Associations of Cardiovascular and Non-Cardiovascular Comorbidities with Dementia Risk in Patients with Diabetes: Results from a Large UK Cohort Study.

BACKGROUND: Type 2 diabetes (T2D) is an established risk factor for dementia. However, it remains unclear whether the presence of comorbidities could further increase dementia risk in diabetes patients. OBJECTIVES: To examine the associations between cardiovascular and non-cardiovascular comorbidities and dementia risk in T2D patients. DESIGN: Population-based cohort study. SETTING: The UK Clinical Practice Research Datalink (CPRD). PARTICIPANTS: 489,205 T2D patients aged over 50 years in the UK CPRD. MEASUREMENTS: Major cardiovascular and non-cardiovascular comorbidities were extracted as time-varying exposure variables. The outcome event was dementia incidence based on dementia diagnosis or dementia-specific drug prescription. RESULTS: During a median of six years follow-up, 33,773 (6.9%) incident dementia cases were observed. Time-varying Cox regressions showed T2D patients with stroke, peripheral vascular disease, atrial fibrillation, heart failure or hypertension were at higher risk of dementia compared to those without such comorbidities (HR [95% CI] = 1.64 [1.59-1.68], 1.37 [1.34-1.41], 1.26 [1.22-1.30], 1.15 [1.11-1.20] or 1.10 [1.03-1.18], respectively). Presence of chronic obstructive pulmonary disease or chronic kidney disease was also associated with increased dementia risk (HR [95% CI] = 1.05 [1.01-1.10] or 1.11 [1.07-1.14]). CONCLUSIONS: A range of cardiovascular and non-cardiovascular comorbidities were associated with further increases of dementia risk in T2D patients. Prevention and effective management of these comorbidities may play a significant role in maintaining cognitive health in T2D patients.

Half of children entitled to free school meals did not have access to the scheme during COVID-19 lockdown in the UK.

OBJECTIVES: The objectives of the study were to investigate access to free school meals (FSMs) among eligible children, to describe factors associated with uptake and to investigate whether receiving FSMs was associated with measures of food insecurity in the UK using the Coronavirus (COVID-19) wave of the UK Household Longitudinal Study. STUDY DESIGN: The study design was cross-sectional analyses of questionnaire data collected in April 2020. METHODS: Six hundred and thirty-five children who were FSM eligible with complete data were included in the analytic sample. Accessing a FSM was defined as receiving a FSM voucher or a cooked meal at school. Multivariable logistic regression was used to investigate (i) associations between characteristics and access to FSMs and (ii) associations between access to FSMs and household food insecurity measures. All analyses accounted for survey design and sample weights to ensure representativeness. RESULTS: Fifty-one percent of eligible children accessed a FSM. Children in junior schools or above (aged 8+ years) (adjusted odds ratio [AOR]: 11.81; 95% confidence interval [CI]: 5.54, 25.19), who belonged to low-income families (AOR: 4.81; 95% CI: 2.10, 11.03) or still attending schools (AOR: 5.87; 95% CI: 1.70, 20.25) were more likely to receive FSMs. Children in Wales were less likely to access FSMs than those in England (AOR: 0.11; 95% CI: 0.03, 0.43). Receiving a FSM was associated with increased odds of recently using a food bank but not reporting feeling hungry. CONCLUSIONS: In the month after the COVID-19 lockdown, 49% of eligible children did not receive any form of FSMs. The present analyses highlight that the voucher scheme did not adequately serve children who could not attend school during the lockdown. Moreover, more needs to be done to support families relying on income-related benefits, who still report needing to access a food bank. As the scheme may be continued in summer or in a potential second wave, large improvements will be needed to improve its reach.

Community-based pilot intervention to tackle childhood obesity: a whole-system approach.

OBJECTIVES: Go-Golborne is a pilot intervention to prevent childhood obesity in the Royal Borough of Kensington and Chelsea between 2014 and 2018. It is a multistrategy approach targeting children aged 0-16 years and their families in all settings where children live, learn and play. This paper describes the methodology and the practical steps in the development of Go-Golborne. STUDY DESIGN: The programme uses a quasi-experimental design for the evaluation of changes in weight status using data from the extended National Child Measurement Programme across local schools. For specific behavioural change objectives, baseline self-reported lifestyle measures will be compared against annual follow-up data over the 3-year study period. Qualitative methods will be used to explore the perceptions of stakeholders and participants and organizational change. METHODS: Go-Golborne aims to mobilize everyone in the community who has a role or interest in shaping the local environment, norms and behaviours across a range of sectors. A community network of local organizations has been established to codesign all programme activities. The Steering Group of Council officers support programme implementation and environmental changes. The programme has identified six specific behaviour change objectives representing the key areas of need in Golborne and all activities in the council and the community target these objectives during specific programme phases. Key components include community capacity building, community-wide social marketing, environment and policy change and evaluation. RESULTS (PROGRESS): The programme is currently at the beginning of its implementation phase with activities in the community and council targeting the first behaviour change objective. CONCLUSIONS: The pilot aims to test the effectiveness of this approach to support behaviour change and prevent unhealthy weight gain in children using multiple strategies. This programme will inform the development of an intervention model that defines essential programme components, accountability of partner organizations delivering obesity prevention programmes and the effective use of existing assets.

