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Background Diabetes mellitus (DM) patients are three times more likely to develop tuberculosis (TB) than the general population. Active TB screening in people with DM is part of a bidirectional approach. The aim of this study was to conduct pragmatic active TB screening among DM patients in four countries to inform policy. Methods DM patients were recruited in Indonesia (n=809), Peru (n=600), Romania (n=603) and South Africa (n=51). TB cases were diagnosed using an algorithm including clinical symptoms and chest X-ray. Presumptive TB patients were examined with sputum smear and culture. Results A total of 171 (8.3%) individuals reported ever having had TB (South Africa, 26%; Indonesia, 12%; Peru, 7%; Romania, 4%), 15 of whom were already on TB treatment. Overall, 14 (0.73% [95% confidence interval 0.40 to 1.23]) TB cases were identified from screening. Poor glucose control, smoking, lower body mass index, education and socio-economic status were associated with newly diagnosed/current TB. Thirteen of the 14 TB cases diagnosed from this screening would have been found using a symptom-based approach. Conclusions These data support the World Health Organization recommendation for routine symptom-based screening for TB in known DM patients in high TB-burden countries. DM patients with any symptoms consistent with TB should be investigated and diagnostic tools should be easily accessible.

Introduction. Studies regarding antibiotics administration during pregnancy and atopic dermatitis (AD) in children are only few. In this context, the objective of our study was to investigate the potential association between the timing of intrauterine exposure to antibiotics or prenatal antibiotic administration in general and AD occurrence in children. Methods. This was a cross-sectional study in 1046 subjects. The exposure to antibiotics during pregnancy was initially evaluated using simple logistic regressions. Then, each period of antibiotics administration was adjusted with the other periods of antibiotics exposure (model 1) and with the other variables associated with AD in our database (model 2). Results. In simple logistic regression analysis, the administration of antibiotics during pregnancy, as a whole period, presented a trend of association with AD (OR = 1.28, %CI: 0.99 – 1.65). When we analyzed antibiotic administration during each trimester of pregnancy, only antibiotherapy during the 3rd trimester was associated with AD (OR = 2.94, %CI: 1.21 – 7.12). After adjusting with all the other important risk factors associated with AD in the database, antibiotics administration during the 3rd trimester of pregnancy was still independently associated with AD (OR=2.64, %CI: 1.01 – 6.91). Conclusion. Antibiotic administration during the 3rd trimester of pregnancy was independently associated with AD in children.

BackgroundDiabetes mellitus (DM) increases active tuberculosis (TB) risk and worsens TB outcomes, jeopardizing TB control especially in TB-endemic countries with rising DM prevalence rates. We assessed DM status and clinical correlates in TB patients across settings in Indonesia, Peru, Romania, and South Africa.MethodsAge-adjusted DM prevalence was estimated using laboratory glycated hemoglobin (HbA1c) or fasting plasma glucose in TB patients. Detailed and standardized sociodemographic, anthropometric, and clinical measurements were made. Characteristics of TB patients with or without DM were compared using multilevel mixed-effect regression models with robust standard errors.ResultsOf 2185 TB patients (median age 36.6 years, 61.2% male, 3.8% human immunodeficiency virus–infected), 12.5% (267/2128) had DM, one third of whom were newly diagnosed. Age-standardized DM prevalence ranged from 10.9% (South Africa) to 19.7% (Indonesia). Median HbA1c in TB–DM patients ranged from 7.4% (Romania) to 11.3% (Indonesia). Compared to those without DM, TB–DM patients were older and had a higher body mass index (BMI) (P value < .05). Compared to those with newly diagnosed DM, TB patients with diagnosed DM had higher BMI and HbA1c, less severe TB, and more frequent comorbidities, DM complications, and hypertension (P value < .05).ConclusionsWe show that DM prevalence and clinical characteristics of TB–DM vary across settings. Diabetes is primarily known but untreated, hyperglycemia is often severe, and many patients with TB–DM have significant cardiovascular disease risk and severe TB. This underlines the need to improve strategies for better clinical management of combined TB and DM.

