Management of type 2 diabetes mellitus in the elderly: role of the pharmacist in a multidisciplinary health care team.
Intensive glycemic control using insulin therapy may be appropriate for many healthy older adults to reduce premature mortality and morbidity, improve quality of life, and reduce health care costs. However, frail elderly people are more prone to develop complications from hypoglycemia, such as confusion and dementia. Overall, older persons with type 2 diabetes mellitus are at greater risk of death from cardiovascular disease (CVD) than from intermittent hyperglycemia; therefore, diabetes management should always include CVD prevention and treatment in this patient population. Pharmacists can provide a comprehensive medication review with subsequent recommendations to individualize therapy based on medical and cognitive status. As part of the patient's health care team, pharmacists can provide continuity of care and communication with other members of the patient's health care team. In addition, pharmacists can act as educators and patient advocates and establish patient-specific goals to increase medication effectiveness, adherence to a medication regimen, and minimize the likelihood of adverse events.


Tactile suppression in goal-directed movement.
Sharing numerous characteristics with suppression in the other senses, tactile suppression is a reliable phenomenon that accompanies movement. By investigating the simplest of movements (e.g., finger flexions), early research tried to explain the origins of the phenomenon in terms of motor command generation together with sensory reafference. Here, we review recent research that has delved into (naturalistic) goal-directed movements. In connection with goal-directed movement, tactile suppression is evident as a decrease in behavioural performance measured shortly prior to, and during, movement execution. It is also reflected in a consistent response bias highlighting the (perceptual) uncertainty of the movement. Goal-directed movement supports the forward model and establishes contextual influences as the defining influences on tactile suppression. Depending on the task at hand, people prioritize a certain percept during movement. Future research, we argue, should focus on studying naturalistic movements, or sequences of movements, that share a common meaning or goal.


Alcohol consumption and risk of prostate cancer: The Harvard Alumni Health Study.
Although many studies suggest that consumption of alcohol increases the risk of several site-specific cancers, the evidence remains unclear for prostate cancer. Few data exist on beverage-specific associations as well as lifetime patterns of alcohol consumption and prostate cancer risk. We prospectively followed 7612 Harvard alumni (mean age 66.6 years) from 1988 through 1993, during which 366 cases of incident prostate cancer occurred. Self-reported alcohol consumption was assessed at baseline from wine, beer, and liquor intake. Previous assessments during college and in 1977 were also available. Overall, the mean total alcohol consumption in 1988 was 123.1 g/week, of which 28.6% was from wine, 15.8% from beer, and 55.6% from liquor. Compared to men reporting almost never drinking alcohol in 1988, the multivariate relative risks (95% CI) for 1 drink/month to < 3 drinks/week, 3 drinks/week to < 1 drink/ day, 1 to < 3 drinks/day, and > or = 3 drinks/day were 1.33 (0.88-2.01), 1.65 (1.12-2.44), 1.85 (1.29-2.64), and 1.33 (0.86-2.05), respectively. Wine or beer consumption was unassociated with prostate cancer; however, moderate liquor consumption was associated with a significant 61-67% increased risk of prostate cancer (P, non-linear trend < 0.001). Men initiating alcohol consumption between 1977 and 1988 had a twofold increased risk of prostate cancer compared to men with almost no alcohol consumption at both times. In contrast to the majority of previous studies, we found a positive association between moderate alcohol consumption and the risk of prostate cancer. Liquor, but not wine or beer, consumption was positively associated with prostate cancer.


Biofunctional Activities of Equisetum ramosissimum Extract: Protective Effects against Oxidation, Melanoma, and Melanogenesis.
Equisetum ramosissimum, a genus of Equisetaceae, is a medicinal plant that can be separated into ethyl acetate (EA), dichloromethane (DM), n-hexane (Hex), methanol (MeOH), and water extracts. EA extract was known to have potent antioxidative properties, reducing power, DPPH scavenging activity, and metal ion chelating activity. This study compared these five extracts in terms of their inhibiting effects on three human malignant melanomas: A375, A375.S2, and A2058. MTT assay presented the notion that both EA and DM extracts inhibited melanoma growth but did not affect the viabilities of normal dermal keratinocytes (HaCaT) or fibroblasts. Western blot analyses showed that both EA and DM extracts induced overexpression of caspase proteins in all three melanomas. To determine their roles in melanogenesis, this study analyzed their in vitro suppressive effects on mushroom tyrosinase. All extracts except for water revealed moderate suppressive effects. None of the extracts affected B16-F10 cells proliferation. EA extract inhibited cellular melanin production whereas DM extract unexpectedly enhanced cellular pigmentation in B16-F10 cells. Data for modulations of microphthalmia-associated transcription factor, tyrosinase, tyrosinase-related protein 1, and tyrosinase-related protein 2 showed that EA extract inhibited protein expression mentioned above whereas DM extract had the opposite effect. Overall, the experiments indicated that the biofunctional activities of EA extract contained in food and cosmetics protect against oxidation, melanoma, and melanin production.


The stability of the Parental Bonding Instrument over a 20-year period.
The Parental Bonding Instrument (PBI) measures the perception of being parented to the age of 16 years. Low scores on the care dimension and high scores on the overprotection dimension are considered to be risk factors of depression. While the PBI has been shown to be a reliable and valid instrument, the stability of the PBI over extended periods (taking into account individual characteristics and life experience) needs to be demonstrated. The PBI was measured in a non-clinical cohort on four waves between 1978 and 1998, along with a series of self-report measures including state depression and neuroticism. Differences in PBI change over time were examined by gender, lifetime major depression diagnosis, and life event variables, as well as by scores on neuroticism and state depression. Acceptable retest coefficients on PBI scores over the 20-year study were found for the cohort. No differences were found in PBI scores over time on the variables examined, including sex and depression measures. The results indicate long-term stability of the PBI over time. The influences of mood state and life experience appear to have little effect on the stability of the perception of parenting as measured by the PBI. The present study increases confidence in the PBI as a valid measure of perceived parenting over extended time periods.


Three-dimensional anatomy and renal concentrating mechanism. II. Sensitivity results.
A mathematical model has been developed to simulate hypertonic urine formation in the renal medulla. The model uses published values of membrane transport parameters, as have other models, but is unique in its representation of the three-dimensional anatomy of the medulla. The model successfully predicts measured fluid flows, osmolarities, and NaCl and urea concentrations. The model results are presented in the companion to this paper [A. S. Wexler, R. E. Kalaba, D. J. Marsh. Am. J. Physiol. 260 (Renal Fluid Electrolyte Physiol. 29): F368-F383, 1991.]. In this paper we provide tests of the sensitivity of model performance to variations in the description of the anatomy and in membrane transport parameters. From these studies we conclude that 1) strict counterflow arrangements are required in the outer stripe to prevent loss of NaCl to the systemic circulation, 2) the radial organization in the inner stripe materially improves performance of the inner medulla, 3) radial organization of the inner medulla is essential to hypertonic urine formation there, 4) the model is most sensitive to variation in collecting duct parameters, and 5) reabsorption of urea in the distal tubule improves system performance. The results support the claim that the three-dimensional structure, as captured in the model, provides a crucial framework for the production of hypertonic urine.


Role of SARA (SMAD anchor for receptor activation) in maintenance of epithelial cell phenotype.
By inducing epithelial-to-mesenchymal transition (EMT), transforming growth factor-beta (TGF-beta) promotes cancer progression and fibrosis. Here we show that expression of the TGF-beta receptor-associated protein, SARA (Smad anchor for receptor activation), decreases within 72 h of exposure to TGF-beta and that this decline is both required and sufficient for the induction of several markers of EMT. It has been suggested recently that expression of the TGF-beta signaling mediators, Smad2 and Smad3, may have different functional effects, with Smad2 loss being more permissive for EMT progression. We find that the loss of SARA expression leads to a concomitant decrease in Smad2 expression and a disruption of Smad2-specific transcriptional activity, with no effect on Smad3 signaling or expression. Further, the effects of inducing the loss of Smad2 mimic those of the loss of SARA, enhancing expression of the EMT marker, smooth muscle alpha-actin. Smad2 mRNA levels are not affected by the loss of SARA. However, the ubiquitination of Smad2 is increased in SARA-deficient cells. We therefore examined the E3 ubiquitin ligase Smurf2 and found that although Smurf2 expression was unaltered in SARA-deficient cells, the interaction of Smad2 and Smurf2 was enhanced. These results describe a significant role for SARA in regulating cell phenotype and suggest that its effects are mediated through modification of the balance between Smad2 and Smad3 signaling. In part, this is achieved by enhancing the association of Smad2 with Smurf2, leading to Smad2 degradation.


Estimation of the total parasite biomass in acute falciparum malaria from plasma PfHRP2.
In falciparum malaria sequestration of erythrocytes containing mature forms of Plasmodium falciparum in the microvasculature of vital organs is central to pathology, but quantitation of this hidden sequestered parasite load in vivo has not previously been possible. The peripheral blood parasite count measures only the circulating, relatively non-pathogenic parasite numbers. P. falciparum releases a specific histidine-rich protein (PfHRP2) into plasma. Quantitative measurement of plasma PfHRP2 concentrations may reflect the total parasite biomass in falciparum malaria. We measured plasma concentrations of PfHRP2, using a quantitative antigen-capture enzyme-linked immunosorbent assay, in 337 adult patients with falciparum malaria of varying severity hospitalised on the Thai-Burmese border. Based on in vitro production rates, we constructed a model to link this measure to the total parasite burden in the patient. The estimated geometric mean parasite burden was 7 x 10(11) (95% confidence interval [CI] 5.8 x 10(11) to 8.5 x 10(11)) parasites per body, and was over six times higher in severe malaria (geometric mean 1.7 x 10(12), 95% CI 1.3 x 10(12) to 2.3 x 10(12)) than in patients hospitalised without signs of severity (geometric mean 2.8 x 10(11), 95% CI 2.3 x 10(11) to 3.5 x 10(11); p < 0.001). Parasite burden was highest in patients who died (geometric mean 3.4 x 10(12), 95% CI 1.9 x 10(12) to 6.3 x 10(12); p = 0.03). The calculated number of sequestered parasites increased with disease severity and was higher in patients with late developmental stages of P. falciparum present on peripheral blood smears. Comparing model and laboratory estimates of the time of sequestration suggested that admission to hospital with uncomplicated malaria often follows schizogony-but in severe malaria is unrelated to stage of parasite development. Plasma PfHRP2 concentrations may be used to estimate the total body parasite biomass in acute falciparum malaria. Severe malaria results from extensive sequestration of parasitised erythrocytes.


