Collaborative Workshops for Community Meaning-Making and Data Analyses: How Focus Groups Strengthen Data by Enhancing Understanding and Promoting Use.
Community-based participatory research is a growing approach, but often includes higher levels of community engagement in the research design and data collection stages than in the data interpretation stage. Involving study participants in this stage could further knowledge justice, science that aligns with and supports social justice agendas. This article reports on two community-based participatory environmental health surveys conducted between 2015 and 2019 in an industrial region near Marseille, France, and focuses specifically on our approach of organizing focus groups to directly involve residents and community stakeholders in the analysis and interpretation process. We found that, in these focus groups, residents triangulated across many different sources of information-study findings, local knowledge, and different types of expert knowledge-to reach conclusions about the health of their community and make recommendations for what should be done to improve community health outcomes. We conclude that involving residents in the data analysis and interpretation stage can promote epistemic justice and lead to final reports that are more useful to community stakeholders and decision-makers.


Staphylococcus aureus Antibiotic Susceptibilities in Infections in an Outpatient Dermatology Office on O'ahu.
Staphylococcus aureus is a pathogen that causes skin and soft tissue infections (SSTIs) in dermatology patients. There is an increasing rate of methicillin-resistant S aureus (MRSA) reported in the dermatology literature since 1987. This report profiles the antibiotic susceptibilities of methicillin-sensitive S aureus (MSSA) and MRSA in an outpatient office in Hawai'i. This is a retrospective study done by chart review from 2012 to 2014. Demographics, anatomical site of infection, clinical diagnoses and antimicrobial susceptibility patterns were analyzed and compared. Of the 66 samples, 57% were males and 43% were females. S aureus was more commonly found in impetigo, folliculitis, furuncles and secondarily infected psoriasis and more commonly located on the extremities. MSSA accounted for 73% (48) of the cases and MRSA accounted for 27% (18) of the cases. The antibiotics most effective against all S aureus cultures for outpatients were linezolid (100%), trimethoprim sulfamethoxazole (95%) and tetracyclines (94%). Linezolid (100%), trimethoprim sulfamethoxazole (100%) were most effective against MRSA isolates. Our S aureus and MRSA antimicrobial susceptibility results are similar to the local Hawai'i outpatient antibiogram collected from a large private laboratory in Hawai'i in 2014 and the current Infectious Disease Society of America guidelines. This study may be helpful in guiding empiric treatment of SSTIs suspected to be caused by S aureus.


Cardiovascular disease in patients with chronic renal impairment: role of natriuretic peptides.
Although there is overwhelming evidence that natriuretic peptides might be helpful in the diagnosis and management of congestive heart failure patients, the relationship among brain natriuretic peptides (BNP), renal function, and the severity of heart failure is less clear. It is obvious that the metabolism and elimination of BNP and N-terminal prohormone brain natriuretic peptide (NT-proBNP) are different with BNP clearance less dependent upon renal function. This paper reviews current data about the diagnostic and predictive role of natriuretic peptides to detect cardiac events in patients with chronic kidney disease. Although BNP and Nt-proBNP can be used to diagnose acute heart failure and may help predict risk and future cardiac events in patients with chronic kidney disease (CKD), a strategy that incorporates their use in daily clinical practice is still lacking.


A-to-I RNA Editing Uncovers Hidden Signals of Adaptive Genome Evolution in Animals.
In animals, the most common type of RNA editing is the deamination of adenosines (A) into inosines (I). Because inosines basepair with cytosines (C), they are interpreted as guanosines (G) by the cellular machinery and genomically encoded G alleles at edited sites mimic the function of edited RNAs. The contribution of this hardwiring effect on genome evolution remains obscure. We looked for population genomics signatures of adaptive evolution associated with A-to-I RNA edited sites in humans and Drosophila melanogaster. We found that single nucleotide polymorphisms at edited sites occur 3 (humans) to 15 times (Drosophila) more often than at unedited sites, the nucleotide G is virtually the unique alternative allele at edited sites and G alleles segregate at higher frequency at edited sites than at unedited sites. Our study reveals that a significant fraction of coding synonymous and nonsynonymous as well as silent and intergenic A-to-I RNA editing sites are likely adaptive in the distantly related human and Drosophila lineages.


Four ways towards tropical herbivore megadiversity.
Most multicellular species alive are tropical arthropods associated with plants. Hence, the host-specificity of these species, and their diversity at different scales, are keys to understanding the assembly structure of global biodiversity. We present a comprehensive scheme in which tropical herbivore megadiversity can be partitioned into the following components: (A) more host plant species per se, (B) more arthropod species per plant species, (C) higher host specificity of herbivores, or (D) higher species turnover (beta diversity) in the tropics than in the temperate zone. We scrutinize recent studies addressing each component and identify methodological differences among them. We find substantial support for the importance of component A, more tropical host species. A meta-analysis of published results reveals intermediate to high correlations between plant and herbivore diversity, accounting for up to 60% of the variation in insect species richness. Support for other factors is mixed, with studies too scarce and approaches too uneven to allow for quantitative summaries. More research on individual components is unlikely to resolve their relative contribution to overall herbivore diversity. Instead, we call for the adoption of more coherent methods that avoid pitfalls for larger-scale comparisons, for studies assessing different components together rather than singly, and for studies that investigate herbivore beta-diversity (component D) in a more comprehensive perspective.


Non-Lyme disease.
Four syndromes of non-Lyme disease are described on the basis of the history and serologic test result. Recognition of non-Lyme disease enables the physician to avoid unnecessary treatment and to keep considering the possibility of alternative diagnoses.


Engineered HaloTag variants for fluorescence lifetime multiplexing.
Self-labeling protein tags such as HaloTag are powerful tools that can label fusion proteins with synthetic fluorophores for use in fluorescence microscopy. Here we introduce HaloTag variants with either increased or decreased brightness and fluorescence lifetime compared with HaloTag7 when labeled with rhodamines. Combining these HaloTag variants enabled live-cell fluorescence lifetime multiplexing of three cellular targets in one spectral channel using a single fluorophore and the generation of a fluorescence lifetime-based biosensor. Additionally, the brightest HaloTag variant showed up to 40% higher brightness in live-cell imaging applications.


[Predictive capability of the TCI Diprifusor system in patients with terminal chronic renal insufficiency].
To evaluate the predictive capability of a target-controlled infusion (TCI) system in patients with terminal chronic renal failure by comparing real drug concentrations with predicted concentrations. Forty ASA II-III patients undergoing kidney transplants were enrolled and grouped by age: group A 18-54 years old and group B 55-80 years old. Propofol was administered through the Diprifusor TCI system (Astra Zeneca) with the target concentration of propofol for induction set at 3 micrograms/mL for group A patients and 2.5 micrograms/mL for group B patients. Arterial blood samples were taken for analysis of drug concentrations at the following times: 2 and 5 minutes after starting the infusion; immediately after the incision; before and 5 minutes after increasing or decreasing the target concentration > 25%; before and 5 minutes after switching off the perfusion for surgery; upon eye opening; and 30 minutes after switching off the infusion pump. The predictive capability of the system was determined by performance error (PE). We calculated bias (%, median PE) and accuracy (%, median absolute PE). Twenty group A and 20 group B patients were studied. The median PEs in groups A and B, respectively, were -3.45 (-20.3-28.4) and -1.1 (-19.7-15.4). Median absolute PEs were 21.2 (11.9-45.1) and 16.3 (11.5-27.4), respectively. The results indicate that the predictive capability of the Diprifusor pharmacokinetic model is acceptable in patients with terminal kidney failure, given the minor bias of 10% to 20% and the degree of accuracy between 20% and 40%.


The role of flow cytometry in the classification of myeloid disorders.
The World Health Organization classification (WHO-HAEM5) and the International Consensus Classification (ICC 2022) of myeloid neoplasms are based on the integration of clinical, morphologic, immunophenotypic, and genomic data. Flow cytometric immunophenotyping (FCIP) allows the identification, enumeration, and characterization of hematopoietic cells, and is therefore a powerful tool in the diagnosis, classification, and monitoring of hematological neoplasms. The vast majority of flow cytometry (FCM) studies in chronic myeloid neoplasms focus on its role in myelodysplastic neoplasms (MDS). FCM can also be helpful for the assessment of myeloproliferative neoplasms (MPN) and MDS/MPN, including the early detection of evolving myeloid or lymphoid blast crisis and the characterization of monocytic subsets. The classification of acute myeloid leukemia (AML) is primarily based on cytogenetic and molecular findings; however, FCIP is needed for subclassification of AML, not otherwise specified (NOS; ICC)/AML defined by differentiation (WHO-HAEM5). The main role of FCM in AML remains in making a rapid diagnosis and as a tool for measurable residual disease monitoring. Machine learning and artificial intelligence approaches can be used to analyze and classify FCM data. This article, based on an invited lecture at the 106th Annual Meeting of the German Society of Pathology in 2023, reviews the role of FCM in the classification of myeloid neoplasms, including recent publications on the application of artificial intelligence.


Effectiveness of the school dental screening programme in stimulating dental attendance for children in need of treatment in Northern Ireland.
The school dental screening programme has been in existence from the beginning of the 20th century yet its value in encouraging attendance among children with a dental health need is not fully established. To evaluate the effectiveness of school dental screening in promoting dental attendance among children with a treatment need and to examine the relative importance of screening, social class and other factors in dental attendance. Sixty-four participating schools were assigned to study and control groups using a stratified, blocked randomisation technique. The study group children received the standard school dental screening and the dental attendance of those with a positive screening result was assessed after 2 months by means of a questionnaire issued to the children's parents. The control group children were not, at this stage, screened, yet their parents received the same questionnaire assessing dental attendance over the 2-month period. However, only questionnaires from control group children who had a positive result at a subsequent screening were retained for analysis. A total of 2,321 children were screened, with 980 having a positive result. The mean dmft of those screening positive was 4.85. In all, 664 completed questionnaires were returned, giving a response rate of 67.8%. Dental attendance was reported among 45.5% of the study group (n=352) in the 2 months following screening. In the same period, 27.6% of the control group (n=312) claimed attendance. The effect was found to be significant among the high employed group (P<0.01) and the unemployed group (P<0.05). School dental screening was capable of stimulating dental attendance. The strong effect among the lowest socio-economic group shows that school dental screening may be used to decrease dental health inequalities.


