Tollip, an early regulator of the acute inflammatory response in the substantia nigra.

BACKGROUND: Tollip is a ubiquitously expressed protein, originally described as a modulator of the IL-1R/TLR-NF-κB signaling pathways. Although this property has been well characterized in peripheral cells, and despite some evidence of its expression in the central nervous system, the role of Tollip in neuroinflammation remains poorly understood. The present study sought to explore the implication of Tollip in inflammation in the substantia nigra pars compacta, the structure affected in Parkinson's disease. METHODS: We first investigated Tollip distribution in the midbrain by immunohistochemistry. Then, we addressed TLR4-mediated response by intra-nigral injections of lipopolysaccharide (LPS), a TLR4 agonist, on inflammatory markers in Tollip knockout (KO) and wild-type (WT) mice. RESULTS: We report an unexpectedly high Tollip immunostaining in dopaminergic neurons of the mice brain. Second, intra-nigral injection of LPS led to increased susceptibility to neuroinflammation in Tollip KO compared to Tollip WT mice. This was demonstrated by a significant increase of tumor necrosis factor alpha (TNF-α), interleukin 1 beta (IL-1ß), interleukin 6 (IL-6), and interferon gamma (IFN-γ) messenger RNA (mRNA) in the midbrain of Tollip KO mice upon LPS injection. Consistently, brain rAAV viral vector transduction with a nuclear factor kappa B (NF-κB)-inducible reporter gene confirmed increased NF-κB activation in Tollip KO mice. Lastly, Tollip KO mice displayed higher inducible NO synthase (iNOS) production, both at the messenger and protein level when compared to LPS-injected WT mice. Tollip deletion also aggravated LPS-induced oxidative and nitrosative damages, as indicated by an increase of 8-oxo-2'-deoxyguanosine and nitrotyrosine immunostaining, respectively. CONCLUSIONS: Altogether, these findings highlight a critical role of Tollip in the early phase of TLR4-mediated neuroinflammation. As brain inflammation is known to contribute to Parkinson's disease, Tollip may be a potential target for neuroprotection.

[Whipple's disease, when to think about it?]. / Maladie de Whipple: quand y penser?

Whipple's disease is a chronic, systemic, bacterial infection caused by Tropheryma whipplei. Its cardinal symptoms include intermittent and recurrent arthralgia or arthritis together with chronic diarrhoea, abdominal pain and weight loss. It may mimick many chronic inflammatory diseases, and the diagnosis remains a challenge. Salivary and faecal quantitative PCR for T. whipplei should be ensued, if positive, by an upper endoscopy for duodenal biopsies. The treatment consists of a combination of oral doxycycline and hydroxychloroquine for 12 months followed by life-long doxycycline. Whipple's disease, although rare, is an entity that should be considered regularly, as its progression may be fatal if left untreated.

[Digestive foreign body management]. / Risques et bénéfices d'une approche interventionnelle face aux corps étrangers digestifs.

Foreign body (FB) ingestion is a frequent reason for gastroenterology consulting. Eighty percent of these ingestions are accidental and observed among paediatric subjects. However, intentional repetitive ingestions are also observed, especially amongst prisoners or psychiatric patients. Most FBs pass throughout the digestive tract without any complication and without any need for surgical or endoscopic intervention. Nevertheless, around 10-20% of cases require an endoscopy examination and 1% will lead to a surgical intervention. Management approaches should favor inter-disciplinarity, balance benefits and risks of FB removal based on its location, and integrate psychiatric comorbidities into the decision process.

[New melanoma immunotherapies: mechanisms of action, efficiency and management of toxicities]. / Nouvelles immunotherapies du mélanome: mécanismes d'action, efficacité et prise en charge des toxicities.

In recent years the therapy of metastatic melanoma has been revolutionized from a disease with very few efficient treatment options to one with access to multiple therapies which can impact on patient survival. Two main classes of therapies have been developed: 1. Immunotherapy by immune checkpoint inhibitors and 2. Small molecule inhibitors of the MAPK pathway. Immunotherapies achieved by either inhibition of CTLA-4 or the PD1/PD-Ll axes are impacting the overall survival in an important fraction of patients. In addition, the side effects of these immune therapy approaches require early detection by all the specialists involved as well as early management according to precise guidelines for optimal outcome.

[Clostridium difficile infections: update on new European recommendations]. / Colite à Clostridium difficile: nouvelles recommandations de prise en charge.

Clostridium difficile infections: update on new European recommandations While metronidazole and vancomycin have been the only drug options to date for the treatment of C. difficile infection, new therapeutic approaches with promising results have recently emerged for the treatment of the first episode and relapses. Fidaxomicin is a new macrocyclic antibiotic more active against C. difficile and with a narrow spectrum allowing preservation of the intestinal microbiota. While having the same efficacy as vancomycin for the treatment of the first episode, this agent is associated with a lower rate of relapse. The highest relapse-free cure rate is achieved through fecal microbiota transplantation, which should be considered for patients with multiple relapses.

