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Biomedical subjects

R Madhavan

Publications and source records attributed to R Madhavan.

At least 19 recordsLinked to original sources
PubMed2001

Exercise testing with gas exchange analysis.

The value of ventilatory gas exchange techniques during exercise testing, including improved precision and a greater yield of clinically useful information, is underscored by a growing body of literature. With technological advances available in the current metabolic systems, the test can be performed with minimal inconvenience to the patient and a minimal time commitment on the part of the operator. Gas exchange techniques have many applications among patients with cardiovascular and pulmonary disease, including the assessment of therapeutic interventions, a better understanding of the pathophysiology of exercise intolerance, and evaluation of disability. Recent studies suggest that the added precision provided by this technology has important prognostic utility. A cardiopulmonary exercise test can supplement other clinical and exercise test information when precision is important, when the patient's symptoms are mixed, or when it is unclear why the patient was referred for testing.

Coronary Disease↗
PubMed2001

Validation of a specific activity questionnaire to estimate exercise tolerance in patients referred for exercise testing.

BACKGROUND: Physical activity and symptom questionnaires have been used as surrogates for exercise testing to estimate a patient's functional capacity and to individualize an exercise testing protocol in accordance with exercise testing guidelines. To validate these approaches, they must be compared with measured oxygen uptake (peak VO (2)). METHODS: Before exercise testing was performed, a brief, self-administered questionnaire (Veterans Specific Activity Questionnaire [VSAQ]) was given to 337 patients referred for exercise testing for clinical reasons. The VSAQ was used to estimate exercise tolerance on the basis of symptoms during daily activities to individualize ramp rates on the treadmill so that the test duration would be approximately 10 minutes. Clinical and demographic variables were added to the VSAQ responses in a stepwise regression model to determine their ability to predict both directly measured peak VO (2) and peak metabolic equivalents (METs) predicted from the treadmill workload. RESULTS: The mean exercise time was 9.6 +/- 3 minutes. Responses to the VSAQ and age were the strongest predictors of both measured and predicted exercise capacity. Small but significant contributions to the explanation of variance in both measured and estimated METs were made by resting heart rate, forced expiratory volume in 1 second expressed as a percentage of normal, exercise capacity predicted for age, and body mass index. The multiple R values from the regression equations for measured and estimated METs were 0.58 and 0.72, respectively. CONCLUSIONS: Estimating a patient's symptoms associated with daily activities along with age are the strongest predictors of a patient's exercise tolerance. The VSAQ, combined with pretest clinical data, predicts the estimated MET value from treadmill speed and grade better than directly measured METs do. When used for estimating a patient's symptom limits to individualize ramp rates on a treadmill, this approach yields an appropriate test duration in accordance with recent exercise testing guidelines.

Activities of Daily Living↗
PubMed2001

Late onset rheumatoid arthritis--a clinical and laboratory study.

AIM: To analyze the clinical and laboratory profile of late onset rheumatoid arthritis in comparison with early onset rheumatoid arthritis. METHODS: Fifty patients who satisfied 1988 American College of Rheumatology criteria for rheumatoid arthritis with the disease onset at 60 years or over were studied. Handred cases of early onset rheumatoid arthritis were taken as controls. All of them were followed up for 18 months. RESULTS: Female to male ratio was 1.6:1 in late onset rheumatoid arthritis and 4:1 in early onset group. Shoulder joint involvement was 48% in late onset and 28% in early onset rheumatoid arthritis. Rheumatoid factors was positive in 36% cases in late onset compared to 60% in controls. Most other clinical, laboratory and radiological features were comparable in both the groups. CONCLUSIONS: Late onset rheumatoid arthritis is characterised by a less female preponderance, more shoulder joint involvement and more seronegativity.

Age of Onset↗
PubMed1999

Phosphorylation of dystrophin and alpha-syntrophin by Ca(2+)-calmodulin dependent protein kinase II.

