Analysis of MUC4 expression in human pancreatic cancer xenografts in immunodeficient mice.
Mucin 4 (MUC4) is a cell surface glycoprotein that is overexpressed in most pancreatic tumors. The aim of the present study was to characterize MUC4 expression in experimental pancreatic cancer in order to clarify the correlation between MUC4 and pancreatic cancer histology in vivo. Pancreatic xenograft tumors were generated in immunodeficient mice (n=15) by subcutaneous injection of MUC4(+) human pancreatic cancer cell lines Capan-1, HPAF-II or CD18/HPAF. MUC4 immunoreactivity was compared between the cancer models. Alpha-smooth muscle actin (α-SMA) was used to identify cancer-associated fibroblasts and the amount of collagen fibers was quantified with sirius red. Tumor incidence was 100%. Tumor size showed no difference across groups (p=0.796). The median MUC4 count was highest in Capan-1 tumors (p=0.002). α-SMA and collagen extent were also highest in Capan-1 tumors (p=0.018). The Capan-1 xenograft model could serve as a valuable resource to test new therapeutic strategies targeting MUC4 in pancreatic cancer.


A co-saliency model of image pairs.
In this paper, we introduce a method to detect co-saliency from an image pair that may have some objects in common. The co-saliency is modeled as a linear combination of the single-image saliency map (SISM) and the multi-image saliency map (MISM). The first term is designed to describe the local attention, which is computed by using three saliency detection techniques available in literature. To compute the MISM, a co-multilayer graph is constructed by dividing the image pair into a spatial pyramid representation. Each node in the graph is described by two types of visual descriptors, which are extracted from a representation of some aspects of local appearance, e.g., color and texture properties. In order to evaluate the similarity between two nodes, we employ a normalized single-pair SimRank algorithm to compute the similarity score. Experimental evaluation on a number of image pairs demonstrates the good performance of the proposed method on the co-saliency detection task.


Early Genital Surgery in Disorders/Differences of Sex Development: Patients' Perspectives.
Controversy continues over a proposed moratorium on elective genital surgery in childhood for disorders/differences of sex development (DSD). Empirical evidence on patient preference is needed to inform decision-making. We conducted a multicentre survey by cross-sectional questionnaire in 14 specialized clinics in six European countries. The sample comprised 459 individuals (≥ 16 years) with a DSD diagnosis, including individuals with congenital adrenal hyperplasia (CAH) (n = 192), XY DSD with prenatal androgen effect (A) (n = 150), and without (nA) (n = 117). Main outcome measures were level of agreement with given statements regarding genital surgery, including clitoris reduction, vaginoplasty, and hypospadias repair. A total of 66% of individuals with CAH and 60% of those with XY DSD-A thought that infancy or childhood were the appropriate age for genital surgery. Females with XY DSD were divided on this issue and tended to prefer vaginoplasty at a later age (XY DSD-A 39%, XY DSD-nA 32%). A total of 47% of males preferred early hypospadias surgery. Only 12% (CAH), 11% (XY DSD-A), and 21% (XY DSD-nA) thought they would have been better off without any surgery in childhood or adolescence. Individuals who had early genital surgery were more likely to approve of it. Outcome data failed to support a general moratorium on early elective genital surgery. Participant perspectives varied considerably by diagnostic category, gender, history of surgery, and contact with support groups. Case-by-case decision-making is better suited to grasping the ethical complexity of the issues at stake.Trial registration: German Clinical Trials Register DRKS00006072.


[Reducing anxiety without deterioration of cognitive functions].
The purpose of the study--demonstrate the ability to reduce anxiety without having a negative impact on concentration and memory. In patients with irritable bowel syndrome studied anxiety, cognitive dysfunction, and memory. Patients received a standard basic therapy or standard treatment with psychotropic medication. Inclusion in the healing process valemidin significantly reduced anxiety in patients without a negative impact on cognitive function. IBS patients receiving basic therapy addition, valemidin, compared with the group of patients receiving only the basic therapy significantly decreased and cognitive dysfunction.


CvManGO, a method for leveraging computational predictions to improve literature-based Gene Ontology annotations.
The set of annotations at the Saccharomyces Genome Database (SGD) that classifies the cellular function of S. cerevisiae gene products using Gene Ontology (GO) terms has become an important resource for facilitating experimental analysis. In addition to capturing and summarizing experimental results, the structured nature of GO annotations allows for functional comparison across organisms as well as propagation of functional predictions between related gene products. Due to their relevance to many areas of research, ensuring the accuracy and quality of these annotations is a priority at SGD. GO annotations are assigned either manually, by biocurators extracting experimental evidence from the scientific literature, or through automated methods that leverage computational algorithms to predict functional information. Here, we discuss the relationship between literature-based and computationally predicted GO annotations in SGD and extend a strategy whereby comparison of these two types of annotation identifies genes whose annotations need review. Our method, CvManGO (Computational versus Manual GO annotations), pairs literature-based GO annotations with computational GO predictions and evaluates the relationship of the two terms within GO, looking for instances of discrepancy. We found that this method will identify genes that require annotation updates, taking an important step towards finding ways to prioritize literature review. Additionally, we explored factors that may influence the effectiveness of CvManGO in identifying relevant gene targets to find in particular those genes that are missing literature-supported annotations, but our survey found that there are no immediately identifiable criteria by which one could enrich for these under-annotated genes. Finally, we discuss possible ways to improve this strategy, and the applicability of this method to other projects that use the GO for curation. DATABASE URL: http://www.yeastgenome.org.


Production of a specific major histocompatibility complex class I-restricted epitope by ubiquitin-dependent degradation of modified ovalbumin in lymphocyte lysate.
Peptide epitopes presented through class I major histocompatability complex (MHC class I) on the cell surface, are generated by proteolytic processing of protein-antigens in the cytoplasm. The length and amino acid sequence determine whether a given peptide can fit into the peptide binding groove of class I heavy chain molecules and subsequently be presented to the immune system. The mode of action of the processing pathway is therefore of great interest. To study the processing mechanism of MHC class I-restricted intracellular antigens, we reconstituted the proteolytic processing of a model antigen in a cell-free system. Incubation of oxidized and urea-treated OVA in lymphocyte lysate resulted in partial degradation of the antigen. Degradation of the antigen depended on the presence of ATP. Addition of methylated ubiquitin abolished the reaction which was then restored by addition of an excess of native ubiquitin, indicating that the breakdown of the antigen in lymphocyte lysate is mediated by the ubiquitin proteolytic system. Upon incubation of modified OVA in lymphocyte lysate, a specific antigenic peptide was generated. The peptide was recognized by cytotoxic T lymphocytes directed against OVA-derived, H-2Kb-restricted peptide (SIINFEKL), and by a monoclonal antibody that recognizes cell-bound Kb-SIINFEKL complexes. Formation of the peptide epitope depended on the presence of ATP and ubiquitin. These results indicate that proteolytic processing of modified OVA is carried out by the ubiquitin-mediated degradation system. The experimental system described provides a tool to analyze the molecular mechanisms underlying the generation of specific, MHC class I-restricted peptide epitopes.


A Systematic Review of Interventions Used to Increase Blood Donor Compliance with Deferral Criteria.
Pre-donation screening of potential blood donors is critical for ensuring the safety of the donor blood supply, and donor deferral as a result of risk factors is practised worldwide. This systematic review was conducted in the context of an expert review convened by the Australian Red Cross Lifeblood in 2013 to consider Lifeblood's injecting drug use (IDU)-related policies and aimed to identify studies assessing interventions to improve compliance with deferral criteria in blood donation settings. MEDLINE/PubMed, OVID Medline, OVID Embase, LILACS, and the Cochrane Library (CENTRAL and DARE) databases were searched for studies conducted within blood donation settings that examined interventions to increase blood donor compliance with deferral criteria. Observational and experimental studies from all geographical areas were considered. Ten studies were identified that tested at least one intervention to improve blood donor compliance with deferral criteria, including computerized interviews or questionnaires, direct and indirect oral questioning, educational materials, and a combination of a tickbox questionnaire and a personal donor interview. High-quality evidence from a single study was provided for the effectiveness of a computerized interview in improving detection of HIV risk behaviour. Low-quality evidence for the effectiveness of computerized interviews was provided by 3 additional studies. Two studies reported a moderate effect of direct questioning in increasing donor deferral, but the quality of the evidence was low. This review identified several interventions to improve donor compliance that have been tested in blood donation settings and provided evidence for the effectiveness of computerized interviews in improving detection of risk factors.


Ceramic phases with one-dimensional long-range order.
Solids are generally classified into three categories based on their atomic arrangement: crystalline, quasicrystalline and amorphous1-4. Here we report MgO and Nd2O3 ceramic phases with special atomic arrangements that should belong to a category of solids different from these three well known categories by combining state-of-the-art atomic-resolution scanning transmission electron microscopy and first-principles calculations. The reported solid structure exhibits a one-dimensional (1D) long-range order with a translational periodicity and is composed of structural units that individually have atomic arrangements similar to those observed in coincidence-site lattice configurations present at grain boundaries. Regardless of the insulating nature of the bulk MgO, the bandgap of which is measured to be 7.4 eV, the MgO 1D ordered structure is a wide-bandgap semiconductor with a bandgap of 3.2 eV owing to this special atomic arrangement. The discovery of 1D ordered structures suggests that the structural categories of solids could be more abundant, with physical properties distinct from their regular counterparts.


Divergent transcriptomic profiles in depressed individuals with hyper- and hypophagia implicating inflammatory status.
Major Depressive Disorder (MDD) is a heterogenous and etiologically complex disease encompassing a broad spectrum of psychopathology, presumably arising from distinct pathophysiological mechanisms. Divergent appetitive phenotypes including Hyperphagic MDD (characterized by an increased appetite) and Hypophagic MDD (characterized by a decrease in appetite) are important clinical characteristics that are closely related to comorbidities, including cardiometabolic disorders. Prior evidence supports the notion that hyperphagia is associated with atypical depression, decreased stress-hormone signaling, a pro-inflammatory status, hypersomnia, and poorer clinical outcomes. Yet, our understanding of the underlying mechanisms of Hyperphagic and Hypophagic MDD is limited, and knowledge of associated biological correlates of these endophenotypes remain fragmented. We performed an exploratory study on peripheral blood RNA profiling using bulk RNAseq in unmedicated individuals with Hyperphagic and Hypophagic MDD (n=8 and n=13, respectively) and discovered individual genes and gene pathways associated with appetitive phenotypes. In addition, we used the Maastricht Acute Stress Task to uncover stress-related transcriptomic profiles in Hyper- and Hypophagic MDD.


