Appropriate maintenance and regeneration of adult endocrine organs is important in both normal physiology and disease. We investigated cell proliferation, movement and differentiation in the adult mouse adrenal cortex, using different 5-bromo-2'-deoxyuridine (BrdU) labelling regimens and immunostaining for phenotypic steroidogenic cell markers. Pulse-labelling showed that cell division was largely confined to the outer cortex, with most cells moving inwards towards the medulla at around 13-20 µm per day, though a distinct labelled cell population remained in the outer 10% of the cortex. Pulse-chase-labelling coupled with phenotypic immunostaining showed that, unlike cells in the inner cortex, most BrdU-positive outer cortical cells did not express steroidogenic markers, while co-staining for BrdU and Ki67 revealed that some outer cortical BrdU-positive cells were induced to proliferate following acute adrenocorticotropic hormone (ACTH) treatment. Extended pulse-chase-labelling identified cells in the outer cortex which retained BrdU label for up to 18-23 weeks. Together, these observations are consistent with the location of both slow-cycling stem/progenitor and transiently amplifying cell populations in the outer cortex. Understanding the relationships between these distinct adrenocortical cell populations will be crucial to clarify mechanisms underpinning adrenocortical maintenance and long-term adaptation to pathophysiological states.
Anti-Yo paraneoplastic cerebellar degeneration (PCD) is a rare autoimmune neurological syndrome characterised by cerebellar symptoms and frequently associated with gynaecological malignancies. While typically preceding the diagnosis of the malignancy, rarely it may present later in the disease course, heralding a recurrence prior to biochemical or radiological confirmation. Disease management is challenging and prognosis remains poor. We present the case of a woman with stage IV ovarian adenocarcinoma who developed anti-Yo PCD 16 months post malignancy diagnosis while receiving bevacizumab maintenance therapy. We review the literature and outline the difficulties in diagnosis and the frequently refractory nature of PCD to available treatments.
Background Neurological COVID-19 disease has been reported widely, but published studies often lack information on neurological outcomes and prognostic risk factors. We aimed to describe the spectrum of neurological disease in hospitalised COVID-19 patients; characterise clinical outcomes; and investigate factors associated with a poor outcome. Methods We conducted an individual patient data (IPD) meta-analysis of hospitalised patients with neurological COVID-19 disease, using standard case definitions. We invited authors of studies from the first pandemic wave, plus clinicians in the Global COVID-Neuro Network with unpublished data, to contribute. We analysed features associated with poor outcome (moderate to severe disability or death, 3 to 6 on the modified Rankin Scale) using multivariable models. Results We included 83 studies (31 unpublished) providing IPD for 1979 patients with COVID-19 and acute new-onset neurological disease. Encephalopathy (978 [49%] patients) and cerebrovascular events (506 [26%]) were the most common diagnoses. Respiratory and systemic symptoms preceded neurological features in 93% of patients; one third developed neurological disease after hospital admission. A poor outcome was more common in patients with cerebrovascular events (76% [95% CI 67–82]), than encephalopathy (54% [42–65]). Intensive care use was high (38% [35–41]) overall, and also greater in the cerebrovascular patients. In the cerebrovascular, but not encephalopathic patients, risk factors for poor outcome included breathlessness on admission and elevated D-dimer. Overall, 30-day mortality was 30% [27–32]. The hazard of death was comparatively lower for patients in the WHO European region. Interpretation Neurological COVID-19 disease poses a considerable burden in terms of disease outcomes and use of hospital resources from prolonged intensive care and inpatient admission; preliminary data suggest these may differ according to WHO regions and country income levels. The different risk factors for encephalopathy and stroke suggest different disease mechanisms which may be amenable to intervention, especially in those who develop neurological symptoms after hospital admission.
Sleep and circadian rhythm disorders are well recognised in both AD (Alzheimer's Disease) dementia and MCI-AD (Mild Cognitive Impairment due to Alzheimer's Disease). Such abnormalities include insomnia, excessive daytime sleepiness, decreased sleep efficiency, increased sleep fragmentation and sundowning. Enhancing understanding of sleep abnormalities may unveil targets for intervention in sleep, a promising approach given hypotheses that sleep disorders may exacerbate AD pathological progression and represent a contributory factor toward impaired cognitive performance and worse quality of life. This may also permit early diagnosis of AD pathology, widely acknowledged as a pre-requisite for future disease-modifying therapies. This study aims to bridge the divide between in-laboratory polysomnographic studies which allow for rich characterisation of sleep but in an unnatural setting, and naturalistic studies typically approximating sleep through use of non-EEG wearable devices. It is also designed to record sleep patterns over a 2 month duration sufficient to capture both infradian rhythm and compensatory responses following suboptimal sleep. Finally, it harnesses an extensively phenotyped population including with AD blood biomarkers. Its principal aims are to improve characterisation of sleep and biological rhythms in individuals with AD, particularly focusing on micro-architectural measures of sleep, compensatory responses to suboptimal sleep and the relationship between sleep parameters, biological rhythms and cognitive performance.This observational cohort study has two arms (AD-MCI / mild AD dementia and aged-matched healthy adults). Each participant undergoes a baseline visit for collection of demographic, physiological and neuropsychological information utilising validated questionnaires. The main study period involves 7 nights of home-based multi-channel EEG sleep recording nested within an 8-week study period involving continuous wrist-worn actigraphy, sleep diaries and regular brief cognitive tests. Measurement of sleep parameters will be at home thereby obtaining a real-world, naturalistic dataset. Cognitive testing will be repeated at 6 months to stratify participants by longitudinal disease progression.This study will generate new insights particularly in micro-architectural measures of sleep, circadian patterns and compensatory sleep responses in a population with and without AD neurodegenerative change. It aims to enhance standards of remotely based sleep research through use of a well-phenotyped population and advanced sleep measurement technology.
