Differences in energy balance-related behaviours in European preschool children: the ToyBox-study.
The aim of the current study was to compare levels of energy balance-related behaviours (physical activity, sedentary behaviour, and dietary behaviours (more specifically water consumption, sugar-sweetened beverage consumption and unhealthy snacking)) in four- to six-year-old preschoolers from six European countries (Belgium, Bulgaria, Germany, Greece, Poland, and Spain) within the ToyBox cross-sectional study. A sample of 4,045 preschoolers (4.77 ± 0.43 years; 52.2% boys) had valid physical activity data (steps per day), parents of 8,117 preschoolers (4.78 ± 0.46 years; 53.0% boys) completed a parental questionnaire with questions on sedentary behaviours (television viewing, computer use, and quiet play), and parents of 7,244 preschoolers (4.77 ± 0.44 years; 52.0% boys) completed a food frequency questionnaire with questions on water consumption, sugar-sweetened beverage consumption and unhealthy snacking. The highest levels of physical activity were found in Spain (12,669 steps/day on weekdays), while the lowest levels were found in Bulgaria and Greece (9,777 and 9,656 steps/day on weekdays, respectively). German preschoolers spent the least amount of time in television viewing (43.3 min/day on weekdays), while Greek preschoolers spent the most time in television viewing (88.5 min/day on weekdays). A considerable amount of time was spent in quiet play in all countries, with the highest levels in Poland (104.9 min/day on weekdays), and the lowest levels in Spain (60.4 min/day on weekdays). Belgian, German, and Polish preschoolers had the lowest intakes of water and the highest intakes of sugar-sweetened beverages. The intake of snacks was the highest in Belgian preschoolers (73.1 g/day) and the lowest in Greek preschoolers (53.3 g/day). Across six European countries, differences in preschoolers' energy balance-related behaviours were found. Future interventions should target European preschoolers' energy balance-related behaviours simultaneously, but should apply country-specific adaptations.


Are adolescent elite athletes less psychologically distressed than controls? A cross-sectional study of 966 Norwegian adolescents.
Psychological distress is increasing among adolescents and clusters with other mental health problems such as eating problems. The aim of this study was to investigate the prevalence of psychological distress among young elite athletes and age-matched controls and whether prevalence figures may be attributed to perfectionism and eating problems. First-year athletes from all Norwegian elite sport high schools (n=711) and 500 students from randomly selected ordinary high schools were eligible for this cross-sectional study. In total, 611 athletes and 355 student controls provided self-report data about psychological distress, perfectionism, and eating problems (ie, body dissatisfaction and a drive for thinness), as well as their physical training/activity. A significantly higher proportion of controls scored above the cutoff point for marked psychological distress. Physical activity above the recommended levels for this age group predicted psychological distress among the controls, while the opposite was found in the student elite athlete sample. In both samples, perfectionistic concerns, ie, concern over mistakes, predicted overall psychological distress. However, among elite athletes, perfectionistic concerns were particularly associated with clinically significant psychological distress. Moreover, the impact of eating problems was negligible. Results from this study highlight the need to target the maladaptive perfectionistic concerns to prevent psychological distress among young athletes as well as among their age-matched nonathlete counterparts.


Translating mouse vocalizations: prosody and frequency modulation.
Mental illness can include impaired abilities to express emotions or respond to the emotions of others. Speech provides a mechanism for expressing emotions, by both what words are spoken and by the melody or intonation of speech (prosody). Through the perception of variations in prosody, an individual can detect changes in another's emotional state. Prosodic features of mouse ultrasonic vocalizations (USVs), indicated by changes in frequency and amplitude, also convey information. Dams retrieve pups that emit separation calls, females approach males emitting solicitous calls, and mice can become fearful of a cue associated with the vocalizations of a distressed conspecific. Because acoustic features of mouse USVs respond to drugs and genetic manipulations that influence reward circuits, USV analysis can be employed to examine how genes influence social motivation, affect regulation, and communication. The purpose of this review is to discuss how genetic and developmental factors influence aspects of the mouse vocal repertoire and how mice respond to the vocalizations of their conspecifics. To generate falsifiable hypotheses about the emotional content of particular calls, this review addresses USV analysis within the framework of affective neuroscience (e.g. measures of motivated behavior such as conditioned place preference tests, brain activity and systemic physiology). Suggested future studies include employment of an expanded array of physiological and statistical approaches to identify the salient acoustic features of mouse vocalizations. We are particularly interested in rearing environments that incorporate sufficient spatial and temporal complexity to familiarize developing mice with a broader array of affective states.


Hyperglycemia attenuates the gastrokinetic effect of erythromycin and affects the perception of postprandial hunger in normal subjects.
The major aims of this study were to determine in normal subjects whether the effects of erythromycin on gastric emptying, postprandial hunger, and fullness are modified by the blood glucose concentration. A total of 10 normal subjects (aged 20-39 years) underwent concurrent measurements of gastric emptying, blood glucose, hunger, and fullness on four separate occasions: twice during euglycemia (approximately 4 mmol/l) and twice during hyperglycemia (approximately 15 mmol/l). Either erythromycin (3 mg/kg) or saline (0.9%) was administered intravenously immediately before ingestion of a radioisotopically labeled solid meal. Gastric emptying was slower (P < 0.0001) during hyperglycemia when compared with euglycemia after both erythromycin and saline administration. During hyperglycemia, erythromycin reduced the lag phase (77.8 +/- 12.6 vs. 20.3 +/- 7.3 min; P < 0.05) but had no effect on the postlag emptying rate (0.32 +/- 0.077% per min vs. 0.24% per min). Hunger decreased (P < 0.001) and fullness increased (P < 0.001) after the meal. Postprandial hunger was less during hyperglycemia after saline infusion (P < 0.05) but not after erythromycin. Hunger was greater after erythromycin during both hyperglycemia and euglycemia (P < 0.05). At a blood glucose concentration of approximately 15 mmol/l, 1) gastric emptying of a solid meal is slower, when compared with euglycemia, even after administration of erythromycin; 2) the effect of erythromycin on gastric emptying of a solid meal is attenuated; and 3) the perception of postprandial hunger is reduced.


Exocytosis, mediatophore, and vesicular Ca2+/H+ antiport in rapid neurotransmission.
In rapid synapses, neurotransmitter quanta are emitted in less than 100 mus, often at a high frequency. Using fast cryofixation of synapses, we found a very brief (2-3 ms) change affecting intramembrane particles in presynaptic membrane. Vesicle openings also occurred but after a significant delay. The particle change is most probably linked to mediatophore, a proteolipid of 220 kDa. Mediatophore aggregates were demonstrated in active zones of the presynaptic membrane. Reconstituted in liposomes, Xenopus oocytes, and neuroblastoma cells, mediatophore releases acetylcholine in a Ca(2+)-dependent and quantal manner, mimicking physiological release. In restricted presynaptic "nanodomains," Ca(2+) concentration explosively reaches a high level and then vanishes with a time constant of 300-400 micros. Among the processes contributing to the fast phase of Ca(2+) buffering, a vesicular Ca(2+)/H(+) antiport plays a major role. Energized by the Vesicular-ATPase-dependent proton gradient, the antiport has a low affinity for Ca(2+). We inactivated the Ca(2+)/H(+) antiport using bafilomycin A1, which annihilates the proton gradient. As a result, the postsynaptic potential was increased in duration for about 3 ms, an effect caused by persistence of transmitter release. A similar change was obtained by replacing extracellular Ca(2+) by strontium, which inhibits the antiport. The antiport function, therefore, is to abbreviate the presynaptic Ca(2+) signal, making transmitter release briefer. This allows transmission to operate at high frequency. Following a brief period of stimulation, calcium transiently accumulates in synaptic vesicles where it is exchanged against transmitter. Calcium is subsequently cleared from the terminal, most probably by exocytosis.


Epigenetic transmission of the impact of early stress across generations.
Traumatic experiences in early life are risk factors for the development of behavioral and emotional disorders. Such disorders can persist through adulthood and have often been reported to be transmitted across generations. To investigate the transgenerational effect of early stress, mice were exposed to chronic and unpredictable maternal separation from postnatal day 1 to 14. We show that chronic and unpredictable maternal separation induces depressive-like behaviors and alters the behavioral response to aversive environments in the separated animals when adult. Most of the behavioral alterations are further expressed by the offspring of males subjected to maternal separation, despite the fact that these males are reared normally. Chronic and unpredictable maternal separation also alters the profile of DNA methylation in the promoter of several candidate genes in the germline of the separated males. Comparable changes in DNA methylation are also present in the brain of the offspring and are associated with altered gene expression. These findings highlight the negative impact of early stress on behavioral responses across generations and on the regulation of DNA methylation in the germline.


Sex Differences in the Effects of Prenatal Bisphenol A Exposure on Genes Associated with Autism Spectrum Disorder in the Hippocampus.
Autism spectrum disorder (ASD) is a neurodevelopmental disorder inexplicably biased towards males. Although prenatal exposure to bisphenol A (BPA) has recently been associated with the ASD risk, whether BPA dysregulates ASD-related genes in the developing brain remains unclear. In this study, transcriptome profiling by RNA-seq analysis of hippocampi isolated from neonatal pups prenatally exposed to BPA was conducted and revealed a list of differentially expressed genes (DEGs) associated with ASD. Among the DEGs, several ASD candidate genes, including Auts2 and Foxp2, were dysregulated and showed sex differences in response to BPA exposure. The interactome and pathway analyses of DEGs using Ingenuity Pathway Analysis software revealed significant associations between the DEGs in males and neurological functions/disorders associated with ASD. Moreover, the reanalysis of transcriptome profiling data from previously published BPA studies consistently showed that BPA-responsive genes were significantly associated with ASD-related genes. The findings from this study indicate that prenatal BPA exposure alters the expression of ASD-linked genes in the hippocampus and suggest that maternal BPA exposure may increase ASD susceptibility by dysregulating genes associated with neurological functions known to be negatively impacted in ASD, which deserves further investigations.


