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Background In recent years, evidence shows that long non-coding RNAs (lncRNAs) are key regulators of gene transcription and play important roles in the pathogenesis of inflammatory bowel diseases. LncRNA are involved in regulation of intestinal epithelial cell apoptosis, cell-cell interactions, enhancing inflammation, among others. Biological therapies, which are considered the most potent for disease control, only benefit one-third of patients. For this reason, a deeper understanding regarding the mechanisms by which biological drugs elicit their effect on intestinal mucosal is needed. Hence, we aimed to unravel the ex vivo modulator effect of infliximab on the lncRNAs expression in intestinal biopsies from patients with Crohn′s Disease (CD). Methods We performed an unbiased transcriptomic analysis of intestinal biopsies from the ileum and colon from 30 patients [active CD = 10, quiescent CD = 10, healthy controls (HC) = 10] to identify lncRNA differentially expressed in the setting of infliximab modulation (Figure 1). Endoscopic biopsies were cultured with or without infliximab, and the transcriptome was determined by stranded total-RNAseq (reagents from Illumina Inc.). We used different databases (Ensembl Biomart, RNAcentral and ToppGene) to search for non-annotated lncRNA information and data on the location (cellular component), biological process and molecular function of differentially expressed lncRNAs. Results Transcriptomic results revealed a widespread dysregulation of lncRNAs in ileum biopsies from patients with active CD, quiescent CD and HC compared to the colon at baseline and after infliximab culture (Figure 2). These differentially expressed lncRNAs were enriched in such pathways as proliferation, apoptosis, migration, inflammatory response of fibroblasts, response to wounding, posttranscriptional regulation of inflammatory genes and activation of the mitogen-activated protein kinase signaling pathways. Regarding the effect of infliximab according to intestinal location, presence of disease and activity, no significant lncRNAs were identified in the different study comparatives. Conclusion We have characterized the basal transcriptomic landscape of lncRNAs in patients with CD (active and quiescent) and HC both in ileum and left colon. However, we have not found differential lncRNA expression due to the effect of infliximab, suggesting that the location (ileum or colon) is more relevant when analyzing differences in lncRNA expression in the intestinal tissue.

Background Inflammatory bowel disease (IBD) is an idiopathic and chronic disorder that include ulcerative colitis (UC) and Crohn’s disease (CD). Both diseases are different but show an uncontrolled intestinal immune response that generate tissue inflammation. Monocytes (Φ) play a key role in the tolerogenic maintenance in the gastrointestinal mucosa. These cells are antigen presenting cells highly specialized to control immune response against gut microbiota and food antigens. It has been previously reported that circulating Φ are recruited by intestinal mucosa in a CCR2 dependent manner. Also, in IBD patients this Φ recruitment is more prominent than in healthy controls (HC) but the specific migration mechanism is still unknown. Methods This is a cross-sectional observational postmarketing study where the modulatory effect of different biologic treatments on samples from patients with endoscopic diagnosis of IBD and HC was studied ex vivo. Peripheral blood mononuclear cells (PBMC) were obtained from 15 patients per group, and were cultured in presence of anti-TNF or vedolizumab. Following culture, surface markers expression was determined hence assessing the differential effect of biological drugs (if any) over the Φ subset in the different groups. After that, the migratory capacity of circulating Φ toward CCL2, CCL25 and MadCam1 from the different study groups was determined. Finally, we evaluated the Φ migratory capacities in presence of biological drugs or with culture media alone. Results Our data showed that within CD14+ population, CD patients presented a higher percentage of CCR5+ and CCR9+ and the surface expression level of CCR2 and CCR9 was increased. In addition, anti-TNF reduced the number of CCR9+ Φ subset in HC. In HC an UC patients vedolizumab reduced the percentage of β7+ Φ (Figure 1). According to the circulating Φ migratory capacity as expected, the migration towards CCL2 was higher than toward culture media (Figure 2). When the effect of biological drugs was evaluated, surprisingly anti-TNF increased the Φ migration. Also, vedolizumab showed a clear tendency to decrease the Φ migration towards CCL2 and MadCam1 in HC and in UC (Figures 3 and 4). Conclusion Circulating Φ from IBD patients express a different migration pattern than HC, being the expression of these molecules modulated by anti-TNF drugs. The capacity of circulating Φ to migrate towards CCL2 is higher than towards culture media. Unexpectedly, anti-TNF increases the migratory capacity of Φ. On other hand, treatment of Φ from HC and UC patients with vedolizumab, induces a clear downward trend of their migratory capacity towards CCL2 and MadCam1

