PubMed Health⌕ Search

Biomedical subjects

V Mehta

Publications and source records attributed to V Mehta.

At least 19 recordsLinked to original sources
PubMed2001

Interleukin-1beta costimulates interferon-gamma production by human natural killer cells.

Natural killer (NK) cells are an early source of immunoregulatory cytokines during the innate immune response to viruses, bacteria, and parasites. NK cells provide requisite IFN-gamma to monocytes for the elimination of obligate intracellular pathogens. IL-1beta is a pro-inflammatory cytokine produced by monocytes (i.e. a monokine) during the early immune response to infection, but its role in promoting human NK cell IFN-gamma production is unknown. The current study examines the ability of the monokine IL-1beta, plus IL-12, to costimulate IFN-gamma production by resting CD56(bright) and CD56(dim) human NK cell subsets. CD56(bright) NK cells stimulated with IL-1beta plus IL-12 produced abundant IFN-gamma protein, while little IFN-gamma was produced in identical cultures of CD56(dim) cells. In addition, upon activation with IL-1beta, CD56(bright) NK cells exhibited considerably greater phosphorylation of extracellular signal-regulated kinases p42/44 as compared to CD56(dim) NK cells. Quantitative PCR analysis showed brisk induction of IFN-gamma gene expression following costimulation with IL-1beta plus IL-12 in CD56(bright) NK cells, but intracellular flow cytometry revealed that only a fraction (42+/-2.3%) of CD56(bright) NK cells account for this high IFN-gamma production. These data suggest that the monokine IL-1beta is a potent costimulus of IFN-gamma production by a subset of NK cells following infectious insult.

CD56 Antigen↗
PubMed2000

Point-of-care versus laboratory measurement of the International Normalized Ratio.

The Notes section welcomes the following types of contributions: (1) practical innovations or solutions to everyday practice problems, (2) substantial updates or elaborations on work previously published by the same authors, (3) important confirmations of research findings previously published by others, and (4) short research reports, including practice surveys, of modest scope or interest. Notes should be submitted with AJHP's manuscript checklist. The text should be concise, and the number of references, tables, and figures should be limited.

Adult↗
PubMed2000

Ligand-dependent regulation of vascular endothelial growth factor and erythropoietin expression by a plasmid-based autoinducible GeneSwitch system.

We investigated the ability of an improved mifepristone-dependent GeneSwitch system to regulate the expression of genes for two therapeutic proteins: vascular endothelial growth factor (VEGF) and erythropoietin. The GeneSwitch system consisted of two plasmids, one encoding the chimeric GeneSwitch protein, the other an inducible transgene. When the constitutive CMV promoter of the GeneSwitch plasmid was replaced by an autoinducible promoter consisting of four copies of GAL4 DNA binding sites linked to a minimal thymidine kinase promoter, the tightness of transgene regulation was improved by an order of magnitude. Quantitative RT-PCR analysis of GeneSwitch mRNA confirmed that the autoinducible promoter was responsive to mifepristone. We demonstrated the ability of the improved GeneSwitch system to regulate the expression of VEGF or erythropoietin in a biologically relevant manner after delivery of plasmids to the hind-limb muscle of adult mice. This ability of the autoinducible GeneSwitch system to regulate the expression of therapeutic proteins in mice indicates its potential for use in human gene therapy applications.

Animals↗
PubMed1999

Ligand-dependent regulation of plasmid-based transgene expression in vivo.

As gene therapy advances, the ability to regulate transgene expression will become paramount for safety and efficacy. In this study, we investigate the ability of the mifepristone-dependent GeneSwitch system to regulate the expression of trangenes delivered to mice by nonviral methods. Two plasmids, one encoding the chimeric GeneSwitch protein, the other an inducible transgene for secreted human placental alkaline phosphatase (SEAP), were delivered to the hind-limb muscles of adult mice. Modulation of the level of secretion of the transgene product into serum was achieved by intraperitoneal administration of low doses of the drug mifepristone (MFP). The EC50 for induction of transgene expression by MFP was 0.03 +/- 0.005 mg/kg. The maximal level of transgene expression after induction was equal to or higher than that displayed by a plasmid driven by the CMV enhancer/promoter. The average magnitude of induction was 14- to 19-fold. Multiple rounds of drug-dependent regulation of transgene expression in vivo were demonstrated. In BALB/c mice, the ability to regulate transgene expression persisted for approximately 3 weeks, until the appearance of neutralizing antibodies to the secreted transgene product. In immune-deficient mice, the ability to repetitively regulate transgene expression persisted for at least 5 weeks. Although the dynamic range of regulation needs improvement, the plasmid-based GeneSwitch system has features that are attractive for gene therapy applications.