Temperature and pressure dependence of protein stability: the engineered fluorescein-binding lipocalin FluA shows an elliptic phase diagram.
We have measured the equilibrium constant for the denaturation transition of the engineered fluorescein-binding lipocalin FluA as a function of pressure and temperature, taking advantage of the fact that the ligand's fluorescence is almost fully quenched when complexed with the folded protein, but reversibly reappears on denaturation. From the equilibrium constant as a function of pressure and temperature all of the involved thermodynamic parameters of protein folding, in particular the changes in entropy and volume, compressibility, thermal expansion, and specific heat, were deduced in a global fitting procedure. Assuming that these parameters are independent of temperature and pressure, we can demonstrate from the ratio of Deltabeta, Deltaalpha(2), DeltaC(p) that the phase diagram of protein folding assumes an elliptic shape. Furthermore, we can show that the thermodynamic condition for such an elliptic phase diagram is related to the degree of correlation between the fluctuations of the changes in volume and enthalpy at the phase boundary. For the protein investigated this correlation is low, as generally expected for highly degenerate systems. Our study suggests that the elliptic phase diagram is a consequence of the inherent conformational disorder of proteins and that it may be viewed as the thermodynamic manifestation of the high degeneracy of conformational energies that is characteristic for this class of macromolecules.


Frontal cortex and reward-guided learning and decision-making.
Reward-guided decision-making and learning depends on distributed neural circuits with many components. Here we focus on recent evidence that suggests four frontal lobe regions make distinct contributions to reward-guided learning and decision-making: the lateral orbitofrontal cortex, the ventromedial prefrontal cortex and adjacent medial orbitofrontal cortex, anterior cingulate cortex, and the anterior lateral prefrontal cortex. We attempt to identify common themes in experiments with human participants and with animal models, which suggest roles that the areas play in learning about reward associations, selecting reward goals, choosing actions to obtain reward, and monitoring the potential value of switching to alternative courses of action.


Transparency window for the absorptive dipole resonance in a symmetry-reduced grating structure.
We demonstrate that a transparency window can be obtained within the absorptive dipole resonant regime, by slightly reducing the symmetric arrangement of a dipole-like bar grating covered by a waveguiding layer. The physical understanding is that, under the condition of reducing the grating symmetry, the lossy dipole plasmon resonance can be completely transferred into the waveguide mode in a way of destructive interference. In accompany with the tunable transparency window modulated by the symmetry-reduced displacement, an ultra high group index (slowing down the light) as well as a vortex distribution of the electromagnetic field is found.


Polygenic Risk and Neural Substrates of Attention-Deficit/Hyperactivity Disorder Symptoms in Youths With a History of Mild Traumatic Brain Injury.
Attention-deficit/hyperactivity disorder (ADHD) is a major sequela of traumatic brain injury (TBI) in youths. The objective of this study was to examine whether ADHD symptoms are differentially associated with genetic risk and brain structure in youths with and without a history of TBI. Medical history, ADHD symptoms, genetic data, and neuroimaging data were obtained from a community sample of youths. ADHD symptom severity was compared between those with and without TBI (TBI n = 418, no TBI n = 3193). The relationship of TBI history, genetic vulnerability, brain structure, and ADHD symptoms was examined by assessing 1) ADHD polygenic score (discovery sample ADHD n = 19,099, control sample n = 34,194), 2) basal ganglia volumes, and 3) fractional anisotropy in the corpus callosum and corona radiata. Youths with TBI reported greater ADHD symptom severity compared with those without TBI. Polygenic score was positively associated with ADHD symptoms in youths without TBI but not in youths with TBI. The negative association between the caudate volume and ADHD symptoms was not moderated by a history of TBI. However, the relationship between ADHD symptoms and structure of the genu of the corpus callosum was negative in youths with TBI and positive in youths without TBI. The identification of distinct ADHD etiology in youths with TBI provides neurobiological insight into the clinical heterogeneity in the disorder. Results indicate that genetic predisposition to ADHD does not increase the risk for ADHD symptoms associated with TBI. ADHD symptoms associated with TBI may be a result of a mechanical insult rather than neurodevelopmental factors.


MRI with state-of-the-art metal artifact reduction after total hip arthroplasty: periprosthetic findings in asymptomatic and symptomatic patients.
To assess the spectrum of periprosthetic MRI findings after primary total hip arthroplasty (THA). This multi-center cohort study analyzed 31 asymptomatic patients (65.7 ± 12.7 years) and 27 symptomatic patients (62.3 ± 11.9 years) between 6 months and 2 years after THA. 1.5-T MRI was performed using Compressed Sensing SEMAC and high-bandwidth sequences. Femoral stem and acetabular cup were assessed for bone marrow edema, osteolysis, and periosteal reaction in Gruen zones and DeLee and Charnley zones. Student t test and Fisher's exact test were performed. The asymptomatic and symptomatic groups showed different patterns of imaging findings. Bone marrow edema was seen in 19/31 (61.3%) asymptomatic and 22/27 (81.5%) symptomatic patients, most commonly in Gruen zones 1, 7, and 8 (p ≥ 0.18). Osteolysis occurred in 14/31 (45.2%) asymptomatic and 14/27 (51.9%) symptomatic patients and was significantly more common in Gruen zone 7 in the symptomatic group (8/27 (29.6%)) compared to the asymptomatic group (2/31 (6.5%)) (p = 0.03). Periosteal reaction was present in 4/31 asymptomatic (12.9%) and 9/27 symptomatic patients (33.3%) and more common in Gruen zones 5 and 6 in the symptomatic group (p = 0.04 and 0.02, respectively). In the acetabulum, bone marrow edema pattern was encountered in 3/27 (11.1%) symptomatic patients but not in asymptomatic patients (p ≥ 0.21). Patient management was altered in 8/27 (29.6%) patients based on MRI findings. Periprosthetic bone marrow edema is common after THA both in asymptomatic and symptomatic patients. Osteolysis and periosteal reaction are more frequent in symptomatic patients. MRI findings led to altered patient management in 29.6% of patients. • Bone marrow edema pattern was frequent in both asymptomatic and symptomatic patients after THA, particularly around the proximal femoral stem in Gruen zones 1, 7, and 8. • Osteolysis was significantly more frequent in symptomatic patients in Gruen zone 7. • Periosteal reaction occurred more frequently in symptomatic patients in Gruen zones 5 and 6.


Emerging Cellular and Molecular Strategies for Enhancing Central Nervous System (CNS) Remyelination.
Myelination is critical for the normal functioning of the central nervous system (CNS) in vertebrates. Conditions in which the development of myelin is perturbed result in severely compromised individuals often with shorter lifespans, while loss of myelin in the adult results in a variety of functional deficits. Although some form of spontaneous remyelination often takes place, the repair process as a whole often fails. Several lines of evidence suggest it is feasible to develop strategies that enhance the capacity of the CNS to undergo remyelination and potentially reverse functional deficits. Such strategies include cellular therapies using either neural or mesenchymal stem cells as well as molecular regulators of oligodendrocyte development and differentiation. Given the prevalence of demyelinating diseases and their effects on the quality of life for affected individuals it is imperative that effective therapies are developed. Here we discuss some of the new approaches to CNS myelin repair that hold promise for reducing the burden of diseases characterized by myelin loss.


Customized models of ocular aberrations across the visual field during accommodation.
We aimed to create individual eye models that accurately reproduce the empirical measurements of wave-front aberrations across the visual field at different accommodative states, thus providing a mechanistic explanation for the changes in the eye's aberration structure due to accommodation. Structural parameters of a generic eye model were optimized using optical design software to account for published measurements of wave-front aberrations measured for 19 individuals at 37 test locations over the central 30°-diameter visual field at eight levels of accommodative demand. Biometric data for individual eyes were used as starting values and normative data were used to constrain optimizations to anatomically reasonable values. Customizations of the accommodating eye model accurately accounted for ocular aberrations over the central 30° of visual field with an averaged root mean square fitting error typically below 0.2 μm at any given field location. Optimized structural parameters of the eye models were anatomically reasonable and changed in the expected way when accommodating. Accuracy for representing spherical aberration was significantly improved by relaxing anatomical constraints on the anterior surface of the lens to compensate for not including gradient-index media. Use of the model to compute pan-retinal image quality revealed large penalties of accommodative lag for activating photoreceptor responses to the retinal image.


White blood cell, neutrophil, and lymphocyte counts in individuals in the evacuation zone designated by the government after the Fukushima Daiichi Nuclear Power Plant accident: the Fukushima Health Management Survey.
Lymphocytes are susceptible to damage from radiation, and the white blood cell (WBC) count, including counts of neutrophils and lymphocytes, is a useful method of dosimetry. According to the basic survey of the Fukushima Health Management Survey (FHMS), among 13 localities where evacuation was recommended, Iitate and Namie had more individuals with external radiation exposure of more than 5 mSv than the other evacuation areas. We analyzed whether or not WBC, neutrophil, and lymphocyte counts decreased after the disaster. The subjects of this study were 45 278 men and women aged 20 to 99 years (18 953 men and 26 325 women; mean age 56 years) in the evacuation zone who participated in the Comprehensive Health Check (CHC) from June 2011 to the end of March 2012. Significant differences were detected in the mean values of WBC, neutrophil, and lymphocyte counts, and for the proportion of individuals under the minimum standard for WBC and neutrophil counts, among the 13 localities. However, the distribution of individuals at each 200-cell/µL increment in lymphocyte count were similar in these areas, and the WBC, neutrophil, and lymphocyte counts did not decrease in Iitate or Namie specifically. No marked effects of radiation exposure on the distribution of WBC counts, including neutrophil and lymphocyte counts were detected within one year after the disaster in the evacuation zone.


The dyadic interaction of relationships and disability type on informal carer subjective well-being.
Care-related factors have frequently been associated with elevated levels of distress and diminished subjective well-being. However, these variables have traditionally been considered independently. The objectives of this study were to explore the subjective well-being of informal carers in Australia and to specifically examine the effect of the dyadic interaction between the caring relationship and type of disability on the subjective well-being of informal carers. Informal carers (n = 4,096) completed the Personal Wellbeing Index (PWI) and Depression and Stress Scales. Analysis of covariance was used to compare the subjective well-being of carers to the general population while controlling for socio-demographic factors. To examine the dyadic relationship, a multivariate analysis of covariance was employed. After socio-demographic variables were controlled, informal carers reported significantly lower PWI scores compared to the general population. The results of the multivariate analysis of covariance revealed a significant interaction between the caring relationship and the type of disability being managed on subjective well-being. No differences were found for symptoms of depression and stress. The findings of this study imply that the detrimental effect of caring on subjective well-being is magnified for carers who support a child with a mental illness or multiple types of disabilities. These carers displayed the lowest levels of subjective well-being, highlighting the dyadic effects of care-related variables. Consideration of these factors is essential to target effective intervention programs for those most at risk of diminished well-being.


