Virtual Coaching and the Reduction of Radial Head Subluxation: A Case Series.

OBJECTIVES: After the establishment of the virtual pediatric emergency medicine clinic at our institution, we noted that several physicians independently began to instruct caregivers virtually on reducing a radial head subluxation. We thus conducted a case series to investigate the number, success, and follow-ups for the virtual reduction of radial head subluxation. METHODS: The electronic medical records at our institution were searched from the inception of the virtual clinic in May 2020 until August 2022 (inclusive), for visits and discharge diagnosis containing the word "elbow" or "arm." RESULTS: Fourteen charts were retrieved; however, 2 were excluded because they were not a suspected radial head subluxation. A virtual reduction was attempted for eight (66.7%) of the 12 patients. In 6 of 8 patients (75.0%), the reduction was deemed successful, and for 2 patients (25.0%), it was deemed unsuccessful. Of the latter, one was found to have a nondisplaced radial neck fracture. All 4 patients (33.3%) for whom a virtual reduction was not attempted were referred to the emergency department. CONCLUSIONS: Virtual video coaching of pulled elbow reduction was completed at our institution with overall good success rate. All the physicians involved noted the essential need and benefits of video conferencing for successfully reducing radial head subluxation. We note that a pediatric population may be more amenable to video-based appointments than other populations due to their caregivers' familiarity with digital technology. Finally, as nonphysician models of healthcare delivery for virtual urgent care visits expand, we propose a checklist based on our experience to ensure patient safety.

Population parameters and conservation implications for one of the world's rarest marine fishes, the red handfish (Thymichthys politus).

Population estimates are required for effective conservation of many rare marine species, but can be difficult to obtain. The critically endangered red handfish (Thymichthys politus) is a coastal anglerfish known only from two fragmented populations in southeast Tasmania, Australia. It is at a high risk of extinction due to low numbers, loss of habitat, and the impacts of climate change. To aid conservation efforts, we provide the first empirical population size estimates of red handfish and investigate other important aspects of the species' life history, such as growth, habitat association, and movement. We surveyed both red handfish local populations via underwater visual census on scuba over 3 years and used photographic mark-recapture techniques to estimate biological parameters. In 2020, the local adult population size was estimated to be 94 (95% confidence interval [CI] 40-231) adults at one site, and 7 (95% CI 5-10) at the other site, suggesting an estimated global population of 101 adults. Movement of individuals was extremely limited at 48.5 m (± 77.7 S.D.) per year. We also found evidence of declining fish density, a declining proportion of juveniles, and increasing average fish size during the study. These results provide a serious warning that red handfish are likely sliding toward extinction, and highlight the urgent need to expand efforts for ex situ captive breeding to bolster numbers in the wild and maintain captive insurance populations, and to protect vital habitat to safeguard the species' ongoing survival in the wild.

ABI5 binding protein2 inhibits ABA responses during germination without ABA-INSENSITIVE5 degradation.

Overexpression of ABA-INSENSITIVE5 binding proteins (AFPs) results in extreme ABA resistance of seeds and failure to acquire desiccation tolerance, at least in part through effects on chromatin modification. We tested the hypothesis that AFPs promote germination in Arabidopsis (Arabidopsis thaliana) by also functioning as adapters for E3 ligases that ubiquitinate ABI5, leading to its degradation. Interactions between AFPs and two well-characterized classes of E3 ligases targeting ABI5, DWD HYPERSENSITIVE TO ABA (DWA)s and KEEP ON GOING, were analyzed by yeast two-hybrid, bimolecular fluorescence complementation, and genetic assays. Although weak direct interactions were detected between AFPs and E3 ligases, loss of function for these E3 ligases did not impair ABA-resistance conferred by overexpression of the YFP-AFP2 fusion. Comparison of ABI5 and AFP2 levels in these lines showed that AFP2 accumulation increased during germination, but that ABI5 degradation followed germination, demonstrating that AFP2 overexpression reduces ABA sensitivity, thereby permitting germination prior to ABI5 degradation. Surprisingly, AFP2 overexpression in the dwa1 dwa2 mutant background produced the unusual combination of extreme ABA resistance and desiccation tolerance, creating an opportunity to separate the underlying biochemical characteristics of ABA sensitivity and desiccation tolerance. Our quantitative proteomics analysis identified at least three-fold more differentially accumulated seed proteins than previous studies. Comparison of dry seed proteomes of wild-type or dwa1 dwa2 mutants with or without AFP2 overexpression allowed us to separate and refine the changes in protein accumulation patterns associated with desiccation tolerance independently of ABA sensitivity, or vice versa, to a subset of cold-induced and defense stress-responsive proteins and signaling regulators.

