Late-Emerging and Resolving Dyslexia: A Follow-Up Study from Age 3 to 14.
This study focuses on the stability of dyslexia status from Grade 2 to Grade 8 in four groups: (a) no dyslexia in either grade (no-dyslexia, n = 127); (b) no dyslexia in Grade 2 but dyslexia in Grade 8 (late-emerging, n = 18); (c) dyslexia in Grade 2 but not in Grade 8 (resolving, n = 15); and (d) dyslexia in both grades (persistent-dyslexia, n = 22). We examined group differences from age 3.5 to age 14 in (a) reading, vocabulary, phonology, letter knowledge, rapid naming, IQ, verbal memory; (b) familial and environmental risk and supportive factors; and (c) parental skills in reading, phonology, rapid naming, verbal memory, and vocabulary. Our findings showed group differences both in reading and cognitive skills of children as well as their parents. Parental education, book-reading frequency, and children's IQ, however, did not differentiate the groups. The children in the persistent-dyslexia group exhibited widespread language and cognitive deficits across development. Those in the resolving group had problems in language and cognitive skills only prior to school entry. In the late-emerging group, children showed clearly compromised rapid naming. Additionally, their parents had the most severe difficulties in rapid naming, a finding that suggests strong genetic liability. The findings show instability in the diagnosis of dyslexia. The members of the late-emerging group did not have a distinct early cognitive profile, so late-emerging dyslexia appears difficult to predict. Indeed, these children are at risk of not being identified and not receiving required support. This study suggests the need for continued monitoring of children's progress in literacy after the early school years.


The effect of wheat prebiotics on the gut bacterial population and iron status of iron deficient broiler chickens.
Currently, there is a lot of interest in improving gut health, and consequently increasing Fe absorption, by managing the colonic microbial population. This is traditionally done by the consumption of probiotics, live microbial food supplements. However, an alternative, and often very effective approach, is the consumption of food ingredients known as prebiotics. Fructans and arabinoxylans are naturally occurring non-digestible oligosaccharides in wheat that exhibit prebiotic properties and may enhance intestinal iron (Fe) absorption. The aim of this study was to assess the effect of prebiotics from wheat on Fe bioavailability in vitro (Caco-2 cells) and in vivo (broiler chickens, Gallus gallus). In the current study, the effect of intra-amniotic administration of wheat samples extracts at 17 d of embryonic incubation on the Fe status and possible changes in the bacterial population in intestinal content of broiler hatchlings were investigated. A group of 144 eggs were injected with the specified solution (1 ml per egg) into the amniotic fluid. Immediately after hatch (21 d) and from each treatment group, 10 chicks were euthanized and their small intestine, liver and cecum were removed for relative mRNA abundance of intestinal Fe related transporters, relative liver ferritin amounts and bacterial analysis of cecal content, respectively. The in vivo results are in agreement with the in vitro observations, showing no differences in the hatchling Fe status between the treatment groups, as Fe bioavailability was not increased in vitro and no significant differences were measured in the intestinal expression of DMT1, Ferroportin and DcytB in vivo. However, there was significant variation in relative amounts of bifidobacteria and lactobacilli in the intestinal content between the treatments groups, with generally more bifidobacteria being produced with increased prebiotic content. In this study we showed that prebiotics naturally found in wheat grains/bread products significantly increased intestinal beneficial bacterial population in Fe deficient broiler chickens. With this short-term feeding trial we were not able to show differences in the Fe-status of broilers. Nevertheless, the increase in relative amounts of bifidobacteria and lactobacilli in the presence of wheat prebiotics is an important finding as these bacterial populations may affect Fe bioavailability in long-term studies.


Survival benefits of different antiadrenergic interventions in pressure overload left ventricular hypertrophy/failure.
We observed previously that in rats with aortic banding (Bd), development of left ventricular (LV) hypertrophy is opposed by beta-blockade, whereas interventions interfering with alpha-adrenoceptor function also inhibit interstitial fibrosis. To assess whether these differential structural effects do translate into different effects on LV function and on heart failure mortality, Bd or sham Bd 8-week-old rats were randomized to vehicle treatment (Vh), chemical sympathectomy ([Sx] 6-hydroxydopamine, 150 mg/kg IP twice a week), beta-adrenoceptor blockade (propranolol [Pro], 40 mg/kg per day PO), or alpha-adrenoceptor blockade (doxazosin [Dox], 5 mg/kg per day PO). After monitoring survival for 10 weeks, the survivors were anesthetized to undergo echocardiography and intraarterial blood pressure measurement. Bd-Vh rats showed increased LV and lung weights, as well as LV dilation, depressed endocardial and midwall fractional shortening and a restrictive transmitral diastolic flow velocity pattern. Compared with Bd-Vh rats, all of the actively treated Bd rats showed less LV hypertrophy, LV dilation, and lung congestion but no less depression of midwall fractional shortening. In contrast, Sx and Dox but not Pro treatment were also associated with lesser degrees of diastolic dysfunction and, even more importantly, with a striking increase in survival (sham banded rats, 100%; Bd-Vh, 40%; Bd-Pro, 51%; Bd-Sx, 83%; and Bd-Dox, 82%). Although Pro, Sx, and Dox provide similar midterm protection from development of LV hypertrophy and dysfunction and from circulatory congestion, only Sx and Dox favorably affected mortality. These findings indicate that in the aortic banding rat model, alpha-adrenoceptors are importantly involved in the pathogenesis of cardiovascular deterioration and disease progression.


"The walls were so damp and cold" fuel poverty and ill health in Northern Ireland: results from a housing intervention.
This article reports the findings from an evaluation of a fuel poverty programme in the Armagh and Dungannon Health Action Zone in Northern Ireland. Focusing on a rural community, it adds to the debate surrounding the hidden nature of rural fuel poverty. As part of the programme, energy efficiency measures, including some central heating systems, were installed in 54 homes. Surveys were conducted both pre and post intervention and analysed to assess any changes. The programme demonstrated that energy efficiency intervention can lead to improvements in health and well being, increased comfort levels in the home and a reduction in the use of health services, therefore having potential cost savings for the NHS. Some households, however, remain in fuel poverty after having full central heating installed, reflecting the significant contribution of low income on the production of fuel poverty. The article concludes by suggesting that interventions in this area require commitment from multiple sectors of society, including health professionals and local communities.


Structural model of the full-length Ser/Thr protein kinase StkP from S. pneumoniae and its recognition of peptidoglycan fragments.
The unique eukaryotic-like Ser/Thr protein kinases of Streptococcus pneumoniae, StkP, plays a primary role in the cell division process. It is composed of an intracellular kinase domain, a transmembrane helix and four extracellular PASTA subunits. PASTA domains were shown to interact with cell wall fragments but the key questions related to the molecular mechanism governing ligand recognition remain unclear. To address this issue, the full-length structural model of StkP was generated by combining small-angle X-ray scattering data with the results of computer simulations. Docking and molecular dynamics studies on the generated three-dimensional model structure reveal the possibility of peptidoglycan fragment binding at the hinge regions between PASTA subunits with a preference for a bent hinge between PASTA3 and PASTA4.


Variation of outdoor illumination as a function of solar elevation and light pollution.
The illumination of the environment undergoes both intensity and spectral changes during the 24 h cycle of a day. Daylight spectral power distributions are well described by low-dimensional models such as the CIE (Commission Internationale de l'Éclairage) daylight model, but the performance of this model in non-daylight regimes is not characterised. We measured downwelling spectral irradiance across multiple days in two locations in North America: One rural location (Cherry Springs State Park, PA) with minimal anthropogenic light sources, and one city location (Philadelphia, PA). We characterise the spectral, intensity and colour changes and extend the existing CIE model for daylight to capture twilight components and the spectrum of the night sky.


Poor health, unhealthy behaviors, and unfavorable work characteristics influence pathways of exit from paid employment among older workers in Europe: a four year follow-up study.
The aim of this study was to get insight into the role of poor health, unhealthy behaviors, and unfavorable work characteristics on exit from paid employment due to disability pension, unemployment, and early retirement among older workers. Respondents of the longitudinal Survey of Health, Ageing, and Retirement in Europe (SHARE) in 11 European countries were selected when (i) aged between 50 years and the country-specific retirement age, (ii) in paid employment at baseline, and (iii) having information on employment status during the 4-year follow-up period (N=4923). Self-perceived health, health behaviors, and physical and psychosocial work characteristics were measured by interview at baseline. Employment status was derived from follow-up interviews after two and four years. Cox proportional hazards regression analyses were used to identify determinants of unemployment, disability pension, and early retirement. Poor health was a risk factor for disability pension [hazard ratio (HR) 3.90, 95% confidence interval (95% CI) 2.51-6.05], and a lack of physical activity was a risk factor for disability pension (HR 3.05, 95% CI 1.68-5.55) and unemployment (HR 1.84, 95% CI 1.13-3.01). A lack of job control was a risk factor for disability pension, unemployment, and early retirement (HR 1.30-1.77). Poor health, a lack of physical activity, and a lack of job control played a role in exit from paid employment, but their relative importance differed by pathway of labor force exit. Primary preventive interventions focusing on promoting physical activity as well as increasing job control may contribute to reducing premature exit from paid employment.


Cannabidiol rather than Cannabis sativa extracts inhibit cell growth and induce apoptosis in cervical cancer cells.
Cervical cancer remains a global health related issue among females of Sub-Saharan Africa, with over half a million new cases reported each year. Different therapeutic regimens have been suggested in various regions of Africa, however, over a quarter of a million women die of cervical cancer, annually. This makes it the most lethal cancer amongst black women and calls for urgent therapeutic strategies. In this study we compare the anti-proliferative effects of crude extract of Cannabis sativa and its main compound cannabidiol on different cervical cancer cell lines. To achieve our aim, phytochemical screening, MTT assay, cell growth analysis, flow cytometry, morphology analysis, Western blot, caspase 3/7 assay, and ATP measurement assay were conducted. Results obtained indicate that both cannabidiol and Cannabis sativa extracts were able to halt cell proliferation in all cell lines at varying concentrations. They further revealed that apoptosis was induced by cannabidiol as shown by increased subG0/G1 and apoptosis through annexin V. Apoptosis was confirmed by overexpression of p53, caspase 3 and bax. Apoptosis induction was further confirmed by morphological changes, an increase in Caspase 3/7 and a decrease in the ATP levels. In conclusion, these data suggest that cannabidiol rather than Cannabis sativa crude extracts prevent cell growth and induce cell death in cervical cancer cell lines.


