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A bidispersive porous material is one which has usual pores but additionally contains a system of micro pores. We consider a fluid-saturated bidispersive porous medium in the vertical layer x ∈(−1/2,1/2) with gravity in the − z (downward) direction. The walls of the layer are maintained at different constant temperatures. A suitable Rayleigh number is defined and we derive a global stability threshold below which no instability may arise. We additionally show that the porous layer is stable for all Rayleigh numbers provided the initial temperature gradient is bounded in a precise sense.

We obtain the linear instability and nonlinear stability thresholds for a prob- lem of thermal convection in a bidispersive porous medium with a single temperature. It is important to note that we show that the linear instability threshold is the same as the nonlinear stability one. This means that the linear theory is capturing completely the physics of the onset of thermal con- vection. This result contrasts with the general theory of thermal convection in a bidispersive porous material where the temperatures in the macropores and micropores are allowed be different. In that case the coincidence of the stability boundaries has not been proved.

Exosomes, nano-sized membrane vesicles, are released by various cells and are found in many human body fluids. They are active players in intercellular communication and have immune-suppressive, immune-regulatory, and immune-stimulatory functions. EBV is a ubiquitous human herpesvirus that is associated with various lymphoid and epithelial malignancies. EBV infection of B cells in vitro induces the release of exosomes that harbor the viral latent membrane protein 1 (LMP1). LMP1 per se mimics CD40 signaling and induces proliferation of B lymphocytes and T cell–independent class-switch recombination. Constitutive LMP1 signaling within B cells is blunted through the shedding of LMP1 via exosomes. In this study, we investigated the functional effect of exosomes derived from the DG75 Burkitt’s lymphoma cell line and its sublines (LMP1 transfected and EBV infected), with the hypothesis that they might mimic exosomes released during EBV-associated diseases. We show that exosomes released during primary EBV infection of B cells harbored LMP1, and similar levels were detected in exosomes from LMP1-transfected DG75 cells. DG75 exosomes efficiently bound to human B cells within PBMCs and were internalized by isolated B cells. In turn, this led to proliferation, induction of activation-induced cytidine deaminase, and the production of circle and germline transcripts for IgG1 in B cells. Finally, exosomes harboring LMP1 enhanced proliferation and drove B cell differentiation toward a plasmablast-like phenotype. In conclusion, our results suggest that exosomes released from EBV-infected B cells have a stimulatory capacity and interfere with the fate of human B cells.

Guardian of the Gut The intestine is able to tolerate continual exposure to large amounts of commensal bacteria and foreign food antigens without triggering an inappropriate inflammatory immune response. In the large intestine, this immunological tolerance is thought to occur via a physical separation between environment and host imposed by a continuous mucous layer built up from the secreted mucin protein, MUC2. However, in the small intestine, this mucous layer is porous, necessitating an additional layer of immune control. Shan et al. (p. 447 , published online 26 September; see the Perspective by Belkaid and Grainger ) now report that in the small intestine, MUC2 plays an active role in immunological tolerance by activating a transcription factor in resident dendritic cells, thereby selectively blocking their ability to launch an inflammatory response. This work identifies MUC2 as a central mediator of immune tolerance to maintain homeostasis in the gut and possibly at other mucosal surfaces in the body.

Teachers should lead classes with more effective and innovative teaching methods (Schleicher, 2012; Benavides, 2010). The culture of lifelong learning is connected with students’ improvement (Darling-Hammond, 2009). The research studies the impact of trainings delivered by CESEDI - a public institution - across ten years and the different school´ organization to permit engagement of teachers as educational leader (named as facilitator). We collected: the quantitative data through a web engine solution based on the Opinio platform. We ran a PCA (Principal Component Analysis) on a part of the questionnaire addressed to the study (n 592) of individual and social factors; the qualitative data with biographical matrix of professional role (n 19). The research shows how a specific role of teacher as facilitator enables the following aspects: leadership empowerment, improvement of teaching, colleagues support for accomplishing the tasks learned, participated decision making. As demonstrated teachers appreciate to be helped by colleagues.

The 2 L polyethylene glycol (PEG) lavage solution has been proved to be similarly safe and effective as 4 L PEG formulations, in spite of the reduced volume.To compare low-volume PEG-based solution combined with ascorbic acid with high-volume PEG-based solution combined with simethicon in terms of efficacy and patient tolerability.This was a single-blind prospective randomized trial. Patients were randomized to receive either 2 L PEG plus ascorbic acid (PEG+Asc) or 4 L PEG plus simethicon (PEG+Sim). The primary endpoint was overall colon cleansing evaluation, assessed by blinded investigators using Aronchick score. Secondary end points included patient compliance and tolerability and adverse events.Sixty patients received PEG+Asc and 60 received PEG+Sim. Overall bowel cleansing score was considered adequate in 81.67% of the PEG+Asc and 80% of the PEG+Sim groups, respectively. Excellent and good ratings were recorded in 11.6% and 38.3% receiving PEG+Asc as compared with 26.6% and 23.3% of patients receiving PEG+Sim. Patient tolerability and safety were similar with both the preparations.According to our data, low-volume PEG+Asc has comparable efficacy, safety, and tolerability as high-volume PEG+Sim; therefore, it can be considered as a good alternative solution for bowel preparation. More improvements are necessary to achieve the target of a perfect preparation.

