All-Cause Mortality and Liver-Related Outcomes Following Successful Antiviral Treatment for Chronic Hepatitis C

BACKGROUND: Antiviral therapy for the hepatitis C virus (HCV) reduces all-cause and liver-related morbidity and mortality. Few studies are available from populations with multiple medical and psychiatric comorbidities where the impact of successful antiviral therapy might be limited. AIM: The purpose of this study was to determine the effect of sustained virologic response (SVR) on all-cause and liver-related mortality in a cohort of HCV patients treated in an integrated hepatitis/mental health clinic. METHODS: This was a retrospective review of all patients who initiated antiviral treatment for chronic HCV between January 1, 1997 and December 31, 2009. Cox regression analysis was used to determine factors involved in all-cause mortality, liver-related events and hepatocellular carcinoma. RESULTS: A total of 536 patients were included in the analysis. Median follow-up was 7.5 years. Liver and non-liver-related mortality occurred in 2.7 and 5.0 % of patients with SVR and in 17.8 and 6.4 % of patients without SVR. In a multivariate analysis, SVR was the only factor associated with reduced all-cause mortality (HR 0.47; 95 % CI 0.26-0.85; p = 0.012) and reduced liver-related events (HR 0.23; 95 % CI 0.08-0.66, p = 0.007). Having stage 4 liver fibrosis increased all-cause mortality (HR 2.50; 95 % CI 1.23-5.08; p = 0.011). Thrombocytopenia at baseline (HR 2.66; 95 % CI 1.22-5.79; p = 0.014) and stage 4 liver fibrosis (HR 4.87; 95 % CI 1.62-14.53; p = 0.005) increased liver-related events. CONCLUSIONS: Despite significant medical and psychiatric comorbidities, SVR markedly reduced liver-related outcomes without a significant change in non-liver-related mortality after a median follow-up of 7.5 years.

Statement on smoking cessation in COPD and other pulmonary diseases and in smokers with comorbidities who find it difficult to quit.

Chronic obstructive pulmonary disease (COPD), lung cancer, asthma and pulmonary tuberculosis are common pulmonary diseases that are caused or worsened by tobacco smoking. Growing observational evidence suggests that symptoms and prognosis of these conditions improve upon smoking cessation. Despite increasing numbers of (small) randomised controlled trials suggesting intensive smoking cessation treatments work in people with pulmonary diseases many patients are not given specific advice on the benefits or referred for intensive cessation treatments and, therefore, continue smoking. This is a qualitative review regarding smoking cessation in patients with COPD and other pulmonary disorders, written by a group of European Respiratory Society experts. We describe the epidemiological links between smoking and pulmonary disorders, the evidence for benefits of stopping smoking, how best to assess tobacco dependence and what interventions currently work best to help pulmonary patients quit. Finally, we describe characteristics and management of any "hardcore" smoker who finds it difficult to quit with standard approaches.

Novel targeted therapies for eosinophil-associated diseases and allergy.

Eosinophil-associated diseases often present with life-threatening manifestations and/or chronic organ damage. Currently available therapeutic options are limited to a few drugs that often have to be prescribed on a lifelong basis to keep eosinophil counts under control. In the past 10 years, treatment options and outcomes in patients with clonal eosinophilic and other eosinophilic disorders have improved substantially. Several new targeted therapies have emerged, addressing different aspects of eosinophil expansion and inflammation. In this review, we discuss available and currently tested agents as well as new strategies and drug targets relevant to both primary and secondary eosinophilic diseases, including allergic disorders.

Evidence for chronic low-grade systemic inflammation in individuals with agoraphobia from a population-based prospective study.