Health indicators in the European regions--ISARE II.
Most comparisons of health data in Europe take place at the national level. However, there is increased interest in looking at health data at a sub-national level. This is because of the increased importance in many European countries, of regions and devolved powers to them. This study aimed to establish the availability of health data at a regional level and to construct an experimental database. Using a network of country correspondents, data were collected on a series of topics from all the regions of that country. In addition, a supplementary list of data was collected from one region of each country. Out of the then 15 Member States of the European Union (EU), 14 countries participated in the study. Thirteen countries were able to supply data. Where data were available, using the criteria we developed, these were of relatively good quality. Data on mortality was most readily available, but data on the important public health topics such as obesity was much more difficult to obtain, and absent in many cases. It is possible to construct a database and a resultant set of indicators for relevant sub-national areas of Member States in the EU. This is not likely to be achieved through current routine data collection systems unless significant changes are made to the data collection processes such as those undertaken by Eurostat. There is, also, an urgent need to introduce comprehensive sub-national data collections on important public health topics such as obesity and smoking.


Characterization of hMTr1, a human Cap1 2'-O-ribose methyltransferase.
Cellular eukaryotic mRNAs are capped at their 5' ends with a 7-methylguanosine nucleotide, a structural feature that has been shown to be important for conferring mRNA stability, stimulating mRNA biogenesis (splicing, poly(A) addition, nucleocytoplasmic transport), and increasing translational efficiency. Whereas yeast mRNAs have no additional modifications to the cap, called cap0, higher eukaryotes are methylated at the 2'-O-ribose of the first or the first and second transcribed nucleotides, called cap1 and cap2, respectively. In the present study, we identify the methyltransferase responsible for cap1 formation in human cells, which we call hMTr1 (also known as FTSJD2 and ISG95). We show in vitro that hMTr1 catalyzes specific methylation of the 2'-O-ribose of the first nucleotide of a capped RNA transcript. Using siRNA-mediated knockdown of hMTr1 in HeLa cells, we demonstrate that hMTr1 is responsible for cap1 formation in vivo.


Fluorogenic nanoreactor assembly with boosted sensing kinetics for timely imaging of cellular hydrogen peroxide.
The precise detection of endogenous H2O2 has been considered to be a useful tool for understanding cell physiology. Here, we have developed a nanoreactor co-incorporated with a H2O2-responsive fluorogenic molecule and a catalytic additive. The fast sensing kinetics allows us to visualize a subcellular response in real-time.


Patients' perceptions of quality of care at an emergency department and identification of areas for quality improvement.
This paper reports a study to identify patient's perceptions of quality of care at an emergency department and areas for quality improvement. Patients are not always satisfied with the care received at emergency departments. More attention needs to be paid to the specific needs and expectations of the non-urgent group of patients, who make up the majority of attenders at many emergency departments. Nurses' and physicians' perceptions about good quality of care do not always agree with patients' perceptions. Instruments measuring patient satisfaction have often been focused on inpatient treatment. A prospective, descriptive survey design was adopted and the study took place in one emergency department at a Swedish university hospital in 2002. The participants were 99 women and 101 men, with an average age of 51 years. The emergency department version of the questionnaire Quality from the Patient's Perspective was used for data collection. Patients estimated quality of care at the emergency department as fairly good, but there were areas in need of improvement. A high percent of inadequate quality was related to the environment in the emergency department. About 20% of patients reported that they did not receive effective pain relief. More than 20% estimated that nurses did not show an interest in their life situation and patients did not receive useful information on self-care and about which physician was responsible for their medical care. The use of a research-based instrument gave valuable information for quality improvement in clinical practice. Many of the identified areas for quality improvement are related to nursing care. Therefore, the importance of nursing care in the emergency department should be highlighted to nurses and physicians and they also need to be more attentive to the need of the individual patient. Identifying areas for quality improvements are important, to know where to take action. These findings may facilitate the work with changing attitudes and working routines, which are needed to deliver effective care and to improve patients' perceptions of quality of care at emergency departments.


The role of synchronised low frequency activity in globus pallidus interna in dystonia.
Here we explore how abnormal spatio-temporal patterning of neuronal activity in the pallidum may contribute to dystonia. A critical feature of this abnormal patterning seems to be excessive synchronisation of neuronal activity over a 4-10 Hz frequency band. This is most readily apparent as fluctuation in the local field potential in this frequency band. Such activity correlates with the level of dystonic muscle activity and is concentrated in the internal segment of the globus pallidus, which is also the optimum surgical target in dystonia. It remains to be seen whether the abnormal low frequency activity is associated with dystonia through an abnormal processing of afferent information in the pallidum or to a more direct influence on the motor drive to dystonic muscles, which involves, at least in part, similar frequencies.


Analysis of repeated low-dose challenge studies.
Preclinical evaluation of candidate human immunodeficiency virus (HIV) vaccines entails challenge studies whereby non-human primates such as macaques are vaccinated with either an active or control vaccine and then challenged (exposed) with a simian-version of HIV. Repeated low-dose challenge (RLC) studies in which each macaque is challenged multiple times (either until infection or some maximum number of challenges is reached) are becoming more common in an effort to mimic natural exposure to HIV in humans. Statistical methods typically employed for the testing for a vaccine effect in RLC studies include a modified version of Fisher's exact test as well as large sample approaches such as the usual log-rank test. Unfortunately, these methods are not guaranteed to provide a valid test for the effect of vaccination. On the other hand, valid tests for vaccine effect such as the exact log-rank test may not be easy to implement using software available to many researchers. This paper details which statistical approaches are appropriate for the analysis of RLC studies, and how to implement these methods easily in SAS or R.


Effect of administration of malathion for 14 days on macrophage function and mast cell degranulation.
Previous studies have shown that acute, oral administration of malathion modulated the humoral immune response to T-cell-dependent antigen, mitogenic responses, macrophage function, and mast cell degranulation. While administration of malathion for 14 days did not affect the generation of an immune response to antigen, it was possible that macrophage and mast cell functions were affected. In this report, the effect of malathion administration for 14 days upon these parameters were assessed. This treatment regimen increased the respiratory burst capacity to a maximal level at a dose of 1 mg/kg/day or greater. The effect of oral administration of malathion for 14 days on the degranulation of mast cells in various organs (heart, skin, and small intestine) and peritoneal lavage fluid was also assessed. At doses of 1 mg/kg/day and above, the number of mast cells that was undegranulated decreased and the number that was severely degranulated increased. There was no change in mast cell integrity in biopsies from heart and skin, and in peritoneal fluid after 14-day administration of 0.1 mg/kg/day. However, the number of mast cells associated with the small intestine that had undergone degranulation was increased at this dose of malathion. These data indicate that repeated administration of malathion increased macrophage function at doses as low as 1 mg/kg/day and led to mast cell degranulation at doses as low as 0.1 mg/kg/day.


Increased nitric oxide synthase activity and expression in the hypothalamus of hindlimb unloaded rats.
Upon return from spaceflight or resumption of normal posture after bed rest, individuals often exhibit cardiovascular deconditioning. Although the mechanisms responsible for cardiovascular deconditioning have yet to be fully elucidated, alterations within the central nervous system have been postulated to be involved. The paraventricular nucleus (PVN) and supraoptic nucleus (SON) of the hypothalamus are important brain regions in control of sympathetic outflow and body fluid homeostasis. Nitric oxide (NO) modulates the activity of PVN and SON neurons, and alterations in NO transmission within these brain regions may contribute to symptoms of cardiovascular deconditioning. The purpose of the present study was to examine nitric oxide synthase (NOS) activity and expression in the PVN and SON of control and hindlimb unloaded (HU) rats, an animal model of cardiovascular deconditioning. The number of neurons exhibiting NOS activity as assessed by NADPH-diaphorase staining was significantly greater in the PVN but not SON of HU rats. Western blot analysis revealed that neuronal NOS (nNOS) but not endothelial NOS (eNOS) protein expression was higher in the PVN of HU rats. In the SON, there was a strong trend for an increase in nNOS (p=0.052) and a significant increase in eNOS expression in HU rats. Our results suggest that increased nNOS in the PVN contributes to autonomic and humoral alterations following cardiovascular deconditioning. In contrast, the functional significance of increases in nNOS and eNOS protein in the SON may be related to alterations in vasopressin release observed previously in HU rats.


Geminate recombination of hydrated electrons in liquid-to-supercritical water studied by ultrafast time-resolved spectroscopy.
Hydrated electrons were prepared by multi-photon ionization of neat water with 266 nm light. Using femtosecond pump-probe spectroscopy the dynamics of geminate recombination of the solvated electrons were studied over a wide temperature (296 K ≤T≤ 660 K) and density (0.18 g cm(-3)≤ρ≤ 1.00 g cm(-3)) range extending from the liquid well into the supercritical phase of water. The probability that hydrated electrons escape an initial recombination was found to strongly decrease with increasing temperature. In contrast, the isothermal density-dependence of this survival probability above the critical temperature was surprisingly weak. The peculiar dependence of the initial electron annihilation process on the thermodynamic state variables is discussed in terms of the Onsager model for initial recombination of ion pairs and an effective shielding of the electrostatic interactions of the recombining partners. A finite escape probability for a dielectric constant approaching unity can be interpreted by the existence of a minor fraction of highly mobile electrons created via autoionization.


Dnmt3a and Dnmt3b Associate with Enhancers to Regulate Human Epidermal Stem Cell Homeostasis.
The genome-wide localization and function of endogenous Dnmt3a and Dnmt3b in adult stem cells are unknown. Here, we show that in human epidermal stem cells, the two proteins bind in a histone H3K36me3-dependent manner to the most active enhancers and are required to produce their associated enhancer RNAs. Both proteins prefer super-enhancers associated to genes that either define the ectodermal lineage or establish the stem cell and differentiated states. However, Dnmt3a and Dnmt3b differ in their mechanisms of enhancer regulation: Dnmt3a associates with p63 to maintain high levels of DNA hydroxymethylation at the center of enhancers in a Tet2-dependent manner, whereas Dnmt3b promotes DNA methylation along the body of the enhancer. Depletion of either protein inactivates their target enhancers and profoundly affects epidermal stem cell function. Altogether, we reveal novel functions for Dnmt3a and Dnmt3b at enhancers that could contribute to their roles in disease and tumorigenesis.


