Genetic predictors of cardiovascular morbidity in Bardet-Biedl syndrome.

Bardet-Biedl syndrome is a rare ciliopathy characterized by retinal dystrophy, obesity, intellectual disability, polydactyly, hypogonadism and renal impairment. Patients are at high risk of cardiovascular disease. Mutations in BBS1 and BBS10 account for more than half of those with molecular confirmation of the diagnosis. To elucidate genotype-phenotype correlations with respect to cardiovascular risk indicators 50 patients with mutations in BBS1 were compared with 19 patients harbouring BBS10 mutations. All patients had truncating, missense or compound missense/truncating mutations. The effect of genotype and mutation type was analysed. C-reactive protein was higher in those with mutations in BBS10 and homozygous truncating mutations (p = 0.013 and p = 0.002, respectively). Patients with mutations in BBS10 had higher levels of C peptide than those with mutations in BBS1 (p = 0.043). Triglyceride levels were significantly elevated in patients with homozygous truncating mutations (p = 0.048). Gamma glutamyl transferase was higher in patients with homozygous truncating mutations (p = 0.007) and heterozygous missense and truncating mutations (p = 0.002) than those with homozygous missense mutations. The results are compared with clinical cardiovascular risk factors. Patients with missense mutations in BBS1 have lower biochemical cardiovascular disease markers compared with patients with BBS10 and other BBS1 mutations. This could contribute to stratification of the clinical service.

Relaxin-3 stimulates the neuro-endocrine stress axis via corticotrophin-releasing hormone.

Relaxin-3 is a member of the insulin superfamily. It is expressed in the nucleus incertus of the brainstem, which has projections to the hypothalamus. Relaxin-3 binds with high affinity to RXFP1 and RXFP3. RXFP3 is expressed within the hypothalamic paraventricular nucleus (PVN), an area central to the stress response. The physiological function of relaxin-3 is unknown but previous work suggests a role in appetite control, stimulation of the hypothalamic-pituitary-gonadal axis and stress. Central administration of relaxin-3 induces c-fos expression in the PVN and increases plasma ACTH levels in rats. The aim of this study was to investigate the effect of central administration of human relaxin-3 (H3) on the hypothalamic-pituitary-adrenal (HPA) axis in male rodents in vivo and in vitro. Intracerebroventricular (i.c.v) administration of H3 (5 nmol) significantly increased plasma corticosterone at 30 min following injection compared with vehicle. Intra-PVN administration of H3 (1.8-1620 pmol) significantly increased plasma ACTH at 1620 pmol H3 and corticosterone at 180-1620 pmol H3 at 30 min following injection compared with vehicle. The stress hormone prolactin was also significantly raised at 15 min post-injection compared with vehicle. Treatment of hypothalamic explants with H3 (10-1000 nM) stimulated the release of corticotrophin-releasing hormone (CRH) and arginine vasopressin (AVP), but H3 had no effect on the release of ACTH from in vitro pituitary fragments. These results suggest that relaxin-3 may regulate the HPA axis, via hypothalamic CRH and AVP neurons. Relaxin-3 may act as a central signal linking nutritional status, reproductive function and stress.

Pregnancy after diabetes obesity surgery (PADOS): Qualitative study of pre-pregnancy care.

Half of all bariatric surgical procedures are in women of childbearing age. Surgery may improve fertility yet exacerbate nutritional deficiencies, that may be disadvantageous to the fetus. A frequently encountered subgroup of obese women have type 2 diabetes. The health risks, to both mother and child, of diabetes in pregnancy are well described including 4.7× risk of stillbirth and 2× risk of congenital abnormality. What is not clear is whether bariatric surgery mitigates or complicates the health consequences of women with obesity and diabetes in pregnancy. In addition the influence of the type of surgery, the optimal interval between surgery and conception and evidence based preconception recommendations are unknown. This study complements wider research aiming to inform optimal management of this patient population. Obese diabetic women require clear guidance regarding pregnancy planning after surgery. This study will develop an understanding of the barriers and facilitators (psychological, behavioural, attitudinal and nutritional) to achieving effective pre-pregnancy health and care in women with type 2 diabetes who have undergone metabolic surgery. Currently women's perception of fertility issues and risks after bariatric surgery is unknown and thus a qualitative interpretive paradigm was chosen. Interviews with the target population will explore decision-making processes; experience regarding metabolic surgery and perceived pregnancy risk. Interviews with a broad range of health professionals involved in bariatric care will include rationale for selected surgical procedure and post surgery referral processes e.g. contraceptive care. This will advance understanding of how to provide targeted support and monitoring.