BACKGROUND Anxiety disorders have been linked to an increased risk of incident coronary heart disease in which inflammation plays a key pathogenic role. To date, no studies have looked at the association between proinflammatory markers and agoraphobia. METHODS In a random Swiss population sample of 2890 persons (35-67 years, 53% women), we diagnosed a total of 124 individuals (4.3%) with agoraphobia using a validated semi-structured psychiatric interview. We also assessed socioeconomic status, traditional cardiovascular risk factors (i.e., body mass index, hypertension, blood glucose levels, total cholesterol/high-density lipoprotein-cholesterol ratio), and health behaviors (i.e., smoking, alcohol consumption, and physical activity), and other major psychiatric diseases (other anxiety disorders, major depressive disorder, drug dependence) which were treated as covariates in linear regression models. Circulating levels of inflammatory markers, statistically controlled for the baseline demographic and health-related measures, were determined at a mean follow-up of 5.5 ± 0.4 years (range 4.7 - 8.5). RESULTS Individuals with agoraphobia had significantly higher follow-up levels of C-reactive protein (p = 0.007) and tumor-necrosis-factor-α (p = 0.042) as well as lower levels of the cardioprotective marker adiponectin (p = 0.032) than their non-agoraphobic counterparts. Follow-up levels of interleukin (IL)-1β and IL-6 did not significantly differ between the two groups. CONCLUSIONS Our results suggest an increase in chronic low-grade inflammation in agoraphobia over time. Such a mechanism might link agoraphobia with an increased risk of atherosclerosis and coronary heart disease, and needs to be tested in longitudinal studies.

Microbiota Promotes Chronic Pulmonary Inflammation by Enhancing IL-17A and Autoantibodies

RATIONALE Changes in the pulmonary microbiota are associated with progressive respiratory diseases including chronic obstructive pulmonary disease. Whether there is a causal relationship between these changes and disease progression remains unknown. OBJECTIVE To investigate the link between an altered microbiota and disease, we utilized a model of chronic lung inflammation in specific pathogen free (SPF) mice and mice depleted of microbiota by antibiotic treatment or devoid of a microbiota (axenic). METHODS Mice were challenged with LPS/elastase intranasally over 4 weeks, resulting in a chronically inflamed and damaged lung. The ensuing cellular infiltration, histological damage and decline in lung function were quantified. MEASUREMENTS AND MAIN RESULTS Similar to human disease, the composition of the pulmonary microbiota was altered in disease animals. We found that the microbiota richness and diversity were decreased in LPS/Elastase-treated mice, with an increased representation of the genera Pseudomonas, Lactobacillus and a reduction in Prevotella. Moreover, the microbiota was implicated in disease development as mice depleted of microbiota exhibited an improvement in lung function, reduction in airway inflammation, decrease in lymphoid neogenesis and auto-reactive antibody responses. The absence of microbial cues also markedly decreased the production of IL-17A, whilst intranasal transfer of fluid enriched with the pulmonary microbiota isolated from diseased mice enhanced IL-17A production in the lungs of antibiotic treated or axenic recipients. Finally, in mice harboring a microbiota, neutralizing IL-17A dampened inflammation and restored lung function. CONCLUSIONS Collectively, our data indicate that host-microbial cross-talk promotes inflammation and could underlie the chronicity of inflammatory lung diseases.

