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C Mohan

Publications and source records attributed to C Mohan.

At least 37 records · Page 2Linked to original sources
PubMed1999

Non-traumatic acute rhabdomyolysis.

A boy developed sudden severe generalized muscle stiffness, bulbar weakness and passed dark coloured urine. Laboratory tests revealed marked elevation of creatinine kinase(CK) levels and myoglobinuria. Histopathology of quadriceps muscle showed features of acute rhabdomyolysis. Patient made complete clinical recovery over a period of three weeks and CK returned to normal level. The possible aetiologies of non-traumatic rhabdomyolysis are discussed and the relevant literature reviewed.

Acute Disease↗
PubMed1999

Basal ganglia calcification.

Basal ganglia calcification (BGC) is now being diagnosed with increasing frequency with widespread application of computed tomography (CT) in clinical practice and is no more considered a rarity. During the period 1987 to 1995, 42 patients were noted to have BGC and it constituted 0.93% of all CT scan of brain carried out during the relevant period. These patients presented with diverse neurological and endocrine disorders i.e., epilepsy (22 patients), mental retardation (five patients), extra-pyramidal syndromes (five patients), abnormal behaviour (three patients), stroke (two patients), raised intracranial tension without localizing signs (one patient), following radiotherapy (one patient), and with hypoparathyroidism (three patients). These patients were noted to have variable degree of calcification in different parts of brain i.e., basal ganglia (42 cases), cerebellum (12 cases) and cerebral cortex (nine cases). Family history of a neurological disorder was available in five patients. This study highlights the fact that calcification of basal ganglia and other parts of the brain is often a nonspecific finding on CT scan and it may not be possible to establish a clinicopathological correlation.

Adolescent↗
PubMed1998

Genetic dissection of SLE pathogenesis. Sle1 on murine chromosome 1 leads to a selective loss of tolerance to H2A/H2B/DNA subnucleosomes.

One of the hallmarks of SLE is the loss of tolerance to chromatin. The genes and mechanisms that trigger this loss of tolerance remain unknown. Our genetic studies in the NZM2410 lupus strain have implicated genomic intervals on chromosomes 1 (Sle1), 4 (Sle2), and 7 (Sle3) as conferring strong lupus susceptibility. Interestingly, B6 mice that are congenic for Sle1 (B6.NZMc1) have elevated IgG antichromatin Abs. This study explores the antinuclear antibody fine specificities and underlying cellular defects in these mice. On the B6 background, Sle1 by itself is sufficient to generate a robust, spontaneous antichromatin Ab response, staining Hep-2 nuclei homogeneously, and reacting primarily with H2A/H2B/DNA subnucleosomes. This targeted immune response peaks at 7-9 mo of age, affects both sexes with equally high penetrance (> 75%), and interestingly, does not "spread" to other subnucleosomal chromatin components. Sle1 also leads to an expanded pool of histone-reactive T cells, which may have a role in driving the anti-H2A/H2B/DNA B cells. However, these mice do not exhibit any generalized immunological defects or quantitative aberrations in lymphocyte apoptosis. We hypothesize that Sle1 may lead to the presentation of chromatin in an immunogenic fashion, or directly impact tolerance of chromatin-specific B cells.

Animals↗
PubMed1998

Accumulation of splenic B1a cells with potent antigen-presenting capability in NZM2410 lupus-prone mice.

OBJECTIVE: In order to shed light on the role of splenic B1 cells in disease pathogenesis in lupus-prone mice, this study was undertaken to determine how efficiently these cells can serve as antigen-presenting cells (APC) and to ascertain which murine lupus susceptibility loci dictate the expansion of these cells. METHODS: Spleens and peritoneal cavities (PerC) of NZM2410 lupus-prone mice, as well as of control B6 and New Zealand white mice, were examined for the prevalence, surface phenotype, and possible anatomic location of B1 cells. The antigen-presenting ability of fluorescence-sorted splenic B1a cells was assessed. Levels of B1 cells were examined in B6 mice congenic for 4 different lupus susceptibility intervals. RESULTS: NZM2410 lupus mice showed an expansion of splenic and PerC B1a cells at all ages. These cells expressed high levels of B71, B72, CD24, lymphocyte function-associated antigen 1, and intercellular adhesion molecule 1, and had the functional capability to serve as APC. Among the lupus susceptibility intervals studied, Sle2, but not Sle1, Sle3, or the H2 locus, affected the expansion of B1 cells. CONCLUSION: These findings raise the possibility that the genetically determined expansion of splenic B1a cells in lupus-prone mice might contribute to disease pathogenesis by augmenting the presentation of autoantigens to pathogenic T cells.

