Practical Guidelines for DNA-Based Testing in Multiple Endocrine Neoplasia Type 1

Multiple endocrine neoplasia type 1 (MEN 1) is an autosomal dominant predisposition to neoplastic lesions of the parathyroid glands, the neuroendocrine pancreas, and the anterior pituitary gland. The predisposing genetic defect was localized to the long arm of chromosome 11 by genetic linkage analysis in three affected families. By analyzing six MEN 1 families with 14 DNA marker systems located close to the MEN 1 gene, we have developed a method to identify carriers of the MEN 1 predisposition. We describe practical aspects of such DNA-based diagnostic procedures

Effects on Metabolic Health after a 1-Year-Lifestyle Intervention in Overweight and Obese Children: A Randomized Controlled Trial

Objective. To evaluate the effect of a family-based intervention on anthropometric and metabolic markers in overweight and obese children. Methods. Overweight or obese 8–12 years olds (n = 93) were randomized into intervention or control groups. The intervention group participated in a program aiming for lifestyle changes regarding food habits and physical activity. Anthropometric measures and venous blood samples were collected from all children at baseline and after 1 year. Results. BMI z-scores decreased in both groups, 0.22 (P = 0.002) and 0.23 (P = 0.003) in intervention and control group, respectively, during the 1-year study, but there was no difference in BMI between the groups at 1-year measurement (P = 0.338). After 1 year, there was a significant difference in waist circumference, waist/hip ratio, and apolipoprotein B/A1 ratio between intervention and control group. Conclusions. The intervention had limited effects on anthropometrics and metabolic markers, which emphasizes the need of preventing childhood overweight and obesity

The Regulation of Commodity Options

To outline further genetic mechanisms of transformation from follicular lymphoma (FL) to diffuse large B-cell lymphoma (DLBCL), we have performed whole genome array-CGH in 81 tumors from 60 patients [29 de novo DLBCL (dnDLBCL), 31 transformed DLBCL (tDLBCL), and 21 antecedent FL]. In 15 patients, paired tumor samples (primary FL and a subsequent tDLBCL) were available, among which three possessed more than two subsequent tumors, allowing us to follow specific genetic alterations acquired before, during, and after the transformation. Gain of 2p15-16.1 encompassing, among others, the REL, BCL11A, USP34, COMMD1, and OTX1 genes was found to be more common in the tDLBCL compared with dnDLBCL (P < 0.001). Furthermore, a high-level amplification of 2p15-16.1 was also detected in the FL stage prior to transformation, indicating its importance during the transformation event. Quantitative real-time PCR showed a higher level of amplification of REL, USP34, and COMMD1 (all involved in the NF kappa B-pathway) compared with BCL11A, which indicates that the altered genes disrupting the NF kappa B pathway may be the driver genes of transformation rather than the previously suggested BCL11A. Moreover, a 17q21.33 amplification was exclusively found in tDLBCL, never in FL (P < 0.04) or dnDLBCL, indicating an upregulation of genes of importance during the later phase of transformation. Taken together, our study demonstrates potential genomic markers for disease progression to clinically more aggressive forms. We also confirm the importance of the TP53-, CDKN2A-, and NF kappa B-pathways for the transformation from FL to DLBCL

Malignant Fibrous Histiocytoma, Aggressive Fibromatosis and Benign Fibrous Tumors Express mRNA for the Metalloproteinase Inducer EMMPRIN and the Metalloproteinases MMP-2 and MT1-MMP

Purpose: Extracellular matrix metalloproteinase inducer (EMMPRIN) has been shown to stimulate fibroblasts to production of matrix metalloproteinases (MMPs). MMPs comprise a family of proteolytic enzymes implicated in the degradation of extracellular matrix which has been proposed to be one of the essential steps in tumor invasion and metastases. In the present study we investigated the expression and location of mRNAs for EMMPRIN, matrix metalloproteinase-2 (MMP-2), and membrane-type 1 matrix metalloproteinase (MT1-MMP) in mesenchymal tumors with different tendencies to recur or metastasize

Maternal pre-pregnancy overweight/obesityand the risk of attention-deficit/hyperactivitydisorder in offspring: a systematic review, meta-analysis and quasi-experimental family-based study

