Dysphagia in Patients with Acute Ischemic Stroke: Early Dysphagia Screening May Reduce Stroke-Related Pneumonia and Improve Stroke Outcomes

Background Dysphagia is associated with poor outcome in stroke patients. Studies investigating the association of dysphagia and early dysphagia screening (EDS) with outcomes in patients with acute ischemic stroke (AIS) are rare. The aims of our study are to investigate the association of dysphagia and EDS within 24 h with stroke-related pneumonia and outcomes. Methods Over a 4.5-year period (starting November 2007), all consecutive AIS patients from 15 hospitals in Schleswig-Holstein, Germany, were prospectively evaluated. The primary outcomes were stroke-related pneumonia during hospitalization, mortality, and disability measured on the modified Rankin Scale ≥2-5, in which 2 indicates an independence/slight disability to 5 severe disability. Results Of 12,276 patients (mean age 73 ± 13; 49% women), 9,164 patients (74%) underwent dysphagia screening; of these patients, 55, 39, 4.7, and 1.5% of patients had been screened for dysphagia within 3, 3 to 72 h following admission. Patients who underwent dysphagia screening were likely to be older, more affected on the National Institutes of Health Stroke Scale score, and to have higher rates of neurological symptoms and risk factors than patients who were not screened. A total of 3,083 patients (25.1%; 95% CI 24.4-25.8) had dysphagia. The frequency of dysphagia was higher in patients who had undergone dysphagia screening than in those who had not (30 vs. 11.1%; p < 0.001). During hospitalization (mean 9 days), 1,271 patients (10.2%; 95% CI 9.7-10.8) suffered from stroke-related pneumonia. Patients with dysphagia had a higher rate of pneumonia than those without dysphagia (29.7 vs. 3.7%; p < 0.001). Logistic regression revealed that dysphagia was associated with increased risk of stroke-related pneumonia (OR 3.4; 95% CI 2.8-4.2; p < 0.001), case fatality during hospitalization (OR 2.8; 95% CI 2.1-3.7; p < 0.001) and disability at discharge (OR 2.0; 95% CI 1.6-2.3; p < 0.001). EDS within 24 h of admission appeared to be associated with decreased risk of stroke-related pneumonia (OR 0.68; 95% CI 0.52-0.89; p = 0.006) and disability at discharge (OR 0.60; 95% CI 0.46-0.77; p < 0.001). Furthermore, dysphagia was independently correlated with an increase in mortality (OR 3.2; 95% CI 2.4-4.2; p < 0.001) and disability (OR 2.3; 95% CI 1.8-3.0; p < 0.001) at 3 months after stroke. The rate of 3-month disability was lower in patients who had received EDS (52 vs. 40.7%; p = 0.003), albeit an association in the logistic regression was not found (OR 0.78; 95% CI 0.51-1.2; p = 0.2). Conclusions Dysphagia exposes stroke patients to a higher risk of pneumonia, disability, and death, whereas an EDS seems to be associated with reduced risk of stroke-related pneumonia and disability

The Transcription Factor T-bet Regulates Mucosal T Cell Activation in Experimental Colitis and Crohn's Disease

The balance between pro and antiinflammatory cytokines secreted by T cells regulates both the initiation and perpetuation of inflammatory bowel diseases (IBD). In particular, the balance between interferon (IFN)-γ/interleukin (IL)-4 and transforming growth factor (TGF)-β activity controls chronic intestinal inflammation. However, the molecular pathways that evoke these responses are not well understood. Here, we describe a critical role for the transcription factor T-bet in controlling the mucosal cytokine balance and clinical disease. We studied the expression and function of T-bet in patients with IBD and in mucosal T cells in various T helper (Th)1- and Th2-mediated animal models of chronic intestinal inflammation by taking advantage of mice that lack T-bet and retroviral transduction techniques, respectively. Whereas retroviral transduction of T-bet in CD62L+ CD4+ T cells exacerbated colitis in reconstituted SCID mice, T-bet–deficient T cells failed to induce colitis in adoptive transfer experiments suggesting that overexpression of T-bet is essential and sufficient to promote Th1-mediated colitis in vivo. Furthermore, T-bet–deficient CD62L− CD4+ T cells showed enhanced protective functions in Th1-mediated colitis and exhibited increased TGF-β signaling suggesting that a T-bet driven pathway of T cell activation controls the intestinal balance between IFN-γ/IL-4 and TGF-β responses and the development of chronic intestinal inflammation in T cell–mediated colitis. Furthermore, TGF-β was found to suppress T-bet expression suggesting a reciprocal relationship between TGF-β and T-bet in mucosal T cells. In summary, our data suggest a key regulatory role of T-bet in the pathogenesis of T cell–mediated colitis. Specific targeting of this pathway may be a promising novel approach for the treatment of patients with Crohn's disease and other autoimmune diseases mediated by Th1 T lymphocytes

Differential IL-21 signaling in APCs leads to disparate Th17 differentiation in diabetes-susceptible NOD and diabetes-resistant NOD.Idd3 mice.

