Fine-mapping butyrophilin family genes revealed several polymorphisms influencing viral genotype selection in hepatitis C infection.

Host-viral genetic interaction has a key role in hepatitis C infection (HCV) and maybe in the viral selection. In a preliminary GWAS analysis, we identified BTN3A2 rs9104 to be associated with HCV genotype 1. Therefore, our aim was to determine the influence of BTN family on the selection of HCV genotype. We performed a fine-mapping analysis of BTN gene region in a cohort of chronic HCV infection (N=841), validating significant results in another independent chronic HCV infection cohort (N=637), according to selection of viral genotype. BTN3A2 rs9104, BTN3A2 rs733528, BTN2A1 rs6929846, BTN2A1 rs7763910 and BTN3A3 rs13220495 were associated with viral genotype selection. Interestingly, BTN3A2 rs9104 GG genotype was closely related to genotype 1 infection (80.7% (394/488) compared with genotype 3 infection (53.5% (23/43); P=0.0001) in patients harboring IL28B-CT/TT genotype, although this effect was not observed in IL28B-CC genotype. Similarly, BTN3A3 rs13220495 CC genotype was linked to genotype 3 infection (100% (32/32)) compared to genotype 1 (87.3% (137/157); P=0.028) in patients harboring IL28B-CC genotype, but did not in IL28B-CT/TT genotype. Genetic variants in the butyrophilin family genes may alter susceptibility to infection, selecting HCV genotype and influencing disease progression. BTN3A2 rs9104 was strongly associated with genotype 1 infection and the haplotype BTN3A3 rs13220495 CC+IL28B genotype CC was universal in patients with hepatitis C genotype 3a.

Hepatitis C virus infection alters lipid metabolism depending on IL28B polymorphism and viral genotype and modulates gene expression in vivo and in vitro.

Hepatitis C virus (HCV) interacts with lipid receptors to enter the cell, circulates as lipoviroparticle and is secreted as VLDL. We aimed to investigate the role of the rs12979860 polymorphism in the IL28B gene in 143 with chronic hepatitis C genotype 1, 144 infected with genotype 3, 90 genotype 4 and 413 noninfected individuals on lipid profile and to test the impact of HCV infection in an in vitro model on VLDL biosynthesis-related gene expression rs12979860 polymorphism was analysed using real-time PCR coupled to Fluorescence Resonance Energy Transfer (FRET). Huh7.5 (rs12979860 CT) and Huh7 (genotype CC) cells were infected with JFH-1 particles and serum from patients infected with genotypes 1 and 3. Gene expression of apolipoprotein B (apoB), microsomal triglyceride transfer protein (MTP), acetyl CoA carboxylase (ACC), diacylglycerol acyltransferase 2 (DGAT2), diacylglycerol acyltransferase 1 (DGAT1) and low-density lipoprotein receptor (LDLr) genes were determined by semiquantitative RT-PCR in vivo and in vitro. Genotype CC rs12979860 polymorphism was associated with significantly higher serum LDL and total cholesterol levels in patients with hepatitis C genotype 1 but not in patients with hepatitis C genotype 3, genotype 4 and control (noninfected) population. Genotype CC was more often seen in genotype 3 and healthy people in comparison with genotype 1; P = 0.001. In vitro results showed that HCV infection promotes lipid metabolism gene expression induction depending on viral genotype, but to a lesser extent in cells with CT genotype. These results demonstrate that IL28B genotype influences lipid metabolism in patients with hepatitis C but not in noninfected and it seems to be viral genotype-mediated. HCV infection modifies lipid-related genes expression (DGAT1 and DGAT2) in cultured cells based on viral genotype and IL28 polymorphism.

[Hypocaloric peripheral parenteral nutrition in postoperative patients (the Europan Project) (II)]. / Estudio de la nutrición parenteral periférica hipocalórica en pacientes posquirúrgicos (proyecto Europan) (II).

