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S Mehta

Publications and source records attributed to S Mehta.

At least 55 records · Page 3Linked to original sources
PubMed2000

Ready access to sialylated oligosaccharide donors.

[formula: see text] Numerous glycoconjugates contain the disaccharide Neu5Ac alpha (2-->3)DGalp. An efficient way to incorporate this disaccharide into synthetic glycoconjugates is to develop a disaccharide building block. This communication reports a chemoenzymatic route to such a building block which requires as few as four steps. Some examples using more chemical steps are also presented, which increase the flexibility. These disaccharide donors were used to prepare synthetic trisaccharides.

Carbohydrate Conformation↗
PubMed2000

Pulmonary microvascular changes during sepsis: evaluation using intravital videomicroscopy.

A variety of pulmonary microvascular changes occur during sepsis. These include abnormal vascular reactivity, leukocyte sequestration, and leakage of protein into the alveoli. Based on intravital videomicroscopy we have developed a method to directly assess in vivo the changes that occur in the pulmonary microcirculation in a rat model of sepsis. Male Sprague-Dawley rats were assigned to control or sepsis groups. Sepsis was induced by cecal ligation and perforation. Twenty four hours later, rats were anesthetized, mechanically ventilated, and their lung prepared for intravital videomicroscopy. A specially designed transparent thoracic window was inserted into the chest wall. The dependent surface of the lung was superfused with saline solution and visualized with an inverted microscope. Vascular contractility, to phenylephrine, (PE) and hypoxia of small (15-25 microm in diameter) and medium (40-50 microm) arterioles was examined. Leukocyte traffic in the pulmonary microcirculation was studied after in vivo labeling of leukocytes with Rhodamine and visualized with fluorescence microscopy. Leak of albumin into the alveolar space was measured with FITC-labeled albumin and fluorescence microscopy. Both small and medium sized pulmonary arterioles in septic animals exhibited attenuated vascular contractility to phenylephrine, but only medium-sized arterioles displayed hypocontractility to hypoxia. Further, in septic animals there was an increase in both the number of stationary leukocytes in the pulmonary microcirculation and an increase in alveolar capillary protein leak. We conclude: (1) direct visualization of the pulmonary microvascular pressor response to hypoxia and PE in the rat is possible using this technique, (2) similar to previous in vitro studies with larger vessels, pulmonary arterioles have an attenuated contractile response to PE and hypoxia in sepsis, and (3) there is an increase in both the number of stationary leukocytes and protein leak into the alveolus in the lungs of septic animals.

Animals↗
PubMed2000

Combined cytotoxic action of paclitaxel and ceramide against the human Tu138 head and neck squamous carcinoma cell line.

PURPOSE: Paclitaxel, a chemotherapeutic agent used in the treatment of recalcitrant ovarian and breast as well as other neoplasms, is being investigated for the treatment of squamous cell carcinoma of the head and neck. Our previous studies have demonstrated that exogenously added ceramide enhances apoptosis in paclitaxel-exposed human leukemic cells. In this study, we showed that exogenous ceramide augmented paclitaxel-induced apoptosis in Tu138 cells in vitro when added simultaneously in combination with the paclitaxel. METHODS: The combined cytotoxic effects of paclitaxel and ceramide exposure against Tu138 cells were assessed by an MTT dye assay, cell cycle analysis, TUNEL (terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling) assay, and isobologram analysis for synergistic activity. RESULTS: The MTT dye assay results indicated augmentation of time- and concentration-dependent paclitaxel-mediated cell cytotoxicity by simultaneous ceramide treatment. Paclitaxel treatment of Tu138 cells also resulted in an accumulation of cells in the G2-M phase of the cell cycle. This paclitaxel-mediated G2-M phase accumulation decreased significantly with the addition of ceramide, indicating that combined paclitaxel/ceramide treatment resulted in the elimination of Tu138 cells from the S and/or G2-M phases of the cell cycle. Furthermore, ceramide enhancement of paclitaxel-mediated apoptosis was also detected by the TUNEL assay. CONCLUSION: Our results suggest that paclitaxel/ceramide combination therapy may be an attractive alternative to conventional methods of chemotherapy for head and neck cancer, and should be further explored.

Carcinoma, Squamous Cell↗
PubMed2000

Steroid hormone contraception and bone mineral density: a cross-sectional study in an international population. The WHO Study of Hormonal Contraception and Bone Health.