Use of pneumococcal vaccine in people with chronic disease in United States

Objective. The risk of complications and deaths related to pneumococcal infections is high among high risk population (i.e. those with chronic diseases such as diabetes or asthma), despite current immunization recommendations. The aim of this study is to evaluate the use of pneumonia vaccine in adults with and without diabetes or asthma by year of age and whether immunization practices conform to policy recommendations. ^ Methods. Data were drawn from 2005 Behavioral Risk Factor Surveillance Study. Age specific estimated counts and proportions of pneumonia vaccination status were computed. The association of socio-demographic factors with vaccination status was estimated from multiple logistic regression and results were presented for adults (18-64yrs) and elderly (65 or older). ^ Results. Overall 12.3% of the adults and 61.5% of elderly reported ever received pneumonia vaccine. 66.8% of diabetics and 72.6% of asthmatics received the vaccine among elderly. 33.4% of diabetics and 21.6% of asthmatics received the vaccine among adults. These numbers are far away from Healthy people 2010 objective coverage rates of 90% for elderly and 60% for high risk adults. Though diabetes was one of the recommendations for the pneumonia vaccine still the status was less than 70% even at older ages. Although asthma was not an indication for pneumonia vaccine, asthmatics still achieved 50% level by an early age of 60 and reached up to 80% at as early as 75 years. In those having both asthma and diabetes, although the curve reaches to 50% level at a very early age of 40yrs, it is not stable until the age of 55 and percentages reached to as high as 90% in older ages. Odds of receiving pneumonia vaccine were high in individuals with diabetes or asthma in both the age groups. But the odds were stronger for diabetics in adults compared to those in the elderly [2.24 CI (2.08-2.42) and 1.32 CI (1.18-1.47)]. The odds were slightly higher in adults than in elderly for asthmatics [1.92 CI (1.80-2.04) and 1.73 CI (1.50-2.00)].The likelihood of vaccination also differed by gender, ethnicity, marital status, income category, having a health insurance, current employment, physician visit in last year, reporting of good to excellent health and flu vaccine status. ^ Conclusion. There is a very high proportion of high risk adults and elderly that remain unvaccinated. Given the proven efficacy and safety of vaccine there is a need for interventions targeting the barriers for under-vaccination with more emphasis on physician knowledge and practice as well as the recipient attitudes.^

Comparing experience of diabetes care with chronic illness care in the primary care clinic using the Patient Assessment of Chronic Illness Care (PACIC)

Purpose. The overall purpose of the study was to evaluate the patient experience relevant to the Chronic Care Model as measured by the PACIC. Chronic illness care of patients with diabetes was compared to those with other chronic illnesses. In addition, chronic illness care of Hispanics was compared to those of other race/ethnicity. ^ Methods. The setting of this study was 20 primary care practices located in San Antonio, TX. The subjects in this study were consecutive adult patients age >18 yrs. Data was collected via a survey (PACIC) administered to 40-60 consecutive adult patients in each primary care clinic who presented for a scheduled appointment. ^ Results. Patient experience of the Chronic Care Model is different among those with diabetes than those with other chronic diseases: those with diabetes report a higher PACIC score. (P = 0.012) Although Hispanic patients report a higher PACIC score, patient experience of the Chronic Care Model among Hispanic patients is not significantly different than that of patients of other race/ethnicity regardless of chronic disease. (P = 0.053) After controlling for the patient characteristics of age, education, health status, and race/ethnicity, the diabetes status of the patient remains significantly associated with the outcome, the PACIC score. (P = 0.033) ^ Conclusions. Diabetes is associated with a greater experience of the Chronic Care model. Contributing factors to diabetes patients’ greater experience of the Chronic Care Model include the greater heath care use and higher self-care needs unique to individuals with diabetes. Special consideration must be given to the specific needs diabetic patients to ensure effective interventions, higher patient education, greater patient compliance, and lower health care costs. ^

BIOLOGICAL MECHANISMS AND CLINICAL IMPLICATIONS OF BCR-ABL-INDUCED MITOCHONDRIAL OXIDATIVE STRESS AND CELL SURVIVAL IN CHRONIC MYELOID LEUKEMIA

