Direct Deleterious Effect Research Articles

Vascular deficits contributing to skeletal fragility in type 1 diabetes.

Over 1 million Americans are currently living with T1D and improvements in diabetes management have increased the number of adults with T1D living into later decades of life. This growing population of older adults with diabetes is more susceptible to aging comorbidities, including both vascular disease and osteoporosis. Indeed, adults with T1D have a 2- to 3- fold higher risk of any fracture and up to 7-fold higher risk of hip fracture compared to those without diabetes. Recently, diabetes-related vascular deficits have emerged as potential risks factors for impaired bone blood flow and poor bone health and it has been hypothesized that there is a direct pathophysiologic link between vascular disease and skeletal outcomes in T1D. Indeed, microvascular disease (MVD), one of the most serious consequences of diabetes, has been linked to worse bone microarchitecture in older adults with T1D compared to their counterparts without MVD. The association between the presence of microvascular complications and compromised bone microarchitecture indicates the potential direct deleterious effect of vascular compromise, leading to abnormal skeletal blood flow, altered bone remodeling, and deficits in bone structure. In addition, vascular diabetic complications are characterized by increased vascular calcification, decreased arterial distensibility, and vascular remodeling with increased arterial stiffness and thickness of the vessel walls. These extensive alterations in vascular structure lead to impaired myogenic control and reduced nitric-oxide mediated vasodilation, compromising regulation of blood flow across almost all vascular beds and significantly restricting skeletal muscle blood flow seen in those with T1D. Vascular deficits in T1D may very well extend to bone, compromising skeletal blood flow control, and resulting in reduced blood flow to bone, thus negatively impacting bone health. Indeed, several animal and ex vivo human studies report that diabetes induces microvascular damage within bone are strongly correlated with diabetes disease severity and duration. In this review article, we will discuss the contribution of diabetes-induced vascular deficits to bone density, bone microarchitecture, and bone blood flow regulation, and review the potential contribution of vascular disease to skeletal fragility in T1D.

A structural equation modelling of the direct and indirect factors associated with functional status over time as measured by WHODAS-32 items among postpartum women in Northwest Ethiopia

IntroductionFull functional status recovery which is a multidimensional concept, that includes personal care, infant and family care, social and occupational activities and adjusting to the role of motherhood may require several months to achieve. However, most study designs on postpartum maternal functional status were cross-sectional, providing limited insights into functional status patterns over time and the mediating relationships among variables associated with it during the postpartum period.ObjectiveTo investigate the patterns of functional status over time and the mediating relationships among variables associated with functional status after childbirth.MethodsFrom October 2020 to March 2021, 775 women in Northwest Ethiopia participated in a community-based follow-up study that was linked to a health institution. Functional status was measured by the Amharic version of WHODAS 2.0 instrument. Structural equation modelling was used to determine the direct and indirect effects of predictor variables on individual domains of functional status as measured by WHODAS 2.0 instrument.ResultsHigher fear of childbirth score, anxiety and PTSD score had a direct deleterious effect (increased risk of functional disability) on the overall functional status and six domains of WHODAS 2.0 (cognition, mobility, self-care, getting along with people, household life activities and community participation) at the first, second and third follow up periods. Higher social support had a direct protective effect (decreased risk of functional disability) on all domains of WHODAS 2.0 and the overall functional status at the three follow up periods. Higher social support had also an indirect protective effect through fear of birth on the six domains of WHODAS 2.0 and the overall functional status throughout the follow up period. Higher PTSD symptom score had also an indirect deleterious effect (increased risk of functional disability) through fear of birth on the overall functional status and six domains of WHODAS 2.0 (higher disability) throughout the follow up period. Complications of delivery management had a direct deleterious effect (increased disability score) on the domains of getting along with people, household life activities, mobility, self-care and community participation and on the overall functional status disability score.ConclusionMaternal functioning in the postpartum period is initially impaired, but improves over time. Despite improvement, maternal morbidities are correlated with worse functioning scores compared to women without these morbidities. Interventions should target on the mediating role of fear of child birth, life threatening event of health risk and PTSD with the deleterious effects of complications of delivery management, poor social support, vaginal mode of delivery, anxiety, poor physical and mental quality of life on functional status of postpartum women.

Autologous organoid co-culture model reveals T cell-driven epithelial cell death in Crohn's Disease.