BACKGROUND: Although diabetic kidney disease demonstrates both familial clustering and single nucleotide polymorphism heritability, the specific genetic factors influencing risk remain largely unknown.METHODS: To identify genetic variants predisposing to diabetic kidney disease, we performed genome-wide association study (GWAS) analyses. Through collaboration with the Diabetes Nephropathy Collaborative Research Initiative, we assembled a large collection of type 1 diabetes cohorts with harmonized diabetic kidney disease phenotypes. We used a spectrum of ten diabetic kidney disease definitions based on albuminuria and renal function.RESULTS: Our GWAS meta-analysis included association results for up to 19,406 individuals of European descent with type 1 diabetes. We identified 16 genome-wide significant risk loci. The variant with the strongest association (rs55703767) is a common missense mutation in the collagen type IV alpha 3 chain (COL4A3) gene, which encodes a major structural component of the glomerular basement membrane (GBM). Mutations in COL4A3 are implicated in heritable nephropathies, including the progressive inherited nephropathy Alport syndrome. The rs55703767 minor allele (Asp326Tyr) is protective against several definitions of diabetic kidney disease, including albuminuria and ESKD, and demonstrated a significant association with GBM width; protective allele carriers had thinner GBM before any signs of kidney disease, and its effect was dependent on glycemia. Three other loci are in or near genes with known or suggestive involvement in this condition (BMP7) or renal biology (COLEC11 and DDR1).CONCLUSIONS: The 16 diabetic kidney disease-associated loci may provide novel insights into the pathogenesis of this condition and help identify potential biologic targets for prevention and treatment.

Diabetic kidney disease (DKD) is a heritable but poorly understood complication of diabetes. To identify genetic variants predisposing to DKD, we performed genome-wide association analyses in 19,406 individuals with type 1 diabetes (T1D) using a spectrum of DKD definitions basedon albuminuria and renal function. We identified 16 genome-wide significant loci. The variant with the strongest association (rs55703767) is a common missense mutation in the collagen type IV alpha 3 chain(COL4A3)gene, which encodes a major structural component of the glomerular basement membrane (GBM) implicated in heritable nephropathies. The rs55703767 minor allele (Asp326Tyr) is protective against several definitions of DKD, including albuminuria and end-stage renal disease. Three other loci are in or near genes with known or suggestive involvement in DKD(BMP7)or renal biology (COLEC11andDDR1). The 16 DKD-associated loci provide novel insights into the pathogenesis of DKD, identifying potential biological targets for prevention and treatment.

Background Insulin resistance (IR) is present in type 1 diabetes mellitus (T1DM) and is suggested to be related to chronic diabetic complications. The primary aim of our study was to assess IR in T1DM patients with and without chronic complications. A secondary aim was to evaluate the possible association between IR and chronic diabetic complications. Methods This cross-sectional study enrolled 272 patients with T1DM. Insulin resistance was quantified using the estimated glucose disposal rate (eGDR). Associations between eGDR and each diabetes complication were first evaluated using binary logistic regression, then multiparametric logistic regression with stepwise selection of covariates. The discriminative value of eGDR was assessed by receiver operating characteristic (ROC) curve analysis. Results Estimated GDR was lower in patients with chronic diabetic complications (6.1 vs 6.9 mg/kg per min [P = 0.02] for retinopathy; 6.3 vs 7.3 mg/kg per min [P < 0.01] for nephropathy; 6.5 vs 7.6 mg/kg per min [P < 0.01] for neuropathy; and 5.2 vs 7.5 mg/kg per min [P < 0.01] for cardiovascular complications). In univariate analysis eGDR was associated all diabetic complications. These associations remained significant after adjustment for different variables in the final regression models. In addition, eGDR was a good discriminator for each diabetic complication, with an area under the curve between 0.609 and 0.759. Conclusions Patients with chronic diabetic complications are more insulin resistant than those without complications. Moreover, IR was independently associated with the presence of each chronic diabetic complication, and seems to be a good discriminator for them all. 摘要 背景 1型糖尿病若存在胰岛素抵抗(Insulin resistance,IR)则提示与慢性糖尿病并发症相关。我们研究的主要目的是评估合并或者不合并慢性并发症的1型糖尿病患者的IR。次要目的是评估IR与慢性糖尿病并发症之间可能存在的关系。 方法 这项横向研究纳入了272名1型糖尿病患者。使用预估葡萄糖处置率(estimated glucose disposal rate,eGDR)来量化胰岛素抵抗。首先使用二元对数回归法,接着使用多参数对数回归法(逐步选择协变量)来评估eGDR与每种糖尿病并发症之间的关系。使用受试者工作特征曲线分析法来评估eGDR的鉴别价值。 结果 合并慢性糖尿病并发症的患者预估的GDR更低(对于视网膜病变来说,分别为6.1与6.9 mg/kg每分钟[P = 0.02] ;对于肾病来说,分别为6.3与7.3 mg/kg/分钟[P < 0.01];对于神经病变来说,分别为6.5与7.6 mg/kg每分钟[P < 0.01];对于心血管并发症来说,分别为5.2与7.5 mg/kg每分钟[P