A Ca(2+)-calmodulin dependent protein kinase activity (DGC-PK) was previously shown to associate with skeletal muscle dystrophin glycoprotein complex (DGC) preparations, and phosphorylate dystrophin and a protein with the same electrophoretic mobility as alpha-syntrophin (R. Madhavan, H.W. Jarrett, Biochemistry 33 (1994) 5797-5804). Here, we show that DGC-PK and Ca(2+)-calmodulin dependent protein kinase II (CaM kinase II) phosphorylate a common site (RSDS(3616)) within the dystrophin C terminal domain that fits the consensus CaM kinase II phosphorylation motif (R/KXXS/T). Furthermore, both kinase activities phosphorylate exactly the same three fusion proteins (dystrophin fusions DysS7 and DysS9, and the syntrophin fusion) out of a panel of eight fusion proteins (representing nearly 100% of syntrophin and 80% of dystrophin protein sequences), demonstrating that DGC-PK and CaM kinase II have the same substrate specificity. Complementing these results, anti-CaM kinase II antibodies specifically stained purified DGC immobilized on nitrocellulose membranes. Renaturation of electrophoretically resolved DGC proteins revealed a single protein kinase band (M(r) approximately 60,000) that, like CaM kinase II, underwent Ca(2+)-calmodulin dependent autophosphorylation. Based on these observations, we conclude DGC-PK represents a dystrophin-/syntrophin-phosphorylating skeletal muscle isoform of CaM kinase II. We also show that phosphorylation of the dystrophin C terminal domain sequences inhibits their syntrophin binding in vitro, suggesting a regulatory role for phosphorylation.

Adenosine Triphosphate↗
PubMed1998

Yotiao, a novel protein of neuromuscular junction and brain that interacts with specific splice variants of NMDA receptor subunit NR1.

The molecular machinery underlying neurotransmitter receptor immobilization at postsynaptic sites is poorly understood. The NMDA receptor subunit NR1 can form clusters in heterologous cells via a mechanism dependent on the alternatively spliced C1 exon cassette in its intracellular C-terminal tail, suggesting a functional interaction between NR1 and the cytoskeleton. The yeast two-hybrid screen was used here to identify yotiao, a novel coiled coil protein that interacts with NR1 in a C1 exon-dependent manner. Yotiao mRNA (11 kb) is present modestly in brain and abundantly in skeletal muscle and pancreas. On Western blots, yotiao appears as an approximately 230 kDa band that is present in cerebral cortex, hippocampus, and cerebellum. Biochemical studies reveal that yotiao fractionates with cytoskeleton-associated proteins and with the postsynaptic density. With regard to immunohistochemistry, two anti-yotiao antibodies display a somatodendritic staining pattern similar to each other and to the staining pattern of NR1. Yotiao was colocalized by double-label immunocytochemistry with NR1 in rat brain and could be coimmunoprecipitated with NR1 from heterologous cells. Thus yotiao is an NR1-binding protein potentially involved in cytoskeletal attachment of NMDA receptors. Consistent with a general involvement in postsynaptic structure, yotiao was also found to be specifically concentrated at the neuromuscular junction in skeletal muscle.

A Kinase Anchor Proteins↗
PubMed1998

Interaction of muscle and brain sodium channels with multiple members of the syntrophin family of dystrophin-associated proteins.

Syntrophins are cytoplasmic peripheral membrane proteins of the dystrophin-associated protein complex (DAPC). Three syntrophin isoforms, alpha1, beta1, and beta2, are encoded by distinct genes. Each contains two pleckstrin homology (PH) domains, a syntrophin-unique (SU) domain, and a PDZ domain. The name PDZ comes from the first three proteins found to contain repeats of this domain (PSD-95, Drosophila discs large protein, and the zona occludens protein 1). PDZ domains in other proteins bind to the C termini of ion channels and neurotransmitter receptors containing the consensus sequence (S/T)XV-COOH and mediate the clustering or synaptic localization of these proteins. Two voltage-gated sodium channels (NaChs), SkM1 and SkM2, of skeletal and cardiac muscle, respectively, have this consensus sequence. Because NaChs are sarcolemmal components like syntrophins, we have investigated possible interactions between these proteins. NaChs copurify with syntrophin and dystrophin from extracts of skeletal and cardiac muscle. Peptides corresponding to the C-terminal 10 amino acids of SkM1 and SkM2 are sufficient to bind detergent-solubilized muscle syntrophins, to inhibit the binding of native NaChs to syntrophin PDZ domain fusion proteins, and to bind specifically to PDZ domains from alpha1-, beta1-, and beta2-syntrophin. These peptides also inhibit binding of the syntrophin PDZ domain to the PDZ domain of neuronal nitric oxide synthase, an interaction that is not mediated by C-terminal sequences. Brain NaChs, which lack the (S/T)XV consensus sequence, also copurify with syntrophin and dystrophin, an interaction that does not appear to be mediated by the PDZ domain of syntrophin. Collectively, our data suggest that syntrophins link NaChs to the actin cytoskeleton and the extracellular matrix via dystrophin and the DAPC.

