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1.
J Binocul Vis Ocul Motil ; 74(1): 17-31, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38421249

RESUMO

Post-stroke visual impairment (PSVI) affects more than 60% of the people who have a stroke but visual function is not routinely assessed in most stroke units. Recent high-quality research in this field has produced evidence-based assessment and management practices for PSVI. Orthoptists have integrated into the stroke care team in the United Kingdom (UK) to provide this valuable service. This paper outlines the development and implementation of the first known orthoptic PSVI service in North America. A pilot program was developed between the Ophthalmology, Neurology, and Physical Medicine and Rehabilitation Departments in Saskatoon, Saskatchewan, Canada. A new referral pathway was established to refer stroke patients with PSVI directly to an orthoptist with specialization in PSVI. Clinical findings from the first year of operation are reported. One hundred and seven visual deficits were suspected by the referring service. Visual field deficits were the most commonly reported PSVI. Diplopia was the most commonly reported oculomotor deficit in this cohort, and visual neglect/inattention was the most common visual perceptual deficit reported. Reading issues were the most commonly reported functional issues. Following assessment by an orthoptist, 45 additional visual deficits were identified and addressed. Stroke patients require assessment and treatment for PSVI. Orthoptists are perfectly suited to PSVI assessment and management. There is an opportunity to increase orthoptists' scope of practice in North America to ensure stroke patients receive specialized vision assessment and treatment.


Assuntos
Oftalmologia , Baixa Visão , Humanos , Canadá , Diplopia , Ortóptica
2.
Ann Transplant ; 29: e941881, 2024 Feb 27.
Artigo em Inglês | MEDLINE | ID: mdl-38409779

RESUMO

BACKGROUND Mitochondrial neurogastrointestinal encephalopathy syndrome (MNGIE) is an autosomal recessive disease caused by thymidine phosphorylase deficiency leading to progressive gastrointestinal dysmotility, cachexia, ptosis, ophthalmoparesis, peripheral neuropathy and leukoencephalopathy. Although liver transplantation corrects thymidine phosphorylase deficiency, intestinal deficiency of the enzyme persists. Retrospective chart review was carried out to obtain clinical, biochemical, and pathological details. CASE REPORT We present a case of liver and subsequent intestine transplant in a 28-year-old man with MNGIE syndrome with gastrointestinal dysmotility, inability to walk, leukoencephalopathy, ptosis, cachexia, and elevated serum thymidine. To halt progression of neurologic deficit, he first received a left-lobe partial liver transplantation. Although his motor deficit improved, gastrointestinal dysmotility persisted, requiring total parenteral nutrition. After exhaustive intestinal rehabilitation, he was listed for intestine transplantation. Two-and-half years after liver transplantation, he received an intestine transplant. At 4 years after LT and 20 months after the intestine transplant, he remains off parenteral nutrition and is slowly gaining weight. CONCLUSIONS This is the first reported case of mitochondrial neurogastrointestinal encephalomyopathy to undergo successful sequential liver and intestine transplantation.


Assuntos
Pseudo-Obstrução Intestinal , Leucoencefalopatias , Encefalomiopatias Mitocondriais , Distrofia Muscular Oculofaríngea , Oftalmoplegia , Oftalmoplegia/congênito , Masculino , Humanos , Adulto , Caquexia , Estudos Retrospectivos , Encefalomiopatias Mitocondriais/cirurgia , Encefalomiopatias Mitocondriais/patologia , Oftalmoplegia/etiologia , Oftalmoplegia/cirurgia , Intestinos/patologia , Fígado/patologia
3.
Can J Neurol Sci ; : 1-8, 2024 Feb 26.
Artigo em Inglês | MEDLINE | ID: mdl-38403588

