Arrayed identification of DNA signatures.
Over the last few years, several initiatives have described efforts to combine previously invented techniques in molecular biology with parallel detection principles to sequence or genotype DNA signatures. The Infinium system from Illumina and the Affymetrix GeneChips are two systems suitable for whole-genome scoring of variable positions. However, directed candidate-gene approaches are more cost effective and several academic groups and the private sector provide techniques with moderate typing throughput combined with large sample capacity suiting these needs. Recently, whole-genome sequencing platforms based on the sequencing-by-synthesis principle were presented by 454 Life Sciences and Solexa, showing great potential as alternatives to conventional genotyping approaches. In addition to these sequencing initiatives, many efforts are pursuing novel ideas to facilitate fast and cost-effective whole genome sequencing, such as ligation-based sequencing. Reliable methods for routine re-sequencing of human genomes as a tool for personalized medicine, however, remain to be developed.


Glia maturation factor gamma regulates the migration and adherence of human T lymphocytes.
Lymphocyte migration and chemotaxis are essential for effective immune surveillance. A critical aspect of migration is cell polarization and the extension of pseudopodia in the direction of movement. However, our knowledge of the underlying molecular mechanisms responsible for these events is incomplete. Proteomic analysis of the isolated leading edges of CXCL12 stimulated human T cell lines was used to identify glia maturation factor gamma (GMFG) as a component of the pseudopodia. This protein is predominantly expressed in hematopoietic cells and it has been shown to regulate cytoskeletal branching. The present studies were undertaken to examine the role of GMFG in lymphocyte migration. Microscopic analysis of migrating T-cells demonstrated that GMFG was distributed along the axis of movement with enrichment in the leading edge and behind the nucleus of these cells. Inhibition of GMFG expression in T cell lines and IL-2 dependent human peripheral blood T cells with shRNAmir reduced cellular basal and chemokine induced migration responses. The failure of the cells with reduced GMFG to migrate was associated with an apparent inability to detach from the substrates that they were moving on. It was also noted that these cells had an increased adherence to extracellular matrix proteins such as fibronectin. These changes in adherence were associated with altered patterns of β1 integrin expression and increased levels of activated integrins as detected with the activation specific antibody HUTS4. GMFG loss was also shown to increase the expression of the β2 integrin LFA-1 and to increase the adhesion of these cells to ICAM-1. The present studies demonstrate that GMFG is a component of human T cell pseudopodia required for migration. The reduction in migration and increased adherence properties associated with inhibition of GMFG expression suggest that GMFG activity influences the regulation of integrin mediated adhesion.


Biological and clinical insights from genetics of insomnia symptoms.
Insomnia is a common disorder linked with adverse long-term medical and psychiatric outcomes. The underlying pathophysiological processes and causal relationships of insomnia with disease are poorly understood. Here we identified 57 loci for self-reported insomnia symptoms in the UK Biobank (n = 453,379) and confirmed their effects on self-reported insomnia symptoms in the HUNT Study (n = 14,923 cases and 47,610 controls), physician-diagnosed insomnia in the Partners Biobank (n = 2,217 cases and 14,240 controls), and accelerometer-derived measures of sleep efficiency and sleep duration in the UK Biobank (n = 83,726). Our results suggest enrichment of genes involved in ubiquitin-mediated proteolysis and of genes expressed in multiple brain regions, skeletal muscle, and adrenal glands. Evidence of shared genetic factors was found between frequent insomnia symptoms and restless legs syndrome, aging, and cardiometabolic, behavioral, psychiatric, and reproductive traits. Evidence was found for a possible causal link between insomnia symptoms and coronary artery disease, depressive symptoms, and subjective well-being.


Requirements of first-principles calculations of X-ray absorption spectra of liquid water.
A computational benchmark study on X-ray absorption spectra of water has been performed by means of transition-potential density functional theory (TP-DFT), damped time-dependent density functional theory (TDDFT), and damped coupled cluster (CC) linear response theory. For liquid water, using TDDFT with a tailored CAM-B3LYP functional and a polarizable embedding, we find that an embedding with over 2000 water molecules is required to fully converge spectral features for individual molecules, but a substantially smaller embedding can be used within averaging schemes. TP-DFT and TDDFT calculations on 100 MD structures demonstrate that TDDFT produces a spectrum with spectral features in good agreement with experiment, while it is more difficult to fully resolve the spectral features in the TP-DFT spectrum. Similar trends were also observed for calculations of bulk ice. In order to further establish the performance of these methods, small water clusters have been considered also at the CC2 and CCSD levels of theory. Issues regarding the basis set requirements for spectrum simulations of liquid water and the determination of gas-phase ionization potentials are also discussed.


Supplementing claims data with outpatient laboratory test results to improve confounding adjustment in effectiveness studies of lipid-lowering treatments.
Adjusting for laboratory test results may result in better confounding control when added to administrative claims data in the study of treatment effects. However, missing values can arise through several mechanisms. We studied the relationship between availability of outpatient lab test results, lab values, and patient and system characteristics in a large healthcare database using LDL, HDL, and HbA1c in a cohort of initiators of statins or Vytorin (ezetimibe & simvastatin) as examples. Among 703,484 patients 68% had at least one lab test performed in the 6 months before treatment. Performing an LDL test was negatively associated with several patient characteristics, including recent hospitalization (OR = 0.32, 95% CI: 0.29-0.34), MI (OR = 0.77, 95% CI: 0.69-0.85), or carotid revascularization (OR = 0.37, 95% CI: 0.25-0.53). Patient demographics, diagnoses, and procedures predicted well who would have a lab test performed (AUC = 0.89 to 0.93). Among those with test results available claims data explained only 14% of variation. In a claims database linked with outpatient lab test results, we found that lab tests are performed selectively corresponding to current treatment guidelines. Poor ability to predict lab values and the high proportion of missingness reduces the added value of lab tests for effectiveness research in this setting.


Communication: Polarization-angle-scanning two-dimensional infrared spectroscopy of antiparallel β-sheet polypeptide: additional dimensions in two-dimensional optical spectroscopy.
A theoretical description of polarization-angle-scanning (PAS) two-dimensional infrared (2DIR) spectroscopy, where the incident beam polarization directions are considered to be novel dimensions in coherent two-dimensional (2D) optical spectroscopy, is presented. To shed light on the underlying principles and to illustrate a potential use of this measurement method, we investigate the PAS 2DIR spectroscopy of an alanine-based antiparallel β-sheet, using the relationships between cross-peak amplitudes and incident beam polarization directions and carrying out numerical simulations. The numerically simulated PAS 2DIR spectra of the antiparallel β-sheet show that the magnitude and sign of the cross peak reflecting the correlation between the two characteristic amide I vibrations change for varying beam polarization directions. This suggests that each individual cross peak in a given 2D spectrum can be selectively eliminated with an appropriate beam polarization configuration, which in turn provides information on the transition dipole angle and possibly on the structure of coupled multichromophoric systems. This novel measurement method combining the polarization-angle-scanning technique with 2D vibrational or electronic spectroscopy would be a useful tool for probing structural changes of nonequilibrium molecular systems and to investigate transfers of population and coherence by monitoring the time-dependent changes of angles between transition dipoles.


Functional interaction of the subunit 3 of RNA polymerase II (RPB3) with transcription factor-4 (ATF4).
RPB3 is a core subunit of RNA polymerase II (pol II) that, together with the RPB11 subunit, forms the heterodimer considered as a functional counterpart of the bacterial alpha subunit homodimer involved in promoter recognition. We previously employed the yeast two-hybrid system and identified an interaction between RPB3 and the myogenic transcription factor myogenin, demonstrating an involvement of this subunit in muscle differentiation. In this paper we report the interaction between RPB3 and another known transcription factor, ATF4. We found that the intensity of the interaction between RPB3 and ATF4 is similar to the one between RPB3 and myogenin. This interaction involves an RPB3 specific region not homologous to the prokaryotic alpha subunit. We demonstrated that RBP3 is able to enhance ATF4 transactivation, whereas the region of RPB3 (Sud) that contacts ATF4, when used as a dominant negative, markedly inhibits ATF4 transactivation activity. Interestingly, ATF4 protein level, as reported for its partner RPB3, increases during C2C7 cell line muscle differentiation.


Fukutin-related protein is essential for mouse muscle, brain and eye development and mutation recapitulates the wide clinical spectrums of dystroglycanopathies.
Mutations in fukutin-related protein (FKRP) cause a common subset of muscular dystrophies characterized by aberrant glycosylation of alpha-dystroglycan (α-DG), collectively known as dystroglycanopathies. The clinical variations associated with FKRP mutations range from mild limb-girdle muscular dystrophy type 2I with predominantly muscle phenotypes to severe Walker-Warburg syndrome and muscle-eye-brain disease with striking structural brain and eye defects. In the present study, we have generated animal models and demonstrated that ablation of FKRP functions is embryonic lethal and that the homozygous-null embryos die before reaching E12.5. The homozygous knock-in mouse carrying the missense P448L mutation almost completely lacks functional glycosylation of α-DG in muscles and brain, validating the essential role of FKRP in the functional glycosylation of α-DG. However, the knock-in mouse survives and develops a wide range of structural abnormalities in the central nervous system, characteristics of neuronal migration defects. The brain and eye defects are highly reminiscent of the phenotypes seen in severe dystroglycanopathy patients. In addition, skeletal muscles develop progressive muscular dystrophy. Our results confirm that post-translational modifications of α-DG are essential for normal development of the brain and eyes. In addition, both the mutation itself and the levels of FKRP expression are equally critical for the survival of the animals. The exceptionally wide clinical spectrums recapitulated in the P448L mice also suggest the involvement of other factors in the disease progression. The mutant mouse represents a valuable model to further elucidate the functions of FKRP and develop therapies for FKRP-related muscular dystrophies.


Opportunities and challenges in energy and electron transfer of nanocluster based hybrid materials and their sensing applications.
This feature article highlights the recent advances of luminescent metal nanoclusters (MNCs) for their potential applications in healthcare and energy-related materials because of their high photosensitivity, thermal stability, low toxicity, and biocompatibility. Current studies reveal that metal cluster based hybrid systems could pave the way for energy harvesting and sensing applications. To begin with, we illustrate general synthesis methodologies for atomically precise metal nanoclusters and discuss the origin of photoluminescence properties and the electronic transitions of nanoclusters. Successively, we discuss the energy transfer and electron transfer processes in metal cluster based hybrid systems with CdTe QDs, carbon dots (C-dots), functionalized DNA and graphene oxide. Finally, we address the potential advantages of metal clusters and their hybrid systems as an optical probe for the selective detection of toxic metal ions. A tentative outlook on fundamental challenges and future opportunities of this research field is highlighted.