Effect of financial incentives on ethnic disparities in smoking cessation interventions in primary care: cross-sectional study.

BACKGROUND: Smoking cessation interventions are underprovided in primary care. Financial incentives may help address this. However, few studies in the UK have examined their impact on disparities in the delivery of smoking cessation interventions. METHODS: Cross-sectional study using 2007 data from 29 general practices in Wandsworth, London, UK. We used logistic regression to examine associations between disease group [cardiovascular disease (CVD), respiratory disease, depression or none of these diseases], ethnicity and smoking outcomes following the introduction of the Quality and Outcomes Framework in 2004. RESULTS: Significantly, more CVD patients had smoking status ascertained compared with those with respiratory disease (89 versus 72%), but both groups received similar levels of cessation advice (93 and 89%). Patients with depression or none of the diseases were less likely to have smoking status ascertained (60% for both groups) or to receive advice (80 and 75%). Smoking prevalence was high, especially for patients with depression (44%). White British patients had higher rates of smoking than most ethnic groups, but black Caribbean men with depression had the highest smoking prevalence (62%). CONCLUSIONS: Smoking rates remain high, particularly for white British and black Caribbean patients. Extending financial incentives to include recording of ethnicity and rewarding quit rates may further improve smoking cessation outcomes in primary care.

Psychosocial characteristics and self-reported functional status in patients on maintenance dialysis in Hungary.

AIMS: This survey was conducted to assess psychosocial problems and functional status among patients on maintenance dialysis in Hungary. METHODS: All adult patients (n = 4,321) receiving maintenance dialysis in the 56 dialysis centers in Hungary in 2006 were approached to participate in a national, cross-sectional survey. Patients completed a brief self-reported questionnaire. Socio-demographic parameters, disease-related information and data about functional status were collected. Self-rated health and depressive symptoms were also assessed. RESULTS: Mean age was 62 ± 14 y; 52% were males. The prevalence of diabetes was 30%. 46% of participants reported having depressive symptoms. Significant functional limitation was frequent. In multivariable regression models, female gender, poor self-reported finances, less education, history of acute myocardial infarction (AMI) or cerebrovascular disease, the presence of visual or hearing impairment and difficulties with basic activities of daily living were independently associated with the presence of depressive symptoms. In a separate model, age, dialysis vintage, history of AMI or cerebrovascular disease, the presence of visual or hearing impairments, difficulties with basic activities of daily living and also having depressive symptoms were independently associated with self-rated health score. CONCLUSIONS: Chronic dialysis patients in Hungary have disadvantaged socioeconomic status, frequent depressive symptoms and many functional limitations. Professional psychosocial help would be particularly important for this underprivileged patient population in addition to high quality dialysis to optimize outcomes.

Migraine is a neuronal disease.

Migraine is a common, paroxysmal, highly disabling primary headache disorder with a genetic background. The primary cause and the origin of migraine attacks are enigmatic. Numerous clinical and experimental results suggest that activation of the trigeminal system (TS) is crucial in its pathogenesis, but the primary cause of this activation is not fully understood. Since activation of the peripheral and central arms of the TS might be related to cortical spreading depression and to the activity of distinct brainstem nuclei (e.g. the periaqueductal grey), we conclude that migraine can be explained as an altered function of the neuronal elements of the TS, the brainstem, and the cortex, the centre of this process comprising activation of the TS. In light of our findings and the literature data, therefore, we can assume that migraine is mainly a neuronal disease.

Amyotrophic lateral sclerosis mutant vesicle-associated membrane protein-associated protein-B transgenic mice develop TAR-DNA-binding protein-43 pathology.

