Rapid genetic engineering of human cytomegalovirus by using a lambda phage linear recombination system: demonstration that pp28 (UL99) is essential for production of infectious virus.
A highly efficient lambda phage recombination system previously utilized for studies of bacterial artificial chromosome (BAC)-maintained mouse chromosomal DNA was adapted for the study of the role of human cytomegalovirus (HCMV)-encoded pp28 (UL99) in virus replication. Incorporating a two-step mutagenesis strategy with blue/white selection in Escherichia coli containing a HCMV AD169 BAC, we have shown that we can rapidly introduce point mutations into the HCMV BAC using linear PCR fragments. All manipulations were carried out in bacteria, which greatly accelerated the introduction and analysis of mutations in the viral genome. Our results indicated that HCMV pp28 was essential for the production of infectious virus and that introduction of a single base change that resulted in loss of the myristylation site on pp28 was also associated with the lack of production of infectious virus. Although the block in the viral morphogenesis cannot be determined from these studies, the latter finding suggested that authentic intracellular localization of pp28, not only the expression of the protein, is required for virus assembly.


Emergency care in rural settings: Can doctors be ethical and survive?
We describe below the pressures of running a small private hospital in an underserved rural area, while providing emergency healthcare for victims of poisonous stings, accidents, and other acute health conditions. Both ethics and law demand that payment is not asked for upfront in emergency cases. Yet patients and their families often fail to pay normal dues for months or even years. It is disturbing to encounter such behaviour even in villages; and doctors in small communities are easy prey. In these conditions can one be true to ethical principles and ensure one's own survival?


Papillary Urothelial Neoplasm of Low Malignant Potential (PUNLMP) After Initial TUR-BT: Comparative Analyses with Noninvasive Low-Grade Papillary Urothelial Carcinoma (LGPUC).
Purpose: To verify if the distinction between papillary urothelial neoplasm of low malignant potential (PUNLMP) and noninvasive low-grade papillary urothelial carcinoma (LGPUC) reflects a different biologic activity. Materials and Methods: We reviewed and analyzed the clinical data from 678 patients who had a diagnosis of PUNLMP (n=53) or noninvasive LGPUC (n=625) after initial TUR-BT for bladder neoplasm between 2000 and 2012. Results: The noninvasive LGPUC group showed a higher frequency of recurrence in comparison with the PUNLMP group (46.7% vs. 30.2%, p=0.022). In contrast, there were no significant differences in progression (15.2% vs. 18.9%, p=0.295) between the two groups. Grade progression was reported in 10 patients (LG: n=5; high grade: n=2; carcinoma in situ: n=3) and stage progression was reported in 2 patients (all: T1) in PUNLMP group. The Kaplan-Meier survival analysis showed significantly decreased 5-year recurrence-free survival (RFS) (50.3% vs. 74.6%, log-rank test, p=0.014) in the noninvasive LGPUC group compared to the PUNLMP group. However, there were no significant differences in progression-free survival (PFS) between the two groups. Multivariate analysis revealed that tumor grades according to 2004 WHO/ISUP classification system (PUNLMP vs. LG) were identified as significant predictors of RFS. However, it was not a significant predictor of both PFS and overall survival. Conclusions: PUNLMP had a substantial number of recurrences (30.2%), although RFS was better than noninvasive LGPUC. In addition, PUNLMP had a similar risk of progression compared with noninvasive LGPUC. Consequently, PUNLMP should be treated in a manner similar to noninvasive LGPUC, and long-term clinical follow-up should be recommended for patients with PUNLMP.


Experimental and mathematical methods for representing relative surface elongation of the ACL.
The common approach to assess the stabilizing role of the ACL in the knee has been to measure the elongation of a few marked fibers in the ligament. A comparison of the relative elongation (RE) of these marked fibers between different specimens and studies is delicate due to the difficulty of marking the same fibers. More consistent comparisons would be achieved if the RE of the whole ligament surface was presented. Hence, we developed a mathematical method leading to a continuous description of the relative elongation of the ligament's surface based on experimental measurements of the RE of five fibers. The ligament fibers of two knee specimens were marked by radiopaque markers and a Roentgen Stereophotogrammetric Analysis system was used to reconstruct the three-dimensional positions of these artificial landmarks. The mathematical procedure used isoparametric cubic splines to interpolate the contours of the insertion sites. The results showed that the general pattern of the RE for both specimens was similar, characterized by an undulation near full flexion. In fact, close to full flexion all the RE of the fibers increased. Such a representation describes the changes in the RE for a given fiber during knee flexion and at the same time characterizes the RE distribution at a given flexion angle.