[Impact of a selective screening for gestational diabetes in a Spanish population].
Recently, the American Diabetes Association (ADA) concluded that pregnant women with low risk factors for gestational diabetes need not to be tested. The aims of this study was to determine the prevalence of gestational diabetes in a Spanish low risk pregnant women population, to analyze the criteria that define low risk pregnancies for gestational diabetes, and to compare the differences in morbidity between pregnant women with and without gestational diabetes. Cohort study of 2,262 gestations (2,085 Caucasians) during a period of 7 years in a reference hospital. The gestational diabetes prevalence was 15%. Two-hundred and seventy-four (12.1%) women were considered as a low risk group for gestational diabetes. Among these, 13 (4.7%) presented gestational diabetes in comparison with 16.6% in the remaining women (p = 0.0001). Gestational diabetes in the low risk pregnant women constituted the 3.8% of all gestational diabetes. We did not find differences in gestational outcomes or fetal antropometry between the groups. The relative risk of macrosomia in the low risk pregnant was 0.9% (95% confidence interval for the mean: 0.86-0.94). In spite of their capacity of identifying current complications, 4% of gestational diabetes would not have been diagnosed with the new ADA criteria. The misdiagnosis will prevent in this small group of women the adoption of preventive measures for subsequent pregnancies and for diabetes in later life.


Licochalcone A induces morphological and biochemical alterations in Schistosoma mansoni adult worms.
This paper is the first report on the in vitro effects of licochalcone A, a chalcone isolated from Glycyrrhiza inflate Batalin (Leguminosae), on Schistosoma mansoni adult worms. In vitro, licochalcone A afforded lethal concentrations for 50% of parasites (LC50) of 9.12±1.1 and 9.52±0.9μM against female and male adult worms, respectively, at 24h. Additionally, the compound reduced the total number of S. mansoni eggs and affected the development of eggs produced by S. mansoni adult worms. Together, the results achieved after 24h showed that licochalcone A was 55.7- and 53.3-fold more toxic to S. mansoni female and male adult worms than to Chinese hamster ovary fibroblasts cells, respectively. Treatment with licochalcone A elicited drastic changes in the tegument of S. mansoni adult worms, as well as mitochondrial alteration and chromatin condensation. Licochalcone A also increased the superoxide anion level and decreased the superoxide dismutase activity in S. mansoni adult worms. Overall, our results indicated that licochalcone A displays in vitro schistosomicidal activity. This effect may result from increased production of reactive oxygen species (ROS) induced by the action of licochalcone A. The resulting ROS could act on the S. mansoni tegument and membranes and help induce the death of S. mansoni adult worms.


Unresolved discrepancies between cannabinoid test results for infant urine.
False-positive drug screen results for tetrahydrocannabinol (THC) have been observed. This study investigated the rate of unconfirmed positive screen results in infant and noninfant urine samples and evaluated possible reasons for differences. The rate of unconfirmed positive THC screen results for urine samples was determined retrospectively in 2 independent data sets (n = 14,859, reference laboratory; n = 21,807, hospital laboratory) by comparing positive immunoassay-based drug screen results with the associated results of confirmation tests. We then assessed the rate of positive THC screens for samples with varying likelihoods of cannabinoid presence to evaluate the contribution of infant-specific urine constituents to positive results. Finally, a method to detect a THC metabolite (11-hydroxy-Δ⁹-THC) that occurs in meconium was developed to determine its prevalence in infant urine. Positive screen results failed to confirm more frequently in samples from infants (47%) than in noninfants (0.8%). The hospital laboratory observed a similar discrepancy with a different immunoassay. Infant samples with a high likelihood of containing cannabinoids despite negative confirmatory results had a similar rate of positive screening results (50%, n = 20), whereas all samples with a low likelihood of containing cannabinoids screened negative (n = 23). 11-Hydroxy-Δ⁹-THC was not detected in any infant urine sample tested (n = 16). Conventional confirmatory methods for THC may be inappropriate for urine samples from infants. Our results suggest that one or more currently unrecognized THC-associated compounds are responsible for positive THC screen results for infant urine, as opposed to an infant-associated interference.


Does the tonsillar surface flora differ in children with and without tonsillar disease?
To investigate whether the tonsillar flora differ in children with and without adenotonsillar disease. Tonsil surface swabs were taken from 218 children indicated for adenotonsillectomy because of moderate symptoms of recurrent tonsillopharyngitis or adenotonsillar hypertrophy (T+Ads group). Control swabs were taken from 100 children without symptoms of adenotonsillar disease who visited the ophthalmology clinic. Potential respiratory pathogens were identified. Potential respiratory pathogens were found in 54% of the T+Ads group, compared to 41% of the control group (p = 0.04). Haemophilus influenzae was the commonest pathogen in both groups, being found in 41% of the T+Ads group and 34% of the control group. Moraxella catarrhalis was found more often in the T+Ads group compared to the control group: 7% vs 0% (p = 0.004). H. influenzae was found in 32% of the children with recurrent tonsillitis, compared to 48% of the children with symptoms of tonsillar hypertrophy (p = 0.03). The prevalence of potential respiratory pathogens on the tonsillar surface of children with moderate symptoms of recurrent tonsillopharyngitis and/or tonsillar hypertrophy differs only slightly from that in children without symptoms of adenotonsillar disease. Variations in the microbial flora do not seem to play an essential role in the predisposition of these children to tonsillar disease.


School-Based Prevention in Very Remote Settings: A Feasibility Trial of Methods and Measures for the Evaluation of a Social Emotional Learning Program for Indigenous Students in Remote Northern Australia.
Purpose: Skills for Life (SFL) is a social-emotional curriculum for Indigenous middle school students that was co-developed with educators and community members in a remote community of northern Australia. This preliminary study aimed to test the feasibility of processes and methods of data-gathering, the reliability of youth self-report measures, and to identify the direction of effects for an evaluation of a longer-term pilot of the curriculum. Design/Methodology/Approach: Indigenous Students in years 7-9 of a remote school participated in SFL over 2 years. The Strengths and Difficulties Questionnaire (SDQ), Kessler 6 (K6), and a purpose-designed Connected Self Scale (CSS) were administered to 63 students pre- and post-program. Findings: Only the K6, Prosocial behavior (SDQ), and two CSS subscales showed sufficient internal consistency for analysis. Change was positive but non-significant for SDQ and CSS. There was evidence of a dosage effect: students receiving the intervention over 2 years showed greater reduction in psychological distress than other students. There was no evidence of iatrogenic effects. Conclusions: The feasibility pilot is a critically important phase in the development of evaluation design and cjhoice of evaluation measures for challenging remote settings. This study found that evaluation of SFL with culturally and linguistically distinct Indigenous middle school students using self-report measures is feasible. However, the SDQ may not be suitable for this project. High levels of psychological distress suggest the need to investigate sources of life stress and potential supports for adolescent resilience in this context. This preliminary pilot aimed to trial methods and measures for evaluation of a social-emotional curriculum developed specifically for remote Australian Indigenous students who are at risk of poor psychosocial outcomes. No studies have examined the appropriateness of standardized self-report measures for evaluation of SEL with this student population in remote school settings.


The impact of hydrophilic emulsifiers on the physico-chemical properties, microstructure, water distribution and in vitro digestibility of proteins in fried snacks based on fish meat.
The present study was aimed at investigating the effect of ionic and non-ionic emulsifiers at 3 different levels of 0.15, 0.30 and 0.45% per 100 g of flour on the physico-chemical properties, microstructure and water distribution of fish-meat based fried snacks. The results showed that the addition of distilled mono-glycerides (DMG) decreased the strength of the starch-protein network which resulted in increased expansion and decreased water holding capacity (WHC). The addition of diacetyl tartaric acid esters of mono-glycerides (DATEM) increased the WHC and the ordered structure between starch and proteins while oil uptake was decreased. Pasting properties such as breakdown, peak viscosity and pasting temperatures were increased with the addition of DATEM compared to DMG and the control indicating the strong interaction among DATEM, starch and proteins. Scanning electron microscopy (SEM) analysis showed that DATEM strengthened the starch-protein matrix and the dense and rigid microstructure with fewer voids while DMG increased the intercellular spaces between the molecules of starch and proteins. Low field nuclear magnetic resonance (LF-NMR) relaxometry analysis revealed that the amount of free water (T21) was decreased and that of bound water (T23) was increased in DATEM samples indicating the strong interaction between emulsifiers and macromolecules compared to the control and DMG. Moreover, protein in vitro digestibility was also increased with the addition of DATEM. The findings suggested that 0.30% DATEM can be used in snacks with improved physico-chemical and functional properties.


Analysis of extracellular vesicle miRNA profiles in heart failure.
Extracellular vesicles (EVs) have recently emerged as an important carrier for various genetic materials including microRNAs (miRs). Growing evidences suggested that several miRs transported by EVs were particularly involved in modulating cardiac function. However, it has remained unclear what miRs are enriched in EVs and play an important role in the pathological condition. Therefore, we established the miR expression profiles in EVs from murine normal and failing hearts and consecutively identified substantially altered miRs. In addition, we have performed bioinformatics approach to predict potential cardiac outcomes through the identification of miR targets. Conclusively, we observed approximately 63% of predicted targets were validated with previous reports. Notably, the predicted targets by this approach were often involved in both beneficial and malicious signalling pathways, which may reflect heterogeneous cellular origins of EVs in tissues. Lastly, there has been an active debate on U6 whether it is a proper control. Through further analysis of EV miR profiles, miR-676 was identified as a superior reference control due to its consistent and abundant expressions. In summary, our results contribute to identifying specific EV miRs for the potential therapeutic targets in heart failure and suggest that miR-676 as a new reference control for the EV miR studies.


