathogens with the lectin domains of SP-D. Respiratory syncytial virus (RSV), the most important viral pathogen of neonates and infants, encodes a highly glycosylated attachment protein, G. Binding studies were performed with G protein from RSV (human, A2 strain) and both native and recombinant human SP-D. The effect of recombinant trimeric SP-D lectin domains (rSP-D) on the interaction between RSV and host cells was determined by two methods: an infectivity study with monolayers of Hep-2C cells and in vivo infections in BALB/c mice. These studies show that full-length and recombinant SP-D bind to RSV G protein in a concentration-dependent manner. Both EDTA and mannan inhibited binding of full-length SP-D. These results indicate that binding occurs via the carbohydrate recognition domain of the SP-D. The recombinant SP-D inhibited RSV infectivity in cell culture in a dose-dependent manner, giving 100% inhibition of replication. Intranasal administration of recombinant SP-D to RSV-infected mice inhibited replication of the virus in the lungs, reducing levels of lung virus by 80%. These results suggest that SP-D plays a major role in clearing RSV from the lungs.

Animals↗
PubMed1999

Pseudoaneurysm of the superficial femoral artery following accidental trauma: result of treatment by percutaneous stent-graft placement.

Accidental trauma frequently involves the extremities, and can extend to involve their blood supply, causing exsanguinating hemorrhage and pseudoaneurysm in the involved blood vessel. This is traditionally managed by surgical repair. We report a case in which control of life-threatening hemorrhage and exclusion of a large, post-traumatic pseudoaneurysm in the superficial femoral artery was performed by a commercially available stent-graft, without complication. This treatment method may be a safe and effective alternative to surgery in selected patients.

Accidents, Traffic↗
PubMed1999

Minimally invasive mitral valve surgery through right anterolateral minithoracotomy.

BACKGROUND: This study evaluates the feasibility of minimally invasive mitral valve surgery. The aim of the study was to minimize surgical access to achieve better cosmetic results, less postoperative discomfort, and faster recovery. METHODS: From September 1997 to October 1998, 76 patients underwent mitral valve surgery through a right anterolateral minithoracotomy at the fourth intercostal space. The mitral valve was either repaired (n = 21) or replaced (n = 55). In all cases, open femoral artery-femoral vein cannulation was used for cardiopulmonary bypass. In 27 cases, an endoluminal aortic clamp was used, but in 49 cases, the aorta was cross-clamped with a transthoracic, sliding-rod-design clamp. RESULTS: There were no approach-related limitations to surgical intervention. Intraoperative transesophageal echocardiography revealed excellent results after valve repair and no paravalvular leak in any patient after mitral valve replacement. Mean duration of intensive care and postoperative hospital stay was 32+/-5.2 hours and 7+/-1.1 days, respectively. There were no major complications related to femoral vessel cannulation. In 1 patient, transient neurological problems developed, with subsequent complete recovery. There was one hospital mortality (85-year-old male patient died of upper GI bleeding). CONCLUSIONS: Minimally invasive port access mitral valve surgery can accelerate recovery and decrease pain, while maintaining overall surgical efficacy. It also provides better cosmetic results to our patients, and now it has become our standard approach for isolated mitral valve surgery.

Adult↗
PubMed1999

Small bowel bacterial overgrowth in subjects living in residential care homes.

OBJECTIVES: in elderly people, bacterial overgrowth of the small bowel may be occult. The significance of positive breath tests are uncertain: many fit elderly subjects with positive tests show no evidence of malabsorption. We assessed the prevalence and significance of bacterial overgrowth in the small bowel in a relatively unselected elderly population. METHODS: residents of seven elderly people's homes had a glucose hydrogen breath test. A medical history and anthropomorphic measurements were recorded. Volunteers with positive breath tests were given doxycycline. After 4 months all volunteers were reassessed. RESULTS: of 140 residents, 62 were tested. Nine (14.5%) had a positive breath test. There was no difference in anthropomorphic and bowel habit data between those with positive and those with negative breath tests. After 4 months of antibiotic treatment, volunteers with a positive breath test had increased weight and body mass index, while those with a negative test had decreased weight and body mass index. CONCLUSIONS: the percentage of volunteers with a positive breath test was much lower than in previous studies. This may be due to the relatively unselected nature of the volunteers. Treatment of bacterial overgrowth resulted in a small but significant improvement in anthropometric indices. The lack of association of positive breath tests with baseline anthropomorphic measurements or bowel habit highlights the occult nature of the bacterial overgrowth and questions its clinical importance.

Aged↗
PubMed1999

A study of lipid peroxide and alpha tocopherol in acute myocardial infarction.

