Bioelectric medicine: unveiling the therapeutic potential of micro-current stimulation.

Bioelectric medicine (BEM) refers to the use of electrical signals to modulate the electrical activity of cells and tissues in the body for therapeutic purposes. In this review, we particularly focused on the microcurrent stimulation (MCS), because, this can take place at the cellular level with sub-sensory application unlike other stimuli. These extremely low-level currents mimic the body's natural electrical activity and are believed to promote various physiological processes. To date, MCS has limited use in the field of BEM with applications in several therapeutic purposes. However, recent studies provide hopeful signs that MCS is more scalable and widely applicable than what has been used so far. Therefore, this review delves into the landscape of MCS, shedding light on the multifaceted applications and untapped potential of MCS in the realm of healthcare. Particularly, we summarized the hierarchical mediation from cell to whole body responses by MCS including its physiological applications. Our final objective of this review is to contribute to the growing body of literature that unveils the captivating potential of BEM, with MCS poised at the intersection of technological innovation and the intricacies of the human body.

Grouping of unused agricultural by-product biomass for fuel conversion in South Korea through multivariate analysis.

While biomass holds significance as a resource, its abundance in South Korea is limited. Therefore, in this study analyzed the chemical characteristics of agricultural by-products produced and evaluated their fuel potentiality. To achieve this objective, multivariate analysis was utilized to create biomass clusters with diverse feature. All investigated biomass types showed heating values of at least 12.6 MJ/kg, adhering to South Korea's Bio-solid recovered fuel (SRF) standard, once the moisture content was reduced to 20 % or less. However, the biomasses only met the heating value of Level 3 of the European standard for SRF, which is at least 15 MJ/kg. Groups were formed based on a multivariate analysis using four variables: the high heating value, and carbon, nitrogen, and ash contents. The groups were centered around wood chips and hog fuel, with a cluster of lignocellulosic biomass materials surrounding them. The clusters formed around four groups. When the biomasses in each group were mixed, the combustion characteristics were compared to the ignition, maximum, and burn-out temperatures. Utilizing biomass grouping, by-products from agriculture and livestock in South Korea can be effectively employed as energy sources.

Evaluation of the adsorption performance and thermal treatment-associated regeneration of adsorbents for formaldehyde removal.

Indoor air pollution remains a major concern, with formaldehyde (HCHO) a primary contributor due to its long emission period and associated health risks, including skin allergies, coughing, and bronchitis. This study evaluated the adsorption performance and economic efficiency of various adsorbents (biochar, activated carbon, zeolites A, X, and Y) selected for HCHO removal. The impact of thermal treatment on adsorbent regeneration was also assessed. The experimental apparatus featured an adsorption column and HCHO concentration meter with an electrochemical sensor designed for adsorption analysis. Zeolite X exhibited the highest adsorption performance, followed by zeolite A, zeolite Y, activated carbon, and biochar. All adsorbents displayed increased HCHO removal rates with an extended length/diameter (L/D) ratio of the adsorption column. Zeolite A demonstrated the highest economic efficiency, followed by zeolite X, activated carbon, zeolite Y, and biochar. Higher L/D ratios improved economic efficiency and prolonged the replacement cycle (the optimal timing for adsorbent replacement to maintain high adsorption performance). Sensitivity analysis of adsorbent regeneration under varying thermal treatment conditions (150, 120, and 80°C) and durations (60, 45, and 30 min) revealed minimal changes in adsorption efficiency (±3%). The results indicated the potential of adsorbent regeneration under energy-efficient thermal treatment conditions (80°C, 30 min). In conclusion, this study underscores the importance of a comprehensive assessment, considering factors such as adsorption performance, replacement cycle, economic efficiency, and regeneration performance for the selection of optimal adsorbents for HCHO adsorption and removal.Implications: This study underscores the importance of adsorption technology for the removal of formaldehyde and similar volatile organic compounds (VOCs), highlighting the potential of alternative adsorbents, such as environmentally friendly biochar, in addition to traditional strategies, such as activated carbon and zeolites. Our findings demonstrate the feasibility of adsorbent regeneration under energy-efficient thermal treatment conditions. These results hold promise for improving indoor air quality, reducing environmental pollutants, and enhancing responses to air contaminants like fine dust and VOCs.

