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Biomedical subjects

S Kapadia

Publications and source records attributed to S Kapadia.

At least 19 recordsLinked to original sources
PubMed2000

Regulation of the bovine kidney microsomal chloride channel p64 by p59fyn, a Src family tyrosine kinase.

p64 is a chloride channel of intracellular membranes which is present in regulated secretory vesicles. Mechanisms by which the p64 channel could be regulated are largely unknown. p59(fyn) is a non-receptor tyrosine kinase of the Src family that has been implicated in a variety of intracellular signaling events. The N-terminal portion of p64 has several potential binding sites for Src family SH2 domains. In this paper, we demonstrate that p64 becomes tyrosine phosphorylated when co-expressed with p59(fyn) in HeLa cells. We show that co-expression of p64 with p59(fyn) renders p64 a ligand for the SH2 domain of p59(fyn) and this SH2 binding is eliminated by treating p64 with alkaline phosphatase. Using site-directed mutagenesis, we find that tyrosine 33 in the p64 sequence is necessary for SH2 binding. We also characterized p64-p59(fyn) interactions using native material from bovine kidney. We found that a small fraction of native kidney p64 can bind Fyn SH2 in vitro. Immunoprecipitation of p64 from solubilized kidney membranes yields a kinase activity with the same mobility by SDS-polyacrylamide gel electrophoresis as authentic bovine p59(fyn). Finally, we demonstrate that co-expression of p64 and p59(fyn) in HeLa cells results in enhanced p64-associated chloride channel activity.

Animals↗
PubMed2000

Nonlinear temporal interactions in click-evoked otoacoustic emissions. I. Assumed model and polarity-symmetry.

Click-evoked otoacoustic emissions (CEOAEs) are reduced in amplitude by the presentation of 'suppressor' clicks that either closely lead or follow the stimulus ('test') clicks. This suppression of the response represents nonlinear temporal interactions between the test and suppressor clicks and/or the CEOAEs they evoke. There are some discrepancies amongst previous reports of the phenomenon, and the underlying mechanisms are not understood. In particular, it is unclear whether the suppression reported simply reflects the compressive nonlinearity of the CEOAE input-output (I-O) function. This paper presents a simple model of the nonlinear interactions between CEOAEs evoked by two closely-spaced clicks. The model shows that suppression as reported may be entirely derived from CEOAE I-O nonlinearity, in combination with the extended duration of the cochlear responses to click stimuli. It is also shown experimentally that suppression is insensitive to the polarities of test and suppressor clicks, which is consistent with the model based on I-O nonlinearity. A companion paper (Kapadia and Lutman, Hear. Res. 146 (2000)) presents experimental findings from a detailed parametric study of nonlinear temporal interactions in CEOAEs in human subjects with normal hearing. The findings are compared with the pattern of results generated by the above model, in order to assess the role of I-O nonlinearity in these nonlinear interactions.

Acoustic Stimulation↗
PubMed2000

Nonlinear temporal interactions in click-evoked otoacoustic emissions. II. Experimental data.

Click-evoked otoacoustic emissions (CEOAEs) are reduced in amplitude by the presentation of 'suppressor' clicks that either closely lead or follow the stimulus ('test') clicks. A model described in a companion paper (Kapadia and Lutman, Hear. Res. 146 (2000) 89-100) shows that such nonlinear temporal interactions, as previously reported, may be explained in terms of the compressive non-linearity of the CEOAE input-output (I-O) function. This paper presents the results of a detailed parametric investigation into such nonlinear interactions, studied in 12 normal adult ears over a wide range of test and suppressor click levels and inter-click intervals. The results differ from those generated by the model in a number of respects. Principally, maximum suppression is generally obtained for suppressors presented in advance of test clicks, rather than co-incident with the test clicks. The amount of advance depends systematically on the two click levels. The measured suppression can also exceed the theoretical maximum allowed by the model. It is concluded that the nonlinear temporal interactions measured do not simply reflect CEOAE I-O function non-linearity. They may, instead, arise from disturbance of the generator elements from their resting state prior to generation of the CEOAE. These results may also have general implications relating to cochlear responses to transient stimuli and indicate the potential of CEOAEs in probing aspects of cochlear mechanics.