Role of the Ca(2+)-sensing receptor in divalent mineral ion homeostasis.
The divalent mineral cations Ca2+ and Mg2+ play many and diverse roles both in the function of cells and in extracellular processes. The metabolism of these cations is a complex process involving the coordinated function of several organ systems and endocrine glands. A recently cloned G-protein-coupled receptor responds to extracellular calcium concentration (Ca2+0-sensing receptor, CaSR) and mediates several of the known effects of Ca2+0 on parathyroid and renal function. The CaSR, which is also expressed in a number of other tissues including thyroidal C-cells, brain and gastrointestinal tract, may function as a Ca2+0 sensor in these tissues as well. Thus, Ca2+0 is a first messenger (or hormone) which, via CaSR-mediated activation of second messenger systems (e.g. phospholipases C and A2, cyclic AMP) leads to altered function of these cells. Several mutations in the human CaSR gene have been identified and shown to cause three inherited diseases of calcium homeostasis, clearly implicating the CaSR as an important component of the homeostatic mechanism for divalent mineral ions. Ca2+ and Mg2+ losses from the body are regulated by altering the urinary excretion of these divalent cations. The localization of the CaSR transcripts and protein in the kidney not only provides a basis for a direct Ca2+0 (or Mg2+0)-mediated regulation of Ca2+ (and Mg2+) excretion but also suggests a functional link between divalent mineral and water metabolism. In the kidney, the thick ascending limb of Henle (TAL) plays crucial roles in regulating both divalent mineral reabsorption and urine concentration. Recent studies have suggested models whereby extracellular Ca2+, via the CaSR expressed in the TAL as well as in the collecting duct system, modulates both Ca2+ 0 and Mg2+ 0 as well as water reabsorbtion. When taken together, these studies suggest that the CaSR not only provides the primary mechanism for Ca2+ 0-mediated regulation of parathyroid hormone secretion from parathyroid glands but also for direct modulation of renal divalent mineral excretion and urinary concentrating ability. These latter functions may furnish a mechanism for integrating and balancing water and divalent cation losses that minimizes the risk of urinary tract stone formation. This mechanism can explain hypercalcemia-mediated polyuria (diabetes insipidus).


Effect of Temperature on Wheat Streak Mosaic Disease Development in Winter Wheat.
Temperature is one of the key factors that influence viral disease development in plants. In this study, temperature effect on Wheat streak mosaic virus (WSMV) replication and in planta movement was determined using a green fluorescent protein (GFP)-tagged virus in two winter wheat cultivars. Virus-inoculated plants were first incubated at 10, 15, 20, and 25°C for 21 days, followed by 27°C for 14 days; and, in a second experiment, virus-inoculated plants were initially incubated at 27°C for 3 days, followed by 10, 15, 20, and 25°C for 21 days. In the first experiment, WSMV-GFP in susceptible 'Tomahawk' wheat at 10°C was restricted at the point of inoculation whereas, at 15°C, the virus moved systemically, accompanied with mild symptoms, and, at 20 and 25°C, WSMV elicited severe WSMV symptoms. In resistant 'Mace' wheat (PI 651043), WSMV-GFP was restricted at the point of inoculation at 10 and 15°C but, at 20 and 25°C, the virus infected systemically with no visual symptoms. Some plants that were not systemically infected at low temperatures expressed WSMV-GFP in regrowth shoots when later held at 27°C. In the second experiment, Tomahawk plants (100%) expressed systemic WSMV-GFP after 21 days at all four temperature levels; however, systemic WSMV expression in Mace was delayed at the lower temperatures. These results indicate that temperature played an important role in WSMV replication, movement, and symptom development in resistant and susceptible wheat cultivars. This study also demonstrates that suboptimal temperatures impair WSMV movement but the virus rapidly begins to replicate and spread in planta under optimal temperatures.


Commercialization of microfluidic point-of-care diagnostic devices.
A large part of the excitement behind microfluidics is in its potential for producing practical devices, but surprisingly few lab-on-a-chip based technologies have been successfully introduced into the market. Here, we review current work in commercializing microfluidic technologies, with a focus on point-of-care diagnostics applications. We will also identify challenges to commercialization, including lessons drawn from our experience in Claros Diagnostics. Moving forward, we discuss the need to strike a balance between achieving real-world impact with integrated devices versus design of novel single microfluidic components.


Comparison of clevudine and entecavir for treatment-naive patients with chronic hepatitis B virus infection: two-year follow-up data.
Clevudine and entecavir are highly potent antiviral agents being used in treatment of chronic hepatitis B. However, no data comparing clinical efficacy and safety of these 2 drugs over a long-term period is available. The aims of this study are to compare virologic, biochemical, and serologic response rates of clevudine and entecavir, as well as treatment failure rates up to 2 years. Data of patients who started clevudine (n = 86) or entecavir (n = 159) as a primary treatment for chronic hepatitis B at Korea University Ansan or Guro Hospital between January 2007 and June 2008 were analyzed. Treatment responses were compared at 3-month intervals up to 24 months. Per protocol analysis showed no difference in virologic responses between the 2 groups at all time points, except at 18 months. When analyzed on intention-to-treat basis for virologic response at 24 months, the response rates were 45.3% in the clevudine group and 72.3% in the entecavir group, which are significantly different (P < 0.001). Rates of biochemical response and HBeAg seroconversion were not significantly different between the groups at all time points. Up to 24 months, antiviral resistance developed in 18 patients (24.4%) in the clevudine group. Clevudine was discontinued owing to muscle-related problems in 10 patients (11.6%). Although both drugs showed potent antiviral activity, entecavir showed better virologic response at 24 months, primarily owing to treatment failures in the clevudine group that were associated with development of drug resistance and muscle-related problems.


Acute and long-term effects of electroconvulsive therapy on human dentate gyrus.
Electroconvulsive therapy (ECT) is the most effective treatment for severe depression, although the underlying mechanisms remain unclear. Animal studies have consistently shown that electroconvulsive stimulation induces neuroplastic changes in the dentate gyrus. To date, few studies have investigated the effect of ECT on human hippocampal subfields. In the current study, structural magnetic resonance imaging (MRI) was conducted in 25 patients with major depressive episodes at 3 time points: before ECT (TP1), after 1 week of the last ECT (TP2) and after 3 months of the last ECT (TP3). Twenty healthy controls were scanned twice with an interval similar to patients between TP1 and TP2. Volumetric analyses of the cornu ammonis (CA)4/dentate gyrus (DG) were performed using the MAGeT-Brain (Multiple Automatically Generated Templates) algorithm. Clinically remitted patients after ECT showed larger volume increases in the right CA4/DG than non-remitted patients. Volume increases in the right CA4/DG were negatively associated with age. Increased CA4/DG volumes after ECT returned to baseline levels after 3 months irrespective of clinical state. ECT-induced volume increase in the CA4/DG was associated with age and clinical remission. These findings are consistent with the neurotrophic processes seen in preclinical studies. Neuroplastic change in the CA4/DG might mediate some of the short-term antidepressant effects of ECT.


General surgery workloads and practice patterns in the United States, 2007 to 2009: a 10-year update from the American Board of Surgery.
To assess changes in general surgery workloads and practice patterns in the past decade. Nearly 80% of graduating general surgery residents pursue additional training in a surgical subspecialty. This has resulted in a shortage of general surgeons, especially in rural areas. The purpose of this study is to characterize the workloads and practice patterns of general surgeons versus certified surgical subspecialists and to compare these data with those from a previous decade. The surgical operative logs of 4968 individuals recertifying in surgery 2007 to 2009 were reviewed. Data from 3362 (68%) certified only in Surgery (GS) were compared with 1606 (32%) with additional American Board of Medical Specialties certificates (GS+). Data from GS surgeons were also compared with data from GS surgeons recertifying 1995 to 1997. Independent variables were compared using factorial ANOVA. GS surgeons performed a mean of 533 ± 365 procedures annually. Women GS performed far more breast operations and fewer abdomen, alimentary tract and laparoscopic procedures compared to men GS (P < 0.001). GS surgeons recertifying at 10 years performed more abdominal, alimentary tract and laparoscopic procedures compared to those recertifying at 20 or 30 years (P < 0.001). Rural GS surgeons performed far more endoscopic procedures and fewer abdominal, alimentary tract, and laparoscopic procedures than urban counterparts (P < 0.001). The United States medical school graduates had similar workloads and distribution of operations to international medical graduates. Compared to 1995 to 1997, GS surgeons from 2007 to 2009 performed more procedures, especially endoscopic and laparoscopic. GS+ surgeons performed 15% to 33% of all general surgery procedures. GS practice patterns are heterogeneous; gender, age, and practice setting significantly affect operative caseloads. A substantial portion of general surgery procedures currently are performed by GS+ surgeons, whereas GS surgeons continue to perform considerable numbers of specialty operations. Reduced general surgery operative experience in GS+ residencies may negatively impact access to general surgical care. Similarly, narrowing GS residency operative experience may impair specialty operation access.


Effects of genetic selection and voluntary activity on the medial gastrocnemius muscle in house mice.
In a previous study, we found that in house mice both genetic selection (10 generations of artificial selection for high voluntary activity on running wheels) and access to running wheels (7-8 weeks) elicited a modest increase in maximal oxygen consumption. Based on these results, we hypothesized that genetic selection would affect the changes in endurance and oxidative capacity of the medial gastrocnemius (MG) muscle induced by wheel access (training response). Wheel access increased the isotonic endurance of the MG in both genetically selected and random-bred (control) mice. However, this exercise-induced improvement in isotonic endurance of the MG was similar between genetically selected and control mice. Wheel access also increased the succinate dehydrogenase activity of MG muscle fibers in both selected and control lines. However, this exercise-induced increase in succinate dehydrogenase activity was comparable between genetically selected and control animals. Taken together, these results indicate that the modest increase in maximal oxygen consumption associated with genetic selection is not reflected by the training-induced changes in oxidative capacity and endurance of MG muscle fibers.


Controlled transport of droplets using conducting polymers.
The controlled transport and delivery of dichloromethane through platinum mesh coated with dodecylbenzenesulfonate-doped polypyrrole is demonstrated upon in situ electrochemical redox switching. Droplets of dichloromethane were observed to pass freely through the mesh upon reduction of the polymer as a result of the release of the surfactant dopant into the dichloromethane and the change in the surface energy of the polymer. Planar and liquid-filled tube configurations are investigated. These concepts are envisaged to prove useful for fluid control in microfluidic devices, in the preparation of microparticles for drug delivery, and in the development of organic microreactors.