Lympho-epithelial interactions between intestinal T resident memory cells (Trm) and the epithelium have been associated with inflammatory bowel disease (IBD) activity. We developed ex vivo autologous organoid-mucosal T cell cocultures to functionally assess lymphoepithelial interactions in Crohn's Disease (CD) patients compared to controls. We demonstrate the direct epithelial cell death induced by autologous mucosal T cells in CD patients but not in controls. These findings were positively correlated with T cell infiltration of the organoids. This potential was inhibited by limiting lympho-epithelial interactions through CD103 and NKG2D blocking antibodies. These data directly demonstrate for the first time the direct deleterious effect of mucosal T cells on the epithelium of CD patients. Such ex-vivo models are promising techniques to unravel the pathophysiology of these diseases and the potential mode of action of current and future therapies.

COVID-19 pandemic and cardiovascular mortality and morbidity in the Czech Republic

Abstract Background During 2020–2021 the Czech Republic was hit by several waves of COVID-19 epidemic. 1,700,000 acquired the disease and in 39,000 this was the main cause of death, making the Czech Republic one of the most affected countries. But there was also a considerable increase in CV (cardiovascular) mortality. Due to repeated lockdowns and further restrictions the CV medical care was restricted. Purpose To learn about the impact of covid pandemics on CV health we performed further analyses. Methods We analysed the 2019–2021 data of CV mortality, CV hospital and outpatient treatments and data on risk profiles of CV patients. The analysis was based on the Czech Mortality and Hospitalization Register and Health Insurance Register (data about health care provided) from the Institute for Health Information and Statistics of the Czech Republic. Results The total CV mortality 2019–2021, after years of declining CV mortality, increased from 47,393 in 2019 to 51,299 in 2021 (8.24%), slightly less in women than in men. The mortality from acute coronary syndrome (ACS, I20–I24) decreased from 4287 to 4182 (2.45%), mortality for chronic CHD (I25) increased from 18,049 to 19,216 (6.47%), for pulmonary embolism (I26) from 824 to 867 (5.2%), for sudden cardiac death and heart arrest from 1143 to 1276 (increase 11.6%). Mortality for heart failure (I50) increased from 5477 to 6728 (22.8%), for stroke (I60-I64) did not change: from 5406 to 5426 (+0.4%), for arterial hypertension increased from 3923 to 4822 (22.9%). There was a shift from inhospital to outhospital CV mortality. Hospital admissions for ACS declined by 40% to recover to former numbers in the second half of 2021. In the outpatient CV care there was a decrease in clinical and laboratory investigations. Based on data from the Czech AH excellence centers of the ESH, with the first lockdown the number of patients attending centers decreased by 90% to recover nearly to previous numbers with lifted restrictions and to decrease less with further waves of epidemics. The patients continued drug treatment and home BP measurements. The laboratory controls of hyperlipidaemias and of diabetes were affected in similar way, the impact on blood pressure, lipid and diabetes control needs further analyses. There was increase in prevalence of obesity and substantial decrease in physical activities. Conclusions In changing CV mortality, not only morbidity and mortality caused by direct deleterious effect of covid infection on CV system (injury to heart muscle, thromboembolic complications, arrhytmias, etc), but also “colateral damage”, caused by compromised CV medical care and prevention should be considered. The most striking increase in mortality we found in heart failure and arterial hypertension, obviously conditions in need of close medical follow up. Only full restitution of complex CV treatment and prevention will restore positive trends in CV morbidity and mortality. Funding Acknowledgement Type of funding sources: None.

P031 Intestinal lymphoepithelial interactions in Crohn’s disease: modeling alphaE-beta7 and NKG2D blockade

