Ultrafast memory loss and energy redistribution in the hydrogen bond network of liquid H2O.
Many of the unusual properties of liquid water are attributed to its unique structure, comprised of a random and fluctuating three-dimensional network of hydrogen bonds that link the highly polar water molecules. One of the most direct probes of the dynamics of this network is the infrared spectrum of the OH stretching vibration, which reflects the distribution of hydrogen-bonded structures and the intermolecular forces controlling the structural dynamics of the liquid. Indeed, water dynamics has been studied in detail, most recently using multi-dimensional nonlinear infrared spectroscopy for acquiring structural and dynamical information on femtosecond timescales. But owing to technical difficulties, only OH stretching vibrations in D2O or OD vibrations in H2O could be monitored. Here we show that using a specially designed, ultrathin sample cell allows us to observe OH stretching vibrations in H2O. Under these fully resonant conditions, we observe hydrogen bond network dynamics more than one order of magnitude faster than seen in earlier studies that include an extremely fast sweep in the OH frequencies on a 50-fs timescale and an equally fast disappearance of the initial inhomogeneous distribution of sites. Our results highlight the efficiency of energy redistribution within the hydrogen-bonded network, and that liquid water essentially loses the memory of persistent correlations in its structure within 50 fs.


Selenium bioavailability modulates the sensitivity of thyroid cells to iodide excess.
Iodide is an essential micronutrient for the synthesis of thyroid hormones and its imbalance is involved in the origin of different thyroid pathological processes. Selenium (Se) is another essential trace element that contributes to thyroid preservation through the control of the redox homeostasis. Different studies have demonstrated that sodium-iodide-symporter (NIS) is downregulated in the presence of iodide excess and Se supplementation reverses this effect. We also demonstrated that NOX4-derived ROS are involved in NIS repression induced by iodide excess. The aim of this study was to investigate how Se bioavailability is decisive in the sensitivity to iodide excess on a differentiated rat thyroid cell line (FRTL-5). We demonstrated that siRNA-mediated silencing of Nox4 suppressed AKT phosphorylation induced by iodide excess. Iodide increases TGF-β1 mRNA expression, AKT phosphorylation, ROS levels and decreases GPX1 and TXRND1 mRNAs expression while Se reversed these effects. Furthermore, iodide induced Nrf2 transcriptional activity only in Se-supplemented cultures, suggesting that Se positively influences Nrf2 activation and selenoenzyme response in FRTL-5. Se, also inhibited NF-κB phosphorylation induced by iodide excess. In addition, we found that iodide excess decreased total phosphatase activity and PTP1B and PTEN mRNA expression. Se supply restored only PTEN mRNA expression. Finally, we studied the 2-α-iodohexadecanal (2-IHD) effects since it has been proposed as intermediary of iodide action on thyroid autoregulation. 2-IHD stimulated PI3K/AKT activity and reduced NIS expression by a ROS-independent mechanism. Also, we found that 2-IHD increased TGF-β1 mRNA and TGF-β inhibitor (SB431542) reverses the 2-IHD inhibitory effect on NIS mRNA expression, suggesting that TGF-β1 signaling pathway could be involved. Although Se reduced 2-IHD-induced TGFB1 levels, it could not reverse its inhibitory effect on NIS expression. Our study suggests that Se bioavailability may improve the expression of antioxidant genes through the activation of Nrf2, interfere in PI3K/AKT signaling and NIS expression by redox modulation.


Early Bactericidal Activity of AZD5847 in Patients with Pulmonary Tuberculosis.
AZD5847 is an oxazolidinone antibiotic with in vitro activity against Mycobacterium tuberculosis The objective of this study was to evaluate the antimycobacterial activity, safety, and pharmacokinetics of AZD5847 in patients with pulmonary tuberculosis. Groups of 15 treatment-naive, sputum smear-positive adults with pulmonary tuberculosis were randomly assigned to receive AZD5847 at one of four doses (500 mg once daily, 500 mg twice daily, 1,200 mg once daily, and 800 mg twice daily) or daily standard chemotherapy. The primary efficacy endpoint was the mean daily rate of change in the log10 number of CFU of M. tuberculosis per milliliter of sputum, expressed as the change in log10 number of CFU per milliliter of sputum per day. The mean 14-day activity of the combination of isoniazid, rifampin, ethambutol, and pyrazinamide (-0.163 log10 CFU/ml sputum/day; 95% confidence interval [CI], -0.193, -0.133 log10 CFU/ml sputum/day) was consistent with that found in previous studies. AZD5847 at 500 mg twice daily significantly decreased the number of CFU on solid medium (-0.039; 95% CI, -0.069, -0.009; P = 0.0048). No bactericidal activity was detected at doses of AZD5847 of 500 mg once daily (mean early bactericidal activity [EBA], 0.02 [95% CI, -0.01, 0.05]), 1,200 mg once daily (mean EBA, 0.02 [95% CI, -0.01, 0.05]), and 800 mg twice daily (mean EBA, 0.02 [95% CI, -0.01, 0.05]). AZD5847 at doses of both 500 mg and 800 mg twice daily also showed an increase in the time to a positive culture in MGIT liquid culture medium. Two serious adverse events (grade 4 thrombocytopenia and grade 4 hyperbilirubinemia) occurred in patients receiving AZD5847 at higher doses. AZD5847 dosed twice daily kills tubercle bacilli in the sputum of patients with pulmonary tuberculosis and has modest early bactericidal activity. (This study has been registered at ClinicalTrials.gov under registration no. NCT01516203.).


Spectral-Coding-Based Compressive Single-Pixel NIR Spectroscopy in the Sub-Millisecond Regime.
In this contribution, we present a high-speed, multiplex, grating spectrometer based on a spectral coding approach that is founded on principles of compressive sensing. The spectrometer employs a single-pixel InGaAs detector to measure the signals encoded by an amplitude spatial light modulator (digital micromirror device, DMD). This approach leads to a speed advantage and multiplex sensitivity advantage atypical for standard dispersive systems. Exploiting the 18.2 kHz pattern rate of the DMD, we demonstrated 4.2 ms acquisition times for full spectra with a bandwidth of 450 nm (5250-4300 cm-1; 1.9-2.33 µm). Due to the programmability of the DMD, spectral regions of interest can be chosen freely, thus reducing acquisition times further, down to the sub-millisecond regime. The adjustable resolving power of the system accessed by means of computer simulations is discussed, quantified for different measurement modes, and verified by comparison with a state-of-the-art Fourier-transform infrared spectrometer. We show measurements of characteristic polymer absorption bands in different operation regimes of the spectrometer. The theoretical multiplex advantage of 8 was experimentally verified by comparison of the noise behavior of the spectral coding approach and a standard line-scan approach.


Time experience during social distancing: A longitudinal study during the first months of COVID-19 pandemic in Brazil.
Social distancing in response to the COVID-19 pandemic brought several modifications in our daily lives. With these changes, some people have reported alterations in their feelings of how fast time was passing. In this study, we assessed whether and how social distancing and the evolution of the COVID-19 pandemic influenced participants' time awareness and production of time intervals. Participants (n = 3855) filled in the first questionnaire approximately 60 days after the start of social distancing in Brazil and weekly questionnaires for 15 weeks during social distancing. Our results indicate that time was perceived as expanded at the beginning, but this feeling decreased across the weeks. Time awareness was strongly associated with psychological factors such as loneliness, stress, and positive emotions, but not with time production. This relation was shown between participants and within their longitudinal reports. Together, our findings show how emotions are a crucial aspect of how time is felt.


Binding of phosphatidic acid by NsD7 mediates the formation of helical defensin-lipid oligomeric assemblies and membrane permeabilization.
Defensins are cationic antimicrobial peptides that serve as important components of host innate immune defenses, often by targeting cell membranes of pathogens. Oligomerization of defensins has been linked to their antimicrobial activity; however, the molecular basis underpinning this process remains largely unclear. Here we show that the plant defensin NsD7 targets the phospholipid phosphatidic acid (PA) to form oligomeric complexes that permeabilize PA-containing membranes. The crystal structure of the NsD7-PA complex reveals a striking double helix of two right-handed coiled oligomeric defensin fibrils, the assembly of which is dependent upon the interaction with PA at the interface between NsD7 dimers. Using site-directed mutagenesis, we demonstrate that key residues in this PA-binding site are required for PA-mediated NsD7 oligomerization and coil formation, as well as permeabilization of PA-containing liposomes. These data suggest that multiple lipids can be targeted to induce oligomerization of defensins during membrane permeabilization and demonstrate the existence of a "phospholipid code" that identifies target membranes for defensin-mediated attack as part of a first line of defense across multiple species.


Serological Survey of Lyssaviruses in Polish Bats in the Frame of Passive Rabies Surveillance Using an Enzyme-Linked Immunosorbent Assay.
Background: Bats are known to host a number of nonpathogenic viruses, as well as highly pathogenic viruses causing fatal diseases like rabies. Serological surveys as part of active and passive bat rabies surveillance mainly use seroneutralization assays, demonstrating the presence of lyssavirus-specific antibodies in a variety of European bats, particularly against European bat lyssaviruses type 1 (EBLV-1). Here, we present the first serological survey in European bats of this kind during which European bats from Poland collected in the frame of passive rabies surveillance between 2012 and 2018, as well as Serotine bats (Eptesicus serotinus) and North American Big Brown bats (Eptesicus fuscus) from previous experimental studies, were tested using a commercial ELISA kit for the detection of anti-lyssavirus antibodies. Results: Lyssavirus-specific antibodies were detected in 35 (30.4%) out of 115 Polish bats of both sexes, representing nine out of 13 identified bat species endemic mainly to Central Southern Europe and Western Asia, i.e., Eptesicus serotinus, Nyctalus noctula, Myotis daubentonii, Plecotus auritus, Vespertillo murinus,Pipistrellus pipistrellus, Pipistrellus pipilstrellus/Pipistrellus pygmaeus, Myotis brandtii, and Barbastella barbastellus. Seroprevalence was highest in bat species of Nyctalus noctula, Eptesicus serotinus, Plecotus auritus, and Myotis daubentonii. More than 60% of the ELISA seropositive bats originated from the voivodeships of Silesia, Lower-Silesian, Warmian-Mazurian, and Mazowian. Rabies-specific antibodies were also found in Eptesicus fuscus bats from North America. Conclusions: The study demonstrates the principal application of the BioPro Rabies ELISA Ab Kit for the detection of anti-lyssavirus specific antibodies in body fluids and serum samples of bats. However, results may only be reliable for North American bats, whereas interpretation of results for European bats per se is difficult because proper validation of the test is hampered by the protected status of these species.