[Food allergy or food intolerance?]. / Allergie ou intolérance alimentaire?

Adverse food reactions can be classified into two main categories depending on wether an immune mechanism is involved or not. The first category includes immune mediated reactions like IgE mediated food allergy, eosinophilic oesophagitis, food protein-induced enterocolitis syndrome and celiac disease. The second category implies non-immune mediated adverse food reactions, also called food intolerances. Intoxications, pharmacologic reactions, metabolic reactions, physiologic, psychologic or reactions with an unknown mechanism belong to this category. We present a classification of adverse food reactions based on the pathophysiologic mechanism that can be useful for both diagnostic approach and management.

[An update on celiac disease]. / Maladie coeliaque: état des lieux.

Celiac disease is a well-known entity in pediatrics and pediatric gastroenterology that is now also frequently encountered in the adult population. Apart from typical symptoms, celiac disease can present with a wide range of manifestations that are sometimes atypical, scarce or purely extraintestinal. Serologic and genetic testing are useful tools in case of low clinical probability in the early diagnostic algorithm. Upper gastrointestinal endoscopy remains the mainstay to confirm the diagnosis especially in atypical clinical presentations. Complications are rare but can be severe. Although gluten-free diet often leads to complete recovery, compliance is not universal and alternative treatment strategies are under investigation.

Macrophages promote epithelial repair through hepatocyte growth factor secretion.

Macrophages play a critical role in intestinal wound repair. However, the mechanisms of macrophage-assisted wound repair remain poorly understood. We aimed to characterize more clearly the repair activities of murine and human macrophages. Murine macrophages were differentiated from bone marrow cells and human macrophages from monocytes isolated from peripheral blood mononuclear cells of healthy donors (HD) or Crohn's disease (CD) patients or isolated from the intestinal mucosa of HD. In-vitro models were used to study the repair activities of macrophages. We found that murine and human macrophages were both able to promote epithelial repair in vitro. This function was mainly cell contact-independent and relied upon the production of soluble factors such as the hepatocyte growth factor (HGF). Indeed, HGF-silenced macrophages were less capable of promoting epithelial repair than control macrophages. Remarkably, macrophages from CD patients produced less HGF than their HD counterparts (HGF level: 84 ± 27 pg/mg of protein and 45 ± 34 pg/mg of protein, respectively, for HD and CD macrophages, P < 0·009) and were deficient in promoting epithelial repair (repairing activity: 90·1 ± 4·6 and 75·8 ± 8·3, respectively, for HD and CD macrophages, P < 0·0005). In conclusion, we provide evidence that macrophages act on wounded epithelial cells to promote epithelial repair through the secretion of HGF. The deficiency of CD macrophages to secrete HGF and to promote epithelial repair might contribute to the impaired intestinal mucosal healing in CD patients.

[Gastrointestinal neuroendocrine tumors: pleomorphic and often ignored]. / Tumeurs neuroendocrines digestives: pléomorphes et souvent ignorées.

Although generally considered as rare, incidence of gastrointestinal neuroendocrine tumors (GI-NETs) is increasing. The general practitioner has thus to be familiar with the vast array of clinical presentations and the growing family of diagnostic tools that can be used. Symptoms can be related to their hormonal production, their local extent or a bleeding complication. The prognosis depends on the grade of tumor, its local extent at diagnosis and its localization. The diagnosis relies on radiologic, endoscopic and nuclear medicine strategies. In case of typical symptoms, a hormonal secretion should be sought. Treatment options are extensive and should be discussed in an interdisciplinary manner.

[Inflammatory bowel disease: a "survival kit" for general practitioners]. / Les maladies inflarnmatoires chroniques de l'intestin: "survival kit" pour internistes et généralistes.

There are approximately 12000 patients suffering from inflammatory bowel disease (IBD) in Switzerland. IBD can be debilitating not only because of the direct consequences in the gut but also because of extraintestinal manifestations. An early diagnosis is the key in defining optimal therapeutic interventions. The management is multidisciplinary and the general practitioner should work in direct collaboration with a gastroenterologist. Optimal management should aim at inducing and maintaining remission as well as reducing the risk of complications such as abcesses, fistulas or colorectal cancer.

[Main therapeutic advances in IBD in 2008]. / Maladies inflammatoires de l'intestin.

A coimmunosuppression with azathioprine or methotrexate in addition to infliximab does not improve the therapeutic efficacy in Crohn's disease but increase the risks of infectious complications and neoplasia.