Methamphetamine self-administration in humans during D-amphetamine maintenance.
Agonist replacement may be a viable treatment approach for managing stimulant use disorders. This study sought to determine the effects of D-amphetamine maintenance on methamphetamine self-administration in stimulant using human participants. We predicted that D-amphetamine maintenance would reduce methamphetamine self-administration. Eight participants completed the protocol, which tested 2 D-amphetamine maintenance conditions in counterbalanced order (0 and 40 mg/d). Participants completed 4 experimental sessions under each maintenance condition in which they first sampled 1 of 4 doses of intranasal methamphetamine (0, 10, 20, or 30 mg). Participants then had the opportunity to respond on a computerized progressive-ratio task to earn portions of the sampled methamphetamine dose. Subject-rated drug effect and physiological measures were completed at regular intervals prior to and after sampling methamphetamine. Methamphetamine was self-administered as an orderly function of dose regardless of the maintenance condition. Methamphetamine produced prototypical subject-rated effects on 12 items of the drug-effects questionnaires, 8 of which were attenuated by D-amphetamine maintenance (eg, increased ratings were attenuated on items such as Any Effect, Like Drug, and Willing to Take Again on the Drug Effect Questionnaire). Methamphetamine produced significant increases in systolic blood pressure, which were attenuated by D-amphetamine maintenance compared to placebo maintenance. Methamphetamine was well tolerated during D-amphetamine maintenance and no adverse events occurred. Although D-amphetamine attenuated some subject-rated effects of methamphetamine, the self-administration results are concordant with those of clinical trials showing that D-amphetamine did not reduce methamphetamine use. Unique pharmacological approaches may be needed for treating amphetamine use disorders.


Visualizing the intellectual structure and recent research trends of diabetic retinopathy.
To analyze the intellectual structure and recent research trends in diabetic retinopathy (DR) and unearth potential knowledge. English DR publication included in this study was exported from the Web of Science Core Collection, and Chinese DR publication was exported from China National Knowledge Infrastructure from the establishment time of the database to 2019. CiteSpace and Microsoft Excel were used to visually analyze DR research, including analysis of the number of publications, highly cited publication analysis, spatial distribution analysis, and keyword co-occurrence analysis. A total of 23 795 English studies and 11 577 Chinese studies, including 2089 studies related to traditional Chinese medicine (TCM), were obtained. The data suggested the following: 1) The number of English and Chinese DR publications increased over time, and the growth rate of English publications was relatively fast. 2) The distribution of international scholars and institutions was close, while the distribution was scattered in China. Shanghai Jiao Tong University has the largest number of publications. Tien-Yin Wong was the core author with the largest number of publications. England and the United States are the core of international DR research cooperation. 3) Optical coherence tomography and risk factors are recent international research hot spots and trends. The difference is that TCM is a recent research trend under DR in China. DR has drawn an increasing amount of attention worldwide. The focus of research in this field has shifted from tertiary type DR treatment to secondary prevention strategies which focus on the screening and monitoring of disease progression. The advantages of TCM in the prevention of DR have attracted attention, and it is worth incorporating this with Western medicine to address this challenge.


The photosensitizing activity of haematoporphyrin on mollicutes.
The photosensitizing activity of haematoporphyrin (HP) on Mycoplasma hominis and Acholeplasma laidlawii was studied as a function of the phase of growth and the amount of sterols in the cell membrane. Less HP was bound to cells when the membrane had a high sterol content. Both strains in the exponential but not in the stationary phase of growth were sensitive to HP treatment (above 1 microgram ml-1) in the dark. Visible light irradiation of HP-loaded cells caused in all cases a decrease of cell survival, with concomitant changes in the pattern of membrane proteins that suggested protein-protein cross-linking, and the appearance of ultrastructural alterations (rounded and lysed cells); the photosensitivity was indirectly related to the sterol content of the cell membrane. On the whole, our findings suggest that the cell membrane is a major target for HP photosensitization of mycoplasma cells.


Heterogeneity in skeletal load adaptation points to a role for modeling in the pathogenesis of osteoporotic fracture.
Genetic, environmental, or hormonal factors may cause heterogeneity in skeletal load response. Individuals with reduced sensitivity to load should require higher strains to generate an adaptive response, consequently have weaker bones and fracture more frequently. The purpose of our study was to determine if stresses (proportional to strains) at the femoral neck under equivalent loads were higher in women with a history of fractures compared with women without fractures. We studied postmenopausal women participating in the Canadian Multicentre Osteoporosis Study who had available hip structure analysis data from dual-energy X-ray absorptiometry scans (n = 2168). Women were categorized into 2 groups based on their number of self-reported fractures. We computed stress (megapascals) at the inferomedial margin of the femoral neck in a one-legged stance mode using a 2-dimensional engineering beam analysis. We used linear regression (SAS 9.3) to determine associations between stress, geometry parameters, and number of fractures. Postmenopausal women with 1 or more fractures had higher stress (2.6%), lower narrow neck bone mineral density (4.2%), cross-sectional area (3.9%), and section modulus (9.6%) than postmenopausal women without fractures (all p < 0.05). These findings provide evidence of heterogeneity in load response and suggest an important role for modeling in the pathogenesis of osteoporotic fracture.


Pharmacokinetic-guided dosing of factor VIII concentrate in a morbidly obese severe haemophilia A patient undergoing orthopaedic surgery.
A 58-year-old morbidly obese male (body mass index: 38 kg/m2) with severe haemophilia A underwent total knee replacement surgery. Perioperatively, factor VIII (FVIII) levels were measured daily and maximum a posteriori (MAP) Bayesian estimation was used to calculate the individual pharmacokinetic (PK) parameters and doses required to obtain prescribed FVIII target levels. In the MAP Bayesian procedure, a population PK model was used in which PK parameters were normalised using body weight. In this specific case, ideal body weight was used to scale the PK parameters instead of actual body weight. Except for the preoperative FVIII level, adequate FVIII levels were achieved during the 10-day perioperative period. During follow-up visits, the knee prosthesis was reported to function adequately.


Increasing access into higher education: Insights from the 2011 African Network on Evidence-to-Action on Disability Symposium - Education Commission.
This article provides some insights into the challenges regarding inclusion in higher education of students with disabilities. It does this by elucidating aspects of the proceedings of the Education Commission at the African Network on Evidence-to-Action on Disability (AfriNEAD) Symposium, which took place in Zimbabwe in November 2011. The presentations specifically focused on the education of people with disabilities from early childhood through to higher education. This article, however, is informed by presentations focusing on increasing access to higher education. The article is focused on the implementation of evidence in practice, research and policies stemming from rigorous debate and scientific foundations, whilst taking into account the dynamic realities of the higher education context. Themes such as the systemic approach needed for inclusion to be successful, increasing access and the dynamic role of students with disabilities are highlighted.


Statistics of the vestibular input experienced during natural self-motion: implications for neural processing.
It is widely believed that sensory systems are optimized for processing stimuli occurring in the natural environment. However, it remains unknown whether this principle applies to the vestibular system, which contributes to essential brain functions ranging from the most automatic reflexes to spatial perception and motor coordination. Here we quantified, for the first time, the statistics of natural vestibular inputs experienced by freely moving human subjects during typical everyday activities. Although previous studies have found that the power spectra of natural signals across sensory modalities decay as a power law (i.e., as 1/f(α)), we found that this did not apply to natural vestibular stimuli. Instead, power decreased slowly at lower and more rapidly at higher frequencies for all motion dimensions. We further establish that this unique stimulus structure is the result of active motion as well as passive biomechanical filtering occurring before any neural processing. Notably, the transition frequency (i.e., frequency at which power starts to decrease rapidly) was lower when subjects passively experienced sensory stimulation than when they actively controlled stimulation through their own movement. In contrast to signals measured at the head, the spectral content of externally generated (i.e., passive) environmental motion did follow a power law. Specifically, transformations caused by both motor control and biomechanics shape the statistics of natural vestibular stimuli before neural processing. We suggest that the unique structure of natural vestibular stimuli will have important consequences on the neural coding strategies used by this essential sensory system to represent self-motion in everyday life.


Small-for-gestational age prevalence risk factors in central Appalachian states with mountain-top mining.
To identify risk factors for small-for-gestational age (SGA) for counties in central Appalachian states (Kentucky (KY), Tennessee (TN), Virginia (VA), and West Virginia (WV)) with varied coal mining activities. Live birth certificate files (1990-2002) were used for obtaining SGA prevalence rates for mothers based on the coal mining activities of their counties of residence, mountain-top mining (MTM) activities, underground mining activities but no mountain-top mining activity (non-MTM), or having no mining activities (non-mining). Co-variable information, including maternal tobacco use, was also obtained from the live birth certificate. Adjusted odds ratios were obtained using multivariable logistic regression comparing SGA prevalence rates for counties with coal mining activities to those without coal mining activities and comparing SGA prevalence rates for counties with coal mining activities for those with and without mountain-top mining activities. Comparisons were also made among those who had reported tobacco use and those who had not. Both tobacco use prevalence and SGA prevalence were significantly greater for mining counties than for non-mining counties and for MTM counties than for non-MTM counties. Adjustment for tobacco use alone explained 50% of the increased SGA risk for mining counties and 75% of the risk for MTM counties, including demographic pre-natal care co-variables that explained 75% of the increased SGA risk for mining counties and 100% of the risk for MTM. The increased risk of SGA was limited to the third trimester births among tobacco users and independent of the mining activities of their counties of residence. This study demonstrates that the increased prevalence of SGA among residents of counties with mining activity was primarily explained by the differences in maternal tobacco use prevalence, an effect that itself was gestational-age dependent. Self-reported tobacco use marked the population at the increased risk for SGA in central Appalachian states. Int J Occup Med Environ Health 2018;31(1):11-23.


Common Complication From Routine Shoulder Surgery: Postoperative Stiffness After Rotator Cuff Repair.
Rotator cuff repair is commonly performed, and stiffness represents one of the most common complications. Unique characteristics of postoperative stiffness, including its natural history and pathoanatomy, differentiate it from other etiologies of shoulder stiffness. Patient risk factors that have been associated with postoperative stiffness should be reviewed to better help clinicians tailor their presurgical risk assessment. Although stiffness in this setting has clinical consequences for patients' postoperative shoulder function, it is important to discuss the important implications of stiffness as it relates to rotator cuff healing. Multiple strategies have been proposed to decrease the incidence of postoperative stiffness. There is evidence to support these preventive strategies, and it has led to author recommendations for treatment of refractory cases and prevention.


