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Throughout history, Dutch maritime endeavours have been sparked by political, economic, military and sociocultural factors. This article focuses on the relationship between religion and maritime entrepreneurship in the Dutch Republic during the Early Modern period, at sea and in overseas territories. For almost two centuries, the deputies of a number of classis assemblies (departments) of the Dutch Reformed Church corresponded with representatives of the Dutch East and West India Companies and with merchant associations trading with Russia, the Baltic, and the Eastern Mediterranean, but also with the board members of the five admiralties in the Netherlands. This article is about the performance of the deputies within the framework of their global maritime and Dutch Reformed network; the construction of this network within the maritime communities in the Republic and abroad; and about the results of the deputies' involvement. [ABSTRACT FROM AUTHOR]

Abstract Background Type 2 diabetes mellitus is a complex, progressive disease which requires a variety of quality improvement strategies. Limited information is available on the feasibility and effectiveness of interdisciplinary diabetes care teams (IDCT) operating on the interface between primary and specialty care. A first study hypothesis was that the implementation of an IDCT is feasible in a health care setting with limited tradition in shared care. A second hypothesis was that patients who make use of an IDCT would have significantly better outcomes compared to non-users of the IDCT after an 18-month intervention period. A third hypothesis was that patients who used the IDCT in an Advanced quality Improvement Program (AQIP) would have significantly better outcomes compared to users of a Usual Quality Improvement Program (UQIP). Methods This investigation comprised a two-arm cluster randomized trial conducted in a primary care setting in Belgium. Primary care physicians (PCPs, n = 120) and their patients with type 2 diabetes mellitus (n = 2495) were included and subjects were randomly assigned to the intervention arms. The IDCT acted as a cornerstone to both the intervention arms, but the number, type and intensity of IDCT related interventions varied depending upon the intervention arm. Results Final registration included 67 PCPs and 1577 patients in the AQIP and 53 PCPs and 918 patients in the UQIP. 84% of the PCPs made use of the IDCT. The expected participation rate in patients (30%) was not attained, with 12,5% of the patients using the IDCT. When comparing users and non-users of the IDCT (irrespective of the intervention arm) and after 18 months of intervention the use of the IDCT was significantly associated with improvements in HbA1c, LDL-cholesterol, an increase in statins and anti-platelet therapy as well as the number of targets that were reached. When comparing users of the IDCT in the two intervention arms no significant differences were noted, except for anti-platelet therapy. Conclusion IDCT's operating on the interface between primary and specialty care are associated with improved outcomes of care. More research is required on what team and program characteristics contribute to improvements in diabetes care. Trial registration NTR 1369.

Abstract Objective To evaluate the barriers and facilitators to high-quality diabetes care as experienced by general practitioners (GPs) who participated in an 18-month quality improvement program (QIP). This QIP was implemented to promote compliance with international guidelines. Methods Twenty out of the 120 participating GPs in the QIP underwent semi-structured interviews that focused on three questions: 'Which changes did you implement or did you observe in the quality of diabetes care during your participation in the QIP?' 'According to your experience, what induced these changes?' and 'What difficulties did you experience in making the changes?' Results Most GPs reported that enhanced knowledge, improved motivation, and a greater sense of responsibility were the key factors that led to greater compliance with diabetes care guidelines and consequent improvements in diabetes care. Other factors were improved communication with patients and consulting specialists and reliance on diabetes nurse educators. Some GPs were reluctant to collaborate with specialists, and especially with diabetes educators and dieticians. Others blamed poor compliance with the guidelines on lack of time. Most interviewees reported that a considerable minority of patients were unwilling to change their lifestyles. Conclusion Qualitative research nested in an experimental trial may clarify the improvements that a QIP may bring about in a general practice, provide insight into GPs' approach to diabetes care and reveal the program's limits. Implementation of a QIP encounters an array of cognitive, motivational, and relational obstacles that are embedded in a patient-healthcare provider relationship.

