Accounting for psychotropic medication changes in prisons: patient and doctor perspectives.
Psychotropic medicines are widely used to treat mental illness; however, people entering prison commonly report that prescribed psychotropic medicines are changed or withdrawn, adding to their distress in difficult times. Drawing on three extracts from a larger qualitative dataset in which patients and doctors were interviewed about psychotropic medication use in English prisons, we combined discursive psychological and Foucauldian discourse analysis techniques to examine how individuals accounted for medication changes. Patients used four discursive strategies to organize descriptions of medication changes: they established entitlement to psychotropic medication, questioned the clinical judgment of prison doctors; highlighted communication problems; and attributed negative health outcomes to medication regime changes. In contrast, we examined an effective defense by a general practitioner, which showed how clinical needs were prioritized over previously held prescriptions when making prescribing decisions. Wider implications for continuity and equivalence of care between prisons and the wider community are discussed.


Review: Sex specific programming: a critical role for the renal renin-angiotensin system.
The "Developmental Origins of Health and Disease" hypothesis has caused resurgence of interest in understanding the factors regulating fetal development. A multitude of prenatal perturbations may contribute to the onset of diseases in adulthood including cardiovascular and renal diseases. Using animal models such as maternal glucocorticoid exposure, maternal calorie or protein restriction and uteroplacental insufficiency, studies have identified alterations in kidney development as being a common feature. The formation of a low nephron endowment may result in impaired renal function and in turn may contribute to disease. An interesting feature in many animal models of developmental programming is the disparity between males and females in the timing of onset and severity of disease outcomes. The same prenatal insult does not always affect males and females in the same way or to the same degree. Recently, our studies have focused on changes induced in the kidney of both the fetus and the offspring, following a perturbation during pregnancy. We have shown that changes in the renin-angiotensin system (RAS) occur in the kidney. The changes are often sex specific which may in part explain the observed sex differences in disease outcomes and severity. This review explores the evidence suggesting a critical role for the RAS in sex specific developmental programming of disease with particular reference to the immediate and long term changes in the local RAS within the kidney.


The biomechanical functions of the iliolumbar ligament in maintaining stability of the lumbosacral junction.
The iliolumbar ligament is one of the three lumbopelvic ligaments. Recent study has shown that the ligament is not present at birth and is formed from metaplasia of the quadratus lumborum muscle at the end of the first decade. To study the biomechanical functions of this ligament, an apparatus was developed using linear variable differential transformers. Twenty fresh cadaveric specimens of the lumbosacral pelvis were tested. The flexibility of the intact lumbar segment was studied before and after the ligaments were divided. Flexion of L5 on S1 was mainly controlled by the posterior band and lateral bending by the anterior band of the ligament. When the L5-S1 disc was degenerated, total division of the ligaments reduced extension during loading. Its effect on torsion was not evident from this study.


Stakeholder Education for Community-Wide Health Initiatives: A Focus on Teen Pregnancy Prevention.
Teen pregnancies and births continue to decline due in part to implementation of evidence-based interventions and clinical strategies. While local stakeholder education is also thought to be critical to this success, little is known about what types of strategies work best to engage stakeholders. With the goal of identifying and describing evidence-based or best practice strategies for stakeholder education in community-based public health initiatives, we conducted a systematic literature review of strategies used for effective stakeholder education. Over 400 articles were initially retrieved; 59 articles met inclusion criteria. Strategies were grouped into four steps that communities can use to support stakeholder education efforts: identify stakeholder needs and resources, develop a plan, develop tailored and compelling messaging, and use implementation strategies. These strategies lay a framework for high-quality stakeholder education. In future research, it is important to prioritize evaluating specific activities taken to raise awareness, educate, and engage a community in community-wide public health efforts.


Wii Fit™ exercise therapy for the rehabilitation of ankle sprains: Its effect compared with physical therapy or no functional exercises at all.
Lateral ankle sprains represent the most common sports-related injuries. The Nintendo Wii Fit™ could be useful in the treatment of ankle sprains. The aim of this study was to compare the effectiveness of exercise training using the Wii Fit™ in ankle sprain patients: (a) with physical therapy; and (b) a control group not receiving any treatment. Ninety lateral ankle sprain patients were randomized to a Wii Fit™, physical therapy, or control group. We assessed the following outcome measures before, and 6 weeks after starting the allocated treatment: Foot and Ankle Ability Measure, pain during rest and walking, delay before return to sport, patient satisfaction, and effectiveness of the allocated treatment. Six weeks after the baseline measures, foot and ankle ability scores had improved in all groups, and pain had decreased during walking (P < 0.050). No between-group differences were detected between Wii Fit™ treatment, and both other groups (P > 0.050). In conclusion, the Wii Fit™ could be used as an exercise therapy to treat ankle sprain patients. However, Wii Fit™ was not more effective than only physical therapy, or no exercise therapy at all. Patients who did not receive treatment showed similar results as people who got any kind of exercise therapy.


Toxic effects of methylated benzo[a]pyrenes in rat liver stem-like cells.
The methylated benzo[a]pyrenes (MeBaPs) are present at significant levels in the environment, especially in the sediments contaminated by petrogenic PAHs. However, the existing data on their toxic effects in vitro and/or in vivo are still largely incomplete. Transcription factor AhR plays a key role in the metabolic activation of PAHs to genotoxic metabolites, but the AhR activation may also contribute to the tumor promoting effects of PAHs. In this study, the AhR-mediated activity of five selected MeBaP isomers was estimated in the DR-CALUX reporter gene assay performed in rat hepatoma cells. Detection of other effects, including induction of CYP1A1, CYP1B1, and AKR1C9 mRNAs, DNA adduct formation, production of reactive oxygen species, oxidation of deoxyguanosine, and cell cycle modulation and apoptosis, was performed in the rat liver epithelial WB-F344 cell line, a model of liver progenitor cells. We identified 1-MeBaP as the most potent inducer of AhR activation, stable DNA adduct formation, checkpoint kinase 1 and p53 phosphorylation, and apoptosis. These effects suggest that 1-MeBaP is a potent genotoxin eliciting a typical sequence of events ascribed to carcinogenic PAHs: induction of CYP1 enzymes, formation of high levels of DNA adducts, activation of DNA damage responses (including p53 phosphorylation), and cell death. In contrast, 10-MeBaP, representing BaP isomers substituted with the methyl group in the angular ring, elicited only low levels DNA adduct formation and apoptosis. Other MeBaPs under study also elicited strong apoptotic responses associated with DNA adduct formation as the prevalent mode of toxic action of these compounds in liver cells. MeBaPs induced a weak production of ROS, which did not lead to significant oxidative DNA damage. Importantly, 1-MeBaP and 3-MeBaP were found to be potent AhR agonists, one order of magnitude more potent than BaP, thus suggesting that the AhR-dependent modulations of gene expression, deregulation of cell survival mechanisms, and further nongenotoxic effects associated with AhR activation may further contribute to their tumor promotion and carcinogenicity.


CD4+CD25+ T regulatory cells control anti-islet CD8+ T cells through TGF-beta-TGF-beta receptor interactions in type 1 diabetes.
Pancreatic lymph node-derived CD4+CD25+ T regulatory (Treg) cells inhibit in situ differentiation of islet-reactive CD8+ T cells into cytotoxic T lymphocytes, thereby preventing diabetes progression. The mechanism by which these Treg cells suppress anti-islet CD8+ T cells is unknown. Here, we show by using a CD8+ T cell-mediated model of type 1 diabetes that transforming growth factor (TGF)-beta-TGF-beta receptor signals are critical for CD4+CD25+ Treg cell regulation of autoreactive islet-specific cytotoxic T lymphocytes. Transgenic expression of tumor necrosis factor alpha from birth to 25 days of age in the islets of B6 mice that constitutively express CD80 on their beta cells results in accumulation of CD4+CD25+TGF-beta+ cells exclusively in the islets and pancreatic lymph nodes, which delays diabetes progression. In contrast, expression of tumor necrosis factor alpha until 28 days of age prevents islet accumulation of CD4+CD25+TGF-beta+ Treg cells, resulting in acceleration to diabetes. Furthermore, adoptive transfer experiments demonstrated that CD4+CD25+ Treg cells could not control naïve or activated islet-reactive CD8+ T cells bearing a dominant negative TGF-beta receptor type II. Our data demonstrate that, in vivo, TGF-beta signaling in CD8+ T cells is critical for CD4+CD25+ Treg cell suppression of islet-reactive CD8+ T cells in type 1 diabetes.


A robust Bayesian meta-analytic approach to incorporate animal data into phase I oncology trials.
Before a first-in-man trial is conducted, preclinical studies are performed in animals to help characterise the safety profile of the new medicine. We propose a robust Bayesian hierarchical model to synthesise animal and human toxicity data, using scaling factors to translate doses administered to different animal species onto an equivalent human scale. After scaling doses, the parameters of dose-toxicity models intrinsic to different animal species can be interpreted on a common scale. A prior distribution is specified for each translation factor to capture uncertainty about differences between toxicity of the drug in animals and humans. Information from animals can then be leveraged to learn about the relationship between dose and risk of toxicity in a new phase I trial in humans. The model allows human dose-toxicity parameters to be exchangeable with the study-specific parameters of animal species studied so far or non-exchangeable with any of them. This leads to robust inferences, enabling the model to give greatest weight to the animal data with parameters most consistent with human parameters or discount all animal data in the case of non-exchangeability. The proposed model is illustrated using a case study and simulations. Numerical results suggest that our proposal improves the precision of estimates of the toxicity rates when animal and human data are consistent, while it discounts animal data in cases of inconsistency.


Granulocyte enriched buffy coat transfusions in neutropenic patients.
Twenty four courses of granulocyte enriched buffy coat transfusions were administered to 22 different infected neutropenic patients. Those patients who received an average of greater than or equal to 13 units per transfusion, which represented a mean of 1.02 X 10(10) granulocytes, had a survival rate of only 30% which was not significantly different from the 28.5% found among patients who received an average of less than or equal to 12 units per transfusion, which represented a mean of .63 X 10(10) granulocytes. In addition, no significant difference in survival rate was found between patients who received a course of greater than or equal to four transfusions and those who received a course of less than or equal to three transfusions. Finally, no significant difference in survival rate was found between patients with acute leukemia and those with other disorders or between patients with positive cultures and those whose cultures were negative. Given the poor clinical results associated with buffy coat transfusions, it is concluded that every effort should be made to recruit single leukapheresis donors for the support of infected neutropenic patients, rather than use granulocyte enriched buffy coats as they are presently produced.


