Browse Health
Neurologist (brain, nervous system)
26 years of experience
Accepting new patients

Education ?

Medical School
Madras Medical College (1984)
Foreign school

Awards & Distinctions ?

Associations
American Board of Psychiatry and Neurology

Affiliations ?

Dr. Madhavan is affiliated with 19 hospitals.

Hospital Affilations

Score

Rankings

  • Rehabilitation Institute of Michigan
    261 Mack Ave, Detroit, MI 48201
    • Currently 4 of 4 crosses
    Top 25%
  • St. Mary Mercy Hospital
    36475 5 Mile Rd, Livonia, MI 48154
    • Currently 4 of 4 crosses
    Top 25%
  • St. Joseph Mercy Oakland
    44405 Woodward Ave, Pontiac, MI 48341
    • Currently 4 of 4 crosses
    Top 25%
  • Huron Valley-Sinai Hospital
    1 William Carls Dr, Commerce Township, MI 48382
    • Currently 4 of 4 crosses
    Top 25%
  • DMC - Sinai-Grace Hospital
    6071 W Outer Dr, Detroit, MI 48235
    • Currently 4 of 4 crosses
    Top 25%
  • Harper University Hospital
    3990 John R St, Detroit, MI 48201
    • Currently 3 of 4 crosses
    Top 50%
  • Detroit Receiving Hospital & University Health Center
    4201 Saint Antoine St, Detroit, MI 48201
    • Currently 3 of 4 crosses
    Top 50%
  • Hurley Medical Center
    1 Hurley Plz, Flint, MI 48503
    • Currently 1 of 4 crosses
  • Hutzel Women's Hospital
    3980 John R St, Detroit, MI 48201
  • Children's Hospital of Michigan
    3901 Beaubien St, Detroit, MI 48201
  • Sinai-Grace Hospital
    6071 W Outer Dr, Detroit, MI 48235
  • Hutzel Hospital
  • HARPER UNIVERSITY HOSPITAL & HUTZEL WOMEN'S HOSPIT
  • Detroit Receiving Hospital
  • Harper Hospital
  • Mich. Orthopaedic Specialty Hospital
  • Detroit Receiving - UHC
  • Sinaigrace Hospital
  • Karmanos Cancer Center
    4100 John R St, Detroit, MI 48201
  • Publications & Research

    Dr. Madhavan has contributed to 51 publications.
    Title Comparison of Outcomes of Nonsurgical Spontaneous Intracerebral Hemorrhage Based on Risk Factors and Physician Specialty.
    Date January 2011
    Journal Journal of Stroke and Cerebrovascular Diseases : the Official Journal of National Stroke Association
    Excerpt

    The authors report the effects of patient risk factors and physician specialty on the clinical outcomes of patients with spontaneous intracerebral hemorrhage (ICH), who were treated nonsurgically at 3 academic medical centers. To our knowledge, there is no reported literature on the effect of physician specialty and outcomes (modified Rankin scale [mRS] score, in-hospital death, and hospital length of stay [LOS]).

    Title The Function of Cortactin in the Clustering of Acetylcholine Receptors at the Vertebrate Neuromuscular Junction.
    Date March 2010
    Journal Plos One
    Excerpt

    Postsynaptic enrichment of acetylcholine receptors (AChRs) at the vertebrate neuromuscular junction (NMJ) depends on the activation of the muscle receptor tyrosine MuSK by neural agrin. Agrin-stimulation of MuSK is known to initiate an intracellular signaling cascade that leads to the clustering of AChRs in an actin polymerization-dependent manner, but the molecular steps which link MuSK activation to AChR aggregation remain incompletely defined.

    Title Calcific Aortic Valve and Spontaneous Embolic Stroke: a Review of Literature.
    Date February 2010
    Journal Journal of the Neurological Sciences
    Excerpt

    Aortic valve calcification is common in the elderly and in patients with congenital bicuspid aortic valve but unlike calcific mitral valve disease it is not a well recognized risk factor for stroke. Although autopsy studies have revealed evidence of systemic embolism in one-third of cases with calcific aortic valves, there is conflicting data from larger clinical studies examining the association between calcific aortic valve and stroke. There are only 8 reported cases of symptomatic stroke from spontaneous cerebral thromboembolism associated with calcific aortic valve in the literature. Computerized tomography (CT) angiography and CT without contrast are modalities of choice to diagnose calcific embolism, while MRI may be useful in delineating the extent of ischemia. Ideal management strategy, the role of antiplatelet therapy, anticoagulation or recommendations for valve replacements are poorly defined. We present a focused literature review on this topic.

    Title Rare Sensory and Autonomic Disturbances Associated with Vitamin B12 Deficiency.
    Date February 2010
    Journal Journal of the Neurological Sciences
    Excerpt

    Vitamin B12 deficiency is an important nutritional disorder causing neurological manifestations of myelopathy, neuropathy and dementia. Sub-acute combined degeneration (SCD) with involvement of the posterior columns in the cervical and thoracic cord is a common presentation of this disorder. In this case report, we describe a 43 year old woman with pernicious anemia and myelopathy with atypical clinical features. The patient presented with motor symptoms, a sensory level and bladder dysfunction. She had severe autonomic disturbances including an episode of unexplained bronchospasm, which has not been previously reported as a manifestation of vitamin B12 deficiency. We review the literature regarding these rarely reported features of vitamin B12 deficiency, and discuss aspects of management of this reversible condition. We emphasize the importance of awareness of autonomic disturbances in B12 deficient individuals.

    Title High Rate of Inappropriate Carotid Endarterectomy in an Urban Medical Center.
    Date September 2009
    Journal Journal of Stroke and Cerebrovascular Diseases : the Official Journal of National Stroke Association
    Excerpt

    Some studies have reported that the appropriateness of carotid endarterectomy (CEA) has dramatically improved in the last two decades. However, these studies did not include the most recent study results for asymptomatic stenosis.

