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Introduction: We previously reported that ATP1A3 c.823G>C (p.Ala275Pro) mutant causes varying phenotypes of alternative hemiplegia of childhood and rapid-onset dystonia-parkinsonism in the same family. This study aims to investigate the function of ATP1A3 c.823G>C (p.Ala275Pro) mutant at the cellular and zebrafish models. Methods: ATP1A3 wild-type and mutant Hela cell lines were constructed, and ATP1A3 mRNA expression, ATP1A3 protein expression and localization, and Na+-K+-ATPase activity in each group of cells were detected. Additionally, we also constructed zebrafish models with ATP1A3 wild-type overexpression (WT) and p.Ala275Pro mutant overexpression (MUT). Subsequently, we detected the mRNA expression of dopamine signaling pathway-associated genes, Parkinson's disease-associated genes, and apoptosisassociated genes in each group of zebrafish, and observed the growth, development, and movement behavior of zebrafish. Results: Cells carrying the p.Ala275Pro mutation exhibited lower levels of ATP1A3 mRNA, reduced ATP1A3 protein expression, and decreased Na+-K+-ATPase activity compared to wild-type cells. Immunofluorescence analysis revealed that ATP1A3 was primarily localized in the cytoplasm, but there was no significant difference in ATP1A3 protein localization before and after the mutation. In the zebrafish model, both WT and MUT groups showed lower brain and body length, dopamine neuron fluorescence intensity, escape ability, swimming distance, and average swimming speed compared to the control group. Moreover, overexpression of both wild-type and mutant ATP1A3 led to abnormal mRNA expression of genes associated with the dopamine signaling pathway and Parkinson's disease in zebrafish, and significantly upregulated transcription levels of bad and caspase-3 in the apoptosis signaling pathway, while reducing the transcriptional level of bcl-2 and the bcl-2/bax ratio. Conclusion: This study reveals that the p.Ala275Pro mutant decreases ATP1A3 protein expression and Na+/K+-ATPase activity. Abnormal expression of either wild-type or mutant ATP1A3 genes impairs growth, development, and movement behavior in zebrafish.
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Introduction: This study aimed to assess the percentage of patients treated according to the European Society for Medical Oncology (ESMO) 2018 guidelines for breakthrough cancer pain (BTcP) and the impact of guidelines adherence on patients' quality of life (QoL). Methods: Adult opioid-tolerant patients diagnosed with BTcP and locally advanced or recurrent metastatic cancer with a life expectancy of >3 months prospectively were included. Patients were followed up for 28 days. Results: Of 127 patients included, 37 were excluded due to the impossibility to establish adherence to the ESMO guidelines. Among the evaluable patients [51.1% female; with mean (SD) age of 66.4 (11.8) years], all were adherent. BTcP was diagnosed by the Association for Palliative Medicine algorithm in 47.8% of patients and by clinical experience in 52.2% of patients. The mean number of daily BTcP episodes ranged between 1 and 8, with a mean (95% CI) severity of 7.3 (7.0; 7.6) at week 0 and 6.2 (5.8; 6.6) at week 4. Time to maximum pain intensity was 3-15â min in 52.2% of patients, and BTcP lasted 30-60â min in 14.4% of patients at week 0 and 4.4% of patients at week 4. Mean (95% CI) treatment effectiveness was 6.6 (6.1; 7.1) at week 0 and 7.4 (7.0; 7.8) at week 4. Median (Q1-Q3) patients' global impression of clinical condition was 4.0 (4.0-4.0) at week 0 and 3.0 (2.0-3.0) at week 4. Conclusion: A clear BTcP assessment and strict follow-up could be crucial to guidelines adherence and for patient's QoL.