RESUMO

BACKGROUND AND PURPOSE: To assess cost-effectiveness of late time-window endovascular treatment (EVT) in a clinical trial setting and a "real-world" setting. METHODS: Data are from the randomized ESCAPE trial and a prospective cohort study (ESCAPE-LATE). Anterior circulation large vessel occlusion patients presenting > 6 hours from last-known-well were included, whereby collateral status was an inclusion criterion for ESCAPE but not ESCAPE-LATE. A Markov state transition model was built to estimate lifetime costs and quality-adjusted life-years (QALYs) for EVT in addition to best medical care vs. best medical care only in a clinical trial setting (comparing ESCAPE-EVT to ESCAPE control arm patients) and a "real-world" setting (comparing ESCAPE-LATE to ESCAPE control arm patients). We performed an unadjusted analysis, using 90-day modified Rankin Scale(mRS) scores as model input and analysis adjusted for baseline factors. Acceptability of EVT was calculated using upper/lower willingness-to-pay thresholds of 100,000 USD/50,000 USD/QALY. RESULTS: Two-hundred and forty-nine patients were included (ESCAPE-LATE:n = 200, ESCAPE EVT-arm:n = 29, ESCAPE control-arm:n = 20). Late EVT in addition to best medical care was cost effective in the unadjusted analysis both in the clinical trial and real-world setting, with acceptability 96.6%-99.0%. After adjusting for differences in baseline variables between the groups, late EVT was marginally cost effective in the clinical trial setting (acceptability:49.9%-61.6%), but not the "real-world" setting (acceptability:32.9%-42.6%). CONCLUSION: EVT for LVO-patients presenting beyond 6 hours was cost effective in the clinical trial setting and "real-world" setting, although this was largely related to baseline patient differences favoring the "real-world" EVT group. After adjusting for these, EVT benefit was reduced in the trial setting, and absent in the real-world setting.

4.
Nature ; 627(8003): 367-373, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-38383788

RESUMO

The posterior parietal cortex exhibits choice-selective activity during perceptual decision-making tasks1-10. However, it is not known how this selective activity arises from the underlying synaptic connectivity. Here we combined virtual-reality behaviour, two-photon calcium imaging, high-throughput electron microscopy and circuit modelling to analyse how synaptic connectivity between neurons in the posterior parietal cortex relates to their selective activity. We found that excitatory pyramidal neurons preferentially target inhibitory interneurons with the same selectivity. In turn, inhibitory interneurons preferentially target pyramidal neurons with opposite selectivity, forming an opponent inhibition motif. This motif was present even between neurons with activity peaks in different task epochs. We developed neural-circuit models of the computations performed by these motifs, and found that opponent inhibition between neural populations with opposite selectivity amplifies selective inputs, thereby improving the encoding of trial-type information. The models also predict that opponent inhibition between neurons with activity peaks in different task epochs contributes to creating choice-specific sequential activity. These results provide evidence for how synaptic connectivity in cortical circuits supports a learned decision-making task.


Assuntos
Tomada de Decisões , Vias Neurais , Lobo Parietal , Sinapses , Cálcio/análise , Cálcio/metabolismo , Tomada de Decisões/fisiologia , Interneurônios/metabolismo , Interneurônios/ultraestrutura , Aprendizagem/fisiologia , Microscopia Eletrônica , Inibição Neural , Vias Neurais/fisiologia , Vias Neurais/ultraestrutura , Lobo Parietal/citologia , Lobo Parietal/fisiologia , Lobo Parietal/ultraestrutura , Células Piramidais/metabolismo , Células Piramidais/ultraestrutura , Sinapses/metabolismo , Sinapses/ultraestrutura , Realidade Virtual , Modelos Neurológicos
5.
Transl Psychiatry ; 14(1): 8, 2024 Jan 08.
Artigo em Inglês | MEDLINE | ID: mdl-38191479

RESUMO

Impaired motivational drive is a key feature of depression. Chronic stress is a known antecedent to the development of depression in humans and depressive-like states in animals. Whilst there is a clear relationship between stress and motivational drive, the mechanisms underpinning this association remain unclear. One hypothesis is that the endocrine system, via corticotropin-releasing hormone (CRH) in the paraventricular nucleus of the hypothalamus (PVN; PVNCRH), initiates a hormonal cascade resulting in glucocorticoid release, and that excessive glucocorticoids change brain circuit function to produce depression-related symptoms. Another mostly unexplored hypothesis is that the direct activity of PVNCRH neurons and their input to other stress- and reward-related brain regions drives these behaviors. To further understand the direct involvement of PVNCRH neurons in motivation, we used optogenetic stimulation to activate these neurons 1 h/day for 5 consecutive days and showed increased acute stress-related behaviors and long-lasting deficits in the motivational drive for sucrose. This was associated with increased Fos-protein expression in the lateral hypothalamus (LH). Direct stimulation of the PVNCRH inputs in the LH produced a similar pattern of effects on sucrose motivation. Together, these data suggest that PVNCRH neuronal activity may be directly responsible for changes in motivational drive and that these behavioral changes may, in part, be driven by PVNCRH synaptic projections to the LH.