Although macrophages (Mϕ) maintain intestinal immune homoeostasis, there is not much available information about their subset composition, phenotype and function in the human setting. Human intestinal Mϕ (CD45+HLA-DR+CD14+CD64+) can be divided into subsets based on the expression of CD11c, CCR2 and CX3CR1. Monocyte-like cells can be identified as CD11chighCCR2+CX3CR1+ cells, a phenotype also shared by circulating CD14+ monocytes. On the contrary, their Mϕ-like tissue-resident counterparts display a CD11c−CCR2−CX3CR1− phenotype. CD11chigh monocyte-like cells produced IL-1β, both in resting conditions and after LPS stimulation, while CD11c− Mϕ-like cells produced IL-10. CD11chigh pro-inflammatory monocyte-like cells, but not the others, were increased in the inflamed colon from patients with inflammatory bowel disease (IBD), including Crohn's disease and ulcerative colitis. Tolerogenic IL-10-producing CD11c− Mϕ-like cells were generated from monocytes following mucosal conditioning. Finally, the colonic mucosa recruited circulating CD14+ monocytes in a CCR2-dependent manner, being such capacity expanded in IBD. Mϕ subsets represent, therefore, transition stages from newly arrived pro-inflammatory monocyte-like cells (CD11chighCCR2+CX3CR1+) into tolerogenic tissue-resident (CD11c−CCR2−CX3CR1−) Mϕ-like cells as reflected by the mucosal capacity to recruit circulating monocytes and induce CD11c− Mϕ. The process is nevertheless dysregulated in IBD, where there is an increased migration and accumulation of pro-inflammatory CD11chigh monocyte-like cells.

Resumen Introduccion La enfermedad de Whipple (EW) es una infeccion sistemica cronica causada por la actinobacteria Tropheryma whipplei (T. whipplei) , que afecta fundamentalmente al intestino delgado, si bien puede tener manifestaciones sobre otros muchos organos, como por ejemplo el sistema nervioso central o el corazon. Manifestaciones clinicas La forma clasica de la enfermedad, que incluye perdida de peso, diarrea, malabsorcion, fiebre y artralgias, es muy rara. Sin embargo, investigaciones recientes muestran una variedad mucho mas amplia de cuadros clinicos relacionados con la infeccion (EW aguda y autolimitada, portadores asintomaticos, EW localizada, EW asociada a inmunosupresion). Diagnostico El diagnostico se suele realizar mediante una endoscopia digestiva alta, que permite demostrar en las biopsias duodenales la presencia de T. whipplei mediante PCR. Tratamiento El tratamiento incluye antibioterapia intravenosa de induccion seguida de tratamientos orales de al menos un ano de duracion. Estos pacientes precisan revisiones clinicas de por vida para controlar las recidivas de la enfermedad.

Although macrophages (Mϕ) maintain intestinal immune homoeostasis, there is not much available information about their subset composition, phenotype and function in the human setting. Human intestinal Mϕ (CD45

