Healthy Volunteer Subjects Research Articles

403 Methodology to evaluate the photosensitivity potential of a systemically administered investigational product in healthy volunteer subjects

403 Methodology to evaluate the photosensitivity potential of a systemically administered investigational product in healthy volunteer subjects

Higher 5-HT1A autoreceptor binding as an endophenotype for major depressive disorder identified in high risk offspring – A pilot study

Higher serotonin-1A (5-HT1A) receptor binding potential (BPF) has been found in major depressive disorder (MDD) during and between major depressive episodes. We investigated whether higher 5-HT1A binding is a biologic trait transmitted to healthy high risk (HR) offspring of MDD probands. Data were collected contemporaneously from: nine HR, 30 depressed not-recently medicated (NRM) MDD, 18 remitted NRM MDD, 51 healthy volunteer (HV) subjects. Subjects underwent positron emission tomography (PET) using [11C]WAY100635 to quantify 5-HT1A BPF, estimated using metabolite, free fraction-corrected arterial input function and cerebellar white matter as reference region. Multivoxel pattern analyses (MVPA) of PET data evaluated group status classification of individuals. When tested across 13 regions of interest, an effect of diagnosis is found on BPF which remains significant after correction for sex, age, injected mass and dose: HR have higher BPF than HV (84.3% higher in midbrain raphe, 40.8% higher in hippocampus, mean BPF across all 13 brain regions is 49.9% ± 11.8% higher). Voxel-level BPF maps distinguish HR vs. HV. Elevated 5-HT1A BPF appears to be a familially transmitted trait abnormality. Future studies are needed to replicate this finding in a larger cohort and demonstrate the link to the familial transmission of mood disorders.

Low-dose IL-2 expands CD4+ regulatory T cells with a suppressive function in vitro via the STAT5-dependent pathway in patients with chronic kidney diseases

Background: Patients with chronic kidney disease (CKD) often have CD4+ regulatory T cells (Tregs) dysfunction and chronic inflammation. We aim to investigate the effect, function, and related mechanism of low-dose IL-2 on CD4+ regulatory T cells expansion in vitro from patients with CKD. Methods: A total of 148 newly diagnosed patients with CKD at Stage III and 35 healthy volunteer subjects were recruited into our studies. The number of peripheral Tregs in peripheral blood mononuclear cells isolated from CKD patients, which were characterized by FACS as CD4+CD25hi and CD4+CD25+FoxP3+. The effect of low-dose IL-2 on expansion of Tregs, and the suppressive function of expanded Tregs were also analyzed by FACS. The levels of FoxP3 mRNA were detected by qRT-PCR. The activation of IL-2 induced Stat5 and blocking experiments were assessed by Western Blotting and FACS. Results: We found that the frequency of peripheral Tregs from CKD patients was significantly lower than that in healthy volunteer subjects. We also showed that IL-2 selectively expanded CD4+CD25hi and CD4+CD25+FoxP3+ regulatory T cells, and also upregulated the expression of FoxP3 mRNA. Our in vitro studies demonstrated that expanded CD4+ regulatory T cells from CKD patients suppressed proinflammatory Th1 and Th17 cell response. Furthermore, STAT5 activation is required for IL-2-induced expansion of regulatory T cells and expression of FoxP3 mRNA from CKD patients. Conclusions: Our findings support the clinical Treg defects in CKD patients with glomerular diseases, and the rationale of evaluating low-dose IL-2 treatment for selectively modulating CD4+ Tregs.

Comparison of Measures of Compensatory Reserve and Tissue Oxygen in Differentiating Tolerance to Simulated Hemorrhage