OBJECTIVE: To evaluate relationships between bone mineral density and use of steroid hormonal contraceptives. METHODS: This was a multicenter cross-sectional study in seven centers in three regions of the developing world from April 1994 to June 1997. Women 30-34 years old attending family planning clinics, with at least 24 months of lifetime use of combined oral contraceptives (OC), depot-medroxyprogesterone acetate (DMPA), or levonorgestrel implants, or no or only short-term (less than 6 months) use of steroid hormonal contraceptives, had bone mineral density (BMD) measured at the distal radius and the midshaft of the ulna using single-photon x-ray absorptiometry. RESULTS: In the study, 2474 women were examined. For OC use, adjusted mean BMD was significantly higher in short-term, current users compared with women who never used hormonal contraceptives. For DMPA and levonorgestrel implants, adjusted mean BMD was statistically significantly lower in short-term current users compared with those who never used hormonal contraceptives. For all three hormonal methods, there were no significant differences in BMD between past users of hormonal contraceptives and never users, even among those who had used the methods for 4 or more years. The magnitude of changes in BMD was small and less than one standard deviation (SD) from the mean of those who never used steroid contraceptives. CONCLUSION: This study suggests that hormonal contraceptive use by young adult women is associated with small changes in BMD that occur early after initiation of use and are reversible.

Adult↗
PubMed2000

Differential markers for regionalization.

OBJECTIVE: To examine the site of delivery for very low birth weight (VLBW) infants and infants with major congenital malformations (MCM) within an established system of perinatal regionalization. STUDY DESIGN: A retrospective study of site of delivery for VLBW infants and infants born with MCM (tracheoesophageal fistula/esophageal atresia, diaphragmatic hernia, or gastroschisis/omphalocele) from 1990 through 1995 in Ohio. RESULTS: A total of 59.8% of VLBW infants and 36.1% of MCM infants were born in a level III hospital. There was a significant trend toward a decrease in VLBW infants (p < 0.01) and an increase in MCM infants (p < 0.05) born in a level III hospital between 1990 and 1995. There were significant regional variations among the six perinatal regions in Ohio in the proportion of both VLBW and MCM infants born in a tertiary center. CONCLUSION: Using the traditional marker of VLBW to assess regionalization in one state, we found significant variation in site of delivery among the perinatal regions and over the time course of the study. The delivery of infants with MCM at level III centers may be an alternative measure of regionalization.

Congenital Abnormalities↗
PubMed2000

Prolonged cyclooxygenase-2 induction in neurons and glia following traumatic brain injury in the rat.

Cyclooxygenase-2 (COX2) is a primary inflammatory mediator that converts arachidonic acid into precursors of vasoactive prostaglandins, producing reactive oxygen species in the process. Under normal conditions COX2 is not detectable, except at low abundance in the brain. This study demonstrates a distinctive pattern of COX2 increases in the brain over time following traumatic brain injury (TBI). Quantitative lysate ribonuclease protection assays indicate acute and sustained increases in COX2 mRNA in two rat models of TBI. In the lateral fluid percussion model, COX2 mRNA is significantly elevated (>twofold, p < 0.05, Dunnett) at 1 day postinjury in the injured cortex and bilaterally in the hippocampus, compared to sham-injured controls. In the lateral cortical impact model (LCI), COX2 mRNA peaks around 6 h postinjury in the ipsilateral cerebral cortex (fivefold induction, p < 0.05, Dunnett) and in the ipsilateral and contralateral hippocampus (two- and six-fold induction, respectively, p < 0.05, Dunnett). Increases are sustained out to 3 days postinjury in the injured cortex in both models. Further analyses use the LCI model to evaluate COX2 induction. Immunoblot analyses confirm increased levels of COX2 protein in the cortex and hippocampus. Profound increases in COX2 protein are observed in the cortex at 1-3 days, that return to sham levels by 7 days postinjury (p < 0.05, Dunnett). The cellular pattern of COX2 induction following TBI has been characterized using immunohistochemistry. COX2-immunoreactivity (-ir) rises acutely (cell numbers and intensity) and remains elevated for several days following TBI. Increases in COX2-ir colocalize with neurons (MAP2-ir) and glia (GFAP-ir). Increases in COX2-ir are observed in cerebral cortex and hippocampus, ipsilateral and contralateral to injury as early as 2 h postinjury. Neurons in the ipsilateral parietal, perirhinal and piriform cortex become intensely COX2-ir from 2 h to at least 3 days postinjury. In agreement with the mRNA and immunoblot results, COX2-ir appears greatest in the contralateral hippocampus. Hippocampal COX2-ir progresses from the pyramidal cell layer of the CA1 and CA2 region at 2 h, to the CA3 pyramidal cells and dentate polymorphic and granule cell layers by 24 h postinjury. These increases are distinct from those observed following inflammatory challenge, and correspond to brain areas previously identified with the neurological and cognitive deficits associated with TBI. While COX2 induction following TBI may result in selective beneficial responses, chronic COX2 production may contribute to free radical mediated cellular damage, vascular dysfunction, and alterations in cellular metabolism. These may cause secondary injuries to the brain that promote neuropathology and worsen behavioral outcome.

