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In this study, we tested whether the commercial transcranial direct current stimulation (tDCS) headset foc.us improves cognitive performance, as advertised in the media. A single-blind, sham-controlled, within-subject design was used to assess the effect of online and off-line foc.us tDCS-applied over the prefrontal cortex in healthy young volunteers ( n = 24) on working memory (WM) updating and monitoring. WM updating and monitoring, as assessed by means of the N-back task, is a cognitive-control process that has been shown to benefit from interventions with CE-certified tDCS devices. For both online and off-line stimulation protocols, results showed that active stimulation with foc.us, compared to sham stimulation, significantly decreased accuracy performance in a well-established task tapping WM updating and monitoring. These results provide evidence for the important role of the scientific community in validating and testing far-reaching claims made by the brain training industry. [ABSTRACT FROM AUTHOR]

Large pores of human cortical bone (> 30 μm) are filled with fluids, essentially consisting of water, suggesting that cortical bone free water can be considered as a reliable surrogate measure of cortical bone porosity and hence quality. Signal from such pores can be reliably captured using Short Echo Time (STE) pulse sequence with echo-time in the range of 1–1.5 msec (which should be judiciously selected correspond to T 2 ⁎ value of free water molecules). Furthermore, it is well-known that cortical bone T 1 -relaxivity is a function of its geometry, suggesting that cortical bone free water increases with age. In this work, we quantified cortical bone free water longitudinal relaxation time (T 1 ) by a Dual-TR technique using STE pulse sequence. In the sequel, we investigated relationship between STE-derived cortical bone free water T 1 -values and age in a group of healthy volunteers (thirty subjects covering the age range of 20–70 years) at 1.5 T. Preliminary results showed that cortical bone free water T 1 highly correlates with age ( r 2 = 0.73, p < 0.0001), representing cortical bone free water T 1 as a reliable indicator of cortical bone porosity and age-related deterioration. It can be concluded that STE-MRI can be utilized as proper alternative in quantifying cortical bone porosity parameters in-vivo , with the advantages of widespread clinical availability and being cost-effective. [ABSTRACT FROM AUTHOR]

Background and Objectives: Canagliflozin is an orally active, reversible, selective sodium-glucose co-transporter-2 inhibitor. A population pharmacokinetic (popPK) model of canagliflozin, including relevant covariates as sources of inter-individual variability, was developed to describe phase I, II, and III data in healthy volunteers and in patients with type 2 diabetes mellitus (T2DM).Methods: The final analysis included 9061 pharmacokinetic (PK) samples from 1616 volunteers enrolled in nine phase I, two phase II, and three phase III studies and was performed using NONMEM(®) 7.1. Inter-individual variability was evaluated using an exponential model and the residual error model was additive in the log domain. The first-order conditional estimation method with interaction was applied and the model was parameterized in terms of rate constants. Covariate effects were explored graphically on empirical Bayes estimates of PK parameters, as shrinkage was low. Clinical relevance of statistically significant covariates was evaluated. The predictive properties of the model were illustrated by prediction-corrected visual predictive checks.Results: A two-compartment PK model with lag-time and sequential zero- and first-order absorption and first-order elimination best described the observed data. Sex, age, and weight on apparent volume of distribution of the central compartment, body mass index on first-order absorption rate constant, and body mass index and over-encapsulation on lag-time, and estimated glomerular filtration rate (eGFR, by MDRD equation), dose, and genetic polymorphism (carriers of UGT1A9*3 allele) on elimination rate constant were identified as statistically significant covariates. The prediction-corrected visual predictive checks revealed acceptable predictive performance of the model.Conclusion: The popPK model adequately described canagliflozin PK in healthy volunteers and in patients with T2DM. Because of the small magnitude of statistically significant covariates, they were not considered clinically relevant. However, dosage adjustments are recommended for T2DM patients with renal impairment (eGFR ≥60 mL/min/1.73 m(2): 100 or 300 mg/day; eGFR of 45 to <60 mL/min/1.73 m(2): 100 mg/day). [ABSTRACT FROM AUTHOR]

Aim Rheumatoid arthritis is characterized by type 17 helper T cell (Th17)/regulatory T cell (Treg) imbalance. The objective of this article is to study whether insufficient apoptosis contributes to the imbalance of Th17/Treg in rheumatoid arthritis. Methods Twenty-one rheumatoid arthritis patients and eight healthy volunteers were involved in this study. The percentage of CD4+ interleukin ( IL)-17+ T cells and CD4+ transcription factor-forkhead box protein 3 (Foxp3)+ T cells were measured by flow cytometry, and active caspase-3 labeling was used to detect early apoptosis. The number of T cell subtypes in peripheral blood between the two groups was compared, as well as the apoptotic ratio. Results Neither the number of Th17 nor Treg cells was significantly different between rheumatoid arthritis patients and healthy controls. However, the number of regulatory T cells positively correlated with erythrocyte sedimentation rate, Disease Activity Score of 28 joints and rheumatoid factor. For the apoptosis of T cell subtypes, the percentage of apoptotic Th17 cells was higher in peripheral blood of rheumatoid arthritis patients compared to controls. Furthermore, peripheral Th17 cells were more sensitive to apoptosis than Treg cells, but there was no difference between rheumatoid arthritis patients and controls. Conclusion It seemed that there was no relationship between the number and apoptosis ratio of peripheral Th17/Treg cells. But the number of Treg cells positively correlated with disease activity. Furthermore, Th17 cells are more sensitive to apoptosis after freezing, especially in RA patients. This serendipitous finding may provide new areas for the further study of these two cell populations. [ABSTRACT FROM AUTHOR]

The purpose of this study was to determine the effects of different therapeutic 1-MHz ultrasound waveforms on endothelial function before and after cyclooxygenase (COX) inhibition. Forty-two healthy volunteers aged 27.2 ± 3.8 y underwent interventions and an evaluation for endothelial function (n = 15; with COX inhibition, n = 15; duration of the vasodilator effect, n = 12) by technique flow-mediated dilation. Continuous ultrasound therapy (0.4 W/cm(2 SATA)), pulsed ultrasound therapy (20% duty cycle, 0.08 W/cm(2 SATA)) or placebo (equipment power off) was randomly applied over the brachial artery for 5 min. COX inhibition (aspirin) was carried out 30 min before treatments. In relation to the placebo, flow-mediated dilation increased by 4.8% using continuous ultrasound and by 3.4% using pulsed ultrasound. After COX, flow-mediated dilation was enhanced by 2.1% by continuous ultrasound and 2.6% by pulsed ultrasound. This vasodilation persisted for 20 min. Continuous and pulsed therapeutic 1-MHz ultrasound waveforms improved endothelial function in humans, which provided them with anti-inflammatory vascular effects. [ABSTRACT FROM AUTHOR]

Exposure to artificial light at night (ALAN) has become increasing common, especially in developed countries. We investigated the effect of dALAN exposure during sleep in healthy young male subjects. A total of 30 healthy young male volunteers from 21 to 29 years old were recruited for the study. They were randomly divided into two groups depending on light intensity (Group A: 5 lux and Group B: 10 lux). After a quality control process, 23 healthy subjects were included in the study (Group A: 11 subjects, Group B: 12 subjects). Subjects underwent an NPSG session with no light (Night 1) followed by an NPSG session randomly assigned to two different dim light conditions (5 or 10 lux, domλ: 501.4 nm) for a whole night (Night 2). We found significant sleep structural differences between Nights 1 and 2, but no difference between Groups A and B. Exposure to dALAN during sleep was significantly associated with increased wake time after sleep onset (WASO;F= 7.273,p= 0.014), increased Stage N1 (F= 4.524,p= 0.045), decreased Stage N2 (F= 9.49,p= 0.006), increased Stage R (F= 6.698,p= 0.017) and non-significantly decreased REM density (F= 4.102,p= 0.056). We found that dALAN during sleep affects sleep structure. Exposure to dALAN during sleep increases the frequency of arousals, amount of shallow sleep and amount of REM sleep. This suggests adverse effects of dALAN during sleep on sleep quality and suggests the need to avoid exposure to dALAN during sleep. [ABSTRACT FROM PUBLISHER]

Objectives: Shear-wave sonoelastography is expected to facilitate low operator dependency, high reproducibility and quantitative evaluation, whereas there are few reports on available normative values of in vivo tissue in head and neck fields. The purpose of this study was to examine the reliabilities on measuring hardness using shear-wave sonoelastography and to clarify normal values of masseter muscle hardness in healthy volunteers. Methods: Phantoms with known hardness ranging from 20 to 140 kPa were scanned with shear-wave sonoelastography, and inter- and intraoperator reliabilities were examined compared with strain sonoelastography. The relationships between the actual and measured hardness were analyzed. The masseter muscle hardness in 30 healthy volunteers was measured using shear-wave sonoelastography. Results: The inter- and intraoperator intraclass correlation coefficients were almost perfect. Strong correlations were seen between the actual and measured hardness. The mean hardness of the masseter muscles in healthy volunteers was 42.82 ± 5.56 kPa at rest and 53.36 ± 8.46 kPa during jaw clenching. Conclusions: The hardness measured with shear-wave sonoelastography showed high-level reliability. Shear-wave sonoelastography may be suitable for evaluation of the masseter muscles. [ABSTRACT FROM AUTHOR]

