Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0011849 (diabetes)
 277,896 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Melioidosis which is infection with Burkholderia pseudomallei, is an important cause of sepsis in India, southeast Asia and northern Australia. Mortality is high and treatment is problematic. Neurological melioidosis is unusual but meningoencephalitis, encephalomyelitis and brain microabscess can occur Dural sinus thrombosis is not an uncommon cerebrovascular disorder with various etiologies. Hypercoagulable state, pregnancy, dehydration, certain blood dyscrasia and contraceptive pills are common causes however meningitis and local head & neck infections may lead to this condition. Dural sinus thrombosis complicating septicemic melioidosis has never been reported. The authors report a 42-year-old Thai man suffering from septicemic melioidosis with dural sinus thrombosis. He had high fever, headache, left hemiparesis, focal seizure and increased intracranial pressure. Diabetes and mild alcoholic cirrhosis were diagnosed in this admission. CT scan, MRI brain and MRV revealed superior saggital sinus thrombosis with complicating venous infarction over right posterior parietal lobe. Hemoculture demonstrated Burkholderia pseudomallei and CSF was acellular Investigations for causes of dural sinus thrombosis were all negative. This patient gradually improved after treatment with ceftazidime, antiepileptic drug and heparin without clinical recurrence. Neuromelioidosis is a rare syndrome that may present as brain abscess, encephalitis or meningoencephalitis. The authors report dural sinus thrombosis associated with septicemic melioidosis. The authors' hypothesis of venous thrombosis in the presented case is sepsis induced hypercoagulable state. Physicians should be aware of cerebral venous thrombosis in case of suspicious melioidosis with neurological involvement. Prompt treatment with intravenous heparin and antibiotic is potentially effective.
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PMID:Dural sinus thrombosis in melioidosis: the first case report. 1657 13

Nonviral gene transfer is markedly enhanced by the application of in vivo electroporation (also denoted electro-gene transfer or electrokinetic enhancement). This approach is safe and can be used to deliver nucleic acid fragments, oligonucleotides, siRNA, and plasmids to a wide variety of tissues, such as skeletal muscle, skin and liver. In this review, we address the principles of electroporation and demonstrate its effectiveness in disease models. Electroporation has been shown to be equally applicable to small and large animals (rodents, dogs, pigs, other farm animals and primates), and this addresses one of the major problems in gene therapy, that of scalability to humans. Gene transfer can be optimized and tissue injury minimized by the selection of appropriate electrical parameters. We and others have applied this approach in preclinical autoimmune and/or inflammatory diseases to deliver either cytokines, anti-inflammatory agents or immunoregulatory molecules. Electroporation is also effective for the intratumoral delivery of therapeutic vectors. It strongly boost DNA vaccination against infectious agents (e.g., hepatitis B virus, human immunodeficiency virus-1) or tumor antigens (e.g., HER-2/neu, carcinoembryonic antigen). In addition, we found that electroporation-enhanced DNA vaccination against islet-cell antigens ameliorated autoimmune diabetes. One of the most likely future applications, however, may be in intramuscular gene transfer for systemic delivery of either endocrine hormones (e.g., growth hormone releasing hormone and leptin), hematopoietic factors (e.g., erythropoietin, GM-CSF), antibodies, enzymes, or numerous other protein drugs. In vivo electroporation has been performed in humans, and it seems likely it could be applied clinically for nonviral gene therapy.
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PMID:Electroporation-enhanced nonviral gene transfer for the prevention or treatment of immunological, endocrine and neoplastic diseases. 1661 Oct 45

Increasing attention is drawn to the contributions of abnormalities in both innate and acquired immune responses to the pathogenesis of autoimmune diseases, such as type 1 diabetes (T1D). Dendritic cells (DC) are critical immune cells linking innate and acquired immune responses and previous studies in NOD mice suggest abnormalities in these cells. To address DC dysregulation we examined kinetic global gene expression in NOD and B6 GM-CSF/IL-4-induced bone marrow-derived DC following lipopolysaccharide (LPS)-stimulation. We identified expression differences in over 300 genes including a cluster of 16 interferon (IFN-alpha/beta) target genes overexpressed in NOD DC. Mechanistically, heightened IFN-alpha/beta responses were not due to increased production of this cytokine, IFN-gamma priming or increased Syk kinase activity. We found, however, heightened responses to IFN-alpha/beta in NOD versus B6 as demonstrated by increased type 1 IFN target gene expression, for example, IRF-7, in NOD DC and macrophages. Analysis of multiple congenic strains demonstrated that the Idd5 susceptibility region largely governed heightened IFN-alpha responses. Of interest, heightened IFN-alpha/beta response in NOD mice was not confined to hematopoietic cells but was also seen in the pancreas and beta cells. Compounding the IFN-alpha response defect, NOD mice harbor significantly more PDC in spleen in comparison to B6 and produce four- to sixfold more IFN-alpha when stimulated with CpG. Finally, treatment of NOD mice with IFN-alpha inducing agents, for example, high-dose poly I:C accelerates diabetes in both female and male mice. The abnormalities in the IFN-alpha/beta axis appear to play a significant role in T1D pathogenesis.
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PMID:Heightened interferon-alpha/beta response causes myeloid cell dysfunction and promotes T1D pathogenesis in NOD mice. 1713 May 37

