Creation of cis-regulatory elements during sea urchin evolution by co-option and optimization of a repetitive sequence adjacent to the spec2a gene.
The creation, preservation, and degeneration of cis-regulatory elements controlling developmental gene expression are fundamental genome-level evolutionary processes about which little is known. Here, we identify critical differences in cis-regulatory elements controlling the expression of the sea urchin aboral ectoderm-specific spec genes. We found multiple copies of a repetitive sequence element termed RSR in genomes of species within the Strongylocentrotidae family, but RSRs were not detected in genomes of species outside Strongylocentrotidae. spec genes in Strongylocentrotus purpuratus are invariably associated with RSRs, and the spec2a RSR functioned as a transcriptional enhancer and displayed greater activity than did spec1 or spec2c RSRs. Single-base pair differences at two cis-regulatory elements within the spec2a RSR increased the binding affinities of four transcription factors, SpCCAAT-binding factor at one element and SpOtx, SpGoosecoid, and SpGATA-E at another. The cis-regulatory elements to which these four factors bound were recent evolutionary acquisitions that acted to either activate or repress transcription, depending on the cell type. These elements were found in the spec2a RSR ortholog in Strongylocentrotus pallidus but not in RSR orthologs of Strongylocentrotus droebachiensis or Hemicentrotus pulcherrimus. Our results indicated that a dynamic pattern of cis-regulatory element evolution exists for spec genes despite their conserved aboral ectoderm expression.


A simple transmission dynamics model for predicting the evolution of COVID-19 under control measures in China.
Epidemic forecasting provides an opportunity to predict geographic disease spread and counts when an outbreak occurs and plays a key role in preventing or controlling their adverse impact. However, conventional prediction models based on complex mathematical modelling rely on the estimation of model parameters, which yields unreliable and unsustainable results. Herein, we proposed a simple model for predicting the epidemic transmission dynamics based on nonlinear regression of the epidemic growth rate and iterative methods, which is applicable to the progression of the COVID-19 outbreak under the strict control measures of the Chinese government. Our model yields reliable and accurate results as confirmed by the available data: we predicted that the total number of infections in mainland China would be 91 253, and the maximum number of beds required for hospitalised patients would be 62 794. We inferred that the inflection point (when the growth rate turns from positive to negative) of the epidemic across China would be mid-February, and the end of the epidemic would be in late March. This model is expected to contribute to resource allocation and planning in the health sector while providing a theoretical basis for governments to respond to future global health crises or epidemics.


The Advantages and Challenges of Diversity in Pharmacogenomics: Can Minority Populations Bring Us Closer to Implementation?
Health disparities exist among minorities in the United States, with differences seen in disease prevalence, mortality, and responses to medications. These differences are multifactorial with genetic variation explaining a portion of this variability. Pharmacogenomics aims to find the effect of genetic variations on drug response, with the goal of optimizing drug therapy and development. Although genome-wide association studies have been useful in unbiasedly surveying the genome for genetic drivers of clinically relevant phenotypes, most of these studies have been conducted in mainly participants of European and Asian descent, contributing to a growing health disparity in precision medicine. Diversity is important to pharmacogenomic studies, and there may be real advantages to the use of these complex genomes in pharmacogenomics. In this review we will outline some of the advantages and confounders of pharmacogenomics in minorities, describe the role of genetic variation in pharmacologic pathways, and highlight a number of population-specific findings.


A global overall dietary index: ODI-R revised to emphasize quality over quantity.
Incorporating the Healthy Eating Index concept, we have developed a global dietary quality index, the Overall Dietary Index (ODI). We have evaluated the relationships between ODI and chronic disease in a 1998 Taiwanese Health Screening program with over 46,000 members (51.2% females) aged 19-84. However, it could not predict health status adequately. Therefore, we revised this ODI which became ODI-R (Revised). The revision added a quality evaluation for staples (whole grains) and protein-rich foods (fish and soy) and reduced the impact of dietary fat quantity. ODI-R comprises nine items with a maximal score of 100. It has 5 food categories: dairy products, protein rich foods (eggs/legumes/fish/meats), vegetables, fruits and cereals; 2 dietary fat qualities (P/S ratio and cholesterol); and 2 descriptors: dietary moderation (alcohol, salt and sugar as one item) and dietary variety. The mean ODI-R was lower than ODI (64.4 vs. 68.1 in men and 65.5 vs. 69.0 in women) and the distribution. The correlations between macronutrients and ODI-R were weaker than for ODI, especially for fat (from +/-0.52 to +/-0.07) as well as for cholesterol and all fatty acid types by degree of saturation. For dietary fiber and micronutrients, the correlations became either less negative or more positive, signaling that the ODI-R reflects food quality more appropriately than ODI in regard to micronutrients. Empirically, a subtraction scoring approach for the overeating of protein rich foods, did not meaningfully decrease ODI-R in Taiwanese elderly or children. ODI-R provides an effective measure of dietary quality over quantity.


Acute and Chronic Lead Exposure in Four Avian Scavenger Species in Switzerland.
Despite irrefutable evidence of its negative impact on animal behaviour and physiology, lethal and sublethal lead poisoning of wildlife is still persistent and widespread. For scavenging birds, ingestion of ammunition, or fragments thereof, is the major exposure route. In this study, we examined the occurrence of lead in four avian scavengers of Switzerland and how it differs between species, regions, and age of the bird. We measured lead concentration in liver and bone of the two main alpine avian scavengers (golden eagle Aquila chrysaetos and bearded vulture Gypaetus barbatus) over the entire area of the Swiss Alps and two of the main avian scavengers occurring in the lowlands of Switzerland (red kite Milvus milvus and common raven Corvus corax). Of those four species, only the bearded vulture is an obligate scavenger. We found that lead burdens in the two alpine avian scavengers were higher than those found for the same species elsewhere in Europe or North America and reached levels compatible with acute poisoning, whereas lead burdens of the two lowland avian scavengers seemed to be lower. Several golden eagles, but only one red kite with abnormally high bone lead concentrations were found. In all four species, a substantial proportion of birds had elevated levels which presumably represent recent (liver lead levels) or past (bone lead levels) uptake of sublethal doses of lead.


Early detection of coronary artery flow and myocardial perfusion impairment in hypertensive patients evidenced by myocardial blush grade (MBG) and thrombolysis in myocardial infarction (TIMI) frame count (TFC).
In hypertensive patients with typical chest pain but absence of coronary stenosis the coronary microcirculation may be impaired, thus, our study aimed to appraise, in these subjects, the role of the coronary microcirculation, assessed by Myocardial Blush Grade (MBG) and Thrombolysis in Myocardial Infarction (TIMI) Frame Count (TFC). A total of 95 subjects with chest pain and uninjured coronary arteries were recruited into the study: 80 subjects were hypertensive while 15 subjects were normotensive. The hypertensive subjects were divided into two subgroups: hypertensive subjects with positive scintigraphy and hypertensive subjects with negative scintigraphy. The TFC, a quantitative method of assessing coronary artery flow, the MBG, an assessment of the level of tissue perfusion, and the Total Myocardial Blush Score (TMBS), the sum of the myocardial blush grades of each coronary territory, were evaluated on the coronary angiogram of every patient. The TFC was higher (p<0.05) in hypertensive subjects than in normotensive subjects. The MBG and the TMBS were lower (p<0.05) in hypertensive subjects than in normotensive subjects. The TFC was higher (p<0.05) in positive scintigraphy than in negative scintigraphy. The MBG was lower (p<0.05) in positive scintigraphy than in negative scintigraphy. The Spearman rank correlation test showed that the TFC and the MBG was inversely associated. The hypertensive subjects had impaired coronary artery flow and myocardial perfusion, documented by the TFC, MBG and myocardial perfusion scintigraphy. These methods may be universally applicable, in fact they are validated and most catheterization laboratories have access to them.


[Cancellation of cataract surgery in a public hospital].
To report the incidence and causes of cataract surgery cancellations in a public hospital. This is a retrospective study, which examined the number of cancellations of cataract surgery during 2009. We analyzed the type of procedure suspended (phacoemulsification or extracapsular extraction), type of anesthesia, gender, age, covenant (public/private) and the main reasons for suspension of the surgeries (clinical causes, institutional or personal). We analyzed 2,965 scheduled cataract surgeries, with 650 cancellations (21.92%). The main reason for the suspension of the procedure was clinical causes (86.90%). The winter months had the highest suspension rates of cataract surgery. The cancellation rate of cataract surgery in Brazilian public system seems to be the same as 10 years ago. The main cause of the suspension should be in clinical conditions (hypertension, diabetes, lack of exams, etc.).


Targeting membrane-bound viral RNA synthesis reveals potent inhibition of diverse coronaviruses including the middle East respiratory syndrome virus.
Coronaviruses raise serious concerns as emerging zoonotic viruses without specific antiviral drugs available. Here we screened a collection of 16671 diverse compounds for anti-human coronavirus 229E activity and identified an inhibitor, designated K22, that specifically targets membrane-bound coronaviral RNA synthesis. K22 exerts most potent antiviral activity after virus entry during an early step of the viral life cycle. Specifically, the formation of double membrane vesicles (DMVs), a hallmark of coronavirus replication, was greatly impaired upon K22 treatment accompanied by near-complete inhibition of viral RNA synthesis. K22-resistant viruses contained substitutions in non-structural protein 6 (nsp6), a membrane-spanning integral component of the viral replication complex implicated in DMV formation, corroborating that K22 targets membrane bound viral RNA synthesis. Besides K22 resistance, the nsp6 mutants induced a reduced number of DMVs, displayed decreased specific infectivity, while RNA synthesis was not affected. Importantly, K22 inhibits a broad range of coronaviruses, including Middle East respiratory syndrome coronavirus (MERS-CoV), and efficient inhibition was achieved in primary human epithelia cultures representing the entry port of human coronavirus infection. Collectively, this study proposes an evolutionary conserved step in the life cycle of positive-stranded RNA viruses, the recruitment of cellular membranes for viral replication, as vulnerable and, most importantly, druggable target for antiviral intervention. We expect this mode of action to serve as a paradigm for the development of potent antiviral drugs to combat many animal and human virus infections.


