Prevalence of hand disorders in type 2 diabetes mellitus and its correlation with microvascular complications.

BACKGROUND: Physicians have long recognized the association between diabetes mellitus and several pathologic conditions of the hand. The most commonly recognized maladies are limited joint mobility (LJM), Dupuytren's disease (DD), trigger finger (TF), and carpal tunnel syndrome (CTS). Incidence of these hand disorders has increased in the setting of diabetes. Collectively, these are described as diabetic hand syndrome. AIM: The aims were to find out the prevalence of hand disorders in diabetic patients, and to study the relation of these hand disorders with microvascular complications. SUBJECTS AND METHODS: This is an observational cross-sectional case-control study done over a period of 1 year Patients of type 2 DM, of age < 65 years, who visited Gandhi Memorial Hospital, Lucknow were enrolled and were described as cases. Age- and sex-matched nondiabetic individuals were taken in the control group. The data were analyzed using software SPSS. SPSS Inc. Released 2008. SPSS Statistics for Windows, Version 17.0. Chicago: SPSS Inc. Means and standard deviations were computed; the Student t-test and Chi-square (χ(2)) test were used as appropriate. RESULTS: A total of 400 subjects were studied, 200 each in the case and control groups. Of total 200 diabetic patients, 30% (60/200) patients had neuropathy, 37.5% (75/200) had nephropathy, and 44.5% (89/200) patients had retinopathy. In the study population, 67% patients were having one or more hand disorders, in which LJM was found in 40.5% (81/200) patients, DD was found in 19% (38/200) patients, TF in 16.5% (33/200), and CTS in 14% (28/200) patients. CONCLUSIONS: This study shows a high prevalence of hand disorders in diabetic patients and also correlates with the duration of type 2 DM, LJM being the most common hand disorder and more common in patients who have microvascular complications.

Weight loss for reduction of proteinuria in diabetic nephropathy: Comparison with angiotensin-converting enzyme inhibitor therapy.

Reduction of weight in obese type 2 diabetes mellitus (T2DM) individuals is emerging as a significant strategy in the reduction of proteinuria in diabetic nephropathy along with control of hyperglycemia, hypertension, and dyslipidemia. The objective was to evaluate the reduction in 24-h proteinuria in T2DM patients with nephropathy by weight loss, with conventional therapy (angiotensin-converting enzyme [ACE] inhibitors) as the control arm. A prospective, randomized controlled trial was conducted between June 2010 and May 2011. T2DM patients with confirmed nephropathy by 24-h urinary protein estimation with a body mass index (BMI) of >25 kg/m(2) were studied. Patients who had nondiabetic nephropathy, uncontrolled hypertension (>125/75 mmHg) irrespective of antihypertensive drugs, excess weight due to edema or obesity due to other specific diseases, alcoholics, smokers, and patients who were on hemodialysis were excluded from the study. The patients were divided into three groups, namely, group A, patients on ACE inhibitor therapy; group B, patients on lifestyle modifications for weight loss; and group C, patients on an antiobesity drug (orlistat) and lifestyle modifications. At the end of 6 months, all the three groups were compared. Data were analyzed using software SPSS version 15.0. This study encompassed a total of 88 patients; 12 patients were dropped during the study period and 76 (group A: 22, group B: 23, and group C: 31) patients remained. The mean age of the patients was 58.36 ± 10.87 years (range: 30-70 years). At baseline, age, gender, mean BMI, waist-to-hip ratio (WHR), and 24-h proteinuria did not vary significantly among the three groups. At 6 months, the mean BMI significantly decreased in group C (P < 0.001) compared to that in the other two groups. Among the parameters BMI and WHR, the proportional form of BMI correlated well with the degree of reduction in proteinuria (r = 0.397, P = 0.01). Reduction in weight using lifestyle modifications and antiobesity drugs might improve renal function and proteinuria safely as observed in obese patients with diabetic nephropathy.

Can Metabolic Factors be used Prognostically for Short-Term Mortality in HIV-Infected Patients?