Type 1 diabetes (T1D) is an autoimmune disease that shows familial aggregation in humans and likely has genetic determinants. Disease linkage studies have revealed many susceptibility loci for T1D in mice and humans. The mouse T1D susceptibility locus insulin-dependent diabetes susceptibility 3 (Idd3), which has a homologous genetic interval in humans, encodes cytokine genes Il2 and Il21 and regulates diabetes and other autoimmune diseases; however, the cellular and molecular mechanisms of this regulation are still being elucidated. Here we show that T cells from NOD mice produce more Il21 and less Il2 and exhibit enhanced Th17 cell generation compared with T cells from NOD.Idd3 congenic mice, which carry the protective Idd3 allele from a diabetes-resistant mouse strain. Further, APCs from NOD and NOD.Idd3 mice played a central role in this differential Th17 cell development, and IL-21 signaling in APCs was pivotal to this process. Specifically, NOD-derived APCs showed increased production of pro-Th17 mediators and dysregulation of the retinoic acid (RA) signaling pathway compared with APCs from NOD.Idd3 and NOD.Il21r-deficient mice. These data suggest that the protective effect of the Idd3 locus is due, in part, to differential RA signaling in APCs and that IL-21 likely plays a role in this process. Thus, we believe APCs provide a new candidate for therapeutic intervention in autoimmune diseases

STAT3 links IL-22 signaling in intestinal epithelial cells to mucosal wound healing

Signal transducer and activator of transcription (STAT) 3 is a pleiotropic transcription factor with important functions in cytokine signaling in a variety of tissues. However, the role of STAT3 in the intestinal epithelium is not well understood. We demonstrate that development of colonic inflammation is associated with the induction of STAT3 activity in intestinal epithelial cells (IECs). Studies in genetically engineered mice showed that epithelial STAT3 activation in dextran sodium sulfate colitis is dependent on interleukin (IL)-22 rather than IL-6. IL-22 was secreted by colonic CD11c+ cells in response to Toll-like receptor stimulation. Conditional knockout mice with an IEC-specific deletion of STAT3 activity were highly susceptible to experimental colitis, indicating that epithelial STAT3 regulates gut homeostasis. STAT3IEC-KO mice, upon induction of colitis, showed a striking defect of epithelial restitution. Gene chip analysis indicated that STAT3 regulates the cellular stress response, apoptosis, and pathways associated with wound healing in IECs. Consistently, both IL-22 and epithelial STAT3 were found to be important in wound-healing experiments in vivo. In summary, our data suggest that intestinal epithelial STAT3 activation regulates immune homeostasis in the gut by promoting IL-22–dependent mucosal wound healing

Abnormal regulation of soluble and anchored IL-6 receptor in monocytes from patients with essential thrombocythemia

Objective: In a previous study, we found increased plasma soluble receptor for interleukin-6 (sIL-6R) levels in patients with essential thrombocythemia (ET) that could promote megakaryopoiesis through IL-6 binding and further interaction with the signal transducer gp130. Here we have searched for the cell source of sIL-6R within mononuclear cells in these patients and the underlying abnormalities involved in its overproduction. Materials and Methods: Thirty patients with the diagnosis of ET were studied. sIL-6R levels were measured by enzyme-linked immunosorbent assay technique in the supernatants of peripheral monocyte and lymphocyte cultures. Expression of membrane-anchored IL-6R was determined by flow cytometry. In order to study the mechanism of sIL-6R production, tumor necrosis factor−α protease inhibitor was added to specifically block IL-6R shedding. Gene expression of sIL-6R levels were evaluated by reverse transcription polymerase chain reaction. Results: Monocytes were the main source of sIL-6R. Besides, in ET patients, monocyte sIL-6R release was higher than that of controls (p = 0.0014). Lymphocytes enhanced monocyte sIL-6R production by cell-mediated contact in normal controls, but this cooperation could not be seen in patients. Membrane expression of IL-6R was increased after monocyte adhesion in ET. sIL-6R synthesis was upregulated in most patients, while messenger RNA was normal. Conclusions: Our results indicate that ET monocytes are responsible for sIL-6R overproduction within mononuclear cells through synthesis upregulation. In addition, the lack of cooperation of lymphocytes in monocyte sIL-6R production in ET could be due to a monocyte abnormality. The agonistic effect of sIL-6R on IL-6 action could contribute to the exacerbated megakaryocytic growth in ET.Fil: Goette, Nora Paula. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones Médicas; Argentina. Consejo Nacional de Investigaciones Cientificas y Tecnicas. Oficina de Coordinacion Administrativa Houssay. Instituto de Investigaciones Medicas; ArgentinaFil: Lev, Paola Roxana. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones Médicas; Argentina. Consejo Nacional de Investigaciones Cientificas y Tecnicas. Oficina de Coordinacion Administrativa Houssay. Instituto de Investigaciones Medicas; ArgentinaFil: Heller, Paula Graciela. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones Médicas; Argentina. Consejo Nacional de Investigaciones Cientificas y Tecnicas. Oficina de Coordinacion Administrativa Houssay. Instituto de Investigaciones Medicas; ArgentinaFil: Glembotsky, Ana Claudia. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones Médicas; Argentina. Consejo Nacional de Investigaciones Cientificas y Tecnicas. Oficina de Coordinacion Administrativa Houssay. Instituto de Investigaciones Medicas; ArgentinaFil: Chazarreta, Carlos Daniel. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones Médicas; Argentina. Consejo Nacional de Investigaciones Cientificas y Tecnicas. Oficina de Coordinacion Administrativa Houssay. Instituto de Investigaciones Medicas; ArgentinaFil: Salim, Juan Pablo. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones Médicas; Argentina. Consejo Nacional de Investigaciones Cientificas y Tecnicas. Oficina de Coordinacion Administrativa Houssay. Instituto de Investigaciones Medicas; ArgentinaFil: Molinas, Felisa Concepcion. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones Médicas; Argentina. Consejo Nacional de Investigaciones Cientificas y Tecnicas. Oficina de Coordinacion Administrativa Houssay. Instituto de Investigaciones Medicas; ArgentinaFil: Marta, Rosana Fernanda. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones Médicas; Argentina. Consejo Nacional de Investigaciones Cientificas y Tecnicas. Oficina de Coordinacion Administrativa Houssay. Instituto de Investigaciones Medicas; Argentin