Cost of depression among adults in Japan in 2005.
Major depression is expected to become the leading contributor to disease burden worldwide by 2020. Previous studies have shown that the societal cost of depression is not less than that of other major illnesses, such as cardiovascular diseases or AIDS. Nevertheless, the cost of depression in Japan has never been examined. The goal of the present study was to estimate the total cost of depression in Japan and to clarify the characteristics of this burden. A prevalence-based approach was adopted to measure the total cost of depression. The total cost of depression was regarded as being comprised of the direct cost, morbidity cost and mortality cost. Diagnoses included in this study were depressive episodes and recurrent depressive disorder according to the ICD-10 or major depressive disorder according to the DSM-IV. Data were collected from publicly available statistics and the World Mental Health Japan Survey database. The total cost of depression among adults in Japan in 2005 was estimated to be ¥2.0 trillion. The direct cost was ¥0.18 trillion. The morbidity cost was ¥0.92 trillion, while the mortality cost was ¥0.88 trillion. The societal costs caused by depression in Japan are enormous, as in other developed countries. Low morbidity costs and extremely high mortality costs are characteristic in Japan. Effective interventions for preventing suicide could reduce the societal costs of depression.


Investigation of molecular mechanism of chronic pain in the anterior cingulate cortex using genetically engineered mice.
Recent advances into the understanding of molecular mechanism of chronic pain have been largely developed through the use of genetic manipulations. This is in part due to the scarcity of selective pharmacological tools, which can be readily solved by creating knockout or transgenic mice. By identifying new genes that are of import, our efforts can then be aimed at studying relevant signaling pathways, and combination of pharmacological manipulations with genetic models can be used to further examine the specific mechanisms involved in chronic pain. In this review, we will examine the genetic models that are currently in use to study chronic pain in the anterior cingulate cortex: knockout mice; transgenic mice; and the strength of combining pharmacology with these genetic models.


The application of GIS in environmental health sciences: opportunities and limitations.
Understanding the complex spatio-temporal relationships between environmental pollution and disease and identifying exposures to environmental hazards in high-risk populations are essential elements of an effective environmental and public health management program. Modern computer technologies, such as geographic information systems (GIS), provide cost-effective tools for evaluating interventions and policies potentially affecting health outcomes. GIS analysis or display of environmental health data is also helpful in explaining disease patterns in terms of relationships with social, institutional, technological, and natural environments. This paper examines major issues related to the application of GIS in environmental health sciences. Specifically, the paper presents and discusses the basic principles, potential benefits, and major limitations of GIS in environmental health research. A real-world example application involving development and implementation of a prototype system called EMPHASIS (EnvironMental and Public Health datA analySIs System) to facilitate management, analysis, display, and presentation of environmental, socio-demographic, and health outcome data in Iowa is described. From the discussions and the example application, it is concluded that GIS can significantly add value to environmental and public health data in areas such as exploratory data analysis, hypotheses generation, confirmatory data analysis, and decision-making. The widespread adoption of GIS in these areas, however, is impeded by issues such as inconsistent spatial scales of the data, data quality and currency, lack of appropriate statistical functions for data analysis and interpretation, and data security and confidentiality.


Beware the black box: investigating the sensitivity of FEA simulations to modelling factors in comparative biomechanics.
Finite element analysis (FEA) is a computational technique of growing popularity in the field of comparative biomechanics, and is an easily accessible platform for form-function analyses of biological structures. However, its rapid evolution in recent years from a novel approach to common practice demands some scrutiny in regards to the validity of results and the appropriateness of assumptions inherent in setting up simulations. Both validation and sensitivity analyses remain unexplored in many comparative analyses, and assumptions considered to be 'reasonable' are often assumed to have little influence on the results and their interpretation. HERE WE REPORT AN EXTENSIVE SENSITIVITY ANALYSIS WHERE HIGH RESOLUTION FINITE ELEMENT (FE) MODELS OF MANDIBLES FROM SEVEN SPECIES OF CROCODILE WERE ANALYSED UNDER LOADS TYPICAL FOR COMPARATIVE ANALYSIS: biting, shaking, and twisting. Simulations explored the effect on both the absolute response and the interspecies pattern of results to variations in commonly used input parameters. Our sensitivity analysis focuses on assumptions relating to the selection of material properties (heterogeneous or homogeneous), scaling (standardising volume, surface area, or length), tooth position (front, mid, or back tooth engagement), and linear load case (type of loading for each feeding type). Our findings show that in a comparative context, FE models are far less sensitive to the selection of material property values and scaling to either volume or surface area than they are to those assumptions relating to the functional aspects of the simulation, such as tooth position and linear load case. Results show a complex interaction between simulation assumptions, depending on the combination of assumptions and the overall shape of each specimen. Keeping assumptions consistent between models in an analysis does not ensure that results can be generalised beyond the specific set of assumptions used. Logically, different comparative datasets would also be sensitive to identical simulation assumptions; hence, modelling assumptions should undergo rigorous selection. The accuracy of input data is paramount, and simulations should focus on taking biological context into account. Ideally, validation of simulations should be addressed; however, where validation is impossible or unfeasible, sensitivity analyses should be performed to identify which assumptions have the greatest influence upon the results.


Focus on Therapeutic Options for Surgically Resectable Pancreatic Adenocarcinoma Based on Novel Biomarkers.
Pancreatic ductal adenocarcinoma remains associated with a poor prognosis, even when diagnosed at an early stage. Consequently, it is imperative to carefully consider the available therapeutic options and tailor them based on clinically relevant biomarkers. In our comprehensive review, we specifically concentrated on the identification of novel predictive and prognostic markers that have the potential to be integrated into multiparametric scoring systems. These scoring systems aim to accurately predict the efficacy of neoadjuvant chemotherapy in surgically resectable pancreatic cancer cases. By identifying robust predictive markers, we can enhance our ability to select patients who are most likely to benefit from neoadjuvant chemotherapy. Furthermore, the identification of prognostic markers can provide valuable insights into the overall disease trajectory and inform treatment decisions. The development of multiparametric scoring systems that incorporate these markers holds great promise for optimizing the selection of patients for neoadjuvant chemotherapy, leading to improved outcomes in resectable pancreatic neoplasia. Continued research efforts are needed to validate and refine these markers and scoring systems, ultimately advancing the field of personalized medicine in pancreatic adenocarcinoma management.


Mms4, a putative transcriptional (co)activator, protects Saccharomyces cerevisiae cells from endogenous and environmental DNA damage.
mms4-1 is one of several Saccharomyces cerevisiae mutants that exhibit an increased sensitivity to methyl methanesulfonate (MMS), but not to UV or X-rays. We have isolated the MMS4 gene by functional complementation of the MMS-sensitive phenotype in the mms4-1 strain. The MMS4 gene encodes a 691-amino acid, 78.7-kDa protein. The deduced Mms4 protein does not show significant homology to any of the known proteins in the database. However, several putative functional domains suggest that it may be a nuclear protein capable of interacting with other proteins. Examination of the mms4delta mutant phenotype indicates that the mutation not only sensitizes DNA to methylating and ethylating agents, but also to other DNA damage that blocks DNA replication. However, the mms4delta mutant appears to be more sensitive to chronic treatment than to acute treatment by DNA-damaging agents. Furthermore, the spontaneous mutation rate increases significantly in the mms4delta mutant. Mms4 alone, when fused to a Gal4 DNA-binding domain, is able to activate P(GAL1)-lacZ and P(GAL1)-HIS3 reporter genes in a two-hybrid system; the Mms4 transactivation domain maps to the highly acidic N-terminal region. These results collectively suggest that Mms4 may function as a transcriptional (co)activator and play an important role in DNA repair and/or synthesis.


Intradiscal O2O3: Rationale, Injection Technique, Short- and Long-term Outcomes for the Treatment of Low Back Pain Due to Disc Herniation.
The management of low back pain should always start with a conservative approach; however, when it fails, intervention is required and at that moment the most appropriate choice remains unclear. Before invasive surgery, minimally invasive techniques can be adopted. In European trials and in a trans-Canadian clinical trial 03 ozone has been used successfully. In total over 50,000 patients have been treated safely. Ozone is a gas normally present in the atmosphere with potent oxidizing power; it has been used for percutaneous intradiscal injection combined with oxygen (O2O3) at very low concentrations for 15 years in Europe. The main indication is back pain with or without radicular pain but without motor deficits, which is refractory to 4-6 weeks of conservative therapies. Its mechanism of action on the disc is mechanical (volume reduction by subtle dehydration of the nucleus pulposis) and antinflammatory. The intradiscal ozone injection is performed with a thin needle (18-22 gauge) image guided by computed tomography or angiofluoroscopy and is usually complimented by periganglionic injection of corticosteroids and anesthetics. This combination gives immediate pain relief and allows time for the ozone to act. It is a cost-effective procedure that presents a very low complication rate (0.1%). The radicular pain is resolved before the back pain does, as is seen with microdiscectomy. Peer-reviewed publications of large randomized trials, case series, and meta analysis from large samples of patients have demonstrated the procedure to be safe and effective in the short and the long terms, with benefits recognized up to 10 years after treatment. We aim to review the principles of action of O2O3 and report the injection techniques, complications, and short- and long-term outcomes.


Challenge exposure of cattle vaccinated with a chemically altered strain of Pasteurella haemolytica.
Calves vaccinated with a chemically altered strain of Pasteurella haemolytica and their nonvaccinated controls were challenge exposed intranasally with the Cooper strain of infectious bovine rhinotracheitis virus. Five days later, the calves were challenge exposed intratracheally with the P haemolytica type A1. Calves that had been vaccinated with large, medium, or small doses of the chemically altered vaccinal strain of P haemolytica had various degrees of resistance to the experimental challenge exposure. Nonvaccinated animals developed severe respiratory tract disease and pneumonia after challenge exposure.