The development of healthy tennis clubs in the Netherlands.
To explore the factors that facilitate or hinder the development of healthy tennis clubs in the Netherlands and to identify suitable interventions that would help clubs to reach 'healthy club' status. A maximum variation, purposive sampling strategy was used to identify and recruit board members (n=16) from 10 Dutch tennis clubs. Data were collected using in-depth interviews based on an interview guide. The interviews explored what steps the clubs had taken to create a healthy tennis club, and what the respondents perceived to be the barriers to reaching healthy club status. The data were analysed using thematic content analysis. An ecological model was used to frame the interpretation of the themes and guide the development of the interventions. Four emerging themes were identified: provision of healthy foods, injury prevention and health services, social health and safety around the club. The main facilitators were found to be support from club management, having appropriate policies in place and having appointed officers. The main barriers were identified as a lack of policy templates, inadequate knowledge of coaches on injury prevention and injury management and fragmented access to relevant information. Guided by an ecological model, this study demonstrates the many factors that influence tennis clubs and the individual members of a healthy tennis club. Using this model, a multilevel intervention framework has been created that could be used by the Royal Netherlands Lawn Tennis Association to increase the number of healthy tennis clubs in the Netherlands.


Peripheral inflammation undermines the plasticity of the isolated spinal cord.
Peripheral capsaicin treatment induces molecular changes that sensitize the responses of nociceptive neurons in the spinal dorsal horn. The current studies demonstrate that capsaicin also undermines the adaptive plasticity of the spinal cord, rendering the system incapable of learning a simple instrumental task. In these studies, male rats are transected at the second thoracic vertebra and are tested 24 to 48 hours later. During testing, subjects receive shock to one hindleg when it is extended (controllable stimulation). Rats quickly learn to maintain the leg in a flexed position. Rats that have been injected with capsaicin (1% or 3%) in the hindpaw fail to learn, even when tested on the leg contralateral to the injection. This learning deficit lasts at least 24 hours. Interestingly, training with controllable electrical stimulation prior to capsaicin administration protects the spinal cord against the maladaptive effects. Rats pretrained with controllable stimulation do not display a learning deficit or tactile allodynia. Moreover, controllable stimulation, combined with naltrexone, reverses the capsaicin-induced deficit. These data suggest that peripheral inflammation, accompanying spinal cord injuries, might have an adverse effect on recovery.


Small size fullerenol nanoparticles suppress lung metastasis of breast cancer cell by disrupting actin dynamics.
Tumor metastasis is the primary cause of mortality in cancer patients. Migratory breast cancer cells in lymphatic and blood vessels seek new sites and form metastatic colonies in the lung and bone, and then these cancer cells often wreak considerable havoc. With advances in nanotechnology, nanomaterials and nanotechnologies are widely applied in tumor therapy. In this paper, small size fullerenol nanoparticles, which are separated by isoelectric focusing electrophoresis (IFE) for discrepancy of isoelectric point (pI), are used in the study of tumor metastasis. In this study, the commendable inhibition of tumor metastasis was uncovered by intravenous injection of purified fullerenol fraction with special surface charge and functional groups, which was separated by IFE for discrepancy of pI. By investigating the actin dynamics in several cancer cell lines, we found these small size fullerenol nanoparticles disturbed actin dynamics. Young's modulus detection and cell migration assays revealed that fullerenol lowered stiffness and restrained migration of breast cancer cells. Filopodia, the main supporting structures of actin bundles, are important for cell motility and adhesion. Scanning electron microscopy showed that fullerenol reduced the number and length of filopodia. Simultaneously, the inhibition of integrin to form clusters on filopodias, which was likely induced by reorganizing of actin cytoskeleton, impacted cancer cell adhesion and motility. With intravenous injection of these fullerenol nanoparticles, tumor metastasis is well inhibited in vivo. The underlying mechanism most likely to be attributed to the effect of fullerenol nanoparticles on disturbing actin dynamics. With the disordered actin fiber, cell function is varied, including decreased cell stiffness, reduced filopodia formation, and inactivated integrin.


High throughput nano-liter RT-qPCR to classify soil contamination using a soil arthropod.
To incorporate genomics data into environmental assessments a mechanistic perspective of interactions between chemicals and induced biological processes needs to be developed. Since chemical compounds with structural similarity often induce comparable biological responses in exposed animals, gene expression signatures can serve as a starting point for the assessment of chemicals and their toxicity, but only when relevant and stable gene panels are available. To design such a panel, we isolated differentially expressed gene fragments from the soil arthropod Folsomia candida, a species often used for ecotoxicological testing. Animals were exposed to two chemically distinct compounds, being a metal (cadmium) and a polycyclic aromatic hydrocarbon (phenanthrene). We investigated the affected molecular responses resulting from either treatment and developed and validated 44 qPCR assays for their responses using a high throughput nano-liter RT-qPCR platform for the analysis of the samples. Suppressive subtractive hybridization (SSH) was used to retrieve stress-related gene fragments. SSH libraries revealed pathways involved in mitochondrial dysfunction and protein degradation for cadmium and biotransformation for phenanthrene to be overrepresented. Amongst a small cluster of SSH-derived cadmium responsive markers were an inflammatory response protein and an endo-glucanase. Conversely, cytochrome P450 family 6 or 9 was specifically induced by phenanthrene. Differential expressions of these candidate biomarkers were also highly significant in the independently generated test sample set. Toxicity levels in different training samples were not reflected by any of the markers' intensity of expressions. Though, a model based on partial least squares differential analysis (PLS-DA) (with RMSEPs between 9 and 22% and R(2)s between 0.82 and 0.97) using gene expressions of 25 important qPCR assays correctly predicted the nature of exposures of test samples. For the application of molecular bio-indication in environmental assessments, multivariate analyses obviously have an added value over univariate methods. Our results suggest that compound discrimination can be achieved by PLS-DA, based on a hard classification of the within-class rankings of samples from a test set. This study clearly shows that the use of high throughput RT-qPCR could be a valuable tool in ecotoxicology combining high throughput with analytical sensitivity.


Three LIF-dependent signatures and gene clusters with atypical expression profiles, identified by transcriptome studies in mouse ES cells and early derivatives.
Mouse embryonic stem (ES) cells remain pluripotent in vitro when grown in the presence of the cytokine Leukaemia Inhibitory Factor (LIF). Identification of LIF targets and of genes regulating the transition between pluripotent and early differentiated cells is a critical step for understanding the control of ES cell pluripotency. By gene profiling studies carried out with mRNAs from ES cells and their early derivatives treated or not with LIF, we have identified i) LIF-dependent genes, highly expressed in pluripotent cells, whose expression level decreases sharply upon LIF withdrawal [Pluri genes], ii) LIF induced genes [Lifind genes] whose expression is differentially regulated depending upon cell context and iii) genes specific to the reversible or irreversible committed states. In addition, by hierarchical gene clustering, we have identified, among eight independent gene clusters, two atypical groups of genes, whose expression level was highly modulated in committed cells only. Computer based analyses led to the characterization of different sub-types of Pluri and Lifind genes, and revealed their differential modulation by Oct4 or Nanog master genes. Individual knock down of a selection of Pluri and Lifind genes leads to weak changes in the expression of early differentiation markers, in cell growth conditions in which these master genes are still expressed. We have identified different sets of LIF-regulated genes depending upon the cell state (reversible or irreversible commitment), which allowed us to present a novel global view of LIF responses. We are also reporting on the identification of genes whose expression is strictly regulated during the commitment step. Furthermore, our studies identify sub-networks of genes with a restricted expression in pluripotent ES cells, whose down regulation occurs while the master knot (composed of OCT4, SOX2 and NANOG) is still expressed and which might be down-regulated together for driving cells towards differentiation.


Micro-computed tomography assessment of the progression of fracture healing in mice.
The mouse fracture model is ideal for research into the pathways of healing because of the availability of genetic and transgenic mice and the ability to create cell-specific genetic mutations. While biomechanical tests and histology are available to assess callus integrity and tissue differentiation, respectively, micro-computed tomography (μCT) analysis has increasingly been utilized in fracture studies because it is non-destructive and provides descriptions of the structural and compositional properties of the callus. However, the dynamic changes of μCT properties that occur during healing are not well defined. Thus, the purpose of this study was to determine which μCT properties change with the progression of fracture repair and converge to values similar to unfractured bone in the mouse femur fracture model. A unilateral femur fracture was performed in C57BL/6 mice and intramedullary fixation performed. Fractured and un-fractured contralateral specimens were harvested from groups of mice between 2 and 12 weeks post-fracture. Parameters describing callus based on μCT were obtained, including polar moment of inertia (J), bending moment of inertia (I), total volume (TV), tissue mineral density (TMD), total bone volume fraction (BV/TV), and volumetric bone mineral density (vBMD). For comparison, plain radiographs were used to measure the callus diameter (D) and area (A); and biomechanical properties were evaluated using either three-point bending or torsion. The μCT parameters J, I, TV, and TMD converged toward their respective values of the un-fractured femurs over time, although significant differences existed between the two sides at every time point evaluated (p<0.05). Radiograph measurement D changed with repair progression in similar manner to TV. In contrast, BV/TV and BMD increased and decreased over time with statistical differences between callus and un-fractured bone occurring sporadically. Similarly, none of the biomechanical properties were found to distinguish consistently between the fractured and un-fractured femur. Micro-CT parameters assessing callus structure and size (J, I, and TV) were more sensitive to changes in callus over time post-fracture than those assessing callus substance (TMD, BV/TV, and BMD). Sample size estimates based on these results indicate that utilization of μCT requires fewer animals than biomechanics and thus is more practical for evaluating the healing femur in the mouse fracture model.


Outcomes of lead revision for myocardial perforation after cardiac implantable electronic device placement.
Cardiac perforation is an infrequent but potentially life-threatening complication associated with placement of a cardiac implantable electronic device (CIED). The objective of this study was to determine the outcomes of percutaneous lead revision in patients who had lead perforation of the myocardium after CIED placement. We reviewed records of 1,458 patients who underwent CIED lead extraction or repositioning. Of these, 31 (2.1%) had the procedure performed for lead perforation as a complication of CIED placement. Demographic, clinical, and follow-up characteristics of the patients were analyzed. Mean (SD) patient age was 65 (23) years. Cardiac perforation was detected within 24 hours after implantation in 9 patients, within 1 month in 17, and greater than 1 month in 5. Pericardiocentesis was performed with a pigtail drainage catheter in place before the lead revision in 17 patients (55%) who had pericardial effusion, with or without hemodynamic compromise. All culprit leads were successfully managed with percutaneous lead removal (n = 3 [10%]), new lead placement (n = 12 [38%]), or lead repositioning (n = 16 [52%]). Of the 17 patients with pericardiocentesis before the reoperation, none had tamponade develop; in contrast, 3 of the remaining 14 patients had tamponade develop and required urgent pericardiocentesis. All patients survived without requiring open chest surgery. Percutaneous removal or repositioning of the perforating lead is feasible and appears effective. Placement of a prophylactic pericardial drain catheter may reduce the incidence of urgent pericardiocentesis during or after a procedure.


