The extinction of the dinosaurs.
Non-avian dinosaurs went extinct 66 million years ago, geologically coincident with the impact of a large bolide (comet or asteroid) during an interval of massive volcanic eruptions and changes in temperature and sea level. There has long been fervent debate about how these events affected dinosaurs. We review a wealth of new data accumulated over the past two decades, provide updated and novel analyses of long-term dinosaur diversity trends during the latest Cretaceous, and discuss an emerging consensus on the extinction's tempo and causes. Little support exists for a global, long-term decline across non-avian dinosaur diversity prior to their extinction at the end of the Cretaceous. However, restructuring of latest Cretaceous dinosaur faunas in North America led to reduced diversity of large-bodied herbivores, perhaps making communities more susceptible to cascading extinctions. The abruptness of the dinosaur extinction suggests a key role for the bolide impact, although the coarseness of the fossil record makes testing the effects of Deccan volcanism difficult.


Digital Approaches to Automated and Machine Learning Assessments of Hearing: Scoping Review.
Hearing loss affects 1 in 5 people worldwide and is estimated to affect 1 in 4 by 2050. Treatment relies on the accurate diagnosis of hearing loss; however, this first step is out of reach for >80% of those affected. Increasingly automated approaches are being developed for self-administered digital hearing assessments without the direct involvement of professionals. This study aims to provide an overview of digital approaches in automated and machine learning assessments of hearing using pure-tone audiometry and to focus on the aspects related to accuracy, reliability, and time efficiency. This review is an extension of a 2013 systematic review. A search across the electronic databases of PubMed, IEEE, and Web of Science was conducted to identify relevant reports from the peer-reviewed literature. Key information about each report's scope and details was collected to assess the commonalities among the approaches. A total of 56 reports from 2012 to June 2021 were included. From this selection, 27 unique automated approaches were identified. Machine learning approaches require fewer trials than conventional threshold-seeking approaches, and personal digital devices make assessments more affordable and accessible. Validity can be enhanced using digital technologies for quality surveillance, including noise monitoring and detecting inconclusive results. In the past 10 years, an increasing number of automated approaches have reported similar accuracy, reliability, and time efficiency as manual hearing assessments. New developments, including machine learning approaches, offer features, versatility, and cost-effectiveness beyond manual audiometry. Used within identified limitations, automated assessments using digital devices can support task-shifting, self-care, telehealth, and clinical care pathways.


A novel wearable device to deliver unconstrained, unpredictable slip perturbations during gait.
Task-specific perturbation training is a widely studied means of fall prevention, utilizing techniques that induce slips or slip-like perturbations during gait. Though effective, these methods only simulate narrow ranges within the larger space of possible slipping conditions encountered in daily life. Here we describe and test a novel, wearable apparatus designed to address these limitations and simulate a diverse range of slipping disturbances. The device consists of wireless triggering and detachable outsole components that provide adequate friction with the floor when secured to the wearer's foot, but suddenly create a low-friction surface underfoot upon release. "Benchtop" tests were carried out to quantify device triggering characteristics (i.e. cutting temperature, release delay) and the resulting friction reduction. The device was also tested on six healthy young adults (3 female, age 23 ± 2.4 years), who walked with and without the device to observe how gait kinematics and spatiotemporal parameters were influenced, then performed 12 walking trials ending with a slip delivered by the device. Each participant also completed a survey to obtain opinions on device safety, device comfort, slip realism, and slip difficulty. A linear mixed effects analysis was employed to compare subject spatiotemporal parameters with and without the apparatus, as well as correlation coefficients and root mean square errors (RMSE) to assess the impact of the device on lower limb gait kinematics. Slip onset phases, distances, directions, velocities, and recovery step locations were also calculated. This device rapidly diminishes available friction from static coefficients of 0.48 to 0.07, albeit after a substantial delay (0.482 ± 0.181 s) between signal reception and outsole release. Strong correlations (R > 0.93) and small RMSE between gait kinematics with and without the device indicate minimal effects on natural gait patterns, however some spatiotemporal parameters were significantly impacted. A diverse range of slip perturbations and recovery steps were successfully elicited by the device. Our results highlight the efficacy and utility of a wearable slipping device to deliver diverse slip conditions. Such an apparatus enables the study of unconstrained slips administered across the gait cycle, as well as during different locomotor behaviors like turning, negotiating slopes, and level changes.


Alcohol Use Disorder and Risk of Suicide in a Swedish Population-Based Cohort.
The authors examined the association between alcohol use disorder (AUD) and risk of suicide, before and after accounting for psychiatric comorbidity, and assessed the extent to which the observed association is due to a potentially causal mechanism or genetic and familial environmental confounding factors that increase risk for both. Longitudinal population-wide Swedish medical, criminal, and pharmacy registries were used to evaluate the risk of death by suicide as a function of AUD history. Analyses employed prospective cohort and co-relative designs, including data on 2,229,880 native Swedes born between 1950 and 1970 and observed from age 15 until 2012. The lifetime rate of suicide during the observation period was 3.54% for women and 3.94% for men with AUD, compared with 0.29% and 0.76% of women and men, respectively, without AUD. In adjusted analyses, AUD remained robustly associated with suicide: hazard ratios across observation periods ranged from 2.61 to 128.0 among women and from 2.44 to 28.0 among men. Co-relative analyses indicated that familial confounding accounted for some, but not all, of the observed association. A substantial and potentially causal relationship remained after accounting for a history of other psychiatric diagnoses. AUD is a potent risk factor for suicide, with a substantial association persisting after accounting for confounding factors. These findings underscore the impact of AUD on suicide risk, even in the context of other mental illness, and implicate the time frame shortly after a medical or criminal AUD registration as critical for efforts to reduce alcohol-related suicide.


[Transamination In Syncytiotrophoblast of Placenta Villi in Parturient Women Suffered the Acute Form of CMV Infection at the Third Trimester of Gestation].
to study the process of proteins transamination in syncytiotrophoblast of placenta villi of women who suffered the acute form of cytomega- lovirus (CMV) infection during pregnancy. 30 pregnant women with CMV infection recurrence at the 25-28th week of pregnancy were examined. The activity of γ-glutamyltransferase in the peripheral blood of pregnant women was determined by spectrophotometry at the device "Stat-Fax-2100" (The USA). Hsp-70 and caspase-3 in placenta homogenate were found out with serological methods. The activity of glutamatdehydrogenase and pyridoxal-5-phosphatase was studied with histochemical method of Z. Loyd at the placenta slice of parturient women. The apoptotic changes in syncytiotrophoblast nuclei were defined by ISEL-method. RESULTS. The peripheral blood of CMV-seropositive parturient women showed a reduction of γ-glutamyltransferase in 1.30 times. Histochemically we identified the reduction of reaction products' concentration in response to pyridoxal-5-phosphate by 2.14 times, to glutamatdehydrogenase by 1,57 times. At the same time there was an increase of caspase-3 in 2,8 times and reduction of Hsp70 in 2.6 times in placenta homogenate. The number of apoptotic changes in syncytio-trophoblast nuclei increased by 4 times. Worsening of CMV infection in the period 25-28 weeks of pregnancy leads to disruption of amino acid metabolism in the placenta, causing structural and functional and metabolic adjustment, and is one of the reasons for slow growth and lack of development of the fetus.


[Changes of mitochondrial oxidation and phosphorylation in the testes of white rats under excessive supply of sodium nitrate into the organism].
The functional state of mitochondria, obtained from the testicles, after chronic intoxication by sodium nitrate (in a dose of 200 mg/kg during 14; 30 and 90 days) was investigated in experiment on white rats. It was revealed, that in dynamics of changes of mitochondrial oxidation and phosphorylation in the testicles under the excessive supply of sodium nitrate into the organism the determined phases should be marked: on the 14th day of intoxication this is the ascending of rate of respiration, on the 30th and 90th day--separation of the mitochondrial oxidation and ADP phosphorylation. It is supposed, that in pathogenesis of these changes the essential role belongs to nitric oxide production.


Influenza A induces dysfunctional immunity and death in MeCP2-overexpressing mice.
Loss of function or overexpression of methyl-CpG-binding protein 2 (MeCP2) results in the severe neurodevelopmental disorders Rett syndrome and MeCP2 duplication syndrome, respectively. MeCP2 plays a critical role in neuronal function and the function of cells throughout the body. It has been previously demonstrated that MeCP2 regulates T cell function and macrophage response to multiple stimuli, and that immune-mediated rescue imparts significant benefit in Mecp2-null mice. Unlike Rett syndrome, MeCP2 duplication syndrome results in chronic, severe respiratory infections, which represent a significant cause of patient morbidity and mortality. Here, we demonstrate that MeCP2Tg3 mice, which overexpress MeCP2 at levels 3- to 5-fold higher than normal, are hypersensitive to influenza A/PR/8/34 infection. Prior to death, MeCP2Tg3 mice experienced a host of complications during infection, including neutrophilia, increased cytokine production, excessive corticosterone levels, defective adaptive immunity, and vascular pathology characterized by impaired perfusion and pulmonary hemorrhage. Importantly, we found that radioresistant cells are essential to infection-related death after bone marrow transplantation. In all, these results demonstrate that influenza A infection in MeCP2Tg3 mice results in pathology affecting both immune and nonhematopoietic cells, suggesting that failure to effectively respond and clear viral respiratory infection has a complex, multicompartment etiology in the context of MeCP2 overexpression.


Marmoset induced pluripotent stem cells: Robust neural differentiation following pretreatment with dimethyl sulfoxide.
The marmoset is an important nonhuman primate model for regenerative medicine. For experimental autologous cell therapy based on induced pluripotent (iPS) cells in the marmoset, cells must be able to undergo robust and reliable directed differentiation that will not require customization for each specific iPS cell clone. When marmoset iPS cells were aggregated in a hanging drop format for 3 days, followed by exposure to dual SMAD inhibitors and retinoic acid in monolayer culture for 3 days, we found substantial variability in the response of different iPS cell clones. However, when clones were pretreated with 0.05-2% dimethyl sulfoxide (DMSO) for 24 hours, all clones showed a very similar maximal response to the directed differentiation scheme. Peak responses were observed at 0.5% DMSO in two clones and at 1% DMSO in a third clone. When patterns of gene expression were examined by microarray analysis, hierarchical clustering showed very similar responses in all 3 clones when they were pretreated with optimal DMSO concentrations. The change in phenotype following exposure to DMSO and the 6 day hanging drop/monolayer treatment was confirmed by immunocytochemistry. Analysis of DNA content in DMSO-exposed cells indicated that it is unlikely that DMSO acts by causing cells to exit from the cell cycle. This approach should be generally valuable in the directed neural differentiation of pluripotent cells for experimental cell therapy.