Animals↗
PubMed1998

Murine lupus: pathogenic mechanisms and genetic origins.

Research in several murine models of lupus, reinforced with patient studies, has served to identify key events leading to lupus nephritis. Among these, anti-nuclear antibody (ANA) induced end-organ damage, production of such ANAs by intrinsically hyperactive B-cells, and antigen-specific, cognate T-cell help have been well documented. Though studies in parallel fields of immunology have uncovered a plethora of molecular defects that can potentially drive these key pathogenic events, the actual molecular defects that are responsible for these events in spontaneous lupus remain unknown. Whereas genetically pre-determined triggers are most likely responsible for each of these pathogenic events, humoral and environmental triggers are likely to exert secondary effects, in attenuating or accentuating these mechanisms. Recent genetic studies in mice have allowed researchers to dissect this complex autoimmune disease into a collection of simpler immunological aberrations. These simpler murine models will facilitate the identification and characterization of the fundamental building blocks of lupus, and advance our understanding of the genetics and pathology of this intriguing disease.

Animals↗
PubMed1997

Genetic dissection of systemic lupus erythematosus pathogenesis: Sle2 on murine chromosome 4 leads to B cell hyperactivity.

Susceptibility to systemic lupus erythematosus in the NZM2410 murine model maps to Sle1, Sle2, Sle3, and the H2 loci. To unravel how these loci contribute to the pathogenesis of lupus, individual NZM2410-derived genomic intervals bearing these loci have been successfully backcrossed onto the resistant C57BL/6 (B6) background. The focus of this study was to understand how Sle2 on murine chromosome 4 impacts the immune system. Compared with C57BL/6 (B6) mice, B6 mice congenic for Sle2 exhibit a variety of immunophenotypes affecting their B cells. They have an early, but transient, expansion of splenic, CD23(low) B cells. Thereafter, their B cells appear activated by surface phenotype and functional criteria, paralleled by elevated serum levels of polyreactive/polyclonal IgM. Importantly, Sle2 leads to a heightened B cell responsiveness to in vitro stimuli and to in vivo antigenic challenge. Finally, they exhibit increased levels of peritoneal and splenic B1 cells. Thus, Sle2 harbors a gene that leads to B cell hyperactivity and elevated B1 cell formation. However, Sle2 by itself on the normal B6 background is insufficient to generate IgG antinuclear Abs (ANA) or nephritis. By reducing the B cell signaling threshold, Sle2 might serve to amplify an ongoing autoimmune response.

Animals↗
PubMed1997

Functional dissection of systemic lupus erythematosus using congenic mouse strains.

We describe the in vivo phenotypes associated with three genomic intervals containing systemic lupus erythematosus (SLE)-susceptibility genes derived from the SLE-prone NZM2410 strain on a C57BL/6 genome. These intervals were identified previously via a genome-wide analysis of SLE susceptibility in a (NZM2410 x C57BL/6)F1 x NZM2410 backcross, and transferred independently on a C57BL/6 background to produce three congenic strains: B6.NZMc1 carrying Sle1, B6.NZMc4 carrying Sle2, and B6.NZMc7 carrying Sle3. B6.NZMc1 develops high titers of IgG anti-nuclear autoantibodies in the absence of any severe nephritis. B6.NZMc4 spontaneously develops elevated levels of IgM, but not IgG Abs against several Ags, indicative of polyclonal activation or polyreactivity affecting the B cell lineage. B6.NZMc7 causes the production of IgM and IgG Abs against both nuclear and non-nuclear Ags and the development of severe lupus nephritis. Therefore, our results show that three defined genomic intervals from the NZM2410 SLE-prone strain each contribute specific component phenotypes that have been associated with SLE, which in combination can mediate severe disease.

Animals↗
PubMed1997

Insulin as a probe of mitochondrial metabolism in situ.