Pregnancy after diabetes obesity surgery (PADOS): Incidence and outcomes.

Half of all bariatric surgical procedures are in women of childbearing age but it remains unclear whether surgery is suitable for women who subsequently conceive: specifically the relative risks and benefits of potential nutrient deficiencies versus weight reduction. We will present data collected from Clinical Practice Research Databases on the maternal and fetal outcomes of pregnancies complicated either by obesity or previous bariatric surgery (BS). Two groups, matched to obese controls for BMI pre-BS and post-BS (at the time of ante-natal booking) will be compared. In this way, the effect of BS on pregnancy outcomes may be examined, independent of its effect on weight. A sub-group of women with antecedent Type 2 diabetes (T2DM) will allow for investigation of the additional impact and persistence of this co-morbidity. This builds upon pilot data collected from a retrospective cohort of women (18-45years) undergoing laparoscopic roux-en-Y (RYGB) surgery over a 24-month period (n=218). After exclusions and loss to follow up, data from 111 patients were analysed; 81 (73%) had conceived prior to RYGB, 20 (18%) became pregnant post RYGB and a further 22 patients (20%) were trying to conceive at the time of data collection. Three women had T2DM which resolved post BS. A suggestion of greater miscarriage risk prior to surgery in this sub-group will be confirmed as more women are recruited. Pregnancy is a frequent desire/occurrence after BS. This database study will advance understanding of the maternal and fetal outcomes of such pregnancies and inform antenatal care.

The prevalence and natural history of pituitary hemorrhage in prolactinoma.

CONTEXT: Incidental pituitary hemorrhage, without full pituitary apoplexy, is a recognized radiological finding, but little information exists on its clinical behavior, with most reports describing surgically treated macroprolactinoma or nonfunctioning adenoma. OBJECTIVE: Our aim was to characterize the prevalence, natural history, and risk factors associated with pituitary hemorrhage in a large clinic prolactinoma population. DESIGN: The design consisted of a retrospective analysis of a clinic population. SETTING: The setting was a tertiary endocrine center in a large teaching hospital. PATIENTS: We studied three hundred sixty-eight patients with prolactinoma. The presence of hemorrhage was documented on magnetic resonance imaging. MAIN OUTCOME MEASURE: The main outcome measures were the prevalence, risk factors, and natural history of pituitary hemorrhage. RESULTS: Pituitary hemorrhage was found in 25 patients, giving an overall prevalence of 6.8%, and was significantly higher in macroprolactinoma (20.3%) compared to microprolactinoma (3.1%, P < .0001). Three patients had classical pituitary apoplexy. The majority of patients in the hemorrhage group had macroprolactinomas (16/25 [64%]) and were women (22/25 [88%]). The proportion of women with macroprolactinoma was higher in the hemorrhage group (14/16 macroprolactinomas [87.5%]) than in the nonhemorrhage group (36/63 macroprolactinomas [57.1%], P = .02). The majority of pituitary hemorrhages (92%) were treated conservatively with dopamine agonist therapy for hyperprolactinemia. Eighty-seven percent of patients had complete resolution of their hemorrhage within 26.6 ± 23.3 (mean ± SD) months. The presence of macroprolactinoma (odds ratio 9.00 [95%CI 3.79-23.88], P < .001) and being female (odds ratio 8.03 [95%confidence interval 1.22-52.95], P = .03) were independently associated with hemorrhage. CONCLUSIONS: These data show that incidental hemorrhage in prolactinoma is not uncommon. It is more likely to occur in macroprolactinoma, where 1 in 5 develop hemorrhage, and is particularly common in women with macroprolactinoma. The majority are asymptomatic and resolve spontaneously.

Central and peripheral administration of human relaxin-2 to adult male rats inhibits food intake.

