Bacteria-induced intestinal cancer in mice with disrupted Gpx1 and Gpx2 genes

Two glutathione peroxidase (GPX) isozymes, GPX-1 and GPX-2 (GPX-GI), are the major enzymes that reduce hydroperoxides in intestinal epithelium. We have previously demonstrated that targeted disruption of both the Gpx1 and Gpx2 genes (GPX-DKO) results in a high incidence of ileocolitis in mice raised under conventional conditions, which include the harboring of Helicobacter species [non-specific-pathogen-free (non-SPF) conditions]. In this study, we have characterized GPX-DKO mice that have microflora-associated intestinal cancers, which are correlated with increased intestinal pathology/inflammation. We found that GPX-DKO mice raised under germ-free conditions have virtually no pathology or tumors. After colonizing germ-free mice with commensal microflora without any known pathogens (SPF), <9% of GPX-DKO mice develop tumors in the ileum or the colon. However, about one-fourth of GPX-DKO mice raised under non-SPF conditions from birth or transferred from SPF conditions at weaning have predominantly ileal tumors. Nearly 30% of tumors are cancerous; most are invasive adenocarcinomas and a few signet-ring cell carcinomas. On the basis of these results, we conclude that GPX-DKO mice are highly susceptible to bacteria-associated inflammation and cancer. The sensitivity exhibited in these mice suggests that peroxidative stress plays an important role in ileal and colonic pathology and inflammation, which can lead to tumorigenesis.     

Combination of alpha-interferon with lamivudine reduces viral breakthrough during long-term therapy

BACKGROUND AND AIM: Viral breakthrough is frequently encountered during long-term lamivudine therapy, mostly associated with YMDD mutants. In this study, we investigated the effects of alpha-interferon (IFN-alpha) combined with lamivudine on the occurrence of viral breakthrough during long-term lamivudine therapy. METHODS: Eighty-three patients with biopsy-proven chronic hepatitis B were randomly allocated to a combination of lamivudine and IFN-alpha (LAM/IFN; n = 41) or lamivudine only (LAM; n = 42), and then followed up for >12 months. We calculated the cumulative rate of undetectable serum HBV-DNA and hepatitis B e antigen (HBeAg) loss, as well as the cumulative occurrence rate of viral breakthrough. We also evaluated the relationship between YMDD mutants and the occurrence of viral breakthrough. RESULTS: There was no difference in cumulative rates of undetectable serum HBV-DNA (100%vs 100% at 24 months, P = 0.13) and cumulative rates of serum HBeAg loss between the LAM/IFN group and the LAM group (49%, 61% and 67%vs 31%, 39% and 42%, respectively, at 12, 24 and 36 months; P = 0.07). The cumulative occurrence rate of viral breakthrough, however, was significantly lower in the LAM/IFN group compared with the LAM group (5%, 20% and 30%vs 10%, 55% and 58%, respectively, at 12, 24 and 36 months; P = 0.006). From the patients with viral breakthrough, YMDD mutants were detected in 82% (18 of 22) of the LAM group in contrast with 56% (five of nine) of the LAM/IFN group in their sera. CONCLUSION: IFN-alpha combined with lamivudine may reduce viral breakthrough during long-term lamivudine therapy, probably by suppressing the appearance of YMDD mutants.     

Clinical diagnosis and assessment of severity of confirmed dengue infections in Vietnamese children: is the world health organization classification system helpful?

Classification of dengue using the current World Health Organization (WHO) system is not straightforward. In a large prospective study of pediatric dengue, no clinical or basic laboratory parameters clearly differentiated between children with and without dengue, although petechiae and hepatomegaly were independently associated with the diagnosis. Among the 712 dengue-infected children there was considerable overlap in the major clinical features. Mucosal bleeding was observed with equal frequency in those with dengue fever and dengue hemorrhagic fever (DHF), and petechiae, thrombocytopenia, and the tourniquet test differentiated poorly between the two diagnostic categories. Fifty-seven (18%) of 310 with shock did not fulfill all four criteria considered necessary for a diagnosis of DHF by the WHO, but use of the WHO provisional classification scheme resulted in considerable over-inflation of the DHF figures. If two separate entities truly exist rather than a continuous spectrum of disease, it is essential that some measure of capillary leak is included in any classification system, with less emphasis on bleeding and a specific platelet count.     

