Low hydration status may be associated with insulin resistance and fat distribution: analysis of the Korea National Health and Nutrition Examination Survey (KNHANES) 2008-2010.

We aimed to identify the association of hydration status with insulin resistance (IR) and body fat distribution. A total of 14 344 adults participated in the Korea National Health and Nutrition Examination Survey 2008-2010. We used urine specific gravity (USG) to indicate hydration status, and HOMA-IR (homoeostasis model assessment of IR) and trunk:leg fat ratio (TLR) as primary outcomes. In multivariate logistic regression, the OR per 0·01 increase in USG for high IR was 1·303 (95 % CI 1·185, 1·433; P < 0·001). In multivariate generalised additive model plots, increased USG showed a J-shaped association with logarithmic HOMA-IR, with the lowest Akaike's information criterion score of USG 1·030. Moreover, increased USG was independently associated with increased trunk fat, decreased leg fat and increased TLR. In mediation analysis, the proportion of mediation effects of USG on TLR via IR was 0·193 (95 % CI 0·132, 0·285; P < 0·001), while the proportion of mediation effects of USG on IR via TLR was 0·130 (95 % CI 0·086, 0·188; P < 0·001). Increased USG, a sign of low hydration status and presumably high vasopressin, was associated with IR and poor fat distribution. Direct effect of low hydration status may be more dominant than indirect effect via IR or fat distribution. Further studies are necessary to confirm our findings.

Clinical, hemispheric, and autonomic changes associated with use of closed-loop, allostatic neurotechnology by a case series of individuals with self-reported symptoms of post-traumatic stress.

BACKGROUND: The objective of this pilot study was to explore the use of a closed-loop, allostatic, acoustic stimulation neurotechnology for individuals with self-reported symptoms of post-traumatic stress, as a potential means to impact symptomatology, temporal lobe high frequency asymmetry, heart rate variability (HRV), and baroreflex sensitivity (BRS). METHODS: From a cohort of individuals participating in a naturalistic study to evaluate use of allostatic neurotechnology for diverse clinical conditions, a subset was identified who reported high scores on the Posttraumatic Stress Disorder Checklist (PCL). The intervention entailed a series of sessions wherein brain electrical activity was monitored noninvasively at high spectral resolutions, with software algorithms translating selected brain frequencies into acoustic stimuli (audible tones) that were delivered back to the user in real time, to support auto-calibration of neural oscillations. Participants completed symptom inventories before and after the intervention, and a subset underwent short-term blood pressure recordings for HRV and BRS. Changes in temporal lobe high frequency asymmetry were analyzed from baseline assessment through the first four sessions, and for the last four sessions. RESULTS: Nineteen individuals (mean age 47, 11 women) were enrolled, and the majority also reported symptom scores that exceeded inventory thresholds for depression. They undertook a median of 16 sessions over 16.5 days, and 18 completed the number of sessions recommended. After the intervention, 89% of the completers reported clinically significant decreases in post-traumatic stress symptoms, indicated by a change of at least 10 points on the PCL. At a group level, individuals with either rightward (n = 7) or leftward (n = 7) dominant baseline asymmetry in temporal lobe high frequency (23-36 Hz) activity demonstrated statistically significant reductions in their asymmetry scores over the course of their first four sessions. For 12 individuals who underwent short-term blood pressure recordings, there were statistically significant increases in HRV in the time domain and BRS (Sequence Up). There were no adverse events. CONCLUSION: Closed-loop, allostatic neurotechnology for auto-calibration of neural oscillations appears promising as an innovative therapeutic strategy for individuals with symptoms of post-traumatic stress. TRIALS REGISTRATION: ClinicalTrials.gov #NCT02709369 , retrospectively registered on March 4, 2016.

Use of an allostatic neurotechnology by adolescents with postural orthostatic tachycardia syndrome (POTS) is associated with improvements in heart rate variability and changes in temporal lobe electrical activity.