AIM: Relaxin is a polypeptide hormone involved in pregnancy and lactation. It is mainly secreted by the corpus luteum and placenta, but is expressed in a number of other tissues, including heart and brain. Within the brain, relaxin is expressed in the olfactory and limbic systems, the cortex and the hypothalamic arcuate nucleus (ARC). Its cognate receptor, relaxin family peptide receptor 1 (RXFP1), is also widely expressed in the brain, including the hypothalamic ARC and paraventricular nucleus (PVN), areas important in appetite regulation. The aim of this study was to investigate whether relaxin influences food intake through central hypothalamic circuits. METHODS: The human form of relaxin, human relaxin-2 (H2) was administered centrally and peripherally to male Wistar rats and food intake measured. Behaviour was also assessed. RESULTS: Intracerebroventricular (ICV) administration of H2 significantly decreased 1-h food intake in the early dark phase [2.95 ± 0.45 g (saline) vs. 0.95 ± 0.18 g (180 pmol H2), p < 0.001]. ICV administration of H2 decreased feeding behaviour and increased grooming and headdown behaviour. Intraparaventricular injections of H2 significantly decreased 1-h food intake in the early dark phase [3.13 ± 0.35 g (saline) vs. 1.35 ± 0.33 g (18 pmol H2), p < 0.01, 1.61 ± 0.31 g (180 pmol H2), p < 0.05 and 1.23 ± 0.32 g (540 pmol H2), p < 0.001]. Intraperitoneal (IP) administration of H2 significantly decreased 1-h food intake in the early dark phase [4.63 ± 0.46 g (vehicle) vs. 3.08 ± 0.15 g (66 nmol H2), p < 0.01, 3.00 ± 0.17 g (200 nmol H2), p < 0.01 and 2.26 ± 0.36 g (660 nmol H2), p < 0.001]. CONCLUSIONS: Central and peripheral administration of H2 reduces the food intake in rats. This effect may be mediated via the PVN and/or other brain regions.

No evidence of an additive inhibitory feeding effect following PP and PYY 3-36 administration.

Pancreatic polypeptide (PP) and peptide YY (PYY) are released by the gut in response to nutrients and inhibit food intake in rodents and humans. We hypothesized that PP and PYY(3-36) would inhibit feeding additively. Fasted male C57BL/6 mice were injected intraperitoneally with saline, PP, PYY(3-36) or PP+PYY(3-36) (n=7-10). Food intake at 1 h was significantly inhibited by 6 nmol kg(-1) PP and by 6 nmol kg(-1) PYY(3-36) (P<0.05) but not significantly following 3 nmol kg(-1) PP+3 nmol kg(-1) PYY(3-36). In a higher dose study 30 nmol kg(-1) PP, 30 nmol kg(-1) PYY(3-36) and 30 nmol kg(-1) PP+30 nmol kg(-1) PYY(3-36) all inhibited 1 h food intake compared with saline (P<0.05) but there was no significant difference in the food intake of the combined group compared with either hormone individually. Subsequently, 16 fasted lean healthy human volunteers (6 men and 10 women) received, in random order, 90 min intravenous infusions of saline, 4 pmol kg(-1)min(-1) PP, 0.4 pmol kg(-1)min(-1) PYY(3-36) and 4 pmol kg(-1)min(-1) PP+0.4 pmol kg(-1)min(-1) PYY(3-36). A pasta lunch was served 60 min following infusion. There was no evidence of a greater decrease in food intake with the combined PP+PYY(3-36) treatment (buffet meal energy intake (KJ): saline 2633+/-204, PP+PYY 2693+/-254, PP 2367+/-199, PYY 2511+/-196). These results suggest that PP and PYY(3-36) do not inhibit feeding additively in rodents or humans.

Relaxin-3 stimulates the hypothalamic-pituitary-gonadal axis.

The hypothalamus plays a key role in the regulation of both energy homeostasis and reproduction. Evidence suggests that relaxin-3, a recently discovered member of the insulin superfamily, is an orexigenic hypothalamic neuropeptide. Relaxin-3 is thought to act in the brain via the RXFP3 receptor, although the RXFP1 receptor may also play a role. Relaxin-3, RXFP3, and RXFP1 are present in the hypothalamic paraventricular nucleus, an area with a well-characterized role in the regulation of energy balance that also modulates reproductive function by providing inputs to hypothalamic gonadotropin-releasing hormone (GnRH) neurons. Other members of the relaxin family are known to play a role in the regulation of reproduction. However, the effects of relaxin-3 on reproductive function are unknown. We studied the role of relaxin-3 in the regulation of the hypothalamo-pituitary-gonadal (HPG) axis. Intracerebroventricular (5 nmol) and intraparaventricular (540-1,620 pmol) administration of human relaxin-3 (H3) in adult male Wistar rats significantly increased plasma luteinizing hormone (LH) 30 min postinjection. This effect was blocked by pretreatment with a peripheral GnRH antagonist. Central administration of human relaxin-2 showed no significant effect on plasma LH. H3 dose-dependently stimulated the release of GnRH from hypothalamic explants and GT(1)-7 cells, which express RXFP1 and RXFP3, but did not influence LH or follicle-stimulating hormone release from pituitary fragments in vitro. We have demonstrated a novel role for relaxin-3 in the stimulation of the HPG axis, putatively via hypothalamic GnRH neurons. Relaxin-3 may act as a central signal linking nutritional status and reproductive function.