Changes in sleep during mid-to-late life are associated with risk for Alzheimer's disease (AD). Mechanistic understanding of this association necessitates measurement tools able to quantify these sleep changes longitudinally and accurately. We conducted a systematic review with meta-analysis of validity studies of non-invasive sleep-measuring devices published since 2015 that record sleep metrics associated with AD in adults over 40 (mean 52.9, SD 6.1 years). We reviewed 52 studies, including 32 wearable and ten non-wearable single or multi-sensor devices validated against polysomnography (minimum one night). The apnoea hypopnoea index and oxygen desaturation index were accurately measured across devices. Total sleep time and sleep efficiency were significantly overestimated (p < 0.001) by mean 33.2 minutes and 7.6%, respectively. Slow wave sleep duration was inaccurately measured except by a headband device with electroencephalography. There was no significant difference in accuracy between participants with and without sleep disorders. Studies were undermined by high risk of bias from closed-access algorithms and classification thresholds, and incomplete reporting of accuracy data. Only one study investigated slow wave activity, and none investigated sleep spindles. Nonetheless, we have identified devices that could be used in future studies of sleep and AD risk and discuss some of the limitations of available research.
A 17-year-old Caucasian male presented with subacute blurred vision, imbalance, headache and fever with recurrent oro-genital ulcerations, arthralgia and acneiform skin lesions (Supplementary Fig. S1, available at Rheumatology online). Examination demonstrated gaze-evoked nystagmus in all eccentric positions and globally brisk reflexes. Fundoscopy revealed perivascular sheathing with retinal ischaemia (Supplementary Fig. S1, available at Rheumatology online). MRI brain showed a lesion extending from the midbrain to thalamus in keeping with the ‘cascade sign’ of neuro-Behçet’s disease (NBD) (Fig. 1) [1, 2]. Cerebrospinal fluid was inflammatory with an aseptic lymphocytosis (238 cells/mm3) and matched oligoclonal bands. He was HLA-B51 positive. The international consensus recommendation criteria for a definite diagnosis of NBD were met. Pulsed intravenous methylprednisolone 1 g was initiated for 5 days followed by a slow oral prednisolone taper with concomitant Inflectra® treatment. There was rapid and complete clinical...
Background: Sleep abnormalities are increasingly recognised to emerge early in dementia, at or before the Mild Cognitive Impairment (MCI) phase. Abnormal sleep accelerates cognitive decline and may directly contribute to pathophysiology. Its accurate measurement is therefore crucial, firstly to characterise sleep abnormalities in early disease potentially facilitating earlier identification of those at risk of dementia and secondly to test sleep intervention efficacy. However, it is our a priori hypothesis that sleep outcomes are reported heterogeneously inhibiting side-by-side comparison of study findings. As a translational step towards informing choice and decisions on optimal measures, this scoping review will describe measurement tools utilised and sleep parameters currently reported in early dementia and MCI. Methods: This scoping review follows the Joanna Briggs Institute Manual for Evidence Synthesis for Scoping Reviews. The search strategy consists of an electronic search of the CINAHL Plus, Embase, Medline, Psychinfo and British Nursing Index databases and date limited to articles published from 2000. Search results will be merged using reference management software and duplicates removed. 10% of returned titles and abstracts will be checked by each reviewing member to ensure continuity of decision making. Full-texts will be reviewed by at least two reviewers with discrepancies resolved by whole team consensus. A PRISMA flow diagram will document the selection process. Extracted data will be analysed and reported narratively. Discussion: This scoping review will identify which sleep parameters are reported and the means by which they are measured in people with MCI or early dementia. We intend to explore differences in reporting practice within group subsets, e.g. by dementia and study subtype. Ethics and dissemination: Ethical approval is not required due to absence of human participants. Results will be published in a peer-reviewed journal and presented at relevant academic conferences. The search strategy will be made available publicly for transparency.
Gloucester Neurology Book Club convened over Zoom for its first meeting in the COVID-19 era to discuss Levels of Life,1 Barnes’ grief memoir. Despite some attendees bemoaning the need to pour their own drinks and failing to unmute microphones, the virtual format was a successful platform for open dialogue on an important and deeply personal topic.
In 2008, Barnes’s wife Pat Kavanagh was diagnosed with a brain tumour, dying just 37 days later. Five years on, Barnes published this short book, split into three sections or levels . All begin with the same concept, linking three seemingly unrelated stories: ‘You put together two things that have not been put together before’.
Barnes begins by constructing a long metaphor with balloon flight and photography representing freedom, heights and imprinting of memories. We learn about 19 century Anglo-French ballooning and the intersecting lives of three celebrated balloonists from the era: English officer, Colonel Fred Burnaby; bohemian French actress, Sarah Bernhardt and French photographer, Nadar, the …
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