Evaluating the fitness consequences of plasticity in tolerance to pesticides.
In a rapidly changing world, phenotypic plasticity may be a critical mechanism allowing populations to rapidly acclimate when faced with novel anthropogenic stressors. Theory predicts that if exposure to anthropogenic stress is heterogeneous, plasticity should be maintained as it allows organisms to avoid unnecessary expression of costly traits (i.e., phenotypic costs) when stressors are absent. Conversely, if exposure to stressors becomes constant, costs or limits of plasticity may lead to evolutionary trait canalization (i.e., genetic assimilation). While these concepts are well-established in theory, few studies have examined whether these factors explain patterns of plasticity in natural populations facing anthropogenic stress. Using wild populations of wood frogs that vary in plasticity in tolerance to pesticides, the goal of this study was to evaluate the environmental conditions under which plasticity is expected to be advantageous or detrimental. We found that when pesticides were absent, more plastic populations exhibited lower pesticide tolerance and were more fit than less plastic populations, likely avoiding the cost of expressing high tolerance when it was not necessary. Contrary to our predictions, when pesticides were present, more plastic populations were as fit as less plastic populations, showing no signs of costs or limits of plasticity. Amidst unprecedented global change, understanding the factors shaping the evolution of plasticity will become increasingly important.


Pro-inflammatory cytokine tumor necrosis factor-alpha induces bone morphogenetic protein-2 in chondrocytes via mRNA stabilization and transcriptional up-regulation.
In articular chondrocytes, the inflammatory cytokine tumor necrosis factor-alpha (TNF-alpha) induces the expression of bone morphogenetic protein-2 (BMP-2), a growth factor known to be involved in the induction of cartilage and bone. A study was performed to clarify the mechanism(s) underlying the induction of BMP-2 in chondrogenic ATDC5 cells and primary cultured adult human articular chondrocytes. In ATDC5 cells, the endogenous BMP-2 expression was consistently low throughout the process of chondrogenic differentiation, and TNF-alpha induced BMP-2 expression only after the cells acquired the chondrogenic phenotype. The results of nuclear run-off assay and cycloheximide treatment consistently indicated that ATDC5 cells acquire the capacity to synthesize BMP-2 mRNA in the nuclei during the differentiation process. In an attempt to explain the discrepancy between the active nuclear mRNA synthesis and the observed low expression level in differentiated ATDC5 cells, the stability of BMP-2 mRNA was evaluated, and the cells were found to regulate the expression of BMP-2 at the post-transcriptional level. Human chondrocytes were confirmed to have a similar post-transcriptional regulation. The result of 3'-rapid amplification of cDNA end revealed that both human and mouse BMP-2 mRNAs contain multiple pentameric AUUUA motifs in a conserved manner in the 3'-untranslated regions, and transient transfection experiments demonstrated that TNF-alpha increases the stability of BMP-2 mRNA through the pentameric motifs. Further experiments revealed that TNF-alpha modulates mRNA stability via p38 signal transduction pathway, whereas the cytokine also augmented the expression of BMP-2 through transcriptional up-regulation via the transcriptional factor NF-kappaB.


Influence of maxillary first molar rotation on the severity of dental class II malocclusion: A cross-sectional study.
The aim of the study was to evaluate and assess the influence of maxillary molar rotation on severity of dental class II malocclusion. The study comprised of 4 different groups namely, 1/4th class II malocclusion, 2/4th class II malocclusion, 3/4th class II malocclusion and full class II malocclusion involving sample size of 20,15,16 and 12. The samples were subjected to digital evaluation of maxillary 1st permanent molar rotation using 4 parameters namely angle of Friel, Ricketts E-Line, angle of Henry and Premolar angle. The results were subjected to statistical analysis using one way ANOVA wherein group IV (Full class II malocclusion) exhibited a greater rotational value. On evaluation, angle of Friel exhibited a mean of 59.6±1.61 degrees, Ricketts E-Line was found to be 12.3±1.77mm while angle of Henry showed a mean of 19±3.19 degrees and premolar angle was 12.5±5.83 degrees. On evaluating molar rotation using angle of Friel, Ricketts E-Line, angle of Henry and premolar angle, full cusp class II malocclusion presented higher degree of mesiopalatal rotation maxillary molar rotation. With increasing mesiopalatal rotation, the severity of molar relation also increased from 1/4th to full class II. Hence the maxillary molar spatial position along the long axis majorly influences the molar relation wherein a full cusp class II molar relation exhibits higher degree of molar rotation.


Use of elemental iodine for shunt infection prophylaxis.
Elemental iodine (I(2)) can kill a broad spectrum of organisms, including bacteria, fungi, and viruses. Furthermore, it is inexpensive, bacterial resistance is unknown, and allergic reactions are rare. Because of these properties, we wanted to determine the concentration of I(2) that would kill Staphylococcus epidermidis and Staphylococcus aureus without causing injury to the central nervous system, in an attempt to further reduce the rates of shunt infections. Bacterial kill studies using S. epidermidis and S. aureus were performed by using Ringer's lactate solution alone or solution containing I(2) at a concentration of 5, 10, 20, 50, 100, or 1000 parts per million (ppm), cefazolin at 1 mg/ml, or bacitracin at 100 units/ml. Twenty-one adult male Wistar rats, in seven groups, underwent a frontoparietal craniectomy. The surfaces of their brains were irrigated for 1 hour with Ringer's lactate solution alone or solution containing I(2) (at the concentrations noted above). After 72 hours of observation, the animals were killed. Their brains were then fixed in formalin, stained with hematoxylin/eosin, and examined. Even with exposure of only 15 seconds to an I(2) solution of 20 ppm, no growth was detected with an inoculum of either bacteria of 100 million. In contrast, the two antibiotics were not nearly as effective as I(2), with kill rates ranging from 19 to 93%. Examination of the rat brains demonstrated no histological changes after subarachnoid exposure to solutions containing 5, 10, 20, or 50 ppm; however, necrosis was observed with concentrations of 100 and 1000 ppm. I(2) can be added to irrigation solutions in sufficient concentrations to be bactericidal without causing any central nervous system injury.


Glycomic analysis of high density lipoprotein shows a highly sialylated particle.
Many of the functional proteins and lipids in high density lipoprotein (HDL) particles are potentially glycosylated, yet very little is known about the glycoconjugates of HDL. In this study, HDL was isolated from plasma by sequential micro-ultracentrifugation, followed by glycoprotein and glycolipid analysis. N-Glycans, glycopeptides, and gangliosides were extracted and purified followed by analysis with nano-HPLC Chip quadrupole time of flight mass spectrometry and MS/MS. HDL particles were found to be highly sialylated. Most of the N-glycans (∼90%) from HDL glycoproteins were sialylated with one or two neuraminic acids (Neu5Ac). The most abundant N-glycan was a biantennary complex type glycan with two sialic acids (Hexose5HexNAc4Neu5Ac2) and was found in multiple glycoproteins using site-specific glycosylation analysis. The observed O-glycans were all sialylated, and most contained a core 1 structure with two Neu5Acs, including those that were associated with apolipoprotein CIII (ApoC-III) and fetuin A. GM3 (monosialoganglioside, NeuAc2-3Gal1-4Glc-Cer) and GD3 (disialoganglioside, NeuAc2-8NeuAc2-3Gal1-4Glc-Cer) were the major gangliosides in HDL. A 60% GM3 and 40% GD3 distribution was observed. Both GM3 and GD3 were composed of heterogeneous ceramide lipid tails, including d18:1/16:0 and d18:1/23:0. This report describes for the first time a glycomic approach for analyzing HDL, highlighting that HDL are highly sialylated particles.


Development and refinement of pregnane X receptor (PXR) DNA binding site model using information theory: insights into PXR-mediated gene regulation.
The pregnane X receptor (PXR) acts as a receptor to induce gene expression in response to structurally diverse xenobiotics through binding as a heterodimer with the 9-cis retinoic acid receptor (RXR) to enhancers in target gene promoters. We identified and estimated the affinities of novel PXR/RXR binding sites in regulated genes and additional genomic targets of PXR with an information theory-based model of the PXR/RXR binding site. Our initial PXR/RXR model, the result of the alignment of 15 previously characterized binding sites, was used to scan the promoters of known PXR target genes. Sites from these genes, with information contents of >8 bits bound by PXR/RXR in vitro, were used to revise the information weight matrix; this procedure was repeated by screening for progressively weaker binding sites. After three iterations of refinement, the model was based on 48 validated PXR/RXR binding sites and has an average information content (Rsequence) of 14.43 +/- 3.21 bits. A scan of the human genome predicted novel PXR/RXR binding sites in the promoters of UGT1A3 (19.78 bits at -8040 and 16.37 bits at -6930) and UGT1A6 (12.74 bits at -9216), both of which were identified previously as targets for PXR. These sites were subsequently demonstrated to specifically bind PXR/RXR in competition electrophoretic mobility shift assays. A strong PXR site was also predicted upstream of the CASP10 gene (18.69 bits at -7872) and was validated by binding studies and reporter assays as a PXR responsive element. This suggests that the PXR-mediated response extends beyond genes involved in drug biotransformation and transport.


Transient global amnesia: emergency department evaluation and management [digest].
Transient global amnesia is a clinically distinct syndrome characterized by the acute inability to form new memories. It can last up to 24 hours. The diagnosis is dependent on eliminating other more serious etiologies including toxic ingestions, acute strokes, complex partial seizures, and central nervous system infections. Transient global amnesia confers no known long-term risks; however, when abnormal signs or symptoms are present, they take precedence and guide the formulation of a differential diagnosis and investigation. In witnessed transient global amnesia with classic features, a minimalist approach is reasonable, avoiding overtesting, inappropriate medication, and medical interventions in favor of observation, ensuring patient safety, and reassuring patients and their families. This review provides a detailed framework for distinguishing transient global amnesia from its dangerous mimics and managing its course in the emergency department. [Points & Pearls is a digest of Emergency Medicine Practice].