Act on the Registration and Evaluation of Chemicals (K-REACH) and replacement, reduction or refinement best practices.
Korea's Act on the Registration and Evaluation of Chemicals (K-REACH) was enacted for the protection of human health and the environment in 2015. Considering that about 2000 new substances are introduced annually across the globe, the extent of animal testing requirement could be overwhelming unless regulators and companies work proactively to institute and enforce global best practices to replace, reduce or refine animal use. In this review, the way to reduce the animal use for K-REACH is discussed. Background of the enforcement of the K-REACH and its details was reviewed along with the papers and regulatory documents regarding the limitation of animal experiments and its alternatives in order to discuss the regulatory adoption of alternative tests. Depending on the tonnage of the chemical used, the data required ranges from acute and other short-term studies for a single exposure route to testing via multiple exposure routes and costly, longer-term studies such as a full two-generation reproducibility toxicity. The European Registration, Evaluation, Authorization and Restriction of Chemicals regulation provides for mandatory sharing of vertebrate test data to avoid unnecessary duplication of animal use and test costs, and obligation to revise data requirements and test guidelines "as soon as possible" after relevant, validated replacement, reduction or refinement (3R) methods become available. Furthermore, the Organization for Economic Cooperation and Development actively accepts alternative animal tests and 3R to chemical toxicity tests. Alternative tests which are more ethical and efficient than animal experiments should be widely used to assess the toxicity of chemicals for K-REACH registration. The relevant regulatory agencies will have to make efforts to actively adopt and uptake new alternative tests and 3R to K-REACH.


Fuzzy neural network with general parameter adaptation for modeling of nonlinear time-series.
By taking advantage of fuzzy systems and neural networks, a fuzzy-neural network with a general parameter (GP) learning algorithm and heuristic model structure determination is proposed in this paper. Our network model is based on the Gaussian radial basis function network (RBFN). We use the flexible GP approach both for initializing the off-line training algorithm and fine-tuning the nonlinear model efficiently in online operation. A modification of the robust unbiasedness criterion using distorter (UCD) is utilized for selecting the structural parameters of this adaptive model. The UCD approach provides the desired modeling accuracy and avoids the risk of over-fitting. In order to illustrate the operation of the proposed modeling scheme, it is experimentally applied to a fault detection application.


A pruning-based disk scheduling algorithm for heterogeneous I/O workloads.
In heterogeneous I/O workload environments, disk scheduling algorithms should support different QoS (Quality-of-Service) for each I/O request. For example, the algorithm should meet the deadlines of real-time requests and at the same time provide reasonable response time for best-effort requests. This paper presents a novel disk scheduling algorithm called G-SCAN (Grouping-SCAN) for handling heterogeneous I/O workloads. To find a schedule that satisfies the deadline constraints and seek time minimization simultaneously, G-SCAN maintains a series of candidate schedules and expands the schedules whenever a new request arrives. Maintaining these candidate schedules requires excessive spatial and temporal overhead, but G-SCAN reduces the overhead to a manageable level via pruning the state space using two heuristics. One is grouping that clusters adjacent best-effort requests into a single scheduling unit and the other is the branch-and-bound strategy that cuts off inefficient or impractical schedules. Experiments with various synthetic and real-world I/O workloads show that G-SCAN outperforms existing disk scheduling algorithms significantly in terms of the average response time, throughput, and QoS-guarantees for heterogeneous I/O workloads. We also show that the overhead of G-SCAN is reasonable for on-line execution.


Ebola virus infection inversely correlates with the overall expression levels of promyelocytic leukaemia (PML) protein in cultured cells.
Ebola virus causes severe, often fatal hemorrhagic fever in humans. The mechanism of escape from cellular anti-viral mechanisms is not yet fully understood. The promyelocytic leukaemia (PML) associated nuclear body is part of the interferon inducible cellular defense system. Several RNA viruses have been found to interfere with the anti-viral function of the PML body. The possible interaction between Ebola virus and the PML bodies has not yet been explored. We found that two cell lines, Vero E6 and MCF7, support virus production at high and low levels respectively. The expression of viral proteins was visualized and quantified using high resolution immunofluorescence microscopy. Ebola encoded NP and VP35 accumulated in cytoplasmic inclusion bodies whereas VP40 was mainly membrane associated but it was also present diffusely in the cytoplasm as well as in the euchromatic areas of the nucleus. The anti-VP40 antibody also allowed the detection of extracellular virions. Interferon-alpha treatment decreased the production of all three viral proteins and delayed the development of cytopathic effects in both cell lines. Virus infection and interferon-alpha treatment induced high levels of PML protein expression in MCF7 but much less in Vero E6 cells. No disruption of PML bodies, a common phenomenon induced by a variety of different viruses, was observed. We have established a simple fixation and immunofluorescence staining procedure that allows specific co-detection and precise sub-cellular localization of the PML nuclear bodies and the Ebola virus encoded proteins NP, VP35 and VP40 in formaldehyde treated cells. Interferon-alpha treatment delays virus production in vitro. Intact PML bodies may play an anti-viral role in Ebola infected cells.


A quantitative study of potassium channel kinetics in rat skeletal muscle from 1 to 37 degrees C.
Potassium currents were measured using the three-microelectrode voltage-clamp technique in rat omohyoid muscle at temperatures from 1 to 37 degrees C. The currents were fitted according to the Hodgkin-Huxley equations as modified for K currents in frog skeletal muscle (Adrian et al., 1970a). The equations provided an approximate description of the time course of activation, the voltage dependence of the time constant of activation (tau n), and the voltage dependence of gK infinity. At higher temperatures the relationship between gK infinity and voltage was shifted in the hyperpolarizing direction. The effect of temperature on tau n was much greater in the cold than in the warm: tau n had a Q10 of nearly 6 at temperatures below 10 degrees C, but a Q10 of only approximately 2 over the range of 30-38 degrees C. The decreasing dependence of tau n on temperature was gradual and the Arrhenius plot of tau n revealed no obvious break-points. In addition to its quantitative effect on activation kinetics, temperature also had a qualitative effect. Near physiological temperatures (above approximately 25 degrees C), the current was well described by n4 kinetics. At intermediate temperatures (approximately 15-25 degrees C), the current was well described by n4 kinetics, but only if the n4 curve was translated rightward along the time axis (i.e., the current had a greater delay than could be accounted for by simple n4 kinetics). At low temperatures (below approximately 15 degrees C), n4 kinetics provided only an approximate fit whether or not the theoretical curve was translated along the time axis. In particular, currents in the cold displayed an initial rapid phase of activation followed by a much slower one. Thus, low temperatures appear to reveal steps in the gating process which are kinetically "hidden" at higher temperatures. Taken together, the effects of temperature on potassium currents in rat skeletal muscle demonstrate that the behavior of potassium channels at physiological temperatures cannot be extrapolated, either quantitatively or qualitatively, from experiments carried out in the cold.


Prolonged Maternal Zika Viremia as a Marker of Adverse Perinatal Outcomes.
Whether prolonged maternal viremia after Zika virus infection represents a risk factor for maternal-fetal transmission and subsequent adverse outcomes remains unclear. In this prospective cohort study in French Guiana, we enrolled Zika virus-infected pregnant women with a positive PCR result at inclusion and noninfected pregnant women; both groups underwent serologic testing in each trimester and at delivery during January-July 2016. Prolonged viremia was defined as ongoing virus detection >30 days postinfection. Adverse outcomes (fetal loss or neurologic anomalies) were more common in fetuses and neonates from mothers with prolonged viremia (40.0%) compared with those from infected mothers without prolonged viremia (5.3%, adjusted relative risk [aRR] 7.2 [95% CI 0.9-57.6]) or those from noninfected mothers (6.6%, aRR 6.7 [95% CI 3.0-15.1]). Congenital infections were confirmed more often in fetuses and neonates from mothers with prolonged viremia compared with the other 2 groups (60.0% vs. 26.3% vs. 0.0%, aRR 2.3 [95% CI 0.9-5.5]).


What kind of diagnosis in a case of mobbing: post-traumatic stress disorder or adjustment disorder?
Over the last decade a consistent increase in stress-related psychological consequences at the workplace, usually called 'mobbing', has been seen. It claimed physical, psychical and social distress as its victims, leading to an increased incidence of many illnesses, such as psychosomatic disorders (ache, high blood pressure, chronic fatigue and insomnia) and psychiatric disturbances (high level of anxiety, depression and suicidal attempts). It was recently demonstrated that mobbing is significantly widespread among healthcare workers, especially among female nurses. In this report, we illustrate the case of a nurse who, after a brilliant career, underwent mobbing at the workplace, showing depression, anxiety and sleep disorders that required hospitalisation and a substantial intervention.


The effect of ethanol on surface of semi-interpenetrating polymer network (IPN) polymer matrix of glass-fibre reinforced composite.
The aim of this laboratory study was to evaluate the effect of ethanol treatment on the surface roughness (Sa), nano-mechanical properties (NMP) and surface characterization of dental fiber reinforced composite (FRC) with semi-interpenetrating polymer network (IPN). A total of 240 FRC specimens with bisphenol A-glycidyl methacrylate - triethyleneglycol dimethacrylate - Poly (methylmetahcrylate) (bis-GMA-TEGDMA-PMMA) IPN matrix system were light cured for 40 s and divided into 2 groups (L and LH). The group LH was further post-cured by heat at 95 °C for 25 min. The specimens were exposed to 99.9%, 70% and 40% for 15, 30, 60 and 120 s respectively. The treated specimens were evaluated for Sa using non-contact profilometer. NMP were determined using nanoindentation technique and chemical characterization was assessed by Fourier Transform-Infrared (FTIR) spectroscopic analyses. Scanning electron microscopic (SEM) images were made to evaluate the surface topographical changes. Both the L and LH group showed changes in the Sa and NMP after being treated by different concentrations of ethanol and at different time interval. The highest Sa was observed with L-group (0.733 μm) treated with 99.9% ethanol for 120 s. Specimens in LH-group treated with 99.9% ethanol for 120 s (1.91 GPa) demonstrated increased nano-hardness, and group treated with 40% ethanol for 120 s demonstrated increased Young's modulus of elasticity (22.90 GPa). FTIR analyses revealed changes in the intensity and bandwidth in both the L and LH groups. The present study demonstrated that both light-cured and heat post-cured FRC were prone for ethanol induced alteration in the surface roughness (Sa), nano-mechanical properties (NMP) and chemical characterization. The interphase between the glass fibers and the organic matrix was affected by ethanol. The changes were considerably less in magnitude in the heat post-cured FRC specimens.