Micro-Current Stimulation Can Modulate the Adipogenesis Process by Regulating the Insulin Signaling Pathway in 3T3-L1 Cells and ob/ob Mice.

Obesity is a disease in which fat is abnormally or excessively accumulated in the body, and many studies have been conducted to overcome it with various techniques. In this study, we evaluated whether micro-current stimulation (MCS) can be applied to prevent obesity by regulating the adipogenesis through 3T3-L1 cells and ob/ob mice. To specify the intensity of MCS, Oil Red O staining was conducted with various intensities of MCS. Based on these, subsequent experiments used 200 and 400 µA for the intensity of MCS. The expressions of insulin signaling pathway-related proteins, including phosphorylation of IGF-1 and IR, were decreased in all MCS groups, and in turn, downstream signals such as Akt and ERK were decreased. In addition, MCS reduced the nucleus translocation of PPAR-γ and decreased the protein expression of C/EBP-α. In the ob/ob mouse model, MCS reduced body weight gain and abdominal adipose tissue volume. In particular, the concentration of triglycerides in serum was also decreased. Taken together, our findings showed that MCS inhibited lipid accumulation by regulating insulin signaling in 3T3-L1, and it was effective at reducing body weight and adipose tissue volume in ob/ob mice. These suggest that MCS may be a useful treatment approach for obesity.

Effects of CYP2C19 genetic polymorphisms on the pharmacokinetics of lacosamide in Korean patients with epilepsy.

OBJECTIVE: Many pharmacokinetic studies of lacosamide (LCM) have been reported, but no large-scale clinical study has been conducted on genetic polymorphisms that affect the metabolism of LCM. Therefore, we designed a pharmacogenetic study of LCM to explore the effect of genetic polymorphisms on serum LCM concentration. We evaluated the pharmacodynamic characteristics of LCM, including clinical efficacy and toxicity. METHODS: Adult patients with epilepsy who received LCM at Seoul National University Hospital were enrolled. Blood samples were obtained from 115 patients taking LCM for more than 1 month with unchanged doses and were used to analyze the serum LCM concentration, the concentration/dose (C/D) ratio and the single nucleotide polymorphisms (SNPs) of the cytochrome P450 (CYP)2C9 and CYP2C19 genes. In addition, clinical information-including efficacy, toxicity, and concomitant drugs-was collected. RESULTS: The serum LCM concentration showed a linear correlation with the daily dose (r = .66, p < .001). In genetic analysis, 43 patients (38.7%) were extensive metabolizers (EMs), 51 (45.9%) were intermediate metabolizers (IMs), and 17 (15.3%) were poor metabolizers (PMs). In the group comparison, mean serum concentrations and the C/D ratio showed significant differences between the three groups (p = .01 and p < .001, respectively). The C/D ratios of IM (27.78) and PM (35.6) were 13% and 39% higher than those of EM (25.58), respectively. In the pharmacodynamic subgroup analysis, patients in the ineffective LCM group had significantly lower serum concentrations (6.39 ± 3.25 vs. 8.44 ± 3.68 µg/ml, p = .024), whereas patients with adverse events had higher serum concentrations than those without adverse events (11.03 ± 4.32 vs. 7.4 ± 3.1 µg/ml, p < .001). Based on this, we suggest a reference range for LCM in the Korean population (6-9 µg/ml). SIGNIFICANCE: Genetic polymorphisms of the CYP2C19 gene affect the serum LCM concentration. Because efficacy and toxicity are apparently related to serum LCM levels, the genetic phenotype of CYP2C19 should be considered when prescribing LCM for patients with epilepsy.

