Activated CD4+ T cells enter the splenic T-cell zone and induce autoantibody-producing germinal centers through bystander activation.

CD4(+) T (helper) cells migrate in huge numbers through lymphoid organs. However, little is known about traffic routes and kinetics of CD4(+) T-cell subsets within different organ compartments. Such information is important because there are indications that CD4(+) T cells may influence the function of microenvironments depending on their developmental stage. Therefore, we investigated the migration of resting (naïve), activated, and recently activated (memory) CD4(+) T cells through the different compartments of the spleen. Resting and recently activated CD4(+) T cells were separated from thoracic duct lymph and activated CD4(+) T cells were generated in vitro by cross-linking the T-cell receptor and CD28. The present study shows that all three CD4(+) T-cell subsets selectively accumulate in the T-cell zone of the spleen. However, only activated T cells induce the formation of germinal centers (GCs) and autoantibodies in rats and mice. Our results suggest that in a two-step process they first activate B cells independent of the T-cell receptor repertoire and CD40 ligand (CD154) expression. The activated B cells then form GCs whereby CD154-dependent T-cell help is needed. Thus, activated T cells may contribute to the development of autoimmune diseases by activating autoreactive B cells in an Ag-independent manner.

The Impact of Body Weight Changes versus Exercise Capacity Changes on Health-Related Factors following a Lifestyle Intervention in Employees with Metabolic Syndrome.

BACKGROUND: Lifestyle changes are a cornerstone in the treatment of metabolic syndrome (MetS). However, evidence as to which components of the MetS and associated aspects of quality of life are driven by weight loss or improvements in exercise capacity are scarce. METHODS: Company employees (n = 302, 48.2 ± 8.2 years, BMI 33.2 ± 5.4 kg/m2) with diagnosed MetS were evaluated after a 6-month telemonitoring-supported intervention (counselling in nutrition and physical activity) or wait-list control (delayed start of the same intervention). RESULTS: Exercise capacity, body mass index (BMI), and MetS severity were improved after the intervention. Multivariable regression models revealed that changes in BMI were associated with changes in three components of MetS (waist circumference, triglycerides, blood glucose), whereas changes in exercise capacity only were associated to one MetS component change (systolic blood pressure) but also improvements in anxiety severity, aspects of quality of life, and work ability. CONCLUSIONS: Both physical activity promotion and diet should be part of a holistic treatment of patients with MetS. However, our data suggest that dietary-induced weight loss might be more successful when aiming at improving MetS risk factors, whereas focusing more on physical activity promotion might be preferred when targeting aspects in quality of life and mental health.

Effectiveness of wearable devices as a support strategy for maintaining physical activity after a structured exercise intervention for employees with metabolic syndrome: a randomized controlled trial.

BACKGROUND: Metabolic syndrome (MetS) is associated with an increased risk for cardiovascular events and high socioeconomic costs. Despite lifestyle interventions focusing on exercise are effective strategies to improve parameters of the above aspects, many programs fail to show sustained effects in the long-term. METHODS: At visit 2 (V2) 129 company employees with diagnosed MetS, who previously participated in a 6-month telemonitoring-supported exercise intervention, were randomized into three subgroups for a 6-month maintenance treatment phase. A wearable activity device was provided to subgroup A and B to assess and to track physical activity. Further subgroup A attended personal consultations with individual instructions for exercise activities. Subgroup C received neither technical nor personal support. 6 months later at visit (V3), changes in exercise capacity, MetS severity, work ability, health-related quality of life and anxiety and depression were compared between the subgroups with an analysis of variance with repeated measurements. RESULTS: The total physical activity (in MET*h/week) declined between visit 2 and visit 3 (subgroup A: V2: 48.0 ± 33.6, V3: 37.1 ± 23.0; subgroup B: V2: 52.6 ± 35.7, V3: 43.8 ± 40.7, subgroup C: V2: 51.5 ± 29.7, V3: 36.9 ± 22.8, for all p = 0.00) with no between-subgroup differences over time (p = 0.68). In all three subgroups the initial improvements in relative exercise capacity and MetS severity were maintained. Work ability declined significantly in subgroup C (V2: 40.3 ± 5.0, V3: 39.1 ± 5.7; p < 0.05), but remained stable in the other subgroups with no between-subgroup differences over time (p = 0.38). Health-related quality of life and anxiety and depression severity also showed no significant differences over time. CONCLUSIONS: Despite the maintenance of physical activity could not be achieved, most of the health related outcomes remained stable and above baseline value, with no difference regarding the support strategy during the maintenance treatment phase. Trial registration The study was completed as a cooperation project between the Volkswagen AG and the Hannover Medical School (ClinicalTrials.gov Identifier: NCT02029131).