Prevalence and causes of amblyopia in an adult population.
The study aimed to determine the prevalence, causes, and associations with amblyopia in a defined older population. In a population-based study, 3654 persons 49 years of age or older from an area west of Sydney, Australia, underwent a detailed eye examination and history, including objective and subjective refraction, cover testing, and retinal and lens photography. Amblyopia was diagnosed in eyes with reduced best-corrected visual acuity in the absence of any other cause. Amblyopia was diagnosed in 118 participants, or 3.2% of the population using a visual acuity criterion of 20/30 or less and 2.9% using a visual acuity criterion of 20/40 or less. Using a two-line visual acuity difference between the eyes, the amblyopia prevalence was 2.6% and 2.5%, respectively, for the above criteria. The underlying amblyogenic causes assessed were anisometropia (50%), strabismus (19%), mixed strabismus and anisometropia (27%), and visual deprivation (4%). The visual acuity of the amblyopic eye was 20/200 or worse (19%), 20/80 to 20/160 (19%), 20/40 to 20/63 (52%), and 20/30 (11%). No statistically significant associations were found between amblyopia and gender or eye affected. The most frequent pattern of strabismus was esotropia, whereas hypermetropia was the most frequent refractive error in amblyopic eyes. The mean age at diagnosis was earlier for strabismic and mixed amblyopia (7.4 years) than for anisometropic amblyopia (12.7 years). This study has provided prevalence and cases of amblyopia in an older population. Amblyopia is a frequent cause of lifelong unilateral visual impairment.


Performance Evaluation of a Restored Dimension TACR Assay: An Automated Platform for Measuring the Whole Blood Tacrolimus Concentration.
Monitoring tacrolimus levels is essential for successful organ transplantation. The Dimension TACR (Siemens Healthcare Diagnostics, USA) is an automated platform used to measure tacrolimus concentrations. Recently, the manufacturer started shipping an assay reagent with improved functions. We evaluated the analytical performance of the improved Dimension TACR assay. The precision was evaluated according to the CLSI EP5-A2 guideline. Two levels of control materials were analyzed twice a day in duplicate for 20 days in the precision study. The linearity was evaluated using five levels of mixed calibrators based on the CLSI EP6-A guideline. A comparison study was conducted based on the CLSI EP9-A3 guideline using liquid chromatography-tandem mass spectrometry (LC-MS/MS). The limit of blank (LoB), limit of detection (LoD), and limit of quantitation (LoQ) were evaluated using CLSI EP17-A2. In the precision analyses, the within-run, between-run, and total coefficients of variation were 5.8%, 4.6%, and 8.1% for the low level control and 4.2%, 2.8%, and 5.9% for the high level, respectively. A linear range of 1.18-8.32 ng/mL was observed. In the comparison study, the correlation coefficient, slope, and intercept were 0.9768, 1.118, and -0.251, respectively. The results of the Dimension TACR assay were slightly higher than those of LC-MS/MS (mean bias 0.64 ng/mL). The LoB, LoD, and LoQ were 0.063 ng/mL, 0.408 ng/mL, and 1.15 ng/mL, respectively. The Dimension TACR assay showed good precision and linearity. Although the results using the Dimension TACR assay were higher than those using mass spectrometry, the differences were acceptable clinically.


Enhanced sensitivity to and classification of volatile carboxylic acids using arrays of linear poly(ethylenimine)-carbon black composite vapor detectors.
Vapor detectors formed from composites of conductors and insulating organic polymers have been tailored to produce increased sensitivity toward specific classes of analyte vapors. Upon exposure to acetic acid at 1% of its vapor pressure, detectors consisting of linear poly(ethylenimine) (1-PEI)-carbon black composites showed an approximately 10(3) increase in signal/noise relative to the performance of typical insulating organic polymer-carbon black composite vapor detectors. Compositional diversity in an array of such vapor detectors was obtained by varying the degree of plasticization of the 1-PEI films. The resulting vapor detector array produced sensitive detection of, and robust discrimination between, various volatile organic acids and relatively little response from nonacidic organic vapors or from water vapor. Measurements of the mass uptake, thickness change, and electrical conductivity of such composites indicate that swelling of the polymer film, and thus its normalized resistance response, is beyond that expected by mass uptake alone upon exposure to acetic acid vapor. This additional thickness increase is attributed to charge-induced polymer swelling occurring from polymer-analyte interactions. Electrical percolation also plays a significant role in producing the large increase in normalized resistance response of these composites upon exposure to acetic acid vapor.


Quantification of the dose of inhaled flour: relation with nonspecific bronchial and immunological reactivities.
The aim of this study was to investigate the relationship between specific bronchial reactivity and respective nonspecific bronchial and immunological reactivities. Twenty-one patients underwent bronchial challenges with lactose and flour. The aerosol of particles was generated by a computer-controlled aerosolizer. Specific bronchial challenge results were expressed as the provocative dose of flour (PDf) that caused a 20% or 15% decrease in the forced expiratory volume in one second (FEV1). For each subject, the decrease in FEV1 observed during the challenge with flour was compared with the calculated lower limit of the 99.7% confidence interval for the lactose challenge. The subjects also underwent a nonspecific challenge with methacholine and a measurement of the specific immunoglobulin E against wheat. The inhalation of lactose did not significantly affect FEV1. Nine subjects had high reactivity to wheat flour with a PDf20 <400 microg. Five subjects had intermediate reactivity: FEV1 fell by <20% but by significantly more than that in the test with lactose. For 7 subjects, there was no significant change in FEVI for inhaled doses of flour over 1390 microg. The results for specific bronchial challenge were significantly correlated with those for the methacholine test (p<0.02). Positive skin tests and specific immunoglobulin E against wheat were observed more frequently in the high reactivity group. Specific bronchial challenge can be performed safely to establish precise dose-response curves. The provocative dose of flour causing a 20% decrease in forced expiratory volume in one second is useful for evaluating the degree of specific reactivity but is not suitable in cases of intermediate reactivity in which comparison with the lactose test is necessary. Specific reactivity is probably a function of immunological and nonspecific bronchial reactivities.


The influence of long-range interaction on the structure of a two-dimensional multi scale potential system.
We present the results of a computer simulation study of a finite temperature phase diagram of two-dimensional and quasi two-dimensional core-softened systems both taking into account long-range Coulomb-like forces and ignoring them. The system structure was determined from analysis of the behavior of radial distribution functions, order parameters and number of nearest neighbors. The system has been shown to have a large number of different phases. We have found that long-range forces substantially affected the structure and the melting point of the system at low and moderate densities, while at high densities the effect of long-range forces was negligible.


Use of a Multi-Sensor Monitoring Device in an Early Post-operative Mobilization Program.
The current study aimed to evaluate the validity and feasibility of using a multi-sensor device to monitor patient mobility in a large postoperative population. In this IRB-approved study, postoperative patient posture was recorded using a multi-sensor monitoring device (ViSi Mobile®) and compared with direct observations of patient physical activity. Retrospective cohort analysis of postoperative patient posture data from January to December 2019 was then performed. Patterns of postoperative mobilization were evaluated. Multi-sensor real-time posture monitoring with the ViSi Mobile® system consistently differentiate between rest and upright posture (sensitivity and specificity, both 100%). During observation of ambulatory events, ViSi Mobile® system correctly recorded a patient's position as upright at each validation time point in 72.7% (8 of 11) of walks. Clinical data from 562 postoperative patients were linked with posture monitoring data. Median duration of posture monitoring was 64 hours (IQR 52.5) and median number of posture positions recorded per patient was 15,370 (IQR 12,685). Median duration of upright position per day was 148.6 minutes (IQR 192.8). Duration in active upright position per day was not associated with risk of readmission (P > .05). Real-time posture data from a multi-sensor monitoring device (ViSi Mobile®) was shown to consistently differentiate rest and active upright position. This novel technology can provide useful insight into adherence and clinical benefit of early mobilization programs.


Modulation of eIF5A1 expression alters xylem abundance in Arabidopsis thaliana.
Eukaryotic translation initiation factor 5A (eIF5A) is thought to facilitate protein synthesis by participating in the nuclear export of specific mRNAs. In Arabidopsis, there are three isoforms of eIF5A. One of them, AteIF5A1, has been shown to be expressed in vascular tissue, specifically developing vessel members, using GUS as a reporter. In order to determine whether AteIF5A1 plays a role in xylem formation, its full-length cDNA was constitutively over-expressed in transgenic Arabidopsis plants. Microscopic analysis revealed that the cross-sectional area of the xylem in the main inflorescence stems of transgenic plants was 1.9-fold higher than those of corresponding inflorescence stems of wild-type plants. In wild-type stems, the primary xylem typically comprised six cell layers and was approximately 105 mum thick, but increased to 9-11 cell layers, 140-155 mum thick, in transgenic stems. Similarly, the secondary xylem increased from six cell layers, approximately 70 mum thick, in control stems to approximately 9 cell layers, 95-105 mum thick, in transgenic stems. Moreover, constitutive down-regulation of AteIF5A1 using antisense technology resulted in the major suppression of xylem formation compared with control plants, and the antisense transgenic plants were also stunted. These data collectively indicate that eIF5A1 plays a role in xylogenesis.


A quantum chemical explanation of the antioxidant activity of flavonoids.
Flavonoids are a group of naturally occurring antioxidants, which over the past years have gained tremendous interest because of their possible therapeutic applicability. The mechanism of their antioxidant activity has been extensively studied over several decades. However, there is still much confusion about the molecular mechanism of radical scavenging and the relationship between structure and activity. Therefore, we have calculated the heat of formation and the geometry of both the parent compound and the corresponding radical using the ab initio program GAMESS. We have compared their differences in energy in order to gain insight into the stability of the radical and the ease with which it is formed. We have also investigated the spin density of the radical, to determine the delocalization possibilities. These calculated data were compared with experimental data from ESR (hyperfine coupling constants) and electrochemical oxidation (Ep/2) and were found to be in good agreement. By comparing the geometries of several flavonoids, we were able to explain the structural dependency of the antioxidant action of these compounds. The extremely good antioxidant activity of the flavonols could be explained by the formation of an intramolecular hydrogen bond.


