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Autism is a highly heritable neurodevelopmental disorder, yet the genetic underpinnings of the disorder are largely unknown. Aberrant brain overgrowth is a well-replicated observation in the autism literature; but association, linkage, and expression studies have not identified genetic factors that explain this trajectory. Few studies have had sufficient statistical power to investigate whole-genome gene expression and genotypic variation in the autistic brain, especially in regions that display the greatest growth abnormality. Previous functional genomic studies have identified possible alterations in transcript levels of genes related to neurodevelopment and immune function. Thus, there is a need for genetic studies involving key brain regions to replicate these findings and solidify the role of particular functional pathways in autism pathogenesis. We therefore sought to identify abnormal brain gene expression patterns via whole-genome analysis of mRNA levels and copy number variations (CNVs) in autistic and control postmortem brain samples. We focused on prefrontal cortex tissue where excess neuron numbers and cortical overgrowth are pronounced in the majority of autism cases. We found evidence for dysregulation in pathways governing cell number, cortical patterning, and differentiation in young autistic prefrontal cortex. In contrast, adult autistic prefrontal cortex showed dysregulation of signaling and repair pathways. Genes regulating cell cycle also exhibited autism-specific CNVs in DNA derived from prefrontal cortex, and these genes were significantly associated with autism in genome-wide association study datasets. Our results suggest that CNVs and age-dependent gene expression changes in autism may reflect distinct pathological processes in the developing versus the mature autistic prefrontal cortex. Our results raise the hypothesis that genetic dysregulation in the developing brain leads to abnormal regional patterning, excess prefrontal neurons, cortical overgrowth, and neural dysfunction in autism.

Molecular analysis of postmortem samples of brain tissue obtained from 11 children with autism showed that the prefrontal and temporal cortexes in 10 of these children had patches of neuronal disorganization. Autism is, in part, a heritable developmental disorder involving macroscopic early brain overgrowth in the majority of cases 1 – 7 and dysfunction 8 that affects several cortical and subcortical regions mediating autistic symptoms, including prefrontal and temporal cortexes. 4 , 9 – 11 The underlying cortical defects remain uncertain. Despite the early diagnosable onset, in more than 40 studies, the average age of patients with autism in postmortem analyses was 22 years. 4 Three previous case studies that evaluated Nissl-stained sections of brains obtained from patients with autism ranging in age from 4 to 60 years described individual instances of heterotopias, slight focal laminar disorganization, 12 , . . .

Background Gene expression assays have been shown to yield high quality genome-wide data from partially degraded RNA samples. However, these methods have not yet been applied to postmortem human brain tissue, despite their potential to overcome poor RNA quality and other technical limitations inherent in many assays. We compared cDNA-mediated annealing, selection, and ligation (DASL)- and in vitro transcription (IVT)-based genome-wide expression profiling assays on RNA samples from artificially degraded reference pools, frozen brain tissue, and formalin-fixed brain tissue. Results The DASL-based platform produced expression results of greater reliability than the IVT-based platform in artificially degraded reference brain RNA and RNA from frozen tissue-based samples. Although data associated with a small sample of formalin-fixed RNA samples were poor when obtained from both assays, the DASL-based platform exhibited greater reliability in a subset of probes and samples. Conclusions Our results suggest that the DASL-based gene expression-profiling platform may confer some advantages on mRNA assays of the brain over traditional IVT-based methods. We ultimately consider the implications of these results on investigations of neuropsychiatric disorders.

Music is a complex acoustic signal that relies on a number of different brain and cognitive processes to create the sensation of hearing. Changes in hearing function are generally not a major focus of concern for persons with a majority of neurodegenerative diseases associated with dementia, such as Alzheimer disease (AD). However, changes in the processing of sounds may be an early, and possibly preclinical, feature of AD and other neurodegenerative diseases. The aim of this chapter is to review the current state of knowledge concerning hearing and music perception in persons who have a dementia as a result of a neurodegenerative disease. The review focuses on both peripheral and central auditory processing in common neurodegenerative diseases, with a particular focus on the processing of music and other non-verbal sounds. The chapter also reviews music interventions used for persons with neurodegenerative diseases.

