52 research outputs found
Exhaustive analysis of BH4 and dopamine biosynthesis genes in patients with Dopa-responsive dystonia
Dopa-responsive dystonia is a childhood-onset dystonic disorder, characterized by a dramatic response to low dose of l-Dopa. Dopa-responsive dystonia is mostly caused by autosomal dominant mutations in the GCH1 gene (GTP cyclohydrolase1) and more rarely by autosomal recessive mutations in the TH (tyrosine hydroxylase) or SPR (sepiapterin reductase) genes. In addition, mutations in the PARK2 gene (parkin) which causes autosomal recessive juvenile parkinsonism may present as Dopa-responsive dystonia. In order to evaluate the relative frequency of the mutations in these genes, but also in the genes involved in the biosynthesis and recycling of BH4, and to evaluate the associated clinical spectrum, we have studied a large series of index patients (n = 64) with Dopa-responsive dystonia, in whom dystonia improved by at least 50% after l-Dopa treatment. Fifty seven of these patients were classified as pure Dopa-responsive dystonia and seven as Dopa-responsive dystonia-plus syndromes. All patients were screened for point mutations and large rearrangements in the GCH1 gene, followed by sequencing of the TH and SPR genes, then PTS (pyruvoyl tetrahydropterin synthase), PCBD (pterin-4a-carbinolamine dehydratase), QDPR (dihydropteridin reductase) and PARK2 (parkin) genes. We identified 34 different heterozygous point mutations in 40 patients, and six different large deletions in seven patients in the GCH1 gene. Except for one patient with mental retardation and a large deletion of 2.3 Mb encompassing 10 genes, all patients had stereotyped clinical features, characterized by pure Dopa-responsive dystonia with onset in the lower limbs and an excellent response to low doses of l-Dopa. Dystonia started in the first decade of life in 40 patients (85%) and before the age of 1 year in one patient (2.2%). Three of the 17 negative GCH1 patients had mutations in the TH gene, two in the SPR gene and one in the PARK2 gene. No mutations in the three genes involved in the biosynthesis and recycling of BH4 were identified. The clinical presentations of patients with mutations in TH and SPR genes were strikingly more complex, characterized by mental retardation, oculogyric crises and parkinsonism and they were all classified as Dopa-responsive dystonia-plus syndromes. Patient with mutation in the PARK2 gene had Dopa-responsive dystonia with a good improvement with l-Dopa, similar to Dopa-responsive dystonia secondary to GCH1 mutations. Although the yield of mutations exceeds 80% in pure Dopa-responsive dystonia and Dopa-responsive dystonia-plus syndromes groups, the genes involved are clearly different: GCH1 in the former and TH and SPR in the late
The Effect of Calcium Ions on Mechanosensation and Neuronal Activity in Proprioceptive Neurons
Proprioception of all animals is important in being able to have coordinated locomotion. Stretch activated ion channels (SACs) transduce the mechanical force into electrical signals in the proprioceptive sensory endings. The types of SACs vary among sensory neurons in animals as defined by pharmacological, physiological and molecular identification. The chordotonal organs within insects and crustaceans offer a unique ability to investigate proprioceptive function. The effects of the extracellular environment on neuronal activity, as well as the function of associated SACs are easily accessible and viable in minimal saline for ease in experimentation. The effect of extracellular [Ca2+] on membrane properties which affect voltage-sensitivity of ion channels, threshold of action potentials and SACs can be readily addressed in the chordotonal organ in crab limbs. It is of interest to understand how low extracellular [Ca2+] enhances neural activity considering the SACs in the sensory endings could possibly be Ca2+ channels and that all neural activity is blocked with Mn2+. It is suggested that axonal excitability might be affected independent from the SAC activity due to potential presence of calcium activated potassium channels (K(Ca)) and the ability of Ca2+ to block voltage gated Na+ channels in the axons. Separating the role of Ca2+ on the function of the SACs and the excitability of the axons in the nerves associated with chordotonal organs is addressed. These experiments may aid in understanding the mechanisms of neuronal hyperexcitability during hypocalcemia within mammals
Better Outcomes for Older people with Spinal Trouble (BOOST) Trial: a randomised controlled trial of a combined physical and psychological intervention for older adults with neurogenic claudication, a protocol
Introduction Neurogenic claudication due to spinal stenosis is common in older adults. The effectiveness of conservative interventions is not known. The aim of the study is to estimate the clinical and cost-effectiveness of a physiotherapist-delivered, combined physical and psychological intervention.