Disease progression and brain atrophy in NMDAR encephalitis: Associated factor & clinical implication.

OBJECTIVE: We investigated the longitudinal pattern, determining factors, and clinical implications of brain volume changes in N-methyl d-aspartate receptor-antibody (NMDAR) encephalitis. METHODS: Baseline clinical profiles, treatment profiles, and outcome measured using the Clinical Assessment Scale in Autoimmune Encephalitis (CASE) and modified Rankin scale (mRS) were obtained from a long-term clinical database documenting an NMDAR encephalitis cohort. In serial MRI, the change in the normalized volume of different brain regions from the baseline evaluation was measured. At each MRI evaluation time point, the cumulative disease burden (CASE score × months) and the cumulative duration of status epilepticus were also evaluated. RESULTS: Thirty-six patients were followed-up for 28.5 months (range 12-63 months). The volume ratio at last MRI to baseline was the lowest in the cerebellum (94.4 ± 5.7%, p < 0.001). Once developed, cerebellar volume reduction followed a progressive course until 2 years from disease onset. The degree of cerebellar volume reduction was positively correlated with mRS and total CASE scores (all, p < 0.001), and CASE scores in the domains of memory, language, and psychiatric problems, gait instability/ataxia, and weakness (all, p < 0.01). In linear mixed model analyses, the degree of cerebellar volume reduction was associated with cumulative disease burden up to 2 years (p < 0.001) and duration of status epilepticus (p < 0.001), and delayed removal of teratoma for ≥1 month (p = 0.006). INTERPRETATION: In NMDAR encephalitis, cerebellar volume reduction was progressive once developed. Cerebellar volume reduction might reflect disease burden and extent of progression and be associated with poor outcomes in multiple functional domains.

Seronegative autoimmune encephalitis: clinical characteristics and factors associated with outcomes.

Seronegative autoimmune encephalitis is autoimmune encephalitis without any identifiable pathogenic antibody. Although it is a major subtype of autoimmune encephalitis, many unmet clinical needs exist in terms of clinical characteristics, treatments and prognosis. In this institutional cohort study, patients diagnosed with seronegative autoimmune encephalitis with available 2-year outcomes were analysed for the disease course, 2-year outcome prediction system, effect of immunotherapy, necessity of further immunotherapy at 6 or 12 months and pattern of brain atrophy. Seronegative autoimmune encephalitis was subcategorized into antibody-negative probable autoimmune encephalitis, autoimmune limbic encephalitis and acute disseminated encephalomyelitis. Poor 2-year outcome was defined by modified Rankin scale scores 3-6, and the 2-year serial data of Clinical Assessment Scales in Autoimmune Encephalitis score was used for longitudinal data analyses. A total of 147 patients were included. The frequency of achieving a good 2-year outcome (modified Rankin scale 0-2) was 56.5%. The antibody-negative probable autoimmune encephalitis subtype exhibited the poorest outcomes, although the baseline severity was similar among the subtypes. The RAPID score, consisting of five early usable clinical factors, refractory status epilepticus, age of onset ≥60 years, probable autoimmune encephalitis (antibody-negative probable autoimmune encephalitis subtype), infratentorial involvement and delay of immunotherapy ≥1 month, was associated with poorer 2-year outcomes. Any immunotherapy was associated with clinical improvement in the patients with low risk for poor 2-year outcomes (RAPID scores 0-1), and the combination immunotherapy of steroid, immunoglobulin, rituximab and tocilizumab was associated with better outcomes in the patients with high risk for poor 2-year outcomes (RAPID scores 2-5). In patients with persistent disease at 6 months, continuing immunotherapy was associated with more improvement, while the effect of continuing immunotherapy for more than 12 months was unclear. In the longitudinal analysis of MRI, the development of cerebellar atrophy indicated poor outcomes, while the absence of diffuse cerebral atrophy or medial temporal atrophy indicated the possibility of a good outcome. This study provides information about the clinical characteristics and courses, the effect of immunotherapy and its duration, and prognostic factors in seronegative autoimmune encephalitis.

