VEGF and mRNA VEGF expression in CSF from Behçet's disease with neurological involvement

Vascular endothelial growth factor (VEGF) stimulates angiogenesis, but is also pro-inflammatory and plays an important role in the development of neurological disease, where it can have both attenuating and exacerbating effects. Several studies have indicated that VEGF-A (VEGF) may play a role in the pathogenesis of neurological inflammatory diseases.To assess the role of VEGF in patients with Behçet's disease with neurological involvement, VEGF was measured in the cerebrospinal fluid (CSF) of 32 patients compared to a group of 12 patients with noninflammatory neurological diseases (NIND) and 14 patients with multiple sclerosis (MS). We have also studied the expression of mRNA-VEGF (VEGF-A) in CSF and in peripheral blood mononuclear cells.The mean VEGF_CSF was significantly increased in neuro-BD and MS patients compared to NIND patients. There was an association between neuro-BD-VEGF_CSF, and leukocyte count. A significant correlation was also observed between neuro-BD-VEGF_CSF and CSF_%CD4 cells. As a measure of the integrity of the blood-brain barrier Q_albumin was found correlated to VEGF_CSF. VEGF mRNA was significantly increased in neuro-BD patients compared to NIND patients.These results indicate that, VEGF may be associated with the increased percentages of CD4 cell subpopulation. The role of VEGF is within the inflammatory cascade in the mediation of blood-brain barrier disruption and not specific to Behçet's.     

N‐acetyl resonances in in vivo and in vitro NMR spectroscopy of cystic ovarian tumors

An unassigned and prominent resonance in the region from δ 2.0–2.1 ppm has frequently been found in the in vivo MR spectra of cancer patients. We demonstrated the presence of this resonance with in vivo MRS in the cyst fluid of a patient with an ovarian tumor. ¹H‐NMRS on the aspirated cyst fluid of this patient confirmed the observation. A complex of resonances was observed between 2.0 and 2.1 ppm. It was also present in 11 additional ovarian cyst fluid samples randomly chosen from our biobank. The resonance complex was significantly more prominent in samples from mucinous tumors than in samples from other histological subtypes. A macromolecule (>10 kDa) was found responsible for this complex of resonances. A correlation spectroscopy (COSY) experiment revealed cross peaks of two different types of bound sialic acid suggesting that N‐glycans from glycoproteins and/or glycolipids cause this resonance complex. In the literature, plasma α‐1 acid glycoprotein (AGP), known for its high content of N‐linked glycans, has been suggested to contribute to the δ 2.0–2.1 spectral region. The AGP cyst fluid concentration did not correlate significantly with the peak height of the δ 2.0–2.1 resonance complex in our study. AGP may be partly responsible for the resonance complex but other N‐acetylated glycoproteins and/or glycolipids also contribute. After deproteinization of the cyst fluid, N‐acetyl‐L ‐aspartic acid (NAA) was found to contribute significantly to the signal in this spectral region in three of the 12 samples. GC‐MS independently confirmed the presence of NAA in high concentration in the three samples, which all derived from benign serous tumors. We conclude that both NAA and N‐acetyl groups from glycoproteins and/or glycolipids may contribute to the δ 2.0–2.1 ppm resonance complex in ovarian cyst fluid. This spectral region seems to contain resonances from biomarkers that provide relevant clinical information on the type of ovarian tumor. Copyright © 2009 John Wiley & Sons, Ltd.     

Improved stent characteristics for prophylaxis of post-ERCP pancreatitis.