Sex determination by three-dimensional geometric morphometrics of the palate and cranial base.
The purpose of this study is to assess sexual dimorphism in the palate and base of adult crania using three-dimensional geometric morphometric methods. The study sample consisted of 176 crania of known sex (94 males, 82 females) belonging to individuals who lived during the 20th century in Greece. The three-dimensional co-ordinates of 30 ectocranial landmarks were digitized using a MicroScribe 3DX contact digitizer. Generalized Procrustes Analysis (GPA) was used to obtain size and shape variables for statistical analysis. Three discriminant function analyses were carried out: (1) using PC scores from Procrustes shape space, (2) centroid size alone, and (3) PC scores of GPA residuals which includes InCS for analysis in Procrustes form space. Results indicate that there are shape differences between sexes. In males, the palate is deepest and more elongated; the cranial base is shortened. Sex-specific shape differences for the cross-validated data give better classification results in the cranial base (77.2%) compared with the palate (68.9%). Size alone yielded better results for cranial base (82%) in opposition to palate (63.1%). As anticipated, the classification accuracy improves when both size and shape are combined (90.4% for cranial base, and 74.8% for palate).


Is Brain Activity during Action Observation Modulated by the Perceived Fairness of the Actor?
Perceiving other people's actions triggers activity in premotor and parietal areas, brain areas also involved in executing and sensing our own actions. Paralleling this phenomenon, observing emotional states (including pain) in others is associated with activity in the same brain areas as activated when experiencing similar emotions directly. This emotion perception associated activity has been shown to be affected by the perceived fairness of the actor, and in-group membership more generally. Here, we examine whether action observation associated brain activity is also affected by the perceived social fairness of the actors. Perceived fairness was manipulated using an alternating iterated Prisoner's Dilemma game between the participant and two confederates, one of whom played fairly and the other unfairly. During fMRI scanning the participants watched movies of the confederates performing object-directed hand actions, and then performed hand actions themselves. Mass-univariate analysis showed that observing the actions triggered robust activation in regions associated with action execution, but failed to identify a strong modulation of this activation based on perceived fairness. Multivariate pattern analysis, however, identified clusters potentially carrying information about the perceived fairness of the actor in the middle temporal gyrus, left postcentral gyrus, right inferior parietal lobule, right middle cingulate cortex, right angular gyrus, and right superioroccipital gyrus. Despite being identified by a whole-brain searchlight analysis (and so without anatomical restriction), these clusters fall into areas frequently associated with action observation. We conclude that brain activity during action observation may be modulated by perceived fairness, but such modulation is subtle; robust activity is associated with observing the actions of both fair and unfair individuals.


Phenotype switching affects biofilm formation by Candida parapsilosis.
Generation of biofilms by the pathogenic yeast Candida parapsilosis is correlated closely with disease. The phenomenon of phenotype switching in 20 isolates of C. parapsilosis was examined and the relationship with biofilm development was investigated. Four stable and heritable phenotypes were identified--crepe, concentric, smooth and crater. Cells from crepe and concentric phenotypes are almost entirely pseudohyphal, whilst cells from smooth and crater phenotypes are mostly yeast-like. The pseudohyphae from concentric phenotypes are approximately 45 % wider than those from crepe cells. The cell size of the smooth phenotype is smaller than those of the other three phenotypes. On polystyrene surfaces, the concentric phenotype generates up to twofold more biofilm than the crepe and crater phenotypes. Smooth phenotypes generate the least biofilm. Concentric phenotypes also invade agar surfaces more than the crepe and crater phenotypes, whilst smooth phenotypes do not invade at all. The smooth phenotype, however, grows significantly faster than the others. The quorum-sensing molecule farnesol inhibits formation of biofilms by the crepe, concentric and crater phenotypes.


COMPUTED TOMOGRAPHIC CHARACTERISTICS OF THE THYROID GLANDS IN EIGHT HYPERTHYROID CATS PRE- AND POSTMETHIMAZOLE TREATMENT COMPARED WITH SEVEN EUTHYROID CATS.
Hyperthyroidism is the most common feline endocrinopathy; thyroid computed tomography (CT) may improve disease detection and methimazole dose selection. Objectives of this experimental pre-post with historical case-control study were to perform thyroid CT imaging in awake or mildly sedated hyperthyroid cats, compare thyroid gland CT appearance in euthyroid and hyperthyroid cats pre- and postmethimazole treatment, and determine whether thyroid size or attenuation correlate with methimazole dose needed for euthyroidism. Premethimazole treatment, eight hyperthyroid cats received CT scans from the head to heart, which were compared to CT of seven euthyroid cats. Total thyroxine levels were monitored every 3-4 weeks. Postmethimazole CT was performed 30 days after achieving euthyroid status. Computed tomography parameters recorded included thyroid length, width, height, attenuation, and heterogeneity. Median time between CT was 70 days (53-213 days). Mild sedation was needed in five hyperthyroid cats premethimazole, and none postmethimazole. Thyroid volume was significantly larger in hyperthyroid cats compared to euthyroid cats (785.0 mm3 vs. 154.9 mm3 ; P = 0.002) and remained unchanged by methimazole treatment (-4.5 mm3; P = 0.50). Thyroid attenuation and heterogeneity decreased with methimazole treatment (96.1 HU vs. 85.9 HU; P = 0.02. 12.4 HU vs. 8.1 HU; P = 0.009). Methimazole dose ranged from 2.5 to 10 mg daily with a positive correlation between pretreatment thyroid gland volume and dose needed to achieve euthyroidism (P = 0.03). Euthyroid and hyperthyroid cats are easily imaged awake or mildly sedated with CT. Methimazole in hyperthyroid cats significantly lowers thyroid attenuation and heterogeneity, but not size.


Cartilage preservation by inhibition of Janus kinase 3 in two rodent models of rheumatoid arthritis.
CP-690550 is a small molecule inhibitor of Janus kinase 3 (JAK3), a critical enzyme in the signaling pathway of multiple cytokines (interleukin (IL)-2, -7, -15 and -21) that are important in various T cell functions including development, activation and homeostasis. The purpose of this study was to evaluate CP-690550 in murine collagen-induced (CIA) and rat adjuvant-induced (AA) models of rheumatoid arthritis (RA). CIA and AA were induced using standard protocols and animals received the JAK3 inhibitor via osmotic mini-pump infusion at doses ranging from 1.5-15 mg/kg/day following disease induction. Arthritis was assessed by clinical scores in the CIA models and paw swelling monitored using a plethysmometer in the AA model until study conclusion, at which time animals were killed and evaluated histologically. CP-690550 dose-dependently decreased endpoints of disease in both RA models with greater than 90% reduction observed at the highest administered dose. An approximate ED50 of approximately 1.5 mg/kg/day was determined for the compound based upon disease endpoints in both RA models examined and corresponds to CP-690550 serum levels of 5.8 ng/ml in mice (day 28) and 24 ng/ml in rats (day 24). The compound also reduced inflammatory cell influx and joint damage as measured histologically. Animals receiving a CP-690550 dose of 15 mg/k/d showed no histological evidence of disease. The efficacy observed with CP-690550 in CIA and AA suggests JAK3 inhibition may represent a novel therapeutic target for the treatment of RA.


[Subcellular fluorescence localization analysis of all SAGA subunits in fission yeast (Schizosaccharomyces pombe)].
SAGA(Spt-Ada-Gcn5 Acetyltransferase complex) is a multi-subunit and conservative transcription complex, which is composed of 19 subunits in fission yeast and regulates the transcription of 10% genes in vivo. Through constructing in situ integrated fluorescence strains, we analyzed subcellular fluorescence localization of all SAGA subunits. Microscopic data showed localization manners could be sorted by 4 types, suggesting that these SAGA subunits may have additional functions besides transcriptional regulation. Subunit Sgf73 is the bridge that connects deubiquitination module and other SAGA modules, lacking of sgf73+ not only significantly reduced nuclear fluorescence localization (NFL) of deubiq-uitination subunits Ubp8, Sgf11, Sus1, but also affected NFL of acetylation subunits Gcn5, Sgf29, Ngg1, and the core structure subunit Spt7.The impact indicates that Sgf73 is important to maintain enzymatic function and stabilization of SAGA. Moreover, deletion of sgf73+ also caused a cytokinesis defect, which is characterized by a multi-nucleus and multi-septum phenotype. Overexpressing ace2+ and mid2+ in Dsgf73, which are key genes involved in septum degradation, showed that ace2+ could not rescue the defect, and mid2+ could only partially compensate for the deficiency, suggesting that Sgf73 may play a role in other pathways that affect cytokinesis.


Methacrylated gelatin and mature adipocytes are promising components for adipose tissue engineering.
In vitro engineering of autologous fatty tissue constructs is still a major challenge for the treatment of congenital deformities, tumor resections or high-graded burns. In this study, we evaluated the suitability of photo-crosslinkable methacrylated gelatin (GM) and mature adipocytes as components for the composition of three-dimensional fatty tissue constructs. Cytocompatibility evaluations of the GM and the photoinitiator Lithium phenyl-2,4,6-trimethylbenzoylphosphinate (LAP) showed no cytotoxicity in the relevant range of concentrations. Matrix stiffness of cell-laden hydrogels was adjusted to native fatty tissue by tuning the degree of crosslinking and was shown to be comparable to that of native fatty tissue. Mature adipocytes were then cultured for 14 days within the GM resulting in a fatty tissue construct loaded with viable cells expressing cell markers perilipin A and laminin. This work demonstrates that mature adipocytes are a highly valuable cell source for the composition of fatty tissue equivalents in vitro. Photo-crosslinkable methacrylated gelatin is an excellent tissue scaffold and a promising bioink for new printing techniques due to its biocompatibility and tunable properties.


