Psychometric testing of the Caring Behaviors Inventory for nursing students.
To test the psychometric properties of the nursing students' version of the 24-item Caring Behaviours Inventory. Caring is at the heart of nursing and should also be a core value in nursing education. Caring can be manifested through measurable behaviours. The Caring Behaviors Inventory is a valid and reliable measure of nurses' caring behaviours in clinical settings. It has already been used among nursing students, but it needs more psychometric testing. Cross-sectional validation study. The questionnaire was filled in by 300 undergraduate nursing students at two Italian universities in May 2016. Exploratory factor analysis was conducted using Mplus maximum likelihood with GEOMIN oblique rotation. A multifaceted approach was used to evaluate the model fit. The STROBE checklist for cross-sectional studies was followed. Four dimensions were identified: "being with," "doing with competence," "responding to individual needs" and "providing effective care." Adequate fit indices and high reliability of the factors were found. Correlations between factors were positive and significant. This study makes it possible to use the same tool to compare the caring practices perceived by students, nurses and patients. Further studies with bigger samples could be stratified to investigate the associations between caring levels and student characteristics. The Caring Behaviors Inventory can be used to call attention to caring in nursing education, helping to make this concept less elusive. The effective self-assessment of nursing students' caring behaviours offers opportunities for reflection on their caring practice. This could improve the caring level of their behaviours in clinical practice and help them to become caring nurses in the future.


Allogeneic haematopoietic stem cell transplantation for mitochondrial neurogastrointestinal encephalomyopathy.
Haematopoietic stem cell transplantation has been proposed as treatment for mitochondrial neurogastrointestinal encephalomyopathy, a rare fatal autosomal recessive disease due to TYMP mutations that result in thymidine phosphorylase deficiency. We conducted a retrospective analysis of all known patients suffering from mitochondrial neurogastrointestinal encephalomyopathy who underwent allogeneic haematopoietic stem cell transplantation between 2005 and 2011. Twenty-four patients, 11 males and 13 females, median age 25 years (range 10-41 years) treated with haematopoietic stem cell transplantation from related (n = 9) or unrelated donors (n = 15) in 15 institutions worldwide were analysed for outcome and its associated factors. Overall, 9 of 24 patients (37.5%) were alive at last follow-up with a median follow-up of these surviving patients of 1430 days. Deaths were attributed to transplant in nine (including two after a second transplant due to graft failure), and to mitochondrial neurogastrointestinal encephalomyopathy in six patients. Thymidine phosphorylase activity rose from undetectable to normal levels (median 697 nmol/h/mg protein, range 262-1285) in all survivors. Seven patients (29%) who were engrafted and living more than 2 years after transplantation, showed improvement of body mass index, gastrointestinal manifestations, and peripheral neuropathy. Univariate statistical analysis demonstrated that survival was associated with two defined pre-transplant characteristics: human leukocyte antigen match (10/10 versus <10/10) and disease characteristics (liver disease, history of gastrointestinal pseudo-obstruction or both). Allogeneic haematopoietic stem cell transplantation can restore thymidine phosphorylase enzyme function in patients with mitochondrial neurogastrointestinal encephalomyopathy and improve clinical manifestations of mitochondrial neurogastrointestinal encephalomyopathy in the long term. Allogeneic haematopoietic stem cell transplantation should be considered for selected patients with an optimal donor.


Thyroid Nodules: Nondiagnostic Cytologic Results according to Thyroid Imaging Reporting and Data System before and after Application of the Bethesda System.
To compare the malignancy rates and the effectiveness of the Thyroid Imaging Reporting and Data System (TIRADS) for risk stratification of nodules with nondiagnostic results classified before and after application of the Bethesda System for Reporting Thyroid Cytopathology. This retrospective study was approved by an institutional review board, with waiver of informed consent. A total of 763 patients with 790 thyroid nodules and nondiagnostic cytologic results were included (mean age ± standard deviation, 52.3 years ± 11.5), 485 nodules from the pre-Bethesda period (from March 2007 to December 2008) and 305 nodules from the post-Bethesda period (from May 2011 to May 2012). A TIRADS category was assigned to each thyroid nodule on the basis of the number of features that appeared suspicious for cancer at ultrasonography (US). Malignancy rates and TIRADS categories during the two periods were compared. Correlation between TIRADS category and malignancy risk between the two periods was evaluated and compared. The malignancy rates of nodules with nondiagnostic cytologic results were not significantly different between the two periods (P = .148). Malignancy risk of TIRADS category 3, 4a, 4b, 4c, and 5 was 1.8%, 5.7%, 4.1%, 29.8%, and 16.7%, for the pre-Bethesda period, and 1.6%, 3.0%, 7.1%, 16.3%, and 25.0% for the post-Bethesda period, respectively. Near-perfect correlation was seen between the TIRADS category and malignancy risk in the post-Bethesda period (r = 0.961, P = .009), while no significant correlation was found in the pre-Bethesda period (r = 0.731, P = .161). Malignancy risk stratification with TIRADS was more effective for nodules with nondiagnostic cytologic results classified according to the Bethesda System. When these Bethesda-classified nodules with nondiagnostic results are evaluated as TIRADS category 3 or 4a, they may be treated conservatively with follow-up US, but when other cytologic classifications are applied, follow-up US and fine- needle aspiration must be considered for nodules showing one or more features suspicious for cancer at US.


The role of emotion regulation in moral judgment.
Moral judgment has typically been characterized as a conflict between emotion and reason. In recent years, a central concern has been determining which process is the chief contributor to moral behavior. While classic moral theorists claimed that moral evaluations stem from consciously controlled cognitive processes, recent research indicates that affective processes may be driving moral behavior. Here, we propose a new way of thinking about emotion within the context of moral judgment, one in which affect is generated and transformed by both automatic and controlled processes, and moral evaluations are shifted accordingly. We begin with a review of how existing theories in psychology and neuroscience address the interaction between emotion and cognition, and how these theories may inform the study of moral judgment. We then describe how brain regions involved in both affective processing and moral judgment overlap and may make distinct contributions to the moral evaluation process. Finally, we discuss how this way of thinking about emotion can be reconciled with current theories in moral psychology before mapping out future directions in the study of moral behavior.


Efficacy and tolerability of anticholinergics in Korean children with overactive bladder: a multicenter retrospective study.
We investigated the efficacy and tolerability of various anticholinergics in Korean children with non-neurogenic overactive bladder (OAB). A total of 326 children (males:females= 157:169) aged under 18 yr (mean age 7.3±2.6 yr) who were diagnosed with OAB from 2008 to 2011 were retrospectively reviewed. The mean duration of OAB symptoms before anticholinergic treatment was 16.9±19.0 months. The mean duration of medication was 5.6±7.3 months. Urgency urinary incontinence episodes per week decreased from 1.9±3.1 to 0.4±1.5 times (P<0.001). The median voiding frequency during daytime was decreased from 9.2±5.4 to 6.3±4.2 times (P<0.001). According to 3-day voiding diaries, the maximum and average bladder capacity were increased from 145.5±66.9 to 196.8±80.3 mL and from 80.8±39.6 to 121.8±56.5 mL, respectively (P<0.001). On uroflowmetry, maximum flow rate was increased from 17.6±8.4 to 20.5±8.2 mL/sec (P<0.001). Adverse effects were reported in 14 (4.3%) children and six children (1.8%) discontinued medication due to adverse effects. Our results indicate that anticholinergics are effective to improve OAB symptoms and tolerability was acceptable without severe complications in children.


Development of a wingless morph in the ladybird beetle, Adalia bipunctata.
Many taxa of winged insects have independently lost the ability to fly and often possess reduced wings. Species exhibiting natural variation in wing morphology provide opportunities to investigate the genetics and developmental processes underlying the evolution of alternative wing morphs. Although many wing dimorphic species of beetles are known, the underlying mechanisms of variation are not well understood in this insect order. Here, we examine wing development of wild type and natural wingless morphs of the two-spot ladybird beetle, Adalia bipunctata. We show that both pairs of wings are distally truncated in the wingless adults. A laboratory population of the wingless morph displays heritable variation in the degree of wing truncation, reflecting reduced growth of the larval wing discs. The coexistence of variable wingless morphs supports the idea that typical monomorphic wingless insects may be the result of a gradual evolution of wing loss. Gene expression patterns in wing discs suggest that the conserved gene network controlling wing development in wild-type Adalia is disrupted in the dorsoventral patterning pathway in the wingless morphs. Previous research on several species of ant has revealed that the anteroposterior wing patterning pathway is disrupted in wingless workers. Future investigations should confirm whether interruptions in both taxa are limited to the patterning pathways found thus far, or whether there are also shared interruption points. Nevertheless, our results highlight that diverse mechanisms of development are likely to underlie the evolution of wingless insects.


Genetic association study for RSV bronchiolitis in infancy at the 5q31 cytokine cluster.
The pathophysiological basis of severe respiratory syncytial virus (RSV) bronchiolitis in infancy is poorly understood and has hindered vaccine development. Studies implicate the cell-mediated immune response in the pathogenesis of the disease. A recent twin study estimated a heritable contribution of 22% to RSV bronchiolitis. Genetic epidemiology provides a new approach to identifying important immune determinants of disease severity. A comprehensive high-density gene-region association study for severe RSV bronchiolitis in infancy at 5q31 across 11 genes including the Th2-cytokine cluster was performed. A haplotype tagging approach was used to analyse genetic variation at 113 single nucleotide polymorphisms (SNPs) in 780 independent cases and 1045 controls. The study had sufficient power to detect small effects, perform extensive haplotype analysis and analyse both a principal phenotype and a refined age-limited phenotype enriched for first-exposure RSV infection. SNP associations were found at IL4 and a highly significant risk haplotype was identified across IL13 CNS-1 and IL4 (odds ratio 1.69, p<0.0001), present in both case-control and family-based analyses. All associations were strongest for a phenotype limited to <6 months of age, implicating this locus in primary RSV disease. The same risk haplotype has previously been shown to be associated with increased IL13 expression. A haplotype at IL13-1L4, which is associated with increased IL13 production, confers an increased risk of severe primary RSV bronchiolitis in early infancy. This study, together with previous studies implicating the same locus in atopic sensitisation, suggests that primary RSV bronchiolitis and atopy share a genetic contribution at the IL13-IL4 locus.


