RESUMO
OBJECTIVE: Radiologically inserted gastrostomy placement may be performed in patients with dysphagia secondary to amyotrophic lateral sclerosis (ALS). This study assessed technical outcomes and complications related to gastrostomy placement in patients with ALS. METHODS: A retrospective review of patients with ALS who underwent gastrostomy placement between 2021 and 2023 was performed. Patient demographics, medical history, ALS disease manifestations, survival, and post-procedural complications were obtained from the electronic medical record. Technical outcomes related to gastrostomy placement were obtained from operative notes and review of procedural imaging. RESULTS: A total of 100 patients were included in the study. The mean duration of ALS diagnosis at time of gastrostomy placement was 1.3 +/-1.2 years. The mean slow vital capacity at time of gastrostomy placement was 54.0 +/-20.2% (range 10-155%). Technical success was 100%, with 91 placed using fluoroscopic guidance and 9 placed with computed tomography guidance. Eighty-three percent of gastrostomies were performed as outpatient procedures, while 17/100 patients were admitted following the procedure for monitoring. Post-procedural adverse events were noted in 21/100 patients (15 mild and 6 moderate or greater). Three patients developed respiratory failure after gastrostomy tube placement and died within 1-week post-procedure. Lower pre-procedural slow vital capacity was associated with higher risk of post-procedural respiratory failure (p = 0.0003*). CONCLUSIONS: Gastrostomy placement in patients with ALS has a high technical success rate and may be performed safely in the outpatient setting in appropriate patients. Patients with low slow vital capacity related to ALS should be admitted post-procedurally for airway monitoring and support.
RESUMO
Objectives: Influenza-like illness (ILI) caused by respiratory viruses results in various respiratory clinical manifestations. The ILI002 prospective observational cohort study aimed to describe viral agents, seasonality, and outcomes of patients with ILI during four seasons in the influenza H1N1-pandemic and post-pandemic years (2010-2014). Methods: Patients from six Mexican hospitals were enrolled from April 2010 to March 2014. Clinical data and nasopharyngeal swabs were obtained and tested for viral respiratory pathogens by real-time reverse-transcription polymerase chain reaction. Results: Of the 5662 enrolled participants, 64.9% were adults and 35.1% were children. Among the 5629 participants with single-pathogen detection, rhinovirus (20.2%), influenza virus (11.2%), respiratory syncytial virus (RSV) (7.2%), and coronavirus (6.8%) were the most frequent pathogens. Co-infection occurred in 14.5% of cases; 49.3% of participants required hospitalization, particularly in RSV cases (42.9% adults, 89.6% children). The mortality rate was 2.8% higher among older adult participants and those with comorbidities. Influenza H1N1 had the highest mortality rate, yet almost half of the deceased had no pathogen. Rhinovirus persisted year-round, while influenza, coronavirus, and RSV peaked during cooler months. Conclusions: Analyses showed that some viruses causing ILI may lead to severe disease and hospitalization irrespective of comorbidities. These findings may help in decision-making about public health policies on prevention measures, vaccination, treatment, and administration of health care.
RESUMO
SARS-CoV-2 is an obligatory intracellular pathogen that requires a lipid bilayer membrane for its transport to build its nucleocapsid envelope and fuse with the host cell. The biological membranes are constituted by phospholipids (PLs), and vitamin E (Vit E) protects them from oxidative stress (OS). The aim of this study was to demonstrate if treatment with Vit E restores the modified profile of the FA in PLs in serum from patients with coronavirus disease-19 (COVID-19). We evaluated Vit E, total fatty acids (TFAs), fatty acids of the phospholipids (FAPLs), total phospholipids (TPLs), 8-isoprostane, thromboxane B2 (TXB2), prostaglandins (PGE2 and 6-keto-PGF1α), interleukin-6 (IL-6), and C-reactive protein (CRP) in serum from 22 COVID-19 patients before and after treatment with Vit E and compared the values with those from 23 healthy subjects (HSs). COVID-19 patients showed a decrease in Vit E, TPLs, FAPLs, and TFAs in serum in comparison to HSs (p ≤ 0.01), and Vit E treatment restored their levels (p ≤ 0.04). Likewise, there was an increase in IL-6 and CRP in COVID-19 patients in comparison with HSs (p ≤ 0.001), and treatment with Vit E decreased their levels (p ≤ 0.001). Treatment with Vit E as monotherapy can contribute to restoring the modified FA profile of the PLs in the SARS-CoV-2 infection, and this leads to a decrease in lipid peroxidation, OS, and the inflammatory process.