BACKGROUND & AIMS: Pancreatic stenting is an effective method to prevent post-endoscopic retrograde cholangiopancreatography (ERCP) pancreatitis in high-risk patients. This retrospective study evaluated the impact of modified stent characteristics on the rate of post-ERCP pancreatitis, spontaneous stent dislodgment, and stent-related sequelae. METHODS: A total of 2283 patients underwent 2447 ERCPs over a 6-year period with placement of 3-4F diameter, unflanged pancreatic stents. The indication for stenting was pancreatitis prophylaxis predominantly in suspected sphincter of Oddi dysfunction (SOD), pancreas divisum therapy, and precut sphincterotomy. An abdominal radiograph was obtained 10-14 days later to assess spontaneous stent passage. Post-ERCP pancreatitis was defined according to established criteria. A total of 479 patients underwent repeat ERCPs after an initial ERCP with pancreatic stent placement. The prestenting pancreatogram was then compared with follow-up studies. RESULTS: The pancreatitis rate with 3F, 4F, 5F, and 6F stents was 7.5%, 10.6%, 9.8%, and 14.6%, respectively (3F vs. 4F, 5F, 6F: P = 0.047). Spontaneous stent dislodgment was 86%, 73%, 67%, and 65%, respectively (3F vs. 4F, 5F, 6F: P < 0.0001). The frequency of ductal changes was 24% in patients with 3-4F stents compared with 80% with 5-6F stents. Ductal perforation from the stents occurred in 3 patients (0.1%). CONCLUSIONS: Small diameter (3-4F), unflanged pancreatic stents are more effective than the traditionally used stents (5-6F) in preventing post-ERCP pancreatitis. Stent-induced ductal changes and the need for endoscopic removal are also significantly less with 3-4F stents. The 3F stent appears to be superior in all aspects studied. Additional studies are needed to define the ideal method to eliminate post-ERCP pancreatitis.     

Gene-based association analysis of survival traits via functional regression-based mixed effect cox models for related samples

The importance to integrate survival analysis into genetics and genomics is widely recognized, but only a small number of statisticians have produced relevant work toward this study direction. For unrelated population data, functional regression (FR) models have been developed to test for association between a quantitative/dichotomous/survival trait and genetic variants in a gene region. In major gene association analysis, these models have higher power than sequence kernel association tests. In this paper, we extend this approach to analyze censored traits for family data or related samples using FR based mixed effect Cox models (FamCoxME). The FamCoxME model effect of major gene as fixed mean via functional data analysis techniques, the local gene or polygene variations or both as random, and the correlation of pedigree members by kinship coefficients or genetic relationship matrix or both. The association between the censored trait and the major gene is tested by likelihood ratio tests (FamCoxME FR LRT). Simulation results indicate that the LRT control the type I error rates accurately/conservatively and have good power levels when both local gene or polygene variations are modeled. The proposed methods were applied to analyze a breast cancer data set from the Consortium of Investigators of Modifiers of BRCA1 and BRCA2 (CIMBA). The FamCoxME provides a new tool for gene-based analysis of family-based studies or related samples.     

Enteral administration of high-fat nutrition before and directly after hemorrhagic shock reduces endotoxemia and bacterial translocation

OBJECTIVE: To determine whether potential enhancement of endotoxin neutralization via high-fat enteral nutrition affects endotoxemia and bacterial translocation after hemorrhage. SUMMARY BACKGROUND DATA: Endotoxin and bacterial translocation due to gut barrier failure are important initiating events in the pathogenesis of sepsis after hemorrhage. Systemic inhibition of endotoxin activity attenuates bacterial translocation and distant organ damage. Triacylglycerol-rich lipoproteins constitute a physiological means of binding and neutralizing endotoxin effectively. We hypothesized that enhancement of triacylglycerol-rich lipoproteins via high-fat enteral nutrition would reduce endotoxemia and prevent bacterial translocation. METHODS: A rat model of nonlethal hemorrhagic shock was used. Hemorrhagic shock (HS) rats were divided into 3 groups: rats starved overnight (HS-S); rats fed with a low-fat enteral diet (HS-LF), and rats receiving a high-fat enteral diet (HS-HF). RESULTS: Circulating triacylglycerol and apolipoprotein B, reflecting the amount of triacylglycerol-rich lipoproteins, were elevated in HS-HF rats compared with both HS-S rats (P 相似文献   

Atrial natriuretic peptide effects on cGMP and cAMP contents in microdissected glomeruli and segments of the rat and rabbit nephrons

A microradioimmunoassay has been developed in order to measure the changes in cGMP cell content induced in vitro by atrial natriuretic peptides (ANP) in either glomeruli or defined portions of tubules microdissected from collagenase treated rat and rabbit kidneys. When tested at 0.1 M or 1 M, all ANP analogues used produced in rat glomeruli a 20–25 fold increase in cGMP accumulation compared to basal values. Threshold responses were obtained with about 1 nM ANP and apparentK _a values ranged between 5 and 50 nM. Atriopeptin III led to similar results in glomeruli isolated from rabbit. Under the same experimental conditions, no cGMP could be detected in any ANP-treated nephron segment from the rat kidney (namely, from the proximal convoluted tubule up to the outer medullary collecting tubule) nor in cortical collecting tubules isolated from the rabbit kidney. Moreover, ANP did not after the forskolin-induced increase in cAMP content in glomeruli or collecting tubules, nor the AVP-induced increase in cAMP content in collecting tubules. Our data confirm the marked effect of ANP on cGMP generation by isolated glomeruli from rat and rabbit; however, they are not competible with a direct action of ANP stimulating cGMP generation in tubules or inhibiting vasopressin-induced cAMP generation in collecting tubules.     