Age-related macular degeneration (AMD) is an age-related disorder that is a global public health problem. The non-enzymatic Maillard reaction results in the formation of advanced glycation end products (AGEs). Accumulation of AGEs in drusen plays a key role in AMD. AGE-reducing drugs may contribute to the prevention and treatment of AGE-related disease. Fructosamine oxidase (FAOD) acts on fructosyl lysine and fructosyl valine. Based upon the published results of fructosamine 3-kinase (FN3K) and FAOD obtained in cataract and presbyopia, we studied ex vivo FAOD treatment as a non-invasive AMD therapy. On glycolaldehyde-treated porcine retinas, FAOD significantly reduced AGE autofluorescence ( p = 0.001). FAOD treatment results in a breakdown of AGEs, as evidenced using UV fluorescence, near-infrared microspectroscopy on stained tissue sections of human retina, and gel permeation chromatography. Drusen are accumulations of AGEs that build up between Bruch's membrane and the retinal pigment epithelium. On microscopy slides of human retina affected by AMD, a significant reduction in drusen surface to 45 ± 21% was observed following FAOD treatment. Enzymatic digestion followed by mass spectrometry of fructose- and glucose-based AGEs (produced in vitro) revealed a broader spectrum of substrates for FAOD, as compared to FN3K, including the following: fructosyllysine, carboxymethyllysine, carboxyethyllysine, and imidazolone. In contrast to FN3K digestion, agmatine (4-aminobutyl-guanidine) was formed following FAOD treatment in vitro. The present study highlights the therapeutic potential of FAOD in AMD by repairing glycation-induced damage.

p120 catenin (p120ctn) is required for the stability of classic cadherins at the cell surface and is thought to play a central role in modulating cell-cell adhesion. Cytoplasmic p120ctn promotes cell motility, and probably other activities, by modulating the activities of RhoA, Rac and Cdc42. E-cadherin is expressed in periportal but not in perivenous hepatocytes. In contrast, all hepatocytes of normal mouse liver express N-cadherin. Cholangiocytes express exclusively E-cadherin. Mice with p120ctn ablation in hepatocytes and cholangiocytes (p120LiKO mice) were generated by Cre-loxP technology. Livers were examined by histological, immunohistochemical, ultrastructural and serum analysis to determine the effect of the p120ctn ablation on liver structure and function. Mouse hepatocyte differentiation and homeostasis were not impaired. However, hepatoblasts differentiated abnormally into hybrid hepato-biliary cells, ductal plate structures were irregular in p120LiKO newborns, and further development of intrahepatic bile ducts was severely impaired. In adults, enrichment of ductular structures was accompanied by portal inflammation and fibrosis. p120LiKO mice did not spontaneously develop hepatocellular carcinoma but initiation of hepatocarcinogenesis by diethylnitrosamine was accelerated. In summary: p120ctn has a critical role in biliary differentiation and is a potent suppressor of liver tumor growth., (Copyright © 2016 Elsevier GmbH. All rights reserved.)

Introduction: The Attitudes to Aging Questionnaire (AAQ) was developed to measure attitudes toward the aging process as a personal experience from the perspective of older people. The present study aimed to validate the French version of the AAQ. Participants and methods: This study examined factor structure, acceptability, reliability and validity of the AAQ's French version in 238 Belgian adults aged 60 years or older. In addition, participants provided information on demographics, self-perception of their mental and physical health (single items), quality of life (WHOQOL-OLD) and social desirability (DS-36). Results: Exploratory Factor Analysis produced a three-factor solution accounting for 36.9% of the variance. No floor or ceiling effects were found. The internal consistency, measured by Cronbach's alpha coefficients for the AAQ subscales were 0.62 (Physical Change), 0.74 (Psychological Growth), and 0.75 (Psychosocial Loss). A priori expected associations were found between AAQ subscales, self-reported health and quality of life, indicating good convergent validity. The scale also showed a good ability to discriminate between people with lower and higher education levels, supporting adequate known-groups validity. Finally, we confirmed the need to control for social desirability biases when assessing self-reported attitudes toward one's own aging. Conclusion: The data support the usefulness of the French version of the AAQ for the assessment of attitudes toward their own aging in older people.