Universal helimagnon and skyrmion excitations in metallic, semiconducting and insulating chiral magnets.
Nearly seven decades of research on microwave excitations of magnetic materials have led to a wide range of applications in electronics. The recent discovery of topological spin solitons in chiral magnets, so-called skyrmions, promises high-frequency devices that exploit the exceptional emergent electrodynamics of these compounds. Therefore, an accurate and unified quantitative account of their resonant response is key. Here, we report all-electrical spectroscopy of the collective spin excitations in the metallic, semiconducting and insulating chiral magnets MnSi, Fe1-xCoxSi and Cu2OSeO3, respectively, using broadband coplanar waveguides. By taking into account dipolar interactions, we achieve a precise quantitative modelling across the entire magnetic phase diagrams using two material-specific parameters that quantify the chiral and the critical field energy. The universal behaviour sets the stage for purpose-designed applications based on the resonant response of chiral magnets with tailored electric conductivity and an unprecedented freedom for an integration with electronics.


Biomarker-related risk for myocardial infarction and serious infections in patients with rheumatoid arthritis: a population-based study.
Rheumatoid arthritis (RA) disease activity and associated systemic inflammation has been associated with serious infection (SIEs), myocardial infarction (MI) and coronary heart disease (CHD) events based on a few registry studies or clinical trials. There are few data from large-scale population-based studies given feasibility challenges in conducting such investigations. Multibiomarker disease activity (MBDA) test scores (n=77 641) were linked to Medicare for US patients with RA. Outcomes of interest were hospitalised pneumonia/sepsis (SIE), MI and a composite CHD outcome. The MBDA score ranges from 1 to 100 and was analysed as time-varying. Cox proportional hazards models evaluated the association between MBDA score and SIEs, MI and CHD events, controlling for potential confounders. A sensitivity analysis excluded C reactive protein (CRP) from the MBDA score. There were 17 433 and 16 796 patients eligible for the SIE and MI/CHD analyses, respectively. Mean (SD) age was 69 (11) years, 79% were women, 81% were white and 38% were disabled. Over 16 424 person-years of follow-up, there were 452 SIE events, 132 MIs and 181 CHD events. Higher MBDA scores were associated with SIEs (HR=1.32, 95% CI 1.23 to 1.41 per 10 unit MBDA score change). For MI/CHD events, a threshold effect was present; higher disease activity by MBDA score was associated with increased MI (HR=1.52, 95% CI 0.92 to 2.49) and CHD rates (HR=1.54, 95% CI 1.01 to 2.34, comparing scores ≥30 vs <30). Analyses of the MBDA score without CRP yielded similar results. Higher MBDA scores were associated with hospitalised infection, MI and CHD events in a large, predominantly older, US RA population.


Predicting Undernutrition at Age 2 Years with Early Attained Weight and Length Compared with Weight and Length Velocity.
To estimate the abilities of weight and length velocities vs attained growth measures to predict stunting, wasting, and underweight at age 2 years. We analyzed data from a community-based cohort study (The Etiology, Risk Factors, and Interactions of Enteric Infections and Malnutrition and the Consequences for Child Health and Development study [MAL-ED] study) in Bhaktapur, Nepal. A total of 240 randomly selected children were enrolled at birth and followed up monthly up to age 24 months. Linear and logistic regression models were used to predict malnutrition at 2 years of age with growth velocity z scores at 0-3, 0-6, 3-6, 6-9, 6-12, and 9-12 months (using the World Health Organization Growth Standards) or attained growth at 0, 3, 6, and 12 months as predictors. At age 2 years, 4% of the children were wasted, 13% underweight, and 21% stunted. Children who were malnourished at age 2 years had lower mean growth z scores already at birth and throughout the study period. Anthropometric indicators in infancy were significant predictors for growth at the age of 2 years during most periods and at most ages in infancy. Weight-for-age z score, length-for-age z score, and weight-for-length z score at age 12 months had excellent areas under the curve (91-95) to predict the value of the same indicator at age 24 months. Maximum area under the curve values for weight and length velocity were somewhat lower (70-84). Growth measured at one time point in infancy was better correlated with undernutrition at age 2 years than growth velocity.


Neoadjuvant bevacizumab and irinotecan versus bevacizumab and temozolomide followed by concomitant chemoradiotherapy in newly diagnosed glioblastoma multiforme: A randomized phase II study.
Surgery followed by radiotherapy and concomitant and adjuvant temozolomide is standard therapy in newly diagnosed glioblastoma multiforme (GBM). Bevacizumab combined with irinotecan produces impressive response rates in recurrent GBM. In a randomized phase II study, we investigated the efficacy of neoadjuvant bevacizumab combined with irinotecan (Bev-Iri) versus bevacizumab combined with temozolomide (Bev-Tem) before, during and after radiotherapy in newly diagnosed GBM. After surgery, patients were randomized to Bev-Iri or Bev-Tem for eight weeks, followed by standard radiotherapy (60 Gy/30 fractions) and concomitant Bev-Iri or Bev-Tem followed by adjuvant Bev-Iri or Bev-Tem for another eight weeks. Bev-Iri: Bevacizumab and irinotecan were given every 14 days before, during and after radiotherapy. Bev-Tem: Bevacizumab was given as in Bev-Iri and temozolomide was given for five days every four weeks before and after radiotherapy and once daily during radiotherapy. The primary endpoint was response after neoadjuvant chemotherapy and a pre-specified response rate of 30% or more was considered of interest for future studies. Secondary endpoints were progression-free survival (PFS) and toxicity. The response rate was 32% (95% CI 17-51%) for Bev-Tem (n = 32) and 23% (95% CI 9-44%) for Bev-Iri (n = 31) (p = 0.56). Median PFS was 7.7 and 7.3 months for Bev-Tem and Bev-Iri, respectively. Hematological toxicity was more frequent with Bev-Tem including one death from febrile neutropenia whereas non-hematological toxicity was manageable. Only the Bev-Tem arm met the pre-specified level of activity of interest. Our results did not indicate any benefit from Bev-Iri in first-line therapy as opposed to Bev-Tem in terms of response and PFS.


Understanding the risks of recent discharge: the phenomenological experiences: trying to survive while living under the proverbial "Sword of Damocles".
Evidence indicates that people whose mental health problems lead them to require psychiatric hospitalization are at a significantly increased risk of suicide, and the period of time immediately following discharge after such hospitalizations appears to be a particularly high-risk time. This paper reports on phenomenological findings from a federally funded, mixed-methods study that sought to better understand the observed increased risk for suicide following discharge from an inpatient psychiatric service. A purposive sample of 20 recently discharged former suicidal inpatients was obtained. Data were collected from the participants in hermeneutic interviews lasting between 1 h and 2 h and analyzed according to van Manen's (1997) interpretation of hermeneutic phenomenology. Two key themes were induced: "Existential Angst at the Prospect of Discharge" and "Trying to Survive While Living Under the Proverbial 'Sword of Damocles'." Each of these was comprised of five themes with the second key theme - the focus of this paper - encompassing the following: "Needing Postdischarge Support," "Feeling Lost, Uncertain and Disorientated," "Feeling Alone and Isolated," "Suicide Remains an Option," and "Engaging in Soothing, Comforting Behaviors." The authors conclude that early exploration of and reconciling patients' expectations regarding inpatient care for their suicidality would appear to be an empirically based intervention that could diminish the postdischarge risk for further suicide attempts.


Social laughter is correlated with an elevated pain threshold.
Although laughter forms an important part of human non-verbal communication, it has received rather less attention than it deserves in both the experimental and the observational literatures. Relaxed social (Duchenne) laughter is associated with feelings of wellbeing and heightened affect, a proximate explanation for which might be the release of endorphins. We tested this hypothesis in a series of six experimental studies in both the laboratory (watching videos) and naturalistic contexts (watching stage performances), using change in pain threshold as an assay for endorphin release. The results show that pain thresholds are significantly higher after laughter than in the control condition. This pain-tolerance effect is due to laughter itself and not simply due to a change in positive affect. We suggest that laughter, through an endorphin-mediated opiate effect, may play a crucial role in social bonding.


Adult-onset leukoencephalopathy, cerebral calcifications, and cysts: An 8-year neuroimaging follow-up of disease progression and histopathological correlation.
Leukoencephalopathy, cerebral calcifications, and cysts (LCC) is an extremely rare neurological disease, also known as Labrune syndrome. The disease more commonly affects children and young adults and the characteristic triple imaging findings are leukoencephalopathy, calcifications and multiple cysts, presenting with a variety of supra- and infratentorial symptoms but lacking for extra-neurological manifestations. Coats plus syndrome and cerebroretinal microangiopathy with calcifications and cysts (CRMCC) share similar neurological findings with LCC, but additionally involves other extra-neurological organs. Tumoral excision is usually required due to mass effect to the eloquent brain of multiple growing cysts or hemorrhages, but the outcome of surgery varies. Here we demonstrate an 8-year neuroimaging study of a rare adult-onset case of LCC with gradual headache, hemiparesis, hand tremors, unstable gait, and seizure attacks despite several times of tumoral excision. Neuroimaging revealed multiple microbleeds and microcalcification in the leukoencephalopathic areas, with increasing calcifications, recurrent previously excised cysts and new cyst formation in the longitudinal neuroimaging follow-ups within the eight years. We believe that LCC involves microangiopathy, which causes blood-brain barrier disruption, myelin serum collection and subsequent growing cysts and dystrophic calcification formation. We provide histopathological correlation in the illustration. Due to the underlying pathomechanism and long-term recurrence nature, patients with a combination of cysts and calcifications on CT scan should be follow up carefully and postoperative recurrence after years may occur.


