High contributions of sea ice derived carbon in polar bear (Ursus maritimus) tissue.
Polar bears (Ursus maritimus) rely upon Arctic sea ice as a physical habitat. Consequently, conservation assessments of polar bears identify the ongoing reduction in sea ice to represent a significant threat to their survival. However, the additional role of sea ice as a potential, indirect, source of energy to bears has been overlooked. Here we used the highly branched isoprenoid lipid biomarker-based index (H-Print) approach in combination with quantitative fatty acid signature analysis to show that sympagic (sea ice-associated), rather than pelagic, carbon contributions dominated the marine component of polar bear diet (72-100%; 99% CI, n = 55), irrespective of differences in diet composition. The lowest mean estimates of sympagic carbon were found in Baffin Bay bears, which were also exposed to the most rapidly increasing open water season. Therefore, our data illustrate that for future Arctic ecosystems that are likely to be characterised by reduced sea ice cover, polar bears will not only be impacted by a change in their physical habitat, but also potentially in the supply of energy to the ecosystems upon which they depend. This data represents the first quantifiable baseline that is critical for the assessment of likely ongoing changes in energy supply to Arctic predators as we move into an increasingly uncertain future for polar ecosystems.


The tricho system: hypertrichosis, radiation, and cancer.
Five women in their 6th to 8th decades were treated for facial hypertrichosis in Erie, Pennsylvania, 30 to 40 years ago. The epilations were performed with an X-ray device called "Tricho System," which was manufactured, sold, and proclaimed safe by its physician-inventor. The beauty shop operator who administered these treatments may or may not have received "instruction" by the company in the operation of the equipment. At varying intervals, each of the 5 women developed radiodermatitis and basal cell and/or squamous cell carcinoma at the sites of epilation. All presented to the plastic surgical service at the Hamot Medical Center in Erie, Pennsylvania. Two underwent massive radical resective surgery, 2 required extensive excision and resurfacing, and 1 refused resective surgery although she had had a previous surgical attempt 17 years earlier. Case histories are presented in detail. This series is representative of the epidemic nature of Tricho-System-induced disease.


Heparanase and COX-2 expression as predictors of lymph node metastasis in large, high-grade breast tumors.
Heparanase (HPA) contributes to breast cancer metastasis by facilitating the breakdown of the basement membrane and extracellular matrix. High expression of HPA is thought to be associated with increased nodal involvement and poor survival in patients with breast cancer. Overexpression of cyclooxygenase-2 (COX-2) in breast cancer is associated with indicators of poor prognosis such as lymph node metastasis, poor differentiation, and large tumor size. The underlying mechanism by which HPA and COX-2 overexpression increases the metastatic potential of breast cancer is not fully-understood. To enhance our understanding over these mechanisms, we aimed to investigate the relationship between the size of the tumor and HPA expression, tumor grade as well as lymph node status in patients with breast cancer. Immunohistochemical analysis of HPA and COX-2 expression was performed on 246 breast tumor samples. The expression of HPA was correlated with COX-2 expression, tumor grade, lymph node status, oestrogen receptor status. The overexpression of HPA and COX-2 was associated with increased likelihood of lymph node positivity in large, high-grade tumors. High-grade tumors with size greater than 20 mm, that overexpressed HPA, were 4-times more likely to be associated with lymph node involvement (OR 4.71, CI 1.21-18.25). Whereas, tumors greater than 20 mm in size were 5-times more likely to metastasize to the regional lymph nodes, if associated with overexpression of COX-2 (OR 5.5, CI 1.2-24.8). Expression of HPA appears to be a key mechanism by which large, high-grade breast tumors metastasize to regional lymph nodes, while COX-2 overexpression may be an independent predictor of lymph node positivity.


Pandemic stressors and vaccine hesitancy among young, pregnant Black people: A qualitative study of health disparities during a global pandemic.
The novel coronavirus 2019 (COVID-19) pandemic exacerbated existing health inequities in the United States, but no studies have focused on the lived experiences of younger Black birthing people. The goal of this qualitative study was to center the experiences of younger pregnant and birthing Black and Biracial people during the pandemic. We recruited 25 Black and Biracial pregnant and birthing people ages 16-23 for individual semi-structured interviews. Participants were asked about experiences with the healthcare system during the pandemic, and interviews were transcribed verbatim and coded for qualitative analysis using nVivo. We adhered to the Consolidated Criteria for Reporting Qualitative Research guidelines. Participants identified pandemic-related stressors such as fears about infection, lack of support, and pressure to get vaccinated. Reasons for vaccine hesitancy included mistrust in the government and racism experienced during reproductive healthcare. Provider appeals highlighting patient autonomy and science were more effective in encouraging vaccine uptake than emotional appeals that made participants feel guilty about potentially infecting loved ones. Restrictions on children and support people created barriers to timely prenatal care and reduced tangible support for young Black and Biracial birthing people during the pandemic. Their vaccine hesitancy was related to mistrust, concerns that the vaccines had not been tested enough prior to roll-out, and possible side effects of the vaccine including infection with the virus and pregnancy loss. Obstetric providers need to understand and recognize the ongoing impact of obstetric and scientific racism on health communication with younger Black and Biracial patients.


Characterizing pore-scale dissolution of organic immiscible liquid in a poorly-sorted natural porous medium.
Synchrotron X-ray microtomography was used to characterize the pore-scale morphology and distribution of an organic immiscible liquid (trichloroethene) during water flushing to examine dissolution dynamics. The experiments were conducted with a natural porous medium that has a large particle-size distribution. The results were compared to those of a previous experiment conducted with a well-sorted natural sand. The median organic-liquid blob volume was smaller, and smaller blobs composed a larger fraction of the distribution, for the poorly sorted medium. In addition, mass removal was less spatially uniform for the poorly sorted medium. The concentration of trichloroethene in the column effluent was monitored during dissolution to assess mass-flux behavior. A first-order mass transfer equation was used to simulate the measured elution curves. Organic-liquid/water interfacial areas measured with microtomography were used as input, and simulated effluent concentrations were compared to the measured effluent concentrations to determine best-fit values for the mass-transfer coefficient. The value obtained for the poorly sorted medium was approximately 10 times smaller than that obtained for the well-sorted medium. This disparity indicates that hydraulic accessibility of the organic liquid is more constrained for the poorly sorted medium, which would be consistent with a more complex pore-scale flow field for the poorly sorted medium.


Cerebral Magnetic Resonance Spectroscopy Demonstrates Long-Term Effect of Bone Marrow Transplantation in α-Mannosidosis.
α-Mannosidosis, OMIM #248500, is an autosomal recessive lysosomal storage disease caused by acidic α-mannosidase deficiency. Treatment options include bone marrow transplantation (BMT) and, possibly in the future, enzyme replacement therapy. Brain magnetic resonance spectroscopy (MRS) enables non-invasive monitoring of cerebral treatment effect. Accumulated cerebral mannose-containing oligosaccharides were demonstrated by MRS in a patient who at age 2 years and 11 months received a BMT from a haploidentical non-carrier sibling. The cerebral mannose-containing oligosaccharides had disappeared as early as 9½ months after BMT. MRS furthermore demonstrated the persistent treatment effect at regular intervals up to 5½ years after BMT. MRS is a non-invasive tool that can demonstrate the effect of BMT treatment. Likewise, MRS may be used to demonstrate the cerebral effect of other potential treatments such as enzyme replacement therapy.


Between the Carlo R. and the Orleannais: public health and maritime prophylaxis in the description of two cases of ships transporting immigrants arriving in the port of Rio de Janeiro, 1893-1907.
We address the changes in Brazilian maritime prophylaxis by studying two cases of immigrant ships arriving at the port of Rio de Janeiro with epidemics onboard. The objective is to understand the etiology, means of prevention and methods used to combat the three diseases subject to international port regulations: yellow fever, bubonic plague and cholera. Until the late nineteenth century, quarantines were one of the main disease prevention practices. In the early twentieth century, microbiology and the concept of vectors in ports sanitation services emerged. Quarantines, which were already being criticized as antiquated and ineffective, were limited to a few cases, and new hygiene methods and technologies began to be applied in port sanitary defense.


Resilience assessment framework for critical infrastructure in a multi-hazard environment: Case study on transport assets.
The exposure of critical infrastructure to natural and human-induced hazards has severe consequences on world economies and societies. Therefore, resilience assessment of infrastructure assets to extreme events and sequences of diverse hazards is of paramount importance for maintaining their functionality. Yet, the resilience assessment commonly assumes single hazards and ignores alternative approaches and decisions in the restoration strategy. It has now been established that infrastructure owners and operators consider different factors in their restoration strategies depending on the available resources and their priorities, the importance of the asset and the level of damage. Currently, no integrated framework that accounts for the nature and sequence of multiple hazards and their impacts, the different strategies of restoration, and hence the quantification of resilience in that respect exists and this is an acknowledged gap that needs urgently filling. This paper provides, for the first time in the literature, a classification of multiple hazard sequences considering their nature and impacts. Subsequently, a novel framework for the quantitative resilience assessment of critical infrastructure, subjected to multiple hazards is proposed, considering the vulnerability of the assets to hazard actions, and the rapidity of the damage recovery, including the temporal variability of the hazards. The study puts forward a well-informed asset resilience index, which accounts for the full, partial or no restoration of asset damage between the subsequent hazard occurrences. The proposed framework is then applied on a typical highway bridge, which is exposed to realistic multiple hazard scenarios, considering pragmatic restoration strategies. The case study concludes that there is a significant effect of the occurrence time of the second hazard on the resilience index and a considerable error when using simple superimposition of resilience indices from different hazards, even when they are independent in terms of occurrence. This potentially concerns all critical infrastructure assets and, hence, this paper provides useful insights for the resilience-based design and management of infrastructure throughout their lifetime, leading to cost savings and improved services. The paper concludes with a demonstration of the importance of the framework and how this can be utilised to estimate the resilience of networks to provide a quantification of the resilience at a regional and country scale.


