Distal colonic Na+ absorption inhibited by luminal P2Y2 receptors

Luminal P2 receptors are ubiquitously expressed in transporting epithelia. In steroid-sensitive epithelia (e.g., lung, distal nephron) epithelial Na⁺ channel (ENaC)-mediated Na⁺ absorption is inhibited via luminal P2 receptors. In distal mouse colon, we have identified that both, a luminal P2Y₂ and a luminal P2Y₄ receptor, stimulate K⁺ secretion. In this study, we investigate the effect of luminal adenosine triphosphate/uridine triphosphate (ATP/UTP) on electrogenic Na⁺ absorption in distal colonic mucosa of mice treated on a low Na⁺ diet for more than 2 weeks. Transepithelial electrical parameters were recorded in an Ussing chamber. Baseline parameters: transepithelial voltage (V _te): −13.7 ± 1.9 mV (lumen negative), transepithelial resistance (R _te): 24.1 ± 1.8 Ω cm², equivalent short circuit current (I _sc): −563.9 ± 63.8 μA/cm² (n = 21). Amiloride completely inhibited I _sc to −0.5 ± 8.5 μA/cm². Luminal ATP induced a slowly on-setting and persistent inhibition of the amiloride-sensitive I _sc by 160.7 ± 29.7 μA/cm² (n = 12, NMRI mice). Luminal ATP and UTP were almost equipotent with IC₅₀ values of 10 μM and 3 μM respectively. In P2Y₂ knock-out (KO) mice, the effect of luminal UTP on amiloride-sensitve Na⁺ absorption was absent. In contrast, in P2Y₄ KO mice the inhibitory effect of luminal UTP on Na⁺ absorption remained present. Semiquantitative polymerase chain reaction did not indicate regulation of the P2Y receptors under low Na⁺ diet, but it revealed a pronounced axial expression of both receptors with highest abundance in surface epithelia. Thus, luminal P2Y₂ and P2Y₄ receptors and ENaC channels co-localize in surface epithelium. Intriguingly, only the stimulation of the P2Y₂ receptor mediates inhibition of electrogenic Na⁺ absorption.     

IVIG enters the central nervous system during treatment of experimental autoimmune encephalomyelitis and is localised to inflammatory lesions

Intravenous immunoglobulin (IVIG) treatment reduces the relapse rate in relapsing–remitting multiple sclerosis (MS) and may interfere with MS pathology through its various anti-inflammatory and immunomodulatory properties. It is presently unknown whether IVIG enters the central nervous system (CNS) in sufficient amounts to influence the local immune response within the brain and spinal cord, or if the treatment effects are entirely due to peripheral actions of IVIG. The purpose of the present study was to evaluate if IVIG radiolabeled with ^99mTc enters the CNS during treatment of experimental autoimmune encephalomyelitis (EAE) in the susceptible rat strain Dark Agouti. After in vivo administration of ^99mTc-IVIG we observed significantly increased accumulation in the brain and spinal cord from rats with EAE. Accumulation of ^99mTc-IVIG was not detectable in CNS tissue from control animals. In peripheral tissue samples minor increases in ^99mTc-IVIG organ binding were observed in the liver and kidney during EAE. Localisation of ^99mTc-IVIG in the brain tissue was visualised by autoradiography and revealed significant accumulation of IVIG only in areas also affected by perivascular inflammation and leakage of serum proteins. In conclusion, the results indicate that significant extravasation of IVIG to the CNS only occurs when blood–brain barrier function is compromised during EAE.     

The effects of human ankle muscle vibration on posture and balance during adaptive locomotion