Learning Separable Filters.
Learning filters to produce sparse image representations in terms of over-complete dictionaries has emerged as a powerful way to create image features for many different purposes. Unfortunately, these filters are usually both numerous and non-separable, making their use computationally expensive. In this paper, we show that such filters can be computed as linear combinations of a smaller number of separable ones, thus greatly reducing the computational complexity at no cost in terms of performance. This makes filter learning approaches practical even for large images or 3D volumes, and we show that we significantly outperform state-of-the-art methods on the curvilinear structure extraction task, in terms of both accuracy and speed. Moreover, our approach is general and can be used on generic convolutional filter banks to reduce the complexity of the feature extraction step.


An alternative view on the task of prognosis.
Prognosis is central to clinical medical practice. In oncology, an accurate prognosis is a key requirement for making the right therapeutical decisions. Prognosis is even more important when medicine extends its predictive capacities using genetic data. Based on statistics and probability, indices, survival curves and prognostic scores are established. Intending to be an objective and neutral description of reality, this kind of prognosis and the corresponding practices of medical care however carry and imply a particular conception of human life and destiny. Medical Humanities can help to develop reflexivity regarding prognostic practices. This paper intends to clarify which particular assumptions are implied in the current way of doing prognosis in medicine, and highlights its advantages and limitations. Prognosis not only describes but also affects present and future patient experience. An alternative view on the task of prognosis is then developed with a broader understanding of the prognostic act. Based on a phenomenology of time, distinguishing between a quantitative chronological understanding of time (chronos) and an experienced qualitative time (kairos), the article contrasts a conception of the prognosis as forecast ('probabilistic prognosis') with a conception of prognosis as perspective ('hermeneutic prognosis'). In probabilistic prognosis, the future is seen as something that can be read from presently accessible signs, as something that we can anticipate within ranges of uncertainty. The patient's lifetime, which has been open toward the future, becomes closed through this kind of prognosis. In a hermeneutic conception of prognosis as a perspective on the future, which is thought of as an open space of possibilities, the future as not-yet is what can be envisioned without being known. A hermeneutic approach emphasizes the meanings of the experience of illness for the patient, helps to improve the practice of prognosis today, and offers caregivers and patients an opportunity for living better.


Susceptibility of bite wound bacteria to seven oral antimicrobial agents, including RU-985, a new erythromycin: considerations in choosing empiric therapy.
The susceptibility of 93 aerobic and 59 anaerobic bacteria isolated from human and animal bite wounds was determined by agar dilution. No agent tested (penicillin, oxacillin, cephalexin, sulfamethoxazole-trimethoprim, minocycline, erythromycin, and RU-965) was consistently active against all isolates. A total of 21% of the Bacteroides species, all isolated from human bites, were resistant to penicillin; 14 and 18% of the Pasteurella multocida isolates were resistant to erythromycin and oxacillin, respectively.


Ubiquitous Pharmacogenomics (U-PGx): The Time for Implementation is Now. An Horizon2020 Program to Drive Pharmacogenomics into Clinical Practice.
Although the clinical validity of a number of pharmacogenetic markers is nowadays a matter of fact, and led authoritative scientific consortia as the Dutch Pharmacogenetic Working Group (DPWG) and the Clinical Pharmacogenomics Implementation Consortium (CPIC) to publish pharmacogenetic guidelines, the clinical implementation in real life remains challenging. Ubiquitous Pharmacogenomics (U-PGx) program is a coordinated effort that put together scientific and clinical expertise in the pharmacogenomic field, to implement the pre-emptive pharmacogenomic approach in the clinical practice in Europe, and to demonstrate its benefit in both patients' clinical outcome and quality of life, with an economic advantage for the healthcare system. The project is conceived as a clinical trial that will compare 4,000 patients, pre-emptively genotyped for a panel of pharmacogenes included in the DPWG guidelines, and treated accordingly, with 4,000 controls treated with the standard of care. All the genetic data will be prospectively collected and fully embedded into the patient's clinical record. An electronic clinical decision support system will be developed to alert physicians and pharmacists when a drug is being prescribed or dispensed to a patient with a risky genotype. U-PGx will test and harmonize this approach in seven healthcare environments (The Netherlands, Spain, UK, Italy, Austria, Greece, Slovenia) to set the basis for a future European healthcare system where an 'effective treatment optimization will be accessible to every European citizen' (www.upgx.eu).


Slow plastic creep of 2D dusty plasma solids.
We report complex plasma experiments, assisted by numerical simulations, providing an alternative qualitative link between the macroscopic response of polycrystalline solid matter to small shearing forces and the possible underlying microscopic processes. In the stationary creep regime we have determined the exponents of the shear rate dependence of the shear stress and defect density, being α=1.15±0.1 and β=2.4±0.4, respectively. We show that the formation and rapid glide motion of dislocation pairs in the lattice are dominant processes.


Tumor Tissue Detection using Blood-Oxygen-Level-Dependent Functional MRI based on Independent Component Analysis.
Accurate delineation of gliomas from the surrounding normal brain areas helps maximize tumor resection and improves outcome. Blood-oxygen-level-dependent (BOLD) functional MRI (fMRI) has been routinely adopted for presurgical mapping of the surrounding functional areas. For completely utilizing such imaging data, here we show the feasibility of using presurgical fMRI for tumor delineation. In particular, we introduce a novel method dedicated to tumor detection based on independent component analysis (ICA) of resting-state fMRI (rs-fMRI) with automatic tumor component identification. Multi-center rs-fMRI data of 32 glioma patients from three centers, plus the additional proof-of-concept data of 28 patients from the fourth center with non-brain musculoskeletal tumors, are fed into individual ICA with different total number of components (TNCs). The best-fitted tumor-related components derived from the optimized TNCs setting are automatically determined based on a new template-matching algorithm. The success rates are 100%, 100% and 93.75% for glioma tissue detection for the three centers, respectively, and 85.19% for musculoskeletal tumor detection. We propose that the high success rate could come from the previously overlooked ability of BOLD rs-fMRI in characterizing the abnormal vascularization, vasomotion and perfusion caused by tumors. Our findings suggest an additional usage of the rs-fMRI for comprehensive presurgical assessment.


Evaluation of young children in household contact with adult multidrug-resistant pulmonary tuberculosis cases.
The prevention and management of multidrug-resistant (MDR) tuberculosis has received much attention, but little attention has been given to children with MDR tuberculosis or children in contact with adults with MDR tuberculosis. The aim of this study was to determine the prevalence of tuberculous infection and disease in childhood contacts of adults with MDR pulmonary tuberculosis. All children <5 years of age in household contact with 75 recently diagnosed adults with MDR pulmonary tuberculosis were evaluated. Evaluation included clinical examination, tuberculin skin test, chest radiography and culture for Mycobacterium tuberculosis from gastric aspirates. One hundred twenty-eight children, median age 27 months, were evaluated. Fifty children had recent contact with other adult tuberculosis cases. Sixty-six children previously had chemoprophylaxis or treatment of whom 36 defaulted treatment or received insufficient chemoprophylaxis. One child had HIV infection. Forty-seven children were classified as noninfected, 66 were considered infected only (Mantoux test, > or = 15 mm) and 15 had disease. Three children, who had not previously received antituberculosis drugs, had positive cultures for M. tuberculosis; all were multidrug-resistant. This study documents the transmission of multidrug-resistant M. tuberculosis to childhood contacts, the development of disease in these contacts and the importance of knowing the index case's M. tuberculosis susceptibility pattern in choosing a proper treatment regimen for the childhood contact.


Photoheterotrophic metabolism of acrylamide by a newly isolated strain of Rhodopseudomonas palustris.
Acrylamide, a neurotoxin and suspected carcinogen, is produced by industrial processes and during the heating of foods. In this study, the microbial diversity of acrylamide metabolism has been expanded through the isolation and characterization of a new strain of Rhodopseudomonas palustris capable of growth with acrylamide under photoheterotrophic conditions. The newly isolated strain grew rapidly with acrylamide under photoheterotrophic conditions (doubling time of 10 to 12 h) but poorly under anaerobic dark or aerobic conditions. Acrylamide was rapidly deamidated to acrylate by strain Ac1, and the subsequent degradation of acrylate was the rate-limiting reaction in cell growth. Acrylamide metabolism by succinate-grown cultures occurred only after a lag period, and the induction of acrylamide-degrading activity was prevented by the presence of protein or RNA synthesis inhibitors. 13C nuclear magnetic resonance studies of [1,2,3-13C]acrylamide metabolism by actively growing cultures confirmed the rapid conversion of acrylamide to acrylate but failed to detect any subsequent intermediates of acrylate degradation. Using concentrated cell suspensions containing natural abundance succinate as an additional carbon source, [13C]acrylate consumption occurred with the production and then degradation of [13C]propionate. Although R. palustris strain Ac1 grew well and with comparable doubling times for each of acrylamide, acrylate, and propionate, R. palustris strain CGA009 was incapable of significant acrylamide- or acrylate-dependent growth over the same time course, but grew comparably with propionate. These results provide the first demonstration of anaerobic photoheterotrophic bacterial acrylamide catabolism and provide evidence for a new pathway for acrylate catabolism involving propionate as an intermediate.


Interference effect in scattering loss of high-index-contrast planar waveguides caused by boundary reflections.
We present theoretical and experimental results on an interference effect caused by boundary reflections on the optical scattering loss in high-index-contrast planar waveguides. Analytical expressions for the polarization-dependent scattering loss are derived using a surface Green's function. For high-index-contrast waveguides of submicrometer dimensions a significant deviation from accepted theory arises, including scattering loss suppression owing to a thin-film interference effect. Our theoretical predictions are confirmed by loss measurements on silicon-on-insulator channel waveguides.


Hericium erinaceus Improves Mood and Sleep Disorders in Patients Affected by Overweight or Obesity: Could Circulating Pro-BDNF and BDNF Be Potential Biomarkers?
Epidemiological data indicate that subjects affected by obesity have an increased risk of developing mood disorders. The relationship between obesity and mood disorders is bidirectional. We assessed whether a Hericium erinaceus treatment improved depression, anxiety, sleep, and binge eating disorders after 8 weeks of supplementation in subjects affected by overweight or obesity under a low calorie diet regimen. Looking for a possible clinical biomarker, we assessed the serum balance between brain-derived neurotrophic factor (BDNF) and its precursor pro-BDNF before and after H. erinaceus supplementation. Seventy-seven volunteers affected by overweight or obesity were recruited at the offices of the Department of Preventive Medicine, Luigi Devoto Clinic of Work, Obesity Centre, at the IRCCS Foundation Policlinico Hospital of Milan (Italy). Patients were recruited only if they had a mood and/or sleep disorder and/or were binge eating as evaluated through self-assessment questionnaires. We used two different enzyme-linked immunosorbent assays kits to discriminate circulating levels of pro-BDNF and BDNF. Eight weeks of oral H. erinaceus supplementation decreased depression, anxiety, and sleep disorders. H. erinaceus supplementation improved mood disorders of a depressive-anxious nature and the quality of the nocturnal rest. H. erinaceus increased circulating pro-BDNF levels without any significant change in BDNF circulating levels.


