Altered functional connectivity in common resting-state networks in patients with major depressive disorder: A resting-state functional connectivity study.

The neural correlates of major depressive disorder (MDD) remain disputed. In the absence of reliable biological markers, the dysfunction and interaction of neural networks have been proposed as pathophysiological neural mechanisms in depression. Here, we examined the functional connectivity (FC) of brain networks. 51 healthy volunteers (mean age 33.57 ± 7.80) and 55 individuals diagnosed with MDD (mean age 33.89 ± 11.00) participated by performing a resting-state (rs) fMRI scan. Seed to voxel FC analyses were performed. Compared to healthy control (HC), MDD patients showed higher connectivity between the hippocampus and the anterior cingulate cortex (ACC) and lower connectivity between the insula and the ACC. The MDD group displayed lower connectivity between the inferior parietal lobule (IPL) and the superior frontal gyrus (SFG). The current data replicate previous findings regarding the cortico-limbic network (hippocampus - ACC connection) and the salience network (insula - ACC connection) and provide novel insight into altered rsFC in MDD, in particular involving the hippocampus - ACC and the insula - ACC connection. Furthermore, altered connectivity between the IPL and SFG indicates that the processing in higher cognitive processes such as attention and working memory is affected in MDD. These data further support dysfunctional neuronal networks as an interesting pathophysiological marker in depression.

Area-level and individual correlates of active transportation among adults in Germany: A population-based multilevel study.

This study aimed at estimating the prevalence in adults of complying with the aerobic physical activity (PA) recommendation through transportation-related walking and cycling. Furthermore, potential determinants of transportation-related PA recommendation compliance were investigated. 10,872 men and 13,144 women aged 18 years or older participated in the cross-sectional 'German Health Update 2014/15 - EHIS' in Germany. Transportation-related walking and cycling were assessed using the European Health Interview Survey-Physical Activity Questionnaire. Three outcome indicators were constructed: walking, cycling, and total active transportation (≥600 metabolic equivalent, MET-min/week). Associations were analyzed using multilevel regression analysis. Forty-two percent of men and 39% of women achieved ≥600 MET-min/week with total active transportation. The corresponding percentages for walking were 27% and 28% and for cycling 17% and 13%, respectively. Higher population density, older age, lower income, higher work-related and leisure-time PA, not being obese, and better self-perceived health were positively associated with transportation-related walking and cycling and total active transportation among both men and women. The promotion of walking and cycling among inactive people has great potential to increase PA in the general adult population and to comply with PA recommendations. Several correlates of active transportation were identified which should be considered when planning public health policies and interventions.

[Metabolic disorders as paraneoplastic syndromes]. / Metabolische Entgleisungen als paraneoplastische Syndrome.

Paraneoplastic syndromes are characterized by the tumor-induced release of peptide hormones and/or the initiation of immune phenomena, which elicit clinical changes and alterations in laboratory parameters independent of the tumor size and spread. In addition to neurological, endocrinal and rheumatological phenotypes, metabolic alterations play a special role in the clinical routine as they commonly present with acute symptoms in an emergency situation and necessitate immediate diagnosis and prompt initiation of treatment. Metabolic alterations within the framework of malignant diseases should be treated in a multidisciplinary team and it is often necessary to perform monitoring and treatment in an intensive care unit. This article focuses on the diagnostic and therapeutic options for metabolic disorders due to paraneoplastic syndromes, such as hypercalcemia, hypocalcemia, hyperglycemia, hypoglycemia and a special variant of tumor-induced metabolic disorders due to tumor lysis syndrome.

Campylobacter jejuni impairs sodium transport and epithelial barrier function via cytokine release in human colon.

This corrects the article DOI: 10.1038/mi.2017.66.

Tricellulin is regulated via interleukin-13-receptor α2, affects macromolecule uptake, and is decreased in ulcerative colitis.

In the two inflammatory bowel diseases, ulcerative colitis (UC) and Crohn's disease (CD), altered expression of tight junction (TJ) proteins leads to an impaired epithelial barrier including increased uptake of luminal antigens supporting the inflammation. Here, we focused on regulation of tricellulin (Tric), a protein of the tricellular TJ essential for the barrier against macromolecules, and hypothesized a role in paracellular antigen uptake. We report that Tric is downregulated in UC, but not in CD, and that its reduction increases the passage of macromolecules. Using a novel visualization method, passage sites were identified at TJ regions usually sealed by Tric. We show that interleukin-13 (IL-13), beyond its known effect on claudin-2, downregulates Tric expression. These two effects of IL-13 are regulated by different signaling pathways: The IL-13 receptor α1 upregulates claudin-2, whereas IL-13 receptor α2 downregulates Tric. We suggest to target the α2 receptor in future developments of therapeutical IL-13-based biologicals.