Losmapimod, a novel p38 mitogen-activated protein kinase inhibitor, in non-ST-segment elevation myocardial infarction: a randomised phase 2 trial.
p38 MAPK inhibition has potential myocardial protective effects. We assessed losmapimod, a potent oral p38 MAPK inhibitor, in patients with non-ST-segment elevation myocardial infarction (NSTEMI) in a double-blind, randomised, placebo-controlled trial. From October, 2009, to November, 2011, NSTEMI patients were assigned oral losmapimod (7·5 mg or 15·0 mg loading dose followed by 7·5 mg twice daily) or matching placebo in a 3:3:2 ratio. Safety outcomes were serious adverse events and alanine aminotransferase (ALT) concentrations over 12 weeks, and cardiac events (death, myocardial infarction, recurrent ischaemia, stroke, and heart failure) at 90 days. Efficacy outcomes were high-sensitivity C-reactive protein (hsCRP) and B-type natriuretic peptide (BNP) concentrations at 72 h and 12 weeks, and troponin I area under the curve (AUC) over 72 h. The losmapimod groups were pooled for analysis. This trial is registered with ClinicalTrials.gov, number NCT00910962. Of 535 patients enrolled, 526 (98%) received at least one dose of study treatment (losmapimod n=388 and placebo n=138). Safety outcomes did not differ between groups. HsCRP concentrations at 72 h were lower in the losmapimod group than in the placebo group (geometric mean 64·1 nmol/L, 95% CI 53·0-77·6 vs 110·8 nmol/L, 83·1-147·7; p=0·0009) but were similar at 12 weeks. Early geometric mean BNP concentrations were similar at 72 h but significantly lower in the losmapimod group at 12 weeks (37·2 ng/L, 95% CI 32·3-42·9 vs 49·4 ng/L, 38·7-63·0; p=0·04). Mean troponin I AUC values did not differ. p38 MAPK inhibition with oral losmapimod was well tolerated in NSTEMI patients and might improve outcomes after acute coronary syndromes. GlaxoSmithKline.


The Magic Velvet Bean of Mucuna pruriens.
Mucuna pruriens (Fabaceae) is an established herbal drug used for the management of male infertility, nervous disorders, and also as an aphrodisiac. It has been shown that its seeds are potentially of substantial medicinal importance. The ancient Indian medical system, Ayurveda, traditionally used M. pruriens, even to treat such things as Parkinson's disease. M. pruriens has been shown to have anti-parkinson and neuroprotective effects, which may be related to its anti-oxidant activity. In addition, anti-oxidant activity of M. pruriens has been also demonstrated in vitro by its ability to scavenge DPPH radicals and reactive oxygen species. In this review the medicinal properties of M. pruriens are summarized, taking in consideration the studies that have used the seeds extracts and the leaves extracts.


Basal insulin: beyond glycemia.
Insulin is a pleiotropic hormone with numerous effects at the cellular, tissue, and organismal levels. Clinicians are familiar with physiological effects of insulin on carbohydrate metabolism, including stimulation of glucose uptake in skeletal muscle and the suppression of glucose production from the liver. Other metabolic effects of insulin include inhibiting the release of free fatty acids from adipose tissue and stimulating the incorporation of amino acids into proteins. Indeed, every organ in the body, including the brain, is a target for insulin action. Insulin resistance, typically defined with respect to glucose metabolism, is a condition in which normal levels of insulin do not trigger the signal for glucose disposition. The effects of insulin resistance and impaired insulin signaling have profound pathophysiologic effects, such as hyperglycemia-induced tissue damage, hypertension, dyslipidemia, metabolic syndrome, and cardiovascular and renal disease. An integrated view of insulin action in all of these tissues may yield improved therapeutic insight and possibly even illuminate new therapeutic opportunities. With the increase in the number of patients diagnosed with prediabetes and diabetes, an updated understanding of the disease and the pharmacologic armamentarium used to treat it is needed to improve outcomes. To help expand the clinical care provider's perspective, this article will provide a provocative discussion about the pathophysiology of diabetes, the role of insulin and insulin resistance, and the clinical efficacy potential of insulin. Understanding the cellular and molecular mechanisms underlying the effects of insulin and how these translate into clinical consequences beyond glycemia will assist primary care physicians in the care of their patients with diabetes and metabolic syndrome.


Failure to rescue in neonatal care.
Failure to rescue (FTR) has been described as the end result of a series of events relating to the environment of care and nursing quality. Only recently has FTR as a process measure been applied to perinatal care settings. Nurses' continuous presence at the bedside puts them in a privileged position to recognize signs of clinical deterioration and to take action. Many factors contribute to nurses' ability to save lives when infants develop complications. Although such factors are often system-related, nurses may be held responsible if they do not act according to an acceptable standard of care. In the neonatal intensive care unit, FTR has not been applied or adopted as a measure of nursing quality. This article describes how FTR is relevant in the neonatal intensive care unit and outlines nursing and system actions that can be taken to rescue some of the hospital's most vulnerable patients.