Resumen La colestasis es un problema clinico muy comun que puede presentarse en pacientes de todos los ambitos. Su variada etiologia hace necesario establecer unas pautas de actuacion claras para llegar a un diagnostico eficaz. El primer paso en la evaluacion de un paciente con colestasis debe ser determinar si esta es debida a causas intra o extrahepaticas. Para ello, tras la realizacion de una historia clinica exhaustiva y una exploracion fisica con especial atencion al hipocondrio derecho, debemos valorar la via biliar mediante una ecografia abdominal. La dilatacion de la via biliar nos orientara hacia causas extrahepaticas y la ausencia de la misma debe hacernos pensar en colestasis intrahepatica. En la colestasis extrahepatica son necesarias pruebas de imagen adicionales para la identificacion de la causa de la obstruccion. En pacientes con sospecha de enfermedad litiasica la colangiopancreatografia retrograda endoscopica (CPRE) es el gold standard , y ademas permite la realizacion de terapeutica. En caso de sospecha de malignidad, debemos realizar una tomografia computadorizada (TC) abdominal que descarte la presencia de neoplasias que producen ictericia indolora o adenopatias metastasicas que produzcan una compresion extrinseca de la via biliar. La lista de causas de colestasis intrahepatica es muy extensa; sin embargo, la realizacion de varias determinaciones analiticas (serologias para virus hepatotropos, anticuerpos antimitocondriales), una historia clinica detallada (consumo de hepatotoxicos o nutricion parenteral total, historia familiar de colestasis, embarazo) y si es necesario una colangiografia (colangitis esclerosante primaria intrahepatica) nos llevaran al diagnostico en la gran mayoria de las ocasiones.

Some new benzocycloheptan-1,5-diones derivatives I (3: R = t-Bu, R' = H; 4: R = Ph, R' = H; 5: R = PhCOCH2, R' = H; 6: R = CH3COCH2, R' = H; 7: R = t-Bu, R' = ethenyle and 8: R = Ph, R' = ethenyle) were synthetized through photocycloaddition of 2-acylindan-1,3-diones 2 with styrene and paradivinylbenzene (pDVB) respectively. The reaction proceeds regioselectively at the endocyclic enol. This regioselectivity was not observed on the linear β-triketones, previously reported [1]. The formation of a double addition product paradi-(2,5-dioxo-6-(2,2-dimethylpropionyl)-benzocycloheptyl)-benzene 9 shows how a network could be formed if these 2-acylindan-1,3-diones 2 moities are graft in side chains of macromolecules. The enolic equilibrium of the obtained benzocycloheptan-1,5- diones derivatives, are discussed. Every products were characterized by means of elemental analysis and IR, UV, 1H and 13C NMR spectroscopies.

Some new benzocycloheptan-1,5-diones derivatives I (3: R = t-Bu, R' = H; 4: R = Ph, R' = H; 5: R = PhCOCH2, R' = H; 6: R = CH3COCH2, R' = H; 7: R = t-Bu, R' = ethenyle and 8: R = Ph, R' = ethenyle) were synthetized through photocycloaddition of 2-acylindan-1,3-diones 2 with styrene and paradivinylbenzene (pDVB) respectively. The reaction proceeds regioselectively at the endocyclic enol. This regioselectivity was not observed on the linear β-triketones, previously reported [1]. The formation of a double addition product paradi-(2,5-dioxo-6-(2,2-dimethylpropionyl)-benzocycloheptyl)-benzene 9 shows how a network could be formed if these 2-acylindan-1,3-diones 2 moities are graft in side chains of macromolecules. The enolic equilibrium of the obtained benzocycloheptan-1,5- diones derivatives, are discussed. Every products were characterized by means of elemental analysis and IR, UV, 1H and 13C NMR spectroscopies.

By constraining the output rate of mobile hosts in a cell via DiffServ configuration mechanisms, it is possible to keep 802.11 networks in a non-saturation state. We present a policy-based management solution for video streaming service provisioning and the system evaluation as a feasible alternative to contribute providing QoS in real time services in wireless environments. A prototype intended for proof of concept has been evaluated in a simulated WLAN making use of real video applications.

