RESUMO
OBJECTIVE: The purpose of this study was to characterize a metabolic brain network associated with X-linked dystonia-parkinsonism (XDP). METHODS: Thirty right-handed Filipino men with XDP (age = 44.4 ± 8.5 years) and 30 XDP-causing mutation negative healthy men from the same population (age = 37.4 ± 10.5 years) underwent [18 F]-fluorodeoxyglucose positron emission tomography. Scans were analyzed using spatial covariance mapping to identify a significant XDP-related metabolic pattern (XDPRP). Patients were rated clinically at the time of imaging according to the XDP-Movement Disorder Society of the Philippines (MDSP) scale. RESULTS: We identified a significant XDPRP topography from 15 randomly selected subjects with XDP and 15 control subjects. This pattern was characterized by bilateral metabolic reductions in caudate/putamen, frontal operculum, and cingulate cortex, with relative increases in the bilateral somatosensory cortex and cerebellar vermis. Age-corrected expression of XDPRP was significantly elevated (p < 0.0001) in XDP compared to controls in the derivation set and in the remaining 15 patients (testing set). We validated the XDPRP topography by identifying a similar pattern in the original testing set (r = 0.90, p < 0.0001; voxel-wise correlation between both patterns). Significant correlations between XDPRP expression and clinical ratings for parkinsonism-but not dystonia-were observed in both XDP groups. Further network analysis revealed abnormalities of information transfer through the XDPRP space, with loss of normal connectivity and gain of abnormal functional connections linking network nodes with outside brain regions. INTERPRETATION: XDP is associated with a characteristic metabolic network associated with abnormal functional connectivity among the basal ganglia, thalamus, motor regions, and cerebellum. Clinical signs may relate to faulty information transfer through the network to outside brain regions. ANN NEUROL 2023;94:684-695.
Assuntos
Distonia , Distúrbios Distônicos , Doenças Genéticas Ligadas ao Cromossomo X , Masculino , Humanos , Adulto , Pessoa de Meia-Idade , Distúrbios Distônicos/diagnóstico por imagem , Distúrbios Distônicos/genética , Distúrbios Distônicos/complicações , Doenças Genéticas Ligadas ao Cromossomo X/diagnóstico por imagem , Doenças Genéticas Ligadas ao Cromossomo X/genética , Distonia/diagnóstico por imagem , Distonia/genética , BiomarcadoresRESUMO
BACKGROUND: X-Linked dystonia-parkinsonism (XDP) is an adult-onset neurodegenerative disorder characterized by rapidly progressive dystonia and parkinsonism. Mosaic Divergent Repeat Interruptions affecting motif Length and Sequence (mDRILS) were recently found within the TAF1 SVA repeat tract and were shown to associate with repeat stability and age at onset in XDP, specifically the AGGG [5'-SINE-VNTR-Alu(AGAGGG)2AGGG(AGAGGG)n] mDRILS. OBJECTIVE: This study aimed to investigate the stability of mDRILS frequencies and stability of (AGAGGG)n repeat length during transmission in parent-offspring pairs. METHODS: Fifty-six families (n = 130) were investigated for generational transmission of repeat length and mDRILS. The mDRILS stability of 16 individuals was assessed at two sampling points 1 year apart. DNA was sequenced with long-read technologies after long-range polymerase chain reaction amplification of the TAF1 SVA. Repeat number and mDRILS were detected with Noise-Cancelling Repeat Finder (NCRF). RESULTS: When comparing the repeat domain, 51 of 65 children had either contractions or expansions of the repeat length. The AGGG frequency remained stable across generations at 0.074 (IQR: 0.069-0.078) (z = -0.526; P = 0.599). However, the median AGGG frequency in children with an expansion (0.072 [IQR: 0.066-0.076]) was lower compared with children with retention or contraction (0.080 [IQR: 0.073-0.083]) (z = -0.007; P = 0.003). In a logistic regression model, the AGGG frequency predicted the outcome of either expansion or retention/contraction when including repeat number and sex as covariates (ß = 80.7; z-score = 2.63; P = 0.0085). The AGGG frequency varied slightly over 1 year (0.070 [IQR: 0.063-0.080] to 0.073 [IQR: 0.069-0.078]). CONCLUSIONS: Our results show that a higher AGGG frequency may stabilize repeats across generations. This highlights the importance of further investigating mDRILS as a disease-modifying factor with generational differences. © 2024 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.
