Journals
2009 EN
Viatonou Saturnin · Dramé Moustapha · Jolly Damien
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Objective To identify factors predictive of rapid cognitive decline (RCD) among elderly subjects aged 75 or over suffering from dementia. Methods The analysis concerned 250 patients drawn from the ‘Sujet Agé Fragile – Evaluation et Suivi’ (SAFES) cohort, presenting a dementia syndrome at inclusion and followed‐up for at least 1 year. RCD was defined as the loss of at least 3 points on the Mini‐Mental State Examination (MMSE) in the follow‐up period of 12 months. All patients underwent a standardised geriatric evaluation. Logistic regression was used to identify factors predictive of RCD. Results In the study sample, 84 patients (33.6%) presented RCD. The factors identified in multivariate analysis as predictive of RCD were: high level of education (OR = 7.8, 95% CI = [1.9–31.2], p = 0.004), risk of depression (OR = 1.8, 95% CI = [1.02–3.18], p = 0.048, and the initial MMSE score (OR = 1.1, 95% CI = [1.0–1.2], p = 0.002). Among subjects with a main caregiver ( n = 177), the predictive factors were malnutrition or risk thereof (OR = 4.2, 95% CI = [1.3–14.1], p = 0.02), risk of a fall (OR = 2.6, 95% CI = [1.1–6.1], p = 0.03, caregiver burden (OR = 2.6, 95% CI = [1.1–6.4], p = 0.04) and initial MMSE score (OR = 1.1, 95% CI = [1.0–1.3], p = 0.004). Conclusions As soon as dementia is diagnosed in elderly subjects, information should be collected about the subject's socioeconomic status, nutritional status, risk of falling, mood state, and caregiver burden. This would enable the provision of appropriate therapeutic care, and make it possible to adapt follow‐up in case of a risk of accelerated cognitive deterioration. Copyright © 2009 John Wiley & Sons, Ltd.
Journals
2009 EN
Galbois Arnaud · Thabut Dominique · Tazi Khalid A.
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High‐density lipoproteins (HDL) are known to neutralize lipopolysaccharide (LPS). Because patients with cirrhosis have lower HDL levels, this may contribute to LPS‐induced ex vivo monocyte overproduction of proinflammatory cytokines. However, the effects of HDL on cytokine production by monocytes from patients with cirrhosis have never been studied. The aim of this study was to determine the effects of HDL on LPS‐induced proinflammatory cytokine production in whole blood and isolated monocytes from patients with severe cirrhosis and controls. Plasma levels of HDL and cytokines were determined. The effects of reconstituted HDL (rHDL) on LPS‐induced cytokine production in whole blood were assessed by cytokine array and on tumor necrosis factor alpha (TNF‐α) and interleukin‐10 (IL‐10) production in isolated monocytes. Plasma HDL levels were significantly lower in patients with cirrhosis than in controls. Plasma levels of TNF‐α and IL‐6 were significantly higher in patients with cirrhosis than in controls. Incubation of rHDL with whole blood prevented LPS‐induced TNF‐α and IL‐6 overproduction in patients with cirrhosis. LPS‐induced TNF‐α production and CD14 expression were significantly more marked in cirrhotic monocytes than in control monocytes, and both decreased significantly after rHDL incubation. LPS‐induced down‐regulation of scavenger receptor, class B, type I (SR‐BI) expression was abolished in cirrhotic monocytes. Conclusions : This study shows that rHDL abolishes the LPS‐induced overproduction of proinflammatory cytokines in whole blood from patients with severe cirrhosis. These results were confirmed in isolated monocytes from these patients. This suggests that administration of rHDL might be a useful strategy for the treatment of cirrhosis to limit LPS‐induced cytokine overproduction. (H EPATOLOGY 2009;49:175‐184.)