Autonomic dysregulation and heterogeneous symptoms characterize postural orthostatic tachycardia syndrome (POTS). This study evaluated the effect of high-resolution, relational, resonance-based, electroencephalic mirroring (HIRREM(®)), a noninvasive, allostatic neurotechnology for relaxation and auto-calibration of neural oscillations, on heart rate variability, brain asymmetry, and autonomic symptoms, in adolescents with POTS. Seven subjects with POTS (three males, ages 15-18) underwent a median of 14 (10-16) HIRREM sessions over 13 (8-17) days. Autonomic function was assessed from 10-min continuous heart rate and blood pressure recordings, pre- and post-HIRREM. One-minute epochs of temporal high-frequency (23-36 Hz) brain electrical activity data (T3 and T4, eyes closed) were analyzed from baseline HIRREM assessment and subsequent sessions. Subjects rated autonomic symptoms before and after HIRREM. Four of seven were on fludrocortisone, which was stopped before or during their sessions. Heart rate variability in the time domain (standard deviation of the beat-to-beat interval) increased post-HIRREM (mean increase 51%, range 10-143, p = 0.03), as did baroreflex sensitivity (mean increase in high-frequency alpha 65%, range -6 to 180, p = 0.05). Baseline temporal electrical asymmetry negatively correlated with change in asymmetry from assessment to the final HIRREM session (p = 0.01). Summed high-frequency amplitudes at left and right temporal lobes decreased a median of 3.8 µV (p = 0.02). There was a trend for improvements in self-reported symptoms related to the autonomic nervous system. Use of HIRREM was associated with reduced sympathetic bias in autonomic cardiovascular regulation, greater symmetry and reduced amplitudes in temporal lobe high-frequency electrical activity, and a trend for reduced autonomic symptoms. Data suggest the potential for allostatic neurotechnology to facilitate increased flexibility in autonomic cardiovascular regulation, possibly through more balanced activity at regions of the neocortex responsible for autonomic management. Clinical trial registry "Tilt Table with Suspected postural orthostatic tachycardia syndrome (POTS) Subjects," Protocol Record: WFUBAHA01.

A Machine Learning Algorithm Facilitates Prognosis Prediction and Treatment Selection for Barcelona Clinic Liver Cancer Stage C Hepatocellular Carcinoma.

PURPOSE: Given its heterogeneity and diverse clinical outcomes, precise subclassification of Barcelona Clinic Liver Cancer stage C (BCLC-C) hepatocellular carcinoma (HCC) is required for appropriately determining patient prognosis and selecting treatment. EXPERIMENTAL DESIGN: We recruited 2,626 patients with BCLC-C HCC from multiple centers, comprising training/test (n = 1,693) and validation cohorts (n = 933). The XGBoost model was chosen for maximum performance among the machine learning (ML) models. Patients were categorized into low-, intermediate-, high-, and very high-risk subgroups based on the estimated prognosis, and this subclassification was named the CLAssification via Machine learning of BCLC-C (CLAM-C). RESULTS: The areas under the receiver operating characteristic curve of the CLAM-C for predicting the 6-, 12-, and 24-month survival of patients with BCLC-C were 0.800, 0.831, and 0.715, respectively-significantly higher than those of the conventional models, which were consistent in the validation cohort. The four subgroups had significantly different median overall survivals, and this difference was maintained among various patient subgroups and treatment modalities. Immune-checkpoint inhibitors and transarterial therapies were associated with significantly better survival than tyrosine kinase inhibitors (TKI) in the low- and intermediate-risk subgroups. In cases with first-line systemic therapy, the CLAM-C identified atezolizumab-bevacizumab as the best therapy, particularly in the high-risk group. In cases with later-line systemic therapy, nivolumab had better survival than TKIs in the low-to-intermediate-risk subgroup, whereas TKIs had better survival in the high- to very high-risk subgroup. CONCLUSIONS: ML modeling effectively subclassified patients with BCLC-C HCC, potentially aiding treatment allocation. Our study underscores the potential utilization of ML modeling in terms of prognostication and treatment allocation in patients with BCLC-C HCC.

Periodic array of polyelectrolyte-gated organic transistors from electrospun poly(3-hexylthiophene) nanofibers.

High-performance organic field-effect transistors (OFETs) based on polyelectrolyte gate dielectric and electrospun poly(3-hexylthiophene) (P3HT) nanofibers were fabricated on a flexible polymer substrate. The use of UV-crosslinked hydrogel including ionic liquids for the insulating layer enabled fast and large-area fabrication of transistor arrays. The P3HT nanofibers were directly deposited on the methacrylated polymer substrate. During UV irradiation through a patterned mask, the methacrylate groups formed covalent bonds with the patterned polyelectrolyte dielectric layer, which provides mechanical stability to the devices. The OFETs operate at voltages of less than 2 V. The average field-effect mobility and on/off ratio were approximately 2 cm(2)/(Vs) and 10(5), respectively.

Molecular expression and functional features of Kv7 channels in human prostate smooth muscle.

