Search results
Found 21052 matches for
Author Correction: Development and validation of an expanded antibody toolset that captures alpha-synuclein pathological diversity in Lewy body diseases (npj Parkinson's Disease, (2023), 9, 1, (161), 10.1038/s41531-023-00604-y)
Correction to: npj Parkinson’s Disease, published online 07 December 2023 In this article, the wrong slot blots of LASH-BL34-45 and BL 4B12 were presented in Figure 2a; the figure should have appeared as shown below. The original article has been corrected. (Figure presented.).
Hydrocortisone Differentially Affects Reinstatement of Pain-related Responses in Patients With Chronic Back Pain and Healthy Volunteers.
Despite the crucial role of effective and sustained extinction of conditioned pain-related fear in cognitive-behavioral treatment approaches for chronic pain, experimental research on extinction memory retrieval in chronic pain remains scarce. In healthy populations, extinction efficacy of fear memory is affected by stress. Therefore, we investigated the effects of oral hydrocortisone administration on the reinstatement of pain-related associations in 57 patients with non-specific chronic back pain (CBP) and 59 healthy control (HC) participants in a differential pain-related conditioning paradigm within a placebo-controlled, randomized, and double-blind design. Participants' skin conductance responses indicate hydrocortisone-induced reinstatement effects in HCs but no observable reinstatement in HCs receiving placebo treatment. Interestingly, these effects were reversed in patients with CBP, that is, reinstatement responses were only observed in the placebo and not in the hydrocortisone group. Our findings corroborate previous evidence of stress-induced effects on extinction efficacy and reinstatement of fear memory in HCs, extending them into the pain context, and call for more research to clarify the role of stress in fear extinction and return of fear phenomena possibly contributing to treatment failure in chronic pain treatment. PERSPECTIVE: Opposing effects in HCs and patients with non-specific CBP may be associated with changes in the patients' stress systems. These findings could be of relevance to optimizing psychological, extinction-based treatment approaches.
Endothelial Jagged1 levels and distribution are post-transcriptionally controlled by ZFP36 decay proteins.
Vascular morphogenesis requires a delicate gradient of Notch signaling controlled, in part, by the distribution of ligands (Dll4 and Jagged1). How Jagged1 (JAG1) expression is compartmentalized in the vascular plexus remains unclear. Here, we show that Jag1 mRNA is a direct target of zinc-finger protein 36 (ZFP36), an RNA-binding protein involved in mRNA decay that we find robustly induced by vascular endothelial growth factor (VEGF). Endothelial cells lacking ZFP36 display high levels of JAG1 and increase angiogenic sprouting in vitro. Furthermore, mice lacking Zfp36 in endothelial cells display mispatterned and increased levels of JAG1 in the developing retinal vascular plexus. Abnormal levels of JAG1 at the sprouting front alters NOTCH1 signaling, increasing the number of tip cells, a phenotype that is rescued by imposing haploinsufficiency of Jag1. Our findings reveal an important feedforward loop whereby VEGF stimulates ZFP36, consequently suppressing Jag1 to enable adequate levels of Notch signaling during sprouting angiogenesis.
Para-infectious brain injury in COVID-19 persists at follow-up despite attenuated cytokine and autoantibody responses.
To understand neurological complications of COVID-19 better both acutely and for recovery, we measured markers of brain injury, inflammatory mediators, and autoantibodies in 203 hospitalised participants; 111 with acute sera (1-11 days post-admission) and 92 convalescent sera (56 with COVID-19-associated neurological diagnoses). Here we show that compared to 60 uninfected controls, tTau, GFAP, NfL, and UCH-L1 are increased with COVID-19 infection at acute timepoints and NfL and GFAP are significantly higher in participants with neurological complications. Inflammatory mediators (IL-6, IL-12p40, HGF, M-CSF, CCL2, and IL-1RA) are associated with both altered consciousness and markers of brain injury. Autoantibodies are more common in COVID-19 than controls and some (including against MYL7, UCH-L1, and GRIN3B) are more frequent with altered consciousness. Additionally, convalescent participants with neurological complications show elevated GFAP and NfL, unrelated to attenuated systemic inflammatory mediators and to autoantibody responses. Overall, neurological complications of COVID-19 are associated with evidence of neuroglial injury in both acute and late disease and these correlate with dysregulated innate and adaptive immune responses acutely.