Stuck at home: Housing demand during the COVID-19 pandemic.
The COVID-19 pandemic induced an increase in both the amount of time that households spend at home and the share of expenditures allocated to at-home consumption. These changes coincided with a period of rapidly rising house prices. We interpret these facts as the result of stay-at-home shocks that increase demand for goods consumed at home as well as the homes that those goods are consumed in. We first test the hypothesis empirically using US cross-county panel data and instrumental variables regressions. We find that counties where households spent more time at home experienced faster increases in house prices. We then study various pandemic shocks using a heterogeneous agent model with general equilibrium in housing markets. Stay-at-home shocks explain around half of the increase in model house prices in 2020. Lower mortgage rates explain around one third of the price rise, while unemployment shocks and fiscal stimulus have relatively small effects on house prices. We find that young households and first-time home buyers account for much of the increase in housing demand during the pandemic, but they are largely crowded out of the housing market by the equilibrium rise in house prices.


Water supplementation of infants in the first month of life.
To describe the prevalence of and risk factors associated with regular water supplementation of neonates. Evaluation of data from the Food and Drug Administration's Infant Feeding Practices Study, a panel study of US women of fairly high socioeconomic status who were followed up from late pregnancy through their infants' first year of life. The sample was drawn from a nationally distributed consumer mail panel. Each mother was asked whether she gave her neonate water at least 3 times per week. A total of 1677 mothers of infants who were neonates in April through November 1993. Percentages of mothers who gave their neonates water at least 3 times a week, considering infant feeding status, mother's education, and family income. About one fourth (24.7%) of the mothers reported giving their neonates water at least 3 times per week. Stratification by feeding practices and socioeconomic factors revealed that 41.6% of mothers who formula-fed their neonates, 47.4% of mothers with less than a high school education, and 35.4% of mothers with an annual family income less than $22,500 gave their neonates water at least 3 times per week. Water supplementation of neonates was a prevalent practice in this cohort of women. Feeding practices, maternal education, and family income were all significant risk factors associated with this behavior.


Tobacco Smoking and the Fecal Microbiome in a Large, Multi-ethnic Cohort.
Increasing evidence suggests that tobacco smoking, a well-known driver of carcinogenesis, influences the gut microbiome; however, these relationships remain understudied in diverse populations. Thus, we performed an analysis of smoking and the gut microbiome in a subset of 803 adults from the multi-ethnic NYU FAMiLI study. We assessed fecal microbiota using 16S rRNA gene sequencing, and clustered samples into Amplicon Sequence Variants using QIIME2. We evaluated inferred microbial pathway abundance using PICRUSt. We compared population β-diversity, and relative taxonomic and functional pathway abundance, between never smokers, former smokers, and current smokers. We found that the overall composition of the fecal microbiome in former and current smokers differs significantly from that of never smokers. The taxa Prevotella and Veillonellaceae were enriched in current and former smokers, whereas the taxa Lachnospira and Tenericutes were depleted, relative to never smokers. These shifts were consistent across racial and ethnic subgroups. Relative to never smokers, the abundance of taxa enriched in current smokers were positively correlated with the imputed abundance of pathways involving smoking-associated toxin breakdown and response to reactive oxygen species (ROS). Our findings suggest common mechanisms of smoking associated microbial change across racial subgroups, regardless of initial microbiome composition. The correlation of these differentials with ROS exposure pathways may suggest a role for these taxa in the known association between smoking, ROS and carcinogenesis. Smoking shifts in the microbiome may be independent of initial composition, stimulating further studies on the microbiome in carcinogenesis and cancer prevention.


Relationship between landing strategy and patellar tendinopathy in volleyball.
The aetiology of patellar tendinopathy (jumper's knee) remains unclear. To see whether landing strategy might be a risk factor for the development of this injury, this study examined whether landing dynamics from drop jumps differed among healthy volleyball players (CON) and volleyball players with a jumper's knee. The patients with jumper's knee were divided into an asymptomatic group with a previous jumper's knee (PJK) and a symptomatic group with a recent jumper's knee (RJK). Inverse dynamics analyses were used to estimate lower extremity joint dynamics from 30, 50 and 70 cm drop jumps in the three groups (CON, n = 8; PJK, n = 7; RJK, n = 9). A univariate repeated measures analysis of variance was used to compare the different landing techniques. Data analysis of the landing dynamics revealed that PJK showed higher knee angular velocities (p<0.01), and higher ankle plantar flexion moment loading rate (p<0.01). Furthermore, strong tendencies of higher loading rate of vertical ground reaction force (p = 0.05) and higher knee extensor moment loading rate (p = 0.08) were found compared with CON. Higher values for peak knee moment, peak knee power and knee work (all p<0.01) were found for CON compared with RJK. The comparison of the two jumper's knee groups yielded higher knee angular velocities (p<0.01), together with higher ankle plantar flexion and knee extensor moment loading rate (p<0.01 and p<0.05, respectively). Where RJK used a landing technique to avoid high patellar tendon loading, PJK used a stiffer landing strategy, which may be a risk factor in the development of patellar tendinopathy.


Economic Assimilation and Skill Acquisition: Evidence From the Occupational Sorting of Childhood Immigrants.
We study the economic assimilation of childhood immigrants to the United States. The linguistic distance between English and the predominant language in one's country of birth interacted with age at arrival is shown to be closely connected to occupational sorting in adulthood. By applying big-data techniques to occupations' detailed skill requirements, we provide evidence that childhood immigrants from English-distant countries who arrived after the primary school years reveal comparative advantages in tasks distinct from those for which (close to) Anglophone immigrants are better suited. Meanwhile, those who arrive at younger ages specialize in a bundle of skills very similar to that supplied by observationally equivalent workers. These patterns emerge even after we net out the effects of formal education. Such findings are compatible with the existence of different degrees of complementarity between relative English-learning potential at arrival and the acquisition of multiple capabilities demanded in the U.S. labor market (math/logic, socioemotional, physical, and communication skills). Consistent with the investment-complementarity argument, we show that linguistic distance and age at arrival also play a significant role on the choice of college major within this population.


Characteristics of crashes that increase the risk of serious injuries.
The advent of Automatic Crash Notification Systems (ACN) offers the possibility of immediately locating crashes and of determining the crash characteristics by analyzing the data transmitted from the vehicle. A challenge to EMS decision makers is to identify those crashes with serious injuries and deploy the appropriate rescue and treatment capabilities. The objective of this paper is to determine the crash characteristics that increase the risk of serious injury. Within this paper, regression models are presented which relate occupant, vehicle and impact characteristics to the probability of serious injury using the Maximum Abbreviated Injury Scale Level (MAIS). The accuracy of proposed models were evaluated using National Automotive Sampling System/ Crashworthiness Data System (NASS/CDS) and Crash Injury Research and Engineering Network (CIREN) case data. Cumulatively, the positive prediction rate of models identifying the likelihood of MAIS3 and higher injuries was 74.2%. Crash mode has a significant influence of injury risk. For crashes with 30 mph deltaV, the risk of MAIS3+ injury for each mode is 38.9%, 83.8%, 47.8% and 19.9% for frontal, near side, far side and rear impact crashes, respectively. In addition to deltaV, a number of crash variables were identified that assist in the accurate prediction of the probability of MAIS 3+ injury. These variables include occupant age, partial ejection, safety belt usage, intrusion near the occupant, and crashes with a narrow object. For frontal crashes, added crash variables include air bag deployment, steering wheel deformation, and multiple impact crashes. The quantitative relationship between each of these crash variables and injury risk has been determined and validated by regression analysis based on NASS/CDS and CIREN data.


Effects of a long-term inhalation of fragrances on the stress-induced immunosuppression in mice.
The aim of this study was to determine the effects of the long-term application of various fragrances on the suppression of immune response induced by high-pressure stress in mice. The immune response was analyzed based on plaque-forming cell (PFC) count, using mice sensitized with sheep red blood cells. The decreased PFC involving thymic involution induced by high-pressure stress in mice was restored by exposing the stressed mice to tuberose, lemon, oakmoss and labdanum for 24 h following exposure to stress. The decreased PFC and thymic involution from stress were restored by exposure to lemon and oakmoss, but not to tuberose and labdanum when the mice were exposed to those fragrances continuously for 3 weeks before the stress was given, followed by exposure to the same fragrances for 24 h after the stress. The decreased PFC and thymic involution from stress were restored by exposure to lemon and labdanum for 24 h after the stress, but not to tuberose over 3 weeks before the stress was given. These data suggest that the neuroimmunomodulatory effects of fragrances may be affected by tolerance depending on the kinds of fragrances in the case of a long-term application.


