Unusual Structural Properties of Switchback DNA.
Synthetic DNA motifs form the basis of nucleic acid nanotechnology, and their biochemical and biophysical properties determine their applications. Here, we present a detailed characterization of switchback DNA, a globally left-handed structure composed of two parallel DNA strands. Compared to a conventional duplex, switchback DNA shows lower thermodynamic stability and requires higher magnesium concentration for assembly, but exhibits a higher biostability against some nucleases. Strand competition and strand displacement experiments show that component sequences have an absolute preference for duplex complements instead of their switchback partners. Further, we hypothesize a potential role for switchback DNA as an alternate structure for short-tandem repeats involved in repeat-expansion diseases. Together with small molecule binding experiments and cell studies, our results open new avenues for synthetic DNA motifs in biology and nanotechnology.


m⁶A mRNA Destiny: Chained to the rhYTHm by the YTH-Containing Proteins.
The control of gene expression is a multi-layered process occurring at the level of DNA, RNA, and proteins. With the emergence of highly sensitive techniques, new aspects of RNA regulation have been uncovered leading to the emerging field of epitranscriptomics dealing with RNA modifications. Among those post-transcriptional modifications, N6-methyladenosine (m6A) is the most prevalent in messenger RNAs (mRNAs). This mark can either prevent or stimulate the formation of RNA-protein complexes, thereby influencing mRNA-related mechanisms and cellular processes. This review focuses on proteins containing a YTH domain (for YT521-B Homology), a small building block, that selectively detects the m6A nucleotide embedded within a consensus motif. Thereby, it contributes to the recruitment of various effectors involved in the control of mRNA fates through adjacent regions present in the different YTH-containing proteins.


Inhibition of allergen-induced dermal eosinophilia by an oxoeicosanoid receptor antagonist in non-human primates.
5-Oxo-6,8,11,14-eicosatetraenoic acid (5-oxo-ETE), acting via the OXE receptor, is unique among 5-lipoxygenase products in its ability to directly induce human eosinophil migration, suggesting its involvement in eosinophilic diseases. To address this hypothesis, we synthesized selective indole-based OXE receptor antagonists. Because rodents lack an OXE receptor orthologue, we sought to determine whether these antagonists could attenuate allergen-induced skin eosinophilia in sensitized monkeys. In a pilot study, cynomolgus monkeys with environmentally acquired sensitivity to Ascaris suum were treated orally with the "first-generation" OXE antagonist 230 prior to intradermal injection of 5-oxo-ETE or Ascaris extract. Eosinophils were evaluated in punch biopsy samples taken 6 or 24 hr later. We subsequently treated captive-bred rhesus monkeys sensitized to house dust mite (HDM) allergen with a more recently developed OXE antagonist, S-Y048, and evaluated its effects on dermal eosinophilia induced by either 5-oxo-ETE or HDM. In a pilot experiment, both 5-oxo-ETE and Ascaris extract induced dermal eosinophilia in cynomolgus monkeys, which appeared to be reduced by 230. Subsequently, we found that the related OXE antagonist S-Y048 is a highly potent inhibitor of 5-oxo-ETE-induced activation of rhesus monkey eosinophils in vitro and has a half-life in plasma of about 6 hr after oral administration. S-Y048 significantly inhibited eosinophil infiltration into the skin in response to both intradermally administered 5-oxo-ETE and HDM. 5-Oxo-ETE may play an important role in allergen-induced eosinophilia. Blocking its effects with S-Y048 may provide a novel therapeutic approach for eosinophilic diseases.


Three-Dimensional Printed Modeling of Diffuse Low-Grade Gliomas and Associated White Matter Tract Anatomy.
Diffuse low-grade gliomas (DLGGs) represent several pathological entities that infiltrate and invade cortical and subcortical structures in the brain. To describe methods for rapid prototyping of DLGGs and surgically relevant anatomy. Using high-definition imaging data and rapid prototyping technologies, we were able to generate 3 patient DLGGs to scale and represent the associated white matter tracts in 3 dimensions using advanced diffusion tensor imaging techniques. This report represents a novel application of 3-dimensional (3-D) printing in neurosurgery and a means to model individualized tumors in 3-D space with respect to subcortical white matter tract anatomy. Faculty and resident evaluations of this technology were favorable at our institution. Developing an understanding of the anatomic relationships existing within individuals is fundamental to successful neurosurgical therapy. Imaging-based rapid prototyping may improve on our ability to plan for and treat complex neuro-oncologic pathology.


Phytate degradation in a mixture of ground wheat and ground defatted soybeans during feed processing: effects of temperature, moisture level, and retention time in small- and medium-scale incubation systems.
The optimal conditions for degradation of phytate (IP6, myo-inositol hexaphosphate) in a mixture of ground wheat and ground defatted soybeans (1:2, w/w) with added exogenous E. coli phytase were investigated at different temperatures (45, 60, 75, and 95 degrees C), moisture levels (25%, 35%, and 45%), and retention times (2-45 min). All treatment combinations were investigated in a small-scale mixer conditioner (experiment 1). The combined 45 degrees C and 45% moisture treatment was most efficient and reduced the content of IP6 by 86% during 45 min of incubation. This treatment combination was applied in a medium-scale mixer conditioner (experiment 2), and 76% reduction of IP6 at 45 min was obtained. During incubation, the content of lower groups of inositol phosphates, such as IP4 (myo-inositol tetraphosphate) and IP3 (myo-inositol triphosphate), increased significantly as the content of IP6 decreased. The major isomer formed was Ins(1,2,5,6)P(4).


Preparation and characterization of reference materials for human pancreatic lipase: BCR 693 (from human pancreatic juice) and BCR 694 (recombinant).
There is a lack of certified reference material (CRM) for lipase catalytic activity. Consequently between-method comparability is very poor. The aim of this study was to produce two lipase CRMs, one from human pancreatic juice (BCR 693), and another using recombinant technologies (BCR 694). Lipase was purified from pancreatic juice, using column chromatography and isoelectric focusing. Recombinant lipase was produced with a transfected cell line and purified with column chromatography. Adding buffered bovine serum albumin and subsequent freeze-drying were used to stabilize both materials. A standardized titrimetric method was employed to compare their catalytic properties to those of two plasma pools of patients suffering from acute pancreatitis. About 5 kU (titrimetry, 37 degrees C) of each material were obtained. They were lyophilized without apparent modifications of their catalytic properties, which stayed identical to those exhibited by the enzyme present in patient's pools. Stability of both materials was estimated at several years when stored in a dry form at -20 degrees C. Both materials appear to have similar catalytic properties and stability and were found commutable as regards a reference method and a routine measurement procedure. An international certification campaign will be carried out to assign values to BCR 693 and BCR 694.


Recent patents in CNS drug discovery: the management of inflammation in the central nervous system.
In recent years, one of the major advances in terms of our understanding of the pathology underlying many neurological conditions has been the realisation that inflammation may play a major role in many acute and chronic conditions. Inflammation is not only involved in acute CNS conditions, such as stroke and traumatic injury, but it is also a central factor in chronic and neurodegenerative conditions such as Alzheimer's disease, Parkinson's disease and multiple sclerosis. There are some key differences between inflammatory processes within the CNS (neuroinflammation) and peripheral inflammation, partly due to the natural compartmentation of the brain by the blood-brain barrier. As a result of these differences, the classical anti-inflammatory agents (steroids and NSAIDs) have not played a major role in the management of CNS inflammatory conditions. In order to address this clinical need, there is significant interest in developing novel anti-inflammatory agents that may help prevent or ameliorate CNS inflammation. In this review, the authors focus on disclosures from the patent literature to give a broad overview of the different approaches that are being taken to try and develop more effective and selective anti-inflammatory agents to manage acute and chronic inflammation in the CNS. A variety of approaches are discussed including modulating the activity of various inflammatory mediators such as cytokines, chemokines and kinins, targeting toll-like receptors as a possible therapeutic intervention, and novel approaches to managing the actions of eicosanoids in neuroinflammation.


Advanced Exergy Analysis in the Dynamic Framework for Assessing Building Thermal Systems.
This work applies the Dynamic Advanced Exergy Analysis (DAEA) to a heating and domestic hot water (DHW) facility supplied by a Stirling engine and a condensing boiler. For the first time, an advanced exergy analysis using dynamic conditions is applied to a building energy system. DAEA provides insights on the components' exergy destruction (ED) by distinguishing the inefficiencies that can be prevented by improving the quality (avoidable ED) and the ones constrained because of technical limitations (unavoidable ED). ED is related to the inherent inefficiencies of the considered element (endogenous ED) and those coming from the interconnections (exogenous ED). That information cannot be obtained by any other approach. A dynamic calculation within the experimental facility has been performed after a component characterization driven by a new grey-box modelling technique, through TRNSYS and MATLAB. Novel solutions and terms of ED are assessed for the rational implementation of the DAEA in building energy installations. The influence of each component and their interconnections are valuated in terms of exergy destruction for further diagnosis and optimization purposes.


[Anti-motion Artifact Performance Test System for Ambulatory ECG Monitoring Equipment].
Anti-motion artifact is one of the most important properties of ambulatory ECG monitoring equipment. At present, there is a lack of standardized means to test the performance of anti-motion artifact. ECG simulator and special conductive leather are used to build the simulator, it is used to simulate human skin, to generate ECG signal input for the ECG monitoring equipment attached to it. The mechanical arm and fixed support are used to build a motion simulation system to fix the conductive leather. The mechanical arm is programmed to simulate various motion states of the human body, so that the ECG monitoring equipment can produce corresponding motion artifacts. The collected ECG signals are read wirelessly, observed, analyzed and compared, and the anti-motion artifact performance of ECG monitoring equipment is evaluated. The test results show that by artificially creating the small difference between the two groups of ambulatory ECG monitoring equipment, the system can accurately test the interference signals introduced under the conditions of controlled movement such as tension and torsion, and compare the advantages and disadvantages. The research shows that the test system can provide convenient and accurate verification means for the research of optimizing anti-motion interference.