In Compressed Sensing (CS) of MRI, optimization of the regularization parameters is not a trivial task. We aimed to establish a method that could determine the optimal weights for regularization parameters in CS of time-of-flight MR angiography (TOF-MRA) by comparing various image metrics with radiologists’ visual evaluation. TOF-MRA of a healthy volunteer was scanned using a 3T-MR system. Images were reconstructed by CS from retrospectively under-sampled data by varying the weights for the L1 norm of wavelet coefficients and that of total variation. The reconstructed images were evaluated both quantitatively by statistical image metrics including structural similarity (SSIM), scale invariant feature transform (SIFT) and contrast-to-noise ratio (CNR), and qualitatively by radiologists’ scoring. The results of quantitative metrics and qualitative scorings were compared. SSIM and SIFT in conjunction with brain masks and CNR of artery-to-parenchyma correlated very well with radiologists’ visual evaluation. By carefully selecting a region to measure, we have shown that statistical image metrics can reflect radiologists’ visual evaluation, thus enabling an appropriate optimization of regularization parameters for CS. [ABSTRACT FROM AUTHOR]

The Internet provides a large source of novel and rewarding stimuli, particularly with respect to sexually explicit materials. Novelty-seeking and cue-conditioning are fundamental processes underlying preference and approach behaviors implicated in disorders of addiction. Here we examine these processes in individuals with compulsive sexual behaviors (CSB), hypothesizing a greater preference for sexual novelty and stimuli conditioned to sexual rewards relative to healthy volunteers. Twenty-two CSB males and forty age-matched male volunteers were tested in two separate behavioral tasks focusing on preferences for novelty and conditioned stimuli. Twenty subjects from each group were also assessed in a third conditioning and extinction task using functional magnetic resonance imaging. CSB was associated with enhanced novelty preference for sexual, as compared to control images, and a generalized preference for cues conditioned to sexual and monetary versus neutral outcomes compared to healthy volunteers. CSB individuals also had greater dorsal cingulate habituation to repeated sexual versus monetary images with the degree of habituation correlating with enhanced preference for sexual novelty. Approach behaviors to sexually conditioned cues dissociable from novelty preference were associated with an early attentional bias to sexual images. This study shows that CSB individuals have a dysfunctional enhanced preference for sexual novelty possibly mediated by greater cingulate habituation along with a generalized enhancement of conditioning to rewards. We further emphasize a dissociable role for cue-conditioning and novelty preference on the early attentional bias for sexual cues. These findings have wider relevance as the Internet provides a broad range of novel and potentially rewarding stimuli. [ABSTRACT FROM AUTHOR]

Background: NUDT15 R139C (rs116855232) is a recently identified genetic factor responsible for thiopurine-induced leukocytopenia and hair loss. In this study, we investigated the association of NUDT15 R139C with 6-thioguanine nucleotide (6-TGN) levels and thiopurine-induced leukocytopenia in Japanese patients with inflammatory bowel disease (IBD).Methods: Two hundred and sixty-four subjects (103 healthy volunteers and 161 IBD patients treated with thiopurines) were enrolled. Genotyping for NUDT15 R139C was performed using Custom TaqMan® SNP genotyping assays.Results: The NUDT15 C/C, C/T, and T/T genotypes were 80.7, 18.2, and 1.1 %, respectively. The allelic frequency was 10.2 %. Among 161 IBD patients, there was no significant difference in 6-TGN levels among the NUDT15 genotypes. Forty-five patients (27.9 %) developed leukocytopenia (WBC <3000/μl), and the C/T and T/T genotypes were significantly associated with the development of leukocytopenia (P = 1.7 × 10(-5)). In these patients, 6-TGN levels were not significantly different between NUDT15 genotypes. NUDT15 R139C was significantly associated with early (<8 weeks) (P = 1.03 × 10(-4)) and late (>8 weeks) leukocytopenia (P = 4.3 × 10(-4)). The decrease in WBC count at 2 and 4 weeks was significantly higher in patients with the C/T or T/T genotypes as compared to the patients with the C/C genotype. All patients with the T/T genotype (n = 2) developed early severe hair loss and severe leukocytopenia (<1000/μl). The logistic regression analysis revealed that NUDT15 R139C was the sole genetic factor responsible for the thiopurine-induced leukocytopenia (P = 0.001).Conclusions: These results suggest that NUDT15 R139C-related thiopurine-induced leukocytopenia is mediated by a 6-TGN-independent mechanism. [ABSTRACT FROM AUTHOR]

Background/Objectives: Ice application is one of the treatment procedures used in hydrotherapy. Though its various physiological/therapeutic effects were reported, ice bag application (IBA) to head and spine on cardiovascular changes were not reported. Hence, this study aims at evaluating the immediate effect of IBA to head and spine on cardiovascular changes in healthy volunteers. Materials and Methods: Twenty-eight subjects were randomized into three sessions ([i] IBA [ii] tap water bag application [TWBA] and [iii] control) and intervention was given in one of the 3-different orders. Systolic blood pressure (SBP), diastolic blood pressure (DBP), and pulse rate (PR) was assessed before and after 20-min of each intervention. Pulse pressure, mean pressure (MP), rate pressure product (RPP), and double product (Do-P) were derived by standard formula. Statistical analysis was performed by repeated measures of analysis of variance and post-hoc analysis with Bonferroni adjustment for multiple comparisons with the use of Statistical Package for Social Sciences version-16. Results: The results showed no significant difference between sessions in all variables. Within-group analysis showed significant reductions in SBP, PR, RPP, Do-P in IBA and TWBA sessions; Significant reduction in DBP, MP in IBA unlike TWBA; and no significant changes in all the variables of control session. Conclusions: Result of our study suggest that though both IBA and TWBA to head and spine might be considered as having effect on improving cardiovascular function in healthy volunteers, IBA to head and spine could be considered as a better choice than TWBA. [ABSTRACT FROM AUTHOR]

Background: Previous research on emotional correlates of individual differences in subjective responses to d-amphetamine has focused on relatively broad personality traits. Yet, emotional functioning is best characterized by several narrow subcomponents, each of which may contribute uniquely to amphetamine response. Here, we examine several specific subdomains of emotional functioning in relation to acute amphetamine response. Method: At a baseline session, healthy stimulant-naive volunteers ( N = 97) completed measures of several subdomains of baseline trait emotional functioning and then completed two counterbalanced experimental sessions during which they received a single oral dose of 20 mg d-amphetamine or placebo. Acute subjective drug response measures were completed at repeated intervals before and after drug administration. Data from subjective measures that were significantly modulated by amphetamine were reduced using principal component analysis (amphetamine or placebo) into three higher-order factors of 'positive mood,' 'arousal,' and 'drug high.' Amphetamine did not significantly alter any 'negative' subjective states. Separate multiple regression analyses were conducted regressing these three drug factors on baseline trait emotional functioning scales. Results: The combined set of trait emotional functioning indicators accounted for approximately 22 % of the variance in acute amphetamine-induced positive mood changes. Greater anticipatory pleasure and greater anxious distress each uniquely predicted greater amphetamine-induced positive mood. Trait emotional functioning did not significantly predict amphetamine-induced changes in arousal or drug high. Discussion: Emotional traits appear to moderate drug-induced positive mood but not other dimensions of amphetamine effects. Different facets of emotional functioning may differentially modulate amphetamine's subjective effect profile. [ABSTRACT FROM AUTHOR]

MicroRNAs are a class of small non-coding RNA that regulate gene expression at a post-transcriptional level. MicroRNAs have been identified in various body fluids under normal conditions and their stability as well as their dysregulation in disease opens up a new field for biomarker study. However, diurnal and day-to-day variation in plasma microRNA levels, and differential regulation between males and females, may affect biomarker stability. A QuantStudio 12K Flex Real-Time PCR System was used to profile plasma microRNA levels using OpenArray in male and female healthy volunteers, in the morning and afternoon, and at four time points over a one month period. Using this system we were able to run four OpenArray plates in a single run, the equivalent of 32 traditional 384-well qPCR plates or 12,000 data points. Up to 754 microRNAs can be identified in a single plasma sample in under two hours. 108 individual microRNAs were identified in at least 80% of all our samples which compares favourably with other reports of microRNA profiles in serum or plasma in healthy adults. Many of these microRNAs, including miR-16-5p, miR-17-5p, miR-19a-3p, miR-24-3p, miR-30c-5p, miR-191-5p, miR-223-3p and miR-451a are highly expressed and consistent with previous studies using other platforms. Overall, microRNA levels were very consistent between individuals, males and females, and time points and we did not detect significant differences in levels of microRNAs. These results suggest the suitability of this platform for microRNA profiling and biomarker discovery and suggest minimal confounding influence of sex or sample timing. However, the platform has not been subjected to rigorous validation which must be demonstrated in future biomarker studies where large differences may exist between disease and control samples. [ABSTRACT FROM AUTHOR]

