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Biomedical subjects

M Shenoy

Publications and source records attributed to M Shenoy.

At least 19 recordsLinked to original sources
PubMed2001

The proteinase-activated receptor 2 is involved in nociception.

The proteinase-activated receptor 2 is expressed on a subset of primary afferent neurons and may participate in the neurogenic component of inflammation. We hypothesized that this receptor may also play a role in neuronal sensitization and contribute to the pathogenesis of pain in inflammatory conditions such as pancreatitis. Using a specific proteinase-activated receptor 2 activating peptide, we found evidence of such sensitization in vitro in the form of enhanced capsaicin- and KCl-evoked release of calcitonin gene-related peptide, a marker for nociceptive signaling. We then demonstrated that injection of the proteinase-activated receptor 2 activating peptide into the pancreatic duct can activate and sensitize pancreas-specific afferent neurons in vivo, as measured by Fos expression in the dorsal horn of the spinal cord. These observations suggest that proteinase-activated receptor 2 contributes to nociceptive signaling and may provide a novel link between inflammation and pain.

Animals↗
PubMed2001

Nerve growth factor regulates VR-1 mRNA levels in cultures of adult dorsal root ganglion neurons.

Nerve growth factor (NGF) regulates the nociceptive properties including sensitivity to capsaicin of a subset of dorsal root ganglion neurons, which express the high-affinity NGF receptor, trkA. Capsaicin sensitivity co-localizes with the expression of a cloned capsaicin receptor, vanilloid receptor type 1 (VR-1), which displays properties similar to the native capsaicin response. To determine whether VR-1 mRNA levels are regulated by NGF, VR-1 mRNA levels and the ability to respond to capsaicin by release of the neuropeptide calcitonin gene related peptide (CGRP) were measured as a function of NGF concentration in cultures of adult dorsal root ganglion neurons. NGF treatment increased both VR-1 mRNA expression and capsaicin evoked release of CGRP. These effects were inhibited by treatment with the trkA inhibitor k252a.

Animals↗
PubMed2001

Gentamicin dosing in neonatal patients.

OBJECTIVE: To compare trough and peak serum gentamicin concentrations in neonatal patients using two dosing regimens. METHOD: A retrospective audit of gentamicin serum concentrations obtained with the current neonatal gentamicin-dosing regimen (regimen 1) was conducted. Results were then compared with the introduction of a new regimen (regimen 2). Preliminary results necessitated a change to a further dosage schedule (regimen 3), where data was again collected. RESULTS: For regimen 1, 79% of patients achieved satisfactory trough concentrations, 30% achieved satisfactory peak concentrations, and 16% achieved a satisfactory combined trough and peak concentration. For regimen 2, 80% of patients achieved satisfactory trough concentrations, 63% achieved satisfactory peak concentrations, and 48% achieved a satisfactory combined trough and peak concentration. For regimen 3, 76% of patients achieved satisfactory trough concentrations, 56% achieved satisfactory peak concentrations, and 45% achieved a satisfactory combined trough and peak concentration. CONCLUSION: Regimen 3 shows a marked improvement in serum gentamicin concentrations. However neonates in the 32-38 weeks post-conceptional age group achieved higher trough and peak serum gentamicin levels than expected. Therefore the dosage interval in this group of neonates will be increased from 18 hourly to 24 hourly dosing, and regimen reaudited.

Anti-Bacterial Agents↗
PubMed2000

Human intestinal epithelial cells express a novel receptor for IgA.

Binding and transport of polymeric Igs (pIgA and IgM) across epithelia is mediated by the polymeric Ig receptor (pIgR), which is expressed on the basolateral surface of secretory epithelial cells. Although an Fc receptor for IgA (FcalphaR) has been identified on myeloid cells and some cultured mesangial cells, the expression of an FcalphaR on epithelial cells has not been described. In this study, binding of IgA to a human epithelial line, HT-29/19A, with features of differentiated colonic epithelial cells, was examined. Radiolabeled monomeric IgA (mIgA) showed a dose-dependent, saturable, and cation-independent binding to confluent monolayers of HT-29/19A cells. Excess of unlabeled mIgA, but not IgG or IgM, competed for the mIgA binding, indicating that the binding was IgA isotype-specific and was not mediated by the pIgR. The lack of competition by asialoorosomucoid and the lack of requirement for divalent cations excluded the possibility that IgA binding to HT-29/19A cells was due to the asialoglycoprotein receptor or beta-1, 4-galactosyltransferase, previously described on HT-29 cells. Moreover, the FcalphaR (CD89) protein and message were undetectable in HT-29/19A cells. FACS analysis of IgA binding demonstrated two discrete populations of HT-29/19 cells, which bound different amounts of mIgA. IgA binding to other colon carcinoma cell lines was also demonstrated by FACS analysis, suggesting that an IgA receptor, distinct from the pIgR, asialoglycoprotein receptor, galactosyltransferase, and CD89 is constitutively expressed on cultured human enterocytes. The function of this novel IgA receptor in mucosal immunity remains to be elucidated.