Animals↗
PubMed2000

Prediction of post-extubation work of breathing.

OBJECTIVE: To evaluate which mode of preextubation ventilatory support most closely approximates the work of breathing performed by spontaneously breathing patients after extubation. DESIGN: Prospective observational design. SETTING: Medical, surgical, and coronary intensive care units in a university hospital. PATIENTS: A total of 22 intubated subjects were recruited when weaned and ready for extubation. INTERVENTIONS: Subjects were ventilated with continuous positive airway pressure at 5 cm H2O, spontaneous ventilation through an endotracheal tube (T piece), and pressure support ventilation at 5 cm H2O in randomized order for 15 mins each. At the end of each interval, we measured pulmonary mechanics including work of breathing reported as work per liter of ventilation, respiratory rate, tidal volume, negative change in esophageal pressure, pressure time product, and the airway occlusion pressure 100 msec after the onset of inspiratory flow, by using a microprocessor-based monitor. Subsequently, subjects were extubated, and measurements of pulmonary mechanics were repeated 15 and 60 mins after extubation. MEASUREMENTS AND MAIN RESULTS: There were no statistical differences between work per liter of ventilation measured during continuous positive airway pressure, T piece, or pressure support ventilation (1.17+/-0.67 joule/L, 1.11+/-0.57 joule/L, and 0.97+/-0.57 joule/L, respectively). However, work per liter of ventilation during all three preextubation modes was significantly lower than work measured 15 and 60 mins after extubation (p < .05). Tidal volume during pressure support ventilation and continuous positive airway pressure (0.46+/-0.11 L and 0.44+/-0.11 L, respectively) were significantly greater than tidal volume during both T-piece breathing and spontaneous breathing 15 mins after extubation (p < .05). Negative change in esophageal pressure, the airway occlusion pressure 100 msec after the onset of inspiratory flow, and pressure time product were significantly higher after extubation than during any of the three preextubation modes (p < .05). CONCLUSIONS: Work per liter of ventilation, negative change in esophageal pressure, the airway occlusion pressure 100 msec after the onset of inspiratory flow, and pressure time product all significantly increase postextubation. Tidal volume during continuous positive airway pressure or pressure support ventilation overestimates postextubation tidal volume.

Aged↗
PubMed2000

Effects of inhaled nitric oxide in a rat model of Pseudomonas aeruginosa pneumonia.