Characteristic clinical features of hepatocellular carcinoma associated with Budd-Chiari syndrome: evidence of different carcinogenic process from hepatitis B virus-associated hepatocellular carcinoma

OBJECTIVE: Budd-Chiari syndrome (BCS) is a known risk factor for hepatocellular carcinoma (HCC). Considering the pathophysiological mechanism of BCS, BCS-associated HCC may have a different carcinogenic process to hepatitis B virus (HBV)-associated HCC, resulting in different characteristic clinical features. METHODS: The clinical, radiological and histopathological characteristics of 15 HCCs associated with BCS were analysed and compared with 211 HBV-associated HCCs. RESULTS: HCC associated with BCS showed a female predominance in contrast to a male predominance in HCC associated with HBV infection. Child classes of BCS-associated HCC patients were not different from the classes of HBV-associated HCC. BCS tended to be associated with the single nodular type of HCC. Only one BCS-associated HCC patient had portal vein invasion at the time of diagnosis, compared with 96 patients with HBV-associated HCC. No HCC patients with BCS showed biliary invasion, compared with 47 HBV-associated HCC patients. The median survival period of HCC patients associated with BCS was 58 months, which was much longer than the median survival period of 10 months in HBV-associated HCC. All of the three BCS-associated HCCs available for histological examination were well differentiated. CONCLUSIONS: Patients with HCC associated with BCS seemed to survive for much longer periods than those with HBV due to the low invasiveness of the tumour. Such unique clinical features may be evidence of different carcinogenic processes in BCS-associated and HBV-associated HCC.     

Issues in the management of endocarditis caused by resistant gram-positive organisms

Most cases of infective endocarditis (IE) are caused by gram-positive bacteria such as enterococci, streptococci, and staphylococci. Increasing resistance among these organisms has eroded the utility of mainstay antibiotics and complicated the management of this difficult-to-treat infection. Clinical experience with newer gram-positive antibiotics to treat IE is limited.     

Ankle-brachial pressure index measured using an automated oscillometric method as a predictor of the severity of coronary atherosclerosis in patients with coronary artery disease

Ankle-brachial pressure index (ABI) measured using a conventional Doppler method is an independent predictor of the number of coronary vessels affected in coronary artery disease (CAD). Recently, a new clinical device has been developed to measure ABI using an oscillometric method. It is unclear whether ABI measured using this device is a significant predictor of the severity of coronary atherosclerosis. We retrospectively included 87 patients from our outpatient clinic who had ever undergone coronary angiography. ABI was determined in all subjects using the new ABI-form device. The lower value of ABI in either limb was used for analysis. We divided our subjects into two groups, with either ABI less than 0.9 or at least 0.9, and compared basal characteristics between groups. We analyzed the relationship between ABI and the severity of CAD. In addition, we calculated the sensitivity, specificity, and positive and negative predictive values of ABI less than 0.9 in predicting multivessel (two-vessel + three-vessel) involvement in our patients. There were 15 patients with ABI less than 0.9 and 72 with ABI at least 0.9. Patients with ABI less than 0.9 were older and had higher plasma levels of uric acid. The prevalence of diabetes mellitus, hypertension, smoking, and diuretic use was significantly higher in patients with ABI less than 0.9. In addition, the group with ABI less than 0.9 had a lower prevalence of one-vessel CAD and higher prevalence of three-vessel or multivessel CAD. The sensitivity, specificity, and positive and negative predictive values of ABI less than 0.9 in predicting multivessel CAD were 22%, 96%, 93%, and 34%, respectively. In conclusion, ABI measured using the automated oscillometric method can be used to predict the severity of coronary atherosclerosis in patients with CAD.     

Treatment of xanthoma disseminatum with cyclophosphamide

Xanthoma disseminatum is a rare non-Langerhans cell (class II) histiocytosis, which is often resistant to treatment. We describe an illustrative case with extensive mucocutaneous, ocular, laryngeal, pituitary and central nervous system involvement, which responded to treatment with cyclophosphamide. The presentation, course and treatment of the condition are reviewed. Many of the non-Langerhans cell histiocytoses represent a spectrum of diseases of dermal dendrocytes ranging from self-limiting and benign conditions to multisystem progressive diseases that respond poorly to treatment and severely impair quality of life. We suggest that chemotherapy should be considered at an early stage in the more aggressive subtypes of non-Langerhans cell histiocytoses.     