Methods and analysis This is a pragmatic, multicentred, randomised controlled trial. Participants are randomised to a combined physical and psychological intervention (Better Outcomes for Older people with Spinal Trouble (BOOST) programme) or best practice advice (control). Community-dwelling adults, 65 years and over, with neurogenic claudication are identified from community and secondary care services. Recruitment is supplemented using a primary care-based cohort. Participants are registered prospectively and randomised in a 2:1 ratio (intervention:control) using a web-based service to ensure allocation concealment. The target sample size is a minimum of 402. The BOOST programme consists of an individual assessment and twelve 90 min classes, including education and discussion underpinned by cognitive behavioural techniques, exercises and walking circuit. During and after the classes, participants undertake home exercises and there are two support telephone calls to promote adherence with the exercises. Best practice advice is delivered in one to three individual sessions with a physiotherapist. The primary outcome is the Oswestry Disability Index at 12 months. Secondary outcomes include the 6 Minute Walk Test, Short Physical Performance Battery, Fear Avoidance Beliefs Questionnaire and Gait Self-Efficacy Scale. Outcomes are measured at 6 and 12 months by researchers who are masked to treatment allocation. The primary statistical analysis will be by ‘intention to treat’. There is a parallel health economic evaluation and qualitative study
The clinical effectiveness of a physiotherapy delivered physical and psychological group intervention for older adults with neurogenic claudication: the BOOST randomised controlled trial.
This is the final version. Available from Oxford University Press via the DOI in this record. BACKGROUND: Neurogenic claudication (NC) is a debilitating spinal condition affecting older adults' mobility and quality of life. METHODS: A randomised controlled trial of 438 participants evaluated the effectiveness of a physical and psychological group intervention (BOOST programme) compared to physiotherapy assessment and tailored advice (best practice advice [BPA]) for older adults with NC. Participants were identified from spinal clinics (community and secondary care) and general practice records and randomised 2:1 to the BOOST programme or BPA. The primary outcome was the Oswestry Disability Index (ODI) at 12 months. Data was also collected at 6 months. Other outcomes included ODI walking item, 6-minute walk test (6MWT) and falls. The primary analysis was intention-to-treat. RESULTS: The average age of participants was 74.9 years (SD 6.0) and 57% (246/435) were female. There was no significant difference in ODI scores between treatment groups at 12 months (adjusted mean difference (MD): -1.4 [95% Confidence Intervals (CI) -4.03, 1.17]), but, at 6 months, ODI scores favoured the BOOST programme (adjusted MD: -3.7 [95% CI -6.27, -1.06]). At 12 months, the BOOST programme resulted in greater improvements in walking capacity (6MWT MD 21.7m [95% CI 5.96, 37.38]) and ODI walking item (MD -0.2 [95% CI -0.45, -0.01]) and reduced falls risk (odds ratio 0.6 [95% CI 0.40, 0.98]) compared to BPA. No serious adverse events were related to either treatment. CONCLUSIONS: The BOOST programme substantially improved mobility for older adults with NC. Future iterations of the programme will consider ways to improve long-term pain related disability.National Institute for Health Research (NIHR
The Clinical Effectiveness of a Physiotherapy Delivered Physical and Psychological Group Intervention for Older Adults With Neurogenic Claudication: The BOOST Randomized Controlled Trial
Background
Neurogenic claudication (NC) is a debilitating spinal condition affecting older adults’ mobility and quality of life.
Methods
A randomized controlled trial of 438 participants evaluated the effectiveness of a physical and psychological group intervention (BOOST program) compared to physiotherapy assessment and tailored advice (best practice advice [BPA]) for older adults with NC. Participants were identified from spinal clinics (community and secondary care) and general practice records and randomized 2:1 to the BOOST program or BPA. The primary outcome was the Oswestry Disability Index (ODI) at 12 months. Data were also collected at 6 months. Other outcomes included ODI walking item, 6-minute walk test (6MWT), and falls. The primary analysis was intention-to-treat.