Alkaline Phosphatase↗
PubMed1999

Increased level and duration of expression in muscle by co-expression of a transactivator using plasmid systems.

Skeletal muscle is an attractive target for gene therapies to treat either local or systemic disorders, as well as for genetic vaccination. An ideal expression system for skeletal muscle would be characterized by high level, extended duration of expression and muscle specificity. Viral promoters, such as the cytomegalovirus (CMV) promoter, produce high levels of transgene expression, which last for only a few days at high levels. Moreover, many promoters lack muscle tissue specificity. A muscle-specific skeletal alpha-actin promoter (SkA) has shown tissue specificity but lower peak activity than that of the CMV promoter in vivo. It has been reported in vitro that serum response factor (SRF) can stimulate the transcriptional activity of some muscle-specific promoters. In this study, we show that co- expression of SRF in vivo is able to up-regulate SkA promoter-driven expression about 10-fold and CMV/SkA chimeric promoter activity by five-fold in both mouse gastrocnemius and tibialis muscle. In addition, co-expression of transactivator with the CMV/SkA chimeric promoter in muscle has produced significantly enhanced duration of expression compared with that shown by the CMV promoter-driven expression system. A dominant negative mutant of SRF, SRFpm, abrogated the enhancement to SkA promoter activity, confirming the specificity of the response. Since all the known muscle-specific promoters contain SRF binding sites, this strategy for enhanced expression may apply to other muscle-specific promoters in vivo.

Actins↗
PubMed1998

Enhancement of graft survival and sensorimotor behavioral recovery in rats undergoing transplantation with dopaminergic cells exposed to glial cell line-derived neurotrophic factor.

OBJECT: The goal of this study was to investigate the ability of fetal dopaminergic neurons to improve complex sensorimotor behavior. METHODS: The authors obtained ventral mesencephalic tissue from 14-day-old rat fetuses. The cells were exposed to glial cell line-derived neurotrophic factor (GDNF) prior to transplantation into rats with unilateral 6-hydroxydopamine lesions of the dopaminergic nigrostriatal pathway. Animals that received 400,000 cells exposed to GDNF demonstrated significant improvement in contralateral forelimb function and showed improvement in rotational behavior faster than animals that received cells not exposed to GDNF. Increasing the number of implanted cells to 800,000 exposed to GDNF did not result in any additional improvement in functional recovery. CONCLUSIONS: As neural grafting procedures in the nervous system evolve and genetically engineered cells or stem cells replace fetal tissue, crucial questions about cell number and trophic regulation will need to be addressed. This study demonstrates that grafting of 400,000 cells exposed to GDNF before transplantation has a beneficial effect in the restoration of complex sensorimotor behavior.

Adrenergic Agents↗
PubMed1997

Neural transplantation in Parkinson's disease.

Parkinson's disease is a neurodegenerative disorder that affects about 1% of Canadians between the ages of fifty and seventy. The medical management for these patients consists of drug therapy that is initially effective but has limited long term benefits and does not alter the progressive course of the disease. The recalcitrance of longstanding Parkinson's disease to medical management has prompted the use of alternative surgical therapies. Many neurosurgical procedures have been utilized in order to improve the disabling symptoms these patients harbour. Although most of the current procedures involve making destructive lesions within various basal ganglia nuclei, neural transplantation attempts to reconstitute the normal nigrostriatal pathway and restore striatal dopamine. The initial success of neural transplantation in the rodent and primate parkinsonian models has led to its clinical application in the treatment of parkinsonian patients. Currently, well over one hundred patients throughout the world have been grafted with fetal tissue in an effort to ameliorate their parkinsonian symptoms. Although the results of neural transplantation in clinical trials are promising, a number of issues need to be resolved before this technology can become a standard treatment option. This review focuses on the current status of neural transplantation in Parkinson's disease within the context of other surgical therapies in current use.

