Trypanocide treatment among adults with chronic Chagas disease living in Santa Fe city (Argentina), over a mean follow-up of 21 years: parasitological, serological and clinical evolution

The efficacy of treatment with nifurtimox and/or benznidazole among adults with chronic Chagas disease with no previous electrocardiographic disturbances was evaluated over a mean follow-up of 21 years, by means of conventional serology, xenodiagnosis, clinical examination, electrocardiograms and chest X-ray. One hundred and eleven patients, between 17 and 46 years old, were studied: 54 underwent treatment (nifurtimox 27, benznidazole 27) and 57 remained untreated (control group). Xenodiagnosis was performed on 65% of them: 36/38 of the treated and 9/34 of the untreated patients had previous positive xenodiagnosis. Post-treatment, 133 xenodiagnoses were performed on 41 patients, all resulting negative. In the control group, 29 xenodiagnoses were performed on 14 patients; 2 resulted positive. Sera stored during the follow-up were simultaneously analyzed through conventional serology tests (IHA; DA-2ME; IIF). The serological evolution in the treated group was: a) 37% underwent negative seroconversion (nifurtimox 11, benznidazole 9); b) 27.8% decreased titers (nifurtimox 9, benznidazole 6), 9 showed inconclusive final serology (nifurtimox 7, benznidazole 2); c) 35.2% remained positive with constant titers (nifurtimox 7; benznidazole 12). The control group conserved the initial antibody levels during the follow-up. In the clinical evolution, 2/54 (3.7%) of the treated and 9/57 (15.8%) of the untreated patients showed electrocardiographic disturbances attributable to Chagas myocardiopathy, with a statistically relevant difference (p<0.05). Treatment caused deparasitation in at least 37% of the chronically infected adults and a protective effect on their clinical evolution.

Adult T-cell leukemia/lymphoma: report of two cases

Adult T-cell leukemia/lymphoma is a lymphoproliferative disorder of mature T lymphocytes associated with infection with human T-cell lymphotrophic virus type I (HTLV-I). Adult T-cell leukemia/lymphoma is characterized by clinical and laboratory polymorphism that allows it to be classified into four distinct subgroups: smoldering, chronic, acute and lymphomatous types. We present here two cases of adult T-cell leukemia/lymphoma, respectively in the acute and lymphomatous forms of the disease. Case 1 was a 35-year-old woman who presented abdominal distension accompanied by hepatosplenomegaly, adenomegaly, skin lesions, positivity for anti-HTLV-I antibodies and leukocytosis with the presence of flower cells. Case 2 was a 38-year-old man who was admitted with generalized lymphadenomegaly, positivity for anti-HTLV-I antibodies, hypercalcemia and osteolytic lesions. In this paper, we correlate the clinical-laboratory findings of these two cases with data in the literature.

Chagas' disease and ageing: the coexistence of other chronic diseases with Chagas' disease in elderly patients

This study aimed to identify the main comorbidities in elderly chagasic patients treated in a reference service and identify possible associations between the clinical form of Chagas' disease and chronic diseases. Ninety patients aged 60 years-old or over were interviewed and their clinical diagnoses recorded. The study population profile was: women (55.6%); median age (67 years); married (51.1%); retired (73.3%); up to four years' education (64.4%); and earning less than two minimum wages (67.8%). The predominant forms of Chagas' disease were the cardiac (46.7%) and mixed forms (30%). There was a greater proportion of mild cardiac dysfunction (84.1%), frequently in association with megaesophagus. The mean number of concurrent diseases was 2.856 ± 1.845, and 33% of the patients had four or more comorbidities. The most frequent were systemic arterial hypertension (56.7%), osteoporosis (23.3%), osteoarthritis (21.2%) and dyslipidemia (20%). Positive correlations were verified between sex and comorbidities and between age group and comorbidities.