The effect of a 12-week low glycaemic index diet on heart disease risk factors and 24 h glycaemic response in healthy middle-aged volunteers at risk of heart disease: a pilot study.

OBJECTIVE: To compare the effects of two energy-restricted healthy diets, one with a low GI and one with a high GI, on heart disease risk factors and weight loss in subjects at risk of heart disease. DESIGN: A 12-week randomized parallel study of low and high GI, healthy eating diets was carried out. SETTING: The study was carried out at the Hammersmith Hospital. SUBJECTS: Eighteen subjects were recruited by advertisement and randomized to one of the two diets. Fourteen completed the study but one was excluded from the final analysis. METHODS: At randomization, subjects were advised to follow the intervention diet for 12 weeks. Before randomization and on completion of the study, anthropometrics, fasting cholesterol and glucose blood tests and 24-h glucose measurements were taken using a continuous glucose monitoring system (CGMS). Statistical analysis was carried out using non-parametric tests. Median (IQR) are presented. RESULTS: A significantly different dietary GI was achieved in the low GI (median: 51.3 (IQR: 51.0-52.0) compared to the high GI (59.3 (59.2-64.0) (P=0.032) group. By week 12, both groups reduced their energy intake by: low GI group: (-)167 ((-)312-(-)123) kcal/day (P=0018) vs high GI group: (-)596 ((-)625-(-)516) (P=0.018) kcal/day, the difference between the groups being significant (P=0.010). However, only the low GI group lost weight ((-)4.0 ((-)4.4-(-)2.4) kg (P=0.018) whereas the high GI group did not significantly change in weight ((-)1.5 ((-)3.6-0.8) kg (P=0.463). By week 12, the low GI group also had a significantly lower 24-h area under the curve (AUC) (7556 (7315-8434) vs 8841 (8424-8846) mmol-h/l (P=0.045) and overnight AUC (2429 (2423-2714) vs 3000 (2805-3072) mmol-h/l (P=0.006) glucose as measured by CGMS. There were no differences in the other heart disease risk factors assessed. CONCLUSIONS: This pilot study provides some evidence that consuming a low GI diet in addition to weight loss and healthy eating may reduce cardiovascular risk. Other potential benefits of GI might have been masked by weight loss in the low GI group. Larger-scale studies need to follow.

Hypothalamic mapping of orexigenic action and Fos-like immunoreactivity following relaxin-3 administration in male Wistar rats.

The insulin superfamily, characterized by common disulphide bonds, includes not only insulin but also insulin-like peptides such as relaxin-1 and relaxin-3. The actions of relaxin-3 are largely unknown, but recent work suggests a role in regulation of food intake. Relaxin-3 mRNA is highly expressed in the nucleus incertus, which has extensive projections to the hypothalamus, and relaxin immunoreactivity is present in several hypothalamic nuclei. In the rat, relaxin-3 binds and activates both relaxin family peptide receptor 1, which also binds relaxin-1, and a previously orphaned G protein-coupled receptor, RXFP3. These receptors are extensively expressed in the hypothalamus. The aims of these studies were twofold: 1) map the hypothalamic site(s) of the orexigenic action of relaxin-3 and 2) examine the site(s) of neuronal activation following central relaxin-3 administration. After microinjection into hypothalamic sites, human relaxin-3 (H3; 180 pmol) significantly stimulated 0- to 1-h food intake in the supraoptic nucleus (SON), arcuate nucleus (ARC), and the anterior preoptic area (APOA) [SON 0.4+/-0.2 (vehicle) vs. 2.9+/-0.5 g (H3), P<0.001; ARC 0.7+/-0.3 (vehicle) vs. 2.7+/-0.2 g (H3), P<0.05; and APOA 0.8+/-0.1 (vehicle) vs. 2.2+/-0.2 g (H3), P<0.05]. Cumulative food intake was significantly increased

Effects of acute and chronic relaxin-3 on food intake and energy expenditure in rats.