A Non-Invasive Technique for Long-Term Monitoring of Gastroesophageal Reflux-A Pilot Study.
Many people suffer from gastric or gastroesophageal reflux disorder (GERD) due to a malfunction of the cardia, the valve between the esophagus and the stomach. GERD is a syndrome caused by the ascent of gastric juices and bile from the stomach. This article proposes a non-invasive impedance measurement method and demonstrates the correlation between GERD and impedance variation between appropriately chosen points on the patient's chest. This method is presented as an alternative to the most widely accepted diagnostic techniques for reflux, such as pH-metry, pH-impedance measurement, and esophageal manometry, which are invasive because they use a probe that is inserted through a nostril and reaches down to the esophagus.


Repeatability of corneal first-surface wavefront aberrations measured with Pentacam corneal topography.
To assess the repeatability of corneal wavefront aberrations derived from Pentacam (Oculus) corneal topography. Flinders Eye Centre, Flinders Medical Centre, Bedford Park, South Australia, Australia. Forty-five normal participants and 10 participants with keratoconus were tested. Intraobserver and interobserver repeatability was determined using 4 observers within and between sessions. Topographical maps were exported to external software, and corneal first-surface wavefront aberrations were calculated using a 10th-order Zernike expansion over a 6.0 mm optical zone. Repeatability was determined with Bland-Altman limits of agreement and expressed as the coefficient of repeatability (COR). Initial data showed high wavefront aberrations in normal participants and poor repeatability. Topographical maps showed extrapolated topography in zones without data acquisition; maps with less than 6.0 mm of complete data were excluded in the final analysis. The mean wavefront aberrations for normal participants remained high, but repeatability improved. The COR relative to the magnitude of wavefront aberrations was high (average 100%) across all modal pairs and orders, although best for total higher-order root mean square. Participants with keratoconus had higher magnitude wavefront aberrations and poorer repeatability but similar COR to average wavefront aberration ratios. Examination of raw elevation data showed poor repeatability. Wavefront aberrations calculated from Pentacam corneal topography were large in magnitude, and reliability was poor, largely due to variability in corneal elevation data. Intraobserver and interobserver reliability within and between sessions was comparable. The Pentacam was not reliable in measuring corneal wavefront aberrations.


The impact of a public-health intervention on sex differentials in childhood mortality in rural Punjab, India.
This paper examines the effects of a public-health intervention program on sex differentials in health and mortality during childhood. Among the different health-service packages offered as part of the experimental design, those including nutritional services seem to have been more successful in reducing excess female mortality. The reason for this success appears to have been careful follow-up of undernourished children by project workers. The results also indicate that, consistent with earlier research, girls with surviving older sisters had higher mortality rates after their first month of life. Contrary to earlier research, however, boys with surviving older brothers also have higher mortality rates, at least between the ages of one and three years. We conclude that these effects for boys and girls cannot be attributed to problems associated with larger family size, since the number of older siblings of the opposite sex (regardless of survival status) does not generally appear to be related to children's chances of survival.


De novo transcriptome assembly and data for the blue-winged teal (Spatula discors).
The blue-winged teal (Spatula discors) is a recreationally and ecologically important dabbling duck species in North America. Transcriptomic data of this species can be used in public and animal health studies given its role as a natural reservoir host for avian influenza, which can be a zoonotic disease of high concern. Ileum and bursa of Fabricius tissues were sampled from six captive raised blue-winged teals, four of the six who were experimentally infected with low-pathogenic avian influenza virus H5N9. RNAseq data were generated from extracted total mRNA from each tissue and pooled to create a de novo assembly of the transcriptome using Trinity. A total of 571,105 transcripts were identified at 449,956 unique unigenes that have been functionally annotated. This transcriptome will be useful for future blue-winged teal gene expression research, especially in hypothesis driven differential expression studies to determine the driving forces of avian influenza host-pathogen interactions, spatial distribution, and transmission.


Indoleamine 2,3-dioxygenase and regulatory T cells in acute myeloid leukemia.
The microenvironment of acute myeloid leukemia (AML) is suppressive for immune cells. Regulatory T cells (Tregs) have been recognized to play a role in helping leukemic cells to evade immunesurveillance. The mesenchymal stem cells (MSCs) are essential contributors in immunomodulation of the microenvironment as they can promote differentiation of Tregs via the indoleamine 2,3-dioxygenase (IDO) pathway. The aim of the present work was to evaluate the expression of IDO in bone marrow derived MSCs and to study its correlation to percentage of Tregs. Thirty-seven adult bone marrow samples were cultured in appropriate culture medium to isolate MSCs. Successful harvest of MSCs was determined by plastic adherence, morphology, and positive expression of CD271 and CD105; negative expression of CD34 and CD45 using flowcytometry. MSCs were examined for IDO expression by immunocytochemistry using anti-IDO monoclonal antibody. CD4+ CD25+ cells (Tregs) were measured in bone marrow samples by flowcytometry. MSCs were successfully isolated from 20 of the 37 bone marrow samples cultured. MSCs showed higher expression of IDO and Tregs percentage was higher in AML patients compared to control subjects (P = 0.002 and P < 0.001, respectively). A positive correlation was found between IDO expression and Tregs percentage (P value = 0.012, r = 0.5). In this study, we revealed an association between high IDO expression in MSCs and elevated levels of Tregs which could have an important role in the pathogenesis of AML, providing immunosuppressive microenvironment.


Secondary capsular laxity of the hip.
We describe a hip condition with a recognisable pattern of clinical signs and radiological findings thought to result from chronic capsular injury. Between June 2006 and October 2009, ten patients (11 hips), four men and six women, were identified with an abnormality of external rotation at the hip joint. A detailed history and clinical examination was undertaken for each patient. Dynamic magnetic resonance imaging of symptomatic and control hips were evaluated for bony and soft tissue appearances. The relative positions of the femoral head and the acetabulum were assessed through a range of hip rotation. In affected hips, a loss of normal log roll recoil was observed. Three distortions of the iliofemoral ligament were identified on axial MR images; thinning at the lateral insertion of the ligament, attenuation of the iliofemoral ligament most noticeably on maximum external rotation (60º) and the appearance of laxity despite full external rotation. Stability of the hip is dependent on the interaction of bony and soft tissue structures. Hip instability is recognised in dysplasia and is known to lead to premature degeneration of the joint. Chronic capsular injury may destabilise previously asymptomatic hips with subsequent development of pain in young, active patients.


Public opinion on alcohol service at licensed premises: a population survey in Stockholm, Sweden 1999-2000.
In 1996, a community alcohol-prevention program focusing on licensed premises was initiated in Stockholm, Sweden. As a part of this initiative, a study has been conducted to investigate the public opinion in Stockholm on different strategies to reduce problems related to alcohol service at licensed premises. A random sample of 1000 people resident in Stockholm County, within the age-group 18-65 years was selected. A postal questionnaire was sent out during the time-period November 1999 and January 2000 (response rate 59%). The questionnaire included questions on background factors, and support for various strategies to reduce intoxication and to prevent violence at licensed premises. The impact of each background factor on level of support for each strategy was analyzed using logistic regression. We found an overall strong support for licensed premises to practice responsible beverage service to reduce intoxication, whereas strategies to reduce availability (e.g., increased alcohol price, reduced open hours) were unpopular. The level of support differed by background factor. Frequent alcohol consumers, men, young people (< or =30 years), and frequent visitors to licensed premises, were less supportive. There is strong popular support for licensed premises to practice responsible beverage service and for stricter enforcement of existing legislation by local authorities.


Majocchi's granuloma: a symptom complex caused by fungal pathogens.
Majocchi's granuloma (MG) is a well-recognized but uncommon infection of dermal and subcutaneous tissues that is caused by mold fungi. Although primarily caused by keratinophilic dermatophytes such as anthropophilic Trichophyton rubrum, species from the Aspergillus and Phoma genera have been occasionally detected as etiologic agents of MG. In both healthy individuals and immunocompromised hosts, MG often presents as nodules, plaques, and papules on areas that are prone to trauma. Although MG generally appears on the upper and lower extremities (forearms, hands, legs, or ankles), it occasionally appears on the scalp and face. The clinical, mycologic, and/or cytologic diagnosis should be confirmed by the demonstration of perifollicular granulomatous inflammation by histologic examination. This review focuses on the clinical presentation, pathogenesis, laboratory diagnostic methods (including the Tzanck smear test), etiologic agents, histopathologic characteristics, and therapeutic approaches to the treatment of MG.


The Norepinephrine Metabolite 3,4-Dihydroxymandelic Acid Is Produced by the Commensal Microbiota and Promotes Chemotaxis and Virulence Gene Expression in Enterohemorrhagic Escherichia coli.
Enterohemorrhagic Escherichia coli (EHEC) is a commonly occurring foodborne pathogen responsible for numerous multistate outbreaks in the United States. It is known to infect the host gastrointestinal tract, specifically, in locations associated with lymphoid tissue. These niches serve as sources of enteric neurotransmitters, such as epinephrine and norepinephrine, that are known to increase virulence in several pathogens, including enterohemorrhagic E. coli The mechanisms that allow pathogens to target these niches are poorly understood. We previously reported that 3,4-dihydroxymandelic acid (DHMA), a metabolite of norepinephrine produced by E. coli, is a chemoattractant for the nonpathogenic E. coli RP437 strain. Here we report that DHMA is also a chemoattractant for EHEC. In addition, DHMA induces the expression of EHEC virulence genes and increases attachment to intestinal epithelial cells in vitro in a QseC-dependent manner. We also show that DHMA is present in murine gut fecal contents and that its production requires the presence of the commensal microbiota. On the basis of its ability to both attract and induce virulence gene expression in EHEC, we propose that DHMA acts as a molecular beacon to target pathogens to their preferred sites of infection in vivo.