Occurrence of dolichocolon without megacolon in chronic Chagas disease patients

INTRODUCTION: Since 1970, lengthening of the rectosigmoid has been suspected to be a solitary manifestation of Chagas colopathy. METHODS: To test this hypothesis, opaque enema was administered on 210 seropositive and 63 seronegative patients, and radiographs in the anteroposterior and posteroanterior positions were examined blind to the serological and clinical findings. The distal colon was measured using a flexible ruler along the central axis of the image from the anus to the iliac crest. RESULTS: Dolichocolon was diagnosed in 31 (14.8%) seropositive and 3 (4.8%) seronegative patients. The mean length was 57.2 (±12.2)cm in seropositive patients and 52.1 (±8.8)cm in the seronegative patients (p = 0.000), that is, the distal colon in Chagas patients was, on average, 5.1cm longer. Seropositive female patients presented a mean length of 58.8 (±12.3)cm, and seronegative female patients presented 53.2 (±9.1)cm (p = 0.002). Seropositive male patients had a mean length of 55 (±11.6)cm, and seronegative male patients had 49.9 (±7.8)cm (p = 0.02). Among 191 patients without megacolon and suspected megacolon, the mean length was 56.3 (±11.6)cm in seropositive individuals and 52 (±8.8)cm in seronegative patients (p = 0.003). Among individuals with distal colon >70cm, there were 31 Chagas patients with mean length of 77.9 (±7.1)cm and three seronegative with 71.3 (±1.1)cm (p = 0.000). Among 179 with distal colon <70cm, seropositive individuals had a mean length of 53.6 (±8.8)cm, and seronegative patients had 51.2 (±7.8)cm (p = 0.059). Serological positive women had longer distal colon than men (p = 0.02), whereas the mean length were the same among seronegative individuals (p = 0.16). CONCLUSIONS: In endemic areas of Brazil Central, solitary dolichocolon is a radiological Chagas disease signal.

Clinical and laboratory characteristics associated with dyslipidemia and liver steatosis in chronic HBV carriers

Introduction Chronic hepatitis B virus (HBV) infection and liver steatosis (LS) are the most common causes of chronic liver disease, and their coexistence is frequently observed in clinical practice. Although metabolic syndrome is the main cause of LS, it has not been associated with HBV infection. The aims of this study were to describe the lipid profile and prevalence of LS among HBV carriers and to identify the characteristics associated with LS in this group. Methods This retrospective cross-sectional study included hepatitis B surface antigen (HBsAg)-positive patients evaluated during 2011 and 2012. Results Of the 83 patients included, the mean age was 46.4±12.5 years, 53% were men, and 9.1% were hepatitis B e antigen (HBeAg) -positive. These patients exhibited the following lipid profile: total cholesterol = 175.4±38.8mg/dL, low-density lipoprotein (LDL) = 113.0±32.7mg/dL, and triglycerides = 91.1±45.2mg/dL. Their fasting glucose was 95.3±14.5g/dL, and fasting insulin was 6.1±5.9µIU/mL. Liver steatosis was observed on abdominal ultrasound in 11.3% of individuals. Factors associated with the presence of LS included higher levels of total cholesterol, prothrombin activity, fasting insulin, and body mass index (BMI) as well as lower levels of aspartate aminotransferase (AST). Conclusions These findings suggest that LS in patients with chronic HBV appears to be a consequence of metabolic alterations and insulin action rather than of viral factors.

Evaluation of antihypertensive drugs in patients with obstructive sleep apnea and in rats submitted to chronic intermittent hypoxia