Predictive role of plasma vascular endothelial growth factor for the effect of celecoxib in advanced non-small cell lung cancer treated with chemotherapy.
The primary purpose of this study is to investigate if pretreatment plasma levels of vascular endothelial growth factor (VEGF) are predictive of the effect of celecoxib on survival in advanced non-small cell lung cancer (NSCLC) treated with palliative chemotherapy. A secondary objective is to describe the course of plasma VEGF levels during and after treatment with cytotoxic chemotherapy combined with celecoxib or placebo. In a previously published double-blind multicenter phase III trial, 316 patients with NSCLC stage IIIB or IV and World Health Organisation (WHO) performance status 0-2 were randomised to receive celecoxib 400mg b.i.d. or placebo in combination with two-drug platinum-based chemotherapy. Chemotherapy cycle length was three weeks and planned duration of chemotherapy was four cycles. Celecoxib was given for a maximum of one year but was stopped earlier in case of disease progression or prohibitive toxicity. In a subset of patients, plasma VEGF levels were examined at onset of treatment and at 6, 12 and 20 weeks. VEGF levels at start of treatment were obtained in 107 patients at four study sites. The median value was 70 pg/ml. Mean values declined during the first 12 weeks and then increased at 20 weeks. A subpopulation treatment effect pattern plot (STEPP) analysis showed an inverse relationship between initial plasma VEGF and the impact of celecoxib on survival with zero effect at 200 pg/ml. The effect on survival by celecoxib in the whole subset of patients was positive (hazard ratio (HR)=0.64 [confidence interval (CI) 0.43-0.95], p=0.028). Low pretreatment plasma levels of VEGF appear to be predictive of a positive effect of celecoxib on survival.


Identification of production challenges and benefits using value chain mapping of egg food systems in Nairobi, Kenya.
Commercial layer and indigenous chicken farming in Nairobi and associated activities in the egg value chains are a source of livelihood for urban families. A value chain mapping framework was used to describe types of inputs and outputs from chicken farms, challenges faced by producers and their disease control strategies. Commercial layer farms were defined as farms keeping exotic breeds of chicken, whereas indigenous chicken farms kept different cross breeds of indigenous chicken. Four focus group discussions were held with producers of these chickens in peri-urban area: Dagoretti, and one informal settlement: Kibera. Qualitative data were collected on interactions between farmers, sources of farm inputs and buyers of poultry products, simple ranking of production challenges, farmers' perception on diseases affecting chicken and strategies for management of sick chicken and waste products. Value chain profiles were drawn showing sources of inputs and channels for distribution of chicken products. Production challenges and chicken disease management strategies were presented as qualitative summaries. Commercial layer farms in Dagoretti kept an average of 250 chickens (range 50-500); while flock sizes in Kibera were 12 chickens (range 5-20). Farms keeping indigenous chicken had an average of 23 chickens (range 8-40) in Dagoretti, and 10 chickens (range 5-16) in Kibera. Commercial layer farms in Dagoretti obtained chicks from distributors of commercial hatcheries, but farms in Kibera obtained chicks from hawkers who in turn sourced them from distributors of commercial hatcheries. Indigenous chicken farms from Dagoretti relied on natural hatching of fertilised eggs, but indigenous chicken farms in Kibera obtained chicks from their social connection with communities living in rural areas. Outlets for eggs from commercial layer farms included local shops, brokers, restaurants and hawkers, while eggs from indigenous chicken farms were sold to neighbours and restaurants. Sieved chicken manure from Dagoretti area was fed to dairy cattle; whereas non-sieved manure was used as fertilizer on crops. Production challenges included poor feed quality, lack of space for expansion, insecurity, occurrence of diseases and lack of sources of information on chicken management. In Kibera, sick and dead chickens were slaughtered and consumed by households; this practice was not reported in Dagoretti. The chicken layer systems contribute to food security of urban households, yet they have vulnerabilities and deficiencies with regard to disease management and food safety that need to be addressed with support on research and extension.


Emergence of MicroRNAs as Key Players in Cancer Cell Metabolism.
Metabolic reprogramming is a hallmark of cancer. MicroRNAs (miRNAs) have been found to regulate cancer metabolism by regulating genes involved in metabolic pathways. Understanding this layer of complexity could lead to the development of novel therapeutic approaches. miRNAs are noncoding RNAs that have been implicated as master regulators of gene expression. Studies have revealed the role of miRNAs in the metabolic reprogramming of tumor cells, with several miRNAs both positively and negatively regulating multiple metabolic genes. The tricarboxylic acid (TCA) cycle, aerobic glycolysis, de novo fatty acid synthesis, and altered autophagy allow tumor cells to survive under adverse conditions. In addition, major signaling molecules, hypoxia-inducible factor, phosphatidylinositol-3 kinase/protein kinase B/mammalian target of rapamycin/phosphatase and tensin homolog, and insulin signaling pathways facilitate metabolic adaptation in tumor cells and are all regulated by miRNAs. Accumulating evidence suggests that miRNA mimics or inhibitors could be used to modulate the activity of miRNAs that drive tumor progression via altering their metabolism. Currently, several clinical trials investigating the role of miRNA-based therapy for cancer have been launched that may lead to novel therapeutic interventions in the future. In this review, we summarize cancer-related metabolic pathways, including glycolysis, TCA cycle, pentose phosphate pathway, fatty acid metabolism, amino acid metabolism, and other metabolism-related oncogenic signaling pathways, and their regulation by miRNAs that are known to lead to tumorigenesis. Further, we discuss the current state of miRNA therapeutics in the clinic and their future potential.


Retrospective analysis of suspected rabies cases reported at bugando referral hospital, mwanza, Tanzania.
The aim of this study was to determine the incidence of humans being bitten by rabies-suspected animals, and the victims' adherence to post-exposure prophylaxis (PEP) regimen. A retrospective analysis of data of victims treated at Bugando Medical Centre during the period 2002-2006 (n=5 years) was done. A total of 767 bite injuries inflicted by rabies-suspected animals were reported, giving a mean annual incidence of ~58 cases per 100,000 (52.5% males, 47.5% females). The proportion of children bitten was relatively higher than that of adults. All victims were treated by using inactivated diploid-cell rabies vaccine and were recommended to appear for the second and third doses. However, only 28% of the victims completed the vaccination regime. Domestic dogs were involved in 95.44% of the human bite cases, whereas cats (3.9%), spotted hyena (Crocuta crocuta) (0.03%), vervet monkey (Cercopithecur aethiops) (0.01%) and black-backed jackal (0.01%) played a minor role. The majority of rabies-suspected case reports were from Nyamagana district and occurred most frequently from June to October each year. In conclusion, this study revealed that incidences of humans being bitten by dogs suspected of rabies are common in Tanzania, involve mostly children, and victims do not comply with the prophylactic regimen. Rigorous surveillance to determine the status of rabies and the risk factors for human rabies, as well as formulation and institution of appropriate rabies-control policies, is required.


Resistance in Maize Inbred Lines to Fusarium verticillioides and Fumonisin Accumulation in South Africa.
Fusarium ear rot of maize, caused by Fusarium verticillioides, is an important disease affecting maize production worldwide. Apart from reducing yield and grain quality, F. verticillioides produces fumonisins which have been associated with mycotoxicoses of animals and humans. Currently, no maize breeding lines are known with resistance to F. verticillioides in South Africa. The objective of this study, therefore, was to evaluate 24 genetically diverse maize inbred lines as potential sources of resistance to Fusarium ear rot and fumonisin accumulation in field trials at Potchefstroom and Vaalharts in South Africa. After artificial silk channel inoculation with F. verticillioides, Fusarium ear rot development was determined at harvest and fumonisins B1, B2, and B3 quantified. A significant inbred line by location effect was observed for Fusarium ear rot severity (P ≤ 0.001), although certain lines proved to be consistently resistant across both locations. The individual inbred lines also differed considerably in fumonisin accumulation between Potchefstroom and Vaalharts, with differentiation between susceptible and potentially resistant inbred lines only being possible at Vaalharts. A greenhouse inoculation trial was then also performed on a subset of potentially resistant and highly susceptible lines. The inbred lines CML 390, CML 444, CML 182, VO 617Y-2, and RO 549 W consistently showed a low Fusarium ear rot (<5%) incidence at both Potchefstroom and Vaalharts and in the greenhouse. Two of these inbred lines, CML 390 and CML 444, accumulated fumonisin levels <5 mg kg-1. These lines could potentially act as sources of resistance for use within a maize breeding program.


The effect of women's status on infant and child mortality in four rural areas of Bangladesh.
In South Asia women are often the primary decision-makers regarding child health care, family health and nutrition. This paper examines the proposition that constraints on women's status adversely affect the survival of their children. Survey data are used to construct indices of women's household autonomy and authority, which are then linked to longitudinal data on survival of their children. Proportional hazard models indicate that enhanced autonomy significantly decreases post-neonatal mortality. Enhanced household authority significantly decreases child mortality. A simulation based on estimated effects of eliminating gender inequality suggests that achieving complete gender equality could reduce child mortality by nearly fifty per cent and post-neonatal mortality by one-third.


Colloid administration normalizes resuscitation ratio and ameliorates "fluid creep".
Although colloid was a component of the original Parkland formula, it has been omitted from standard Parkland resuscitation for over 30 years. However, some burn centers use colloid as "rescue" therapy for patients who exhibit progressively increasing crystalloid requirements, a phenomenon termed "fluid creep." We reviewed our experience with this procedure. With Institutional Review Board approval, we reviewed all adult patients with > or =20%TBSA burns admitted from January 1, 2005, through December 31, 2007, who completed formal resuscitation. Patients were resuscitated using the Parkland formula, adjusted to maintain urine output of 30 to 50 ml/hr. Patients who required greater amounts of fluid than expected were given a combination of 5% albumin and lactated Ringer's until fluid requirements normalized. Results were expressed as an hourly ratio (I/O ratio) of fluid infusion (ml/kg/%TBSA/hr) to urine output (ml/kg/hr). Predicted values for this ratio vary for individual patients but are usually less than 0.5 to 1.0. Fifty-two patients were reviewed, of whom 26 completed resuscitation using crystalloid alone, and the remaining 26 required albumin supplementation (AR). The groups were comparable in age, gender, weight, mortality, and time between injury and admission. AR patients had larger total and full-thickness burns and more inhalation injuries. Patients managed with crystalloid alone maintained mean resuscitation ratios from 0.13 to 0.40, whereas AR patients demonstrated progressively increasing ratios to a maximum mean of 1.97, until albumin was started. Administration of albumin produced a dramatic and precipitous return of ratios to within predicted ranges throughout the remainder of resuscitation. No patient developed abdominal compartment syndrome. Measuring hourly I/O ratios is an effective means of expressing and tracking fluid requirements. The addition of colloid to Parkland resuscitation rapidly reduces hourly fluid requirements, restores normal resuscitation ratios, and ameliorates fluid creep. This practice can be applied selectively as needed using predetermined algorithms.