RESUMO
BACKGROUND: Human induced pluripotent stem cell (iPSC)-derived peripheral sensory neurons present a valuable tool to model human diseases and are a source for applications in drug discovery and regenerative medicine. Clinically, peripheral sensory neuropathies can result in maladies ranging from a complete loss of pain to severe painful neuropathic disorders. Sensory neurons are located in the dorsal root ganglion and are comprised of functionally diverse neuronal types. Low efficiency, reproducibility concerns, variations arising due to genetic factors and time needed to generate functionally mature neuronal populations from iPSCs remain key challenges to study human nociception in vitro. Here, we report a detailed functional characterization of iPSC-derived sensory neurons with an accelerated differentiation protocol ("Anatomic" protocol) compared to the most commonly used small molecule approach ("Chambers" protocol). Anatomic's commercially available RealDRG™ were further characterized for both functional and expression phenotyping of key nociceptor markers. METHODS: Multiple iPSC clones derived from different reprogramming methods, genetics, age, and somatic cell sources were used to generate sensory neurons. Manual patch clamp was used to functionally characterize both control and patient-derived neurons. High throughput techniques were further used to demonstrate that RealDRGs™ derived from the Anatomic protocol are amenable to high throughput technologies for disease modelling. RESULTS: The Anatomic protocol rendered a purer culture without the use of mitomycin C to suppress non-neuronal outgrowth, while Chambers differentiations yielded a mix of cell types. Chambers protocol results in predominantly tonic firing when compared to Anatomic protocol. Patient-derived nociceptors displayed higher frequency firing compared to control subject with both, Chambers and Anatomic differentiation approaches, underlining their potential use for clinical phenotyping as a disease-in-a-dish model. RealDRG™ sensory neurons show heterogeneity of nociceptive markers indicating that the cells may be useful as a humanized model system for translational studies. CONCLUSIONS: We validated the efficiency of two differentiation protocols and their potential application for functional assessment and thus understanding the disease mechanisms from patients suffering from pain disorders. We propose that both differentiation methods can be further exploited for understanding mechanisms and development of novel treatments in pain disorders.
Assuntos
Células-Tronco Pluripotentes Induzidas , Humanos , Células-Tronco Pluripotentes Induzidas/metabolismo , Reprodutibilidade dos Testes , Células Receptoras Sensoriais/metabolismo , Dor/metabolismo , Diferenciação Celular/fisiologiaRESUMO
Type II pneumocytes are the target of the SARS-CoV-2 virus, which alters their redox homeostasis to increase reactive oxygen species (ROS). Melatonin (MT) has antioxidant proprieties and protects mitochondrial function. In this study, we evaluated whether treatment with MT compensated for the redox homeostasis alteration in serum from COVID-19 patients. We determined oxidative stress (OS) markers such as carbonyls, glutathione (GSH), total antioxidant capacity (TAC), thiols, nitrites (NO2-), lipid peroxidation (LPO), and thiol groups in serum. We also studied the enzymatic activities of glutathione peroxidase (GPx), glutathione-S-transferase (GST), reductase (GR), thioredoxin reductase (TrxR), extracellular superoxide dismutase (ecSOD) and peroxidases. There were significant increases in LPO and carbonyl quantities (p ≤ 0.03) and decreases in TAC and the quantities of NO2-, thiols, and GSH (p < 0.001) in COVID-19 patients. The activities of the antioxidant enzymes such as ecSOD, TrxR, GPx, GST, GR, and peroxidases were decreased (p ≤ 0.04) after the MT treatment. The treatment with MT favored the activity of the antioxidant enzymes that contributed to an increase in TAC and restored the lost redox homeostasis. MT also modulated glucose homeostasis, functioning as a glycolytic agent, and inhibited the Warburg effect. Thus, MT restores the redox homeostasis that is altered in COVID-19 patients and can be used as adjuvant therapy in SARS-CoV-2 infection.
