Cerebrospinal fluid irisin and lipoxin A4 are reduced in elderly Brazilian individuals with depression: Insight into shared mechanisms between depression and dementia.

INTRODUCTION: Depression is frequent among older adults and is a risk factor for dementia. Identifying molecular links between depression and dementia is necessary to shed light on shared disease mechanisms. Reduced brain-derived neurotrophic factor (BDNF) and neuroinflammation are implicated in the pathophysiology of depression and dementia. The exercise-induced hormone, irisin, increases BDNF and improves cognition in animal models of Alzheimer's disease. Lipoxin A4 is a lipid mediator with anti-inflammatory activity. However, the roles of irisin and lipoxin A4 in depression remain to be determined. METHODS: In the present study, blood and CSF were collected from 61 elderly subjects, including individuals with and without cognitive impairment. Screening for symptoms of depression was performed using the 15-item Geriatric Depression Scale (GDS-15). RESULTS: CSF irisin and lipoxin A4 were positively correlated and reduced, along with a trend of BDNF reduction, in elderly individuals with depression, similar to previous observations in patients with dementia. DISCUSSION: Our findings provide novel insight into shared molecular signatures connecting depression and dementia.

Modeling Alzheimer's Disease Using Human Brain Organoids.

Alzheimer's disease (AD) is the primary cause of dementia, to date. The urgent need to understand the biological and biochemical processes related to this condition, as well as the demand for reliable in vitro models for drug screening, has led to the development of novel techniques, among which stem cell methods are of utmost relevance for AD research, particularly the development of human brain organoids. Brain organoids are three-dimensional cellular aggregates derived from induced pluripotent stem cells (iPSCs) that recreate different neural cell interactions and tissue characteristics in culture. Here, we describe the protocol for the generation of brain organoids derived from AD patients and for the analysis of AD-derived pathology. AD organoids can recapitulate beta-amyloid and tau pathological features, making them a promising model for studying the molecular mechanisms underlying disease and for in vitro drug testing.

Age-linked suppression of lipoxin A4 associates with cognitive deficits in mice and humans.

Age increases the risk for cognitive impairment and is the single major risk factor for Alzheimer's disease (AD), the most prevalent form of dementia in the elderly. The pathophysiological processes triggered by aging that render the brain vulnerable to dementia involve, at least in part, changes in inflammatory mediators. Here we show that lipoxin A4 (LXA4), a lipid mediator of inflammation resolution known to stimulate endocannabinoid signaling in the brain, is reduced in the aging central nervous system. We demonstrate that genetic suppression of 5-lipoxygenase (5-LOX), the enzyme mediating LXA4 synthesis, promotes learning impairment in mice. Conversely, administration of exogenous LXA4 attenuated cytokine production and memory loss induced by inflammation in mice. We further show that cerebrospinal fluid LXA4 is reduced in patients with dementia and positively associated with cognitive performance, brain-derived neurotrophic factor (BDNF), and AD-linked amyloid-ß. Our findings suggest that reduced LXA4 levels may lead to vulnerability to age-related cognitive disorders and that promoting LXA4 signaling may comprise an effective strategy to prevent early cognitive decline in AD.

In Vivo and In Vitro Models of Hepatocellular Carcinoma: Current Strategies for Translational Modeling.

Hepatocellular carcinoma (HCC) is the sixth most common cancer worldwide and the third leading cause of cancer-related death globally. HCC is a complex multistep disease and usually emerges in the setting of chronic liver diseases. The molecular pathogenesis of HCC varies according to the etiology, mainly caused by chronic hepatitis B and C virus infections, chronic alcohol consumption, aflatoxin-contaminated food, and non-alcoholic fatty liver disease associated with metabolic syndrome or diabetes mellitus. The establishment of HCC models has become essential for both basic and translational research to improve our understanding of the pathophysiology and unravel new molecular drivers of this disease. The ideal model should recapitulate key events observed during hepatocarcinogenesis and HCC progression in view of establishing effective diagnostic and therapeutic strategies to be translated into clinical practice. Despite considerable efforts currently devoted to liver cancer research, only a few anti-HCC drugs are available, and patient prognosis and survival are still poor. The present paper provides a state-of-the-art overview of in vivo and in vitro models used for translational modeling of HCC with a specific focus on their key molecular hallmarks.

Cerebrospinal Fluid Neurotransmitters, Cytokines, and Chemokines in Alzheimer's and Lewy Body Diseases.