Safeguarding the provision of ecosystem services in catchment systems.
A narrow technocentric focus on a few favored ecosystem services (generally provisioning services) has led to ecosystem degradation globally, including catchment systems and their capacities to support human well-being. Increasing recognition of the multiple benefits provided by ecosystems is slowly being translated into policy and some areas of practice, although there remains a significant shortfall in the incorporation of a systemic perspective into operation management and decision-making tools. Nevertheless, a range of ecosystem-based solutions to issues as diverse as flooding and green space provision in the urban environment offers hope for improving habitat and optimization of beneficial services. The value of catchment ecosystem processes and their associated services is also being increasingly recognized and internalized by the water industry, improving water quality and quantity through catchment land management rather than at greater expense in the treatment costs of contaminated water abstracted lower in catchments. Parallel recognition of the value of working with natural processes, rather than "defending" built assets when catchment hydrology is adversely affected by unsympathetic upstream development, is being progressively incorporated into flood risk management policy. This focus on wider catchment processes also yields a range of cobenefits for fishery, wildlife, amenity, flood risk, and other interests, which may be optimized if multiple stakeholders and their diverse value systems are included in decision-making processes. Ecosystem services, particularly implemented as a central element of the ecosystem approach, provide an integrated framework for building in these different perspectives and values, many of them formerly excluded, into commercial and resource management decision-making processes, thereby making tractable the integrative aspirations of sustainable development. This can help redress deeply entrenched inherited assumptions, habits, and vested interests, replacing them in many management situations with wider recognition of the multiple values of ecosystems and their services. Global interest in taking an ecosystem approach is promoting novel scientific and policy thinking, yet there is a shortfall in its translation into practical management tools. Professional associations may have key roles to play in breaking down barriers to the "mainstreaming" of systemic perspectives into common practice, particularly through joining u different sectors of society essential to their implementation and ongoing adaptive management.


p53 haplotype determination in breast cancer.
Inheritance of certain germ line haplotypes consisting of three biallelic polymorphisms of p53 has been proposed as a risk factor for breast cancer and colorectal cancer [A. Själander et al., Carcinogenesis (Lond.), 17: 1313-1316, 1996, and Carcinogenesis (Lond.), 16: 1461-1464, 1995]. In their studies, pairwise haplotypes of these three polymorphisms were estimated. Extended haplotypes were further projected from the pairwise combinations. To overcome the necessity to estimate pairwise and extended haplotype frequencies, a PCR method has been developed to determine the absolute extended p53 haplotypes in diploid genomes. The method requires allele-specific PCR, confirmed by restriction analysis, and successive amplicon analysis. It has been applied to a nested case-control study of breast cancer (284 subjects; 99 cases and 185 controls; 182 Caucasians, 56 Hispanics, and 46 African-Americans). Evidence is presented that minor variants of the intron 3, codon 72, and intron 6 polymorphisms were moderately elevated in Caucasian breast cancer cases (intron 3, P = 0.03 for genotype and P = 0.01 for allelic frequency; codon 72, P = 0.07 for genotype and P = 0.054 for allelic frequency; and intron 6, P = 0.02 for genotype and P = 0.02 for allele frequency). Accordingly, analysis of haplotype distributions suggested an association of minor p53 haplotypes with breast cancer risk in Caucasians (P = 0.07). The relative allelic frequencies in breast cancer cases compared with controls also differed by age and menopausal status; the 1-2-1 haplotype was overrepresented in postmenopausal cases (P = 0.02) and cases older than 50 years (P = 0.02), whereas the other minor haplotypes (1-1-2 and rare variants) were overrepresented in premenopausal cases (P = 0.003) and cases 50 years of age and younger (P = 0.02). Genotype distributions at each locus and for all control groups were consistent with Hardy-Weinberg equilibria. Differences in haplotype distribution were associated with ethnicity (Caucasians versus African-Americans and Caucasians versus Hispanics, P < 0.001). The new haplotyping method may be useful in the study of gene-environment interactions.


The concentration data of fluoride and health risk assessment in drinking water in the Ardakan city of Yazd province, Iran.
According to the World Health Organization (WHO) reports, Iran is located in the global fluoride belts, so that is why carrying out extended research on this contaminant anion in water supplies must be considered. Due to the various industries in the Ardakan city, this region is severely suffering from fluoride contamination. This study was designed to investigate the fluoride concentration and its distribution pattern as well as related health risk assessment in groundwater resources of 28 villages of the Ardakan city in Yazd province using SPADNS method according to standard instructions. Our results show that, the average concentration of fluoride was 2.92 mg/l (range: 0.9-6 mg/l), also in half of the villages, the concentration range of this element was over than standard level (1.5 mg/l) given by WHO rules. In addition, risk assessment results showed that HQ value is higher than 1 in 46.4% of samples of groundwater resources in age groups of infants, children, teenagers and adults. Therefore, it is necessary to take measures to reduce fluoride concentration in drinking water in order to control resultant fluorosis. Actions should be implemented to enhance monitoring of fluoride levels to avoid the potential risk of high Fluoride concentration.


Criminal Activity or Treatable Health Condition? News Media Framing of Opioid Analgesic Abuse in the United States, 1998-2012.
Opioid analgesic abuse is a complex and relatively new public health problem, and to date little is known about how the news media frame the issue. To better understand how this issue has been framed in public discourse, an analysis was conducted of the volume and content of news media coverage of opioid analgesic abuse over a 15-year period from 1998 to 2012 (N=673 news stories). A 70-item structured coding instrument was used to measure items in four domains that prior research suggests can influence public attitudes about health and social issues: causes, solutions, and consequences of the problem and individual depictions of persons who abuse opioid analgesics. Although experts have deemed opioid analgesic abuse a public health crisis, results of our study suggest that the news media more often frame the problem as a criminal justice issue. The most frequently mentioned cause of the problem was illegal drug dealing, and the most frequently mentioned solutions were law enforcement solutions designed to arrest and prosecute the individuals responsible for diverting opioid analgesics onto the illegal market. Prevention-oriented approaches, such as prescription drug-monitoring programs, were mentioned more frequently in the latter years of the study period, but less than 5% of news stories overall mentioned expanding substance abuse treatment, and even fewer mentioned expanding access to evidence-based medication-assisted treatments, such as buprenorphine. Findings underscore the need for a concerted effort to reframe opioid analgesic abuse as a treatable condition addressable via well-established public and behavioral health approaches.


How predation and landscape fragmentation affect vole population dynamics.
Microtine species in Fennoscandia display a distinct north-south gradient from regular cycles to stable populations. The gradient has often been attributed to changes in the interactions between microtines and their predators. Although the spatial structure of the environment is known to influence predator-prey dynamics of a wide range of species, it has scarcely been considered in relation to the Fennoscandian gradient. Furthermore, the length of microtine breeding season also displays a north-south gradient. However, little consideration has been given to its role in shaping or generating population cycles. Because these factors covary along the gradient it is difficult to distinguish their effects experimentally in the field. The distinction is here attempted using realistic agent-based modelling. By using a spatially explicit computer simulation model based on behavioural and ecological data from the field vole (Microtus agrestis), we generated a number of repeated time series of vole densities whose mean population size and amplitude were measured. Subsequently, these time series were subjected to statistical autoregressive modelling, to investigate the effects on vole population dynamics of making predators more specialised, of altering the breeding season, and increasing the level of habitat fragmentation. We found that fragmentation as well as the presence of specialist predators are necessary for the occurrence of population cycles. Habitat fragmentation and predator assembly jointly determined cycle length and amplitude. Length of vole breeding season had little impact on the oscillations. There is good agreement between our results and the experimental work from Fennoscandia, but our results allow distinction of causation that is hard to unravel in field experiments. We hope our results will help understand the reasons for cycle gradients observed in other areas. Our results clearly demonstrate the importance of landscape fragmentation for population cycling and we recommend that the degree of fragmentation be more fully considered in future analyses of vole dynamics.


Accelerated Training of Skilled Birth Attendants in a Marginalized Population on the Thai-Myanmar Border: A Multiple Methods Program Evaluation.
To evaluate a skilled birth attendant (SBA) training program in a neglected population on the Thai-Myanmar border, we used multiple methods to show that refugee and migrant health workers can be given effective training in their own environment to become SBAs and teachers of SBAs. The loss of SBAs through resettlement to third countries necessitated urgent training of available workers to meet local needs. All results were obtained from student records of theory grades and clinical log books. Qualitative evaluation of both the SBA and teacher programs was obtained using semi-structured interviews with supervisors and teachers. We also reviewed perinatal indicators over an eight-year period, starting prior to the first training program until after the graduation of the fourth cohort of SBAs. Four SBA training programs scheduled between 2009 and 2015 resulted in 79/88 (90%) of students successfully completing a training program of 250 theory hours and 625 supervised clinical hours. All 79 students were able to: achieve pass grades on theory examination (median 80%, range [70-89]); obtain the required clinical experience within twelve months; achieve clinical competence to provide safe care during childbirth. In 2010-2011, five experienced SBAs completed a train-the-trainer (TOT) program and went on to facilitate further training programs. Perinatal indicators within Shoklo Malaria Research Unit (SMRU), such as place of birth, maternal and newborn outcomes, showed no significant differences before and after introduction of training or following graduate deployment in the local maternity units. Confidence, competence and teamwork emerged from qualitative evaluation by senior SBAs working with and supervising students in the clinics. We demonstrate that in resource-limited settings or in marginalized populations, it is possible to accelerate training of skilled birth attendants to provide safe maternity care. Education needs to be tailored to local needs to ensure evidence-based care of women and their families.


Cardiovascular manifestations of sickle cell disease.
Sickle cell disease (SCD) is the most frequent genetic haemoglobinopathy worldwide. Early childhood mortality has dramatically decreased in high-income countries, and most patients now survive beyond the 5th decade. However, in the aging SCD population, the morbidity related to chronic organ damage, especially kidney and heart, has become a major concern. While pulmonary hypertension has attracted most attention, it appears that this condition is frequently linked to left heart failure (HF). Accordingly, SCD-associated cardiomyopathy is emerging as a major cause of reduced quality of life and early mortality in these patients. The diagnosis of this particular phenotype of high-output HF is challenging. Exercise intolerance and dyspnoea in SCD patients are linked to multiple causes including chronic anaemia. Moreover, echocardiographic features are unusual and can be misinterpreted. The classical diagnosis algorithm for HF is generally not suitable in SCD patients, and HF is poorly recognized and mostly diagnosed at a late congestive stage in routine practice. Such patients need to be identified at an earlier stage of myocardial dysfunction via improved phenotyping. This constitutes the first step towards further investigations in SCD needed to improve the prognosis and the quality of life. This article provides an updated review of the recent advances in the pathophysiology and diagnosis, and in addition, perspectives of new therapeutic approaches in SCD-related cardiac manifestations.


Conditional Born-Oppenheimer Dynamics: Quantum Dynamics Simulations for the Model Porphine.
We report a new theoretical approach to solve adiabatic quantum molecular dynamics halfway between wave function and trajectory-based methods. The evolution of a N-body nuclear wave function moving on a 3N-dimensional Born-Oppenheimer potential-energy hyper-surface is rewritten in terms of single-nuclei wave functions evolving nonunitarily on a 3-dimensional potential-energy surface that depends parametrically on the configuration of an ensemble of generally defined trajectories. The scheme is exact and, together with the use of trajectory-based statistical techniques, can be exploited to circumvent the calculation and storage of many-body quantities (e.g., wave function and potential-energy surface) whose size scales exponentially with the number of nuclear degrees of freedom. As a proof of concept, we present numerical simulations of a 2-dimensional model porphine where switching from concerted to sequential double proton transfer (and back) is induced quantum mechanically.