Animals↗
PubMed1997

Characterization of frozen glucose solutions.

Reducing sugars may be used as additives in freeze-dried formulations. The purpose of this study is to examine the effect of freezing on nonequilibrated glucose solutions using FT-Raman spectroscopy. The methods used solutions freshly prepared from either alpha- or beta-crystalline glucose, frozen at different time intervals after dissolution. Solutions frozen immediately after dissolution showed peaks in the anomeric region of the spectrum characteristic of those observed for the parent crystalline form. No change occurred in these spectra after 24 hr in the frozen state. Solutions prepared from either alpha- or beta-crystalline glucose and left for 24 hr at room temperature before freezing showed the presence of both anomers. The glass transition temperature of maximally freeze-concentrated solutions of beta-glucose, frozen immediately after dissolution, was found to be approximately 3 degrees C lower than for solutions prepared from alpha-glucose. Freezing appears to halt the interconversion of glucose anomers, enabling the formation of predominantly alpha- or beta-frozen solutions which exhibit different properties. Freezing of nonequilibrated solutions of reducing sugars may lead to variation in the properties of freeze-dried formulations.

Calorimetry, Differential Scanning↗
PubMed1997

Late results and reoperation after repair of complete and partial atrioventricular canal defect.

Advances in surgical technique and postoperative care have resulted in substantial improvement in the operative mortality after repair of atrioventricular canal defects. However, significant late morbidity and the need for reoperation complicate the medium and long-term results in these patients. Left atrioventricular valve regurgitation, residual or recurrent intracardiac shunting, and subaortic stenosis are the principle causes of late morbidity after repair of complete and partial atrioventricular canal defects. This article describes the incidence and etiology of these complications, as well as the methods of diagnosis and management.

Aortic Valve Stenosis↗
PubMed1996

Working memory in temporal lobe epilepsy: an event-related potential study.

Event-related potentials (ERPs) were recorded to a digit-probe identification and matching task (modified 'Sternberg paradigm') in 29 patients with temporal lobe epilepsy (TLE) and 26 healthy subjects. Our main aim was to identify the neurophysiological correlates of abnormal short term memory function in patients with TLE. Neuropsychological tests allowed the definition and comparison of two patient groups according to the presence or absence of memory dysfunction. These two groups did not differ significantly in mean age, education years, IQ, seizure duration, seizure frequency, anti-epileptic drug (AED) regimes, or on findings on neuroimaging. ERPs recorded under different levels of memory load were analysed both by conventional component identification and by an objective computer method of determining mean amplitudes of multiple 50 ms epochs (MMA analysis). We found that some significant abnormalities were common to both groups of patients; these included slow reaction times, a reduced amplitude of the N170 wave (and the corresponding 157-210 ms epoch in the MMA analysis) and a broad late negative shift between 577 and 735 ms. Other findings, including a significantly reduced performance accuracy as the level of memory load increased, were restricted to patients with abnormal memory function. The ERP changes that were specific to these patients occurred within a latency band of 200-420 ms and included a relatively preserved, but delayed P250 component and a delayed and attenuated N290 wave. When compared with either healthy subjects or with patients with normal memory, the responses in patients with abnormal memory showed an abnormal 'positive shift' between 262 and 315 ms after probe presentation and a further positive shift between 315 and 420 ms as memory load increased. These abnormalities of 'memory scanning' ERPs in patients with TLE which paralleled neuropsychological and behavioural evidence of memory dysfunction, and which occurred in the section of the response that is sensitive to memory loading in healthy subjects, provide further objective evidence that abnormalities of short term memory processes contribute to the memory deficits of TLE.

Adult↗
PubMed1996

Acute hydrocephalus following aneurysmal subarachnoid hemorrhage.

