Liver inflammation is greater in nonalcoholic steatohepatitis (NASH) than steatosis, suggesting that immune responses contribute to nonalcoholic fatty liver disease (NAFLD) progression. Livers normally contain many natural killer T (NKT) cells that produce factors that modulate inflammatory and fibrogenic responses. Such cells are relatively depleted in steatosis, but their status in more advanced NAFLD is uncertain. We hypothesized that NKT cells accumulate and promote fibrosis progression in NASH. We aimed to determine if livers become enriched with NKT cells during NASH-related fibrosis; identify responsible mechanisms; and assess if NKT cells stimulate fibrogenesis. NKT cells were analyzed in wildtype mice and Patched-deficient (Ptc 1/2 ) mice with an overly active Hedgehog (Hh) pathway, before and after feeding methionine choline-deficient (MCD) diets to induce NASH-related fibrosis. Effects of NKT cell-derived factors on hepatic stellate cells (HSC) were examined and fibrogenesis was evaluated in CD1d-deficient mice that lack NKT cells. NKT cells were quantified in human cirrhotic and nondiseased livers. During NASH-related fibrogenesis in wildtype mice, Hh pathway activation occurred, leading to induction of factors that promoted NKT cell recruitment, retention, and viability, plus liver enrichment with NKT cells. Ptc 1/2 mice accumulated more NKT cells and developed worse liver fibrosis; CD1d-deficient mice that lack NKT cells were protected from fibrosis. NKT cell-conditioned medium stimulated HSC to become myofibroblastic. Liver explants were 2-fold enriched with NKT cells in patients with non-NASH cirrhosis, and 4-fold enriched in patients with NASH cirrhosis. Conclusion: Hh pathway activation leads to hepatic enrichment with NKT cells that contribute to fibrosis progression in NASH.

Hh pathway activation promotes many processes that occur during fibrogenic liver repair. Whether the Hh pathway modulates the outcomes of virally-mediated liver injury has never been examined. Gene-profiling studies of human hepatocellular carcinomas (HCC) demonstrate Hh pathway activation in HCCs related to chronic infection with hepatitis B virus (HBV) or hepatitis C virus (HCV). Because most HCC develop in cirrhotic livers, we hypothesized that Hh pathway activation occurs during fibrogenic repair of liver damage due to chronic viral hepatitis, and that Hh-responsive cells mediate disease progression and hepatocarciongenesis in chronic viral hepatitis. Immunohistochemistry and qRTPCR analysis were used to analyze Hh pathway activation and identify Hh-responsive cell types in liver biopsies from 45 patients with chronic HBV or HCV. Hh signaling was then manipulated in cultured liver cells to directly assess the impact of Hh activity in relevant cell types. We found increased hepatic expression of Hh ligands in all patients with chronic viral hepatitis, and demonstrated that infection with HCV stimulated cultured hepatocytes to produce Hh ligands. The major cell populations that expanded during cirrhosis and HCC (i.e., liver myofibroblasts, activated endothelial cells, and progenitors expressing markers of tumor stem/initiating cells) were Hh-responsive, and higher levels of Hh pathway activity associated with cirrhosis and HCC. Inhibiting pathway activity in Hh-responsive target cells reduced fibrogenesis, angiogenesis, and growth. Conclusions HBV/HCV infection increases hepatocyte production of Hh ligands and expands types of Hh-responsive cells that promote liver fibrosis and cancer.

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In order to investigate epidemiological aspects of hepatocellular carcinoma (HCC) in Brazil, basic informations about cases diagnosed from January 1992 to December 1994 were requested to several medical centers of different Brazilian States. A simple questionnaire included age, sex, alcohol abuse (over 80g/day), associated liver cirrhosis, persistent HBV infection (HBsAg), HCV infection (anti-HCV) and serum levels of alpha fetoprotein. 287 cases, over 16 years old, from 19 medical centers of 8 States (Pará, Bahia, Minas Gerais, Espirito Santo, Rio de Janeiro, São Paulo, Paraná and Rio Grande do Sul) were analysed. The results showed: (a) Mean age was 56.3 +/- 14.4 for men and 54.7 +/- 16.8 yr for women and the male/female ratio was 3.4:1. (b) 69.6% were caucasians, 21.8% mullatoes, 4.8% orientals and 3.7% blacks. (c) HBsAg (+) in 77/236 cases (41.6%) without differences between males and females. (d) Anti-HCV (+) in 52/193 cases (26.9%). (e) 7/180 cases were positive both for HBsAg and anti-HCV (3.8%). (f) There was chronic alcoholism in 88/235 cases (37%). (g) HCC was found in cirrhotic livers in 71.2% of 202 cases in which the presence or absence of cirrhosis was reported. (h) Alpha-fetoprotein above 20 ng/ml was found in 124/172 cases (72%) and above 500 ng/ml only in 40 cases (23.2%). These results showed that the HCC in Brazil has an intermediate epidemiological pattern as compared to those from areas of low and high incidence of the tumor. In spite of the high frequency of the association of HCC with the HBV and/or HCV infections, 42% of 180 cases were negative both for HBsAg and anti-HCV, indicating the possible role of other etiological factors. The comparison of data from different States showed some regional differences: higher frequency of associated HBsAg in Pará, Bahia, Minas Gerais and Espírito Santo, higher frequency of associated HCV infection in Rio de Janeiro, São Paulo and States of the Southern region and low frequency of associated liver cirrhosis in Salvador and Rio de Janeiro (55.5 and 50% respectively). Further investigation will be necessary to study the presence of other possible etiological factors as aflatoxins, suggested by the favourable climatic conditions for food contamination by fungi in the majority Brazilian regions.