RESUMO: A hipertensão arterial (HA) é uma patologia altamente prevalente, embora claramente subdiagnosticada, em doentes com síndrome de apneia obstrutiva do sono (SAOS). Estas duas patologias apresentam uma estreita relação e a monitorização ambulatória da pressão arterial (MAPA), por um período de 24 horas, parece ser o método mais preciso para o diagnóstico de hipertensão em doentes com SAOS. No entanto, esta ferramenta de diagnóstico para além de ser dispendiosa e envolver um número acrescido de meios técnicos e humanos, é mais morosa e, por conseguinte, não é utilizada por rotina no contexto do diagnóstico da SAOS. Por outro lado, apesar da aplicação de pressão positiva contínua nas vias aéreas (CPAP – Continous Positive Airway Pressure) ser considerada a terapêutica de eleição para os doentes com SAOS, o seu efeito no abaixamento da pressão arterial (PA) parece ser modesto, exigindo, por conseguinte, a implementação concomitante de terapêutica anti-hipertensora. Acontece que são escassos os dados relativos aos regimes de fármacos anti-hipertensores utilizados em doentes com SAOS e, acresce ainda que, as guidelines terapêuticas para o tratamento farmacológico da HA, neste grupo particular de doentes, permanecem, até ao momento, inexistentes. A utilização de modelos animais de hipóxia crónica intermitente (CIH), que mimetizam a HA observada em doentes com SAOS, revela-se extremamente importante, uma vez que se torna imperativo identificar fármacos que promovam um controle adequado da PA neste grupo de doentes. No entanto, estudos concebidos com o intuito de investigar o efeito anti-hipertensor dos fármacos neste modelo animal revelam-se insuficientes e, por outro lado, os escassos estudos que testaram fármacos anti-hipertensores neste modelo não foram desenhados para responder a questões de natureza farmacológica. Acresce ainda que se torna imprescindível garantir a escolha de um método para administração destes fármacos que seja não invasivo e que minimize o stress do animal. Embora a gavagem seja uma técnica indiscutivelmente eficaz e amplamente utilizada para a administração diária de fármacos a animais de laboratório, ela compreende uma sequência de procedimentos geradores de stress para os animais e, que podem por conseguinte, constituir um viés na interpretação dos resultados obtidos. O objectivo global da presente investigação translacional foi contribuir para a identificação de fármacos anti-hipertensores mais efectivos para o tratamento da HT nos indivíduos com SAOS e investigar mecanismos subjacentes aos efeitos sistémicos associadas à SAOS bem como a sua modulação por fármacos anti-hipertensores. Os objectivos específicos foram: em primeiro lugar,encontrar novos critérios, baseados nas medidas antropométricas, que permitam a identificação de doentes com suspeita de SAOS, que erroneamente se auto-classifiquem como nãohipertensos, e desta forma promover um uso mais criterioso do MAPA; em segundo lugar, investigar a existência de uma hipotética associação entre os esquemas de fármacos antihipertensores e o controle da PA (antes e após a adaptação de CPAP) em doentes com SAOS em terceiro lugar, avaliar a eficácia do carvedilol (CVD), um fármaco bloqueador β-adrenérgico não selectivo com actividade antagonista α1 intrínseca e propriedades anti-oxidantes num modelo animal de hipertensão induzida pela CIH; em quarto lugar, explorar os efeitos da CIH sobre o perfil farmacocinético do CVD; e, em quinto lugar, investigar um método alternativo à gavagem para a administração crónica de fármacos anti-hipertensores a animais de laboratório. Com este intuito, na primeira fase deste projecto, fizemos uso de uma amostra com um número apreciável de doentes com SAOS (n=369), que acorreram, pela primeira vez, à consulta de Patologia do Sono do CHLN e que foram submetidos a um estudo polissonográfico do sono, à MAPA e que preencheram um questionário que contemplava a obtenção de informação relativa ao perfil da medicação anti-hipertensora em curso. Numa segunda fase, utilizámos um modelo experimental de HT no rato induzida por um paradigma de CIH. Do nosso trabalho resultaram os seguintes resultados principais: em primeiro lugar, o índice de massa corporal (IMC) e o perímetro do pescoço (PP) foram identificados como preditores independentes de “auto-classificação errónea” da HA em doentes com suspeita de SAOS; em segundo lugar, não encontramos qualquer associação com significado estatístico entre os vários esquemas de fármacos anti-hipertensores bem como o número de fármacos incluídos nesse esquemas, e o controle da PA (antes e depois da adaptação do CPAP); em terceiro lugar, apesar das doses de 10, 30 e 50 mg/kg de carvedilol terem promovido uma redução significativa da frequência cardíaca, não foi observado qualquer decréscimo na PA no nosso modelo animal; em quarto lugar, as razões S/(R+S) dos enantiómeros do CVD nos animais expostos à CIH e a condições de normóxia revelaram-se diferentes; e, em quinto lugar, a administração oral voluntária mostrou ser um método eficaz para a administração diária controlada de fármacos anti-hipertensores e que é independente da manipulação e contenção do animal. Em conclusão, os resultados obtidos através do estudo clínico revelaram que o controle da PA, antes e após a adaptação do CPAP, em doentes com SAOS é independente, quer do esquema de fármacos anti-hipertensores, quer do número de fármacos incluídos num determinado esquema. Os nossos resultados salientam ainda a falta de validade da chamada self-reported hypertension e sugerem que em todos os doentes com suspeita de SAOS, com HA não diagnosticada e com um IMC e um PP acima de 27 kg/m2 e 39 cm, respectivamente, a confirmação do diagnóstico de HA deverá ser realizada através da MAPA, ao invés de outros métodos que com maior frequência são utilizados com este propósito. Os resultados obtidos no modelo animal de HA induzida pela CIH sugerem que o bloqueio do sistema nervoso simpático, juntamente com os supostos efeitos pleiotrópicos do CVD, não parece ser a estratégia mais adequada para reverter este tipo particular de hipertensão e indicam que as alterações farmacocinéticas induzidas pela CIH no ratio S/(R+S) não justificam a falta de eficácia anti-hipertensora do CVD observada neste modelo animal. Por último, os resultados do presente trabalho suportam ainda a viabilidade da utilização da administração oral voluntária, em alternativa à gavagem, para a administração crónica de uma dose fixa de fármacos anti-hipertensores.