Hypoplastic left heart syndrome.
Hypoplastic left heart syndrome (HLHS) refers to the abnormal development of the left-sided cardiac structures, resulting in obstruction to blood flow from the left ventricular outflow tract. In addition, the syndrome includes underdevelopment of the left ventricle, aorta, and aortic arch, as well as mitral atresia or stenosis. HLHS has been reported to occur in approximately 0.016 to 0.036% of all live births. Newborn infants with the condition generally are born at full term and initially appear healthy. As the arterial duct closes, the systemic perfusion becomes decreased, resulting in hypoxemia, acidosis, and shock. Usually, no heart murmur, or a non-specific heart murmur, may be detected. The second heart sound is loud and single because of aortic atresia. Often the liver is enlarged secondary to congestive heart failure. The embryologic cause of the disease, as in the case of most congenital cardiac defects, is not fully known. The most useful diagnostic modality is the echocardiogram. The syndrome can be diagnosed by fetal echocardiography between 18 and 22 weeks of gestation. Differential diagnosis includes other left-sided obstructive lesions where the systemic circulation is dependent on ductal flow (critical aortic stenosis, coarctation of the aorta, interrupted aortic arch). Children with the syndrome require surgery as neonates, as they have duct-dependent systemic circulation. Currently, there are two major modalities, primary cardiac transplantation or a series of staged functionally univentricular palliations. The treatment chosen is dependent on the preference of the institution, its experience, and also preference. Although survival following initial surgical intervention has improved significantly over the last 20 years, significant mortality and morbidity are present for both surgical strategies. As a result pediatric cardiologists continue to be challenged by discussions with families regarding initial decision relative to treatment, and long-term prognosis as information on long-term survival and quality of life for those born with the syndrome is limited.


The Use and Underuse of Model Systems in Infectious Disease Ecology and Evolutionary Biology.
AbstractEver since biologists began studying the ecology and evolution of infectious diseases (EEID), laboratory-based model systems have been important for developing and testing theory. Yet what EEID researchers mean by the term "model systems" and what they want from them is unclear. This uncertainty hinders our ability to maximally exploit these systems, identify knowledge gaps, and establish effective new model systems. Here, we borrow a definition of model systems from the biomolecular sciences to assess how EEID researchers are (and are not) using 10 key model systems. According to this definition, model systems in EEID are not being used to their fullest and, in fact, cannot even be considered model systems. Research using these systems consistently addresses only two of the three fundamental processes that underlie disease dynamics-transmission and disease, but not recovery. Furthermore, studies tend to focus on only a few scales of biological organization that matter for disease ecology and evolution. Moreover, the field lacks an infrastructure to perform comparative analyses. We aim to begin a discussion of what we want from model systems, which would further progress toward a thorough, holistic understanding of EEID.


Functional analysis of missense variants in the TRESK (KCNK18) K channel.
A loss of function mutation in the TRESK K2P potassium channel (KCNK18), has recently been linked with typical familial migraine with aura. We now report the functional characterisation of additional TRESK channel missense variants identified in unrelated patients. Several variants either had no apparent functional effect, or they caused a reduction in channel activity. However, the C110R variant was found to cause a complete loss of TRESK function, yet is present in both sporadic migraine and control cohorts, and no variation in KCNK18 copy number was found. Thus despite the previously identified association between loss of TRESK channel activity and migraine in a large multigenerational pedigree, this finding indicates that a single non-functional TRESK variant is not alone sufficient to cause typical migraine and highlights the genetic complexity of this disorder.


Intra-species diversity between seven Bifidobacterium adolescentis strains identified by genome-wide tiling array analysis.
Six Bifidobacterium adolescentis strains, JCM1275, JCM1251, JCM7044, JCM7045, JCM7046, and 9-124, were analyzed using a tiling array designed according to the full genome sequence of ATCC15703. The results demonstrated deletion clusters along with single-gene mutations and deletions. Most deletions concerned genes involved in polysaccharide and cell-surface biogenesis. A dendrogram illustrating the deletions and mutations is presented and the evolution of B. adolescentis is discussed.


Human WISP1v, a member of the CCN family, is associated with invasive cholangiocarcinoma.
Family members of the connective tissue growth factor, cysteine-rich 61, nephroblastoma over-expressed gene (CCN) encode cysteine-rich secreted proteins with roles in human fibrotic disorders and tumor progression. In this study, we identified a CCN family member, WISP1v, as over-expressed in human cholangiocarcinomas. Genetic analysis of WISP1v was performed on surgically resected specimens of cholangiocarcinoma. The WISP1v biological effects were analyzed using the HuCCT1 human cholangiocarcinoma cell line. The WISP1v gene was expressed in 19 of 39 cholangiocarcinoma tissues (49%) but not in normal livers. Expression of WISP1v was significantly associated with lymphatic and perineural invasion of tumor cells (P <.05), as well as a poor clinical prognosis (P <.01). In the intraductal papillary cholangiocarcinomas, WISP1v was detected only in the cases with duct wall invasion but not in the cases without duct wall invasion (P <.05). No mutation of WISP1v gene was detected in the examined samples. In vitro analysis revealed that WISP1v stimulated the invasive phenotype of cholangiocarcinoma cells with activation of both p38 and p42/p44 mitogen-activated protein kinases (MAPKs). Furthermore, WISP1v-induced cholangiocarcinoma invasion was significantly suppressed by the p38 MAPK inhibitor SB203580 but not by the p42/p44 MAPK kinase (MEK) inhibitor PD98059. Our findings suggest that WISP1v-mediated signaling is involved in the generation of invasive cellular properties and leads to progression of cholangiocarcinoma.


Staff Satisfaction, Ethical Concerns, and Burnout in the New York City Jail Health System.
This article reviewed a program evaluation conducted among correctional health care staff in New York City (NYC) using a 68-question electronic survey to assess satisfaction, attitudes, and beliefs in relation to ethics and burnout of health care employees in NYC jails. Descriptive statistics were tabulated and reviewed, and further assessment of burnout and ethics was performed through group sessions with participants. This evaluation has led to changes in agency policies and procedures and an emphasis on the human rights issue of the dual loyalty challenges that the security setting places on the overall mission to care for patients.


Genome-Wide DNA Methylation and Gene Expression Profiles in Cows Subjected to Different Stress Level as Assessed by Cortisol in Milk.
Dairy cattle health, wellbeing and productivity are deeply affected by stress. Its influence on metabolism and immune response is well known, but the underlying epigenetic mechanisms require further investigation. In this study, we compared DNA methylation and gene expression signatures between two dairy cattle populations falling in the high- and low-variant tails of the distribution of milk cortisol concentration (MC), a neuroendocrine marker of stress in dairy cows. Reduced Representation Bisulfite Sequencing was used to obtain a methylation map from blood samples of these animals. The high and low groups exhibited similar amounts of methylated CpGs, while we found differences among non-CpG sites. Significant methylation changes were detected in 248 genes. We also identified significant fold differences in the expression of 324 genes. KEGG and Gene Ontology (GO) analysis showed that genes of both groups act together in several pathways, such as nervous system activity, immune regulatory functions and glucocorticoid metabolism. These preliminary results suggest that, in livestock, cortisol secretion could act as a trigger for epigenetic regulation and that peripheral changes in methylation can provide an insight into central nervous system functions.


Peripartal anti-SARS-CoV-2-IgA/IgG in asymptomatic pregnant women during regional SARS-CoV-2-outbreak.
The Severe Acute Respiratory Distress Corona Virus 2 (SARS-CoV-2) pandemic poses special challenges for the society and especially the medical staff. Even if a rather mild course is assumed among pregnant women the measures to prevent transmission of the infection are of outstanding importance. To screen asymptomatic pregnant women during admission to our university maternal hospital we focused on anti-SARS-CoV-2-specific IgG and IgA antibody responses. Hundred and fifty one women admitted to the hospital for childbirth or caesarean delivery were included. In case of suspicious anti-SARS-CoV-2-antibody levels an RT-PCR was performed to confirm an ongoing infection with SARS-CoV-2. A total of 89% showed negative results for anti-SARS-CoV-2-IgA antibodies, whereas 3% were borderline and 7% positive (both labeled as suspicious). In only one patient with suspicious serology we detected SARS-CoV-2-RNA in the following RT-PCR. 2% presented anti-SARS-CoV-2-IgG antibodies, all being positive for anti-SARS-CoV-2-IgA. The observed positive rate of our study collective of 10.6% seemed much higher than the expected one (1.3%) based on the reports of the Robert Koch Institute and the specifications given by the test's manufacturer. The expected positive predictive value (PPV) was 4.3-6.7 times higher than the observed one. To our knowledge this is the first report of anti-SARS-CoV-2-antibody levels in the peripartum period of asymptomatic women. As the positive anti-SARS-CoV-2 serology poorly correlated with the confirmatory RT-PCR and the fact that mainly the detection of the virus by PCR correlates with the patient's infectiousness we suggest to rather perform a SARS-CoV-2-PCR-based admission screening in perinatal centers to prevent the spread of the disease.


A web-based programme for person-centred learning and support designed for preschool children with long-term illness: a pilot study of a new intervention.
For children living with long-term illness, school age is a risk period with regard to psychosocial ill health and poor compliance with treatment. There is a need for methods to promote health, well-being, and self-esteem. This study describes a new concept for supporting children, person-centred web-based learning and support, which has been tested in 12 preschool children and incorporates learning about feelings, relationships, and the right to integrity. SKYPE was used for conversations between the child and the web teacher. Methods. The programme was developed and tested in two steps. The conversations were tape-recorded and analysed using phenomenography. The questions addressed concerned the quality of the intervention process: accessibility of intervention, learning content and support, and identification of measurable items and patterns. Findings. The children found it interesting to communicate with their web teacher using SKYPE. The story about Max and Sara served as a good basis for discussion, and development was found in the learning process. The children were able to talk about relations and feelings and developed an understanding for use in new situations in their daily lives. Items and patterns that are useful for research and documentation were identified, for example, well-being, resources, needs, and wishes.


