Les maladies infectieuses ont encore un bel avenir [Infectious diseases have again a good future!].

Invasive fungal diseases (IFDs) have become major causes of morbidity and mortality among highly immunocompromised patients. Authoritative consensus criteria to diagnose IFD have been useful in establishing eligibility criteria for antifungal trials. There is an important need for generation of consensus definitions of outcomes of IFD that will form a standard for evaluating treatment success and failure in clinical trials. Therefore, an expert international panel consisting of the Mycoses Study Group and the European Organization for Research and Treatment of Cancer was convened to propose guidelines for assessing treatment responses in clinical trials of IFDs and for defining study outcomes. Major fungal diseases that are discussed include invasive disease due to Candida species, Aspergillus species and other molds, Cryptococcus neoformans, Histoplasma capsulatum, and Coccidioides immitis. We also discuss potential pitfalls in assessing outcome, such as conflicting clinical, radiological, and/or mycological data and gaps in knowledge.

Association between valvular surgery and mortality among patients with infective endocarditis complicated by heart failure.

Context Heart failure (HF) is the most common complication of infective endocarditis. However, clinical characteristics of HF in patients with infective endocarditis, use of surgical therapy, and their associations with patient outcome are not well described.Objectives To determine the clinical, echocardiographic, and microbiological variables associated with HF in patients with definite infective endocarditis and to examine variables independently associated with in-hospital and 1-year mortality for patients with infective endocarditis and HF, including the use and association of surgery with outcome.Design, Setting, and Patients The International Collaboration on Endocarditis-Prospective Cohort Study, a prospective, multicenter study enrolling 4166 patients with definite native- or prosthetic-valve infective endocarditis from 61 centers in 28 countries between June 2000 and December 2006.Main Outcome Measures In-hospital and 1-year mortality.Results Of 4075 patients with infective endocarditis and known HF status enrolled, 1359 (33.4% [95% CI, 31.9%-34.8%]) had HF, and 906 (66.7% [95% CI, 64.2%-69.2%]) were classified as having New York Heart Association class III or IV symptom status. Within the subset with HF, 839 (61.7% [95% CI, 59.2%-64.3%]) underwent valvular surgery during the index hospitalization. In-hospital mortality was 29.7% (95% CI, 27.2%-32.1%) for the entire HF cohort, with lower mortality observed in patients undergoing valvular surgery compared with medical therapy alone (20.6% [95% CI, 17.9%-23.4%] vs 44.8% [95% CI, 40.4%-49.0%], respectively; P < .001). One-year mortality was 29.1% (95% CI, 26.0%-32.2%) in patients undergoing valvular surgery vs 58.4% (95% CI, 54.1%-62.6%) in those not undergoing surgery (P < .001). Cox proportional hazards modeling with propensity score adjustment for surgery showed that advanced age, diabetes mellitus, health care-associated infection, causative microorganism (Staphylococcus aureus or fungi), severe HF (New York Heart Association class III or IV), stroke, and paravalvular complications were independently associated with 1-year mortality, whereas valvular surgery during the initial hospitalization was associated with lower mortality.Conclusion In this cohort of patients with infective endocarditis complicated by HF, severity of HF was strongly associated with surgical therapy and subsequent mortality, whereas valvular surgery was associated with lower in-hospital and 1-year mortality.

Clinical characteristics and outcome of patients admitted to a medico-surgical ICU requiring non invasive ventilation (NIV) for hypercapnic respiratory failure

Introduction: Because it decreases intubation rate and mortality, NIV has become first-line treatment in case of hypercapnic respiratory failure (HRF). Whether this approach is equally successful for all categories of HRF patients is however debated. We assessed if any clinical characteristics of HRF patients were associated with NIV intensity, success, and outcome, in order to identify prognostic factors. Methods: Retrospective analysis of the clinical database (clinical information system and MDSi) of patients consecutively admitted to our medico-surgical ICU, presenting with HRF (defined as PaCO2 >50 mm Hg), and receiving NIV between January 2009 and December 2010. Demographic data, medical diagnoses (including documented chronic lung disease), reason for ICU hospitalization, recent surgical interventions, SAPS II and McCabe scores were extracted from the database. Total duration of NIV and the need for tracheal intubation during the 5 days following the first hypercapnia documentation, as well as ICU and hospital mortality were recorded. Results are reported as median [IQR]. Comparisons with Chi2 or Kruskal-Wallis tests, p <0.05 (*). Results: 164 patients were included, 45 (27.4%) of whom were intubated after 10 [2-34] hours, after having received 7 [2-19] hours of NIV. NIV successful patients received 15 [5-22] hours of NIV for up to 5 days. Intubation was correlated with increased ICU (20% vs. 3%, p <0.001) and hospital (46.7% vs. 30.2, p >0.05) mortality. Conclusions: A majority of patients requiring NIV for hypercapnic respiratory failure in our ICU have no diagnosed chronic pulmonary disease. These patients tend to have increased ICUand hospital mortality. The majority of patients were non-surgical, a feature correlated with increased hospital mortality. Beside usual predictors of severity such as age and SAPS II, absence of diagnosed chronic pulmonary disease and non-operative state appear to be associated with increased mortality. Further studies should explore whether these patients are indeed more prone to an adverse outcome and which therapeutic strategies might contribute to alter this course.

