Inspiratory muscle training and endurance: a central metabolic control perspective.
The efficacy of inspiratory muscle training (IMT) has been the subject of considerable controversy in terms of whether it is beneficial to endurance athletes and because a convincing physiological rationale has not been identified to explain its mechanism of action. Early studies suggested that IMT was an ineffectual intervention for gains in either maximal aerobic power or endurance-specific performance. More rigorous recent research supports the observation that maximal aerobic power is not receptive to IMT; however, closer evaluation of both early and contemporary research indicates that responses to endurance-specific performance tests are sensitive to IMT. As the aim of endurance training is to improve endurance performance rather than maximal aerobic power, it is plausible that IMT may be useful in specific performance-related circumstances. Performance adaptations following IMT appear to be connected with posttraining reports of attenuated effort sensations, but this common observation has tended to be overlooked by researchers in preference for a reductionist explanation. This commentary examines the pertinent research and practical performance implications of IMT from the holistic perspective of complex central metabolic control.


Identification of common genetic risk variants for autism spectrum disorder.
Autism spectrum disorder (ASD) is a highly heritable and heterogeneous group of neurodevelopmental phenotypes diagnosed in more than 1% of children. Common genetic variants contribute substantially to ASD susceptibility, but to date no individual variants have been robustly associated with ASD. With a marked sample-size increase from a unique Danish population resource, we report a genome-wide association meta-analysis of 18,381 individuals with ASD and 27,969 controls that identified five genome-wide-significant loci. Leveraging GWAS results from three phenotypes with significantly overlapping genetic architectures (schizophrenia, major depression, and educational attainment), we identified seven additional loci shared with other traits at equally strict significance levels. Dissecting the polygenic architecture, we found both quantitative and qualitative polygenic heterogeneity across ASD subtypes. These results highlight biological insights, particularly relating to neuronal function and corticogenesis, and establish that GWAS performed at scale will be much more productive in the near term in ASD.


Perception of different formats of front-of-pack nutrition labels according to sociodemographic, lifestyle and dietary factors in a French population: cross-sectional study among the NutriNet-Santé cohort participants.
Four formats for a front-of-pack (FOP) nutrition label are currently considered in France: the Nutriscore (or 5-Colour Nutrition Label, developed by a public research team), the SENS (supported by retailers), Multiple Traffic Lights (MTL, currently used in UK) and a modified version of the Reference Intakes (mRIs, supported by industry). Our objective was to investigate the perception of these FOP labels, according to sociodemographic, lifestyle and dietary factors. Cross-sectional study. Web-based French cohort. FOP labels perception. Participants in the NutriNet-Santé cohort received a specific questionnaire on the perceptions of the four label formats identified. Sociodemographic, lifestyle and dietary data (three 24-hours dietary records) were collected through self-administered questionnaires. Mutually exclusive clusters of FOP labels perception were identified through a multiple correspondence analysis followed by a hierarchical clustering procedure. Sociodemographic, lifestyle and dietary factors associated with the clusters were explored using multivariable multinomial logistic regression. All analyses were weighted according to 2009 French census data. Among the 21,702 participants in the study, the Nutriscore received the most important number of favourable responses on positive perception dimensions by participants, followed by MTL and SENS. The five identified clusters were characterised by marked preferences for Nutriscore (cluster 1, 43.2% of participants, crude n=9,399), MTL (cluster 2, 27.3%, crude n=6,163), SENS (cluster 3, 17.05%, crude n=3,546), mRIs (cluster 4, 7.31%, crude n=1,632) and none of the presented formats (cluster 5, 5.10%, crude n=965). The cluster 1 (Nutriscore) was associated with lower adherence to nutritional recommendations, while cluster 2 (MTL) was associated with younger age and higher level of education. The Nutriscore appears to have a wide reach in the population and to appeal to subjects with lower adherence to nutritional recommendations.


Joubert Syndrome and related disorders.
Joubert syndrome (JS) and related disorders (JSRD) are a group of developmental delay/multiple congenital anomalies syndromes in which the obligatory hallmark is the molar tooth sign (MTS), a complex midbrain-hindbrain malformation visible on brain imaging, first recognized in JS. Estimates of the incidence of JSRD range between 1/80,000 and 1/100,000 live births, although these figures may represent an underestimate. The neurological features of JSRD include hypotonia, ataxia, developmental delay, intellectual disability, abnormal eye movements, and neonatal breathing dysregulation. These may be associated with multiorgan involvement, mainly retinal dystrophy, nephronophthisis, hepatic fibrosis and polydactyly, with both inter- and intra-familial variability. JSRD are classified in six phenotypic subgroups: Pure JS; JS with ocular defect; JS with renal defect; JS with oculorenal defects; JS with hepatic defect; JS with orofaciodigital defects. With the exception of rare X-linked recessive cases, JSRD follow autosomal recessive inheritance and are genetically heterogeneous. Ten causative genes have been identified to date, all encoding for proteins of the primary cilium or the centrosome, making JSRD part of an expanding group of diseases called "ciliopathies". Mutational analysis of causative genes is available in few laboratories worldwide on a diagnostic or research basis. Differential diagnosis must consider in particular the other ciliopathies (such as nephronophthisis and Senior-Loken syndrome), distinct cerebellar and brainstem congenital defects and disorders with cerebro-oculo-renal manifestations. Recurrence risk is 25% in most families, although X-linked inheritance should also be considered. The identification of the molecular defect in couples at risk allows early prenatal genetic testing, whereas fetal brain neuroimaging may remain uninformative until the end of the second trimester of pregnancy. Detection of the MTS should be followed by a diagnostic protocol to assess multiorgan involvement. Optimal management requires a multidisciplinary approach, with particular attention to respiratory and feeding problems in neonates and infants. Cognitive and behavioral assessments are also recommended to provide young patients with adequate neuropsychological support and rehabilitation. After the first months of life, global prognosis varies considerably among JSRD subgroups, depending on the extent and severity of organ involvement.


Dopamine-induced protection against indomethacin-evoked intestinal lesions in rats--role of anti-intestinal motility mediated by D2 receptors.
Although it is known that dopamine prevents various gastrointestinal lesions, the underlying mechanism remains unclear. In the present study, we examined the protective effect of dopamine on indomethacin-induced small intestinal lesions, in relation to intestinal hypermotility. Male SD rats received indomethacin (10 mg/kg) subcutaneously (s.c.), and the small intestine was examined for lesions 24 hr later. Dopamine (1-10 mg/kg) or atropine (3 mg/kg) was administered s.c. twice, 30 min before and 8 hr after indomethacin, while sulpiride (3 mg/kg) and domperidone (3 mg/kg), the dopamine D2 receptor antagonists, or yohimbine (10 mg/kg), the alpha2-adrenoceptor antagonist, were administered s.c. twice, 30 min before each dosing of dopamine. Intestinal motility was measured using a balloon under urethane anesthesia. Indomethacin caused severe lesions in the small intestine, mainly both the jejunum and ileum. The intestinal ulcerogenic response to indomethacin was dose-dependently prevented by dopamine as well as atropine. The protective effect of dopamine was almost totally antagonized by domperidone and sulpiride but not by yohimbine. On the other hand, indomethacin markedly enhanced intestinal motility, and the hypermotility response was also prevented by dopamine as well as atropine. Both sulpiride and domperidone, but not yohimbine, also antagonized the inhibitory effect of dopamine on the indomethacin-induced intestinal hypermotility. These results suggest that dopamine protects the small intestine against indomethacin-induced damage, probably by inhibiting the intestinal hypermotility mediated by dopamine D2 receptors.


Highly variable microbiota development in the chicken gastrointestinal tract.
Studies investigating the role that complex microbiotas associated with animals and humans play in health and wellbeing have been greatly facilitated by advances in DNA sequencing technology. Due to the still relatively high sequencing costs and the expense of establishing and running animal trials and collecting clinical samples, most of the studies reported in the literature are limited to a single trial and relatively small numbers of samples. Results from different laboratories, investigating similar trials and samples, have often produced quite different pictures of microbiota composition. This study investigated batch to batch variations in chicken cecal microbiota across three similar trials, represented by individually analysed samples from 207 birds. Very different microbiota profiles were found across the three flocks. The flocks also differed in the efficiency of nutrient use as indicated by feed conversion ratios. In addition, large variations in the microbiota of birds within a single trial were noted. It is postulated that the large variability in microbiota composition is due, at least in part, to the lack of colonisation of the chicks by maternally derived bacteria. The high hygiene levels maintained in modern commercial hatcheries, although effective in reducing the burden of specific diseases, may have the undesirable effect of causing highly variable bacterial colonization of the gut. Studies in humans and other animals have previously demonstrated large variations in microbiota composition when comparing individuals from different populations and from different environments but this study shows that even under carefully controlled conditions large variations in microbiota composition still occur.


Full-range polarization-sensitive swept-source optical coherence tomography by simultaneous transversal and spectral modulation.
Polarization-sensitive swept-source optical coherence tomography (PS-SS-OCT) is used to measure three-dimensional phase-retardation images of birefringent biological tissue in vivo. PS-SS-OCT with continuous source polarization modulation is used to multiplex the incident states of polarization in the signal frequency of each A-scan. Although it offers the advantage of measurement speed that is as high as that of standard SS-OCT, its disadvantage is low axial measurement range. To overcome this drawback, we employed the B-M-mode scan (BM-scan) method, which removes complex conjugate ambiguity by applying phase modulation along the transversal scanning direction. Since polarization modulation and BM-scan are applied in different scanning directions, these methods can be combined to make the optimum use of both full range and polarization-sensitive imaging. Phase fluctuations that cause measurement failure were numerically canceled before demodulating the B-scan oriented modulation. After removing complex conjugate artifacts, the axial measurement range was 5.35 mm, and the signal-to-conjugate ratio was 40.5 dB. We demonstrated retinal imaging using the PS-SS-OCT system with a frequency-swept laser at a center wavelength of 1064 nm and an axial resolution of 11.4 microm in tissue. Full-range polarization-sensitive retinal images showed characteristic birefringence of fibrous tissues such as retinal nerve fiber, sclera, and lamina cribrosa.


