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ObjectiveSkewed T helper (TH) cell responses and specific functions of TH1, TH2, TH17, and Treg cells have been implicated in the pathogenesis of inflammatory bowel disease (IBD) that led to the establishment of the pathogenic TH1/TH2 and TH17/Treg cell imbalance paradigms. However, the relevant TH cell population driving mucosal inflammation is still unknown.MethodsWe performed a comprehensive TH cell profiling of circulating and intestinal lymphocytes isolated from patients with Crohn’s disease (CD; n = 69) and ulcerative colitis (UC; n = 41) undergoing endoscopy or surgical resection and compared them with healthy controls (n = 45). Mucosal inflammation was assessed endoscopically and histologically. TH cells were analyzed by flow cytometric evaluation of cytokine production and differentiation marker expression.ResultsSpecialized TH cell populations were enriched in the intestinal mucosa compared with peripheral blood. Specifically, we observed a concomitant upregulation of TH17 cells and Tregs in active inflammatory lesions in patients with both CD and UC compared with quiescent/mildly inflamed lesions and healthy tissue. Of note, interferon γ+ interleukin (IL)-17+coproducing CD4+ T cells with high expression of T-bet, CD26, and IL-22 resembling recently described pathogenic TH17 cells were specifically enriched in the inflamed mucosal tissue.ConclusionsOur results argue against the controversial TH1/TH2 or TH17/Treg paradigms. In contrast, they suggest that a subpopulation of TH17 cells sharing a TH1 signature may be specifically involved in intestinal inflammation in CD and UC. These findings provide a better understanding of IBD pathogenesis and may help explain the efficacy of anti-IL-12p40/IL-23 and failure of anti-IL-17A therapies despite the enrichment of TH17 cells.

Statins reduce cardiovascular events in persons with type 2 diabetes mellitus. This study randomly assigned patients with type 2 diabetes receiving hemodialysis to receive 20 mg of atorvastatin per day or matching placebo. Atorvastatin reduced all cardiac events combined but not all cerebrovascular events combined or total mortality. In patients with type 2 diabetes receiving hemodialysis and 20 mg of atorvastatin per day, atorvastatin reduced all cardiac events combined but not all cerebrovascular events combined or total mortality. Primary and secondary prevention trials, including those involving persons with diabetes mellitus, have documented substantial cardiovascular benefit from the administration of statins. 1 , 2 The recent Collaborative Atorvastatin Diabetes Study (CARDS) reported a decrease in deaths from cardiovascular causes among persons with type 2 diabetes mellitus in the absence of marked renal insufficiency. 3 There are no prospective data on the effects of statins in patients with end-stage renal disease with type 2 diabetes mellitus who are receiving hemodialysis, although type 2 diabetes is the most common diagnosis among patients at excessive risk of cardiovascular events 4 whose condition requires hemodialysis in both . . .

Background Fecal incontinence is a common and severely disabling disorder. For patients with severe fecal incontinence, surgery may prove to be the only adequate treatment option. Methods This study reports on 43 patients that were treated with a prosthetic sphincter system between 2005 and 2009 in three coloproctological centres. Main Outcome Measures: complications, anal pressures before and after surgery, fecal continence score. Results The new artificial sphincter system significantly improves continence but leads to some complications in clinical practice. After implantation of the device, continence improved significantly (Keller & Jostarndt continence score 2.6 to 14.3 (P < 0.01)). With the band activated, resting pressure improved significantly as compared to baseline (10.7 mmHg vs. 66.1 mm Hg, P < 0.01). The same holds for anal sphincter squeeze pressure (32.2 mmHg versus 85.9 mm Hg, P < 0.01). Complications occurred in 21 patients (48.8%): 10 surgical and 13 technical. Two patients were affected by both technical and surgical problems. The median time of the occurrence was 3 months postop. In five patients difficulties arose within the first postoperative month leading to explantation of the device in three patients. 90% of complications occurred in the first year. Conclusions The soft anal band of AMI (AAS), a new artificial anal sphincter, improves severe anal incontinence, but it must be regarded as a last treatment option to avoid a stoma.

