Colonization with Helicobacter is concomitant with modified gut microbiota and drastic failure of the immune control of Mycobacterium tuberculosis.

Epidemiological and experimental observations suggest that chronic microbial colonization can impact the immune control of other unrelated pathogens contracted in a concomitant or sequential manner. Possible interactions between Mycobacterium tuberculosis infection and persistence of other bacteria have scarcely been investigated. Here we demonstrated that natural colonization of the digestive tract with Helicobacter hepaticus in mice is concomitant with modification of the gut microbiota, subclinical inflammation, and drastic impairment of immune control of the growth of subsequently administered M. tuberculosis, which results in severe lung tissue injury. Our results provided insights upon the fact that this prior H. hepaticus colonization leads to failures in the mechanisms that could prevent the otherwise balanced cross-talk between M. tuberculosis and the immune system. Such disequilibrium ultimately leads to the inhibition of control of mycobacterial growth, outbreak of inflammation, and lung pathology. Among the dysregulated immune signatures, we noticed a correlation between the detrimental lung injury and the accumulation of activated T-lymphocytes. Our findings suggest that the impact of prior Helicobacter spp. colonization and subsequent M. tuberculosis parasitism might be greater than previously thought, which is a key point given that both species are among the most frequent invasive bacteria in human populations.

Oocyte-specific inactivation of Omcg1 leads to DNA damage and c-Abl/TAp63-dependent oocyte death associated with dramatic remodeling of ovarian somatic cells.

Aberrant loss of oocytes following cancer treatments or genetic mutations leads to premature ovarian insufficiency (POI) associated with endocrine-related disorders in 1% of women. Therefore, understanding the mechanisms governing oocyte death is crucial for the preservation of female fertility. Here, we report the striking reproductive features of a novel mouse model of POI obtained through oocyte-specific inactivation (ocKO) of Omcg1/Zfp830 encoding a nuclear zinc finger protein involved in pre-mRNA processing. Genetic ablation of OMCG1 in early growing oocytes leads to reduced transcription, accumulation of DNA double-strand breaks and subsequent c-Abl/TAp63-dependent oocyte death, thus uncovering the key role of OMCG1 for oocyte genomic integrity. All adult Omcg1(ocKO) females displayed complete elimination of early growing oocytes and sterility. Unexpectedly, mutant females exhibited a normal onset of puberty and sexual receptivity. Detailed studies of Omcg1(ocKO) ovaries revealed that the ovarian somatic compartment underwent a dramatic structural and functional remodeling. This allowed the cooperation between oocyte-depleted follicles and interstitial tissue to produce estradiol. Moreover, despite early folliculogenesis arrest, mutant mice exhibited sexual cyclicity as shown by cyclical changes in estrogen secretion, vaginal epithelium cytology and genital tract weight. Collectively, our findings demonstrate the key role of Omcg1 for oocyte survival and highlight the contribution of p63 pathway in damaged oocyte elimination in adulthood. Moreover, our findings challenge the prevailing view that sexual cyclicity is tightly dependent upon the pace of folliculogenesis and luteal differentiation.

Histological and molecular biology diagnosis of neurocysticercosis in a patient without history of travel to endemic areas: case report.

BACKGROUND: in endemic areas, neurocysticercosis appears mainly as a single, large, spherical and non-enhancing intracranial cyst. CASE PRESENTATION: an atypical case of neurocysticercosis (NCC) in a French Caucasian, without history of travel to endemic areas, was confirmed by histology and molecular speciation. Imaging was atypical, showing several hook-bearing scolices visible in the cyst, while the serology employed was non-contributary. CONCLUSIONS: NCC should be considered when multiple taeniid scolices are observed within the same cystic lesion.

A global analysis of mucormycosis in France: the RetroZygo Study (2005-2007).

