Computational analysis of dynamical responses to the intrinsic pathway of programmed cell death.
Multicellular organisms shape development and remove aberrant cells by programmed cell death ("apoptosis"). Because defective cell death (too little or too much) is implicated in various diseases (like cancer and autoimmunity), understanding how apoptosis is regulated is an important goal of molecular cell biologists. To this end, we propose a mathematical model of the intrinsic apoptotic pathway that captures three key dynamical features: a signal threshold to elicit cell death, irreversible commitment to the response, and a time delay that is inversely proportional to signal strength. Subdividing the intrinsic pathway into three modules (initiator, amplifier, executioner), we use computer simulation and bifurcation theory to attribute signal threshold and time delay to positive feedback in the initiator module and irreversible commitment to positive feedback in the executioner module. The model accounts for the behavior of mutants deficient in various genes and is used to design experiments that would test its basic assumptions. Finally, we apply the model to study p53-induced cellular responses to DNA damage. Cells first undergo cell cycle arrest and DNA repair, and then apoptosis if the damage is beyond repair. The model ascribes this cell-fate transition to a transformation of p53 from "helper" to "killer" forms.


Abnormal primary and permanent dentitions with ectodermal symptoms predict WNT10A deficiency.
The WNT10A protein is critical for the development of ectodermal appendages. Variants in the WNT10A gene may be associated with a spectrum of ectodermal abnormalities including extensive tooth agenesis. In seven patients with severe tooth agenesis we identified anomalies in primary dentition and additional ectodermal symptoms, and assessed WNT10A mutations by genetic analysis. Investigation of primary dentition revealed peg-shaped crowns of primary mandibular incisors and three individuals had agenesis of at least two primary teeth. The permanent dentition was severely affected in all individuals with a mean of 21 missing teeth. Primary teeth were most often present in positions were succedaneous teeth were missing. Furthermore, most existing molars had taurodontism. Light, brittle or coarse hair was reported in all seven individuals, hyperhidrosis of palms and soles in six individuals and nail anomalies in two individuals. The anomalies in primary dentition preceded most of the additional ectodermal symptoms. Genetic analysis revealed that all seven individuals were homozygous or compound heterozygous for WNT10A mutations resulting in C107X, E222X and F228I. We conclude that tooth agenesis and/or peg-shaped crowns of primary mandibular incisors, severe oligodontia of permanent dentition as well as ectodermal symptoms of varying severity may be predictors of bi-allelic WNT10A mutations of importance for diagnosis, counselling and follow-up.


Participation in Organized Sports and Self-Organized Physical Activity: Associations with Developmental Factors.
Engagement in organized sports is associated with developmental factors, such as, healthy growth, cognitive abilities, psychological well-being and lower substance use. Research also suggest that the spontaneous free play that characterises self-organized physical activity (PA) provides young people with opportunities to learn social skills, such as self-regulation and conflict-resolution skills. We assessed associations between participation in the two activity types and several demographics along with developmental factors (e.g., body mass index (BMI)). Data was from a representative sample of 2060 students attending 38 schools in Norway (mean age (Mage) = 15.29, standard deviation (SD) = 1.51; 52% females). Results indicated that while engagement in organized sports was more related to developmental factors, relative to self-organized PA, engaging concurrently in both activities for at least an hour a week was more developmentally beneficial than engaging only in one for the same amount of time. Thus, PA programmes for students will enhance their effectiveness if they focus on structured activities but also self-organized activities where students can coordinate themselves.


Will tuberculosis become resistant to all antibiotics?
The discovery of high prevalences of antibiotic resistance in some pathogens, in some parts of the world, has provoked fears of a widespread loss of drug efficacy. Here, we use a mathematical model to investigate the evolution of resistance to four major anti-tuberculosis drugs (isoniazid, rifampicin, ethambutol and streptomycin) in 47 sites around the world. The model provides a new method of estimating the relative risk of treatment failure for patients carrying drug-resistant strains and the proportion of patients who develop resistance after failing treatment. Using estimates of these two quantities together with other published data, we reconstructed the epidemic spread of isoniazid resistance over the past 50 years. The predicted median prevalence of resistance among new cases today was 7.0% (range 0.9-64.3%), close to the 6.3% (range 0-28.1%) observed. Predicted and observed prevalences of resistance to isoniazid plus rifampicin (multidrug-resistant or MDR-TB) after 30 years of combined drug use were also similar, 0.9% (0.1-5.9%) and 1.0% (range 0-14.1%), respectively. With current data, and under prevailing treatment practices, it appears that MDR-TB will remain a localized problem, rather than becoming a global obstacle to tuberculosis control. To substantiate this result, further measurements are needed of the relative fitness of drug-resistant strains.


[Obesity in CKD].
Metabolic syndrome, characterized by truncal obesity, hypertriglyceridemia, elevated blood pressure, and insulin resistance, is recognized increasingly as a major risk factor for kidney disease and also is a common feature of patients who are on dialysis. Obesity is considered a major generator of metabolic syndrome. Early in the course of obesity-initiated metabolic syndrome, structural and functional changes similar to diabetic kidney disease occur. Previous studies examined the histologic and functional changes that occur in the kidney in the early stages of obesity caused by a high-fat diet. They reported that a high-fat diet caused increased arterial pressure, hyperinsulinemia, activation of the renin-angiotensin system, glomerular hyperfiltration, and structural changes in the kidney that may be the precursors of more severe glomerular injury associated with prolonged obesity. Among several factors causing renal injury, Rho-kinase also plays an important role in the pathogenesis of obesity-related renal disease. We further propose that perinephric adipose tissues could be a source of inflammatory chemokines, which acts in concert with the renal Rho-kinase stimulated in situ to exacerbate renal inflammation. In this review, we note the mechanisms inducing chronic kidney disease (CKD) by obesity, especially the relation between insulin resistance and CKD.


Recruiting and retaining postpartum women from areas of social disadvantage in a weight-loss trial--an assessment of strategies employed in the WeighWell feasibility study.
Little is known about the response of post-partum women from deprived backgrounds to weight management interventions, however behavioural intervention trials in disadvantaged communities are often characterised by recruitment difficulties. Recruitment and retention is key to the robust conduct of an effective trial, and exploratory work is essential prior to a definitive randomised controlled trial. This paper describes strategies used to recruit to the WeighWell feasibility study, which aimed to recruit 60 overweight or obese post-partum women living in areas of deprivation to a trial of a weight-loss intervention. Recruitment strategies included the following: (1) distribution of posters and 'business cards'; (2) newspaper advertisements; (3) visits to community groups; and (4) personalised letters of invitation sent via the National Health Service (NHS). Potential participants were screened for eligibility following response to a Freephone number. Body mass index was calculated using self-reported body weight and height. Over 6 months, 142 women responded of whom 65 (46%) met the eligibility criteria. The most effective methods for recruiting eligible women and those who went on to complete the study (n = 36) were visits to community groups (37% and 42%, respectively), personalised letters (26% and 17%, respectively) and posters and 'business cards' (22% and 31%, respectively). These results emphasise the need to utilise a range of strategies beyond traditional NHS settings. Current approaches might be enhanced by sending personal contact letters via their General Practitioner to women identified as eligible at post-natal discharge. Under-reporting of body weight by self-report suggests that a threshold lower than 25 kg/m(2) should be utilised for screening purposes.


Factors Affecting Match Outcome in Elite Australian Football: A 14-Year Analysis.
Effects of fixture and team characteristics on match outcome in elite Australian football were quantified using data accessed at AFLtables.com for 5109 matches for seasons 2000 to 2013. Aspects of each match included number of days' break between matches (≤7 d vs ≥8 d), location (home vs away), travel status (travel vs no travel), and differences between opposing teams' mean age, body mass, and height (expressed as quintiles). A logistic-regression version of the generalized mixed linear model estimated each effect, which was assessed with magnitude-based inference using 1 extra win or loss in every 10 matches as the smallest important change. For every 10 matches played, the effects were days' break, 0.1 ± 0.3 (90% CL) wins; playing away, 1.5 ± 0.6 losses; traveling, 0.7 ± 0.6 losses; and being in the oldest, heaviest, or shortest, quintile, 1.9 ± 0.4, 1.3 ± 0.4, and 0.4 ± 0.4 wins, respectively. The effects of age and body-mass difference were not reduced substantially when adjusted for each other. All effects were clear, mostly at the 99% level. The effects of playing away, travel, and age difference were not unexpected, but the trivial effect of days' break and the advantage of a heavier team will challenge current notions about balancing training with recovery and about team selection.


Treatment Stage Migration Maximizes Survival Outcomes in Patients with Hepatocellular Carcinoma Treated with Sorafenib: An Observational Study.
Level I evidence supports the use of sorafenib in patients with Barcelona Clinic Liver Cancer (BCLC) stage C hepatocellular carcinoma, where heterogeneity in efficacy exists due to varying clinicopathologic features of the disease. We evaluated whether prior treatment with curative or locoregional therapies influences sorafenib-specific survival. From a prospective data set of 785 consecutive patients from international specialist centres, 264 patients (34%) were treatment naïve (TN) and 521 (66%) were pre-treated (PT), most frequently with transarterial chemoembolization (n = 413; 79%). The primary endpoint was overall survival (OS) from sorafenib initiation with prognostic factors tested on uni- and multivariate analyses. Median OS for the entire cohort was 9 months; the median sorafenib duration was 2.8 months, with discontinuation being secondary to progression (n = 454; 58%) or toxicity (n = 149; 19%). PT patients had significantly longer OS than TN patients (10.5 vs. 6.6 months; p < 0.001). Compared to TN patients, PT patients had a better Child-Pugh (CP) class (CP A: 57 vs. 47%; p < 0.001) and a lower BCLC stage (BCLC A-B, 40 vs. 30%; p = 0.007). PT status preserved an independent prognostic role (p = 0.002) following adjustment for BCLC stage, α-fetoprotein, CP class, aetiology, and post-sorafenib treatment status. PT patients were more likely to receive further anticancer treatment after sorafenib (31 vs. 9%; p < 0.001). Patients receiving sorafenib after having failed curative or locoregional therapies survive longer and are more likely to receive further treatment after sorafenib. This suggests an incremental benefit to OS from sequential exposure to multiple lines of therapy, justifying treatment stage migration in eligible patients.