Cytoplasmic ubiquitin-positive inclusions containing TAR-DNA-binding protein-43 (TDP-43) within motor neurons are the hallmark pathology of sporadic amyotrophic lateral sclerosis (ALS). TDP-43 is a nuclear protein and the mechanisms by which it becomes mislocalized and aggregated in ALS are not properly understood. A mutation in the vesicle-associated membrane protein-associated protein-B (VAPB) involving a proline to serine substitution at position 56 (VAPBP56S) is the cause of familial ALS type-8. To gain insight into the molecular mechanisms by which VAPBP56S induces disease, we created transgenic mice that express either wild-type VAPB (VAPBwt) or VAPBP56S in the nervous system. Analyses of both sets of mice revealed no overt motor phenotype nor alterations in survival. However, VAPBP56S but not VAPBwt transgenic mice develop cytoplasmic TDP-43 accumulations within spinal cord motor neurons that were first detected at 18 months of age. Our results suggest a link between abnormal VAPBP56S function and TDP-43 mislocalization.

Syntheses, transformations and pharmaceutical applications of kynurenic acid derivatives.

The syntheses and transformations of 4-hydroxyquinoline-2-carboxylic acid, kynurenic acid, are reviewed, and special attention is paid to the pharmacological activities and pharmaceutical applications of its derivatives.

Kynurenines in chronic neurodegenerative disorders: future therapeutic strategies.

Parkinson's, Alzheimer's and Huntington's diseases are chronic neurodegenerative disorders of a progressive nature which lead to a considerable deterioration of the quality of life. Their pathomechanisms display some common features, including an imbalance of the tryptophan metabolism. Alterations in the concentrations of neuroactive kynurenines can be accompanied by devastating excitotoxic injuries and metabolic disturbances. From therapeutic considerations, possibilities that come into account include increasing the neuroprotective effect of kynurenic acid, or decreasing the levels of neurotoxic 3-hydroxy-L-kynurenine and quinolinic acid. The experimental data indicate that neuroprotection can be achieved by both alternatives, suggesting opportunities for further drug development in this field.

Assessment of an electron-impact GC-MS method for organic acids and glycine conjugates in amniotic fluid.

We assessed the reliability of a method designed for common electron-impact GC-MS systems to determine in a single run most organic acids and glycine conjugates of clinical interest in amniotic fluid. Suitable sensitivity was achieved by dividing the selected-ion chromatogram into 12 time segments during which the monitoring dwelt on specific ions. Twelve metabolites were simultaneously quantified in amniotic fluid, with performances ranging from very good to clinically acceptable. The total coefficient of variation was 2.5-14.1% and the detection limit was well below the lower value of the physiological range. For five other metabolites, the precision was lower and/or the detection limit was near the physiological range. The method was clinically assessed by the prenatal detection of three cases of tyrosinaemia type I and one case of propionic acidaemia. Analytical and clinical evaluation of the method showed that GC-MS with electron-impact fragmentation can be an informative analytical approach for low-level organic acids in physiological fluids. Apart from the case of glycine conjugates, the method shows a fair reliability for amniotic fluid analysis, which might warrant its use for prenatal diagnosis of organic acidurias. However, this method cannot replace procedures using isotopic internal standards, nor GC-MS based on chemical ionization fragmentation, which remain confirmatory analytical methods of choice.

[Medical genetics service]. / Le Service de Génétique Médicale.

Created in 1987, the department of medical genetics finds its origins in molecular endocrinology research which had developed from the seventies at the Institut de Recherche Interdisciplinaire en Biologie Humaine et Moléculaire (IRIBHM) of the Faculty of Medicine. After its fusion with the Center of Human Genetics of the ULB, in 1992, the department is composed of three units: the lab of molecular genetics and oncology, the lab of cytogenetics and a clinical genetics unit. One thousand consultations of genetic counseling and more than 15,000 molecular or cytogenetic diagnostic procedures are performed annually. The development of the clinical activities was paralleled by a very active research activity, resulting in a series of "firsts". Amongst the main results are: the identification of the first mutations responsible for congenital hypothyroidism; the molecular cloning of the TSH receptor and of a series of "orphan" G protein-coupled receptors; the identification of a novel neuropeptide, nociceptin, by the first example of "reverse pharmacology"; the identification of olfactory receptors on the sperm of mammals, including man; the identification in molecular terms of the mechanisms responsible for acquired and hereditary hyperthyroidisms; the identification of the chemokine receptor CCR5 as the major coreceptor of HIV-1, and of the prevalent mutation of CCR5 conferring resistance to HIV to about 1% of the European population.

[Individual genetic counseling and collective screening strategies in particular at-risk populations]. / Conseil génétique individuel et stratégies collectives de dépistage dans des populations à risque particulier.