a first course of endovenous corticosteroids ECT in our tertiary center. Methods: All UC patients admitted to the hospital for an acute flare requiring EC between January 2007 and March 2012 were reviewed. We included only the patients with a first-initial course EC since UC diagnosis time. We defined as “responders” when patients achieved clinical remission in the first seven days of EC and “no responders” when patients needed a rescue therapy because of no clinical response after 7 days of EC. Demographic and clinical features were obtained from the medical records until October 2012. Results: A total of 41 episodes were collected during this period and 14 (34%) completed inclusion criteria. EC “response” was obtained in 9 patients (9/14; 60%, 5F/4M, mean age 36 years). Half of them (5/9), the diagnosis of UC concurred with the hospitalization and EC therapy. After a median follow-up of 24 months (6 56), 4 patients (44%) needed treatment escalation by using IMM for steroid-dependency and 2 (22%) of them used granulocyte aphaeresis before a-TNF therapy. No surgeries were observed in this group. Five patients were EC “no responders” (5/14; 40%, 4F/1M, mean age 30 years). A-TNF therapy was used in 1 patient and 4 received Cyclosporine A (CyA) for steroid-refractoriness and 3 were newly UC diagnose. One patient underwent total colectomy 10 days after EC beginning without further complication or treatment. After 36 months (5 63), 4 patients started IMM (80%) and 1 started a-TNF (20%) but developed a tuberculosis (TBC) infection and after TBC treatment remained with only IMM therapy. Nowadays, 2 more patients (40%) were considered for a-TNF because steroiddependency after acute flare (mean time 6 months). No other surgeries were produced during follow-up. Conclusions: In our center, about half of patients developed a “no responder” to EC flare and most of them will need a-TNF for maintenance therapy even after use of CyA treatment mainly because of steroid-dependence. Even when the UC patients respond to EC, about 40% of them require IMM and even a-TNF for again for steroid-dependence.

Background: Most of the studies on the natural history of CD include small cohorts with less than 5 years of follow-up. Aims: To study the natural history of CD in a cohort with more than 10 years of evolution. To identify predictive factors of bad outcome. Methods: A retrospective study including CD patients with more than 10 years of evolution was performed. The study population was divided into 3 groups by year of diagnosis (Group A = 1985 1991, Group B = 1992 1997, Group C = 1998 2001). Survival curves were compared with the Kaplan Meier test. Cox regression analysis was performed to identify predictive factors of surgery in these patients. Results: 133 patients with CD were included. Mean followup was 17 years (range 3 51). 29% presented changes in disease behaviour. At baseline, the proportion of patients with stricturing behaviour was 11%, while 9% had penetrating behaviour. At the end of follow-up, these figures were 23% and 24% respectively. 43% of these changes occurred within the first 5 years of follow-up. There was an increasing and earlier use of thiopurines over time: 10 years after diagnosis the proportion of patients on thiopurines was 40% in group A, 59% in group B, and 82% in group C (p < 0.001), and the median time to start of thiopurines was 130, 83 and 39 months respectively.

Background: The efficacy of thiopurines in Crohn’s disease has been shown in clinical trials and their use has increased over the past decades. However, it is unclear whether early and widespread use of these drugs may reduce surgical requirements in routine practice, or may change the long-term outcome of Crohn’s disease. Aims: To assess the impact of thiopurine treatment on the outcome of Crohn’s disease. Methods: A retrospective study including Crohn’s disease patients was performed. Patients who had received thiopurines at appropriate doses (azathioprine 2.5mg/kg and mercaptopurine 1.5mg/kg) were reviewed. Data from flares, hospitalizations, surgeries, corticosteroid use and complications during the 12 months before and after the introduction of thiopurines were compared. Patients with incomplete data in their medical records were excluded. Results: Seventy-eight patients with Crohn’s disease who had received thiopurine treatment were included. Mean time of evolution was 16 years (range 8 41 years). Thiopurine treatment reduced the number of flares (1.15 vs 0.28, p < 0.001), hospitalizations (1.05 vs 0.34, p < 0.001), corticosteroid requirements (1.17 cycles vs 0.28 cycles, p < 0.001) and number of surgeries (0.76 vs 0.29, p < 0.05) (figure 1).

