Subgingival Microbiota and Longitudinal Glucose Change: The Oral Infections, Glucose Intolerance and Insulin Resistance Study (ORIGINS).

Microbial communities along mucosal surfaces throughout the digestive tract are hypothesized as risk factors for impaired glucose regulation and the development of clinical cardiometabolic disease. We investigated whether baseline measures of subgingival microbiota predicted fasting plasma glucose (FPG) longitudinally. The Oral Infections, Glucose Intolerance and Insulin Resistance Study (ORIGINS) enrolled 230 diabetes-free adults (77% female) aged 20 to 55 y (mean ± SD, 34 ± 10 y) from whom baseline subgingival plaque and longitudinal FPG were measured. DNA was extracted from subgingival plaque, and V3 to V4 regions of the 16S rRNA gene were sequenced. FPG was measured at baseline and again at 2 y; glucose change was defined as follow-up minus baseline. Multivariable linear models regressed 2-y glucose change onto baseline measures of community diversity and abundances of 369 individual taxa. A microbial dysbiosis index (MDI) summarizing top individual taxa associated with glucose change was calculated and used in regression models. Models were adjusted for age, sex, race/ethnicity, education, smoking status, body mass index, and baseline glucose levels. Statistical significance was based on the false discovery rate (FDR; <0.05) or a Bonferroni-corrected P value of 1 × 10-4, derived from the initial 369 hypothesis tests for specific taxa. Mean 2-y FPG change was 1.5 ± 8 mg/dL. Baseline levels of 9 taxa predicted FPG change (all FDR <0.05), among which Stomatobaculum sp oral taxon 097 and Atopobium spp predicted greater FPG change, while Leptotrichia sp oral taxon 498 predicted lesser FPG change (all 3 P values, Bonferroni significant). The MDI explained 6% of variation in longitudinal glucose change (P < 0.001), and baseline glucose levels explained 10% of variation (P < 0.0001). FPG change values ± SE in the third versus first tertile of the MDI were 4.5 ± 0.9 versus 1.6 ± 0.9 (P < 1 × 10-4). Subgingival microbiota predict 2-y glucose change among diabetes-free men and women.

Physical training in patients with chronic heart failure enhances the expression of genes encoding antioxidative enzymes.

OBJECTIVES: We sought to determine whether the benefit of training for vasodilation in the skeletal muscle vasculature of patients with chronic heart failure (CHF) is likely to be caused at the molecular level primarily by increased nitric oxide (NO) production or decreased inactivation of NO. BACKGROUND: Physical training reverses endothelium dysfunction in patients with CHF, mediated by increased NO bioactivity. Some animal studies support a mechanism whereby training results in increased vascular NO levels by sustained transcriptional activation of the endothelial NO synthase (eNOS) gene, presumably due to shear stress. The mechanism has not been addressed in patients with CHF. METHODS: The steady state transcript levels for eNOS and two other shear stress regulated genes (angiotensin-converting enzyme [ACE] and prostacyclin synthase [PGI2S]) were measured in samples of skeletal muscle from patients with CHF before and after 12 weeks of training. Transcript levels were measured in the same samples for two genes encoding antioxidant enzymes, copper zinc superoxide dismutase (Cu/Zn SOD) and glutathione peroxidase (GSH-Px). Untrained patients served as controls. RESULTS: As expected, training significantly enhanced peak oxygen uptake in the patients with CHF. Training did not increase steady-state transcript levels for eNOS, ACE or PGI2S. In striking contrast, training increased the expression of the antioxidative enzyme genes by approximately 100%. CONCLUSIONS: Our results do not support a model of benefit from training by increased eNOS expression. However, the data are entirely consistent with the alternative hypothesis, that reduced oxidative stress may account for the increase in vascular NO-mediated vasodilation. Insight into the mechanism may be relevant when considering therapies for exercise-intolerant patients with CHF.

Value of quantitative analysis of mitral regurgitation jet eccentricity by color flow Doppler for identification of flail leaflet.

Early surgical intervention improves the outcome of patients with mitral regurgitation (MR) secondary to flail leaflet. Current criteria for the diagnosis of flail leaflet require a detailed definition of mitral valve anatomy, which is often challenging by transthoracic echocardiography (TTE) and, occasionally, even by transesophageal echocardiography (TEE). We studied 57 patients (mean age 63 +/- 15 years) with anatomically confirmed flail mitral leaflet and a control group of 57 patients (mean age 68 +/-14 years) with at least moderate MR but no flail leaflet. In patients with flail mitral leaflet, the mean angle formed by the axis of the MR jet and the plane of the mitral annulus was 33 +/- 11 degrees and 29 +/- 16 degrees when measured with TTE and TEE, respectively. In controls the mean angle was 66 +/- 16 degrees and 66 +/- 17 degrees by TTE and TEE, respectively (p <0.0001). Based on receiver- operating characteristic analysis, the optimal cutoff jet angle value for diagnosing flail mitral leaflet was 45 degrees with TTE (sensitivity 88%, specificity 88%), and 47 degrees by TEE (sensitivity 88%, specificity 88%). MR jet angles < or =45 degrees were also correctly identified by visual assessment of TTE images in >90% of cases, with good interobserver agreement (k = 0.76). Thus, quantitative analysis of MR jet eccentricity by color flow Doppler is highly sensitive and specific for diagnosing flail mitral leaflet.

