RESUMEN
Cyclic adenosine monophosphate (cAMP) is a canonical intracellular messenger playing diverse roles in cell functions. In neurons, cAMP promotes axonal growth during early development, and mediates sensory transduction and synaptic plasticity after maturation. The molecular cascades of cAMP are well documented, but its spatiotemporal profiles associated with neuronal functions remain hidden. Hence, we developed a genetically encoded cAMP indicator based on a bacterial cAMP-binding protein. This indicator "gCarvi" monitors [cAMP]i at 0.2 to 20 µM with a subsecond time resolution and a high specificity over cyclic guanosine monophosphate (cGMP). gCarvi can be converted to a ratiometric probe for [cAMP]i quantification and its expression can be specifically targeted to various subcellular compartments. Monomeric gCarvi also enables simultaneous multisignal monitoring in combination with other indicators. As a proof of concept, simultaneous cAMP/Ca2+ imaging in hippocampal neurons revealed a tight linkage of cAMP to Ca2+ signals. In cerebellar presynaptic boutons, forskolin induced nonuniform cAMP elevations among boutons, which positively correlated with subsequent increases in the size of the recycling pool of synaptic vesicles assayed using FM dye. Thus, the cAMP domain in presynaptic boutons is an important determinant of the synaptic strength.
Asunto(s)
AMP Cíclico , Colorantes Fluorescentes , Hipocampo , Imagen Molecular , Neuronas , Animales , AMP Cíclico/metabolismo , Proteína Receptora de AMP Cíclico/metabolismo , GMP Cíclico/metabolismo , Proteínas de Escherichia coli/metabolismo , Colorantes Fluorescentes/química , Proteínas Fluorescentes Verdes/química , Hipocampo/metabolismo , Humanos , Ratones , Imagen Molecular/métodos , Neuronas/metabolismo , Terminales Presinápticos/metabolismoRESUMEN
STUDY DESIGN: Experimental study. OBJECTIVES: To compare lipid profiles during moderate-intensity exercise between persons with cervical spinal cord injuries (SCIC) and able-bodied controls (AB). SETTING: Wakayama Medical University, Japan. METHODS: Six participants with SCIC and six AB performed 30-min arm-crank exercise at 50% VO2peak. Blood samples were collected before (PRE), immediately (POST), and 60 min after exercise (REC). Concentrations of serum free fatty acids ([FFA]s), total ketone bodies ([tKB]s), acetoacetic acid ([AcAc]s), insulin ([Ins]s), and plasma catecholamines and glucose ([Glc]p) were assessed. RESULTS: Catecholamine concentrations in SCIC were lower than AB throughout the experiment (P < 0.001) and remained unchanged, while increased at POST in AB (P < 0.01). [FFA]s remained unchanged in both groups with no differences between groups. [tKB]s in SCIC tended to increase at REC from PRE (P = 0.043), while remaining unchanged in AB (P > 0.42). [AcAc]s in SCIC increased at REC from PRE and POST (P < 0.01) while remaining unchanged in AB (interactions of Group × Time P = 0.014). [Glc]p and [Ins]s were comparable between the groups throughout the study. CONCLUSION: Serum ketone bodies in SCIC increased after exercise while remaining unchanged in AB, suggesting that suppressed uptakes of serum ketone bodies from blood to the muscles in SCIC would partially contribute the increased serum ketones.
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Médula Cervical , Traumatismos de la Médula Espinal , Humanos , Traumatismos de la Médula Espinal/diagnóstico , Estudios Prospectivos , Cetonas , Cuerpos Cetónicos , CatecolaminasRESUMEN
AIM: To investigate whether the early initiation of neuraxial analgesia prolongs the duration of electively induced labor in Japanese multiparous women. METHODS: This retrospective study included multiparous term women who underwent elective induction of labor using combined spinal-epidural analgesia at the Showa University Hospital between October 2018 and March 2021. The participants were divided into two groups: early and late. If neuraxial analgesia was initiated when the cervical dilation was ≤3 cm, the patient was included in the early group. The remaining patients were included in the late group. The obstetric and neonatal outcomes were compared between the two groups. The primary outcome was the duration of delivery. The secondary outcomes were the rates of instrumental and cesarean deliveries. RESULTS: Two hundred and ninety-seven women (early group = 139, late group = 158) were included in the analysis. The duration of the first stage of labor did not differ significantly between the early and late groups (median: 232 vs. 260 min, p = 0.35). Similarly, there was no significant difference in the duration of the second stage (37 vs. 40 min, p = 0.20). Moreover, the rates of instrumental and cesarean deliveries did not differ significantly between the groups, and the neonatal outcomes were comparable. CONCLUSION: Early initiation of neuraxial analgesia in the elective induction of parous Japanese women did not prolong the duration of delivery. Our results suggest that neuraxial analgesia may be initiated whenever a parturient desires it.