Background Vein of Galen malformations (VOGMs) are rare and complex congenital arteriovenous fistulas. The clinical and radiological features of VOGMs and their relation to clinical outcomes are not fully characterized. Objective To examine the clinical and radiological features of VOGMs and the predictors of outcome in patients. Methods We retrospectively reviewed the available imaging and medical records of all patients with VOGMs treated at the University of California, San Francisco between 1986 and 2013. Radiological and clinical features were identified. We applied the modified Rankin Scale to determine functional outcome by chart review. Predictors of outcome were assessed by χ2 analyses. Results Forty-one cases were confirmed as VOGM. Most patients (78%) had been diagnosed with VOGM in the first year of life. Age at treatment was bimodally distributed, with predominantly urgent embolization at <10 days of age and elective embolization after 1 year of age. Patients commonly presented with hydrocephalus (65.9%) and congestive heart failure (61.0%). Mixed-type (31.7%) VOGM was more common in our cohort than purely mural (29.3%) or choroidal (26.8%) types. The most common feeding arteries were the choroidal and posterior cerebral arteries. Transarterial embolization with coils was the most common technique used to treat VOGMs at our institution. Functional outcome was normal or only mildly disabled in 50% of the cases at last follow-up (median=3 years, range=0–23 years). Younger age at first diagnosis, congestive heart failure, and seizures were predictive of adverse clinical outcome. The survival rate in our sample was 78.0% and complete thrombosis of the VOGM was achieved in 62.5% of patients. Conclusions VOGMs continue to be challenging to treat and manage. Nonetheless, endovascular approaches to treatment are continuing to be refined and improved, with increasing success. The neurodevelopmental outcomes of affected children whose VOGMs are treated may be good in many cases.

Gene expression assays have been shown to yield high quality genome-wide data from partially degraded RNA samples. However, these methods have not yet been applied to postmortem human brain tissue, despite their potential to overcome poor RNA quality and other technical limitations inherent in many assays. We compared cDNA-mediated annealing, selection, and ligation (DASL)- and in vitro transcription (IVT)-based genome-wide expression profiling assays on RNA samples from artificially degraded reference pools, frozen brain tissue, and formalin-fixed brain tissue. The DASL-based platform produced expression results of greater reliability than the IVT-based platform in artificially degraded reference brain RNA and RNA from frozen tissue-based samples. Although data associated with a small sample of formalin-fixed RNA samples were poor when obtained from both assays, the DASL-based platform exhibited greater reliability in a subset of probes and samples. Our results suggest that the DASL-based gene expression-profiling platform may confer some advantages on mRNA assays of the brain over traditional IVT-based methods. We ultimately consider the implications of these results on investigations of neuropsychiatric disorders.

Incidence of kidney failure with replacement therapy During 2022, 1471 new patients entered the KFRT programme at an incidence of 197.5 per million population (pmp), an 0.34% increase compared with 2021. Since the establishment of the Renal Registry in 1995, the number of new patients increased by 139%, from 615 per year (95.1 pmp) in 1996 to a peak of 1471 per year (197.5 pmp) in 2022 (Fig 1). The overall peritonitis rate among patients receiving continuous ambulatory PD has greatly improved, from 0.55 episode per patient-year in 1999 to 0.27 episode per patient-year in 2022. [...]patients receiving automated PD had a peritonitis rate of 0.23 episode per patient-year, which was better than the rate among patients receiving continuous ambulatory PD. Haemodialysis As of 31 December 2022, there were 2452 patients receiving HD in the Renal Registry, representing a prevalence of 329 pmp; this rate constituted a 2.0% increase compared with 2021. The proportion of HD among all KFRT treatment modalities also increased from 11% in 1996 to 17.6% in 2022, resulting in the HD-to-PD ratio of 0.37:1. Since the introduction of the nocturnal home dialysis programme in 2006 and New Generation Home HD in 2020, HA home HD services have expanded. Infection remained the most common cause of death among KFRT patients (46.0% in 2022), followed by cardiovascular disease (26.2%) and cerebrovascular disease (4.1%) [online supplementary Fig 3]. Because of improved hepatitis treatment for transplant recipients, liver failure has caused [lesser than]1% of deaths in recent years.

