IL28B alleles associated with poor hepatitis C virus (HCV) clearance protect against inflammation and fibrosis in patients infected with non-1 HCV genotypes

Genetic polymorphisms near IL28B are associated with spontaneous and treatment-induced clearance of hepatitis C virus (HCV), two processes that require the appropriate activation of the host immune responses. Intrahepatic inflammation is believed to mirror such activation, but its relationship with IL28B polymorphisms has yet to be fully appreciated. We analyzed the association of IL28B polymorphisms with histological and follow-up features in 2335 chronically HCV-infected Caucasian patients. Assessable phenotypes before any antiviral treatment included necroinflammatory activity (n = 1,098), fibrosis (n = 1,527), fibrosis progression rate (n = 1,312), and hepatocellular carcinoma development (n = 1,915). Associations of alleles with the phenotypes were evaluated by univariate analysis and multivariate logistic regression, accounting for all relevant covariates. The rare G allele at IL28B marker rs8099917-previously shown to be at risk of treatment failure-was associated with lower activity (P = 0.04), lower fibrosis (P = 0.02) with a trend toward lower fibrosis progression rate (P = 0.06). When stratified according to HCV genotype, most significant associations were observed in patients infected with non-1 genotypes (P = 0.003 for activity, P = 0.001 for fibrosis, and P = 0.02 for fibrosis progression rate), where the odds ratio of having necroinflammation or rapid fibrosis progression for patients with IL28B genotypes TG or GG versus TT were 0.48 (95% confidence intervals 0.30-0.78) and 0.56 (0.35-0.92), respectively. IL28B polymorphisms were not predictive of the development of hepatocellular carcinoma. CONCLUSION: In chronic hepatitis C, IL28B variants associated with poor response to interferon therapy may predict slower fibrosis progression, especially in patients infected with non-1 HCV genotypes.     

Tratamiento quirúrgico de la mediastinitis necrosante descendente

Introduction

Descending necrotizing mediastinitis (DNM) is a serious infection which occurs as a complication of oropharyngeal infection. Its surgical management and the routine transthoracic approach remain controversial. In this article we report our experience in the management of this disease, and review the different surgical approaches that have been reported in the medical literature.

Material and methods

A retrospective review was made of the clinical records of 29 patients treated between 1988 and 2009. Several demographic variables were analyzed, origin of the initial infection, stage of the disease according to Endo's classification, surgical technique and outcome.

Results

Surgical treatment consisted of both cervical and mediastinal drainage and radical debridement. The mediastinal drainage was made through a transcervical approach in 10 cases and transthoracic in 19, depending on the extent of the mediastinitis. The outcome was satisfactory in 24 patients and 5 died (mortality 17.2%).

Conclusions

According to our results and the conclusions of the main authors, we recommend a prompt and aggressive surgery with a transthoracic approach in cases of widespread DNM.     

Connectionist diagnosis of lexical disorders in aphasia

Background: In the cognitive neurolinguistic approach to lexical deficits in aphasia, impaired levels of processing are localised in a cognitive model. Model-oriented treatment may target these impaired components. Thus a precise assessment of the disorder is crucial. Connectionist models add to this by using computer simulation to specify the details of the functioning of these components. The connectionist semantic-phonological model of lexical access (Dell, Martin, & Schwartz, 2007 Dell, G. S., Martin, N. and Schwartz, M. F. 2007. A case-series test of the interactive two-step model of lexical access: Predicting word repetition from picture naming. Journal of Memory and Language, 56: 490–520. [Crossref], [PubMed], [Web of Science ®] , [Google Scholar]; Schwartz, Dell, Martin, Gahl, & Sobel, 2006 Schwartz, M. F., Dell, G. S., Martin, N., Gahl, S. and Sobel, P. 2006. A case-series test of the interactive two-step model of lexical access: Evidence from picture naming. Journal of Memory and Language, 54: 223–264.  [Google Scholar]) explores the impairment by simulating error patterns in naming and repetition.

Aims: The purpose of the present study was to investigate the model's range of application as a diagnostic tool, and to derive recommendations for the model's use in clinical settings.

Methods & Procedures: We demonstrate how we adapted the error analysis to 15 German-speaking patients with aphasia, analysed the model's accuracy in assessing naming and repetition disorders, and explained deviations between the error pattern produced by each patient and the one produced by the model's simulation by appealing to an extended version of the model.

Outcomes & Results: Overall, the model yielded good fits of the patients' error patterns. Larger model–patient deviations could be explained by the model's limited set of lesionable components.

Conclusions: The “connectionist diagnosis” of naming and repetition disorders in the semantic-phonological model is a reasonable tool in model-oriented assessment. However, the diagnosis needs to be complemented by further language tests.     

Comprehensive PKD1 and PKD2 Mutation Analysis in Prenatal Autosomal Dominant Polycystic Kidney Disease

Prenatal forms of autosomal dominant polycystic kidney disease (ADPKD) are rare but can be recurrent in some families, suggesting a common genetic modifying background. Few patients have been reported carrying, in addition to the familial mutation, variation(s) in polycystic kidney disease 1 (PKD1) or HNF1 homeobox B (HNF1B), inherited from the unaffected parent, or biallelic polycystic kidney and hepatic disease 1 (PKHD1) mutations. To assess the frequency of additional variations in PKD1, PKD2, HNF1B, and PKHD1 associated with the familial PKD mutation in early ADPKD, these four genes were screened in 42 patients with early ADPKD in 41 families. Two patients were associated with de novo PKD1 mutations. Forty patients occurred in 39 families with known ADPKD and were associated with PKD1 mutation in 36 families and with PKD2 mutation in two families (no mutation identified in one family). Additional PKD variation(s) (inherited from the unaffected parent when tested) were identified in 15 of 42 patients (37.2%), whereas these variations were observed in 25 of 174 (14.4%, P=0.001) patients with adult ADPKD. No HNF1B variations or PKHD1 biallelic mutations were identified. These results suggest that, at least in some patients, the severity of the cystic disease is inversely correlated with the level of polycystin 1 function.     

