The Netherlands Arrhythmogenic Cardiomyopathy Registry: design and status update.

BACKGROUND: Clinical research on arrhythmogenic cardiomyopathy (ACM) is typically limited by small patient numbers, retrospective study designs, and inconsistent definitions. AIM: To create a large national ACM patient cohort with a vast amount of uniformly collected high-quality data that is readily available for future research. METHODS: This is a multicentre, longitudinal, observational cohort study that includes (1) patients with a definite ACM diagnosis, (2) at-risk relatives of ACM patients, and (3) ACM-associated mutation carriers. At baseline and every follow-up visit, a medical history as well information regarding (non-)invasive tests is collected (e. g. electrocardiograms, Holter recordings, imaging and electrophysiological studies, pathology reports, etc.). Outcome data include (non-)sustained ventricular and atrial arrhythmias, heart failure, and (cardiac) death. Data are collected on a research electronic data capture (REDCap) platform in which every participating centre has its own restricted data access group, thus empowering local studies while facilitating data sharing. DISCUSSION: The Netherlands ACM Registry is a national observational cohort study of ACM patients and relatives. Prospective and retrospective data are obtained at multiple time points, enabling both cross-sectional and longitudinal research in a hypothesis-generating approach that extends beyond one specific research question. In so doing, this registry aims to (1) increase the scientific knowledge base on disease mechanisms, genetics, and novel diagnostic and treatment strategies of ACM; and (2) provide education for physicians and patients concerning ACM, e. g. through our website ( www.acmregistry.nl ) and patient conferences.

Thermodynamic temperature assignment to the point of inflection of the melting curve of high-temperature fixed points.

The thermodynamic temperature of the point of inflection of the melting transition of Re-C, Pt-C and Co-C eutectics has been determined to be 2747.84 ± 0.35 K, 2011.43 ± 0.18 K and 1597.39 ± 0.13 K, respectively, and the thermodynamic temperature of the freezing transition of Cu has been determined to be 1357.80 ± 0.08 K, where the ± symbol represents 95% coverage. These results are the best consensus estimates obtained from measurements made using various spectroradiometric primary thermometry techniques by nine different national metrology institutes. The good agreement between the institutes suggests that spectroradiometric thermometry techniques are sufficiently mature (at least in those institutes) to allow the direct realization of thermodynamic temperature above 1234 K (rather than the use of a temperature scale) and that metal-carbon eutectics can be used as high-temperature fixed points for thermodynamic temperature dissemination. The results directly support the developing mise en pratique for the definition of the kelvin to include direct measurement of thermodynamic temperature.

Pilot testing of a mindfulness- and acceptance-based intervention for increasing cardiorespiratory fitness in sedentary adults: A feasibility study.

OBJECTIVE: Vigorous physical activity (PA) has been promoted for improving cardiorespiratory fitness (CRF). However, therapeutic techniques designed to engage participants in vigorous PA have fallen short; one reason for this may be the unpleasant physical sensations associated with vigorous exercise (e.g., temporary shortness of breath and mild muscle soreness). Mindfulness and acceptance-based therapies such as Acceptance and Commitment Therapy (ACT) may be helpful at improving adherence to vigorous PA levels. In this open clinical trial, we sought to demonstrate the feasibility and acceptability of a mindfulness- and acceptance-based intervention for increasing CRF in sedentary adults and to generate initial outcomes data. DESIGN: Participants (N=24) engaged in a 10-week fitness walking program while attending regular group sessions based on ACT. MAIN OUTCOME MEASURES AND RESULTS: The feasibility and acceptability of the intervention were demonstrated through high levels of walking adherence (89.30%) and group session attendance (85.50%). A large significant decrease in total 1-mile walk test time [t(18)=4.61, p=.0002, d=.64] and a moderate significant increase in estimated VO2max [t(18)=-4.05, p=.0007, d=-.43] were observed. Analyses indicated a large significant increase in exercise-related experiential acceptance [t(18)=-9.19, p <.0001, d=-2.09]. CONCLUSION: This study demonstrates the feasibility and acceptability of an ACT-based intervention for supporting participation in vigorous PA in sedentary individuals.

Response to an exercise intervention after endometrial cancer: differences between obese and non-obese survivors.

