Flecainide reduces ventricular arrhythmias via a mechanism that differs from that of β-blockers in catecholaminergic polymorphic ventricular tachycardia

AbstractBackgroundCatecholaminergic polymorphic ventricular tachycardia (CPVT) is an inherited arrhythmia syndrome characterized by episodic ventricular tachycardia induced by adrenergic stress. Although β-blockers are used as first-line therapy, their therapeutic effects are largely incomplete. Flecainide has recently been shown to modify the molecular defects in CPVT. The aim of this study was to investigate the effects of flecainide as an add-on to conventional therapy on exercise-induced ventricular arrhythmia and compare them with those of conventional therapy alone.MethodsThe study included 5 CPVT patients with a mutation in RYR2. They experienced episodic arrhythmic events despite conventional β-blocker therapy and were therefore given flecainide in addition. The effects of the addition of flecainide therapy on ventricular arrhythmia during exercise testing were compared with those of conventional therapy alone.ResultsBoth β-blockers alone and with additional flecainide increased the maximal workload attained at the onset of ventricular arrhythmia; however, only flecainide increased the sinus rate at the onset of ventricular arrhythmias. Furthermore, flecainide increased the exercise capacity by preventing exercise-induced arrhythmias. During a follow-up period of 17±2 months, 1 patient experienced recurrent arrhythmic episodes that were associated with noncompliance. All patients reported improvements in their ability to perform the activities of daily living.ConclusionFlecainide effectively reduced ventricular arrhythmias via a mechanism that differs from that of β-blockers in genotype-positive patients with CPVT. The specific effects of flecainide may be critical in the improvement noted in the patients' ability to perform daily activities

Effect of Major Diseases on Productivity of a Large Dairy Farm in a Temperate Zone in Japan

The objective of the present study was to investigate the associations between major diseases (clinical mastitis, peracute mastitis, metabolic disorders, peripartum disorders) and four parameters related to productivity (305-day milk yield, number of days open, culling rate, death rate) on a large dairy farm in a temperate zone with approximately 2500 Holstein cows. Data were collected from 2014 to 2018 and involved 9663 calving records for 4256 cows. We found negative effects of clinical mastitis, peracute mastitis, metabolic disorders, and peripartum disorders on the productivity of cows. Clinical-mastitis-suffered cows with multiple diseases had more days open compared with those with clinical mastitis alone and the healthy group, and they had a higher death rate than the healthy group, whereas there was no difference in death rate between the clinical mastitis only and healthy groups. Cows suffering from peracute mastitis, metabolic disorders, and peripartum disorders with either single or multiple diseases exhibited reduced productivity compared with the healthy group. Our findings clearly show that major diseases of cows in a temperate zone have severely negative effects on their productivity

Association of abnormal carbon dioxide levels with poor neurological outcomes in aneurysmal subarachnoid hemorrhage: a retrospective observational study

Abstract Background In patients with aneurysmal subarachnoid hemorrhage (SAH), an association between hypocapnia and poor clinical outcomes has been reported. However, the optimal arterial carbon dioxide tension (PaCO2) remains unknown. The present retrospective study aimed to examine the association of abnormal PaCO2 levels with neurological outcomes and investigate the optimal target PaCO2 level in patients with SAH. Methods We retrospectively selected consecutive adult patients hospitalized in the intensive care unit (ICU) for SAH between January 2009 and April 2017. Univariate and multivariate analyses were performed to identify the independent predictors of unfavorable neurological outcomes (i.e., modified Rankin scale score of 3–6 on hospital discharge). Results Among 158 patients with SAH, 73 had unfavorable neurological outcomes. During the first 2 weeks in the ICU, the median number of PaCO2 measurements per patient was 43. The factors significantly associated with unfavorable neurological outcomes were age, Hunt and Kosnik grade, maximum lactate levels during the first 24 h, and maximum (odds ratio [OR], 1.12; 95% confidence interval [CI], 1.03–1.21; p < 0.01) and minimum PaCO2 levels (OR, 0.81; 95% CI, 0.72–0.92; p < 0.01). Receiver operating characteristic curve analysis revealed that the cutoff range of PaCO2 was 30.2–48.3 mmHg. Unfavorable neurological outcomes were noted in 78.8% of patients with PaCO2 levels outside this range and in 22.8% of patients with PaCO2 levels within this range. Conclusions Both the maximum and minimum PaCO2 levels during ICU management in patients with SAH were significantly associated with unfavorable neurological outcomes. Further prospective studies are required to validate our findings and explore their clinical implications. Our findings may provide a scientific rationale for these future prospective studies