Arabidopsis eIF5A3 influences growth and the response to osmotic and nutrient stress.
AteIF5A3, one of three genes encoding eukaryotic translation initiation factor 5A (eIF5A) in Arabidopsis thaliana, and corresponding genes PdeIF5A3 from Populus deltoides (eastern cottonwood) and SleIF5A4 from Solanum lycopersicum (tomato) were constitutively over-expressed in A. thaliana. The resultant transgenic plants exhibited enhanced vegetative and reproductive growth. Indeed, the increase in seed yield relative to empty vector controls for the PdeIF5A3 over-expressing plants ranged from 50% to 300% depending on the line. The PdeIF5A3 over-expressing plants also exhibited enhanced fitness when exposed to osmotic and nutrient (N, P and K) stress. The spatial localization of AteIF5A3 was visualized by confocal microscopy using transgenic plants expressing P(AteIF5A3) :GFP-AteIF5A3. GFP fluorescence reflecting expression of AteIF5A3 was detectable in the phloem, particularly companion cells, of roots, stems and leaves, in the epidermal cells of the root tip, in the columella cells of the root cap and in the chalazal tissue of fertilized ovules, which all play a pivotal role in nutrient or hormone translocation. Thus, AteIF5A3 appears to be involved in supporting growth and to play a regulatory role in the response of plants to sub-lethal osmotic and nutrient stress.


Census parcels cropping system classification from multitemporal remote imagery: a proposed universal methodology.
A procedure named CROPCLASS was developed to semi-automate census parcel crop assessment in any agricultural area using multitemporal remote images. For each area, CROPCLASS consists of a) a definition of census parcels through vector files in all of the images; b) the extraction of spectral bands (SB) and key vegetation index (VI) average values for each parcel and image; c) the conformation of a matrix data (MD) of the extracted information; d) the classification of MD decision trees (DT) and Structured Query Language (SQL) crop predictive model definition also based on preliminary land-use ground-truth work in a reduced number of parcels; and e) the implementation of predictive models to classify unidentified parcels land uses. The software named CROPCLASS-2.0 was developed to semi-automatically perform the described procedure in an economically feasible manner. The CROPCLASS methodology was validated using seven GeoEye-1 satellite images that were taken over the LaVentilla area (Southern Spain) from April to October 2010 at 3- to 4-week intervals. The studied region was visited every 3 weeks, identifying 12 crops and others land uses in 311 parcels. The DT training models for each cropping system were assessed at a 95% to 100% overall accuracy (OA) for each crop within its corresponding cropping systems. The DT training models that were used to directly identify the individual crops were assessed with 80.7% OA, with a user accuracy of approximately 80% or higher for most crops. Generally, the DT model accuracy was similar using the seven images that were taken at approximately one-month intervals or a set of three images that were taken during early spring, summer and autumn, or set of two images that were taken at about 2 to 3 months interval. The classification of the unidentified parcels for the individual crops was achieved with an OA of 79.5%.


A computational model of the fetal circulation to quantify blood redistribution in intrauterine growth restriction.
Intrauterine growth restriction (IUGR) due to placental insufficiency is associated with blood flow redistribution in order to maintain delivery of oxygenated blood to the brain. Given that, in the fetus the aortic isthmus (AoI) is a key arterial connection between the cerebral and placental circulations, quantifying AoI blood flow has been proposed to assess this brain sparing effect in clinical practice. While numerous clinical studies have studied this parameter, fundamental understanding of its determinant factors and its quantitative relation with other aspects of haemodynamic remodeling has been limited. Computational models of the cardiovascular circulation have been proposed for exactly this purpose since they allow both for studying the contributions from isolated parameters as well as estimating properties that cannot be directly assessed from clinical measurements. Therefore, a computational model of the fetal circulation was developed, including the key elements related to fetal blood redistribution and using measured cardiac outflow profiles to allow personalization. The model was first calibrated using patient-specific Doppler data from a healthy fetus. Next, in order to understand the contributions of the main parameters determining blood redistribution, AoI and middle cerebral artery (MCA) flow changes were studied by variation of cerebral and peripheral-placental resistances. Finally, to study how this affects an individual fetus, the model was fitted to three IUGR cases with different degrees of severity. In conclusion, the proposed computational model provides a good approximation to assess blood flow changes in the fetal circulation. The results support that while MCA flow is mainly determined by a fall in brain resistance, the AoI is influenced by a balance between increased peripheral-placental and decreased cerebral resistances. Personalizing the model allows for quantifying the balance between cerebral and peripheral-placental remodeling, thus providing potentially novel information to aid clinical follow up.


Differences in the effect of exercise interventions between prefrail older adults and older adults without frailty: A pilot study.
We aimed to clarify whether there are differences in the effect of exercise interventions between prefrail older adults and older adults without frailty. The participants were community-dwelling older adults (mean age 75.1 ± 5.1 years). The participants were instructed to use a training method at home to prevent frailty. The effects of the intervention were evaluated at 4 months. Outcome measures were the Timed Up and Go test, grip strength, one leg balance, knee extension strength and the fall risk index. The present study used the criteria for frailty status of the National Center for Geriatrics and Gerontology in Japan. The studied sample included prefrail participants (n = 17) and robust participants (n = 24). We compared the value of outcome measures before and after the intervention in each group using two-way repeated measures analysis of variance. There were significant differences for the group effect for one leg balance (P < 0.01), and there were significant differences for the time effect for Timed Up and Go, one leg balance and knee extension strength (P < 0.01). In these outcomes, there were no significant interactions between frailty status and intervention. Four prefrail participants (mean age 78.0 ± 3.8 years) returned to the robust status after the intervention. No participants became frail. These results suggest that we can expect similar interventional effects for prefrail older adults and robust older adults. It is important that a frail status be prevented in prefrail older adults by using an exercise intervention. Further studies are required to determine the different effects of exercise intervention on prefrail status compared with frailty status in community-dwelling older adults. Geriatr Gerontol Int 2017; 17: 1265-1269.


Nutrition guidelines for undergraduate medical curricula: a six-country comparison.
To assess nutrition curriculum guidelines for undergraduate medical education in the United States, Canada, the United Kingdom, Republic of Ireland, Australia, and New Zealand to highlight potential opportunities for shared learning on the advancement of nutrition in medical education. A comprehensive list of professional bodies, councils, organizations, and other groups relevant to education or nutrition was compiled for each country after a review of relevant white and gray literature. All documents that were published from 2000 onwards, and that provided guidance on nutrition education within undergraduate medical education for one of the identified countries were included in the review. Each curriculum guideline was evaluated for 1) the organization's or group's role in undergraduate medical education; 2) the extent of nutrition-related recommendations; and 3) mandatory implementation. In the countries reviewed, a total of six nutrition-related curriculum guidelines were identified. All countries, aside from the Republic of Ireland, currently have externally visible curriculum guidelines to inform medical schools in undergraduate nutrition education, yet there is little evidence of mandatory enforcement. Curriculum guidelines predominantly focus on basic nutrition principles, nutrition assessment, the role of nutrition in health, interdisciplinary teamwork, and the provision of nutrition counseling. Notable differences exist regarding the scope and detail of curriculum guidelines for the reviewed countries. There are promising developments in nutrition curriculum guidelines for medical schools within the reviewed countries. Differences in the scope and detail of nutrition curriculum guidelines may influence the nutrition education provided to medical students, and the subsequent nutrition care provided by doctors in these countries. Consideration is required as to how to monitor and evaluate the nutrition competence of doctors in relation to routine health care practices, as well as the impact of their competency levels on patients' nutrition behavior and health outcomes.


Promoter architecture of mouse olfactory receptor genes.
Odorous chemicals are detected by the mouse main olfactory epithelium (MOE) by about 1100 types of olfactory receptors (OR) expressed by olfactory sensory neurons (OSNs). Each mature OSN is thought to express only one allele of a single OR gene. Major impediments to understand the transcriptional control of OR gene expression are the lack of a proper characterization of OR transcription start sites (TSSs) and promoters, and of regulatory transcripts at OR loci. We have applied the nanoCAGE technology to profile the transcriptome and the active promoters in the MOE. nanoCAGE analysis revealed the map and architecture of promoters for 87.5% of the mouse OR genes, as well as the expression of many novel noncoding RNAs including antisense transcripts. We identified candidate transcription factors for OR gene expression and among them confirmed by chromatin immunoprecipitation the binding of TBP, EBF1 (OLF1), and MEF2A to OR promoters. Finally, we showed that a short genomic fragment flanking the major TSS of the OR gene Olfr160 (M72) can drive OSN-specific expression in transgenic mice.


Decannulation and survival following tracheostomy in an intensive care unit.
We investigated the long-term outcome of patients requiring tracheostomy in an intensive care unit (ICU) in an attempt to identify risk factors that would indicate a low probability of early decannulation. A retrospective study was conducted of a consecutive series of 106 patients who underwent tracheostomy in the period between January 1, 2001, and December 31, 2001, during their admission to the ICU at the Royal Melbourne Hospital, Melbourne, Australia. There were 61 male and 39 female patients with a median age of 65 years. The indications for tracheostomy were prolonged mechanical ventilation (47), tracheobronchial toilet or risk of aspiration (45), and an unstable or obstructed airway (8). Thirty-seven patients died during the study period. All surviving patients were successfully decannulated (median cannulation time, 25 days). Patients with tracheostomies inserted for an unstable or obstructed airway had a significantly shorter cannulation time (median time of 13 days) as compared to the other two indications (mechanical ventilation, 25 days; risk of aspiration, 33 days; log-rank test, chi2(2) = 14.62 and p = .0007). Multivariate analysis showed that the effect of an unstable or obstructed airway was independent of the remaining group variables. We conclude that ICU patients who need a tracheostomy have a high mortality rate. Only the indication for tracheostomy insertion predicts early decannulation, and other patient variables are not significant predictors.