Nano-Bio-Genesis: tracing the rise of nanotechnology and nanobiotechnology as 'big science'.
Nanotechnology research has lately been of intense interest because of its perceived potential for many diverse fields of science. Nanotechnology's tools have found application in diverse fields, from biology to device physics. By the 1990s, there was a concerted effort in the United States to develop a national initiative to promote such research. The success of this effort led to a significant influx of resources and interest in nanotechnology and nanobiotechnology and to the establishment of centralized research programs and facilities. Further government initiatives (at federal, state, and local levels) have firmly cemented these disciplines as 'big science,' with efforts increasingly concentrated at select laboratories and centers. In many respects, these trends mirror certain changes in academic science over the past twenty years, with a greater emphasis on applied science and research that can be more directly utilized for commercial applications.We also compare the National Nanotechnology Initiative and its successors to the Human Genome Project, another large-scale, government funded initiative. These precedents made acceptance of shifts in nanotechnology easier for researchers to accept, as they followed trends already established within most fields of science. Finally, these trends are examined in the design of technologies for detection and treatment of cancer, through the Alliance for Nanotechnology in Cancer initiative of the National Cancer Institute. Federal funding of these nanotechnology initiatives has allowed for expansion into diverse fields and the impetus for expanding the scope of research of several fields, especially biomedicine, though the ultimate utility and impact of all these efforts remains to be seen.


Increased oxidative stress as a mechanism for decreased BDNF levels in acute manic episodes.
There is a growing amount of data indicating that alterations in brain-derived neurotrophic factor and increased oxidative stress may play a role in the pathophysiology of bipolar disorder. In light of recent evidence demonstrating that brain-derived neurotrophic factor levels are decreased in situations of increased oxidative stress, we have examined the correlation between serum thiobarbituric acid reactive substances, a measure of lipid peroxidation, and serum brain-derived neurotrophic factor levels in bipolar disorder patients during acute mania and in healthy controls. Serum thiobarbituric acid reactive substances and brain-derived neurotrophic factor levels were negatively correlated in bipolar disorder patients (r = -0.56; p = 0.001), whereas no significant correlation was observed in the control group.. These results suggest that alterations in oxidative status may be mechanistically associated with abnormal low levels of brain-derived neurotrophic factor observed in individuals with bipolar disorder.


Nudging in nursing.
Nudging is a concept in behavioural science, political theory and economics that proposes indirect suggestions to try to achieve non-forced compliance and to influence the decision making and behaviour of groups and individuals. Researchers in medical ethics are currently discussing whether nudging is ethically permissible in healthcare. In this article, we examine current knowledge about how different decisions (rational and pre-rational decisions, major and minor decisions) are made and how this decision-making process pertains to patients. We view this knowledge in light of the nursing project and the ongoing debate regarding the ethical legitimacy of nudging in healthcare. We argue that it is insufficient to discuss nudging in nursing and healthcare in light of free will and patient autonomy alone. Sometimes, nurses must take charge and exhibit leadership in the nurse-patient relationship. From the perspective of nursing as leadership, nudging becomes a useful tool for directing and guiding patients towards the shared goals of health, recovery and independence and away from suffering. The use of nudging in nursing to influence patients' decisions and actions must be in alignment with the nursing project and in accordance with patients' own values and goals.


X-RIM: Extreme Recurrent Independent Mechanisms for Noise-resistant and Interpretable Stroke Risk Prediction.
Stroke is a leading cause of mortality and long-term disability worldwide. An accurate stroke risk prediction is crucial for its early detection and prevention. Using deep learning to exploit patients' time-series electronic health records (EHRs) has been shown as a promising and efficient solution for such a prediction. Although time-series data could be more informative than a single cross-section in time, real-world time-series EHRs usually have a significantly high missing rate due to irregular patient visits. This could undermine sequential data's benefits unless a proper deep-learning model design is adopted. Furthermore, deep models have long been challenged for their interpretability, which is especially crucial for medical applications. In this study, we propose an extreme design based on the concept of recurrent independent mechanisms (RIM), termed extreme RIM (X-RIM). With no need for imputation, X-RIM utilizes the information of each input feature's temporal records through independent recurrent modules. Experiments on real-world data from the National Taiwan University Hospital showed that, in terms of the area under the precision-recall curve (AUPRC), the area under the receiver-operating characteristics curve (AUROC), and Youden Index, X-RIM (AUPRC: 0.210; AUROC: 0.764; Youden: 0.373) outperformed the classic risk score CHA2DS2-VASc (AUPRC: 0.103; AUROC: 0.650; Youden: 0.223) and other benchmarks in stroke risk prediction. Additional experiments also indicate that individual feature contributions to a prediction could be evaluated intuitively under X-RIM's independent structure to enhance interpretability.


Hepatoprotective Potency of Chrysophanol 8-O-Glucoside from Rheum palmatum L. against Hepatic Fibrosis via Regulation of the STAT3 Signaling Pathway.
Rhubarb is a well-known herb worldwide and includes approximately 60 species of the Rheum genus. One of the representative plants is Rheum palmatum, which is prescribed as official rhubarb due to its pharmacological potential in the Korean and Chinese pharmacopoeia. In our bioactive screening, we found out that the EtOH extract of R. palmatum inhibited hepatic stellate cell (HSC) activation by transforming growth factor β1 (TGF-β1). Chemical investigation of the EtOH extract led to the isolation of chrysophanol 8-O-glucoside, which was determined by structural analysis using NMR spectroscopic techniques and electrospray ionization mass spectrometry (ESIMS). To elucidate the effects of chrysophanol 8-O-glucoside on HSC activation, activated LX-2 cells were treated for 48 h with chrysophanol 8-O-glucoside, and α-SMA and collagen, HSC activation markers, were measured by comparative quantitative real-time PCR (qPCR) and western blotting analysis. Chrysophanol 8-O-glucoside significantly inhibited the protein and mRNA expression of α-SMA and collagen compared with that in TGF-β1-treated LX-2 cells. Next, the expression of phosphorylated SMAD2 (p-SMAD2) and p-STAT3 was measured and the translocation of p-STAT3 to the nucleus was analyzed by western blotting analysis. The expression of p-SMAD2 and p-STAT3 showed that chrysophanol 8-O-glucoside strongly downregulated STAT3 phosphorylation by inhibiting the nuclear translocation of p-STAT3, which is an important mechanism in HSC activation. Moreover, chrysophanol 8-O-glucoside suppressed the expression of p-p38, not that of p-JNK or p-Erk, which can activate STAT3 phosphorylation and inhibit MMP2 expression, the downstream target of STAT3 signaling. These findings provided experimental evidence concerning the hepatoprotective effects of chrysophanol 8-O-glucoside against liver damage and revealed the molecular basis underlying its anti-fibrotic effects through the blocking of HSC activation.


[Distribution of specific signals of different modality in the associative parietal area of the cat cortex].
In cats under nembutal anesthesia eliciting specific early components of association responses, the drug parietal distribution upon forepaw and thalamic stimulation was studied: relay somatic-ventrobasal complex (VB) and association nuclei, transmitting specific visual impulses in pulvinar (Pul) and lateral-posterior (LP) areas. Signals of maximum intensity were observed in response to peripheral and central stimulation near somatic area and in response to Pul and LP stimulation in the medial part of parietal cortex. Besides, a general principle revealing more intensive signals of different modality in the areas near lateral sulcus than in other parietal areas was established. The difference in processing of specific polysensory signals in various parietal areas and consequently, different involvement of the latter into the systemic action of the brain was proved, this being related to the character of topical organization of these signals.


Novel adenovirus encoded virus-like particles displaying the placental malaria associated VAR2CSA antigen.
The malaria parasite Plasmodium falciparum presents antigens on the infected erythrocyte surface that bind human receptors expressed on the vascular endothelium. The VAR2CSA mediated binding to a distinct chondroitin sulphate A (CSA) is a crucial step in the pathophysiology of placental malaria and the CSA binding region of VAR2CSA has been identified as a promising vaccine target against placental malaria. Here we designed adenovirus encoded virus-like particles (VLP) by co-encoding Simian Immunodeficiency Virus (SIV) gag and VAR2CSA. The VAR2CSA antigen was fused to the transmembrane (TM) and cytoplasmic tail (CT) domains of either the envelope protein of mouse mammary tumour virus (MMTV) or the hemagglutinin (HA) of influenza A. For a non-VLP incorporation control, a third design was made where VAR2CSA was expressed without TM-CT domains. In the primary immunogenicity study in Balb/c mice, VAR2CSA fused to HA TM-CT was significantly superior in inducing ID1-ID2a specific antibodies after the first immunization. A sequential study was performed to include a comparison to the soluble VAR2CSA protein vaccine, which has entered a phase I clinical trial (NCT02647489). The results revealed the induction of higher antibody responses and increased inhibition of parasite binding to CSA using either VAR2CSA HA TM-CT or VAR2CSA MMTV TM-CT as priming vaccines for protein double-boost immunizations, compared to protein prime-double boost regimen. Analysis of pooled serum samples on peptide arrays revealed a unique targeting of several epitopes in mice that had been primed with VAR2CSA HA TM-CT. Consequently, modification of VLP anchors is an important point of optimization in virus-encoded retroviral VLP-based vaccines, and adenovirus VLPs boosted by recombinant proteins offer hope of increasing the levels of protective VAR2CSA specific antibodies.