Key innovations and island colonization as engines of evolutionary diversification: a comparative test with the Australasian diplodactyloid geckos.
The acquisition of key innovations and the invasion of new areas constitute two major processes that facilitate ecological opportunity and subsequent evolutionary diversification. Using a major lizard radiation as a model, the Australasian diplodactyloid geckos, we explored the effects of two key innovations (adhesive toepads and a snake-like phenotype) and the invasion of new environments (island colonization) in promoting the evolution of phenotypic and species diversity. We found no evidence that toepads had significantly increased evolutionary diversification, which challenges the common assumption that the evolution of toepads has been responsible for the extensive radiation of geckos. In contrast, a snakelike phenotype was associated with increased rates of body size evolution and, to a lesser extent, species diversification. However, the clearest impact on evolutionary diversification has been the colonization of New Zealand and New Caledonia, which were associated with increased rates of both body size evolution and species diversification. This highlights that colonizing new environments can drive adaptive diversification in conjunction or independently of the evolution of a key innovation. Studies wishing to confirm the putative link between a key innovation and subsequent evolutionary diversification must therefore show that it has been the acquisition of an innovation specifically, not the colonization of new areas more generally, that has prompted diversification.


Role of IGF binding protein-1 in the dawn phenomenon and glycemic control in children and adolescents with IDDM.
To clarify the involvement of IGF binding protein (IGFBP)-1 in the dawn rise in plasma glucose and in the overall glycemic control in patients with IDDM. Seventy patients with IDDM were divided into three groups according to pubertal development. Blood samples were obtained for measuring plasma glucose, IGFBP-1, and free insulin at 2200, 0500, and 0700 over a 2-day period. Levels of HbA1c, IGF-1, and IGFBP-3 were determined at 0700. Urinary growth hormone (GH) was collected overnight. To examine its frequency, the dawn phenomenon was defined on the basis of the following: 1) change in plasma glucose from 0500 to 0700, 2) plasma glucose level at 0700, and 3) no antecedent hypoglycemia. There was a statistically significant link between the dawn changes in plasma glucose and IGFBP-1 (r = 0.37, P < 0.01). The former was not related to the change in free insulin or to the overnight urinary GH level. In stepwise regression analyses, plasma glucose at 0700 = 0.03 IGFBP-1 (P < 0.01) + 0.525 HbA1c (P < 0.01) + 3.696 (R2 = 51%). Approximately half of the patients in each group exhibited the dawn phenomenon; 38% of patients with HbA1c < 8% also showed the dawn phenomenon. We have demonstrated a statistically significant link between the morning risk in IGFBP-1 and plasma glucose. The free fraction of IGF-1 modulated by acute changes in IGFBP-1 may play a direct role. The dawn phenomenon may occur regardless of pubertal stage or glycemic control in children and adolescents with IDDM.


Combined genomic expressions as a diagnostic factor for oral squamous cell carcinoma.
Trends in genetics are transforming in order to identify differential coexpressions of correlated gene expression rather than the significant individual gene. Moreover, it is known that a combined biomarker pattern improves the discrimination of a specific cancer. The identification of the combined biomarker is also necessary for the early detection of invasive oral squamous cell carcinoma (OSCC). To identify the combined biomarker that could improve the discrimination of OSCC, we explored an appropriate number of genes in a combined gene set in order to attain the highest level of accuracy. After detecting a significant gene set, including the pre-defined number of genes, a combined expression was identified using the weights of genes in a gene set. We used the Principal Component Analysis (PCA) for the weight calculation. In this process, we used three public microarray datasets. One dataset was used for identifying the combined biomarker, and the other two datasets were used for validation. The discrimination accuracy was measured by the out-of-bag (OOB) error. There was no relation between the significance and the discrimination accuracy in each individual gene. The identified gene set included both significant and insignificant genes. One of the most significant gene sets in the classification of normal and OSCC included MMP1, SOCS3 and ACOX1. Furthermore, in the case of oral dysplasia and OSCC discrimination, two combined biomarkers were identified. The combined expression revealed good performance in the validation datasets. The combined genomic expression achieved better performance in the discrimination of different conditions than a single significant gene. Therefore, it could be expected that accurate diagnosis for cancer could be possible with a combined biomarker.


Worries, 'weirdos', neighborhoods and knowing people: a qualitative study with children and parents regarding children's independent mobility.
This qualitative study involved focus groups with 132 children and 12 parents in primary and secondary schools in metropolitan and regional areas of Victoria, Australia, to explore experiences and perceptions of children's independent mobility. The study highlights the impact of family routines, neighborhood characteristics, social norms and reference points for decision making. Children reported a wider range of safety concerns than parents, including harm from strangers or traffic, bullying, or getting lost. Children expressed great delight in being independent, often seeking to actively influence parents' decision making. Children's independent mobility is a developmental process, requiring graduated steps and skill building.


Chromosomal abnormalities in hepatic cysts point to novel polycystic liver disease genes.
Autosomal dominant polycystic liver disease (ADPLD) is caused by variants in PRKCSH, SEC63, and LRP5, whereas autosomal dominant polycystic kidney disease is caused by variants in PKD1 and PKD2. Liver cyst development in these disorders is explained by somatic loss-of-heterozygosity (LOH) of the wild-type allele in the developing cyst. We hypothesize that we can use this mechanism to identify novel disease genes that reside in LOH regions. In this study, we aim to map abnormal genomic regions using high-density SNP microarrays to find novel PLD genes. We collected 46 cysts from 23 patients with polycystic or sporadic hepatic cysts, and analyzed DNA from those cysts using high-resolution microarray (n=24) or Sanger sequencing (n=22). We here focused on regions of homozygosity on the autosomes (>3.0 Mb) and large CNVs (>1.0 Mb). We found frequent LOH in PRKCSH (22/29) and PKD1/PKD2 (2/3) cysts of patients with known heterozygous germline variants in the respective genes. In the total cohort, 12/23 patients harbored abnormalities outside of familiar areas. In individual ADPLD cases, we identified germline events: a 2q13 complex rearrangement resulting in BUB1 haploinsufficiency, a 47XXX karyotype, chromosome 9q copy-number loss, and LOH on chromosome 3p. The latter region was overlapping with an LOH region identified in two other cysts. Unique germline and somatic abnormalities occur frequently in and outside of known genes underlying cysts. Each liver cyst has a unique genetic makeup. LOH driver gene BUB1 may imply germline causes of genetic instability in PLD.


Translational control of insulin biosynthesis. Evidence for regulation of elongation, initiation and signal-recognition-particle-mediated translational arrest by glucose.
The biosynthesis of insulin in the islets of Langerhans is strongly controlled at the translational level by glucose. We have used a variety of experimental approaches in efforts to dissect the mechanisms underlying the stimulatory effect of glucose. To assess its effects on rates of peptide-chain elongation, isolated rat islets were labelled with [3H]leucine at different glucose concentrations in the presence or absence of low concentrations of cycloheximide. Under these conditions, at glucose concentrations up to 5.6 mM, endogenous insulin mRNA did not become rate-limiting for the synthesis of insulin, whereas stimulation of non-insulin protein synthesis was abolished by cycloheximide at all glucose concentrations, indicating either that insulin synthesis is selectively regulated at the level of elongation at glucose concentrations up to 5.6 mM, or that at these concentrations inactive insulin mRNA is transferred to an actively translating pool. Glucose-induced changes in the intracellular distribution of insulin mRNA in cultured islets were assessed by subcellular fractionation and blot-hybridization using insulin cDNA probes. At glucose concentrations above 3.3 mM, cytoplasmic insulin mRNA was increasingly transferred to fractions co-sedimenting with ribosomes, and relatively more of the ribosome-associated insulin mRNA became membrane-associated, consistent with effects of glucose above 3.3 mM on both the initiation of insulin mRNA and SRP (signal recognition particle)-mediated transfer of cytosolic nascent preproinsulin to the endoplasmic reticulum. When freshly isolated islets were homogenized and incubated with 125I-Tyr-tRNA, run-off incorporation of 125I into preproinsulin was increased by prior incubation of the islets at 16.7 mM-glucose. The addition of purified SRP receptor increased the run-off incorporation of [125I]iodotyrosine into preproinsulin, especially when the islets had been preincubated at 16.7 mM-glucose. These findings taken together suggest that glucose may stimulate elongation rates of nascent preproinsulin at concentrations up to 5.6 mM, stimulates initiation of protein synthesis involving both insulin and non-insulin mRNA at concentrations above 3.3 mM, and increases the transfer of initiated insulin mRNA molecules from the cytoplasm to microsomal membranes by an SRP-mediated mechanism that involves the modification of interactions between SRP and its receptor.