Chronic myeloid leukemia (CML), a myeloproliferative disorder, represents approximately 15-20% of all adult leukemia. The development of CML is clearly linked to the constitutively active protein-tyrosine kinase BCR-ABL, which is encoded by BCR-ABL fusion gene as the result of chromosome 9/22 translocation (Philadelphia chromosome). Previous studies have demonstrated that oxidative stress-associated genetic, metabolic and biological alterations contribute to CML cell survival and drug refractory. Mitochondria and NAD(P)H oxidase (NOX) are the major sources of BCR-ABL-induced cellular reactive oxygen species (ROS) production. However, it is still unknown how CML cells maintain the altered redox status, while escaping from the persistent oxidative stress-induced cell death. Therefore, elucidation of the mechanisms by which CML cells cope with oxidative stress will provide new insights into CML leukemogenesis. The major goal of this study is to identify the survival factors protecting CML cells against oxidative stress and develop novel therapeutic strategies to overcome drug resistance. Several experimental models were used to test CML cell redox status and cellular sensitivity to oxidative stress, including BCR-ABL inducible cell lines, BCR-ABL stably transformed cell lines and BCR-ABL-expressing CML blast crisis cells with differential BCL-XL/BCL-2 expressions. Additionally, an artificial CML cell model with heterogenic BCL-XL/BCL-2 expression was established to assess the correlation between differential survival factor expression patterns and cell sensitivity to Imatinib and oxidative stress. In this study, BCL-XL and GSH have been identified as the major survival factors responsive to BCR-ABL-promoted cellular oxidative stress and play a dominant role in regulating the threshold of oxidative stress-induced apoptosis. Cell survival factors BCL-XL and BCL-2 differentially protect mitochondria under oxidative stress. BCL-XL is an essential survival factor in preventing excessive ROS-induced cell death while BCL-2 seems to play a relatively minor role. Furthermore, the redox modulating reagent β-phenethyl isothiocyanate (PEITC) has been found to efficiently deplete GSH and induce potent cell killing effects in drug-resistant CML cells. Combination of PEITC with BCL-XL/BCL2 inhibitor ABT737 or suppression of BCL-XL by BCR-ABL inhibitor Gleevec dramatically sensitizes CML cells to apoptosis. These results have suggested that elevation of BCL-XL and cellular GSH are important for the development of CML, and that redox-directed therapy is worthy of further clinical investigations in CML.

A multidisciplinary reference framework to support innovative design, implementation and assessment of chronic care models