Cancer Core Europe: A European cancer research alliance realizing a research infrastructure with critical mass and programmatic approach to cure cancer in the 21st century.
Translational cancer research covers the whole cancer research continuum from basic to preclinical to early clinical, late clinical and outcomes research. Basic-preclinical research is the "engine" for early clinical research bridging the early translational research gap. Cancer Core Europe has been created to construct a sustainable, high level, shared research infrastructure platform with research collaborations and taskforces (data sharing, clinical trials, genomics, immunotherapy, imaging, legal & ethical problems, and education & training) having representatives from all seven member centres, in a controlled expansion model. In parallel, a consortium of ten cancer prevention centres was established, Cancer Prevention Europe, to support the complete cancer prevention research continuum. Cancer Core Europe is launching at present the Basket of Baskets trial, which is the largest personalized cancer medicine trial effort in Europe. At present, Cancer Core Europe and Cancer Prevention Europe are in the process of integrating therapeutics and prevention strategies to address in partnership the increasing cancer problem. By offering innovative approaches for cancer research, links to the healthcare systems, development of quality-assured multidisciplinary cancer care, as well as the assessment of long-term outcomes, the infrastructure is expected to serve as a hub to connect with other centres in Europe as well as on other continents. In this manner Cancer Core Europe and Cancer Prevention Europe prepare to tackle the "Mission on Cancer", with infrastructure and proofs of concept for therapeutics and prevention, research for assessment of effectiveness, health economics and added value for patients and the healthcare systems.


The beneficial effects of purple yam (Dioscorea alata L.) resistant starch on hyperlipidemia in high-fat-fed hamsters.
In this study, we investigated the interventional effect of resistant starch (RS) obtained from purple yam (Dioscorea alata L.) on regulating lipid metabolism and gut microbiota in hyperlipidemic hamsters. Compared to low level RS (LR) treatment, high dosage of RS (HR) administration in hamsters was shown to be more efficient in controlling the body weight and adipose tissue mass, and increased high-density lipoprotein cholesterol (HDL-C) concentration and decreased triglyceride (TG), total cholesterol (TC), and low-density lipoprotein cholesterol (LDL-C) concentrations were observed. Fat accumulation in the liver was reduced by RS, and the injury caused due to a high-fat diet on the histomorphology of the cecum and colon was repaired. Furthermore, HR altered the gut community composition by increasing the relative abundances of Bifidobacteria, Lactobacillus, Coprococcus, and Allobaculum, while decreasing Parabacteroides and Dorea. Probiotics, such as Bifidobacteria and Lactobacillus, were dramatically increased and highly correlated with blood lipid levels. These results suggested that the usage of RS obtained from purple yam could ameliorate lipid metabolism in association with gut microbiota modulation, which could provide references for further medication.


Role of E6 in Maintaining the Basal Cell Reservoir during Productive Papillomavirus Infection.
Papillomaviruses exclusively infect stratified epithelial tissues and cause chronic infections. To achieve this, infected cells must remain in the epithelial basal layer alongside their uninfected neighbors for years or even decades. To examine how papillomaviruses achieve this, we used the in vivo MmuPV1 (Mus musculus papillomavirus 1) model of lesion formation and persistence. During early lesion formation, an increased cell density in the basal layer, as well as a delay in the infected cells' commitment to differentiation, was apparent in cells expressing MmuPV1 E6/E7 RNA. Using cell culture models, keratinocytes exogenously expressing MmuPV1 E6, but not E7, recapitulated this delay in differentiation postconfluence and also grew to a significantly higher density. Cell competition assays further showed that MmuPV1 E6 expression led to a preferential persistence of the cell in the first layer, with control cells accumulating almost exclusively in the second layer. Interestingly, the disruption of MmuPV1 E6 binding to MAML1 protein abrogated these phenotypes. This suggests that the interaction between MAML1 and E6 is necessary for the lower (basal)-layer persistence of MmuPV1 E6-expressing cells. Our results indicate a role for E6 in lesion establishment by facilitating the persistence of infected cells in the epithelial basal layer, a mechanism that is most likely shared by other papillomavirus types. Interruption of this interaction is predicted to impede persistent papillomavirus infection and consequently provides a novel treatment target. IMPORTANCE Persistent infection with high-risk HPV types can lead to development of HPV-associated cancers, and persistent low-risk HPV infection causes problematic diseases, such as recurrent respiratory papillomatosis. The management and treatment of these conditions pose a considerable economic burden. Maintaining a reservoir of infected cells in the basal layer of the epithelium is critical for the persistence of infection in the host, and our studies using the mouse papillomavirus model suggest that E6 gene expression leads to the preferential persistence of epithelial cells in the lower layers during stratification. The E6 interaction with MAML1, a component of the Notch pathway, is required for this phenotype and is linked to E6 effects on cell density and differentiation. These observations are likely to reflect a common E6 role that is preserved among papillomaviruses and provide us with a novel therapeutic target for the treatment of recalcitrant lesions.


Effect of alkyl branches on the thermal stability of quaternary ammonium cations in organic electrolytes for electrochemical double layer capacitors.
Quaternary ammoniums are cations having widespread use in organic electrolytes for high performance electrochemical double layer capacitors (EDLCs) due to their various advantages such as high electrochemical stability and inexpensive production cost. However, the decomposition of quaternary ammoniums via Hofmann elimination hinders their applications for EDLCs operating at elevated temperatures. This study systematically investigates the reactivity of four different quaternary ammoniums (tetraethyl-, triethylmethyl-, diethyldimethyl-, and trimethylethyl-ammonium) in EDLC by utilizing density functional theory calculations and Brownian dynamics simulations complemented with molecular dynamics simulations. It is found that ammonium stability reduces upon increasing the number of ethyl branches that have a stronger positive charge than the methyl groups. However, the contribution of the entropy change to the reaction free energy makes trimethylethylammonium less stable than diethyldimethylammonium at room temperature although the former has less ethyl branches than the latter. Trimethylethylammonium becomes the most stable at a high temperature of 488 K above which the activation free energy becomes effectively negligible and thus the number of reactive sites determines the overall stability. The fundamental understanding of the ammonium decompositions through Hofmann elimination demonstrated in this study is expected to contribute to developing new long-life organic electrolyte systems for high-temperature applications.


Extracellular Vesicles in the Intrauterine Environment: Challenges and Potential Functions.
Extracellular vesicles (EVs), including exosomes (30-150 nm) and microvesicles (100-1500 nm), play important roles in mediating cell-cell communication. Such particles package distinct cargo elements, including lipids, proteins, mRNAs, microRNAs, and DNA, that vary depending on the cell of origin and its phenotype. This cargo can be horizontally transferred to target cells where its components can reprogram the recipient cell to modify its function. EVs have been identified within the uterine cavity of women, sheep, and mice, where they contribute to the microenvironment of sperm transport, and of blastocyst and endometrial preparation for implantation. It is likely that exosomes and microvesicles carry different cargo and coordinate different roles in this intrauterine environment. Understanding and defining these subtypes of EVs is important for future functional studies and clinical translation. Here we critically review the various purification and validation procedures for extracellular vesicle analysis and discuss what is known of endometrial-derived exosome cargo and of their hormonal regulation. The current knowledge of the functions of uterine exosomes, with respect to sperm transport and function, and of their actions on trophectodermal cells to promote implantation are summarized and evaluated in their physiological context. Given the potential importance of this form of cell-cell interactions within the reproductive tract, the critical issues discussed will guide new insights in this rapidly expanding field.


Cell-to-cell and long-distance trafficking of the green fluorescent protein in the phloem and symplastic unloading of the protein into sink tissues.
Macromolecular trafficking within the sieve element-companion cell complex, phloem unloading, and post-phloem transport were studied using the jellyfish green fluorescent protein (GFP). The GFP gene was expressed in Arabidopsis and tobacco under the control of the AtSUC2 promoter. In wild-type Arabidopsis plants, this promoter regulates expression of the companion cell-specific AtSUC2 sucrose-H+ symporter gene. Analyses of the AtSUC2 promoter-GFP plants demonstrated that the 27-kD GFP protein can traffic through plasmodesmata from companion cells into sieve elements and migrate within the phloem. With the stream of assimilates, the GFP is partitioned between different sinks, such as petals, root tips, anthers, funiculi, or young rosette leaves. Eventually, the GFP can be unloaded symplastically from the phloem into sink tissues, such as the seed coat, the anther connective tissue, cells of the root tip, and sink leaf mesophyll cells. In all of these tissues, the GFP can traffic cell to cell by symplastic post-phloem transport. The presented data show that plasmodesmata of the sieve element-companion cell complex, as well as plasmodesmata into and within the analyzed sinks, allow trafficking of the 27-kD nonphloem GFP protein. The data also show that the size exclusion limit of plasmodesmata can change during organ development. The results are also discussed in terms of the phloem mobility of assimilates and of small, low molecular weight companion cell proteins.


Video Modeling Use in Work Occupations for People With Autism: A Systematic Review.
Occupational therapy practitioners should use evidence-based practices, such as video modeling, to address work occupations supporting people with autism spectrum disorder, including those with co-occurring intellectual and developmental disabilities. To examine the evidence and relevance of video modeling supporting engagement in work occupations for people with autism and to translate these findings to occupational therapy practice. Cochrane Collection Plus, CINAHL, PubMed, ERIC, ProQuest, and peer-reviewed occupational therapy literature from 2008 to 2018. Study Selection and Data Collection: This review followed Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Study selection and data collection focused on occupational therapy scope of practice, autism spectrum disorder, co-occurring intellectual and developmental disabilities, video modeling, and work occupations for people age 16 yr and older. A total of 464 articles were screened. Six articles met inclusion criteria. Results indicated moderate evidence for video modeling to support work occupations for people with autism, specifically employment seeking and acquisition and specific job-performance skills. Samples were limited to people younger than age 28 yr and represented varied intellectual abilities, indicating potential for benefits across the spectrum of cognitive functioning. This systematic review highlights the promising potential of video modeling to address work occupations for people with autism. However, more rigorous effectiveness research is needed, including studies by occupational therapy practitioners. What This Article Adds: Occupational therapy expertise paired with video modeling, as a strengths-based, client-centered, customizable, socially acceptable intervention, can provide meaningful support for work occupations.