Regulation of ILT3 gene expression by processing of precursor transcripts in human endothelial cells.

Immunoglobulin-like transcript (ILT)-3 is a transmembrane receptor, which belongs to the immunoglobulin superfamily. In previous studies, we showed that allospecific CD8+CD28- T suppressor cells (Ts) induce the expression of ILT3 in human endothelial cells (EC) rendering them tolerogenic. Using a polymerase chain reaction (PCR)-based approach, we now demonstrate by cell fractionation and sequencing studies that ILT3 precursor RNA is expressed and retained in nuclei of resting EC. Ts interaction with EC or exposure of EC to interleukin-10 (IL-10) and interferon alpha (IFN-alpha) triggers processing of ILT3 pre-mRNA. Western blot analysis showed that the expression of the mature ILT3 transcript is accompanied by production of ILT3 protein.

Chromosome polymorphisms and natural selection in Leptysma argentina (Orthoptera). IV. Survival selection acts on karyotype polymorphisms at the adult stage and before.

Deviation from formal null models and the comparisons between age classes are amongst the most direct methods of demonstrating ongoing natural selection. We have sampled 207 males from a population of the grasshopper Leptysma argentina at the onset and the end of the adult life span for this species; generations are synchronical and do not overlap. The karyotypic frequencies for a fusion (F) and a supernumerary segment (s1) were examined. The young male sample was heterogeneous and did not fit to the Hardy-Weinberg proportions, whereas the aged male sample did not deviate from H-W expectations in both analyses. Likewise, the young male sample showed fitness heterosis for the s1 carriers that are fusion homozygotes. We interpreted the significant results of karyotype frequency in both samples as the result of survival selection. Evidently natural selection acts on male adult viability as well as on other fitness components prior to adult survival, thus changing karyotype frequencies between generations. Likewise, we also detected a strong interaction between polymorphisms, whereas heterosis for s1 heterozygotes might be contributing to the maintenance of the s1 polymorphism. The actual target of selection remains unidentified.

Chromosome inversion polymorphisms influence morphological traits in Trimerotropis pallidipennis (Orthoptera).

Trimerotropis pallidipennis is a New World grasshopper whose South-American populations are polymorphic for six pericentric inversions. Previous work has demonstrated that the frequences of these inversions correlate with climatic variables, and hence a possible adaptive pattern was put forward. In the present work we analysed a sample of a natural population of T pallidipennis to ascertain whether the chromosomal inversions have effects on exophenotypes. Two hundred and sixty-eight males coming from a natural population at Uspallata, Mendoza Province, Argentina were analysed, and it was observed that most inversions had significant effects on phenotypes. Furthermore, some body size-related characteristics (such as tegmina length) were correlated with the number of inversions. Individuals from populations at higher altitude or latitude (i.e., at lower minimum temperatures), along with higher frequencies of standard sequences, were significantly smaller, and this coherence between interpopulational with intrapopulational results may indicate that the diminished body size of the standard sequence-carrying individuals may be caused by an effect of the inversions, or genes within the inversions, on body size. We finally put forward the hypothesis that reduced body size in a context of reduced minimum temperature may be a response to shortened development season, and so smaller individuals may be advantageous.

Inversion polymorphisms and natural selection in Trimerotropis pallidipennis (Orthoptera).

Grasshoppers have been much less studied than Drosophila when it comes to inversion polymorphisms, despite the occurrence of this rearrangement in several species of grasshoppers. In the present study, 354 males from a natural population of the New World species Trimerotropis pallidipennis, polymorphic for 6 pericentric inversions in 4 chromosome pairs, were sampled at the beginning and at the end of the adult life span. This sampling, along with the fact that generations in this grasshopper are annual and discrete, was done to detect differential adult male longevity among karyotypes and departures from formal null models, such as gametic phase equilibrium. These methods allow the detection of natural selection taking place in the wild. The comparison between age classes showed that some inversions were significantly more frequent in one sample, thus revealing the operation of natural selection. Gametic phase disequilibrium was detected in the sample of aged males but not in the sample of young ones. Furthermore, here we aim to detect the phenotypic targets of longevity selection by examining morphometric characters, in order to have a clearer idea of the relation between inversions and natural selection in this species. These results corroborate previous studies that suggested that the inversions are involved in natural selection, and an adaptive model has been proposed for the pattern of inversion frequencies throughout several populations at different altitudes and latitudes.

Chiasma interference is blind to centromeres.