---------------------------- ABSTRACT: Hypertension (HT) is a highly prevalent condition, although under diagnosed, in patients with obstructive sleep apnea (OSA). These conditions are closely related and 24-hour ambulatory blood pressure monitoring (ABPM) seems to be the most accurate measurement for diagnosing hypertension in OSA. However, this diagnostic tool is expensive and time-consuming and, therefore, not routinely used. On the other hand, although continuous positive airway pressure (CPAP) is considered the gold standard treatment for symptomatic OSA, its lowering effect on blood pressure (BP) seems to be modest and, therefore, concomitant antihypertensive therapy is still required. Data on antihypertensive drug regimens in patients with OSA are scarce and specific therapeutic guidelines for the pharmacological treatment of hypertension in these patients remain absent. The use of animal models of CIH, which mimic the HT observed in patients with OSA, is extremely important since it is imperative to identify preferred compounds for an adequate BP control in this group of patients. However, studies aimed at investigating the antihypertensive effect of antihypertensive drugs in this animal model are insufficient, and most reports on CIH animal models in which drugs have been tested were not designed to respond to pharmacological issues. Moreover, when testing antihypertensive drugs (AHDs) it becomes crucial to ensure the selection of a non-invasive and stress-free method for drug delivery. Although gavage is effective and a widely performed technique for daily dosing in laboratory rodents, it comprises a sequence of potentially stressful procedures for laboratory animals that may constitute bias for the experimental results. The overall goal of the present translational research was to contribute to identify more effective AHDs for the treatment of hypertension in patients with OSA and investigate underlying mechanisms of systemic effects associated with OSA, as well as its modulation by AHDs. The specific aims were: first, to find new predictors based on anthropometric measures to identify patients that misclassify themselves as non-hypertensive, and thereby promote the selective use of ABPM; second, to investigate a hypothetical association between ongoing antihypertensive regimens and BP control rates in patients with OSA, before and after CPAP adaptation; third, to determine, in a rat model of CIH-induced hypertension, the efficacy of carvedilol (CVD), a nonselective beta-blocker with intrinsic anti-α1-adrenergic activity and antioxidant properties; fourth, to explore the effects of CIH on the pharmacokinetics profile of CVD and fifth, to investigate an alternative method to gavage, for chronic administration of AHDs to laboratory rats. For that, in the first phase of this project, we used a sizeable sample of patients with OSA (n=369), that attended a first visit at Centro Hospitalar Lisboa Norte, EPE Sleep Unit, and underwent overnight polysomnography, 24-h ABPM and filled a questionnaire that included ongoing antihypertensive medication profile registration. In the second phase, a rat experimental model of HT induced by a paradigm of CIH that simulates OSA was used. The main findings of this work were: first, body mass index (BMI) and neck circumference (NC) were identified as independent predictors of hypertension misclassification in patients suspected of OSA; second, in patients with OSA, BP control is independent of both the antihypertensive regimen and the number of antihypertensive drugs, either before or after CPAP adaptation; third, although the doses of 10, 30 and 50 mg/Kg of CVD promoted a significant reduction in heart rate, no decrease in mean arterial pressure was observed; fourth, the S/(R+S) ratios of CVD enantiomers, between rats exposed to CIH and normoxic conditions, were different and fifth, voluntary ingestion proved to be an effective method for a controlled daily dose administration, with a define timetable, that is independent of handling and restraint procedures. In conclusion, the clinical study showed that BP control in OSA patients is independent of both the antihypertensive regimen and the number of antihypertensive drugs. Additionally, our results highlight the lack of validity of self-reported hypertension and suggest that all patients suspected of OSA with undiagnosed hypertension and with a BMI and NC above 27 Kg/m2 and 39 cm should be screened for hypertension, through ABPM. The results attained in the rat model of HT related to CIH suggest that the blockade of the sympathetic nervous system together with the putative pleiotropic effects of carvedilol is not able to revert hypertension induced by CIH and point out that the pharmacokinetic changes induced by CIH on S/(R+S) ratio are not apparently responsible for the lack of efficacy of carvedilol in reversing this particular type of hypertension. Finally, the results here presented support the use of voluntary oral administration as a viable alternative to gavage for chronic administration of a fixed dose of AHDs.