Enhanced depressor effect of bromocriptine in the DOCA/NaCl hypertensive rat.
To elucidate the role of the dopaminergic system in the maintenance of hypertension in the deoxycorticosterone acetate (DOCA)/NaCl hypertensive rat, the responses of mean arterial pressure (MAP), plasma norepinephrine (NE), epinephrine (E), and prolactin (PRL) to intravenous (iv) administration of bromocriptine, a dopamine agonist, and hexamethonium bromide, a ganglion blocker, were examined in conscious, unrestrained 4-wk DOCA/NaCl hypertensive rats. Bromocriptine was administered to adrenomedullectomized (ADMX) rats to assess the role of the adrenal medulla in its depressor effect. Bromocriptine (50, 250, and 500 micrograms/kg) and hexamethonium (3 and 30 mg/kg) caused dose-dependent decreases in MAP that were greater in DOCA/NaCl rats than in uninephrectomized controls. Basal plasma NE, E, and PRL were significantly higher in DOCA/NaCl rats than in controls. Bromocriptine (500 micrograms/kg iv) decreased plasma PRL to undetectable levels and increased plasma E significantly without changing NE levels in DOCA/NaCl and uninephrectomized control rats. In ADMX rats bromocriptine (500 micrograms/kg iv) decreased MAP, PRL, and NE without affecting E levels. These results suggest that the depressor response to bromocriptine could be related to inhibition of sympathetic outflow without participation of the adrenal medulla. The hyperprolactinemia and enhanced depressor response to bromocriptine observed in DOCA/NaCl animals suggest that the dopaminergic system might be altered in this model of hypertension.


Neutrophil and Macrophage Cell Surface Colony-Stimulating Factor 1 Shed by ADAM17 Drives Mouse Macrophage Proliferation in Acute and Chronic Inflammation.
Macrophages are prominent cells in acute and chronic inflammatory diseases. Recent studies highlight a role for macrophage proliferation post-monocyte recruitment under inflammatory conditions. Using an acute peritonitis model, we identify a significant defect in macrophage proliferation in mice lacking the leukocyte transmembrane protease ADAM17. The defect is associated with decreased levels of macrophage colony-stimulating factor 1 (CSF-1) in the peritoneum and is rescued by intraperitoneal injection of CSF-1. Cell surface CSF-1 (csCSF-1) is one of the substrates of ADAM17. We demonstrate that both infiltrated neutrophils and macrophages are major sources of csCSF-1. Furthermore, acute shedding of csCSF-1 following neutrophil extravasation is associated with elevated expression of iRhom2, a member of the rhomboid-like superfamily, which promotes ADAM17 maturation and trafficking to the neutrophil surface. Accordingly, deletion of hematopoietic iRhom2 is sufficient to prevent csCSF-1 release from neutrophils and macrophages and to prevent macrophage proliferation. In acute inflammation, csCSF-1 release and macrophage proliferation are self-limiting due to transient leukocyte recruitment and temporally restricted csCSF-1 expression. In chronic inflammation, such as atherosclerosis, the ADAM17-mediated lesional macrophage proliferative response is prolonged. Our results demonstrate a novel mechanism whereby ADAM17 promotes macrophage proliferation in states of acute and chronic inflammation.


Chemical attenuation of arsenic by soils across two abandoned mine sites in Korea.
The chemical attenuation of As by soils from abandoned mine sites was evaluated. Several soil samples, including As contaminated soil from the mine impacted areas, as well as As-free soils down-gradient from the mine sites, were collected across abandoned mine sites. Leaching and adsorption experiments were conducted under batch and 1-D water flow conditions. The cumulative As mass from 10 step sequential leaching experiments with six As contaminated soils, using 10 mM CaCl₂ solution, was less than 1% of the total As present in soils, indicating that As in contaminated soils is strongly adsorbed onto soil particles, which can serve as a long term potential As source. As adsorption by As-free soils was clearly nonlinear, with Freundlich N values (sorption nonlinearity) ranging from 0.56 to 0.87. Both the total As content in mine soils and the concentration-specific adsorption coefficient for arsine-free soils were best described by coupling the pH with various forms of Fe/Al oxides. In the breakthrough curves (BTCs) for As contaminated soils, an initial high concentration of As (called first-flush) was observed, and this flush export leveled off after the displacement of a few pore volumes. In the BTCs from layered soils, where clean down-gradient soils were overloaded above the mine soil, the appearance of measurable As was retarded, showing that the As attenuation by soils was effective in a flow water system. Also, the observed perturbation in the concentration of As during flow interruption supports that leaching/attenuation of As via flowing water occurs under nonequilibrium conditions. The results from both batch leaching/adsorption and column displacement experiments strongly suggested that the leaching of As from mine soils was rate limited and the risk of As leaching from soils can be mitigated by attenuation mechanisms, such as adsorption, provided by down-gradient clean soils.


Adverse childhood exposures and alcohol dependence among seven Native American tribes.
Alcohol abuse and alcoholism are leading causes of death among Native Americans. Little is known about the impact of negative childhood exposures, including parental alcoholism, childhood maltreatment, and out-of-home placement, on risk of lifetime DSM-IV (Diagnostic and Statistical Manual of Mental Disorders, 4th edition) diagnosis of alcohol dependence in this population. Face-to-face interviews were conducted with 1660 individuals from seven Native American tribes from 1998 to 2001. Logistic regression was used to estimate the impact of specific types and number of different adverse childhood experiences on alcohol dependence. Relationships between tribe-specific cultural characteristics and alcohol dependence were also examined. There were significant tribal differences in rates of alcohol dependence and several adverse childhood exposures. Lifetime prevalence of alcohol dependence was high among all tribes (men: 21%-56%, women: 17%-30%), but one (men: 1%, women: 2%). High prevalence rates were documented for one or more types of adverse childhood experiences (men: 74%-100%; women: 83%-93%). For men, combined physical and sexual abuse significantly increased the likelihood of subsequent alcohol dependence (odds ratio [OR]=1.58; 95% confidence interval [CI], 1.10-2.27). For women, sexual abuse (OR=1.79; 95% CI, 1.21-2.66) and boarding school attendance increased the odds of alcohol dependence (OR=1.57; 95% CI, 1.03-2.40). Two separate patterns of dose-response relationships were observed for men and women. Significant inter-tribal differences in rates of alcohol dependence remained after accounting for tribe-specific cultural factors and geographic region. Effects of childhood exposures on high-risk behaviors emphasize screening for violence in medical settings and development of social and educational programs for parents and children living on and near tribal reservations.


Interaction between genetic and dietary factors determines beta-cell function in Psammomys obesus, an animal model of type 2 diabetes.
The gerbil Psammomys obesus develops nutrition-dependent diabetes. We studied the interaction between diet and diabetic predisposition for beta-cell function. A 4-day high-energy (HE) diet induced a 3-, 4-, and 1.5-fold increase in serum glucose, insulin, and triglycerides, respectively, in diabetes-prone (DP) but not diabetes-resistant (DR) P. obesus. Hyperglycemia and concurrent 90% depletion of islet immunoreactive insulin stores were partially corrected by an 18-h fast. In vitro early insulin response to glucose was blunted in both DR and DP perifused islets. The HE diet augmented early and late insulin response in DR islets, whereas in DP islets, secretion progressively declined. Dose-response studies showed a species-related increase in islet glucose sensitivity, further augmented in DP P. obesus by a HE diet, concomitant with a decreased threshold for glucose and a 55% reduction in maximal response. These changes were associated with a fourfold increase in glucose phosphorylation capacity in DP islets. There were no differences in islet glucokinase (GK) and hexokinase (HK) Km; however, GK Vmax was 3.7- to 4.6-fold higher in DP islets, and HK Vmax was augmented 3.7-fold by the HE diet in DP islets. We conclude that the insulin-resistant P. obesus has an inherent deficiency in insulin release. In the genetically predisposed P. obesus (DP), augmented islet glucose phosphorylation ability and diet-induced reduction of the glucose threshold for secretion may lead to inadequate insulin secretion and depletion of insulin stores in the presence of caloric abundance. Thus, genetic predisposition and beta-cell maladaptation to nutritional load seem to determine together the progression to overt diabetes in this species. It is hypothesized that similar events may occur in obese type 2 diabetic patients.


Real-time monitoring of protein conformational changes using a nano-mechanical sensor.
Proteins can switch between different conformations in response to stimuli, such as pH or temperature variations, or to the binding of ligands. Such plasticity and its kinetics can have a crucial functional role, and their characterization has taken center stage in protein research. As an example, Topoisomerases are particularly interesting enzymes capable of managing tangled and supercoiled double-stranded DNA, thus facilitating many physiological processes. In this work, we describe the use of a cantilever-based nanomotion sensor to characterize the dynamics of human topoisomerase II (Topo II) enzymes and their response to different kinds of ligands, such as ATP, which enhance the conformational dynamics. The sensitivity and time resolution of this sensor allow determining quantitatively the correlation between the ATP concentration and the rate of Topo II conformational changes. Furthermore, we show how to rationalize the experimental results in a comprehensive model that takes into account both the physics of the cantilever and the dynamics of the ATPase cycle of the enzyme, shedding light on the kinetics of the process. Finally, we study the effect of aclarubicin, an anticancer drug, demonstrating that it affects directly the Topo II molecule inhibiting its conformational changes. These results pave the way to a new way of studying the intrinsic dynamics of proteins and of protein complexes allowing new applications ranging from fundamental proteomics to drug discovery and development and possibly to clinical practice.


Comparing the effects of an acute bout of physical exercise with an acute bout of interactive mental and physical exercise on electrophysiology and executive functioning in younger and older adults.
Physical exercise has been shown to improve cognitive and neural functioning in older adults. The current study compared the effects of an acute bout of physical exercise with a bout of interactive mental and physical exercise (i.e., "exergaming") on executive (Stroop) task performance and event-related potential (ERP) amplitudes in younger and older adults. Results revealed enhanced executive task performance in younger and older adults after exercise, with no differences in performance between exercise conditions. Stroop (RT) performance in older adults improved more than in younger adults from pre- to post-exercise. A significant increase in EEG amplitude from pre- to post-exercise was found at the Cz site from 320 to 700 ms post-stimulus for both younger and older adults, with older adults demonstrating a larger Stroop interference effect. While younger adults exhibited overall greater EEG amplitudes than older adults, they showed no differences between congruent and incongruent trials (i.e., minimal interference). Compared to peers with higher BMI (body mass index), older adults with lower BMI showed a greater reduction in Stroop interference effects from pre- to post-exercise. The beneficial effects of an acute bout of physical exercise on cognitive and neural functioning in younger and older adults were confirmed, with no difference between standard exercise and exergaming. Findings suggest that BMI, sometimes used as a proxy for fitness level, may modulate benefits that older adults derive from an acute bout of exercise. Findings have implications for future research that seeks to investigate unique effects of exergaming when compared to standard physical exercise.