An HIV-1 vaccine remains elusive, in part because various factors limit the quantity and quality of the antibodies raised against the viral envelope glycoprotein complex (Env). We hypothesized that targeting Env vaccines directly to B cells, by fusing them to molecules that bind and activate these cells, would improve Env-specific antibody responses. Therefore, we fused trimeric Env gp140 to A PRoliferation-Inducing Ligand (APRIL), B-cell Activating Factor (BAFF), and CD40 Ligand (CD40L). The Env-APRIL, Env-BAFF, and Env-CD40L gp140 trimers all enhanced the expression of activation-induced cytidine deaminase (AID), the enzyme responsible for inducing somatic hypermutation, antibody affinity maturation, and antibody class switching. They also triggered IgM, IgG, and IgA secretion from human B cells in vitro . The Env-APRIL trimers induced higher anti-Env antibody responses in rabbits, including neutralizing antibodies against tier 1 viruses. The enhanced Env-specific responses were not associated with a general increase in total plasma antibody concentrations, indicating that the effect of APRIL was specific for Env. All the rabbit sera raised against gp140 trimers, irrespective of the presence of CD40L, BAFF, or APRIL, recognized trimeric Env efficiently, whereas sera raised against gp120 monomers did not. The levels of trimer-binding and virus-neutralizing antibodies were strongly correlated, suggesting that gp140 trimers are superior to gp120 monomers as immunogens. Targeting and activating B cells with a trimeric HIV-1 Env-APRIL fusion protein may therefore improve the induction of humoral immunity against HIV-1.

Objective— Our aim was to analyze the regulation of CC Chemokine ligand 20 (CCL20) by LDL in human vascular smooth muscle cells (VSMC). Methods and Results— In asymptomatic subjects, circulating CCL20 levels were higher in patients with hypercholesterolemia (18.5±3.2 versus 9.1±1.3 pg/mL; P Conclusion— This study identifies CCL20 in atherosclerotic lesions and recognizes this chemokine as a mediator highly sensitive to the inflammatory response elicited by LDL.

Adaptive co-evolution of mammals and bacteria has led to the establishment of complex commensal communities on mucosal surfaces. In spite of having available a wealth of immune-sensing and effector mechanisms capable of triggering inflammation in response to microbial intrusion, mucosal immune cells establish an intimate dialogue with microbes to generate a state of hyporesponsiveness against commensals and active readiness against pathogens. A key component of this homeostatic balance is IgA, a noninflammatory antibody isotype produced by mucosal B cells through class switching. This process involves activation of B cells by IgA-inducing signals originating from mucosal T cells, dendritic cells, and epithelial cells. Here, we review the mechanisms by which mucosal B cells undergo IgA diversification and production and discuss how the study of primary immunodeficiencies facilitates better understanding of mucosal IgA responses in humans.

Background : Fast-track program has been applied in several surgical fields. However, currently many surgical patients are elderly over 70 years of age, and discussion about the application of such protocols for elderly patients is inadequate. Materials and methods : The present study was designed to consider the safety and feasibility of application of a fast-track program after colorectal surgery in elderly patients. A total of 76 elderly patients with colorectal cancer who underwent laparoscopic colorectal resection were randomly assigned to receive either the fast-track care program ( n = 40) or the conventional perioperative care protocol (control group, n = 36). The fast track protocol included no preoperative mechanical bowel irrigation, immediate oral alimentation and earlier postoperative ambulation exercise. The length of postoperative hospital stay, the length of time to regain bowel function and the rate of postoperative complications were compared between the two groups. Results : The length of time to regain bowel function, including the passage of flatus [32 (24–40) h vs 42 (32–52) h], and to start a liquid diet (13 [10–16] h v/s 43 [36–50] h) were significantly shorter in patients receiving the fast track care protocol compared with those receiving the conventional care protocol. A shorter duration of postoperative hospital stay was recorded in patients receiving the fast-track program than in those receiving conventional care [6 (5–7) days v/s 9.5 (7–12) days]. A reduced percentage of patients who developed general complications was also observed in the fast-track group (5.0% v/s 18%). Conclusion : Fast-track after laparoscopic colorectal surgery can be safely applied in carefully selected elderly patients older than age 70 years. The fast-track recovery program resulted in a more rapid postoperative recovery, earlier discharge from hospital and fewer general complications compared with a conventional postoperative protocol.