Assuntos
Antioxidantes , Tratamento Farmacológico da COVID-19 , COVID-19 , Homeostase , Melatonina , Oxirredução , Estresse Oxidativo , SARS-CoV-2 , Melatonina/uso terapêutico , Melatonina/farmacologia , Humanos , Oxirredução/efeitos dos fármacos , COVID-19/metabolismo , COVID-19/virologia , COVID-19/sangue , Homeostase/efeitos dos fármacos , Antioxidantes/metabolismo , Antioxidantes/uso terapêutico , Estresse Oxidativo/efeitos dos fármacos , Masculino , Feminino , Pessoa de Meia-Idade , SARS-CoV-2/efeitos dos fármacos , Peroxidação de Lipídeos/efeitos dos fármacos , Idoso , Adulto , Espécies Reativas de Oxigênio/metabolismo , Glutationa/metabolismo , Glutationa/sangueRESUMO
PIEZO1 is a mechanosensitive ion channel expressed in various organs, including but not limited to the brain, heart, lungs, kidneys, bone, and skin. PIEZO1 has been implicated in astrocyte, microglia, capillary, and oligodendrocyte signaling in the mammalian cortex. Using murine embryonic frontal cortex tissue, we examined the protein expression and functionality of PIEZO1 channels in cultured networks leveraging substrate-integrated microelectrode arrays (MEAs) with additional quantitative results from calcium imaging and whole-cell patch-clamp electrophysiology. MEA data show that the PIEZO1 agonist Yoda1 transiently enhances the mean firing rate (MFR) of single units, while the PIEZO1 antagonist GsMTx4 inhibits both spontaneous activity and Yoda1-induced increase in MFR in cortical networks. Furthermore, calcium imaging experiments revealed that Yoda1 significantly increased the frequency of calcium transients in cortical cells. Additionally, in voltage clamp experiments, Yoda1 exposure shifted the cellular reversal potential towards depolarized potentials consistent with the behavior of PIEZO1 as a non-specific cation-permeable channel. Our work demonstrates that murine frontal cortical neurons express functional PIEZO1 channels and quantifies the electrophysiological effects of channel activation in vitro. By quantifying the electrophysiological effects of PIEZO1 activation in vitro, our study establishes a foundation for future investigations into the role of PIEZO1 in neurological processes and potential therapeutic applications targeting mechanosensitive channels in various physiological contexts.
RESUMO
Hiatal hernia is a frequent pathology in the population; however, the most frequent hiatal hernia is type I, which accounts for up to 95% incidence, types II, III, and IV being less frequent and representing between 5% and 15%, and even less common are giant hernias. The definition of the giant hernia is still not exact in the literature; some authors define giant or massive hiatal hernia as one in which the hernia occupies more than 30% of the stomach and/or passes from other abdominal structures to the thorax. We describe the case of a patient with gastrointestinal symptomology without response to a proton pump inhibitor, with base exacerbation that required imaging studies, showing a large hernia defect passing to the thorax from abdominal organs (stomach, spleen, mesenteric fat), as well as alteration of the gastric and spleen axis with ascent in pancreatic body and tail, which corresponds to a giant hiatal hernia. Said pathology is very infrequent, with recurrences and postoperative complications. Our patient recovered from the surgical procedure with therapeutic success.
RESUMO
Background: Human Bocaviruses (HBoV) can cause acute respiratory tract infections. High coinfection rates cloud its pathogenicity. This study sought to describe the clinical features of HBoV1 disease in children and adults with Influenza-like illness (ILI), exploring associations between viral load, clinical features, and seasonality. Methods: Patients who tested positive for HBoV1 by polymerase chain reaction, enrolled from April 2010 to March 2014 in the ILI002 prospective observational cohort study were included in this cross-sectional nested study. Participants were included in ILI002 if they presented with signs and/or symptoms suggestive of influenza-like illness. Samples were tested for viral load, and NP1 and VP1/VP2 phylogenetic analyses, except for the samples lacking suitable and viable clinical material for genotyping. Findings: We identified HBoV1 in 157 (2.8%) of participants. Prevalence was 4.5% in children and 1.8% in adults. Single HBoV1 detection occurred in 41.1% and 46.3% of children and adults, respectively. Children commonly experienced fever (83.3%), cough with sputum (74.4%), and shortness of breath (72.2%). In the multivariate analysis