Long-term type 1 diabetes impairs decidualization and extracellular matrix remodeling during early embryonic development in mice

Introduction: Endometrial decidualization and associated extracellular matrix (ECM) remodeling are critical events to the establishment of the maternal-fetal interface and successful pregnancy. Here, we investigated the impact of type 1 diabetes on these processes during early embryonic development, in order to contribute to the understanding of the maternal factors associated to diabetic embryopathies. Methods: Alloxan-induced diabetic Swiss female mice were bred after different periods of time to determine the effects of diabetes progression on the development of gestational complications. Furthermore, the analyses focused on decidual development as well as mRNA expression, protein deposition and ultrastructural organization of decidual ECM. Results: Decreased number of implantation sites and decidual dimensions were observed in the group mated 90-110 days after diabetes induction (D), but not in the 50-70D group. Picrosirius staining showed augmentation in the fibrillar collagen network in the 90e110D group and, following immunohistochemical examination, that this was associated with increase in types I and V collagens and decrease in type III collagen and collagen-associated proteoglycans biglycan and lumican. qPCR, however, demonstrated that only type I collagen mRNA levels were increased in the diabetic group. Alterations in the molecular ratio among distinct collagen types and proteoglycans were associated with abnormal collagen fibrillogenesis, analyzed by transmission electron microscopy. Conclusions: Our results support the concept that the development of pregnancy complications is directly related with duration of diabetes (progression of the disease), and that this is a consequence of both systemic factors (i.e. disturbed maternal endocrine-metabolic profile) and uterine factors, including impaired decidualization and ECM remodeling

Worldwide spread of Dengue virus type 1

BACKGROUND: DENV-1 is one of the four viral serotypes that causes Dengue, the most common mosquito-borne viral disease of humans. The prevalence of these viruses has grown in recent decades and is now present in more than 100 countries. Limited studies document the spread of DENV-1 over the world despite its importance for human health. METHODOLOGY/PRINCIPAL FINDINGS: We used representative DENV-1 envelope gene sequences to unravel the dynamics of viral diffusion under a Bayesian phylogeographic approach. Data included strains from 45 distinct geographic locations isolated from 1944 to 2009. The estimated mean rate of nucleotide substitution was 6.56 × 10⁻⁴ substitutions/site/year. The larger genotypes (I, IV and V) had a distinctive phylogenetic structure and since 1990 they experienced effective population size oscillations. Thailand and Indonesia represented the main sources of strains for neighboring countries. Besides, Asia broadcast lineages into the Americas and the Pacific region that diverged in isolation. Also, a transmission network analysis revealed the pivotal role of Indochina in the global diffusion of DENV-1 and of the Caribbean in the diffusion over the Americas. CONCLUSIONS/SIGNIFICANCE: The study summarizes the spatiotemporal DENV-1 worldwide spread that may help disease control.

QTc interval and resting heart rate as long-term predictors of mortality in type 1 and type 2 diabetes mellitus: a 23-year follow-up

We evaluated the association of QT interval corrected for heart rate (QT(c)) and resting heart rate (rHR) with mortality (all-causes, cardiovascular, cardiac, and ischaemic heart disease) in subjects with type 1 and type 2 diabetes.

Apolipoprotein B as a long-term predictor of mortality in type 1 diabetes mellitus: a 15-year follow up

To evaluate the association of apolipoprotein B (apo B) with mortality due to all causes, to cardiac disease and to ischaemic heart disease (IHD) in subjects with type 1 diabetes mellitus.

Characteristics, determinants, and clinical relevance of CD4 T cell recovery to <500 cells/microL in HIV type 1-infected individuals receiving potent antiretroviral therapy