Ab initio molecular dynamics simulation of the energy-relaxation process of the protonated water dimer.
Relaxation processes of the energy-rich protonated water dimer H+(H2O)2 were investigated by the ab initio molecular dynamics (AIMD) method. At first, the energy-rich H+(H2O)2 was reproduced by simulating a collision reaction between the protonated water monomer H3O+ and H2O. Next it was collided with N2 in order to observe the effects of intramolecular vibration redistribution and intermolecular energy transfer. Forty-eight AIMD simulations of the collision of H+(H2O)2 with N2 were performed by changing the initial orientation and the time interval between two collisions. It was revealed that the amount of energy transferred from H+(H2O)2 to N2 decreased the longer the time interval. The relationship between the intermolecular energy transfer and the vibrational states was examined with the use of an energy-transfer spectrogram (ETS), which is an analysis technique combining energy density analysis and short-time Fourier transform. The ETS demonstrates a characteristic vibrational mode for the energy transfer, which corresponds to the stretching of the hydrogen bond between H+(H2O)2 and N2 in an active complex.


Semi-automated detection of cervical spinal cord compression with the Spinal Cord Toolbox.
Degenerative cervical spinal cord compression is becoming increasingly prevalent, yet the MRI criteria that define compression are vague, and vary between studies. This contribution addresses the detection of compression by means of the Spinal Cord Toolbox (SCT) and assesses the variability of the morphometric parameters extracted with it. Prospective cross-sectional study. Two types of MRI examination, 3 and 1.5 T, were performed on 66 healthy controls and 118 participants with cervical spinal cord compression. Morphometric parameters from 3T MRI obtained by Spinal Cord Toolbox (cross-sectional area, solidity, compressive ratio, torsion) were combined in multivariate logistic regression models with the outcome (binary dependent variable) being the presence of compression determined by two radiologists. Inter-trial (between 3 and 1.5 T) and inter-rater (three expert raters and SCT) variability of morphometric parameters were assessed in a subset of 35 controls and 30 participants with compression. The logistic model combining compressive ratio, cross-sectional area, solidity, torsion and one binary indicator, whether or not the compression was set at level C6/7, demonstrated outstanding compression detection (area under curve =0.947). The single best cut-off for predicted probability calculated using a multiple regression equation was 0.451, with a sensitivity of 87.3% and a specificity of 90.2%. The inter-trial variability was better in Spinal Cord Toolbox (intraclass correlation coefficient was 0.858 for compressive ratio and 0.735 for cross-sectional area) compared to expert raters (mean coefficient for three expert raters was 0.722 for compressive ratio and 0.486 for cross-sectional area). The analysis of inter-rater variability demonstrated general agreement between SCT and three expert raters, as the correlations between SCT and raters were generally similar to those of the raters between one another. This study demonstrates successful semi-automated compression detection based on four parameters. The inter-trial variability of parameters established through two MRI examinations was conclusively better for Spinal Cord Toolbox compared with that of three experts' manual ratings.


Advances in the Treatment of Mucoepidermoid Carcinoma.
Mucoepidermoid carcinoma (MEC) represents 10-15% of salivary neoplasms. Due to their low incidence, it is challenging to conduct clinical trials and develop treatment guidelines. Although surgery is the most common approach for a resectable tumor, various treatment options such as chemotherapy, radiotherapy, and immunotherapy have been investigated. There is a need to implement a standardized treatment protocol to effectively manage MEC as it is a common histological subtype. Furthermore, it has become essential to assess chromosomal and genetic abnormalities recently identified with MEC, including alterations of CDKN2A, TP53, CDKN2B, BAP1, etc. These mutations are involved in the transformation of low-grade tumors to high-grade tumors, presenting a vital tool for evaluating the aggressive behavior of this carcinoma. Detailed immunohistochemical and translocation studies can help develop targeted therapies and monitor treatment response. Therefore, biomarker-driven research will immensely improve the outcome, especially in advanced cases. Based on thorough histology and chromosomal translocations, a more personalized treatment plan can improve the overall disease outcome. The purpose of this article is to elaborate on the current treatment advancements, particularly chemotherapy and targeted therapy, as an effective treatment modality for the management of MEC and highlight the comparison with traditional treatment approaches.


Gender, race, and socioeconomic status affects outcomes after lung cancer resections in the United States.
The effect of gender, race, and socioeconomic status on contemporary outcomes after lung cancer resections has not been comprehensively evaluated across the United States. We hypothesized that risk-adjusted outcomes for lung cancer resections would not be influenced by these factors. From 2003 to 2007, 129,207 patients undergoing lung cancer resections were evaluated using the Nationwide Inpatient Sample (NIS) database. Multiple regression analysis was used to estimate the effects of gender, race, and socioeconomic status on risk-adjusted outcomes. Average patient age was 66.8±10.5 years. Women accounted for 5.0% of the total study population. Among racial groups, whites underwent the largest majority of operations (86.2%), followed by black (6.9%) and Hispanic (2.8%) races. Overall the incidence of mortality was 2.9%, postoperative complications were 30.4%, and pulmonary complications were 22.0%. Female gender, race, and mean income were all multivariate correlates of adjusted mortality and morbidity. Black patients incurred decreased risk-adjusted morbidity and mortality compared with white patients. Hispanics and Asians demonstrated decreased risk-adjusted complication rates. Importantly low income status independently increased the adjusted odds of mortality. Female gender is associated with decreased mortality and morbidity after lung cancer resections. Complication rates are lower for black, Hispanic, and Asian patients. Low socioeconomic status increases the risk of in-hospital death. These factors should be considered during patient risk stratification for lung cancer resection.


Cultural stereotypes as gatekeepers: increasing girls' interest in computer science and engineering by diversifying stereotypes.
Despite having made significant inroads into many traditionally male-dominated fields (e.g., biology, chemistry), women continue to be underrepresented in computer science and engineering. We propose that students' stereotypes about the culture of these fields-including the kind of people, the work involved, and the values of the field-steer girls away from choosing to enter them. Computer science and engineering are stereotyped in modern American culture as male-oriented fields that involve social isolation, an intense focus on machinery, and inborn brilliance. These stereotypes are compatible with qualities that are typically more valued in men than women in American culture. As a result, when computer science and engineering stereotypes are salient, girls report less interest in these fields than their male peers. However, altering these stereotypes-by broadening the representation of the people who do this work, the work itself, and the environments in which it occurs-significantly increases girls' sense of belonging and interest in the field. Academic stereotypes thus serve as gatekeepers, driving girls away from certain fields and constraining their learning opportunities and career aspirations.


Frequent loss of heterozygosity at the TEL gene locus in acute lymphoblastic leukemia of childhood.
TEL is a new member of the ETS family of transcription factors which is rearranged in a number of hematologic malignancies with translocations involving chromosome band 12p13. In some cases, both TEL alleles are affected, resulting in loss of wild-type TEL function in the leukemic cells. In addition, 5% of children with acute lymphoblastic leukemia (ALL) have 12p12-p13 deletions, suggesting that a tumor suppressor gene resides on 12p. These observations led us to consider whether TEL loss of function may contribute to the pathogenesis of ALL. In this report we show that the TEL gene maps between the polymorphic markers D12S89 and D12S98, and we use these flanking markers to screen paired diagnosis and remission samples from 81 children with ALL for loss of heterozygosity (LOH) at the TEL gene locus. Fifteen percent of informative patients showed TEL LOH which was not evident on cytogenetic analysis. Detailed examination of patients with LOH at this locus showed that the critically deleted region included two candidate tumor suppressor genes: TEL and KIP1, the gene encoding the cyclin-dependent kinase inhibitor p27. These studies show that LOH at the TEL locus is a frequent finding in childhood ALL.


Attitudes to research ethical committees.
A questionnaire on the attitudes towards the functions of research ethical committees was sent to members of selected research ethical committees in Wessex and some controls. Almost all respondents felt there was a need for ethical review of research projects; 42 per cent thought there was a need for some training before joining a committee; 67 per cent thought the system could be improved and 47 per cent thought that monitoring or follow-up procedures should be adopted. Ethical committees were thought to be purely advisory, as opposed to mandatory, by 33 per cent, and 63 per cent thought they should restrict their review to ethical problems as opposed to scientific or design problems. Views about the function of non-medical members ranged from 'none at all' to 'very important'. Of the 10 controls who were asked whether they would become a member of an ethical committee if asked, seven said that on balance they would and the reasons stated varied from the view that it was a 'very important committee' to the feeling that it was 'a necessary but irksome job'.


Pre-clinical evaluation of ceramic femoral head resurfacing prostheses using computational models and mechanical testing.
Ceramic-on-ceramic hip resurfacing can potentially offer the bone-conserving advantages of resurfacing while eliminating metal ion release. Thin-walled ceramic resurfacing heads are conceivable following developments in the strength and reliability of ceramic materials, but verification of new designs is required. The present study aimed to develop a mechanical pre-clinical analysis verification process for ceramic resurfacing heads, using the DeltaSurf prosthesis design as a case study. Finite element analysis of a range of in vivo scenarios was used to design a series of physiologically representative mechanical tests, which were conducted to verify the strength of the prosthesis. Tests were designed to simulate ideal and worst-case in vivo loading and support, or to allow comparison with a clinically successful metallic device. In tests simulating ideal loading and support, the prosthesis sustained a minimum load of 39 kN before fracture, and survived 10 000 000 fatigue cycles of 0.534 kN to 5.34 kN. In worst-case tests representing a complete lack of superior femoral head bone support or pure cantilever loading of the prosthesis stem, the design demonstrated strength comparable to that of the equivalent metal device. The developed mechanical verification test programme represents an improvement in the state of the art where international test standards refer largely to total hip replacement prostheses. The case study's novel prosthesis design performed with considerable safety margins compared with extreme in vivo loads, providing evidence that the proposed ceramic resurfacing heads should have sufficient strength to perform safely in vivo. Similar verification tests should be designed and conducted for novel ceramic prosthesis designs in the future, leading the way to clinical evaluation.