The effects of acute and repeated intraparaventricular (iPVN) administration of human relaxin-3 (H3) were examined on food intake, energy expenditure, and the hypothalamo-pituitary thyroid axis in male Wistar rats. An acute high dose iPVN injection of H3 significantly increased food intake 1 h post-administration [0.4+/-0.1 g (vehicle) vs 1.6+/-0.5 g (180 pmol H3), 2.4+/-0.5 g (540 pmol H3) and 2.2+/-0.5 g (1,620 pmol H3), p<0.05 for all doses vs vehicle]. Repeated iPVN H3 injection (180 pmol/twice a day for 7 days) significantly increased cumulative food intake in ad libitum fed animals compared with vehicle [211.8+/-7.1 g (vehicle) vs 261.6+/-6.7 g (ad libitum fed H3), p<0.05]. Plasma leptin was increased in the H3 ad libitum fed group. Plasma thyroid stimulating hormone was significantly decreased after acute and repeated administration of H3. These data suggest H3 may play a role in long-term control of food intake.

Central relaxin-3 administration causes hyperphagia in male Wistar rats.

Relaxin-3 (INSL-7) is a recently discovered member of the insulin superfamily. Relaxin-3 mRNA is expressed in the nucleus incertus of the brainstem, which has projections to the hypothalamus. Relaxin-3 binds with high affinity to the LGR7 receptor and to the previously orphan G protein-coupled receptor GPCR135. GPCR135 mRNA is expressed predominantly in the central nervous system, particularly in the paraventricular nucleus (PVN). The presence of relaxin-3 and these receptors in the PVN led us to investigate the effect of central administration of relaxin-3 on food intake in male Wistar rats. The receptor involved in mediating these effects was also investigated. Intracerebroventricular injections of human relaxin-3 (H3) to satiated rats significantly increased food intake 1 h post administration in the early light phase [0.96 +/- 0.16 g (vehicle) vs. 1.81 +/- 0.21 g (180 pmol H3), P < 0.05] and the early dark phase [2.95 +/- 0.45 g (vehicle) vs. 4.39 +/- 0.39 g (180 pmol H3), P < 0.05]. Intra-PVN H3 administration significantly increased 1-h food intake in satiated rats in the early light phase [0.34 +/- 0.16 g (vehicle) vs. 1.23 +/- 0.30 g (18 pmol H3), P < 0.05] and the early dark phase [4.43 +/- 0.32 g (vehicle) vs. 6.57 +/- 0.42 g (18 pmol H3), P < 0.05]. Feeding behavior increased after intra-PVN H3. Equimolar doses of human relaxin-2, which binds the LGR7 receptor but not GPCR135, did not increase feeding. Hypothalamic neuropeptide Y, proopiomelanocortin, or agouti-related peptide mRNA expression did not change after acute intracerebroventricular H3. These results suggest a novel role for relaxin-3 in appetite regulation.

Peptide YY and appetite control.

Peptide YY (PYY) is an important gut hormone synthesized and secreted by the gastrointestinal tract. Peripheral administration of PYY(3-36), one of the circulating forms of PYY, is known to inhibit food intake. This anorexigenic effect is masked by stress inhibition of appetite, and it is therefore important for animals to be thoroughly acclimatised for PYY(3-36) to be effective. Evidence suggests that PYY(3-36) acts via the hypothalamic Y(2) receptor. Levels of the anorexigenic hormone PYY(3-36) are low in overweight volunteers and could provide an important therapeutic avenue in the quest to combat the obesity epidemic.

Deep vein thrombosis followed by internal jugular vein thrombosis as a complication of in vitro fertilization in a woman heterozygous for the prothrombin 3' UTR and factor V Leiden mutations.

Thrombosis of the internal jugular vein is a rare event but one that can have serious consequences. Most cases reported in the literature have occurred in patients with indwelling central venous catheters, in association with head and neck sepsis, or in hypercoagulable states. However, a small number of cases have been associated with in vitro fertilization and more often with the ovarian hyperstimulation syndrome (OHSS). We report the case of a 30-year-old woman heterozygous for both the prothrombin 3' UTR mutation and for the factor V Leiden mutation who presented with a proximal deep vein thrombosis following in vitro fertilization. She subsequently developed an internal jugular vein thrombosis extending into the subclavian and axillary vein despite therapeutic anticoagulation with a low molecular weight heparin. Thromboembolic events can occur in the absence of other clinical features of OHSS, especially in patients with underlying prothrombotic abnormalities. Neck pain and swelling in a pregnant woman, especially one that has undergone in vitro fertilization, should be taken seriously and investigated with duplex scanning and/or MRI. Women with a personal or family history of thrombosis undergoing in vitro fertilization should be made fully aware of the potential thrombotic risks and should be considered for a thrombophilia screen.