The relationship between physical fitness and clustered risk, and tracking of clustered risk from adolescence to young adulthood: eight years follow-up in the Danish Youth and Sport Study

INTRODUCTION: Cardiovascular disease (CVD) is usually caused by high levels of many risk factors simultaneously over many years. Therefore, it is of great interest to study if subjects stay within rank order over time in both the biological risk factors and the behaviour that influences these risk factors. Many studies have described stability (tracking) in single risk factors, especially in children where hard endpoints are lacking, but few have analysed tracking in clustered risk. METHODS: Two examinations were conducted 8 years apart. The first time, 133 males and 172 females were 16–19 years of age. Eight years later, 98 males and 137 females participated. They were each time ranked into quartiles by sex in four CVD risk factors all related to the metabolic syndrome. Risk factors were the ratio between total cholesterol and HDL, triglyceride, systolic BP and body fat. The upper quartile was defined as being at risk, and if a subject had two or more risk factors, he/she was defined as a case (15–20 % of the subjects). Odds ratios (OR) for being a case was calculated between quartiles of fitness in both cross-sectional studies. The stability of combined risk was calculated as the OR between cases and non-cases at the first examination to be a case at the second examination. RESULTS: ORs for having two or more risk factors between quartiles of fitness were 3.1, 3.8 and 4.9 for quartiles two to four, respectively. At the second examination, OR were 0.7, 3.5 and 4.9, respectively. The probability for "a case" at the first examination to be "a case" at the second was 6.0. CONCLUSIONS: The relationship between an exposure like physical fitness and CVD risk factors is much stronger when clustering of risk factors are analysed compared to the relationship to single risk factors. The stability over time in multiple risk factors analysed together is strong. This relationship should be seen in the light of moderate or weak tracking of single risk factors, and is strong evidence for early intervention in children where risk factors cluster

High brain serotonin levels in migraine between attacks:A 5-HT₄ receptor binding PET study

Migraine has been hypothesized to be a syndrome of chronic low serotonin (5-HT) levels, but investigations of brain 5-HT levels have given equivocal results. Here, we used positron emission tomography (PET) imaging of the 5-HT4 receptor as a proxy for brain 5-HT levels. Given that the 5-HT4 receptor is inversely related to brain 5-HT levels, we hypothesized that between attacks migraine patients would have higher 5-HT4 receptor binding compared to controls. Eighteen migraine patients without aura (migraine free >48 h), and 16 age- and sex-matched controls underwent PET scans after injection of [11C]SB207145, a specific 5-HT4 receptor radioligand. An investigator blinded to group calculated a neocortical mean [11C]SB207145 binding potential (BPND). Three migraine patients reported a migraine attack within 48 h after the scan and were excluded from the primary analysis. Comparing 15 migraine patients and 16 controls, we found that migraine patients have significantly lower neocortical 5-HT4 receptor binding than controls (0.60 ± 0.09 vs. 0.67 ± 0.05, p = .024), corrected for 5-HTTLPR genotype, sex and age. We found no association between 5-HT4 receptor binding and attack frequency, years with migraine or time since last migraine attack. Our finding of lower 5-HT4 receptor binding in migraine patients is suggestive of higher brain 5-HT levels. This is in contrast with the current belief that migraine is associated with low brain 5-HT levels. High brain 5-HT levels may represent a trait of the migraine brain or it could be a consequence of migraine attacks. Keywords: Headache, Pain, Neuroimaging, Brain, Serotonergic mechanism

Novel de novo BRCA2 mutation in a patient with a family history of breast cancer

<p>Abstract</p> <p>Background</p> <p><it>BRCA2 </it>germ-line mutations predispose to breast and ovarian cancer. Mutations are widespread and unclassified splice variants are frequently encountered. We describe the parental origin and functional characterization of a novel <it>de novo BRCA2 </it>splice site mutation found in a patient exhibiting a ductal carcinoma at the age of 40.</p> <p>Methods</p> <p>Variations were identified by denaturing high performance liquid chromatography (dHPLC) and sequencing of the <it>BRCA1 </it>and <it>BRCA2 </it>genes. The effect of the mutation on splicing was examined by exon trapping in COS-7 cells and by RT-PCR on RNA isolated from whole blood. The paternity was determined by single nucleotide polymorphism (SNP) microarray analysis. Parental origin of the <it>de novo </it>mutation was determined by establishing mutation-SNP haplotypes by variant specific PCR, while <it>de novo </it>and mosaic status was investigated by sequencing of DNA from leucocytes and carcinoma tissue.</p> <p>Results</p> <p>A novel <it>BRCA2 </it>variant in the splice donor site of exon 21 (nucleotide 8982+1 G→A/c.8754+1 G→A) was identified. Exon trapping showed that the mutation activates a cryptic splice site 46 base pairs 3' of exon 21, resulting in the inclusion of a premature stop codon and synthesis of a truncated BRCA2 protein. The aberrant splicing was verified by RT-PCR analysis on RNA isolated from whole blood of the affected patient. The mutation was not found in any of the patient's parents or in the mother's carcinoma, showing it is a <it>de novo </it>mutation. Variant specific PCR indicates that the mutation arose in the male germ-line.</p> <p>Conclusion</p> <p>We conclude that the novel <it>BRCA2 </it>splice variant is a <it>de novo </it>mutation introduced in the male spermatozoa that can be classified as a disease causing mutation.</p