Analysis of viral RNA persistence in seawater by reverse transcriptase-PCR.
It is important to determine the stability of naked viral RNA in seawater, since false-positive results can occur when reverse transcriptase-PCR (RT-PCR) is used to detect viruses if the RT-PCR amplifies free RNA instead of RNA from intact viruses. An acid guanidinium thiocyanate-phenol-chloroform method was used to extract total RNA from a filtered poliovirus cell culture suspension. The sensitivity of detection in this viral RNA study was 600 fg when RT-PCR was used. The extracted total RNA was seeded into filtered and unfiltered seawater, and the resulting preparations were incubated at 4 degrees C and at room temperature (23 +/- 1 degrees C). Our results showed that the seeded RNA was more stable in filtered seawater than in unfiltered seawater at both temperatures. The viral RNA could not be detected by the RT-PCR after 2 days of incubation in unfiltered seawater and after 28 days of incubation in filter-sterilized seawater. Therefore, because of the relatively short life of viral RNA in natural water, the detection of virus in environmental samples by the RT-PCR was mainly due to the presence of well-protected viral particles and not due to the presence of naked viral RNA.


Thromboprophylaxis and Bleeding Complications in Orthopedic and Trauma Patients: A Systematic Review.
This systematic review was conducted to investigate the effects of currently used chemoprophylactic modalities to assess concerns regarding their usage. Preventive benefits of thromboprophylaxis were weighed against potential complications in orthopedic and trauma patients. The Ovid MEDLINE® database was used to identify relevant studies. The authors independently screened the initial study articles by title and abstract, eliminating articles not dealing with venous thromboembolism (VTE) chemoprophylaxis in orthopedic or trauma populations. The remaining articles were assessed for eligibility through full-text analysis. The analyzed studies within this review suggested that Factor Xa inhibitors and direct oral anticoagulants hold promise as safe and potentially more effective thromboprophylactic entities when compared to low molecular weight heparin in trauma and orthopedic patients. Thromboprophylaxis had little to no effect on major bleeding incidence, although we could not definitively conclude there was no effect on overall bleeding. Early thromboprophylaxis, especially when identifiable risk factors are present, can improve VTE prevention without changing major bleeding rates. Additionally, we could not conclude whether extended prophylaxis affects VTE incidence, although it seemed to have no effect on major bleeding. Finally, we determined that thromboprophylaxis in the lower extremity trauma population is questionable without the presence of underlying risk factors.


Oxygen stripes in La0.5Ca0.5MnO3 from ab initio calculations.
We investigate the electronic, magnetic, and orbital properties of La0.5Ca0.5MnO3 perovskite by means of an ab initio electronic structure calculation within the Hartree-Fock approximation. Using the experimental crystal structure reported by Radaelli et al. [Phys. Rev. B 55, 3015 (1997)]], we find a charge-ordering stripelike ground state. The periodicity of the stripes, and the insulating magnetic structure, consisting of antiferromagnetically coupled zigzag chains, are in agreement with neutron x-ray and electron diffraction experiments. However, the detailed structure is more complex than that envisaged by simple models of charge and orbital order on Mn d levels alone, and is better described as a charge-density wave of oxygen holes, coupled to the Mn spin/orbital order.


Meta-analysis of gender differences in efficacy outcomes for HIV-positive subjects in randomized controlled clinical trials of antiretroviral therapy (2000-2008).
Women are often underrepresented in randomized clinical trials (RCT) of HIV-1 drugs. As a result, determining whether women have different virologic outcomes compared to men is not always possible because the gender-related analyses usually lack statistical power. To address this important public health concern, the Food and Drug Administration's (FDA) Division of Antiviral Products (DAVP) created a database including 20,328 HIV-positive subjects from 40 RCTs in 18 New Drug Applications (NDAs) submitted to the FDA between 2000 and 2008. These RCTs were conducted for at least 48 weeks in duration and were used to support approval of new molecular entity, new formulation, or major label change. To delineate potential gender differences in antiretroviral treatment (ART), we evaluated the percentage of subjects with HIV RNA less than 50 copies per milliliter at 48 weeks. Analyses of the database represent the most systematic review of gender-related ART efficacy data to date. Overall, the meta-analyses did not demonstrate statistically or clinically significant gender differences in virologic outcome at week 48. However, the corresponding subgroup analyses appear to show several statistically significant gender differences favoring males.


Metal-ion-specific screening of charge effects in protein amide H/D exchange and the Hofmeister series.
In this study, protein charge ladders and mass spectrometry were used to quantify how metal cations in the Hofmeister series (Na(+), K(+), Li(+), Mg(2+), and Ca(2+)) permute the effects of lysine acetylation on the rate of amide H/D exchange in a representative protein (myoglobin, Mb). The successive acetylation of up to 18 Lys-ε-NH3(+) groups in Mb caused a linear decrease in its global rate of amide H/D exchange (as measured by mass spectrometry), despite also decreasing the thermostability of Mb by >10 °C. The ability of a metal cation to screen kinetic electrostatic effects during H/D exchange-and to abolish the protective effect of acetylation against H/D exchange-was found to depend on the position of the cation in the Hofmeister series. Na(+) and K(+) cations did not fully equalize the rates of H/D exchange among each "rung" of the charge ladder, whereas Mg(2+) and Ca(2+) did equalize rates without eliminating the hydrophobic core of the protein (i.e., without unfolding Mb); Li(+) exhibited intermediate effects. The ability of Mg(2+) and Ca(2+) to completely screen electrostatic effects associated with the H/D exchange of charge isomers of Mb suggests that Mg(2+) or Ca(2+) (but not Na(+) or K(+)) can be used to quantify the magnitude by which electrostatic charge contributes to the observed rates of amide H/D exchange in proteins.


Kinetics of chymotrypsin- and papain-catalysed synthesis of [leucine]enkephalin and [methionine]enkephalin.
The proteinase-catalysed synthesis of [Leu]enkephalin and [Met]enkephalin was studied kinetically. N alpha-t-Butoxycarbonyl-amino acids and peptides or their ethyl esters served as acyl donors, and amino acid phenylhydrazides were used as acyl acceptors. Initial-velocity measurements of alpha-chymotrypsin-catalysed peptide synthesis gave rise to kinetic patterns that are compatible with a ping-pong mechanism modified by a hydrolytic branch. Initial-rate and alternative-substrate inhibition patterns for papain-controlled peptide-bond formation are consistent with a sequential ordered mechanism with the acyl donor as the obligatory first substrate. On the basis of the observed kinetic features, reaction mechanisms are proposed for chymotrypsin- and papain-catalysed peptide synthesis that inversely equal those describing the pathways of proteolysis. The respective initial-velocity expressions for bireactant systems are given, along with the numerical values of the corresponding kinetic parameters.


Growth and metabolic consequences of growth hormone treatment in prepubertal short normal children.
Growth and the metabolic effects of growth hormone were monitored in a randomised, controlled group of 41 short, normal, prepubertal children. The treated group received daily injections of growth hormone as Genotropin (Kabi Pharmacia) 30 IU/m2/week. Fifteen children in the treated group (21 children) have completed three years of treatment, have grown significantly more than 14 (of 20) untreated children, and have a significantly greater adult height prediction. They do, however, remain leaner (body fat 13.5% in the treated group, 18% in the untreated group) and relatively hyperinsulinaemic (insulin 66.7 pmol/l in the treated group, 44.5 in the untreated group) after three years compared with untreated children. Although growth hormone appears to improve the height potential of prepubertal short normal children, the long term outcome is still uncertain.


A conserved role of IQGAP1 in regulating TOR complex 1.
Defining the mechanisms that control cell growth and division is crucial to understanding cell homeostasis, which impacts human diseases such as cancer and diabetes. IQGAP1, a widely conserved effector and/or regulator of the GTPase CDC42, is a putative oncoprotein that controls cell proliferation; however, its mechanism in tumorigenesis is unknown. The mechanistic target of rapamycin (mTOR) pathway, the center of cell growth control, is commonly activated in human cancers, but has proved to be an ineffective clinical target because of an incomplete understanding of its mechanisms in cell growth inhibition. Using complementary studies in yeast and mammalian cells, we examined a potential role for IQGAP1 in regulating the negative feedback loop (NFL) of mTOR complex 1 (mTORC1) that controls cell growth. Two-hybrid screens identified the yeast TORC1-specific subunit Tco89p as an Iqg1p-binding partner, sharing roles in rapamycin-sensitive growth, axial-bud-site selection and cytokinesis, thus coupling cell growth and division. Mammalian IQGAP1 binds mTORC1 and Akt1 and in response to epidermal growth factor (EGF), cells expressing the mTORC1-Akt1-binding region (IQGAP1(IR-WW)) contained attenuated phosphorylated ERK1/2 (ERK1/2-P) activity and inactive glycogen synthase kinase 3α/β (GSK3α/β), which control apoptosis. Interestingly, these cells displayed a high level of Akt1 S473-P, but an attenuated level of the mTORC1-dependent kinase S6K1 T389-P and induced mTORC1-Akt1- and EGF-dependent transformed phenotypes. Moreover, IQGAP1 appears to influence cell abscission and its activity is elevated in carcinoma cell lines. These findings support the hypothesis that IQGAP1 acts upstream on the mTORC1-S6K1→Akt1 NFL and downstream of it, to couple cell growth and division, and thus like a rheostat, regulates cell homeostasis, dysregulation of which leads to tumorigenesis or other diseases. These results could have implications for the development of the next generation of anticancer therapeutics.


Current Perspectives and Unmet Needs of Primary Immunodeficiency Care in Asia Pacific.
Background: The Asia Pacific Society for Immunodeficiencies (APSID) conducted nine primary immunodeficiency (PID) Schools in 5 years since inauguration to provide PID care training for early career physicians in Asia Pacific, a region with divergent needs in PID resources and training. Objective: To identify differences in PID patient care resource and training needs across Asia Pacific and propose a corresponding action plan. Methods: The Human Development Index (HDI) indicates the degree of socio-economic development in each country/region. Information related to investigations and learning issues were extracted from the abstracts and personal statements from all Schools and mapped onto resource and training needs. Correlations between HDI and country/region-specific parameters were tested by two-tailed Pearson correlation. Results: A total of 427 abstracts were received in nine Schools between 2015 and 2020, predominantly on immunodeficiencies affecting cellular and humoral immunity. Genetic confirmation was described in 61.8% of abstracts, and its absence negatively correlated with HDI (r = -0.696, p = 0.004). Essential immunologic and genetic tests were not available in 25.4 and 29.5% of abstracts, respectively, and their absence negatively correlated with HDI (r = -0.788, p < 0.001; r = -0.739, p = 0.002). HDI positively correlated with average testing level (r = 0.742, p = 0.002). Cases from medium-HDI countries/regions focused on learning how to investigate a patient for PIDs in cases of severe or atypical infections, whereas those from very-high-HDI countries/regions, from which most faculty members originated, listed hematopoietic stem cell transplantation and gene therapy, newborn screening, and research as learning issues more frequently. Conclusion: There are unique HDI-related PID resource and training needs in each country/region. APSID proposes HDI group-specific strategies to improve PID care and education in her member countries/regions. Further quantitative analysis of needs in PID care in Asia Pacific is needed for lobbying governments to increase their support for PID care and research.