Campylobacter jejuni impairs sodium transport and epithelial barrier function via cytokine release in human colon.

Campylobacter jejuni is the most prevalent cause of foodborne bacterial enteritis worldwide. Patients present with diarrhea and immune responses lead to complications like arthritis and irritable bowel syndrome. Although studies exist in animal and cell models, we aimed at a functional and structural characterization of intestinal dysfunction and the involved regulatory mechanisms in human colon. First, in patients' colonic biopsies, sodium malabsorption was identified as an important diarrheal mechanism resulting from hampered epithelial ion transport via impaired epithelial sodium channel (ENaC) ß- and γ-subunit. In addition, barrier dysfunction from disrupted epithelial tight junction proteins (claudin-1, -3, -4, -5, and -8), epithelial apoptosis, and appearance of lesions was detected, which cause leak-flux diarrhea and can perpetuate immune responses. Importantly, these effects in human biopsies either represent direct action of Campylobacter jejuni (ENaC impairment) or are caused by proinflammatory signaling (barrier dysfunction). This was revealed by regulator analysis from RNA-sequencing (cytometric bead array-checked) and confirmed in cell models, which identified interferon-γ, TNFα, IL-13, and IL-1ß. Finally, bioinformatics' predictions yielded additional information on protective influences like vitamin D, which was confirmed in cell models. Thus, these are candidates for intervention strategies against C. jejuni infection and post-infectious sequelae, which result from the permissive barrier defect along the leaky gut.

Architectural and functional alterations of the small intestinal mucosa in classical Whipple's disease.

Classical Whipple's disease (CWD) affects the gastrointestinal tract and rather elicits regulatory than inflammatory immune reactions. Mechanisms of malabsorption, diarrhea, and systemic immune activation are unknown. We here analyzed mucosal architecture, barrier function, and immune activation as potential diarrheal trigger in specimens from 52 CWD patients. Our data demonstrate villus atrophy and crypt hyperplasia associated with epithelial apoptosis and reduced alkaline phosphatase expression in the duodenum of CWD patients. Electrophysiological and flux experiments revealed increased duodenal permeability to small solutes and macromolecules. Duodenal architecture and permeability ameliorated upon antibiotic treatment. Structural correlates for these alterations were concordant changes of membranous claudin-1, claudin-2, claudin-3, and tricellulin expression. Tumor necrosis factor-α and interleukin-13 were identified as probable mediators of epithelial apoptosis, and altered tight junction expression. Increased serum markers of microbial translocation and their decline following treatment corroborated the biological significance of the mucosal barrier defect. Hence, mucosal immune responses in CWD elicit barrier dysfunction. Diarrhea is caused by loss of absorptive capacity and leak flux of ions and water. Downregulation of tricellulin causes increased permeability to macromolecules and subsequent microbial translocation contributes to systemic inflammation. Thus, therapeutic strategies to reconstitute the mucosal barrier and control inflammation could assist symptomatic control of CWD.

Claudin-2-mediated cation and water transport share a common pore.

AIM: Claudin-2 is a tight junction protein typically located in 'leaky' epithelia exhibiting large paracellular permeabilities like small intestine and proximal kidney tubule. Former studies revealed that claudin-2 forms paracellular channels for small cations like sodium and potassium and also paracellular channels for water. This study analyses whether the diffusive transport of sodium and water occurs through a common pore of the claudin-2 channel. METHODS: Wild-type claudin-2 and different claudin-2 mutants were expressed in MDCK I kidney tubule cells using an inducible system. Ion and water permeability and the effect of blocking reagents on both were investigated on different clones of the mutants. RESULTS: Neutralization of a negatively charged cation interaction site in the pore with the mutation, D65N, decreased both sodium permeability and water permeability. Claudin-2 mutants (I66C and S68C) with substitution of the pore-lining amino acids with cysteine were used to test the effect of steric blocking of the claudin-2 pore by thiol-reactive reagents. Addition of thiol-reactive reagents to these mutants simultaneously decreased conductance and water permeability. Remarkably, all experimental perturbations caused parallel changes in ion conductance and water permeability, disproving different or independent passage pathways. CONCLUSION: Our results indicate that claudin-2-mediated cation and water transport are frictionally coupled and share a common pore. This pore is lined and determined in permeability by amino acid residues of the first extracellular loop of claudin-2.