Acoustic Stimulation↗
PubMed1999

Prognosis of patients with vascular disease after clinical evaluation and dobutamine stress echocardiography.

BACKGROUND: Coronary disease is an important cause of long-term morbidity in patients needing major vascular surgery. We sought to assess the efficacy of preoperative clinical evaluation and the detection of inducible ischemia for prediction of immediate and long-term cardiac outcomes of patients undergoing vascular surgery. METHODS: In 233 patients undergoing vascular procedures, we assessed risk clinically on the basis of Eagle's criteria. Dobutamine echocardiography was performed with a standard protocol and results were classified as showing ischemia, scar, or a normal response. Patients were observed perioperatively, and late follow-up (28 +/- 13 months) was completed in all surgical survivors. A composite end point of cardiac death, myocardial infarction, and unstable and progressive angina requiring late revascularization was used to judge event-free survival. RESULTS: Of 233 patients undergoing preoperative dobutamine echocardiography, 39 (17%) had inducible ischemia and 36 (15%) had scar. Perioperative events occurred in 8 patients (3%). None of the patients with ischemia had perioperative events, reflecting the effect of revascularization in 9 patients. Late events occurred in 36 patients; ischemia on preoperative stress testing was a predictor of these events even after adjusting for clinical variables and left ventricular dysfunction (relative risk = 3.3; 95% confidence interval 1.6 to 6.8; P =.001). The association of ischemia with clinical predictors was associated with incrementally worse outcome. CONCLUSION: In addition to perioperative assessment, the combined use of clinical and dobutamine echocardiographic evaluation may stratify the risk of late cardiac events.

Adrenergic beta-Agonists↗
PubMed1999

Targeted expression of calcitonin gene-related peptide to osteoblasts increases bone density in mice.

The neuropeptide calcitonin gene-related peptide (CGRP) is concentrated in fine sensory nerve endings innervating all tissues, including bone. CGRP inhibits osteoclasts, stimulates insulin-like growth factor I and inhibits tumor necrosis factor alpha production by osteoblasts in vitro. To investigate the role of CGRP in bone in vivo, mice were engineered to express CGRP in osteoblasts by placing the human CGRP gene under the control of the rat osteocalcin promoter (Ost-CGRP tg+ mice). Calvaria cultures from transgene positive (tg+), but not tg- mice, produced bioactive CGRP. Trabecular bone density and bone volume, determined by peripheral quantitative computed tomography and bone histomorphometry, respectively, were higher in tg+ than tg- littermates. This increase in bone volume was associated with an increased bone formation rate. Trabecular bone density decreased in tg+ mice as a result of ovariectomy, but remained higher than in sham tg- mice. Targeting CGRP to osteoblasts appears to favor the establishment of a higher trabecular bone mass in mice.

Animals↗
PubMed1998

Differential expression of heat shock proteins in normal and failing human hearts.

BACKGROUND: Heat shock proteins (hsp) constitute an endogenous stress response that protects cells from injury. Most work on these important proteins has focused on the immediate response to acute stress in cell culture systems and mammalian models of heart disease. Little is known about the expression of the hsps in human hearts. We were interested in whether there was increased expression of the hsps in heart failure, a setting of chronic, sustained stress. Five different hsps were examined: hsp27, hsp60, hsp72, hsc70 and hsp90. METHODS AND RESULTS: Three groups of explanted hearts were studied: dilated cardiomyopathy (DCM), ischemic cardiomyopathy (IHD), and normal controls. Western-blotting with a standard curve of purified protein on each blot was used to quantify the expression of the hsps. Hsp27 was increased almost two-fold in DCM compared to normal hearts, and was significantly greater than in IHD hearts. Levels of hsp60 were doubled in both DCM and IHD hearts (P < 0.05). Hsp72, hsc70 and hsp90 were not significantly changed. CONCLUSIONS: This study shows for the first time that differential changes in hsp levels occur in end-stage heart failure. Since hsps can render cells resistant to apoptosis, and are associated with the mitochondria and the cytoskeleton, which are known to be abnormal in heart failure, these studies may lead to new insights into the pathogenesis of cardiac decompensation.

Adult↗
PubMed1998

The role of cytokines in the failing human heart.