BACKGROUND: Alzheimer's disease (AD) and Lewy body disease (LBD) are complex neurodegenerative disorders that have been associated with brain inflammation and impaired neurotransmission. OBJECTIVE: We aimed to determine concentrations of multiple cytokines, chemokines, and neurotransmitters previously associated with brain inflammation and synapse function in cerebrospinal fluid (CSF) from AD and LBD patients. METHODS: We examined a panel of 50 analytes comprising neurotransmitters, cytokines, chemokines, and hormones in CSF in a cohort of patients diagnosed with mild cognitive impairment (MCI), AD, LBD, or non-demented controls (NDC). RESULTS: Among neurotransmitters, noradrenaline (NA) was increased in AD CSF, while homovanillic acid (HVA), a dopamine metabolite, was reduced in both AD and LBD CSF relative to NDC. Six cytokines/chemokines out of 30 investigated were reliably detected in CSF. CSF vascular endothelial growth factor (VEGF) was significantly reduced in LBD patients relative to NDC. CONCLUSIONS: CSF alterations in NA, HVA, and VEGF in AD and LBD may reflect pathogenic features of these disorders and provide tools for improved diagnosis. Future studies are warranted to replicate current findings in larger, multicenter cohorts.

Occult hepatitis B virus infection in patients with chronic liver disease due to hepatitis C virus and hepatocellular carcinoma in Brazil.

BACKGROUND: The prevalence and consequences of occult HBV infection in patients with chronic liver disease by HCV remain unknown. AIMS: To evaluate the prevalence of occult HBV infection in a population of HCV-infected patients with hepatocellular carcinoma. METHODS: The serum samples were tested for HBV DNA by nested PCR and liver tissue analysis was carried out using the immunohistochemical technique of 66 HBsAg-negative patients: 26 patients with chronic hepatitis by HCV (group 1), 20 with hepatocellular carcinoma related to chronic infection by HCV (group 2) and 20 with negative viral markers for hepatitis B and C (control group). RESULTS: Occult HBV infection was diagnosed in the liver tissue of 9/46 (19.5%) HCV-infected patients. Prevalence of occult B infection was evaluated in the HCV-infected patients with and without hepatocellular carcinoma, and there were seven (77.7%) of whom from group 2, conferring a 35% prevalence of this group. No serum sample was positive for HBV DNA in the three groups. CONCLUSION: Occult infection B is frequently detected in liver tissue of HCV-infected patients, especially in cases of hepatocellular carcinoma. However large studies are needed to confirm that co-infection could determine a worse progress of chronic liver disease in this population.

Occult hepatitis B virus infection in patients with chronic liver disease due to hepatitis C virus and hepatocellular carcinoma in Brazil

BACKGROUND: The prevalence and consequences of occult HBV infection in patients with chronic liver disease by HCV remain unknown. AIMS: To evaluate the prevalence of occult HBV infection in a population of HCV-infected patients with hepatocellular carcinoma. METHODS: The serum samples were tested for HBV DNA by nested PCR and liver tissue analysis was carried out using the immunohistochemical technique of 66 HBsAg-negative patients: 26 patients with chronic hepatitis by HCV (group 1), 20 with hepatocellular carcinoma related to chronic infection by HCV (group 2) and 20 with negative viral markers for hepatitis B and C (control group). RESULTS: Occult HBV infection was diagnosed in the liver tissue of 9/46 (19.5 percent) HCV-infected patients. Prevalence of occult B infection was evaluated in the HCV-infected patients with and without hepatocellular carcinoma, and there were seven (77.7 percent) of whom from group 2, conferring a 35 percent prevalence of this group. No serum sample was positive for HBV DNA in the three groups. CONCLUSION: Occult infection B is frequently detected in liver tissue of HCV-infected patients, especially in cases of hepatocellular carcinoma. However large studies are needed to confirm that co-infection could determine a worse progress of chronic liver disease in this population.

RACIONAL: A prevalência e as conseqüências da infecção oculta pelo VHB em pacientes com infecção crônica pelo VHC permanecem desconhecidas. OBJETIVO: Avaliar a prevalência da infecção oculta pelo VHB em uma população de pacientes infectados com o VHC e carcinoma hepatocelular. MÉTODOS: Amostras de soro foram testadas para o DNA do VHB por "nested" PCR e análise do tecido hepático utilizando imunoistoquímica de 66 pacientes HBsAg negativos: 26 pacientes com hepatite crônica pelo VHC (grupo 1), 20 com carcinoma hepatocelular relacionado ao VHC (grupo 2) e 20 com marcadores negativos para os vírus das hepatites B e C (grupo controle). RESULTADOS: Infecção oculta pelo VHB foi diagnosticada no tecido hepático de 9/46 (19.5 por cento) pacientes com infecção pelo VHC. A prevalência foi avaliada nos pacientes com VHC com e sem carcinoma hepatocelular, estando presente em sete (77.7 por cento) deste último grupo, conferindo 35 por cento de infecção oculta pelo VHB nos pacientes com carcinoma hepatocelular. Nenhuma amostra de soro foi positiva para o DNA-VHB nos três grupos. CONCLUSÃO: A infecção oculta B é freqüentemente detectada no tecido hepático de pacientes infectados com VHC, especialmente nos casos de carcinoma hepatocelular. Entretanto, outros estudos com maior número de pacientes são necessários para confirmar se a co-infecção determina a progressão da doença hepática nesta população.