Managing the double burden: pregnancy and labor-intensive time use in rural China, Mexico, and Tanzania.
Labor-intensive work is often a way of life for women living in rural areas of developing countries. The physical exertion involved in such work may result in poor health outcomes for mothers and infants when continued through pregnancy. Using longitudinal data from China, Mexico, and Tanzania, we examine the relationship between pregnancy and four time-use outcomes, measured as hours spent in the past week on: (1) housework, (2) caregiving, (3) agricultural work, and (4) self-employment or nonagricultural work outside the home. An individual fixed-effects approach is adopted to overcome the potential time-invariant woman-level endogeneity of pregnancy status. With few exceptions, we do not find significantly different time-use patterns between pregnant and nonpregnant women. The assumption that women decrease labor-intensive work in developing countries during pregnancy needs revisiting and may have implications for both women's livelihood programming and assistance during childbearing periods.


High salt lysates: a simple method to store blood samples without refrigeration for subsequent use with DNA probes.
Blood specimens to be tested for the presence of Plasmodium falciparum using specific DNA probes can be stored as high salt lysates (HSL) without refrigeration. The lysates are prepared from 100 microliter blood samples by a simple 3-step procedure using 2 volumes of H2O to lyse the erythrocytes (step I), 1 volume of a detergent/EDTA mix to lyse the parasites (step II), followed by the addition of 1 volume cesium trifluoroacetate (CsTFA) (step III). The parasite DNA was found to be undegraded, as shown by the unaltered pattern of repetitive sequences obtained after storage of up to 1 month at 37 degrees C, due to the inhibition of DNA degrading enzymes by the cesium salt. The bulk of protein can be removed from the samples by a 1-step precipitation. The addition of 0.3 volumes of a mixture of ethanol: chloroform: isoamyl alcohol (2.5:1:0.04 v/v) precipitates greater than 90% of the proteins from the lysates, leaving greater than 86% of the parasite DNA in the supernatant. The reduced protein content of the samples, when applied to solid supports, results in an increased signal: background ratio on autoradiograms.


Defining "significant weight loss" in atypical anorexia nervosa.
Atypical anorexia nervosa (AAN) is defined by the symptoms of anorexia nervosa in the presence of "significant weight loss" in individuals who are not underweight. Description of current weight in AAN has been limited, significant weight loss has not been defined, and the distinction between having AAN versus having weight suppression has not been examined. Secondary analyses were conducted with data from an epidemiological study of women (n = 1,640) and men (n = 794). Three definitions of significant weight loss (5, 10, and 15%) for AAN were tested in comparisons with controls and a DSM-5 eating disorder group (DSM-5 ED) on measures of eating pathology and clinical significance using ANCOVA and logistic regression, controlling for age and body mass index. Secondary analyses compared AAN to a weight suppressed group (WS-only) and a cognitive concerns group (COG-only). Across weight loss thresholds, ≥25% of adults with AAN were currently overweight/obese. At the 5% and 10% definitions, AAN was associated with elevated eating pathology and distress relative to controls, WS-only, and COG-only in women and men. Women with AAN endorsed less eating pathology and distress than DSM-5 ED at some weight loss definitions, whereas men with AAN did not differ from DSM-5 ED in eating pathology or distress. Results support that even a 5% weight loss, combined with cognitive concerns, may produce a group with a clinically significant eating disorder. AAN was observed in both healthy weight and overweight/obese adults, highlighting the importance of screening for restrictive eating disorders at all weights.


Evaluation of Sex Differences in the Potential of Δ9-Tetrahydrocannabinol, Cannabidiol, Cannabidiolic Acid, and Oleoyl Alanine to Reduce Nausea-Induced Conditioned Gaping Reactions in Sprague-Dawley Rats.
Introduction: Cancer patients report nausea as a side effect of their chemotherapy treatment. Using the pre-clinical rodent model of acute nausea-lithium chloride (LiCl)-induced conditioned gaping-our group has demonstrated that exogenous cannabinoids may have antinausea potential. Materials and Methods: With the goal of evaluating the role of sex as a factor in pre-clinical research, we first compared the conditioned gaping reactions produced by varying doses of LiCl in male and female rats using the taste reactivity test (Experiment 1). Results: LiCl produced dose-dependent conditioned gaping similarly in male and female rats with the highest dose (127.2 mg/kg) producing robust conditioned gaping, with this dose used in subsequent experiments. Next, we examined the antinausea potential of THC (Experiment 2), CBD (Experiment 3), cannabidiolic acid (CBDA; Experiment 4) and oleoyl alanine (OlAla; Experiment 5) in both male and female rats. THC, CBD, CBDA, and OlAla dose dependently reduced conditioned gaping in both male and female rats in a similar manner. Conclusions: These results suggest that cannabinoids may be equally effective in treating nausea in both males and females.


An audit of gynae-oncology practices in ovarian cancer treatment based on enhanced recovery after surgery (ERAS) protocol amongst two gynae-oncology units, in UK and in Pakistan.
To compare peri-operative practices and complications in ovarian cancer patients undergoing upfront surgery for primary disease under enhanced recovery after surgery protocol and traditional practices. The retrospective cross-sectional study was done at the gynaecology departments of St Georges Hospital, United Kingdom, and the Aga Khan Hospital, Pakistan, and comprised data of an equal number of ovarian cancer patients from each centre who underwent ovarian cancer surgery from January 2015 to December 2016. The former centre practiced the enhanced recovery after surgery protocol, while the latter centre followed traditional practices. Data was analysed using SPSS 19. Of the 100 patients, there were 50(50%) in each group. Baseline variables were comparable except for diabetes which was more prevalent in the local group (p=0.03). Mechanical bowel preparation was performed in 47(94%) of local patients compared to 1(2%) in the other group, while the duration for nil-per-mouth status as well as the use of nasogastric tube and peritoneal drain were significantly different (p<0.05). Epidural anaesthesia was used in 39(78%) of patients in Pakistan compared to 4(8%) in the United Kingdom. The duration of thromboprophylaxis was also significantly different (p<0.05). Implementation of enhanced recovery after surgery protocol was found to have the potential to improve postoperative outcomes and good functional recovery without compromising patient safety.


Pain control in terminal disease.
Pain control is recognised as perhaps the most important single objective in the patient with terminal disease. Cancer, cardiovascular disease and obstructive airways disease are foremost among many causes of pain requiring control in the terminal phase. Spiritual, emotional, religious and socio-economic factors are important in raising or lowering the pain threshold. Analgesic strategies include use of drugs, neurosurgery, radiotherapy and supportive measures which may be brought to bear singly or in combination as required. Pain is clinically classified as being acute or chronic, by the type of patient, and by a series of common pain syndromes and their pathological mechanisms. General concepts of control of pain and discomfort in disease are discussed, together with a brief comment on epidemiology, in the first part of the article. Rationale is then discussed under the following headings: (i) principles of pain control; (ii) causes of pain; and (iii) analgesic modalities and factors impinging on their efficacy.


Dietary sugarcane bagasse and coarse particle size of corn are beneficial to performance and gizzard development in broilers fed normal and high sodium diets.
An experiment was conducted to evaluate the effects of sugarcane bagasse (SB) and particle size on broiler performance, gizzard development, ileal microflora, litter quality, and bird welfare under a wet litter challenge model. A total of 672 one-day-old Ross 308 male broilers was allocated to 48 pens using a 2 × 2 × 2 factorial arrangement of treatments with corn particle size-coarse 3,576 μm (CC) or fine 1,113 μm (FC) geometric mean diameter, SB - 0 or 2% and sodium (Na) - 0.16 or 0.40% with increased Na level to induce wet litter. A 3-way particle size × Na × SB interaction (P < 0.05) was observed for weight gain at d 10. Birds fed FC showed a higher weight gain compared to birds fed CC when 0.40% Na without SB diet or 0.16% Na with 2% SB diet was offered. A significant particle size × SB interaction was observed at d 24 on feed conversion ratio (FCR; P < 0.001) and weight gain (P < 0.05). FCR was reduced by 2% SB supplementation in birds fed CC but increased in birds fed FC. Further, weight gain of birds fed 2% SB was higher in birds fed CC but not in those fed FC. On d 35, birds fed 2% SB had a higher weight gain (P < 0.001) compared to those without SB, and a SB × particle size interaction on relative gizzard weight (P < 0.05) and pH (P < 0.05) was present. SB reduced gizzard pH and increased the relative gizzard weight in birds fed the FC diet but not the CC diet (P < 0.05). Counts of ileal Bacillus spp. were increased in birds fed SB (P < 0.05) on d 24. No effects of SB and particle size on litter quality and bird welfare were observed, but higher Na increased litter moisture and footpad dermatitis (FPD) scores (P < 0.001). These findings suggest that SB independently or in combination with CC improves performance in older birds regardless of Na level in diets, possibly through improved gizzard development and gut microflora of birds.


[Adherence, self-efficacy, physician visits in a clinical trial over 6 months in multiple sclerosis patients].
Lack of treatment adherence is a significant issue in multiple sclerosis (MS). The aim of this project was to examine whether establishing an observational situation in the context of a non-interventional study could positively affect the treatment adherence, quality of life as well as patient satisfaction in 206 MS patients treated with Copaxone(®). Apart from 3 standardised, anonymous surveys no further measures were taken. Self-efficacy increased in the patients, which was also reflected in a decline in physician visits in the monitoring period. The number of consultations initiated by the patient decreased very much between the second and third patient surveys. In the quality of life area "health", there was a significant improvement. After 3 months there was a discontinuation rate of 10.4%; after 6 months 8.8%. Even though this was not a controlled study, these results could indicate that, on a short-term basis, patients can be motivated to adhere--probably as a result of the psychological aspects of the observational situation. However, long-term changes in behaviour can probably only be achieved through qualified training.


P2Z purinoceptor-associated pores induced by extracellular ATP in macrophages and J774 cells.
Millimolar concentrations of extracellular ATP (ATPo) can induce the permeabilization of plasma membranes of macrophages and other bone marrow-derived cells to low-molecular-weight solutes, a phenomenon that is the hallmark of P2Z purinoceptors. However, patch-clamp and whole cell electrophysiological experiments have so far failed to demonstrate the existence of any ATPo-induced P2Z-associated pores underlying this permeabilization phenomenon. Here, we describe ATPo-induced pores of 409 +/- 33 pS recorded using cell-attached patch-clamp experiments performed in macrophages and J774 cells. These pores are voltage dependent and display several properties of the P2Z-associated permeabilization phenomenon: they are permeable to both large cations and anions, such as tris(hydroxymethyl)aminomethane, N-methyl-D-glucamine, and glutamate; their opening is favored at temperatures higher than 30 degrees C; they are blocked by oxidized ATP and Mg2+; and they can be triggered by 3'-O-(4-benzoylbenzoyl)-ATP but not by UTP or ADP. We conclude that the pores described in this report are associated with the P2Z permeabilization phenomenon.