The value of taking an 'ethics history'.
To study the value of taking an ethics history as a means of assessing patients' preferences for decision making and for their relatives' involvement. Questionnaire administered by six junior doctors to 56 mentally competent patients, admitted into general and geriatric medical beds. A large district general hospital in the United Kingdom. To establish whether patients were adequately informed about their illness and whether they minded the information being communicated to their relatives. To establish their preference regarding truthful disclosure and participation in decision making with risk attached. To establish whether they wished to be involved in CPR decision making, and if not, who should make the decision. To establish whether they knew of living wills and whether they had any advance directives. Twenty-four (43%) were inadequately informed of their illness. Forty-six (82%) said they would want to know were something serious to be found. Twenty-eight (50%) wanted to make their own decision if requiring risky treatment and 11 (20%) wanted family members involved. Thirty-one (55%) wanted to make a cardiopulmonary resuscitation (CPR) decision and five of these decisions differed from those made by the doctors. Twenty-five (45%) preferred the doctors to decide. Eleven (20%) of the patients had heard of living wills but only one had executed such a will. Seven (13%) of the patients wished to provide advance directives. Three (5%) did not find the history taking helpful but none were discomforted. Taking an ethics history is a simple means of obtaining useful information about patients' preferences.


Parental hope for children with advanced cancer.
Previous work suggests that parents of children with cancer can remain hopeful despite receiving prognostic information, but we know little about what hope means to such parents, or the extent to which parents can feel hopeful even while facing the child's impending death. We audiotaped conversations between clinicians and parents of 32 children with relapsed or refractory cancer, and then interviewed parents about their hopes and expectations for their child. Parent statements about prognosis in interviews mirrored those made by clinicians during discussions about the child's diagnosis with refractory or relapsed cancer. Clinicians used language referring to hope during these conversations but did not ask parents directly about their hopes. Parents expressed a range of hopes for their children, from hopes related to cure or treatment response, to quality of life, normalcy, and love and relationships for the child. For most parents, expectations about prognosis were not aligned with their hopes for the child; for example, many parents hoped for a cure and also reported that they did not believe cure was possible. Many parents were able to acknowledge this incongruence. Parents accurately conveyed the reality of their child's serious condition in the setting of advanced cancer, and yet maintained hope. Hopes were not limited to hope for cure/treatment response. Clinicians should be encouraged to engage in direct conversations about hope with parents as a means to elicit realistic hopes that can help to focus the most meaningful plans for the child and family.


Comparison of indocyanine green-near-infrared fluorescence guided and traditional mediastinal lymphadenectomy during radical esophagectomy: A randomized controlled trial.
The extent of lymph node dissection during radical esophagectomy remains a controversial topic. Thus, this study mainly aimed to explore the location of sentinel lymph nodes in esophageal squamous cell carcinoma and the application value of the indocyanine green-near-infrared fluorescence system in lymphadenectomy. This randomized controlled clinical trial (ClinicalTrials.gov, NCT04615806) included 42 participants without neoadjuvant therapy who were lymph node negative based on positron emission tomography/computed tomography findings. Traditional esophagectomy with indocyanine green-near-infrared fluorescence imaging was performed after injecting 0.5 mL indocyanine green (1.25 mg/mL) into the esophageal submucosa in the 4 peritumoral quadrants. The primary endpoint was to determine the location of the sentinel lymph node in esophageal squamous cell carcinoma based on postoperative pathologic reports. A total of 40 patients, with 20 in each group, were included in the final analysis. In the indocyanine green group, indocyanine green-near-infrared fluorescence imaging was successful in all subjects. Seven cases (cases 2, 3, 9, 11, 17, 18, and 20) in the indocyanine green group exhibited lymph node metastases, all of which were near-infrared positive. The detection rate, positive predictive value, negative predictive value, sensitivity, and specificity were 100% (20 of 20 cases), 8.7% (13/150), 100% (265/265), 100% (13/13), and 65.9% (265/402), respectively. All near-infrared-negative lymph nodes were nonmetastatic lymph nodes. In addition, the number of mediastinal lymph nodes resected in the indocyanine green group was significantly higher than in the non-indocyanine green group. Indocyanine green-near-infrared might be an important and promising technique in predicting sentinel lymph nodes of esophageal squamous cell carcinoma and could significantly improve the detection rate of lymph nodes of esophageal squamous cell carcinoma.


Sexuality and childbirth: a qualitative analysis of women who had a waterbirth.
Waterbirth is associated with a less painful childbirth, enhanced couples' intimacy, and positive feelings toward women's bodies and sexuality. In a qualitative, descriptive case study involving 21 participants, we examined the sexual experiences-during childbirth and postpartum-of women who had a waterbirth in a hospital environment. Women discussed their sexuality in the intrapartum and postpartum period after having a waterbirth in public or private hospitals. Two main themes were developed from the data analysis: 'women's sexual pleasure during waterbirth' and 'sexuality after childbirth'. Experiences included transcendence during waterbirth, a feeling that it represented a unique experience, and couples' more positive feelings about intimacy. The shared representations of women suggest that waterbirth can be a calming, joyful event for couples. During this process, they felt that it was a loving, shared event. In addition, after childbirth women experienced positive feelings toward their bodies and sexuality (including orgasm), as well as closer intimacy with their partners.


Patterns and severity of conduction abnormalities in Guillain-Barré syndrome.
Whether the conduction abnormalities and lesions underlying them are randomly distributed throughout the peripheral nervous system (PNS) or certain regions are selectively more vulnerable to attack is an unresolved question in Guillain-Barré syndrome (GBS). To examine this question, 15 cases of GBS were comprehensively examined using electrophysiological techniques which allowed close examination, quantitation and comparison of conduction abnormalities in motor and sensory fibres of the upper limb between the spinal cord and the distal extremities of the nerve fibres. Comparison of these studies with results expected in a model where the chances of conduction failure were uniformly distributed led to the conclusion that conduction slowing and block were not uniformly distributed in most cases. Conduction block was maximal in the terminal segment distal to the wrist and to a lesser extent both conduction block and conduction slowing were disproportionately greater across the elbow and in the axillary to spinal root segments in over one half of the cases. These findings support the hypothesis that certain regions, perhaps because of relative deficiencies of the blood-nerve barrier, may be more vulnerable in GBS than other regions.


A comparison of food portion size estimation methods among 11-12 year olds: 3D food models vs an online tool using food portion photos (Intake24).
Technology has advanced bringing new cost-effective methods to measure food intake. The aim of the study was to compare food and drink portion estimates from a traditional portion estimation method using 3D food models with portion estimates using an online dietary recall tool, Intake24. 11-12 year old children were recruited from secondary schools in Newcastle upon Tyne. Each pupil completed a two-day food diary followed by an interview during which pupils estimated food portion sizes using a range of 3D food models. They also completed Intake24 for the same 2 days. Bland Altman analyses were used to compare mean intake for each method. Seventy pupils completed both portion estimation methods. There was good agreement in food weight estimations between the two methods (geometric mean ratio 1.00), with limits of agreement ranging from minus 35% to plus 53%. Intake24 provided estimates of energy intake that were 1% lower on average than estimates of energy intake using the food models. Mean intakes of all macro and micronutrients using Intake24 were within 6% of the food model estimates. The findings suggest that there was little difference in portion estimations from the two methods, allowing comparisons to be made between Intake24 data and food diary data collected from same age pupils using 3D food models in previous years.


Cognitive overcontrol as a trait marker in anorexia nervosa? Aberrant task- and response-set switching in remitted patients.
Individuals with anorexia nervosa (AN) often present inflexible behaviors and rigid thinking styles, which may contribute to disorder maintenance. Studies of set shifting have documented impairments in AN, but results have varied across samples. Moreover, the hypothesis that deficient set shifting may constitute an endophenotype rests largely on observations made with neuropsychological tests with limited ability to isolate component cognitive control processes. The current behavioral study used a task switching paradigm with a demonstrated ability to fractionate the hierarchical organization underlying task- and response-set shifting in 22 weight-recovered women with a history of AN (recAN) relative to 22 age-matched healthy controls. Whereas recAN performed generally more accurately than healthy controls, they also responded more slowly. Despite slower performance, however, recAN error rates did not exhibit the characteristic improvement in task switching on trials with a concurrent response switch-an interaction thought to index efficient action sequencing and the hierarchical control of behavior. These results were not mediated by comorbid symptoms, but no relationships with clinical measures were detected. Inefficient set shifting in AN may be related to a general tendency to sustain a high level of cognitive control (as evident here in a robust speed-accuracy trade-off), which interferes with context-sensitive regulation of processing priorities (as evident here in an atypical interaction between task and response switching). Although scarring effects cannot be excluded and the generalizability of our findings needs to be tested, the current observations in recAN provide novel evidence that altered set shifting may be a trait marker of the disorder. (PsycINFO Database Record (c) 2019 APA, all rights reserved).


Twenty-year review of revision stapedectomy.
To evaluate surgical findings and techniques, patient management techniques, and audiometric results of 522 revision stapedectomies. Retrospective chart review. Tertiary otologic referral center. A total of 522 revision stapedectomies over a 20-year period in Warren, Ohio, and Israel. The audiologic criterion for revision was an air-bone gap greater than 20 dB over the three-frequency range 0.5 to 2 kHz. Of the 522 revision cases, a total of 483 patients were operated on to improve hearing. The remainder of the patients were operated on for various other noted reasons. Closure of the air-bone gap to within 10 dB was achieved in 71% of patients (343 of 483). The mean pure-tone average improvement was 17.8 dB, with an average postoperative air-bone gap of 7.3 dB. The most common surgical findings were prosthesis malfunction at the oval window, incus, or both (58%). Since beginning the use of the Argon laser for surgical problems, the success rate has increased to 80%. A subgroup of 35 Argon laser revision stapedectomies resulted in a larger hearing gain (25.2 dB) and 91.4% closure of the air-bone gap to less than 10 dB. More than 70% of revision stapedectomy cases for hearing improvement have had successful closure of their air-bone gap. Since the introduction of the laser 5 years ago, the success rate has increased to 80%. In those specific cases where the laser was required, the success rate increased to 91.4%. Regardless of the revision technique, hearing results were the least successful when the incus could not be used for reconstruction.