Genetic Testing in Parkinson's Disease.

Genetic testing for persons with Parkinson's disease is becoming increasingly common. Significant gains have been made regarding genetic testing methods, and testing is becoming more readily available in clinical, research, and direct-to-consumer settings. Although the potential utility of clinical testing is expanding, there are currently no proven gene-targeted therapies, but clinical trials are underway. Furthermore, genetic testing practices vary widely, as do knowledge and attitudes of relevant stakeholders. The specter of testing mandates financial, ethical, and physician engagement, and there is a need for guidelines to help navigate the myriad of challenges. However, to develop guidelines, gaps and controversies need to be clearly identified and analyzed. To this end, we first reviewed recent literature and subsequently identified gaps and controversies, some of which were partially addressed in the literature, but many of which are not well delineated or researched. Key gaps and controversies include: (1) Is genetic testing appropriate in symptomatic and asymptomatic individuals without medical actionability? (2) How, if at all, should testing vary based on ethnicity? (3) What are the long-term outcomes of consumer- and research-based genetic testing in presymptomatic PD? (4) What resources are needed for clinical genetic testing, and how is this impacted by models of care and cost-benefit considerations? Addressing these issues will help facilitate the development of consensus and guidelines regarding the approach and access to genetic testing and counseling. This is also needed to guide a multidisciplinary approach that accounts for cultural, geographic, and socioeconomic factors in developing testing guidelines. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Overexpression of ABI5 Binding Proteins Suppresses Inhibition of Germination Due to Overaccumulation of DELLA Proteins.

Abscisic acid (ABA) and gibberellic acid (GA) antagonistically regulate many aspects of plant growth, including seed dormancy and germination. The effects of these hormones are mediated by a complex network of positive and negative regulators of transcription. The DELLA family of proteins repress GA response, and can promote an ABA response via interactions with numerous regulators, including the ABA-insensitive (ABI) transcription factors. The AFP family of ABI5 binding proteins are repressors of the ABA response. This study tested the hypothesis that the AFPs also interact antagonistically with DELLA proteins. Members of these protein families interacted weakly in yeast two-hybrid and bimolecular fluorescence complementation studies. Overexpression of AFPs in sleepy1, a mutant that over-accumulates DELLA proteins, suppressed DELLA-induced overaccumulation of storage proteins, hyperdormancy and hypersensitivity to ABA, but did not alter the dwarf phenotype of the mutant. The interaction appeared to reflect additive effects of the AFPs and DELLAs, consistent with action in convergent pathways.

Cathepsin B p.Gly284Val Variant in Parkinson's Disease Pathogenesis.

Parkinson's disease (PD) is generally considered a sporadic disorder, but a strong genetic background is often found. The aim of this study was to identify the underlying genetic cause of PD in two affected siblings and to subsequently assess the role of mutations in Cathepsin B (CTSB) in susceptibility to PD. A typical PD family was identified and whole-exome sequencing was performed in two affected siblings. Variants of interest were validated using Sanger sequencing. CTSB p.Gly284Val was genotyped in 2077 PD patients and 615 unrelated healthy controls from the Czech Republic, Ireland, Poland, Ukraine, and the USA. The gene burden analysis was conducted for the CTSB gene in an additional 769 PD probands from Mayo Clinic Florida familial PD cohort. CTSB expression and activity in patient-derived fibroblasts and controls were evaluated by qRT-PCR, western blot, immunocytochemistry, and enzymatic assay. The CTSB p.Gly284Val candidate variant was only identified in affected family members. Functional analysis of CTSB patient-derived fibroblasts under basal conditions did not reveal overt changes in endogenous expression, subcellular localization, or enzymatic activity in the heterozygous carrier of the CTSB variant. The identification of the CTSB p.Gly284Val may support the hypothesis that the CTSB locus harbors variants with differing penetrance that can determine the disease risk.

