The genetic architecture of the human cerebral cortex

The cerebral cortex underlies our complex cognitive capabilities, yet little is known about the specific genetic loci that influence human cortical structure. To identify genetic variants that affect cortical structure, we conducted a genome-wide association meta-analysis of brain magnetic resonance imaging data from 51,665 individuals. We analyzed the surface area and average thickness of the whole cortex and 34 regions with known functional specializations. We identified 199 significant loci and found significant enrichment for loci influencing total surface area within regulatory elements that are active during prenatal cortical development, supporting the radial unit hypothesis. Loci that affect regional surface area cluster near genes in Wnt signaling pathways, which influence progenitor expansion and areal identity. Variation in cortical structure is genetically correlated with cognitive function, Parkinson's disease, insomnia, depression, neuroticism, and attention deficit hyperactivity disorder

Minimal information for studies of extracellular vesicles (MISEV2023): From basic to advanced approaches

Extracellular vesicles (EVs), through their complex cargo, can reflect the state of their cell of origin and change the functions and phenotypes of other cells. These features indicate strong biomarker and therapeutic potential and have generated broad interest, as evidenced by the steady year-on-year increase in the numbers of scientific publications about EVs. Important advances have been made in EV metrology and in understanding and applying EV biology. However, hurdles remain to realising the potential of EVs in domains ranging from basic biology to clinical applications due to challenges in EV nomenclature, separation from non-vesicular extracellular particles, characterisation and functional studies. To address the challenges and opportunities in this rapidly evolving field, the International Society for Extracellular Vesicles (ISEV) updates its 'Minimal Information for Studies of Extracellular Vesicles', which was first published in 2014 and then in 2018 as MISEV2014 and MISEV2018, respectively. The goal of the current document, MISEV2023, is to provide researchers with an updated snapshot of available approaches and their advantages and limitations for production, separation and characterisation of EVs from multiple sources, including cell culture, body fluids and solid tissues. In addition to presenting the latest state of the art in basic principles of EV research, this document also covers advanced techniques and approaches that are currently expanding the boundaries of the field. MISEV2023 also includes new sections on EV release and uptake and a brief discussion of in vivo approaches to study EVs. Compiling feedback from ISEV expert task forces and more than 1000 researchers, this document conveys the current state of EV research to facilitate robust scientific discoveries and move the field forward even more rapidly

Genomic investigations of unexplained acute hepatitis in children

Since its first identification in Scotland, over 1,000 cases of unexplained paediatric hepatitis in children have been reported worldwide, including 278 cases in the UK1. Here we report an investigation of 38 cases, 66 age-matched immunocompetent controls and 21 immunocompromised comparator participants, using a combination of genomic, transcriptomic, proteomic and immunohistochemical methods. We detected high levels of adeno-associated virus 2 (AAV2) DNA in the liver, blood, plasma or stool from 27 of 28 cases. We found low levels of adenovirus (HAdV) and human herpesvirus 6B (HHV-6B) in 23 of 31 and 16 of 23, respectively, of the cases tested. By contrast, AAV2 was infrequently detected and at low titre in the blood or the liver from control children with HAdV, even when profoundly immunosuppressed. AAV2, HAdV and HHV-6 phylogeny excluded the emergence of novel strains in cases. Histological analyses of explanted livers showed enrichment for T cells and B lineage cells. Proteomic comparison of liver tissue from cases and healthy controls identified increased expression of HLA class 2, immunoglobulin variable regions and complement proteins. HAdV and AAV2 proteins were not detected in the livers. Instead, we identified AAV2 DNA complexes reflecting both HAdV-mediated and HHV-6B-mediated replication. We hypothesize that high levels of abnormal AAV2 replication products aided by HAdV and, in severe cases, HHV-6B may have triggered immune-mediated hepatic disease in genetically and immunologically predisposed children

<it>Legionella pneumophila</it> infection presenting as headache, confusion and dysarthria in a human immunodeficiency virus-1 (HIV-1) positive patient: case report