BACKGROUND: Metabolic abnormalities are common throughout the course of human immunodeficiency virus (HIV) infection and may occur either due to HIV infection or as a result of side effects of antiretroviral therapy. It has been established that dyslipidemia and dysglycemia associated with HIV disease reduce the long-term survival of the patients, but their role for predicting prognosis of short-term mortality in HIV patients is unknown. AIM: To study dyslipidemia and dysglycemia as a prognostic indicator for short-term mortality (<3 months) in HIV patients. SUBJECTS AND METHODS: An observational, prospective study was conducted at a tertiary care center over a period of 6 months. Consecutive HIV-positive patients hospitalized (both, HIV status known prior to hospitalization and the diagnosis made for the first time at admission) in medical wards from March to May 2010 were studied. All patients had their random blood sugars, fasting blood sugars (if possible), fasting lipid profile, and cluster of differentiation 4 (CD4) counts tested at the time of enrollment. The patients were followed for a period of 3 months, at the end of which they were categorized as survivors and non-survivors, and the demographic, clinical, and investigational parameters were compared between the above groups. Data was analyzed by applying Mann-Whitney U test, two sample t-test, Fisher-Exact test, and stepwise logistic regression analysis of significance, using the computer-based program, Stata, version 11.1. RESULTS: A total of 82 patients were enrolled for the study of which 64 (78.05%) were males and 18 (21.95%) were females, with a mean (SD) age of 34.00 (7.0) years. The mean CD4 count was 206.23 (129.5) cells/mm(3). The overall mortality within 3 months was 20.7% (17/82). Mycobacterium tuberculosis as opportunistic infection was found in 42 patients, out of which 13 expired (P=0.02). Patients with low high-density lipoprotein (HDL) and hypertriglyceridemia (adjusted OR = 22.92, P value = 0.03, adjusted OR = 3.4, P value = 0.02, respectively) had high likelihood of mortality within 3 months. CONCLUSIONS: Low HDL and hypertriglyceridemia also appear to be promising short-term mortality markers in HIV patients apart from established factors like low CD4 counts, co-morbid conditions, and opportunistic infections like M. tuberculosis infection. This study warrants further studies with a larger sample size to establish HDL and triglyceride as markers of disease progression and short-term mortality in HIV-infection.

Correlation of acanthosis nigricans with insulin resistance, anthropometric, and other metabolic parameters in diabetic Indians.

INTRODUCTION: Acanthosis nigricans is a non-specific reaction pattern that may accompany obesity, diabetes, excess corticosteroids, pineal tumors, malignancies, and other endocrine disorders. It is considered a cutaneous marker of tissue insulin resistance. AIMS AND OBJECTIVES: To determine the prevalence of acanthosis nigricans in type 2 diabetes mellitus (DM) and its correlation with various anthropometric measurements and insulin resistance by HOMA-IR and other metabolic parameters. MATERIALS AND METHODS: One hundred and fifty consecutive subjects with newly diagnosed type 2 DM, attending the endocrinology OPD of LLRM Medical College, Meerut were studied. Acanthosis was graded based on standard scale of 0-4 as described by Burke et al. Anthropometric data were obtained and insulin resistance calculated as HOMA-IR from fasting insulin and fasting blood sugar values. RESULTS: The average age of the study population was 45.2 years, with male to female ratio of 1:5. The prevalence of acanthosis in males was 56.67% and in females was 86.92%. The acanthosis neck severity grading had a statistically significant correlation with fasting glucose levels, fasting insulin levels, and insulin resistance values: HOMA-IR, HOMA-S, and HOMA-B (P < 0.05). Other acanthosis parameters such as axillary grading, acanthosis at knuckles, and skin tags, did not have a statistically significant correlation with insulin resistance. CONCLUSION: Acanthosis nigricans neck severity grading correlates well with insulin resistance and can be used as a clinical surrogate for assessment of severity of insulin resistance.

Atypical presentations of Wolframs syndrome.