We report a significantly higher prevalence of intestinal nematodes in patients with pulmonary tuberculosis (TB) compared to a matched control group: 33/57 (57.8%) in patients with TB and 18/86 (20.9%) in the control group; OR=5.19; 95% CI= 2.33-11.69; p=0.000). When TB patients eosinophilia was also significantly higher among those with intestinal parasites (69.8%) compared to those without this condition (45.6%). We hypothesized that the immune modulation induced by nematodes is a factor that enhances TB infection/ progression and that eosinophilia seen in TB patients is a consequence of helminth infection. Key-words: Tuberculosis. Helminthiasis. Strongyloidiasis. Mycobacterium tuberculosis.Resumo Nesta comunicação relatamos uma prevalência significativamente maior de nematóides intestinais em pacientes com tuberculose pulmonar (TB), comparada a um grupo controle pareado: 33/57 (57,8%) nos pacientes com TB e 18/86 (20,9%) no grupo controle; OR=5.19; IC a 95%= 2.33-11.69;p=0.000). Dentre os pacientes com TB, a eosinofilia foi significativamente maior nos pacientes com nematóides intestinais (69,8%) comparados àqueles sem parasitas (45,6%). Nossa hipótese é que a imunomodulação induzida por nematóides é fator facilitador da infecção/progressão da doença na TB e que a eosinofilia frequentemente vista em pacientes com TB é secundária à infecção helmíntica.

, stool specimens of children less than 2 years of age with diarrhoea (n5218) and without diarrhoea (n586), living in Vitó ria, Espírito Santo, Brazil, were examined for the presence of diarrhoeagenic Escherichia coli. E. coli isolates were tested by colony blot hybridization with specific DNA probes designed to detect EPEC, ETEC, EIEC, EAEC, DAEC and EHEC/STEC. Diarrhoeagenic E. coli strains were detected as the sole pathogen in stools of 92 (30.3 %) children, including 72 (33.0 %) with diarrhoea and 20 (23.2 %) without diarrhoea. DAEC was the most frequent pathotype and was found significantly more often from patients (18.3 %) than from controls (8.1 %) (P,0.05), particularly among children more than 1 year of age (P50.01). Atypical EPEC and EAEC isolates were isolated from both patients (5.5 % and 4.6 %, respectively) and controls (6.9 % and 6.9 %, respectively). ETEC was more frequently isolated from patients (3.2 %) than controls (1.2 %). Typical EPEC (0.9 %) and EIEC (0.4 %) isolates were detected only in children with diarrhoea. In conclusion, our data suggest that DAEC should be considered potential pathogens in the region of Brazil studied. INTRODUCTIONDiarrhoeagenic Escherichia coli constitute an important group of pathogens associated with enteric diseases. Six E. coli pathotypes associated with diarrhoea are currently recognized: enteropathogenic E. coli (EPEC), enterotoxigenic E. coli (ETEC), enteroinvasive E. coli (EIEC), enterohaemorrhagic E. coli (EHEC) or Shiga toxin-producing E. coli (STEC), enteroaggregative E. coli (EAEC), and diffusely adherent E. coli (DAEC). EPEC are divided into typical (tEPEC) and atypical (aEPEC) subgroups depending on the presence or absence of the EPEC adherence factor (EAF) plasmid, respectively (Nataro & Kaper, 1998).Each type of diarrhoeagenic E. coli is defined on the basis of distinct virulence characteristics, and DNA probes for these characteristics have been developed to distinguish types of diarrhoeagenic E. coli from each other and from nonpathogenic E. coli strains of normal flora (Nataro & Kaper, 1998).It has become clear that there are regional differences in the relative prevalence of the different types of diarrhoeagenic E. coli and such differences may affect the overall regional prevalence of diarrhoeal diseases. In Brazil, several studies have investigated the relative prevalence of diarrhoeagenic E. coli among children with and without diarrhoea. However, most of these studies have been performed predominantly in the cities of São Paulo and Rio de Janeiro, two large urban centres in south-eastern Brazil (Rosa et al., 1998;Gomes et al., 1991;Scaletsky et al., 1999Scaletsky et al., , 2002bRegua-Mangia et al., 2004;Araujo et al., 2007). The aim of the present study was to determine the relative prevalence and the role of the different E. coli pathotypes as cause of acute diarrhoea in the city of Vitó ria, Espírito Santo, another large urban centre in south-eastern Brazil, where childhood diarrhoea is endemic.Abbreviations: DAEC, diffusely adherent E. c...