Diversity of naturally occurring Epstein-Barr virus revealed by nucleotide sequence polymorphism in hypervariable domains in the BamHI K and N subgenomic regions.
The extent of nucleotide sequence microheterogeneity varies among subgenomic regions of Epstein-Barr virus (EBV). We examined, in EBV-carrying lymphoid cell lines, the extent of polymorphism in EBV DNA fragments amplified from the BamHI E, K, N and Z regions, and then investigated the diversity of the more hypervariable regions in tissues and body fluids. In cell lines, sequence dissimilarities in a genotype-specifying fragment of the EBNA-3C gene varied from < 1-4% within each genotype; dissimilarities in the first intron of the BZLF- 1 gene were < 2% within each genotype. By contrast, dissimilarities in a C-terminal unique domain of the EBNA-1 gene, and in a fragment that encompasses and is upstream of the LMP-1 start codon, varied between 2 and 7% and were not genotype-specific. The sequence diversity in BamHI K and N regions was then examined in tissues and body fluids by single-strand conformation polymorphism (SSCP) analysis and cycle sequencing. Extensive inter-host diversity was observed, whether the host was co-infected by human immunodeficiency virus (HIV) or not. In the oral cavity of HIV-infected patients, inter-compartmental EBV diversity could be demonstrated, even between sites that were anatomically proximate. Studies of BamHI K clones derived from EBV in oral lesions revealed infection by multiple variants. Identification of hypermutable loci within the EBV genome such as those located in the BamHI K and N regions should permit fine discrimination of individual EBV variants.


Injury prevention in sport: not yet part of the game?
There is a saying in sport that "injury is just part of the game". In other words, injury in sport is seen as inevitable. To examine progress toward reaching the contrary position that "injury prevention is just part of the game". The four steps of van Mechelen's "sequence of prevention" model provide a structure for examining progress. What is known about the size of the problem (step 1)? Most is known about more serious injuries and about injuries in élite and professional sport. Least is known about less serious injuries, injury in community level and amateur sport, and injury occurring in recreational activities. What is known about risk factors (step 2)? Despite calls for analytic studies since the early 1980s, few such studies have been reported in the literature. What is known about the effectiveness of preventive measures (step 3)? Few randomized controlled trials have been reported in the literature. Are there systems in place to monitor sports injury (step 4)? Examples are given of systems in North America, Europe, and Australasia. With a few exceptions, progress has not gone beyond step 1 in van Mechelen's model. Challenges for the future include: deciding where research efforts should be placed, standardization of definitions and methods of data collection and reporting, identification of risk factors and mechanisms of injury, and the evaluation of interventions. Finally, if the field of sports injury prevention is to advance, multidisciplinary collaboration will be required, along with the involvement of the sports community.


Cardiovascular risk assessment of atypical antipsychotic drugs in a zebrafish model.
The zebrafish model has been developed and evaluated for its ability to predict the toxicity of chemicals. Zebrafish additionally serve as an excellent model for assessing drug-induced cardiotoxicity, although zebrafish and mammalian hearts differ in structure. Recently, regulatory authorities have expressed concerns about a possible relationship between antipsychotics and risk of QTc interval prolongation, serious arrhythmia and sudden cardiac death. In the current study, we performed a cardiovascular risk assessment of six atypical antipsychotic drugs in zebrafish, specifically, aripiprazole, clozapine, olanzapine, quetiapine, risperidone and ziprasidone. Visual endpoints, such as lethality, edema (the presence of heart and trunk edema), hemorrhage (clustering of a pool of blood in an area outside the normal circulation), abnormal body shape (including bent or misshapen caudal region of the larvae) and motility, were evaluated as general toxicity endpoints, and the heart beat rate calculated as the cardiovascular toxicity endpoint. The zebrafish model facilitates determination of the heart beat rate, and may thus be an attractive screening tool for cardiovascular risk assessment of atypical antipsychotic drugs to understand the variations in response to QT-prolonging drugs.


Gene-environment interdependence.
Behavioural genetics was initially concerned with partitioning population variance into that due to genetics and that due to environmental influences. The implication was that the two were separate and it was assumed that gene-environment interactions were usually of so little importance that they could safely be ignored. Theoretical considerations suggested that that was unlikely to be true and empirical findings are now accumulating on the demonstrated and replicated biological interactions between identified common single genetic variants and the operation of environmentally mediated risks. The paper outlines the evidence and considers why it is changing concepts in ways that matter.


Enzyme-induced and tumor-targeted drug delivery system based on multifunctional mesoporous silica nanoparticles.
Functional mesoporous silica particles have attracted growing research interest for controlled drug delivery in targeted cancer therapy. For the purpose of efficient targeting tumor cells and reducing the adverse effect of antitumor drug doxorubicin (DOX), biocompatible and enzyme-responsive mesoporous silica nanoparticles (MSNs) with tumor specificity were desired. To construct these functional MSNs, the classic rotaxane structure formed between alkoxysilane tether and α-cyclodextrin (α-CD) was employed to anchor onto the orifices of MSNs as gatekeeper in this work. After subsequent modification by multifunctional peptide (azido-GFLGR7RGDS with tumor-targeting, membrane-penetrating, and cathepsin B-responsive functions) to stabilize the gatekeeper, the resulting functional MSNs showed a strong ability to load and seal DOX in their nanopores. When incubating these DOX-loaded MSNs with tumor and normal cells, the nanoparticles could efficiently employ their surface-encoded RGDS and continuous seven arginine (R7) sequences to target tumor cells, penetrate the cell membrane, and enter tumor cells. Because cathepsin B overexpressed in late endosomes and lysosomes of tumor cells could specifically hydrolyze GFLG sequences of the nanovalves, the DOX-loaded MSNs showed an "off-on" drug release behavior that ∼80% loaded DOX could be released within 24 h and thus showed a high rate of apoptosis. Furthermore, in vitro cellular experiments indicated that DOX-loaded MSNs (DOX@MSN-GFLGR7RGDS/α-CD) had high growth inhibition toward αvβ3-positive HeLa cancerous cells. The research might offer a practical way for designing the tumor-targeted and enzyme-induced drug delivery system for cancer therapy.


Hemispheric extra-ventricular glioneurocytoma: a clinicopathological review with detailed immunohistochemical profile.
Glioneuronal tumors have recently been recognized in the WHO Classification of Tumors of the Central Nervous System, 2007 [14]. However, the entities included in this category do not encompass all the glioneuronal tumors encountered during practice. We characterize a new entity called glioneurocytoma (GNC) showing distinct morphology with glial and neuronal differentiation. We reviewed 10 cases of glioneurocytomas diagnosed in our department during 2003 and 2004, with emphasis on clinicopathological features, immunohistochemical profile, genetic aberrations and prognosis. The cases included in the study showed equal gender distribution and age range of 23-40 years and mean age of 34.4 years at the time of initial presentation. Most of the tumors were centered in the frontal lobe. In our study, GFAP was the most sensitive and relatively specific marker for glial differentiation and remains the marker of choice for glial differentiation. CD56 and S100 protein were sensitive but non-specific. Vimentin, CD57 and NF were non-contributory in the immunohistochemical work up of glioneurocytomas. We concluded that the diagnosis of glioneurocytomas requires attention to morphological details and proper immunohistochemical assessment, using a panel of both glial and neuronal markers. Particular attention is recommended to the existence of the intermediate neurocytic cells which may be unique for these tumors. Future implication with full molecular analysis for gene expression profiling is suggested for proper and accurate identifying this entity.


Prednisolone is associated with a worse bone mineral density in primary adrenal insufficiency.
Patients with primary adrenal insufficiency (PAI) or congenital adrenal hyperplasia (CAH) receive life-long glucocorticoid (GC) therapy. Daily GC doses are often above the physiological cortisol production rate and can cause long-term morbidities such as osteoporosis. No prospective trial has investigated the long-term effect of different GC therapies on bone mineral density (BMD) in those patients. To determine if patients on hydrocortisone (HC) or prednisolone show changes in BMD after follow-up of 5.5 years. To investigate if BMD is altered after switching from immediate- to modified-release HC. Prospective, observational, longitudinal study with evaluation of BMD by DXA at visit1, after 2.2 ± 0.4 (visit2) and after 5.5 ± 0.8 years (visit3) included 36 PAI and 8 CAH patients. Thirteen patients received prednisolone (age 52.5 ± 14.8 years; 8 women) and 31 patients received immediate-release HC (age 48.9 ± 15.8 years; 22 women). Twelve patients on immediate-release switched to modified-release HC at visit2. Prednisolone showed significantly lower Z-scores compared to HC at femoral neck (-0.85 ± 0.80 vs -0.25 ± 1.16, P < 0.05), trochanter (-0.96 ± 0.62 vs 0.51 ± 1.07, P < 0.05) and total hip (-0.78 ± 0.55 vs 0.36 ± 1.04, P < 0.05), but not at lumbar spine, throughout the study. Prednisolone dose decreased by 8% over study time, but no significant effect was seen on BMD. BMD did not change significantly after switching from immediate- to modified-release HC. The use of prednisolone as hormone replacement therapy results in significantly lower BMD compared to HC. Patients on low-dose HC replacement therapy showed unchanged Z-scores within the normal reference range during the study period.


Structure and function of connective tissue in cardiac muscle: collagen types I and III in endomysial struts and pericellular fibers.
Heart myocytes and capillaries are enmeshed in a complex array of connective tissue structures arranged in several levels of organization: epimysium, the sheath of connective tissue that surrounds muscles; perimysium, which is associated with groups of cells; and endomysium, which surrounds and interconnects individual cells. The present paper is a review of work in this field with an emphasis on new, unpublished findings, including composition of endomysial fibers and disposition of newly described perimysial fibers. The role of scanning electron microscopy in the development of current understanding is also outlined. Biaxially arranged epimysial fibers form a sheath around papillary muscles and trabeculae that becomes increasingly well-oriented with the muscle axis during stretch. Perimysial structures are associated with groups of cells, and include weaves and septa of collagen, tendon-like fibers between weaves, ribbon-like fibers perpendicular to myocytes, and the newly described coiled perimysial fibers, which form an array in parallel with the myocytes and the epimysial net. The endomysium includes struts that bridge cells and pericellular fibers; both contain collagen types I and III. The evidence for the latter is presented in this paper and depends upon the use of antibody localization with fluorescent markers in light microscopy and colloidal gold for scanning electron microscopy. The implications of the composition of collagen fibers for myocardial function are discussed in relation to intra-cellular and other extra-cellular structures.