    Title Transmembrane Mechanisms in the Assembly of the Postsynaptic Apparatus at the Neuromuscular Junction.
    Date December 2008
    Journal Chemico-biological Interactions
    Excerpt

    The vertebrate neuromuscular junction (NMJ) is marked by molecular specializations that include postsynaptic clusters of acetylcholine receptor (AChR) and acetylcholinesterase (AChE). Whereas AChRs are aggregated in the postsynaptic muscle membrane to a density of 10,000/mum(2), AChE is concentrated, also to a high density, in the synaptic basement membrane (BM). In recent years considerable progress has been made in understanding the cellular and molecular mechanisms of AChR clustering. It is known that during the early stages of motoneuron-muscle interaction, the nerve-secreted proteoglycan agrin activates the muscle-specific kinase MuSK, which leads to the formation of a postsynaptic cytoskeletal scaffold that immobilizes and concentrates AChRs through a process generally accepted to involve diffusion-mediated trapping of the receptors. We have recently tested this diffusion-trap model at the single molecule level for the first time by using quantum-dot labeling to track individual AChRs during NMJ development. Our results showed that single AChRs exhibit Brownian-type movement, with diffusion coefficients of 10(-11) to 10(-9)cm(2)/s, until they become immobilized at "traps" assembled in response to synaptogenic stimuli. Thus, free diffusion of AChRs is an integral part of their clustering mechanism. What is the mechanism for AChE clustering? We previously showed that the A(12) asymmetric form of AChE binds to perlecan, a heparan-sulfate proteoglycan which in turn interacts with the transmembrane dystroglycan complex. Through this linkage AChE becomes bound to the muscle membrane and, like AChRs, may exhibit lateral mobility along the membrane. Consistent with this idea, pre-existent AChE at the cell surface becomes clustered together with AChRs following synaptogenic stimulation. Future studies testing diffusion-mediated trapping of AChE should provide insights into the synaptic localization of BM-bound molecules at the NMJ.

    Title Higher Risk Factor Burden and Worse Outcomes in Urban Carotid Endarterectomy Patients.
    Date November 2008
    Journal Stroke; a Journal of Cerebral Circulation
    Excerpt

    BACKGROUND AND PURPOSE: Previous multicenter carotid endarterectomy (CEA) studies had screening criteria for patient comorbidities and very few blacks. We assessed the hypothesis that CEA results from two urban hospitals would approximate those of the previous multicenter trials. METHODS: A retrospective chart review was completed at two urban hospitals for CEA procedures done in 2003 and 2004. Demographic information and past medical history was recorded. In hospital perioperative complications (stroke or myocardial infarction [MI]) were noted. We calculated an expected perioperative stroke rate based on trial figures and our proportion of symptomatic and asymptomatic patients. RESULTS: Patients in our cohort had significantly higher rates of hypertension, diabetes, smoking, black race, and elderly status compared to previous trials. The expected perioperative stroke was 3.1%, and the observed stroke rate was 4.7% (P=0.36). Observed rates of MI (6.7%, P<0.001)) and stroke or MI (11.3%, P<0.0001) were higher than expected based on the previous trials. The stroke or MI rate in black subjects was higher (15.4% versus 5.6%, P=0.065) and this was significant at the hospital with lower CEA volume. CONCLUSIONS: In two urban hospitals, CEA results were significantly worse than previous trials. Patient selection is likely to play a role because our cohort had higher numbers of hypertensives, diabetics, smokers, blacks, and elderly patients. Clinicians need to carefully consider the risk/benefit ratio of CEA in urban patients because our study shows that these patients have a large number of medical comorbidities and worse outcomes after CEA.

    Title The Function of Shp2 Tyrosine Phosphatase in the Dispersal of Acetylcholine Receptor Clusters.
    Date August 2008
    Journal Bmc Neuroscience
    Excerpt

    BACKGROUND: A crucial event in the development of the vertebrate neuromuscular junction (NMJ) is the postsynaptic enrichment of muscle acetylcholine (ACh) receptors (AChRs). This process involves two distinct steps: the local clustering of AChRs at synapses, which depends on the activation of the muscle-specific receptor tyrosine kinase MuSK by neural agrin, and the global dispersal of aneural or "pre-patterned" AChR aggregates, which is triggered by ACh or by synaptogenic stimuli. We and others have previously shown that tyrosine phosphatases, such as the SH2 domain-containing phosphatase Shp2, regulate AChR cluster formation in muscle cells, and that tyrosine phosphatases also mediate the dispersal of pre-patterned AChR clusters by synaptogenic stimuli, although the specific phosphatases involved in this latter step remain unknown. RESULTS: Using an assay system that allows AChR cluster assembly and disassembly to be studied separately and quantitatively, we describe a previously unrecognized role of the tyrosine phosphatase Shp2 in AChR cluster disassembly. Shp2 was robustly expressed in embryonic Xenopus muscle in vivo and in cultured myotomal muscle cells, and treatment of the muscle cultures with an inhibitor of Shp2 (NSC-87877) blocked the dispersal of pre-patterned AChR clusters by synaptogenic stimuli. In contrast, over-expression in muscle cells of either wild-type or constitutively active Shp2 accelerated cluster dispersal. Significantly, forced expression in muscle of the Shp2-activator SIRPalpha1 (signal regulatory protein alpha1) also enhanced the disassembly of AChR clusters, whereas the expression of a truncated SIRPalpha1 mutant that suppresses Shp2 signaling inhibited cluster disassembly. CONCLUSION: Our results suggest that Shp2 activation by synaptogenic stimuli, through signaling intermediates such as SIRPalpha1, promotes the dispersal of pre-patterned AChR clusters to facilitate the selective accumulation of AChRs at developing NMJs.