The natriuretic peptides (NPs), atrial natriuretic peptide (ANP), brain natriuretic peptide (BNP) and C-type natriuretic peptide (CNP), have vasoactive functions that concern humans and most animals, but their specific effects on cerebral circulation are poorly understood. We therefore examined the responsiveness of cerebral arteries to different doses of the natriuretic peptides in animals and humans. We conducted a dose-response experiment in guinea pigs ( in vitro ) and a double-blind, three-way cross-over study in healthy volunteers ( in vivo ). In the animal experiment, we administered cumulative doses of NPs to pre-contracted segments of cerebral arteries. In the main study, six healthy volunteers were randomly allocated to receive two intravenous doses of ANP, BNP or CNP, respectively, over 20 min on three separate study days. We recorded blood flow velocity in the middle cerebral artery ( V MCA ) by transcranial Doppler. In addition, we measured temporal and radial artery diameters, headache response and plasma concentrations of the NPs. In guinea pigs, ANP and BNP but not CNP showed significant dose-dependent relaxation of cerebral arteries. In healthy humans, NP infusion had no effect on mean V MCA , and we found no difference in hemodynamic responses between the NPs. Furthermore, natriuretic peptides did not affect temporal and radial artery diameters or induce headache. In conclusion, natriuretic peptides in physiological and pharmacological doses do not affect blood flow velocity in the middle cerebral artery or dilate extracerebral arteries in healthy volunteers. [ABSTRACT FROM AUTHOR]

A feasibility study on the applicability of an ultrasound decorrelation method to urinary flow imaging was carried out in 20 healthy male volunteers, to provide a basis for a non-invasive approach to diagnose bladder outlet obstruction. Each volunteer voided five times in a flow meter in standing position. During each voiding, ultrasound radiofrequency frames were acquired transperineally at different flow rates. The results indicated that the decrease in correlation (decorrelation) of ultrasound radiofrequency signals had no unique relation with flow rate, but decreased distinctively with urinary flow velocity. In most of the healthy volunteers, the decorrelation was small because of the low flow velocity. However, because of the different flow velocities in volunteers, the variation in slope between volunteers was statistically significant. Therefore, it is probably possible to use the decorrelation method to differentiate between healthy persons and patients with obstruction. [ABSTRACT FROM AUTHOR]

Introduction: Recently, we showed that the length of cardiac mucosa in healthy volunteers correlated with age and obesity. We have now examined the immunohistological characteristics of this expanded cardia to determine whether it may be due to columnar metaplasia of the distal oesophagus. Methods: We used the squamocolumnar junction (SCJ), antral and body biopsies from the 52 Helicobacter pylori-negative healthy volunteers who had participated in our earlier physiological study and did not have hiatus hernia, transsphincteric acid reflux, Barrett's oesophagus or intestinal metaplasia (IM) at cardia. The densities of inflammatory cells and reactive atypia were scored at squamous, cardiac and oxyntocardiac mucosa of SCJ, antrum and body. Slides were stained for caudal type homeobox 2 (CDX-2), villin, trefoil factor family 3 (TFF-3) and liver-intestine (LI)-cadherin, mucin MUC1, Muc-2 and Muc-5ac. In addition, biopsies from 15 Barrett's patients with/ without IM were stained and scored as comparison. Immunohistological characteristics were correlated with parameters of obesity and high-resolution pH metry recording. Results: Cardiac mucosa had a similar intensity of inflammatory infiltrate to non-IM Barrett's and greater than any of the other upper GI mucosae. The immunostaining pattern of cardiac mucosa most closely resembled non-IM Barrett's showing only slightly weaker CDX-2 immunostaining. In distal oesophageal squamous mucosa, expression of markers of columnar differentiation (TFF-3 and LI-cadherin) was apparent and these correlated with central obesity (correlation coefficient (CC)=0.604, p=0.001 and CC=0.462, p=0.002, respectively). In addition, expression of TFF-3 in distal oesophageal squamous mucosa correlated with proximal extension of gastric acidity within the region of the lower oesophageal sphincter (CC=-0.538, p=0.001). Conclusions: These findings are consistent with expansion of cardia in healthy volunteers occurring by squamo columnar metaplasia of distal oesophagus and aggravated by central obesity. This metaplastic origin of expanded cardia may be relevant to the substantial proportion of cardia adenocarcinomas unattributable to H. pylori or transsphincteric acid reflux. [ABSTRACT FROM AUTHOR]

At present it remains elusive to what extent motor-cortical alpha (8–12 Hz) and beta (13–30 Hz) oscillations are associated with motor sequence learning. In order to interact with motor-cortical oscillations, the present study applied transcranial alternating current stimulation (tACS) at 10 Hz, 20 Hz and sham stimulation over the left primary motor cortex (M1) during a serial reaction time task (SRTT) in 13 healthy volunteers. In a control experiment, tACS at 35 Hz was applied in another sample of 13 volunteers. The participants performed the task with the right hand. A sequential pattern was interleaved by a randomly varying pattern serving as interference from sequence learning. Reaction times were determined as dependent variable. Both 10 and 20 Hz tACS facilitated SRTT acquisition in contrast to sham and 35 Hz tACS. After acquisition, the interfering condition led to increased reaction times comparable to baseline level during 10 Hz, sham and 35 Hz tACS. In contrast, during 20 Hz tACS the initial learning success was retained despite interference. While motor-cortical tACS at 10 and 20 Hz likewise facilitates the acquisition, tACS at 20 Hz frequency additionally stabilizes the newly learned motor sequence indicated by less susceptibility to interference. [ABSTRACT FROM AUTHOR]

Purpose: This study aimed to evaluate the kinematics of the flexor pollicis longus tendon (FPL) at the wrist by examining the movement of the FPL on the distal radius during various wrist and finger motions using transverse ultrasound in healthy volunteers. Methods: Forty-eight wrists of 24 asymptomatic volunteers were examined by transverse ultrasound to observe the location of the FPL on the distal radius at 5 wrist positions (neutral, 60° dorsal flexion, 60° palmar flexion, 40° ulnar deviation, and 10° radial deviation) with all 5 fingers in full extension and full flexion, and isolated thumb in full flexion, respectively. Results: We found that the FPL was situated statistically significantly more ulnodorsally at the wrist dorsal and ulnar deviation positions, more ulnopalmarly at the wrist palmar flexion position, and more radiopalmarly at the wrist radial deviation-position than at the wrist neutral position with all 5 fingers at full extension. Especially, it moved statistically significantly most ulnodorsally at the wrist dorsal flexion position during finger motion. The FPL moved most statistically significantly ulnopalmarly at the wrist palmar flexion position with all 5 fingers in full extension among all wrist positions during finger motion. During finger motion, the wrist dorsal flexion position induced significant displacement of the FPL to the distal radius and compressed it between the flexor tendons and the distal radius. The average distance between the FPL and the volar surface of the distal radius in the palmar-dorsal direction at wrist dorsal flexion position in all fingers at full flexion was 1.9 mm, the smallest among all wrist positions during finger motion. Conclusions: There is a significant relationship between the transverse movement of the FPL at the distal radius and wrist and finger motions. Our findings indicated that the irritation of the FPL caused by the movement of both the FPL itself and of the flexor digitorum superficialis and profundus is most induced with the wrist in dorsal flexion with all 5 fingers at full flexion compared to other wrist positions during finger motion. This wrist position might be the optimum one at which to evaluate the irritation of the FPL from volar locking plates in patients with distal radius fracture. We believe that our transverse ultrasound results can play a role in the gaining of a better understanding of the kinematics of the FPL. Moreover, they have potential to lead to improved diagnosis of and treatment for fractures of the distal radius and help to minimize the risk of FPL rupture related to volar locking plates. [ABSTRACT FROM AUTHOR]