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Background: This Obesity Medicine Association (OMA) Clinical Practice Statement (CPS) details assessment and management of the child with overweight or obesity. The term "child" is defined as the child between 2 and 12 years of age. Because children are in a continual state of development during this age range, we will specify when our discussion applies to subsets within this age range. For the purposes of this CPS, we will use the following definitions: overweight in the child is a body mass index (BMI) ≥ 85th and <95th percentile, obesity in the child is a BMI ≥95th percentile, and severe obesity is a BMI ≥120% of the 95th percentile. Methods: The information and clinical guidance in this OMA Clinical Practice Statement are based on scientific evidence, supported by medical literature, and derived from the clinical perspectives of the authors. Results: This OMA Clinical Practice Statement provides an overview of prevalence of disease in this population, reviews precocious puberty in the child with obesity, discusses the current and evolving landscape of the use of anti-obesity medications in children in this age range, discusses the child with obesity and special health care needs, and reviews hypothalamic obesity in the child. Conclusions: This OMA Clinical Practice Statement on the child with obesity is an evidence based review of the literature and an overview of current recommendations. This CPS is intended to provide a roadmap to the improvement of the health of children with obesity, especially those with metabolic, physiological, psychological complications and/or special healthcare needs. This CPS addresses treatment recommendations and is designed to help the clinician with clinical decision making.
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Rapid-onset obsessive-compulsive disorder (OCD) has been classically described in the context of infectious and autoimmune stressors, most famously PANDAS (pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections) and then PANS (pediatric autoimmune neuropsychiatric syndrome). PANS itself, however, specifically excludes neurological and medical disorders, including seizures, from the diagnostic criteria. Changes in affect, such as depression/anxiety and new-onset psychosis, have been previously described in the post-seizure period but often self-resolve. To the best of our knowledge, neither rapid onset nor exacerbation of OCD have been previously reported in a post-seizure patient. We present the case of a four-year five-month-old male with a history of poor weight gain who presented to the emergency department for a seizure in the context of hypoglycemia. During the hospital course and within one month following discharge, he became significant for a myriad of new behaviors, rituals, and even visual hallucinations. We propose that the seizure itself is a highly unique and likely neurophysiological stressor. We consider neurologically exacerbated OCD to be an area ripe for further investigation.
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Analgesia following acute traumatic fracture remains a clinical challenge. Pain relief via peripheral nerve stimulation (PNS) is a promising treatment modality due to its opioid-sparing effects and rapid, reversible sensory blockade without motor blockade. We present the case of a patient who suffered a traumatic tibial plateau fracture. A popliteal sciatic PNS device was placed on postoperative day 1 following inadequate pain control. The patient reported marked pain relief, a significant reduction in morphine milligram equivalent (MME) utilization, and improved early functional recovery. The PNS lead was removed at the patient's 2-month follow-up visit without any adverse events.
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BACKGROUND: Clinical evidence for the rapidity and effectiveness of fentanyl buccal soluble film (FBSF) in reducing pain intensity of breakthrough cancer pain (BTcP) remains inadequate. This study aimed to evaluate the efficacy of FBSF proportional to the around-the-clock (ATC) opioid regimens in rapidly relieving the intensity of BTcP episodes by determining the percentage of patients requiring further dose titration. METHODS: The study procedure included a dose-finding period followed by a 14-day observation period. Pain intensity was recorded with a Numeric Rating Scale (NRS) at onset and 5, 10, 15, and 30 min after FBSF self-administration. Meaningful pain relief was defined as the final NRS score ≤ 3. Satisfaction survey was conducted for each patient after treatment using the Global Satisfaction Scale. RESULTS: A total of 63 BTcP episodes occurred in 30 cancer patients. Only one patient required rescue medication at first BTcP episode and then achieved meaningful pain relief after titrating FBSF by 200 µg. Most BTcP episodes relieved within 10 min. Of 63 BTcP episodes, 30 (47.6%), 46 (73.0%), and 53 (84.1%) relieved within 5, 10, and 15 min after FBSF administration. Only grade 1/2 adverse events were reported, including somnolence, malaise, and dizziness. Of the 63 BTcP episodes, 82.6% were rated as excellent/good satisfaction with FBSF. CONCLUSION: FBSF can be administrated "on demand" by cancer patients at the onset of BTcP, providing rapid analgesia by achieving meaningful pain relief within 10 min. TRIAL REGISTRATION: This study was retrospectively registered 24 December, 2021 at Clinicaltrial.gov (NCT05209906): https://clinicaltrials.gov/study/NCT05209906 .