BACKGROUND: Mucormycosis is a deadly invasive fungal infection whose characteristics are only partially understood. METHODS: Data on mucormycosis obtained in France between 2005 and 2007 from 2 notification systems were merged. The 2008 European Organisation for Research and Treatment of Cancer/Mycoses Study Group definition criteria were applied and risk factors for death were analyzed by hazard ratios (HRs) calculated from the Cox proportional hazards regression model. RESULTS: A total of 101 cases (60 proven, 41 probable), mostly in men (58%) >50 years (mean age, 50.7 ± 19.9) were recorded. Hematological malignancies represented 50% (median time for occurrence, 8.8 months after disease onset), diabetes 23%, and trauma 18% of cases. Sites of infection were lungs (28%; 79% in hematology patients), rhinocerebral (25%; 64% in diabetic patients), skin (20%), and disseminated (18%). Median time between first symptoms and diagnosis was 2 weeks. The main fungal species were Rhizopus oryzae (32%) and Lichtheimia species (29%). In cases where the causative species was identified, R. oryzae was present in 85% of rhinocerebral forms compared with only 17% of nonrhinocerebral forms (P < .001). Treatment consisted of surgery in 59% and antifungals in 87% of cases (liposomal amphotericin B in 61%). Ninety-day survival was 56%; it was reduced in cases of dissemination compared with rhinocerebral (HR, 5.38 [2.0-14.1]; P < .001), pulmonary (HR, 2.2 [1.0-4.7]; P = .04), or skin localization (HR, 5.73 [1.9-17.5]; P = .002); survival was reduced in cases of hematological malignancies compared with diabetes mellitus (HR, 2.3 [1.0-5.2]; P < .05) or trauma (HR, 6.9 [1.6-28.6], P = .008) and if ≥2 underlying conditions (HR, 5.9 [1.8-19.0]; P = .004). Mucormycosis localization remained the only independent factor associated with survival. CONCLUSIONS: This 3-year study performed in one country shows the diverse clinical presentation of mucormycosis with a high prevalence of primary skin infection following trauma and a prognosis significantly influenced by localization.

Clinical relevance of cagA and vacA gene polymorphisms in Helicobacter pylori isolates from Senegalese patients.

The molecular epidemiology of Helicobacter pylori in Africa is poorly documented. From January 2007 to December 2008, we investigated 187 patients with gastric symptoms in one of the main tertiary hospitals in Dakar, Senegal. One hundred and seventeen patients were culture-positive for H. pylori. Polymorphisms in vacA and cagA status were investigated by PCR; the 3'-region of cagA was sequenced, and EPIYA motifs were identified. Bacterial heterogeneity within individuals was extensively assessed by using an approach based on vacA and cagA heterogeneity. Fourteen per cent of H. pylori-positive patients displayed evidence of mixed infection, which may affect disease outcome. Patients with multiple vacA alleles were excluded from subsequent analyses. Among the final study population of 105 patients, 29 had gastritis only, 61 had ulcerated lesions, and 15 had suspicion of neoplasia based on endoscopic findings. All cases of suspected neoplasia were histologically confirmed as gastric cancer (GC). The cagA gene was present in 73.3% of isolates. CagA proteins contained zero (3.7%), one (93.9%) or two (2.4%) EPIYA-C segments, and all were western CagA. Most of the isolates possessed presumed high-vacuolization isotypes (s1i1m1 (57.1%) or s1i1m2 (21.9%)). Despite the small number of cases, GC was associated with cagA (p 0.03), two EPIYA-C segments in the C-terminal region of CagA (p 0.03), and the s1 vacA allele (p 0.002). Multiple EPIYA-C segments were less frequent than reported in other countries, possibly contributing to the low incidence of GC in Senegal.

Short-chain fatty acids and polyamines in the pathogenesis of necrotizing enterocolitis: Kinetics aspects in gnotobiotic quails.