Penetrative convection in an anisotropic porous medium is simulated via internal heating. We consider both internal heat sources and sinks, where the porous medium has constant anisotropic thermal diffusivity and non-homogeneous permeability. Both linear instability and global nonlinear energy stability analyses are performed. By adopting a differential constraint approach, the nonlinear stability boundaries are shown to be sharp when compared with the linear instability thresholds. In contrast, it is shown that adopting a standard energy analysis does not yield sharp results.

Introduccion La hipoxia participa en el desarrollo de enfermedades cardiovasculares por la regulacion coordinada de multiples genes, incluidos aquellos implicados en la sintesis/reparacion de la matriz extracelular (MEC). La lisil oxidasa (LOX), enzima implicada en la maduracion de la MEC, parece tener un papel clave en el mantenimiento de la homeostasis del endotelio. Nuestro objetivo fue determinar si la hipoxia modula la expresion de la LOX en celulas endoteliales. Metodos La expresion de LOX en celulas endoteliales bovinas de aorta (BAEC) y humanas de vena de cordon umbilical (HUVEC) se determino mediante PCR a tiempo real. La actividad enzimatica de LOX se analizo mediante un metodo fluorimetrico de alta sensibilidad y la actividad transcripcional de LOX, mediante estudios de transfeccion transitoria. Resultados La hipoxia (1% de O 2 ) incremento la expresion de LOX en celulas BAEC y HUVEC (aproximadamente, 3 veces) en condiciones en que este estimulo indujo los valores del factor inducible por hipoxia-1α (HIF-1α), la expresion de VEGF y la formacion de neovasos. Este efecto se asocio a un aumento en la actividad enzimatica LOX. Analogamente, la incubacion de celulas endoteliales con dimetil oxal glicina, inhibidor de prolil hidroxilasas, incremento la concentracion de ARNm de LOX. La inhibicion de la transcripcion con 5,6-diclorobencimidazol previno este efecto, lo que indica la implicacion de un mecanismo transcripcional. Mediante estudios de transfeccion transitoria determinamos que tanto la hipoxia como la sobreexpresion de HIF-1α incrementa la actividad del promotor de LOX de forma similar. Conclusiones La hipoxia induce la expresion y la actividad de LOX en celulas endoteliales por un mecanismo transcripcional en el que estaria implicado HIF-1.

Linear and nonlinear stability analises of vertical throughflow in a fluid layer, where the density is quadratic in temperature, are studied. To avoid the loss of key terms a weighted functional is used in the energy analysis. Both conditional and unconditional thresholds are derived. When the throughflow is ascending the linear and nonlinear boundaries show substantially agreement. The linear boundary remains close to the conditional nonlinear bioundary for descending throughflow, whilst the unconditional threshold begins to diverge.

The paper presents an overview of the common regulatory framework for railway safety. Safety levels in the Community railway system are generally high, in particular compared to road transport. However, it is necessary to very least maintain safety during the liberalization process and, in line with technical and scientific progress, to further improve it, when reasonably practicable, taking into account the competitiveness of the rail transport mode. The paper will analyze the requirements present in the common standards and will propose a guide to choose the best method for the risk evaluation.

Lymphatic malformation or lymphangioma is a benign proliferation of the lymphatics accounting for 4% of all vascular malformations and 26% of all benign vascular tumors. There are several reports about genital lymphangiomas mimicking venereal lesions, such as genital warts. Hereby we described a case of a 24 year old man affected by multiple vesicles and warts in genital area. All hematological and biochemical parameters, Human Immunodeficiency Virus (HIV) and Treponema Pallidum tests, C1-Inhibitor and C1-Q values were within limits. An accurate fulguration and wide excision of bigger lesions were performed. Histological examination showed numerous dilated lymphatic vessels in the superficial dermis with infiltration of inflammatory cells, that is a histopathological picture compatible with genital lymphangioma. Considering our clinical suspicion of condylomatosis, HPV (Human Papilloma Virus) Polimerase Chain Reaction (PCR) Genotyping, named INNOLiPA test, was performed, that revealed a genital infection by HPV - genotype 6. We think that our case can be considered an example of HPV infection and acquired genital lymphangioma overlap clinical syndrome. The patient presented any lesions one year after the procedure at follow-up examination.Una malformazione linfatica o linfangioma è una proliferazione benigna di vasi linfatici che costituisce il 4% di tutte le malformazioni linfatiche ed il 26% di tutti I tumori vascolari benigni. Ci sono alcuni reports di casi di linfangiomi genitali che simulano clinicamente lesioni veneree, come ad esempio condilomi genitali. Descriviamo qui un caso di un maschio di 24 anni affetto da multiple vescicole e lesioni condilomatose nell’area genitale. Tutti i parametri ematologici e biochimici, i tests per infezioni da HIV e Treponema Pallidum, i valori di C1- inibitore e C1-Q erano nella norma. È stata eseguita un’accurata bonifica con elettrofolgorazione ed un’ampia escissione bioptica delle lesioni più grandi. L’esame istologico ha rivelato numerosi vasi linfatici dilatati presenti nel derma superficiale con infiltrato di cellule infiammatorie, compatibile con la diagnosi di linfangioma genitale. Considernado però il nostro sospetto clinico di condilomatosi, è stato eseguito il test di genotipizzazione delle cellule in esame con la reazione a catena della polimerasi (PCR), denominato INNO – LiPA test, che ha evidenziato anche un’infezione da papilloma virus umano (HPV) – genotipo 6. Il paziente non ha presentato alcuna lesione un anno dopo la procedura. È quindi molto probabile che la proliferazione linfangiomatosa sia stata stimolata, nel caso descritto, da un’infezione da HPV e che il paziente abbia presentato una sindrome clinica caratterizzata dalla sovrapposizione di lesioni tipiche di ambedue le condizioni. In letteratura sono descritti casi di linfagiomi genitali che “mimano” lesioni condilomatose, in realtà con l’estensione dell’utilizzo di metodiche di biologia molecolare quale è l’ INNO -Lipa, non escludiamo che possano incrementarsi le diagnosi di linfangioma e infezione da HPV coesistenti nel medesimo paziente.