OBJECTIVE: Antimicrobial effects of nitric oxide (NO) have been demonstrated in vitro against a variety of infectious pathogens, yet in vivo evidence of a potential therapeutic role for exogenous NO as an antimicrobial agent is limited. Thus, we assessed the effects of inhaled NO on pulmonary infection, leukocyte infiltration, and NO synthase (NOS) activity in a rat model of Pseudomonas aeruginosa pneumonia. DESIGN: Controlled animal study. SETTING: Research laboratory of an academic institution. SUBJECTS: Male Sprague-Dawley rats. INTERVENTIONS: After intratracheal instillation of either P. aeruginosa or saline (sham), rats were randomly exposed to either 40 ppm of inhaled NO or room air (RA) for 24 hrs before they were killed. MEASUREMENTS AND MAIN RESULTS: Inhaled NO in pneumonia rats markedly reduced pulmonary bacterial load (0.02+/-0.01% vs. 0.99+/-0.59% of bacterial input in pneumonia with room air, p < .05) and pulmonary myeloperoxidase activity, a marker of leukocyte infiltration (21.7+/-3.8 vs. 55.0+/-8.1 units in pneumonia with room air, p < .05), but had no effect on systemic hemodynamics or gas exchange. Pneumonia was associated with enhanced pulmonary NOS activity (8.8+/-2.4 vs. 0.2+/-0.1 pmol citrulline/min/mg protein in sham, p < .01) and increased plasma levels of nitrites/nitrates (NOx-; 45+/-7 vs. 16+/-3 micromol/L in sham, p < .01). Inhaled NO therapy attenuated the pneumonia-induced increase in pulmonary calcium-independent NOS activity (p < .05) and markedly increased plasma NOx- levels. Exposure of P. aeruginosa in culture to 40 ppm of ambient NO confirmed a delayed antibacterial effect of NO in vitro. CONCLUSIONS: Inhaled NO has an important antibacterial effect both in vitro and in vivo against P. aeruginosa and is associated with reduced pulmonary leukocyte infiltration in vivo. These results in a rat model of P. aeruginosa pneumonia suggest that future studies should address the possible clinical effects of inhaled NO therapy in pneumonia.

Administration, Inhalation↗
PubMed2000

Effects of continuous positive airway pressure on cardiac volumes in patients with ischemic and dilated cardiomyopathy.

The effects of continuous positive airway pressure (CPAP) on left (LV) and right ventricular (RV) volumes in patients with congestive heart failure (CHF) have not been studied. We hypothesized that CPAP would cause greater reductions in cardiac volumes in CHF patients with idiopathic dilated cardiomyopathy (IDC) than in those with ischemic cardiomyopathy (IsC), because their ventricles are more compliant. The effects of a 30-min CPAP application at 10 cm H(2)O on RV and LV end-diastolic (EDV) and end-systolic volumes (ESV), determined by radionuclide angiography, were therefore tested in 22 patients with CHF due to IsC (n = 13) or IDC (n = 9). CPAP-induced reductions in LVEDV, LVESV, RVEDV, and RVESV were significantly greater (p < 0.05) in the IDC than in the IsC group. Whereas in the IsC group CPAP caused no significant changes in LV or RV volumes, in the IDC group it induced significant reductions in RVEDV (527 +/- 77 ml to 354 +/- 50 ml, p = 0.03) and RVESV (400 +/- 78 ml to 272 +/- 54 ml, p = 0.04) that were greater than any reductions in LVEDV and LVESV. We conclude that CPAP causes greater short-term reductions in RV and LV volumes in CHF patients with IDC than in those with IsC, and that among patients with IDC, CPAP causes greater reductions in RV than in LV volumes.

Aged↗
PubMed1999

Contribution of nitric oxide synthases 1, 2, and 3 to airway hyperresponsiveness and inflammation in a murine model of asthma.

Asthma is a chronic disease characterized by increased airway responsiveness and airway inflammation. The functional role of nitric oxide (NO) and the various nitric oxide synthase (NOS) isoforms in human asthma is controversial. To investigate the role of NO in an established model of allergic asthma, mice with targeted deletions of the three known isoforms of NOS (NOS1, 2, and 3) were studied. Although the inducible (NOS2) isoform was significantly upregulated in the lungs of ovalbumin (OVA)-sensitized and -challenged (OVA/OVA) wild-type (WT) mice and was undetectable in similarly treated NOS2-deficient mice, airway responsiveness was not significantly different between these groups. OVA/OVA endothelial (NOS3)-deficient mice were significantly more responsive to methacholine challenge compared with similarly treated NOS1 and NOS1&3-deficient mice. Airway responsiveness in OVA/OVA neuronal (NOS1)-deficient and neuronal/endothelial (NOS1&3) double-deficient mice was significantly less than that observed in similarly treated NOS2 and WT groups. These findings demonstrate an important function for the nNOS isoform in controlling the inducibility of airway hyperresponsiveness in this model of allergic asthma.

Animals↗
PubMed1999

Akt-dependent potentiation of L channels by insulin-like growth factor-1 is required for neuronal survival.

