Peripheral injection of sauvagine prevents repeated colorectal distension-induced visceral pain in female rats

We investigated the effects of peripheral injection of sauvagine, a CRF2>CRF1 receptor (corticotropin-releasing factor) agonist compared with CRF, on two sets of tonic colorectal distension (CRDs 30, 40, 50 mmHg, 3-min on/off)-induced visceromotor response (VMR) measured as area under the curve (AUC) of abdominal muscle contraction in conscious female rats. Sauvagine (10 or 20 microg/kg, s.c.) abolished the 226.7+/-64.3% and 90.4+/-38.1% increase in AUC to the 2nd CRD compared with the 1st CRD (performed 30 min before) in female Fisher and Sprague-Dawley (SD) rats, respectively. CRF had no effect while the CRF1 antagonist, antalarmin (20 mg/kg, s.c.), alone or with sauvagine, blocked the enhanced response to the 2nd CRD, performed 60 min after the 1st CRD, and reduced further the AUC by 33.5+/-23.3% and 63.5+/-7.2%, respectively in Fisher rats. These data suggest that peripheral CRF2 receptor activation exerts antinociceptive effects on CRD-induced visceral pain, whereas CRF1 contributes to visceral sensitization.     

Formin-2 is required for spindle migration and for the late steps of cytokinesis in mouse oocytes

Female meiotic divisions in higher organisms are asymmetric and lead to the formation of a large oocyte and small polar bodies. These asymmetric divisions are due to eccentric spindle positioning which, in the mouse, requires actin filaments. Recently Formin-2, a straight actin filaments nucleator, has been proposed to control spindle positioning, chromosome segregation as well as first polar body extrusion in mouse oocytes. We reexamine here the possible role of Formin-2 during mouse meiotic maturation by live videomicroscopy. We show that Formin-2 controls first meiotic spindle migration to the cortex but not chromosome congression or segregation. We also show that the lack of first polar body extrusion in fmn2(-/-) oocytes is not due to a lack of cortical differentiation or central spindle formation but to a defect in the late steps of cytokinesis. Indeed, Survivin, a component of the passenger protein complex, is correctly localized on the central spindle at anaphase in fmn2(-/-) oocytes. We show here that attempts of cytokinesis in these oocytes abort due to phospho-myosin II mislocalization.     

A multi-population phenome-wide association study of genetically-predicted height in the Million Veteran Program

BackgroundHeight has been associated with many clinical traits but whether such associations are causal versus secondary to confounding remains unclear in many cases. To systematically examine this question, we performed a Mendelian Randomization-Phenome-wide association study (MR-PheWAS) using clinical and genetic data from a national healthcare system biobank.Methods and findingsAnalyses were performed using data from the US Veterans Affairs (VA) Million Veteran Program in non-Hispanic White (EA, n = 222,300) and non-Hispanic Black (AA, n = 58,151) adults in the US. We estimated height genetic risk based on 3290 height-associated variants from a recent European-ancestry genome-wide meta-analysis. We compared associations of measured and genetically-predicted height with phenome-wide traits derived from the VA electronic health record, adjusting for age, sex, and genetic principal components. We found 345 clinical traits associated with measured height in EA and an additional 17 in AA. Of these, 127 were associated with genetically-predicted height at phenome-wide significance in EA and 2 in AA. These associations were largely independent from body mass index. We confirmed several previously described MR associations between height and cardiovascular disease traits such as hypertension, hyperlipidemia, coronary heart disease (CHD), and atrial fibrillation, and further uncovered MR associations with venous circulatory disorders and peripheral neuropathy in the presence and absence of diabetes. As a number of traits associated with genetically-predicted height frequently co-occur with CHD, we evaluated effect modification by CHD status of genetically-predicted height associations with risk factors for and complications of CHD. We found modification of effects of MR associations by CHD status for atrial fibrillation/flutter but not for hypertension, hyperlipidemia, or venous circulatory disorders.ConclusionsWe conclude that height may be an unrecognized but biologically plausible risk factor for several common conditions in adults. However, more studies are needed to reliably exclude horizontal pleiotropy as a driving force behind at least some of the MR associations observed in this study.     

Imbalance of Circulating Monocyte Subsets and PD-1 Dysregulation in Q Fever Endocarditis: The Role of IL-10 in PD-1 Modulation