Previous studies are inconclusive concerning the association between maternal pre-pregnancy overweight/obesity and risk of attention-deficit/hyperactivity disorder (ADHD) in offspring. We therefore conducted a systematic review and meta-analysis to clarify this association. To address the variation in confounding adjustment between studies, especially inadequate adjustment of unmeasured familial confounding in most studies, we further performed cousin and sibling comparisons in a nationwide population-based cohort in Sweden. Methods We searched PubMed, Embase and PsycINFO during 1975–2018. We used random-effects models to calculate pooled risk ratios (RRs) with 95% confidence interval. In the population-based study, Cox proportional hazard models were used to calculate the unadjusted hazard ratios (HRs) and HRs adjusted for all confounders identified in previous studies. Stratified Cox models were applied to data on full cousins and full siblings to further control for unmeasured familial confounding. Results Eight cohorts with a total of 784 804 mother–child pairs were included in the meta-analysis. Maternal overweight [RRoverweight = 1.31 (1.25–1.38), I2 = 6.80%] and obesity [RRobesity = 1.92 (1.84–2.00), I2 = 0.00%] were both associated with an increased risk of ADHD in offspring. In the population-based cohort of 971 501 individuals born between 1992 and 2004, unadjusted Cox models revealed similar associations [HRoverweight = 1.30 (1.28–1.34), HRobesity = 1.92 (1.87–1.98)]. These associations gradually attenuated towards the null when adjusted for measured confounders [HRoverweight = 1.21 (1.19–1.25), HRobesity = 1.60 (1.55–1.65)], unmeasured factors shared by cousins [HRoverweight = 1.10 (0.98–1.23), HRobesity = 1.44 (1.22–1.70)] and unmeasured factors shared by siblings [HRoverweight = 1.01 (0.92–1.11), HRobesity = 1.10 (0.94–1.27)]. Conclusion Pre-pregnancy overweight/obesity is associated with an increased risk of ADHD in offspring. The observed association is largely due to unmeasured familial confounding.publishedVersio

Effects on Metabolic Health after a 1-Year-Lifestyle Intervention in Overweight and Obese Children: A Randomized Controlled Trial

Objective. To evaluate the effect of a family-based intervention on anthropometric and metabolic markers in overweight and obese children. Methods. Overweight or obese 8-12 years olds (n = 93) were randomized into intervention or control groups. The intervention group participated in a program aiming for lifestyle changes regarding food habits and physical activity. Anthropometric measures and venous blood samples were collected from all children at baseline and after 1 year. Results. BMI z-scores decreased in both groups, 0.22 (P = 0.002) and 0.23 (P = 0.003) in intervention and control group, respectively, during the 1-year study, but there was no difference in BMI between the groups at 1-year measurement (P = 0.338). After 1 year, there was a significant difference in waist circumference, waist/hip ratio, and apolipoprotein B/A1 ratio between intervention and control group. Conclusions. The intervention had limited effects on anthropometrics and metabolic markers, which emphasizes the need of preventing childhood overweight and obesity

Планування ЗЕД на підприємствах малого та середнього бізнесу

Pheochromocytomas (PCC) and abdominal paragangliomas (PGL) display a highly diverse genetic background and recent gene expression profiling studies have shown that PCC and PGL (together PPGL) alter either kinase signaling pathways or the pseudo-hypoxia response pathway dependent of the genetic composition. Recurrent mutations in the Harvey rat sarcoma viral oncogene homolog (HRAS) have recently been verified in sporadic PPGLs. In order to further establish the HRAS mutation frequency and to characterize the associated expression profiles of HRAS mutated tumors, 156 PPGLs for exon 2 and 3 hotspot mutations in the HRAS gene was screened, and compared with microarray-based gene expression profiles for 93 of the cases. The activating HRAS mutations G13R, Q61R, and Q61K were found in 10/142 PCC (7.0%) and a Q61L mutation was revealed in 1/14 PGL (7.1%). All HRAS mutated cases included in the mRNA expression profiling grouped in Cluster 2, and 21 transcripts were identified as altered when comparing the mutated tumors with 91 HRAS wild-type PPGL. Somatic HRAS mutations were not revealed in cases with known PPGL susceptibility gene mutations and all HRAS mutated cases were benign. The HRAS mutation prevalence of all PPGL published up to date is 5.2% (49/950), and 8.8% (48/548) among cases without a known PPGL susceptibility gene mutation. The findings support a role of HRAS mutations as a somatic driver event in benign PPGL without other known susceptibility gene mutations. HRAS mutated PPGL cluster together with NF1- and RET-mutated tumors associated with activation of kinase-signaling pathways.Funding Agencies|Swedish Cancer Foundation; StratCan; Swedish Research Council; Cancer Research Foundations of Radiumhemmet; Karolinska Institutet; Stockholm County Council</p

Frequent Promoter Hypermethylation of the APC and RASSF1A Tumour Suppressors in Parathyroid Tumours