BACKGROUND: Relaxation of prostate smooth muscle tone is a key strategy for the medical treatment of lower urinary tract symptoms (LUTS) in men. However, potassium channel's physiological role inhuman prostatic smooth muscle (HPrSM) has yet to be determined. OBJECTIVES: In this study, we examined the molecular characteristics and physiological roles of Kv7 channels in HPrSM. MATERIALS AND METHODS: The expressions of KCNQ1-5 (Kv7 channel pore-forming α-subunits) and KCNE1-5 (ß-regulatory subunits) isoforms in HPrSM were examined using real-time PCR. The relaxation effect of ML213 was investigated by cumulatively adding ML213 to the prostate strips. Kv7 currents were recorded using an amphotericin-B perforated patch-clamp technique. RESULTS: In HPrSM cells, KCNQ4, KCNQ5, and KCNE4 isoforms were predominantly expressed, while KCNQ1, KCNQ5, and KCNE3 isoforms were the most abundantly expressed in human prostatic tissues. Western blot analysis revealed the protein expression of the Kv7.1, 7.4, and 7.5 channel subtypes in human prostate tissues (n = 3). ML213 (an activator of Kv7.2/7.4/7.5) induced the concentration-dependent relaxation of HPrSM strips (n = 15, p = 0.001), and this effect was attenuated by pretreatment with XE991 (a Kv7.1-7.5 blocker). In electrophysiology studies, ML213 significantly increased the amplitude of whole-cell Kv7 currents in HPrSM cells. ML213-induced outward currents were greater than retigabine (a Kv7.2-7.5 channel activator). The subsequent addition of XE991 completely inhibited the ML213-induced currents (n = 9, p < 0.01 vs. ML213). ML213 hyperpolarized the HPrSM cell membrane potential and was fully reversed by XE991. In situ PLA revealed the colocalization of heteromeric KV7.4/KV7.5 channels in HPrSM cells. CONCLUSIONS: Our findings suggest that Kv7.4 and 7.5 channels in prostatic smooth muscle play a critical role in the regulation of HPrSM tone and that Kv7 channel subtypes may be novel therapeutic targets for the treatment of LUTS associated with BPH.

Effects of an Allostatic Closed-Loop Neurotechnology (HIRREM) on Brain Functional Connectivity Laterality in Military-Related Traumatic Stress.

BACKGROUND AND PURPOSE: Brain asymmetries are reported in posttraumatic stress disorder, but many aspects of laterality and traumatic stress remain underexplored. This study explores lateralization changes in resting state brain network functional connectivity in a cohort with symptoms of military-related traumatic stress, associated with use of a closed-loop neurotechnology, HIRREM. METHODS: Eighteen participants (17 males, mean age 41 years [SD = 7]) received 19.5 (1.1) HIRREM sessions over 12 days. Whole brain resting magnetic resonance imaging was done pre- and post-HIRREM. Laterality of functional connectivity was assessed on a whole brain basis, and in six predefined networks or regions. Laterality of connectivity within networks or regions was assessed separately from laterality of connections between networks or regions. RESULTS: Before HIRREM, significant laterality effects of connection type (ipsilateral for either side, or contralateral in either direction) were observed for the whole brain, within networks or regions, and between networks or regions. Post-HIRREM, there were significant changes for within-network or within-region analysis in the motor network, and changes for between-network or between-region analyses for the salience network and the motor cortex. CONCLUSIONS: Among military service members and Veterans with symptoms of traumatic stress, asymmetries of network and brain region connectivity patterns were identified prior to usage of HIRREM. A variety of changes in lateralized patterns of brain connectivity were identified postintervention. These laterality findings may inform future studies of brain connectivity in traumatic stress disorders, with potential to point to mechanisms of action for successful intervention.

High-resolution, relational, resonance-based, electroencephalic mirroring (HIRREM) improves symptoms and autonomic function for insomnia: A randomized, placebo-controlled clinical trial.