BACKGROUND: Wolfram syndrome is a rare hereditary or sporadic neurodegenerative disorder also known as DIDMOAD. The classically described presentation is of insulin-dependent diabetes, followed by optic atrophy, central diabetes insipidus, and sensory neural deafness. Also included are less well-described presentations of Wolframs syndrome. We here present three cases of atypical presentation of this syndrome. CASE 1: A 15-year-old boy with insulin-dependent diabetes was presented for evaluation of depressive symptoms associated with suicidal tendency. Neuropsychiatric manifestations are described with Wolframs syndrome, and wolframin gene, in recessive inheritance, is associated with psychiatric illnesses without other manifestations of Wolframs syndrome. CASE 2: A 17-year-old diabetic boy on insulin with good control of blood sugar presented for evaluation of delayed puberty. Central hypogonadism and other anterior pituitary hormone dysfunctions are the less publicized hormone dysfunctions in Wolframs syndrome. CASE 3: A 23-year-old female who was on insulin for diabetes for the past 14 years, got admitted for evaluation of sudden loss of vision. This patient had developed a vitreous hemorrhage and, on evaluation, was found to have optic atrophy, sensory neural hearing loss, and diabetes insipidus, and presented differently from the gradual loss of vision described in Wolframs syndrome. CONCLUSION: Wolframs syndrome being a multisystem degenerative disorder can have myriad other manifestations than the classically described features. Neuropsychiatric manifestations, depression with suicidal risk, central hypogonadism, and secondary adrenal insufficiency are among the less well-described manifestations of this syndrome.

Can Metabolic Factors be Used Prognostically for Short-Term Mortality in HIV-Infected Patients?

Background: Metabolic abnormalities are common throughout the course of human immunodeficiency virus (HIV) infection and may occur either due to HIV infection or as a result of side effects of antiretroviral therapy. It has been established that dyslipidemia and dysglycemia associated with HIV disease reduce the long-term survival of the patients; but their role for predicting prognosis of short-term mortality in HIV patients is unknown. Aim: To study dyslipidemia and dysglycemia as a prognostic indicator for short-term mortality (3 months) in HIV patients. Subjects and Methods: An observational; prospective study was conducted at a tertiary care center over a period of 6 months. Consecutive HIV-positive patients hospitalized (both; HIV status known prior to hospitalization and the diagnosis made for the first time at admission) in medical wards from March to May 2010 were studied. All patients had their random blood sugars; fasting blood sugars (if possible); fasting lipid profile; and cluster of differentiation 4 (CD4) counts tested at the time of enrollment. The patients were followed for a period of 3 months; at the end of which they were categorized as survivors and non-survivors; and the demographic; clinical; and investigational parameters were compared between the above groups. Data was analyzed by applying Mann-Whitney U test; two sample t-test; Fisher-Exact test; and stepwise logistic regression analysis of significance; using the computer-based program; Stata; version 11.1. Results: A total of 82 patients were enrolled for the study of which 64 (78.05) were males and 18 (21.95) were females; with a mean (SD) age of 34.00 (7.0) years. The mean CD4 count was 206.23 (129.5) cells/mm 3 . The overall mortality within 3 months was 20.7 (17/82). Mycobacterium tuberculosis as opportunistic infection was found in 42 patients; out of which 13 expired (P

Can Metabolic Factors be Used Prognostically for Short-term Mortality in HIV-infected Patients?

