Differential effect of T-type voltage-gated calcium channel disruption on renal plasma flow and glomerular filtration rate in vivo

Voltage-gated Ca2+ (Cav) channels play an essential role in the regulation of renal blood flow and glomerular filtration rate (GFR). Because T-type Cav channels are differentially expressed in pre- and postglomerular vessels, it was hypothesized that they impact renal blood flow and GFR differentially. The question was addressed with the use of two T-type Cav knockout (Cav3.1−/− and Cav3.2−/−) mouse strains. Continuous recordings of blood pressure and heart rate, para-aminohippurate clearance (renal plasma flow), and inulin clearance (GFR) were performed in conscious, chronically catheterized, wild-type (WT) and Cav3.1−/− and Cav3.2−/− mice. The contractility of afferent and efferent arterioles was determined in isolated perfused blood vessels. Efferent arterioles from Cav3.2−/− mice constricted significantly more in response to a depolarization compared with WT mice. GFR was increased in Cav3.2−/− mice with no significant changes in renal plasma flow, heart rate, and blood pressure. Cav3.1−/− mice had a higher renal plasma flow compared with WT mice, whereas GFR was indistinguishable from WT mice. No difference in the concentration response to K+ was observed in isolated afferent and efferent arterioles from Cav3.1−/− mice compared with WT mice. Heart rate was significantly lower in Cav3.1−/− mice compared with WT mice with no difference in blood pressure. T-type antagonists significantly inhibited the constriction of human intrarenal arteries in response to a small depolarization. In conclusion, Cav3.2 channels support dilatation of efferent arterioles and affect GFR, whereas Cav3.1 channels in vivo contribute to renal vascular resistance. It is suggested that endothelial and nerve localization of Cav3.2 and Cav3.1, respectively, may account for the observed effects. </jats:p

Ecophysiological interpretation of oxygen consumption rates and enzymatic activities of deep-sea copepods

We measured oxygen consumption rates, the activities of citrate synthase (CS) and lactate dehydrogenase (LDH) and protein contents for over 30 species of deep-sea pelagic Copepoda. The lowest oxygen consumption rates were measured in Euaugaptilus magnus and the highest rates were measured in Paraeuchaeta tonsa. Weight-specific oxygen consumption rates declined significantly with increasing size of the organism. None of the biochemical parameters were particularly good predictors of metabolic rate. Although linear regressions of LDH activity and protein content against oxygen consumption were statistically significant, R2 values for the relationships were very low. CS activity was not significantly correlated with metabolic rate. The highest CS activities were measured in Pleurontarnrna abdominalis and Calanus pacificus, which were the 2 smallest and shallowest-living species in our investigation. The lowest CS activities were measured in Euaugaptilus antarcticus and Pachyptilus pacificus. Disseta scopularis had the highest LDH activities and Onchocalanus rnagnus had the lowest LDH activities. Over all specimens, there were statistically significant increases in weight-specific activities of CS and LDH as a function of body mass. There was much greater variation in glycolytic potential as indicated by LDH activity than in CS activities. Epipelagic copepods apparently rely less on glycolytic energy sources than do mesopelagic and bathypelagic copepods. Higher LDH activities of larger Copepoda may indicate a greater dependence on LDH for burst swimming in large species compared with smaller ones or a reliance on glycolytic abilities for sustained swimming during vertical migrations. Our enzyme data do not support the suggestion that high LDH activities are adaptations to the very low oxygen concentrations found in the oxygen minimum layer. Enzymatic ratios were used to interpret lifestyle, and deep-sea copepods fell into 3 metabolic groups, 'muscular sinkers', 'thin-muscled floaters' and 'giants', that were related to morphological pattern and behaviour. The effect of hydrostatic pressure on the metabolic rate of an undescribed, but very common, species of Megacalanus was investigated and found to be non-significant. Copepods do not display the depth-related declines in metabolic rates that are found in shrimps, fishes and cephalopods.Keywords: Citrate synthase, Enzyme activity, Lactate dehydrogenase, Respiration, Copepoda, Zooplankton, Deep sea, CrustaceaKeywords: Citrate synthase, Enzyme activity, Lactate dehydrogenase, Respiration, Copepoda, Zooplankton, Deep sea, Crustace

Adiposity, Dysmetabolic Traits, and Earlier Onset of Female Puberty in Adolescent Offspring of Women With Gestational Diabetes Mellitus: A Clinical Study Within the Danish National Birth Cohort

