Receptor activator for NF-κB ligand in acute myeloid leukemia: expression, function, and modulation of NK cell immunosurveillance.

The TNF family member receptor activator for NF-κB ligand (RANKL) and its receptors RANK and osteoprotegerin are key regulators of bone remodeling but also influence cellular functions of tumor and immune effector cells. In this work, we studied the involvement of RANK-RANKL interaction in NK cell-mediated immunosurveillance of acute myeloid leukemia (AML). Substantial levels of RANKL were found to be expressed on leukemia cells in 53 of 78 (68%) investigated patients. Signaling via RANKL into the leukemia cells stimulated their metabolic activity and induced the release of cytokines involved in AML pathophysiology. In addition, the immunomodulatory factors released by AML cells upon RANKL signaling impaired the anti-leukemia reactivity of NK cells and induced RANK expression, and NK cells of AML patients displayed significantly upregulated RANK expression compared with healthy controls. Treatment of AML cells with the clinically available RANKL Ab Denosumab resulted in enhanced NK cell anti-leukemia reactivity. This was due to both blockade of the release of NK-inhibitory factors by AML cells and prevention of RANK signaling into NK cells. The latter was found to directly impair NK anti-leukemia reactivity with a more pronounced effect on IFN-γ production compared with cytotoxicity. Together, our data unravel a previously unknown function of the RANK-RANKL molecule system in AML pathophysiology as well as NK cell function and suggest that neutralization of RANKL with therapeutic Abs may serve to reinforce NK cell reactivity in leukemia patients.

Intermittent ketoconazole therapy of chronic mucocutaneous candidiasis in childhood.

We report the clinical and laboratory findings in two children with chronic mucocutaneous candidiasis (CMC) treated successfully with intermittent long-term ketoconazole therapy. Both had chronic infection of the nails, skin and mucous membranes with positive cultures for candida. Both were resistant to multiple local and systemic antifungal agents. After institution of ketoconazole therapy there was a dramatic improvement with clearing of the oral (one week), skin (two months) and nail lesions (5 months). After 8 months the drug was stopped and clinical remission persisted for 10 and 7 months respectively. Relapse of oral candidiasis was treated with a short course of ketoconazole (4-16 weeks) leading to complete healing of the lesions. Clinical improvement was not related to an amelioration in lymphocyte transformation. There was no change in the progressive deterioration of the lymphocyte responses to candida antigen which was probably due to persisting candida cell wall components (e.g. mannan).

Lipophilicity and its relationship with passive drug permeation.

In this review, we first summarize the structure and properties of biological membranes and the routes of passive drug transfer through physiological barriers. Lipophilicity is then introduced in terms of the intermolecular interactions it encodes. Finally, lipophilicity indices from isotropic solvent systems and from anisotropic membrane-like systems are discussed for their capacity to predict passive drug permeation across biological membranes such as the intestinal epithelium, the blood-brain barrier (BBB) or the skin. The broad evidence presented here shows that beyond the predictive power of lipophilicity parameters, the various intermolecular forces they encode allow a mechanistic interpretation of passive drug permeation.

Contrôle d'une épidémie d'entérocoques résistant à la vancomycine dans plusieurs hôpitaux de Suisse romande [Control of an outbreak of vancomycin-resistant enterococci in several hospitals of western Switzerland].

An outbreak of vancomycin-resistant enterococci (VRE) occurred in 2011 in several hospitals of western Switzerland. Given that VRE can spread rapidly within hospitals and due to the potential transfer of resistance genes to other nosocomial pathogens like MRSA, stringent control measures were implemented. Excellent coordination of control measures between partner healthcare settings was successful in stopping the outbreak.

Beta-lactams against methicillin-resistant Staphylococcus aureus.

Methicillin-resistant Staphylococcus aureus (MRSA) have developed resistance to virtually all non-experimental antibiotics. They are intrinsically resistant to beta-lactams by virtue of newly acquired low-affinity penicillin-binding protein 2A (PBP2A). Because PBP2A can build the wall when other PBPs are blocked by beta-lactams, designing beta-lactams capable of blocking this additional target should help solve the issue. Older molecules including penicillin G, amoxicillin and ampicillin had relatively good PBP2A affinities, and successfully treated experimental endocarditis caused by MRSA, provided that the bacterial penicillinase could be inhibited. Newer anti-PBP2A beta-lactams with over 10-fold greater PBP2A affinities and low minimal inhibitory concentrations were developed, primarily in the cephem and carbapenem classes. They are also very resistant to penicillinase. Most have demonstrated anti-MRSA activity in animal models of infection, and two--the carbapenem CS-023 and the cephalosporin ceftopibrole medocaril--have proceeded to Phase II and Phase III clinical evaluation. Thus, clinically useful anti-MRSA beta-lactams are imminent.