Asunto(s)
Analgesia Epidural , Analgesia Obstétrica , Trabajo de Parto , Embarazo , Recién Nacido , Humanos , Femenino , Estudios Retrospectivos , Analgesia Obstétrica/métodos , Cesárea , Dolor , Analgesia Epidural/métodos , Parto Obstétrico/métodosRESUMEN
BACKGROUND: Prodromal Alzheimer's disease offers an opportunity to test the effect of drugs that modify the deposition of amyloid in the brain before the onset of dementia. Verubecestat is an orally administered ß-site amyloid precursor protein-cleaving enzyme 1 (BACE-1) inhibitor that blocks production of amyloid-beta (Aß). The drug did not prevent clinical progression in a trial involving patients with mild-to-moderate dementia due to Alzheimer's disease. METHODS: We conducted a randomized, double-blind, placebo-controlled, 104-week trial to evaluate verubecestat at doses of 12 mg and 40 mg per day, as compared with placebo, in patients who had memory impairment and elevated brain amyloid levels but whose condition did not meet the case definition of dementia. The primary outcome was the change from baseline to week 104 in the score on the Clinical Dementia Rating Scale-Sum of Boxes (CDR-SB; scores range from 0 to 18, with higher scores indicating worse cognition and daily function). Secondary outcomes included other assessments of cognition and daily function. RESULTS: The trial was terminated for futility after 1454 patients had been enrolled; 485 had been assigned to receive verubecestat at a dose of 12 mg per day (the 12-mg group), 484 to receive verubecestat at a dose of 40 mg per day (the 40-mg group), and 485 to receive placebo. A total of 234 patients, 231 patients, and 239 patients per group, respectively, completed 104 weeks of the trial regimen. The estimated mean change from baseline to week 104 in the CDR-SB score was 1.65 in the 12-mg group, 2.02 in the 40-mg group, and 1.58 in the placebo group (P = 0.67 for the comparison between the 12-mg group and the placebo group and P = 0.01 for the comparison between the 40-mg group and the placebo group), suggesting a worse outcome in the higher-dose group than in the placebo group. The estimated rate of progression to dementia due to Alzheimer's disease was 24.5, 25.5, and 19.3 events per 100 patient-years in the 12-mg group, the 40-mg group, and the placebo group, respectively (hazard ratio for 40 mg vs. placebo, 1.38; 97.51% confidence interval, 1.07 to 1.79, not adjusted for multiple comparisons), favoring placebo. Adverse events were more common in the verubecestat groups than in the placebo group. CONCLUSIONS: Verubecestat did not improve clinical ratings of dementia among patients with prodromal Alzheimer's disease, and some measures suggested that cognition and daily function were worse among patients who received verubecestat than among those who received placebo. (Funded by Merck Sharp & Dohme; ClinicalTrials.gov number, NCT01953601.).
Asunto(s)
Enfermedad de Alzheimer/prevención & control , Precursor de Proteína beta-Amiloide/antagonistas & inhibidores , Disfunción Cognitiva/tratamiento farmacológico , Óxidos S-Cíclicos/uso terapéutico , Tiadiazinas/uso terapéutico , Anciano , Péptidos beta-Amiloides/análisis , Química Encefálica , Disfunción Cognitiva/patología , Óxidos S-Cíclicos/efectos adversos , Progresión de la Enfermedad , Método Doble Ciego , Inhibidores Enzimáticos/efectos adversos , Inhibidores Enzimáticos/uso terapéutico , Femenino , Hipocampo/patología , Humanos , Análisis de Intención de Tratar , Imagen por Resonancia Magnética , Masculino , Tamaño de los Órganos , Placa Amiloide/diagnóstico por imagen , Tomografía de Emisión de Positrones , Síntomas Prodrómicos , Tiadiazinas/efectos adversos , Insuficiencia del TratamientoRESUMEN
PURPOSE: We aimed to investigate whether out-patient rehabilitation with the same concept as physiatrist and registered therapist operating rehabilitation (PROr) would improve activities of daily living in out-patients with chronic cerebrovascular disorder and whether the improvements were related to the frequency and/or time of therapy. METHODS: Out-patients with chronic cerebrovascular disorder, who visited a clinic affiliated with a university hospital for at least a month between April 2010-September 2020, were retrospectively selected. Changes in the functional independence measure (FIM) from the first visit to the 12th month were calculated. Patients were stratified into two subgroups: improved and non-improved groups. The frequency and time of physical and occupational therapies and total rehabilitation were compared between the groups. RESULTS: Initially, 174 patients were selected and 125 were excluded based on the exclusion criteria. Three patients terminated rehabilitation because of improvements. In 18 of 49 patients, FIM improved at the 12th month by 4.9 [3.1-6.8] (mean [95% CI]). The frequency was â¼2 times/week with no differences between the groups. Physical therapy time/day was higher in the improved group (74.7 [66.7-82.7] min) than the non-improved group (50.7 [44.3-57.0] min; P<0. 001). The total rehabilitation time/day was 121.9 [107.8-136.0] min in the improved group, which was higher than the non-improved group: 97.9 [87.7-107.9] (P=0.001). CONCLUSIONS: Approximately 40% of the patients displayed improved FIM even during the chronic phase, and the improved out-patients took PROr for at least 108 min/day and twice a week. A longer rehabilitation time would be reinforced by patients' motivation.