Purpose: To determine the pharmacokinetics of the p110α-selective inhibitor alpelisib (BYL719) in humans, to identify metabolites in plasma and excreta, and to characterize pathways of biotransformation.Methods: Four healthy male volunteers received a single oral dose of [(14)C]-labeled alpelisib (400 mg, 2.78 MBq). Blood, urine, and feces samples were collected throughout the study. Total radioactivity was measured by liquid scintillation counting, and metabolites were quantified and identified by radiometry and mass spectrometry. Complementary in vitro experiments characterized the hydrolytic, oxidative, and conjugative enzymes involved in metabolite formation.Results: Over 50 % of [(14)C] alpelisib was absorbed, with a T(max) of 2 h and an elimination half-life from plasma of 13.7 h. Over the first 12 h, exposure to alpelisib and the primary metabolite M4 was 67.9 and 26.7 % of total drug-related material in circulation, respectively. Mass balance was achieved, with 94.5 % of administered radioactivity recovered in excreta. In total, 38.2 % of alpelisib was excreted unchanged, while 39.5 % was excreted as M4. Based on the excreta pools analyzed, excretion occurred mainly via feces (79.8 % of administered dose); 13.1 % was excreted via urine. In vitro experiments showed that spontaneous and enzymatic hydrolysis contributed to M4 formation, while CYP3A4-mediated oxidation and UGT1A9-mediated glucuronidation formed minor metabolites. Alpelisib was well tolerated, and no new safety concerns were raised during this study.Conclusions: Alpelisib was rapidly absorbed and cleared by multiple metabolic pathways; the primary metabolite M4 is pharmacologically inactive. Alpelisib has limited potential for drug-drug interactions and is therefore a promising candidate for combination therapy. [ABSTRACT FROM AUTHOR]

Introduction: Although prostatitis is a common male urinary tract infection, clinical diagnosis of prostatitis is difficult. The developmental mechanism of prostatitis is not yet unraveled which led to the elaboration of various biomarkers. As changes in asparagineTinked-(N-)-glycosylation were observed between healthy volunteers (HV), patients with benign prostate hyperplasia and prostate cancer patients, a difference could exist in biochemical parameters and urinary N-glycosylation between HV and prostatitis patients. We therefore investigated if prostatic protein glycosylation could improve the diagnosis of prostatitis. Materials and methods: Differences in serum and urine biochemical markers and in total urine N-glycosylation profile of prostatic proteins were determined between HV (N = 66) and prostatitis patients (N = 36). Additionally, diagnostic accuracy of significant biochemical markers and changes in N-glycosylation was assessed. Results: Urinary white blood cell (WBC) count enabled discrimination of HV from prostatitis patients (P < 0.001). Urinary bacteria count allowed for discriminating prostatitis patients from HV (P < 0.001). Total amount of biantennary structures (urinary 2A/MA marker) was significantly lower in prostatitis patients compared to HV (P < 0.001). Combining the urinary 2A/MA marker and urinary WBC count resulted in an AUC of 0.79,95% confidence interval (Cl) = (0.70-0.89) which was significantly better than urinary WBC count (AUC = 0.70,95% Cl = [0.59-0.82], P = 0.042) as isolated test. Conclusions: We have demonstrated the diagnostic value of urinary N-glycosylation profiling, which shows great potential as biomarker for prostatitis. Further research is required to unravel the developmental course of prostatic inflammation. [ABSTRACT FROM AUTHOR]

Introduction: The mechanical properties of hamstring muscles are usually inferred from global passive torque/angle relationships, in combination with adjoining tissues crossing the joint investigated. Shear modulus measurement provides an estimate of changes in muscle-tendon stiffness and passive tension. This study aimed to assess the passive individual behavior of each hamstring muscle in different stretching positions using shear wave elastography. Methods/Results: The muscle shear modulus of each hamstring muscle was measured during a standardized slow passive knee extension (PKE, 80% of maximal range of motion) on eighteen healthy male volunteers. Firstly, we assessed the reliability of the measurements. Results were good for semitendinosus (ST, CV: 8.9%-13.4%), semimembranosus (SM, CV: 10.3%-11.2%) and biceps femoris long-head (BF-lh, CV: 8.6%-13.3%), but not for biceps femoris short-head (BF-sh, CV: 20.3%-44.9%). Secondly, we investigated each reliable muscle in three stretch positions: 70°, 90° and 110° of hip flexion. The results showed different values of shear modulus for the same amount of perceived stretch, with the highest measurements in the high-flexed hip situation. Moreover, individual muscles displayed different values, with values increasing or BF-lh, SM and ST, respectively. The inter-subject variability was 35.3% for ST, 27.4% for SM and 30.2% for BF-lh. Conclusion: This study showed that the hip needs to be high-flexed to efficiently tension the hamstrings, and reports a higher muscle-tendon stress tolerance at 110° of hip angle. In addition muscles have different passive behaviors, and future works will clarify if it can be linked with rate of injury. [ABSTRACT FROM AUTHOR]

Globally, suicide and HIV/AIDS remain two of the greatest healthcare issues, particularly in low- and middle-income countries. Several studies have observed a relationship between suicidal behaviour and HIV/AIDS. Materials and Methods. The main objective of this research was to determine the prevalence of elevated risk of suicidal ideation in HIV-positive persons immediately following voluntary HIV counselling and testing (VCT). The study sample consisted of adult volunteers attending the VCT clinic at a university-affiliated, general state hospital. Participants completed a sociodemographic questionnaire, Beck’s Hopeless Scale, and Beck’s Depression Inventory. Results. A significantly elevated risk of suicidal ideation was found in 83.1% of the patients who tested seropositive. Despite a wide age range in the cohort studied, the majority of patients with suicidal ideation were males in the younger age group (age < 30 years), consistent with the age-related spread of the disease and an increase in suicidal behaviour in younger people. Relevant associated variables are discussed. Conclusion. The results serve as important markers that could alert healthcare professionals to underlying suicide risks in HIV-positive patients. It is recommended that screening for elevated risk of suicidal ideation and prevention of suicidal behaviour should form a routine aspect of comprehensive patient care at VCT clinics. [ABSTRACT FROM AUTHOR]

Background: Improving gastric accommodation and gastric emptying is an attractive physiological treatment target in patients with functional dyspepsia (FD). We evaluated the effect of DA-9701, a new drug for FD, on gastric motor function after a meal in healthy volunteers using magnetic resonance imaging (MRI). Methods: Forty healthy volunteers were randomly allocated to receive either DA-9701 or placebo. After 5 days of treatment, subjects underwent gastric MRI (60 min before and 15, 30, 45, 60, 90, and 120 min after a liquid test meal). Gastric volume was measured through 3-dimensional reconstruction from MRI data. We analyzed 4 outcome variables including changes in total gastric volume (TGV), proximal TGV, and proximal to distal TGV ratio after a meal and gastric emptying rates after adjusting values at the pre-test meal. Results: Changes in TGV and proximal TGV after a meal did not differ between the DA-9701 and placebo groups (difference between groups -25.9 mL, 95% confidence interval [CI] -54.0 to 2.3 mL, P = 0.070 and -2.9 mL, 95% CI -30.3 to 24.5 mL, P = 0.832, respectively). However, pre-treatment with DA-9701 increased postprandial proximal to distal TGV ratio more than placebo (difference between groups 0.93, 95% CI 0.08 to 1.79, P = 0.034). In addition, pre-treatment with DA-9701 significantly increased gastric emptying as compared with placebo (mean difference between groups 3.41%, 95% CI 0.54% to 6.29%, P = 0.021, by mixed model for repeated measures). Conclusion: Our results suggested that DA-9701 enhances gastric emptying and does not significantly affect gastric accommodation in healthy volunteers. Further studies to confirm whether DA-9701 enhances these gastric motor functions in patients with FD are warranted. Trial Registration: ClinicalTrials.gov [ABSTRACT FROM AUTHOR]

Previous work in animals has shown that dopamine (DA) in cortex and striatum plays an essential role in stress processing. For the first time, we systematically reviewed the in vivo evidence for DAergic stress processing in health and psychopathology in humans. All studies included ( n studies = 25, n observations = 324) utilized DA D2/3 positron emission tomography and measured DAergic activity during an acute stress challenge. The evidence in healthy volunteers (HV) suggests that physiological, but not psychological, stress consistently increases striatal DA release. Instead, increased medial prefrontal cortex (mPFC) DAergic activity in HV was observed during psychological stress. Across brain regions, stress-related DAergic activity was correlated with the physiological and psychological intensity of the stressor. The magnitude of stress-induced DA release was dependent on rearing conditions, personality traits and genetic variations in several SNPs. In psychopathology, preliminary evidence was found for stress-related dorsal striatal DAergic hyperactivity in psychosis spectrum and a blunted response in chronic cannabis use and pain-related disorders, but results were inconsistent. Physiological stress-induced DAergic activity in striatum in HV may reflect somatosensory properties of the stressor and readiness for active fight-or-flight behavior. DAergic activity in HV in the ventral striatum and mPFC may be more related to expectations about the stressor and threat evaluation, respectively. Future studies with increased sample size in HV and psychopathology assessing the functional relevance of stress-induced DAergic activity, the association between cortical and subcortical DAergic activity and the direct comparison of different stressors are necessary to conclusively elucidate the role of the DA system in the stress response. [ABSTRACT FROM AUTHOR]