Dog Visiting Programs for Managing Depressive Symptoms in Older Adults: A Meta-Analysis.
Depressive symptoms are highly prevalent in older adults and may contribute to functional impairment at old age. Animal-assisted interventions (AAIs), including interventions involving dog visiting, are increasingly recognized as an innovative approach to ameliorate social, behavioral, psychological, and physical outcomes among older adults. However, available data on their potential to manage depressive symptoms in the aging population are not clear cut. The aim of this review was to conduct a meta-analysis of all prospective controlled studies evaluating the effects of dog visiting on depressive symptoms in older adults. A comprehensive literature search was conducted on the electronic databases PubMed and Scopus. Included articles were published between 1980 and 2017 and report controlled empirical studies of dog visiting interventions to ameliorate depressive symptoms in older adults. There was substantial heterogeneity between included studies, which varied in their methodological quality, sample size, and other key features. Notwithstanding such methodological variety, results all go in the same direction and indicate a large beneficial effect of interventions involving dog visiting on depressive symptoms. This analysis confirms the potential value of dog visiting in ameliorating depressive symptoms in institutionalized and noninstitutionalized older adults. This is in line with previous research indicating AAIs as promising complementary programs for preserving/enhancing emotional and behavioral function in aged individuals. More research is still needed to allow AAIs to be effectively introduced in clinical practice.


Parents in adult psychiatric care and their children: a call for more interagency collaboration with social services and child and adolescent psychiatry.
A parental mental illness affects all family members and should warrant a need for support. To investigate the extent to which psychiatric patients with underage children are the recipients of child-focused interventions and involved in interagency collaboration. Data were retrieved from a psychiatric services medical record database consisting of data regarding 29,972 individuals in southern Sweden and indicating the patients' main diagnoses, comorbidity, children below the age of 18, and child-focused interventions. Among the patients surveyed, 12.9% had registered underage children. One-fourth of the patients received child-focused interventions from adult psychiatry, and out of these 30.7% were involved in interagency collaboration as compared to 7.7% without child-focused interventions. Overall, collaboration with child and adolescent psychiatric services was low for all main diagnoses. If a patient received child-focused interventions from psychiatric services, the likelihood of being involved in interagency collaboration was five times greater as compared to patients receiving no child-focused intervention when controlled for gender, main diagnosis, and inpatient care. Psychiatric services play a significant role in identifying the need for and initiating child-focused interventions in families with a parental mental illness, and need to develop and support strategies to enhance interagency collaboration with other welfare services.


Dental Caries, Race and Incident Ischemic Stroke, Coronary Heart Disease, and Death.
Dental caries is a highly prevalent disease worldwide. In the United States, untreated dental caries is present in >1 in 5 adults. The objective of this study was to determine the relationship between dental caries and incident ischemic stroke, coronary heart disease (CHD) events, and death. The dental cohort (n=6351) of the ARIC study (Atherosclerosis Risk in Communities) was followed for incident ischemic stroke, CHD event, and all-cause mortality. Of all the participants at visit 4 (n=11 656), those who were unable to go through dental examination, or with prevalent ischemic stroke and CHD events, were excluded. The full-mouth dental examination was conducted at visit 4 (1996-1998), assessing dental caries. The dose response of decayed, missing, and filled surfaces due to caries was assessed and related to the outcome. Outcomes were assessed through the end of 2019. Additionally, the effect of regular dental care utilization on dental caries was evaluated. Participants with ≥1 dental caries had an increased risk of stroke (adjusted hazard ratio [HR], 1.40 [95% CI, 1.10-1.79]) and death (adjusted HR, 1.13 [95% CI, 1.01-1.26]) but not for CHD events (adjusted HR, 1.13 [95% CI, 0.93-1.37]). The association of dental caries and ischemic incident stroke was significantly higher in the African American population compared with the White subgroup (interaction term P=0.0001). Increasing decayed, missing, and filled surfaces were significantly associated with stroke (adjusted HR, 1.006 [95% CI, 1.001-1.011]) and death (adjusted HR, 1.003 [95% CI, 1.001-1.005]) but not CHD (adjusted HR, 1.002 [95% CI, 1.000-1.005]). Regular dental care utilization lowered (adjusted odds ratio, 0.19 [95% CI, 0.16-0.22]; P<0.001) the chance of caries. Among the cohort, dental caries was independently associated with the risk of ischemic stroke and death, with the effect higher in African American participants. Regular dental care utilization was associated with a lower chance of caries, emphasizing its relevance in the prevention of these events.


Sources of diel variation in energetic physiology in an Arctic-breeding, diving seaduck.
Diel variation in baseline glucocorticoid (GC) secretion influences energetics and foraging behaviors. In temperate breeding, diurnal vertebrates, studies have shown that daily patterns of baseline GC secretion are influenced by environmental photoperiod, with baseline GCs peaking prior to sunrise to stimulate waking and foraging behaviors. Measures of physiological energy acquisition are also expected to peak in response to foraging activity, but their relationship to GC levels have not been well studied. In contrast to temperate breeding species, virtually nothing is known about diel GC and energetic metabolite secretion in Arctic breeding species, which experience almost constant photoperiods in spring and summer. Using a ten-year dataset, we examined the daily, 24-h pattern of baseline corticosterone (CORT) and triglyceride (TRIG) secretion in approximately 800 female pre-breeding Arctic-nesting common eiders (Somateria mollissima). We related these traits to environmental photoperiod and to tidal cycle. In contrast to temperate breeding species, we found that that neither time of day nor tidal trend predicted diel variation in CORT or TRIG secretion in Arctic-breeding eiders. Given the narrow window of opportunity for breeding in polar regions, we suggest that eiders must decouple their daily foraging activity from light and tidal cycles if they are to accrue sufficient energy for successful breeding. As CORT is known to influence foraging behavior, the absence of a distinct diel pattern of CORT secretion may therefore be an adaptation to optimize reproductive investment and likelihood for success in some polar-breeding species.


Patterns of Genome-Wide Variation, Population Differentiation and SNP Discovery of the Red Banded Stink Bug (Piezodorus guildinii).
Unravelling the details of range expansion and ecological dominance shifts of insect pests has been challenging due to the lack of basic knowledge about population structure, gene flow, and most importantly, how natural selection is affecting the adaptive process. Piezodous guildinii is an emerging pest of soybean in the southern region of the United States, and increasingly important in Brazil in recent years. However, the reasons P. guildinii is gradually becoming more of a problem are questions still mostly unanswered. Here, we have genotyped P. guildinii samples and discovered 1,337 loci containing 4,083 variant sites SNPs that were used to estimate genetic structure and to identify gene candidates under natural selection. Our results revealed the existence of a significant genetic structure separating populations according to their broad geographic origin, i.e., U.S. and Brazil, supported by AMOVA (FGT = 0.26), STRUCTURE, PCA, and FST analyses. High levels of gene flow or coancestry within groups (i.e., within countries) can be inferred from the data, and no spatial pattern was apparent at the finer scale in Brazil. Samples from different seasons show more heterogeneous compositions suggesting mixed ancestry and a more complex dynamic. Lastly, we were able to detect and successfully annotated 123 GBS loci (10.5%) under positive selection. The gene ontology (GO) analysis implicated candidate genes under selection with genome reorganization, neuropeptides, and energy mobilization. We discuss how these findings could be related to recent outbreaks and suggest how new efforts directed to better understand P. guildinii population dynamics.


Peripheral blood monocyte subsets predict antiviral response in chronic hepatitis C.
Hepatitis C virus infection evolves into chronic progressive liver disease in a significant percentage of patients. Monocytes constitute a diverse group of myeloid cells that mediate innate and adaptive immune response. In addition to proinflammatory CD16+ monocytes, a Tie-2+ subgroup - Tie-2 expressing monocytes (TEMs) - that has robust proangiogenic potential has been recently defined. To study the heterogeneity of peripheral blood monocytes in chronic hepatitis C (CHC) patients and to examine their proposed pathophysiological roles on disease progression and response to antiviral therapy. We studied CD16+ and Tie-2+ peripheral monocyte subpopulations in 21 healthy subjects and 39 CHC patients in various stages of disease and responses to antiviral treatment using flow cytometry. Expression profiles of proangiogenic and tissue remodelling factors in monocyte supernatants were measured using ELISA and protein arrays. Intrahepatic expression of CD14, CD31 and Tie-2 was analysed using immunofluorescence. Increases of certain peripheral monocyte subsets were observed in the blood of CHC patients, wherein those cells with proinflammatory (CD16+) or proangiogenic (TEMs) potential expanded (P < 0.005, both). Notably, TEMs were significantly increased in nonresponders, particularly those with lower CD16 expression. In addition, many angiogenic factors were differentially expressed by peripheral monocytes from control or CHC patients, such as angiopoietin-1 and angiogenin (P < 0.05). Interestingly, intrahepatic TEMs were distinguished within portal infiltrates of CHC patients. These findings suggest for the first time the relevance of peripheral monocytes phenotypes for the achievement of response to treatment. Hence, the study of monocyte subset regulation might effect improved CHC prognoses and adjuvant therapies.


A computational analysis of sonic booms penetrating a realistic ocean surface.
The last decade has seen a revival of sonic boom research, a direct result of the projected market for a new breed of supersonic passenger aircraft, its design, and its operation. One area of the research involves sonic boom penetration into the ocean, one concern being the possible disturbance of marine mammals from the noise generated by proposed high-speed civil transport (HSCT) flyovers. Although theory is available to predict underwater sound levels due to a sonic boom hitting a homogeneous ocean with a flat surface, theory for a realistic ocean, one with a wavy surface and bubbles near the surface, is missing and will be presented in this paper. First, reviews are given of a computational method to calculate the underwater pressure field and the effects of a simple wavy ocean surface on the impinging sonic boom. Second, effects are described for the implementation of three additional conditions: a sonic boom/ocean "wavelength" comparison, complex ocean surfaces, and bubbles near the ocean surface. Overall, results from the model suggest that the realistic ocean features affect the penetrating proposed HSCT sonic booms by modifying the underwater sound-pressure levels only about 1 decibel or less.