Asunto(s)
Trastornos Cerebrovasculares , Rehabilitación de Accidente Cerebrovascular , Actividades Cotidianas , Trastornos Cerebrovasculares/diagnóstico , Enfermedad Crónica , Humanos , Pacientes Ambulatorios , Recuperación de la Función , Estudios RetrospectivosRESUMEN
BACKGROUND: Alzheimer's disease is characterized by the deposition of amyloid-beta (Aß) plaques in the brain. Aß is produced from the sequential cleavage of amyloid precursor protein by ß-site amyloid precursor protein-cleaving enzyme 1 (BACE-1) followed by γ-secretase. Verubecestat is an oral BACE-1 inhibitor that reduces the Aß level in the cerebrospinal fluid of patients with Alzheimer's disease. METHODS: We conducted a randomized, double-blind, placebo-controlled, 78-week trial to evaluate verubecestat at doses of 12 mg and 40 mg per day, as compared with placebo, in patients who had a clinical diagnosis of mild-to-moderate Alzheimer's disease. The coprimary outcomes were the change from baseline to week 78 in the score on the cognitive subscale of the Alzheimer's Disease Assessment Scale (ADAS-cog; scores range from 0 to 70, with higher scores indicating worse dementia) and in the score on the Alzheimer's Disease Cooperative Study Activities of Daily Living Inventory scale (ADCS-ADL; scores range from 0 to 78, with lower scores indicating worse function). RESULTS: A total of 1958 patients underwent randomization; 653 were randomly assigned to receive verubecestat at a dose of 12 mg per day (the 12-mg group), 652 to receive verubecestat at a dose of 40 mg per day (the 40-mg group), and 653 to receive matching placebo. The trial was terminated early for futility 50 months after onset, which was within 5 months before its scheduled completion, and after enrollment of the planned 1958 patients was complete. The estimated mean change from baseline to week 78 in the ADAS-cog score was 7.9 in the 12-mg group, 8.0 in the 40-mg group, and 7.7 in the placebo group (P=0.63 for the comparison between the 12-mg group and the placebo group and P=0.46 for the comparison between the 40-mg group and the placebo group). The estimated mean change from baseline to week 78 in the ADCS-ADL score was -8.4 in the 12-mg group, -8.2 in the 40-mg group, and -8.9 in the placebo group (P=0.49 for the comparison between the 12-mg group and the placebo group and P=0.32 for the comparison between the 40-mg group and the placebo group). Adverse events, including rash, falls and injuries, sleep disturbance, suicidal ideation, weight loss, and hair-color change, were more common in the verubecestat groups than in the placebo group. CONCLUSIONS: Verubecestat did not reduce cognitive or functional decline in patients with mild-to-moderate Alzheimer's disease and was associated with treatment-related adverse events. (Funded by Merck; ClinicalTrials.gov number, NCT01739348 .).
Asunto(s)
Enfermedad de Alzheimer/tratamiento farmacológico , Secretasas de la Proteína Precursora del Amiloide/antagonistas & inhibidores , Ácido Aspártico Endopeptidasas/antagonistas & inhibidores , Óxidos S-Cíclicos/uso terapéutico , Tiadiazinas/uso terapéutico , Actividades Cotidianas , Anciano , Anciano de 80 o más Años , Enfermedad de Alzheimer/psicología , Péptidos beta-Amiloides/análisis , Péptidos beta-Amiloides/líquido cefalorraquídeo , Biomarcadores/líquido cefalorraquídeo , Química Encefálica/efectos de los fármacos , Cognición/efectos de los fármacos , Óxidos S-Cíclicos/efectos adversos , Relación Dosis-Respuesta a Droga , Método Doble Ciego , Femenino , Humanos , Masculino , Persona de Mediana Edad , Pruebas Neuropsicológicas , Tiadiazinas/efectos adversos , Insuficiencia del TratamientoRESUMEN
In the phase 3 EPOCH trial (Clinicaltrials.gov; NCT01739348), treatment with the BACE inhibitor verubecestat failed to improve cognition in patients with mild-to-moderate Alzheimer's disease, but was associated with reduced hippocampal volume after 78 weeks as assessed by MRI. The aims of the present exploratory analyses were to: (i) characterize the effect of verubecestat on brain volume by evaluating the time course of volumetric MRI changes for a variety of brain regions; and (ii) understand the mechanism through which verubecestat might cause hippocampal (and other brain region) volume loss by assessing its relationship to measures of amyloid, neurodegeneration, and cognition. Participants were aged 55-85 years with probable Alzheimer's disease dementia and a Mini Mental State Examination score ≥15 and ≤26. MRIs were obtained at baseline and at Weeks 13, 26, 52 and 78 of treatment. MRIs were segmented using Freesurfer and analysed using a tensor-based morphometry method. PET amyloid data were obtained with 18F-flutemetamol (Vizamyl®) at baseline and Week 78. Standardized uptake value ratios were generated with subcortical white matter as a reference region. Neurofilament light chain in the CSF was assessed as a biomarker of neurodegeneration. Compared with placebo, verubecestat showed increased MRI brain volume loss at Week 13 with no evidence of additional loss through Week 78. The verubecestat-related volumetric MRI loss occurred predominantly in amyloid-rich brain regions. Correlations between amyloid burden at baseline and verubecestat-related volumetric MRI reductions were not significant (r = 0.05 to 0.26, P-values > 0.27). There were no significant differences between verubecestat and placebo in changes from baseline in CSF levels of neurofilament light chain at Week 78 (increases of 7.2 and 14.6 pg/ml for verubecestat versus 19.7 pg/ml for placebo, P-values ≥ 0.1). There was a moderate correlation between volumetric MRI changes and cognitive decline in all groups including placebo at Week 78 (e.g. r = -0.45 to -0.55, P < 0.001 for whole brain), but the correlations were smaller at Week 13 and significant only for the verubecestat groups (e.g. r = -0.15 and -0.11, P < 0.04 for whole brain). Our results suggest that the verubecestat-associated MRI brain volume loss is not due to generalized, progressive neurodegeneration, but may be mediated by specific effects on BACE-related amyloid processes.