Levamisole induces interleukin-18 and shifts type 1/type 2 cytokine balance.
Immune responses can be classified, according to the predominant cytokines involved, into type 1 (featuring interferon-gamma, IFN-gamma) and type 2 (featuring interleukin-4, IL-4); imbalance between type 1 and type 2 cytokine compartments has been implicated in many human diseases. Levamisole is a drug with an unknown mode of action that has been used to boost immunity in infectious diseases including leprosy, and in some cancers. To test the hypothesis that levamisole acts by inducing a shift to a type 1 immune response, we used Brown Norway (BN) rats, which are markedly biased to type 2 responses. BN rats treated with levamisole showed a dose-dependent rise in serum IFN-gamma and fall in serum immunoglobulin E (IgE) level. Detailed analysis of cytokine gene expression showed upregulation of IFN-gamma and downregulation of IL-4 messenger RNA. This coincided with marked upregulation of IL-18, a recently characterized cytokine with potent activity in stimulating IFN-gamma production. IL-12 was not induced. Further, the type 2 response induced in BN rats by mercuric chloride was markedly attenuated when rats were pretreated with levamisole: there was a 2-log reduction in maximum serum IgE level and marked attenuation of IL-4 gene upregulation. These data indicate that levamisole acts by resetting the immune balance towards a type 1 response via induction of IL-18. Our findings provide a direction for development of more specific immunomodulating therapy.


Vulnerability of global food production to extreme climatic events.
It is known that the frequency, intensity or duration of the extreme climatic events have been changing substantially. The ultimate goal of this study was to identify current vulnerabilities of global primary food production against extreme climatic events, and to discuss potential entry points for adaptation planning by means of an explorative vulnerability analysis. Outcomes of this analysis were demonstrated as a composite index where 118 country performances in maintaining safety of food production were compared and ranked against climate change. In order to better interpret the results, cluster analysis technique was used as a tool to group the countries based on their vulnerability index (VI) scores. Results suggested that one sixth of the countries analyzed were subject to high level of exposure (0.45-1), one third to high to very high level of sensitivity (0.41-1) and low to moderate level of adaptive capacity (0-0.59). Proper adaptation strategies for reducing the microbial and chemical contamination of food products, soil and waters on the field were proposed. Finally, availability of data on food safety management systems and occurrence of foodborne outbreaks with global coverage were proposed as key factors for improving the robustness of future vulnerability assessments.


Characteristics, treatment, and nursing care of patients infected by Sars-CoV-2 hospitalized in intensive care units: multicenter study of colombian hospitals.
To describe the clinical characteristics, treatment, evolution, and nursing care of adult patients with severe acute respiratory distress syndrome who were positive for SARS-CoV-2 and hospitalized in intensive care units (ICUs) during the first peak of the pandemic in Colombia, 2020. Multicenter descriptive study of four high-complexity hospitals in Colombia, which included 473 consecutive adult patients admitted to intensive care units with a confirmed diagnosis of SARS CoV-2. Sociodemographic and clinical information - comorbidities, treatment and evolution - and nursing care provided were included. Of the patients included, 43.7% died, 88.8% had pneumonia, and 60.2% developed respiratory distress syndrome. Most of those who died were men. Those who died had a median age of 68.4 years and a higher frequency of comorbidities (hypertension, cardiovascular disease, chronic obstructive pulmonary disease, and higher body mass index). They were admitted to the ICU with higher rate of dyspnea, lower oxygen saturation, and higher score of multiorgan failure. They also more often required mechanical ventilation and pronation therapy and were given more vasopressors and renal replacement therapy. People with severe acute respiratory distress syndrome due to COVID-19 who were hospitalized in the ICU had a high risk of death, especially older patients; males; those with cardiovascular, respiratory, and hypertension comorbidities; those who needed mechanical ventilation; and those with an elevated SOFA score. The nursing care of these critically ill patients focused on respiratory care and the prevention of associated complications.


Subepidermal calcified nodule.
Subepidermal calcified nodules are rarely seen and are classified under idiopathic subepidermal calcifications. They commonly affect children. It is most frequently encountered in the face, and it is less common in the extremities. Here, we present a case where the lesion was localized on the knees of a 23-year-old female patient.


Comparison of uptitration of gliclazide with the addition of rosiglitazone to gliclazide in patients with type 2 diabetes inadequately controlled on half-maximal doses of a sulphonylurea.
Patients with type 2 diabetes who are inadequately controlled on a half-maximal dose of a sulphonylurea may be managed by either increasing the dose of sulphonylurea or adding another agent. In this study, 471 patients inadequately controlled (fasting plasma glucose [FPG] >or=7.0 and <or=15.0 mmol/l) on 160 mg/day gliclazide were randomised to receive either the addition of rosiglitazone (4 mg b.i.d.) or to have their gliclazide uptitrated to a maximum of 320 mg/day during a 26-week treatment period. A reduction in HbA(1c) of 1.3% ( p=0.0001) was observed in the combination treatment group compared to the uptitrated gliclazide group after 26 weeks. The proportion of patients who achieved an HbA(1c) value <7% was also greater in this group (48% vs. 22%). FPG was reduced by 3.0 mmol/l ( p=0.0001) in the rosiglitazone plus gliclazide group compared to the uptitrated gliclazide group after 26 weeks. The improved efficacy of the combination treatment was accompanied by increased incidence of signs or symptoms suggestive of hypoglycaemia compared with uptitrating the gliclazide dose (6% vs. 2%). Only 1% of patients reported severe hypoglycaemia. The combination treatment led to increases in plasma lipoproteins, and more patients experienced oedema (11% vs. 3%). A significant increase in body weight was observed in patients receiving rosiglitazone plus gliclazide versus uptitrated gliclazide (3.4 kg; p=0.0001). The addition of rosiglitazone (4 mg b.i.d.) to gliclazide (160 mg/day) was well tolerated, and significantly more effective in improving glycaemia than uptitrating gliclazide to 320 mg/day.


Redesigning enzyme topology by directed evolution.
Genetic selection was exploited in combination with structure-based design to transform an intimately entwined, dimeric chorismate mutase into a monomeric, four-helix-bundle protein with near native activity. Successful reengineering depended on choosing a thermostable starting protein, introducing point mutations that preferentially destabilize the wild-type dimer, and using directed evolution to optimize an inserted interhelical turn. Contrary to expectations based on studies of other four-helix-bundle proteins, only a small fraction of possible turn sequences (fewer than 0.05 percent) yielded well-behaved, monomeric, and highly active enzymes. Selection for catalytic function thus provides an efficient yet stringent method for rapidly assessing correctly folded polypeptides and may prove generally useful for protein design.


Structure of the BH3 domains from the p53-inducible BH3-only proteins Noxa and Puma in complex with Mcl-1.
Pro-survival proteins in the B-cell lymphoma-2 (Bcl-2) family have a defined specificity profile for their cell death-inducing BH3-only antagonists. Solution structures of myeloid cell leukaemia-1 (Mcl-1) in complex with the BH3 domains from Noxa and Puma, two proteins regulated by the tumour suppressor p53, show that they bind as amphipathic alpha-helices in the same hydrophobic groove of Mcl-1, using conserved residues for binding. Thermodynamic parameters for the interaction of Noxa, Puma and the related BH3 domains of Bmf, Bim, Bid and Bak with Mcl-1 were determined by calorimetry. These unstructured BH3 domains bind Mcl-1 with affinities that span 3 orders of magnitude, and binding is an enthalpically driven and entropy-enthalpy-compensated process. Alanine scanning analysis of Noxa demonstrated that only a subset of residues is required for interaction with Mcl-1, and these residues are localised to a short highly conserved sequence motif that defines the BH3 domain. Chemical shift mapping of Mcl-1:BH3 complexes showed that Mcl-1 engages all BH3 ligands in a similar way and that, in addition to changes in the immediate vicinity of the binding site, small molecule-wide structural adjustments accommodate ligand binding. Our studies show that unstructured peptides, such as the BH3 domains, behave like their structured counterparts and can bind tightly and selectively in an enthalpically driven process.


Substratal idiothetic navigation of rats is impaired by removal or devaluation of extramaze and intramaze cues.
The spatial orientation of vertebrates is implemented by two complementary mechanisms: allothesis, processing the information about spatial relationships between the animal and perceptible landmarks, and idiothesis, processing the substratal and inertial information produced by the animal's active or passive movement through the environment. Both systems allow the animal to compute its position with respect to perceptible landmarks and to the already traversed portion of the path. In the present study, we examined the properties of substratal idiothesis deprived of relevant exteroceptive information. Rats searching for food pellets in an arena formed by a movable inner disk and a peripheral immobile belt were trained in darkness to avoid a 60 degrees sector; rats that entered this sector received a mild foot shock. The punished sector was defined in the substratal idiothetic frame, and the rats had to determine the location of the shock sector with the use of substratal idiothesis only, because all putative intramaze cues were made irrelevant by angular displacements of the disk relative to the belt. Striking impairment of place avoidance by this "shuffling procedure" indicates that effective substratal idiothesis must be updated by exteroceptive intramaze cues.


Modulation of Bcl-x Alternative Splicing Induces Apoptosis of Human Hepatic Stellate Cells.
Liver fibrosis is a major cause of morbidity and mortality worldwide due to chronic viral hepatitis and, more recently, from fatty liver diseases. Activation and proliferation of hepatic stellate cells (HSCs) represent a key aspect of fibrogenesis and are associated with progressive reduction of HSC apoptosis. Bcl-x, an antiapoptotic member of Bcl-2 gene family, plays a role in apoptosis regulation in mammalian cells. Through alternative splicing, the Bcl-x gene yields two major protein isoforms with opposing functions, antiapoptotic Bcl-xL and proapoptotic Bcl-xS. This study aimed to investigate the role of Bcl-x and its alternate splicing in HSC apoptosis. The results indicated that the expression of Bcl-xL was dramatically higher than Bcl-2 in activated human HSCs. The relative expression of Bcl-xL over Bcl-xS increased gradually when HSCs were activated in cell culture, which was consistent with the increase in apoptosis resistance of activated HSCs. Redirection of Bcl-x splicing by an antisense oligonucleotide from the antiapoptotic isoform to the proapoptotic isoform induced death of HSCs without other apoptosis stimuli. We conclude that Bcl-x plays a role in regulation of HSC apoptosis and modulation of Bcl-x alternative splicing may become a novel molecular therapy for liver fibrosis.