Amino Acid Sequence↗
PubMed1995

Interactions between dystrophin glycoprotein complex proteins.

The organization of the dystrophin glycoprotein complex (DGC) was studied by investigating interactions between its components. For this purpose, mouse dystrophin and syntrophin-1 (alpha-syntrophin) sequences were expressed as chimeric fusion proteins and used in overlay binding experiments to probe gel blots of purified rabbit muscle DGC. In order to identify the DGC proteins that bind to different regions of dystrophin, the amino-terminal 385 amino acids, the unique carboxy-terminal domain (amino acids 3266-3678), and the adjacent cysteine-rich region of dystrophin homologous to alpha-actinin (amino acids 3074-3265) were expressed as separate fusion proteins. The cysteine-rich sequences of dystrophin predominantly bound adhalin (gp50) and to full length dystrophin suggesting that these sequences may also be important to dystrophin dimerization. The carboxy-terminal domain sequences strongly bound all of the DGC syntrophins and weakly, adhalin, while the amino-terminal sequences of dystrophin bound none of the proteins of this complex. Fusion proteins containing alpha-syntrophin sequences bound not only to dystrophin but also to all three DGC syntrophins, adhalin, and gp35. The interactions identified here were used to refine the existing model of DGC organization to make it consistent with the current data.

Animals↗
PubMed1994

Calmodulin-activated phosphorylation of dystrophin.

Purified dystrophin glycoprotein complex (DGC) contains an endogenous protein kinase activity which phosphorylates dystrophin. Mg2+ (or Mn2+) and ATP are required for this phosphorylation. Ca(2+)-calmodulin increases the rate of phosphorylation of dystrophin 12-fold relative to the EGTA control, while other protein kinase activators, cAMP and cGMP, have no effect. Phosphorylation of other proteins in the DGC preparation was observed, with a 59-kDa protein also being phosphorylated in a calmodulin-dependent manner. These phosphorylations were all on serine residues. The DGC protein kinase activity also phosphorylates syntide-2, a peptide substrate for CaM kinase II, and antibodies raised against CaM kinase II cross-react with DGC blotted onto nitrocellulose. Further, purified, baculovirus-expressed CaM kinase II phosphorylates dystrophin and also phosphorylates at least one of the peptides of dystrophin which is phosphorylated by the DGC protein kinase activity, as shown by tryptic peptide maps. CaM kinase II also phosphorylates other proteins present in the DGC preparation that are phosphorylated by the endogenous protein kinase. Finally, dystrophin sequence 2618-3074, produced by recombinant techniques, is phosphorylated by both the DGC protein kinase and purified CaM kinase II. Since dystrophin and two other DGC components have also been shown to bind calmodulin, two important components of signal transduction--calmodulin binding and protein phosphorylation--operate in the DGC.

Animals↗
PubMed1992

Calmodulin specifically binds three proteins of the dystrophin-glycoprotein complex.

Dystrophin is the approximately 400,000 Da. protein (p400K) product of the Duchenne muscular dystrophy gene locus. In the sarcolemma membrane, it is associated with several other proteins, many of which are glycoproteins (abbreviated gp) and include gp156K, p59K, gp50K, gp43K, gp35K, and p25K. Here, we show that dystrophin, gp156K, and p59K are calmodulin-binding proteins, the binding is Ca(2+)-dependent, and of high-affinity similar to that seen with calmodulin-activated enzymes. Two putative calmodulin-binding sequences were identified, one at either end of the dystrophin sequence.

