Bridging basic science and clinical research - The EASL Monothematic Conference on Translational Research in Viral Hepatitis.

The EASL Monothematic Conference on Translational Research in Viral Hepatitis brought together a group of leading scientists and clinicians working on both, basic and clinical aspects of viral hepatitis, thereby building bridges from bench to bedside. This report recapitulates the presentations and discussions at the conference held in Lyon, France on November 29-30, 2013. In recent years, great advances have been made in the field of viral hepatitis, particularly in hepatitis C virus (HCV) infection. The identification of IL28B genetic polymorphisms as a major determinant for spontaneous and treatment-induced HCV clearance was a seminal discovery. Currently, hepatologists are at the doorstep of even greater advances, with the advent of a wealth of directly acting antivirals (DAAs) against HCV. Indeed, promising results have accumulated over the last months and few years, showing sustained virological response (SVR) rates of up to 100% with interferon-free DAA combination therapies. Thus, less than 25years after its identification, HCV infection may soon be curable in the vast majority of patients, highlighting the great success of HCV research over the last decades. However, viral hepatitis and its clinical complications such as liver cirrhosis and hepatocellular carcinoma (HCC) remain major global challenges. New therapeutic strategies to tackle hepatitis B virus (HBV) and hepatitis D virus (HDV) infection are needed, as current therapies have undeniable limitations. Nucleoside/nucleotide analogues (NUC) can efficiently control HBV replication and reduce or even reverse liver damage. However, these drugs have to be given for indefinite periods in most patients to maintain virological and biochemical responses. Although sustained responses off treatment can be achieved by treatment with (pegylated) interferon-α, only about 10-30% of patients effectively resolve chronic hepatitis B. It was the goal of this conference to review the progress made over the last years in chronic viral hepatitis research and to identify key questions that need to be addressed in order to close the gap between basic and clinical research and to develop novel preventive and treatment approaches for this most common cause of liver cirrhosis and HCC.

Restoration of lymphoid organ integrity through the interaction of lymphoid tissue-inducer cells with stroma of the T cell zone.

The generation of lymphoid microenvironments in early life depends on the interaction of lymphoid tissue-inducer cells with stromal lymphoid tissue-organizer cells. Whether this cellular interface stays operational in adult secondary lymphoid organs has remained elusive. We show here that during acute infection with lymphocytic choriomeningitis virus, antiviral cytotoxic T cells destroyed infected T cell zone stromal cells, which led to profound disruption of secondary lymphoid organ integrity. Furthermore, the ability of the host to respond to secondary antigens was lost. Restoration of the lymphoid microanatomy was dependent on the proliferative accumulation of lymphoid tissue-inducer cells in secondary lymphoid organs during the acute phase of infection and lymphotoxin alpha(1)beta(2) signaling. Thus, crosstalk between lymphoid tissue-inducer cells and stromal cells is reactivated in adults to maintain secondary lymphoid organ integrity and thereby contributes to the preservation of immunocompetence.

Human epidermal Langerhans cells express the tight junction protein claudin-1 and are present in human genetic claudin-1 deficiency (NISCH syndrome).

Claudin-1 (CLDN1) is a structural tight junction (TJ) protein and is expressed in differentiating keratinocytes and Langerhans cells in the epidermis. Our objective was to identify immunoreactive CLDN1 in human epidermal Langerhans cells and to examine the pattern of epidermal Langerhans cells in genetic human CLDN1 deficiency [neonatal ichthyosis, sclerosing cholangitis (NISCH) syndrome]. Epidermal cells from healthy human skin labelled with CLDN1-specific antibodies were analysed by confocal laser immunofluorescence microscopy and flow cytometry. Skin biopsy sections of two patients with NISCH syndrome were stained with an antibody to CD1a expressed on epidermal Langerhans cells. Epidermal Langerhans cells and a subpopulation of keratinocytes from healthy skin were positive for CLDN1. The gross number and distribution of epidermal Langerhans cells of two patients with molecularly confirmed NISCH syndrome, however, was not grossly altered. Therefore, CLDN1 is unlikely to play a critical role in migration of Langerhans cells (or their precursors) to the epidermis or their positioning within the epidermis. Our findings do not exclude a role of this TJ molecule once Langerhans cells have left the epidermis for draining lymph nodes.