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Analgésicos Opioides , Dor Irruptiva , Fentanila , Humanos , Fentanila/uso terapêutico , Fentanila/administração & dosagem , Feminino , Masculino , Dor Irruptiva/tratamento farmacológico , Dor Irruptiva/etiologia , Pessoa de Meia-Idade , Analgésicos Opioides/uso terapêutico , Analgésicos Opioides/administração & dosagem , Idoso , Administração Bucal , Adulto , Medição da Dor/métodos , Dor do Câncer/tratamento farmacológico , Manejo da Dor/métodos , Manejo da Dor/normas , Manejo da Dor/estatística & dados numéricos , Neoplasias/complicações , Neoplasias/tratamento farmacológico , Idoso de 80 Anos ou maisRESUMO
Hodgkin's lymphoma is a B-cell neoplasm that typically manifests with gradual lymphadenopathy progression over weeks to months. However, we present an exceptional case of Hodgkin's lymphoma marked by an unusually rapid development of lymphadenopathy within an hour. A 30-year-old male presented with a left neck swelling that occurred within an hour and then remained stable in size for three days, prompting an investigation revealing widespread lymphadenopathy consistent with Hodgkin's lymphoma. This case outlines the importance of recognizing and investigating unusual presentations of Hodgkin's lymphoma promptly, emphasizing the necessity for expedited diagnosis and intervention.
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Neurological manifestations with basal ganglia involvement following Hymenoptera stings are rare and clinically ill-defined conditions. We present a patient with acute parkinsonism non-responsive to levodopa, who developed striatal lesions after a hornet sting. We report his response to immunomodulatory treatment and subsequent clinical and brain magnetic resonance imaging (MRI) follow-up. We also searched the literature for patients with acute extrapyramidal syndromes following an insect sting. Fourteen cases have been published; 12 of them are reviewed here. The majority of cases presented with symmetric akinetic syndrome with axial rigidity and/or gait impairment. Six patients were treated with levodopa and only two of these had a modest response to therapy. Brain MRI/computed tomography scan revealed lesions of the basal ganglia, which resulted in fatal outcome in four patients, whereas only one achieved complete recovery. Clinicians should be aware of this rare but devastating cause of acute-onset parkinsonism and specific clinical presentation of this condition, and should consider prompt and prolonged immunomodulatory treatment to prevent irreversible basal ganglia damage.
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Aims: This study delves into the two-year opioid prescription trends in the Local Sanitary Agency Naples 3 South, Campania Region, Italy. The research aims to elucidate prescribing patterns, demographics, and dosage categories within a population representing 1.7% of the national total. Perspectives on artificial intelligence research are discussed. Methods: From the original dataset, spanning from January 2022 to October 2023, we processed multiple variables including demographic data, medications, dosages, drug consumption, and administration routes. The dispensing quantity was calculated as defined daily doses (DDD). Results: The analysis reveals a conservative approach to opioid therapy. In subjects under the age of 20, prescriptions accounted for 2.1% in 2022 and declined to 1.4% in 2023. The drug combination paracetamol/codeine was the most frequently prescribed, followed by tapentadol. Approximately two-thirds of the consumption pertains to oral formulations. Transdermal formulations were 15% (fentanyl 9.8%, buprenorphine 5.1%) in 2022; and 16.6% (fentanyl 10%, buprenorphine 6.6%) in 2023. These data were confirmed by the DDD analysis. The trend analysis demonstrated a significant reduction ( p < 0.001) in the number of prescribed opioids from 2022 to 2023 in adults (40-69 years). The study of rapid-onset opioids (ROOs), drugs specifically used for breakthrough cancer pain, showed higher dosage (>267 mcg) consumption among women, whereas a lower dosage (<133 mcg) was calculated for men. Fentanyl pectin nasal spray accounted for approximately one-fifth of all ROOs. Conclusion: Despite limitations, the study provides valuable insights into prescribing practices involving an important study population. The findings underscore the need for tailored approaches to prescribing practices, recognizing the complexities of pain management in different contexts. This research can contribute to the ongoing discourse on opioid use, advocating for innovative strategies that optimize therapeutic outcomes while mitigating potential risks.