Immobilization of antimicrobial peptide IG-25 onto fluoropolymers via fluorous interactions and click chemistry.
We report a practical method for biofunctionalization of fluoropolymers based on noncovalent, fluorous interactions and click chemistry that allows incorporation of biomolecules under physiological solutions. We demonstrate the method by immobilization of an antimicrobial peptide (AMP) on fluorous thin films and fluorosilicone contact lens. The fluorous surfaces were dip-coated with fluorous-tagged oligo(ethylene) chain terminated with a reactive group, such as an alkynyl group. This simple step generates a "clickable" surface. The noncovalent fluorous interaction was strong enough to allow subsequent covalent attachment of IG-25, a truncated version of the most extensively studied human AMP LL-37. The attachment was through copper-catalyzed click reaction between the alkynyl group on the surface and the azido-OEG tag at the N-terminus of IG-25. In comparison to surfaces presenting IG-25 randomly bound via carbodiimide chemistry, the surfaces presenting IG-25 tethering to the surface at the N-terminus via click chemistry displayed higher antibacterial activities against an ocular pathogen Pseudomonas aeruginosa (strain PA-O1).


Schistosoma japonicum and occult blood loss in endemic villages in Leyte, the Philippines.
Schistosoma japonicum has been related to anemia, but the mechanisms mediating this relationship remain unresolved. The primary objective of this study was to assess the role of occult blood loss in mediating S. japonicum-associated anemia after adjusting for age, sex, socioeconomic status (SES), and other helminth infections. The secondary objective was to identify intensity categories of risk for occult blood loss for Trichuris and hookworm after adjustment for the presence of other helminth infections. The role of occult blood loss in mediating S. japonicum-associated anemia was studied cross-sectionally in 729 individuals 8-30 years old in Leyte, The Philippines. Three stool specimens were examined in duplicate for helminth eggs. Hemoglobin, fecal occult blood loss, and anemia were measured and related to the presence and intensity of helminths. Multivariate models were made to adjust for confounding by other helminths and SES. In multivariate models, hemoglobin significantly decreased with increasing infection intensity of S. japonicum, hookworm, and T. trichuria (P < 0.0031, P < 0.0001, and P < 0.0001, respectively). Individuals with higher intensities S. japonicum and T. trichuria were significantly more likely to be fecal occult positive (odds ratio [OR] = 3.54; P = 0.008 and OR = 2.68; P = 0.013, respectively), although this was not true for individuals with hookworm. Additionally, individuals with higher intensities of S. japonicum, hookworm, and T. trichuria were all more likely to be anemic (OR = 3.7, P = 0.0002; OR = 5.3, P = 0.0003; and OR = 1.6, P = 0.021, respectively). It is likely that occult blood loss plays a role only at heavier intensity S. japonicum infections and some other mechanism, such as anemia of inflammation, may be contributing to anemia.


Patterns and predictors of sleep quality before, during, and after hospitalization in older adults.
The impact of hospitalization on sleep in late-life is underexplored. The current study examined patterns of sleep quality before, during, and following hospitalization, investigated predictors of sleep quality patterns, and examined predictors of classification discordance between two suggested clinical cutoffs used to demarcate poor/good sleep. This study included older adults (n = 163; mean age 79.7 ± 6.9 years, 31% female) undergoing inpatient post-acute rehabilitation. Upon admission to inpatient post-acute rehabilitation, patients completed the Pittsburgh Sleep Quality Index (PSQI) retrospectively regarding their sleep prior to hospitalization. They subsequently completed the PSQI at discharge, and 3 months, 6 months, 9 months, and 1 year post discharge. Patient demographic and clinical characteristics (pain, depression, cognition, comorbidity) were collected upon admission. Using latent class analysis methods, older adults could be classified into (1) Consistently Good Sleepers and (2) Chronically Poor Sleepers based on patterns of self-reported sleep quality pre-illness, during, and up to 1 year following inpatient rehabilitation. This pattern was maintained regardless of the clinical cutoff employed (> 5 or > 8). Logistic regression analyses indicated that higher pain and depressive symptoms were consistently associated with an increased likelihood of being classified as a chronic poor sleeper. While there was substantial classification discordance based on clinical cutoff employed, no significant predictors of this discordance emerged. Clinicians should exercise caution in assessing sleep quality in inpatient settings. Alterations in the cutoffs employed may result in discordant clinical classifications of older adults. Pain and depression warrant detailed considerations when working with older adults on inpatient units when poor sleep is a concern.


Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor Treatment Response in Advanced Lung Adenocarcinomas with G719X/L861Q/S768I Mutations.
Epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) is the standard therapy for advanced lung adenocarcinomas with common EGFR mutations. Preclinical studies have suggested that uncommon G719X, L861Q, and S768I mutations are also sensitive to EGFR-TKIs. However, the efficacy of EGFR-TKIs in patients with these uncommon mutations remains unclear. A nationwide survey was performed to collect data from gefitinib and erlotinib treatment outcomes of patients with stage IIIB/IV lung adenocarcinoma bearing EGFR G719X/L861Q/S768I mutations. The results were compared with those regarding patients with exon 19 deletions or L858R mutations. One hundred and sixty-one patients with uncommon EGFR mutations were enrolled from 18 institutes throughout Taiwan. Mutations of G719X, L861Q, S768I, G719X + L861Q, and G719X + S768I were observed in 78, 57, 7, 9, and 10 patients, respectively. After receiving EGFR-TKI treatment, patients with uncommon mutations exhibited a significantly inferior tumor response rate (41.6% vs. 66.5%; p < 0.001) and progression-free survival (median, 7.7 vs. 11.4 months; p < 0.001) than patients with common mutations. Among the patients who used EGFR-TKIs as first-line treatment, there was a significant difference in overall survival between these two groups of patients (median, 24.0 vs. 29.7 months; p = 0.005). Gefitinib and erlotinib are active in patients with G719X/L861Q/S768I mutations; however, less effective than in those with common mutations.


GSK-3 as potential target for therapeutic intervention in cancer.
The serine/threonine kinase glycogen synthase kinase-3 (GSK-3) was initially identified and studied in the regulation of glycogen synthesis. GSK-3 functions in a wide range of cellular processes. Aberrant activity of GSK-3 has been implicated in many human pathologies including: bipolar depression, Alzheimer's disease, Parkinson's disease, cancer, non-insulin-dependent diabetes mellitus (NIDDM) and others. In some cases, suppression of GSK-3 activity by phosphorylation by Akt and other kinases has been associated with cancer progression. In these cases, GSK-3 has tumor suppressor functions. In other cases, GSK-3 has been associated with tumor progression by stabilizing components of the beta-catenin complex. In these situations, GSK-3 has oncogenic properties. While many inhibitors to GSK-3 have been developed, their use remains controversial because of the ambiguous role of GSK-3 in cancer development. In this review, we will focus on the diverse roles that GSK-3 plays in various human cancers, in particular in solid tumors. Recently, GSK-3 has also been implicated in the generation of cancer stem cells in various cell types. We will also discuss how this pivotal kinase interacts with multiple signaling pathways such as: PI3K/PTEN/Akt/mTORC1, Ras/Raf/MEK/ERK, Wnt/beta-catenin, Hedgehog, Notch and others.


Membrane trafficking in neuronal maintenance and degeneration.
Defects in membrane trafficking and degradation are hallmarks of most, and maybe all, neurodegenerative disorders. Such defects typically result in the accumulation of undegraded proteins due to aberrant endosomal sorting, lysosomal degradation, or autophagy. The genetic or environmental cause of a specific disease may directly affect these membrane trafficking processes. Alternatively, changes in intracellular sorting and degradation can occur as cellular responses of degenerating neurons to unrelated primary defects such as insoluble protein aggregates or other neurotoxic insults. Importantly, altered membrane trafficking may contribute to the pathogenesis or indeed protect the neuron. The observation of dramatic changes to membrane trafficking thus comes with the challenging need to distinguish pathological from protective alterations. Here, we will review our current knowledge about the protective and destructive roles of membrane trafficking in neuronal maintenance and degeneration. In particular, we will first focus on the question of what type of membrane trafficking keeps healthy neurons alive in the first place. Next, we will discuss what alterations of membrane trafficking are known to occur in Alzheimer's disease and other tauopathies, Parkinson's disease, polyQ diseases, peripheral neuropathies, and lysosomal storage disorders. Combining the maintenance and degeneration viewpoints may yield insight into how to distinguish when membrane trafficking functions protectively or contributes to degeneration.


The Maudsley Outpatient Study of Treatments for Anorexia Nervosa and Related Conditions (MOSAIC): Comparison of the Maudsley Model of Anorexia Nervosa Treatment for Adults (MANTRA) with specialist supportive clinical management (SSCM) in outpatients with broadly defined anorexia nervosa: A randomized controlled trial.
Anorexia nervosa (AN) in adults has poor outcomes, and treatment evidence is limited. This study evaluated the efficacy and acceptability of a novel, targeted psychological therapy for AN (Maudsley Model of Anorexia Nervosa Treatment for Adults; MANTRA) compared with Specialist Supportive Clinical Management (SSCM). One hundred forty-two outpatients with broadly defined AN (body mass index [BMI] ≤ 18.5 kg/m²) were randomly allocated to receive 20 to 30 weekly sessions (depending on clinical severity) plus add-ons (4 follow-up sessions, optional sessions with dietician and with carers) of MANTRA (n = 72) or SSCM (n = 70). Assessments were administered blind to treatment condition at baseline, 6 months, and 12 months after randomization. The primary outcome was BMI at 12 months. Secondary outcomes included eating disorders symptomatology, other psychopathology, neuro-cognitive and social cognition, and acceptability. Additional service utilization was also assessed. Outcomes were analyzed using linear mixed models. Both treatments resulted in significant improvements in BMI and reductions in eating disorders symptomatology, distress levels, and clinical impairment over time, with no statistically significant difference between groups at either 6 or 12 months. Improvements in neuro-cognitive and social-cognitive measures over time were less consistent. One SSCM patient died. Compared with SSCM, MANTRA patients rated their treatment as significantly more acceptable and credible at 12 months. There was no significant difference between groups in additional service consumption. Both treatments appear to have value as first-line outpatient interventions for patients with broadly defined AN. Longer term outcomes remain to be evaluated.