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Journals
2009 EN
Dagher Ibrahim · Nguyen Tuan Huy · GroyerPicard MarieThérèse
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The feasibility of ex vivo gene therapy as an alternative to liver transplantation for the treatment of liver metabolic diseases needs to be analyzed in large animal models. This approach requires appropriate gene transfer vectors and effective hepatocyte engraftment. Lentiviral vectors have the ability to transduce nondividing differentiated cells, such as hepatocytes, and portal vein occlusion increases hepatocyte engraftment. We investigated whether reversible portal vein embolization combined with ex vivo lentivirus‐mediated gene transfer is an effective approach for successful hepatocyte engraftment in nonhuman primates and whether the transgene remains expressed in the long term in transplanted hepatocytes in situ . Simian hepatocytes were isolated after left lobe resection, and the left and right anterior portal branches of animals were embolized with absorbable material. Isolated hepatocytes were labeled with Hoechst dye or transduced in suspension with lentiviruses expressing green fluorescent protein under the control of the human apolipoprotein A‐II promoter and transplanted via the inferior mesenteric vein. The whole procedure was well tolerated. The embolized liver was revascularized within 2 weeks. The volume of nonembolized liver increased from 38.7% ± 0.8% before embolization to 55.9% ± 1% after embolization and hepatocytes significantly proliferated (10.5% ± 0.4% on day 3 after embolization). Liver repopulation after transplantation with Hoechst‐labeled hepatocytes was 7.4% ± 1.2%. Liver repopulation was 2.1% ± 0.2% with transduced hepatocytes, a proportion similar to that obtained with Hoechst‐labeled cells, given that the mean transduction efficacy of simian hepatocyte population was 34%. Transgene expression persisted at 16 weeks after transplantation. Conclusion: We have developed a new approach to improve hepatocyte engraftment and to express a transgene in the long term in nonhuman primates. This strategy could be suitable for clinical applications. (H EPATOLOGY 2009.)
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Journals
2009 EN
Moucari Rami · Mackiewicz Vincent · Lada Olivier
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Pegylated interferon alfa‐2a (PEG‐IFN) may induce sustained virological response (SVR) in 20% of hepatitis B e antigen (HBeAg)‐negative chronic hepatitis B (CHB) patients. In addition, loss of hepatitis B surface antigen (HBsAg) is achieved with a 10% yearly rate after treatment cessation in sustained responders. The aim of this study was to assess on‐treatment serum HBsAg kinetics to predict SVR in HBeAg‐negative patients treated with PEG‐IFN. Forty‐eight consecutive patients were treated with PEG‐IFN (180 μg/week) for 48 weeks. Serum hepatitis B virus (HBV) DNA (COBAS TaqMan) and HBsAg (Abbott Architect HBsAg QT assay) were assessed at baseline, during treatment (weeks 12, 24, and 48), and during follow‐up (weeks 72 and 96). SVR was defined as undetectable serum HBV DNA (<70 copies/mL) 24 weeks after treatment cessation. Twenty‐five percent of patients achieved SVR. They were not different from those who failed treatment regarding age, sex, ethnicity, HBV genotype, baseline serum HBV DNA and HBsAg levels, or liver histology. During treatment, serum HBsAg levels decreased only in patients who developed SVR, with mean decreases of 0.8 ± 0.5, 1.5 ± 0.6, and 2.1 ± 1.2 log 10 IU/mL at weeks 12, 24, and 48, respectively. A decrease of 0.5 and 1 log 10 IU/mL in serum HBsAg levels at weeks 12 and 24 of therapy, respectively, had high predictive values of SVR (negative predictive value [NPV] 90%, positive predictive value [PPV] 89% for week 12; NPV 97%, PPV 92% for week 24). HBsAg loss was observed in three patients, all with SVR. Conclusion: Early serum HBsAg drop has high predictive values of SVR to PEG‐IFN in HBeAg‐negative CHB patients. Serum quantitative HBsAg may be a useful tool to optimize the management of PEG‐IFN therapy in these patients. (H EPATOLOGY 2009.)