Glucocorticoid-induced leucine zipper governs the therapeutic potential of mesenchymal stem cells by inducing a switch from pathogenic to regulatory Th17 cells in a mouse model of collagen-induced arthritis.
Mesenchymal stem cells (MSCs) are potent immunosuppressive cells that have shown promise in the treatment of rheumatoid arthritis (RA). Deciphering the intrinsic characteristics of MSCs that correlate with their biologic activity will facilitate their clinical use. Recently, the role of glucocorticoid-induced leucine zipper (GILZ) in the development of RA has been documented. The aim of this study was to evaluate whether GILZ expression by MSCs may contribute to their therapeutic effect. MSCs were isolated from GILZ-deficient (GILZ(-/-) ) mice and wild-type mice. MSCs (1 × 10(6) cells) were injected twice via the tail vein into mice with collagen-induced arthritis (CIA). In vitro, we showed that GILZ is a key factor involved in the immunosuppressive potential of MSCs. MSCs derived from GILZ(-/-) mice did not suppress the proliferation of CD4+ T cells and were less efficient than MSCs derived from WT mice in altering Th17 cell polarization. Thus, we investigated the role of GILZ in an experimental model of arthritis and demonstrated that although WT MSCs significantly reduced paw swelling in arthritic mice, GILZ(-/-) MSCs did not. Moreover, the magnitude of the effects of GILZ(-/-) MSCs on Th17 cell frequency was significantly lower than that of WT MSCs. The therapeutic effect of MSCs correlated with the generation of Treg cells bearing the CD4 + RORγt+IL-17(low) IL-10+ signature, and Th17 cell polarization was GILZ dependent. This study demonstrates that GILZ has an essential role in the therapeutic effectiveness of MSCs in arthritis by favoring Th17 cell polarization toward a regulatory phenotype. Therefore, potentiation of GILZ expression in MSCs could represent a means to enhance their therapeutic effect in autoimmune diseases.


Tailor-made biochar systems: Interdisciplinary evaluations of ecosystem services and farmer livelihoods in tropical agro-ecosystems.
Organic matter management is key to sustain ecosystem services provided by soils. However, it is rarely considered in a holistic view, considering local resources, agro-environmental effects and harmonization with farmers' needs. Organic inputs, like compost and biochar, could represent a sustainable solution to massive current challenges associated to the intensification of agriculture, in particular for tropical regions. Here we assess the potential of agricultural residues as a resource for farmer communities in southwestern India to reduce their dependency on external inputs and sustain ecosystem services. We propose a novel joint evaluation of farmers' aspirations together with agro-environmental effects of organic inputs on soils. Our soil quality evaluation showed that biochar alone or with compost did not improve unilaterally soils in the tropics (Anthroposol, Ferralsol and Vertisol). Many organic inputs led to an initial decrease in water-holding capacities of control soils (-27.3%: coconut shell biochar with compost on Anthroposol). Responses to organic matter inputs for carbon were strongest for Ferralsols (+33.4% with rice husk biochar), and mostly positive for Anthroposols and Vertisols (+12.5% to +13.8% respectively). Soil pH responses were surprisingly negative for Ferralsols and only positive if biochar was applied alone (between -5.6% to +1.9%). For Anthroposols and Vertisols, highest increases were achieved with rice husk biochar + vermicomposts (+7.2% and +5.2% respectively). Our socio-economic evaluation showed that farmers with a stronger economical position showed greater interest towards technology like biochar (factor 1.3 to 1.6 higher for farmers cultivating Anthroposols and/or Vertisols compared to Ferralsols), while poorer farmers more skepticism, which may lead to an increased economical gap within rural communities if technologies are not implemented with long-term guidance. These results advocate for an interdisciplinary evaluation of agricultural technology prior to its implementation as a development tool in the field.


Maternal vitamin D status and risk of pre-eclampsia: a systematic review and meta-analysis.
Although several studies have investigated the association between maternal serum vitamin D levels and risk of pre-eclampsia, findings are inconsistent. This systematic review and meta-analysis of published observational studies was conducted to summarize the evidence on the association between maternal serum vitamin D levels and risk of pre-eclampsia. PubMed, ISI (Web of science), SCOPUS, SCIRUS, Google Scholar, and EMBASE databases were searched to identify related articles published through December 2012. For systematic review, we found 15 articles that assessed the association between maternal serum vitamin D levels and risk of pre-eclampsia. The meta-analysis was done on 8 studies that reported odds ratios or relative risks for pre-eclampsia. Between-study heterogeneity was examined using Cochran's Q test and I(2). Subgroup analysis and meta-regression were used to find possible sources of heterogeneity. The meta-analysis on 8 relevant papers revealed an overall significant association between vitamin D deficiency and risk of pre-eclampsia; however, there was significant between-study heterogeneity (I(2) = 52.7%; P = .039). In the subgroup analysis, we found that the overall effect was significant for studies that defined vitamin D deficiency as 25(OH)D ≤ 50 nmol/L (20 ng/mL), but not for those that considered it as <38 nmol/L (15.2 ng/mL). The association was seen for "cohort or nested case-control studies" as well as for "cross-sectional or case-control studies" (2.78; 1.45-5.33; P = .002). When the analysis was done by study location, the associations remained significant only for studies that came from the United States. There was a significant relationship between vitamin D deficiency and increased risk of pre-eclampsia. Further studies are required, particularly in developing countries.


Arterial stiffness is increased in nondiabetic, nonhypertensive postmenopausal women with nonalcoholic fatty liver disease.
The purpose of this study was to assess the relationship between nonalcoholic fatty liver disease (NAFLD) and arterial stiffness in nondiabetic, nonhypertensive postmenopausal women with and without metabolic syndrome. We divided 1007 postmenopausal women into two groups (NAFLD and controls) and then three groups (NAFLD with metabolic syndrome, NAFLD without metabolic syndrome, and controls), respectively. To exclude the influence of confounding factors, we studied a specifically selected group with no additional cardiovascular risk. Carotid intima-media thickness (CIMT), carotid-femoral pulse wave velocity (cf-PWV), and flow-mediated dilatation (FMD) were measured in all study patients and controls. Patients with NAFLD had significantly greater CIMT than did controls (P < 0.001). cf-PWV was also significantly higher in patients with NAFLD than in controls (P < 0.001). We found significantly decreased FMD in patients with NAFLD than in control patients (P < 0.001). Although patients with NAFLD and metabolic syndrome had greater CIMT and cf-PWV and less FMD than healthy patients did (P < 0.05), there were no significant differences in CIMT, cf-PWV, and FMD (P > 0.05) between patients with NAFLD with and without metabolic syndrome. The presence of NAFLD is associated with an increased risk of arterial stiffness in postmenopausal women, independent of the presence of metabolic syndrome.


PSA repeatedly fluctuating levels are reassuring enough to avoid biopsy?
Prostate-specific antigen (PSA) levels can show wide fluctuations when repeatedly measured. Here we investigatewd if: (a) biopsy timing influences the prostate cancer (PC) detection rate in patients with fluctuating PSA (flu-PSA) in comparison with patients with steadily increasing PSA (si-PSA); (b) PSA slope estimated in patients with flu-PSA predicts a different risk of cancer detection; (c) flu-PSA and si-PSA patients develop PC in topographically different sites; (d) the behaviour of pre-operative PSA is an expression of a disease with defferent characteristics to the following radical prostatectomy. The study involved 211 patients who underwent at least a second biopsy after a first negative prostate biopsy. PSA Slope, PSA velocity (PSAV) and PSA doubling time (PSADT) were estimated. Flu-PSA level was defined as a PSA series with at least one PSA value lower than the one immediately preceding it. 82 patients had flu-PSA levels and 129 si-PSA levels. There were no significant differences between the two groups in terms of cancer detection, clinical or pathological stage, but the si-PSA group with cancer had a higher Gleason score. No difference was found for PSA Slope between flu-PSA patients with cancer and those without. Our study demonstrates no difference in PC detection rate at repeat biopsy between patients with flu or si-PSA levels. PSA Slope, PSAV and PSADT were not found helpful tools in cancer detection.


The Australian Palliative Care Outcomes Collaboration (PCOC)--measuring the quality and outcomes of palliative care on a routine basis.
Australia is leading the way in establishing a national system (the Palliative Care Outcomes Collaboration - PCOC) to measure the outcomes and quality of specialist palliative care services and to benchmark services across the country. This article reports on analysis of data collected routinely at point-of-care on 5939 patients treated by the first fifty one services that voluntarily joined PCOC. By March 2009, 111 services have agreed to join PCOC, representing more than 70% of services and more than 80% of specialist palliative care patients nationally. All states and territories are involved in this unique process that has involved extensive consultation and infrastructure and close collaboration between health services and researchers. The challenges of dealing with wide variation in outcomes and practice and the progress achieved to date are described. PCOC is aiming to improve understanding of the reasons for variations in clinical outcomes between specialist palliative care patients and differences in service outcomes as a critical step in an ongoing process to improve both service quality and patient outcomes.


[Prognosis factors associated with the progression of preeclampsia to eclampsia].
This study was undertaken to determine the prognosis value of laboratory and clinical findings in the progression of preeclampsia to eclampsia. Nausea and vomiting and glucose level > 105 mg/dL, serum creatinine level > 1.0 mg/dL, aspartate aminotransferase level > 35 IU/L, alanine aminotransferase level > 40 IU/L and lactate deshiydrogenase level > 450 IU/L can be used to estimate the risk for the advancement to eclampsia. This information could be helpful to the clinician for management purposes.


