Ultrastructural development and cellular kinetics in intestinal epithelium

Despite the increased knowledge in the various fields of molecular biology the regulation of cell proliferation and differentiation in higher organisms has remained an intrigueing, complex problem in developmental biology. In some instances growth during embryonic or postnatal development is characterized by on increase in cell size without on accompanying increase in cell number like for instance in the postnatal development of cerebellum (Leblond1 1964). In most cases, however, growth is accompanied by an increase in cell number and a concurrent production of intercellular substance. In these so-called 11 expanding cell populations" the ability to divide is not restricted to a certain fraction of the population but nearly all cells ore able to proliferate as for instance during development or regeneration of liver. Cell renewing systems are characterized by an equilibrium between cell production and cell loss. Such systems are not only present during foetal development but they also occur in adult life. Examples are skin, mucous membranes, testis, bone marrow and intestinal epithelium. Such systems generally consist of a proliferative cell comportment, in which stem cells maybe present, a differentiation compartmP-nt where specific cellular characteristics are being developed and a functional compartment. These cell renewal systems have frequently been used for the study of regulation processes involved in cell proliferation and differentiation. More insight in these regulatory mechanisms are likely to contribute to the understanding of malignant cell growth

Work in progress: developing tools that support the design of easily maintainable rolling stock

Maintenance activities strongly influence the operational availability and life cycle costs of rolling stock. To achieve an effective and efficient maintenance process, it is essential that the design of the trains and its maintenance service are well-aligned. We conduct research on how the design of industrial equipment, such as rolling stock, and the design of its maintenance service influence the maintenance process. We use our findings for the development of methods and tools that support the use of maintenance knowledge in the equipment design process. An example of a past train development project shows that re- designing the mounting construction of a compressor has led to lower maintenance costs and a higher availability of both the trains and the maintenance resources. Based on such examples from industry and from findings in the literature, we expect that our research can contribute to better design decisions, which ultimately results in production systems that are cost-effective over their whole life tim

Towards structured integration of maintenance knowledge in industrial equipment design

Industrial equipment requires maintenance to remain operational. The level of maintenance that is required, and how easily it can be executed, is affected by the characteristics of the equipment. Therefore, design decisions have a strong influence on the effectiveness and efficiency of the maintenance process. Ideally, the design of the equipment should be aligned with the design of the maintenance service. Relevant knowledge about the relationships between them is available in both the literature and in practice. It is essential to bring this knowledge into the equipment design process, but suitable design support for this remains lacking. Therefore, we propose to conduct research on how this knowledge can be systematically integrated into the design process. The final goal of the research is to develop design support that leads to an improved quality of design decisions, so that production systems with an increased life cycle performance will be achieved

Exploring the reach and program use of Hello World, an email-based health promotion program for pregnant women in the Netherlands

<p>Abstract</p> <p>Background</p> <p>In 2006, the Dutch government initiated Hello World, an email-based program promoting healthy lifestyles among pregnant women through quizzes with pregnancy-related questions. In 2008, an updated version was released.</p> <p>The present study aimed to (1) examine the reach of Hello World and the representativeness of its users for all pregnant women in the Netherlands, (2) explore the relationship between program engagement and lifestyle characteristics, and (3) explore the relationship between the program content participants accessed (content on smoking, physical activity, and nutrition) and their lifestyle characteristics.</p> <p>Methods</p> <p>Data from 4,363 pregnant women were included. After registration, women received an online questionnaire with demographic and lifestyle questions. To evaluate their representativeness, their demographic characteristics were compared with existing data for Dutch (pregnant) women. Women were classified on the following lifestyle characteristics: smoking, nutrition, physical activity, and pre-pregnancy weight status. Program use was tracked and the relationships between lifestyle characteristics, program engagement, and the percentage of smoking, physical activity, and nutrition questions accessed after opening a quiz were explored using Mann–Whitney U tests and Kruskal-Wallis tests.</p> <p>Results</p> <p>Hello World reached ±4% of its target population. Ten percent of participants were low educated and 22% immigrants. On average, women received 6.1 (SD:2.8) quiz emails and opened 32% of the associated quizzes (2.0, SD:2.1). A significant positive association was found between the number of quizzes opened and the number of healthy lifestyle characteristics. After opening a quiz, women accessed most smoking, nutrition, and physical activity questions. Significant relationships were found between several lifestyle characteristics and the percentage of smoking, physical activity, and nutrition questions accessed. However, between-group differences were small, quiz topics were largely unrelated to their lifestyle characteristics, and inconsistencies were found regarding the directions of these associations.</p> <p>Conclusions</p> <p>Hello World reached ±4% of its target population, which is lower than the reach of its previous version (±8%). Relatively few low educated and immigrant women registered for the program. Active participation in the program was positively associated with the number of healthy behaviours participants engaged in. The program content participants chose to access was largely unrelated to their lifestyle characteristics.</p