Zebrafish midbrain slow-amplifying progenitors exhibit high levels of transcripts for nucleotide and ribosome biogenesis.
Investigating neural stem cell (NSC) behaviour in vivo, which is a major area of research, requires NSC models to be developed. We carried out a multilevel characterisation of the zebrafish embryo peripheral midbrain layer (PML) and identified a unique vertebrate progenitor population. Located dorsally in the transparent embryo midbrain, these large slow-amplifying progenitors (SAPs) are accessible for long-term in vivo imaging. They form a neuroepithelial layer adjacent to the optic tectum, which has transitory fast-amplifying progenitors (FAPs) at its margin. The presence of these SAPs and FAPs in separate domains provided the opportunity to data mine the ZFIN expression pattern database for SAP markers, which are co-expressed in the retina. Most of them are involved in nucleotide synthesis, or encode nucleolar and ribosomal proteins. A mutant for the cad gene, which is strongly expressed in the PML, reveals severe midbrain defects with massive apoptosis and sustained proliferation. We discuss how fish midbrain and retina progenitors might derive from ancient sister cell types and have specific features that are not shared with other SAPs.


Type 2 diabetes mellitus in childhood: obesity and insulin resistance.
As rates of childhood obesity climb, type 2 diabetes mellitus has increasingly been diagnosed in children and adolescents, with the highest incidence occurring among youth from racial and ethnic minority backgrounds. The serious complications associated with type 2 diabetes mellitus make it essential for physicians to be aware of risk factors and screening guidelines, allowing for earlier patient diagnosis and treatment. It is also important for physicians to be aware of the treatment options available, including weight control through diet and exercise as well as common pharmacotherapeutic options.


Return to the past: the case for antibody-based therapies in infectious diseases.
In the preantibiotic era, passive antibody administration (serum therapy) was useful for the treatment of many infectious diseases. The introduction of antimicrobial chemotherapy in the 1940s led to the rapid abandonment of many forms of passive antibody therapy. Chemotherapy was more effective and less toxic than antibody therapy. In this last decade of the 20th century the efficacy of antimicrobial chemotherapy is diminishing because of the rapidly escalating number of immunocompromised individuals, the emergence of new pathogens, the reemergence of old pathogens, and widespread development of resistance to antimicrobial drugs. This diminishment in the effectiveness of chemotherapy has been paralleled by advances in monoclonal antibody technology that have made feasible the generation of human antibodies. This combination of factors makes passive antibody therapy an option worthy of serious consideration. We propose that for every pathogen there exists an antibody that will modify the infection to the benefit of the host. Such antibodies are potential antimicrobial agents. Antibody-based therapies have significant advantages and disadvantages relative to standard chemotherapy. The reintroduction of antibody-based therapy would require major changes in the practices of infectious disease specialists.


c-MYC Expression Is a Possible Keystone in the Colorectal Cancer Resistance to EGFR Inhibitors.
Alterations in the transcriptional factor c-MYC could be involved in the anti-EGFR resistance in metastatic colorectal cancer (mCRC). The c-MYC expression was evaluated in 121 RAS and BRAF wild-type mCRC before treatment with anti-EGFR+Folfiri therapy and in 33 subsequent metastases collected during target therapy (TT) or in TT resistance phase. We analyzed the expression and the functional role of some c-MYC linked miRNAs (miR-31-3p, miR-143 and miR-145) in our patient group and in two CRC cell lines, also performing a c-MYC target PCR array. Patients with higher c-MYC expression (HME) showed a significant lower PFS and OS when compared to those with low c-MYC expression (LME). HME pattern was significantly more frequent in the metastases after TT and significantly associated to anti-EGFR molecular resistance alterations. We also found a significant correlation between the expression of the above-mentioned c-MYC linked miRNAs, c-MYC level and anti-EGFR resistance. Moreover, expression gene profiling pointed out the pivotal role of c-MYC in CRC-related cell-cycle, apoptosis, signal transduction and cell-growth pathways. c-MYC expression might distinguish patients with a lower PFS and OS in anti-EGFR treated mCRC. The individuation of some miRNAs involved in the c-MYC pathway regulation and the downstream c-MYC effector genes could provide a new possible target to overcome the anti-EGFR resistance in mCRC.


A ChIP-Seq benchmark shows that sequence conservation mainly improves detection of strong transcription factor binding sites.
Transcription factors are important controllers of gene expression and mapping transcription factor binding sites (TFBS) is key to inferring transcription factor regulatory networks. Several methods for predicting TFBS exist, but there are no standard genome-wide datasets on which to assess the performance of these prediction methods. Also, it is believed that information about sequence conservation across different genomes can generally improve accuracy of motif-based predictors, but it is not clear under what circumstances use of conservation is most beneficial. Here we use published ChIP-seq data and an improved peak detection method to create comprehensive benchmark datasets for prediction methods which use known descriptors or binding motifs to detect TFBS in genomic sequences. We use this benchmark to assess the performance of five different prediction methods and find that the methods that use information about sequence conservation generally perform better than simpler motif-scanning methods. The difference is greater on high-affinity peaks and when using short and information-poor motifs. However, if the motifs are specific and information-rich, we find that simple motif-scanning methods can perform better than conservation-based methods. Our benchmark provides a comprehensive test that can be used to rank the relative performance of transcription factor binding site prediction methods. Moreover, our results show that, contrary to previous reports, sequence conservation is better suited for predicting strong than weak transcription factor binding sites.


Are efforts to attract graduate applicants to UK medical schools effective in increasing the participation of under-represented socioeconomic groups? A national cohort study.
Attracting graduates was recommended as a means of diversifying the UK medical student population. Graduates now make up nearly a quarter of the total medical student population. Research to date has focused on comparing the sociodemographic characteristics of applicants to and/or students on traditional and graduate entry programmes (GEMs), yet GEMs account for only 40% of the graduate medical student population. Thus, we aimed to compare the sociodemographic characteristic and outcomes of graduates and non-graduate applicants across a range of programmes. This was an observational study of 117 214 applicants to medicine who took the UK Clinical Aptitude Test (UKCAT) from 2006 to 2014 and who applied to medical school through Universities and Colleges Admissions Service (UCAS). We included applicant demographics, UKCAT total score and offers in our analysis. Applicants were assigned as graduates or non-graduates on the basis of their highest qualification. Multiple logistic regression was used to predict the odds of receiving an offer, after adjusting for confounders. Irrespective of graduate or non-graduate status, most applicants were from the highest socioeconomic groups and were from a white ethnic background. Receiving an offer was related to gender and ethnicity in both graduates and non-graduates. After adjusting for UKCAT score, the OR of an offer for graduates versus non-graduates was approximately 0.5 (OR=0.48, 95% CI 0.46 to 0.49). Our findings indicate that the aim of diversifying the medical student population on socioeconomic grounds by attracting graduates has been only marginally successful. Graduate applicants from widening access backgrounds are less likely than others to be offered a place at medical school. Different approaches must be considered if medicine is to attract and select more socially diverse applicants.


Haemoglobin, magnetic resonance imaging markers and cognition: a subsample of population-based study.
Low haemoglobin is highly prevalent among the elderly and has been associated with dementia. However, the mechanisms underlying this association with cognitive dysfunction, either through cerebrovascular disease or neurodegeneration, remain poorly understood. We aimed to examine the association of decreased haemoglobin levels with markers of cerebral small vessel disease (CSVD), neurodegeneration and cognitive impairment in an elderly Asian population. A total of 796 Chinese, Malay and Indian participants aged 60 years and older from the Epidemiology of Dementia in Singapore study were included in this study. After providing information on demographics, anthropometry and cardiovascular risk factors, participants underwent 3-T brain magnetic resonance imaging (MRI) to measure markers of CSVD, including cerebral microbleeds, cortical cerebral microinfarcts, lacunes, enlarged perivascular spaces and white matter hyperintensities, as well as neurodegenerative markers, including cortical thickness and subcortical structure volumes quantified using FreeSurfer. Cognition was assessed using a detailed neuropsychological assessment. Logistic and linear regression models were constructed, adjusting for age, gender, education, race, body mass index, smoking, hypertension, hyperlipidaemia, diabetes, glomerular filtration rate and other MRI markers, to test the association between haemoglobin levels and the MRI markers and cognition. Decreased haemoglobin levels were associated with cerebral microbleeds, specifically lobar microbleeds (OR, 1.21; 95% CI, 1.04-1.40; p = 0.015). Decreased haemoglobin levels were also associated with occipital cortical thinning (mean difference, - 0.011; 95% CI, - 0.019, - 0.004; p = 0.003) and smaller accumbens volume (mean difference, - 0.01; 95% CI, - 0.02, 0.00; p = 0.005). A significant association was also observed between decreased haemoglobin levels and poorer global cognitive performance (mean difference, - 0.04; 95% CI, - 0.09, 0.00; p = 0.048). In cognitive domain analysis, associations were again observed between decreased haemoglobin levels and worse performance on attention (mean difference, - 0.05; 95% CI, - 0.10, - 0.01; p = 0.028) and language (mean difference, - 0.06; 95% CI, - 0.12, 0.00; p = 0.048) domains; however, these associations did not survive multiple comparison. Decreased haemoglobin levels were associated with lobar microbleeds, neurodegenerative markers and cognitive dysfunction. Future studies should ascertain whether iron, folate or vitamin B12 supplementation is able to ameliorate the onset and progression of cognitive impairment and dementia associated with low haemoglobin.


A Golden-Gate Based Cloning Toolkit to Build Violacein Pathway Libraries in Yarrowia lipolytica.
Violacein is a naturally occurring anticancer therapeutic compound with deep purple color. In this work, we harnessed the modular and combinatorial feature of a Golden Gate assembly method to construct a library of violacein producing strains in the oleaginous yeast Yarrowia lipolytica, where each gene in the violacein pathway was controlled by three different promoters with varying transcriptional strength. After optimizing the linker sequence and the Golden Gate reaction, we achieved high transformation efficiency and obtained a panel of representative Y. lipolytica recombinant strains. By evaluating the gene expression profile of 21 yeast strains, we obtained three colorful compounds in the violacein pathway: green (proviolacein), purple (violacein), and pink (deoxyviolacein). Our results indicated that strong expression of VioB, VioC, and VioD favors violacein production with minimal byproduct deoxyvioalcein in Y. lipolytica, and high deoxyviolacein production was found strongly associated with the weak expression of VioD. By further optimizing the carbon to nitrogen ratio and cultivation pH, the maximum violacein reached 70.04 mg/L with 5.28 mg/L of deoxyviolacein in shake flasks. Taken together, the development of Golden Gate cloning protocols to build combinatorial pathway libraries, and the optimization of culture conditions set a new stage for accessing the violacein pathway intermediates and engineering violacein production in Y. lipolytica. This work further expands the toolbox to engineering Y. lipolytica as an industrially relevant host for plant or marine natural product biosynthesis.