Asunto(s)
Enfermedad de Alzheimer/tratamiento farmacológico , Secretasas de la Proteína Precursora del Amiloide/antagonistas & inhibidores , Ácido Aspártico Endopeptidasas/antagonistas & inhibidores , Encéfalo/diagnóstico por imagen , Óxidos S-Cíclicos/uso terapéutico , Inhibidores Enzimáticos/uso terapéutico , Tiadiazinas/uso terapéutico , Anciano , Anciano de 80 o más Años , Enfermedad de Alzheimer/diagnóstico por imagen , Enfermedad de Alzheimer/psicología , Péptidos beta-Amiloides/metabolismo , Encéfalo/efectos de los fármacos , Imagen de Difusión Tensora , Método Doble Ciego , Femenino , Hipocampo/diagnóstico por imagen , Hipocampo/efectos de los fármacos , Humanos , Imagen por Resonancia Magnética , Masculino , Pruebas de Estado Mental y Demencia , Persona de Mediana Edad , Proteínas de Neurofilamentos/líquido cefalorraquídeo , Tomografía de Emisión de Positrones , Resultado del Tratamiento , Sustancia Blanca/diagnóstico por imagen , Sustancia Blanca/metabolismoRESUMEN
BACKGROUND: The aim of this randomized, double-blind trial was to evaluate the safety and tolerability profile, including cardiac safety, of sugammadex-mediated recovery from neuromuscular block in participants undergoing surgery who met the American Society of Anesthesiologists (ASA) Physical Class 3 or 4 criteria. Specifically, this study assessed the impact of sugammadex on cardiac adverse events (AEs) and other prespecified AEs of clinical interest. METHODS: Participants meeting ASA Class 3 and 4 criteria were stratified by ASA Class and NMBA (rocuronium or vecuronium) then randomized to one of the following: 1) Moderate neuromuscular block, sugammadex 2 mg/kg; 2) Moderate neuromuscular block, neostigmine and glycopyrrolate (neostigmine/glycopyrrolate); 3) Deep neuromuscular block, sugammadex 4 mg/kg; 4) Deep neuromuscular block, sugammadex 16 mg/kg (rocuronium only). Primary endpoints included incidences of treatment-emergent (TE) sinus bradycardia, TE sinus tachycardia and other TE cardiac arrhythmias. RESULTS: Of 344 participants randomized, 331 received treatment (61% male, BMI 28.5 ± 5.3 kg/m2, age 69 ± 11 years). Incidence of TE sinus bradycardia was significantly lower in the sugammadex 2 mg/kg group vs neostigmine/glycopyrrolate. The incidence of TE sinus tachycardia was significantly lower in the sugammadex 2 and 4 mg/kg groups vs neostigmine/glycopyrrolate. No significant differences in other TE cardiac arrythmias were seen between sugammadex groups and neostigmine/glycopyrrolate. There were no cases of adjudicated anaphylaxis or hypersensitivity reactions in this study. CONCLUSIONS: Compared with neostigmine/glycopyrrolate, incidence of TE sinus bradycardia was significantly lower with sugammadex 2 mg/kg and incidence of TE sinus tachycardia was significantly lower with sugammadex 2 mg/kg and 4 mg/kg. These results support the safety of sugammadex for reversing rocuronium- or vecuronium-induced moderate and deep neuromuscular block in ASA Class 3 or 4 participants. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT03346057 .
Asunto(s)
Bradicardia/inducido químicamente , Bloqueo Neuromuscular , Sugammadex/efectos adversos , Taquicardia/inducido químicamente , Anciano , Colinérgicos/administración & dosificación , Colinérgicos/efectos adversos , Método Doble Ciego , Femenino , Glicopirrolato/administración & dosificación , Glicopirrolato/efectos adversos , Humanos , Masculino , Neostigmina/administración & dosificación , Neostigmina/efectos adversos , Fármacos Neuromusculares no Despolarizantes/administración & dosificación , Rocuronio/administración & dosificación , Rocuronio/efectos adversos , Sugammadex/administración & dosificación , Bromuro de Vecuronio/administración & dosificación , Bromuro de Vecuronio/efectos adversosRESUMEN
BACKGROUND: We compared outcomes and toxicities between concurrent retrograde super-selective intra-arterial chemoradiotherapy (IACRT) and concurrent systemic chemoradiotherapy (SCRT) for gingival carcinoma (GC). METHODS: We included 84 consecutive patients who were treated for non-metastatic GC ≥ stage III, from 2006 to 2018, in this retrospective analysis (IACRT group: n = 66; SCRT group: n = 18). RESULTS: The median follow-up time was 24 (range: 1-124) months. The median prescribed dose was 60 (6-70.2) Gy (IACRT: 60 Gy; SCRT: 69 Gy). There were significant differences between the two groups in terms of 3-year overall survival (OS; IACRT: 78.8, 95% confidence interval [CI]: 66.0-87.6; SCRT: 50.4, 95% CI: 27.6-73.0; P = 0.039), progression-free survival (PFS; IACRT: 75.6, 95% CI: 62.7-85.2; SCRT: 42.0, 95% CI: 17.7-70.9; P = 0.028) and local control rates (LC; IACRT: 77.2, 95% CI: 64.2-86.4; SCRT: 42.0, 95% CI: 17.7-70.9; P = 0.015). In univariate analysis, age ≥ 65 years, decreased performance status (PS) and SCRT were significantly associated with worse outcomes (P < 0.05). In multivariate analysis, age ≥ 65 years, clinical stage IV, and SCRT were significantly correlated with a poor OS rate (P < 0.05). Patients with poorer PS had a significantly worse PFS rate. Regarding acute toxicity, 22 IACRT patients had grade 4 lymphopenia, and osteoradionecrosis was the most common late toxicity in both groups. CONCLUSIONS: This is the first report to compare outcomes from IACRT and SCRT among patients with GC. ALL therapy related toxicities were manageable. IACRT is an effective and safe treatment for GC.