Antibody Specificity↗
PubMed2000

Nerve growth factor expression is up-regulated in the rat model of L-arginine-induced acute pancreatitis.

BACKGROUND & AIMS: In somatic pain models, increases in nerve growth factor (NGF) are linked to the development of pain and hyperalgesia. The aim of this study was to examine a rat model of acute necrotizing pancreatitis for changes in NGF expression. METHODS: NGF protein and messenger RNA (mRNA) levels in the pancreas were correlated with histopathologic changes during the course of acute necrotizing pancreatitis in rats induced by the intraperitoneal injection of L-arginine. Immunohistochemistry for NGF localization was performed on the pancreatic tissue. RESULTS: Two phases of NGF production were observed in the inflamed pancreas: an early release from pancreatic islets at 2 and 6 hours and a later increase in mRNA (18-fold at maximum) at 3 days and in protein levels (7-fold at maximum) at 5 days coinciding with maximum parenchymal necrosis. The intense NGF-like immunoreactivity was observed predominantly in the ductal cells in pancreas from rats with pancreatitis at 5 days. CONCLUSIONS: The development of acute necrotizing pancreatitis in this model leads to a significant increase in NGF production and appears to shift the major cellular sites of NGF production from the islets to the ductal cells. It is conceivable that NGF production in the inflamed pancreas is responsible for plastic changes in the sensory neurons that mediate peripheral sensitization and contribute to the generation of pain.

Animals↗
PubMed2000

Spontaneous coronary artery dissection presenting as acute myocardial infarction.

Spontaneous coronary artery dissection is a rare entity being increasingly diagnosed as a cause of acute myocardial infarction, especially in cases of low cardiac risk female patients. This is one such case report of a black female patient, who suffered an acute anterior wall myocardial infarction due to an idiopathic spontaneous coronary artery dissection of the left anterior descending artery. She was treated with a thrombolytic agent in the acute phase, uneventfully. An urgent coronary angiogram demonstrated an intimal tear with a dissection of the left anterior descending artery. She survived the acute event and her subsequent hospital course was uncomplicated. Hence she was treated medically for her ischemic event and left ventricular systolic dysfunction with a favorable outcome. This case is yet another report of a survivor treated with a thrombolytic agent for the acute myocardial infarction due to spontaneous coronary artery dissection.

Adult↗
PubMed1999

Free secretory component as a standardization protein for nasopharyngeal specimens from children with upper respiratory tract infection.

Free secretory component (FSC) has been recommended as a reliable protein for correction of the unknown dilution in tracheal aspirate samples from preterm infants. To investigate whether FSC would also provide a valid standardization protein for samples of nasopharyngeal secretions, this study determined the intersubject variation and the alteration over time in the concentrations of FSC in nasal secretions from 35 children (median age 14 months) who participated in an antibiotic efficacy trial. Nasopharyngeal aspirates were obtained at enrolment and after 2-3 d. FSC in the specimens was quantified by a direct enzyme immunoassay. The concentrations of FSC in the nasal secretions ranged from 0.08 to 189.6 microg ml(-1) (median 12.3 microg ml(-1); the ratio of the highest to the lowest concentrations was 2370, the difference between the 90th and 10th percentile concentrations was 189-fold and the difference between the 75th and 25th percentile values was 26. FSC concentrations were significantly lower in children aged < or =12 months (median 2.2 microg ml(-1) than in the older children (median 21.5 microg ml(-1); p = 0.035). Between the first and the follow-up specimens, 65% of the children had > or =2-fold difference in the levels of FSC in the secretions. Because an optimal standardization protein should show minimal variation between individuals and over time, FSC may not be a suitable protein for correction of the unknown dilution of nasopharyngeal specimens from children with upper respiratory tract infection.

Child, Preschool↗
PubMed1999

Quantification of cytokines and inflammatory mediators in samples of nasopharyngeal secretions with unknown dilution.