Assuntos
Hormônio Adrenocorticotrópico , Hormônio Liberador da Corticotropina , Animais , Humanos , Motivação , Hormônios Liberadores de Hormônios Hipofisários , Optogenética , Hipotálamo , Glucocorticoides , Neurônios , Sacarose
7.
Cytotherapy ; 26(1): 88-95, 2024 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-37747395

RESUMO

BACKGROUND AND AIMS: As cell and gene therapy (CGT) has grown in availability and scope, more unapproved regenerative medicine is being marketed to the public. It is essential that health care providers have sufficient knowledge and comfort to determine whether treatments are properly regulated and address these topics with patients. Due to the applicability of CGT to genetic disease, genetic counselors could be key in providing education and answering patients' questions about these topics. However, previous studies have focused only on physicians' knowledge and comfort with CGT and unapproved regenerative medicine. The purpose of this study was to assess genetic counselors' self-reported knowledge and comfort discussing these topics with patients and to explore what factors predict increased knowledge and comfort. METHODS: The authors designed an online survey distributed to genetic counselors who were part of the National Society of Genetic Counselors Student Research Program e-mail list. The survey addressed genetic counselors' demographics, practice experience with CGT, education about CGT, knowledge and comfort. RESULTS: The survey was completed by 144 genetic counselors. The best predictor of increased knowledge and comfort was experience discussing CGT in practice. In addition, those who worked at an institution at which CGT trials were offered had greater knowledge and comfort. However, most genetic counselors reported their knowledge was not sufficient to address questions from patients, and most had little-to-no knowledge or comfort determining whether a trial was properly regulated. There was no correlation between education and either knowledge or comfort; however, most participants desired more education about these topics. CONCLUSIONS: This study suggests that genetic counselors who (i) have experience with CGT in practice or (ii) work at institutions at which CGT trials are offered may have better knowledge regarding CGT. These results may help identify individuals and/or institutions in whom increasing knowledge regarding CGT could be beneficial. This is crucial as CGT becomes mainstream, leading to more widely marketed unapproved regenerative medicine. Several gaps in knowledge and comfort were identified, including participants' ability to determine whether a treatment is properly regulated. Further research is needed to better characterize the educational needs of genetic counselors surrounding these topics to address these gaps.


Assuntos
Conselheiros , Aconselhamento Genético , Humanos , Aconselhamento Genético/métodos , Inquéritos e Questionários , Terapia Baseada em Transplante de Células e Tecidos , Medicina Regenerativa
8.
Can J Neurol Sci ; : 1-6, 2023 Oct 05.
Artigo em Inglês | MEDLINE | ID: mdl-37795832

RESUMO

BACKGROUND AND PURPOSE: Numerous studies have shown longer pre-hospital and in-hospital workflow times and poorer outcomes in women after acute ischemic stroke (AIS) in general and after endovascular treatment (EVT) in particular. We investigated sex differences in acute stroke care of EVT patients over 5 years in a comprehensive Canadian provincial registry. METHODS: Clinical data of all AIS patients who underwent EVT between January 2017 and December 2022 in the province of Saskatchewan were captured in the Canadian OPTIMISE registry and supplemented with patient data from administrative data sources. Patient baseline characteristics, transport time metrics, and technical EVT outcomes between female and male EVT patients were compared. RESULTS: Three-hundred-three patients underwent EVT between 2017 and 2022: 144 (47.5%) women and 159 (52.5%) men. Women were significantly older (median age 77.5 [interquartile range: 66-85] vs.71 [59-78], p < 0.001), while men had more intracranial internal carotid artery occlusions (48/159 [30.2%] vs. 26/142 [18.3%], p = 0.03). Last-known-well to comprehensive stroke center (CSC)-arrival time (median 232 min [interquartile range 90-432] in women vs. 230 min [90-352] in men), CSC-arrival-to-reperfusion time (median 108 min [88-149] in women vs. 102 min [77-141] in men), reperfusion status (successful reperfusion 106/142 [74.7%] in women vs. 117/158 [74.1%] in men) as well as modified Rankin score at 90 days did not differ significantly. This held true after adjusting for baseline variables in multivariable analyses. CONCLUSION: While women undergoing EVT in the province of Saskatchewan were on average older than men, they were treated just as fast and achieved similar technical and clinical outcomes compared to men.