BACKGROUND: A reduced platelet survival time has been described in asthmatic patients. There is also good evidence that platelets are involved in aspirin induced asthma. Since aspirin intolerant patients usually suffer from an active disease and often require anti-inflammatory treatment, it has been suggested that platelet survival time may be shorter in aspirin intolerant asthmatic subjects than in aspirin tolerant subjects. The objective of this study was to investigate this hypothesis. METHODS: Thirteen asthmatic subjects (six aspirin tolerant and seven aspirin intolerant) in a stable clinical condition and ten healthy subjects were studied. Platelet kinetics and survival time were measured with indium-111 labelled autologous platelets. RESULTS: Mean (SD) platelet sequestration ratios in the spleen and liver were lower in asthmatic (2.3 (0.9) and 0.6 (0.2) respectively) than in healthy subjects (3.2 (0.7) and 1.1 (0.4) respectively). However, mean (SD) platelet survival time in asthmatic subjects (8 (2.7) days) did not differ from that in healthy subjects (7.6 (1.1) days). No differences were observed in platelet kinetics between aspirin tolerant and aspirin intolerant patients. CONCLUSIONS: These results suggest the existence of an active non-splenic pool of platelets in patients with asthma. However, they failed to show platelet kinetic differences among asthmatic subjects with and without aspirin intolerance and do not support previous studies suggesting an altered platelet survival in stable asthma.

Resume As model reactions pertaining to the syntheses of carpaine, cassine and related alkaloids, various 2,6-dialkyl 3-piperidinols were prepared and their stereochemistry established by NMR and IR spectroscopy. In all cases but one, these model piperidinols were shown to possess an all-cis structure, as for cassine and carpaine themselves.

Increased concentrations of factor VIII-related antigen(VIIIR:AG), factor VIII procoagulant activity (VIII:C) and factor VIII von Willebrand activity (VIIIR:WF) were found in plasma of patients with evidence of advanced hepatic cirrhosis. There was no correlation among the three plasmatic activities of factor VIII complex as opposed to those existing in normal individuals. The mobility of the (VIIIR:AG) as detected by crossed electrophoresis was normal.On the other hand, washed platelets from those patients showed a defective Ristocetin-induced aggregation with normal platelet poor plasma (PPP). The platelet (VIIIR:AG) was quantitatively and qualitatively normal.

Defective ADP-induced platelet aggregation has been observed in patients treated with streptokinase. This same effect appears “in vitro” when adding SK to platelet rich plasma (PRP). Classic hemophilia and normal platelet poor plasmas (PPP) treated with SK inhibit the aggregation of washed platelets; plasmin-treated normal human serum also shows an inhibitory effect on platelet aggregation. However, von Willebrand SK-treated plasmas do not inhibit the aggregation of washed platelets. The same results appear when plasmas are previously treated with a rabbit antibody to human factor VIII.This confirms that the antiaggregating effect is mainly linked to the digested factor VIII related antigen.The inhibition of ADP-induced platelet aggregation has been proved in gel filtration-isolated and washed platelets from SK-treated PRP.Defective ristocetin-induced platelet aggregation has also been observed- This action does not appear in washed platelets from SK-treated PRP in presence of normal PPP, but it does in presence of SK-treated PPP, which suggests that the inhibition of the ristocetin-induced aggregation is due to the lack of factor VIII and not to the factor VIII-related products.Heparin, either “in vivo” or “in vitro”, has corrected the antiaggregating effect of SK.

Endometriosi; Planificació sanitària; Model d'atenció Endometriosis; Planificación sanitaria; Modelo de atención Endometriosis; Health planning; Attention model El Model d’atenció a l’endometriosi a Catalunya estableix les bases per a l’ordenació dels serveis assistencials que intervenen en el procés integral d’atenció a les dones afectades amb endometriosi, inclou aspectes clínics, aspectes assistencials i aspectes d’ordenació de circuits assistencials, que venen determinats per les actuacions necessàries per donar una atenció integral a les dones afectades.