Development of Ligands for the Super Conserved Orphan G Protein-Coupled Receptor GPR27 with Improved Efficacy and Potency.
The orphan G protein-coupled receptor GPR27 appears to play a role in insulin production, secretion, lipid metabolism, neuronal plasticity, and l-lactate homeostasis. However, investigations on the function of GPR27 are impaired by the lack of potent and efficacious agonists. We describe herein the development of di- and trisubstituted benzamide derivatives 4a-e, 7a-z, and 7aa-ai, which display GPR27-specific activity in a β-arrestin 2 recruitment-based assay. Highlighted compounds are PT-91 (7p: pEC50 6.15; Emax 100%) and 7ab (pEC50 6.56; Emax 99%). A putative binding mode was revealed by the docking studies of 7p and 7ab with a GPR27 homology model. The novel active compounds exhibited no GPR27-mediated activation of G proteins, indicating that the receptor may possess an atypical profile. Compound 7p displays high metabolic stability and brain exposure in mice. Thus, 7p represents a novel tool to investigate the elusive pharmacology of GPR27 and assess its potential as a drug target.


Effectiveness of laparoscopic cadaveric dissection in enhancing resident comprehension of pelvic anatomy.
Anatomic instruction during preclinical years of medical school has been in decline recently. There is evidence that residents already lose a considerable portion of basic anatomic knowledge in the transition from student to clinician, and this deficit is even more dramatic in residents who start their training with a decreased understanding of anatomy. We questioned whether anatomy could be adequately retaught to new residents as surgical anatomy. In an effort to address this deficiency, we developed a program to teach pelvic anatomy in fresh cadavers using a laparoscopic approach. The purpose of this investigation is to determine if such a program is effective in enhancing residents' pelvic anatomy comprehension. An obstetrics and gynecology residency was divided into intervention (n = 15) and control (n = 13) groups. The intervention was a 4-hour laparoscopic dissection in a fresh cadaver. Outcomes measures included a multiple-choice test, practical exam, faculty evaluation, and satisfaction assessment. The faculty evaluation and satisfaction assessment used a visual analog scale. Univarate and nonparametric analysis were used when appropriate. Initial test scores (p = 0.32), faculty evaluations (p = 0.25), and satisfaction scores (p = 0.17) were similar. Both groups improved their anatomic knowledge based on test scores (p = 0.004) and faculty evaluations (p < 0.001), and final test scores were not significantly different (p = 0.19). Data measured on a 10-cm visual analog scale suggested higher faculty evaluations in the intervention group (14mm versus 10.3mm, (p = 0.23). Similarly there were higher scores on the cadaver test in the intervention group (65% versus 50%), (p = 0.13). The intervention group was significantly more satisfied with their anatomic training (16.1 mm versus-10.1 mm, p = 0.001). This study did not have sufficient power to demonstrate that a single laparoscopic cadaveric dissection improves cognitive measures of anatomic perception, but suggested that it improves spatial perception of anatomy and is perceived by residents to be a valuable educational approach.


Facilitating open-science with realistic fMRI simulation: validation and application.
With advances in methods for collecting and analyzing fMRI data, there is a concurrent need to understand how to reliably evaluate and optimally use these methods. Simulations of fMRI data can aid in both the evaluation of complex designs and the analysis of data. We present fmrisim, a new Python package for standardized, realistic simulation of fMRI data. This package is part of BrainIAK: a recently released open-source Python toolbox for advanced neuroimaging analyses. We describe how to use fmrisim to extract noise properties from real fMRI data and then create a synthetic dataset with matched noise properties and a user-specified signal. We validate the noise generated by fmrisim to show that it can approximate the noise properties of real data. We further show how fmrisim can help researchers find the optimal design in terms of power. The fmrisim package holds promise for improving the design of fMRI experiments, which may facilitate both the pre-registration of such experiments as well as the analysis of fMRI data.


Fitness differences between parapatric lake and stream stickleback revealed by a field transplant.
Molecular comparisons of populations diverging into ecologically different environments often reveal strong differentiation in localized genomic regions, with the remainder of the genome being weakly differentiated. This pattern of heterogeneous genomic divergence, however, is rarely connected to direct measurements of fitness differences among populations. We here do so by performing a field enclosure experiment in threespine stickleback fish residing in a lake and in three replicate adjoining streams, and displaying weak yet heterogeneous genomic divergence between these habitats. Tracking survival over 29 weeks, we consistently find that lake genotypes transplanted into the streams suffer greatly reduced viability relative to local stream genotypes and that the performance of F1 hybrid genotypes is intermediate. This observed selection against migrants and hybrids combines to a total reduction in gene flow from the lake into streams of around 80%. Overall, our study identifies a strong reproductive barrier between parapatric stickleback populations, and cautions against inferring weak fitness differences between populations exhibiting weak overall genomic differentiation.


Fatal Suicide and Modelling its Risk Factors in a Prevalent Area of Iran.
This paper aimed to study the epidemiology of suicide and causes related to fatal suicide in Ilam province, west of Iran. All data related to attempted suicide and fatal suicide during 2011-2012 were extracted from the suicide registry of authorized directorates in Ilam Province, Iran. Risk factors for fatal suicide were evaluated using logistic regression modeling and discrimination of model assessed using ROC curve. A total of 1537 registered cases were analyzed, among which 130 were recorded as fatal suicides (1227 attempted suicides). Overall, 805 (52.4%) cases were female, 9.2% had a history of suicide, 59.3% were married and 63.3% of cases were aged under 24 years. The most common suicide method was overdose of medications (75.5%). In multivariable analysis, male gender (OR: 0.50; CI 95% 0.25 to 0.99) and higher education (OR: 0.36; CI 95% 0.20 to 0.65) were protective factors and application of physical methods (OR: 11.61; 95% CI 5.40 to 24.95) was a risk factor for fatal suicide. Female gender, low education level and use of physical methods of suicide were revealed as risk factors of fatal suicide. We suggest population based case-control studies based on the suicide registry data for further assessing the risk factors of suicide in Ilam.


One-Pot Approach to Synthesize Tough and Cell Adhesive Double-Network Hydrogels Consisting of Fully Synthetic Materials of Self-Assembling Peptide and Poly(ethylene glycol).
Hydrogels with a double network (DN) structure are compelling biomaterials, holding potential for use as artificial extracellular matrices. Generally, the DN approach imparts hydrogels with high mechanical strength and cell-adhesive properties. However, achieving this often demands a complex multistep process involving potentially hazardous free-radical polymerization, which can result in toxicity. This limits their broad biological applications. In this work, we introduce a straightforward yet biocompatible method to fabricate tough and cell-adhesive DN hydrogels using entirely synthetic materials: the self-assembling peptide (RADA16) and poly(ethylene glycol) (PEG). An in situ mixing of these components leads to the sequential formation of DN hydrogels─first through the self-assembly of the RADA16 peptide and then via chemical cross-linking between PEG molecules. Hydrogels produced this way exhibited up to a 10-fold increase in fracture energy, and cells seeded on their surfaces showcased good attachment. Our design underscores the efficacy of the DN approach and the promising applications of peptides in tissue engineering.


Outbreak of equine herpesvirus type 1 myeloencephalitis: new insights from virus identification by PCR and the application of an EHV-1-specific antibody detection ELISA.
Five of 10 pregnant, lactating mares, each with a foal at foot, developed neurological disease. Three of them became recumbent, developed complications and were euthanased; of the two that survived, one aborted an equine herpesvirus type 1 (EHV-1)-positive fetus 68 days after the first signs were observed in the index case and the other gave birth to a healthy foal on day 283 but remained ataxic and incontinent. The diagnosis of EHV-1 myeloencephalitis was supported by postmortem findings, PCR identification of the virus and by serological tests with an EHV-1-specific ELISA. At the time of the index case, the 10 foals all had a heavy mucopurulent nasal discharge, and PCR and the ELISA were used to detect and monitor EHV-1 infection in them. The status of EHV-1 infection in the five in-contact mares was similarly monitored. Sera from three of the affected mares, taken seven days after the index case were negative or had borderline EHV-1-specific antibody titres. In later serum samples there was an increase in the titres of EHV-1-specific antibody in two of the affected mares. In contrast, sera from the five unaffected in-contact mares were all EHV-1-antibody positive when they were first tested seven or 13 days after the index case.


Sequential serological studies of homosexual men with and without HIV infection. Epstein-Barr virus activation preceding and following HIV seroconversion.
Viral cofactors may be important in the pathogenesis of HIV infection and the development of AIDS, but their role is still imperfectly understood. Sequential serological studies were performed in a cohort of 100 homosexual men and 70 matched healthy controls over a mean period of 4 years. Of the patients, 18 were found to be HIV+ on admission to the study and 15 seroconverted to HIV+ during the follow up (seroconversion group). Serum antibodies of both IgG and IgA isotypes against Epstein-Barr virus (EBV) and cytomegalovirus (CMV) were determined. IgG antibodies indicate past infection, while a marked increase in IgG titre or a positive IgA titre were taken to indicate active infection or reactivated latent infection. EBV and CMV infections were about two to four times more prevalent in the homosexual men both HIV- and HIV+, compared with controls. Active infections were increased in the homosexual men and particularly in the HIV+ patients. The seroconversion group revealed activation of both EBV and CMV following HIV infection. When the antibody profile of seroconverting patients at the time preceding seroconversion was compared with a matched group of 39 homosexual men who remained HIV-, no change was found in CMV antibodies, but four out of 15 (26.6%) of the patients had high titres of anti-EBV IgA preceding seroconversion, as compared with only one out of 39 (2.6%) of HIV- homosexual men (P less than 0.05). This suggests a role for EBV reactivation in the pathogenesis of HIV infection in some patients.


The limits of intimate citizenship: reproduction of difference in Flemish-Ethiopian 'adoption cultures'.
The concept of 'intimate citizenship' stresses the right of people to choose how they organize their personal lives and claim identities. Support and interest groups are seen as playing an important role in the pursuit of recognition for these intimate choices, by elaborating visible and positive cultures that invade broader public spheres. Most studies on intimate citizenship take into consideration the exclusions these groups encounter when negotiating their differences with society at large. However, much less attention is paid to the ways in which these groups internalize the surrounding ideologies, identity categories and hierarchies that pervade society and constrain their recognition as full citizens. In contrast, this paper aims to emphasize the reproduction of otherness within alternative spheres of life, and to reveal the ambiguities and complexities involved in their dialectic relationship with society at large. To address this issue, the paper focuses on the role that 'adoption cultures' of Flemish adoptive parents with children from Ethiopia play in the pursuit of being recognized as 'proper' families and full citizens. The ethnographic research among adoptive parents and adoption professionals shows a defensive discourse and action that aims at empowering against potential problems, as well as a tendency to other the adoptive child by pathologizing its non-normativity. By showing the strong embeddedness of adoptive families' practices of familial and cultural construction in larger cultural frames of selfing and othering, characterized by biologism and nativism, one begins to understand the limits of their capacity to realize full citizenship.