Effects of Cycling Versus Running Training on Sprint and Endurance Capacity in Inline Speed Skating

The purpose of this study was to compare the effects of running versus cycling training on sprint and endurance capacity in inline speed skating. Sixteen elite athletes (8 male, 8 female, 24 ± 8 yrs) were randomly assigned into 2 training groups performing either 2 session per week of treadmill running or ergometer cycling in addition to 3 skating specific sessions (technique, plyometrics, parkour) for 8 weeks. Training intensity was determined within non-specific (cycling or running) and effects on specific endurance capacity within a specific incremental exercise test. Before and after the intervention all athletes performed a specific (300m) and one non-specific (30s cycling or 200m running) all-out sprint test according to the group affiliation. To determine the accumulation of blood lactate (BLa) and glucose (BGL) 20 μl arterialized blood was drawn at rest, as well as in 1 min intervals for 10 min after the sprint test. The sport-specific peak oxygen uptake (VO₂ peak) was significantly increased (+17%; p = 0.01) in both groups and highly correlated with the sprint performance (r = -0.71). BLa values decreased significantly (-18%, p = 0.02) after the specific sprint test from pre to post-testing without any group effect. However, BGL values only showed a significant decrease (-2%, p = 0.04) in the running group. The close relationship between aerobic capacity and sprint performance in inline speed skating highlights the positive effects of endurance training. Although both training programs were equally effective in improving endurance and sprint capacities, the metabolic results indicate a faster recovery after high intensity efforts for all athletes, as well as a higher reliance on the fat metabolism for athletes who trained in the running group.

Key points

• In addition to a highly developed aerobic performance inline speed skaters also require a highly trained anaerobic capacity to be effective in the sprint sections such as the mass start, tactical attacks and finish line sprint.
• An 8-week low-intensity endurance training program of either cycling or running training combined with additional routine training improves classical aerobic characteristics (17% increase of VO₂ peak), as well as values for acceleration and speed.
• Athletes who trained in the running group demonstrated a higher reliance on the fat metabolism in the sport-specific post-testing.
• The significant reduction in anaerobic ATP turnover during repeated sprints appears to be partially compensated by an increase in VO₂ in subsequent sprint. The results revealed a close relationship between the aerobic capacity and sprint performance in inline speed skating.

Key words: Aerobic metabolism, blood glucose concentration, all-out sprint test     

Behavioral and neural responses to gustatory stimuli delivered non-contingently through intra-oral cannulas

The act of eating requires a decision by an animal to place food in its mouth. The reasons to eat are varied and include hunger as well as the food's expected reward value. Previous studies of tastant processing in the rat primary gustatory cortex (GC) have used either anesthetized or awake behaving preparations that yield somewhat different results. Here we have developed a new preparation in which we explore the influences of intra-oral and non-contingent tastant delivery on rats' behavior and on their GC neural responses. We recorded single-unit activity in the rat GC during two sequences of tastant deliveries, PRE and POST, which were separated by a waiting period. Six tastants ranging in hedonic value from sucrose to quinine were delivered in the first two protocols called 4TW and L-S. In the third one, the App L-S protocol, only hedonically positive tastants were used. In the 4TW protocol, tastants were delivered in blocks whereas in the two L-S protocols tastants were randomly interleaved. In the 4TW and L-S protocols the probability of ingesting tastants in the PRE sequence decreased exponentially with the trial number. Moreover, in both protocols this decrease was greater in the POST than in the PRE sequence likely because the subjects learned that unpleasant tastants were to be delivered. In the App L-S protocol the decrease in ingestion was markedly slower than in the other protocols, thus supporting the hypothesis that the decrease in appetitive behavior arises from the non-contingent intra-oral delivery of hedonically negative tastants like quinine. Although neuronal responses in the three protocols displayed similar variability levels, significant differences existed between the protocols in the way the variability was partitioned between chemosensory and non-chemosensory neurons. While in the 4TW and L-S protocols the former population displayed more changes than the latter, in the App L-S protocol variability was homogeneously distributed between the two populations. We posit that these tuning changes arise, at least in part, from compounds released upon ingestion, and also from differences in areas of the oral cavity that are bathed as the animals ingest or reject the tastants.     

“I don't want to look like an AIDS victim”: A New Zealand case study of facial lipoatrophy

The development of antiretroviral (ARV) drugs to treat HIV has turned what was once a death sentence into a chronic disorder. However, a focus on absence of disease in the form of an undetectable viral load and the dismissal of the so‐called “cosmetic” complications of the disease ignores perceptions of health and well‐being of those living with HIV. Facial lipoatrophy is a stigmatising side effect of treatment for HIV as it betrays the presence of the virus within the body. The study took a longitudinal qualitative approach, interviewing 11 people twice over a period of 1 year on their experience of living with HIV. Two participants were given cameras and asked to take photos which represented what it was like for them to live with this condition and were interviewed four times at four monthly intervals. This paper looks at one man's struggle to conceal or veil his facial lipoatrophy. His story is presented in the form of “selfies” and extracts from in‐depth interviews. It tells of an emotional (ongoing) journey of frustration, anger, excitement, depression and resignation which had a profound effect on his sense of social and psychological well‐being. This suggests a more holistic approach to treating people living with HIV is needed. While an undetectable viral load is indeed vital, it should not be seen as the only essential outcome of treatment.