Differential Viral Fitness Between H1N1 and H3N8 Avian Influenza Viruses Isolated from Mallards (Anas platyrhynchos).
Homosubtypic and heterosubtypic immunity in mallards (Anas platyrhynchos) play an important role in the avian influenza virus (AIV) diversity. The mechanisms of AIV replication among wild birds and the role of immunity in AIV diversity have thus not been completely clarified. During the monitoring of AI circulation among wild waterfowl in 2007-2008, two viruses (H3N8 and H1N1) were isolated from ducks caught in a funnel trap located in La Hulpe wetland in Belgium. H3N8 viruses were revealed to be more prevalent in the mallard population than was H1N1, which might suggest a better adaptation to this species. In order to investigate this hypothesis, we characterized both isolated viruses biologically by experimental inoculation. Virus excretion and humoral response induced by both isolated viruses were evaluated in mallards after a first infection followed by a homo- or heterosubtypic reinfection under controlled experimental conditions. The H1N1 virus had a delayed peak of excretion of 4 days compared to the H3N8, but the virus shedding was more limited, earlier, and shorter after each reinfection. Moreover, the H3N8 virus could spread to all ducks after homo- or heterosubtypic reinfections and during a longer period. Although the humoral response induced by both viruses after infection and reinfection could be detected efficiently by competitive ELISA, only a minimal H1 antibody response and almost no H3-specific antibodies could be detected by the HI test. Our results suggest that the H3N8 isolate replicates better in mallards under experimental controlled conditions.


Compartmental architecture and dynamics of hematopoiesis.
Blood cell formation is maintained by the replication of hematopoietic stem cells (HSC) that continuously feed downstream "compartments" where amplification and differentiation of cells occurs, giving rise to all blood lineages. Whereas HSC replicate slowly, committed cells replicate faster as they become more differentiated. We propose a multi-compartment model of hematopoiesis, designed on the principle of cell flow conservation under stationary conditions. Cells lost from one compartment due to differentiation are replaced by cells from the upstream compartment. We assume that there is a constant relationship between cell input and output in each compartment and fix the single parameter of the model using data available for granulocyte maturation. We predict that approximately 31 mitotic events separate the HSC from the mature cells observed in the circulation. Besides estimating the number of compartments, our model allows us to estimate the size of each compartment, the rate of cell replication within each compartment, the mean time a given cell type contributes to hematopoiesis, the amplification rate in each compartment, as well as the mean time separating stem-cell replication and mature blood-cell formation. Despite its simplicity, the model agrees with the limited in vivo data available and can make testable predictions. In particular, our prediction of the average lifetime of a PIG-A mutated clone agrees closely with the experimental results available for the PIG-A gene mutation in healthy adults. The present elucidation of the compartment structure and dynamics of hematopoiesis may prove insightful in further understanding a variety of hematopoietic disorders.


Oregon's Psychiatric Security Review Board: a comprehension system for managing insanity acquittees.
The insanity defense is a particularly controversial aspect of the interaction between law and mental health. During the past decade, many states have revised or abolished their insanity defenses. Oregon, however, chose in 1974 to retain its existing defense and create a new, unique system for the post-adjudication management of insanity acquitees. Oregon's legislature established the Psychiatric Security Review Board (PSRB), which is composed of five part-time members drawn from different disciplines, to conduct periodic hearings to determine the placement and supervision of defendants who successfully raise the insanity defense and remain mentally ill and dangerous. The PSRB has received national attention as a promising approach to managing mentally ill offenders. The authors first describe the structure and operation of the Oregon system. Then they summarize the empirical studies they have conducted of the PSRB in action.


Psychosocial responses to disaster: An Asian perspective.
The psychological and psychiatric impact of great natural disasters are beginning to be understood leading to new methods of prevention, intervention and mitigation. There is limited data from the Asian continent, however, which has been the location of some of the greatest disasters of recent times. In this paper, we outline the psychosocial intervention efforts from nine Asian nations when confronted with large-scale natural catastrophic events. These include reports from situations where local services have some capacity to respond as well as those where services are destroyed or overwhelmed. From this it is possible to draw some general principles of psychosocial disaster intervention: (1) Assessment of disaster, extant service systems and incoming resources. (2) Assessment of help-seeking pathways and cultural models of illness. (3) Facilitation and support for family reunion, identification of the dead and cultural and religious practices to address death and grief. (4) Foster and bolster community group activities where possible. (5) Psychosocial training of community, aid and health workers using a train the trainer model to promote case identification, psychoeducation and intervention, with specific emphasis on vulnerable groups, especially children. (6) Promote general community psychoeducation. (7) Train medical and health staff in basic psychiatric and psychological assessment and intervention for post-traumatic stress, mood and anxiety disorders. (8) Minimise risk factors for psychiatric morbidity such as displacement and loss of gainful activity. (9) Reshape mental health systems recognising the long-term psychiatric sequelae of disaster. The collective learnt experience from Asian natural disasters may be constructively used to plan strategies to respond appropriately to the psychosocial consequences of disaster both within Asia and in the rest of the world.


Using MATLAB software with Tomcat server and Java platform for remote image analysis in pathology.
The Matlab software is a one of the most advanced development tool for application in engineering practice. From our point of view the most important is the image processing toolbox, offering many built-in functions, including mathematical morphology, and implementation of a many artificial neural networks as AI. It is very popular platform for creation of the specialized program for image analysis, also in pathology. Based on the latest version of Matlab Builder Java toolbox, it is possible to create the software, serving as a remote system for image analysis in pathology via internet communication. The internet platform can be realized based on Java Servlet Pages with Tomcat server as servlet container. In presented software implementation we propose remote image analysis realized by Matlab algorithms. These algorithms can be compiled to executable jar file with the help of Matlab Builder Java toolbox. The Matlab function must be declared with the set of input data, output structure with numerical results and Matlab web figure. Any function prepared in that manner can be used as a Java function in Java Servlet Pages (JSP). The graphical user interface providing the input data and displaying the results (also in graphical form) must be implemented in JSP. Additionally the data storage to database can be implemented within algorithm written in Matlab with the help of Matlab Database Toolbox directly with the image processing. The complete JSP page can be run by Tomcat server. The proposed tool for remote image analysis was tested on the Computerized Analysis of Medical Images (CAMI) software developed by author. The user provides image and case information (diagnosis, staining, image parameter etc.). When analysis is initialized, input data with image are sent to servlet on Tomcat. When analysis is done, client obtains the graphical results as an image with marked recognized cells and also the quantitative output. Additionally, the results are stored in a server database. The internet platform was tested on PC Intel Core2 Duo T9600 2.8 GHz 4 GB RAM server with 768x576 pixel size, 1.28 Mb tiff format images reffering to meningioma tumour (x400, Ki-67/MIB-1). The time consumption was as following: at analysis by CAMI, locally on a server - 3.5 seconds, at remote analysis - 26 seconds, from which 22 seconds were used for data transfer via internet connection. At jpg format image (102 Kb) the consumption time was reduced to 14 seconds. The results have confirmed that designed remote platform can be useful for pathology image analysis. The time consumption is depended mainly on the image size and speed of the internet connections. The presented implementation can be used for many types of analysis at different staining, tissue, morphometry approaches, etc. The significant problem is the implementation of the JSP page in the multithread form, that can be used parallelly by many users. The presented platform for image analysis in pathology can be especially useful for small laboratory without its own image analysis system.


The tattooing paradox: are studies of acute hepatitis adequate to identify routes of transmission of subclinical hepatitis C infection?
The Hepatitis Branch of the Centers for Disease Control and Prevention does not recommend routine regulation and inspection of tattoo parlors because surveillance of hepatitis C virus (HCV)-positive acute hepatitis cases rarely identifies tattooing in the incubation period. However, the majority of seroepidemiological studies agree that tattooing is a strong, independent risk factor for subclinical HCV seropositivity. We postulated that this paradox might be explained if transmission of HCV by tattooing generally caused subclinical HCV seropositivity without the acute hepatitis syndrome. We reanalyzed data from a prior seroepidemiological study of 626 consecutive patients who were unaware of their HCV serologic status and whose risk factors were ascertained by interview of an internist. Separate multiple logistic regression models were developed to predict a history of the acute hepatitis syndrome and HCV seropositivity. A history of injection-drug use was strongly associated with both HCV seropositivity (adjusted odds ratio [AOR], 7.2; 95% confidence interval [CI], 3.1-16.5) and a history of acute hepatitis (AOR, 5.9; 95% CI, 2.5-13.8), whereas having a commercially applied tattoo was strongly associated with HCV seropositivity (AOR, 6.5; 95% CI, 2.9-14.4) but not with a history of acute hepatitis (AOR, 1.2; 95% CI, 0.5-3.3). Intravenous injection of relatively large quantities of innocula of HCV may be more likely to result in the relatively rare acute HCV hepatitis syndrome, whereas intradermal exposure to small quantities of innocula may cause only subclinical HCV infections. If so, public policy on regulation and inspection of tattoo parlors should be determined by seroepidemiological studies rather than by the Sentinel Counties Study of acute hepatitis cases.


Modified double-eyelid blepharoplasty using the single-knot continuous buried non-incisional technique.
Buried non-incisional double-eyelid blepharoplasty is a popular aesthetic procedure. Although various modified continuous suture techniques have been used to create a more natural appearance and to reduce downtime, complications such as loosening of the double fold, asymmetry, and foreign body reactions have been observed. This study included 250 patients who underwent double-eyelid blepharoplasty between March 1997 and November 2012 using a modified single-knot continuous buried non-incisional technique. With 4 stab incisions in the upper eyelids, one of two needles loaded with double-armed 7-0 nylon was passed in one direction alternately through the dermis and the conjunctiva, while the other needle was passed subconjunctivally in the opposite direction. Both ends of the sutures were knotted within a lateral stab incision of the upper eyelids and were buried in the orbicularis oculi muscle. Most patients displayed satisfactory aesthetic results, and no significant complications occurred. There was no obvious regression of the double fold; however, 3 patients required reoperation to correct loosening of the fold on one side during the follow-up period. One patient presented with the suture knot subcutaneously, and the knot was removed in the clinic. The modified single-knot continuous buried non-incisional technique is a simple and less time-consuming method for a durable double fold and provides satisfactory aesthetic results.