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Distúrbios Distônicos , Doenças Genéticas Ligadas ao Cromossomo X , Fator de Transcrição TFIID , Humanos , Masculino , Doenças Genéticas Ligadas ao Cromossomo X/genética , Doenças Genéticas Ligadas ao Cromossomo X/fisiopatologia , Distúrbios Distônicos/genética , Feminino , Fator de Transcrição TFIID/genética , Adulto , Pessoa de Meia-Idade , Fatores Associados à Proteína de Ligação a TATA/genética , Idoso , Histona AcetiltransferasesRESUMO
While many genetic causes of movement disorders have been identified, modifiers of disease expression are largely unknown. X-linked dystonia-parkinsonism (XDP) is a neurodegenerative disease caused by a SINE-VNTR-Alu(AGAGGG)n retrotransposon insertion in TAF1, with a polymorphic (AGAGGG)n repeat. Repeat length and variants in MSH3 and PMS2 explain â¼65% of the variance in age at onset (AAO) in XDP. However, additional genetic modifiers are conceivably at play in XDP, such as repeat interruptions. Long-read nanopore sequencing of PCR amplicons from XDP patients (n = 202) was performed to assess potential repeat interruption and instability. Repeat-primed PCR and Cas9-mediated targeted enrichment confirmed the presence of identified divergent repeat motifs. In addition to the canonical pure SINE-VNTR-Alu-5'-(AGAGGG)n, we observed a mosaic of divergent repeat motifs that polarized at the beginning of the tract, where the divergent repeat interruptions varied in motif length by having one, two, or three nucleotides fewer than the hexameric motif, distinct from interruptions in other disease-associated repeats, which match the lengths of the canonical motifs. All divergent configurations occurred mosaically and in two investigated brain regions (basal ganglia, cerebellum) and in blood-derived DNA from the same patient. The most common divergent interruption was AGG [5'-SINE-VNTR-Alu(AGAGGG)2AGG(AGAGGG)n], similar to the pure tract, followed by AGGG [5'-SINE-VNTR-Alu(AGAGGG)2AGGG(AGAGGG)n], at median frequencies of 0.425 (IQR: 0.42-0.43) and 0.128 (IQR: 0.12-0.13), respectively. The mosaic AGG motif was not associated with repeat number (estimate = -3.8342, P = 0.869). The mosaic pure tract frequency was associated with repeat number (estimate = 45.32, P = 0.0441) but not AAO (estimate = -41.486, P = 0.378). Importantly, the mosaic frequency of the AGGG negatively correlated with repeat number after adjusting for age at sampling (estimate = -161.09, P = 3.44 × 10-5). When including the XDP-relevant MSH3/PMS2 modifier single nucleotide polymorphisms into the model, the mosaic AGGG frequency was associated with AAO (estimate = 155.1063, P = 0.047); however, the association dissipated after including the repeat number (estimate = -92.46430, P = 0.079). We reveal novel mosaic divergent repeat interruptions affecting both motif length and sequence (DRILS) of the canonical motif polarized within the SINE-VNTR-Alu(AGAGGG)n repeat. Our study illustrates: (i) the importance of somatic mosaic genotypes; (ii) the biological plausibility of multiple modifiers (both germline and somatic) that can have additive effects on repeat instability; and (iii) that these variations may remain undetected without assessment of single molecules.
Assuntos
Distúrbios Distônicos , Doenças Genéticas Ligadas ao Cromossomo X , Doenças Neurodegenerativas , Humanos , Endonuclease PMS2 de Reparo de Erro de Pareamento , Distúrbios Distônicos/genética , Doenças Genéticas Ligadas ao Cromossomo X/genéticaRESUMO
Magnetic resonance-guided focused ultrasound (MRgFUS) is a non-invasive lesioning technique used to treat movement disorders such as essential tremor (ET), Parkinson's disease (PD), and X-linked dystonia-parkinsonism (XDP). We would like to report our experience in establishing and developing our MRgFUS program and preliminary results. Adult patients with tremor-dominant PD (TDPD), ET, and XDP were considered for initial screening (neurologic evaluation, skull density ratio [SDR] determination). Eligible patients underwent secondary screening (neurosurgical and neuropsychological evaluation, psychiatric and medical clearance). During the procedure, a neuro-anesthesiologist and neurologist were also present to monitor the patient and perform neurologic evaluation, respectively. Clinical follow-up was scheduled at 2 weeks post-treatment, then at every 3 months. A total of 30 patients underwent MRgFUS treatment: 22 TDPD, 6 XDP, and 2 ET. The mean age was 55.7 years, and majority were male (86.7%). Mean disease duration was 8.6 years. Mean SDR was 0.46. The targets for TDPD and ET were the contralateral ventral intermediate nucleus of the thalamus; for XDP, it was the pallidothalamic tract. The mean maximum temperature was 59.8oC; number of sonocations, 7.3; and treatment time, 64.6 min. Majority of patients improved after the procedure. Transient intraprocedural adverse events (headache, dizziness) were reported in 20% of patients while post-procedural events (mild weakness, numbness) were seen in 16.7%. Only 26.7% of patients had follow-up data. Despite the unique challenges encountered, MRgFUS treatment is feasible in resource-limited settings. Additional steps would have to be made to develop and improve the program.