Designing of reverse vending machine to improve its sorting efficiency for recyclable materials for its application in convenience stores.

Plastics have multiple applications in disposable products, high-end technology parts, etc., owing to their functionality and manufacturing flexibility. However, their increased use has increased the global proportion of plastic wastes, which creates a serious environmental issue, thereby, creating a demand for plastic waste management techniques. Improving the efficiency of resource recovery by appropriate sorting and collection systems is necessary for successful plastic recycling. Therefore, this study proposed a three-step optimization process of a reverse vending machine (RVM), a small automatic recyclable waste sorter/collector system, for acquiring an optimal design and enhanced efficiency. The RVM system categorized recyclable wastes as plastics, glass, and cans using barcode, vision, and near infrared sensors. The average sorting efficiency of the designed RVM system was 94%, 95% for polyethylene terephthalate, and 98% for glass bottles. Therefore, the RVM system, with the average sorting efficiency of 95%, is suitable for application in on-site sorting in small-sized areas, such as convenience stores, which generate wastes on a small scale.Implications: This study proposed a three-step optimization process of a reverse vending machine (RVM), a small automatic recyclable waste sorter/collector system, for acquiring an optimal design and enhanced efficiency. The RVM system is suitable for application in on-site sorting in small-sized areas, such as convenience stores, which generate wastes on a small scale.

Teratoma Removal, Steroid, IVIG, Rituximab and Tocilizumab (T-SIRT) in Anti-NMDAR Encephalitis.

In anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis, we analysed the efficacy of a combined immunotherapy protocol consisting of teratoma removal, steroid, intravenous immunoglobulin (IVIG), rituximab and tocilizumab (T-SIRT). This cohort study included seventy-eight consecutive patients treated for anti-NMDAR encephalitis between Jan 2014 and Oct 2019 in a national referral hospital. Detailed 2-year disease time course was analysed using Clinical Assessment Scale for Autoimmune Encephalitis (CASE) scores at every 2 weeks for 12 weeks from baseline, every month for the next 3 months and then every 3 months. Treatment regimens at each time point were categorized as SI, SIR, or SIRT with/without teratoma removal (T). Adverse events were classified according to the Common Terminology Criteria for Adverse-Events (CTCAE v5.0), where a severe adverse event was defined as an adverse event with CATAE grade 4. In a linear mixed model analysis, using the SIRT regimen was more effective than SIR or SI regimens in lowering CASE scores (P < 0.001 and P = 0.001, respectively). The presence of teratoma (P = 0.001), refractory status epilepticus (P < 0.001) and a higher CASE score at baseline (P < 0.001) predicted a higher CASE score at each time point. Completion of the (T)-SIRT regimen within 1 month of onset resulted in better 1-year improvements in CASE score (P < 0.001) and modified Rankin scale scores (P = 0.001), compared to those of using other regimens within 1 month or delaying teratoma removal for more than 1 month. Pneumonia was a frequent adverse event (52/78, 66.7%) in the whole study population and neutropenia was frequent during SIRT (11/52, 21.2%), but the regimen was well tolerated in most patients. We concluded that the early application of combined immunotherapy consisting of T-SIRT had better efficacy than was found for delayed or partial application of this combination in anti-NMDAR encephalitis.

Tolerability of lacosamide rapid dose titration: A randomized, multicenter, prospective, open-label study.