Abstract Background T resident memory (Trm) cells in the intestinal mucosa and in particular subpopulations expressing phenotypic markers such as alphaE-beta7 or NKG2D have been associated with chronic inflammatory bowel disease (IBD) activity. We hypothesize that these populations may have a direct deleterious impact on the intestinal epithelium in IBD. Methods The phenotypic study of mucosal lymphocytes was performed in two prospective cohorts: ELYP including patients with active IBD before initiation of biotherapy and REMIND including patients with ileal Crohn’s disease (CD) requiring ileocaecal resection. These analyses were performed before initiation of treatment and one year after continuous therapy in the ELYP cohort and on the resection specimen in the REMIND cohort. An innovative ex vivo autologous organoid-mucosal T cell coculture model was developed using the REMIND cohort specimens for patients and healthy ileum from individuals without IBD for controls (Figure 1). T cell infiltration within the organoid and epithelial cell death were assessed by confocal microscopy. A panel of 30 cytokines was quantified in the supernatants of cocultures. Figure 1 Results In the ELYP cohort, before the start of treatment, IBD patients had lower expression of alphaE-beta7 and NKG2D on mucosal CD8 T cells. While alphaE-beta7 and NKG2D expression on mucosal CD8 T cells had returned to normal in endoscopic responders, it remained decreased in non-responders. Similarly, the inflammatory mucosa of the REMIND surgical specimens had lower levels of CD4 and CD8 T cells expressing alphaE-beta7 and NKG2D compared with controls and non-inflamed regions. We developed a coculture model between mucosal lymphocytes and organoids generated under autologous conditions. We showed an increase in apoptotic cell death in epithelial cells from CD patients which was not found in control cocultures. There was a significant correlation between the degree of epithelial cell death and T cell infiltration (Figure 2). Various proinflammatory cytokines such as IFNgamma, TNFalpha, IL-6 and IL- 17a were also increased in the supernatants. The use of antibodies blocking the alphaE-beta7 and NKG2D pathways of interest inhibited this effect by different mechanisms (Figure 3) While anti-beta7 and anti-NKG2D had comparable effects in terms of cell death inhibition, only anti-beta7 reduced T cell infiltration. Anti-NKG2D had no effect on cell infiltration but a reduction of perforin was observed in the supernatants. Figure 2 Figure 3 CC= Coculture Conclusion These data demonstrate for the first time the direct cytotoxic deleterious effect of mucosal T cells on the epithelium of CD patients using a novel coculture model. AlphaE-beta7 and NKG2D pathways appear to be relevant in this process.

Design and Fabrication of Biological Wires for Cardiac Fibrosis Disease Modeling.

Extensive progress has been made in developing engineered models for elucidating human cardiac disease. Cardiac fibrosis is often associated with all forms of cardiac disease and has a direct deleterious effect on cardiac function. As currently there is no effective therapeutic strategy specifically designed to target fibrosis, in vitro diagnostic platforms for drug testing have generated significant interest. In this context, we have developed an innovative approach to generate human cardiac fibrotic tissues on Biowire II platform and established a compound screening system. The disease model is constructed to recapitulate contractile, biomechanical, and electrophysiological complexities of fibrotic myocardium. Additionally, an integrated model with fibrotic and healthy cardiac tissues coupled together can be created to mimic focal fibrosis. The methods for constructing the Biowire fibrotic model will be described here.

Pathophysiological Mechanisms in Neurodevelopmental Disorders Caused by Rac GTPases Dysregulation: What's behind Neuro-RACopathies.

Rho family guanosine triphosphatases (GTPases) regulate cellular signaling and cytoskeletal dynamics, playing a pivotal role in cell adhesion, migration, and cell cycle progression. The Rac subfamily of Rho GTPases consists of three highly homologous proteins, Rac 1–3. The proper function of Rac1 and Rac3, and their correct interaction with guanine nucleotide-exchange factors (GEFs) and GTPase-activating proteins (GAPs) are crucial for neural development. Pathogenic variants affecting these delicate biological processes are implicated in different medical conditions in humans, primarily neurodevelopmental disorders (NDDs). In addition to a direct deleterious effect produced by genetic variants in the RAC genes, a dysregulated GTPase activity resulting from an abnormal function of GEFs and GAPs has been involved in the pathogenesis of distinctive emerging conditions. In this study, we reviewed the current pertinent literature on Rac-related disorders with a primary neurological involvement, providing an overview of the current knowledge on the pathophysiological mechanisms involved in the neuro-RACopathies.

Effects of the Topical Administration of Semaglutide on Retinal Neuroinflammation and Vascular Leakage in Experimental Diabetes.