Delivery of health care for cardiovascular and metabolic diseases among people living with HIV/AIDS in African countries: a systematic review protocol.
People living with HIV (PLHIV) in African countries are living longer due to the rollout of antiretroviral drug therapy programs, but they are at increasing risk of non-communicable diseases (NCDs). However, there remain many gaps in detecting and treating NCDs in African health systems, and little is known about how NCDs are being managed among PLHIV. Developing integrated chronic care models that effectively prevent and treat NCDs among PLHIV requires an understanding of the current patterns of care delivery and the major barriers and facilitators to health care. We present a systematic review protocol to synthesize studies of healthcare delivery for an important subset of NCDs, cardiovascular and metabolic diseases (CMDs), among African PLHIV. We plan to search electronic databases and reference lists of relevant studies published in African settings from January 2003 to the present. Studies will be considered if they address one or both of our major objectives and focus on health care for one or more of six interrelated CMDs (ischemic heart disease, stroke, heart failure, hypertension, diabetes, and hyperlipidemia) in PLHIV. Our first objective will be to estimate proportions of CMD patients along the "cascade of care"-i.e., screened, diagnosed, aware of the diagnosis, initiated on treatment, adherent to treatment, and with controlled disease. Our second objective will be to identify unique barriers and facilitators to health care faced by PLHIV in African countries. For studies deemed eligible for inclusion, we will assess study quality and risk of bias using previously published criteria. We will extract study data using standardized instruments. We will meta-analyze quantitative data at each level of the cascade of care for each CMD (first objective). We will use meta-synthesis techniques to understand and integrate qualitative data on health-related behaviors (second objective). CMDs and other NCDs are becoming major health concerns for African PLHIV. The results of our review will inform the development of research into chronic care models that integrate care for HIV/AIDS and CMDs among PLHIV. Our findings will be highly relevant to health policymakers, administrators, and practitioners in African settings. PROSPERO CRD42015029375.


Measurement of physical activity in older adult interventions: a systematic review.
Interventions to promote physical activity (PA) among older adults can positively impact PA behaviour and other health outcomes. Measurement of PA must be valid and reliable; however, the degree to which studies employ valid and reliable measures of PA is unclear. The purpose of this systematic review was to evaluate the measurement tools used in interventions to increase PA among older adults (65+ years), including both self-report measures and objective measures. In addition, the implications of these different measurement tools on study results were evaluated and discussed. Four electronic research databases (MEDLINE, PsychINFO, Web of Science and EBSCO) were used to identify published intervention studies measuring the PA behaviour of adults over 65 years of age. Studies were eligible if: (1) PA was an outcome; (2) there was a comparison group and (3) the manuscript was published in English. Data describing measurement methods and properties were extracted and reviewed. Of the 44 studies included in this systematic review, 32 used self-report measures, 9 used objective measures and 3 used both measures. 29% of studies used a PA measure that had neither established validity nor reliability, and only 63% of measures in the interventions had established both validity and reliability. Only 57% of measures had population-specific reliability and 66% had population-specific validity. A majority of intervention studies to help increase older adult PA used self-report measures, even though many have little evidence of validity and reliability. We recommend that future researchers utilise valid and reliable measures of PA with well-established evidence of psychometric properties such as hip-accelerometers and the Community Health Activities Model Program for Seniors (CHAMPS) Physical Activity Questionnaire for Older Adults.


Avoiding the invasion of H2O into Y2Mo3O12 by coating with C3N4 to improve negative thermal expansion properties.
The hygroscopicity of Y2Mo3O12 has serious influences on its mechanic and negative thermal expansion (NTE) properties. The reported partial ion substitution for Y3+ in Y2Mo3O12 could reduce the hygroscopicity, however, the expected NTE properties disappear disappointedly. In this investigation, it is found that avoiding the invasion of crystal water and extending the NTE temperature range of Y2Mo3O12 to room temperature could be realized together by heating with CO(NH2)2. The X-ray diffraction patterns, infrared absorption spectra, scanning electron microscopy images and X-ray photoelectron spectra suggest the formation of small hydrophobic molecules (C3N4, C, etc.) coated on the surface, which could clog the microchannels in Y2Mo3O12 to avoid the invasion of crystal water. The investigation paves a way to improve the NTE properties by neglecting the influences of water molecules on the stretching vibrations of MoO4 tetrahedra and the transverse vibrations of bridge oxygen atoms.