OBJECTIVE: Currently recommended dosing of lacosamide often necessitates long titration periods. However, the use of a regimen consisting of initial loading dose of 200 mg followed by a maintenance dose of 200 mg/day in practice suggests tolerability of more rapid titration schedules. We aimed to clarify whether the shortened titration schedule affects tolerability of lacosamide. METHODS: We evaluated the safety of two rapid titration protocols designed to reach the target dose of 400 mg/day within 1 week, and the conventional weekly titration protocol (reaching the target dose of 400 mg/day in three weeks). The ≥50% responder rate and steady-state plasma concentration of lacosamide were also analyzed. Adverse events were assessed at 1 week and 5 weeks after reaching the target dose. RESULTS: Seventy-five patients with epilepsy were enrolled and evenly distributed to three titration protocols, from which 5 patients were lost to follow-up and excluded from the safety analysis. Discontinuation of lacosamide or dose reductions due to adverse events occurred in 32 patients (46%), of whom a large majority (74%) had experienced adverse events after reaching 400 mg/day, demonstrating apparent dose-dependency. There was no difference in safety outcomes among the three titration groups. Concomitant use of sodium channel blockers significantly increased the risk of adverse events. CONCLUSION: Rapid titration protocols for lacosamide were not associated with an increased risk of adverse events compared to the conventional weekly titration protocol. Uptitration of lacosamide at shorter intervals to an effective target dosage may be feasible in appropriate clinical situations.

Usefulness of saliva for perampanel therapeutic drug monitoring.

OBJECTIVE: Therapeutic drug monitoring (TDM) of antiepileptic drugs (AEDs) helps optimize drug management for patients with epilepsy. Salivary testing is both noninvasive and easy, and has several other advantages. Due to technical advances, salivary TDM has become feasible for several drugs, including AEDs, and its value has been investigated. Until recently, saliva TDM of perampanel (PER) had not been reported. The purpose of our study was to confirm whether saliva is a biological substitute for plasma in PER TDM. METHODS: Adult patients diagnosed with epilepsy who received PER from August 2018 to March 2019 at Seoul National University Hospital were enrolled. Total and free PER were measured in simultaneously obtained plasma and saliva samples using liquid chromatography-tandem mass spectrometry (LC-MS/MS) and high-performance liquid chromatographic (HPLC). We examined the correlations between saliva and plasma PER concentrations and whether the use of concomitant medications classified as cytochrome P450 (CYP)3A4 inducers affected the correlations. RESULTS: Thirty patients were enrolled, aged 16 to 60; 10 (33%) were women. Patients received 2 to 12 mg (mean, 6 mg) of PER. The average total and free concentrations of PER were 343.02 (46.6-818.0) and 1.53 (0.51-2.92) ng/mL in plasma and 9.74 (2.21-33.0) and 2.83 (1.01-6.8) ng/mL in saliva, respectively. A linear relationship was observed between the total PER concentrations in saliva and the total and free PER concentrations in plasma (both P < .001; r = .678 and r = .619, respectively). The change in the PER concentration caused by the CYP3A4 inducer did not affect the correlation between saliva and plasma concentrations (all P < .001). SIGNIFICANCE: The PER concentration in saliva was correlated with that in plasma. This correlation was not affected by CYP3A4 inducers. Our results demonstrate for the first time that PER is measurable in saliva and suggest the potential for the clinical application of the saliva PER TDM matrix.

Efficacy of atomoxetine versus midodrine for neurogenic orthostatic hypotension.

OBJECTIVE: The efficacy and safety of 1-month atomoxetine and midodrine therapies were compared. Three-month atomoxetine and combination therapies were investigated for additional benefits. METHODS: This prospective open-label randomized trial included 50 patients with symptomatic neurogenic orthostatic hypotension (nOH). The patients received either atomoxetine 18 mg daily or midodrine 5 mg twice daily and were evaluated 1 and 3 months later. Those who still met the criteria for nOH at 1 month received both midodrine and atomoxetine for an additional 2 months, and if not, they continued their initial medication. The primary outcome was an improvement in orthostatic blood pressure (BP) drop (maximum BP change from supine to 3 min after standing) at 1 month. The secondary endpoints were symptom scores, percentage of patients with nOH at 1 and 3 months. RESULTS: Patients with midodrine or atomoxetine treatment showed comparative improvement in the orthostatic BP drop, and overall only 26.2% of the patients had nOH at 1 month, which was similar between the treatment groups. Only atomoxetine resulted in significant symptomatic improvements at 1 month. For those without nOH at 1 month, there was additional symptomatic improvement at 3 months with their initial medication. For those with nOH at 1 month, the combination treatment resulted in no additional improvement. Mild-to-moderate adverse events were reported by 11.6% of the patients. INTERPRETATION: One-month atomoxetine treatment was effective and safe in nOH patients. Atomoxetine improved orthostatic BP changes as much as midodrine and was better in terms of ameliorating nOH symptoms.