Carrier screening for recessive disorders together with prenatal diagnosis offered in at risk pregnancies can achieve efficient prevention of genetic diseases occurring with particularly high frequencies in specific populations. In this context, genetic counseling, which should be available to each at risk couple, must be integrated into a more elaborate framework geared towards informing the target population. Dramatically different outcomes of carrier screening programmes implemented in the past illustrate the conditions for success or failure. The need to target selected ethnic groups accounts for most of the problems encountered: underpriviledged minorities, risk of discrimination and, most importantly, cultural gaps leading to refusal of prenatal diagnosis and/or of selective abortion. In order to achieve prevention through screening programmes, the tests should therefore be preceded by dissemination of adequate information into the target population, followed by genetic counseling for at risk couples, addressing cultural differences. Prenatal diagnosis should always be proposed, but never imposed on these couples. Finally, these screening programmes must be underpinned by comprehensive subsidies covering not only the tests but also education and counseling that should always be provided with the tests. In terms of public health, this is the price for a cost-effective genetic screening programme.

Preimplantation genetic diagnosis for medium-chain acyl-CoA dehydrogenase (MCAD) deficiency.

Medium-chain acyl-CoA dehydrogenase (MCAD) deficiency is the most common defect in fatty acid oxidation. The disease is inherited in an autosomal recessive fashion (carrier frequency around 1 in 70) and probably affects as many as 1 in 10000 new-borns. Affected children usually present within the two first years of life with recurrent episodes of hypoketotic hypoglycaemia and lethargy leading to death in approximately 25% of the cases. One mutation (c985A-->G) accounts for approximately 90% of the carrier chromosomes. We developed a preimplantation genetic diagnosis (PGD) strategy for MCAD for a couple who had already lost two affected children. When tested on heterozygous lymphoblasts, the amplification efficiency was 67 out of 71 (94%) and the allele drop-out rate was 0 out of 67. The patient became pregnant after one PGD cycle during which two embryos were replaced. The twin pregnancy was checked by chorionic villus sampling (CVS) and was shown to be unaffected. The twins have been born and are healthy.

Unilateral bowing of long bones and multiple congenital anomalies in a child born to a mother with gestational diabetes.

We report on a new-born girl with multiple congenital anomalies consisting of major skeletal anomalies restricted to the left side, cleft palate, ventricular and atrial septal defect, retromicrognathia, short neck, dysplastic low-set ears and large birth weight. The left-side bony anomalies include shortening and bowing of the femur and tibia, hypoplasia of the fibula, hip dislocation, clubfoot and mild shortening of the long tubular bones in the left arm with elbow dislocation. The pregnancy was complicated by insulin-dependent gestational diabetes mellitus in the mother. The radiographic features were not consistent with the diagnosis of campomelic dysplasia, kyphomelic dysplasia or other skeletal dysplasias characterized by bowing and shortening of the long bones. To our knowledge, the multiple congenital anomalies, including major skeletal malformations, present in our case have never been simultaneously reported until now. A maternal diabetes syndrome in this infant is probable. The occurrence of major congenital malformations in offspring of women with gestational diabetes is reviewed and discussed. We provide evidence that gestational diabetes mellitus could be teratogenic. We recommend a careful diabetic control in every woman with a history of gestational diabetes.

Cutaneous porphyria in a neonate with tyrosinaemia type 1.

UNLABELLED: A term infant born to consanguineous parents presented at birth with hypoglycaemia, thrombocytopenia, coagulopathy and hyperbilirubinaemia associated with polycythaemia due to delayed cord clamping. Despite phototherapy and correction of polycythaemia by partial exchange transfusion, coagulopathy, hypoglycaemia and conjugated hyperbilirubinaemia persisted, suggesting hepatic failure. Metabolic work-up led to the diagnosis of tyrosinaemia type 1 on day 4. Two--(2-nitro-4-trifluoromethylbenzoyl)--1,3 cyclohexanedione (NTBC) treatment, started on day 5, resulted in progressive clinical improvement and unambiguous biochemical response. Severe skin purpuric lesions occurred in areas exposed to phototherapy. These resolved slowly after its discontinuation. Urine analysis sampled just before and 6 days after starting NTBC treatment showed high levels of type 1 coproporphyrin isomers. Such findings do not seem directly related to tyrosinaemia type 1 where succinylacetone inhibits delta-aminolevulinic acid (delta-ALA) dehydratase and where the accumulation of delta-ALA results in neurotoxicity without photosensitivity. CONCLUSION: We describe a cutaneous form of porphyria in a neonate presenting with severe liver failure due to tyrosinaemia type 1. This porphyria is tentatively attributed to a secondary accumulation of coproporphyrins due to cholestasis, as reported in the bronze baby syndrome and recently described in neonates with purpuric phototherapy-induced eruption, rather than to a primary defect of porphyrin metabolism. The hypothesis of a direct effect of tyrosinaemia type 1 on porphyrin excretion is also discussed.