of children, significant positive associations were detected between viral loads and age (0.20 [95% CI: 0.07, 0.33]), and the presence of fever (2.64 [95% CI: 1.35, 3.94]), nasal congestion (1.03 [95% CI: 0.07, 1.99]), dry cough (1.32 [95% CI: 0.42, 2.22]), chest congestion (1.57 [95% CI: 0.33, 2.80]), red eyes (1.25 [95% CI: 0.35, 2.14]), cough with sputum (1.79 [95% CI: 0.80, 2.78]), and other signs and symptoms such as chills, dizziness, and diaphoresis (1.73 [95% CI: 0.19, 3.27]). In contrast, significant negative associations were found between viral loads and percent neutrophils on the blood count (-0.04 [95% CI: -0.06, -0.02]), fatigue (-1.60 [95% CI: -2.46, -0.74]) and the presence of other symptoms or signs, including adenopathy and rash (-1.26 [95% CI: -2.31, -0.21]). Adults commonly experienced sore throat (73.1%), fatigue (77.4%), and headache (73.1%). In the multivariate analysis of adults, significant positive associations were detected between viral load and body mass index (0.13 [95% CI: 0.04, 0.21]), and the presence of confusion (1.54 [95% CI: 0.55, 2.53]), and sore throat (1.03 [95% CI: 0.20, 1.85]), and significant negative associations were detected between viral load and chest congestion (-1.16 [95% CI: -2.07, -0.24]). HBoV1 was detected throughout the year irrespective of season, temperature, and humidity. Interpretation: This study demonstrated the importance of detecting HBoV1 in patients with influenza-like illness either as single infection or co-infection, in both adults and children, and improves the characterization of HBoV1 seasonality, clinical features, and viral load. Phylogenetic analyses show a high conservation. Funding: The Mexican Emerging Infectious Diseases Clinical Research Network (LaRed), CONACYT (Fondo Sectorial SSA/IMSS/ISSSTE, Projects No. 71260 and No. 127088), Fondos federales no. HIM/2015/006, NIAID, NIH through a contract with Westat, Inc. (HHSN2722009000031, HHSN27200002), NCI, NIH (75N91019D00024, 75N91019F00130). Additional information at the end of the manuscript.
RESUMO
BACKGROUND. High-frequency jet ventilation (HFJV) facilitates accurate probe placement in percutaneous ablation of lung tumors but may increase risk for adverse events, including systemic air embolism. OBJECTIVE. The purpose of this study was to compare major adverse events and procedural efficiency of percutaneous lung ablation with HFJV under general anesthesia to spontaneous respiration (SR) under moderate sedation. METHODS. This retrospective study included consecutive adults who underwent CT-guided percutaneous cryoablation of one or more lung tumors with HFJV or SR between January 1, 2017, and May 31, 2023. We compared major adverse events (Common Terminology Criteria for Adverse Events grade ≥ 3) within 30 days postprocedure and hospital length of stay (HLOS) of 2 days or more using logistic regression analysis. We compared procedure time, room time, CT guidance acquisition time, CT guidance radiation dose, total radiation dose, and pneumothorax using generalized estimating equations. RESULTS. Overall, 139 patients (85 women, 54 men; median age, 68 years) with 310 lung tumors (82% metastases) underwent 208 cryoablations (HFJV, n = 129; SR, n = 79). HFJV showed greater rates than SR for the treatment of multiple tumors per session (43% vs 19%, respectively; p = .02) and tumors in a nonperipheral location (48% vs 24%, p < .001). Major adverse event rate was 8% for HFJV and 5% for SR (p = .46). No systemic air embolism occurred. HLOS was 2 days or more in 17% of sessions and did not differ significantly between HFJV and SR (p = .64), including after adjusting for probe number per session, chronic obstructive pulmonary disease, and operator experience (p = .53). Ventilation modalities showed no significant difference in procedure time, CT guidance acquisition time, CT guidance radiation dose, or total radiation dose (all p > .05). Room time was longer for HFJV than SR (median, 154 vs 127 minutes, p < .001). For HFJV, the median anesthesia time was 136 minutes. Ventilation modalities did not differ in the frequencies of pneumothorax or pneumothorax requiring chest tube placement (both p > .05). CONCLUSION. HFJV appears to be as safe as SR but had longer room times. HFJV can be used in complex cases without significantly impacting HLOS of 2 days or more, procedure time, or radiation exposure. CLINICAL IMPACT. Selection of the ventilation modality during percutaneous lung ablation should be based on patient characteristics and anticipated procedural requirements as well as operator preference.