Neratinib Plus Paclitaxel vs Trastuzumab Plus Paclitaxel in Previously Untreated Metastatic ERBB2-Positive Breast Cancer: The NEfERT-T Randomized Clinical Trial.
Efficacious ERBB2 (formerly HER2 or HER2/neu)-directed treatments, in addition to trastuzumab and lapatinib, are needed. To determine whether neratinib, an irreversible pan-ERBB tyrosine kinase inhibitor, plus paclitaxel improves progression-free survival compared with trastuzumab plus paclitaxel in the first-line treatment of recurrent and/or metastatic ERBB2-positive breast cancer. In the randomized, controlled, open-label NEfERT-T trial conducted from August 2009 to December 2014 at 188 centers in 34 countries in Europe, Asia, Africa, and North America, 479 women with previously untreated recurrent and/or metastatic ERBB2-positive breast cancer were randomized to 1 of 2 treatment arms (neratinib-paclitaxel [n = 242] or trastuzumab-paclitaxel [n = 237]). Women with asymptomatic central nervous system metastases were eligible, and randomization was stratified by prior trastuzumab and lapatinib exposure, hormone-receptor status, and region. Women received neratinib (240 mg/d orally) or trastuzumab (4 mg/kg then 2 mg/kg weekly), each combined with paclitaxel (80 mg/m2 on days 1, 8, and 15 every 28 days). Primary prophylaxis for diarrhea was not mandatory. The primary outcome was progression-free survival. Secondary end points were response rate, clinical benefit rate, duration of response, frequency, and time to symptomatic and/or progressive central nervous system lesions, and safety. The intent-to-treat population comprised 479 women 18 years or older (neratinib-paclitaxel, n = 242; trastuzumab-paclitaxel, n = 237) randomized and stratified in their respective treatment arms by prior trastuzumab and lapatinib exposure, hormone-receptor status, and region. Median progression-free survival was 12.9 months (95% CI, 11.1-14.9) with neratinib-paclitaxel and 12.9 months (95% CI, 11.1-14.8) with trastuzumab-paclitaxel (hazard ratio [HR], 1.02; 95% CI, 0.81-1.27; P =.89). With neratinib-paclitaxel, the incidence of central nervous system recurrences was lower (relative risk, 0.48; 95% CI, 0.29-0.79; P = .002) and time to central nervous system metastases delayed (HR, 0.45; 95% CI, 0.26-0.78; P = .004). Common grade 3 to 4 adverse events were diarrhea (73 of 240 patients [30.4%] with neratinib-paclitaxel and 9 of 234 patients [3.8%] with trastuzumab-paclitaxel), neutropenia (31 patients [12.9%] vs 34 patients [14.5%]) and leukopenia (19 patients [7.9%] vs 25 patients [10.7%]); no grade 4 diarrhea was observed. In first-line ERBB2-positive metastatic breast cancer, neratinib-paclitaxel was not superior to trastuzumab-paclitaxel in terms of progression-free survival. In spite of similar overall efficacy, neratinib-paclitaxel may delay the onset and reduce the frequency of central nervous system progression, a finding that requires a larger study to confirm. clinicaltrials.gov Identifier: NCT00915018.


Sex Differences in the Presentation of Body Dysmorphic Disorder in a Community Sample of Adolescents.
The current study sought to explore sex differences in the presentation of probable full-syndrome and subthreshold body dysmorphic disorder (BDD) in adolescents from an Australian community sample. Specifically, it examined sex differences in the types of BDD symptoms endorsed, body areas of concern, and the association with elevated symptoms of comorbid disorders. In male participants, it also compared the presenting features of those with and without muscle dysmorphia. Of 3,149 adolescents assessed using self-report questionnaires, 162 (5.1%) reported probable BDD (57.4% male, Mage = 14.89 years, SD = 1.33, primarily from Oceanian or European cultural backgrounds). All participants completed measures of BDD symptoms; past mental health service use; and symptoms of anxiety, depression, obsessive-compulsive disorder, and eating disorders. Male participants completed additional measures of quality of life, drive for muscularity, hyperactivity, conduct disorder, peer problems, and emotional symptoms. Controlling for demographic variables that varied by sex, male and female participants reported similar BDD symptom severity, rates of most elevated comorbid symptoms, and mental health service use. Concerns regarding muscularity, breasts/nipples, and thighs differed by sex. Female participants were more likely than male participants to report elevated generalized anxiety symptoms. In male participants, muscle dysmorphia was not associated with greater severity across most measures. The presenting features of BDD were broadly similar in male and female participants, and in male participants with and without muscle dysmorphia. Future research should seek to increase mental health service use in adolescents with BDD and to improve rates of disorder detection in clinical settings.


Hispanic women's health care provider control expectations: the influence of fatalism and acculturation.
In order to understand how culture influences Hispanic women's views about their health care provider (HCP), we examined the relationship between acculturation and fatalism in the HCP control expectations of Hispanic women. (A HCP control expectation is the extent to which an individual believes that her HCP has control over her health.) We predicted that acculturation would be negatively associated with HCP control expectations, and fatalism would be positively associated with HCP control expectations. A group of 1,027 young Hispanic women (mean age 21.24 years; SD=2.46) who were University of Texas Medical Branch clinic patients completed a comprehensive survey. Structural equation modeling was employed and, as predicted, acculturation was negatively associated with HCP control expectations (p<.001) and fatalism was positively associated (p<.001). Understanding fatalism, acculturation, and their influence on HCP control expectations will help us understand this population's perceptions of their HCPs. This knowledge will assist HCPs in providing culturally competent care which will increase adherence to medical treatment and screening guidelines.


Application of a pentafluorobenzyl bromide derivatization method in gas chromatography/mass spectrometry of trace levels of halogenated phenols in air, water and sediment samples.
An analytical method using pentafluorobenzyl bromide (PFBB) derivatization and gas chromatography/mass spectrometry (GC/MS) has been applied to identify and quantify chloro-, bromo- and dichlorophenols in air, water and sediment samples. Phenols in air sample were collected with a PS-2 Sep-PAK cartridge, and eluted with 2-propanol. For water and sediment samples, liquid-liquid extraction with dichloromethane was carried out, and the solvent was exchanged to 2-propanol. The phenols in the solution reacted with PFBB to form the corresponding pentafluorobenzyl esters. After extracting the derivatives into hexane, the determination was carried out by GC/MS with selected-ion monitoring. The detection limits of phenols in air, water and sediment were 0.0033 - 0.0073 microg/m3, 0.0066 - 0.0147 microg/L and 0.33 - 0.73 microg/kg, respectively. More than 90% recoveries of the halogenated phenols were obtained from real environmental samples spiked by the halogenated phenols. The three isomers of mono-chlorophenols were detected in sediment samples in the range of 5.2 - 9.2 microg/kg in wet weight basis.


Perspectives on validation of high-throughput assays supporting 21st century toxicity testing.
In vitro high-throughput screening (HTS) assays are seeing increasing use in toxicity testing. HTS assays can simultaneously test many chemicals but have seen limited use in the regulatory arena, in part because of the need to undergo rigorous, time-consuming formal validation. Here we discuss streamlining the validation process, specifically for prioritization applications. By prioritization, we mean a process in which less complex, less expensive, and faster assays are used to prioritize which chemicals are subjected first to more complex, expensive, and slower guideline assays. Data from the HTS prioritization assays is intended to provide a priori evidence that certain chemicals have the potential to lead to the types of adverse effects that the guideline tests are assessing. The need for such prioritization approaches is driven by the fact that there are tens of thousands of chemicals to which people are exposed, but the yearly throughput of most guideline assays is small in comparison. The streamlined validation process would continue to ensure the reliability and relevance of assays for this application. We discuss the following practical guidelines: (1) follow current validation practice to the extent possible and practical; (2) make increased use of reference compounds to better demonstrate assay reliability and relevance; (3) de-emphasize the need for cross-laboratory testing; and (4) implement a web-based, transparent, and expedited peer review process.


Inferring Atmospheric Particulate Matter Concentrations from Chinese Social Media Data.
Although studies have increasingly linked air pollution to specific health outcomes, less well understood is how public perceptions of air quality respond to changing pollutant levels. The growing availability of air pollution measurements and the proliferation of social media provide an opportunity to gauge public discussion of air quality conditions. In this paper, we consider particulate matter (PM) measurements from four Chinese megacities (Beijing, Shanghai, Guangzhou, and Chengdu) together with 112 million posts on Weibo (a popular Chinese microblogging system) from corresponding days in 2011-2013 to identify terms whose frequency was most correlated with PM levels. These correlations are used to construct an Air Discussion Index (ADI) for estimating daily PM based on the content of Weibo posts. In Beijing, the Chinese city with the most PM as measured by U.S. Embassy monitor stations, we found a strong correlation (R = 0.88) between the ADI and measured PM. In other Chinese cities with lower pollution levels, the correlation was weaker. Nonetheless, our results show that social media may be a useful proxy measurement for pollution, particularly when traditional measurement stations are unavailable, censored or misreported.


Evaluation of carcinogenic risk in friction product workers.
Mortality rates of two cohorts of asbestos friction product (FP) workers were studied in comparison with the population of the adjoining towns over periods of 20 and 40 years respectively. The second cohort was subdivided into 3 subcohorts exposed to chrysotile asbestos (CA), vulcanization and/or polymerization vapours and gases (VPGV) and asbestos bakelite (AB) or asbestos rubber (AR) dusts. In the first cohort no deaths from lung cancer were recorded, even though the total tumour mortality was higher than in the general population. In the second cohort an excess tumour mortality was observed in the first subcohort for stomach cancer only. In the other two subcohorts the expected rates were higher for all the tumour sites. Following intraperitoneal injection of CA, AB and AR dusts, malignant tumours developed in 31.5% of the rats which received CA, and in about 10% of the rats which were injected with AB and AR dusts. Also, the mean longevity of CA-treated animals was significantly lower than in the other two groups. Thus, the carcinogenic risk was real in the group of FP production workers with significant CA exposure only.


Visualization and thermodynamic encoding of single-molecule partition function projections.
Ensemble averaging of molecular states is fundamental for the experimental determination of thermodynamic quantities. A special case occurs for single-molecule investigations under equilibrium conditions, for which free energy, entropy and enthalpy at finite temperatures are challenging to determine with ensemble averaging alone. Here we report a method to directly record time-averaged equilibrium probability distributions by confining an individual molecule to a nanoscopic pore of a two-dimensional metal-organic nanomesh, using temperature-controlled scanning tunnelling microscopy. We associate these distributions with partition function projections to assess real-space-projected thermodynamic quantities, aided by computational modelling. The presented molecular dynamics-based analysis is able to reproduce experimentally observed projected microstates with high accuracy. By an in silico customized energy landscape, we demonstrate that distinct probability distributions can be encrypted at different temperatures. Such modulation provides means to encode and decode information into position-temperature space.


Deconstructing radiation hormesis.
This paper explores some factors that may explain why the possibility of hormesis has not been embraced by the radiation protection community. If shown to be sustainable, hormesis might ameliorate several serious issues plaguing radiation protection including the high economic cost of environmental regulatory compliance and public fear of radiation exposure. Some but not all analyses of data from various sources, including the Japanese survivors of the atomic bombs and residential radon studies, suggest that low levels of ionizing radiation may be beneficial to human health. The evidence, however, has not been viewed as compelling for the following reasons: (1) Data in support of radiation hormesis in human populations is limited and much of it is based on re-evaluation of selected epidemiological data that has been used to test a different hypothesis; (2) Hormetic effects are weak and inconsistent, and are subject to large statistical uncertainties as is the case for carcinogenic effects at small doses; (3) A consensus is lacking on how hormesis should be defined and quantified; and (4) It is unclear how hormesis can be incorporated into the regulatory framework when beneficial health effects exceed the requirement for protection of health.


