The role of apoptosis in the complex pathogenesis of the most common obstetrics and gynaecology diseases.

PURPOSE: We aimed to assess the etiological role of apoptotic genes Bcl-2 and Bax in the background of major obstetric and gynaecological diseases. METHODS: Placental tissue samples were collected from 101 pregnancies with intrauterine growth restriction and 104 pregnancies with premature birth with 140 controll samples from term, eutrophic newborns. In addition, gene expression assessment of the genes Bax and Bcl-2 was performed in 101 uterine leiomyoma tissue samples at our disposal with 110 control cases. Gene expression levels were assessed by PCR method. RESULTS: The expression of the Bcl-2 gene was decreased in placental samples with intrauterine growth restriction. Significant overexpression of the proapoptotic Bax gene was detected in samples from premature infants. Antiapoptotic Bcl-2 gene expression was found to be significantly increased in fibroid tissues. CONCLUSION: Apoptosis plays a crucial role in the development of the most common OB/GYN conditions. Decrease in the placental expression of the antiapoptotic gene Bcl-2 may upset the balance of programmed cell death.

Circulating Pro-Neurotensin in gestational diabetes mellitus.

BACKGROUND AND AIMS: Pro-Neurotensin (NT), a stable surrogate parameter of NT, has recently been introduced as a peptide predicting the development of obesity, diabetes mellitus, cardiovascular diseases, and cardiovascular mortality. However, regulation of Pro-NT in gestational diabetes mellitus (GDM) remains uninvestigated. METHODS AND RESULTS: Pro-NT was quantified in 74 women with GDM, 74 healthy, gestational age-matched, pregnant controls, as well as in a second cohort comprising of 74 healthy, non-pregnant control women, using a chemiluminometric sandwich immunoassay. Pro-NT was correlated to measures of obesity, hypertension, glucose and lipid metabolism, renal function, and inflammation. Mean ± standard deviation of circulating Pro-NT levels were not significantly different in women with GDM (100.2 ± 75.7 pmol/l) as compared to healthy, pregnant controls (103.2 ± 37.4 pmol/l) and healthy, non-pregnant female controls (105.9 ± 38.9 pmol/l) (p = 0.661). Homeostasis model assessment of insulin resistance (HOMA-IR) and creatinine positively correlated with serum Pro-NT in multivariate regression analysis. In contrast, free fatty acids (FFA) were inversely correlated with circulating Pro-NT. Results sustained adjustment for pregnancy status. CONCLUSIONS: Circulating Pro-NT is not independently associated with GDM, but is with HOMA-IR, creatinine, and FFA even after adjustment for pregnancy status.

Spatial Characterization of Soybean Yield and Quality (Amino Acids, Oil, and Protein) for United States.

Continued economic relevancy of soybean is a function of seed quality. The objectives of this study were to: (i) assess the spatial association between soybean yield and quality across major US soybean producing regions, (ii) investigate the relationship between protein, oil, and yield with amino acids (AAs) composition, and (iii) study interrelationship among essential AAs in soybean seed. Data from soybean testing programs conducted across 14 US states from 2012 to 2016 period (n = 35,101 data points) were analyzed. Results indicate that for each Mg ha-1 yield increase, protein yield increased by 0.35 Mg protein ha-1 and oil yield improved by 0.20 Mg oil ha-1. Essential AA concentrations exhibit a spatial autocorrelation and there was a negative relationship between concentration of AA, protein, and oil, with latitude. There was a positive interrelationship with different degree of strength among all AAs, and the correlation between Isoleucine and Valine was the strongest (r = 0.93) followed by the correlation among Arginine, Leucine, Lysine, and Threonine (0.71 < r < 0.88). We concluded that the variability in genotype (G) x management (M) x environment (E) across latitudes influencing yield also affected soybean quality; AA, protein, and oil content in a similar manner.

The BDNF Val66Met polymorphism is associated with lower BMI, lower postprandial glucose levels and elevated carbohydrate intake in children and adolescents.

