In Hospital Outcome of Acute Anterior Myocardial Infarction in Diabetic and Non-Diabetic Patients

Background: Patients with acute anterior myocardial infarction and diabetes have a poor prognosis. Objectives: To see the in-hospital outcome of acute anterior myocardial infarction in diabetic and non-diabetic patients. Methodology: This cross-sectional observational study was conducted in the Department of Cardiology, Sylhet MAG Osmani Medical College Hospital, Sylhet over a period of two years from July 2015 to June 2017. A total of 100 acute anterior MI patients (50 diabetic and 50 non diabetic) were included in this study. Acute anterior MI patients admitted after 6 hours of symptom onset or who did not receive streptokinase were excluded. Results: Male predominance was obvious in both groups [40 (80%) versus 42 (84%); p>0.05] in diabetic and non-diabetic group respectively. Mean age was 53.34 ± 11.32 and 54.84 ± 14.12 years in diabetic and non-diabetic groups respectively. Dyslipidemia [6 (12%) versus 6 (12%); p >0.05], Smoking [32 (64%) versus 34 (68%); p >0.05] and Family history of cardiovascular disease [6 (12%) versus 4 (8%); p >0.05] were similar among diabetic and non-diabetic respectively. Hypertension was found more among non-diabetic [27 (54%) versus 19 (38%); p>0.05] but difference was not statistically significant. Diabetic group had more Apical Anterior MI [22 (44%) versus 19 (38%); p<0.05] and Extensive Anterior MI [20 (40%) versus 11 (22%); p<0.05] while non-diabetic group had more Septal MI [10 (20%) versus 3 (6%); p<0.05] and Mid Anterior MI [10 (20%) versus 4 (8%); p<0.05]. LV ejection fraction was found significantly low in diabetic patients [43.96 ± 5.95 versus 53.68 ± 6.36; p<0.01]. Killip Class III was more in diabetic [24 (48%) versus 9 (18%); p<0.01] and Killip Class I was more in non-diabetic group [18 (36%) versus 3 (6%); p<0.01] according to Killip classification of HF which was statistically significant between the two groups. Atrial Fibrillation was more in diabetics [6 (12%) versus 1 (2%); p<0.05] while sinus tachycardia was more among non-diabetics [20 (40%) versus 5 (10%); p<0.05] which are statistically significant. Diabetic group had more acute MR [2 (4%) versus 0 (0%); p>0.05] but was not significant. Death was more in diabetic group than that of non-diabetic group [7 (14%) versus 3 (6%); p>0.05] but it was statistically not significant. Conclusion: It is concluded from the present study that in hospital outcomes of acute anterior myocardial infarction are worse in diabetic patients than in non-diabetic patients

Redox biology of Mycobacterium tuberculosis H37Rv: protein-protein interaction between GlgB and WhiB1 involves exchange of thiol-disulfide

