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Biomedical subjects

N Shah

Publications and source records attributed to N Shah.

At least 91 records · Page 5Linked to original sources
PubMed2000

Conditional expression of a Gi-coupled receptor causes ventricular conduction delay and a lethal cardiomyopathy.

Cardiomyopathy is a major cause of morbidity and mortality. Ventricular conduction delay, as shown by prolonged deflections in the electrocardiogram caused by delayed ventricular contraction (wide QRS complex), is a common feature of cardiomyopathy and is associated with a poor prognosis. Although the G(i)-signaling pathway is up-regulated in certain cardiomyopathies, previous studies suggested this up-regulation was compensatory rather than a potential cause of the disease. Using the tetracycline transactivator system and a modified G(i)-coupled receptor (Ro1), we provide evidence that increased G(i) signaling in mice can result in a lethal cardiomyopathy associated with a wide QRS complex arrhythmia. Induced expression of Ro1 in adult mice resulted in a >90% mortality rate at 16 wk, whereas suppression of Ro1 expression after 8 wk protected mice from further mortality and allowed partial improvement in systolic function. Results of DNA-array analysis of over 6,000 genes from hearts expressing Ro1 are consistent with hyperactive G(i) signaling. DNA-array analysis also identified known markers of cardiomyopathy and hundreds of previously unknown potential diagnostic markers and therapeutic targets for this syndrome. Our system allows cardiomyopathy to be induced and reversed in adult mice, providing an unprecedented opportunity to dissect the role of G(i) signaling in causing cardiac pathology.

Animals↗
PubMed2000

Unmasking of primary hyperaldosteronism by renal transplantation.

BACKGROUND: Primary hyperaldosteronism is an uncommon cause of hypertension in the general population. Given the mechanism of action of aldosterone clinical manifestations may not occur in the setting of end stage renal disease. However, if a successful renal transplant is performed clinical manifestations may occur. METHODS: We present a case of a patient with a preexisting adrenal adenoma who only presented with clinical signs of hyperaldosteronism after renal transplantation. Patients' work-up included plasma aldosterone, plasma renin activity, serum cortisol, and estimation of trans tubular potassium gradient. RESULTS: The patient's serum aldosterone was markedly elevated with a relatively suppressed plasma renin activity. Trans tubular potassium gradient was high in the presence of hypokalemia. CONCLUSION: Previously silent hyperaldosteronism may be unmasked by a successful renal transplant.

Adenoma↗
PubMed2000

Improved antioxidant status among HIV-infected injecting drug users on potent antiretroviral therapy.

Low serum antioxidant levels in HIV-infected people have been attributed to altered metabolism associated with excess oxidative stress. We conducted a study to examine serum antioxidant levels in 175 HIV-positive and 210 HIV-negative injecting drug users (IDUs) in Baltimore, Maryland. At the time of data collection, 30 of the HIV-positive IDUs were receiving antiretroviral therapies (ART) including a protease inhibitor (PI), 43 ART without a PI, 22 monotherapies, and 80 not on any ART. Serum antioxidants examined included retinol, alpha-tocopherol and gamma-tocopherol, alpha-carotene and beta-carotene, lycopene, lutein/zeaxanthin, and beta-cryptoxanthin. Mean serum levels of lycopene and lutein/zeaxanthin were significantly lower in HIV-positive IDUs than HIV-negative IDUs. Contrary to the findings in other studies, however, levels of the remaining antioxidants in HIV-positive study subjects were not lower than in HIV-negative study subjects. In fact, serum alpha-tocopherol levels were significantly higher in HIV-positive IDUs than HIV-negative IDUs (medians = 744 microg/dl and 718 microg/dl, respectively; p = .04). Among HIV-positive study subjects, there were significant differences in antioxidant levels by ART regimen. In multivariate models adjusting for injecting drug use, dietary intake, supplement intake, gender, and alcohol intake, significant overall differences by ART regimen were observed for alpha-tocopherol, beta-carotene, and beta-cryptoxanthin. Serum levels of these three antioxidants were significantly higher in the PI group than in the other three ART groups combined (p = .0008, 0.02, and 0.02, respectively). These data provide indirect evidence of the effectiveness of PIs in lowering oxidative stress levels in HIV-positive IDUs.