Assuntos
Criocirurgia , Ventilação em Jatos de Alta Frequência , Neoplasias Pulmonares , Humanos , Masculino , Feminino , Ventilação em Jatos de Alta Frequência/métodos , Neoplasias Pulmonares/cirurgia , Idoso , Estudos Retrospectivos , Criocirurgia/métodos , Pessoa de Meia-Idade , Tomografia Computadorizada por Raios X/métodos , Complicações Pós-Operatórias , Radiografia Intervencionista/métodos , Respiração , Idoso de 80 Anos ou mais , Tempo de Internação/estatística & dados numéricosRESUMO
PURPOSE: Giredestrant is an investigational next-generation, oral, selective estrogen receptor antagonist and degrader for the treatment of estrogen receptor-positive (ER+) breast cancer. We present the primary analysis results of the phase Ia/b GO39932 study (NCT03332797). PATIENTS AND METHODS: Patients with ER+, HER2-negative locally advanced/metastatic breast cancer previously treated with endocrine therapy received single-agent giredestrant (10, 30, 90, or 250 mg), or giredestrant (100 mg) ± palbociclib 125 mg ± luteinizing hormone-releasing hormone (LHRH) agonist. Detailed cardiovascular assessment was conducted with giredestrant 100 mg. Endpoints included safety (primary), pharmacokinetics, pharmacodynamics, and efficacy. RESULTS: As of January 28, 2021, with 175 patients enrolled, no dose-limiting toxicity was observed, and the MTD was not reached. Adverse events (AE) related to giredestrant occurred in 64.9% and 59.4% of patients in the single-agent ± LHRH agonist and giredestrant + palbociclib ± LHRH agonist cohorts, respectively (giredestrant-only-related grade 3/4 AEs were reported in 4.5% of patients across the single-agent cohorts and 3.1% of those with giredestrant + palbociclib). Dose-dependent asymptomatic bradycardia was observed, but no clinically significant changes in cardiac-related outcomes: heart rate, blood pressure, or exercise duration. Clinical benefit was observed in all cohorts (48.6% of patients in the single-agent cohort and 81.3% in the giredestrant + palbociclib ± LHRH agonist cohort), with no clear dose relationship, including in patients with ESR1-mutated tumors. CONCLUSIONS: Giredestrant was well tolerated and clinically active in patients who progressed on prior endocrine therapy. Results warrant further evaluation of giredestrant in randomized trials in early- and late-stage ER+ breast cancer.
Assuntos
Neoplasias da Mama , Carbolinas , Piperazinas , Piridinas , Humanos , Feminino , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/genética , Receptor ErbB-2/genética , Receptor ErbB-2/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Receptores de Estrogênio , Hormônio Liberador de Gonadotropina/agonistasRESUMO
Introducción: El análisis de la situación de salud es una investigación primordial que se realiza en el sistema de salud cubano, en el que se estudia la salud, los elementos que la determinan y las formas de mejorarla. Objetivo: Evaluar la propuesta de diseño de un esquema que contribuya a la mejora del aprendizaje del análisis de la situación de salud de la comunidad para los residentes de la especialidad Medicina General Integral, pertenecientes a la Universidad de Ciencias Médicas de Guantánamo. Método: Se realizó una investigación pedagógica de tipo descriptiva en la antes mencionada institución durante el período marzo-julio de 2022. De un universo de 67 profesores que aceptaron participar, se seleccionaron 26 por muestreo intencional. Para obtener los datos primarios fueron aplicados tres cuestionarios tipo Likert para evaluar el esquema, en consideración con la estructura, la funcionalidad y el aporte en el aprendizaje. Dichos cuestionarios incluyeron las respuestas: Totalmente en desacuerdo, En desacuerdo, Ni de acuerdo ni en desacuerdo, De acuerdo y Totalmente de acuerdo. Los datos se resumieron en números absolutos y porcentajes. Se presentaron en tablas de distribución de frecuencias. Resultados: Los subtotales de respuestas Totalmente de acuerdo y De acuerdo sobre la evaluación estructural y funcional, así como la influencia que se espera de este para mejorar el aprendizaje del análisis de situación de salud, se consideraron adecuados al superar el estándar. Conclusiones: El esquema propuesto es evaluado como adecuado en estructura y funcionalidad. Se considera positiva la influencia que se espera de este para mejorar el aprendizaje del análisis de situación de salud de la comunidad.(AU)
