MODY patients exhibit shorter telomere length than non-diabetic subjects.

BACKGROUND: Given the increasing evidence supporting the association between telomere shortening and diabetes, the aim of the present work was to establish whether MODY patients suffer a reduction in telomere lenght (TL) due to oxidative stress produced by chronic hyperglycemia, despite not presenting insulin resistance or inflammation. METHODS: We analysed clinical and biochemical parameters in 35 MODY2 and 12 MODY3 patients compared with 48 control subjects. The absolute telomere length (aTL) of peripheral blood leukocytes was measured using the quantitative polymerase chain reaction (qPCR). RESULTS: A significant negative correlation was observed between aTL and age in the whole population, among MODY patients and in each subtype studied, MODY2 and MODY3, which allowed us to validate the method. We found, for the first time, that MODY patients have shorter aTL with respect to non-diabetic controls (6.49 ± 3.31 kbp vs 11.13 ± 7.82 kbp, p = .006). However, no differences were found between MODY2 and MODY3. In addition, aTL showed a negative correlation with duration of the disease and fasting plasma glucose (FPG) levels in MODY patients in general and also with HbA1c in MODY2 patients in particular. CONCLUSIONS: Both MODY2 and MODY3 types present telomere shortening, which, at least partly, responds to HbA1c and FPG levels. These findings suggest comparable mechanisms underlying the attrition of TL. Taken together, our results on aTL in MODY patients may provide a parameter relatively easy and inexpensive to quantify in order to measure the impact of high glucose levels and potentially carry out antidiabetic treatment with stricter targets.

Increased chemerin serum levels in hyperandrogenic and normoandrogenic women from Argentina with polycystic ovary syndrome.

AIM: To assess serum chemerin levels and investigate the association of chemerin with the hyperandrogenic and normoandrogenic phenotypes of Polycystic Ovary Syndrome (PCOS) and with the metabolic status of the analyzed population. MATERIAL AND METHODS: A cross-sectional study was conducted on 106 women with PCOS and 60 healthy controls from Argentina. Patients were classified as showing a hyperandrogenic or normoandrogenic phenotype. Participants underwent anthropometric and clinical evaluation and markers of cardiovascular risk, insulin resistance, metabolic syndrome (MS), and serum chemerin levels were assessed. RESULTS: PCOS patients showed increased levels of chemerin. In adjusted models for age and body mass index (BMI), chemerin was associated with markers of metabolic status. The analysis of chemerin levels considering the cutoff values of BMI, homeostatic model of insulin sensitivity (HOMA-IR) and TG/HDL marker showed that PCOS patients always presented higher levels of chemerin than controls. PCOS group showed increased chemerin levels independently of the presence of MS. CONCLUSION: PCOS patients always showed increased levels of chemerin independently of their phenotype and presence of overweight, as well as higher levels of chemerin than controls when considering the cutoff values of HOMA-IR and TG/HDL. Therefore, argentine women with PCOS display increased chemerin levels independently of their metabolic or androgenic status.

Immunological and clinical characteristics of latent autoimmune diabetes in the elderly.