OBJECTIVE We evaluated the predictive value and clinical benefit of urinary kidney injury molecule (KIM)-1 for progression of diabetic nephropathy (DN) in type 1 diabetes. We also investigated its causal role for the decrease of estimated glomerular filtration rate (eGFR) by a Mendelian randomization (MR) approach. RESEARCH DESIGN AND METHODS We followed 1,573 patients with type 1 diabetes for 6 years. KIM-1 was measured at baseline and normalized with urinary creatinine. KIM-1 predictive value was evaluated by Cox regression, while its added predictive benefit was evaluated using a panel of statistical indexes. The causality for the loss of renal function was evaluated with MR, utilizing the top signal from our genome-wide association study (GWAS) as the instrumental variable. RESULTS KIM-1 was not an independent predictor of progression of DN when adjusted for albumin excretion rate (AER) and added no prognostic benefit to AER or eGFR. In multiple regressions, KIM-1 was associated with lower eGFR independently of diabetes duration (β = −4.066; P < 0.0001) but not of AER. In our GWAS, rs2036402 in the KIM1 gene was strongly associated with KIM-1 (β = −0.51; P = 6.5 × 10−38). In the MR, KIM-1 was associated with lower eGFR, independently of diabetes duration and AER (β = −5.044; P = 0.040), suggesting a causal relationship. CONCLUSIONS KIM-1 did not predict progression to end-stage renal disease independently of AER and added no prognostic benefit to current biomarkers. Nevertheless, the MR showed that the inverse association of increased KIM-1 levels with lower eGFR is likely to represent a causal link.

Insulin resistance (IR) is a fundamental disorder of type 2 Diabetes Mellitus (DM), but it is also involved in the etiopathogenesis of type 1 DM, with important implications in the onset and progression of micro- and macrovascular complications in type 1 DM. Overweight plays the main role in the increased incidence of both types of DM, exacerbating IR. The epidemic increase of overweight and obesity makes it difficult to diagnose the exact phenotype of DM, as IR and autoimmunity often coexist. Many studies showed an increase in incidence of micro- and macrovascular complications in patients with type 1 DM with IR, compared to patients with type 1 DM without IR. The gold standard of IR evaluation is represented by the method of euglycemic-hyperinsulinemic clamp, applied on a reduced scale in research. Thus, it is necessary to identify early IR markers (clinical or biological markers), less laboured ones, that could be used on a large scale in current medical practice, for the IR determination in type 1 DM. Clinicians and health experts should prevent/ reduce the epidemic of overweight and obesity in young people, thus decreasing IR, and implicitly the chronic complications of DM.