The presence of insulin resistance and comparison of various insulin sensivity indices in women with androgenetic alopecia.
We aimed to identify the association of female androgenetic alopecia with insulin resistance and to evaluate various simple insulin sensitivity indices and beta cell function in women with androgenetic alopecia (AGA). A cross-sectional study was performed in 66 non-obese women (24-44 years old), 41 with AGA alone and 25 healthy individuals. Blood glucose, insulin, c-peptide levels, oral glucose tolerance test (OGTT); insulin sensitivity and beta cell function indices derived from a single blood sample and OGTT were determined and compared in the two groups. Women with AGA had impaired glucose tolerance (IGT) rates of 12.5%. In the control group IGT was 0%. Fasting glucose, c-peptide, insulin were higher in AGA group. When the indices were evaluated, Raynaud index, FIRI and HOMA-IR results found to be higher in the AGA group than in controls (p < 0.05, for all). Fasting insulin(-1), GIR, FIRI(-1), QUICKY index, ISI HOMA, HOMA-IS results were lower in AGAs than in controls (p < 0.05, for all). Our study showed that women with AGA alone were more insulin resistant than healthy subjects. We suggest that beta cell function and insulin sensitivity indices are useful methods for measuring insulin resistance in AGAs, and HOMA-IR is a good predictor of insulin resistance. We propose that OGTT should be applied in women with AGA.


Human exposure and health effects of inorganic and elemental mercury.
Mercury is a toxic and non-essential metal in the human body. Mercury is ubiquitously distributed in the environment, present in natural products, and exists extensively in items encountered in daily life. There are three forms of mercury, i.e., elemental (or metallic) mercury, inorganic mercury compounds, and organic mercury compounds. This review examines the toxicity of elemental mercury and inorganic mercury compounds. Inorganic mercury compounds are water soluble with a bioavailability of 7% to 15% after ingestion; they are also irritants and cause gastrointestinal symptoms. Upon entering the body, inorganic mercury compounds are accumulated mainly in the kidneys and produce kidney damage. In contrast, human exposure to elemental mercury is mainly by inhalation, followed by rapid absorption and distribution in all major organs. Elemental mercury from ingestion is poorly absorbed with a bioavailability of less than 0.01%. The primary target organs of elemental mercury are the brain and kidney. Elemental mercury is lipid soluble and can cross the blood-brain barrier, while inorganic mercury compounds are not lipid soluble, rendering them unable to cross the blood-brain barrier. Elemental mercury may also enter the brain from the nasal cavity through the olfactory pathway. The blood mercury is a useful biomarker after short-term and high-level exposure, whereas the urine mercury is the ideal biomarker for long-term exposure to both elemental and inorganic mercury, and also as a good indicator of body burden. This review discusses the common sources of mercury exposure, skin lightening products containing mercury and mercury release from dental amalgam filling, two issues that happen in daily life, bear significant public health importance, and yet undergo extensive debate on their safety.


Climate change and variability impacts on grazing herds: Insights from a system dynamics approach for semi-arid Australian rangelands.
Grazing livestock are an important source of food and income for millions of people worldwide. Changes in mean climate and increasing climate variability are affecting grasslands' carrying capacity, thus threatening the livelihood of millions of people as well as the health of grassland ecosystems. Compared with cropping systems, relatively little is known about the impact of such climatic changes on grasslands and livestock productivity and the adaptation responses available to farmers. In this study, we analysed the relationship between changes in mean precipitation, precipitation variability, farming practices and grazing cattle using a system dynamics approach for a semi-arid Australian rangeland system. We found that forage production and animal stocking rates were significantly affected by drought intensities and durations as well as by long-term climate trends. After a drought event, herd size recovery times ranged from years to decades in the absence of proactive restocking through animal purchases. Decreases in the annual precipitation means or increases in the interannual (year-to-year) and intra-annual (month-to-month) precipitation variability, all reduced herd sizes. The contribution of farming practices versus climate effect on herd dynamics varied depending on the herd characteristics considered. Climate contributed the most to the variance in stocking rates, followed by forage productivity levels and feeding supplementation practices (with or without urea and molasses). While intensification strategies and favourable climates increased long-term herd sizes, they also resulted in larger reductions in animal numbers during droughts and raised total enteric methane emissions. In the face of future climate trends, the grazing sector will need to increase its adaptability. Understanding which farming strategies can be beneficial, where, and when, as well as the enabling mechanisms required to implement them, will be critical for effectively improving rangelands and the livelihoods of pastoralists worldwide.


[18F]Flutemetamol amyloid-beta PET imaging compared with [11C]PIB across the spectrum of Alzheimer's disease.
The aim was to identify the amyloid beta (Aβ) deposition by positron emission tomography (PET) imaging with the (18)F-labeled Pittsburgh compound B (PIB) derivative [(18)F]flutemetamol (FMM) across a spectrum of Alzheimer's disease (AD) and to compare Aβ deposition between [(18)F]FMM and [(11)C]PIB PET imaging. The study included 36 patients with AD, 68 subjects with mild cognitive impairment (MCI), 41 older healthy controls (HC) (aged ≥56), 11 young HC (aged ≤45), and 10 transitional HC (aged 46-55). All 166 subjects underwent 30-min static [(18)F]FMM PET 85 min after injection, 60-min dynamic [(11)C]PIB PET, and cognitive testing. [(18)F]FMM scans were assessed visually, and standardized uptake value ratios (SUVR) were defined quantitatively in regions of interest identified on coregistered MRI (cerebellar cortex as a reference region). The PIB distribution volume ratios (DVR) were determined in the same regions. Of 36 AD patients, 35 had positive scans, while 36 of 41 older HC subjects had negative scans. [(18)F]FMM scans had a sensitivity of 97.2% and specificity of 85.3% in distinguishing AD patients from older HC subjects, and a specificity of 100% for young and transitional HC subjects. The [(11)C]PIB scan had the same results. Interreader agreement was excellent (kappa score = 0.81). The cortical FMM SUVR in AD patients was significantly greater than in older HC subjects (1.76 ± 0.23 vs 1.30 ± 0.26, p < 0.01). Of the MCI patients, 68 had a bimodal distribution of SUVR, and 29 of them (42.6%) had positive scans. Cortical FMM SUVR values were strongly correlated with PIB DVR (r = 0.94, n = 145, p < 0.001). [(18)F]FMM PET imaging detects Aβ deposition in patients along the continuum from normal cognitive status to dementia of AD and discriminates AD patients from HC subjects, similar to [(11)C]PIB PET.


[INMERSION IN HOT WATER: A NATURAL HELPER IN LABOUR].
The pain during the birth process is the result of a pile of physiological, psychological and socio-cultural stimulus. In our society, epidural analgesia is the most common technique used in obstetrics to relieve this pain, despite not being harmless. However, there are other complementary techniques based on methods that have demonstrated analgesic effects and they benefit of lacking adverse effects either on the mother or on the fetus. Among these methods is the immersion in warm water (WI). The aim of this review is to show the usefulness, advantages and disadvantages of WI, to make it an accessible resource for pregnant women and those who are responsible for their care. Literature review about Water Immersion during the first and second stage of labor. The WI as a method to relieve discomfort and pain during labor was popularized by the obstetrician Michel Odent in 7980s. The Spanish Society of Gynecology and Obstetrics, among other associations, highly recommend its use during the cervical dilation period. It is benificial for the mother blood circulation, psychologically and for body mechanics; however, this use in the second stage of labor seems to be more controversial. WI is an analgesic non-invasive, accessible and affordable. Its use is associated with lower rates of intervention by professionals and provide a more focused attention on the needs of pregnant women.


Etiology and Surgical Management of Cervical Spinal Epidural Abscess (SEA):: A Systematic Review.
Systematic analysis and review. Evaluation of the presentation, etiology, management strategies (including both surgical and nonsurgical options), and neurological functional outcomes in patients with cervical spinal epidural abscess (SEA). The PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) criteria were used to create a framework based on which articles pertaining to cervical SEA were chosen for review following a search of the Ovid and PubMed databases using the search terms "epidural abscess" and "cervical." Included studies needed to have at least 4 patients aged 18 years or older, and to have been published within the past 20 years. Database searches yielded 521 potential articles in PubMed and 974 potential articles in Ovid. After review, 11 studies were ultimately identified for inclusion in this systematic review. Surgery appears to be a well-tolerated management strategy with limited complications for patients with cervical SEA. However, the quantity of data comparing medical and surgical treatment of cervical SEA is limited and the bulk of the data is derived from low quality studies. Data reporting was heterogeneous among studies making it difficult to draw discrete conclusions. Early surgical intervention may be appropriate in selected patients with cervical epidural abscess, but it is not clear what distinguishes these patients from those who are successfully managed nonoperatively.


Colorimetric in situ hybridization identifies MYC gene signal clusters correlating with increased copy number, mRNA, and protein in diffuse large B-cell lymphoma.
Abnormalities of the MYC oncogene on chromosome 8 are characteristic of Burkitt lymphoma and other aggressive B-cell lymphomas, including diffuse large B-cell lymphoma (DLBCL). We recently described a colorimetric in situ hybridization (CISH) method for detecting extra copies of the MYC gene in DLBCL and the frequent occurrence of excess copies of discrete MYC signals in the context of diploidy or polyploidy of chromosome 8, which correlated with increased mRNA signals. We further observed enlarged MYC signals, which were counted as a single gene copy but, by their dimension and unusual shape, likely consisted of "clusters" of MYC genes. In this study, we sought to further characterize these clusters of MYC signals by determining whether the presence of these correlated with other genetic features, mRNA levels, protein, and overall survival. We found that MYC clusters correlated with an abnormal MYC locus and with increased mRNA. MYC mRNA correlated with protein levels, and both increased mRNA and protein correlated with poorer overall survival. MYC clusters were seen in both the germinal center and activated B-cell subtypes of DLBCL. Clusters of MYC signals may be an underappreciated, but clinically important, feature of aggressive B-cell lymphomas with potential prognostic and therapeutic relevance.