9.
Cell Rep ; 42(10): 113241, 2023 10 31.
Artigo em Inglês | MEDLINE | ID: mdl-37819759

RESUMO

Lysine succinylation is a subtype of protein acylation associated with metabolic regulation of succinyl-CoA in the tricarboxylic acid cycle. Deficiency of succinyl-CoA synthetase (SCS), the tricarboxylic acid cycle enzyme catalyzing the interconversion of succinyl-CoA to succinate, results in mitochondrial encephalomyopathy in humans. This report presents a conditional forebrain-specific knockout (KO) mouse model of Sucla2, the gene encoding the ATP-specific beta isoform of SCS, resulting in postnatal deficiency of the entire SCS complex. Results demonstrate that accumulation of succinyl-CoA in the absence of SCS leads to hypersuccinylation within the murine cerebral cortex. Specifically, increased succinylation is associated with functionally significant reduced activity of respiratory chain complex I and widescale alterations in chromatin landscape and gene expression. Integrative analysis of the transcriptomic data also reveals perturbations in regulatory networks of neuronal transcription in the KO forebrain. Together, these findings provide evidence that protein succinylation plays a significant role in the pathogenesis of SCS deficiency.


Assuntos
Mitocôndrias , Succinato-CoA Ligases , Humanos , Animais , Camundongos , Mitocôndrias/metabolismo , Acil Coenzima A/metabolismo , Succinato-CoA Ligases/genética , Succinato-CoA Ligases/metabolismo , Camundongos Knockout
10.
Stroke ; 54(11): 2724-2736, 2023 11.
Artigo em Inglês | MEDLINE | ID: mdl-37675613

RESUMO

BACKGROUND: Emerging data suggest that direct oral anticoagulants may be a suitable choice for anticoagulation for cerebral venous thrombosis (CVT). However, conducting high-quality trials in CVT is challenging as it is a rare disease with low rates of adverse outcomes such as major bleeding and functional dependence. To facilitate the design of future CVT trials, SECRET (Study of Rivaroxaban for Cerebral Venous Thrombosis) assessed (1) the feasibility of recruitment, (2) the safety of rivaroxaban compared with standard-of-care anticoagulation, and (3) patient-centered functional outcomes. METHODS: This was a phase II, prospective, open-label blinded-end point 1:1 randomized trial conducted at 12 Canadian centers. Participants were aged ≥18 years, within 14 days of a new diagnosis of symptomatic CVT, and suitable for oral anticoagulation; they were randomized to receive rivaroxaban 20 mg daily, or standard-of-care anticoagulation (warfarin, target international normalized ratio, 2.0-3.0, or low-molecular-weight heparin) for 180 days, with optional extension up to 365 days. Primary outcomes were annual rate of recruitment (feasibility); and a composite of symptomatic intracranial hemorrhage, major extracranial hemorrhage, or mortality at 180 days (safety). Secondary outcomes included recurrent venous thromboembolism, recanalization, clinically relevant nonmajor bleeding, and functional and patient-reported outcomes (modified Rankin Scale, quality of life, headache, mood, fatigue, and cognition) at days 180 and 365. RESULTS: Fifty-five participants were randomized. The rate of recruitment was 21.3 participants/year; 57% of eligible candidates consented. Median age was 48.0 years (interquartile range, 38.5-73.2); 66% were female. There was 1 primary event (symptomatic intracranial hemorrhage), 2 clinically relevant nonmajor bleeding events, and 1 recurrent CVT by day 180, all in the rivaroxaban group. All participants in both arms had at least partial recanalization by day 180. At enrollment, both groups on average reported reduced quality of life, low mood, fatigue, and headache with impaired cognitive performance. All metrics improved markedly by day 180. CONCLUSIONS: Recruitment targets were reached, but many eligible participants declined randomization. There were numerically more bleeding events in patients taking rivaroxaban compared with control, but rates of bleeding and recurrent venous thromboembolism were low overall and in keeping with previous studies. Participants had symptoms affecting their well-being at enrollment but improved over time. REGISTRATION: URL: https://www. CLINICALTRIALS: gov; Unique identifier: NCT03178864.