INTRODUCTION: Effective insomnia interventions that also address autonomic dysregulation are lacking. We evaluate high-resolution, relational, resonance-based, electroencephalic mirroring (HIRREM® ), in a randomized, controlled clinical trial. HIRREM is a noninvasive, closed-loop, allostatic, acoustic stimulation neurotechnology, to support self-optimization of brain rhythms. METHODS: One hundred and seven adults (mean age 45.7, SD ± 5.6, 73 women), with Insomnia Severity Index (ISI) scores of ≥15, received ten, 90-min sessions of HIRREM, with tones linked to brainwaves (LB, 56), or random tones not linked to brainwaves (NL, 51), as an active, sham placebo. Outcomes were obtained at enrollment (V1), 1-7 days (V2), 8-10 weeks (V3), and 16-18 weeks (V4) after intervention. Primary outcome was differential change in ISI from V1 to V3. Secondary measures assessed depression (BDI), anxiety (BAI), quality of life (EQ-5D), and a sleep diary. Ten minute recordings of HR and BP allowed analysis of heart rate variability (HRV) and baroreflex sensitivity (BRS). RESULTS: Of 107 randomized, 101 completed the intervention. Intention-to-treat analysis (107) of change from V1 to V3 revealed a mean reduction of ISI in NL of -4.93 (SE ± 0.76) points, with additional, significant reduction of -2.05 points (0.74) in LB (total reduction of -6.98, p = .045). Additional reduction of -2.30 points (0.76) was still present in the LB at V4 (p = .058). Total ISI reduction from V1 to V4 was -5.90 points for NL and -7.93 points in LB. There were group differences (p < .05) for multiple HRV and BRS measures (rMSSD, SDNN, HF alpha, and Seq ALL), as well as total sleep time, sleep onset latency, and sleep efficiency. There were no serious adverse events. CONCLUSIONS: Results of this controlled clinical trial showed clinically relevant reduction of insomnia symptoms with HIRREM, over, and above an active, sham control, with associated, durable improvement in autonomic cardiovascular regulation.

Pilot Trial of a Noninvasive Closed-Loop Neurotechnology for Stress-Related Symptoms in Law Enforcement: Improvements in Self-Reported Symptoms and Autonomic Function.

BACKGROUND: Law enforcement officers have decreased life expectancy, attributed to work-related exposure to traumatic stress and circadian disruption. Autonomic dysregulation is reported with traumatic stress and chronic insomnia. OBJECTIVE: We explore potential benefits for reduced symptoms related to stress and insomnia and improved autonomic function associated with open label use of high-resolution, relational, resonance-based, electroencephalic mirroring (HIRREM®), in a cohort of sworn law enforcement personnel. METHODS: Closed-loop noninvasive therapies utilizing real-time monitoring offer a patient-centric approach for brain-based intervention. HIRREM® is a noninvasive, closed-loop, allostatic, neurotechnology that echoes specific brain frequencies in real time as audible tones to support self-optimization of brain rhythms. Self-report symptom inventories done before and after HIRREM included insomnia (ISI), depression (CES-D), traumatic stress (PCL-C), anxiety (GAD-7), perceived stress (PSS), and quality of life (EQ-5D). Ten-minute recordings of heart rate and blood pressure allowed analysis of baroreflex sensitivity (BRS) and heart rate variability (HRV). RESULTS: Fifteen participants (1 female), mean (SD) age 45.7 (5.6), received 12.2 (2.7) HIRREM sessions, over 7.9 in-office days. Data were collected at baseline, and at 22.8 (9.2), and 67.2 (14.1) days after intervention. All symptom inventories improved significantly (P < .01), with durability for 2 months after completion of the intervention. The use of HIRREM was also associated with significant increases (P < .001) in HRV measured as rMSSD and BRS measured by high-frequency alpha index. There were no serious adverse events or drop outs. CONCLUSION: These pilot data provide the first report of significant symptom reductions, and associated improvement in measures of autonomic cardiovascular regulation, with the use of HIRREM in a cohort of law enforcement personnel. Randomized clinical trials are warranted.

A Copernican Approach to Brain Advancement: The Paradigm of Allostatic Orchestration.

There are two main paradigms for brain-related science, with different implications for brain-focused intervention or advancement. The paradigm of homeostasis ("stability through constancy," Walter Cannon), originating from laboratory-based experimental physiology pioneered by Claude Bernard, shows that living systems tend to maintain system functionality in the direction of constancy (or similitude). The aim of physiology is to elucidate the factors that maintain homeostasis, and therapeutics aim to correct abnormal factor functions. The homeostasis paradigm does not formally recognize influences outside its controlled experimental frames and it is variable in its modeling of neural contributions. The paradigm of allostatic orchestration (PAO) extends the principle of allostasis ("stability through change") as originally put forth by Peter Sterling. The PAO originates from an evolutionary perspective and recognizes that biological set points change in anticipation of changing environments. The brain is the organ of central command, orchestrating cross-system operations to support optimal behavior at the level of the whole organism. Alternative views of blood pressure regulation and posttraumatic stress disorder (PTSD) illustrate differences between the paradigms. For the PAO, complexities of top-down neural effects and environmental context are foundational (not to be "factored out"), and anticipatory regulation is the principle of their interface. The allostatic state represents the integrated totality of brain-body interactions. Health itself is an allostatic state of optimal anticipatory oscillation, hypothesized to relate to the state of criticality, a mathematical point of poise between phases, on the border between order and disorder (or the "edge of chaos"). Diseases are allostatic states of impaired anticipatory oscillations, demonstrated as rigidifications of set points across the brain and body (disease comorbidity). Conciliation of the paradigms is possible, with "reactive homeostasis" resolved as an illusion stemming from the anticipation of environmental monotony. Considerations are presented with respect to implications of the two paradigms for brain-focused intervention or advancement; the hypothesis that the state of criticality is a vehicle for evolutionary processes; concordance with a philosophy of freedom based on ethical individualism as well as self-creativity, non-obsolescence, empowerment, and citizenship; and concluding reflections on the science and ethics of the placebo, and the potential for virtuous cycles of brain-Anthropocene interactions.