BackgroundWe previously reported that average measurements of compensatory reserve (CRM) and muscle oxygen saturation (SmO2) obtained from a large cohort of humans provided earlier indication of reduced central blood volume than standard vital signs (e.g., blood pressure, heart rate, arterial oxygen saturation). Additionally, CRM was more sensitive and specific in earlier prediction of decompensation than SmO2 overall.ObjectiveIn the present study, we hypothesized that CRM derives its superior predictive qualities from its ability to differentiate between individuals with high (HT) and low (LT) tolerance to central hypovolemia compared with measures of SmO2.MethodsContinuous noninvasive measures of CRM (calculated from feature changes in the photoplethysmographic arterial waveforms) were collected from 55 healthy volunteer subjects before and during stepwise lower body negative pressure (LBNP) to the point of presyncope. Near infrared spectroscopy was used on the forearm to obtain measures of deep SmO2, hydrogen ion concentration ([H+]), and hemoglobin volume (HbT; decreases reflect vasoconstriction). Using a progressively increasing stepwise protocol, tolerance group was defined by those subjects who did (HT) or did not (LT) complete 60 mmHg LBNP. Data were analyzed using generalized estimating equations (GEE) to account for the repeated measures design.ResultsOf 55 participants, there were 35 (64%) HT and 20 (36%) LT, 26 (47%) males and 29 females (53%), with a mean age of 28 years (SD=7), height of 172 cm (SD=10) and weight of 72 kg (SD=15). CRM decreased by 97% in a linear fashion across progressive LBNP levels from baseline to −90 mm Hg, while SmO2 decreased by only 39% from baseline to −90 mm Hg. The slope for CRM values across progressive LBNP levels differed significantly between LT and HT individuals (slope difference −0.14; p=0.03). The slope for SmO2 values did not differ between LT and HT individuals across LBNP levels (slope difference=0.06; p=0.18).ConclusionConsistent with our hypothesis, CRM exhibited greater reduction across progressive LBNP levels than SmO2. These data support the notions that: 1) CRM can enable more accurate triage of casualties than SmO2 due to superior ability to differentiate those individuals at highest risk for shock; and 2) continuous monitoring of CRM can allow for earlier detection of continued casualty deterioration.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Electroencephalographic modulations during an open- or closed-eyes motor task.

There is fundamental knowledge that during the resting state cerebral activity recorded by electroencephalography (EEG) is strongly modulated by the eyes-closed condition compared to the eyes-open condition, especially in the occipital lobe. However, little research has demonstrated the influence of the eyes-closed condition on the motor cortex, particularly during a self-paced movement. This prompted the question: How does the motor cortex activity change between the eyes-closed and eyes-open conditions? To answer this question, we recorded EEG signals from 15 voluntary healthy subjects who performed a simple motor task (i.e., a voluntary isometric flexion of the right-hand index) under two conditions: eyes-closed and eyes-open. Our results confirmed strong modulation in the mu rhythm (7–13 Hz) with a large event-related desynchronisation. However, no significant differences have been observed in the beta band (15–30 Hz). Furthermore, evidence suggests that the eyes-closed condition influences the behaviour of subjects. This study gives us greater insight into the motor cortex and could also be useful in the brain-computer interface (BCI) domain.

Standardization of impulse oscillometry and the generation of pilot equations to generate reference values in the Central Military Hospital

Introduction: Impulse oscillometry is a test that evaluates the respiratory mechanics by the application of small pulses of pressure, which produce fl ow oscillations to a certain frequency. Its main application is in the study of the illnesses of the small airline. The integrated software of the test equipment generates predictive values for each of the oscillometric parameters, based on German population data. Objective: To standardize the impulse oscillometry test in order to design pilot equations for reference values in our population. Material and methods: We performed a pilot, experimental, analytical, longitudinal study with healthy volunteer subjects. Spirometry and impulse oscillometry tests were performed, both basal impedances, resistances, and reactances of the respiratory system to and after bronchodilator application; we measured and registered the 5, 10, 15, and 20 Hz. The results were analyzed by sex, age, height, and weight. The analysis was performed using a model of multiple linear retrogression. Results: A total of 127 healthy participants were recruited, 51.5% men (68) and 48.5% (64) women, with an average age of 39.65 ± 15.26 years; their height was an average of 1.63 ± 0.09 m. It was proved that the gender infl uences the oscillometry values of tidal volume (VT), the impedance, the resistances and reactance area (p < 0.05), but not the reactances (XRs) (p > 0.05); this parameter is mainly associated with the size (r = 0.727, r2 = 0.528). The age influences the oscillometry values since the resistances (Rrs) are lower in the youngest groups; the BMI and the weight had no influence on the values of IOS. Conclusions: This study provides pilot reference equations for the common indexes of impulse oscillometry in Mexican subjects, in order to integrate this test of pulmonary function to facilitate the detection of functional alterations in the small airline. We suggest more studies should be done on Mexican population, and especially on people of advanced age, to confi rm our results and to provide a more solid base for the equations of reference to IOS, with clinical and epidemiologic purposes.