Purpose The purpose of this study was to assess primary healing, recurrence and continence after endoanal advancement flap repair (EAFR). Patients and methods Seventy-seven patients with fistulas-in-ano of different etiologies received endoanal advancement flap repair between 1997 and 2009. This is a prospective, non-randomized, single-centre, single-surgeon study. Results Follow-up data was available for 71 patients. 47.9 % had cryptoglandular fistulas. In 40.8 %, the fistulas were due to chronic inflammatory bowel disease. In 11.3 %, the fistula was a consequence of treatment for cancer. Primary healing was observed in 41 of the cases (57.7 %). The median time to recurrence was 27 months (mean 43.43 ± 48.11) and differed significantly across the patient groups: cryptoglandular origin 51 months (mean 57.09 ± 52.57), condition after cancer treatment 43 months (mean 31 ± 23.142), inflammatory bowel disease 11 months (mean 23.65 ± 32.47) ( p  < 0.01). Preoperatively, 31 (44.3 %) of the patients had impaired continence vs 30 (42.9 %) postoperatively. Overall, postoperative mean Cleveland Clinic incontinence score values improved significantly (preoperative 3.74 ± 4.558 vs postoperative 2.68 ± 4.752, p  = 0.03). Conclusions Full-thickness endoanal advancement flap repair is a successful treatment option for a range of fistula etiologies. Overall, fistula aetiology proved to be prognostically more relevant than fistula location. Fistulas associated with chronic inflammatory bowel disease were found to have a significantly higher rate of recurrence and shorter time to recurrence at long-term follow-up. Repeat interventions do not negatively impact postoperative continence.

Patients with type 2 diabetes on dialysis are at a substantially increased risk of cardiovascular and cerebrovascular diseases. Dyslipidemia characterized by moderately elevated low-density lipoprotein cholesterol and high triglycerides and low high-density lipoprotein cholesterol levels is common in this population. We hypothesized that 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors would reduce vascular morbidity and mortality in this patient group. The ‘Deutsche Diabetes Dialyse Studie’ (4D study) is a prospective, randomized, double-blind study involving 178 dialysis centers throughout Germany. Between March 1998 and October 2002, 1,255 patients were randomized to either atorvastatin 20 mg or placebo; 677 men and 578 women, aged 30–83 years, have been enrolled. The study will be terminated as soon as the predefined number of 424 patients with primary combined end points (i.e., cardiovascular death, nonfatal myocardial infarction, or fatal/nonfatal stroke) will have occurred. The total cohort had the following characteristics at baseline: the mean age was 65.7 years, 54% were men, 89% had a history of hypertension, 21% had coronary artery disease, 17.8% had a history of stroke or a transient ischemic attack, and 45% suffered from peripheral arterial disease. The mean time interval between the diagnosis of diabetes and the onset of dialysis was 17.4 years. On average, the patients were on hemodialysis for 8.3 months. Mean lipid and lipoprotein levels were: total cholesterol 219 ± 43 mg/dl, low-density lipoprotein cholesterol 126 ± 30 mg/dl, high-density lipoprotein cholesterol 36 ± 13 mg/dl, and triglycerides 264 ± 167 mg/dl. The results of the study will provide important information on the efficacy and safety of atorvastatin to support its use in patients with an impaired renal function who are at a high risk of vascular morbidity and mortality.

Conflicting results of preoperative radiochemotherapy in patients with esophageal cancer have been obtained; only patients with a complete pathological response seem to benefit from this therapy. However, there is evidence that preoperative radiochemotherapy leads to considerable postoperative morbidity. Therefore, postoperative morbidity was retrospectively investigated in 82 patients with an esophageal cancer who received preoperative radiochemotherapy. One hundred twenty-two consecutively operated on patients were included (1991 to 2001). Preoperative radiochemotherapy was initiated in 1994 for cT >1, cNx, cM0 regardless of histology (n = 82); 36 Gy was applied (1.8 Gy daily, days 1 to 5, weeks 1 to 4), concurrently 5-fluorouracil (500 mg/m 2 days 1 to 5, weeks 1 to 4), and cisplatin (20 mg/m 2 days 1 to 5, weeks 1 and 4). Postoperative morbidity was categorized as surgery- and nonsurgery-related morbidity. Survival was calculated by the Kaplan-Meier method. Results were stratified into histology and compared with patients who were operated on only (n = 40). Complete pathological response after preoperative radiochemotherapy was achieved in 22%. An increase in surgery-related morbidity was observed after preoperative radiochemotherapy due to lesion of recurrent nerve (38% versus 12.5%, P = 0.009), as well as a marked difference in pulmonary morbidity (57% versus 37.5%, P = 0.05). The proportion of combined morbidity was increased after preoperative radiochemotherapy (49.4% versus 15%, P = 0.02), which led to a considerable prolongation of postoperative hospital stay (33 versus 21 days median, P = 0.0022). Patients with a longer postoperative hospital stay (>30 days; 43.2%) lived significantly shorter than patients with a shorter postoperative hospital stay (56.8%, P = 0.001). There was no statistical survival benefit in the neoadjuvant treated group. However, calculation of long-term survival revealed a significant survival advantage in patients with squamous cell cancer and a complete pathological response compared with patients without response (median 642 days versus 302, P = 0.026). Perioperative morbidity was significantly increased after preoperative radiochemotherapy. Long-term survival was clearly affected by the length of postoperative stay. Therefore, we need better patient selection for application of preoperative radiochemotherapy.