Hoy en día, por primera vez en la historia, la mayor parte de la población podrá vivir hasta los sesenta años y más (United Nations, 2015). Sin embargo, todavía existe poca evidencia que demuestre que las personas mayores, estén viviendo con mejor salud que sus padres, a la misma edad, ya que la mayoría de los problemas de salud en edades avanzadas están asociados a las enfermedades crónicas (WHO, 2015). Los sistemas sanitarios de los países desarrollados funcionan adecuadamente cuando se trata del cuidado de enfermedades agudas, pero no son lo suficientemente eficaces en la gestión de las enfermedades crónicas. Durante la última década, se han realizado esfuerzos para mejorar esta gestión, por medio de la utilización de estrategias de prevención y de reenfoque de la provisión de los servicios de atención para la salud (Kane et al. 2005). Según una revisión sistemática de modelos de cuidado de salud, comisionada por el sistema nacional de salud Británico, pocos modelos han conceptualizado cuáles son los componentes que hay que utilizar para proporcionar un cuidado crónico efectivo, y estos componentes no han sido suficientemente estructurados y articulados. Por lo tanto, no hay suficiente evidencia sobre el impacto real de cualquier modelo existente en la actualidad (Ham, 2006). Las innovaciones podrían ayudar a conseguir mejores diagnósticos, tratamientos y gestión de pacientes crónicos, así como a dar soporte a los profesionales y a los pacientes en el cuidado. Sin embargo, la forma en las que estas innovaciones se proporcionan no es lo suficientemente eficiente, efectiva y amigable para el usuario. Para mejorar esto, hace falta crear equipos de trabajo y estrategias multidisciplinares. En conclusión, hacen falta actividades que permitan conseguir que las innovaciones sean utilizadas en los sistemas de salud que quieren mejorar la gestión del cuidado crónico, para que sea posible: 1) traducir la “atención sanitaria basada en la evidencia” en “conocimiento factible”; 2) hacer frente a la complejidad de la atención sanitaria a través de una investigación multidisciplinaria; 3) identificar una aproximación sistemática para que se establezcan intervenciones innovadoras en el cuidado de salud. El marco de referencia desarrollado en este trabajo de investigación es un intento de aportar estas mejoras. Las siguientes hipótesis han sido propuestas: Hipótesis 1: es posible definir un proceso de traducción que convierta un modelo de cuidado crónico en una descripción estructurada de objetivos, requisitos e indicadores clave de rendimiento. Hipótesis 2: el proceso de traducción, si se ejecuta a través de elementos basados en la evidencia, multidisciplinares y de orientación económica, puede convertir un modelo de cuidado crónico en un marco descriptivo, que define el ciclo de vida de soluciones innovadoras para el cuidado de enfermedades crónicas. Hipótesis 3: es posible definir un método para evaluar procesos, resultados y capacidad de desarrollar habilidades, y asistir equipos multidisciplinares en la creación de soluciones innovadoras para el cuidado crónico. Hipótesis 4: es posible dar soporte al desarrollo de soluciones innovadoras para el cuidado crónico a través de un marco de referencia y conseguir efectos positivos, medidos en indicadores clave de rendimiento. Para verificar las hipótesis, se ha definido una aproximación metodológica compuesta de cuatro Fases, cada una asociada a una hipótesis. Antes de esto, se ha llevado a cabo una “Fase 0”, donde se han analizado los antecedentes sobre el problema (i.e. adopción sistemática de la innovación en el cuidado crónico) desde una perspectiva multi-dominio y multi-disciplinar. Durante la fase 1, se ha desarrollado un Proceso de Traducción del Conocimiento, elaborado a partir del JBI Joanna Briggs Institute (JBI) model of evidence-based healthcare (Pearson, 2005), y sobre el cual se han definido cuatro Bloques de Innovación. Estos bloques consisten en una descripción de elementos innovadores, definidos en la fase 0, que han sido añadidos a los cuatros elementos que componen el modelo JBI. El trabajo llevado a cabo en esta fase ha servido también para definir los materiales que el proceso de traducción tiene que ejecutar. La traducción que se ha llevado a cabo en la fase 2, y que traduce la mejor evidencia disponible de cuidado crónico en acción: resultado de este proceso de traducción es la parte descriptiva del marco de referencia, que consiste en una descripción de un modelo de cuidado crónico (se ha elegido el Chronic Care Model, Wagner, 1996) en términos de objetivos, especificaciones e indicadores clave de rendimiento y organizada en tres ciclos de innovación (diseño, implementación y evaluación). Este resultado ha permitido verificar la segunda hipótesis. Durante la fase 3, para demostrar la tercera hipótesis, se ha desarrollado un método-mixto de evaluación de equipos multidisciplinares que trabajan en innovaciones para el cuidado crónico. Este método se ha creado a partir del método mixto usado para la evaluación de equipo multidisciplinares translacionales (Wooden, 2013). El método creado añade una dimensión procedural al marco. El resultado de esta fase consiste, por lo tanto, en una primera versión del marco de referencia, lista para ser experimentada. En la fase 4, se ha validado el marco a través de un caso de estudio multinivel y con técnicas de observación-participante como método de recolección de datos. Como caso de estudio se han elegido las actividades de investigación que el grupo de investigación LifeStech ha desarrollado desde el 2008 para mejorar la gestión de la diabetes, actividades realizadas en un contexto internacional. Los resultados demuestran que el marco ha permitido mejorar las actividades de trabajo en distintos niveles: 1) la calidad y cantidad de las publicaciones; 2) se han conseguido dos contratos de investigación sobre diabetes: el primero es un proyecto de investigación aplicada, el segundo es un proyecto financiado para acelerar las innovaciones en el mercado; 3) a través de los indicadores claves de rendimiento propuestos en el marco, una prueba de concepto de un prototipo desarrollado en un proyecto de investigación ha sido transformada en una evaluación temprana de una intervención eHealth para el manejo de la diabetes, que ha sido recientemente incluida en Repositorio de prácticas innovadoras del Partenariado de Innovación Europeo en Envejecimiento saludable y activo. La verificación de