Use of alcohol and drugs in the view of people living with HIV/AIDS: a qualitative study.

OBJECTIVE: To investigate the meaning of the experiences of patients infected by HIV using antiretroviral therapy, regarding the use of alcohol and drugs. STUDY DESIGN: A qualitative phenomenological study. METHOD: A total of 25 patients receiving antiretroviral treatment participated in the investigation, of which 14 were male and 11 were females, who expressed their feelings and perceptions through participation in focus groups and the interpretation of costumes. The empirical material was transcribed in full and later organized and analyzed using the phenomenological method. RESULTS: Based on this amusing experience we realized that participants were unaware of the effects of the use of alcohol and drugs in the AIDS progression. Since they have kept with their smoking and alcoholism habits to be accepted in a social group and consequently prevent prejudice. We believe that our health education strategy was adequate to improve antiretroviral therapy, since it helped in subject comprehension and patients self-care body expression. CONCLUSION: This phenomenological study made it possible to understand the experience of patients living with HIV regarding the use of alcohol and drugs, and contributes to the planning and implementation of intervention programs based on a participative model of care, with a view to prioritizing the holistic aspects involved in the treatment of people living with HIV/AIDS.

Effectiveness and safety of ombitasvir, paritaprevir, ritonavir ± dasabuvir ± ribavirin: An early access programme for Spanish patients with genotype 1/4 chronic hepatitis C virus infection.

Over the last 5 years, therapies for hepatitis C virus (HCV) infection have improved significantly, achieving sustained virologic response (SVR) rates of up to 100% in clinical trials in patients with HCV genotype 1. We investigated the effectiveness and safety of ombitasvir/paritaprevir/ritonavir±dasabuvir in an early access programme. This was a retrospective, multicentre, national study that included 291 treatment-naïve and treatment-experienced patients with genotype 1 or 4 HCV infection. Most patients (65.3%) were male, and the mean age was 57.5 years. The mean baseline viral load was 6.1 log, 69.8% had HCV 1b genotype, 72.9% had cirrhosis and 34.7% were treatment-naïve. SVR at 12 weeks posttreatment was 96.2%. Four patients had virological failure (1.4%), one leading to discontinuation. There were no statistical differences in virological response according to genotype or liver fibrosis. Thirty patients experienced serious adverse events (SAEs) (10.3%), leading to discontinuation in six cases. Hepatic decompensation was observed in five patients. Four patients died during treatment or follow-up, three of them directly related to liver failure. Multivariate analyses showed a decreased probability of achieving SVR associated with baseline albumin, bilirubin and Child-Pugh score B, and a greater probability of developing SAEs related to age and albumin. This combined therapy was highly effective in clinical practice with an acceptable safety profile and low rates of treatment discontinuation.

Successful treatment of hepatitis C virus infection with sofosbuvir and simeprevir in the early phase of an allogeneic stem cell transplant.

Currently, a lack of consensus exists on how to manage a hepatitis C virus (HCV) infection after allogeneic hematopoietic stem cell transplantation (allo-HSCT). Ribavirin alone, or in combination with interferon, has been the mainstream therapy for HCV infection after transplantation. However, very few patients have been regularly treated owing to concerns about poor tolerability, frequent side effects, and limited efficacy. The present case illustrates the striking efficacy of the combination therapy of sofosbuvir with simeprevir, early after transplantation, as it was able to completely eliminate viral replication within 1 month of initiation of treatment. Moreover, tolerance was good, with only minor interactions between the immunosuppressive drugs. This case report supports the feasibility of using this combination therapy early after allo-HSCT for patients with HCV infection.

Shared changes in gene expression in frontal cortex of four genetically modified mouse models of depression.