Telemonitoring-Supported Exercise Training in Employees With Metabolic Syndrome Improves Liver Inflammation and Fibrosis.

INTRODUCTION: Metabolic syndrome (MetS) is a major health problem worldwide and the main risk factor for metabolic-associated fatty liver disease (MAFLD). Established treatment options are lifestyle interventions facilitating dietary change and increased physical activity. Here, we tested the effect of a telemonitoring-supported intervention on liver parameter of inflammation and fibrosis in individuals with MetS. METHODS: This was a prospective, randomized, parallel-group, and assessor-blind study performed in workers of the main Volkswagen factory (Wolfsburg, Germany). Volunteers with diagnosed MetS were randomly assigned (1:1) to a 6-month lifestyle intervention focusing on supervised, activity-tracker-guided exercise or to a waiting-list control group. This secondary analysis assessed the effect of the intervention on liver enzymes and MAFLD-related parameters. RESULTS: We screened 543 individuals between October 10, 2017, and February 27, 2018, of whom 314 were randomly assigned to the intervention group (n = 160) or control group (n = 154). Liver transaminases, alkaline phosphatase, and gamma-glutamyl transferase significantly decreased after 6 months in the intervention group compared with the CG. Furthermore, an aspartate aminotransferase-to-platelet ratio index score as a marker for liver fibrosis significantly decreased in the intervention group. These improvements were associated with changes in obesity and exercise capacity. DISCUSSION: A 6-month lifestyle intervention based on exercise training with individualized telemonitoring-based supervision led to improvements of liver inflammation and fibrosis in employees with MetS. Therefore, this intervention shows therapeutic potential for individuals at high risk of MAFLD (ClinicalTrials.gov Identifier: NCT03293264).

Employers With Metabolic Syndrome and Increased Depression/Anxiety Severity Profit Most From Structured Exercise Intervention for Work Ability and Quality of Life.

BACKGROUND: Major depressive disorder and anxiety disorders are associated with less productivity, earlier retirement, and more sick-days at the workplace. These associations also exist for patients with metabolic syndrome. For both, exercise is a generally recommended part of multimodal treatments. However, for individuals with metabolic syndrome, in which depression and anxiety is more prevalent and severe, evidence for the efficacy of exercise interventions is limited. METHODS: Company employees with diagnosed metabolic syndrome (n=314, age: 48 ± 8 yrs) were randomized to a 6-month exercise intervention (150 min per week) or wait-list control. Participants received individual recommendations for exercise activities by personal meetings, telephone, or via a smartphone app. Physical activities were supervised and adapted using activity monitor data transferred to a central database. Work ability (work ability index), depression severity and anxiety severity [hospital anxiety and depression scale (HADS)], and health-related quality of live [short form 36 (SF-36)] were assessed. RESULTS: We included 314 subjects from which 287 finished the intervention. Total work ability, depression- and anxiety severity, and the mental component score of the SF-36 improved after 6 months exercise compared to controls. After baseline stratification for normal (HADS scores 0-7) and increased depression- and anxiety scores (HADS scores 8-21) individuals with increased severity scores had similar age, body composition, blood lipids, and cardiorespiratory fitness compared to those with normal scores, but lower total work ability and component sum scores of health-related quality of life. After 6 months total work ability increased in the exercise group compared to controls with the magnitude of the observed increase being significantly greater for subjects with increased depression- and anxiety severity at baseline compared to those with normal severity scores. CONCLUSIONS: A 6-month exercise intervention for company employees with metabolic syndrome showed strongest effects on self-perceived work ability in individuals with mild to severe depression- and anxiety severity. This suggests exercise programs offered to workers with metabolic syndrome not only reduces individual disease risk but may also reduce healthcare and employers costs arising from metabolic syndrome and mental disease conditions. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov, identifier NCT03293264.