OBJECTIVE Offspring of pregnancies affected by gestational diabetes mellitus (GDM) are at increased risk of the development of type 2 diabetes. However, the extent to which these dysmetabolic traits may be due to offspring and/or maternal adiposity is unknown. We examined body composition and associated cardiometabolic traits in 561 9- to 16-year-old offspring of mothers with GDM and 597 control offspring. RESEARCH DESIGN AND METHODS We measured anthropometric characteristics; puberty status; blood pressure; and fasting glucose, insulin, C-peptide, and lipid levels; and conducted a DEXA scan in a subset of the cohort. Differences in the outcomes between offspring of mothers with GDM and control subjects were examined using linear and logistic regression models. RESULTS After adjustment for age and sex, offspring of mothers with GDM displayed higher weight, BMI, waist-to-hip ratio (WHR), systolic blood pressure, and resting heart rate and lower height. Offspring of mothers with GDM had higher total and abdominal fat percentages and lower muscle mass percentages, but these differences disappeared after correction for offspring BMI. The offspring of mothers with GDM displayed higher fasting plasma glucose, insulin, C-peptide, HOMA-insulin resistance (IR), and plasma triglyceride levels, whereas fasting plasma HDL cholesterol levels were decreased. Female offspring of mothers with GDM had an earlier onset of puberty than control offspring. Offspring of mothers with GDM had significantly higher BMI, WHR, fasting glucose, and HOMA-IR levels after adjustment for maternal prepregnancy BMI, and glucose and HOMA-IR remained elevated in the offspring of mothers with GDM after correction for both maternal and offspring BMIs. CONCLUSIONS In summary, adolescent offspring of women with GDM show increased adiposity, an adverse cardiometabolic profile, and earlier onset of puberty among girls. Increased fasting glucose and HOMA-IR levels among the offspring of mothers with GDM may be explained by the programming effects of hyperglycemia in pregnancy. </jats:sec

Influence of fractional flow reserve on grafts patency. Systematic review and patient-level meta-analysis

Objective: To investigate the impact of invasive functional guidance for coronary artery bypass graft surgery (CABG) on graft failure. Background: Data on the impact of fractional flow reserve (FFR) in guiding CABG are still limited. Methods: Systematic review and individual patient data meta-analysis were performed. Primary objective was the risk of graft failure, stratified by FFR. Risk estimates are reported as odds ratios (ORs) derived from the aggregated data using random-effects models. Individual patient data were analyzed using mixed effect model to assess relationship between FFR and graft failure. This meta-analysis is registered in PROSPERO (CRD42020180444). Results: Four prospective studies comprising 503 patients referred for CABG, with 1471 coronaries, assessed by FFR were included. Graft status was available for 1039 conduits at median of 12.0 [IQR 6.6; 12.0] months. Risk of graft failure was higher in vessels with preserved FFR (OR 5.74, 95% CI 1.71–19.29). Every 0.10 FFR units decrease in the coronaries was associated with 56% risk reduction of graft failure (OR 0.44, 95% CI 0.34 to 0.59). FFR cut-off to predict graft failure was 0.79. Conclusion: Surgical grafting of coronaries with functionally nonsignificant stenoses was associated with higher risk of graft failure

Influence of fractional flow reserve on grafts patency: Systematic review and patient-level meta-analysis.

To investigate the impact of invasive functional guidance for coronary artery bypass graft surgery (CABG) on graft failure. Data on the impact of fractional flow reserve (FFR) in guiding CABG are still limited. Systematic review and individual patient data meta-analysis were performed. Primary objective was the risk of graft failure, stratified by FFR. Risk estimates are reported as odds ratios (ORs) derived from the aggregated data using random-effects models. Individual patient data were analyzed using mixed effect model to assess relationship between FFR and graft failure. This meta-analysis is registered in PROSPERO (CRD42020180444). Four prospective studies comprising 503 patients referred for CABG, with 1471 coronaries, assessed by FFR were included. Graft status was available for 1039 conduits at median of 12.0 [IQR 6.6; 12.0] months. Risk of graft failure was higher in vessels with preserved FFR (OR 5.74, 95% CI 1.71-19.29). Every 0.10 FFR units decrease in the coronaries was associated with 56% risk reduction of graft failure (OR 0.44, 95% CI 0.34 to 0.59). FFR cut-off to predict graft failure was 0.79. Surgical grafting of coronaries with functionally nonsignificant stenoses was associated with higher risk of graft failure