BACKGROUND: The amino acid-changing exonic variant rs6265 (Val66Met polymorphism) in the brain-derived neurotrophic factor (BDNF) has been linked to obesity in several genotype-phenotype association studies. OBJECTIVE: To identify metabolic factors by which this effect might be conveyed, we aimed to investigate its correlation with (i) obesity, (ii) metabolic parameters, (iii) serum levels of BDNF and (iv) measures of energy intake in children and adolescents. METHODS: We genotyped the variant in 2131 subjects (age 6-18 years) and checked for an association with obesity. Secondly, we correlated the genotype with parameters of glucose and lipid metabolism (fasting/postprandial glucose and insulin levels, HbA1c, homeostasis model assessment, Matsuda, high-density lipoprotein, low-density lipoprotein, total cholesterol and triglycerides) in a smaller subset of 845 subjects. We determined BDNF serum levels in 177 individuals by enzyme-linked immunosorbent assay and assessed the association with genotype and metabolic parameters. Finally, we investigated the association between genotype and macronutrient intake from self-reported food diaries (n = 146). RESULTS: The minor Met allele was associated with lower BMI standard deviation score (p = 0.002). Post-pubertal Met allele carriers showed lower postprandial glucose levels and a lower HbA1c (ß = 0.15, p = 0.046 and ß = 0.27, p = 0.012, respectively). Neither the genotype nor any of the metabolic parameters correlated with BDNF serum levels. We observed an increased total calorie intake (ß = -0.21, p = 0.007) with increased carbohydrate and protein intake (ß = -0.22, p = 0.005 and ß = -0.14, p = 0.028, respectively) in Met allele carriers. CONCLUSIONS: We confirmed the association of the minor Met allele with lower BMI in children and provide new data that it is associated with lower postprandial glucose in post-pubertal subjects. Moreover, Met allele carriers reported to consume more carbohydrates and proteins.

New risk and protective factors for severe hypoglycaemia in people with type 1 diabetes.

AIMS: To evaluate risk factors for severe hypoglycaemia (SH) in patients with type 1 diabetes (T1DM). METHODS AND RESULTS: Retrospective observational and comparative study. All SH occurring between 2007 and 2014 in a German population (Lippe-Detmold) were captured. Characteristics of patients with T1DM and SH were compared with a control group being equivalent concerning age, diabetes duration, HbA1c, comorbidity, and ß-blocker treatment. SH was defined as a symptomatic event requiring treatment with intravenous glucose or glucagon administration and being confirmed by a blood glucose measurement of <2.8 mmol/l. Predictive factors for SH were analysed by a multivariable regression model. As many as 405 cases of SH in T1DM occurred in 206 subjects; 50% of episodes were related to 31 patients who experienced ≥3 SH. Need for nursing care (OR 4.88), treatment with NPH (OR 3.68), and impaired hypoglycaemia awareness (OR 2.06) were the strongest risk factors for SH (all p < 0.05, all pFDR-adjusted < 0.10; false discovery rate (FDR)). Depression (OR 0.14), treatment with CSII (OR 0.39) and short-acting insulin analogues (OR 0.31) appeared to be protective (all p < 0.10; FDR-adjusted). The probability of SH onset was significantly higher in patients who had previously experienced recurrent SH episodes. ß-Blocker treatment did not appear to be a risk factor. CONCLUSION: The complex risk for SH in people with T1DM can be reduced by treatment with CSII and short-acting analogues. Future structures of diabetes care will be challenged by the need of treating increasingly geriatric subjects with T1DM having a high risk of SH.

Novel genes on rat chromosome 10 are linked to body fat mass, preadipocyte number and adipocyte size.