Lewis Score on Capsule Endoscopy as a Predictor of the Risk for Crohn's Disease-Related Emergency Hospitalization and Clinical Relapse in Patients with Small Bowel Crohn's Disease.
Small bowel capsule endoscopy (CE) is a useful tool for evaluating the mucosal changes in patients with Crohn's disease (CD). The Lewis score (LS) on CE could be used to objectively assess the inflammatory activity of the small bowel mucosa. However, only few reports on the correlation between the LS and CD prognosis exist. This study is aimed at evaluating the clinical significance of the LS by determining the cutoff value of the LS that could predict CD-related emergency hospitalization. This retrospective single-center study included 125 patients who underwent CE for small bowel CD. Eighty-six patients whose treatment was not changed after CE were analyzed. Inflammatory activity was assessed with the LS. We examined the clinical course of the patients who could be observed for 1 year after CE and investigated the LS cutoff value that could predict CD-related emergency hospitalization within 1 year. We also examined the hospitalization-free and clinical relapse-free rates using the LS cutoff value and evaluated the factors related to emergency hospitalization. The LS cutoff value that could predict CD-related emergency hospitalization within 1 year was 264 (area under the curve, 0.92 (P < 0.001); sensitivity, 0.80; and specificity, 0.94). The cumulative hospitalization-free rate and cumulative clinical relapse-free rate were significantly higher in patients with a LS < 264 (P < 0.001). Multivariate analysis showed that a LS < 264 was a statistically significant factor (P = 0.001; 95% CI, 0.010-0.308). A LS of 264 is a useful cutoff value that could predict CD-related emergency hospitalization. This LS cutoff value may help determine treatment strategies for CD.


Using an ensemble of statistical metrics to quantify large sets of plant transcription factor binding sites.
From initial seed germination through reproduction, plants continuously reprogram their transcriptional repertoire to facilitate growth and development. This dynamic is mediated by a diverse but inextricably-linked catalog of regulatory proteins called transcription factors (TFs). Statistically quantifying TF binding site (TFBS) abundance in promoters of differentially expressed genes can be used to identify binding site patterns in promoters that are closely related to stress-response. Output from today's transcriptomic assays necessitates statistically-oriented software to handle large promoter-sequence sets in a computationally tractable fashion. We present Marina, an open-source software for identifying over-represented TFBSs from amongst large sets of promoter sequences, using an ensemble of 7 statistical metrics and binding-site profiles. Through software comparison, we show that Marina can identify considerably more over-represented plant TFBSs compared to a popular software alternative. Marina was used to identify over-represented TFBSs in a two time-point RNA-Seq study exploring the transcriptomic interplay between soybean (Glycine max) and soybean rust (Phakopsora pachyrhizi). Marina identified numerous abundant TFBSs recognized by transcription factors that are associated with defense-response such as WRKY, HY5 and MYB2. Comparing results from Marina to that of a popular software alternative suggests that regardless of the number of promoter-sequences, Marina is able to identify significantly more over-represented TFBSs.


Photon-correlation spectroscopy for small spherical inclusions in a micrometer-sized electrodynamically levitated droplet.
Micrometer-sized droplets of saturated sodium chloride solution were captured in an electrodynamic levitator and maintained at constant diameter for several days at a time. Both pure droplets and droplets containing 0.5-microm subparticles (guests) were studied by means of 90-deg scattering of polarized laser light. Analysis of the correlation function for the intensity of the scattered light gave characteristic decay times of &~9 ms, which has a good correspondence with the physical parameters of the solution and the size of the subparticles. Longer characteristic times are measures of morphological features of the electromagnetic field intensity in the host particles. A new phenomenon was observed when the exit polarizer was crossed to the input polarization. Scattered light corresponding to light from the guest particles could only be visualized from a shell near the exterior of the sphere and not from the interior of the host droplet.


Systemic immune response and virus persistence after foot-and-mouth disease virus infection of naïve cattle and cattle vaccinated with a homologous adenovirus-vectored vaccine.
In order to investigate host factors associated with the establishment of persistent foot-and-mouth disease virus (FMDV) infection, the systemic response to vaccination and challenge was studied in 47 steers. Eighteen steers that had received a recombinant FMDV A vaccine 2 weeks earlier and 29 non-vaccinated steers were challenged by intra-nasopharyngeal deposition of FMDV A24. For up to 35 days after challenge, host factors including complete blood counts with T lymphocyte subsets, type I/III interferon (IFN) activity, neutralizing and total FMDV-specific antibody titers in serum, as well as antibody-secreting cells (in 6 non-vaccinated animals) were characterized in the context of viral infection dynamics. Vaccination generally induced a strong antibody response. There was a transient peak of FMDV-specific serum IgM in non-vaccinated animals after challenge, while IgM levels in vaccinated animals did not increase further. Both groups had a lasting increase of specific IgG and neutralizing antibody after challenge. Substantial systemic IFN activity in non-vaccinated animals coincided with viremia, and no IFN or viremia was detected in vaccinated animals. After challenge, circulating lymphocytes decreased in non-vaccinated animals, coincident with viremia, IFN activity, and clinical disease, whereas lymphocyte and monocyte counts in vaccinated animals were unaffected by vaccination but transiently increased after challenge. The CD4(+)/CD8(+) T cell ratio in non-vaccinated animals increased during acute infection, driven by an absolute decrease of CD8(+) cells. The incidence of FMDV persistence was 61.5 % in non-vaccinated and 54.5 % in vaccinated animals. Overall, the systemic factors examined were not associated with the FMDV carrier/non-carrier divergence; however, significant differences were identified between responses of non-vaccinated and vaccinated cattle.


Dimerization leads to changes in APP (amyloid precursor protein) trafficking mediated by LRP1 and SorLA.
Proteolytic cleavage of the amyloid precursor protein (APP) by α-, β- and γ-secretases is a determining factor in Alzheimer's disease (AD). Imbalances in the activity of all three enzymes can result in alterations towards pathogenic Aβ production. Proteolysis of APP is strongly linked to its subcellular localization as the secretases involved are distributed in different cellular compartments. APP has been shown to dimerize in cis-orientation, affecting Aβ production. This might be explained by different substrate properties defined by the APP oligomerization state or alternatively by altered APP monomer/dimer localization. We investigated the latter hypothesis using two different APP dimerization systems in HeLa cells. Dimerization caused a decreased localization of APP to the Golgi and at the plasma membrane, whereas the levels in the ER and in endosomes were increased. Furthermore, we observed via live cell imaging and biochemical analyses that APP dimerization affects its interaction with LRP1 and SorLA, suggesting that APP dimerization modulates its interplay with sorting molecules and in turn its localization and processing. Thus, pharmacological approaches targeting APP oligomerization properties might open novel strategies for treatment of AD.


100-million-year dynasty of giant planktivorous bony fishes in the Mesozoic seas.
Large-bodied suspension feeders (planktivores), which include the most massive animals to have ever lived, are conspicuously absent from Mesozoic marine environments. The only clear representatives of this trophic guild in the Mesozoic have been an enigmatic and apparently short-lived Jurassic group of extinct pachycormid fishes. Here, we report several new examples of these giant bony fishes from Asia, Europe, and North America. These fossils provide the first detailed anatomical information on this poorly understood clade and extend its range from the lower Middle Jurassic to the end of the Cretaceous, showing that this group persisted for more than 100 million years. Modern large-bodied, planktivorous vertebrates diversified after the extinction of pachycormids at the Cretaceous-Paleogene boundary, which is consistent with an opportunistic refilling of vacated ecospace.


Recovery and resilience after a nuclear power plant disaster: a medical decision model for managing an effective, timely, and balanced response.
Resilience after a nuclear power plant or other radiation emergency requires response and recovery activities that are appropriately safe, timely, effective, and well organized. Timely informed decisions must be made, and the logic behind them communicated during the evolution of the incident before the final outcome is known. Based on our experiences in Tokyo responding to the Fukushima Daiichi nuclear power plant crisis, we propose a real-time, medical decision model by which to make key health-related decisions that are central drivers to the overall incident management. Using this approach, on-site decision makers empowered to make interim decisions can act without undue delay using readily available and high-level scientific, medical, communication, and policy expertise. Ongoing assessment, consultation, and adaption to the changing conditions and additional information are additional key features. Given the central role of health and medical issues in all disasters, we propose that this medical decision model, which is compatible with the existing US National Response Framework structure, be considered for effective management of complex, large-scale, and large-consequence incidents.


Optimization of retroviral vector-mediated gene transfer into endothelial cells in vitro.
Retroviral vector-mediated gene transfer into endothelial cells is relatively inefficient with transduction rates as low as 1-2% in vitro and even lower in vivo. To increase the efficiency of gene transfer into endothelial cells, we used retroviral vectors expressing beta-galactosidase and urokinase and measured endothelial cell transduction efficiencies with quantitative assays for beta-galactosidase and urokinase protein. We evaluated several techniques reported to improve the efficiency of retroviral transduction in vitro, including 1) extended periods of exposure to vector, 2) repeated exposures to vector, 3) maximization of the ratio of vector particles to endothelial cells by increasing the volume and concentration of vector particles or by decreasing the number of endothelial cells exposed, 4) cocultivation of endothelial cells with vector-producing cells, and 5) variation of the type and concentration of polycation used with the retroviral vector. Only the use of more concentrated (higher titer) vector-containing supernatant and the use of the polycation DEAE-dextran improved the efficiency of gene transfer into endothelial cells in vitro. In an optimized transduction protocol, a 60-second exposure to 1 mg/ml DEAE-dextran followed by a single 6-hour exposure to supernatant of a titer of 10(5)-10(6) colony-forming units/ml resulted in transduction efficiencies of 50-90% with both vectors. Decreasing the time of the supernatant exposure to 15 minutes permitted transduction efficiencies of 15-20% while significantly minimizing the duration of the transduction. Therefore, the optimized protocol allows high efficiency in vitro gene transfer into endothelial cells within several hours. The briefer protocol may prove useful for in vivo gene transfer in which the time of exposure to the supernatant is limited.


IGF2 mRNA binding protein-2 is a tumor promoter that drives cancer proliferation through its client mRNAs IGF2 and HMGA1.
The gene encoding the Insulin-like Growth Factor 2 mRNA binding protein 2/IMP2 is amplified and overexpressed in many human cancers, accompanied by a poorer prognosis. Mice lacking IMP2 exhibit a longer lifespan and a reduced tumor burden at old age. Herein we show in a diverse array of human cancer cells that IMP2 overexpression stimulates and IMP2 elimination diminishes proliferation by 50-80%. In addition to its known ability to promote the abundance of Insulin-like Growth Factor 2/IGF2, we find that IMP2 strongly promotes IGF action, by binding and stabilizing the mRNA encoding the DNA binding protein HMGA1, a known oncogene. HMGA1 suppresses the abundance of IGF binding protein 2/IGFBP2 and Grb14, inhibitors of IGF action. IMP2 stabilization of HMGA1 mRNA plus IMP2 stimulated IGF2 production synergistically drive cancer cell proliferation and account for IMP2's tumor promoting action. IMP2's ability to promote proliferation and IGF action requires IMP2 phosphorylation by mTOR.