Ictal aphasia in LGI1-related autosomal dominant epilepsy with auditory features.

Autosomal dominant epilepsy with auditory features (OMIM 600512) is characterised by focal seizures with distinctive auditory auras and/or ictal aphasia. We describe a 17-year-old girl with recurrent attacks of ictal aphasia and rare nocturnal convulsions. She had a four-generation paternal family history of epilepsy. Her father and aunt perceived bells ringing at the onset of seizures. Sequence analysis of the leucine-rich glioma-inactivated 1 (LGI1) gene identified a novel heterozygous variant in the proband and her father. LGI1-related genetic epilepsy has a benign clinical course with a favourable response to anti-seizure medications. Auditory or vertiginous seizures may be mistaken for peripheral audio-vestibular symptoms, while complex auditory ictal symptoms may be misattributed to primary psychiatric disorders. Recognising this distinctive inherited syndrome should prompt targeted analysis of the LGI1 gene.

Estimating animal population size with very high-resolution satellite imagery.

Very high-resolution (VHR) satellite sensors can be used to estimate the size of animal populations, a critical factor in wildlife management, and acquire animal spatial distributions in an economical, easy, and precise way. We developed a method for satellite population size estimation that includes a noninvasive photogrammetry, from which the animal's average orthographic area is calculated, and an imagery interpretation method that estimates population size based on the ratio of an observed animal population area to the average individual area. As a proof of concept, we used this method to estimate the population size of Whooper Swans (Cygnus cygnus) in a national nature reserve in China. To reduce errors, the reserve was subdivided into regions of interest based on locations of Whooper Swan and background brightness. Estimates from the satellite pixels were compared with manual counts made over 2 years, at 3 locations, and in 3 land-cover types. Our results showed 1124 Whooper Swans occupied a national nature reserve on 15 February 2013, and the average percent error was 3.16% (SE = 1.37). These results demonstrate that our method produced robust data for population size estimation that were indistinguishable from manual count data. Our method may be used generally to estimate population sizes of visible and gregarious animals that exhibit high contrast relative to their environments and may inform estimations of populations in complex backgrounds.

Estimación del Tamaño de las Poblaciones Animales Mediante Imágenes Satelitales de Muy Alta Resolución Resumen Los sensores satelitales de muy alta resolución (VHR) pueden utilizarse para estimar el tamaño de las poblaciones animales, un factor muy importante para el manejo de fauna, y para adquirir las distribuciones espaciales de los animales de una manera económica, sencilla y precisa. Desarrollamos un método para la estimación satelital del tamaño poblacional que incluye fotogrametría no invasiva, a partir de la cual se calcula el área ortogonal promedio del animal, y un método de interpretación de imágenes que estima el tamaño poblacional con base en la proporción del área poblacional observada de un animal con respecto al área individual promedio. Como demostración conceptual, usamos este método para estimar el tamaño poblacional del cisne trompetista (Cygnus cygnus) dentro de una reserva natural nacional en China. Para reducir los errores, subdividimos la reserva en regiones de interés con base en las ubicaciones de los cisnes y el brillo del fondo. Las estimaciones a partir de los pixeles satelitales fueron comparadas con los conteos manuales realizados a lo largo de dos años en tres ubicaciones y en tres tipos de cobertura de suelo. Nuestros resultados mostraron a 1124 cisnes ocupando una reserva natural nacional el 15 de febrero de 2013 y el error porcentual promedio fue de 3.15% (SE 1.37). Estos resultados demostraron que nuestro método produjo datos sólidos para la estimación del tamaño poblacional que eran indistinguibles de los datos obtenidos mediante el conteo manual. Nuestro método puede usarse de manera generalizada para estimar el tamaño poblacional de especies gregarias y visibles que exhiben un contraste alto en relación con su entorno y puede orientar las estimaciones de poblaciones con fondos complejos.

Effect of the COVID-19 Pandemic on Patient Volumes, Acuity, and Outcomes in Pediatric Emergency Departments: A Nationwide Study.