Towards fast, rigorous and efficient conformational sampling of biomolecules: Advances in accelerated molecular dynamics.
Accelerated molecular dynamics (aMD) has been proven to be a powerful biasing method for enhanced sampling of biomolecular conformations on general-purpose computational platforms. Biologically important long timescale events that are beyond the reach of standard molecular dynamics can be accessed without losing the detailed atomistic description of the system in aMD. Over other biasing methods, aMD offers the advantages of tuning the level of acceleration to access the desired timescale without any advance knowledge of the reaction coordinate. Recent advances in the implementation of aMD and its applications to small peptides and biological macromolecules are reviewed here along with a brief account of all the aMD variants introduced in the last decade. In comparison to the original implementation of aMD, the recent variant in which all the rotatable dihedral angles are accelerated (RaMD) exhibits faster convergence rates and significant improvement in statistical accuracy of retrieved thermodynamic properties. RaMD in conjunction with accelerating diffusive degrees of freedom, i.e. dual boosting, has been rigorously tested for the most difficult conformational sampling problem, protein folding. It has been shown that RaMD with dual boosting is capable of efficiently sampling multiple folding and unfolding events in small fast folding proteins. RaMD with the dual boost approach opens exciting possibilities for sampling multiple timescales in biomolecules. While equilibrium properties can be recovered satisfactorily from aMD-based methods, directly obtaining dynamics and kinetic rates for larger systems presents a future challenge. This article is part of a Special Issue entitled Recent developments of molecular dynamics.


A small earthquake?
In recent years, concerns about health and healthcare have been expressed by the public, the profession, patients and politicians. These are neither new nor confined to the UK. Doctors were not always held in high public esteem; that had been earned over the last 150 years through scientific discoveries such as anaesthesia which revolutionised patient care. The turbulence of the last few years has a number of causes, including increasing patient expectations. Perhaps inevitably it has again called into question the relationship between government, the public and the profession. The resulting debate has been more widespread and better informed than previous episodes of dissent, perhaps indicating a greater willingness on the part of all three parties to assess their relationship anew. Any such assessment would no doubt have to accept the current workforce difficulties experienced by many doctors and other healthcare professionals practising in unsatisfactory circumstances.


Trends in medicines procurement by the Brazilian federal government from 2006 to 2013.
The costs of medicines pose a growing burden on healthcare systems worldwide. A comprehensive understanding of current procurement processes provides strong support for the development of effective policies. This study examined Brazilian Federal Government pharmaceutical procurement data provided by the Integrated System for the Administration of General Services (SIASG) database, from 2006 to 2013. Medicine purchases were aggregated by volume and expenditure for each year. Data on expenditure were adjusted for inflation using the Extended National Consumer Price Index (IPCA) for December 31, 2013. Lorenz distribution curves were used to study the cumulative proportion of purchased therapeutic classes. Expenditure variance analysis was performed to determine the impact of each factor, price and/or volume, on total expenditure variation. Annual expenditure on medicines increased 2.72 times, while the purchased volume of drugs increased 1.99 times. A limited number of therapeutic classes dominated expenditure each year. Drugs for infectious diseases drove the increase in expenditures from 2006 to 2009 but were replaced by antineoplastic and immunomodulating agents beginning in 2010. Immunosuppressants (L04), accounted for one third of purchases since 2010, showing the most substantial growth in expenditures during the period (250-fold increase). The overwhelming price-related increase in expenditures caused by these medicines is bound to have a relevant impact on the sustainability of the pharmaceutical supply system. We observed increasing trends in expenditures, especially in specific therapeutic classes. We propose the development and implementation of better medicine procurement systems, and strategies to allow for monitoring of product price, effectiveness, and safety. This must be done with ongoing assessment of pharmaceutical innovations, therapeutic value and budget impact.


Aspects of health-related microbiology of the Subin, an urban river in Kumasi, Ghana.
The aim of this study was to assess the influence of urban waste, sewage and other human centred activities on the microbiological quality of the river Subin, which flows through the metropolis of Kumasi, Ghana, and serves as drinking water for communities downstream. Three sites, Racecourse, Asafo and Asago, on the Subin were monitored over a year for total coliforms, faecal coliforms, enterococci and biochemical oxygen demand. Bacterial indicator numbers (geometric mean 100 ml(-1)) varied from 1.61 x 10(9) to 4.06 x 10(13) for total coliforms, 9.75 x 10(8) to 8.98 x 10(12) for faecal coliforms and 1.01 x 10(2) to 6.57 x 10(6) for enterococci. There was a consistent increase in bacterial loading as the river flows from the source (Racecourse) through Kumasi. Bacterial numbers were significantly (p < or = 0.05) higher during the rainy season compared with the dry (harmattan) season. The biochemical oxygen demand ranged from 8 mg l(-1) at the source of the river to 419 mg l(-1) at Asago; none of the sites achieved internationally accepted standards for water quality. The River Subin becomes grossly polluted as it flows through Kumasi and at Asago, a rural community downstream of Kumasi that abstracts water from the river for drinking, this probably contributes to the observed high levels of diarrhoeal disease.


Beta glucuronidase and hyperbilirubinaemia in breast fed infants of diabetic mothers.
A prospective study was performed comparing bilirubin concentrations in 10 breast fed term infants of diabetic mothers (IDM) to those of 10 breast fed normal term infants. The beta-glucuronidase concentrations in serum and breast milk were assayed in the respective mothers. Significantly higher bilirubin concentrations were noted in the IDM group. Serum and breast milk beta-glucuronidase concentrations were significantly higher in diabetic mothers as compared with those of non-diabetic mothers. We suggest that the high concentration of beta-glucuronidase in breast milk of diabetic mothers is an additional important cause leading to hyperbilirubinaemia in their breast fed infants.


A Rare Complication Developing After Hematopoietic Stem Cell Transplantation: Wernicke's Encephalopathy.
Thiamine is a water-soluble vitamin. Thiamine deficiency can present as a central nervous system disorder known as Wernicke's encephalopathy, which classically manifests as confusion, ataxia, and ophthalmoplegia. Wernicke's encephalopathy has rarely been reported following hematopoietic stem cell transplantation. Herein, we report Wernicke's encephalopathy in a patient with acute myeloid leukemia who had been receiving prolonged total parenteral nutrition after haploidentical allogeneic hematopoietic stem cell transplantation. To the best of our knowledge, this is the first case reported from Turkey in the literature.


The influence of lead on the protein metabolism of the brain.
Female rats were poisoned with a blood lead level of 30 micrograms/100 ml. 60 days after starting poisoning the animals were paired. The cronic lead treatment was continued even after birth. By this way the newborns were poisoned via mother's milk and 3 weeks later lead poisoned dry food was given until the animals had reached of body weight of 150--180 g. Then they were injected 8.33 mCi 3H leucine and killed at 1, 7, 24, 48 hours and ten days later. Comparing with unpoisoned control animals the lead treated show partly striking differences in the incorporation rates of 3H leucine. The differences were evident within the cornu ammonis, dentate fascia, precentral gyrus and frontal gyrus. In order to get further informations histochemical reactions were performed. Excepted the reaction of alpha-naphtylesterase all reactions were changed by lead-treatment of the animals: acid phosphatase, alkaline phosphatase, cytochrome-c-oxidase and acetylcholine esterase.


Single and combined effect of retinoic acid and rapamycin modulate the generation, activity and homing potential of induced human regulatory T cells.
Adoptive transfer of CD4+CD25+FOXP3+ regulatory T cells (Treg cells) has been successfully utilized to treat graft versus host disease and represents a promising strategy for the treatment of autoimmune diseases and transplant rejection. The aim of this study was to evaluate the effects of all-trans retinoic acid (atRA) and rapamycin (RAPA) on the number, phenotype, homing markers expression, DNA methylation, and function of induced human Treg cells in short-term cultures. Naive T cells were polyclonally stimulated and cultured for five days in the presence of different combinations of IL-2, TGF-β1, atRA and RAPA. The resulting cells were characterized by the expression of FOXP3, activation, surface and homing markers. Methylation of the Conserved Non-coding Sequence 2 was also evaluated. Functional comparison of the different culture conditions was performed by suppression assays in vitro. Culturing naive human T cells with IL-2/TGFβ1 resulted in the generation of 54.2% of Treg cells (CD4+CD25+FOXP3+) whereas the addition of 100 nM atRA increased the yield of Treg cells to 66% (p = 0.0088). The addition of RAPA did not increase the number of Treg cells in any of these settings. Treg cells generated in the presence of atRA had an increased expression of the β7 integrin to nearly 100% of the generated Treg cells, while RAPA treated cells showed enhanced expression of CXCR4. The differential expression of homing molecules highlights the possibility of inducing Treg cells with differential organ-specific homing properties. Neither atRA nor RAPA had an effect on the highly methylated CNS2 sites, supporting reports that their contribution to the lineage stability of Treg cells is not mediated by methylation changes in this locus. Treg cells generated in the presence of RAPA show the most potent suppression effect on the proliferation of effector cells.


Unexpected genetic diversity among and within populations of the toxic dinoflagellate Alexandrium catenella as revealed by nuclear microsatellite markers.
Since 1998, blooms of Alexandrium catenella associated with paralytic shellfish poisoning have been repeatedly reported for Thau Lagoon (French Mediterranean coast). Based on data obtained for rRNA gene markers, it has been suggested that the strains involved could be closely related to the Japanese temperate Asian ribotype of the temperate Asian clade. In order to gain more insight into the origin of these organisms, we carried out a genetic analysis of 61 Mediterranean and 23 Japanese strains using both ribosomal and microsatellite markers. Whereas the phylogeny based on ribosomal markers tended to confirm the previous findings, the analysis of microsatellite sequences revealed an unexpected distinction between the French and Japanese populations. This analysis also highlighted great intraspecific diversity that was not detected with the classical rRNA gene markers. The Japanese strains are divided into two differentiated A. catenella lineages: the Sea of Japan lineage and the east coast lineage, which includes populations from the Inland Sea and the Pacific Ocean. A. catenella strains isolated from Thau Lagoon belong to another lineage. These findings indicate that microsatellite markers are probably better suited to investigations of the population genetics of this species that is distributed worldwide. Finally, application of the population genetics concepts available for macroorganisms could support new paradigms for speciation and migration in phytoplankton assemblages.