CXCR3-dependent accumulation and activation of perivascular macrophages is necessary for homeostatic arterial remodeling to hemodynamic stresses.
Sustained changes in blood flow modulate the size of conduit arteries through structural alterations of the vessel wall that are dependent on the transient accumulation and activation of perivascular macrophages. The leukocytic infiltrate appears to be confined to the adventitia, is responsible for medial remodeling, and resolves once hemodynamic stresses have normalized without obvious intimal changes. We report that inward remodeling of the mouse common carotid artery after ligation of the ipsilateral external carotid artery is dependent on the chemokine receptor CXCR3. Wild-type myeloid cells restored flow-mediated vascular remodeling in CXCR3-deficient recipients, adventitia-infiltrating macrophages of Gr1(low) resident phenotype expressed CXCR3, the perivascular accumulation of macrophages was dependent on CXCR3 signaling, and the CXCR3 ligand IP-10 was sufficient to recruit monocytes to the adventitia. CXCR3 also contributed to selective features of macrophage activation required for extracellular matrix turnover, such as production of the transglutaminase factor XIII A subunit. Human adventitial macrophages displaying a CD14(+)/CD16(+) resident phenotype, but not circulating monocytes, expressed CXCR3, and such cells were more frequent at sites of disturbed flow. Our observations reveal a CXCR3-dependent accumulation and activation of perivascular macrophages as a necessary step in homeostatic arterial remodeling triggered by hemodynamic stress in mice and possibly in humans as well.


Myocardial Infarction Activates CCR2(+) Hematopoietic Stem and Progenitor Cells.
Following myocardial infarction (MI), myeloid cells derived from the hematopoietic system drive a sharp increase in systemic leukocyte levels that correlates closely with mortality. The origin of these myeloid cells, and the response of hematopoietic stem and progenitor cells (HSPCs) to MI, however, is unclear. Here, we identify a CCR2(+)CD150(+)CD48(-) LSK hematopoietic subset as the most upstream contributor to emergency myelopoiesis after ischemic organ injury. This subset has 4-fold higher proliferation rates than CCR2(-)CD150(+)CD48(-) LSK cells, displays a myeloid differentiation bias, and dominates the migratory HSPC population. We further demonstrate that the myeloid translocation gene 16 (Mtg16) regulates CCR2(+) HSPC emergence. Mtg16(-/-) mice have decreased levels of systemic monocytes and infarct-associated macrophages and display compromised tissue healing and post-MI heart failure. Together, these data provide insights into regulation of emergency hematopoiesis after ischemic injury and identify potential therapeutic targets to modulate leukocyte output after MI.


Compact and phase-error-robust multilayered AWG-based wavelength selective switch driven by a single LCOS.
A novel liquid crystal on silicon (LCOS)-based wavelength selective switch (WSS) is proposed, fabricated, and demonstrated. It employs a multilayered arrayed waveguide grating (AWG) as a wavelength multiplex/demultiplexer. The LCOS deflects spectrally decomposed beams channel by channel and switches them to desired waveguide layers of the multilayered AWG. In order to obtain the multilayered AWG with high yield, phase errors of the AWG is externally compensated for by an additional phase modulation with the LCOS. This additional phase modulation is applied to the equivalent image of the facet of the AWG, which is projected by a relay lens. In our previously-reported WSS configuration, somewhat large footprint and increased cost were the drawbacks, since two LCOSs were required: one LCOS was driven for the inter-port switching operation, and the other was for the phase-error compensation. In the newly proposed configuration, on the other hand, both switching and compensation operations are performed using a single LCOS. This reduction of the component count is realized by introducing the folded configuration with a reflector. The volume of the WSS optics is 80 × 100 × 60 mm3, which is approximately 40% smaller than the previous configuration. The polarization-dependent loss and inter-channel crosstalk are less than 1.5 dB and -21.0 dB, respectively. An error-free transmission of 40-Gbit/s NRZ-OOK signal through the WSS is successfully demonstrated.


Improved health outcomes in urban slums through infrastructure upgrading.
The world is rapidly urbanizing with over half the population now living in urban areas. As the urban population grows, so does the proportion of these persons living in slums where conditions are deplorable. These conditions concentrate health hazards leading to higher rates of morbidity and mortality. This growing problem creates a unique challenge for policymakers and public health practitioners. While the Millennium Development Goals (MDGs) aim to address these conditions and standards for water and sanitation as well as pertinent health outcomes, little evidence on interventions exists to guide policymakers. Upgrades in slum household water and sanitation systems have not yet been rigorously evaluated to demonstrate whether there is a direct link to improved health outcomes. This study aims to show that slum upgrading as carried out in Ahmedabad, India, led to a significant decline in waterborne illness incidence. We employ a quasi-experimental regression model using health insurance claims (for 2001-2008) as a proxy for passive surveillance of disease incidence. We found that slum upgrading reduced a claimant's likelihood of claiming for waterborne illness from 32% to 14% and from 25% to 10% excluding mosquito-related illnesses. This study shows that upgrades in slum household infrastructure can lead to improved health outcomes and help achieve the MDGs. It also provides guidance on how upgrading in this context using microfinance and a public-private partnership can provide an avenue to affect positive change.


Epidemiological and morphological characteristics of incomplete ossification of the dorsal neural arch of the atlas in dogs with atlantoaxial instability.
OBJECTIVE To retrospectively evaluate the epidemiological and morphological features and outcome of surgical treatment of incomplete ossification of the dorsal neural arch of the atlas (IODA) in dogs with atlantoaxial instability (AAI). ANIMALS 106 AAI-affected dogs that underwent ventral fixation of the atlantoaxial joint. PROCEDURES Medical records and CT images for each dog were reviewed. Dogs were allocated to 1 of 2 groups on the basis of the presence or absence of IODA or of dens abnormalities (DAs) in CT images. RESULTS Of the 106 dogs with AAI, 75 had and 31 did not have IODA; 70 had and 36 did not have DAs. Incomplete ossification was present in the cranialmost, central, or caudalmost portion of the dorsal neural arch of the atlas in 59, 39, and 28 dogs, respectively; 2 or 3 portions were affected in 29 and 11 dogs, respectively. The mean CT value (in Hounsfield units) for the midline of the dorsal neural arch of the atlas in dogs with IODA was significantly lower than that for the same site in the dogs without IODA. The mean age at surgery for dogs with central IODA was significantly higher than that of the non-IODA group. The severity of spinal cord injury before or after atlantoaxial ventral fixation did not differ between the IODA and non-IODA groups. CONCLUSIONS AND CLINICAL RELEVANCE Results indicated that concomitant DAs or IODA is common in dogs with AAI. In dogs with incomplete ossification in the central part of the dorsal neural arch of the atlas, surgical treatment of AAI generally occurs at a middle to advanced age.


NDR Kinases Are Essential for Somitogenesis and Cardiac Looping during Mouse Embryonic Development.
Studies of mammalian tissue culture cells indicate that the conserved and distinct NDR isoforms, NDR1 and NDR2, play essential cell biological roles. However, mice lacking either Ndr1 or Ndr2 alone develop normally. Here, we studied the physiological consequences of inactivating both NDR1 and NDR2 in mice, showing that the lack of both Ndr1/Ndr2 (called Ndr1/2-double null mutants) causes embryonic lethality. In support of compensatory roles for NDR1 and NDR2, total protein and activating phosphorylation levels of the remaining NDR isoform were elevated in mice lacking either Ndr1 or Ndr2. Mice retaining one single wild-type Ndr allele were viable and fertile. Ndr1/2-double null embryos displayed multiple phenotypes causing a developmental delay from embryonic day E8.5 onwards. While NDR kinases are not required for notochord formation, the somites of Ndr1/2-double null embryos were smaller, irregularly shaped and unevenly spaced along the anterior-posterior axis. Genes implicated in somitogenesis were down-regulated and the normally symmetric expression of Lunatic fringe, a component of the Notch pathway, showed a left-right bias in the last forming somite in 50% of all Ndr1/2-double null embryos. In addition, Ndr1/2-double null embryos developed a heart defect that manifests itself as pericardial edemas, obstructed heart tubes and arrest of cardiac looping. The resulting cardiac insufficiency is the likely cause of the lethality of Ndr1/2-double null embryos around E10. Taken together, we show that NDR kinases compensate for each other in vivo in mouse embryos, explaining why mice deficient for either Ndr1 or Ndr2 are viable. Ndr1/2-double null embryos show defects in somitogenesis and cardiac looping, which reveals their essential functions and shows that the NDR kinases are critically required during the early phase of organogenesis.


Algebraic and numerical analysis of imaging properties of thin tunable-focus fluidic membrane lenses with parabolic surfaces.
The theory of third-order aberrations for a system of rotationally symmetric thin tunable-focus fluidic membrane lenses with parabolic surfaces is described. A complex analysis of the third-order design of tunable fluidic lenses is performed considering all types of primary aberrations. Moreover, formulas are derived for the calculation of the change of aberration coefficients of the parabolic tunable fluidic membrane lens with respect to the wavelength. It is shown that spherical aberration of a simple tunable-focus fluidic membrane lens with parabolic surfaces can be corrected, which is not possible with a classical spherical lens. The presented analysis is explained on examples. Derived formulas make possible to calculate parameters of optical systems with fluidic membrane lenses with small residual aberrations.


Time distribution of injury-related in-hospital mortality in a trauma referral center in South of Iran (2010-2015).
In Iran, there are no studies addressing trauma death timing and factors affecting time of death after injuries. This study aimed to examine time distribution of trauma deaths in an urban major trauma referral center with respect to victims' injury characteristics during 2010 to 2015.This was a cross-sectional study of adult trauma-related in-hospital deaths resulting from traffic-related accidents, falls, and violence-related injuries. Information on injury characteristics and time interval between admission and death was extracted from 3 hospital databases. Mortality time distribution was analyzed separately in the context of each baseline variable.A total of 1117 in-hospital deaths (mean age 47.6 ± 22.2 years, 80% male) were studied. Deaths timing followed an extremely positive skewed bimodal distribution with 1 peak during the first 24 hours of admission (41.6% of deaths) and another peak starting from the 7th day of hospitalization to the end of first month (27.7% of total). Subjects older than 65 years were more likely to die after 24 hours compared to younger deceased (P = .031). More than 70% of firearm-related deaths and 48% of assault-related mortalities occurred early, whereas 67% and 66% of deaths from falls and motorcycle accidents occurred late (P < .001). Over 57% of deaths from severe thoracic injuries occurred early, whereas this value was only 37% for central nervous system injuries (P < .001). From 2010 to 2015, percentage of late deaths decreased significantly from 68% to 54% (P < .001).Considering 1 prehospital peak of mortality and 2 in-hospital peaks, mortality time distribution follows the old trimodal pattern in Shiraz. This distribution is affected by victims' age, injury mechanism, and injured body area. Although such distribution reflects a relatively lower quality of care comparing to mature trauma systems, a change toward expected bimodal pattern has started.


