Summary
The gastrointestinal tract is covered by mucus that has different properties in the stomach, small intestine, and colon. The large highly glycosylated gel‐forming mucins MUC2 and MUC5AC are ...the major components of the mucus in the intestine and stomach, respectively. In the small intestine, mucus limits the number of bacteria that can reach the epithelium and the Peyer's patches. In the large intestine, the inner mucus layer separates the commensal bacteria from the host epithelium. The outer colonic mucus layer is the natural habitat for the commensal bacteria. The intestinal goblet cells secrete not only the MUC2 mucin but also a number of typical mucus components: CLCA1, FCGBP, AGR2, ZG16, and TFF3. The goblet cells have recently been shown to have a novel gate‐keeping role for the presentation of oral antigens to the immune system. Goblet cells deliver small intestinal luminal material to the lamina propria dendritic cells of the tolerogenic CD103+ type. In addition to the gel‐forming mucins, the transmembrane mucins MUC3, MUC12, and MUC17 form the enterocyte glycocalyx that can reach about a micrometer out from the brush border. The MUC17 mucin can shuttle from a surface to an intracellular vesicle localization, suggesting that enterocytes might control and report epithelial microbial challenge. There is communication not only from the epithelial cells to the immune system but also in the opposite direction. One example of this is IL10 that can affect and improve the properties of the inner colonic mucus layer. The mucus and epithelial cells of the gastrointestinal tract are the primary gate keepers and controllers of bacterial interactions with the host immune system, but our understanding of this relationship is still in its infancy.
Highlights ► We explored NT-proBNP and fibulin-1 in Africans and Caucasians. ► A positive relationship exists between NT-proBNP and fibulin-1 in African men. ► This association remains independent of ...age, blood pressure and kidney function. ► Our results suggest possible early vascular changes present in this population. ► This was confirmed in younger African men, increasing their risk for cardiac damage.
The distal colon functions as a bioreactor and harbors an enormous amount of bacteria in a mutualistic relationship with the host. The microbiota have to be kept at a safe distance to prevent ...inflammation, something that is achieved by a dense inner mucus layer that lines the epithelial cells. The large polymeric nets made up by the heavily O-glycosylated MUC2 mucin forms this physical barrier. Proteomic analyses of mucus have identified the lectin-like protein ZG16 (zymogen granulae protein 16) as an abundant mucus component. To elucidate the function of ZG16, we generated recombinant ZG16 and studied Zg16−/− mice. ZG16 bound to and aggregated Gram-positive bacteria via binding to the bacterial cell wall peptidoglycan. Zg16−/− mice have a distal colon mucus layer with normal thickness, but with bacteria closer to the epithelium. Using distal colon explants mounted in a horizontal perfusion chamber we demonstrated that treatment of bacteria with recombinant ZG16 hindered bacterial penetration into the mucus. The inner colon mucus of Zg16−/− animals had a higher load of Gram-positive bacteria and showed bacteria with higher motility in the mucus close to the host epithelium compared with cohoused littermate Zg16+/+. The more penetrable Zg16−/− mucus allowed Gram-positive bacteria to translocate to systemic tissues. Viable bacteria were found in spleen and were associated with increased abdominal fat pad mass in Zg16−/− animals. The function of ZG16 reveals a mechanism for keeping bacteria further away from the host colon epithelium.