Indocyanine green based fluorescent polymeric nanoprobes for in vitro imaging.
Indocyanine green (ICG) provides an advantage in the imaging of deep tumors as it can reach deeper location without being absorbed in the upper layers of biological tissues in the wavelengths, which named "therapeutic window" in the tissue engineering. Unfortunately, rapid elimination and short-term stability in aqueous media limited its use as a fluorescence probe for the early detection of cancerous tissue. In this study, stabilization of ICG was performed by encapsulating ICG molecules into the biodegradable polymer composited with poly(l-lactic acid) and poly(ε-caprolactone) via a simple one-step multiaxial electrospinning method. Different types of coaxial and triaxial structure groups were performed and compared with single polymer only groups. Confocal microscopy was used to image the encapsulated ICG (1 mg/mL) within electrospun nanofibers and in vitro ICG uptake by MIA PaCa-2 pancreatic cancer cells. Stability of encapsulated ICG is demonstrated by the in vitro sustainable release profile in PBS (pH = 4 and 7) up to 21 days. These results suggest the potential of the ability of internalization and accommodation of ICG into the pancreatic cell cytoplasm from in vitro implanted ICG-encapsulated multiaxial nanofiber mats. ICG-encapsulated multilayer nanofibers may be promising for the local sustained delivery system to eliminate loss of dosage caused by direct injection of ICG-loaded nanoparticles in systemic administration.


Construction of synthetic nucleoli in human cells reveals how a major functional nuclear domain is formed and propagated through cell division.
Human cell nuclei are functionally organized into structurally stable yet dynamic bodies whose cell cycle inheritance is poorly understood. Here, we investigate the biogenesis and propagation of nucleoli, sites of ribosome biogenesis and key regulators of cellular growth. Nucleolar and cell cycles are intimately connected. Nucleoli disappear during mitosis, reforming around prominent uncharacterized chromosomal features, nucleolar organizer regions (NORs). By examining the effects of UBF depletion on both endogenous NORs and synthetic pseudo-NORs, we reveal its essential role in maintaining competency and establishing a bookmark on mitotic NORs. Furthermore, we demonstrate that neo-NORs, UBF-binding site arrays coupled with rDNA transcription units, direct the de novo biogenesis of functional compartmentalized neonucleoli irrespective of their site of chromosomal integration. For the first time, we establish the sequence requirements for nucleolar biogenesis and provide proof that this is a staged process where UBF-dependent mitotic bookmarking precedes function-dependent nucleolar assembly.


Genetic Alterations of Periampullary and Pancreatic Ductal Adenocarcinoma: An Overview.
Pancreatic Ductal AdenoCarcinoma (PDAC) is one of the most lethal malignancies of all solid cancers. Precancerous lesions for PDAC include PanIN, IPMNs and MCNs. PDAC has a poor prognosis with a 5-year survival of approximately 6%. Whereas Periampulary AdenoCarcinoma (PAC) having four anatomic subtypes, pancreatic, Common Bile Duct (CBD), ampullary and duodenum shows relative better prognosis. The highest incidence of PDAC has been reported with black with respect to white population. Similarly, incidence rate of PAC also differs with different ethnic populations. Several lifestyle, environmental and occupational exposures including long-term diabetes, obesity, and smoking, have been linked to PDAC, however, for PAC the causal risk factors were poorly described. It is now clear that PDAC and PAC are a multi-stage process resulting from the accumulation of genomic alterations in the somatic DNA of normal cells as well as inherited mutations. Approximately 10% of PDAC have a familial inheritance. Germline mutations in CDKN2A, BRCA2, STK11, PALB2, PRSS1, etc., as well as certain syndromes have been well associated with predisposition to PDAC. KRAS, CDKN2A, TP53 and SMAD4 are the 4 "mountains" (high-frequency driver genes) which have been known to earliest somatic alterations for PDAC while relatively less frequent in PAC. Our understanding of the molecular carcinogenesis has improved in the last few years due to extensive research on PDAC which was not well explored in case of PAC. The genetic alterations that have been identified in PDAC and different subgroups of PAC are important implications for the development of genetic screening test, early diagnosis, and prognostic genetic markers. The present review will provide a brief overview of the incidence and prevalence of PDAC and PAC, mainly, increased risk in India, the several kinds of risk factors associated with the diseases as well as required genetic alterations for disease initiation and progression.


A randomized trial of a parent-based intervention on drinking behavior among incoming college freshmen.
Despite research suggesting that parental involvement can affect alcohol involvement among adolescents, few studies have focused on parent-based alcohol prevention strategies among college undergraduates. We report the results of a randomized trial of a parent-based intervention (PBI) in a sample of college freshmen. Across two cohorts, 724 incoming freshman-parent dyads completed baseline assessments and were randomly assigned to PBI or intervention as usual (an alcohol fact sheet for parents). Student follow-up assessments were completed at 4 and 8 months. Two-part latent growth curve modeling was used to test hypothesized intervention effects. Outcome variables were drinks per week (past month), heavy episodic drinking (past 2 weeks), and alcohol-related problems (past 3 months). Over the 8-month follow-up period, PBI had a significant effect on drinks per week but not heavy episodic drinking or alcohol-related problems. Specifically, compared with students in the intervention-as-usual condition, students receiving the PBI were significantly less likely to transition from nondrinker to drinker status and showed less growth in drinking over the freshman year. However, the direct PBI effect on growth was qualified by a PBI x Gender interaction, with probes indicating that the effect applied to women but not men in the PBI condition. This study extends previous research by demonstrating the potential utility for PBIs to decrease the likelihood of transitioning into drinker status and, at least for women, for slowing growth in drinking over the freshman year.


Estimation of age dependent penetrance in facioscapulohumeral muscular dystrophy by minimising ascertainment bias.
In any family study using information gathered retrospectively, the influence of the method of ascertainment on the observed segregation ratio in sibships needs careful consideration. The study of kindred members from outside the area of primary ascertainment is invaluable in providing segregation data with minimal ascertainment bias. For facioscapulohumeral muscular dystrophy (FSHD), using this approach, and based on the presence or absence of characteristic clinical signs rather than on an historical account of age at onset, estimates were derived for penetrance of the FSHD gene of less than 5% for ages 0 to 4 years, 21% for ages 5 to 9, 58% for ages 10 to 14, 86% for ages 15 to 19, and 95% penetrance for age 20 years and over. No difference between families was identified. These figures should facilitate genetic counselling and the interpretation of genetic linkage study results in FSHD.


Poly ADP-ribosylation in two L5178Y murine lymphoma sublines differentially sensitive to DNA-damaging agents.
To characterize the response to X-irradiation of the poly ADP-ribosylation system in two closely related murine lymphoma sublines, L5178Y-R (LY-R) and L5178Y-S (LY-S), with differential sensitivity to various DNA damaging agents (UV-C and ionizing radiation, hydrogen peroxide). LY cells were X-irradiated (2 Gy). NAD+ was determined in cell extracts by high-pressure liquid chromatography. ADP-ribose polymers were purified and analysed by densitometry after polyacrylamide gel electrophoresis. Nuclear matrix proteins were separated by SDS-polyacrylamide gel electrophoresis and processed for ADP-ribose polymer blots to estimate their ability to bind poly(ADP-ribose). In the radiosensitive LY-S cells, the constitutive levels of ADP-ribose polymers were twofold higher than in radioresistant LY-R cells, but unresponsive to a challenge with 2 Gy X-rays. The concentrations of NAD+ - the substrate for poly(ADP-ribose) synthesis - were identical in the two cell lines. X-rays (2 Gy) depleted NAD+ only in LY-S cells. These cells also produced shorter poly(ADP-ribose) molecules as compared with LY-R cells. Nuclear matrix preparations of LY-S cells exhibited lower poly(ADP-ribose)-binding capacity than those of LY-R cells. The results demonstrate disturbances in the poly ADP-ribosylation response of the radiosensitive LY-S cells and reduced poly(ADP-ribose)-binding affinity of the nuclear matrix of these cells.


Low social support and poor emotional regulation are associated with increased stress hormone reactivity to mental stress in systemic hypertension.
There is strong evidence for a physiological hyperreactivity to stress in systemic hypertension, but data on associated or potentially moderating psychological factors are scarce. The objective of the study was to identify psychological correlates of physiological stress reactivity in systemic hypertension. This was a cross-sectional, quasi-experimentally controlled study. Study participants underwent an acute standardized psychosocial stress task combining public speaking and mental arithmetic in front of an audience. The study was conducted in the population in the state of Zurich, Switzerland. Subjects included 22 hypertensive and 26 normotensive men (mean +/- sem 44 +/- 2 yr). We assessed the psychological measures social support, emotional regulation, and cognitive appraisal of the stressful situation. Moreover, we measured salivary cortisol and plasma epinephrine and norepinephrine before and after stress and several times up to 60 min thereafter as well as blood pressure and heart rate. We found poorer hedonistic emotional regulation (HER) and lower perceived social support in hypertensives, compared with normotensives (P < 0.01). Compared with normotensives, hypertensives showed higher cortisol, epinephrine, and norepinephrine secretions after stress (P < 0.038) as well as higher systolic and diastolic blood pressure (P < 0.001). Cortisol reactivity and norepinephrine secretion were highest in hypertensive men with low HER (P < 0.05). In contrast, hypertensives with high HER did not significantly differ from normotensives in both cortisol and norepinephrine secretion after stress. Epinephrine secretion was highest in hypertensives with low social support but was not different between hypertensives with high social support and normotensives. The findings suggest that both low social support and low HER are associated with elevated stress hormone reactivity in systemic hypertension.


