MEP1A allele for meprin A metalloprotease is a susceptibility gene for inflammatory bowel disease

The MEP1A gene, located on human chromosome 6p (mouse chromosome 17) in a susceptibility region for inflammatory bowel disease (IBD), encodes the alpha-subunit of metalloproteinase meprin A, which is expressed in the intestinal epithelium. This study shows a genetic association of MEP1A with IBD in a cohort of ulcerative colitis (UC) patients. There were four single-nucleotide polymorphisms in the coding region (P=0.0012-0.04), and one in the 3'-untranslated region (P=2 x 10(-7)) that displayed associations with UC. Moreover, meprin-alpha mRNA was decreased in inflamed mucosa of IBD patients. Meprin-alpha knockout mice exhibited a more severe intestinal injury and inflammation than their wild-type counterparts following oral administration of dextran sulfate sodium. Collectively, the data implicate MEP1A as a UC susceptibility gene and indicate that decreased meprin-alpha expression is associated with intestinal inflammation in IBD patients and in a mouse experimental model of IBD.

Loss of alpha10beta1 integrin expression leads to moderate dysfunction of growth plate chondrocytes

Integrin alpha10beta1 is a collagen-binding integrin expressed on chondrocytes. In order to unravel the role of the alpha10 integrin during development, we generated mice carrying a constitutive deletion of the alpha10 integrin gene. The mutant mice had a normal lifespan and were fertile but developed a growth retardation of the long bones. Analysis of the skeleton revealed defects in the growth plate after birth characterized by a disturbed columnar arrangement of chondrocytes, abnormal chondrocyte shape and reduced chondrocyte proliferation. Electron microscopy of growth plates from newborn mice revealed an increased number of apoptotic chondrocytes and reduced density of the collagen fibrillar network compared to these structures in control mice. These results demonstrate that integrin alpha10beta1 plays a specific role in growth plate morphogenesis and function.

Human internal thoracic arteries from diabetic patients are resistant to endothelial dysfunction

The aim of this analysis was to compare vasoreactive properties of internal thoracic arteries (ITA) grafts from diabetic (DM) to those of non-diabetic (ND) patients. Ring segments of ITA, taken from patients undergoing coronary artery bypass grafting, were suspended in organ bath chambers filled with modified Krebs-Henseleit solution and contractile responses to potassium chloride (KCl), noradrenaline (NA), endothelin-1 (ET-l), and endothelium-dependent relaxant responses to acetylcholine (ACH) were recorded isometrically. The receptor-mediated agonists NA and ET-1 stimulated ITA from both groups within similar concentration ranges while ITA from DM patients proved to be significantly more sensitive to KCl than ITA from ND. Furthermore, maximal contractile responses indicated that KCl (3.79 +/- 0.30 g, n = 7 in DM and 2.50 +/- 0.23 g, n = 29 in ND, P < 0.05) evoked significantly higher responses in ITA from DM as compared to the ND control group while both NA and ET-l stimulated ITA from both groups with similar efficacies. Endothelium-dependent relaxant responses to ACH proved to be similar in both groups when expressed as percentages of the pre-existing tone. The present data support the contention that in comparison to ND controls arteries from DM patients are more sensitive to depolarization but endothelial dysfunction is less frequent in human ITA than expected from observations in systemic vascular beds.

Nervous system dysfunction in Henoch-Schonlein syndrome: systematic review of the literature

OBJECTIVE: CNS or peripheral nervous system dysfunction sometimes occurs in Henoch-Schönlein patients. METHODS: We review all Henoch-Schönlein cases published after 1969 with CNS dysfunction without severe hypertension and neuroimaging studies (n = 35), cranial or peripheral neuropathy (n = 15), both CNS and peripheral nervous system dysfunction without severe hypertension (n = 2) or nervous system dysfunction with severe hypertension (n = 2). Forty-four of the 54 patients were <20 years of age. RESULTS: In patients with CNS dysfunction without or with severe hypertension the following presentations were observed in decreasing order of frequency: altered level of consciousness, convulsions, focal neurological deficits, visual abnormalities and verbal disability. Imaging studies disclosed the following lesions: vascular lesions almost always involving two or more vessels, intracerebral haemorrhage, posterior subcortical oedema, diffuse brain oedema and thrombosis of the superior sagittal sinus. Following lesions were noted in the subjects with cranial or peripheral neuropathy without severe hypertension: peroneal neuropathy, peripheral facial palsy, Guillain-Barré syndrome, brachial plexopathy, posterior tibial nerve neuropathy, femoral neuropathy, ulnar neuropathy and mononeuritis multiplex. Persisting signs of either CNS (n = 9) or peripheral (n = 1) nervous system dysfunction were sometimes reported. CONCLUSIONS: In Henoch-Schönlein syndrome, signs of nervous system dysfunction are uncommon but clinically relevant. This review helps clinicians managing Henoch-Schönlein syndrome with nervous system dysfunction.