BACKGROUND: The genetic architecture of obesity is multifactorial. We have previously identified a quantitative trait locus (QTL) on rat chromosome 10 in a F2 cross of Wistar Ottawa Karlsburg (WOKW) and Dark Agouti (DA) rats responsible for obesity-related traits. The QTL was confirmed in congenic DA.WOKW10 rats. To pinpoint the region carrying causal genes, we established two new subcongenic lines, L1 and L2, with smaller refined segments of chromosome 10 to identify novel candidate genes. METHODS: All lines were extensively characterized under different diet conditions. We employed transcriptome analysis in visceral adipose tissue (VAT) by RNA-Seq technology to identify potential underlying genes in the segregating regions. Three candidate genes were measured in human paired samples of VAT and subcutaneous (SC) AT (SAT) (N=304) individuals with a wide range of body weight and glucose homeostasis parameters. RESULTS: DA.WOKW and L1 subcongenic lines were protected against body fat gain under high-fat diet (HFD), whereas L2 and DA had significantly more body fat after high-fat feeding. Interestingly, adipocyte size distribution in SAT and epigonadal AT of L1 subcongenic rats did not undergo typical ballooning under HFD and the number of preadipocytes in AT was significantly elevated in L2 compared with L1 and parental rats. Transcriptome analysis identified three candidate genes in VAT on rat chromosome 10. In humans, these candidate genes were differentially expressed between SAT and VAT. Moreover, HID1 mRNA significantly correlates with parameters of obesity and glucose metabolism. CONCLUSIONS: Our data suggest novel candidate genes for obesity that map on rat chromosome 10 in an interval 102.2-104.7 Mb and are strongly associated with body fat mass regulation, preadipocyte number and adipocyte size in rats. Among those genes, AT head involution defective (HID1) mRNA expression may be relevant for human fat distribution and glucose homeostasis.

Association of metabolic parameters and rs726344 in FNDC5 with serum irisin concentrations.

BACKGROUND/OBJECTIVES: Irisin has been suggested as a novel myokine with beneficial effects in rodents. However, previous data in humans showed conflicting results regarding its association with metabolic phenotypes and regulation of secretion. Furthermore, although an association of rs726344 in FNDC5 (fibronectin type III domain containing 5) coding for irisin with insulin sensitivity was reported, the effects of genetic variation at this locus on irisin serum levels have not been investigated, so far. Therefore, we investigated circulating irisin and the associations with rs726344 in a cohort of >1000 subjects. SUBJECTS/METHODS: Irisin serum concentrations were measured with enzyme-linked immunosorbent assay. Associations with metabolic parameters including renal function, glucose and lipid metabolism, inflammation, as well as adipokine profiles, were assessed in regression models. Dynamic changes of serum irisin were investigated during oral glucose tolerance test (OGTT) in a subset of the cohort (n=136). rs726344 was genotyped in all subjects and analyzed for associations with serum irisin and traits of the metabolic syndrome. RESULTS: Irisin was negatively associated with fat mass, fasting glucose and dyslipidemia but not with other adipokines. Moreover, irisin decreased during an OGTT in a subcohort comprising subjects with normal glucose tolerance, impaired fasting glucose, impaired glucose tolerance and type 2 diabetes mellitus. rs726344 was not associated with serum irisin levels or with other anthropometric and biochemical parameters. CONCLUSIONS: Circulating irisin levels are associated with a beneficial metabolic profile but not with other adipokines and not with rs726344 in our cohort. Our data suggest a potential favorable role of irisin in the regulation of metabolism.

Serum adiponectin and progranulin levels are associated with gallstone disease.

BACKGROUND/AIM: Aberrant adipokine serum concentrations are associated with a variety of obesity-related diseases. This study was designed to investigate the putative role of the adipokines adiponectin, chemerin, progranulin, vaspin, fibroblast growth factor 21 (FGF21) and adipocyte fatty acid binding protein (AFABP) in gallstone disease. METHODS: Serum levels of adiponectin, chemerin, progranulin, vaspin, FGF21 and AFABP of 189 gallstone patients and 833 healthy controls were measured by enzyme-linked immunosorbent assays. RESULTS: Increased adiponectin levels were nominally associated with lower gallstone risk in women (p=0.036, odds ratio (OR) 0.47, 95% confidence interval (CI) [0.23; 0.95]). Furthermore progranulin serum concentrations in men were significantly elevated in gallstone carriers in comparison to controls (p=0.012, OR 6.1, 95% CI [1.5; 24.9]). Serum levels of chemerin, vaspin, FGF21 and AFABP did not differ between controls and subjects with gallstones. CONCLUSION: Our data further support a protective effect of adiponectin on gallstone risk and suggest a role of progranulin in the pathophysiology of cholelithiasis. Nevertheless, longitudinal data and functional analyses would be required to assess the pathogenetic link between gallstone formation and adipokine serum levels.

