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Biomedical subjects

J Dhawan

Publications and source records attributed to J Dhawan.

At least 19 recordsLinked to original sources
PubMed2002

Does cardiologist- or radiographer-operated fluoroscopy and image acquisition influence optimization of patient radiation exposure during routine coronary angiography?

The operator of radiation exposure during coronary angiography varies between different centres. The purpose of this study was to explore whether radiation dose was lower during cardiologist- or radiographer-controlled radiation exposure and to determine if the grade of cardiologist performing angiography influenced radiation dose. Patients were randomly allocated either to cardiologist- or radiographer-controlled radiation exposure during coronary angiography. Screening time and radiation dose during fluoroscopy and image acquisition, measured by dose-area product meter, were recorded. Mean radiation dose during cardiologist-controlled radiation exposure (n=176) of 15.6 Gy cm(2) (95% confidence interval (CI), 14.4-16.8) was significantly lower than that produced by the radiographer-controlled group (n=192) of 17.3 Gy cm(2) (95% CI, 16.2-18.6) (p<0.044). There was no significant difference in screening times produced by the two groups of radiation exposure operators. The difference in radiation dose produced by the two operator groups was principally owing to exposure produced at image acquisition. Irrespective of radiation exposure operator, consultant cardiologists produced significantly lower screening times and radiation doses compared with registrars. During routine coronary angiography, radiographer-controlled radiation exposure does not reduce screening time or radiation dose. Senior cardiologists produce the lowest radiation doses during coronary angiography when they are responsible for radiation exposure.

Body Height↗
PubMed2001

What is the optimal medical management of ischaemic heart failure?

Ischaemic heart disease is probably the most important cause of heart failure. All patients with heart failure may benefit from treatment designed to retard progressive ventricular dysfunction and arrhythmias. Patients with heart failure due to ischaemic heart disease may also, theoretically, benefit from treatments designed to relieve ischaemia and prevent coronary occlusion and from revascularisation. However, there is little evidence to show that effective treatments, such as angiotensin converting enzyme (ACE) inhibitors and beta-blockers, exert different effects in patients with heart failure with or without coronary disease. Moreover, there is no evidence that treatment directed specifically at myocardial ischaemia, whether or not symptomatic, or coronary disease alters outcome in patients with heart failure. Some agents, such as aspirin, designed to reduce the risk of coronary occlusion appear ineffective or harmful in patients with heart failure. There is no evidence, yet, that revascularisation improves prognosis in patients with heart failure, even in patients who are demonstrated to have extensive myocardial hibernation. On current evidence, revascularisation should be reserved for the relief of angina. Large-scale, randomised controlled trials are currently underway investigating the role of specific treatments targeted at coronary syndromes in patients who have heart failure. The CHRISTMAS study is investigating the effects of carvedilol in a large cohort of patients with and without hibernating myocardium. The WATCH study is comparing the efficacy of aspirin, clopidogrel and warfarin. The HEART-UK study is assessing the effect of revascularisation on mortality in patients with heart failure and myocardial hibernation. Smaller scale studies are currently assessing the safety and efficacy of statin therapy in patients with heart failure. Only when the results of these and other studies are known will it be possible to come to firm conclusions about whether patients with heart failure and coronary disease should be treated differently from other patients with heart failure due to left ventricular systolic dysfunction.

Adrenergic beta-Antagonists↗
PubMed2001

New-onset palpitations in general practice: assessing the discriminant value of items within the clinical history.