Relevance of dihydropyrimidine-dehydrogenase and thymidylate-synthase in patients with pancreatic neuroendocrine neoplasms treated with 5-FU-based chemotherapy.

BACKGROUND: Chemotherapy with 5-FU and Streptozotocin (STZ) is recommended as first-line treatment in patients with metastatic pancreatic neuroendocrine neoplasms (PNEN). However, data about biomarkers involved in the 5-FU metabolism to predict response are still limited. OBJECTIVES: Evaluation of clinicopathological features and potential predictive and prognostic markers of patients with PNEN treated with 5-FU based regimens. PATIENTS AND METHODS: We retrospectively analyzed 41 patients with PNEN who were treated at the University Hospital Marburg between 2000 and 2013. Dihydropyrimidine-Dehydrogenase (DPD) and Thymidylate-Synthase (TS) expression was correlated with treatment response in 19 patients who had available tumour tissue and response data. The median overall survival (OS) and progression free survival (PFS) were calculated using Kaplan-Meier and Cox regression methods, respectively. RESULTS: The median PFS in patients receiving 5-FU/STZ was 17 months with a median OS of 50 months. Objective response rate (ORR) and disease control rate (DCR) were 32% and 73%, respectively. Biochemical response (p = 0.005) and high DPD expression (p = 0.018) were predictive markers of response to 5-FU-based chemotherapy. Univariate analysis identified Ki-67 > 10%, no biochemical response, positive 5-HIAA levels and TS deficiency as independent risk factors for shorter PFS. Moreover, performance status (PS) ≥1 was an independent risk factors for impaired OS. CONCLUSIONS: DPD expression and biochemical response represent promising predictive biomarkers for response to 5-FU based chemotherapy. Moreover, Ki-67, PS and TS are independent prognostic markers of OS and PFS in patients with PNEN.

[A 59-year-old patient with recurrent flushes and bland hepatic cyst]. / 59-jähriger Patient mit rezidivierendem Erröten bei blander Leberzyste.

A 59-year-old patient was admitted to hospital with recurrent flush symptoms and pathologically elevated 5-hydroxyindoleacetic acid (5-HIAA) levels in urine. A known cystic lesion of the liver which had been followed for years by ultrasound examinations and was regarded as a bland hepatic cyst was identified as a metastasis of a neuroendocrine neoplasm of the ileum. In two sequential surgical interventions the primary tumor with mesenteric lymph node metastases as well as the cystic liver metastasis could be resected. After surgical treatment an R1 situation at the mesenteric site and suspicious para-aortic lymph nodes remained. The long established treatment of factor-V Leiden mutation by anticoagulation with phenprocoumon was supplemented by deep subcutaneous injection of lanreotide autogel every 4 weeks. Currently, there is no evidence for progressive disease and the patient is without clinical signs of a carcinoid syndrome.

Differential control of sex differences in estrogen receptor α in the bed nucleus of the stria terminalis and anteroventral periventricular nucleus.

The principal nucleus of the bed nucleus of the stria terminalis (BNSTp) and anteroventral periventricular nucleus of the hypothalamus (AVPV) are sexually dimorphic, hormone-sensitive forebrain regions. Here we report a profound sex difference in estrogen receptor-α (ERα) immunoreactivity (IR) in the BNSTp, with robust ERα IR in females and the near absence of labeling in males. This sex difference is due to the suppression of ERα IR by testicular hormones in adulthood: it was not present at birth and was not altered by neonatal treatment of females with estradiol; gonadectomy of adult males increased ERα IR to that of females, whereas gonadectomy of adult females had no effect. Treating gonadally intact males with an aromatase inhibitor partially feminized ERα IR in the BNSTp, suggesting that testicular suppression required aromatization. By contrast, in AVPV we found a modest sex difference in ERα IR that was relatively insensitive to steroid manipulations in adulthood. ERα IR in AVPV was, however, masculinized in females treated with estradiol at birth, suggesting that the sex difference is due to organizational effects of estrogens. The difference in ERα IR in the BNSTp of males and females appears to be at least in part due to greater expression of mRNA of the ERα gene (Esr1) in females. The sex difference in message is smaller than the difference in immunoreactivity, however, suggesting that posttranscriptional mechanisms also contribute to the pronounced suppression of ERα IR and presumably to functions mediated by ERα in the male BNSTp.