[Health education for chronic liver and pancreatic diseases: Discussion groups "chronic liver disease" (CL), "chronic pancreatic disease" (CP)].
The article deals with our experience in the educational programs for patients with chronic liver diseases and chronic pancreatic diseases.The structure of our educational programs is modular, the main event is the discussion group "Chronic Liver Diseases" (CL) (2 meetings are headed by physicians, 1 by psychologists, duration in all 3,6 hours) respectively the discussion group "Chronic Pancreatic Diseases" (CP) (2 meetings headed by physicians, 1 by nutrition consultants, duration in all 2,6 hours). As needed, additional modules can be added, for example specific seminars in case of alcohol abuse or educational programs for diabetics. The average number of participants is between 7 - 15 persons in the discussion group CL, respectively 11 - 20 in the discussion group CP. An overhead projector is used to address the various topics, the patients are encouraged to actively participate in the discussion. The contents can be found in a structured curriculum and focus on anatomical basics, diagnostic and therapeutic aspects, physical fitness and performance in professional life.


Microbiome Shapes the T Cell Receptor Repertoire among CD4+CD8+ Thymocytes.
The microbiome shapes the mature T cell receptor (TCR) repertoire and thereby influences pathogen control. To investigate microbiome influences on T cells at an earlier, immature stage, we compared single-cell TCR transcript sequences between CD4+CD8+ (double-positive) thymocytes from gnotobiotic [E. coli mono-associated (Ec)] and germ-free (GF) mice. Identical TCRβ transcripts (termed repeat, REP) were more often shared between cells of individual Ec mice compared to GF mice (Fishers Exact test, p < 0.0001). Among Ec REPs, a cluster of Vβ genes (Vβ12-1, 12-2, 13-1, and 13-2, termed 12-13) was well represented, whereas 12-13 sequences were not detected among GF REPs (Fishers Exact test, p = 0.046). Vα genes located in the distal region of the TCRα locus were more frequently expressed in Ec mice compared to GF mice, both among REPs and total sequences (Fishers Exact test, p = 0.009). Results illustrate how gut bacteria shape the TCR repertoire, not simply among mature T cells, but among immature CD4+CD8+ thymocytes.


Modern unexplored martial arts - what can mixed martial arts and Brazilian Jiu-Jitsu do for youth development?
Contemporarily, two martial arts have emerged as highly popular among youth; Mixed Martial Arts (MMA) and Brazilian Jiu-Jitsu (BJJ). Despite their popularity, we know little of how they affect individuals sociopsychologically. The current study sought to explore how the currently underexplored martial art disciplines may contribute to sociopsychological development among young people. In addition, it was investigated whether individuals who are predisposed to different traits may favour one sport over the other. This study was conducted with a longitudinal design; over the course of 5 months, 113 participants completed training in either condition. The results show that both groups displayed increased self-control and pro-social behaviour; however, MMA practitioners also reported increased aggressiveness, whereas BJJ practitioners experienced a decline in aggression. Accordingly, individuals who trained in MMA displayed substantially higher pre-existing aggression levels than the BJJ practitioners. The current results further corroborate research suggesting that modern martial arts and MMA may not be suitable for at-risk youth to practice, whereas traditional martial arts and sports with a healthy philosophical foundation may be effective in reducing antisocial behaviour while enhancing socially desirable behaviour among young people.


A large-scale outbreak of bovine ephemeral fever in Turkey, 2012.
Regional cases of bovine ephemeral fever (BEF) were documented previously in Turkey. Previous cases were confirmed in South-East Turkey with low cow mortality. Recent BEF-suspected outbreaks with high mortality were documented in many regions of Turkey in 2012. The aim of study was the epidemiological examination of the outbreak and molecular characterization of the viruses detected from the outbreak. For this reason, blood samples were collected from BEF-suspected outbreak regions. From the results of RT-PCR, high rate of BEF-suspected samples (48/60 or 80%) was found positive for BEF virus (BEFV) RNA. The nucleotide sequences of the G1 region of G gene of BEFV in the current study during the 2012 outbreak were grouped into cluster II of BEFV. It was suggested that BEFV may be spread out to other neighbor countries in the future years.


Molecular imaging in cardiovascular diseases.
Cardiovascular diseases remain the leading cause of morbidity and mortality in industrialized and developing countries. In clinical practice, the in-vivo identification of atherosclerotic lesions, which can lead to complications such as heart attack or stroke, remains difficult. Imaging techniques provide the reference standard for the detection of clinically significant atherosclerotic changes in the coronary and carotid arteries. The assessment of the luminal narrowing is feasible, while the differentiation of stable and potentially unstable or vulnerable atherosclerotic plaques is currently not possible using non-invasive imaging. With high spatial resolution and high soft tissue contrast, magnetic resonance imaging (MRI) is a suitable method for the evaluation of the thin arterial wall. In clinical practice, native MRI of the vessel wall already allows the differentiation and characterization of components of atherosclerotic plaques in the carotid arteries and the aorta. Additional diagnostic information can be gained by the use of non-specific MRI contrast agents. With the development of targeted molecular probes, that highlight specific molecules or cells, pathological processes can be visualized at a molecular level with high spatial resolution. In this review article, the development of pathophysiological changes leading to the development of the arterial wall are introduced and discussed. Additionally, principles of contrast enhanced imaging with non-specific contrast agents and molecular probes will be discussed and latest developments in the field of molecular imaging of the vascular wall will be introduced. Molecular magnetic resonance imaging has great potential to improve the in vivo characterization of atherosclerotic plaques. Based on the molecular information is feasible to enable a better differentiation of stable and unstable (vulnerable) atherosclerotic plaques.


Prevalence and profile of obsessive-compulsive trait in patients with chronic migraine and medication overuse.
Patients with chronic migraine (CM) and medication overuse headache (MOH) have high frequency of psychiatric comorbidity or psychopathological traits, the presence of which can influence the clinical course. The presence of subclinical obsessive compulsive disorder (OCD) is underestimated in migraine patients. The aim of this study was to estimate the prevalence and profile of obsessive-compulsive (OBS) trait in a sample of CM patients with MOH using the OBS questionnaire of Spectrum Collaborative Project. According to the new international classification of headache disorders (ICHD-III beta) criteria, 106 patients (15 M, 91 F, mean age 47.3 years) were selected in a consecutive clinical series. Our results showed that 36 % of patients with CM and MOH were positive at OBS-questionnaire. As far as the profile of OBS trait, we performed an evaluation of prevalence of items separating the first part of the questionnaire (childhood/adolescence and doubts in lifetime) from the other five domains: 21 % of the patients showed prevalence of items in childhood/adolescence domain; 79 % in doubts in lifetime domain; as for other five domains, 10.5 % of patients had prevalence of pathological answers among hypercontrol, 5.2 % in spending time, 23.7 % in perfectionism, 29 % in repetition and automation, and 31.5 % in specific themes (obsessive thoughts). The presence of subclinical OCD in migraine patients, and the link between progression to CM, particularly through MO, and OBS trait is still not well defined. The use of specific tools to assess this possible comorbidity should be encouraged in clinical and research settings.


Cognitive, perceptual-speed, and psychomotor determinants of individual differences during skill acquisition.
The authors describe a series of experiments that explore 3 major ability determinants of individual differences in skill acquisition in the context of prior theory (e.g., P.L. Ackerman, 1988) and subsequent empirical and theoretical research. Experiment 1 assessed the predictability of individual differences in asymptotic skill levels on the Kanfer-Ackerman Air Traffic Controller (ATC) task. Experiment 2 provided an exploration of the construct space underlying perceptual-speed abilities. Experiment 3 concerned an evaluation of theoretical predictions for individual differences in performance over skill development in a complex air traffic control simulation task (TRACON) and the ATC task, with an extensive battery of general and perceptual-speed measures, along with a newly developed PC-based suite of psychomotor ability measures. Evidence addressing the predictability of individual differences in performance at early, intermediate, and asymptotic levels of practice is presented.


Nonenhanced MR angiography.
While nonenhanced magnetic resonance (MR) angiographic methods have been available since the earliest days of MR imaging, prolonged acquisition times and image artifacts have generally limited their use in favor of gadolinium-enhanced MR angiographic techniques. However, the combination of recent technical advances and new concerns about the safety of gadolinium-based contrast agents has spurred a resurgence of interest in methods that do not require exogenous contrast material. After a review of basic considerations in vascular imaging, the established methods for nonenhanced MR angiographic techniques, such as time of flight and phase contrast, are considered and their advantages and disadvantages are discussed. This article then focuses on new techniques that are becoming commercially available, such as electrocardiographically gated partial-Fourier fast spin-echo methods and balanced steady-state free precession imaging both with and without arterial spin labeling. Challenges facing these methods and possible solutions are considered. Since different imaging techniques rely on different mechanisms of image contrast, recommendations are offered for which strategies may work best for specific angiographic applications. Developments on the horizon include techniques that provide time-resolved imaging for assessment of flow dynamics by using nonenhanced approaches.


Computer use in diagnosis, prognosis, and therapy.
Computers are used to influence diagnostic and therapeutic decisions. The computer's information-handling capabilities allow it to serve as a reliable extension of the physician's memory and expander of the physician's information and synthesized knowledge resources. Computers have been used to facilitate decisions through organization of patient data, improved classification of patients, decision analysis in clinical settings, and simulation of expert clinical reasoning. Computer programs are more successful in narrow, constrained, single arenas of medicine with much underlying pathophysiologic understanding and where decisions are based largely on hard laboratory data. New models of synthetic reasoning that simulate expert clinical behavior show promise of supporting complicated decisions concerning problems of multiple diseases. All systems are confronted by problems of consensus and authority of the underlying information used.