Elastofibroma dorsi: clinicopathological analysis of 71 cases.
Elastofibroma dorsi (ELD) is a rare soft tissue benign tumor of the chest wall. So far, only a few large series have been reported in the English literature and, to the best of our knowledge, radiological assessment and clinical management remain without consensus. The aim of this study is to provide, on the basis of a single-institutional, homogeneous and large experience, ample evidences to support etiological and "clinical-usefulness-grade" classification hypotheses. We report observational information on 71 ELD cases and, on the basis of these, we discuss the clinical onset features, radiological and surgical characteristics, as well as pathological and immunohistochemical evidences. In the period between January 1994 and September 2009, 71 consecutive patients (23 male and 48 female; mean age: 60.2 years; standard deviation [SD] ± 8.3 years) with ELD diagnosis were surgically treated at our institution. ELD was right sided in 34 patients (47.9%), left in 25 (35.2%), and bilateral in 12 (16.9%). In nine patients, ELD were diagnosed synchronously and three metachronously. Thirty-eight patients (53.5%) had no significant symptoms; 33 (46.5%) reported a clunking sensation or a localized scapular swelling during the shoulder movements. Sixty-six (93%) patients underwent surgical excision with radical intent while in five patients, a biopsy-only procedure was undertaken. Mean hospital stay was 3.0 days (SD ± 1.2 days) with a morbidity of 10.6% (one case of major postoperative bleeding requested a surgical revision of the hemostasis). At the univariate analysis, the probability of occurrence of morbidity increases with tumor size. All operated patients are alive and well at follow-up with no sign of recurrence and complete resolution of the symptomatology. ELD is relatively uncommon, benign, and well controlled by radical surgery.


An analysis of the 5-hydroxytryptamine (serotonin) receptor subtypes of central neurones of Helix aspersa.
1. Intracellular recordings were made from identified neurones in the central nervous system of Helix aspersa. Two types of cell were used, those excited by 5-hydroxytryptamine (5-HT) and acetylcholine and those inhibited by 5-HT and dopamine. The actions of a range of 5-HT agonists and antagonists were tested for their ability to interact with 5-HT receptors. 2. 5-Carboxyamidotryptamine, alpha-methyl-5-HT and N-methyl-5-HT were active on cells excited by 5-HT, with similar potencies to 5-HT. Only 5-carboxyamidotryptamine and 5-methoxytryptamine were equiactive with 5-HT on cells inhibited by 5-HT. Most of the non-indole analogues were inactive or very weak agonists on both receptors. 3. MDL 72222 was the most active antagonist tested against 5-HT excitation, showing some selectivity for 5-HT over acetylcholine. Cinanserin and ketanserin also showed selectivity for 5-HT over acetylcholine. 4. Tryptamine was inhibitory on both cell types and was a potent antagonist of 5-HT excitation, showing selectivity for 5-HT over acetylcholine. 5. It is concluded that the 5-HT excitatory receptor recognizes the indole nucleus with substitution on position 5, save for 5-fluorotryptamine which was inhibitory. It does not appear that these 5-HT receptors can be classified in terms of the vertebrate subtypes of 5-HT receptor. However, it should be noted that only two receptor subtypes located on a small number of neurones were studied in these experiments and other 5-HT receptor suptypes may be located on other groups of neurones and peripheral tissues. These receptors may recognize other 5-HT receptor ligands including non-indoles.


Unsaturated fatty acids supplementation reduces blood lead level in rats.
Some dietary factors could inhibit lead toxicity. The aim of this study was to evaluate the effect of dietary compounds rich in unsaturated fatty acids (FA) on blood lead level, lipid metabolism, and vascular reactivity in rats. Serum metallothionein and organs' lead level were evaluated with the aim of assessing the possible mechanism of unsaturated FA impact on blood lead level. For three months, male Wistar rats that were receiving drinking water with (100 ppm Pb) or without lead acetate were supplemented per os daily with virgin olive oil or linseed oil (0.2 mL/kg b.w.) or egg derived lecithin fraction: "super lecithin" (50 g/kg b.w.). Mesenteric artery was stimulated ex vivo by norepinephrine (NE) administered at six different doses. Lecithin supplementation slightly reduced pressor responses of artery to NE. Lead administered to rats attenuated the beneficial effect of unsaturated FA on lipid metabolism and vascular reactivity to adrenergic stimulation. On the other hand, the super lecithin and linseed oil that were characterized by low omega-6 to omega-3 ratio (about 1) reduced the blood lead concentration. This effect was observed in lead poisoned rats (p < 0.0001) and also in rats nonpoisoned with lead (p < 0.05).


Perinatal fluoxetine exposure results in social deficits and reduced monoamine oxidase gene expression in mice.
Perinatal antidepressant drug exposure increases risk for autism spectrum disorder, yet the molecular and neurobehavioral effects of maternal antidepressant drug use on offspring remain poorly understood. In this study, we administered the selective serotonin reuptake inhibitor (SSRI) fluoxetine non-invasively to female mice throughout gestation and early lactation, and then examined social interaction behaviors in offspring. In addition, we measured whole brain gene expression levels of monoamine oxidase A (MAOA), the primary metabolizing enzyme for serotonin. We found deficits in sociability and social novelty-seeking behavior in the juvenile offspring of SSRI-treated mice, and these behaviors persisted into young adulthood. Furthermore, we found decreased MAOA expression in the brains of offspring of SSRI-treated mice. Our findings suggest that exposure to antidepressants during the prenatal and early postnatal period may negatively affect social development. Moreover, reduced MAOA expression may play a role in the mechanistic pathway linking SSRI exposure and behavioral deficits symptomatic of autism.


The psychological significance of human startle eyeblink modification: a review.
The human startle eyeblink reflex is reliably modified by both cognitive and emotional processes. This review provides a comprehensive survey of the current literature on human startle modification and its psychological significance. Issues raised for short lead interval startle inhibition include its interpretation as a measure of protection of processing, sensorimotor gating and early attentional processing. For long lead interval effects, interpretations related to attentional and emotional processing are discussed. Also reviewed are clinical applications to information processing dysfunctions in the schizophrenia spectrum disorders, and to emotional processing disorders. Finally, an integrative summary that incorporates most of the cognitive findings is presented and directions for future research are identified regarding both cognitive and emotional modification of startle.


Coached practice using ERCP mechanical simulator improves trainees' ERCP performance: a randomized controlled trial.
Preliminary data suggested that simulation practice using an endoscopic retrograde cholangiopancreatography (ERCP) mechanical simulator (EMS) improved trainees' skill. The aims of the current study were to confirm the impact of coached EMS practice at the beginning of ERCP training and to investigate whether subsequent uncoached EMS practice provides additional benefit. Trainees entering ERCP training in 2008 (n = 8) and 2009 (n = 8) at two referral medical centers were randomized to receive a coached EMS practice either with (2009) or without (2008) subsequent uncoached practices or only routine training (controls). The outcome measures were successful deep biliary cannulation by the trainee and overall performance score as rated by blinded trainers, during the subsequent 3 months of clinical practice. Trainees undergoing single and multiple EMS practices were more likely than controls to achieve successful biliary cannulation (single: adjusted odds ratio [aOR] 2.89, 95 % confidence interval [CI] 2.21 - 3.80 [P < 0.001]; multiple: 3.09, 95 %CI 1.13 - 8.46 [P = 0.028]) and to have superior overall performance scores (aOR 3.29, 95 %CI 1.37 - 7.91 [P = 0.008] and 6.92, 95 %CI 3.77 - 12.69 [P < 0.001], respectively). The benefit of single and multiple EMS practices on overall performance score remained significant after adjustment for success or failure of deep biliary cannulation (aOR 2.98, 95 %CI 1.38 - 6.43 [P = 0.005] and 6.09, 95 %CI 2.40 - 15.45 [P < 0.001], respectively). The benefits of single vs. multiple EMS practices were not statistically different. Coached simulation using EMS improved novice trainees' success of biliary cannulation and overall ERCP performance. Additional uncoached practices did not appear to provide further benefit. Trainees should undergo a coached EMS practice at the beginning of ERCP training.


Comorbid Premenstrual Dysphoric Disorder in Women with Bipolar Disorder: Management Challenges.
Bipolar disorder (BD) and premenstrual dysphoric disorder (PMDD) are two cyclic mood illnesses, sometimes presenting together. Their comorbidity appears to be linked to common biological mechanisms and usually results in more severity of mood symptoms and a poorer long-term outcome. Nevertheless, the management of comorbid PMDD/BD has been scarcely studied. Therefore, the aim of the present paper was to review the published literature on the treatment of comorbid PMDD/BD and to provide point-by-point hypotheses to address these complex clinical cases. We searched PubMed to identify the studies focused on the treatment and management of comorbid PMDD/BD using the following search words, alone and in combination: premenstrual dysphoric disorder, bipolar disorder, comorbid, treatment, management, pharmacotherapy, psychotherapy. The search was conducted on the 1st of June 2019 and yielded 55 records. Four papers met our inclusion/exclusion criteria and were therefore included in our qualitative synthesis. Integrating the few data pertaining to the treatment of comorbid PMDD/BD with the large amount of published data on the two conditions separately, we can suggest that the management of comorbid PMDD/BD needs as a first step to stabilize the bipolar symptoms by means of optimal dosages of mood stabilizers. Then, in euthymic BD patients, the PMDD symptoms could be treated with estroprogestins (first-line treatment). On the contrary, during acute phases of BD, antidepressants (for major depressive episodes) and atypical antipsychotics/hormonal modulators (for manic episodes) could be considered as promising add-on treatments to mood stabilizers. In case of resistant PMDD/BD symptoms, combined strategies should be taken into account, as well as alternative treatments, such as lifestyle changes. In conclusion, RCTs on comorbid PMDD/BD are still lacking. The management of this complex condition is therefore challenging and it requires a tailored treatment.


Neutrophils influence the level of antigen presentation during the immune response to protein antigens in adjuvants.
Neutrophils modulated Ag presentation following immunization with Ags in CFA or IFA or alum. The neutrophils had an important negative role in the CD4 T cell and B cell responses to three protein Ags: hen egg white lysozyme, OVA, and listeriolysin O. In their absence (by depleting with Abs for only the first 24 h, or using genetically neutropenic mice), the cellular responses increased several-fold. The CD8 response was not affected or slightly decreased. Competition for Ag between the presenting cells and the neutrophils, as well as an effect on the response to Ag-bearing dendritic cells (DCs), was documented. Neutrophils entered the draining lymph nodes rapidly and for a brief period of several hours, localizing mainly to the marginal sinus and superficial cortex. There they established brief contact with DCs and macrophages. Moreover, neutrophils imprinted on the quality of the subsequent DC-T cell interactions, despite no physical contact with them; by intravital microscopy, the clustering of Ag-specific T cells and DCs was improved in neutropenic mice. Thus, neutrophils are obligate cells that briefly enter sites of immunization and set the level of Ag presentation. A brief depletion may have a considerably positive impact on vaccination.