[Permanent auricular paralysis. Report of 2 cases with different response to auricular stimulation].
Two well documented cases of permanent atrial standstill are reported. Both fulfilled the diagnostic criteria of absence of electrical and mechanical atrial activity. The importance of response to electrical stimuli and escape rhythm is discussed within the context of a severe, irreversible and evolutive disease.


Preoperative intervention for smoking cessation: A systematic review.
Smoking is associated with increased postoperative complications. Pre-surgical smoking cessation remains a challenge. Our aim was to summarize pre-hospital smoking cessation interventions and impact on smoking cessation rates. Independent review of English language articles identified from systematic searches of MEDLINE, PubMed, PsycInfo, Embase, Web of Science, and Cumulative Index to Nursing & Allied Health Literature databases from 1998 to 2019 was performed (PROSPERO registration number CRD42021247927). Studies of adult patients enrolled in a pre-hospital smoking cessation intervention were included. Studies with historical controls or only self-reported outcomes were excluded. Nine articles including 1762 patients were identified. Exhaled CO was used to confirm cessation. Six studies reported smoking status day of surgery. Interventions included NRT, hand-held technology, e-cigarettes, decision aids/counseling and medications. Four studies demonstrated a difference in smoking cessation rates. Ethics and study appraisal were assessed using ROB2. Based on the variability of interventions, settings, and outcomes, best practice for successful pre-hospital smoking cessation in surgery clinics would benefit from ongoing investigation.


Factors associated with early introduction of formula and/or solid, semi-solid or soft foods in seven Francophone West African countries.
The aim of this study was to identify factors associated with early introduction of formula and/or solid, semi-solid or soft foods to infants aged three to five months in seven Francophone West African countries. The sources of data for the analyses were the most recent Demographic and Health Survey datasets of the seven countries, namely Benin (BDHS, 2012), Burkina Faso (BFDHS, 2010), Cote d'Ivoire (CIDHS, 2011-2012), Guinea (GDHS, 2012), Mali (MDHS, 2012-2013), Niger (NDHS, 2012) and Senegal (SDHS, 2010). The study used multiple logistic regression methods to analyse the factors associated with early introduction of complementary feeding using individual-, household- and community-level determinants. The sample was composed of 4158 infants aged between three and five months with: 671 from Benin, 811 from Burkina Faso, 362 from Cote d'Ivoire, 398 from Guinea, 519 from Mali, 767 from Niger and 630 from Senegal. Multiple analyses indicated that in three of the seven countries (Benin, Guinea and Senegal), infants who suffered illnesses, such as diarrhoea and acute respiratory infection, were significantly more likely to be introduced to formula and/or solid, semi-solid or soft foods between the age of three and five months. Other significant factors included infants who: were born in second to fourth position (Benin), whose mothers did not attend any antenatal clinics (Burkina Faso and Niger), were male (Cote d'Ivoire and Senegal), lived in an urban areas (Senegal), or were delivered by traditional birth attendants (Guinea, Niger and Senegal). Programmes to discourage early introduction of formula and/or solid, semi-solid or soft foods in these countries should target the most vulnerable segments of the population in order to improve exclusive breastfeeding practices and reduce infant mortality.


Expression of the cytoplasmic nucleolin for post-transcriptional regulation of macrophage colony-stimulating factor mRNA in ovarian and breast cancer cells.
The formation of the mRNP complex is a critical component of translational regulation and mRNA decay. Both the 5' and 3'UTRs of CSF-1 mRNA are involved in post-transcriptional regulation. In CSF-1 mRNA, a small hairpin loop structure is predicted to form at the extreme 5' end (2-21nt) of the 5'UTR. Nucleolin binds the hairpin loop structure in the 5'UTR of CSF-1 mRNA and enhances translation, while removal of this hairpin loop nucleolin binding element dramatically represses translation. Thus in CSF-1 mRNA, the hairpin loop nucleolin binding element is critical for translational regulation. In addition, nucleolin interacts with the 3'UTR of CSF-1 mRNA and facilitates the miRISC formation which results in poly (A) tail shortening. The overexpression of nucleolin increases the association of CSF-1 mRNA containing short poly (A)n≤26, with polyribosomes. Nucleolin both forms an mRNP complex with the eIF4G and CSF-1 mRNA, and is co-localized with the eIF4G in the cytoplasm further supporting nucleolin's role in translational regulation. The distinct foci formation of nucleolin in the cytoplasm of ovarian and breast cancer cells implicates the translational promoting role of nucleolin in these cancers.


Long-term EKG monitoring in patients with cerebrovascular insufficiency.
Cardiac dysrhythmia may be responsible for signs of cerebrovascular insufficiency in some patients. Ten patients with cerebrovascular insufficiency were monitored for up to 24 hours with the Holter EKG monitor. Eight of the patients had transient ischemic attacks and two had mild deficits from a completed stroke. Eight of the ten patients had associated abnormal cerebral angiography, the most frequent finding being carotid stenosis. Holter EKG monitor in these ten patients showed no abnormalities in four patients. The remaining six had a variety of cardiac dysrhythmias. Although there were a variety of cardiac, cerebrovascular, and neurological abnormalities in these ten patients, six of these patients had a disturbance in cardiac rhythm or conduction which could have been directly associated with or suggest an etiology for the patient's neurological event.


What comprises clinical experience in recognizing depression?: the primary care clinician's perspective.
Depression is a highly prevalent condition in primary care settings. In our previously reported work, we investigated the processes and conditions that influence primary care clinicians' recognition of depression. Three conditions influence the recognition of depression: familiarity with the patient, time available, and clinical experience. This article further describes the role of clinical experience in depression care. The grounded theory method was used to guide data collection and analysis. In-depth, in-person interviews were conducted with a purposeful sample of 8 clinicians. All interviews were audiotaped and transcribed. We identified 3 areas that comprise clinical experience relevant to depression care: (1) knowing one's professional role, (2) knowing oneself, and (3) knowing one's patients. In knowing one's professional role, 4 subdimensions were identified: (1) becoming familiar with illness patterns and clinical skills, (2) learning what works in the real world, (3) understanding what being a doctor is about, and (4) thinking of the whole person. The analysis indicated that clinical experience results from professional and personal growth during interactions with patients. The outcome of this developmental process was the achievement of comfort with depression care, a critical mediating variable that influenced primary care clinicians' recognition of depression. The developmental process of attaining comfort in managing depression warrants further exploration. Developing interventions to speed this process offers another approach to enhancing care for the management of depression.


Influence of the Natural Zeolite Particle Size Toward the Ammonia Adsorption Activity in Ceramic Hollow Fiber Membrane.
Natural zeolite is widely used in removing ammonia via adsorption process because of its superior ion-exchange properties. Ceramic particle size affects the adsorptivity of particles toward ammonia. In this study, hollow fiber ceramic membrane (HFCM) was fabricated from natural zeolite via phase inversion. The effect of natural zeolite particle size toward the properties and performance of HFCM was evaluated. The results show that the HFCM with smaller particle sizes exhibited a more compact morphological structure with better mechanical strength. The adsorption performance of HFCM was significantly improved with smaller particle sizes because of longer residence time, as proven by the lower water permeability. A high adsorption performance of 96.67% was achieved for HFCM with the smallest particle size (36 μm). These findings provide a new perspective on the promising properties of the natural zeolite-derived HFCM for ammonia removal.


Gabapentin activates spinal noradrenergic activity in rats and humans and reduces hypersensitivity after surgery.
Gabapentin has been reported to inhibit various acute and chronic pain conditions in animals and humans. Although the efficacy of gabapentin depends on the alpha2delta subunit of voltage-gated calcium channels, its analgesic mechanisms in vivo are still unknown. Here, the authors tested the role of spinal noradrenergic inhibition in gabapentin's analgesia for postoperative pain. Gabapentin was administered orally and intracerebroventricularly to rats on the day after paw incision, and withdrawal threshold to paw pressure was measured. The authors also measured cerebrospinal fluid concentration of norepinephrine and postoperative morphine use after surgery in patients who received oral placebo or gabapentin. Both oral and intracerebroventricular gabapentin attenuated postoperative hypersensitivity in rats in a dose-dependent manner. This effect of gabapentin was blocked by intrathecal administration of the alpha2-adrenergic receptor antagonist idazoxan and the G protein-coupled inwardly rectifying potassium channel antagonist tertiapin-Q, but not by atropine. In humans, preoperative gabapentin, 1,200 mg, significantly increased norepinephrine concentration in cerebrospinal fluid and decreased morphine requirements. These data suggest that gabapentin activates the descending noradrenergic system and induces spinal norepinephrine release, which produces analgesia via spinal alpha2-adrenoceptor stimulation, followed by activation of G protein-coupled inwardly rectifying potassium channels. The authors' clinical data suggest that gabapentin activates the descending noradrenergic system after preoperative oral administration at the time of surgery. These data support a central mechanism of oral gabapentin to reduce postoperative pain and suggest that this effect could be magnified by treatments that augment the effect of norepinephrine release.


A monitoring and feedback tool embedded in a counselling protocol to increase physical activity of patients with COPD or type 2 diabetes in primary care: study protocol of a three-arm cluster randomised controlled trial.
Physical activity is important for a healthy lifestyle. Although physical activity can delay complications and decrease the burden of the disease, the level of activity of patients with chronic obstructive pulmonary disease (COPD) or type 2 Diabetes Mellitus (DM2) is often far from optimal. To stimulate physical activity, a monitoring and feedback tool, consisting of an accelerometer linked to a smart phone and webserver (It's LiFe! tool), and a counselling protocol for practice nurses in primary care was developed (the Self-management Support Program). The main objective of this study is to measure the longitudinal effects of this counselling protocol and the added value of using the tool. This three-armed cluster randomised controlled trial with 120 participants with COPD and 120 participants with DM2 (aged 40-70), compares the counselling protocol with and without the use of the tool (group 1 and 2) with usual care (group 3). Recruitment takes place at GP practices in the southern regions of the Netherlands. Randomisation takes place at the practice level. The intended sample (three arms of 8 practices) powers the study to detect a 10-minute difference of moderate and intense physical activity per day between groups 1 and 3. Participants in the intervention groups have to visit the practice nurse 3-4 times for physical activity counselling, in a 4-6-month period. Specific activity goals tailored to the individual patient's preferences and needs will be set. In addition, participants in group 1 will be instructed to use the tool in daily life. The primary outcome, physical activity, will be measured in all groups with a physical activity monitor (PAM). Secondary outcomes are quality of life, general - and exercise - self-efficacy, and health status. Follow-up will take place after 6 and 9 months. Separately, a process evaluation will be conducted to explore reasons for trial non-participation, and the intervention's acceptability for participating patients and nurses. Results of this study will give insight into the effects of the It's LiFe! monitoring and feedback tool combined with care from a practice nurse for people with COPD or DM2 on physical activity. ClinicalTrials.gov: NCT01867970.