A usability study of a computerized decision aid to help patients with, early stage papillary thyroid carcinoma in, decision-making on adjuvant radioactive iodine treatment.
We tested the usability of a patient-directed decision aid (DA), intended for patients with early stage papillary thyroid carcinoma (PTC) deciding to accept or reject adjuvant radioactive iodine (RAI) treatment. This decision is complicated by uncertainty of the medical evidence relating to potential treatment benefits. The DA was tested by 12 thyroid cancer survivors, 7 thyroid specialty physicians, and 30 lay individuals with no history of thyroid cancer. The participants completed the System Usability Scale for human-computer interaction questionnaire. The medical knowledge of lay participants was assessed before and after DA exposure. Qualitative participant feedback was obtained by thinking aloud during DA use, as well as from interviews. Participants generally found the usability of the DA acceptable. The DA significantly increased medical knowledge. In spite of some physicians' concerns about disclosure of treatment controversy and evidence uncertainty, it was found to be acceptable to non-physicians. A computerized DA on RAI treatment is acceptable to physicians and non-physicians and can improve medical knowledge. In counseling patients about complex medical decisions, disclosure of uncertainty related to medical evidence may be acceptably conveyed using a DA.


A scoping review of studies on the health impact of electronic nicotine delivery systems.
We conducted a scoping review of studies on health outcomes from electronic nicotine delivery systems (ENDS). The objective was to identify, narratively synthesize, assess the strength and quality of evidence and critically appraise studies that have reported disease end points associated with the use of ENDS. We included published literature on the health impact of ENDS from 01/01/2015 until 01/02/2020 following the PRISMA guidelines using PubMed, Embase, Scopus and Google Scholar. The database search identified 755 studies, and other sources 265; 37 studies met final eligibility criteria. Levels of evidence included 24(65%) cross-sectional, one (2.7%) case-control and six (16%) case studies, four (11%) cohort studies, one (2.7%) randomized controlled trial (RCT) and one (2.7%) meta-analysis; 27(73%) studies reported only on harms, eight (22%) reported on benefits, two (2%) on benefits and harms. Quality ratings were poor in 20 (54%), fair in 9(24%) and good in 8(22%) of studies. In our review, ENDS was not shown to be causative for harmful cardiovascular disease (CVD) outcomes and shown to be beneficial for hypertensive patients. Switching from cigarettes to e-cigarettes resulted in reduced exacerbations of chronic obstructive pulmonary disease (COPD), with no evidence of long-term deterioration in lung function. Mental Health, cancer and mortality were not adequately studied to form any consensus. Our review has not demonstrated ENDS to be causative of harmful CVD outcomes; furthermore switching from cigarettes to e-cigarettes was associated with improved hypertensive control and reduced exacerbations of COPD, with no evidence of increased asthma risk or long-term respiratory harm. Mental health, cancer and mortality outcomes have not been adequately studied to form a conclusion. Overall, the findings of our review did not provide evidence to counter the consensus held by many that ENDS use is safer than the risks posed from smoking cigarettes.


Canine thyroid carcinoma.
Malignant thyroid carcinomas are relatively common in dogs. The majority of tumors are unilateral and nonfunctional. Before deciding on treatment options, it is important to determine whether the tumor is freely moveable or fixed and invasive into adjacent tissues. Thyroidectomy is recommended for unilateral, mobile thyroid carcinomas. Radiation therapy or radioactive iodine therapy are recommended for dogs with invasive or bilateral thyroid carcinomas. The role of adjunctive chemotherapy is poorly defined, but should be considered in dogs with high-risk tumors, such as large or bilateral thyroid carcinomas. The prognosis is good following surgical treatment of mobile thyroid tumors and irradiation of fixed thyroid carcinomas, with median survival times greater than 3 years.


Reflections in a stock pond: are anthropogenically derived freshwater ecosystems natural, artificial, or something else?
"A skyscraper is as natural as a bird's nest" -Alan Watts. For millennia, people have altered freshwater ecosystems directly through water development and indirectly by global change and surrounding land-use activities. In these altered ecosystems, human impacts can be subtle and are sometimes overlooked by the people who manage them. This article provides two case studies near Boulder, Colorado that demonstrate how perceptions regarding these ecosystems affect their management. These examples are typical of lakes and streams along the Front Range of Colorado that are simultaneously natural and social in origin. Although natural, many of the region's freshwater ecosystems are affected by ongoing ecologic, hydrologic, chemical, and geomorphic modifications produced by human activity. People and nature are both active participants in the production of these freshwater ecosystems. The concept of "hybridity," borrowed from geographers and social scientists, is useful for describing landscapes of natural and social origin. Hybrid freshwater ecosystems are features of the humanized landscape and are derived from deliberate cultural activities, nonhuman physical and biological processes, and incidental anthropogenic disturbance. Our perceptions of "natural" freshwater ecosystems and what definitions we use to describe them influences our view of hybrid systems and, in turn, affects management decisions regarding them. This work stresses the importance of understanding the underlying societal forces and cultural values responsible for the creation of hybrid freshwater ecosystems as a central step in their conservation and management.


SET domain proteins modulate chromatin domains in eu- and heterochromatin.
The SET domain is a 130-amino acid, evolutionarily conserved sequence motif present in chromosomal proteins that function in modulating gene activities from yeast to mammals. Initially identified as members of the Polycomb- and trithorax-group (Pc-G and trx-G) gene families, which are required to maintain expression boundaries of homeotic selector (HOM-C) genes, SET domain proteins are also involved in position-effect-variegation (PEV), telomeric and centromeric gene silencing, and possibly in determining chromosome architecture. These observations implicate SET domain proteins as multifunctional chromatin regulators with activities in both eu- and heterochromatin--a role consistent with their modular structure, which combines the SET domain with additional sequence motifs of either a cysteine-rich region/zinc-finger type or the chromo domain. Multiple functions for chromatin regulators are not restricted to the SET protein family, since many trx-G (but only very few Pc-G) genes are also modifiers of PEV. Together, these data establish a model in which the modulation of chromatin domains is mechanistically linked with the regulation of key developmental loci (e.g. HOM-C).


Synthesis and phototoxicity of isomeric 7,9-diglutathione pyrrole adducts: Formation of reactive oxygen species and induction of lipid peroxidation.
Pyrrolizidine alkaloids (PAs) are hepatotoxic, genotoxic, and carcinogenic in experimental animals. Because of their widespread distribution in the world, PA-containing plants are probably the most common poisonous plants affecting livestock, wildlife, and humans. Upon metabolism, PAs generate reactive dehydro-PAs and other pyrrolic metabolites that lead to toxicity. Dehydro-PAs are known to react with glutathione (GSH) to form 7-GSH-(+/-)-6,7-dihydro-7-hydroxy-1-hydroxymethyl-5H-pyrrolizine (7-GS-DHP) in vivo and in vitro and 7,9-diGS-DHP in vitro. To date, the phototoxicity of GS-DHP adducts has not been well studied. In this study, we synthesized 7-GS-DHP, a tentatively assigned 9-GS-DHP, and two enantiomeric 7,9-diGS-DHP adducts by reaction of dehydromonocrotaline with GSH. The two 7,9-diGS-DHPs were separated by high performance liquid chromatography (HPLC) and their structures were characterized by 1H nuclear magnetic resonance (NMR) and 1H-1H correlation spectroscopy (COSY) NMR spectral analysis. Photoirradiation of 7-GS-DHP, 9-GS-DHP, and the two 7,9-diGS-DHPs as well as dehydromonocrotaline, dehydroheliotrine, and the 7-R enantiomer of DHP (DHR), by UVA light at 0 J/cm2, 14 J/cm2, and 35 J/cm2 in the presence of a lipid, methyl linoleate, all resulted in lipid peroxidation in a light dose-responsive manner. The levels of lipid peroxidation induced by the two isomeric 7,9-diGS-DHPs were significantly higher than that by 7-GS-DHP and 9-GS-DHP. When 7,9-diGS-DHP was irradiated in the presence of sodium azide (NaN3), the level of lipid peroxidation decreased; lipid peroxidation was enhanced when methanol was replaced by deuterated methanol. These results suggest that singlet oxygen is a product induced by the irradiation of 7,9-diGS-DHP. When irradiated in the presence of superoxide dismutase (SOD), the level of lipid peroxidation decreased, indicating that lipid peroxidation is also mediated by superoxide. These results indicate that lipid peroxidation is mediated by reactive oxygen species (ROS). These results suggest that 7,9-diGS-DHPs are phototoxic, generating lipid peroxidation mediated by ROS.


Effect of intake of different dietary protein sources on plasma amino acid profiles at rest and after exercise.
The authors undertook 2 crossover-designed studies to characterize plasma amino acid (AA) responses to the intake of 20 g of protein. In Study 1, 15 untrained and overnight-fasted subjects consumed 20 g protein from skim milk, soy milk, beefsteak, boiled egg, and a liquid meal supplement. In Study 2, 10 fasted endurance-trained subjects consumed 20 g protein from a protein-rich sports bar at rest and after a 60-min submaximal ride. Plasma AA concentrations were measured immediately before and for 180 min after food ingestion using a gas-chromatography flame-ionization detection technique. A pharmacokinetic analysis was undertaken for profiles of total AAs (TAA), essential AAs, branched-chain AAs (BCAA), and leucine. Although area-under-the-curve values for plasma TAA were similar across protein sources, the pattern of aminoacidemia showed robust differences between foods, with liquid forms of protein achieving peak concentrations twice as quickly after ingestion as solid protein-rich foods (e.g., ~50 min vs ~100 min) and skim milk achieving a significantly faster peak leucine concentration than all other foods (~25 min). Completing exercise before ingesting protein sources did not cause statistically significant changes in the pattern of delivery of key AAs, BCAAs, and leucine apart from a 20-40% increase in the rate of elimination. These results may be useful to plan the type and timing of intake of protein-rich foods to maximize the protein synthetic response to various stimuli such as exercise.