BACKGROUND: The CD4 T cell count recovery in human immunodeficiency virus type 1 (HIV-1)-infected individuals receiving potent antiretroviral therapy (ART) shows high variability. We studied the determinants and the clinical relevance of incomplete CD4 T cell restoration. METHODS: Longitudinal CD4 T cell count was analyzed in 293 participants of the Swiss HIV Cohort Study who had had a plasma HIV-1 RNA load <1000 copies/mL for > or =5 years. CD4 T cell recovery was stratified by CD4 T cell count 5 years after initiation of ART (> or =500 cells/microL was defined as a complete response, and <500 cells/microL was defined as an incomplete response). Determinants of incomplete responses and clinical events were evaluated using logistic regression and survival analyses. RESULTS: The median CD4 T cell count increased from 180 cells/microL at baseline to 576 cells/microL 5 years after ART initiation. A total of 35.8% of patients were incomplete responders, of whom 47.6% reached a CD4 T cell plateau <500 cells/microL. Centers for Disease Control and Prevention HIV-1 disease category B and/or C events occurred in 21% of incomplete responders and in 14.4% of complete responders (P>.05). Older age (adjusted odds ratio [aOR], 1.71 per 10-year increase; 95% confidence interval [CI], 1.21-2.43), lower baseline CD4 T cell count (aOR, 0.37 per 100-cell increase; 95% CI, 0.28-0.49), and longer duration of HIV infection (aOR, 2.39 per 10-year increase; 95% CI, 1.19-4.81) were significantly associated with a CD4 T cell count <500 cells/microL at 5 years. The median increases in CD4 T cell count after 3-6 months of ART were smaller in incomplete responders (P<.001) and predicted, in conjunction with baseline CD4 T cell count and age, incomplete response with 80% sensitivity and 72% specificity. CONCLUSION: Individuals with incomplete CD4 T cell recovery to <500 cells/microL had more advanced HIV-1 infection at baseline. CD4 T cell changes during the first 3-6 months of ART already reflect the capacity of the immune system to replenish depleted CD4 T lymphocytes.

Prevalence of cholecystolithiasis and its management among kidney/pancreas-transplanted type 1 (insulin-dependent) diabetic patients

BACKGROUND: Simultaneous pancreas/kidney transplantation (SPK) should be the procedure of choice for (pre)uremic patients with type 1 diabetes. All standard immunosuppressive protocols for SPK include a calcineurin-inhibitor. Both calcineurin inhibitors, cyclosporine (CyA) and probably tacrolimus (FK506) too, are associated with the occurrence of cholelithiasis due to their metabolic side effects. PATIENTS AND METHODS: We evaluated the prevalence of cholelithiasis in 83 kidney/pancreas transplanted type I-diabetic patients (46 males, 37 females, mean age 42.8 +/- 7.5 years) by conventional B-mode ultrasound 5 years after transplantation. 56 patients received CyA (group 1) and 27 received tacrolimus (group 2) as first-line-immunosuppressive drug. Additional immunosuppression consisted of steroids, azathioprine or mycophenolate mofetil. Additionally, laboratory analyses of cholestasis parameters (gamma-GT and alcalic phosphatasis) were performed. RESULTS: In total, 23 patients (28%) revealed gallstones and 52 patients (62%) revealed a completely normal gallbladder. In eight patients (10%) a cholecystectomy was performed before or during transplantation because of already known gallstones. No concrements in the biliary ducts (choledocholithiasis) could be detected. In group 2 the number of patients with gallstones was slightly lower (22%) compared with group 1 patients (30%), but without statistical significance. - Cholestasis parameters were not increased and HbA1c values were normal in both groups of patients. CONCLUSION: The prevalence of biliary disease in kidney/pancreas transplanted type I-diabetic patients with 28% is increased in comparison to the general population (10-15%). Lithogenicity under tacrolimus seems to be lower as under cyclosporine based immunosuppressive drug treatment. We recommend regular sonographical examinations to detect an acute or chronic cholecystis as early as possible, which may develop occultly in these patients.

CD4+ T cell count recovery in HIV type 1-infected patients is independent of class of antiretroviral therapy

BACKGROUND: In recent years, treatment options for human immunodeficiency virus type 1 (HIV-1) infection have changed from nonboosted protease inhibitors (PIs) to nonnucleoside reverse-transcriptase inhibitors (NNRTIs) and boosted PI-based antiretroviral drug regimens, but the impact on immunological recovery remains uncertain. METHODS: During January 1996 through December 2004 [corrected] all patients in the Swiss HIV Cohort were included if they received the first combination antiretroviral therapy (cART) and had known baseline CD4(+) T cell counts and HIV-1 RNA values (n = 3293). For follow-up, we used the Swiss HIV Cohort Study database update of May 2007 [corrected] The mean (+/-SD) duration of follow-up was 26.8 +/- 20.5 months. The follow-up time was limited to the duration of the first cART. CD4(+) T cell recovery was analyzed in 3 different treatment groups: nonboosted PI, NNRTI, or boosted PI. The end point was the absolute increase of CD4(+) T cell count in the 3 treatment groups after the initiation of cART. RESULTS: Two thousand five hundred ninety individuals (78.7%) initiated a nonboosted-PI regimen, 452 (13.7%) initiated an NNRTI regimen, and 251 (7.6%) initiated a boosted-PI regimen. Absolute CD4(+) T cell count increases at 48 months were as follows: in the nonboosted-PI group, from 210 to 520 cells/muL; in the NNRTI group, from 220 to 475 cells/muL; and in the boosted-PI group, from 168 to 511 cells/muL. In a multivariate analysis, the treatment group did not affect the response of CD4(+) T cells; however, increased age, pretreatment with nucleoside reverse-transcriptase inhibitors, serological tests positive for hepatitis C virus, Centers for Disease Control and Prevention stage C infection, lower baseline CD4(+) T cell count, and lower baseline HIV-1 RNA level were risk factors for smaller increases in CD4(+) T cell count. CONCLUSION: CD4(+) T cell recovery was similar in patients receiving nonboosted PI-, NNRTI-, and boosted PI-based cART.