Ready: how to keep your customers coming back.
Customer service is a major, but often overlooked, issue in health care today. While other industries and organizations recognize how good customer relations can affect long-term success, many health care providers have yet to learn this valuable lesson. The Ritz-Carlton, which won the prestigious Baldridge Award for service, has a well-earned reputation for excellent customer service. Like health care providers, this hotel industry icon hires hourly workers, puts them in uniform and has them work in teams. Unlike health care, however, The Ritz-Carlton seems to be able to generate a much higher level of customer satisfaction. How? This chapter illustrates the techniques the hotel chain uses to accomplish its goal and how these important tools can apply to the health care industry.


Augmented and Virtual Reality in Anatomical Education - A Systematic Review.
Learning anatomy traditionally has depended on traditional techniques like human cadaveric dissection and the use of textbooks. As technology advances at an ever-rapid speed, there are revolutionary ways to learn anatomy. A number of technologies, techniques and methodologies are utilised in anatomical education, but ones specifically receiving a lot of interest and traction is that of augmented reality and virtual reality. Although there has been a surge in interest in the use of these technologies, the literature is sparse in terms of its evaluation as to the effectiveness of such tools. Therefore, the purpose of this study is to examine in greater detail the literature specifically to see what the best practice in this field could be. By undertaking a systematic review using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, we searched for articles in both Web of Science and PubMed. Using the terms "augmented reality and teaching anatomy" yielded 88 articles. We then used "virtual reality and teaching anatomy" which resulted in 200 articles. We examined these articles, including that on augmented reality and virtual reality used to teach anatomy to undergraduate and postgraduate students, residents, dentistry, nursing and veterinary students. Articles were excluded if they were systematic reviews, literature reviews, review articles, news articles, articles not written in English and any literature that presented how a virtual model was created without the evidence of students testing it. The inclusion and exclusion criteria for virtual reality were the same as augmented reality. In addition, we examined the articles to identify if they contained data which was quantitative, qualitative or both. The articles were further separated into those which were pro, neutral or against for the use of these digital technologies. Of the 288 articles, duplicate articles totalling 67 were removed and 134 articles were excluded according to our exclusion criteria. Of the 31 articles related to augmented reality, 30 were pro, one neutral and no articles against the use of this technology. Fifty-six articles related to virtual reality were categorised resulted in 45 pro, eight neutral and three against the use of this technology. Overall, the results indicate most articles identified related to both virtual and augmented reality were for the use of those technologies, than neutral or against. This systemic review highlights the recent advances of both augmented reality and virtual reality to implementing the technology into the anatomy course.


Phenolic profile, antioxidant capacity and anti-inflammatory activity of Anethum graveolens L. essential oil.
This study reports the chemical composition, antioxidant and anti-inflammatory properties of Anethum graveolens essential oil and its main compounds. The essential oil was obtained from the aerial parts of the plant by hydrodistillation and analysed by using GC/MS. α-Phellandrene (19.12%), limonene (26.34%), dill ether (15.23%), sabinene (11.34%), α-pinene (2%), n-tetracosane (1.54%), neophytadiene (1.43%), n-docosane (1.04), n-tricosane (1%), n-nonadecane (1%), n-eicosane (0.78%), n-heneicosane (0.67%), β-myrcene (0.23%) and α-tujene (0.21%) were found to be the major constituents of the oil. A. graveolens oil exhibit a higher activity in each antioxidant system with a special attention for β-carotene bleaching test (IC50: 15.3 μg/mL) and reducing power (EC50: 11.24 μg/mL). The TLC-bioautography screening and fractionation resulted in the separation of the main antioxidant compounds, which were identified as limonene (45%) and sabinene (32%). The essential oil and its main compounds exhibited a potent NO-scavenging effect and inhibited the expression of inducible NO synthase.


Review of Health Consequences of Electronic Cigarettes and the Outbreak of Electronic Cigarette, or Vaping, Product Use-Associated Lung Injury.
Electronic cigarettes (e-cigarettes) are battery-operated devices to insufflate nicotine or other psychoactive e-liquid aerosols. Despite initial claims of e-cigarettes as a nicotine-cessation device, aggressive marketing of e-cigarettes has led to an explosion in adolescents' and young adults' use over the last few years. Coupled with a lack of adequate investigation and regulation of e-cigarettes, the USA is facing an outbreak of e-cigarette, or vaping, product use-associated lung injury (EVALI) starting in mid-2019. While little long-term health hazard data are available, the components and constituents of e-cigarettes may adversely impact health. Propylene glycol and glycerin are humectants (water-retaining excipients) that generate pulmonary irritants and carcinogenic carbonyl compounds (e.g., formaldehyde, acetaldehyde, and acrolein) when heated in e-cigarettes. Metals contained in heating coils and cartridge casings may leach metals such as aluminum, chromium, iron, lead, manganese, nickel, and tin. Flavoring agents are considered safe for ingestion but lack safety data for inhalational exposures. Diacetyl, a common buttery flavoring agent, has known pulmonary toxicity with inhalational exposures leading to bronchiolitis obliterans. In 2019, clusters of lung injury associated with e-cigarette use were identified in Wisconsin and Illinois. Patients with EVALI present with a constellation of respiratory, gastrointestinal, and constitutional symptoms. Radiographically, patients have bilateral ground glass opacifications. As of February 18, 2020, the Centers for Disease Control has identified 2807 hospitalized patients diagnosed with either "confirmed" or "probable" EVALI in the US. Currently, vitamin E acetate (VEA) used as a diluent in tetrahydrocannabinol vape cartridges is implicated in EVALI. VEA cuts tetrahydrocannabinol oil without changing the appearance or viscosity. When inhaled, pulmonary tissue lacks the mechanism to metabolize and absorb VEA, which may lead to its accumulation. While most EVALI patients were hospitalized, treatment remains largely supportive, and use of corticosteroids has been associated with clinical improvement. The outbreak of EVALI highlights the need for regulation of e-cigarette devices and e-liquids. Clinicians need to be aware of the health hazards of e-cigarettes and be vigilant in asking about vaping.


Neonatal infection-induced memory impairment after lipopolysaccharide in adulthood is prevented via caspase-1 inhibition.
We have reported that neonatal infection leads to memory impairment after an immune challenge in adulthood. Here we explored whether events occurring as a result of early infection alter the response to a subsequent immune challenge in adult rats, which may then impair memory. In experiment 1, peripheral infection with Escherichia coli on postnatal day 4 increased cytokines and corticosterone in the periphery, and cytokine and microglial cell marker gene expression in the hippocampus of neonate pups. Next, rats treated neonatally with E. coli or PBS were injected in adulthood with lipopolysaccharide (LPS) or saline and killed 1-24 h later. Microglial cell marker mRNA was elevated in hippocampus in saline controls infected as neonates. Furthermore, LPS induced a greater increase in glial cell marker mRNA in hippocampus of neonatally infected rats, and this increase remained elevated at 24 h versus controls. After LPS, neonatally infected rats exhibited faster increases in interleukin-1beta (IL-1beta) within the hippocampus and cortex and a prolonged response within the cortex. There were no group differences in peripheral cytokines or corticosterone. In experiment 2, rats treated neonatally with E. coli or PBS received as adults either saline or a centrally administered caspase-1 inhibitor, which specifically prevents the synthesis of IL-1beta, 1 h before a learning event and subsequent LPS challenge. Caspase-1 inhibition completely prevented LPS-induced memory impairment in neonatally infected rats. These data implicate IL-1beta in the set of immune/inflammatory events that occur in the brain as a result of neonatal infection, which likely contribute to cognitive alterations in adulthood.


Sensory discrimination: decision process.
1. This paper and a following paper deal with problems, such as the following, that arise in experimental studies of the neural mechanisms underlying sensory discrimination: What measures of neural activity are relevant in such a study? How can sample data from the responses of single neurons be combined to represent the information relayed by a population of neurons? How can neural data be compared with results from psychophysical studies? What assumptions are implicit in any such comparison? What are the implications of assumptions that neurons respond independently or that they have homogeneous response properties? How can neural codes be assessed in a systematic way? Can psychophysical and neurophysiological observations be combined to infer mechanisms or relationships in the processes underlying discrimination? All of these questions require some theoretical framework before they can be answered. These papers set out such a framework, they deal with most of those questions, and they provide practicable formulas for relating sample data from neurophysiological experiments to behavioral measures derived from psychophysical experiments. 2. The processes that intervene between a relatively peripheral array of neural activity and a subject's decision in a discrimination task are split into two sections: a) the ascending sensory processes that provide the final patterns of neural activity on which discrimination is based, and b) a process that yields decisions of the type required by the experimental design used in the psychophysical study. The approach is to develop a theory of the decision process in this paper, and then to expand it to incorporate the ascending processes in the following paper. 3. The decision theory deals with a class of experimental designs in which a subject is required to make a decision about two stimuli S1 and S2 (e.g., S1 is larger than S2, S2 is the same as S1, S2 was the modified stimulus, and so on). A mathematical representation for experimental designs of this type is developed. 4. The decision process is analyzed in two forms: a) a multivariate form in which the discrimination decision results directly from multidimensional neural representation of the two stimuli, and b) a vivariate form in which the final representation of each stimulus is a unidimensional variable. Conditions required for equivalence of these formulations are examined. 5. The theory includes as explicit variables a) the experimental design, b) the subject's discrimination strategy, c) bias, d) memory variance, e) bias variance, f) variance in the final neural representations of the stimuli, and g) their functional dependence on the stimuli that they represent. 6. Formulas are developed for the expected values of commonly used psychophysical measures such as the classical psychometric function, receiver operating characteristic (ROC) functions, discriminatory separation index (d'), and the difference limen. 7. Optimum discrimination behavior is analyzed.


Molecular tuning of odorant receptors and its implication for odor signal processing.
The discovery of the odorant receptor (OR) family by Buck and Axel in 1991 provided a quantum jump in our understanding of olfactory function. However, the study of the responsiveness of ORs to odor ligands was challenging due to the difficulties in deorphanizing the receptors. In this manuscript, we review recent findings of OR responsiveness that have come about through improved OR deorphanization methods, site-directed mutagenesis, structural modeling studies, and studies of OR responses in situ in olfactory sensory neurons. Although there has been a major leap in our understanding of receptor-ligand interactions and how these contribute to the input to the olfactory system, an improvement of our understanding of receptor structure and dynamics and interactions with intracellular and extracellular proteins is necessary.