BACKGROUND: Latent autoimmune diabetes in adults (LADA) is determined by both a noninsulin-dependent clinical presentation and an autoimmune pathogenic process. Glutamic acid decarboxylase antibody (GADA) constitutes the most important marker, although IA-2A and ZnT8A also define LADA presentation. Type 2 diabetes mellitus (T2DM) is the most prevalent type particularly over 65 years old. Studies about autoimmunity in this age group are scarce. OBJECTIVE: The aim of this work was to determine whether three autoantibodies for diabetes autoimmunity were present in elderly T2DM patients, and to assess the distinctive clinical features of autoantibody-positive patients. RESEARCH DESIGN AND METHODS: We recruited 153 patients with diabetes with onset of diabetes after 65 years of age and a BMI under 30 kg/m2 . RESULTS: The prevalence of at least one of the autoantibodies was 15.68% (24/153). The most prevalent autoantibody was GADA with 8.49% (13/153), followed by ZnT8A with 6.50% (10/153) and IA2A with 1.96% (3/153). The autoimmunity-positive group presented higher HbA1c (7.01 ± 1.98 vs 6.35 ± 1.01; P = 0.007) and more prevalent insulin therapy (25% vs 10.85%; P = 0.047). GADA-positive patients with diabetes presented higher FPG (7.79 ± 3.79 mmol/L vs 6.43 ± 1.6 mmol/L; P = 0.014) and insulin therapy more frequently (46% vs 10.71%; p = 0.015). GADA titre levels in the individuals with BMI under 27 kg/m2 were higher (35.00 ± 4.20) than those in the group with BMI over 27 kg/m2 (8.83 ± 3.041; P = 0.0005). CONCLUSION: Autoantibodies GADA and Znt8A may be useful markers in identifying a subgroup of older patients with a clinical presentation of diabetes which could be characterized as latent autoimmune diabetes in the elderly.

- 174 G>C IL-6 polymorphism and primary iron overload in male patients.

Primary iron overload (IO) is commonly associated with mutations in the hereditary hemochromatosis gene (HFE). Nonetheless, other genetic variants may influence the development of IO beyond HFE mutations. There is a single nucleotide polymorphism (SNP) at - 174 G>C of the interleukin (IL)-6 gene which might be associated with primary IO. Our aim was to study the association between the SNP - 174 G>C gene promoter of IL-6 and primary IO in middle-aged male patients. We studied 37 men with primary IO diagnosed by liver histology. Controls were age-matched male volunteers (n = 37). HFE mutations and the SNP - 174 G>C gene promoter of IL-6 were evaluated by PCR-RFLP. Logistic regression was used to evaluate the association between primary IO and SNP - 174 G>C gene promoter of IL-6. Patients and control subjects were in Hardy-Weinberg equilibrium for the SNP - 174 G>C gene promoter of IL-6 (p = 0.17). Significantly different genotype frequencies were observed between patients (43% CC, 43% CG, and 14% GG) and control subjects (10% CC, 41% CG, and 49% GG) (OR = 4.09, 95% CI = 2.06-8.13; p < 0.0001). The multiple logistic regression analysis showed that IO was significantly associated with CC homozygosis in the SNP - 174 G>C gene promoter of IL-6 (OR = 6.3, 95% CI = 1.9-21.4; p < 0.005) in a model adjusted by age and body mass index. In conclusion, CC homozygosis in the SNP - 174 G>C gene promoter of IL-6 can be proposed as one of the gene variants influencing iron accumulation in male adults with HFE mutations. Studies in larger cohorts are warranted.

Multiple copy number variants in a pediatric patient with Hb H disease and intellectual disability.

Two distinct syndromes that link α-thalassemia and intellectual disability (ID) have been described: ATR-X, due to mutations in the ATRX gene, and ATR-16, a contiguous gene deletion syndrome in the telomeric region of the short arm of chromosome 16. A critical region where the candidate genes for the ID map has been established. In a pediatric patient with Hemoglobin H disease, dysmorphic features and ID, 4 novel and clinically relevant Copy Number Variants were identified. PCR-GAP, MLPA and FISH analyses established the cause of the α-thalassemia. SNP-array analysis revealed the presence of 4 altered loci: 3 deletions (arr[hg19]Chr16(16p13.3; 88,165-1,507,988) x1; arr[hg19]Chr6(6p21.1; 44,798,701-45,334,537) x1 and arr[hg19]Chr17(17q25.3; 80,544,855-81,057,996) x1) and a terminal duplication (arr[hg19]Chr7(7p22.3-p22.2; 4,935-4,139,785) x3). The -α(3.7) mutation and the ∼1.51 Mb in 16p13.3 are involved in the alpha-thalassemic phenotype. However, the critical region for ATR-16 cannot be narrowed down. The deletion affecting 6p21.1 removes the first 2 exons and part of intron 2 of the RUNX2 gene. Although heterozygous loss of function mutations affecting this gene have been associated with cleidocranial dysplasia, the patient does not exhibit pathognomonic signs of this syndrome, possibly due to the fact that the isoform d of the transcription factor remains unaffected. This work highlights the importance of searching for cryptic deletions in patients with ID and reiterates the need of the molecular analysis when it is associated to microcytic hypochromic anemia with normal iron status.