Immunological Modulation in Long-Term Karate Practitioners.

Karate is a Japanese martial arts system with potential physical and psychological benefits. However, karate has been scarcely investigated from a psychobiological perspective, and its effects on the immune system remain virtually unknown. We designed the present study with the aim of analyzing the effects of karate practice on immunological parameters. 27 healthy male volunteer subjects participated in the study, 15 in the experimental group and 12 in the control. Experimental subjects were all karate players who had practiced this martial art for a minimum of three years attending regular lessons at a karate training center, in the evening, two to three days per week. Blood samples for the quantification of immunological parameters (total leukocytes, neutrophils, monocytes, eosinophils, basophils, lymphocytes, IgG, IgA, and IgM) were taken in both groups. A t-test for independent groups was performed in each dependent variable; a value of p<0.05 was considered to be significant. Karate practitioners exhibited a significantly higher number of total leukocytes (p<0.02), monocytes (p<0.01), and lymphocytes (p<0.01), a higher percentage of monocytes (p<0.01), and greater serum concentrations of IgG (p<0.02) and IgM (p<0.01). Our findings show that long-term karate practice is related to a broad modulation of immune parameters, including total and specific leukocyte counts, as well as immunoglobulin concentrations. This peculiar immunomodulatory profile, apart from its psychobiological relevance, may have noteworthy clinical implications.

Small-Particle Hyaluronic Acid Gel Treatment of Photoaged Hands.

Aging hands tend to lose subcutaneous volume resulting in prominence of the underlying vessels, tendons, and bone contributing to an aged appearance. Dermal fillers have been successfully used to improve the appearance of the aging dorsal hand. The objective is to evaluate the safety and efficacy of a small-particle hyaluronic acid (SPHA) injectable gel for the treatment of photoaged volume loss of the hands. This is an open-label, prospective, randomized, interventional, study. Twenty-five healthy female volunteer subjects aged 40 to 70 years with photoaged thinning of the hands received an injection of an SPHA gel to the dorsal aspect of 1 hand. Subjects were followed up for 6 months. The hands were evaluated at regular intervals according to a 5-point validated hand grading scale. The average hand grading scores demonstrated statistically significant improvement at all time points compared with baseline. Eighty-eight percent to 100% of subjects achieved improvement at 1 month after treatment, and 50% to 83% maintained at least 1 point improvement at 6 months. There were no adverse events reported. The investigated SPHA is a safe and effective method for improving the thinned and photoaged appearance of the hands.

Surface electromyography low-frequency content: Assessment in isometric conditions after electrocardiogram cancellation by the Segmented-Beat Modulation Method

Abstract Background Surface electromyography (SEMG) is widely used in clinics for assessing muscle functionality. All procedures proposed for noise reduction alter SEMG spectrum, especially in the low-frequency band (below 30 Hz). Indeed, low-frequency band is generally addressed to motion artifacts and electrocardiogram (ECG) interference without any further investigation on the possibility of SEMG having significant spectral content. The aim of the present study was evaluating SEMG frequency content to understand if low-frequency spectral content is negligible or, on the contrary, represents a significant SEMG portion potentially providing relevant clinical information. Method Isometric recordings of five muscles (sternocleidomastoideus, erectores spinae at L4, rectus abdominis, rectus femoris and tibialis anterior) were acquired in 10 young healthy voluntary subjects. These recordings were not affected by motion artifacts by construction and were pre-processed by the Segmented-Beat Modulation Method for ECG deletion before performing spectral analysis. Results Results indicated that SEMG frequency content is muscle and subject dependent. Overall, the 50th[25th;75th] percentiles spectrum median frequency and spectral power below 30 Hz were 74[54; 87] Hz and 18[10; 31] % of total (0–450 Hz) spectral power. Conclusions Low-frequency spectral content represents a significant SEMG portion and should not be neglected.

Endocrine Modulation in Long-Term Karate Practitioners.