Limitations and vulnerabilities of the neonatal cardiovascular system: considerations for anesthetic management.
Development of the cardiovascular system through the last trimester of pregnancy and the subsequent neonatal period is profound. Morphological changes within the myocardium make the heart vulnerable to challenges such as fluid shifts and anesthetic drugs. The sensitivity of the myocardium to metabolic challenges and potential harm of drugs needed to maintain adequate blood pressure and cardiac output are highlighted. Traditional monitoring under anesthesia has focussed on maintaining oxygenation and heart rate in the neonate with less attention paid to blood pressure, cardiac output, and more importantly organ well-being. There is now a better understanding of the limitations of blood pressure homeostasis in the neonate and the potential consequences of marginal hypoperfusion. This article highlights some of these vulnerabilities particularly as they relate to anesthesia and surgery in the very young.


Structural and biomechanical basis of sexual dimorphism in femoral neck fragility has its origins in growth and aging.
The structural basis for sex differences in femoral neck (FN) fragility was studied in 1196 subjects and 307 patients with hip fracture. The absolute and relative patterns of modeling and remodeling on the periosteal and endocortical envelopes during growth and aging produce changes in FN geometry and structure that results in FN fragility in both sexes and sexual dimorphism in hip fracture risk in old age. Femoral neck (FN) fragility in old age is usually attributed to age-related bone loss, while the sex differences in hip fracture rate are attributed to less bone loss in men than in women. The purpose of this study was to define the structural and biomechanical basis underlying the increase in FN fragility in elderly men and women and the structural basis of sex differences in hip fracture incidence in old age. We measured FN dimensions and areal bone mineral density in 1196 healthy subjects (801 females) 18-92 years of age and 307 patients (180 females) with hip fracture using DXA. We then used the DXA-derived FN areal bone mineral density (BMD) and measured periosteal diameter to estimate endocortical diameter, cortical thickness, section modulus (a measure of bending strength), and buckling ratio (indices for structural stability). Neither FN cortical thickness nor volumetric density differed in young adult women and men after height and weight adjustment. The sex differences in geometry were confined to the further displacement of the cortex from the FN neutral axis in young men, which produced 13.4% greater bending strength than in young women. Aging amplified this geometric difference; widening of the periosteal and endocortical diameters continued in both sexes but was greater in men, shifting the cortex even further from the neutral axis maintaining bending strength in men, not in women. In both sexes, less age-related periosteal than endocortical widening produced cortical thinning increasing the risk for structural failure by local buckling of the enlarged thin walled FN. Relative to age-matched controls, women and men with hip fractures had reduced cortical thickness, but FN periosteal diameter was increased in women and reduced in men, differences are likely to be originated in growth. The absolute and relative patterns of modeling and remodeling on the periosteal and endocortical envelopes during growth and aging produce changes in FN diameters, cortical thickness, and geometry that results in FN fragility in both sexes and sexual dimorphism in hip fracture risk in old age.


Mitochondrial Protein Turnover Is Critical for Granulosa Cell Proliferation and Differentiation in Antral Follicles.
Granulosa cell (GC) proliferation is essential for follicular development. FSH is a key factor in GC proliferation, and a continuous supply of high levels of ATP is necessary for cell proliferation. However, genes encoding proteins of the glycolytic pathways are poorly expressed in GCs. Therefore, we hypothesized that mitochondrial gene expression and protein synthesis play a primary role in ATP production during GC proliferation. To test this hypothesis, we performed an in vivo study of GCs collected from 23-day-old mice ovaries with or without equine chorionic gonadotropin (eCG) priming. It was observed that mitochondrial activity with membrane potential, expression of protein-coding genes (Nd1-6, Cytb, Atpase6,8) and transcription-related genes (Polrmt, Tfam, Tfb2m), copy number of mitochondrial (mt-)DNA, and protein synthesis were increased in GCs after 24 hours of eCG injection and mostly maintained elevated up to 48 hours. Therefore, we performed in vitro culture of GCs in DMEM medium supplemented with FSH, testosterone, and serum and containing different glucose concentrations with or without d-chloramphenicol (CRP) for 24 hours. GC proliferation and ATP production were observed to be independent of glucose concentration. Furthermore, FSH-induced mitochondrial activity with membrane potential, ATP content, BrdU-incorporated cell proliferation, intensity of mt-ND1 and mt-ND6 proteins, and expressions of marker genes for proliferation and differentiation were significantly decreased by CRP treatment. These results revealed the crucial role of mitochondria in the supply of ATP and the necessity of mitochondrial gene expression and protein synthesis in not only the proliferation but also the differentiation of GCs during follicular development.


Genetic variability, combining ability and molecular diversity-based parental line selection for heterosis breeding in field corn (Zea mays L.).
The demand of maize crop is increasing day by day, hence to reduce the production and demand gap, there is a need to extract the high yielding parental lines to improve per se yield of the hybrids, which could help to enhance the productivity in maize crops. The present investigation was carried out to select the best medium maturing inbred lines, among a set of 118 inbred lines. Based on the Duncan multiple range test, out of 118 lines, 16 inbred lines were selected on the basis of its high yield per se and flowering time. The molecular diversity was carried out using SSR markers linked to heterotic QTL and up on diversity analysis it classified selected genotypes in to three distinct groups. Among the selected inbred lines, a wider genetic variability and molecular diversity were observed. A total of 39 test crosses were generated after classifying 16 inbred lines in to three testers and thirteen lines (based on per se grain yield and molecular diversity) and crossing them in line × tester manner. Combining ability analysis of these parental lines showed that female parents, PML 109, PML 110, PML 111, PML 114 and PML 116 showed additive effect for KRN and grain yield, whereas male parents, PML 46, and PML 93 showed epistatic effect for KRN and PML 102 showed epistatic effect for grain yield. The generated information in the present investigation may be exploited for heterosis breeding in filed corn. To tackle the balanced dietary requirement of Indian population; we focused to enhance the productivity of maize hybrids using genetically broad based, elite, diverse inbred lines. Combination of selection criterion, not only augment the productivity but also improves the quality of hybrid/s.


Adolescent marijuana and alcohol use: the role of parents and peers revisited.
The present study focuses on the role of deviant peers, parent child-rearing practices, and parent alcohol use in the initiation of marijuana and alcohol use during adolescence. Composite measures of Deviant Peers and Parental Monitoring were used that incorporate both the parents' and child's report of these variables as well as the parents' report of their own alcohol use and the adolescent's report of marijuana and alcohol use. Multiple regression analyses incorporating Parental Monitoring, Mother Alcohol Use, and Deviant Peers as independent variables revealed significant standardized b coefficients for Deviant Peers predicting alcohol use, and both Parental Monitoring and Deviant Peers predicting marijuana use. A profile analysis showed that delinquent drug users had lower parental monitoring and more deviant peers than nondelinquent drug users or abstainers. However, a group of youngsters were identified who reported some substance use but were not antisocial; these youngsters resembled abstainers in respect to the degree that they were monitored by parents and exposed to deviant peers. Taking these results into consideration, along with longitudinal studies on adolescent delinquency and adult alcoholism, it is hypothesized that adolescent delinquency and drug use are outcomes of disrupted family processes and exposure to deviant peers, and that adolescents who are both antisocial and use drugs may be at higher risk for eventual substance abuse.


A population ecology perspective on the functioning and future of health information organizations.
Increasingly, health care providers need to exchange information to meet policy expectations and business needs. A variety of health information organizations (HIOs) provide services to facilitate health information exchange (HIE). However, the future of these organizations is unclear. The aim of this study was to explore the environmental context, potential futures, and survivability of community HIOs, enterprise HIEs, and electronic health record vendor-mediated exchange using the population ecology theory. Qualitative interviews with 33 key informants representing each type of HIE organization were analyzed using template analysis. Community HIOs, enterprise HIEs, and electronic health record vendors exhibited a high degree of competition for resources, especially in the area of exchange infrastructure services. Competition resulted in closures in some areas. In response to environmental pressures, each organizational type was endeavoring to differentiate its services and unique use case, as well as pursing symbiotic relationships or attempting resource partitioning. HIOs compete for similar resources and are reacting to environmental pressures to better position themselves for continued survival and success. Our ecological research perspective helps move the discourse away from situation of a single exchange organization type toward a view of the broader dynamics and relationships of all organizations involved in facilitating HIE activities. HIOs are attempting to partition the environment and differentiate services. HIE options should not be construed as an "either/or" decision, but one where multiple and complementary participation may be required.


Sorting preference in children with autism: the dominance of concrete features.
The current study investigates preference to sort objects on the basis of either concrete or abstract features in children with and without autism. Participants were asked to sort a set of books into two groups that could be differentiated according to concrete (color, size) or abstract criteria (category membership: sports/games). The results showed that those with autism, unlike controls, were significantly more likely to sort according to a concrete criterion. In a further phase of testing, those with autism still did not sort according to abstract criteria, even when this was the only basis for sorting systematically. The findings are interpreted as evidence for a preference in autism to process concrete over abstract features of stimuli.


A Discriminative Single-Shot Segmentation Network for Visual Object Tracking.
Template-based discriminative trackers are currently the dominant tracking paradigm due to their robustness, but are restricted to bounding box tracking and a limited range of transformation models, which reduces their localization accuracy. We propose a discriminative single-shot segmentation tracker - D3S 2, which narrows the gap between visual object tracking and video object segmentation. A single-shot network applies two target models with complementary geometric properties, one invariant to a broad range of transformations, including non-rigid deformations, the other assuming a rigid object to simultaneously achieve robust online target segmentation. The overall tracking reliability is further increased by decoupling the object and feature scale estimation. Without per-dataset finetuning, and trained only for segmentation as the primary output, D3S 2 outperforms all published trackers on the recent short-term tracking benchmark VOT2020 and performs very close to the state-of-the-art trackers on the GOT-10k, TrackingNet, OTB100 and LaSoT. D3S 2 outperforms the leading segmentation tracker SiamMask on video object segmentation benchmarks and performs on par with top video object segmentation algorithms.


Nerve injuries about the elbow in the athlete.
The athlete's elbow is a remarkable example of motion, strength, and durability. The stress placed on the elbow during sport, including the throwing motion, may lead to soft-tissue ligamentous and nerve injury. The thrower's elbow illustrates one example of possible nerve injury about the elbow in sport, related to chronic repetitive tensile and compressive stresses to the ulnar nerve associated with elbow flexion and valgus position. Besides the throwing athlete, nerve injury from high-energy direct-impact forces may also damage nerves around the elbow in contact sports. Detailed history and physical examination can often make the diagnosis of most upper extremity neuropathies. The clinician must be aware of the possibility of isolated or combined nerve injury as far proximal as the cervical nerve roots, through the brachial plexus, to the peripheral nerve terminal branches. Electrodiagnostic studies are occasionally beneficial for diagnosis with certain nerves. Nonoperative management is often successful in most elbow and upper extremity neuropathies. If conservative treatment fails, then surgical treatment should address all potentially offending structures. In the presence of medial laxity and concurrent ulnar neuritis, the medial ulnar collateral ligament warrants surgical treatment, in addition to transposition of the ulnar nerve. The morbidity of open surgical decompression of nerves in and around the elbow is potentially career threatening in the throwing athlete. This mandates an assessment of the adequacy of the nonsurgical treatment and a thorough preoperative discussion of the risks and benefits of surgery.