Evaluation of antioxidant activity by chemiluminescence.
A sensitive and simple chemiluminescent method for measuring antioxidant activity was developed. The method is based on antioxidant-dependent quenching of chemiluminescence generated from lipid hydroperoxide and isoluminol/microperoxidase reagent. This method was used to evaluate the antioxidant ability of various antioxidants by measuring the half-inhibition concentration (IC50). The results were compared to those measured with an oxygen electrode method. They were approximately similar in pattern and level, although there was some discrepancy, which was assumed to be due to a possible difference in the reaction mechanisms of the two methods. This method also suggested an additive property of antioxidant activity with different antioxidants. Thus, the present method was used to evaluate the total antioxidant activity in biological tissues such as rat serum, human saliva, and green tea.


Stem Rust Resistance in A-Genome Diploid Relatives of Wheat.
Wheat stem rust, caused by Puccinia graminis f. sp. tritici, has been effectively controlled through the use of genetic resistance. P. graminis f. sp. tritici race TTKSK (Ug99) possesses virulence to many resistance genes that have been used in wheat breeding worldwide. One strategy to aid breeders in developing resistant cultivars is to utilize resistance genes transferred from wild relatives to wheat. Stem rust resistance genes have previously been introgressed from Triticum monococcum to wheat. In order to identify additional resistance genes, we screened 1,061 accessions of T. monococcum and 205 accessions of T. urartu against race TTKSK and four additional P. graminis f. sp. tritici races: TTTTF, TRTTF, QFCSC, and MCCFC. A high frequency of the accessions (78.7% of T. monococcum and 93.0% of T. urartu) were resistant to P. graminis f. sp. tritici race TTKSK, with infection types ranging from 0 to 2+. Among these resistant accessions, 55 T. monococcum accessions (6.4% of the total) were also resistant to the other four races. Associations of resistance in T. monococcum germplasm to different races indicated the presence of genes conferring resistance to multiple races. Comparing the observed infection type patterns to the expected patterns of known genes indicated that previously uncharacterized genes for resistance to race TTKSK exist in both T. monococcum and T. urartu.


Educating and training India's next generation of in vivo pharmacologists.
The Indian Pharmaceutical Industry is undergoing rapid development and expansion. Critical to this process, and the future of drug discovery in India is the continued education and training of integrative or in vivo pharmacologists, equipped with the knowledge, skills and expertise to undertake studies using laboratory animals. Modern in vivo pharmacologists not only require manual or technical skills, but a much broader education including in animal welfare, ethics, the principles of the replacement, refinement and reduction of animals in research, and nonanimal alternative techniques. This education, training, and continued professional development throughout their careers can be provided, in part, through the use of online e-learning resources. While many excellent resources exist, they are hard to locate and not widely known to the community. To address this issue, Education and Training Resources in In vivo Sciences, a free website which provides access to free open access e-learning resources in in vivo pharmacology was developed. Use of this resource by researchers and educators will result in better-trained researchers and members of ethical review committees, which in turn will raise animal welfare standards, minimize the pain, suffering and distress of laboratory animals, and enhance scientific research.


Optogenetic acidification of synaptic vesicles and lysosomes.
Acidification is required for the function of many intracellular organelles, but methods to acutely manipulate their intraluminal pH have not been available. Here we present a targeting strategy to selectively express the light-driven proton pump Arch3 on synaptic vesicles. Our new tool, pHoenix, can functionally replace endogenous proton pumps, enabling optogenetic control of vesicular acidification and neurotransmitter accumulation. Under physiological conditions, glutamatergic vesicles are nearly full, as additional vesicle acidification with pHoenix only slightly increased the quantal size. By contrast, we found that incompletely filled vesicles exhibited a lower release probability than full vesicles, suggesting preferential exocytosis of vesicles with high transmitter content. Our subcellular targeting approach can be transferred to other organelles, as demonstrated for a pHoenix variant that allows light-activated acidification of lysosomes.


A human PKD1 transgene generates functional polycystin-1 in mice and is associated with a cystic phenotype.
Three founder transgenic mice were generated with a 108 kb human genomic fragment containing the entire autosomal dominant polycystic kidney disease (ADPKD) gene, PKD1, plus the tuberous sclerosis gene, TSC2. Two lines were established (TPK1 and TPK3) each with approximately 30 copies of the transgene. Both lines produced full-length PKD1 mRNA and polycystin-1 protein that was developmentally regulated, similar to the endogenous pattern, with expression during renal embryogenesis and neonatal life, markedly reduced at the conclusion of renal development. Tuberin expression was limited to the brain. Transgenic animals from both lines (and the TPK2 founder animal) often displayed a renal cystic phenotype, typically consisting of multiple microcysts, mainly of glomerular origin. Hepatic cysts and bile duct proliferation, characteristic of ADPKD, were also seen. All animals with two copies of the transgenic chromosome developed cysts and, in total, 48 of the 100 transgenic animals displayed a cystic phenotype. To test the functionality of the transgene, animals were bred with the Pkd1(del34) knockout mouse. Both transgenic lines rescued the embryonically lethal Pkd1(del34/del34) phenotype, demonstrating that human polycystin-1 can complement for loss of the endogenous protein. The rescued animals were viable into adulthood, although more than half developed hepatic cystic disease in later life, similar to the phenotype of older Pkd1(del34/+) animals. The TPK mice have defined a minimal area that appropriately expresses human PKD1. Furthermore, this model indicates that over-expression of normal PKD1 can elicit a disease phenotype, suggesting that the level of polycystin-1 expression may be relevant in the human disease.


Phase II study of combination chemotherapy with docetaxel and carboplatin for locally advanced or recurrent cervical cancer.
The efficacy and toxicity of combination chemotherapy with docetaxel + carboplatin were evaluated in patients with locally advanced or recurrent cervical cancer. A total of 71 patients with cervical cancer were enrolled into this trial, and 66 patients were considered eligible. The patients were administered docetaxel at 60 mg/m2 followed by carboplatin based on area under the curve of 6, both by intravenous infusion, every 3 weeks, with the treatment repeated for 1 to 6 cycles depending on the goal of the therapy. The response was evaluated based on the Response Evaluation Criteria in Solid Tumors criteria. Toxicity to chemotherapy was evaluated according to the National Cancer Institute Common Toxicity Criteria. Of the 66 eligible patients, 62 had locally advanced cervical cancer with no history of previous treatment, whereas 4 patients had recurrent cervical cancer. A total 149 cycles of chemotherapy were administered, with a median of 2.3 cycles (range, 1-6) per patient. The overall clinical response rate was 63.7% (44/66, 95% confidence interval, 52.1-75.3). In the neoadjuvant chemotherapy setting, the overall clinical response rate was 69.3% (43/62; 43/62, 95% confidence interval, 57.8-80.8), and the response rates in patients with squamous cell carcinoma and nonsquamous cell carcinoma were 69.7% (23/33, 95% confidence interval, 54.0-85.4) and 68.9% (20/29, 95% confidence interval, 52.1-85.7), respectively. On the other hand, in patients with recurrent cervical cancer, the overall response rate was 25.0% (1/4, 95% confidence interval, -17.4 to 67.4). Nonhematological toxicities were mainly grade 1 or 2. Hematological toxicity was encountered mostly in the form of neutropenia and thrombocytopenia. Combination chemotherapy with docetaxel + carboplatin is a safe and well-tolerated treatment for patients with advanced cervical cancer and is effective against not only squamous cell carcinoma, but also adenocarcinoma.


Pharmacogenomics and pharmacogenetics of cholesterol-lowering therapy.
Cholesterol-lowering therapy is the central approach in the primary and secondary prevention of cardiovascular disease, the leading cause of death in industrialized countries. 3-Hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors (statins) are currently the most potent and widely used cholesterol-lowering drugs. Large-scale clinical trials unequivocally demonstrated the efficacy of statin treatment in reducing the risk of cardiovascular events. In general, HMG-CoA reductase inhibitors are well tolerated, although in a minority of patients severe adverse effects like myopathy or rhabdomyolysis may develop. The incidence of this potentially life-threatening side effects increases with co-adminstration of drugs that are metabolized via the same pharmacokinetic pathways or at high-dose statin therapy. The recent focus on the pleiotropic effects of statins that are more frequently observed at higher doses and the conclusion drawn from the large statin trials that low-density lipoprotein (LDL)-cholesterol is "the lower the better", may need careful consideration in individuals at risk of adverse drug reactions. On the other hand, not all patients respond to statin therapy with a reduction in coronary heart disease (CHD) risk. It is therefore of interest to develop diagnostic test systems, which would allow to identify patients at increased risk of adverse drug reactions or patients with a lack of therapeutic effect. Beside exogenous factors, genetic variability determines the response of an individual to drug therapy and the analysis of genetic variants affecting pharmacokinetic or pharmacodynamic aspects of drug therapy is the subject of pharmacogenomics. This review summarizes current knowledge of the pharmacology and the pharmacogenomics of statin therapy.


Staphylococcus cohnii: a case report on an unusual pathogen.
Coagulase-negative staphylococci have become increasingly important causes of infection in predisposed hosts. such as patients receiving immunosuppressive therapy and broad-spectrum antimicrobial drugs, patients who have prosthetic devices, or those who have prolonged hospital or intensive care unit stays. However, human infections caused by Staphylococcus cohnii rarely have been reported in the literature. In this report, we review the current literature and describe a 38 year-old immunosuppressed woman who developed catheter-related S. cohnii bacteremia. The case illustrates why microbiology laboratories under certain circumstances should identify coagulase-negative staphylococci to the species level. This information may be critical because it may allow clinicians to identify the source of the infecting organism and to choose appropriate antibiotics. Yet in this era of cost containment many laboratories may decrease costs by decreasing services, including species identification.