Poesia epica e letteratura femminile nell'Italia del XVII secolo: "L'Enrico, ovvero Bisanzio acquistato" (1635) di Lucrezia Marinelli

Nella mia tesi di dottorato mi concentro sul poema di Lucrezia Marinelli, L'Enrico, ovvero Bisanzio acquistato, pubblicato a Venezia nel 1635, indagando le strategie messe in atto dall'autrice per rivisitare il genere epico in un'ottica di riscatto femminile. Rispetto al canone epico e, in particolare, al modello di riferimento - la Gerusalemme liberata del Tasso - le vicende nodali sono, infatti, riscritte da un punto di vista chiaramente femminile. Pur occupandomi principalmente dell'opera di Marinelli, in alcuni casi nel corso del mio lavoro propongo dei confronti con altri poemi epici e cavallereschi prodotti da donne - in particolare I tredici canti del Floridoro di Moderata Fonte (1581) - volti a mostrare come le scrittrici avessero degli intenti comuni, dialogando in maniera critica con i modelli maschili da cui, tuttavia, traggono ispirazione. Nei primi capitoli del mio lavoro prendo in esame alcuni personaggi tradizionali dell'epica (le guerriere, la maga, ...) presenti ne L'Enrico e ne ripercorro gli episodi topici (le sortite notturne, l'eroe sull'isola, ...) dimostrando come, pur inserendosi coerentemente nel genere epico, siano caratterizzati in modo sostanzialmente diverso rispetto alla precedente tradizione maschile. Il primo capitolo si concentra sulle figure di guerriere, le quali presentano - rispetto ai precedenti modelli - differenze notevoli: non si lasciano coinvolgere in vicende amorose e non finiscono per essere sottomesse o uccise da un uomo, mantenendo così coerentemente intatti i valori di forza e indipendenza. Neppure la maga sull'isola - presa in esame nel capitolo dedicato alle Altre figure di donne idealizzate - è coinvolta in vicende sentimentali o caratterizzata sensualmente. L'autrice la rappresenta, non alla stregua di una tentatrice al servizio delle forze del male, ma come una donna colta, casta e disposta ad aiutare il cavaliere naufragato sulla sua isola. Nello stesso capitolo sono indagate anche altre figure femminili idealizzate, per taluni aspetti meno innovative, ma ugualmente interessanti: la Vergine, la personificazione di Venezia e la Musa. Queste rappresentazioni dal carattere iconico, presentano, infatti, diverse caratteristiche in comune con i personaggi più attivi del poema, le guerriere e la maga. Il capitolo Delle pene e delle tragedie amorose è dedicato all'amore e ai suoi esiti tragici. Le figure di donna coinvolte sono le madri, le mogli e Idillia, in cui è riconoscibile il personaggio topico della "damigella in difficoltà". Queste protagoniste, destinate a soffrire perché abbandonate dall'uomo che amano - il quale sente più forte il richiamo della guerra rispetto a quello dell'amore - servono da exempla, dimostrando che attaccamento affettivo e dipendenza conducono inesorabilmente all'infelicità. Rispetto al canone epico Marinelli riscatta alcune figure femminili, permettendo alle sue guerriere di prendersi la rivincita, vendicando la morte di eroine quali Camilla e Clorinda. Conseguentemente, alcuni guerrieri sono destinati a morire per mano di una donna. Nel quarto capitolo, mi concentro proprio su La sconfitta degli eroi, mettendo in luce come l'autrice proponga una sua personale regola del contrappasso, volta a cambiare (e addirittura invertire) le sorti dei personaggi che animano il suo poema. Questi aspetti risultano essere ancora più significativi se confrontati con l'opera - data alle stampe per la prima volta nel 1600 - intitolata Nobiltà et eccellenza delle donne. In questo trattato Marinelli sosteneva la superiorità del genere femminile su quello maschile. Alcune delle posizioni assunte nello scritto giovanile sono confermate dai personaggi e dalle vicende che animano l'Enrico. Confronti puntuali fra trattato e poema epico sono effettuati nell'ultimo capitolo del mio lavoro, sottolineando come fra le due opere vi siano delle affinità volte a confermare l'eccellenza delle donne.

Early blood exchange transfusion in malignant pertussis: A case report.

OBJECTIVE:: To report early blood exchange transfusion in malignant pertussis and a favorable clinical outcome. SETTING:: A pediatric intensive care unit in a tertiary hospital in Geneva, Switzerland. DESIGN:: A descriptive case report. PATIENT:: An 8-wk-old girl was diagnosed with malignant pertussis (extreme leukocytosis, seizures, pneumonia, and secondary severe hypoxic respiratory failure associated with pulmonary hypertension). After administration of a one-volume blood exchange transfusion, a rapid decrease in white blood cell count (from 119,000/mm to 36,500/mm) was observed and followed by clinical improvement and favorable outcome despite the initial presence of all described risk factors associated with a high mortality. CONCLUSION:: The use of exchange blood transfusion early in the course of the disease might help to prevent a fatal outcome of malignant pertussis.

VOLUMES RELIES du Cabinet des titres : recherches de noblesse, armoriaux, preuves, histoires généalogiques. Terrier de la seigneurie de Louverny, relevant du comté de Rethel, fait pour Gracien de Bournonville. (1539).

Copie collationnée faite en 1573, suivie de quelques autres pièces concernant la même seigneurie.

The human epidermal differentiation complex: cornified envelope precursors, S100 proteins and the 'fused genes' family.