A Behaviorally Informed Mobile App to Improve the Nutritional Quality of Grocery Shopping (SwapSHOP): Feasibility Randomized Controlled Trial.
BACKGROUND: Interventions targeting the nutritional quality of grocery shopping have the potential to help improve diet and health outcomes. OBJECTIVE: This study aims to assess the feasibility and acceptability of receiving advice on healthier food purchases through SwapSHOP, a behaviorally informed smartphone app that allows users to scan barcodes of grocery products from the United Kingdom, providing nutritional information and personalized swap suggestions to encourage healthier purchases. METHODS: We randomized adult volunteers in a 6-arm parallel-group controlled feasibility trial. Participants used the SwapSHOP app to record their grocery shopping during a 2-week run-in period and were individually randomized in a 3:1 ratio to either intervention or control arms within 3 strata related to a nutrient of concern of their choice: saturated fat (SFA), sugar, or salt. Participants randomized to the intervention received the SwapSHOP app with a healthier swap function, goal setting, and personalized feedback. Participants in the control group were instructed to use a simpler version of the app to log all their food purchases without receiving any guidance or advice. The primary outcome was the feasibility of progression to a full trial, including app use and follow-up rates at 6 weeks. The secondary outcomes included other feasibility outcomes, process and qualitative measures, and exploratory effectiveness outcomes to assess changes in the nutrient content of the purchased foods. RESULTS: A total of 112 participants were randomized into 3 groups: SFA (n=38 intervention and n=13 control), sugar (n=40 intervention and n=15 control), and salt (n=5 intervention and n=1 control, not analyzed). The 2 progression criteria were met for SFA and sugar: 81% (30/37) and 87% (34/39) of intervention participants in the SFA and sugar groups, respectively, used the app to obtain healthier swaps, and 89% (68/76) of intervention participants and 96% (23/24) of control participants completed follow-up by scanning all purchases over the follow-up period. The process and qualitative outcomes suggested that the intervention was acceptable and has the potential to influence shopping behaviors. There were reductions of -0.56 g per 100 g (95% CI -1.02 to -0.19) in SFA and -1 g per 100 g (95% CI -1.97 to -0.03) in total sugars across all food purchases in the intervention groups. CONCLUSIONS: People were willing to use the SwapSHOP app to help reduce sugar and SFA (but not salt) in their grocery shopping. Adherence and follow-up rates suggest that a full trial is feasible. Given the suggestive evidence indicating that the intervention resulted in reductions in sugars and SFA, a definitive trial is necessary to target improvements in health outcomes. TRIAL REGISTRATION: International Standard Randomised Controlled Trial Number ISRCTN13022312; https://doi.org/10.1186/ISRCTN13022312.
P59 Acute varicella zoster encephalitis? Don’t forget the treatment!
ObjectivesEducate physicians on the need for monitoring of Aciclivir levels in renal failure.DesignRetrospective case report.Subjects59 year old woman presented with acute psychosis following recent herpes zoster treated with oral Aciclovir.MethodsData collection from; original casenotes, electronic laboratory records, electronic picture archiving and communication system (PACS).ResultsLumbar puncture showed raised protein (0.92 g/L), CSF:serum glucose ratio(0.9), 36 WBCs/cmm(72% polymorphs) and detection of VZV DNA. MRI brain only revealed intracranial-hypotension secondary to lumbar puncture. Despite absence of VZV DNA on surveillance lumbar puncture, she remained minimally responsive. Aciclovir levels were significantly elevated post-dose at 32.7 mg/L (cutoff 10.8 mg/L) and a sedation hold revealed temporal correlation of pre-dose levels (6.4 mg/L) with improvement of GCS, strongly implicating Aciclovir as causative agent. Rapid resolution of encephalopathy occurred upon cessation with no residual neurological compromise.ConclusionsAciclovir neurotoxicity mimics zoster-related encephalitis and VZV DNA is commonly detected in cerebrospinal fluid of patient’s with herpes zoster (Rudzeket al. 2007). Our case highlights the need for vigilance of Aciclovir-neurotoxicity in renal failure patients.ReferenceRudzek D, Piskunova N, Zampachova E. High variability in viral load in cerebrospinal fluid from patients with herpes simplex and varicella-zoster infections of the central nervous system. Clinical Microbiology and Infection2007;13(12):1217–1219.