Assuntos
Tromboembolia Venosa , Trombose Venosa , Humanos , Feminino , Adolescente , Adulto , Pessoa de Meia-Idade , Masculino , Rivaroxabana/efeitos adversos , Anticoagulantes/efeitos adversos , Tromboembolia Venosa/induzido quimicamente , Estudos Prospectivos , Estudos de Viabilidade , Qualidade de Vida , Canadá , Hemorragia/induzido quimicamente , Trombose Venosa/tratamento farmacológico , Hemorragias Intracranianas/induzido quimicamente , Cefaleia
12.
Interv Neuroradiol ; : 15910199231196614, 2023 Aug 22.
Artigo em Inglês | MEDLINE | ID: mdl-37608547

RESUMO

BACKGROUND: In areas with high population spread such as Saskatchewan, it can be challenging to provide timely endovascular stroke treatment (EVT) to patients living far away from comprehensive stroke centres (CSC). We assessed the association of geography, stroke timing and weather conditions on EVT workflow times and clinical outcomes in Saskatchewan. METHODS: We included patients who underwent EVT between January 2017 and December 2022 in the province of Saskatchewan, Canada. Univariable and multivariable associations of time from last known well-to-CSC arrival, CSC arrival-to-reperfusion, and 90-day modified Rankin Score (mRS) with driving distance from patient home to CSC, transport mode, outdoor temperature and stroke timing (day & time) were assessed using descriptive statistics and multivariable regression. RESULTS: Three-hundred-three patients in the province of Saskatchewan underwent EVT between January 2017 and December 2022. Distance from patient home to CSC (beta-coefficient per 10 km increase = 0.02, 95% CI: 0.01-0.03) and direct to CSC transport (beta-coefficient = -0.76, 95% CI = -1.01-[-0.51]) were associated with last known well to CSC arrival time. In-hospital stroke (beta-coefficient = 0.37, 95% CI: 0.16-0.58), direct-to-CSC transfer (beta-coefficient = 0.27, 95% CI: 0.13-0.41) and daytime stroke onset (beta-coefficient = -0.15, 95% CI: -0.28-[-0.04]) were associated with time from CSC arrival to reperfusion. No association with 90-day mRS was seen. CONCLUSION: Geographic factors and stroke timing were associated with EVT workflow times. However, no association with clinical outcomes was seen, suggesting that EVT patients living remote areas of Saskatchewan have similar benefit from EVT compared to urban areas. Every effort should be made to offer timely EVT to patients from remote areas.

13.
Mol Genet Metab ; 140(3): 107668, 2023 11.
Artigo em Inglês | MEDLINE | ID: mdl-37549443

RESUMO

Very long-chain acyl-CoA dehydrogenase (VLCAD) deficiency (VLCADD) is a relatively common inborn error of metabolism, but due to difficulty in accurately predicting affected status through newborn screening, molecular confirmation of the causative variants by sequencing of the ACADVL gene is necessary. Although the ACMG/AMP guidelines have helped standardize variant classification, ACADVL variant classification remains disparate due to a phenotype that can be nonspecific, the possibility of variants that produce late-onset disease, and relatively high carrier frequency, amongst other challenges. Therefore, an ACADVL-specific variant curation expert panel (VCEP) was created to facilitate the specification of the ACMG/AMP guidelines for VLCADD. We expect these guidelines to help streamline, increase concordance, and expedite the classification of ACADVL variants.