Occult HBV infection status among chronic hepatitis C and hemodialysis patients in Northeastern Egypt: regional and national overview

INTRODUCTION: Occult hepatitis B infection (OBI) is considered to be one of the major risks for patients suffering from end-stage renal disease (ESRD) on regular hemodialysis (HD) and patients with chronic hepatitis C virus (HCV) infection. This study compared the prevalence of OBI among these two high-risk groups in the Suez Canal region, Northeastern Egypt, to obtain a better national overview of the magnitude of OBI in this region. METHODS: Serum samples were collected from 165 HD patients and 210 chronic HCV-infected patients. Anti-HCV antibody, hepatitis B surface antigen (HBsAg), total hepatitis B core (anti-HBc) antibody, and hepatitis B surface antibody (anti-HBs) were detected by enzyme-linked immunosorbent assay (ELISA). HCV RNA was detected using a quantitative real-time RT-PCR assay, and HBV was detected using a nested PCR. RESULTS: All patients were negative for HBsAg. A total of 49.1% and 25.2% of the patients in the HD and HCV groups, respectively, were anti-HBc-positive. In addition, more anti-HBs-positive patients were detected in the HD group compared to the HCV group (52.1% and 11.4%, respectively). Three cases were positive for HBV DNA in the HD group, while eighteen positive cases were detected in the HCV group. Both study groups showed significant differences in serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) level as well as anti-HBc, anti-HBs and HBV-DNA positivity. CONCLUSIONS: OBI was more prevalent among chronic HCV patients than HD patients in the Suez Canal region, Egypt, with rates of 8.5% and 1.8%, respectively. However, more precise assessment of this infection requires regular patient follow-up using HBV DNA detection methods.