Association between Dairy Product Consumption and Incidence of Total Hip Arthroplasty for Osteoarthritis.
The aim of this prospective cohort study was to determine whether dairy product consumption was associated with the incidence of total hip arthroplasty for osteoarthritis (OA). There were 38,924 participants from the Melbourne Collaborative Cohort Study who had dairy product consumption recorded in 1990-1994. The incidence of total hip arthroplasty for OA during 2001-2013 was determined by linking cohort records to the Australian Orthopaedic Association National Joint Replacement Registry. Over an average of 11.8 years of followup, 1505 total hip arthroplasties for OA were identified (524 in men, 981 in women). In men, a 1 SD increase in dairy product consumption was associated with a 21% increased incidence of total hip arthroplasty for OA (HR 1.21, 95% CI 1.10-1.33), with a dose-response relationship observed for quartiles of dairy product consumption (p for trend = 0.001). These results were independent of age, body mass index, country of birth, education, smoking status, vigorous physical activity, calcium supplementation, energy consumption, circulating 25-hydroxy vitamin D, hypertension, and diabetes. No significant association was observed for women (HR 1.02, 95% CI 0.95-1.09). Increasing dairy product consumption was associated with an increased risk of total hip arthroplasty for men with OA, with no significant association observed for women. Understanding the mechanisms may help identify strategies to prevent hip OA, particularly for men.


Structure dynamics of HIV-1 Env trimers on native virions engaged with living T cells.
The HIV-1 envelope glycoprotein (Env) mediates viral entry into the host cell. Although the highly dynamic nature of Env intramolecular conformations has been shown with single molecule spectroscopy in vitro, the bona fide Env intra- and intermolecular mechanics when engaged with live T cells remains unknown. We used two photon fast fluorescence lifetime imaging detection of single-molecule Förster Resonance Energy Transfer occurring between fluorescent labels on HIV-1 Env on native virions. Our observations reveal Env dynamics at two levels: transitions between different intramolecular conformations and intermolecular interactions between Env within the viral membrane. Furthermore, we show that three broad neutralizing anti-Env antibodies directed to different epitopes restrict Env intramolecular dynamics and interactions between adjacent Env molecules when engaged with living T cells. Importantly, our results show that Env-Env interactions depend on efficient virus maturation, and that is disrupted upon binding of Env to CD4 or by neutralizing antibodies. Thus, this study illuminates how different intramolecular conformations and distribution of Env molecules mediate HIV-1 Env-T cell interactions in real time and therefore might control immune evasion.


Measurement of some potentially hazardous materials in the atmosphere of rubber factories.
Two separate topics of work are outlined: methods for the measurement of chlorinated monomers in PVC and polychloroprene, and also methods for the measurement of these materials in factory air. Typical results which have been obtained in supplies of raw materials, in finished products, and in the working atmosphere at manufacturing operations are given. The second topic concerns the measurement of benzo[a]pyrene in the atmosphere of a tire manufacturing plant. This material is present in trace quantities in the mineral oils and carbon blacks used by the industry. The atmospheric concentrations present at various processes in this plant were measured on a daily basis over a period of two years, and the results obtained compared with results taken concurrently from an outside air station. It is shown that no significant quantities of benzo[a]pyrene are produced by tire manufacturing operations.


Gbx2 plays an essential but transient role in the formation of thalamic nuclei.
Unlike the laminar arrangement of neurons in the neocortex, thalamic neurons aggregate to form about dozens of nuclei, many of which make topographic connections with specific areas in the neocortex. The molecular mechanisms underlying the formation of thalamic nuclei remain largely unknown. Homeodomain transcription factor Gbx2 is specifically expressed in the developing thalamus. Deleting Gbx2 leads to severe disruption of the histogenesis of the thalamus in mice, demonstrating an essential role of Gbx2 in this brain structure. Using inducible genetic fate mapping, we have previously shown that the neuronal precursors for different sets of thalamic nuclei have distinctive onset and duration of Gbx2 expression, suggesting that the dynamic expression of Gbx2 plays an important role in the specification and differentiation of thalamic nuclei. Here, we showed that the Gbx2 lineage exclusively gives rise to neurons but not glia in the thalamus. We performed conditional deletion to examine the temporal requirements of Gbx2 in the developing thalamus in mice. Corresponding to the dynamic and differential expression of Gbx2 in various thalamic nucleus groups, deleting Gbx2 at different embryonic stages disrupts formation of distinct sets of thalamic nuclei. Interestingly, different thalamic nuclei have remarkably different requirements of Gbx2 for the survival of thalamic neurons. Furthermore, although Gbx2 expression persists in many thalamic nuclei until adulthood, only the initial expression of Gbx2 following neurogenesis is crucial for the differentiation of thalamic nuclei. Our results indicate that the dynamic expression of Gbx2 may act as an important determinant in coupling with other developmental programs to generate distinct thalamic nuclei.


Comparing alternative methods of measuring cumulative risk based on multiple risk indicators: Are there differential effects on children's externalizing problems?
This study examined several alternative methods to measure cumulative risk (CR) based on multiple risk indicators. Several methods for measuring CR are presented and their conceptual and methodological assumptions are assessed. More specifically, at the individual risk level, we examined the implications of various measurement approaches (i.e., dichotomous, proportion- and z-scores). At the composite level, we measured CR as an observed score, and compared this approach with two variable-centered approaches (consisting of reflective and formative indicators) and two person-centered approaches (consisting of latent class analysis and latent profile analysis). A decision tree was proposed to aid researchers in comparing and choosing the alternative methods. Using a sample of 169 low-income families (children approximately 5 years old, 51% girls; 74% African American, and their primary caregiver), we specified models to represent each of the alternative methods. Across models, the multiple risk composite was based on a set of 12 individual risk indicators including low maternal education, hunger, meal and money unpredictability, maternal psychopathology, maternal substance use, harsh parenting, family stress, and family violence. For each model, we estimated the effect size of the composite CR variable on children's externalizing problems. Results indicated that the variable-centered CR composites had larger effects than the observed summary score CR indices and the person-centered methods.


Common genetic variation in the Estrogen Receptor Beta (ESR2) gene and osteoarthritis: results of a meta-analysis.
The objective of this study was to examine the relationship between common genetic variation of the ESR2 gene and osteoarthritis. In the discovery study, the Rotterdam Study-I, 7 single nucleotide polymorphisms (SNPs) were genotyped and tested for association with hip (284 cases, 2772 controls), knee (665 cases, 2075 controls), and hand OA (874 cases, 2184 controls) using an additive model. In the replication stage one SNP (rs1256031) was tested in an additional 2080 hip, 1318 knee and 557 hand OA cases and 4001, 2631 and 1699 controls respectively. Fixed- and random-effects meta-analyses were performed over the complete dataset including 2364 hip, 1983 knee and 1431 hand OA cases and approximately 6000 controls. The C allele of rs1256031 was associated with a 36% increased odds of hip OA in women of the Rotterdam Study-I (OR 1.36, 95% CI 1.08-1.70, p = 0.009). Haplotype analysis and analysis of knee- and hand OA did not give additional information. With the replication studies, the meta-analysis did not show a significant effect of this SNP on hip OA in the total population (OR 1.06, 95% CI 0.99-1.15, p = 0.10). Stratification according to gender did not change the results. In this study, we had 80% power to detect an odds ratio of at least 1.14 for hip OA (α = 0.05). This study showed that common genetic variation in the ESR2 gene is not likely to influence the risk of osteoarthritis with effects smaller than a 13% increase.


A multiplex approach to molecular detection of Brucella abortus and/or Mycobacterium bovis infection in cattle.
A multiplex amplification and detection platform for the diagnosis of Mycobacterium bovis and Brucella abortus infection simultaneously in bovine milk and nasal secretions was developed. This system (designated the bovine pathogen detection assay [BPDA]-PCR) consists of duplex amplification of species-specific targets (a region of the BCSP31K gene of B. abortus and a repeat-sequence region in the hsp65 gene of M. bovis, respectively). This is followed by a solid-phase probe capture hybridization of amplicons for detection. On the basis of spiking experiments with normal milk, the analytical sensitivity of the assay was 800 CFU equivalents/ml of milk for B. abortus and as low as 4 CFU equivalents per ml of milk for M. bovis. BPDA-PCR was validated with 45 liver samples from lemmings experimentally infected with B. abortus. The assay sensitivity, based on culture status as a "gold standard," was 93.9%. In this experiment, BPDA-PCR also identified five culture-negative liver samples as positive (41.7%). Field studies for the evaluation of BPDA-PCR were performed with samples from dairy animals from geographically distinct regions (India, Mexico, and Argentina). A high prevalence of shedding of B. abortus (samples from India) and M. bovis (samples from Mexico) was identified by BPDA-PCR. In samples from India, B. abortus shedding was identified in 86% of milk ring test-positive animals (n = 15) and 80% of milk ring test-negative cows (n = 5). In samples from Mexico, M. bovis was identified by PCR in 32.6% of pools (n = 46) of milk that each contained milk from 10 animals and in 56.2% of nasal swabs (n = 121) from cattle from tuberculin test-positive herds. In contrast, the Argentine cattle (n = 70) had a modest prevalence of M. bovis shedding in nasal swabs (2.9%) and milk (1.4%) and of B. abortus in milk (11.4%). On the basis of these analyses, we identify BPDA-PCR as an optimal tool for both screening of herds and testing of individual animals in a disease eradication program. A combination of the duplex assay, screening of milk samples in pools, and the proposed algorithm provides a highly sensitive, cost-effective, and economically viable alternative to serological testing.