"Outlet obstruction" is a complex functional disorder compelling patients to exhausting uneffective attempts to void. This study was designed to compare the effectiveness and a safety of the endorectal proctopexy (internal Delorme) vs STARR procedure in two groups of patients.A total of 66 patients with rectocele and associated mucosal prolapse or anorectal intussusception between January 2006 and June 2010 were randomly assigned to Group # 1 Endorectal proctopexy with levatorplasty (ERPP) and Group # 2 STARR. Patients were assessed one week, six and twelve months after the operation. Operative time, postoperative pain, day of discharge and late complications was recorded. The time of recovery of work was also assessed. The continence score was updated with a constipation questionnaire. Quality of life after the operation and the overall grade of satisfaction were assessed and compared with radiological findings. All patients were reassessed after one year.The results in the two groups of patients show no significant difference between ERPP and STARR: the improvement in symptoms is similar but significant and well definite in both groups with a low incidence of postoperative complications. STARR procedure is just faster to perform even if more expensive. Dyspareunia slightly improved mainly in ERPP group, due probably to scar distention.The results of our experience indicate a significant improvement of symptoms with both techniques. The overall incidence rate of postoperative complications is low and similar between the two groups. As economical consideration, ERPP is less expensive.

Fast-track program has been applied in several surgical fields. However, currently many surgical patients are elderly over 70 years of age, and discussion about the application of such protocols for elderly patients is inadequate.The present study was designed to consider the safety and feasibility of application of a fast-track program after colorectal surgery in elderly patients. A total of 76 elderly patients with colorectal cancer who underwent laparoscopic colorectal resection were randomly assigned to receive either the fast-track care program (n = 40) or the conventional perioperative care protocol (control group, n = 36). The fast track protocol included no preoperative mechanical bowel irrigation, immediate oral alimentation and earlier postoperative ambulation exercise. The length of postoperative hospital stay, the length of time to regain bowel function and the rate of postoperative complications were compared between the two groups.The length of time to regain bowel function, including the passage of flatus [32 (24-40) h vs 42 (32-52) h], and to start a liquid diet (13 [10-16] h v/s 43 [36-50] h) were significantly shorter in patients receiving the fast track care protocol compared with those receiving the conventional care protocol. A shorter duration of postoperative hospital stay was recorded in patients receiving the fast-track program than in those receiving conventional care [6 (5-7) days v/s 9.5 (7-12) days]. A reduced percentage of patients who developed general complications was also observed in the fast-track group (5.0% v/s 18%).Fast-track after laparoscopic colorectal surgery can be safely applied in carefully selected elderly patients older than age 70 years. The fast-track recovery program resulted in a more rapid postoperative recovery, earlier discharge from hospital and fewer general complications compared with a conventional postoperative protocol.

Innate lymphoid cells (ILCs) regulate stromal cells, epithelial cells and cells of the immune system, but their effect on B cells remains unclear. Here we identified RORγt(+) ILCs near the marginal zone (MZ), a splenic compartment that contains innate-like B cells highly responsive to circulating T cell-independent (TI) antigens. Splenic ILCs established bidirectional crosstalk with MAdCAM-1(+) marginal reticular cells by providing tumor-necrosis factor (TNF) and lymphotoxin, and they stimulated MZ B cells via B cell-activation factor (BAFF), the ligand of the costimulatory receptor CD40 (CD40L) and the Notch ligand Delta-like 1 (DLL1). Splenic ILCs further helped MZ B cells and their plasma-cell progeny by coopting neutrophils through release of the cytokine GM-CSF. Consequently, depletion of ILCs impaired both pre- and post-immune TI antibody responses. Thus, ILCs integrate stromal and myeloid signals to orchestrate innate-like antibody production at the interface between the immune system and circulatory system.