BACKGROUND: Palpitations are non-specific, with less than half of patients experiencing palpitations having a cardiac arrhythmia. Currently it seems that there is little evidence available to assist GPs in discriminating between patients complaining of palpitations who have significant cardiac arrhythmias and those who do not. OBJECTIVES: Our aim was to estimate discriminant functions for specific items of clinical information in relation to the categorization of a patient (aged over 18 years) with a symptom of new-onset palpitations presenting to primary care. METHODS: A network of 62 GPs spread amongst 36 practices agreed to recruit patients with new-onset palpitations over the course of a 9-month study period. Patients consenting to be involved in the study were asked a number of questions, focusing particularly on the medical history, and were requested to complete a Hospital Anxiety and Depression Scale. Each patient was also provided with a RhythmCard cardiac event recorder for up to 2 weeks and was asked to record their heart rhythm if they experienced palpitations. Odds ratios (adjusted for age and sex) were used to compare the clinical information obtained from patients with the final diagnosis. RESULTS: Of the 139 patients with palpitations presenting to GPs, it would appear that males [odds ratio = 2.1 (1.0-4.5)], those with regular palpitations [odds ratio = 2.5 (1.0-5.8)], those experiencing palpitations at work [odds ratio = 3.0 (1.3-7.2)] and those experiencing palpitations affected by sleeping (odds ratio = 3.3 (1.4-7.7)] were more likely to have a cardiac cause for their palpitations. Similar findings were made in an analysis focusing solely on the 81 patients with a RhythmCard result. Furthermore, amongst this group, it is interesting to note that patients with regular palpitations were more than twice as likely to have a 'significant' cardiac arrhythmia as a cause for their palpitations. There were suggestions of dose-response effects between the rate of the palpitation, the duration of the palpitation and the likelihood of it being a 'significant' arrhythmia. CONCLUSIONS: This study provides some information on the characteristics of patients reporting palpitations to GPs who may have 'significant' cardiac arrhythmias. Based on this work, we believe that a larger community-based study would be worthwhile and would provide useful and useable clinical discriminant information for GPs in the settings where they work and amongst the types of patients they encounter.

Adult↗
PubMed2001

Distinct changes in intranuclear lamin A/C organization during myoblast differentiation.

Intranuclear lamin foci or speckles have been observed in various cell types. In order to explore the possibility of changes in internal lamin organization during muscle differentiation, we have examined the appearance of A-type lamin speckles that associate with RNA splicing factor speckles in C2C12 myoblasts and myotubes. Lamin speckles were observed in dividing myoblasts but disappeared early during the course of differentiation in postmitotic myocytes, and were absent in myotubes and muscle fibers. However, no changes were seen in the typical peripheral organization of lamins A/C or B1 or in RNA splicing factor speckles. Lamin speckles were also absent in quiescent myoblasts but reappeared as cells were reactivated to enter the cell cycle. These changes were not observed in other quiescent cell types. Immunoblot analysis indicated that the abundance and migration of lamins A and C was not altered in differentiated myoblasts. When myotube or quiescent myoblast nuclei were extracted with nucleases and detergent, a uniformly stained internal lamina was revealed, indicating that lamins A/C were antigenically masked in these cells, probably owing to structural reorganization of the lamina during differentiation or quiescence. Our results suggest that muscle cell differentiation is accompanied by regulated rearrangements in the organization of the A-type lamins.

Animals↗
PubMed1998

Evidence of oxidative stress in mdx mouse muscle: studies of the pre-necrotic state.

Considerable evidence indicates that free radical injury may underlie the pathologic changes in muscular dystrophies from mammalian and avian species. We have investigated the role of oxidative injury in muscle necrosis in mice with a muscular dystrophy due to a defect in the dystrophin gene (the mdx strain). In order to avoid secondary consequences of muscle necrosis, all experiments were done on muscle prior to the onset of the degenerative process (i.e. during the 'pre-necrotic' phase) which lasted up to 20 days of age in the muscles examined. In pre-necrotic mdx muscle, there was an induction of expression of genes encoding antioxidant enzymes, indicative of a cellular response to oxidative stress. In addition, the levels of lipid peroxidation were greater in mdx muscle than in the control. Since the free radical nitric oxide (NO*) has been shown to mediate oxidative injury in various disease states, and because dystrophin has been shown to form a complex with the enzyme nitric oxide synthase, we examined pre-necrotic mdx muscle for evidence of NO*-mediated injury by measuring cellular nitrotyrosine formation. By both immunohistochemical and electrochemical analyses, no evidence of increased nitrotyrosine levels in mdx muscle was detected. Therefore, although no relationship with NO*-mediated toxicity was found, we found evidence of increased oxidative stress preceding the onset of muscle cell death in dystrophin-deficient mice. These results lend support to the hypothesis that free radical-mediated injury may contribute to the pathogenesis of muscular dystrophies.