Feasible evaluation of PQ bypass results with duplex ultrasound

Publisher Copyright: © 2019 Sciendo. All rights reserved. Copyright: Copyright 2020 Elsevier B.V., All rights reserved.Patients with peripheral arterial disease (PAD) have substantially impaired health-related quality of life (HR-QoL). Chronic lower limb ischaemia due to the atherosclerotic occlusion of infra-inguinal arteries is one of the most important causes of invalidity among smokers over the age of fifty. Historically, these lesions were treated by open bypass surgery. Less invasive endovascular revascularisation methods are available to treat short lesions, while treatment of long lesions are lacking. Fully endovascular trans-venous femoro-popliteal bypass (PQ Bypass, Inc., Sunnyvale, CA, USA) to treat long femoral lesions has been developed recently. The objective of the study was to evaluate duplex ultrasound (DUS) as a tool to follow up patients after PQ bypass proce¬ dure. A prospective clinical study was conducted at one clinical site. DUS of treated arteries and femoral vein was performed before the procedure, 30 days, 6 months, and 12 months in follow-up period by 2 independent radiologists. Ankle-brachial index (ABI) evaluation was performed at all visits. Thirty-five patients (35 limbs) treated with PQ bypass were enrolled in the study. Median age was 63.6 years (ranged 50 to 87 years). There was 100% successful evaluation of all pa¬ tients at all clinical visits available. Deviation of the DUS results was found within the accepted standard limit between two radiologists. Twelve months after the PQ procedure, 28 (80.0%) PQ stent-grafts were still functioning without DUS signs of stenosis, while seven (20.0%) limbs expe¬ rienced varying degrees of stent malfunction. PQ stent-graft occlusion was detected in five (14.3%) - 1 (2.9%) patients at one-month follow-up, 3 (8.6%) at six months and 1 (2.9%) at twelve months follow-up period, respectively. PQ stent-graft proximal junction stenosis was detected in one patient (2.9%) at six months and distal junction stenosis in one patient (2.9%) at twelve months follow-up, respectively. Despite of graft occlusion found with DUS, two patients had no severe worsening of post-operative ABI. DUS is a reliable method to evaluate patients after PQ bypass procedure and has higher sensitivity than ABI to follow-up patients after PQ proce¬ dure, especially in asymptomatic stent stenosis. Regular and timely use of DUS during the postoperative period may help to recognise potential complications and provide effective treat¬ ment..publishersversionPeer reviewe

Heterogeneity in glucose response curves during an oral glucose tolerance test and associated cardiometabolic risk

We aimed to examine heterogeneity in glucose response curves during an oral glucose tolerance test with multiple measurements and to compare cardiometabolic risk profiles between identified glucose response curve groups. We analyzed data from 1,267 individuals without diabetes from five studies in Denmark, the Netherlands and the USA. Each study included between 5 and 11 measurements at different time points during a 2-h oral glucose tolerance test, resulting in 9,602 plasma glucose measurements. Latent class trajectories with a cubic specification for time were fitted to identify different patterns of plasma glucose change during the oral glucose tolerance test. Cardiometabolic risk factor profiles were compared between the identified groups. Using latent class trajectory analysis, five glucose response curves were identified. Despite similar fasting and 2-h values, glucose peaks and peak times varied greatly between groups, ranging from 7-12 mmol/L, and 35-70 min. The group with the lowest and earliest plasma glucose peak had the lowest estimated cardiovascular risk, while the group with the most delayed plasma glucose peak and the highest 2-h value had the highest estimated risk. One group, with normal fasting and 2-h values, exhibited an unusual profile, with the highest glucose peak and the highest proportion of smokers and men. The heterogeneity in glucose response curves and the distinct cardiometabolic risk profiles may reflect different underlying physiologies. Our results warrant more detailed studies to identify the source of the heterogeneity across the different phenotypes and whether these differences play a role in the development of type 2 diabetes and cardiovascular disease

Non-disjunction of chromosome 13

We performed a molecular study with 21 microsatellites on a sample of 82 trisomy 13 conceptuses, the largest number of cases studied to date. The parental origin was determined in every case and in 89% the extra chromosome 13 was of maternal origin with an almost equal number of maternal MI and MII errors. The latter finding is unique among human autosomal trisomies, where maternal MI (trisomies 15, 16, 21, 22) or MII (trisomy 18) errors dominate. Of the nine paternally derived cases five were of MII origin but none arose from MI errors. There was some evidence for elevated maternal age in cases with maternal meiotic origin for liveborn infants. Maternal and paternal ages were elevated in cases with paternal meiotic origin. This is in contrast to results from a similar study of non-disjunction of trisomy 21 where paternal but not maternal age was elevated. We find clear evidence for reduced recombination in both maternal MI and MII errors and the former is associated with a significant number of tetrads (33%) that are nullichiasmate, which do not appear to be a feature of normal chromosome 13 meiosis. This study supports the evidence for subtle chromosome-specific influences on the mechanisms that determine non-disjunction of human chromosomes, consistent with the diversity of findings for other trisomie