Despite repeated attempts to develop a unifying hypothesis that explains the clinical syndrome of heart failure, no single conceptual paradigm has withstood the test of time. In this regard, recent studies have shown that a class of biologically active molecules, generically referred to as cytokines, are overexposed in heart failure. This article will review recent clinical and experimental material that suggest proinflammatory (stress activated) cytokines such as tumor necrosis factor-alpha (TFN-alpha), interleukin-1 (IL-1), and interleukin-6 (IL-6) may play a role in the pathogenesis of congestive heart failure. The scope of this article includes an overview of the biology of cytokines in the heart, as well as review of the clinical studies that have documented elevated levels of cytokines and cytokine receptors in patients with heart failure.

Animals↗
PubMed1998

Tissue repair in the fetal intestinal tract occurs with adhesions, fibrosis, and neovascularization.

Cutaneous wound healing in the fetus can occur in a nonfibrotic, regenerative manner. However, other fetal tissues such as bone and stomach heal with scar formation. In light of potential ramifications for adult hollow visceral scarring (biliary and intestinal strictures), this study was undertaken to determine if tubular visceral tissue repair in the fetus is regenerative or fibrotic. Fetal rabbits underwent laparotomy on day 24 of gestation, during which a controlled intestinal enterotomy was created and suture repaired immediately using microsurgical techniques. Maternal rabbits and adult male rabbits also underwent enterotomy and repair. After 5 days all animals were sacrificed and the wounds analyzed histologically by a pathologist in a blinded fashion. All animals demonstrated a similar degree of peri-intestinal adhesion formation. Fetal and maternal wounds contained fibroblastic and smooth muscle cell proliferation, mild inflammatory infiltration, and new blood vessel formation. The male adult wounds demonstrated a more pronounced fibrovascular healing response. Immunohistochemical staining for CD31 (endothelial cell marker) was quantitated on a scale of 0 to 4+, indicating degree of neovascularization. The mean scores for the fetal and maternal groups were similar (1.70 +/- 0.68 and 1.23 +/- 1.07 respectively), but were significantly greater for male adults (2.93 +/- 0.12; p = 0.001 by analysis of variance). The results of this study indicate that hollow visceral tissue repair in the fetal rabbit intestine occurs in a similar fibrotic manner as adult healing. This provides further evidence that regenerative healing in the fetus is not ubiquitous. Differences in the degrees of fibrosis and neovascularization between adult male and pregnant female wounds deserve further investigation.

Animals↗
PubMed1998

Progressive septal and palatal perforation secondary to intranasal cocaine abuse.

Septal perforation from intranasal cocaine abuse is well recognised. We present a case of progressive septal as well as palatal perforation. Progression from septal perforation to palatal perforation occurred after cessation of intranasal cocaine abuse. This patient had a weakly positive cytoplasmic antineutrophilic cytoplasmic antibody (C-ANCA) but no histologic evidence of Wegener's Granulomatosis. The differential diagnosis for septal and palatal perforation is reviewed. This case represents the fifth reported case of palatal perforation secondary to cocaine abuse in the literature, and the second associated with positive C-ANCA.

Administration, Intranasal↗
PubMed1998

On borderline phenomena.

The author describes his struggle to resolve some theoretical and technical problems posed by borderline patients. For this he has made use of an ancient Indian myth of King Trishanku taken from Bhagwat Puran--the Hindu Book of Genesis. He has tried to demonstrate, step by step, how fruitfully this myth has helped him to understand such patients. Special emphasis has been laid on the language used by borderline patients. The contrary and apparently meaningless nature of this language is likened to the formulation of King Trishanku's unique desire, 'to go to heaven without actually dying'. The author then proceeds to show that this language is not quite as meaningless as it appears to be--that it is the result of a complicated system of projective identification devised by these patients to manipulate their objects in order to achieve their own omnipotent ends. Detailed clinical examples are given to describe the handling of the problems of appropriation, manipulation and consequent suspended state of such patients. Taken from three different stages of various analyses these examples show how a very slow and gradual change was brought about in the mental structures of the patients treated by the author.

Adult↗
PubMed1997

Cardiac outcomes in coronary patients with submaximum dobutamine stress echocardiography.