Particle anisotropy tunes emergent behavior in active colloidal systems.
Studies of active particle systems have demonstrated that particle anisotropy can impact the collective behavior of a system, motivating a systematic study. Here, we report a systematic computational investigation of the role of anisotropy in shape and active force director on the collective behavior of a two-dimensional active colloidal system. We find that shape and force anisotropy can combine to produce critical densities both lower and higher than those of disks. We demonstrate that changing particle anisotropy tunes what we define as a "collision efficiency" of inter-particle collisions in leading to motility-induced phase separation (MIPS) of the system. We use this efficiency to determine the relative critical density across systems. Additionally, we observe that local structure in phase-separated clusters is the same as the particle's equilibrium densest packing, suggesting a general connection between equilibrium behavior and non-equilibrium cluster structure of self-propelled anisotropic particles. In engineering applications for active colloidal systems, shape-controlled steric interactions such as those described here may offer a simple route for tailoring emergent behaviors.


Application of Bayesian evidence synthesis to modelling the effect of ketogenic therapy on survival of high grade glioma patients.
Ketogenic therapy in the form of ketogenic diets or calorie restriction has been proposed as a metabolic treatment of high grade glioma (HGG) brain tumors based on mechanistic reasoning obtained mainly from animal experiments. Given the paucity of clinical studies of this relatively new approach, our goal is to extrapolate evidence from the greater number of animal studies and synthesize it with the available human data in order to estimate the expected effects of ketogenic therapy on survival in HGG patients. At the same time we are using this analysis as an example for demonstrating how Bayesianism can be applied in the spirit of a circular view of evidence. A Bayesian hierarchical model was developed. Data from three human cohort studies and 17 animal experiments were included to estimate the effects of four ketogenic interventions (calorie restriction/ketogenic diets as monotherapy/combination therapy) on the restricted mean survival time ratio in humans using various assumptions for the relationships between humans, rats and mice. The impact of different biological assumptions about the relevance of animal data for humans as well as external information based on mechanistic reasoning or case studies was evaluated by specifying appropriate priors. We provide statistical and philosophical arguments for why our approach is an improvement over existing (frequentist) methods for evidence synthesis as it is able to utilize evidence from a variety of sources. Depending on the prior assumptions, a 30-70% restricted mean survival time prolongation in HGG patients was predicted by the models. The highest probability of a benefit (> 90%) for all four ketogenic interventions was obtained when adopting an enthusiastic prior based on previous case reports together with assuming synergism between ketogenic therapies with other forms of treatment. Combinations with other treatments were generally found more effective than ketogenic monotherapy. Combining evidence from both human and animal studies is statistically possible using a Bayesian approach. We found an overall survival-prolonging effect of ketogenic therapy in HGG patients. Our approach is best compatible with a circular instead of hierarchical view of evidence and easy to update once more data become available.


Keratoacanthoma and squamous cell carcinoma are distinct from a molecular perspective.
Keratoacanthoma is a controversial entity. Some consider keratoacanthoma as a variant of squamous cell carcinoma, whereas others see it as a distinct self-resolving squamoproliferative lesion. Our objective is to examine the relationship of keratoacanthoma with squamous cell carcinoma and normal skin by using DNA microarrays. DNA microarray studies were performed on formalin-fixed and paraffin-embedded blocks from ten cases of actinic keratoacanthoma utilizing the U133plus2.0 array. These results were compared with our previously developed microarray database of ten squamous cell carcinoma and ten normal skin samples. Keratoacanthoma demonstrated 1449 differentially expressed genes in comparison with squamous cell carcinoma (>5-fold change: P<0.01) with 908 genes upregulated and 541 genes downregulated. Keratoacanthoma showed 2435 differentially expressed genes in comparison with normal skin (>5-fold change: P<0.01) with 1085 genes upregulated and 1350 genes downregulated. The most upregulated genes, comparing keratoacanthoma with normal skin included MALAT1, S100A8, CDR1, TPM4, and CALM1. The most downregulated genes included SCGB2A2, DCD, THRSP, ADIPOQ, adiponectin, and ADH1B. The molecular biological pathway analysis comparing keratoacanthoma with normal skin showed that cellular development, cellular growth and proliferation, cell death/apoptosis, and cell cycle pathways are prominently involved in the pathogenesis of keratoacanthoma. The most enriched canonical pathways were clathrin-mediated endocytosis signaling, molecular mechanisms of cancer and integrin signaling. The distinctive gene expression profile of keratoacanthoma reveals that it is molecularly distinct from squamous cell carcinoma. The molecular pathways and genes differentially expressed in comparing keratoacanthoma with normal skin suggest that keratoacanthoma is a neoplasm that can regress due to upregulation of the cell death/apoptosis pathway.


Epidural morphine for outpatients with severe anginal pain.
Seven patients who had chronic coronary artery disease and had undergone coronary artery bypass surgery still suffered from anginal attacks several times daily despite optimal medical treatment. An epidural system of analgesia was implanted subcutaneously and treatment with epidural morphine started. The morphine was administered by the patients themselves or members of their family. During a median observation time of four months (range three to 11) all patients were free of pain while receiving this treatment.


The mTORC1 Complex Is Significantly Overactivated in SDHX-Mutated Paragangliomas.
We aimed at exploring the activation pattern of the mTOR pathway in sporadic and hereditary pheochromocytomas (PCCs) and paragangliomas (PGLs). A total of 178 PCCs and 44 PGLs, already characterized for the presence of germline mutations in VHL, RET, NF1, MAX, SDHA, SDHB, SDHC, and SDHD as well as somatic mutations in VHL, RET, H-RAS, and MAX, were included in 5 tissue microarrays and tested using immunohistochemistry for mTOR and Rictor as well as the phosphorylated forms of mTOR, p70S6K, AMPK, AKT, 4EBP1, S6, and Raptor. The positive correlation among most of the molecules investigated proved the functional activation of the mTOR pathway in PCCs/PGLs. Total mTOR, p-S6K and p-S6, and mTORC1-associated molecules p-Raptor and p-AMPK were all significantly overexpressed in PGLs rather than in PCCs, and in the head and neck rather than in abdominal locations. None of the markers, except for the low expression of p-mTOR, was associated with malignancy. Cluster 1 PCCs/PGLs had higher total mTOR, p-Raptor, and p-S6 expression than cluster 2 PCCs/PGLs. In contrast, p-mTOR and mTORC2-associated molecule Rictor were significantly overexpressed in cluster 2 tumors. Within cluster 1, molecules active in the mTORC1 complex were significantly overexpressed in SDHX- as compared to VHL-mutated tumors. In summary, the mTOR pathway is activated in a high proportion of PCCs/PGLs, with a preferential overactivation of the mTORC1 complex in PGLs of the head and neck and/or harboring SDHX mutations.


Demonstration of Normal and Abnormal Fetal Brains Using 3D Printing from In Utero MR Imaging Data.
3D printing is a new manufacturing technology that produces high-fidelity models of complex structures from 3D computer-aided design data. Radiology has been particularly quick to embrace the new technology because of the wide access to 3D datasets. Models have been used extensively to assist orthopedic, neurosurgical, and maxillofacial surgical planning. In this report, we describe methods used for 3D printing of the fetal brain by using data from in utero MR imaging.


Short-term changes of blood pressure and aortic stiffness in older patients after transcatheter aortic valve implantation.
Both aortic valve stenosis and aortic stiffness are moderators of arterio ventricular coupling and independent predictors of cardiovascular morbidity and mortality. Studies on the effect of transcatheter aortic valve implantation (TAVI) on aortic functional properties are limited. We performed a study to investigate the possible short-term changes in aortic stiffness and other aortic functional properties after TAVI in older patients. TAVI Care&Cure is an observational ongoing study including consecutive patients undergoing a TAVI procedure. Central and peripheral hemodynamic measurements were measured non invasively 1 day before (T-1) and 1 day after (T+1) TAVI using a validated oscillometric method using a brachial cuff (Mobil-O-Graph). 40 patients were included. Mean aortic valve area at baseline was 0.76±0.24 cm2. Indices of severity of aortic valve stenosis improved significantly. Systolic blood pressure (SBP) dropped by 8.5%, from 130.3±22.9 mmHg to 119.5±15.8 mmHg (p=0.005). Diastolic blood pressure (DBP) dropped by 13.1% from 74.8±14.5 mmHg to 65.0±11.3 mmHg (p<0.001). The arterial pulse wave velocity (aPWV) decreased from 12.05±1.99 m/s to 11.6±1.56 m/s (p=0.006). Patients with high aPWV at baseline showed a significantly larger reduction in SBP in comparison to patients with low aPWV: - 20.3 mmHg (-14.1%) vs - 3.1 mmHg (-2.6%), respectively (p=0.033). The same trend was found for the DBP: -16.2 (-20.4%) vs -4.5 mmHg (-6.3%) for high vs low aPWV at baseline (p=0.037). We found short-term changes in blood pressure and aortic stiffness after TAVI. The amplitude of the changes was the largest in patients with elevated aortic stiffness at baseline.


Resistin induces multidrug resistance in myeloma by inhibiting cell death and upregulating ABC transporter expression.
Despite advances in therapy, multiple myeloma remains incurable, with a high frequency of relapse. This suggests the need to identify additional factors that contribute to drug resistance. Our previous studies revealed that bone marrow adipocytes promote resistance to chemotherapy in myeloma through adipocyte-secreted adipokines, but the mechanism underlying this effect and the specific adipokines involved are not well understood. We proposed to determine the role of resistin, an adipokine that is secreted by adipocytes, in chemotherapy resistance in myeloma. We found that resistin abrogated chemotherapy-induced apoptosis in established myeloma cell lines and primary myeloma samples. Resistin inhibited chemotherapy-induced caspase cleavage through the NF-κB and PI3K/Akt pathways. Resistin also increased the expression and drug efflux function of ATP-binding cassette (ABC) transporters in myeloma cells through decreasing the expression of both DNA methyltransferases DNMT1 and DNMT3a and the methylation levels of ABC gene promoters. In vivo studies further demonstrated the protective effect of resistin in chemotherapy-induced apoptosis. Our study thus reveals a new biological function of resistin in the pathogenesis of myeloma, with the implication that targeting resistin could be a potential strategy to prevent or overcome multidrug resistance in myeloma.