This study aimed to identify whether genetic manipulation of four systems implicated in the pathogenesis of depression converge on shared molecular processes underpinning depression-like behaviour in mice. Altered 5HT function was modelled using the 5-HT transporter knock out mouse, impaired glucocorticoid receptor (GR) function using an antisense-induced knock down mouse, disrupted glutamate function using a heterozygous KO of the vesicular glutamate transporter 1 gene, and impaired cannabinoid signalling using the cannabinoid 1 receptor KO mouse. All 4 four genetically modified mice were previously shown to show exaggerated helpless behaviour compared to wild-type controls and variable degrees of anxiety and anhedonic behaviour. mRNA was extracted from frontal cortex and hybridised to Illumina microarrays. Combined contrast analysis was used to identify genes showing different patterns of up- and down-regulation across the 4 models. 1823 genes were differentially regulated. They were over-represented in gene ontology categories of metabolism, protein handling and synapse. In each model compared to wild-type mice of the same genetic background, a number of genes showed increased expression changes of >10%, other genes showed decreases in each model. Most of the genes showed mixed effects. Several previous array findings were replicated. The results point to cellular stress and changes in post-synaptic remodelling as final common mechanisms of depression and resilience.

Clinical evaluation of drug-induced hepatitis.

OBJECTIVE: To ascertain the epidemiological characteristics, clinical symptoms, and evolution of drug-induced hepatitis over the last 22 years. EXPERIMENTAL DESIGN AND SUBJECTS: An observational, retrospective study between 1982 and 1993, and prospective study between 1994 and 2003. All patients in our department diagnosed with having drug-induced hepatitis were studied analyzing epidemiological (age, sex, cases per year, hospitalization) and clinical features (previous liver disease, hepatic symptoms, laboratory results), and follow-up (complete recovery or chronicity). RESULTS: A total of 61 patients were diagnosed as having drug-induced hepatitis, 26 men and 35 women (57%), mean age 52.4 years +/- 17 years, of which 72.2% were older than 40 years. A total of 43% were admitted to hospital. In 87% of cases, two or more drugs were involved, the most frequent being antituberculosis (19 cases), psychotropic (26 cases), and non-steroidal anti-inflammatory drugs (45 cases). Evolution showed that 94% of patients recovered after the withdrawal of suspected causal drugs. CONCLUSIONS: The incidence of drug-induced hepatitis is higher in patients over 40 years of age, it being more common in females. Non-steroidal anti-inflammatory, psychotropic, and anti-tuberculosis agents were the main drugs involved. Most patients made a complete recovery after withdrawal of the suspected causal drug.

Clinical value of increased serum creatinine concentration as predictor of short-term outcome in decompensated cirrhosis.

BACKGROUND: The purpose of this study was to assess whether serum creatinine concentration alone or associated with other biological parameters was an independent predictor of short-term mortality in patients with decompensated cirrhosis. METHODS: A total of 212 consecutive episodes of decompensated cirrhosis in patients admitted to the hospital between January 1999 and December 2001 were reviewed retrospectively. Depending on a serum creatinine concentration equal to or greater than 1.5 mg/dL at the time of admission, patients were divided into decompensated cirrhosis with renal failure (101 episodes in 59 patients, aged 69.8 +/- 10 years) and without renal failure (111 episodes in 61 patients, aged 64.5 +/- 13 years). Outcome (alive, death) during the episode of decompensation of liver disease and outcome at 90 days after admission were assessed. RESULTS: Differences in the frequency of variables according to outcome in the overall episodes of decompensated cirrhosis with and without renal failure showed significant differences between patients who died and those who were alive both at hospital discharge and at 90 days in serum bilirubin, Child-Pugh score, MELD (model for end-stage liver disease) score, and serum creatinine levels. In the multivariate analysis, serum creatinine was not an independent predictor of outcome. The prediction accuracy according to the area under the ROC (receiver operating characteristic) curve was greater for the MELD scale than for serum creatinine. CONCLUSIONS: Serum creatinine concentration is a parameter that should be included in the prognostic assessment of patients with decompensated cirrhosis, but should be combined with other specific parameters of liver function, such as bilirubin, albumin, and the international normalized ratio (INR) for prothrombin time.

Influence of age and date of infection on distribution of hepatitis C virus genotypes and fibrosis stage.

The objective of this study was to assess the influence of age and date of acquisition of hepatitis C virus (HCV) infection on the distribution of genotypes and the progression of fibrosis in HCV-infected patients who were born in Spain and had their habitual place of residence in this country. Genotypic analysis was performed in 375 patients in whom it was possible to establish the year of HCV infection because the mode of transmission was known (transfusion, injection drug use, blood donor, or epidemic outbreak). In 298 patients with liver biopsy, fibrosis stage was related to age at infection, duration of infection, alcohol consumption, and HCV genotype. HCV subtype 1b was almost exclusively detected among transfusion recipients, but the onset of intravenous drug addiction was associated with the introduction of HCV genotypes other than 1b among injecting users with subsequent spread to other exposure risk groups. Fibrosis progression was influenced by alcohol consumption, increased duration of infection, and older age at infection. In summary, spread of intravenous drug use determined HCV infection by genotypes other than 1b. The risk of fibrosis progression was influenced more by age at viral acquisition and alcohol consumption than by the infecting genotype.