Fat depot-specific mRNA expression of novel loci associated with waist-hip ratio.

OBJECTIVE: We hypothesized that genes within recently identified loci associated with waist-hip ratio (WHR) exhibit fat depot-specific mRNA expression, which correlates with obesity-related traits. METHODS: Adipose tissue (AT) mRNA expression of 6 genes (TBX15/WARS2, STAB1, PIGC, ZNRF3 and GRB14) within these loci showing coincident cis-expression quantitative trait loci was measured in 222 paired samples of human visceral (vis) and subcutaneous (sc) AT. The relationship of mRNA expression levels with obesity-related quantitative traits was assessed by Pearson's correlation analyses. Multivariate linear relationships were assessed by generalized linear regression models. RESULTS: Whereas only PIGC, ZNFR3 and STAB1 mRNA expression in sc AT correlated nominally with WHR (P<0.05, adjusted for age and sex), mRNA expression of all studied genes in at least one of the fat depots correlated significantly with vis and/or sc fat area (P ranging from 0.05 to 4.0 × 10(6), adjusted for age and sex). Consistently, the transcript levels of WARS, PIGC and GRB14 were nominally associated with body mass index (BMI) (P ranging from 0.02 to 9.2 × 10(5), adjusted for age and sex). Moreover, independent of sex, obesity and diabetes status, differential expression between vis and sc AT was observed for all tested genes (P<0.01). Finally, the rs10195252 T-allele was nominally associated with increased GRB14 sc mRNA expression (P=0.025 after adjusting for age, sex and BMI). CONCLUSIONS: Our data including the inter-depot variability of mRNA expression suggests that genes within the WHR-associated loci might be involved in the regulation of fat distribution.

Genetic variation in the vaspin gene affects circulating serum vaspin concentrations.

OBJECTIVE: Visceral adipose tissue-derived serine protease inhibitor (vaspin) is an adipokine potentially linking obesity, insulin resistance and type 2 diabetes. Here, we searched for genetic determinants that could explain the variability in serum vaspin concentrations. RESEARCH DESIGN AND METHODS: First, we conducted a genome-wide association study (GWAS) for serum vaspin in the Sorbs cohort (N=826). Subsequently, 26 single-nucleotide polymorphisms (SNPs) covering genetic variation in the vaspin locus were genotyped in the Sorbs. In addition, we measured serum vaspin concentrations in 1806 samples from Augsburg/the Cooperative Health Research in the Region of Augsburg (KORA) for replication of the association signals. Finally, we conducted association analyses of vaspin SNPs with metabolic traits in the Sorbs (N=1013), KORA (N=1813) and a further cohort from Germany (Leipzig: N=1857). RESULTS: Six SNPs mapping between serpinA1 and serpinA4, including the vaspin locus, on chromosome 14 reached P-values < or = 10(-8) in the GWAS in the Sorbs. The fine mapping of variants within the vaspin locus in the Sorbs and subsequent replication in the KORA sample revealed several SNPs significantly associated with serum vaspin concentrations reaching P-values of up to 10(-35). However, no significant association with type 2 diabetes or related traits was found in either cohort after the Bonferroni correction for multiple comparisons. CONCLUSION: Our data show that the variability in serum vaspin concentrations might be explained by its genetic variants.

Genetic variants in GCKR, GIPR, ADCY5 and VPS13C and the risk of severe sulfonylurea-induced hypoglycaemia in patients with type 2 diabetes.