Metabolic abnormalities are common throughout the course of human immunodeficiency virus (HIV) infection and may occur either due to HIV infection or as a result of side effects of antiretroviral therapy. It has been established that dyslipidemia and dysglycemia associated with HIV disease reduce the long-term survival of the patients; but their role for predicting prognosis of short-term mortality in HIV patients is unknown. Aim: To study dyslipidemia and dysglycemia as a prognostic indicator for short-term mortality (3 months) in HIV patients. Subjects and Methods: An observational; prospective study was conducted at a tertiary care center over a period of 6 months. Consecutive HIV-positive patients hospitalized (both; HIV status known prior to hospitalization and the diagnosis made for the first time at admission) in medical wards from March to May 2010 were studied. All patients had their random blood sugars; fasting blood sugars (if possible); fasting lipid profile; and cluster of differentiation 4 (CD4) counts tested at the time of enrollment. The patients were followed for a period of 3 months; at the end of which they were categorized as survivors and non-survivors; and the demographic; clinical; and investigational parameters were compared between the above groups. Data was analyzed by applying Mann-Whitney U test; two sample t-test; Fisher-Exact test; and stepwise logistic regression analysis of significance; using the computer-based program; Stata; version 11.1. Results: A total of 82 patients were enrolled for the study of which 64 (78.05) were males and 18 (21.95) were females; with a mean (SD) age of 34.00 (7.0) years. The mean CD4 count was 206.23 (129.5) cells/mm 3 . The overall mortality within 3 months was 20.7(17/82). Mycobacterium tuberculosis as opportunistic infection was found in 42 patients; out of which 13 expired (P

The Caenorhabditis elegans SH2 domain-containing protein tyrosine phosphatase PTP-2 participates in signal transduction during oogenesis and vulval development.

Src homology-2 (SH2) domain-containing protein tyrosine phosphatases (SHPs) have been identified as either positive or negative regulators of signaling events downstream of receptor protein tyrosine kinases (R-PTKs). We describe here our characterization of ptp-2, a Caenorhabditis elegans gene that encodes a 668-amino-acid SHP. We isolated a recessive ptp-2 loss-of-function allele, op194, that lacks the conserved protein tyrosine phosphatase catalytic domain by screening for transposon-mediated deletion mutations. Homozygous ptp-2(op194) hermaphrodites exhibit a completely penetrant zygotic semisterile/maternal effect lethal phenotype, characterized by the presence of abnormally large oocytes in the zygotic semisterile animals. These phenotypes indicate that PTP-2 activity is essential for proper oogenesis. Gain-of-function let-60 ras alleles rescued the defects associated with ptp-2(op194), suggesting that LET-60 Ras acts downstream of, or in parallel to, PTP-2 during oogenesis. Although ptp-2 function is not required for normal vulval development, ptp-2(op194) altered significantly the vulval phenotypes caused by mutations in several genes of the inductive signaling pathway. The penetrance of the multivulva phenotype caused by loss-of-function mutations in lin-15, and gain-of-function mutations in let-23 or let-60 ras, was reduced by ptp-2(op194). Moreover, ptp-2(op194) increased the penetrance of the vulvaless phenotype conferred by a weak loss-of-function sem-5 allele. Taken together, our genetic data positions PTP-2 activity downstream of LET-23 in the vulval induction signaling pathway. Although PTP-2 functions to transmit a requisite signal during oogenesis, PTP-2 function during C. elegans vulval cell differentiation appears to be directed at regulating the overall strength of the inductive signal, which may contribute to the quantitative differences in signaling required for the proper specification of the 1 degrees , 2 degrees , and 3 degrees vulval cell fates.

Distinct STAT structure promotes interaction of STAT2 with the p48 subunit of the interferon-alpha-stimulated transcription factor ISGF3.

Cells express a variety of STAT (signal transducer and activator of transcription) transcription factors that are structurally homologous and yet function specifically in response to particular cytokines. The functions of the individual STATs are dependent on distinct protein-protein interactions. STAT1 and STAT2 are activated by tyrosine phosphorylation in response to type I interferons-alpha/beta (IFN-alpha/beta) and subsequently form a multimeric transcription factor designated the IFN-alpha-stimulated gene factor 3 (ISGF3). ISGF3 is a unique STAT complex because it also contains a non-STAT molecule, p48, which is a critical DNA-binding component. We provide evidence that STAT2 specifically interacts with p48 in vivo before and after IFN-alpha stimulation. The specificity of ISGF3 formation is therefore a result of the distinct nature of the STAT2 molecule. Coimmunoprecipitation assays demonstrate p48 association with STAT2 but not STAT1. Hybrid STAT2. STAT1 molecules were used to identify a region of STAT2 which specifically associates with p48. The region of STAT2 interaction spans an amino-terminal region of two predicted coiled coils. The studies demonstrate the in vivo existence of a STAT2.p48 complex and a distinct STAT2.STAT1 complex after IFN-alpha stimulation. Data suggest that distinct bipartite complexes STAT2.p48 and STAT2.STAT1 translocate to the nucleus and associate on the DNA target site as ISGF3.

