Gene expression profiles of immune mediators and histopathological findings in animal models of leptospirosis: comparison between susceptible hamsters and resistant mice.

Leptospirosis is a widespread zoonosis characterized by multiple organ failure and variable host susceptibility toward pathogenic Leptospira strains. In this study, we put the role of inflammatory mediators in parallel with bacterial burdens and organ lesions by comparing a susceptible animal model, the hamster, and a resistant one, the Oncins France 1 (OF1) mouse, both infected with virulent Leptospira interrogans serovar Icterohaemorrhagiae strain Verdun. Histological observations evidenced edema, congestion, hemorrhage, and inflammatory infiltration in the organs of hamsters, in contrast to limited changes in mice. Using reverse transcription-quantitative PCR techniques, we showed that the relative Leptospira burden progressively increased in hamster tissues, while a rapid clearance was observed in mouse tissues. The early regulation of the proinflammatory mediators interleukin-1ß (IL-1ß), IL-6, tumor necrosis factor alpha, and cyclo-oxygenase-2 and the chemokines gamma interferon-inducible protein 10 kDa/CXCL10 and macrophage inflammatory protein-1α/CCL3 in mouse tissues contrasted with their delayed and massive overexpression in hamster tissues. Conversely, the induction of the anti-inflammatory cytokine IL-10 was faster in the resistant than in the susceptible animal model. The role of these cytokines in the pathophysiology of leptospirosis and the implications of their differential regulation in the development of this disease are discussed.

Iron and exercise induced alterations in antioxidant status. Protection by dietary milk proteins.

Lipid peroxidation stress induced by iron supplementation can contribute to the induction of gut lesions. Intensive sports lead to ischemia reperfusion, which increases free radical production. Athletes frequently use heavy iron supplementation, whose effects are unknown. On the other hand, milk proteins have in vitro antioxidant properties, which could counteract these potential side effects. The main aims of the study were: (1) to demonstrate the effects of combined exercise training (ET) and iron overload on antioxidant status; (2) to assess the protective properties of casein in vivo; (3) to study the mechanisms involved in an in vitro model. Antioxidant status was assessed by measuring the activity of antioxidant enzymes (superoxide dismutase (SOD); glutathione peroxidase (GSH-Px)), and on the onset of aberrant crypts (AC) in colon, which can be induced by lipid peroxidation. At day 30, all ET animals showed an increase in the activity of antioxidant enzymes, in iron concentration in colon mucosa and liver and in the number of AC compared to untrained rats. It was found that Casein's milk protein supplementation significantly reduced these parameters. Additional information on protective effect of casein was provided by measuring the extent of TBARS formation during iron/ascorbate-induced oxidation of liposomes. Free casein and casein bound to iron were found to significantly reduce iron-induced lipid peroxidation. The results of the overall study suggest that Iron supplementation during intensive sport training would decrease anti-oxidant status. Dietary milk protein supplementation could at least partly prevent occurrence of deleterious effects to tissue induced by iron overload.

[Active WHO class IV lupus nephritis in a patient treated with etanercept for a psoriasic arthritis]. / Néphropathie lupique stade IV chez une patiente traitée par étanercept pour un rhumatisme psoriasique.

INTRODUCTION: Drug-induced lupus nephritis in patients treated with TNF α inhibitor is a rare adverse effect. Anti-TNF α therapies are commonly associated with the induction of auto-antibodies, whereas anti-TNF α-induced lupus is rare, most frequently involving arthritis and cutaneous lesions. However, several renal involvement has been reported. OBSERVATION: A 26-year old woman with a history of psoriasic arthritis treated with TNF α inhibitor (etanercept) presented with a biopsy-proved class IV lupus nephritis. The diagnosis of drug-induced lupus nephritis was probable and anti-TNF α therapy was discontinued. Standard lupus nephritis therapy was then started with prednisolone pulses and mycophenolate mofetil (MMF). Two weeks later, a septic shock following a leg cellulitis was caused by Pseudomonas aeruginosa and had a fatal evolution despite MMF withdrawal, adapted antibiotherapy and large wound excision. DISCUSSION: Our therapy was not different than for other class IV lupus nephritis. Our observation highlights two points: first the attributability to etanercept in lupic manifestations in our patient and second the therapeutic strategy in this particular case of drug-induced lupus. CONCLUSION: We reported a possible first case of IV lupus nephritis induced by anti-TNF α with a fatal evolution.

Mitochondrial adaptations to steatohepatitis induced by a methionine- and choline-deficient diet.

Nonalcoholic fatty liver disease (NAFLD) has become common liver disease in Western countries. There is accumulating evidence that mitochondria play a key role in NAFLD. Nevertheless, the mitochondrial consequences of steatohepatitis are still unknown. The bioenergetic changes induced in a methionine- and choline-deficient diet (MCDD) model of steatohepatitis were studied in rats. Liver mitochondria from MCDD rats exhibited a higher rate of oxidative phosphorylation with various substrates, a rise in cytochrome oxidase (COX) activity, and an increased content in cytochrome aa3. This higher oxidative activity was associated with a low efficiency of the oxidative phosphorylation (ATP/O, i.e., number of ATP synthesized/natom O consumed). Addition of a low concentration of cyanide, a specific COX inhibitor, restored the efficiency of mitochondria from MCDD rats back to the control level. Furthermore, the relation between respiratory rate and protonmotive force (in the nonphosphorylating state) was shifted to the left in mitochondria from MCDD rats, with or without cyanide. These results indicated that, in MCDD rats, mitochondrial ATP synthesis efficiency was decreased in relation to both proton pump slipping at the COX level and increased proton leak although the relative contribution of each phenomenon could not be discriminated. MCDD mitochondria also showed a low reactive oxygen species production and a high lipid oxidation potential. We conclude that, in MCDD-fed rats, liver mitochondria exhibit an energy wastage that may contribute to limit steatosis and oxidative stress in this model of steatohepatitis.