Altered modulation of soluble guanylate cyclase by nitric oxide in patients with liver disease.

The glutamate-nitric oxide-cGMP pathway is impaired in brain in vivo in animal models of chronic moderate hyperammonemia either with or without liver failure. The impairment occurs at the level of activation of soluble guanylate cyclase by nitric oxide (NO). It has been suggested that the impairment of this pathway may be responsible for some of the neurological alterations found in hyperammonemia and hepatic encephalopathy. Soluble guanylate cyclase is also present in lymphocytes. Activation of guanylate cyclase by NO is also altered in lymphocytes from hyperammonemic rats or from rats with portacaval anastomosis. We assessed whether soluble guanylate cyclase activation was also altered in human patients with liver disease. We studied activation of soluble guanylate cyclase in lymphocytes from 77 patients with liver disease and 17 controls. The basal content of cGMP in lymphocytes was decreased both in patients with liver cirrhosis and in patients with chronic hepatitis. In contrast, cGMP concentration was increased in plasma from patients with liver disease. Activation of guanylate cyclase by NO was also altered in liver disease and was higher in lymphocytes from patients with cirrhosis or hepatitis than that in lymphocytes from controls. Successful treatment with interferon of patients with hepatitis C reversed all the above alterations. Altered modulation of soluble guanylate cyclase by NO in liver disease may play a role in the neurological and hemodynamic alterations in these patients.

[Comorbidity in children and adolescents with attention-deficit disorder: preliminary results]. / Comorbidade em crianças e adolescentes com transtorno do déficit de atenção: resultados preliminares.

Thirty-four children and adolescents with ages from 6 to 16 years having a diagnosis of attention-deficit hyperactivity disorder (ADHD)according to DSM-IV criteria were examined. Psychiatric comorbidity was evaluated through a standard questionnaire given to parents. There was a significant comorbidity (85,7%) in the sample, oppositional-defiant disorder (20,6%) and conduct disorder (39,2%) being the most common comorbid diagnosis. At least two diagnosis other than ADHD could be found in 57% of the sample. Major depression was seen in four cases and anxiety states (generalized anxiety disorder, separation anxiety and phobias) were seen in 34.3% of the sample. Comorbidity modifies prognosis in a significant way and may suggest specific therapeutic interventions according to each case. Frequent comorbidity may suggest the need for diagnostic interviews that covers other psychiatric disorders.

Nickel, cobalt and chromium-induced cytotoxicity and intracellular accumulation in human hacat keratinocytes.

Nickel, cobalt and chromium can induce allergic contact dermatitis (ACD) and may provoke irritant reactions in the skin. This study aimed at investigating cytotoxicity and cell viability along with intracellular metal accumulation in HaCaT human keratinocytes exposed to soluble forms of nickel, cobalt or chromium. The EC50 (24 h) values as detected by MTT test were 30 microM for sodium chromate (Na2CrO4), 475 microM for cobalt chloride (CoCl2) and 600 microM for nickel chloride (NiCl2). Chromium chloride (CrCl3) was not toxic up to 1 mM. No clear effects were observed after 4 h, but 24-h treatments with 1 mM CoCl2 or 10 microM Na2CrO(4) were found to almost completely abolish the ability of the cells to form colonies, whilst 1 mM NiCl2 reduced cellular survival to only 70% of control cultures. Intracellular accumulation of metals was evaluated by the use of radioisotopes at the EC50 value and at 1/10-1/5 of this concentration. Accumulation of Na2(51)CrO4 was linear with increasing dose. This was not the case for 63NiCl2 and 58CoCl2. All the metals were accumulated preferentially in the cytosols; 96% or more for 63NiCl2, approximately 90% for 58CoCl2 and 60-70% for Na2(51)CrO4. Finally, it was observed that HaCaT human keratinocytes can concentrate the metals present in the media up to 3.9 and 12.5 times for NiCl2 and CoCl2, respectively, and up to 167 for Na2CrO4. These striking metal intracellular accumulation patterns, which have not been earlier described in keratinocytes, highlight the relevance of searching for specific biomarkers of early cellular toxic effects, such as cytosolic proteins that bind the metals.