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Recent studies have reported the presence of autoantibodies against zinc finger and SCAN domain-containing protein 1 (ZSCAN1) in the sera of patients with rapid-onset obesity with hypoventilation, hypothalamic and autonomic dysregulation (ROHHAD) syndrome associated with neuroendocrine tumors, suggesting immunologic and paraneoplastic processes as the pathologic underpinnings. Moreover, several hypothalamic regions, including the subfornical organ (SFO), were reported to exhibit antibody reactivity in a patient with ROHHAD syndrome not associated with a tumor. Whether ROHHAD syndrome not associated with a tumor is associated with anti-ZSCAN1 autoantibodies remains unclear. We used a comprehensive protein array analysis to identify candidate molecules in the sera of patients with ROHHAD syndrome and identified ZSCAN1 as a target antigen. We also found that ZSCAN1 was co-expressed at the site of antibody reactivity to the IgG in the patient serum observed in mouse SFOs and an enzyme-linked immunosorbent assay showed that >85% of the patients with ROHHAD syndrome were positive for anti-ZSCAN1 autoantibodies. These results suggest anti-ZSCAN1 autoantibodies as a feasible diagnostic marker in ROHHAD syndrome regardless of the presence of a tumor.
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Doenças Hipotalâmicas , Tumores Neuroendócrinos , Obesidade Infantil , Humanos , Animais , Camundongos , Autoanticorpos , Síndrome , Hipoventilação/diagnósticoRESUMO
Breakthrough pain is transitory pain that occurs despite the use of opioids for background pain control. Breakthrough pain occurs in 40% to 80% of patients with cancer pain. Despite effective analgesic therapy, patients and their caregivers often feel that their pain is not sufficiently controlled. Therefore, an improved understanding of breakthrough pain and its management is essential for all physicians caring for patients with cancer. This article reviews the definition, clinical manifestations, accurate diagnostic strategies, and optimal treatment options for breakthrough pain in patients with cancer. This review focuses on the efficacy and safety of rapid-onset opioids, which are the primary rescue drugs for breakthrough pain.
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Persons who have renounced a prior transgender identification, often after some degree of social and medical transition, are increasingly visible. We recruited 78 US individuals ages 18-33 years who previously identified as transgender and had stopped identifying as transgender at least six months prior. On average, participants first identified as transgender at 17.1 years of age and had done so for 5.4 years at the time of their participation. Most (83%) participants had taken several steps toward social transition and 68% had taken at least one medical step. By retrospective reports, fewer than 17% of participants met DSM-5 diagnostic criteria for Gender Dysphoria in Childhood. In contrast, 53% of participants believed that "rapid-onset gender dysphoria" applied to them. Participants reported a high rate of psychiatric diagnoses, with many of these prior to trans-identification. Most participants (N = 71, 91%) were natal females. Females (43%) were more likely than males (0%) to be exclusively homosexual. Participants reported that their psychological health had improved dramatically since detransition/desistance, with marked decreases in self-harm and gender dysphoria and marked increases in flourishing. The most common reason given for initial trans-identification was confusing mental health issues or reactions to trauma for gender dysphoria. Reasons for detransition were more likely to reflect internal changes (e.g., the participants' own thought processes) than external pressures (e.g., pressure from family). Results suggest that, for some transgender individuals, detransition is both possible and beneficial.