Calcineurin Dysregulation Underlies Spinal Cord Injury-Induced K+ Channel Dysfunction in DRG Neurons.
Dysfunction of the fast-inactivating Kv3.4 potassium current in dorsal root ganglion (DRG) neurons contributes to the hyperexcitability associated with persistent pain induced by spinal cord injury (SCI). However, the underlying mechanism is not known. In light of our previous work demonstrating modulation of the Kv3.4 channel by phosphorylation, we investigated the role of the phosphatase calcineurin (CaN) using electrophysiological, molecular, and imaging approaches in adult female Sprague Dawley rats. Pharmacological inhibition of CaN in small-diameter DRG neurons slowed repolarization of the somatic action potential (AP) and attenuated the Kv3.4 current. Attenuated Kv3.4 currents also exhibited slowed inactivation. We observed similar effects on the recombinant Kv3.4 channel heterologously expressed in Chinese hamster ovary cells, supporting our findings in DRG neurons. Elucidating the molecular basis of these effects, mutation of four previously characterized serines within the Kv3.4 N-terminal inactivation domain eliminated the effects of CaN inhibition on the Kv3.4 current. SCI similarly induced concurrent Kv3.4 current attenuation and slowing of inactivation. Although there was little change in CaN expression and localization after injury, SCI induced upregulation of the native regulator of CaN 1 (RCAN1) in the DRG at the transcript and protein levels. Consistent with CaN inhibition resulting from RCAN1 upregulation, overexpression of RCAN1 in naive DRG neurons recapitulated the effects of pharmacological CaN inhibition on the Kv3.4 current and the AP. Overall, these results demonstrate a novel regulatory pathway that links CaN, RCAN1, and Kv3.4 in DRG neurons. Dysregulation of this pathway might underlie a peripheral mechanism of pain sensitization induced by SCI.SIGNIFICANCE STATEMENT Pain sensitization associated with spinal cord injury (SCI) involves poorly understood maladaptive modulation of neuronal excitability. Although central mechanisms have received significant attention, recent studies have identified peripheral nerve hyperexcitability as a driver of persistent pain signaling after SCI. However, the ion channels and signaling molecules responsible for this change in primary sensory neuron excitability are still not well defined. To address this problem, this study used complementary electrophysiological and molecular methods to determine how Kv3.4, a voltage-gated K+ channel robustly expressed in dorsal root ganglion neurons, becomes dysfunctional upon calcineurin (CaN) inhibition. The results strongly suggest that CaN inhibition underlies SCI-induced dysfunction of Kv3.4 and the associated excitability changes through upregulation of the native regulator of CaN 1 (RCAN1).


X-ray ptychographic and fluorescence microscopy of frozen-hydrated cells using continuous scanning.
X-ray microscopy can be used to image whole, unsectioned cells in their native hydrated state. It complements the higher resolution of electron microscopy for submicrometer thick specimens, and the molecule-specific imaging capabilites of fluorescence light microscopy. We describe here the first use of fast, continuous x-ray scanning of frozen hydrated cells for simultaneous sub-20 nm resolution ptychographic transmission imaging with high contrast, and sub-100 nm resolution deconvolved x-ray fluorescence imaging of diffusible and bound ions at native concentrations, without the need to add specific labels. By working with cells that have been rapidly frozen without the use of chemical fixatives, and imaging them under cryogenic conditions, we are able to obtain images with well preserved structural and chemical composition, and sufficient stability against radiation damage to allow for multiple images to be obtained with no observable change.


Lipaemia, inflammation and atherosclerosis: novel opportunities in the understanding and treatment of atherosclerosis.
Atherosclerosis is the major cause of death in the world. Fasting and postprandial hyperlipidaemia are important risk factors for coronary heart disease (CHD). Recent developments have undoubtedly indicated that inflammation is pathophysiologically closely linked to atherogenesis and its clinical consequences. Inflammatory markers such as C-reactive protein (CRP), leucocyte count and complement component 3 (C3) have been linked to CHD and to hyperlipidaemia and several other CHD risk factors. Increases in these markers may result from activation of endothelial cells (CRP, leucocytes, C3), disturbances in adipose tissue fatty acid metabolism (CRP, C3), or from direct effects of CHD risk factors (leucocytes). It has been shown that lipoproteins, triglycerides, fatty acids and glucose can activate endothelial cells, most probably as a result of the production of reactive oxygen species. Similar mechanisms may also lead to leucocyte activation. Increases in triglycerides, fatty acids and glucose are common disturbances in the metabolic syndrome and are most prominent in the postprandial phase. People are in a postprandial state most of the day, and this phase is proatherogenic. Inhibition of the activation of leucocytes, endothelial cells, or both, is an interesting target for intervention, as activation is obligatory for adherence of leucocytes to the endothelium, thereby initiating atherogenesis. Potential interventions include the use of unsaturated long-chain fatty acids, polyphenols, antioxidants, angiotensin converting enzyme inhibitors and high-dose aspirin, which have direct anti-inflammatory and antiatherogenic effects. Furthermore, peroxisome proliferator activating receptor gamma (PPARgamma) agonists and statins have similar properties, which are in part independent of their lipid-lowering effects.


Left ventricular pulsus alternans in patients with hypertrophic cardiomyopathy and severe obstruction to left ventricular outflow.
Left ventricular pulsus alternans (LVPA), a rhythmic beat to beat variation in left ventricular systolic pressure and outflow gradient, was noted in 35 of 200 ventricular systolic pressure and outflow gradient, was noted in 35 of 200 patients with hypertrophic cardiomyopathy undergoing hemodynamic study. LVPA was not associated with significant systemic pulsus alternans nor right ventricular pulsus alternans. All patients with LVPA had severe outflow gradients at rest or during provocation. Of 61 patients with severe basal outflow gradients (greater than 80 mm Hg), 12 demonstrated LVPA at rest. Eight of these patients underwent ventricular septal myotomy-myectomy; all had successful abolition of basal outflow gradient. Of the seven of these eight patients who underwent postoperative hemodynamic study and who were in sinus rhythm, none demonstrated LVPA. Eleven of 60 patients with basal outflow gradients ranging from 10 to 70 mm Hg demonstrated LVPA during maneuvers provocative for outflow gradients (mean gradient 90 +/- 37 mm Hg). Two of these patients underwent ventricular septal myotomy-myectomy; neither had a gradient nor LVPA during provocation postoperatively. Twelve additional patients with basal outflow gradients ranging from 0 to 115 mm Hg had LVPA after ectopic beats, generally occurring during maneuvers provocative for outflow gradients, associated with severe outflow gradients (mean gradient 130 +/- 39 mm Hg) during the postextrasystolic beat. None of the 41 patients without an outflow gradient, basal or during provocation, was found to have LVPA. Thus LVPA is commonly seen in during provocation, was found to have LVPA. Thus LVPA is commonly seen in patients with hypertrophic cardiomyopathy and severe left ventricular outflow gradients and may represent inadequate left ventricular contractile function in the presence of high left ventricular systolic pressures.


Effects of Si-Jun-Zi decoction polysaccharides on cell migration and gene expression in wounded rat intestinal epithelial cells.
Si-Jun-Zi decoction (SJZD), a traditional Chinese herbal prescription, has been used clinically for treating patients with disorders of the digestive system. Previous studies indicated that the polysaccharides of SJZD (SJZPS) are the active components contributing towards its pharmacological effects in improving gastrointestinal function and immunity. However, the protective and restitutive effects on intestinal epithelial cells remain unknown. In the present study, SJZPS were first extracted and chemically characterized. Then their stimulatory and restitutive effects on intestinal epithelial cells (IEC-6 cells) were elicited by different in vitro models including migration of wounded IEC-6 cells and cell proliferation. Results indicated that SJZPS not only protects the cells against the harmful impairment of indomethacin but also enhances re-epithelialization of a wounded monolayer at an optimal dose of 100 mug/ml at 24 h incubation. To elucidate the modulatory effect of SJZPS on wounded IEC-6 cells at the molecular level, an oligonucleotide microarray was employed to study differential gene expression of SJZPS-treated IEC-6 cells and the candidate genes were validated by RT-PCR. There was increased expression of genes coding for ion channels and transporters, which are critical to cell migration and restoration of wounded intestinal cells, suggesting a possible mechanism for re-epithelialization. In conclusion, our data show for the first time that SJZPS can enhance intestinal restitution and protect against indomethacin-induced damage of intestinal epithelial cells. These findings provide new insight into the mechanism of action of a traditional Chinese herbal prescription, SJZD, in intestinal wound restitution.


Is Sodium Carbonate in Snuff a Causative Factor for Oral Mucosal Lesions: A Cross-sectional Analysis.
Nicotine absorption through the mucous membrane is directly proportional to pH, so the snuff is buffered to pH of 8-9 by adding sodium carbonate. The objective of the present study is to assess the impact of various forms of sodium carbonate in snuff on mucosal conditions. The present cross-sectional study was conducted on 284 participants. Snuff users adding sodium carbonate were further splitted into two groups, that is, one group using sodium carbonate in premixed form, that is, (already mixed within pouches) and other group adding sodium carbonate separately (freshly mixed). The parametric one-way (ANOVA) of variance, stepwise regression analysis, and multiple logistic regression analysis have been done to narrate the relationship between variables of different forms of sodium carbonate in snuff and different oral conditions. The statistics of our study reveals highly significant relationship between snuff users using sodium carbonate in freshly mixed (0.001**) form than that of premixed form (P = 0.030*). The present study narrates that there seems to be liaison between the use of sodium carbonate in snuff and oral mucosal lesions.


Sexual and other noninjection risks for HBV and HCV seroconversions among noninjecting heroin users.
Many heroin users do not inject drugs but may still be at risk of infection with human immunodeficiency virus (HIV), hepatitis B virus (HBV), and hepatitis C virus (HCV), via sexual or other noninjection-related activity. Noninjecting heroin users (NIUs) in New York City who were recruited and prospectively followed during March 1996-February 2003 were tested for anti-HIV, anti-hepatitis B core antigen, and anti-HCV and were interviewed about their sexual and other noninjecting risk. A seroconversion is represented by the first positive test result after the last negative test result. Hazard ratios (HRs) (P<.05) were estimated by use of Cox proportional hazards regression. Of 253 HIV-negative participants, 2 seroconverted (0.29/100 person-years at risk [pyar]); of 184 HBV-negative participants, 16 (3.3/100 pyar); and, of 219 HCV-negative participants, 16 (2.7/100 pyar). Independent predictors of seroconversion were, for HBV, being a female who engages in unprotected receptive anal sex (HR, 6.8), having short-term sex partners (HR, 6.2), and being a male with male sex partners (HR, 5.7); for HCV, being a male who receives money/drugs for sex (HR, 5.6) and sharing noninjecting crack-use equipment (HR, 4.5). NIUs are at considerable risk of HBV infection via high-risk sex; and, for HCV, via high-risk sexual activity and the sharing of noninjecting crack-use equipment. Interventions in NIUs must seek to reduce high-risk sexual activity and the sharing of noninjecting drug-use equipment.