This study evaluated the prediction of cardiac events (cardiac death, myocardial infarction, unstable angina, or late myocardial revascularization) in patients with submaximum responses to dobutamine stress, defined by attainment of <85% age-predicted heart rate. Of 1,772 patients undergoing dobutamine echocardiography over a 2-year period, 425 had a submaximum heart rate response. After exclusion of patients treated with beta-adrenoceptor blocking agents, 255 patients formed the study group. In these patients, the test was terminated after administration of the maximum dose of 40 microg/kg/min of dobutamine with atropine (end of protocol, n = 186), severe angina, ischemic ST-segment changes, or intolerable side effects (n = 69). Dobutamine-induced changes (ischemia, viability, or both) were detected in 46 patients, involving ischemia in 133 segments, viability in 23, and ischemia and viability in 16 segments. Patients were followed for an interval of 28 +/- 17 months; 5 (1.2%) were lost to follow-up. Of the medically treated patients, cardiac events occurred in 73 of 228 (31%), including cardiac death in 25 (11%), nonfatal myocardial infarction in 11 (4.8%), severe unstable angina in 35 (15%), and late revascularization in 2 (0.9%). Cardiac events occurred in 11 of 30 (36%) with inducible abnormalities, and 62 of 198 without inducible abnormalities (31%, p = NS). Thus, cardiac event rates are high in patients with inadequate chronotropic responses to dobutamine stress, irrespective of whether stress-induced changes are detected. A negative dobutamine echocardiogram at submaximum heart rate should be considered nondiagnostic.

Aged↗
PubMed1997

Are normal hearing thresholds a sufficient condition for click-evoked otoacoustic emissions?

Transiently evolked otoacoustic emissions (TEOAE) have been reported in several studies as absent in a small minority of normal ears. Other studies have reported TEOAEs in all normal ears. Differences between studies may arise directly from criteria for TEOAE identification, criteria for selection of normals, or statistically due to limited sample sizes. In order to understand and model cochlear processes involved in TEOAE generation, it needs to be known whether the presence of normal hearing leads automatically to generation of TEOAEs. The present study set out to establish in a large sample if any ears could be found that lacked TEOAEs despite normal hearing threshold levels (HTL). A total of 397 ears from highly cooperative adult subjects were examined under laboratory conditions. Using cross correlation between replicate nonlinear waveforms as the criterion, TEOAEs were present in 99.2% of the sample (lower CI 98.1%). However, careful visual assessment of the recorded waveforms for the remaining ears did not unequivocally show absence of TEOAE characteristics in any ear with normal HTLs. While TEOAE strength varies widely among ears, no clear evidence was found to show that TEOAEs can be absent when HTLs are normal.

Acoustic Stimulation↗
PubMed1996

Tumor necrosis factor-alpha and tumor necrosis factor receptors in the failing human heart.

BACKGROUND: Tumor necrosis factor-alpha (TNF-alpha) is a proinflammatory cytokine that produces negative inotropic effects in the heart. Recently, elevated levels of TNF-alpha have been reported in patients with advanced congestive heart failure. Although TNF-alpha is thought to exert its deleterious effects by binding to two cell surface receptors, TNFR1 and TNFR2, the level of expression and regulation of TNF receptors in the heart in cardiac disease states is not known. METHODS AND RESULTS: We examined mRNA and protein levels for TNFR1, TNFR2, and TNF-alpha in explanted hearts from organ donors as well as in patients with end-stage dilated cardiomyopathy (DCM) and ischemic heart disease (IHD). Northern blot analysis revealed that mRNA for TNFR1 and TNFR2 was present in nonfailing, DCM, and IHD hearts. TNFR1 and TNFR2 receptor protein levels, as measured by ELISA, were decreased 60% in DCM and IHD patients compared with nonfailing hearts (P < .005). To determine a potential mechanism for the decrease in TNF receptor expression, we measured levels of circulating soluble TNF receptors (sTNFRs) in DCM and IHD patients. This analysis showed that there was a significant one-and-a-half to threefold increase in sTNFRs in DCM (P < .03) and IHD patients (P < .001). Another important finding was that TNF-alpha mRNA and TNF-alpha protein were present in the explanted hearts from DCM and IHD patients but not in nonfailing hearts. CONCLUSIONS: In summary, the results of this study constitute the initial demonstration that TNF receptor proteins are dynamically regulated in patients with advanced congestive heart failure. Moreover, the observation that failing hearts express elevated levels of TNF-alpha suggests that overexpression of this cytokine may be one of several different maladaptive mechanisms responsible for the progressive cardiac decompensation that occurs in advanced heart failure.