This study investigated the contribution of ankle muscle proprioception to the control of dynamic stability and lower limb kinematics during adaptive locomotion, by using mechanical vibration to alter the muscle spindle output of individuals' stance limbs. It was hypothesised that muscle length information from the ankle of the stance limb provides information describing location as well as acceleration of the centre of mass (COM) with respect to the support foot during the swing phase of locomotion. Our prediction, based on this hypothesis was that ankle muscle vibration would cause changes to the position and acceleration of the COM and/or compensatory postural responses. Vibrators were attached to both the stance limb ankle plantarflexors (at the Achilles tendon) and the opposing dorsiflexor muscle group (over tibialis anterior). Participants were required to walk along a 9-m travel path and step over any obstacles placed in their way. There were three task conditions: (1) an obstacle (15 cm in height) was positioned at the midpoint of the walkway prior to the start of the trial, (2) the same obstacle was triggered to appear unexpectedly one step in front of the participant at the walkway midpoint and (3) the subjects' walking path remained clear. The participants' starting position was manipulated so that the first step over the obstacle (when present) was always performed with their right leg. For each obstacle condition participants experienced the following vibration conditions: no vibration, vibration of the left leg calf muscles or vibration of the anterior compartment muscles of the lower left leg. Vibration began one step before the obstacle at left leg heel contact and continued for 1 s. Vibrating the ankle muscles of the stance limb during the step over an obstacle resulted in significant changes to COM behaviour [measured as displacement, acceleration and position with respect to the centre of pressure (COP)] in both the medial/lateral (M/L) and anterior/posterior planes. There were also significant task-specific changes in stepping behaviour associated with COM control (measured as peak M/L acceleration, M/L foot displacement and COP position under the stance foot during the step over the obstacle). The results provide strong evidence that the primary endings of ankle muscle spindles play a significant role in the control of posture and balance during the swing phase of locomotion by providing information describing the movement of the body's COM with respect to the support foot. Our results also provide supporting evidence for the proposal that there are context-dependent changes in muscle spindle sensitivity during human locomotion.     

hace1 Influences zebrafish cardiac development via ROS‐dependent mechanisms

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Local expression of interleukin‐2 by B16 melanoma cells results in decreased tumour growth and long‐term tumour dormancy

The tumour microenvironment is complex containing not only neoplastic cells but also a variety of host cells. The heterogeneous infiltrating immune cells include subsets of cells with opposing functions, whose activities are mediated either directly or through the cytokines they produce. Systemic delivery of cytokines such as interleukin‐2 ( IL‐2) has been used clinically to enhance anti‐tumour responses, but these molecules are generally thought to have evolved to act locally in a paracrine fashion. In this study we examined the effect of local production of IL‐2 on the growth and the immune response to B16 melanoma cells. We found that the local production of IL‐2 enhances the number of interferon‐γ‐expressing CD8 T and natural killer cells in the tumour, as well as inducing expression of vascular cell adhesion molecule 1 on tumour vessels. These responses were largely absent in interferon‐γ knockout mice. The expression of IL‐2 in the tumour microenvironment decreases tumour growth despite also enhancing Foxp3⁺ CD4⁺ regulatory T cells and anti‐inflammatory cytokines such as IL‐10. Higher levels of IL‐2 in the tumour microenvironment eliminated the progressive growth of the B16 cells in vivo, and this inhibition was dependent on the presence of either T cells or, to a lesser extent, natural killer cells. Surprisingly however, the B16 tumours were not completely eliminated but instead were controlled for an extended period of time, suggesting that a form of tumour dormancy was established.     

High-sensitivity C-reactive protein, adiposity, and blood pressure in the Yakut of Siberia.

C-reactive protein (CRP), an acute-phase reactant and marker of inflammatory response, is known to be an important predictor of future cardiovascular mortality, independent of other risk factors. The purpose of this research was to investigate the association between CRP, adiposity, and blood pressure in the Yakut, an indigenous Siberian population undergoing rapid cultural change. We conducted a cross-sectional study of 265 healthy Yakut adults in six villages in rural northeastern Siberia. Plasma CRP was measured by high-sensitivity immunoturbidimetric assay. The median CRP value was 0.85 mg/l, with values for the 25th, 50th, and 75th percentiles of 0.30, 0.85, and 2.28 mg/l, respectively. CRP was positively associated with age (r = 0.19; P = 0.002), but not plasma lipids or smoking status. CRP was associated with measures of central adiposity and characteristics of the metabolic syndrome, particularly in women. We found significantly higher CRP across quintiles (Q) of waist circumference for women (difference = 0.7 mg/l; P = 0.035), but not men (difference = 0.36 mg/l; P = 0.515). CRP was significantly associated with systolic blood pressure in men (difference, Q1 vs. Q5 = 1.1 mg/l; P = 0.044) but not women (difference, Q1 vs. Q5 = 0.03 mg/l; P = 0.713) after adjusting for age, waist circumference, and smoking status. CRP in the Yakut was considerably lower than was reported for other populations. The low CRP levels may be explained in part by a low prevalence of abdominal obesity. Among the Yakut, the high physical-activity demands of a traditional herding lifeway likely play a role through high energy expenditure and maintenance of negative energy balance. Our findings underscore the need for further research on the metabolic activity of adipose tissue, blood pressure, and inflammatory activation in non-Western populations.     