The biology of developmental plasticity and the Predictive Adaptive Response hypothesis.
Many forms of developmental plasticity have been observed and these are usually beneficial to the organism. The Predictive Adaptive Response (PAR) hypothesis refers to a form of developmental plasticity in which cues received in early life influence the development of a phenotype that is normally adapted to the environmental conditions of later life. When the predicted and actual environments differ, the mismatch between the individual's phenotype and the conditions in which it finds itself can have adverse consequences for Darwinian fitness and, later, for health. Numerous examples exist of the long-term effects of cues indicating a threatening environment affecting the subsequent phenotype of the individual organism. Other examples consist of the long-term effects of variations in environment within a normal range, particularly in the individual's nutritional environment. In mammals the cues to developing offspring are often provided by the mother's plane of nutrition, her body composition or stress levels. This hypothetical effect in humans is thought to be important by some scientists and controversial by others. In resolving the conflict, distinctions should be drawn between PARs induced by normative variations in the developmental environment and the ill effects on development of extremes in environment such as a very poor or very rich nutritional environment. Tests to distinguish between different developmental processes impacting on adult characteristics are proposed. Many of the mechanisms underlying developmental plasticity involve molecular epigenetic processes, and their elucidation in the context of PARs and more widely has implications for the revision of classical evolutionary theory.


[Relaparotomy in children].
Specific features of the course of complicated and noncomplicated postoperative period were studied in 21,294 children. Data of 682 relaparotomies were analyzed. The definition of the term "relaparotomy" and classification of relaparotomies are given.


Screening of HaCaT clones for CCL20 gene knockout and preliminary exploration of gene-targeting vector transfection approaches in this cell line.
Inhibition of CC chemokine ligand 20 (CCL20), which is expressed by human keratinocytes after proinflammatory cytokine stimulation, may reduce migration of recipient Langerhans cells into tissue-engineered allogeneic skin grafts and minimize immune rejection by the recipient. Here, we screened CCL20 gene knockout clones in the human immortalized skin keratinocyte line HaCaT and tested multiple transfection methods for optimal efficiency. The CCL20 gene was PCR amplified from HaCaT genomic DNA. Both the short arm (1,969 bp) and long arm (2,356 bp) of human CCL20 were cloned into ploxP-targeting vectors at either side of the neomycin resistance cassette, respectively. The resulting ploxP-hCCL20-targeting vector was linearized and electroporated into HaCaT. The positive HaCaT clones were screened under the pressure of both G418 and GANC, and identified by PCR and Southern blot. The ploxP-hCCL20-EGFP fluorescent expression vector was also constructed and transfected into 293FT and HaCaT cells by jetPEI liposome and nucleofection electroporation for evaluating the transfect efficiency under fluorescent microscope. The replacement targeting vector ploxP-hCCL20 (11.9 kb) for exon 2 of the human CCL20 gene was successfully constructed and transfected into HaCaT cells. The selected HaCaT clones did not show any evidence of CCL20 gene knockout by either PCR or Southern blot analysis. We also successfully constructed a fluorescent expression vector ploxP-hCCL20-EGFP (13.3 kb) to assess possible reasons for gene-targeting failure. Transfection efficiencies of ploxP-hCCL20-EGFP into 293FT and HaCaT cell lines by jetPEI liposome were 75.1 ± 3.4% and 1.3 ± 0.2%, respectively. The transfection efficiency of ploxP-hCCL20-EGFP into HaCaT cells using nucleofection electroporation was 0.3±0.1% (P=0.000), but the positive control vector pmaxGFP (3,490 bp) using the same method was 38.3 ± 2.8%. Overall low transfection efficiencies of ploxP-hCCL20-EGFP into HaCaT cells, regardless of transfection method, may either be due to the high molecular weight of the vector or to the fact that this particular cell line may be inherently difficult to transfect.


Solution structure of the orphan nuclear receptor rev-erb beta response element by 1H, 31P NMR and molecular simulation*.
Rev-erb beta is an orphan receptor that binds as a homodimer or as a monomer to DNA. The solution structure of the non-palindromic 15 bp DNA duplex d(TAGAATGTAGGTCAG), the response element of Rev-erb beta for monomeric binding, was determined by 1H and 31P NMR, energy minimization with NMR-derived restraints for distances and NOE back-calculation methods. The refined final structures have the typical overall features of B-type DNA. However, titration of this 15 bp duplex with ReDBD, the DNA binding domain of Rev-erb beta, showed large shifts of imino protons and 31P signals, suggesting major conformational changes.


Cooperative therapeutic effects of androgen ablation and adenovirus-mediated herpes simplex virus thymidine kinase gene and ganciclovir therapy in experimental prostate cancer.
Adenovirus-mediated transduction of the herpes simplex thymidine kinase gene (HSV-tk) in conjunction with ganciclovir (GCV) has been shown to result in significant growth suppression and to enhance survival in a model of mouse prostate cancer. However, this therapeutic activity is not sustained, because in most cases tumors eventually regrow and ultimately cause the death of the host. Androgen ablation, an inducer of apoptosis in prostate cells which is used widely as palliative therapy in patients with prostate cancer, was combined with HSV-tk plus GCV using an androgen-sensitive mouse prostate cancer cell line. The combination of castration and HSV-tk plus GCV led to markedly enhanced tumor growth suppression in both subcutaneous and orthotopic models compared with either treatment alone and resulted in an enhanced survival in which combination-treated animals lived twice as long as controls in the subcutaneous model and over 50% longer than controls in the orthotopic model. Further analysis of apoptotic activity demonstrated high levels of apoptosis only in combined androgen ablation and HSV-tk plus GCV-treated tumors after 14 days of growth in an androgen-depleted environment and 8 days after HSV-tk plus GCV therapy. At this time, the apoptotic index, but not the percent of necrotic tissue, was significantly higher for combination therapy-treated tumors relative to control-treated tumors or either treatment alone. These data indicate that the therapeutic effects of androgen ablation and HSV-tk plus GCV are cooperative and that increased apoptosis may, in part, underlie these activities.


Cortical mechanisms and cues for action.
Monkeys have more highly developed brains and are more intelligent than rats; yet rats learn some tasks as efficiently as monkeys. For example, rats are as quick at discovering which of two doors hides food or how to open the doors. Presumably tasks of this sort do not greatly tax cortical associative mechanisms since the animals have only to cumulate facts about objects. It is argued that cortical mechanisms are crucial for the ability to relate together information that is presented at different times or in different places. After removal of parts of frontal cortex monkeys can still associate cues that are presented together but they are poor at relating cues that are presented apart.


Induction of an unusual type of shared phosphorylation in human and avian cells by tumor-promoting phorbol esters or transformation.
Alterations in patterns of protein phosphorylation after exposure to phorbol esters were compared in chicken embryo fibroblasts and KD cells (a human fibroblast line) by two-dimensional gel electrophoresis. A substantial increase in phosphorylation was observed of a major, markedly acidic protein of pI = 4.5 in two-dimensional gels of each cell type. However, the apparent molecular weights of these phosphoproteins differed substantially in the two species with a molecular weight of 67,000 in chicken fibroblasts and one of 80,000 in human KD cells. Both phosphoproteins, termed 67K and 80K respectively, contained phosphoserine and a small amount of phosphothreonine, but no detectable level of phosphotyrosine. Tryptic and chymotryptic phosphopeptide maps of 67K were nearly identical to those of 80K. These results indicate that they are related molecules, even though considerably different in apparent molecular weight, and that the induction of phosphorylation of these closely related, major, acidic phosphoproteins by phorbol esters is conserved from avian to human cells. In chicken embryo fibroblasts infected by a temperature-sensitive mutant of Rous sarcoma virus, phosphorylation of 67K was found to be elevated at 36 degrees C (transformed phenotype) compared to 41.5 degrees C (normal). Although the function of these closely related 67K and 80K phosphoproteins is unknown, the elevated level of phosphorylation could be involved in some aspects of transformation, and the increase is mimicked by treatment with phorbol esters.


An epidemiological study of petroleum refinery employees.
A cohort study of 14179 current and former Chevron USA employees at the Richmond and El Segundo, California, refineries was conducted. The cohort consisted of everyone working at either refinery for a minimum of one year. The observed mortality of the cohort, by cause, was compared with the expected based on the United States mortality rates, standardised for age, race, sex, and calendar time. Analyses by refinery, job category, hire date, duration of employment, and latency were performed. For the entire cohort, mortality from all causes was 72.4% of that expected, a deficit that was statistically significant. In addition, a significantly lower mortality was found for all forms of cancer combined, digestive cancer, lung cancer, heart disease, non-malignant respiratory disease, diseases of the digestive system, and accidents. Only lymphopoietic cancer showed a pattern of increased risk suggestive of a possible relation to an occupational exposure. The excess appears confined to cancer of lymphatic tissue (not leukaemias) at Richmond, and only among those hired before 1948. A follow up case analysis of the deaths from lymphatic cancer failed to identify a common exposure pattern.


Activation of CMV promoter-controlled glycosyltransferase and beta -galactosidase glycogenes by butyrate, tricostatin A, and 5-aza-2'-deoxycytidine.
Cytomegalovirus (CMV) immediate early promoter is a powerful promoter frequently used for driving the expression of transgenes in mammalian cells. However, this promoter gradually becomes silenced in stably transfected cells. We employed Chinese Hamster Ovary (CHO) and human pancreatic cancer (Panc 1) cells stably tansfected with three glycogenes driven by a CMV promoter to study the activation of silenced glycogenes. We found that butyrate, tricostatin A (TSA), and 5-aza-2'-deoxycytidine (5-Aza-dC) can activate these CMV-driven glycogenes. The increase in mRNA and protein of a glycogene occurred 8-10 h after butyrate treatment, suggesting an indirect effect of butyrate in the activation of the transgene. The enhanced expression of the trangenes by butyrate and TSA, known inhibitors of histone deacetylase, was independent of the transgene or cell type. However, the transgene can be activated by these two agents in only a fraction of the cells derived from a single clone, suggesting that inactivation of histone deacetylase can only partially explain silencing of the transgenes. Combination treatment of one or both agents with 5-Aza-dC, a known inhibitor of DNA methylase, resulted in a synergistic activation of the transgene, suggesting a cross-talk between histone acetylation and DNA demethylation. Understanding the mechanisms of the inactivation and reactivation of CMV promoter-controlled transgenes should help develop an effective strategy to fully activate the CMV promoter-controlled therapeutic genes silenced by the host cells.