Hippocampal TET1 and TET2 Expression and DNA Hydroxymethylation Are Affected by Physical Exercise in Aged Mice.
The function of 5-hydroxymethylcytosine (5hmC) is poorly understood. 5hmC is an epigenetic modification of DNA, resulting from the oxidation of 5-methylcytosine (5mC) by the Fe2+, and 2-oxoglutarate-dependent, 10-11 translocation methylcytosine dioxygenases (TET1, TET2, and TET3). Recent evidence suggests that, in addition to being an intermediate in active demethylation, 5hmC may also have an epigenetic role. 5hmC is enriched in the adult brain, where it has been implicated in regulating neurogenesis. The rate of adult neurogenesis decreases with age, however physical exercise has been shown to counteract this deficit. Here, we investigated the impact of voluntary exercise on the age-related changes of TET1, TET2, expression and 5hmC content in the hippocampus and hypothalamus. For this purpose, we used voluntary exercise in young adult (3 months) and aged (18 months) mice as a rodent model of healthy brain aging. We measured the levels of hippocampal and hypothalamic TET1, TET2 mRNA, and 5hmC and memory [Object Location (OL) test] in mice that either exercised for 1 month or remained sedentary. While aging was associated with decreased TET1 and TET2 expression, voluntary exercise counteracted the decline in expression. Moreover, aged mice that exercised had higher hippocampal 5hmC content in the promoter region of miR-137, an miRNA involved in adult neurogenesis. Exercise improved memory in aged mice, and there was a positive correlation between 5hmC miR-137 levels and performance in the OL test. In the hypothalamus neither exercise nor aging affected TET1 or TET2 expression. These results suggest that exercise partially restores the age-related decrease in hippocampal TET1 and TET2 expression, which may be linked to the improvement in memory. Future studies should further determine the specific genes where changes in 5hmC levels may mediate the exercise-induced improvements in memory and neurogenesis in aged animals.


Hyalinizing clear cell carcinoma: report of eight cases and a review of literature.
Hyalinizing clear cell carcinoma (HCCC) is an extremely rare neoplasm with a female predominance, composed of nests of monomorphic clear cells within a hyaline stroma. This tumor often follows an indolent course and treatment includes wide surgical excision with or without adjuvant radiotherapy. We report eight cases of HCCC identified at two academic institutions in six women and two men, ranging in age from 25 to 86 years. Histologically, all cases demonstrated cords, trabeculae, and nests of monomorphic clear cells as well as cells with eosinophilic granular cytoplasm. Mild cellular atypia was occasionally seen and mitoses were very rare. Seven cases demonstrated a hyalinized stroma, and one case, a myxoid stroma. Immunohistochemically, the tumor cells were positive for epithelial markers and negative for desmin and actin. Seven cases were negative for S-100. Cells were also positive for periodic acid-Schiff and negative for mucin. The important clinicopathologic features and the differential diagnoses of HCCC, as well as a review of the literature are discussed.


Intermittent versus continuous feeding in critically ill adults.
Early enteral nutrition is recommended in critically ill adult patients. The optimal method of administering enteral nutrition remains unknown. Continuous enteral nutrition administration in critically ill patients remains the most common practice worldwide; however, its practice has recently been called into question in favor of intermittent enteral nutrition administration, where volume is infused multiple times per day. This review will outline the key differences between continuous and intermittent enteral nutrition, describe the metabolic responses to continuous and intermittent enteral nutrition administration and outline recent studies comparing continuous with intermittent enteral nutrition administration on outcomes in critically ill adults. In separate studies, healthy humans and critically ill patients receiving intermittent nutrition (infused over 3 h) had improved whole body protein balance from negative to positive. These studies did not have an isonitrogenous control group. A randomized controlled trial of intermittent bolus versus continuous enteral nutrition in healthy humans found that intermittent bolus feeding increased mesenteric arterial blood flow, increased insulin and peptide YY and reduced blood glucose concentration. A randomized controlled trial comparing intermittent bolus to continuous enteral nutrition in critically ill patients did not demonstrate clinically relevant differences in glycemic variability, insulin use or tube feeding volume or caloric intake between the two groups. Studies in healthy humans suggest that intermittent nutrient administration, as opposed to continuous, improves whole body protein synthesis. Unfortunately, similarly designed studies are lacking for critically ill patients. Future studies evaluating the impact of intermittent versus continuous nutrition administration on critical care outcomes should take into account factors such as protein quantity, protein quality and delivery route (enteral and/or parenteral). Until further studies are conducted in critically ill patients, a recommendation for or against intermittent nutrition delivery cannot be made.


Nonequilibrium pattern formation in strongly interacting driven colloids.
Dynamical instabilities are discussed for strongly interacting colloidal suspensions which are driven into nonequilibrium by an external field in the limit where hydrodynamic interactions can be neglected. Brownian dynamics computer simulations indicate that stripe-like patterns of particles driven alike are spontaneously formed if the external drive exceeds a critical strength. Recent previous studies of stripe formation obtained for symmetric equimolar mixtures in the steady state are reviewed. These results are then extended in two directions: first, we show that stripe-like segregation occurs also in asymmetric mixtures and observe an additional compression/expansion effect in the stripes composed of the small/large particles. Second, we study the relaxation into the stripe-patterned steady state starting from a uniform demixed state and show that different transient processes such as jamming, anisotropic coarsening and void formation are relevant on the route into the stratified steady state.


Fluid movement and creativity.
Cognitive scientists describe creativity as fluid thought. Drawing from findings on gesture and embodied cognition, we hypothesized that the physical experience of fluidity, relative to nonfluidity, would lead to more fluid, creative thought. Across 3 experiments, fluid arm movement led to enhanced creativity in 3 domains: creative generation, cognitive flexibility, and remote associations. Alternative mechanisms such as enhanced mood and motivation were also examined. These results suggest that creativity can be influenced by certain types of physical movement.


Spatial and temporal changes in the expression of fibroglycan (syndecan-2) during mouse embryonic development.
Fibroglycan (syndecan-2) is a member of a family of cell surface heparan sulfate proteoglycans that interact with adhesion molecules, growth factors and a variety of other effector systems that support the shaping, maintenance and repair of an organism. To investigate this apparent redundancy of proteoglycans at the cell surface, we have studied the expression of fibroglycan in the mouse embryo and compared this expression with that of syndecan-1. The characterisation of mouse embryo cDNA clones that crosshybridized to human fibroglycan-cDNA predicted that murine and human fibroglycan were highly similar in structure. Consistently, the analysis of transfectant cells, murine cell lines and embryo extracts indicated that the murine proteoglycan reacted specifically with monoclonal antibody 10H4 developed against the human protein. Fibroglycan, as detected by monoclonal antibody 10H4 in sections of embryonic tissues, occurred exclusively on mesenchymal cells that represented the putative precursors of the hard and connective tissue cells. No fibroglycan was detected in epithelia or in muscle cells. Areas where fibroglycan was particularly abundant were sites of high morphogenetic activity where intense cell-cell and cell-matrix interactions are known to occur (e.g. the epithelial-mesenchymal interfaces, the prechondrogenic and preosteogenic mesenchymal condensations). The expression of fibroglycan was weak in the early embryo, culminated during the morphogenetic phase and at the moment of cell lineage differentiation, and persisted in the perichondrium, periosteum and connective tissue cells. Syndecan-1, in contrast, was primarily detected in epithelia, and transiently in some mesenchymal cells, with mesenchymal localisations that did not or only partially overlap with those of fibroglycan. In situ hybridization analyses confirmed these expression patterns at the transcriptional level, identifying mesenchymal cells as the major source of fibroglycan production. These data indicate that the expression of fibroglycan occurs along unique and developmentally regulated patterns, and suggest that fibroglycan and syndecan-1 may have distinctive functions during tissue morphogenesis and differentiation.


The control of developmental phase transitions in plants.
Plant development progresses through distinct phases: vegetative growth, followed by a reproductive phase and eventually seed set and senescence. The transitions between these phases are controlled by distinct genetic circuits that integrate endogenous and environmental cues. In recent years, however, it has become evident that the genetic networks that underlie these phase transitions share some common factors. Here, we review recent advances in the field of plant phase transitions, highlighting the role of two microRNAs - miR156 and miR172 - and their respective targets during these transitions. In addition, we discuss the evolutionary conservation of the functions of these miRNAs in regulating the control of plant developmental phase transitions.


Transforming growth factor-β stimulates Smad1/5 signaling in pulmonary artery smooth muscle cells and fibroblasts of the newborn mouse through ALK1.
The intracellular signaling mechanisms through which TGF-β regulates pulmonary development are incompletely understood. Canonical TGF-β signaling involves Smad2/3 phosphorylation, Smad2/3·Smad4 complex formation and nuclear localization, and gene regulation. Here, we show that physiologically relevant TGF-β1 levels also stimulate Smad1/5 phosphorylation, which is typically a mediator of bone morphogenetic protein (BMP) signaling, in mouse pup pulmonary artery smooth muscle cells (mPASMC) and lung fibroblasts and other interstitial lung cell lines. This cross-talk mechanism likely has in vivo relevance because mixed Smad1/5/8·Smad2/3 complexes, which are indicative of TGF-β-stimulated Smad1/5 activation, were detected in the developing mouse lung using a proximity ligation assay. Although mixed Smad complexes have been shown not to transduce nuclear signaling, we determined that TGF-β stimulates nuclear localization of phosphorylated Smad1/5 and induces the expression of prototypical BMP-regulated genes in the mPASMC. Small-molecule kinase inhibitor studies suggested that TGF-β-regulated Smad1/5 phosphorylation in these cells is mediated by TGF-β-type I receptors, not BMP-type I receptors, but possibly the accessory activin-like kinase (ALK1) receptor. Although work by others suggested that ALK1 is expressed exclusively in endothelial cells in the vasculature, we detected ALK1 mRNA and protein expression in mPASMC in vitro and in mouse pup lungs. Moreover, using an antimurine ALK1 antibody and mPASMC, we determined that ALK1 regulates Smad1/5 phosphorylation by TGF-β. Together, these studies characterize an accessory TGF-β-stimulated BMP R-Smad signaling mechanism in interstitial cells of the developing lung. They also indicate the importance of considering alternate Smad pathways in studies directed at determining how TGF-β regulates newborn lung development.