Molecular epidemiology of hepatitis C virus subtype 3a in injecting drug users.

Hepatitis C virus subtype 3a (HCV-3a) originates from Asia and has spread widely among injecting drug users as well as other patient groups in industrialized countries. HCV subtype 3a infection remains highly prevalent and frequently transmitted in the population of intravenous drug users. The objective of this study was to understand better the mechanisms of the worldwide HCV-3a epidemics in drug users. Ninety-three sera from HCV-3a-infected IDUs from France, the United States, Brazil, Argentina, and Australia were studied. Phylogenetic analyses of the non-structural 5B region showed no specific clustering according to the continent of the patient's origin. Non-exclusive clusters of viral sequences from South America, Australia, and California were observed, but topologies were not supported by strong bootstrap values. The results suggest that HCV-3a has been transmitted from a common origin through a unique worldwide epidemic that rapidly spread among drug users. Regional transmission occurred in the recent past, leading to an embryonic genetic diversification of HCV-3a among local injecting drug user population.

Strong association between genotype F and hepatitis B virus (HBV) e antigen-negative variants among HBV-infected argentinean blood donors.

A number of reports have indicated an increased risk of cirrhosis and hepatocellular carcinoma in hepatitis B virus (HBV)-infected individuals carrying HBV e antigen (HBeAg)-negative variants. Although distinct core promoter and precore mutations distributed according to geographical locality and viral genotype have been reported, epidemiological data from South America are still scarce. The prevalences of HBV genotypes and core promoter and precore polymorphisms in 75 HBeAg-negative Argentinean blood donors were surveyed. The observed frequencies of HBV genotypes were 64.0% for genotype F, 17.3% each for genotypes A and D, and 1.3% for genotype C. Genotype F strains were widely distributed and significantly more prevalent in the northern region of the country (P < 0.001). An overall high proportion of a stop codon mutation (UAG) at precore codon 28 (66.7%) was observed. Wild-type codon 28 (UGG) was present in 29.3% of the samples, and the remaining 4.0% of samples had mixed variants. The combination of A at nucleotide (nt) 1762 and G at nt 1764 of the core promoter was found in 58.7% of the samples. The variant profiles--T at nt 1762 and A at nt 1764 or A at nt 1762 and A at nt 1764--were detected in 28.0 and 1.3% of the samples, respectively. The observed core promoter polymorphisms could not be related to the ratio of HBeAg to anti-HBeAg antibody, HBV genotype, or precore codon 28 status. Nevertheless, a clear association of genotype F and a precore stop codon mutation was found (P < 0.05). In conclusion, HBV genotype F and mutant codon 28 strains predominated and were strongly associated in a geographically broad Argentinean blood donor population.

Rapid detection of resistance against rifampicin in isolates of Mycobacterium tuberculosis from Brazilian patients using a reverse-phase hybridization assay.

The main objective of this study was to evaluate INNO-LiPA Rif.TB and to determine the frequency of mutations in rpoB in rifampicin-resistant Mycobacterium tuberculosis isolates of Brazilian tuberculosis patients. We used the reverse hybridization assay on 113 resistant and 15 sensitive clinical isolates of M. tuberculosis and on reference strains belonging to 37 different species. All MTB complex strains and none of the other strains reacted with the MTB complex-specific probe, meaning that the assay is 100% specific and 100% sensitive for detection of strains of the MTB complex. In 80 resistant strains, mutations causing S531L (n=55), H526Y (n=9), H526D (n=12) or D516V (n=9) were detected while in 30 strains, mutations were present but their exact nature was not determined by the assay (DeltaS patterns). All sensitive strains had the sensitive genotype while among resistant isolates, a sensitive genotype was obtained in three due to the absence of mutations in the hot spot region, demonstrating an assay accuracy of 97.6% for detection of drug susceptibility. In 10 resistant cultures, two or more mutations were detected and in five, mixed sensitive and resistant genotypes were observed. The sensitivity of the assay for detection of resistant organisms in a mixture with sensitive ones were 2% and 70%, respectively, considering the appearance and disappearance of the R2 and S2 bands. The sensitivity to detect heteroresistance is similar to that of the proportion method when a specific probe for the mutation is present but the performance of the assay in the patient population will depend on the frequency of mutation distribution.

