Breakpoint mapping of 13 large parkin deletions/duplications reveals an exon 4 deletion and an exon 7 duplication as founder mutations

Early-onset Parkinson’s disease (EOPD) has been associated with recessive mutations in parkin (PARK2). About half of the mutations found in parkin are genomic rearrangements, i.e., large deletions or duplications. Although many different rearrangements have been found in parkin before, the exact breakpoints involving these rearrangements are rarely mapped. In the present study, the exact breakpoints of 13 different parkin deletions/duplications, detected in 13 patients out of a total screened sample of 116 EOPD patients using Multiple Ligation Probe Amplification (MLPA) analysis, were mapped using real time quantitative polymerase chain reaction (PCR), long-range PCR and sequence analysis. Deletion/duplication-specific PCR tests were developed as a rapid and low cost tool to confirm MLPA results and to test family members or patients with similar parkin deletions/duplications. Besides several different deletions, an exon 3 deletion, an exon 4 deletion and an exon 7 duplication were found in multiple families. Haplotype analysis in four families showed that a common haplotype of 1.2 Mb could be distinguished for the exon 7 duplication and a common haplotype of 6.3 Mb for the deletion of exon 4. These findings suggest common founder effects for distinct large rearrangements in parkin

Dysregulated Expression of Both the Costimulatory CD28 and Inhibitory CTLA-4 Molecules in PB T Cells of Advanced Cervical Cancer Patients Suggests Systemic Immunosuppression Related to Disease Progression

Cervical cancer (CC) occurs more frequently in women who are immunosuppressed, suggesting that both local and systemic immune abnormalities may be involved in the evolution of the disease. Costimulatory CD28 and inhibitory CTLA-4 molecules expressed in T cells play a key role in the balanced immune responses. There has been demonstrated a relation between CD28, CTLA-4, and IFN genes in susceptibility to CC, suggesting their importance in CC development. Therefore, we assessed the pattern of CD28 and CTLA-4 expression in T cells from PB of CC patients with advanced CC (stages III and IV according to FIGO) compared to controls. We also examined the ability of PBMCs to secrete IFN-gamma. We found lower frequencies of freshly isolated and ex vivo stimulated CD4 + CD28+ and CD8 + CD28+ T cells in CC patients than in controls. Loss of CD28 expression was more pronounced in the CD8+ T subset. Markedly increased proportions of CTLA-4+ T cells in CC patients before and after culture compared to controls were also observed. In addition, patients’ T cells exhibited abnormal kinetics of surface CTLA-4 expression, with the peak at 24 h of stimulation, which was in contrast to corresponding normal T cells, revealing maximum CTLA-4 expression at 72 h of stimulation. Of note, markedly higher IFN-gamma concentrations were shown in supernatants of stimulated PBMCs from CC patients. Conclusions: Our report shows the dysregulated CD28 and CTLA-4 expression in PB T cells of CC patients, which may lead to impaired function of these lymphocytes and systemic immunosuppression related to disease progression

A many-analysts approach to the relation between religiosity and well-being

The relation between religiosity and well-being is one of the most researched topics in the psychology of religion, yet the directionality and robustness of the effect remains debated. Here, we adopted a many-analysts approach to assess the robustness of this relation based on a new cross-cultural dataset (N=10,535 participants from 24 countries). We recruited 120 analysis teams to investigate (1) whether religious people self-report higher well-being, and (2) whether the relation between religiosity and self-reported well-being depends on perceived cultural norms of religion (i.e., whether it is considered normal and desirable to be religious in a given country). In a two-stage procedure, the teams first created an analysis plan and then executed their planned analysis on the data. For the first research question, all but 3 teams reported positive effect sizes with credible/confidence intervals excluding zero (median reported β=0.120). For the second research question, this was the case for 65% of the teams (median reported β=0.039). While most teams applied (multilevel) linear regression models, there was considerable variability in the choice of items used to construct the independent variables, the dependent variable, and the included covariates