Animals↗
PubMed1997

Asian Indians, coronary artery disease, and physical exercise.

OBJECTIVE: To evaluate the relation of physical activity to different clinical and biochemical risk factors for coronary artery disease among people from different ethnic groups with angiographically proven coronary artery disease. SUBJECTS: British Asians, Indian Asians, and white people suffering from coronary artery disease, and their respective controls. INTERVENTIONS: History, physical examination, coronary angiography (at baseline), laboratory investigations. MAIN OUTCOME MEASURES: Relation of physical activity level to serum insulin, glucose, cholesterol, triglycerides, and high density lipoproteins, systolic and diastolic blood pressures, and body mass index in patients and controls. RESULTS: 391 male patients were studied, of whom 260 (66.5%) were classified as sedentary. Mean serum insulin at 0, 1, and 2 hours after 75 g oral glucose was higher among the sedentary population (17.1 v 11.6, 88.2 v 62.1, and 57.9 v 36.2 microU/ml, respectively (all p < 0.0001). Mean body mass index was also higher among the sedentary population (25.53 v 23.95, p < 0.0001), as were mean serum triglycerides (1.85 v 1.60 mmol/l, p < 0.01) and systolic and diastolic blood pressures (133.9 v 129.4, p < 0.05, and 81.1 v 79.0, p < 0.01). There was no difference in the mean serum cholesterol and high density lipoprotein between the two groups. British Asians were the most sedentary and Indian Asians the most physically active. CONCLUSIONS: There are marked differences in the level of physical activity among the various ethnic groups in the United Kingdom. In each ethnic group, physical activity reduced mean serum insulin, body mass index, and serum triglycerides and had a favourable effect on systolic and diastolic blood pressures. Promotion of physical activity could be of value for the Asian community in the United Kingdom.

Apolipoproteins↗
PubMed1996

Myoblast-mediated expression of colony stimulating factor-1 (CSF-1) in the cytokine-deficient op/op mouse.

The osteopetrotic (op/op) mouse lacks colony stimulating factor-1 (CSF-1) due to an inactivating mutation in the CSF-1 gene. Intramuscular transplantation of engineered myoblasts was used to introduce CSF-1 into the circulation of op/op mice. The CSF-1 cDNA was introduced into C2C12 mouse myoblasts in culture using retroviral mediated gene transfer. Upon transplantation into the skeletal muscle of mutant mice, physiological levels of the cytokine were achieved systemically and elicited a biological response: circulating monocytes were induced. Howvever, both circulating CSF-1 levels and the induction of monocytes were transient. Analysis of the site of cell transplantation revealed local changes that may account for the transience of serum cytokine levels. Macrophage markers were induced in muscle tissue implanted with CSF-1 expressing myoblasts: c-fms, the CSF-1 receptor as well as the lineage-restricted antigen F4/80. We propose that in addition to CSF-1 clearance by Kupffer cells of the liver, macrophages that accumulated at the site of cell transplantation bound the CSF-1 produced by the muscle cell transplants, precluding the sustained release of this cytokine into the systemic circulation. Our studies also revealed that damage to muscle caused during cell transplantation or by freeze injury resulted in the accumulation of macrophages in op/op mouse muscle tissue. Indeed, op/op mice were fully capable of regenerating injured muscle suggesting the presence of as yet unidentified CSF-1-independent factors capable of generating macrophages that presumably participate in tissue remodeling in this cytokine-deficient mouse.

Animals↗
PubMed1996

Anchorage-dependent control of muscle-specific gene expression in C2C12 mouse myoblasts.