Prevalence of methicillin resistant Staphylococcus aureus, multidrug resistant and extended spectrum β-lactamase producing gram negative bacilli causing wound infections at a tertiary care hospital of Nepal.
Treatment and prevention of wound infection continues to be a challenging issue in clinical settings of Nepal especially in the context of globally growing problem of antimicrobial resistance. Study on opportunistic pathogens and sensitivity to commonly prescribed local antimicrobial agents are cardinal to reduce the disease burden of wound infections. The aim of this study was to determine the prevalence and antimicrobial susceptibility pattern of methicillin resistant Staphylococcus aureus (MRSA) and extended spectrum β-lactamase (ESBL) producing bacteria from wound infections of patients at a tertiary care hospital in Nepal. Pus specimens were processed using standard microbiological procedures. Antimicrobial susceptibility test was performed following the modified Kirby Bauer disc diffusion technique. Clinical information of patients was obtained from preformed questionnaire and hospital record. One hundred eighty two pus specimens from wounds of different body parts: leg, hand, backside, abdominal part, foot, breast and chest, head and neck region were collected and analyzed; 113 bacterial isolates were isolated showing the overall bacterial growth rate of 62%, where the highest rate was among patients of ≤10 years age group (82.1%). A higher rate (68.5%) of bacterial isolates were from inpatients (p < 0.05). Among 116 bacterial isolates, Staphylococcus aureus was the most predominant bacteria (56.9%) followed by Escherichia coli (8.6%), coagulase negative staphylococci (7.8%), Acinetobacter spp. (5.2%), Klebsiella pneumoniae (5.2%), Pseudomonas aeruginosa (4.3%), Enterococcus spp. (4.3%), Citrobacter freundii (2.6%), Proteus vulgaris (1.6%) and P. mirabilis (0.9%). Both Gram positive (73.3%) and negative (78.8%) isolates showed high frequency of sensitive to gentamycin. Among S. aureus isolates, 60.6% were MRSA strains, whereas 40% of K. pneumoniae and 33.3% of C. freundii were ESBL producing bacteria followed by E. coli (25%). It is thus paramount to address the burden of silently and speedily increasing infections caused by drug resistant strains of MRSA and ESBL in Nepal.


Interleukin 17 levels are increased in juvenile idiopathic arthritis synovial fluid and induce synovial fibroblasts to produce proinflammatory cytokines and matrix metalloproteinases.
Cytokines are the major mediators of joint damage in chronic arthritis. Data on synovial fluid (SF) concentration of Th17 cell-derived cytokine interleukin 17 (IL-17) in patients with juvenile idiopathic arthritis (JIA) are sparse. We measured levels of IL-17 in SF specimens from children with enthesitis-related arthritis (ERA) and polyarticular JIA (poly-JIA), and studied the ability of IL-17 to produce matrix metalloproteinases (MMP) and cytokines by fibroblast-like synoviocytes (FLS) from patients with ERA. IL-17 levels were measured in SF of patients with ERA (n = 43), poly-JIA (n = 17), rheumatoid arthritis (RA; n = 35), and osteoarthritis (OA; n = 10) by ELISA. In patients with JIA, 10 paired serum samples were also assayed. FLS were cultured from SF of patients with ERA and subsequently stimulated for 48 h by IL-17 or tumor necrosis factor-alpha. Later the production of IL-6, IL-8, MMP-1, MMP-3, and tissue inhibitor of metalloproteinase (TIMP)-1 was measured in the culture supernatants by ELISA. Median IL-17 levels in SF were higher in patients with JIA [28 pg/ml (range 0-200)] compared to OA [0 pg/ml (range 0-84); p < 0.001] and RA (p < 0.05). The levels were comparable between poly-JIA patients and the ERA group. The median SF IL-17 levels were significantly higher compared to serum levels in children with JIA (p < 0.005). In ERA, SF IL-17 correlated with number of swollen joints (r = 0.35; p < 0.05), number of joints with limited mobility (r = 0.55; p < 0.001), and number of tender joints (r = 0.46; p < 0.01); however, no correlation was seen with erythrocyte sedimentation rate. IL-17 induced FLS to produce IL-6, IL-8, MMP-3, and MMP-1. However, there was no effect on the production of TIMP. Increased IL-17 levels in ERA SF correlate with disease activity and this may be due to increased production of MMP and cytokines by IL-17.


Extracellular factors and immunosuppressive drugs influencing insulin secretion of murine islets.
Approximately 60% of transplanted islets undergo apoptosis within the first week post-transplantation into the liver attributed to poor engraftment, immune rejection and toxicity of immunosuppressive drugs. Understanding how extracellular matrix (ECM) components, immunosuppressive drugs and proinflammatory cytokines affect insulin secretion will contribute to an improved clinical outcome of islet transplantations. In this study, functional activity of isolated murine islets was measured by glucose-stimulated insulin secretion (GSIS) and by electrophysiological measurements using patch-clamp. Cultivating islets with soluble fibronectin or laminin, as opposed to with coated laminin, markedly increased GSIS. Addition of cyclosporin A reduced GSIS and suppressed glucose-induced spike activity. Tacrolimus affected neither GSIS nor spike activity, indicating a different mechanism. To evaluate the influence of proinflammatory cytokines, islets were incubated with interleukin (IL)-1β, tumour necrosis factor (TNF)-α or with supernatants from cultured Kupffer cells, the main mediators of inflammation in the hepatic sinusoids. IL-1β exerted a bimodal effect on insulin secretion, stimulating below 2 ng/ml and suppressing above 10 ng/ml. Soluble laminin in combination with a stimulatory IL-1β concentration further increased insulin secretion by 20% compared to IL-1β alone, while with high IL-1β concentrations soluble laminin slightly attenuated GSIS inhibition. TNF-α alone did not affect GSIS, but with stimulatory IL-1β concentrations completely abolished it. Similarly, supernatants derived from Kupffer cells exerted a bimodal effect on GSIS. Our data suggest that improved insulin secretion of transplanted islets could be achieved by including soluble laminin and low IL-1β concentrations in the islet cultivation medium, and by a simultaneous inhibition of cytokine secretion from Kupffer cells.


Precision Medicine for Neonatal Sepsis.
Neonatal sepsis remains a significant cause of morbidity and mortality especially in the preterm infant population. The ability to promptly and accurately diagnose neonatal sepsis based on clinical evaluation and laboratory blood tests remains challenging. Advances in high-throughput molecular technologies have increased investigations into the utility of transcriptomic, proteomic and metabolomic approaches as diagnostic tools for neonatal sepsis. A systems-level understanding of neonatal sepsis, obtained by using omics-based technologies (at the transcriptome, proteome or metabolome level), may lead to new diagnostic tools for neonatal sepsis. In particular, recent omic-based studies have identified distinct transcriptional signatures and metabolic or proteomic biomarkers associated with sepsis. Despite the emerging need for a systems biology approach, future studies have to address the challenges of integrating multi-omic data with laboratory and clinical meta-data in order to translate outcomes into precision medicine for neonatal sepsis. Omics-based analytical approaches may advance diagnostic tools for neonatal sepsis. More research is needed to validate the recent systems biology findings in order to integrate multi-dimensional data (clinical, laboratory and multi-omic) for future translation into precision medicine for neonatal sepsis. This review will discuss the possible applications of omics-based analyses for identification of new biomarkers and diagnostic signatures for neonatal sepsis, focusing on the immune-compromised preterm infant and considerations for clinical translation.


Assessment and Treatment of Patients With Type 2 Myocardial Infarction and Acute Nonischemic Myocardial Injury.
Although coronary thrombus overlying a disrupted atherosclerotic plaque has long been considered the hallmark and the primary therapeutic target for acute myocardial infarction (MI), multiple other mechanisms are now known to cause or contribute to MI. It is further recognized that an MI is just one of many types of acute myocardial injury. The Fourth Universal Definition of Myocardial Infarction provides a taxonomy for acute myocardial injury, including 5 subtypes of MI and nonischemic myocardial injury. The diagnosis of MI is reserved for patients with myocardial ischemia as the cause of myocardial injury, whether attributable to acute atherothrombosis (type 1 MI) or supply/demand mismatch without acute atherothrombosis (type 2 MI). Myocardial injury in the absence of ischemia is categorized as acute or chronic nonischemic myocardial injury. However, optimal evaluation and treatment strategies for these etiologically distinct diagnoses have yet to be defined. Herein, we review the epidemiology, risk factor associations, and diagnostic tools that may assist in differentiating between nonischemic myocardial injury, type 1 MI, and type 2 MI. We identify limitations, review new research, and propose a framework for the diagnostic and therapeutic approach for patients who have suspected MI or other causes of myocardial injury.


Maternal high fat diet during pregnancy and lactation alters hepatic expression of insulin like growth factor-2 and key microRNAs in the adult offspring.
miRNAs play important roles in the regulation of gene functions. Maternal dietary modifications during pregnancy and gestation have long-term effects on the offspring, but it is not known whether a maternal high fat (HF) diet during pregnancy and lactation alters expression of key miRNAs in the offspring. We studied the effects of maternal HF diet on the adult offspring by feeding mice with either a HF or a chow diet prior to conception, during pregnancy and lactation, and all offspring were weaned onto the same chow diet until adulthood. Maternal HF fed offspring had markedly increased hepatic mRNA levels of peroxisome proliferator activated receptor-alpha (ppar-alpha) and carnitine palmitoyl transferase-1a (cpt-1a) as well as insulin like growth factor-2 (Igf2). A HF diet induced up-regulation of ppar-alpha and cpt-1a expression in the wild type but not in Igf2 knock out mice. Furthermore, hepatic expression of let-7c was also reduced in maternal HF fed offspring. Among 579 miRNAs measured with microarray, ~23 miRNA levels were reduced by ~1.5-4.9-fold. Reduced expression of miR-709 (a highly expressed miRNA), miR-122, miR-192, miR-194, miR-26a, let-7a, let7b and let-7c, miR-494 and miR-483* (reduced by ~4.9 fold) was validated by qPCR. We found that methyl-CpG binding protein 2 was the common predicted target for miR-709, miR-let7s, miR-122, miR-194 and miR-26a using our own purpose-built computer program. Maternal HF feeding during pregnancy and lactation induced co-ordinated and long-lasting changes in expression of Igf2, fat metabolic genes and several important miRNAs in the offspring.