Assuntos
Erros Inatos do Metabolismo Lipídico , Doenças Mitocondriais , Doenças Musculares , Humanos , Recém-Nascido , Acil-CoA Desidrogenase de Cadeia Longa/genética , Síndrome Congênita de Insuficiência da Medula Óssea/genética , Testes Genéticos , Variação Genética , Erros Inatos do Metabolismo Lipídico/diagnóstico , Erros Inatos do Metabolismo Lipídico/genética , Doenças Mitocondriais/genética , Doenças Musculares/genética
14.
Genet Med ; 25(11): 100950, 2023 11.
Artigo em Inglês | MEDLINE | ID: mdl-37551667

RESUMO

PURPOSE: Coffin-Siris and Nicolaides-Baraitser syndromes are recognizable neurodevelopmental disorders caused by germline variants in BAF complex subunits. The SMARCC2 BAFopathy was recently reported. Herein, we present clinical and molecular data on a large cohort. METHODS: Clinical symptoms for 41 novel and 24 previously published affected individuals were analyzed using the Human Phenotype Ontology. For genotype-phenotype correlations, molecular data were standardized and grouped into non-truncating and likely gene-disrupting (LGD) variants. Missense variant protein expression and BAF-subunit interactions were examined using 3D protein modeling, co-immunoprecipitation, and proximity-ligation assays. RESULTS: Neurodevelopmental delay with intellectual disability, muscular hypotonia, and behavioral disorders were the major manifestations. Clinical hallmarks of BAFopathies were rare. Clinical presentation differed significantly, with LGD variants being predominantly inherited and associated with mildly reduced or normal cognitive development, whereas non-truncating variants were mostly de novo and presented with severe developmental delay. These distinct manifestations and non-truncating variant clustering in functional domains suggest different pathomechanisms. In vitro testing showed decreased protein expression for N-terminal missense variants similar to LGD. CONCLUSION: This study improved SMARCC2 variant classification and identified discernible SMARCC2-associated phenotypes for LGD and non-truncating variants, which were distinct from other BAFopathies. The pathomechanism of most non-truncating variants has yet to be investigated.


Assuntos
Anormalidades Múltiplas , Deficiência Intelectual , Micrognatismo , Transtornos do Neurodesenvolvimento , Humanos , Anormalidades Múltiplas/genética , Face , Micrognatismo/genética , Deficiência Intelectual/genética , Deficiência Intelectual/complicações , Fácies , Fenótipo , Proteínas de Ligação a DNA/genética , Fatores de Transcrição/genética
15.
Neuromodulation ; 26(7): 1412-1423, 2023 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-37486284

RESUMO

OBJECTIVES: The aim of this prospective, single-blinded, dose-response study was to evaluate the safety and efficacy of a novel, paresthesia-free (subperception) spinal cord stimulation (SCS) waveform designed to target dorsal horn dendrites for the treatment of chronic neuropathic low back pain (LBP). MATERIALS AND METHODS: Twenty-seven participants with chronic neuropathic LBP were implanted with a commercial SCS system after a successful trial of SCS therapy. Devices were programmed to deliver the investigative waveform (100 Hz, 1000 µs, T9/T10 bipole) at descending stimulation perception threshold amplitudes (80%, 60%, 40%). Programs were evaluated at six, ten, and 14 weeks, after which participants selected their preferred program, with more follow-up at 26 weeks (primary outcomes). Participants were blinded to the nature of the programming. Pain score (visual analog scale [VAS]), Brief Pain Inventory (BPI), quality of life (EQ-5D-5L), and health status (36-Item Short Form [SF-36]) were measured at baseline and follow-ups. Responder rate, treatment satisfaction, clinician global impression of change, and adverse events (AEs) also were evaluated. RESULTS: Mean (± SD) baseline VAS was 72.5 ± 11.2 mm. At 26 weeks (n = 26), mean change from baseline in VAS was -51.7 mm (95% CI, -60.7 to -42.7; p < 0.001), with 76.9% of participants reporting ≥50% VAS reduction, and 46.2% reporting ≥80% VAS reduction. BPI, EQ-5D-5L, and SF-36 scores were all statistically significantly improved at 26 weeks (p < 0.001), and 100% of participants were satisfied with their treatment. There were no unanticipated AEs related to the study intervention, device, or procedures. CONCLUSIONS: This novel, paresthesia-free stimulation waveform may be a safe and effective option for patients with chronic neuropathic LBP eligible for SCS therapy and is deliverable by all current commercial SCS systems. CLINICAL TRIAL REGISTRATION: This study is registered on anzctr.org.au with identifier ACTRN12618000647235.