Type 2 diabetes and major depression are disorders that are mutual risk factors and may share similar pathophysiological mechanisms. To further understand these shared mechanisms, the purpose of our study was to examine the biochemical basis of depression in patients with type 2 diabetes using proton MRS. Patients with type 2 diabetes and major depression (n=20) were scanned along with patients with diabetes alone (n=24) and healthy controls (n=21) on a 1.5 T MRI/MRS scanner. Voxels were placed bilaterally in dorsolateral white matter and the subcortical nuclei region, both areas important in the circuitry of late-life depression. Absolute values of myo-inositol, creatine, N-acetyl aspartate, glutamate, glutamine, and choline corrected for CSF were measured using the LC-Model algorithm. Glutamine and glutamate concentrations in depressed diabetic patients were significantly lower (p<0.001) in the subcortical regions as compared to healthy and diabetic control subjects. Myo-inositol concentrations were significantly increased (p<0.05) in diabetic control subjects and depressed diabetic patients in frontal white matter as compared to healthy controls. These findings have broad implications and suggest that alterations in glutamate and glutamine levels in subcortical regions along with white matter changes in myo-inositol provide important neurobiological substrates of mood disorders.
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PMID:Measurement of brain metabolites in patients with type 2 diabetes and major depression using proton magnetic resonance spectroscopy. 1718 Jan 24

Viral infections are associated epidemiologically with the expression of type 1 diabetes in humans, but the mechanisms underlying this putative association are unknown. To investigate the role of viruses in diabetes, we used a model of viral induction of autoimmune diabetes in genetically susceptible biobreeding diabetes-resistant (BBDR) rats. BBDR rats do not develop diabetes in viral-Ab-free environments, but approximately 25% of animals infected with the parvovirus Kilham rat virus (KRV) develop autoimmune diabetes via a mechanism that does not involve beta cell infection. Using this model, we recently documented that TLR agonists synergize with KRV infection and increase disease penetrance. We now report that KRV itself activates innate immunity through TLR ligation. We show that KRV infection strongly stimulates BBDR splenocytes to produce the proinflammatory cytokines IL-6 and IL-12p40 but not TNF-alpha. KRV infection induces high levels of IL-12p40 by splenic B cells and Flt-3-ligand-induced bone marrow-derived dendritic cells (DCs) but only low levels of IL-12p40 production by thioglycolate-elicited peritoneal macrophages or GM-CSF plus IL-4-induced bone marrow-derived DCs. KRV-induced cytokine production is blocked by pharmacological inhibitors of protein kinase R and NF-kappaB. Genomic KRV DNA also induces BBDR splenocytes and Flt-3L-induced DCs from wild-type but not TLR9-deficient mice to produce IL-12p40; KRV-induced up-regulation of B lymphocytes can be blocked by TLR9 antagonists including inhibitory CpG and chloroquine. Administration of chloroquine to virus-infected BBDR rats decreases the incidence of diabetes and decreases blood levels of IL-12p40. Our data implicate the TLR9-signaling pathway in KRV-induced innate immune activation and autoimmune diabetes in the BBDR rat.
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PMID:TLR9-signaling pathways are involved in Kilham rat virus-induced autoimmune diabetes in the biobreeding diabetes-resistant rat. 1720 29

Type 1 diabetes (T1D) is a polygenic autoimmune disease with a strong HLA association particularly, HLA-DQ8. We investigated whether islet-specific expression of granulocyte/macrophage colony-stimulating factor (Ins.GM-CSF) in A Beta degrees.NOD.DQ8 mice (HLA-DQ8 transgenic mice on a NOD background lacking endogenous mouse MHC class II molecules) would predispose to development of spontaneous autoimmune diabetes. A Beta degrees.NOD.DQ8 mice expressing GM-CSF in the pancreatic ss cells (8+ G+) as well as litter mates lacking either HLA-DQ8 (8 - G+) or GM-CSF (8+ G -) or both (8 - G -) exhibited insulitis and sialadenitis of varying degrees. But none of the mice progressed to develop T1D. Other than the marked mononuclear cell infiltration in livers of mice expressing GM-CSF irrespective of HLA-DQ8 expression (8+ G+ or 8 - G+), no other changes were observed in the animals. Thus, we have shown for the first time that expression of HLA-DQ8 in the diabetes-predisposing mileu of NOD genetic background is not sufficient to predispose to development of autoimmune diabetes even when the potent immunostimulatory cytokine, GM-CSF is expressed in the pancreatic islets.
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PMID:Autoimmunity in HLA-DQ8 transgenic mice expressing granulocyte/macrophage-colony stimulating factor in the beta cells of islets of Langerhans. 1745 15