In the study of inflammatory mechanisms in the upper respiratory tract, the unknown dilution of collected samples of nasal secretions poses a serious problem for interpretation of the measured concentrations of various substances in the specimens. We investigated the magnitude of the dilution problem in a true clinical research situation and determined the validity of using the levels of total protein, albumin, and secretory IgA in nasal secretions to correct for the unknown dilution. The study samples consisted of simultaneously obtained nasopharyngeal aspirates and nasal lavage specimens from 52 children with upper respiratory tract infection. The dilution factors of the nasal lavage specimens varied widely between 1.8 and 432 (median, 11.2). Of the three proteins studied, total protein had the narrowest inter-subject variation in the nasal secretions of the children and thus seemed to provide the best standardization method for comparing levels of substances between individuals. Concentrations of IL-6 standardized with total protein correlated significantly better with the true IL-6 concentrations in the nasal secretions than did IL-6 levels measured in the nasal lavage specimens without standardization (p = 0.049). These findings suggest that the most common current practice of measuring substances in nasopharyngeal specimens, i.e. measuring without correction for the dilution, may produce "false-negative" results. Potentially important information on inflammatory mechanisms may be undetected if false-negative results mask real differences between groups. The use of exogenous markers of dilution might improve the accuracy of quantifying substances in nasal secretions.

Acute Disease↗
PubMed1997

Experimental autoimmune myasthenia gravis in B10.BV8S2 transgenic mice: preferential usage of TCRAV1 gene by lymphocytes responding to acetylcholine receptor.

Multiple TCRBV genes have been implicated in experimental autoimmune myasthenia gravis (EAMG) pathogenesis in susceptible H-2(b) strains of mice. We studied the contribution of specific TCRBV and AV genes in EAMG pathogenesis using B10.BV8S2 transgenic mice (H-2[b]). The TCR transgenic mice predominantly have TCRBV8S2 transgene, but can use any of the endogenous AV gene repertoire. The transgenic mice were immunized with acetylcholine receptor (AChR) in CFA and evaluated for EAMG pathogenesis. Although the lymphocyte responses to AChR in B10.BV8S2 transgenic and nontransgenic TCR wild-type mice were equivalent, a marked reduction in lymphocyte response to the dominant AChR alpha chain peptide 146-162 was observed in the TCR transgenic mice. After boosting with AChR in CFA, anti-AChR Abs were detected in the serum, and 14 of 42 (33%) of the TCR transgenic mice developed clinical EAMG. Furthermore, EAMG in TCR transgenic mice was prevented by treatment with mAb to TCRBV8, which depleted BV8-expressing T cells. Cloning and sequencing of TCRAV genes from AChR-reactive T cells from B10.BV8S2 transgenic mice revealed a pattern of restricted TCRAV gene usage. The majority (60%) of the clones sequenced showed a sequence identical with that of the TCRAV1S8 gene. In the normal spleen cells of TCR transgenic mice, AV gene usage was more random. Thus, despite the presence of a complete endogenous TCRAV repertoire in B10.BV8S2 transgenic mice, T cells responding to AChR preferentially used a single endogenous TCRAV gene, thus implicating the involvement of the TCRAV1S8 gene in EAMG pathogenesis.

Animals↗
PubMed1995

IFN-alpha treatment suppresses the development of experimental autoimmune myasthenia gravis.

Myasthenia gravis (MG) is an Ab-mediated autoimmune neuromuscular disease and is linked to MHC class II beta-chain polymorphism. Corticosteroids and azathioprine are the primary immunosuppressive drugs used in the treatment of MG. These drugs have significant side effects and have limited efficacy. Therefore, drugs with fewer side effects and greater efficacy are being sought. IFN-alpha is a potent immunomodulator and has been shown to down-regulate MHC class II expression on lymphoid cells. MHC class II expression is critical for the development of experimental autoimmune myasthenia gravis (EAMG). Because of the immunomodulating effects of IFN-alpha and its effect on the MHC class II expression, we tested the therapeutic efficacy of IFN-alpha on EAMG induced by immunization with acetylcholine receptor (AChR) in CFA. IFN-alpha (10(5) IU three times weekly for 5 wk) treatment started 1 wk after the second immunization with AChR in CFA, when autoimmunity to AChR is well established, reduced the incidence of clinical EAMG by more than 50% in two separate experiments (p = 0.04 and 0.008). Therefore, IFN-alpha could be a potential agent for the control of MG, and other Ab-mediated autoimmune diseases.

Animals↗
PubMed1995

TCR gene usage in experimental autoimmune myasthenia gravis pathogenesis. Usage of multiple TCRBV genes in the H-2b strains.