Hemodynamics Prior to Valve Replacement for Severe Aortic Stenosis and Pulmonary Hypertension during Long-Term Follow-Up.
(1) Background: Pulmonary hypertension after aortic valve replacement (AVR; post-AVR PH) carries a poor prognosis. We assessed the pre-AVR hemodynamic characteristics of patients with versus without post-AVR PH. (2) Methods: We studied 205 patients (mean age 75 ± 10 years) with severe AS (indexed aortic valve area 0.42 ± 0.12 cm2/m2, left ventricular ejection fraction 58 ± 11%) undergoing right heart catheterization (RHC) prior to surgical (70%) or transcatheter (30%) AVR. Echocardiography to assess post-AVR PH, defined as estimated systolic pulmonary artery pressure > 45 mmHg, was performed after a median follow-up of 15 months. (3) Results: There were 83/205 (40%) patients with pre-AVR PH (defined as mean pulmonary artery pressure (mPAP) ≥ 25 mmHg by RHC), and 24/205 patients (12%) had post-AVR PH (by echocardiography). Among the patients with post-AVR PH, 21/24 (88%) had already had pre-AVR PH. Despite similar indexed aortic valve area, patients with post-AVR PH had higher mPAP, mean pulmonary artery wedge pressure (mPAWP) and pulmonary vascular resistance (PVR), and lower pulmonary artery capacitance (PAC) than patients without. (4) Conclusions: Patients presenting with PH roughly one year post-AVR already had worse hemodynamic profiles in the pre-AVR RHC compared to those without, being characterized by higher mPAP, mPAWP, and PVR, and lower PAC despite similar AS severity.


Conservation and divergence in the AGAMOUS subfamily of MADS-box genes: evidence of independent sub- and neofunctionalization events.
The MADS-box gene AGAMOUS (AG) plays a key role in determining floral meristem and organ identities. We identified three AG homologs, EScaAG1, EScaAG2, and EScaAGL11 from the basal eudicot Eschscholzia californica (California poppy). Phylogenetic analyses indicate that EScaAG1 and EScaAG2 are recent paralogs within the AG clade, independent of the duplication in ancestral core eudicots that gave rise to the euAG and PLENA (PLE) orthologs. EScaAGL11 is basal to core eudicot AGL11 orthologs in a clade representing an older duplication event after the divergence of the angiosperm and gymnosperm lineages. Detailed in situ hybridization experiments show that expression of EScaAG1 and EScaAG2 is similar to AG; however, both genes appear to be expressed earlier in floral development than described in the core eudicots. A thorough examination of available expression and functional data in a phylogenetic context for members of the AG and AGL11 clades reveals that gene expression has been quite variable throughout the evolutionary history of the AG subfamily and that ovule-specific expression might have evolved more than twice. Although sub- and neofunctionalization are inferred to have occurred following gene duplication, functional divergence among orthologs is evident, as is convergence, among paralogs sampled from different species. We propose that retention of multiple AG homologs in several paralogous lineages can be explained by the conservation of ancestral protein activity combined with evolutionarily labile regulation of expression in the AG and AGL11 clades such that the collective functions of the AG subfamily in stamen and carpel development are maintained following gene duplication.


Development of a FRET biosensor with high specificity for Akt.
The serine/threonine kinase Akt plays a critical role in cell proliferation, survival, and tumorigenesis. As a central kinase in the phosphatidylinositol 3-kinase pathway, its activation mechanism at the plasma membrane has been well characterized. However, the subcellular Akt activity in living cells is still largely unknown. Fluorescence resonance energy transfer (FRET)-based biosensors have emerged as indispensable tools to visualize the subcellular activities of signaling molecules. In this study, we developed a highly specific FRET biosensor for Akt based on the Eevee backbone, called Eevee-iAkt. Using inhibitors targeting kinases upstream and downstream of Akt, we showed that Eevee-iAkt specifically monitors Akt activity in living cells. To visualize Akt activity at different subcellular compartments, we targeted Eevee-iAkt to raft and non-raft regions of the plasma membrane, mitochondria, and nucleus in HeLa and Cos7 cells. Interestingly, we revealed substantial differences in Akt activation between HeLa and Cos7 cells upon epidermal growth factor (EGF) stimulation: Akt was transiently activated in HeLa cells with comparable levels at the plasma membrane, cytosol, and mitochondria. In contrast, sustained and spatially localized Akt activation was observed in EGF-stimulated Cos7 cells. We found high Akt activity at the plasma membrane, low activity in the cytosol, and no detectable activity at the mitochondria and nucleus in Cos7 cells. The Eevee-iAkt biosensor was shown to be a valuable tool to study the functional relationship between subcellular Akt activation and its anti-apoptotic role in living cells.


Understanding delay in accessing specialist emergency eye care in a developing country: eye trauma in Tanzania.
To determine the extent and reasons for delay in accessing specialist eye care following a significant eye injury. Mixed methods study involving 93 consecutive admissions to Kilimanjaro Christian Medical Center, Tanzania (KCMC). Semi-structured interviews were conducted and supplemented by a review of medical notes. A statistical analysis of delay and predictor variables was conducted. Framework analysis of interviews was conducted. Ninety of 93 patients took part. Significant visual loss was determined in 95.5% of affected eyes on arrival. The mean delay for treatment was 6.8 days. Of participants, 61.1% visited some health facility within 24 hours, and 82.2% within 48 hours. Injury on a weekend, using topical drops and visiting other health facilities before KCMC were independently associated with delay greater than 24 hours and greater than 48 hours, female gender with was associated with delay greater than 24 hours. Patient journeys involved key milestones and processes. Journeys were frequently "circular," involving delays caused by repeated visits to health units unable to treat the injury, often on a health worker's advice. Systems problems included unclear referral systems and opening times, frequent staff absence and unqualified staff deputizing. Individual health workers had an important influence on delay but their performance appeared variable. They influenced patient journeys positively when they made an accurate diagnosis, referred directly to KCMC, discussed practicalities and communicated the seriousness of the injury, the need for urgent treatment and the adverse consequences of delay. There is significant delay in accessing appropriate specialist care following eye injury in Tanzania, much of which occurs after first visiting a health facility. We present a new model of delay that may help guide interventions to reduce this delay.


Correlation of ethanol concentrations in blood and saliva.
1. The concentrations of ethanol in blood, mixed saliva obtained before and after rinsing and drying the mouth and parotid saliva have been monitored in 12 healthy subjects after the ingestion of alcohol. 2. A highly significant linear correlation was found between blood and the three types of saliva examined from 20 min after completion of drinking. 3. Blood and mixed saliva samples were obtained from 20 patients attending the Casualty Department with evidence of ethanol intoxication. A similar correlation was obtained. 4. These results show that salivary ethanol may be used as an index of blood ethanol concentrations, provided that the salivary sample is not obtained within 20 min of the ingestion of alcohol.


Conceptual issues related to the construction of prescriptive standards for the evaluation of postnatal growth of preterm infants.
Monitoring and interpreting the growth of preterm infants is a major clinical task for neonatologists. The effectiveness of this process depends upon the robustness of the standard selected. Concerns have been raised regarding the nature of the charts currently being used, as well as their appropriateness for present-day neonatal care. To overcome these problems, there is a need for new prescriptive standards based on a population of preterm infants without evidence of impaired fetal growth and born to low-risk women followed up since early pregnancy for precise gestational age dating. Preterm infants contributing to the new standards should be free of congenital malformations and major clinical conditions associated with impaired postnatal growth. These infants should receive standardised, evidence-based clinical care and should follow current feeding recommendations based on exclusive/predominant breastfeeding. This strategy should provide a population that is conceptually as close as possible to the prescriptive approach used for the construction of the WHO infant and child growth standards. New international standards constructed in this way should contribute to the evidence-based care of these preterm infants.


Antimicrobial activity of Nigella sativa L. seed oil against multi-drug resistant Staphylococcus aureus isolated from diabetic wounds.
Microbial resistance to existing antibiotics has led to an increase in the use of medicinal plants that show beneficial effects for various infectious diseases. The study evaluates the susceptibility of multidrug resistant Staphylococcus aureus to Nigella sativa oil. Staphylococcus aureus was isolated from 34 diabetic patient's wounds attending the Renaissance hospital, Nsukka, Southeast Nigeria. The isolates were characterized and identified using standard microbiological techniques. Isolates were cultured and a comparative In vitro antibiotic susceptibility test was carried out using the disk diffusion method. Of the 34 samples collected, 19(56%) showed multidrug resistance to the commonly used antibiotics. Nigella sativa oil was then studied for antibacterial activity against these multidrug resistant isolates of Staphylococcus aureus in varying concentration by well diffusion method. The oil showed pronounced dose dependent antibacterial activity against the isolates. Out of 19 isolates, 8(42%) were sensitive to undiluted oil sample; 4(21%) of these showed sensitivity at 200 mg/ml, 400 mg/ml and 800 mg/ml respectively. Eleven (58%) of the isolates were completely resistant to all the oil concentrations. The present study, reports the isolation of multi-drug resistant S. aureus from diabetic wounds and that more than half of isolates were susceptible to different concentrations N. sativa oil.


Chemotherapy-induced mesenchymal stem cell damage in patients with hematological malignancy.
Hematopoietic recovery after high-dose chemotherapy (HDC) in the treatment of hematological diseases may be slow and/or incomplete. This is generally attributed to progressive hematopoietic stem cell failure, although defective hematopoiesis may be in part due to poor stromal function. Chemotherapy is known to damage mature bone marrow stromal cells in vitro, but the extent to which marrow mesenchymal stem cells (MSCs) are damaged by HDC in vivo is largely unknown. To address this question, the phenotype and functional properties of marrow MSCs derived from untreated and chemotherapeutically treated patients with hematological malignancy were compared. This study demonstrates a significant reduction in MSC expansion and MSC CD44 expression by MSCs derived from patients receiving HDC regimens, thus implicating potential disadvantages in the use of autologous MSCs in chemotherapeutically pretreated patients for future therapeutic strategies. The clinical importance of these HDC-induced defects we have observed could be determined through prospective randomized trials of the effects of MSC cotransplantation on hematopoietic recovery in the setting of HDC with and without hematopoietic stem cell rescue.