    Title Multi-site Stimulation Quiets Network-wide Spontaneous Bursts and Enhances Functional Plasticity in Cultured Cortical Networks.
    Date March 2008
    Journal Conference Proceedings : ... Annual International Conference of the Ieee Engineering in Medicine and Biology Society. Ieee Engineering in Medicine and Biology Society. Conference
    Excerpt

    We culture high-density cortical cultures on multi-electrode arrays (MEAs), which allow us to stimulate and record from thousands of neurons. One of the modes of activity in these high-density cultures is dish-wide synchronized bursting. Unlike in vivo, these synchronized patterns persist for the lifetime of the culture. Such aberrant patterns of activity might be due to the fact that cortical cultures are sensory-deprived and arrested in development. We have devised methods to control this spontaneous activity by multi-electrode electrical stimulation and to study long-term functional neural plasticity, on a background of such burst-quieting stimulation. Here, we investigate whether burst quieting reveals long-term plasticity induced by tetanic stimulation. Spatio-temporal activity patterns (STAPs) that result from probe pulses were clustered and quantified in quieted and non-quieted cultures. Burst-quieted cultures show more tetanus-induced functional change than cultures which are allowed to express spontaneous bursts. The methods developed for this study will help in the understanding of network dynamics and appreciation of their role in long-term plasticity and information processing in the brain.

    Title Regulation of Ach Receptor Clustering by the Tyrosine Phosphatase Shp2.
    Date December 2007
    Journal Developmental Neurobiology
    Excerpt

    At the vertebrate neuromuscular junction (NMJ), postsynaptic aggregation of muscle acetylcholine receptors (AChRs) depends on the activation of MuSK, a muscle-specific tyrosine kinase that is stimulated by neural agrin and regulated by muscle-intrinsic tyrosine kinases and phosphatases. We recently reported that Shp2, a tyrosine phosphatase containing src homology two domains, suppressed MuSK-dependent AChR clustering in cultured myotubes, but how this effect of Shp2 is controlled has remained unclear. In this study, biochemical assays showed that agrin-treatment of C2 mouse myotubes enhanced the tyrosine phosphorylation of signal regulatory protein alpha1 (SIRPalpha1), a known activator of Shp2, and promoted SIRPalpha1's interaction with Shp2. Moreover, in situ experiments revealed that treatment of myotubes with the Shp2-selective inhibitor NSC-87877 increased spontaneous and agrin-induced AChR clustering, and that AChR clustering was also enhanced in myotubes ectopically expressing inactive (dominant-negative) Shp2; in contrast, AChR clustering was reduced in myotubes expressing constitutively active Shp2. Significantly, expression of truncated (nonShp2-binding) and full-length (Shp2-binding) forms of SIRPalpha1 in myotubes also increased and decreased AChR clustering, respectively, and coexpression of truncated SIRPalpha1 with active Shp2 and full-length SIRPalpha1 with inactive Shp2 reversed the actions of the exogenous Shp2 proteins on AChR clustering. These results suggest that SIRPalpha1 is a novel downstream target of MuSK that activates Shp2, which, in turn, suppresses AChR clustering. We propose that an inhibitory loop involving both tyrosine kinases and phosphatases sets the level of agrin/MuSK signaling and constrains it spatially to help generate high-density AChR clusters selectively at NMJs.

    Title Plasticity of Recurring Spatiotemporal Activity Patterns in Cortical Networks.
    Date November 2007
    Journal Physical Biology
    Excerpt

    How do neurons encode and store information for long periods of time? Recurring patterns of activity have been reported in various cortical structures and were suggested to play a role in information processing and memory. To study the potential role of bursts of action potentials in memory mechanisms, we investigated patterns of spontaneous multi-single-unit activity in dissociated rat cortical cultures in vitro. Spontaneous spikes were recorded from networks of approximately 50 000 neurons and glia cultured on a grid of 60 extracellular substrate- embedded electrodes (multi-electrode arrays). These networks expressed spontaneous culture- wide bursting from approximately one week in vitro. During bursts, a large portion of the active electrodes showed elevated levels of firing. Spatiotemporal activity patterns within spontaneous bursts were clustered using a correlation-based clustering algorithm, and the occurrences of these burst clusters were tracked over several hours. This analysis revealed spatiotemporally diverse bursts occurring in well-defined patterns, which remained stable for several hours. Activity evoked by strong local tetanic stimulation resulted in significant changes in the occurrences of spontaneous bursts belonging to different clusters, indicating that the dynamical flow of information in the neuronal network had been altered. The diversity of spatiotemporal structure and long-term stability of spontaneous bursts together with their plastic nature strongly suggests that such network patterns could be used as codes for information transfer and the expression of memories stored in cortical networks.

    Title Involvement of P120 Catenin in Myopodial Assembly and Nerve-muscle Synapse Formation.
    Date January 2007
    Journal Journal of Neurobiology
    Excerpt

    At developing neuromuscular junctions (NMJs), muscles initially contact motor axons by microprocesses, or myopodia, which are induced by nerves and nerve-secreted agrin, but it is unclear how myopodia are assembled and how they influence synaptic differentiation at the NMJ. Here, we report that treatment of cultured muscle cells with agrin transiently depleted p120 catenin (p120ctn) from cadherin junctions in situ, and increased the tyrosine phosphorylation and decreased the cadherin-association of p120ctn in cell extracts. Whereas ectopic expression of wild-type p120ctn in muscle generated myopodia in the absence of agrin, expression of a specific dominant-negative mutant form of p120ctn, which blocks filopodial assembly in nonmuscle cells, suppressed nerve- and agrin-induction of myopodia. Significantly, approaching neurites triggered reduced acetylcholine receptor (AChR) clustering along the edges of muscle cells expressing mutant p120ctn than of control cells, although the ability of the mutant cells to cluster AChRs was itself normal. Our results indicate a novel role of p120ctn in agrin-induced myopodial assembly and suggest that myopodia increase muscle-nerve contacts and muscle's access to neural agrin to promote NMJ formation.