MODBASE, a database of annotated comparative protein structure models.
MODBASE (http://guitar.rockefeller.edu/modbase) is a relational database of annotated comparative protein structure models for all available protein sequences matched to at least one known protein structure. The models are calculated by MODPIPE, an automated modeling pipeline that relies on PSI-BLAST, IMPALA and MODELLER. MODBASE uses the MySQL relational database management system for flexible and efficient querying, and the MODVIEW Netscape plugin for viewing and manipulating multiple sequences and structures. It is updated regularly to reflect the growth of the protein sequence and structure databases, as well as improvements in the software for calculating the models. For ease of access, MODBASE is organized into different datasets. The largest dataset contains models for domains in 304 517 out of 539 171 unique protein sequences in the complete TrEMBL database (23 March 2001); only models based on significant alignments (PSI-BLAST E-value < 10(-4)) and models assessed to have the correct fold are included. Other datasets include models for target selection and structure-based annotation by the New York Structural Genomics Research Consortium, models for prediction of genes in the Drosophila melanogaster genome, models for structure determination of several ribosomal particles and models calculated by the MODWEB comparative modeling web server.


Radiation therapy for palliation of sarcoma metastases: a unique and uniform hypofractionation experience.
Radiotherapy (RT) is our preferred modality for local palliation of metastatic soft tissue sarcoma (STS). A short and intense course of RT is usually needed for rapid palliation and local control of metastatic disease. Seventeen patients at a median age of 61 had symptomatic metastatic sarcoma and required rapid palliation. The symptoms related to the metastases were either pain or discomfort. All patients were treated by a short and intensive course of administration: 39 Gy were given in 13 fractions of 3 Gy/day, 5 times a week. Median follow-up period was 25 weeks. The treatment was well tolerated. Acute side effects included grade one skin toxicity. No wound complications were noted among those undergoing surgery. Late side effects included skin pigmentation and induration of irradiated soft tissues. Durable pain control was achieved in 12 out 15 cases treated for gross metastases. Tumor progression was seen in the 3 other cases within a period of two to nine months. Among 5 lesions which were irradiated as an adjunctive treatment following resection, no local recurrence was observed. The results of this series, although limited in size, point to the safety and feasibility of hypofractionated RT for palliation of musculoskeletal metastases from sarcoma.


Anti-inflammatory doses of ibuprofen: effect on neutrophils and exercise-induced muscle injury.
The purpose of the study was to determine the effect of anti-inflammatory doses of ibuprofen on neutrophils, neutrophil O2* production, and markers of muscle injury. Males (n=10) performed 2 bouts of one-arm eccentric exercise on opposite arms separated by three weeks. Subjects received 2400 mg x d(-1) of ibuprofen or a placebo 5 d before exercise and during 10 d of recovery. Measurements were made before the treatments, pre-exercise, at 4 h, and at 1, 2, 3, 4 and 10 d post-exercise. Circulating neutrophil counts were similar between the treatments at the sampling points. Neutrophil counts were higher (p<0.05) for ibuprofen and were elevated (p<0.05) at 4h post-exercise relative to pre-exercise in both treatments. Stimulated neutrophil O2* production was lower for ibuprofen relative to placebo at pre-exercise and was increased (p<0.05) at 4 h and 4 d of both treatments. CK activity at 3 d post-exercise was lower (p<0.05) for ibuprofen relative to placebo. Isometric strength, soreness, tenderness, and arm angles were similar between the treatments. In conclusion, anti-inflammatory doses of ibuprofen reduced CK activity but not the neutrophil response or other indirect markers of muscle injury during recovery from eccentric arm exercise.


Tumorigenicity and intracisternal A-particle expression of hybrids between murine myeloma and lymphocytes.
Hybrids of BALB/c lymphocytes and a murine myeloma, a tumor that expresses intracisternal A-particles, were obtained with polyethylene glycol as the fusogen. The karyotype, tumorigenicity, and A-particle expression of the hybrid clones were assessed. All the hybrid clones analyzed were tumorigenic and expressed intracisternal A-particles even when they were the result of a fusion event between two lymphocytes and one myeloma cell in which no loss of chromosomes was detected. The tumors that developed following inoculation of hybrid cells into BALB/c mice (1 x 10(6) cells/mouse) were karyotypically identical to the inoculated cells. It appears that the two myeloma cell phenotypic traits analyzed (tumorigenicity and A-particle expression) are dominant.


Non-invasive assessment of liver steatosis and fibrosis in HIV/HCV- and HCV- infected patients.
Conflicting data have been reported on the prevalence of liver steatosis, its risk factors and its relationship with fibrosis in patients with human immunodeficiency virus (HIV)/hepatitis C virus (HCV) co-infection or with HCV mono-infection. The study aims were to assess steatosis prevalence and its risk factors in both HCV groups. We also evaluated whether steatosis was linked with advanced fibrosis. Sixty-eight HIV/HCV co-infected and 69 HCV mono-infected patients were consecutively enrolled. They underwent liver ultrasonography and transient elastography. Bright liver echo-pattern was used to diagnose steatosis; advanced fibrosis was defined as liver stiffness ≥ 9.5 kPa and FIB-4 values ≥ 3.25. The optimal stiffness cut-off according to FIB-4 ≥ 3.25 was evaluated by ROC analysis. No significant difference was found in steatosis-prevalence between mono- and co-infected patients (46.3 vs. 51.4%). Steatosis was associated with triglycerides and impaired fasting glucose/diabetes in HCV mono-infected, with lipodystrophy, metabolic syndrome, total-cholesterol and triglycerides in co-infected patients. Stiffness ≥ 9.5 was significantly more frequent in co-infection (P < 0.003). Advanced fibrosis wasn't significantly associated with steatosis. The area under the ROC curve was 0.85 (95% CI 0.79-0.9). On multivariate analysis steatosis was associated with triglycerides in both HCV mono- and co-infected groups (P < 0.02; P < 0.03). Although steatosis was common in both HCV mono- and co-infected patients, it was not linked with advanced fibrosis. Triglycerides were independent predictors of steatosis in either of the HCV-groups. Dietary interventions and lifestyle changes should be proposed to prevent metabolic risk factors.


SpAHA1 and SpSOS1 Coordinate in Transgenic Yeast to Improve Salt Tolerance.
In plant cells, the plasma membrane Na+/H+ antiporter SOS1 (salt overly sensitive 1) mediates Na+ extrusion using the proton gradient generated by plasma membrane H+-ATPases, and these two proteins are key plant halotolerance factors. In the present study, two genes from Sesuvium portulacastrum, encoding plasma membrane Na+/H+ antiporter (SpSOS1) and H+-ATPase (SpAHA1), were cloned. Localization of each protein was studied in tobacco cells, and their functions were analyzed in yeast cells. Both SpSOS1 and SpAHA1 are plasma membrane-bound proteins. Real-time polymerase chain reaction (PCR) analyses showed that SpSOS1 and SpAHA1 were induced by salinity, and their expression patterns in roots under salinity were similar. Compared with untransformed yeast cells, SpSOS1 increased the salt tolerance of transgenic yeast by decreasing the Na+ content. The Na+/H+ exchange activity at plasma membrane vesicles was higher in SpSOS1-transgenic yeast than in the untransformed strain. No change was observed in the salt tolerance of yeast cells expressing SpAHA1 alone; however, in yeast transformed with both SpSOS1 and SpAHA1, SpAHA1 generated an increased proton gradient that stimulated the Na+/H+ exchange activity of SpSOS1. In this scenario, more Na+ ions were transported out of cells, and the yeast cells co-expressing SpSOS1 and SpAHA1 grew better than the cells transformed with only SpSOS1 or SpAHA1. These findings demonstrate that the plasma membrane Na+/H+ antiporter SpSOS1 and H+-ATPase SpAHA1 can function in coordination. These results provide a reference for developing more salt-tolerant crops via co-transformation with the plasma membrane Na+/H+ antiporter and H+-ATPase.


Usefulness of the Brief Pain Inventory in Patients with Opioid Addiction Receiving Methadone Maintenance Treatment.
Chronic pain is implicated as a risk factor for illicit opioid use among patients with opioid addiction treated with methadone. However, there exists conflicting evidence that supports and refutes this claim. These discrepancies may stem from the large variability in pain measurement reported across studies. We aim to determine the clinical and demographic characteristics of patients reporting pain and evaluate the prognostic value of different pain classification measures in a sample of opioid addiction patients. Multi-center prospective cohort study. Methadone maintenance treatment facilities for managing patients with opioid addiction. This study includes participants from the Genetics of Opioid Addiction (GENOA) prospective cohort study. We assessed the prognostic value of different pain measures for predicting opioid relapse. Pain measures include the Brief Pain Inventory (BPI) and patients' response to a direct pain question all study participants were asked from the GENOA case report form (CRF) "are you currently experiencing or have been diagnosed with chronic pain?" Performance characteristics of the GENOA CRF pain measure was estimated with sensitivity and specificity using the BPI as the gold standard reference. Prognostic value was assessed using pain classification as the primary independent variable in an adjusted analysis using 1) the percentage of positive opioid urine screens and 2) high-risk opioid use (= 50% positive opioid urine screens) as the dependent variables in a linear and logistic regression analyses, respectively. Among participants eligible for inclusion (n = 444) the BPI was found to be highly sensitive, classifying a large number of GENOA participants with pain (n = 281 of the 297 classified with pain, 94.6%) in comparison to the GENOA CRF (n = 154 of 297 classified with pain, 51.8%). Participants concordantly classified as having pain according to the GENOA CRF and BPI were found to have an estimated 7.79% increase in positive opioid urine screens (estimated coefficient: 7.79; 95% CI 0.74, 14.85: P = 0.031) and a 4 times greater odds (odds ratio [OR]: 4.10 P = 0.008; 95% CI: 1.44, 11.63) of engaging in a "high risk" level of illicit opioids use. The prognostic relevance of pain classification was not maintained for the additional participants classified by the BPI (n = 143 discordant). These results suggest that while the BPI may be more sensitive in capturing pain among patients with opioid addiction, this tool is of less value for predicting the impact of pain on illicit opioid use for opioid addiction patients on methadone maintenance treatment. The GENOA CRF showed high predictive ability, whereby patients classified according to the GENOA CRF are at serious risk for opioid relapse. Using the appropriate tool to assess pain in opioid addiction may serve to improve the current detection and management of comorbid pain. We caution the interpretation of these result since they are still reflective of participants already maintained on an opioid substitution therapy (OST), which can largely differ from patients who drop out of methadone maintenance treatment (MMT) or never seek treatment altogether.