The aim of this chapter is to present a study of individual and organizational factors that facilitated the transfer of classroom teaching models for elementary and middle school teachers. We discuss the results of an action research project devoted to in-service training for teachers in Italy. We use a longitudinal case study approach with four waves of data collection on a group of 24 subjects along a period of 2 years. The four measurement occasions are: three during the 2 years of the training program and the fourth, 6 months later, during teachers’ professional activities. The Learning Transfer System Inventory, adapted to the school setting, has been used together with a checklist to codify teacher and students behavior during the classroom activities, with observational task released six times during the 2 years.

The gastrointestinal tract is the predominant site of extranodal non-Hodgkin lymphomas. Multiple lynphomatous polyposis is a type of appearance of mantle cell lymphoma. It is characterized by multiple polypoid lesions involving long gastrointestinal tracts and it accounts for only approximately 1-2% of non-Hodgkin lymphomas. A 78 years old patient was admitted to our Department of General Surgery with rectal bleeding, abdominal pain and weight loss. Multiple lymphomatous polyposis was detected by endoscopy. Endoscopic biopsies confirmed the diagnosis of mantle cell lymphoma. The patient was transferred to the Department of Hematology for cycles of chemotherapy.

Structural stability is studied in the problem of a fluid saturating a porous medium of Forchheimer type when the density of the fluid has a cubic temperature dependence. This problem allows the possibility of resonance between internal layers in thermal convection. In this paper we investigate continuous dependence on the heat source, this source being an important quantity in the resonance problem.

Anal fissure is a tear in the lining of the anal canal distal to the dentate line, which most commonly occurs in the posterior midline. Anal fissure was defined chronic if the patient presented with history of anal pain during defecation for at least 2 months with the observation of sphincter fibers at the base of the lesion. One hundred and forty-two consecutive patients with a chronic anal fissure with hypertonicity of internal sphincter on proctological examination were selected for this study from October 2008 to October 2010. Patients enrolled for the study were randomized to two groups by using a computer-generated list. Patients who underwent lateral internal sphincterotomy (LIS) were operated as day surgery procedures under local or epidural anesthesia. Patients randomized to conservative treatment were prescribed to use warm anal dilator with a nifedipine ointment 5 min twice daily for 4 weeks. Patients were clinically examined after 2, 4 and 8 weeks of treatment to evaluate if there was complete healing of the fissure. All patients were required to record pain after the first defecation, on 3rd and 7th postoperative day on a self-administered VAS scale in cm (0-10). Sixty-eight patients were randomly assigned to LIS, 74 to the conservative approach. Fifty-one patients of topical nifedipine group (68.9 %) and 60 patients of LIS group (88.2 %) presented an anal fissure healed at 8 weeks with a p value of 0.0077. As regards post-operative pain, 43 patients of LIS group (63.2 %) and 25 patients of topical nifedipine group (33.7 %) referred first defecation as painless. In the topical nifedipine group 43 (58.1 %) after 3 days since treatment and 35 (47.3 %) after 7 days had pain. In the LIS group 22 (32.3 %) after 3 days and 9 (13.2 %) after 7 days referred pain. There was no statistical difference between LIS and topical nifedipine group concerning side effects. Lateral internal sphincterotomy is an effective, less painful, fast recovery treatment for chronic anal fissure. Incontinence rate is overestimated and often the fear of a continence disturbance, albeit with a low incidence following surgery, may obscure the need to relieve symptoms which may be so severe as to make the patient's life intolerable.

A nonlinear energy stability analysis of the onset of convection for fluids with viscosity convex nonincreasing function of temperature, is performed. It is shown that condition assuring linear stability, assures nonlinear (conditional) asymptotic stability too.