Examining the associations between sex trade involvement, rape, and symptomatology of sexual abuse trauma.
The high prevalence of rape and sexual trauma symptomatology among women involved in street-based sex trades is well-established. Because prior research has lacked appropriate, non-sex trade involved comparison groups, it is unknown whether differences exist among similarly situated women who do and do not trade sex. This article explores experiences of childhood and adult rape and symptomatology of sexual abuse trauma among a community-based sample of 322 women who use methamphetamine in San Francisco, California, 61% of whom were involved in the sex trade. Study participants were recruited via respondent-driven sampling and eligible if they were cisgender women, aged 18 or older, current methamphetamine users, and sexually active with at least one cisgender man in the past 6 months. The dependent variable was sexual abuse trauma symptomatology, as measured by the Sexual Abuse Trauma Index (SATI) subscale of the Trauma Symptom Checklist-40 (TSC-40), and the explanatory variable was sex trade involvement. Potential covariates were age, current homelessness, methamphetamine dependence, and experiences of childhood and adult rape. Sixty-one percent of participants had a SATI subscale score suggestive of sexual abuse trauma. The overall prevalence of rape in childhood and adulthood was 52% and 73%, respectively. In bivariate analysis, sex trade involvement and all of the potential covariates except for homelessness and age were associated with a SATI score suggestive of sexual abuse trauma. In multivariate models controlling for significant covariates, there was no longer a statistically significant association between sex trade involvement or childhood rape and an elevated SATI score. Elevated levels of psychological dependence on methamphetamine and experiences of rape as an adult were still associated with a high SATI score. These findings highlight that urban poor women, regardless of sex trade involvement, suffer high levels of rape and related trauma symptomatology.


Treatment of Multiple-Resistant and/or Recurrent Cutaneous Warts With Squaric Acid Dibutylester: A Randomized, Double-blind, Vehicle-controlled Clinical Trial.
Contact immunotherapy with squaric acid dibutylester (SADBE) for cutaneous warts has been reported to be effective, although no controlled studies are available so far. The aim of this study was to evaluate the efficacy of SADBE on cutaneous warts by a randomized, double-blind, vehicle-controlled, clinical trial. Thirty-six patients were randomly assigned to SADBE (18 cases) or vehicle (18 cases) group. At 8 weeks, subjects were clinically evaluated for number/size reduction rate and for Investigator Global Assessment. Those who showed improvement extended therapy up to 40 weeks, whereas those who showed unresponsiveness were either switched to SADBE application for up to 48 weeks (if in the vehicle group) or withdrawn from the study (if under SADBE). At 8 weeks, a significant reduction in wart number (P = 0.020) and size (P = 0.010) in the SADBE group, with clearing rates of 41.2% versus 12.5% in the SADBE and vehicle groups, respectively, was observed. Nine remaining SADBE responders who underwent treatment extension up to 40 weeks achieved clearing versus 2 patients of the vehicle group who remained unresponsive. Clearing was obtained in 81.8% of patients who underwent previous ineffective vehicle treatment and had been switched to SADBE. Squaric acid dibutylester is an effective therapeutic option and is significantly more effective than vehicle.


Targeting and managing behavioral symptoms in individuals with dementia: a randomized trial of a nonpharmacological intervention.
To test the effects of an intervention that helps families manage distressing behaviors in family members with dementia. Two-group randomized trial. In home. Two hundred seventy-two caregivers and people with dementia. Up to 11 home and telephone contacts over 16 weeks by health professionals who identified potential triggers of patient behaviors, including communication and environmental factors and patient undiagnosed medical conditions (by obtaining blood and urine samples) and trained caregivers in strategies to modify triggers and reduce their upset. Between 16 and 24 weeks, three telephone contacts reinforced strategy use. Primary outcomes were frequency of targeted problem behavior and caregiver upset with and confidence managing it at 16 weeks. Secondary outcomes were caregiver well-being and management skills at 16 and 24 weeks and caregiver perceived benefits. Prevalence of medical conditions for intervention patients were also examined. At 16 weeks, 67.5% of intervention caregivers reported improvement in targeted problem behavior, compared with 45.8% of caregivers in a no-treatment control group (P=.002), and reduced upset with (P=.03) and enhanced confidence managing (P=.01) the behavior. Additionally, intervention caregivers reported less upset with all problem behaviors (P=.001), less negative communication (P=.02), less burden (P=.05), and better well-being (P=.001) than controls. Fewer intervention caregivers had depressive symptoms (53.0%) than control group caregivers (67.8%, P=.02). Similar caregiver outcomes occurred at 24 weeks. Intervention caregivers perceived more study benefits (P<.05), including ability to keep family members home, than controls. Blood and urine samples of intervention patients with dementia showed that 40 (34.1%) had undiagnosed illnesses requiring physician follow-up. Targeting behaviors upsetting to caregivers and modifying potential triggers improves symptomatology in people with dementia and caregiver well-being and skills.


Linear mtDNA fragments and unusual mtDNA rearrangements associated with pathological deficiency of MGME1 exonuclease.
MGME1, also known as Ddk1 or C20orf72, is a mitochondrial exonuclease found to be involved in the processing of mitochondrial DNA (mtDNA) during replication. Here, we present detailed insights on the role of MGME1 in mtDNA maintenance. Upon loss of MGME1, elongated 7S DNA species accumulate owing to incomplete processing of 5' ends. Moreover, an 11-kb linear mtDNA fragment spanning the entire major arc of the mitochondrial genome is generated. In contrast to control cells, where linear mtDNA molecules are detectable only after nuclease S1 treatment, the 11-kb fragment persists in MGME1-deficient cells. In parallel, we observed characteristic mtDNA duplications in the absence of MGME1. The fact that the breakpoints of these mtDNA rearrangements do not correspond to either classical deletions or the ends of the linear 11-kb fragment points to a role of MGME1 in processing mtDNA ends, possibly enabling their repair by homologous recombination. In agreement with its functional involvement in mtDNA maintenance, we show that MGME1 interacts with the mitochondrial replicase PolgA, suggesting that it is a constituent of the mitochondrial replisome, to which it provides an additional exonuclease activity. Thus, our results support the viewpoint that MGME1-mediated mtDNA processing is essential for faithful mitochondrial genome replication and might be required for intramolecular recombination of mtDNA.


Can load carriage system weight, design and placement affect pain and discomfort? A systematic review.
A systematic review of the literature was conducted to answer the following questions: 1. Does usage or weight of load carriage system cause pain, perceived exertion or discomfort? 2. Can load carriage system placement on the spine influence pain, perceived exertion or discomfort? 3. Can load carriage system design influence the amount of pain, perceived exertion or discomfort caused by their use? Eight databases were searched. Each included study was analysed and quality appraised by two independent reviewers. Forty-seven articles that addressed the research questions were included in the study. Significant variability in the study design and populations of the studies prevented data pooling and the evidence is conflicting. However, qualitative synthesis of the studies shows that carrying loads may provoke low back pain; and it may also trigger neck, thoracic and shoulder pain. Backpack weight can influence perceived pain, however other factors are involved. There is conflicting but positive evidence on the correlation between backpack load carrying and experiencing pain during different stages of life. The research to date is lacking with the most commonly identified methodological deficiencies being poor overall design, the lack of justification of sample size, providing training sessions for examiners, and not utilising calibrated, valid and reliable instruments for measurement.


An unusual cytochrome o'-type cytochrome c oxidase in a Bacillus cereus cytochrome a3 mutant has a very high affinity for oxygen.
Bacillus cereus strain PYM1 is a mutant unable to synthesize haem A or spectrally detectable cytochromes aa3 or caa3. The nature of the remaining oxidase(s) catalysing oxygen uptake has been studied. Respiratory oxidase activities and the levels of cytochromes b and c increased 2.6- to 4.2-fold on transition from exponential growth, in either of two media, to sporulation stage III, as previously observed for the parent wild-type strain. NADH oxidase activity at both stages of culture was several-fold higher than ascorbate plus tetramethyl-p-phenylenediamine (TMPD) oxidase activity, consistent with the TMPD- phenotype of strain PYM1. Oxidase activity with ascorbate as substrate was significant even in the absence of TMPD as electron mediator, suggesting that the terminal oxidase receives electrons from a cytochrome c. Carbon monoxide (CO) difference spectra of membranes were obtained using various reductants (ascorbate +/- TMPD, NADH, dithionite) and revealed a haemoprotein resembling cytochrome o'. The CO complex of this cytochrome was photodissociable: the photodissociation spectrum (photolysed minus CO-ligated) exhibited a trough at 416 nm and a peak at 436 nm, together with minor features in the alpha/beta region of the spectrum, consistent with the presence of a cytochrome o'-like pigment. CO recombination occurred at -85 to -95 degrees C. No other haemoproteins showing photoreversible CO binding under these conditions were detected. Evidence that this pigment was the oxidase responsible for substrate oxidation was obtained by photodissociating the CO complex at subzero temperatures in the presence of oxygen; this resulted in faster ligand recombination, attributed to oxygen binding, and extensive oxidation of cytochromes c and b. The oxygen affinity of the oxidase was determined by using the deoxygenation of oxyleghaemoglobin as a sensitive reporter of dissociated oxygen concentration. A single oxidase was revealed with a K(m) for oxygen of about 8 nM; this is one of the highest affinities yet reported for a terminal oxidase.


Exploring and exploiting the therapeutic potential of glycoconjugates.
Carbohydrates, either bound to proteins or in lipids, play essential roles as communication molecules in many intercellular and intracellular processes. In particular, carbohydrates are important mediators of cell-cell recognition events and have been implicated in related processes such as cell signaling regulation, cellular differentiation and immune response. This diverse utility has long suggested the power of carbohydrates in therapeutic approaches. This Concepts article highlights the recent potential uses of glycoconjugates as therapeutics, with particular reference to glycopeptides, glycoproteins, glycodendrimers, and glycoarrays.


Simulating far infrared spectra of Zn1-xMnxSe/GaAs epifilms, MnSe/ZnSe superlattices and predicting impurity modes of N, P defects in Zn1-xMnxSe.
A comprehensive lattice dynamical study is reported to emphasize the vibrational behavior of perfect/imperfect zinc-blende (zb) ZnSe, MnSe and Zn1-xMnxSe alloys. Low temperature far-infrared (FIR) reflectivity measurements performed on a series of molecular beam epitaxy grown Zn1-xMnxSe/GaAs (001) epilayers have a typical 'intermediate-phonon-mode' behavior. Besides perceiving ZnSe- and MnSe-like TO-phonon resonances, the study also revealed a weak Mn alloy-disorder mode below MnSe band. A classical effective-medium theory of multilayer optics is used to evaluate dielectric tensors of both epilayers and substrate for simulating reflectivity and transmission spectra of ultrathin epifilms and superlattices at near normal and/or oblique incidence. In the framework of a realistic rigid-ion model and exploiting an average t-matrix Greens function (ATM-GF) theory we appraised the vibrational properties of nitrogen and phosphorous doped Zn-Mn chalcogenides. Lattice relaxations around isolated NSe (PSe) defects in ZnSe and zb MnSe are evaluated by first principles bond-orbital model that helped construct perturbation models for simulating the localized vibrational modes (LVMs). Calculated shift of impurity modes for isotopic 14NSe (15NSe) defects in ZnSe offered a strong revelation of an inflexible defect-host interaction. By retaining force constant change parameter of 14NSe (15NSe) in heavily N-doped ZnSe, the ATM-GF theory predicted (a) three non-degenerate LVMs for the photoluminescence defect center VSe-Zn-14NSe (VSe-Zn-15NSe) of Cs symmetry, and (b) six impurity modes for the second nearest-neighbor NSe-Zn-NSe pair defect of C2v symmetry. From the range of simulated defect modes, we have ruled out the possibility of N-pairs and justified the presence of VSe-Zn-NSe complex centers - likely to be responsible for the observed large absorption bandwidth in highly N-doped ZnSe. High resolution measurements of FIR absorption and/or Raman scattering spectroscopy are needed to validate the accuracy of our theoretical conjectures.