Tissue transglutaminase (TG2) acting as G protein protects hepatocytes against Fas-mediated cell death in mice.

Tissue transglutaminase (TG2) is a protein cross-linking enzyme known to be expressed by hepatocytes and to be induced during the in vivo hepatic apoptosis program. TG2 is also a G protein that mediates intracellular signaling by the alpha-1b-adrenergic receptor (AR) in liver cells. Fas/Fas ligand interaction plays a crucial role in various liver diseases, and administration of agonistic anti-Fas antibodies to mice causes both disseminated endothelial cell apoptosis and fulminant hepatic failure. Here we report that an intraperitoneal dose of anti-Fas antibodies, which is sublethal for wild-type mice, kills all the TG2 knock-out mice within 20 hours. Although TG2-/- thymocytes exposed to anti-Fas antibodies die at the same rate as wild-type mice, TG2-/- hepatocytes show increased sensitivity toward anti-Fas treatment both in vivo and in vitro, with no change in their cell surface expression of Fas, levels of FLIP(L) (FLICE-inhibitory protein), or the rate of I-kappaBalpha degradation, but a decrease in the Bcl-xL expression. We provide evidence that this is the consequence of the impaired AR signaling that normally regulates the levels of Bcl-xL in the liver. In conclusion, our data suggest the involvement of adrenergic signaling pathways in the hepatic regeneration program, in which Fas ligand-induced hepatocyte proliferation with a simultaneous inhibition of the Fas-death pathway plays a determinant role.

Liver enzyme elevation after lamivudine withdrawal in HIV-hepatitis B virus co-infected patients: the Swiss HIV Cohort Study.

Background The principal causes of liver enzyme elevation among HIV-hepatitis B virus (HBV) co-infected patients are the hepatotoxic effects of antiretroviral therapy (ART), alcohol abuse, ART-induced immune reconstitution and the exacerbation of chronic HBV infection. Objectives To investigate the incidence and severity of liver enzyme elevation, liver failure and death following lamivudine (3TC) withdrawal in HIV-HBV co-infected patients. Methods Retrospective analysis of the Swiss HIV Cohort Study database to assess the clinical and biological consequences of the discontinuation of 3TC. Variables considered for analysis included liver enzyme, HIV virological and immunological parameters, and medication prescribed during a 6-month period following 3TC withdrawal. Results 3TC was discontinued in 255 patients on 363 occasions. On 147 occasions (109 patients), a follow-up visit within 6 months following 3TC withdrawal was recorded. Among these patients, liver enzyme elevation occurred on 42 occasions (29%), three of them (2%) with severity grade III and five of them (3.4%) with severity grade IV elevations (as defined by the AIDS Clinical Trials Group). Three patients presented with fulminant hepatitis. One death (0.7%) was recorded. Conclusions HBV reactivation leading to liver dysfunction may be an under-reported consequence of 3TC withdrawal in HIV-HBV co-infected patients. Regular monitoring of HBV markers is warranted if active therapy against HBV is discontinued.