It has long been assumed, since the early works of Mather, that the centromere plays a central role in chiasma position determination, so much so that in all sequential models chiasma determination was supposed to start or finish at this point. More specifically, it has been assumed that the centromere acts as a barrier to the transmission of interference, so that a chiasma in the vicinity of a centromere would not affect the probability of chiasma formation across at this point. Some statistical analyses seemed to ratify this supposition. However, a reassessment of the literature led us to the conclusion that the statistical analyses that were not flawed were consistent in showing that interference may act across the centromere. Using large sets of chiasma data from the grasshoppers Leptysma argentina and Chorthippus brunneus and applying statistical approaches that involved either the calculation of coincidence or correlating the distances between the centromere and the nearest chiasma in either arm, it is concluded: 1. that interference acts across the centromere; 2. that the action of interference is not changed by the presence of an intervening centromere.

Inversion polymorphisms in Trimerotropis pallidipennis (Orthoptera): clinical variation along an altitudinal gradient.

Six populations of Trimerotropis pallidipennis located along an altitudinal gradient in the Antinaco-Los Colorados valley (La Rioja, Argentina), were cytologically analysed. The male karyotype consists of 23 chromosomes (22 + XO) with three long pairs submetacentric, the X-chromosome metacentric and the remaining ones basically acrocentric. Populations from La Rioja were polymorphic for seven pericentric inversions. Correlations between chromosome frequencies and altitude were statistically tested. In most cases, variables were either positively or negatively related in a significant fashion. As a consequence, mean populational heterozygosis (measured as the mean number of heteromorphic bivalents per individual per population) was also positively correlated with altitude. These results suggest that altitude (or other correlated environmental variable) may exert a differential selective pressure on coadapted gene blocks in the mutually inverted sequences. The possible relation of these results with the central-marginal model is discussed.

Chromosomal polymorphism, morphometric traits and mating success in Leptysma argentina Bruner (Orthoptera).

The South-American species Leptysma argentina Bruner is polymorphic for a centric fusion between chromosomal pairs 3 and 6 (fusion 3/6). Cytogenetic and morphological studies revealed that fusion 3/6 significantly increases some morphometric variables in males. A selection components study showed that the fusion is positively selected for longevity, the direct effect being exerted on thorax height. Moreover, a unisexual approach revealed that sexual male selection acts by increasing third femur length. In the present study the effect of fusion 3/6 on morphometric variables and the effect of body size and karyotype on mating success in both males and females were analysed through a bisexual approach. Total body length (TL) and third femur length (FL) were significantly larger amongst the fusion carrier females. Besides, the largest females and the carriers of the fusion have increased mating success. The selection differential suggests that directional sexual selection favours the females with increased TL and fusion dosage; however, the selection gradient revealed that none of the variables here analysed is a direct target of sexual selection. The male sexual selection study agrees with previous results, showing the importance of the third pair of legs in male mating success among grasshoppers.

Chromosomal polymorphism, morphological traits and male mating success in Leptysma argentina (Orthoptera).

Leptysma argentina (Acrididae: Orthoptera) is polymorphic for a centric fusion between pairs 3 and 6 of its basic chromosomal complement. With the aim of carrying out an analysis of selection components in this species, male mating success, in relation to karyotype and three morphometric traits, was assessed by using experimental contests with four males and one female per mating cage. Karyotype was assessed in terms of fused chromosome 3/6 dosage and coded as "0", "1" and "2" for unfused homozygotes, heterozygotes and fusion homozygotes, respectively. The individual ANOVA showed significant differences between "successful" and "unsuccessful" males in all four measured characters. Fusion carriers showed a higher relative fitness. Since the phenotypic correlations among traits were significant, the selective effects were assessed by means of a multivariate analysis, which demonstrated that selection acted significantly on femur length only, selection on karyotype being indirect. Given that the fusion frequency has been constant since 1985, the presence of selective trade-offs cannot be ruled out.

Dose-dependent blockade of the angiotensin II type 1 receptor with losartan in normal volunteers.

Losartan, an angiotensin II type 1 receptor (AT1) antagonist, was developed as a more specific alternative to angiotensin-converting enzyme (ACE) inhibitors. At a daily dose of 50 mg, losartan is currently evaluated in large outcome trials involving patients with hypertension and postmyocardial infarction. The current study evaluated the level and duration of blockade of a pressor response to angiotensin II by 50 and 150 mg of losartan, compared with 32 mg of candesartan. Eight normotensive volunteers were randomly assigned to a single dose of losartan 50 or 150 mg, candesartan 32 mg, or placebo. Subjects were re-randomized after a 2-week washout period to complete all four study arms. Radial artery systolic pressure response to exogenous angiotensin II was measured at 2, 6, 12, and 24 h after administration of drug. Losartan 50 mg reduced the pressure response to exogenous angiotensin II significantly only at 6 h. In contrast, candesartan and losartan 150 mg produced a greater reduction in the pressure response to angiotensin II throughout the 24-h period. This suppression was not paralleled by a reduction in resting systemic arterial pressure. Higher doses than 50 mg of losartan might be evaluated to elicit optimal clinical effects.