Our previous studies have demonstrated that expression of growth-associated genes is regulated by the adhesive state of the cell. To understand the role of cell adhesion in regulating the switch from growth to differentiation, we are studying the differentiation of mouse myoblasts into multinucleated contractile myotubes. In this report, we describe a novel means of culturing C2C12 myoblasts that permits an analysis of the role of cell adhesion in regulating the sequential induction of muscle-specific genes that control myogenesis. Suspension of an asynchronous, proliferating population of myoblasts in a viscous gel of methylcellulose dissolved in medium containing 20% serum induces growth arrest in G0 phase of the cell cycle without a concomitant induction of muscle-specific genes. Reattachment to a solid substratum in 20% serum, 0.5 nM bFGF, or 10 nM IGF-1 rapidly activates entry of the quiescent cells into G1 followed by a synchronous progression of the cell population through into S phase. bFGF or IGF-1 added separately facilitate only one passage through the cell cycle, whereas 20% serum or the two growth factors added together support multiple cell divisions. Adhesion of suspended cells in DMEM alone or with 3 nM IGF-1 induces myogenesis as evidenced by the synthesis of myogenin and myosin heavy chain (MHC) proteins followed by fusion into myotubes. bFGF completely inhibits this differentiation process even in the presence of myogenic doses of IGF-1. Addition of 3 nM IGF-1 to quiescent myoblasts maintained in suspension culture in serum-free conditions does not induce myogenin or MHC expression. Thus, adhesion is a requirement for the induction of muscle gene expression in mouse myoblasts. The development of a muscle cell culture environment in which proliferating myoblasts can be growth arrested in G0 without activating muscle-specific gene expression provides a means of analyzing the synchronous activation of either the myogenic or growth programs and how adhesion affects each process, respectively.

Animals↗
PubMed1996

Coronary heart disease risks in Asian Indians.

An increased prevalence of coronary heart disease in Asian Indian both from the native country and the immigrant population has been known for some time. With around 15,000,000 Asian Indians living outside India including 1,500,000 in the UK and 1,000,000 in the US, various pathogenic factors have attracted great interest in the recent past. Prevention strategies have been recommended based on these findings. Insulin resistance, central obesity and lipid abnormalities such as high triglyceride levels, low HDL levels and high lipoprotein(a) levels have been documented. This predisposition to accelerated atherosclerosis is genetically determined but is being enhanced by change in lifestyle, or 'westernization'. An increased prevalence of coronary heart disease because of these changes in lifestyle is seen in India itself, where differences are found between urban and rural populations. This tendency seems to be noticed early in life, and hence the need for early prevention strategies are discussed.

Adult↗
PubMed1995

Tetracycline-regulated gene expression following direct gene transfer into mouse skeletal muscle.

For most experimental and therapeutic applications of gene transfer, regulation of the timing and level of gene expression is preferable to constitutive gene expression. Among the systems that have been developed for pharmacologically controlled gene expression in mammalian cells, the bacterial tetracycline (tet)-responsive system has the advantage that it is dependent on a drug (tet) that is both highly specific and non-toxic. The tet-responsive system has been previously used to modulate expression of cell cycle regulatory proteins in cultured cells, reporter genes in plants and transgenic mice and reporter genes directly injected into the heart. Here we show that orally or parenterally administered tet regulates expression of tet-responsive plasmids injected directly into mouse skeletal muscle. Reporter gene expression was suppressed by two orders of magnitude in the presence of tet, and that suppression was reversed when tet was withdrawn. These data show that skeletal muscle offers an accessible and well characterized target tissue for tet-controlled expression of genes in vivo, suggesting applications to developmental studies and gene therapy.

Animals↗
PubMed1995

Are Asian coronary arteries smaller than Caucasian? A study on angiographic coronary artery size estimation during life.

Asian immigrants to the UK have a higher mortality from coronary artery disease (CAD) than native Caucasians. There is a clinical impression that Asians have smaller coronary arteries than Caucasians. In the present study, consecutive series of 72 male Caucasian and 70 male Asian patients undergoing diagnostic coronary angiography were recruited. Measurements of proximal disease-free segments of the three major coronary arteries were made using the catheter tip as the calibrating object. Electronic callipers were used for all measurements. Total coronary artery diameter was derived by adding the diameters of right, left anterior descending and circumflex arteries. Asians had significantly smaller total vessel diameter compared to Caucasians. They also had smaller body surface areas. This observation has important therapeutic implications regarding coronary intervention in this ethnic group already suffering excess mortality from CAD.

Anthropometry↗
PubMed1994

Relationship between angiographically assessed coronary artery disease, plasma insulin levels and lipids in Asians and Caucasians.