Sexual dysfunction in multiple sclerosis

Multiple sclerosis is a chronic disease that commonly affects young adults who may be sexually active. Sexual dysfunction is a significant, but often underestimated, symptom of multiple sclerosis, affecting 50-90% of men and 40-80% of women. The types of sexual dysfunction can be categorized in terms of the normal sexual response cycle: sexual interest/desire dysfunction (reduced libido), sexual arousal dysfunction (including erectile dysfunction) and ejaculatory and orgasmic dysfunction. Sexual dysfunction may not only be due to lesions affecting the neural pathways involved in physiological function (primary dysfunction), but also result from general physical disabilities (secondary dysfunction) or psychological and emotional issues (tertiary dysfunction). Comprehensive management should address all these possible contributing problems. Specific pharmacotherapy is only currently available for erectile dysfunction. This review summarizes the available information about sexual dysfunction in men and women with multiple sclerosis.

The blood-brain and the blood-cerebrospinal fluid barriers: function and dysfunction

The central nervous system (CNS) is tightly sealed from the changeable milieu of blood by the blood-brain barrier (BBB) and the blood-cerebrospinal fluid (CSF) barrier (BCSFB). While the BBB is considered to be localized at the level of the endothelial cells within CNS microvessels, the BCSFB is established by choroid plexus epithelial cells. The BBB inhibits the free paracellular diffusion of water-soluble molecules by an elaborate network of complex tight junctions (TJs) that interconnects the endothelial cells. Combined with the absence of fenestrae and an extremely low pinocytotic activity, which inhibit transcellular passage of molecules across the barrier, these morphological peculiarities establish the physical permeability barrier of the BBB. In addition, a functional BBB is manifested by a number of permanently active transport mechanisms, specifically expressed by brain capillary endothelial cells that ensure the transport of nutrients into the CNS and exclusion of blood-borne molecules that could be detrimental to the milieu required for neural transmission. Finally, while the endothelial cells constitute the physical and metabolic barrier per se, interactions with adjacent cellular and acellular layers are prerequisites for barrier function. The fully differentiated BBB consists of a complex system comprising the highly specialized endothelial cells and their underlying basement membrane in which a large number of pericytes are embedded, perivascular antigen-presenting cells, and an ensheathment of astrocytic endfeet and associated parenchymal basement membrane. Endothelial cell morphology, biochemistry, and function thus make these brain microvascular endothelial cells unique and distinguishable from all other endothelial cells in the body. Similar to the endothelial barrier, the morphological correlate of the BCSFB is found at the level of unique apical tight junctions between the choroid plexus epithelial cells inhibiting paracellular diffusion of water-soluble molecules across this barrier. Besides its barrier function, choroid plexus epithelial cells have a secretory function and produce the CSF. The barrier and secretory function of the choroid plexus epithelial cells are maintained by the expression of numerous transport systems allowing the directed transport of ions and nutrients into the CSF and the removal of toxic agents out of the CSF. In the event of CNS pathology, barrier characteristics of the blood-CNS barriers are altered, leading to edema formation and recruitment of inflammatory cells into the CNS. In this review we will describe current knowledge on the cellular and molecular basis of the functional and dysfunctional blood-CNS barriers with focus on CNS autoimmune inflammation.

Impaired verbal memory in Parkinson disease: relationship to prefrontal dysfunction and somatosensory discrimination

OBJECTIVE: To study the neurocognitive profile and its relationship to prefrontal dysfunction in non-demented Parkinson's disease (PD) with deficient haptic perception. METHODS: Twelve right-handed patients with PD and 12 healthy control subjects underwent thorough neuropsychological testing including Rey complex figure, Rey auditory verbal and figural learning test, figural and verbal fluency, and Stroop test. Test scores reflecting significant differences between patients and healthy subjects were correlated with the individual expression coefficients of one principal component, obtained in a principal component analysis of an oxygen-15-labeled water PET study exploring somatosensory discrimination that differentiated between the two groups and involved prefrontal cortices. RESULTS: We found significantly decreased total scores for the verbal learning trials and verbal delayed free recall in PD patients compared with normal volunteers. Further analysis of these parameters using Spearman's ranking correlation showed a significantly negative correlation of deficient verbal recall with expression coefficients of the principal component whose image showed a subcortical-cortical network, including right dorsolateral-prefrontal cortex, in PD patients. CONCLUSION: PD patients with disrupted right dorsolateral prefrontal cortex function and associated diminished somatosensory discrimination are impaired also in verbal memory functions. A negative correlation between delayed verbal free recall and PET activation in a network including the prefrontal cortices suggests that verbal cues and accordingly declarative memory processes may be operative in PD during activities that demand sustained attention such as somatosensory discrimination. Verbal cues may be compensatory in nature and help to non-specifically enhance focused attention in the presence of a functionally disrupted prefrontal cortex.