Radiation and SN38 treatments modulate the expression of microRNAs, cytokines and chemokines in colon cancer cells in a p53-directed manner.
Aberrant expression of miRNAs, cytokines and chemokines are involved in pathogenesis of colon cancer. However, the expression of p53 mediated miRNAs, cyto- and chemokines after radiation and SN38 treatment in colon cancer remains elusive. Here, human colon cancer cells, HCT116 with wild-type, heterozygous and a functionally null p53, were treated by radiation and SN38. The expression of 384 miRNAs was determined by using the TaqMan® miRNA array, and the expression of cyto- and chemokines was analyzed by Meso-Scale-Discovery instrument. Up- or down-regulations of miRNAs after radiation and SN38 treatments were largely dependent on p53 status of the cells. Cytokines, IL-6, TNF-α, IL-1β, Il-4, IL-10, VEGF, and chemokines, IL-8, MIP-1α were increased, and IFN-γ expression was decreased after radiation, whereas, IL-6, IFN-γ, TNF-α, IL-1β, Il-4, IL-10, IL-8 were decreased, and VEGF and MIP-1α were increased after SN38 treatment. Bioinformatic analysis pointed out that the highly up-regulated miRNAs, let-7f-5p, miR-455-3p, miR-98, miR-155-5p and the down-regulated miRNAs, miR-1, miR-127-5p, miR-142-5p, miR-202-5p were associated with colon cancer pathways and correlated with cyto- or chemokine expression. These miRNAs have the potential for use in colon cancer therapy as they are related to p53, pro- or anti-inflammatory cyto- or chemokines after the radiation and SN38 treatment.


A pain assessment scale for population-based studies: development and validation of the pain module of the Standard Evaluation Questionnaire.
The objectives of this study were to develop and validate a tool for assessing pain in population-based observational studies and to develop three subscales for back/neck, upper extremity and lower extremity pain. Based on a literature review, items were extracted from validated questionnaires and reviewed by an expert panel. The initial questionnaire consisted of a pain manikin and 34 items relating to (i) intensity of pain in different body regions (7 items), (ii) pain during activities of daily living (18 items) and (iii) various pain modalities (9 items). Psychometric validation of the initial questionnaire was performed in a random sample of the German-speaking Swiss population. Analyses included tests for reliability, correlation analysis, principal components factor analysis, tests for internal consistency and validity. Overall, 16,634 of 23,763 eligible individuals participated (70%). Test-retest reliability coefficients ranged from 0.32 to 0.97, but only three coefficients were below 0.60. Subscales were constructed combining four items for each of the subscales. Item-total coefficients ranged from 0.76 to 0.86 and Cronbach's alpha were 0.75 or higher for all subscales. Correlation coefficients between subscales and three validated instruments (WOMAC, SPADI and Oswestry) ranged from 0.62 to 0.79. The final Pain Standard Evaluation Questionnaire (SEQ Pain) included 28 items and the pain manikin and accounted for the multidimensionality of pain by assessing pain location and intensity, pain during activity, triggers and time of onset of pain and frequency of pain medication. It was found to be reliable and valid for the assessment of pain in population-based observational studies.


Application of cellular automata approach for cloud simulation and rendering.
Current techniques for creating clouds in games and other real time applications produce static, homogenous clouds. These clouds, while viable for real time applications, do not exhibit an organic feel that clouds in nature exhibit. These clouds, when viewed over a time period, were able to deform their initial shape and move in a more organic and dynamic way. With cloud shape technology we should be able in the future to extend to create even more cloud shapes in real time with more forces. Clouds are an essential part of any computer model of a landscape or an animation of an outdoor scene. A realistic animation of clouds is also important for creating scenes for flight simulators, movies, games, and other. Our goal was to create a realistic animation of clouds.


Laparoscopic management of moderate: Severe endometriosis.
To assess the feasibility of laparoscopic surgery in cases of moderate-severe endometriosis. A prospective study was carried out in a tertiary centre over a period of 2 years. Moderate to severe endometriosis was defined by revised American fertility society (rAFS) classification (41 patients). Various procedures were done to provide symptomatic relief. Feasibility of laparoscopic surgery and various patient parameters were analysed. Various procedures like adhesiolysis in POD, excision of endometriomas, resection of endometriotic nodules in the recto-vaginal septum, ureterolysis and total laparoscopic hysterectomy with/ without oophorectomy were done. Majority of patients underwent cystectomy for endometriomas (53.6%) or adhesiolysis with excision of endometriotic nodule (36.5%). Total laparoscopic hysterectomy with or without ooperectomy was done in 31.7% patients. Of the total 9 patients with primary infertility and moderate-severe endometriosis, 5 patients (55.5%) conceived after surgery. There is good evidence that in experienced hands laparoscopic surgery helps in long-term symptomatic relief, improves pregnancy rates and reduces recurrence of disease with largely avoiding complications.


Effect of adsorption kinetics on dissociation of DNA-nucleobases on gold nanoparticles under pulsed laser illumination.
Photothermal therapy is a novel approach to destroy cancer cells by an increase of temperature due to laser illumination of gold nanoparticles (GNPs) that are incorporated into the cells. Here, we study the decomposition of DNA nucleobases via irradiation of gold nanoparticles with ns-laser pulses. The kinetics of the adsorption and decomposition process is described by a theoretical model based on the Langmuir assumptions and correlated with experimentally determined reaction rates revealing a strong influence of the nucleobase specific adsorption. Beside the four nucleobases, their brominated analogs, which are potential radiosensitizers in cancer therapy, are also investigated and show a significant modification of the decomposition rates. The fastest decomposition rates are observed for adenine, 8-bromoadenine, 8-bromoguanine and 5-bromocytosine. These results are in good agreement with the relative adsorption rates that are determined from the aggregation kinetics of the GNPs taking the effect of an inhomogeneous surface into account. For adenine and its brominated analog, the decomposition products are further analyzed by surface enhanced Raman scattering (SERS) indicating a strong fragmentation of the molecules into their smallest subunits.


Delivering cancer care: a model from the West Midlands.
It would seem that time, tide and wind are favourably set for a shift in the organisation of cancer services. Let us test the hypotheses outlined in this brief paper and see if these changes will bring about demonstrable benefit.


Updated norovirus outbreak management and disease prevention guidelines.
Noroviruses are the most common cause of epidemic gastroenteritis, responsible for at least 50% of all gastroenteritis outbreaks worldwide, and a major cause of foodborne illness. In the United States, approximately 21 million illnesses attributable to norovirus are estimated to occur annually. Since 2001, when the most recent norovirus recommendations were published (CDC. "Norwalk-like viruses." Public health consequences and outbreak management. MMWR 2001;50[No. RR-9]), substantial advances have been made in norovirus epidemiology, immunology, diagnostic methods, and infection control. As molecular diagnostic techniques have improved in performance and become more widely available, detection and reporting of norovirus outbreaks have increased. Although the inability to culture human noroviruses in vitro has hampered progress, assessment of the performance of disinfectants has been facilitated by the discovery of new, cultivable surrogates for human noroviruses. In addition, the periodic emergence of epidemic strains (from genogroup II type 4, GII.4) and outbreaks in specific populations (e.g., the elderly in nursing homes) have been characterized. This report reviews these recent advances and provides guidelines for outbreak management and disease prevention. These recommendations are intended for use by public health professionals investigating outbreaks of acute gastroenteritis, including state and local health authorities, as well as academic and research institutions.


Transmission and cross-mating of high-level resistance Plasmodium falciparum dihydrofolate reductase haplotypes in The Gambia.
A high-level pyrimethamine resistance Plasmodium falciparum lineage with triple dihydrofolate reductase (dhfr) mutations prevails across Africa. However, additional minority lineages were seen. We examined transmission success of mutant dhfr haplotypes among 22 children in The Gambia and 60 infected Anopheles gambiae mosquitoes fed on their blood. Additional polymorphic genes of the gametocyte-specific protein (pfg377) and merozoite surface protein-1 (MSP-1) were examined. Similarities were seen between pfg377 and MSP-1 alleles in children and mosquitoes and evidence of cross-mating between different parasite genotypes was seen in some infected mosquitoes, reflecting high transmission success of existing clones. With regard to dhfr, 16 haplotypes were seen among the children: 2 carried double mutations and 14 carried triple mutations. However, only nine haplotypes, all with triple mutations, were detected among mosquitoes. A single triple-mutant dhfr haplotype, similar to that in other countries in Africa, predominated among children (42%) and mosquitoes (60%), supporting the hypothesis of migration of this haplotype across Africa. However, evidence of cross-mating between the above haplotypes signifies the role of local evolution.


The effect of charge separation on the phase behavior of dipolar colloidal rods.
Colloids with anisotropic shape and charge distribution can assemble into a variety of structures that could find use as novel materials for optical, photonic, electronic and structural applications. Because experimental characterization of the many possible types of multi-shape and multipolar colloidal particles that could form useful structures is difficult, the search for novel colloidal materials can be enhanced by simulations of colloidal particle assembly. We have simulated a system of dipolar colloidal rods at fixed aspect ratio using discontinuous molecular dynamics (DMD) to investigate how the charge separation of an embedded dipole affects the types of assemblies that occur. Each dipolar rod is modeled as several overlapping spheres fixed in an elongated shape to represent excluded volume and two smaller, embedded spheres to represent the charges that make up the extended dipole. Large charge separations predominately form structures where the rods link head-to-tail while small charge separations predominately form structures where the rods stack side-by-side. Rods with small charge separations tend to form dense aggregates while rods with large charge separations tend to form coarse gel-like structures. Structural phase boundaries between fluid, string-fluid, and "gel" (networked) phases are mapped out and characterized as to whether they have global head-to-tail or global side-by-side order. A structural coarsening transition is observed for particles with large charge separations in which the head-tail networks thicken as temperature is lowered due to an increased tendency to form side-by-side structures. Triangularly connected networks form at small charge separations; these may be useful for encapsulating smaller particles.