OBJECTIVES: The aim of this study was to quantify the effect of the COVID-19 pandemic on pediatric emergency department (ED) utilization and outcomes. METHODS: This study is an interrupted-time-series observational study of children presenting to 11 Canadian tertiary-care pediatric EDs. Data were grouped into weeks in 3 study periods: prepandemic (January 1, 2018-January 27, 2020), peripandemic (January 28, 2020-March 10, 2020), and early pandemic (March 11, 2020-April 30, 2020). These periods were compared with the same time intervals in the 2 preceding calendar years. Primary outcomes were number of ED visits per week. The secondary outcomes were triage acuity, hospitalization, intensive care unit (ICU) admission, mortality, length of hospital stay, ED revisits, and visits for trauma and mental health concerns. RESULTS: There were 577,807 ED visits (median age, 4.5 years; 52.9% male). Relative to the prepandemic period, there was a reduction [-58%; 95% confidence interval (CI), -63% to -51%] in the number of ED visits during the early-pandemic period, with concomitant higher acuity. There was a concurrent increase in the proportion of ward [odds ratio (OR), 1.39; 95% CI, 1.32-1.45] and intensive care unit (OR, 1.20; 95% CI, 1.01-1.42) admissions, and trauma-related ED visits among children less than 10 years (OR, 1.51; 95% CI, 1.45-1.56). Mental health-related visits in children declined in the early-pandemic period (in <10 years, -60%; 95% CI, -67% to -51%; in children ≥10 years: -56%; 95% CI, -63% to -47%) relative to the pre-COVID-19 period. There were no differences in mortality or length of stay; however, ED revisits within 72 hours were reduced during the early-pandemic period (percent change: -55%; 95% CI, -61% to -49%; P < 0.001). CONCLUSIONS: After the declaration of the COVID-19 pandemic, dramatic reductions in pediatric ED visits occurred across Canada. Children seeking ED care were sicker, and there was an increase in trauma-related visits among children more than 10 years of age, whereas mental health visits declined during the early-pandemic period. When faced with a future pandemic, public health officials must consider the impact of the illness and the measures implemented on children's health and acute care needs.

Prognostic value of colonic and peripheral venous lactate measurements in horses with large colon volvulus.

OBJECTIVE: To determine the prognostic value of (1) colonic venous lactate or peripheral lactate values obtained before and after manual correction of a large colon volvulus and (2) a combination of variables including pelvic flexure biopsy. STUDY DESIGN: Prospective clinical study. ANIMALS: Forty adult horses in which large colon volvulus was diagnosed intraoperatively. METHODS: Colonic venous, peripheral venous, and arterial blood samples were collected to measure lactate values before and after manual correction. Mucosal biopsy samples were obtained in cases that underwent enterotomy or colonic resection and anastomosis. Interstitium to crypt (I:C) ratio and hemorrhage scores were measured. Optimal cutoff values were determined by receiver operator curve analysis, and associations between variables and short-term outcome were determined by univariable regression. Short-term survival was defined as horses being discharged from the hospital. P ≤ .05 was considered significant. RESULTS: No association was found between colonic venous lactate values before (P = .011) or after (P = .201) manual correction of large colon volvulus and determination of short-term outcome. Peripheral venous lactate at admission ≥3.2 mmol/L and after manual correction ≥5 mmol/L, arterial lactate postmanual correction ≥3.53 mmol/L, and histomorphometric measurements of mucosal hemorrhage ≥3 and I:C ratio > 1 were associated with poor short-term outcome. CONCLUSION: Peripheral lactate values, histomorphometric measures of I:C ratio, and hemorrhage score provided prognostic information that could help guide recommendations made to owners. CLINICAL SIGNIFICANCE: Peripheral lactate values after manual correction provide important intraoperative diagnostic information to assist in predicting case outcome in the operative and immediately postoperative period.

Factors Associated With Discharge Home After Transfer to a Pediatric Emergency Department.