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Disforia de Gênero , Minorias Sexuais e de Gênero , Pessoas Transgênero , Transexualidade , Masculino , Feminino , Humanos , Adulto Jovem , Estudos Retrospectivos , Transexualidade/psicologia , Pessoas Transgênero/psicologia , Saúde Mental , Disforia de Gênero/diagnóstico , Disforia de Gênero/psicologia , Identidade de GêneroRESUMO
We report ATP1A3-associated rapid-onset dystonia-parkinsonism with an atypical presentation including myoclonus and exaggerated startle in four patients. Their prominence over parkinsonism prompted consideration of a syndromic diagnosis of myoclonus dystonia. ATP1α3 dysfunction in GABAergic neurons could explain these examination findings. The spectrum of ATP1A3-associated movement disorders includes myoclonus-dystonia.
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Distonia , Distúrbios Distônicos , Mioclonia , Transtornos Parkinsonianos , Humanos , Distonia/complicações , Mioclonia/complicações , Mioclonia/diagnóstico , Mutação , Distúrbios Distônicos/complicações , Distúrbios Distônicos/diagnóstico , Distúrbios Distônicos/genética , Transtornos Parkinsonianos/complicações , Transtornos Parkinsonianos/genética , ATPase Trocadora de Sódio-PotássioRESUMO
Background: Endobronchial ultrasound-guided transbronchial fine needle aspiration (EBUS-FNA) has revolutionized the diagnostic and staging approach to non-small cell carcinoma and thoracic lymphadenopathy. However, obstacles to efficacy of rapid on-site evaluation (ROSE) of the samples include variability in sample quality and slow and cumbersome process in the procedure room leading to extended procedure time. The purpose of this pilot study was to evaluate the feasibility and specimen quality of lymph node biopsies prepared through a novel automated system for automated fixation, drying and staining compared to standard slide preparation method. Methods: We performed a prospective, single-center pilot feasibility study of patients undergoing EBUS. Samples were split into conventional standard of care (SOC) slide preparation and preparation using the device ("instrument"). Pathologists compared the SOC slides to the slides prepared by the automated system and assessed the following metrics: nuclear and cytoplasmic quality, presence of debris/artifact, staining quality, creation of a monolayer, and ease of adequacy/diagnosis assessment. A score between 1 (lowest quality) and 3 (highest quality) was assigned to the above metrics. Results: Sixty patients were recruited. One to three lymph nodes were sampled for each patient for a total of 72 samples collected. The mean scores of each assessment category showed no statistical difference between the two preparation techniques except for improved monolayer creation in the instrument samples. Thirty of thirty-one (96.8%) paired samples in the final analysis showed diagnostic equivalency between the automated slides and conventional slides; the discordant pairing was reported to be suspicious on the instrument sample and atypical on the SOC. Conclusions: Study results suggest that slides prepared by the automated system are of adequate quality for adequacy assessment with diagnostic concordance when compared to SOC slides.
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The purpose of these experiments was to determine if the increase in vascular conductance following a single muscle contraction (50% of maximal voluntary contraction) (6 male and 6 female subjects) was altered during baroceptor loading and unloading. Rapid onset vasodilation (ROV) was determined by measuring brachial artery blood flow (Doppler ultrasound) and blood pressure (Finapress monitor). Brachial artery vascular conductance was calculated by dividing blood flow by mean arterial pressure. ROV was described by the area under the Δvascular conductance (VC)-time curve during the 30 s following muscle contraction. ROV was determined using chamber pressures of +20, +10, 0, -10, -20, and -40 mmHg (lower body positive and negative pressure, LBPP, and LBNP). We tested the hypothesis that the impact of baroreceptor loading and unloading produces a proportion change in ROV. The level of ROV following each contraction was proportional to the peak force (r2 = 0.393, P = 0.0001). Peak force was therefore used as a covariate in further analysis. ROV during application of -40 mmHg LBNP (0.345 ± 0.229 mL·mmHg-1) was lower than that observed at Control (0.532 ± 0.284 mL·mmHg-1, P = 0.034) and +20 mmHg LBPP (0.658 ± 0.364 mL·mmHg-1, P = 0.0008). ROV was linearly related to chamber pressure from -40 to +20 mmHg chamber pressure (r2 = 0.512, P = 0.022, n = 69) and from -20 to +10 mmHg chamber pressure (r2= 0.973, P < 0.0425, n = 45), Overall, vasoconstrictor tone altered with physiologically relevant baroreceptor loading and unloading resulted in a proportion change in ROV.NEW & NOTEWORTHY Rapid onset vasodilation (ROV) was linearly related to the peak force of each single 1-s muscle contraction. In addition, ROV is reduced by baroreceptor unloading (LBNP: -10, -120, and -40 mmHg) and increased by baroreceptor loading (LBPP: +10 and +20 mmHg). Without accounting for peak force and the level of baroreceptor engagement makes comparison of ROV in subjects of differing muscle size or strength untenable.