BACKGROUND: Parathyroid adenomas constitute the most common entity in primary hyperparathyroidism, and although recent advances have been made regarding the underlying genetic cause of these lesions, very little data on epigenetic alterations in this tumour type exists. In this study, we have determined the levels of promoter methylation regarding the four tumour suppressor genes APC, RASSF1A, p16(INK4A) and RAR-beta in parathyroid adenomas. In addition, the levels of global methylation were assessed by analyzing LINE-1 repeats. METHODOLOGY/PRINCIPAL FINDINGS: The sample collection consisted of 55 parathyroid tumours with known HRPT2 and/or MEN1 genotypes. Using Pyrosequencing analysis, we demonstrate APC promoter 1A and RASSF1A promoter hypermethylation in the majority of parathyroid tumours (71% and 98%, respectively). Using TaqMan qRT-PCR, all tumours analyzed displayed lower RASSF1A mRNA expression and higher levels of total APC mRNA than normal parathyroid, the latter of which was largely conferred by augmented APC 1B transcription levels. Hypermethylation of p16(INK4A) was demonstrated in a single adenoma, whereas RAR-beta hypermethylation was not observed in any sample. Moreover, based on LINE-1 analyses, parathyroid tumours exhibited global methylation levels within the range of non-neoplastic parathyroid tissues. CONCLUSIONS/SIGNIFICANCE: The results demonstrate that APC and RASSF1A promoter hypermethylation are common events in parathyroid tumours. While RASSF1A mRNA levels were found downregulated in all tumours investigated, APC gene expression was retained through APC 1B mRNA levels. These findings suggest the involvement of the Ras signaling pathway in parathyroid tumorigenesis. Additionally, in contrast to most other human cancers, parathyroid tumours were not characterized by global hypomethylation, as parathyroid tumours exhibited LINE-1 methylation levels similar to that of normal parathyroid tissues

Diet quality, stress and common mental health problems: A cohort study of 121,008 adults

Background & aims Overall diet quality may partially mediate the detrimental effects of stress and neuroticism on common mental health problems: stressed and/or neurotic individuals may be more prone to unhealthy dietary habits, which in turn may contribute to depression and anxiety. Lifestyle interventions for depressed, anxious or at-risk individuals hinge on this idea, but evidence to support such pathway is missing. Here, we aim to prospectively evaluate the role of overall diet quality in common pathways to developing depression and anxiety. Methods At baseline, N = 121,008 individuals from the general population (age 18–93) completed an extensive food frequency questionnaire, based on which overall diet quality was estimated. Participants also reported on two established risk factors for mental health problems, i.e. past-year stress exposure (long-term difficulties, stressful life-events) and four neuroticism traits (anger-hostility, self-consciousness, impulsivity, vulnerability). Depression and anxiety were assessed at baseline and follow-up (n = 65,342, +3.6 years). Overall diet quality was modeled as a mediator in logistic regression models predicting the development of depression and anxiety from common risk factors. Results High stress and high neuroticism scores were - albeit weakly - associated with poorer diet quality. Poor diet quality, in turn, did not predict mental health problems. Overall diet quality did not mediate the relationship between stress/neuroticism and common mental health problems: effects of stress, neuroticism and stress-by-neuroticism interactions on mental health problems at follow-up consisted entirely of direct effects (98.6%–100%). Conclusions Diet quality plays no mediating role in two established pathways to common mental health problems. As overall diet quality was reduced in stressed and neurotic individuals, these groups may benefit from dietary interventions. However, such interventions are unlikely to prevent the onset or recurrence of depression and anxiety.publishedVersio

Co-Designing with Extreme Users: A Framework for User Participation in Design Processes

The demand for user participation in design processes is increasing, and there is a need to formulate guidance on how to involve disabled users and their representative organisations. Their participation contributes an extreme user perspective to the design process. The aim of this study was to develop an empirically grounded framework for user participation in co-design processes, involving the users with wide range of characteristics. The study was theoretically grounded in ‘participatory design’ and ‘value sensitive design’ and used an exploratory study design with online workshops to iteratively collect and analyse data. All participants collaborated on an online Miro-board to identify themes and formulate guiding principles for the framework. We propose a framework consisting of three themes: participation fundamentals, participation ethics and participation practicalities, entailing 11 guiding principles. By applying this framework, the premises, methods and activities in the design process will be accessible to all participants, and user participation in design projects will become more transparent, equitable and easier to implement. It will enable all users, people with disabilities and others, to participate and contribute to a design that can be used by the widest range of people