Patients suffering from persistent orofacial pain may sporadically report that the painful area feels 'swollen' or 'differently,' a phenomenon that may be conceptualized as a perceptual distortion because there are no clinical signs of swelling present. Our aim was to investigate whether standardized experimental pain and sensory deprivation of specific orofacial test sites would lead to changes in the size perception of these face areas. Twenty-four healthy participants received either 0.2 mL hypertonic saline (HS) or local anesthetics (LA) into six regions (buccal, mental, lingual, masseter muscle, infraorbital and auriculotemporal nerve regions). Participants estimated the perceived size changes in percentage (0 % = no change, −100 % = half the size or +100 % = double the size), and somatosensory function was checked with tactile stimuli. The pain intensity was rated on a 0-10 Verbal Numerical Rating Scale (VNRS), and sets of psychological questionnaires were completed. HS and LA were associated with significant self-reported perceptual distortions as indicated by consistent increases in perceived size of the adjacent face areas ( P ≤ 0.050). Perceptual distortion was most pronounced in the buccal region, and the smallest increase was observed in the auriculotemporal region. HS was associated with moderate levels of pain VNRS = 7.3 ± 0.6. Weak correlations were found between HS-evoked perceptual distortion and level of dissociation in two regions ( P < 0.050). Experimental pain and transient sensory deprivation evoked perceptual distortions in all face regions and overall demonstrated the importance of afferent inputs for the perception of the face. We propose that perceptual distortion may be an important phenomenon to consider in persistent orofacial pain conditions. [ABSTRACT FROM AUTHOR]

The agreement between humans and algorithms on whether an event-related potential (ERP) is present or not and the level of variation in the estimated values of its relevant features are largely unknown. Thus, the aim of this study was to determine the categorical and quantitative agreement between manual and automated methods for single-trial detection and estimation of ERP features. To this end, ERPs were elicited in sixteen healthy volunteers using electrical stimulation at graded intensities below and above the nociceptive withdrawal reflex threshold. Presence/absence of an ERP peak (categorical outcome) and its amplitude and latency (quantitative outcome) in each single-trial were evaluated independently by two human observers and two automated algorithms taken from existing literature. Categorical agreement was assessed using percentage positive and negative agreement and Cohen’s κ, whereas quantitative agreement was evaluated using Bland-Altman analysis and the coefficient of variation. Typical values for the categorical agreement between manual and automated methods were derived, as well as reference values for the average and maximum differences that can be expected if one method is used instead of the others. Results showed that the human observers presented the highest categorical and quantitative agreement, and there were significantly large differences between detection and estimation of quantitative features among methods. In conclusion, substantial care should be taken in the selection of the detection/estimation approach, since factors like stimulation intensity and expected number of trials with/without response can play a significant role in the outcome of a study. [ABSTRACT FROM AUTHOR]

Preclinical development of new biological entities (NBEs), such as human protein therapeutics, requires considerable expenditure of time and costs. Poor prediction of pharmacokinetics in humans further reduces net efficiency. In this study, we show for the first time that pharmacokinetic data of NBEs in humans can be successfully obtained early in the drug development process by the use of microdosing in a small group of healthy subjects combined with ultrasensitive accelerator mass spectrometry (AMS). After only minimal preclinical testing, we performed a first-in-human phase 0/phase 1 trial with a human recombinant therapeutic protein (RESCuing Alkaline Phosphatase, human recombinant placental alkaline phosphatase [hRESCAP]) to assess its safety and kinetics. Pharmacokinetic analysis showed dose linearity from microdose (53 μg) [14C]-hRESCAP to therapeutic doses (up to 5.3 mg) of the protein in healthy volunteers. This study demonstrates the value of a microdosing approach in a very small cohort for accelerating the clinical development of NBEs. [ABSTRACT FROM AUTHOR]

Background/Aims: IgA nephropathy (IgAN) is the most common form of primary glomerulonephritis, and often aggravates by mucosal infection. Secretory IgA (SIgA) is the dominant immunoglobulin in mucosal immunity, and is deposited in the mesangium in IgAN. The biological effects of SIgA on mesangial cells are poorly understood. Methods: Deposition of SIgA in frozen renal sections from IgAN patients was detected and the association between deposition of SIgA and patients characteristics was analyzed. The biological effects of SIgA and polymeric IgA (pIgA) on human renal mesangial cells were compared. We also studied the molecular mechanism of microRNA regulating the inflammatory effects of SIgA on mesangial cells. Results: Fifty-five of 176 patients had SIgA deposition with higher incidence of infection history and hematuria, lower serum cystatin C, β2 microglobulin, blood urea nitrogen and T-grade in the Oxford classification, compared with patients without SIgA deposition. SIgA stimulated mesangial cells at a higher ratio of proliferation and higher production of interleukin (IL)-6, IL-8, monocyte chemotactic protein 1, transforming growth factor-β1 and fibronectin, compared with SIgA from healthy volunteers. The proliferation and cytokines production in mesangial cells stimulated by SIgA were significantly lower than that stimulated by pIgA. miR- 16 targeted the 3'-untranslated region of IL-6 and suppressed its translation in mesangial cells induced by SIgA. Conclusions: The biological effects of SIgA on mesangial cells differ from those of pIgA. SIgA stimulates mesangial cell proliferation and production of proinflammatory cytokines. IL-6 production is regulated by miR-16 in mesangial cells. [ABSTRACT FROM AUTHOR]

Background: The patients with essential hypertension are increasing all over the world. There may be development of insulin resistance and hyperinsulinemia in essential hypertension. An association between essential hypertension and defective insulin secretion has been identified. Insulin resistance is the fundamental defect in the development of type 2 diabetes mellitus, hypertension and cardiovascular diseases. Objective: To observe the insulin resistance in adult male with essential hypertension. Methods: This is a cross sectional study was conducted in the Department of Physiology, Dhaka Medical College, Dhaka, Bangladesh from July 2012 to June 2013. A total number of 150 male subjects were selected with age ranging from 25-45 years. Seventy five male essential hypertensives were enrolled from Out- patient Department of Medicine, Dhaka Medical College Hospital, Dhaka. Otherwise healthy 75 of similar age were studied as control. Insulin resistance was assessed by HOMA-IR method. Fasting serum insulin level was measured by ELISA and fasting blood glucose by glucose oxidase method. Unpaired Student's 't' and Pearson's correlation coefficient (r) tests were performed for statistical analyses. Results: Current study reveals that essential hypertension has positive and significant relationship with fasting serum insulin level and insulin resistance. Conclusion: Incidence of insulin resistance is higher in essential hypertensive subjects in comparison to the control subjects. More in-depth prospective research is advocated to find remedies for common Bangladeshi patients. [ABSTRACT FROM AUTHOR]

Rationale: Hypnotics are widely used to treat insomnia but adverse effects of different hypnotics, especially benzodiazepine receptor agonists, are getting more attention lately. The effects of novel hypnotics have not been fully examined. Objective: This study aims to assess the effects of two hypnotics, ramelteon and triazolam, on driving performance, cognitive function, and equilibrium function. Methods: In this double-blinded, three-way crossover trial, 17 healthy males received acute doses of 8 mg ramelteon, 0.125 mg triazolam, and placebo. The subjects were administered three driving tasks-road-tracking, car-following, and harsh-braking-using a driving simulator and three cognitive tasks-Continuous Performance Test, N-back Test, and Trail-Making Test-at baseline and at 1 and 4 h post-dosing. The Stanford Sleepiness Scale scores and computerized posturography were also assessed. Results: In the driving simulations, ramelteon and triazolam increased the number of subjects who slid off the road. Triazolam increased the standard deviation of lateral position compared to ramelteon and placebo at 1 h post-dosing. Ramelteon and triazolam significantly increased the time to complete of Trail-Making Test part A and the environmental area in posturography compared to placebo at 1 and 4 h post-dosing. Ramelteon and triazolam significantly increased subjective sleepiness compared to placebo at 1 h post-dosing. Conclusions: Ramelteon may affect road-tracking performance, visual attention and/or psychomotor speed measured by Trail-Making Test part A, and body balance in acute dosing. Lower dose of triazolam also impaired performance worse than ramelteon. Physicians should consider risks and benefits when prescribing both drugs, especially in the initial period of administration. [ABSTRACT FROM AUTHOR]