Indocyanine green video-angiography in neurosurgery: a glance beyond vascular applications.
Indocyanine green video angiography (ICG-VA) is a non invasive, easy to use and a very useful tool for various neurosurgical procedures. Initially introduced in vascular neurosurgery since 2003, it's applications have broadened over time, both in vascular applications and in other neurosurgical fields. The objective of our study is to review all published literature about ICG-VA, cataloguing its different applications. A systematic review of all pertinent literature articles published from January 2003 to May 2014 using Pubmed access was performed using pertinent keywords; cross check of references of selected articles was performed in order to complete bibliographical research. Results of research were grouped by pathology. The paper systematically analyses ICG-VA different applications in neurosurgery, from vascular neurosurgery to tumor resection and endoscopic applications, focusing on reported advantages and disadvantages, and discussing future perspectives.


Level discrimination of single tones in a multitone complex by normal-hearing and hearing-impaired listeners.
A conditional-on-a-single-stimulus (COSS) analysis procedure [B. G. Berg, J. Acoust. Soc. Am. 86, 1743-1746 (1989)] was used to estimate how well normal-hearing and hearing-impaired listeners selectively attend to individual spectral components of a broadband signal in a level discrimination task. On each trial, two multitone complexes consisting of six octave frequencies from 250 to 8000 Hz were presented to listeners. The levels of the individual tones were chosen independently and at random on each presentation. The target tone was selected, within a block of trials, as the 250-, 1000-, or 4000-Hz component. On each trial, listeners were asked to indicate which of the two complex sounds contained the higher level target. As a group, normal-hearing listeners exhibited greater selectivity than hearing-impaired listeners to the 250-Hz target, while hearing-impaired listeners showed greater selectivity than normal-hearing listeners to the 4000-Hz target, which is in the region of their hearing loss. Both groups of listeners displayed large variability in their ability to selectively weight the 1000-Hz target. Trial-by-trial analysis showed a decrease in weighting efficiency with increasing frequency for normal-hearing listeners, but a relatively constant weighting efficiency across frequency for hearing-impaired listeners. Interestingly, hearing-impaired listeners selectively weighted the 4000-Hz target, which was in the region of their hearing loss, more efficiently than did the normal-hearing listeners.


Sentiment of Emojis.
There is a new generation of emoticons, called emojis, that is increasingly being used in mobile communications and social media. In the past two years, over ten billion emojis were used on Twitter. Emojis are Unicode graphic symbols, used as a shorthand to express concepts and ideas. In contrast to the small number of well-known emoticons that carry clear emotional contents, there are hundreds of emojis. But what are their emotional contents? We provide the first emoji sentiment lexicon, called the Emoji Sentiment Ranking, and draw a sentiment map of the 751 most frequently used emojis. The sentiment of the emojis is computed from the sentiment of the tweets in which they occur. We engaged 83 human annotators to label over 1.6 million tweets in 13 European languages by the sentiment polarity (negative, neutral, or positive). About 4% of the annotated tweets contain emojis. The sentiment analysis of the emojis allows us to draw several interesting conclusions. It turns out that most of the emojis are positive, especially the most popular ones. The sentiment distribution of the tweets with and without emojis is significantly different. The inter-annotator agreement on the tweets with emojis is higher. Emojis tend to occur at the end of the tweets, and their sentiment polarity increases with the distance. We observe no significant differences in the emoji rankings between the 13 languages and the Emoji Sentiment Ranking. Consequently, we propose our Emoji Sentiment Ranking as a European language-independent resource for automated sentiment analysis. Finally, the paper provides a formalization of sentiment and a novel visualization in the form of a sentiment bar.


Complete Genome Sequence of Shewanella sp. Strain TH2012, Isolated from Shrimp in a Cultivation Pond Exhibiting Early Mortality Syndrome.
Here, we present the complete genome sequence of a Shewanella isolate, TH2012, from a shrimp pond in which shrimp exhibited early mortality syndrome (EMS)/acute hepatopancreatic necrosis disease (AHPND). The complete genome of TH2012 has a prophage-like element and a number of potential virulence factors, making TH2012 a possible contributing factor to EMS outbreaks.


Global atmospheric change: potential health effects of acid aerosol and oxidant gas mixtures.
Inhalation toxicology experiments in whole animals have demonstrated a remarkable lack of toxicity of sulfuric acid in the form of respirable aerosols, especially in rats and nonhuman primates. Thus, much of the current experimental emphasis has shifted to the evaluation of the potential health effects of acid aerosols as components of mixtures. Rats have been concurrently exposed to mixtures of ozone or nitrogen dioxide with respirable-sized aerosols of sulfuric acid, ammonium sulfate, or sodium chloride, or to each pollutant individually. Their responses to such exposures have been evaluated by various quantitative biochemical analysis of lung tissue or wash fluids ("lavage fluid") or by quantitative morphological methods ("morphometry"). Such studies have mainly been performed in the acute time frame due to the inherent limitations of the most sensitive assays available and have generally involved exposures for 1 to 9 days, depending on the assays used. Good correlations were found between the most sensitive biochemical indicators of lung damage (protein content of lung lavage fluid or whole lung tissue and lung collagen synthesis rate) and the exposure concentration of oxidant gas present alone or in mixtures with acidic aerosols showing interactive effects. Synergistic interaction between ozone and sulfuric acid aerosol was demonstrated to occur at environmentally relevant concentrations of both pollutants by several of the analytical methods used in this study. Such interactions were demonstrated at concentrations of ozone as low as 0.12 ppm and of sulfuric acid aerosol at concentrations as low as 5 to 20 micrograms/m3.(ABSTRACT TRUNCATED AT 250 WORDS)


Changing ovarian stimulation parameters in a subsequent cycle does not increase the number of euploid embryos.
To compare the euploidy outcome in patients that underwent 2 ovarian stimulation cycles with trophectoderm biopsy. Retrospective repeated-measures cohort study. University-based fertility center. A total of 116 patients, from 2011 through 2013, that underwent 2 ovarian stimulation cycles followed by trophectoderm biopsy with array comparative genomic hybridization. Days of stimulation, average diameter of the 2 lead follicles on day of trigger, dose of gonadotropins, type of cycle (gonadotropin-releasing hormone [GnRH] antagonist, GnRH-antagonist plus clomiphene citrate [CC], microdose GnRH agonist). Number of euploid embryos. Patients were analyzed based on whether they had ≥1 euploid embryos in their first cycle vs. none. There was no increase in the number of euploid embryos with more days of stimulation or increases in the dose of gonadotropins in either group. Significantly more euploid embryos were seen in patients who had no euploid embryo(s) in the first cycle (Group 0) that had CC added to a GnRH-antagonist cycle (1.11 more euploid embryos) or were triggered when follicle sizes were 2 mm larger (0.40 euploid embryos), but these increases were not significant compared with a control group. Patients with euploid embryo(s) in the first cycle (Group 1) had significantly more euploid embryos when daily dose was increased by 75-149 international units, but this relationship was not significant compared with a control group with no increase in daily dose. No specific intervention increased the number of euploid embryos within the same patient any more than simply repeating a similar stimulation cycle. An attempt was made to control for interpatient variability, but individual patients have considerable intercycle variability.


Hydroxyl radical photoproduction in the sea and its potential impact on marine processes.
Photochemical production rates and steady-state concentrations of hydroxyl radicals (.OH) were measured in sunlight-irradiated seawater. Values ranged from 110 nanomolar per hour and 12 x 10(-18) molar in coastal surface water to 10 nanomolar per hour and 1.1 x 10(-18) molar in open ocean surface water. The wavelengths responsible for this production are in the ultraviolet B region (280 to 320 nanometers) of the solar spectrum. Dissolved organic matter (DOM) appears to be the main source for .OH over most of the oceans, but in upwelling areas nitrite and nitrate photolysis may also be important. DOM in the deep sea is degraded more readily by .OH (and its daughter radicals), by a factor of 6 to 15, than is DOM in open-ocean surface water. This finding may in part bear on major discrepancies among current methods for measuring dissolved organic carbon in seawater.


The importance of identification when measuring performance in addiction treatment.
Background: Identifying and effectively treating individuals with substance use disorders (SUDs) is an important priority for state Medicaid programs, given the enormous toll that SUDs take on individuals, their families, and their communities. In this paper, we describe how the Healthcare Effectiveness Data and Information Set (HEDIS) measure "Identification of Alcohol and Other Drug Services" can be used, along with eligible population prevalence rates, to expand states' ability to track how well their Medicaid programs identify enrollees with SUDs and link them with treatment (measured by initiation and engagement performance measures). Methods: We use the 2009 Medicaid MAX data on utilization and enrollment along with information from the National Survey of Drug Use and Health (NSDUH) to obtain state-level estimates of alcohol and drug abuse and dependence among Medicaid beneficiaries for 7 illustrative states. We calculate identification, initiation, and engagement measures using specifications from the National Committee on Quality Assurance (NCQA). Results: NSDUH data showed that the eligible population prevalence rate (the average rate of alcohol or drug abuse or dependence) among the 7 states was 10.0%, whereas the average identification rate was 2.9%. The gap between the prevalence and identification rates ranged from 5.1% to 11.0% among the 7 states. The initiation rates ranged from 36.9% to 57.1%. The states' engagement rates ranged from 11.8% to 31.1%, although rates differ by age, gender, and race/ethnicity in some states. Conclusion: Including identification along with initiation and engagement measures allows states to determine how well they are performing in a more complete spectrum from need, to recognition and documentation of enrollees with SUDs, to initiation of treatment, to continuation of early treatment.