Adult↗
PubMed2000

The use of chlorambucil with prednisone in the treatment of pemphigus.

BACKGROUND: Chlorambucil is an alkylating agent that preferentially affects B cells over T cells and has been shown to be effective in the treatment of bullous pemphigoid. OBJECTIVE: Our purpose was to determine whether chlorambucil is effective in the treatment of pemphigus. METHODS: We retrospectively reviewed the medical records of 9 patients with pemphigus (7 with pemphigus vulgaris and 2 with pemphigus foliaceus) in whom therapy with other immunosuppressive regimens failed and who were subsequently treated with chlorambucil and prednisone. RESULTS: There was clinical improvement in 6 of 9 patients and a decrease in indirect immunofluoresent antibody titers in 3 of the 5 patients who had titers drawn before and after treatment with chlorambucil. Three of the 9 patients failed treatment with chlorambucil, as evidenced by lack of improvement of lesions. CONCLUSION: Chlorambucil may be a potential adjuvant therapeutic approach with steroid-sparing effects in patients with pemphigus who have failed treatment with other immunosuppressive regimens.

Adult↗
PubMed2000

Subcutaneous microdialysis in rats correlates with carbamazepine concentrations in plasma and brain.

Microdialysis simplifies the measurement of pharmacokinetics in pharmacodynamically relevant tissues. Microdialysis permits serial measurements of unbound drug concentration. The objective of the present work was to study rats to correlate plasma carbamazepine pharmacokinetics with subcutaneous and brain tissues. Microdialysis probes were inserted into the jugular vein, the brain, and subcutaneous tissue in Sprague-Dawley rats. After receiving single doses of carbamazepine, 12 mg/kg i.p., pharmacokinetic sampling occurred simultaneously from three microdialysis sites. Microdialysis sampled unbound carbamazepine and carbamazepine-10, 11-epoxide concentrations. Concentrations measured in brain, subcutaneous, and plasma correlated with each other. Except where differences were anticipated, pharmacokinetic parameters, including half-life and time to maximum concentration, were the same regardless of measurement site. The present study suggests microdialysis may allow pharmacokinetic measurements in peripheral physiological spaces that are surrogates for the pharmacologically relevant tissue.

Animals↗
PubMed2000

Receptor mediated endocytosis by mesangial cells modulates transmigration of macrophages.

BACKGROUND: Accumulation of immune complexes in the mesangium is a common finding. Since migration of macrophages (Mphi) in the mesangium has been demonstrated to be an important event in the development of glomerular lesions, we studied the role of immune complexes and mesangial cell (MC) interaction in the transmigration (Tm) of Mphi. METHODS: To determine the effect of MC and immune complexes (aggregated IgG, IgGAg) on transmigration of Mphi. MC were incubated with or without IgGAg in the lower compartment of a modified Boyden Chamber. To determine the effects of the secretory products (as a result of endocytosis of IgGAg by mesangial cells), MC-IgAg conditioned media was prepared and placed in the lower compartment of the Boyden chamber. We evaluated the effects of MC alone, MC + IgGAg, or MC-IgGAg conditioned media on the transmigration of macrophages across a filter. To determine the effect of free radicals on MC-IgAg endocytosis-induced Mphi migration we evaluated the effect of free radical scavengers such as dimethyl thiourea (DMTU) and tetramethylthiourea (TMTU) in MC-IgAg endocytosis-induced Mphi migration. To determine the role of chemokines in MC-IgAs endocytosis-induced Mphi migration we evaluated the effect of ani-MCP-1 antibodies on MC-IgAg endocytosis-induced Mphi migration, and also studied the effects of IgAg on MC mRNA expression of MCP-1 and RANTES. In addition, we evaluated the role of Fc receptors and actin cytoskeleton of MC in transmigration of Mphi. RESULTS: Mesangial cell endocytosis of IgG aggregates (IgGAg) is associated with enhanced (P < 0.001) transmigration of Mphi (control, 11.2 +/- 0.2 vs. MC + IgGAg, 22.1 +/- 0.9 migrated Mphi/field). IgGAg also induced MC mRNA expression for RANTES and MCP-1 on MC. DMTU and TMTU attenuated (P < 0.001) the MC + IgGAg-induced migration of Mphi as well as IgGAg-induced mRNA expression for RANTES and MCP-1. MC and IgGAg interaction products (MC-IgGAg conditioned media) also increased (P < 0.01) transmigration of Mphi (control, 18.3 +/- 1.7 vs. MC-IgGAg conditioned media, 30.7 +/- 0.6 Mphi/field). This effect of MC-IgGAg conditioned media on the migration of macrophages was dose dependent. Anti-MCP-1 antibody partially inhibited MC-IgGAg-induced migration of macrophages. MC and monomeric IgG (MIgG) interaction (MC-MIgG conditioned media) showed a lower (P < 0.05) migration of Mphi, when compared to the MC-IgGAg conditioned media. MC-IgGAg conditioned media prepared from cytochalasin B pretreated MCs also showed a lower (P < 0.001) migration of Mphi when compared with MC-IgGAg conditioned media-induced migration. CONCLUSIONS: These results indicate that MC-IgGAg conditioned media-induced transmigration of macrophages may be mediated through the generation of RANTES and MCP-1 by MC.