Transcatheter therapy of anomalous systemic venous drainage.
Anomalous drainage of the right superior caval vein into the left atrium is a rare congenital anomaly that causes cyanosis and occult infection owing to right-to-left shunting. Transcatheter management of this anomaly is unique and rarely reported. We report a 32-year-old man with a history of brain abscess, who was diagnosed with an anomalous right superior caval vein draining to the left atrium; right upper pulmonary vein and right middle pulmonary vein draining into the inferior portion of the right superior caval vein; and a left superior caval vein draining into the right atrium through the coronary sinus without a bridging vein. Pre-procedural planning was guided by three-dimensional printed model. The right superior caval vein was occluded with a 16-mm Amplatzer muscular Ventricular Septal Defect occluder inferior to the azygous vein, but superior to the entries of right upper and middle pulmonary veins. This diverted the right superior caval vein flow to the inferior caval vein system through the azygos vein in a retrograde manner and allowed the right upper pulmonary vein and right middle pulmonary vein flow to drain into the left atrium normally, achieving exclusion of right-to-left shunting and allowing normal drainage of pulmonary veins into the left atrium. At the 6-month follow-up, his saturation improved from 93 to 97% with no symptoms of superior caval vein syndrome.


Encoding strategy for maximum noise tolerance bidirectional associative memory.
In this paper, the basic bidirectional associative memory (BAM) is extended by choosing weights in the correlation matrix, for a given set of training pairs, which result in a maximum noise tolerance set for BAM. We prove that for a given set of training pairs, the maximum noise tolerance set is the largest, in the sense that this optimized BAM will recall the correct training pair if any input pattern is within the maximum noise tolerance set and at least one pattern outside the maximum noise tolerance set by one Hamming distance will not converge to the correct training pair. This maximum tolerance set is the union of the maximum basins of attraction. A standard genetic algorithm (GA) is used to calculate the weights to maximize the objective function which generates a maximum tolerance set for BAM. Computer simulations are presented to illustrate the error correction and fault tolerance properties of the optimized BAM.


Report of a rare case and review of adult intestinal duplication at the opposite side of mesenteric margin.
To study the previously discovered clinical entity of adult intestinal duplication and its treatment, and propose an extension to its existing classification. We report the case of an adult male with abdominal pain, constipation and vomiting. This patient underwent surgical separation of adhesions, reduction of torsion and intestinal decompression. Postoperative pathological findings confirmed the rare diagnosis of intestinal duplication. Adult intestinal duplication is quite rare. Its clinical manifestations are nonspecific. From this finding of intestinal duplication originating at the opposite side of the mesenteric margin, a further extension of the existing anatomical classification is proposed.


The Child Problematic Traits Inventory in China: A multiple informant-based validation study.
The aim of this study was to further test the reliability and validity of a newly developed instrument designed to assess psychopathic traits in children, the Child Problematic Traits Inventory (CPTI). Teachers and mothers of 686 approximately 6- to 12-year-old children (48.1% girls) completed the CPTI. Confirmatory factor analyses supported the proposed 3-factor structure of the CPTI teacher and parent versions and good to excellent internal consistency of the teacher- and mother-based CPTI scores were found. The validity of the teacher- and mother-based CPTI scores was supported by revealing the expected relations with conduct problems, hyperactivity, and various dimensions of temperament. In conclusion, the results suggest that the CPTI holds promise as a teacher- and parent-rated tool for assessing psychopathic traits in Chinese children, although more research is needed to see if these findings can be generalized to other Chinese samples and settings. (PsycINFO Database Record


Diagnosis of gastrointestinal T-cell lymphomas in routinely processed tissues.
Diagnosis of primary gastrointestinal T-cell lymphomas is often problematic because lymphoma may not be suspected clinically or on resection, and tissue may not be frozen for immunophenotyping. Furthermore, ulceration and inflammation and the polymorphous character of the lesions makes evaluation difficult. Only approximately 150 cases have been reported, fewer than 20 from North America. We have tried to establish a reliable approach to the diagnosis of gastrointestinal lymphomas of T-cell phenotype in routinely processed tissue. Sections from five primary gastrointestinal T-cell lymphomas were stained with a panel of 13 antibodies reactive in routinely fixed, paraffin-embedded tissue. These included antibodies to pan-T- and pan-B-cell antigens (CD3, CD20), B- and T-cell-associated antigens (CD43, CD45R0; CDw75, CD74), antigens expressed by activated T-cells (HLA-DR, CD30), leukocyte antigens (CD45, CD15), and macrophage markers (MAC-387, HAM-56). All stained positively with T-cell markers MT-1 and Leu-22, four with UCHL-1, and three with anti-CD3 polyclonal antibody. B-cell markers identified by L-26 and LN-1 were negative in all five, whereas LN-2 was expressed in two. Two expressed HLA-DR; all were Ber-H2 negative. Two had an abnormal phenotype: one was Leu-M1 positive, and one LCA negative. Ten B-cell gastrointestinal lymphoma controls were negative for MT-1, Leu-22, and CD3, and nine were negative for UCHL-1. Nine were positive for the B-cell marker L-26, eight for LN-2, and seven for LN-1. All tumors were negative for monocyte-macrophage markers. This antibody panel provides a reliable means for identifying gastrointestinal T-cell lymphomas in paraffin sections. Use of a panel is advisable because of variation in expression and preservation of antigens, and to detect abnormal phenotypes. Application of this approach may facilitate the diagnosis of gastrointestinal T-cell lymphomas both prospectively and in archival material, and thereby encourage studies of the behavior and treatment of these neoplasms.


Full-text publication of abstract-presented work in sport and exercise psychology.
Meetings promote information sharing, but do not enable full dissemination of details. A systematic search was conducted for abstracts presented at the 2010 and 2011 Association of Applied Sport Psychology Annual Conferences to determine the full-text dissemination rate of work presented in abstract form and investigate factors influencing this rate. Systematic searches were sequentially conducted to determine whether the abstract-presented work had been published in full-text format in the 5 years following presentation. If a potential full-text publication was identified, information from the conference abstract (eg, results, number of participants in the sample(s), measurement tools used and so on) was compared with the full text to ensure the two entities represented the same body of work. Abstract factors of interest were assessed using logistic regression. Ninety-four out of 423 presented abstracts (22.2%) were published in full text. Odds of full-text publication increased if the abstract was from an international institution, presented in certain conference sections or presented as a lecture. Those attending professional conferences should be cautious when translating data presented at conferences into their applied work because of the low rate of peer-reviewed and full-text publication of the information.


A randomized, placebo-controlled study of the effects of telcagepant on exercise time in patients with stable angina.
Telcagepant is a calcitonin gene-related peptide (CGRP) receptor antagonist being evaluated for acute migraine treatment. CGRP is a potent vasodilator that is elevated after myocardial infarction, and it delays ischemia during treadmill exercise. We tested the hypothesis that CGRP receptor antagonism does not reduce treadmill exercise time (TET). The effects of supratherapeutic doses of telcagepant on TET were assessed in a double-blind, randomized, placebo-controlled, two-period, crossover study in patients with stable angina and reproducible exercise-induced angina. Patients received telcagepant (600 mg, n = 46; and 900 mg, n = 14) or placebo and performed treadmill exercise at T(max) (2.5 h after the dose). The hypothesis that telcagepant does not reduce TET was supported if the lower bound of the two-sided 90% confidence interval (CI) for the mean treatment difference (telcagepant-placebo) in TET was more than -60 s. There were no significant between-treatment differences in TET (mean treatment difference: -6.90 (90% CI: -17.66, 3.86) seconds), maximum exercise heart rate, or time to 1-mm ST-segment depression using pooled data or with stratification for dose.


Radiographic and geometric anatomy of the scapula.
In an effort to study anatomic parameters of the scapula that may be of clinical importance, scapulae were harvested from cadavers and stripped of their soft tissues. For each scapula, three roentgenograms then were obtained: a Y-scapular view, an axillary lateral view, and a glenoid fossa (or true anteroposterior) view. Computed tomographic pneumoarthrograms and randomly selected antero-posterior chest roentgenograms of skeletally mature adults were studied also to measure further roentgenographic parameters of the normal scapula. The geometric anatomy of the scapula is of fundamental importance in the pathomechanics of rotator cuff disease, total shoulder arthroplasty, and recurrent shoulder dislocation. This study presents in detail the exact geometry of scapula anatomy, giving precise figures for distances, angles, and radii of curvature of the scapula. All results then are discussed in terms of their clinical relevance to the above problems.


Human immunodeficiency virus type 1 virions composed of unprocessed Gag and Gag-Pol precursors are capable of reverse transcribing viral genomic RNA.
The structural proteins and enzymes of the human immunodeficiency virus type 1 core are translated as part of two polyprotein precursors, Gag and Gag-Pol, which are cleaved by a virally encoded protease. Viruses grown in the presence of inhibitors of the protease contain core particles that are aberrantly assembled, and upon infection of susceptible cells, they do not synthesize viral DNA. Through the use of a proteinase inhibitor (A77003), we determined that the viral reverse transcriptase can efficiently synthesize viral DNA as part of the unprocessed Gag-Pol precursor. We also found that the stabilities of core particles composed of unprocessed precursors were considerably enhanced. These observations suggest that for viruses composed of unprocessed precursors, replication is interrupted before the reverse transcription step.