Functional Brain Network Changes Following Use of an Allostatic, Closed-Loop, Acoustic Stimulation Neurotechnology for Military-Related Traumatic Stress.

BACKGROUND AND PURPOSE: Post-traumatic stress disorder is associated with connectivity changes in the default mode, central executive, and salience networks, and other brain regions. This study evaluated changes in network connectivity associated with usage of High-resolution, relational, resonance-based electroencephalic mirroring (HIRREM® ; Brain State Technologies, Scottsdale, AZ), a closed-loop, allostatic, acoustic stimulation neurotechnology, for military-related traumatic stress. METHODS: Eighteen participants (17 males, mean age 41 years [SD = 7], 15 active duty) enrolled in an IRB approved pilot trial for symptoms of military-related traumatic stress. Participants received 19.5 (1.1) HIRREM sessions over 12 days. Symptoms, physiological and functional measures, and whole brain resting MRI were collected before and after HIRREM. Six whole brain functional networks were evaluated using summary variables and community structure of predefined networks. Pre to postintervention change was analyzed using paired-sample statistical tests. RESULTS: Postintervention, there was an overall increase in connectivity of the default mode network (P = .0094). There were decreases of community structure in both the anterior portion of the default mode (medial prefrontal cortex, P = .0097) and in the sensorimotor (P = .005) network. There were no statistically significant changes at the whole brain level, or in the central executive, salience, or other networks analyzed. Participants demonstrated significant improvements in clinical symptoms, as well as autonomic cardiovascular regulation, which have been reported previously. CONCLUSIONS: Use of closed-loop, allostatic, acoustic stimulation neurotechnology (HIRREM) was associated with connectivity changes in the default mode and sensorimotor networks, in directions that may have explained the subjects' clinical improvements.

Efficacy and safety of mirodenafil, a new oral phosphodiesterase type 5 inhibitor, for treatment of erectile dysfunction.

INTRODUCTION: Mirodenafil is a newly developed oral phosphodiesterase type 5 inhibitor, currently under investigation as a treatment for erectile dysfunction (ED). AIM: We investigated the efficacy and safety of on demand mirodenafil therapy at fixed doses (50 and 100 mg) in Korean men with a broad range of ED. METHODS: A multicenter, randomized, double-blind, placebo-controlled, parallel-group, fixed-dose study was conducted with 223 subjects who were randomized to placebo or mirodenafil at fixed doses of 50 or 100 mg for 12 weeks on an "as needed" basis. MAIN OUTCOME MEASURES: Primary efficacy measures were scores on the International Index of Erectile Function (IIEF) Question 3 (Q3) and Question 4 (Q4). Secondary efficacy measures included all domain scores of the IIEF, Sexual Encounter Profile Question 2 (SEP2), Sexual Encounter Profile Question 3 (SEP3), the Global Assessment Question (GAQ), and the Life Satisfaction Checklist (LSC). Safety assessments included laboratory tests, vital signs, physical examination, 12-lead electrocardiogram recordings, and patients' reporting of adverse events. RESULTS: Mirodenafil 50 and 100 mg groups showed a significantly greater increase in IIEF Q3 (P = 0.0001, P < 0.0001, respectively) and Q4 scores (both P < 0.0001) at the end point compared with the placebo group. And mirodenafil in both doses significantly improved the scores of all five domains of the IIEF, SEP2, and SEP3 as well as the percentages of patients responding positively to the GAQ compared with the placebo group. As for LSC scores, the two mirodenafil groups showed significantly greater improvements in items regarding life as a whole, sexual life, and partner relationship than the placebo group. Most treatment-associated adverse events were of mild intensity, resolving spontaneously. CONCLUSIONS: Mirodenafil, in doses of 50 or 100 mg, significantly improved erectile function and were well tolerated in a representative population of Korean men with broad-spectrum ED of various etiologies and severities.