Aims: To analyse whether care trajectories (CT) were associated with increased prevalence of parenteral hypoglycemic treatment (PHT=insulin or GLP-1 analogues), statin therapy or RAAS-inhibition. Introduced in 2009 in Belgium, CTs target patients with type 2 diabetes mellitus (T2DM), in need for or with PHT., Methods: Retrospective study based on a registry with 97 general practitioners. The evolution in treatment since 2006 was compared between patients with vs. without a CT, using longitudinal logistic regression., Results: Comparing patients with (N=271) vs. without a CT (N=4424), we noted significant differences (p<0.05) in diabetes duration (10.1 vs. 7.3 years), HbA1c (7.5 vs. 6.9%), LDL-C (85 vs. 98mg/dl), microvascular complications (26 vs. 16%). Moreover, in 2006, parenteral treatment (OR 52.1), statins (OR 4.1) and RAAS-inhibition (OR 9.6) were significantly more prevalent (p<0.001). Between 2006 and 2011, the prevalence rose in both groups regarding all three treatments, but rose significantly faster (p<0.05) after 2009 in the CT-group., Conclusions: Patients enrolled in a CT differ from other patients even before the start of this initiative with more intense hypoglycemic and cardiovascular treatment. Yet, they presented higher HbA1c-levels and more complications. Enrolment in a CT is associated with additional treatment intensification., (Copyright © 2015 Primary Care Diabetes Europe. Published by Elsevier Ltd. All rights reserved.)

Background: Although older cancer survivors commonly report psychosocial problems, the impact of both cancer and ageing on the occurrence of these problems remains largely unknown. The evolution of depression, cognitive functioning, and fatigue was evaluated in a group of older cancer patients in comparison with a group of younger cancer patients and older persons without cancer., Methods: Older (≥70 years) and younger cancer patients (50-69 years) with breast or colorectal cancer stage I-III, and older persons without cancer (≥70 years) were included. Data were collected at baseline and one year follow-up and were available for 536 persons. Depression was evaluated with the 15-item Geriatric Depression Scale. Cognitive functioning was measured with the cognitive functioning subscale of the European Organization for Research and Treatment of Cancer. Fatigue was measured with a Visual Analogue Scale. Risk factors for depression, cognitive functioning, and fatigue were analysed using multivariate logistic regression analyses. Risk factors included cancer- and ageing-related factors such as functional status, cancer treatment, and comorbidities., Results: The evolution of psychosocial problems was similar for the group of older (N = 125) and younger cancer patients (N = 196): an increase in depression (p < 0.01), slight worsening in cognitive functioning (p = 0.01), and no clear change in fatigue. Also, compared to the group of people without cancer (N = 215), the differences were small and after one year of follow-up only depression was more frequent in older cancer patients compared to older persons without cancer (18% versus 9%, p = 0.04). In multivariate analyses the main risk factors for psychosocial problems after one year follow-up were changes in functional status and presence of baseline depression, fatigue, or cognitive impairment., Conclusion: Over the course of one year after a diagnosis of cancer, cancer patients face increasing levels of depression and increasing difficulties in cognitive functioning. The main risk factor for psychosocial problems was presence of the problem at baseline. This calls for regular screening for psychosocial problems and exchange of information on psychosocial functioning between different health care providers and settings during the treatment and follow-up trajectory of cancer patients.

The conserved alphaherpesvirus US3 tegument protein induces rearrangements of the actin cytoskeleton, consisting of protrusion formation and stress fiber breakdown. Although US3 does not affect levels of total actin protein, it remains unclear whether US3 modulates the total levels of filamentous (F) actin. In this report, we show that the pseudorabies virus (PRV) US3 protein, via its kinase activity, leads to disassembly of F-actin in porcine ST cells. F-actin disassembly has been reported before to contribute to host cell entry of HIV. In line with this, in the current study, we report that US3 has a previously uncharacterized role in viral genome delivery to the nucleus, since quantitative polymerase chain reaction (qPCR) assays on nuclear fractions demonstrated a reduced nuclear delivery of US3null PRV compared to wild type PRV genomes. Treatment of cells with the actin depolymerizing drug cytochalasin D enhanced virus genome delivery to the nucleus, particularly of US3null PRV, supporting a role for F-actin disassembly during certain aspects of viral entry. In conclusion, the US3 kinase of PRV leads to F-actin depolymerization, and US3 and F-actin disassembly contribute to viral genome delivery to the nucleus., (Copyright © 2015 Elsevier B.V. All rights reserved.)