The 'sleeve' anastomosis method for hemodialysis shunts: an eleven-year follow-up study.
The problem of long form fistula for hemodialysis is well known among vascular surgeons because of frequent thromboses in anastomotic place. One of the pro-thrombotic factors is suture in the vessel's lumen. Since the 'sleeve' method prevents this, the patency rate should improve. One hundred and eighty-two (182) patients were operated using the "sleeve" method. The operation was done under local anaesthesia and the first step was the dissection of the cephalic vein and the radial artery. Using Prolene 7-0 the artery and the vein were connected as follows: the first suture was placed intramuraly about 5 mm from the artery edge to the vein edge. The second suture (placed in the same way) was on the opposite side. The end of the radial artery was placed into the lumen of the cephalic vein and the sutures were tied. Two additional sutures were placed between them. Finally, four sutures were added to keep the artery in the vein. In our hands the patency rate of 'sleeve' arterio-venous fistulas was high: 95% after one month, 86% after one year, 64% after 5 years and 57% after 10 and 11 years. Every 'sleeve' fistula provided adequate blood flow, which increased during the follow-up period. The authors consider the "sleeve" fistula method as the primary choice because of its simplicity and excellent long-term patency.


The influence of valence on the functional activities of monoclonal anti-L3T4 antibodies. Discrimination of signaling from other effects.
Anti-L3T4 antibodies have different functional effects on different ligands that activate a cloned, L3T4+ helper T cell line. It is reported here that some of these effects involve positive or negative signaling induced by cross-linking L3T4 molecules, because such effects are not observed using the Fab fragment of anti-L3T4. However, the Fab fragment does inhibit responses to antigen:self class II major histocompatibility complex (MHC) and to anti-T cell receptor monoclonal antibodies directed at a particular V region epitope. The finding that the Fab fragment of anti-L3T4, which does not block binding of anti-T cell receptor V region antibodies and does not negative signal can still block activation by such antibodies suggests an intimate association of L3T4 with the T3: alpha: beta T cell receptor complex. This association may normally be induced by interaction of both structures with antigen:self class II MHC complexes. The data also support the hypothesis that cross-linking the L3T4 molecule in the absence of engagement of the T3: alpha: beta complex generates negative or inhibitory signals. Thus, L3T4 plays a central role in the process of class II MHC-restricted T cell antigen recognition and activation.


Complexes of neutralizing and non-neutralizing affinity matured Fabs with a mimetic of the internal trimeric coiled-coil of HIV-1 gp41.
A series of mini-antibodies (monovalent and bivalent Fabs) targeting the conserved internal trimeric coiled-coil of the N-heptad repeat (N-HR) of HIV-1 gp41 has been previously constructed and reported. Crystal structures of two closely related monovalent Fabs, one (Fab 8066) broadly neutralizing across a wide panel of HIV-1 subtype B and C viruses, and the other (Fab 8062) non-neutralizing, representing the extremes of this series, were previously solved as complexes with 5-Helix, a gp41 pre-hairpin intermediate mimetic. Binding of these Fabs to covalently stabilized chimeric trimers of N-peptides of HIV-1 gp41 (named (CCIZN36)3 or 3-H) has now been investigated using X-ray crystallography, cryo-electron microscopy, and a variety of biophysical methods. Crystal structures of the complexes between 3-H and Fab 8066 and Fab 8062 were determined at 2.8 and 3.0 Å resolution, respectively. Although the structures of the complexes with the neutralizing Fab 8066 and its non-neutralizing counterpart Fab 8062 were generally similar, small differences between them could be correlated with the biological properties of these antibodies. The conformations of the corresponding CDRs of each antibody in the complexes with 3-H and 5-Helix are very similar. The adaptation to a different target upon complex formation is predominantly achieved by changes in the structure of the trimer of N-HR helices, as well as by adjustment of the orientation of the Fab molecule relative to the N-HR in the complex, via rigid-body movement. The structural data presented here indicate that binding of three Fabs 8062 with high affinity requires more significant changes in the structure of the N-HR trimer compared to binding of Fab 8066. A comparative analysis of the structures of Fabs complexed to different gp41 intermediate mimetics allows further evaluation of biological relevance for generation of neutralizing antibodies, as well as provides novel structural insights into immunogen design.


Machine Learning Methods for Automatic Silent Speech Recognition Using a Wearable Graphene Strain Gauge Sensor.
Silent speech recognition is the ability to recognise intended speech without audio information. Useful applications can be found in situations where sound waves are not produced or cannot be heard. Examples include speakers with physical voice impairments or environments in which audio transference is not reliable or secure. Developing a device which can detect non-auditory signals and map them to intended phonation could be used to develop a device to assist in such situations. In this work, we propose a graphene-based strain gauge sensor which can be worn on the throat and detect small muscle movements and vibrations. Machine learning algorithms then decode the non-audio signals and create a prediction on intended speech. The proposed strain gauge sensor is highly wearable, utilising graphene's unique and beneficial properties including strength, flexibility and high conductivity. A highly flexible and wearable sensor able to pick up small throat movements is fabricated by screen printing graphene onto lycra fabric. A framework for interpreting this information is proposed which explores the use of several machine learning techniques to predict intended words from the signals. A dataset of 15 unique words and four movements, each with 20 repetitions, was developed and used for the training of the machine learning algorithms. The results demonstrate the ability for such sensors to be able to predict spoken words. We produced a word accuracy rate of 55% on the word dataset and 85% on the movements dataset. This work demonstrates a proof-of-concept for the viability of combining a highly wearable graphene strain gauge and machine leaning methods to automate silent speech recognition.


Fresh osteochondral total ankle allograft transplantation for the treatment of ankle arthritis.
Fresh osteochondral total ankle allograft transplantation has been reported in the literature with survival rates between 50% and 92% at 1- to 12-years followup. The goal of this study was to present the results of total ankle allografts from another institution. Twenty-nine patients underwent osteochondral total ankle transplant at our institution between July 2003 and July 2005. The mean patient age was 41 years old and the mean followup duration was 2 years. At followup, 14 of the 29 transplants had been revised to a repeat ankle transplant, prosthetic total ankle arthroplasty, or bone block arthrodesis. In addition, 6 of the remaining 15 transplants were deemed to be radiographic failures due to allograft fracture, allograft collapse, or progressive loss of joint space. The remaining 9 allografts (31%) were considered successes. In comparing the success versus the failure group, patients who were older, who had a lower body-mass index, and who had minimal preoperative angular deformity did significantly better. This is the largest series of osteochondral total ankle allograft transplants reported in the literature to date. There is an extremely high rate of failure associated with this procedure, and we currently consider it only rarely in patients who are too young for ankle replacement, have excellent range of motion, low body mass index, normal radiographic alignment, and who refuse arthrodesis.


Effects of chain length of saturated fatty acids on Aβ generation in SH-SY5Y cells.
Many studies have shown that saturated fat diet increases the risk of AD. Recently saturated very long chain fatty acids (VLCFAs) have been found be accumulated in AD patients. The variety of saturated fatty acids are found in the diets and human bodies. However, it is not clear which one or more fatty acids are involved in AD pathogenesis. This study investigated the effects of three saturated fatty acids with different carbon chain length (C16:0, C20:0, and C26:0) on amyloid precursor protein (APP) processing and amyloid-β peptide (Aβ) generation. Here, SH-SY5Y cells were treated with vehicle, C16:0, C20:0, and C26:0 (10 μmol/L, 24 h). Compared to the vehicle, C16:0 did not cause any significantly change in APP processing and Aβ generation. C20:0 and C26:0 increased Aβ levels and the expressions of APP, β- and γ-secretase and decreased the expression of α-secretase, and C26:0 had the strongest effects among three fatty acids. Moreover, C20:0 and C26:0 significantly increased reactive oxygen species (ROS), and C16:0 had no such effect. These data indicate that saturated fatty acids with different carbon chain length (C16:0, C20:0 and C26:0) have different effects on the process of Aβ generation, and fatty acids with longer chain (C20:0 and C26:0) have more potential to promote Aβ production and an underlying mechanism of fatty acids action may be related to the elevated oxidative stress. This work supports saturated very long chain fatty acids may play a potential role in the pathogenesis of AD.


Human immunodeficiency virus-mononuclear phagocyte interactions: emerging avenues of biomarker discovery, modes of viral persistence and disease pathogenesis.
Mononuclear phagocytes (MP; bone marrow monocyte-derived macrophages, histiocytes, alveolar macrophages, Kupffer cells, perivascular macrophages, and microglia) function as sentry and surveillance cells by acting as debris scavengers, killers of microbial pathogens, and regulators of immune responses. Interestingly, these same cells are reservoirs and vehicles of dissemination for the human immunodeficiency virus (HIV). How virus alters the MP immunoregulatory activities so it can complete its own life cycle and affect disease is only recently being unravelled. Physiologic, anatomic and functional changes also underlie virus-MP interactions and include multinucleated giant cell formation, changes in ion channel expression and cell volume, and robust secretory responses with the production of numerous secretory factors affecting tissue injury. The balance between such MP activities and ability to both mobilize an adaptive immune response to thwart viral growth underlies the progression of viral infection and clinical disease. This review serves to discuss the functions of MP in HIV disease by bringing together what is known with what remains unknown. The advent of functional genomics and proteomics has opened the ways to address the intricacies of viral-host interactions and has provided new avenues for therapeutic interventions and disease monitoring that takes advantage of specific intracellular relationships between the virus and its host cell.


p53 Mutation as Plausible Predictor for Endocrine Resistance Therapy in Luminal Breast Cancer.
Endocrine therapy resistance in Luminal Breast Cancer is a significant issue to be tackled, but currently, no specific biomarker could be used to anticipate this event. p53 mutation is widely known as one of Breast Cancer's most prominent genetic alterations. Its mutation could generate various effects in Estrogen Receptor and Progesterone Receptor molecular works, tangled in events leading to the aggravation of endocrine therapy resistance. Hence the possibility of p53 mutation utilization as an endocrine therapy resistance predictive biomarker is plausible. The purpose of this review is to explore the latest knowledge of p53 role in Estrogen Receptor and Progesterone Receptor molecular actions, thus aggravating the Endocrine Therapy resistance in Luminal Breast Cancer, from which we could define possibilities and limitations to utilize p53 as the predictive biomarker of endocrine therapy resistance in Luminal Breast Cancer.