Nickel-induced proteins in human HaCaT keratinocytes: annexin II and phosphoglycerate kinase.

It has been established in previous in vitro experiments with human HaCaT keratinocytes that nickel becomes cytotoxic at concentrations higher than 100 microM and that it is accumulated mainly in the cytosolic fraction (Ermolli et al., 2000). The aim of this work was to search possible biomarkers of metal insult, i.e. nickel-binding proteins or proteins differentially expressed in the cytosolic fraction of nickel-exposed cells (up to 1 mM nickel) as compared to controls. Cytosolic proteins were studied by isoelectric focusing (IEF) and two-dimensional gel electrophoresis (2-DE). Separation by IEF revealed nickel-induced changes in the abundance of cytosolic proteins as visualised with nickel-nitrilo-triacetic-alkaline phosphatase (Ni-NTA-AP) in blots. The cytosolic fraction of cells incubated with nickel, at concentrations over 100 microM, showed nickel binding components which were absent or present in significantly lower amounts in control cells. These proteins had isoelectric points (pIs) 6.9, 7.7 and 8.5. After 2-DE silver- and protein staining significantly increased abundance of four proteins was observed. Their pI values corresponded to those of the nickel binding ones seen after IEF. A protein with pI 6.9 had a molecular weight estimated to 38 kDa, two proteins with pI around 7.7 showed molecular weights of 57 and 22 kDa, respectively and another protein with pI of 8.5 had a molecular weight of 33 kDa. The increased abundance of these components, both in IEF experiments and in 2-DE, correlated with the nickel concentration in the culture media. N-terminal amino acid sequencing and database search allowed identification of one a protein as phosphoglycerate kinase and another one as annexin II. The involvement of these proteins in cellular functions and their possible implications in the mechanism of nickel toxicity in keratinocytes are discussed. Some of these proteins may be biomarker candidates for effects of nickel exposure in human keratinocytes.

Prevalence of hepatitis C virus in patients with lichen planus of the oral cavity and chronic liver disease.

Lichen planus (LP) may represent a mucosal reaction to a variety of factors including hepatitis C virus (HCV) infection. We compared the prevalence of HCV infection in patients with LP of the oral mucosa and chronic liver disease (LP-CLD) with those suffering exclusively from LP or from chronic liver disease (CLD). A total of 267 outpatients participated in a prospective study. There were 41 patients in the LP-CLD group, 128 in the LP group, and 98 in the CLD group. The diagnosis of LP was based on typical macroscopic and histopathologic features and the diagnosis of liver disease on liver histology. Serum samples were screened for anti-HCV antibodies. In 89 patients, serum HCV RNA was also measured. The overall prevalence of anti-HCV antibodies was 29.2% (78/267 patients). Serum HCV RNA levels were positive in 96.2% of anti-HCV-positive patients and in none of anti-HCV-negative subjects. Anti-HCV-positivity was more frequent in the groups of LP-CLD (78%) and CLD (42.8%) than in the LP group (3.1%). It is concluded that HCV infection plays an etiopathogenetic role in CLD associated with oral LP, whereas according to the present findings, the majority of patients suffering exclusively from oral LP are not infected by the HCV.

Predictors of morbidity and mortality after the first episode of upper gastrointestinal bleeding in liver cirrhosis.