In type 1 diabetes, cardiovascular disease (CVD) and diabetic nephropathy progress in parallel, thereby potentiating the risk of premature death during their development. Since urinary liver-type fatty acid binding protein (L-FABP) predicts the progression of diabetic nephropathy, the aim of this study was to investigate whether urinary L-FABP also predicts cardiovascular outcomes and mortality. We tested our hypothesis in a Finnish cohort of 2329 individuals with type 1 diabetes and a median follow-up of 14.1 years. The L-FABP to creatinine ratio was determined from baseline urine samples. The predictive value of urinary L-FABP was evaluated using Cox regression models, while its added predictive benefit for cardiovascular outcomes and mortality was evaluated using a panel of statistical indexes. Urinary L-FABP predicted incident stroke independently of traditional risk factors (HR 1.33 [95% CI 1.20, 1.49]) and after further adjustment for eGFR (HR 1.28 [95% CI 1.14, 1.44]) or AER (HR 1.24 [95% CI 1.06, 1.44]). In addition, it predicted mortality independently of traditional risk factors (HR 1.34 [95% CI 1.24, 1.45]), and after adjustment for eGFR (HR 1.29 [95% CI 1.18, 1.39]) or AER (HR 1.22 [95% CI 1.09, 1.36]). Urinary L-FABP was as good a predictor as eGFR or AER, and improved the AUC for both outcomes on top of traditional risk factors, with no reclassification benefit (integrated discrimination improvement/net reclassification improvement) for stroke or mortality when AER or eGFR were added to traditional risk factors. However, urinary L-FABP was not a predictor of other cardiovascular endpoints (coronary artery disease, peripheral vascular disease and overall CVD events) when adjusted for the AER. Urinary L-FABP is an independent predictor of stroke and mortality in individuals with type 1 diabetes.

Item does not contain fulltext Diabetes triples the risk for active tuberculosis, thus the increasing burden of type 2 diabetes will help to sustain the present tuberculosis epidemic. Recommendations have been made for bidirectional screening, but evidence is scarce about the performance of specific tuberculosis tests in individuals with diabetes, specific diabetes tests in patients with tuberculosis, and screening and preventive therapy for latent tuberculosis infections in individuals with diabetes. Clinical management of patients with both diseases can be difficult. Tuberculosis patients with diabetes have a lower concentration of tuberculosis drugs and a higher risk of drug toxicity than tuberculosis patients without diabetes. Good glycaemic control, which reduces long-term diabetes complications and could also improve tuberculosis treatment outcomes, is hampered by chronic inflammation, drug-drug interactions, suboptimum adherence to drug treatments, and other factors. Besides drug treatments for tuberculosis and diabetes, other interventions, such as education, intensive monitoring, and lifestyle interventions, might be needed, especially for patients with newly diagnosed diabetes or those who need insulin. From a health systems point of view, delivery of optimum care and integration of services for tuberculosis and diabetes is a huge challenge in many countries. Experience from the combined tuberculosis and HIV/AIDS epidemic could serve as an example, but more studies are needed that include economic assessments of recommended screening and systems to manage concurrent tuberculosis and diabetes.

Sex and genetic variation influence the risk of developing diabetic nephropathy and ESRD in patients with type 1 diabetes. We performed a genome-wide association study in a cohort of 3652 patients from the Finnish Diabetic Nephropathy (FinnDiane) Study with type 1 diabetes to determine whether sex-specific genetic risk factors for ESRD exist. A common variant, rs4972593 on chromosome 2q31.1, was associated with ESRD in women (P5×10(-8)) but not in men (P=0.77). This association was replicated in the meta-analysis of three independent type 1 diabetes cohorts (P=0.02) and remained significant for women (P5×10(-8); odds ratio, 1.81 [95% confidence interval, 1.47 to 2.24]) upon combined meta-analysis of the discovery and replication cohorts. rs4972593 is located between the genes that code for the Sp3 transcription factor, which interacts directly with estrogen receptor α and regulates the expression of genes linked to glomerular function and the pathogenesis of nephropathy, and the CDCA7 transcription factor, which regulates cell proliferation. Further examination revealed potential transcription factor-binding sites within rs4972593 and predicted eight estrogen-responsive elements within 5 kb of this locus. Moreover, we found sex-specific differences in the glomerular expression levels of SP3 (P=0.004). Overall, these results suggest that rs4972593 is a sex-specific genetic variant associated with ESRD in patients with type 1 diabetes and may underlie the sex-specific protection against ESRD.