Effect of coenzyme Q10 intake on endogenous coenzyme Q content, mitochondrial electron transport chain, antioxidative defenses, and life span of mice.
The main purpose of this study was to determine whether intake of coenzyme Q10, which can potentially act as both an antioxidant and a prooxidant, has an impact on indicators of oxidative stress and the aging process. Mice were fed diets providing daily supplements of 0, 93, or 371 mg CoQ10 /kg body weight, starting at 3.5 months of age. Effects on mitochondrial superoxide generation, activities of oxidoreductases, protein oxidative damage, glutathione redox state, and life span of male mice were determined. Amounts of CoQ9 and CoQ10, measured after 3.5 or 17.5 months of intake, in homogenates and mitochondria of liver, heart, kidney, skeletal muscle, and brain increased with the dosage and duration of CoQ10 intake in all the tissues except brain. Activities of mitochondrial electron transport chain oxidoreductases, rates of mitochondrial O2-* generation, state 3 respiration, carbonyl content, glutathione redox state of tissues, and activities of superoxide dismutase, catalase, and glutathione peroxidase, determined at 19 or 25 months of age, were unaffected by CoQ10 administration. Life span studies, conducted on 50 mice in each group, showed that CoQ10 administration had no effect on mortality. Altogether, the results indicated that contrary to the historical view, supplemental intake of CoQ10 elevates the endogenous content of both CoQ9 and CoQ10, but has no discernable effect on the main antioxidant defenses or prooxidant generation in most tissues, and has no impact on the life span of mice.


Prenatal exposure to toluene results in abnormal neurogenesis and migration in rat somatosensory cortex.
Toluene inhalant abuse during pregnancy may result in growth-retarded microcephalic newborns who subsequently demonstrate developmental impairment. By using a rat model of toluene-abuse embryopathy, we studied the effects of prenatal toluene exposure on the generation and migration of cortical neurons. Dams were exposed by gavage to either corn oil or toluene diluted in corn oil on d 6-21 of gestation. The time of origin of cortical neurons was determined in the mature pups of dams injected with the thymidine analogue 5'-bromodeoxyuridine on 1 d during the period from d 13-21 of gestation. 5'-Bromodeoxyuridine-labeled neurons were identified by immunohistochemistry in a 400-microm-wide column of somatosensory cortex. The brains of the toluene-exposed pups had a significant reduction in the number of neurons within each cortical layer (p < 0.001). Depending on the cortical layer, the generation of neurons in the toluene-exposed pups was delayed by 1 or 2 d. In addition, the brains of the toluene-exposed pups also showed evidence of abnormal neuronal migration. However, there were no differences in either brain weight or body weight between the control and toluene-exposed pups. These observations suggest that although prenatal toluene exposure results in abnormal neuronal proliferation and migration, brain weight in the toluene-exposed pups may be preserved by enhanced development of glia or the neuropil.


Prevalence of obesity in Great Britain.
Since 1980 the prevalence of obesity in Great Britain in adults has almost trebled. Latest figures show that 23% of men and 25% of women were obese in 2002. In children, obesity prevalence is lower but the increase in the prevalence of overweight is similar to the rise in obesity in adults. Data from national surveys also show that there are marked differences in the prevalence of obesity that underpin health inequalities. Obesity is higher in low social classes, some ethnic minority groups particularly from South Asia and in Scotland and Wales relative to England.


[1,2,3]Triazolo[1,5-a]pyridyl phosphines reflecting the influence of phosphorus lone pair orientation on spectroscopic properties.
A series of new triazolopyridine-based phosphines has been prepared. These compounds revealed unexpected spectroscopic patterns. In particular, the NMR spectra are highly dependent on the relative conformational preference of the phosphine substituent at C7. Here, we report on their complete NMR analysis, X-ray structures and DFT calculations that confirm the particular arrangement of the phosphorus lone pair orbital related to the substituent pattern of the chosen phosphine.


Family Acculturation in Host and Immigrant Couples: Dyadic Research in an Italian Context.
The purpose of this research is to study acculturation strategies and attitudes in central and peripheral domains of host and immigrant couples in an Italian context. The participants were 60 dyads (30 host couples and 30 immigrant couples) who completed a questionnaire based on the Relative Acculturation Extended Model (RAEM). Based on the analysis, we found that the general acculturation attitude preferred by immigrant couples is integration, and Italian couples prefer that immigrants adopt it. Furthermore, Italian partners show moderate internal agreement, whereas immigrant couples show a high degree of agreement. In both groups, the level of agreement between dyadic members is only partially determined by their membership within a social group. The socio-cultural context has a significant role in the internal similarity of Italian couples. In contrast, there is dyadic agreement within immigrant couples.


'Read-through marking' reveals differential nucleotide composition of read-through and truncated cDNAs in iCLIP.
We established a modified iCLIP protocol, called 'read-through marking', which facilitates the detection of cDNAs that have not been truncated upon encountering the RNA-peptide complex during reverse transcription (read-through cDNAs). A large proportion of these cDNAs would be undesirable in an iCLIP library, as it could affect the resolution of the method. To this end, we added an oligonucleotide to the 5'-end of RNA fragments-a 5'-marker-to mark the read-through cDNAs. By applying this modified iCLIP protocol to PTBP1 and eIF4A3, we found that the start sites of read-through cDNAs are enriched in adenosines, while the remaining cDNAs have a markedly different sequence content at their starts, preferentially containing thymidines. This finding in turn indicates that most of the reads in our iCLIP libraries are a product of truncation with valuable information regarding the proteins' RNA-binding sites. Thus, cDNA start sites confidently identify a protein's RNA-crosslink sites and we can account for the impact of read-through cDNAs by commonly adding a 5'-marker.


Expert Consensus and Narrative Review on the Management of Multiple Sclerosis in the Arabian Gulf in the COVID-19 Era: Focus on Disease-Modifying Therapies and Vaccination Against COVID-19.
This article describes consensus recommendations from an expert group of neurologists from the Arabian Gulf region on the management of relapsing multiple sclerosis (RMS) in the COVID-19 era. MS appears not to be a risk factor for severe adverse COVID-19 outcomes (though patients with advanced disability or a progressive phenotype are at higher risk). Disease-modifying therapy (DMT)-based care appears generally safe for patients with MS who develop COVID-19 (although there may be an increased risk of adverse outcomes with anti-CD20 therapy). Interferon-β, teriflunomide, dimethyl fumarate, glatiramer acetate, natalizumab and cladribine tablets are unlikely to increase the risk of infection; fingolimod, anti-CD20 agents and alemtuzumab may confer an intermediate risk. Existing DMT therapy should be continued at this time. For patients requiring initiation of a DMT, all currently available DMTs except alemtuzumab can be started safely at this time; initiate alemtuzumab subject to careful individual risk-benefit considerations. Patients should receive vaccination against COVID-19 where possible, with no interruption of existing DMT-based care. There is no need to alter the administration of interferon-β, teriflunomide, dimethyl fumarate, glatiramer acetate, natalizumab, fingolimod or cladribine tablets for vaccination; new starts on other DMTs should be delayed for up to 6 weeks after completion of vaccination to allow the immune response to develop. Doses of the Oxford University/AstraZeneca vaccine may be scheduled around doses of anti-CD20 or alemtuzumab. Where white cell counts are suppressed by treatment, these should be allowed to recover before vaccination.


Examining the Reversibility of Long-Term Behavioral Disruptions in Progeny of Maternal SSRI Exposure.
Serotonergic dysregulation is implicated in numerous psychiatric disorders. Serotonin plays widespread trophic roles during neurodevelopment; thus perturbations to this system during development may increase risk for neurodevelopmental disorders. Epidemiological studies have examined association between selective serotonin reuptake inhibitor (SSRI) treatment during pregnancy and increased autism spectrum disorder (ASD) risk in offspring. It is unclear from these studies whether ASD susceptibility is purely related to maternal psychiatric diagnosis, or if treatment poses additional risk. We sought to determine whether maternal SSRI treatment alone or in combination with genetically vulnerable background was sufficient to induce offspring behavior disruptions relevant to ASD. We exposed C57BL/6J or Celf6+/- mouse dams to fluoxetine (FLX) during different periods of gestation and lactation and characterized offspring on tasks assessing social communicative interaction and repetitive behavior patterns including sensory sensitivities. We demonstrate robust reductions in pup ultrasonic vocalizations (USVs) and alterations in social hierarchy behaviors, as well as perseverative behaviors and tactile hypersensitivity. Celf6 mutant mice demonstrate social communicative deficits and perseverative behaviors, without further interaction with FLX. FLX re-exposure in adulthood ameliorates the tactile hypersensitivity yet exacerbates the dominance phenotype. This suggests acute deficiencies in serotonin levels likely underlie the abnormal responses to sensory stimuli, while the social alterations are instead due to altered development of social circuits. These findings indicate maternal FLX treatment, independent of maternal stress, can induce behavioral disruptions in mammalian offspring, thus contributing to our understanding of the developmental role of the serotonin system and the possible risks to offspring of SSRI treatment during pregnancy.


Bedrock composition regulates mountain ecosystems and landscape evolution.
Earth's land surface teems with life. Although the distribution of ecosystems is largely explained by temperature and precipitation, vegetation can vary markedly with little variation in climate. Here we explore the role of bedrock in governing the distribution of forest cover across the Sierra Nevada Batholith, California. Our sites span a narrow range of elevations and thus a narrow range in climate. However, land cover varies from Giant Sequoia (Sequoiadendron giganteum), the largest trees on Earth, to vegetation-free swaths that are visible from space. Meanwhile, underlying bedrock spans nearly the entire compositional range of granitic bedrock in the western North American cordillera. We explored connections between lithology and vegetation using measurements of bedrock geochemistry and forest productivity. Tree-canopy cover, a proxy for forest productivity, varies by more than an order of magnitude across our sites, changing abruptly at mapped contacts between plutons and correlating with bedrock concentrations of major and minor elements, including the plant-essential nutrient phosphorus. Nutrient-poor areas that lack vegetation and soil are eroding more than two times slower on average than surrounding, more nutrient-rich, soil-mantled bedrock. This suggests that bedrock geochemistry can influence landscape evolution through an intrinsic limitation on primary productivity. Our results are consistent with widespread bottom-up lithologic control on the distribution and diversity of vegetation in mountainous terrain.