Evolutionary genetics of arbuscular mycorrhizal fungi - causes and consequences of multiple genomes in Glomus intraradices

Résumé Les champignons endomycorhiziens arbusculaires (CEA) forment des symbioses avec la plupart des plantes terrestres. Les CEA influencent la croissance des plantes et la biodiversité. Ils sont supposés avoir évolué de manière asexuée pendant au moins 400 millions d'années et aucune diversification morphologique majeure n'a été constatée. Pour ces raisons, les CEA sont considérés comme d'anciens asexués. Très peu d'espèces sont connues actuellement. Les individus de ces champignons contiennent des noyaux génétiquement différents dans un cytoplasme continu. La signification évolutive, la variabilité et la maintenance des génomes multiples au sein des individus sont inconnues. Ce travail a démontré qu'une population du CEA Glomus intraradices est génétiquement très variable. Nous avons conclu que les plantes hôtes plutôt que la différenciation géographique devraient être responsables de cette grande diversité. Puis nous avons cherché l'existence de recombinaison entre génotypes dans une population. Nous avons détecté un groupe recombinant au sein de la population, ce qui met en doute l'état d'anciens asexués des CEA. Nous avons également détecté l'occurrence de fusions d'hyphes et l'échange de noyaux entre isolats génétiquement différents. La descendance hybride issue de cet échange était viable et distincte phénotypiquement des isolats parentaux. En résumé, ce travail identifie des événements cruciaux dans le cycle de vie des CEA qui ont le potentiel d'influencer l'évolution de génomes multiples. L'étude des conséquences de ces événements sur les interactions avec les plantes hôtes pourrait éclaircir significativement la compréhension de la symbiose entre plantes et CEA. Abstract Arbuscular mycorrhizal fungi (AMF) are important symbionts of most land plants. AMF influence plant growth and biodiversity. Very few extant species are described. AMF are thought to have evolved asexually for at least 400 million years and no major morphological diversification has occurred. Due to these reasons, they were termed `ancient asexuals'. Fungal individuals harbour genetically different nuclei in a continuous cytoplasm. The variability, maintenance and evolutionary significance of multiple genomes within individuals are unknown. This work showed that a population of the AMF Glomus intraradices harbours very high genetic diversity. We concluded that host plants rather than geographic differentiation were responsible for this diversity. Furthermore, we investigated whether recombination occurred among genotypes of a G. intraradices population. The identification of a core group of recombining genotypes in the population refutes the assumption of ancient asexuality in AMF. We found that genetically different isolates can form hyphal fusions and exchange nuclei. The hybrid progeny produced by the exchange was viable and phenotypically distinct from the parental isolates. Taken together, this work provided evidence for key events in the AMF life cycle, that influence the evolution of multiple genomes. Studying the consequences of these events on the interaction with host plants may significantly further the understanding of the AMF-plant symbiosis.

Early Stage Primary Bone Lymphoma: A Retrospective, Multicenter Rare Cancer Network Study

Purpose/Objective(s): Primary bone lymphoma (PBL) represents less than 1% of all malignant lymphomas, and 4-5% of all extranodal lymphomas. In this study, we assessed the disease profile, outcome, and prognostic factors in patients with stage I and II PBL.Materials/Methods: Between 1987 and 2008, 116 consecutive patients with PBL treated in 13 RCNinstitutions were included in this study. Inclusion criteriawere: age.17 yrs, PBLin stage I and II, andminimum6months follow-up. The median agewas 51 yrs (range: 17-93).Diagnosticwork-up included plain boneXray (74%of patients), scintigraphy (62%), CT-scan (65%),MRI (58%), PET (18%), and bone-marrow biopsy (84%).All patients had biopsy-proven confirmation of non-Hodgkin's lymphoma (NHL). The histopathological type was predominantly diffuse large B-cell lymphoma (78%) and follicular lymphoma (6%), according to theWHOclassification. One hundred patients had a high-grade, 7 intermediate and 9 low-gradeNHL. Ninety-three patients had anAnn-Arbor stage I, and 23 had a stage II. Seventy-seven patients underwent chemoradiotherapy (CXRT), 12 radiotherapy (RT) alone, 10 chemotherapy alone (CXT), 9 surgery followed by CXRT, 5 surgery followed by CXT, and 2 surgery followed by RT. One patient died before treatment.Median RT dosewas 40Gy (range: 4-60).Themedian number ofCXTcycleswas 6 (range, : 2-8).Median follow-upwas 41months (range: 6-242).Results: Following treatment, the overall response rate was 91% (CR 74%, PR 17%). Local recurrence was observed in 12 (10%) patients, and systemic recurrence in 17 (15%) patients. Causes of death included disease progression in 16, unrelated disease in 6, CXT-related toxicity in 1, and secondary cancer in 2 patients. The 5-yr overall survival (OS), disease-free survival (DFS), lymphoma- specific survival (LSS), and local control (LC) were 76%, 69%, 78%, and 92%, respectively. In univariate analyses (log-rank test), favorable prognostic factors for survival were: age\50 years (p = 0.008), IPI score #1 (p = 0.009), complete response (p\0.001), CXT (p = 0.008), number of CXT cycles $6 (p = 0.007), and RT dose . 40 Gy (p = 0.005). In multivariate analysis age, RT dose, complete response, and absence of B symptoms were independent factors influencing the outcome. There were 3 patients developing grade 3 or more (CTCAE.V3.0) toxicities.Conclusions: This large multicenter study, confirms the relatively good prognosis of early stage PBL, treated with combined CXRT. Local control was excellent, and systemic failure occurred infrequently. A sufficient dose of RT (. 40 Gy) and completeCXT regime (. 6 cycles) were associated with a better outcome. Combined modality appears to be the treatment of choice.Author Disclosure: L. Cai, None; M.C. Stauder, None; Y.J. Zhang, None; P. Poortmans, None; Y.X. Li, None; N. Constantinou, None; J. Thariat, None; S. Kadish, None; M. Ozsahin, None; R.O. Mirimanoff, None.