las 4 hipótesis ha permitido demonstrar la hipótesis principal de este trabajo de investigación: es posible contribuir a crear un puente entre la atención sanitaria y la innovación y, por lo tanto, mejorar la manera en que el cuidado crónico sea procurado en los sistemas sanitarios. ABSTRACT Nowadays, for the first time in history, most people can expect to live into their sixties and beyond (United Nations, 2015). However, little evidence suggests that older people are experiencing better health than their parents, and most of the health problems of older age are linked to Chronic Diseases (WHO, 2015). The established health care systems in developed countries are well suited to the treatment of acute diseases but are mostly inadequate for dealing with CDs. Healthcare systems are challenging the burden of chronic diseases by putting more emphasis on the prevention of disease and by looking for new ways to reorient the provision of care (Kane et al., 2005). According to an evidence-based review commissioned by the British NHS Institute, few models have conceptualized effective components of care for CDs and these components have been not structured and articulated. “Consequently, there is limited evidence about the real impact of any of the existing models” (Ham, 2006). Innovations could support to achieve better diagnosis, treatment and management for patients across the continuum of care, by supporting health professionals and empowering patients to take responsibility. However, the way they are delivered is not sufficiently efficient, effective and consumer friendly. The improvement of innovation delivery, involves the creation of multidisciplinary research teams and taskforces, rather than just working teams. There are several actions to improve the adoption of innovations from healthcare systems that are tackling the epidemics of CDs: 1) Translate Evidence-Based Healthcare (EBH) into actionable knowledge; 2) Face the complexity of healthcare through multidisciplinary research; 3) Identify a systematic approach to support effective implementation of healthcare interventions through innovation. The framework proposed in this research work is an attempt to provide these improvements. The following hypotheses have been drafted: Hypothesis 1: it is possible to define a translation process to convert a model of chronic care into a structured description of goals, requirements and key performance indicators. Hypothesis 2: a translation process, if executed through evidence-based, multidisciplinary, holistic and business-oriented elements, can convert a model of chronic care in a descriptive framework, which defines the whole development cycle of innovative solutions for chronic disease management. Hypothesis 3: it is possible to design a method to evaluate processes, outcomes and skill acquisition capacities, and assist multidisciplinary research teams in the creation of innovative solutions for chronic disease management. Hypothesis 4: it is possible to assist the development of innovative solutions for chronic disease management through a reference framework and produce positive effects, measured through key performance indicators. In order to verify the hypotheses, a methodological approach, composed of four Phases that correspond to each one of the stated hypothesis, was defined. Prior to this, a “Phase 0”, consisting in a multi-domain and multi-disciplinary background analysis of the problem (i.e.: systematic adoption of innovation to chronic care), was carried out. During phase 1, in order to verify the first hypothesis, a Knowledge Translation Process (KTP) was developed, starting from the JBI Joanna Briggs Institute (JBI) model of evidence-based healthcare was used (Pearson, 2005) and adding Four Innovation Blocks. These blocks represent an enriched description, added to the JBI model, to accelerate the transformation of evidence-healthcare through innovation; the innovation blocks are built on top of the conclusions drawn after Phase 0. The background analysis gave also indication on the materials and methods to be used for the execution of the KTP, carried out during phase 2, that translates the actual best available evidence for chronic care into action: this resulted in a descriptive Framework, which is a description of a model of chronic care (the Chronic Care Model was chosen, Wagner, 1996) in terms of goals, specified requirements and Key Performance Indicators, and articulated in the three development cycles of innovation (i.e. design, implementation and evaluation). Thanks to this result the second hypothesis was verified. During phase 3, in order to verify the third hypothesis, a mixed-method to evaluate multidisciplinary teams working on innovations for chronic care, was created, based on a mixed-method used for the evaluation of Multidisciplinary Translational Teams (Wooden, 2013). This method adds a procedural dimension to the descriptive component of the Framework, The result of this phase consisted in a draft version of the framework, ready to be tested in a real scenario. During phase 4, a single and multilevel case study, with participant-observation data collection, was carried out, in order to have a complete but at the same time multi-sectorial evaluation of the framework. The activities that the LifeStech research group carried out since 2008 to improve the management of diabetes have been selected as case study. The results achieved showed that the framework allowed to improve the research activities in different directions: the quality and quantity of the research publications that LifeStech has issued, have increased substantially; 2 project grants to improve the management of diabetes, have been assigned: the first is a grant funding applied research while the second is about accelerating innovations into the market; by using the assessment KPIs of the framework, the proof of concept validation of a prototype developed in a research project was transformed into an early stage assessment of innovative eHealth intervention for Diabetes Management, which has been recently included in the repository of innovative practice of the European Innovation Partnership on Active and Health Ageing initiative. The verification of the 4 hypotheses lead to verify the main hypothesis of this research work: it is possible to contribute to bridge the gap between healthcare and innovation and, in turn, improve the way chronic care is delivered by healthcare systems.