Genes of intestinal Escherichia coli and their relation to the inflammatory activity in patients with ulcerative colitis and Crohn’s disease

Escherichia coli gene fimA was the most frequent gene that occurred in the intestine of all investigated groups. All subjects with fimA gene had significantly higher values of tumor necrosis factor alpha (TNF-α) and CRP than those with other E. coli genes. There was also a tendency to increased serum interleukin (IL)-6 levels in patients carrying the fimA gene; however, no relation was observed to serum IL-8 and IL-10. Patients with Crohn’s disease had significantly higher IL-6 than those with ulcerative colitis (UC) and controls. The highest levels of TNF-α were detected in the UC group. There were no significant differences in serum IL-8 and IL-10 between all three groups. The presence of E. coli gene fimA in the large bowel of patients with IBD is related to the immunological activity of the disease which may be important from the aspect of therapeutical strategy

Regulation of human intestinal T-cell responses by type 1 interferon-STAT1 signaling is disrupted in inflammatory bowel disease

This work was supported by a research fellowship grant from the Crohn’s and Colitis in Childhood Research Association (CICRA) and a small project grant from Crohn’s and Colitis UK (CCUK). We would like to acknowledge Professor Ian Sanderson, who helped with the initial design of this work, and provided important support throughout. We would also like to thank Dr Gary Warne for his advice and assistance in the use of the sorting by flow cytometry. We would also like to thank Dr Raj Lahiri and Professor Graham Foster for the kind gift of the primers for the ISGs (2’5’ OAS and MxA)

A role for CD47 in the development of experimental colitis mediated by SIRPα+CD103− dendritic cells

Mesenteric lymph node (mLN) CD103 (αE integrin)+ dendritic cells (DCs) induce regulatory T cells and gut tolerance. However, the function of intestinal CD103− DCs remains to be clarified. CD47 is the ligand of signal regulatory protein α (SIRPα) and promotes SIRPα+ myeloid cell migration. We first show that mucosal CD103− DCs selectively express SIRPα and that their frequency was augmented in the lamina propria and mLNs of mice that developed Th17-biased colitis in response to trinitrobenzene sulfonic acid. In contrast, the percentage of SIRPα+CD103− DCs and Th17 responses were decreased in CD47-deficient (CD47 knockout [KO]) mice, which remained protected from colitis. We next demonstrate that transferring wild-type (WT), but not CD47 KO, SIRPα+CD103− DCs in CD47 KO mice elicited severe Th17-associated wasting disease. CD47 expression was required on the SIRPα+CD103− DCs for efficient trafficking to mLNs in vivo, whereas it was dispensable on both DCs and T cells for Th17 polarization in vitro. Finally, administration of a CD47-Fc molecule resulted in reduced SIRPα+CD103− DC–mediated Th17 responses and the protection of WT mice from colitis. We thus propose SIRPα+CD103− DCs as a pathogenic DC subset that drives Th17-biased responses and colitis, and the CD47–SIRPα axis as a potential therapeutic target for inflammatory bowel disease