[Physical activity: results of the German Health Interview and Examination Survey for Adults (DEGS1)]. / Körperliche Aktivität : Ergebnisse der Studie zur Gesundheit Erwachsener in Deutschland (DEGS1).

Regular physical activity can have a positive effect on health at any age. Today's lifestyles, however, can often be characterised as sedentary. Therefore, the promotion of physical activity and sports has become an integral part of public health measures. The representative data of adults aged 18 to 79 years in Germany obtained from the "German Health Interview and Examination Survey for Adults" (DEGS1) provide an overview of self-estimated current physical activity behaviour. The results show that one third of the adult population claims to pay close attention to reaching a sufficient level of physical activity and one fourth participates in sports for at least 2 h/week on a regular basis. Thus, the percentage of adults regularly engaged in sports has increased compared to the previous "German National Health Interview and Examination Survey 1998". Still, four out of five adults do not achieve at least 2.5 h/week of moderate-intensity physical activity as recommended by the World Health Organisation. Consequently, future individual-level and population-level interventions should focus on target group-specific measures while continuing to promote regular physical activity in all segments of the population. An English full-text version of this article is available at SpringerLink as supplemental.

[Cardiorespiratory fitness among adults in Germany: results of the German Health Interview and Examination Survey for Adults (DEGS1)]. / Kardiorespiratorische Fitness bei Erwachsenen in Deutschland: Ergebnisse der Studie zur Gesundheit Erwachsener in Deutschland (DEGS1).

A high level of fitness is an indicator for a good health state. Therefore, cardiorespiratory fitness was examined in the cross-sectional German Health Interview Survey for Adults (DEGS1). Data from 3030 test-qualified adults between 18 and 64 years old were assessed by means of a standardized submaximal cycle ergometer test. Test-qualified participants were significantly younger, more often men, less often obese and showed a better health state than those who were not test-qualified. The calculated physical work capacity at 75 % of the age-predicted maximum heart rate (PWC75%) in watts per kg bodyweight was among men 1.52 and among women 1.15. PWC75% declines by 4.2 % per age decade for men and 4.8 % for women. A higher socioeconomic status (SES) is associated with better fitness among women. No significant association was observed between SES and fitness among men. These findings can be used to develop target-group specific health-promotion interventions in order to enhance cardiorespiratory fitness. It is planned to calculate updated PWC reference values based on the DEGS1 data. An English full-text version of this article is available at SpringerLink as supplemental.

[Measurement of cardiorespiratory fitness in the German Health Interview and Examination Survey for Adults (DEGS1)]. / Messung der kardiorespiratorischen Fitness in der Studie zur Gesundheit Erwachsener in Deutschland (DEGS1).

A state of good fitness is related to a better health state and a lower mortality risk. In the German Health Interview and Examination Survey for Adults (DEGS1), aerobic fitness was measured among adults between 18 and 64 years old using a submaximal cycle ergometry test. The total sample comprised 5,263 persons, amongst those 3,111 were categorized as being test-qualified according to the Physical Activity Readiness-Questionnaire. There were 3,030 persons who absolved a submaximal exercise test according to the exercise protocol of the WHO (25/25/2). The test-participation rate was 57.2 % in relation to the total sample and 97.4 % among test-qualified persons. Apart from the continuous heart-rate monitoring, capillary blood was taken prior to starting the test and at the end of each workload stage for performing blood lactate analyses. The test ended when 85 % of the age-predicted maximal heart rate was exceeded. In all 11.9 % of the tests were terminated earlier, the mean exercise duration was 10.8 min, and the anticipated submaximal exertion in the highest workload stage was on average achieved with a mean of 15 on the 20-point RPE scale. The nationwide data can now be used for the national health monitoring system, epidemiological research and for the calculation of reference values. An English full-text version of this article is available at SpringerLink as supplemental.

[A 79-year-old man with B symptoms and jaw claudication]. / B-Symptomatik und Kauclaudicatio bei einem 79-jährigen Patienten.