Behavioral effects of ketamine and toxic interactions with psychostimulants.
The anesthetic drug ketamine (KT) has been reported to be an abused drug and fatal cases have been observed in polydrug users. In the present study, considering the possibility of KT-enhanced toxic effects of other drugs, and KT-induced promotion of an overdose without making the subject aware of the danger due to the attenuation of several painful subjective symptoms, the intraperitoneal (i.p.) KT-induced alterations in behaviors and toxic interactions with popular co-abused drugs, the psychostimulants cocaine (COC) and methamphetamine (MA), were examined in ICR mice. A single dose of KT caused hyperlocomotion in a low (30 mg/kg, i.p.) dose group, and hypolocomotion followed by hyperlocomotion in a high (100 mg/kg, i.p.) dose group. However, no behavioral alterations derived from enhanced stress-related depression or anxiety were observed in the forced swimming or the elevated plus-maze test. A single non-fatal dose of COC (30 mg/kg, i.p.) or MA (4 mg/kg, i.p.) caused hyperlocomotion, stress-related depression in swimming behaviors in the forced swimming test, and anxiety-related behavioral changes (preference for closed arms) in the elevated plus-maze test. For the COC (30 mg/kg) or MA (4 mg/kg) groups of mice simultaneously co-treated with KT, the psychostimulant-induced hyperlocomotion was suppressed by the high dose KT, and the psychostimulant-induced behavioral alterations in the above tests were reversed by both low and high doses of KT. For the toxic dose COC (70 mg/kg, i.p.)- or MA (15 mg/kg, i.p.)-only group, mortality and severe seizures were observed in some animals. In the toxic dose psychostimulant-KT groups, KT attenuated the severity of seizures dose-dependently. Nevertheless, the mortality rate was significantly increased by co-treatment with the high dose KT. Our results demonstrated that, in spite of the absence of stress-related depressive and anxiety-related behavioral alterations following a single dose of KT treatment, and in spite of the KT-induced anticonvulsant effects and attenuation of stress- and anxiety-related behaviors caused by COC or MA, the lethal effects of these psychostimulants were increased by KT.


A novel GDP-dependent pyruvate kinase isozyme from Toxoplasma gondii localizes to both the apicoplast and the mitochondrion.
We previously reported a cytosolic pyruvate kinase (EC 184.108.40.206) from Toxoplasma gondii (TgPyKI) that differs from most eukaryotic pyruvate kinases in being regulated by glucose 6-phosphate rather than fructose 1,6-diphosphate. Another putative pyruvate kinase (TgPyKII) was identified from parasite genome, which exhibits 32% amino acid sequence identity to TgPyKI and retains pyruvate kinase signature motifs and amino acids essential for substrate binding and catalysis. Whereas TgPyKI is most closely related to plant/algal enzymes, phylogenetic analysis suggests a proteobacterial origin for TgPyKII. Enzymatic characterization of recombinant TgPyKII shows a high pH optimum at 8.5, and a preference for GDP as a phosphate recipient. Catalytic activity is independent of K+, and no allosteric or regulatory effects were observed in the presence of fructose 1,6-diphosphate, fructose 2,6-diphosphate, glucose 6-phosphate, ribose 5-phosphate, AMP, or ATP. Unlike TgPyKI, native TgPyKII activity was exclusively associated with the membranous fraction of a T. gondii tachyzoite lysate. TgPyKII possesses a long N-terminal extension containing five putative start codons before the conserved region and localizes to both apicoplast and mitochondrion by immunofluorescence assay using native antibody and fluorescent protein fusion to the N-terminal extension. Further deletional and site-directed mutagenesis suggests that a translation product from 1st Met is responsible for the localization to the apicoplast, whereas one from 3rd Met is for the mitochondrion. This is the first study of a potential mitochondrial pyruvate kinase in any system.


Culturally-sensitive weight loss program produces significant reduction in weight, blood pressure, and cholesterol in eight weeks.
Dietary and behavioral needs of special populations are rarely considered in traditional weight loss programs. This study assessed the impact of culturally-sensitive modifications to the Duke University Rice Diet weight loss program for African-American dieters. The study was a randomized modified cross-over study in which volunteers received either early or delayed weight loss intervention. Final outcomes were measured at 8 weeks. At the onset of the study, there were 56 African American participants, however, only 44 (79%) completed the study. The eight-week intervention was a modified 1000-calorie/day version of the Rice Diet. Modifications to the program included decreased cost, culturally-sensitive recipes, addressing attitudes about exercise, and including family members in weight loss efforts. Average weight loss for subjects completing the program was 14.8 pounds (SD = 6.8 pounds). BMI decreased from 37.8 kg/m2 to 35.3 kg/m2 (p < 0.01). Total cholesterol levels decreased from 199.2 mg/dL to 185.4 mg/dL (p < 0.01); systolic and diastolic blood pressure decreased by 4.3 mmHg (p < 0.01) and 2.4 mmHg (p < 0.05), respectively. The control group showed no significant change in any outcome measures. We found that diet programs can be successfully tailored to incorporate the needs of African-Americans. Most importantly, these dietary program changes can lead to significant improvement in clinical parameters. Additional studies are necessary to determine the permanence of these short-term changes.


Results from nationwide hepatitis B serosurvey in Cambodia using simple and rapid laboratory test: implications for National Immunization Program.
Chronic liver infection and cancer in the western Pacific region is disproportionate to the population globally. This study provides the first nationwide estimates of hepatitis B surface antigen (HBsAg) seroprevalence in Cambodia among children five year of age. Using a simple and rapid test for HBsAg and multi-stage stratified cluster sampling design, we estimated HBsAg seroprevalence to be 3.5% (95% confidence interval = 2.4-4.8%) among five-year old children. Triangulating the results with other studies, we demonstrate the importance of interrupting perinatal transmission and one-time catch-up vaccination of older children born before nationwide introduction of vaccination for effective hepatitis B control in Cambodia and for reaching the disease control goal of less than 2% chronic infection rates among children > or = 5 years of age. The results demonstrate the feasibility of conducting nationwide serosurveys using simple and rapid tests to evaluate the impact of hepatitis B vaccination programs in lieu of standard enzyme-linked immunosorbent assays.


The prognostic value of excision repair cross-complementation group 1 (ERCC1) in patients with small cell lung cancer (SCLC) receiving platinum-based chemotherapy: evidence from meta-analysis.
Recently, the correlation between the efficacy of platinum-based chemotherapy and ERCC1 expression in patients with SCLC has attracted wide-spread attention, and a lot of investigations have been conducted, whereas conflicting results were presented. Therefore, we performed the present meta-analysis of eligible studies to derive a more precise evaluation of the association between ERCC1 expression and the clinical outcome in SCLC patients receiving platinum-based chemotherapy. A literature search for relevant studies was conducted in the electronic databases of PubMed, EMBASE and Web of Science. The inclusive criteria were SCLC patients treated by platinum-based chemotherapy, and evaluated the relationship between ERCC1 expression and the clinical outcomes [including overall response rate (ORR), overall survival (OS) or progression-free survival (PFS)]. Odds ratio (OR) or hazard ratio (HR) with 95% confidence interval (CI) was calculated to assess the risk. A total of nine studies including 1129 patients were included in final analysis. Our analysis indicated that positive/high ERCC1 expression was associated with unfavorable OS (HR = 1.18, 95%CI = 1.02-1.37) and PFS (HR = 1.46, 95%CI = 1.14-1.88). Subgroup analysis according to disease stage suggested the significant relationship was found in limited stage (LS-SCLC), but not in extensive stage (ES-SCLC). However, no significant association was found between ERCC1 expression and ORR. Our analysis suggested ERCC1 expression may be a prognostic factor in SCLC patients receiving platinum-based chemotherapy, especially for LS-SCLC.


Body schematics: on the role of the body schema in embodied lexical-semantic representations.
Words denoting manipulable objects activate sensorimotor brain areas, likely reflecting action experience with the denoted objects. In particular, these sensorimotor lexical representations have been found to reflect the way in which an object is used. In the current paper we present data from two experiments (one behavioral and one neuroimaging) in which we investigate whether body schema information, putatively necessary for interacting with functional objects, is also recruited during lexical processing. To this end, we presented participants with words denoting objects that are typically brought towards or away from the body (e.g., cup or key, respectively). We hypothesized that objects typically brought to a location on the body (e.g., cup) are relatively more reliant on body schema representations, since the final goal location of the cup (i.e., the mouth) is represented primarily through posture and body co-ordinates. In contrast, objects typically brought to a location away from the body (e.g., key) are relatively more dependent on visuo-spatial representations, since the final goal location of the key (i.e., a keyhole) is perceived visually. The behavioral study showed that prior planning of a movement along an axis towards and away from the body facilitates processing of words with a congruent action semantic feature (i.e., preparation of movement towards the body facilitates processing of cup.). In an fMRI study we showed that words denoting objects brought towards the body engage the resources of brain areas involved in the processing information about human bodies (i.e., the extra-striate body area, middle occipital gyrus and inferior parietal lobe) relatively more than words denoting objects typically brought away from the body. The results provide converging evidence that body schema are implicitly activated in processing lexical information.


Global soil nitrous oxide emissions since the preindustrial era estimated by an ensemble of terrestrial biosphere models: Magnitude, attribution, and uncertainty.
Our understanding and quantification of global soil nitrous oxide (N2 O) emissions and the underlying processes remain largely uncertain. Here, we assessed the effects of multiple anthropogenic and natural factors, including nitrogen fertilizer (N) application, atmospheric N deposition, manure N application, land cover change, climate change, and rising atmospheric CO2 concentration, on global soil N2 O emissions for the period 1861-2016 using a standard simulation protocol with seven process-based terrestrial biosphere models. Results suggest global soil N2 O emissions have increased from 6.3 ± 1.1 Tg N2 O-N/year in the preindustrial period (the 1860s) to 10.0 ± 2.0 Tg N2 O-N/year in the recent decade (2007-2016). Cropland soil emissions increased from 0.3 Tg N2 O-N/year to 3.3 Tg N2 O-N/year over the same period, accounting for 82% of the total increase. Regionally, China, South Asia, and Southeast Asia underwent rapid increases in cropland N2 O emissions since the 1970s. However, US cropland N2 O emissions had been relatively flat in magnitude since the 1980s, and EU cropland N2 O emissions appear to have decreased by 14%. Soil N2 O emissions from predominantly natural ecosystems accounted for 67% of the global soil emissions in the recent decade but showed only a relatively small increase of 0.7 ± 0.5 Tg N2 O-N/year (11%) since the 1860s. In the recent decade, N fertilizer application, N deposition, manure N application, and climate change contributed 54%, 26%, 15%, and 24%, respectively, to the total increase. Rising atmospheric CO2 concentration reduced soil N2 O emissions by 10% through the enhanced plant N uptake, while land cover change played a minor role. Our estimation here does not account for indirect emissions from soils and the directed emissions from excreta of grazing livestock. To address uncertainties in estimating regional and global soil N2 O emissions, this study recommends several critical strategies for improving the process-based simulations.