Telemonitoring-supported exercise training, metabolic syndrome severity, and work ability in company employees: a randomised controlled trial.

BACKGROUND: Metabolic syndrome is a predisposing factor for cardiovascular and metabolic disease, but also has socioeconomic relevance by affecting the health and productivity of workers. We tested the effect of regular telemonitoring-supported physical activity on metabolic syndrome severity and work ability in company employees. METHODS: This was a prospective, randomised, parallel-group, and assessor-blind study done in workers in the main Volkswagen factory (Wolfsburg, Germany). Volunteers with diagnosed metabolic syndrome according to American Heart Association/National Heart, Lung, and Blood Institute criteria were randomly assigned (1:1) to a 6-month lifestyle intervention focusing on regular exercise (exercise group), or to a waiting-list control group, using a computer-based assignment list with variable block length. Participants in the exercise group received individual recommendations for exercise at face-to-face meetings and via a smartphone application, with the aim of doing 150 min physical activity per week. Activities were supervised and adapted using activity-monitor data, which were transferred to a central database. Participants in the control group continued their current lifestyle and were informed about the possibility to receive the supervised intervention after study completion. The primary outcome was the change in metabolic syndrome severity (metabolic syndrome Z score) after 6 months in the intention-to treat population. This trial is registered with ClinicalTrials.gov, number NCT03293264, and is closed to new participants. FINDINGS: 543 individuals were screened between Oct 10, 2017, and Feb 27, 2018, of whom 314 (mean age 48 years [SD 8]) were randomly assigned to receive the intervention (n=160; exercise group) or to a waiting list (n=154; control group). The mean metabolic syndrome Z score for the exercise group was significantly reduced after the 6-month intervention period (0·93 [SD 0·63] before and 0·63 [0·64] after the intervention) compared with the control group (0·95 [0·55] and 0·90 [0·61]; difference between groups -0·26 [95% CI -0·35 to -0·16], p<0·0001). We documented 11 adverse events in the exercise group, with only one event (a twisted ankle) regarded as directly caused by the intervention. INTERPRETATION: A 6-month exercise-focused intervention using telemonitoring systems reduced metabolic syndrome severity. This form of intervention shows significant potential to reduce disease risk, while also improving mental health, work ability, and productivity-related outcomes for employees at high risk for cardiovascular and metabolic disease. FUNDING: Audi BKK health insurance and the German Research Foundation through the Cluster of Excellence REBIRTH.

Diagnostic and therapeutic yield of push-and-pull enteroscopy for symptomatic small bowel Crohn's disease strictures.

OBJECTIVE: Crohn's disease is frequently complicated by obstructive symptoms secondary to small bowel strictures that cannot be accessed by conventional endoscopy. Push-and-pull enteroscopy is a new endoscopic tool that might allow not only diagnostic work-up but also therapeutic interventions of these strictures. The purpose of this study was to evaluate the feasibility and safety of push-and-pull enteroscopy in the treatment of symptomatic small bowel Crohn's disease strictures. METHODS: Between September 2003 and May 2006, 19 consecutive patients with known or suspected Crohn's disease and symptomatic small bowel strictures were subjected to push-and-pull enteroscopy and included in our analysis. RESULTS: With push-and-pull enteroscopy at least one small bowel stricture was accessed in each patient. On the basis of endoscopic assessment strictures in nine patients were not amenable to endoscopic therapy because of anatomical reasons (3/9) or severe inflammatory activity within the stenotic segment (6/9). They underwent direct surgery or intensified immunomodulatory treatment, respectively. In 10 patients with 13 strictures we performed 15 dilations in combination with push-and-pull enteroscopy under fluoroscopic guidance. Technical success was achieved in 8/10 patients, symptomatic relief with avoidance of surgery was achieved in 6/10 patients who remained symptom free during a mean follow-up period of 10 months (range, 4-16 months). No complications were encountered after dilation. CONCLUSIONS: Push-and-pull enteroscopy is very useful for diagnosis and directing therapy in patients with Crohn's disease-associated strictures within the small bowel. Balloon dilation with the push-and-pull enteroscopy device appears safe and effective and can be considered as an alternative to surgery in selected patients with medically refractory strictures.