A Many-analysts Approach to the Relation Between Religiosity and Well-being

The relation between religiosity and well-being is one of the most researched topics in the psychology of religion, yet the directionality and robustness of the effect remains debated. Here, we adopted a many-analysts approach to assess the robustness of this relation based on a new cross-cultural dataset (N = 10, 535 participants from 24 countries). We recruited 120 analysis teams to investigate (1) whether religious people self-report higher well-being, and (2) whether the relation between religiosity and self-reported well-being depends on perceived cultural norms of religion (i.e., whether it is considered normal and desirable to be religious in a given country). In a two-stage procedure, the teams first created an analysis plan and then executed their planned analysis on the data. For the first research question, all but 3 teams reported positive effect sizes with credible/confidence intervals excluding zero (median reported β = 0.120). For the second research question, this was the case for 65% of the teams (median reported β = 0.039). While most teams applied (multilevel) linear regression models, there was considerable variability in the choice of items used to construct the independent variables, the dependent variable, and the included covariates

Mental and Social Health of Children and Adolescents With Pre-existing Mental or Somatic Problems During the COVID-19 Pandemic Lockdown

Background: The COVID-19 lockdown increases psychological problems in children and adolescents from the general population. Here we investigate the mental and social health during the COVID-19 lockdown in children and adolescents with pre-existing mental or somatic problems. Methods: We included participants (8-18 years) from a psychiatric (N = 249) and pediatric (N = 90) sample, and compared them to a general population sample (N = 844). Measures were assessed during the first lockdown (April-May 2020) in the Netherlands. Main outcome measures were Patient-Reported Outcomes Measurement Information System (PROMIS (R)) domains: Global Health, Peer Relationships, Anxiety, Depressive Symptoms, Anger, and Sleep-Related Impairment, as reported by children and youth. Additionally, socio-demographic variables, COVID-19-related questions, changes in atmosphere at home from a parent and child perspective, and children's experiences of lockdown regulations were reported by parents. Results: On all measures except Global Health, the pediatric sample reported least problems. The psychiatric sample reported significantly more problems than the general population sample on all measures except for Anxiety and Peer Relationships. Having a COVID-19 affected friend/relative and a COVID-19 related change in parental work situation negatively moderated outcome, but not in the samples with pre-existing problems. All parents reported significant decreases in atmosphere at home, as did children from the general population. Conclusion: We observed significant differences in mental and social health between three child and adolescent samples during the COVID-19 pandemic lockdown and identified COVID-19-related factors influencing mental and social health

The effects of COVID‐19 on child mental health: Biannual assessments up to April 2022 in a clinical and two general population samples

Abstract Background The COVID‐19 pandemic has had an acute impact on child mental and social health, but long‐term effects are still unclear. We examined how child mental health has developed since the start of the COVID‐19 pandemic up to 2 years into the pandemic (April 2022). Methods We included children (age 8–18) from two general population samples (N = 222–1333 per measurement and N = 2401–13,362 for pre‐covid data) and one clinical sample receiving psychiatric care (N = 334–748). Behavioral questionnaire data were assessed five times from April 2020 till April 2022 and pre‐pandemic data were available for both general population samples. We collected parent‐reported data on internalizing and externalizing problems with the Brief Problem Monitor and self‐reported data on Anxiety, Depressive symptoms, Sleep‐related impairments, Anger, Global health, and Peer relations with the Patient‐Reported Outcomes Measurement Information System (PROMIS®). Results In all samples, parents reported overall increased internalizing problems, but no increases in externalizing problems, in their children. Children from the general population self‐reported increased mental health problems from before to during the pandemic on all six PROMIS domains, with generally worst scores in April 2021, and scores improving toward April 2022 but not to pre‐pandemic norms. Children from the clinical sample reported increased mental health problems throughout the pandemic, with generally worst scores in April 2021 or April 2022 and no improvement. We found evidence of minor age effects and no sex effects. Conclusions Child mental health in the general population has deteriorated during the first phase of the COVID‐19 pandemic, has improved since April 2021, but has not yet returned to pre‐pandemic levels. Children in psychiatric care show worsening of mental health problems during the pandemic, which has not improved since. Changes in child mental health should be monitored comprehensively to inform health care and policy

Donor versus no-donor comparison of newly diagnosed myeloma patients included in the HOVON-50 multiple myeloma study.