Five southern German university centers cooperated in comparing the effect of surgical vs. nonsurgical therapy strategies on survival and sphincter preservation in the treatment of anal cancer. A standardized questionnaire was used to evaluate retrospectively (mean follow-up 30 months) treatment strategy and outcome (survival, colostomy rate, colostomy-free survival) in patients treated between 1987 and 1996. Of the 142 patients 65% had squamous cell, 20% basaloid, 6% adeno-, and 1% undifferentiated carcinoma (8% histology not recorded); 9% were classified in UICC stage I, 37% in stage II, 25% in stage III, and 4% in stage IV (25% not recorded). Primary treatment consisted of local excision (10%), excision plus radio- and/or chemotherapy (17%), radiotherapy (20%), radiochemotherapy (28%), or colostomy with or without resection, radiotherapy, and chemotherapy (23%). We observed no difference between these treatment groups in overall (P = 0.43) or colostomy-free survival (P = 0.14, log-rank). Primary colostomy was prevented in 77% of cases and decreased over the years. Mean overall survival (in months) was 42 in stage I, 38 in stage II, and 25 in stage III (P = 0.0013); mean colostomy-free survival was 36 in stage I, 26 in stage II, and 16 in stage III (P = 0.0021, log-rank). Outcome was not significantly related to therapeutic strategy (surgery or radio-chemotherapy. Primary surgical and nonsurgical strategies in treating anal cancer thus produced similar results, although radiochemotherapy is usually recommended for sphincter-endangering anal cancer. Challenges to be met in the future include the prevention of metastasis and long-term preservation of anal sphincter function.

Pathogenic variants in the Cu/Zn superoxide dismutase ( SOD1 ) gene can be detected in approximately 2% of sporadic and 11% of familial amyotrophic lateral sclerosis (ALS) patients in Europe. We analyzed the clinical phenotypes of 83 SOD1 -ALS patients focusing on patients carrying the most frequent (likely) pathogenic variants (R116G, D91A, L145F) in Germany. Moreover, we describe the effect of tofersen treatment on ten patients carrying these variants. R116G patients showed the most aggressive course of disease with a median survival of 22.0 months compared to 198.0 months in D91A and 87.0 months in L145F patients (HR 7.71, 95% CI 2.89–20.58 vs. D91A; p < 0.001 and HR 4.25, 95% CI 1.55–11.67 vs. L145F; p = 0.02). Moreover, R116G patients had the fastest median ALSFRS-R progression rate with 0.12 (IQR 0.07–0.20) points lost per month. Median diagnostic delay was 10.0 months (IQR 5.5–11.5) and therefore shorter compared to 57.5 months (IQR 14.0–83.0) in D91A (p < 0.001) and 21.5 months (IQR 5.8–38.8) in L145F (p = 0.21) carriers. As opposed to D91A carriers (50.0%), 96.2% of R116G (p < 0.001) and 100.0% of L145F (p = 0.04) patients reported a positive family history. During tofersen treatment, all patients showed a reduction of neurofilament light chain (NfL) serum levels, independent of the SOD1 variant. Patients with SOD1 -ALS carrying R116G, D91A, or L145F variants show commonalities, but also differences in their clinical phenotype, including a faster progression rate with shorter survival in R116G, and a comparatively benign disease course in D91A carriers.

What does it mean to \"fit in?\" This volume of essays demystifies the discourse on identity, challenging common assumptions about role of similarity in inclusion and exclusion. Armed with intimate knowledge of local social structures, these essays tease out the ways in which ethnicity, religion and nationalism are used for social integration.

ALS is a fatal motor neuron disease that displays a broad variety of phenotypes ranging from early fatal courses to slowly progressing and rather benign courses. Such divergence can also be seen in genetic ALS cases with varying phenotypes bearing specific mutations, suggesting epigenetic mechanisms like DNA methylation act as disease modifiers. However, the epigenotype dictated by, in addition to other mechanisms, DNA methylation is also strongly influenced by the individual’s genotype. Hence, we performed a DNA methylation study using EPIC arrays on 7 monozygotic (MZ) twin pairs discordant for ALS in whole blood, which serves as an ideal model for eliminating the effects of the genetic-epigenetic interplay to a large extent. We found one CpG site showing intra-pair hypermethylation in the affected co-twins, which maps to the Glutamate Ionotropic Receptor Kainate Type Subunit 1 gene (GRIK1). Additionally, we found 4 DMPs which were subsequently confirmed using 2 different statistical approaches. Differentially methylated regions or blocks could not be detected within the scope of this work. In conclusion, we revealed that despite a low sample size, monozygotic twin studies discordant for the disease can bring new insights into epigenetic processes in ALS, pointing to new target loci for further investigations.