Duchenne muscular Dystrophy (DMD) is a progressive degenerative muscle disease, affecting, among others, the upper extremities. Effective hand rehabilitation can improve the hand function of people ...with DMD. To reach this goal, we first need to gain more insight into the hand cognitive-motor performance of people with DMD. This is the first study employing a systematic analysis on multi-finger, cognitive-motor performance of people with DMD. For this purpose, we propose an active dynamic visuo-motor task. The task employed six visual stimuli, a subset of which was activated at each trial. The stimuli were activated with a frequency of 1, 2, 3 and 4 Hz. Eight healthy participants and three participants with DMD performed the task. Additionally, the healthy participants performed seven sessions, and we assessed the training effects. Task-related cognitive-motor performance was evaluated using information transfer rate (ITR) and perceived workload. Regarding ITR, healthy participants performed significantly better than DMD participants; however, this was more evident for trials involving more than three fingers. Workload showed no difference between the healthy and the DMD groups. Healthy participants significantly improved their performance during training. Our results suggest that hand rehabilitation of people with DMD should consider multi-finger dynamic training. However, additional research with more people with DMD is needed for further generalization of our conclusions.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Breast cancer has for long been recognized as a highly diverse tumor group, but the underlying genetic basis has been elusive. Here, we report an extensive molecular characterization of a collection ...of 41 human breast cancer cell lines. Protein and gene expression analyses indicated that the collection of breast cancer cell lines has retained most, if not all, molecular characteristics that are typical for clinical breast cancers. Gene mutation analyses identified 146 oncogenic mutations among 27 well-known cancer genes, amounting to an average of 3.6 mutations per cell line. Mutations in genes from the p53, RB and PI3K tumor suppressor pathways were widespread among all breast cancer cell lines. Most important, we have identified two gene mutation profiles that are specifically associated with luminal-type and basal-type breast cancer cell lines. The luminal mutation profile involved E-cadherin and MAP2K4 gene mutations and amplifications of Cyclin D1, ERBB2 and HDM2, whereas the basal mutation profile involved BRCA1, RB1, RAS and BRAF gene mutations and deletions of p16 and p14ARF. These subtype-specific gene mutation profiles constitute a genetic basis for the heterogeneity observed among human breast cancers, providing clues for their underlying biology and providing guidance for targeted pharmacogenetic intervention in breast cancer patients.
Department of Cardiology, Leiden University Medical Center, Leiden, The Netherlands
Submitted 7 April 2006
; accepted in final form 22 May 2006
We characterized hemodynamics and systolic and ...diastolic right ventricular (RV) function in relation to structural changes in the rat model of monocrotaline (MCT)-induced pulmonary hypertension. Rats were treated with MCT at 30 mg/kg body wt (MCT30, n = 15) and 80 mg/kg body wt (MCT80, n = 16) to induce compensated RV hypertrophy and RV failure, respectively. Saline-treated rats served as control (Cont, n = 13). After 4 wk, a pressure-conductance catheter was introduced into the RV to assess pressure-volume relations. Subsequently, rats were killed, hearts and lungs were rapidly dissected, and RV, left ventricle (LV), and interventricular septum (IVS) were weighed and analyzed histochemically. RV-to-(LV + IVS) weight ratio was 0.29 ± 0.05 in Cont, 0.35 ± 0.05 in MCT30, and 0.49 ± 0.10 in MCT80 ( P < 0.001 vs. Cont and MCT30) rats, confirming MCT-induced RV hypertrophy. RV ejection fraction was 49 ± 6% in Cont, 40 ± 12% in MCT30 ( P < 0.05 vs. Cont), and 26 ± 6% in MCT80 ( P < 0.05 vs. Cont and MCT30) rats. In MCT30 rats, cardiac output was maintained, but RV volumes and filling pressures were significantly increased compared with Cont (all P < 0.05), indicating RV remodeling. In MCT80 rats, RV systolic pressure, volumes, and peak wall stress were further increased, and cardiac output was significantly decreased (all P < 0.05). However, RV end-systolic and end-diastolic stiffness were unchanged, consistent with the absence of interstitial fibrosis. MCT-induced pressure overload was associated with a dose-dependent development of RV hypertrophy. The most pronounced response to MCT was an overload-dependent increase of RV end-systolic and end-diastolic volumes, even under nonfailing conditions.
right ventricular hypertrophy; right ventricular failure; pressure-volume relations
Address for reprint requests and other correspondence: P. Steendijk, Dept. of Cardiology, C5-P, Leiden Univ. Medical Center, PO Box 9600, 2300 RC Leiden, The Netherlands (e-mail: p.steendijk{at}lumc.nl )
Background Marked changes in the prevalence of noncommunicable diseases such as obesity, diabetes, and cardiovascular disease have occurred in developed and developing countries in recent decades. ...The overarching aim of the study is to examine the relationship of societal influences on human lifestyle behaviors, cardiovascular risk factors, and incidence of chronic noncommunicable diseases. Methods The Prospective Urban Rural Epidemiology (PURE) study is a large-scale epidemiological study that plans to recruit approximately 140,000 individuals residing in >600 communities in 17 low-, middle-, and high-income countries around the world. Individual data collection includes medical history, lifestyle behaviors (physical activity and dietary profile), blood collection and storage for biochemistry and future genetic analysis, electrocardiogram, and anthropometric measures. In addition, detailed information is being collected with respect to 4 environmental domains of interest—the built environment, nutrition and associated food policy, psychosocial/socioeconomic factors, and tobacco environment. A minimum follow-up of 10 years is currently planned. Results This report describes the design, justification, and methodology of the PURE study. The PURE study has been recruiting since 2002 and has enrolled 139,506 individuals by March 31, 2009. Conclusions The PURE study builds on the work and experience gained through conduct of the INTERHEART study. Its design and extensive data collection are geared toward addressing major questions on causation and development of the underlying determinants of cardiovascular disease in populations at varying stages of epidemiologic transition.