Presença de auto-anticorpos não-tireóide-específicos no soro de pacientes com hipotireoidismo auto-imune / Presence of nonthyroid-specific autoantibodies in autoimmune hypothyroidism

Auto-anticorpos contra componentes não-específicos da tireóide foram encontrados no soro de pacientes com doença auto-imune da tireóide. Neste estudo avaliamos a presença de auto-anticorpos antinucleares (ANA), antimitocôndria (anti-MC) no soro de pacientes com hipotireoidismo auto-imune (HA), comparando-os a controles saudáveis. Estudamos 70 pacientes com hipotireoidismo auto-imune (tireoidite de Hashimoto ou tireoidite atrófica) e 70 controles saudáveis (sem diagnóstico de doença auto-imune e tireoidiana), todos do sexo feminino, com média de idade de 50,2 anos (+ 15,9) e 49,6 anos (+ 14,4), respectivamente. O ANA, detectado através do sistema Inno-LIA ANA (Innogenetics, Bélgica), foi positivo em 26 por cento dos pacientes com HA e em 14 por cento dos controles, não sendo esta diferença significativa (p = 0,09). Não houve diferença entre tempo de doença ou idade entre os grupos ANA positivo ou negativo. Anticorpos anti-ML e anti-Mc foram negativos em todas as amostras, sendo analisados através de imunofluorescência indireta. Concluímos que pacientes com hipotireoidismo auto-imune não apresentaram maior incidência de auto-anticorpos não-específicos para tireóide do que controles saudáveis. Ressaltamos, contudo, que a associação entre doenças auto-imunes da tireóide e outras doenças auto-imunes é fato incontestável, podendo ocorrer em qualquer período no curso de sua evolução. Portanto avaliações regulares são recomendadas.

High prevalence of human papillomavirus (HPV) infections and high frequency of multiple HPV genotypes in human immunodeficiency virus-infected women in Brazil.

A group of 208 human immunodeficiency virus (HIV)-infected women in Brazil were studied for the presence of human papillomavirus with the general SPF(10) PCR primer set. Virtually all (98%) women were found positive for human papillomavirus (HPV) DNA. Genotyping by the reverse hybridization line probe assay (HPV-LiPA) revealed a high prevalence of multiple genotypes (78.9% of the cases), with an average of 3.1 genotypes per patient (range, 1 to 10 genotypes). HPV 6 was the most prevalent genotype and was observed in 80 (39.2%) patients, followed by types 51 (31.9%), 11 (26.0%), 18 (24.0%), and 16 (22.5%). Of the genotypes detected, 40.9% were low-risk genotypes. Twenty-two (10.5%) patients showed normal (Pap I) cytology, 149 (71.6%) patients had inflammation (Pap II), and 28 patients (13.4%) had a Pap III score. The prevalence of high-risk genotypes increased with the cytological classification. There were no significant associations between the number of HPV genotypes detected and the cytological classification, HIV viral load, and CD4 count in these patients. In conclusion, the highly sensitive SPF(10) LiPA system shows that a very high proportion of HIV-infected women in Brazil are infected with HPV and often carry multiple HPV genotypes.

Prevalence of hepatitis C infection in patients with non-Hodgkin's lymphomas.

Several studies have suggested an association between hepatitis C virus (HCV) and low-grade B-cell non-Hodgkin's lymphomas. The results, however, have been controversial. Italian and Japanese studies have reported a 40% prevalence rate, but the data were not confirmed by English and Canadian studies. We evaluated the prevalence of HCV infection in 109 patients with non-Hodgkin's lymphomas, and compared it with a control group composed of 67 patients with Hodgkin's disease and 31 patients with chronic lymphocytic leukemia. The prevalence of HCV infection was also determined in blood donors. HCV infection was detected using second and third generation anti-HCV ELISA. Positive results were additionally confirmed using Inno-LIA AbIII and/or RNA-HCV by PCR. Immunohistochemical stains were used to determine B or T cell lineage when the morphological analysis was not sufficient for lymphoma classification. HCV infection was detected in 9% of patients with non-Hodgkin's lymphomas, in 2% of patients in the control group (p=0.036), and in 1.2% of blood donors. There was no difference in the prevalence of HCV infection between patients with B or T cell lymphomas. Blood transfusions or previous surgeries, both risk factors for HCV infection, were detected in 90% of the patients with a positive anti-HCV test, in average 17 and 36 years before the diagnosis of lymphoma, respectively. Seventy percent of the patients with non-Hodgkin's lymphomas and a positive anti-HCV test presented evidence of chronic liver disease when the lymphoma was diagnosed. This study suggests the presence of an association between HCV infection and non-Hodgkin's lymphomas in Brazil.