Replication history of B lymphocytes reveals homeostatic proliferation and extensive antigen-induced B cell expansion

The contribution of proliferation to B lymphocyte homeostasis and antigen responses is largely unknown. We quantified the replication history of mouse and human B lymphocyte subsets by calculating the ratio between genomic coding joints and signal joints on kappa-deleting recombination excision circles (KREC) of the IGK-deleting rearrangement. This approach was validated with in vitro proliferation studies. We demonstrate that naive mature B lymphocytes, but not transitional B lymphocytes, undergo in vivo homeostatic proliferation in the absence of somatic mutations in the periphery. T cell–dependent B cell proliferation was substantially higher and showed higher frequencies of somatic hypermutation than T cell–independent responses, fitting with the robustness and high affinity of T cell–dependent antibody responses. More extensive proliferation and somatic hypermutation in antigen-experienced B lymphocytes from human adults compared to children indicated consecutive responses upon additional antigen exposures. Our combined observations unravel the contribution of proliferation to both B lymphocyte homeostasis and antigen-induced B cell expansion. We propose an important role for both processes in humoral immunity. These new insights will support the understanding of peripheral B cell regeneration after hematopoietic stem cell transplantation or B cell–directed antibody therapy, and the identification of defects in homeostatic or antigen-induced B cell proliferation in patients with common variable immunodeficiency or another antibody deficiency

A systematic review of the cost-effectiveness of worksite physical activity and/or nutrition programs

Objective The aim of this study was to appraise and summarize the evidence on the cost-effectiveness of worksite physical activity and/or nutrition programs. Methods We searched EMBASE, MEDLINE, SportDiscus, PsycInfo, NIOSHTIC-2, NHSEED, HTA, and Econlit for studies published up to 14 January 2011. Additionally, we searched for articles by reviewing references, searching authors' databases, and contacting authors of included studies. Two researchers independently selected articles. Articles had to include a cost-effectiveness and/or cost-utility analysis comparing a worksite physical activity and/or nutrition program to usual care or an abridged version of the program. Data were extracted on study characteristics and results. Two researchers independently assessed the risk of bias using the Consensus on Health Economic Criteria list (CHEC-list). Results Ten studies (18 programs) were included. More than 50% of the studies fulfilled 11 (58%) of the 19 CHEC-list items. From various perspectives, worksite nutrition and worksite physical activity and nutrition programs (N=6) were more costly and more effective in reducing body weight than usual care. When only intervention costs were considered, most worksite nutrition (N=4/5) and worksite physical activity and nutrition programs (N=5/6) were more costly and more effective in reducing cholesterol level and cardiovascular disease risks, respectively. Conclusions The cost-effectiveness of more costly and more effective programs depends on the "willingness to pay" for their effects. It is unknown how much decision-makers are willing to pay for reductions in body weight, cholesterol level, and cardiovascular disease risks. Therefore, conclusions about the cost-effectiveness of worksite physical activity and/or nutrition programs cannot be made. There is substantial need for improvement of the methodological quality of studies and particular emphasis should be placed on the handling of uncertainty. This work is licensed under a Creative Commons Attribution 4.0 International License

Effectiveness and cost-effectiveness of a blended exercise intervention for patients with hip and/or knee osteoarthritis:Study protocol of a randomized controlled trial

Background Exercise therapy in patients with hip and/or knee osteoarthritis is effective in reducing pain, increasing physical activity and physical functioning, but costly and a burden for the health care budget. A web-based intervention is cheap in comparison to face-to-face exercise therapy and has the advantage of supporting in home exercises because of the 24/7 accessibility. However, the lack of face-to-face contact with a professional is a disadvantage of web-based interventions and is probably one of the reasons for low adherence rates. In order to combine the best of two worlds, we have developed the intervention e-Exercise. In this blended intervention face-to-face contacts with a physical therapist are partially replaced by a web-based exercise intervention. The aim of this study is to investigate the short- (3 months) and long-term (12 months) (cost)-effectiveness of e-Exercise compared to usual care physical therapy. Our hypothesis is that e-Exercise is more effective and cost-effective in increasing physical functioning and physical activity compared to usual care. Methods/Design This paper presents the protocol of a prospective, single-blinded, multicenter cluster randomized controlled trial. In total, 200 patients with OA of the hip and/or knee will be randomly allocated into either e-Exercise or usual care (physical therapy). E-Exercise is a 12-week intervention, consisting of maximum five face-to-face physical therapy contacts supplemented with a web-based program. The web-based program contains assignments to gradually increase patients’ physical activity, strength and stability exercises and information about OA related topics. Primary outcomes are physical activity and physical functioning. Secondary outcomes are health related quality of life, self-perceived effect, pain, tiredness and self-efficacy. All measurements will be performed at baseline, 3 and 12 months after inclusion. Retrospective cost questionnaires will be sent at 3, 6, 9 and 12 months and used for the cost-effectiveness and cost-utility analysis. Discussion This study is the first randomized controlled trial in the (cost)-effectiveness of a blended exercise intervention for patients with osteoarthritis of the hip and/or knee. The findings will help to improve the treatment of patients with osteoarthritis. Keywords: Osteoarthritis, Physical activity, Blended care e-Healt