Thymidylate kinase from Acetabularia. II. Regulation during the life cycle.
The activity of dTMP kinase (EC 22.214.171.124) was estimated during the development of Acetabularia. Enzyme activity was increased at the beginning of the generative phase. Regulation of the dTMP kinase activity was observed even in the absence of the nucleus. More than 30 days after enucleation the enzyme activity increased two- to threefold. The increase in activity was inhibited by puromycin and cycloheximide but not by rifampicin and chloramphenicol. These results indicate that the enzyme is coded by the nuclear genome and translated on 80 S ribosomes. From mixing experiments with low-activity and high-activity cell extracts it is concluded that the regulation is due to de novo synthesis of the enzyme.


On Monolayer Formation of Pyrenebutyric Acid on Graphene.
As a two-dimensional material with high charge carrier mobility, graphene may offer ultrahigh sensitivity in biosensing. To realize this, the first step is to functionalize the graphene. This is commonly done by using 1-pyrenebutyric acid (PBA) as a linker for biomolecules. However, the adsorption of PBA on graphene remains poorly understood despite reports of successful biosensors functionalized via this route. Here, the PBA adsorption on graphene is characterized through a combination of Raman spectroscopy, ab initio calculations, and spectroscopic ellipsometry. The PBA molecules are found to form a self-assembled monolayer on graphene, the formation of which is self-limiting and Langmuirian. Intriguingly, in concentrated solutions, the PBA molecules are found to stand up and stack horizontally with their edges contacting the graphene surface. This morphology could facilitate a surface densely populated with carboxylic functional groups. Spectroscopic analyses show that the monolayer saturates at 5.3 PBA molecules per nm2 and measures ∼0.7 nm in thickness. The morphology study of this PBA monolayer sheds light on the π-π stacking of small-molecule systems on graphene and provides an excellent base for optimizing functionalization procedures.


CRISPR-Cas9 Mediated Stable Expression of Exogenous Proteins in the CHO Cell Line through Site-Specific Integration.
Chinese hamster ovary (CHO) cells are a popular choice in biopharmaceuticals because of their beneficial traits, including high-density suspension culture, safety, and exogenously produced proteins that closely resemble natural proteins. Nevertheless, a decline in the expression of exogenous proteins is noted as culture time progresses. This is a consequence of foreign gene recombination into chromosomes by random integration. The current investigation employs CRISPR-Cas9 technology to integrate foreign genes into a particular chromosomal location for sustained expression. Results demonstrate the successful integration of enhanced green fluorescent protein (EGFP) and human serum albumin (HSA) near base 434814407 on chromosome NC_048595.1 of CHO-K1 cells. Over 60 successive passages, monoclonal cell lines were produced that consistently expressed all relevant external proteins without discernible variation in expression levels. In conclusion, the CHO-K1 cell locus, NC_048595.1, proves an advantageous locus for stable exogenous protein expression. This study provides a viable approach to establishing a CHO cell line capable of enduring reliable exogenous protein expression.


Evaluation of how different implementation strategies of an injury prevention programme (FIFA 11+) impact team adherence and injury risk in Canadian female youth football players: a cluster-randomised trial.
Injury prevention programme delivery on adherence and injury risk, specifically involving regular supervisions with coaches and players on programme execution on field, has not been examined. The objective of this cluster-randomised study was to evaluate different delivery methods of an effective injury prevention programme (FIFA 11+) on adherence and injury risk among female youth football teams. During the 4-month 2011 football season, coaches and 13-year-old to 18-year-old players from 31 tier 1-3 level teams were introduced to the 11+ through either an unsupervised website ('control') or a coach-focused workshop with ('comprehensive') and without ('regular') additional supervisions by a physiotherapist. Team and player adherence to the 11+, playing exposure, history and injuries were recorded. Teams in the comprehensive and regular intervention groups demonstrated adherence to the 11+ programme of 85.6% and 81.3% completion of total possible sessions, compared to 73.5% for teams in the control group. These differences were not statistically significant, after adjustment for cluster by team, age, level and injury history. Compared to players with low adherence, players with high adherence to the 11+ had a 57% lower injury risk (IRR 0.43, 95% CI 0.19 to 1.00). However, adjusting for covariates, this between-group difference was not statistically significant (IRR=0.44, 95% CI 0.18 to 1.06). Following a coach workshop, coach-led delivery of the FIFA 11+ was equally successful with or without the additional field involvement of a physiotherapist. Proper education of coaches during an extensive preseason workshop was more effective in terms of team adherence than an unsupervised delivery of the 11+ programme to the team. ISRCTN67835569.


Non-equilibrium gating in cardiac Na+ channels: an original mechanism of arrhythmia.
Many long-QT syndrome (LQTS) mutations in the cardiac Na+ channel result in a gain of function due to a fraction of channels that fail to inactivate (burst), leading to sustained current (Isus) during depolarization. However, some Na+ channel mutations that are causally linked to cardiac arrhythmia do not result in an obvious gain of function as measured using standard patch-clamp techniques. An example presented here, the SCN5A LQTS mutant I1768V, does not act to increase Isus (<0.1% of peak) compared with wild-type (WT) channels. In fact, it is difficult to reconcile the seemingly innocuous kinetic alterations in I1768V as measured during standard protocols under steady-state conditions with the disease phenotype. We developed new experimental approaches based on theoretical analyses to investigate Na+ channel gating under non-equilibrium conditions, which more closely approximate physiological changes in membrane potential that occur during the course of a cardiac action potential. We used this new approach to investigate channel-gating transitions that occur subsequent to channel activation. Our data suggest an original mechanism for development of LQT-3 arrhythmias. This work demonstrates that a combination of computational and experimental analysis of mutations provides a framework to understand complex mechanisms underlying a range of disorders, from molecular defect to cellular and systems function.


Glucose transporter glut-1 expression correlates with tumor hypoxia and predicts metastasis-free survival in advanced carcinoma of the cervix.
Hypoxic tumors are known to be more malignant, to be more likely to metastasize, and to have a poor prognosis. They are also radio- and chemoresistant. For this reason, it is desirable that a clinically useful marker of hypoxia is found, so that treatment with radiotherapy and bioreductive chemotherapy can be rationally applied to individual patients. Glut-1 is a facilitative glucose transporter that is ubiquitously expressed in normal tissue and expressed at higher levels in a number of tumors. Its potential as an intrinsic hypoxia marker arises from its dual control in hypoxic conditions by reduced oxidative phosphorylation and the hypoxia-inducible factor (HIF-1) oxygen-sensing pathway. Eppendorf histography, by virtue of its proven predictive qualities, is a suitable gold standard used in our laboratory to validate new hypoxia markers. Using this technique, pretreatment pO(2) measurements were performed on 54 patients with locally advanced cervical carcinoma. Then, immunohistochemical staining was used to detect Glut-1 protein in individual tumor biopsy sections. Both measurements were made before initiation of treatment. By using a low-tech scoring system, pO(2) was found to correlate weakly with Glut-1 score (r = 0.28; P = 0.04). To extrapolate this correlation to the known adverse effects of tumor hypoxia on outcome, we examined the prognostic significance of Glut-1 staining in a retrospective series of 121 patients. An absence of Glut-1 significantly increased the likelihood of metastasis-free survival (P = 0.022) but did not significantly effect disease-free or recurrence-free survival. These findings suggest that Glut-1 be an intrinsic marker of hypoxia that can easily be applied in a clinical setting.


The effects of uncoupling protein 1 and beta3-adrenergic receptor gene polymorphisms on weight loss and lipid profiles in obese women.
The purpose of this study was to investigate whether the genetic polymorphisms of the uncoupling protein 1 (UCP1) and beta 3 adrenergic receptor (beta3-AR) were associated with differences in weight loss and lipid profiles in obese premenopausal women exposed to low-calorie meal replacements over a period of six weeks. Forty women between the ages of 20 and 35 were randomly divided into two groups, each of which consumed one of two low-calorie meal replacements containing either white rice or mixed rice. Although body weight, body mass index (BMI), blood glucose concentration, triglycerides, total cholesterol (TC), and high-density lipoprotein cholesterol (HDL-C) were not significantly different by the UCP1 genotype in the white rice group, there were significant differences in body weight (p = 0.041), BMI (p = 0.027), and blood glucose concentration (p = 0.047) between carriers and non-carriers of the G allele in the mixed rice group after the six-week meal replacement intervention. The beta3-AR polymorphism showed no apparent affect on these parameters. Dietary fiber affects weight gain since it is closely related with absorption of nutrients. As a result, the AA type UCP1 genotype produced significant weight loss in the mixed rice group, but not in the white rice group.


Interleukin-18 and the risk of coronary heart disease in European men: the Prospective Epidemiological Study of Myocardial Infarction (PRIME).
Interleukin (IL)-18 promotes atherosclerotic plaque growth and vulnerability. It is unknown, however, whether elevations of circulating IL-18 precede the onset of coronary events in apparently healthy individuals. We evaluated the relationship between baseline plasma levels of IL-18 and the subsequent incidence of coronary events over a 5-year follow-up in the Prospective Epidemiological Study of Myocardial Infarction (PRIME),which included 10 600 healthy European men aged 50 to 59 years at baseline. Analysis was performed in a nested case-control manner comparing 335 cases with a coronary event to 670 age-matched controls. Baseline levels of IL-18 were significantly higher in men who developed a coronary event than in controls (225.1 versus 203.9 pg/mL, P=0.005). After adjustment for most potential confounders, including C-reactive protein, IL-6, and fibrinogen, the relative risk of future coronary events associated with increasing tertiles of IL-18 was 1.65 (95% CI 1.14 to 2.40, P=0.008) in Northern Ireland, 1.29 (95% CI 0.96 to 1.73, P=0.09) in France, and 1.42 (95% CI 1.13 to 1.79, P=0.003) in both populations combined (P=0.31 for the test of homogeneity between populations). In all models, IL-18 made an independent contribution to the prediction of risk over lipids or other inflammatory markers such as C-reactive protein, IL-6, or fibrinogen. Plasma IL-18 level was identified as an independent predictor of coronary events in healthy, middle-aged European men. Determination of circulating IL-18 might improve the prediction of coronary events.