Experimental autoimmune myasthenia gravis (EAMG) is an Ab-mediated autoimmune disease. The pathogenic auto-antibody production depends on the activation of CD4+ cells after their TCR interact with dominant T cell epitopes within acetylcholine receptor (AChR) in the context of the MHC class II molecule. In vitro analysis suggested that the TCRBV6 was the predominant TCR that recognized AChR and one of the dominant epitopes, alpha 146-162, in C57BL6 (B6, H-2b) mice. However, in vivo depletion of TCRBV6 cells in H-2b mice by anti-TCRBV6 mAb neither suppressed the in vitro immune response to AChR nor prevented development of EAMG. Moreover, B10.TCRc (H-2b) strain with a genomic deletion of TCRBV genes including TCRBV6, and B10.V beta 8.2 transgenic mice with a restricted TCRBV8S2 T cell repertoire, responded to AChR, alpha 146-162, and developed EAMG after immunizations with AChR/CFA. These data suggest that more than one TCRBV-bearing cell having the affinity for AChR-dominant peptides is involved in pathogenesis. Therefore, depletion of a single TCRBV (e.g., TCRBV6) with mAb may not be sufficient to completely suppress the response to AChR and development of EAMG. However, if a similar amino acid sequence in the TCR-VDJ (e.g., CDR3) region among different TCRBV gene(s) could be involved in recognizing the dominant AChR epitope(s), then motif-specific mAb reactive to the common motif within the VDJ region of different TCR could be used to eliminate the T cell clones involved in EAMG.

Animals↗
PubMed1994

Effect of MHC class I and CD8 cell deficiency on experimental autoimmune myasthenia gravis pathogenesis.

MHC class I and CD8+ cell deficiency have either prevented systemic lupus erythematosus-like disease in mice or enhanced type I diabetes in nonobese diabetic mice. To study the involvement of MHC class I and class I-restricted CD8+ T cells in the induction of a classical Ab-mediated disease, experimental autoimmune myasthenia gravis (EAMG), we immunized beta 2 microglobulin (beta 2-m) gene-disrupted (beta 2 m-/-) C57BL10 (B10) mice, deficient in class I gene expression and CD8+ cells, and heterozygous (beta 2-m+/-) B10 mice with normal expression of class I molecules and sufficient CD8+ cells with Torpedo acetylcholine receptor in CFA, and assessed them for clinical and immunopathologic manifestations of EAMG. Despite MHC class I and CD8+ cell deficiency, beta 2-m-/- mice developed EAMG. Moreover, the incidence of EAMG in the beta 2-m-/- mice was higher than that of beta 2-m+/- heterozygous mice with normal class I expression and frequency of CD8+ cells. The finding provided direct genetic evidence against a pathogenic effector role in C57BL10 mice for MHC class I molecule and class I-restricted CD8+ T cells in EAMG pathogenesis.

Animals↗
PubMed1994

Major histocompatibility complex class II gene disruption prevents experimental autoimmune myasthenia gravis.

To analyze the impact of lack of MHC class II gene expression, and to demonstrate the direct genetic evidence for the involvement of the MHC class II gene product in the development of experimental autoimmune myasthenia gravis (EAMG), MHC class II gene-disrupted C57BL6 mutant (-/-) and EAMG-susceptible MHC class II wild-type C57BL6 mice (+/+) were evaluated for the clinical and immunopathologic manifestations of EAMG. The deficiency of MHC class II, and therefore, CD4+ T cells, completely prevented the C57BL6 MHC class II mutant (-/-) mice from mounting an autoimmune response to the nicotinic acetylcholine receptor. Further, the mutant (-/-) mice failed to show any immunopathologic and clinical manifestations of EAMG. The data unequivocally provide direct genetic evidence for the essential role of MHC class II molecules in the induction of EAMG, and rule out any pathogenic effector role for MHC class I-restricted CD8+ T cells, gamma delta TCR-bearing cells, or NK cells, which are intact in the MHC class II mutant mice in the induction of EAMG.

Animals↗
PubMed1994

The pathogenic role of acetylcholine receptor alpha chain epitope within alpha 146-162 in the development of experimental autoimmune myasthenia gravis in C57BL6 mice.

One of the dominant T cell epitopes in the acetylcholine receptor (AChR) alpha chain lies within the region 146-162 and has been implicated in the pathogenesis of experimental autoimmune myasthenia gravis (EAMG) in C57BL6 (B6) mice. To directly examine the pathogenic potential of alpha 146-162 in EAMG, B6 mice were primed with AChR in complete Freunds adjuvant (CFA) and subsequently boosted twice with either alpha 146-162 or a control peptide in CFA. Seventy percent of the mice boosted with alpha 146-162 developed muscle weakness characteristic of EAMG, while none of the mice boosted with the control peptide showed any clinical signs of the disease. Thus, the data provided evidence for epitope within AChR alpha 146-162 as one of the EAMG-inducing pathogenic epitopes in B6 mice.

Amino Acid Sequence↗