The impact of the EU regulatory constraint of transgenic crops on farm income.
World population and the need for nutritious food continue to grow. For 14 years farmers from a range of countries across the globe have been accessing transgenic technologies either to reduce crop production costs, increase yield and/or to exploit a range of rotational benefits. In 2009 134 Mha of transgenic crops was grown. The arable area of the EU 27 is approximately 102 Mha; however, only about 0.1 Mha of transgenic crops, mainly maize in Spain, is grown in the EU. This is in part due to limited approvals before the establishment of a moratorium on the cultivation of transgenic crops. In this paper we estimate the revenue foregone by EU farmers, based on the potential hectarages of IR and HT transgenic crops that have been economically successful elsewhere if they were to be grown in areas of the EU where farmers could expect an overall financial benefit. This benefit would accrue primarily from reduced input costs. We estimate that if the areas of transgenic maize, cotton, soya, oil seed rape and sugar beet were to be grown where there is agronomic need or benefit then farmer margins would increase by between €443 and €929 M/year. It is noted that this margin of revenue foregone is likely to increase if the current level of approval and growth remains low, as new transgenic events come to market and are rapidly taken up by farmers in other parts of the world.


Preventing falls in older people: risk factors and primary prevention through physical activity.
Falls among older people represent a major public health issue, which can in part be tackled through an integrated falls service combining both primary and secondary prevention. Many falls can be prevented following comprehensive assessment to identify risk factors and to plan interventions to eliminate them or ameliorate their effect. Community nursing staff are well placed to undertake such risk assessments and can instigate programmes of primary prevention designed to reduce the likelihood of a person falling. Increased physical activity among older people represents one element of a prevention programme. While this is beneficial for the older person's general health and well-being, certain types of exercise can also be used to reduce falls in individuals with muscle weakness, reduced mobility and balance problems. With the exception of balance training the evidence base related to exercise and falls prevention is patchy; Carter et al (2001) suggest that as yet there is insufficient evidence to suggest an optimum exercise programme for falls prevention. Each person should therefore be individually assessed and the results used to identify what type of exercise they might benefit from in order to address a specific risk factor. Once an appropriate form of exercise has been identified, practitioners should put the older person in contact with a physical activity coordinator to assist them in accessing an exercise programme.


Ultrasonographic assessment of flexor tendon mobilization: effect of different protocols on tendon excursion.
Different mobilization protocols have been proposed for rehabilitation after hand flexor tendon repair to provide tendon excursion sufficient to prevent adhesions. Several cadaver studies have shown that the position of the neighboring fingers influences tendon excursions of the injured finger. We hypothesized that the positions of adjacent fingers influence the long finger flexor digitorum profundus tendon excursion, measured both absolutely and relative to the surrounding tissue of the tendon. Long finger flexor digitorum profundus tendon excursions and surrounding tissue movement were measured in zone V in eleven healthy subjects during three different rehabilitation protocols and two experimental models: (1) an active four-finger mobilization protocol, (2) a passive four-finger mobilization protocol, (3) a modified Kleinert mobilization protocol, (4) an experimental modified Kleinert flexion mobilization model, and (5) an experimental modified Kleinert extension mobilization model. Tendon excursions were measured with use of a frame-to-frame analysis of high-resolution ultrasound images. The median absolute long finger flexor digitorum profundus tendon excursions were 23.4, 17.8, 10.0, 13.9, and 7.6 mm for the active four-finger mobilization protocol, the passive four-finger mobilization protocol, the modified Kleinert mobilization protocol, the experimental modified Kleinert flexion mobilization model, and the experimental modified Kleinert extension mobilization model, respectively, and these differences were all significant (p ≤ 0.041). The corresponding relative flexor digitorum profundus tendon excursions were 11.2, 8.5, 7.2, 10.4, and 5.6 mm. Active four-finger mobilization protocol excursions were significantly (p = 0.013) greater than passive four-finger mobilization protocol excursions but were not significantly greater than experimental modified Kleinert flexion mobilization model excursions (p =0.213). The present study demonstrated large and significant differences among the different rehabilitation protocols and experimental models in terms of absolute and relative tendon displacement. More importantly, the present study clearly demonstrated the influence of the position of the adjacent fingers on the flexor tendon displacement of the finger that is mobilized.


Early Exposure to Respiratory Allergens by Placental Transfer and Breastfeeding.
The relationship between allergen exposure and the onset of or protection from allergic diseases remains unclear. Many factors could be related to immunological responses, such as the age when the exposure occurs, type of allergen, timing, dose, and allergen route. In this study, we investigated whether exposure to respiratory allergens could occur in pregnancy or early life. In particular, we assessed whether Der p 1 and Blo t 5, as well as specific antibodies against these allergens, could be detected in 90 paired cord blood and colostrum samples. Der p 1 was detected in 58.6% of colostrum and 29% of cord blood samples, whereas Blot 5 was positive in 41.3% and 9.6% of the samples, respectively. Similar to specific IgA, which could be detected in all samples for both mites, specific IgG was found in a high number of colostrum samples, 93.5% and 94.8% for Dp and Bt, respectively. Although allergens were not detected in all cord blood samples, a high percentage of them (≥95%) were positive for specific IgM to both mites in cord blood samples, suggesting that neonates can be exposed and sensitized to airborne allergens during pregnancy. Many studies have attempted to correlate allergen exposure or its prevention in early infancy with the onset of or protection from allergic diseases. However, conflicting and inconsistent data do not show a clear correlation with or suggest a way to prevent allergen sensitization. Nevertheless, these unconvincing results could be better understood if the relationship with many aspects of allergen exposure after pregnancy could be clarified. Thus, it is necessary to address basic issues related to allergen exposure, including the development of reproducible, standardized and reliable methods, and to determine how and where the exposure occurs.


Stress and Health in Nursing Students: The Nurse Engagement and Wellness Study.
Evidence suggests that behavioral, social, and environmental factors may modify the effects of life stress on health and performance of new nurses as they transition to hospitals. The aim of this study was to describe the methods of a project designed to investigate the role of social, behavioral, and environmental factors in modifying the adverse effects of stress on new nurses and to discuss demographic, health, and life stress characteristics of the cohort at baseline. A prospective cohort design was used to conduct a comprehensive assessment of health endpoints, life stress, behaviors, personal traits, social factors, indicators of engagement and performance, and environmental exposures in nursing students. Adjusted odds ratios and analyses of covariance were used to examine associations between these factors at baseline. Health indicators in the cohort were comparable or better than in the broader United States population, and lifetime stress exposure was lower than among students from other majors. Exposure to more lifetime stressors was associated with greater risk for various health conditions, including hypertension, diabetes, and depression. Conversely, better social, environmental, behavioral, and personal profiles were associated with protective effects for the same health conditions. These data comprehensively summarize the lives of predominately Hispanic nursing students and highlight risk and resilience factors associated with their health and well-being. The findings are timely, as the nursing field diversifies in preparation to care for a diverse and aging population. Comprehensively assessing stress-health relationships among student nurses ought to inform the policies, practices, and curricula of nursing schools to better prepare nurses to thrive in the often-strenuous healthcare environment.


Dielectric properties of high-kappa oxides: theory and experiment for Lu2O3.
We present a combined experimental and theoretical analysis of the dielectric and vibrational properties of crystalline lutetium oxide in its ground-state bixbyite structure. The vibrational dielectric function of Lu2O3 thin films grown by atomic-layer deposition was studied by infrared transmission and reflection-absorption spectroscopies, selectively accessing transverse and longitudinal optical frequencies. The static dielectric constant is extracted analyzing the infrared response. We also present first-principles density-functional linear-response calculations, which are in close agreement with experiment, and provide insight into the microscopic nature of vibrational spectra and dielectric properties.


Atherosclerosis-susceptible and atherosclerosis-resistant pigeon aortic cells express different genes in vivo.
Spontaneous atherosclerosis in the White Carneau (WC-As) pigeon is inherited as a single gene disorder, and its progression closely mirrors the human disease. Representational difference analysis and microarray were used to identify genes that were differentially expressed between the susceptible WC-As and resistant Show Racer (SR-Ar) aortic tissue. The RNA extracted from 1-d-old squab aortas was used to make cDNA for each experiment. Fifty-six unique genes were found using representational difference analysis, with 25 exclusively expressed in the WC-As, 15 exclusive to the SR-Ar, and 16 nonexclusive genes having copy number variation between breeds. Caveolin and β-actin were expressed in the WC-As, whereas the proteasome maturation protein and the transcription complex CCR4-NOT were exclusive to the SR-Ar. Microarray analysis revealed 48 genes with differential expression. Vascular endothelial growth factor and p53 binding protein were among the 17 genes upregulated in the WC-As. Thirty-one genes were upregulated in the SR-Ar including the transforming growth factor-β signaling factor SMAD2 and heat shock protein 90. Genes representing several biochemical pathways were distinctly different between breeds. The most striking divergences were in cytoskeletal remodeling, proteasome activity, cellular respiration, and immune response. Actin cytoskeletal remodeling appears to be one of the first differences between susceptible and resistant breeds, lending support to the smooth muscle cell phenotypic reversion hypothesis of human atherogenesis.


The Age in Swimming of Champions in World Championships (1994⁻2013) and Olympic Games (1992⁻2012): A Cross-Sectional Data Analysis.
(1) Background: We investigated the age of swimming champions in all strokes and race distances in World Championships (1994⁻2013) and Olympic Games (1992⁻2012); (2) Methods: Changes in age and swimming performance across calendar years for 412 Olympic and world champions were analysed using linear, non-linear, multi-level regression analyses and MultiLayer Perceptron (MLP); (3) Results: The age of peak swimming performance remained stable in most of all race distances for world champions and in all race distances for Olympic champions. Longer (i.e., 200 m and more) race distances were completed by younger (-20 years old for women and -22 years old for men) champions than shorter (i.e., 50 m and 100 m) race distances (-22 years old for women and -24 years old for men). There was a sex difference in the age of champions of -2 years with a mean age of -21 and -23 years for women and men, respectively. Swimming performance improved in most race distances for world and Olympic champions with a larger trend of increase in Olympic champions; (4) Conclusion: Swimmers at younger ages (<20 years) may benefit from training and competing in longer race distances (i.e., 200 m and longer) before they change to shorter distances (i.e., 50 m and 100 m) when they become older (>22 years).