Non-seasonality of births in Tierra del Fuego (Chile).
Tierra del Fuego is situated at the southern tip of the American continent, which conditions its environmental and climatic characteristics. The colonizing population arrived, at the end of the 19th century, from other Chilean regions (particularly from Chiloé) and diverse European countries, especially Britain and Croatia, but also Germany, Spain and Italy. In the present study, the existence of a seasonal pattern in 5430 births registered in the Chilean population of Tierra del Fuego from 1890 to 1995 was analysed. The analysis showed no seasonal distribution of births in the periods 1890-1920 and from 1946 to the present day, a phenomenon rarely reported in the literature. The absence of seasonality in birth distribution could be related to the great diversity in the origins of the population's families, the constant renovation of this and the declining importance of the administrative capital of the province of Tierra del Fuego, Porvenir, in favour of Punta Arenas, capital of the Magellanic region. In the period of maximum development of the capital of the province, a seasonal pattern was detected with a peak in April and a trough in October, which corresponds with a maximum of conceptions in July and, in general, during the early southern winter and a decline in births from late spring to mid-summer, with a trough in January. This birth distribution is interpreted as a subordination of activity and social life to the annual sheep cycle. In addition to temporal trends, the influence on the observed patterns of environmental parameters, father's occupation, seasonality of marriage and the origin of the parents were analysed.


A mammalian iron ATPase induced by iron.
While molecular mechanisms for iron entry and storage within cells have been elucidated, no system to mediate iron efflux has been heretofore identified. We now describe an ATP requiring iron transporter in mammalian cells. (55)Fe is transported into microsomal vesicles in a Mg-ATP-dependent fashion. The transporter is specific for ferrous iron, is temperature- and time-dependent, and detected only with hydrolyzable nucleotides. It differs from all known ATPases and appears to be a P-type ATPase. The Fe-ATPase is localized together with heme oxygenase-1 to microsomal membranes with both proteins greatly enriched in the spleen. Iron treatment markedly induces ATP-dependent iron transport in RAW 264.7 macrophage cells with an initial phase that is resistant to cycloheximide and actinomycin D and a later phase that is inhibited by these agents. Iron release, elicited in intact rats by glycerol-induced rhabdomyolysis, induces ATP-dependent iron transport in the kidney. Mice with genomic deletion of heme oxygenase-1 have selective tissue iron accumulation and display augmented ATP-dependent iron transport in those tissues that accumulate iron.


Determination of the relationship between mortality and SOFA, qSOFA, MASCC scores in febrile neutropenic patients monitored in the intensive care unit.
Febrile neutropenia (FN) is a hematological emergency. It is challenging and confusing for the clinicians to make the decision of the febrile neutropenic patients under chemotherapy to be monitored at intensive care unit (ICU). The aim of this study was to define the factors supporting decision-making for the critical patients with febrile neutropenia. The data of 60 patients, who were taken to the ICU while they were under treatment in the Hematology Clinic with a diagnosis of febrile neutropenia, were analyzed retrospectively, in order to identify clinically useful prognostic parameters. The ICU mortality rate was 80%. Mortality was significantly associated with higher sequential organ failure assessment score (SOFA), quick sequential organ failure assessment score (qSOFA), and hematological SOFA (SOFAhem) scores on admission. All cases having SOFA score 10 and above and qSOFA score 2 and above died. In multivariate analysis, qSOFA score was found to be statistically significant in predicting mortality in regard to ICU admission (p = 0.004). Mortality of febrile neutropenic patients admitted to ICU is high. It would be appropriate to determine the extent of organ dysfunction instead of underlying disease, for making the decision of ICU admission. It should be noticed that the risk mortality is high for the FN cases with SOFA score 10 or above, qSOFA score 2 or above, and in need of mechanical ventilation and positive inotropic support; hence, early intervention is recommended. In our study, the most significant parameter in predicting ICU mortality was found to be qSOFA.


Iron-induced L1210 cell growth: evidence of a transferrin-independent iron transport.
L1210 leukemic cells can be cultured continuously in serum-free medium supplemented merely with either transferrin or iron salts. No transferrin or transferrin-like molecules were detected in the conditioned medium from cells established in serum-free medium plus iron. In these cells, iron uptake was found to occur through a saturable transport system exhibiting the properties of an allosteric regulatory protein. This transferrin-independent iron transport coexisted with transferrin-mediated iron uptake. When the iron concentration in the medium is less than 0.1 microM, transferrin must be present in the culture medium in order to observe cell growth. Under these culture conditions, a 16- to 18-h treatment with a 1 mM concentration of the iron chelator desferrioxamine resulted in less than 20% DNA synthesis compared to control cultures. DNA synthesis was reinitiated without a lag time after addition of 1 mM ferric citrate to the culture medium. No heme synthesis was needed to observe this DNA synthesis. However, in the presence of the antioxidant propyl gallate the reinitiation of DNA synthesis was abolished. Ferricyanide could not replace ferric citrate as a stimulant of DNA synthesis. Cytofluorometric analysis has shown that nearly 10% of the cells treated by desferrioxamine were blocked in G2 + M phase of cell cycle, suggesting that, in addition to DNA synthesis, iron chelation also blocked other mechanisms critical for cell growth.


An assessment of driving fitness in patients with visual impairment to understand the elevated risk of motor vehicle accidents.
To assess the driving fitness of patients with glaucoma by identifying specific areas and degrees of visual field impairment that threaten safe driving. Case-control study. This prospective study included 36 patients with advanced glaucoma, defined as Humphrey field analyzer (HFA; 24-2 SITA standard program) measurements of mean deviation in both eyes of worse than -12 dB, and 36 age-matched and driving exposure time-matched normal subjects. All participants underwent testing in a novel driving simulator (DS) system. Participants were recruited between September 2010 and January 2012. The number of collisions with simulated hazards and braking response time in 14 DS scenarios was recorded. Monocular HFA 24-2 test results from both eyes were merged to calculate the binocular integrated visual field (IVF). The position of the IVF subfields in which the collision-involved patients had lower sensitivity than the collision-uninvolved patients was compared with the track of the hazard. The cut-off value to predict an elevated risk of collisions was determined, as were its sensitivity and specificity, with the area under the receiver operating characteristic (AUROC) curve. Patients with advanced glaucoma were involved in a significantly higher number of collisions in the DS than the age-matched and driving exposure time-matched normal subjects (119 vs 40, respectively, p<0.0001), especially in four specific DS scenarios. In these four scenarios, IVF sensitivity was significantly lower in the collision-involved patients than in the collision-uninvolved patients in subfields on or near the track of the simulated hazard (p<0.05). The subfields with the largest AUROC curve had values ranging from 0.72 to 0.91 and were located in the paracentral visual field just below the horizontal. Our novel DS system effectively assessed visual impairment, showing that simulators may have future potential in educating patients.


Intensity noise in high-frequency range of an external cavity diode laser and its reduction by second harmonic generation.
Characteristics of intensity noise of optically pumped vertical-cavity surface-emitting lasers and solid-state lasers, induced by the beating of the main lasing mode and non-lasing side modes and its reduction, have been reported in recent years. The mode beating noise of an external cavity diode laser composed of an electrically pumped edge-emitting laser diode chip is studied experimentally in this Letter. The noises due to the beating of the main mode with the first- to third-order side modes are observed, and multiple sub-peaks in the beating noise are measured. It is assumed that the new phenomena are coming from the enhanced four-wave mixing in the longer-active medium. Intensity noise reduction is also demonstrated by using the second harmonic generation of a beta barium borate crystal as a nonlinear absorber.


What concentration of tranexamic acid is needed to inhibit fibrinolysis? A systematic review of pharmacodynamics studies.
: Intravenous tranexamic acid (TXA) reduces death because of bleeding in patients with trauma and postpartum haemorrhage. However, in some settings intravenous injection is not feasible. To find different routes of administration, we first need to determine the minimal concentration of TXA in the blood that is required to inhibit fibrinolysis.We conducted a systematic review of in-vitro and in-vivo pharmacodynamics studies. We searched MEDLINE, EMBASE, OviSP, and ISI Web of Science from database inception to November 2017 for all in-vitro (including simulated clotting models) or in-vivo studies reporting the relationship between the TXA concentration in blood or plasma and any reliable measure of fibrinolysis.We found 21 studies of which 20 were in vitro and one was in vivo. Most in-vitro studies stimulated fibrinolysis with tissue plasminogen activator and measured fibrinolysis using viscoelastic, optical density, or immunological assays. TXA concentrations between 10 and 15 mg/l resulted in substantial inhibition of fibrinolysis, although concentrations between 5 and 10 mg/l were partly inhibitory.TXA concentrations of 10-15 mg/l may be suitable targets for pharmacokinetic studies, although TXA concentrations above 5 mg/l may also be effective.


Fair and just culture, team behavior, and leadership engagement: The tools to achieve high reliability.
Disparate health care provider attitudes about autonomy, teamwork, and administrative operations have added to the complexity of health care delivery and are a central factor in medicine's unacceptably high rate of errors. Other industries have improved their reliability by applying innovative concepts to interpersonal relationships and administrative hierarchical structures (Chandler 1962). In the last 10 years the science of patient safety has become more sophisticated, with practical concepts identified and tested to improve the safety and reliability of care. Three initiatives stand out as worthy regarding interpersonal relationships and the application of provider concerns to shape operational change: The development and implementation of Fair and Just Culture principles, the broad use of Teamwork Training and Communication, and tools like WalkRounds that promote the alignment of leadership and frontline provider perspectives through effective use of adverse event data and provider comments. Fair and Just Culture, Teamwork Training, and WalkRounds are described, and implementation examples provided. The argument is made that they must be systematically and consistently implemented in an integrated fashion. There are excellent examples of institutions applying Just Culture principles, Teamwork Training, and Leadership WalkRounds--but to date, they have not been comprehensively instituted in health care organizations in a cohesive and interdependent manner. To achieve reliability, organizations need to begin thinking about the relationship between these efforts and linking them conceptually.