Subretinal neovascular membranes complicating uveitis : frequency, treatments and visual outcome

RESUME Les membranes néovasculaires (MNV) compliquent diverses pathologies ophtalmiques. Elles sont à l'origine d'une importante baisse de l'acuité visuelle lorsque elles se situent à proximité de la fovéa. A l'heure actuelle, peu de données relatives à leur association aux pathologies inflammatoires de l'oeil (uvéites) existent. Dans ce travail, la fréquence de MNV a été évaluée parmi 643 patients avec uvéite. Leur impact sur l'acuité visuelle ainsi que le pronostic en fonction des différents traitements effectués ont été étudiés. Les dossiers des 643 patients souffrant d'uvéite ont été étudiés. Les patients présentant une MNV ont été classés en trois groupes en fonction de l'importance de l'inflammation intraoculaire: élevée (2+ cellules dans le vitré), moyenne (1/2+ à 1+ cellules dans le vitré) ou absente (0 cellules dans le vitré). L'évolution de l'acuité visuelle fut considérée comme favorable (+VA: maintient de l'acuité visuelle ou gain d'une ou plusieurs lignes de Snellen) ou défavorable (-VA: perte d'une ou plusieurs lignes Snellen). Chez 9 patients, le traitement instauré a consisté, initialement, en l'administration orale de corticostéroïdes (CST) à haute dose qui, dans le cas d'évolution favorable (-FVA ou régression angiographique de la MNV), était arrêtée en doses dégressives. Dans les évolutions défavorables (-VA ou progression angiographique de la MNV), les CST étaient maintenus à dose moyenne en complémentation d'un traitement par thérapie laser (photothérapie dynamique (PDT), thermothérapie transpupillaire (TTT) ou laser Argon). Ce protocole thérapeutique ne fut appliqué chez trois patients en raison de la non disponibilité de PDT ou d'un diagnostic manqué d'uvéite. Douze patients sur 643 avec uvéite ont présenté une MNV. L'impact visuel moyen était de 4.5 lignes de Snellen et le temps moyen de suivi était de 19.5 mois. Deux patients avec inflammation intraoculaire élevée ont évolué favorablement sous CST seuls. Huit patients avec inflammation intraoculaire moyenne ont évolué favorablement sous CST seuls chez trois patients, alors que quatre patients ont nécessité une thérapie laser additionnelle. Le dernier patient ne fut traité que par thérapie laser sans CST (diagnostic manqué d'uvéite). Deux patients sans inflammation intraoculaire ont eu un pronostic défavorable sous CST seuls (pas d'autre alternative thérapeutique). Notre étude a démontré que les MNV sont une complication rare de l'uvéite qui, après traitement adéquat, ont un pronostic visuel relativement favorable. Bien que les CST semblent être la première modalité thérapeutique, les traitements laser devraient être adoptés tôt dans les situations d'inflammation intraoculaire moyenne ou absente.

Methicillin-resistant Staphylococcus aureus with intermediate susceptibility to vancomycin: are strict additional contact measures sufficient?

Background: A hospitalised patient infected with MRSA was found to harbour a VISA strain after 6 weeks of treatment with vancomycin. Additional contact measures were reinforced according to CDCs recommendations. We decide to evaluate if these applied control measures were effective. Objective: To evaluate the efficacy of strict additional contact measures to contain the dissemination of VISA from an infected patient. Methods: All patients from the unit were screened weekly for MRSA during a 6-week period, whereas health care workers (HCW) were screened only once. Screening specimen included nose, throat, groin, and clinical specimens for patients, and only nose and throat for HCW. Broth enrichment and chromogenic agar (MRSA-select) were used for MRSA detection. All MRSA isolates were tested on Van screen plates, and growing colonies were tested for MIC of vancomycin. MIC was performed using Etest. Population analysis was done for VISA confirmation. One strain per person was typed by Double Locus Sequence Typing (based on clfB and spa sequencing). Results: 66 patients hospitalized in the same service during the 6 weeks and 55 HCW were screened for MRSA and VISA. MRSA was found in 16/66 (24%) patients and 1/55 (2%) HCW. 16/17 MRSA from patients belonged to the same genotype that the VISA strain. The remaining patient had a MRSA identical to the HCW isolate. Among the 16 MRSA isolates sharing the same genotype than the VISA strain, two showed Etests vancomycin MIC of only 4 mg/L. MIC results were confirmed by the population analysis. They were not considered as VISA, but as MRSA with increased vancomycin MICs. Both isolates were obtained from two roommates. Conclusion: Strict additional contact measures were found to be effective to contain VISA dissemination. However, the identification of two isolates with increased vancomycin MIC (4 mg/L) in two roommates raised the question of the need to routinely test this susceptibility and of adequate control measures for patients harbouring such isolates.

Dénervation rénale pour le traitement de l'hypertension artérielle résistante: proposition pour une attitude multidisciplinaire commune [Renal denervation in resistant hypertension: proposal for a common multidisciplinary attitude].

The prevalence of resistant hypertension ranges between 5-30%. Patients with resistant hypertension are at increased risk of cardiovascular events. Radiofrequency renal denervation is a recent and promising technique that can be used in the setting of resistant hypertension. However, long-term safety and efficacy data are lacking and evidence to use this procedure outside the strict setting of resistant hypertension is missing. The aim of the article is to propose a common work-up for nephrologists, hypertensiologists, cardiologists and interventional radiologists in order to avoid inappropriate selection of patients and a possible misuse of this procedure.