Adoption and use of electronic health records among federally qualified health centers grew substantially during 2010-12.
Federally qualified health centers play an important role in providing health care to underserved populations. Recent substantial federal investments in health information technology have enabled health centers to expand their use of electronic health record (EHR) systems, but factors associated with adoption are not clear. We examined 2010-12 administrative data from the Health Resources and Services Administration's Uniform Data System for more than 1,100 health centers. We found that in 2012 nine out of ten health centers had adopted a EHR system, and half had adopted EHRs with basic capabilities. Seven in ten health centers reported that their providers were receiving meaningful-use incentive payments from the Centers for Medicare and Medicaid Services (CMS). Only one-third of health centers had EHR systems that could meet CMS's stage 1 meaningful-use core requirements. Health centers that met the stage 1 requirements had more than twice the odds of receiving quality recognition, compared with centers with less than basic EHRs. Policy initiatives should focus assistance on EHR capabilities with slower uptake; connect providers with technical assistance to support implementation; and leverage the connection between meaningful use and quality recognition programs.


Handlebar palsy--a compression syndrome of the deep terminal (motor) branch of the ulnar nerve in biking.
We describe 3 patients who developed a severe palsy of the intrinsic ulnar supplied hand muscles after bicycle riding. Clinically and electrophysiologically all showed an isolated lesion of the deep terminal motor branch of the ulnar nerve leaving the hypothenar muscle and the distal sensory branch intact. This type of lesion at the canal of Guyon is quite unusual, caused in the majority of cases by chronic external pressure over the ulnar palm. In earlier reports describing this lesion in bicycle riders, most patients experienced this lesion after a long distance ride. Due to the change of riding position and shape of handlebars (horn handle) in recent years, however, even a single bicycle ride may be sufficient to cause a lesion of this ulnar branch. Especially in downhill riding, a large part of the body weight is supported by the hand on the corner of the handlebar leading to a high load at Guyon's canal. As no sensory fibres are affected, the patients are not aware of the ongoing nerve compression until a severe lesion develops. Individual adaptation of the handlebar and riding position seems to be crucial for prevention of this type of nerve lesion.


Natural tannins as anti-SARS-CoV-2 compounds.
Tannins are polyphenols enriched in wood, bark, roots, leaves, seeds and fruits of a variety of plants. Over the last two decades, there has been an increasing interest in understanding the biological functions of tannins and their applications as antioxidants, anticancer drugs, and food additives. Since the outbreak of the COVID-19 pandemic, much effort has been devoted to finding an expedient cure. Tannins have been put forward as having possible anti-COVID-19 properties; however, owing to the profuse nature of the structurally diverse derivatives of tannins, the tannin species in the family associated with an indication of anti-COVID-19 have been poorly defined, compounded by frequent terminology misnomers. This article reviews the tannin family in fruits and the current knowledge about the activities of the compounds with regard to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). It will aid molecular and cellular biologists in developing natural anti-viral chemicals as means of overcoming the current and future pandemics.


G alpha i2 and ZAP-70 mediate RasGRP1 membrane localization and activation of SDF-1-induced T cell functions.
RasGRP1, a Ras guanine-nucleotide exchange factor, critically mediates T cell development and function and controls immunodeficiency and autoimmunity. In this study, we describe a unique mechanism of mobilization and activation of RasGRP1 in response to SDF-1, a chemokine that signals via the G protein-coupled receptor CXCR4. Depletion of RasGRP1 impaired SDF-1-stimulated human T cell migration, expression of the activation marker CD69, and activation of the ERK MAPK pathway, indicating that RasGRP1 mediates SDF-1 functions. SDF-1 treatment caused RasGRP1 to localize to the plasma membrane to activate K-Ras and to the Golgi to activate N-Ras. These events were required for cellular migration and for ERK activation that mediates downstream transcriptional events in response to SDF-1. SDF-1-dependent localization of RasGRP1 did not require its diacylglycerol-binding domain, even though diacyglycerol was previously shown to mediate localization of RasGRP1 in response to Ag stimulation. This domain was, however, required for activity of RasGRP1 after its localization. Intriguingly, SDF-1 treatment of T cells induced the formation of a novel molecular signaling complex containing RasGRP1, Gαi2, and ZAP-70. Moreover, SDF-1-mediated signaling by both Gi proteins and ZAP-70 was required for RasGRP1 mobilization. In addition, RasGRP1 mobilization and activation in response to SDF-1 was dependent on TCR expression, suggesting that CXCR4 heterodimerizes with the TCR to couple to ZAP-70 and mobilize RasGRP1. These results increase understanding of the molecular mechanisms that mediate SDF-1 effects on T cells and reveal a novel mechanism of RasGRP1 regulation. Other G protein-coupled receptors may similarly contribute to regulation of RasGRP1.


The Association Between Tobacco Control Policy and Educational Inequalities in Smoking Cessation in the Netherlands from 1988 Through 2011.
Tobacco control policies seemed to have failed to reduce socioeconomic inequalities in smoking in the past. It has been argued that a comprehensive mix of policies is needed. Our aim was to assess whether tobacco control policy development in the Netherlands between 1988 and 2011 was associated with educational inequalities in smoking cessation and cigarette consumption. Data were derived from the cross-sectional Dutch Continuous Survey of Smoking Habits, with a study sample of 259,140 respondents from 1988 through 2011. Outcomes were the quit ratio and mean number of cigarettes smoked per day. The determinant was the Tobacco Control Scale (TCS). We used multilevel logistic regression modeling, with years, quarters, and individuals as levels, and controlled for sex, age, and time. A significant association between the TCS and smoking cessation was found in 2001-2011, but not in 1988-2000. Associations for low- and high-education groups were similar (OR = 1.23; 95% CI = 1.12-1.34 and OR = 1.17; 95% CI = 1.03-1.32 respectively). The TCS was not significantly associated with the number of cigarettes smoked per day for either the low- or high-education groups (B = -0.09; 95% CI = -0.46-0.27 and B = -0.59; 95% CI = -1.24-0.06 respectively). Strong tobacco control policies introduced in the Netherlands after 2000 were positively associated with national trends in smoking cessation, whereas weaker policies introduced gradually before 2000 were not. However, these measures do not seem to have either widened or narrowed educational inequalities in smoking cessation rates-both groups benefitted about equally.


Inbreeding depression across a nutritional stress continuum.
Many natural populations experience inbreeding and genetic drift as a consequence of nonrandom mating or low population size. Furthermore, they face environmental challenges that may interact synergistically with deleterious consequences of increased homozygosity and further decrease fitness. Most studies on inbreeding-environment (I-E) interactions use one or two stress levels, whereby the resolution of the possible stress and inbreeding depression interaction is low. Here we produced Drosophila melanogaster replicate populations, maintained at three different population sizes (10, 50 and a control size of 500) for 25 generations. A nutritional stress gradient was imposed on the replicate populations by exposing them to 11 different concentrations of yeast in the developmental medium. We assessed the consequences of nutritional stress by scoring egg-to-adult viability and body mass of emerged flies. We found: (1) unequivocal evidence for I-E interactions in egg-to-adult viability and to a lesser extent in dry body mass, with inbreeding depression being more severe under higher levels of nutritional stress; (2) a steeper increase in inbreeding depression for replicate populations of size 10 with increasing nutritional stress than for replicate populations of size 50; (3) a nonlinear norm of reaction between inbreeding depression and nutritional stress; and (4) a faster increase in number of lethal equivalents in replicate populations of size 10 compared with replicate populations of size 50 with increasing nutritional stress levels. Our data provide novel and strong evidence that deleterious fitness consequences of I-E interactions are more pronounced at higher nutritional stress and at higher inbreeding levels.


Monitoring the Long-Term Degradation Behavior of Biomimetic Bioadhesive Using Wireless Magnetoelastic Sensor.
The degradation behavior of a tissue adhesive is critical to its ability to repair a wound while minimizing prolonged inflammatory response. Traditional degradation tests can be expensive to perform, as they require large numbers of samples. The potential for using magnetoelastic resonant sensors to track bioadhesive degradation behavior was investigated. Specifically, biomimetic poly (ethylene glycol)- (PEG-) based adhesive was coated onto magnetoelastic (ME) sensor strips. Adhesive-coated samples were submerged in solutions buffered at multiple pH levels (5.7, 7.4 and 10.0) at body temperature (37 °C) and the degradation behavior of the adhesive was tracked wirelessly by monitoring the changes in the resonant amplitude of the sensors for over 80 days. Adhesive incubated at pH 7.4 degraded over 75 days, which matched previously published data for bulk degradation behavior of the adhesive while utilizing significantly less material (∼10(3) times lower). Adhesive incubated at pH 10.0 degraded within 25 days while samples incubated at pH 5.7 did not completely degrade even after 80 days of incubation. As expected, the rate of degradation increased with increasing pH as the rate of ester bond hydrolysis is higher under basic conditions. As a result of requiring a significantly lower amount of samples compared to traditional methods, the ME sensing technology is highly attractive for fully characterizing the degradation behavior of tissue adhesives in a wide range of physiological conditions.


Hepatitis B virus X protein overcomes the growth-inhibitory potential of retinoic acid by downregulating retinoic acid receptor-beta2 expression via DNA methylation.
Aberrant promoter methylation of retinoic acid receptor-beta(2) (RAR-beta(2)) is frequently detected in hepatitis B virus (HBV)-positive hepatocellular carcinoma (HCC); however, the mechanism of methylation and its biological significance are unknown. This study showed that HBx, the principal oncogene product of HBV, induced promoter hypermethylation of RAR-beta(2) via upregulation of DNA methyltransferases 1 and 3a, resulting in downregulation of its expression in human HCC cells. In addition, HBx abolished the potential of retinoic acid (RA) to downregulate levels of G(1)-checkpoint regulators including p16, p21 and p27, resulting in activation of E2F1 in the presence of RA. As a consequence, HBx-expressing cells were less susceptible to RA-induced cell growth inhibition compared with control cells. These effects almost completely disappeared when levels of RAR-beta(2) in HBx-expressing cells were restored by treatment with a universal DNA methylation inhibitor, 5-aza-2'-deoxycytidine. As RAR-beta(2) is a major executor of the anti-tumour potential of RA, its epigenetic downregulation by HBx is likely to be an important step during HBV-mediated tumorigenesis.