Marivirga atlantica sp. nov., isolated from seawater and emended description of the genus Marivirga.
A novel Gram-stain-negative, aerobic, orange-pigmented, non-flagellated, gliding, rod-shaped bacterium, designated strain SM1354(T) was isolated from surface seawater of the Atlantic Ocean. The strain hydrolysed gelatin and DNA but did not reduce nitrate. It grew at 4-40 °C and with 0.5-11% (w/v) NaCl. Phylogenetic analysis of the 16S rRNA gene sequences revealed that strain SM1354(T) belonged to the genus Marivirga with 96.0-96.2% sequence similarities to known species of the genus Marivirga . The major fatty acids of strain SM1354(T) were iso-C15 : 0, iso-C15 : 1 G, iso-C17 : 03-OH and summed feature 3 (C16 : 1ω7c and/or iso-C15 : 02-OH). Polar lipids of strain SM1354(T) included phosphatidylethanolamine, three unidentified lipids and one unidentified aminolipid and aminophospholipid. The major respiratory quinone of strain SM1354(T) was menaquinone 7 (MK-7). The genomic DNA G+C content of strain SM1354(T) was 33.9 ± 0.4 mol%. On the basis of the results of the polyphasic characterization in this study, it is proposed that strain SM1354(T) represents a novel species of the genus Marivirga , namely Marivirga atlantica sp. nov. The type strain of Marivirga atlantica is SM1354(T) ( =CCTCC AB 2014242(T) =JCM 30305(T)). An emended description of the genus Marivirga is also proposed.


Magnetic induction of hyperthermia by a modified self-learning fuzzy temperature controller.
The aim of this study involved developing a temperature controller for magnetic induction hyperthermia (MIH). A closed-loop controller was applied to track a reference model to guarantee a desired temperature response. The MIH system generated an alternating magnetic field to heat a high magnetic permeability material. This wireless induction heating had few side effects when it was extensively applied to cancer treatment. The effects of hyperthermia strongly depend on the precise control of temperature. However, during the treatment process, the control performance is degraded due to severe perturbations and parameter variations. In this study, a modified self-learning fuzzy logic controller (SLFLC) with a gain tuning mechanism was implemented to obtain high control performance in a wide range of treatment situations. This implementation was performed by appropriately altering the output scaling factor of a fuzzy inverse model to adjust the control rules. In this study, the proposed SLFLC was compared to the classical self-tuning fuzzy logic controller and fuzzy model reference learning control. Additionally, the proposed SLFLC was verified by conducting in vitro experiments with porcine liver. The experimental results indicated that the proposed controller showed greater robustness and excellent adaptability with respect to the temperature control of the MIH system.


Gastrin regulates the TFF2 promoter through gastrin-responsive cis-acting elements and multiple signaling pathways.
Trefoil family factor 2 (TFF2) is expressed in gastrointestinal epithelial cells where it serves to maintain mucosal integrity and promote epithelial repair. The peptide hormone, gastrin, stimulates acid secretion but also induces proliferation of the acid-secreting mucosa. Because the relationship between these peptides of overlapping function is not understood, we chose to investigate the regulatory effect of gastrin on TFF2 expression. The expression of mRNA and protein of TFF2 was determined by RT-PCR and immunohistochemical staining, respectively. A series of truncated and mutant murine TFF2 promoter constructs was generated. Promoter activity was assessed using dual luciferase reporter assays. Gastrin-responsive DNA-binding sites in the TFF2 promoter were evaluated by electrophoretic mobility shift assay. Gastrin significantly increased the level of endogenous mRNA of TFF2 in the gastrin receptor-expressing AGS-E gastric cancer cell line in a time- and dose-dependent manner. TFF2 protein expression in the gastric fundus was elevated in hypergastrinemic (INS-GAS) transgenic mice and reduced in gastrin-deficient mice. Gastrin treatment increased TFF2 promoter activity through cis-acting regions, containing CCAATA- and GC-rich enhancers. Pretreatment with Y-F476, a gastrin/CCK(B) receptor antagonist, abolished gastrin-dependent promoter activity. Inhibitors of protein kinase C (PKC), mitogen/extracellular signal-regulated kinase (MEK1), and phosphatidylinositol 3-kinase (PI 3-kinase) reduced gastrin-dependent TFF2 promoter activity, whereas an epithelial growth factor receptor (EGFR) inhibitor had no effect. We found that gastrin regulates TFF2 transcription through a GC-rich DNA-binding site and a PKC-, MEK1- and PI 3-kinase-dependent but EGFR-independent pathway. Regulation of TFF2 by gastrin may play a role in the maintenance and repair of the gastrointestinal mucosa.


Anti-stress effects of the hydroalcoholic extract of Rosa gallica officinalis in mice.
Rosa gallica, a plant of the Rosa genus, has been used widely since the 13th century and is cultivated in many areas as a medicinal plant for the preparation of herbal medicines. However, details of the neuropsychological effects of R. gallica remain unclear; therefore we aimed to investigate the neuropsychological effects of a water-soluble extract of R. gallica in male C57BL/6N mice under normal conditions and under chronic stress. We administered a water-soluble extract of R. gallica to mice and performed a series of behavioral experiments to compare the treated animals with the untreated controls. No significant differences in activity level, anxiety-like behavior, depression-like behavior, body weight, and body temperature were observed between R. gallica-treated mice and control mice. However, in mice subjected to chronic stress, the observed decrease in activity was smaller in the R. gallica-treated mice than in the control mice. The oral administration of R. gallica did not affect the normal behavior of mice. However, when the mice were subjected to stress, R. gallica exerted an anti-stress effect. Therefore, R. gallica has potential as a medicinal plant for the purpose of stress prevention.


Speech perception in older hearing impaired listeners: benefits of perceptual training.
Hearing aids (HAs) only partially restore the ability of older hearing impaired (OHI) listeners to understand speech in noise, due in large part to persistent deficits in consonant identification. Here, we investigated whether adaptive perceptual training would improve consonant-identification in noise in sixteen aided OHI listeners who underwent 40 hours of computer-based training in their homes. Listeners identified 20 onset and 20 coda consonants in 9,600 consonant-vowel-consonant (CVC) syllables containing different vowels (/ɑ/, /i/, or /u/) and spoken by four different talkers. Consonants were presented at three consonant-specific signal-to-noise ratios (SNRs) spanning a 12 dB range. Noise levels were adjusted over training sessions based on d' measures. Listeners were tested before and after training to measure (1) changes in consonant-identification thresholds using syllables spoken by familiar and unfamiliar talkers, and (2) sentence reception thresholds (SeRTs) using two different sentence tests. Consonant-identification thresholds improved gradually during training. Laboratory tests of d' thresholds showed an average improvement of 9.1 dB, with 94% of listeners showing statistically significant training benefit. Training normalized consonant confusions and improved the thresholds of some consonants into the normal range. Benefits were equivalent for onset and coda consonants, syllables containing different vowels, and syllables presented at different SNRs. Greater training benefits were found for hard-to-identify consonants and for consonants spoken by familiar than unfamiliar talkers. SeRTs, tested with simple sentences, showed less elevation than consonant-identification thresholds prior to training and failed to show significant training benefit, although SeRT improvements did correlate with improvements in consonant thresholds. We argue that the lack of SeRT improvement reflects the dominant role of top-down semantic processing in processing simple sentences and that greater transfer of benefit would be evident in the comprehension of more unpredictable speech material.


Resection of posterior clinoid meningioma through retrosigmoid approach: concepts and nuances.
Meningiomas arising from the posterior clinoid process pose a great surgical challenge because of their location and propensity to cause critical neurovascular compression. The authors' patient was a 66-year-old female who had a large posterior clinoid meningioma with significant brainstem compression that was operated on through the retrosigmoid approach. This 3D surgical video emphasizes the various technical concepts that are important to preserving compressed neural and vascular structures during the surgery. It would also be interesting to note the extent of visualization around the posterior clinoid region gained through a retrosigmoid corridor. The video can be found here: https://youtu.be/CBmT_0ov0YA .


[Validation of a questionnaire on attitudes and practice of physical activity and other healthy habits through the Delphi method].
Physical inactivity and sedentary lifestyle are an emerging individual, familiar and social public health problem. The aim of this work was to validate a new questionnaire to know the attitude towards physical activity and other habits in adolescents. The Delphi method was used. It was developed in three phases: an initial phase of selection of the panel of experts, an exploratory phase in two rounds of voting using a Likert scale of 1 to 5, and statistical and qualitative analysis of the experts' contributions. The criteria for the choice of items were: average >3.5 and factor V of Aiken ≥0.7. Reliability was assessed with the Cronbach alpha coefficient. A pilot test was carried out to assess the understanding of the instrument. 21 experts agreed to participate. Their participation was 100% in the first round and 95.2% in the second one. Seven items did not meet the criteria. The final questionnaire included 93 questions and 11 dimensions: data of the student, father, mother, physical activity in the educational center, transportation, free time, psychosocial aspects of physical activity, attitude towards physical activity, food, other habits and health perception. A Cronbach's alpha of 0.974 was obtained. The results support the reliability and validity of the questionnaire. The Delphi method proved to be a useful technique for the proposed objective.


Menetrier's disease: report of a transient case associated with chylous ascites.
We present a case of transient Menetrier's disease (MD) that was associated with chylous ascites. Using immunohistochemistry, we studied the expression of transforming growth factor alpha in this patient's gastric mucosa biopsy over time; a growth factor that has previously been shown to play an active role in the pathogenesis of MD. Excessive expression and altered localization of transforming growth factor alpha was observed while the patient had active disease with return to the normal pattern after resolution of the disease. This case is the first one reported of transient MD associated with chylous ascites; it lends further credible evidence to the concept that altered transforming growth factor alpha expression may play an important role in the pathogenesis of MD.


A high-speed hydroplane accident.
This report records the investigation into a high-speed hydroplane accident in which the driver died. He was ejected head first into the water at 117 to 126 ft/sec (80 to 85 mph), suffering brain damage and a fractured skull. Suggestions are made to minimize the effects of these inevitable crashes.