Rho GTPases are key regulators of actin and microtubule dynamics and organization. Increasing evidence shows that many viruses have evolved diverse interactions with Rho GTPase signaling and manipulate them for their own benefit. In this review, we discuss how Rho GTPase signaling interferes with many steps in the viral replication cycle, especially entry, replication, and spread. Seen the diversity between viruses, it is not surprising that there is considerable variability in viral interactions with Rho GTPase signaling. However, several largely common effects on Rho GTPases and actin architecture and microtubule dynamics have been reported. For some of these processes, the molecular signaling and biological consequences are well documented while for others we just begin to understand them. A better knowledge and identification of common threads in the different viral interactions with Rho GTPase signaling and their ultimate consequences for virus and host may pave the way toward the development of new antiviral drugs that may target different viruses.

Objectives: To picture the 10-year evolution of renal function in patients with type 2 diabetes mellitus (T2DM) and chronic kidney disease (CKD) and to describe the risk factors for severe decline., Setting: Primary registration network with 97 general practitioners working in 55 practices sending routinely collected patient data., Participants: From the database, we selected all patients aged 40 years or older with T2DM and at least two creatinine measurements in two different years with an interval of at least 3 months. Based on the last available value of estimated glomerular filtration rate calculated by the modification of diet in renal disease (MDRD) equation, patients were divided into grades of CKD. Severe decline (decline of >4 mL/min/year) and 'certain drop' (CD, year-to-year decline >10 mL/min) were determined in patients with CKD. Determinants of severe decline and CD were investigated with logistic regression and longitudinal logistic regression analysis, respectively., Primary Outcome Measure: Kidney function (MDRD)., Results: 4041 patients, 1980 women, were included. The mean age was 71 years, mean diabetes duration was 7.7 years; 1514 (38%) suffered from CKD, 231 (15%) presented with severe decline and 18% of the patients with CKD presented with two or more CDs. Younger age, male gender, mean glycated haemoglobin and a higher number of CDs were significantly associated with the presence of severe decline (p<0.05); statins and higher diastolic blood pressure were significantly associated with the absence of severe decline (p<0.001). ACE inhibitors, other antihypertensive drugs and antidiabetic drugs including insulin therapy were specific determinants of CD., Conclusions: CKD is highly prevalent in patients with T2DM; a minority of patients evolve into severe decline that is associated with younger age, male gender, 'CD' and manageable factors such as blood pressure, blood glucose, associated drugs prescriptions and statin therapy. Further prospective observational and experimental research is needed to clarify the nature of those associations.

The conserved alphaherpesviral serine/threonine kinase US3 causes dramatic actin rearrangements, associated with increased viral spread. Here, we show that US3 of pseudorabies virus (PRV) leads to activation (dephosphorylation) of the central actin regulator cofilin. A mutation that impairs US3 kinase activity and the group I p21-activated kinase inhibitor IPA-3 inhibited US3-mediated cofilin activation. Additionally, expression of phosphomimetic S3D cofilin significantly suppressed the ability of US3 to cause cell projections and cell rounding. In conclusion, the US3 kinase of PRV leads to activation (dephosphorylation) of cofilin, and cofilin contributes to US3-mediated actin rearrangements.

We have previously shown that the porcine alphaherpesvirus pseudorabies virus (PRV) efficiently interferes with phosphorylation of the eukaryotic translation initiation factor eIF2α. Inhibition of phosphorylation of eIF2α has been reported earlier for the closely related alphaherpesvirus herpes simplex virus 1 (HSV-1) through its ICP34.5 and US11 proteins. PRV, however, does not encode an ICP34.5 or US11 orthologue. Assays using cycloheximide, UV-inactivated PRV, or phosphonoacetic acid (PAA) showed that de novo expression of one or more (immediate) early viral protein(s) is required for interference with eIF2α phosphorylation. In line with this, a time course assay showed that eIF2α phosphorylation was abolished within 2 h after PRV inoculation. PRV encodes only one immediate-early protein, IE180, the orthologue of HSV-1 ICP4. As reported earlier, a combinational treatment of cells with cycloheximide and actinomycin D allowed expression of IE180 without detectable expression of the US3 early protein in PRV-infected cells. This led to a substantial reduction in eIF2α phosphorylation levels, indicative for an involvement of IE180. In support of this, transfection of IE180 also potently reduced eIF2α phosphorylation. IE180-mediated interference with eIF2α phosphorylation was not cell type dependent, as it occurred both in rat neuronal 50B11 cells and in swine testicle cells. Inhibition of the cellular phosphatase PP1 impaired PRV-mediated interference with eIF2α phosphorylation, indicating that PP1 is involved in this process. In conclusion, the immediate-early IE180 protein of PRV has the previously uncharacterized ability to suppress phosphorylation levels of the eukaryotic translation initiation factor eIF2α.