Purpose Karate is a martial arts discipline which is widely practiced in the Western world as a form of self-defense, as well as a discipline to achieve physical and mental balance. However, little is known with respect to its specific psychobiological effects, particularly in relation to the influence that it may exert on the endocrine system. Thus, in the present study, we examined the effects of karate on several hormonal parameters of the Hypothalamic-Pituitary-Adrenal and Hypothalamic-Pituitary-Thyroid axes in long-time practitioners. Methods Twenty-two healthy volunteer subjects (12 experimental and 10 controls) participated in the study. Experimental subjects were karate players with a minimum of 3 years of practice in this discipline. Blood samples for the quantification of hormonal parameters were taken in both groups. The Mann-Whitney U test was performed for each variable in order to analyze the differences between groups. Results Statistically significant differences were found in cortisol and thyroid hormones, with the karate group showing lower levels of these hormones as compared to control. Conclusions These findings, therefore, reveal that long-term karate practice is associated with a significant endocrine modulation, which suggests interesting psychobiological and clinical implications. Further research is needed to verify these preliminary results, as well as properly assessing its possible use as a psychosomatic intervention tool.

Effect of Baroreceptor Sensitivity on Outcomes in Patients with Acute Spontaneous Intracerebral Hemorrhage.

Reduced baroreflex sensitivity (BRS) has been reported in patients with acute cardiovascular events. We tested the hypothesis that BRS is substantially reduced in patients with spontaneous intracerebral hemorrhage (ICH) and that BRS can predict treatment outcomes. We examined BRS and other cardiovascular autonomic parameters in 35 patients with ICH over the course of 30 days. Cardiovascular autonomic parameters also were evaluated in 30 healthy volunteer subjects during the study period. Outcome was assessed at 30 days with the modified Rankin Scale (mRS). Good outcome was defined as an mRS <1, whereas patients defined as having a poor outcome had either an mRS ≥2 or died shortly after the stroke event. Twenty patients had a poor outcome, and 15 patients had a good outcome. BRS values in the patients with poor outcome group were lower in comparison with the healthy subjects, and BRS values in patients with poor outcomes were significantly lower than that those in patients with good outcomes on day 1, day 4, and day 10. BRS was associated independently with outcome and the cut-off value of BRS on day 1 in the poor outcome group was 6.79. Based on our results, BRS value at admission is a more powerful predictor of outcome than the Glasgow Coma Scale score at admission. An assay of BRS could be added as a biomarker for outcome prediction among patients with spontaneous ICH in clinical practice.

Feasibility of a Powered Knee Joint in Providing Stance and Swing Phase Knee Flexion when Using a Knee-Ankle-Foot Orthosis

ABSTRACT Background The aim of this study was to develop a new stance control knee-ankle-foot orthosis (SCKAFO) and determine its efficacy on specific spatiotemporal and kinematic parameters. Method Seven healthy volunteer subjects participated in this study. After orthotic gait training, subjects participated in a four-part data collection session that consisted of gait evaluation with normal walking, SCKAFO with locked knee joint, SCKAFO without initial flexion (IF) mode, and SCKAFO with IF mode. Results Walking with any of the control knee-ankle-foot orthoses (KAFOs) produced a significant reduction in walking speed compared with normal walking. There was no significant difference in walking speed between the SCKAFO with and without IF. There was significantly higher knee flexion in stance phase when walking with the SCKAFO with IF compared with the other types of KAFO, but there was no significant difference between normal walking and SCKAFO with IF. In wearing SCKAFO with IF, the mean of the hip flexion was not significantly altered compared with normal walking. Hip abduction was also significantly reduced during walking with stance control (SC) mode compared to KAFO with locked knee joint. Conclusion Knee-ankle-foot orthosis with new powered knee joint has benefits over existing assistive KAFOs with locked and SC knee joints.

Comparing the effectiveness and wash-off resistance of skin barrier creams: a healthy volunteer study.

Preventing moisture damage and breakdown of the skin can be a particular challenge for patients with incontinence. The level of protection offered by various skin protectant products can vary according to the chemical nature of the formulation and can decrease following wash procedures. The aim of this study was to compare five silicone-containing skin barrier creams indicated for use on incontinence-associated dermatitis (IAD) in terms of their resistance to a standardised wash cycle in healthy volunteer subjects. A skin surface hygrometer (Skicon 200EX) evaluated skin surface conduction non-invasively on 36 non-patient subjects using a high-frequency (3.5MHz) electric current. This provided an index of the degree of protection given by barrier products after a single application and also any reduction in barrier properties after a repeated wash procedure. Medi Derma-S barrier cream (MDS), Cavilon barrier cream (CBC) and LBF barrier cream (LBF) all demonstrated statistically significant differences (p<0.001) in the Skicon values following the first moisture challenge compared with Medihoney (MH), Remedy barrier cream (RBC) and the untreated control. All other comparisons were not significant (p>0.05). Statistical analysis following four moisture challenges reflected the results following the first, whereby Skicon values following treatment with MDS, CBC and LBF was significantly different compared with MH, RBC and the untreated control. Again, all other comparisons were not significant (p>0.05). When expressed as percentage barrier effectiveness, the results show a similar pattern to the absolute Skicon values. The results of this study show that there were differences between the barrier creams in terms of the initial moisture challenge and the resistance to wash-off following a repeated standardised wash procedure. It was concluded that MDS, CBC and LBF barrier cream all showed significant and equally effective moisture barrier protection and wash-off resistance.