Ig heavy chain gene rearrangements in T-cell acute lymphoblastic leukemia exhibit predominant DH6-19 and DH7-27 gene usage, can result in complete V-D-J rearrangements, and are rare in T-cell receptor αβ lineage

Rearranged IGH genes were detected by Southern blotting in 22% of 118 cases of T-cell acute lymphoblastic leukemia (ALL) and involved monoallelic and biallelic rearrangements in 69% (18/26) and 31% (8/26) of these cases, respectively. IGH gene rearrangements were found in 19% (13/69) of CD3- T- ALL and in 50% of TCRγδ+ T-ALL (12/24), whereas only a single TCRαβ+ T- ALL (1/25) displayed a monoallelic IGH gene rearrangement. The association with the T-cell receptor (TCR) phenotype was further supported by the striking relationship between IGH and TCR delta (TCRD) gene rearrangements, ie, 32% of T-ALL (23/72) with monoallelic or biallelic TCRD gene rearrangements had IGH gene rearrangements, whereas only 1 of 26 T-ALL with biallelic TCRD gene deletions contained a monoallelic IGH gene rearrangement. Heteroduplex polymerase chain reaction (PCR) analysis with VH and DH family- specific primers in combination with a JH consensus primer showed a total of 39 clonal products, representing 7 (18%) VH-(DH-)JH joinings and 32 (82%) DH- JH rearrangements. Whereas the usage of VH gene segments was seemingly random, preferential usage of DH6-19 (45%) and DH7-27 (21%) gene segments was observed. Although the JH4 and JH6 gene segments were used most frequently (33% and 21%, respectively), a significant proportion of joinings (28%) used the most upstream JH1 and JH2 gene segments, which are rarely used in precursor-B-ALL and normal B cells (1% to 4%). In conclusion, the high frequency of incomplete DH-JH rearrangements, the frequent usage of the more downstream DH6-19 and DH7-27 gene segments, and the most upstream JH1 and JH2 gene segments suggests a predominance of immature IGH rearrangements in immature (non-TCRαβ+) T-ALL as a result of continuing V(D)J recombinase activity. More mature αβ-lineage T-ALL with biallelic TCRD gene deletions apparently have switched off their recombination machinery and are less prone to cross-lineage IGH gene rearrangements. The combined results indicate that IGH gene rearrangements in T-ALL are postoncogenic processes, which are absent in T-ALL with deleted TCRD genes and completed TCR alpha (TCRA) gene rearrangements.</p

Involvement of Artemis in nonhomologous end-joining during immunoglobulin class switch recombination

DNA double-strand breaks (DSBs) introduced in the switch (S) regions are intermediates during immunoglobulin class switch recombination (CSR). These breaks are subsequently recognized, processed, and joined, leading to recombination of the two S regions. Nonhomologous end-joining (NHEJ) is believed to be the principle mechanism involved in DSB repair during CSR. One important component in NHEJ, Artemis, has however been considered to be dispensable for efficient CSR. In this study, we have characterized the S recombinational junctions from Artemis-deficient human B cells. Sμ–Sα junctions could be amplified from all patients tested and were characterized by a complete lack of “direct” end-joining and a remarkable shift in the use of an alternative, microhomology-based end-joining pathway. Sμ–Sγ junctions could only be amplified from one patient who carries “hypomorphic” mutations. Although these Sμ–Sγ junctions appear to be normal, a significant increase of an unusual type of sequential switching from immunoglobulin (Ig)M, through one IgG subclass, to a different IgG subclass was observed, and the Sγ–Sγ junctions showed long microhomologies. Thus, when the function of Artemis is impaired, varying modes of CSR junction resolution may be used for different S regions. Our findings strongly link Artemis to the predominant NHEJ pathway during CSR