Microbial diversity in fecal samples depends on DNA extraction method: easyMag DNA extraction compared to QIAamp DNA stool mini kit extraction.
There are challenges, when extracting bacterial DNA from specimens for molecular diagnostics, since fecal samples also contain DNA from human cells and many different substances derived from food, cell residues and medication that can inhibit downstream PCR. The purpose of the study was to evaluate two different DNA extraction methods in order to choose the most efficient method for studying intestinal bacterial diversity using Denaturing Gradient Gel Electrophoresis (DGGE). In this study, a semi-automatic DNA extraction system (easyMag®, BioMérieux, Marcy I'Etoile, France) and a manual one (QIAamp DNA Stool Mini Kit, Qiagen, Hilden, Germany) were tested on stool samples collected from 3 patients with Inflammatory Bowel disease (IBD) and 5 healthy individuals. DNA extracts obtained by the QIAamp DNA Stool Mini Kit yield a higher amount of DNA compared to DNA extracts obtained by easyMag® from the same fecal samples. Furthermore, DNA extracts obtained using easyMag® seemed to contain inhibitory compounds, since in order to perform a successful PCR-analysis, the sample should be diluted at least 10 times. DGGE performed on PCR from DNA extracted by QIAamp DNA Stool Mini Kit DNA was very successful. QIAamp DNA Stool Mini Kit DNA extracts are optimal for DGGE runs and this extraction method yields a higher amount of DNA compared to easyMag®.


Country clustering applied to the water and sanitation sector: a new tool with potential applications in research and policy.
The fields of global health and international development commonly cluster countries by geography and income to target resources and describe progress. For any given sector of interest, a range of relevant indicators can serve as a more appropriate basis for classification. We create a new typology of country clusters specific to the water and sanitation (WatSan) sector based on similarities across multiple WatSan-related indicators. After a literature review and consultation with experts in the WatSan sector, nine indicators were selected. Indicator selection was based on relevance to and suggested influence on national water and sanitation service delivery, and to maximize data availability across as many countries as possible. A hierarchical clustering method and a gap statistic analysis were used to group countries into a natural number of relevant clusters. Two stages of clustering resulted in five clusters, representing 156 countries or 6.75 billion people. The five clusters were not well explained by income or geography, and were distinct from existing country clusters used in international development. Analysis of these five clusters revealed that they were more compact and well separated than United Nations and World Bank country clusters. This analysis and resulting country typology suggest that previous geography- or income-based country groupings can be improved upon for applications in the WatSan sector by utilizing globally available WatSan-related indicators. Potential applications include guiding and discussing research, informing policy, improving resource targeting, describing sector progress, and identifying critical knowledge gaps in the WatSan sector.


Nanotopographical regulation of pancreatic islet-like cluster formation from human pluripotent stem cells using a gradient-pattern chip.
Bioengineering approaches to regulate stem cell fates aim to recapitulate the in vivo microenvironment. In recent years, manipulating the micro- and nano-scale topography of the stem cell niche has gained considerable interest for the purposes of controlling extrinsic mechanical cues to regulate stem cell fate and behavior in vitro. Here, we established an optimal nanotopographical system to improve 3-dimensional (3D) differentiation of pancreatic cells from human pluripotent stem cells (hPSCs) by testing gradient-pattern chips of nano-scale polystyrene surface structures with varying sizes and shapes. The optimal conditions for 3D differentiation of pancreatic cells were identified by assessing the expression of developmental regulators that are required for pancreatic islet development and maturation. Our results showed that the gradient chip of pore-part 2 (Po-2, 200-300 nm diameter) pattern was the most efficient setting to generate clusters of pancreatic endocrine progenitors (PDX1+ and NGN3+) compared to those of other pore diameters (Po-1, 100-200 or Po-3, 300-400 nm) tested across a range of pillar patterns and flat surfaces. Furthermore, the Po-2 gradient pattern-derived clusters generated islet-like 3D spheroids and tested positive for the zinc-chelating dye dithizone. The spheroids consisted of more than 30% CD200 + endocrine cells and also expressed NKX6.1 and NKX2.2. In addition, pancreatic β- cells expressing insulin and polyhormonal cells expressing both insulin and glucagon were obtained at the final stage of pancreatic differentiation. In conclusion, our data suggest that an optimal topographical structure for differentiation to specific cell types from hPSCs can be tested efficiently by using gradient-pattern chips designed with varying sizes and surfaces. STATEMENT OF SIGNIFICANCE: Our study provides demonstrates of using gradient nanopatterned chips for differentiation of pancreatic islet-like clusters. Gradient nanopatterned chips are consisted of two different shapes (nanopillar and nanopore) in three different ranges of nano sizes (100-200, 200-300, 300-400 nm). We found that optimal nanostructures for differentiation of pancreatic islet-like clusters were 200-300 nm nano pores. Cell transplantation is one of the major therapeutic option for type 1 diabetes mellitus (DM) using stem cell-derived β-like cells. We generated 50 um pancreatic islet-like clusters in size, which would be an optimal size for cell transplantation. Futuremore, the small clusters provide a powerful source for cell therapy. Our findings suggest gradient nanopatterned chip provides a powerful tool to generate specific functional cell types of a high purity for potential uses in cell therapy development.