Cancer rehabilitation. An analysis of 36 program approaches.
Information about comprehensive rehabilitation for patients with cancer is limited. Only a few descriptions of existing models are found in the literature. A survey questionnaire concerning the description and operation of cancer rehabilitation programs was developed and mailed to identified programs in 95 facilities throughout the country. Thirty-six facilities responded with data appropriate for analysis of their method of organization, treatment approaches, team composition, program emphasis, evaluation procedures, and program results. A literature and survey analysis provide support for an interdisciplinary team approach for rehabilitation of cancer patients disabled by the disease or its treatment. In addition, the survey shows favorable acceptance and success of cancer rehabilitation programs, especially in community hospital settings.


A novel smartphone-based intervention targeting sleep difficulties in individuals experiencing psychosis: A feasibility and acceptability evaluation.
Cognitive Behavioural Therapy (CBT) is an effective psychological intervention for sleep difficulties and has been used successfully in individuals with psychosis. However, access is restricted due to lack of resources and staff training. Delivering CBT for sleep problems using smartphone technology may facilitate wider access. This study aimed to evaluate the feasibility, acceptability and potential usefulness of a guided, smartphone-based CBT intervention targeting sleep disturbance for individuals with psychosis. Participants with psychosis spectrum diagnoses were recruited to a single-arm, uncontrolled study and engaged with the seven-module programme via smartphone app for six weeks with therapist support. Feasibility was assessed by rates of referral, recruitment and completion. Acceptability was assessed by app usage, a satisfaction questionnaire and qualitative analysis of participants' semi-structured interview. Pre- and post-intervention assessment of sleep, psychotic experiences, mood, well-being and functioning was conducted. Mean change confidence intervals were calculated and reported as an indication of usefulness. Fourteen individuals consented to participation, and eleven completed the post-intervention assessment. On average, each participant engaged with 5.6 of 7 available modules. Qualitative feedback indicated the intervention was considered helpful and would be recommended to others. Suggested improvements to app design were provided by participants. Potential treatment benefits were observed for sleep difficulties, and all outcomes considered, except frequency of hallucinatory experiences. It is feasible and acceptable to deliver therapist-guided CBT for sleep problems by smartphone app for individuals with psychosis. This method provides a low-intensity, accessible intervention, which could be offered more routinely. Further research to determine treatment efficacy is warranted.


Mechanism of change in the orientation of the articular process of the zygapophyseal joint at the thoracolumbar junction.
The orientation of the superior articular processes in thoracic and lumbar vertebrae differs. The present study was undertaken to investigate the possible mechanism for the change from a posterolaterally facing superior articular surface in the thoracic region to a posteromedially facing curved articular surface in the lumbar region. The material of the study consisted of dry macerated bones of 44 adult human vertebral columns. The orientation of the superior articular process and its relation to the mamillary tubercle (process) was examined between T9 and L5 vertebrae in each column. An abrupt change from the thoracic to lumbar type of articular process was observed in 3 columns (7 %). Forty-one (93 %) columns showed a gradual change extending over either 2 or 3 successive vertebrae. The present study suggests that the change in the orientation of the superior articular process, from the coronal to the sagittal plane (sagittalisation), occurs due to the change in the direction of weight transmission through zygapophyseal joints at the thoracolumbar junction. It was observed that the gradual sagittalisation of the superior articular process in the transitional zone brought it close to the mamillary tubercle which eventually fused with it. Thus the study suggests that the characteristic posteromedially facing concave superior articular process of lumbar vertebrae may have formed because of the fusion of the articular process and the mamillary tubercle.


The mediating and moderating roles of the cognitive triad on adolescent suicidal ideation.
Adolescent suicide has been a major concern in Taiwan and continues to be an important research issue for mental health workers. The cognitive triad, which refers to an adolescent's views of the self, the world, and the future, was found previously to be related to both depressive symptoms and suicidal ideation. However, researchers have paid less attention to exploring the roles of mediation and moderation which the cognitive triad plays in the relationship between depressive symptoms and suicidal ideation. To test the mediating and moderating effects of the cognitive triad on the relationship between depressive symptoms and suicidal ideation in a sample of school-aged adolescents. A cross-sectional and correlational design was used in this study. Instruments were administered anonymously to a sample of 1,245 school-aged adolescents recruited from nine middle and high schools of Taipei City. Instruments used included the Children's Depression Inventory, the Cognitive Triad Inventory for Children, and the Positive and Negative Suicide Ideation. Regression analysis revealed that the cognitive triad significantly mediated and moderated the relationship between depressive symptoms and suicidal ideation. These findings have implications for theoretical development and health policies related to suicide prevention programs in schools.


NGS Analysis Confirms Common TP53 and RB1 Mutations, and Suggests MYC Amplification in Ocular Adnexal Sebaceous Carcinomas.
Ocular adnexal (OA) sebaceous carcinomas generally demonstrate more aggressive clinical and histopathological phenotypes than extraocular cases, but the molecular drivers implicated in their oncogenesis remain poorly defined. A retrospective review of surgical and ocular pathology archives identified eleven primary resection specimens of OA sebaceous carcinomas with adequate tissue for molecular analysis; two extraocular cases were also examined. Next-generation sequencing was used to evaluate mutations and copy number changes in a large panel of cancer-associated genes. Fluorescence in situ hybridization (FISH) confirmed MYC copy number gain in select cases, and immunohistochemistry to evaluate MYC protein expression. The commonest mutations occurred in TP53 (10/13) and RB1 (7/13). Additional mutations in clinically actionable genes, or mutations with a frequency of at least 25%, included the NF1 (3/12), PMS2 (4/12), ROS1 (3/12), KMT2C (4/12), MNX1 (6/12), NOTCH1 (4/12), PCLO (3/12), and PTPRT (3/12) loci. Low level copy number gain suggestive of amplification of the MYC locus was seen in two cases, and confirmed using FISH. MYC protein expression, as assessed by immunohistochemistry, was present in almost all sebaceous carcinoma cases. Our findings support the concept that alterations in TP53 and RB1 are the commonest alterations in sebaceous carcinoma, and suggest that MYC may contribute to the oncogenesis of these tumors.


Protocol for a study of the psychosocial determinants of health in early childhood among children with cystic fibrosis.
To investigate the causal associations between family relationships, family functioning, social circumstances and health outcomes in young children with cystic fibrosis. The anticipated health gains for patients with cystic fibrosis, promised by early diagnosis through newborn screening, have yet to be fully realized, despite advances in cystic fibrosis health care with aggressive management in multidisciplinary clinics and the development of specific medications. Adverse psychosocial functioning may underpin the current lack of progress as it is well recognized that compromised early parent-child attachment relationship experiences and adverse social circumstances have negative impacts on lifelong health status and health resource use, even in healthy children. A cross-sectional (initial) and longitudinal (progressive), multicentre study of children aged 3 months-6 years with cystic fibrosis, who have been diagnosed by newborn screening. Questionnaire and observational measures of parent psychosocial functioning, parenting and parent-child attachment and social markers; and including clinical outcomes of regular health surveillance with clinical, lung imaging (computerized tomography) and bronchoalveolar lavage for airway microbiology and inflammation. This will be the first study to investigate the causal effect of psychosocial functioning, parenting and attachment on physical health outcome measures in children with cystic fibrosis.


Creation of a new class of radiosensitizers for glioblastoma based on the mibefradil pharmacophore.
Glioblastoma (GBM) is the most common primary malignant tumor of the central nervous system with a dismal prognosis. Locoregional failure is common despite high doses of radiation therapy, which has prompted great interest in developing novel strategies to radiosensitize these cancers. Our group previously identified a calcium channel blocker (CCB), mibefradil, as a potential GBM radiosensitizer. We discovered that mibefradil selectively inhibits a key DNA repair pathway, alternative non-homologous end joining. We then initiated a phase I clinical trial that revealed promising initial efficacy of mibefradil, but further development was hampered by dose-limiting toxicities, including CCB-related cardiotoxicity, off-target hERG channel and cytochrome P450 enzymes (CYPs) interactions. Here, we show that mibefradil inhibits DNA repair independent of its CCB activity, and report a series of mibefradil analogues which lack CCB activity and demonstrate reduced hERG and CYP activity while retaining potency as DNA repair inhibitors. We present in vivo pharmacokinetic studies of the top analogues with evidence of brain penetration. We also report a targeted siRNA-based screen which suggests a possible role for mTOR and Akt in DNA repair inhibition by this class of drugs. Taken together, these data reveal a new class of mibefradil-based DNA repair inhibitors which can be further advanced into pre-clinical testing and eventually clinical trials, as potential GBM radiosensitizers.


Significance of cytologically normal endometrial cells in cervical smears from postmenopausal women.
To determine the significance of cytologically normal endometrial cells in cervicovaginal (CV) smears from postmenopausal women over age 55 years. From January 1995 to January 1998, 220 women had CV smears demonstrating cytologically normal endometrial cells. The menopausal status, hormone replacement therapy (HRT) and information related to subsequent CV smears and endometrial sampling within 12 months of the initial diagnosis was recorded. Eighty-one of the 220 cases (36.8%) had histologic sampling of the endometrium. Thirty-four of 81 (42%) showed no endometrial pathology. Endometrial pathology was identified in 28 of 81 (34%), of which 19 were endometrial polyps (23.4%), 4 were endometrial hyperplasia (4.9%), 4 were endometrial carcinoma (4.9%) and 1 was a leiomyoma (1.2%). Nineteen (23.4%) were insufficient for diagnosis. Ninety-one of 220 women were on HRT, and 129 were not. In the group without HRT, endometrial disease was identified in 22/51 (43%) cases as compared to 6/30 (20%) in the group with HRT (P < .001). Endometrial carcinoma was identified in three (5.8%) cases and one (3.3%) case without and with HRT, respectively. Although the finding of normal endometrial cells in Pap smears from postmenopausal women was without any clinical significance in the majority of women in this study, in a small number it was associated with endometrial hyperplasia and carcinoma. Women who were not on HRT had a higher incidence of endometrial pathology.