Additive fabrication of SiO2-based micro-optics with lag-free depth and reduced roughness.
Ultra-thin optical components with high design flexibility are required for various applications in today's optical and imaging systems, and this is why the use of diffractive optical elements (DOEs) is rapidly increasing. They can be used for multiple optical systems because of their compact size, increased design flexibility, and ease of mass production. Unfortunately, most existing DOEs are fabricated using conventional etching-based methods, resulting in high surface roughness and aspect ratio-dependent etching rate. Furthermore, when small feature size and large feature size patterns co-exist in the same DOE design, the etching depth differs significantly in the same design, called reactive-ion etching (RIE) lag. All these artifacts lead to a reduction in the diffraction efficiency of DOEs. To overcome the drawbacks of etching-based fabrication methods, we propose an alternative method for fabricating DOEs without RIE lag and with improved surface smoothness. The method consists of additively growing multilevel microstructures of SiO2 material deposited by the plasma-enhanced chemical vapor deposition (PECVD) method onto the substrate followed by liftoff. We demonstrate the effectiveness of the fabrication methods with representative DOEs for imaging and laser beam shaping applications.


Gleaning bat echolocation calls do not elicit antipredator behaviour in the Pacific field cricket, Teleogryllus oceanicus (Orthoptera: Gryllidae).
Bats that glean prey (capture them from surfaces) produce relatively inconspicuous echolocation calls compared to aerially foraging bats and could therefore be difficult predators to detect, even for insects with ultrasound sensitive ears. In the cricket Teleogryllus oceanicus, an auditory interneuron (AN2) responsive to ultrasound is known to elicit turning behaviour, but only when the cricket is in flight. Turning would not save a cricket from a gleaning bat so we tested the hypothesis that AN2 elicits more appropriate antipredator behaviours when crickets are on the ground. The echolocation calls of Nyctophilus geoffroyi, a sympatric gleaning bat, were broadcast to singing male and walking female T. oceanicus. Males did not cease singing and females did not pause walking more than usual in response to the bat calls up to intensities of 82 dB peSPL. Extracellular recordings from the cervical connective revealed that the echolocation calls elicited AN2 action potentials at high firing rates, indicating that the crickets could hear these stimuli. AN2 appears to elicit antipredator behaviour only in flight, and we discuss possible reasons for this context-dependent function.


Variants in the ITPA gene protect against ribavirin-induced hemolytic anemia and decrease the need for ribavirin dose reduction.
In a genome-wide association study of patients being treated for chronic hepatitis C, 2 functional variants in ITPA that cause inosine triphosphatase (ITPase) deficiency were shown to protect against ribavirin (RBV)-induced hemolytic anemia during early stages of treatment. We aimed to replicate this finding in an independent cohort from the Study of Viral Resistance to Antiviral Therapy of Chronic Hepatitis C and to investigate the effects of these variants beyond week 4. Genetic material was available from 318 patients. The ITPA variants, rs1127354 (exon 2, P32T) and rs7270101 (intron 2, splice altering), were genotyped and tested for association with hemoglobin (Hb) reduction at week 4. An ITPase deficiency variable was defined that combined both ITPA variants according to documented effect on ITPase activity. We investigated the impact of ITPA variants on Hb levels over the course of therapy and on the need for RBV dose reduction. The final analysis included 304 patients with genotype 1 hepatitis C virus (167 white patients and 137 black patients). The polymorphisms rs1127354 and rs7270101 were associated with Hb reduction at week 4 (P = 3.1 × 10(-13) and 1.3 × 10(-3), respectively). The minor alleles of each variant protected against Hb reduction. Combining the variants into the ITPase deficiency variable strengthened the association (P = 2.4 × 10(-18)). The ITPase deficiency variable was associated with lower rates of anemia over the entire treatment period (48 weeks), as well as a lower rate of anemia-related RBV dose reduction (hazard ratio, 0.52; P = .0037). No association with sustained virological response was observed. Two polymorphisms that cause ITPase deficiency are strongly associated with protection from RBV-induced hemolytic anemia and decrease the need for RBV dose reduction.


DNA Methylation Dynamics During the Differentiation of Retinal Progenitor Cells Into Retinal Neurons Reveal a Role for the DNA Demethylation Pathway.
To evaluate the contribution of the DNA methylation and DNA demethylation pathways in retinal development, we studied DNA methylation in retinal progenitor cells (RPCs) and retinal neurons using a combination of whole genome bisulfite sequencing (WGBS) data obtained in our study and WGBS data collected from previous studies. The data was analyzed using Hidden Markov Model- and change point-based methods to identify methylome states in different segments of the studied genomes following genome annotation. We found that promoters of rod and cone phototransduction genes and rod photoreceptor genes, but not genes required for the development and function of other retinal phenotypes, were highly methylated in DNA isolated from human and murine fetal retinas (which mostly contain RPCs) and postnatal murine RPCs. While these highly methylated genomic regions were inherited by non-photoreceptor phenotypes during RPC differentiation, the methylation of these promoters was significantly reduced during RPC differentiation into photoreceptors and accompanied by increased expression of these genes. Our analysis of DNA methylation during embryogenesis revealed low methylation levels in genomic regions containing photoreceptor genes at the inner cell mass stage, but a sharp increase in methylation at the epiblast stage, which remained the same later on (except for DNA demethylation in photoreceptors). Thus, our data suggest that the DNA demethylation pathway is required for photoreceptor phenotypes in the developing retina. Meanwhile, the role of the DNA methylation and DNA demethylation pathways during RPC differentiation into non-photoreceptor retinal phenotypes might be less important.


Synaptonemal complex analysis of mouse chromosomal rearrangements. IV. Synapsis and synaptic adjustment in two paracentric inversions.
Two paracentric inversions in the mouse, In (1) 1 Rk and In (2) 5 Rk, have been studied in surface microspreads of spermatocytes from heterozygotes. At zytogene, synaptic initiation occurs independently in three regions: within the inversion, and without, on either side. Synaptonemal complex (SC) formation is restricted to homologous regions, resulting in inversion loops in all early pachytene spermatocytes. An adjusting phase then occurs during pachytene in which the inversion loop is reduced by desynapsis of homologously synapsed SC, followed immediately by non-homologous synapsis with the alternate pairing partner, progressing from the ends toward the middle. Adjustment occurs during the first half of pachytene, but is not closely synchronized with sub-stage. It is complete by late pachytene, the loop having been eliminated in all cases and replaced by "straight" SCs in which the inverted region is heterosynapsis. Synapsis in the adjustment phase is evidently permitted only after the homosynaptic phase, and is indifferent to homology. It may lead to hetersynapsis, as in the inversion region, or to synapsis of homologous regions not synapsed at zytogene. The anaphase bridge frequency, a measure of crossing over within the inversion, is about 34% for both inversions studied, indicating that such crossovers do not block adjustment, that crossing over probably occurs before or during the adjustment period, and that there is some crossover suppression. The last could be the consequence of blocking by desynapsis/heterosynapsis. Synaptic adjustment appears to be a general phenomenon that occurs to varying extents in different forms. A hypothetical scheme for two phases of synapsis is proposed: at zytogene, a basic propensity for indifferent SC formation is limited by a restricting condition to synapsis between homologous regions, Subsequently, the restriction is lifted, whereupon synaptic instability is resolved by desynapsis, followed by resynapsis that is indifferent to homology, but that results in a topologically more stable structure.


The protein phosphatase PPKL is a key regulator of daughter parasite development in Toxoplasma gondii.
Apicomplexan parasites, including Toxoplasma gondii, encode many plant-like proteins, which play significant roles and present attractive targets for drug development. In this study, we have characterized the plant-like protein phosphatase PPKL, which is unique to the parasite and absent in its mammalian host. We have shown that its localization changes as the parasite divides. In non-dividing parasites, it is present in the cytoplasm, nucleus, and preconoidal region. As the parasite begins division, PPKL is enriched in the preconoidal region and the cortical cytoskeleton of nascent parasites. Later in the division, PPKL is present in the basal complex ring. Conditional knockdown of PPKL showed that it is essential for parasite propagation. Moreover, parasites lacking PPKL exhibit uncoupling of division, with normal DNA duplication but severe defects in forming daughter parasites. While PPKL depletion does not impair the duplication of centrosomes, it affects the stability of cortical microtubules. Both co-immunoprecipitation and proximity labeling identified the kinase DYRK1 as a potential functional partner of PPKL. Complete knockout of DYRK1 causes parasites to exhibit division defects with predominantly asynchronous divisions. Global phosphoproteomics analysis revealed a significant increase in phosphorylation of the microtubule-associated protein SPM1 in PPKL-depleted parasites, suggesting that PPKL regulates cortical microtubules by mediating the phosphorylation state of SPM1. More importantly, the phosphorylation of cell cycle-associated kinase Crk1, a known regulator of daughter cell assembly, is altered in PPKL-depleted parasites. Thus, we propose that PPKL regulates daughter parasite development by influencing the Crk1-dependent signaling pathway. IMPORTANCE Toxoplasma gondii can cause severe disease in immunocompromised or immunosuppressed patients and during congenital infections. Treating toxoplasmosis presents enormous challenges since the parasite shares many biological processes with its mammalian hosts, which results in significant side effects with current therapies. Consequently, proteins that are essential and unique to the parasite represent favorable targets for drug development. Interestingly, Toxoplasma, like other members of the phylum Apicomplexa, has numerous plant-like proteins, many of which play crucial roles and do not have equivalents in the mammalian host. In this study, we found that the plant-like protein phosphatase PPKL appears to be a key regulator of daughter parasite development. With the depletion of PPKL, the parasite shows severe defects in forming daughter parasites. This study provides novel insights into the understanding of parasite division and offers a new potential target for the development of antiparasitic drugs.