Morphologic and morphometric evaluation of pancreatic islets in chronic Chagas' disease

PURPOSE: Hyperglycemia and abnormal glucose tolerance tests observed in some patients with chronic Chagas' disease suggest the possibility of morphological changes in pancreatic islets and/or denervation. The purpose of this study was to describe the morphology and morphometry of pancreatic islets in chronic Chagas' disease. METHODS: Morphologic and computerized morphometric studies were performed in fragments of the head, body, and tail regions of the pancreas obtained at necropsies of 8 normal controls and 17 patients with chronic Chagas' disease: 8 with the digestive form (Megas) and 9 with the congestive heart failure form. RESULTS: The Megas group had a larger (p < 0.05) pancreatic islet area in the tail of the pancreas (10649.3 ± 4408.8 µm²) than the normal control (9481.8 ± 3242.4 µm²) and congestive heart failure (9475.1 ± 2104.9 µm²) groups; likewise, the density of the pancreatic islets (PI) was greater (1.2 ± 0.7 vs. 0.9 ± 0.6 vs. 1.9 ± 1.0 PI/mm², respectively). In the tail region of the pancreas of patients with the Megas form, there was a significant and positive correlation (r = +0.73) between the area and density of pancreatic islets. Discrete fibrosis and leukocytic infiltrates were found in pancreatic ganglia and pancreatic islets of the patients with Chagas' disease. Trypanosoma cruzi nests were not observed in the examined sections. Individuals with the Megas form of Chagas' disease showed increased area and density of pancreatic islets in the tail of the pancreas. CONCLUSION: The observed morphometric and morphologic alterations are consistent with functional changes in the pancreas, including glycemia and insulin disturbances.

Effects of Yoga in Patients with Chronic Heart Failure: A Meta-Analysis

The use of yoga as an effective cardiac rehabilitation in patients with chronic heart failure (CHF) remains controversial. We performed a meta-analysis to examine the effects of yoga on exercise capacity and health-related quality of life (HRQOL) in patients with CHF. Methods: We searched MEDLINE, Cochrane Central Register of Controlled Trials, Excerpta Medica database, LILACS, Physiotherapy Evidence Database, The Scientific Electronic Library Online, and Cumulative Index to Nursing and Allied Health (from the earliest date available to December 2013) for randomized controlled trials (RCTs) examining the effects of yoga versus exercise and/or of yoga versus control on exercise capacity (peakVO2) and quality-of-life (HRQOL) in CHF. Two reviewers selected studies independently. Weighted mean differences (WMDs) and 95% confidence intervals (CIs) were calculated, and heterogeneity was assessed using the I2 test. Two studies met the selection criteria (total: 30 yoga and 29 control patients). The results suggested that yoga compared with control had a positive impact on peak VO2 and HRQOL. Peak VO2, WMD (3.87 95% CI: 1.95 to 5.80), and global HRQOL standardized mean differences (-12.46 95% CI: -22.49 to -2.43) improved in the yoga group compared to the control group. Yoga enhances peak VO2 and HRQOL in patients with CHF and could be considered for inclusion in cardiac rehabilitation programs. Larger RCTs are required to further investigate the effects of yoga in patients with CHF.

Left Atrial Function in Patients with Chronic Chagasic Cardiomyopathy

Background:Chagas disease is a cause of dilated cardiomyopathy, and information about left atrial (LA) function in this disease still lacks.Objective:To assess the different LA functions (reservoir, conduit and pump functions) and their correlation with the echocardiographic parameters of left ventricular (LV) systolic and diastolic functions.Methods:10 control subjects (CG), and patients with Chagas disease as follows: 26 with the indeterminate form (GI); 30 with ECG alterations (GII); and 19 with LV dysfunction (GIII). All patients underwent M-mode and two-dimensional echocardiography, pulsed-wave Doppler and tissue Doppler imaging.Results:Reservoir function (Total Emptying Fraction: TEF): (p <0.0001), lower in GIII as compared to CG (p = 0.003), GI (p <0.001) and GII (p <0.001). Conduit function (Passive Emptying Fraction: PEF): (p = 0.004), lower in GIII (GIII and CG, p = 0.06; GI and GII, p = 0.06; and GII and GIII, p = 0.07). Pump function (Active Emptying Fraction: AEF): (p = 0.0001), lower in GIII as compared to CG (p = 0.05), GI (p<0.0001) and GII (p = 0.002). There was a negative correlation of E/e’average with the reservoir and pump functions (TEF and AEF), and a positive correlation of e’average with s’ wave (both septal and lateral walls) and the reservoir, conduit and pump LA functions.Conclusion:An impairment of LA functions in Chagas cardiomyopathy was observed.