09.36 A tumultuous case of episodic apnoea
Glycine-receptor(GlyR) antibodies are well defined in progressive encephalomyelitis with rigidity and myoclonus (PERM), and are associated with a limited spectrum of immunotherapy-responsive syndromes. Whilst paradigms of autoantibody pathogenicity have been proposed, the trigger and propagation of GlyR antibodies remains unclear. We herein describe and define clinical and immunobiological observations of a GlyR antibody positive patient with PERM with the rare association of an ovarian teratoma.A 36-year-old woman presented with subacute axial and limb rigidity, stimulus-sensitive myoclonus, startle, ataxia, anxiety and episodic apnoea. GlyR antibodies were present in serum and CSF. CT revealed a 53 mm left ovarian teratoma. Despite improvement following immunotherapy, she relapsed with respiratory arrest, therefore removal of the left ovarian teratoma was performed.The fresh teratoma tissue was cultured in B-cell stimulating and plasma cell maintaining conditions, based on similar work with ovarian teratomas from patients with NMDAR-antibody encephalitis (Makuch et al., Annals of Neurology 2018).This teratoma secreted GlyR antibodies into culture supernatants consistent with intra-tumoral synthesis of glycine-receptor antibodies. Whilst marked post-surgical improvement was observed, relapses persisted in correspondence with persistent glycine-receptor antibodies.Our case highlights key areas for clinical consideration; GlyR antibody-mediated disease can be paraneoplastic in nature; ovarian teratomas can produce pathogenic autoantibodies; late tumour removal or immunotherapy worsens prognosis.
Premorbid brain structure influences risk of amyotrophic lateral sclerosis.
BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a disease of the motor network associated with brain structure and functional connectivity alterations that are implicated in disease progression. Whether such changes have a causal role in ALS, fitting with a postulated influence of premorbid cerebral architecture on the phenotypes associated with neurodegenerative disorders is not known. METHODS: This study considered causal effects and shared genetic risk of 2240 structural and functional MRI brain scan imaging-derived phenotypes (IDPs) on ALS using two sample Mendelian randomisation, with putative associations further examined with extensive sensitivity analysis. Shared genetic predisposition between IDPs and ALS was explored using genetic correlation analysis. RESULTS: Increased white matter volume in the cerebral hemispheres was causally associated with ALS. Weaker causal associations were observed for brain stem grey matter volume, parieto-occipital white matter surface and volume of the left thalamic ventral anterior nucleus. Genetic correlation was observed between ALS and intracellular volume fraction and isotropic free water volume fraction within the posterior limb of the internal capsule. CONCLUSIONS: This study provides evidence that premorbid brain structure, in particular white matter volume, contributes to the risk of ALS.
Elevated genetic risk for multiple sclerosis emerged in steppe pastoralist populations.
Multiple sclerosis (MS) is a neuro-inflammatory and neurodegenerative disease that is most prevalent in Northern Europe. Although it is known that inherited risk for MS is located within or in close proximity to immune-related genes, it is unknown when, where and how this genetic risk originated1. Here, by using a large ancient genome dataset from the Mesolithic period to the Bronze Age2, along with new Medieval and post-Medieval genomes, we show that the genetic risk for MS rose among pastoralists from the Pontic steppe and was brought into Europe by the Yamnaya-related migration approximately 5,000 years ago. We further show that these MS-associated immunogenetic variants underwent positive selection both within the steppe population and later in Europe, probably driven by pathogenic challenges coinciding with changes in diet, lifestyle and population density. This study highlights the critical importance of the Neolithic period and Bronze Age as determinants of modern immune responses and their subsequent effect on the risk of developing MS in a changing environment.
Altered Impulsivity Across Drug-Naïve Parkinsonism, Isolated Rapid Eye Movement Sleep Behavior Disorder, and Their High-Risk Relatives.
OBJECTIVE: To determine multidimensional impulsivity levels across different early stages of α-synucleinopathy. METHODS: This cross-sectional study investigated motor and decisional impulsivity levels using a panel of computerized tasks among drug-naïve parkinsonism patients, isolated/idiopathic rapid eye movement sleep behavior disorder (iRBD) patients and their first-degree relatives (iRBD-FDRs), and control participants. Trait impulsivity and impulse control behaviors were assessed by self-reported questionnaires. RESULTS: A total of 27 drug-naïve parkinsonism patients, 157 iRBD patients, 66 iRBD-FDRs, and 82 control participants were recruited. Parkinsonism and iRBD patients had fewer numbers of extracted beads in beads task 1 and 2 (both p