Retinoic acid receptor γ (Rarg) and nuclear receptor subfamily 5, group A, member 2 (Nr5a2) promote conversion of fibroblasts to functional neurons.
Somatic cells can be reprogrammed to neurons and various other cell types with retrovirus or lentivirus. The limitation of this technology is that these genome-integration viruses may increase the risk of gene mutation and cause insertional mutagenesis. We recently found that non-integration adenovirus carrying neuronal transcription factors can induce fibroblasts to neurons. However, the conversion efficiency by the adenovirus is lower than that of the retrovirus or lentivirus. Therefore, it is crucial to identify other factors or chemical compounds to obtain neurons with high efficiency. In this study we show that the combination of Rarg (retinoic acid receptor γ) and Nr5a2 (nuclear receptor subfamily 5, group A, member 2; also known as Lrh-1 (liver receptor homologue 1)) rapidly promote the iN cell maturation within 1 week and greatly facilitate the conversion with neuronal purities of ∼50% and yields of >130%. They also improve neuronal pattern formation, electrophysiological characteristics, and functional integration in vivo. Moreover, the chemical compound agonists to Rarg and Nr5a2 function effectively as well. This approach may be used for the generation and application of iN cells in regenerative medicine.


Pyridoxamine, an inhibitor of advanced glycation reactions, also inhibits advanced lipoxidation reactions. Mechanism of action of pyridoxamine.
Maillard or browning reactions lead to formation of advanced glycation end products (AGEs) on protein and contribute to the increase in chemical modification of proteins during aging and in diabetes. AGE inhibitors such as aminoguanidine and pyridoxamine (PM) have proven effective in animal model and clinical studies as inhibitors of AGE formation and development of diabetic complications. We report here that PM also inhibits the chemical modification of proteins during lipid peroxidation (lipoxidation) reactions in vitro, and we show that it traps reactive intermediates formed during lipid peroxidation. In reactions of arachidonate with the model protein RNase, PM prevented modification of lysine residues and formation of the advanced lipoxidation end products (ALEs) N(epsilon)-(carboxymethyl)lysine, N(epsilon)-(carboxyethyl)lysine, malondialdehyde-lysine, and 4-hydroxynonenal-lysine. PM also inhibited lysine modification and formation of ALEs during copper-catalyzed oxidation of low density lipoprotein. Hexanoic acid amide and nonanedioic acid monoamide derivatives of PM were identified as major products formed during oxidation of linoleic acid in the presence of PM. We propose a mechanism for formation of these products from the 9- and 13-oxo-decadienoic acid intermediates formed during peroxidation of linoleic acid. PM, as a potent inhibitor of both AGE and ALE formation, may prove useful for limiting the increased chemical modification of tissue proteins and associated pathology in aging and chronic diseases, including both diabetes and atherosclerosis.


Psoriasis and Sleep Apnea: A Danish Nationwide Cohort Study.
Psoriasis and sleep apnea are associated with significant morbidity and mortality. Although both diseases have been linked with systemic inflammation, studies on their potential bidirectional association are lacking. We investigate the potential association between psoriasis and sleep apnea. All Danish citizens age 18 y or older between January 1, 1997 and December 31, 2011 (n = 5,522,190) were linked at individual level in nationwide registries. Incidence rates (IRs) per 10,000 person-years were calculated and incidence rate ratios (IRRs) adjusted for age, sex, socioeconomic status, smoking history, alcohol abuse, medication, and comorbidity were estimated by Poisson regression. There were 53,290, 6,885, 6,348, and 39,908 incident cases of mild psoriasis, severe psoriasis, psoriatic arthritis, and sleep apnea, respectively. IRRs (95% confidence interval) for sleep apnea were 1.30 (1.17-1.44), 1.65 (1.23-2.22), and 1.75 (1.35-2.26) in subjects with mild and severe psoriasis, and psoriatic arthritis, and IRRs for mild and severe psoriasis, and psoriatic arthritis in sleep apnea without continuous positive airway pressure (CPAP) therapy were 1.62 (1.41-1.86), 2.04 (1.47-2.82), and 1.94 (1.34-2.79), respectively. In patients with sleep apnea and CPAP therapy (i.e., severe sleep apnea) the IRRs were 1.82 (1.43-2.33), 3.27 (2.03-5.27), and 5.59 (3.74-8.37), respectively. Psoriasis was associated with increased risk of sleep apnea, and sleep apnea was associated with increased risk of psoriasis. The clinical significance of this bidirectional relationship warrants further study.


Dentin matrix protein 1 and dentin sialophosphoprotein in human sound and carious teeth: an immunohistochemical and colorimetric assay.
Dentin matrix protein 1 (DMP1) and dentin sialophosphoprotein (DSPP) are extracellular matrix proteins produced by odontoblasts involved in the dentin mineralization. The aim this study was to compare the distribution of DMP1 and DSPP in human sound dentin vs human sclerotic dentin. Sixteen sound and sixteen carious human molars were selected, fixed in paraformaldehyde and processed for immunohistochemical detection of DMP1 and DSPP by means of light microscopy, transmission electron microscopy (TEM) and high-resolution field emission in-lens scanning electron microscopy (FEI-SEM). Specimens were submitted to a pre-embedding or a post-embedding immunolabeling technique using primary antibodies anti DMP1 and anti-DSPP and gold-conjugated secondary antibodies. Other samples were processed for the detection of DMP1 and DSPP levels. Dentin from these samples was mechanically fractured to powder, then a protein extraction and a protein level detection assay were performed. DMP1 and DSPP were more abundant in carious than in sound samples. Immunohistochemical analyses in sclerotic dentin disclosed a high expression of DMP1 and DSPP inside the tubules, suggesting an active biomineralization of dentin by odontoblasts. Furthermore, the detection of small amounts of these proteins inside the tubules far from the carious lesion, as shown in the present study, is consistent with the hypothesis of a preventive defense of all dentin after a noxious stimulus has undermined the tooth.


Caveolin-1-mediated apolipoprotein A-I membrane binding sites are not required for cholesterol efflux.
Caveolin-1 (Cav1), a structural protein required for the formation of invaginated membrane domains known as caveolae, has been implicated in cholesterol trafficking and homeostasis. Here we investigated the contribution of Cav1 to apolipoprotein A-I (apoA-I) cell surface binding and intracellular processing using mouse embryonic fibroblasts (MEFs) derived from wild type (WT) or Cav1-deficient (Cav1(-/-)) animals. We found that cells expressing Cav1 have 2.6-fold more apoA-I binding sites than Cav1(-/-) cells although these additional binding sites are not associated with detergent-free lipid rafts. Further, Cav1-mediated binding targets apoA-I for internalization and degradation and these processes are not correlated to cholesterol efflux. Despite lower apoA-I binding, cholesterol efflux from Cav1(-/-) MEFs is 1.7-fold higher than from WT MEFs. Stimulation of ABCA1 expression with an LXR agonist enhances cholesterol efflux from both WT and Cav1(-/-) cells without increasing apoA-I surface binding or affecting apoA-I processing. Our results indicate that there are at least two independent lipid binding sites for apoA-I; Cav1-mediated apoA-I surface binding and uptake is not linked to cholesterol efflux, indicating that membrane domains other than caveolae regulate ABCA1-mediated cholesterol efflux.


The symptomatic adult flatfoot: Is there a relationship between severity and degree of pre-existing arthritis in the foot and ankle?
The acquired adult flatfoot deformity (AFFD) is a potentially debilitating foot condition with a prevalence thought to be between 3 %-10 %. To the authors' best knowledge, no association has been described between severity of AFFD and degree of pre-existing ankle or foot arthritis. The degree and pattern of preexisting ipsilateral arthritis of the foot and ankle was investigated in those with symptomatic AFFD presenting to hospital. Retrospective observational study between May 2015 and May 2018, of patients who presented to our tertiary clinic with symptomatic AFFD. Radiographs of one hundred and forty-eight (n=148) patients were reviewed, excluding those with charcot arthropathy, previous trauma or coalition. The primary outcome measure was severity of OA in the ankle, subtalar, talonavicular and calcaneocuboid joints. Secondary outcome was severity of radiographic planovalgus deformity. The independant variables used were age and severity of planovalgus deformity as measured by the Meary angle, calcaneal pitch and medial cuneiform-fifth metatarsal height. A linear regression model was carried out on the outcomes. Median age was 60.0 years (IQR 22). There were 56 males to 92 females, with 75 left sided deformities observed and 73 right sided. With increasing severity of planovalgus measurements, there was no significant association observed in severity of arthritis in the ankle joint (p = 0.766), subtalar joint (p = 0.090), talonavicular joint (p = 0.256) and calcaneocuboid joint (p = 0.091). With increasing age, there was significance observed in degree of ankle arthritis, subtalar, talonavicular and calcaneocuboid joints (p = 0.001). There was no significant correlation observed with age for the angular break of Meary's line (p = 0.73), calcaneal pitch (0.262) and medial cuneiform-fifth metatarsal height (p = 0.937). This observational study shows no significant association between severity of radiographic planovalgus deformity and pre-existing arthritis of the ankle, hindfoot and midtarsal joints.


It's a Long Way to the Top: Determinants of Developmental Pathways in Paralympic Sport.
The literature suggests that the current athlete development models do not reflect the multifaceted developmental pathways in Paralympic sport. This study aimed to analyze how parasport athletes progress through developmental phases of an athletic career pathway by comparing differences in their trajectories based on the nature of the impairment (acquired or congenital), age, and sex. A total of 345 para-athletes representing 15 sports completed an online survey. Results showed that the developmental phases for athletes with acquired impairment are of shorter duration, taking 4.5 years to progress from the attraction to the elite phase, while athletes with congenital impairment take 6 years. Athletes with congenital impairment start in parasport approximately 8 years younger and win medals in international competitions 7 years earlier than athletes with acquired impairment. Insights gathered in this study have the potential to enhance further thinking toward the genesis of specific models of para-athlete development.