The US3 protein is a unique protein kinase only present in the Alphaherpesvirinae subfamily of the herpesviruses. Studies performed with several alphaherpesviruses demonstrated that the US3 protein is involved in cytoskeleton modifications during viral infection and displays anti-apoptotic activity. However, the US3 protein of BoHV-5 has not been studied up to now. As reported for other alphaherpesviruses, our results showed that BoHV-5 US3 confers resistance against apoptosis and induces cytoskeletal reorganization leading to cell rounding, actin stress fiber breakdown and cell projections that interconnect cells. The expression of a kinase-dead version of BoHV-5 US3 showed that the anti-apoptotic activity and the induction of cell projections are kinase-dependent whereas kinase activity is not absolutely required for actin stress fiber breakdown. Besides, the kinase-dead version of US3, but not the wild type protein, was found excluded from the nucleus. These results constitute the first report on the BoHV-5 US3 functions, and highlight that there are functional differences and similarities among US3 proteins of different alphaherpesviruses., (Copyright © 2011 Elsevier B.V. All rights reserved.)

Herpesviruses constitute a very large and diverse family of DNA viruses, which can generally be subdivided in alpha-, beta- and gammaherpesvirus subfamilies. Increasing evidence indicates that many herpesviruses interact with cytoskeleton-regulating Rho GTPase signaling pathways during different phases of their replication cycle. Because of the large differences between herpesvirus subfamilies, the molecular mechanisms and specific consequences of individual herpesvirus interactions with Rho GTPase signaling may differ. However, some evolutionary distinct but similar general effects on Rho GTPase signaling and the cytoskeleton have also been reported. Examples of these include Rho GTPase-mediated nuclear translocation of virus during entry in a host cell and Rho GTPase-mediated viral cell-to-cell spread during later stages of infection. The current review gives an overview of both general and individual interactions of herpesviruses with Rho GTPase signaling.

Phosphorylation represents one the most abundant and important posttranslational modifications of proteins, including viral proteins. Virus-encoded serine/threonine protein kinases appear to be a feature that is unique to large DNA viruses. Although the importance of these kinases for virus replication in cell culture is variable, they invariably play important roles in virus virulence. The current review provides an overview of the different viral serine/threonine protein kinases of several large DNA viruses and discusses their function, importance, and potential as antiviral drug targets.

Background: Because many patients in usual care reach the diabetes treatment goals, it may be more efficacious to focus quality improvement efforts on those general practice populations requiring additional support. We therefore developed a tool based on a composite end point considering blood pressure, lipids, and glycaemia., Methods: We created an aggregated z(A)-score, calculated as the average of 3 z-scores testing whether the mean practice values of hemoglobin A1c, low density lipoprotein cholesterol, and systolic blood pressure are significantly higher than the corresponding ADA-target (respectively 7%, 100 mg/dL, and 130 mm Hg). This score was used with 100 general practitioners who participated in a Quality Improvement Program. We defined the cut-off value (COV) to determine "Practices Requiring Support" (z(A)

Two major structural elements of a cell are the cytoskeleton and the lipid membranes. Actin and cholesterol are key components of the cytoskeleton and membranes, respectively, and are involved in a plethora of different cellular processes. This review summarizes and discusses the interaction of alphaherpesviruses with actin and cholesterol during different stages of the replication cycle: virus entry, replication and assembly in the nucleus, and virus egress. Elucidating these interactions not only yields novel insights into the biology of these important pathogens, but may also shed new light on cell biological aspects of actin and cholesterol, and lead to novel avenues in the design of antiviral strategies., (Copyright 2010 Elsevier B.V. All rights reserved.)