The effect of training on responses of beta-endorphin and other pituitary hormones to insulin-induced hypoglycemia.
We studied whether the previously reported intensified beta-endorphin response to exercise after training might result from a training-induced general increase in anterior pituitary secretory capacity. Identical hypoglycemia was induced by insulin infusion in 7 untrained (VO2max 49 +/- 4 ml X (kg X min)-1, mean and SE) and 8 physically trained (VO2max 65 +/- 4 ml X (kg X min)-1) subjects. In response to hypoglycemia, levels of beta-endorphin and prolactin immunoreactivity in serum increased similarly in trained (from 41 +/- 2 pg X ml-1 and 6 +/- 1 pg X ml-1 before hypoglycemia to 103 +/- 11 pg X ml-1 and 43 +/- 9 pg X ml-1 during recovery, P less than 0.05) and untrained (from 35 +/- 7 pg X ml-1 and 7 +/- 2 pg X ml-1 to 113 +/- 18 pg X ml-1 and 31 +/- 8 pg X ml-1, P less than 0.05) subjects. Growth hormone (GH) was higher 90 min after glucose nadir in trained (61 +/- 13 mU X l-1) than in untrained (25 +/- 6 mU X l-1) subjects (P less than 0.05). Levels of thyrotropin (TSH) changed in neither of the groups. It is concluded that, in contrast to what has been formerly proposed, training does not result in a general increase in secretory capacity of the anterior pituitary gland. TSH responds to hypoglycemia neither in trained nor in untrained subjects. Finally, differences in beta-endorphin responses to exercise between trained and untrained subjects cannot be ascribed to differences in responsiveness to hypoglycemia.


New oral anticoagulants increase risk for gastrointestinal bleeding: a systematic review and meta-analysis.
A new generation of oral anticoagulants (nOAC), which includes thrombin and factor Xa inhibitors, has been shown to be effective, but little is known about whether these drugs increase patients' risk for gastrointestinal bleeding (GIB). Patients who require OAC therapy frequently have significant comorbidities and may also take aspirin and/or thienopyridines. We performed a systematic review and meta-analysis of the risk of GIB and clinically relevant bleeding in patients taking nOAC. We queried MEDLINE, EMbase, and the Cochrane library (through July 2012) without language restrictions. We analyzed data from 43 randomized controlled trials (151,578 patients) that compared nOAC (regardless of indication) with standard care for risk of bleeding (19 trials on GIB). Odds ratios (ORs) were estimated using a random-effects model. Heterogeneity was assessed with the Cochran Q test and the Higgins I(2) test. The overall OR for GIB among patients taking nOAC was 1.45 (95% confidence interval [CI], 1.07-1.97), but there was substantial heterogeneity among studies (I2, 61%). Subgroup analyses showed that the OR for atrial fibrillation was 1.21 (95% CI, 0.91-1.61), for thromboprophylaxis after orthopedic surgery the OR was 0.78 (95% CI, 0.31-1.96), for treatment of venous thrombosis the OR was 1.59 (95% CI, 1.03-2.44), and for acute coronary syndrome the OR was 5.21 (95% CI, 2.58-10.53). Among the drugs studied, the OR for apixaban was 1.23 (95% CI, 0.56-2.73), the OR for dabigatran was 1.58 (95% CI, 1.29-1.93), the OR for edoxaban was 0.31 (95% CI, 0.01-7.69), and the OR for rivaroxaban was 1.48 (95% CI, 1.21-1.82). The overall OR for clinically relevant bleeding in patients taking nOAC was 1.16 (95% CI, 1.00-1.34), with similar trends among subgroups. Studies on treatment of venous thrombosis or acute coronary syndrome have shown that patients treated with nOAC have an increased risk of GIB, compared with those who receive standard care. Better reporting of GIB events in future trials could allow stratification of patients for therapy with gastroprotective agents.


Ethnicity, socioeconomic position and severity of problems as predictors of mental health care use in 5- to 8-year-old children with problem behaviour.
Empirical research on mental health care use and its determinants in young school-aged children is still scarce. In this study, we investigated the role of ethnicity, socioeconomic position (SEP) and perceived severity by both parents and teachers on mental health care use in 5- to 8-year old children with emotional and/or behavioural problems. Data from 1,269 children with a high score([P90) on the Strengths and Difficulties Questionnaire (SDQ) in the school year 2008–2009 were linked to psychiatric case register data over the years 2010–2011. Cox proportional hazards models were used to predict mental health care use from ethnicity, SEP and perceived severity of the child's problems. During the follow-up period, 117 children with high SDQ scores (9.2 %) had used mental health care for the first time. Ethnic minority children were less likely to receive care than Dutch children (HR Moroccan/Turkish:0.26; 95 % CI 0.13-0.54, HR other ethnicity: 0.26; 95 %CI 0.12-0.58). No socioeconomic differences were found.After correction for previous care use, ethnicity and parental perceived severity, impact score as reported by teachers was significantly associated with mental healthcare use (HR 1.58; 95 % CI 1.01–2.46). Ethnicity is an important predictor of mental health care use in young children. Already in the youngest school-aged children, ethnic differences in the use of mental health care are present.A distinct predictor of care use in this age group is severity of emotional and behavioural problems as perceived by teachers. Therefore, teachers may be especially helpful in the process of identifying young children who need specialist mental health care.


Psychological Well-Being Among Internally Displaced Adolescents and the Effect of Psychopathology on PTSD Scores Depends on Gender.
The purpose of this cross-sectional study was to investigate the post-traumatic symptoms and psychological well-being among internally displaced (ID) adolescents in the early phase of the conflict in the southeast part of Turkey and clarify the effect of psychopathology on PTSD scores depends on gender. With the help of the results of our study, we aimed to enhance our understanding of adolescent mental health. Our study was completed with 102 ID adolescents (42 boys, 60 girls). Our results showed that ID adolescents flee from conflict had significantly higher levels of mental disorders and PTSD. Girls show higher rates of PTSD symptoms than boys and there was no significant interactive effect of gender and emotional, behavioral and peer problems on PTSD. However, boys with ADHD seem to be more prone to develop PTSD than girls. We aimed to highlight the challenges facing adolescents forced to flee from conflict zones who were temporarily relocated. These results may help us to enlighten our understanding of ID adolescents and may suggest more studies to provide beneficial gender-specific intervention program.


Reimagining Pharmaceutical Market Exclusivities: Should the Duration of Guaranteed Monopoly Periods Be Value Based?
To describe the main features of a pharmaceutical market in which the duration of guaranteed monopoly periods would correspond to a new pharmaceutical product's value. After reviewing patent and regulatory exclusivity-based mechanisms for protecting prescription drug markets from competition to incentivize drug innovation in developed countries, we model market protection mechanisms within the current framework to give the longest-lasting market protections to drug developers that bring the most affordable products to market with highest public health and clinical value. An approach tying pharmaceutical market exclusivity to value would have 3 main features. First, it would be based on regulatory exclusivity (ie, the drug regulator refrains from authorizing generic entry for a certain amount of time), rather than patents. Second, the duration of exclusivity period would be pegged to the magnitude of a product's anticipated health impact and its proposed price by using modified methods from the field of health technology assessment. Third, the duration of the value-based exclusivity period would be reassessed routinely 3 years after the product's launch to account for its real-world effectiveness. Linking a drug's proposed price to the duration of its regulatory-based exclusivities would both incentivize the development of high impact, low-cost products and motivate drug developers to introduce these products at lower prices.


Geometric atlas: modeling the cortex as an organized surface.
Recent atlases of the cortical surface are based on a modelization of the cerebral cortex as a topological sphere. This captures effectively its organization as a regular bidimensional sheet of layers parallel to the surface and with perpendicular cortical columns. Yet, while in the vertical direction cortices are almost the same throughout phylia, in the sense of its surface the cerebral cortex is one of the most variable and distinctive parts of the nervous system. Indeed, gyri and sulci appear to have a crucial organizing role in an architectonic, connectional, and functional sense. This organization is not explicitly captured by the surface model of the cortex. We propose a geometric model of the cortical anatomy based on flat representations of principal sulci obtained from surface reconstructions of MRI data, and on neuroanatomical and theoretical considerations concerning the folding patterns of the cortex. The cortex is modeled by a sphere where primary sulci are included as axes. The arrangement of the axes is a simplification of the arrangement of principal sulci observed in flat stereographic representations of the whole cortical surface. The position of secondary and tertiary sulci is then defined by a field of orientations parallel and orthogonal to the axes. We consider the use of the geometric model as a synthetic reference cortex for addressing reconstructions of cortical surfaces. We present a method which establishes a bijection between the geometric model and a cortical surface reconstruction by using the axes of the model as boundary conditions for a set of partial differential equations solved over both surfaces. Using the geometric model as atlas provides a natural parameterization of the cortical surface that, unlike angular coordinates, allows for a localization based on the surface distance to its main organizing landmarks and folding patterns.


Fetal liver cells transplanted in utero rescue the osteopetrotic phenotype in the oc/oc mouse.
Autosomal recessive osteopetrosis (ARO) is a group of genetic disorders that involve defects that preclude the normal function of osteoclasts, which differentiate from hematopoietic precursors. In half of human cases, ARO is the result of mutations in the TCIRG1 gene, which codes for a subunit of the vacuolar proton pump that plays a fundamental role in the acidification of the cell-bone interface. Functional mutations of this pump severely impair the resorption of bone mineral. Although postnatal hematopoietic stem cell transplantation can partially rescue the hematological phenotype of ARO, other stigmata of the disease, such as secondary neurological and growth defects, are not reversed. For this reason, ARO is a paradigm for genetic diseases that would benefit from effective prenatal treatment. Using the oc/oc mutant mouse, a murine model whose osteopetrotic phenotype closely recapitulates human TCIRG1-dependent ARO, we report that in utero transplantation of adult bone marrow hematopoietic stem cells can correct the ARO phenotype in a limited number of mice. Here we report that in utero injection of allogeneic fetal liver cells, which include hematopoietic stem cells, into oc/oc mouse fetuses at 13.5 days post coitum produces a high level of engraftment, and the oc/oc phenotype is completely rescued in a high percentage of these mice. Therefore, oc/oc pathology appears to be particularly sensitive to this form of early treatment of the ARO genetic disorder.


Dangling bond dynamics on the silicon (100)-2x1 surface: dissociation, diffusion, and recombination
The dynamics of dangling bond (DB) diffusion was studied after deuterium desorption from the silicon (100)-2x1 surface. At elevated temperatures, paired DB sites produced after desorption unpaired as deuterium atoms hopped from adjacent dimers. Below 620 kelvin, the unpaired configuration most commonly observed corresponded to two DBs on adjacent silicon dimers. At higher temperatures, unpaired DBs executed one-dimensional walks along the dimer rows, and recombination was observed with the same partner after walks lasting many minutes. The frequency and extent of these excursions increased with temperature. Above 660 kelvin, complete dissociation was observed and was sometimes followed by recombination by means of partner exchange. The implications for low-temperature materials growth are discussed.