Asunto(s)
Neoplasias Gingivales/tratamiento farmacológico , Neoplasias Gingivales/radioterapia , Anciano , Anciano de 80 o más Años , Femenino , Neoplasias Gingivales/mortalidad , Humanos , Masculino , Persona de Mediana Edad , Pronóstico , Análisis de Supervivencia , Resultado del TratamientoRESUMEN
OBJECTIVES: To compare the outcomes of radical prostatectomy (RP), intensity-modulated radiation therapy (IMRT), and low-dose-rate brachytherapy (BT) using propensity score matching analysis in patients with clinically localized prostate cancer. METHODS: A group of 2273 patients with clinically localized prostate cancer between January 2004 and December 2015 at the Yokohama City University hospital were identified. The records of 1817 of these patients, who were followed up for a minimum of 2 years, were reviewed; 462 were treated with RP, 319 with IMRT, and 1036 with BT. The patients were categorized according to the National Comprehensive Cancer Network risk classification criteria, and biochemical outcomes and overall survival rates were examined. Biochemical failure for RP was defined as prostate-specific antigen (PSA) levels > 0.2 ng/ml, and for IMRT and BT as nadir PSA level + 2 ng/ml. Propensity scores were calculated using multivariable logistic regression based on covariates, including the patient's age, preoperative PSA, Gleason score, number of positive cores, and clinical T stage. RESULTS: Median follow-up was 77 months for the RP, 54 months for IMRT, and 66 months for BT patients. After the propensity scores were adjusted, a total of 372 (186 each) and 598 (299 each) patients were categorized into RP vs IMRT and RP vs BT groups, respectively. Kaplan-Meier analysis did not show any statistically significant differences in terms of overall survival rate between these groups (RP vs IMRT: p = 0.220; RP vs BT: p = 0.429). IMRT was associated with improved biochemical failure-free survival compared to RP in all risk groups (high-risk: p < 0.001; intermediate-risk: p = 0.009; low-risk: p = 0.001), whereas significant differences were observed only in the intermediate-risk group (p = 0.003) within the RP vs BT group. CONCLUSION: The results of our propensity score analysis of mid-term localized prostate cancer treatment outcomes demonstrated no significant differences in the overall survival rate. Despite the difference in biochemical failure definition between surgery and radiotherapeutic approaches, the results of this study demonstrate improved biochemical control favoring IMRT and BT as compared to RP.
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Braquiterapia , Puntaje de Propensión , Prostatectomía , Neoplasias de la Próstata/radioterapia , Neoplasias de la Próstata/cirugía , Radioterapia de Intensidad Modulada , Anciano , Humanos , Masculino , Persona de Mediana Edad , Prostatectomía/métodos , Neoplasias de la Próstata/mortalidad , Neoplasias de la Próstata/patología , Estudios Retrospectivos , Tasa de Supervivencia , Resultado del TratamientoRESUMEN
INTRODUCTION: The APECS and AMARANTH trials showed that beta-secretase (BACE) inhibitors verubecestat and lanabecestat failed to slow cognitive and functional decline in individuals with prodromal or early Alzheimer's disease. Here, the performance on secondary and exploratory cognitive measures in both studies is reported. METHODS: APECS (verubecestat) and AMARANTH (lanabecestat) were randomized, double-blind, placebo-controlled, parallel-group, 104-week clinical trials conducted by different sponsors. Measures included the 3-Domain Composite Cognition Score (CCS-3D), Repeatable Battery for the Assessment of Neuropsychological Status (RBANS), Letter/Category Fluency, and Digit Symbol Coding. RESULTS: Verubecestat showed worsening on the CCS-3D Total Score, Episodic Memory, and Attention/Processing Speed domains. Lanabecestat showed worsening on the RBANS Total Score, Immediate Memory, and Visuospatial/Constructional Indexes. Both BACE inhibitors showed worsening on Digit Symbol Coding and improvements on Letter/Category Fluency. DISCUSSION: In both studies, many measures showed treatment-associated cognitive worsening, whereas verbal fluency tasks showed improvement.