Animals↗
PubMed2000

Large-scale discovery and genotyping of single-nucleotide polymorphisms in the mouse.

Single-nucleotide polymorphisms (SNPs) have been the focus of much attention in human genetics because they are extremely abundant and well-suited for automated large-scale genotyping. Human SNPs, however, are less informative than other types of genetic markers (such as simple-sequence length polymorphisms or microsatellites) and thus more loci are required for mapping traits. SNPs offer similar advantages for experimental genetic organisms such as the mouse, but they entail no loss of informativeness because bi-allelic markers are fully informative in analysing crosses between inbred strains. Here we report a large-scale analysis of SNPs in the mouse genome. We characterized the rate of nucleotide polymorphism in eight mouse strains and identified a collection of 2,848 SNPs located in 1,755 sequence-tagged sites (STSs) using high-density oligonucleotide arrays. Three-quarters of these SNPs have been mapped on the mouse genome, providing a first-generation SNP map of the mouse. We have also developed a multiplex genotyping procedure by which a genome scan can be performed with only six genotyping reactions per animal.

Animals↗
PubMed2000

A pilot study of postoperative CHART and CHARTWEL in head and neck cancer.

A Phase II pilot study of continuous hyperfractionated accelerated radiotherapy (CHART)/CHART weekend less (CHARTWEL) was carried out in the postoperative treatment of patients with squamous cell carcinoma of the head and neck. Twenty-four patients (17 male, seven female) with a median age of 64 years (range 34-80) were treated with postoperative radiotherapy between 1991 and 1999. All patients presented with primary squamous cell carcinoma, which, at surgery, had shown adverse pathological factors for recurrence. Intermediate risk was determined by the presence of two of the following factors: margins 5 mm, Stage T3/T4, perineural or vascular invasion, poor differentiation, oral primary, multicentric primary, and more than four positive lymph nodes. High-risk factors included the presence of extracapsular spread and/or incomplete resection margins, or the presence of four of the factors defining intermediate risk. The patients were treated using a CHART (n = 11) or a CHARTWEL (n = 13) schedule, administering a dose between 49.5 Gy and 54 Gy. High-risk factors were present in 18/24 patients. Treatment was commenced from a median time of 6.9 weeks (range 4.4-16.6) after radical surgery. All patients completed treatment. A confluent radiation mucositis occurred in 20/23 evaluable patients, which settled in 4-10 weeks after commencing radiotherapy. Moderate dysphagia was observed in 13 patients. Mild subcutaneus oedema was noted in 11 patients from 12 weeks after treatment. No significant late toxicity has been observed. Over a median follow up-period of 17 months, local control has been maintained in 17 patients (71%). Seven patients have relapsed and died of disease. A mean survival of 24 months (range 1-84) has been observed. This pilot study demonstrates acceptable morbidity for CHART/CHARTWEL in the postoperative setting. A prospective multicentre randomized trial using an accelerated schedule of radiotherapy versus conventional fractionation for the radical postoperative treatment of primary head and neck cancer is currently in preparation.