Human leukocyte antigen associations in postural tachycardia syndrome.

Associations between human leukocyte antigen (HLA) and postural orthostatic tachycardia syndrome (POTS) have not been investigated. We included patients diagnosed with POTS and showing orthostatic heart rate increases ≥ 50 during orthostatic vital sign measurement or experiencing syncope/near-syncope while standing (prominent POTS; n = 17). DQB1*06:09 was present in seven (41%) patients, a significantly higher percentage than in healthy Koreans (7%; odds ratio [OR] 8.7, 95% confidence interval [CI] 3.1-24.3, corrected P = 3.2 × 10-4) and epilepsy controls (8%; OR 7.9, 95% CI 2.7-23.5, corrected P = 3.2 × 10-4). Six (35.3%) carried the A*33:03-B*58:01-C*03:02-DRB1*13:02-DQB1*06:09 haplotype. The results signify an autoimmune etiology in prominent POTS.

A numerical study on the behavior of coastal waste particles in a wind-power sorting system for renewable fuel production.

In this study, a Computational Fluid Dynamics (CFD) to analyze the coastal waste particles in a wind-power sorting system is applied to produce renewable fuel using commercial CFD package (ANSYS-CFX code). The numerical methodology results predicted various coastal waste shredded inside the sorting machine. Furthermore, to identify the effect of working conditions on separation characteristics, a parametric study is performed. These study findings will offer appropriate a wind-power sorting conditions according to the purpose of using coastal waste. Under basic conditions, the characteristics of coastal waste particle behavior and the sorting of waste particles were analyzed, and the behavioral changes of diverse particles were identified by changing the airflow rate to improve the sorting performance. As a result, an appropriate airflow rate, Qair = 85 m3/min, at which the change in the airflow rate can simultaneously meet the conditions for both the recovery of the combustibles and the removal of the incombustibles, was selected with the selection efficiency rate was 92%, and the combustibles content was 99%. Based on the results of the analysis, the particle characteristics of sorting were identified to reduce and recycle the coastal waste.

Delayed orthostatic hypotension: Severity of clinical symptoms and response to medical treatment.

INTRODUCTION: Severity of orthostatic intolerance and the benefit of medical treatment in patients with delayed OH have not been elucidated. This study aimed to compare the symptom severity between classic and delayed OH and evaluate the efficacy of midodrine or pyridostigmine in patients with delayed OH. METHODS: This was an adjunctive study of previously reported randomized, open-label clinical trials evaluating the efficacy and safety of midodrine or pyridostigmine for classic OH. Seventeen patients with delayed OH were enrolled and also received midodrine (2.5 mg twice a day) or pyridostigmine (30 mg twice a day) alone or combined. Result of initial orthostatic vital sign and questionnaires were compared between the patients with delayed OH and previously reported 87 patients with classic OH. Delayed OH patients were followed up at 1 and 3 months post-treatment and the vital sign measurements and questionnaires were repeated during the follow-up period. RESULTS: Questionnaire scores regarding OH-related symptoms, depression and health-related quality of life (HRQOL) were comparable between the classic and delayed OH patients at baseline. OH-related symptoms and depression were significantly improved after 3 months of medical treatment. CONCLUSION: Patients with delayed OH exhibited orthostatic intolerance similar to that of classic OH. This study shows that these patients may benefit from medical treatment with either midodrine or pyridostigmine.