BACKGROUND/AIMS: Upper gastrointestinal (GI) bleeding is one of the most frequent causes of morbidity and mortality in the course of liver cirrhosis. The aim of this study was to determine the independent predictors of morbidity, mortality, and survival after the first episode of GI bleeding in patients with liver cirrhosis. METHODS: In a retrospective study of 403 cirrhotic patients who were admitted in the period January 1982 to December 1994 because of a first episode of GI hemorrhage, epidemiological factors, bleeding-related variables and cirrhosis-related variables that may be associated with hepatic and extrahepatic complications, mortality at 48 h and 6 weeks, and survival up to 30 June 1996 were assessed. RESULTS: Forty-five percent of patients developed hepatic and/or extrahepatic complications, with a mortality rate of 7.4% at 48 h and 24% at 6 weeks. Renal failure, rebleeding, hepatocellular carcinoma, and hepatic encephalopathy were independent predictors of mortality. The Kaplan-Meier method showed a median survival of 30.9+/-4.5 months (95% confidence interval 22 to 39.7 months). The cumulative percentage of survivors was 60.2% at 1 year, 33.6% at 5 years, and 14% at 10 years. In a Cox's multiple regression analysis, age, hepatic encephalopathy, hepatocellular carcinoma, Child-Pugh grade, and renal failure were independently associated with long-term survival. CONCLUSIONS: The first episode of GI bleeding in patients with liver cirrhosis is associated with high morbidity and mortality. Renal failure, rebleeding, hepatocellular carcinoma, and hepatic encephalopathy were independent risk factors for early death.

Effects of trace metal compounds on HIV-1 reverse transcriptase: an in vitro study.

The effect of 44 different metal ions (Ag+, Al3+, As(O-)2, Au3+, Ba2+, Be2+, Bi3+, Cd2+, Ce3+, CO2+, Cr(O2-)4, Cr3+, Cs+, Cu2+, Fe3+, Fe2+, Ga3+, Ge4+, Hg2+, Ir4+, La3+, Li+, Mn2+, MO6+, Ni2+, OS4+, Pb2+, Pt4+, Rb+, Rh3+, Sb5+, Se(O2-)4, Se(O2-)3, Sn2+, Sr2+, Th4+, T1+, U(O2+)2, V(O-)3, VO2+, W(O2-)4, Y3+, Zn2+, and Zr4+) on the activity of the reverse transcriptase (RT) of the human immunodeficiency virus (HIV-1) was investigated in vitro. For this study, the RT activity assay was carried out by means of an enzyme-linked immunosorbent assay (ELISA) kit, using the template/primer hybrid poly(A) oligo(dT)15, which required some modifications: (1) possible interfering metal chelators (such as EDTA) in the original lysis buffer were avoided, and a new buffer (50 mM Tris-NO3, pH 7.8) was used throughout; (2) an amount of 2 ng of RT per well was considered to be optimal after checking the linearity of the reaction with increasing amounts of enzyme; (3) an incubation temperature of 37 degrees C and an incubation time of 1 h were chosen after preliminary studies in a wide range of temperature and time. At an incubation temperature > or = 40 degrees C, there was a dramatic loss of enzymatic activity. In addition, when RT alone was preincubated for 1 h at 5 degrees C, 25 degrees C, and 37 degrees C, there was a large (83%) loss of activity at 37 C as compared to that at 5 degrees C. These results are indicative of enzyme thermolability, which is higher in the absence of substrates. The effect of metal ions on RT activity was tested using two different metal salt concentrations (10(-4) M and 10(-5) M). Under such experimental conditions, the presence of five metal ions (Pt4+, Ag+, Rh3+, Zn2+, and Hg2+) decreased the RT activity in a dose-response fashion. The observed order of effectiveness with respect to inhibition was Pt4+ > Ag+ > Rh3+ > Zn2+ = Hg2+. Estimated mean inhibitory concentrations (IC50) were 7.8 microM for (NH4)2PtCl6, 14.1 microM for AgNO3, 46.8 microM for RhCl3, 53.7 microM for Zn(SO)4, and 56.2 microM for Hg(NO3)2. Because these data are of the same order of magnitude as the corresponding values related to other RT inhibitors used in anti-AIDS therapy, metal compounds or their derivatives could give an interesting contribution in the development of new RT inhibitors for clinical use.

Serum malondialdehyde: possible use for the clinical management of chronic hepatitis C patients.

