Hypomagnesemia in persons with type 1 diabetes:associations with clinical parameters and oxidative stress

Background: Among persons with type 1 diabetes mellitus (T1DM) low concentrations of magnesium have been reported. Previous (small) studies also suggested a relation of hypomagnesemia with (poor) glycaemic control and complications. We aimed to investigate the magnitude of hypomagnesemia and the associations between magnesium with parameters of routine T1DM care in a population of unselected outpatients. Methods: As part of a prospective cohort study, initially designed to measure quality of life and oxidative stress, data from 207 patients with a mean age of 45 [standard deviation (SD) 12] years, 58% male, diabetes duration 22 [interquartile range (IQR) 16, 31] years and glycated haemoglobin (HbA1c) of 60 (SD 11) mmol/mol [7.6 (SD 1.0)%] were examined. Hypomagnesemia was defined as a concentration below Results: Mean magnesium concentration was 0.78 (SD 0.05) mmol/l. A deficiency was present in 4.3% of participants. Among these persons, mean concentration was 0.66 (SD 0.03) mmol/l. There was no correlation between magnesium and HbA1c at baseline (r = -0.014, p = 0.843). In multivariable analysis, free thiols (reflecting the degree of oxidative stress) were significantly and negatively associated with magnesium concentrations. Conclusion: In this cohort of T1DM outpatients, the presence of hypomagnesemia was infrequent and, if present, relative mild. Magnesium was not associated with glycaemic control nor with presence of micro- and macrovascular complications. Although these results need confirmation, in particular the negative association of magnesium with free thiols, this suggests that hypomagnesemia is not a relevant topic in routine care for people with T1DM

The acceptance and use of the e-Health instrument 'The personal health check' in four Dutch municipalities:Lessons learned

This pilot study assessed the acceptance and use of the e-Health instrument “the Personal Health Check” (PHC) among clients and professionals in primary care settings. By filling in the online PHC instrument, participants were provided insights into their health and lifestyle. When results revealed an increased health risk, participants were advised to undertake additional lab tests measuring blood pressure and haemaglobin levels. Based on the online questionnaire and optional lab tests, participants then received a report that included individually-tailored feedback from the e-Health application about personal health risks and suggestions for health interventions. The PHC was implemented in 2016 in four Dutch municipalities that determined which neighbourhood(s) the PHC targeted and how participants were invited. The Unified Theory of Acceptance and Use of Technology was used as a theoretical framework to address our research questions. Methods used to assess acceptance were: PHC instrument data, data from additional questionnaires completed by PHC participants, focus groups with PHC participants and professionals in primary care, and telephone interviews with non-responders to the invitation to participate in the online PHC. Of the 21,735 invited, 12% participated. Our results showed that participants and professionals in this pilot were predominantly positive about the PHC. Participants reported that they made an effort to apply the PHC lifestyle advice they received. Almost all had the knowledge and resources needed to use the PHC online instrument. Invitations from general practitioners almost doubled participation relative to invitations from the sponsoring municipalities. The overall low response rate, however, suggests that the PHC is unsuitable as a foundation on which to develop local public health policy

Dwarfism with joint laxity in Friesian horses is associated with a splice site mutation in B4GALT7

Background: Inbreeding and population bottlenecks in the ancestry of Friesian horses has led to health issues such as dwarfism. The limbs of dwarfs are short and the ribs are protruding inwards at the costochondral junction, while the head and back appear normal. A striking feature of the condition is the flexor tendon laxity that leads to hyperextension of the fetlock joints. The growth plates of dwarfs display disorganized and thickened chondrocyte columns. The aim of this study was to identify the gene defect that causes the recessively inherited trait in Friesian horses to understand the disease process at the molecular level. Results: We have localized the genetic cause of the dwarfism phenotype by a genome wide approach to a 3 Mb region on the p-arm of equine chromosome 14. The DNA of two dwarfs and one control Friesian horse was sequenced completely and we identified the missense mutation ECA14:g.4535550C> T that cosegregated with the phenotype in all Friesians analyzed. The mutation leads to the amino acid substitution p.(Arg17Lys) of xylosylprotein beta 1,4-galactosyltransferase 7 encoded by B4GALT7. The protein is one of the enzymes that synthesize the tetrasaccharide linker between protein and glycosaminoglycan moieties of proteoglycans of the extracellular matrix. The mutation not only affects a conserved arginine codon but also the last nucleotide of the first exon of the gene and we show that it impedes splicing of the primary transcript in cultured fibroblasts from a heterozygous horse. As a result, the level of B4GALT7 mRNA in fibroblasts from a dwarf is only 2 % compared to normal levels. Mutations in B4GALT7 in humans are associated with Ehlers-Danlos syndrome progeroid type 1 and Larsen of Reunion Island syndrome. Growth retardation and ligamentous laxity are common manifestations of these syndromes. Conclusions: We suggest that the identified mutation of equine B4GALT7 leads to the typical dwarfism phenotype in Friesian horses due to deficient splicing of transcripts of the gene. The mutated gene implicates the extracellular matrix in the regular organization of chrondrocyte columns of the growth plate. Conservation of individual amino acids may not be necessary at the protein level but instead may reflect underlying conservation of nucleotide sequence that are required for efficient splicing