Efficacy of Propranolol, Bisoprolol, and Pyridostigmine for Postural Tachycardia Syndrome: a Randomized Clinical Trial.

Postural tachycardia syndrome (POTS) is a form of dysautonomia which presents with complex symptoms including orthostatic intolerance. Several medications are prescribed for POTS; however, the efficacy of sustained medical treatment has not been well-investigated. Here, we conducted a 2 × 2 factorial design, randomized, clinical trial of a 3-month medical treatment regimen in POTS patients. Patients were randomly allocated to 4 treatment groups (Group 1: propranolol; Group 2: bisoprolol; Group 3: propranolol + pyridostigmine; Group 4: bisoprolol + pyridostigmine). The orthostatic intolerance questionnaire (OIQ), Beck depression inventory-II (BDI-II), and short-form health survey (SF-36) were conducted at baseline, 1 and 3 months after treatment. Seventy-seven patients who completed the 3-month follow-up were analyzed. In total, every clinical score improved significantly after medical treatment. The OIQ score was significantly lower than that at baseline (18.5 ± 6.7) after 1 month (12.5 ± 4.5, P < 0.01), which decreased further after 3 months (7.8 ± 5.7, P < 0.01). The OIQ score improvements were consistent across every treatment group. In the subgroup analysis of 59 patients who did not receive antidepressants, the BDI-II score significantly decreased after treatment, regardless of the regimen. Physical components of the SF-36 improved after 3 months in every group, while mental components improved only in Group 3. The amount of changes in each score was similar among groups throughout the comparisons. Sustained medical treatment is beneficial to POTS patients, not only for orthostatic intolerance symptoms but also for depression and diminished quality of life, even without prescriptions for antidepressants. The efficacy of each regimen in POTS patients was comparable. TRIAL REGISTRATION: NCT02171988.

Efficacy of single or combined midodrine and pyridostigmine in orthostatic hypotension.

OBJECTIVE: To evaluate the long-term (for up to 3 months) efficacy and safety of single or combined therapy with midodrine and pyridostigmine for neurogenic orthostatic hypotension (OH). METHODS: This was a randomized, open-label clinical trial. In total, 87 patients with symptomatic neurogenic OH were enrolled and randomized to receive 1 of 3 treatments: midodrine only, pyridostigmine only, or midodrine + pyridostigmine. The patients were followed up at 1 and 3 months after treatment. The primary outcome measures were improvement in orthostatic blood pressure (BP) drop at 3 months. Secondary endpoints were improvement of the orthostatic BP drop at 1 month and amelioration of the questionnaire score evaluating OH-associated symptoms. RESULTS: Orthostatic systolic and diastolic BP drops improved significantly at 3 months after treatment in all treatment groups. Orthostatic symptoms were significantly ameliorated during the 3-month treatment, and the symptom severity was as follows: midodrine only < midodrine + pyridostigmine < pyridostigmine only group. Mild to moderate adverse events were reported by 11.5% of the patients. CONCLUSIONS: Single or combination treatment with midodrine and pyridostigmine was effective and safe in patients with OH for up to 3 months. Midodrine was better than pyridostigmine at improving OH-related symptoms. CLINICALTRIALSGOV IDENTIFIER: NCT02308124. CLASSIFICATION OF EVIDENCE: This study provides Class IV evidence that for patients with neurogenic OH, long-term treatment with midodrine alone, pyridostigmine alone, or both midodrine and pyridostigmine is safe and has similar effects in improving orthostatic BP drop up to 3 months.

Association of blood pressure variability with orthostatic intolerance symptoms.