Response to the 2011 Great East Japan Earthquake and Tsunami disaster.
We revisited the lessons of the 2011 Great East Japan Earthquake Tsunami disaster specifically on the response and impact, and discussed the paradigm shift of Japan's tsunami disaster management policies and the perspectives for reconstruction. Revisiting the modern histories of Tohoku tsunami disasters and pre-2011 tsunami countermeasures, we clarified how Japan's coastal communities have prepared for tsunamis. The discussion mainly focuses on structural measures such as seawalls and breakwaters and non-structural measures of hazard map and evacuation. The responses to the 2011 event are discussed specifically on the tsunami warning system and efforts to identify the tsunami impacts. The nation-wide post-tsunami survey results shed light on the mechanisms of structural destruction, tsunami loads and structural vulnerability to inform structural rehabilitation measures and land-use planning. Remarkable paradigm shifts in designing coastal protection and disaster mitigation measures were introduced, leading with a new concept of potential tsunami levels: Prevention (Level 1) and Mitigation (Level 2) levels according to the level of 'protection'. The seawall is designed with reference to Level 1 tsunami scenario, while comprehensive disaster management measures should refer to Level 2 tsunami for protection of human lives and reducing potential losses and damage. Throughout the case study in Sendai city, the proposed reconstruction plan was evaluated from the tsunami engineering point of view to discuss how the post 2011 paradigm was implemented in coastal communities for future disaster mitigation. The analysis revealed that Sendai city's multiple protection measures for Level 2 tsunami will contribute to a substantial reduction of the tsunami inundation zone and potential losses, combined with an effective tsunami evacuation plan.


Covered stent placement for neurovascular disease.
We describe an endovascular technique in which covered stents were used to occlude a parent vessel. In one patient, with a giant paraclinoid aneurysm, a Gortex-covered Palmaz stent was used to occlude the cervical internal carotid artery and to create thrombosis in the aneurysm. In the second patient, with a high-flow vertebrojugular fistula, a hooded stent provided definitive treatment after an attempt to close the fistula by detachable balloon therapy failed. Follow-up of these patients revealed stable stent position and no untoward effects of permanent vessel occlusion.


A Holistic Multi Evidence Approach to Study the Fragmentation Behaviour of Crystalline Mannitol.
Mannitol is an essential excipient employed in orally disintegrating tablets due to its high palatability. However its fundamental disadvantage is its fragmentation during direct compression, producing mechanically weak tablets. The primary aim of this study was to assess the fracture behaviour of crystalline mannitol in relation to the energy input during direct compression, utilising ball milling as the method of energy input, whilst assessing tablet characteristics of post-milled powders. Results indicated that crystalline mannitol fractured at the hydrophilic (011) plane, as observed through SEM, alongside a reduction in dispersive surface energy. Disintegration times of post-milled tablets were reduced due to the exposure of the hydrophilic plane, whilst more robust tablets were produced. This was shown through higher tablet hardness and increased plastic deformation profiles of the post-milled powders, as observed with a lower yield pressure through an out-of-die Heckel analysis. Evaluation of crystal state using x-ray diffraction/differential scanning calorimetry showed that mannitol predominantly retained the β-polymorph; however x-ray diffraction provided a novel method to calculate energy input into the powders during ball milling. It can be concluded that particle size reduction is a pragmatic strategy to overcome the current limitation of mannitol fragmentation and provide improvements in tablet properties.


High-sensitivity MALDI-TOF MS quantification of anthrax lethal toxin for diagnostics and evaluation of medical countermeasures.
Inhalation anthrax has a rapid progression and high fatality rate. Pathology and death from inhalation of Bacillus anthracis spores are attributed to the actions of secreted protein toxins. Protective antigen (PA) binds and imports the catalytic component lethal factor (LF), a zinc endoprotease, and edema factor (EF), an adenylyl cyclase, into susceptible cells. PA-LF is termed lethal toxin (LTx) and PA-EF, edema toxin. As the universal transporter for both toxins, PA is an important target for vaccination and immunotherapeutic intervention. However, its quantification has been limited to methods of relatively low analytic sensitivity. Quantification of LTx may be more clinically relevant than LF or PA alone because LTx is the toxic form that acts on cells. A method was developed for LTx-specific quantification in plasma using anti-PA IgG magnetic immunoprecipitation of PA and quantification of LF activity that co-purified with PA. The method was fast (<4 h total time to detection), sensitive at 0.033 ng/mL LTx in plasma for the fast analysis (0.0075 ng/mL LTx in plasma for an 18 h reaction), precise (6.3-9.9% coefficient of variation), and accurate (0.1-12.7%error; n ≥ 25). Diagnostic sensitivity was 100% (n = 27 animal/clinical cases). Diagnostic specificity was 100% (n = 141). LTx was detected post-antibiotic treatment in 6/6 treated rhesus macaques and 3/3 clinical cases of inhalation anthrax and as long as 8 days post-treatment. Over the course of infection in two rhesus macaques, LTx was first detected at 0.101 and 0.237 ng/mL at 36 h post-exposure and increased to 1147 and 12,107 ng/mL in late-stage anthrax. This demonstrated the importance of LTx as a diagnostic and therapeutic target. This method provides a sensitive, accurate tool for anthrax toxin detection and evaluation of PA-directed therapeutics.


Effectiveness of the TEI Program for Bullying and Cyberbullying Reduction and School Climate Improvement.
The increase in the prevalence of bullying and cyberbullying in recent years worldwide is undeniable. Although several intervention programs oriented towards the reduction of bullying and cyberbullying have been developed and implemented, significant disparities have been found regarding their efficacy. In most of the cases, the lack of the implementation of interventions involving all of the school community could be on the basis of this limited efficacy. The present study aimed to evaluate the effectiveness of the TEI Program, an intervention based on peer tutoring, in the reduction of bullying and cyberbullying, and in the improvement of school climate. The design of the study was quasi-experimental, in which 2057 Spanish students (aged 11 to 16 years) participated from 22 schools, and were randomly assigned to the experimental group (10 schools, 987 students) or the control group (12 schools, 1070 students). The obtained results showed a significant reduction in bullying behavior, peer victimization, fighting, cyberbullying and cybervictimization in the experimental group after the intervention implementation. Similarly, a significant improvement in factors of school climate was found only in this group. The obtained results demonstrated that the TEI program is effective in reducing bully and cyberbully behavior, and at the same time, improving the school climate.


Cloning and expression of a Bacteroides succinogenes mixed-linkage beta-glucanase (1,3-1,4-beta-D-glucan 4-glucanohydrolase) gene in Escherichia coli.
A pseudorandom genomic library of Bacteroides succinogenes DNA, cloned into pUC8 in Escherichia coli, was screened for beta-glucanase activity on 0.1% lichenan plates. Six high-activity clones, containing identical 5.2-kilobase inserts of B. succinogenes DNA, were obtained. The clones exhibited activity solely on beta-glucan substrates containing beta-(1----3)(1----4) linkages, thus manifesting a specific fibrolytic enzyme previously unrecognized in B. succinogenes. A subclone (pJI10) of the original insert (1.35 kilobases in size) expressed full beta-glucanase activity under control of its own promoter. The expression of beta-glucanase in pJI10 appeared subject to catabolite regulation by glucose. Detailed analysis of enzyme activity in the parental and deleted derivatives, subcloned into pUC18 and pUC19, suggested that the apparent glucose repression was an artifact arising as a consequence of interactions with the lac transcriptional unit in the plasmid vector.


Visualisation of lymphoid organ development.
This chapter provides information on imaging tools that can be employed to visualise and study lymphoid organ development. We focus on the use of genetically modified mouse models that take advantage of fluorescent protein expression in discrete cell populations, thus allowing live cell imaging during lymphoid organogenesis. We discuss approaches that allow characterisation of the cell types involved in the formation of lymphoid organs, including (i) functional assays in explant organ cultures and (ii) high-resolution whole-mount immunostaining methods, which are useful for the characterisation of specific cell populations in the context of the whole developing organ.


Decarboxylative allylations of ester enolate equivalents.
A variety of ester enolate equivalents are generated in situ and undergo α-allylation in high yields via palladium-catalyzed decarboxylative allylation. The transformations are complete within very short reaction times under ambient conditions. Synthesis of α-allylated acyl derivatives provides access to other carboxylic acid and alcohol derivatives via acyl group substitution or reduction.


DPP-4 inhibitors: a promising therapeutic approach against Alzheimer's disease.
Alzheimer's disease (AD), the commonest cause of dementia in ageing adults, is characterized by gradual cognitive impairment and severe functional disability. Key pathophysiological hallmarks involve amyloid-β (Aβ) accumulation, tau hyper-phosphorylation and neuronal loss. Despite extensive basic and clinical investigations, the etiology of the disease remains elusive, although several risk factors have been associated with its development. Current pharmacotherapies including achetylocholinesterase inhibitors and memantine fail to halt disease progression. Interestingly, type 2 diabetes mellitus (T2DM) and AD share several common characteristics, including Aβ deposition, insulin resistance, degeneration, mitochondrial dysfunction, oxidative stress and excessive inflammation. Recent experimental and clinical evidence indicates that dipeptidyl peptidase-4 (DPP-4) inhibitors, being currently used for T2DM therapy, may also prove effective for AD treatment. They may specifically suppress Aβ accumulation, tau hyper-phosphorylation, neuroinflammation, mitochondrial dysfunction and reactive oxygen species (ROS) formation, resulting in the inhibition of cognitive impairment. In this review, we discuss the encouraging current data regarding the molecular and clinical effects of DPP-4 inhibitors in AD, highlighting the need of future studies elucidating their functional role in addressing this incurable disease.


Subwavelength surface-relief gratings for stellar coronagraphy.
We present a new design of a phase mask coronagraph implemented with subwavelength diffractive optical elements consisting of optimized surface-relief gratings. Phase mask coronagraphy is a recent technique that seeks to accommodate both high dynamic and high angular resolution imaging of faint sources around bright astrophysical objects such as exoplanets orbiting their host stars. The original design we propose is a new, integrated, and flexible solution to the pi phase-shift chromaticity of the phase mask coronagraphs. It will allow broadband observations, i.e., shorter integration times and object characterizations, by means of spectroscopic analysis. The feasibility of the component manufacturing is also considered through a tolerance study.