Safety and Tolerability of Sodium Thiosulfate in Patients with an Acute Coronary Syndrome Undergoing Coronary Angiography:A Dose-Escalation Safety Pilot Study (SAFE-ACS)

Background. In animal studies, hydrogen sulfide (H2S) has been shown to protect the heart from ischemia-reperfusion injury. This study evaluates the safety and tolerability of the H2S donor sodium thiosulfate (STS) in patients with acute coronary syndrome (ACS). Methods. Eighteen patients, undergoing coronary angiography for ACS, received STS intravenously immediately after arrival at the catheterization laboratory according to a “3 + 3 dose-escalation design” with fixed dosing endpoint (0, 2.5, 5, 10, 12.5, and 15 grams). This first dose STS was combined with verapamil and nitroglycerin required for transradial procedures. A second dose STS was administered 6 hours later. Primary endpoint was dose-limiting toxicity, defined as significant hemodynamic instability or death up to 24 hours or before discharge from the coronary care unit. Secondary outcomes included the occurrence of anaphylaxis, nausea, vomiting, and systolic blood pressure (SBP) course. Results. Sixteen patients received two dosages of STS and two patients one dosage. None of the patients reached the primary endpoint, nor experienced a serious adverse event. We observed a clinically well-tolerated decline in SBP 1 hour after administration of the first STS dose and concomitant verapamil/nitroglycerin. SBP for all patients together reduced 16.8 (8.1–25.5) mmHg (P=0.0008). No significant decline in SBP occurred after the second dose. Mild nausea was observed in one patient. Conclusion. This is the first report on sodium thiosulfate administration in patients with acute coronary syndromes. Our data suggest that sodium thiosulfate was well tolerated in this setting. The potential benefit of this intervention has to be examined in larger studies

Lifestyle coaches as a central professional in the health care network?:Dynamic changes over time using a network analysis

BackgroundOverweight and obesity are problems that are increasing globally in both children as well as adults, and may be prevented by adopting a healthier lifestyle. Lifestyle coaches counsel overweight and obese children (and their parents) as well as adults in initiating and maintaining healthier lifestyle behaviours. It is currently unclear whether this novel professional in the Dutch health care system functions as a linchpin in networks that evolve around lifestyle-related health problems. The aim of the present study is to investigate the formation and development of networks of lifestyle coaches and their positions within these networks.MethodsIn this longitudinal study, key professionals and professionals within relevant organisations in the Coaching on Lifestyle (CooL) care networks were asked to fill in three online questionnaires. Respondents were asked to indicate whether they collaborated with each of the specified professionals in the context of CooL. The overall network structures and the central role of the lifestyle coaches were examined by using network analysis.ResultsThe results showed that the networks in three out of four regions were relatively centralised, but that none of the networks were dense, and that the professionals seemed to collaborate less with others over time. Half of the lifestyle coaches had a high number of collaborations and a central position within their networks, which also increased over time. In half of the regions, the lifestyle coaches had increased their role as consultants, while their role as gatekeeper and liaison decreased over time. In most regions, the sector of lifestyle coaches had a central position in their networks in just one measurement. Other central sectors were the local sports organisation, public health services, youth health care and the municipal government.ConclusionsOverall, we cannot conclude that more central and denser networks were formed during the study period. In addition, the lifestyle coaches were not often positioned as a central sector within these networks. Entrepreneurial, network and brokering competences are required for lifestyle coaches to build up denser networks.Trial registrationNTR6208; date registered: 13-01-2017; retrospectively registered; Netherlands Trial Register

Perceived barriers and facilitators of the implementation of a combined lifestyle intervention with a financial incentive for chronically ill patients