Q fever endocarditis, a severe complication of Q fever, is associated with a defective immune response, the mechanisms of which are poorly understood. We hypothesized that Q fever immune deficiency is related to altered distribution and activation of circulating monocyte subsets. Monocyte subsets were analyzed by flow cytometry in peripheral blood mononuclear cells from patients with Q fever endocarditis and controls. The proportion of classical monocytes (CD14⁺CD16⁻ monocytes) was similar in patients and controls. In contrast, the patients with Q fever endocarditis exhibited a decrease in the non-classical and intermediate subsets of monocytes (CD16⁺ monocytes). The altered distribution of monocyte subsets in Q fever endocarditis was associated with changes in their activation profile. Indeed, the expression of HLA-DR, a canonical activation molecule, and PD-1, a co-inhibitory molecule, was increased in intermediate monocytes. This profile was not restricted to CD16⁺ monocytes because CD4⁺ T cells also overexpressed PD-1. The mechanism leading to the overexpression of PD-1 did not require the LPS from C. burnetii but involved interleukin-10, an immunosuppressive cytokine. Indeed, the incubation of control monocytes with interleukin-10 led to a higher expression of PD-1 and neutralizing interleukin-10 prevented C. burnetii-stimulated PD-1 expression. Taken together, these results show that the immune suppression of Q fever endocarditis involves a cross-talk between monocytes and CD4⁺ T cells expressing PD-1. The expression of PD-1 may be useful to assess chronic immune alterations in Q fever endocarditis.     

In vitro and in vivo SAR of pyrido[3,4-d]pyramid-4-ylamine based mGluR1 antagonists

The SAR of a series of novel pyrido[3,4-d]pyramid-4-ylamine mGluR1 antagonists is described. The multiple of the unbound K_i in cerebrospinal fluid necessary to give morphine like analgesic effects in an electromyograph pinch model in rodents is determined and the effect of structure on CNS penetration examined.     

Association of Group B Streptococcus Colonization and Bovine Exposure: A Prospective Cross-Sectional Cohort Study

Background

While Group B Streptococcus (GBS) human colonization and infection has long been suspected as originating from cows, several investigators have suggested that ongoing interspecies GBS transmission is unlikely due to genotyping data demonstrating that human and bovine-derived GBS strains represent mostly distinct populations. The possibility of ongoing transmission between humans and their livestock has not been systematically examined.

Methodology/Principal Findings

To examine ongoing interspecies transmission, we conducted a prospective cross-sectional cohort study of 68 families and their livestock. Stool specimens were collected from 154 people and 115 livestock; GBS was detected in 19 (12.3%) humans and 2 (1.7%) animals (bovine and sheep). Application of multilocus sequence typing (MLST) identified 8 sequence types (STs or clones), with STs 1 and 23 predominating. There were 11 families in which two members submitted stools and at least one had GBS colonization. In 3 of these families, both members (consisting of couples) were colonized, yielding a co-colonization rate of 27% (95% CI: 7%–61%). Two of these couples had strains with identical MLST, capsule (cps) genotype, susceptibility, and RAPD profiles. One couple co-colonized with ST-1 (cps5) strains also had a bovine colonized with the identical strain type. On multivariate analysis of questionnaire data, cattle exposure was a predictor of GBS colonization, with each unit increase in days of cattle exposure increasing the odds of colonization by 20% (P = 0.02). These results support interspecies transmission with additional evidence for transmission provided by the epidemiological association with cattle exposure.

Conclusions/Significance

Although GBS uncommonly colonizes livestock stools, increased frequency of cattle exposure was significantly associated with human colonization and one couple shared the same GBS strains as their bovine suggesting intraspecies transmission. These results set the framework for GBS as a possible zoonotic infection, which has significant public health implications.     

Hip Fracture Incidence in Relation to Age,Menopausal Status,and Age at Menopause: Prospective Analysis

Background

Bone mineral density is known to decrease rapidly after the menopause. There is limited evidence about the separate contributions of a woman''s age, menopausal status and age at menopause to the incidence of hip fracture.

Methods and Findings

Over one million middle-aged women joined the UK Million Women Study in 1996–2001 providing information on their menopausal status, age at menopause, and other factors, which was updated, where possible, 3 y later. All women were registered with the UK National Health Service (NHS) and were routinely linked to information on cause-specific admissions to NHS hospitals. 561,609 women who had never used hormone replacement therapy and who provided complete information on menopausal variables (at baseline 25% were pre/perimenopausal and 75% postmenopausal) were followed up for a total of 3.4 million woman-years (an average 6.2 y per woman). During follow-up 1,676 (0.3%) were admitted to hospital with a first incident hip fracture. Among women aged 50–54 y the relative risk (RR) of hip fracture risk was significantly higher in postmenopausal than premenopausal women (adjusted RR 2.22, 95% confidence interval [CI] 1.22–4.04; p = 0.009); there were too few premenopausal women aged 55 y and over for valid comparisons. Among postmenopausal women, hip fracture incidence increased steeply with age (p<0.001), with rates being about seven times higher at age 70–74 y than at 50–54 y (incidence rates of 0.82 versus 0.11 per 100 women over 5 y). Among postmenopausal women of a given age there was no significant difference in hip fracture incidence between women whose menopause was due to bilateral oophorectomy compared to a natural menopause (adjusted RR 1.20, 95% CI 0.94–1.55; p = 0.15), and age at menopause had little, if any, effect on hip fracture incidence.