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Tremor Essencial , Imageamento por Ressonância Magnética , Humanos , Masculino , Feminino , Pessoa de Meia-Idade , Tremor Essencial/terapia , Idoso , Adulto , Filipinas , Doença de Parkinson/terapia , Resultado do Tratamento , Região de Recursos LimitadosRESUMO
Transcranial magnetic resonance-guided focused ultrasound (MRgFUS) is a noninvasive method for controlling tremor and has recently been used in patients with X-linked dystonia-parkinsonism (XDP). This study aims to determine the improvement in dystonia and parkinsonism in patients with XDP after MRgFUS pallidothalamic tractotomy. This prospective study will be conducted at the Philippine General Hospital, University of the Philippines Manila. The primary outcome measure is the change in the pre- and post-treatment XDP-Movement Disorder Society of the Philippines Scale scores. In addition, demographic and clinical data will be collected, including the Burke-Fahn-Marsden Dystonia Rating Scale, Part III of the Movement Disorder Society-Unified Parkinson's disease Rating Scale score, XDP clinical and functional stage, the five-level EuroQol five-dimensional questionnaire, Montreal Cognitive Assessment scores, MRgFUS treatment parameters, and adverse events. Patients will be assessed within 24 hours of treatment, then at 2 weeks, 3 months, 6 months, 9 months, and 12 months post-treatment. This protocol was approved by the University of the Philippines Manila Research Ethics Board (UPMREB 2022-0271-01). Data collection began in January 2023. This protocol has been registered with ClinicalTrials.gov: Trial Registration number: NCT05592028.
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Distonia , Transtornos dos Movimentos , Humanos , Espectroscopia de Ressonância Magnética , Filipinas , Estudos ProspectivosRESUMO
BACKGROUND: A dengue vaccine, dengvaxia, was licensed for the first time in 2015. It was approved for use in 11 countries where dengue infection is endemic, including the Philippines. In November 2017, controversy arose in the Philippines regarding the dengvaxia vaccine. We hypothesized that the dengvaxia controversy might be correlated with immunization coverage in the Philippines. METHODS: We performed an analytical and infodemiological study on web-based interest in dengvaxia, both globally and in 18 dengue endemic countries, from 2015 to 2020 using Google Trends™. Comparisons were made with search trends for the components of the National Immunization Program (NIP) and vaccine coverage by computing the Pearson product-moment correlation coefficient (r) between each variable. RESULTS: Among the 18 countries included, the Philippines had the highest search volume index for dengvaxia, with peaks in searches coinciding with that of worldwide search trends. There was no correlation between the relative search volume for dengvaxia with that of vaccines included in the NIP in the Philippines from 2015 to 2020. There was no significant correlation between web-based interest in dengvaxia and the estimated immunization coverage from 2015 to 2019. CONCLUSION: There was no significant correlation between web-based interest in dengvaxia, the vaccines in the NIP, and national immunization coverage.
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Vacinas contra Dengue , Dengue , Vacinas , Humanos , Dengue/epidemiologia , Dengue/prevenção & controle , Cobertura Vacinal , Vacinação , Filipinas , Programas de ImunizaçãoRESUMO
OBJECTIVE: Bacterial meningitis is associated with high morbidity and mortality if not treated early. Due to the high disease burden, there are barriers in the provision of healthcare services for these patients, especially in low- to middle-income countries, such as the Philippines. We aimed to give an overview of healthcare services delivery and identify gaps in the provision of care for patients with bacterial meningitis in the Philippines. METHOD: We conducted a scoping review on the available literature on the epidemiology, research, health services delivery, diagnostics and management of Filipino patients with bacterial meningitis. A qualitative summary of the results was conducted to provide an overview of the findings. RESULTS: There is a paucity of epidemiological data and research on bacterial meningitis. Healthcare expenditure remains out-of-pocket, with limited coverage from the national health insurance programme. There is an inadequate number of neurologists as well as inequities in the distribution of manpower and facilities due to the devolution of the healthcare system. Diagnosis remains a challenge due to the inaccessibility of tests for CSF analysis. Costs of antibiotics, adjunctive treatment, neurosurgical interventions and rehabilitation are also prohibitive. Outbreaks can be prevented by strengthening existing surveillance systems and improving vaccination coverage against the most common causative organisms. CONCLUSION: Enormous challenges still exist with regards to health services delivery in patients with bacterial meningitis in the Philippines in terms of epidemiologic data and research, access to healthcare facilities and diagnostic tools, healthcare costs, surveillance systems and immunisation against causative pathogens.