  The skin is essential for survival and protects our body against biological attacks, physical stress, chemical injury, water loss, ultraviolet radiation and immunological impairment. The epidermal barrier constitutes the primordial frontline of this defense established during terminal differentiation. During this complex process proliferating basal keratinocytes become suprabasally mitotically inactive and move through four epidermal layers (basal, spinous, granular and layer, stratum corneum) constantly adapting to the needs of the respective cell layer. As a result, squamous keratinocytes contain polymerized keratin intermediate filament bundles and a water-retaining matrix surrounded by the cross-linked cornified cell envelope (CE) with ceramide lipids attached on the outer surface. These cells are concomitantly insulated by intercellular lipid lamellae and hold together by corneodesmosmes. Many proteins essential for epidermal differentiation are encoded by genes clustered on chromosomal human region 1q21. These genes constitute the 'epidermal differentiation complex' (EDC), which is divided on the basis of common gene and protein structures, in three gene families: (i) CE precursors, (ii) S100A and (iii) S100 fused genes. EDC protein expression is regulated in a gene and tissue-specific manner by a pool of transcription factors. Among them, Klf4, Grhl3 and Arnt are essential, and their deletion in mice is lethal. The importance of the EDC is further reflected by human diseases: FLG mutations are the strongest risk factor for atopic dermatitis (AD) and for AD-associated asthma, and faulty CE formation caused by TG1 deficiency causes life-threatening lamellar ichthyosis. Here, we review the EDC genes and the progress in this field.

Rapid Improvement in Health-Related Quality of Life (HRQoL) in Gouty Arthritis Patients Treated with Canakinumab (ACZ885) Compared to Triamcinolone Acetonide

Background: Gouty arthritis is a painful inflammatory disease with a significant impact on patients' HRQoL. In gouty arthritis, the inflammatory response is initiated by interleukin-1b (IL-1b) release, due to activation of the NALP3 inflammasome by MSU crystals. Canakinumab, a fully human anti-IL-1b antibody has a long half-life and has been shown to control inflammation in gouty arthritis. This study evaluated changes in HRQoL in gouty arthritis patients following treatment with canakinumab or triamcinolone acetonide (TA).Methods: This was an 8-week, dose-ranging, multi-center, active controlled, single-blind study. Patients (>=18 to <=80 years) experiencing an acute gouty arthritis flare, refractory to or contraindicated to NSAlDs and/or colchicine, were randomized to canakinumab 10, 25, 50, 90, 150 mg sc or TA 40 mg im. HRQoL was assessed as an exploratory endpoint at baseline and different pre-specified time-points using patient reported outcomes evaluating general mental and physical component summary scores and subscale scores of SF-36® (acute version 2) and functional disability (HAQ-DI©). We report HRQoL results for canakinumab 150 mg, the dose that was selected for the Phase III studies.Results: Baseline assessments showed a major impact on the HRQoL during acute gouty arthritis. Compared to TA, canakinumab 150 mg showed greater improvements in SF-36® physical and mental component summary and subscale scores at 7 days post-dose.In the canakinumab 150 mg group, the most severe impairment at baseline was reported for physical functioning and bodily pain; levels of 41.5 and 36.0, respectively, which improved within 7 days to 80.0 and 72.2 (mean increases of 39.0 and 35.6) approaching levels of the general US population (84.2 and 75.2). 8 weeks post-dose patients reached levels of 86.1 and 86.6 (mean increases of 44.6 and 50.6 for physical functioning and bodily pain, respectively) and these were higher than levels seen in the general US population. This was in contrast to patients treated with TA, who showed less improvement within 7 days (mean increases of 23.3 and 21.3 for physical function and bodily pain, respectively). None of the scores reached levels of the general US population 8 weeks post-dose. Functional disability scores, as measured by the HAQ-DI© decreased in both treatment groupsConclusions: All canakinumab doses showed a rapid improvement in physical and mental well-being of gouty arthritis patients based on SF-36® scores, in particular the 150 mg dose. In contrast to the TA group, patients treated with canakinumab showed improvement within 7 days in physical function and bodily pain approaching levels of the general population. The 150 mg dose of canakinumab was selected for further development in Phase III studies.

Tuning In to Sound: Frequency-Selective Attentional Filter in Human Primary Auditory Cortex.

Cocktail parties, busy streets, and other noisy environments pose a difficult challenge to the auditory system: how to focus attention on selected sounds while ignoring others? Neurons of primary auditory cortex, many of which are sharply tuned to sound frequency, could help solve this problem by filtering selected sound information based on frequency-content. To investigate whether this occurs, we used high-resolution fMRI at 7 tesla to map the fine-scale frequency-tuning (1.5 mm isotropic resolution) of primary auditory areas A1 and R in six human participants. Then, in a selective attention experiment, participants heard low (250 Hz)- and high (4000 Hz)-frequency streams of tones presented at the same time (dual-stream) and were instructed to focus attention onto one stream versus the other, switching back and forth every 30 s. Attention to low-frequency tones enhanced neural responses within low-frequency-tuned voxels relative to high, and when attention switched the pattern quickly reversed. Thus, like a radio, human primary auditory cortex is able to tune into attended frequency channels and can switch channels on demand.