The prenatal diet can program an individual's cardiovascular system towards later higher resting blood pressure and kidney dysfunction, but the extent to which these programmed responses are directly determined by the timing of maternal nutritional manipulation is unknown. In the present study we examined whether maternal nutrient restriction targeted over the period of maximal placental growth, i.e. days 28-80 of gestation, resulted in altered blood pressure or kidney development in the juvenile offspring. This was undertaken in 6-month-old sheep born to mothers fed control (100-150 % of the recommended metabolisable energy (ME) intake for that stage of gestation) or nutrient-restricted (NR; 50 % ME; n 6) diets between days 28 and 80 of gestation. Controls were additionally grouped according to normal (.3, n 7) or low body condition score (LBCS; ,2, n 6), thereby enabling us to examine the effect of maternal body composition on later cardiovascular function. From day 80 to term (approximately 147 d) all sheep were fed to 100 % ME. Offspring were weaned at 12 weeks and pasture-reared until 6 months of age when cardiovascular function was determined. Both LBCS and NR sheep tended to have lower resting systolic (control, 85 (SE 2); LBCS, 77 (SE 3); NR, 77 (SE 3) mmHg) and diastolic blood pressure relative to controls. Total nephron count was markedly lower in both LBCS and NR relative to controls (LBCS, 59 (SE 6); NR, 56 (SE 12) %). Our data suggest that maternal body composition around conception is as important as the level of nutrient intake during early pregnancy in programming later cardiovascular health.

Background Primary hyperparathyroidism (PHPTH) is a common endocrine disorder and an estimated 10% of cases are hereditary, related to syndromes including; multiple endocrine neoplasia (MEN) type 1, MEN type 4, MEN2A and hereditary hyperparathyroidism‐jaw tumour syndrome. Establishing the underlying genetic cause for PHPTH allows for personalized and cost‐effective management. Familial hypocalicuric hypercalcaemia (FHH) is a benign disorder of hypercalcaemia associated with an inappropriately low urinary calcium excretion, which is quantified by the calcium creatinine clearance ratio (CCCR). Recent NHS England National Genomic Test Directory testing criteria for familial hyperparathyroidism state testing patients presenting with PHPTH and CCCR > 0.02 presenting (i) <35 years of age, or (ii) <45y with one of (a) multiglandular disease, or (b) hyperplasia on histology, or (c) ossifying fibroma(s) of the maxilla and/ or mandible, or (d) a family history of unexplained PHPTH. The testing criterion for FHH is a CCCR < 0.02. Aims and Methods A retrospective review of patients referred for genetic testing over a 4 year period for suspected hereditary HPTH was performed. Genetic analysis was performed by next‐generation sequencing of the following genes; MEN1, CDC73, CASR, CDKN1A, CDKN1B, CDKN2B, CDKN2C, RET, GCM2, GNA11, and AP2S1 in NHS‐accredited Regional Genetic laboratories. Aims of this study were to better define testing criteria for suspected hereditary PHPTH in a UK cohort. Results A total of 121 patients were included in this study (92 female) with a mean age of 41 years (SD 17). A pathogenic germline variant was identified in 16% (n = 19). A pathogenic variant was identified in the PHPTH genes CDC73 in a single patient and MEN1 in six patients (6% of total), in the FHH genes, CASR in 11 patients and AP2S1 in a single paediatric case (10% of total). A variant of uncertain significance (VUS) was identified in eight patients (6%) but over the course of this study familial segregation studies and computational analysis enabled re‐classification of four of the variants, with two VUS’s in the CASR gene being upgraded to likely pathogenic variants. Age at diagnosis and multiglandular disease as sole risk factors were not predictive of a pathogenic germline variant in this cohort but a positive family history was strongly predictive (P = .0002). A significant difference in the mean calcium creatinine clearance ratio (CCCR) in those patients with an identified CASR pathogenic variant versus those without (P = .0001) was demonstrated in this study. Thirty‐three patients were aged over 50 years and the diagnostic rate of a pathogenic variant was 15.1% in those patients >50 years of age compared to 15.9% in those <50 years. Five patients >50 years and with a CCCR of <0.01, were diagnosed with a pathogenic variant in CASR. Conclusion Family history was the strongest predictor of hereditary PHPTH in this cohort. This study has highlighted the importance of re‐evaluating VUS’s in order to inform patient management a...