Further evidence for autosomal dominant inheritance and ectodermal abnormalities in Kabuki syndrome.

Most cases with Kabuki syndrome (KS) were reported sporadically. Recently, a few familial cases of KS were reported. This report provides further evidence that the KS is inherited as a dominant trait with variable expressivity. The proposita is an 18-month-old girl with facial findings characteristic of Kabuki syndrome, prominent fingertip-pads, a midsagittal cleft of vertebral body D4, hypotonia, and psychomotor retardation. Her mother had a similar facial appearance, prominent, cup-shaped ears, an abnormal dentition, early breast development, and low-normal intelligence. Because mother and daughter both had evident Kabuki syndrome, we conclude that KS in this family is inherited as a dominant trait. Further family history supports this finding. Microscopic examination of the hair of the proposita shows abnormalities consisting of trichorrhexis nodosa, twisting of the hairshafts, and irregularity of the diameter of the hair, as was described recently in a patient with KS. This could be another occasional finding in this syndrome, but further studies are required. The presence of abnormal hair, nails, and the commonly described tooth abnormalities in KS further suggest ectodermal involvement in this syndrome.

Delineation of two distinct 6p deletion syndromes.

Deletions of the short arm of chromosome 6 are relatively rare, the main features being developmental delay, craniofacial malformations, hypotonia, and defects of the heart and kidney, with hydrocephalus and eye abnormalities occurring in some instances. We present the molecular cytogenetic investigation of six cases with 6p deletions and two cases with unbalanced translocations resulting in monosomy of the distal part of 6p. The breakpoints of the deletions have been determined accurately by using 55 well-mapped probes and fluorescence in situ hybridization (FISH). The cases can be grouped into two distinct categories: interstitial deletions within the 6p22-p24 segment and terminal deletions within the 6p24-pter segment. Characteristics correlating with specific regions are: short neck, clinodactyly or syndactyly, brain, heart and kidney defects with deletions within 6p23-p24; and corneal opacities/iris coloboma/Rieger anomaly, hypertelorism and deafness with deletions of 6p25. The two cases with unbalanced translocations presented with a Larsen-like syndrome including some characteristics of the 6p deletion syndrome, which can be explained by the deletion of 6p25. Such investigation of cytogenetic abnormalities of 6p using FISH techniques and a defined set of probes will allow a direct comparison of reported cases and enable more accurate diagnosis as well as prognosis in patients with 6p deletions.

Noonan-like phenotype in monozygotic twins with a duplication-deficiency of the long arm of chromosome 18 resulting from a maternal paracentric inversion.

We report on newborn monozygotic twins with a Noonan-like phenotype, and multiple congenital anomalies due to a monocentric recombinant chromosome 18. The mother carried a paracentric inversion of the long arm of chromosome 18, inv(18)(q21.1q22.3). Cytogenetic, fluorescent in situ hybridization, comparative genomic hybridization and DNA marker analyses allowed the delineation of the deleted (18q22.3-qter) and duplicated (18q12.1-q21.1) chromosomal regions in the recombinant chromosome 18, and suggest that this duplication-deletion chromosome 18 resulted from breakage of a dicentric recombinant chromosome 18 with subsequent reconstitution of telomeric sequences on the long arm. Marked variability is observed in the phenotypic expression of the same chromosomal anomaly in these monozygotic twins. The clinical findings of these patients are compared with those reported in proximal 18q-duplication and distal 18q-deletion patients. The clinical features of both infants are compatible with Noonan syndrome, suggesting that a locus for this syndrome may be located on the long arm of chromosome 18.

Alveolar soft-part sarcoma: further evidence by FISH for the involvement of chromosome band 17q25.

A cytogenetic study of an alveolar soft-part sarcoma, a rare tumor of probably myogenic origin, demonstrated a t(X;17)(p11;q25) as the sole chromosomal abnormality. Dual- and triple-color fluorescence in situ hybridization, performed on metaphase and interphase cells, confirmed the translocation between chromosomes X and 17 and demonstrated that this translocation resulted in loss of 17q25. Involvement of 17q25 has been described in four previously published cases of alveolar soft-part sarcoma, but without further characterization. Compared to our karyotype, it seems that the derivative chromosome 17 observed in the reported cases could also be the result of a t(X;17) with possible loss of the 17q25 band. If so, a 17q25 deletion and/or chromosome rearrangement between Xp and 17q leading either to a gene fusion or gene disruption could play an important role in the pathogenesis of alveolar soft-part sarcoma.