[Molecular bases of α-thalassemia in Argentina]. / Bases moleculares de alfa-talasemia en la Argentina.

The α-thalassemia is one of the most common hereditary disorders worldwide. Currently, molecular diagnostics is the only available tool to achieve an accurate diagnosis. The purpose of this study was to characterize the molecular bases of these syndromes in our environment and to establish genotype-phenotype associations. Through a combination of different molecular techniques and fluorescent in situ hybridization (FISH),we were able to find α-thalassemic mutations in 145 of the 184 patients (78.8%) studied with hematological parameters compatible with α-thalassemia. Deletions of the α-globin genes resulted the major molecular cause of the disease, and the most frequent mutation was -α(3.7), found in homozygous and heterozygous genotypes. In patients with α° phenotypes, other prevalent mutations were( _MED) and (_CAL/CAMP). The description of a sub-telomeric deletion in a patient with α-thalassemia and mental retardation was also achieved. ß-thalassemic mutations in heterozygous state were found in 7.6% of the patients, who presented α-thalassemic clinical features (microcytosis and Hb A2levels below 3.5%). Hematologic profiles for the α+ and α° genotypes were established for adult and pediatric patients. Hopefully, this work will provide guidelines for the detection of possible α-thalassemic carriers. It also highlights the collaborative work of hematologists, the biochemical and molecular biology laboratory and genetists, in order to provide appropriate genetic counseling.

Association between ß2-adrenoceptor (ADRB2) haplotypes and insulin resistance in PCOS.

OBJECTIVE: The aim of this study was to explore ß2-adrenoceptor (ADRB2) haplotype associations with phenotypes and quantitative traits related to insulin resistance (IR) and the metabolic syndrome (MS) in a polycystic ovary syndrome (PCOS) population. A secondary purpose was to assess the association between ADRB2 haplotype and PCOS. DESIGN: Genetic polymorphism analysis. Cross-sectional case-control association study. SETTING: Medical University Hospital and research laboratory. PATIENTS: One hundred and sixty-five unrelated women with PCOS and 116 unrelated women without PCOS (control sample). MEASUREMENTS: Clinical and biochemical measurements, and ADRB2 genotyping in PCOS patients and control subjects. METHODS: ADRB2 haplotypes (comprising rs1042711, rs1801704, rs1042713 and rs1042714 in that order), genotyping and statistical analysis to evaluate associations with continuous variables and traits related to IR and MS in a PCOS population. Associations between ADRB2 haplotypes and PCOS were also assessed. RESULTS: We observed an age-adjusted association between ADRB2 haplotype CCGG and lower insulin (P = 0·018) and HOMA (P = 0·008) in the PCOS sample. Interestingly, the expected differences in surrogate measures of IR between cases and controls were not significant in CCGG/CCGG carriers. In the case-control study, genotype CCGG/CCGG was associated with a 14% decrease in PCOS risk (P = 0·043), taking into account confounding variables. CONCLUSIONS: Haplotype I (CCGG) has a protective role for IR and MS in PCOS.

A clinical overview of non-motor symptoms in Parkinson's Disease.