Rationale: Benzodiazepines, such as diazepam, are anxiolytic-sedative drugs, used for the treatment of several different disorders. The pharmacological mechanism of action of benzodiazepines is well understood; however, it remains unclear which neural networks and systems are involved in translating these neurochemical actions into their therapeutic effects. Objectives: The objective of this study was to investigate the effects of 7-day diazepam administration compared to placebo on resting-state functional connectivity in healthy adults independent of any task. Methods: Thirty-four healthy participants were randomly assigned to receive either diazepam ( N = 17) or placebo (15 mg daily for 7 days) and underwent resting-state functional magnetic resonance acquisition. Model-free data analysis was performed using independent component analysis and dual regression. Results: Consistent with previous research, 11 resting-state networks were identified. Increased connectivity in response to diazepam administration was found in the medial visual network and middle/inferior temporal network. Diazepam did not cause any decreases in functional connectivity. Conclusions: Diazepam administration increases functional connectivity in areas of emotional processing independent of any task. Diazepam also enhanced functional connectivity in the medial visual system, which is a brain region rich in GABA receptors, and shows high binding of GABAergic drugs. These increases in functional connectivity are characteristic of CNS depressants. [ABSTRACT FROM AUTHOR]

Background Pneumococcal disease remains an important health priority despite successful implementation of pneumococcal conjugate vaccines (PCVs) in infant immunization programs, mainly due to the emergence of diseases caused by serotypes not included in licensed PCVs. A 15-valent pneumococcal conjugate vaccine (PCV-15) containing the 7 serotypes (4, 6B, 9V, 14, 18C, 19F, and 23F) included in licensed PCV-7 available at study initiation plus 8 additional serotypes (1, 3, 5, 6A, 7F, 19A, 22F, 33F) was developed and evaluated in healthy adults 18–45 years of age. Methods Sixty subjects received one dose of PCV-15 or PCV-7. Injection-site and systemic adverse events (AEs) were collected for 14-days postvaccination and serious AEs were collected for 30-days postvaccination. Safety laboratory tests (hematology, chemistry, and urinalysis) were evaluated prior to vaccination and 14-days postvaccination. Serotype-specific IgG and opsonophagocytic killing activity (OPA) responses to 15 serotypes included in PCV-15 were measured immediately prior to vaccination and 30-days postvaccination. Results AE incidences were comparable between vaccine groups although numerically higher frequencies of erythema (33.3% versus 13.3%), swelling (50.0% versus 23.3%), and myalgia (63.3% versus 36.7%) were reported among PCV-15 versus PCV-7 recipients. Majority of AEs, irrespective of vaccine received, were transient and of mild-to-moderate intensity. No clinically significant differences were observed when comparing AE duration and severity. No laboratory abnormalities, vaccine-related SAEs or discontinuations from the study due to AEs were reported. IgG concentrations for the shared serotypes substantially increased postvaccination at comparable levels between recipients of PCV-15 and PCV-7. Substantial increases in antibody (IgG and OPA) responses to 8 serotypes unique to PCV-15 were observed in PCV-15 recipients. Slight increases to 2 serotypes unique to PCV-15, serotypes 6A and 19A, were also noted in PCV-7 recipients. Conclusion PCV-15 displays an acceptable safety profile and induces IgG and OPA responses to all serotypes included in the vaccine. [ABSTRACT FROM AUTHOR]

The medial prefrontal cortex (mPFC) is known to be associated with food representation and monitoring of eating behaviour, but the neural mechanisms underlying attitudes towards food are still unclear. Transcranial magnetic stimulation (TMS) was used in combination with the implicit association test (IAT) to investigate the causal role of mPFC in controlling implicit food evaluation in healthy volunteers. Participants performed an IAT on tasty and tasteless food to test TMS interaction with food evaluation. Moreover, IATs assessing self-related concepts and attitude towards flowers and insects were carried out to control whether TMS could also affect self-representation or, more in general, the cognitive mechanisms required by the IAT. TMS was applied over mPFC; the left parietal cortex (lPA) was also stimulated as control site. Results revealed that mPFC-TMS selectively affected IAT on food, increasing implicit preference for tasty than tasteless food, only in a subgroup of participants who did not show extreme explicit evaluation for tasty and tasteless food. This demonstrates that mPFC has a critical causal role in monitoring food preference and highlights the relevance of considering individual differences in studying food representation and neural mechanisms associated with eating behaviour. [ABSTRACT FROM AUTHOR]

Background and Objectives An experimental design was used to test whether self-reported, psychophysiological and symptomatic stress-responses increase as a function of the underlying vulnerability to psychosis as proposed by vulnerability-stress-models. Methods Stress-responses of participants with psychotic disorders ( PSY , n = 35) were compared to those of participants with attenuated positive symptoms ( AS , n = 29), first-degree relatives of persons with psychotic disorders ( REL , n = 26), healthy controls ( HC , n = 28) and controls with depression ( DEP , n = 30). Using a repeated measures design, participants were assigned to a noise stressor, a social stressor and a no stress condition in random order. Stress-responses were assessed via self-report, salivary cortisol levels, heart rate and skin conductance levels. State-paranoia and depression were assessed with clinical scales. Results PSY reported to be significantly more stressed than HC , AS and REL across all conditions which went along with increased heart rate and decreased overall cortisol release. In contrast, AS showed elevated levels of cortisol. PSY showed a stronger response of self-reported stress to the noise condition compared to the no stress condition than HC , but no stronger response than the other samples. Furthermore, the stressors did not trigger stronger psychophysiological responses or symptom-increases in PSY . Limitations The social stressor was brief and not individualized and did not have an effect on cortisol. Conclusions The findings support the notion that subjective stress-responsiveness increases with vulnerability, but not the assumption that symptoms arise directly as a function of stress and vulnerability. Also, the generally high levels of arousal seem to be more relevant to psychosis than the responsiveness to specific stressors. [ABSTRACT FROM AUTHOR]

Background/Objectives:The superiority of cholecalciferol (D3) over ergocalciferol (D2) in sustaining serum 25-hydroxy vitamin D (25OHD) levels is controversial. To compare D2 with D3 we performed a single-blind, placebo-controlled randomized trial spanning 11 weeks.Subjects/Methods:Healthy volunteers (n=33, aged 33.4±6 years) were divided into three groups (n=11, each): D2, D3 and placebo. Treatment started with a loading dose (100 000 IU) followed by 4800 IU/day (d) between d7 and d20 and follow-up until d77. Serum samples were obtained at baseline and at days 3, 7, 14, 21, 35, 49, 63 and 77.Results:Baseline 25OHD values in the D2 group were lower than those in the D3 and placebo groups (P<0.01). Placebo 25OHD levels never changed. As after the loading dose both D2 and D3 groups had reached similar 25OHD levels, we tested equivalence of the area under the concentration × time curve (AUC) between d7 and d77. The AUC was 28.6% higher for D3 compared with D2, and both were higher with respect to placebo. At d77, D2 25OHD levels were higher than those at baseline, but similar to placebo; both were lower than D3 (P<0.04). According to raw data, the elimination half-life of 25OHD was 84 and 111 days under D2 and D3 supplementation, respectively; after subtracting the placebo values, the corresponding figures were 33 and 82 days.Conclusions:D2 and D3 were equally effective in elevating 25OHD levels after a loading dose. In the long term, D3 seems more appropriate for sustaining 25OHD, which could be relevant for classic and non-classic effects of vitamin D. [ABSTRACT FROM AUTHOR]

Background The 2010-2014 HIV/AIDS French program recommends using HIV rapid diagnostic tests in family practice. Our aim was to assess the acceptability and feasibility of the RDT in family practice in France. Methods The first part of this study was to determine the opinions of family practitioners (FPs) concerning the news guidelines for screening and the possible use of rapid HIV tests in their practice. The second part was a feasibility study of the actual use of rapid HIV tests given to FPs during six months. The third part was a qualitative analysis of experience feedback to determine the impediments to using rapid HIV tests. Results Seventy-seven percent of the 352 FPs interviewed were favorable to rapid HIV tests use. The three main impediments were: misinterpretation of test result, complexity of quality control, and lack of training: 23 of the 112 FPs having volunteered to evaluate the rapid HIV tests followed the required training session. Sixty-nine tests were handed out, and three rapid HIV tests were used; the qualitative study involved 12 FPs. The participants all agreed on the difficult use of rapid HIV tests in daily practice. The main reasons were: too few opportunities or requests for use, complex handling, difficulties in proposing the test, fear of having to announce seropositivity, significantly longer consultation. Conclusion Although FPs are generally favorable to rapid HIV tests use in daily practice, the feasibility and contribution of rapid HIV tests are limited in family practice. [ABSTRACT FROM AUTHOR]