OBJECTIVE: The objective of this paper is to describe baseline differences between obese and non-obese endometrial cancer survivor in anthropometrics, exercise behavior, fitness, heart rate and blood pressure, and quality of life, and to analyze whether the effect of a home-based exercise intervention on these outcomes differed for obese and non-obese participants. METHODS: One hundred post-treatment Stage I-IIIa endometrial cancer survivors participated in a single arm 6month study in which they received a home-based exercise intervention. Cardiorespiratory fitness, anthropometrics, and exercise behavior were measured every two months, and quality of life (QOL) and psychological distress were measured at baseline and 6months. RESULTS: Adjusting for potential confounders, at baseline obese survivors had poorer cardiorespiratory fitness (p=.002), higher systolic blood pressure (p=.018), and lower physical functioning (p<.001) and ratings of general health (p=.002), and more pain (p=.037) and somatization (.002). Significant improvements were seen in exercise behavior, resting heart rate, systolic blood pressure, and multiple QOL domains over the course of the intervention. Obese survivors had less improvement in exercise behavior and cardiorespiratory fitness than non-obese survivors, but there were no differences with regard to improvements in QOL and stress. CONCLUSIONS: Home based exercise interventions are beneficial to endometrial cancer survivors, including those whose BMI is in the obese range. While obese survivors have lower levels of physical activity and fitness, they experienced similar activity, fitness, quality of life and mental health benefits. Exercise should be encouraged in endometrial cancer survivors, including those who are obese.

Geographical distribution of plakophilin-2 mutation prevalence in patients with arrhythmogenic cardiomyopathy.

Arrhythmogenic cardiomyopathy (AC) is characterised by myocardial fibrofatty tissue infiltration and presents with palpitations, ventricular arrhythmias, syncope and sudden cardiac death. AC is associated with mutations in genes encoding the desmosomal proteins plakophilin-2 (PKP2), desmoplakin (DSP), desmoglein-2 (DSG2), desmocollin-2 (DSC2) and junctional plakoglobin (JUP). In the present study we compared 28 studies (2004-2011) on the prevalence of mutations in desmosomal protein encoding genes in relation to geographic distribution of the study population. In most populations, mutations in PKP2 showed the highest prevalence. Mutation prevalence in DSP, DSG2 and DSC2 varied among the different geographic regions. Mutations in JUP were rarely found, except in Denmark and the Greece/Cyprus region.

Image quality assessment of the right ventricle with three different delayed enhancement sequences in patients suspected of ARVC/D.

Histopathologic findings in arrhythmogenic right ventricular cardiomyopathy/dysplasia (ARVC/D) are replacement of the normal myocardium with fatty and fibrous elements with preferential involvement of the right ventricle. The right ventricular fibrosis can be visualised by post-gadolinium delayed enhancement inversion recovery imaging (DE imaging). We compared the image quality of three different gradient echo MRI sequences for short axis DE imaging of the right ventricle (RV). We retrospectively analysed MRI scans performed between February 2005 and December 2008 in 97 patients (mean age: 41.2 years, 67% men) suspected of ARVC/D. For DE imaging either a 2D Phase Sensitive (PSIR), a 2D (2D) or a 3D (3D) inversion recovery sequence was used in respectively 38, 32 and 27 MRI-examinations. The RV, divided in 10 segments, was assessed for image quality by two radiologists in random sequence. A consensus reading was performed if results differed between the two readings. Image quality was good in 24% of all segments in the 3D group, 66% in the 2D group and 79% in the PSIR group. Poor image quality was observed in 51% (3D), 10% (2D), and 2% (PSIR) of all segments. Exams were considered suitable for clinical use in 7% of exams in the 3D group, 75% of exams in the 2D group and 90% of exams of the PSIR group. Breathing-artifacts occurred in 22% (3D), 59% (2D) and 53% (PSIR). Motion-artifacts occurred in 56% (3D), 28% (2D) and 29% (PSIR). Post-gadolinium imaging using the PSIR sequence results in better and more consistent image quality of the RV compared to the 2D and 3D sequences.

Recurrent and founder mutations in the Netherlands : Plakophilin-2 p.Arg79X mutation causing arrhythmogenic right ventricular cardiomyopathy/dysplasia.