Impact of a Biological Chelator, Lanmodulin, on Minor Actinide Aqueous Speciation and Transport in the Environment.
Minor actinides are major contributors to the long-term radiotoxicity of nuclear fuels and other radioactive wastes. In this context, understanding their interactions with natural chelators and minerals is key to evaluating their transport behavior in the environment. The lanmodulin family of metalloproteins is produced by ubiquitous bacteria and Methylorubrum extorquens lanmodulin (LanM) was recently identified as one of nature's most selective chelators for trivalent f-elements. Herein, we investigated the behavior of neptunium, americium, and curium in the presence of LanM, carbonate ions, and common minerals (calcite, montmorillonite, quartz, and kaolinite). We show that LanM's aqueous complexes with Am(III) and Cm(III) remain stable in carbonate-bicarbonate solutions. Furthermore, the sorption of Am(III) to these minerals is strongly impacted by LanM, while Np(V) sorption is not. With calcite, even a submicromolar concentration of LanM leads to a significant reduction in the Am(III) distribution coefficient (Kd, from >104 to ∼102 mL/g at pH 8.5), rendering it even more mobile than Np(V). Thus, LanM-type chelators can potentially increase the mobility of trivalent actinides and lanthanide fission products under environmentally relevant conditions. Monitoring biological chelators, including metalloproteins, and their biogenerators should therefore be considered during the evaluation of radioactive waste repository sites and the risk assessment of contaminated sites.


Blood Pressure Trajectories and the Risk of Intracerebral Hemorrhage and Cerebral Infarction: A Prospective Study.
The association between long-term blood pressure (BP) patterns in community-dwelling adults and risk of intracerebral hemorrhage and cerebral infarction is not well characterized. This prospective study included 79 385 participants, free of stroke, myocardial infarction, and cancer in or before 2010 (baseline). Systolic BP trajectories were identified using latent mixture modeling with data from 2006, 2008, and 2010. Incident cases of intracerebral hemorrhage and cerebral infarction occurred during 2010 to 2014, confirmed by review of medical records, by 3 physicians. We identified 5 distinct systolic BP trajectories during 2006 to 2010. Each of the trajectories was labeled according to their BP range and pattern over time: normotensive-stable (n=26 740), prehypertension-stable (n=35 674), stage 1 hypertension-increasing (n=8215), stage 1 hypertension-decreasing (n=6422), and stage 2 hypertension-stable (n=2334). We documented 1034 incident cases of cerebral infarction and 187 cases of intracerebral hemorrhage. Although the prehypertension-stable trajectory exhibited systolic BP range within the normal range (120-140 mm Hg) during 2006 to 2010, this group had higher stroke risk relative to the normotensive-stable group (<120 mm Hg) (adjusted hazard ratio was 3.11 for intracerebral hemorrhage and 1.99 for cerebral infarction; P<0.001 for both), after adjusting for possible confounders. Individuals in the stage 2 hypertension-stable systolic BP trajectory (175-179 mm Hg) had the highest risk of intracerebral hemorrhage (adjusted hazard ratio was 12.4) and cerebral infarction (adjusted hazard ratio was 5.07), relative to the normotensive-stable group (P<0.001 for both). BP trajectories were associated with the risk of stroke and increasing BP trajectories within the currently designated normal range may still increase the risk for stroke.


Early interprofessional interactions: does student age matter?
In this mixed-method evaluation we report on student responses to an introductory interprofessional learning event, accessed by ten professions within six months of commencing their chosen professional curricula. Of 898 students, 754 (84%) completed pre and post course questionnaires, and 81 took part in uni-professional focus groups. Student responses were compared with those of 14 facilitators. Younger students entering straight from school achieved more learning outcomes and were more positive about the learning than older students (e.g., undergraduate medics, range p = 0.001-0.011; graduate medics, range p = 0.001-0.819). Mature entrants valued interprofessional education, but preferred to interact with students of a similar age demanding a more challenging and relevant set of learning resources, sensitive to their prior life experience. Positive and negative stereotyping was differently constructed between younger and older students. The views of facilitators endorsed the lack of engagement of mature learners compared to their younger counterparts. The study highlights the need to consider age when bringing together large numbers of different professions for their first taste of interprofessional education.


[Chemotherapy at home. A new methodology].
Evolution in concepts relative to administration of cytotoxic drugs has reinforced interest in the use of continuous infusion therapy, a method providing a twofold increase in upper respiratory and digestive tract cancer response. A new method, developed by the authors since early 1985 allows the use of chemotherapy over 5 to 10 days in the patient's home. Preliminary results show an increase in efficacy of the therapy, and a marked improvement in the patient's comfort, suggesting that the indications for this new method should be enlarged.


Occupational Hazards among Healthcare Workers in Africa: A Systematic Review.
While all healthcare workers are exposed to occupational hazards, workers in sub-Saharan Africa have higher rates of occupational exposure to infectious diseases than workers in developed countries. Identifying prevalence and context of exposure to blood and bloodborne pathogens may help guide policies for prevention. This systematic review examined occupational exposure rates to blood and bloodborne pathogen among healthcare workers in sub-Saharan Africa. In November 2017, a comprehensive literature search was conducted to identify studies reporting exposure of health workers in African coutnries to blood and bodily fluids. Title, abstract and full text screening were used to narrow our search. Studies more than 10 years old, or published in non-English languages were excluded. Fifteen studies reported a variety of exposures. The lifetime prevalence of needlestick injury ranged from 22-95%, and one-year prevalence ranged from 39-91%. Studies included a range of descriptive statistics of knowledge, attitudes, practice and access factors related to exposures. Two studies reported 21-32% of respondents linked poor knowledge or training with prevention of needlestick injuries. Rates of recapping needles ranged from 12-57% in four studies. Attitudes were generally positive toward occupational safety procedures while access was poor. The high burden of blood and bloodborne pathogen exposures demonstrated here indicates a high risk for contracting bloodborne illnesses. Although the data are sparse, implementation of preventative policies based on current knowledge remains critical to minimize risk and reduce exposure. There remains a pressing need for high quality data on occupational hazards to identify the burden of exposures and inform preventive policies in Sub-Saharan Africa. Additional studies are needed to determine whether differential exposures exist between professions and the associations with knowledge, attitudes, practices, and access factors to create targeted strategies to diminish occupational hazards.


Active heterodimers are formed from human DNA topoisomerase II alpha and II beta isoforms.
DNA topoisomerase II is a nuclear enzyme essential for chromosome dynamics and DNA metabolism. In mammalian cells, two genetically and biochemically distinct topoisomerase II forms exist, which are designated topoisomerase II alpha and topoisomerase II beta. In our studies of human topoisomerase II, we have found that a substantial fraction of the enzyme exists as alpha/beta heterodimers in HeLa cells. The ability to form heterodimers was verified when human topoisomerases II alpha and II beta were coexpressed in yeast and investigated in a dimerization assay. Analysis of purified heterodimers shows that these enzymes maintain topoisomerase II specific catalytic activities. The natural existence of an active heterodimeric subclass of topoisomerase II merits attention whenever topoisomerases II alpha and II beta function, localization, and cell cycle regulation are investigated.


Transient electroosmosis of a Maxwell fluid in a rotating microchannel.
The transient electroosmotic flow of Maxwell fluid in a rotating microchannel is investigated both analytically and numerically. We bring out the complex dynamics of the flow during the transience due to the combination of rotation and rheological effects. We show the regimes of operation under which our analysis holds the most significance. We also shed some light on the volumetric flow rate characteristics as dictated by the underlying flow physics. Mainly we show and analyze the various regimes of operation under which viscoelastic effects actuated by electroosmotic forcing dominate over Coriolis forces and vice versa, which has not been studied before. We also observe that the analytical solution compares well with the numerical solution. We believe that the results from the present study could potentially have far reaching applications in bio-fluidic microsystems where fluids such as blood, mucus and saliva may be involved.


NFAT dysregulation by increased dosage of DSCR1 and DYRK1A on chromosome 21.
Trisomy 21 results in Down's syndrome, but little is known about how a 1.5-fold increase in gene dosage produces the pleiotropic phenotypes of Down's syndrome. Here we report that two genes, DSCR1 and DYRK1A , lie within the critical region of human chromosome 21 and act synergistically to prevent nuclear occupancy of NFATc transcription factors, which are regulators of vertebrate development. We use mathematical modelling to predict that autoregulation within the pathway accentuates the effects of trisomy of DSCR1 and DYRK1A, leading to failure to activate NFATc target genes under specific conditions. Our observations of calcineurin-and Nfatc-deficient mice, Dscr1- and Dyrk1a-overexpressing mice, mouse models of Down's syndrome and human trisomy 21 are consistent with these predictions. We suggest that the 1.5-fold increase in dosage of DSCR1 and DYRK1A cooperatively destabilizes a regulatory circuit, leading to reduced NFATc activity and many of the features of Down's syndrome. More generally, these observations suggest that the destabilization of regulatory circuits can underlie human disease.


Assessing bioequivalence of antiepileptic drugs: are the current requirements too permissive?
In order to evaluate the permissiveness of current bioequivalence requirements for antiepileptic drugs we investigated how accurate Cmax and AUC0-t of generic antiepileptic drugs approved in Brazil are in comparison to reference products. Data collected from assessment reports of approved bioequivalence studies archived in the Brazilian regulatory agency in 2007-2012 were: geometric mean ratios and 90% confidence intervals (CI) for Cmax and AUC0-t, intra-subject variability (CV) of Cmax and AUC0-t and number of subjects. The average difference in Cmax and AUC0-t between generic and reference products was 5% and 3%, respectively. Maximum deviation from 1.00 of the CI of Cmax can achieve 15-20% (demonstrated in 27% of studies); for AUC0-t, 25% of studies showed the deviation can be >10%. All studies that used adequate number of subjects for a 90% CI of 0.90-1.11 complied with it for AUC0-t, except one of carbamazepine, but only 33% complied with it for both AUC0-t and Cmax. The CV was strongly correlated to the maximum CI deviation for AUC0-t (CV of approximately 15% corresponding to deviation of 10%). Studies that presented maximum CI deviation ≤ 10 % together with CV ≤ 15% for AUC0-t represented 65% of the total. Weaker correlation was observed for Cmax and no correlation was seen between maximum CI deviation and number of subjects. Modification in legislation for bioequivalence of antiepileptic drugs is suggested, not only with constraint of AUC0-t 90% CI to 0.90-1.11, but also with limitation of the CV to 15%, as to assure similar variance in pharmacokinetics and diminish the risk of critical plasma-level fluctuation when switching between generic and reference formulations. Although most generics presented differences ≤ 10% in AUC0-t compared to their references, some narrow therapeutic index drugs displayed differences that could be clinically significant after product substitution.