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Enfermedad de Alzheimer/tratamiento farmacológico , Cognición/efectos de los fármacos , Óxidos S-Cíclicos/uso terapéutico , Imidazoles/uso terapéutico , Compuestos de Espiro/uso terapéutico , Tiadiazinas/uso terapéutico , Resultado del Tratamiento , Anciano , Método Doble Ciego , Femenino , Humanos , MasculinoRESUMEN
STUDY DESIGN: Experimental study. OBJECTIVE: Individuals with spinal cord injuries (SCI) may present with impaired sympathetic control over thermoregulatory responses to environmental and exercise stressors, which can impact regional core temperature (Tcore) measurement. The purpose of this study was to investigate whether regional differences in Tcore responses exist during exercise in individuals with SCI. SETTING: Rehabilitation centre in Wakayama, Japan. METHODS: We recruited 12 men with motor-complete SCI (7 tetraplegia, 5 paraplegia) and 5 able-bodied controls to complete a 30-min bout of arm-cycling exercise at 50% VÌO2 peak reserve. Tcore was estimated using telemetric pills (intestinal temperature; Tint) and esophageal probes (Teso). Heat storage was calculated from baseline to 15 and 30 min of exercise. RESULTS: At 15 min of exercise, elevations in Teso (Δ0.39 ± 0.22 °C; P < 0.05), but not Tint (Δ0.04 ± 0.18 °C; P = 0.09), were observed in able-bodied men. At 30 min of exercise, men with paraplegia and able-bodied men both exhibited increases in Teso (paraplegia: Δ0.56 ± 0.30 °C, P < 0.05; able-bodied men: Δ0.60 ± 0.31 °C, P < 0.05) and Tint (paraplegia: Δ0.38 ± 0.33 °C, P < 0.05; able-bodied men: Δ0.30 ± 0.30 °C, P < 0.05). Teso began rising 7.2 min earlier than Tint (pooled, P < 0.01). Heat storage estimated by Teso was greater than heat storage estimated by Tint at 15 min (P = 0.02) and 30 min (P = 0.03) in men with paraplegia. No elevations in Teso, Tint, or heat storage were observed in men with tetraplegia. CONCLUSIONS: While not interchangeable, both Teso and Tint are sensitive to elevations in Tcore during arm-cycling exercise in men with paraplegia, although Teso may have superior sensitivity to capture temperature information earlier during exercise.
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Regulación de la Temperatura Corporal/fisiología , Temperatura Corporal/fisiología , Ejercicio Físico/fisiología , Traumatismos de la Médula Espinal/fisiopatología , Adulto , Esófago , Prueba de Esfuerzo , Humanos , Intestinos , Masculino , Extremidad SuperiorRESUMEN
OBJECTIVE: This study aims to evaluate local control and intermediate-term cosmetic outcome in patients with cancer of the nose treated with intensity-modulated radiotherapy (IMRT). METHODS: From June 2008 to September 2015, 36 consecutive patients presenting with nasal cavity, ala of the nose, or nasal vestibule tumors were treated at the Department of Radiation Oncology, University Hospital Zurich either postoperatively (n = 14; 3/14 with nasal ablation) or with definitive IMRT (n = 22). Of these 36 patients, 8 presented with recurrent disease after surgery only and 1/36 with N1 disease. Concurrent systemic therapy was administered in 18/36 patients (50%). Nasal follow-up (FU) imaging documentation of 13 patients with preserved organ and >6 months FU offers a pre/post IMRT FU comparison. In addition, these patients' subjective evaluation of cosmesis was assessed. RESULTS: Mean/median FU was 41/33 months (range 5-92 months). Salvage ablation with curative intent was undergone by 3 patients with local relapse after definitive (n = 2) and postoperative (n = 1) IMRT. The 3year local control, ultimate local control, and overall survival rates were 90, 97, and 90 %, respectively. Subjective and objective cosmetic outcome after IMRT is very satisfying so far. CONCLUSION: IMRT for nasal tumors was found to be effective and well tolerated. Intermediate-term cosmetic results are good. Radical surgical procedures may be saved for curative salvage treatment.
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Neoplasias Nasales/psicología , Neoplasias Nasales/radioterapia , Tratamientos Conservadores del Órgano/métodos , Satisfacción del Paciente , Radioterapia Conformacional/métodos , Radioterapia Conformacional/psicología , Adulto , Anciano , Anciano de 80 o más Años , Técnicas Cosméticas/psicología , Femenino , Humanos , Estudios Longitudinales , Masculino , Persona de Mediana Edad , Neoplasias Nasales/diagnóstico , Tratamientos Conservadores del Órgano/psicología , Terapia Recuperativa/métodos , Resultado del TratamientoRESUMEN
TomoDirect (TD) is an intensity-modulated radiotherapy system that uses a fixed gantry angle instead of rotational beam delivery. Here, we investigated the effect of the multiple beam technique of TomoDirect on dose distribution compared with commonly-used tangential beams. We included 45 consecutive patients with right breast cancer who underwent postoperative radiotherapy in our institute in the present study. Clinical target volume (CTV) was the whole right breast. The planning target volume (PTV) was created by expanding the CTV by a 0.5 cm margin. Paired TD plans were generated for each patient; a two-beam plan using paired tangential beams and a six-beam plan with four additional beams with modified gantry angles of ± 5° from the original tangential beam set. A prescribed dose of 50 Gy was defined for 50% isodoses of the PTV. The six-beam plan delivered significantly more homogeneous doses to the PTV than the two-beam plan; and the mean dose to the PTV in the six-beam plan more closely reflected the prescribed dose. V20Gy and mean dose to the right lung and mean dose to the whole body were also significantly decreased in the six-beam plan. However, duration of radiation exposure was 1 min longer in the six-beam plan than in the two-beam plan. The dose distribution to the target and organs at risk were improved with the six-beam plan relative to the two-beam plan without increasing the whole-body radiation dose. The six-beam plan using TD is a simple technique that can be routinely applied to whole-breast irradiation in clinical practice.