OBJECTIVES: The transfer of children from community emergency departments (EDs) to tertiary care pediatric EDs for investigations, interventions, or a second opinion is common. In order to improve health care system efficiency, we must have a better understanding of this population and identify areas for education and capacity building. METHODS: We conducted a retrospective chart review of all patients (aged 0-17 years) who were transferred from community ED to a pediatric ED from November 2013 to November 2014. The primary outcome was the frequency of referred patients who were discharged home from the pediatric ED. RESULTS: Two hundred four patients were transferred from community EDs in the study period. One hundred thirteen children (55.4%) were discharged home from the pediatric ED. Presence of inpatient pediatric services (P = 0.04) at the referral hospital and a respiratory diagnosis (P = 0.03) were independently associated with admission to the children's hospital. In addition, 74 patients (36.5%) had no critically abnormal vital signs at the referral hospital and did not require any special tests, interventions, consultations, or admission to the children's hospital. Younger age (P = 0.03), lack of inpatient pediatric services (P = 0.04), and a diagnosis change (P = 0.03) were independently associated with this outcome. CONCLUSIONS: More than half of patients transferred to the pediatric tertiary care ED did not require admission, and more than one third did not require special tests, interventions, consults, or admission. Many of these patients were likely transferred for a second opinion from a pediatric emergency medicine specialist. Education and real-time videoconferencing consultations using telemedicine may help to reduce the frequency of transfers for a second opinion and contribute to cost savings over the long term.

Guillain-Barré syndrome mimicking botulism in early disease course.

A 42-year-old man, returning to Europe after a 2-month stay in China, reported cough and runny nose. Five days later, he developed neck discomfort and rapidly evolving weakness, spreading from his arms to the facial, bulbar and neck muscles, and then the legs. He developed dysphagia and breathlessness, and was intubated in the emergency department. Cerebrospinal fluid showed mildly elevated protein. On day 2 he had fixed dilated pupils, with absent oculocephalic reflexes, and a flaccid upper limb paralysis. MR scans of the brain and spinal cord were normal. The early features of descending weakness, bulbar involvement and fixed dilated pupils made it difficult to distinguish between Guillain-Barré syndrome and botulism, and early investigations were inconclusive. We initially gave both botulinum antitoxin and intravenous immunoglobulin, but initially delayed plasma exchange as this would have removed the botulinum antitoxin. Diagnostic testing for botulism has low sensitivity, so we urge pre-emptive treatment if it is clinically suspected.

ABI5-binding proteins (AFPs) alter transcription of ABA-induced genes via a variety of interactions with chromatin modifiers.

KEY MESSAGE: Overexpression of ABI5/ABF binding proteins (AFPs) results in extreme ABA resistance of seeds via multiple mechanisms repressing ABA response, including interactions with histone deacetylases and the co-repressor TOPLESS. Several ABI5/ABF binding proteins (AFPs) inhibit ABA response, resulting in extreme ABA resistance in transgenic Arabidopsis overexpression lines, but their mechanism of action has remained obscure. By analogy to the related Novel Interactor of JAZ (NINJA) protein, it was suggested that the AFPs interact with the co-repressor TOPLESS to inhibit ABA-regulated gene expression. This study shows that the AFPs that inhibit ABA response have intrinsic repressor activity in a heterologous system, which does not depend on the domain involved in the interaction with TOPLESS. This domain is also not essential for repressing ABA response in transgenic plants, but does contribute to stronger ABA resistance. Additional interactions between some AFPs and histone deacetylase subunits were observed in yeast two-hybrid and bimolecular fluorescence assays, consistent with a more direct mechanism of AFP-mediated repression of gene expression. Chemical inhibition of histone deacetylase activity by trichostatin A suppressed AFP effects on a small fraction of the ABI5-regulated genes tested. Collectively, these results suggest that the AFPs participate in multiple mechanisms modulating ABA response, including both TOPLESS-dependent and -independent chromatin modification.

Dancing for Parkinson Disease: A Randomized Trial of Irish Set Dancing Compared With Usual Care.