Background: An unexpected increase in the rate of severe diabetic retinopathy was observed in the Semaglutide in Subjects with Type 2 Diabetes (SUSTAIN)-6 clinical trial. Although this effect was attributed to a rapid decrease in blood glucose levels, a direct deleterious effect of semaglutide on the retina could not be ruled out. In order to shed light on this issue, we have performed a study aimed at testing the direct effect of semaglutide administered by eye drops on retinal neuroinflammation and microvascular abnormalities using the db/db mouse model. Methods: Eye drops containing semaglutide (0.33 mg/mL; 5 μL once/daily) or vehicle (PBS; 5 μL once daily) were administered for 15 days. Results: We found that semaglutide significantly reduced glial activation, as well as the retinal expression of Nuclear factor kB (NF-κB), proinflammatory cytokines (IL-1β, IL-6, IL-18) and Intercellular Adhesion Molecule (ICAM)-1. In addition, semaglutide prevented the apoptosis of cells from the retinal ganglion layer and activated the protein kinase B (AKT) pathway. Finally, a dramatic decrease in vascular leakage was observed in db/db mice treated with semaglutide. All these findings were observed without any change in blood glucose levels and, therefore, can be directly attributed to semaglutide. Conclusions: These experimental findings point to a beneficial rather than a deleterious effect of semaglutide on the retina of subjects with diabetes.

204-OR: ADA Presidents’ Select Abstract: Cardiovascular Autonomic Neuropathy Is Associated with Rapid Kidney Function Decline in Type 2 Diabetes: Findings from the ACCORD Trial

Cardiovascular autonomic neuropathy (CAN) has been shown to predict progressive kidney function decline among persons with type 1 diabetes. We aimed to determine whether CAN has a similar effect on kidney function decline in type 2 diabetes (T2D). To this end, we investigated the association between measures of CAN obtained at baseline and GFR decline during a 5-year follow-up among T2D participants in the Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial. CAN was defined as ECG-derived heart rate variability indices being below the 5th percentile of the normal distribution (standard deviation of all normal-to-normal R-R intervals [SDNN] <8.2 ms and root mean square of successive differences between normal-to-normal R-R intervals [rMSSD] <8.0 ms). eGFR slopes were estimated by linear regression among participants with ≥3 eGFR measurements during follow up. Of the 6,805 ACCORD participants who had valid measures of CAN and eGFR slope, 1,327 (19.5%) had evidence of CAN at baseline. CAN independently predicted a steeper eGFR decline during follow-up (beta=-0.44 ml/min/1.73m2/year, P=0.0007); 24.6% of participants with CAN at baseline experienced subsequent eGFR loss ≥5 ml/min/1.73m2 per year as compared to 18.6% of participants without CAN (OR=1.39 [1.18 - 1.64], P<0.0001, after adjustment for age, sex, duration of diabetes, BMI, HbA1c, eGFR, urinary albumin-creatinine ratio, and positive CVD history at baseline). Consistent with these findings, in a time-to-event analysis, baseline CAN was associated with a 40% increase in the risk of experiencing a ≥40% eGFR loss during follow-up (adjusted HR=1.40 [1.20-1.63], P<0.0001). In summary, CAN was an independent predictor of kidney function loss in T2D participants. Further studies are needed to understand whether this association reflects a shared etiology of CAN and diabetic kidney disease or a direct deleterious effect of autonomic nervous system alterations on kidney function. Disclosure Y. Tang: None. C. Bueno junior: None. H. Shah: None. L. Ang: None. R. Pop-busui: Advisory Panel; Self; Novo Nordisk, Consultant; Self; Averitas Pharma, Bayer Inc., Boehringer Ingelheim Pharmaceuticals, Inc., Nevro Corp., Regenacy. A. Doria: None. Funding National Heart, Lung, and Blood Institute N01-HC-95178, N01-HC-95179, N01-HC-95180, N01-HC-95181, N01-HC-95182, N01-HC-95183, N01-HC-95184, IAA-Y1-HC-9035, IAA-Y1-HC-1010)

The role of defects and characterisation of tensile behaviour of EBM Additive manufactured Ti-6Al-4V: An experimental study at elevated temperature

The use of the Electron Beam Melting (EBM) Additive Manufacturing (AM) process to fabricate parts for applications which require strength and reliability is limited. EBM parts suffer from manufacturing defects and poor surface finish, and its strength properties can be dependent on strain rates and temperature. In this paper, the effects of parameters such as the strain rate, temperature, surface finish and build orientation together with the role of defects on tensile properties of EBM Ti-6Al-4V alloy have been studied and discussed. Due to reduced material density and multiplication rate of dislocations, a significant decrease in material tensile strength but an increase in material ductility was observed for tests on machined specimens at higher temperatures. Surface nucleating micro-cracks (poor surface finish) and inherent internal defects caused a reduction in tensile strength and material ductility for the as-built specimens. Coalescence of small size spherical pores and the presence of large voids have a direct deleterious effect on the ductility of Ti-6Al-4V alloy. The orientations of voids, difference in thermal history resulting into different microstructures, presence of grain boundary α and alignment of prior columnar β grains with respect to the loading direction for vertical and horizontal built specimens are the reasons for observed anisotropy in material strength of EBM Ti-6Al-4V alloy. The interaction effects of different parameters are also discussed, and it is suggested that these parameters should be optimised, in addition to the process parameters, to make AM parts using the EBM process which can reliably and safely be used for load bearing applications.