Aims: To evaluate the effectiveness of a two-arm quality improvement program (QIP) to support general practice with limited tradition in chronic care on type 2 diabetes patient outcomes., Methods: During 18 months, we performed a cluster randomized trial with randomization of General Practices. The usual QIP (UQIP: 53 GPs, 918 patients) merged standard interventions including evidence-based treatment protocol, annual benchmarking, postgraduate education, case-coaching for GPs and patient education. The advanced QIP (AQIP: 67 GPs, 1577 patients) introduced additional interventions focussing on intensified follow-up, shared care and patient behavioural changes. Main outcomes were HbA1c, systolic blood pressure (SBP), and low density lipoprotein cholesterol (LDL-C), analyzed by generalized estimating equations and linear mixed models., Results: In UQIP, endpoints improved significantly after intervention: HbA1c -0.4%, 95% CI [-0.4; -0. 3]; SBP -3mmHg, 95% CI [-4; -1]; LDL-C -13mg/dl, 95% CI [-15; -11]. In AQIP, there were no significant additional improvements in outcomes: HbA1c -0.4%, 95% CI [-0.4; -0.3]; SBP -4mmHg, 95% CI [-5; -2]; LDL-C -14mg/dl, 95% CI [-15; -11]., Conclusions: A multifaceted program merging standard interventions in support of general practice induced significant improvements in the quality of diabetes care. Intensified follow-up in AQIP with focus on shared care and patient behaviour changes did not yield additional benefit.

p21-activated protein kinases (Paks) are cytosolic serine/threonine protein kinases that act as effectors for small (p21) GTPases of the Cdc42 and Rac families. It has long been established that Paks play a major role in a host of vital cellular functions such as proliferation, survival and motility, and abnormal Pak function is associated with a number of human diseases. Here, we discuss emerging evidence that these enzymes also play a major role in the entry, replication and spread of many important pathogenic human viruses, including HIV. Careful assessment of the potential role of Paks in antiviral immunity will be pivotal to evaluate thoroughly the potential of agents that inhibit Pak as a new class of anti-viral therapeutics.

Many herpesviruses interfere with the MHC I antigen-processing pathway in order to limit elimination by cytotoxic T-lymphocytes. For varicelloviruses, the largest subgroup of alphaherpesviruses, two viral proteins have been reported to downregulate MHC I cell surface expression: UL49.5 for BoHV-1, PRV, and EHV-1 and the US3 orthologue for VZV. Here, we report that PRV reduces MHC I cell surface expression during infection in a cell-type-dependent manner. In ST cells, a kinase-active US3 was necessary but not sufficient to downregulate cell surface MHC I expression, whereas US3 was not required in PK-15 cells and porcine alveolar macrophages (PAM). MHC I downregulation was not (PAM, ST) or only partly (PK-15) dependent on UL49.5. In conclusion, we show that the mechanism(s) of PRV-mediated cell surface MHC I downregulation are cell-type-dependent, with variable roles for US3, UL49.5, and additional, yet unidentified early viral proteins.

The US3 protein is a viral serine/threonine kinase that is conserved among all members of the Alphaherpesvirinae. The US3 protein of different alphaherpesviruses causes dramatic alterations in the actin cytoskeleton, such as the disassembly of actin stress fibers and formation of cell projections, which have been associated with increased intercellular virus spread. Here, we find that inhibiting group A p21-activated kinases (PAKs), which are key regulators in Cdc42/Rac1 Rho GTPase signaling pathways, impairs US3-mediated actin alterations. By using PAK1(-/-) and PAK2(-/-) mouse embryo fibroblasts (MEFs), we show that US3-mediated stress fiber disassembly requires PAK2, whereas US3-mediated cell projection formation mainly is mediated by PAK1, also indicating that PAK1 and PAK2 can have different biological effects on the organization of the actin cytoskeleton. In addition, US3 was found to bind and phosphorylate group A PAKs. Lack of group A PAKs in MEFs was correlated with inefficient virus spread. Thus, US3 induces its effect on the actin cytoskeleton via group A PAKs.

Different viruses exploit the host cytoskeleton to facilitate replication and spread. The conserved US3 protein of the alphaherpesvirus pseudorabies virus induces actin stress fiber disassembly and formation of actin-containing cell projections, which are associated with enhanced intercellular virus spread. Proteins of members of other virus families, notably vaccinia virus F11L protein and human immunodeficiency virus Nef protein, induce actin rearrangements that are very similar to those induced by US3. Interestingly, unlike F11L and Nef, the US3 protein displays serine/threonine kinase activity. Here, we report that the kinase activity of pseudorabies virus US3 is absolutely required for its actin modulating activity. These data show that different viruses have developed independent mechanisms to induce very similar actin rearrangements.