Background The clinical utility of personal genomic information in identifying individuals at increased risks for dyslipidemia and cardiovascular diseases remains unclear. Methods We used data from Biobank Japan ( n  = 70,657–128,305) and developed novel East Asian-specific genome-wide polygenic risk scores (PRSs) for four lipid traits. We validated ( n  = 4271) and subsequently tested associations of these scores with 3-year lipid changes in adolescents ( n  = 620), carotid intima-media thickness (cIMT) in adult women ( n  = 781), dyslipidemia ( n  = 7723), and coronary heart disease (CHD) ( n  = 2374 cases and 6246 controls) in type 2 diabetes (T2D) patients. Results Our PRSs aggregating 84–549 genetic variants (0.251 < correlation coefficients ( r ) < 0.272) had comparably stronger association with lipid variations than the typical PRSs derived based on the genome-wide significant variants (0.089 <  r  < 0.240). Our PRSs were robustly associated with their corresponding lipid levels (7.5 × 10 − 103  <  P  < 1.3 × 10 − 75 ) and 3-year lipid changes (1.4 × 10 − 6  <  P  < 0.0130) which started to emerge in childhood and adolescence. With the adjustments for principal components (PCs), sex, age, and body mass index, there was an elevation of 5.3% in TC ( β  ± SE = 0.052 ± 0.002), 11.7% in TG ( β  ± SE = 0.111 ± 0.006), 5.8% in HDL-C ( β  ± SE = 0.057 ± 0.003), and 8.4% in LDL-C ( β  ± SE = 0.081 ± 0.004) per one standard deviation increase in the corresponding PRS. However, their predictive power was attenuated in T2D patients (0.183 <  r  < 0.231). When we included each PRS (for TC, TG, and LDL-C) in addition to the clinical factors and PCs, the AUC for dyslipidemia was significantly increased by 0.032–0.057 in the general population (7.5 × 10 − 3  <  P  < 0.0400) and 0.029–0.069 in T2D patients (2.1 × 10 − 10  <  P  < 0.0428). Moreover, the quintile of TC-related PRS was moderately associated with cIMT in adult women ( β  ± SE = 0.011 ± 0.005, P trend  = 0.0182). Independent of conventional risk factors, the quintile of PRSs for TC [OR (95% CI) = 1.07 (1.03–1.11)], TG [OR (95% CI) = 1.05 (1.01–1.09)], and LDL-C [OR (95% CI) = 1.05 (1.01–1.09)] were significantly associated with increased risk of CHD in T2D patients (4.8 × 10 − 4  <  P  < 0.0197). Further adjustment for baseline lipid drug use notably attenuated the CHD association. Conclusions The PRSs derived and validated here highlight the potential for early genomic screening and personalized risk assessment for cardiovascular disease.

Transcriptional repression of methylated genes can be mediated by the methyl-CpG binding protein MeCP2. Here we show that human Brahma (Brm), a catalytic component of the SWI/SNF-related chromatin-remodeling complex, associates with MeCP2 in vivo and is functionally linked with repression. We used a number of different molecular approaches and chromatin immunoprecipitation strategies to show a unique cooperation between Brm, BAF57 and MeCP2. We show that Brm and MeCP2 assembly on chromatin occurs on methylated genes in cancer and the gene FMR1 in fragile X syndrome. These experimental findings identify a new role for SWI/SNF in gene repression by MeCP2.