Perspectives on Gender in Science, Technology, and Innovation: A Review of Sub-Saharan Africa's Science Granting Councils and Achieving the Sustainable Development Goals.
Africa's focus on science, technology, and innovation (STI) has grown over the last decade, with emerging examples of good practice. There are however numerous challenges to sustainable development in Africa; for example, inequalities within and among African countries are rising and enormous disparities of opportunity, wealth, and power persist. While policy makers and organizations have put increasing emphasis on integrating gender into STI policies and initiatives as a means to achieve gender equality for all women and girls, inequality remains a key challenge to continental sustainable development. STI funders such as the Science Granting Councils (SGCs) in Africa are key players in national innovation systems. They advise and facilitate policy and program development, disburse funds, build research capacity, set and monitor research agendas, manage bilateral and multilateral STI agreements, and assess the communication, uptake, and impact of research. They, therefore, have a major role to play in enabling countries to achieve SDG5. This study assessed the current actions in gender mainstreaming across the SGCs and the status of gender research and collaboration in participating countries. Our findings provide evidence of uneven progress in promoting gender equality in the operations of the SGCs, including funding research and promoting the integration of gender dimensions in research content and curricula. All SGCs emphasized national commitments to gender, and the importance of gender in STI, but acknowledged that at the structural and institutional levels there was a misalignment between policy and practice. As expected, more men than women were employed across most levels at the SGCs and held positions of seniority and decision making. Most of the SGCs had very limited or no gender-related funding programs to promote gender and STI or to eliminate the barriers that women scholars face. This resulted in persistent inequalities in who received funding, the size of the grants they received, and in the knowledge production, collaboration, and the impact on their country's gender-related research. These findings suggest that SGCs need to strengthen their actions to mainstream gender if they are to achieve success with SDG5.


Therapeutic limitations in tumor-specific CD8+ memory T cell engraftment.
Adoptive immunotherapy with cytotoxic T lymphocytes (CTL) represents an alternative approach to treating solid tumors. Ideally, this would confer long-term protection against tumor. We previously demonstrated that in vitro-generated tumor-specific CTL from the ovalbumin (OVA)-specific OT-I T cell receptor transgenic mouse persisted long after adoptive transfer as memory T cells. When recipient mice were challenged with the OVA-expressing E.G7 thymoma, tumor growth was delayed and sometimes prevented. The reasons for therapeutic failures were not clear. OT-I CTL were adoptively transferred to C57BL/6 mice 21-28 days prior to tumor challenge. At this time, the donor cells had the phenotypical and functional characteristics of memory CD8+ T cells. Recipients which developed tumor despite adoptive immunotherapy were analyzed to evaluate the reason(s) for therapeutic failure. Dose-response studies demonstrated that the degree of tumor protection was directly proportional to the number of OT-I CTL adoptively transferred. At a low dose of OT-I CTL, therapeutic failure was attributed to insufficient numbers of OT-I T cells that persisted in vivo, rather than mechanisms that actively suppressed or anergized the OT-I T cells. In recipients of high numbers of OT-I CTL, the E.G7 tumor that developed was shown to be resistant to fresh OT-I CTL when examined ex vivo. Furthermore, these same tumor cells no longer secreted a detectable level of OVA. In this case, resistance to immunotherapy was secondary to selection of clones of E.G7 that expressed a lower level of tumor antigen. Memory engraftment with tumor-specific CTL provides long-term protection against tumor. However, there are several limitations to this immunotherapeutic strategy, especially when targeting a single antigen. This study illustrates the importance of administering large numbers of effectors to engraft sufficiently efficacious immunologic memory. It also demonstrates the importance of targeting several antigens when developing vaccine strategies for cancer.


Burden of rare deleterious variants in WNT signaling genes among 511 myelomeningocele patients.
Genes in the noncanonical WNT signaling pathway controlling planar cell polarity have been linked to the neural tube defect myelomeningocele. We hypothesized that some genes in the WNT signaling network have a higher mutational burden in myelomeningocele subjects than in reference subjects in gnomAD. Exome sequencing data from 511 myelomeningocele subjects was obtained in-house and data from 29,940 ethnically matched subjects was provided by version 2 of the publicly available Genome Aggregation Database. To compare mutational burden, we collapsed rare deleterious variants across each of 523 human WNT signaling genes in case and reference populations. Ten WNT signaling genes were disrupted with a higher mutational burden among Mexican American myelomeningocele subjects compared to reference subjects (Fishers exact test, P ≤ 0.05) and seven different genes were disrupted among individuals of European ancestry compared to reference subjects. Gene ontology enrichment analyses indicate that genes disrupted only in the Mexican American population play a role in planar cell polarity whereas genes identified in both populations are important for the regulation of canonical WNT signaling. In summary, evidence for WNT signaling genes that may contribute to myelomeningocele in humans is presented and discussed.


Heterochromatin controls γH2A localization in Neurospora crassa.
In response to genotoxic stress, ATR and ATM kinases phosphorylate H2A in fungi and H2AX in animals on a C-terminal serine. The resulting modified histone, called γH2A, recruits chromatin-binding proteins that stabilize stalled replication forks or promote DNA double-strand-break repair. To identify genomic loci that might be prone to replication fork stalling or DNA breakage in Neurospora crassa, we performed chromatin immunoprecipitation (ChIP) of γH2A followed by next-generation sequencing (ChIP-seq). γH2A-containing nucleosomes are enriched in Neurospora heterochromatin domains. These domains are comprised of A·T-rich repetitive DNA sequences associated with histone H3 methylated at lysine-9 (H3K9me), the H3K9me-binding protein heterochromatin protein 1 (HP1), and DNA cytosine methylation. H3K9 methylation, catalyzed by DIM-5, is required for normal γH2A localization. In contrast, γH2A is not required for H3K9 methylation or DNA methylation. Normal γH2A localization also depends on HP1 and a histone deacetylase, HDA-1, but is independent of the DNA methyltransferase DIM-2. γH2A is globally induced in dim-5 mutants under normal growth conditions, suggesting that the DNA damage response is activated in these mutants in the absence of exogenous DNA damage. Together, these data suggest that heterochromatin formation is essential for normal DNA replication or repair.


Proinflammatory effects of diesel exhaust particles from moderate blend concentrations of 1st and 2nd generation biodiesel in BEAS-2B bronchial epithelial cells-The FuelHealth project.
Biodiesel fuel fuels are introduced at an increasing extent as a more carbon-neutral alternative to reduce CO2-emissions, compared to conventional diesel fuel. In the present study we have investigated the impact of increasing the use of 1st generation fatty acid methyl ester (FAME) biodiesel from current 7% blend (B7) to 20% blend (B20), or by increasing the biodiesel content by adding 2nd generation hydrotreated vegetable oil (HVO) based biodiesel (SHB; Synthetic Hydrocarbon Biofuel) on toxicity of diesel exhaust particles (DEP) in an in vitro system. Human bronchial epithelial BEAS-2B cells were exposed for 4 and 20h to DEP from B7, B20 and SHB at different concentrations, and examined for effects on gene expression of interleukin 6 (IL-6), CXCL8 (IL-8), CYP1A1 and heme oxygenase-1 (HO-1). The results show that both B20 and SHB were more potent inducers of IL-6 expression compared to B7. Only B20 induced statistically significant increases in CXCL8 expression. By comparison the rank order of potency to induce CYP1A1 was SHB>B7>B20. No statistically significant difference were observed form HO-1 expression, suggesting that the differences in cytokine responses were not due to oxidative stress. The results show that even moderate increases in biodiesel blends, from 7% to 20%, may increase the proinflammatory potential of emitted DEP in BEAS-2B cells. This effect was observed for both addition of 1st generation FAME and 2nd generation HVO biodiesel.


Stereoacuity norms in young children.
Stereoacuity was investigated in 3- to 5-year-old children and in adults by using four commercially available stereotests (the Frisby, Randot circles, Random-Dot E (RDE), and TNO tests) and by using an experimental stereotest. Comparative reanalysis was also made of data obtained from other studies of the RDE and Titmus circles tests. Stereoacuity norms are proposed for 3- to 5-year-old children for each of the commercially available tests. Factors influencing stereoacuity threshold differences among the different tests are discussed. The results on all tests are consistent with the hypothesis that binocular visual development is incomplete at 5 years of age.


Block of single L-type Ca2+ channels in skeletal muscle fibers by aminoglycoside antibiotics.
The activity of single L-type Ca2+ channels was recorded from cell-attached patches on acutely isolated skeletal muscle fibers from the mouse. The experiments were concerned with the mechanism by which aminoglycoside antibiotics inhibit ion flow through the channel. Aminoglycosides produced discrete fluctuations in the single-channel current when added to the external solution. The blocking kinetics could be described as a simple bimolecular reaction between an aminoglycoside molecule and the open channel. The blocking rate was found to be increased when either the membrane potential was made more negative or the concentration of external permeant ion was reduced. Both of these effects are consistent with a blocking site that is located within the channel pore. Other features of block, however, were incompatible with a simple pore blocking mechanism. Hyperpolarization enhanced the rate of unblocking, even though an aminoglycoside molecule must dissociate from its binding site in the channel toward the external solution against the membrane field. Raising the external permeant ion concentration also enhanced the rate of unblocking. This latter finding suggests that aminglycoside affinity is modified by repulsive interactions that arise when the pore is simultaneously occupied by a permeant ion and an aminoglycoside molecule.


Prevalence of mitral valve prolapse in residents living at moderately high altitude.
Prolapse of mitral valve leaflets is a frequent disorder and the most common cause of severe mitral regurgitation in western countries. However, little is known about the effects of altitude on mitral valve prolapse. We studied the prevalence and echocardiographic characteristics of mitral valve prolapse at moderately high altitude and sea level. A total of 936 consecutive subjects who were admitted to 2 study institutions at Kars, Turkey (1750 m) and Istanbul, Turkey (7 m) were enrolled in this study to determine prevalence of mitral valve prolapse. Demographic and 2-dimensional echocardiographic characteristics of participants were recorded. Prevalence of mitral valve prolapse was found to be significantly higher in people living at moderate altitude compared with those living at sea level (6.2% vs 2.0%; P = .007). Overall echocardiographic features regarding valve thickness (4.1 ± 0.80 mm vs 3.6 ± 0.66 mm; P = 0.169), maximal valve prolapse (4.6 ± 2.08 mm vs 3.9 ± 0.91 mm; P = .093), and frequency of mitral regurgitation (89% vs 73%; P = .65) were similar between groups, although anterior valve prolapse was seen more frequently at moderate altitude (50% vs 11%; P = .056) and posterior leaflet prolapse was significantly more frequent at sea level (66% vs 10%; P = .002). Mitral valve prolapse is more frequently observed at moderately high altitudes. Further studies are needed to determine clinical importance of our findings.