<p>Abstract</p> <p>Background</p> <p><it>Mycobacterium tuberculosis</it>, an intracellular pathogen encounters redox stress throughout its life inside the host. In order to protect itself from the redox onslaughts of host immune system, <it>M. tuberculosis </it>appears to have developed accessory thioredoxin-like proteins which are represented by ORFs encoding WhiB-like proteins. We have earlier reported that WhiB1/Rv3219 is a thioredoxin like protein of <it>M. tuberculosis </it>and functions as a protein disulfide reductase. Generally thioredoxins have many substrate proteins. The current study aims to identify the substrate protein(s) of <it>M. tuberculosis </it>WhiB1.</p> <p>Results</p> <p>Using yeast two-hybrid screen, we identified alpha (1,4)-glucan branching enzyme (GlgB) of <it>M. tuberculosis </it>as a interaction partner of WhiB1. <it>In vitro </it>GST pull down assay confirmed the direct physical interaction between GlgB and WhiB1. Both mass spectrometry data of tryptic digests and <it>in vitro </it>labeling of cysteine residues with 4-acetamido-4' maleimidyl-stilbene-2, 2'-disulfonic acid showed that in GlgB, C⁹⁵and C⁶⁵⁸are free but C¹⁹³and C⁶¹⁷form an intra-molecular disulfide bond. WhiB1 has a C³⁷XXC⁴⁰motif thus a C⁴⁰S mutation renders C³⁷to exist as a free thiol to form a hetero-disulfide bond with the cysteine residue of substrate protein. A disulfide mediated binary complex formation between GlgB and WhiB1C⁴⁰S was shown by both in-solution protein-protein interaction and thioredoxin affinity chromatography. Finally, transfer of reducing equivalent from WhiB1 to GlgB disulfide was confirmed by 4-acetamido-4' maleimidyl-stilbene-2, 2'-disulfonic acid trapping by the reduced disulfide of GlgB. Two different thioredoxins, TrxB/Rv1471 and TrxC/Rv3914 of <it>M. tuberculosis </it>could not perform this reaction suggesting that the reduction of GlgB by WhiB1 is specific.</p> <p>Conclusion</p> <p>We conclude that <it>M. tuberculosis </it>GlgB has one intra-molecular disulfide bond which is formed between C¹⁹³and C⁶¹⁷. WhiB1, a thioredoxin like protein interacts with GlgB and transfers its electrons to the disulfide thus reduces the intra-molecular disulfide bond of GlgB. For the first time, we report that GlgB is one of the <it>in vivo </it>substrate of <it>M. tuberculosis </it>WhiB1.</p

Large scale analyses of genotype-phenotype relationships of glycine decarboxylase mutations and neurological disease severity.

Monogenetic diseases provide unique opportunity for studying complex, clinical states that underlie neurological severity. Loss of glycine decarboxylase (GLDC) can severely impact neurological development as seen in non-ketotic hyperglycinemia (NKH). NKH is a neuro-metabolic disorder lacking quantitative predictors of disease states. It is characterized by elevation of glycine, seizures and failure to thrive, but glycine reduction often fails to confer neurological benefit, suggesting need for alternate tools to distinguish severe from attenuated disease. A major challenge has been that there are 255 unique disease-causing missense mutations in GLDC, of which 206 remain entirely uncharacterized. Here we report a Multiparametric Mutation Score (MMS) developed by combining in silico predictions of stability, evolutionary conservation and protein interaction models and suitable to assess 251 of 255 mutations. In addition, we created a quantitative scale of clinical disease severity comprising of four major disease domains (seizure, cognitive failure, muscular and motor control and brain-malformation) to comprehensively score patient symptoms identified in 131 clinical reports published over the last 15 years. The resulting patient Clinical Outcomes Scores (COS) were used to optimize the MMS for biological and clinical relevance and yield a patient Weighted Multiparametric Mutation Score (WMMS) that separates severe from attenuated neurological disease (p = 1.2 e-5). Our study provides understanding for developing quantitative tools to predict clinical severity of neurological disease and a clinical scale that advances monitoring disease progression needed to evaluate new treatments for NKH

Genomic Expression Analyses Reveal Lysosomal, Innate Immunity Proteins, as Disease Correlates in Murine Models of a Lysosomal Storage Disorder