Adult↗
PubMed1996

Proinflammatory cytokine levels in patients with depressed left ventricular ejection fraction: a report from the Studies of Left Ventricular Dysfunction (SOLVD).

OBJECTIVES: This study sought to assess proinflammatory cytokine levels in patients in the studies of left ventricular dysfunction trial (SOLVD) in relation to both their New York Heart Association functional classification and their neurohormonal status before randomization. BACKGROUND: Elevated levels of tumor necrosis factor-alpha have been identified in 30% to 40% of patients with heart failure. However, it is unclear which subsets of patients with heart failure elaborate tumor necrosis factor-alpha. It is also unclear what the mechanism for the increased expression of proinflammatory cytokines is. METHODS: Tumor necrosis factor-alpha and interleukin-6 levels were analyzed by enzymes-linked immunoassay using randomly selected plasma samples from patients in functional classes I to III who were enrolled in neurohormonal substudies of the SOLVD trial; age-matched healthy subjects served as the control group. RESULTS: Plasma levels of tumor necrosis factor-alpha (p < 0.001) were elevated in patients in functional classes I to III ([mean +/- SD] 1.95 +/- 0.54, 2.63 +/- 0.48, 6.4 +/- 1.9 pg/ml, respectively) compared with age-matched control subjects (0.75 +/- 0.05 pg/ml) and were progressively elevated in relation to decreasing functional status of the patient. Plasma levels of interleukin-6 (p < 0.001) were elevated in patients in functional classes I to III (3.3 +/- 0.55, 6.2 +/- 1.1, 5.22 +/- 0.9 pg/ml, respectively) compared with age-matched control subjects (1.8 +/- 0.5 pg/ml and were progressively elevated in relation to decreasing functional status of the patient. Cox proportional-hazards analysis showed that there was a trend toward significance between plasma tumor necrosis factor-alpha (p < 0.07) and survival, whereas there was no significant relation for plasma interleukin-6 (p < 0.72). Except for atrial natriuretic factor, which correlated weakly (r = 0.23, p = 0.04) with circulating tumor necrosis factor-alpha levels, there was no significance correlation between neurohormonal and proinflammatory cytokine levels. CONCLUSIONS: Circulating levels of proinflammatory cytokines increase in patients as their functional heart failure classification deteriorates. Moreover, activation of the neurohumoral axis is unlikely to completely explain the elaboration of proinflammatory cytokines in heart failure.

Aged↗
PubMed1995

Expression and functional significance of tumor necrosis factor receptors in human myocardium.

BACKGROUND: Tumor necrosis factor-alpha (TNF-alpha), a proinflammatory cytokine with potent negative inotropic properties, is elaborated in septic shock, acute myocarditis, reperfusion injury, and congestive heart failure. TNF-alpha acts by binding to two specific receptors: TNFR1 and TNFR2. However, neither the presence nor the significance of TNF receptors has been studied in the adult mammalian heart. METHODS AND RESULTS: In the present study, we showed that the adult heart expresses mRNA and receptor proteins for TNFR1 and TNFR2. Moreover, immunohistochemical staining studies localized TNFR1 and TNFR2 to the cardiac myocyte, providing a potential signaling pathway for the deleterious effects of TNF-alpha. The functional significance of the expression of TNFR1 and TNFR2 was explored with the use of a simple cell motion assay in which we assessed the effect(s) of TNF-alpha mutants known to bind selectively to human TNFR1 and TNFR2. We showed that the negative inotropic effect of wild-type TNF-alpha in isolated feline cardiac myocytes was mimicked by the TNF mutant that binds to TNFR1, whereas the TNF mutant that binds to TNFR2 had no significant effect on cell motion. CONCLUSIONS: Results of the present study show that the adult human heart expresses both mRNA and receptor proteins for TNFR1 and TNFR2; moreover, the negative inotropic effects of TNF-alpha in adult cardiac myocytes appear to be initiated by activation of TNFR1.

Adolescent↗