Development and Validation of a Portable and Inexpensive Tool to Measure the Drop Vertical Jump Using the Microsoft Kinect V2.

Background:Noncontact anterior cruciate ligament (ACL) injury in adolescent female athletes is an increasing problem. The knee-ankle separation ratio (KASR), calculated at initial contact (IC) and peak flexion (PF) during the drop vertical jump (DVJ), is a measure of dynamic knee valgus. The Microsoft Kinect V2 has shown promise as a reliable and valid marker-less motion capture device.Hypothesis:The Kinect V2 will demonstrate good to excellent correlation between KASR results at IC and PF during the DVJ, as compared with a “gold standard” Vicon motion analysis system.Study Design:Descriptive laboratory study.Level of Evidence:Level 2.Methods:Thirty-eight healthy volunteer subjects (20 male, 18 female) performed 5 DVJ trials, simultaneously measured by a Vicon MX-T40S system, 2 AMTI force platforms, and a Kinect V2 with customized software. A total of 190 jumps were completed. The KASR was calculated at IC and PF during the DVJ. The intraclass correlation coefficient (ICC) assessed the degree of KASR agreement between the Kinect and Vicon systems.Results:The ICCs of the Kinect V2 and Vicon KASR at IC and PF were 0.84 and 0.95, respectively, showing excellent agreement between the 2 measures. The Kinect V2 successfully identified the KASR at PF and IC frames in 182 of 190 trials, demonstrating 95.8% reliability.Conclusion:The Kinect V2 demonstrated excellent ICC of the KASR at IC and PF during the DVJ when compared with the Vicon system. A customized Kinect V2 software program demonstrated good reliability in identifying the KASR at IC and PF during the DVJ.Clinical Relevance:Reliable, valid, inexpensive, and efficient screening tools may improve the accessibility of motion analysis assessment of adolescent female athletes.

Medication overuse reinstates conditioned pain modulation in women with migraine.

Background This study investigated the effects of medication overuse and withdrawal on modulation of pain processing in women with migraine. Temporal summation of laser-evoked thermal pain was used to measure the effects of conditioned pain modulation. Methods 36 female participants (12 healthy volunteers, 12 with episodic migraine and 12 with medication overuse headache) were included in a two session protocol. Medication overuse headache subjects were also tested three weeks after medication overuse headache withdrawal. Mechanical and laser-evoked thermal pain thresholds were measured on the back of the non-dominant hand where, later, temporal summation of laser-evoked thermal pain to repetitive thermal stimuli was elicited for 30 min, at an intensity producing moderate pain. Between the 10th and 20th minutes, the contralateral foot was immersed into a water bath at a not painful (30℃) or painfully cold (8℃; conditioned pain modulation) temperature. Results Episodic migraine, medication overuse headache and medication overuse headache withdrawal were associated with an increase in extracephalic temporal summation of laser-evoked thermal pain as compared to healthy volunteer subjects, while there was no alteration of laser-evoked thermal and mechanical extracephalic pain thresholds in these subjects. Conditioned pain modulation was highly efficient in temporal summation of laser-evoked thermal pain in healthy volunteer subjects, with a solid post-effect (reduction of pain). Conditioned pain modulation was still present, but reduced, in episodic migraine. By contrast, conditioned pain modulation was normal in medication overuse headache and strongly reduced in medication overuse headache withdrawal. Furthermore, in medication overuse headache withdrawal, the post-effect was no longer a decrease, but a facilitation of pain. Conclusions These data show that a decrease in conditioned pain modulation does not underlie medication overuse headache in women. On the contrary, medication overuse reinstated conditioned pain modulation in female migraine patients. They also identify different phenotypes of pain modulation in migraine patients. Registration number N° 2008-A00471-54.