Artificial Intelligence in Medical Education: Best Practices Using Machine Learning to Assess Surgical Expertise in Virtual Reality Simulation.
Virtual reality simulators track all movements and forces of simulated instruments, generating enormous datasets which can be further analyzed with machine learning algorithms. These advancements may increase the understanding, assessment and training of psychomotor performance. Consequently, the application of machine learning techniques to evaluate performance on virtual reality simulators has led to an increase in the volume and complexity of publications which bridge the fields of computer science, medicine, and education. Although all disciplines stand to gain from research in this field, important differences in reporting exist, limiting interdisciplinary communication and knowledge transfer. Thus, our objective was to develop a checklist to provide a general framework when reporting or analyzing studies involving virtual reality surgical simulation and machine learning algorithms. By including a total score as well as clear subsections of the checklist, authors and reviewers can both easily assess the overall quality and specific deficiencies of a manuscript. The Machine Learning to Assess Surgical Expertise (MLASE) checklist was developed to help computer science, medicine, and education researchers ensure quality when producing and reviewing virtual reality manuscripts involving machine learning to assess surgical expertise. This study was carried out at the McGill Neurosurgical Simulation and Artificial Intelligence Learning Centre. The authors applied the checklist to 12 articles using machine learning to assess surgical expertise in virtual reality simulation, obtained through a systematic literature review. Important differences in reporting were found between medical and computer science journals. The medical journals proved stronger in discussion quality and weaker in areas related to study design. The opposite trends were observed in computer science journals. This checklist will aid in narrowing the knowledge divide between computer science, medicine, and education: helping facilitate the burgeoning field of machine learning assisted surgical education.


Antenatal depression and anxiety and early pregnancy BMI among White British and South Asian women: retrospective analysis of data from the Born in Bradford cohort.
Maternal obesity has severe physical impacts such as increased chances of pre-eclampsia and gestational diabetes. However, mental health impacts are given less attention within antenatal care. Evidence suggests that women with obesity carry increased risk of maternal depression and anxiety, however, this association is not well researched amongst South Asian women in the UK who are vulnerable to both. The aim of this study was to investigate the association between antenatal depression and anxiety and early pregnancy BMI, within and between White British and South Asian women, using data from the Born in Bradford cohort. Depression and anxiety were assessed using the General Health Questionnaire (GHQ); a GHQ score of > 0 for the depression subscale and > 6 for anxiety. Mother's BMI was stratified into six World Health Organisation BMI categories (underweight, recommended, overweight or obese class 1-3). To determine associations, univariate and multivariate logistic regression models (adjusting for maternal age, education, deprivation and smoking) were used. There were 7824 women included (3514 White British and 4310 South Asian). South Asian women were more likely to have depression than White British (43.3% vs 36.1% p < 0.0001) and less likely to have anxiety (45.3% vs 48.4% p < 0.01). There were no significant associations between BMI and depression or anxiety in South Asian women. White British women with an overweight BMI had higher odds of anxiety compared with women with a recommended BMI (Adjusted Odds Ratio 1.25, 95% Confidence Interval 1.05-1.47). No significant associations were observed for other BMI categories. Smoking was a risk factor for antenatal depression (AOR 1.32, 95% CI 1.12-1.56; AOR 2.08, 95% CI 1.49-2.91) and anxiety (AOR 1.34, 95% CI 1.14-1.57; (AOR 2.87, 95% CI 2.02-4.07) in both White British and South Asian women, respectively. Although South Asian women have a higher prevalence of depression than White women in this cohort, the known associations between maternal obesity and anxiety do not appear to be present. More studies are needed using validated depression tools for South Asian pregnant women. Mental health screening during antenatal care is important for South Asian women, with factors such as smoking considered.


Fluorescent chemosensors: the past, present and future.
Fluorescent chemosensors for ions and neutral analytes have been widely applied in many diverse fields such as biology, physiology, pharmacology, and environmental sciences. The field of fluorescent chemosensors has been in existence for about 150 years. In this time, a large range of fluorescent chemosensors have been established for the detection of biologically and/or environmentally important species. Despite the progress made in this field, several problems and challenges still exist. This tutorial review introduces the history and provides a general overview of the development in the research of fluorescent sensors, often referred to as chemosensors. This will be achieved by highlighting some pioneering and representative works from about 40 groups in the world that have made substantial contributions to this field. The basic principles involved in the design of chemosensors for specific analytes, problems and challenges in the field as well as possible future research directions are covered. The application of chemosensors in various established and emerging biotechnologies, is very bright.


The use of ultrasound to detect occult or unsuspected fractures in child abuse.
Occult fractures due to child abuse can be difficult to identify because there is usually no history of trauma, and chief complaints are vague. In addition, the osseous injuries are often subtle, becoming obvious only after healing begins. Missed injuries can lead to inappropriate disposition of a patient and can cause children to be placed at high risk for further injury and death. It is therefore imperative that these children be diagnosed as soon as possible. Ultrasound has some properties that are desirable for detecting fractures, especially in children. Ultrasound waves are almost completely reflected by cortical bone. Thus, fractures easily appear on an ultrasound screen. The cartilaginous nature of pediatric bones makes some fractures difficult to identify on x-ray. The nature of ultrasound waves, however, allows the cartilaginous areas of pediatric bones to be identified. This brief report presents 2 cases of children younger than 1 year presenting with vague complaints (limp, irritability) without a history of trauma. Both children underwent bedside ultrasound by a pediatric emergency medicine physician with training in emergency ultrasound. The bedside ultrasound led to the identification of occult or unsuspected fractures in both children, and state social services were notified. In both cases, the cause of the fracture was determined to be from abuse, and necessary measures were taken to ensure the child's future safety. This report demonstrates that ultrasound may be useful for early identification of some types of occult or unsuspected fractures commonly seen in cases of child abuse.


Phase II Studies with Refametinib or Refametinib plus Sorafenib in Patients with RAS-Mutated Hepatocellular Carcinoma.
Purpose: Refametinib, an oral MEK inhibitor, has demonstrated antitumor activity in combination with sorafenib in patients with RAS-mutated hepatocellular carcinoma (HCC). Two phase II studies evaluated the efficacy of refametinib monotherapy and refametinib plus sorafenib in patients with RAS-mutant unresectable or metastatic HCC.Patients and Methods: Eligible patients with RAS mutations of cell-free circulating tumor DNA (ctDNA) determined by beads, emulsion, amplification, and magnetics technology received twice-daily refametinib 50 mg ± sorafenib 400 mg. Potential biomarkers were assessed in ctDNA via next-generation sequencing (NGS).Results: Of 1,318 patients screened, 59 (4.4%) had a RAS mutation, of whom 16 received refametinib and 16 received refametinib plus sorafenib. With refametinib monotherapy, the objective response rate (ORR) was 0%, the disease control rate (DCR) was 56.3%, overall survival (OS) was 5.8 months, and progression-free survival (PFS) was 1.9 months. With refametinib plus sorafenib, the ORR was 6.3%, the DCR was 43.8%, OS was 12.7 months, and PFS was 1.5 months. In both studies, time to progression was 2.8 months. Treatment-emergent toxicities included fatigue, hypertension, and acneiform rash. Twenty-seven patients had ctDNA samples available for NGS. The most frequently detected mutations were in TERT (63.0%), TP53 (48.1%), and β-catenin (CTNNB1; 37.0%).Conclusions: Prospective testing for RAS family mutations using ctDNA was a feasible, noninvasive approach for large-scale mutational testing in patients with HCC. A median OS of 12.7 months with refametinib plus sorafenib in this small population of RAS-mutant patients may indicate a synergistic effect between sorafenib and refametinib-this preliminary finding should be further explored. Clin Cancer Res; 24(19); 4650-61. ©2018 AACR.


Do "Girls Just Wanna Have Fun?" Participation Trends and Motivational Profiles of Women in the Birkebeiner Races, Norway's Ultimate Mass Participation Ski Event.
Mass participation sporting events (MPSEs) are viewed as encouraging regular exercise in the population, but concerns have been expressed about the extent to which they are inclusive for women. This study focuses on an iconic cross-country skiing MPSE in Norway, the Birkebeiner race (BR), which includes different variants (main, Friday, half-distance, and women-only races). In order to shed light on women's participation in this specific MPSE, as well as add to the understanding of women's MPSEs participation in general, this study was set up to: (i) analyze trends in women's participation, (ii) examine the characteristics, and (iii) identify key factors characterizing the motivational profile of women in different BR races, with emphasis on the full-distance vs. the women-only races. Entries in the different races throughout the period 1996-2018 were analyzed using an autoregressive model. Information on women's sociodemographic characteristics, sport and exercise participation, and a range of psychological variables (motives, perceptions, overall satisfaction, and future participation intention) were extracted from a market survey and analyzed using a machine learning (ML) approach (n = 1,149). Additionally, qualitative information generated through open-ended questions was analyzed thematically (n = 116). The relative prevalence of women in the main BR was generally low (< 20%). While the other variants contributed to boosting women's participation in the overall event, a future increment of women in the main BR was predicted, with women's ratings possibly matching the men's by the year 2034. Across all races, most of the women were physically active, of medium-high income, and living in the most urbanized region of Norway. Satisfaction and future participation intention were relatively high, especially among the participants in the women-only races. "Exercise goal" was the predominant participation motive. The participants in women-only races assigned greater importance to social aspects, and perceived the race as a tradition, whereas those in the full-distance races were younger and gave more importance to performance aspects. These findings corroborate known trends and challenges in MPSE participation, but also contribute to greater understanding in this under-researched field. Further research is needed in order to gain more knowledge on how to foster women's participation in MPSEs.