BACKGROUND: Acute hydrocephalus is a potentially treatable cause of early neurological deterioration after aneurysmal subarachnoid hemorrhage (SAH). METHODS: A retrospective study of 105 consecutive cases of aneurysmal SAH was undertaken to determine those factors significantly related to the development of acute hydrocephalus. Acute hydrocephalus was diagnosed when the bicaudate index was greater than the 95th percentile for age on a CT scan within 72 hours of the ictus. RESULTS: Thirty-one percent of the patients developed acute hydrocephalus. Grade of SAH was a significant factor for the development of acute hydrocephalus on univariate analysis as 87% of patients with acute hydrocephalus (29/32) presented with at least grade 3 (Hunt-Hess) SAH (P < 0.05). In addition, posterior circulation aneurysms on univariate analysis were associated with acute hydrocephalus (p < 0.05). Both premorbid hypertension and intraventricular blood (p < 0.05) were predictors for acute hydrocephalus, whereas intracisternal blood, age and sex were not. On multivariate linear regression analysis, factors found to be significantly associated with acute hydrocephalus were premorbid hypertension, intraventricular blood, CSF diversion and definitive shunt procedures. External ventricular drainage was not associated with any instances of rebleeding. Thirty-seven percent (10/27) of patients with acute hydrocephalus who survived were improved by pre-operative external ventricular drainage. CONCLUSIONS: Patients with acute hydrocephalus following SAH can be safely treated with external ventricular drainage. Multiple factors can be identified to predict those patients who will develop acute hydrocephalus post aneurysmal rupture. Approximately 30% of those patients with acute hydrocephalus will require definitive shunt placement. Acute hydrocephalus occurred in 31% of aneurysmal SAH patients in this series.

Acute Disease↗
PubMed1995

Sucrose reduces the efficiency of protein denaturation by a chaotropic agent.

Sugars and polyols are used to stabilize proteins. The degree of stabilization conferred on a model protein by sucrose was calculated in terms of the free energy of folding. Phosphoglycerate kinase (PGK) was denatured by guanidine hydrochloride (GuHCl) in different sucrose concentrations. The linear extrapolation method [1,2] was used to calculate the free energy of folding in the absence of denaturant. Although sucrose increased the concentration of GuHCl required to unfold the protein, the free energy of folding in water was unchanged. In order to probe the nature of the stabilizing effect of sucrose, an FT-Raman spectroscopic study of denaturant-polyol systems was undertaken. Investigations of interactions between GuHCl, urea or formamide and polyhydric compounds, revealed no evidence for hydrogen bonding or dipole-dipole associations. Polyhydric compounds caused minor changes in denaturant spectra although the converse was not observed. The structure of deuterated water changed on addition of denaturants. For non-ionic denaturants, addition of polyhydric solutes countered this change in water structure. Thus polyhydric compounds oppose the effect of denaturants on water structure. The observed increase in GuHCl concentration required to unfold PGK in the presence of sucrose may be attributed to this property of sucrose.

Formamides↗
PubMed1995

Surface expression of beta 2-microglobulin-associated thymus-leukemia antigen is independent of TAP2.

Mouse thymus-leukemia antigen (TL), like other major histocompatibility complex (MHC) class I-b antigens, displays signs of a specialized function. It is normally expressed at high levels on immature thymocytes and at moderate levels on gut epithelium and activated mature T cells. A promoter/enhancer region unique among class I genes accounts for this narrow range of tissue distribution. Like most other class I molecules, TL is dependent upon endogenous beta 2-microglobulin (beta 2m) for transport to the surface. However, here we show that unlike most other MHC class I molecules, TL is expressed efficiently in the absence of functional transporter associated with antigen processing subunit 2 (TAP2). A putative fourth TLa gene cloned from A.SL1 cells was expressed in RMA and RMA-S cells. In bulk transformants, TL expression is higher in TAP2-RMA-S cells than in wild-type RMA cells, and is not elevated by incubation at reduced temperatures or exposure to exogenous beta 2m. Analysis of immunoprecipitated molecules by polyacrylamide gel electrophoresis in the presence of sodium dodecyl sulfate indicates that TL is processed normally in RMA-S cells and is associated with beta 2m both intracellularly and at the cell surface. However, TL heavy chains expressed on the cell surface in the absence of TAP2 are cleaved to a predominant 38 kDa fragment, presumably the result of an altered conformation that renders TL more susceptible to proteolysis. These results suggest that while TL may normally acquire TAP2-dependent peptides, this class I-b molecule does not require them for efficient export to, and stable expression at the cell surface.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1995

N-acetylaspartate as an acetyl source in the nervous system.