EBF contains a novel zinc coordination motif and multiple dimerization and transcriptional activation domains.

Early B cell factor (EBF) was identified and cloned as a transcription factor expressed specifically in B lymphocytes and adipocytes. This protein was also identified as olfactory factor 1 (Olf-1) in olfactory neurons. In this study, we analyzed the structural requirements for DNA binding, homodimerization and transcriptional activation by EBF. A carboxyl-terminal region, containing a repeat of alpha-helices related to the helix-loop-helix motif, is important for dimerization of EBF in solution and can confer dimerization upon a heterologous DNA binding protein. The amino-terminal DNA binding domain by itself is monomeric, but can mediate assembly of dimers on optimized and correctly spaced half-sites. Mutational analysis of the DNA binding domain of EBF indicated that a novel zinc coordination motif consisting of H-X3-C-X2-C-X5-C is important for DNA recognition. Deletion analysis and transfer of regions of EBF onto a heterologous DNA binding domain identified a serine/threonine-rich transcriptional activation domain. Moreover, the DNA binding domain of EBF can mediate transcriptional activation from optimized binding sites. Thus, EBF contains both a complex DNA binding domain that allows for dimerization and transcriptional activation, and additional dimerization and activation domains.

Tyrosine phosphorylation is required for activation of an alpha interferon-stimulated transcription factor.

The signal transduction pathway of alpha interferon utilizes tyrosine phosphorylation to transmit a signal generated at the cell surface to the transcriptional machinery in the nucleus. Activation of the interferon pathway initiates with the binding of alpha interferon to its cell surface receptor. The ligand-receptor complex signals the activation of a latent cytoplasmic transcription factor. The active form of the interferon-stimulated gene factor (ISGF3) is phosphorylated on tyrosine residues. ISGF3 subsequently translocates to the nucleus and binds to a DNA sequence, the interferon-stimulated response element, found within the promoter of inducible genes. ISGF3 is a multicomponent factor consisting of four proteins of 113 kDa, 91 kDa, 84 kDa, and 48 kDa. Three proteins consistent with sizes of 113 kDa, 91 kDa, and 84 kDa copurify with ISGF3 and are phosphorylated on tyrosine residues after stimulation by alpha interferon. Tyrosine phosphorylation is essential for activation of ISGF3. Genistein, a tyrosine kinase inhibitor, blocks the appearance of ISGF3 and blocks the transcriptional stimulation of interferon-induced genes. This study shows that tyrosine phosphorylation provides a link between the interferon-receptor complex at the plasma membrane and specific activation of gene expression in the nucleus.

Repression of the interferon signal transduction pathway by the adenovirus E1A oncogene.

The signal transduction pathway initiated by type I interferon (alpha and beta interferons) is inhibited by expression of the adenovirus type 5 E1A oncogene. Cotransfection analyses with the E1A oncogene and an interferon-stimulated reporter gene show that mutations within an amino-terminal domain of the E1A oncoprotein are defective in transcriptional repression. Cotransfection experiments also revealed that the transcriptional repression is mediated through the interferon-stimulated response element (ISRE) found within the promoter of interferon-stimulated genes. Since interferon treatment activates a latent cytoplasmic DNA-binding factor that can recognize the ISRE and subsequently stimulate transcription, the appearance of this factor was analyzed in a cell line that constitutively expresses the E1A oncogene. The DNA binding activity of this transcriptional activator was found to be inhibited in the E1A-expressing cell line. In vitro cytoplasmic mixing experiments with extracts from control and E1A-expressing cells identified a specific component of this multimeric transcription factor to be defective.