Although Parkinson's disease (PD) is diagnosed on the basis of motor symptoms, including slowness of movement, tremor, rigidity and difficulties with balance and walking, now we are aware that non-motor symptoms are highly prevalent, since they can anticipate motor symptoms and can cause severe consequences. Several studies have shown that non-motor symptoms, such as depression, anxiety and apathy, psychosis (e.g., hallucinations, delusions), sleep disturbance, and pain may have a greater adverse impact on quality of life and health economics compared with motor symptoms. Non-motor symptoms can be divided into four domains: neuropsychiatric (e.g., depression, anxiety, apathy, hallucinations, dementia), autonomic (e.g., constipation, orthostatic hypotension, urinary changes, sweating abnormalities), sleep (e.g., insomnia, sleep fragmentation, excessive daytime sleepiness, rapid eye movement, sleep behavioural disorder, restless leg syndrome), and sensory dysfunction (e.g., pain, olfactory dysfunction). This review addresses diagnosis and treatment of these disorders. The causative mechanisms remain complex, since they reflect the widespread brainstem and cortical pathology of PD, with involvement of several neurotransmitters, including dopamine (DA), serotonin, norepinephrine, and acetylcholine. The diagnosis is often challenging, especially for psychiatric disorders, and in particular affective disorders, because somatic features of psychopathology may overlap with the movement disorder itself. Treatments used are limited and psychiatric drugs may not be as effective as in general population. Evidence based medicine is quite poor and it still requires well-designed clinical studies.

Polycystic ovary syndrome in Latin American populations: What is known and what remains unresolved.

Polycystic ovary syndrome (PCOS) is one of the main endocrine and reproductive disorders affecting women in their reproductive age. The syndrome is considered a multifactorial pathology. Therefore, genetic susceptibility and environmental factors contribute to PCOS development and phenotypic manifestation. Ethnicity and socioeconomic factors influence the development of PCOS and could affect the possibility of its diagnosis. Latin America is a unique case of study because of the heterogeneity within the region, complex socioeconomic status, and the mixed ancestry found in these populations. Up-to-date, most studies have focused on developed countries' populations, and there is a lack of evidence regarding Latin-American countries. We propose to review the state of the art of PCOS knowledge regarding Latin American populations, including the metabolic and reproductive aspects of the syndrome and the different influencing factors, and suggest future directions to deepen the study of PCOS.

Phenotype similarities in automatically grouped T2D patients by variation-based clustering of IL-1ß gene expression.

Background: Analyzing longitudinal gene expression data is extremely challenging due to limited prior information, high dimensionality, and heterogeneity. Similar difficulties arise in research of multifactorial diseases such as Type 2 Diabetes. Clustering methods can be applied to automatically group similar observations. Common clinical values within the resulting groups suggest potential associations. However, applying traditional clustering methods to gene expression over time fails to capture variations in the response. Therefore, shape-based clustering could be applied to identify patient groups by gene expression variation in a large time metabolic compensatory intervention. Objectives: To search for clinical grouping patterns between subjects that showed similar structure in the variation of IL-1ß gene expression over time. Methods: A new approach for shape-based clustering by IL-1ß expression behavior was applied to a real longitudinal database of Type 2 Diabetes patients. In order to capture correctly variations in the response, we applied traditional clustering methods to slopes between measurements. Results: In this setting, the application of K-Medoids using the Manhattan distance yielded the best results for the corresponding database. Among the resulting groups, one of the clusters presented significant differences in many key clinical values regarding the metabolic syndrome in comparison to the rest of the data. Conclusions: The proposed method can be used to group patients according to variation patterns in gene expression (or other applications) and thus, provide clinical insights even when there is no previous knowledge on the subject clinical profile and few timepoints for each individual.

[Obesity and risk factors for metabolic syndrome in young people with type 1 diabetes]. / Obesidad y factores de riesgo del síndrome metabólico en jóvenes con diabetes tipo 1.