Malarial Related Myopathies: A Rhabdomyolysis Story

Malaria is amongst the most prevalent and epidemiologically relevant global parasitic protozoan infections. It is infecting millions of people annually, especially in south east Asia and sub Saharan Africa. Its morbidity and mortality still cannot be controlled entirely and elimination is still far away. Children and pregnant women are among the most vulnerable group in the population. Its pathobiology have related to cause direct or indirect deleterious effect on the patient’s skeletal muscle, named rhabdomyolysis. Eventhough it is very rare, but potentially fatal and lethal. Three mechanism of malaria related rhabdomyolysis are very intense inflammatory response, extensive red cells sequestration in muscle capillaries due to severe anemia and the parasite toxin’s, will lead to or add risks of complication. Derangement of specific type of muscle, named the skeletal and cardiac, is amongst the earliest sign of severe malaria. Further study need to be conducted in the future, especially on important topics about mechanism and its effect, signaling pathways, best practice on laboratory approach and management strategy best practice.

SUN-562 Long-Term Mental Stress Implications to Cardiovascular Disease in an Aged Mouse Model

While clinical evidence indicates that exposure to mental stress is a linked to a two-fold increased risk for coronary heart disease, even independently from traditional risk factors, the underlying direct mechanisms between psychological stress and cardiovascular health status has not been determined. A growing aging population of adults 65 and older represents a particular patient population vulnerable to chronic mental stressors due to a decline in normal physiologic functions. The decrease in function of the cardiovascular system that occurs during aging leads to the activation of pathological processes associated with an increased risk for heart disease. Using a mouse model of mental stress induced by restraint, we mimic the biochemical and physiologic changes observed in chronically stressed humans, which is characterized by an increase in circulating glucocorticoids, such as cortisol. Middle-aged mice (6 months old) as well as old-aged mice (18 months old) were used to differentiate the effects of aging on the burden of mental stress associated cardiovascular disease. Genes implicated in cardiomyopathy and CVD were found to be significantly up-regulated, not only immediately after a two-week stress period, but remained significantly up-regulated after the mice were allowed to recover stress-free for 5 weeks. Gene expression of the glucocorticoid receptor was down-regulated following exposure to chronic stress, suggesting an involvement of the hypothalamic-pituitary axis negative feedback loop. Gene expression of markers for hypertrophy (MHY7, ACTA1, NPPB) were upregulated and persisted in upregulation after mice were allowed to recover. Hypertrophy was further indicated by heart weight to tibia length ratios. Significant changes in aortic samples also implicate an involvement of the vasculature. Chronic stress in humans and mice leads to an increase in inflammatory and pro-coagulant markers. In our study, inflammatory markers (LCN, IL-6, IL-17c, PTGS2) were shown to be significantly increased immediately after the period of chronic stress, however the markers return to non-significant levels when mice were allowed a recovery period. Chronic mental stress has a lasting and direct deleterious effect on the cardiovascular system and it is essential to understand these implications in an aging population.

Constructing construction careers: the case for the building trades

PurposeThis paper discusses the well-publicized labor shortages in the building trades, reviews the causes for the deficiencies, and presents prescriptions for how career counselors and schools can play a critical role in encouraging young adults to consider construction occupations.Design/methodology/approachUsing data from government agencies, trade organizations, and scholarly publications, this paper describes the categories of the building trades as well as their employment trends and compensation prospects. It also reviews the personal and environmental factors that could lead to the “construction of a construction career.”FindingsThis article documents the reasons for the labor shortages in the construction industry and then offers recommendation on how younger adults could be encouraged to consider the building trades as viable career alternatives.Social implicationsLabor shortages in the construction industry have a direct and indirect deleterious effect on the economic well-being of every country. This article provides suggestions on how to inspire young adults to consider the building trades as worthwhile career pursuits.Originality/valueThere is a limited amount of scholarly attention given to career decision making related to occupations that do not require a college degree, including the building trades. This paper attempts to fill this gap in the literature by focusing on the individual characteristics and environmental factors that might prompt consideration of a career in the building trades. It also describes the educational, governmental, and corporate initiatives that work to encourage individuals, working in conjunction with their career counselors, to consider careers in the construction industry.

