Distension-induced gastric accommodation in functional dyspepsia: effect of autonomic manipulation

Functional dyspepsia (FD) is associated with impaired gastric accommodation and autonomic dysregulation. The aim of this study was to investigate the effects of autonomic manipulation on distension-induced gastric accommodation in subjects with and without FD, using a newly developed gastric barostat paradigm. Twelve healthy subjects (HS) and 18 subjects with FD had four barostat examinations each: no intervention, intravenous atropine (1 mg), vagal stimulation (mental relaxation with deep breathing) and acute stress stimulation (serial subtraction task). Intrabag pressure increased from 1 to 15 mmHg in 5 min (ramp phase), and was maintained at 15 mmHg for 5 min (tonic phase). Volume responses were analysed using predefined parameters. There were no significant group differences in accommodation variables between HS and subjects with FD. The FD group could be subdivided into two distinct subgroups: subgroup 1 (n = 7, 38%) with low maximum volume and accommodation rate, and subgroup 2 with normal accommodation (n = 11). In subgroup 1, but not in subgroup 2 atropine increased maximum volume and accommodation rate substantially. Neither mental stress nor mental relaxation changed any of the accommodation variables. In a subgroup of subjects with FD, impairment of distension-induced gastric accommodation can be improved by cholinergic blockade, but not by acute physiological autonomic manipulation.     

Enhanced chondrogenesis and Wnt signaling in PTH-treated fractures.

Studies have shown that systemic PTH treatment enhanced the rate of bone repair in rodent models. However, the mechanisms through which PTH affects bone repair have not been elucidated. In these studies we show that PTH primarily enhanced the earliest stages of endochondral bone repair by increasing chondrocyte recruitment and rate of differentiation. In coordination with these cellular events, we observed an increased level of canonical Wnt-signaling in PTH-treated bones at multiple time-points across the time-course of fracture repair, supporting the conclusion that PTH responses are at least in part mediated through Wnt signaling. INTRODUCTION: Since FDA approval of PTH [PTH(1-34); Forteo] as a treatment for osteoporosis, there has been interest in its use in other musculoskeletal conditions. Fracture repair is one area in which PTH may have a significant clinical impact. Multiple animal studies have shown that systemic PTH treatment of healing fractures increased both callus volume and return of mechanical competence in models of fracture healing. Whereas the potential for PTH has been established, the mechanism(s) by which PTH produces these effects remain elusive. MATERIALS AND METHODS: Closed femoral fractures were generated in 8-wk-old male C57Bl/6 mice followed by daily systemic injections of either saline (control) or 30 microg/kg PTH(1-34) for 14 days after fracture. Bones were harvested at days 2, 3, 5, 7, 10, 14, 21, and 28 after fracture and analyzed at the tissue level by radiography and histomorphometry and at the molecular and biochemical levels level by RNase protection assay (RPA), real-time PCR, and Western blot analysis. RESULTS: Quantitative muCT analysis showed that PTH treatment induced a larger callus cross-sectional area, length, and total volume compared with controls. Molecular analysis of the expression of extracellular matrix genes associated with chondrogenesis and osteogenesis showed that PTH treated fractures displayed a 3-fold greater increase in chondrogenesis relative to osteogenesis over the course of the repair process. In addition, chondrocyte hypertrophy occurred earlier in the PTH-treated callus tissues. Analysis of the expression of potential mediators of PTH actions showed that PTH treatment significantly induced the expression of Wnts 4, 5a, 5b, and 10b and increased levels of unphosphorylated, nuclear localized beta-catenin protein, a central feature of canonical Wnt signaling. CONCLUSIONS: These results showed that the PTH-mediated enhancement of fracture repair is primarily associated with an amplification of chondrocyte recruitment and maturation in the early fracture callus. Associated with these cellular effects, we observed an increase in canonical Wnt signaling supporting the conclusion that PTH effects on bone repair are mediated at least in part through the activation of Wnt-signaling pathways.     

Cardiovascular protection from alcoholic drinks: scientific basis of the French Paradox.

This article discusses the cardiovascular protection afforded by low to moderate consumption of ethanol and the role of ethanol-induced preconditioning. Ethanol, a compound that is found in many popular beverages, has a whole range of cardiovascular protective effects when consumed in low to moderate doses. Although they have yet to be totally clarified, recent data suggest that a combination of several actions at the biochemical and molecular levels play a role in this protection. These include favorable changes in lipid metabolism, antioxidant effects, changes in hemostasis and platelet aggregation, arterial vasodilation mediated by NO release, induction of the expression of cardioprotective proteins, insulin sensitization and lower levels of inflammatory markers. Special emphasis will be given to ethanol-induced preconditioning. Some of the compounds present in red and white wine, such as resveratrol and quercetin, are also partly responsible for some of the cardioprotective effects of alcoholic drinks. These are due to antioxidant effects and changes in platelet aggregation, endothelial function and inflammatory response. The last part of the paper will focus on the clinical applications and possibilities raised by these new findings.     

Unplanned splenectomy during oesophagectomy does not affect survival.