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Journals
2009 EN
Lewin Maïté · Vilgrain Valérie · Ozenne Violaine
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The development of sclerosing cholangitis (SC) is observed in up to 50% of children followed up for autoimmune hepatitis (AIH). In adults, the prevalence is less known, although a recent study found evidence of SC in 10% of AIH patients using magnetic resonance cholangiopancreatography (MRCP). The aim of this study was to assess prospectively the prevalence of SC in adults with AIH. Fifty‐nine consecutive patients with AIH diagnosed according to International Autoimmune Hepatitis Group score (women, 71%; mean age, 48 years; cirrhosis, 23%) underwent both MRCP and percutaneous liver biopsy. Twenty‐seven patients with cirrhosis of nonbiliary or non‐autoimmune etiology served as controls. Fourteen AIH patients (24%) showed mild MRCP abnormalities of intrahepatic bile ducts (IHBDs). None had abnormal common bile duct or convincing evidence of SC on MRCP or biopsy. A diagnosis of overlapping SC was nevertheless retained in one patient with MRCP abnormalities who subsequently developed symptomatic cholestasis despite corticosteroid therapy. Fibrosis score was the only independent parameter associated with bile duct abnormalities on MRCP (odds ratio 2.4; 95% confidence interval 1.4‐4.7) and the percentage of patients with IHBD MRCP abnormalities was not different among F3‐F4 AIH patients (n = 24) and cirrhotic controls (46% versus 59%; NS). Conclusion: In this cohort of adult patients with AIH, the prevalence of SC was much lower than previously reported (1.7%). Mild MRCP abnormalities of IHBD were seen in a quarter of patients, but these abnormalities resulted from hepatic fibrosis and not SC. In the absence of cholestatic presentation, MRCP screening does not seem justified in adult‐onset AIH. (H EPATOLOGY 2009.)
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2009 EN
Nahon Pierre · Sutton Angela · Rufat Pierre
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Alcohol increases reactive oxygen species (ROS) formation in hepatocyte mitochondria and by reduced nicotinamide adenine dinucleotide phosphate oxidases and myeloperoxidase (MPO) in Kupffer cells and liver‐infiltrating neutrophils. Manganese superoxide dismutase (MnSOD) converts superoxide anion into hydrogen peroxide, which, unless detoxified by glutathione peroxidase or catalase (CAT), can form the hydroxyl radical with iron. Our aim was to determine whether Ala16Val‐superoxide dismutase 2 (SOD2), G‐463A‐MPO, or T‐262C‐CAT dimorphisms modulate the risks of hepatocellular carcinoma (HCC) and death in alcoholic cirrhosis. Genotypes and the hepatic iron score were assessed in 190 prospectively followed patients with alcoholic cirrhosis. During follow‐up (61.1 ± 2.7 months), 51 patients developed HCC, and 71 died. The T‐262C‐CAT dimorphism did not modify hepatic iron, HCC, or death. The GG‐MPO genotype did not modify iron but increased the risks of HCC and death. The hazard ratio (HR) was 4.7 (2.1–10.1) for HCC and 3.6 (1.9–6.7) for death. Carriage of one or two Ala‐SOD2 allele(s) was associated with higher liver iron scores and higher risks of HCC and death. The 5‐year incidence of HCC was 34.4% in patients with both the GG‐MPO genotype and one or two Ala‐SOD2 alleles, 5.1% in patients with only one of these two traits, and 0% in patients with none of these traits. Corresponding 5‐year death rates were 37.6%, 11.6%, and 5%. Conclusion: The combination of the GG‐MPO genotype (leading to high MPO expression) and at least one Ala‐SOD2 allele (associated with high liver iron score) markedly increased the risks of HCC occurrence and death in patients with alcoholic cirrhosis. (H EPATOLOGY 2009.)
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Journals
2009 EN
Lushnikova Irina · Skibo Galina · Muller Dominique
+1 more
Patterns of activity that induce synaptic plasticity at excitatory synapses, such as long‐term potentiation, result in structural remodeling of the postsynaptic spine, comprising an enlargement of the spine head and reorganization of the postsynaptic density (PSD). Furthermore, spine synapses represent complex functional units in which interaction between the presynaptic varicosity and the postsynaptic spine is also modulated by surrounding astroglial processes. To investigate how activity patterns could affect the morphological interplay between these three partners, we used an electron microscopic (EM) approach and 3D reconstructions of excitatory synapses to study the activity‐related morphological changes underlying induction of synaptic potentiation by theta burst stimulation or brief oxygen/glucose deprivation episodes in hippocampal organotypic slice cultures. EM analyses demonstrated that the typical glia‐synapse organization described in in vivo rat hippocampus is perfectly preserved and comparable in organotypic slice cultures. Three‐dimensional reconstructions of synapses, classified as simple or complex depending upon PSD organization, showed significant changes following induction of synaptic potentiation using both protocols. The spine head volume and the area of the PSD significantly enlarged 30 min and 1 h after stimulation, particularly in large synapses with complex PSD, an effect that was associated with a concomitant enlargement of presynaptic terminals. Furthermore, synaptic activity induced a pronounced increase of the glial coverage of both pre‐ and postsynaptic structures, these changes being prevented by application of the NMDA receptor antagonist D‐2‐amino‐5‐phosphonopentanoic acid. These data reveal dynamic, activity‐dependent interactions between glial processes and pre‐ and postsynaptic partners and suggest that glia can participate in activity‐induced structural synapse remodeling. © 2009 Wiley‐Liss, Inc.