High and low atherosclerosis groups.
Aortic and coronary atherosclerosis were studied in two groups, the "high atherosclerosis group" and the "low atherosclerosis group". The latter may be considered as showing basic levels of atherosclerosis in the different communities. The development of lesions in the two groups occurred in parallel, but earlier in the high group. Sex differences in the two groups were similar to those in the whole material. Generally speaking, inter-town comparisons were similar in each group and similar to those for deaths from all causes, a notable exception being the prevalence of coronary stenosis. The findings indicate that the groups can be used as reference groups, but only for material drawn from the same source.


A rationally designed fluorescent probe for sulfur dioxide and its derivatives: applications in food analysis and bioimaging.
Exogenous sulfur dioxide (SO2) and its derivatives (SO32-/HSO3-) have been extensively utilized in food preservation and endogenous SO2 is recognized as a significant gaseous signaling molecule that can mediate various physiological processes. Overproduction and/or extensive intake of these species can trigger allergic reactions and even tissue damage. Therefore, it is highly desirable to monitor SO2 and its derivatives effectively and quantitatively both in vitro and in vivo. Herein, a new mitochondria-targeted fluorescent probe (PIB) had been constructed, which could ratiometrically recognize SO2 and its derivatives with excellent sensitivity (DL = 15.9 nM) and a fast response time (200 s). The obtained high selectivity and good adaptability of this SO2-specific probe in a wide pH range (6.5-10.0) allowed for quantitatively tracking of SO2 and its derivatives in real food samples (granulated sugar, crystal sugar, and white wine). In addition, PIB could locate at mitochondrion and was capable of imaging exogenous/endogenous SO2 in the cells and zebrafish. In particular, our findings represented one of the rare examples that have demonstrated endogenous SO2 is closely related with the apoptosis of cells. Importantly, probe PIB was successfully employed for in situ metabolic localization in mouse organs, implying the potential applications of our probe in further exploration on SO2-releated pathological and physiological processes.


Sarco(endo)plasmic reticulum Ca2+ pump isoform SERCA3 is more resistant than SERCA2b to peroxide.
Sarco(endo)plasmic reticulum Ca2+ pumps are encoded by genes SERCA1, SERCA2, and SERCA3. Most tissues express SERCA2 Ca2+ pumps (splice SERCA2b) which are inactivated by reactive oxygen. In contrast, SERCA3 is expressed in tissues such as tracheal epithelium, mast cells, lymphoid cells, and aortic endothelium, which are frequently exposed to oxidative stress. Therefore, we compared SERCA3 and SERCA2b proteins for their sensitivity to oxidation. We isolated microsomes from HEK-293 cells overexpressing SERCA3 or SERCA2b. We incubated the microsomes with different concentrations of hydrogen peroxide and then determined Ca2+ pump activities in them in the following three assay systems: ATP-dependent oxalate-stimulated azide-insensitive 45Ca2+ uptake by the microsomal vesicles, Ca(2+)-Mg(2+)-ATPase, and Ca(2+)-dependent acylphosphate formation. Peroxide inhibited the pump activities in microsomes with half-maximal inhibitory concentration (IC50) values of 69 +/- 14, 66 +/- 13, and 84 +/- 15 microM for the 45Ca2+ uptake, Ca(2+)-Mg(2+)-ATPase, and the acylphosphate formation reactions, respectively. However, for microsomes from SERCA3-expressing cells, the corresponding values of IC50 for peroxide were 274 +/- 47, 857 +/- 110, and 746 +/- 40 microM. Thus, in each assay system, the resistance to inactivation by peroxide was significantly (P < 0.05) higher for the SERCA3 protein than for SERCA2b. The SERCA3 resistance to oxidants may aid the cells expressing it to function during exposure to oxidative stress.


Expression of gamma-glutamylcysteine synthetase mRNA in regenerating rat liver.
Changes in the level of GSH and gamma-Glutamylcysteine Synthetase (gamma-GCS) activity with time were determined during regeneration of rat liver after partial hepatectomy. The GSH level and gamma-GCS activity increased in regenerating rat liver, reaching a maximum (2.1- and 1.5-fold that in sham-operated controls) on day 2, respectively. Furthermore, gamma-GCS mRNA expression increased within 24 h and reached maximum on day 2. These results suggest that the increased GSH level in regenerating rat liver after partial hepatectomy is associated with the transcriptional activation of gamma-GCS gene and the sequence elevation in gamma-GCS activity.


The burden of osteoporosis in Brazil.
Osteoporotic fractures impose severe physical, psychosocial, and financial burden both to the patient and the society. Studies on the prevalence of osteoporosis and fragility fractures in Brazil show a wide variation, due to differences in sample size, the population studied, and methodologies. Few studies have been conducted in Brazil about the cost-effectiveness analyses of different intervention options aimed at the diagnosis and treatment of osteoporosis. Investigation and treatment strategies based on cost-effectiveness and scientific evidence are essential in the preparation of public health policies with the ultimate goal of reducing the incidence of fractures and, consequently, the direct and indirect costs associated with them. This article reviews the Brazilian burden of osteoporosis in terms of the prevalence and fractures attributable to the disease, the costs related to the investigation and management, as well as the impact of osteoporosis on the population as a whole and on affected individuals.


Managing genetic discrimination: strategies used by individuals found to have the Huntington disease mutation.
The introduction of predictive testing for Huntington disease (HD) over 20 years ago has led to the advent of a new group of individuals found to have the HD mutation that are currently asymptomatic, yet destined in all likelihood to become affected at some point in the future. Genetic discrimination, a social risk associated with predictive testing, is the differential treatment of individuals based on genotypic difference rather than physical characteristics. While evidence for genetic discrimination exists, little is known about how individuals found to have the HD mutation cope with the potential for or experiences of genetic discrimination. The purpose of this study was to explore how individuals found to have the HD mutation manage the risk and experience of genetic discrimination. Semi-structured individual interviews were conducted with 37 individuals who were found to have the HD mutation and analysed using grounded theory methods. The findings suggest four main strategies: "keeping low", minimizing, pre-empting and confronting genetic discrimination. Strategies varied depending on individuals' level of engagement with genetic discrimination and the nature of the experience (actual experience of genetic discrimination or concern for its potential). This exploratory framework may explain the variation in approaches and reactions to genetic discrimination among individuals living with an increased risk for HD and may offer insight for persons at risk for other late-onset genetic diseases to cope with genetic discrimination.


GABAergic hub neurons orchestrate synchrony in developing hippocampal networks.
Brain function operates through the coordinated activation of neuronal assemblies. Graph theory predicts that scale-free topologies, which include "hubs" (superconnected nodes), are an effective design to orchestrate synchronization. Whether hubs are present in neuronal assemblies and coordinate network activity remains unknown. Using network dynamics imaging, online reconstruction of functional connectivity, and targeted whole-cell recordings in rats and mice, we found that developing hippocampal networks follow a scale-free topology, and we demonstrated the existence of functional hubs. Perturbation of a single hub influenced the entire network dynamics. Morphophysiological analysis revealed that hub cells are a subpopulation of gamma-aminobutyric acid-releasing (GABAergic) interneurons possessing widespread axonal arborizations. These findings establish a central role for GABAergic interneurons in shaping developing networks and help provide a conceptual framework for studying neuronal synchrony.


Restoration of interferon responses of adenovirus E1A-expressing HT1080 cell lines by overexpression of p48 protein.
We have previously shown that both alpha interferon (IFN-alpha) and IFN-gamma signaling pathways are blocked in HeLa cells expressing the adenovirus E1A proteins (G. T. Leonard and G. C. Sen, Virology 224:25-33, 1996). Here, we report that in two other E1A-expressing cell lines derived from the HT1080 cells, neither IFN-alpha nor IFN-gamma could induce the transcription of genes containing the IFN-stimulated response element (ISRE). In contrast, IFN-gamma-mediated signaling to the gamma-activated sequence was unimpaired in these cells. This dichotomy was due to a lowered level of functional p48 protein but not of STAT1 protein in the E1A-expressing HT1080 cells. When p48 was overexpressed in those cells by stably transfecting a p48 expression vector, both types of IFN could effectively induce the transcription of ISRE-driven genes. Consequently, IFN-alpha was highly effective in inhibiting the replication of encephelomyocarditis virus in the E1A-expressing cells, which also overexpressed p48. These results reinforce the general conclusion that adenovirus E1A proteins block IFN signaling pathways by lowering the functional levels of one or more components of the trans-acting complexes that activate the transcription of IFN-stimulated genes.


Comparison of objective and subjective assessments of sleep time in subjects with bipolar disorder.
Sleep disturbance is a core feature of bipolar disorder. To date there are a limited number of studies that compare subjective and objective measures of sleep in populations of subjects with mood disorders. This study evaluated the relationship between subjective and objective measurements of total sleep time (TST) in a bipolar type I disorder (BD I) population. Thirty-nine subjects diagnosed with BD I participated in the study. Mood symptoms were assessed via YMRS and IDS-30-C. Subjects wore an actigraph device and maintained a sleep diary for seven consecutive days. Differences between TST as estimated via sleep diaries and actigraphy were calculated. Objective and subjective measures of TST were significantly correlated (r=0.5151, p=0.0008). Secondary analysis revealed that the severity of depressive symptoms did correlate to this discrepancy (t=2.65, p=0.01). The impact that medications have on the accuracy of TST reported was not investigated. Also, sleep diaries may have acted to prompt subjects to pay closer attention to their sleep habits and therefore more accurately report TST than in the average clinical setting. The results of the current study demonstrate a significant correlation between the estimation of TST as measured objectively via actigraphy and subjectively via sleep diaries in BD patients. Mood symptomotology might impact the accuracy of TST reported. Further study is warranted.


Use of an in vitro immunoselected tumor line to identify shared melanoma antigens recognized by HLA-A*0201-restricted T cells.
An immunoselected melanoma cell line that had lost expression of the dominant melanoma antigens MART-1 and gp100 was generated in an attempt to identify previously unknown tumor antigens. After repeated stimulation with the autologous immunoselected tumor line, a number of HLA-A*0201-restricted T-cell clones were established from the peripheral blood of a single melanoma patient. One T-cell clone (C-22) recognized 14 of 16 HLA-A2+ melanoma cell lines, as well as HLA-A2+ melanocytes but recognized neither HLA-A2+ fibroblasts nor autologous B cells. Screening of an autologous cDNA library resulted in the isolation of a transcript identical to an entry in the expressed sequence tag database. Northern blot analysis revealed that this gene was expressed in most melanoma cell lines and melanocytes but not in normal tissues. The peptide epitope (AMF-GREFCYA) recognized by clone C-22 was identified based on studies of the recognition of truncated cDNAs and the use of the consensus HLAA*0201 binding motif. A second T-cell clone (C-29) was found to recognize a new tyrosinase-related protein 2 epitope (455-463; YAIDLPVSV) in an HLA-A*0201-restricted manner. Together, these results provide additional targets that can be used for the development of immunotherapeutic protocols in HLA-A2+ melanoma patients and demonstrate the utility of immunoselected tumor lines for the identification of new melanoma antigens.