Risk factors for pediatric arachnoid cyst rupture/hemorrhage: a case-control study.
As the availability of imaging modalities has increased, the finding of arachnoid cysts has become common. Accurate patient counseling regarding physical activity or risk factors for cyst rupture or hemorrhage has been hampered by the lack of definitive association studies. This case-control study evaluated factors that are associated with arachnoid cyst rupture (intracystic hemorrhage, adjacent subdural hematoma, or adjacent subdural hygroma) in pediatric patients with previously asymptomatic arachnoid cysts. Patients with arachnoid cysts and intracystic hemorrhage, adjacent subdural hygroma, or adjacent subdural hematoma treated at a single institution from 2005 to 2010 were retrospectively identified. Two unruptured/nonhemorrhagic controls were matched to each case based on patient age, sex, anatomical cyst location, and side. Risk factors evaluated included arachnoid cyst size, recent history of head trauma, and altitude at residence. The proportion of imaged arachnoid cysts that presented either originally or subsequently with a rupture or hemorrhage was 6.0%. Larger cyst size, as defined by maximal cyst diameter, was significantly associated with cyst rupture/hemorrhage (P < .001). When dichotomized with a 5-cm cutoff, 9/13 larger cysts ruptured and/or hemorrhaged, whereas only 5/29 smaller cysts ruptured/hemorrhaged (odds ratio = 16.5 (confidence interval [2.5, ∞]). A recent history of head trauma was also significantly associated with the outcome (P < .001; odds ratio = 25.1 (confidence interval [4.0, ∞]). Altitude was not associated with arachnoid cyst rupture or hemorrhage. This case-control study suggests that larger arachnoid cyst size and recent head trauma are risk factors for symptomatic arachnoid cyst rupture/hemorrhage.


Free energy landscapes of sodium ions bound to DMPC-cholesterol membrane surfaces at infinite dilution.
Exploring the free energy landscapes of metal cations on phospholipid membrane surfaces is important for the understanding of chemical and biological processes in cellular environments. Using metadynamics simulations we have performed systematic free energy calculations of sodium cations bound to DMPC phospholipid membranes with cholesterol concentration varying between 0% (cholesterol-free) and 50% (cholesterol-rich) at infinite dilution. The resulting free energy landscapes reveal the competition between binding of sodium to water and to lipid head groups. Moreover, the binding competitiveness of lipid head groups is diminished by cholesterol contents. As cholesterol concentration increases, the ionic affinity to membranes decreases. When cholesterol concentration is greater than 30%, the ionic binding is significantly reduced, which coincides with the phase transition point of DMPC-cholesterol membranes from a liquid-disordered phase to a liquid-ordered phase. We have also evaluated the contributions of different lipid head groups to the binding free energy separately. The DMPC's carbonyl group is the most favorable binding site for sodium, followed by DMPC's phosphate group and then the hydroxyl group of cholesterol.


A randomised double-blind trial of phenylephrine and metaraminol infusions for prevention of hypotension during spinal and combined spinal-epidural anaesthesia for elective caesarean section.
Prophylactic vasopressor administration is commonly recommended to reduce maternal hypotension during spinal anaesthesia for caesarean section. Metaraminol has undergone limited investigation in obstetric anaesthesia for this purpose, particularly in comparison with phenylephrine. In this multicentre, randomised, double-blind, non-inferiority study, we compared prophylactic phenylephrine or metaraminol infusions, started immediately after spinal anaesthesia, in 185 women who underwent elective caesarean section. Phenylephrine was initially infused at 50 μg.min-1 , and metaraminol at 250 μg.min-1 . The primary outcome was the difference in umbilical arterial pH between groups; secondary outcomes included other neonatal acid-base measures, and maternal haemodynamic changes. The mean (SD) umbilical arterial pH was 7.28 (0.06) in the phenylephrine group vs. 7.31 (0.04) in the metaraminol group (p = 0.0002). The estimated mean (95%CI) pH difference of 0.03 (0.01-0.04) was above the pre-determined lower boundary of clinical non-inferiority, and also met the criterion for superiority. Umbilical artery lactate concentration was 2.8 (1.2) mmol.l-1 in the phenylephrine group vs. 2.3 (0.7) mmol.l-1 in the metaraminol group (p = 0.0018). Apgar scores did not significantly differ between groups. There was a higher incidence of hypotension, defined as systolic arterial pressure < 90% baseline, in the phenylephrine group; there was a higher incidence of hypertension and severe hypertension (systolic arterial pressure > 110% and > 120% baseline, respectively) in the metaraminol group. There was no significant difference between groups in the incidence of nausea, vomiting or maternal bradycardia. We conclude that, when used as an infusion to prevent hypotension after spinal anaesthesia for elective caesarean section, metaraminol is at least non-inferior to phenylephrine with respect to neonatal acid-base outcomes.


Probabilistic genotyping software: An overview.
The interpretation of mixed profiles from DNA evidentiary material is one of the more challenging duties of the forensic scientist. Traditionally, analysts have used a "binary" approach to interpretation where inferred genotypes are either included or excluded from the mixture using a stochastic threshold and other biological parameters such as heterozygote balance, mixture ratio, and stutter ratios. As the sensitivity of STR multiplexes and capillary electrophoresis instrumentation improved over the past 25 years, coupled with the change in the type of evidence being submitted for analysis (from high quality and quantity (often single-source) stains to low quality and quantity (often mixed) "touch" samples), the complexity of DNA profile interpretation has equally increased. This review provides a historical perspective on the movement from binary methods of interpretation to probabilistic methods of interpretation. We describe the two approaches to probabilistic genotyping (semi-continuous and fully continuous) and address issues such as validation and court acceptance. Areas of future needs for probabilistic software are discussed.


Factors Associated with the Decline of Kidney Function Differ among eGFR Strata in Subjects with Type 2 Diabetes Mellitus.
Introduction. There is no report about risk factors for renal deterioration according to the clinical stage, divided by the estimated glomerular filtration rate (eGFR) in type 2 diabetes. Materials and Methods. We evaluated the factors correlated with the annual eGFR decline in 1303 subjects with type 2 diabetes whose eGFR was ≥30 mL/min/1.73 m(2). eGFR strata were defined by baseline eGFR value as follows: stratum 1: ≥90, stratum 2: ≥60, <90, and stratum 3: ≥30, <60. Results. The annual eGFR decline was 2.3 ± 5.4 mL/min/1.73 m(2) in overall subjects. Multiple linear regression analysis demonstrated that age, male sex, systolic blood pressure, logarithmically transformed albumin excretion rate (AER), eGFR strata, and hemoglobin concentration were significantly correlated with the annual eGFR decline. When stratified by eGFR, the factors that showed a significant correlation were different among eGFR strata. AER was significantly correlated with annual eGFR decline in all eGFR strata. Hemoglobin concentration showed a significant correlation only in the advanced eGFR stratum. Conclusion. The factors correlated with the annual eGFR decline were different among eGFR strata in type 2 diabetes mellitus, and hemoglobin concentration and AER were important factors for renal deterioration, especially in the advanced eGFR stratum.


Isolation of N-vinylprotoporphyrin IX after hepatic cytochrome P450 inactivation by 3-[(arylthio)ethyl]sydnone in chick embryos pretreated with phenobarbital, glutethimide, dexamethasone, and beta-naphthoflavone: differential inhibition of ferrochelatase by N-vinylprotoporphyrin regioisomers.
Several xenobiotics caused hepatic porphyrin accumulation through mechanism-based inactivation of cytochrome P450(P450) and heme alkylation. Loss of iron from the alkylated heme results in formation of an N-alkylporphyrin, which is a potent inhibitor of ferrochelatase. N-Vinylprotoporphyrin IX (N-vinylPP) was identified in chick embryo liver after in ovo administration of 3-[(arylthio)ethyl]sydnone (TTMS). Pretreatment of chick embryos with beta-naphthoflavone, which causes a 90-fold increase in P450 1A levels, did not increase the formation of N-vinylPP after TTMS administration, showing that the heme moiety of P450 1A does not contribute to the formation of N-vinylPP. Increased amounts of N-vinylPP were isolated from dexamethasone-, phenobarbital-, and glutethimide-pretreated chick embryos, and it is possible that P450 2H and/or a P450 3A-like isozyme contributes to the formation of N-vinylPP. The ring B-substituted (NB) regioisomer of N-vinylPP constituted the lowest percentage of the total regioisomers (9-13%) in untreated and drug-induced chick embryos, thus supporting the concept that ring B of heme is occluded by a protein residue in the P450 active site. Previously, the finding that the NB regioisomer of N-ethylprotoporphyrin IX had one fifth the potency of the ring A-substituted (NA) regioisomer as a ferrochelatase inhibitor led to a proposal that an A-C ring tilt was important in N-alkylprotoporphyrins for ferrochelatase inhibition. The finding in the present study that the NA and NB regioisomers of N-vinylPP are equipotent does not support the above proposal. The ring C-substituted (NC) and ring D-substituted (ND) regioisomers of N-vinylPP had low potency.


Corticolimbic dopamine neurotransmission is temporally dissociated from the cognitive and locomotor effects of phencyclidine.
The behavioral syndrome produced by phencyclidine (PCP) and its analog ketamine represents a pharmacological model for some aspects of schizophrenia. Despite the multifaceted properties of these drugs, the main mechanism for their psychotomimetic and cognitive-impairing effects has been thought heretofore to involve the corticolimbic dopamine system. The present study examined the temporal relationship between alterations in corticolimbic dopamine and glutamate neurotransmission and two dopamine-dependent behavioral effects of PCP in the rodent that have relevance to the clinical phenomenology, namely, impairment of working memory, which is used to model the frontal lobe deficits associated with schizophrenia, and hyperlocomotion, which is used as a predictor of the propensity of a drug to elicit or exacerbate psychosis. PCP increased dopamine and glutamate efflux in the prefrontal cortex and nucleus accumbens, as measured by microdialysis. The increase in dopamine in both regions remained elevated well above baseline 2.5 hr after the injection, at which time the experiment was terminated. However, locomotor activity returned to baseline in <2 hr after injection. Furthermore, impaired performance in a discrete trial delayed alternation task, a rodent working memory task, was only evident up to 60 min after PCP injection; animals tested 80 min after injection, when cortical dopamine release was elevated at 300% of baseline, did not exhibit impaired performance. These findings indicate that activation of dopamine neurotransmission is not sufficient to sustain PCP-induced locomotion and impairment of working memory. Thus, effects of PCP, including a glutamatergic hyperstimulation, may be necessary to account for the psychotomimetic and cognitive-impairing effects of this drug.