Mapping of three novel loci for non‐syndromic autosomal recessive mental retardation (NS‐ARMR) in consanguineous families from Pakistan

Rafiq MA, Ansar M, Marshall CR, Noor A, Shaheen N, Mowjoodi A, Khan MA, Ali G, Amin‐ud‐Din M, Feuk L, Vincent JB, Scherer SW. Mapping of three novel loci for non‐syndromic autosomal recessive mental retardation (NS‐ARMR) in consanguineous families from Pakistan. To date, of 13 loci with linkage to non‐syndromic autosomal recessive mental retardation (NS‐ARMR), only six genes have been established with associated mutations. Here we present our study on NS‐ARMR among the Pakistani population, where people are traditionally bound to marry within the family or the wider clan. In an exceptional, far‐reaching genetic survey we have collected more than 50 consanguineous families exhibiting clinical symptoms/phenotypes of NS‐ARMR. In the first step, nine families (MR2‐9 and MR11) with multiple affected individuals were selected for molecular genetic studies. Two families (MR3, MR4) showed linkage to already know NS‐ARMR loci. Fifteen affected and 10 unaffected individuals from six (MR2, MR6, MR7, MR8, MR9 and MR11) families were genotyped by using Affymetrix 5.0 or 6.0 single‐nucleotide polymorphism (SNP) microarrays. SNP microarray data was visually inspected by dChip and genome‐wide homozygosity analysis was performed by HomozygosityMapper. Additional mapping was performed (to exclude false‐positive regions of homozygosity called by HomozygosityMapper and dChip) on all available affected and unaffected members in seven NS‐ARMR families, using microsatellite markers. In this manner we were able to map three novel loci in seven different families originating from different areas of Pakistan. Two families (MR2, MR5) showed linkage on chromosome 2p25.3‐p25.2. Three families (MR7, MR8, and MR9) that have been collected from the same village and belong to the same clan were mapped on chromosome 9q34.3. MR11 maps to a locus on 9p23‐p13.3. Analysis of MR6 showed two positive loci, on chromosome 1q23.2‐q23.3 and 8q24.21‐q24.23. Genotyping in additional family members has so far narrowed, but not excluded the 1q locus. In summary, through this study we have identified three new loci for NS‐ARMR, namely MRT14, 15 and 16.     

Apolipoprotein B 3'-VNTR polymorphism in Eastern European populations

Apolipoprotein B 3' (3' ApoB) minisatellite polymorphism was studied in healthy unrelated individuals from the Russian Federation and the Republic of Belarus, in 10 populations from five ethnic groups: Russians, Byelorussians, Adygeis, Kalmyks and Yakuts. The analysis was carried out using PCR and electrophoresis followed by silver staining. Overall, 25 alleles of the 3' ApoB minisatellite, ranging from 25 to 55 repeats, were detected. Heterozygosity indices were high and varied from 0.73 to 0.84. The distributions of alleles of this minisatellite in the Caucasoid populations (Russians, Byelorussians and Adygeis) had a bimodal character, whereas that for Mongoloid populations (Kalmyks and Yakuts) had a unimodal distribution. Nei's genetic distances between the populations studied and some reference populations of Europe and Asia were estimated. Despite their allele distribution homogeneity, different East Slavonic ethnic groups were clearly resolved by multidimensional analyses. The East Slavonic and Adygei populations revealed a high similarity with European Caucasoids. The Mongoloid populations (Kalmyks and Yakuts) were considerably different from those of the European Caucasoid populations, but were similar to other Asian Mongoloid populations. The results demonstrate the variability of 3' ApoB minisatellite polymorphism not only in distant populations but also, to a certain extent, in genetically relative ones.