Hypocaloric peripheral parenteral nutrition (HPPN) appears to be indicated in patients in a situation of moderate malnutrition who are to undergo a short period of fasting following surgery. Our aim was to determine the utility of the contribution of parenteral solutions of amino acids (AA) with limited caloric supply in the post-surgical patient, using different nutritional evaluation parameters. We examined 75 post-surgical patients who met at least two of the three criteria established as malnutrition: 1) albumin < 3 g/dl; 2) pre-albumin < 21 mg/dl; 3) bodyweight of less than 95% of the ideal weight. They were divided into four groups: a control group, of 15 patients undergoing standard fluid therapy; Group I, 20 patients with nutritional support of glucose +AA; Group II, 20 patients with glycerol +AA; and Group III of 20 patients with sorbitol-xylitol +AA. The most significant data encountered were a rapid recovery of short half-life proteins (pre-albumin and retinol), a less negative nitrogen balance, and a greater decrease of urinary 3-methylhistidine, when HPPN was used. A notable increase was also obtained in the majority of AAs and of the G and M immunoglobulin plasmatic figures in the groups treated. In terms of complications, a greater percentage of wound dehiscences appeared in the control group than in those treated (13.3 vs 5%) while, on the other hand, there was a higher incidence of catheter-induced phlebitis in groups undergoing HPPN. We conclude that HPPN is a valid nutritional support in post-surgical patients with more or less significant malnutrition, and when the gastro-intestinal tract cannot be used, for whatever reason, during the first week following the operation.

Identity and conflicts in the ethics of neural implants.

The development of neuroprosthetics has given rise to significant theoretical and practical challenges concerning personal identity. The Extended Mind Theory (EMT) attempts to provide an answer to these challenges by arguing that the mind and the external world are co-extensive to the point that both can make a seamless unified entity. The EMT also proposes that physical states determine the nature of mental states. Here, we propose a non-deterministic and less locationist view of mental states that we will call iEMT. The iEMT articulates, firstly, that the co-extensivity of the mind and the world does not justify the dissolution of the mind in the objects of the external world with which the mind interacts. Consequently, the agent's mind is still part of his unique personal identity. Secondly, neural implants cannot be regarded as mere replacement parts in the context of a weak concept of personal identity. Thirdly, there are no compelling reasons to believe or to fear that neuroprosthetics can alter personal identity at the profound level.

Insulin resistance predicts sustained virological response to treatment of chronic hepatitis C independently of the IL28b rs12979860 polymorphism.

BACKGROUND: Insulin resistance has been strongly associated with the attainment of sustained viral response (SVR) in hepatitis C patients. AIM: To determine, in a cohort of Spanish patients with chronic hepatitis C treated with peginterferon plus ribavirin (P+R), whether insulin resistance predicts SVR independently of interleukin-28B rs12979860 polymorphism. METHODS: Insulin resistance was measured as [HOMA-IR = Insulin (IU/mL)*glucose (mmol/L)/22.5]. Genotype, viral load and histological fibrosis using Scheuer score were also measured. Binary logistic regression analysis was used for statistical purposes. RESULTS: In a cohort of 240 patients [78% genotype 1, 24% showing advanced fibrosis, 71% high viral load (≥800 000 IU/mL), 31% IL28b genotype CC and 50% with HOMA >2] treated with P+R, 126 (53%) reached SVR. HOMA-IR index (HOMA <2: 63% vs. HOMA >2: 42%; P = 0.001 and IL28b (genotype CC: 68% vs. genotype CT/TT: 45%; P = 0.002) were significantly associated with SVR. In multivariable logistic regression analysis in the overall cohort, variables independently associated were: viral genotype OR: 0.29 (95% CI: 0.11-0.78), P = 0.01; fibrosis OR: 1.62 (95% CI: 1.22-2.16), P = 0.001; HOMA-IR OR: 1.22 (95% CI: 1.02-1.47), P = 0.03; and IL28B genotype OR: 2.43 (95% CI: 1.45-4.07), P = 0.001. The analyses also showed that degree of steatosis, HOMA-IR >2, mild fibrosis and IL28B CC genotype were significantly related to SVR in patients infected with HCV genotypes 1&4, but not in those with genotypes 2&3. No differences were seen in glucose, insulin level or HOMA-IR index segregated according to IL28B genotypes. CONCLUSION: Our results suggest that insulin resistance, fibrosis stage and IL28B polymorphisms were independent variables associated with sustained viral response.