CYP1A1 expression and organochlorine pesticides level in the etiology of bladder cancer in North Indian population.
Urinary bladder cancer (UBC) is one of the most common malignancies worldwide. The etiology of UBC is multifactorial and includes both exogenous and endogenous factors. Exogenous risk factors include exposure to heavy metals, aromatic amines, and environmental pollutants including pesticides such as organochlorine pesticides (OCPs). Environmental factors alone are incapable of directly producing DNA damage and may require activation by phase I metabolizing enzymes like cytochrome P450 in order to become active carcinogen. The present study is designed to study CYP1A1 gene expression, OCP level in cases of UBC, as well as to explore the plausible role of gene-environment interaction in the etiology of UBC among North Indian population. A total of 60 cases with equal number of controls were enrolled under this study, the OCP levels were estimated using gas chromatography, CYP1A1 mRNA expression was quantified by real-time quantitative polymerase chain reaction, and fold change was calculated using the ΔΔCt method. In the present study, the levels of OCP were found to be significantly higher with the upregulation of CYP1A1 mRNA expression among UBC cases as compared to controls. While putting multiple linear regression, it has been observed that there is a significant interaction between the levels of OCPs and ΔCt value of CYP1A1 gene taken into account hematuria episodes as dependent variable. The study concludes that when there is predisposition of OCPs and upregulation of CYP1A1 gene, then the result will be an increment in hematuria episodes which indicates that gene-environment interaction plays a significant role in the causation of UBC among North Indian population.


Growth and water use of Eucalyptus grandis and Pinus radiata plantations irrigated with effluent.
We studied the growth and water balance of young plantations of Pinus radiata D. Don and Eucalyptus grandis W. Hill ex Maiden irrigated with effluent for 3 years in a climate of high net evaporation. The plantations were irrigated weekly with secondary-treated municipal effluent at the estimated water-use rate, or at nominally twice or half this rate. Control plots were irrigated with bore water at their estimated water-use rate. Both species grew rapidly when irrigated with either effluent or bore water. The eucalypts irrigated with effluent at the estimated water-use rate closed canopy in 24 months, and at 34 months, mean dominant height was 12.1 m, stand basal area was 12.2 m(2) ha(-1), volume was 51.2 m(3) ha(-1), LAI was 5.7, and foliage mass was 6.5 Mg ha(-1). The pines in the corresponding effluent treatment had not closed canopy by 34 months. At this time, mean height was 5.0 m, stand basal area was 9.6 m(2) ha(-1), volume was 29.7 m(3) ha(-1), LAI was 3.5, and foliage mass was 7.3 Mg ha(-1). Water use by eucalypts was consistently higher than by pines, commensurate with their more rapid early growth, but the difference was not in proportion to the difference in leaf area. In the third year (when the eucalypts had a closed canopy), the eucalypts used 22% more water than the pines, but the annual mean LAI of the eucalypts was three times greater than that of the pines. The results suggest that (1) plantation water use by the two species on the same site will be similar for the same stage of canopy development, (2) eucalypts are not inherently more profligate consumers of water than pines when soil water is not limiting, and (3) stomatal control limits growth and water use of E. grandis in arid environments.


The potential to improve diabetes control with vitamin D replacement in African American patients: case report and literature review.
African Americans have a higher prevalence of Diabetes mellitus and associated complications. The prevalence of Vitamin D deficiency is also higher in African Americans. We report an African American veteran who was followed for a period of 10 years in the Endocrine clinic for insulin-requiring diabetes. Despite intensive, medical, nutritional and educational efforts during that period, no discernible progress was made in achieving any improvement in glycemic control. The patient appeared to be noncompliant with recommended strategies to improve glycemia. The patient was seen recently and was found to be profoundly Vitamin D deficient with a 25 (OH) Vitamin D level of 11.6 ng/ml [30-100 ng/ml]. While patient did not wish to change his insulin regimen or diabetic management, he was willing to accept Vitamin D therapy. Replacement with Vitamin D was associated with significant improvement in glycosylated hemoglobin to previously unmatched levels of glycemic control. We discuss the multiple potential mechanisms by which improved Vitamin D status may result in improved diabetes control. Given the current pandemic of Vitamin D deficiency and the plethora of potential benefits, we recommend maintaining adequate Vitamin D reserves in diabetic patients with a special emphasis on minority populations.


The role of seaweed as a potential dietary supplementation for enteric methane mitigation in ruminants: Challenges and opportunities.
Seaweeds are macroalgae, which can be of many different morphologies, sizes, colors, and chemical profiles. They include brown, red, and green seaweeds. Brown seaweeds have been more investigated and exploited in comparison to other seaweed types for their use in animal feeding studies due to their large sizes and ease of harvesting. Recent in vitro and in vivo studies suggest that plant secondary compound-containing seaweeds (e.g., halogenated compounds, phlorotannins, etc.) have the potential to mitigate enteric methane (CH4) emissions from ruminants when added to the diets of beef and dairy cattle. Red seaweeds including Asparagopsis spp. are rich in crude protein and halogenated compounds compared to brown and green seaweeds. When halogenated-containing red seaweeds are used as the active ingredient in ruminant diets, bromoform concentration can be used as an indicator of anti-methanogenic properties. Phlorotannin-containing brown seaweed has also the potential to decrease CH4 production. However, numerous studies examined the possible anti-methanogenic effects of marine seaweeds with inconsistent results. This work reviews existing data associated with seaweeds and in vitro and in vivo rumen fermentation, animal performance, and enteric CH4 emissions in ruminants. Increased understanding of the seaweed supplementation related to rumen fermentation and its effect on animal performance and CH4 emissions in ruminants may lead to novel strategies aimed at reducing greenhouse gas emissions while improving animal productivity.


lncRNA TUG1 as potential novel biomarker for prognosis of cardiovascular diseases.
Globally, cardiovascular diseases (CVDs) are among the leading causes of death. In light of the high prevalence and mortality of CVDs, it is imperative to understand the molecules involved in CVD pathogenesis and the signaling pathways that they initiate. This may facilitate the development of more precise and expedient diagnostic techniques, the identification of more effective prognostic molecules and the identification of potential therapeutic targets. Numerous studies have examined the role of lncRNAs, such as TUG1, in CVD pathogenesis in recent years. According to this review article, TUG1 can be considered a biomarker for predicting the prognosis of CVD.


The synergism of n-hexane-induced neurotoxicity by methyl isobutyl ketone following subchronic (90 days) inhalation in hens: induction of hepatic microsomal cytochrome P-450.
The effect of methyl isobutyl ketone (MiBK) on n-hexane-induced neurotoxicity was investigated via inhalation in seven groups of five hens each for 90 days followed by a 30-day observation period. One group was exposed to vapors containing 1000 ppm n-hexane and another group to vapors having 1000 ppm MiBK. Four groups were exposed simultaneously to 1000 ppm of n-hexane and 100, 250, 500, or 1000 ppm MiBK. Another group was exposed similarly to ambient air in an exposure chamber and used as a control. Hens continuously exposed to 1000 ppm MiBK developed leg weakness with subsequent recovery, while inhalation of the same concentration of n-hexane produced mild ataxia. Hens exposed to mixtures of n-hexane and MiBK developed clinical signs of neurotoxicity, the severity of which depended on the MiBK concentration. Thus, all hens exposed to 1000 ppm n-hexane in combination with 250, 500, or 1000 ppm MiBK progressed to paralysis. Hens continuously exposed to 1000/100 n-hexane/MiBK showed severe ataxia which did not change during the observation period. The neurologic dysfunction in hens exposed simultaneously to n-hexane and MiBK was accompanied by large swollen axons and degeneration of the axon and myelin of the spinal cord and peripheral nerves. The results indicate that the nonneurotoxic chemical MiBK synergized the neurotoxic action of the weak neurotoxicant n-hexane since the coneurotoxicity coefficient for joint exposure was more than two times the additive effect of each treatment alone. In another experiment, to investigate the mechanism of MiBK synergism of n-hexane neurotoxicity, continuous inhalation for 50 days of 1000 ppm n-hexane had no effect on hen hepatic microsomal enzymes, whereas inhalation of 1000 ppm MiBK for 50 days or a mixture of 1000 ppm of each of n-hexane and MiBK for 30 days significantly induced aniline hydroxylase activity and cytochrome P-450 contents in hen liver microsomes. Liver microsomal proteins from these hens and from hens treated with beta-naphthoflavone (beta-NF) and phenobarbital (PB) were analyzed by sodium dodecyl sulfate-polyacrylamide gel electrophoresis. While beta-NF increased the 55-kDa band (1408%), PB, MiBK, and MiBK/n-hexane increased the protein band (49 kDa) (258, 335, and 253%, respectively), indicating that MiBK induces chicken hepatic cytochrome P-450. The results suggest that the synergistic action of MiBK on n-hexane neurotoxicity may be related to its ability to induce liver microsomal cytochrome P-450, resulting in increased metabolic activation of n-hexane to more potent neurotoxic metabolites.


MHC control of cell position in vitro.
Two-dimensional sorting-out behaviour (segregation) in mixtures of pulmonary endothelial cell lines derived from congenic strains of mice was examined using dense confluent cultures in which mitosis is rare. Cell MHC type was detected by autoradiographic labelling or by immunofluorescence techniques. For autoradiography cultures of one type were previously labelled with [3H]thymidine and one component of the mixed cell types was prepared from these cultures. Autoradiographs were prepared from the fixed cultures. Counts of contiguous neighbours (labelled or unlabelled around a randomly chosen central labelled cell) were made: these were analysed statistically using a new model for such a system. The results show that segregation of a clustering type took place if the alleles of the D locus in the H-2 complex were mismatched in the mixed strains, but that matching at the IC locus (or some locus to the right of IJ) overrides the effect of D mismatch. After 2 days culture sorting-out was easily detectable when the cells were stained for their histocompatibility antigens and groups of up to 12 cells of the same type were associated together.