Variability of high-pass resolution perimetry in normals and patients with idiopathic intracranial hypertension.
High-pass resolution perimetry, or the "ring test," is a recently developed type of acuity perimetry. To determine its test-retest variability, we studied 10 normals and 10 patients with idiopathic intracranial hypertension (IIH) by testing both eyes four separate times. There was no increase in variability from the center out to 21 degrees of visual field eccentricity. However, there was a significant increase from 22 degrees to 29 degrees in both normals and IIH patients. Unlike light sensitivity threshold automated perimetry, with an increase in threshold level there was no significant increase in variability in either normals or patients. This may be because of the test's method, which thresholds by target size rather than intensity. As expected, there was a large intersubject variability in the patients, with the visual fields being significantly disturbed by analysis of total field, quadrants, concentric rings, and anatomic nerve fiber bundle regions. Surprisingly, there was no significant difference in the total within subject variability of normals and patients. Because with the ring test there is no increase in variability with an increase in threshold, this method of perimetry may have great utility for following patients with disturbed visual fields. The ring test appears to have advantages that promote low test-retest variability.


Nanoscale Reduced Graphene Oxide-Mediated Photothermal Therapy Together with IDO Inhibition and PD-L1 Blockade Synergistically Promote Antitumor Immunity.
Despite the potential efficacy of immune checkpoint blockade for effective treatment of cancer, this therapeutic modality is not generally curative, and only a fraction of patients respond. Combination approaches provide strategies to target multiple antitumor immune pathways to induce synergistic antitumor immunity. Here, a multi-combination immunotherapy, including photothermal therapy (PTT), indoleamine-2,3-dioxygenase (IDO) inhibition, and programmed cell death-ligand 1 (PD-L1) blockade, is introduced for inducing synergistic antitumor immunity. We designed a multifunctional IDO inhibitor (IDOi)-loaded reduced graphene oxide (rGO)-based nanosheets (IDOi/rGO nanosheets) with the properties to directly kill tumor cells under laser irradiation and in situ trigger antitumor immune response. In vivo experiments further revealed that the triggered immune response can be synergistically promoted by IDO inhibition and PD-L1 blockade; the responses included the enhancement of tumor-infiltrating lymphocytes, including CD45+ leukocytes, CD4+ T cells, CD8+ T cells, and NK cells; the inhibition of the immune suppression activity of regulator T cells (Tregs); and the production of INF-γ. We also demonstrate that the three combinations of PTT, IDO inhibition, and PD-L1 blockade can effectively inhibit the growth of both irradiated tumors and tumors in distant sites without PTT treatment. This work can be thought of as an important proof of concept to target multiple antitumor immune pathways to induce synergistic antitumor immunity.


Coordinated alterations in RNA splicing and epigenetic regulation drive leukaemogenesis.
Transcription and pre-mRNA splicing are key steps in the control of gene expression and mutations in genes regulating each of these processes are common in leukaemia1,2. Despite the frequent overlap of mutations affecting epigenetic regulation and splicing in leukaemia, how these processes influence one another to promote leukaemogenesis is not understood and, to our knowledge, there is no functional evidence that mutations in RNA splicing factors initiate leukaemia. Here, through analyses of transcriptomes from 982 patients with acute myeloid leukaemia, we identified frequent overlap of mutations in IDH2 and SRSF2 that together promote leukaemogenesis through coordinated effects on the epigenome and RNA splicing. Whereas mutations in either IDH2 or SRSF2 imparted distinct splicing changes, co-expression of mutant IDH2 altered the splicing effects of mutant SRSF2 and resulted in more profound splicing changes than either mutation alone. Consistent with this, co-expression of mutant IDH2 and SRSF2 resulted in lethal myelodysplasia with proliferative features in vivo and enhanced self-renewal in a manner not observed with either mutation alone. IDH2 and SRSF2 double-mutant cells exhibited aberrant splicing and reduced expression of INTS3, a member of the integrator complex3, concordant with increased stalling of RNA polymerase II (RNAPII). Aberrant INTS3 splicing contributed to leukaemogenesis in concert with mutant IDH2 and was dependent on mutant SRSF2 binding to cis elements in INTS3 mRNA and increased DNA methylation of INTS3. These data identify a pathogenic crosstalk between altered epigenetic state and splicing in a subset of leukaemias, provide functional evidence that mutations in splicing factors drive myeloid malignancy development, and identify spliceosomal changes as a mediator of IDH2-mutant leukaemogenesis.


The Israeli Experience with the "Green Pass" Policy Highlights Issues to Be Considered by Policymakers in Other Countries.
In the first half of 2021, Israel had been ahead of other countries concerning the speed of its rollout and coverage of COVID-19 vaccinations. During that time, Israel had implemented a vaccine certificate policy, the "Green Pass Policy" (GPP), to reduce virus spread and to allow the safe relaxation of COVID-19 restrictions in a time of great uncertainty. Based on an analysis of GPP regulations and public statements compiled from the Israeli Ministry of Health website, we describe the design and implementation of the GPP. We also look back and discuss lessons learned for countries that are considering a GPP policy, given the current upsurge of the Delta variant as of summer 2021. To reduce equity concerns when introducing a GPP, all population groups should be eligible for the vaccine (contingent on approval from the manufacturer) and have access to it. Alternatively, health authorities can grant temporary certificates based on a negative test. We also highlight the fact that in practice, there will be gaps between the GPP regulations and implementation. While some places might require a GPP without legal need, others will not implement it despite a legal obligation. The GPP regulations should have standardised epidemiological criteria, be implemented gradually, remain flexible, and change according to the epidemiological risks.


The effects of mechanical loading and gadolinium concentration on the change of T1 and quantification of glycosaminoglycans in articular cartilage by microscopic MRI.
Microscopic MRI (µMRI) T1 experiments were carried out to investigate the strain dependence of the T1 change and glycosaminoglycans (GAG) quantification in articular cartilage at a spatial resolution of 17.6 µm. Both native and trypsin-degraded specimens were immersed in various concentrations of gadolinium (Gd) (up to 1 mM) and imaged at different strains (up to 50% strains). Adjacent specimens were treated identically and analyzed biochemically by an inductively coupled plasma optical emission spectrometer. The T1 profile in the native tissue was found to be both strain-dependent and depth-dependent, while there was no obvious depth-dependence in the degraded tissue. For the native tissue, compression reduced the tissue T1 when Gd in the solution was low (less than 0.4 mM) and increased the tissue T1 when Gd in the solution was high. A set of critical points, where the tissue T1 showed no change at a certain Gd concentration between two different loadings, was observed for the first time in the native tissue. It is concluded that the GAG quantification by MRI was accurate as long as the Gd concentration in the solution reached at least 0.2 mM (tissue not loaded) or 0.4 mM (tissue loaded).


[Life expectancy after gastric resection for gastroduodenal ulcer].
Retrospective analysis of 1045 patients who had had a Billroth II partial gastric resection for benign gastroduodenal ulcers revealed a significantly shorter life expectancy for them than for a control group matched for age and sex (mean and maximal periods of observation 14.6 and 22 years, median 17.6 years; 15 217 observation years). After resection for duodenal ulcer there were more deaths from bronchial carcinoma, liver cirrhosis or suicide than after resection for gastric ulcer. Gastric stump carcinoma was more frequent in patients with gastric ulcer and was the cause of death in 5.8% of all patients who had died after the fifth postoperative year. The results suggest that life expectancy after gastric resection depends less on the operation than on the existing risk factors.


Detection of RTX toxin genes in gram-negative bacteria with a set of specific probes.
The family of RTX (RTX representing repeats in the structural toxin) toxins is composed of several protein toxins with a characteristic nonapeptide glycine-rich repeat motif. Most of its members were shown to have cytolytic activity. By comparing the genetic relationships of the RTX toxin genes we established a set of 10 gene probes to be used for screening as-yet-unknown RTX toxin genes in bacterial species. The probes include parts of apxIA, apxIIA, and apxIIIA from Actinobacillus pleuropneumoniae, cyaA from Bordetella pertusis, frpA from Neisseria meningitidis, prtC from Erwinia chrysanthemi, hlyA and elyA from Escherichia coli, aaltA from Actinobacillus actinomycetemcomitans and lktA from Pasteurella haemolytica. A panel of pathogenic and nonpathogenic gram-negative bacteria were investigated for the presence of RTX toxin genes. The probes detected all known genes for RTX toxins. Moreover, we found potential RTX toxin genes in several pathogenic bacterial species for which no such toxins are known yet. This indicates that RTX or RTX-like toxins are widely distributed among pathogenic gram-negative bacteria. The probes generated by PCR and the hybridization method were optimized to allow broad-range screening for RTX toxin genes in one step. This included the binding of unlabelled probes to a nylon filter and subsequent hybridization of the filter with labelled genomic DNA of the strain to be tested. The method constitutes a powerful tool for the assessment of the potential pathogenicity of poorly characterized strains intended to be used in biotechnological applications. Moreover, it is useful for the detection of already-known or new RTX toxin genes in bacteria of medical importance.


MS-Based Analytical Techniques: Advances in Spray-Based Methods and EI-LC-MS Applications.
Mass spectrometry is the most powerful technique for the detection and identification of organic compounds. It can provide molecular weight information and a wealth of structural details that give a unique fingerprint for each analyte. Due to these characteristics, mass spectrometry-based analytical methods are showing an increasing interest in the scientific community, especially in food safety, environmental, and forensic investigation areas where the simultaneous detection of targeted and nontargeted compounds represents a key factor. In addition, safety risks can be identified at the early stage through online and real-time analytical methodologies. In this context, several efforts have been made to achieve analytical instrumentation able to perform real-time analysis in the native environment of samples and to generate highly informative spectra. This review article provides a survey of some instrumental innovations and their applications with particular attention to spray-based MS methods and food analysis issues. The survey will attempt to cover the state of the art from 2012 up to 2017.