HACEK infective endocarditis: characteristics and outcomes from a large, multi-national cohort.

The HACEK organisms (Haemophilus species, Aggregatibacter species, Cardiobacterium hominis, Eikenella corrodens, and Kingella species) are rare causes of infective endocarditis (IE). The objective of this study is to describe the clinical characteristics and outcomes of patients with HACEK endocarditis (HE) in a large multi-national cohort. Patients hospitalized with definite or possible infective endocarditis by the International Collaboration on Endocarditis Prospective Cohort Study in 64 hospitals from 28 countries were included and characteristics of HE patients compared with IE due to other pathogens. Of 5591 patients enrolled, 77 (1.4%) had HE. HE was associated with a younger age (47 vs. 61 years; p<0.001), a higher prevalence of immunologic/vascular manifestations (32% vs. 20%; p<0.008) and stroke (25% vs. 17% p = 0.05) but a lower prevalence of congestive heart failure (15% vs. 30%; p = 0.004), death in-hospital (4% vs. 18%; p = 0.001) or after 1 year follow-up (6% vs. 20%; p = 0.01) than IE due to other pathogens (n = 5514). On multivariable analysis, stroke was associated with mitral valve vegetations (OR 3.60; CI 1.34-9.65; p<0.01) and younger age (OR 0.62; CI 0.49-0.90; p<0.01). The overall outcome of HE was excellent with the in-hospital mortality (4%) significantly better than for non-HE (18%; p<0.001). Prosthetic valve endocarditis was more common in HE (35%) than non-HE (24%). The outcome of prosthetic valve and native valve HE was excellent whether treated medically or with surgery. Current treatment is very successful for the management of both native valve prosthetic valve HE but further studies are needed to determine why HE has a predilection for younger people and to cause stroke. The small number of patients and observational design limit inferences on treatment strategies. Self selection of study sites limits epidemiological inferences.

Ejaculation failure on the day of oocyte retrieval for IVF: case report.

Unexpected ejaculation failure on the day of oocyte retrieval for IVF occurs once or twice a year in our Reproductive Medicine Unit, where approximately 500 oocyte retrievals are performed each year. Two clinical situations which occurred in 2001 are presented. In the first case, sperm were finally obtained by epididymal aspiration and resulted in the fertilization of five oocytes by ICSI. The transfer of two fresh embryos did not result in a pregnancy and the three supernumerary zygotes were cryopreserved. The male patient presented an anxio-depressive episode necessitating psychiatric hospitalization 1 week after the oocyte retrieval. In the second case, no sperm were obtained and the four oocytes were therefore lost. The couple went through a crisis in their relationship and tried another cycle of IVF 10 months later, after the preventive cryopreservation of a sperm sample. On the day of oocyte retrieval the patient was unable to produce a fresh sample but three zygotes were obtained through ICSI using the back-up cryopreserved sperm. Two embryos were transferred but no pregnancy ensued. The clinical decision-making processes for these two cases are described, as well as the measures employed to help prevent these unfortunate situations.

Inflammatory markers and incident heart failure risk in older adults: the Health ABC (Health, Aging, and Body Composition) study.