Multi-frequency surface plasmons supported with a nanoscale non-uniform 2D electron gas formed due to a polar catastrophe at the oxide interface, dispersions, diffractions, and beyond.
Recently, 2D electron gases (2DEGs) formed at oxide interfaces are drawing increasing attention as they cause a myriad of intriguing phenomena. As ideal platforms in supporting surface plasmon polaritons (SPPs) without metallic constituents, such 2DEGs are favorable in non-linear plasmonics for ultra-low total Joule dissipation. Convincingly, an increase in the interfacial electron density (IIED) formed at the interface of indium-tin-oxide and LiNbO3 composite slab is responsible for a number of interesting phenomena, which are hardly explained with the conventional photorefractive theoretical framework but can be satisfactorily elucidated via SPP excitation and resultant colossal non-linear effects. Since the polar-catastrophe-led IIED is universal to all combinations of highly polar ferroelectric oxides (FOs) and less polar transparent conducting oxides (TCOs), a systematic theoretical treatment of an FO/TCO system is pivotal to a variety of promising applications. In this study, the nanometer scale 2DEG at the FO/TCO interface is illustrated theoretically with the Thomas-Fermi screening picture, by taking into account the spontaneous polarization, along with related boundary conditions. The local plasma frequency of 2DEGs can be increased up to the UV regime for the composite slabs discussed, which are suitable for highly desirable visible applications. The SPP dispersion relationship was given for the 2DEG layer sandwiched between the FO slab and the unmodified TCO layer. To further take the non-uniform nature of IIED into account, dramatic dispersions of dielectric permittivity and index of refraction were simulated with a very broad range, hinting at different ways for meeting phase matching conditions and slowing the light for non-linear plasmonic applications, which are confirmed experimentally.


Current practice of conventional intermittent hemodialysis for acute kidney injury.
The use of conventional intermittent hemodialysis (IHD) represents a mainstay of supportive care of patients with acute kidney injury (AKI). However, a number of fundamental questions regarding the optimal management of IHD remain unanswered after more than six decades of renal replacement therapy (RRT). This review summarizes current evidence regarding the timing of initiation of intermittent hemodialysis, the comparative outcomes (mortality and recovery of renal function), the prescription of the intensity of this therapy and discontinuation of dialysis. The way conventional IHD is performed has an impact on the outcome of sick patients with AKI. The value of regular education and training of those who provide IHD cannot be emphasized enough. However, we must be realistic in our expectations that no mode of RRT per se will substantially alter the excessive mortality of critically ill-patients with AKI.


Radio-guided surgical biopsy for the diagnosis of suspected osseous metastases.
Radioisotope bone scanning is frequently employed in staging malignancies. However, false positive results are common, and biopsy is usually required. In the absence of plain radiographic abnormalities or local symptoms, localization of the area of abnormal tracer activity at the time of open rib or sternum biopsy may be difficult. It often requires resection of a large portion of one or more ribs or other bones to assure that the target area was biopsied, and still the area in question is commonly missed. In this setting, the newly-developed, small gamma probe is now used as a tool to allow precise intraoperative localization of increased tracer activity in the target bone. The use of gamma counting is an easy, highly accurate aid (100% sensitivity) to localize areas of abnormal radioisotope uptake in suspected asymptomatic osseous metastases, usually for open biopsy of a rib. The use of this technique obviates the need to obtain intraoperative localizing radiographs to confirm accurate rib identification, thereby substantially decreasing operative time.


Influence of lactation on rate of disappearance of ethanol in the rat.
The rate of blood ethanol disappearance was significantly increased in lactating rats compared to virgin controls and parturient rats that had their offspring removed in birth. Liver but not kidney size was also increased in lactating rats.


Methylopila musalis sp. nov., an aerobic, facultatively methylotrophic bacterium isolated from banana fruit.
A newly isolated, facultatively methylotrophic bacterium (strain MUSA(T)) was investigated. The isolate was strictly aerobic, Gram-stain-negative, asporogenous, motile, rod-shaped and multiplied by binary fission. The strain utilized methanol, methylamine and an apparently narrow range of multi-carbon compounds, but not methane, dichloromethane or CO2/H2, as the carbon and energy sources. Growth occurred at pH 5.5-9.5 (optimum, pH 7.0) and 16-40 °C (optimum, 28-30 °C). The major fatty acids of methanol-grown cells were C18 : 1ω7c, C18 : 0 and 11-methyl-C18 : 1ω7c . The predominant phospholipids were phosphatidylethanolamine, phosphatidylcholine, phosphatidylglycerol and phosphatidylmonomethylethanolamine. The major ubiquinone was Q-10. The strain had methanol and methylamine dehydrogenases as well as the enzymes of the N-methylglutamate pathway (lyases of γ-glutamylmethylamide and N-methylglutamate). C1 assimilation occurs via the isocitrate lyase-negative serine pathway. Ammonium was assimilated by glutamate dehydrogenase and the glutamate cycle (glutamate synthase/glutamine synthetase). The DNA G+C content of the strain was 64.5 mol% (determined from the melting temperature). Based on 16S rRNA gene sequence similarity (97.0-98.9 %) and DNA-DNA relatedness (36-38 %) with representatives of the genus Methylopila (Methylopila capsulata IM1(T) and Methylopila jiangsuensis JZL-4(T)) the isolate was classified as a novel species of the genus Methylopila, for which the name Methylopila musalis sp. nov. is proposed. The type strain is MUSA(T) ( = VKM B-2646(T) = DSM 24986(T) = CCUG 61696(T)).


How much bias results if a quasi-experimental design combines local comparison groups, a pretest outcome measure and other covariates?: A within study comparison of preschool effects.
This study uses a within study comparison design (WSC) to conduct a novel test of how much causal bias results when researchers use a nonequivalent comparison group design type (NECGD) that combines: (a) a comparison group local to the treatment group; (b) a pretest measure of the study outcome; and (c) a rich set of 19 other multidimensional covariates. Most prior WSCs have dealt with the bias consequences of only 1 of these, revealing that each routinely reduces bias but does not necessarily eliminate it. Thus, a need exists to identify NECGDs that more robustly eliminate bias. This study is the first to examine how combining the 3 bias-control mechanisms above affects bias. The intervention we examine is a prekindergarten mathematics curriculum, for which a randomized control trial (RCT) produces a positive 1-year math effect. Final bias in the NECGD is assessed as the difference between its impact and that of the RCT when each design has the same intervention, outcome, and estimand. Over the many specifications we explore, NECGD bias is less than .10 standard deviations, indicating that minimal bias results when an NECGD combines all 3 design elements. The factorial design we use in this study also tests the bias associated with seven other NECGD types. Comparing the total pattern of results shows that the minimal bias when all 3 elements are combined is uniquely attributable to the locally chosen comparison group and not the availability of a pretest or other covariates. In actual research practice, it is impossible to predict in advance which design elements will affect bias by how much in any given application. So further research is needed to probe whether the simultaneous use of all three design elements achieves minimal bias dependably across diverse applications and not just in the preschool math context examined here. (PsycInfo Database Record (c) 2020 APA, all rights reserved).


Identification of the Rayleigh surface waves for estimation of viscoelasticity using the surface wave elastography technique.
The purpose of this Letter to the Editor is to demonstrate an effective method for estimating viscoelasticity based on measurements of the Rayleigh surface wave speed. It is important to identify the surface wave mode for measuring surface wave speed. A concept of start frequency of surface waves is proposed. The surface wave speeds above the start frequency should be used to estimate the viscoelasticity of tissue. The motivation was to develop a noninvasive surface wave elastography (SWE) technique for assessing skin disease by measuring skin viscoelastic properties. Using an optical based SWE system, the author generated a local harmonic vibration on the surface of phantom using an electromechanical shaker and measured the resulting surface waves on the phantom using an optical vibrometer system. The surface wave speed was measured using a phase gradient method. It was shown that different standing wave modes were generated below the start frequency because of wave reflection. However, the pure symmetric surface waves were generated from the excitation above the start frequency. Using the wave speed dispersion above the start frequency, the viscoelasticity of the phantom can be correctly estimated.


Desires vs. conditions: A qualitative study exploring the factors affecting the place of death of child with cancer in Turkey.
The purpose of this study was to describe factors affecting the place of death of children with cancer at the end of life. The descriptive phenomenological approach was used. Eighteen mothers who lost their children to cancer participated in in-depth interviews. Data were analysed using MAXQDA software version. Codes and categories were developed inductively from participants' narratives. The factors affecting the place of death of children were categorised into two main themes: (1) desires and (2) conditions. Most of the mothers reported that their deceased children wanted to be with their families at the end of life and they wanted to go home. The conditions related to health services were defined as the barriers to the death of their children in the places of death preferred by the mothers. The desire to be close to the child was the main factor affecting the parents' decisions. The findings revealed the prevailing circumstances in the death place decision beyond parental desires. These were the child's health conditions, physical conditions of hospitals, and the lack of home care and paediatric palliative care services, which were factors related to the system, and the lack of other options for parents.


Laboratory evaluation of the Baxter Patient-Controlled Analgesia Infusor System: a disposable patient-controlled analgesia device.
The purpose of this study was to determine the accuracy of bolus-demand volumes obtained from the Baxter Patient-Controlled Analgesia Infusor System, a disposable patient-controlled analgesia device. An automated system was used to make demands in a pattern designed to simulate those made by a patient in the first 24 postoperative hours. Following this, a pattern of varying short interdemand intervals was used to evaluate performance of the device when demands were made near the nominal lockout interval of 6 min. Finally, a prolonged array of short interdemand intervals was used to evaluate performance as the reservoir of the devices became exhausted. Ten devices were tested. One device failed; after 70 min of testing the reservoir burst. The mean delivery of the remaining nine devices for the first 24 h of testing was 92.6% of nominal (SD = 3.9%). Evaluation near the nominal lockout interval revealed a departure of delivered volume from nominal (worst = 73.9% at an interdemand interval of 6 min). As the reservoir became exhausted, delivery increased to a maximum value, ranging from 118% to 137% of nominal, before falling to zero. In general, the devices performed consistently and the departures from nominal delivery were not considered to be of clinical significance.