The short-term blood pressure variability (BPV) reflects autonomic regulatory mechanisms. However, the influence of BPV in orthostatic intolerance (OI) is unknown. Herein, we assessed BPV profiles in patients with OI and determined their association with orthostatic symptoms. In this cross-sectional study, we prospectively enrolled 126 patients presenting with OI at the Seoul National University Hospital from December 2014 to August 2016. Among them, those with other neurological diseases (n = 8) and insufficient BP measurements (n = 15) were excluded. The degree of OI symptoms were measured using the self-administered orthostatic intolerance questionnaire (OIQ). All patients underwent ambulatory BP monitoring and we calculated the standard deviation and coefficient of variation as a measure of BPV. The mean age was 48.6 years and the average of the total OIQ score was 11.6. The severe OI group had higher BPV values than the mild group, although mean BP profiles did not differ significantly. Correlation analysis demonstrated that the orthostatic symptoms were positively correlated with diastolic BPV for the total and awake periods. Multiple linear regression analysis revealed that diastolic BPV (B = 0.46, p = 0.031) and current smoking (B = 4.687, p = 0.018) were independent factors for higher OI symptom scores after adjusting for covariates. The results of the current study demonstrated that a positive correlation exists between BPV and OI symptoms. Further studies are required to confirm the present findings and understand the neural mechanisms contributing to the excessive BPV in patients with OI.

Ions from Solution to the Gas Phase: A Molecular Dynamics Simulation of the Structural Evolution of Substance P during Desolvation of Charged Nanodroplets Generated by Electrospray Ionization.

Molecular dynamics (MD) simulations are used to model changes in the conformational preferences of a model peptide during the transition from a hydrated environment (charged nanodroplet generated by electrospray ionization) to the solvent-free peptide ion. The charged droplet consists of ∼2400 water molecules, 22 hydronium ions, and 10 chloride and contains a single Substance P (SP) [SP + 3H]3+ ion (SP3+; amino acid sequence RPKPQQFFGLM-NH2). Initially, droplet shrinkage involves a combination of solvent evaporation and ejection of excess charge, primarily hydronium ions. Further droplet shrinkage leads to a series of fission events, which includes the loss of some Cl- ions. SP3+ ions adapt to the smaller size droplet through small conformational changes that result in coiling of the hydrophobic C-terminus of the peptide on or near the droplet surface, intramolecular interactions involving the hydrophilic N-terminus of the peptide, and water-mediated interactions between the SP3+ ion and H3O+ and Cl- ions. Calculated collision cross sections (CCS) for SP3+ ions at various stages of desolvation are consistent with the results obtained from cryogenic ion mobility-mass spectrometry (cryo-IM-MS) measurements. Specifically, early in the decay of the charged droplet SP3+ ions favor an extended conformation, whereas a compact conformer is favored during the final stages of dehydration.

Long-Lived Intermediates in a Cooperative Two-State Folding Transition.

Biomolecular folding often occurs through a cooperative two-state reactant ↔ product transition; the term cooperative does not convey that intermediate structures are nonexistent but rather that these states are not observable by existing experimental techniques. Because of this, few intermediates have been studied and characterized. Recently, ion mobility spectrometry (IMS) measurements revealed that the oligomer polyproline-13 (Pro13, which in propanol (PrOH) favors the right-handed helical PPI structure having adjacent pyrrolidine rings in a cis configuration) folds through six sequential long-lived intermediates as it converts to the all-trans-configured PPII structure that is favored in aqueous solutions. Here, we examine the PPIPrOH → PPIIaq folding transition for a HisPro13 sequence, i.e., Pro13 having a single histidine residue added to the N-terminus. Remarkably, the IMS measurements show that, upon addition of histidine, all of the IMS peaks associated with intermediate structures disappear. Instead, HisPro13 folds via a cooperative two-state transition, delayed by a significant induction period. The induction period is temperature dependent-shifting the transition to longer times at lower temperatures. Equilibrium studies show that the HisPro13 PPIPrOH → PPIIaq transition is endothermic but favored entropically. From these clues, we propose a sequential folding mechanism and develop a model that suggests that ∼13-17 long-lived intermediates are likely responsible for the induction period. In this model, intermediates are separated by average individual activation barriers of ∼90 kJ·mol-1, and are entropically favorable.