Interleukin 1 Receptor-Like 1 Protein (ST2) is a Potential Biomarker for Cardiomyopathy in Duchenne Muscular Dystrophy.

Duchenne muscular dystrophy (DMD) is a rare, fatal X-linked disorder characterized by the lack of dystrophin, a key sarcolemma muscle protein.Cardiac failure is a significant cause of death in DMD subjects. The purpose of our research was to identify potential cardiac serum biomarkers associated with DMD cardiomyopathy. This is an observational, case-controlled study using subjects from the CINRG DMD natural history study with cardiomyopathy (ejection fraction (EF) <55%; shortening fraction (SF) <28%), subjects without cardiomyopathy (EF≥55%; SF≥28%) compared to normal healthy volunteer subjects. The DMD with cardiomyopathy group had significantly lower average EF and SF (EF=45±10/SF=25±2%) than the DMD without cardiomyopathy group (EF=58±5% and SF=32±3%; p<0.01). Among a selected set of potential biomarkers for cardiomyopathy (MMP9, BNP, GAL3, CRP, LEP, TNC, TLR4 and ST2) we validated ST2 as significantly elevated in the serum of DMD cardiomyopathy group (35,798±4884pg/mL) compared to normal controls (9940±2680pg/mL; p<0.01; n=6). Matrix metallopeptidase 9 (MMP9) levels were found significantly increased in both DMD groups compared to controls (p<0.01). No significant differences were seen in BNP, GAL3, CRP, LEP, TNC or TLR4 levels. Increased ST2 levels were found in serum of DMD subjects compared to healthy volunteers and further elevated in DMD subjects with cardiomyopathy. Future studies correlating cardiomyopathy with ST2 levels may allow for improved non-invasive monitoring of cardiac disease in DMD subjects.

Use of Electrical Impedance Spectroscopy in vivo to Distinguish Active and Rest Stages of Salivary Glands

Xerostomia, or dry mouth syndrome, is one of the radiation therapy (RT)-induced side effects experienced by head and neck cancer patients. Measuring the severity of xerostomia can be performed by several techniques such as measuring the differential weight of dental rolls placed in the mouth for a fixed time period, measuring the electromyographic activity of musculus digastricus, using parotid cup, and electrophysiological measurements by electrical impedance. The present study focuses on detecting the change in bioimpedance around the oral cavity when salivation is induced using lime juice on healthy human subjects. In this study, impedance changes between stimulated and resting states of the salivary glands for 31 healthy volunteers were measured and analyzed. Pre- and post-stimulation impedance measurement was performed on healthy volunteer subjects using impedance spectroscopy over 50 frequencies ranging from 10 kHz to 1 MHz. The electrical properties of salivary glands were extracted by fitting the measured admittance data to the well-known Cole model. Comparison of measured electrical properties of gland at the resting and stimulated states reveals the changes in the intra- and extra-cellular spaces of salivary gland as a result of saliva secretion. Statistical analysis of the spectroscopy data collected shows that there is a significant difference in electrical properties of tissue between resting and stimulated states of the salivary activity. These electrical impedance spectroscopy measurements will be used to benchmark changes of impedance due to salivary gland stimulation.

Neurophysiological effects of low and high frequency rTMS on long latency auditory evoked potentials

Objectives Long latency auditory evoked potentials (LLAEP; N1a, N1b, N1c and P2) involving local and global auditory processes were investigated in order to examine the impact of low-(LF) and high-frequency (HF) repetitive transcranial magnetic stimulation (rTMS) on the cortical excitability of the temporal cortex. We hypothesized that both stimulation frequencies have the same modulation effect, in accordance with clinical data showing a reduction of auditory verbal hallucinations (AVH) after LF- and HF-temporal rTMS in patients with schizophrenia. Methods In 30 right-handed healthy volunteer subjects enrolled in a crossover trial, we studied the changes of LLAEP before and after neuronavigated LF- and HF-rTMS protocols over the left temporal cortex. The target was defined using fMRI (comprehensive versus listening contrasted auditory task). We studied changes in latencies, amplitudes, surface potential maps and cortical generators (swLORETA). N1a generators are mainly located in the temporal cortex while N1b, N1c and P2 generators are located mainly in the frontal cortex. Results While no effect on N1a was observed, similar inhibitory effect of both rTMS frequencies on LLAEP amplitudes was obtained for N1b, N1c and P2. The study of surface potential maps and cortical generators noticed some differences regarding the auditory processes: HF-rTMS produced earlier, more diffused and more right-lateralized effects than LF-rTMS. Conclusions While N1a may only reflect auditory processes, later cortical responses such as N1c and P2 may reflect more integrative, cognitive, attentional processing, in addition to auditory processes. Thus, beyond local inhibitory effects, rTMS, and particularly HF-rTMS, exerted a remote modulation effect on the frontal cortex that might be involved in the attentional processes. This could be an explanation for the therapeutic effect of temporal HF-rTMS on AVHs in patients with schizophrenia.