Impact of Exposure to Dim Light at Night on Sleep in Female and Comparison with Male Subjects.
Light pollution has become a social and health issue. We performed an experimental study to investigate impact of dim light at night (dLAN) on sleep in female subjects, with measurement of salivary melatonin. The 25 female subjects (Group A: 12; Group B: 13 subjects) underwent a nocturnal polysomnography (NPSG) session with no light (Night 1) followed by an NPSG session randomly assigned to two conditions (Group A: 5; Group B: 10 lux) during a whole night of sleep (Night 2). Salivary melatonin was measured before and after sleep on each night. For further investigation, the female and male subjects of our previous study were collected (48 subjects), and differences according to gender were compared. dLAN during sleep was significantly associated with decreased total sleep time (TST; F=4.818, p=0.039), sleep efficiency (SE; F=5.072, p=0.034), and Stage R latency (F=4.664, p=0.041) for female subjects, and decreased TST (F=14.971, p<0.001) and SE (F=7.687, p=0.008), and increased wake time after sleep onset (F=6.322, p=0.015) and Stage R (F=5.031, p=0.03), with a night-group interaction (F=4.579, p=0.038) for total sample. However, no significant melatonin changes. There was no significant gender difference of the impact of dLAN on sleep, showing the negative changes in the amount and quality of sleep and the increase in REM sleep in the both gender group under 10 lux condition. We found a negative impact of exposure to dLAN on sleep in female as well as in merged subjects. REM sleep showed a pronounced increase under 10 lux than under 5 lux in merged subjects, suggesting the possibility of subtle influences of dLAN on REM sleep.


Rhenium (I) Complexes as Probes for Prokaryotic and Fungal Cells by Fluorescence Microscopy: Do Ligands Matter?
Re(I) complexes have exposed highly suitable properties for cellular imaging (especially for fluorescent microscopy) such as low cytotoxicity, good cellular uptake, and differential staining. These features can be modulated or tuned by modifying the ligands surrounding the metal core. However, most of Re(I)-based complexes have been tested for non-walled cells, such as epithelial cells. In this context, it has been proposed that Re(I) complexes are inefficient to stain walled cells (i.e., cells protected by a rigid cell wall, such as bacteria and fungi), presumably due to this physical barrier hampering cellular uptake. More recently, a series of studies have been published showing that a suitable combination of ligands is useful for obtaining Re(I)-based complexes able to stain walled cells. This review summarizes the main characteristics of different fluorophores used in bioimage, remarking the advantages of d6-based complexes, and focusing on Re(I) complexes. In addition, we explored different structural features of these complexes that allow for obtaining fluorophores especially designed for walled cells (bacteria and fungi), with especial emphasis on the ligand choice. Since many pathogens correspond to bacteria and fungi (yeasts and molds), and considering that these organisms have been increasingly used in several biotechnological applications, development of new tools for their study, such as the design of new fluorophores, is fundamental and attractive.


Role of CEACAM1 and CEACAM20 in an in vitro model of prostate morphogenesis.
CEACAM20, a novel member of the CEACAM1 gene family with expression limited to the lumen of small intestine, testes, and prostate, is co-expressed with CEACAM1 in adult prostate tissue and down-regulated to the same extent as CEACAM1 in prostate cancer. Since prostate cancer often involves loss of epithelial lumen formation, we hypothesized that CEACAM20 and CEACAM1 play important roles in lumen formation of normal prostate epithelium. When prostate cells were grown on Matrigel as a source of extracellular matrix (ECM), they differentiated into acinar structures with single tubules and well-defined lumina closely resembling embryonic prostate organoids. Confocal microscopic analysis revealed restriction of CEACAM20 to acini and CEACAM1 to tubule structures, respectively. Inhibition of CEACAM1 with antibodies or soluble CEACAM1 or antisense oligonucleotides inhibited tubule formation by over 50% while the remaining tubules were stunted. Inhibition of CEACAM20 with antisense oligonucleotides completely inhibited tubule formation and stunted the growth of acini. We conclude that CEACAM20 and CEACAM1 not only mark the lumina of adult prostate tissue but also play a critical role in the vitro generation of prostate organoids.


Neuropsychological correlates of syndromes in schizophrenia.
On the basis of Liddle's three-syndrome model of schizophrenia, it was predicted that: (1) symptoms of psychomotor poverty would be particularly correlated with impaired performance on neuropsychological tests likely to reflect functioning of the dorsolateral prefrontal cortex; (2) disorganisation would be particularly correlated with impaired performance on tests sensitive to medio-basal prefrontal functioning; and (3) reality distortion would be particularly correlated with measures sensitive to temporal lobe functioning. The above hypotheses were tested on 87 subjects with a confirmed diagnosis of schizophrenia. Patients' symptoms were scored for each of the three syndromes. Patients completed six neuropsychological tests designed to measure impairment in specific areas of the brain. There was no support for the first two hypotheses. There was, however, evidence of a specific relationship between reality distortion and neuropsychological performance usually considered to be related to left temporal lobe functioning. Although not directly supporting the first two hypotheses; the results are, in general, consistent with there being different cortical-subcortical circuits associated with each of psychomotor poverty and disorganisation. Temporal lobe functioning appears to have particular significance for the reality distortion syndrome.


Duloxetine and other antidepressants in the treatment of patients with fibromyalgia.
To review the use of duloxetine, a new selective serotonin and norepinephrine reuptake inhibitor (SNRI), and other antidepressants in the treatment of patients with fibromyalgia. Two randomized, placebo-controlled, double-blind, parallel-group, 12-week trials of duloxetine in the treatment of fibromyalgia were reviewed. Other published, randomized, placebo-controlled, double-blind trials, and meta-analyses of antidepressant treatment of fibromyalgia were identified by a PubMed search that was augmented by reference cross-check. Duloxetine has been shown to be an effective and safe treatment for many of the symptoms associated with fibromyalgia, particularly for women. Other selective SNRIs also show promise in the treatment of fibromyalgia. Until recently, tricyclic agents that have serotonin and norepinephrine reuptake inhibitory activity had been the most commonly studied group of antidepressants, and they are effective in treating pain and other symptoms associated with fibromyalgia, although their use may be limited by safety and tolerability concerns. There are few randomized, controlled studies of selective serotonin reuptake inhibitors in fibromyalgia, and the results have been mixed. Antidepressants play an important role in the treatment of patients with fibromyalgia. Agents with dual effects on serotonin and norepinephrine appear to have more consistent benefits than selective serotonin antidepressants for the treatment of persistent pain associated with fibromyalgia.


Histone acetylation in astrocytes suppresses GFAP and stimulates a reorganization of the intermediate filament network.
Glial fibrillary acidic protein (GFAP) is the main intermediate filament in astrocytes and is regulated by epigenetic mechanisms during development. We demonstrate that histone acetylation also controls GFAP expression in mature astrocytes. Inhibition of histone deacetylases (HDACs) with trichostatin A or sodium butyrate reduced GFAP expression in primary human astrocytes and astrocytoma cells. Because splicing occurs co-transcriptionally, we investigated whether histone acetylation changes the ratio between the canonical isoform GFAPα and the alternative GFAPδ splice variant. We observed that decreased transcription of GFAP enhanced alternative isoform expression, as HDAC inhibition increased the GFAPδ∶GFAPα ratio. Expression of GFAPδ was dependent on the presence and binding of splicing factors of the SR protein family. Inhibition of HDAC activity also resulted in aggregation of the GFAP network, reminiscent of our previous findings of a GFAPδ-induced network collapse. Taken together, our data demonstrate that HDAC inhibition results in changes in transcription, splicing and organization of GFAP. These data imply that a tight regulation of histone acetylation in astrocytes is essential, because dysregulation of gene expression causes the aggregation of GFAP, a hallmark of human diseases like Alexander's disease.


Examining pretrial publicity in a shadow jury paradigm: issues of slant, quantity, persistence and generalizability.
The purpose of this study was to examine the influence of pretrial publicity (PTP) on mock juror decision making. Specifically, we examined the influence of quantity and slant of the PTP (proprosecution vs. prodefense), the persistence of PTP effects over time, and whether the PTP effects demonstrated in research laboratories would also occur in more naturalistic settings (generalizability). Using a shadow jury paradigm we examined these effects using a real trial as stimulus. Mock jurors included 115 jury-eligible community members who were naturally exposed to PTP in the venue in which the actual case occurred and 156 who were experimentally exposed. We found mock jurors were significantly influenced by both the slant and quantity of the PTP to which they were exposed, such that those exposed to proprosecution or prodefense PTP tended to render decision in support of the party favored in the PTP, and those exposed to greater quantities of PTP tended to be more biased. Additionally, PTP effects persisted throughout the course of the trial and continued to influence judgments in face of trial evidence and arguments. A finding of no significant difference in the effect of exposure slant between the naturally exposed and experimentally exposed samples provides support for the external validity of laboratory studies examining PTP effects. This research helps address some of the concerns raised by courts with regard to the durability of PTP effects and the application of laboratory findings to real world settings.


Adverse drug reactions of non-opioid and opioid analgesics reported to Croatian national authority from 2007 to 2014.
Adverse drug reactions (ADRs) are commonly observed in the health services because of system weaknesses and individual errors. Analgesics are widely used and it can be expected that with the increased use one can expect increased number of ADRs of analgesics. The aim of this study was to analyze ADRs of non-opioid and opioid analgesics reported to the Croatian Agency for Medicinal Products and Medical Devices (HALMED) from 2007 to 2014. HALMED provided data on generic drug name, year of the ADR report, type of report, institution, reporting person, patient's age, sex and ADR type. In the analyzed period 796 ADRs of analgesics were reported, of which 367 (46%) were serious ADRs. Number of ADR reports was continuously increasing during the analyzed period. There were 20 analgesics that had ≥5 reports, making 597 (75%) of all ADR reports for analgesics. The most common adverse reaction reports of those 20 analgesics referred to individual drugs (n=16; 80%). Most of the ADR reports were filed by physicians (n=257; 43%), followed by pharmacists (n=252; 42%). Most side effects (n=572; 96%) were reported spontaneously through appropriate forms by patients or health professionals. ADRs were most commonly reported in women (n=352; 59%) and most of them have occurred in adults (n=354; 59%). The most common ADRs of opioid and non-opioid analgesics have been reported on the skin and mucous membranes. Most serious ADRs were result of action of opioid analgesics. Number of ADR reports in Croatia is continuously increasing and a considerable number of them refers to serious ADRs. To keep better track of medications and ADRs it is necessary to educate and encourage health professionals and patients in reporting side effects.