Changes in the clinical presentation of diabetes mellitus in childhood and adolescence associated with obesity have resulted in an overlap of the two most common types of diabetes with a greater clinical heterogeneity. In order to characterize the type of diabetes at onset and assess the effect of obesity, 50 children with diabetes were studied. The patients were divided into two groups according to their nutritional status at diagnosis (over-weight/obese vs. normal weight). Insulin reserve was evaluated by measuring basal C-peptide and stimulated C-peptide in response to a mixed meal (MMTT) as well as HLA-DQB1 genotype, antibodies, and family history of risk factors for metabolic disease. Of all 50 patients, 38% was overweight/obese, 84% had a positive family history of metabolic syndrome, 82% had positive antibodies, and 100% were positive for the high-risk HLA-DQB1 genotype. No significant differences were found in fasting C-peptide or glycemic index/C-peptide levels between the two groups. In the overweight/obese group C-peptide response to MMTT showed higher levels at 60 and 120 minutes (p = 0.02 and 0.03) and the area under the curve for C-peptide was also higher (1.77 ng / ml vs. 5.5 ng/ ml, p = 0.0007) than in the normal-weight group. In conclusion, overweight/obese patients with type 1A diabetes had a greater pancreatic reserve, suggesting that nutritional status may accelerate disease onset.

Fetal programming by androgen excess impairs liver lipid content and PPARg expression in adult rats.

It is known that prenatal hyperandrogenization induces alterations since early stages of life, contributing to the development of polycystic ovary syndrome affecting the reproductive axis and the metabolic status, thus promoting others associated disorders, such as dyslipidemia, insulin resistance, liver dysfunction, and even steatosis. In this study, we aimed to evaluate the effect of fetal programming by androgen excess on the hepatic lipid content and metabolic mediators at adult life. Pregnant rats were hyperandrogenized with daily subcutaneous injections of 1 mg of free testosterone from days 16 to 19 of pregnancy. The prenatally hyperandrogenized (PH) female offspring displayed two phenotypes: irregular ovulatory phenotype (PHiov) and anovulatory phenotype (PHanov), with different metabolic and endocrine features. We evaluated the liver lipid content and the main aspect of the balance between fatty acid (FA) synthesis and oxidation. We investigated the status of the peroxisomal proliferator-activated receptors (PPARs) alpha and gamma, which act as lipid mediators, and the adipokine chemerin, one marker of liver alterations. We found that prenatal hyperandrogenization altered the liver lipid profile with increased FAs levels in the PHanov phenotype and decreased cholesterol content in the PHiov phenotype. FA metabolism was also disturbed, including decreased mRNA and protein PPARgamma levels and impaired gene expression of the main enzymes involved in lipid metabolism. Moreover, we found low chemerin protein levels in both PH phenotypes. In conclusion, these data suggest that prenatal hyperandrogenization exerts a negative effect on the liver and alters lipid content and metabolic mediators' expression at adult age.

Telomere Length Differently Associated to Obesity and Hyperandrogenism in Women With Polycystic Ovary Syndrome.

Background: Polycystic Ovary Syndrome (PCOS) often present metabolic disorders and hyperandrogenism (HA), facts that may influence the telomere length (TL). Aims: To compare the absolute TL (aTL) between women with PCOS and control women, and their association with the presence of obesity and HA parameters. Materials and methods: The PCOS group included 170 unrelated women outpatients and the control group, 64 unrelated donor women. Anthropometric, biochemical-clinical parameters and androgen profile were determined. The PCOS patients were divided accordingly to the presence of obesity and androgenic condition. The aTL was determined from peripheral blood leukocytes by Real Time quantitative PCR. Results: Women with PCOS exhibited a significantly longer aTL than controls after age adjustment (p=0.001). A stepwise multivariate linear regression in PCOS women, showed that WC (waist circumference) contributed negatively (b=-0.17) while testosterone levels contributed positively (b=7.24) to aTL. The non-Obese PCOS (noOB-PCOS) presented the longest aTL when compared to controls (p=0.001). Meanwhile, the aTL was significantly higher in the hyperandrogenic PCOS phenotype (HA-PCOS) than in the controls (p=0.001) and non hyperandrogenic PCOS phenotype (NHA-PCOS) (p=0.04). Interestingly, when considering obesity and HA parameters in PCOS, HA exerts the major effect over the aTL as non-obese HA exhibited the lengthiest aTL (23.9 ± 13.13 Kbp). Conversely, the obese NHA patients showed the shortest aTL (16.5 ± 10.59 Kbp). Conclusions: Whilst a shorter aTL could be related to the presence of obesity, a longer aTL would be associated with HA phenotype. These findings suggest a balance between the effect produced by the different metabolic and hormonal components, in PCOS women.