Bionic intelligent ankle-foot prosthesis based on the conjugate curved surface.
Given the poor biomimetic motion of traditional ankle-foot prostheses, it is of great significance to develop an intelligent prosthesis that can realize the biomimetic mechanism of human feet and ankles. To this end, we presented a bionic intelligent ankle-foot prosthesis based on the complex conjugate curved surface. The proposed prosthesis is mainly composed of the rolling conjugated joints with a bionic design and the carbon fiber energy-storage foot. We investigated the flexibility of the prosthetic ankle joint movement, and the ability of the prosthetic foot to absorb ground impact during the gait cycle. Experimental results showed the matching of the ankle/toe position relationship of the human foot during simulated walking, which is helpful to realize the biomimetic motion of the human foot and ankle. It can also help therapists and clinicians provide better rehabilitation for lower-limb amputees.


Metastatic ovarian squamous cell carcinoma.
Ovarian squamous cell carcinoma is usually associated with germ cell tumours (dermoid cyst) or endometriosis in primary cancer. While tumour metastasis to the ovary is common and often bilateral in over 50 percent of cases, metastatic cervical squamous cell carcinoma to the ovary is infrequent compared to adenocarcinoma from other extraovarian primaries and the cervix. We report two cases of unilateral metastatic ovarian squamous cell carcinoma from the uterine cervix in two women aged 38 years and 48 years, respectively. They presented with abdominopelvic masses, clinically thought to be tuberculosis and primary ovarian tumour, respectively. Both had laparotomy which revealed multinodular ovarian masses with extensive extra-ovarian involvement of the corpus and uterine cervix by tumour and omental seedlings. Tissue microscopy showed total replacement of ovarian stroma by tumour with necrotic foci and containing infiltrating nests and cords of malignant squamous cells with prominent intercellular bridges. No evidence of teratoma or endometriosis was seen in the histology sections. They were both diagnosed with metastatic ovarian squamous cell carcinoma with advanced stage disease primary in the uterine cervix. Ovarian metastatic squamous cell carcinoma from the uterine cervix may occur with advanced stage cervical carcinoma. Unilateral multinodular ovarian mass with extensive extra-ovarian tumour involvement should raise suspicion of metastasis rather than of primary tumour. Early and prompt diagnosis is desirable in the management of these patients.


Hydrogen sulfide and resolution of acute inflammation: A comparative study utilizing a novel fluorescent probe.
Hydrogen sulfide is an essential gasotransmitter associated with numerous pathologies. We assert that hydrogen sulfide plays an important role in regulating macrophage function in response to subsequent inflammatory stimuli, promoting clearance of leukocyte infiltrate and reducing TNF-α levels in vivo following zymosan-challenge. We describe two distinct methods of measuring leukocyte hydrogen sulfide synthesis; methylene blue formation following zinc acetate capture and a novel fluorescent sulfidefluor probe. Comparison of these methods, using pharmacological tools, revealed they were complimentary in vitro and in vivo. We demonstrate the application of sulfidefluor probe to spectrofluorimetry, flow cytometry and whole animal imaging, to monitor the regulation of hydrogen sulfide synthesis in vivo during dynamic inflammatory processes. Both methodologies revealed that granulocyte infiltration negatively affects hydrogen sulfide synthesis. Our report offers an insight into the profile of hydrogen sulfide synthesis during inflammation and highlight opportunities raised by the development of novel fluorescent hydrogen sulfide probes.


Influence of DARPP-32 genetic variation on BOLD activation to happy faces.
Dopaminergic pathways play a crucial role in reward processing, and advanced age can modulate its efficiency. DARPP-32 controls dopaminergic function and is a chemical nexus of reward processing. In 61 younger (20-30 years) and older adults (54% ♀) (65-74 years), we examined how blood-oxygen-level dependent (BOLD) activation to emotional faces, vary over genotypes at three single nucleotide polymorphism (SNPs), coding for DARPP-32 (rs879606; rs907094; 3764352). We also assessed age-magnification of DARPP-32 effects on BOLD activation. We found that major homozygote G, T or A genotypes, with higher cortical expression of DARPP-32, higher dopamine receptor efficacy, and greater bias toward positive cues, had increased functional connectivity in cortical-subcortical circuits in response to happy faces, engaging the dorsal prefrontal cortex (DLPFC), fusiform gyrus (FG) and the midbrain (MB). Local BOLD response to happy faces in FG, and MB was age-dependent, so that older carriers of the major G, T or A alleles showed lesser activation than minor genotypes. These genetic variants of DARPP-32 did not modulate BOLD response to angry faces, or engagement of the inferior occipital gyrus, to happy or angry faces. Taken together our results lend support for a potential role of DARPP-32 genetic variants in neural response to potential reward triggering cues.


First-line antiretroviral therapy with efavirenz plus tenofovir disiproxil fumarate/emtricitabine or rilpivirine plus tenofovir disiproxil fumarate/emtricitabine: a durability comparison.
The aim of this study was to compare the durabilities of efavirenz (EFV) and rilpivirine (RPV) in combination with tenofovir/emtricitabine (TDF/FTC) in first-line regimens. A multicentre prospective and observational study was carried out. We included all patients participating in the Italian Cohort Naive Antiretrovirals (ICONA) Foundation Study who started first-line combination antiretroviral therapy (cART) with TDF/FTC in combination with RPV or EFV, with a baseline viral load < 100 000 HIV-1 RNA copies/mL. Survival analyses using Kaplan-Meier (KM) curves and Cox regression with time-fixed covariates at baseline were employed. Overall, 1490 ART-naïve patients were included in the study, of whom 704 were initiating their first cART with EFV and 786 with RPV. Patients treated with EFV, compared with those on RPV, were older [median 36 (interquartile range (IQR) 30-43) years vs. 33 (IQR 27-39) years, respectively; P < 0.001], were more frequently at Centers for Disease Control and Prevention (CDC) stage C (3.1% vs. 1.4%, respectively; P = 0.024), and had a lower median baseline CD4 count [340 (IQR 257-421) cells/μL vs. 447 (IQR 347-580) cells/μL, respectively; P < 0.001] and a higher median viral load [4.38 (IQR 3.92-4.74) log10 copies/mL vs. 4.23 (IQR 3.81-4.59) log10 copies/mL, respectively], (P = 0.004). A total of 343 patients discontinued at least one drug of those included in the first cART regimen, more often EFV (26%) than RPV (13%), by 2 years (P < 0.0001). After adjustment, patients treated with EFV were more likely to discontinue at least one drug for any cause [relative hazard (RH) 4.09; 95% confidence interval (CI) 2.89-5.80], for toxicity (RH 2.23; 95% CI 1.05-4.73) for intolerance (RH 5.17; 95% CI 2.66-10.07) and for proactive switch (RH 10.96; 95% CI 3.17-37.87) than those starting RPV. In our nonrandomized comparison, RPV was better tolerated, less toxic and showed longer durability than EFV, without a significant difference in rates of discontinuation because of failures.


Effects of oral L-carnitine administration in narcolepsy patients: a randomized, double-blind, cross-over and placebo-controlled trial.
Narcolepsy is a sleep disorder characterized by excessive daytime sleepiness, cataplexy, and rapid eye movement (REM) sleep abnormalities. A genome-wide association study (GWAS) identified a novel narcolepsy-related single nucleotide polymorphism (SNP), which is located adjacent to the carnitine palmitoyltransferase 1B (CPT1B) gene encoding an enzyme involved in β-oxidation of long-chain fatty acids. The mRNA expression levels of CPT1B were associated with this SNP. In addition, we recently reported that acylcarnitine levels were abnormally low in narcolepsy patients. To assess the efficacy of oral L-carnitine for the treatment of narcolepsy, we performed a clinical trial administering L-carnitine (510 mg/day) to patients with the disease. The study design was a randomized, double-blind, cross-over and placebo-controlled trial. Thirty narcolepsy patients were enrolled in our study. Two patients were withdrawn and 28 patients were included in the statistical analysis (15 males and 13 females, all with HLA-DQB1*06:02). L-carnitine treatment significantly improved the total time for dozing off during the daytime, calculated from the sleep logs, compared with that of placebo-treated periods. L-carnitine efficiently increased serum acylcarnitine levels, and reduced serum triglycerides concentration. Differences in the Japanese version of the Epworth Sleepiness Scale (ESS) and the Medical Outcomes Study 36-Item Short-Form Health Survey (SF-36) vitality and mental health subscales did not reach statistical significance between L-carnitine and placebo. This study suggests that oral L-carnitine can be effective in reducing excessive daytime sleepiness in narcolepsy patients. University hospital Medical Information Network (UMIN) UMIN000003760.


Effects of the olfactory environment and nutrition on the ability of male Mediterranean fruit flies to endure starvation.
The Mediterranean fruit fly, Ceratitis capitata (Wiedemann) (Diptera: Tephritidae), is targeted for control using the sterile insect technique (SIT). For this technique to succeed, released males must be able to compete with wild males for copulations. Male success is mediated by survival in the field often in adverse conditions. Manipulation of the postteneral environment experienced by sterile males before release has been shown to affect male sexual success and survival. The objectives of this study were to determine how various diets, combined with exposure to volatiles containing alpha-copaene, affect the ability of male Mediterranean fruit flies (from a wild and two unisexual strains) to withstand starvation. Accordingly, we maintained males on one of eight regimes combing a diet of either sugar, sugar and protein, a protein pulse or apricot, with or without the aroma of the sexual stimulant alpha-copaene. The apricot diet was associated with the lowest ability to resist starvation. The sugar-only diet was associated with the highest ability to resist starvation by sterile males. Exposure to alpha-copaene, in combination with the apricot diet, had a significant negative effect on the ability of males (from all strains) to resist starvation relative to other regimes examined. We conclude that the holding regimes that elicit the best sexual performance from males paradoxically also hasten their demise, probably by initiating an irreversible metabolic cascade. The search for the optimal prerelease regime continues.


[Dynamics of agglutination in birds artificially infected with Salmonella gallinarum-pullorum and Salmonella typhimurium and treated with sulfaguanidine and furazolidone].
Canadian Leghorn chickens were used to study the effect of sulfaguanidine and furazolidon on the dynamics of blood agglutinin formation. The birds were artificially infected with Salmonella gallinarum-pullorum and Salmonella typhimurium. At various intervals following infection they were treated with sulfaguanidine 1% tablets and 0.04% furazolidon. The level of agglutinins was determined by the methods of Huddleson (whole blood agglutination reaction), the fast serum agglutination, the method after Wright, and the indirect hemagglutination reaction. It was found that the agglutinin level in birds treated in the course of ten days with the chemotherapeutics mentioned prior to their infection did not change. The use of these chemotherapeutics parallel to the infection of the test birds and ten days later inhibited agglutinin formation. This was more pronouncedly expressed in birds treated with furazolidon. The delayed use of these therapeutic means did not inhibit substantially the level of blood agglutinins.