A common cofilin activity cycle in invasive tumor cells and inflammatory cells.
In many cell types, the formation of membrane protrusions and directional migration depend on the spatial and temporal regulation of the actin-binding protein cofilin. Cofilin, which is important for the regulation of actin-polymerization initiation, increases the number of actin free barbed ends through three mechanisms: its intrinsic actin-nucleation activity; binding and severing of existing actin filaments; and recycling actin monomers from old filaments to new ones through its actin-depolymerization activity. The increase in free barbed ends that is caused by cofilin initiates new actin polymerization, which can be amplified by the actin-nucleating ARP2/3 complex. Interestingly, different cell systems seem to have different mechanisms of activating cofilin. The initial activation of cofilin in mammary breast tumors is dependent on PLCgamma, whereas cofilin activation in neutrophils is additionally dependent on dephosphorylation, which is promoted through Rac2 signaling. Although the literature seems to be confusing and inconsistent, we propose that all of the data can be explained by a single activity-cycle model. In this Opinion, we give an overview of cofilin activation in both tumor cells and inflammatory cells, and demonstrate how the differences in cofilin activation that are observed in various cell types can be explained by different starting points in this single common activity cycle.


Elevated microRNA miR-21 levels in pancreatic cyst fluid are predictive of mucinous precursor lesions of ductal adenocarcinoma.
Biomarkers for the diagnostic classification of pancreatic cysts are urgently needed. Deregulated microRNA (miRNAs) expression is widespread in pancreatic cancer. We assessed whether aberrant miRNAs in pancreatic cyst fluid could be used as potential biomarkers for cystic precursor lesions of pancreatic cancer. Cyst fluid specimens were prospectively collected from 40 surgically resected pancreatic cysts, and small RNAs were extracted. The 'mucinous' cohort included 14 intraductal papillary mucinous neoplasms (including 3 with an associated adenocarcinoma) and 10 mucinous cystic neoplasms; the 'nonmucinous' cohort included 11 serous cystadenomas and 5 other benign cysts. Quantitative reverse transcription PCR was performed for five miRNAs (miR-21, miR-155, miR-221, miR-17-3p, miR-191), which were previously reported as overexpressed in pancreatic adenocarcinomas. Significantly higher expression of miR-21, miR-221, and miR-17-3p was observed in the mucinous versus nonmucinous cysts (p < 0.01), with the mean relative fold differences being 7.0-, 7.9-, and 5.4-fold, respectively. Receiver operating characteristic curves demonstrated the highest median area under the curve for miR-21, with a median specificity of 76%, at a sensitivity of 80%. This pilot study demonstrates that profiling miRNAs in pancreatic cyst fluid samples is feasible and can yield potential biomarkers for the classification of cystic lesions of the pancreas. and IAP.


Upgrading Kolbe Electrolysis-Highly Efficient Production of Green Fuels and Solvents by Coupling Biosynthesis and Electrosynthesis.
The chemical industry is transitioning to more sustainable and biobased processes. One key element of this transition is coupling energy fluxes and feedstock utilization for optimizing processes, routes and efficiencies. Here, we show for the first time the coupling of the Kolbe electrolysis at the anode with a subsequent microbial conversion of the cathodically produced co-product hydrogen. Kolbe electrolysis of valeric acid yields the liquid drop-in fuel additive n-octane. Subsequently, the solvent isopropanol is produced by resting Cupriavidus necator cells using gaseous electrolysis products (esp. CO2 and H2 ). The resting microbial cells show carbon efficiencies of up to 41 % and Coulombic/Faradaic efficiencies of 60 % and 80 % for anodic and cathodic reactions, respectively. The implementation of a paired electrolyser resulted in superior process performances with overall efficiencies of up to 64.4 %.


Seminoma and embryonal carcinoma footprints identified by analysis of integrated genome-wide epigenetic and expression profiles of germ cell cancer cell lines.
Originating from Primordial Germ Cells/gonocytes and developing via a precursor lesion called Carcinoma In Situ (CIS), Germ Cell Cancers (GCC) are the most common cancer in young men, subdivided in seminoma (SE) and non-seminoma (NS). During physiological germ cell formation/maturation, epigenetic processes guard homeostasis by regulating the accessibility of the DNA to facilitate transcription. Epigenetic deregulation through genetic and environmental parameters (i.e. genvironment) could disrupt embryonic germ cell development, resulting in delayed or blocked maturation. This potentially facilitates the formation of CIS and progression to invasive GCC. Therefore, determining the epigenetic and functional genomic landscape in GCC cell lines could provide insight into the pathophysiology and etiology of GCC and provide guidance for targeted functional experiments. This study aims at identifying epigenetic footprints in SE and EC cell lines in genome-wide profiles by studying the interaction between gene expression, DNA CpG methylation and histone modifications, and their function in the pathophysiology and etiology of GCC. Two well characterized GCC-derived cell lines were compared, one representative for SE (TCam-2) and the other for EC (NCCIT). Data were acquired using the Illumina HumanHT-12-v4 (gene expression) and HumanMethylation450 BeadChip (methylation) microarrays as well as ChIP-sequencing (activating histone modifications (H3K4me3, H3K27ac)). Results indicate known germ cell markers not only to be differentiating between SE and NS at the expression level, but also in the epigenetic landscape. The overall similarity between TCam-2/NCCIT support an erased embryonic germ cell arrested in early gonadal development as common cell of origin although the exact developmental stage from which the tumor cells are derived might differ. Indeed, subtle difference in the (integrated) epigenetic and expression profiles indicate TCam-2 to exhibit a more germ cell-like profile, whereas NCCIT shows a more pluripotent phenotype. The results provide insight into the functional genome in GCC cell lines.


Error-prone replication of oxidatively damaged DNA by a high-fidelity DNA polymerase.
Aerobic respiration generates reactive oxygen species that can damage guanine residues and lead to the production of 8-oxoguanine (8oxoG), the major mutagenic oxidative lesion in the genome. Oxidative damage is implicated in ageing and cancer, and its prevalence presents a constant challenge to DNA polymerases that ensure accurate transmission of genomic information. When these polymerases encounter 8oxoG, they frequently catalyse misincorporation of adenine in preference to accurate incorporation of cytosine. This results in the propagation of G to T transversions, which are commonly observed somatic mutations associated with human cancers. Here, we present sequential snapshots of a high-fidelity DNA polymerase during both accurate and mutagenic replication of 8oxoG. Comparison of these crystal structures reveals that 8oxoG induces an inversion of the mismatch recognition mechanisms that normally proofread DNA, such that the 8oxoG.adenine mismatch mimics a cognate base pair whereas the 8oxoG.cytosine base pair behaves as a mismatch. These studies reveal a fundamental mechanism of error-prone replication and show how 8oxoG, and DNA lesions in general, can form mismatches that evade polymerase error-detection mechanisms, potentially leading to the stable incorporation of lethal mutations.


Myopic deconvolution of adaptive optics images by use of object and point-spread function power spectra: reply to comment.
Partial correction in adaptive optics (AO) is well understood now. This partial correction is due to the limitations of the AO system performance, which leaves residual phase fluctuations in the instrument pupil. Knowledge of these residuals allows the optical transfer function (OTF) of the high-angular-resolution imaging system to be estimated accurately. Therefore, light scattering by aerosols cannot be invoked to justify the shape of an AO partial-correction OTF in astronomical conditions. The light scattering does not modify the high-angular-resolution OTF but merely contributes to a slight increase of the sky background.


A more comprehensive modeling of atomic force microscope cantilever.
This paper focuses on the development of a complete model of an atomic force microscope (AFM) micro-cantilever beam, based on considering the effects of four major factors in modeling the cantilever. They are: rotary inertia and shear deformation of the beam and mass and rotary inertia of the tip. A method based on distributed-parameter modeling approach is proposed to solve the governing equations. The comparisons generally show a very good agreement between the present results and the results of other investigators. As expected, rotary inertia and shear deformation of the beam decrease resonance frequency especially at high ratio of cantilever thickness to its length, and it is relatively more pronounced for higher-order frequencies, than lower ones. Mass and rotary inertia of the tip have similar effects when the mass-ratio of the tip to the cantilever is high. Moreover, the influence of each of these four factors, thickness of the cantilever, density of the tip and inclination of the cantilever on the resonance frequencies has been investigated, separately. It is felt that this work might help the engineers in reducing AFM micro-cantilever design time, by providing insight into the effects of various parameters with the micro-cantilever.


Fate of the atrioventricular endocardial cushions in the developing chick heart.
To determine the fate of the atrioventricular endocardial cushions in cardiac development, we used staining methods for extracellular fibronectin, which is abundant in the endocardial cushions, and actin, which is abundant in the myocytes. White Leghorn chick embryo hearts were harvested at Hamburger and Hamilton stages 26 to 36, and serial sections of the atrioventricular valve region were stained. Before atrioventricular valve formation, fibronectin and actin staining reveal separation between the fibronectin-rich endocardial cushions and the actin-rich myocardial layer. The developing mitral valve leaflets at all of the observed stages contain a fibronectin-rich matrix but no actin-rich myocytes. In contrast, the tricuspid band includes both fibronectin matrix and actin-rich cells. We conclude that the mitral valve leaflets in the chick form predominantly from the endocardial cushion tissue, and the tricuspid band receives contributions from both the endocardial cushions and surrounding myocardium.


Comorbid Analysis of Genes Associated with Autism Spectrum Disorders Reveals Differential Evolutionary Constraints.
The burden of comorbidity in Autism Spectrum Disorder (ASD) is substantial. The symptoms of autism overlap with many other human conditions, reflecting common molecular pathologies suggesting that cross-disorder analysis will help prioritize autism gene candidates. Genes in the intersection between autism and related conditions may represent nonspecific indicators of dysregulation while genes unique to autism may play a more causal role. Thorough literature review allowed us to extract 125 ICD-9 codes comorbid to ASD that we mapped to 30 specific human disorders. In the present work, we performed an automated extraction of genes associated with ASD and its comorbid disorders, and found 1031 genes involved in ASD, among which 262 are involved in ASD only, with the remaining 779 involved in ASD and at least one comorbid disorder. A pathway analysis revealed 13 pathways not involved in any other comorbid disorders and therefore unique to ASD, all associated with basal cellular functions. These pathways differ from the pathways associated with both ASD and its comorbid conditions, with the latter being more specific to neural function. To determine whether the sequence of these genes have been subjected to differential evolutionary constraints, we studied long term constraints by looking into Genomic Evolutionary Rate Profiling, and showed that genes involved in several comorbid disorders seem to have undergone more purifying selection than the genes involved in ASD only. This result was corroborated by a higher dN/dS ratio for genes unique to ASD as compare to those that are shared between ASD and its comorbid disorders. Short-term evolutionary constraints showed the same trend as the pN/pS ratio indicates that genes unique to ASD were under significantly less evolutionary constraint than the genes associated with all other disorders.