    Title Association of Functional and Health Status Measures in Heart Failure.
    Date October 2006
    Journal Journal of Cardiac Failure
    Excerpt

    BACKGROUND: A wide variety of instruments have been used to assess the functional capabilities and health status of patients with chronic heart failure (HF), but it is not known how well these tests are correlated with one another, nor which one has the best association with measured exercise capacity. METHODS AND RESULTS: Forty-one patients with HF were assessed with commonly used functional, health status, and quality of life measures, including maximal cardiopulmonary exercise testing, the Duke Activity Status Index (DASI), the Veterans Specific Activity Questionnaire (VSAQ), the Kansas City Cardiomyopathy Questionnaire (KCCQ), and 6-minute walk distance. Pretest clinical variables, including age, resting pulmonary function tests (forced expiratory volume in 1 s and forced vital capacity), and ejection fraction (EF) were also considered. The association between performance on these functional tools, clinical variables, and exercise test responses including peak VO2 and the VO2 at the ventilatory threshold, was determined. Peak oxygen uptake (VO2) was significantly related to VO2 at the ventilatory threshold (r = 0.76, P < .001) and estimated METs from treadmill speed and grade (r = 0.72, P < .001), but had only a modest association with 6-minute walk performance (r = 0.49, P < .01). The functional questionnaires had modest associations with peak VO2 (r = 0.37, P < .05 and r = 0.26, NS for the VSAQ and DASI, respectively). Of the components of the KCCQ, peak VO2 was significantly related only to quality of life score (r = 0.46, P < .05). Six-minute walk performance was significantly related to KCCQ physical limitation (r = 0.53, P < .01) and clinical summary (r = 0.44, P < .05) scores. Among pretest variables, only age and EF were significantly related to peak VO2 (r = -0.58, and 0.46, respectively, P < .01). Multivariately, age and KCCQ quality of life score were the only significant predictors of peak VO2, accounting for 72% of the variance in peak VO2. CONCLUSION: Commonly used functional measures, symptom tools, and quality of life assessments for patients with HF are poorly correlated with one another and are only modestly associated with exercise test responses. These findings suggest that exercise test responses, non-exercise test estimates of physical function, and quality of life indices reflect different facets of health status in HF and one should not be considered a surrogate for another.

    Title Hgf Induction of Postsynaptic Specializations at the Neuromuscular Junction.
    Date April 2006
    Journal Journal of Neurobiology
    Excerpt

    A critical event in the formation of vertebrate neuromuscular junctions (NMJs) is the postsynaptic clustering of acetylcholine receptors (AChRs) in muscle. AChR clustering is triggered by the activation of MuSK, a muscle-specific tyrosine kinase that is part of the functional receptor for agrin, a nerve-derived heparan sulfate proteoglycan (HSPG). At the NMJ, heparan sulfate (HS)-binding growth factors and their receptors are also localized but their involvement in postsynaptic signaling is poorly understood. In this study we found that hepatocyte growth factor (HGF), an HS-binding growth factor, surrounded muscle fibers and was localized at NMJs in rat muscle sections. In cultured Xenopus muscle cells, HGF was enriched at spontaneously occurring AChR clusters (hot spots), where HSPGs were also concentrated, and, following stimulation of muscle cells by agrin or cocultured neurons, HGF associated with newly formed AChR clusters. HGF presented locally to cultured muscle cells by latex beads induced new AChR clusters and dispersed AChR hot spots, and HGF beads also clustered phosphotyrosine, activated c-Met, and proteins of dystrophin complex; clustering of AChRs and associated proteins by HGF beads required actin polymerization. Lastly, although bath-applied HGF alone did not induce new AChR clusters, addition of HGF potentiated agrin-dependent AChR clustering in muscle. Our findings suggest that HGF promotes AChR clustering and synaptogenic signaling in muscle during NMJ development.

    Title Molecular Regulation of Postsynaptic Differentiation at the Neuromuscular Junction.
    Date March 2006
    Journal Iubmb Life
    Excerpt

    The neuromuscular junction (NMJ) is a synapse that develops between a motor neuron and a muscle fiber. A defining feature of NMJ development in vertebrates is the re-distribution of muscle acetylcholine (ACh) receptors (AChRs) following innervation, which generates high-density AChR clusters at the postsynaptic membrane and disperses aneural AChR clusters formed in muscle before innervation. This process in vivo requires MuSK, a muscle-specific receptor tyrosine kinase that triggers AChR re-distribution when activated; rapsyn, a muscle protein that binds and clusters AChRs; agrin, a nerve-secreted heparan-sulfate proteoglycan that activates MuSK; and ACh, a neurotransmitter that stimulates muscle and also disperses aneural AChR clusters. Moreover, in cultured muscle cells, several additional muscle- and nerve-derived molecules induce, mediate or participate in AChR clustering and dispersal. In this review we discuss how regulation of AChR re-distribution by multiple factors ensures aggregation of AChRs exclusively at NMJs.

    Title Sweet's Syndrome with Tendinitis.
    Date February 2006
    Journal The Journal of the Association of Physicians of India
    Excerpt

    A 30 years man presented with fever and skin manifestations in the form of multiple tender, erythematous, asymmetric nodules and papules predominantly over the upper arms and back. The nodules were coalescing to form irregular sharply demarcated plaques over the forearms and thighs. There were pustules over the nodules. He also had tendoachilles tendinitis. The total leucocyte count, differential count and skin biopsy confirmed the diagnosis of Sweet's syndrome (acute febrile neutrophilic dermatosis). This patient, a case of Idiopathic Sweet's syndrome with tendoachilles tendinitis responded to oral corticosteroids.