Endoscopic interventions in the small bowel using double balloon enteroscopy: feasibility and limitations.

BACKGROUND: Double-balloon enteroscopy (DBE) is a new endoscopic tool that not only allows diagnostic workup of small bowel diseases, but also makes it possible to carry out therapeutic interventions. However, for a variety of reasons, endoscopic therapy appears to be more difficult to carry out deep in the small bowel than in the upper or lower gastrointestinal tract. AIM: The purpose of this study was to evaluate the acute technical success and acute complication rate of DBE. PATIENTS: Between June 2003 and July 2006, 353 patients (152 women, 201 men; mean age 60.3 +/- 17.1 yr) with suspected or known small bowel disease underwent 635 consecutive DBE procedures. The majority of the patients were suffering from midgastrointestinal bleeding (N = 210, 60%). The overall diagnostic yield was 75% (265/353) for relevant lesions in the small bowel. The overall therapeutic yield was 67% (236/353). METHODS: Endoscopic therapy was performed in 59% of these patients (139/236). All therapeutic interventions were done in an inpatient manner. The majority of the procedures were carried out with the patients under conscious sedation (N = 130, 73%); sedation with propofol was administered in 37 (20.8%) and with a combination of propofol and meperidine in 11 (6.2%) investigations. RESULTS: A total of 178 therapeutic procedures was carried out. A median of 270 cm of the small bowel was visualized using the oral route and a median of 150 cm using the anal route. The investigation time averaged 78 +/- 30 minutes. The endoscopic treatments included argon plasma coagulation (APC, 102 treatment sessions), injection therapy (N = 2), a combination of APC and injection (N = 6), polypectomies (N = 46), dilation therapy (N = 18), and foreign-body extraction (N = 3). In 6/178 cases (3.4%), polypectomy (N = 2), dilation (N = 3), and implantation of a self-expanding metal stent (N = 1) could not be performed successfully for technical or anatomical reasons. Severe treatment-associated complications occurred in six of the 178 therapeutic procedures (3.4%) and 4/139 patients (2.9%), consisting of bleeding (N = 2) and perforation (N = 3) during and after polypectomy of large polyps (>3 cm in size), as well as one case of segmental enteritis after APC. CONCLUSIONS: Endoscopic therapeutic interventions can be performed safely even in the more difficult conditions of the small bowel in the majority of patients. Polypectomy of large polyps appears to be the procedure associated with the highest risk.

Prospective evaluation of a new high-power argon plasma coagulation system (hp-APC) in therapeutic gastrointestinal endoscopy.

OBJECTIVE: The aim of this study was to prospectively evaluate a new high-power argon plasma coagulation system (hp-APC) in therapeutic gastrointestinal (GI) endoscopy. MATERIAL AND METHODS: From February to June 2005, 216 patients (167 M (77.3%), mean age 66 years) underwent treatment with hp-APC in a total of 275 sessions. Main indications were additive ablation therapy in Barrett's esophagus, palliative treatment of esophageal cancer, gastric polyps/carcinomas, angiodysplasias, Zenker's diverticula, and duodenal adenomas. The new hp-APC device (VIO 300 D with APC 2) was used (15-120 W) in upper GI endoscopy, push-enteroscopy, and double-balloon enteroscopy. RESULTS: The mean number of treatment sessions required was 1.7 (1-5). For palliative tumor ablation in the esophagus, the number of sessions was 2.3 (1-5). Minor complications (pain, dysphagia, neuromuscular irritation, asymptomatic gas accumulation in the intestinal wall) were observed in 29/216 patients (13.4%). Major complications (perforation, stenosis occurred) in 2 patients (0.9%). CONCLUSIONS: Hp-APC appears to be safe and effective in the treatment of various GI condition using different types of endoscopes including double-balloon enteroscopy. Because of the low number of treatment sessions required, hp-APC could be used as an alternative to Nd:YAG laser treatment in tumor debulking.

Curative endoscopic resection of early esophageal adenocarcinomas (Barrett's cancer).