JC virus-specific immune responses in human immunodeficiency virus type 1 patients with progressive multifocal leukoencephalopathy

Progressive multifocal leukoencephalopathy (PML) is a frequently fatal disease caused by uncontrolled polyomavirus JC (JCV) in severely immunodeficient patients. We investigated the JCV-specific cellular and humoral immunity in the Swiss HIV Cohort Study. We identified PML cases (n = 29), as well as three matched controls per case (n = 87), with prospectively cryopreserved peripheral blood mononuclear cells and plasma at diagnosis. Nested controls were matched according to age, gender, CD4(+) T-cell count, and decline. Survivors (n = 18) were defined as being alive for >1 year after diagnosis. Using gamma interferon enzyme-linked immunospot assays, we found that JCV-specific T-cell responses were lower in nonsurvivors than in their matched controls (P = 0.08), which was highly significant for laboratory- and histologically confirmed PML cases (P = 0.004). No difference was found between PML survivors and controls or for cytomegalovirus-specific T-cell responses. PML survivors showed significant increases in JCV-specific T cells (P = 0.04) and immunoglobulin G (IgG) responses (P = 0.005). IgG responses in survivors were positively correlated with CD4(+) T-cell counts (P = 0.049) and negatively with human immunodeficiency virus RNA loads (P = 0.03). We conclude that PML nonsurvivors had selectively impaired JCV-specific T-cell responses compared to CD4(+) T-cell-matched controls and failed to mount JCV-specific antibody responses. JCV-specific T-cell and IgG responses may serve as prognostic markers for patients at risk.

Normal VLDL metabolism despite altered lipoprotein composition in type 1 diabetes mellitus

Patients with type 1 diabetes are at increased risk of cardiovascular disease, which may be related to abnormal lipid metabolism. Secretion and clearance of VLDL apolipoprotein B100 (apoB) are important determinants of plasma lipid concentrations and are known to be influenced by hormones, including insulin and growth hormone.

A Communication Platform for Tele-monitoring and Tele-management of Type 1 Diabetes

Type 1 diabetes mellitus is a chronic disease characterized by blood glucose levels out of normal range due to inability of insulin production. This dysfunction leads to many short- and long-term complications. In this paper, a system for tele-monitoring and tele-management of Type 1 diabetes patients is proposed, aiming at reducing the risk of diabetes complications and improving quality of life. The system integrates Wireless Personal Area Networks (WPAN), mobile infrastructure, and Internet technology along with commercially available and novel glucose measurement devices, advanced modeling techniques, and tools for the intelligent processing of the available diabetes patients information. The integration of the above technologies enables intensive monitoring of blood glucose levels, treatment optimisation, continuous medical care, and improvement of quality of life for Type 1 diabetes patients, without restrictions in everyday life activities.

Genetic and hormonal factors modulate spreading depression and transient hemiparesis in mouse models of familial hemiplegic migraine type 1.

Familial hemiplegic migraine type 1 (FHM1) is an autosomal dominant subtype of migraine with aura that is associated with hemiparesis. As with other types of migraine, it affects women more frequently than men. FHM1 is caused by mutations in the CACNA1A gene, which encodes the alpha1A subunit of Cav2.1 channels; the R192Q mutation in CACNA1A causes a mild form of FHM1, whereas the S218L mutation causes a severe, often lethal phenotype. Spreading depression (SD), a slowly propagating neuronal and glial cell depolarization that leads to depression of neuronal activity, is the most likely cause of migraine aura. Here, we have shown that transgenic mice expressing R192Q or S218L FHM1 mutations have increased SD frequency and propagation speed; enhanced corticostriatal propagation; and, similar to the human FHM1 phenotype, more severe and prolonged post-SD neurological deficits. The susceptibility to SD and neurological deficits is affected by allele dosage and is higher in S218L than R192Q mutants. Further, female S218L and R192Q mutant mice were more susceptible to SD and neurological deficits than males. This sex difference was abrogated by ovariectomy and senescence and was partially restored by estrogen replacement, implicating ovarian hormones in the observed sex differences in humans with FHM1. These findings demonstrate that genetic and hormonal factors modulate susceptibility to SD and neurological deficits in FHM1 mutant mice, providing a potential mechanism for the phenotypic diversity of human migraine and aura.