Aberrant responses in social interaction of dopamine transporter knockout mice

The dopamine (DA) transporter (DAT) controls the temporal and spatial resolution of dopaminergic neurotransmission. Disruption of the Dat1 gene in mice leads to increased extracellular DA concentrations and reduced expression of D1- and D2-like receptors in striatum. The mutants are hyperactive in the open field and they display deficits in learning and memory. In humans, dopaminergic dysfunction has been associated with a number of different psychiatric disorders and some of these conditions are accompanied by abnormal social responses. To determine whether social responses were also impaired in DAT knockout (KO) mice, behaviors of group- and isolation-housed animals were compared. All group-housed animals readily established hierarchies. However, the social organizations of the mutants were changed over time. Under both group- and isolation-housed conditions, mutants exhibited increased rates of reactivity and aggression following mild social contact. In isolation, exposure to a novel environment exacerbated these abnormal responses. Regardless of housing context, stereotyped and perseverative patterns of social responses were a common feature of the KO repertoire. In fact, many abnormal behaviors were due to the emergence and predominance of these inflexible behaviors. These data suggest that KO mice may serve as a useful animal model for understanding not only how DA dysfunction contributes to social abnormalities, but also how behavioral inflexibility distorts their social responses.     

Continuous cytosine-b-D-arabinofuranoside infusion reduces ectopic granule cells in adult rat hippocampus with attenuation of spontaneous recurrent seizures following pilocarpine-induced status epilepticus

Brief or prolonged seizures induce various patterns of plasticity. Axonal or dendritic remodelling and development of ectopic granule cells have been described in the hilus and molecular layer of the adult rodent hippocampus. Hippocampal cell proliferation also occurs after seizures. However, whether the seizure-induced cell proliferation plays a pathological or reparative role in the epileptic brain is unknown. In this study, we attempted to suppress the seizure-induced cell proliferation with the antimitotic agent cytosine-b-D-arabinofuranoside (Ara-C) and to examine the development of spontaneous recurrent seizures (SRS). Experimental status epilepticus was induced with pilocarpine, and Ara-C or vehicle alone was infused continuously with an osmotic minipump. SRS were video-monitored. BrdU immunohistochemistry was used for the spatial and temporal analysis of hippocampal cell proliferation, and double labelling with NeuN, calbindin and GFAP antibodies was performed for the differentiation of BrdU-positive cells. Timm staining was also performed for evaluation of mossy fibre sprouting (MFS). With continuous Ara-C infusion, the likelihood of developing SRS was decreased and, during the latent period, the development of ectopic granule cells in the hilus and new glia in the CA1 area was reduced when compared with the vehicle-infused group, while MFS was not altered. The results suggest that the hippocampal cell proliferation plays a pro-epileptogenic role rather than a compensatory role, and that the epileptogenic process may be associated with the generation of new glia in the CA1 area and/or new neurons in the dentate gyrus, particularly the ectopically located hilar granule cells.     

A fatal case of hepatic failure possibly induced by nitrosofenfluramine: a case report

A 42-year-old female developed fulminant hepatic failure after having ingested an undetermined quantity of a herbal product over a period of approximately four months prior to the onset of her illness. Clinically, the cause of liver failure was assessed to be drug-induced and she eventually underwent total hepatectomy, with porto-caval shunting, in anticipation of a living-unrelated liver transplant. Unfortunately, her condition deteriorated and she died less than 48 hours post-operatively, approximately three weeks post-admission. An autopsy showed that the subject was deeply jaundiced and severely obese (BMI: 47.1 kg m(-2)), with evidence of diffuse haemorrhage, including the presence of 1.35 l of blood in the peritoneal cavity. The liver had been removed and was later recovered as a formalin-fixed specimen which was markedly contracted, comprising multiple micronodules interspersed with extensive areas of dense fibrotic tissue. Histologically, there was massive necrosis of the hepatic parenchyma, such that the residual hepatocytes were disposed as nodules displaying variable cellular regeneration and ballooning degeneration, attended by florid ductal proliferation and mixed inflammatory infiltrates. Infective, autoimmune, metabolic, vascular, neoplastic and most other natural causes of massive hepatocellular necrosis were effectively excluded. Analysis of the post-mortem blood samples yielded fluconazole, metronidazole, frusemide, lignocaine and tramadol, (therapeutic agents administered to the patient during her last illness). Subsequent analysis of the residual capsules revealed that they were adulterated by fenfluramine, N-nitrosofenfluramine (1.3-1.6 mg per capsule), nicotinamide (13.3-15.6 mg per capsule) and thyroid extract. None of the herbal ingredients is currently known to be hepatotoxic and much the same applies to fenfluramine, nicotinamide (except when taken in mega-doses) and thyroid extract. However, as nitrosamines are known to be variably hepatotoxic, it would be reasonable to surmise that, in the absence of a more plausible cause of liver damage, N-nitrosofenfluramine was the likely cause of massive hepatocellular necrosis in this instance.