OBJECTIVE: Severe hypoglycaemia (SH) induced by sulfonylureas is a life-threatening condition. We hypothesized that recently identified polymorphisms associated with insulin secretion in GCKR, GIPR, ADCY5 and VPS13C genes affect the response to sulfonylureas in patients with type 2 diabetes (T2D) and so, result in reduced risk for SH. RESEARCH DESIGN AND METHODS: We assessed the prevalence of GCKR, GIPR, ADCY5 and VPS13C polymorphisms in a case-control study including 111 patients with SH and 100 patients with T2D but without a history of SH. All patients were treated with the sulfonylurea drugs glimepiride, glibenclamide or gliquidon. SH was defined as a symptomatic event with blood glucose of <50 mg/dl requiring treatment with intravenous glucose. RESULTS: In logistic regression analyses, a low HbA(1c) and a higher sulfonylurea dose appeared to be the only predictors of SH (P=0.001 and P=0.04, respectively). There was no significant difference in the genotype distribution between the control group and the cases with SH for any of the investigated polymorphisms (OR and 95% confidence intervals - 0.90 (0.59-1.38) for GCKR; 1.11 (0.67-1.85) for GIPR; 0.75 (0.48-1.17) for ADCY5; 1.43 (0.95-2.15) for VPS13C; all P-values >0.05). Also, there was no significant effect of the examined genetic variants on HbA1c levels (all P-values >0.05 adjusted for age, sex, BMI, diabetes duration, sulfonylurea dose). CONCLUSIONS: We found no detectable effect (with an OR >2.1) of the variants in GCKR, GIPR, ADCY5 and VPS13C on the response to sulfonylurea treatment, indicating that these variants are not significantly contributing to the risk of SH in patients with T2D.

Functional relevance of genes implicated by obesity genome-wide association study signals for human adipocyte biology.

AIMS/HYPOTHESIS: Genome-wide association studies (GWAS) have identified numerous single-nucleotide polymorphisms associated with obesity, consequently implying a role in adipocyte biology for many closely residing genes. We investigated the functional relevance of such genes in human adipocytes. METHODS: We selected eight genes (BDNF, MAF, MTCH2, NEGR1, NPC1, PTER, SH2B1 and TMEM18) from obesity GWAS and analysed their effect in human adipogenesis using small interfering (si)RNA-mediated knockdown, their regulation by metabolic agents in adipocytes and pre-adipocytes, and gene expression in paired samples of human fat biopsies (68 non-obese, 165 obese) by quantitative real-time PCR. RESULTS: We show a two- to threefold upregulation of MAF, MTCH2 and NEGR1 and a two- to fourfold downregulation of BDNF and PTER during adipogenesis. Knockdown of BDNF (mean ± SEM; 83.8 ± 4.7% of control; p = 0.0002), MTCH2 (72.7 ± 9.5%; p = 0.0006), NEGR1 (70.2 ± 5.7%; p < 0.0001) and TMEM18 (70.8 ± 6.1%; p < 0.0001) significantly inhibited adipocyte maturation, while knockdown of the other proteins had no effect. Insulin slightly induced MAF (1.65-fold; p = 0.0009) and MTCH2 (1.72-fold; p < 0.0001), while it suppressed BDNF (59.6%; p = 0.0009), NEGR1 (58.0%; p = 0.0085) and TMEM18 (69.3%; p = 0.0377) in adipocytes. The synthetic glucocorticoid dexamethasone suppressed MAF (45.7%; p = 0.0022), BDNF (66.6%; p = 0.0012) and TMEM18 (63.5%; p = 0.0181), but induced NEGR1 (3.2-fold; p = 0.0117) expression. Furthermore, MTCH2, NEGR1 and TMEM18 were differentially expressed in subcutaneous and visceral adipose tissue. TMEM18 expression was decreased in the adipose tissue of obese patients, and negatively correlated with anthropometric variables and adipocyte size. CONCLUSIONS/INTERPRETATION: Our results imply a regulatory role for TMEM18, BDNF, MTCH2 and NEGR1 in adipocyte differentiation and biology. In addition, we show a variation of MAF expression during adipogenesis, while NPC1, PTER and SH2B1 were not regulated.