Background: Most quality improvement programs in diabetes care incorporate aspects of clinician education, performance feedback, patient education, care management, and diabetes care teams to support primary care physicians. Few studies have applied all of these dimensions to address clinical inertia., Aim: To evaluate interventions to improve adherence to evidence-based guidelines for diabetes and reduce clinical inertia in primary care physicians., Design: Two-arm cluster randomized controlled trial., Participants: Primary care physicians in Belgium., Interventions: Primary care physicians will be randomly allocated to 'Usual' (UQIP) or 'Advanced' (AQIP) Quality Improvement Programs. Physicians in the UQIP will receive interventions addressing the main physician, patient, and office system factors that contribute to clinical inertia. Physicians in the AQIP will receive additional interventions that focus on sustainable behavior changes in patients and providers., Outcomes: Primary endpoints are the proportions of patients within targets for three clinical outcomes: 1) glycosylated hemoglobin < 7%; 2) systolic blood pressure differences < or =130 mmHg; and 3) low density lipoprotein/cholesterol < 100 mg/dl. Secondary endpoints are individual improvements in 12 validated parameters: glycosylated hemoglobin, low and high density lipoprotein/cholesterol, total cholesterol, systolic blood pressure, diastolic blood pressure, weight, physical exercise, healthy diet, smoking status, and statin and anti-platelet therapy. PRIMARY AND SECONDARY ANALYSIS: Statistical analyses will be performed using an intent-to-treat approach with a multilevel model. Linear and generalized linear mixed models will be used to account for the clustered nature of the data, i.e., patients clustered withinimary care physicians, and repeated assessments clustered within patients. To compare patient characteristics at baseline and between the intervention arms, the generalized estimating equations (GEE) approach will be used, taking the clustered nature of the data within physicians into account. We will also use the GEE approach to test for differences in evolution of the primary and secondary endpoints for all patients, and for patients in the two interventions arms, accounting for within-patient clustering.

The vitamin D binding protein (DBP) is the major carrier protein for vitamin D metabolites in plasma. Polymorphisms in DBP have been described to be associated with an increased bone fracture risk and diabetes. The present study investigates the influence of both phenotypic and (TAAA)(n)-Alu repeat DBP-polymorphism and DBP-concentration on bone mineral density, body composition, bone turnover- and metabolic markers in a cohort of ambulatory elderly men. We included 211 men (>70 years) in this study. Bone mineral density (BMD) was determined by dual energy X-ray absorptiometry. Bone turnover was assessed by measurement of serum osteocalcin, serum and urinary C-terminal telopeptides of type I collagen and urinary deoxypyridinoline, together with 25(OH)-vitamin D and 1,25(OH)(2)-vitamin D concentrations. DBP-phenotypes were determined electrophoretically and the (TAAA)(n)-Alu repeat polymorphism was determined by polymerase chain reaction. Body composition was estimated using bioelectrical impedance analysis, together with handgrip and arm strength, fasting serum glucose and leptin concentrations. No differences in BMD or bone turnover markers among DBP-phenotypes or (TAAA)(n)-genotypes were observed in this study. Serum 25(OH)-vitamin D was comparable among DBP-variants and did not relate to DBP-concentrations, whereas 1,25(OH)(2)-vitamin D was different among DBP-phenotypes and was correlated positively with DBP-concentrations. DBP-concentrations related positively to body mass index, fat mass, leptin and glucose concentration. The correlation with leptin remained significant after correction for fat mass. Fasting glucose concentrations were different among DBP-phenotypes, whereas no difference was observed between (TAAA)(n)-genotypes. In conclusion, serum 1,25(OH)(2)-vitamin D concentrations are codetermined by DBP-phenotypes and DBP-concentrations. No major effect of DBP-polymorphism was demonstrated on BMD, bone turnover markers or body composition.