Aged↗
PubMed2000

Characterization of fine particulate matter produced by combustion of residual fuel oil.

Combustion experiments were carried out on four different residual fuel oils in a 732-kW boiler. PM emission samples were separated aerodynamically by a cyclone into fractions that were nominally less than and greater than 2.5 microns in diameter. However, examination of several of the samples by computer-controlled scanning electron microscopy (CCSEM) revealed that part of the PM2.5 fraction consists of carbonaceous cenospheres and vesicular particles that range up to 10 microns in diameter. X-ray absorption fine structure (XAFS) spectroscopy data were obtained at the S, V, Ni, Fe, Cu, Zn, and As K-edges and at the Pb L-edge. Deconvolution of the X-ray absorption near edge structure (XANES) region of the S spectra established that the dominant molecular forms of S present were sulfate (26-84% of total S) and thiophene (13-39% of total S). Sulfate was greater in the PM2.5 samples than in the PM2.5+ samples. Inorganic sulfides and elemental sulfur were present in lower percentages. The Ni XANES spectra from all of the samples agreed fairly well with that of NiSO4, while most of the V spectra closely resembled that of vanadyl sulfate (VO.SO4.xH2O). The other metals investigated (i.e., Fe, Cu, Zn, and Pb) also were present predominantly as sulfates. Arsenic was present as an arsenate (As+5). X-ray diffraction patterns of the PM2.5 fraction exhibit sharp lines due to sulfate compounds (Zn, V, Ni, Ca, etc.) superimposed on broad peaks due to amorphous carbons. All of the samples contain a significant organic component, with the loss on ignition (LOI) ranging from 64 to 87% for the PM2.5 fraction and from 88 to 97% for the PM2.5+ fraction. Based on 13C nuclear magnetic resonance (NMR) analysis, the carbon is predominantly condensed in graphitic structures. Aliphatic structure was detected in only one of seven samples examined.

Air Pollution↗
PubMed2000

Impact of hypoxemia on the performance of cerebral oximeter in volunteer subjects.

Adverse neurological events during hypoxic episodes in high-risk patients or in patients not thought to be at risk while undergoing procedures increase morbidity and mortality. The ability to reliably monitor cerebral oxygenation could serve as an indicator for the need of therapeutic intervention and it's overall effect. This study was designed to verify the reliability of the only commercially available continuous noninvasive monitor, the INVOS 3100 (Somanetics Corp., Troy, MI), in subjects with varying levels of hypoxemia. Six adult volunteer subjects were enrolled. After placement of electrocardiogram (EKG), noninvasive blood pressure (NIBP), pulse oximeter (SpO2), cerebral oximeter (rSO2), a 20 g radial artery catheter, and a 4 F oximetric jugular bulb catheter, the subjects were given hypoxic mixtures to breathe to varying levels of desaturation. Arterial and mixed venous blood was drawn for blood-gas analysis at each level of O2 saturation. The cerebral hemoglobin saturation value from the cerebral oximeter was compared to the combined brain saturation using the formula: estimated field saturation between the light source and the detector (fSO2) = 0.25 x the arterial oxygen saturation (SaO2) + 0.75 x the jugular bulb venous oxygen saturation (SjvO2), (fSO2 = 0.25 SaO2 + 0.75 SjvO2). Statistical analysis demonstrated a correlation of 0.67 between rSO2 and fSO2 and a bias of -3.1% with a precision of 12.1%. Minimal bias of 0.38% and precision of 6.22% were calculated for transitional error. We concluded from the study that rSO2 may serve as a reliable indicator of changes in brain oxygenation induced by hypoxemia.

Adult↗
PubMed2000

Radial aplasia, poikiloderma and auto-immune enterocolitis--new syndrome or severe form of Rothmund-Thomson syndrome?

A syndrome is described in three isolated patients in whom the main features are bilateral radial aplasia, short stature, an inflammatory based 'elastic' pyloric stenosis, a pan-enteric inflammatory gut disorder that appears to be due to an autoimmune process, and poikiloderma. Other features in individual cases include cleft palate, micrognathia, anal atresia, patellar aplasia/hypoplasia and sensorineural deafness. This combination may represent a severe form of Rothmund-Thomson syndrome or possibly a previously unrecognized condition.