To understand the role of N-acetylaspartate (NAA) as an acetyl donor, we investigated the metabolism of NAA in brain and liver slice preparations. The tissue slices were incubated with [14C-acetyl]NAA (SA = 3 microCi/mumol) or [14C]acetate (SA = 3 microCi/mumol) for 2 h. The tissue was homogenized and was extracted using chloroform/methanol (2:1). The aqueous phase was initially analyzed using anion exchange HPLC while the lipid phase was analyzed using a two-dimensional TLC system. Further resolution of the NAA peak from the anion exchange HPLC was performed using a reverse phase HPLC system. The aqueous phase of both the liver and brain samples incubated with [14C-acetyl]NAA revealed similar patterns of three distinct radioactivity peaks corresponding to NAA, acetate and an early eluting unknown molecule. Further resolution of the NAA peak using reverse phase HPLC indicated that it corresponded to NAA and acetyl CoA. There was significant incorporation of radioactivity into various lipid components in both the brain and liver samples. Patterns similar to that observed with NAA were detected in the case of [14C]acetate in both the brain and liver slice preparations. These results demonstrate that NAA metabolism is not restricted to the nervous system, although its biosynthesis is. It is clear that acetyl moiety of NAA is incorporated into lipids and partially hydrolyzed to free acetate in both brain and liver preparations. Further, production of acetyl CoA from NAA indicates that the acetyl group of NAA is incorporated into lipids and perhaps other acetylated molecules via the acetyl CoA route. A working hypothesis on the metabolic role of NAA is presented.

Acetylation↗
PubMed1995

Prenatal testosterone differentially masculinizes tonic and surge modes of luteinizing hormone secretion in the developing sheep.

In sheep, prenatal exposure to androgens during a critical period for sexual differentiation can masculinize tonic luteinizing hormone (LH) secretion and defeminize the LH surge. The present study investigated the possible independent control of these two modes of LH secretion, as revealed by their developmental history. Specifically, we tested the hypothesis that separate critical periods exist for androgenization of tonic and surge LH secretion. Pregnant ewes were treated weekly with testosterone cypionate (200 mg in oil). As a control and to induce robust masculinization of reproductive neuroendocrine function, one group of females received testosterone from day 30 to 86 of gestation (LONG group). To determine if masculinization of tonic LH secretion develops separately from that of the LH surge, two additional groups were treated from day 30 to 51 (EARLY group) or 65-86 (LATE group). At birth, the external genitalia of the LONG- and EARLY-treated females were masculinized; those of the LATE-treated group were normal. At 2 weeks of age, all androgenized females, together with normal males and females (n = 8 each), were gonadectomized and steroids replaced using an estradiol-filled Silastic capsule. First, to determine the timing of the pubertal decrease in steroid sensitivity, circulating LH was monitored twice weekly. Second, to test the function of the LH surge system, LH was measured every 1-2 h for 60 h after an acute increase in estradiol at 9 months of age. With regard to tonic LH secretion, in control males and LONG-treated females, a sustained increase in tonic LH in the presence of constant steroid feedback occurred at 7.1 +/- 0.3 and 10.9 +/- 1.7 weeks of age, respectively (mean +/- SE). In control females, tonic LH increased at 27.1 +/- 0.8 weeks. Despite the differences in their genitalia, EARLY and LATE testosterone treatment produced intermediate effects: LH secretion increased at 19.3 +/- 1.2 and 20.4 +/- 0.8 weeks, respectively. In response to acute estradiol stimulation, all control females produced a surge of LH that peaked 18.4 +/- 0.6 h after steroid treatment. For the control males and LONG-treated females, LH concentrations were not sustained above unsuppressed pretreatment levels throughout the 60-hour sampling period. All but 4 of the 18 EARLY- and LATE-treated females responded to estradiol stimulation with a surge of LH that peaked at 29.8 +/- 1.6 and 31.8 +/- 1.3 h, significantly later than that of control females.(ABSTRACT TRUNCATED AT 400 WORDS)

Age Factors↗
PubMed1995

Surgical management of the patient with a thyroid disorder.

In this article, fundamental thyroid physiology and diagnostic procedures in the elderly patient are described. Emphasis is placed on performing nonthyroid surgery in elderly patients with hypo- or hyperthyroidism. The management of the thyroid nodule in the elderly patient is also described with a detailed algorithmic approach. Preoperative and intraoperative cardiac risk assessment and monitoring in elderly patients undergoing nonthyroid as well as thyroid surgery are also described.

Aged↗