OBJECTIVE Diabetic nephropathy (DN) has mainly been considered a glomerular disease, although tubular dysfunction may also play a role. This study assessed the predictive value for progression of a tubular marker, urinary liver-type fatty acid–binding protein (L-FABP), at all stages of DN. RESEARCH DESIGN AND METHODS At baseline, 1,549 patients with type 1 diabetes had an albumin excretion rate (AER) within normal reference ranges, 334 had microalbuminuria, and 363 had macroalbuminuria. Patients were monitored for a median of 5.8 years (95% CI 5.7–5.9). In addition, 208 nondiabetic subjects were studied. L-FABP was measured by ELISA and normalized with urinary creatinine. Different Cox proportional hazard models for the progression at every stage of DN were used to evaluate the predictive value of L-FABP. The potential benefit of using L-FABP alone or together with AER was assessed by receiver operating characteristic curve analyses. RESULTS L-FABP was an independent predictor of progression at all stages of DN. As would be expected, receiver operating characteristic curves for the prediction of progression were significantly larger for AER than for L-FABP, except for patients with baseline macroalbuminuria, in whom the areas were similar. Adding L-FABP to AER in the models did not significantly improve risk prediction of progression in favor of the combination of L-FABP plus AER compared with AER alone. CONCLUSIONS L-FABP is an independent predictor of progression of DN irrespective of disease stage. L-FABP used alone or together with AER may not improve the risk prediction of DN progression in patients with type 1 diabetes, but further studies are needed in this regard.

The increasing prevalence of chronic kidney disease (CKD) and diabetes over the last decade has resulted in increasing numbers of frail older patients with a combination of these conditions. Current treatment guidelines may not necessarily be relevant for such patients, who are mostly excluded from the trials upon which these recommendations are based. There is a paucity of data upon which to base the management of older patients with CKD. Nearly all current guidelines recommend less-tight glycaemic control for the older population, citing the lack of proven medium-term benefits and concerns about the high short-term risk of hypoglycaemia. However, reports from large landmark trials have shown potential benefits for both microvascular and macrovascular complications, though the relevance of these findings to this specific population is uncertain. The trials have also highlighted potential alternative explanations for the hazards of intensive glycaemic control. These include depression, low endogenous insulin reserve, low body mass index and side effects of the medication. Over the last few years, newer classes of hypoglycaemic drugs with a lower risk of hypoglycaemia have emerged. This article aims to present a balanced view of advantages and disadvantages of intense glycaemic control in this group of patients, which we hope will help the clinician and patient to come to an individualized management approach.

Upon the invasion of the host by microorganisms, innate immunity is triggered through pathogen recognition by pattern recognition receptors (PRRs). Toll-like receptors (TLRs) are the best-studied class of PRRs, and they recognize specific pathogen-associated molecular patterns (PAMPs) from various microorganisms. A large number of studies have shown that genetic variation in TLRs may influence susceptibility to infections. We assessed the genetic variation of TLR2 , which encodes one of the most important TLRs, in various populations around the globe and correlated it with changes in the function of the molecule. The three best-known nonsynonymous TLR2 polymorphisms (1892C>A, 2029C>T, and 2258G>A) were assessed in different populations from the main continental masses: Romanians, Vlax-Roma, Dutch (European populations), Han Chinese (East Asia), Dogon, Fulani (Africa), and Trio Indians (America). The 2029C>T polymorphism was absent in both European and non-European populations, with the exception of the Vlax-Roma, suggesting that this polymorphism most likely arose in Indo-Aryan people after migration into South Asia. The 1892C>A polymorphism that was found exclusively in European populations, but not in Asian, African, or American volunteers, probably occurred in proto-Indo-Europeans. Interestingly, 2258G>A was present only in Europeans, including Vlax-Roma, but at a very low frequency. The differential pattern of the TLR2 polymorphisms in various populations may explain some of the differences in susceptibility to infections between these populations.