    Title Controlling Bursting in Cortical Cultures with Closed-loop Multi-electrode Stimulation.
    Date August 2005
    Journal The Journal of Neuroscience : the Official Journal of the Society for Neuroscience
    Excerpt

    One of the major modes of activity of high-density cultures of dissociated neurons is globally synchronized bursting. Unlike in vivo, neuronal ensembles in culture maintain activity patterns dominated by global bursts for the lifetime of the culture (up to 2 years). We hypothesize that persistence of bursting is caused by a lack of input from other brain areas. To study this hypothesis, we grew small but dense monolayer cultures of cortical neurons and glia from rat embryos on multi-electrode arrays and used electrical stimulation to substitute for afferents. We quantified the burstiness of the firing of the cultures in spontaneous activity and during several stimulation protocols. Although slow stimulation through individual electrodes increased burstiness as a result of burst entrainment, rapid stimulation reduced burstiness. Distributing stimuli across several electrodes, as well as continuously fine-tuning stimulus strength with closed-loop feedback, greatly enhanced burst control. We conclude that externally applied electrical stimulation can substitute for natural inputs to cortical neuronal ensembles in transforming burst-dominated activity to dispersed spiking, more reminiscent of the awake cortex in vivo. This nonpharmacological method of controlling bursts will be a critical tool for exploring the information processing capacities of neuronal ensembles in vitro and has potential applications for the treatment of epilepsy.

    Title Tyrosine Phosphatase Regulation of Musk-dependent Acetylcholine Receptor Clustering.
    Date August 2005
    Journal Molecular and Cellular Neurosciences
    Excerpt

    During vertebrate neuromuscular junction (NMJ) development, nerve-secreted agrin induces acetylcholine receptor (AChR) clustering in muscle by activating the muscle-specific tyrosine kinase MuSK. Recently, it has been recognized that MuSK activation-dependent AChR clustering occurs in embryonic muscle even in the absence of agrin, but how this process is regulated is poorly understood. We report that inhibition of tyrosine phosphatases in cultured C2 mouse myotubes using pervanadate enhanced MuSK auto-activation and agrin-independent AChR clustering. Moreover, phosphatase inhibition also enlarged the AChR clusters induced by agrin in these cells. Conversely, in situ activation of MuSK in cultured Xenopus embryonic muscle cells, either focally by anti-MuSK antibody-coated beads or globally by agrin, stimulated downstream tyrosine phosphatases, which could be blocked by pervanadate treatment. Immunoscreening identified Shp2 as a major tyrosine phosphatase in C2 myotubes and down-regulation of its expression by RNA interference alleviated tyrosine phosphatase suppression of MuSK activation. Significantly, depletion of Shp2 increased both agrin-independent and agrin-dependent AChR clustering in myotubes. Our results suggest that muscle tyrosine phosphatases tightly regulate MuSK activation and signaling and support a novel role of Shp2 in MuSK-dependent AChR clustering.

    Title Psoriatic Arthritis.
    Date September 2004
    Journal The Journal of the Association of Physicians of India
    Excerpt

    AIM OF THE STUDY: To evaluate the clinical pattern of psoriatic arthritis in patients attending a tertiary referral centre in South India. METHODOLOGY: Case records of one hundred and sixteen patients with psoriatic arthritis (PsA) who had attended our Rheumatology Department were analysed using demographic, clinical, laboratory and radiographic variables and the data were compared with other studies. RESULTS: Among 116 patients, 78 were males and 38 were females (ratio 2:1). Peak incidence (69%) was in the fourth and fifth decades. One patient had juvenile psoriatic arthritis (onset <16 years of age). Symmetric polyarthritis (48.3%) was the commonest subtype. Arthritis followed the skin lesions in 50.8% of patients, preceded in 12.1% and occurred simultaneously in 37.1%. Knee (66.4%) was the commonest joint involved. Extra-articular features like sausage digits (19%), enthesitis (7.8%) and eye manifestations (1.7%) like conjunctivitis and uveitis were observed. Psoriasis vulgaris (81%) was the commonest psoriatic lesion. Scalp (57.8%) was the most common hidden site. All the three patients with DIP arthritis alone had nail lesions. ESR and C-reactive protein were elevated in 51.7% and 43.9% of patients respectively. Rheumatoid factor was positive in 3.4 % and antinuclear antibody (ANA) was present in 5.4% (3/56) of patients. HIV infection was detected in 2.3% (1/44) of patients. Radiographic features like sacroiliitis (11.2%), calcaneal spur (7.8%), erosions (5.2%) and syndesmophytes (5.2%) were observed. One patient had 'pencil-in-cup deformity'. CONCLUSION: Psoriatic arthritis is more common in males. Symmetric polyarthritis is the commonest subtype. Arthritis commonly follows the skin lesions. Psoriasis vulgaris is the most common skin lesion and scalp is the commonest hidden site. ESR and CRP can be normal in psoriatic arthritis.

    Title A Synaptic Balancing Act: Local and Global Signaling in the Clustering of Ach Receptors at Vertebrate Neuromuscular Junctions.
    Date July 2004
    Journal Journal of Neurocytology
    Excerpt

    The clustering of acetylcholine receptors (AChRs) in muscle is a hallmark step in the development of vertebrate neuromuscular junctions (NMJs). It involves localized signaling, which is initiated by the activation of MuSK (muscle-specific kinase) and leads to the concentration and cytoskeletal anchoring of AChRs at the synapse, and global signaling, which traverses the muscle to disperse extra-synaptic AChR clusters. Here we review some of the recent findings that indicate important roles for the actin cytoskeleton and tyrosine phosphatases in mediating these processes.