Assuntos
Atenção à Saúde , Meningites Bacterianas/epidemiologia , Humanos , Meningites Bacterianas/microbiologia , Meningites Bacterianas/prevenção & controle , Programas Nacionais de Saúde , Filipinas/epidemiologiaRESUMO
INTRODUCTION: The Philippine CORONA Study was a multicenter, retrospective, cohort study of 10,881 coronavirus disease 2019 (COVID-19) admissions between February and December 2020. METHODS: Subgroup analysis was done on clinical outcomes of mortality, respiratory failure, duration of ventilator dependence, intensive care unit (ICU) admission, length of ICU stay, and length of hospital stay among older persons and persons with dementia. RESULTS: The adjusted hazard ratios for mortality among the mild and severe cases were significantly higher by 3.93, 95% CI [2.81, 5.50] and by 1.81, 95% CI [1.43, 2.93], respectively, in older persons compared to younger adults. The adjusted hazard ratios for respiratory failure in older persons were increased by 2.65, 95% CI [1.92, 3.68] and by 1.27, 95% CI [1.01, 1.59] among the mild and severe cases, respectively. The adjusted hazard ratio for ICU admission in older persons was higher by 1.95, 95% CI [1.47, 2.59] among the mild cases. The adjusted hazard ratios for mortality and ICU admission in persons with dementia were higher by 7.25, 95% CI [2.67, 19.68] and by 4.37, 95% CI [1.08, 17.63], respectively, compared to those without dementia. CONCLUSION: Older age and dementia significantly increased the risk of mortality, respiratory failure, and ICU admission among COVID-19 patients.
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COVID-19 , Demência , Insuficiência Respiratória , Humanos , Idoso , Idoso de 80 Anos ou mais , Estudos Retrospectivos , Estudos de Coortes , Filipinas , Mortalidade HospitalarRESUMO
BACKGROUND: Status epilepticus (SE) is a neurological emergency necessitating rapid seizure control to prevent long-term consequences. Perampanel (PER) is a novel selective, noncompetitive alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic (AMPA) receptor antagonist that demonstrated efficacy and safety in lithium-pilocarpine models of SE; however, data in humans are limited. This systematic review was performed to assess the efficacy and safety of PER in patients with SE, RSE, and SRSE. METHODS: We searched MEDLINE (accessed through PubMed), Embase, Scopus, Cochrane Library, and ClinicalTrials.gov from inception until May 30, 2021 to identify all human studies on PER for the treatment of SE of any type and etiology. An additional search was performed on DANS Easy Archive, in which OpenGrey data were stored, from inception until January 10, 2022 and conference proceedings by the International League Against Epilepsy from 2011 onward. The GRADE (Grades of Recommendation, Assessment, Development and Evaluation) approach was used to assess the overall certainty of the body of evidence. RESULTS: Twenty-one studies (7 case reports, 9 case series, and 5 retrospective cohort studies) were included with a total of 369 cases of SE in 368 patients aged 11â¯months to 99â¯years, of which 56.2% were female. Seizures of the majority were refractory (nâ¯=â¯220), super refractory SE (nâ¯=â¯70), or either (nâ¯=â¯81) with prominent motor symptoms (nâ¯=â¯284) and are associated with a structural etiology (nâ¯=â¯218). The number of antiseizure medications and/or anesthetics used prior to PER ranged from 1 to 13. PER was administered in 324 cases and was initiated at a dose of 2-36â¯mg between 30â¯min to 59â¯days from SE onset. SE cessation ranged from 1â¯h to 4â¯weeks from PER initiation. A total of 119 cases (36.6%) were considered PER responders. According to the GRADE approach, there is very low certainty of evidence for all outcomes. CONCLUSIONS: The real-world data of PER as a possible therapeutic option in SE of any type are increasing. However, there is very low certainty of evidence for its use and this requires further clinical studies to establish the appropriate timing, dosing, and titration that are efficacious and safe for SE cessation.