Intestinal metaplasia of human stomach displays distinct patterns of mucin (MUC1, MUC2, MUC5AC, and MUC6) expression.
Intestinal metaplasia is a well-established premalignant condition of the stomach that is characterized by mucin carbohydrate modifications defined by histochemical methods. The purpose of the present study was to see whether the expression of mucin core proteins was modified in the different types of intestinal metaplasia and to evaluate the putative usefulness of mucins as "molecular markers" in this setting. We used a panel of monoclonal antibodies with well-defined specificities to MUC1, MUC2, MUC5AC, and MUC6 to characterize the expression pattern of mucins. In contrast to normal gastric mucosa, the complete form or type I intestinal metaplasia (n = 20) displayed little or no expression of MUC1, MUC5AC, or MUC6 in the metaplastic cells and strong expression of the intestinal mucin MUC2 in the goblet cells of all cases. The incomplete forms of intestinal metaplasia, type II (n = 25) and type III (n = 16), expressed MUC1 and MUC5AC in every case, both in goblet and in columnar cells. MUC6 was also expressed in 16 cases of type II intestinal metaplasia and in 11 cases of type III intestinal metaplasia. The intestinal mucin MUC2 was expressed in every case of incomplete intestinal metaplasia, mostly in goblet cells. The mucin expression profile in the different types of intestinal metaplasia allows the identification of two patterns: one defined by decreased levels of expression of "gastric" mucins (MUC1, MUC5AC, and MUC6) and expression of MUC2 intestinal mucin, which corresponds to type I intestinal metaplasia, and the other defined by coexpression of "gastric mucins" (MUC1, MUC5AC, and MUC6) together with the MUC2 mucin, encompassing types II and III intestinal metaplasia. Our results challenge the classical sequential pathway of intestinal metaplasia (from type I to type III via a type II intermediate step).


Exposure to volatile organic compounds induces cardiovascular toxicity that may involve DNA methylation.
Volatile organic compounds (VOCs) are common air pollutants and water contaminants. We previously found maternal exposure to VOCs was associated with offspring congenital heart disease (CHD). However, little information is available about the effects of VOCs on cardiovascular development at embryonic stage and the underlying mechanism remains unclear. In this study, we aimed to investigate the effects of a mixture of six VOCs on cardiovascular development in zebrafish embryos. Embryos were exposed to different concentrations of VOCs mixture (32mg/L, 64mg/L and 128mg/L) for 96hours, cardiovascular abnormalities including elongated heart shape, increased distance between sinus venosus and bulbus arteriosus, slowed circulation and altered heart rate were observed in a dose- and time-dependent manner. Meanwhile, VOCs exposure increased global DNA methylation levels in embryos. Analysis identified hundreds of differentially methylated sites and the enrichment of differentially methylated sites on cardiovascular development. Two differentially methylated-associated genes involved in MAPK pathway, hgfa and ntrk1, were identified to be the potential genes mediating the effects of VOCs. By enzyme-linked immunosorbent assay, altered human serum hgf and ntrk1 levels were detected in abnormal pregnancies exposed to higher VOCs levels with fetal CHD. For the first time, our study revealed exposure to VOCs induced severe cardiovascular abnormalities in zebrafish embryos. The toxicity might result from alterations in DNA methylation and corresponding expression levels of genes involved in MAPK pathway. Our study provides important information for the risk of VOCs exposure on embryonic cardiovascular development.


Wavelength-Shift-Based Colorimetric Sensing for Peroxide Number of Edible Oil Using CsPbBr3 Perovskite Nanocrystals.
The peroxide number of edible oil relates to its quality. The classical determination methods for the peroxide number are still unsatisfactory due to their complexity and poor reproducibility in the analytical process and their incapability of field rapid detection. In this study, a novel wavelength-shift-based visual method has been developed for the peroxide number determination of edible oil using halide perovskite nanocrystals (CsPbBr3 NCs). In the analysis, the edible oil sample underwent redox reactions with a part of oleylammonium iodide (OLAM-I) in advance. Then, the halogen exchange occurred between the added CsPbBr3 NCs and the iodide ions from the residual OLAM-I. The resulting wavelength shift of the fluorescence emission reflects the peroxide number in the edible oil sample. Under the ultraviolet light excitation at 365 nm, the apparent color of the photoluminescence could directly be compared with a color chart to determine and qualify the peroxide number. Using the approach, the visual detection of the peroxide number of edible oil samples on site could be realized. The detection process takes only ∼15 min and is convenient and accurate.


Anaphylaxis risk factors for hospitalization and intensive care: A comparison between adults and children in an upstate New York emergency department.
Background: Anaphylaxis is an acute, systemic allergic reaction that can be life threatening, and with an increasing incidence and costs associated with hospitalization and intensive care. Objective: To assess the risk factors for hospitalization by comparing pediatric and adult patients. Methods: We performed a retrospective chart review for patients with anaphylactic reactions who presented to the Albany Medical Center emergency department between 2005 and 2012. Results: We identified 267 anaphylactic reactions in 258 patients (143 adults). Of those, 128 (48%) were not coded as anaphylaxis despite fulfilling diagnostic criteria. Foods were the most common trigger both in adults and children. Factors associated with increased odds of hospitalization (intensive care unit [ICU] and hospital floor combined) included a severity score of 3 in both children (odds ratio [OR] 41.86 [95% confidence interval {CI}, 2.9-602.48], p = 0.006) and adults (OR 32.52 [95% CI, 6.28-168.35], p < 0.001), and those who received multiple doses of epinephrine in children (OR 15.36 [95% CI, 1.9-121.4], p = 0.009) and adults (OR 11.49 [95% CI, 3.08-44.13], p < 0.001). Patient characteristics associated with ICU admission in children and adults combined included Medicare and/or Medicaid insurance (OR 4.96 [95% CI, 1.14-21.67], p = 0.023), cutaneous symptoms (OR 0.19 [95% CI, 0.04-0.79], p = 0.23), and cardiovascular symptoms (OR 5.8 [95% CI, 1.16-28.87], p = 0.032). Conclusion: Anaphylaxis remains underrecognized and improperly treated in the emergency department. Severity of symptoms and receiving multiple doses of epinephrine were associated with hospitalization in both children and adults. Medicare and/or Medicaid insurance, and cardiovascular or cutaneous symptoms were characteristics associated with ICU admission in our cohort.


Concomitant Fundoplication With Gastrostomy: A Two-State Comparison Showing Continued Use of Reflux Medications.
We sought to determine whether practice differences for fundoplication exist between 2 geographically distinct states, and to determine the reflux medication use pattern associated with concomitant fundoplication. A retrospective observational cohort study of children in Colorado (CO) and North Carolina (NC) insured by Medicaid from 2006 to 2008. Children who received a surgical gastrostomy during the study period were included, and our primary outcome measure was the performance of a concomitant gastric fundoplication. Thirty-day prescription fills for reflux medications were examined before and after gastrostomy procedure. We examined 969 surgical gastrostomy admission in both states over the 3-year study period (CO, n = 341 and NC, n = 628). Patients in each state had similar age (median age, 6 months, P = 0.97). Use of pH probe (CO: 15%, NC: 11%) and diagnosis of reflux (CO: 84%, NC: 72%) differed in each state. Concomitant fundoplication was performed in 60% of patients in CO and 43% in NC (P < 0.01). Age less than 6 months was associated with an increased adjusted odds of fundoplication in CO (OR 9.77, CI, 3.91, 24.43), but less so in NC (OR 2.73, CI, 1.48, 5.04). Among patients undergoing gastrostomy, the proportion of patients on reflux medication 4 to 6 months post-discharge did not differ between those receiving fundoplication and those that did not in either state. Rates of concomitant fundoplication varied in the 2 states despite patients having similar demographic and clinical characteristics. Antireflux surgery was not associated with a reduction in reflux medications in either state.


Long-term effect of telmisartan on Alzheimer's amyloid genesis in SHR-SR after tMCAO.
Telmisartan is expected to reduce not only the level of blood pressure but also neuroinflammation and neurotoxicity via pleiotrophic effects as a metabo-sartan. We examined the effects of telmisartan on Alzheimer's disease (AD) pathology in spontaneously hypertensive rat stroke resistant (SHR-SR) after transient middle cerebral artery occlusion (tMCAO) by giving either telmisartan at 0 (vehicle), 0.3 mg/kg/day (low dose, with no reduction of blood pressure), or 3 mg/kg/day (high dose, with a significant reduction of blood pressure) p.o. from 3 months (M) of age, and performed immunohistological analysis at 6, 12, and 18 M of age. The numbers of amyloid β (Aβ)-positive neurons in the cerebral cortex and hippocampus and senile plaque (SP) in the ipsilateral cerebral cortex progressively increased with age until 18 M in the SHR-SR after tMCAO. On the other hand, low-dose telmisartan significantly reduced the number of Aβ-positive neuron as well as SP at 6, 12, and 18 M. High-dose telmisartan showed further reductions of the above AD pathology. The present study suggests that telmisartan reduced both intracellular Aβ and extracellular SP accumulations after tMCAO in SHR-SR, with a further improvement by combined BP lowering. Such a strong effect of telmisartan could provide a preventative approach for AD in post-stroke patients with hypertension.


"The multimodal approach for ventilator-associated pneumonia prevention"-requirements for nationwide implementation.
The multimodal approach for ventilator-associated pneumonia (VAP) prevention has been shown to be a successful strategy in reducing VAP rates in many intensive care units (ICU) in some countries. The simultaneous application of several measures or "bundles" to reduce VAP rates has achieved a higher impact than the progressive implementation of the individual interventions. The ultimate objective of recommendation bundles is their integration in the culture of routine healthcare of the staff in charge of ventilated patients for accomplished rates to persist over time. The noteworthy elements of this new strategy include the selection of the individual recommendations of the bundle, education of care workers (HCW) in the culture of patient safety, audit of compliance with the recommendations, commitment of the hospital management to support implementation, nomination and empowerment of local leaders of the projects in ICUs, both physicians and nurses, and the continuous collection of VAP episodes. The implementation of this new strategy is not an easy task, as both its inherent strength and important barriers to its application have become evident, which need to be overcome for maximal reduction of VAP rates.