Despite years of investigation, pathogenesis of necrotizing enterocolitis (NEC) remains elusive. Bacterial metabolites were implicated by several authors but their roles remain controversial. The aim of our study was to investigate the role of SCFAs and polyamines through a kinetic study of histological and macroscopical digestive lesions in monobiotic quails. Germ-free quails, inoculated with a Clostridium butyricum strain involved in a NEC case, were fed or not with a diet including lactose (7%). Quails were sacrificed at various times between D7 and D24 after bacterial inoculation. NEC-like lesions, i.e. thickening, pneumatosis, and hemorrhages, occurred only in lactose-fed quails and increased with time. The main histological characteristics were infiltrates of mononuclear cells, then heterophilic cells, then gas cyst and necrosis. The first event observed, before histological and macroscopical lesions, is a high production of butyric acid, which precedes an increase of iNOS gene expression. No difference in polyamines contents depending on the diet was observed. These results show the major role of butyric acid produced by commensal bacteria in the onset of the digestive lesions.

Interferon gamma-signature transcript profiling and IL-23 upregulation in response to Helicobacter pylori infection.

Helicobacter pylori infection is the major cause of gastroduodenal pathologies including gastric cancer. The long persistence of bacteria and the type of immune and inflammatory response determine the clinical issue. In this study, the global gene expression profile after 6 and 12 months of H. pylori infection was investigated in the mouse stomach, using the Affymetrix GeneChip Mouse Expression Array A430. Genes related to the inflammatory and immune responses were focused. Levels of selected transcripts were confirmed by reverse transcription polymerase chain reaction. Twenty- five and nineteen percent of the differentially expressed genes observed at 6 and 12 months post-infection respectively, were related to immune response. They are characterized by an interferon (IFN)gamma-dependent expression associated to a T helper 1 (Th1) polarised response. In-depth analysis revealed that an up-regulation of IL-23p19, took place in the stomach of H. pylori infected-mice. Strong IL-23p19 levels were also confirmed in gastric biopsies from H. pylori-infected patients with chronic gastritis, as compared to healthy subjects. Our microarray analysis revealed also, a high decrease of H+K+-ATPase transcripts in the presence of the H. pylori infection. Association of gastric Th1 immune response with hypochlorhydria through the down-regulation of H+K+-ATPase contributes to the genesis of lesions upon the H. pylori infection. Our data highlight that the up-regulation of IL-23 and of many IFNgamma signature transcripts occur early on during the host response to H. pylori, and suggest that this type of immune response may promote the severity of the induced gastric lesions.

[Cutaneous, pulmonary and bone aspergillosis in a patient presumed immunocompetent presenting subacute cutaneous lupus erythematosus]. / Aspergillose cutanée, pulmonaire et osseuse chez un malade ayant un lupus érythémateux cutané subaigu sans déficit immunitaire associé.

INTRODUCTION: We report a case of cutaneous, pulmonary and bone aspergillosis successfully treated after many years of progression in a patient presumed immunocompetent presenting subacute cutaneous lupus erythematosus. CASE-REPORT: A 43-year-old man, treated with thalidomide for subacute cutaneous lupus erythematosus, presented chest pain with haemoptysis and dyspnea. A pulmonary nodule was detected but the microbiological investigation was negative. The histological examination showed granuloma with round structures. No cause was found. Three years later, skin lesions appeared on the patient's face concomitantly with a pulmonary relapse. Histopathological examination of these lesions demonstrated septate hyphae. Aspergillus fumigatus was isolated in skin and lung. Disseminated aspergillosis was then diagnosed as spondylodiscitis developed. Treatment with combined voriconazole and caspofungin produced significant and rapid improvement of lesions. DISCUSSION: While aspergillosis is commonly seen in immunocompetent patients, angiotropic dissemination points to cellular immunodepression. Our patient, however, was not presenting immunodepression. We discuss the possible contributory role of thalidomide in dissemination of aspergillosis given that the literature to date contains only one reported case of cutaneous aspergillosis secondary to A. fumigatus in an immunocompetent patient. We would also point out the specific histopathological pattern of this disseminated aspergillosis with both septate hyphae and round structures. Invasive aspergillosis is highly lethal but the chances of recovery are now greater thanks to new antifungal agents.