Epidemiologic characteristics of primary homicides in the United States.
Homicide is one of the five leading causes of death for all persons 1-44 years of age. Over half of the homicides occurring in 1979 did not involve the perpetration of another crime. The authors have defined these as primary homicides and suggest that these deaths require the formulation of public health and social services prevention strategies. An epidemiologic assessment of primary homicides in the United States for 1976 through 1979 showed the following. Sixty per cent of primary homicides were male victim/male offender events; 40% involved a female as a victim and/or as an offender. Three per cent of primary homicides were female victim/female offender events; 97% involved a male as a victim and/or as an offender. Primary homicides involving female victims or offenders were more frequently intrafamilial than those involving males, but rates of intrafamilial homicides by males were greater than those involving females. The preponderance of all primary homicides occurred between acquaintances, but the relationship between victim and offender varied with age, sex, and race. The weapons used varied with the victim's and offender's age, sex, and race, and with the relationship between victim and offender. Based on the described patterns, prevention measures should be divided into three broad areas: intrafamilial violence, extrafamilial violence, and male patterns of aggression. Key target populations for the first area include females, rural households, and the very young or very old. A key target population for the second area is teenage males.


Reticular basement membrane fragmentation and potential epithelial mesenchymal transition is exaggerated in the airways of smokers with chronic obstructive pulmonary disease.
In COPD, the airways are chronically inflamed, and we have now observed fragmentation of the reticular basement membrane (Rbm). This appears to be a hallmark of the process known as epithelial mesenchymal transition (EMT), in which epithelial cells migrate through the Rbm and differentiate into fibroblasts. The aim of this study was to confirm the extent and relevance of Rbm fragmentation in smokers and patients with COPD, and to undertake a preliminary analysis of some classical markers of EMT. Endobronchial biopsies from current smokers (CS; n = 17) and ex-smokers with COPD (ES; n = 15), smokers with normal lung function (NS; n = 16) and never-smoking control subjects (NC; n = 15) were stained for the EMT markers, S100A4, vimentin, epidermal growth factor receptor and matrix metalloproteinase-9. Compared with NC, there was significant Rbm fragmentation in the CS, ES and NS groups, which was positively associated with smoking history in subjects with COPD. Staining for basal epithelial S100A4, epithelial epidermal growth factor receptor and matrix metalloproteinase-9 in cells within Rbm clefts, and for S100A4 in Rbm cells, was increased in the CS, NS and ES groups compared with the NC group. There was also increased Rbm cell S100A4 staining in the CS group compared with the ES and NS groups. Basal epithelial cell staining for S100A4 was inversely correlated with airflow limitation. Double staining for both S100A4 and vimentin further strengthened the likelihood that these changes represented active EMT. This is the first detailed description of fragmentation and cellularity of the Rbm in smokers, which were most marked in subjects with COPD. The data are consistent with active EMT in these subjects.


Increased risk of stroke among men with erectile dysfunction: a nationwide population-based study.
Previous cross-sectional studies have suggested that erectile dysfunction (ED) represents an independent risk factor for future cardiovascular events. However, very few studies have attempted to examine the association between ED and subsequent stroke. The aim of this study is to estimate the risk of stroke during a 5-year follow-up period after the first ambulatory care visit for the treatment of ED using nationwide, population-based data and a retrospective case-control cohort design in Taiwan. This study used data sourced from the "Longitudinal Health Insurance Database." The study cohort comprised 1,501 patients who received a principal diagnosis of ED between 1997 and 2001 and 7,505 randomly selected subjects as the comparison cohort. Each patient (N = 9,006) was then individually tracked for 5 years from their index ambulatory care visit to identify those who had diagnosed episodes of stroke. Stratified Cox proportional hazard regressions were performed as a means of comparing the 5-year stroke-free survival rate for the two cohorts. Of the sampled patients, 918 (10.2%) developed stroke within the 5-year follow-up period, that is, 188 individuals (12.5% of the patients with ED) from the study cohort and 730 individuals (9.7% of patients in the comparison cohort) from the comparison cohort. The log-rank test indicated that patients with ED had significantly lower 5-year stroke-free survival rates than those in the comparison cohort (P < 0.001). After adjusting for the patient's monthly income, geographical location, hypertension, diabetes, coronary heart disease, peripheral vascular disease, atrial fibrillation, and hyperlipidemia, patients with ED were more likely to have a stroke during the 5-year follow-up period than patients in the comparison cohort (hazard ratio = 1.29, 95% confidence interval = 1.08 - 1.54, P < 0.01). These results suggest that ED is a surrogate marker for future stroke in men.


Element concentrations in pelagic Sargassum along the Mexican Caribbean coast in 2018-2019.
The massive influx of pelagic Sargassum spp. (sargasso) into the Mexican Caribbean Sea has caused major deterioration of the coastal environment and has affected the tourism industry as well as livelihoods since 2015. Species of Sargassum have high capacity to absorb metals; thus, leachates of sargasso may contribute to contamination by potentially toxic metals when they drain into the sea and into the groundwater when dumped in inadequate land deposits. Valorization of sargasso would contribute to sustainable management; therefore, knowledge on potentially toxic metal content is necessary to define possible uses of the algae. We present concentrations of 28 elements measured using a non-destructive X-ray fluorescence analyzer (XRF) in 63 samples of sargasso collected between August 2018 and June 2019 from eight localities along ∼370 km long coastline of the Mexican Caribbean Sea. The sargasso tissues contained detectable concentrations of Al, As, Ca, Cl, Cu, Fe, K, Mg, Mn, Mo, P, Pb, Rb, S, Si, Sr, Th, U, V, and Zn. The element concentration in sargasso varied on spatial and temporal scales, which likely depended on the previous trajectory of the pelagic masses, and whether these had (or had not) passed through contaminated areas. Total arsenic concentration varied between 24-172 ppm DW, exceeding the maximum limit for seaweed intended as animal fooder (40 ppm DW) in 86% of the samples. For valorization, we recommend analyses of metal contents as a mandatory practice or avoiding uses for nutritional purposes. The high arsenic content is also of concern for environmental contamination of the sea and aquifer.


Adherence to community versus facility-based delivery of monthly malaria chemoprevention with dihydroartemisinin-piperaquine for the post-discharge management of severe anemia in Malawian children: A cluster randomized trial.
The provision of post-discharge malaria chemoprevention (PMC) in children recently admitted with severe anemia reduces the risk of death and re-admissions in malaria endemic countries. The main objective of this trial was to identify the most effective method of delivering dihydroartemesinin-piperaquine to children recovering from severe anemia. This was a 5-arm, cluster-randomized trial among under-5 children hospitalized with severe anemia at Zomba Central Hospital in Southern Malawi. Children were randomized to receive three day treatment doses of dihydroartemesinin-piperaquine monthly either; 1) in the community without a short text reminder; 2) in the community with a short message reminder; 3) in the community with a community health worker reminder; 4) at the facility without a short text reminder; or 5) at the facility with a short message reminder. The primary outcome measure was adherence to all treatment doses of dihydroartemesinin-piperaquine and this was assessed by pill-counts done by field workers during home visits. Poisson regression was utilized for analysis. Between March 2016 and October 2018, 1460 clusters were randomized. A total of 667 children were screened and 375 from 329 clusters were eligible and enrolled from the hospital. Adherence was higher in all three community-based compared to the two facility-based delivery (156/221 [70·6%] vs. 78/150 [52·0%], IRR = 1·24,95%CI 1·06-1·44, p = 0·006). This was observed in both the SMS group (IRR = 1·41,1·21-1·64, p<0·001) and in the non-SMS group (IRR = 1·37,1·18-1·61, p<0·001). Although adherence was higher among SMS recipients (98/148 66·2%] vs. non-SMS 82/144 (56·9%), there was no statistical evidence that SMS reminders resulted in greater adherence ([IRR = 1·03,0·88-1·21, p = 0·68). When compared to the facility-based non-SMS arm (control arm), community-based delivery utilizing CHWs resulted in higher adherence [39/76 (51·3%) vs. 54/79 (68·4%), IRR = 1·32, 1·14-1·54, p<0·001]. Community-based delivery of dihydroartemesinin-piperaquine for post-discharge malaria chemoprevention in children recovering from severe anemia resulted in higher adherence compared to facility-based methods. NCT02721420; ClinicalTrials.gov.


Chemosensitizing Properties of β-Caryophyllene and β-Caryophyllene Oxide in Combination with Doxorubicin in Human Cancer Cells.
The natural sesquiterpenes β-caryophyllene (CRY) and β-caryophyllene oxide (CRYO) were evaluated for their potential chemosensitizing properties. CRY and CRYO cytotoxicity was tested against the Caco-2, CCRF/CEM and CEM/ADR5000 human cancer cell lines. Furthermore, combination experiments were carried out in order to study the ability of the sesquiterpenes to increase doxorubicin cytotoxicity. The possible interference of CRY and CRYO with functionality of ATP-binding cassette (ABC)-transporters was also investigated by Rhodamine123 efflux assay. Despite a low cytotoxicity, both substances were able to enhance the cytotoxicity of doxorubicin in all cell lines, with CRYO being the most effective reversal agent. Both sesquiterpenes were also able to increase the Rho123 content into cells, likely due to inhibition of the efflux pumps. Our results highlight a potential role of CRY and CRYO as new chemosensitizing agents for doxorubicin chemotherapy and to re-sensitize cancer-resistant cells.


Disabled people in Britain and the impact of the COVID-19 pandemic.
This paper reports on in-depth qualitative interviews conducted with 69 disabled people in England and Scotland, and with 28 key informants from infrastructure organisations in the voluntary and statutory sectors, about the impact of COVID-19, and measures taken to control it. Participants were recruited through voluntary organisations. As with everyone, the Pandemic has had a huge impact: we discuss the dislocations it has caused in everyday life; the failures of social care; the use of new technologies; and participants' view on leadership and communication. We conclude with suggestions for urgent short term and medium term responses, so that the United Kingdom and other countries can respond better to this and other pandemics, and build a more inclusive world.