High-fat enteral nutrition reduces endotoxin, tumor necrosis factor-alpha and gut permeability in bile duct-ligated rats subjected to hemorrhagic shock

BACKGROUND/AIMS: Cholestatic patients are prone to septic complications after major surgery due to an increased susceptibility to endotoxin and hypotension. High-fat enteral nutrition reduces endotoxin after hemorrhagic shock. However, it is unknown whether this nutritional intervention is protective in biliary obstruction. We investigated the effect of high-fat enteral nutrition on endotoxin, tumor necrosis factor-alpha (TNF-alpha) and intestinal permeability in cholestatic rats subjected to hemorrhagic shock. METHODS: Bile duct-ligated (BDL) rats were fasted or fed with low-fat or high-fat enteral nutrition before hemorrhagic shock. Blood and tissue samples were taken after 90 min. RESULTS: Plasma endotoxin decreased after hemorrhagic shock in BDL-rats fed with high-fat nutrition compared to fasted (P<0.01) and low-fat treated rats (P<0.05). Additionally, circulating TNF-alpha was reduced in BDL-rats pretreated with high-fat nutrition compared to fasted rats (P<0.01). The increased intestinal permeability to macromolecules was reduced by high-fat enteral nutrition, whereas bacterial translocation did not significantly change. Simultaneously, tight junction distribution in ileum and colon was disrupted in non-treated BDL-rats but remained unchanged in high-fat pretreated BDL-rats. CONCLUSIONS: High-fat enteral nutrition protects against endotoxin-mediated complications independently of intraluminal bile. These results provide a potential new strategy to prevent endotoxin-mediated complications in cholestatic patients undergoing major surgery.     

Allosteric modulation of the GABA(A) receptor in rat hypothalamus by somatostatin is altered by stress

1. This autoradiographic study was conducted to investigate somatostatin modulation of GABA(A) receptor binding in hypothalamic structures of immobilization-stressed rats. 2. GABA(A) receptor binding was labelled with [35S]-t- butylbicyclophosphorothionate (TBPS), which binds in or near the chloride channel. 3. Several structures of the rat hypothalamus (i.e. the peri- and paraventricular nuclei) display an increase in [35S]-TBPS binding as well as an alteration of the modulatory effect of somatostatin on the GABA(A) receptor complex under stress. Furthermore, these results demonstrate for the first time that somatostatin is particularly effective in modifying [35S]-TBPS binding to the GABA(A) receptor in rat hypothalamus.     

Apolipoprotein CI knock-out mice display impaired memory functions

The ε4 allele of apolipoprotein E (APOE4), which is a well established genetic risk factor for development of Alzheimer's disease (AD), is in genetic disequilibrium with the H2 allele of apolipoprotein C1 (APOC1), giving rise to increased expression of apoC-I. This raises the possibility that the H2 allele of APOC1, either alone or in combination with APOE4, provides a major risk factor for AD. In line herewith, we previously showed that mice overexpressing human APOC1 display impaired learning and memory functions. Here, we tested the hypothesis that the absence of Apoc1 expression in mice may improve memory functions. In contrast with our expectations, Apoc1(-/-) mice showed impaired hippocampal-dependent memory functions, as judged from their performance in the object recognition task (p < 0.001) as compared to their wild-type littermates. No gross changes in brain morphology or in brain sterol concentrations were detected in knockout mice compared to wild-type littermates. Apoc1 deficiency reduced the expression of ApoE mRNA (-25%, p < 0.05), but not ApoE protein levels. In line with a role for apoC-I in inflammatory processes, we observed significantly increased mRNA concentrations of the proinflammatory marker tumor necrosis factor α and oxidative stress related heme oxygenase 1 (Hmox1) in the absence of glial activation. In conclusion, the absence of ApoC-I results in impaired memory functions, which is, together with previous data, suggestive of an important, bell-shaped gene-dose dependent role for ApoC-I in appropriate brain functioning. The relative contributions of the H2 allele of APOC1 and/or APOE4 in the risk assessment in AD remain to be determined.