Oral alitretinoin: a review of the clinical pharmacokinetics and pharmacodynamics.

Alitretinoin is an endogenous retinoid related to vitamin A. Studies have shown that oral alitretinoin is effective and well tolerated in the treatment of severe chronic hand eczema. This review summarizes the clinical pharmacokinetic and pharmacodynamic data from a number of studies involving alitretinoin. These include the effect of food on the pharmacokinetics of alitretinoin, interactions between alitretinoin and ketoconazole, simvastatin or cyclosporin A, the effect of alitretinoin on the pharmacokinetics of a combined oral contraceptive, alitretinoin in seminal fluid after repeated dosing, and the pharmacokinetics of alitretinoin and its metabolites in a clinical setting.

Number and sex ratio of children and impact of parental diabetes in individuals with Type 1 diabetes.

OBJECTIVE: To assess the number and sex ratio of children in individuals with Type 1 diabetes mellitus and the influence of parental diabetes on age at onset of Type 1 diabetes in our cohort. METHODS: In a cross-sectional study in a German region comprising 350,000 inhabitants, 697 subjects with Type 1 diabetes (364 women, 333 men) underwent a standardized assessment regarding the number and sex of their children and the family history of diabetes. RESULTS: Compared with 1.36 children per woman in the German background population, the total fertility rate in the calendar year of 2010 in our female cohort with Type 1 diabetes (age 18-49 years) was 0.88. Men with Type 1 diabetes had a fertility rate of 0.65. More men (51.1%) than women (35.7%; P < 0.0001) were childless. Twenty per cent of all women aged 41-45 years in the background population were childless compared with 36.2% of all women and 52% of all men in this specific age group from our cohort. The sex ratio of female vs. male offspring of individuals with Type 1 diabetes did not differ significantly from the expected 1:1 ratio. Maternal Type 1 or Type 2 diabetes increased the age at onset of Type 1 diabetes from 22.9 ± 13.7 (no maternal diabetes) to 28.6 ± 16.8 and 30.1 ± 15.1 years (p < 0.0001), respectively. CONCLUSIONS: Compared with the German reference population, individuals with Type 1 diabetes had significantly fewer children and were more often childless. The sex ratio female vs. male offspring of women and men with Type 1 diabetes was unaffected. Maternal history of Type 1 and Type 2 diabetes was associated with a significant later onset of Type 1 diabetes.

Metabolic and genetic predictors of circulating adipocyte fatty acid-binding protein.

BACKGROUND: Adipocyte fatty acid-binding protein (AFABP) was recently introduced as a novel adipokine playing an important role in glucose homeostasis. In this study, we investigated the relationship between serum AFABP levels and metabolic, as well as cardiovascular parameters, in the self-contained population of Sorbs. Furthermore, we conducted a genome-wide association study on serum AFABP concentrations in the Sorbs and we separately analyzed the effects of two common variants in the FABP4 gene on AFABP serum concentration. METHODS: Serum AFABP concentrations were quantified by enzyme-linked immunosorbent assay and correlated with metabolic and cardiovascular parameters, as well as inflammatory markers and renal function, in 868 well-characterized non-diabetic Sorbs from Germany. RESULTS: Median AFABP serum concentrations were 1.5-fold higher in female subjects (23.03 µg l(-1)) as compared to male subjects (15.86 µg l(-1)). Waist-to-height ratio and glomerular filtration rate were independently associated with AFABP concentrations in multiple regression analysis in both female and male subjects. The genome-wide scan for association of single-nucleotide polymorphisms with serum AFABP levels in the Sorbs revealed 39 loci reaching P-values <10(-4). Two single-nucleotide polymorphisms, rs16909187 and rs10808846, representing common genetic variation in FABP4 did not show any effect on serum AFABP concentrations in our study cohort. CONCLUSION: AFABP serum concentrations are determined by parameters of fat distribution, renal function and gender.

The promoter variant -803 G>A in the RBP4 gene is not associated with BMI, metabolic parameters or blood pressure in Caucasian children.