Effect of Roux-en-Y Gastric Bypass on Lipoprotein Metabolism and Markers of HDL Functionality in Morbid Obese Patients.

PURPOSE: Morbid obesity represents the most severe form of obesity and surgical intervention would be its only successful treatment. Bariatric surgery could generate modifications in carbohydrate metabolism and in lipid profile plus lipoprotein-associated proteins and enzymes, such as lipoprotein-associated phoslipase A2 (Lp-PLA2), cholesteryl ester transfer protein (CETP), and paraoxonase (PON) 1. The aim of the present study was to analyze changes in inflammation markers, carbohydrate metabolism, and lipid parameters in patients who underwent bariatric surgery. METHODS: Thirty-seven patients with morbid obesity were recruited. Evaluations were performed before (T0) and 1 (T1) and 6 (T2) months after surgery. Glucose, insulin, high-sensitivity C-reactive protein (hsCRP), triglycerides, total cholesterol, high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol, apolipoproteins (apo) A-I, and B plus Interleukin 1ß and 6 levels in addition to CETP, Lp-PLA2, and PON 1 activities were determined. RESULTS: Body mass index decreased at T1 and T2 (p < 0.01). An improvement in all markers of insulin resistance (p < 0.05) was observed at T1. hsCRP levels diminished at T2 (p < 0.05). Triglyceride levels decreased at T1 and T2 (p < 0.05). HDL-C and apo A-I showed a decrease at T1 which was completely reversed at T2 (p < 0.05). Lp-PLA2 activity increased at T1, which was reversed at T2 (p < 0.05), and CETP activity was diminished at T2 (p < 0.05). PON and ARE activities decreased at T1 and partially recovered at T2 (p < 0.05). CONCLUSIONS: These results would be indicative of a favorable effect of bariatric surgery on markers of carbohydrate metabolism and cardiovascular disease lipid risk factors.

Relationship between the IL-1ß serum concentration, mRNA levels and rs16944 genotype in the hyperglycemic normalization of T2D patients.

To evaluate Interleukin 1-beta (IL-1ß) serum and mononuclear leucocyte mRNA levels, also rs16944 (-511C/T) genotype, in relation to hyperglycemic normalization in Type 2 diabetes (T2D) patients, we recruited 30 individuals recently T2D diagnosed with hyperglycemia studied at basal time and after 6 and 12 months of the normalization treatment. At basal time, the T polymorphic allele of the rs16944 was associated with lower IL-1ß mRNA expression (p = 0.006); and higher glucose level was positive correlated to IL-1ß protein levels (p = 0.015). After treatment, the individuals showed a significant decrease in glucose level (p = 0.003), but they did not express significant changes in the IL-1ß serum levels. Surprisingly, we observed that the greater decreases in glucose level were associated to increased IL-1ß serum levels (p = 0.040). This is the first follow-up study evaluating IL-1ß mRNA expression and serum levels in hyperglycemic T2D individuals and after glycemic normalization treatment. The current results contribute to the knowledge of the relationship between inflammation and glucose metabolism in T2D.

Leukocyte telomere length is associated with iron overload in male adults with hereditary hemochromatosis.