Abnormalities, Multiple↗
PubMed2000

Three-dimensional diffuse optical mammography with ultrasound localization in a human subject.

We describe an approach that combines clinical ultrasound and photon migration techniques to enhance the sensitivity and information content of diffuse optical tomography. Measurements were performed on a postmenopausal woman with a single 1.8 x 0.9 cm malignant ductal carcinoma in situ approximately 7.4 mm beneath the skin surface (UCI IRB protocol 95-563). The ultrasound-derived information about tumor geometry enabled us to segment the breast tissue into tumor and background regions. Optical data was obtained with a multifrequency, multiwavelength hand-held frequency-domain photon migration backscattering probe. The optical properties of the tumor and background were then computed using the ultrasound-derived geometrical constraints. An iterative perturbative approach, using parallel processing, provided quantitative information about scattering and absorption simultaneously with the ability to incorporate and resolve complex boundary conditions and geometries. A three to four fold increase in the tumor absorption coefficient and nearly 50% reduction in scattering coefficient relative to background was observed (lambda = 674, 782, 803, and 849 nm). Calculations of the mean physiological parameters reveal fourfold greater tumor total hemoglobin concentration [Hbtot] than normal breast (67 microM vs 16 microM) and tumor hemoglobin oxygen saturation (SOx) values of 63% (vs 73% and 68% in the region surrounding the tumor and the opposite normal tissue, respectively). Comparison of semi-infinite to heterogeneous models shows superior tumor/background contrast for the latter in both absorption and scattering. Sensitivity studies assessing the impact of tumor size and refractive index assumptions, as well as scan direction, demonstrate modest effects on recovered properties.

Absorption↗
PubMed2000

Synergy of L-arginine and growth hormone (GH)-releasing peptide-2 on GH release: influence of gender.

We test the hypotheses that 1) growth hormone (GH)-releasing peptide-2 (G) synergizes with L-arginine (A), a compound putatively achieving selective somatostatin withdrawal and 2) gender modulates this synergy on GH secretion. To these ends, 18 young healthy volunteers (9 men and 9 early follicular phase women) each received separate morning intravenous infusions of saline (S) or A (30 g over 30 min) or G (1 microg/kg) or both, in randomly assigned order. Blood was sampled at 10-min intervals for later chemiluminescence assay of serum GH concentrations. Analysis of covariance revealed that the preinjection (basal) serum GH concentrations significantly determined secretagogue responsiveness and that sex (P = 0.02) and stimulus type (P < 0.001) determined the slope of this relationship. Nested ANOVA applied to log-transformed measures of GH release showed that gender determines 1) basal rates of GH secretion, 2) the magnitude of the GH secretory response to A, 3) the rapidity of attaining the GH maximum, and 4) the magnitude or fold (but not absolute) elevation in GH secretion above preinjection basal, as driven by the combination of A and G. In contrast, the emergence of the G and A synergy is sex independent. We conclude that gender modulates key facets of basal and A/G-stimulated GH secretion in young adults.

Activity Cycles↗
PubMed2000

Synergy of L-arginine and GHRP-2 stimulation of growth hormone in men and women: modulation by exercise.

We investigated the ability of exercise, a multipathway, potent, physiological stimulus for GH release, to alter the synergistic interaction of L-arginine (A) and GH-related peptide (GHRP)-2 (G) observed at rest and the ability of gender to further modulate this putative interaction. Subjects (9 men and 9 early follicular phase women) completed 30 min of constant load aerobic exercise in combination with intravenous infusions of saline (S), A (30 g over 30 min), G (1 microg/kg bolus), or both (AG) in separate study sessions in randomly assigned order. Measures of GH release were logarithmically transformed for statistical analysis. Similar to rest, exercise maintained the rank order (AG > G > A > S) of effective stimulation of GH release for the key response measures in men or women, a gender disparity in the time to reach the maximal serum GH concentration, the calculated endogenous GH half-life, and the observed effect of preinfusion (basal) serum GH concentrations on determining secretagogue responsiveness. Exercise potentiated the individual stimulatory actions of A and G, while blunting the relative magnitude of the synergistic (supra-additive) interaction observed at rest. We infer from the present data that 1) exercise is likely to induce release of both GHRH and somatostatin, 2) L-arginine may facilitate the effect of exercise by limiting somatostatin release, 3) GHRP-2 could further enhance the stimulatory impact of exercise by opposing central actions of somatostatin and/or heightening endogenous GHRH release, and 4) gender strongly controls the relative but not absolute magnitude of A/G synergy both at rest and after exercise.