Animals↗
PubMed1992

Effect of bed time intermediate acting insulin in NIDDM subjects refractory to a combination of sulphonylureas and biguanides.

The effect of a single dose of intermediate acting (Lente) insulin given subcutaneously at 9.00 P.M. in 22 NIDDM subjects refractory to a combination of Sulphonylureas and Biguanides was analysed. Euglycemia was achieved and maintained during the study period of three months with a mean insulin requirement of 14.22 +/- 5.98 units/day. Plasma FFA, Total cholesterol, triglyceride and VLDL-cholesterol also showed significant reduction. The level of FFA modulates hepatic glucose production, which in turn correlates positively with the fasting blood glucose. The therapeutic modality of bed time Lente Insulin based on physiological principles is an effective way of achieving glycemic control in NIDDM subjects who have become non-responsive to oral hypoglycemic agents.

Biguanides↗
PubMed1992

Subcutaneous insulin pulse therapy.

Subcutaneous Insulin Pulse Therapy (SIPT) consists of administration of small doses of regular insulin hourly or two hourly in the subcutaneous tissue of anterior abdominal wall through a scalp vein needle. Fifteen Non-Insulin Dependent Diabetes Mellitus (NIDDM) subjects, 8 males and 7 females with mean ages 58 +/- 8.7 years and mean duration of diabetes 11.7 +/- 9.1 years and mean BMI 25.2 +/- 5.64 were admitted for elective surgery. Glycemic control was attempted preoperatively with multiple pre-meal doses of Actrapid MC with a single injection of Monotard MC at bed time. The mean fasting plasma glucose in the 15 subjects with this insulin regimen was 321.28 +/- 69.32 mgm% and the insulin requirement per day was 106.87 +/- 35.77 units. The subjects were put on SIPT for 48 to 72 hours. During SIPT the mean fasting plasma glucose dropped to 123.2 +/- 74.11 mgm% and this marked decline in fasting plasma glucose value was statistically significant (P < .05). The insulin requirement during SIPT was 96.42 +/- 31.36 units, similar to the previous regimen (NS). The subjects were switched back to conventional insulin therapy after SIPT during which period the mean fasting plasma glucose was 125.82 +/- 34.50 mgm% and this value was again significantly lower than the pre SIPT fasting plasma glucose value (P < .05). Insulin requirement during conventional insulin therapy after SIPT was reduced to 71 +/- 21.89 units/day. This dose was significantly lower than the insulin dose administered during SIPT (P < .05).(ABSTRACT TRUNCATED AT 250 WORDS)

Abdominal Muscles↗
PubMed1991

Calmodulin-binding proteins also have a calmodulin-like binding site within their structure. The flip-flop model.

The flip-flop model is a mechanistic model proposed to describe how calmodulin activates enzymes. One prediction based upon this model is that calmodulin-activated enzymes would contain a calmodulin-like binding site which, among other attributes, would bind the peptide melittin. Five purified calmodulin-activated enzymes, namely calcineurin, myosin light chain kinase, phosphorylase b kinase, phosphodiesterase, and NAD kinase, were all found to bind biotinylated melittin and to also bind an antimelittin antibody and biotinylated calmodulins. Using gel blots of crude tissue extracts (rat brain and Arabidopsis), most proteins did not bind any of the probes and thus do not have these characteristics. However, among those which bind any of these probes, a strong correlation was found between those proteins which bind biotinylated calmodulins and those which bind melittin and antimelittin. Gel blots of phosphorylase b kinase demonstrate that the alpha, beta, and gamma subunits all bind calmodulin and melittin. A putative calmodulin-like binding site sequence was identified in eight enzymes or subunits which may play an important role in both melittin binding and calmodulin-dependent regulation of these enzymes.

Amino Acid Sequence↗
PubMed1991

Progressive systemic sclerosis in south India.