Assuntos
Dor Crônica , Dor Lombar , Doenças do Sistema Nervoso Periférico , Estimulação da Medula Espinal , Humanos , Dor Crônica/diagnóstico , Dor Crônica/terapia , Dor Lombar/diagnóstico , Dor Lombar/terapia , Parestesia/diagnóstico , Parestesia/terapia , Estudos Prospectivos , Qualidade de Vida , Medula Espinal , Estimulação da Medula Espinal/efeitos adversos , Estimulação da Medula Espinal/métodos , Resultado do Tratamento
16.
Int J Mol Sci ; 24(13)2023 Jun 27.
Artigo em Inglês | MEDLINE | ID: mdl-37445899

RESUMO

Biallelic pathogenic variants in subunits of succinyl-CoA synthetase (SCS), a tricarboxylic acid (TCA) cycle enzyme, are associated with mitochondrial encephalomyopathy in humans. SCS catalyzes the interconversion of succinyl-CoA to succinate, coupled to substrate-level phosphorylation of either ADP or GDP, within the TCA cycle. SCS-deficient encephalomyopathy typically presents in infancy and early childhood, with many patients succumbing to the disease during childhood. Common symptoms include abnormal brain MRI, basal ganglia lesions and cerebral atrophy, severe hypotonia, dystonia, progressive psychomotor regression, and growth deficits. Although subunits of SCS were first identified as causal genes for progressive metabolic encephalomyopathy in the early 2000s, recent investigations are now beginning to unravel the pathomechanisms underlying this metabolic disorder. This article reviews the current understanding of SCS function within and outside the TCA cycle as it relates to the complex and multifactorial mechanisms underlying SCS-related mitochondrial encephalomyopathy.


Assuntos
Encefalomiopatias Mitocondriais , Succinato-CoA Ligases , Pré-Escolar , Humanos , Encefalomiopatias Mitocondriais/genética , Encefalomiopatias Mitocondriais/metabolismo , Mitocôndrias/metabolismo , Succinato-CoA Ligases/genética , Succinato-CoA Ligases/metabolismo , Estresse Oxidativo
17.
Sci Rep ; 13(1): 11561, 2023 07 18.
Artigo em Inglês | MEDLINE | ID: mdl-37464016

RESUMO

Unmyelinated non-peptidergic nociceptors (NP afferents) arborise in lamina II of the spinal cord and receive GABAergic axoaxonic synapses, which mediate presynaptic inhibition. However, until now the source of this axoaxonic synaptic input was not known. Here we provide evidence that it originates from a population of inhibitory calretinin-expressing interneurons (iCRs), which correspond to lamina II islet cells. The NP afferents can be assigned to 3 functionally distinct classes (NP1-3). NP1 afferents have been implicated in pathological pain states, while NP2 and NP3 afferents also function as pruritoceptors. Our findings suggest that all 3 of these afferent types innervate iCRs and receive axoaxonic synapses from them, providing feedback inhibition of NP input. The iCRs also form axodendritic synapses, and their targets include cells that are themselves innervated by the NP afferents, thus allowing for feedforward inhibition. The iCRs are therefore ideally placed to control the input from non-peptidergic nociceptors and pruritoceptors to other dorsal horn neurons, and thus represent a potential therapeutic target for the treatment of chronic pain and itch.


Assuntos
Nociceptores , Medula Espinal , Animais , Camundongos , Calbindina 2 , Células do Corno Posterior , Medula Espinal/fisiologia , Sinapses
18.
bioRxiv ; 2023 Jun 05.
Artigo em Inglês | MEDLINE | ID: mdl-37333120

RESUMO

Unmyelinated non-peptidergic nociceptors (NP afferents) arborise in lamina II of the spinal cord and receive GABAergic axoaxonic synapses, which mediate presynaptic inhibition. However, until now the source of this axoaxonic synaptic input was not known. Here we provide evidence that it originates from a population of inhibitory calretinin-expressing interneurons (iCRs), which correspond to lamina II islet cells. The NP afferents can be assigned to 3 functionally distinct classes (NP1-3). NP1 afferents have been implicated in pathological pain states, while NP2 and NP3 afferents also function as pruritoceptors. Our findings suggest that all 3 of these afferent types innervate iCRs and receive axoaxonic synapses from them, providing feedback inhibition of NP input. The iCRs also form axodendritic synapses, and their targets include cells that are themselves innervated by the NP afferents, thus allowing for feedforward inhibition. The iCRs are therefore ideally placed to control the input from non-peptidergic nociceptors and pruritoceptors to other dorsal horn neurons, and thus represent a potential therapeutic target for the treatment of chronic pain and itch.