In the present study the association between angiographically demonstrated coronary artery disease lipid subfractions and insulin in Caucasians, Asian migrants to the UK and Asians in India was studied. Patients having at least one angiographic lesion of more than 50% were recruited and angiograms scored by two independent observers, blindly. There were 87 Caucasian, 83 British Asian and 30 Indian Asian patients. Lipid subfractions measured were cholesterol, HDL cholesterol, triglyceride, apo A1, apo B, Lp(a). Estimation of glucose and insulin was carried out at fasting and after two hours of oral 75 g glucose. Asians were younger than Caucasians. They did not differ in their body mass index, systolic and diastolic blood pressure or cigarette consumption. In all three ethnic groups cholesterol, LDL cholesterol and apo B showed significant positive association. Insulin levels at fasting or post glucose challenge failed to show any association. Apo B may be an additional marker for coronary artery disease in the ethnic groups studied.

Adult↗
PubMed1994

Insulin resistance, high prevalence of diabetes, and cardiovascular risk in immigrant Asians. Genetic or environmental effect?

OBJECTIVES: To compare the prevalence of diabetes, hyperinsulinaemia, and associated metabolic abnormalities in immigrant Asians, Asians in India, and native white British men. DESIGN: Case control study. SETTING: Wythenshawe Hospital, Manchester, United Kingdom, and Maulana Azad Medical School, New Delhi, India. SUBJECTS: Men with angiographically proved coronary artery disease; 83 British Asians, 87 white men, and 30 Indian Asians with age matched controls. INTERVENTIONS: Fasting lipid concentrations, serum glucose, and total insulin concentrations were measured in the fasting state and one and two hours after a 75 g glucose load by mouth. All subjects had a physical examination by the same observer. RESULTS: Asians in the United Kingdom and in India had a higher prevalence of diabetes and impaired glucose tolerance than the white British men. Patients in all three ethnic groups had higher total insulin concentrations than their controls in the fasting state and after the glucose load. British Asian and Indian Asian patients and controls had higher total insulin concentrations than the white men in the fasting state and after the glucose load. Total insulin concentrations were similar in British and Indian Asians, though fasting concentrations were higher in British Asians than Indian Asians. White men had similar cholesterol, lower triglyceride, and higher high density lipoprotein cholesterol concentrations than Asians in the United Kingdom and in India. British Asian patients had higher cholesterol concentrations and British Asian controls had higher triglyceride concentrations than the Indian Asian groups. Asian patients and controls were more active. British and Indian Asian patients had higher waist to hip ratios than controls. The waist to hip ratio was positively correlated with insulin and triglyceride concentrations and negatively correlated with the high density lipoprotein cholesterol concentration. Fasting insulin and high density lipoprotein concentrations were independent predictors of coronary artery disease in white men, whereas in British Asians the waist to hip ratio was the strongest independent predictor. In Indian Asians the waist to hip ratio and high density lipoprotein concentration were independent predictors of coronary artery disease. CONCLUSIONS: Central obesity in the subgroups of Asians studied showed a close association with hyperinsulinaemia and the risk of coronary artery disease. A predisposition to insulin resistance and its metabolic abnormalities in this group of Asians seems to be genetically determined, environmental changes after migration having only a small additional effect.

Asia↗
PubMed1994

Angiographic comparison of coronary artery disease between Asians and Caucasians.