Ceramide triggers metacaspase-independent mitochondrial cell death in yeast.
The activation of ceramide-generating enzymes, the blockade of ceramide degradation, or the addition of ceramide analogues can trigger apoptosis or necrosis in human cancer cells. Moreover, endogenous ceramide plays a decisive role in the killing of neoplastic cells by conventional anticancer chemotherapeutics. Here, we explored the possibility that membrane-permeable C2-ceramide might kill budding yeast (Saccharomyces cerevisiae) cells under fermentative conditions, where they exhibit rapid proliferation and a Warburg-like metabolism that is reminiscent of cancer cells. C2-ceramide efficiently induced the generation of reactive oxygen species (ROS), as well as apoptotic and necrotic cell death, and this effect was not influenced by deletion of the sole yeast metacaspase. However, C2-ceramide largely failed to cause ROS hypergeneration and cell death upon deletion of the mitochondrial genome. Thus, mitochondrial function is strictly required for C2-ceramide-induced yeast lethality. Accordingly, mitochondria from C2-ceramide-treated yeast cells exhibited major morphological alterations including organelle fragmentation and aggregation. Altogether, our results point to a pivotal role of mitochondria in ceramide-induced yeast cell death.


Peptides of pineal gland and thymus prolong human life.
Researchers of the St. Petersburg Institute of Bioregulation and Gerontology of the North-Western Branch of the Russian Academy of Medical Sciences and the Institute of Gerontology of the Ukrainian Academy of Medical Sciences (Kiev) clinically assessed the geroprotective effects of thymic (Thymalin) and pineal (Epithalamin) peptide bioregulators in 266 elderly and older persons during 6-8 years. The bioregulators were applied for the first 2-3 years of observation. The obtained results convincingly showed the ability of the bioregulators to normalize the basic functions of the human organism, i.e. to improve the indices of cardiovascular, endocrine, immune and nervous systems, homeostasis and metabolism. Homeostasis restoration was accompanied by a 2.0-2.4-fold decrease in acute respiratory disease incidence, reduced incidence of the clinical manifestations of ischemic heart disease, hypertension disease, deforming osteoarthrosis and osteoporosis as compared to the control. Such a significant improvement in the health state of the peptide-treated patients correlated with decreased mortality rate during observation: 2.0-2.1-fold in the Thymalin-treated group; 1.6-1.8-fold in the Epithalamin-treated group; 2.5-fold in the patients treated with Thymalin plus Epithalamin as compared to the control. A separate group of patients was treated with Thymalin in combination with Epithalamin annually for 6 years and their mortality rate decreased 4.1 times as compared to the control. The obtained data confirmed the high geroprotective efficacy of Thymalin and Epithalamin and the expediency of their application in medicine and social care for health maintenance and age-related pathology prevention in persons over 60 to prolong their active longevity.


Chronosequencing methanogenic archaea in ancient Longji rice Terraces in China.
Chronosequences of ancient rice terraces serve as an invaluable archive for reconstructions of historical human-environment interactions. Presently, however, these reconstructions are based on traditional soil physico-chemical properties. The microorganisms in palaeosols have been unexplored. We hypothesized that microbial information can be used as an additional proxy to complement and consolidate archaeological interpretations. To test this hypothesis, the palaeoenvironmental methanogenic archaeal DNA in Longji Terraces, one of the famous ancient terraces in China, dating back to the late Yuan Dynasty (CE 1361-1406), was chronosequenced by high-throughput sequencing. It was found that the methanogenic archaeal abundance, diversity and community composition were closely associated with the 630years of rice cultivation and in line with changes in multi-proxy data. Particularly, the centennial- and decadal-scale influences of known historical events, including social turbulences (The Taiping Rebellion, CE 1850-1865), palaeoclimate changes (the Little Ice Age) and recorded natural disasters (earthquakes and inundation), on ancient agricultural society were clearly echoed in the microbial archives as variations in alpha and beta diversity. This striking correlation suggests that the microorganisms archived in palaeosols can be quantitatively and qualitatively analyzed to provide an additional proxy, and palaeo-microbial information could be routinely incorporated in the toolkit for archaeological interpretation.


Atomic-resolution crystal structures of B-DNA reveal specific influences of divalent metal ions on conformation and packing.
Crystal structures of B-form DNA have provided insights into the global and local conformational properties of the double helix, the solvent environment, drug binding and DNA packing. For example, structures of the duplex with sequence CGCGAATTCGCG, the Dickerson-Drew dodecamer (DDD), established a unique geometry of the central A-tract and a hydration spine in the minor groove. However, our knowledge of the various interaction modes between metal ions and DNA is very limited and almost no information exists concerning the origins of the different effects on DNA conformation and packing exerted by individual metal ions. Crystallization of the DDD duplex in the presence of Mg(2+)and Ca(2+)yields different crystal forms. The structures of the new Ca(2+)-form and isomorphous structures of oligonucleotides with sequences GGCGAATTCGCG and GCGAATTCGCG were determined at a maximum resolution of 1.3 A. These and the 1.1 A structure of the DDD Mg(2+)-form have revealed the most detailed picture yet of the ionic environment of B-DNA. In the Mg(2+)and Ca(2+)-forms, duplexes in the crystal lattice are surrounded by 13 magnesium and 11 calcium ions, respectively.Mg(2+)and Ca(2+)generate different DNA crystal lattices and stabilize different end-to-end overlaps and lateral contacts between duplexes, thus using different strategies for reducing the effective repeat length of the helix to ten base-pairs. Mg(2+)crystals allow the two outermost base-pairs at either end to interact laterally via minor groove H-bonds, turning the 12-mer into an effective 10-mer. Ca(2+)crystals, in contrast, unpair the outermost base-pair at each end, converting the helix into a 10-mer that can stack along its axis. This reduction of a 12-mer into a functional 10-mer is followed no matter what the detailed nature of the 5'-end of the chain: C-G-C-G-A-ellipsis, G-G-C-G-A-ellipsis, or a truncated G-C-G-A-ellipsis Rather than merely mediating close contacts between phosphate groups, ions are at the origin of many well-known features of the DDD duplex structure. A Mg(2+)coordinates in the major groove, contributing to kinking of the duplex at one end. While Ca(2+)resides in the minor groove, coordinating to bases via its hydration shell, two magnesium ions are located at the periphery of the minor groove, bridging phosphate groups from opposite strands and contracting the groove at one border of the A-tract.


The evolutionary consequences of erroneous protein synthesis.
Errors in protein synthesis disrupt cellular fitness, cause disease phenotypes and shape gene and genome evolution. Experimental and theoretical results on this topic have accumulated rapidly in disparate fields, such as neurobiology, protein biosynthesis and degradation and molecular evolution, but with limited communication among disciplines. Here, we review studies of error frequencies, the cellular and organismal consequences of errors and the attendant long-range evolutionary responses to errors. We emphasize major areas in which little is known, such as the failure rates of protein folding, in addition to areas in which technological innovations may enable imminent gains, such as the elucidation of translational missense error frequencies. Evolutionary responses to errors fall into two broad categories: adaptations that minimize errors and their attendant costs and adaptations that exploit errors for the organism's benefit.


A new strategy for surface modification of polysulfone membrane by in situ imprinted sol-gel method for the selective separation and screening of L-Tyrosine as a lung cancer biomarker.
In this work, a novel method based on in situ molecularly imprinted sol-gel for the surface modification of a polysulfone membrane (PSM) was developed. A modified molecularly imprinted sol-gel polysulfone membrane (MSM) was placed in a homemade plastic tube and coupled on-line with LC/MS/MS for the selective extraction and screening of l-Tyrosine (Tyr) as a tentative lung cancer biomarker in human plasma samples. The existence of molecularly imprinted sol-gel layers on both sides of a PSM was examined using scanning electron microscopy (SEM). To evaluate the role of precursor in the extraction performance, repeatability, and selectivity of developed method, three precursors, 3-(propylmethacrylate) trimethoxysilane (P1), 3-(triethoxysilyl)-propylamine (P2), tetraethyl orthosilicate (P3), individually and together were used for treatment of PSM. Our investigation showed that a single precursor's route is more repeatable, straightforward, precise, accurate, and selective for the extraction of Tyr in plasma samples. Moreover, to achieve the best conditions and extraction efficiency, the effect of influential parameters, including the conditioning, washing, and elution of solvents, sample flow rate, loading time, desorption time, loading sample volume, salt effect, pH, and adsorption capacity for the most efficiently prepared membranes were truly investigated. The non-molecularly imprinted sol-gel polysulfone membrane (NSM) was prepared as a blank via the same process but in the absence of the Tyr. The LOD (S/N = 3/1) was 0.1 nmol L(-1) and the LOQ (S/N = 10/1) was 0.34 nmol L(-1) for Tyr in the plasma samples. The linearity for the Tyr was in the range of 0.34-2000 nmol L(-1) in the plasma samples. The coefficients of determination values were ≥0.998 for all runs. The extraction recovery was between 80%-85% for Tyr in the plasma samples. In addition, MSM could be used for up to 50 extractions without a significant change in recovery percentage.


Neurocognitive and behavioral profiles of children with Landau-Kleffner syndrome.
This is a retrospective study of 14 cases of children with Landau-Kleffner syndrome (LKS), the most prominent feature of which is acquired aphasia. These children were followed at a tertiary care pediatric epilepsy center. From the research data base, all LKS cases with neuropsychological evaluation were extracted. Children ranged in age from 6 to 13 years (M = 9.12; SD = 2.19) at the time of assessment (1 to 10 years post-onset). The majority of the children were white males, and all but one continued to experience seizure activity. Global intellectual functioning ranged from 59 to 101 (M = 82.07; SD = 12.14). Across the 14 cases reviewed, the neuropsychological profiles are considered in the context of neurological and syndrome-related factors. For these cases, 86% demonstrated continued expressive, and 50% had receptive language problems with 57% exhibiting poor auditory processing. Furthermore, 50 to 57% had deficits in auditory working memory and verbal memory. Academically, the majority had poor reading fluency and comprehension; 50% exhibited difficulty with mathematics. Finally, 57% evidenced attentional or other behavioral problems. Better understanding of LKS can assist in targeted assessment and intervention planning.