Toward a science of tumor forecasting for clinical oncology.
We propose that the quantitative cancer biology community makes a concerted effort to apply lessons from weather forecasting to develop an analogous methodology for predicting and evaluating tumor growth and treatment response. Currently, the time course of tumor response is not predicted; instead, response is only assessed post hoc by physical examination or imaging methods. This fundamental practice within clinical oncology limits optimization of a treatment regimen for an individual patient, as well as to determine in real time whether the choice was in fact appropriate. This is especially frustrating at a time when a panoply of molecularly targeted therapies is available, and precision genetic or proteomic analyses of tumors are an established reality. By learning from the methods of weather and climate modeling, we submit that the forecasting power of biophysical and biomathematical modeling can be harnessed to hasten the arrival of a field of predictive oncology. With a successful methodology toward tumor forecasting, it should be possible to integrate large tumor-specific datasets of varied types and effectively defeat one cancer patient at a time.


Relationships among physical inactivity, deconditioning, and walking impairment in persons with multiple sclerosis.
We have previously proposed a conceptual model of physical inactivity, physiological deconditioning, and walking impairment in persons with multiple sclerosis (MS) that suggests engaging in physical activity and improving physiological conditioning may lead to improvements in walking performance. This cross-sectional study examined the nature of associations among physical activity, aerobic capacity, and walking performance in persons with MS and healthy controls. The sample included 31 persons with MS and 31 controls matched by age, sex, height, and weight. Participants completed the 6-minute walk (6MW), wore an ActiGraph model GT3X accelerometer for 7 days as an objective measure of physical activity (expressed as time spent in moderate-to-vigorous physical activity [MVPA]), and completed an incremental exercise test on a cycle ergometer as a measure of aerobic capacity (VO2peak). Hierarchical linear regression analyses indicated that MVPA and VO2peak partially explained group differences in 6MW performance (R = 0.782), although group remained a significant predictor of 6MW performance (β = 0.304; P < 0.001). Path analysis indicated that group had both statistically significant direct and indirect effects on 6MW performance, and the indirect effect operated through pathways involving MVPA and VO2peak. These results provide direct preliminary evidence that physiological deconditioning, perhaps occurring as a result of physical inactivity, may explain variability in walking impairment in persons with MS. These findings support the design and implementation of targeted interventions for improving walking impairment in this population. for more insights from the authors (see Supplemental Digital Content 1, http://links.lww.com/JNPT/A93).


Carriage of methicillin-resistant Staphylococcus pseudintermedius in dogs--a longitudinal study.
Methicillin-resistant S. pseudintermedius strains (MRSP) are reported with increasing frequency in bacterial cultures from dogs. The objectives of this study were to determine whether MRSP could be found in dogs several months after a clinically apparent infection and whether the length of carriage varied depending on systemic antimicrobial treatment, diagnosis at time of the first positive MRSP culture and the presence of skin disease or wounds. Thirty-one dogs previously diagnosed with a clinical infection were sampled repeatedly for a minimum of eight months or, with the exception of two dogs, until two consecutive negative results were obtained. Five specified locations were sampled, and the results were evaluated to determine future recommendations concerning sample strategies when screening for MRSP carriage. Information was collected from medical records and questionnaires to evaluate factors that may influence length of carriage. The overall median length of MRSP carriage was 11 months (48 weeks). The presence of wounds and signs of dermatitis did not influence length of carriage. Systemic treatment for three weeks or longer with antimicrobial agents to which the bacterium was resistant was associated with prolonged carriage compared to dogs treated for a shorter period of time. Three of five dogs treated with an antimicrobial to which their MRSP-isolates were susceptible (tetracycline) were found to still be MRSP-positive when sampled after the end of treatment. Wound samples had the highest positive MRSP yield (81%) for the positive sample sites, compared to less than 70% for each of the other four sample sites. Cultures from the nostrils were less likely to detect MRSP carriage relative to the pharynx, perineum, wounds and the corner of the mouth. Dogs can carry MRSP for more than a year after a clinically apparent infection. Systemic antimicrobial treatment of infections with antimicrobial agents to which the MRSP-bacteria are resistant should be avoided when possible in dogs with possible or confirmed MRSP carriage or infection, since it may prolong time of MRSP carriage. Simultaneous sampling of pharynx, perineum, and the corner of the mouth as well as wounds when present is recommended when screening for MRSP. Cultures from nostrils were shown to be less likely to detect MRSP carriage.


Repeated intravenous cocaine administration: locomotor activity and dopamine D2/D3 receptors.
The dopamine D3 receptor has been implicated as a possible mediator in the reinforcement or abuse of psychostimulants such as cocaine. The present studies examined the effects of repeated (14 day) intravenous cocaine administration (saline vehicle, 0.5, 1.0 and 3.0 mg/kg) on locomotor activity and dopamine D2 and D3 receptor density in the rat striatum and nucleus accumbens. Male Sprague-Dawley rats (n = 40) were implanted with an intravenous access port and allowed to recover for 2 days. An additional group of naive rats was included to control for surgical/injection stress (n = 10). Following 2 days of habituation trials, total, peripheral and central activity (photocell interruptions) data were collected during alternate daily 60-minute test sessions. Repeated cocaine treatment resulted in a significant dose-dependent increase in striatal D3 receptors which was predicted by daily 60-minute central locomotor activity. Conversely, D3 receptors in the nucleus accumbens exhibited a significant dose-dependent reduction which was predicted by the initial 5 minutes of central locomotor activity observed on peak sensitization days (days 6, 8 and 10). Sensitization to the locomotor stimulatory effects of cocaine was dose-dependent, with the time to peak sensitization day following the rank order of 0.5 > 1.0 > 3.0 mg/kg. The density of D2 receptors in the striatum and nucleus accumbens was unchanged by cocaine administration. These data suggest striatal and nucleus accumbens D3 receptor involvement in the expression of cocaine-induced behavioral sensitization. Thus, the D3 receptors in the striatum and nucleus accumbens may be differentially involved in the locomotor stimulation (striatal D3) and reinforcing aspects (nucleus accumbens D3) of repeated cocaine administration.


[Prolonged prevention of venous thromboembolic complications (VTECS): who is it indicated for and how should it be carried out?].
The publication contains a review of present-day positions on prolonged prevention of venous thromboembolic complications. This is followed by considering the role of risk factors, probabilistic value of prognostic scales, as well as reflecting the provisions of the recent Russian and international consensus documents concerned. Careful consideration is given to the major possible parameters a physician could be guided by in real clinical practice while choosing and deciding upon appropriate terms of prevention. Also shown are possibilities of using novel oral anticoagulants in practical implementation of such regimens.


Effective Dimensionality Reduction for Visualizing Neural Dynamics by Laplacian Eigenmaps.
With the development of neural recording technology, it has become possible to collect activities from hundreds or even thousands of neurons simultaneously. Visualization of neural population dynamics can help neuroscientists analyze large-scale neural activities efficiently. In this letter, Laplacian eigenmaps is applied to this task for the first time, and the experimental results show that the proposed method significantly outperforms the commonly used methods. This finding was confirmed by the systematic evaluation using nonhuman primate data, which contained the complex dynamics well suited for testing. According to our results, Laplacian eigenmaps is better than the other methods in various ways and can clearly visualize interesting biological phenomena related to neural dynamics.


Investigating glutamatergic mechanism in attention and impulse control using rats in a modified 5-choice serial reaction time task.
The 5-choice serial reaction time task (5CSRTT) has been widely used to study attention and impulse control in rodents. In order to mimic cognitive impairments in psychiatry, one approach has been to use acute administration of NMDA antagonists. This disruption in glutamatergic transmission leads to impairments in accuracy, omissions, and premature responses although findings have been inconsistent. In this study, we further investigated glutamatergic mechanisms using a novel version of the 5CSRTT, which we have previously shown to be more sensitive to cognitive enhancers. We first investigated the effects of systemic treatment with NMDA antagonists. We also carried out a preliminary investigation using targeted medial prefrontal cortex infusions of a NMDA antagonist (MK801), mGluR2/3 antagonist (LY341495), and mGluR7 negative allosteric modulator (MMPIP). Acute systemic administration of the different NMDA antagonists had no specific effects on accuracy. At higher doses PCP, ketamine, and memantine, increased omissions and affected other measures suggesting a general disruption in task performance. Only MK801 increased premature responses, and reduced omissions at lower doses suggesting stimulant like effects. None of the NMDA antagonists affected accuracy or any other measures when tested using a short stimulus challenge. Infusions of MK801 had no effect on accuracy but increased premature responses following infralimbic, but not prelimbic infusion. LY341495 had no effects in either brain region but a decrease in accuracy was observed following prelimbic infusion of MMPIP. Contrary to our hypothesis, disruptions to glutamate transmission using NMDA antagonists did not induce any clear deficits in accuracy in this modified version of the 5CSRTT. We also found that the profile of effects for MK801 differed from those observed with PCP, ketamine, and memantine. The effects of MK801 in the infralimbic cortex add to the literature indicating this brain region and glutamate play an important role in impulse control.


Area and mammalian elevational diversity.
Elevational gradients hold enormous potential for understanding general properties of biodiversity. Like latitudinal gradients, the hypotheses for diversity patterns can be grouped into historical explanations, climatic drivers, and spatial hypotheses. The spatial hypotheses include the species-area effect and spatial constraint (mid-domain effect null models). I test these two spatial hypotheses using regional diversity patterns for mammals (non-volant small mammals and bats) along 34 elevational gradients spanning 24.4 degrees S-40.4 degrees N latitude. There was high variability in the fit to the species-area hypothesis and the mid-domain effect. Both hypotheses can be eliminated as primary drivers of elevational diversity. Area and spatial constraint both represent sources of error rather than mechanisms underlying these mammalian diversity patterns. Similar results are expected for other vertebrate taxa, plants, and invertebrates since they show comparable distributions of elevational diversity patterns to mammalian patterns.


Metabolic syndrome, or What you will: definitions and epidemiology.
The metabolic syndrome is a clustering of risk factors which predispose an individual to cardiovascular morbidity and mortality. There is general consensus regarding the main components of the syndrome (glucose intolerance, obesity, raised blood pressure and dyslipidaemia [elevated triglycerides, low levels of high-density lipoprotein cholesterol]) but different definitions require different cut points and have different mandatory inclusion criteria. Although insulin resistance is considered a major pathological influence, only the World Health Organization (WHO) and European Group for the study of Insulin Resistance (EGIR) definitions include it amongst the diagnostic criteria and only the International Diabetes Federation (IDF) definition has waist circumference as a mandatory component. The prevalence of metabolic syndrome within individual cohorts varies with the definition used. Within each definition, the prevalence of metabolic syndrome increases with age and varies with gender and ethnicity. There is a lack of diagnostic concordance between different definitions. Only about 30% of people could be given the diagnosis of metabolic syndrome using most definitions, and about 3540% of people diagnosed with metabolic syndrome are only classified as such using one definition. There is currently debate regarding the validity of the term metabolic syndrome, but the presence of one cardiovascular risk factor should raise suspicion that additional risk factors may also be present and encourage investigation. Individual risk factors should be treated.