    Title The Involvement of Calcineurin in Acetylcholine Receptor Redistribution in Muscle.
    Date December 2003
    Journal Molecular and Cellular Neurosciences
    Excerpt

    In this study the intracellular signaling involved in acetylcholine receptor (AChR) redistribution in muscle was investigated. In cultured Xenopus embryonic muscle cells, both the dispersal of preexisting AChR clusters and the induction of new AChR clusters by growth factor-coated polystyrene beads were inhibited by two specific antagonists of the ser/thr phosphatase calcineurin (CaN), Cyclosporin A, (CsA) and FK-506, but not by KN-93 that blocks CaM kinases. Moreover, CaN inhibition decreased AChR clustering in Xenopus muscle cells by beads coated with antibodies that cross-link and activate the agrin receptor MuSK (muscle-specific kinase) and reduced the agrin-induced tyrosine phosphorylation of MuSK in cultured mouse (C2) myotubes. Last, the length and the number of AChR clusters generated by agrin in C2 myotubes were decreased by treatment with CsA, but not KN-93, and following the forced expression of a dominant negative CaN mutant in these cells, but not wild-type CaN or reporter green fluorescent protein. Collectively, our results support a role for CaN signaling in the redistribution of AChRs in muscle induced by synaptogenic signals.

    Title Transient Ischaemic Attacks : New Approaches to Management.
    Date June 2003
    Journal Cns Drugs
    Excerpt

    The fact that transient ischaemic attacks are a harbinger for the possible development of ischaemic stroke has been recognised for several decades. However, within the past decade, our concepts regarding transient ischaemic attacks as a distinct entity from stroke and the prognosis for transient ischaemic attack patients have been challenged. In addition, clinical trials have clarified that modern transient ischaemic attack management is more complex than in the past, with the addition of newer pharmacological options to the stroke prevention armamentarium. Recent information regarding newer antiplatelet agents is reviewed in this article, along with results of clinical trials pertaining to warfarin in stroke prevention. The evolving role of statins, ACE inhibitors and estrogen replacement is reviewed. Finally, the appropriate use of surgery following transient ischaemic attacks is outlined. Recent studies have shown that many patients will benefit from a multimodal pharmacological approach following transient cerebral ischaemia, and the potential for combination therapy is highlighted.

    Title Clinical Spectrum of Inflammatory Myositis in South India--a Ten Year Study.
    Date February 2003
    Journal The Journal of the Association of Physicians of India
    Excerpt

    OBJECTIVE: To describe the clinical spectrum of inflammatory myopathies at a referral hospital in South India. METHODS: Patients were assessed for the pattern of muscle involvement, for the presence of arthritis, Raynaud's phenomenon, interstitial lung disease (ILD) and cardiac involvement. Muscle enzymes, electromyogram (EMG) and muscle biopsies were done. RESULTS: Eighty seven patients with inflammatory myopathies were encountered over 10 years. These included 24 with adult polymyositis, 26 with adult dermatomyositis, one with amyopathic dermatomyositis, five with juvenile myositis, one with dermatomysitis following carcinoma breast and 30 with overlap with other connective tissue diseases. There was a female preponderance (M:F = 1:2.35) except in juvenile myosits group (M:F = 1.5:1). The mean age of onset in years was 33.26 in adult polymyositis, 35.03 in adult dermatomyositis, 7.4 in juvenile dermatomyositis, 42 in malignancy-associated dermatomyositis and 25.51 in the overlap group. Proximal muscle weakness was seen in 98.8% patients, dysphagia in 33.3%, distal muscle weakness in 12.5%, respiratory muscle weakness in 9.2% and dysphonia in 4.6%. Other features included arthritis 35.63%, interstitial lung disease (ILD) 9.2%, Raynaud's 5.7%, myocarditis 4.6% and conduction disturbances 1.15%. Eleveated muscle enzymes were seen in 85.1% patients. Eletromyogram was positive in 66.6%. Muscle biopsy was positive in 85.29%. Anti-nuclear antibody was positive in 67.24%. All received steroids, non-responders needed methotrexate (13 patients) or azathioprine (11 patients). Death occurred in 10 (seven with dermatomyositis predominantly due to respiratory involvement and three with overlap). CONCLUSION: There was female preponderance except in juvenile myositis group. Proximal muscle weakness was the commonest feature. ILD was the commonest respiratory problem, while myocarditis was the commonest cardiac problem seen. Response to therapy and prognosis in polymyositis were good with no mortality during the study period. Death in the dermatomyositis group was mainly due to respiratory involvement.

    Title Stroke Trials: What Have We Learned?
    Date December 2002
    Journal Neurological Research
    Excerpt

    We reviewed the recent, major, therapeutic trials of intravenous thrombolytic therapy and ancrod for ischemic stroke. Randomized, controlled studies of acute ischemic stroke treatment were reviewed. Several post-FDA approval intravenous tPA studies were reviewed to understand the experience of this medication in practice. STAT trial was the major study using ancrod. Of multiple intravenous thrombolytic studies, the NINDS study of intravenous tPA was the only study to demonstrate a significantly higher percentage of patients with complete recovery or minimal deficit at three months. Studies in communities utilizing intravenous tPA for stroke illustrate the need for close adherence to the NINDS study protocol or else the risk of tPA use may exceed the benefits.

    Title Hla Class I and Class Ii Association with Ankylosing Spondylitis in a Southern Indian Population.
    Date July 2002
    Journal Annals of the New York Academy of Sciences
    Excerpt

    Ankylosing spondylitis (AS) is a chronic inflammatory condition associated with HLA B27. But the association is not absolute. Hence association with other HLA class I antigens and class II alleles was studied in a southern Indian population. Sixty-five patients with primary AS were typed serologically for HLA class I antigens. Age- and sex-matched disease controls (37 with enterogenic reactive arthritis [ReA] and 25 with undifferentiated spondyloarthropathy [UnSpA]) and 124 healthy controls were studied. PCR-based DNA-SSO typing for DQA1 and DQB1 was performed on 20 patients with AS and 38 healthy controls. Twenty-three patients with AS and 39 controls were typed for DRB1 alleles. HLA B27 was positive in 76.9 % of the cases of AS (RR 811), 59.5% of those with ReA (RR 9.3), and 40% of the patients with UnSpA (RR 9.3), while none of the controls were B27 positive. The P value for positive association was highly significant for B27 in all the three groups. B27 positivity was associated with earlier age of onset of disease in all the diseases compared to the B27-negative group. HLA Cw2 was positively associated with AS (P highly significant; OR 52) and ReA (P = 0.0003; OR 14.2). HLA A1 and CW6 were significantly negatively associated only with AS (P = 0.0001 and 0.00004 and OR 0.25 and 0.02, respectively). None of the HLA class II alleles were significantly associated with AS. The apparent association with DRB1*11 (P = 0.03) was lost after Yates correction.