AGS3, an alpha(1-3)glucan synthase gene family member of Aspergillus fumigatus, modulates mycelium growth in the lung of experimentally infected mice.

The cell wall of human fungal pathogen Aspergillus fumigatus protects the fungus against threats from environment and interacts with the host immune system. Alpha(1-3)glucan is the major polysaccharide of Aspergillus fumigatus cell wall, and it has been shown to contribute to the virulence of diverse fungal pathogens. In A. fumigatus, three putative alpha(1-3)glucan synthase genes AGS1, AGS2 and AGS3 have been identified. AGS1 is responsible for cell wall alpha(1-3)glucan biosynthesis, but strains with deletions of either AGS1 or AGS2 are not defective in virulence [Beauvais, A., Maubon, D., Park, S., Morelle, W., Tanguy, M., Huerre, M., Perlin, D.S., Latgé, J. P., 2005. Two alpha(1-3) glucan synthases with different functions in Aspergillus fumigatus. Appl. Environ. Microbiol. 71, 1531-1538]. In contrast, we present evidence that AGS3 is also responsible for cell wall alpha(1-3)glucan biosynthesis and can modulate the virulence of A. fumigatus. An AGS3 deletion strain was found to produce faster and more robust disease than the parental strain in an experimental mouse model of aspergillosis. The apparent hyper-virulence in the AGS3-deleted mutant was correlated with an increased melanin content of the conidial cell wall, a better resistance to reactive oxygen species and a quicker germination rate. These results suggest an indirect role for AGS3 in virulence through an adaptive mechanism.

[Histology of liver lesions due to Schistosoma mekongi. About six cases with severe portal hypertension operated in Cambodia]. / Lesions histologiques hépatiques de la schistosomose due a Schistosoma mekongi. A propos de six cas avec hypertension portale sévère opérés au Cambodge.

Schistosomiasis mekongi was shown to be endemic, along the Mekong River, in northern Cambodia, affecting many patients with portal hypertension. Surgical procedures were proposed to some patients with digestive haemorrhage history to avoid fatal recurrence. The aim of our study was to evaluate the intensity of the liver fibrosis among these patients. During surgical treatment, liver biopsies were collected, fixed in Bouin or in formalin and processed at the Institut Pasteur of Cambodia. Sections were stained by H&E, Masson's trichrome, PAS, Ziehl-Neelsen's method and Congo Red. A total of six biopsies from patients aged 16-36 were analysed. There was complete disorganization of hepatic architecture with fibrous enlargement of portal tracts and some portal-portal bridging fibrosis, but there was no cirrhosis. In portal areas, there was blood vessel congestion and thrombosis with inflammation. Bile ducts were normal. In the parenchyma, congestion of sinusoidal capillaries was combined with focal mononuclear inflammatory infiltrate. There was no steatosis, no necrosis, no cholestasis, no iron accumulation and no amyloidosis. Numerous eggs of Schistosoma mekongi were observed in five cases, mostly in fibrous areas and more rarely in the parenchyma. Eggs were round or oval, measuring 60 x 40 microns with an acid-fast thin hyaline wall. Some eggs were surrounded by epithelioid and giant cell reaction. In conclusion, our findings illustrated a surprisingly high degree of fibrosis among young adults which contrasts with other schistosomiasis.

[Place of surgery in the prevention of recurrences of digestive haemorrhages at the patients presenting a portal hypertension due to Schistosoma mekongi]. / Place de la chirurgie dans la prévention des récidives d'hémorragies digestives chez les sujets présentant une hypertension portale due a Schistosoma mekongi.