BACKGROUND: Arrhythmogenic right ventricular cardiomyopathy/dysplasia (ARVC/D) is an inherited cardiac disease with reduced penetrance and a highly variable expression. Mutations in the gene encoding the plakophilin-2 gene (PKP2) are detected in about 50% of ARVC/D patients. The p.Arg79X mutation in PKP2 has been identified in Europe and North America and has been functionally characterised. We evaluated the prevalence of the p.Arg79X mutation in PKP2 in the Dutch population. METHODS: Twelve index patients and 41 family members were evaluated in three university hospitals in the Netherlands. The diagnosis of ARVC/D was established according to the recently revised Task Force Criteria. Segregation of the p.Arg79X mutation was studied and haplotypes were reconstructed to determine whether the p.Arg79X mutation was a recurrent or a founder mutation. RESULTS: The p.Arg79X mutation in PKP2 was identified in 12 index patients. Haplotype analysis revealed a shared haplotype among Dutch p.Arg79X mutation carriers, indicating a common founder. Six index patients (50%) had a first- or second-degree relative who had died of sudden cardiac death below 40 years of age. At age 60, only 60% of the mutation carriers had experienced any symptoms. There was no significant difference in symptom-free survival and event-free survival between men and women. CONCLUSION: We have identified the largest series of patients with the same desmosome gene mutation in ARVC/D reported to date. This p.Arg79X mutation in PKP2 is a founder mutation in the Dutch population. The phenotypes of PKP2 p.Arg79X mutation carriers illustrate the clinical variability and reduced penetrance often seen in ARVC/D. (Neth Heart J 2010;18:583-91.).

An approach based on the SIR measurement model for determining the ionization chamber efficiency curves, and a study of 65Zn and 201Tl photon emission intensities.

The measurement model used to determine ionization chamber efficiency curves accounts from the outset for impurity corrections and beta spectrum shapes. The curves are represented by exponentials of polynomials whose coefficients are adjusted using non-linear least-squares minimization. The curves are validated by comparing with SIR key comparison reference values (KCRVs) and other published curves. The associated covariance matrix is also evaluated. Deviations from model predictions for 65Zn and 201Tl using recommended nuclear data are studied.

Neuroborreliosis causing focal cerebral arteriopathy in a child.

A 9-year-old girl presented with an acute right-sided hemiparesis. Initially, the clinical presentation and stable vasculopathic abnormalities on MR and conventional angiography were suspicious of a so-called "transient cerebral arteriopathy". Mild but persistent pleocytosis and an elevated CSF IgG index led to an extensive search for infectious and immunological causes of cerebral vasculitis, eventually revealing neuroborreliosis. Although rare, infectious and potentially treatable causes of arterial ischemic stroke should be considered in every child with a documented cerebral arteriopathy.

An investigation of the variables associated with normal and delayed hospital discharge following first time isolated coronary artery bypass graft surgery.

The optimum day for discharge after coronary artery bypass graft (CABG) surgery has been subject to some debate yet there has been a steady increase in the number of patients discharged within 5 days of surgery. Delayed discharges may result in the under use of surgical capacity and impact upon patient outcomes. The author conducted a retrospective; correlational study of 333 patients to investigate the variables associated with delayed discharge after CABG. The results suggest it is possible to identify patients likely to achieve a 5-day discharge from their age and Parsonnet score [Circulation, 79(Suppl. I), 1989, 3.]. The introduction of a policy of adopting a 5-day discharge for those patients could maximise surgical capacity and improve patient outcomes. Further prospective study is recommended after the policy has been implemented to evaluate the effectiveness of age and Parsonnet score to predict a 5-day discharge.

An automatic algorithm for immunoassay curve calibration using controlled quadratic splines.

An algorithm is described for the calibration of immunoassay curves. It employs a quadratic spline as the approximating function. The number and positions of the knots of the spline are chosen adaptively. The behaviour of the spline is controlled so that it preserves the key properties of the underlying function.

Site-specific renal cytotoxicity and cell proliferation in male rats exposed to petroleum hydrocarbons.

The pathologic significance of intracytoplasmic protein droplet accumulation within renal tubular epithelial cells induced experimentally in male rats after exposure to various environmental chemicals, such as unleaded gasoline (UG), is poorly understood. 2,2,4-Trimethylpentane (TMP), a component of UG, also is a potent inducer of protein droplets in male rats. This study documents a strong correlation between protein droplet accumulation, single cell necrosis, and regeneration of the male F344 rat nephron during a 3-week exposure regimen to a wide dose range of inhaled UG or gavaged TMP covering several orders of magnitude (2 to 2000 ppm of UG and 0.2 to 50 mg/kg of TMP, respectively). Autoradiographic analyses of various segments of the nephron were conducted after continuous administration of [methyl-3H]thymidine via osmotic pumps implanted during the last week of UG or TMP exposure. The P2 segment of the proximal tubule of control rats from both experiments had a higher rate of cell turnover (approximately 11%) than the adjacent P1 (approximately 2%) or P3 segments (approximately 3%). The P2 segment of rats exposed to UG or TMP responded with additional dose-related (up to 6-fold) increases in cell turnover. The extent and localization of cell proliferation closely paralleled the extent and severity of accumulation of crystalloid protein droplets and single cell necrosis. Biochemical and immunohistochemical studies have shown that protein droplets in male, but not female rats, consist primarily of alpha-2u-globulin, a low molecular weight protein synthesized by the liver under androgenic control. Increased cell turnover in the P2 segment of male rats may be related to altered catabolism of alpha-2u-globulin. This accelerated cell proliferation may be an essential factor in the development of renal cancer in male rats exposed to UG or other volatile hydrocarbons.