Our previous studies of insulin action have led us to the finding that insulin acts specifically on the mitochondrial Krebs cycle to stimulate, by 30%, the oxidation of carbons 2 and 3 of pyruvate to CO2. Insulin also stimulates the oxidation of both carbons of acetate. These carbons can be converted to CO2 only after passing through all of the reactions of the Krebs cycle more than once. Carboxyl groups, such as number 1 of pyruvate, are oxidized to CO2 without any effect of insulin, and can be converted to CO2 by extramitochondrial enzyme. We conclude that insulin must act on the complete intramitochondrial cycle and not on the four enzymes of the Krebs cycle which are present in the cytoplasm. The path taken by those carbons affected by insulin is traced through the complete Krebs cycle, and the necessity for this effect to be mitochondrial has been verified by demonstration of the same specific effect of insulin on the oxidation of the 2 and 3 carbons of succinate. The use of this phenomenon is proposed for the study not only of human diabetes, but of all mitochondrial disorders, by using 14C specifically labeled tracers in culture or biopsy material, or 13C labeled tracer material in vivo.

Animals↗
PubMed1996

Nucleosomal peptide epitopes for nephritis-inducing T helper cells of murine lupus.

Nucleosome-specific T helper (Th) cells provide major histocompatibility complex class II-restricted, cognate help to nephritogenic antinuclear autoantibody-producing B cells in lupus. However, the lupus Th cells do not respond when components of the nucleosome, such as free DNA or histones, are individually presented by antigen-presenting cells. Thus critical peptide epitopes for the pathogenic Th cells are probably protected during uptake and processing of the native nucleosome particle as a whole. Therefore, herein we tested 145 overlapping peptides spanning all four core histones in the nucleosome. We localized three regions in core histones, one in H2B at amino acid position 10-33 (H2B(10-33)), and two in H4, at position 16-39 (H4(16-39)) and position 71-94 (H4(71-94)), that contained the peptide epitopes recognized by the pathogenic autoantibody-inducing Th cells of lupus. The peptide autoepitopes also triggered the pathogenic Th cells of (SWR x NZB)F1 lupus mice in vivo to induce the development of severe lupus nephritis. The nucleosomal autoepitopes stimulated the production of Th1-type cytokines, consistent with immunoglobulin IgG2a, IgG2b, and IgG3 being the isotypes of nephritogenic autoantibodies induced in the lupus mice. Interestingly, the Th cell epitopes overlapped with regions in histones that contain B cell epitopes targeted by autoantibodies, as well as the sites where histones contact with DNA in the nucleosome. Identification of the disease-relevant autoepitopes in nucleosomes will help in understanding how the pathogenic Th cells of spontaneous systemic lupus erythematosus emerge, and potentially lead to the development of peptide-based tolerogenic therapy for this major autoimmune disease.

Amino Acid Sequence↗
PubMed1996

Perfluorocarbon emulsion prevents eicoasanoid release in skeletal muscle ischemia and reperfusion.

Eicosanoids play an important role in mediating deleterious effects following skeletal muscle ischemia-reperfusion injury. It has previously been shown that oxygenated perfluorocarbon emulsion (O2 Fluosol-DA 20%) decreases the amount of muscle necrosis and neutrophil sequestration when given during the reperfusion phase following skeletal muscle ischemia. As thromboxane is known to alter the endothelial cytoskeleton, thereby favoring diapedesis of neutrophils, the effects of O2 Fluosol-DA 20% on thromboxane release in a canine gracilis muscle model were investigated. The gracilis muscle on one randomly selected side of 14 adult mongrel dogs (body-weight 22-26 kg) was subjected to 6 h of normothermic ischemia followed by 48 h of normothermic reperfusion. The control group (n = 7) underwent ischemia-reperfusion, but without any pharmacological intervention. The Fluosol group (n = 7) were infused with O2 Fluosol-DA 20% (4.3(0.2) ml O2/100 ml) at 12 ml/min for 40 min via the gracilis artery following the ischemic period. Thromboxane B2 levels were measured from blood samples obtained at pre-ischemia, and at 1 h and 48 h of reperfusion. The gracilis muscles were harvested at the end of the experiment and extent of muscle necrosis quantitated by serial transections, nitroblue tetrazolium staining and computed planimetry. The mean(s.e.m.) muscle necrosis in the control group (59(6)%) was significantly higher than in the Fluosol group (22(5)%, P < 0.05, t-test). Thromboxane levels (pg/ml) in the control group at 1 h of reperfusion were significantly higher than the pre-ischemic and 48-h reperfusion levels (7286(1383) versus 1336(592) and 2314(1297), P < 0.05 by ANOVA and Student-Newman-Keuls test). The thromboxane level in the Fluosol group at 1 h reperfusion was significantly lower than the control group (2700(556) and 7286(1383) pg/ml, respectively; P < 0.05, t-test). In contrast, there was no statistically significant difference between thromboxane levels in the Fluosol group at 1 h reperfusion compared with levels at pre-ischemia and 48 h reperfusion (2700(556) versus 1336(592) and 1400(474). Thus, perfluorocarbons are effective in decreasing skeletal muscle necrosis, probably by maintaining the endothelial integrity and preventing vasospasm, secondary to their inhibitory effect on thromboxane release. Perfluorocarbons may also minimize some of the deleterious pulmonary effects known to be caused by increased levels of eicosanoids during reperfusion.