Quelling targets the rDNA locus and functions in rDNA copy number control.
RNA silencing occurs in a broad range of organisms. Although its ancestral function is probably related to the genome defense mechanism against repetitive selfish elements, it has been found that RNA silencing regulates different cellular processes such as gene expression and chromosomal segregation. In Neurospora crassa, a RNA silencing mechanism, called quelling, acts to repress the expression of transgenes and transposons, but until now no other cellular functions have been shown to be regulated by this mechanism. Here, we detected by northern blotting endogenous short interfering RNA (siRNAs) from the repetitive ribosomal DNA locus (rDNA) that are loaded onto the argonaute protein QDE-2. Moreover, we found a bidirectional transcription that can generate double strand RNA (dsRNA) molecules. Interestingly, quelling mutants have a reduced rDNA gene copy number. Our finding could suggest a new biological function for RNA silencing in the maintenance of the integrity and stability of the Neurospora rDNA locus.


Changes in ponderal index and body mass index across childhood and their associations with fat mass and cardiovascular risk factors at age 15.
Little is known about whether associations between childhood adiposity and later adverse cardiovascular health outcomes are driven by tracking of overweight from childhood to adulthood and/or by vascular and metabolic changes from childhood overweight that persist into adulthood. Our objective is to characterise associations between trajectories of adiposity across childhood and a wide range of cardiovascular risk factors measured in adolescence, and explore the extent to which these are mediated by fat mass at age 15. Using data from the Avon Longitudinal Study of Parents and Children, we estimated individual trajectories of ponderal index (PI) from 0-2 years and BMI from 2-10 years using random-effects linear spline models (N = 4601). We explored associations between PI/BMI trajectories and DXA-determined total-body fat-mass and cardiovascular risk factors at 15 years (systolic and diastolic blood pressure, fasting LDL- and HDL-cholesterol, triglycerides, C-reactive protein, glucose, insulin) with and without adjustment for confounders. Changes in PI/BMI during all periods of infancy and childhood were associated with greater DXA-determined fat-mass at age 15. BMI changes in childhood, but not PI changes from 0-2 years, were associated with most cardiovascular risk factors in adolescence; associations tended to be strongest for BMI changes in later childhood (ages 8.5-10), and were largely mediated by fat mass at age 15. Changes in PI/BMI from 0-10 years were associated with greater fat-mass at age 15. Greater increases in BMI from age 8.5-10 years are most strongly associated with cardiovascular risk factors at age 15, with much of these associations mediated by fat-mass at this age. We found little evidence supporting previous reports that rapid PI changes in infancy are associated with future cardiovascular risk. This study suggests that associations between early overweight and subsequent adverse cardiovascular health are largely due to overweight children tending to remain overweight.


Anemia Treatment by Erythropoiesis-stimulating Agents during the 6 Months before the Initiation of Hemodialysis: Comparison of Darbepoetin Alfa and Continuous Erythropoietin Receptor Activator.
Anemia in chronic kidney disease (CKD) is a risk factor for cardiovascular diseases and is treated by long-acting erythropoiesis-stimulating agents (ESAs). Although the results of previous studies have shown that hemoglobin levels could not be maintained at the initiation of dialysis in CKD patients treated with recombinant human erythropoietin, it remains undetermined whether long-acting ESAs are effective in preventing the progression of anemia at the initiation of dialysis. In the present study, hemoglobin levels in 40 CKD patients treated with darbepoetin alfa (DA) and 15 CKD patients treated with a continuous erythropoietin receptor activator (CERA) were retrospectively compared during the 6 months period before the initiation of dialysis. Results showed that DA and CERA both maintained hemoglobin levels at around 10 g/dL from 6 months to 1 month before dialysis. However, hemoglobin levels at the initiation of dialysis significantly decreased to 9.1 ± 1.2 g/dL in the DA group and to 9.0 ± 1.0 g/dL in the CERA group. Although the total doses of ESAs used during the 6-month period were similar between the two groups, DA-treated CKD patients received subcutaneous injections more frequently than did patients treated with CERA. These results suggest that CKD patients require more intense ESA therapy to prevent a decline in hemoglobin levels at the initiation of dialysis, including those treated with long-acting ESAs. The results also raise the possibility that CERA is more useful than DA for reducing the number of injections during the pre-dialysis period.


Pramipexole in levodopa-treated Parkinson disease patients of African, Asian, and Hispanic heritage.
Little is known regarding the effects of antiparkinsonian drugs in US racial or ethnic minorities. : To evaluate the safety, tolerability, and efficacy of adjunctive pramipexole in Parkinson disease (PD) patients of African, Asian, or Hispanic heritage stably treated with levodopa. Multicenter, parallel-group, double-blind, randomized, placebo-controlled trial. : Seventeen Parkinson Study Group sites in the United States and Puerto Rico. One hundred forty-four PD patients of African, Asian, or Hispanic heritage enrolled from January 1997 to August 1998 and observed until October 1998. Subjects received pramipexole or placebo (3:1 ratio), 0.375 mg/d to a maximum tolerated dose (<or=4.5 mg/d) over a 6-week period, achieving optimum levels (0.375, 1.5, 3.0, or 4.5 mg/d) in the 4-week maintenance period. Change in the sum of the Unified Parkinson's Disease Rating Scale parts 2 (activities of daily living) and 3 (motor) from baseline to week 10. Parkinsonism improved (mean [SD] reduction in Unified Parkinson's Disease Rating Scale activities of daily living + motor score at 10 weeks, 10.27 [11.96] pramipexole vs 6.54 [13.58] placebo, P = 0.012) and was similar in each group. Adverse events occurred in 85.3% on pramipexole and 68.6% on placebo. Hallucinations and insomnia were more common on pramipexole than placebo (18 vs 0, P = 0.023, and 15 vs 0, P = 0.045, respectively). Pramipexole is an effective adjunctive antiparkinsonian therapy in PD patients of African, Asian, and Hispanic heritage. Tolerability and safety overall were similar among the groups, but differences in profiles of adverse effects and tolerability were suggested.


Stimulation of rat hepatocyte fibronectin production by monocyte-conditioned medium is due to interleukin 6.
In this report, conditioned media from LPS-stimulated monocytes increased rat hepatocyte production of fibronectin (Fn) in a dose-dependent manner. Preincubation of the conditioned media with anti-IL-6, but not with anti-IL-1 alpha, anti-IL-1 beta, or anti-TNF, completely neutralized the Fn-stimulating activity. 10-100 pg/ml of rIL-6 was sufficient to increase Fn production. Neither IL-1 nor TNF had an effect on Fn production. The Fn-stimulating activity of IL-6 could be specifically neutralized only with anti-IL-6, but not with anti-IL-1 or anti-TNF. The increased Fn produced was shown to be of the plasma rather than the cellular form. These results demonstrate that IL-6 is the factor in monocyte-conditioned media that stimulates Fn production, and that IL-6 is the monokine tested with such activity.


Utilizing Liposomal Quercetin and Gallic Acid in Localized Treatment of Vaginal Candida Infections.
Vulvovaginal candidiasis (VVC) is a widely spread fungal infection that causes itching, pain and inflammation at the vaginal site. Although common, currently available treatment suffers from limited efficacy and high recurrence. In addition, the growing problem of resistance to azole drugs used in current treatments emphasizes the need for superior treatment options. Antimicrobial polyphenols are an attractive approach offering multitargeting therapy. We aimed to develop novel liposomes for simultaneous delivery of two polyphenols (quercetin, Q, and gallic acid, GA) that, when released within the vaginal cavity, act in synergy to eradicate infection while alleviating the symptoms of VVC. Q was selected for its anti-itching and anti-inflammatory properties, while GA for its reported activity against Candida. Novel liposomes containing only Q (LP-Q), only GA (LP-GA) or both polyphenols (LP-Q+GA) were in the size range around 200 nm. Q was efficiently entrapped in both LP-Q and in LP-Q+GA (85%) while the entrapment of GA was higher in LP-Q+GA (30%) than in LP-GA (25%). Liposomes, especially LP-Q+GA, promoted sustained release of both polyphenols. Q and GA acted in synergy, increasing the antioxidant activities of a single polyphenol. Polyphenol-liposomes were not cytotoxic and displayed stronger anti-inflammatory effects than free polyphenols. Finally, LP-GA and LP-Q+GA considerably reduced C. albicans growth.


Weighted Hierarchical Grammatical Evolution.
Grammatical evolution (GE) is one of the most widespread techniques in evolutionary computation. Genotypes in GE are bit strings while phenotypes are strings, of a language defined by a user-provided context-free grammar. In this paper, we propose a novel procedure for mapping genotypes to phenotypes that we call weighted hierarchical GE (WHGE). WHGE imposes a form of hierarchy on the genotype and encodes grammar symbols with a varying number of bits based on the relative expressive power of those symbols. WHGE does not impose any constraint on the overall GE framework, in particular, WHGE may handle recursive grammars, uses the classical genetic operators, and does not need to define any bound in advance on the size of phenotypes. We assessed experimentally our proposal in depth on a set of challenging and carefully selected benchmarks, comparing the results of the standard GE framework as well as two of the most significant enhancements proposed in the literature: 1) position-independent GE and 2) structured GE. Our results show that WHGE delivers very good results in terms of fitness as well as in terms of the properties of the genotype-phenotype mapping procedure.