[Lymphomatous optic neuropathy (author's transl)].
Seven cases of involvement of the optic nerve in malignant lymphoma are reported. These may be classified into two types according to the type of optic nerve lesion, i.e., orbital and intracranial lymphomatous optic neuropathy. Characteristic ocular symptoms in cases of orbital lymphomatous optic neuropathy are as follows: 1) rapidly progressive exophthalmos, 2) symptoms similar to orbital phlegmone, 3) rapidly progressing and marked impairment of vision with central scotoma, and 4) recovery of visual function after treatment. Ocular symptoms in cases of intracranial lymphomatous optic neuropathy are as follows: 1) as an initial symptom, cranial nerve palsy, 2) subsequently, rapidly progressing impairment of vision and 3) after unilateral impairment of vision, bilateral impairment within a few weeks. -- Furthermore, the causes of impaired vision are discussed with reference to histopathological findings in the two autopsy cases.


What is OSHA and how does it impact i.v. nurses?
A brief history of why the Occupational Safety and Health Administration (OSHA) was created and the purpose of OSHA is provided. Both employee and employer rights and responsibilities are discussed briefly. The process for enacting standards intended to protect employees is described followed by a detailed discussion of OSHA's standard, which relates directly to the practice of intravenous nurses.


Scrounging by foragers can resolve the paradox of enrichment.
Theoretical models of predator-prey systems predict that sufficient enrichment of prey can generate large amplitude limit cycles, paradoxically causing a high risk of extinction (the paradox of enrichment). Although real ecological communities contain many gregarious species, whose foraging behaviour should be influenced by socially transmitted information, few theoretical studies have examined the possibility that social foraging might resolve this paradox. I considered a predator population in which individuals play the producer-scrounger foraging game in one-prey-one-predator and two-prey-one-predator systems. I analysed the stability of a coexisting equilibrium point in the one-prey system and that of non-equilibrium dynamics in the two-prey system. The results revealed that social foraging could stabilize both systems, and thereby resolve the paradox of enrichment when scrounging behaviour (i.e. kleptoparasitism) is prevalent in predators. This suggests a previously neglected mechanism underlying a powerful effect of group-living animals on the sustainability of ecological communities.


Selective neuronal cell attachment to a covalently patterned monoamine on fluorinated ethylene propylene films.
The patterned covalent surface addition of a monoamine to fluorinated ethylene propylene films (FEP) controls both cellular attachment and differentiation in defined media conditions. A radio frequency glow discharge (RFGD) process was used to replace FEP surface fluorine atoms with hydroxyl groups. The primary amine was then covalently attached by polymerizing aminopropyl-triethoxysilane (APTES) via the hydroxyl functionalities. The selective attachment of cells to the APTES regions was determined to be dependent upon the initial adsorption of albumin to the patterned FEP membrane. Albumin was determined to enhance cellular attachment to the APTES regions and prevent attachment to the unmodified FEP areas for both an NB2a neuroblastoma cell line and primary rat endothelial cells. If albumin were not preadsorbed onto the membrane, selective attachment to the modified regions would not occur. Radiolabeling albumin with 125I demonstrated the preference of albumin for adsorption onto the monoamine surface where the cells preferentially attached. Both hydrophobic and ionic forces contributed to the adsorption process. Although selective cellular attachment to the patterned APTES regions could be achieved by albumin preadsorption to the surface, the neuroblastoma cells did not significantly differentiate unless additional serum components were supplemented to the media.


Analysis of missense variation in human BRCA1 in the context of interspecific sequence variation.
Interpretation of results from mutation screening of tumour suppressor genes known to harbour high risk susceptibility mutations, such as APC, BRCA1, BRCA2, MLH1, MSH2, TP53, and PTEN, is becoming an increasingly important part of clinical practice. Interpretation of truncating mutations, gene rearrangements, and obvious splice junction mutations, is generally straightforward. However, classification of missense variants often presents a difficult problem. From a series of 20,000 full sequence tests of BRCA1 carried out at Myriad Genetic Laboratories, a total of 314 different missense changes and eight in-frame deletions were observed. Before this study, only 21 of these missense changes were classified as deleterious or suspected deleterious and 14 as neutral or of little clinical significance. We have used a combination of a multiple sequence alignment of orthologous BRCA1 sequences and a measure of the chemical difference between the amino acids present at individual residues in the sequence alignment to classify missense variants and in-frame deletions detected during mutation screening of BRCA1. In the present analysis we were able to classify an additional 50 missense variants and two in-frame deletions as probably deleterious and 92 missense variants as probably neutral. Thus we have tentatively classified about 50% of the unclassified missense variants observed during clinical testing of BRCA1. An internal test of the analysis is consistent with our classification of the variants designated probably deleterious; however, we must stress that this classification is tentative and does not have sufficient independent confirmation to serve as a clinically applicable stand alone method.


The complete mitochondrial genome of the black surfperch, Embiotoca jacksoni: Selection and substitution rates among surfperches (Embiotocidae).
The complete 16,515bp nucleotide sequence of the mitochondrial genome was determined for the black surfperch, Embiotoca jacksoni (Perciformes: Embiotocidae). The black surfperch mitochondrial genome contains 13 protein-coding genes, two ribosomal RNA genes, 22 transfer RNA genes, and the non-coding control region (D-loop), the gene order of which is identical to that observed in most vertebrates. The protein-coding gene sequences of E. jacksoni mitochondrial DNA were compared with two other embiotocid surfperches with available complete mitochondrial genomes, Cymatogaster aggregata and Ditrema temminckii. Across all mitochondrial protein-coding genes in surfperches the weighted average substitution rate was 2.079% per My and average dN/dS ratios for each protein-coding gene ranged from 0.016 in CytB to 0.608 in ND3. Substitution rates and dN/dS ratios were relatively high for ATP8 compared to other protein-coding genes. Although most protein-coding genes showed signals of purifying selection, we found evidence for positive selection in ND3 in E. jacksoni.


Theoretical investigation of the mechanism, kinetics and subsequent degradation products of the NO3 radical initiated oxidation of 4-hydroxy-3-hexanone.
The oxidation mechanism of 4-hydroxy-3-hexanone (CH3CH2C(O)CH(OH)CH2CH3) initiated by NO3 radicals in the nighttime is investigated systematically by applying quantum theoretical methods. According to thermodynamic research, the process of H-abstraction on the -CH- group adjacent to the hydroxyl group is the most dominant pathway with the lowest activation energy. The analysis of Mulliken charge charts and molecular electrostatic potential maps illustrate that C-H bonds are the active sites of the reaction, and the calculated C-H bond dissociation energy of the CH3CH2C(O)CH(OH)CH2CH3 molecule further confirms that α-CH is the most easily activated. Individual rate constants for five H-abstraction pathways are calculated by canonical variational theory coupled with small curvature tunneling method over the temperature range of 260-330 K, and the branching ratios are also evaluated. A total rate constant of 1.18 × 10-15 cm3 per molecule per s is obtained at 298 K, which is in good agreement with the reported experimental value. A negative temperature dependence is observed in the titular reaction. The subsequent degradation processes of the advantageous product alkyl radical (CH3CH2C˙(OH)COCH2CH3) are carried out in a NO-rich environment, and propionic acid, NO2 and ozone are obtained as the major final products. The nighttime atmospheric lifetime of 4-hydroxy-3-hexanone is estimated to be around 19 days, indicating that it has impact at night. The titular reaction rate constants are fitted to a three-parameter Arrhenius formula.


Isotretinoin and cutaneous helper T-cell lymphoma (mycosis fungoides).
Retinoids, including isotretinoin, have demonstrated antiproliferative and antineoplastic activity in laboratory and clinical trials. In a phase II trial, 25 patients with extensive mycosis fungoides were evaluated for response to isotretinoin. There was a 44% (11 patients) objective clinical response rate with three clinical complete responses without concomitant evidence of pathologic clearing of the disease. An additional 24% (six patients) showed a minor degree of clinical improvement. The median time to response was two months (range, 0.5 to eight months) and the median response duration was eight months or longer (range, one to 25 months). Chronic toxic reactions consisted primarily of drying of the skin and mucous membranes and resulted in dose reduction in the majority of patients. It is concluded that isotretinoin produces significant clinical benefit to some patients with mycosis fungoides.


Drugs to foster kidney regeneration in experimental animals and humans.
The incidence of kidney diseases is increasing worldwide and they are emerging as a major public health problem. Once mostly considered inexorable, renal disease progression can now be halted and lesions can even regress with drugs such as angiotensin-converting enzyme inhibitors (ACEi) and angiotensin II type I receptor blockers, indicating the possibility of kidney repair. The discovery of renal progenitor cells lining the Bowman capsule of adult rat and human kidneys has shed light on the mechanism of repair by ACEi. Parietal progenitors are a reservoir of cells that contribute to podocyte turnover in physiological conditions. In the early phases of renal disease these progenitors migrate chaotically and subsequently proliferate, accumulating in Bowman's space. The abnormal behavior of parietal progenitors is sustained by the activation of CXCR4 receptors in response to an increased production of the chemokine SDF-1 by podocytes activated by the inflammatory environment. Ang II, via the AT1 receptor, also contributes to progenitor cell proliferation. The CXCR4/SDF-1 and Ang II/AT1 receptor pathogenic pathways both pave the way for lesion formation and subsequent sclerosis. ACEi normalize the CXCR4 and AT1 receptor expression on progenitors, limiting their proliferation, concomitant with the regression of hyperplastic lesions in animals, and in a patient with crescentic glomerulopathy. Understanding the molecular and cellular determinants of regeneration triggered by renoprotective drugs will reveal novel pathways that might be challenged or targeted by pharmacological therapy.


Medical examinations and appeals for NJ public service workers.
The state of New Jersey has more than 200,000 employees in merit system jobs, who are covered by the Department of Personnel's formal hiring mechanism, including a medical examination and appeals process in which physicians play an important role. The State Medical Examiners Panel provides an innovative and practical approach to supply the Merit System Board with independent and objective findings and medical recommendations regarding the appeals. This article summarizes this process and discusses the structure, functions, and outcomes of the medical examiners Panel.