Asians in the United Kingdom surpass the already high mortality from coronary artery disease seen in Caucasians. In the present study, the angiographic features of consecutive series of 87 Caucasians, 83 British Asian and 30 Asian patients in India with coronary artery disease were assessed. Blood samples at fasting and after ingestion of 75 g of dextrose were taken to assess the extent of diabetes. Fasting blood samples were also taken for measurement of cholesterol, high-density lipoprotein cholesterol and triglyceride. Coronary angiograms were scored by two independent observers who were blinded to the patients' ethnic origin. The Asians were younger than the Caucasians, but did not differ in their body mass index, systolic or diastolic blood pressure or in cigarette consumption. Lipids were similar apart from Indian Asians having lower cholesterol than British Asians, and Caucasians having lower triglyceride than Asians. There were more diabetics in Asians than in Caucasians. Asians in Britain wait longer than Caucasians and Asians in India from onset of angina to undergoing coronary angiography. The presence of triple vessel disease was not significantly different (P = 0.19) in the three groups, that is, 38%, 43% and 27% in Caucasians, British Asians and Indian Asians, respectively. The geometric mean coronary score was 26.3 (C.I. 22.6-30.6), 25.3 (C.I. 21.8-29.4), and 25.2 (C.I. 19.6-32.5) in Caucasians, British Asians and Indian Asians, respectively. This difference was not significant (P = 0.92). Total number of lesions more than three were similar, that is, in 25% Caucasian, 41% British Asian and 40% Indian Asian patients (P < 0.10). British Asians had less proximal disease (P = 0.0002), and Indian Asians less distal disease (P = 0.003) compared to Caucasians. Non-discrete (long) lesions were more prevalent in Asians than Caucasians (P = 0.0005) The total number of lesions more than three in diabetic Asians was significantly more than in the non-diabetic, 71% versus 31% in British Asians (P = 0.002) and 90% versus 15% in Indian Asians (P= 0.0001). The relationship between diabetes and long lesions in both British and Indian Asians was highly significant (P < 0.00001 and P < 0.001, respectively). Thus severity and extent of coronary disease is no different in Asians as compared to Caucasians. Diabetes is perhaps responsible for the more diffuse disease seen in Asians.

Asia↗
PubMed1993

Myoblasts in pattern formation and gene therapy.

The tissues of a multicellular animal are composed of diverse cell types arranged in a precisely organized pattern. Features unique to muscle allow an analysis of pattern formation and maintenance in mammals. The progeny of single cells can be taken full cycle from the animal to the culture dish and back to the animal where they fuse into mature myofibers of the host. These features not only facilitate the use of genetically engineered myoblasts in studies of pattern formation, but also in cell-mediated gene therapy: a novel mode of drug delivery for the treatment of muscle and nonmuscle diseases such as hemophilia, cardiac disease and cancer.

Animals↗
PubMed1991

Systemic delivery of human growth hormone by injection of genetically engineered myoblasts.

A recombinant gene encoding human growth hormone (hGH) was stably introduced into cultured myoblasts with a retroviral vector. After injection of genetically engineered myoblasts into mouse muscle, hGH could be detected in serum for 3 months. The fate of injected myoblasts was assessed by coinfecting the cells with two retroviral vectors, one encoding hGH and the other encoding beta-galactosidase from Escherichia coli. These results provide evidence that myoblasts, which can fuse into preexisting multinucleated myofibers that are vascularized and innervated, may be advantageous as vehicles for systemic delivery of recombinant proteins.

Animals↗
PubMed1991

Cell adhesion regulates pro-alpha 1(I) collagen mRNA stability and transcription in mouse fibroblasts.

Adhesive interactions are important modulators of cellular phenotype. Previously, we demonstrated that quiescent, suspension-arrested cells are not equivalent to density-arrested cells in their patterns of gene expression (Dhawan, J., and Farmer, S.R. (1990) J. Biol. Chem. 265, 9015-9021). In particular, pro-alpha 1(I) collagen expression depended strongly on the extent of cell adhesion. In this paper, we demonstrate that the adhesion-induced rise in collagen gene expression is due to regulation at multiple levels. Steady state levels of pro-alpha 1(I) collagen mRNA increased up to 10-fold by 6 h after replating suspended cells, and this rise is blocked by inhibition of protein synthesis. Transcription of the pro-alpha 1(I) collagen gene was measured by run-on assay as well as by activation of a rat alpha 1(I) promoter-chloramphenicol acetyltransferase reporter gene construct. Both assays reveal a 5-fold depression of pro-alpha 1(I) collagen gene transcription in suspended cells. Reattachment of suspended cells resulted in the activation of alpha 1(I) gene transcription by 2-h postreplating, reaching a 3-5-fold level of induction by 18 h. The pro-alpha 1(I) collagen mRNA was substantially more labile in suspended cells than in adherent cells (t1/2 values of approximately 2 h in nonadherent cells and greater than 8 h in exponentially growing or density-arrested cells). Furthermore, reattachment of suspended cells for 18 h resulted in a stabilization of collagen mRNA. We conclude that cell adhesion regulates pro-alpha 1(I) collagen gene expression selectively and at transcriptional and posttranscriptional sites.

Animals↗