OBJECTIVE: To examine the feasibility of a randomized controlled study design and to explore the benefits of a set dancing intervention compared with usual care. DESIGN: Randomized controlled design, with participants randomized to Irish set dance classes or a usual care group. SETTING: Community based. PARTICIPANTS: Individuals with idiopathic Parkinson disease (PD) (N=90). INTERVENTIONS: The dance group attended a 1.5-hour dancing class each week for 10 weeks and undertook a home dance program for 20 minutes, 3 times per week. The usual care group continued with their usual care and daily activities. MAIN OUTCOME MEASURES: The primary outcome was feasibility, determined by recruitment rates, success of randomization and allocation procedures, attrition, adherence, safety, willingness of participants to be randomized, resource availability, and cost. Secondary outcomes were motor function (motor section of the Unified Parkinson's Disease Rating Scale), quality of life (Parkinson's Disease Questionnaire-39), functional endurance (6-min walk test), and balance (mini-BESTest). RESULTS: Ninety participants were randomized (45 per group). There were no adverse effects or resource constraints. Although adherence to the dancing program was 93.5%, there was >40% attrition in each group. Postintervention, the dance group had greater nonsignificant gains in quality of life than the usual care group. There was a meaningful deterioration in endurance in the usual care group. There were no meaningful changes in other outcomes. The exit questionnaire showed participants enjoyed the classes and would like to continue participation. CONCLUSIONS: For people with mild to moderately severe PD, set dancing is feasible and enjoyable and may improve quality of life.

Genetics of Frontotemporal Dementia.

Frontotemporal dementia (FTD) is the second most common cause of dementia following Alzheimer's disease (AD). Between 20 and 50% of cases are familial. Mutations in MAPT, GRN and C9orf72 are found in 60% of familial FTD cases. C9orf72 mutations are the most common and account for 25%. Rarer mutations (<5%) occur in other genes such as VPC, CHMP2B, TARDP, FUS, ITM2B, TBK1 and TBP. The diagnosis is often challenging due to symptom overlap with AD and other conditions. We review the genetics, clinical presentations, neuroimaging, neuropathology, animal studies and therapeutic trials in FTD. We describe clinical scenarios including the original family with the tau stem loop mutation (+14) and also the recently discovered 'missing tau' mutation +15 that 'closed the loop' in 2015.

Closing the tau loop: the missing tau mutation.

Frontotemporal lobar degeneration comprises a group of disorders characterized by behavioural, executive, language impairment and sometimes features of parkinsonism and motor neuron disease. In 1994 we described an Irish-American family with frontotemporal dementia linked to chromosome 17 associated with extensive tau pathology. We named this disinhibition-dementia-parkinsonism-amyotrophy complex. We subsequently identified mutations in the MAPT gene. Eleven MAPT gene splice site stem loop mutations were identified over time except for 5' splice site of exon 10. We recently identified another Irish family with autosomal dominant early amnesia and behavioural change or parkinsonism associated with the 'missing' +15 mutation at the intronic boundary of exon 10. We performed a clinical, neuropsychological and neuroimaging study on the proband and four siblings, including two affected siblings. We sequenced MAPT and performed segregation analysis. We looked for a biological effect of the tau variant by performing real-time polymerase chain reaction analysis of RNA extracted from human embryonic kidney cells transfected with exon trapping constructs. We found a c.915+15A>C exon 10/intron 10 stem loop mutation in all affected subjects but not in the unaffected. The c.915+15A>C variant caused a shift in tau splicing pattern to a predominantly exon 10+ pattern presumably resulting in predominant 4 repeat tau and little 3 repeat tau. This strongly suggests that the c.915+15A>C variant is a mutation and that it causes frontotemporal dementia linked to chromosome 17 in this pedigree by shifting tau transcription and translation to +4 repeat tau. Tau (MAPT) screening should be considered in families where amnesia or atypical parkinsonism coexists with behavioural disturbance early in the disease process. We describe the final missing stem loop tau mutation predicted 15 years ago. Mutations have now been identified at all predicted sites within the 'stem' when the stem-loop model was first proposed and no mutations have been found within the 'loop' region as expected. Therefore we 'close the tau loop' having 'opened the loop' 21 years ago.

An evaluation of the role of environmental factors in the disease penetrance of cervical dystonia.

