Synthesis and DNA-binding of Metallocyclic Architectures

A new family of cationic N-heterocyclic ligand derivatives was prepared and characterised. Among these compounds are halide salts of the dications [Y(spacer)Y]2+, each of which comprise two N heterocyclic donor groups (Y = 4,4′-bipy, pyz, apyz, apym) linked by a conformationally flexible spacer such as (CH2)n, α,α′-xylylene, 2,6-lutidylene or thiabicyclo[3.3.1]nonane-2,6 diyl. The diquaternary halide salts were converted to NO3- and PF6- salts, and interaction of these bridging ligands with labile palladium(II) and platinum(II) precursors afforded several multinuclear complexes. Bis(4,4′-bipyridinium) dications were incorporated into the dinuclear macrocycles [M2(2,2′ bipy)2{4,4′ bipy(CH2)n4,4′-bipy}2]8+ (M = Pd, Pt; n = 4, 6), cis [Pd2Cl4{4,4′ bipy(CH2)34,4′-bipy}2]4+, [Pt2(dppp)2{4,4′-bipy(1,2-xylylene)4,4′-bipy}2]8+ and cis-[Pt2Cl4{4,4′-bipy(1,2-xylylene)4,4′-bipy}2]4+. While bis(pyrazinium) analogues were unreactive towards the palladium(II) and platinum(II) precursors, the doubly deprotonated bis(3 aminopyrazinium) and bis(2 aminopyrimidinium) derivatives served as charge-neutral quadruply-bridging ligands in the complexes [Pt4(2,2′ bipy)4{apyz(CH2)6apyz–2H}2]8+ and [Pt4(2,2′ bipy)4{apym(CH2)5apym–2H}2]8+, both of which feature Pt(II). Pt(II) interactions. Larger species formed when the diamine O,O′-bis(2-aminoethyl)octadeca(ethylene glycol) (PEGda) was treated with cis dinitratopalladium(II) and platinum(II) precursors. The resulting complexes [M(N,N)(PEGda)]2+ (M = Pd, Pt; N,N = 2,2′-bipy, en, tmeda) possessed great size (62 membered chelate rings) and aqueous solubility. DNA-binding studies were conducted with selected complexes in order to investigate the types of interactions these species might participate in. Equimolar mixtures containing either the 16mer duplex DNA D2 or the single strand D2a and palladium(II)/platinum(II) complexes were prepared and analysed by negative-ion ESI MS. Studies of D2/Pd(II) mixtures suggested extensive fragmentation was occuring, and the use of [Pd(tmeda)(PEGda)]2+ and [Pd2(2,2′-bipy)2{4,4′-bipy(CH2)44,4′-bipy}2]8+ resulted in D2 adducts of [Pd(tmeda)]2+ and [4,4′-bipy(CH2)44,4′-bipy]2+, respectively. Decomposition also occurred when D2a was used, although 1 : 1 adducts were observed with [Pd(tmeda)(PEGda)]2+, [Pd(2,2′ bipy)(PEGda)]2+ and [Pd2(2,2′-bipy)2{4,4′-bipy(CH2)44,4′-bipy}2]8+. The low intensities of these adducts indicated that they are unstable towards ESI MS. Analogous ESI-MS experiments using platinum(II) derivatives were performed and, in contrast to those with palladium(II), indicated that the complexes remained largely intact. ESI-MS analysis of D2/Pt(II) mixtures allowed for the detection of 1 : 1 D2 adducts of [Pt(en)(PEGda)]2+, [Pt(tmeda)(PEGda)]2+ and [Pt2(2,2′-bipy)2{4,4′-bipy(CH2)44,4′-bipy}2]8+. Intensities of the adduct ions suggested the greater charge and aryl surface area allow the dinuclear species to bind D2 most strongly. Both [Pt(2,2′-bipy)(Mebipy)2]4+ and [Pt(2,2′ bipy)(NH3)2]2+ gave rise to 1 : 2 adducts of D2, although the latter was found to be a weaker binder, perhaps owing to its lower charge. Data obtained using 1 : 5 (D2 : complex) mixtures were consistent with the results above and suggested that D2 can bind more molecules of daunomycin than any of the platinum(II) species. Analyses of D2a/Pt(II) mixtures gave results similar to those obtained with D2, although fragmentation was more pronounced, indicating that the nucleobases in D2a play more significant roles in mediating decomposition than those in D2, in which they are paired in a complementary manner. Investigations into the effects of selected platinum(II) complexes on the thermal denaturation of calf-thymus DNA (CT-DNA) in solution were conducted. Both [Pt2(2,2′ bipy)2{4,4′-bipy(CH2)64,4′-bipy}2]8+ and [Pt(2,2′-bipy)(Mebipy)2]4+ greatly stabilised CT-DNA, most likely by intercalation. In contrast, [Pt(tmeda)(PEGda)]2+ and [Pt(en)(PEGda)]2+ (as well as PEGda) caused negligible changes in melting temperature (∆Tm), suggesting that these interact weakly with CT-DNA. Data for [Pt(2,2′ bipy)(PEGda)]2+ and [Pt(2,2′-bipy)(NH3)2]2+ indicated that these species perhaps intercalate CT-DNA, with similar ∆Tm values for both complexes implying that PEGda does not play a major role in binding. While findings from ESI-MS experiments were similar to those from the thermal denaturation experiments, discrepancies between results from the two methods could be found. In particular, fragmentation of cyclic species during ESI-MS caused the binding strength of the species to be underestimated when this method was employed