Gap filling of 3-D microvascular networks by tensor voting.
We present a new algorithm which merges discontinuities in 3-D images of tubular structures presenting undesirable gaps. The application of the proposed method is mainly associated to large 3-D images of microvascular networks. In order to recover the real network topology, we need to fill the gaps between the closest discontinuous vessels. The algorithm presented in this paper aims at achieving this goal. This algorithm is based on the skeletonization of the segmented network followed by a tensor voting method. It permits to merge the most common kinds of discontinuities found in microvascular networks. It is robust, easy to use, and relatively fast. The microvascular network images were obtained using synchrotron tomography imaging at the European Synchrotron Radiation Facility. These images exhibit samples of intracortical networks. Representative results are illustrated.


Efficacy and safety of micafungin versus intravenous itraconazole as empirical antifungal therapy for febrile neutropenic patients with hematological malignancies: a randomized, controlled, prospective, multicenter study.
Micafungin, a clinically important echinocandin antifungal drug, needs to be investigated as empirical therapy in febrile neutropenia in comparison with azole compounds. A prospective randomized study was conducted to compare clinical outcomes between micafungin and intravenous itraconazole as an empirical therapy for febrile neutropenia in hematological malignancies. The antifungal drug (micafungin 100 mg or itraconazole 200 mg IV once daily) was given for high fever that was sustained despite the administration of appropriate antibiotics. Treatment success was determined by composite end points based on breakthrough invasive fungal infection (IFI), survival, premature discontinuation, defervescence, and treatment of baseline fungal infection. Duration of fever, hospital stay, and overall survival (OS) were studied. A total of 153 patients were randomized to receive micafungin or itraconazole. The overall success rate was 7.1 % point higher in the micafungin group (64.4 vs. 57.3 %, p = 0.404), satisfying the statistical criteria for the non-inferiority of micafungin. The duration of fever and hospital stay were significantly shorter in the micafungin group (6 vs. 7 days, p = 0.014; 22 vs. 27 days, p = 0.033, respectively). Grade 3 adverse events including hyperbilirubinemia (2 vs. 7), elevation of transaminase levels (2 vs. 4), electrolyte imbalance (1 vs. 2), atrial fibrillation (1 vs. 0), and anaphylaxis (1 vs. 0) occurred in 7 and 13 patients in the micafungin (10.4 %) and itraconazole (18.8 %) groups, respectively. Micafungin, when compared with itraconazole, had favorably comparable success rate and toxicity profiles on febrile neutropenia in patients with hematological malignancies. In addition, it showed superior effect on shortening the hospital stay.


Bipolar disorder in Asia: Illness course and contributing factors.
Epidemiological studies analysing the course of Bipolar Disorder (BD) are relatively rare in the Asian context, contributing to the uncertainty regarding the prevalent course patterns and factors influencing such patterns. The current review identifies the regional characteristics of BD course patterns and the associated factors. A review of the existing literature was done using 'PubMed' and 'Cochrane' databases which yielded 145 studies including those from all 48 Asian countries. Relevant discussions from the Western literature were incorporated. Regional and cross-national studies reveal a mania-predominant course in BD in Asian countries. Prolonged depressive episodes and comorbid anxiety disorders worsen the course of BD-II. Certain risk factors such as the young age of onset and greater episode frequency are useful predictors of bipolar diatheses. Substance use disorder comorbidity is more prevalent in males whereas depression and suicidal behaviours are more frequent in females with BD. Comorbid anxiety and personality disorders also encumber the illness course. Logistic reasons and ignorance of side-effects were specifically associated with poor adherence. An 'eveningness' chronotype and poor sleep quality were associated with frequent recurrences. Seasonal patterns vary among men and women, especially for depressive episodes. The effects of treatment and childhood BD course features were not discussed. There are region-specific characteristics in bipolar illness course and factors influencing such course patterns compared to the rest of the World. Future research from Asia shall attempt to study the neurobiological underpinnings of such characteristics and plan appropriate strategies to address the same.


A population-based study of homicide deaths in Ontario, Canada using linked death records.
Homicide - a lethal expression of violence - has garnered little attention from public health researchers and health policy makers, despite the fact that homicides are a cause of preventable and premature death. Identifying populations at risk and the upstream determinants of homicide are important for addressing inequalities that hinder population health. This population-based study investigates the public health significance of homicides in Ontario, Canada, over the period of 1999-2012. We quantified the relative burden of homicides by comparing the socioeconomic gradient in homicides with the leading causes of death, cardiovascular disease (CVD) and neoplasm, and estimated the potential years of life lost (PYLL) due to homicide. We linked vital statistics from the Office of the Registrar General Deaths register (ORG-D) with Census and administrative data for all Ontario residents. We extracted all homicide, neoplasm, and cardiovascular deaths from 1999 to 2012, using International Classification of Diseases codes. For socioeconomic status (SES), we used two dimensions of the Ontario Marginalization Index (ON-Marg): material deprivation and residential instability. Trends were summarized across deprivation indices using age-specific rates, rate ratios, and PYLL. Young males, 15-29 years old, were the main victims of homicide with a rate of 3.85 [IC 95%: 3.56; 4.13] per 100,000 population and experienced an upward trend over the study period. The socioeconomic neighbourhood gradient was substantial and higher than the gradient for both cardiovascular and neoplasms. Finally, the PYLL due to homicide were 63,512 and 24,066 years for males and females, respectively. Homicides are an important cause of death among young males, and populations living in disadvantaged neighbourhoods. Our findings raise concerns about the burden of homicides in the Canadian population and the importance of addressing social determinants to address these premature deaths.


Identification of angiotensin-I-converting enzyme inhibitory peptides derived from sodium caseinate hydrolysates produced by Lactobacillus helveticus NCC 2765.
Angiotensin-I-converting enzyme (ACE) inhibitory activity was identified in milk proteins fermented with Lactobacillus (Lb.) helveticus NCC 2765 (Nestle Culture Collection, Vers-chez-les-Blanc, Switzerland). Hydrolyzing sodium caseinate for 1 and 2 h inhibited ACE activity, as measured by an in vitro ACE inhibition test. The hydrolysates with the highest ACE inhibitory potential were fractionated by gel permeation chromatography and their low molecular weight fractions collected. These fractions were subsequently subfractionated by reverse-phase high-pressure liquid chromatography. Several hydrophobic subfractions showed high ACE inhibitory potential, and their peptide composition was determined using an ion trap mass spectrometer equipped with an elctrospray ionization source. Analysis of the low molecular weight fraction identified 14 peptides with known antihypertensive activity and 1 with previously described opioid activity. On the basis of the peptide composition of active subfractions, two potentially active novel sequences were defined, and the following synthetic peptides were synthesized: FVAPFPEVFG (alphaS1 39-48), ENLLRFFVAPFPEVFG (alphaS1 33-48), NENLLRFFVAPFPEVFG (alphaS1 32-48), LNENLLRFFVAPFPEVFG (alphaS1 31-48), NLHLPLPLL (beta 147-155), ENLHLPLPLL (beta 146-155), and VENLHLPLPLL (beta 145-155). The ACE inhibitory potential of these synthetic peptides was assessed, and IC50 values were determined. NLHLPLPLL (beta 147-155), which was the only synthetic peptide also present in the sodium caseinate hydrolysates, and NENLLRFFVAPFPEVFG (alphaS1 32-48) showed the highest inhibition of ACE activity, with IC50 values of 15 and 55 microM, respectively. Furthermore, the stability of all synthetic peptides was assessed using an in vitro model simulating gastric digestion. The beta-casein-derived peptides remained intact following the successive hydrolysis by pepsin and pancreatin, whereas alphaS1-casein-derived peptides were degraded by pepsin.


The orphan nuclear receptor, liver receptor homolog-1, regulates cholesterol side-chain cleavage cytochrome p450 enzyme in human granulosa cells.
After ovulation, there is a shift in ovarian steroidogenesis from an estrogen-producing ovarian follicle to a progesterone-producing corpus luteum. The first step in human ovarian steroidogenesis is catalyzed by cholesterol side-chain cleavage cytochrome P450 (CYP11A1) enzyme. Steroidogenic factor-1 is an orphan nuclear receptor that regulates several steroidogenic enzymes, including CYP11A1. Liver receptor homolog-1 (LRH-1) is another orphan nuclear receptor that is expressed in the human ovary. After ovulation there is a down-regulation in steroidogenic factor-1, which is associated with an up-regulation of LRH-1 expression. These changes coincide with increased level of CYP11A1 expression in human corpus luteum. In this study, we examined the role of LRH-1 in the regulation of human granulosa cell CYP11A1 expression. Cotransfection of human granulosa cell tumor cells with CYP11A1 promoter and LRH-1 expression vector resulted in a significant increase in CYP11A1 expression. Deletion analysis revealed two putative LRH-1 binding sites at -1580 and -40, which was confirmed by EMSA. Dosage-sensitive sex-reversal-adrenal hypoplasia congenita critical region on the X chromosome, gene-1 inhibited LRH-1 stimulated CYP11A1 expression, and that was not overcome by the presence of PKA agonist. We conclude that CYP11A1 expression in human granulosa cells is regulated by LRH-1. We propose that LRH-1 could be the major transcription factor for the post-ovulatory surge in human ovarian steroidogenesis.