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Neoplasias de la Mama/radioterapia , Dosificación Radioterapéutica , Planificación de la Radioterapia Asistida por Computador/métodos , Radioterapia Asistida por Computador/métodos , Radioterapia de Intensidad Modulada/métodos , Adulto , Anciano , Femenino , Humanos , Persona de Mediana Edad , Dispersión de Radiación , Resultado del TratamientoRESUMEN
BACKGROUND: PDE10A inhibition represents a potential mechanism for treating schizophrenia. PDE10A inhibitors increase cyclic nucleotides in striatal neurons, thereby mimicking the effects of dopamine receptor D2 antagonists and D1 agonists. We evaluated the PDE10A inhibitor MK-8189 for treating schizophrenia. METHODS: Randomized, double-blind, placebo and active-controlled, phase 2a, multicenter, inpatient trial in adults experiencing an acute episode of schizophrenia. Participants were randomized 2:2:1 to once-daily MK-8189 12 mg, placebo, or risperidone 6 mg (active control) for 4-weeks. The primary outcome was change-from-baseline in total score on the Positive and Negative Syndrome Scale (PANSS) at 4 weeks. RESULTS: The number of treated participants was 90 for MK-8189, 89 for placebo, and 45 for risperidone. MK-8189 demonstrated a trend towards improvement versus placebo for change-from-baseline in PANSS total score after 4 weeks (difference = -4.7 [95 % CI: -9.8,0.5], P = 0.074). The active control risperidone was superior to placebo on PANNS total score (difference = -7.3 [95 % CI: -14.0,-0.6], P = 0.033), demonstrating assay sensitivity, while MK-8189 and risperidone did not significantly differ (difference = 2.6 [95 % CI: -4.0,9.2], P = 0.440). MK-8189 had a nominally significant effect on PANSS positive subscale score compared to placebo (difference = -2.2 [95 % CI: -3.8,-0.5], P = 0.011). Discontinuation of MK-8189 treatment due to an adverse event was low (<10 %). Extrapyramidal symptoms occurred with MK-8189 but were mostly mild and transient. Compared with placebo, MK-8189 reduced body weight while risperidone increased weight. CONCLUSIONS: These findings suggest that PDE10A inhibition may produce antipsychotic effects and associated weight loss and that further trials with PDE10A inhibitors are warranted. TRIAL REGISTRATION: Clinicaltrials.gov identifier: NCT03055338.
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Antipsicóticos , Hidrolasas Diéster Fosfóricas , Pirimidinas , Risperidona , Esquizofrenia , Compuestos de Azufre , Adulto , Femenino , Humanos , Masculino , Persona de Mediana Edad , Adulto Joven , Enfermedad Aguda , Antipsicóticos/farmacología , Antipsicóticos/efectos adversos , Antipsicóticos/administración & dosificación , Método Doble Ciego , Evaluación de Resultado en la Atención de Salud , Inhibidores de Fosfodiesterasa/efectos adversos , Inhibidores de Fosfodiesterasa/farmacología , Inhibidores de Fosfodiesterasa/uso terapéutico , Hidrolasas Diéster Fosfóricas/metabolismo , Prueba de Estudio Conceptual , Pirimidinas/efectos adversos , Pirimidinas/farmacología , Pirimidinas/uso terapéutico , Risperidona/farmacología , Risperidona/efectos adversos , Risperidona/administración & dosificación , Esquizofrenia/tratamiento farmacológico , Compuestos de Azufre/efectos adversos , Compuestos de Azufre/farmacología , Compuestos de Azufre/uso terapéuticoRESUMEN
PURPOSE: This study aimed to analyze treatment outcomes and prognostic markers, including immune and inflammatory factors, of postoperative radiation therapy (RT) administered to patients with cholangiocarcinoma (CCA). METHODS: We retrospectively included 59 patients with CCA who underwent surgery and postoperative RT with curative intent from 2004 to 2019. Patients received external irradiation (50 Gy in 25 fractions) using three-dimensional RT. We analyzed prognostic factors of inflammation, such as pre-RT platelet count, hemoglobin, lymphocyte count ratio (LCR) of the leukocyte count, platelet-to-lymphocyte ratio (PLR), and neutrophil-to-lymphocyte ratio (NLR). RESULTS: Tumor stages were distributed as follows: I (n = 8), II (n = 25), III (n = 15), and IVA (n = 11). The median follow-up was 24 months. Two-year overall survival (OS), cause-specific survival (CSS), progression-free survival (PFS), and locoregional control (LRC) rates were 59.5%, 62.0%, 40.1%, and 66.7%, respectively. Univariate analysis revealed that lower LCR was significantly associated with shorter PFS (p = 0.0446). There was no significant difference between the median baseline values of PLR and NLR; and age ≥75, positive regional lymph node metastases (N+), and chemotherapy after RT were significantly associated with poor OS. Multivariate analysis revealed a significant association of N+ with worse OS, PFS, and CSS and that lower LCR was significantly associated with better PFS (p = 0.0234). Among late toxicity events, two patients (3.38%) were suspected with therapy-related liver toxicity. CONCLUSIONS: Lower LCR before RT was a better prognostic factor for postoperative RT of patients with CCA.