Inflammasome-activated caspase 7 cleaves PARP1 to enhance the expression of a subset of NF-κB target genes.

Caspase 1 is part of the inflammasome, which is assembled upon pathogen recognition, while caspases 3 and/or 7 are mediators of apoptotic and nonapoptotic functions. PARP1 cleavage is a hallmark of apoptosis yet not essential, suggesting it has another physiological role. Here we show that after LPS stimulation, caspase 7 is activated by caspase 1, translocates to the nucleus, and cleaves PARP1 at the promoters of a subset of NF-κB target genes negatively regulated by PARP1. Mutating the PARP1 cleavage site D214 renders PARP1 uncleavable and inhibits PARP1 release from chromatin and chromatin decondensation, thereby restraining the expression of cleavage-dependent NF-κB target genes. These findings propose an apoptosis-independent regulatory role for caspase 7-mediated PARP1 cleavage in proinflammatory gene expression and provide insight into inflammasome signaling.

Hospital outbreak of methicillin-resistant Staphylococcus aureus caused by a new, possibly hyperepidemic variant from a previously sporadic strain.

Objective: To describe an ongoing outbreak that tripled the annual detection of methicillin-resistant Staphylococcus aureus (MRSA) carriage in a tertiary care hospital. Methods: Active surveillance of MRSA is performed since 20 years in our hospital. Our protocol includes screening of patients transferred from high-incidence health-care institutions or countries, roommates of new MRSA cases, and wards where _2 patients acquired MRSA during the same week. Contact precautions are used for known carriers. PFGE was used for molecular typing until 2004, and was then replaced by Double-Locus Sequence Typing (DLST). Results: A median yearly incidence of 173 new carriers of MRSA was observed from 2002 to 2007. Since September 2008, an increasing number of new cases were observed, mainly as successive clusters limited to distinct wards, reaching a total of 398 until October 2009. The yearly incidence of new cases rose to 275 in 2008 and 613 in 2009. 60% of the cases were due to one strain: DLST 4−4, ST 228, SCCmecI. The incidence of new cases due to the previously predominant strains remained unchanged. The epidemic strain corresponded to a new variant of a clone responsible for a previous outbreak in 2001, and only sporadically isolated (mean of 20 cases/year) since then. A case- control study documented a significant association between acquisition of the epidemic strain and a stay in intensive and intermediary care units, a highest number of internal transfers, but did not identify a point source of transmission. Infection control practices and antibiotic policy had remained unchanged for several years. Compliance with handhygiene as monitored yearly was on the rise. Screening of 313 healthcare workers only found one carrier of the epidemic strain lately in the outbreak. Additional infection control measures were enforced, including screening at ICU admission and discharge with PCR-based rapid test, routine screening for all patients leaving epidemic wards, introduction of PCR-based rapid test for contact tracing, additional working forces for environmental disinfection, and hospital-wide education of healthcare workers. However, the outbreak was still ongoing after 5 months. Conclusions: Factors linked to the dissemination of this new variant in our institution remain undetermined. This unresolved outbreak suggests that this new variant acquired hyperepidemic properties, which calls for further investigations.

Assessment of drug compliance in patients with high blood pressure resistant to antihypertensive therapy.

The persistence of high blood pressure under antihypertensive treatment (resistant hypertension) entails an increased cardiovascular risk. It occurs in three of ten treated hypertensive patients, and has several possible contributing factors, notably insufficient therapeutic adherence. There are a number of ways to evaluate whether patients take their medication as prescribed. These include interviewing the patient, pill counting, prescription follow-up, assay of drugs in blood or urine, and use of electronic pill dispensers. None is perfect. However, the essential is to discuss with the patient the importance of complying with the treatment as soon as it is prescribed for the first time, and not waiting for the appearance of resistant hypertension. The measurement of blood pressure outside the medical office and the monitoring of adherence may help to identify patients in whom hypertension is truly resistant and so to tailor the measures required to improve the control of blood pressure in the most appropriate manner.

Therapy of steroid-resistant inflammatory bowel disease.

Background and Aims: Although systemic corticosteroids are successfully administered for the induction of clinical response and remission in the majority of patients with inflammatory bowel disease (IBD) presenting with a flare, a proportion of these patients demonstrate a primary nonresponse to steroids or in the case of an initial response, they develop a resistance or a steroid dependence. Long-term therapy with corticosteroids for treatment of IBD should be avoided, given the high frequency of adverse treatment effects. Knowledge about treatment strategies in case of steroid nonresponse is therefore highly relevant. Methods: A systematic literature research was performed using Medline and Embase to summarize the currently recommended treatment strategies for steroid-resistant IBD. Results: Treatment of steroid-resistant Crohn's disease is based on the introduction of immunomodulators such as azathioprine, 6-mercaptopurine or methotrexate, the anti-TNF drugs infliximab, adalimumab and certolizumab pegol. In the case of steroid resistance in ulcerative colitis, aminosalicylates, the above-mentioned immunomodulators, infliximab, adalimumab or calcineurin inhibitors such as ciclosporin or tacrolimus may be administered. Conclusion: This review summarizes the current evidence for treating steroid-resistant IBD.