Results
The average age of participants was 74.9 years (standard deviation [SD] 6.0) and 57% (246/435) were female. There was no significant difference in ODI scores between treatment groups at 12 months (adjusted mean difference [MD]: −1.4 [95% confidence intervals (CI) −4.03, 1.17]), but, at 6 months, ODI scores favored the BOOST program (adjusted MD: −3.7 [95% CI −6.27, −1.06]). At 12 months, the BOOST program resulted in greater improvements in walking capacity (6MWT MD: 21.7m [95% CI 5.96, 37.38]) and ODI walking item (MD: −0.2 [95% CI −0.45, −0.01]) and reduced falls risk (odds ratio: 0.6 [95% CI 0.40, 0.98]) compared to BPA. No serious adverse events were related to either treatment.
Conclusions
The BOOST program substantially improved mobility for older adults with NC. Future iterations of the program will consider ways to improve long-term pain-related disability.
Clinical Trials Registration Number: ISRCTN1269867
Spermatogenesis-Specific Features of the Meiotic Program in Caenorhabditis elegans
In most sexually reproducing organisms, the fundamental process of meiosis is implemented concurrently with two differentiation programs that occur at different rates and generate distinct cell types, sperm and oocytes. However, little is known about how the meiotic program is influenced by such contrasting developmental programs. Here we present a detailed timeline of late meiotic prophase during spermatogenesis in Caenorhabditis elegans using cytological and molecular landmarks to interrelate changes in chromosome dynamics with germ cell cellularization, spindle formation, and cell cycle transitions. This analysis expands our understanding C. elegans spermatogenesis, as it identifies multiple spermatogenesis-specific features of the meiotic program and provides a framework for comparative studies. Post-pachytene chromatin of spermatocytes is distinct from that of oocytes in both composition and morphology. Strikingly, C. elegans spermatogenesis includes a previously undescribed karyosome stage, a common but poorly understood feature of meiosis in many organisms. We find that karyosome formation, in which chromosomes form a constricted mass within an intact nuclear envelope, follows desynapsis, involves a global down-regulation of transcription, and may support the sequential activation of multiple kinases that prepare spermatocytes for meiotic divisions. In spermatocytes, the presence of centrioles alters both the relative timing of meiotic spindle assembly and its ultimate structure. These microtubule differences are accompanied by differences in kinetochores, which connect microtubules to chromosomes. The sperm-specific features of meiosis revealed here illuminate how the underlying molecular machinery required for meiosis is differentially regulated in each sex
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Effect of Hydrocortisone on Mortality and Organ Support in Patients With Severe COVID-19: The REMAP-CAP COVID-19 Corticosteroid Domain Randomized Clinical Trial.
Importance: Evidence regarding corticosteroid use for severe coronavirus disease 2019 (COVID-19) is limited. Objective: To determine whether hydrocortisone improves outcome for patients with severe COVID-19. Design, Setting, and Participants: An ongoing adaptive platform trial testing multiple interventions within multiple therapeutic domains, for example, antiviral agents, corticosteroids, or immunoglobulin. Between March 9 and June 17, 2020, 614 adult patients with suspected or confirmed COVID-19 were enrolled and randomized within at least 1 domain following admission to an intensive care unit (ICU) for respiratory or cardiovascular organ support at 121 sites in 8 countries. Of these, 403 were randomized to open-label interventions within the corticosteroid domain. The domain was halted after results from another trial were released. Follow-up ended August 12, 2020. Interventions: The corticosteroid domain randomized participants to a fixed 7-day course of intravenous hydrocortisone (50 mg or 100 mg every 6 hours) (n = 143), a shock-dependent course (50 mg every 6 hours when shock was clinically evident) (n = 152), or no hydrocortisone (n = 108). Main Outcomes and Measures: The primary end point was organ support-free days (days alive and free of ICU-based respiratory or cardiovascular support) within 21 days, where patients who died were assigned -1 day. The primary analysis was a bayesian cumulative logistic model that included all patients enrolled with severe COVID-19, adjusting for age, sex, site, region, time, assignment to interventions within other domains, and domain and intervention eligibility. Superiority was defined as the posterior probability of an odds ratio greater than 1 (threshold for trial conclusion of superiority >99%). Results: After excluding 19 participants who withdrew consent, there were 384 patients (mean age, 60 years; 