Seventy eight patients with progressive systemic sclerosis (PSS) were seen over a period of 14 years. They were analysed after clinical, haematological, biochemical, immunological and radiological investigations for comparison with other Indian and Western studies. Nine of the 78 were cases of childhood PSS. There was a female preponderance (3.9:1) and the peak age of occurrence was the 4th decade (32.1%). Arthralgia (53.8%) and skin thickening (70.5%) were the common presenting symptoms. Raynaud's phenomenon (28.2%) was less common. Involvement of the skin was present in all the patients and skin biopsy was positive in 96% of the cases. Joints were affected in 66.7%; internal organs were involved in 52.6%. Antinuclear antibody was positive in 56.8%. Abnormal echocardiography (37.6%) and barium studies (20.4%) were seen. Restrictive airway pattern by pulmonary function test was present in 55%. Death occurred in 5 patients, of whom 3 died of severe pulmonary hypertension.

Adolescent↗
PubMed1990

Pattern of rheumatic diseases in south India. IV. Clinical profile of juvenile rheumatoid arthritis.

An analysis of 100 consecutive cases of juvenile rheumatoid arthritis from South India revealed a male preponderance (62%), a lower incidence of the systemic onset variety (10%) and equal incidence of systemic features when compared with the West. Knees and ankles were the joints commonly involved. The incidence of elevated erythrocyte sedimentation rate and C reactive protein, with haemoglobin levels below 10 g/dl was highest in the systemic onset variety. The polyarticular and systemic onset group responded well to aspirin, while the pauciarticular group responded well to indomethacin.

Arthritis, Juvenile↗
PubMed1990

Pattern of rheumatic diseases in south India. V. Ankylosing spondylitis. A clinical and radiological study.

One hundred and two patients from South India with primary ankylosing spondylitis (AS) were analysed clinically and radiologically. The mean age of onset was 26 years, with a male to female ratio of 16:1. Eleven patients presented as juvenile ankylosing spondylitis. The mode of presentation of AS included axial involvement in 59, peripheral arthritis in 38, heel pain in 18 and acute anterior uveitis (AAU) in 11. The overall incidence of extra axial features was high (90 patients). These included subjects with peripheral arthritis (49), heel pain (35), AAU (14), rib pain (11), aortic regurgitation (8), apical pulmonary fibrosis (5), mitral regurgitation (2) and conduction defects (2). Peripheral arthritis was characteristically asymmetrical and oligo articular, and involved lower limb joints. No renal involvement was noticed. Radiologically, bilateral sacroilitis was seen in 80% of cases.

Adolescent↗
PubMed1989

Fibrodysplasia (myositis) ossificans progressiva in Dominica.

Fibrodysplasia (myositis) ossificans progressiva is a rare but severely disabling disease in which ossification forms within muscle and leads to progressive restriction of the movements of the jaw, neck, shoulders and hips. Shortening of the big toes is usually present. It is important to recognise this disease as avoidance of intra-muscular injections, surgery and trauma reduces the risk of further ossification.

Adult↗
PubMedDate not supplied

Childhood systemic lupus erythematosus in south India.

Out of 330 adult Systemic Lupus Erythematosus (SLE) cases who attended the Rheumatic Care Centre, Government General Hospital, 59 children were analysed. There was no case with onset before the age of 5 years. There were 49 females and 110 males (M:F = 1:4.9). The initial manifestations were fever (67%), arthritis (61%), skin rash (59%) and lymphadenopathy (27.1%). There was no case of Raynaud's phenomenon. Only 10.1% of patients presented with thrombocytopenic purpura. In the cumulative clinical features, arthritis in 86.6%, fever in 79.8%, skin rash in 69.4%, lymphadenopathy in 61% and hepatosplenomegaly in 39.9% were observed. Renal involvement was seen in 49.1%, neuropsychiatric manifestations in 27.1%, pleuropulmonary in 22% and cardiac manifestations in 10.2%. Anaemia was seen in 50.8%, leukopenia in 18.4%, thrombocytopenia in 11.8%, ANA in 100%, anti-dsDNA in 92.3%, anti-Sm in 34.7%, anti-SSA in 38.5%, anti-SSB in 15.4%, ACL in 30.8%, low C3 in 50% and false positive VDRL in 3.3%. Death occurred in 8 children, 3 due to infection, 2 due to renal causes, 1 due to cardiac and 2 due to central nervous system involvement.

Adult↗