Blood cultures in sick children.
Blood cultures (BCs) are frequently performed in sick children. A recent audit of BCs among adult patients documented high rates of contamination by coagulase-negative staphylococci (CoNS). To describe BC contamination rates and common pathogenic organisms causing bloodstream infection in children at a tertiary- level children's hospital. BC results for children admitted to Red Cross War Memorial Children's Hospital from 2008 to 2012 were extracted from the National Health Laboratory Service database. Pathogenic and non-pathogenic (contaminated) growth on BCs in children <1 year of age and >1 year of age, were analysed. Data analysis was performed using Epi Info version 3.5.1. A total of 47 677 BCs were performed in the 5-year period. The proportion of contaminated specimens ranged between 5.9% and 7.2% per year (p=0.4). CoNS was the predominant isolate in 53.8% of all contaminated BCs. Children <1 year of age experienced higher contamination rates than children >1 year of age (8.7% v. 4.7%; relative risk 1.84; 95% confidence interval (CI) 1.71 - 1.97). Pathogenic organisms were isolated in 6.2% (95% CI 6.0 - 6.4) of all BC specimens. Among Gram-positive organisms, the proportion of Streptococcus pneumoniae isolates declined from 14.3% to 4.7% (p<0.00001), while there was a significant increase in Gram-negative organisms (51.8% - 57.9%; p=0.04) over the 5-year period. Klebsiella pneumoniae, the predominant Enterobacteriaceae isolated, decreased from 45.8% to 31.7% (p=0.004). This study identified unacceptably high BC contamination rates, emphasising the importance of collecting BC specimens under sterile conditions.


Sperm mitochondrial mutations as a cause of low sperm motility.
We report the unique case of a 28-year-old man who, in spite of having a varicocele and a sperm concentration of 5 million/mL, of which 10% were motile and 20% had normal forms (oligoasthenoteratozoospermia [OAT]), was fertile. This was confirmed by paternity testing using 16 autosomal and 6 Y-chromosomal short tandem repeat (STR) loci. An analysis of mitochondrial genes that included cytochrome oxidase I (COI), cytochrome oxidase II (COII), adenosine triphosphate synthase6 (ATPase6), ATPase8, transfer ribonucleic acid (tRNA) serine I, tRNA lysine, and NADH dehydrogenase3 (ND3) revealed, for the first time, 9 missense and 27 silent mutations in the sperm's mitochondrial DNA (mtDNA) but not in the DNA from the blood cells. There was a 2-nucleotide deletion in the mitochondrial COII genes, introducing a stop codon, which might be responsible for low sperm motility.


Heterogeneous relationships of squamous and basal cell carcinomas of the skin with smoking: the UK Million Women Study and meta-analysis of prospective studies.
Published findings on the associations between smoking and the incidence of cutaneous squamous cell carcinoma (SCC) and basal cell carcinoma (BCC) are inconsistent. We aimed to generate prospective evidence on these relationships overall and by anatomical site. We followed 1,223,626 women without prior cancer by electronic linkage to national cancer registration data. Questionnaire information about smoking and other factors was recorded at recruitment (1996-2001) and every 3-5 years subsequently. Cox regression yielded adjusted relative risks (RRs) comparing smokers versus never-smokers. After 14 (SD4) years follow-up per woman, 6699 had a first registered cutaneous SCC and 48,666 a first BCC. In current versus never-smokers, SCC incidence was increased (RR = 1.22, 95% CI 1.15-1.31) but BCC incidence was decreased (RR = 0.80, 0.78-0.82). RRs varied substantially by anatomical site; for the limbs, current smoking was associated with an increased incidence of SCC (1.55, 1.41-1.71) and a decreased incidence of BCC (0.72, 0.66-0.79), but for facial lesions there was little association of current smoking with either SCC (0.93, 0.82-1.06) or BCC (0.92, 0.88-0.96). Findings in meta-analyses of results from this and seven other prospective studies were largely dominated by the findings in this study. Smoking-associated risks for cutaneous SCC and BCC are in the opposite direction to each other and appear to vary by anatomical site.


The Association Between Body Mass Index (BMI) and Back or Leg Pain in Patients With Spinal Conditions: Results from the Genodisc Study.
A prospective observational study. The aim of this study was to identify the relationship between obesity, quantified by body mass index (BMI), and both back and leg pain in spinal patients. Obesity and back pain are massive public health problems. Given the poor correlation between pain and a pathological change in the spine, further investigation is required into other, nonpathological predictors such as obesity. The Genodisc Study was one of the largest cross-sectional studies of patients presenting to tertiary spinal units and recruited from six centers in four European countries. In total, 2636 patients were recruited over a 5-year period between 2008 and 2013. Both back and leg pain were scored by patients in the range of 0 to 10. Linear regression was used to model the relationship between BMI and pain. Potential confounders included in the model were age, Zung Depression score, episodes of sport, gender, disability benefit, family history, previous surgery, smoking status, work type, clinical diagnosis, and relevant comorbidities. Back and leg pain outcomes were modeled separately. The study included 1160 men and 1349 women with a mean age of 50.9 years and mean BMI of 27.2 kg/m. In our fully adjusted model, a 5-point increase in BMI was associated with greater leg [0.19 units (95% confidence interval 0.08-0.31)] but not back [0.10 units (95% CI -0.02 to 0.22)] pain scores. Although this relationship was statically significant, given the small magnitude of the relationship, the clinical significance is limited. Similarly, female gender, heavy workload, rheumatoid arthritis, previous spine surgery, and depression were associated with higher back and leg pain. In this large observational study of spine patients presenting to tertiary European centers, obesity, as measured by increased BMI, was associated with greater leg pain. 2.


Has your patient's multiple sclerosis lesion burden or brain atrophy actually changed?
Changes in mean magnetic resonance imaging (MRI)-derived measurements between patient groups are often used to determine outcomes in therapeutic trials and other longitudinal studies of multiple sclerosis (MS). However, in day-to-day clinical practice the changes within individual patients may also be of interest In this paper, we estimated the measurement error of an automated brain tissue quantification algorithm and determined the thresholds for statistically significant change of MRI-derived T2 lesion volume and brain atrophy in individual patients. Twenty patients with MS were scanned twice within 30 min. Brain tissue volumes were measured using the computer algorithm. Brain atrophy was estimated by calculation of brain parenchymal fraction. The threshold of change between repeated scans that represented statistically significant change beyond measurement error with 95% certainty was 0.65 mL for T2 lesion burden and 0.0056 for brain parenchymal fraction. Changes in lesion burden and brain atrophy below these thresholds can be safely (with 95% certainty) explained by measurement variability alone. These values provide clinical neurologists with a useful reference to interpret MRI-derived measures in individual patients.


Responsiveness of peripheral veins to vasodilators and the effect of nifedipine on alpha-adrenergic responsiveness in hypertension.
Vasodilators have varying hemodynamic properties that may be important in determining their efficacy for different disorders. We used the dorsal hand vein technique to measure the effects of several vasodilators infused locally and to measure the action of systemically administered nifedipine. The venodilatory effects of hydralazine, verapamil, diazoxide, and nitroglycerin were determined in peripheral veins of healthy subjects. The potency (ED50, the dose producing half-maximal response) was as follows: nitroglycerin (0.0007 micrograms/min) greater than verapamil (6.5 micrograms/min) greater than diazoxide (75 micrograms/min) greater than hydralazine (660 micrograms/min). The effect of oral nifedipine on alpha-adrenergic responsiveness of hand veins was determined. Nifedipine given in therapeutic doses for the treatment of hypertension was associated with a threefold increase in the ED50 for phenylephrine (92 to 277 ng/min; p less than 0.05) and norepinephrine (2.9 to 11.5 ng/min; p less than 0.05). Therapeutic doses of nifedipine are associated with measurable shifts in the dose-response curves to these two alpha-adrenergic agonists in the hand vein. The hand vein technique can be used not only to compare the potency of locally infused drugs but also to measure venous effects of vasoactive drugs at therapeutic concentrations achieved after systemic administration.


Deciphering why Salmonella Gallinarum is less invasive in vitro than Salmonella Enteritidis.
Salmonella Gallinarum and Salmonella Enteritidis are genetically closely related however associated with different pathologies. Several studies have suggested that S. Gallinarum is less invasive in vitro than S. Enteritidis. In this study we confirm that the S. Gallinarum strains tested were much less invasive than the S. Enteritidis strains tested in cells of avian or human origin. In addition, the S. Gallinarum T3SS-1-dependent ability to invade host cells was delayed by two to three hours compared to S. Enteritidis, indicating that T3SS-1-dependent entry is less efficient in S. Gallinarum than S. Enteritidis. This was neither due to a decreased transcription of T3SS-1 related genes when bacteria come into contact with cells, as transcription of hilA, invF and sipA was similar to that observed for S. Enteritidis, nor to a lack of functionality of the S. Gallinarum T3SS-1 apparatus as this apparatus was able to secrete and translocate effector proteins into host cells. In contrast, genome comparison of four S. Gallinarum and two S. Enteritidis strains revealed that all S. Gallinarum genomes displayed the same point mutations in each of the main T3SS-1 effector genes sipA, sopE, sopE2, sopD and sopA.


Increased mortality in patients with severe traumatic brain injury treated without intracranial pressure monitoring.
Evidence-based guidelines recommend intracranial pressure (ICP) monitoring for patients with severe traumatic brain injury (TBI), but there is limited evidence that monitoring and treating intracranial hypertension reduces mortality. This study uses a large, prospectively collected database to examine the effect on 2-week mortality of ICP reduction therapies administered to patients with severe TBI treated either with or without an ICP monitor. From a population of 2134 patients with severe TBI (Glasgow Coma Scale [GCS] Score <9), 1446 patients were treated with ICP-lowering therapies. Of those, 1202 had an ICP monitor inserted and 244 were treated without monitoring. Patients were admitted to one of 20 Level I and two Level II trauma centers, part of a New York State quality improvement program administered by the Brain Trauma Foundation between 2000 and 2009. This database also contains information on known independent early prognostic indicators of mortality, including age, admission GCS score, pupillary status, CT scanning findings, and hypotension. Age, initial GCS score, hypotension, and CT scan findings were associated with 2-week mortality. In addition, patients of all ages treated with an ICP monitor in place had lower mortality at 2 weeks (p = 0.02) than those treated without an ICP monitor, after adjusting for parameters that independently affect mortality. In patients with severe TBI treated for intracranial hypertension, the use of an ICP monitor is associated with significantly lower mortality when compared with patients treated without an ICP monitor. Based on these findings, the authors conclude that ICP-directed therapy in patients with severe TBI should be guided by ICP monitoring.