Introduction: The analysis of the health situation is a fundamental investigation carried out in the Cuban health system, in which health is studied, the elements that determine it and the ways to improve it. Objective: To evaluate the design proposal of a scheme that contributes to the improvement of learning of the analysis of the health situation of the community for the residents of the Comprehensive General Medicine specialty, belonging to the Universidad de Ciencias Médicas de Guantánamo. Method: A descriptive pedagogical research was carried out in the aforementioned institution during the period March-July 2022. From a universe of 67 teachers who agreed to participate, 26 were selected by intentional sampling. To obtain primary data, three Likert-type questionnaires were applied to evaluate the scheme, taking into consideration the structure, functionality and contribution to learning. These questionnaires included the responses: Totally disagree, Disagree, Neither agree nor disagree, Agree and Totally agree. Data were summarized in absolute numbers and percentages. They were presented in frequency distribution tables. Results: The subtotals of Completely Agree and Agree responses on the structural and functional evaluation, as well as the expected influence of this to improve the learning of health situation analysis, were considered adequate when exceeding the standard. Conclusions: The proposed scheme is evaluated as adequate in structure and functionality. The influence expected from this to improve learning about the analysis of the community's health situation is considered positive.(AU)
Introdução: A análise da situação sanitária é uma investigação fundamental realizada no sistema de saúde cubano, no qual se estuda a saúde, os elementos que a determinam e as formas de melhorá-la. Objetivo: Avaliar a proposta de desenho de um esquema que contribua para a melhoria da aprendizagem da análise da situação de saúde da comunidade para os residentes da especialidade Medicina Geral Integral, pertencente à Universidad de Ciencias Médicas de Guantánamo. Método: Foi realizada uma pesquisa pedagógica descritiva na referida instituição durante o período de março a julho de 2022. De um universo de 67 professores que aceitaram participar, 26 foram selecionados por amostragem intencional. Para obtenção dos dados primários, foram aplicados três questionários do tipo Likert para avaliação do esquema, levando em consideração a estrutura, funcionalidade e contribuição para a aprendizagem. Esses questionários incluíram as respostas: Discordo totalmente, Discordo, Nem concordo nem discordo, Concordo e Concordo totalmente. Os dados foram resumidos em números absolutos e porcentagens. Eles foram apresentados em tabelas de distribuição de frequência. Resultados: Os subtotais das respostas Concordo Totalmente e Concordo na avaliação estrutural e funcional, bem como a influência esperada desta para melhorar a aprendizagem da análise da situação de saúde, foram considerados adequados quando excedem o padrão. Conclusões: O esquema proposto é avaliado como adequado em estrutura e funcionalidade.A influência que se espera disto para melhorar a aprendizagem sobre a análise da situação de saúde da comunidade é considerada positiva.(AU)
RESUMO
Background: Human induced pluripotent stem cell (iPSC)-derived peripheral sensory neurons present a valuable tool to model human diseases and are a source for applications in drug discovery and regenerative medicine. Clinically, peripheral sensory neuropathies can result in maladies ranging from a complete loss of pain to severe painful neuropathic symptoms. Sensory neurons are located in the dorsal root ganglion and are comprised of functionally diverse neuronal types. Low efficiency, reproducibility concerns, variations arising due to genetic factors and time needed to generate functionally mature neuronal populations from iPSCs for disease modelling remain key challenges to study human nociception in vitro. Here, we report a detailed characterization of iPSC-derived sensory neurons with an accelerated differentiation protocol ("Anatomic" protocol) compared to the most commonly used small molecule approach ("Chambers" protocol). Methods: Multiple iPSC clones derived from different reprogramming methods, genetics, age, and somatic cell sources were used to generate sensory neurons. Expression profiling of sensory neurons was performed with Immunocytochemistry and in situ hybridization techniques. Manual patch clamp and high throughput cellular screening systems (Fluorescence imaging plate reader, automated patch clamp and multi-well microelectrode arrays recordings) were applied to functionally characterize the generated sensory neurons. Results: The Anatomic protocol rendered a purer culture without the use of mitomycin C to suppress non-neuronal outgrowth, while Chambers differentiations yielded a mix of cell types. High throughput systems confirmed functional expression of Na+ and K+ ion channels. Multi-well microelectrode recordings display spontaneously active neurons with sensitivity to increased temperature indicating expression of heat sensitive ion channels. Patient-derived nociceptors displayed higher frequency firing compared to control subject with both, Chambers and Anatomic differentiation approaches, underlining their potential use for clinical phenotyping as a disease-in-a-dish model. Conclusions: We validated the efficiency of two differentiation protocols and their potential application for understanding the disease mechanisms from patients suffering from pain disorders. We propose that both differentiation methods can be further exploited for understanding mechanisms and development of novel treatments in pain disorders.