[Quantitative assessment of the intensity of the invasion of Opisthorchis felineus in man].
Basing on calculated data, the authors have revealed a relationship between the efficacy of coproovoscopic methods of opisthorchiasis diagnosis and the intensity of invasion and amount of feces in the sample analyzed. The ranges of application of simple coproovoscopic methods were defined; among other things, the use of a simple Cato's method was validated for epidemiologic studies in a focus with the invasion intensity of more than 35-50 eggs in 1 g of feces.


Developmental Analysis of Mimulus Seed Transcriptomes Reveals Functional Gene Expression Clusters and Four Imprinted, Endosperm-Expressed Genes.
The double fertilization of the female gametophyte initiates embryogenesis and endosperm development in seeds via the activation of genes involved in cell differentiation, organ patterning, and growth. A subset of genes expressed in endosperm exhibit imprinted expression, and the correct balance of gene expression between parental alleles is critical for proper endosperm and seed development. We use a transcriptional time series analysis to identify genes that are associated with key shifts in seed development, including genes associated with secondary cell wall synthesis, mitotic cell cycle, chromatin organization, auxin synthesis, fatty acid metabolism, and seed maturation. We relate these genes to morphological changes in Mimulus seeds. We also identify four endosperm-expressed transcripts that display imprinted (paternal) expression bias. The imprinted status of these four genes is conserved in other flowering plants, suggesting that they are functionally important in endosperm development. Our study explores gene regulatory dynamics in a species with ab initio cellular endosperm development, broadening the taxonomic focus of the literature on gene expression in seeds. Moreover, it is the first to validate genes with imprinted endosperm expression in Mimulus guttatus, and will inform future studies on the genetic causes of seed failure in this model system.


Impact of endoscopic sinus surgery on the quality of life of patients with nasal polyposis.
Chronic sinusitis with polyposis (CSWP) is associated with high direct and indirect annual costs. This condition affects several aspects of daily life, and CSWP patients usually suffer from decreased quality of life (QOL). Treatment with functional endoscopic sinus surgery (FESS) is reported to improve the QOL of patients with CS. Here we evaluated the factors that affected QOL improvement in CSWP patients who were candidates for FESS. All patients with CSWP who were treated at the Imam Khomeini Hospital Complex in Tehan, Iran that were candidates for FESS were recruited. Patients with systemic or neurologic diseases that could affect their QOL were excluded. Clinical signs were recorded before and after FESS using the sinonasal outcome test (SNOT-22) and QOL questionnaires. The patient's history of allergic rhinitis, aspirin sensitivity, asthma and smoking was recorded. QOL and associations with clinical features were evaluated within twelve months after FESS. The study included 47 patients with a mean age of 39.5 +/- 15.4 years (61.7% women). FESS resulted in significant improvements in QOL based on the SNOT-22 and QOL questionnaires (p = 0.0001 for both). Septal deviation was the only single characteristic that was significantly associated with QOL improvements. FESS significantly improved the QOL of patients with CSWP. However, patients with septal deviation benefited the most from FESS.


Pulse oximetry screening for detection of congenital heart defects at 1646 m in Albuquerque, New Mexico.
To determine the false-positive rate of pulse oximetry screening at moderate altitude, presumed to be elevated compared with sea level values and assess change in false-positive rate with time. We retrospectively analysed 3548 infants in the newborn nursery in Albuquerque, New Mexico, (elevation 5400 ft) from July 2012 to October 2013. Universal pulse oximetry screening guidelines were employed after 24 hours of life but before discharge. Newborn babies between 36 and 36 6/7 weeks of gestation, weighing >2 kg and babies >37 weeks weighing >1.7 kg were included in the study. Log-binomial regression was used to assess change in the probability of false positives over time. Of the 3548 patients analysed, there was one true positive with a posteriorly-malaligned ventricular septal defect and an interrupted aortic arch. Of the 93 false positives, the mean pre- and post-ductal saturations were lower, 92 and 90%, respectively. The false-positive rate before April 2013 was 3.5% and after April 2013, decreased to 1.5%. There was a significant decrease in false-positive rate (p = 0.003, slope coefficient = -0.082, standard error of coefficient = 0.023) with the relative risk of a false positive decreasing at 0.92 (95% CI 0.88-0.97) per month. This is the first study in Albuquerque, New Mexico, reporting a high false-positive rate of 1.5% at moderate altitude at the end of the study in comparison to the false-positive rate of 0.035% at sea level. Implementation of the nationally recommended universal pulse oximetry screening was associated with a high false-positive rate in the initial period, thought to be from the combination of both learning curve and altitude. After the initial decline, it remained steadily elevated above sea level, indicating the dominant effect of moderate altitude.


Effect of calcium on RNA content in meristematic cells of pea (Pisum sativum L.) roots treated with toxic metals.
RNA content in nucleolus, nucleus and cytoplasm in meristematic cells of pea roots growing for 144 h in the presence of calcium and/or toxic metals (Cd2+, Cr3+, Pb2+) was examined using cytophotometric procedures, after staining with gallocyanine. The effect of treatment with tested metals was twofold: on the one hand, it considerably reduced RNA content in the nucleolus, on the other it enhanced RNA level in the nucleus and most visibly in the cytoplasm, resulting in the increase in total amount of RNA in cells of pea roots. The presence of calcium in metal solutions in different ways affected RNA content in meristematic cells of pea. In roots treated with cadmium, the addition of calcium ions diminished the toxic effect of that metal, as demonstrated by an increase in RNA content in the nucleolus, although reduction of RNA amount in the nucleus, cytoplasm and in whole cell was observed. A clearly stimulative effect of calcium was noted in material grown in the presence of chromium or lead, where a high increase in RNA content in nucleolus, nucleus and cytoplasm took place.


Sleep deprivation reduces perceived emotional intelligence and constructive thinking skills.
Insufficient sleep can adversely affect a variety of cognitive abilities, ranging from simple alertness to higher-order executive functions. Although the effects of sleep loss on mood and cognition are well documented, there have been no controlled studies examining its effects on perceived emotional intelligence (EQ) and constructive thinking, abilities that require the integration of affect and cognition and are central to adaptive functioning. Twenty-six healthy volunteers completed the Bar-On Emotional Quotient Inventory (EQi) and the Constructive Thinking Inventory (CTI) at rested baseline and again after 55.5 and 58 h of continuous wakefulness, respectively. Relative to baseline, sleep deprivation was associated with lower scores on Total EQ (decreased global emotional intelligence), Intrapersonal functioning (reduced self-regard, assertiveness, sense of independence, and self-actualization), Interpersonal functioning (reduced empathy toward others and quality of interpersonal relationships), Stress Management skills (reduced impulse control and difficulty with delay of gratification), and Behavioral Coping (reduced positive thinking and action orientation). Esoteric Thinking (greater reliance on formal superstitions and magical thinking processes) was increased. These findings are consistent with the neurobehavioral model suggesting that sleep loss produces temporary changes in cerebral metabolism, cognition, emotion, and behavior consistent with mild prefrontal lobe dysfunction.


Elevated CO2 increases plant uptake of organic and inorganic N in the desert shrub Larrea tridentata.
Resource limitations, such as the availability of soil nitrogen (N), are expected to constrain continued increases in plant productivity under elevated atmospheric carbon dioxide (CO(2)). One potential but under-studied N source for supporting increased plant growth under elevated CO(2) is soil organic N. In arid ecosystems, there have been no studies examining plant organic N uptake to date. To assess the potential effects of elevated atmospheric CO(2) on plant N uptake dynamics, we quantified plant uptake of organic and inorganic N forms in the dominant desert shrub Larrea tridentata under controlled environmental conditions. Seedlings of L. tridentata were grown in the Mojave Desert (NV, USA) soils that had been continuously exposed to ambient or elevated atmospheric CO(2) for 8 years at the Nevada Desert FACE Facility. After 6 months of growth in environmentally controlled chambers under ambient (380 micromol mol(-1)) or elevated (600 micromol mol(-1)) CO(2), pots were injected with stable isotopically labeled sole-N sources ((13)C-[2]-(15)N glycine, (15)NH(4) (+), or (15)NO(3) (-)) and moved back to their respective chambers for the remainder of the study. Plants were destructively harvested at 0, 2, 10, 24, and 49 days. Plant uptake of soil N derived from glycine, NH(4) (+), and NO(3) (-) increased under elevated CO(2) at days 2 and 10. Further, root uptake of organic N as glycine occurred as intact amino acid within the first hour after N treatment, indicated by approximately 1:1 M enrichment ratios of (13)C:(15)N. Plant N uptake responses to elevated CO(2) are often species-specific and could potentially shift competitive interactions between co-occurring species. Thus, physiological changes in root N uptake dynamics coupled with previously observed changes in the availability of soil N resources could impact plant community structure as well as ecosystem nutrient cycling under increasing atmospheric CO(2) levels in the Mojave Desert.


Disseminated malignancies masquerading as cardiovascular implantable electronic devices infections.
Disruption of a previously well-healed cardiovascular implantable electronic device (CIED) pocket is usually presumed to be secondary to infection and current guidelines recommend the removal of the generator and all leads. We present our experience of CIED pocket disruptions thought to be due to infection and referred to our institution for lead extraction but instead proved to be the first manifestations of disseminated malignancies. Out of 1001 consecutive patients referred to our institution for transvenous lead extraction, two patients were found to have CIED pocket disruptions due to metastatic deposits. In both cases, subjects presented with increased swelling and discomfort of CIED pockets during device follow-up without any signs or symptoms of sepsis and negative cultures. The cause was presumed to be due to infection as it is not uncommon for CIED pocket infections to be diagnosed based purely on clinical appearances of the pocket and negative cultures. Both CIED systems were successfully extracted. At the time of surgery, the scar tissue within the pockets was atypical and histological specimens were sent for analysis. This confirmed diffuse large-cell lymphoma and metastatic lung adenocarcinoma as the causes of CIED pocket disruption. Malignancy should be considered as a differential diagnosis in CIED pocket disruptions, particularly those associated with negative cultures and histological analysis of tissue specimens removed from the pocket should be considered at the time of CIED extraction.