The direct deleterious effect of Th17 cells in the nervous system compartment in multiple sclerosis and experimental autoimmune encephalomyelitis: one possible link between neuroinflammation and neurodegeneration

Abstract The processes of demyelination and neurodegeneration in the central nervous system (CNS) of multiple sclerosis (MS) patients and experimental autoimmune encephalomyelitis (EAE) are secondary to numerous pathophysiological mechanisms. One of the main cellular players is the Th17 lymphocyte. One of the major functions described for Th17 cells is the upregulation of pro-inflammatory cytokines, such as IL-17 at the level of peripheral and CNS inflammation. This review will focus on the newly described and unexpected, direct role played by the Th17 cells in the CNS of MS patients and EAE models. Th17 and their main cytokine, IL-17, are actively involved in the onset and maintenance of the immune cascade in the CNS compartment as Th17 were found to achieve brain-homing potential. Direct interaction of myelin oligodendrocyte glycoprotein - specific Th17 with the neuronal cells firstly induces demyelination and secondly, extensive axonal damage. The Th17 cells promote an inflammatory B cell response beyond the BBB through the presence of infiltrating Th follicles. Due to their role in preventing remyelination and direct neurotoxic effect, Th17 cells might stand for an important connection between neuroinflammation and neurodegeneration in a devastating disease like MS. The Th17 cell populations have different mechanisms of provoking an autoimmune attack not only in the periphery but also in the CNS of MS patients.

Mannose-binding lectin has a direct deleterious effect on ischemic brain microvascular endothelial cells

Mannose-binding lectin (MBL), an initiator of the lectin pathway, is detrimental in ischemic stroke. MBL deposition on the ischemic endothelium indicates the beginning of its actions, but downstream mechanisms are not clear yet. We investigated MBL interactions with the ischemic endothelium by exposing human brain microvascular endothelial cells (hBMECs) to protocols of ischemia. Cells were exposed to hypoxia or oxygen–glucose deprivation (OGD), and re-oxygenated with human serum (HS) or recombinant MBL (rhMBL). Hypoxic hBMECs re-oxygenated with HS showed increased complement system activation (C3c deposition, +59%) and MBL deposition (+93%) than normoxic cells. Super-resolution microscopy showed MBL internalization in hypoxic cells and altered cytoskeletal organization, indicating a potential MBL action on the endothelial structure. To isolate MBL effect, hBMECs were re-oxygenated with rhMBL after hypoxia/OGD. In both conditions, MBL reduced viability (hypoxia: −25%, OGD: −34%) compared to conditions without MBL, showing a direct toxic effect. Ischemic cells also showed greater MBL deposition (hypoxia: +143%, OGD: +126%) than normoxic cells. These results were confirmed with primary hBMECs exposed to OGD (increased MBL-induced cell death: +226%, and MBL deposition: +104%). The present findings demonstrate that MBL can exert a direct deleterious effect on ischemic brain endothelial cells in vitro, independently from complement activation.

Bile Modulates Secretion of Incretins and Insulin: A Study of Human Extrahepatic Cholestasis.

Changes in bile flow after bariatric surgery may beneficially modulate secretion of insulin and incretins, leading to diabetes remission. However, the exact mechanism(s) involved is still unclear. Here, we propose an alternative method to investigate the relationship between alterations in physiological bile flow and insulin and incretin secretion by studying changes in gut-pancreatic function in extrahepatic cholestasis in nondiabetic humans. To pursue this aim, 58 nondiabetic patients with recent diagnosis of periampullary tumors underwent an oral glucose tolerance test (OGTT), and a subgroup of 16 patients also underwent 4-hour mixed meal tests and hyperinsulinemic-euglycemic clamps. The analysis of the entire cohort revealed a strong inverse correlation between total bilirubin levels and insulinogenic index. When subjects were divided on the basis of bilirubin levels, used as a marker of altered bile flow, subjects with high bilirubin levels displayed inferior glucose control and decreased insulin secretion during the OGTT. Altered bile flow elicited a markedly greater increase in glucagon and glucagon-like peptide 1 (GLP-1) secretion at fasting state, and following the meal, both glucagon and GLP-1 levels remained increased over time. Conversely, Glucose-dependent insulinotropic polypeptide (GIP) levels were comparable at the fasting state, whereas the increase following meal ingestion was significantly blunted with high bilirubin levels. We reveal strong correlations between total bilirubin and glucagon and GLP-1 levels. Our findings suggest that acute extrahepatic cholestasis determines major impairment in enteroendocrine gut-pancreatic secretory function. The altered bile flow may determine a direct deleterious effect on β-cell function, perhaps mediated by the impairment of incretin hormone function.

