Hepatic stellate cell activation in liver transplant patients with hepatitis C recurrence and in non-transplanted patients with chronic hepatitis C.

The pathogenic mechanisms of accelerated graft fibrosis in hepatitis C recurrence after liver transplantation (LT) are not well established. The aim of the study was to assess whether a greater activation of hepatic stellate cells (HSC), the major collagen-producing cells in the liver, can occur in these patients as compared to non-LT patients with chronic hepatitis C. We determined the amount of activated HSC by computer-based morphometric analysis of alpha-smooth muscle actin (alphaSMA)-positive cells and the hepatic TGFbeta(1) expression by immunohistochemistry in 46 LT patients with hepatitis C recurrence, 35 non-LT patients with chronic hepatitis C, and 16 controls. Hepatic alphaSMA and TGFbeta(1) expression was higher in LT patients with hepatitis C recurrence than in controls and was correlated with fibrosis stage and progression rate. No significant difference in alphaSMA and TGFbeta(1) expression was observed between LT and non-LT patients with hepatitis C, with the exception of a higher transforming growth factor beta-1 (TGFbeta(1)) expression in non-LT patients in the early stages of fibrosis. LT patients receiving cyclosporine (CsA) or tacrolimus (FK) had a similar fibrosis progression rate and alphaSMA and TGFbeta(1) expression. In conclusion, the accelerated fibrosis observed in LT patients with hepatitis C recurrence does not seem to be related to a greater amount of activated HSC and TGFbeta(1) expression in the grafts of these patients as compared to non-LT patients with chronic hepatitis C. In LT patients, the amount of activated HSC and TGFbeta(1) expression correlated with fibrosis stage and progression, without any apparent influence of the type of calcineurin inhibitor administered.     

The main features of central 5-HT1 receptors

The 5-HT1 receptor family comprises five different pharmacologic subtypes, designated 5-HT1A, 5-HT1B, 5-HT1C, 5-HT1D, and 5-HT1E, whose common property is to bind 5-HT with nanomolar affinity. Recent investigations with molecular biology approaches led to the cloning and sequencing of 5-HT1A receptors in the rat and in the human, and of the 5-HT1C receptor in the rat. Although the 5-HT1A and 5-HT1C protein binding subunits exhibit the same structure with seven hydrophobic transmembrane domains, an extracellular N terminal and an intracellular C tail, their respective amino-acid sequences are markedly different. Indeed, a higher degree of sequence homology is found between the 5-HT1C and 5-HT2 receptors than between the former and 5-HT1A receptors, suggesting that the 5-HT1C subtype in fact belongs to the 5-HT2 class of central 5-HT receptors. All other 5-HT1 receptor subtypes are negatively coupled to adenylyl cyclase, whereas the 5-HT1C subtype, like 5-HT2 receptors, is positively coupled to phospholipase C. The respective regional distributions and regulatory properties, as well as pending questions regarding the ultrastructural localization, synthesis, mutual interactions, and axonal flow of 5-HT1 receptor subtypes, are also discussed.     

Predicting spontaneous early neurological recovery after acute ischemic stroke

We assessed predictors of spontaneous early neurological recovery after acute ischemic stroke by means of multivariate analysis in a cohort of 1,473 consecutive patients treated at one academic center. At hospital discharge, spontaneous neurological improvement or good outcome was defined as grades 0-2 of the Rankin scale, and poor outcome (no improvement or in-hospital death) as grades 3-5. Spontaneous recovery of neurological deficit at the time of discharge from the hospital was observed in 16% of patients with cerebral infarction (n = 238). Dysarthria-clumsy hand syndrome improved in 44% of patients and was the only variable significantly associated with in-hospital functional recovery in three logistic regression models that in addition to lacunar syndromes, included demographic variables, cardiovascular risk factors, and clinical variables [odds ratio (OR) 2.56], neuroimaging findings (OR 2.48), and outcome data (OR 2.39), respectively. Clinical factors related to severity of infarction available at stroke onset have a predominant influence upon in-hospital outcome and may help clinicians to assess prognosis more accurately. Our work gives a contribution into prognostic factors after acute ischemic stroke. With regard to patterns of stroke, dysarthria-clumsy hand syndrome was a significant predictor of spontaneous in-hospital recovery in ischemic stroke patients.     

Propyl gallate delays senescence in Drosophila melanogaster

The effect of propyl gallate (PGL) on life span in Drosophila was investigated. Four groups of flies were supplemented as follows: group 1, no PGL; group 2, no PGL supplement until 28 days followed by 0.3% PGL for remaining life span; group 3, 0.3% PGL from 7 days to 28 days, then none for remaining life span; and group 4, 0.3% PGL from 7 days until death. In all cases, PGL significantly increased mean life span. The largest increase in mean life span (34.2%) was in the group receiving PGL for the entire life span (group 4). Increases of 14.6% and 14.7% were measured in groups 2 and 3, respectively.     

Natural infection of Oryctolagus cuniculus (Lagomorpha, Leporidae) by Gongylonema neoplasticum (Nematoda, Gongylonematidae) in Portugal

Gongylonema neoplasticum was identified in the oesophagus of 14 wild rabbits (Oryctolagus cuniculus) from Portugal. This is the first record of Gongylonema neoplasticum in a naturally infected lagomorph species in Europe. This paper presents the most relevant measurements of adult worms and some of their surface features seen by scanning electron microscopy. Epidemiological aspects of G. neoplasticum such as geographical distribution, host spectrum and biological features are discussed.     