A 79-year-old patient presented with weight loss, subfebrile body temperature and unclear jaw pain. After ruling out malignant and infectious causes, positron emission tomography-computed tomography (PET-CT) revealed markedly elevated glucose utilization of the large thoracic and upper limb arteries, suggesting systemic vasculitis. Color-coded duplex sonography confirmed thickening of the wall of the external carotid artery consistent with vasculitis. The patient was diagnosed with giant cell arteritis involving the large thoracic arteries and the upper limb arteries but without involvement of the superficial temporal artery. Based on the involvement of the external carotid artery, the jaw pain could be classified as jaw claudication. Clinical and laboratory remission was achieved with systemic glucocorticoids which could subsequently be tapered. The patient is well and asymptomatic 12 months after diagnosis and 2 months without steroids.

[The influence of Nintendo-Wii® bowling upon residents of retirement homes]. / Auswirkungen von Nintendo-Wii® Bowling auf Altenheimbewohner.

The few studies dealing with the positive effects of health and well-being of older people are only one-sided. The aim of the study therefore was to analyze the effects of Nintendo-Wii® bowling on daily function, state of dementia, quality of life, cognition and motor skills in retirement home inhabitants. The study was performed with 27 study participants (13 women, 14 men) between the ages of 49 and 95 years (mean = 71, SD = 14). They were randomly assigned to a control group (KG) and an intervention group (IG). Between pre- and posttest, the IG played 60 min/twice a week Nintendo-Wii® Bowling over 6 weeks. The improvement of IG was significant in the analysis of variance concerning strength (arm curls: F df = 2 = 7.199; p = 0,013; η(2) = 0,231) and showed a significant trend concerning coordination (tracking lines: F df = 2 = 3.99; p = 0,058; η(2) = 0,154) compared with KG. The area of rapidity (catching bars: F df = 2 = 28.511; p = 0,008; η(2) = 0,279) showed a significant decline in the IG compared with the KG. However, closer examination shows that the short time of intervention and the wide age range could have affected the results. Thus, further studies should take these critical aspects into consideration.

New developments in pancreatic cancer treatment.

Pancreatic ductal adenocarcinomas belong to the most aggressive solid malignancies. The devastating prognosis of this tumor entity is associated with a high degree of resistance to systemic therapy approaches. Although new combination chemotherapy regimens have recently demonstrated a significant survival benefit compared to gemcitabine-based therapies, the search for novel treatment options still remains a huge challenge. After numerous potential targets have proven to be futile in clinical trials, recent efforts have been made to both improve drug delivery and to identify drugs targeting novel signalling pathways within the tumors including the putative stem cell compartment and the tumor stroma. Furthermore, predictive markers are needed to define tailored treatment regimens according to the molecular profile of individual tumors. In this review, current therapeutic strategies as well as emerging avenues for systemic therapy and response prediction for individualized therapy of pancreatic cancer patients are discussed which are currently evaluated to overcome the highly drug-resistant phenotype of this malignancy.

Successful selective internal radiotherapy (SIRT) in a patient with a malignant solid pseudopapillary pancreatic neoplasm (SPN).

Solid pseudopapillary neoplasms of the pancreas (SPNs, Gruber-Frantz-Tumor) are a rare entity representing 1-5% of all exocrine pancreatic tumors. The pseudocystic lesions preferentially affect young females <30 years, are mostly benign (∼90%) and normally present with unspecific symptoms. We describe the case of a 16-years-old Asian woman that was initially diagnosed with an SPN in the pancreatic head with mesenterial and hepatic metastases. After diagnosis, an extensive tumor resection was performed including pyloric-preserving pancreatic head resection followed by sequential resection of all hepatic metastases. After the patient was diagnosed with a hepatic recurrence and high intrahepatic tumor load, we chose a multimodal procedure and performed a selective internal radiotherapy (SIRT). Four years after SIRT and 10 years after initial diagnosis of metastatic SPN, the patient is in a good condition without any evidence for hepatic recurrence. This case represents a rare clinical course of a malignant and invasive SPN with an exceptionally long survival despite of high initial tumor burden. The selective internal radiotherapy is a suitable approach for inducing long-term remissions of the strongly vascularized liver metastases.

[Overview of primary prevention measures to promote physical activity in Germany]. / Überblick über primärpräventive Maßnahmen zur Förderung von körperlicher Aktivität in Deutschland.

This article provides an overview of primary prevention measures to promote physical activity. First, health-related recommendations for physical activity are presented together with a brief description of the frequency and determinants of physical activity. Prevention measures in Germany to promote physical activity are categorized taking into account the respective level of intervention (individual, setting, population) and contextual reference (with and without relying on structural conditions). Typical preventive measures to promote physical activity will be presented along with some examples. This is followed by concluding remarks about the current state in the area of preventive measures in Germany for the promotion of physical activity.