Alternative nighttime nutrition regimens in glycogen storage disease type I: a controlled crossover study

BACKGROUND Traditional approaches for nighttime glycemic control in glycogen storage disease type I (GSDI) include continuous tube feeding, or ingestion of uncooked corn starch (CS) at bedtime. A modified corn starch (MCS) has been shown to prolong euglycemia in some patients. The aim of this study was to evaluate whether stable nighttime glucose control can be achieved with other types of slowly digested carbohydrates in adult GSDI patients. METHODS In this cross-over study, nocturnal glucose control and fasting times were assessed with three different nocturnal nutrition regimens in five patients, using continuous glucose monitoring (CGMS) in an outpatient everyday life setting. For each patient, continuous glucose profiles were measured after ingestion of (1) CS, (2) MCS or (3) a pasta meal at bedtime, during 5 to 6 consecutive nights for each regimen. RESULTS Stable nocturnal glucose control was achieved for all patients with a pasta meal, with a mean duration of glycemia >3.5 mmol/l of 7.6 h (range 5.7-10.8), and >4 mmol/l of 7 h (5.2-9.2), similar to CS and MCS. Fasting glucose before breakfast on workdays (after 7.1 ± 0.8 h) was not significantly different between the three interventions (CS 4.1 ± 0.5 mmol/l, MCS 4.6 ± 0.7 mmol/l, pasta 4.3 ± 0.9 mmol/l). During prolonged fasting on weekends, longer duration of normoglycemia was achieved with CS or MCS than with pasta. CONCLUSION Consumption of cooked pasta is a suitable and more palatable alternative to uncooked corn starch to achieve nighttime glucose control in adult patients with GSDI.

Age Related Differences in Individual Quality of Life Domains in Youth with Type 1 Diabetes.

BACKGROUND: Investigating individual, as opposed to predetermined, quality of life domains may yield important information about quality of life. This study investigated the individual quality of life domains nominated by youth with type 1 diabetes. METHODS: Eighty young people attending a diabetes summer camp completed the Schedule for the Evaluation of Individual Quality of Life-Direct Weighting interview, which allows respondents to nominate and evaluate their own quality of life domains. RESULTS: The most frequently nominated life domains were 'family', 'friends', 'diabetes', 'school', and 'health' respectively; ranked in terms of importance, domains were 'religion', 'family', 'diabetes', 'health', and 'the golden rule'; ranked in order of satisfaction, domains were 'camp', 'religion', 'pets', and 'family' and 'a special person' were tied for fifth. Respondent age was significantly positively associated with the importance of 'friends', and a significantly negatively associated with the importance of 'family'. Nearly all respondents nominated a quality of life domain relating to physical status, however, the specific physical status domain and the rationale for its nomination varied. Some respondents nominated 'diabetes' as a domain and emphasized diabetes 'self-care behaviors' in order to avoid negative health consequences such as hospitalization. Other respondents nominated 'health' and focused more generally on 'living well with diabetes'. In an ANOVA with physical status domain as the independent variable and age as the dependent variable, participants who nominated 'diabetes' were younger (M = 12.9 years) than those who nominated 'health' (M = 15.9 years). In a second ANOVA, with rationale for nomination the physical status domain as the independent variable, and age as the dependent variable, those who emphasized 'self care behaviors' were younger (M = 11.8 years) than those who emphasized 'living well with diabetes' (M = 14.6 years). These differences are discussed in terms of cognitive development and in relation to the decline in self-care and glycemic control often observed during adolescence. CONCLUSIONS: Respondents nominated many non-diabetes life domains, underscoring that QOL is multidimensional. Subtle changes in conceptualization of diabetes and health with increasing age may reflect cognitive development or disease adjustment, and speak to the need for special attention to adolescents. Understanding individual quality of life domains can help clinicians motivate their young patients with diabetes for self-care. Future research should employ a larger, more diverse sample, and use longitudinal designs.