Prediction of 24-h and 6-h Periods before Calving Using a Multimodal Tail-Attached Device Equipped with a Thermistor and 3-Axis Accelerometer through Supervised Machine Learning

In this study, we developed calving prediction models for 24-h and 6-h periods before calving using data on physiological (tail skin temperature) and behavioral (activity intensity, lying time, posture change, and tail raising) parameters obtained using a multimodal tail-attached device (tail sensor). The efficiencies of the models were validated under tethering (tie-stall) and untethering (free-stall and individual pen) conditions. Data were collected from 33 and 30 pregnant cattle under tethering and untethering conditions, respectively, from approximately 15 days before the expected calving date. Based on pre-calving changes, 40 features (8 physiological and 32 behavioral) were extracted from the sensor data, and one non-sensor-based feature (days to the expected calving date) was added to develop models using a support vector machine. Cross-validation showed that calving within the next 24 h under tethering and untethering conditions was predicted with a sensitivity of 97% and 93% and precision of 80% and 76%, respectively, while calving within the next 6 h was predicted with a sensitivity of 91% and 90% and precision of 88% and 90%, respectively. Calving prediction models based on the tail sensor data with supervised machine learning have the potential to achieve effective calving prediction, irrespective of the cattle housing conditions

Tunnel Formation Inferred from the I-Form Structures of the Proton-Driven Protein Secretion Motor SecDF

Protein secretion mediated by SecYEG translocon and SecA ATPase is enhanced by membrane-embedded SecDF by using proton motive force. A previous structural study of SecDF indicated that it comprises 12 transmembrane helices that can conduct protons and three periplasmic domains, which form at least two characterized transition states, termed the F and I forms. We report the structures of full-length SecDF in I form at 2.6- to 2.8-A resolution. The structures revealed that SecDF in I form can generate a tunnel that penetrates the transmembrane region and functions as a proton pathway regulated by a conserved Asp residue of the transmembrane region. In one crystal structure, periplasmic cavity interacts with a molecule, potentially polyethylene glycol, which may mimic a substrate peptide. This study provides structural insights into the Sec protein translocation that allows future analyses to develop a more detailed working model for SecDF

Identification of Risk Factors for Coronary Artery Disease in Asymptomatic Patients with Type 2 Diabetes Mellitus

Background: Patients with diabetes mellitus (DM) are a high-risk group for coronary artery disease (CAD). In the present study, we investigated predictive factors to identify patients at high risk of CAD among asymptomatic patients with type 2 DM based on coronary computed tomographic angiography (CCTA) findings. Methods: A single-center prospective study was performed on 452 consecutive patients with type 2 DM who were provided with a weekly hospital-based diabetes education program between 3 October 2015, and 31 March 2020. A total of 161 consecutive asymptomatic patients (male/female: 111/50, age: 57.3 &plusmn; 9.3 years) with type 2 DM without any known CAD underwent CCTA. Based on conventional coronary risk factors and non-invasive examination, i.e., measurement of intima-media thickness, subcutaneous and visceral fat area, a stress electrocardiogram test, and the Agatston score, patients with obstructive CAD, CT-verified high-risk plaques (CT-HRP), and optimal revascularization within 90 days were evaluated. Results: Current smoking (OR, 4.069; 95% C.I., 1.578&ndash;10.493, p = 0.0037) and the Agatston score &ge;100 (OR, 18.034; 95% C.I., 6.337&ndash;51.324, p = 0.0001) were independent predictive factors for obstructive CAD, while current smoking (OR, 5.013; 95% C.I., 1.683&ndash;14.931, p = 0.0038) was an independent predictive factor for CT-HRP. Furthermore, insulin treatment (OR, 5.677; 95% C.I., 1.223&ndash;26.349, p = 0.0266) was the only predictive factor that correlated with optimal revascularization within 90 days. Conclusions: In asymptomatic patients with type 2 DM, current smoking, an Agatston score &ge;100, and insulin treatment were independent predictive factors of patients being at high-risk for CAD. However, non-invasive examinations except for Agatston score were not independent predictors of patients being at high risk of CAD