"I prefer a male nurse to a female nurse": patients' preference for, and satisfaction with nursing care provided by male nurses at the Komfo Anokye teaching hospital.
Although most male nurses join the profession for self-actualisation, the cultural and societal stereotyping of male nurses as "He-Man", "gay" and "troublemakers", and their marginalisation at the hospital during certain personal and intimate care procedures, tend to deepen the existing gender discrimination prevalent within the nursing profession. This study therefore assessed patients' preference for, and satisfaction with nursing care provided by male nurses at the medical and surgical wards of Komfo Anokye Teaching Hospital [KATH]. An inferential cross-sectional study design, in which the prevalence of a condition among an identified population is determined, was used. Using convenience sampling, 150 respondents who meet certain practical criteria and are available and willing to participate were sampled. Data from a context-based research instrument on the opinion, preference and satisfaction of patients with male nursing were analysed using χ 2 test, Mann Whitney U test, ordinal logistic regression and logistic regression. The study indicates that more females than males had ever been attended to by a male nurse for the period considered by the study, and females described male nurses as polite and courteous and were comfortable with their treatment. Being single [OR = 0.111, 95% CI (0.013-0.928)] and professing Islamic faiths [OR = 36.533, 95% CI (2.116-630.597)] were functions of respondents' preference for a male nurse. Significantly too, affiliating to a religious sect (OR = 2.347, 95% CI [0.076-1.630]) and being educated (OR = 1.387, 95% CI [0.040-0.615]), were associated with higher odds of falling in one of the higher categories of satisfaction with nursing care provided by male nurses as against the lower categories. Although marital status, religious affiliation and educational level were the significant predictors of patients' preference for, and satisfaction with care provided by male nurses, the effect of the other variables should not be overlooked. The finding disproves assertions on the negative effect of religion on male nurses. It is recommended that public awareness be created on the role of male nurses in the healthcare delivery system to promote acceptance of gender diversity in the nursing profession.


Association between degradation of pharmaceuticals and endocrine-disrupting compounds and microbial communities along a treated wastewater effluent gradient in Lake Mead.
The role of microbial communities in the degradation of trace organic contaminants in the environment is little understood. In this study, the biotransformation potential of 27 pharmaceuticals and endocrine-disrupting compounds was examined in parallel with a characterization of the native microbial community in water samples from four sites variously impacted by urban run-off and wastewater discharge in Lake Mead, Nevada and Arizona, USA. Samples included relatively pristine Colorado River water at the upper end of the lake, nearly pure tertiary-treated municipal wastewater entering via the Las Vegas Wash, and waters of mixed influence (Las Vegas Bay and Boulder Basin), which represented a gradient of treated wastewater effluent impact. Microbial diversity analysis based on 16S rRNA gene censuses revealed the community at this site to be distinct from the less urban-impacted locations, although all sites were similar in overall diversity and richness. Similarly, Biolog EcoPlate assays demonstrated that the microbial community at Las Vegas Wash was the most metabolically versatile and active. Organic contaminants added as a mixture to laboratory microcosms were more rapidly and completely degraded in the most wastewater-impacted sites (Las Vegas Wash and Las Vegas Bay), with the majority exhibiting shorter half-lives than at the other sites or in a bacteriostatic control. Although the reasons for enhanced degradation capacity in the wastewater-impacted sites remain to be established, these data are consistent with the acclimatization of native microorganisms (either through changes in community structure or metabolic regulation) to effluent-derived trace contaminants. This study suggests that in urban, wastewater-impacted watersheds, prior exposure to organic contaminants fundamentally alters the structure and function of microbial communities, which in turn translates into greater potential for the natural attenuation of these compounds compared to more pristine sites.


Quantifying parasite presence in relation to biological parameters of harbour porpoises Phocoena phocoena stranded on the Dutch coast.
Harbour porpoises are often found to be infected by endoparasites in several organs including the lungs and stomach as well as the heart, liver and ears. Nevertheless there is still little knowledge about the impact, ecology, transmission, and virulence of these parasitic infections. Here, we profile the presence of parasites in 4 frequently infected organs (lungs, stomach, liver and ears) in relation to biological parameters of harbour porpoises stranded along the Dutch coastline between December 2008 and December 2013. We found that parasites were common, with prevalence of 68% in lungs, 74.4% in ears, 26% in stomach and 23.5% in liver. We used generalised linear models to further quantify parasite presence in relation to biological data gathered during necropsy (sex, body length and nutritive condition). Body length (used as a proxy for age) was significant in explaining parasite presence for all organs with increasing probability of having the parasite with increasing body length. For the parasitic infections in the ears and stomach the nutritive condition was an additional significant factor, with a higher probability of parasite presence in porpoises in a poorer nutritive condition. The results of this study can be used as a baseline for assessing parasite presence in harbour porpoises and are a first step towards linking parasite infections to basic biological data gathered during necropsy.


Bar-HRM for Authentication of Plant-Based Medicines: Evaluation of Three Medicinal Products Derived from Acanthaceae Species.
Medicinal plants are used as a popular alternative to synthetic drugs, both in developed and developing countries. The economic importance of the herbal and natural supplement industry is increasing every year. As the herbal industry grows, consumer safety is one issue that cannot be overlooked. Herbal products in Thai local markets are commonly sold without packaging or labels. Plant powders are stored in large bags or boxes, and therefore buying local herbal products poses a high risk of acquiring counterfeited, substituted and/or adulterated products. Due to these issues, a reliable method to authenticate products is needed. Here DNA barcoding was used in combination with High Resolution Melting analysis (Bar-HRM) to authenticate three medicinal Acanthaceae species (Acanthus ebracteatus, Andrographis paniculata and Rhinacanthus nasutus) commonly used in Thailand. The rbcL barcode was selected for use in primers design for HRM analysis to produce standard melting profiles of the selected species. Melting data from the HRM assay using the designed rbcL primers showed that the three chosen species could be distinguished from each other. HRM curves of all fifteen test samples indicated that three of tested products did not contain the indicated species. Two closely related species (A. paniculata and R. nasutus), which have a high level of morphological similarity, were interchanged with one another in three tested products. Incorrect information on packaging and labels of the tested herbal products was the cause of the results shown here. Morphological similarity among the species of interest also hindered the collection process. The Bar-HRM method developed here proved useful in aiding in the identification and authentication of herbal species in processed samples. In the future, species authentication through Bar-HRM could be used to promote consumer trust, as well as raising the quality of herbal products.


[[General Practitioners and Public Health in Italy: Medical Office of Doctor Sgandurra from Farindola (Abruzzi, Central Italy)].]
Until the so-called sanitary reform (1978), which introduced a Beveridge' system, in Italy existed a peculiar kind of general practitioner, paid by municipalities, who ensured healthcare to those not covered by social insurance. In small towns those physicians also carried out the finction of Health Officers, performing Public Health duties. We had the possibility to study the very large archive of one of them, doctor Sgandurrafrom Farindola, a village in the Abruzzi Region (central Italy): in the paper we briefly analyse six public health acts that he issued in the first half of the 1950s.


Evaluation of melanin production by Sporothrix luriei.
There is a paucity of studies on the cell biology of Sporothrix luriei, the less common of the pathogenic Sporothrix species worldwide. The production of DHN-melanin, eumelanin, and pyomelanin were evaluated on the mycelial and yeast forms of the S. luriei ATCC 18616 strain. The mycelial form of this species produced only pyomelanin, which protected the fungus against environmental stressors such as ultraviolet light, heat, and cold. The yeast form was unable to produce any of the tested melanin types. The lack of melanin in the parasitic form of S. luriei may be an explanation for its low frequency in human infections.


Study of the measurement and predictive validity of the Functional Movement Screen.
The aim of the study was to evaluate the reported measurement capabilities and predictive validity of the Functional Movement Screen (FMS) for injury. This was a prospective observational longitudinal study of 24 male footballers from a single team in England, alongside analysis of an existing database over one season (September 2015-May 2016). A preseason FMS was carried out with scores recorded by an experienced assessor and derived, retrospectively, from the three-dimensional movement data that were simultaneously captured. The assessor scores were compared with the photogrammetric system to determine measurement validity, and predictive validity was quantified by assessing sensitivity and specificity (cut-off score of 14). The real-time assessor score matched the photogrammetric score awarded for one of the participants, was higher than the photogrammetric system for 22 participants and was lower than the photogrammetric system in 1 participant. There was no discernible relationship between FMS scores and the competencies required to be met as per the rules articulated for the allocation of a score. A higher number of total injuries were associated with higher FMS scores, whether determined through real-time assessment or codification of kinematic variables. Additionally, neither method of score determination was able to prospectively identify players at risk of serious injury. The FMS does not demonstrate the properties essential to be considered as a measurement scale and has neither measurement nor predictive validity. A possible reason for these observations could be the complexity in the instructions associated with the scale. Further work on eliminating redundancies and improving the measurement properties is recommended.


Brazilian transcultural adaptation of an instrument on communicative strategies of caregivers of elderly with dementia.
Communication with patients with dementia may be a difficult task for caregivers. The aim of this study was to produce a Brazilian transcultural adaptation of an instrument developed in Canada, called the Small Communication Strategies Scale, composed of 10 items constructed from 10 communicative strategies most recurrent in a literature survey. Drawing on understanding of the construction of the Small Communication Strategies Scale (SCSS), a Brazilian Portuguese version of the instrument was devised through the following steps: translation, back-translation and semantic-cultural adaptation by a specialized linguist in English-Portuguese translations and application of the comprehension test for the version produced in a group of caregivers of elderly individuals with dementia. The transcultural equivalence process was performed and two items of the SCSS needed adapting to the Brazilian context. After changes suggested by a specialized linguist, the final version was applied to 34 caregivers and the transcultural equivalence considered satisfactory. The Brazilian version of the instrument was successfully transculturally adapted for future validation and application in Brazil.