Background  This study aims to describe barriers and facilitators of the implementation of a combined lifestyle intervention (CLI) in primary care for patients with chronic disease. The aim of CLI to help patients to create a healthy lifestyle and to maintain this healthy lifestyle. During a CLI a patient receives advice and counselling to improve health-related behavior such as physical activity and diet. Special attention was given to the influence of adding a health promoting financial incentive (HPFI) for the participants to the CLI.  Methods  Twenty-four semi-structured interviews within six care groups were performed between July and October 2017. The interviews were transcribed verbatim and coded by two researchers independently.  Results  Respondents mentioned several preferred characteristics of the CLI such as easy accessibility of the intervention site and the presence of health care professionals during exercise sessions. Moreover, factors that could influence implementation (such as attitude of the health care professionals) and preconditions for a successful implementation of a CLI (such as structural funding and good infrastructure) were identified. Overall, positive HPFIs (e.g. a reward) were preferred over negative HPFIs (e.g. a fine). According to the respondents, HPFIs could positively influence the degree of participation, and break down barriers for participating in and finishing the CLI.  Conclusions  Multiple barriers and facilitators for successful implementation of a CLI were identified. For successful implementing CLIs, a positive attitude of all stakeholders is essential and specific preconditions should be fulfilled. With regard to adding a HPFI, more research is needed to identify the attitude of specific target groups towards an HPFI

The relationship of peritubular capillary density with glomerular volume and kidney function in living kidney donors

Background: Peritubular capillary rarefaction plays an important role in the progression of chronic kidney disease. Little is known about the relation between peritubular capillary density, glomerular volume and filtration rate in the healthy kidney. Methods: In this single-center study, we included 69 living kidney donors who donated between 2005 and 2008 and had representative renal biopsies available. In all donors, glomerular filtration rate was measured using 125I-Iothalamate before donation and at five years after donation. Before donation, the increase in glomerular filtration rate after dopamine stimulation was measured. Glomerular volume and peritubular capillary density were determined in biopsies taken at the time of transplantation. Pearson’s correlation coefficient and linear regression were used to assess relations between parameters.Results: Mean donor age was 52 ± 11 years and mean measured glomerular filtration rate was 119 ± 22 mL/min before donation and 82 ± 15 mL/min at five years after donation. While peritubular capillary density (measured by either number of peritubular capillaries/50,000 μm2 or number of peritubular capillaries/tubule) was not associated with measured glomerular filtration rate before or after donation, number of peritubular capillaries/tubule was associated with the increase in measured glomerular filtration rate after dopamine stimulation (St.β = 0.33, p = 0.004), and correlated positively with glomerular volume (R = 0.24, p = 0.047). Glomerular volume was associated with unstimulated measured glomerular filtration rate before donation (St.β = 0.31, p = 0.01) and at five years (St.β = 0.30, p = 0.01) after donation, independent of age.Conclusions: In summary, peritubular capillary density was not related to unstimulated kidney function before or after kidney donation, in contrast to glomerular volume. However, number of peritubular capillaries/tubule correlated with the increase in glomerular filtration rate after dopamine stimulation in healthy kidneys, and with glomerular volume. These findings suggest that peritubular capillary density and glomerular volume differentially affect kidney function in healthy living kidney donors. Graphical abstract: [Figure not available: see fulltext.]</p

CUBN as a Novel Locus for End-Stage Renal Disease: Insights from Renal Transplantation

Chronic kidney disease (CKD) is a complex disorder. As genome-wide association studies identified cubilin gene CUBN as a locus for albuminuria, and urinary protein loss is a risk factor for progressive CKD, we tested the hypothesis that common genetic variants in CUBN are associated with end-stage renal disease (ESRD) and proteinuria. First, a total of 1142 patients with ESRD, admitted for renal transplantation, and 1186 donors were genotyped for SNPs rs7918972 and rs1801239 (case-control study). The rs7918972 minor allele frequency (MAF) was higher in ESRD patients comparing to kidney donors, implicating an increased risk for ESRD (OR 1.39, p = 0.0004) in native kidneys. Second, after transplantation recipients were followed for 5.8 [3.8–9.2] years (longitudinal study) documenting ESRD in transplanted kidneys – graft failure (GF). During post-transplant follow-up 92 (9.6%) cases of death-censored GF occurred. Donor rs7918972 MAF, representing genotype of the transplanted kidney, was 16.3% in GF vs 10.7% in cases with functioning graft. Consistently, a multivariate Cox regression analysis showed that donor rs7918972 is a predictor of GF, although statistical significance was not reached (HR 1.53, p = 0.055). There was no association of recipient rs7918972 with GF. Rs1801239 was not associated with ESRD or GF. In line with an association with the outcome, donor rs7918972 was associated with elevated proteinuria levels cross-sectionally at 1 year after transplantation. Thus, we identified CUBN rs7918972 as a novel risk variant for renal function loss in two independent settings: ESRD in native kidneys and GF in transplanted kidneys