Time to reimbursement (TTR) of new anticancer medicines differs between countries and contributes to unequal access. We aimed to investigate TTR of new anticancer medicines and explore factors ...influencing the reimbursement process in seven high-income European countries.
We carried out a retrospective case study of anticancer medicines with European Union Market Access (EU-MA) and a positive Committee for Medicinal Products for Human Use opinion from 2016 until 2021 with subsequent national reimbursement approval (NRA). The National Health Technology Assessment (HTA) and reimbursement websites of Germany, France, UK, the Netherlands, Belgium, Norway and Switzerland were used to identify TTR, defined as time from EU-MA to NRA. Additionally, we investigated medication-, country-, indication- and pharma-related factors potentially influencing TTR.
Thirty-five medicines were identified for which TTR ranged from -81 days to 2320 days (median 407 days). At data cut-off, 16 (46%) were reimbursed in all seven countries. Overall, the shortest TTR was in Germany (median 3 days, all medicines reimbursed <5 days). The time limit for reimbursement of 180 days stated by the Council of European Communities after the EU-MA (EU Transparency Directive) was met for 100% of included medicines in Germany, 51% in France, 29% in the UK and the Netherlands, 14% in Switzerland, 6% in Norway and 3% in Belgium. The TTR was significantly different between countries (P < 0.001). In multivariate analysis, factors associated with shorter TTR were higher gross domestic product (GDP), absence of a pre-assessment procedure and submission by a big pharmaceutical company.
TTR of anticancer medicines varies significantly between seven high-income European countries and leads to inequality in access. Among explored medication-, country-, indication- and pharma-related factors we found that a high GDP, the absence of a pre-assessment procedure and submission by big pharmaceutical companies were associated with shorter TTR.
•Time from approval to reimbursement for new anticancer medicines is long, even in most high-income European countries.•Large differences exist for TTR between seven high-income European countries.•Factors contributing to a short TTR are no pre-assessment procedure, high GDP and Big-12 pharmaceutical company medicines.
Introduction
Due to interindividual variation in desmopressin response, non‐severe haemophilia A patients require desmopressin testing prior to therapeutic treatment. However, adequate response or ...frequency of blood sampling is not standardised in international guidelines. Consequently, various definitions and blood sampling protocols are currently applied. Interestingly, sustainability of desmopressin response is not incorporated into these definitions.
Aim
To study desmopressin response rates in a cohort of non‐severe haemophilia A patients using currently accepted desmopressin response definitions. This, in order to formulate a standardised, uniform response which includes information on sustainability and to design a standardised blood sampling protocol.
Methods
Currently used desmopressin responses in non‐severe haemophilia A patients were derived from a literature search. Actual desmopressin response rates were individualised in 105 non‐severe HA patients from the Erasmus University Medical Centre and classified according to current varying definitions.
Results
Five response definitions were evaluated, three of which included only factor VIII (FVIII):C cut‐off levels and two also incorporated FVIII:C‐fold increase over baseline. FVIII:C‐fold increase showed no association with desmopressin response sustainability. FVIII:C 1 hour after infusion (<0.30, ≥0.30‐0.49, ≥0.50‐0.79 and ≥0.80 IU/mL) was, however, indicative of desmopressin response after 6 hours.
Conclusion
We suggest standardised desmopressin response based on clinically relevant FVIII:C levels, e.g. 0.30 and 0.50 IU/mL. In addition, patients with <0.30 IU/mL FVIII:C after 1 hour (non‐responder) or ≥0.80 IU/mL (sustained responder) do not require subsequent blood sampling. However, patients with ≥0.30‐0.79 IU/mL FVIII:C after 1 hour should undergo blood sampling after 6 hours to additionally determine response sustainability.
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