29% female) randomized to the fixed-dose (n = 137), shock-dependent (n = 146), and no (n = 101) hydrocortisone groups; 379 (99%) completed the study and were included in the analysis. The mean age for the 3 groups ranged between 59.5 and 60.4 years; most patients were male (range, 70.6%-71.5%); mean body mass index ranged between 29.7 and 30.9; and patients receiving mechanical ventilation ranged between 50.0% and 63.5%. For the fixed-dose, shock-dependent, and no hydrocortisone groups, respectively, the median organ support-free days were 0 (IQR, -1 to 15), 0 (IQR, -1 to 13), and 0 (-1 to 11) days (composed of 30%, 26%, and 33% mortality rates and 11.5, 9.5, and 6 median organ support-free days among survivors). The median adjusted odds ratio and bayesian probability of superiority were 1.43 (95% credible interval, 0.91-2.27) and 93% for fixed-dose hydrocortisone, respectively, and were 1.22 (95% credible interval, 0.76-1.94) and 80% for shock-dependent hydrocortisone compared with no hydrocortisone. Serious adverse events were reported in 4 (3%), 5 (3%), and 1 (1%) patients in the fixed-dose, shock-dependent, and no hydrocortisone groups, respectively. Conclusions and Relevance: Among patients with severe COVID-19, treatment with a 7-day fixed-dose course of hydrocortisone or shock-dependent dosing of hydrocortisone, compared with no hydrocortisone, resulted in 93% and 80% probabilities of superiority with regard to the odds of improvement in organ support-free days within 21 days. However, the trial was stopped early and no treatment strategy met prespecified criteria for statistical superiority, precluding definitive conclusions. Trial Registration: ClinicalTrials.gov Identifier: NCT02735707
Effects of eight neuropsychiatric copy number variants on human brain structure
Many copy number variants (CNVs) confer risk for the same range of neurodevelopmental symptoms and psychiatric conditions including autism and schizophrenia. Yet, to date neuroimaging studies have typically been carried out one mutation at a time, showing that CNVs have large effects on brain anatomy. Here, we aimed to characterize and quantify the distinct brain morphometry effects and latent dimensions across 8 neuropsychiatric CNVs. We analyzed T1-weighted MRI data from clinically and non-clinically ascertained CNV carriers (deletion/duplication) at the 1q21.1 (n = 39/28), 16p11.2 (n = 87/78), 22q11.2 (n = 75/30), and 15q11.2 (n = 72/76) loci as well as 1296 non-carriers (controls). Case-control contrasts of all examined genomic loci demonstrated effects on brain anatomy, with deletions and duplications showing mirror effects at the global and regional levels. Although CNVs mainly showed distinct brain patterns, principal component analysis (PCA) loaded subsets of CNVs on two latent brain dimensions, which explained 32 and 29% of the variance of the 8 Cohen’s d maps. The cingulate gyrus, insula, supplementary motor cortex, and cerebellum were identified by PCA and multi-view pattern learning as top regions contributing to latent dimension shared across subsets of CNVs. The large proportion of distinct CNV effects on brain morphology may explain the small neuroimaging effect sizes reported in polygenic psychiatric conditions. Nevertheless, latent gene brain morphology dimensions will help subgroup the rapidly expanding landscape of neuropsychiatric variants and dissect the heterogeneity of idiopathic conditions
Australian marine protected areas
Marine protected areas (MPAs) are sites in the ocean and coastal sea that are dedicated to the conservation of biodiversity, fisheries, ecosystem services and cultural values. MP As range from small, highly protected marine reserves through to large, multiple-use marine parks, such as the Great Barrier Reef Marine Park of Queensland, Australia. This chapter identifies the major policy events and phases of MPA development in Australia, and explores the role and effectiveness of MP As in conserving Australia's marine environment. The governance of Australian MPAs is complex; the responsibility for their declaration and management is shared between the Australian (Commonwealth), State and Territory Governments. Progress in the declaration and management of MP As is not uniform across Australia, with some jurisdictions performing better than others. Australia is considered a world leader in the science and implementation of MPAs. However, there are serious weaknesses in the design of MP As in Commonwealth waters due to the locating of new MPAs where they are least controversial and least costly. Considerable further effort is needed to create an effective national programme for delivering biodiversity conservation in Australia waters. This is particularly important because Australia's oceans face an unprecedented set of pressures from accelerating climate change and coastal development
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