We report the results of a retrospective study on the frequency of intestinal nematodes among 198 alcoholic and 440 nonalcoholic patients at the University Hospital Cassiano Antonio Moraes in Vitória, ES, Brazil. The control sample included 194 nonalcoholic patients matched according to age, sex and neighborhood and a random sample of 296 adults admitted at the same hospital. Stool examination by sedimentation method (three samples) was performed in all patients. There was a significantly higher frequency of intestinal nematodes in alcoholics than in controls (35.3% and 19.2%, respectively), due to a higher frequency of Strongyloides stercoralis (21.7% and 4.1%, respectively). Disregarding this parasite, the frequency of the other nematodes was similar in both groups. The higher frequency of S. stercoralis infection in alcoholics could be explained by immune modulation and/or by some alteration in corticosteroid metabolism induced by chronic ethanol ingestion. Corticosteroid metabolites would mimic the worm ecdisteroids, that would in turn increase the fecundity of females in duodenum and survival of larvae. Consequently, the higher frequency of Strongyloides larvae in stool of alcoholics does not necessarily reflect an increased frequency of infection rate, but only an increased chance to present a positive stool examination using sedimentation methods. Key-words: Alcoholism. Strongyloidiasis. Strongyloides stercoralis. Intestinal nematodes.Resumo Foi feito um estudo retrospectivo da freqüência de nematóides intestinais em 198 alcoolistas e em 440 controles, não alcoólatras, atendidos no Hospital Universitário C.A. Morais, em Vitória, ES. O grupo controle foi formado por 194 pacientes não alcoólatras, pareados por idade, sexo e procedência, e por 296 pacientes adultos, internados no mesmo hospital, escolhidos aleatoriamente. Fez-se exame parasitológico pelo método de sedimentação em todos os casos. Houve uma freqüência signifcativamente maior de nematóides intestinais no grupo de alcoólatras do que nos controles (35,3% e 18,7%, respectivamente), devido a freqüência maior de Strongyloides stercoralis (21,7% e 4,1%, respectivamente). A freqüência dos outros nematóides foi semelhante nos dois grupos. A maior freqüência de S. sterocralis nos alcoólatras poderia ser explicada pela imunomodulação induzida pela ingestão abusiva de etanol e/ou por alteração do metabolismo dos corticosteróides induzidas pelo etanol, aumentando a quantidade de metabólitos que podem mimetizar os ecdisteróides do verme, aumentando a fecundidade das fêmeas no duodeno e a sobrevivência das larvas. Desse modo, a maior freqüência de S. stercoralis nos alcoólatras não refletiria um real aumento na prevalência, mas sim um aumento na positividade do exame parasitólogico devido ao aumento do número de larvas rabdtóides eliminadas pelas fêmeas no duodeno.

SummaryResistance to intracellular pathogens such as Mycobacterium leprae is dependent upon an effective T helper type 1 (Th1)-type immune response. On the other hand, intestinal helminths are known to subvert the host's immune response towards to either a Th2-type immune response or a regulatory T cell up-regulation, which may affect the host's ability to mount an effective response to mycobacteria. Here, we report a significant association between intestinal helminth infections and lepromatous leprosy [odds ratio (OR), 10·88; confidence interval (CI) 95%: 4·02-29·4; P < 0·001]. We also observed that the frequency of intestinal helminths correlated strongly with the mycobacterial index (r = 0·982, P < 0·01). Corroborating with our hypothesis, intracellular levels of interferon-g were decreased significantly in leprosy patients co-infected with intestinal helminths when compared to leprosy patients without worms. Conversely, lepromatous leprosy patients with intestinal worms produced higher levels of both interleukin (IL)-4 and IL-10. Our results suggest that a pre-existing infection by intestinal helminths may facilitate the establishment of M. leprae infection or its progression to more severe forms of leprosy.