Diabetic nephropathy has an unclarified pathogenesis, with multifactorial aetiology which includes metabolic and haemodynamic abnormalities, aberrant signaling of numerous cytokines or growth factors and genetic susceptibility. Inflammation and low birth weight seems to be predisposing factors for diabetic nephropathy. In both processes levels of L-selectin (CD62L) may play an important role. The genetic heritability of diabetic nephropathy and CD62L levels sustain the investigation of relationship between LECAM polymorphisms and the disease risk. The aim of the study was to investigate a possible relationship between Pro213Ser polymorphism in LECAM-1 gene and advanced stages of diabetic nephropathy in type 1 diabetes. We enrolled unrelated Caucasian patients with type 1 diabetes mellitus, fall into control group – diabetic patients with duration of disease over 20 years without microalbuminuria (n = 83) and nephropathy group – patients with overt nephropathy or end stage renal disease – ESRD (n = 121). Pro213Ser polymorphism genotyping was achieved using PCR-RFLP technique. Genotype spread analysis indicates that ProSer and SerSer are more frequent in the nephropathy group (ProSer = 41.95% and SerSer = 6.02 %), compared with the control group (ProSer = 20.53% and SerSer = 1.73%). The corrected OR's due to the small number of patients pointed the possibility that the 213Ser is the risk allele (ORSer = 1.634; p=0.04), and 213Pro is the protective one (ORPro = 0.602; p=0.04) regarding diabetic nephropathy. Thus our results suggest a possible association between the P213S polymorphism and advanced stages of diabetic nephropathy in type 1 diabetic patients. Additional researches are required in order to acknowledge the mentioned results and to clarify the mechanism by which this polymorphism intervenes in the disease pathogenesis.

Several studies examined the relationship between birth weight and atopic diseases, but no consensus has yet been reached regarding the results. The purpose of this paper was to perform a meta-analysis of the existing studies regarding the role of birth weight in the occurrence of atopic dermatitis. We carried out an extensive search in the international databases (Pubmed, Cochrane Library, and Web of Knowledge). We selected the cross-sectional, case-control, and cohort studies which analyzed the role of birth weight in the occurrence of atopic dermatitis. We performed a meta-analysis of the selected studies, and calculated the odds ratio (OR) and corresponding 95% confidence intervals (95% CI). We included 10 studies in the final meta-analysis, which comprised 110974 patients. Weight classification was in compliance with Pediatric Nutrition Surveillance System (PedNSS) Health Indicators. In the first meta-analysis, we selected patients with low weight (below 2500 g) and atopic dermatitis and compared them with those with normal weight (2500 - 4000 g) and atopic dermatitis. The analysis showed that low birth weight represents a protective factor in the occurrence of atopic dermatitis (OR = 0.68, CI: 0.63 - 0.75, P0.0001). In the second meta-analysis, we compared patients with high weight (over 4000 g) and atopic dermatitis with those with normal weight and atopic dermatitis. The results indicated that increased birth weight represents a risk factor for atopic dermatitis (OR = 1.1; CI: 1.02 - 1.17; P = 0.01) Thus, low birth weight represents a protective factor for the occurrence of atopic dermatitis and high birth weight represents a risk factor for the occurrence of this disease.

OBJECTIVE Osteopontin (OPN) is a multifunctional protein suggested to be a player in the arterial disease of patients with type 2 diabetes. However, its role for complications in patients with type 1 diabetes (T1D) is unknown. We therefore investigated the associations between OPN and diabetic vascular complications and all-cause mortality in patients with T1D. RESEARCH DESIGN AND METHODS Serum OPN was measured in 2,145 adults with T1D without end-stage renal disease (ESRD; dialysis or transplantation) as part of the Finnish Diabetic Nephropathy (FinnDiane) Study. Data on renal status, cardiovascular disease (CVD), and all-cause mortality during follow-up were verified from medical files, hospital discharge registries, and the Finnish National Death Registry, respectively. The median follow-up time was 10.5 (interquartile range 8.9–11.8) years. RESULTS Serum OPN was higher at baseline in patients who developed incident microalbuminuria (16.0 ± 0.9 vs. 14.1 ± 0.2 µg/L; P = 0.04), progressed to ESRD (28.3 ± 1.7 vs. 15.4 ± 0.2 µg/L; P < 0.001), suffered an incident CVD event (20.2 ± 1.2 vs. 15.5 ± 0.2 µg/L; P < 0.001), or died (23.3 ± 1.4 vs. 15.8 ± 0.2 µg/L; P < 0.001) during follow-up. In multivariate Cox regression analysis, OPN was independently associated with the development of incident microalbuminuria, an incident CVD event, and death, after adjustments for associated risk factors. Even after calculating reclassification indexes, OPN was predictive of CVD and all-cause mortality beyond the Framingham risk score covariates and hs-CRP. CONCLUSIONS Serum OPN is a strong predictor of incipient diabetic nephropathy, a first-ever CVD event, and all-cause mortality in patients with T1D. Serum OPN may be of clinical significance for the risk prediction of CVD events in patients with T1D.