Thirty patients of acute myocardial infarction proven by electrocardiography (ECG) and enzymes were included in the study. All of them received streptokinase. A single lead showing the largest ST elevation, a proportional value for the shift in ST segment > or = 0.5 was taken as criteria for reperfusion. ECG was recorded at 0 hour, 3 hours and 72 hours. At the start of streptokinase and 3 hours after, marker of free radical activity malondialdehyde (MDA) and antioxidant alpha tocopherol was measured. Mean value of serum alpha tocopherol level at start of streptokinase (t0) 10.03 +/- 2.5 micrograms/ml and at (t3) 3 hours after streptokinase was 8.60 +/- 2.6 micrograms/ml (P < 0.001) and mean value of serum lipid peroxidation level was 6.86 +/- 2.92 nanomol/ml at t(o) and at t3 value was 8.4 +/- 3.88 (P < 0.012) in successfully reperfused patients. In unsuccessful reperfusion group serum alpha tocopherol level at t(o) was 8.89 +/- 2.55 micrograms/ml and at t3 8.23 +/- 2.9 micrograms/ml (p > 0.05). Serum lipid peroxidation level in the same group at t0 was 6.53 +/- 2.26 nanomol/ml and at t3 was 6.29 +/- 2.27 nanomol/ml (p > 0.05). The increase in free radical marker MDA and decrease in one of the important antioxidant alpha tocopherol suggest that free radicals are increased after coronary vessels open up. As a result reperfused patients may be at risk of free radical mediated injury which may deny him the full benefit of reperfusion.

Adult↗
PubMed1998

Induction of TNF-alpha release from human buffy coat cells by Pseudomonas aeruginosa is reduced by lung surfactant protein A.

Lipopolysaccharide (LPS) induction of TNF-alpha release is a central event in the pathophysiology of gram-negative bacterial septicaemia. Lung surfactant protein A (SP-A) mediates pathogen/host cell interactions. Binding of SP-A to Pseudomonas aeruginosa LPS and the effects of SP-A with LPS or whole bacteria on buffy coat cells were investigated. SP-A interacts with P. aeruginosa LPS in a concentration and calcium dependent manner, either through the lipid A portion of LPS or through another lectin/carbohydrate interaction. SP-A decreased TNF-alpha secretion induced by bacteria or LPS from buffy coat cells, in a concentration dependent manner.

Apoproteins↗
PubMed1998

Treatment of superficial basal cell carcinoma and squamous cell carcinoma in situ with a high-energy pulsed carbon dioxide laser.

BACKGROUND: High-energy pulsed carbon dioxide (CO2) lasers have been used extensively to resurface wrinkled and photodamaged skin with a low risk of scarring. Results of histological studies demonstrate precise ablation depths in treated skin with minimal thermal damage to underlying tissue. Our objective was to determine if a pulsed CO2 laser could effectively ablate superficial malignant cutaneous neoplasms (superficial multifocal basal cell carcinoma [BCC] and squamous cell carcinoma [SCC] in situ). OBSERVATIONS: Thirty superficial neoplasms (17 BCCs and 13 SCCs) and their surrounding 3-mm margins were treated with either 2 or 3 passes of a pulsed CO2 laser (500 mJ, 2-4 W) using a 3-mm collimated handpiece. The treated areas were subsequently excised and evaluated histologically by serial sectioning at 5-micron intervals for residual tumor at the deep and lateral margins. Average patient age was greater for those with SCCs than for those with BCCs (76.5 vs 56.7 years; P = .001). The average tumor thickness of SCC in situ was significantly greater than that of superficial BCC (0.57 vs 0.34 mm; P = .01). All (9 of 9 patients) BCCs were completely ablated with 3 passes, and residual tumor in the deep margins was seen in 5 of 8 patients treated with 2 passes of the pulsed CO2 laser (P = .005). Incomplete vaporization of the SCC depth was seen in 3 of 7 patients treated with 3 passes and in 2 of 6 patients treated with 2 passes. Those SCCs incompletely treated were significantly thicker than those completely ablated (0.65 vs 0.41 mm; P = .01). Positive lateral margins were seen in 1 BCC and 3 SCC specimens. CONCLUSIONS: Pulsed CO2 laser treatment can be effective in ablating superficial BCC. Treatment of the neoplasm and a minimum of 4-mm margins with 3 passes (500 mJ, 2-4 W) is recommended for complete vaporization using this laser system. Because 3 passes did not completely ablate all SCC in situ, use of this modality alone is not recommended for treatment of thick or keratotic lesions. No direct comparison of efficacy can be made with other destructive modalities that have not been evaluated with comparably sensitive histological techniques. Further study is needed to establish any cosmetic advantage of pulsed CO2 lasers over other destructive modalities for treatment of superficial malignant neoplasms and long-term cure rates.

Adult↗
PubMed1998

P-selectin binds to bacterial lipopolysaccharide.

Multiple organ failure associated with disseminated intravascular coagulation is a frequent complication in septic shock patients. Accumulation of platelets and neutrophils in the organs contributes to the manifestation of lipopolysaccharide (LPS)-induced organ failure. Although a direct interaction between LPS and platelets is well documented, the nature of the surface receptor for LPS on platelets is unknown. In this article we show that P-selectin is a receptor for LPS. The binding of LPS to P-selectin is independent of Ca2+, and is blocked by antibodies to P-selectin, lipid A and fucoidan. Platelets pre-treated with thrombin showed fourfold higher binding of fluorescein isothiocyanate (FITC)-conjugated LPS compared to untreated platelets and the binding of FITC-conjugated LPS to platelets was blocked in the presence of anti-P-selectin antibodies. It is likely that the binding of LPS via P-selectin on activated platelets or epithelium could have a significant role in the pathophysiology of organ failure in septic shock.

Blood Platelets↗