Guidelines for identifying homologous recombination events in influenza A virus.
The rapid evolution of influenza viruses occurs both clonally and non-clonally through a variety of genetic mechanisms and selection pressures. The non-clonal evolution of influenza viruses comprises relatively frequent reassortment among gene segments and a more rarely reported process of non-homologous RNA recombination. Homologous RNA recombination within segments has been proposed as a third such mechanism, but to date the evidence for the existence of this process among influenza viruses has been both weak and controversial. As homologous recombination has not yet been demonstrated in the laboratory, supporting evidence, if it exists, may come primarily from patterns of phylogenetic incongruence observed in gene sequence data. Here, we review the necessary criteria related to laboratory procedures and sample handling, bioinformatic analysis, and the known ecology and evolution of influenza viruses that need to be met in order to confirm that a homologous recombination event occurred in the history of a set of sequences. To determine if these criteria have an effect on recombination analysis, we gathered 8307 publicly available full-length sequences of influenza A segments and divided them into those that were sequenced via the National Institutes of Health Influenza Genome Sequencing Project (IGSP) and those that were not. As sample handling and sequencing are executed to a very high standard in the IGSP, these sequences should be less likely to be exposed to contamination by other samples or by laboratory strains, and thus should not exhibit laboratory-generated signals of homologous recombination. Our analysis shows that the IGSP data set contains only two phylogenetically-supported single recombinant sequences and no recombinant clades. In marked contrast, the non-IGSP data show a very large amount of potential recombination. We conclude that the presence of false positive signals in the non-IGSP data is more likely than false negatives in the IGSP data, and that given the evidence to date, homologous recombination seems to play little or no role in the evolution of influenza A viruses.


A relationship between apoptosis and flow during programmed capillary regression is revealed by vital analysis.
Previous analyses of developmentally programmed capillary regression suggested two distinct causes of vascular endothelial cell (VEC) death. The first appeared to be macrophage-dependent (Lang, R. A. and Bishop, M. J. (1993) Cell 74, 453-462) while the second was proposed to result from cessation of blood flow (Lang, R. A., Lustig, M., Francois, F., Sellinger, M. and Plesken, H. (1994). Development 120, 3395-3403). Combined, these analyses suggested a model in which initial, macrophage-mediated endothelial cell apoptosis blocked blood flow within a capillary segment and, as a consequence, caused apoptosis of all remaining cells in the affected segment. In the current study, we have tested this model using a new method that combines vital and histological analyses as a means of determining the fate of whole capillary segments and individual cells in vivo. This technique revealed that one of the first events in regression was the apoptosis of a single VEC in otherwise normal, flowing capillary segments (initiating apoptosis). These isolated, dying VECs projected into and restricted the capillary lumen, imposing either a temporary or permanent block to blood flow. Following cessation of flow, synchronous apoptosis of VECs occurred (secondary apoptosis). In addition, a quantitative analysis revealed a reciprocal relationship between plasma flow and VEC apoptosis. These observations are consistent with a model for capillary regression in which macrophages induce apoptosis in a limited number of VECs and, as a consequence of a block to blood flow, also cause apoptosis in those remaining.


How magic changes our expectations about autism.
In the vanishing-ball illusion, the magician's social cues misdirect the audience's expectations and attention so that the audience "sees" a ball vanish in the air. Because individuals with autism spectrum disorder (ASD) are less sensitive to social cues and have superior perception for nonsocial details compared with typically developing individuals, we predicted that they would be less susceptible to the illusion. Surprisingly, the opposite result was found, as individuals with ASD were more susceptible to the illusion than a comparison group. Eye-tracking data indicated that subtle temporal delays in allocating attention might explain their heightened susceptibility. Additionally, although individuals with ASD showed typical patterns of looking to the magician's face and eyes, they were slower to launch their first saccade to the face and had difficulty in fixating the fast-moving observable ball. Considered together, the results indicate that individuals with ASD have difficulties in rapidly allocating attention toward both people and moving objects.


Effects of the nanostructure and nanoporosity on bioactive nanohydroxyapatite/reconstituted collagen by electrodeposition.
Hydroxyapatite (HA)/collagen composites were reported to induce bony growth. Various methods for preparing HA-based composites have been investigated as potential biomaterials for bone substitutes. However, no method can generate a thick nanoporous HA. A novel bone regenerative nanocomposite consisting of nano-hydroxyapatite (HA), nano-amorphous calcium phosphate (ACP) and reconstituted collagen by electrodeposition was designed in this research. Specimens with and without nanoporosity were evaluated using electrochemical measurements, material analyses, and cell-material interactions. The results showed that reconstituted collagen/nano-(HA and ACP) illustrated a multinanoporous structure and enhanced biocompatibility. Nanocomposite was comprised to nano-(HA and ACP) and reconstituted collagen. The core cell structure was formed during electrodeposition. Nanoporosity and nanostructure were observed as formation of nanocomposite. The nano-(HA and ACP) phases were essentially composed of a nanoporous and nanostructural biocomposite. Reconstituted collagen incorporation with the nanoporous and nanostructural biocomposite significantly facilitated the osteogenic differentiation of mesenchymal stem cells. Reconstituted collagen was covered with nano-(HA and ACP), profoundly impacting the enhancement of biocompatibility on application of implant and tissue engineering. The bioactive nano-HA/reconstituted collagen-induced osteogenic differentiation of mesenchymal stem cells enables to enhance bone growth/repair and osseointegration.


Activity-dependent fluorescent staining and destaining of living vertebrate motor nerve terminals.
Living motor nerve terminals from several species can be stained in an activity-dependent fashion by certain styryl dyes, such as RH414, RH795, and a new dye, FM1-43, which can be imaged independently of the others. The dyes evidently become trapped within recycled synaptic vesicles. In frog cutaneus pectoris muscle, bright fluorescent spots spaced regularly along the length of the nerve terminals appear after stimulation in the presence of the dye. The spots align well with postsynaptic ACh receptors and are persistent for many hours, unless further stimulation is given, in which case the spots disappear. Destaining, like staining, requires transmitter release and proceeds gradually over several minutes at high stimulus frequencies (e.g., 30 Hz), and fluorescent spots in the same terminal disappear at about the same rate. We suggest that each spot is a cluster of hundred of synaptic vesicles and that the mechanism of staining involves the ability of the dyes to partition reversibly into the outer leaflet of surface membranes, without being able to penetrate the entire membrane thickness. Then, during endocytosis following transmitter release, dye molecules become trapped in recycled synaptic vesicle membranes. The dyes therefore make it possible optically to study vesicle exocytosis and recycling in living nerve terminals in real time, and should be useful for marking terminals in a variety of preparations according to their level of activity.


Liquid ammonia as a dipolar aprotic solvent for aliphatic nucleophilic substitution reactions.
The rate constants for the reactions of a variety of nucleophiles reacting with substituted benzyl chlorides in liquid ammonia (LNH(3)) have been determined. To fully interpret the associated linear free-energy relationships, the ionization constants of phenols ions in liquid ammonia were obtained using UV spectra. These equilibrium constants are the product of those for ion-pair formation and dissociation to the free ions, which can be separated by evaluating the effect of added ammonium ions. There is a linear relationship between the pK(a) of phenols in liquid ammonia and those in water of slope 1.68. Aminium ions exist in their unprotonated free base form in liquid ammonia and their ionization constants could not be determined by NMR. The rates of solvolysis of substituted benzyl chlorides in liquid ammonia at 25 °C show a Hammett ρ of zero, having little or no dependence upon ring substituents, which is in stark contrast with the hydrolysis rates of substituted benzyl halides in water, which vary 10(7) fold. The rate of substitution of benzyl chloride by substituted phenoxide ions is first order in the concentration of the nucleophile indicative of a S(N)2 process, and the dependence of the rate constants on the pK(a) of the phenol in liquid ammonia generates a Brønsted β(nuc) = 0.40. Contrary to the solvolysis reaction, the reaction of phenoxide ion with 4-substituted benzyl chlorides gives a Hammett ρ = 1.1, excluding the 4-methoxy derivative, which shows the normal positive deviation. The second order rate constants for the substitution of benzyl chlorides by neutral and anionic amines show a single Brønsted β(nuc) = 0.21 (based on the aqueous pK(a) of amine), but their dependence on the substituent in substituted benzyl chlorides varies with a Hammett ρ of 0 for neutral amines, similar to that seen for solvolysis, whereas that for amine anions is 0.93, similar to that seen for phenoxide ion.


An aromatic sensor with aversion to damaged strands confers versatility to DNA repair.
It was not known how xeroderma pigmentosum group C (XPC) protein, the primary initiator of global nucleotide excision repair, achieves its outstanding substrate versatility. Here, we analyzed the molecular pathology of a unique Trp690Ser substitution, which is the only reported missense mutation in xeroderma patients mapping to the evolutionary conserved region of XPC protein. The function of this critical residue and neighboring conserved aromatics was tested by site-directed mutagenesis followed by screening for excision activity and DNA binding. This comparison demonstrated that Trp690 and Phe733 drive the preferential recruitment of XPC protein to repair substrates by mediating an exquisite affinity for single-stranded sites. Such a dual deployment of aromatic side chains is the distinctive feature of functional oligonucleotide/oligosaccharide-binding folds and, indeed, sequence homologies with replication protein A and breast cancer susceptibility 2 protein indicate that XPC displays a monomeric variant of this recurrent interaction motif. An aversion to associate with damaged oligonucleotides implies that XPC protein avoids direct contacts with base adducts. These results reveal for the first time, to our knowledge, an entirely inverted mechanism of substrate recognition that relies on the detection of single-stranded configurations in the undamaged complementary sequence of the double helix.


Acetylation of H2A.Z is a key epigenetic modification associated with gene deregulation and epigenetic remodeling in cancer.
Histone H2A.Z (H2A.Z) is an evolutionarily conserved H2A variant implicated in the regulation of gene expression; however, its role in transcriptional deregulation in cancer remains poorly understood. Using genome-wide studies, we investigated the role of promoter-associated H2A.Z and acetylated H2A.Z (acH2A.Z) in gene deregulation and its relationship with DNA methylation and H3K27me3 in prostate cancer. Our results reconcile the conflicting reports of positive and negative roles for histone H2A.Z and gene expression states. We find that H2A.Z is enriched in a bimodal distribution at nucleosomes, surrounding the transcription start sites (TSSs) of both active and poised gene promoters. In addition, H2A.Z spreads across the entire promoter of inactive genes in a deacetylated state. In contrast, acH2A.Z is only localized at the TSSs of active genes. Gene deregulation in cancer is also associated with a reorganization of acH2A.Z and H2A.Z nucleosome occupancy across the promoter region and TSS of genes. Notably, in cancer cells we find that a gain of acH2A.Z at the TSS occurs with an overall decrease of H2A.Z levels, in concert with oncogene activation. Furthermore, deacetylation of H2A.Z at TSSs is increased with silencing of tumor suppressor genes. We also demonstrate that acH2A.Z anti-correlates with promoter H3K27me3 and DNA methylation. We show for the first time, that acetylation of H2A.Z is a key modification associated with gene activity in normal cells and epigenetic gene deregulation in tumorigenesis.