Improvements in Heart Rate Variability, Baroreflex Sensitivity, and Sleep After Use of Closed-Loop Allostatic Neurotechnology by a Heterogeneous Cohort.

BACKGROUND: Heart rate variability (HRV) is an indicator of dynamic adaptability of the autonomic nervous system. Few interventions target upstream, cerebral cortex components of the heart-brain system for autonomic management. We report changes in HRV and baroreflex sensitivity (BRS), associated with use of a noninvasive, closed-loop, allostatic, computer-guided, acoustic stimulation neurotechnology. METHODS: Over 5 years, 220 subjects with heterogeneous neurological, cardiovascular, and psychophysiological conditions consecutively enrolled in a naturalistic, single-arm study exploring clinical effects associated with use of the neurotechnology. Of those, 202 completed the study protocol and 160 had recordings adequate to analyze HRV and BRS. Mean age was 44.0 (SD 19.4), with 130 women. Participants received a mean of 16.1 (5.2) sessions, over 24.2 days (23.3), with 9.5 (3.8) actual intervention days. Sessions included real-time analysis of brain electrical activity and software algorithm-guided translation of selected frequencies into patterns of acoustic stimulation (audible tones of variable pitch and timing), to facilitate auto-calibration of neural oscillations. Outcomes including 10-min supine, at-rest recordings of blood pressure and heart rate, and inventories for insomnia (ISI) and depression (CES-D or BDI-II), were obtained at baseline and 15.3 (16.7) days after the last session. RESULTS: Compared to baseline, significant increases (all p < 0.001) were observed for measures of HRV across all participants including the mean percentage change for SDNN 24.2% (SE 0.04), and RMSSD, 42.2% (0.08), and BRS [Sequence Up, 55.5% (0.09), Sequence Down, 77.6% (0.23), and Sequence All, 53.7% (0.07)]. Significant improvements were noted in SAP, MAP, and DAP, as well as natural log of HF, and total power. Self-reported ISI was reduced (ISI, -6.4 points, SD 5.6, p < 0.001). The proportion reporting clinically significant depressive symptoms reduced from 48.2% at baseline to 22.1% at follow-up. Linear regression showed that rightward asymmetry predicted lower SDNN (p = 0.02). Exploratory analysis showed a trend for improved balance of temporal lobe high-frequency amplitudes over the course of initial sessions. CONCLUSION: These findings indicate that use of a noninvasive, allostatic, closed-loop neurotechnology appears to have robust potential for public health efforts to support greater flexibility in autonomic cardiovascular regulation, through self-optimization of electrical activity at the level of the brain.

Successful use of closed-loop allostatic neurotechnology for post-traumatic stress symptoms in military personnel: self-reported and autonomic improvements.

BACKGROUND: Military-related post-traumatic stress (PTS) is associated with numerous symptom clusters and diminished autonomic cardiovascular regulation. High-resolution, relational, resonance-based, electroencephalic mirroring (HIRREM®) is a noninvasive, closed-loop, allostatic, acoustic stimulation neurotechnology that produces real-time translation of dominant brain frequencies into audible tones of variable pitch and timing to support the auto-calibration of neural oscillations. We report clinical, autonomic, and functional effects after the use of HIRREM® for symptoms of military-related PTS. METHODS: Eighteen service members or recent veterans (15 active-duty, 3 veterans, most from special operations, 1 female), with a mean age of 40.9 (SD = 6.9) years and symptoms of PTS lasting from 1 to 25 years, undertook 19.5 (SD = 1.1) sessions over 12 days. Inventories for symptoms of PTS (Posttraumatic Stress Disorder Checklist - Military version, PCL-M), insomnia (Insomnia Severity Index, ISI), depression (Center for Epidemiologic Studies Depression Scale, CES-D), and anxiety (Generalized Anxiety Disorder 7-item scale, GAD-7) were collected before (Visit 1, V1), immediately after (Visit 2, V2), and at 1 month (Visit 3, V3), 3 (Visit 4, V4), and 6 (Visit 5, V5) months after intervention completion. Other measures only taken at V1 and V2 included blood pressure and heart rate recordings to analyze heart rate variability (HRV) and baroreflex sensitivity (BRS), functional performance (reaction and grip strength) testing, blood and saliva for biomarkers of stress and inflammation, and blood for epigenetic testing. Paired t-tests, Wilcoxon signed-rank tests, and a repeated-measures ANOVA were performed. RESULTS: Clinically relevant, significant reductions in all symptom scores were observed at V2, with durability through V5. There were significant improvements in multiple measures of HRV and BRS [Standard deviation of the normal beat to normal beat interval (SDNN), root mean square of the successive differences (rMSSD), high frequency (HF), low frequency (LF), and total power, HF alpha, sequence all, and systolic, diastolic and mean arterial pressure] as well as reaction testing. Trends were seen for improved grip strength and a reduction in C-Reactive Protein (CRP), Angiotensin II to Angiotensin 1-7 ratio and Interleukin-10, with no change in DNA n-methylation. There were no dropouts or adverse events reported. CONCLUSIONS: Service members or veterans showed reductions in symptomatology of PTS, insomnia, depressive mood, and anxiety that were durable through 6 months after the use of a closed-loop allostatic neurotechnology for the auto-calibration of neural oscillations. This study is the first to report increased HRV or BRS after the use of an intervention for service members or veterans with PTS. Ongoing investigations are strongly warranted. TRIAL REGISTRATION: NCT03230890 , retrospectively registered July 25, 2017.