Serum lipid peroxidation products are increased in inflammatory liver disease and, as we previously reported, also in chronic hepatitis C. We have performed a specific assay of malondialdehyde, the reported most abundant product of lipid peroxidation, in serum of twenty four chronic hepatitis C patients, before, during, and after interferon treatment. Liver biopsies were performed in each patient before and after interferon treatment. The results show higher serum malondialdehyde values in chronic hepatitis C patients than healthy subjects (n = 68) before interferon treatment (p < .001). Mean value of serum malondialdehyde levels after interferon treatment was significantly lower than before it (p < .002). Associating the histopathological findings in each of the 48 biopsies performed, with serum malondialdehyde and alanine aminotransferase activity levels, of the sample obtained the same day of biopsy, a much better correspondence with the histopathological severity was observed for malondialdehyde concentration than for alanine aminotransferase activity. These levels decreased significantly after interferon treatment. However, when the patients were grouped in responding (group I; n = 9) and non-responding (group II; n = 15) to interferon treatment, according to the histopathological findings before and after interferon, the values of group I before interferon treatment were significantly higher than group II (p < .03). Thus, a potential predictive value could be ascribed to the serum malondialdehyde levels before interferon treatment in these patients. We propose the utility of the specific assay of malondialdehyde for the clinical management of chronic hepatitis C patients.

Incidence and risk factors for hepatocellular carcinoma in 967 patients with cirrhosis.

PURPOSE: To determine the incidence of hepatocellular carcinoma in cirrhosis and to examine the influence of age and sex, and the contribution of etiological factors. METHODS: 967 patients with liver cirrhosis and free of hepatocellular carcinoma were enrolled in this longitudinal, retrospective and observational study. Monitoring for hepatocellular carcinoma was scheduled at 3- to 6-month intervals. The mean (+/-SD) length of follow-up was 60.3+/-51.7 months (range 6 258). RESULTS: During the observation period, hepatocellular carcinoma developed in 64 patients. The calculated annual incidence was 2.1%. The probability of being free of liver cancer was 92% at 5 years, 80% at 10 years, and 69% at 15 years. Age was the only independent risk factor for the development of malignancy in the multivariate analysis. There were no differences according to male sex, alcohol abuse, and chronic hepatitis B and C virus infection. CONCLUSIONS: The annual incidence of hepatocellular carcinoma was 2.1%. These results, although confirming that age is a risk factor for hepatocellular carcinoma in cirrhosis, indicate that alcohol abuse, male sex, and concurrent hepatitis B and C virus infection do not involve a higher risk of developing liver cancer.

Influence of pretreatment lesions on histologic response to interferon therapy in chronic hepatitis C.

We have assessed the predictive value of the grade of pretreatment liver lesions on histologic response to interferon therapy in patients with chronic hepatitis C. In 93 patients with chronic hepatitis C virus (HCV) infection who showed an initial response to interferon therapy, HCV RNA load and serum aminotransferase levels together with grade of liver histologic lesions were assessed at baseline and 6 months after treatment cessation. Regression of portal and periportal necroinflammation was observed only in sustained responders (normalization of aminotransferase levels and HCV RNA clearance). Neither short-term response nor the absence of virus was associated with significant histologic changes in the liver biopsies. Logistic regression analysis showed that pretreatment histologic lesion was an independent predictive factor of biologic response in the histologic regression of lesions 6 months after cessation of interferon treatment. In conclusion, a dense inflammatory necrotic activity is a positive predictor of histologic response in interferon-treated patients with HCV.

Prevalence and incidence of gallstones in liver cirrhosis.

BACKGROUND: Our aim was to assess the prevalence and incidence of gallstone disease in patients with liver cirrhosis and to identify risk factors for cholecystolithiasis. METHODS: We studied a cohort of 313 patients with liver cirrhosis confirmed by histology and/or laparoscopy and 357 patients free of liver disease, who had been referred for ultrasonographic examination of the upper abdomen. Hepatobiliary ultrasonography was performed when liver cirrhosis was diagnosed and every 6 months thereafter. Risk factors for cholelithiasis (age, gender, diet, pregnancy, diabetes, family history of cholelithiasis, etiology of cirrhosis, decompensated disease) were assessed. RESULTS: The overall prevalence of gallstones in cirrhotic patients was 23.3%. In controls, the overall prevalence of cholecystolithiasis was 16.8%. After a median follow-up period of 65 months, 30 patients developed gallstones. The calculated annual incidence was 3.4%. CONCLUSIONS: Given that the prevalence of gallstone disease is higher in cirrhotics than in noncirrhotic patients, cirrhosis of the liver may be considered a risk factor for cholecystolithiasis.