In spite of a decrease of the prevalence of hepato-splenic schistosomiasis thanks to mass-treatment with Praziquentel from December 1994 till now (CNM - MSF - WHO - Health Provincial Director) of target-populations in Kratie Province, severe cases of portal hypertension are not exceptional (digestive bleedings, after rupture of oesophageal varices). Out of 106 cases of portal hypertension: alI patients have had clinical survey biological tests (liver function, haematology and serology). Most of them had ultrasonography (Aloka 55,500 Sound 3.5 MHz). Nearly half of the group of 153 patients has never had bleedings. More than 45 were not eligible for surgery for different reasons: severe anaemia (few possibilities for massive transfusion in Cambodia), serology (S. mekongi) + but also hepatitis B or C +, hepatic biological exams (hepatic insufficiency). So we decided for eleven of them to use a surgical decompression procedure in order to decrease portal hypertension and the porto-systemic gradient. After defining portal hypertension, specific clinical features of portal hypertension (secondary to Schistosomiasis) the authors report eleven cases who were operated on (2000-2002): 4 mesenterico-cave shunt with interposition of a graft (Drapanas' procedure), 1 operation of HASSAB (after splenectomy), 6 proximal spleno-renal diversion (after splenectomy). After studying the results of the eleven patients, discussion with other surgical procedures, particularly endoscopic procedures is developed. The follow-up of these patients during at least five years is mandatory to give guidelines for post-systemic shunts to prevent rebleeding (near other methods). Treated too late, schistosomiasis has no benefit from drugs (Praziquentel). After a mean period of forty two months, the following results are: mortality: one case (10 days after operation): hepatic insufficiency (group Child B/C). morbidity: one occlusion of the small intestine, after 4 months (debridment), operated at the Provincial hospital of Kratie (case no1). Ten patients resume work, family and social life between Kratie and Sambor in 2002. No rebleeding. No encephalopathy.

Two alpha(1-3) glucan synthases with different functions in Aspergillus fumigatus.

Alpha(1-3) glucan is a main component of the Aspergillus fumigatus cell wall. In spite of its importance, synthesis of this amorphous polymer has not been investigated to date. Two genes in A. fumigatus, AGS1 and AGS2, are highly homologous to the AGS genes of Schizosaccharomyces pombe, which encode putative alpha(1-3) glucan synthases. The predicted Ags proteins of A. fumigatus have an estimated molecular mass of 270 kDa. AGS1 and AGS2 were disrupted in A. fumigatus. Both Deltaags mutants have similar altered hyphal morphologies and reduced conidiation levels. Only Deltaags1 presented a reduction in the alpha(1-3) glucan content of the cell wall. These results showed that Ags1p and Ags2p were functionally different. The cellular localization of the two proteins was in agreement with their different functions: Ags1p was localized at the periphery of the cell in connection with the cell wall, whereas Ags2p was intracellularly located. An original experimental model of invasive aspergillosis based on mixed infection and quantitative PCR was developed to analyze the virulence of A. fumigatus mutant and wild-type strains. Using this model, it was shown that the cell wall and morphogenesis defects of Deltaags1 and Deltaags2 were not associated with a reduction in virulence in either mutant. This result showed that a 50% reduction in the content of the cell wall alpha(1-3) glucan does not play a significant role in A. fumigatus pathogenicity.

[Disseminated histoplasmosis: an atypical ulcerous form in an HIV-infected patient]. / Histoplasmose disséminée: forme ulcéreuse atypique chez un malade infecté par le VIH.

INTRODUCTION: Histoplasma capsulatum var capsulatum is a dimorphic fungi predominating on the American continent. It is responsible for disseminated histoplasmosis associated with AIDS. The presentation in the form of cutaneous ulceration is uncommon and misleading. OBSERVATION: A 25 year-old man presented with 3 ulcerations, of 2 to 4 cm in diameter, localized on the lower lip and knees. The patient exhibited fever, alteration in his general status of health and a pulmonary interstitial syndrome. He was seropositive for the human immunodeficiency syndrome (HIV). His lymphocyte CD4+ level was of 1/mm3. Diagnosis of histoplasmosis was established by direct examination and culture of the cutaneous ulcerations and bronchoalveolar washing fluid. DISCUSSION: The clinical aspect of cutaneous localizations of disseminated histoplasmosis is usually multiple, disseminated, papular or nodular-type lesions. Ulcerations represent less than 20% of the cases described. In our patient, the aspect of the lesions at first evoked cutaneous leishmaniosis. Direct mycological examination followed by culture confirmed the final diagnosis.