BACKGROUND: Hereditary hemochromatosis (HH) is a primary iron overload (IO) condition. Absolute telomere length (ATL) is a marker of cellular aging and DNA damage associated with chronic diseases and mortality. AIM: To evaluate the relationship between ATL and IO in patients with HH. METHODS: Cross-sectional study including 25 patients with HH: 8 with IO and 17 without IO (ferritin < 300 ng/ml) and 25 healthy controls. Inclusion criteria were: age > 18 years, male sex and HH diagnosis. Patients with diabetes or other endocrine and autoimmune diseases were excluded. ATL was measured by real-time PCR. RESULTS: HH patients with IO were older (P<0.001) and showed higher ferritin concentration (P<0.001). Patients with HH, disregarding the iron status, showed higher glucose and body mass index (BMI) than controls (both P<0.01). ATL was shorter in patients with IO than controls [with IO: 8 (6-14), without IO: 13 (9-20), and controls: 19 (15-25) kilobase pairs, P<0.01]; with a linear trend within groups (P for trend <0.01). Differences in ATL remained statistically significant after adjusting by age, BMI and glucose (P<0.05). DISCUSSION: Patients with IO featured shorter ATL while patients without IO showed only mild alterations vs. controls. Screening for IO is encouraged to prevent iron-associated cellular damage and early telomere attrition.

Pro12Ala polymorphism of the peroxisome proliferatoractivated receptor-gamma gene is associated with metabolic syndrome and surrogate measures of insulin resistance in healthy men: interaction with smoking status.

BACKGROUND: The Pro12Ala polymorphism (rs1801282), a nonsynonymous substitution of peroxisome proliferator-activated receptor-gamma (PPARG), has been robustly associated with type 2 diabetes. However, its role in metabolic syndrome (MetS) remains poorly understood. The associations among rs1801282, MetS and surrogate measures of insulin resistance (IR) were investigated in the present study. METHODS AND RESULTS: A cross-sectional population-based survey of 572 unrelated healthy male Argentinian blood donors with normal findings on medical examination and not taking any medication was conducted. MetS was assessed using the National Cholesterol Education Program/Adult Treatment Panel III (NCEP/ATP III) criteria, and the HOMA-IR, and QUICKI were calculated. Genotyping of rs1801282 was performed using RFLP-PCR. The prevalence of MetS was 26.2%. The Pro/Ala genotype (and the Ala12 allele) was associated with a high risk for MetS (odds ratio (OR) 1.67 [95% confidence interval (CI) 1.03-2.72], P=0.0394). This was highlighted among nonsmokers (OR 2.20 [95%CI 1.25-3.88], P=0.0059). ANCOVA confirmed an interaction between smoking status and this association (P=0.031). Ala12 carriers had a higher waist circumference than noncarriers (P=0.0065). Among nonsmokers, surrogates of IR, such as HOMA-IR, were significantly higher in Ala12 carriers than in noncarriers (P<0.05). CONCLUSIONS: Healthy men, in particular nonsmokers, carrying the Ala12 allele of PPARG rs1801282 polymorphism, have a high risk for MetS and IR.

Getting to Know the Gut Microbial Diversity of Metropolitan Buenos Aires Inhabitants.

In recent years, the field of immunology has been revolutionized by the growing understanding of the fundamental role of microbiota in the immune system function. The immune system has evolved to maintain a symbiotic relationship with these microbes. The aim of our study was to know in depth the uncharacterized metagenome of the Buenos Aires (BA) city population and its metropolitan area, being the second most populated agglomeration in the southern hemisphere. For this purpose, we evaluated 30 individuals (age: 35.23 ± 8.26 years and BMI: 23.91 ± 3.4 kg/m2), from the general population of BA. The hypervariable regions V3-V4 of the bacterial 16S gene was sequenced by MiSeq-Illumina system, obtaining 47526 ± 4718 sequences/sample. The dominant phyla were Bacteroidetes, Firmicutes, Proteobacteria, Verrucomicrobia, and Actinobacteria. Additionally, we compared the microbiota of BA with other westernized populations (Santiago de Chile, Rosario-Argentina, United States-Human-microbiome-project, Bologna-Italy) and the Hadza population of hunter-gatherers. The unweighted UniFrac clustered together all westernized populations, leaving the hunter-gatherer population from Hadza out. In particular, Santiago de Chile's population turns out to be the closest to BA's, principally due to the presence of Verrucomicrobiales of the genus Akkermansia. These microorganisms have been proposed as a hallmark of a healthy gut. Finally, westernized populations showed more abundant metabolism related KEEG pathways than hunter-gatherers, including carbohydrate metabolism (amino sugar and nucleotide sugar metabolism), amino acid metabolism (alanine, aspartate and glutamate metabolism), lipid metabolism, biosynthesis of secondary metabolites, and sulfur metabolism. These findings contribute to promote research and comparison of the microbiome in different human populations, in order to develop more efficient therapeutic strategies for the restoration of a healthy dialogue between host and environment.