BACKGROUND: In view of the increasing incidence of adenocarcinoma in Barrett's esophagus and the mortality and high morbidity rates associated with surgical therapy for this condition, safe and effective but less invasive methods of treatment are needed. OBJECTIVE: To evaluate efficacy and safety of endoscopic resection in these patients. DESIGN: Single-center prospective study. SETTING: Teaching hospital, conducted between October 1996 and September 2003. PATIENTS: A total of 100 consecutive patients (mean age, 62.1 +/- 10.9 years; range, 31-86 years) with low-risk adenocarcinoma of the esophagus (macroscopic types I, IIa, IIb, and IIc; lesion diameter up to 20 mm; mucosal lesion without invasion into lymph vessels and veins; and histologic grades G1 and G2) arising in Barrett's metaplasia. INTERVENTIONS: Endoscopic resection with the suck-and-cut technique. MAIN OUTCOME MEASUREMENTS: Complete local remission. RESULTS: A total of 144 resections (1.47 per patient) were performed without technical problems. No major complications and only 11 minor ones (bleedings without decrease of Hb >2 g/dL; treated with injection therapy) occurred. Complete local remission was achieved in 99 of the 100 patients after 1.9 months (range, 1-18 months) and a maximum of 3 resections. During a mean follow-up period of 36.7 months, recurrent or metachronous carcinomas were found in 11% of the patients, but successful repeat treatment with endoscopic resection was possible in all of these cases. The calculated 5-year survival rate was 98%. Two patients died of other causes. LIMITATIONS: Nonblinded, nonrandomized study. CONCLUSIONS: Endoscopic resection is associated with favorable outcomes for low-risk patients with early esophageal adenocarcinoma (Barrett's carcinoma).

Push-and-pull enteroscopy using the double-balloon technique (double-balloon enteroscopy) for the diagnosis of Meckel's diverticulum in adult patients with GI bleeding of obscure origin.

BACKGROUND: Meckel's diverticulum (MD) occurs in 2-3% of the population. Although the clinical, histopathologic, and radiologic features of the complications of MD are well known, the diagnosis may be difficult before surgery. CASE REPORT: Three patients (age 22-34 yr, two women) presenting with gastrointestinal (GI) bleeding of obscure origin underwent multiple endoscopic and radiologic tests including capsule endoscopy and Tc-99m pertechnetate scintigraphy before push-and-pull enteroscopy using a double-balloon technique (double-balloon enteroscopy). Double-balloon enteroscopy was performed in all three patients using oral and anal approaches to evaluate the entire intestine. In one case, MD was detected using the oral route; the diagnosis was confirmed using the anal approach. In two patients, the lumen of MD was disclosed using the anal route. No procedure-related complications occurred. Push-and-pull enteroscopy was the only nonsurgical procedure that provided a precise diagnosis. All patients underwent surgical resection of the diverticulum. In one case, ectopic gastric tissue was found histologically. No further bleeding occurred during follow-up (6-9 months). CONCLUSIONS: Keeping the low sensitivity of Tc-99m scintigraphy in the adult population in mind, double-balloon enteroscopy might be the modality of choice in young adult patients with acute recurrent GI bleeding of obscure origin and a suspected diagnosis of MD.

Prospective comparison of push enteroscopy and push-and-pull enteroscopy in patients with suspected small-bowel bleeding.

BACKGROUND AND AIMS: The management of patients with suspected mid-gastrointestinal bleeding has in the past been difficult, as push enteroscopy (PE) only allows limited endoscopic access for diagnosis and treatment. Recently published uncontrolled data on push-and-pull enteroscopy (PPE) using the double-balloon technique suggest that this new method has a high diagnostic yield and therapeutic efficacy. A prospective controlled study was therefore carried out to compare PPE with PE as the common nonsurgical gold standard method. METHODS: The diagnostic yield, complications, and various examination parameters were compared in 52 consecutive patients with suspected mid-gastrointestinal bleeding who were evaluated with both enteroscopy methods. RESULTS: No relevant complications were observed with either method. Sedoanalgesia, examination times, and X-ray exposure were lower with PE. The insertion depth was significantly greater with PPE than with PE (230 cm vs 80 cm, p < 0.0001). The overall diagnostic yield with PPE (38 of 52 patients, 73%) and the results of oral PPE only (33 of 52 patients, 63%) were superior to those with PE (23 of 52 patients, 44%; p < 0.0001). PPE identified additional lesions in deeper parts of the small bowel in PE-positive patients in 78% of cases (18 of 23 patients). CONCLUSIONS: For endoscopic examination of the small bowel in patients with suspected mid-gastrointestinal bleeding, PPE is superior to PE with regard to the length of small bowel visualized, as well as the diagnostic yield. As the method also allows endoscopic treatment to be carried out, PPE should always be considered before open surgery and intraoperative endoscopy in patients with mid-gastrointestinal bleeding.