Background Baricitinib (bari) and tofacitinib (tofa) are selective JANUS kinase inhibitors (JAKi). In biochemical assays, bari exhibits greatest potency against JAK1 and JAK2, whereas that for tofa is against JAK1 and JAK3. Objectives To determine whether differences in JAKi specificity translate to differences in cellular signal transduction in leukocyte subpopulations stimulated by cytokines, indicated by inhibition of signal transducers of activator transcription (STATs) phosphorylation. Methods Peripheral blood mononuclear cells (PBMC) were obtained from healthy donors (n=6). Leukocyte preparations were incubated with JAKi using a 7 point dose range, 2.44–10,000 nM, for 1 hour before cytokine stimulation. The half maximum inhibitory concentration (IC 50 ) values were determined by plotting the mean fluorescence intensity of cytokine-stimulated and nonstimulated samples in phenotypically gated leukocyte subpopulations. 1 Results IC 50 values for bari and tofa were similar for interleukin-6 (IL-6) across leukocyte subsets. Differences were observed for other cytokines. The IC 50 across leukocyte subpopulations stimulated with the same cytokine varied 2–3 fold per compound (Table). The most significant differences between JAKi IC 50 values were for cytokines that use JAK1/3. Tofa was a more potent inhibitor of IL-2, IL-4, IL-15, and IL-21 induced STAT phosphorylation than bari. Both compounds inhibited IL-10 stimulation of pSTAT3 and IFN-α stimulation of pSTAT1, pSTAT3, and pSTAT5 similarly. Inhibition of IFN-α pSTAT3 and pSTAT5 were similar for both JAKi, although less potent in inhibiting STAT1 phosphorylation. Bari and tofa inhibited GM-CSF (JAK2) and G-CSF and IFNg signaling, with bari exhibiting a greater effect in monocytes than tofa. Conclusions The differences in IC 50 for key cytokine stimuli suggest fundamental functional differences across classes of JAKi. The potency of JAKi varied between different leukocyte subpopulations and is STAT substrate dependent. At the clinical level, therefore, these agents should not be considered biologically equivalent. A practical consequence is that determination of JAKi potency on IC 50 based solely on a nongated whole blood assay would not detect differential responses of leukocyte subpopulations by JAKi. References Krutzik, et al. Nat Methods. 2006 May;3(5): 361–368. Disclosure of Interest I. McInnes Grant/research support from: Pfizer, UCB, Janssen, Astra Zeneca, Consultant for: Eli Lilly and Company, Pfizer, Galapagos, AbbVie, UCB, Janssen, Novartis, R. Higgs Shareholder of: Eli Lilly and Company, Employee of: Eli Lilly and Company, G. Rocha Shareholder of: Eli Lilly and Company, Employee of: Eli Lilly and Company, X. Zhang Shareholder of: Eli Lilly and Company, Employee of: Eli Lilly and Company, J. Lee Shareholder of: Eli Lilly and Company, Employee of: Eli Lilly and Company, T. Wehrman: None declared, W. Macias Shareholder of: Eli Lilly and Company, Employee of: Eli Lilly and Company, S. Zuckerman Shareholder of: Eli Lilly and Company, Employee of: Eli Lilly and Company, P. Taylor Grant/research support from: UCB, GlaxoSmithKline, Celgene, Consultant for: UCB, Eli Lilly and Company, Pfizer, Galapagos, Merck, GlaxoSmihKline, AbbVie, Takeda, Bristol-Myers Squibb

We employ recent ideas of C.I. Christov and of A. Morro to develop a theory for diffusion of a solute in a Darcy porous medium taking convection effects into account. The key point is that the solute evolution is not governed by a parabolic system of equations. Indeed, the theory developed is basically hyperbolic. This still leads to a model which allows for convective (gravitational) overturning in a porous layer, but in addition to the classical mode of stationary convection instability there is the possibility of oscillating convection being dominant for a lower salt Rayleigh number, if the relaxation time is sufficiently large.

Convection problem in anisotropic and inhomogeneous porous media has been analysed. In particular, the effect of variable permeability and thermal diffusivity with respect to the vertical direction, has been studied. Linear and nonlinear stability analysis of the conduction solution have been performed.

Comparisons of transcatheter aortic valve implantation (TAVI) to surgical aortic valve replacement (SAVR) in patients with severe aortic stenosis remain sparse or limited by a short follow-up. We sought to evaluate early and midterm outcomes of consecutive patients (n = 618) undergoing successful TAVI (n = 218) or isolated SAVR (n = 400) at 2 centers. The primary end point was incidence of Valvular Academic Research Consortium–defined major adverse cerebrovascular and cardiac events (MACCEs) up to 1 year. Control of potential confounders was attempted with extensive statistical adjustment by covariates and/or propensity score. In-hospital MACCEs occurred in 73 patients (11.8%) and was more frequent in patients treated with SAVR compared to those treated with TAVI (7.8% vs 14.0%, p = 0.022). After addressing potential confounders using 3 methods of statistical adjustment, SAVR was consistently associated with a higher risk of MACCEs than TAVI, with estimates of relative risk ranging from 2.2 to 2.6 at 30 days, 2.3 to 2.5 at 6 months, and 2.0 to 2.2 at 12 months. This difference was driven by an adjusted increased risk of life-threatening bleeding at 6 and 12 months and stroke at 12 months with SAVR. Conversely, no differences in adjusted risk of death, stroke and myocardial infarction were noted between TAVI and SAVR at each time point. In conclusion, in a large observational registry with admitted potential for selection bias and residual confounding, TAVI was not associated with a higher risk of 1-year MACCEs compared to SAVR.

Neutrophils use immunoglobulins to clear antigen, but their role in immunoglobulin production is unknown. Here we identified neutrophils around the marginal zone (MZ) of the spleen, a B cell area specialized in T cell-independent immunoglobulin responses to circulating antigen. Neutrophils colonized peri-MZ areas after postnatal mucosal colonization by microbes and enhanced their B cell-helper function after receiving reprogramming signals, including interleukin 10 (IL-10), from splenic sinusoidal endothelial cells. Splenic neutrophils induced immunoglobulin class switching, somatic hypermutation and antibody production by activating MZ B cells through a mechanism that involved the cytokines BAFF, APRIL and IL-21. Neutropenic patients had fewer and hypomutated MZ B cells and a lower abundance of preimmune immunoglobulins to T cell-independent antigens, which indicates that neutrophils generate an innate layer of antimicrobial immunoglobulin defense by interacting with MZ B cells.