Bayesian semi-supervised learning for uncertainty-calibrated prediction of molecular properties and active learning.
Predicting bioactivity and physical properties of small molecules is a central challenge in drug discovery. Deep learning is becoming the method of choice but studies to date focus on mean accuracy as the main metric. However, to replace costly and mission-critical experiments by models, a high mean accuracy is not enough: outliers can derail a discovery campaign, thus models need to reliably predict when it will fail, even when the training data is biased; experiments are expensive, thus models need to be data-efficient and suggest informative training sets using active learning. We show that uncertainty quantification and active learning can be achieved by Bayesian semi-supervised graph convolutional neural networks. The Bayesian approach estimates uncertainty in a statistically principled way through sampling from the posterior distribution. Semi-supervised learning disentangles representation learning and regression, keeping uncertainty estimates accurate in the low data limit and allowing the model to start active learning from a small initial pool of training data. Our study highlights the promise of Bayesian deep learning for chemistry.


Emerging strategies for combination checkpoint modulators in cancer immunotherapy.
Current immune checkpoint-modulating agents have demonstrated clinical efficacy in certain tumor types, particularly those with a high burden of tumor-specific neoantigens, high tumor-mutational burden, and abundant tumor-infiltrating T cells. However, these tumors often stop responding, with signs of T cells exhaustion, decreased T cell effector function, and upregulated inhibitory checkpoints. To enhance antitumor immunity and rescue exhausted T cells, newer inhibitory and stimulatory checkpoint modulators are being tested as monotherapy or in combination with approved checkpoint inhibitors. In contrast, tumors with low tumor-mutational burden, low neoantigen burden, and a paucity of T cells are immunologically "cold," and therefore first require the addition of agents to facilitate the induction of T cells into tumors. Cold tumors also often recruit immunosuppressive cell subsets, including regulatory T cells, myeloid-derived suppressor cells, and macrophages, and secrete immunosuppressive soluble cytokines, chemokines, and metabolites. To unleash an optimal antitumor immune response, combinatorial therapeutics that combine immune checkpoints with other modalities, such as vaccines, are being developed. From current preclinical data, it appears that combinatorial strategies will provide robust and durable responses in patients with immunologically cold cancers.


Lyme disease. A neuro-ophthalmologic view.
Lyme borreliosis is a spirochetal infection with a potential to produce a clinical disease in the human host with protean manifestations as diverse as the spectrum of disease caused by Treponema pallidum. Neuro-ophthalmologic manifestations of Lyme borreliosis are emphasized in this short review. A brief historical chronicle of Lyme disease is offered. Potential pitfalls in the diagnosis of Lyme disease with an emphasis on false negative serology and currently available diagnostic modalities are presented. Therapeutic options for Lyme borreliosis are briefly reviewed.


Forgive to live: forgiveness, health, and longevity.
This study examined multiple types of forgiveness as predictors of mortality and potential psychosocial, spiritual, and health mechanisms of the effects of forgiveness on longevity. Data from a nationally representative sample of United States adults ages 66 and older assessed forgiveness, health, religiousness/spirituality, and socio-demographics (N = 1,232). God's unconditional forgiveness and conditional forgiveness of others initially emerged as statistically significant predictors of mortality risk. However, only conditional forgiveness of others remained a significant predictor of mortality after controlling for religious, socio-demographic, and health behavior variables. Mediators of the association between conditional forgiveness of others and mortality were examined, and a statistically significant indirect effect was identified involving physical health. These findings suggest that conditional forgiveness of others is associated with risk for all-cause mortality, and that the mortality risk of conditional forgiveness may be conferred by its influences on physical health.


Changes in Diverse Sexual and Contraceptive Behaviors Across College.
Researchers have made repeated calls for a better understanding of normative sexuality development during adolescence and young adulthood. We examined how the occurrence of seven penetrative, nonpenetrative, and contraceptive behaviors changed longitudinally across seven waves, and how individual (gender) and contextual (romantic relationship status) factors related to these changes in a sample of college students (N = 730, M age = 18.4 at Semester 1; 51% female; 26% Hispanic/Latino American, 22% Black/African American, 30% Asian American/Pacific Islander, 45% White/European American). Across college, reported kissing, touching, performing and receiving oral sex, and penetrative sex rates increased, and contraception use (any type) and condom use (in particular) rates decreased, demonstrating changes with age independent of young adults' romantic relationship experiences. Rates of all sexual behaviors were higher, and of contraception use lower, when students were in serious romantic relationships. Contraception use decreased more for men than for women, particularly in semesters men were not in serious relationships. Condom use decreased for men, and for women in semesters they were in serious relationships. Findings demonstrate normative trends in sexuality development, as well as suggesting the value of enhanced sexual health promotion programming, with a particular focus on contraceptive behaviors, across college.