Double-balloon enteroscopy (push-and-pull enteroscopy) of the small bowel: feasibility and diagnostic and therapeutic yield in patients with suspected small bowel disease.

BACKGROUND: Double-balloon enteroscopy (push-and-pull enteroscopy) is a new method that allows complete visualization, biopsy, and treatment in the small bowel. This study evaluated the feasibility and the diagnostic and the therapeutic yield of double-balloon enteroscopy (push-and-pull enteroscopy) in comparison with current imaging methods. METHODS: Between March 2003 and November 2004, 248 consecutive double-balloon enteroscopies (push-and-pull enteroscopies) were performed in a prospective study in 137 patients with suspected small-bowel disease (60 women, 77 men; mean age 56.6 +/- 17.8 years), most with chronic GI bleeding (66%). The examinations were carried out after negative evaluations with other methods or to allow biopsy or treatment in patients with known small-bowel findings. RESULTS: There were no relevant technical problems or severe complications. On average, 240 +/- 100 cm of the small bowel was visualized by using the oral route and 140 +/- 90 cm was visualized by using the anal route. The investigation time averaged 73.5 +/- 25 minutes. The overall diagnostic yield was 80% (109/137 patients). The main diagnosis was angiodysplasia (40/109; 37%); erosions and ulcerations of various etiologies were found in 27% (29/109). Polyps and tumors were identified, including malignancy, in 25% (27/109). Other findings were detected in a further 11%. No relevant pathology was found in 20%. Subsequent treatment was influenced by the results in 104 patients (76%): endoscopic therapy in 57 (41.5%), medical treatment in 23 (17%), and surgery in 24 (17.5%). CONCLUSIONS: Double-balloon enteroscopy (push-and-pull enteroscopy) is safe and easily conducted. Visualization and tissue sampling are possible in the entire small bowel by using the oral and anal approaches, and treatment is possible in the same way as in standard endoscopy, avoiding open surgery. If further prospective studies confirm its value, double-balloon enteroscopy (push-and-pull enteroscopy) may become a standard method of diagnostic and therapeutic endoscopy in the small bowel.

Influence of patient selection on the outcome of capsule endoscopy in patients with chronic gastrointestinal bleeding.

BACKGROUND: In chronic gastrointestinal bleeding, success rates in the range of 48% to 76% have been reported for diagnosing clear bleeding sources using capsule endoscopy. The influence of patient selection on the numbers of positive findings yielded by capsule endoscopy is as yet unclear. METHODS: From April 2001 to June 2003, capsule endoscopy was carried out in 74 of a total of 127 patients (58%) who presented for capsule endoscopy with a high suspicion of gastrointestinal bleeding in the small-bowel region. Seventy of the 74 patients were included in the analysis. This group of patients was divided into a study group (32 patients) and a post-study group (38 patients), and the two groups were compared. RESULTS: Stricter patient selection was carried out in the study group than in the post-study group: 49% of those in the study group underwent capsule endoscopy, compared with 65% of those in the post-study group. The overall success rate for detecting relevant bleeding sources was 54%; in the study group, the rate was 66%; whereas in the post-study group, it was only 45%. Significant differences observed between the two groups of patients included the lowest hemoglobin value (5.9+/-1.4 g/dL in the study group, compared with 7.7+/-2.1 g/dL in the post-study group) and transfusion requirements (a median of 10 units in the study group, vs. 2 units in the post-study group). None of the patients who had a minimum hemoglobin value >or=10 g/dL had a positive capsule result. CONCLUSIONS: Patient selection has a considerable influence on the success rate of capsule endoscopy. In patients with chronic gastrointestinal bleeding, the minimum hemoglobin value and transfusion requirements appear to be the decisive parameters.