Incidence trends in the anatomic location of primary malignant brain tumors in the United States: 1992-2006.
This study sought to determine incidence trends of the anatomical origin of primary malignant brain tumors. Incidence data for histologically confirmed brain tumors were obtained from the Los Angeles County Cancer Surveillance Program (LAC), the California Cancer Registry (CCR), and the National Cancer Institute's Surveillance, Epidemiology, and End Results (SEER) program for 1992 to 2006. Age-adjusted incidence rates (AAIR) and annual percent changes (APC) were calculated by histologic subtypes and anatomic subsites. Statistical analyses were performed using the SEER*Stat analytic software and SAS statistical software. Increased AAIRs of frontal (APC +2.4% to +3.0%, P ≤ 0.001) and temporal (APC +1.3% to +2.3%, P ≤ 0.027) lobe glioblastoma multiforme (GBM) tumors were observed across all registries, accompanied by decreased AAIRs in overlapping region GBMs (-2.0% to -2.8% APC, P ≤ 0.015). The AAIRs of GBMs in the parietal and occipital lobes remained stable. The AAIR of cerebellar GBMs increased according to CCR (APC +11.9%, P < 0.001). The AAIR of all gliomas, which includes all anatomical subsites, decreased (-0.5% to -0.8% APC, P ≤ 0.034). Low-grade and anaplastic astrocytomas demonstrated decreased AAIRs in the majority of brain regions. Data from 3 major cancer registries demonstrate increased incidences of GBMs in the frontal lobe, temporal lobe, and cerebellum, despite decreased incidences in other brain regions. Although this may represent an effect of diagnostic bias, the incidence of both large and small tumors increased in these regions. The cause of these observed trends is unknown.


Alternative polyadenylation analysis in animals and plants: newly developed strategies for profiling, processing and validation.
Alternative polyadenylation is an essential RNA processing event that contributes significantly to regulation of transcriptome diversity and functional dynamics in both animals and plants. Here we review newly developed next generation sequencing methods for genome-wide profiling of alternative polyadenylation (APA) sites, bioinformatics pipelines for data processing and both wet and dry laboratory approaches for APA validation. The library construction methods LITE-Seq (Low-Input 3'-Terminal sequencing) and PAC-seq (PolyA Click sequencing) tag polyA+ cDNA, while BAT-seq (BArcoded, three-prime specific sequencing) and PAPERCLIP (Poly(A) binding Protein-mediated mRNA 3'End Retrieval by CrossLinking ImmunoPrecipitation) enrich polyA+ RNA. Interestingly, only WTTS-seq (Whole Transcriptome Termini Site sequencing) targets both polyA+ RNA and polyA+ cDNA. Varieties of bioinformatics pipelines are well established to pursue read quality control, mapping, clustering, characterization and pathway analysis. The RHAPA (RNase H alternative polyadenylation assay) and 3'RACE-seq (3' rapid amplification of cDNA end sequencing) methods directly validate APA sites, while WTSS-seq (whole transcriptome start site sequencing), RNA-seq (RNA sequencing) and public APA databases can serve as indirect validation methods. We hope that these tools, pipelines and resources trigger huge waves of interest in the research community to investigate APA events underlying physiological, pathological and psychological changes and thus understand the information transfer events from genome to phenome relevant to economically important traits in both animals and plants.


Treatment Considerations of Clinical Physician on Hypertension Management in Asia.
There are important differences in the lifestyle and cardiovascular disease risks between Asian and Western populations. The objective of this survey was to investigate the awareness of these factors in the practice of hypertension management among Asian physicians. General practitioners and specialists in Asia were surveyed by questionnaire with regard to their management of hypertension. Physicians attending international conferences or meetings on hypertension between March and May 2014 were asked to participate. In their treatment of hypertensive patients, 87% of the 133 respondents said they considered the Asian lifestyle and region-specific characteristics of hypertension in their treatment decisions, while just less than 11% did not. Almost all physicians (92%) recognized the necessity for an Asian-specific guideline for the management of hypertension. For patients with diabetes, 37% and 59% of the respondents used target systolic blood pressure (SBP) levels of 140 mmHg and 130 mmHg, respectively; for elderly patients, 37% and 53% of respondents used target SBP levels of 140 and l50 mmHg, respectively. Forty-eight percent of Asian physicians used calcium channel blockers as the first-line choice of antihypertensive drug while 34% selected angiotensin II receptor blockers, 14% angiotensin converting enzyme inhibitors and 3% diuretics. Asian physicians consider that an Asian-specific guideline is needed for hypertension management in the Asian population.


Cod Gadus morhua and climate change: processes, productivity and prediction.
Environmental factors act on individual fishes directly and indirectly. The direct effects on rates and behaviour can be studied experimentally and in the field, particularly with the advent of ever smarter tags for tracking fishes and their environment. Indirect effects due to changes in food, predators, parasites and diseases are much more difficult to estimate and predict. Climate can affect all life-history stages through direct and indirect processes and although the consequences in terms of growth, survival and reproductive output can be monitored, it is often difficult to determine the causes. Investigation of cod Gadus morhua populations across the whole North Atlantic Ocean has shown large-scale patterns of change in productivity due to lower individual growth and condition, caused by large-scale climate forcing. If a population is being heavily exploited then a drop in productivity can push it into decline unless the level of fishing is reduced: the idea of a stable carrying capacity is a dangerous myth. Overexploitation can be avoided by keeping fishing mortality low and by monitoring and responding rapidly to changes in productivity. There are signs that this lesson has been learned and that G. morhua will continue to be a mainstay of the human diet.


Cell density in the border zone around old small human brain infarcts.
Nine brain autopsy cases of small old cerebral infarcts were selected for neuropathological studies. Eight of the patients had cortical infarcts, in two cases with extension into the striate body. In one case the infarct involved the striate body only. The density of neurons and glial cells was measured in the coronal and the horizontal planes at various distances from the margin of the infarct. Corresponding counting points in the contralateral hemisphere served as control. On light microscopy, the infarcted cortex was irregularly shaped, but on serial sections the bulging parts appeared to be cut off from the infarcted tissue ("pseudo-infarct islands"). The zone of transition from infarcted to normal brain tissue was less than a few mm wide. In one patient, tomographic measurements of the cerebral blood flow (CBF) and a CT scan could be compared with the neuropathological findings. In this patient, CBF in the surroundings of the infarct was decreased despite a normal neuronal density. The study supports the traditional view held by pathologists that a sharp transition exists between infarcted and normal brain tissue and suggests that the hypoperfusion zone surrounding the region of complete infarction may be due to mechanisms other than selective loss of neurons.


Drug addict deaths in the Nordic countries: a study based on medicolegally examined cases in the five Nordic countries in 1991.
The study includes medicolegally examined deaths among drug addicts in 1991 in the five Nordic countries: Denmark, Finland, Iceland, Norway and Sweden. A common definition of 'drug addict' was applied by the participating countries. The greatest number of drug addict deaths per 10(5) inhabitants was observed in Denmark followed, in descending order by Norway, Sweden, Finland and finally Iceland with only four deaths. The main difference between the countries was found in the number of fatal poisonings. The distribution according to geographical regions showed that about half of all drug addict deaths occurred in the metropolitan areas. Of the capitals, the greatest number of fatal poisonings per 10(5) inhabitants was seen in Oslo, followed by Copenhagen with a similar number, Stockholm with only the half, and Helsinki with a quarter. Heroin/morphine dominated as cause of death in fatal poisonings in Norway and Sweden. In Denmark, heroin/morphine caused about half of the fatal poisonings only, and nearly one third of the fatal poisonings was caused by methadone. Except for two cases in Sweden, methadone deaths were not seen in the other Nordic countries. Amphetamine caused one tenth of the fatal poisonings in Sweden. In Finland only one tenth of the deaths were caused by heroin/morphine and more by codeine, ethylmorphine and different drugs and poisons not classified in Single Convention on Narcotic Drugs 1961 or the International Convention on Psychotropic Substances 1971. A widespread use of alcohol, cannabis and benzodiazepines, diazepam especially, was seen in all the countries.


Phosphoinositide 3-kinase signalling pathways.
Phosphoinositide 3-kinases (PI3Ks) phosphorylate the 3'-OH position of the inositol ring of inositol phospholipids, producing three lipid products: PtdIns(3)P, PtdIns(3,4)P(2) and PtdIns(3,4,5)P(3). These lipids bind to the pleckstrin homology (PH) domains of proteins and control the activity and subcellular localisation of a diverse array of signal transduction molecules. Three major classes of signalling molecule are regulated by binding of D-3 phosphoinositides to PH domains: guanine-nucleotide-exchange proteins for Rho family GTPases, the TEC family tyrosine kinases such as BTK and ITK in B and T lymphocytes, respectively, and the AGC superfamily of serine/threonine protein kinases. These molecules are activated by a variety of extracellular stimuli and have been implicated in a wide range of cellular processes, including cell cycle progression, cell growth, cell motility, cell adhesion and cell survival.


Transforming primary healthcare by including the stakeholders involved in delivering care to people living in poverty: EQUIhealThY study protocol.
Ensuring access to timely and appropriate primary healthcare for people living in poverty is an issue facing all countries, even those with universal healthcare systems. The transformation of healthcare practices and organization could be improved by involving key stakeholders from the community and the healthcare system in the development of research interventions. The aim of this project is to stimulate changes in healthcare organizations and practices by encouraging collaboration between care teams and people living in poverty. Our objectives are twofold: 1) to identify actions required to promote the adoption of professional practices oriented toward social competence in primary care teams; and 2) to examine factors that would encourage the inclusion of people living in poverty in the process of developing social competence in healthcare organizations. This study will use a participatory action research design applied in healthcare organizations. Participatory research is an increasingly recognized approach that is helpful for involving the people for whom the research results are intended. Our research team consists of 19 non-academic researchers, 11 academic researchers and six partners. A steering committee composed of academic researchers and stakeholders will have a decision-making role at each step, including knowledge dissemination and recommendations for new interventions. In this project we will adopt a multiphase approach and will use a variety of methods, including photovoice, group discussions and interviews. The proposed study will be one of only a few using participatory research in primary care to foster changes aimed at enhancing quality and access to care for people living in poverty. To our knowledge this will be the first study to use photovoice in healthcare organizations to promote new interventions. Our project includes partners who are targeted for practice changes and improvements in delivering primary care to persons living in poverty. By involving knowledge users, including service recipients, our study is more likely to produce a transformation of professional practices and encourage healthcare organizations to take into account the needs of persons living in poverty.