Relationship between Corrected-QT Intervals and Other ECG Characteristics with Methadone Dose in Methadone Maintenance Treatment (MMT) Patients and Healthy Subjects: A Case- Control Study

Abstract Background: In this study we assessed the relationship between corrected-QT intervals and other ECG characteristics with methadone dose and other parameters in MMT patients and healthy subjects. Methods: This was a case-control study which was carried out on patients underwent MMT and healthy control group who had been referred to Ebne-Sina academic hospital, Mashhad during 2014 - 2015. At the time of the study, 40 patients who received MMT therapy for at least 6 months and 40 voluntary healthy subjects who matched on age and sex enrolled in the study. 12-lead ECG was performed for all the patients. Mean QT interval, PR interval and QRS duration in every 12 leads were documented for each patient in maximum. Results: To evaluate the patients, we divided 80 patients into two groups: 40 patients under treatment with Methadone and 40 voluntary participants as control group. There were 20 males and 20 females in each group. Duration of addiction was 214.80  126.99 months in MMT group. Significant differences were observed in PRi between the patient and control groups (P = 0.007), and also between methadone dose and PRi (r = 0.468, P = 0.038) in males. QTc prolongation was reported in 4 patients of addicted group (10%). All of the QTc prolongation patients were female (P = 0.037). There was significant relationship between PRi and weight (P = 0.015), addiction period (P = 0.011), methadone treatment period (P = 0.018) as well as methadone dosage (P = 0.14). Methadone cut off point of 65 mg had a significant relationship with systolic blood pressure (P = 0.002), diastolic blood pressure (P = 0.013), QTCi (P = 0.016) and QRS (P = 0.044); however, no significant relationship was reported with PRi (P = 0.451). Conclusions:We found that there is no exact dosage of methadone in which the side effects such as TdP (Torsade de pointes) or QTc prolongation can be predicted. Female gender and methadone dosage 65 mg were risk factors of our study for QTc prolongation which may result in subsequent deteriorated conditions.

An Insight into the Changes in Skin Texture and Properties following Dietary Intervention with a Nutricosmeceutical Containing a Blend of Collagen Bioactive Peptides and Antioxidants

Background: Skin aging is a multifactorial phenomenon which causes alterations in skin physiological functions and, most visibly, phenotypic changes. In particular, during the aging process, hyaluronic acid, collagen, and elastin fibers undergo structural and functional changes. Aims: This study aimed to give an insight into the photo-protective benefits and efficacy of an oral liquid nutricosmeceutical containing collagen bioactive peptides and antioxidants to counteract the signs of aging. Methods: A double-blind, randomized, placebo-controlled clinical trial was conducted by an independent esthetic clinic on 120 healthy volunteer subjects for 90 days. Subjects were divided into 2 groups: 60 subjects consumed 1 bottle (50 mL) of the nutricosmeceutical daily and the other 60 consumed 1 bottle (50 mL) of the placebo. Outcome measures were related to skin elasticity (expressed as Young's elasticity modulus) and skin architecture (histological analysis). In addition, the subjects recruited in this study underwent observational assessments through self-assessment questionnaires. Results and Conclusions: Overall, we demonstrated a significant increase in skin elasticity (+7.5%), p ≤ 0.001 and an improvement in skin texture after daily oral consumption of the nutricosmeceutical. We also obtained a positive patient feedback through the self-assessment questionnaires. Taken together these results show that this nutricosmeceutical supplement may have photo-protective effects and help improve skin health.