Validation of the modified Fresno test: assessing physical therapists' evidence based practice knowledge and skills.
Health care educators need valid and reliable tools to assess evidence based practice (EBP) knowledge and skills. Such instruments have yet to be developed for use among physical therapists. The Fresno Test (FT) has been validated only among general practitioners and occupational therapists and does not assess integration of research evidence with patient perspectives and clinical expertise. The purpose of this study was to develop and validate a modified FT to assess EBP knowledge and skills relevant to physical therapist (PT) practice. The FT was modified to include PT-specific content and two new questions to assess integration of patient perspectives and clinical expertise with research evidence. An expert panel reviewed the test for content validity. A cross-sectional cohort representing three training levels (EBP-novice students, EBP-trained students, EBP-expert faculty) completed the test. Two blinded raters, not involved in test development, independently scored each test. Construct validity was assessed through analysis of variance for linear trends among known groups. Inter and intra-rater reliability, internal consistency, item discrimination index, item total correlation, and difficulty were analyzed. Among 108 participants (31 EBP-novice students, 50 EBP-trained students, and 27 EBP-expert faculty), there was a statistically significant (p < 0.0001) difference in total score corresponding to training level. Total score reliability and psychometric properties of items modified for discipline-specific content were excellent [inter-rater (ICC (2,1)] = 0.91); intra-rater (ICC (2,1)] = 0.95, 0.96)]. Cronbach's alpha was 0.78. Of the two new items, only one had strong psychometric properties. The 13-item modified FT presented here is a valid, reliable assessment of physical therapists' EBP knowledge and skills. One new item assesses integration of patient perspective as part of the EBP model. Educators and researchers may use the 13-item modified FT to evaluate PT EBP curricula and physical therapists' EBP knowledge and skills.


Quantum QSAR of the antirhinoviral activity of 9-benzylpurines.
The antirhinoviral activity of previously described 9-benzylpurines was quantitatively analysed using Huckel molecular orbital generated electronic parameters and physicochemical properties of substituents. Correlations with the activity against each of several serotypes of the virus were obtained but very few common requirements emerged. Our results emphasise the difficulties in identifying a compound with optimum structural features for broad spectrum antirhinovirus activity.


Non-conventional treatment of hepatic failures.
It is our intention to present a short review of various approaches to the non-conventional treatment of hepatic failures of the fulminant type. Our review is directed to the scientist, technologist, and clinician with a budding interest in the hepatic assist area. We shall discuss parabiosis, liver transplants, and various extracorporeal devices including hemoperfusion, hemodialysis, and enzymic detoxification systems. We feel that the present technological approaches to the treatment of hepatic failure are very primitive at this stage. Some of the recent advances are very encouraging, and it is our opinion that these approaches show great promise in the long term.


A genomewide scan for age-related macular degeneration provides evidence for linkage to several chromosomal regions.
We report the results of a genomewide scan for age-related macular degeneration (AMD) in 158 multiplex families. AMD classification was based on fundus photography and was assigned a grade ranging from 1 (no disease) to 5 (exudative disease). Genotyping was performed by the National Heart, Lung, and Blood Institute Mammalian Genotyping Service at Marshfield (404 short tandem repeat markers). The sample included 158 families with two or more siblings with AMD, 490 affected individuals, 101 unaffected individuals, and 38 whose affection status was unknown. Relative pairs included 511 affected sibling, 28 avuncular, 53 cousin, 7 grandparent-grandchild, and 9 grand-avuncular pairs. Two-point parametric and multipoint parametric and nonparametric analyses were performed. Maximum two-point LOD scores of 1.0-2.0 were found for markers on chromosomes 1, 2, 8, 10, 14, 15, and 22. Multipoint analyses were consistent with the two-point results for chromosomes 1, 2, 8, 10, and 22 and provided evidence for additional linkage regions on chromosomes 3, 6, 8, 12, 16, and X. Our signals on chromosomes 1q, 6p, and 10q are consistent with some other previously published results. Significant linkage to AMD was found for one marker on chromosome 2, two adjacent markers on chromosome 3, two adjacent markers on chromosome 6, and seven contiguous markers on chromosome 8, with empirical P values of .00001. The consistency of many of the other signals across both two-point and multipoint, as well as parametric and nonparametric, analyses indicate several other regions worthy of follow-up.


Individual variability among autochthonous sheep in Northern Tunisia to infection by abomasum nematodes and Babesia/Theileria parasites.
In Tunisia, livestock plays an important role in the economy; unfortunately, Tunisian sheep population faces several health challenges. The aim of this trial was to study phenotypic variability of four local sheep breeds and strains to abomasum nematodes infection and to Babesia/Theileria parasites. Faeces, blood and abomasum contents were collected from 310 sheep slaughtered in eight commercial slaughterhouses across North Tunisia. Haematological and biochemical parameters were assessed. DNA was extracted and catch-all primers were used to detect both Theileria spp. and Babesia spp. DNA. Faecal egg counts (FEC) was quantitatively assessed using simple flotation technique followed by McMaster technique. Male and female worms were collected from all abomasum contents and counted under a stereomicroscope. The percentage of faeces samples positive for GIN's eggs was 30.82%. After worms' recovery, the infection prevalence was estimated to 75.90%. The overall infection prevalence by Babesia spp. and Theileria spp. was 4.21%. The dispersion of observations plots obtained by principal component analysis (PCA) showed two clusters of individuals. The first cluster contains animals having positive Babesia/Theileria PCR, presence of nematodes in the abomasum contents and relatively low total worm count (TWC < 500) expect one animal which was found bearing high TWC (>500). In this same group, with a suspected form of resistance, animals showed normal values of albumin and normal haematological parameters (red blood cell count [RBC], haemoglobin [Hb] and packed cell volume [PCV]). The second cluster represents all the other observations in which subgroups of animals were distinguished on the basis of their potential resistance to abomasum nematodes. Multiple correlations showed significant positive correlations between RBC/Hb, RBC/PCV, PCV/Hb and FEC/TWC. Significant negative correlations were observed between TWC/RBC and TWC/Hb. It is concluded that the phenotypic variability among local sheep breeds is essential for more advanced genetic and genomic studies.


RNA Editing in Glioma as a Sexually Dimorphic Prognostic Factor That Affects mRNA Abundance in Fatty Acid Metabolism and Inflammation Pathways.
RNA editing alters the nucleotide sequence and has been associated with cancer progression. However, little is known about its prognostic and regulatory roles in glioma, one of the most common types of primary brain tumors. We characterized and analyzed RNA editomes of glioblastoma and isocitrate dehydrogenase mutated (IDH-MUT) gliomas from The Cancer Genome Atlas and the Chinese Glioma Genome Atlas (CGGA). We showed that editing change during glioma progression was another layer of molecular alterations and that editing profiles predicted the prognosis of glioblastoma and IDH-MUT gliomas in a sex-dependent manner. Hyper-editing was associated with poor survival in females but better survival in males. Moreover, noncoding editing events impacted mRNA abundance of the host genes. Genes associated with inflammatory response (e.g., EIF2AK2, a key mediator of innate immunity) and fatty acid oxidation (e.g., acyl-CoA oxidase 1, the rate-limiting enzyme in fatty acid β-oxidation) were editing-regulated and associated with glioma progression. The above findings were further validated in CGGA samples. Establishment of the prognostic and regulatory roles of RNA editing in glioma holds promise for developing editing-based therapeutic strategies against glioma progression. Furthermore, sexual dimorphism at the epitranscriptional level highlights the importance of developing sex-specific treatments for glioma.


Nicotine increases heart adenosine release, oxygen consumption, and contractility.
The effect of nicotine on adenosine release, oxygen consumption, and contractility was investigated in perfused rat hearts. Continuous infusion of nicotine into the perfusing physiological saline (PS) elicited a propranolol (10(-6) M) sensitive transient elevation of developed left ventricular pressure (LVP) and maximum rates of left ventricular pressure development and relaxation (+/- dP/dtmax) within 20 s, which subsequently declined to maintained elevated plateau levels by 1 min. The continuous infusions of nicotine to achieve PS concentrations of 5 X 10(-4), 1 X 10(-4), or 5 X 10(-5) M, respectively resulted in significant increases in the mean plateau levels of LVP (33.4, 10.1, or 6.3%), +dP/dtmax (26.3, 10.8, or 6.9%) and-dP/dtmax (35.0, 11.9, or 9.0%) at 1 min. The inclusion of propranolol (10(-6) M) with or without atropine (10(-6) M) did not alter these maintained plateau responses to nicotine. During the plateau phase of the contractile response oxygen consumption of the hearts was significantly elevated by 36, 19, or 11%, and mean levels for adenosine in the coronary effluent rose by 261, 76, or 74% in response to 5 X 10(-4), 1 X 10(-4), or 5 X 10(-5) M nicotine, respectively. Nicotine did not influence [14C]adenosine uptake by the hearts. These results suggest that nicotine is capable of 1) augmenting cardiac contractility and oxygen consumption independent of beta-adrenergic or muscarinic influence, and 2) elevating the appearance of adenosine in the coronary circulation presumably by enhancing myocardial production of the nucleoside.


Ca2+ influx and ATP release mediated by mechanical stretch in human lung fibroblasts.
One cause of progressive pulmonary fibrosis is dysregulated wound healing after lung inflammation or damage in patients with idiopathic pulmonary fibrosis and severe acute respiratory distress syndrome. The mechanical forces are considered to regulate pulmonary fibrosis via activation of lung fibroblasts. In this study, the effects of mechanical stretch on the intracellular Ca(2+) concentration ([Ca(2+)]i) and ATP release were investigated in primary human lung fibroblasts. Uniaxial stretch (10-30% in strain) was applied to fibroblasts cultured in a silicone chamber coated with type I collagen using a stretching apparatus. Following stretching and subsequent unloading, [Ca(2+)]i transiently increased in a strain-dependent manner. Hypotonic stress, which causes plasma membrane stretching, also transiently increased the [Ca(2+)]i. The stretch-induced [Ca(2+)]i elevation was attenuated in Ca(2+)-free solution. In contrast, the increase of [Ca(2+)]i by a 20% stretch was not inhibited by the inhibitor of stretch-activated channels GsMTx-4, Gd(3+), ruthenium red, or cytochalasin D. Cyclic stretching induced significant ATP releases from fibroblasts. However, the stretch-induced [Ca(2+)]i elevation was not inhibited by ATP diphosphohydrolase apyrase or a purinergic receptor antagonist suramin. Taken together, mechanical stretch induces Ca(2+) influx independently of conventional stretch-sensitive ion channels, the actin cytoskeleton, and released ATP.