Segmental intelligibility of four currently used text-to-speech synthesis methods.
The study investigated the segmental intelligibility of four currently available text-to-speech (TTS) products under 0-dB and 5-dB signal-to-noise ratios. The products were IBM ViaVoice version 5.1, which uses formant coding, Festival version 1.4.2, a diphone-based LPC TTS product, AT&T Next-Gen, a half-phone-based TTS product that uses harmonic-plus-noise method for synthesis, and FlexVoice2, a hybrid TTS product that combines concatenative and formant coding techniques. Overall, concatenative techniques were more intelligible than formant or hybrid techniques, with formant coding slightly better at modeling vowels and concatenative techniques marginally better at synthesizing consonants. No TTS product was better at resisting noise interference than others, although all were more intelligible at 5 dB than at 0-dB SNR. The better TTS products in this study were, on the average, 22% less intelligible and had about 3 times more phoneme errors than human voice under comparable listening conditions. The hybrid TTS technology of FlexVoice had the lowest intelligibility and highest error rates. There were discernible patterns of errors for stops, fricatives, and nasals. Unrestricted TTS output--e-mail messages, news reports, and so on--under high noise conditions prevalent in automobiles, airports, etc. will likely challenge the listeners.


Invasive Bacterial Pathogens and their Antibiotic Susceptibility Patterns in Jimma University Specialized Hospital, Jimma, Southwest Ethiopia.
Presence of microorganisms in the circulating blood whether continuously or intermittently is a threat to every organ in the body. Approximately 200,000 cases of bacteraemia occur annually with mortality rates ranging from 20-50%. Early diagnosis and appropriate treatment of these infections can make the difference between life and death. The aim of the present study was to determine the bacterial flora of the blood stream infections and their antibiotic susceptibility pattern. A cross sectional study was conducted on 260 adult febrile patients in Jimma University Specialized Hospital from 27 October 2009 to 26 March 2010. The positive blood cultures were examined and the organisms were identified as per standard procedures. Antimicrobial testing was performed for all isolates by disk diffusion techniques, according to Clinical Laboratory Standards Institute guide lines. The data was analyzed using SPSS for windows version 16 and Microsoft Office Excel. From the total of two hundred sixty blood specimens only 23(8.8%) were positive to seven different types of bacteria. The isolated bacteria were: Coagulase negative staphylococci 6(26.1%), S. aureus 5 (21.7%), S. pyogens 3 (13.0%), E. coli 4(17.4%), K. pneumoniae 3(13.0%), Salmonella spp. 1(4.3%), and Citrobacter spp. 1(4.3%). The isolates showed high rates of resistance to most antibiotics tested. The range of resistance for gram positive bacteria were 0% to 85.7%, and for gram negative from 0% to 100%. None of the isolates were resistance to ciprofloxacin and ceftriaxone. Our study result showed the presence of invasive bacterial pathogens with high rate of resistance to most commonly used antibiotics used to treat bacterial infections. Therefore, timely investigation of bacterial flora of the blood stream infections and monitoring of their antibiotic resistance pattern plays an important role in reduction of the incidence of blood stream infections.


Information on ancestry from genetic markers.
It is possible to estimate the proportionate contributions of ancestral populations to admixed individuals or populations using genetic markers, but different loci and alleles vary considerably in the amount of information that they provide. Conventionally, the allele frequency difference between parental populations (delta) has been used as the criterion to select informative markers. However, it is unclear how to use delta for multiallelic loci, or populations formed by the mixture of more than two groups. Moreover, several other factors, including the actual ancestral proportions and the relative genetic diversities of the parental populations, affect the information provided by genetic markers. We demonstrate here that using delta as the sole criterion for marker selection is inadequate, and we propose, instead, to use Fisher's information, which is the inverse of the variance of the estimated ancestral contributions. This measure is superior because it is directly related to the precision of ancestry estimates. Although delta is related to Fisher's information, the relationship is neither linear nor simple, and the information can vary widely for markers with identical deltas. Fortunately, Fisher's information is easily computed and formally extends to the situation of multiple alleles and/or parental populations. We examined the distribution of information for SNP and microsatellite loci available in the public domain for a variety of model admixed populations. The information, on average, is higher for microsatellite loci, but exceptional SNPs exceed the best microsatellites. Despite the large number of genetic markers that have been identified for admixture analysis, it appears that information for estimating admixture proportions is limited, and estimates will typically have wide confidence intervals.


Efficient, multiple-range random walk algorithm to calculate the density of states.
We present a new Monte Carlo algorithm that produces results of high accuracy with reduced simulational effort. Independent random walks are performed (concurrently or serially) in different, restricted ranges of energy, and the resultant density of states is modified continuously to produce locally flat histograms. This method permits us to directly access the free energy and entropy, is independent of temperature, and is efficient for the study of both 1st order and 2nd order phase transitions. It should also be useful for the study of complex systems with a rough energy landscape.


Microbiological effects of a routine treatment for decontaminating hide-on carcasses at a large beef packing plant.
To investigate the microbiological effects of a hide-on carcass decontaminating treatment recently implemented at a beef packing plant, carcasses undergoing routine processing at the plant were sampled during successive periods in January/February, April/May, and September/October. During each period, samples were collected from carcasses before and after the decontamination of hide-on carcasses, after skinning, before decontamination of the skinned carcasses, and at the end of the carcass dressing process. At each stage of processing during each period, samples were obtained by swabbing an area of 1,000 cm(2) on each of 25 carcasses. Aerobes, coliforms, and Escherichia coli were enumerated. In most samples, coliforms were predominantly E. coli. In all three periods, the log mean numbers of aerobes and E. coli recovered from hides before decontamination were between 6.6 and 6.8 and between 5.3 and 5.9 log CFU/1,000 cm(2), respectively. The log mean numbers of aerobes recovered from decontaminated hides were 6.6 log CFU/1,000 cm(2) in January/February and April/May but 5.4 log CFU/1,000 cm(2) in September/October. The log total numbers of E. coli recovered from decontaminated hides in January/February and April/May were 2.4 and 3.8 log CFU/25,000 cm(2), respectively, but no E. coli was recovered from such carcasses in September/October. Log total numbers of aerobes and E. coli recovered from skinned or dressed carcasses were mostly >4 and between 1 and 2 log CFU/25,000 cm(2), respectively. Typing of 480 E. coli isolates by multiple-locus variable-number tandem repeat analysis (MLVA) identified 218 MLVA types. Most isolates recovered from carcasses in different periods or at different stages of processing were of different MLVA types. However, small numbers of MLVA types were recovered in more than one period or from both hides before and after decontamination and skinned or dressed carcasses. The findings show that the hide-decontaminating treatment disrupted the usual transfer of E. coli from hides to meat surfaces during carcass skinning.


in silico surveillance: evaluating outbreak detection with simulation models.
Detecting outbreaks is a crucial task for public health officials, yet gaps remain in the systematic evaluation of outbreak detection protocols. The authors' objectives were to design, implement, and test a flexible methodology for generating detailed synthetic surveillance data that provides realistic geographical and temporal clustering of cases and use to evaluate outbreak detection protocols. A detailed representation of the Boston area was constructed, based on data about individuals, locations, and activity patterns. Influenza-like illness (ILI) transmission was simulated, producing 100 years of in silico ILI data. Six different surveillance systems were designed and developed using gathered cases from the simulated disease data. Performance was measured by inserting test outbreaks into the surveillance streams and analyzing the likelihood and timeliness of detection. Detection of outbreaks varied from 21% to 95%. Increased coverage did not linearly improve detection probability for all surveillance systems. Relaxing the decision threshold for signaling outbreaks greatly increased false-positives, improved outbreak detection slightly, and led to earlier outbreak detection. Geographical distribution can be more important than coverage level. Detailed simulations of infectious disease transmission can be configured to represent nearly any conceivable scenario. They are a powerful tool for evaluating the performance of surveillance systems and methods used for outbreak detection.


Magnetic resonance imaging atlas of the cervical spine musculature.
The anatomy of the cervical spine musculature visible on magnetic resonance (MR) images is poorly described in the literature. However, the correct identification of individual muscles is clinically important because certain conditions of the cervical spine, for example whiplash associated disorders, idiopathic neck pain, cervical nerve root avulsion and cervical spondylotic myelopathy, are associated with different morphological changes in specific muscles visible on MR images. Knowledge of the precise structure of different cervical spine muscles is crucial when comparisons with the contralateral side or with normal are required for accurate description of imaging pathology, management and assessment of treatment efficacy. However, learning the intricate arrangement of 27 muscles is challenging. A multi-level cross-sectional depiction combined with three-dimensional reconstructions could facilitate the understanding of this anatomically complex area. This paper presents a comprehensive series of labeled axial MR images from one individual and serves as a reference atlas of the cervical spine musculature to guide clinicians, researchers, and anatomists in the accurate identification of these muscles on MR imaging. Clin. Anat. 29:643-659, 2016. © 2016 Wiley Periodicals, Inc.


Existence of stoichiometric amounts of an intrinsic ATPase inhibitor and two stabilizing factors with mitochondrial ATP synthase in yeast.
Two proteinaceous factors, 15K and 9K proteins, which acted together to stabilize the inactivated yeast F1F0-ATPase-inhibitor complex [Hashimoto, T., et al. (1984) J. Biochem. 95, 131-136] were hardly distinguishable from the sigma and epsilon subunits, respectively, of yeast F1-ATPase by sodium dodecyl sulfate (SDS) polyacrylamide gel electrophoresis. However, they were clearly distinguishable from these subunits by analyses of the sequences at their amino terminals and by immunoblotting combined with SDS polyacrylamide gel electrophoresis. The two stabilizing factors and an ATPase inhibitor existed in mitochondria in equimolar ratios to F1-ATPase. These three protein factors were not present in purified F1-ATPase or in F1F0-ATPase preparations, but remained in the mitochondrial membranes after extraction of F1F0-ATPase with Triton X-100. These observations strongly suggest that the two stabilizing factors and the ATPase inhibitor form a regulatory substructure of mitochondrial ATP synthase, in addition to the F1 and F0 subunits.