Validation of Plasma Proteomic Biomarkers Relating to Brain Amyloid Burden in the EMIF-Alzheimer's Disease Multimodal Biomarker Discovery Cohort.
We have previously investigated, discovered, and replicated plasma protein biomarkers for use to triage potential trials participants for PET or cerebrospinal fluid measures of Alzheimer's disease (AD) pathology. This study sought to undertake validation of these candidate plasma biomarkers in a large, multi-center sample collection. Targeted plasma analyses of 34 proteins with prior evidence for prediction of in vivo pathology were conducted in up to 1,000 samples from cognitively healthy elderly individuals, people with mild cognitive impairment, and in patients with AD-type dementia, selected from the EMIF-AD catalogue. Proteins were measured using Luminex xMAP, ELISA, and Meso Scale Discovery assays. Seven proteins replicated in their ability to predict in vivo amyloid pathology. These proteins form a biomarker panel that, along with age, could significantly discriminate between individuals with high and low amyloid pathology with an area under the curve of 0.74. The performance of this biomarker panel remained consistent when tested in apolipoprotein E ɛ4 non-carrier individuals only. This blood-based panel is biologically relevant, measurable using practical immunocapture arrays, and could significantly reduce the cost incurred to clinical trials through screen failure.


Comparison of knowledge on travel related health risks and their prevention among humanitarian aid workers and other travellers consulting at the Institut Pasteur travel clinic in Paris, France.
Non-Governmental Organization (NGO) workers are a group of travellers highly exposed to infectious diseases due to the conditions and duration of their stay. Yet little is known about their knowledge concerning travel related health risks and their prevention. From July to September 2008 a self-administered questionnaire was given to all NGO workers coming for pre-travel consultation and to a comparison group of non-NGO travellers. It examined traveller's knowledge about malaria, traveller's diarrhea, transmission routes of infectious diseases and vaccine availability in both groups. 249 NGO employees and 304 non-NGO travellers were surveyed. Mean age (33.7 vs 34.7 years) and sex ratio (M/F 1.16 vs 1.29) were comparable in both groups. Travel destination was more often Africa (75% vs 39%) and duration of travel was longer in the NGO group (75% vs 15% more than 1 month). NGO travellers had significantly better knowledge about the transmission routes of infectious diseases : percentages of accurate answers varied from 20% for Japanese encephalitis, 31% for yellow fever and 41% for hepatitis A to 70% for dengue and 96% for malaria, versus respectively 9%, 17%, 40%, 54% and 94% for the comparison group. However no differences were observed between the two groups concerning the means to prevent malaria or traveller's diarrhea, or the symptoms necessitating medical consultation. In the sub-group analyses medical professionals (23% of the NGO group) performed better than other NGO workers. Even though the knowledge was slightly better in the NGO group, there are still important gaps and a combined effort of all actors is needed to improve the security of expatriated humanitarian aid workers, in particular for the non-medical staff.


A molecular map of mesenchymal tumors.
Bone and soft tissue tumors represent a diverse group of neoplasms thought to derive from cells of the mesenchyme or neural crest. Histological diagnosis is challenging due to the poor or heterogenous differentiation of many tumors, resulting in uncertainty over prognosis and appropriate therapy. We have undertaken a broad and comprehensive study of the gene expression profile of 96 tumors with representatives of all mesenchymal tissues, including several problem diagnostic groups. Using machine learning methods adapted to this problem we identify molecular fingerprints for most tumors, which are pathognomonic (decisive) and biologically revealing. We demonstrate the utility of gene expression profiles and machine learning for a complex clinical problem, and identify putative origins for certain mesenchymal tumors.


Blood pressure dynamics during pregnancy and spontaneous preterm birth.
The objective of the study was to examine whether blood pressure in early pregnancy and its rise in the second half of gestation are associated with spontaneous preterm birth in healthy, normotensive, nulliparous women. We included 5167 women with singleton gestation who participated in the World Health Organization Calcium Supplementation for the Prevention of Preeclampsia Trial. Systolic, diastolic, and mean arterial blood pressure and pulse pressure at baseline (12-19 weeks of gestation) and at the midthird trimester (30-34 weeks) were calculated. Rise in blood pressure was the difference between the midthird trimester and baseline. Preterm birth was defined as early preterm (less than 34 completed weeks) and late preterm birth (34-36 weeks). Women experiencing early or late preterm birth had over 10 mm Hg and 3 mm Hg higher rise, respectively, in systolic, diastolic, and mean arterial blood pressure than women delivering at term. A rise in systolic pressure over 30 mm Hg or diastolic pressure over 15 mm Hg was associated with a statistically significant 2- to 3-fold increase in risk of spontaneous preterm birth. An excessive rise in either systolic or diastolic blood pressures from early pregnancy to the midthird trimester is associated with spontaneous preterm birth in a dose-response pattern.