Autoimmune diabetes results from a breakdown of self-tolerance that leads to T cell-mediated beta-cell destruction. Abnormal maturation and other defects of dendritic cells (DCs) have been associated with the development of diabetes. Evidence is accumulating that self-tolerance can be restored and maintained by semimature DCs induced by GM-CSF. We have investigated whether GM-CSF is a valuable strategy to induce semimature DCs, thereby restoring and sustaining tolerance in NOD mice. We found that treatment of prediabetic NOD mice with GM-CSF provided protection against diabetes. The protection was associated with a marked increase in the number of tolerogenic immature splenic DCs and in the number of Foxp3+CD4+CD25+ regulatory T cells (Tregs). Activated DCs from GM-CSF-protected mice expressed lower levels of MHC class II and CD80/CD86 molecules, produced more IL-10 and were less effective in stimulating diabetogenic CD8+ T cells than DCs of PBS-treated NOD mice. Adoptive transfer experiments showed that splenocytes of GM-CSF-protected mice did not transfer diabetes into NOD.SCID recipients. Depletion of CD11c+ DCs before transfer released diabetogenic T cells from the suppressive effect of CD4+CD25+ Tregs, thereby promoting the development of diabetes. These results indicated that semimature DCs were required for the sustained suppressive function of CD4+CD25+ Tregs that were responsible for maintaining tolerance of diabetogenic T cells in NOD mice.
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PMID:Granulocyte-macrophage colony-stimulating factor prevents diabetes development in NOD mice by inducing tolerogenic dendritic cells that sustain the suppressive function of CD4+CD25+ regulatory T cells. 1778 99

The aim of this study was to assess if differences in etiology and risk factors among 372 cases of bacterial meningitis acquired after surgery (PM) or in community (CBM) have impact on outcome of infected patients. Among 372 cases of bacterial meningitis within last 17 years from 10 major Slovak hospitals, 171 were PM and 201 CBM. Etiology, risk factors such as underlying disease, cancer, diabetes alcoholism, surgery, VLBW, ENT infections, trauma, sepsis were recorded and mortality, survival with sequellae, therapy failure were compared in both groups. Significant differences in etiology and risk factors between both groups were reported. Those after neurosurgery had more frequently Coagulase negative staphylococci (p<0.001), Enterobacteriaceae (p=0.01) and Acinetobacter baumannii (p=0.0008) isolated from CSF and vice versa Streptococcus pneumoniae (p<0.001), Neisseria meningitis (p<0.001) and Haemophillus influenza (p=0.0009) were more commonly isolated from CSF in CBM. Neurosurgery (p<0.001), sepsis (p=0.006), VLBW neonates (p=0.00002) and cancer (p=0.0007) were more common in PM and alcohol abuse (p<0.001) as well as otitis/sinusitis (p<0.001) and Roma ethnic group (p=0.001) in CAM. Initial treatment success was significantly more frequently observed among CAM (p<0.001) but cure after modification was more common in PM (p=0.002). Therefore outcome in both groups was similar (14.6% vs. 12.4%, p=NS).
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PMID:Comparison of postsurgical and community acquired bacterial meningitis--analysis of 372 cases within a nationwide survey. 1803 Feb 63

Central nervous system tuberculosis (TB) was identified in 20 cases of unexplained encephalitis referred to the California Encephalitis Project. Atypical features (encephalitic symptoms, rapid onset, age) and diagnostic challenges (insensitive cerebrospinal fluid [CSF] TB PCR result, elevated CSF glucose levels in patients with diabetes, negative result for tuberculin skin test) complicated diagnosis.
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PMID:Diagnostic challenges of central nervous system tuberculosis. 1876 24

Myeloid cells from non-obese diabetic (NOD) mouse and human type 1 diabetic (T1D) patients overexpress granulocyte-macrophage colony stimulation factor (GM-CSF). This overproduction prolongs the activation of signal transduction and activator of transcription 5 (STAT5) proteins, involved in GM-CSF-induced control of myeloid cell gene expression. We found that GM-CSF can regulate the binding of STAT5 on the promoter of its own gene, Csf2, within regions previously identified as sites of chromatin epigenetic modification important to the regulation of GM-CSF during myeloid differentiation and inflammation. We found multiple sequence polymorphisms within NOD mouse chromosome 11 Idd4.3 diabetes susceptibility region that alter STAT5 GAS binding sequences within the Csf2 promoter. STAT5 binding at these sites in vivo is increased significantly in GM-CSF-stimulated-bone marrow cells and in unactivated, high GM-CSF-producing macrophages from NOD mice as compared to non-autoimmune C57BL/6 mouse myeloid cells. Thus, GM-CSF overproduction by NOD myeloid cells may be perpetuating a positive epigenetic regulatory feedback on its own gene expression through its induction of STAT5 binding to its promoter. These findings suggest that aberrant STAT5 binding at epigenetic regulatory sites may contribute directly to immunopathology through cytokine-induced gene expression dysregulation that can derail myeloid differentiation and increase inflammatory responsiveness.
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PMID:GM-CSF induces STAT5 binding at epigenetic regulatory sites within the Csf2 promoter of non-obese diabetic (NOD) mouse myeloid cells. 1894 91


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