Aperistaltic effect of hyoscine N-butylbromide versus glucagon on the small bowel assessed by magnetic resonance imaging

The aim of this prospective study was to compare the intraindividual aperistaltic effect of 40 mg hyoscine N-butylbromide (HBB/Buscopan) with that of 1 mg glucagon on small bowel motility by using magnetic resonance imaging (MRI). Ten healthy volunteers underwent two separate 1.5-T MRI studies (HBB/glucagon) after a standardized oral preparation with an aqueous solution of Gd-DOTA and ispaghula (Metamucil). A 2D T1-w GRE sequence was acquired (TR 2.7 ms/TE 1.3 ms, temporal resolution 0.25 s) before and after intravenous (i.v.) drug administration and motility was followed over 1 h. On the resulting images the cross-sectional luminal diameters were assessed and plotted over time. Baseline motility frequency, onset of aperistalsis, duration of arrest, reappearance of motility and return to normal motility were analysed. Significant differences regarding reliability and duration of aperistalsis were observed. In the HBB group aperistalsis lasted a mean of 6.8 +/- 5.3 min compared with 18.3 +/- 7 min after glucagon (p < 0.0001). In 50% of cases HBB did not accomplish aperistalsis, whereas glucagon always succeeded (p = 0.05). There were no significant differences in terms of baseline and end frequencies for the onset of aperistalsis (22.2 +/- 37.5 s HBB/13.4 +/- 9.2 s glucagon, p = 0.1), nor for the return to normal motility. Arrest of small bowel motion is achieved more reliably and lasts significantly longer after i.v. administration of 1 mg glucagon compared with 40 mg HBB.

Neurally adjusted ventilatory assist decreases ventilator-induced lung injury and non-pulmonary organ dysfunction in rabbits with acute lung injury

OBJECTIVE: To determine if neurally adjusted ventilatory assist (NAVA) that delivers pressure in proportion to diaphragm electrical activity is as protective to acutely injured lungs (ALI) and non-pulmonary organs as volume controlled (VC), low tidal volume (Vt), high positive end-expiratory pressure (PEEP) ventilation. DESIGN: Prospective, randomized, laboratory animal study. SUBJECTS: Twenty-seven male New Zealand white rabbits. INTERVENTIONS: Anesthetized rabbits with hydrochloric acid-induced ALI were randomized (n = 9 per group) to 5.5 h NAVA (non-paralyzed), VC (paralyzed; Vt 6-ml/kg), or VC (paralyzed; Vt 15-ml/kg). PEEP was adjusted to hemodynamic goals in NAVA and VC6-ml/kg, and was 1 cmH2O in VC15-ml/kg. MEASUREMENTS AND MAIN RESULTS: PaO2/FiO2; lung wet-to-dry ratio; lung histology; interleukin-8 (IL-8) concentrations in broncho-alveolar-lavage (BAL) fluid, plasma, and non-pulmonary organs; plasminogen activator inhibitor type-1 and tissue factor in BAL fluid and plasma; non-pulmonary organ apoptosis rate; creatinine clearance; echocardiography. PEEP was similar in NAVA and VC6-ml/kg. During NAVA, Vt was lower (3.1 +/- 0.9 ml/kg), whereas PaO2/ FiO2, respiratory rate, and PaCO2 were higher compared to VC6-ml/kg (p<0.05 for all). Variables assessing ventilator-induced lung injury (VILI), IL-8 levels, non-pulmonary organ apoptosis rate, and kidney as well as cardiac performance were similar in NAVA compared to VC6-ml/kg. VILI and non-pulmonary organ dysfunction was attenuated in both groups compared to VC15-ml/kg. CONCLUSIONS: In anesthetized rabbits with early experimental ALI, NAVA is as effective as VC6-ml/kg in preventing VILI, in attenuating excessive systemic and remote organ inflammation, and in preserving cardiac and kidney function.