Animals↗
PubMed1995

Interaction between CD40 and its ligand gp39 in the development of murine lupus nephritis.

We investigated the role of gp39-CD40 interaction in the development of glomerulonephritis in lupus mice. In contrast to normal mice, lupus mice had much higher percentages of intensely gp39+ T cells in their spleens even at the preautoimmune age of 1 mo, and the further increase in gp39 expression by anti-CD3 Ab stimulation was markedly greater in lupus T cells. The pathogenic autoantibody-inducing ability of Th clones and splenic Th cells from lupus mice could be blocked in vitro by anti-gp39 Ab. Acceleration of lupus nephritis by the transfer of pathogenic autoantibody-inducing Th clones in vivo could also be completely blocked by anti-gp39 Ab. Surprisingly, a brief treatment of lupus mice with anti-gp39 Ab had a sustained beneficial effect on their spontaneous disease long after the Ab had been cleared from their systems. Only three injections of anti-gp39 Ab given to prenephritic lupus mice at 3 mo of age markedly delayed and reduced the incidence of lupus nephritis up to 12 mo of age by which time almost all the control mice had developed severe glomerulonephritis. Remarkably, pathogenic Th cells were left intact in these anti-gp39-treated mice but their B cells could not produce pathogenic autoantibodies even 9 mo after the therapy. Our studies suggest that blocking the interaction between gp39 on pathogenic Th cells and CD40 on lupus B cells at a crucial window of time delays the expansion autoimmune memory B cells resulting in long-term therapeutic benefits.

Animals↗
PubMed1995

Lupus: key pathogenic mechanisms and contributing factors.

The past 30 years of research on murine and human systemic lupus erythematosus has served to identify an array of immunological aberrations--some shared, some unique, some primary, others secondary-- that may underlie this disease. In integrating these findings, it appears that at least four distinct pathogenic events characterize lupus: (1) Anti-DNA Abs and immune complexes induce renal damage; (2) B-cells produce pathogenic anti-DNA antibodies; (3) Th cells drive lupus B-cells; and (4) Increased concentrations and abnormal presentation of nucleosomes. The purpose of this review is to examine the roles of these four events in the pathogenesis of lupus and to identify the different factors that can precipitate these pathogenic events.

Animals↗
PubMed1995

Mechanisms of the pathogenic autoimmune response in lupus: prospects for specific immunotherapy.

A major step towards understanding the basic mechanism of systemic lupus erythematosus (SLE), the prototypic autoimmune disease that develops spontaneously, has been the identification of nucleosomes as a primary immunogen in this disease. The production of pathogenic autoantibodies in SLE results from an MHC class-II-restricted, cognate interaction between select populations of T helper cells and B cells that are specific for nucleosomal components. These observations pave the way for specific immunotherapy that blocks this pathogenic T and B cell interaction.

Animals↗
PubMed1995

Impaired mitochondrial protein synthesis in streptozotocin diabetic rat hepatocytes.

Diabetes is associated with decreased protein synthesis; however, there have been very few studies on the effects of insulin or diabetes on mitochondrial protein synthesis. We have recently shown that insulin has a direct stimulatory effect on mitochondrial protein synthesis in isolated rat hepatocytes. In this study we demonstrate that mitochondrial protein synthesis is severely curtailed in hepatocytes isolated from diabetic rats and is unresponsive to in vitro insulin addition. Treatment of diabetic rats with insulin for three days partially restored tracer carbon incorporation in mitochondrial proteins. These results suggest that insulin stimulates hepatic mitochondrial protein synthesis which is significantly impaired in diabetes.

Animals↗