Introduction. Milligan-Morgan haemorrhoidectomy performed with LigaSure system (LS) seems to be mainly effective where a large tissue demolition is required. This randomized study is designed to compare LigaSure haemorrohidectomy with conventional diathermy (CD) for treatment of IV-degree haemorrhoids. Methods. 52 patients with IV-degree haemorrhoids were randomized to two groups (conventional diathermy versus LigaSure haemorrhoidectomy). They were evaluated on the basis of the following main outcomes: mean operative time, postoperative pain, day of discharge, early and late complications. The time of recovery of work was also assessed. All patients had a minimum follow-up of twelve months (range 12–24). All data were statistically evaluated. Results. 27 patients were treated by conventional diathermy, 25 by LigaSure. The mean operative time was significantly shorter in LS, such as postoperative pain, mainly lower on the third and fourth postoperative day: moreover pain disappeared earlier in LS than CD. The time off-work was shorter in LS, while there was no difference in hospital stay and overall complications rate. Conclusions. LigaSure is an effective instrument when a large tissue demolition is required. This study supports its use as treatment of choice for IV degree haemorrhoids, even if the procedure is more expansive than conventional operation.

A model for double-diffusive convection in an anisotropic porous layer with a constant throughflow is explored, with penetrative convection being simulated via an internal heat source. Both linear instability and nonlinear stability analyses are performed to assess the suitability of linear theory to predict the destabilisation of the throughflow. It is shown that due to oscillatory instability modes, there are three distinct regions, where increasing the ascending throughflow from rest actually has a stabilising effect, before following the standard destabilisation and stabilisation pattern. This is a previously unobserved phenomenon. The agreement between the linear and nonlinear thresholds is substantial when a small descending throughflow is introduced, although this does deteriorate for ascending throughflow.

The onset of penetrative convection in an anisotropic porous medium, for fluids with quadratic density law, is considered. In particular the effect of anisotropic permeability and thermal diffusivity, have been taken into account. The critical curves for the linear and nonlinear theories, global and local, are presented and compared.

Sufficient conditions ensuring the onset of penetrative convection in an anisotropic porous medium are determined, taking into account the effects of non homogeneous permeability and thermal diffusivity, respectively. A linear instability analysis has been performed.

Hypoxia induces apoptosis but also triggers adaptive mechanisms to ensure cell survival. Here we show that the prosurvival effects of hypoxia-inducible factor 1 (HIF-1) in endothelial cells are mediated by neuron-derived orphan receptor 1 (NOR-1). The overexpression of NOR-1 decreased the rate of endothelial cells undergoing apoptosis in cultures exposed to hypoxia, while the inhibition of NOR-1 increased cell apoptosis. Hypoxia upregulated NOR-1 mRNA levels in a time- and dose-dependent manner. Blocking antibodies against VEGF or SU5614 (a VEGF receptor 2 inhibitor) did not prevent hypoxia-induced NOR-1 expression, suggesting that NOR-1 is not induced by the autocrine secretion of VEGF in response to hypoxia. The reduction of HIF-1 alpha protein levels by small interfering RNAs, or by inhibitors of the phosphatidylinositol-3 kinase (PI3K)/Akt pathway or mTOR, significantly counteracted hypoxia-induced NOR-1 upregulation. Intracellular Ca(2+) was involved in hypoxia-induced PI3K/Akt activation and in the downstream NOR-1 upregulation. A hypoxia response element mediated the transcriptional activation of NOR-1 induced by hypoxia as we show by transient transfection and chromatin immunoprecipitation assays. Finally, the attenuation of NOR-1 expression reduced both basal and hypoxia-induced cIAP2 (cellular inhibitor of apoptosis protein 2) mRNA levels, while NOR-1 overexpression upregulated cIAP2. Therefore, NOR-1 is a downstream effector of HIF-1 signaling involved in the survival response of endothelial cells to hypoxia.

The linear and nonlinear stability analysis of the motionless state (conduction solution) and of a vertical throughflow in an anisotropic porous medium is performed. In particular, the effect of a nonhomogeneous porosity and a constant anisotropic thermal diffusivity have been taken into account.