The BCL-6 proto-oncogene controls germinal-centre formation and Th2-type inflammation.
Structural alterations of the promoter region of the BCL-6 proto-oncogene represent the most frequent genetic alteration associated with non-Hodgkin lymphoma, a malignancy often deriving from germinal-centre B cells. The BCL-6 gene encodes a zinc-finger transcriptional repressor normally expressed in both B cells and CD4+ T cells within germinal centres, but its precise function is unknown. We show that mice deficient in BCL-6 displayed normal B-cell, T-cell and lymphoid-organ development but have a selective defect in T-cell-dependent antibody responses. This defect included a complete lack of affinity maturation and was due to the inability of follicular B cells to proliferate and form germinal centres. In addition, BCL-6-deficient mice developed an inflammatory response in multiple organs characterized by infiltrations of eosinophils and IgE-bearing B lymphocytes typical of a Th2-mediated hyperimmune response. Thus, BCL-6 functions as a transcriptional switch that controls germinal centre formation and may also modulate specific T-cell-mediated responses. Altered expression of BCL-6 in lymphoma represents a deregulation of the pathway normally leading to B cell proliferation and germinal centre formation.


The Influence of University Students' Stress Mindsets on Health and Performance Outcomes.
Emerging evidence indicates that holding particular stress mindsets has favorable implications for peoples' health and performance under stress. The aim of the current study was to examine the processes by which implicit and explicit stress mindsets relate to health- and performance-related outcomes. Specifically, we propose a stress beliefs model in which somatic responses to stress and coping behaviors mediate the effect of stress mindsets on outcomes. Undergraduate university students (N = 218, n = 144 females) aged 17- 25 years completed measures of stress mindset, physical and psychological wellbeing, perceived stress, perceived somatic responses to stress, proactive behaviors under stress, and an implicit association test assessing an implicit stress mindset. At the end of the semester, students' academic performance was collected from university records. Path analysis indicated significant indirect effects of stress mindset on psychological wellbeing and perceived stress through proactive coping behaviors and perceived somatic symptoms. Stress mindset directly predicted perceived stress and physical wellbeing, and physical wellbeing and academic performance were predicted by stress mindset through perceived somatic symptoms. Implicit stress mindset did not predict proactive behavior as anticipated. Current findings indicate that behaviors with the goal of proactively meeting demands under stress and perceived somatic symptoms are important mediators of the effect of stress mindset on health- and performance-related outcomes. The findings from this study provide formative data that can inform the development of future interventions aiming to encourage more adaptive responses to stress.


A new look at XXYY syndrome: medical and psychological features.
XXYY syndrome occurs in approximately 1:18,000-1:40,000 males. Although the physical phenotype is similar to 47,XXY (tall stature, hypergonadotropic hypogonadism, and infertility), XXYY is associated with additional medical problems and more significant neurodevelopmental and psychological features. We report on the results of a cross-sectional, multi-center study of 95 males age 1-55 with XXYY syndrome (mean age 14.9 years), describing diagnosis, physical features, medical problems, medications, and psychological features stratified by age groups. The mean age of diagnosis was 7.7 years. Developmental delays and behavioral problems were the most common primary indication for genetic testing (68.4%). Physical and facial features varied with age, although hypertelorism, clinodactyly, pes planus, and dental problems were common across all age groups. Tall stature was present in adolescents and adults, with a mean adult stature of 192.4 cm (SD 7.5; n = 22). Common medical problems included allergies and asthma (>50%), congenital heart defects (19.4%), radioulnar synostosis (17.2%), inguinal hernia and/or cryptorchidism (16.1%), and seizures (15%). Medical features in adulthood included hypogonadism (100%), DVT (18.2%), intention tremor (71%) and type II diabetes (18.2%). Brain MRI (n = 35) showed white matter abnormalities in 45.7% of patients and enlarged ventricles in 22.8%. Neurodevelopmental and psychological difficulties were a significant component of the behavioral phenotype, with developmental delays and learning disabilities universal but variable in severity. Twenty-six percent had full-scale IQs in the range of intellectual disability (MR), and adaptive functioning was significantly impacted with 68% with adaptive composite scores <70. Rates of neurodevelopmental disorders, including ADHD (72.2%), autism spectrum disorders (28.3%), mood disorders (46.8%), and tic disorders (18.9%), were elevated with 55.9% on psychopharmacologic medication overall. Recommendations for evaluation and treatment are summarized.


Ready for handwriting? A reference data study on handwriting readiness assessments.
Early evaluation of writing readiness is essential to predict and prevent handwriting difficulties and its negative influences on school occupations. An occupation-based measurement for kindergarten children has been previously developed: Writing Readiness Inventory Tool In Context (WRITIC). In addition, to assess fine motor coordination two tests are frequently used in children with handwriting difficulties: the modified Timed Test of In-Hand Manipulation (Timed TIHM) and the Nine-Hole Peg Test (9-HPT). However, no Dutch reference data are available. To provide reference data for (1) WRITIC, (2) Timed-TIHM and (3) 9-HPT for handwriting readiness assessment in kindergarten children. Three hundred and seventy-four children from Dutch kindergartens in the age of 5 to 6.5 years (5.6±0.4 years, 190 boys/184 girls) participated in the study. Children were recruited at Dutch kindergartens. Full classes of the last year were tested, children were excluded if there was a medical diagnosis such as a visual, auditory, motor or intellectual impairment that hinder handwriting performance. Descriptive statistics and percentiles scores were calculated. The score of the WRITIC (possible score 0-48 points) and the performance time on the Timed-TIHM and 9-HPT are classified as percentile scores lower than the 15th percentile to distinguish low performance from adequate performance. The percentile scores can be used to identify children that are possibly at risk developing handwriting difficulties in first grade. WRITIC scores ranged from 23 to 48 (41±4.4), Timed-TIHM ranged from 17.9 to 64.5 seconds (31.4± 7.4 seconds) and 9-HPT ranged from 18.2 to 48.3 seconds (28.4± 5.4). A WRITIC score between 0-36, a performance time of more than 39.6 seconds on the Timed-TIHM and more than 33.8 seconds on the 9-HPT were classified as low performance. The reference data of the WRITIC allow to assess which children are possibly at risk developing handwriting difficulties.


Imaging of perineural tumor spread from palatal carcinoma.
Carcinomas of the hard or soft palate are known to spread perineurally along palatine branches of the maxillary nerve. Imaging of perineural tumor spread from the palate has been underemphasized in the imaging literature. We report the findings from eight patients in whom spread from primary cancers of the palate was seen along the palatine nerves. Indications of perineural spread include enlargement or excessive enhancement of a nerve, or abnormal density/signal intensity, enhancement, or widening of the pterygopalatine fossa, cavernous sinus, or Meckel's cave.


Backbone dynamics and refined solution structure of the N-terminal domain of DNA polymerase beta. Correlation with DNA binding and dRP lyase activity.
Mammalian DNA polymerase beta functions in the base excision DNA repair pathway filling in short patches (1-5 nt) in damaged DNA and removing deoxyribose 5'-phosphate from the 5'-side of damaged DNA. The backbone dynamics and the refined solution structure of the N-terminal domain of beta-Pol have been characterized in order to establish the potential contribution(s) of backbone motion to the DNA binding and deoxyribose 5'-phosphate lyase function of this domain. The N-terminal domain is formed from four helices packed as two antiparallel pairs with a 60 degrees crossing between the pairs. The RMSD of the NMR conformers (residues 13-80) is 0.37 A for the backbone heavy atoms and 0.78 A for all heavy atoms. NMR characterization of the binding site(s) for a ssDNA-5mer, ssDNA-8mer, ssDNA-9mer, and dsDNA-12mer shows a consensus surface for the binding of these various DNA oligomers, that surrounds and includes the deoxyribose 5'-phosphate lyase active site region. Connection segments between helices 1 and 2 and between helices 3 and 4 each contribute to DNA binding. Helix-3-turn-helix-4 forms a helix-hairpin-helix motif. The highly conserved hairpin sequence (LPGVG) displays a significant degree of picosecond time-scale motion within the backbone, that is possibly important for DNA binding at the phosphodiester backbone. An Omega-loop connecting helices 1 and 2 and helix-2 itself display significant exchange contributions (R(ex)) at the backbone amides due to apparent conformational type motion on a millisecond time-scale. This motion is likely important in allowing the Omega-loop and helix-2 to shift toward, and productively interact with, gapped DNA. The deoxyribose 5'-phosphate lyase catalytic residues that include K72 which forms the Schiff's base, Y39 which is postulated to promote proton transfer to the aldehyde, and K35 which assists in phosphate elimination, show highly restricted backbone motion. H34, which apparently participates in detection of the abasic site hole and assists in the opening of the hemiacetal, shows conformational exchange.


Variable phenotypes in velocardiofacial syndrome with chromosomal deletion.
Velocardiofacial syndrome (VCF) has overlapping features with DiGeorge sequence; both result from a developmental field defect and probably represent contiguous gene deletion syndromes. The association of chromosome 22q11 deletion with DiGeorge sequence led us to do molecular analysis of chromosome 22 in 18 patients with VCF, who ranged in age from 6 to 42 years. All 18 patients had monosomy for the chromosome region 22q11. Retrospectively, we correlated the presence of the deletion with various clinical findings: 100% had cleft palate, 67% the facial phenotype, 83% cardiac disease, 94% learning disabilities, 70% ophthalmologic findings, 50% short stature, 22% psychiatric disorders, and 17% hypocalcemia. Both severely phenotypically affected and mildly affected patients had the deletion. These findings stress the importance of continued surveillance of all patients with VCF for the many medical problems that may not be present at initial diagnosis. We conclude that the presence of the gene deletion does not predict the phenotypic expression in VCF. Further studies to characterize the size of the gene deletion may facilitate better prediction of the phenotype.


Tropical influenza and weather variability among children in an urban low-income population in Bangladesh.
Influenza seasonality in the tropics is poorly understood and not as well documented as in temperate regions. In addition, low-income populations are considered highly vulnerable to such acute respiratory disease, owing to limited resources and overcrowding. Nonetheless, little is known about their actual disease burden for lack of data. We therefore investigated associations between tropical influenza incidence and weather variability among children under five in a poor urban area of Dhaka, Bangladesh. Acute respiratory illness data were obtained from a population-based respiratory and febrile illness surveillance dataset of Kamalapur, a low-income urban area in southeast Dhaka. Analyzed data were from January 2005 through December 2008. Nasopharyngeal wash specimens were collected from every fifth eligible surveillance participant during clinic visits to identify influenza virus infection with viral culture and reverse transcriptase-polymerase chain reaction. Time series analysis was conducted to determine associations between the number of influenza cases per week and weather factors. Zero-inflated Poisson and generalized linear Poisson models were used in the analysis for influenza A and B, respectively. Influenza A had associations with minimum temperature, relative humidity (RH), sunlight duration, and rainfall, whereas only RH was associated with influenza B. Although associations of the other weather factors varied between the two subtypes, RH shared a similar positive association when humidity was approximately 50-70%. Our findings of a positive RH association is consistent with prior studies, and may suggest the viral response in the tropics. The characteristics of settlement areas, population demographics, and typical overcrowding of urban poverty may also contribute to different impacts of rainfall from higher economic population. Further investigations of associations between tropical influenza and weather variability for urban low-income populations are required for better understanding.