OBJECTIVE: There are limited and conflicting data available concerning the incidence of inadvertent splenectomy and its impact on the outcome in patients who have undergone oesophagectomy. The aim of this study is to identify the factors associated with a likelihood of inadvertent splenectomy and its influence on early and long-term outcome in patients having oesophagectomy for oesophageal carcinoma. METHODS: A consecutive series of 738 oesophagectomies performed between 1991 and 2004 was analysed. In our practice, the spleen was removed only if damaged intraoperatively. Routine chemo- and immunoprophylaxis would subsequently be used. Multivariate analysis with logistic and Cox models determined significant variables. RESULTS: Of the 738 oesophagectomies, 48 (6.5%) had splenectomy. Neoadjuvant chemotherapy was administered to a minority of patients; none subsequently had splenectomy. There were significant differences between types of operation (Ivor-Lewis 18 (9.0%), left thoracolaparotomy 14 (9.9%) and left thoracophrenotomy 15 (3.9%), p=0.01). Splenectomy was more common with advanced N stage disease (OR=0.44 [0.20-0.95]; p=0.04). Splenectomy resulted in more blood transfusions (median, 2 units vs 0 units; p=0.03) more anastomotic leaks (7 [14.6%] vs 42 [6.1%]; p=0.02) but not an increase in pulmonary complications (p=0.64) or in-hospital mortality (1 [4.6%] vs 37 [5.4%]; p=0.30). Splenectomy did not significantly affect median survival (551 [332-770] days vs 627 [554-700] days; p=0.63). CONCLUSION: Although inadvertent splenectomy increased the morbidity of oesophagectomy, it did not impair survival. Type of operation and advanced N stage are important risks for splenectomy. Though best avoided, most of the consequences of splenectomy can be managed. An unexpected relationship between splenectomy and anastomotic leaks needs further investigation.     

Structural white matter abnormalities in patients with idiopathic dystonia

We investigated whether structural white matter abnormalities, in the form of disruption of axonal coherence and integrity as measured with diffusion tensor imaging (DTI), constitute an underlying pathological mechanism of idiopathic dystonia (ID), independent of genotype status. We studied seven subjects with ID: all had cervical dystonia as their main symptom (one patient also had spasmodic dysphonia and two patients had concurrent generalized dystonia, both DYT1‐negative). We compared DTI MR images of patients with 10 controls, evaluating differences in mean diffusivity (MD) and fractional anisotropy (FA). ID was associated with increased FA values in the thalamus and adjacent white matter, and in the white matter underlying the middle frontal gyrus. ID was also associated with increase in MD in adjacent white matter to the pallidum and putamen bilaterally, left caudate, and in subcortical hemispheric regions, including the postcentral gyrus. Abnormal FA and MD in patients with ID indicate that abnormal axonal coherence and integrity contribute to the pathophysiology of dystonia. These findings suggest that ID is not only a functional disorder, but also associated with structural brain changes. Impaired connectivity and disrupted flow of information may contribute to the impairment of motor planning and regulation in dystonia. © 2006 Movement Disorder Society     

Effect of female sex hormone supplementation and withdrawal on gastrointestinal and colonic transit in postmenopausal women

Females are disproportionately affected by constipation, which is often aggravated during pregnancy. Bowel function also changes during the luteal phase of the menstrual cycle. The aim was to compare the effects of acute administration of female sex steroids on gastric emptying, small bowel transit and colonic transit in healthy postmenopausal subjects. A second aim was to determine whether withdrawal of the hormones was associated with a change in transit. Forty-nine postmenopausal females were randomized to receive for 7 days 400 mg day(-1) micronized progesterone, 0.2 mg day(-1) oestradiol, combination of the two, or placebo. Treatment groups were balanced on age. Participants underwent whole gut transit measurement by scintigraphy using a 99m-labeled technetium-egg meal and 111-labeled indium-charcoal via a delayed-release capsule. Transit measurement was repeated after withdrawal of the study medications. The primary endpoints were ascending colon (AC) emptying half-life time (t1/2) and colonic geometric centre (GC) at 24 h. Secondary analysis variables were GC at 4 and 48 h, gastric emptying t1/2 and colonic filling at 6 h. There was a significant overall effect of progesterone on colonic transit with shorter AC emptying t1/2 and significantly greater colonic GC at 48 h. No transit endpoints were altered by oestradiol or combined hormonal treatment relative to placebo. Oestradiol and progesterone resulted in looser stool consistency. Withdrawal of the hormone supplement was not associated with significant alteration in transit. Micronized progesterone does not retard colonic transit in postmenopausal females.     

Zinc takes the center stage: its paradoxical role in Alzheimer’s disease

There is compelling evidence that the etiology of Alzheimer’s disease (AD) involves characteristic amyloid-β (Aβ) deposition, oxidative stress, and anomalous metal–Aβ protein interaction. New studies have implicated redox active metals such as copper, iron, and zinc as key mediating factors in the pathophysiology of Alzheimer’s disease. There is also evidence that drugs with metal chelating properties could produce a significant reversal of amyloid-β plaque deposition in vitro and in vivo. This paper reviews current observations on the etiologic role of zinc in AD. We also discuss the interactions of zinc and copper with Aβ, a factor that purportedly facilitates disease processes. Finally, we review the protective role of zinc against Aβ cytotoxicity and hypothesize how the apparent effect of zinc on AD pathology may be paradoxical, The Zinc Paradox. Indeed, complex pathologic stressors inherent to the Alzheimer’s diseased brain dictate whether or not zinc will be neuroprotective or neurodegenerative. Further research on the zinc paradox in AD is needed in order to elucidate the exact role zinc plays in AD pathogenesis.