Vasopeptidase inhibition with omapatrilat in chronic heart failure: acute and long-term hemodynamic and neurohumoral effects

OBJECTIVES: We investigated the acute and long-term hemodynamic and neurohumoral effects of the vasopeptidase inhibitor omapatrilat in human heart failure. BACKGROUND: Angiotensin-converting enzyme (ACE) inhibition constitutes a major advance in the treatment of chronic heart failure (CHF). Simultaneous inhibition of both neutral endopeptidase and ACE with omapatrilat may represent a new treatment strategy in CHF. METHODS: Three hundred and sixty-nine patients with symptomatic heart failure were randomized to double-blind treatment with omapatrilat (first 190 patients: 2.5 mg, 5 mg or 10 mg; last 179 patients: 2.5 mg, 20 mg or 40 mg once daily) for 12 weeks. RESULTS: Acutely, the 10 mg, 20 mg and 40 mg doses of omapatrilat produced greater reductions in pulmonary capillary wedge pressure (PCWP), systolic blood pressure (SBP) and systemic vascular resistance compared with 2.5 mg. Higher doses were associated with greater increases in vasodilator and natriuretic peptides, in addition to ACE inhibition. After 12 weeks, omapatrilat 20 mg and 40 mg showed greater falls from baseline in PCWP (40 mg: 0 h to 12 h average change -7.3 +/- 0.8 mm Hg) and SBP (40 mg: -11.7 +/- 1.7 mm Hg) than 2.5 mg (both p < 0.01 vs. 2.5 mg). The incidence of adverse experiences and patient withdrawal were similar in all groups. CONCLUSIONS: In CHF, the acute hemodynamic benefit seen with higher doses of omapatrilat was associated with increases in plasma vasodilator and natriuretic peptide levels in addition to ACE inhibition. After 12 weeks, the hemodynamic benefit was maintained. Omapatrilat may be a promising new agent in CHF.     

Experimental acute alcohol pancreatitis‐related liver damage and endotoxemia: synbiotics but not metronidazole have a protective effect

OBJECTIVE: The aim of this study was to test the effect of gut manipulation by either novel synbiotics or by metronidazole on either endotoxemia or the severity of liver damage in the course of acute pancreatitis from alcohol ingestion. METHODS: Sprague–Dawley rats were fed for 1 week through an intragastric tube a liquid diet with either: (i) 1 mL t.i.d. of a mixture of synbiotics (Lactobacillus acidophilus, Lactobacillus helveticus and Bifidobacterium in an enriched medium); (ii) 20 mg/kg t.i.d. metronidazole; or (iii) standard diet. Then, acute pancreatitis was induced by caerulein and when the disease was full‐blown, rats were fed an alcohol‐rich diet. Synbiotic and metronidazole treatment was given for a further 2 weeks. Transaminase and endotoxemia levels were measured before treatment, after 6 h, after 24 h and 2 weeks later, at the time the rats were killed. Liver samples were obtained for histological analysis. RESULTS: Synbiotics but not metronidazole improved the acute pancreatitis‐induced increase in endotoxemia and transaminase levels. The addition of alcohol worsened these variables to a limited extent in the synbiotic‐treated group, while metronidazole had a negative effect on liver damage. CONCLUSIONS: Gut flora pretreatment with synbiotics was able to effectively protect against endotoxin/bacterial translocation, as well as liver damage in the course of acute pancreatitis and concomitant heavy alcohol consumption. The beneficial effect of synbiotics on liver histology seems to be correlated with endotoxemia. Metronidazole did not produce such a beneficial effect; in fact, it further worsened liver damage when alcohol was added to the background of ongoing acute pancreatic inflammation.     

Gesture imitation in autism: II. Symbolic gestures and pantomimed object use

We report an experimental study of imitation of two types of meaningful gestures: (a) social-communicative gestures, and (b) pantomimed actions with objects (including counterfunctional object use) by children and adolescents with autism. Controls were (a) children with nonautistic developmental delays, matched for chronological age and receptive language age, and (b) typically developing children matched for receptive language. Children in both comparison groups imitated actions more accurately than did children with autism, who nonetheless demonstrated understanding of the meaning of the gestures. However, the autistic group tended to have difficulty naming gestures and also was less able than controls to produce actions on verbal request. Children with lower levels of language ability, including those with autism, had difficulty imitating unconventional use of objects, instead using the object for their conventional functions. The discussion addresses the implications of these results and our own previous related findings for representational and executive accounts of praxic deficits in autistic spectrum disorders.     

Hair cortisol in mother–child dyads: examining the roles of maternal parenting and stress in the context of early childhood adversity

European Child & Adolescent Psychiatry - Physiological stress is thought to be one way that early adversity may impact children's health. How this occurs may be related to parental factors...     

Effect of shared care on blood pressure in patients with chronic kidney disease: a cluster randomised controlled trial

Background

Chronic kidney disease (CKD) is highly prevalent in patients with diabetes or hypertension in primary care. A shared care model could improve quality of care in these patients

Aim

To assess the effect of a shared care model in managing patients with CKD who also have diabetes or hypertension.

Design and setting

A cluster randomised controlled trial in nine general practices in The Netherlands.

Method

Five practices were allocated to the shared care model and four practices to usual care for 1 year. Primary outcome was the achievement of blood pressure targets (130/80 mmHg) and lowering of blood pressure in patients with diabetes mellitus or hypertension and an estimated glomerular filtration rate (eGFR)<60ml/min/1.73m².

Results

Data of 90 intervention and 74 control patients could be analysed. Blood pressure in the intervention group decreased with 8.1 (95% CI = 4.8 to 11.3)/1.1 (95% CI = −1.0 to 3.2) compared to −0.2 (95% CI = −3.8 to 3.3)/−0.5 (95% CI = −2.9 to 1.8) in the control group. Use of lipid-lowering drugs, angiotensin-system inhibitors and vitamin D was higher in the intervention group than in the control group (73% versus 51%, 81% versus 64%, and 15% versus 1%, respectively, [P = 0.004, P = 0.01, and P = 0.002]).

Conclusion

A shared care model between GP, nurse practitioner and nephrologist is beneficial in reducing systolic blood pressure in patients with CKD in primary care.     

Selective breeding in domestic dogs: How selecting for a short face impacted canine neuroanatomy

The range of cranial morphology seen in domestic dogs (Canis lupus familiaris) is a direct result of thousands of years of selective breeding. This article is the first to investigate how selection for reduced faces in brachycephalic dogs impacted the neuroanatomy of the canine brain through the analysis of endocasts. Previous research has demonstrated global effects on the shape of the bony cranium as the result of these breeding practices; however, these studies have largely focused on the bony structures of the skull and failed to consider the influence of facial reduction on the soft tissues of the brain. We generated endocasts from an existing set of clinically-obtained CT scans representing a variety of dogs with various cranial morphologies. These dogs represented four breeds as well as a comparative sample of dogs of unknown breed. We recorded three-dimensional coordinate data for 31 landmarks representing various gyri, sulci, and other neuroanatomical landmarks that allowed us to analyze differences in shape of the endocasts. Through geometric morphometric analyses, we determined that the endocast shape variance in this sample is correlated with cephalic index, and thus the selection for facial reduction has caused a perceivable effect on canine neuroanatomy. Additionally, we found the majority of the shape variance in the sample to be associated with olfactory anatomy; however, the rest of the morphology also correlates with cephalic index. The results of this article indicate that modern breeding practices and the selection for dogs with short faces have significantly influenced canine neuroanatomy.