Assuntos
Anticonvulsivantes , Estado Epiléptico , Anticonvulsivantes/uso terapêutico , Feminino , Humanos , Lactente , Nitrilas/uso terapêutico , Piridonas , Estudos Retrospectivos , Estado Epiléptico/diagnóstico , Estado Epiléptico/tratamento farmacológicoRESUMO
BACKGROUND: Patients and their caregivers, including clinicians and educators, use web-based search engines to access healthcare-related information from the internet. Online search behavior analysis has been used to obtain insights on health information demand. OBJECTIVES: We aimed to describe the online search behavior for autoimmune encephalitis, autoimmune seizures, and autoimmune encephalitis (AE) worldwide over time through the analysis of search volumes made on Google. METHODS: In this infodemiological study, we retrieved search volume indices for the keyword "autoimmune encephalitis (search term)", "autoimmune seizures (search term)", and "autoimmune encephalitis (search term)" based on worldwide search data from January 01, 2004 to October 31, 2021, using Google Trends. We performed a descriptive analysis of search volume patterns, including related topics and queries. RESULTS: There was a progressive increase in search volume numbers over time for the keyword "autoimmune encephalitis", "autoimmune seizures", and "autoimmune epilepsy" with no annual seasonal variation. Peak search volumes for these keywords were recorded in July 2018, February 2005, December 2012, respectively. The greatest search volume for "autoimmune encephalitis" was recorded in Singapore, followed by Australia, the United States of America, the Philippines, and New Zealand, whereas it was highest in the United States for "autoimmune seizures" and "autoimmune epilepsy". The most searched topics were related to definition, causes, symptoms, diagnosis, and treatment. All related topics and queries increased in volume by more than 5000-fold over time. CONCLUSIONS: This study showed an uptrend in the online search interest on autoimmune encephalitis, autoimmune seizures, and autoimmune epilepsy over time, which may reflect the increased awareness of the condition by the public and the medical community. Information on online health information-seeking behavior may be obtained from Google Trends data despite its limitations.
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Encefalite , Epilepsia , Encefalite/epidemiologia , Epilepsia/epidemiologia , Doença de Hashimoto , Humanos , Infodemiologia , Internet , Ferramenta de Busca , Convulsões , Estados UnidosRESUMO
BACKGROUND: Neurology residents are particularly vulnerable to burnout because of the novel logistical and clinical challenges brought about by the coronavirus disease 2019 (COVID-19) pandemic. Despite its implications, knowledge on burnout and its predictors among neurology residents is lacking. This study aimed to determine the prevalence of burnout among neurology residents during the pandemic, to compare burnout subscale scores and sociodemographic and work characteristics, and to explore residents' perceptions on how to address burnout. METHODS: We conducted a cross-sectional survey among all 120 residents from the nine institutions in the Philippines offering neurology residency programs from March to August 2020. We obtained sociodemographic and work characteristics using questionnaire. We measured burnout using the Maslach Burnout Inventory. We performed an inductive thematic analysis to analyze perceptions on how to reduce burnout. RESULTS: The response rate was 71.67% (86/120). The mean age was 30.1 ± 3.1 years. Using predefined subscale critical boundaries, the prevalence of burnout was 94% (95% CI 89, 99). The lack of compensation and number of on-duty days influenced emotional exhaustion scores. The number of on-duty days influenced depersonalization scores. Thematic analysis revealed five themes: increasing manpower; self-care; reducing clerical tasks; improving work environment; and adequate compensation. CONCLUSIONS: The prevalence of burnout among neurology residents during the COVID-19 pandemic was alarmingly high. Reforms in hiring policies, work-hour management, manpower organization, work environment, and logistics may be considered.
Assuntos
COVID-19 , Internato e Residência , Neurologia , Adulto , Esgotamento Psicológico , Estudos Transversais , Humanos , Neurologia/educação , Pandemias , SARS-CoV-2 , Inquéritos e QuestionáriosRESUMO
BACKGROUND: The conduct of patient consults greatly changed during the time of the COVID-19 pandemic. There was a decrease in face-to-face patient consults and enhanced utilization of virtual consults. Infodemiological studies, using Google Trends, focus on internet search trends that may reflect public interest and awareness in diseases and as a proxy of public health risk perception. OBJECTIVES: We aimed to investigate the online behavior of internet users on teleneurology, telehealth, and telemedicine during the time of the pandemic, as reflected in search volume indices (SVI) projected in Google Trends. METHODS: We used the data from Google Trends to quantify the interest of internet users in teleneurology, telehealth, and telemedicine. These keywords were entered in Google Trends as search terms. Data included were searches conducted from 2016 to 2020 to depict the transition into the pandemic. RESULTS: The SVI of teleneurology was unchanged during the 5-year period search relative to the SVIs of telehealth and telemedicine. Contrary to the noted worldwide increase in the SVI of telehealth and telemedicine during the year of pandemic, teleneurology's SVI remained stable despite the increase of its utilization. Focusing on teleneurology, the highest SVI was observed in 2018. CONCLUSION: There was an increase in the SVI of telehealth and telemedicine, possibly implying an increase in the general awareness of these virtual methods of health care, as catalyzed by the pandemic. However, the stable SVI of teleneurology may signify that the public awareness regarding it remained unchanged despite the increase in application in clinics and hospitals.