Biological stress systems, adverse life events and the onset of chronic multisite musculoskeletal pain : a 6-year cohort study

Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.

First National Conference on Chronic Disease Prevention and Control : identifying effective strategies : September 9-11, 1986, Atlanta, Ga. : conference summary /

"March 1987."

Facilities and services for long-term chronic illness and convalescent care in the metropolitan St. Louis area; a study of present bed availabilities and future requirements for long-term care in chronic hospitals, chronic care units of general hospitals and skilled nursing homes.

Includes bibliography.

Steatosis in chronic hepatitis C: Association with increased messenger RNA expression of collagen I, tumor necrosis factor-α and cytochrome P450 2E1

Background: Increased levels of tumor necrosis factor (TNF)-alpha and oxidative stress have been implicated as factors contributing to hepatic injury in fatty liver diseases. As steatosis is associated with an accelerated progression of fibrosis in chronic hepatitis C (HCV), we hypothesized that the messenger (m)RNA expression of genes involved with the production of reactive oxygen species, inflammation and cellular injury would be increased in liver tissue from subjects with steatosis and chronic HCV. Methods: Real-time polymerase chain reaction was performed to determine relative mRNA expression levels of collagen I, TNF-alpha, cytochrome P450 2E1 (CYP 2E1), transforming growth factor-beta1 and CD14 in liver biopsies from 38 patients with chronic HCV. The mRNA expression levels were compared between subjects with and without steatosis, fibrosis, and inflammation. Results: Multivariate analysis demonstrated that collagen I mRNA expression was increased by 199% in steatosis (P = 0.02), 85% in moderate to severe fibrosis (P = 0.02) and 157% in inflammation (P = 0.03). Livers of patients with steatosis also had an increase in TNF-alpha mRNA expression by 50% (P = 0.03) and CYP 2E1 expression by 37% (P = 0.04) compared with non-steatotic livers. Tumor necrosis factor-alpha protein was localized to Kupffer cells, bile ducts and portal inflammatory cells by immunohistochemistry. Conclusion: Increased expression of TNF-alpha may be involved in the pathogenesis of liver injury and progression of fibrosis in individuals who have steatosis in association with chronic HCV. (C) 2003 Blackwell Publishing Asia Pty Ltd.

Mapping of autosomal recessive chronic distal spinal muscular atrophy to chromosome 11q13

Distal spinal muscular atrophy is a heterogeneous group of neuromuscular disorders caused by progressive anterior born cell degeneration and characterized by progressive motor weakness and muscular atrophy, predominantly in the distal parts of the limbs. Here we report on chronic autosomal recessive distal spinal muscular atrophy in a large, inbred family with onset at various ages. Because this condition had some of the same clinical features as spinal muscular atrophy with respiratory distress, we tested the disease gene for linkage to chromosome 11q and mapped the disease locus to chromosome 11q13 in the genetic interval that included the spinal muscular atrophy with respiratory distress gene (D11S1889-D11S1321, Z(max) = 4.59 at theta = 0 at locus D11S4136). The sequencing of IGHMBP2, the human homologue of the mouse neuromuscular degeneration gene (nmd) that accounts for spinal muscular atrophy with respiratory distress, failed to detect any mutation in our chronic distal spinal muscular atrophy patients, suggesting that spinal muscular atrophy with respiratory distress and chronic distal spinal muscular atrophy are caused by distinct genes located in the so-me chromosomal region. In addition, the high intrafamilial variability in age at onset raises the question of whether nonallelic modifying genes could be involved in chronic distal spinal muscular atrophy.