Effects of silver nanoparticles on soil enzyme activities with and without added organic matter.
The effects of silver nanoparticles (AgNPs) on terrestrial ecosystems need to be better understood and assessed. Cationic silver (Ag+) has well-documented toxicity against bacteria, but it is not clear what will be the effect of nanoscale Ag. In the present study, the potential effects of AgNPs were investigated in soils by measuring activity of the enzymes phosphomonoesterase, arylsulfatase, β-D-glucosidase, and leucine-aminopeptidase. The toxicity of AgNPs was compared with that of ionic Ag, and the ameliorating effects of soil organic matter were evaluated. To this end, 2 soils with different organic matter contents were artificially contaminated with either AgNPs or Ag-acetate at equivalent total Ag concentrations. In general, enzyme activities were inhibited as a function of the Ag concentration in the soil. In the AgNP exposures, only a small fraction of the AgNP was actually truly dissolved (found in the <1-nm fraction), suggesting that the particulate forms of AgNPs resulted in a significant inhibition of soil enzymes. The addition of organic matter to the soils appeared to enhance enzyme activities; however, the mechanism of organic matter action is not clear given that dissolved Ag concentrations were similar in both the organic-matter–amended and unamended soils. The present study shows that the AgNP produces significant negative effects on the soil enzyme activities tested. The Ag chemical speciation measurements suggested that the AgNP caused greater toxic effects to the soil enzymes at the low Ag concentrations. For the larger concentrations of total soil Ag, causes of the negative effects on enzyme activities are less obvious but suggest that colloidal forms of Ag play a role.


Recovery and analysis of transcriptome subsets from pooled single-cell RNA-seq libraries.
Single-cell RNA sequencing (scRNA-seq) methods generate sparse gene expression profiles for thousands of single cells in a single experiment. The information in these profiles is sufficient to classify cell types by distinct expression patterns but the high complexity of scRNA-seq libraries often prevents full characterization of transcriptomes from individual cells. To extract more focused gene expression information from scRNA-seq libraries, we developed a strategy to physically recover the DNA molecules comprising transcriptome subsets, enabling deeper interrogation of the isolated molecules by another round of DNA sequencing. We applied the method in cell-centric and gene-centric modes to isolate cDNA fragments from scRNA-seq libraries. First, we resampled the transcriptomes of rare, single megakaryocytes from a complex mixture of lymphocytes and analyzed them in a second round of DNA sequencing, yielding up to 20-fold greater sequencing depth per cell and increasing the number of genes detected per cell from a median of 1313 to 2002. We similarly isolated mRNAs from targeted T cells to improve the reconstruction of their VDJ-rearranged immune receptor mRNAs. Second, we isolated CD3D mRNA fragments expressed across cells in a scRNA-seq library prepared from a clonal T cell line, increasing the number of cells with detected CD3D expression from 59.7% to 100%. Transcriptome resampling is a general approach to recover targeted gene expression information from single-cell RNA sequencing libraries that enhances the utility of these costly experiments, and may be applicable to the targeted recovery of molecules from other single-cell assays.


Agreement between Direct Fluorescent Microscopy and Ziehl-Neelsen Concentration Techniques in Detection of Pulmonary Tuberculosis in Northwest Ethiopia.
The sensitivity of smear microscopy for diagnosis of tuberculosis might be improved through treatment of sputum with sodium hypochlorite and application of fluorescent microscopy. This study aimed to determine the agreement between direct Fluorescent Microscopy and Ziehl-Neelsen concentration technique by their ability of detecting acid fast bacilli in resource poor settings. A cross sectional study was conducted at Gondar University Referral Hospital, Northwest Ethiopia. Three sputum specimens were collected from consecutive TB suspects. Direct and concentrated sputum smears were air-dried, heat-fixed and stained by auramine O and Ziehl-Neelsen staining techniques respectively. The stained slides were examined for acid fast bacilli using direct Fluorescent Microscopy and Ziehl-Neelsen concentration techniques. Of 293 specimens, 4.4% and 2.4 % were AFB positive by direct fluorescent microscopy and Ziehl-Neelsen bleach concentrated techniques respectively. There was high percentage of tuberculosis positivity from early morning sputum samples (2.4%) compared to first spot (1.4%) and second spot (1.7%) sputum samples when using Ziehl-Neelsen sodium hypochlorite concentration technique. A moderate agreement was seen between the two methods (Kappa=0.484, P value<0.001). Direct fluorescent microscopy has shown high positivity rate compared to Ziehl-Neelsen concentration technique. A moderate agreement was seen between the two methods. Thus, Ziehl-Neelsen bleach sedimentation technique is recommended for detection of pulmonary tuberculosis at peripheral health service level when Fluorescent Microscopy is not available.


Prevalence and causes of vision loss in sub-Saharan Africa: 1990-2010.
To estimate the magnitude, temporal trends and subregional variation in the prevalence of blindness, and moderate/severe vision impairment (MSVI) in sub-Saharan Africa. A systematic review was conducted of published and unpublished population-based surveys as part of the Global Burden of Disease, Risk Factors and Injuries Study 2010. The prevalence of blindness and vision impairment by country and subregion was estimated. In sub-Saharan Africa, 52 studies satisfied the inclusion criteria. The estimated age-standardised prevalence of blindness decreased by 32% from 1.9% (95% CI 1.5% to 2.2%) in 1990 to 1.3% (95% CI 1.1% to 1.5%) in 2010 and MSVI by 25% from 5.3% (95% CI 0.2% to 0.3%) to 4.0% (95% CI 0.2% to 0.3%) over that time. However, there was a 16% increase in the absolute numbers with blindness and a 28% increase in those with MSVI. The major causes of blindness in 2010 were; cataract 35%, other/unidentified causes 33.1%, refractive error 13.2%, macular degeneration 6.3%, trachoma 5.2%, glaucoma 4.4% and diabetic retinopathy 2.8%. In 2010, age-standardised prevalence of MSVI in Africa was 3.8% (95% CI 3.1% to 4.7%) for men and 4.2% (95% CI 3.6% to 5.3%) for women with subregional variations from 4.1% (95% CI 3.3% to 5.4%) in West Africa to 2.0% (95% CI 1.5% to 3.3%) in southern Africa for men; and 4.7% (95% CI 3.9% to 6.0%) in West Africa to 2.3% (95% CI 1.7% to 3.8%) in southern Africa for women. The age-standardised prevalence of blindness and MSVI decreased substantially from 1990 to 2010, although there was a moderate increase in the absolute numbers with blindness or MSVI. Significant subregional and gender disparities exist.


Heightened interferon-gamma production by mononuclear cells from bladder cancer patients.
Interferon-gamma (IFN-gamma) production by peripheral blood leukocytes from bladder cancer patients was compared with that of patients with prostate cancer and benign prostatic hyperplasia, nontumor-bearing patients with bacterial infections, and normal controls. Leukocyte preparations including mononuclear cells isolated on a Ficoll-Hypaque density gradient (Fraction 2) and glass-nonadherent mononuclear cells (Fraction 3) were stimulated with Protein A from Staphylococcus aureus, and IFN-gamma production was monitored 24 hr later. The class of interferon produced was identified by antibody neutralization experiments which clearly showed S. aureus Protein A-induced interferon to be IFN-gamma. There was significantly heightened IFN-gamma production by Fraction 3 cells from bladder cancer patients and patients with bacterial infections. Heightened IFN-gamma production by bladder cancer patients was not observed in the Fraction 2 cells. No correlation was observed between IFN-gamma production and patients with invasive or noninvasive bladder cancer, but IFN-gamma production was lower in patients having Stage C or D tumors than in those having Stage A or B tumors. These results in conjunction with previous reports demonstrating heightened IFN-gamma production during periods of antigenic stimulation suggest that bladder tumors may induce a cell-mediated immune response in the host as evidenced by the elevation in IFN-gamma production. Moreover, the results suggest that macrophages may be important regulators of IFN-gamma production in bladder cancer patients.


All-fiber-integrated soliton-similariton laser with in-line fiber filter.
We demonstrate an all-fiber-integrated Er-doped fiber laser operating in the soliton-similariton mode-locking regime. In the similariton part of the cavity, a self-similarly evolving parabolic pulse with highly linear chirp propagates in the presence of normal dispersion. Following an in-line fiber-based birefringent filter, the pulse evolves into a soliton in the part of the cavity with anomalous dispersion. The similariton and the soliton pulses are dechirped to 75.5 and 167.2 fs, respectively, outside of the cavity. Mode-locked operation is very robust, owing to the influence of the two similariton and soliton attractors that predominate each half of the laser cavity. The experimental results are supported with numerical simulations, which provide good agreement.


[Enhancement by blood transfusions of transplanted tumor growth in mice].
It has been demonstrated that the renal graft survival was prolonged after blood transfusion. The immunological action of blood transfusion in the host is not clear yet. The effect of blood transfusion on transplanted tumor growth in mice was examined. Using C3H/He (H-2k), AKR (H-2k), C57BL/6 (H-2b), and (C57BL/6xDBA/2)F1 (H-2b,d)mice, mutually different transfusion combinations were prepared. MH134 cells (hepatoma) originated from C3H/He mice or Lewis lung carcinoma cells originated from C57BL/6 mice were grafted beneath the back skin of mice on the second week after transfusion, and size of the tumor was measured. The results showed that 1) blood transfusion among mice with the same H-2 systems had no enhancing effect on grafted tumor growth, 2) blood transfusion among mice with different H-2 systems markedly enhanced the tumor growth, although different in degrees, 3) In the experiments of component transfusions, transfusion of lymphoid cells also enhanced the tumor growth, but not erythrocytes. The results of these experiments clearly showed the differential effects of allogeneic or syngeneic blood transfusion on transplanted tumor growth in mice.