Low birthweight is associated with a higher incidence of type 2 diabetes over two decades independent of adult BMI and genetic predisposition

Aims/hypothesis: Low birthweight is a risk factor for type 2 diabetes. Most previous studies are based on cross-sectional prevalence data, not designed to study the timing of onset of type 2 diabetes in relation to birthweight. We aimed to examine associations of birthweight with age-specific incidence rate of type 2 diabetes in middle-aged to older adults over two decades. Methods: Adults aged 30–60 years enrolled in the Danish Inter99 cohort in 1999–2001 (baseline examination), with information on birthweight from original birth records from 1939–1971 and without diabetes at baseline, were eligible. Birth records were linked with individual-level data on age at diabetes diagnosis and key covariates. Incidence rates of type 2 diabetes as a function of age, sex and birthweight were modelled using Poisson regression, adjusting for prematurity status at birth, parity, polygenic scores for birthweight and type 2 diabetes, maternal and paternal diabetes history, socioeconomic status and adult BMI. Results: In 4590 participants there were 492 incident type 2 diabetes cases during a mean follow-up of 19 years. Type 2 diabetes incidence rate increased with age, was higher in male participants, and decreased with increasing birthweight (incidence rate ratio [95% CI per 1 kg increase in birthweight] 0.60 [0.48, 0.75]). The inverse association of birthweight with type 2 diabetes incidence was statistically significant across all models and in sensitivity analysis. Conclusions/interpretation: A lower birthweight was associated with increased risk of developing type 2 diabetes independent of adult BMI and genetic risk of type 2 diabetes and birthweight

Sydney College of the Arts handbook

2002 handbook for Sydney College of the Arts (SCA

Social Capital, Network Governance and Social Innovation: Towards a New Paradigm?

Limited knowledge and empirical evidence exist so far on how governance is related to social capital, and to comprehensively evaluate the effects of collaborative public-private partnerships in rural development actions, and whether these elements foster socially innovative actions. The book chapter begins to address these knowledge gaps. It highlights the conceptual framework linking social capital and network governance and identifies specific approaches to analysing governance. Moreover, it conceptually identifies the key elements for assessing governance mechanisms in the LEADER approach and explains its adoption in the evaluation method proposed in the book. The chapter concludes by outlining how social capital and governance may support social innovation, a topic which is developed more comprehensively in relation to LEADER's specific contribution in the final chapter of the same book

Identification of genetic variants associated with a wide spectrum of phenotypes clinically diagnosed as Sanfilippo and Morquio syndromes using whole genome sequencing

Mucopolysaccharidoses (MPSs) are inherited lysosomal storage disorders (LSDs). MPSs are caused by excessive accumulation of mucopolysaccharides due to missing or deficiency of enzymes required for the degradation of specific macromolecules. MPS I-IV, MPS VI, MPS VII, and MPS IX are sub-types of mucopolysaccharidoses. Among these, MPS III (also known as Sanfilippo) and MPS IV (Morquio) syndromes are lethal and prevalent sub-types. This study aimed to identify causal genetic variants in cases of MPS III and MPS IV and characterize genotype-phenotype relations in Pakistan. We performed clinical, biochemical and genetic analysis using Whole Genome Sequencing (WGS) in 14 Pakistani families affected with MPS III or MPS IV. Patients were classified into MPS III by history of aggressive behaviors, dementia, clear cornea and into MPS IV by short trunk, short stature, reversed ratio of upper segment to lower segment with a short upper segment. Data analysis and variant selections were made based on segregation analysis, examination of known MPS III and MPS IV genes, gene function, gene expression, the pathogenicity of variants based on ACMG guidelines and in silico analysis. In total, 58 individuals from 14 families were included in the present study. Six families were clinically diagnosed with MPS III and eight families with MPS IV. WGS revealed variants in MPS-associated genes including NAGLU, SGSH, GALNS, GNPTG as well as the genes VWA3B, BTD, and GNPTG which have not previously associated with MPS. One family had causal variants in both GALNS and BTD. Accurate and early diagnosis of MPS in children represents a helpful step for designing therapeutic strategies to protect different organs from permanent damage. In addition, pre-natal screening and identification of genetic etiology will facilitate genetic counselling of the affected families. Identification of novel causal MPS genes might help identifying new targeted therapies to treat LSDs