OBJECTIVE: Studies in adults identified the -803 G>A promoter polymorphism (rs3758539) in the RBP4 gene (RBP4) as a functional variant conferring an increased risk for obesity and type 2 diabetes. METHODS: We genotyped this polymorphism in a cohort of 304 lean and 283 obese children to assess a potential association with early onset obesity and blood pressure and evaluated the effect of this SNP on metabolic parameters in a smaller subset. RESULTS: The allele frequency of -803 G>A was similar in obese compared to lean subjects (0.159 vs. 0.191, P=0.318). We did not detect an association of the variant with adiposity parameters nor with parameters of glucose and lipid metabolism or blood pressure in quantitative analyses. CONCLUSION: Our study revealed that the promoter polymorphism -803 G>A in RBP4 is not associated with BMI, metabolic parameters or blood pressure in Caucasian children.

Atrial remodeling and novel pharmacological strategies for antiarrhythmic therapy in atrial fibrillation.

Atrial fibrillation (AF) is the most common arrhythmia in clinical practice. It can occur at any age, however, it becomes extremely common in the elderly, with a prevalence approaching more than 20% in patients older than 85 years. AF is associated with a wide range of cardiac and extra-cardiac complications and thereby contributes significantly to morbidity and mortality. Present therapeutic approaches to AF have major limitations, which have inspired substantial efforts to improve our understanding of the mechanisms underlying AF, with the premise that improved knowledge will lead to innovative and improved therapeutic approaches. Our understanding of AF pathophysiology has advanced significantly over the past 10 to 15 years through an increased awareness of the role of "atrial remodeling". Any persistent change in atrial structure or function constitutes atrial remodeling. Both rapid ectopic firing and reentry can maintain AF. Atrial remodeling has the potential to increase the likelihood of ectopic or reentrant activity through a multitude of potential mechanisms. The present paper reviews the main novel results on atrial tachycardia-induced electrical, structural and contractile remodeling focusing on the underlying pathophysiological and molecular basis of their occurrence. Special attention is paid to novel strategies and targets with therapeutic significance for atrial fibrillation.

Association and evolutionary studies of the melatonin receptor 1B gene (MTNR1B) in the self-contained population of Sorbs from Germany.

AIMS: Several polymorphisms of the melatonin receptor 1B gene (MTNR1B) have been shown to be associated with elevated fasting plasma glucose and impaired early insulin release. The aim of this study was to assess the effects of MTNR1B variants on traits related to the metabolic syndrome in the self-contained population of Sorbs from Germany. As comprehensive studies concerning the conservation of MTNR1B are lacking, we also evaluated natural selection in vertebrates and human populations at this locus. METHODS: Five single nucleotide polymorphisms representing all blocks of linkage disequilibrium within and surrounding the MTNR1B locus were genotyped in 937 Sorbs for association analyses on metabolic traits related to Type 2 diabetes. The associations were assessed by regression analyses, the conservation between species was investigated with phylogenetic analysis by maximum likelihood (PAML). In addition, various tests of population genetic measures (e.g. fixation index, Tajima's D) were performed. RESULTS: Previously reported association between MTNR1B variants (rs10830963, rs4753426) and oral glucose tolerance test-derived indices of ß-cell function (homeostasis model assessment-B, P = 3.7 × 10⁻6 and P = 0.004, respectively), as well as insulin (fasting insulin: P=2×10⁻³ and P=0.02; 30-min insulin: P = 2.1 × 10⁻4 and P=0.03, respectively) and fasting glucose (rs10830963, P=1.2×10⁻6) parameters could be replicated in the present study. Phylogenetic analysis by maximum likelihood analyses showed that the gene was strongly conserved between species (ω=0.2583). Structures important for the receptor function are also conserved. On the lineage leading to human adaptive selection was present (ω=1.1030). Population genetic measures further indicated natural selection. CONCLUSIONS: Our data support the physiologic importance of MTNR1B in the context of glucose homeostasis and suggest evidence of selection at this locus.