[Mitochondrial dysfunction during sepsis, impact and possible regulating role of hypoxia-inducible factor-1alpha]

There is a direct correlation between the development of the multiple organ dysfunction syndrome (MODS) and the elevated mortality associated with sepsis. The mechanisms responsible for MODS development are being studied, however, the main efforts regarding MODS evaluation have focused on oxygen delivery optimization and on the modulation of the characteristic inflammatory cascade of sepsis, all with negative results. Recent studies have shown that there is development of tissue acidosis, even when there are normal oxygen conditions and limited presence of tissue cellular necrosis or apoptosis, which would indicate that cellular energetic dysfunction may be a central element in MODS pathogenesis. Mitochondrias are the main source of cellular energy, central regulators of cell death and the main source for reactive oxygen species. Several mechanisms contribute to mitochondrial dysfunction during sepsis, that is blockage of pyruvate entry into the Krebs cycle, oxidative phosphorylation substrate use in other enzymatic complexes, enzymatic complex inhibition and membrane damage mediated by oxidative stress, and reduction in mitochondrial content. Hypoxia-inducible factor-1alpha (HIF-1alpha) is a nuclear transcription factor with a central role in the regulation of cellular oxygen homeostasis. Its induction under hypoxic conditions is associated to the expression of hundreds of genes that coordinate the optimization of cellular oxygen delivery and the cellular energy metabolism. HIF-1alpha can also be stabilized under normoxic condition during inflammation and this activation seems to be associated with a prominent pro-inflammatory profile, with lymphocytes dysfunction, and to a reduction in cellular oxygen consumption. Further studies should establish a role for HIF-1alpha as a therapeutic target.

The role of psychological stress in inflammatory bowel disease: quality assessment of methods of 18 prospective studies and suggestions for future research

BACKGROUND: Enquiries among patients on the one hand and experimental and observational studies on the other suggest an influence of stress on inflammatory bowel diseases (IBD). However, since this influence remains hypothetical, further research is essential. We aimed to devise recommendations for future investigations in IBD by means of scrutinizing previously applied methodology. METHODS: We critically reviewed prospective clinical studies on the effect of psychological stress on IBD. Eligible studies were searched by means of the PubMed electronic library and through checking the bibliographies of located sources. RESULTS: We identified 20 publications resulting from 18 different studies. Sample sizes ranged between 10 and 155 participants. Study designs in terms of patient assessment, control variables, and applied psychometric instruments varied substantially across studies. Methodological strengths and weaknesses were irregularly dispersed. Thirteen studies reported significant relationships between stress and adverse outcomes. CONCLUSIONS: Study designs, including accuracy of outcome assessment and repeated sampling of outcomes (i.e. symptoms, clinical, and endoscopic), depended upon conditions like sample size, participants' compliance, and available resources. Meeting additional criteria of sound methodology, like taking into account covariates of the disease and its course, is strongly recommended to possibly improve study designs in future IBD research.

Low bone mineral density, renal dysfunction, and fracture risk in HIV infection: a cross-sectional study

BACKGROUND: Reduced bone mineral density (BMD) is common in adults infected with human immunodeficiency virus (HIV). The role of proximal renal tubular dysfunction (PRTD) and alterations in bone metabolism in HIV-related low BMD are incompletely understood. METHODS: We quantified BMD (dual-energy x-ray absorptiometry), blood and urinary markers of bone metabolism and renal function, and risk factors for low BMD (hip or spine T score, -1 or less) in an ambulatory care setting. We determined factors associated with low BMD and calculated 10-year fracture risks using the World Health Organization FRAX equation. RESULTS: We studied 153 adults (98% men; median age, 48 years; median body mass index, 24.5; 67 [44%] were receiving tenofovir, 81 [53%] were receiving a boosted protease inhibitor [PI]). Sixty-five participants (42%) had low BMD, and 11 (7%) had PRTD. PI therapy was associated with low BMD in multivariable analysis (odds ratio, 2.69; 95% confidence interval, 1.09-6.63). Tenofovir use was associated with increased osteoblast and osteoclast activity (P< or = .002). The mean estimated 10-year risks were 1.2% for hip fracture and 5.4% for any major osteoporotic fracture. CONCLUSIONS: In this mostly male population, low BMD was significantly associated with PI therapy. Tenofovir recipients showed evidence of increased bone turnover. Measurement of BMD and estimation of fracture risk may be warranted in treated HIV-infected adults.