Exploring views on medical care for people with intellectual disabilities: an international concept mapping study

Contains fulltext : 253060.pdf (Publisher’s version ) (Open Access

Fitness helpt mensen met een verstandelijke beperking

Item does not contain fulltex

A pro-active health assessment instrument for people with intellectual disabilities. Towards reducing health inequities

Contains fulltext : 197555.pdf (publisher's version ) (Open Access)Radboud University, 4 december 2018Promotores : Schrojenstein Lantman, H.M.J. van, Assendelft, W.J.J. Co-promotores : Lucassen, P.L.B.J., Olde Hartman, T.C

[Psychotropic drug prescription to people with intellectual disability in GP practices]

Item does not contain fulltextAntipsychotic drugs are more often prescribed in primary care to people with intellectual disability (ID) with challenging behaviour, sometimes even without a diagnosis, than to those with a diagnosed mental illness. This is shown in a large cohort study in the United Kingdom in primary care and in a Dutch study in three residential care facilities. This prescription behaviour is undesirable. There is no evidence for the effectiveness of off-label prescription. Antipsychotic drugs can cause (serious) side effects. Active monitoring for these side effects is required as people with ID seldom complain. Challenging behaviour can be provoked by somatic illnesses. The Dutch study showed that antipsychotic drug reduction in people with ID with challenging behaviour led to improved behaviour and improvement of physical parameters. A skilled multidisciplinary team of professionals can help with alternative management strategies for challenging behaviour. These teams should be made available for primary care services

Zorg voor mensen met verstandelijke beperkingen in de eerste lijn.

Item does not contain fulltex

Development of a health assessment instrument for people with intellectual disabilities: a Delphi study

Item does not contain fulltextBackground: People with intellectual disabilities (IDs) experience health inequalities. Applying health assessments is one way of diminishing these inequalities. A health assessment instrument can support general practitioners (GPs) in providing better medical care to people with ID. Objectives: The aim of this study was to determine which items should be part of a health assessment instrument for people with ID to be used in primary care. Methods: This Delphi consensus study was conducted among 24 GP experts and 21 ID physicians. We performed three anonymous sequential online questionnaire rounds. We started with 82 'general' items and 14 items concerning physical and additional examinations derived from the international literature and a focus group study among Dutch GPs. We definitely included items if more than 75% of the GP experts agreed on their inclusion. Results: The participation rate in all rounds was above 88%. The expert groups proposed 10 new items. Consensus was reached on 64 'general' items related to highly prevalent diseases, public health and health promotion. Consensus was also reached on 18 physical and additional examination items. Conclusions: For the first time, experts in a Delphi study were able to arrive at a selection of items for a health assessment instrument for people with ID. The overall agreement among the GPs and ID physicians was good. Because the experts prefer that patients complete the health assessment questionnaire at home, questions that cover these items must be formulated clearly

All-cause and cause-specific mortality among people with and without intellectual disabilities during the COVID-19 pandemic in the Netherlands: a population-based cohort study.