OBJECTIVES: The purpose of this study was to evaluate the association between inflammation and heart failure (HF) risk in older adults. BACKGROUND: Inflammation is associated with HF risk factors and also directly affects myocardial function. METHODS: The association of baseline serum concentrations of interleukin (IL)-6, tumor necrosis factor-alpha, and C-reactive protein (CRP) with incident HF was assessed with Cox models among 2,610 older persons without prevalent HF enrolled in the Health ABC (Health, Aging, and Body Composition) study (age 73.6 +/- 2.9 years; 48.3% men; 59.6% white). RESULTS: During follow-up (median 9.4 years), HF developed in 311 (11.9%) participants. In models controlling for clinical characteristics, ankle-arm index, and incident coronary heart disease, doubling of IL-6, tumor necrosis factor-alpha, and CRP concentrations was associated with 29% (95% confidence interval: 13% to 47%; p < 0.001), 46% (95% confidence interval: 17% to 84%; p = 0.001), and 9% (95% confidence interval: -1% to 24%; p = 0.087) increase in HF risk, respectively. In models including all 3 markers, IL-6, and tumor necrosis factor-alpha, but not CRP, remained significant. These associations were similar across sex and race and persisted in models accounting for death as a competing event. Post-HF ejection fraction was available in 239 (76.8%) cases; inflammatory markers had stronger association with HF with preserved ejection fraction. Repeat IL-6 and CRP determinations at 1-year follow-up did not provide incremental information. Addition of IL-6 to the clinical Health ABC HF model improved model discrimination (C index from 0.717 to 0.734; p = 0.001) and fit (decreased Bayes information criterion by 17.8; p < 0.001). CONCLUSIONS: Inflammatory markers are associated with HF risk among older adults and may improve HF risk stratification.

Abnormal Lung Function and Risk for Heart Failure in the Elderly: The Health, Aging, and Body Composition Study

Background: Chronic obstructive pulmonary disease (COPD) has been associated with increased risk for heart failure (HF). The impact of subclinical abnormal spirometric findings on HF risk among older adults without history of COPD is not well elucidated. Methods: We evaluated 2125 participants (age 73.6±2.9 years; 50.5% men; 62.3% white; 45.6/9.4% past/current smokers; body mass index [BMI] 27.2±4.6 kg/m2) without prevalent COPD or HF who underwent baseline spirometry in the Health ABC Study. Abnormal lung function was defined either as forced vital capacity (FVC) below lower limit of normal (LLN) or forced expiratory volume in 1st sec (FEV1) to FVC ratio below LLN. Results: On follow-up (median, 9.4 years), 68 of 350 (19.4%) participants with abnormal lung function developed HF, as compared to 172 of 1775 (9.7%) participants with normal lung function (hazard ratio [HR], 2.31; 95% confidence interval [CI], 1.74 -3.06; P<.001). This increased risk persisted after adjusting for all other independent predictors of HF in the Health ABC Study, BMI, incident coronary events, and several inflammatory markers (HR, 1.82; 95% CI, 1.30 -2.54; P<.001), and remained constant over time. Baseline FVC and FEV1 had a linear association with HF risk (Figure). In adjusted models, HF risk increased by 21% (95% CI, 10 -36%) per 10% decrease in FVC and 18% (95% CI, 10 -28%) per 10% decrease in FEV1 (both P<.001); this association persisted among participants with normal lung function at baseline. Findings were consistent across sex, race, and smoking status. Conclusions: Subclinical abnormal spirometric findings are prevalent among older adults and are independently associated with risk for incident HF.

Identification of an agrin mutation that causes congenital myasthenia and affects synapse function.

We report the case of a congenital myasthenic syndrome due to a mutation in AGRN, the gene encoding agrin, an extracellular matrix molecule released by the nerve and critical for formation of the neuromuscular junction. Gene analysis identified a homozygous missense mutation, c.5125G>C, leading to the p.Gly1709Arg variant. The muscle-biopsy specimen showed a major disorganization of the neuromuscular junction, including changes in the nerve-terminal cytoskeleton and fragmentation of the synaptic gutters. Experiments performed in nonmuscle cells or in cultured C2C12 myotubes and using recombinant mini-agrin for the mutated and the wild-type forms showed that the mutated form did not impair the activation of MuSK or change the total number of induced acetylcholine receptor aggregates. A solid-phase assay using the dystrophin glycoprotein complex showed that the mutation did not affect the binding of agrin to alpha-dystroglycan. Injection of wild-type or mutated agrin into rat soleus muscle induced the formation of nonsynaptic acetylcholine receptor clusters, but the mutant protein specifically destabilized the endogenous neuromuscular junctions. Importantly, the changes observed in rat muscle injected with mutant agrin recapitulated the pre- and post-synaptic modifications observed in the patient. These results indicate that the mutation does not interfere with the ability of agrin to induce postsynaptic structures but that it dramatically perturbs the maintenance of the neuromuscular junction.