Colonization behaviors of mountain pine beetle on novel hosts: Implications for range expansion into northeastern North America.
As climates change, thermal limits may no longer constrain some native herbivores within their historical ranges. The mountain pine beetle, Dendroctonus ponderosae Hopkins, is a tree-killing bark beetle native to western North America that is currently expanding its range. Continued eastward expansion through the newly invaded and novel jack pine (Pinus banksiana Lamb.) trees of the Canadian boreal forest could result in exposure of several species of novel potential host pines common in northeastern North America to this oligophagous herbivore. Due to the tightly co-evolved relationship between mountain pine beetle and western pine hosts, in which the insect utilizes the defensive chemistry of the host to stimulate mass attacks, we hypothesized that lack of co-evolutionary association would affect the host attraction and acceptance behaviors of this insect among novel hosts, particularly those with little known historical association with an aggressive stem-infesting insect. We studied how beetle behavior differed among the various stages of colonization on newly cut logs of four novel potential pine host species; jack, red (P. resinosa Ait.), eastern white (P. strobus L.) and Scots (P. sylvestris L.) pines, as well as two historical hosts, ponderosa (P. ponderosa Dougl. ex. Laws. var. scopulorum Engelm.) and lodgepole (P. contorta Dougl. var. latifolia Engelm.) pines. Overall, we found that beetle colonization behaviors at each stage in the colonization process differ between pine hosts, likely due to differing chemical and physical bark traits. Pines without co-evolved constitutive defenses against mountain pine beetle exhibited reduced amounts of defensive monoterpenoid chemicals; however, such patterns also reduced beetle attraction and colonization. Neither chemical nor physical defenses fully defended trees against the various stages of host procurement that can result in tree colonization and death.


Activating protein-1, nuclear factor-kappaB, and serum response factor as novel target molecules of the cancer-amplified transcription coactivator ASC-2.
ASC-2 was recently discovered as a cancer-amplified transcription coactivator molecule of nuclear receptors, which interacts with multifunctional transcription integrators steroid receptor coactivator-1 (SRC-1) and CREB-binding protein (CBP)/p300. Herein, we report the identification of three mitogenic transcription factors as novel target molecules of ASC-2. First, the C-terminal transactivation domain of serum response factor (SRF) was identified among a series of ASC-2-interacting proteins from the yeast two-hybrid screening. Second, ASC-2 specifically interacted with the activating protein-1 (AP-1) components c-Jun and c-Fos as well as the nuclear factor-kappaB (NFkappaB) components p50 and p65, as demonstrated by the glutathione S-transferase pull-down assays as well as the yeast two-hybrid tests. In cotransfection of mammalian cells, ASC-2 potentiated transactivations by SRF, AP-1, and NFkappaB in a dose-dependent manner, either alone or in conjunction with SRC-1 and p300. In addition, ASC-2 efficiently relieved the previously described transrepression between nuclear receptors and either AP-1 or NFkappaB. Overall, these results suggest that the nuclear receptor coactivator ASC-2 also mediates transactivations by SRF, AP-1, and NFkappaB, which may contribute to the putative, ASC-2-mediated tumorigenesis.


Effects of lead on Na⁺, K⁺-ATPase and hemolymph ion concentrations in the freshwater mussel Elliptio complanata.
Freshwater mussels are an imperiled fauna exposed to a variety of environmental toxicants such as lead (Pb) and studies are urgently needed to assess their health and condition to guide conservation efforts. A 28-day laboratory toxicity test with Pb and adult Eastern elliptio mussels (Elliptio complanata) was conducted to determine uptake kinetics and to assess the toxicological effects of Pb exposure. Test mussels were collected from a relatively uncontaminated reference site and exposed to a water-only control and five concentrations of Pb (as lead nitrate) ranging from 1 to 245 μg/L in a static renewal test with a water hardness of 42 mg/L. Endpoints included tissue Pb concentrations, hemolymph Pb and ion (Na⁺, K⁺, Cl⁻, Ca²⁺) concentrations, and Na⁺, K⁺-ATPase enzyme activity in gill tissue. Mussels accumulated Pb rapidly, with tissue concentrations increasing at an exposure-dependent rate for the first 2 weeks, but with no significant increase from 2 to 4 weeks. Mussel tissue Pb concentrations ranged from 0.34 to 898 μg/g dry weight, were strongly related to Pb in test water at every time interval (7, 14, 21, and 28 days), and did not significantly increase after day 14. Hemolymph Pb concentration was variable, dependent on exposure concentration, and showed no appreciable change with time beyond day 7, except for mussels in the greatest exposure concentration (245 μg/L), which showed a significant reduction in Pb by 28 days, suggesting a threshold for Pb binding or elimination in hemolymph at concentrations near 1000 μg/g. The Na⁺, K⁺-ATPase activity in the gill tissue of mussels was significantly reduced by Pb on day 28 and was highly correlated with tissue Pb concentration (R² = 0.92; P = 0.013). The Na⁺, K⁺-ATPase activity was correlated with reduced hemolymph Na⁺ concentration at the greatest Pb exposure when enzyme activity was at 30% of controls. Hemolymph Ca²⁺ concentration increased significantly in mussels from the greatest Pb exposure and may be due to remobilization from the shell in an attempt to buffer the hemolymph against Pb uptake and toxicity. We conclude that Na⁺, K⁺-ATPase activity in mussels was adversely affected by Pb exposure, however, because the effects on activity were variable at the lower test concentrations, additional research is warranted over this range of exposures.