It's a wonderful life: is it possible to say that a severely disabled child has been harmed by the mere fact of being born?
"It's a Wonderful Life," the title of Frank Capra's classic 1946 movie, seems to encapsulate a fundamental all-American conviction. Unsurprisingly, several courts and jurists have applied the movie-title maxim as the ultimate retort to one of the most intriguing questions in modern tort discourse: Is it possible to say that a severely disabled child has been harmed by the mere fact of being born? Wrongful life claimants answer in the affirmative, whereas Capra's aphorism makes a compelling counter-argument. In my opinion, the contrasting views represent equally legitimate subjective beliefs rather than objective truths, so neither may ever prevail. Without a satisfactory solution from conventional wisdom, the life-as-injury debate may be the Gordian knot of tort law. The purpose of this Article is to cut, rather than untie, the knot: Allow the child to recover without challenging or validating the deep-seated perception of life. Part I shows that hostility to liability in tort for wrongful life is almost universal, crossing lands and seas. Part II argues that this demurral is ultimately rooted in the absence of one of the central components of the cause of action. A tort action must fail because of the inability--both logical and practical--to establish "harm" under the traditional definition of this term. Part III opines that because the Gordian knot of tort law cannot be untied, it must be cut altogether. We must replace the traditional tort framework, which gives rise to an insoluble problem, with a more promising contractual framework inspired by the celebrated case of Hawkins v. McGee. In my view, the child may base an action on the claim that the defendant promised the parents that the child would be born without a certain defect and that the promise went unfulfilled. In formal terms, the child is an intended third party beneficiary of the contract between the parents and the consultant in which the latter warranted birth without a particular disability. The warranty of the future child's physical integrity and health, an integral and inseparable part of the contract, should form the basis of the child's cause of action.


Determinants of perceived insufficient milk among new mothers in León, Nicaragua.
Breastfeeding has been shown to improve maternal and child health. In Nicaragua, the primary risk of death and disability-adjusted life years among children under 5 years of age is suboptimal breastfeeding. Although the Nicaraguan Ministry of Health promotes exclusive breastfeeding from within the first half hour through the first 6 months of life, less than a third of children in the country under 6 months of age are exclusively breastfed. As part of a larger, mixed-methods study, 21 semi-structured, in-depth interviews were conducted with new mothers recruited from three primary health centers between June and August 2015 in order to identify the social, cultural, and structural factors that contribute to infant feeding practices and the discrepancy between recommendations and practices among mothers who delivered at an urban public hospital in León, Nicaragua. Audio recordings were transcribed verbatim, and interview transcripts were coded and analyzed by a three-member team using a grounded theory approach. Findings highlight a widespread perception of insufficient milk among mothers that influenced early cessation of exclusive breastfeeding and other infant feeding practices. This perception stemmed from anxiety about meeting infant nutritional needs and infant satiety, anxiety about maternal nutrition, advice from and role modeling of family members about mixed feeding, and perceived infant feeding norms. Results suggest that support modeled after the 10 steps of the Baby-friendly Hospital Initiative as well as strengthened policy-level support are needed. Community interventions that address cultural and structural barriers to improve breastfeeding practices may also help to increase breastfeeding rates.


A Randomized Clinical Trial of Immediate versus Delayed Glasses for Moderate Hyperopia in 1- and 2-Year-Olds.
Two strategies were compared for managing moderate hyperopia without manifest strabismus among 1- and 2-year-old children: (1) immediate prescription of glasses versus (2) observation without glasses unless reduced distance visual acuity (VA), reduced stereoacuity, or manifest strabismus. Prospective randomized clinical trial. A total of 130 children aged 1 to 2 years with hyperopia between +3.00 diopters (D) and +6.00 D spherical equivalent (SE) in at least 1 eye, anisometropia ≤1.50 D SE, and astigmatism ≤1.50 D based on cycloplegic refraction and no manifest strabismus. Participants were randomly assigned to glasses (1.00 D less than full cycloplegic hyperopia) versus observation and followed every 6 months for 3 years. Glasses were prescribed to those assigned to observation if they met prespecified deterioration criteria of distance VA or near stereoacuity below age norms, or development of manifest strabismus. At the 3-year primary outcome examination, participants were classified as failing the randomized management regimen if distance VA or stereoacuity was below age norms or manifest strabismus was observed (each with and without correction in trial frames, confirmed by masked retest, irrespective of whether deterioration had occurred previously), or if strabismus surgery had been performed. Of the 106 participants (82%) completing the 3-year primary outcome examination, failure occurred in 11 (21%) of 53 in the glasses group and 18 (34%) of 53 in the observation group (difference = -13%; 95% confidence interval [CI], -31 to 4; P = 0.14). Sixty-two percent (95% CI, 49-74) in the observation group and 34% (95% CI, 23-48) in the glasses group met deterioration criteria (requiring glasses if not wearing). For 1- and 2-year-olds with uncorrected moderate hyperopia (+3.00 D to +6.00 D SE), our estimates of failure, after 3 years of 6-month follow-ups, are inconclusive and consistent with a small to moderate benefit or no benefit of immediate prescription of glasses compared with careful observation (with glasses only if deteriorated).


CONSANGUINEOUS MARRIAGE IN JORDAN: AN UPDATE.
This study examined the recent level, trends and determinants of consanguineous marriage in Jordan using time-series data from the Jordan Population and Family Health Surveys (JPFHSs). According to the 2012 JPFHS, 35% of all marriages were consanguineous in Jordan in 2012. There has been a declining trend in consanguinity in the country, with the rate decreasing from a level of 57% in 1990. Most consanguineous marriage in 2012 were first cousin marriages, constituting 23% of all marriages and 66% of all consanguineous marriages. The data show that women with a lower age at marriage, older marriage cohort, larger family size, less than secondary level of education, rural place of residence, no employment, no exposure to mass media, a monogamous marriage, a husband with less than higher level of education and lower economic status, and those from the Badia region, were more likely to have a consanguineous marriage. Increasing age at marriage, level of education, urbanization and knowledge about the health consequences of consanguinity, and the ongoing socioeconomic and demographic transition in the country, will be the driving forces for further decline in consanguinity in Jordan.


Caregiver Perspectives About Using Antipsychotics and Other Medications for Symptoms of Dementia.
To avoid "chemical restraints," policies and guidelines have been implemented to curb the use of medications for behavioral and psychological symptoms of dementia (BPSD). Antipsychotics have been particularly targeted because of their rare severe side effects. Consequently, caregiver directed non-pharmacologic therapies have increased while medication use for BPSD has diminished. Despite such initiatives, however, antipsychotics continue to be prescribed "off-label" for roughly 20% of nursing home patients. How caregivers impact management approaches and prescribing decisions for BPSD, including antipsychotic use, is poorly understood. Aim: assesses experiences and perceptions of family and nursing caregivers regarding factors influencing medication decisions for BPSD. Semi-structured interviews, analyzed via template, immersion and crystallization, and thematic development. Thirty-two participants from Northwestern Virginia representing five groups of caregivers for dementia patients were interviewed: families of community-dwelling, assisted living, and nursing home patients, and nurses from the same assisted living/nursing home facilities. Caregivers described three major themes regarding medications: (a) Systemic barriers exist for non-pharmacologic BPSD therapies. (b) Medications have few barriers, and seem generally effective and safe. (c) When non-pharmacologic measures fail, medications, including antipsychotics, may be necessary and appropriate for palliation of patient distress. To further reduce medications for BPSD, obstacles to services and alternative therapies must be mitigated. Caregiver perceptions that medications are generally safe and effective contribute to their continued use. Guidelines and policies for BPSD management should incorporate the caregiver position that medications, including antipsychotics, are sometimes justified and required to alleviate patient suffering.


Fabricating micro-Bragg reflectors in 3-D photorefractive waveguides.
Bragg reflectors as small as optical waveguides can be used at the intersections of waveguides as spectral filters, beam splitters, or beam combiners. We present the concept of fabricating small Bragg reflectors in photorefractive waveguides and show the spectral selectivity of these micro-Bragg reflectors fabricated in a lithium niobate crystal. We also show that we can fabricate waveguide structures simultaneously with the micro-Bragg reflector, by using a crystal whose c-axis is directed 45 degree off the optical axis of the fabrication beam. The reflectivity of the micro-Bragg reflector was smaller than 0.01 and was not large enough for the immediate use.


How to think, say, or do precisely the worst thing for any occasion.
In slapstick comedy, the worst thing that could happen usually does: The person with a sore toe manages to stub it, sometimes twice. Such errors also arise in daily life, and research traces the tendency to do precisely the worst thing to ironic processes of mental control. These monitoring processes keep us watchful for errors of thought, speech, and action and enable us to avoid the worst thing in most situations, but they also increase the likelihood of such errors when we attempt to exert control under mental load (stress, time pressure, or distraction). Ironic errors in attention and memory occur with identifiable brain activity and prompt recurrent unwanted thoughts; attraction to forbidden desires; expression of objectionable social prejudices; production of movement errors; and rebounds of negative experiences such as anxiety, pain, and depression. Such ironies can be overcome when effective control strategies are deployed and mental load is minimized.


Changes in intra-abdominal pressure and central venous and brain venous blood pressure in patients during extracorporeal circulation.
The aim was to analyze IAP changes and the relationships between IAP, CVP, and brain venous blood pressure, which are still unknown, in patients undergoing coronary artery bypass grafting (CABG) with extracorporeal circulation. Twenty-five male patients (aged 53-67 years) underwent CABG under general anesthesia with normovolemic hemodilution. IAPs were measured in the urinary bladder, CVP by left internal jugular vein cannulation, and brain venous blood pressure by retrograde cannulation of the right jugular vein bulb (JVP, jugular vein pressure) at seven time-points: 1) after induction of anesthesia before the operation, 2) during internal thoracic artery preparation, 3) 10 minutes after heart-lung machine disconnection, 4) after procedure completion, before sending the patient to the intensive postoperative care unit, 5) one hour after the procedure, 6) 6 hours after the procedure, and 7) 18 hours after the procedure. IAP increased from points 3 to 6. CVP increased from points 3, 4, and 5 and decreased at point 7. Similar changes were noted in JVP. There were significant correlations between IAP and CVP at points 1, 2, 3, 4, and 5, IAP and JVP at points 3, 4, and 5, and CVP and JVP at all points. The overall analysis showed correlations between IAP and CVP and JVP and very strong correlation between CVP and JVP. 1) CABG with extracorporeal circulation resulted in increases in IAP, CVP, and brain venous blood pressure. 2) The changes in CVP and brain venous blood pressure correlated with intra-abdominal pressure.