Item does not contain fulltextTo prospectively evaluate allogeneic stem cell transplantation (allo-SCT) for myeloma as part of first-line therapy, a donor versus no-donor analysis was performed of patients treated in the HOVON-50 study, a study that was originally designed to examine thalidomide combined with intensive therapy. Two hundred sixty patients having received an autologous-SCT fulfilled the criteria to be included, 138 patients without an HLA-identical sibling donor and 122 patients with a donor. After a median follow-up of 77 months, complete remission, progression-free survival (PFS), and overall survival were not significantly different between the 2 groups. PFS at 6 years was 28% for patients with a donor versus 22% for patients without a donor (P = .19) and overall survival at 6 years from high-dose melphalan was 55%, irrespective of having a donor (P = .68). Cumulative incidence of nonrelapse mortality at 6 years after autologous-SCT was 16% in the donor group versus 3% in the no-donor group (P < .001). However, PFS was significantly prolonged in the 99 patients who actually proceeded to allo-SCT compared with the 115 patients who continued maintenance or received a second high-dose melphalan, but the difference did not translate into a prolonged survival benefit. These results do not support a general application of allo-SCT in all myeloma patients as part of first-line therapy

Internalizing problems before and during the COVID-19 pandemic in independent samples of Dutch children and adolescents with and without pre-existing mental health problems

The aim of the study was to assess internalizing problems before and during the pandemic with data from Dutch consortium Child and adolescent mental health and wellbeing in times of the COVID-19 pandemic, consisting of two Dutch general population samples (GS) and two clinical samples (CS) referred to youth/psychiatric care. Measures of internalizing problems were obtained from ongoing data collections pre-pandemic (NGS = 35,357; NCS = 4487) and twice during the pandemic, in Apr–May 2020 (NGS = 3938; clinical: NCS = 1008) and in Nov–Dec 2020 (NGS = 1489; NCS = 1536), in children and adolescents (8–18 years) with parent (Brief Problem Monitor) and/or child reports (Patient-Reported Outcomes Measurement Information System®). Results show that, in the general population, internalizing problems were higher during the first peak of the pandemic compared to pre-pandemic based on both child and parent reports. Yet, over the course of the pandemic, on both child and parent reports, similar or lower levels of internalizing problems were observed. Children in the clinical population reported more internalizing symptoms over the course of the pandemic while parents did not report differences in internalizing symptoms from pre-pandemic to the first peak of the pandemic nor over the course of the pandemic. Overall, the findings indicate that children and adolescents of both the general and clinical population were affected negatively by the pandemic in terms of their internalizing problems. Attention is therefore warranted to investigate long-term effects and to monitor if internalizing problems return to pre-pandemic levels or if they remain elevated post-pandemic

Parkinson disease and comorbid cerebrovascular disease.

Contains fulltext : 81814.pdf (publisher's version ) (Closed access)Optimal management of chronic diseases not only requires tackling of the primary disease processes, but also necessitates timely recognition and treatment of comorbid conditions. In this article, we illustrate this two-pronged approach for two common age-related disorders: Parkinson disease (PD) and cerebrovascular disease (CVD). We first discuss the pathophysiological mechanisms that could provide a link between PD and CVD. Patients with PD have a series of risk factors that could promote development of CVD, but also have several protective factors. We then review the available clinical, radiological and neuropathological evidence to support an association between these two conditions. We conclude by discussing the potential implications for clinical practice, highlighting how comorbid CVD could alter the clinical presentation of PD and reviewing the possibilities for prevention and secondary prophylaxis. Additional research will be needed to fully evaluate the prevalence and clinical relevance of comorbid CVD in PD. Pending further evidence, we recommend that cerebral neuroimaging should be considered if patients with initially uncomplicated PD develop-either acutely or chronically-prominent and/or treatment-resistant gait impairment, postural instability, depression, cognitive decline, or urinary incontinence. Finding comorbid CVD in such patients could have prognostic implications, and could necessitate treatment to arrest further progression of CVD