Intra-genomic variation in Symbiodinium correlates negatively with photosynthetic efficiency and coral host performance

Reef-building corals are nutritionally dependent on the symbiotic alga Symbiodinium and may therefore select for high-performing symbiont lineages. However, the effects of fine-scale genetic variation within symbiont populations on host performance are not well understood. Applying quantitative PCR (qPCR) to Pocillopora damicornis colonies from Lord Howe Island (Australia), we estimated the relative abundance of intra-genomically variable (IGV) Symbiodinium cells and those with homogeneous rDNA sequence repeats. We then analysed their physical status and photosynthetic performance at both ambient and extreme summer temperatures (25 and 29 °C, respectively) in a closed-system oxygen flux chamber. The proportion of IGV Symbiodinium was negatively correlated with photosynthetic production and efficiency, and under thermal stress, colonies dominated by IGV cells could only meet respiratory demands at high irradiance (> 250 µmol photons m−2 s−1). IGV Symbiodinium were also estimated to be 50% larger by volume, occurred at lower density, and had higher chlorophyll c2/a ratios. The comparatively poor performance of heterogeneous Symbiodinium cells suggests either a direct deleterious effect of IGV or reduced performance in putative inter-lineage recombinants, whose genomes feature ITS2 variants from both parental ribotypes. While it remains unclear whether the mixed rDNA arrays result from somatic mutation or recombination, our results demonstrate that the beneficial capacity of symbionts can vary within Symbiodinium populations, with potential implications for host fitness.

Accumulation of transposable elements in selfing populations of Arabidopsis lyrata supports the ectopic recombination model of transposon evolution

Transposable elements (TE) can constitute a large fraction of plant genomes, yet our understanding of their evolution and fitness effect is still limited. Here we tested several models of evolution that make specific predictions about differences in TE abundance between selfing and outcrossing taxa, and between small and large populations. We estimated TE abundance in multiple populations of North American Arabidopsis lyrata differing in mating system and long-term size, using transposon insertion display on several TE families. Selfing populations had higher TE copy numbers per individual and higher TE allele frequencies, supporting models which assume that selection against TEs acts predominantly against heterozygotes via the process of ectopic recombination. In outcrossing populations differing in long-term size, the data supported neither a model of density-regulated transposition nor a model of direct deleterious effect. Instead, the population structure of TEs revealed that outcrossing populations tended to split into western and eastern groups - as previously detected using microsatellite markers - whereas selfing populations from west and east were less differentiated. This, too, agrees with the model of ectopic recombination. Overall, our results suggest that TE elements are nearly neutral except for their deleterious potential to disturb meiosis in the heterozygous state.

Diabetes mellitus as a cause of end-stage renal disease in Europe: signs of improvement.

Diabetes mellitus as a cause of end-stage renal disease in Europe: signs of improvement.

Comparação da prevalência de métodos de perda de peso pré‐competição em judocas de diferentes categorias

Judo athletes often use in previous periods of competitions, methods for rapid weight loss. This purpose of this practice is benefit the athlete, competing in a lower weight category and tries to regain weight in a short space of time between the weigh‐in and competition. However, the use of this practice without professional supervision may be harmful to the health of the athlete. ObjectiveInvestigate the methods and strategies used for weight loss in judo competitors at the national level and different categories. Methods60 athletes the national levels, male and female, of different ages (juvenile, junior, senior and master) answered a questionnaire regarding the use or not of methods for weight loss and what are the strategies loss weight often used in the pre‐competition period. Results80% (juvenile), 69.6% (junior), 88.9% (senior) and 100% (master) use methods of weight loss pre‐competition, and 70% (juvenile), 69.6% (junior), 77.8% (senior) and 77.7% (master) reported their performance impaired by the use of these strategies. ConclusionWe found that a much higher judo athletes from different age categories, makes use of methods or strategies for rapid weight loss. This fact has shown a direct deleterious effect on the physical and emotional performance of athletes during competitions.