Usefulness of follow-up after pancreatoduodenectomy for carcinoma of the ampulla of Vater.

BACKGROUND: The prognosis for carcinoma of the ampulla of Vater (CAV) is better than for pancreatic cancer. The 5-year survival median rate after resection of CAV is 45%, but late recurrences remain possible. Several survival factors have been identified (lymph nodes, perineural invasion), but few data are available on the type of recurrences, their impact and their management. PATIENTS AND METHODS: A total of 41 patients treated by pancreatoduodenectomy (PD) for CAV from 1980 to 2003 were studied retrospectively. Patient selection, long-term survival recurrence rate and recurrence treatment were reviewed. Univariate and multivariate proportional hazards analysis were conducted on this series. RESULTS: The mean follow-up was 48 months. Five-year survival was 62.8%. Eleven patients had recurrences (6-67 months). Recurrence was associated with time to all-causes death (hazard ratio [HR] 4.3, p=0.003). Factors predictive of recurrence were perineural invasion (HR 5.3, p=0.02), lymph node invasion (HR 5.3, p=0.02) and differentiation (HR 0.2, p=0.05). Three patients underwent surgical R0 treatment of their recurrences. Two who presented with solitary liver metastasis are alive and disease-free. CONCLUSIONS: Recurrence represents a serious threat in the prognosis of CAV after surgery. Some of these recurrences, in particular liver metastases, are accessible for a curative treatment. This finding supports the usefulness of a close and long-term follow-up after surgery to improve survival of patients with CAV, especially in the group of patients with a good prognosis.

Long term highly saturated fat diet does not induce NASH in Wistar rats.

BACKGROUND: Understanding of nonalcoholic steatohepatitis (NASH) is hampered by the lack of a suitable model. Our aim was to investigate whether long term high saturated-fat feeding would induce NASH in rats. METHODS: 21 day-old rats fed high fat diets for 14 weeks, with either coconut oil or butter, and were compared with rats feeding a standard diet or a methionine choline-deficient (MCD) diet, a non physiological model of NASH. RESULTS: MCDD fed rats rapidly lost weight and showed NASH features. Rats fed coconut (86% of saturated fatty acid) or butter (51% of saturated fatty acid) had an increased caloric intake (+143% and +30%). At the end of the study period, total lipid ingestion in term of percentage of energy intake was higher in both coconut (45%) and butter (42%) groups than in the standard (7%) diet group. No change in body mass was observed as compared with standard rats at the end of the experiment. However, high fat fed rats were fattier with enlarged white and brown adipose tissue (BAT) depots, but they showed no liver steatosis and no difference in triglyceride content in hepatocytes, as compared with standard rats. Absence of hepatic lipid accumulation with high fat diets was not related to a higher lipid oxidation by isolated hepatocytes (unchanged ketogenesis and oxygen consumption) or hepatic mitochondrial respiration but was rather associated with a rise in BAT uncoupling protein UCP1 (+25-28% vs standard). CONCLUSION: Long term high saturated fat feeding led to increased "peripheral" fat storage and BAT thermogenesis but did not induce hepatic steatosis and NASH.

Polyunsaturated fatty acid deficiency reverses effects of alcohol on mitochondrial energy metabolism.

BACKGROUND/AIMS: Polyunsaturated fatty acids (PUFA) deficiency is common in patients with alcoholic liver disease. The suitability of reversing such deficiency remains controversial. The aim was to investigate the role played by PUFA deficiency in the occurrence of alcohol-related mitochondrial dysfunction. METHODS: Wistar rats were fed either a control diet with or without alcohol (control and ethanol groups) or a PUFA deficient diet with or without alcohol (PUFA deficient and PUFA deficient+ethanol groups). After 6 weeks, liver mitochondria were isolated for energetic studies and fatty acid analysis. RESULTS: Mitochondria from ethanol fed rats showed a dramatic decrease in oxygen consumption rates and in cytochrome oxidase activity. PUFA deficiency showed an opposite picture. PUFA deficient+ethanol group roughly reach control values, regarding cytochrome oxidase activity and respiratory rates. The relationship between ATP synthesis and respiratory rate was shifted to the left in ethanol group and to the right in PUFA-deficient group. The plots of control and PUFA deficient+ethanol groups were overlapping. Phospholipid arachidonic over linoleic ratio closely correlated to cytochrome oxidase and oxygen uptake. CONCLUSIONS: PUFA deficiency reverses alcohol-related mitochondrial dysfunction via an increase in phospholipid arachidonic over linoleic ratio, which raises cytochrome oxidase activity. Such deficiency may be an adaptive mechanism.