Management of chronic pancreatitis

Chronic pancreatitis (CP) is an inflammatory disorder that results in permanent impairment of the glandular anatomy of the pancreas with or without functional abnormalities. The pathogenesis of CP is usually unclear, except in the case of alcohol-induced disease. The most common symptoms of CP are abdominal pain, diarrhea, and weight loss often requiring recurring hospitalization. Over time, pancreatic endocrine and exocrine dysfunction may develop as the disease progresses, and a variety of complications can occur. Among the possible complications are nutrient malabsorption and diabetes mellitus. The treatment of CP is difficult and challenging for every physician. Relieving pain is the first step in treating CP. This symptom needs to be controlled, often with narcotics, which can cause dependence. Diarrhea usually indicates the presence of steatorrhea, which is often treated with a high-calorie, high-protein, and low-fat diet to minimize symptoms of the underlying disease and to promote weight retention or gain. Pancreatic replacement therapy is used to combat maldigestion and malabsorption. Patients with diabetes may need insulin therapy for glycemic control. The use of parenteral nutrition for bowel rest is a standard approach in patients with symptomatic CP. The use of jejunal enteral feeding recently has been evaluated for efficacy in CP patients. The role of pancreatic endotherapy in the management of CP is evolving. Several reports have suggested that endoscopic therapy aimed at decompressing the obstructed pancreatic duct can be associated with pain relief in some patients. Surgery should be considered in patients who fail medical therapy.

Prevalence of anaemia in inflammatory bowel disease in Switzerland: A cross-sectional study in patients from private practices and university hospitals

BACKGROUND: Anaemia represents a common complication of inflammatory bowel disease (IBD). Most studies on anaemia in IBD patients have been performed in tertiary referral centres (RC) and data from gastroenterologic practices (GP) are lacking. We investigated the frequency and severity of anaemia in IBD patients from tertiary referral centres and gastroenterologic practices compared to the general population. METHODS: Data were acquired from patients included in the Swiss IBD Cohort Study. IBD activity was evaluated by CDAI and modified Truelove and Witts severity index (MTWSI). Anaemia was defined as haemoglobin ≤120g/L in women and ≤130g/L in men. RESULTS: 125 patients from RC (66 with Crohn's disease (CD) and 59 with ulcerative colitis (UC)) and 116 patients from GP (71 CD and 45 UC) were included and compared to 6074 blood donors. Anaemia was found in 21.2% (51/241) of the IBD patients and more frequently in patients from RC as compared to GP and healthy controls (28.8% vs. 12.9% vs. 3.4%; P<0.01). IBD patients from RC suffered more frequently from active disease compared to IBD patients in GP (36% vs. 23%, P=0.032). Supplementation therapy (iron, vitamin B12, folic acid) was performed in 40% of anaemic IBD patients in GP as compared to 43% in RC. CONCLUSIONS: Anaemia is a common complication in patients with IBD and significantly more prevalent in patients from referral centres as compared to patients from gastroenterologic practices. Physicians treating IBD patients should pay attention to the presence of anaemia and ensure sufficient supplementation therapy.

A shift from oral to intravenous iron supplementation therapy is observed over time in a large swiss cohort of patients with inflammatory bowel disease

BACKGROUND In 2007, leading international experts in the field of inflammatory bowel disease (IBD) recommended intravenous (IV) iron supplements over oral (PO) ones because of superior effectiveness and better tolerance. We aimed to determine the percentage of patients with IBD undergoing iron therapy and to assess the dynamics of iron prescription habits (IV versus PO). METHODS We analyzed anonymized data on patients with Crohn's disease and ulcerative colitis extracted from the Helsana database. Helsana is a Swiss health insurance company providing coverage for 18% of the Swiss population (1.2 million individuals). RESULTS In total, 629 patients with Crohn's disease (61% female) and 398 patients with ulcerative colitis (57% female) were identified; mean observation time was 31.8 months for Crohn's disease and 31.0 months for ulcerative colitis patients. Of all patients with IBD, 27.1% were prescribed iron (21.1% in males; 31.1% in females). Patients treated with steroids, immunomodulators, and/or anti-tumor necrosis factor drugs were more frequently treated with iron supplements when compared with those not treated with any medications (35.0% versus 20.9%, odds ratio, 1.94; P < 0.001). The frequency of IV iron prescriptions increased significantly from 2006 to 2009 for both genders (males: from 2.6% to 10.1%, odds ratio = 3.84, P < 0.001; females: from 5.3% to 12.1%, odds ratio = 2.26, P = 0.002), whereas the percentage of PO iron prescriptions did not change. CONCLUSIONS Twenty-seven percent of patients with IBD were treated with iron supplements. Iron supplements administered IV were prescribed more frequently over time. These prescription habits are consistent with the implementation of guidelines on the management of iron deficiency in IBD.