The role of Serratia marcescens porins in antibiotic resistance

The outer membrane permeability of Serratia marcescens was studied by comparing porin-deficient mutants with their parental strains. Omp1-deficient strains were selected by moxalactam resistance, whereas mutants lacking the Omp2 porin were obtained by experimental infection with the SMP2 phage, whose primary receptor is the Omp2 porin. The role of porins was demonstrated in quinolone accumulation assays, where semiquantitative differences in accumulation were observed. Permeability coefficients to cephaloridine of Omp1 mutants were determined and compared with those of the parental strain. The clinical isolates S. marcescens HCPR1 and 866 showed 30- to 200-fold reduced permeability coefficients when Omp1 porin was absent.     

Relevance of HIV-1-specific CD4+ helper T-cell responses during structured treatment interruptions in patients with CD4+ T-cell nadir above 400/mm3

OBJECTIVES: To analyze the dynamics of both HIV-1-specific CD4 and CD8 T-cell responses during structured treatment interruptions (STIs) in chronically HIV-1-infected (CHI) patients and to correlate them with the viral set point achieved. METHODS: Forty-five early-stage CHI patients who were on highly active antiretroviral therapy (HAART) for at least 1 year and underwent STI were included. Plasma viral load (VL), peripheral blood mononuclear cell (PBMC) lymphoproliferative (LPR) response to HIV p24 protein, and HIV-1 epitope-specific interferon-gammarelease from CD8 T cells were measured over a minimum study period of 2 years. RESULTS: VL set point during final STI was both significantly lower than, and positively correlated to, baseline VL (P < 0.0001: mean VL reduction 0.77 log10, and r = 0.42, P = 0.004, respectively). CD4 LPRs to p24 increased significantly (P = 0.001) between day 0 of the first STI cycle and 4th STI but decreased thereafter. VL set point during final STI was significantly and negatively correlated with LPRs to p24 at both 2nd STI and 4th STI. Nevertheless, at week 52, 12 weeks after the end of the last STI, LPRs were weak and transient in all patients and were not correlated with VL set point. Moreover, the magnitude and breadth of HIV-1-specific CD8 T-cell responses increased significantly (P < 0.0001) between day 0 and week 52. The largest increases occurred during the final STI. Even though VL reached set point by week 12 of the final STI, HIV-1-specific CD8 T-cell responses did not stabilize but rather increased until the end of the follow-up and did not correlate with plasma VL (r = 0.01, P = 0.88). CONCLUSIONS: STIs do not lead to control of viral replication in CHI patients, probably due to the fact that boosted CTL responses lack strong and durable helper T-cell responses. To reset the VL set point, new approaches that effectively augment and preserve helper T-cell responses should be investigated.     

Mutation analysis of the SDHD gene in four kindreds with familial paraganglioma: description of one novel germline mutation.

The familial paraganglioma syndrome is an autosomal dominant disorder characterized by the presence of carotid body paragangliomas and, less frequently, paragangliomas of the glomus jugulare, glomus vagale, and adrenal pheochromocytomas. Germline mutations of the genes for succinate dehydrogenase subunits D, B, or C (SDHD, SDHB, SDHC) have been identified in some kindreds with familial paraganglioma. In this study, we report the clinicopathologic features of four different kindreds with familial paraganglioma, which were screened for germline mutations in the SDHD gene. DNA was obtained from tumor and normal tissue, as well as from peripheral blood. Mutation analysis was performed by single-strand conformation polymorphism analysis and DNA sequencing. SDHD germline mutations were detected in the affected family members of the four families, as well as in several asymptomatic carriers. An identical mutation in exon 4 of SDHD (334-337delACTG) was identified in two apparently unrelated kindreds. The third family showed a germline mutation in exon 2 (W43X). The mutations present in these three families had been previously described in Spanish families, suggesting a founder effect. The fourth family exhibited a mutation in exon 2 of SDHD (170-171delTT), which had not been previously identified. The affected family members of the four kindreds showed paragangliomas, located in the head and neck region, and all of them were benign. These results confirm that genetic testing of SDHD may be a powerful tool for the identification of the syndrome in patients with multiple or bilateral paragangliomas.     

Cathepsin B expression in colorectal carcinomas correlates with tumor progression and shortened patient survival.

Cathepsin B is a lysosomal cysteine proteinase that has the ability to degrade several extracellular matrix components at both neutral and acidic pH and has been implicated in the progression of several human and rodent tumors. We have studied the expression of cathepsin B in human colorectal tissues using a monospecific polyclonal rabbit antibody raised against human liver cathepsin B. In immunoblots of normal and neoplastic colorectal tissues this antibody specifically recognized only cathepsin B. We studied 101 cases of formalin-fixed, paraffin-embedded tissue (15 normal mucosa, 17 adenomas, and 69 carcinomas). Epithelial cells of normal mucosa and adenomas were either negative or showed a weak granular reactivity located in the paranuclear and apical cytoplasm of superficial cells. Small clusters of histiocytes were also positive in the region of the superficial area of the lamina propria. In carcinomas, increased expression of cathepsin B correlated with advanced stage of the disease. Increased immunoreactivity of cathepsin B in malignant cells was associated with either a diffuse cytoplasmic staining or was polarized to the basal pole of the cells. This is in contrast to the punctate paranuclear staining pattern observed in normal colonic mucosal cells. In tumor stromal cells, increased expression of the enzyme correlated with neoplastic progression. Expression of high levels of cathepsin B in the tumor epithelial cells was associated with a significantly shorter survival of the patients. In conclusion, our results indicate that cathepsin B expression is up-regulated in human colorectal carcinomas compared with normal mucosa and adenomas and correlates with tumor progression.