Diabetic nephropathy in African-Americans with type 1 diabetes: The new Jersey 725 study

Diabetic nephropathy is the most common cause of end-stage renal disease (ESRD) in the United States. African-Americans and patients with type 1 diabetes (T1D) are at increased risk. We studied the rate and factors that influenced progression of glomerular filtration rate (GFR) in 401 African-American T1D patients who were followed for 6 years through the observational cohort New Jersey 725 study. Patients with ESRD and/or GFR<20 ml/min were excluded. The mean (SD) baseline GFR was 106.8 (27.04) ml/min and it decreased by 13.8 (mean, SD 32.2) ml/min during the 6-year period (2.3 ml/min/year). In patients with baseline macroproteinuria, GFR decreased by 31.8 (39.0) ml/min (5.3 ml/min/year) compared to 8.2 (mean, SD 27.6) ml/min (1.3 ml/min/year) in patients without it (p<0.00001). Six-year GFR fell to <20 ml/min in 5.25% of all patients, but in 16.8% of macroproteinuric patients.^ A model including baseline GFR, proteinuria category and hypertension category, explained 35% of the 6-year GFR variability (p<0.0001). After adjustment for other variables in the model, 6-year GFR was 24.9 ml/min lower in macroproteinuric patients than in those without proteinuria (p=0.0001), and 12.6 ml/min lower in patients with treated but uncontrolled hypertension compared to normotensive patients (p=0.003). In this sample of patients, with an elevated mean glycosylated hemoglobin of 12.4%, glycemic control did not independently influence GFR deterioration, nor did BMI, cholesterol, gender, age at diabetes onset or socioeconomic level.^ Taken together, our findings suggest that proteinuria and hypertension are the most important factors associated with GFR deterioration in African-American T1D patients.^

Micronutrient intakes and their associations with markers of inflammation, subclinical atherosclerosis, cardiovascular disease, type II diabetes and metabolic syndrome

We investigated cross-sectional associations between intakes of zinc, magnesium, heme- and non heme iron, beta-carotene, vitamin C and vitamin E and inflammation and subclinical atherosclerosis in the Multi-Ethnic Study of Atherosclerosis (MESA). We also investigated prospective associations between those micronutrients and incident MetS, T2D and CVD. Participants between 45-84 years of age at baseline were followed between 2000 and 2007. Dietary intake was assessed at baseline using a 120-item food frequency questionnaire. Multivariable linear regression and Cox proportional hazard regression models were used to evaluate associations of interest. Dietary intakes of non-heme iron and Mg were inversely associated with tHcy concentrations (geometric means across quintiles: 9.11, 8.86, 8.74, 8.71, and 8.50 µmol/L for non-heme iron, and 9.20, 9.00, 8.65, 8.76, and 8.33 µmol/L for Mg; ptrends <0.001). Mg intake was inversely associated with high CC-IMT; odds ratio (95% CI) for extreme quintiles 0.76 (0.58, 1.01), ptrend: 0.002. Dietary Zn and heme-iron were positively associated with CRP (geometric means: 1.73, 1.75, 1.78, 1.88, and 1.96 mg/L for Zn and 1.72, 1.76, 1.83, 1.86, and 1.94 mg/L for heme-iron). In the prospective analysis, dietary vitamin E intake was inversely associated with incident MetS and with incident CVD (HR [CI] for extreme quintiles - MetS: 0.78 [0.62-0.97] ptrend=0.01; CVD: 0.69 [0.46-1.03]; ptrend =0.04). Intake of heme-iron from red meat and Zn from red meat, but not from other sources, were each positively associated with risk of CVD (HR [CI] - heme-iron from red meat: 1.65 [1.10-2.47] ptrend = 0.01; Zn from red meat: 1.51 [1.02 - 2.24] ptrend =0.01) and MetS (HR [CI] - heme-iron from red meat: 1.25 [0.99-1.56] ptrend =0.03; Zn from red meat: 1.29 [1.03-1.61]; ptrend = 0.04). All associations evaluated were similar across different strata of gender, race-ethnicity and alcohol intake. Most of the micronutrients investigated were not associated with the outcomes of interest in this multi-ethnic cohort. These observations do not provide consistent support for the hypothesized association of individual nutrients with inflammatory markers, MetS, T2D, or CVD. However, nutrients consumed in red meat, or consumption of red meat as a whole, may increase risk of MetS and CVD.^