The contribution of heredity to the interindividual variability of maximum oxygen uptake and of cardiac size and function of healthy male twins, age 18 to 31 years, was studied to evaluate the role of the heart in the inheritance of aerobic power. Twelve pairs of monozygotic and 12 pairs of dizygotic twins were examined. Weight (p less than 0.05), relative weight (Quetelet index) (p less than 0.01) and skinfold thickness (p less than 0.01) were found to be genetically determined, as well as heart rate at rest (p less than 0.05) and systolic blood pressure (p less than 0.05). Genetic variation was significant (p less than 0.05) both for absolute and for weight-adjusted oxygen uptake, measured at peak exercise on the bicycle ergometer. However, the influence of inheritance on aerobic power was not associated with a significant genetic effect on the end-diastolic left ventricular internal diameter or on its fractional shortening as assessed by echocardiography. Genetic variation had a significant (p less than 0.05) effect on left ventricular mass, but this could be attributed to the inheritance of body size. These data indicate that cardiac factors are not significantly involved in the inheritance of aerobic power and suggest that cardiac hypertrophy in athletes is secondary to training.

Sixteen male bicyclists and 16 control subjects were studied to assess whether the left ventricular hypertrophy of athletes is associated with changes in diastolic left ventricular function. The cyclists had a larger left ventricular internal diameter on echocardiography (55.2 versus 47.9 mm; p less than 0.001) and a disproportionate increase in wall thickness relative to the internal diameter (0.48 versus 0.41; p less than 0.01), indicating a mixed eccentric-concentric type of hypertrophy. Left ventricular inflow Doppler velocimetry showed similar results in athletes and control subjects for peak flow velocities in the atrial contraction phase (30 versus 32 cm/s; p = NS) and in the early diastolic rapid filling phase (71 versus 67 cm/s; p = NS). The similar ratio of both velocities, that is, 0.43 in the cyclists and 0.49 in the control subjects, suggests that left ventricular distensibility is unaltered in cyclists. It is concluded that the left ventricular hypertrophy observed in cyclists is not associated with changes in ventricular stiffness, as estimated from left ventricular inflow Doppler velocimetry.

Nine female runners and 9 matched control subjects were investigated with echocardiography and Doppler velocimetry to assess cardiac structure and systolic and diastolic left ventricular (LV) function at rest. LV mass was considerably larger in the athletes (171 vs 123 g; P less than 0.01). Minute distance, the Doppler index of cardiac output, was similar in runners and controls; the lower heart rate (P less than 0.01) of the athletes was associated with a higher stroke distance (P less than 0.05). The latter could be attributed to a larger end-diastolic LV internal diameter (46 vs 43 mm; P less than 0.05); wall stress and the various indices of systolic LV function were not different between runners and controls. Early diastolic LV function, estimated from the velocity of LV relaxation and the LV inflow pattern, and late diastolic function, assessed by Doppler velocimetry, were similar in runners and controls. The unchanged ratio of the peak velocities of LV filling during atrial contraction and early filling (0.49 vs 0.44; NS) indicates that LV distensibility is unaltered in the athletes. In conclusion, the higher left ventricular mass of female runners is not associated with changes of systolic and diastolic LV function.

To assess left ventricular structure and function at rest and during exercise in endurance athletes, 10 elite marathon runners, aged 28 to 37 years, and 10 matched nonathletes were studied by echocardiography and supine bicycle ergometry. Each athlete's best marathon time was less than 2 h 16 min. Echocardiography was performed at rest, at a 60 W work load and at an individually adjusted work load, at which heart rate was 110 beats/min (physical working capacity 110 [PWC110]). Oxygen uptake at PWC110 averaged (+/- SD) 1.14 +/- 0.2 liters/min in the nonathletes and 2.0 +/- 0.2 liters/min in the runners (p less than 0.001). The left ventricular internal diameter at end-diastole was similar at the three activity levels in the control subjects but increased significantly from rest to exercise in the runners (p less than 0.001). Left ventricular systolic meridional wall stress remained unchanged during exercise in the nonathletes but was significantly higher at PWC110 in the athletes (p less than 0.05). Both the systolic peak velocity of posterior wall endocardial displacement and fractional shortening of the left ventricular internal diameter increased with exercise; at PWC110 the endocardial peak velocity was higher in the runners than in the control subjects (p less than 0.01). The endocardial peak velocity during relaxation was comparable in athletes and control subjects at rest, increased similarly at a 60 W work load, but was higher in the runners at PWC110 (p less than 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)