Hepatitis C prevalence and risk factors in hemodialysis patients in Central Brazil: a survey by polymerase chain reaction and serological methods

An hemodialysis population in Central Brazil was screened by polymerase chain reaction (PCR) and serological methods to assess the prevalence of hepatitis C virus (HCV) infection and to investigate associated risk factors. All hemodialysis patients (n=428) were interviewed in eight dialysis units in GoiÔnia city. Blood samples were collected and serum samples screened for anti-HCV antibodies by an enzyme-linked immunosorbent assay (ELISA). Positive samples were retested for confirmation with a line immunoassay (LIA). All samples were also tested for HCV RNA by the PCR. An overall prevalence of 46.7 percent (CI 95 percent: 42-51.5) was found, ranging from 20.7 percent (CI 95 percent: 8.8-38.1) to 90.4 percent (CI 95 percent: 79.9-96.4) depending on the dialysis unit. Of the 428 patients, 185 were found to be seropositive by ELISA, and 167 were confirmed positive by LIA, resulting in an anti-HCV prevalence of 39 percent. A total of 131 patients were HCV RNA-positive. HCV viremia was present in 63.5 percent of the anti-HCV-positive patients and in 10.3 percent of the anti-HCV-negative patients. Univariate analysis of risk factors showed that the number of previous blood transfusions, transfusion of blood before mandatory screening for anti-HCV, length of time on hemodialysis, and treatment in multiple units were associated with HCV positivity. However, multivariate analysis revealed that blood transfusion before screening for anti-HCV and length of time on hemodialysis were significantly associated with HCV infection in this population. These data suggest that nosocomial transmission may play a role in the spread of HCV in the dialysis units studied. In addition to anti-HCV screening, HCV RNA detection is necessary for the diagnosis of HCV infection in hemodialysis patients

Hepatitis B virus infection profile in Central Brazilian hemodialysis population

A hepatite B tem sido uma grande ameaca aos pacientes de hemodialise. Para investigar o perfil da infeccao pelo virus da hepatite B (VHB) na populacao de hemodialise de Goiania - Brasil Central, 282 pacientes foram estudados. A prevalencia de marcadores do VHB (AgHBs, anti-HBc e anti-HBs) foi de 56,7 por cento (IC 95 por cento: 51,1 - 62,7) variando de 33,3 por cento a 77,7 por cento entre as unidades de dialise. O VHB-DNA foi detectado nas amostras AgHBs positivas em 67,6 por cento e 88,2 por cento, nas AgHBs e AgHBe em 91,3 por cento e 100 por cento, e nas AgHBe e anti-HBe e soro reativas em 18,2 por cento e 63,6 por cento por hibridizacao e PCR, respectivamente. O tempo de tratamento hemodialitico mostrou-se estatisticamente associado a soropositividade ao VHB. Somente 10 por cento dos pacientes relataram vacinacao para a hepatite B. Assim, uma prevalencia elevada para infeccao pelo VHB nesta populacao e o risco aumentado do tempo de tratamento hemodialitico sugerem a transmissao ambiental deste virus...

Soroprevalência do vírus da hepatite C na populaçäo em diálise de Goiânia, GO / Prevalence of hepatitis C virus among dialysis population in Goiânia, Goiás State, Brazil

Um estudo soroepidemiológico para anticorpo do vírus da hepatite C (anti-VHC) foi realizado na populaçäo em diálise de Goiânia, com objetivo de avaliar a soroprevalência do vírus e sua associaçäo com possíveis fatores de risco. Foram estudados 173 pacientes com idade variando de 10- 70 anos, 35,3 por cento (61/173) apresentaram soropositividade pelo ELISA de segunda geraçäo e 25 por cento (44/173) pelo INNO-LIA. Uso de drogas, hábitos sexuais, número de tranfusöes e atividade de transaminases näo apresentaram relaçäo significativa com a soropositividade. A permanência no tratamento e o uso da hemodiálise apresentaram correlaçäo positiva com o anti-VHC (p<0,05). Os dados sugerem que a hepatite C tem alta prevalência nos pacientes em hemodiálise e que o tempo em tratamento é um fator de risco para adquirir a infecçäo