BACKGROUND: Adult onset primary torsion dystonia (AOPTD) is a poorly penetrant autosomal dominant disorder; most gene carriers are non-manifesting despite having reached an adequate age for penetrance. It is hypothesised that genetic, epigenetic and environmental factors may exert protective or deleterious effects on penetrance of AOPTD. By examining environmental exposure history in cervical dystonia patients and their similarly aged unaffected siblings we aimed to determine the role of previous environmental exposures in relation to disease penetrance. METHODS: A case-control study of 67 patients with cervical dystonia and 67 of their age-matched unaffected siblings was performed. Past environmental exposures were assessed using a detailed 124-question standardised questionnaire. RESULTS: By univariate analysis, cervical dystonia patients, compared to their unaffected siblings, had an increased frequency of a history of car accidents with hospital attendance (OR 10.1, 95% CI 2.1 to 47.4, p=0.004) and surgical episodes (OR 6.5, 95% CI 1.76 to 23.61, p=0.005). Following multivariate analysis, car accidents with hospital attendance (OR 7.3, 95% CI 1.4 to 37.6, p=0.017) and all surgical episodes (OR 4.9, 95% CI 1.24 to 19.31, p=0.023) remained significantly associated with case status. CONCLUSIONS: Cervical dystonia patients had a history, prior to symptom onset, of significantly more frequent episodes of surgery and of car accidents with hospital attendance than their age-matched unaffected siblings. Soft tissue trauma appears to increase risk of development of cervical dystonia in genetically predetermined individuals.

VPS35 mutations in Parkinson disease.

The identification of genetic causes for Mendelian disorders has been based on the collection of multi-incident families, linkage analysis, and sequencing of genes in candidate intervals. This study describes the application of next-generation sequencing technologies to a Swiss kindred presenting with autosomal-dominant, late-onset Parkinson disease (PD). The family has tremor-predominant dopa-responsive parkinsonism with a mean onset of 50.6 ± 7.3 years. Exome analysis suggests that an aspartic-acid-to-asparagine mutation within vacuolar protein sorting 35 (VPS35 c.1858G>A; p.Asp620Asn) is the genetic determinant of disease. VPS35 is a central component of the retromer cargo-recognition complex, is critical for endosome-trans-golgi trafficking and membrane-protein recycling, and is evolutionarily highly conserved. VPS35 c.1858G>A was found in all affected members of the Swiss kindred and in three more families and one patient with sporadic PD, but it was not observed in 3,309 controls. Further sequencing of familial affected probands revealed only one other missense variant, VPS35 c.946C>T; (p.Pro316Ser), in a pedigree with one unaffected and two affected carriers, and thus the pathogenicity of this mutation remains uncertain. Retromer-mediated sorting and transport is best characterized for acid hydrolase receptors. However, the complex has many types of cargo and is involved in a diverse array of biologic pathways from developmental Wnt signaling to lysosome biogenesis. Our study implicates disruption of VPS35 and retromer-mediated trans-membrane protein sorting, rescue, and recycling in the neurodegenerative process leading to PD.

Translation initiator EIF4G1 mutations in familial Parkinson disease.

Genome-wide analysis of a multi-incident family with autosomal-dominant parkinsonism has implicated a locus on chromosomal region 3q26-q28. Linkage and disease segregation is explained by a missense mutation c.3614G>A (p.Arg1205His) in eukaryotic translation initiation factor 4-gamma (EIF4G1). Subsequent sequence and genotype analysis identified EIF4G1 c.1505C>T (p.Ala502Val), c.2056G>T (p.Gly686Cys), c.3490A>C (p.Ser1164Arg), c.3589C>T (p.Arg1197Trp) and c.3614G>A (p.Arg1205His) substitutions in affected subjects with familial parkinsonism and idiopathic Lewy body disease but not in control subjects. Despite different countries of origin, persons with EIF4G1 c.1505C>T (p.Ala502Val) or c.3614G>A (p.Arg1205His) mutations appear to share haplotypes consistent with ancestral founders. eIF4G1 p.Ala502Val and p.Arg1205His disrupt eIF4E or eIF3e binding, although the wild-type protein does not, and render mutant cells more vulnerable to reactive oxidative species. EIF4G1 mutations implicate mRNA translation initiation in familial parkinsonism and highlight a convergent pathway for monogenic, toxin and perhaps virally-induced Parkinson disease.