Doctor-based basic cardiopulmonary resuscitation course: an alternative to the conventional approach.
United Christian Hospital initiated a doctor-based cardiopulmonary resuscitation (CPR) Program. It is a two-hour, focused, adult CPR course, suitable for adults of different age groups and of different educational levels. The course was rated highly by the participants. Most trainees acquired CPR knowledge and skills, and had confidence to perform CPR. This type of training could improve the rate of bystander CPR for out-of-hospital cardiac arrest patients in this region. Avoiding the complexity and pass-fail psychology that is used in the traditional CPR training curriculum, it can be an alternative to the traditional four-hour instructor-based Basic Life Support (BLS) course.


In vivo imaging of the human cornea with high-speed and high-resolution Fourier-domain full-field optical coherence tomography.
Corneal evaluation in ophthalmology necessitates cellular-resolution and fast imaging techniques that allow for accurate diagnoses. Currently, the fastest volumetric imaging technique is Fourier-domain full-field optical coherence tomography (FD-FF-OCT), which uses a fast camera and a rapidly tunable laser source. Here, we demonstrate high-resolution, high-speed, non-contact corneal volumetric imaging in vivo with FD-FF-OCT that can acquire a single 3D volume with a voxel rate of 7.8 GHz. The spatial coherence of the laser source was suppressed to prevent it from focusing on a spot on the retina, and therefore, exceeding the maximum permissible exposure (MPE). The inherently volumetric nature of FD-FF-OCT data enabled flattening of curved corneal layers. The acquired FD-FF-OCT images revealed corneal cellular structures, such as epithelium, stroma and endothelium, as well as subbasal and mid-stromal nerves.


Translating the Social-Ecological Perspective Into Multilevel Interventions for Family Planning: How Far Are We?
Scholars and practitioners frequently make recommendations to develop family planning interventions that are "multilevel." Such interventions take explicit account of the role of environments by incorporating multilevel or social-ecological frameworks into their design and implementation. However, research on how interventions have translated these concepts into practice in the field of family planning-and generally in public health-remains scarce. This article seeks to review the current definitions of multilevel interventions and their operationalization in the field of family planning. First, we highlight the divergent definitions of multilevel interventions and show the persistent ambiguity around this term. We argue that interventions involving activities at several levels but lacking targets (i.e., objectives) to create change on more than one level have not incorporated a social-ecological framework and should therefore not be considered as "multilevel." In a second step, we assess the extent to which family planning interventions have successfully incorporated a social-ecological framework. To this end, the 63 studies featured in Mwaikambo et al.'s systematic review on family planning interventions were reexamined. This assessment indicates that the multilevel or social-ecological perspective has seldom been translated into interventions. Specifically, the majority of interventions involved some form of activity at the community and/or organizational level, yet targeted and measured intrapersonal change as opposed to explicitly targeting/measuring environmental modification.


Macrolide and clindamycin resistance in Streptococcus milleri group isolates from the airways of cystic fibrosis patients.
Organisms belonging to the Streptococcus milleri group (SMG) are known for their role in pyogenic infections but have recently been implicated as etiological agents of pulmonary exacerbation in adult patients with cystic fibrosis (CF). The prolonged exposure of CF patients to antibiotics prompted us to investigate the susceptibility profiles of 118 SMG isolates from the airways of CF patients to 12 antibiotics compared to 43 SMG isolates from patients with invasive infections. We found that approximately 60% of all isolates failed to grow using the standard medium for disc diffusion, Mueller-Hinton blood agar (MHBA), so we explored the usefulness of brain heart infusion (BHI) agar for susceptibility testing. Zone-of-inhibition comparisons between BHI and MHBA showed strong correlations for six antibiotics, and interpretations were similar for both medium types. For ceftriaxone and cefepime, both groups of isolates were highly susceptible. Tetracycline resistance levels were comparable between the two groups (22% in CF isolates and 17.4% in invasive isolates). However, more than half of the CF isolates were not susceptible to azithromycin, erythromycin, and clindamycin, compared to 11%, 13%, and 6.5% of invasive isolates, respectively. There were 5-fold and 8-fold increased risks of azithromycin and clindamycin resistance, respectively, for the isolates from the airways of CF patients relative to the invasive isolates. Macrolide resistance was strongly linked to chronic azithromycin therapy in CF patients. This study shows that BHI agar is a suitable alternative for antimicrobial susceptibility testing for the SMG and that SMG isolates from the airways of CF patients are more resistant to macrolides and clindamycin than strains isolated from patients with invasive infections.


Recovery Kinetics of Radiographic and Implant-Related Revision Patients Following Adult Spinal Deformity Surgery.
Prior studies have observed similar health-related quality of life (HRQL) in revisions and nonrevision (NR) patients following adult spinal deformity (ASD) correction. However, a novel comparison approach may allow better comparisons in spine outcomes groups. To determine if ASD revisions for radiographic and implant-related complications undergo a different recovery than NR patients. Inclusion: ASD patients with complete HRQL (Oswestry Disability Index, Short-Form-36 version 2 (SF-36), Scoliosis Research Society [SRS]-22) at baseline, 6 wk, 1 yr, 2 yr. Generated revision groups: nonrevision (NR), revised-complete data (RC; with follow-up 2 yr after revision), and revised-incomplete data (RI; without 2-yr follow-up after revision). In a traditional analysis, analysis of variance (ANOVA) compared baseline HRQLs to follow-up changes. In a novel approach, integrated health state was normalized at baseline using area under curve analysis before ANOVA t-tests compared follow-up statuses. Two hundred fifty-eight patients were included with 50 undergoing reoperations (19.4%). Rod fractures (n = 15) and proximal joint kyphosis (n = 9) were most common. In standard HRQL analysis, comparing RC index surgery and RC revision surgery HRQLS revealed no significant differences throughout the 2-yr follow-up from either the initial index or revision procedure. Using normalized HRQL/integrated health state, RI displayed worse scores in SF-36 Physical Component Score, SRS activity, and SRS appearance relative to NR (P < .05), indicating less improvement over the 2-yr period. RC were significantly worse than RI in SF-36 Mental Component Score, SRS mental, SRS satisfaction, and SRS total (P < .05). ASD patients indicated for revisions for radiographic and implant-related complications differ significantly in their overall 2-yr recovery compared to NR, using a normalized integrated health state method. Traditional methods for analyzing revision patients' recovery kinetics may overlook delayed improvements.


Parkinson's disease: an update for dentists.
One of the diseases that will afflict the growing number of elderly American dental patients is Parkinson's disease, yet few dental articles and textbooks address the condition. This article reviews the clinical and diagnostic features, pathophysiology, management, and dental concerns in patients with Parkinson's disease who undergo dental care.


Stability and drug release studies of an antimycotic nanomedicine using HPLC, dynamic light scattering and atomic force microscopy.
Much attention has been paid to nanoparticle-based drug delivery systems to selectively deliver drugs to target organs and tissues. In this study, AmBisome, an antimycotic nanomedicine containing amphotericin B, was chosen as a typical nanomedicine, and analyzed using dynamic light scattering (DLS), an easy method to measure size, and size distribution, atomic force microscopy (AFM) and high-performance liquid chromatography (HPLC). AFM allowed the analysis of shape, besides a detailed size and size distribution. HPLC is useful to quantify the released amount of amphotericin B as it succeeded in a rapid separation of AmBisome and free amphotericin B. The aggregation or collapse of AmBisome and release of amphotericin B occurred upon 75% methanol addition or dilution with buffer around pH 4. Therefore, it is important to analyze nanomedicines using multiple analytical methods, and to integrate them for the quality and quantity evaluation of nanomedicines.


Mechanism of the increase in cation permeability of human erythrocytes in low-chloride media. Involvement of the anion transport protein capnophorin.
When human erythrocytes are suspended in low-Cl- media (with sucrose replacing Cl-), there is a large increase in both the net efflux and permeability of K+. A substantial portion (greater than 70% with Cl- less than 12.5 mM) of this K+ efflux is inhibited by the anion exchange inhibitor DIDS (4,4'-diisothiocyanostilbene-2,2'-disulfonic acid). This inhibition cannot be explained as an effect of DIDS on net Cl- permeability (Pcl) and membrane potential, but rather represents a direct effect on the K+ permeability. When cells are reacted with DIDS for different times, the inhibition of K+ efflux parallels that of Cl- exchange, which strongly indicates that the band 3 anion exchange protein (capnophorin) mediates the net K+ flux. Since a noncompetitive inhibitor of anion exchange, niflumic acid, has no effect on net K+ efflux, the net K+ flow does not seem to involve the band 3 conformational change that mediates anion exchange. The data suggest that in low-Cl- media, the anion selectivity of capnophorin decreases so that it can act as a very low-conductivity channel for cations. Na+ and Rb+, as well as K+, can utilize this pathway.


Inappropriate hospital care and severity of illness: results from a nationwide study.
Little is known about the clinical characteristics of hospital patients who do not meet standard utilization review criteria for acute care settings. This study examined whether patients with either inappropriate hospital admissions or days of care were less severely ill on a number of indicators compared to those designated as appropriate by a widely used utilization review instrument. Using data from a probability sample of 6063 medical and surgical hospitalizations at 50 Department of Veterans Affairs medical centers, we found strong associations between the appropriateness of admissions and days of care and four indicators of severity of illness. These results suggest that utilization management programs and preadmission screening probably successfully screen out less severely ill patients who have less need of hospital-level services.


Association of smooth membranes with spindle microtubules in the arterial smooth muscle cell.
Smooth membrane-limited vesicles and cisternae are closely associated with spindle microtubules in mitotic pulmonary trunk smooth muscle cells of the rabbit. This may play a regulatory role in the structure-function integrity of the spindle.


Quality of life in caregivers of young children with Prader-Willi syndrome.
This study aimed to measure quality of life (QOL) in primary caregivers of young childrenwith Prader-Willi syndrome (PWS). The caregivers of 32 children aged from 6.1 to 71.2 months completed the Chinese version of the World Health Organization Quality of Life-BREF (WHOQOL-BREF). We also evaluated the social adaption capacity of these children with Infants-Junior Middle School Students' Social-Life Abilities Scale. Correlation test was used to explore the related factors to caregivers' QOL. Caregivers of young children with PWS had significantly lower QOL. The correlation analyses revealed that caregivers' QOL was lower in children with young age, combined diseases or symptoms or poor social adaption, or caregivers having concerns about the child. Rearing a chilld with PWS may lead to decreased QOL. Psychological status of caregivers should be highlighted and social support should be given to families with PWS children.