SummaryThrombin is a multifunctional serine protease generated at the site of vascular injury that transforms fibrinogen into fibrin, activates blood platelets and elicits multiple effects on a variety of cell types including endothelial cells, vascular smooth muscle cells (VSMC), monocytes,T lymphocytes and fibroblasts. Cellular effects of thrombin are mediated by protease-activated receptors (PARs), members of the G protein-coupled receptors that carry their own ligand which remains cryptic until unmasked by proteolytic cleavage. Thrombin signalling in platelets contributes to haemostasis and thrombosis. In normal arteries PARs are mainly expressed in endothelial cells, while their expression in VSMC is limited. Endothelial PARs participate in the regulation of vascular tone, vascular permeability and endothelial secretory activity while in VSMC they mediate contraction, migration, proliferation, hypertrophy and production of extra-cellular matrix. PARs contribute to the pro-inflammatory phenotype observed in endothelial dysfunction and their up-regulation inVSMC seems to be a key element in the pathogenesis of atherosclerosis and restenosis. In the last years a myriad of studies have emphasized the critical role of PAR signalling in thrombin mediated effects in haemostasis, inflammation, cancer and embryonic development. Lately, PARs have become a therapeutic target to inhibit platelet aggregation and thrombosis. Early data from a clinical trial (TRA-PCI) to evaluate safety and efficacy of a potent new oral thrombin receptor antagonist (TRA) have promisingly indicated that overallTRA treatment reduces adverse event rates without an increase in bleeding risk. In this paper we review cellular responses triggered by thrombin and their implication in vascular pathophysiology.

INTRODUCTION: Mucocele is a rare pathology of the appendix characterized by expansion of the lumen for a slow storage of mucous. Represents the 0.2-0.3% of all the appendectomies. Clinical signs and the symptoms are similar to those of the acute appendicitis, while the disease is occasionally recorded and the diagnosis is essentially histological. AIM OF STUDY: To recall the clinical and anatomopathological features of mucocele evaluating the possible evolutions of this rare appendicular pathology according to the updating reports of the literature. MATERIALS AND METHODS: Study of a clinical case. DISCUSSION: In this study diagnostic chriteria and prognostic factors are revised. Authors evaluate anatomopathological classification, possibility of evolution in a preneoplastic and neoplastic lesion and association with other colon cancers. The surgical treatment is evaluated too. CONCLUSIONS: A correct preoperative mucocele diagnosis is emphasized as indispensable in the choice of the proper surgical treatment since a good prognosis is consequent to a radical treatment.

Neuron-derived orphan receptor-1 (NOR-1) is a nuclear receptor recently involved in the onset and development of atherosclerosis. NOR-1 is induced in a cell-specific manner by extracellular stimuli. NOR-1 is over-expressed in human atherosclerotic plaques and in porcine arteries subjected to angioplasty, is induced by growth factors in vascular cells and it has been involved in cell migration and proliferation. This article examines the mechanisms that regulate NOR-1 in vascular cells and the effects of NOR-1 knockdown on cell growth induced by mitogens, in particular thrombin. Mitogenic stimuli up-regulates NOR-1 in endothelial cells (ECs) through multiple pathways, including increase of cytosolic calcium, activation of protein kinase C, mitogen-activated protein kinase (MAPK) (ERK1/2 and p38 MAPK) and downstream activation of cAMP response element binding protein (CREB). Inhibition of protease-activated receptor-1 (PAR-1) abolished thrombin-induced NOR-1 up-regulation and DNA synthesis. NOR-1 knockdown reduces DNA synthesis and EC re-growth in an in vitro model of wound repair. NOR-1 could be regarded as a new target to prevent endothelial effects triggered by thrombin and other mitogens.

The splenic marginal zone (MZ) generates prompt antibody responses to blood-borne antigens through a unique subset of innate-like B cells that closely interact with poorly characterized stromal cells. We found that human MZ contained fibroblast-like marginal reticular cells (MRCs) that expressed MAdCAM-1 along with the stromal molecules Thy-1, thrombomodulin, ICAM-1 and VCAM-1, but lacked the endothelial molecules CD31, CD34 and von Willebrand factor. Similar to stromal lymphoid tissue organizers, MRCs up-regulated the adhesion molecules ICAM-1 and VCAM-1 in response to LT and TNF. Moreover, MRCs exposed to microbial TLR ligands, released the B cell-stimulating factors BAFF, APRIL and IL-6, which delivered survival, proliferation, class switching and plasma cell differentiation signals to MZ B cells. Plasma cells emerging from this pathway showed either T cell-dependent or T cell-independent ontogenetic features, and released IgM antibodies to conserved carbohydrate and lipid antigens shared by commensal and pathogenic bacteria. These antibodies decreased in splenectomized individuals. Finally, TLR-primed MRCs produced retinoic acid, which elicited MZ B cell expression of the gut-homing receptors a4b7 and CCR9. These findings indicate that MRCs have unique B cell-helper properties that could be harnessed to enhance vaccine-induced antibody responses systemically and perhaps at mucosal sites of antigen entry.

The penetrative convection in a horizontal binary fluid mixture layer with an internal heating due to a quadratic concentration source, according to the Darcy-Oberbeque-Boussinesq model, is considered. Conditions guaranteeing the onset of penetrative convection are obtained.

By using weighted energy methods, a condition assuring nonlinear global stability for a large class of flows in a wedge is proved.