Vaccines for children and adults with chronic lung disease: efficacy against acute exacerbations.
Acute exacerbations of chronic lung disease are usually associated with viral and bacterial pathogens. They contribute to declining lung function, poor quality of life and exert an excess burden on individuals, families, communities and the healthcare sector. Hence, preventing exacerbations is important in clinical management. Several vaccines providing protection against respiratory pathogens (Streptococcus pneumoniae, Bordetella pertussis and influenza) that can trigger exacerbations are available, but evidence to support their effectiveness in preventing exacerbations of chronic lung disease is limited. Candidate vaccines in pre-clinical or clinical development phases include those targeting Haemophilus influenzae, Moraxella catarrhalis, Staphylococcus aureus, Pseudomonas aeruginosa, respiratory syncytial virus and human rhinoviruses. However, it is likely to be several years before vaccines against these pathogens are available for children and adults with chronic lung diseases. For vaccination to play an important role in managing chronic lung disease efforts need to be directed at understanding how various pathogens cause exacerbations and alter long-term lung function.


Plasma tocopherol levels in term infants fed breast milk or proprietary formulae.
Plasma tocopherol levels were compared at 2 days and 2 weeks in 27 normal term infants fed breast milk or one of two proprietary formulae. Levels rose from cord values of approximately 0.6 to 1 mg/dl at 2 days and 1.6 mg/dl at 2 weeks. There were no significant differences between the three groups. Current levels of tocopherol supplementation in infant formulae result in plasma levels comparable to those achieved with breast milk in healthy term infants.


Feasibility and acceptability of using information visualizations to improve HIV-related communication in a limited-resource setting: a short report.
Infographics (visualizations that present information) can assist clinicians to offer health information to patients with low health literacy in an accessible format. In response, we developed an infographic intervention to enhance clinical, HIV-related communication. This study reports on its feasibility and acceptability at a clinical setting in the Dominican Republic. We conducted in-depth interviews with physicians who administered the intervention and patients who received it. We conducted audio-recorded interviews in Spanish using semi-structured interview guides. Recordings were professionally transcribed verbatim then analyzed using descriptive content analysis. Physician transcripts were deductively coded according to constructs of Bowen et al.'s feasibility framework and patient transcripts were inductively coded. Three physicians and 26 patients participated. Feasibility constructs endorsed by physicians indicated that infographics were easy to use, improved teaching, and could easily be incorporated into their workflow. Coding of patient transcripts identified four categories that indicated the intervention was acceptable and useful, offered feedback regarding effective clinical communication, and recommended improvements to infographics. Taken together, these data indicate our intervention was a feasible and acceptable way to provide clinical, HIV-related information and provide important recommendations for future visualization design as well as effective clinical communication with similar patient populations.


Do smokers support smoke-free laws to help themselves quit smoking? Findings from a longitudinal study.
A growing number of smokers support smoke-free laws. The theory of self-control provides one possible explanation for why smokers support laws that would restrict their own behaviour: the laws could serve as a self-control device for smokers who are trying to quit. To test the hypothesis that support for smoke-free laws predicts smoking cessation. We used longitudinal data (1999-2000) from a US national sample of adult smokers (n=6415) from the Current Population Survey, Tobacco Use Supplements. At baseline, smokers were asked whether they made a quit attempt in the past year. They were also asked whether they thought smoking should not be allowed in hospitals, indoor sporting events, indoor shopping malls, indoor work areas, restaurants, or bars and cocktail lounges. At 1-year follow-up, smokers were asked whether they had quit smoking. Smokers who supported smoke-free laws were more likely to have made a recent quit attempt. At 1-year follow-up, those who supported smoke-free laws in 4-6 venues were more likely to have quit smoking (14.8%) than smokers who supported smoke-free laws in 1-3 venues (10.6%) or smokers who supported smoke-free laws in none of the venues (8.0%). These differences were statistically significant in multivariate analyses controlling for demographics. Support for smoke-free laws among smokers correlates with past quit attempts and predicts future quitting. These findings are consistent with the hypothesis that some smokers support smoke-free laws because the laws could help them quit smoking.


Results of combined-modality therapy for limited-stage small cell lung carcinoma in the elderly.
A Phase III trial was conducted by the North Central Cancer Treatment Group to determine whether chemotherapy (etoposide and cisplatin) plus either twice-daily radiotherapy (BIDRT) or once-daily radiotherapy (QDRT) resulted in a better outcome for patients with limited-stage small cell lung carcinoma (LD-SCLC). No difference in survival was identified between the two arms. The current analysis examined the relation between age and outcome for patients treated during this trial. The current study included 263 patients with LD-SCLC and an Eastern Cooperative Oncology Group performance status of < or = 2 who were randomized to receive QDRT or split-course BIDRT. The outcomes of the 209 (79%) younger patients (age < 70 years old) were compared with the 54 (21%) elderly patients (age > or = 70 years old). Elderly patients presented with significantly greater weight loss and poorer performance status. The 2-year and 5-year survival rates were 48% and 22% for younger patients compared with 33% and 17% for older patients (P = 0.14). One specific toxicity (i.e., Grade > or = 4 pneumonitis [according to National Cancer Institute Common Toxicity Criteria]) occurred in 0% of those patients age < 70 years compared with 6% of older patients (P = 0.008). Grade 5 toxicity occurred in 1 of 209 (0.5%) patients age < 70 years compared with 3 of 54 (5.6%) older patients (P = 0.03). Despite having more weight loss, poorer performance status, increased pulmonary toxicity, and more deaths due to treatment, survival was not found to be significantly worse in older individuals. Fit elderly patients with LD-SCLC can receive combined-modality therapy with the expectation of relatively favorable long-term survival. Future research should focus on ways to decrease toxicity especially in the elderly.


Plasma Zonulin Levels in Childhood Nephrotic Syndrome.
Objective: We conducted this study to test the hypothesis that plasma zonulin levels are elevated in pediatric patients with nephrotic syndrome compared to healthy controls. Study Design: Plasma zonulin levels were measured by ELISA in 114 children enrolled in the NEPTUNE study. Clinical and laboratory data were retrieved from the NEPTUNE database. Results: The median age of the patients was 10 (IQR = 5 to 14) years, 59 were male, 64 had minimal change disease, 47 focal segmental glomerulosclerosis, median eGFR was 96 (IQR = 80 to 114) ml/min/1.73 m2, and median urine protein:creatinine ratio was 0.5 (IQR = 0.1 to 3.4) (g:g). The plasma zonulin level was 14.2 ± 5.0 vs. 10.2 ± 2.5 ng/ml in healthy adults in a report using the same assay kit, P = 0.0025. These findings were confirmed in an independent cohort of children with nephrotic syndrome compared to healthy age-matched controls, P = 0.01. Zonulin concentrations did not differ in children with minimal change disease vs. focal segmental glomerulosclerosis, frequently relapsing vs. steroid-dependent vs. steroid-resistant clinical course, and were not influenced by the immunosuppressive treatment regimen. There was no relationship between plasma zonulin levels and the absolute or percentage change in proteinuria from enrollment until the time of the zonulin assay. Conclusion: Plasma zonulin levels are elevated in childhood nephrotic syndrome regardless of level of proteinuria or specific treatment. The cause of the high plasma zonulin levels and whether zonulin contributes to glomerular injury requires further study.


Fertility restoration with spermatogonial stem cells.
This review evaluates the state of the art in terms of challenges and strategies used to restore fertility with spermatogonial stem cells retrieved from prepubertal boys affected by cancer. Although these boys do not yet produce spermatozoa, the only option to preserve their fertility is cryopreservation of spermatogonial stem cells in the form of testicular cell suspensions or whole tissue pieces. Different techniques have been described to achieve completion of spermatogenesis from human, spermatogonial stem cells but none is yet ready for clinical application. A crucial point to address is gaining a full understanding of spermatogonial stem cell niche pathophysiology, where germ cells undergo proliferation and differentiation. Various fertility restoration approaches will be presented depending on the presence of an intact niche, dissociated niche, or reconstituted niche. Testicular organoids open the way to providing further insights into the niche. They can recreate the three-dimensional architecture of the testicular microenvironment in vitro, allowing a large number of applications, from physiology to drug toxicity investigations. In addition to the full elucidation of the niche microenvironment, achieving fertility restoration from cryopreserved human spermatogonial stem cells implies overcoming other important challenges. Testicular organoids might prove to be essential tools to progress in this field.


β-alanine Supplementation Fails to Increase Peak Aerobic Power or Ventilatory Threshold in Aerobically Trained Males.
The purpose of the present study was to determine the effect of 30 days of β-alanine supplementation on peak aerobic power and ventilatory threshold (VT) in aerobically fit males. Fourteen males (28.8 ± 9.8 yrs) were assigned to either a β-alanine (SUPP) or placebo (PLAC) group; groups were matched for VT as it was the primary outcome measure. β-alanine supplementation consisted of 3 g/day for 7 days, and 6 g/day for the remaining 23 days. Before and after the supplementation period, subjects performed a continuous, graded cycle ergometry test to determine VO2 peak and VT. Metabolic data were analyzed using a 2 × 2 ANOVA with repeated measures. Thirty days of β-alanine supplementation (SUPP) did not increase VO2 peak (4.05 ± 0.6 vs. 4.14 ± 0.6 L/min) as compared to the placebo (PLAC) group (3.88 ± 0.2 vs. 3.97 ± 0.2 L/min) (p > .05). VT did not significantly improve in either the SUPP (3.21 ± 0.5 vs. 3.33 ± 0.5 L/min) or PLAC (3.19 ± 0.1 vs. 3.20 ± 0.1 L/min) group (p > .05). In conclusion, 30 days of β-alanine supplementation had no effect on VO2 peak or VT in aerobically trained athletes.


Prediction of the phase equilibria of methane hydrates using the direct phase coexistence methodology.
The direct phase coexistence method is used for the determination of the three-phase coexistence line of sI methane hydrates. Molecular dynamics (MD) simulations are carried out in the isothermal-isobaric ensemble in order to determine the coexistence temperature (T3) at four different pressures, namely, 40, 100, 400, and 600 bar. Methane bubble formation that results in supersaturation of water with methane is generally avoided. The observed stochasticity of the hydrate growth and dissociation processes, which can be misleading in the determination of T3, is treated with long simulations in the range of 1000-4000 ns and a relatively large number of independent runs. Statistical averaging of 25 runs per pressure results in T3 predictions that are found to deviate systematically by approximately 3.5 K from the experimental values. This is in good agreement with the deviation of 3.15 K between the prediction of TIP4P/Ice water force field used and the experimental melting temperature of ice Ih. The current results offer the most consistent and accurate predictions from MD simulation for the determination of T3 of methane hydrates. Methane solubility values are also calculated at the predicted equilibrium conditions and are found in good agreement with continuum-scale models.