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COVID-19 , Neurologia/tendências , Telemedicina/tendências , Hospitais , Humanos , Neurologia/métodos , Pandemias , Telemedicina/métodosRESUMO
BACKGROUND: While most large studies on the possible association of COVID-19 and stroke were done in high-income countries, only a few studies consisting of small sample populations have been done in low- to middle-income countries like the Philippines. OBJECTIVES: To determine the risk factors of stroke among hospitalized COVID19 patients in the Philippines; to determine the possible association between these risk factors and stroke among the same cohort; and to determine if there is an association between mortality and stroke in this same group. METHODOLOGY: We obtained relevant clinical and neurological, including stroke data from the Philippine CORONA study, an observational study involving 10,881 patients with COVID-19 admitted in 37 referral hospitals from all over the Philippines. RESULTS: The incidence of stroke among patients with COVID-19 was 3.4% (n = 367). There were more deaths among patients with stroke and COVID-19 than those without stroke and COVID-19 (42.2% vs 14.7%, p < 0.01). In addition, more patients with stroke were admitted in the ICU (43.3% vs 15.0%, p < 0.01) regardless of cause. Smoking (OR: 1.5, 95% CI: 1.3 to 1.7, p < 0.0001), hypertension (OR:1.75, 95% CI:1.53 to 1.97, p < 0.0001), presence of heart failure (OR: 1.4, 95% CI: 1.07 to 1.86, p = 0.01), presence of any neurologic co-morbidities (OR: 1.4, 95% CI:1.11 to 1.46, p = 0.004), and history of stroke (OR:2.3, 95% CI:1.82 to 2.97, p < 0.0001) had direct significant correlation with stroke; while being a health care worker (OR: 0.5, 95% CI: 0.33 to 0.70, p < 0.0004) had an inverse significant association with stroke. CONCLUSION: COVID-19 stroke patients in the Philippines have a higher mortality and ICU admission rates than patients with COVID-19 alone or COVID-19 stroke patients from developed countries. Our cohort has similar cardiovascular and metabolic risk factors to western patients with stroke, highlighting that COVID-19 may only have a small contribution to stroke incidence.
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COVID-19 , Acidente Vascular Cerebral , Humanos , Incidência , Filipinas/epidemiologia , Acidente Vascular Cerebral/diagnóstico , Acidente Vascular Cerebral/epidemiologia , Acidente Vascular Cerebral/complicações , Fatores de Risco , Estudos RetrospectivosRESUMO
X-linked dystonia-parkinsonism (XDP) is a severe neurodegenerative disorder that manifests as adult-onset dystonia combined with parkinsonism. A SINE-VNTR-Alu (SVA) retrotransposon inserted in an intron of the TAF1 gene reduces its expression and alters splicing in XDP patient-derived cells. As a consequence, increased levels of the TAF1 intron retention transcript TAF1-32i can be found in XDP cells as compared to healthy controls. Here, we investigate the sequence of the deep intronic region included in this transcript and show that it is also present in cells from healthy individuals, albeit in lower amounts than in XDP cells, and that it undergoes degradation by nonsense-mediated mRNA decay. Furthermore, we investigate epigenetic marks (e.g., DNA methylation and histone modifications) present in this intronic region and the spanning sequence. Finally, we show that the SVA evinces regulatory potential, as demonstrated by its ability to repress the TAF1 promoter in vitro. Our results enable a better understanding of the disease mechanisms underlying XDP and transcriptional alterations caused by SVA retrotransposons.
Assuntos
Distúrbios Distônicos/genética , Doenças Genéticas Ligadas ao Cromossomo X/genética , Transtornos Parkinsonianos/genética , Retroelementos/genética , Transcrição Gênica/genética , Adolescente , Adulto , Metilação de DNA/genética , Feminino , Histona Acetiltransferases/genética , Humanos , Íntrons/genética , Masculino , Pessoa de Meia-Idade , Regiões Promotoras Genéticas/genética , Elementos Nucleotídeos Curtos e Dispersos/genética , Fatores Associados à Proteína de Ligação a TATA/genética , Fator de Transcrição TFIID/genética , Adulto JovemRESUMO
X-linked dystonia parkinsonism (XDP) is a neurodegenerative disorder that has received significant interest on several fronts. Although much still remains to be elucidated regarding the disease cause, a robust amount of data has been produced in recent years compared to when it was first described in 1976. The debilitating nature of the overlapping dystonia and parkinsonism that characterizes this disorder has fueled much of the interest in unraveling its cause, clinical presentation, symptom progression, treatment and impact on the afflicted patients as well as their caregivers. Having made several significant advances in genetic studies, neuropathology, neurophysiology and clinical characterization, we are entering a new threshold in the study of this disorder, hopefully bringing us closer to potential treatments and possible cures. This review will focus on new information gathered regarding the motor and non-motor features of XDP, deep brain stimulation (DBS) as a potential treatment for XDP and the utility of the recently validated XDP-Movement Disorder Society of the Philippines (MDSP)-rating scale.