Extracorporeal photopheresis in the treatment of acute graft-versus-host disease: A multicenter experience.
Extracorporeal photopheresis (ECP) is one of the second-line treatment strategies in steroid-refractory acute graft-versus-host disease (aGvHD). We aimed to share our multicenter experience using ECP in our steroid-refractory aGvHD patients. A retrospective observational series of 75 aGvHD patients from 4 transplant centers were analyzed. All ECP procedures were performed with the off-line system. All patients received ECP as second-line therapy. 74.7 % of aGvHD patients were grade 3 or 4. The overall response rate was 42.7 % (32/75) in aGvHD including 17 complete responses (22.7 %). Median follow-up was 6 months (range, 1-68). Median overall survival (OS) was 5 months for non-responders and 68 months for responders (p < 0.001). Twenty-seven (36 %) patients are alive, and 48 (64 %) patients have died. Early initiated ECP could be an effective treatment alternative in patients with steroid-refractory aGvHD.


Systemic enzyme therapy in oncology: effect and mode of action.
Plant extracts with a high content of proteolytic enzymes have been used for a long time in traditional medicine. Besides proteolytic enzymes from plants, 'modern' enzyme therapy additionally includes pancreatic enzymes. The therapeutic use of proteolytic enzymes is partly based on scientific studies and is partly empirical. The aim of the current review is to provide an overview of clinical trials of systemic enzyme therapy in oncology, and to discuss the evidence for their possible mechanisms of action. Clinical studies of the use of proteolytic enzymes in oncology have mostly been carried out on an enzyme preparation consisting of a combination of papain, trypsin and chymotrypsin. This review of these studies showed that enzyme therapy can reduce the adverse effects caused by radiotherapy and chemotherapy. There is also evidence that, in some types of tumours, survival may be prolonged. The beneficial effect of systemic enzyme therapy seems to be based on its anti-inflammatory potential. However, the precise mechanism of action of systemic enzyme therapy remains unsolved. The ratio of proteinases to antiproteinases, which is increasingly being used as a prognostic marker in oncology, appears to be influenced by the oral administration of proteolytic enzymes, probably via an induction of the synthesis of antiproteinases. Furthermore, there are numerous alterations of cytokine composition during therapy with orally administered enzymes, which might be an indication of the efficacy of enzyme therapy. Effects on adhesion molecules and on antioxidative metabolism are also reviewed.


Micro- and nanoplastics interact with conventional pollutants on microalgae: Synthesis through meta-analysis.
MICRO: and nanoplastics (MNPs) have been found to occur intensively in aquatic environments, along with other conventional pollutants (Po) such as heavy metals, pesticides, pharmaceuticals, etc. However, our understanding of how MNPs and Po interact on aquatic primary producers is fragmented. We performed a quantitative meta-analysis based on 933 published experimental assessments from 44 studies to examine the coupled effects of MNPs and Po on microalgae. Although the results based on interaction type frequency (the proportion of each interaction type in all results) revealed dominantly additive interactions (56%) for overall physiological performance, an overall antagonistic effect was observed based on the mean interaction effect sizes. A higher proportion of antagonistic interaction type frequency was found in marine species compared to fresh species. The antagonistic effects were particularly significant for growth, oxidative responses, and photosynthesis, which could be attributed to the adsorption effect of MNPs on Po and thus the decreasing concentrations of pollutants in the medium. Larger-sized, negatively charged or uncharged and aged MNPs had higher proportions of antagonistic effects compared to smaller-sized, positively charged and virgin MNPs, due to their stronger adsorption capacity to Po. This study provides a comprehensive insight into the interactive effects of MNPs and Po on microalgae.


Chronic mustard toxicity on the testis: a historical cohort study two decades after exposure.
We aimed to assess the long-term toxic effects of sulphur mustard (SM) on the testis and male fertility two decades after exposure. A historical cohort study was conducted in 2005. Sixty-four SM-exposed and 64 matched SM-unexposed casualties of the Iraq-Iran conflict were enrolled. Fecundity status, semen indices, hormonal assay results and testis histopathology were evaluated. Male factor infertility was diagnosed in 23 and 5% of married exposed and unexposed casualties, respectively (p < 0.01). All semen indices declined over the 15 years since 1990 among the exposed group. Furthermore, all indices with the exception of sperm motility were significantly lower in the exposed than in unexposed men. The follicle-stimulating hormone level was higher in the infertile than in fertile exposed men (p < 0.001). Testis histopathology of the azoospermic men showed complete absence of spermatogenesis with only Sertoli cells in the seminiferous tubules. SM can be gonadotoxic and its chronic toxicity may be permanent. Germ cells are probably the most susceptible gonadal cells to SM.


Interleukin-1β level in peri-implant crevicular fluid and its correlation with the clinical and radiographic parameters.
Assessing only the clinical and radiographic parameters for evaluation of dental implants may not be enough as they often reflect extensive inflammatory changes in the periodontal tissues. As peri-implant crevicular fluid (PICF) can give us a more prompt and objective measure of the disease activity, the purpose of this case series is to assess the peri-implant health status of single tooth dental implants not only clinically and radiographically but also biochemically. Thirteen patients were subjected to dental implants at single edentulous sites using a conventional surgical approach. At baseline, 6 months, and 12 months after implant placement, the clinical and radiographic parameters were recorded. Additionally, IL-1β in PICF was estimated using the ELISA kit at 6(th) and 12(th) month. The clinical and radiographic parameters differed significantly around the implants at different time intervals with IL-1β levels showing highly significant differences between 6 months (31.79 ± 12.26 pg/μl) and 12 months (113.09 ± 51.11 pg/μl). However, Spearman's correlation coefficient showed no correlation with the clinical and radiographic parameters. Assessment of the various parameters confirmed that all the implants had a healthy peri-implant status. Although the levels of IL-1β in PICF were elevated at the 12(th) month, they were well within the healthy range as observed by previous studies. This indicates that IL-1β, a biochemical marker, can be used as an adjunct to clinical and radiographic parameters in the assessment of EARLY inflammatory changes around implants.


Neurturin overexpression in skin enhances expression of TRPM8 in cutaneous sensory neurons and leads to behavioral sensitivity to cool and menthol.
Neurturin (NRTN) is a member of the glial cell line-derived neurotrophic factor family of ligands that exerts its actions via Ret tyrosine kinase and GFRα2. Expression of the Ret-GFRα2 coreceptor complex is primarily restricted to the peripheral nervous system and is selectively expressed by sensory neurons that bind the isolectin B(4) (IB(4)). To determine how target-derived NRTN affects sensory neuron properties, transgenic mice that overexpress NRTN in keratinocytes (NRTN-OE mice) were analyzed. Overexpression of NRTN increased the density of PGP9.5-positive, but not calcitonin gene-related peptide-positive, free nerve endings in footpad epidermis. GFRα2-immunopositive somata were hypertrophied in NRTN-OE mice. Electron microscopic analysis further revealed hypertrophy of unmyelinated sensory axons and a subset of myelinated axons. Overexpression of NRTN increased the relative level of mRNAs encoding GFRα2 and Ret, the ATP receptor P2X(3) (found in IB(4)-positive, GFRα2-expressing sensory neurons), the acid-sensing ion channel 2a, and transient receptor potential cation channel subfamily member M8 (TRPM8) in sensory ganglia. Behavioral testing of NRTN-OE mice revealed an increased sensitivity to mechanical stimuli in glabrous skin of the hindpaw. NRTN-OE mice also displayed increased behavioral sensitivity to cool temperature (17°C-20°C) and oral sensitivity to menthol. The increase in cool and menthol sensitivity correlated with a significant increase in TRPM8 expression and the percentage of menthol-responsive cutaneous sensory neurons. These data indicate that the expression level of NRTN in the skin modulates gene expression in cutaneous sensory afferents and behavioral sensitivity to thermal, chemical, and mechanical stimuli.


Jakinibs: a new class of kinase inhibitors in cancer and autoimmune disease.
Cytokines are critical for normal cell growth and immunoregulation but also contribute to growth of malignant cells and drive immune-mediated disease. A large subset of immunoregulatory cytokines uses the type I and type II cytokine receptors and pharmacological targeting of these cytokines/cytokines receptors has proven to be efficacious in treating immune and inflammatory diseases. These receptors rely on Janus family of kinases (Jaks) for signal transduction. Recently the first Jak inhibitor (jakinib) has been approved by the FDA and a second has been recommended for approval. Many other Jakinibs are likely to follow and in this brief review, we will discuss the state-of-the art of this new class of pharmacological agents.


[The effect of exogenous heparin on the processes of colony formation from myeloid precursors and the formation of erythroblastic islets].
Experiments were conducted on Wistar rats to study the comparative effect of exogenous administration of heparin (250 U) on the colony forming ability of committed myeloid precursors and the formation of erythroblast islets (EI). The results were recorded for 5 days. On the basis of the obtained data a primary selective effect of heparin on the granulocytic-macrophagal colony forming units in the diffusion chamber was revealed. The process of EI formation is affected only in the late periods (3rd-5th day) against the background of sharply stimulated myelopoiesis. A significant reduction of the number of EI is noted in this period.


Life history and ossification patterns in Miguashaia bureaui reveal the early evolution of osteogenesis in coelacanths.
The study of development is critical for revealing the evolution of major vertebrate lineages. Coelacanths have one of the longest evolutionary histories among osteichthyans, but despite access to extant representatives, the onset of their weakly ossified endoskeleton is still poorly understood. Here we present the first palaeohistological and skeletochronological study of Miguashaia bureaui from the Upper Devonian of Canada, pivotal for exploring the palaeobiology and early evolution of osteogenesis in coelacanths. Cross sections of the caudal fin bones show that the cortex is made of layers of primary bone separated by lines of arrested growth, indicative of a cyclical growth. The medullary cavity displays remnants of calcified cartilage associated with bony trabeculae, characteristic of endochondral ossification. A skeletochronological analysis indicates that rapid growth during a short juvenile period was followed by slower growth in adulthood. Our new analysis highlights the life history and palaeoecology of Miguashaia bureaui and reveals that, despite differences in size and habitat, the poor endoskeletal ossification known in the extant Latimeria chalumnae can be traced back at least 375 million years ago.