<p>Abstract</p> <p>Background</p> <p><it>Legionella pneumophila</it> is a common cause of community-acquired pneumonia. Central nervous system dysfunction is common, and diagnosis in the absence of pulmonary symptoms can be challenging. Here we describe an atypical clinical presentation of <it>Legionella</it> infection in a patient with HIV who was found to have an unusual neuroradiologic lesion that further served to obscure the diagnosis. This is the first such description in a patient with Legionellosis and HIV coinfection.</p> <p>Case presentation</p> <p>A 43 year-old HIV positive man presented to our hospital with dysarthria, fevers, headache, and altered mental status. Initial work-up revealed pneumonia and a lesion of the splenium of the corpus callosum on magnetic resonance imaging. He was subsequently diagnosed with <it>Legionella</it> pneumonia and treated with complete symptom resolution.</p> <p>Conclusions</p> <p>Neurologic abnormalities are frequent in Legionellosis, but the diagnosis may be difficult in the absence of overt respiratory symptoms and in the presence of HIV coinfection. A high index of suspicion and early initiation of empiric antibiotics is imperative since early treatment may help prevent long-term sequelae. Neuroimaging abnormalities, though rare, can help the physician narrow down the diagnosis and avoid unnecessary invasive testing. Future studies should aim to elucidate the as yet unknown role of neuroimaging in the diagnoses and prognostication of Legionellosis, as well as the interaction between <it>Legionella</it> infection and HIV.</p

Associations of Lower Extremity Peripheral Nerve Impairment and Risk of Dementia in Black and White Older Adults

Background and objectivesPeripheral nerve impairments and dementia are common among older adults and share risk factors. However, few studies have examined whether peripheral nerve function and dementia are associated. We evaluated whether lower extremity peripheral nerve impairments were associated with higher incidence of dementia and whether associations differed by comorbidity subgroups (diabetes, low vitamin B12, and APOE ε4 allele carriers).MethodsWe studied Black and White Health, Aging, and Body Composition Study participants 70 to 79 years of age and without dementia at enrollment. Lower extremity sensory and motor peripheral nerve function was measured at year 4 (the analytic baseline of this study). Sensory nerve impairments were measured with monofilament (1.4 g, 10 g) and vibration threshold of the toe. Monofilament insensitivity was defined as unable to detect monofilament (3 of 4 touches), and vibration detection impairment was defined as &gt;130 μm. Fibular motor impairments were defined as &lt;1 mV compound motor action potential (CMAP) amplitude and slow nerve conduction velocity &lt;40 m/s. Incident dementia over the following 11 years was determined from medical records, cognitive scores, and medications. Cox proportional hazard models adjusted for demographics and health conditions assessed associations of nerve impairments with incident dementia.ResultsAmong 2,174 participants (52% women, 35% Black), 45% could not detect monofilament 1.4 g, 9% could not detect monofilament 10 g, 6% could not feel vibration, 10% had low CMAP amplitude, and 24% had slow conduction velocity. Monofilament 10 g (hazard ratio [HR] 1.35, 95% CI 0.99-1.84) and vibration detection insensitivity (HR 1.73, 95% CI 1.24-2.40) were associated/borderline associated with a higher risk of dementia after covariate adjustment. Estimates were elevated but not significant for monofilament 1.4 g, CMAP amplitude, and conduction velocity (p &gt; 0.05). Increasing number of peripheral nerve impairments was associated with higher risk of dementia in a graded fashion; for ≥3 impairments, the HR was 2.37 (95% CI 1.29-4.38). In subgroup analyses, effect estimates were generally higher among those with diabetes, low vitamin B12, and APOE ε4 allele except for vibration detection.DiscussionPeripheral nerve impairments, especially sensory, were associated with a higher risk of dementia even after adjustment for age and other health factors. These associations may represent a shared susceptibility to nervous system degeneration