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Distonia , Distúrbios Distônicos , Doenças Genéticas Ligadas ao Cromossomo X , Transtornos Parkinsonianos , Distúrbios Distônicos/genética , Distúrbios Distônicos/terapia , Doenças Genéticas Ligadas ao Cromossomo X/genética , Doenças Genéticas Ligadas ao Cromossomo X/terapia , Humanos , Transtornos Parkinsonianos/genética , Transtornos Parkinsonianos/terapia , FilipinasRESUMO
Our study aimed to determine the effects of new-onset neurological symptoms (NNS) on clinically relevant outcomes in hospitalized patients with COVID-19 infection. We conducted a nationwide, comparative, retrospective, cohort study among adult, hospitalized COVID-19 patients involving 37 hospital sites from various regions in the Philippines. We included a total of 10,881 patients with confirmed COVID-19 infection (2008 had NNS while 8873 did not have NNS). The adjusted hazard ratios (aHRs) for mortality among the mild and severe cases were significantly higher by 1.660 (95% CI 1.132-2.435) and by 1.352 (95% CI 1.042-1.752), respectively, in the NNS group compared to those in the non-NNS group. The aHRs for respiratory failure in the NNS group were significantly increased by 1.914 (95% CI 1.346-2.722), by 1.614 (95% CI 1.260-2.068), and by 1.234 (95% CI 1.089-1.398) among the mild, severe, and critical cases, respectively. The aHRs for ICU admission in the NNS group were still significantly higher by 1.973 (95% CI 1.457-2.673) and by 1.831 (95% CI 1.506-2.226) among the mild and severe cases, respectively. Patients who had NNS were not significantly associated with a longer duration of ventilator dependence (adjusted odds ratio (aOR) 0.954, 95% CI 0.772-1.179), longer ICU stay (aOR 0.983, 95% CI 0.772-1.252) and longer hospital admission (aOR 1.045, 95% CI 0.947-1.153). The presence of NNS significantly increases the risk of mortality, respiratory failure and ICU admission among COVID-19 patients. Registration and associated protocol publication: ClinicalTrials.gov website (NCT04386083); Espiritu AI, Sy MCC, Anlacan VMM, Jamora RDG. The Philippine COVID-19 Outcomes: a Retrospective study Of Neurological manifestations and Associated symptoms (The Philippine CORONA study): a protocol study. BMJ Open. 2020;10:e040944.
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COVID-19 , Adulto , Estudos de Coortes , Humanos , Unidades de Terapia Intensiva , Filipinas/epidemiologia , Estudos Retrospectivos , SARS-CoV-2RESUMO
X-linked dystonia-parkinsonism (XDP) is a debilitating movement disorder endemic to the Panay Island, Philippines. Most studies focus on motor symptoms, hence we reviewed the neurocognitive profile of XDP patients. Neurocognitive testing of XDP patients focused on five domains: general intellectual functioning, episodic memory, language, attention and executive function, and affect. Twenty-nine genetically confirmed patients were included. Twenty-six (89.6%) had impairments in one or more domains, while only three had no impairment in any domain. Attention and executive function was the most commonly affected domain (n = 23, 79.3%). Deficits in general intellect, episodic memory, attention and executive function and affect were seen in our subset of XDP patients. The striatal pathology affecting the frontostriatal circuitry mandating these cognitive processes is mainly implicated in these impairments. The results of our study provided further evidence on the extent of cognitive impairment in XDP using a select battery of neurocognitive tests.