Conclusions

At around the time of the menopause, hip fracture incidence is about twice as high in postmenopausal than in premenopausal women, but this effect is short lived. Among postmenopausal women, age is by far the main determinant of hip fracture incidence and, for women of a given age, their age at menopause has, at most, a weak additional effect. Please see later in the article for the Editors'' Summary     

Urocortin 2 acts centrally to delay gastric emptying through sympathetic pathways while CRF and urocortin 1 inhibitory actions are vagal dependent in rats

We characterized the influence of the selective corticotropin-releasing factor 2 (CRF(2)) receptor agonist human urocortin 2 (Ucn 2), injected intracisternally, on gastric emptying and its mechanism of action compared with intracisternal CRF or urocortin (Ucn 1) in conscious rats. The methylcellulose phenol red solution was gavaged 20 min after peptide injection, and gastric emptying was measured 20 min later. The intracisternal injection of Ucn 2 (0.1 and 1 microg) and Ucn 1 (1 microg) decreased gastric emptying to 37.8 +/- 6.9%, 23.1 +/- 8.6%, and 21.6 +/- 5.9%, respectively, compared with 58.4 +/- 3.8% after intracisternal vehicle. At lower doses, Ucn 2 (0.03 microg) and Ucn 1 (0.1 microg) had no effect. The CRF(2) antagonist astressin(2)-B (3 microg ic) antagonized intracisternal Ucn 2 (0.1 microg) and CRF (0.3 microg)-induced inhibition of gastric emptying. Vagotomy enhanced intracisternal Ucn 2 (0.1 or 1 microg)-induced inhibition of gastric emptying compared with sham-operated group, whereas it blocked intracisternal CRF (1 microg) inhibitory action (45.5 +/- 8.4% vs. 9.7 +/- 9.7%). Sympathetic blockade by bretylium prevented intracisternal and intracerebroventricular Ucn 2-induced delayed gastric emptying, whereas it did not influence intravenous Ucn 2-, intracisternal CRF-, and intracisternal Ucn 1-induced inhibition of gastric emptying. Prazosin abolished the intracisternal Ucn 2 inhibitory effect, whereas yohimbine and propranolol did not. None of the pretreatments modified basal gastric emptying. These data indicate that intracisternal Ucn 2 induced a central CRF(2)-mediated inhibition of gastric emptying involving sympathetic alpha(1)-adrenergic mechanisms independent from the vagus contrasting with the vagal-dependent inhibitory actions of CRF and Ucn 1.     

Lack of interaction between peripheral injection of CCK and obestatin in the regulation of gastric satiety signaling in rodents

Obestatin is a new peptide for which anorexigenic effects were recently reported in mice. We investigate whether peripheral injection of obestatin or co-injection with cholecystokinin (CCK) can modulate food intake, gastric motor function (intragastric pressure and emptying) and gastric vagal afferent activity in rodents. Obestatin (30, 100 and 300 microg/kg, i.p.) did not influence cumulative food intake for the 2h post-injection in rats or mice nor gastric emptying in rats. In rats, obestatin (300 microg/kg) did not modify CCK (1 microg/kg, i.p.)-induced significant decrease in food intake (36.6%) and gastric emptying (31.0%). Furthermore, while rats injected with CCK (0.3 microg/kg, i.v.) displayed gastric relaxation, no change in gastric intraluminal pressure was elicited by obestatin (300 microg/kg, i.v.) pre- or post-CCK administration. In in vitro rat gastric vagal afferent preparations, 20 units that had non-significant changes in basal activity after obestatin at 30 microg responded to CCK at 10 ng by a 182% increase. These data show that obestatin neither influences cumulative food intake, gastric motility or vagal afferent activity nor CCK-induced satiety signaling.     

CRF receptor antagonist astressin-B reverses and prevents alopecia in CRF over-expressing mice

Corticotropin-releasing factor (CRF) signaling pathways are involved in the stress response, and there is growing evidence supporting hair growth inhibition of murine hair follicle in vivo upon stress exposure. We investigated whether the blockade of CRF receptors influences the development of hair loss in CRF over-expressing (OE)-mice that display phenotypes of Cushing''s syndrome and chronic stress, including alopecia. The non-selective CRF receptors antagonist, astressin-B (5 µg/mouse) injected peripherally once a day for 5 days in 4–9 months old CRF-OE alopecic mice induced pigmentation and hair re-growth that was largely retained for over 4 months. In young CRF-OE mice, astressin-B prevented the development of alopecia that occurred in saline-treated mice. Histological examination indicated that alopecic CRF-OE mice had hair follicle atrophy and that astressin-B revived the hair follicle from the telogen to anagen phase. However, astressin-B did not show any effect on the elevated plasma corticosterone levels and the increased weights of adrenal glands and visceral fat in CRF-OE mice. The selective CRF₂ receptor antagonist, astressin₂-B had moderate effect on pigmentation, but not on hair re-growth. The commercial drug for alopecia, minoxidil only showed partial effect on hair re-growth. These data support the existence of a key molecular switching mechanism triggered by blocking peripheral CRF receptors with an antagonist to reset hair growth in a mouse model of alopecia associated with chronic stress.