[Polymorphism in CYP11alpha and CYP17 genes and the etiology of hyperandrogenism in patients with polycystic ovary syndrome]. / Polimorfismos en los genes CYP11alpha y CYP17 y etiología del hiperandrogenismo en pacientes con poliquistosis ovárica.

The polycystic ovary syndrome (PCOS) is a heterogeneous multifactorial endocrine metabolic disorder with genetic predisposition affecting 6% of women in the reproductive age. This syndrome is characterized by the presence of oligo-anovulation, hyperandrogenism and polycystic ovaries. Several genes have been postulated as responsible for the etiology of this disorder. Among these genes are those encoding the enzymes involved in the ovarian androgen biosynthesis. Two of the candidate genes are the CYP17 and the CYP11alpha, encoding the 17-alpha-hydroxylase (P45017alpha) and the cholesterol side chain cleavage (P450scc) respectively. The polymorphisms of these genes are linked to the development of an hyperandrogenic phenotype. The aim of this work was to analyze the allelic frequencies of such polymorphisms in a cohort of women with PCOS and to compare them with those of healthy women. Furthermore, the correlation between each allelic variant and the corresponding hyperandrogenic phenotype was also assessed. Therefore, 65 patients and 58 age matched healthy controls were analyzed. The serum levels of testosterone and the frequency of each polymorphism were determined. When the PCOS population was analyzed, a significant statistical difference was found when relating the group with the highest androgenemia level with the presence of A2/A2 genotype of CYP 17 gene, and a higher level of circulating androgen was found in PCO women carrying the 216- allele of CYP11alpha gene (that did not reach statistical significance). Our results suggest that both alleles play a minor role in the development of PCOS and could be a genetic risk marker of the hyperandrogenic phenotype.

Inhibition of Osteoblast Function by Brucella abortus is Reversed by Dehydroepiandrosterone and Involves ERK1/2 and Estrogen Receptor.

Brucella abortus induces an inflammatory response that stimulates the endocrine system resulting in the secretion of cortisol and dehydroepiandrosterone (DHEA). Osteoarticular brucellosis is the most common presentation of the active disease in humans, and we have previously demonstrated that B. abortus infection inhibits osteoblast function. We aimed to evaluate the role of cortisol and DHEA on osteoblast during B. abortus infection. B. abortus infection induces apoptosis and inhibits osteoblast function. DHEA treatment reversed the effect of B. abortus infection on osteoblast by increasing their proliferation, inhibiting osteoblast apoptosis, and reversing the inhibitory effect of B. abortus on osteoblast differentiation and function. By contrast, cortisol increased the effect of B. abortus infection. Cortisol regulates target genes by binding to the glucocorticoid receptor (GR). B. abortus infection inhibited GRα expression. Cell responses to cortisol not only depend on GR expression but also on its intracellular bioavailability, that is, dependent on the activity of the isoenzymes 11ß-hydroxysteroid dehydrogenase (HSD) type-1, 11ß-HSD2 (which convert cortisone to cortisol and vice versa, respectively). Alterations in the expression of these isoenzymes in bone cells are associated with bone loss. B. abortus infection increased 11ß-HSD1 expression but had no effect on 11ß-HSD2. DHEA reversed the inhibitory effect induced by B. abortus infection on osteoblast matrix deposition in an estrogen receptor- and ERK1/2-dependent manner. We conclude that DHEA intervention improves osteoblast function during B. abortus infection making it a potential candidate to ameliorate the osteoarticular symptoms of brucellosis.