Effects of acupressure therapy for patients having prolonged mechanical ventilation support.
This paper reports an investigation of the effects of acupressure therapy on dyspnoea, anxiety and physiological indicators of heart rate and respiratory rate in patients with chronic obstructive pulmonary disease having mechanical ventilation support. Patients with chronic obstructive pulmonary disease who are using mechanical ventilation often experience dyspnoea and anxiety, which affects successful ventilator use. The study had an experimental blocking design, using sex, age and length of ventilator use as a blocking factor. Qualified patients in two intermediate respiratory intensive care units were randomly assigned to an acupressure group and a comparison group. A total of 52 patients with chronic obstructive pulmonary disease in northern Taiwan participated. Those in the experimental group received daily acupressure therapy and massage treatment for 10 days. Patients in the comparison group received massage treatment and handholding. The primary outcome measures were the visual analogue scales for dyspnoea and anxiety, and physiological indicators of heart rate and respiratory rate. Data were collected every day from baseline (day 1), during the treatment (days 2-10) and follow-up (days 11-17). Data were analysed using generalized estimation equations. The study was carried out in 2003. Patients with chronic obstructive pulmonary disease who were using prolonged mechanical ventilatory support experienced high levels of dyspnoea and anxiety. Dyspnoea (P = 0.009), anxiety (P = 0.011) and physiological indicators (P < 0.0001) in the acupressure group improved statistically significantly over time when compared with those of the comparison group. This results support the suggestion that acupressure therapy could decrease sympathetic stimulation and improve perceived symptoms of dyspnoea and anxiety in patients with chronic obstructive pulmonary disease who are using prolonged mechanical ventilation.


Water/air mass stopping power ratios for megavoltage photon and electron beams.
Water/air mass stopping power ratios have been calculated for 5, 10, 20 and 30 MeV electron beams and various photon beams from 60Co to 31 MV betatron. The stopping power ratios have been evaluated by applying a modified version of the Spencer-Attix theory to depth-dependent electron flux spectra computed by the Monte Carlo method. Results are presented for three values of the cavity size parameter delta, 0.001, 0.01 and 0.1 MeV, and also for a Bragg-Gray cavity. For the electron beams, the results are compared to Berger's comprehensive computations. In the case of the photon beams, such a rigorous evaluation of the stopping power ratio has not been carried out previously. It is shown that the currently used approximate Bragg-Gray ratios are as much as 2% too low for high energy photon beams, and that there is a difference of about 1% between values for betatron (thin target) and linac (thick target) beams of the same maximum photon energy.


How the noninflammasome NLRs function in the innate immune system.
NLR (nucleotide-binding domain, leucine-rich repeat-containing) proteins have rapidly emerged as central regulators of immunity and inflammation with demonstrated relevance to human diseases. Much attention has focused on the ability of several NLRs to activate the inflammasome complex and drive proteolytic processing of inflammatory cytokines; however, NLRs also regulate important inflammasome-independent functions in the immune system. We discuss several of these functions, including the regulation of canonical and noncanonical NF-kappaB activation, mitogen-activated protein kinase activation, cytokine and chemokine production, antimicrobial reactive oxygen species production, type I interferon production, and ribonuclease L activity. We also explore the mechanistic basis of these functions and describe current challenges in the field.


Chronic wasting disease: fingerprinting the culprit in risk assessments.
Transmissible spongiform encephalopathies (prion diseases) in animals may be associated with a zoonotic risk potential for humans as shown by the occurrence of variant Creutzfeldt-Jakob disease in the wake of the bovine spongiform encephalopathy epidemic. Thus, the increasing exposure of humans in North America to cervid prions of chronic wasting disease (CWD) in elk and deer has prompted comprehensive risk assessments. The susceptibility of humans to CWD infections is currently under investigation in different studies using macaques as primate models. The necessity for such studies was recently reinforced when disease-associated prion protein and its seeding activity were detected in muscles of clinically inconspicuous CWD-infected white-tailed deer. Increasing evidence points to the existence of different CWD strains, and CWD prions may also change or newly emerge over time. Therefore, CWD isolates examined in macaques should be characterized as precisely as possible for their molecular identity. On this basis other CWD field samples collected in the past, present or future could be systematically compared with macaque-tested inocula in order to assess whether they are covered by the ongoing risk assessments in primates. CWD typing by Fourier transform-infrared spectroscopy of pathological prion protein may provide a method of choice for this purpose.


[Flu virion as a substrate for proteolytic enzymes].
The proteolysis of flu virions of the strain A/Puerto Rico/8/34 (subtype H1N1) by enzymes of various classes was studied to develop an approach to the study of the structural organization and interaction of the basic protein components of the virion environment: hemagglutinin (HA), transmembrane homotrimeric glycoprotein, and matrix protein M1 forming a layer under the lipid membrane. Among the tested proteolytic enzymes and enzymic preparations (thermolysin, trypsin, chymotrypsin, subtilisin Carlsberg, pronase, papain, and bromelain), the cysteine proteases bromelain and papain and the enzymic preparation pronase efficiently deleted HA ectodomains, while chymotrypsin, trypsin, and subtilisin Carlsberg deleted only a part of them. An analysis by MALDI TOF mass spectrometry allowed us to locate the sites of HA hydrolysis by various enzymic preparations. Bromelain, papain, trypsin, and pronase split the polypeptide chain after the K177 residue located before the transmembrane domain (HA2 185-211). Subtilisin Carlsberg hydrolyzed the peptide bond at other neighboring points: after L178 (a basic site) or V176. The hydrolytic activity of bromelain measured by a highly specific chromogenic substrate of cysteine proteases Glp-Phe-Ala-pNA was almost three times higher in the presence of 5 mM beta-mercaptoethanol than in the presence of 50 mM. However, the complete removal of exodomains of HA, HA, and low-activity enzyme by the HA high- and low-activity enzyme required identical time intervals. In the absence of the reducing reagent, the removal of HA by bromelain proceeded a little more slowly and was accompanied by significant fragmentation of protein Ml1. The action of trans-epoxysuccinyl-L-leucylamido)butane (E-64), a specific inhibitor of cysteine proteases, and HgCl2 on the hydrolysis of proteins HA and M1 by bromelain was investigated.


Cloud drop number concentrations over the western North Atlantic Ocean: seasonal cycle, aerosol interrelationships, and other influential factors.
Cloud drop number concentrations (N d) over the western North Atlantic Ocean (WNAO) are generally highest during the winter (DJF) and lowest in summer (JJA), in contrast to aerosol proxy variables (aerosol optical depth, aerosol index, surface aerosol mass concentrations, surface cloud condensation nuclei (CCN) concentrations) that generally peak in spring (MAM) and JJA with minima in DJF. Using aircraft, satellite remote sensing, ground-based in situ measurement data, and reanalysis data, we characterize factors explaining the divergent seasonal cycles and furthermore probe into factors influencing N d on seasonal timescales. The results can be summarized well by features most pronounced in DJF, including features associated with cold-air outbreak (CAO) conditions such as enhanced values of CAO index, planetary boundary layer height (PBLH), low-level liquid cloud fraction, and cloud-top height, in addition to winds aligned with continental outflow. Data sorted into high- and low-N d days in each season, especially in DJF, revealed that all of these conditions were enhanced on the high-N d days, including reduced sea level pressure and stronger wind speeds. Although aerosols may be more abundant in MAM and JJA, the conditions needed to activate those particles into cloud droplets are weaker than in colder months, which is demonstrated by calculations of the strongest (weakest) aerosol indirect effects in DJF (JJA) based on comparing N d to perturbations in four different aerosol proxy variables (total and sulfate aerosol optical depth, aerosol index, surface mass concentration of sulfate). We used three machine learning models and up to 14 input variables to infer about most influential factors related to N d for DJF and JJA, with the best performance obtained with gradient-boosted regression tree (GBRT) analysis. The model results indicated that cloud fraction was the most important input variable, followed by some combination (depending on season) of CAO index and surface mass concentrations of sulfate and organic carbon. Future work is recommended to further understand aspects uncovered here such as impacts of free tropospheric aerosol entrainment on clouds, degree of boundary layer coupling, wet scavenging, and giant CCN effects on aerosol-N d relationships, updraft velocity, and vertical structure of cloud properties such as adiabaticity that impact the satellite estimation of N d.


Molecular characterization of hemoglobin D Punjab traits and clinical-hematological profile of the patients.
Hemoglobin (Hb) D hemoglobinopathies are widespread diseases in northwestern India and usually present with mild hemolytic anemia and mild to moderate splenomegaly. The heterozygous form of Hb D is clinically silent, but coinheritance of Hb D with Hb S or beta-thalassemia produces clinically significant conditions like thalassemia intermedia of moderate severity. Under heterozygous conditions with coinheritance of alpha and beta-thalassemia, patients show a degree of clinical variability. Thus, our aim was to molecularly characterize the Hb D trait among individuals who were clinically symptomatic because of co-inheritance of alpha deletions or any beta-globin gene mutations. This was a cross-sectional study conducted in an autonomous tertiary-care hospital. Complete blood count and red cell indices were measured using an automated cell analyzer. Quantitative assessment of hemoglobin Hb F, Hb A, Hb A2 and Hb D was performed by means of high performance liquid chromatography (HPLC). DNA extraction was done using the phenol-chloroform method. Molecular analyses on common alpha deletions and common beta mutations were done using the Gap polymerase chain reaction and Amplification Refractory Mutation System, respectively. We evaluated 30 patients and found clinical variation in the behavior of Hb D traits. In six patients, the Hb D traits were clinically symptomatic and behaved like those of thalassemia intermedia. Molecular characterization showed that three out of these six were IVS-1-5 positive. HPLC may not be the gold standard for diagnosing symptomatic Hb D Punjab traits. Hence, standard confirmation should include molecular studies.