Upper limb vibration prototype with sports and rehabilitation applications: development, evaluation and preliminary study.
Vibration stimulation as an exercise intervention has been studied increasingly for its potential benefits and applications in sports and rehabilitation. Vibratory exercise devices should be capable of generating highly precise and repeatable vibrations and should be capable of generating a range of vibration amplitudes and frequencies in order to provide different training protocols. Many devices used to exercise the upper body provide limited variations to exercise regimes mostly due to the fact that only vibration frequency can be controlled. The authors present an upper limb vibration exercise device with a novel actuator system and design which attempts to address these limitations. Preliminary results show that this device is capable of generating highly precise and repeatable vibrations with independent control over amplitude and frequency. Furthermore, the results also show that this solution provides a higher neuromuscular stimulation (i.e. electromyography activity) when compared with a control condition. The portability of this device is an advantage, and though in its current configuration it may not be suitable for applications requiring higher amplitude levels the technology is scalable.


Referral patterns, treatment choices, and outcomes in locoregional esophageal cancer: a population-based analysis of elderly patients.
PURPOSE To determine the impact of demographics and comorbidity on access to specialists' services, treatment, and outcome for patients with locoregional esophageal cancer. PATIENTS AND METHODS We performed a retrospective cohort study of 3,538 patients older than age 65 years who were diagnosed with locoregional esophageal cancer between 1991 and 1999 in one of 11 regions monitored by the Surveillance, Epidemiology, and End Results tumor program. We examined linked Medicare claims for assessment by a surgeon, radiation oncologist, or medical oncologist and subsequent treatment with surgery, radiation, or chemotherapy. Logistic regression analyses were performed for seeing a specialist and for undergoing treatment according to age, sex, race, socioeconomic status, geographic region, and presence of comorbidities. Cox proportional hazards analyses were performed to estimate hazard ratios (HRs) for survival with and without adjustment for treatment received. Results Seeing a cancer specialist depended especially on age and region of diagnosis. These same factors were also related to subsequent treatment decisions, but associations were reversed in some regions, such that treatment depended less on region. Older patients had poorer survival (HR = 2.0 for 85+ v 65 to 69 years), which was partly explained by treatment received (HR decreased to 1.5 when adjusted for treatment). CONCLUSION Older patients have less intensive treatment of esophageal cancer, which is explained by both a lower rate of seeing a cancer specialist and by less intensive treatment once seen. Referring physicians and treating specialists must ensure that elderly patients are not deprived of the opportunity to consider all of their treatment options.


Steady-spectrum contexts and perceptual compensation for reverberation in speech identification.
Perceptual compensation for reverberation was measured by embedding test words in contexts that were either spoken phrases or processed versions of this speech. The processing gave steady-spectrum contexts with no changes in the shape of the short-term spectral envelope over time, but with fluctuations in the temporal envelope. Test words were from a continuum between "sir" and "stir." When the amount of reverberation in test words was increased, to a level above the amount in the context, they sounded more like "sir." However, when the amount of reverberation in the context was also increased, to the level present in the test word, there was perceptual compensation in some conditions so that test words sounded more like "stir" again. Experiments here found compensation with speech contexts and with some steady-spectrum contexts, indicating that fluctuations in the context's temporal envelope can be sufficient for compensation. Other results suggest that the effectiveness of speech contexts is partly due to the narrow-band "frequency-channels" of the auditory periphery, where temporal-envelope fluctuations can be more pronounced than they are in the sound's broadband temporal envelope. Further results indicate that for compensation to influence speech, the context needs to be in a broad range of frequency channels.


A novel molecular modelling study of inhibitors of the 17alpha-hydroxylase component of the enzyme system 17alpha-hydroxylase/17,20-lyase (P-450(17alpha)).
The enzyme 17alpha-hydroxylase/17,20-lyase (P-450(17alpha) has recently become the focus of research into the fight against hormone dependent prostate cancer. However, the specific nature of this enzyme, in particular, the dual role of its active site, remains unknown. In our drive to elucidate further information regarding P-450(17alpha), and in light of our experience of other cytochrome P-450 enzymes, we chose to consider each part of this complex enzyme separately (i.e. the 17alpha-hydroxylase (17alpha-OHase) and the 17,20-lyase components). We therefore initiated a series of molecular modelling studies involving the construction of a 'substrate heme complex' for each of the two components. Here, we consider the construction and use of the complex for the 17alpha-OHase component of this enzyme. Using this approach, we have successfully considered: the binding of steroidal and non-steroidal reversible inhibitors: the structural features necessary for potent inhibition: and, rationalised the mode of action of a number of compounds whose inhibitory activity has not been previously explained, for example aminoglutethimide (an inhibitor of another related cytochrome P-450 enzyme, aromatase AR). The study concludes that the ability of the inhibitors of 17alpha-OHase to undergo polar polar interaction with the active site and for the compounds to closely mimic the substrate plane is a major factor in determining potency. Factors such as log P (log of the partition coefficient value for the distribution of a compound between octanol and water) would then appear to determine the extent of overall inhibitory activity. Overall, the study suggests that the novel substrate-heme complex approach has provided a good approximation of the 17alpha-OHase active site and has proved to be a useful tool in drug design and discovery.


Weed or wheel! FMRI, behavioural, and toxicological investigations of how cannabis smoking affects skills necessary for driving.
Marijuana is the most widely used illicit drug, however its effects on cognitive functions underlying safe driving remain mostly unexplored. Our goal was to evaluate the impact of cannabis on the driving ability of occasional smokers, by investigating changes in the brain network involved in a tracking task. The subject characteristics, the percentage of Δ(9)-Tetrahydrocannabinol in the joint, and the inhaled dose were in accordance with real-life conditions. Thirty-one male volunteers were enrolled in this study that includes clinical and toxicological aspects together with functional magnetic resonance imaging of the brain and measurements of psychomotor skills. The fMRI paradigm was based on a visuo-motor tracking task, alternating active tracking blocks with passive tracking viewing and rest condition. We show that cannabis smoking, even at low Δ(9)-Tetrahydrocannabinol blood concentrations, decreases psychomotor skills and alters the activity of the brain networks involved in cognition. The relative decrease of Blood Oxygen Level Dependent response (BOLD) after cannabis smoking in the anterior insula, dorsomedial thalamus, and striatum compared to placebo smoking suggests an alteration of the network involved in saliency detection. In addition, the decrease of BOLD response in the right superior parietal cortex and in the dorsolateral prefrontal cortex indicates the involvement of the Control Executive network known to operate once the saliencies are identified. Furthermore, cannabis increases activity in the rostral anterior cingulate cortex and ventromedial prefrontal cortices, suggesting an increase in self-oriented mental activity. Subjects are more attracted by intrapersonal stimuli ("self") and fail to attend to task performance, leading to an insufficient allocation of task-oriented resources and to sub-optimal performance. These effects correlate with the subjective feeling of confusion rather than with the blood level of Δ(9)-Tetrahydrocannabinol. These findings bolster the zero-tolerance policy adopted in several countries that prohibits the presence of any amount of drugs in blood while driving.


Phylogenetic reconstruction from transpositions.
Because of the advent of high-throughput sequencing and the consequent reduction in the cost of sequencing, many organisms have been completely sequenced and most of their genes identified. It thus has become possible to represent whole genomes as ordered lists of gene identifiers and to study the rearrangement of these entities through computational means. As a result, genome rearrangement data has attracted increasing attentions from both biologists and computer scientists as a new type of data for phylogenetic analysis. The main events of genome rearrangements include inversions, transpositions and transversions. To date, GRAPPA and MGR are the most accurate methods for rearrangement phylogeny, both assuming inversion as the only event. However, due to the complexity of computing transposition distance, it is very difficult to analyze datasets when transpositions are dominant. We extend GRAPPA to handle transpositions. The new method is named GRAPPA-TP, with two major extensions: a heuristic method to estimate transposition distance, and a new transposition median solver for three genomes. Although GRAPPA-TP uses a greedy approach to compute the transposition distance, it is very accurate when genomes are relatively close. The new GRAPPA-TP is available from http://phylo.cse.sc.edu/. Our extensive testing using simulated datasets shows that GRAPPA-TP is very accurate in terms of ancestor genome inference and phylogenetic reconstruction. Simulation results also suggest that model match is critical in genome rearrangement analysis: it is not accurate to simulate transpositions with other events including inversions.


Effect of brain acetylcholine depletion on bicuculline-induced cardiovascular and locomotor responses.
Both GABAergic and cholinergic systems are involved in central cardiovascular regulation. Previous studies have shown that GABAA receptor antagonists cause increases in blood pressure, heart rate and locomotor activity. In this study, we examined the role of the depletion of brain acetylcholine on the cardiovascular responses and locomotor activity induced by bicuculline methiodide in conscious Sprague-Dawley rats. The doses of 0.3 and 0.5 nmol of intracerebroventricular bicuculline methiodide produced increases in blood pressure, heart rate and locomotor activity. The dose of 18 nmol of hemicholinium-3 to deplete brain acetylcholine was given intracerebroventricularly one hour prior to bicuculline methiodide. The pressor responses to bicuculline methiodide in animals pretreated with the hemicholinium-3 were higher than those seen in saline-pretreated groups, but locomotor activity and heart rate responses to bicuculline methiodide remained unchanged in hemicholinium-3 pretreatment group. On the other hand, high dose of bicuculline methiodide (0.5 nmol) caused convulsions in some animals pretreated with hemicholinium-3 whereas bicuculline methiodide, alone, did not cause any seizure activity. In conclusion, it seems likely that endogenous brain acetylcholine could be a modulator of GABAA receptor-mediated blood pressure control.