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Neoplasias de los Conductos Biliares , Colangiocarcinoma , Humanos , Pronóstico , Estudios Retrospectivos , Linfocitos/patología , Plaquetas/patología , Colangiocarcinoma/radioterapia , Colangiocarcinoma/cirugía , Neutrófilos/patología , Neoplasias de los Conductos Biliares/radioterapia , Neoplasias de los Conductos Biliares/cirugía , Conductos Biliares IntrahepáticosRESUMEN
The aim of this study was to assess renal functions and endocrine responses to arm exercise in persons with cervical spinal cord injury (CSCI) under euhydrated conditions (free drinking of water), and to determine the physiological effects of exercise on renal function in these subjects. Eleven CSCI individuals (spinal lesions between C6 and C8, American Spinal Injury Association impairment scale A) and nine able-bodied (AB) persons rested for 30 min before performing 30 min arm-crank ergometer exercises at 50% of their maximum oxygen consumption, followed by 60-min of rest/recovery. Urine and blood samples were collected before and immediately after the exercise and recovery period. The CSCI patients showed no increase in plasma adrenaline and plasma renin activity compared with the AB controls, but showed similar changes in plasma aldosterone and the plasma antidiuretic hormone in response to the exercise. Creatinine clearance, osmolal clearance, free water clearance, and the fractional excretion of Na+ did not change during exercise in both groups of subjects, however free water clearance in the CSCI group was higher than in the AB group throughout the study. These findings suggested that activated plasma aldosterone without an increase in adrenaline or renin activity during exercise in CSCI individuals may reflect an adaptation to the disturbance of the sympathetic nervous system to compensate for renal function. As a result, no adverse effects of exercise on renal function in CSCI patients were observed.
RESUMEN
Background: The prevalence of treatment-resistant depression (TRD) among patients with pharmaceutically treated depression (PTD) varies greatly in publications. The aim of this study is to estimate the prevalence of TRD using 2 large claims databases in the US.Methods: This cross-sectional study used data from the Humana and Optum databases. Patients aged ≥ 18 years who had at least 1 diagnosis of major depressive disorder (ICD-10-CM codes: F32.xx, F33.xx) and 1 antidepressant prescription filled in 2018 were identified as having PTD. Among patients with PTD, TRD was defined as experiencing failure of treatment with at least 2 antidepressants with ≥ 4 weeks of adequate treatment. We estimated the age- and gender-standardized prevalence of TRD and then used logistic regression to investigate if TRD risk varies by age, sex, race, and geographic region. Finally, we described the timeline of TRD development in incident PTD patients.Results: We identified 296,055 and 277,941 patients with PTD in the Humana and Optum databases, among whom 17,640 (6.0%) and 16,131 (5.8%) had TRD. After age and sex standardization, TRD prevalence among PTD patients was 6.8% in Humana vs 5.8% in Optum. Females, middle-aged adults, and White patients had higher risk of TRD. The median time from index antidepressant use to TRD was about 6 months in incident PTD patients.Conclusions: The prevalence of TRD among patients with PTD was similar in the 2 databases. TRD prevalence varies by sex, race, and age, with a higher prevalence in females, White patients, and those in the age group of 45-64 years. However, the absolute differences were small.
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Trastorno Depresivo Resistente al Tratamiento/epidemiología , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Antidepresivos/uso terapéutico , Estudios Transversales , Bases de Datos Factuales , Trastorno Depresivo Resistente al Tratamiento/tratamiento farmacológico , Femenino , Humanos , Masculino , Persona de Mediana Edad , Prevalencia , Estados Unidos/epidemiología , Adulto JovenRESUMEN
BACKGROUND/AIM: This study aimed to evaluate the outcome of radiation therapy for patients with distant lymph node (LN) metastases, without organ metastases from uterine cervical cancer (UCC). PATIENTS AND METHODS: Twenty-six patients with UCC with distant LN metastases received radiotherapy and were retrospectively analyzed. The sites of distant LN metastasis were as follows; Supraclavicular in 19, inguinal in nine, axillary in four, and others in three. The mean dose prescribed for these was 50 (range=40-60) Gy. RESULTS: The 2-year overall, cause-specific, and progression-free survival, and local control of primary tumor rates were 51.3%, 51.3%, 46.9%, and 67.9%. In multivariate analysis, performance status ≥1 (p=0.007), para-aortic LN metastases (p=0.001), and lack of high-dose-rate intracavitary brachytherapy (p=0.033) were significantly associated with poor overall survival. Performance status ≥1 (p=0.004), and para-aortic LN metastases (p=0.014) were significantly associated with poor cause-specific survival. CONCLUSION: This study demonstrated favorable local control in patients with UCC with distant LN metastases.
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Neoplasias del Cuello Uterino , Femenino , Humanos , Ganglios Linfáticos/patología , Metástasis Linfática , Estadificación de Neoplasias , Estudios Retrospectivos , Neoplasias del Cuello Uterino/patología , Neoplasias del Cuello Uterino/radioterapiaRESUMEN
BACKGROUND/AIM: The aim of this study was to define the outcome of radiation therapy for vulvar carcinoma, and to investigate the effectiveness of therapeutic and prophylactic inguinal lymph node (ILN) irradiation. Because reports about the treatment of ILN were limited. PATIENTS AND METHODS: Thirty consecutive vulvar carcinoma patients were treated using external beam radiation therapy (EBRT) for definitive disease (n=25) or postoperatively (n=5). Twenty-four (80%) had squamous cell carcinoma (SCC). Tumor stages (2002 UICC) ranged from 0 to IVB, with no distant metastases. RESULTS: The median total prescribed dose for primary tumor was 64.8 Gy. The 2-year overall survival rate was 25.3%. The outcome was significantly better in patients with ILNs<30 mm (p=0.005) and patients receiving prescribed doses >60 Gy (p=0.002). CONCLUSIONS: ILN diameters ≤30 mm and prescribed doses over 60 Gy were associated with ILN control in patients with vulvar carcinoma.