Research into microscopic structure and essential oils of endemic medicinal plant species Satureja subspicata Bartl. ex Vis. (Lamiaceae).
In this study we looked into the cells and histological organization of leaves (Saturejae folium) as well as a phyto-chemical composition of overground parts (Saturejae herba) of endemic species Satureja subspicata Bartl. ex Vis. (Lamiaceae) collected during year 2003 on south slopes of mountain Velez in Herzegovina. Microscopic organization was analyzed in wet slides using light microscope. Estimation of stomata index was done according to Ph. Yug. IV. Chemical composition of overground material extracts was determined by thin layer chromatography (TLC) using thymol as a reference. In our research we found the following: Leaf structure of the analyzed species Satureja subspicata points at numerous specificities in anatomical and histological sense. In histological sense, leaf is of ventral type, with differentiated upper and lower epidermis and palisade and spongy tissue in between. Stoma index assigned according to Ph. Yug. IV leads to a conclusion that it is the case of diastitic stomata, which is common feature of most species from Lamiaceae family. Comparative qualitative analysis of essential oils in species Satureja subspicata showed similarities with other species from Lamiaceae family such as Thymus L. (thymol). In fact, we found more common substances that are part of the species Satureja montana L. extract, but in different concentrations.


Combined analysis of microsatellite instability and K-ras mutation increases detection incidence of normal samples from colorectal cancer patients.
Microsatellite instability (MI) and K-ras oncogene mutation have been widely used as biomarkers of genetic changes in colorectal cancer (CRC). Each of these biomarkers was independently found in normal-appearing colonic mucosa at stages preceding the development of CRC, albeit at a relatively low incidence. To assess the potential value of combined MI and K-ras mutation analysis in the detection of normal-appearing colonic mucosa samples taken from patients with CRC, we have chosen to analyze multiple (3-7) normal colonic mucosa samples and the respective colorectal tumor tissues from 20 patients with CRC. As a control, we have used 54 normal mucosa samples obtained from 9 autopsies of patients without CRC. In at least 1 of 5 loci analyzed, MI was found in 8 of 20 patients via analysis of multiple normal-appearing colonic mucosa samples from each patient. Combined analysis of MI and mutant ras alleles in normal-appearing colonic mucosa samples enabled the identification of 11 of 20 patients with CRC. None of the 54 normal colonic mucosa samples obtained from 9 patients without CRC were found to carry mutant ras or MI. The ability to detect 55% of patients with CRC via the analysis of normal mucosa samples provides an important advance in our approach toward early detection of individuals who may be at risk to develop this tumor type.


Nonlocal dispersion cancellation using entangled photons.
A pair of optical pulses traveling through two dispersive media will become broadened and, as a result, the degree of coincidence between the optical pulses will be reduced. For a pair of entangled photons, however, nonlocal dispersion cancellation in which the dispersion experienced by one photon cancels the dispersion experienced by the other photon is possible. In this paper, we report an experimental demonstration of nonlocal dispersion cancellation using entangled photons. The degree of two-photon coincidence is shown to increase beyond the limit attainable without entanglement. Our results have important applications in fiber-based quantum communication and quantum metrology.


Visualizing the growth and dynamics of liquid-ordered domains during lipid bilayer folding in a microfluidic chip.
A microfluidic platform enabling optical monitoring of bilayer lipid membrane formation by a new monolayer folding process is described. The thermoplastic chips integrate dried lipid films that are rehydrated by microfluidic perfusion, which enables delivery of lipid-laden air bubbles across a membrane-supporting aperture. As in traditional Montal-Mueller bilayer formation, lipid monolayers are delivered independently to each side of the aperture, thereby allowing asymmetric lipid composition in the resulting bilayer to be achieved. Confocal microscopy is used to image the monolayer folding process, and reveals the growth and dynamics of asymmetric liquid-ordered domains during bilayer stabilization.


Epithelial Smad4 Deletion Up-Regulates Inflammation and Promotes Inflammation-Associated Cancer.
Chronic inflammation is a predisposing condition for colorectal cancer. Many studies to date have focused on proinflammatory signaling pathways in the colon. Understanding the mechanisms that suppress inflammation, particularly in epithelial cells, is critical for developing therapeutic interventions. Here, we explored the roles of transforming growth factor β (TGFβ) family signaling through SMAD4 in colonic epithelial cells. The Smad4 gene was deleted specifically in adult murine intestinal epithelium. Colitis was induced by 3 rounds of dextran sodium sulfate in drinking water, after which mice were observed for up to 3 months. Nontransformed mouse colonocyte cell lines and colonoid cultures and human colorectal cancer cell lines were analyzed for responses to TGFβ1 and bone morphogenetic protein 2. Dextran sodium sulfate treatment was sufficient to drive carcinogenesis in mice lacking colonic Smad4 expression, with resulting tumors bearing striking resemblance to human colitis-associated carcinoma. Loss of SMAD4 protein was observed in 48% of human colitis-associated carcinoma samples as compared with 19% of sporadic colorectal carcinomas. Loss of Smad4 increased the expression of inflammatory mediators within nontransformed mouse colon epithelial cells in vivo. In vitro analysis of mouse and human colonic epithelial cell lines and organoids indicated that much of this regulation was cell autonomous. Furthermore, TGFβ signaling inhibited the epithelial inflammatory response to proinflammatory cytokines. TGFβ suppresses the expression of proinflammatory genes in the colon epithelium, and loss of its downstream mediator, SMAD4, is sufficient to initiate inflammation-driven colon cancer. Transcript profiling: GSE100082.


Regulation of Caenorhabditis elegans male mate searching behavior by the nuclear receptor DAF-12.
Coordination of animal behavior with reproductive status is often achieved through elaboration of hormones by the gonad. In the nematode Caenorhabditis elegans, adult males explore their environment to locate mates. Mate searching is regulated by presence of mates, nutritional status, and a signal from the gonad. Here we show that the gonadal signal acts via the nuclear receptor DAF-12, a protein known to regulate several C. elegans life-history traits. DAF-12 has both activational and organizational functions to stimulate exploratory behavior and acts downstream of the gonadal signal, outside of the gonad. DAF-12 acts upstream of sensory input from mating partners and physiological signals indicating nutritional status. Mate searching was rescued in germ-line ablated animals, but not if both germ line and somatic gonad were ablated, by a precursor of the DAF-12 ligand, dafachronic acid (DA). The results are interpreted to suggest that the germ line produces a DA precursor that is converted to DA outside of the germ line, possibly in the somatic gonad. As it does in other pathways in which it functions, in regulation of male mate searching behavior DAF-12 acts at a choice point between alternatives favoring reproduction (mate searching) vs. survival (remaining on food).


ARNO and ARF6 regulate axonal elongation and branching through downstream activation of phosphatidylinositol 4-phosphate 5-kinase alpha.
In the developing nervous system, controlled neurite extension and branching are critical for the establishment of connections between neurons and their targets. Although much is known about the regulation of axonal development, many of the molecular events that regulate axonal extension remain unknown. ADP-ribosylation factor nucleotide-binding site opener (ARNO) and ADP-ribosylation factor (ARF)6 have important roles in the regulation of the cytoskeleton as well as membrane trafficking. To investigate the role of these molecules in axonogenesis, we expressed ARNO and ARF6 in cultured rat hippocampal neurons. Expression of catalytically inactive ARNO or dominant negative ARF6 resulted in enhanced axonal extension and branching and this effect was abrogated by coexpression of constitutively active ARF6. We sought to identify the downstream effectors of ARF6 during neurite extension by coexpressing phosphatidyl-inositol-4-phosphate 5-Kinase alpha [PI(4)P 5-Kinase alpha] with catalytically inactive ARNO and dominant negative ARF6. We found that PI(4)P 5-Kinase alpha plays a role in neurite extension and branching downstream of ARF6. Also, expression of inactive ARNO/ARF6 depleted the actin binding protein mammalian ena (Mena) from the growth cone leading edge, indicating that these effects on axonogenesis may be mediated by changes in cytoskeletal dynamics. These results suggest that ARNO and ARF6, through PI(4)P 5-Kinase alpha, regulate axonal elongation and branching during neuronal development.


[Clinical features and prognostic factors of parainfluenza virus infections in adult patients].
Objective: To explore the clinical features and prognostic factors of parainfluenza viral lower respiratory tract infections in adults. Methods: A total of 70 patients withpositive nucleic acid of parainfluenza virus (PIV) admitted to China-Japan Friendship Hospital between August 2016 and November 2019 were enrolled. Multiplex real-time polymerase chain reaction (RT-PCR) assays for viral detection were implemented to specimens (nasopharynx swab, sputum or bronchoalveolar lavage) obtained from all the patients, which was consistent with the diagnosis of lower respiratory tract infection. Patients were divided into two groups depending on the status of immune function (immunocompromised group, n=26; immunocompetent group, n=44), and patients were divided into PIV infection group (n=43) and mixed infection group (n=27) according to whether there was mixed infection. Characteristics including age, gender, underlying diseases, symptoms, disease severity, imaging manifestations, etiology, respiratory failure, mechanical ventilation, vasoactive drug, antimicrobial drug and 30-day mortality between the groups were compared, and the prognostic factors of PIV infections were investigated using Cox regression. Results: The peak incidence of PIV infection time was in May, August, September and December, accounting for 58.6% of all cases. The enrolled 70 cases included 43 cases with pneumonia, 16 cases with interstitial lung disease and infection, 7 cases with bronchiectasis and infection, and 4 cases with acute exacerbation of chronic obstructive pulmonary disease. Eight patients (11.4%) had no underlying diseases, 21 patients (30.0%) had respiratory failure, 18 patients (25.7%) were treated with mechanical ventilation, 15 patients (21.4%) died within 30 days after admission. The pneumonia severity index score, percentage of patients with ground-glass opacity according CT scan, with honeycomb or reticular pattern, with mechanical ventilation, with respiratory failure, with ICU admission, and 30-day mortality in immunocompromised group were higher than those of immunocompetent group [(91.5 vs 84.0), (60.0% vs 34.1%), (44.0% vs 11.4%), (42.3% vs 15.9%), (50.0% vs 18.2%), (38.5% vs 22.7%), (34.6% vs 13.6%)] (all P<0.05). There were 27 cases (38.6%) with mixed infection, including 17 viruses (24.3%), 19 bacteria (27.1%), 14 (20.0%) fungi (PCP, aspergillus) and 1 (1.4%) Mycobacterium intracellulare. Sixteen patients (59.3%) in the mixed infection group were immunocompromised patients and 21 patients (77.8%) had chronic lung disease. Cox regression analysis showed that mechanical ventilation and interstitial lung disease were independent predictors of prognosis in all patients, and mechanical ventilation was an independent predictor of prognosis in PIV infection group. Conclusions: Most of the patients with PIV lower respiratory tract infection in adults are complicated with underlying diseases and mixed infection, with a high 30-day mortality. Interstitial lung disease and mechanical ventilation indicate poor prognosis in these patients.