Relating severe poverty and chronic poverty

The severely poor are very poor since their consumption is far below the absolute poverty line, and the chronically poor are very poor since their consumption persists for long periods below the absolute poverty line. A combination of chronic poverty and severe poverty (CSP) must represent the very worst instance of poverty. Yet the exercise in this paper of asking simple questions about CSP shows large research gaps. Quantified statements on CSP at the country level can be made for just 14 countries, and at the household level in just six countries. This data suggests a positive correlation between severe poverty and chronic poverty, both at the country level and the household level. Understanding the CSP relationship – whether it is strong, where it arises, what causes it – may improve our explanation of observed cross-country variation in the elasticity between macroeconomic growth and poverty reduction, and why within countries, some households take better advantage of opportunities afforded by macroeconomic growth. Some limited data suggests similarity in socioeconomic characteristics of the severe poor and the chronic poor in terms of location, household size, gender, education and economic sector of work. Of concern is that microlongitudinal datasets drop large proportions of their base year samples, and how this affects our understanding of CSP is not well evaluated. On causal mechanisms, evidence suggests that CSP may be caused by parental CSP (i.e. an intergenerational CSP cycle) and in households not previously poor, CSP may be caused by a morbidity cycle.

Genetic variation in IL28B is associated with chronic hepatitis C and treatment failure: a genome-wide association study.

BACKGROUND & AIMS: Hepatitis C virus (HCV) induces chronic infection in 50% to 80% of infected persons; approximately 50% of these do not respond to therapy. We performed a genome-wide association study to screen for host genetic determinants of HCV persistence and response to therapy. METHODS: The analysis included 1362 individuals: 1015 with chronic hepatitis C and 347 who spontaneously cleared the virus (448 were coinfected with human immunodeficiency virus [HIV]). Responses to pegylated interferon alfa and ribavirin were assessed in 465 individuals. Associations between more than 500,000 single nucleotide polymorphisms (SNPs) and outcomes were assessed by multivariate logistic regression. RESULTS: Chronic hepatitis C was associated with SNPs in the IL28B locus, which encodes the antiviral cytokine interferon lambda. The rs8099917 minor allele was associated with progression to chronic HCV infection (odds ratio [OR], 2.31; 95% confidence interval [CI], 1.74-3.06; P = 6.07 x 10(-9)). The association was observed in HCV mono-infected (OR, 2.49; 95% CI, 1.64-3.79; P = 1.96 x 10(-5)) and HCV/HIV coinfected individuals (OR, 2.16; 95% CI, 1.47-3.18; P = 8.24 x 10(-5)). rs8099917 was also associated with failure to respond to therapy (OR, 5.19; 95% CI, 2.90-9.30; P = 3.11 x 10(-8)), with the strongest effects in patients with HCV genotype 1 or 4. This risk allele was identified in 24% of individuals with spontaneous HCV clearance, 32% of chronically infected patients who responded to therapy, and 58% who did not respond (P = 3.2 x 10(-10)). Resequencing of IL28B identified distinct haplotypes that were associated with the clinical phenotype. CONCLUSIONS: The association of the IL28B locus with natural and treatment-associated control of HCV indicates the importance of innate immunity and interferon lambda in the pathogenesis of HCV infection.

Altered NKG2D function in NK cells induced by chronic exposure to NKG2D ligand-expressing tumor cells.