Spectral and thermodynamic properties of Ag(I), Au(III), Cd(II), Co(II), Fe(III), Hg(II), Mn(II), Ni(II), Pb(II), U(IV), and Zn(II) binding by methanobactin from Methylosinus trichosporium OB3b.

Methanobactin (mb) is a novel chromopeptide that appears to function as the extracellular component of a copper acquisition system in methanotrophic bacteria. To examine this potential physiological role, and to distinguish it from iron binding siderophores, the spectral (UV-visible absorption, circular dichroism, fluorescence, and X-ray photoelectron) and thermodynamic properties of metal binding by mb were examined. In the absence of Cu(II) or Cu(I), mb will bind Ag(I), Au(III), Co(II), Cd(II), Fe(III), Hg(II), Mn(II), Ni(II), Pb(II), U(VI), or Zn(II), but not Ba(II), Ca(II), La(II), Mg(II), and Sr(II). The results suggest metals such as Ag(I), Au(III), Hg(II), Pb(II) and possibly U(VI) are bound by a mechanism similar to Cu, whereas the coordination of Co(II), Cd(II), Fe(III), Mn(II), Ni(II) and Zn(II) by mb differs from Cu(II). Consistent with its role as a copper-binding compound or chalkophore, the binding constants of all the metals examined were less than those observed with Cu(II) and copper displaced other metals except Ag(I) and Au(III) bound to mb. However, the binding of different metals by mb suggests that methanotrophic activity also may play a role in either the solubilization or immobilization of many metals in situ.

Role of cysteine residues in the function of human UDP glucuronosyltransferase isoform 1A1 (UGT1A1).

Bilirubin glucuronidation, catalysed by UGT1A1 [UGT (UDP glucuronosyltransferase) isoform 1A1, EC 2.4.1.17], is critical for biliary elimination of bilirubin. UGT1A1 deficiency causes CN-1 (Crigler-Najjar syndrome type 1), which is characterized by potentially lethal unconjugated hyperbilirubinaemia. Nucleotide sequence analysis of UGT1A1 in two CN-1 patients revealed that patient A was homozygous for a nt 530 G-->A (where nt 530 G-->A means guanine to adenine transition at nucleotide 530) mutation, predicting a C177Y substitution, and patient B had a nt 466 T-->C mutation on one allele and a nt 1070 A-->G mutation on the other, predicting a C156R and a Q357R substitution respectively. All 11 cysteine residues of mature human UGT1A1 are highly conserved in other human UGT isoforms and in rat, mouse and Rhesus monkey UGT1A1, suggesting their functional importance. Expression of mutagenized UGT1A1 plasmids showed that substitution of any of the seven cysteine residues located within the endoplasmic reticulum cisternae (including those mutated in patients A and B) abolished UGT1A1 activity or markedly increased its apparent K(m) for bilirubin. Substitution of the three cysteine residues within the C-terminal cytosolic tail had minimal effect on basal UGT1A1 activity, but prevented UGT1A1 activation by UDP-GlcNAc. N-Ethylmaleimide did not inhibit UGT1A1 activity in native microsomes, but prevented UGT1A1 activation by UDP-GlcNAc and inhibited the activity in digitonin-permeabilized microsomes. Dithiothreitol did not affect UGT1A1 activity in human liver microsomes. Together, the results suggested that free thiol groups, but not disulphide bonding, of seven cysteine residues within the intracisternal region of human UGT1A1 are important for its catalytic activity, while cysteine residues in the cytosolic domain may be involved in its physiological activation by UDP-GlcNAc.