Electroencephalogram beta power assay: a promising diagnosis tool of cognitive impairment in early time after cerebral hemorrhage.
Cerebral hemorrhage (CH) could affect the cerebral function on specific cognitive abilities and lead to the cognitive decline or cognitive dysfunction. Electroencephalogram (EEG) is a relatively cheap and easy usable tool, which could reflect the cerebral function of the patients. A total of 170 patients (patients with and without cognitive impairment) with CH and 120 normal healthy controls were recruited from September 2008 to June 2012 at the Department of Neurology. EEG studies were carried out to analyze the cerebral function in all the subjects. Correlation, clustering and concordance analysis were performed to analyze the relationship between EEG power and Montreal cognitive assessment (MoCA) scores. The effects of EEG analysis were assessed to diagnosis the cognitive impairment. The results were showed that patients with cognitive impairment had a significantly decreased EEG beta power (0.771 ± 0.149 μV 2 ) compared with the normal cognitive function (1.654 ± 0.186 μV 2 , P < 0.01) or normal healthy controls (1.703 ± 0.216 μV 2 , P < 0.01). Significantly positive correlation (r = 0.90174, P < 0.001) was discovered between relative beta power and hemorrhage type, while significantly negative correlations between the relative beta power and hemorrhage size and amount were also observed (r =-0.81235 and r =-0.90136, respectively, all P < 0.001). There was a better concordance between K-means clustering algorithm calculating of the relative beta power and MoCA scores (κ =0.913, P < 0.001). The cognitive impairment post hemorrhage was positively correlated to hemorrhage type and negatively correlated with hemorrhage size and amount. The analysis method of EEG beta power abnormality holds a promise to assess the cognitive impairment post CH.


Violation of the constant genetic effect assumption can result in biased estimates for non-linear Mendelian randomization.
Non-linear Mendelian randomization is an extension of conventional Mendelian randomization that performs separate instrumental variable analyses in strata of the study population with different average levels of the exposure. The approach estimates a localized average causal effect function, representing the average causal effect of the exposure on the outcome at different levels of the exposure. The commonly-used residual method for dividing the population into strata works under the assumption that the effect of the genetic instrument on the exposure is linear and constant in the study population. However, this assumption may not hold in practice. We use the recently developed doubly-ranked method to re-analyse various datasets previously analysed using the residual method. In particular, we consider a genetic score for 25-hydroxyvitamin D [25(OH)D] used in a recent non-linear Mendelian randomization analysis to assess the potential effect of vitamin D supplementation on all-cause mortality. The effect of the genetic score on 25(OH)D concentrations varies strongly, with a five-fold difference in the estimated genetic association with the exposure in the lowest and highest decile groups. Evidence for a protective causal effect of vitamin D supplementation on all-cause mortality in low vitamin D individuals is evident for the residual method, but not for the doubly-ranked method. We show that the constant genetic effect assumption is more reasonable for some exposures, and less reasonable for others. If the doubly-ranked method indicates that this assumption is violated, then estimates from both the residual and doubly-ranked methods can be biased, although bias was smaller on average in the doubly-ranked method. Analysts wanting to perform non-linear Mendelian randomization should compare results from both the residual and doubly-ranked methods, as well as considering transforming the exposure for the residual method to reduce heterogeneity in the genetic effect on the exposure.


Black Garlic and Its Bioactive Compounds on Human Health Diseases: A Review.
Black garlic (BG) is a form of aged garlic obtained from raw garlic (Allium sativum) via Millard reaction under high temperature (60-90 °C) and humidity (70-90%) for a period of time. Several studies reported higher contents of water-soluble antioxidants compounds (S-allyl cysteine, S-allyl-mercapto cysteine), 5-hydroxymethylfurfural, organosulfur compounds, polyphenol, volatile compounds, and products of other Millard reactions compared to fresh garlic after the thermal processing. Recent studies have demonstrated that BG and its bioactive compounds possess a wide range of biological activities and pharmacological properties that preserve and show better efficacy in preventing different types of diseases. Most of these benefits can be attributed to its anti-oxidation, anti-inflammation, anti-obesity, hepatoprotection, hypolipidemia, anti-cancer, anti-allergy, immunomodulation, nephroprotection, cardiovascular protection, and neuroprotection. Substantial studies have been conducted on BG and its components against different common human diseases in the last few decades. Still, a lot of research is ongoing to find out the therapeutic effects of BG. Thus, in this review, we summarized the pre-clinical and clinical studies of BG and its bioactive compounds on human health along with diverse bioactivity, a related mode of action, and also future challenges.


Bladder distention and pyelectasis in the male fetus: causes, comparisons, and contrasts.
The objective of this paper was to determine if prenatal sonographic findings can accurately differentiate between the causes of bladder distention and pyelectasis in the male fetus. Twenty-one cases were evaluated for the presence of oligohydramnios, posterior urethral dilation, bladder wall thickening, urachal patency, cortical thinning, cortical cysts, and increased renal echogenicity. Postnatal diagnosis included posterior urethral valves (10 cases), prune belly syndrome (four cases), vesicoureteral reflux (four cases), left ureterovesical junction obstruction (one case), and nonrefluxing, nonobstructive megacystis-megaureter (two cases). Oligohydramnios was present in eight of 10 cases of posterior urethral valves and in one of four cases of prune belly syndrome. A dilated posterior urethra was noted in seven of 10 cases of posterior urethral valves and transiently in two of four cases of prune belly syndrome. Bladder wall thickening developed in all cases of posterior urethral valves and was noted in two of four patients with prune belly syndrome. A patent urachus likewise was identified in two of four cases of prune belly syndrome. The presence of oligohydramnios, progressive bladder wall thickening, and dilated posterior urethra was most suggestive of posterior urethral valves, whereas the presence of a patent urachus was most suggestive of prune belly syndrome. The presence of pyelectasis and megacystis without additional amniotic fluid, bladder, urethral, or renal abnormalities was most suggestive of vesicoureteral reflux, ureterovesical junction obstruction, or nonrefluxing, nonobstructive megacystis-megaureter. Owing to the overlap and evolution of these findings, close follow-up evaluation is recommended.


[Primary cholangiocarcinoma associated with Caroli disease].
A 68 years old male presented with right hypochondrium abdominal pain and jaundice with no other clinical finding. CAT Scan and Ultrasonography showed right lobe bile duct dilatation. Magnetic Resonance Cholangiopancreatography gave an outstanding vision of a restricted right lobe bile duct dilatation associated to choledocholithiasis. A right hepatectomy and bile duct exploration were performed. The histopathological study disclosed a Caroli disease associated to a primary cholangiocarcinoma. Caroli disease is a congenital disorder characterized by intrahepatic cystic bile duct dilatation with a high risk association with cholangiocarcinoma.


Effect of Body Composition Methodology on Heritability Estimation of Body Fatness.
Heritability estimates of human body fatness vary widely and the contribution of body composition methodology to this variability is unknown. The effect of body composition methodology on estimations of genetic and environmental contributions to body fatness variation was examined in 78 adult male and female monozygotic twin pairs reared apart or together. Body composition was assessed by six methods - body mass index (BMI), dual energy x-ray absorptiometry (DXA), underwater weighing (UWW), total body water (TBW), bioelectric impedance (BIA), and skinfold thickness. Body fatness was expressed as percent body fat, fat mass, and fat mass/height2 to assess the effect of body fatness expression on heritability estimates. Model-fitting multivariate analyses were used to assess the genetic and environmental components of variance. Mean BMI was 24.5 kg/m2 (range of 17.8-43.4 kg/m2). There was a significant effect of body composition methodology (p<0.001) on heritability estimates, with UWW giving the highest estimate (69%) and BIA giving the lowest estimate (47%) for fat mass/height2. Expression of body fatness as percent body fat resulted in significantly higher heritability estimates (on average 10.3% higher) compared to expression as fat mass/height2 (p=0.015). DXA and TBW methods expressing body fatness as fat mass/height2 gave the least biased heritability assessments, based on the small contribution of specific genetic factors to their genetic variance. A model combining DXA and TBW methods resulted in a relatively low FM/ht2 heritability estimate of 60%, and significant contributions of common and unique environmental factors (22% and 18%, respectively). The body fatness heritability estimate of 60% indicates a smaller contribution of genetic variance to total variance than many previous studies using less powerful research designs have indicated. The results also highlight the importance of environmental factors and possibly genotype by environmental interactions in the etiology of weight gain and the obesity epidemic.


[Febrile convulsions, Treatment and prognosis].
Epidemiological data indicate that the long-term prognosis in the vast majority of children with febrile seizures is good. Three main problems are important for the treatment: febrile seizures are extremely upsetting for the parents, the recurrence rate is 30-40% and the febrile status occurs unpredictably and is potentially damaging to the CNS. There is universal agreement that daily prophylaxis with valproate, primidone, or phenobarbital should only be used in highly selected cases, if at all. The effectiveness of phenytoin and carbamazepine has not been documented. Antipyretic treatment does not reduce the recurrence rate. Intermittent diazepam prophylaxis at times of fever may or may not reduce the recurrence rate significantly, but there is no data to suggest that it improves the long-term outcome, as compared with short-term seizure control, in terms of IQ, cognition, academic progress, motor control, and subsequent epilepsy. Acute anticonvulsive treatment with rectal diazepam in solution or other benzodiazepines is effective in aborting recurrent seizures with almost the effectiveness of i.v. treatment and is safe, simple, and easy to use for the parents. The long-term prognosis is probably uninfluenced by the type of treatment given in early childhood. It has not been established that acute anticonvulsive treatment with benzodiazepine is better than placebo.