[Analysis of adherence and efficiency when replacing an antiretroviral therapy with efavirenz-emtricitabine-tenofovir in a single daily dose]. / Análisis del cambio en la adherencia y eficiencia del tratamiento antirretroviral con el uso de efavirenz-emtricitabina-tenofovir en dosis única diaria.

OBJECTIVE: To analyse whether the change of antiretroviral therapy to efavirenz/emtricitabine/tenofovir in a single daily dose (EETu) increases adherence and maintains effectiveness, and establish the cost increase caused by the change. METHODS: An observational, retrospective, and intra-subject study, performed in the outpatient dispensing unit. The study period was 1 year (6 months before and 6 months after the change). Computer dispensing records and days of hospitalisation during the study period were reviewed, and the difference in treatment adherence calculated. To determine the effectiveness of treatment, viral load and CD4 lymphocytes data before and after the change were reviewed. The cost before and after treatment for each patient was determined, and therefore the annual cost increase and the incremental cost per patient. RESULTS: The study included 127 patients. The difference in adherence was 0.6%. The percentage of poor adherence was 35.4% and 40.9% before and after the treatment change, respectively. The levels of CD4 lymphocytes and viral load did not change significantly with treatment. The economic analysis revealed an annual increase of 25,374.60 and €199.80 per patient. CONCLUSIONS: The use of EETu did not improve the control of HIV infection in terms of effectiveness and adherence, and resulted in increased economic costs. Therefore, its choice as antiretroviral treatment will have to be based on criteria other than those described above.

Adherence to treatment in multiple sclerosis.

OBJECTIVE: To find out if patients with multiple sclerosis adhere to treatment with beta interferons and glatiramer acetate, the percentage of withdrawal and its causes. METHODS: Observational, longitudinal, prospective, national, multicentre study which selected multiple sclerosis patients who attended the hospital pharmacy department to collect their medication. The main variable was the adherence percentage during a year, measured as the relationship between the dose of the dispensed and necessary drug. Treatment withdrawals and their causes were then measured. RESULTS: Over a six-month period, 543 patients from 39 pharmacy departments were included. The average time exposed to the drugs during the study period was 312 days and the average adherence in this period was 61.5% (95% CI: 59.4-63.5). Thirty-four (6.26%) of the 543 study participants withdrew treatment, which for most cases was decided by the doctor. CONCLUSIONS: Multiple sclerosis patients' treatment adherence during a period of one year has been lower than the ideal. The causes should therefore be analysed and corrective measures established.

Subclinical hepatic encephalopathy predicts the development of overt hepatic encephalopathy.

OBJECTIVES: In patients with compensated liver cirrhosis the clinical repercussions of detecting subclinical hepatic encephalopathy (SHE) are unclear. We present a long-term follow-up study in cirrhotic patients to examine the relationship between SHE and subsequent episodes of overt hepatic encephalopathy. METHODS: A total of 63 cirrhotic patients were studied by Number Connection Test and auditory evoked potentials. We determined glutamine, ammonia, zinc, glutamate, urea, and ratio of branched chain amino acids to aromatic amino acids, and Child-Pugh classification. RESULTS: Of 63 patients, 34 (53%) exhibited SHE. Nineteen out of 63 (30%) developed overt hepatic encephalopathy during follow-up. Hepatic encephalopathy in follow-up was related to alcoholic etiology, ammonia, glutamine, zinc, ratio of branched chain amino acids to aromatic amino acids, liver function, presence of esophageal varices, and detection of SHE (84% of patients who exhibited hepatic encephalopathy in follow-up showed SHE). In Cox-regression, glutamine levels, SHE, esophageal varices, and Child-Pugh class were the independent variables related to hepatic encephalopathy in follow-up. CONCLUSIONS: SHE (defined on the basis of number connection test or auditory evoked potentials alteration) could predict a subsequent episode of overt hepatic encephalopathy. Lower glutamine levels, presence of esophageal varices, and liver dysfunction were also related to the development of overt hepatic encephalopathy.