NKG2D is an activation receptor that allows natural killer (NK) cells to detect diseased host cells. The engagement of NKG2D with corresponding ligand results in surface modulation of the receptor and reduced function upon subsequent receptor engagement. However, it is not clear whether in addition to modulation the NKG2D receptor complex and/or its signaling capacity is preserved. We show here that the prolonged encounter with tumor cell-bound, but not soluble, ligand can completely uncouple the NKG2D receptor from the intracellular mobilization of calcium and the exertion of cell-mediated cytolysis. However, cytolytic effector function is intact since NKG2D ligand-exposed NK cells can be activated via the Ly49D receptor. While NKG2D-dependent cytotoxicity is impaired, prolonged ligand exposure results in constitutive interferon gamma (IFNgamma) production, suggesting sustained signaling. The functional changes are associated with a reduced presence of the relevant signal transducing adaptors DNAX-activating protein of 10 kDa (DAP-10) and killer cell activating receptor-associated protein/DNAX-activating protein of 12 kDa (KARAP/DAP-12). That is likely the consequence of constitutive NKG2D engagement and signaling, since NKG2D function and adaptor expression is restored to normal when the stimulating tumor cells are removed. Thus, the chronic exposure to tumor cells expressing NKG2D ligand alters NKG2D signaling and may facilitate the evasion of tumor cells from NK cell reactions.

Redirection of T cells by delivering a transgenic mouse-derived MDM2 tumor antigen-specific TCR and its humanized derivative is governed by the CD8 coreceptor and affects natural human TCR expression.

Retroviral transfer of T cell antigen receptor (TCR) genes selected by circumventing tolerance to broad tumor- and leukemia-associated antigens in human leukocyte antigen (HLA)-A*0201 (A2.1) transgenic (Tg) mice allows the therapeutic reprogramming of human T lymphocytes. Using a human CD8 x A2.1/Kb mouse derived TCR specific for natural peptide-A2.1 (pA2.1) complexes comprising residues 81-88 of the human homolog of the murine double-minute 2 oncoprotein, MDM2(81-88), we found that the heterodimeric CD8 alpha beta coreceptor, but not normally expressed homodimeric CD8 alpha alpha, is required for tetramer binding and functional redirection of TCR- transduced human T cells. CD8+T cells that received a humanized derivative of the MDM2 TCR bound pA2.1 tetramers only in the presence of an anti-human-CD8 anti-body and required more peptide than wild-type (WT) MDM2 TCR+T cells to mount equivalent cytotoxicity. They were, however, sufficiently effective in recognizing malignant targets including fresh leukemia cells. Most efficient expression of transduced TCR in human T lymphocytes was governed by mouse as compared to human constant (C) alphabeta domains, as demonstrated with partially humanized and murinized TCR of primary mouse and human origin, respectively. We further observed a reciprocal relationship between the level of Tg WT mouse relative to natural human TCR expression, resulting in T cells with decreased normal human cell surface TCR. In contrast, natural human TCR display remained unaffected after delivery of the humanized MDM2 TCR. These results provide important insights into the molecular basis of TCR gene therapy of malignant disease.

Aspergillus fumigatus fungus ball in hospitalized patients with chronic pulmonary disease: usefulness of double immunodiffusion test as a screening procedure

Double immunodiffusion (DID) was used as a screening test for the diagnosis of aspergillosis. Three hundred and fifty patients were tested, all of them referred from a specialized chest disease hospital and without a definitive etiological diagnosis. When DID was positive addtional information such as clinical history and radiographic findings were requested and also surgical specimens were obtained whenever possible. Specific precipitin hamds for Aspergillus fumigatus antigen were found in 29 (8.3%) of 350 patients sera. Nineteen (65.5%) of the 29 patients with positive serology were recognized as having a fungus ball by X-rays signs in 17 or by pathological examination in 2 or by both in 8 patients. This two-year prospective study has shown that pulmonary aspergillos is a considerable problem among patiens admitted to a Chest Diseases Hospital, especially in those with pulmonary cavities or bronchiectasis.