Functional reorganization and stability of somatosensory-motor cortical topography in a tetraplegic subject with late recovery.
The functional organization of somatosensory and motor cortex was investigated in an individual with a high cervical spinal cord injury, a 5-year absence of nearly all sensorymotor function at and below the shoulders, and rare recovery of some function in years 6-8 after intense and sustained rehabilitation therapies. We used functional magnetic resonance imaging to study brain activity to vibratory stimulation and voluntary movements of body parts above and below the lesion. No response to vibratory stimulation of the hand was observed in the primary somatosensory cortex (SI) hand area, which was conversely recruited during tongue movements that normally evoke responses only in the more lateral face area. This result suggests SI reorganization analogous to previously reported neuroplasticity changes after peripheral lesions in animals and humans. In striking contradistinction, vibratory stimulation of the foot evoked topographically appropriate responses in SI and second somatosensory cortex (SII). Motor cortex responses, tied to a visuomotor tracking task, displayed a near-typical topography, although they were more widespread in premotor regions. These findings suggest possible preservation of motor and some somatosensory cortical representations in the absence of overt movements or conscious sensations for several years after spinal cord injury and have implications for future rehabilitation and neural-repair therapies.


Effects of aspirin on vitreous/preretinal hemorrhage in patients with diabetes mellitus. Early Treatment Diabetic Retinopathy Study report no. 20.
To assess whether the use of aspirin exacerbates the severity or duration of vitreous/preretinal hemorrhages in patients with diabetic retinopathy. The Early Treatment Diabetic Retinopathy Study (ETDRS), a multicenter randomized clinical trial, was designed to assess the effect of photocoagulation and aspirin on 3711 patients with mild to severe nonproliferative or early proliferative diabetic retinopathy. Patients were randomly assigned to either an aspirin (650 mg/d) or a placebo group. One eye of each patient was randomly assigned to early photocoagulation and the other to deferral of photocoagulation. The severity and duration of the vitreous/preretinal hemorrhages were determined from gradings of the annual, seven standard stereoscopic field, fundus photographs. Clinical examinations scheduled every 4 months also provided information on the presence and duration of hemorrhages. Annual fundus photographs of eyes assigned to deferral of photocoagulation revealed vitreous/preretinal hemorrhages at some time during follow-up in 564 patients (30%) assigned to the placebo group and 585 patients (32%) assigned to the aspirin group (P = .48). Based on gradings of fundus photographs, there were no statistical differences in the severity of vitreous/preretinal hemorrhages (P = .11) or their rate of resolution (P = .86) between the groups. Clinical examination of eyes assigned to deferral of photocoagulation revealed 721 eyes (39%) assigned to the aspirin group and 689 (37%) assigned to the placebo group that had vitreous/preretinal hemorrhages during the course of the study (P = .30). Again, no statistically significant difference was found between the rates of resolution, as assessed clinically, between the two treatment groups (P = .43). As previously reported, the use of aspirin did not increase the occurrence of vitreous/preretinal hemorrhages in patients enrolled in the ETDRS. The data presented in this report demonstrate that the severity and duration of these hemorrhages were not significantly affected by the use of aspirin and that there were no ocular contraindications to its use (650 mg/d) in persons with diabetes who require it for treatment of cardiovascular disease or for other medical indications.


Classification of intestinal T-cell receptor repertoires using machine learning methods can identify patients with coeliac disease regardless of dietary gluten status.
In coeliac disease (CeD), immune-mediated small intestinal damage is precipitated by gluten, leading to variable symptoms and complications, occasionally including aggressive T-cell lymphoma. Diagnosis, based primarily on histopathological examination of duodenal biopsies, is confounded by poor concordance between pathologists and minimal histological abnormality if insufficient gluten is consumed. CeD pathogenesis involves both CD4+ T-cell-mediated gluten recognition and CD8+ and γδ T-cell-mediated inflammation, with a previous study demonstrating a permanent change in γδ T-cell populations in CeD. We leveraged this understanding and explored the diagnostic utility of bulk T-cell receptor (TCR) sequencing in assessing duodenal biopsies in CeD. Genomic DNA extracted from duodenal biopsies underwent sequencing for TCR-δ (TRD) (CeD, n = 11; non-CeD, n = 11) and TCR-γ (TRG) (CeD, n = 33; non-CeD, n = 21). We developed a novel machine learning-based analysis of the TCR repertoire, clustering samples by diagnosis. Leave-one-out cross-validation (LOOCV) was performed to validate the classification algorithm. Using TRD repertoire, 100% (22/22) of duodenal biopsies were correctly classified, with a LOOCV accuracy of 91%. Using TCR-γ (TRG) repertoire, 94.4% (51/54) of duodenal biopsies were correctly classified, with LOOCV of 87%. Duodenal biopsy TRG repertoire analysis permitted accurate classification of biopsies from patients with CeD following a strict gluten-free diet for at least 6 months, who would be misclassified by current tests. This result reflects permanent changes to the duodenal γδ TCR repertoire in CeD, even in the absence of gluten consumption. Our method could complement or replace histopathological diagnosis in CeD and might have particular clinical utility in the diagnostic testing of patients unable to tolerate dietary gluten, and for assessing duodenal biopsies with equivocal features. This approach is generalisable to any TCR/BCR locus and any sequencing platform, with potential to predict diagnosis or prognosis in conditions mediated or modulated by the adaptive immune response. © 2020 The Authors. The Journal of Pathology published by John Wiley & Sons, Ltd. on behalf of The Pathological Society of Great Britain and Ireland.


Reading ability is negatively related to Stroop interference.
Stroop interference is often taken as evidence for reading automaticity even though young and poor readers, who presumably lack reading automaticity, present strong interference. Here the relationship between reading skills and Stroop interference was studied in a 7th-grade sample. Greater interference was observed in children diagnosed with reading disability (dyslexia) than in unimpaired children. Moreover, poorer reading skills were found to correlate with greater Stroop interference in the general school population. In correlation and regression analyses, interference was primarily associated with reading speed, with an additional unique contribution of reading accuracy. Color naming errors were few and not comparably related to reading skills. The relation of reading skill to Stroop interference was examined in computational modeling simulations. The production model of Roelofs [Roelofs, A. (2003). Goal-referenced selection of verbal action: modeling attentional control in the Stroop task. Psychological Review, 110, 88-125], in which interference is primarily due to word stimuli having direct access to word form encoding whereas color naming must pass through concept activation and lemma selection, was found to account well for the human data after imposing covariation constraints on parameters controlling word processing and blocking latency, in modifications not affecting the model's previous fit to other data. The connectionist model of Cohen, Dunbar, and McClelland [Cohen, J. D., Dunbar, K., & McClelland, J. L. (1990). On the control of automatic processes: a parallel distributed processing account of the Stroop effect. Psychological Review, 97, 332-361], in which interference is caused by differential route strength, implementing an automaticity account, approximated the observed patterns with network-wide parameter manipulations not specific to reading, such as processing speed and response threshold, likely to affect previously optimized performance. On the basis of the empirical and modeling data we argue for a direct link between reading skill and interference, beyond the effects of executive functioning.


A prospective study of the associations among housing status and costs of services in a homeless population.
The complex needs of homeless populations result in use of a wide range of services and high costs for housing programs and psychiatric and general medical care. Allocation of resources often is not congruent with assessed needs. A series of cost-congruence hypotheses was developed to test assumptions that needs are associated with resources provided for appropriate services in homeless populations. Individuals (N=255) who were homeless were followed for two years and were categorized by housing status over time (consistently housed, housed late, lost housing, or consistently homeless). Detailed information about the individuals was obtained at baseline, and follow-up data were collected one and two years later. Extensive data about the costs of services provided by type (medical, psychiatric, substance abuse, and homeless maintenance and amelioration) were derived from 23 agencies, and service use information was collected from the agencies and by self-report. Multiple regression models were used to test the hypotheses. Medical, psychiatric, and homeless maintenance costs varied by housing status. Serious mental illness predicted costs for psychiatric services, as expected, but also costs for substance abuse services and acute behavioral health care and total costs. Alcohol use disorders predicted substance abuse service costs. This study followed a homeless cohort prospectively and provided estimates of costs of service use derived from a large number of agencies. This research increases the understanding of patterns of service use in a homeless population and informs the provision of services appropriate to the complex needs of this difficult-to-serve population.


Autophagy in Adipocyte Browning: Emerging Drug Target for Intervention in Obesity.
Autophagy, lipophagy, and mitophagy are considered to be the major recycling processes for protein aggregates, excess fat, and damaged mitochondria in adipose tissues in response to nutrient status-associated stress, oxidative stress, and genotoxic stress in the human body. Obesity with increased body weight is often associated with white adipose tissue (WAT) hypertrophy and hyperplasia and/or beige/brown adipose tissue atrophy and aplasia, which significantly contribute to the imbalance in lipid metabolism, adipocytokine secretion, free fatty acid release, and mitochondria function. In recent studies, hyperactive autophagy in WAT was observed in obese and diabetic patients, and inhibition of adipose autophagy through targeted deletion of autophagy genes in mice improved anti-obesity phenotypes. In addition, active mitochondria clearance through activation of autophagy was required for beige/brown fat whitening - that is, conversion to white fat. However, inhibition of autophagy seemed detrimental in hypermetabolic conditions such as hepatic steatosis, atherosclerosis, thermal injury, sepsis, and cachexia through an increase in free fatty acid and glycerol release from WAT. The emerging concept of white fat browning-conversion to beige/brown fat-has been controversial in its anti-obesity effect through facilitation of weight loss and improving metabolic health. Thus, proper regulation of autophagy activity fit to an individual metabolic profile is necessary to ensure balance in adipose tissue metabolism and function, and to further prevent metabolic disorders such as obesity and diabetes. In this review, we summarize the effect of autophagy in adipose tissue browning in the context of obesity prevention and its potential as a promising target for the development of anti-obesity drugs.


Antiangogenic effect of selected phytochemicals.
Angiogenesis, the formation of new blood vessels from a preexisting vascular network is considered a key step in tumour growth, invasion, and metastasis. Recent studies show that several natural compounds inhibit angiogenesis and nowadays numerous bioactive plant compounds are tested for their antiangiogenic potential. This review examines current knowledge regarding the antiangiogenic potential of several phytochemicals, including polyphenols resveratrol and curcumin as well as miscellaneous compounds from garlic, Hypericum perforatum, Panax ginseng, Coptis chinensis and Rheum palmatum.