A Preliminary Study of the Effectiveness of an Allostatic, Closed-Loop, Acoustic Stimulation Neurotechnology in the Treatment of Athletes with Persisting Post-concussion Symptoms.

BACKGROUND: Effective interventions are needed for individuals with persisting post-concussion symptoms. High-resolution, relational, resonance-based, electroencephalic mirroring (HIRREM®) is an allostatic, closed-loop, acoustic stimulation neurotechnology, designed to facilitate relaxation and self-optimization of neural oscillations. METHODS: Fifteen athletes (seven females, mean age 18.1 years, SD 2.6) with persisting post-concussion symptoms received 18.7 (SD 6.0) HIRREM sessions over a mean of 29.6 (SD 23.2) days, including 11.3 (SD 4.6) in office days. Pre- and post-HIRREM measures included the Rivermead Post-Concussion Symptoms Questionnaire (RPQ, n = 12), the Insomnia Severity Index (ISI, n = 15), the Center for Epidemiologic Studies Depression Scale (CES-D, n = 10), short-term blood pressure and heart rate recordings for measures of autonomic cardiovascular regulation (n = 15), and reaction time by the drop-stick method (n = 7). All participants were asked about their physical activity level and sports participation status at their post-HIRREM data collection visit and 1 to 3 months afterward. RESULTS: At the post-HIRREM visit, subjects reported improvements in all three inventories (RPQ mean change 19.7, SD 11.4, Wilcoxon p = 0.001; ISI mean change -4.1, SD 4.1, Wilcoxon p = 0.003; CES-D mean change -12.0, SD 10.0, Wilcoxon p = 0.004), including statistically significant reductions in 14 of the 16 individual items of the RPQ. There were also statistically significant improvements in baroreflex sensitivity, heart rate variability in the time domain (SDNN), and drop-stick reaction testing (baseline mean distance of 23.8 cm, SD 5.6, decreased to 19.8 cm, SD 4.6, Wilcoxon p = 0.016). Within 3 months of the post-HIRREM data collection, all 15 had returned to full exercise and workouts, and ten had returned to full participation in their athletic activity. CONCLUSIONS: The use of HIRREM by a series of athletes with persisting post-concussion symptoms was associated with a range of improvements including, for the majority, return to full participation in their sport. The findings do not appear to be consistent with constituents of the placebo effect. A larger controlled trial is warranted.

Clematis mandshurica protected to apoptosis of rat chondrocytes.

OBJECTIVE: To investigate the effect of SKI 306X, a purified extract from the mixture of three herbs, i.e. Clematis mandshurica, Trichosanthes kirilowii and Prunella vulgaris, on apoptosis in chondrocytes. DESIGN: Rat chondrocyte cell line RCJ3.1C.18 cells were incubated with 1 microM staurosporin and SKI 306X or each of its components. Cell viability was determined by trypan blue exclusion assay. Induction of apoptosis was determined by nuclear condensation or fragmentation after Hoechst staining. Amount of apoptosis was quantified both by nuclear morphology and flow cytometry. Expression level of Bcl-2, and caspase-3 and PARP activations were assayed by Western blot. RESULTS: SKI 306X significantly prevented staurosporin-induced apoptosis. Among its three components, only Clematis mandshurica significantly decreased the amount of staurosporin-induced apoptosis. Although the level of Bcl-2 expression was decreased after staurosporin treatment, it was sustained after the combination treatment with Clematis mandshurica. Whereas staurosporin induced the degradation of 32 kDa caspase-3 precursor and the production of 85-kDa cleavage products of PARP in a time-dependent fashion, Clematis mandshurica treatment prevented those manifestations. CONCLUSIONS: Pharmacological efficacy of SKI 306X protecting osteoarthritis in part may result from the inhibition of apoptosis in chondrocytes by Clematis mandshurica.

Cell culture models and animal models of viral hepatitis. Part II: hepatitis C.

The lack of a preventive vaccine, coupled with common unresponsiveness to treatment and coinfection with HIV, has made HCV a major threat to public health. The authors review in vitro and in vivo models that are being used to study HCV and to develop new treatments and preventive measures.