Limited protective effect of the CCR5Delta32/CCR5Delta32 genotype on human immunodeficiency virus infection incidence in a cohort of patients with hemophilia and selection for genotypic X4 virus.
The relationship among CCR5 genotype, cytomegalovirus infection, and disease progression and death was studied among 159 human immunodeficiency virus (HIV)-infected patients with hemophilia. One patient (0.6%) had the CCR5Delta32/CCR5Delta32 genotype (which occurs in approximately 2% of the Scandinavian population) and a rapid disease course. His HIV V3 region contained genotypic features attributable to X4 virus and resembled functionally verified X4 virus and virus from patients treated with a CD4 cell-stimulating drug, tucaresol. Age-related differences in disease progression rate and survival time were seen for CCR5/CCR5 patients. Surprisingly, no protective effect of the CCR5/CCR5Delta32 genotype on disease progression or survival was seen for children but was evident for adults. Age group-related immunologic differences might explain this variation, and transmission route and/or viral phenotype variation within donor virus may be related to the limited protection of the CCR5Delta32/CCR5Delta32 genotype. Sequence comparisons indicate that X4 virus can be selected in vivo due to either absence of CCR5 receptors or relative increase of CXCR4 receptors.


Indirect effects of exercise on emotional eating through psychological predictors of weight loss in women.
An improved understanding of how weight-loss interventions might be tailored to improve emotional eating is required. This study aimed to assess mediation of the relationship between increased exercise and decreased emotional eating so that behavioral treatments might be optimized. After randomization, women with obesity (N = 108; mean age = 48 years) were assigned to either a previously tested treatment of manual-based self-help for nutrition and exercise plus brief phone follow-ups, or a new protocol of cognitive-behavioral methods of exercise support intended to carry-over psychological improvements to better controlled eating and weight loss. A community-based field setting was incorporated. Validated self-report measures were administered over 6 months. Significant overall improvements in exercise outputs, emotional eating, mood, and self-regulation and self-efficacy for controlled eating were found. The newly developed treatment protocol demonstrated significantly greater improvements in exercise outputs and self-regulation. In a multiple mediation analysis, changes in self-regulation, self-efficacy, and mood significantly mediated the relationship between changes in exercise and emotional eating. Changes in self-efficacy and mood were significant independent mediators. Within follow-up analyses, the substitution of emotional eating subscales that addressed specific moods, and a subscale of self-efficacy for controlled eating that addressed that factor specifically in the presence of negative emotions, yielded results generally consistent with those of the multiple mediation analysis. Results suggested a psychological pathway of exercise's association with emotional eating changes in women with obesity. Guided by the present findings, tailoring exercise support and leveraging it to induce specific psychological improvements might reduce emotional eating and improve weight-management outcomes.


Germ cell transplantation and the study of testicular function.
Spermatogonial stem cell transplantation is a novel technique in which donor testicular cells are transferred into recipient testes. A population of germ cells from a transgenic or mutant donor is introduced into the seminiferous tubules of recipient testes by microinjection. Following injections, spermatogonial stem cells can colonize the recipient testis, initiate spermatogenesis and produce sperm capable of fertilization. This technique will allow scientists to: (1) investigate fundamental aspects of spermatogenesis; (2) provide a method to regenerate spermatogenesis in infertile individuals; and (3) genetically manipulate spermatogonial stem cells to develop transgenic animals.


Regulatory T cells control type I food allergy to Beta-lactoglobulin in mice.
Regulatory T cells contribute to peripheral immune tolerance, yet their ability to control immediate-type hypersensitivity (ITH) reactions involved in IgE-mediated food allergy is still poorly documented. We investigated in mice whether CD4+CD25+ regulatory T cells could control ITH to β-lactoglobulin (BLG), a major allergen in cow's milk. C3H/HeOuJ mice were sensitized by repeated oral gavage with BLG plus cholera toxin as adjuvant and orally challenged with BLG alone to elicit allergic symptoms. Mice were treated with the anti-CD25 mAb (PC61) before sensitization. Oral sensitization (afferent phase of ITH) was assessed by production of BLG-specific serum antibodies and Th1/Th2-type cytokines by specific CD4+ T cells in mesenteric lymph nodes. ITH was elicited by oral BLG challenge (efferent phase of ITH) and we monitored symptom scores, numbers and function of intestinal mast cells and serum level of the mucosal mast cell protease mMCP-1. Upon oral BLG challenge, orally sensitized mice developed only mild clinical signs. Anti-CD25 mAb-treated mice exhibited enhancement of both BLG-specific CD4+ T cell priming with IL-4, IL-5, IL-13 and IFN-γ production and total IgE, and BLG-specific IgE, IgG1 and IgG2a in serum. Anti-CD25 mAb treatment caused more severe symptoms upon BLG challenge, which correlated with enhanced serum levels of the mucosal mast cell protease mMCP-1. These data document that constitutive CD4+CD25+ regulatory T cells alleviate clinical signs of ITH to dietary BLG by modulating the priming of BLG-specific T and B cell responses during oral sensitization and enhancing mast cell degranulation.


Dissociation of the role of the prelimbic cortex in interval timing and resource allocation: beneficial effect of norepinephrine and dopamine reuptake inhibitor nomifensine on anxiety-inducing distraction.
Emotional distracters impair cognitive function. Emotional processing is dysregulated in affective disorders such as depression, phobias, schizophrenia, and post-traumatic stress disorder (PTSD). Among the processes impaired by emotional distracters, and whose dysregulation is documented in affective disorders, is the ability to time in the seconds-to-minutes range, i.e., interval timing. Presentation of task-irrelevant distracters during a timing task results in a delay in responding suggesting a failure to maintain subjective time in working memory, possibly due to attentional and working memory resources being diverted away from timing, as proposed by the Relative Time-Sharing (RTS) model. We investigated the role of the prelimbic cortex in the detrimental effect of anxiety-inducing task-irrelevant distracters on the cognitive ability to keep track of time, using local infusions of norepinephrine and dopamine reuptake inhibitor (NDRI) nomifensine in a modified peak-interval procedure with neutral and anxiety-inducing distracters. Given that some anti-depressants have beneficial effects on attention and working memory, e.g., decreasing emotional response to negative events, we hypothesized that nomifensine would improve maintenance of information in working memory in trials with distracters, resulting in a decrease of the disruptive effect of emotional events on the timekeeping abilities. Our results revealed a dissociation of the effects of nomifensine infusion in prelimbic cortex between interval timing and resource allocation, and between neutral and anxiety-inducing distraction. Nomifensine was effective only during trials with distracters, but not during trials without distracters. Nomifensine reduced the detrimental effect of the distracters only when the distracters were anxiety-inducing, but not when they were neutral. Results are discussed in relation to the brain circuits involved in RTS of resources, and the pharmacological management of affective disorders.


Using maps to communicate environmental exposures and health risks: Review and best-practice recommendations.
Graphical materials can be effective communication tools, and maps in particular are a potentially powerful means of conveying spatial information. Previous reviews have provided insights on the application of cartographic best practices, pitfalls to avoid, and considerations related to risk perception and communication, but none has reviewed primary studies of the effectiveness or utility of maps to users, nor have they addressed the issue from the perspective of health literacy, environmental health literacy, or public health ethics. To systematically identify and review the literature pertaining to evaluation of maps in general, or specific map features, as environmental exposure and health risk communication tools; to formulate best-practice recommendations; and to identify future research priorities. A health science librarian searched the literature for commentaries, reviews, and primary studies. Titles, abstracts, and full-text papers were screened for inclusion, and details of methods and results were extracted from 4 reviews and commentaries and 18 primary studies. This was supplemented by one additional review and 13 additional primary studies pertaining to use of maps for communication about wildfires and floods. One additional paper was identified by reviewing reference lists of all relevant papers. and Discussion: While there are significant gaps in the evidence, we formulated best practice recommendations highlighting the perspectives of health literacy and environmental health literacy. Key recommendations include: understanding the map developer's societal role and mental model underlying map design; defining, understanding and iteratively engaging with map users; informing map design using key theoretical constructs; accounting for factors affecting risk perception; adhering to risk communication principles and cartographic best practices; and considering environmental justice and public health ethics implications. Recommendations for future research are also provided.


Tocilizumab for Treatment of Mechanically Ventilated Patients With COVID-19.
Severe coronavirus disease 2019 (COVID-19) can manifest in rapid decompensation and respiratory failure with elevated inflammatory markers, consistent with cytokine release syndrome for which IL-6 blockade is an approved treatment. We assessed effectiveness and safety of IL-6 blockade with tocilizumab in a single-center cohort of patients with COVID-19 requiring mechanical ventilation. The primary endpoint was survival probability postintubation; secondary analyses included an ordinal illness severity scale integrating superinfections. Outcomes in patients who received tocilizumab compared with tocilizumab-untreated controls were evaluated using multivariable Cox regression with propensity score inverse probability of treatment weighting (IPTW). 154 patients were included, of whom 78 received tocilizumab and 76 did not. Median follow-up was 47 days (range, 28-67). Baseline characteristics were similar between groups, although tocilizumab-treated patients were younger (mean: 55 vs 60 years), less likely to have chronic pulmonary disease (10% vs 28%), and had lower D-dimer values at time of intubation (median: 2.4 vs 6.5 mg/dL). In IPTW-adjusted models, tocilizumab was associated with a 45% reduction in hazard of death (HR, .55; 95% CI, .33-.90) and improved status on the ordinal outcome scale [OR per 1-level increase, .58; .36-.94). Although tocilizumab was associated with an increased proportion of patients with superinfections (54% vs 26%; P < .001), there was no difference in 28-day case fatality rate among tocilizumab-treated patients with versus without superinfection (22% vs 15%; P = .42). Staphylococcus aureus accounted for ~50% of bacterial pneumonia. In this cohort of mechanically ventilated COVID-19 patients, tocilizumab was associated with lower mortality despite higher superinfection occurrence.