The purpose of this study was to investigate the effect of changes in the seasonal thermal environment and illuminance on sleep in older men by using actigraphy. Eight healthy male volunteers with a mean age of 64 ± 1 years served as subjects. The measurements were obtained in 4 consecutive seasons: spring, summer, autumn, and winter. The activity level and illuminance were monitored using a wrist actigraph system with illuminance meter for 5 consecutive days. Sleep parameters were determined using an actigraph-based, sleep-wake identification algorithm. The temperature and humidity in the bedroom of the subjects' homes were measured continuously for 5 days. During the actigraphic measurement, skin temperature and the temperature and humidity of the microclimate were measured continuously for 2 nights. Bedroom nocturnal Ta and humidity was significantly higher in the summer than in the other seasons. Sleep efficiency was worst in the summer due to the increased number and duration of nocturnal awakenings. However, a significant difference was not found in the subjective evaluation of sleep among the 4 seasons. The correlations between the sleep parameters and environmental factors such as temperature, humidity, and illuminance levels measured at the same time showed that increased lighting level before the sleep prolongs the bedtime and wake time after sleep onset, and became wake-up time earlier. Increased ta, humidity, and lighting level during the sleep period mount up the wake time after sleep onset and impaired the sleep efficiency index. [ABSTRACT FROM AUTHOR]

Purpose: To compare the pharmacokinetics of intravenous (IV), oral immediate-release (IR) and oral modified-release (MR) formulations of mavoglurant in healthy subjects, and to assess the food effect on the MR formulation's input characteristics. Methods: Plasma concentration-time data from two clinical studies in healthy volunteers were pooled and analysed using NONMEM®. Drug entry into the systemic circulation was modelled using a sum of inverse Gaussian (IG) functions as an input rate function, which was estimated specifically for each formulation and food state. Results: Mavoglurant pharmacokinetics was best described by a two-compartment model with a sum of either two or three IG functions as input function. The mean absolute bioavailability from the MR formulation (0.387) was less than from the IR formulation (0.436). The MR formulation pharmacokinetics were significantly impacted by food: bioavailability was higher (0.508) and the input process was shorter (complete in approximately 36 versus 12 h for the fasted and fed states, respectively). Conclusions: Modelling and simulation of mavoglurant pharmacokinetics indicate that the MR formulation might provide a slightly lower steady-state concentration range with lower peaks (possibly better drug tolerance) than the IR formulation, and that the MR formulation's input properties strongly depend on the food conditions at drug administration. [ABSTRACT FROM AUTHOR]

Purpose To investigate suggestion-induced placebo effects in inflammatory skin reactions. Methods A healthy sample of volunteers (N = 48) attended two laboratory sessions. In each, a local short term inflammatory skin reaction was induced with histamine. Participants were told that one session was a control session and the other was a treatment session in which an antihistamine cream would be applied to the arm to reduce the size of the weal and the experience of itch. Inert aqueous cream was applied in both sessions. Participants were randomly allocated to undergo either the control or the treatment session first. Results The placebo manipulation successfully reduced self-reported itch from the control to the placebo treatment session, but no placebo effect was demonstrated in weal size. Order effects were observed such that only those who underwent control procedures first had a smaller weal in the placebo treatment session as compared to the control session. The same order effect was seen for reported itch at one minute post histamine administration, but this disappeared at the three and five minute measures. Conclusion Findings suggest that explicit verbal suggestion can reduce the experience of itch. In addition to conscious awareness, a concrete representation of the suggested changes gained from prior experience to the stimulus may be an important component of placebo effects on inflammatory skin reactions. [ABSTRACT FROM AUTHOR]

There is great interest about the therapeutic potentialities of transcutaneous vagus nerve stimulation (tVNS) applied to neuropsychiatric disorders. However, the mechanisms of action of tVNS and its impact on cortical excitability are unclear. To this regard, transcranial magnetic stimulation (TMS) can be useful because it is able of evaluating non-invasively excitatory and inhibitory circuitry of the human cortex. Aim of the present study is to investigate the effects of tVNS on cerebral cortex excitability in healthy volunteers by means of TMS. Ten healthy subjects participated in this randomized placebo-controlled double-blind study. Real tVNS was administered at left external acoustic meatus, while sham stimulation was performed at left ear lobe, both of them for 60 min. We evaluated motor thresholds, motor evoked potential amplitude, recruitment curves, and short-interval intracortical inhibition (SICI) in right and left motor cortex. Such parameters were evaluated before and 60 min after the exposure to tVNS, for both the real and the sham stimulation. Cardiovascular parameters were monitored during the stimulation. A generalized linear model for repeated measures was implemented to assess the effect of time and stimulation type on cardiovascular and neurophysiological variables. SICI, a double-pulse TMS paradigm informative of GABA-A activity, was significantly increased in right motor cortex after real tVNS. Other neurophysiological parameters, as well as cardiovascular variables, remained unchanged. Our findings confirm that tVNS is a safe and effective way to stimulate vagus nerve and provide innovative data about the possible mechanisms of action that supports the potential therapeutic application of this technique. [ABSTRACT FROM AUTHOR]

Introduction Frontal lobe oxygenation (ScO2) is assessed by spatially resolved near-infrared spectroscopy ( SR- NIRS) although it seems influenced by extra-cerebral oxygenation. We aimed to quantify the impact of extra-cerebral oxygenation on two SR- NIRS derived ScO2. Methods Multiple regression analysis estimated the influence of extra-cerebral oxygenation as exemplified by skin oxygenation (SskinO2) on ScO2 in 21 healthy subjects exposed to whole-body exercise in hypoxia (FiO2 = 12%; n = 10) and normoxia ( n = 12), whole-body heating, hyperventilation ( n = 21), administration of norepinephrine with and without petCO2-correction ( n = 15), phenylephrine and head-up tilt ( n = 7). ScO2 was assessed simultaneously by NIRO-200 NX (SniroO2) and INVOS-4100 (SinvosO2). Arterial (SaO2) and jugular bulb oxygen saturations (SjO2) were obtained. Results The regression analysis indicated that SinvosO2 reflects 46% arterial, 14% jugular, 35% skin and 4% oxygenation of tissues not interrogated. SinvosO2 follows a calculated estimate of cerebral capillary oxygenation ( r = 0·67; P<0·0001). In contrast, the NIRO-200 NX-determined ScO2 did not correlate with the estimate of cerebral oxygenation ( r = 0·026; P = 0·71). Conclusion For all interventions, 35% of the INVOS-4100 signal reflected extra-cerebral oxygenation while, on the other hand, NIRO-200 NX did not follow changes in a calculated estimate of cerebral capillary oxygenation. Thus, the NIRO-200 NX and INVOS-4100 do not provide for unbiased evaluation of the cerebral signal. [ABSTRACT FROM AUTHOR]

Background: It is assumed that different pain phenotypes are based on varying molecular pathomechanisms. Distinct ion channels seem to be associated with the perception of cold pain, in particular TRPM8 and TRPA1 have been highlighted previously. The present study analyzed the distribution of cold pain thresholds with focus at describing the multimodality based on the hypothesis that it reflects a contribution of distinct ion channels. Methods: Cold pain thresholds (CPT) were available from 329 healthy volunteers (aged 18 – 37 years; 159 men) enrolled in previous studies. The distribution of the pooled and log-transformed threshold data was described using a kernel density estimation (Pareto Density Estimation (PDE)) and subsequently, the log data was modeled as a mixture of Gaussian distributions using the expectation maximization (EM) algorithm to optimize the fit. Results: CPTs were clearly multi-modally distributed. Fitting a Gaussian Mixture Model (GMM) to the log-transformed threshold data revealed that the best fit is obtained when applying a three-model distribution pattern. The modes of the identified three Gaussian distributions, retransformed from the log domain to the mean stimulation temperatures at which the subjects had indicated pain thresholds, were obtained at 23.7 °C, 13.2 °C and 1.5 °C for Gaussian #1, #2 and #3, respectively. Conclusions: The localization of the first and second Gaussians was interpreted as reflecting the contribution of two different cold sensors. From the calculated localization of the modes of the first two Gaussians, the hypothesis of an involvement of TRPM8, sensing temperatures from 25 – 24 °C, and TRPA1, sensing cold from 17 °C can be derived. In that case, subjects belonging to either Gaussian would possess a dominance of the one or the other receptor at the skin area where the cold stimuli had been applied. The findings therefore support a suitability of complex analytical approaches to detect mechanistically determined patterns from pain phenotype data. [ABSTRACT FROM AUTHOR]