Emergence of Escherichia coli isolates producing conjugative plasmid-mediated DHA-1 beta-lactamase in a Korean university hospital.
Seven isolates of cefoxitin-resistant Escherichia coli with an inducible phenotype were detected between November 2002 and July 2003 in a Korean hospital. Conjugations were tested by the filter mating method using azide-resistant E. coli J53 as the recipient. All isolates and their transconjugants were tested for broth microdilution minimum inhibitory concentrations, isoelectric focusing (IEF), polymerase chain reaction (PCR) for SHV, TEM, CTX-M and DHA-derived beta-lactamases, and DNA sequencing. XbaI-digested genomic DNA bands of the seven isolates were separated by pulsed-field gel electrophoresis (PFGE). IEF, PCR and sequence analysis revealed that all isolates possessed a blaTEM-1-like and a blaDHA-1 gene. Two isolates also carried the blaCTX-M-14 gene. Transfer of the resistance by conjugation experiments of all seven isolates was successful, suggesting that the blaDHA-1-containing plasmids in the E. coli isolates were self-transmissible. The isolates were recovered from patients in wards or an intensive care unit, all of which had been exposed to beta-lactams before isolation of the DHA-1 producers. Five patterns among the seven isolates were demonstrated by PFGE; sporadic infections with E. coli possessing an inducible beta-lactam resistance phenotype were found. DHA-1 encoded by conjugative plasmids conferred the resistance phenotype. The spread of the DHA-1 producers was due to both clonal spread and horizontal transfer of the resistance gene.


Temperature gradient affects differentiation of gene expression and SNP allele frequencies in the dominant Lake Baikal zooplankton species.
Local adaptation and phenotypic plasticity are main mechanisms of organisms' resilience in changing environments. Both are affected by gene flow and are expected to be weak in zooplankton populations inhabiting large continuous water bodies and strongly affected by currents. Lake Baikal, the deepest and one of the coldest lakes on Earth, experienced epilimnion temperature increase during the last 100 years, exposing Baikal's zooplankton to novel selective pressures. We obtained a partial transcriptome of Epischura baikalensis (Copepoda: Calanoida), the dominant component of Baikal's zooplankton, and estimated SNP allele frequencies and transcript abundances in samples from regions of Baikal that differ in multiyear average surface temperatures. The strongest signal in both SNP and transcript abundance differentiation is the SW-NE gradient along the 600+ km long axis of the lake, suggesting isolation by distance. SNP differentiation is stronger for nonsynonymous than synonymous SNPs and is paralleled by differential survival during a laboratory exposure to increased temperature, indicating directional selection operating on the temperature gradient. Transcript abundance, generally collinear with the SNP differentiation, shows samples from the warmest, less deep location clustering together with the southernmost samples. Differential expression is more frequent among transcripts orthologous to candidate thermal response genes previously identified in model arthropods, including genes encoding cytoskeleton proteins, heat-shock proteins, proteases, enzymes of central energy metabolism, lipid and antioxidant pathways. We conclude that the pivotal endemic zooplankton species in Lake Baikal exists under temperature-mediated selection and possesses both genetic variation and plasticity to respond to novel temperature-related environmental pressures.


Preoperative Plasma miRNA Levels Predict Prognosis in Early-stage Malignant Melanoma.
Non-invasive circulating tumor biomarkers in liquid biopsy, such as microRNAs (miRNA), provide for better personalization of treatment strategies. The aim of our study was to assess the prognosis of patients with melanoma undergoing tumor resection with curative intent based on analysis of selected circulating miRNAs. A total of 22 patients with stage I to III melanoma were enrolled into this prospective study. Plasma samples were obtained pre-surgery and early post-surgery from peripheral blood draws. A panel of 23 candidate miRNAs was designed and expression of miRNAs were analyzed by reverse transcription-quantitative polymerase chain reaction with exogenous reference control cel-miR-39-3p. Higher preoperative expression levels of miR-99a (p=0.008), miR-320 (p=0.009), miR-1908 (p=0.001), miR-494 (p=0.018) and miR-4487 (p=0.048) were associated with a shorter disease-free interval. Similarly, higher preoperative plasma levels of miR-99a (p=0.017), miR-221 (p=0.026), miR-320 (p=0.016), miR-494 (p=0.009), miR-1260 (p=0.026) and miR-1908 (p=0.024) were associated with worse overall survival. No significant differences between pre- and postoperative plasma miRNA levels were observed. Liquid biopsy is a minimally-invasive approach which can lead to a better understanding of cancer behavior and offers the possibility of precise patient prognosis, allowing selection of the most appropriate treatment. Our study showed that preoperative plasma levels of miR-99a, miR-221, miR-320, miR-494, miR-1908 and miR-4487 were associated with disease-free interval and overall survival of patients with early-stage melanoma. This approach may help in decision-making about the appropriateness of modern adjuvant treatment administration in patients with resectable melanoma.


Seed mucilage improves seedling emergence of a sand desert shrub.
The success of seedling establishment of desert plants is determined by seedling emergence response to an unpredictable precipitation regime. Sand burial is a crucial and frequent environmental stress that impacts seedling establishment on sand dunes. However, little is known about the ecological role of seed mucilage in seedling emergence in arid sandy environments. We hypothesized that seed mucilage enhances seedling emergence in a low precipitation regime and under conditions of sand burial. In a greenhouse experiment, two types of Artemisia sphaerocephala achenes (intact and demucilaged) were exposed to different combinations of burial depth (0, 5, 10, 20, 40 and 60 mm) and irrigation regimes (low, medium and high, which simulated the precipitation amount and frequency in May, June and July in the natural habitat, respectively). Seedling emergence increased with increasing irrigation. It was highest at 5 mm sand burial depth and ceased at burial depths greater than 20 mm in all irrigation regimes. Mucilage significantly enhanced seedling emergence at 0, 5 and 10 mm burial depths in low irrigation, at 0 and 5 mm burial depths in medium irrigation and at 0 and 10 mm burial depths in high irrigation. Seed mucilage also reduced seedling mortality at the shallow sand burial depths. Moreover, mucilage significantly affected seedling emergence time and quiescence and dormancy percentages. Our findings suggest that seed mucilage plays an ecologically important role in successful seedling establishment of A. sphaerocephala by improving seedling emergence and reducing seedling mortality in stressful habitats of the sandy desert environment.


Current therapies in treatment and prevention of fracture wound biofilms: why a multifaceted approach is essential for resolving persistent infections.
Traumatic orthopedic injuries, particularly extremity wounds, are a significant cause of morbidity. Despite prophylactic antibiotic treatment and surgical intervention, persistent infectious complications can and do occur. Persistent bacterial infections are often caused by biofilms, communities of antibiotic tolerant bacteria encased within a matrix. The structural and metabolic differences in this mode of growth make treatment difficult. Herein, we describe both established and novel, experimental treatments targeted at various stages of wound healing that are specifically aimed at reducing and eliminating biofilm bacteria. Importantly, the highly tolerant nature of these bacterial communities suggests that most singular approaches could be circumvented and a multifaceted, combinatorial approach will be the most effective strategy for treating these complicated infections.


Modular intervention to improve paternal involvement and support for better infant and young child feeding in a district of coastal South India: a randomized controlled trial protocol.
Background: The major determinant to the well-being of infants and young children (IYC) is their feeding practices. These practices are the responsibility of both parents, meaning that fathers have an equal role to mothers. Fathers' involvement can have an impact on the overall health of the children. Despite this, paternal involvement towards IYC feeding (IYCF) have not been studied adequately. Methods: This randomized control trial (n=120) will be conducted among fathers of infants (children aged <1 year) and young children (children aged 12-23 months) in selected households in Dakshina Kannada District of the southern Indian State of Karnataka. The study will be conducted after an initial baseline assessment on awareness, attitude and involvement of fathers in IYCF. Fathers with scores less than the 50 th percentile in the practice component will be categorized as fathers with poor involvement and will be potential participants for the trial. A visual module will be developed and validated for improving paternal involvement in IYCF. Using a simple randomization technique, the participants will be allocated to modular intervention and control group (1:1 allocation). Each participant in the intervention arm will be visited once a month to implement the module, for six months on a one-to-one basis. Following the intervention, a post-test assessment will be done for both groups to measure the level of paternal involvement in IYCF. Ethics and dissemination: Approval has been obtained from the Institutional Ethics Committee of Kasturba Medical College, Mangalore, India. The dissemination plans include scientific conferences and publication in scientific journals. Registration: The study is registered with Clinical Trial Registry of India ( CTRI/2017/06/008936).


Polybrene inhibits human mesenchymal stem cell proliferation during lentiviral transduction.
Human mesenchymal stem cells (hMSCs) can be engineered to express specific genes, either for their use in cell-based therapies or to track them in vivo over long periods of time. To obtain long-term expression of these genes, a lentivirus- or retrovirus-mediated cell transduction is often used. However, given that the efficiency with these viruses is typically low in primary cells, additives such as polybrene are always used for efficient viral transduction. Unfortunately, as presented here, exposure to polybrene alone at commonly used concentratons (1-8 µg/mL) negatively impacts hMSC proliferation in a dose-dependent manner as measured by CyQUANT, EdU incorporation, and cell cycle analysis. This inhibition of proliferation was observable in culture even 3 weeks after exposure. Culturing the cells in the presence of FGF-2, a potent mitogen, did not abrogate this negative effect of polybrene. In fact, the normally sharp increase in hMSC proliferation that occurs during the first days of exposure to FGF-2 was absent at 4 µg/mL or higher concentrations of polybrene. Similarly, the effect of stimulating cell proliferation under simulated hypoxic conditions was also decreased when cells were exposed to polybrene, though overall proliferation rates were higher. The negative influence of polybrene was, however, reduced when the cells were exposed to polybrene for a shorter period of time (6 hr vs 24 hr). Thus, careful evaluation should be done when using polybrene to aid in lentiviral transduction of human MSCs or other primary cells, especially when cell number is critical.


Lipid-anchored Proteasomes Control Membrane Protein Homeostasis.
Protein degradation in eukaryotic cells is mainly carried out by the 26S proteasome, a macromolecular complex not only present in the cytosol and nucleus but also associated with various membranes. How proteasomes are anchored to the membrane and the biological meaning thereof have been largely unknown in higher organisms. Here we show that N-myristoylation of the Rpt2 subunit is a general mechanism for proteasome-membrane interaction. Loss of this modification in the Rpt2-G2A mutant cells leads to profound changes in the membrane-associated proteome, perturbs the endomembrane system and undermines critical cellular processes such as cell adhesion, endoplasmic reticulum-associated degradation (ERAD) and membrane protein trafficking. Rpt2 G2A/G2A homozygous mutation is embryonic lethal in mice and is sufficient to abolish tumor growth in a nude mice xenograft model. These findings have defined an evolutionarily conserved mechanism for maintaining membrane protein homeostasis and underscored the significance of compartmentalized protein degradation by m yristoyl- a nchored p roteasomes (MAPs) in health and disease.