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Pressorreceptores , Vasodilatação , Humanos , Masculino , Feminino , Pressorreceptores/fisiologia , Vasodilatação/fisiologia , Hemodinâmica , Pressão Sanguínea/fisiologia , Pressão Negativa da Região Corporal Inferior , Frequência Cardíaca/fisiologiaRESUMO
Here, we report the case of a rare and complex disorder, rapid-onset obesity with hypothalamic dysfunction, hypoventilation, autonomic dysregulation, and neuroendocrine tumor (ROHHADNET) syndrome, in a three-year-old girl with no significant medical history. This is the first such case reported from the UAE. ROHHADNET is a rare disorder of respiratory control and autonomic nervous system regulation with endocrine abnormalities. It typically presents in children older than 18 months with rapid weight gain. This is a challenging diagnosis as there is no clear diagnostic test, and treatment is essentially supportive. This report describes a case of ROHHADNET syndrome in a previously well child who presented with rapid weight gain followed by ophthalmoplegia, dysphagia, electrolyte disturbance, and other comorbidities. The paper outlines in detail the clinical course, investigations, and management of ROHHADNET syndrome. Cerebrospinal fluid analysis revealed oligoclonal bands, which have been reported in only two other cases of ROHHADNET syndrome. Our goal in reporting this case is to increase awareness of this condition among clinicians to facilitate early diagnosis and timely management.
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The rapid onset of life-threatening clinical manifestations in venomous snake bite could be due to an intravenous bite. This article seeks to review and consider the clinical implications, pathophysiology, and management of this rare route of snake envenomation broadly by venomous snakes which are little described in the available literature.
Résumé L'apparition rapide des manifestations cliniques potentiellement mortelles dans la morsure de serpent venimeux pourrait être due à une morsure intraveineuse. Cet article vise à revoir et à considérer les implications cliniques, la physiopathologie et la gestion de cette rare itinéraire d'envenomations de serpents largement par des serpents venimeux qui sont peu décrits dans la littérature disponible. Mots-clés: Effondrement cardiovasculaire, morsure de serpent intraveineuse, début rapide de la mort, envenimation de serpent.
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Mordeduras de Serpentes , Animais , Humanos , Mordeduras de Serpentes/complicações , Mordeduras de Serpentes/terapia , Antivenenos/uso terapêutico , SerpentesRESUMO
Biallelic mutations in GBA1 cause the lysosomal storage disorder Gaucher disease, and carriers of GBA1 variants have an increased risk of Parkinson's disease (PD). It is still unknown whether GBA1 variants are also associated with other movement disorders. We present the case of a woman with type 1 Gaucher disease who developed acute dystonia and parkinsonism at 35 years of age during a recombinant enzyme infusion treatment. She developed severe dystonia in all extremities and a bilateral pill-rolling tremor that did not respond to levodopa treatment. Despite the abrupt onset of symptoms, neither Sanger nor whole genome sequencing revealed pathogenic variants in ATP1A3 associated with rapid-onset dystonia-parkinsonism (RDP). Further examination showed hyposmia and presynaptic dopaminergic deficits in [18F]-DOPA PET, which are commonly seen in PD but not in RDP. This case extends the spectrum of movement disorders reported in patients with GBA1 mutations, suggesting an intertwined phenotype.