Multiplicative Forests for Continuous-Time Processes.
Learning temporal dependencies between variables over continuous time is an important and challenging task. Continuous-time Bayesian networks effectively model such processes but are limited by the number of conditional intensity matrices, which grows exponentially in the number of parents per variable. We develop a partition-based representation using regression trees and forests whose parameter spaces grow linearly in the number of node splits. Using a multiplicative assumption we show how to update the forest likelihood in closed form, producing efficient model updates. Our results show multiplicative forests can be learned from few temporal trajectories with large gains in performance and scalability.


[Retinopathy in the newborn. Nursing care].
The use of oxygen as treatment for cardiorespiratory pathology in newborns is an accepted, regular practice. The prolonged use and high concentration of oxygen in premature newborn infants has been associated with an increase in cases of Proliferate Retinopathy in Premature Infants. This article publishes the results obtained over the past two years from the application of a treatment procedure which followed the recommendations made by the Standards Commission of the Spanish Association of Pediatricians regarding the measurement, administration and monitoring of oxygen to at risk newborn infants while evaluating the number of cases of retinopathy and their severity. Included in this study are all the newborns attended to at the Neonatal Intensive Care Unit of the "Arquitecto Marcide-Novoa Santos" Clinical Hospital in Ferrol from March 1995 to February 1997 which weighed less than 1500 grams or were born before the 36th week of gestation and received oxygen at a concentration above 50%. We encountered one case of level 3 retinopathy. In this case, we noticed a significant relationship among the point of gestation completed at birth, weight at birth and the severity of Proliferate Retinopathy in Premature Infants. We also proved that a painstaking control of oxygen allows a medical team to lower the degree of retinopathy in premature infants.


Isotretinoin vs etretinate therapy in generalized pustular and chronic psoriasis.
The clinical response to isotretinoin (13-cis-retinoic acid) in 11 patients with generalized pustular psoriasis was evaluated. Control of pustulation and systemic symptoms was achieved in ten cases, but additional therapy was required to produce complete clearing of all psoriatic lesions. Also, the efficacy of isotretinoin and etretinate in the treatment of chronic plaque psoriasis was compared in 29 patients. Isotretinoin was found to be less effective than etretinate in the treatment of chronic plaque psoriasis.


Hemostatic therapy in experimental intracerebral hemorrhage associated with rivaroxaban.
Rivaroxaban has recently been approved for stroke prevention in atrial fibrillation. However, lack of an effective antidote represents a major concern in the event of intracerebral hemorrhage (ICH). The aims of the present study were to establish a murine model of ICH associated with rivaroxaban, and to examine the effectiveness of different hemostatic factors in preventing excess hematoma expansion. In C57BL/6 mice receiving 10 or 30 mg/kg rivaroxaban by gastric gavage, plasma concentration, prothrombin time, and coagulation factor activities were measured repeatedly. Thirty minutes after inducing ICH by intrastriatal collagenase-injection, mice received an intravenous injection of either saline, prothrombin complex concentrate (100 U/kg), murine fresh frozen plasma (200 μL), or recombinant human Factor VIIa (1 mg/kg). ICH volume was quantified on brain cryosections and using hemoglobin spectrophotometry 24 hours later. Rivaroxaban in 30 mg/kg dose substantially increased the hematoma volume in ICH induced by 0.060 U collagenase. Prothrombin complex concentrate, fresh frozen plasma, or Factor VIIa prevented excess hematoma expansion caused by anticoagulation. Prevention of hematoma expansion by prothrombin complex concentrate was dose-dependent. None of the 3 agents completely corrected the prolonged prothrombin time, although they restored the activities of deficient FII and X. Prothrombin complex concentrate, Factor VIIa, and fresh frozen plasma prevent excess intracerebral hematoma expansion in a murine ICH model associated with rivaroxaban. The efficacy and safety of this reversal strategy must be further evaluated in clinical studies.


Interleukin-2 (IL-2) gene therapy with allogeneic fibroblasts in the CT-26 model of murine colorectal carcinoma.
We previously demonstrated the efficacy of a genetically engineered vaccine composed of syngeneic tumor cells mixed with syngeneic, IL-2 gene transduced fibroblasts in the CT-26 model of murine colorectal carcinoma. In this report, we describe a more practical approach to fibroblast mediated IL-2 gene therapy that employs syngeneic tumor cells mixed with allogeneic, IL-2 gene transduced fibroblasts. BALB/c mice were challenged with an injection of CT-26, 14 days following immunization with IL-2 modified syngeneic BALB/c 3T3 (H-2(d)) or allogeneic C3H 3T3 (H-2(k)) fibroblasts mixed with irradiated CT-26. Both syngeneic and allogeneic IL-2 modified fibroblasts provided significantly better protection compared to animals treated with control fibroblasts (syngeneic IL-2 fibroblasts 32/40-80% vs. control 15/45-33%, p<0.01; allogeneic IL-2 fibroblasts 25/37-68% vs. control 15/45-3345, p<0.01). There was no statistically significant difference between the groups immunized with syngeneic or allogeneic IL-2 modified fibroblasts. These findings support the evaluation of allogeneic IL-2 modified fibroblasts as a practical form of cytokine gene therapy for cancer.


A two-stage approach for improved prediction of residue contact maps.
Protein topology representations such as residue contact maps are an important intermediate step towards ab initio prediction of protein structure. Although improvements have occurred over the last years, the problem of accurately predicting residue contact maps from primary sequences is still largely unsolved. Among the reasons for this are the unbalanced nature of the problem (with far fewer examples of contacts than non-contacts), the formidable challenge of capturing long-range interactions in the maps, the intrinsic difficulty of mapping one-dimensional input sequences into two-dimensional output maps. In order to alleviate these problems and achieve improved contact map predictions, in this paper we split the task into two stages: the prediction of a map's principal eigenvector (PE) from the primary sequence; the reconstruction of the contact map from the PE and primary sequence. Predicting the PE from the primary sequence consists in mapping a vector into a vector. This task is less complex than mapping vectors directly into two-dimensional matrices since the size of the problem is drastically reduced and so is the scale length of interactions that need to be learned. We develop architectures composed of ensembles of two-layered bidirectional recurrent neural networks to classify the components of the PE in 2, 3 and 4 classes from protein primary sequence, predicted secondary structure, and hydrophobicity interaction scales. Our predictor, tested on a non redundant set of 2171 proteins, achieves classification performances of up to 72.6%, 16% above a base-line statistical predictor. We design a system for the prediction of contact maps from the predicted PE. Our results show that predicting maps through the PE yields sizeable gains especially for long-range contacts which are particularly critical for accurate protein 3D reconstruction. The final predictor's accuracy on a non-redundant set of 327 targets is 35.4% and 19.8% for minimum contact separations of 12 and 24, respectively, when the top length/5 contacts are selected. On the 11 CASP6 Novel Fold targets we achieve similar accuracies (36.5% and 19.7%). This favourably compares with the best automated predictors at CASP6. Our final system for contact map prediction achieves state-of-the-art performances, and may provide valuable constraints for improved ab initio prediction of protein structures. A suite of predictors of structural features, including the PE, and PE-based contact maps, is available at http://distill.ucd.ie.


Size-controlled and redox-responsive supramolecular nanoparticles.
Control over the assembly and disassembly of nanoparticles is pivotal for their use as drug delivery vehicles. Here, we aim to form supramolecular nanoparticles (SNPs) by combining advantages of the reversible assembly properties of SNPs using host-guest interactions and of a stimulus-responsive moiety. The SNPs are composed of a core of positively charged poly(ethylene imine) grafted with β-cyclodextrin (CD) and a positively charged ferrocene (Fc)-terminated poly(amidoamine) dendrimer, with a monovalent stabilizer at the surface. Fc was chosen for its loss of CD-binding properties when oxidizing it to the ferrocenium cation. The ionic strength was shown to play an important role in controlling the aggregate growth. The attractive supramolecular and repulsive electrostatic interactions constitute a balance of forces in this system at low ionic strengths. At higher ionic strengths, the increased charge screening led to a loss of electrostatic repulsion and therefore to faster aggregate growth. A Job plot showed that a 1:1 stoichiometry of host and guest moieties gave the most efficient aggregate growth. Different stabilizers were used to find the optimal stopper to limit the growth. A weaker guest moiety was shown to be less efficient in stabilizing the SNPs. Also steric repulsion is important for achieving SNP stability. SNPs of controlled particle size and good stability (up to seven days) were prepared by fine-tuning the ratio of multivalent and monovalent interactions. Finally, reversibility of the SNPs was confirmed by oxidizing the Fc guest moieties in the core of the SNPs.


[The molecular genetics of meningiomas and genotypic/phenotypic correlations].
The WHO classification divides meningiomas in three grades. In grade 1 tumors, by far the most common (90 p. cent), inactivation of the NF2 gene (associated to the loss of chromosome 22) is the most frequent alteration. However, a subset of grade 1 meningiomas does not involve the NF2 gene and is less likely to evolve towards higher grade tumors. After NF2 inactivation, additional events may occur and are related to greater aggressiveness, such as loss of 1p, 14q, 10 q and 9p chromosomes, reactivation of telomerase, inactivation of the p16/CDKN2A gene. All these alterations are much more frequent in grades 2 (atypical) and 3 (malignant) of the WHO classification. In addition to reviewing the available literature, we pooled together the individual cases in order to refine the correlation between genotype and phenotype (histological grading, location) and to propose a model for tumoral progression of meningiomas.


Expression of antisense RNA against initiation factor eIF-4E mRNA in HeLa cells results in lengthened cell division times, diminished translation rates, and reduced levels of both eIF-4E and the p220 component of eIF-4F.
HeLa cells were transformed to express antisense RNA against initiation factor eIF-4E mRNA from an inducible promoter. In the absence of inducer, these cells (AS cells) were morphologically similar to control cells but grew four- to sevenfold more slowly. Induction of antisense RNA production was lethal. Both eIF-4E mRNA and protein levels were reduced in proportion to the degree of antisense RNA expression, as were the rates of protein synthesis in vivo and in vitro. Polysomes were disaggregated with a concomitant increase in ribosomal subunits. Translation in vitro was restored by addition of the initiation factor complex eIF-4F but not by eIF-4E alone. Immunological analysis revealed that the p220 component of eIF-4F was decreased in extracts of AS cells and undetectable in AS cells treated with inducer, suggesting that p220 and eIF-4E levels are coordinately regulated. eIF-4A, another component of eIF-4F, was unaltered.