Ferristatin II promotes degradation of transferrin receptor-1 in vitro and in vivo.
Previous studies have shown that the small molecule iron transport inhibitor ferristatin (NSC30611) acts by down-regulating transferrin receptor-1 (TfR1) via receptor degradation. In this investigation, we show that another small molecule, ferristatin II (NSC8679), acts in a similar manner to degrade the receptor through a nystatin-sensitive lipid raft pathway. Structural domains of the receptor necessary for interactions with the clathrin pathway do not appear to be necessary for ferristatin II induced degradation of TfR1. While TfR1 constitutively traffics through clathrin-mediated endocytosis, with or without ligand, the presence of Tf blocked ferristatin II induced degradation of TfR1. This effect of Tf was lost in a ligand binding receptor mutant G647A TfR1, suggesting that Tf binding to its receptor interferes with the drug's activity. Rats treated with ferristatin II have lower TfR1 in liver. These effects are associated with reduced intestinal (59)Fe uptake, lower serum iron and transferrin saturation, but no change in liver non-heme iron stores. The observed hypoferremia promoted by degradation of TfR1 by ferristatin II appears to be due to induced hepcidin gene expression.


[Usher syndrome: clinical features, diagnostic options, and therapeutic prospects].
Usher syndrome denotes a clinically and genetically heterogeneous combination of retinitis pigmentosa and sensorineural deafness. The division into subtypes I, II, and III is based on the degree of hearing loss: Type I is characterized by deafness from birth together with ataxia and retarded motor development, type II by a stationary deafness of a moderate degree, and type III by a progressive deafness with adult onset. In Germany, Usher syndrome currently bears particular relevance because in January 2009 a new compulsory screening of auditory function in newborn infants was introduced. Consequently, it can be expected that a higher number of patients with Usher syndrome will be identified in early childhood and referred to ophthalmologists. The focus of this work is to introduce the typical clinical picture of Usher syndrome, summarize diagnostic options, and give an overview of therapeutic strategies.


Testing the role of expansion in the prospective control of locomotion.
The constant bearing angle (CBA) strategy is a prospective strategy that permits the interception of moving objects. The purpose of the present study is to test this strategy. Participants were asked to walk through a virtual environment and to change, if necessary, their walking speed so as to intercept approaching targets. The targets followed either a rectilinear or a curvilinear trajectory and target size was manipulated both within trials (target size was gradually changed during the trial in order to bias expansion) and between trials (targets of different sizes were used). The curvature manipulation had a large effect on the kinematics of walking, which is in agreement with the CBA strategy. The target size manipulations also affected the kinematics of walking. Although these effects of target size are not predicted by the CBA strategy, quantitative comparisons of observed kinematics and the kinematics predicted by the CBA strategy showed good fits. Furthermore, predictions based on the CBA strategy were deemed superior to predictions based on a required velocity (V (REQ)) model. The role of target size and expansion in the prospective control of walking is discussed.


Chronic Pulmonary Aspergillosis in Post Tuberculosis Patients in Indonesia and the Role of LDBio Aspergillus ICT as Part of the Diagnosis Scheme.
Chronic pulmonary aspergillosis (CPA) is a common sequela of pulmonary tuberculosis (TB). The diagnosis of CPA is difficult and often misdiagnosed as smear-negative TB in endemic settings. Aspergillus IgG detection is the cornerstone of CPA diagnosis. There are a lack of studies on the prevalence of CPA in GeneXpert/smear-negative TB patients in Indonesia, despite a high number of TB cases. This study aims to determine the CPA rate in HIV-negative, GeneXpert-negative patients presenting with symptoms following completion of TB therapy and to evaluate the performance of LDBio Aspergillus immunochromatographic technology (ICT) lateral flow assay in the diagnosis of CPA. CPA was diagnosed on the basis of symptoms for ≥3 months, characteristic chest imaging and positive Aspergillus culture. Twenty (22%) out of 90 patients met the criteria for CPA. The LDBio test was positive in 16 (80%) CPA patients and in 21 (30%) non-CPA patients (p < 0.001) with 80% sensitivity and 70% specificity. Logistic regression revealed a positive LDBio Aspergillus ICT result, smoking history and diabetes to be important predictors of CPA diagnosis. Although CPA is an unrecognised disease in Indonesia, this study suggests that more than one in five GeneXpert negative patients with persistent symptoms following completion of TB therapy may have CPA.


ATP-induced relaxation of porcine retinal arterioles in vitro depends on prostaglandin E synthesized in the perivascular retinal tissue.
It has been shown that inhibition of prostaglandin synthesis in the perivascular retinal tissue can prevent the relaxation of retinal arterioles induced by N-methyl-d-aspartic acid (NMDA) and adenosine triphosphate (ATP). The purpose of the present study was to identify the prostaglandins involved in this retina-dependent relaxation. Porcine retinal arterioles were mounted in a myograph for isometric tone measurements. The effect of the prostaglandins (PGs) PGE(2), PGF(2α), PGD(2), and PGI(2) and of thromboxane A(2) (TXA(2)) on vascular tone was recorded before and after removal of the perivascular retina, and the specificity of the responses were confirmed by blocking with specific antagonists. Finally, the coupling between prostaglandins found to have a specific vasoactive effect, dependent on the perivascular retina, and the individual vasorelaxing effects of NMDA, ATP, and adenosine were studied. All prostaglandins tested showed a significant relaxation of precontracted arterioles at the highest concentrations, whereas PGF(2α) induced a significant constriction of isolated noncontracted arterioles. In the presence of perivascular retinal tissue, the dilating effect of PGE(2) increased significantly, an effect that was blocked by a prostaglandin E prostanoid (EP(1)) receptor blocker, whereas PGD(2) induced a dual response, with a significant contraction at low concentrations and a significant dilation at high concentrations. Inhibition of the cyclo-oxygenase (COX) enzyme with ibuprofen, as well as the EP(1) receptor, blocked the vasodilating effect of ATP, but not that of NMDA and adenosine, in the presence of perivascular retinal tissue. ATP-induced vasodilation depends on the production of PGE in the perivascular retina. However, the regulation of retinal arteriolar tone involves COX products other than PGE.


Glycopeptides from the surface of control and virus-transformed cells.
Glycopeptides were removed by trypsin digestion from the surface of control cells and cells transformed by Rous sarcoma virus, murine sarcoma virus, or polyoma virus. After digestion with pronase, the glycopeptides were analyzed by gel filtration. The elution profiles suggest that there are differences in the glycopeptides from the surface of control cells and those from transformed cells.


The psychiatrist in the surgical intensive care unit. II. A consideration of staff roles.
The stresses present within the Surgical Intensive Care Unit (SICU) affect both patients and staff. The liaison psychiatrist attached to the unit helps in identifying and neutralizing tension displaced from its source. Death, although commonplace on the unit, often engenders strong feelings in the staff. Pulmonary patients, especially those who must be weaned from the respirator, also increase the psychological strain on the staff beyond the necessary effort involved in physical caretaking. Aside from emotional difficulty presented by working with very sick patients, there exists group pressures resulting from hierachy within the staff. Here, particularly, the psychiatrist can promote understanding and reduce polarization.


Dead reckoning: demographic determinants of the accuracy of mortality risk perceptions.
General patterns of bias in risk beliefs are well established in the literature, but much less is known about how these biases vary across the population. Using a sample of almost 500 people, the regression analysis in this article yields results consistent with the well-established pattern that small risks are overassessed and large risks are underassessed. The accuracy of these risk beliefs varies across demographic factors, as does the switch point at which people go from underassessment to overassessment, which we found to be 1500 deaths annually for the full sample. Better educated people have more accurate risk beliefs, and there are important differences in the risk perception by race and gender that also may be of policy interest.


Processive action of T4 endonuclease V on ultraviolet-irradiated DNA.
The action of the dimer-specific endonuclease V of bacteriophage T4 was studied on UV-irradiated, covalently-closed circular DNa. Form I ColE1 DNA preparations containing average dimer frequencies ranging from 2.5 to 35 pyrimidine dimers per molecule were treated with T4 endonuclease V and analysed by agarose gel electrophoresis. At all dimer frequencies examined, the production of form III DNA was linear with time and the double-strand scissions were made randomly on the ColE1 DNA genome. Since the observed fraction of form III DNA increased with increasing dimer frequency but the initial rate of loss of form I decreased with increasing dimer frequency, it was postulated that multiple single-strand scissions could be produced in a subset of the DNA population while some DNA molecules contained no scissions. When DNA containing an average of 25 dimers per circle was incubated with limiting enzyme concentrations, scissions appeared at most if not all dimmer sites in some molecules before additional strand scissions were produced in other DNA molecules. The results support a processive model for the interaction of T4 endonuclease V with UV-irradiated DNA.


Noninvasive genetic population survey of snow leopards (Panthera uncia) in Kangchenjunga conservation area, Shey Phoksundo National Park and surrounding buffer zones of Nepal.
The endangered snow leopard is found throughout major mountain ranges of Central Asia, including the remote Himalayas. However, because of their elusive behavior, sparse distribution, and poor access to their habitat, there is a lack of reliable information on their population status and demography, particularly in Nepal. Therefore, we utilized noninvasive genetic techniques to conduct a preliminary snow leopard survey in two protected areas of Nepal. A total of 71 putative snow leopard scats were collected and analyzed from two different areas; Shey Phoksundo National Park (SPNP) in the west and Kangchanjunga Conservation Area (KCA) in the east. Nineteen (27%) scats were genetically identified as snow leopards, and 10 (53%) of these were successfully genotyped at 6 microsatellite loci. Two samples showed identical genotype profiles indicating a total of 9 individual snow leopards. Four individual snow leopards were identified in SPNP (1 male and 3 females) and five (2 males and 3 females) in KCA. We were able to confirm the occurrence of snow leopards in both study areas and determine the minimum number present. This information can be used to design more in-depth population surveys that will enable estimation of snow leopard population abundance at these sites.