BACKGROUND: Although high rates of COVID-19-related deaths have been reported for people with intellectual disabilities during the first 2 years of the pandemic, it is unknown to what extent the pandemic has impacted existing mortality disparities for people with intellectual disabilities. In this study, we linked a Dutch population-based cohort that contained information about intellectual disability statuses with the national mortality registry to analyse both cause-specific and all-cause mortality in people with and without intellectual disabilities, and to make comparisons with pre-pandemic mortality patterns. METHODS: This population-based cohort study used a pre-existing cohort that included the entire Dutch adult population (everyone aged ≥18 years) on Jan 1, 2015, and identified people with presumed intellectual disabilities through data linkage. For all individuals within the cohort who died up to and including Dec 31, 2021, mortality data were obtained from the Dutch mortality register. Therefore, for each individual in the cohort, information was available about demographics (sex and date of birth), indicators of intellectual disability, if any, based on chronic care and (social) services use, and in case of death, the date and underlying cause of death. We compared the first 2 years of the COVID-19 pandemic (2020 and 2021) with the pre-pandemic period (2015-19). The primary outcomes in this study were all-cause and cause-specific mortality. We calculated rates of death and generated hazard ratios (HRs) using Cox regression analysis. FINDINGS: At the start of follow-up in 2015, 187 149 Dutch adults with indicators of intellectual disability were enrolled and 12·6 million adults from the general population were included. Mortality from COVID-19 was significantly higher in the population with intellectual disabilities than in the general population (HR 4·92, 95% CI 4·58-5·29), with a particularly large disparity at younger ages that declined with increasing age. The overall mortality disparity during the COVID-19 pandemic (HR 3·38, 95% CI 3·29-3·47) was wider than before the pandemic (3·23, 3·17-3·29). For five disease groups (neoplasms; mental, behavioural, and nervous system; circulatory system; external causes; and other natural causes) higher mortality rates were observed in the population with intellectual disabilities during the pandemic than before the pandemic, and the pre-pandemic to during the pandemic difference in mortality rates was greater in the population with intellectual disabilities than in the general population, although relative mortality risks for most other causes remained within similar ranges compared with pre-pandemic years. INTERPRETATION: The impact of the COVID-19 pandemic on people with intellectual disabilities has been greater than reflected by COVID-19-related deaths alone. Not only was the mortality risk from COVID-19 higher in people with intellectual disabilities than in the general population, but overall mortality disparities were also further exacerbated during the first 2 years of the pandemic. For disability-inclusive future pandemic preparedness this excess mortality risk for people with intellectual disabilities should be addressed. FUNDING: Dutch Ministry of Health, Welfare, and Sport and Netherlands Organization for Health Research and Development

"Constructing a health assessment questionnaire for people with intellectual disabilities: A cognitive interview study"

Contains fulltext : 220418.pdf (Publisher’s version ) (Closed access)INTRODUCTION: Health assessment instruments can help to raise awareness among general practitioners of specific health problems in people with intellectual disabilities (PID). The present authors developed a health assessment questionnaire using the cognitive interview technique (CI) to improve the comprehensibility. The utility of this approach to questionnaire development involving PID is assessed. METHOD: A qualitative approach using the CI was employed. The study included PID and their caregivers. The present authors interviewed 14 participants in 5 subsequent rounds. After each round, the questionnaire was adjusted until saturation was reached. RESULTS: Three hundred and sixty three identified problems led to 316 changes to the questionnaire. Most problems (102) concerned the comprehension of the question, followed by problems in the "missing answer categories" and "inaccurate instruction" section. CONCLUSION: The comprehensible health assessment questionnaire can help PID to take an active role in communication with their GP. The use of CI helped to improve the questionnaire. CI is a usable and valuable procedure for PID