    Title Igm, Igg, and Iga Response to Enterobacteria in Patients with Ankylosing Spondylitis in Southern India.
    Date July 2002
    Journal Annals of the New York Academy of Sciences
    Excerpt

    IgM, IgA, and IgG response to three different antigenic preparations-lipopolysaccharide (LPS), culture supernatant proteins, and outer membrane protein (OMP) of Klebsiella pneumoniae, Escherichia coli and Salmonella typhi-were measured in the sera of 20 patients with primary ankylosing spondylitis (AS), 10 with enterogenic reactive arthritis (ReA) (disease controls), and 15 voluntary blood donors (healthy controls) by ELISA using biotinylated anti-human immunoglobulins M, G, and A. Serum immunoglobulin levels were measured by immunoturbidimetric assay in 20 AS patients, 20 patients with enterogenic reactive arthritis (ReA), 20 with ulcerative colitis (UC), and 20 voluntary blood donors. Student's t-test was applied for comparison. Compared to healthy controls, AS patients showed significantly elevated IgG response against culture supernatant proteins of all the three organisms (P <0.05), LPS of E. coli (P < 0.05) and Klebsiella (P < 0.005), as well as OMP only of Klebsiella pneumoniae. This was reflected as significantly elevated IgG level in AS compared to controls (P < 0.05 vs. ReA and 0.005 vs. UC and healthy controls). This suggests the involvement of outer membrane proteins of Klebsiella pneumoniae in the pathogenic mechanism of ankylosing spondylitis.

    Title Class Ii Mhc Alleles in Rheumatoid Arthritis in Tamilnadu, India: is There an Association?
    Date July 2002
    Journal Annals of the New York Academy of Sciences
    Excerpt

    Rheumatoid arthritis (RA) was reported to be associated with class II MHC alleles in different ethnic populations. A similar study was undertaken to determine the association of class II MHC with RA patients of Tamilnadu (Tamil-speaking Hindus), India. Thirty patients with RA and 39 healthy controls were included. Polymorphic second exons of the DRB1, DQA1, and DQB1 genes were amplified and subjected to SSOP typing. No allele was found to be significantly associated with RA. However DRB1*11 (P = 0.01) and DQB1*0302 (P = 0.02) were significantly associated with rheumatoid factor-positive RA patients. (All the DRB1*11-positive RA patients had either *04 or *10 allele as their second allele. This study is first of its kind in this population.

    Title Exercise Testing with Gas Exchange Analysis.
    Date February 2002
    Journal Cardiology Clinics
    Excerpt

    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.

    Title Validation of a Specific Activity Questionnaire to Estimate Exercise Tolerance in Patients Referred for Exercise Testing.
    Date December 2001
    Journal American Heart Journal
    Excerpt

    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.

    Title Late Onset Rheumatoid Arthritis--a Clinical and Laboratory Study.
    Date May 2001
    Journal The Journal of the Association of Physicians of India
    Excerpt

    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.

    Title Juvenile Rheumatoid Arthritis--madras Experience.
    Date June 2000
    Journal Indian Journal of Pediatrics
    Excerpt

    In a prospective study of 1,053 consecutive children who attended the Rheumatic Care Centre, Government General Hospital, Madras from 1991 to 1995, 331 children fulfilled the criteria proposed by the American Rheumatism Association as modified by Cassidy et al for the diagnosis of Juvenile Rheumatoid Arthritis. These children were thoroughly examined and investigated and classified into 3 onset types which was then sub-classified into early entry and late entry groups based on the duration of illness. Other arthritic conditions were excluded. There were 44 cases belonging to Systemic onset, 171 belonging to polyarticular onset and 116 belonging to oligoarticular onset type. In the systemic onset type 44/44 patients had fever, 40/44 had lymphadenopathy and 19/44 had skin rash; wrists and knees 31/44 were the most commonly involved joints; neck involvement was present in 13/44 of the cases; ANA was positive in 5/44 cases and anaemia was seen in 24/44 cases. In polyarticular onset type wrists 119/171, knees 143/171, hip joints 105/171 and ankles 113/171 were commonly involved; in the RF +ve subtype 3/23 had subcutaneous nodules and 7/23 were positive for ANA; in the Rf -ve subtype 59/148 were positive for ANA. In the oligoarticular subtype-1 ANA was positive in all cases but iridocyclitis was not seen in any case. In oligoarticular subtype-2 HLA B27 was positive in 13/26 cases while Sacroilitis was seen in 16/26 cases. In oligoarticular type-3 HLA B27 was negative.

    Title Phosphorylation of Dystrophin and Alpha-syntrophin by Ca(2+)-calmodulin Dependent Protein Kinase Ii.
    Date November 1999
    Journal Biochimica Et Biophysica Acta
    Excerpt

    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.

    Title Yotiao, a Novel Protein of Neuromuscular Junction and Brain That Interacts with Specific Splice Variants of Nmda Receptor Subunit Nr1.
    Date April 1998
    Journal The Journal of Neuroscience : the Official Journal of the Society for Neuroscience
    Excerpt

    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.

    Title Interaction of Muscle and Brain Sodium Channels with Multiple Members of the Syntrophin Family of Dystrophin-associated Proteins.
    Date January 1998
    Journal The Journal of Neuroscience : the Official Journal of the Society for Neuroscience
    Excerpt

    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.

    Title Interactions Between Dystrophin Glycoprotein Complex Proteins.
    Date November 1995
    Journal Biochemistry
    Excerpt

    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.

    Title Childhood Systemic Lupus Erythematosus in South India.
    Date December 1994
    Journal Indian Journal of Pediatrics
    Excerpt

    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.