<div><p>Niemann-Pick Type C (NPC) disease is a rare, genetic, lysosomal disorder with progressive neurodegeneration. Poor understanding of the pathophysiology and a lack of blood-based diagnostic markers are major hurdles in the treatment and management of NPC and several additional, neurological lysosomal disorders. To identify disease severity correlates, we undertook whole genome expression profiling of sentinel organs, brain, liver, and spleen of <em>Balb/c Npc1^−/−</em> mice relative to <em>Npc1^+/−</em> at an asymptomatic stage, as well as early- and late-symptomatic stages. Unexpectedly, we found prominent up regulation of innate immunity genes with age-dependent change in their expression, in all three organs. We shortlisted a set of 12 secretory genes whose expression steadily increased with age in both brain and liver, as potential plasma correlates of neurological and/or liver disease. Ten were innate immune genes with eight ascribed to lysosomes. Several are known to be elevated in diseased organs of murine models of other lysosomal diseases including Gaucher’s disease, Sandhoff disease and MPSIIIB. We validated the top candidate lysozyme, in the plasma of <em>Npc1^−/−</em> as well as <em>Balb/c Npc1^nmf164</em> mice (bearing a point mutation closer to human disease mutants) and show its reduction in response to an emerging therapeutic. We further established elevation of innate immunity in <em>Npc1^−/−</em> mice through multiple functional assays including inhibition of bacterial infection as well as cellular analysis and immunohistochemistry. These data revealed neutrophil elevation in the <em>Npc1</em>^−/− spleen and liver (where large foci were detected proximal to damaged tissue). Together our results yield a set of lysosomal, secretory innate immunity genes that have potential to be developed as pan or specific plasma markers for neurological diseases associated with lysosomal storage and where diagnosis is a major problem. Further, the accumulation of neutrophils in diseased organs (hitherto not associated with NPC) suggests their role in pathophysiology and disease exacerbation.</p> </div

Top 20 up regulated genes in liver of <i>Npc1^−/−</i> mice across three age groups (20–71 days).

<p>Genes marked in bold are related to innate immunity and the genes marked in bold and also underlined are innate immunity genes catalogued by InnateDB.</p

Attenuated proliferation of <i>S. typhimurium</i> in (A) spleen and (B) liver of <i>Npc1^−/−</i> mice.

<p><i>Npc1</i>^+/+, <i>Npc1^+/− and Npc1</i>^−/−, mice (age 6–8 weeks) were infected with <i>S. typhimurium</i> (1×10⁴ CFU) by i.p injection. At 48 hpi, mice were sacrificed, organs isolated and bacterial CFU were determined. The data obtained from 3 independent experiments are shown. n = 10 for <i>Npc1</i>^+/+ and <i>Npc1</i>^−/− and n = 8 for <i>Npc1</i>^+/−. Error bar show the mean±SEM. Student’s <i>t</i> test was carried out to determine the statistical significance.</p

Top 20 up regulated genes in spleen of <i>Npc1^−/−</i> mice across three age groups (20–71 days).

<p>Genes marked in bold are related to innate immunity and the genes marked in bold and also underlined are innate immunity genes catalogued by InnateDB.</p

Enrichment of top 10 biofunctions pathways in brain, liver and spleen of <i>Npc1</i>^−/− mice. (A)

<p>The top 10 biofunctions pathways derived from IPA analyses of differentially expressed genes in the brain of <i>Npc1</i>^−/− mice and ranked by ‘p values’ (lowest to highest) are shown. The numbers along each bar represent the total number of differentially expressed genes (both up and down regulated) categorized in each biofunction (see also <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0048273#pone.0048273.s007" target="_blank">Table S4</a>). A total of 53 genes (45 up and 8 down regulated) associated with immune response were enriched in the brain of <i>Npc1</i>^−/− across all time points (B) Bar diagram shows the top 10 biofunctions enriched in the liver of <i>Npc1</i>^−/− compared to <i>Npc1</i>^+/−. A total of 209 genes (159 up and 50 down regulated) associated with the immune response were enriched in the liver of <i>Npc1</i>^−/− across all time points (see also <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0048273#pone.0048273.s007" target="_blank">Table S4</a>). (C) Bar diagram shows the top 10 biofunctions enriched in the spleen of <i>Npc1</i>^−/− compared to <i>Npc1</i>^+/−. A total of 58 genes (49 up and 9 down regulated) associated with the immune response were enriched in the spleen of <i>Npc1</i>^−/− across all time points (see <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0048273#pone.0048273.s007" target="_blank">Table S4</a>).</p

Top 20 up regulated genes in brain of <i>Npc1^−/−</i> mice across the life span (20–84 days).

<p>Genes marked in bold are related to innate immunity and the genes marked in bold and also underlined are innate immunity genes catalogued by InnateDB.</p