Conceptualizing the commercial determinants of dietary behaviors associated with obesity: A systematic review using principles from critical interpretative synthesis.
Unhealthy diet is an important preventable risk factor for overweight and obesity. Identifying the key drivers of an unhealthy diet is an important public health aim. "Big Food" has been identified as an influential factor shaping dietary behavior and obesity, and their practices have broadly been labeled as the "commercial determinants of obesity," but there is a lack of definitions and conceptualizations for these terms. This review aimed to synthesize literature on the commercial determinants of dietary behavior associated with obesity. It presents the development of an integrative definition and a conceptual framework involving potential influences on dietary behavior, and it examines the prevalence of certain narratives within papers that focus on children and adolescents. Four electronic databases (Ovid MEDLINE, PubMed, Web of Science, and Scopus) were searched up to December 2020. Eighty-one articles met the inclusion criteria: they were published in a peer-reviewed academic journal, described a practice from the food/beverage industry in relation to dietary behavior or obesity. Data were integrated using critical interpretative synthesis. The commercial determinants of dietary behavior are conceptualized in terms of three corporate spheres of action-political and legal; production, processing and design; and marketing and preference shaping-which enable powerful food industry to successfully pursue their business, market, and political objectives. The most frequently reported sphere of action targeting children and adolescents was marketing and preference shaping. In the included literature, the commercial determinants of dietary behavior associated with obesity have been conceptualized as being part of a complex system where corporate practices are enabled by power structures. The proposed framework can facilitate a structured identification and systematic study of the impact of specific aspects of food industry's strategies and increase opportunities for primary prevention by anticipating industry responses and by discouraging corporate practices that harm health.


Fabrication of multi-functional molecular tunnelling junctions by click chemistry.
Continuous advancement in molecular electronics demands increasing functionality and diversity of integrated molecular junctions; however, single-functional molecular junctions fail to meet these requirements. In this article, we propose the use of a widely applicable and efficient click reaction on the surface to modify self-assembled monolayers (SAMs) to achieve multifunctional molecular tunnelling junctions, current rectification and memristance, on a single chip. This approach has allowed us to meet the growing demand for versatility and functionality in molecular electronic devices.


Saccadic head rotations during walking in the stalk-eyed fly (Cyrtodiopsis dalmanni).
In stalk-eyed flies (Diopsidae), the eyes are positioned at the end of rigid peduncles protruding laterally from the head. Sexual selection for eye span in male Cyrtodiopsis dalmanni results in eye span that exceeds body length and exceeds the eye span of females. We studied whether the twofold higher moment of inertia (MOI) of the male head results in a reduced head rotation velocity during turning. We analysed films of flies performing walking turns and compared the head kinematics between the sexes. The significance of head rotation to turning was evaluated from the turning kinematics of flies with immobilized (glued) heads. Male and female C. dalmanni rotated their heads relative to the surrounding environment 1.55-fold (male) and 1.65-fold (female) faster than the angular velocity of the body by performing rapid head saccades. During the larger turns, flies with immobilized heads were unable to reorient gaze as fast as the control flies. Despite the larger MOI of the head, male C. dalmanni match the head saccade of females suggesting that eye span elongation is coupled by an adaptation of the neck apparatus to rotate the wider head.


Linking family economic pressure and supportive parenting to adolescent health behaviors: two developmental pathways leading to health promoting and health risk behaviors.
Adolescent health behaviors, especially health risk behaviors, have previously been linked to distal (i.e., family economic pressure) and proximal (i.e., parental support) contributors. However, few studies have examined both types of contributors along with considering health promoting and health risk behaviors separately. The present study investigated the influences of family economic hardship, supportive parenting as conceptualized by self-determination theory, and individual psychosocial and behavioral characteristics (i.e., mastery and delinquency, respectively) on adolescents' health promoting and health risk behaviors. We used structural equation modeling to analyze longitudinal data from a sample of Caucasian adolescent children and their mothers and fathers (N = 407, 54 % female) to examine direct and indirect effects, as well as gender symmetry and asymmetry. Findings suggest that family economic pressure contributed to adolescent mastery and delinquency through supportive parenting. Further, supportive parenting indirectly affected adolescent health risk behaviors only through delinquency, whereas supportive parenting indirectly influenced health promoting behaviors only through mastery, suggesting different developmental pathways for adolescent health risk and health promoting behaviors. Testing for gender symmetry of the full model showed that maternal and paternal parenting contributed to females' health risk behaviors directly, while maternal and paternal parenting contributed to males' health risk behaviors through delinquency. Gender symmetry was largely unsupported. The study highlights key direct and indirect pathways to adolescent health risk and health promoting behaviors within a family stress model and self-determination theory framework, and also highlights important gender differences in these developmental pathways.


Age-related Notch-4 quiescence is associated with altered wall remodeling during vein graft adaptation.
The link of aging to specific mechanisms of vascular biology is not well understood. We have previously shown that aging is associated with increased vein graft wall thickness and that this process involves the VEGF-Delta/Notch-ephrin/Eph cascade. Therefore, we examined whether Dll-4 or Notch-4 are differentially expressed, according to age, during vein graft adaptation. Vein grafts were performed in 6-mo and 24-mo Fischer 344 rats. Gene expression was analyzed by quantitative real-time PCR, and the distribution of Dll-4 and Notch-4 was observed by immunofluorescence. The expression of Dll-4 and Notch-4 was reduced in vein grafts performed in aged rats compared with the expression in young adult rats. Both Dll-4 and Notch-4 were distributed in vein graft endothelium as well as the outer adventitia, with reduced amounts in the outer adventitia of aged vein grafts. Aged veins had reduced eNOS membrane targeting and colocalization with caveolin-1 as well as reduced eNOS protein expression in comparison to young adult veins. In an exchange model between young and aged animals, heterogeneous vein grafts (Yo(Ag) and Ag(Yo)) showed significantly thicker neointima compared with young (Yo(Yo)) controls, and had Notch-4-positive cells, but not Dll-4-positive cells, diminished in the adventitia. Vein grafts that were air-denuded of endothelium did not show any adaptation to the arterial environment and also lacked both Dll-4 and Notch-4 expression at 3 wk. During vein graft adaptation to the arterial environment, both Dll-4 and Notch-4 expression are down-regulated in an aged, but not a young, background. Loss of Notch-4 is associated with loss of attenuation of neointima. The delta-Notch signaling pathway may be active during vein graft adaptation.


Using natural language processing to explore heterogeneity in moral terminology in palliative care consultations.
High quality serious illness communication requires good understanding of patients' values and beliefs for their treatment at end of life. Natural Language Processing (NLP) offers a reliable and scalable method for measuring and analyzing value- and belief-related features of conversations in the natural clinical setting. We use a validated NLP corpus and a series of statistical analyses to capture and explain conversation features that characterize the complex domain of moral values and beliefs. The objective of this study was to examine the frequency, distribution and clustering of morality lexicon expressed by patients during palliative care consultation using the Moral Foundations NLP Dictionary. We used text data from 231 audio-recorded and transcribed inpatient PC consultations and data from baseline and follow-up patient questionnaires at two large academic medical centers in the United States. With these data, we identified different moral expressions in patients using text mining techniques. We used latent class analysis to explore if there were qualitatively different underlying patterns in the PC patient population. We used Poisson regressions to analyze if individual patient characteristics, EOL preferences, religion and spiritual beliefs were associated with use of moral terminology. We found two latent classes: a class in which patients did not use many expressions of morality in their PC consultations and one in which patients did. Age, race (white), education, spiritual needs, and whether a patient was affiliated with Christianity or another religion were all associated with membership of the first class. Gender, financial security and preference for longevity-focused over comfort focused treatment near EOL did not affect class membership. This study is among the first to use text data from a real-world situation to extract information regarding individual foundations of morality. It is the first to test empirically if individual moral expressions are associated with individual characteristics, attitudes and emotions.


Early effects of eccentric contractions on muscle glucose uptake.
Muscle-damaging eccentric exercise impairs muscle glucose uptake several hours to days after exercise. Little, however, is known about the acute effects of eccentric exercise on contraction- and insulin-induced glucose uptake. This study compares glucose uptake rates in the first hours following eccentric, concentric, and isometric contractions with and without insulin present. Isolated rat extensor digitorum longus muscles were exposed to either an eccentric, concentric, or isometric contraction protocol, and muscle contractions were induced by electric stimulation that was identical between contraction protocols. In eccentric and concentric modes, length changes of 0.6 or 1.2 mm were used during contractions. Both contraction- and insulin-induced glucose uptake were assessed immediately and 2 h after contractions. Glucose uptake increased significantly following all modes of contraction and was higher after eccentric contractions with a stretch of 1.2 mm compared with the remaining contraction groups when assessed immediately after contractions [eccentric (1.2 mm) > eccentric (0.6 mm), concentric (1.2 mm), concentric (0.6 mm), isometric > rest; P < 0.05]. After 2 h, contraction-induced glucose uptake was still higher than noncontracting levels, but with no difference between contraction modes. The presence of insulin increased glucose uptake markedly, but this response was blunted by, respectively, 39-51% and 29-36% ( P < 0.05) immediately and 2 h after eccentric contractions stretched 1.2 mm compared with concentric and isometric contractions. The contrasting early effects of eccentric contractions on contraction- and insulin-induced glucose uptake suggest that glucose uptake is impaired acutely following eccentric exercise because of reduced insulin responsiveness. NEW & NOTEWORTHY This study shows that, in isolated rat muscle, muscle-damaging eccentric contractions result in a transient increase in contraction-induced glucose uptake compared with isometric and concentric contractions induced by identical muscle activation protocols. Furthermore, our results demonstrate that, in contrast, the insulin-stimulated glucose uptake is impaired immediately following muscle-damaging eccentric contractions.


Measures of Human Mobility Using Mobile Phone Records Enhanced with GIS Data.
In the past decade, large scale mobile phone data have become available for the study of human movement patterns. These data hold an immense promise for understanding human behavior on a vast scale, and with a precision and accuracy never before possible with censuses, surveys or other existing data collection techniques. There is already a significant body of literature that has made key inroads into understanding human mobility using this exciting new data source, and there have been several different measures of mobility used. However, existing mobile phone based mobility measures are inconsistent, inaccurate, and confounded with social characteristics of local context. New measures would best be developed immediately as they will influence future studies of mobility using mobile phone data. In this article, we do exactly this. We discuss problems with existing mobile phone based measures of mobility and describe new methods for measuring mobility that address these concerns. Our measures of mobility, which incorporate both mobile phone records and detailed GIS data, are designed to address the spatial nature of human mobility, to remain independent of social characteristics of context, and to be comparable across geographic regions and time. We also contribute a discussion of the variety of uses for these new measures in developing a better understanding of how human mobility influences micro-level human behaviors and well-being, and macro-level social organization and change.