    Title Calmodulin-activated Phosphorylation of Dystrophin.
    Date June 1994
    Journal Biochemistry
    Excerpt

    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.

    Title Effect of Bed Time Intermediate Acting Insulin in Niddm Subjects Refractory to a Combination of Sulphonylureas and Biguanides.
    Date September 1993
    Journal The Journal of the Association of Physicians of India
    Excerpt

    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.

    Title Subcutaneous Insulin Pulse Therapy.
    Date February 1993
    Journal The Journal of the Association of Physicians of India
    Excerpt

    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)

    Title Calmodulin Specifically Binds Three Proteins of the Dystrophin-glycoprotein Complex.
    Date July 1992
    Journal Biochemical and Biophysical Research Communications
    Excerpt

    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.

    Title Progressive Systemic Sclerosis in South India.
    Date October 1991
    Journal The Journal of the Association of Physicians of India
    Excerpt

    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.

    Title Pattern of Rheumatic Diseases in South India. Iv. Clinical Profile of Juvenile Rheumatoid Arthritis.
    Date May 1991
    Journal The Journal of the Association of Physicians of India
    Excerpt

    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.

    Title Pattern of Rheumatic Diseases in South India. V. Ankylosing Spondylitis. A Clinical and Radiological Study.
    Date May 1991
    Journal The Journal of the Association of Physicians of India
    Excerpt

    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.

    Title Calmodulin-binding Proteins Also Have a Calmodulin-like Binding Site Within Their Structure. The Flip-flop Model.
    Date February 1991
    Journal The Journal of Biological Chemistry
    Excerpt

    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.

    Title Fibrodysplasia (myositis) Ossificans Progressiva in Dominica.
    Date July 1989
    Journal The West Indian Medical Journal
    Excerpt

    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.

    Title Prognostic Indicators in Indian Childhood Cirrhosis.
    Date April 1982
    Journal Indian Journal of Pediatrics
    Title Height, Weight, Height Velocity and Weight Velocity of Bengali Hindu Children from Birth to 18 Months.
    Date March 1971
    Journal Indian Journal of Pediatrics
    Title Predictors of Stroke in Patients with Severe Systolic Dysfunction in Sinus Rhythm: Role of Echocardiography.
    Date
    Journal International Journal of Cardiology
    Excerpt

    Congestive heart failure in sinus rhythm ranks second after atrial fibrillation (AF) among cardiogenic risk-factors for stroke. Clinical and echocardiographic predictors of stroke in this high-risk population remain poorly defined.

    Title Withdrawn: Clinical and Echocardiographic Predictors of Cerebrovascular Events and Left Ventricular Thrombus in Patients with Severe Systolic Dysfunction in Sinus Rhythm.
    Date
    Journal Journal of the Neurological Sciences
    Excerpt

    This article has been withdrawn at the request of the editor. The Publisher apologizes for any inconvenience this may cause. The full Elsevier Policy on Article Withdrawal can be found at http://www.elsevier.com/locate/withdrawalpolicy.

    Title Clinical Profiles, Complications, and Disability in Cocaine-related Ischemic Stroke.
    Date
    Journal Journal of Stroke and Cerebrovascular Diseases : the Official Journal of National Stroke Association
    Excerpt

    Cocaine use is associated with ischemic stroke through unique mechanisms, including reversible vasospasm, drug-induced arteritis, enhanced platelet aggregation, cardioembolism, and hypertensive surges. To date, no study has described disability in patients with cocaine-related ischemic stroke. The present study compared risk factors, comorbidities, complications, laboratory findings, medications, and outcomes in patients with cocaine-related (n = 41) and non-cocaine-related (n = 221) ischemic stroke (n = 147) and transient ischemic attack (n = 115) in 3 academic hospitals. The patients with cocaine-related stroke were younger (mean age, 51.9 years vs 59.1 years; P = .0008) and more likely to be smokers (95% vs 62.9%; P < .004). The prevalence of arrhythmias was significantly higher in the patients with cocaine-related stroke, and that of diabetes was significantly higher in those with non-cocaine-related strokes. The prevalence of hypertension and lipid profiles were similar in the 2 groups; however, those with cocaine-related stroke were less likely to receive statins. Antiplatelet use was similar in the 2 groups. Survivors of both groups had similar modified Rankin scores and lengths of hospital stay. In the older urban population, smoking and cocaine use may coexist with other cerebrovascular risk factors, and cocaine-related strokes have similar morbidities and mortality as non-cocaine-related strokes. Moreover, because the patients with cocaine-related stroke is younger, they have an earlier morbidity. New strategies for effective stroke prevention interventions are needed in this subgroup.

    Title Real-time Brain Oscillation Detection and Phase-locked Stimulation Using Autoregressive Spectral Estimation and Time-series Forward Prediction.
    Date
    Journal Ieee Transactions on Bio-medical Engineering
    Excerpt

    Neural oscillations are important features in a working central nervous system, facilitating efficient communication across large networks of neurons. They are implicated in a diverse range of processes such as synchronization and synaptic plasticity, and can be seen in a variety of cognitive processes. For example, hippocampal theta oscillations are thought to be a crucial component of memory encoding and retrieval. To better study the role of these oscillations in various cognitive processes, and to be able to build clinical applications around them, accurate and precise estimations of the instantaneous frequency and phase are required. Here, we present methodology based on autoregressive modeling to accomplish this in real time. This allows the targeting of stimulation to a specific phase of a detected oscillation. We first assess performance of the algorithm on two signals where the exact phase and frequency are known. Then, using intracranial EEG recorded from two patients performing a Sternberg memory task, we characterize our algorithms phaselocking performance on physiologic theta oscillations: optimizing algorithm parameters on the first patient using a genetic algorithm, we carried out cross-validation procedures on subsequent trials and electrodes within the same patient, as well as on data recorded from the second patient.

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