Evaluation of the placental environment with a new in vitro model of histocultures of early and term placentae: determination of cytokine and chemokine expression profiles.

We aimed to set up and validate a new in vitro model of placental histocultures, for the evaluation of cytokine and chemokine profiles of the placental environment, over a long culture period. Micro-explant cultures from 6 early and 6 term placentae were set up on collagen sponge gel supports at a liquid/air interface. At various times during culture, we analyzed tissue morphology and cell death by microscopy and quantified beta-hCG production and mRNA levels for beta-hCG and insulin-like 4 (INSL4). Levels of IL-6, LIF, TNF alpha, IL-10, IFN-gamma, IL-16 and RANTES in the medium were measured by ELISA on days 1, 4 and 7 of culture. SDF-1 mRNA expression was determined by real-time PCR at the same time points. Histocultures from early and term placentae remained viable until day 10. High levels of IL-6 and LIF production, low levels of TNF alpha, IL-10 and IFN-gamma production and significant SDF-1 expression were observed. These data indicate that placental histoculture is a suitable and reliable in vitro model for studying the placental environment.

Multiple cerebral abscesses as a complication of Mycobacterium fortuitum infection.

Mycobacterium fortuitum is a rapidly growing, nontuberculous mycobacteria that has rarely been associated with central nervous system impairment. We describe the case of a patient who developed multiple cerebral abscesses revealing Mycobacterium fortuitum infection. Brain biopsy specimens showed suppurative, noncaseating, granulomatous inflammation consisting of epithelioid histiocytes and multinucleated giant cells. All clinical signs and CT scan cerebral lesions disappeared after institution of appropriate antimycobacterial therapy.

[Cervical cancers diagnosed at the Pasteur Institute of Madagascar from 1992 to 2002]. / Bilan des cancers du col utérin diagnostiqués à l'Institut Pasteur de Madagascar de 1992 à 2002.

In Madagascar, the epidemiological data actualized concerning the cancer of the collus of uterus are not available because of the absence of register of cancer. The objective of this study is to achieve a first assessment of the problem, to complete the epidemiological knowledge, to point out the tool of precoce detection of the precancerous lesions, to propose the measures aiming to improve the management of the patients and to contribute to the institution of a register of cancer. This is a retrospective survey on the frequency of the cancer of the cervix observed from 1992 to 2002 about 23,908 withdrawals addressed to the Institut Pasteur de Madagascar for anatomopathological exam and 12,605 cervical smears for cytological exam. In pathological anatomy, 2,621 (63.4%) of 4,136 cases of diagnosed cancer, have been observed in women. 687 cases (26.2%) of them were localized in the collus. The 3/4 of the cancers of the cervix is invasive and the mean age is 48.2 years old at the time of diagnosis. The cytology detects only 74 cases of invasive cancer of which most don't have an histological confirmation. 274 pre-lesions of cervix cancer were diagnosed for this period, the majority lesions are cytological diagnosis. In spite of a non representative recruitment of the general population, and by the number of withdrawals considered, these results may represent indicators of the epidemiological situation and justify the institution of program to detect the precancerous lesions in a national scale.

[First cases of imported cutaneous leishmaniasis in Bangui Central African Republic: efficacy of metronidazole]. / Premier cas de leishmaniose cutaneé d'importation à Bangui en République Centrafricaine: efficacité du métronidazole.

Cutaneous leishmaniasis is an uncommon disease in the Central African Republic (CAR). The purpose of this report is to present a case that was imported into Bangui, CAR from the neighboring Republic of Chad. The polymorphous aspects of lesions and the spectrum of laboratory findings associated with the disease in this patient are described. Oral treatment with metronidazole led to rapid resolution with minimal scarring.