The capability of quickly (as soon as possible) producing fast uncorrected and accurate isometric force impulses was examined to assess the motor efficiency of patients with moderate to severe traumatic brain injury (TBI) and good motor recovery at a clinical evaluation. Twenty male right-handed patients with moderate to severe TBI and 24 age-matched healthy male right-handed controls participated in the study. The experimental task required subjects to aim brief and uncorrected isometric force impulses to targets visually presented along with subjects' force displays. Both TBI patients and controls were able to produce force impulses whose mean peak amplitudes varied proportionally to the target load with no detectable group difference. Patients with TBI, however, were slower than controls in initiating their responses (reaction times [RTs] were longer by 125 msec) and were also slower during the execution of their motor responses, reaching the peak forces requested 23 msec later than controls (time to peak force: 35% delay). Further, their mean dF/dt (35 kg/sec) was slower than that of controls (53 kg/sec), again indicating a 34% impairment with respect to controls. Overall, patients with TBI showed accurate but delayed and slower isometric force impulses. Thus, an evaluation taking into account also response time features is more effective in picking up motor impairments than the standard clinical scales focusing on accuracy of movement only. [ABSTRACT FROM AUTHOR]

Novel pharmacological treatments targeting alpha 7 nicotinic acetylcholine receptor (α7 nAChR) hypofunction in schizophrenia have shown mixed success in ameliorating cognitive impairments associated with this disorder. Choline, a selective agonist at α7 receptors is increased with oral administration of cytidine 5′-diphosphocholine (CDP-choline), the cognitive effects of which were assessed in healthy volunteers. Using the CogState test battery, behavioral performance in schizophrenia-relevant cognitive domains was assessed in 24 male participants following a single low (500 mg) and moderate (1000 mg) dose of CDP-choline. Relative to placebo, CDP-choline improved processing speed, working memory, verbal learning, verbal memory, and executive function in low baseline performers, while exerting no effects in medium baseline performers, and diminishing cognition in high baseline performers. Dose effects varied with cognitive domain but were evident with both the 500 mg and 1000 mg doses. These preliminary findings of cognitive enhancement in relatively impaired performers are consistent with the α7 receptor mechanism and support further trials with CDP-choline as a potential pro-cognitive strategy for cognitive impairment in schizophrenia. [ABSTRACT FROM AUTHOR]

Background Symptoms of irritable bowel syndrome ( IBS) are frequently reported to be exacerbated by stress. Animal studies suggest that corticotrophin releasing hormone ( CRH) mediates the effect of stress on the bowel. We have shown that stressed IBS patients with diarrhea have constricted small bowels. We hypothesized that we could mimic this effect by applying experimental stress in the form of either hand immersion in ice water or CRH injection in healthy volunteers ( HV). Methods The postprandial effect of the cold pressor test (repeated hand immersion in ice cold water) and injection of CRH, were assessed vs control in two groups of 18 HVs. Key Results CRH produced a significant rise from baseline salivary cortisol levels ( p = 0.004) not seen with the cold pressor test. Small bowel water content ( SBWC) fell postprandially on all four treatments. SBWC was significantly reduced by both stressors but CRH caused a greater effect ( anova, p < 0.003 vs p = 0.02). Ascending colon ( AC) volume was greater after CRH injection compared with saline ( p = 0.002) but no differences were seen with the cold pressor test vs warm water. Postprandial increase in colon volume was also reduced by CRH which also increased the sensations of distension and bloating. Conclusions & Inferences Two experimental stressors were shown to constrict the small bowel, mimicking the effect previously seen in IBS-D patients. CRH increased the volume of the AC. We speculate that stress accelerates transfer of water from the small bowel to the AC. [ABSTRACT FROM AUTHOR]

Hypocitraturia, hypokaliuria, and increased oxidative stress are common lithogenic risk factors found in nephrolithiasis patients, especially in Thailand. We previously developed lime powder regimen (LPR), and demonstrated that LPR delivered citraturic, alkalinizing, and antioxidative effects in kidney stone patients. In this study, in vitro anti-lithogenic activity, in vivo acute toxicity, and crossover-designed phase 1 trial (in 13 healthy volunteers) of LPR were investigated. LPR inhibited the growth of calcium oxalate monohydrate (COM) crystals in dose-dependent manner, and inhibited the intracellular production of reactive oxygen species (ROS) in COM-treated HK-2 cells. LPR did not significantly alter viability of HK-2 cells. No acute toxicity was detected in mice orally fed with LPR (10 g/kg). No adverse effect and complaint of LPR ingestion (5 g/dose) were observed in the tested volunteers. Plasma citrate was elevated at 30 min after LPR load, which was higher than the water load control. Plasma potassium was significantly elevated at 30 min after LPR load and remained high for 2 h, and at 2 h, it was significantly higher than the water load. Urinary citrate was significantly increased at 1 h after LPR load and remained high for 2 h, and at 2 h, it was significantly higher than the water load. Urinary potassium was significantly increased at 1 h after LPR load and remained high for 3 h, and its levels at 1, 2, and 3 h were significantly higher than the water load. Urinary total antioxidant status was significantly increased at 2 h after LPR load. In conclusion, LPR had an inhibitory effect on COM growth and exerted as antioxidant to attenuate ROS production in the COM-treated renal tubular cells. LPR provided citraturic, kaliuric, and antioxidative responses in healthy individuals without any adverse events. This suggests that LPR is well tolerated and safe for daily consumption. [ABSTRACT FROM AUTHOR]

Aim:To investigate the QT/QTc effects of orally administered moxifloxacin in healthy Chinese volunteers.Methods:This was a single-blinded, randomized, single-dose, placebo-controlled, two-period cross-over study. A total of 24 healthy Chinese volunteers were enrolled, randomly assigned to two groups: one group received moxifloxacin (400 mg, po) followed by placebo with a 7-d interval, another group received placebo followed by moxifloxacin with a 7-d interval. On the days of dosing, 12-lead 24 h Holter ECGs were recorded and evaluated by an ECG laboratory blind to the treatments. Blood samples were collected to determine plasma concentrations of moxifloxacin.Results:The orally administered moxifloxacin significantly prolonged the mean QTc at all time points except 0.5 h post-dose. The largest time-matched difference in the QTcI was 8.35 ms (90% CI: 5.43, 11.27) at 4 h post-dose. The peak effect on QTcF was 9.35 ms (90% CI: 6.36, 12.34) at 3 h post-dose. A pharmacokinetic-QTc model suggested a 2.084 ms increase in the QTc interval for every 1000 ng/mL increase in plasma concentration of moxifloxacin. In addition, the orally administered moxifloxacin was well tolerated by the subjects.Conclusion:Orally administered moxifloxacin significantly prolongs QTc, which supports its use as a positive control in ICH-E14 TQT studies in Chinese volunteers. [ABSTRACT FROM AUTHOR]

About 700,000 Accredited Social Health Activists (ASHA) have been deployed as community health volunteers throughout India over the last few years. The objective of our study was to assess adherence to selection criteria in the recruitment of ASHA workers and to assess their performance against their job descriptions in Karnataka state, India. A cross-sectional survey, using a combination of quantitative and qualitative methods, was undertaken in 2012. Three districts, 12 taluks (subdistricts), and 300 villages were selected through a sequential sampling scheme. For the quantitative survey, 300 ASHAs and 1,800 mothers were interviewed using sets of structured questionnaire. For the qualitative study, programme officers were interviewed via in-depth interviews and focus group discussions. Mean±SD age of ASHAs was 30.3±5.0 years, and about 90% (261/294) were currently married, with eight years of schooling. ASHAs were predominantly (>80%) involved in certain tasks: home-visits, antenatal counselling, delivery escort services, breastfeeding advice, and immunization advice. Performance was moderate (40-60%) for: drug provision for tuberculosis, caring of children with diarrhoea or pneumonia, and organizing village meetings for health action. Performance was low (<25%) for advice on: contraceptive-use, obstetric danger sign assessment, and neonatal care. This was self-reported by ASHAs and corroborated by mothers. In conclusion, ASHA workers were largely recruited as per preset selection criteria with regard to age, education, family status, income, and residence. The ASHA workers were found to be functional in some areas with scope for improvement in others. The role of an ASHA worker was perceived to be more of a link-worker/facilitator rather than a community health worker or a social activist. [ABSTRACT FROM AUTHOR]

Habituation is considered one of the most basic mechanisms of learning. Habituation deficit to several sensory stimulations has been defined as a trait of migraine brain and also observed in other disorders. On the other hand, analytic information processing style is characterized by the habit of continually evaluating stimuli and it has been associated with migraine. We investigated a possible correlation between lack of habituation of evoked visual potentials and analytic cognitive style in healthy subjects. According to Sternberg-Wagner self-assessment inventory, 15 healthy volunteers (HV) with high analytic score and 15 HV with high global score were recruited. Both groups underwent visual evoked potentials recordings after psychological evaluation. We observed significant lack of habituation in analytical individuals compared to global group. In conclusion, a reduced habituation of visual evoked potentials has been observed in analytic subjects. Our results suggest that further research should be undertaken regarding the relationship between analytic cognitive style and lack of habituation in both physiological and pathophysiological conditions. [ABSTRACT FROM AUTHOR]