Sleep-disordered breathing (SDB) encompasses a spectrum of conditions that can lead to altered sleep homeostasis. In particular, obstructive sleep apnoea (OSA) is the most common form of SDB and is associated with adverse cardiometabolic manifestations including hypertension, metabolic syndrome and type 2 diabetes, ultimately increasing the risk of cardiovascular disease. The pathophysiological basis of these associations may relate to repeated intermittent hypoxia and fragmented sleep episodes that characterize OSA which drive further mechanisms with adverse metabolic and cardiovascular consequences. The associations of OSA with type 2 diabetes and the metabolic syndrome have been described in studies ranging from epidemiological and observational studies to controlled trials investigating the effects of OSA therapy with continuous positive airway pressure (CPAP). In recent years, there have been rising prevalence rates of diabetes and obesity worldwide. Given the established links between SDB (in particular OSA) with both conditions, understanding the potential influence of OSA on the components of the metabolic syndrome and diabetes and the underlying mechanisms by which such interactions may contribute to metabolic dysregulation are important in order to effectively and holistically manage patients with SDB, type 2 diabetes or the metabolic syndrome. In this article, we review the literature describing the associations, the possible underlying pathophysiological mechanisms linking these conditions and the effects of interventions including CPAP treatment and weight loss.

Overall, insulin therapy confers significant HbA1c reduction and weight increase in patients with T2D. The responsiveness to insulin therapy however appears to depend on baseline age, BMI, HbA1c and insulin regime. Clinicians should take these factors into consideration when making a decision to initiate insulin therapy in patients with T2D.

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Background It is recognised that sleep-disordered breathing (SDB), in particular, obstructive sleep apnoea (OSA) is associated with obesity and diabetes. The complications of OSA include dysregulation of metabolic and cardiovascular homeostasis. With the growing population of diabetes and obesity globally, it is becoming apparent that identifying and screening patients who are at risk is becoming increasingly crucial. Many patients may remain unaware of the potential diagnosis and continue to be undiagnosed. The high prevalence of OSA poses a demanding challenge to healthcare providers in order to provide sufficient resources and facilities for patient diagnosis and treatment.

In this study, we report for the first time, urinary proteomic profile analyses using CE-MS in OSA and non-OSA obese groups. The differences in urinary proteomic profiles prior to adjustment for multiple testing, with increased metabolic syndrome in obese OSA subjects, suggest that there may be a role for CE-MS in characterising urinary profiles in severely obese populations with OSA.

Obstructive sleep apnea is associated with obesity and metabolic syndrome, leading to greater cardiovascular risk. Severely obese patients with obstructive sleep apnea may still be at risk of adverse health outcomes, even without previous cardiovascular disease. Pulse wave analysis non-invasively measures peripheral pulse waveforms and derives measures of haemodynamic status, including arterial stiffness, augmentation pressure and subendocardial viability ratio. We hypothesized that the presence of obstructive sleep apnea in severe obesity, even in the absence of an antecedent history of cardiovascular disease, would affect measurements derived from pulse wave analysis. Seventy-two severely obese adult subjects [obstructive sleep apnea 47 (body mass index 42 AE 7 kg m À2), without obstructive sleep apnea (non-OSA) 25 (body mass index 40 AE 5 kg m À2)] were characterised using anthropo-metric, respiratory and cardio-metabolic parameters. Groups were similar in age, body mass index and gender. More subjects with obstructive sleep apnea had metabolic syndrome [obstructive sleep apnea 60%, without obstructive sleep apnea (non-OSA) 12%]. Those with obstructive sleep apnea had greater arterial stiffness, augmentation pressure and decreased subendocardial viability ratio (all P < 0.001), with significantly higher systolic (P = 0.003), diastolic (P = 0.04) and mean arterial pressures (P = 0.004) than patients without obstructive sleep apnea (non-OSA). Arterial stiffness correlated with mean arterial blood pressure (P = 0.003) and obstructive sleep apnea severity (apnea-hypopnea index; P < 0.001). apnea-hypopnea index significantly predicted arterial stiffness in multiple regression analysis, but components of the metabolic syndrome did not. Thus, patients with obstructive sleep apnea with severe obesity have increased arterial stiffness that may potentially influence cardiovascular risk independently of metabolic abnormalities. The presence of obstructive sleep apnea in severe obesity identifies a group at high cardiovascular risk; clinicians should ensure that risk factors are managed appropriately in this group whether or not treatment of obstructive sleep apnea is offered or accepted by patients. IN TROD UCTI ON Obstructive sleep apnea (OSA) is a common condition, with prevalence in middle-aged men and women at 4% and 2%, respectively (Young et al., 1993). Obesity is an important risk factor for OSA, with prevalence estimates in severe obesity between 40% and 90% (Schwartz et al., 2008). OSA is characterised by repetitive intermittent hypoxia, periodic arousals and sleep fragmentation, with cardiovascular and metabolic sequelae. Randomised trials have shown that OSA treatment with continuous positive airway pressure (CPAP) can improve hypertension and atherosclerosis (Drager et al., ª 2014 European Sleep Research Society 700