19.
J Vet Med Educ ; 50(2): 192-204, 2023 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-35312469

RESUMO

The push for competency-based veterinary medical education by accrediting bodies has led to the inclusion of non-technical skills within curricula. Communication, self-awareness, and cultural humility are considered essential for post-graduate success. To facilitate skills development, veterinary educators have incorporated a variety of modalities including lecture, group discussions, virtual and peer-assisted learning, role play, video review of consultations, and simulated clients (SCs). The overarching goal is developing students into self-reflective practitioners through exposure to clinical scenarios that enhance and embody diversity. Decision making about case management is subject to stereotypes, bias, and assumptions. Racial and ethnic disparities reported in health care can adversely impact patient outcomes. This study was conducted to evaluate communication training and diversity among SC pools within veterinary colleges. A questionnaire was electronically disseminated to assistant/associate deans and/or directors of curriculum/education at 54 American Veterinary Medical Association Council on Education-accredited or provisionally accredited colleges of veterinary medicine. Twenty-one institutions are represented within the data set. Participating institutions summarized their communication curricula: 18 (85.71%) used SCs. Over 55% of these did not track SC demographic data or social identities; among institutions that did track, SCs were primarily monolingual English-speaking (77%), non-disabled (94.2%), white (90.4%), non-Hispanic/Latinx (98.6%) women (57%) over age 56 (64%). Sixteen institutions agreed with the statement "I do not feel that our SC pool is adequately diverse." Respondents shared that lack of time and capacity for recruitment were barriers to diversifying SC pools and proposed strategies to improve outreach.


Assuntos
Educação em Veterinária , Feminino , Animais , Masculino , Currículo , Educação Baseada em Competências , Inquéritos e Questionários , Comunicação
20.
Can J Neurol Sci ; 50(3): 389-392, 2023 05.
Artigo em Inglês | MEDLINE | ID: mdl-35581931

RESUMO

BACKGROUND: There is definitive evidence for effectiveness of thrombectomy for acute stroke with large vessel occlusion (LVO). A clinical tool to identify patients with LVO is therefore required for effective triage and prehospital decision making. We developed the FAST VAN tool, which follows from the Heart and Stroke Foundation FAST stroke screen, with the addition of cortical features of vision, aphasia, and neglect, to differentiate from lacunar syndromes. METHODS: Consecutive acute stroke alerts initiated by emergency medical services (EMS) were prospectively analyzed from April 2017 to Jan 2021. FAST VAN signs were recorded by first responders who had received online education about the tool. These findings were compared to the presence or absence of LVO on CT angiography. Analysis was also performed by appropriateness for comprehensive stroke centers (CSC) transfer if no LVO was present. EMS providers were surveyed regarding ease of use in terms of learning the tool and using in real-world practice. RESULTS: Data from 1080 consecutive acute strokes included 440 patients considered to have VAN signs by EMS. Fifty-four percent of VAN-positive patients showed LVO on CTA. Sensitivity, specificity, and accuracy were 86%, 75%, and 77%, respectively. In 204 false-positive cases, 143 (70%) were considered appropriate for evaluation at the CSC. EMS providers reported high satisfaction with learning and using the tool. DISCUSSION: The FAST VAN tool for identification of LVO meets desired characteristics of an effective screening tool in ease of use, efficiency, and accuracy. Aphasia remains the most challenging cortical feature to identify accurately.


Assuntos
Afasia , Isquemia Encefálica , Serviços Médicos de Emergência , Acidente Vascular Cerebral , Humanos , Valor Preditivo dos Testes , Acidente Vascular Cerebral/complicações , Acidente Vascular Cerebral/diagnóstico por imagem , Triagem , Afasia/etiologia , Isquemia Encefálica/diagnóstico , Estudos Retrospectivos
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