Several studies examined the relationship between birth weight and atopic diseases, but no consensus has yet been reached regarding the results.The purpose of this paper was to perform a meta-analysis of the existing studies regarding the role of birth weight in the occurrence of atopic dermatitis. We carried out an extensive search in the international databases (Pubmed, Cochrane Library, and Web of Knowledge). We selected the cross-sectional, case-control, and cohort studies which analyzed the role of birth weight in the occurrence of atopic dermatitis. We performed a meta-analysis of the selected studies, and calculated the odds ratio (OR) and corresponding 95% confidence intervals (95% CI). We included 10 studies in the final meta-analysis, which comprised 110974 patients. Weight classification was in compliance with Pediatric Nutrition Surveillance System (PedNSS) Health Indicators. In the first meta-analysis, we selected patients with low weight (below 2500 g) and atopic dermatitis and compared them with those with normal weight (2500 – 4000 g) and atopic dermatitis. The analysis showed that low birth weight represents a protective factor in the occurrence of atopic dermatitis (OR = 0.68, CI: 0.63 – 0.75, PThus, low birth weight represents a protective factor for the occurrence of atopic dermatitis and high birth weight represents a risk factor for the occurrence of this disease.

AIMS/HYPOTHESIS: Diabetic nephropathy is a major diabetic complication, and diabetes is the leading cause of end-stage renal disease (ESRD). Family studies suggest a hereditary component for diabetic nephropathy. However, only a few genes have been associated with diabetic nephropathy or ESRD in diabetic patients. Our aim was to detect novel genetic variants associated with diabetic nephropathy and ESRD.METHODS: We exploited a novel algorithm, 'Bag of Naive Bayes', whose marker selection strategy is complementary to that of conventional genome-wide association models based on univariate association tests. The analysis was performed on a genome-wide association study of 3,464 patients with type 1 diabetes from the Finnish Diabetic Nephropathy (FinnDiane) Study and subsequently replicated with 4,263 type 1 diabetes patients from the Steno Diabetes Centre, the All Ireland-Warren 3-Genetics of Kidneys in Diabetes UK collection (UK-Republic of Ireland) and the Genetics of Kidneys in Diabetes US Study (GoKinD US).RESULTS: Five genetic loci (WNT4/ZBTB40-rs12137135, RGMA/MCTP2-rs17709344, MAPRE1P2-rs1670754, SEMA6D/SLC24A5-rs12917114 and SIK1-rs2838302) were associated with ESRD in the FinnDiane study. An association between ESRD and rs17709344, tagging the previously identified rs12437854 and located between the RGMA and MCTP2 genes, was replicated in independent case-control cohorts. rs12917114 near SEMA6D was associated with ESRD in the replication cohorts under the genotypic model (p CONCLUSIONS/INTERPRETATION: This study supports the previously identified findings on the RGMA/MCTP2 region and suggests novel susceptibility loci for ESRD. This highlights the importance of applying complementary statistical methods to detect novel genetic variants in diabetic nephropathy and, in general, in complex diseases.

Spinal muscular atrophy (SMA) is a frequent neuromuscular disorder caused by motoneuronal apoptosis, as a result of SMN (Survival Motor Neuron) protein deficiency. Although the SMA determining gene was identified, the molecular mechanism of the disease is not clearly understood, due to the heterogeneity of clinical manifestations. Trying to complete the molecular describing SMA picture, by identifying potential modulators factors, we investigated the relationship between phosphatidylinositol 3-kinase p85 regulatory subunit gene (PIK3R1) and SMA pathology. As IGF signaling pathway has been reported to play an important role in motoneurons survival and PIK3 is a key element of this cascade signaling, we focused on the relationship between PIK3R1 gene Met326Ile polymorphism and SMA type I, the most severe form of the disease. A total of 80 subjects (40 SMA type I patients and 40 unrelated healthy controls) were included in the study. The statistical analyzes performed consequently to the genotyping by mismatch PCR-RFLP method, revealed that Met326Ile polymorphism is not associated with SMA type I disease: ORMet/Met = 0.398 with a p = 0.072 meanwhile ORMet = 0.495, p = 0.063. However, the Cochrane – Armitage test indicated that there is a statistically association trend between the analyzed polymorphism and SMA type I pathology: ORMet = 0.438, p = 0.032. We concluded that additional researches with an increased subjects number and replicates studies in other populations will clarify the investigated relationship and it may contribute to the SMA molecular mechanism understanding.