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Journals
2009 EN
Seebach Dieter · Widmer Hans · Capone Stefania
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The previously reported ( Helv. Chim. Acta 2008 , 91 , 2035) derivatives of octreotide ( 1 ) with a (CF 3 )‐Trp substitution, i.e. , 3 , and with open‐chain structures, i.e. , 2, 4 , and 5 , have been tested for their affinities to hsst 1–5 receptors and subjected to a detailed NMR analysis. Their affinities vary from 15 n M to 5 μ M , as compared to 0.6 n M to 0.8 μ M for octreotide itself ( Table 1 ). This decreased bioactivity may have had to be expected for the open‐chain compounds 4 and 5 ; possible reasons for this decrease in the case of CF 3 derivative of octreotide, 3 , are discussed. NMR Analysis ( Tables 2 and 3 ) provides evidence for increased dynamics of all new derivatives 2 – 5 . The dynamics of the octreotide molecule 1 was analyzed by (natural‐abundance) longitudinal 13 C‐T 1 ‐relaxation time measurements ( Table 4 ), from which the conclusion is drawn that the backbone of the macrocycle is rather rigid on the time scale of this method.
Journals
2009 EN
Koolen David A. · Pfundt Rolph · de Leeuw Nicole
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Microarray‐based copy number analysis has found its way into routine clinical practice, predominantly for the diagnosis of patients with unexplained mental retardation. However, the clinical interpretation of submicroscopic copy number variants (CNVs) is complicated by the fact that many CNVs are also present in the general population. Here we introduce and discuss a workflow that can be used in routine diagnostics to assess the clinical significance of the CNVs identified. We applied this scheme to our cohort of 386 individuals with unexplained mental retardation tested using a genome‐wide tiling‐resolution DNA microarray and to 978 additional patients with mental retardation reported in 15 genome‐wide microarray studies extracted from the literature. In our cohort of 386 patients we identified 25 clinically significant copy number losses (median size 2.6 Mb), nine copy number gains (median size 2.0 Mb), and one mosaic numerical chromosome aberration. Accordingly, the overall diagnostic yield of clinically significant CNVs was 9.1%. Taken together, our cohort and the patients described in the literature include a total of 1,364 analyses of DNA copy number in which a total of 11.2% (71.9% losses, 19.6% gains, 8.5% complex) could be identified, reflecting the overall diagnostic yield of clinically significant CNVs in individuals with unexplained mental retardation. Hum Mutat 0, 1–10, 2008. © 2008 Wiley‐Liss, Inc.
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Journals
2009 EN
Warcoin Mathilde · Lespinasse James · Despouy Gilles
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Biallelic mutations in the NBN/NBS1 gene are the cause of Nijmegen breakage syndrome (NBS), a severe pediatric disease characterized by dysmorphy with a bird‐like face, microcephaly, growth retardation, immune deficiency, and proneness to cancer. We here report two adult siblings that are compound heterozygotes for two previously unreported NBN nonsense mutations. These patients presented with the unique clinical symptom of fertility defects. Contrasting with the absence of any developmental abnormality, biological analyses revealed defects similar to those observed in NBS patients, including chromosomal instability, cellular hyperradiosensitivity and checkpoint defects as measured by radioresistant DNA synthesis (RDS). NBN mutations should thus be considered a new cause of infertility, and should be searched for if associated with the biological abnormalities of NBS. Hum Mutat 0, 1–7, 2008. © 2008 Wiley‐Liss, Inc.
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