Assuntos
Distúrbios Distônicos , Doenças Genéticas Ligadas ao Cromossomo X , Cognição , Corpo Estriado , Doenças Genéticas Ligadas ao Cromossomo X/genética , HumanosRESUMO
X-Linked Dystonia-Parkinsonism (XDP) is a neurodegenerative disease affecting individuals with ancestry to the island of Panay in the Philippines. In recent years there has been considerable progress at elucidating the genetic basis of XDP and candidate disease mechanisms in patient-derived cellular models, but the neural substrates that give rise to XDP in vivo are still poorly understood. Previous studies of limited XDP postmortem brain samples have reported a selective dropout of medium spiny neurons within the striatum, although neuroimaging of XDP patients has detected additional abnormalities in multiple brain regions beyond the basal ganglia. Given the need to fully define the CNS structures that are affected in this disease, we created a brain bank in Panay to serve as a tissue resource for detailed studies of XDP-related neuropathology. Here we describe this platform, from donor recruitment and consent to tissue collection, processing, and storage, that was assembled within a predominantly rural region of the Philippines with limited access to medical and laboratory facilities. Thirty-six brains from XDP individuals have been collected over an initial 4 years period. Tissue quality was assessed based on histologic staining of cortex, RNA integrity scores, detection of neuronal transcripts in situ by fluorescent hybridization chain reaction, and western blotting of neuronal and glial proteins. The results indicate that this pipeline preserves tissue integrity to an extent compatible with a range of morphologic, molecular, and biochemical analyses. Thus the algorithms that we developed for working in rural communities may serve as a guide for establishing similar brain banks for other rare diseases in indigenous populations.
Assuntos
Distonia , Distúrbios Distônicos , Doenças Neurodegenerativas , Encéfalo/diagnóstico por imagem , Distúrbios Distônicos/genética , Doenças Genéticas Ligadas ao Cromossomo X , HumanosRESUMO
BACKGROUND: The internet has made significant contributions towards health education. Analyzing the pattern of online behavior regarding meningitis and vaccinations may be worthwhile. It is hypothesized that the online search patterns in meningitis are correlated with its number of cases and the search patterns of its related vaccines. METHODS: This was an infodemiological study that determined the relationship among online search interest in meningitis, its worldwide number of cases and its associated vaccines. Using Google Trends™ Search Volume Indices (SVIs), we evaluated the search queries "meningitis," "pneumococcal vaccine," "BCG vaccine," "meningococcal vaccine" and "influenza vaccine" in January 2021, covering January 2008 to December 2020. Spearman rank correlation was used to determine correlations between these queries. RESULTS: The worldwide search interest in meningitis from 2008 to 2020 showed an average SVI of 46 ± 8.8. The most searched topics were symptoms, vaccines, and infectious agents with SVIs of 100, 52, and 39, respectively. The top three countries with the highest search interest were Ghana, Kazakhstan, and Kenya. There were weak, but statistically significant correlations between meningitis and the BCG (ρ = 0.369, p < 0.001) and meningococcal (ρ = 0.183, p < 0.05) vaccines. There were no statistically significant associations between the number of cases, influenza vaccine, and pneumococcal vaccine. CONCLUSION: The relationships among the Google SVIs for meningitis and its related vaccines and number of cases data were inconsistent and remained unclear. Future infodemiological studies may expand their scopes to social media, semantics, and big data for more robust conclusions.
Assuntos
Bases de Dados Factuais , Serviços de Informação/estatística & dados numéricos , Meningite/patologia , Vacinas Meningocócicas/administração & dosagem , Vacina BCG/administração & dosagem , Países Desenvolvidos , Países em Desenvolvimento , Carga Global da Doença , Humanos , Serviços de Informação/tendências , Masculino , Meningite/epidemiologia , Meningite/prevenção & controleRESUMO
BACKGROUND: The status of research and scientific outputs with regards to bacterial central nervous system (CNS) infection in southeast Asia (SEA) is unknown. This study aimed to analyze and compare bacterial CNS infection research output of SEA countries in terms of bibliometric indices. METHODS: The major electronic databases (MEDLINE, Scopus, Embase, CENTRAL, Clinicaltrials.gov and WPRIM) were searched for studies on bacterial CNS infection in SEA until August 31, 2020. Frequencies, percentages and Spearman's rho correlations were used. RESULTS: There was a total of 648 unique studies on bacterial CNS infection in SEA and it was 657 when double-counted (collaborative studies between SEA countries). Thailand (n=148, 22.5%) and Vietnam (n=142, 21.6%) had the highest number of publications. The most common type of research publication was the case report / case series (n=160, 24.7%). Tuberculous meningitis/tuberculoma (n=176, 26.7%) was the most common topic. This study showed that the %GDP for research and development (R&D) was associated with a higher number of research output. However, the GDP per capita was not associated with any of the bibliometric indices. The total number of neurologists was associated with all of the bibliometric analysis. CONCLUSION: Bacterial CNS infection research output in SEA countries was low in terms of quantity. The %GDP for R&D was associated with the number of research publications. The total number of neurologists was associated with all of the bibliometric indices.