RESUMO
Glucose represents the principal brain energy source. Thus, not unexpectedly, genetic glucose transporter 1 (Glut1) deficiency (G1D) manifests with encephalopathy. G1D seizures, which constitute a prominent disease manifestation, often prove refractory to medications but may respond to therapeutic diets. These seizures are associated with aberrant thalamocortical oscillations as inferred from human electroencephalography and functional imaging. Mouse electrophysiological recordings indicate that inhibitory neuron failure in thalamus and cortex underlies these abnormalities. This provides the motivation to develop a neural circuit testbed to characterize the mechanisms of thalamocortical synchronization and the effects of known or novel interventions. To this end, we used mouse thalamocortical slices on multielectrode arrays and characterized spontaneous low frequency oscillations and less frequent 30-50 Hz or gamma oscillations under near-physiological bath glucose concentration. Using the cortical recordings from layer IV among other regions recorded, we quantified oscillation epochs via an automated wavelet-based algorithm. This method proved analytically superior to power spectral density, short-time Fourier transform or amplitude-threshold detection. As expected from human observations, increased bath glucose reduced the lower frequency oscillations while augmenting the gamma oscillations, likely reflecting strengthened inhibitory neuron activity, and thus decreasing the low:high frequency ratio (LHR). This approach provides an ex vivo method for the evaluation of mechanisms, fuels, and pharmacological agents in a crucial G1D epileptogenic circuit.
RESUMO
Glucose represents the principal brain energy source. Thus, not unexpectedly, genetic glucose transporter 1 (Glut1) deficiency (G1D) manifests with encephalopathy. G1D seizures, which constitute a prominent disease manifestation, often prove refractory to medications but may respond to therapeutic diets. These seizures are associated with aberrant thalamocortical oscillations as inferred from human electroencephalography and functional imaging. Mouse electrophysiological recordings indicate that inhibitory neuron failure in thalamus and cortex underlies these abnormalities. This provides the motivation to develop a neural circuit testbed to characterize the mechanisms of thalamocortical synchronization and the effects of known or novel interventions. To this end, we used mouse thalamocortical slices on multielectrode arrays and characterized spontaneous low frequency oscillations and less frequent 30-50 Hz or gamma oscillations under near-physiological bath glucose concentration. Using the cortical recordings from layer IV, we quantified oscillation epochs via an automated wavelet-based algorithm. This method proved analytically superior to power spectral density, short-time Fourier transform or amplitude-threshold detection. As expected from human observations, increased bath glucose reduced the lower frequency oscillations while augmenting the gamma oscillations, likely reflecting strengthened inhibitory neuron activity. This approach provides an ex vivo method for the evaluation of mechanisms, fuels, and pharmacological agents in a crucial G1D epileptogenic circuit.
RESUMO
Although ablations are performed with conscious sedation or general anesthesia, microwave ablations can be painful post procedure. Newer analgesic modalities, including regional blocks, have promoted the proliferation of less invasive anesthesia care for ablative procedures. This study evaluates whether bilateral paravertebral blocks reduce the need for additional analgesics in comparison to unilateral blocks in microwave ablations. In this retrospective study, individuals undergoing microwave ablation who underwent unilateral versus bilateral nerve blocks at a single institution from 2017 to 2019 were compared. Categorical variables were analyzed using Pearson's chi-squared tests. Comparisons of means were completed using multiple T-tests corrected using the Holm-Sidak method with α = 0.05. Regression modeling was used to identify factors related to increased MME (milligram morphine equivalent) usage and post-procedure admission rates. A total of 106 patients undergoing 112 liver MWA procedures were included in this analysis, with patients receiving either a bilateral or unilateral block. Pre-procedural characteristics demonstrated no significant differences in age or gender. Bilateral blocks were associated with decreased usage of gabapentin (14% vs. 0%, p = 0.01) and a lower rate of post-procedure admissions (OR 0.23, p = 0.003). Therefore, when using paravertebral blocks, bilateral blocks are superior to unilateral blocks, as demonstrated by decreased rates of hospital admission and reduced use of systemic neuropathic pain medication. Additionally, reducing post-procedural MME may reduce the rate of admission to the hospital.