[Peroperative echography in 14 cases of pancreatic insulinoma and gastrinoma].
Fourteen cases of endocrine tumors (10 insulinomas and 4 gastrinomas) were to studied by intraoperative ultrasonography (IOU). Localization was established by preoperative ultrasonography in 1/14, by CT scan in 1/11, by arteriography in 6/12 and by pancreatic venous sampling in 7/8. Tumor size ranged from 0.5 cm to 2.5 cm. Manual palpation was positive in 10/14. The tumor was accurately and completely localized by IOU in 9/10 insulinomas: the one false negative was probably due to micro-adenoma. The intrapancreatic tumor was localized only in 1/14 gastrinomas. Intraoperative sonography localized lymph nodes in all cases. One distal pancreatectomy was improperly performed because of an accessory spleen. After reviewing 59 other cases in the literature, we propose: a) to abandon venous sampling in insulinomas because of adequate performance of IOU; b) to use IOU as a complementary investigative method along with other preoperative methods of localization in gastrinoma.


Global SUMOylation facilitates the multimodal neuroprotection afforded by quercetin against the deleterious effects of oxygen/glucose deprivation and the restoration of oxygen/glucose.
The putative neuroprotective properties of various flavonoids have long been reported. Among this class of chemicals, quercetin, a major flavone/flavonol naturally occurring in plants, deserves focused attention because of the myriad of beneficial effects observed in various in vitro and in vivo models of central nervous system damage/degeneration. However, the mechanisms governing the beneficial outcomes mediated by quercetin remain to be elucidated. In an effort to define the underlying molecular mechanisms, our study employed human/rat neuroblastoma cell lines (SHSY5Y and B35, respectively) and E18-derived rat primary cortical neurons upon which the effects of various flavonoids were examined. Of note, increases in the levels of global SUMOylation, a post-translational modification with the Small Ubiquitin-like MOdifier (SUMO) were pronounced. Quercetin treatment increased SUMOylation levels in both SHSY5Y cells and rat cortical neurons in a dose and time-dependent manner, possibly via the direct inactivation of certain SENPs (SUMO-specific isopeptidases). Of particular interest, cells treated with quercetin displayed increased tolerance to oxygen/glucose deprivation exposure, an in vitro model of ischemia. SHSY5Y cells treated with quercetin also increased the expression of Nrf2 (via a decrease in the levels of Keap1), heme oxygenase-1 (HO-1), and nitric oxide synthase 1 (NOS1), which provide further protection from oxidative stress. In addition, the increased SUMOylation of HIF-1α was noted and deemed to be significant. We hypothesize that SUMOylated HIF-1α plays a fundamental role in the protection afforded and may underlie some of quercetin's ability to protect cells from oxygen/glucose deprivation-induced cell death, via an up-regulation of HO-1 and NOS1, which ultimately leads to the induction of pro-life NOS1/protein kinase G signaling. Quercetin acts to increase survival in the face of ischemia via an increase of SENP3 expression, the possible inactivation of SENPs 1/2, and via a decrease in KEAP1 levels (thereby increasing Nrf2 stability). These changes may then lead to increase in HIF-1α SUMOylation and HO-1 activation, followed by an up-regulation of NOS1/PKG signaling. Pathways altered via quercetin treatment within our experimental system are represented by blue arrowheads. Solid black arrows represent relationships that have been explored while a dotted arrow represents a relationship that has yet to be confirmed.


Policies on return and reintegration of displaced healthcare workers towards rebuilding conflict-affected health systems: a review for The Lancet-AUB Commission on Syria.
War and armed conflicts severely disrupt all health system components, including the healthcare workforce. Although data is limited on the scale of health care worker (HCW) displacement in conflict zones, it is widely acknowledged that conflict conditions result in the displacement of a significant portion of qualified HCWs from their country of origin. While voluntary HCW return is integral to health system rebuilding in conflict-affected and post-conflict settings, there has been little exploration of the nature of national or international policies which encourage HCW return and reintegration to their home countries in the post-conflict period. We conducted a systematic review to identify policies and policy recommendations intended to facilitate the return of displaced HCWs to their home countries and acknowledge their contribution to rebuilding the post-conflict health system. We searched three bibliographic databases and a range of organisational and national health agency websites to identify peer-reviewed articles and grey literature published in English or Arabic between 1 January 1990 to 24 January 2021, and extracted relevant information. We classified policies and policy recommendations using an adapted version of the UNHCR 4Rs Framework. We identified nine peer-review articles and four grey literature reports that fit our inclusion criteria, all of which were published in English. These covered issues of repatriation (n = 3), reintegration (n = 2), health system rehabilitation and reconstruction (n = 2); six documents covered several of these themes. Information was available for nine conflict contexts: Afghanistan, Iraq, Kosovo, Lebanon, Namibia, Northern Uganda, South Sudan, Timor Leste, and Zimbabwe. Findings demonstrate that health system rebuilding and rehabilitation serve as precursors and reinforcers of the successful return, repatriation, and reintegration of displaced HCWs. Despite the significant numbers of HCWs displaced by conflict, this study identified few specific policies and limited information explicitly focused on the repatriation and reintegration of such workers to their home country in the post-conflict period. Additional research is needed to understand the particular barriers faced by conflict-displaced HCWs in returning to their home country. Conflict-affected and post-conflict states should develop policies and initiatives that address factors within and beyond the health sector to encourage displaced HCW return and provide sustainable reintegration solutions for those who return to post-conflict health systems.


Physician implicit attitudes and stereotypes about race and quality of medical care.
Recent reports speculate that provider implicit attitudes about race may contribute to racial/ethnic health care disparities. We hypothesized that implicit racial bias exists among pediatricians, implicit and explicit measures would differ and implicit measures may be related to quality of care. A single-session, Web survey of academic pediatricians in an urban university measured implicit racial attitudes and stereotypes using a measure of implicit social cognition, the Implicit Association Test (IAT). Explicit (overt) attitudes were measured by self-report. Case vignettes were used to assess quality of care. We found an implicit preference for European Americans relative to African Americans, which was weaker than implicit measures for others in society (mean IAT score = 0.18; P = 0.01; Cohen's d = 0.41). Physicians held an implicit association between European Americans relative to African Americans and the concept of "compliant patient" (mean IAT score = 0.25; P = 0.001; Cohen's d = 0.60) and for African Americans relative to European Americans and the concept of "preferred medical care" (mean IAT score =-0.21; P = 0.001; Cohen's d = 0.64). Medical care differed by patient race in 1 of 4 case vignettes. No significant relationship was found between implicit and explicit measures, or implicit measures and treatment recommendations. Pediatricians held less implicit race bias compared with other MDs and others in society. Among pediatricians we found evidence of a moderate implicit "perceived patient compliance and race" stereotype. Further research is needed to explore whether physician implicit attitudes and stereotypes about race predict quality of care.


[Primary decompressive craniectomy in patients with aneurysmatic subarachnoid hemorrhage. Results of a pilot study in 11 cases].
Despite the scientific and technical advances of recent years, aneurysmal subarachnoid hemorrhage (aSAH) continues to present a high morbidity and mortality. This fact, together with the impressive results of the primary decompressive craniotomy (PDC) in the malignant infarction of the middle cerebral artery suggests a possible beneficial effect of decompressive technique in aSAH. We present our experience of a pilot study that PDC was used in patients with poorgrade aSAH with associated intracerebral hematoma. Between March 1st, 2002 and 31st April, 2008, 342 patients with aneurysmatic subarachnoid hemorrhage (aSAH) were treated at our hospital. Of these, 64 had a poor neurological grade (scores of 4 or 5 of the World Federation of Neurosurgical Societies) at the time of admission. The present study examines 11 of those patients who underwent PDC, which is performed in the same clipping and / or evacuation of an associated hematoma. In three patients PDC was performed after endovascular aneurysm treatment because of the need to evacuate an associated hematoma. In the eight remaining patients, PDC was performed in the same clipping and evacuation of the associated hematoma. Outcome evaluation of these eleven patients was conducted 1 year after the operation assessed by the Glasgow Outcome Scale. Six patients survived, and four of them with good results. The PDC was effective in controlling intracranial pressure in all six surviving patients. However, two of these six patients had unfavorable outcomes. Of the five who didn't survive, one patient died from a delayed epidural-subgaleal hematoma as a complication of the decompressive technique, and the other four patients died because of refractory intracranial hypertension. Primary DC may be beneficial in selected subgroups of patients with poor-grade aSAH. However, there is a lack of definitive evidence to support a clear recommendation for its use.


Non-canonical Wnt signaling through Wnt5a/b and a novel Wnt11 gene, Wnt11b, regulates cell migration during avian gastrulation.
Knowledge of the molecular mechanisms regulating cell ingression, epithelial-mesenchymal transition and migration movements during amniote gastrulation is steadily improving. In the frog and fish embryo, Wnt5 and Wnt11 ligands are expressed around the blastopore and play an important role in regulating cell movements associated with gastrulation. In the chicken embryo, although Wnt5a and Wnt5b are expressed in the primitive streak, the known Wnt11 gene is expressed in paraxial and intermediate mesoderm, and in differentiated myocardial cells, but not in the streak. Here, we identify a previously uncharacterized chicken Wnt11 gene, Wnt11b, that is orthologous to the frog Wnt11 and zebrafish Wnt11 (silberblick) genes. Chicken Wnt11b is expressed in the primitive streak in a pattern similar to chicken Wnt5a and Wnt5b. When non-canonical Wnt signaling is blocked using a Dishevelled dominant-negative protein, gastrulation movements are inhibited and cells accumulate in the primitive streak. Furthermore, disruption of non-canonical Wnt signaling by overexpression of full-length or dominant-negative Wnt11b or Wnt5a constructions abrogates normal cell migration through the primitive streak. We conclude that non-canonical Wnt signaling, mediated in part by Wnt11b, is important for regulation of gastrulation cell movements in the avian embryo.