Diabetic kidney disease, or diabetic nephropathy (DN), is a major complication of diabetes and the leading cause of end-stage renal disease (ESRD) that requires dialysis treatment or kidney transplantation. In addition to the decrease in the quality of life, DN accounts for a large proportion of the excess mortality associated with type 1 diabetes (T1D). Whereas the degree of glycemia plays a pivotal role in DN, a subset of individuals with poorly controlled T1D do not develop DN. Furthermore, strong familial aggregation supports genetic susceptibility to DN. However, the genes and the molecular mechanisms behind the disease remain poorly understood, and current therapeutic strategies rarely result in reversal of DN. In the GEnetics of Nephropathy: an International Effort (GENIE) consortium, we have undertaken a meta-analysis of genome-wide association studies (GWAS) of T1D DN comprising ∼2.4 million single nucleotide polymorphisms (SNPs) imputed in 6,691 individuals. After additional genotyping of 41 top ranked SNPs representing 24 independent signals in 5,873 individuals, combined meta-analysis revealed association of two SNPs with ESRD: rs7583877 in the AFF3 gene (P = 1.2×10−8) and an intergenic SNP on chromosome 15q26 between the genes RGMA and MCTP2, rs12437854 (P = 2.0×10−9). Functional data suggest that AFF3 influences renal tubule fibrosis via the transforming growth factor-beta (TGF-β1) pathway. The strongest association with DN as a primary phenotype was seen for an intronic SNP in the ERBB4 gene (rs7588550, P = 2.1×10−7), a gene with type 2 diabetes DN differential expression and in the same intron as a variant with cis-eQTL expression of ERBB4. All these detected associations represent new signals in the pathogenesis of DN., Author Summary The global prevalence of diabetes has reached epidemic proportions, constituting a major health care problem worldwide. Diabetic kidney disease, or diabetic nephropathy (DN)—the major long term microvascular complication of diabetes—is associated with excess mortality among patients with type 1 diabetes. Even though DN has been shown to cluster in families, the underlying genetic and molecular pathways remain poorly defined. We have undertaken the largest genome-wide association study and meta-analysis to date on DN and on its most severe form of kidney disease, end-stage renal disease (ESRD). We identified new loci significantly associated with diabetic ESRD: AFF3 and an intergenic locus on chromosome 15q26 residing between RGMA and MCTP2. Our functional analyses suggest that AFF3 influences renal tubule fibrosis, a pathological hallmark of severe DN. Another locus in ERBB4 was suggestively associated with DN and resides in the same intronic region as a variant affecting the expression of ERBB4. Subsequent pathway analysis of the genes co-expressed with ERBB4 indicated involvement of fibrosis.

Both diabetes mellitus and allergic diseases presented an ascendant trend in the last years. The association between the two diseases represents an extremely discussed subject from the pathophysiological and clinical point of view, since the two diseases should exclude each other, but a unitary conclusion has not been reached yet. Objectives. The aim of this study is to perform a systematic review and a meta- analysis of the existent studies regarding the association between these two pathologies. Material and Method. We carried out an extensive search in the international databases, where we identified 557 articles treating these subjects, but only 12 articles have analyzed the relation between type 1 diabetes and atopic dermatitis. Results. The meta-analysis comprised 81519 subjects and suggests that the occurrence of type 1 diabetes is protective for atopic dermatitis (OR=0,68, CI=0,61-0,77, p

Bronchial asthma, despite the theoretical and experimental medical progress, remains the most frequently seen chronic disease of the children and has a heavy impact on global morbidity and mortality. The inadequate psychological approach to the asthmatic child and his family can be responsible for this failure in asthma control. We present here the psychosomatic characteristics of the child with asthma and his parents. Some suggestions are made, concerning the correct approach to the patient and parents: how to address parents' trust in current diagnostic and therapeutic resources (in steroids, especially), their personal beliefs regarding asthma and how to tackle the drift towards unconventional medicine.