Inpatient Postpartum Long-Acting Reversible Contraception and Sterilization in the United States, 2008-2013.
To measure rates of long-acting reversible contraception (LARC), including intrauterine devices and contraceptive implants, and tubal sterilization during delivery hospitalizations and correlates of their use. This retrospective cohort study used the 2008-2013 National Inpatient Sample, a publicly available all-payer database. We identified delivery hospitalizations with the International Classification of Diseases, 9th Revision, Clinical Modification codes for intrauterine device insertion, contraceptive implant insertion, and tubal sterilization. We used weighted multivariable logistic regression to examine associations between predictors (age, delivery mode, medical comorbidity, payer, hospital type, geographic region, and year) and likelihood of LARC and sterilization and to compare characteristics of LARC and sterilization users. Our sample included 4,691,683 discharges, representing 22,667,204 delivery hospitalizations. Long-acting reversible contraception insertion increased from 1.86 per 10,000 deliveries (2008-2009) to 13.5 per 10,000 deliveries (2012-2013; P<.001); tubal sterilization remained stable (711-683 per 10,000 deliveries; P=.24). In multivariable analysis adjusting for all predictors, compared with neither LARC nor sterilization, LARC use was highest among women with medical comorbidities (count per 10,000 deliveries: 15.04, standard error 2.11, adjusted odds ratio [OR] 1.92, 95% confidence interval [CI] 1.72-2.13), nonprivate payer (13.50, standard error 2.14, adjusted OR 5.23, 95% CI 3.82-7.16), and at urban teaching hospitals (14.92, standard error 2.25, adjusted OR 20.85, 95% CI 12.73-34.15). Sterilization was least likely among women aged 24 years or younger (251.04, standard error 4.88, adjusted OR 0.12 95% CI 0.12-0.13, compared with 35 years or older) and most likely with cesarean delivery (1,568.74, standard error 20.81, adjusted OR 6.25, 95% CI 5.88-6.63). Comparing only LARC and sterilization users, LARC users tended to have nonprivate insurance (84.95% compared with 57.17%, adjusted OR 1.90, 95% CI 1.38-2.63) and deliver at urban teaching hospitals (94.65% compared with 45.47%, adjusted OR 38.39, 23.52-62.64) in later study years (2012-2013; 55.72% compared with 32.18%, adjusted OR 8.26, 95% CI 4.42-15.44, compared with 2008-2009). Long-acting reversible contraception insertion increased from 1.86 to 13.5 per 10,000 deliveries but remained less than 2% of the sterilization rate. Inpatient postpartum LARC insertion is more likely among sicker, poorer women delivering at urban teaching hospitals.


Intracranial Hemorrhage After Reperfusion Therapies in Acute Ischemic Stroke Patients.
Reperfusion therapies are the mainstay of acute ischemic stroke (AIS) treatments and overall improve functional outcome. Among the established complications of intravenous (IV) tissue-type plasminogen activator (tPA), intracranial hemorrhage (ICH) is by far the most feared and has been extensively described by seminal works over the last two decades. Indeed, IV tPA is associated with increased odds of any ICH and symptomatic ICH responsible for increased mortality rate during the first week after an AIS. Despite these results, IV tPA has been found beneficial in several pioneering randomized trials and improves functional outcome at 3 months. Endovascular therapy (EVT) combined with IV tPA for AIS patients consecutive to an anterior circulation large-vessel occlusion does not increase ICH occurrence. Of note, EVT following IV tPA leads to significantly higher rates of early reperfusion than with IV tPA alone, with no difference in ICH, which challenges the paradigm of reperfusion as a major prognostic factor for ICH complications. However, several blood biomarkers (glycemia, platelet and neutrophil count), clinical factors (age, AIS severity, blood pressure management, diabetes mellitus), and neuroradiological factors (cerebral microbleeds, infarct size) have been identified as risk factors for ICH after reperfusion therapy. In the years to come, the ultimate goal will be to further improve either reperfusion rates and functional outcome, while reducing hemorrhagic complications. To this end, various approaches being investigated are discussed in this review, such as blood-pressure control after reperfusion or the use of new antiplatelet agents as an adjunct to IV tPA and exhibit reduced hemorrhagic potential during the early phase of AIS.


Life course social roles and women's health in mid-life: causation or selection?
To investigate whether relations between social roles and health are explained by health selection into employment and parenthood by examining the influence of early health on relations between long term social role histories and health in mid-life. Prospective, population based, birth cohort study. Women from a national British cohort born in 1946, including 1171 women with a valid measure of self reported health at age 54 and valid work and family role measures at ages 26, 36, 43, and 53, as well as 1433 women with a valid body mass index (BMI) measure at age 53 and valid work and family role measures at ages 26, 36, 43, and 53. Self reported health at age 54 and obesity at age 53, taken from objective height and weight measures conducted by a survey nurse during face to face interviews in respondents' homes. Women who occupied multiple roles over the long term reported relatively good health at age 54 and this was not explained by early health. Women with weak long term ties to the labour market were more likely to be obese at age 53. Examination of body mass index (BMI) from age 15 showed that long term homemakers were larger than other women from age 26, but their mean BMI increased significantly more with age than that of other women. Relations between social roles and health were generally not explained by health selection into employment and parenthood, although some health selection may occur for obesity.


Phthalate esters and childhood asthma: A systematic review and congener-specific meta-analysis.
Exposure to phthalate esters (PAEs) has been associated with childhood asthma, but the congener-specific effects of PAEs on childhood asthma were unclear. We aimed to systematically review and meta-analyze observational studies on the associations between specific effects of PAEs and the risk of childhood asthma. Relevant studies were identified by searching three databases up to October 20, 2016. The reference lists of the retrieved articles were also reviewed. We included observational studies that reported risk estimates with 95% confidence intervals (CIs) for the associations between phthalate exposure and the risk of childhood asthma. Fixed-effects models were generally applied to calculate pooled risk estimates. When heterogeneity was present, random-effects models were applied. A total of nine studies featuring 43 data points were included in our final meta-analyses. Results indicated that the benzyl butyl phthalate (BBzP) exposure had a significant association with the risk of childhood asthma. The Odd Ratios (ORs) were from 1.39 to 1.41 for different combination strategies. Subgroup analyses by different exposure period or samples used showed that prenatal exposure to BBzP had a stronger association with the risk of childhood asthma (OR = 1.38, 95% CI = 1.09-1.75), compared to those with postnatal exposure. Besides, the association was evident when the phthalate exposure was measured from dust samples. The OR for the associations between di-2-ethylhexyl phthalate (DEHP) in dust and childhood asthma was 2.71 (95% CI = 1.39-5.28), and 2.08 (95% CI = 1.10-3.92) for BBzP. Our study suggested a positive association between DEHP and BBzP exposure and childhood asthma. Future studies are warranted to identify the underlying mechanisms of the association.


Exergonic and Spontaneous Production of Radicals through Beryllium Bonds.
High-level ab initio calculations show that the formation of radicals, by the homolytic bond fission of Y-R (Y=F, OH, NH2 ; R=CH3 , NH2 , OH, F, SiH3 , PH2 , SH, Cl, NO) bonds is dramatically favored by the association of the molecule with BeX2 (X=H and Cl) derivatives. This finding is a consequence of two concomitant effects, the significant activation of the Y-R bond after the formation of the beryllium bond, and the huge stabilization of the F(.) (OH(.) , NH2 (.) ) radical upon BeX2 attachment. In those cases where R is an electronegative group, the formation of the radicals is not only exergonic, but spontaneous.


Information and consumer choice: the value of publicized health plan ratings.
We use data on the enrollment decisions of federal annuitants to estimate the influence of publicized ratings on health plan choice. We focus on the impact of ratings disseminated by the National Committee for Quality Assurance (NCQA), and use our estimates to calculate the value of the information. Our approach exploits a novel feature of the data-the availability of non-public plan ratings-to correct for a source of bias that is inherent in studies of consumer responsiveness to information on product quality: since publicized ratings are correlated with other quality signals known to consumers (but unobserved by researchers), the estimated influence of ratings is likely to be overstated. We control for this bias by comparing the estimated impact of publicized ratings to the estimated impact of ratings that were never disclosed. The results indicate that NCQA's plan ratings had a meaningful influence on individuals' choices, particularly for individuals choosing a plan for the first time. Although we estimate that a very small fraction of individual decisions were materially affected by the information, for those that were affected the implied utility gains are substantial.


Genome-wide linkage analysis to identify chromosomal regions affecting phenotypic traits in the chicken. IV. Metabolic traits.
The current study is a comprehensive genome analysis to detect QTL affecting metabolic traits in chickens. Two unique F(2) crosses generated from a commercial broiler male line and 2 genetically distinct inbred lines (Leghorn and Fayoumi) were used in the present study. The plasma glucagon, insulin, lactate, glucose, tri-iodothyronine, thyroxine, insulin-like growth factor I, and insulin-like growth factor II concentrations at 8 wk were measured in the 2 F(2) crosses. Birds were genotyped for 269 microsatellite markers across the entire genome. The program QTL Express was used for QTL detection. Significance levels were obtained using the permutation test. For the 10 traits, a total of 6 and 9 significant QTL were detected at a 1% chromosome-wise significance level, of which 1 and 6 were significant at the 5% genome-wise level for the broiler-Leghorn cross and broiler-Fayoumi cross, respectively. Most QTL for metabolic traits in the present study were detected in Gga 2, 6, 8, 9, 13, and Z for the broiler-Leghorn cross and Gga 1, 2, 4, 7, 8, 13, 17, and E47 for the broiler-Fayoumi cross. Phenotypic variation for each trait explained by all QTL across genome ranged from 2.73 to 14.08% in the broiler-Leghorn cross and from 6.93 to 21.15% in the broiler-Fayoumi cross. Several positional candidate genes within the QTL region for metabolic traits at the 1% chromosome-wise significance level are biologically associated with the regulation of metabolic pathways of insulin, triiodothyronine, and thyroxine.