The insulin-like growth factor-1 (IGF-1)/receptor tyrosine kinase recently has been shown to mediate neuronal survival and potentiate the activity of specific calcium channel subtypes; survival requires Akt, a serine/threonine kinase. We demonstrate here that Akt mediates the IGF-1-induced potentiation of L channel currents, but not that of N channels. Transient expression of wild-type, dominant-negative, and constitutively active forms of Akt in cerebellar granule neurons causes, respectively, no change in IGF-1/L channel potentiation, complete inhibition of potentiation, and a dramatic increase in basal L currents accompanied by the loss of ability to induce further increases. In no case is the IGF-1 potentiation of N currents affected. We additionally find that IGF-1 partially mediates granule neuron survival via L channel activity and that Akt-dependent L channel modulation is a necessary component. Interestingly, very brief exposure (1 min) to IGF-1 triggers nearly complete survival and requires L channel activity. These results strongly suggest that neuronal receptor tyrosine kinases can control long-term calcium-dependent processes via the rapid control of voltage-sensitive channels.

Animals↗
PubMed1999

Exertional leg symptoms other than intermittent claudication are common in peripheral arterial disease.

BACKGROUND: Epidemiological data show that most community-dwelling men and women with lower-extremity peripheral arterial disease (PAD) do not have typical symptoms of intermittent claudication. We compared the prevalence of intermittent claudication, leg symptoms other than intermittent claudication, and absence of exertional leg symptoms between patients with PAD identified from a blood flow laboratory (group 1), patients with PAD in a general medicine practice (group 2), and control patients without PAD (group 3). METHODS: Numbers of participants in groups 1, 2, and 3 were 137, 26, and 105, respectively. Patients with previously diagnosed PAD were excluded from groups 2 and 3. All participants underwent ankle-brachial index measurement and were administered the San Diego claudication questionnaire to assess leg symptoms. RESULTS: Within groups 1, 2, and 3, prevalences of intermittent claudication were 28.5% (n = 39), 3.8% (n = 1), and 3.8% (n= 4), respectively. Prevalences of exertional leg symptoms other than intermittent claudication were 56.2% (n= 77), 42.3% (n= 11), and 19.0% (n = 20), respectively. Absence of exertional leg symptoms was reported by 15.3% (n= 21), 53.8% (n= 14), and 77.1% (n=81), respectively. Among patients with PAD, older age, male sex, diabetes mellitus, and group 2 vs group 1 status were associated independently with absence of exertional leg symptoms in multivariable regression analysis. Lower ankle-brachial index levels and group 1 vs group 2 status were associated with intermittent claudication. CONCLUSIONS: Clinical manifestations of PAD are diverse, particularly among patients identified by ankle-brachial index screening. Exertional leg symptoms other than intermittent claudication are common in PAD. Patients with PAD who are older, male, diabetic, or identified with ankle-brachial index screening in a primary care setting are more likely to have asymptomatic PAD.

Age Factors↗
PubMed1999

Glucocorticoids inhibit the expression of calcium-dependent potassium channels in vascular smooth muscle.

Increased calcium-activated potassium channel (KCa) activity in vascular smooth muscle (VSM) cells leads to a relaxation response counteracting the effects of high blood pressure. Since chronic exposure to glucocorticoids (GC) can be associated with an increase in blood pressure, we reasoned that GCs might modify the expression of KCa channels resulting in a net rise in vascular tone. To test this hypothesis, primary cultures of rat VSM cells were exposed to (a) RU 28362 (a pure glucocorticoid receptor agonist), 1 microM; (b) corticosterone 10 nM + carbenoxolone (an inhibitor of bidirectional VSM 11beta-OH steroid dehydrogenase), 1 microM; (c) 11-dehydrocorticosterone (a biologically inactive metabolite), 10 nM + carbenoxolone; (d) carbenoxolone alone; or (e) aldosterone 10 nM for periods of up to 72 h. Proteins were then extracted and Western blots prepared. Gels were probed with a rabbit-derived polyclonal antibody directed against KCa channel protein. The experimental procedure was repeated on separate sets of VSM cells to ensure reproducibility. Expression of KCa channel protein was diminished in VSM cells incubated with corticosterone + carbenoxolone and with RU 28362 after 24 h and remained low at 72 h. Expression of KCa protein in cells exposed to 11-dehydrocorticosterone + carbenoxolone, carbenoxolone alone, and aldosterone was either similar to controls or mildly increased over the 72 h. These data are consistent with the hypothesis that GCs diminish the expression of KCa protein. Diminished KCa expression could contribute to the observed increase in vascular tone following chronic GC exposure.

Androstanols↗