Cdc42-interacting protein 4 promotes breast cancer cell invasion and formation of invadopodia through activation of N-WASp.
In the earliest stages of metastasis, breast cancer cells must reorganize the cytoskeleton to affect cell shape change and promote cell invasion and motility. These events require the cytoskeletal regulators Cdc42 and Rho, their effectors such as N-WASp/WAVE, and direct inducers of actin polymerization such as Arp2/3. Little consideration has been given to molecules that shape the cell membrane. The F-BAR proteins CIP4, TOCA-1, and FBP17 generate membrane curvature and act as scaffolding proteins for activated Cdc42 and N-WASp. We found that expression of CIP4, but not TOCA-1 or FBP17, was increased in invasive breast cancer cell lines in comparison with weakly or noninvasive breast cancer cell lines. Endogenous CIP4 localized to the leading edge of migrating cells and to invadopodia in cells invading gelatin. Because CIP4 serves as a scaffolding protein for Cdc42, Src, and N-WASp, we tested whether loss of CIP4 could result in decreased N-WASp function. Interaction between CIP4 and N-WASp was epidermal growth factor responsive, and CIP4 silencing by small interfering RNA caused decreased tyrosine phosphorylation of N-WASp at a Src-dependent activation site (Y256). CIP4 silencing also impaired the migration and invasion of MDA-MB-231 cells and was associated with decreased formation of invadopodia and gelatin degradation. This study presents a new role for CIP4 in the promotion of migration and invasion of MDA-MB-231 breast cancer cells and establishes the contribution of F-BAR proteins to cancer cell motility and invasion.


A Survey of Automatic Facial Micro-Expression Analysis: Databases, Methods, and Challenges.
Over the last few years, automatic facial micro-expression analysis has garnered increasing attention from experts across different disciplines because of its potential applications in various fields such as clinical diagnosis, forensic investigation and security systems. Advances in computer algorithms and video acquisition technology have rendered machine analysis of facial micro-expressions possible today, in contrast to decades ago when it was primarily the domain of psychiatrists where analysis was largely manual. Indeed, although the study of facial micro-expressions is a well-established field in psychology, it is still relatively new from the computational perspective with many interesting problems. In this survey, we present a comprehensive review of state-of-the-art databases and methods for micro-expressions spotting and recognition. Individual stages involved in the automation of these tasks are also described and reviewed at length. In addition, we also deliberate on the challenges and future directions in this growing field of automatic facial micro-expression analysis.


Coaxial additive manufacture of biomaterial composite scaffolds for tissue engineering.
An inherent difficulty associated with the application of suitable bioscaffolds for tissue engineering is the incorporation of adequate mechanical characteristics into the materials which recapitulate that of the native tissue, whilst maintaining cell proliferation and nutrient transfer qualities. Biomaterial composites fabricated using rapid prototyping techniques can potentially improve the functionality and patient-specific processing of tissue engineering scaffolds. In this work, a technique for the coaxial melt extrusion printing of core-shell scaffold structures was designed, implemented and assessed with respect to the repeatability, cell efficacy and scaffold porosity obtainable. Encapsulated alginate hydrogel/thermoplastic polycaprolactone (Alg-PCL) cofibre scaffolds were fabricated. Selective laser melting was used to produce a high resolution stainless steel 316 L coaxial extrusion nozzle, exhibiting diameters of 300 μm/900 μm for the inner and outer nozzles respectively. We present coaxial melt extrusion printed scaffolds of Alg-PCL cofibres with ~0.4 volume fraction alginate, with total fibre diameter as low as 600 μm and core material offset as low as 10% of the total diameter. Furthermore the tuneability of scaffold porosity, pore size and interconnectivity, as well as the preliminary inclusion, compatibility and survival of an L-929 mouse fibroblast cell-line within the scaffolds were explored. This preliminary cell work highlighted the need for optimal material selection and further design reiteration in future research.


The role of complement factor C3 in lipid metabolism.
Abundant reports have shown that there is a strong relationship between C3 and C3a-desArg levels, adipose tissue, and risk factors for cardiovascular disease, metabolic syndrome and diabetes. The data indicate that complement components, particularly C3, are involved in lipid metabolism. The C3 fragment, C3a-desArg, functions as a hormone that has insulin-like effects and facilitates triglyceride metabolism. Adipose tissue produces and regulates the levels of complement components, which promotes generation of inflammatory initiators such as the anaphylatoxins C3a and C5a. The anaphylatoxins trigger a cyto/chemokine response in proportion to the amount of adipose tissue present, and induce inflammation and mediate metabolic effects such as insulin resistance. These observations support the concept that complement is an important participant in lipid metabolism and in obesity, contributing to the metabolic syndrome and to the low-grade inflammation associated with obesity.


Pu-erh tea polysaccharides decrease blood sugar by inhibition of α-glucosidase activity in vitro and in mice.
Type 2 diabetes is mainly induced by environmental factors such as being overweight, decreased physical activity and inbalanced energy metabolism, such as pancreatic beta-cell dysfunction and peripheral insulin resistance. Acarbose, a microbial carbohydrate and an alpha-glucosidase inhibitor, is currently a useful agent for attenuating type 2 diabetes. However, it is usually accompanied by many side effects, such as abdominal distention, flatulence, diarrhea and meteorism. These side effects may be caused by its strong inhibition of alpha-amylase, leading to the accumulation of several undigested carbohydrates. The bacteria residing in the colon can further ferment the undigested carbohydrate to release gas. Finding a new alpha-glucosidase inhibitor with a low inhibitory effect on alpha-amylase is highly anticipated. In this report we describe a group of carbohydrates found in pu-erh tea polysaccharide (PTPS) that can inhibit alpha-glucosidase but have less of an inhibitory effect on alpha-amylase. The preliminary experiments on mice indicate that PTPS might be better than acarbose at suppressing blood glucose after oral administration of a carbohydrate diet; it is recommended that further clinical trials are required in type 2 diabetes in future studies.


Study on the effects of blueberry treatment on histone acetylation modification of CCl4-induced liver disease in rats.
The objective of this study was to investigate the effects of blueberry treatment on histone acetylation modification of carbon tetrachloride (CCl4)-induced liver disease in rats. Laboratory rats were randomly divided into control, hepatic fibrosis, blueberry treatment, blueberry intervention, and natural recovery groups. Rats in the model groups were treated with CCl4 administered subcutaneously at 4- and 8-week intervals, and then executed. Both the 4- and 8-week treatment groups were treated with blueberry juice for 8 weeks, and then executed after 12 and 16 weeks, respectively. Following the experiment, four liver function and hepatic fibrosis indices were measured. Liver index was calculated, hematoxylin-eosin staining was conducted, and H3K9, H3K14, and H3K18 expressions were evaluated among the nuclear proteins of the liver tissues. No differences in alanine transaminase were noted between the control and intervention groups, but significant differences were detected among the model, treatment, and natural recovery groups (P < 0.01). Significant differences were also observed in aspartate transaminase, hyaluronic acid, and collagen IV among the model, treatment, intervention, and natural recovery groups (P < 0.01, P < 0.01, P < 0.01). Liver index, and H3K9 and H3K14 expression were significantly different among the model groups (P < 0.05 and P < 0.01), whereas H3K18 expression was dramatically different among model, treatment, intervention, and natural recovery groups (P < 0.01). Following blueberry treatment, rat liver function and hepatic fibrosis improved, potentially indicating that blueberry components could regulate histone acetylation and improve liver pathologic changes in rats with CCl4-induced disease.


Pyogenic cervical osteomyelitis presenting as a massive prevertebral abscess in a patient with rheumatoid arthritis.
Pre-existing rheumatoid arthritis appeared to have masked the diagnosis and contributed to a succession of hazardous events in a 58-year-old man with pyogenic cervical osteomyelitis. A massive prevertebral abscess and near asphyxiation finally led to the diagnosis of an indolent Staphylococcus aureus infection in a course marked by antecedent staphylococcal sepsis, a series of dangerous cervical spine chiropractic manipulations in the presence of advanced bony destruction, and, ultimately, cervical spine bony collapse and gibbus formation. The absence of myelopathy despite long-standing progressive advanced destruction is noteworthy. The roentgenologic documentation of this progression was unique. This appears to be the first fully documented case of cervical spine osteomyelitis presenting as a prevertebral abscess in a patient with rheumatoid arthritis.


Upregulation of calpastatin in regenerating and developing rat liver: role in resistance against hepatotoxicity.
Acute liver failure induced by hepatotoxic drugs results from rapid progression of injury. Substantial research has shown that timely liver regeneration can prevent progression of injury leading to a favorable prognosis. However, the mechanism by which compensatory regeneration prevents progression of injury is not known. We have recently reported that calpain released from necrotic hepatocytes mediates progression of liver injury even after the hepatotoxic drug is cleared from the body. By examining expression of calpastatin (CAST), an endogenous inhibitor of calpain in three liver cell division models known to be resistant to hepatotoxicity, we tested the hypothesis that increased CAST in the dividing hepatocytes affords resistance against progression of injury. Liver regeneration that follows CCl(4)-induced liver injury, 70% partial hepatectomy, and postnatal liver development were used. In all three models, CAST was upregulated in the dividing/newly divided hepatocytes and declined to normal levels with the cessation of cell proliferation. To test whether CAST overexpression confers resistance against hepatotoxicity, CAST was overexpressed in the livers of normal SW mice using adenovirus before challenging them with acetaminophen (APAP) overdose. These mice exhibited markedly attenuated progression of liver injury and 57% survival. Whereas APAP-bioactivating enzymes and covalent binding of the APAP-derived reactive metabolites remained unaffected, degradation of calpain specific target substrates such as fodrin was significantly reduced in these mice. In conclusion, CAST overexpression could be used as a therapeutic strategy to prevent progression of liver injury where liver regeneration is severely hampered.