Fate of gap junctions in isolated adult mammalian cardiomyocytes.
The fate of gap junctions in dissociated adult myocytes, maintained for up to 22 hours in culture medium, was investigated by semiquantitative analysis of thin sections and by freeze-fracture electron microscopy. Gap junctions in the dissociated myocyte are intact bimembranous structures seen either as invaginated surface-located structures or as annular profiles in the cytoplasm. Surface-located junctions are sealed from the exterior by a sheet of nonjunctional membrane originating (together with the "outer" junctional membrane) from the formerly neighboring cell. Serial sectioning was used to establish that at least part of the annular gap junction population in the freshly isolated myocyte represents truly discrete cytoplasmic vesicles; thus, some gap junctions are rapidly endocytosed after myocyte separation. Analysis of the surface-located-to-annular gap junction ratio suggested that no further endocytosis occurred in rabbit and cat myocytes maintained for 22 and 15 hours, respectively. Guinea pig myocytes, by contrast, did appear to continue endocytosis in culture. Analysis of the distance of gap junctional structures from the cell surface suggested that little if any inward migration of gap junction vesicles occurred. Hypoxia had no detectable effect on the internalization or inward movement of gap junctions. The quantity of ultrastructurally detectable gap junction membrane appeared to remain constant over time, as did the incidence of "complex structures" (i.e., annular gap junction profiles with features previously suggested to represent degradation). New gap junction formation was negligible, and a reappraisal of the nature of "complex structures" led to the conclusion that the origin of these structures need not be related to degradation. Taken together, the findings suggest that degradation and disappearance of gap junctional membrane after isolation of the mature myocyte constitute a much slower process than previously believed, and the possibility that the cardiac gap junction protein has a longer half-life than its counterpart in liver remains open.


The Nithsdale schizophrenia surveys. IX: Akathisia, parkinsonism, tardive dyskinesia and plasma neuroleptic levels.
Of all known schizophrenics living in Nithsdale, south-west Scotland, 146 (88%) were examined for the presence of the three principal movement disorders secondary to antipsychotic medication, namely akathisia, tardive dyskinesia and Parkinsonism. Of these, 18% had akathisia, 5% pseudoakathisia, 29% tardive dyskinesia, 8% persistent tardive dyskinesia, and 27% Parkinsonism. No movement disorder was seen in 445, 36% had one and 20% had more than one movement disorder. Plasma neuroleptic levels at the time of clinical assessment were measured by the radioreceptor technique. Correlations between dose and plasma level were low; the ratio of mean plasma concentration to mean dose was greatest with fluphenazine decanoate and lowest for sulpiride. The concentration:dose ratio was higher in the elderly. There was no relationship between neuroleptic levels and akathisia, Parkinsonism or tardive dyskinesia. Additional psychotropic medication influenced neuroleptic levels. In 9% of patients receiving oral antipsychotic medication, no drug was detected in plasma.


Heritable components of the human fecal microbiome are associated with visceral fat.
Variation in the human fecal microbiota has previously been associated with body mass index (BMI). Although obesity is a global health burden, the accumulation of abdominal visceral fat is the specific cardio-metabolic disease risk factor. Here, we explore links between the fecal microbiota and abdominal adiposity using body composition as measured by dual-energy X-ray absorptiometry in a large sample of twins from the TwinsUK cohort, comparing fecal 16S rRNA diversity profiles with six adiposity measures. We profile six adiposity measures in 3666 twins and estimate their heritability, finding novel evidence for strong genetic effects underlying visceral fat and android/gynoid ratio. We confirm the association of lower diversity of the fecal microbiome with obesity and adiposity measures, and then compare the association between fecal microbial composition and the adiposity phenotypes in a discovery subsample of twins. We identify associations between the relative abundances of fecal microbial operational taxonomic units (OTUs) and abdominal adiposity measures. Most of these results involve visceral fat associations, with the strongest associations between visceral fat and Oscillospira members. Using BMI as a surrogate phenotype, we pursue replication in independent samples from three population-based cohorts including American Gut, Flemish Gut Flora Project and the extended TwinsUK cohort. Meta-analyses across the replication samples indicate that 8 OTUs replicate at a stringent threshold across all cohorts, while 49 OTUs achieve nominal significance in at least one replication sample. Heritability analysis of the adiposity-associated microbial OTUs prompted us to assess host genetic-microbe interactions at obesity-associated human candidate loci. We observe significant associations of adiposity-OTU abundances with host genetic variants in the FHIT, TDRG1 and ELAVL4 genes, suggesting a potential role for host genes to mediate the link between the fecal microbiome and obesity. Our results provide novel insights into the role of the fecal microbiota in cardio-metabolic disease with clear potential for prevention and novel therapies.


Metabolic syndrome and its components are associated with increased thyroid volume and nodule prevalence in a mild-to-moderate iodine-deficient area.
Metabolic syndrome (MetS) is a cluster of metabolic abnormalities with insulin resistance (IR) as a major component. It has been recently questioned whether MetS and its related components are associated with functional and morphological alterations of the thyroid gland. The aim of our study is to examine thyroid volume and nodule prevalence in a case-control study of patients with MetS in a mild-to-moderate iodine-deficient area. Two hundred and seventy-eight patients with MetS were randomly matched for age, gender, and smoking habits with 261 subjects without MetS. Serum TSH, free tri-iodothyronine and thyroxine, and the level of IR, which was estimated by the homeostasis model assessment for IR, as well as other MetS parameters were evaluated. Thyroid ultrasonography was performed in all subjects. All subjects with thyroid nodules >1 cm were offered to undergo thyroid fine needle aspiration biopsy. TSH was significantly positively correlated with the presence of MetS diagnosis. There was no association between free thyroid hormone levels and MetS and its related components. Mean thyroid volume was significantly higher in patients with MetS than in controls (17.5 + or - 5.5 vs 12.2 + or - 4.2 ml, P<0.0001). Also the percentage of patients with thyroid nodules was significantly higher in patients with MetS (50.4 vs 14.6%, P<0.0001). Subjects were also divided into two groups according to the presence of IR. The group of subjects with IR had increased thyroid volume and nodule formation. The odds ratio for the development of thyroid nodule in the presence of IR was 3.2. TSH as well as all MetS components were found to be independent predictors for thyroid volume increase. IR but not TSH was found to be correlated with thyroid nodule formation. Thyroid cancer was diagnosed in 3 out of 38 patients with MetS who agreed to have a biopsy (7.9%). None of the subjects in the control group was diagnosed to have thyroid cancer. The results suggest that patients with MetS have significantly increased thyroid volume and nodule prevalence. Multivariate regression analysis model demonstrated that the presence of IR contributed substantially to this increased risk. Our data provide the first evidence that IR is an independent risk factor for nodule formation in an iodine-deficient environment.


Double-stranded DNA binding properties of Saccharomyces cerevisiae DNA polymerase epsilon and of the Dpb3p-Dpb4p subassembly.
DNA polymerase epsilon (Pol epsilon) of Saccharomyces cerevisiae participates in many aspects of DNA replication, as well as in DNA repair. In order to clarify molecular mechanisms employed in the multiple tasks of Pol epsilon, we have been characterizing the interaction between Pol epsilon and DNA. Analysis of the four-subunit Pol epsilon complex by gel mobility shift assay revealed that the complex binds not only to single-stranded (ss) DNA but also equally well to double-stranded (ds) DNA. A truncated polypeptide consisting of the N-terminal domain of Pol2p catalytic subunit binds to ssDNA but not to dsDNA, indicating that the Pol2p C-terminal domain and/or the auxiliary subunits are involved in the dsDNA-binding. The dsDNA-binding by Pol epsilon does not require DNA ends or specific DNA sequences. Further analysis by competition experiments indicated that Pol epsilon contains at least two distinct DNA-binding sites, one of which binds exclusively to ssDNA and the other to dsDNA. The dsDNA-binding site, however, is suggested to also bind ssDNA. The DNA polymerase activity of Pol epsilon is inhibited by ssDNA but not by dsDNA. Furthermore, purification of the Pol epsilon auxiliary subunits Dpb3p and Dpb4p revealed that these proteins form a heterodimer and associate with dsDNA. Pol epsilon has multiple sites at which it interacts with DNA. One of these sites has a strong affinity for dsDNA, a feature that is not generally associated with DNA polymerases. Involvement of the Dpb3p-Dpb4p complex in the dsDNA-binding of Pol epsilon is inferred.


Mesenchymal stem cells for the treatment of multiple sclerosis and other neurological diseases.
The rationale for use of adult stem cells as a treatment for neurological diseases such as multiple sclerosis arose from the hope that they had the capacity to foster repair of the CNS through tissue integration and differentiation into neural cells. Evidence from preclinical studies suggested that mesenchymal stem cells (MSCs), a subset of adult progenitor cells, are an effective therapy in preclinical animal models of neurological diseases such as experimental autoimmune encephalomyelitis, a model for multiple sclerosis, and stroke. In experimental autoimmune encephalomyelitis, intravenous injection of MSCs ameliorates clinical course and decreases demyelination, immune infiltrates, and axonal loss. Surprisingly, these effects do not require full CNS engraftment by MSCs, but rely on the capacity of MSCs to inhibit pathogenic immune responses and release neuroprotective and pro-oligodendrogenic molecules favouring tissue repair. These results led to the conclusion that therapeutic use of MSCs should initially focus on individuals with multiple sclerosis and persistent inflammation. Small clinical studies in different neurological diseases have suggested that MSCs are safe, paving the road for larger phase 2 studies addressing the effect of MSCs on clinical outcomes and markers of disease activity.


A ketogenic diet as a potential novel therapeutic intervention in amyotrophic lateral sclerosis.
The cause of neuronal death in amyotrophic lateral sclerosis (ALS) is uncertain but mitochondrial dysfunction may play an important role. Ketones promote mitochondrial energy production and membrane stabilization. SOD1-G93A transgenic ALS mice were fed a ketogenic diet (KD) based on known formulations for humans. Motor performance, longevity, and motor neuron counts were measured in treated and disease controls. Because mitochondrial dysfunction plays a central role in neuronal cell death in ALS, we also studied the effect that the principal ketone body, D-beta-3 hydroxybutyrate (DBH), has on mitochondrial ATP generation and neuroprotection. Blood ketones were > 3.5 times higher in KD fed animals compared to controls. KD fed mice lost 50% of baseline motor performance 25 days later than disease controls. KD animals weighed 4.6 g more than disease control animals at study endpoint; the interaction between diet and change in weight was significant (p = 0.047). In spinal cord sections obtained at the study endpoint, there were more motor neurons in KD fed animals (p = 0.030). DBH prevented rotenone mediated inhibition of mitochondrial complex I but not malonate inhibition of complex II. Rotenone neurotoxicity in SMI-32 immunopositive motor neurons was also inhibited by DBH. This is the first study showing that diet, specifically a KD, alters the progression of the clinical and biological manifestations of the G93A SOD1 transgenic mouse model of ALS. These effects may be due to the ability of ketone bodies to promote ATP synthesis and bypass inhibition of complex I in the mitochondrial respiratory chain.