High postpartum rates of sexually transmitted infections among teens: pregnancy as a window of opportunity for prevention.
To identify incidence and predictors of Chlamydia trachomatis and Neisseria gonorrhoeae among postpartum adolescents. These estimates are compared to similar estimates among a cohort of non-pregnant, sexually active teens. 203 pregnant and 208 non-pregnant adolescents aged 14-19 years were recruited from 10 community based health clinics in Connecticut, United States. Structured interviews and sexually transmitted infection (STI) testing using ligase chain reaction (LCR) were conducted at a baseline visit (during the third trimester for the pregnant adolescents), and at 6 and 12 month follow up visits (3 and 9 months post partum, for those pregnant at baseline). Among pregnant teens, new infections of C trachomatis and N gonorrhoeae increased from 7.1% at the 6 month follow up interview to 14.3% at the 12 month follow up interview; among non-pregnant teens, new infections remained relatively stable over the 6 and 12 month follow up interviews (9.0% to 8.3%) (group by time interaction, p = 0.005). C trachomatis and N gonorrhoeae prevalence was 1.9 times higher (95% CI: 0.97 to 3.89, p = 0.06) among teens in the late postpartum follow up compared to the non-pregnant teens, controlling for baseline STIs. Predictors of postpartum STIs included having a new partner and number of partners per year of sexual activity. Postpartum adolescents are vulnerable to STIs. Routine prenatal and postpartum care provide unique opportunities to promote condom use and other risk reduction interventions among adolescents. If sustained post partum, long term reproductive health can be promoted.


Effect of the addition of glycosaminoglycans on bone and cartilaginous development of broiler chickens.
Locomotion issues in broiler production may decrease performance (carcass yield and traits) and lead to high financial losses. This study evaluates the addition of glucosaminoglycans in broiler diets to minimize the lack of proper bone development and joint weakening. The experiment was conducted using 2,160 broilers randomly distributed in a factorial pattern (3 × 3) using 3 levels of glucosamine sulfate (0, 0.12, and 0.24%) and 3 levels of chondroitin sulfate addition (0, 0.08, and 0.16%). Eight repetitions were used for each treatment, distributed in 72 pens with 30 broilers each. There was a quadratic effect on feed conversion for broilers from 1 to 42 d old (P = 0.0123) for the addition of chondroitin, and better feed conversion was obtained by adding 0.08% of chondroitin. The relative tibia weight, the width of the proximal epiphysis and diaphysis presented a linear increased effect in broilers at 42 d old. An interaction was found between the amount of chondroitin × glucosamine and the number of chondrocytes in the proximal cartilage of the tibia (P = 0.0072). There was a quadratic effect of glucosamine levels (P = 0.0107) in the birds that had received the 0.16% addition of chondroitin, and the presence of 0.18% glucosamine increased the number chondrocytes in the cartilage of broilers. These results provide the first evidence that broilers may benefit from increased dietary chondroitin sulfate. These results indicate that the addition of glucosamine and chondroitin sulfates in broiler feed rations might alleviate leg conditions and decrease financial losses in the broiler industry.


An Optoelectronic System for Measuring the Range of Motion in Healthy Volunteers: A Cross-Sectional Study.
Background and Objectives: Within the clinical evaluation of multiple pathologies of the lower limb, the measurement of range of motion (ROM) of its joints is fundamental. To this end, there are various tools, from the goniometer as a reference to more recent devices such as inclinometry-based applications, photo capture applications, or motion capture systems. This study aimed to assess the validity, intra-rater, and inter-rater reliability of the VeloFlex system (VS), which is a new camera-based tool designed for tracking joint trajectories and measuring joint ROM. Materials and Methods: Thirty-five healthy volunteers (16 females; aged 18-61 years) participated in this study. All participants were assessed on two separate occasions, one week apart. During the first assessment session, measurements were obtained using a goniometer and the VS, whereas, in the second session, only the VS was used. In each assessment session, nine active movements were examined. For each movement, three trials were tested, and the mean of these three measures was used for analysis. To evaluate the concurrent validity and agreement, the Pearson correlation coefficient (r) and Bland-Altmann plots were used. Intra-rater and inter-rater reliability were evaluated using intra-class correlation (ICC), standard error of measurement (SEM), and minimal detectable change (MDC). Results: Both devices showed excellent correlations for all movements (r ranged from 0.992 to 0.999). The intra-rater reliability of the VS was excellent (ICC ranged from 0.93 to 0.99), SEMs ranged from 0.53% to 2.61% and the MDC ranged from 0.68° to 3.26°. The inter-rater reliability of the VS was also excellent (ICC ranged from 0.88 to 0.98), SEMs ranged from 0.81% to 4.76% and the MDC ranged from 2.27° to 4.42°. Conclusions: The VS is a valid and reliable tool for the measurement of ROM of lower limb joints in healthy subjects.


Methyl donor deficiency affects small-intestinal differentiation and barrier function in rats.
Dietary methyl donors and their genetic determinants are associated with Crohn's disease risk. We investigated whether a methyl-deficient diet (MDD) may affect development and functions of the small intestine in rat pups from dams subjected to the MDD during gestation and lactation. At 1 month before pregnancy, adult females were fed with either a standard food or a diet without vitamin B12, folate and choline. A global wall hypotrophy was observed in the distal small bowel (MDD animals 0·30 mm v. controls 0·58 mm; P< 0·001) with increased crypt apoptosis (3·37 v. 0·4%; P< 0·001), loss of enterocyte differentiation in the villus and a reduction in intestinal alkaline phosphatase production. Cleaved caspase-3 immunostaining (MDD animals 3·37% v. controls 0·4%, P< 0·001) and the Apostain labelling index showed increased crypt apoptosis (3·5 v. 1·4%; P= 0·018). Decreased proliferation was observed in crypts of the proximal small bowel with a reduced number of minichromosome maintenance 6 (MDD animals 52·83% v. controls 83·17%; P= 0·048) and proliferating cell nuclear antigen-positive cells (46·25 v. 59 %; P= 0·05). This lack of enterocyte differentiation in the distal small bowel was associated with an impaired expression of β-catenin and a decreased β-catenin-E-cadherin interaction. The MDD affected the intestinal barrier in the proximal small bowel by decreasing Paneth cell number after immunostaining for lysosyme (MDD animals 8·66% v. controls 21·66%) and by reducing goblet cell number and mucus production after immunostaining for mucin-2 (crypts 8·66 v. 15·33%; villus 7 v. 17%). The MDD has dual effects on the small intestine by producing dramatic effects on enterocyte differentiation and barrier function in rats.


Assessing the Potential of Brain-Computer Interface Multiplayer Video Games using c-VEPs: A Pilot Study.
Video games have become a common and widespread form of entertainment, while non-invasive brain-computer interfaces (BCI) are emerging as potential alternative communication technologies. Combining BCIs and video games can enhance the gaming experience and make it accessible to motor-disabled individuals. Recently, code-modulated visual evoked potentials (c-VEP) have been proposed as a novel control signal able to achieve high performance with short calibration times. However, there are still no video games that use c-VEPs as a control signal. The aim of this pilot study is to develop an implementation of the 'Connect 4' multiplayer video game using a c-VEP-based BCI and test it with 10 healthy users. Participants were paired to compete in matches and carried out individual tasks. The results showed that the participants were able to control the game with an average accuracy of 94.10% and a selection time of 5.25 seconds per command, outperforming previous approaches. This suggests that the proposed video game is feasible and c-VEPs can provide smooth BCI control.


[The participation of protein synthesis in the K+-dependent activation of hormonal biosynthesis in the adrenal cortex of guinea pigs].
An in vitro effect of cycloheximide (CHI), an inhibitor of protein synthesis, on the stimulation of steroidogenesis, caused by a rise of K+ concentration in a medium from 1 to 10 mM, was studied. A rise of a K+ level in the incubation of guinea-pig adrenocortical sections resulted in enhanced protein synthesis and activation of aldosterone and corticosterone synthesis from cholesterol. CHI addition completely suppressed these effects of K+. Comparison of incorporation of a cholesterol and corticosterone mark in aldosterone suggests that a rise of a K+ level within physiological limits enhanced hormone biosynthesis at the stage of splitting off a lateral cholesterol chain. The authors discuss a possible involvement of protein synthesis, stimulated by a high K+ concentration, in acceleration of final reactions of aldosterone biosynthesis.


Cell surface characteristics of coagulase-negative staphylococci and their adherence to fluorinated poly(ethylenepropylene).
The ability of 21 nonencapsulated and 15 encapsulated coagulase-negative staphylococci (CNS) to adhere to xylene in xylene-water emulsions and to fluorinated poly(ethylenepropylene) (FEP) films revealed remarkable differences. Nonencapsulated CNS strains adhered well to FEP, whereas their adherence to xylene ranged widely. Encapsulated strains with low adherence to xylene showed slight adherence to FEP. Encapsulated strains which adhered well to xylene ranged widely in their adherence to FEP. It was concluded that results obtained from the xylene adherence test were not predictive of the adherence of CNS to the hydrophobic FEP surface. The number of nonwashed, slime-producing CNS strains adhering to FEP was similar to that of washed bacteria of the same strains. Bacterial adherence to FEP was decreased when FEP films were exposed to a solution containing extracellular products (EP) obtained from a slime-producing CNS strain. Bacterial adherence to xylene also decreased when the bacterial suspensions contained EP. Apparently, initial adherence of CNS to FEP and xylene is hampered by EP. Nonencapsulated and encapsulated CNS pretreated with proteolytic enzymes failed to adhere to xylene and FEP, indicating that intact surface proteins or constituents associated with surface proteins mediated their adherence to xylene and FEP. Freeze-etch replicas of a CNS strain adhering to FEP showed a smooth, flattened area on the bacterial surface at the contact site of the bacteria with the FEP, indicating that an external layer was present at the bacterial surface.


3did: a catalog of domain-based interactions of known three-dimensional structure.
The database of 3D interacting domains (3did, available online for browsing and bulk download at http://3did.irbbarcelona.org) is a catalog of protein-protein interactions for which a high-resolution 3D structure is known. 3did collects and classifies all structural templates of domain-domain interactions in the Protein Data Bank, providing molecular details for such interactions. The current version also includes a pipeline for the discovery and annotation of novel domain-motif interactions. For every interaction, 3did identifies and groups different binding modes by clustering similar interfaces into 'interaction topologies'. By maintaining a constantly updated collection of domain-based structural interaction templates, 3did is a reference source of information for the structural characterization of protein interaction networks. 3did is updated every 6 months.