Association between PGC-1alpha gene polymorphisms and type 2 diabetes risk: a case-control study of an Iranian population.
The peroxisome proliferator-activated receptor gamma coactivator-1alpha (PGC-1alpha) gene could play a role in the onset of type 2 diabetes mellitus. The aim of this study was to explore the possible associations among polymorphisms Gly482Ser, Thr394Thr and Thr528Thr of the PGC-1alpha gene and the risk of type 2 diabetes in Kurdish-Iranians. DNA specimens from all 173 type 2 diabetes subjects and 173 normoglycemic subjects were genotyped by the polymerase chain reaction-restriction fragment length polymorphism method. Genotypic and allelic frequencies were analyzed in each group. Serum lipids, fasting glucose, fasting serum insulin, homeostasis model assessment of insulin resistance and glycated hemoglobin levels were determined using the conventional methods. The data were analyzed using SPSS software. The GA genotype of Gly482Ser was associated with a significant susceptibility for type 2 diabetes (odds ratio 5.23, p<0.000). Furthermore, the GA genotype of Thr528Thr had a higher risk for type 2 diabetes (odds ratio 2.37, p<0.002). Normoglycemic persons carrying the GA+AA genotypes of Gly482Ser variation had significantly lower high-density lipoprotein cholesterol in comparison with persons having GG genotype. In comparison with GG genotype carriers, normoglycemic subjects carrying the GA+AA genotypes of Thr394Thr variation had significantly higher fasting blood sugar, fasting serum insulin and homeostasis model assessment of insulin resistance. Normoglycemic subjects with the GA+AA genotypes of Thr528Thr variation had significantly higher levels of low-density lipoprotein cholesterol compared with subjects having the GG genotype. Type 2 diabetes subjects carrying the GA+AA genotypes of this polymorphism had significantly higher waist-hip ratio in comparison with the GG genotype carriers. We also found that haplotype 394-GG/482-GA/528-GG of PGC-1alpha was significantly associated with higher risk of type 2 diabetes. Our findings revealed significant associations between PGC-1alpha Gly482Ser and Thr528Thr polymorphisms and type 2 diabetes in Kurdish-Iranians.


Differential expression of stress and immune response pathway transcripts and miRNAs in normal human endothelial cells subjected to fractionated or single-dose radiation.
Although modern radiotherapy technologies can precisely deliver higher doses of radiation to tumors, thus, reducing overall radiation exposure to normal tissues, moderate dose, and normal tissue toxicity still remains a significant limitation. The present study profiled the global effects on transcript and miR expression in human coronary artery endothelial cells using single-dose irradiation (SD, 10 Gy) or multifractionated irradiation (MF, 2 Gy × 5) regimens. Longitudinal time points were collected after an SD or final dose of MF irradiation for analysis using Agilent Human Gene Expression and miRNA microarray platforms. Compared with SD, the exposure to MF resulted in robust transcript and miR expression changes in terms of the number and magnitude. For data analysis, statistically significant mRNAs (2-fold) and miRs (1.5-fold) were processed by Ingenuity Pathway Analysis to uncover miRs associated with target transcripts from several cellular pathways after irradiation. Interestingly, MF radiation induced a cohort of mRNAs and miRs that coordinate the induction of immune response pathway under tight regulation. In addition, mRNAs and miRs associated with DNA replication, recombination and repair, apoptosis, cardiovascular events, and angiogenesis were revealed. Radiation-induced alterations in stress and immune response genes in endothelial cells contribute to changes in normal tissue and tumor microenvironment, and affect the outcome of radiotherapy.


Temporomandibular Disorders among Dutch Adolescents: Prevalence and Biological, Psychological, and Social Risk Indicators.
To assess the prevalence rates of pain-related temporomandibular disorders (TMDs) and temporomandibular joint (TMJ) sounds in a large group of Dutch adolescents, aged between 12 and 18 years and to determine if the same biological, psychological, and social risk indicators are related to both TMD pain and TMJ sounds. In this cross-sectional questionnaire survey, 4,235 questionnaires were analyzed, with an about equal gender distribution. The overall prevalence of pain-related TMDs was 21.6% (26.1% for girls and 17.6% for boys) and that of TMJ sounds was 15.5% (19.3% for girls and 11.7% for boys). Logistic regression analyses revealed that the following variables appeared to be the strongest predictors of TMD pain: female gender, increasing age, sleep bruxism, biting on lips and/or cheeks, stress, and feeling sad. Regarding self-reported TMJ sounds, the multiple regression model revealed that female gender, increasing age, awake bruxism, and biting on lips and/or cheeks were the strongest predictors. TMDs are a common finding among Dutch adolescents. Except for the psychological factors that appeared to be associated with TMD pain only, pain-related TMDs and TMJ sounds shared similar biological risk indicators.


Enhanced osteogenesis of multilayered pore-closed microsphere-immobilized hydroxyapatite scaffold via sequential delivery of osteogenic growth peptide and BMP-2.
Since many complex physiological processes are controlled by multiple biomolecules, comprehensive regulation of bone tissue regeneration may be more effectively achieved by administering more than one type of biofactor. Thus, we propose a novel bone tissue engineering scaffold incorporating a multiple peptide-based drug delivery vehicle for accelerated bone regeneration. Pore-closed poly(lactic-co-glycolic acid) (PLGA) microspheres with a surface structure of multilayer polyelectrolytes ((Ha-Cs)2-Hep-BMP-2-Hep-(Cs-Ha)2) were prepared as multi-barrier microcarriers for osteogenic growth peptide (OGP). In addition, BMP-2 loading was achieved via a pore-closing process and layer-by-layer (LbL) assembly technique, followed by immobilization on the surface of a highly interconnected porous hydroxyapatite (HA) scaffold. On the basis of such a construction, sequential delivery of OGP and BMP-2 occurred in a coordinated manner through an orchestrated sequence of spatial changes, targeting different bone healing stages. The in vitro studies showed that OGP release was minimal (<11.7%) in the first 15 d but accelerated remarkably thereafter, while at least 56.3% of BMP-2 payload was released at this time and subsequent release was only marginal. In addition, scaffolds carrying dual-biofactor exhibited a stronger ability to induce bone marrow mesenchymal stem cell (BMSC) differentiation toward osteoblasts than those incorporating OGP or BMP-2 alone and factor-free scaffolds in terms of alkaline phosphatase (ALP) activity and osteogenic gene and protein (Runx2, COL I, and OCN) expression. The results of in vitro cell culturing demonstrated the roles of BMP-2 in osteogenic differentiation early as well as the effect of OGP on accelerated proliferation and maturation of osteoblast precursors at a later stage. Further in vivo osteogenesis studies also revealed that the dual biofactor-loaded scaffold manifested the best repair efficacy due to a potential synergistic effect of BMP-2 and OGP. Collectively, our findings suggested that such a dual delivery system may provide a therapeutic strategy sequentially targeting multiple events or mechanisms during bone healing and was proved to be a promising therapeutic scaffold for future use in bone tissue regeneration.


Yield of repeated screening for abdominal aortic aneurysm after a 4-year interval. Aneurysm Detection and Management Veterans Affairs Cooperative Study Investigators.
Little is known about the rate at which new abdominal aortic aneurysms (AAAs) develop or whether screening older men for AAA, if undertaken, should be limited to once in a lifetime or repeated at intervals. A large population of veterans, aged 50 through 79 years, completed a questionnaire and underwent ultrasound screening for AAA. Of these, 5151 without AAA on the initial ultrasound (defined as infrarenal aortic diameter of 3.0 cm or larger) were selected randomly to be invited for a second ultrasound screening after an interval of 4 years. Local records and national databases were searched to identify deaths and AAA diagnoses made during the study interval in subjects who did not attend the rescreening. Of the 5151 subjects selected for a second screening, 598 (11.6%) had died (none due to AAA), and 20 (0.4%) had an interim diagnosis of AAA. A second screening was performed on 2622 (50.9%), of whom 58 (2.2%; 95% confidence interval, 1.6%-2.8%) had new AAA. Three new AAAs were 4.0 to 4.9 cm, 10 were 3.5 to 3.9 cm, and 45 were 3.0 to 3.4 cm. Independent predictors of new AAA at the second screening included current smoker (odds ratio, 3.09; 95% confidence, 1.74-5.50), coronary artery disease (odds ratio, 1.81; 95% confidence interval, 1.07-3.07), and, in a separate model using a composite variable, any atherosclerosis (odds ratio, 1.97; 95% confidence interval, 1.16-3.35). Adding the interim and rescreening diagnosis rates suggests a 4-year incidence rate of 2.6%. Rescreening only in subjects with infrarenal aortic diameter of 2.5 cm or greater on the initial ultrasound would have missed more than two thirds of the new AAAs. A second screening is of little practical value after 4 years, mainly because the AAAs detected are small. However, the incidence that we observed suggests that a second screening after longer intervals (ie, more than 8 years) may provide yields similar to those seen in initial screening and therefore warrants further study.


Evidence for inhibition of fusion of lysosomal and prelysosomal compartments with phagosomes in macrophages infected with pathogenic Mycobacterium avium.
Bone marrow-derived cultured macrophages were infected with the pathogenic organism Mycobacterium avium. Immediately after infection and at 1 to 28 days later, cells either were stained for acid phosphatase activity or given horseradish peroxidase, which served as a pinocytotic marker. With the former, fusions between phagosomes and lysosomes exclusively were assessed; with the latter, those between phagosomes and both pinosomes and lysosomes were determined. As a control, similar experiments were undertaken by infecting macrophages with gamma ray-killed M. avium and the nonpathogenic live organisms Mycobacterium aurum and Bacillus subtilis. After infection with live M. avium, fusions between phagosomes and acid phosphatase-positive vesicles (lysosomes) were inhibited. The same inhibition was observed whether phagosomes contained damaged or structurally intact (presumed to be live) bacteria, except for the early time points. This inhibition was, however, partial, suggesting that some of the live bacteria are resistant to the hydrolytic enzymes of the phagolysosomal environment. Fusions between horseradish peroxidase-positive vesicles (pinosomes and lysosomes) and phagosomes depended upon the morphological state of the bacteria. Damaged bacteria did not inhibit fusions, whereas with intact bacteria, a partial inhibition which increased with time was observed. The two types of experiment suggest that viable M. avium can impair phagosome-pinosome fusions.