Adult↗
PubMed2000

Genetic studies in neural tube defects. NTD Collaborative Group.

Neural tube defects (NTD) are one of the most common birth defects and are caused by both environmental and genetic factors. The approach to identifying the genes predisposing to NTD, through linkage analysis and candidate gene analysis, is reviewed along with characteristics of a large, nationally ascertained cohort of families. Results from specific assessments of p53, PAX3 and MTHFR failed to suggest that these genes play a major role in NTD development in these families. Advances in genetic laboratory and statistical techniques have made this a prime opportunity for investigation into the causes of complex disorders, such as NTD. However, traditional approaches may prove to be challenging due to the difficulty of ascertaining samplable multiplex families.

Animals↗
PubMed2000

Oral estradiol administration modulates continuous intravenous growth hormone (GH)-releasing peptide-2-driven GH secretion in postmenopausal women.

Exactly how estradiol (E2) regulates the human GH-insulin-like growth factor I axis is not known. Here, we explore the impact of oral E2 supplementation on the stimulatory actions of a potent and specific synthetic GH-releasing peptide (GHRP), GHRP-2. To this end, we studied 10 healthy postmenopausal women following the administration of placebo or 17beta-estradiol (1 mg twice daily orally) for 7-12 days in a prospectively randomized, double-blind, within-subject crossover design. To drive GH secretion via the GHRP-receptor/ effector pathway, we infused GHRP-2 (1 microg/kg x h) or saline continuously iv for 24 h. Deconvolution analysis was used to quantitate the separate basal and pulsatile modes of GH secretion based on 24-h serum GH concentrations profiles collected at 10-min intervals and assayed by chemiluminescence. As complementary (nonpulsatile) measures, we used the approximate entropy (ApEn) statistic and cosine regression to define feedback-dependent and circadian-related changes, respectively. E2 administration amplified the mass of GH secreted per burst by 1.9-fold over placebo, 24-h GHRP-2 infusion by 7.0-fold, and, the two agonists together by 8.8-fold (P < 10(-14)). Intravenous GHRP-2 infusion augmented the basal (nonpulsatile) rate of GH secretion by 4.4-fold (P < 10(-4)). E2 treatment had no effect alone, but doubled the stimulatory effect of GHRP-2, on basal GH secretion. Neither E2 nor GHRP-2 influenced 24-h GH pulse frequency, interburst interval, half-life or pulse duration. Combined E2 and GHRP-2 elevated the ApEn of GH secretory profiles significantly above control, thereby indicating a marked alteration of within-axis feedback control (P = 0.00033). Dual stimulation with E2 and GHRP-2 also synergistically increased the amplitude (by 11-fold, P < 10(-11)) and the mesor (by 10-fold, P < 10(-10)) of the 24-h GH rhythm. Infusion of GHRP-2 advanced the GH acrophase (time of daily maximum of GH release) by 8.75 h, whereas combined treatment with E2 and GHRP-2 normalized the acrophase. Cross-correlation analysis showed that GHRP-2 infusion (but not E2 administration) significantly synchronized paired 24-h serum GH concentration profiles (P < 10(-3)). In summary, short-term oral E2 replacement in post-menopausal women strongly modulates the actions of a synthetic hexapeptide GH secretagogue on three quantifiable modes of GH secretion [i.e. 1) basal (nonpulsatile) GH release; 2) feedback-dependent ApEn; and 3) the mesor, amplitude and timing of the 24-h GH rhythm]. Moreover, a continuous GHRP-2 stimulus also synchronizes inter diem GH secretory patterns. The present pharmacological study, thus, offers a further framework for exploring the nature of the interactions of E2 with the GHRP-receptor/effector pathway in the aging and/or gonadoprival human.

Administration, Oral↗