Covariance among premating, post-copulatory and viability fitness components in Drosophila melanogaster and their influence on paternity measurement.
In polyandrous mating systems, male fitness depends on success in premating, post-copulatory and offspring viability episodes of selection. We tracked male success across all of these episodes simultaneously, using transgenic Drosophila melanogaster with ubiquitously expressed green fluorescent protein (i.e. GFP) in a series of competitive and noncompetitive matings. This approach permitted us to track paternity-specific viability over all life stages and to distinguish true competitive fertilization success from differential early offspring viability. Relationships between episodes of selection were generally not present when paternity was measured in eggs; however, positive correlations between sperm competitive success and offspring viability became significant when paternity was measured in adult offspring. Additionally, we found a significant male × female interaction on hatching success and a lack of repeatability of offspring viability across a focal male's matings, which may underlay the limited number of correlations found between episodes of selection.


Classification of immature mosquito species according to characteristics of the larval habitat in the subtropical province of Chaco, Argentina.
To classify mosquito species based on common features of their habitats, samples were obtained fortnightly between June 2001-October 2003 in the subtropical province of Chaco, Argentina. Data on the type of larval habitat, nature of the habitat (artificial or natural), size, depth, location related to sunlight, distance to the neighbouring houses, type of substrate, organic material, vegetation and algae type and their presence were collected. Data on the permanence, temperature, pH, turbidity, colour, odour and movement of the larval habitat's water were also collected. From the cluster analysis, three groups of species associated by their degree of habitat similarity were obtained and are listed below. Group 1 consisted of Aedes aegypti. Group 2 consisted of Culex imitator, Culex davisi, Wyeomyia muehlensi and Toxorhynchites haemorrhoidalis separatus. Within group 3, two subgroups are distinguished: A (Psorophora ferox, Psorophora cyanescens, Psorophora varinervis, Psorophora confinnis, Psorophora cingulata, Ochlerotatus hastatus-oligopistus, Ochlerotatus serratus, Ochlerotatus scapularis, Culex intrincatus, Culex quinquefasciatus, Culex pilosus, Ochlerotatus albifasciatus, Culex bidens) and B (Culex maxi, Culex eduardoi, Culex chidesteri, Uranotaenia lowii, Uranotaenia pulcherrima, Anopheles neomaculipalpus, Anopheles triannulatus, Anopheles albitarsis, Uranotaenia apicalis, Mansonia humeralis and Aedeomyia squamipennis). Principal component analysis indicates that the size of the larval habitats and the presence of aquatic vegetation are the main characteristics that explain the variation among different species. In contrast, water permanence is second in importance. Water temperature, pH and the type of larval habitat are less important in explaining the clustering of species.


Antibody inhibitors to von Willebrand factor metalloproteinase and increased binding of von Willebrand factor to platelets in ticlopidine-associated thrombotic thrombocytopenic purpura.
Thrombotic thrombocytopenic purpura (TTP) affects 1 in 1600 to 1 in 5000 patients who receive ticlopidine, but little is known about the pathogenesis of this complication. To investigate whether von Willebrand factor (vWF), which has been associated with idiopathic TTP, is involved in the pathogenesis of ticlopidine-associated TTP. Case series. Three tertiary care, university-affiliated medical centers. Seven patients who developed TTP 2 to 7 weeks after initiation of ticlopidine therapy. Controls were 7 consecutive patients without thrombocytopenia who had been receiving ticlopidine for 3 to 5 weeks and 10 randomly selected hospitalized patients. Platelet-bound vWF in patients' EDTA-anticoagulated whole blood samples; vWF proteinase activity in patients' plasma samples; inhibitory activity of IgG isolated from patients' plasma samples against the proteinase from the controls' plasma samples; and vWF multimeric patterns in patients' EDTA-anticoagulated plasma samples. Binding of vWF to single platelets was increased in the three patients tested during the most thrombocytopenic phase of TTP episodes. Initial plasma samples from all seven patients lacked the largest vWF multimers and were severely deficient in vWF metalloproteinase. IgG molecules, isolated from plasma samples of five patients, inhibited metalloproteinase in plasma samples from the controls. In patients examined, these abnormalities resolved upon the remission that accompanied plasma exchange and discontinuation of ticlopidine therapy. In the patients who developed ticlopidine-associated TTP, autoantibodies to the vWF metalloproteinase were formed; this led to the same type of vWF abnormalities observed in patients with idiopathic acute TTP. The findings suggest that failure to process large and unusually large vWF multimers in vivo caused binding of vWF to platelets, systemic platelet thrombosis, and TTP.


Clinical and Genetic Characteristics of Familial Hypercholesterolemia at Sultan Qaboos University Hospital in Oman.
We sought to describe the clinical and genetic characteristics of patients with familial hypercholesterolemia (FH) that presented to the lipid clinic at Sultan Qaboos University Hospital, Muscat, Oman. Patients who presented with high low-density lipoprotein cholesterol (LDL-C) levels (> 189.0 mg/dL or 4.9 mmol/L) were recruited to the study. FH was diagnosed according to the Dutch Lipid Clinic Network criteria. Analyses were performed using univariate statistics. The study enrolled 450 patients with a mean age of 48.0±12.0 years, 56.0% (n = 252) were males and 11.3% (n = 51) were smokers. At admission, the proportion of 'probable/definite', 'possible', and 'unlikely' FH were 27.6% (n = 124), 70.0% (n = 315), and 2.4% (n = 11), respectively. Overall, 26.0% (n = 117) of patients had hypertension, 22.4% (n = 101) had a history of coronary artery disease, and 17.3% (n = 78) had diabetes mellitus. Those with 'probable/definite' FH were more likely to be prescribed high-intensity statin therapy (75.8% vs. 54.5%; p < 0.001) and statin ezetimibe combination (50.8% vs. 27.3%; p < 0.001) when compared to the 'unlikely' FH cohort. Additionally, those with very high atherosclerotic vascular disease (ASCVD) risk were also associated with high-intensity statin therapy (54.7% vs. 42.7%; p = 0.006) and statin ezetimibe combination (26.4% vs. 17.2%; p = 0.023). Patients with 'probable/definite' FH were less likely to achieve their LDL-C goal attainment compared to those with 'unlikely' FH (13.0% vs. 57.1%; p < 0.001). Furthermore, those with very high ASCVD risk were less likely to achieve their LDL-C goals compared to the high ASCVD risk cohort (9.6% vs. 32.0%; p < 0.001). FH patients are underdiagnosed, undertreated, and less likely to attain their LDL-C goals in Oman.


CXCR3 Identifies Human Naive CD8+ T Cells with Enhanced Effector Differentiation Potential.
In mice, the ability of naive T (TN) cells to mount an effector response correlates with TCR sensitivity for self-derived Ags, which can be quantified indirectly by measuring surface expression levels of CD5. Equivalent findings have not been reported previously in humans. We identified two discrete subsets of human CD8+ TN cells, defined by the absence or presence of the chemokine receptor CXCR3. The more abundant CXCR3+ TN cell subset displayed an effector-like transcriptional profile and expressed TCRs with physicochemical characteristics indicative of enhanced interactions with peptide-HLA class I Ags. Moreover, CXCR3+ TN cells frequently produced IL-2 and TNF in response to nonspecific activation directly ex vivo and differentiated readily into Ag-specific effector cells in vitro. Comparative analyses further revealed that human CXCR3+ TN cells were transcriptionally equivalent to murine CXCR3+ TN cells, which expressed high levels of CD5. These findings provide support for the notion that effector differentiation is shaped by heterogeneity in the preimmune repertoire of human CD8+ T cells.


Is Healthier Nutrition Behaviour Associated with Better Self-Reported Health and Less Health Complaints? Evidence from Turku, Finland.
We examined nutrition behaviour, self-reported health and 20 health complaints of undergraduates in Finland. Students at the University of Turku in Finland participated in a cross-sectional online survey (N = 1189). For nutrition behaviour, we computed two composite food intake pattern scores (sweets, cakes and snacks; and fruits and vegetables), a dietary guideline adherence index and the subjective importance of healthy eating. Multinomial logistic regression assessed the association of students' nutrition behaviour with three levels of self-reported health, controlling for many potential confounders (age, sex, living with partner, economic situation, moderate physical activity, Faculty and BMI). Factor analysis of the 20 health complaints revealed three components (psychological, pains/aches and circulatory/breathing symptoms). Multiple linear regression tested the association of students' eating habits with the three components of health complaints, controlling for the same confounders. Fruits and raw and cooked vegetable consumption, dietary guideline adherence index and subjective importance of healthy eating were highest among students with excellent/very good self-reported health, exhibiting a decreasing trend for those individuals with poor/fair self-reported health. High levels of psychological symptoms were associated with decreased consumption of fruits and vegetables, less dietary guideline adherence and less subjective importance of healthy eating. Pain/aches symptoms were associated with a higher consumption of sweets, cookies and snacks and a lower adherence to dietary guidelines. More healthy nutrition behaviour was consistently associated with better self-reported health and less health complaints. Of the four nutrition behaviour indicators we employed, the dietary guideline adherence index was the best indicator and exhibited the most consistent associations with self-reported health and health complaints.


Creating beauty: creativity compensates for low physical attractiveness when individuals assess the attractiveness of social and romantic partners.
Although creativity is attractive in a potential mate, it is unclear (i) whether the effects of creativity on attractiveness generalize to other social contexts and (ii) whether creativity has equivalent effects on men's and women's attractiveness. As social knowledge of creativity may either enhance or 'offset' the appeal of social partners who differ in physical attractiveness, three repeated measures experiments were conducted to directly address these issues. Here, participants rated a series of face-text pairs for attractiveness on trials that differed in one of four combinations of facial attractiveness (attractive and less attractive) and creativity (creative and less creative), rating story-tellers in two experiments (short interpretations of an identical painting) and creative ideas in a further experiment (alternative uses for an everyday object). Regardless of the sex of the judge, creativity and facial attractiveness had independent effects on men's overall attractiveness (initial experiment) and, in further experiments, more substantial effects on the attractiveness of men with less attractive faces than men with attractive faces (when using a different measure of creativity) and specific effects on the attractiveness of individuals with less attractive faces (when using different face stimuli). Collectively, across three experiments, these findings suggest that creativity may compensate for putative cues to lower biological 'quality' and that the benefits of creativity to social groups more generally enhance attraction to creative men (in two experiments) and creative men and women (one experiment). More broadly, the data suggest that species can integrate knowledge of cognitive intelligence with visual cues to biological 'quality' to facilitate mate and/or ally choice.