2,2,4-Trimethylpentane-induced nephrotoxicity. I. Metabolic disposition of TMP in male and female Fischer 344 rats.

2,2,4-Trimethylpentane (TMP), a component of unleaded gasoline, causes nephrotoxicity in male, but not in female, rats. In the present study, male and female Fischer 344 rats were treated with a single oral dose of [14C]TMP (4.4 mmol/kg; 2 microCi/mmol). Radiolabeled material in kidney, liver, and plasma was determined at 4, 8, 12, 24, and 48 hr after dosing. Maximum concentration of TMP-derived radioactivity in kidney, liver, and plasma of male rats was found after 12 hr (1252, 1000, and 403 nmol eq/g, respectively), whereas those measured in females were found after 8 hr (577, 1163, and 317 nmol eq/g, respectively). A selective retention of the TMP-derived radiolabel in the kidneys of male rats was noted when peak tissue concentration was expressed as a percentage of administered dose. Kidney concentrations of TMP-derived radiolabel increased in a nonlinear, but dose-dependent, manner; the kidney to plasma ratio was greater at low doses than at higher doses. Increased retention of radiolabel material in the kidney was associated with a significant increase in renal concentration of the male-rat-specific protein, alpha 2u-globulin, 24 and 48 hr after TMP administration. Total radioactivity collected in urine 48 hr after TMP administration was similar in males and females (32 and 31% of dose). Identification and quantitation of the urinary metabolites of TMP showed that both male and female rats metabolize TMP via the same pathway and at a similar rate. Female rats, however, excreted more conjugates of 2,4,4-trimethyl-2-pentanol in urine than males. 2,4,4-Trimethyl-2-pentanol was the major metabolite present in the male rat kidney, but was absent in the female rat kidney. The renal retention of 2,4,4-trimethyl-2-pentanol appears to account for the delayed clearance observed in the disposition of [14C]TMP-derived radiolabel. Based on the concomitant accumulations in renal alpha 2u-globulin concentration and renal 2,4,4-trimethyl-2-pentanol concentration, an association is speculated between these two components. The male-rat-specific accumulation of 2,4,4-trimethyl-2-pentanol may therefore reflect the accumulation of a "metabolite-alpha 2u-globulin" complex. This may be relevant to the male-rat-specific nephrotoxicity produced by TMP.

Unexpected increase in catecholamines in adrenals of rats treated with 3-deazaadenosine.

Using electrochemical detection, 3-deazaadenosine, a proximal inhibitor of methylation via the inhibition of S-adenosylhomocysteine hydrolase, perturbed the metabolism of catecholamines in the adrenals of rats. In adrenals of rats treated with 3-deazaadenosine, both norepinephrine and epinephrine increased significantly by about two-fold. 3-Deazaadenosine may inhibit the release of catecholamines from the adrenals by affecting membrane functions of the adrenals.

Synthesis and biological properties of N2-substituted spin-labeled analogues of actinomycin D.

We have synthesized N2-[4-(2,2,6,6-tetramethyl-1-piperidinyloxy)]actinomycin D And the related 1,2-diaminoethane and 1,3-diaminopropane derivatives and evaluated their biological properties. Binding studies with the spin-labeled actinomycin D analogues and DNA were carried out by using circular dichroism, electron spin resonance, and thermal denaturation. These studies have suggested that the derivatives bind to DNA and that their DNA-binding modes are similar but not identical. Spin-labeled actinomycin D derivatives were less potent in inhibiting Escherichia coli DNA-dependent RNA polymerase reaction than actinomycin D and were less toxic to L1210 cells in vitro than the parent compound. Spin-labeled actinomycin D derivatives were more common than the parent compounds against P-388 leukemia cells in vitro with little or no toxicity.