Competition and allostery govern substrate selectivity of cyclooxygenase-2.
Cyclooxygenase-2 (COX-2) oxygenates arachidonic acid (AA) and its ester analog, 2-arachidonoylglycerol (2-AG), to prostaglandins (PGs) and prostaglandin glyceryl esters (PG-Gs), respectively. Although the efficiency of oxygenation of these substrates by COX-2 in vitro is similar, cellular biosynthesis of PGs far exceeds that of PG-Gs. Evidence that the COX enzymes are functional heterodimers suggests that competitive interaction of AA and 2-AG at the allosteric site of COX-2 might result in differential regulation of the oxygenation of the two substrates when both are present. Modulation of AA levels in RAW264.7 macrophages uncovered an inverse correlation between cellular AA levels and PG-G biosynthesis. In vitro kinetic analysis using purified protein demonstrated that the inhibition of 2-AG oxygenation by high concentrations of AA far exceeded the inhibition of AA oxygenation by high concentrations of 2-AG. An unbiased systems-based mechanistic model of the kinetic data revealed that binding of AA or 2-AG at the allosteric site of COX-2 results in a decreased catalytic efficiency of the enzyme toward 2-AG, whereas 2-AG binding at the allosteric site increases COX-2's efficiency toward AA. The results suggest that substrates interact with COX-2 via multiple potential complexes involving binding to both the catalytic and allosteric sites. Competition between AA and 2-AG for these sites, combined with differential allosteric modulation, gives rise to a complex interplay between the substrates, leading to preferential oxygenation of AA.


Deliberate self-harm in nondepressed substance-dependent patients.
The lifetime diagnosis of substance dependence syndrome is a major risk factor for attempting suicide. The systematic study of various risk factors of suicide in substance-dependent patients in Indian population will have far-reaching implications about the understanding of disorder. The objective was to study the sociodemographic and clinical factors associated with deliberate self-harm (DSH) in nondepressed substance-dependent patients. Participants included 60 male inpatients (30 patients with DSH and 30 without DSH) fulfilling International Classification of Diseases, Tenth Revision Diagnostic Criteria for Research for substance dependence syndrome, aged between 18 and 60 years, with Hamilton Depression Rating Scale score fewer than 7. They were assessed using Addiction Severity Index, Presumptive Stressful Life Event Scale, State-Trait Anger Expression Inventory, Lubben Social Network Scale, International Personality Disorder Examination, Risk Rescue Rating Scale, and Global Assessment of Functioning. Patients with DSH had significantly higher rates of opioid dependence (P < .05), risk of isolation (P < 0.001), the number of life events (P < 0.001), anger trait and anger expression (P < 0.001), personality disorder (P < 0.05), the number of substance use problems and lower social functioning (P < 0.001), as compared with those without DSH (P < 0.001). There was no significant correlation between Risk Rescue Rating Scale with sociodemographic and clinical variables. The study demonstrated that patients with opioid dependence, high risk of isolation, the greater number of life events, higher anger trait and anger expression, personality disorder, low social functioning, and greater number of substance use problems have risk for DSH.


Hypoxia-inducible factor-1alpha and -2alpha are expressed in most rectal cancers but only hypoxia-inducible factor-1alpha is associated with prognosis.
The hypoxia-mediated response of tumours is a major determining factor in growth and metastasis. Understanding tumour biology under hypoxic conditions is crucial for the development of antiangiogenic therapy. Using one of the largest cohorts of rectal adenocarcinomas to date, this study investigated hypoxia-inducible factor-1alpha (HIF-1alpha) and HIF-2alpha protein expression in relation to rectal cancer recurrence and cancer-specific survival. Patients (n=90) who had undergone surgery for rectal adenocarcinoma, with no prior neoadjuvant therapy or metastatic disease, and for whom adequate follow-up data were available were selected. Microvessel density (MVD), HIF-1alpha and HIF-2alpha expressions were assessed immunohistologically with the CD34 antibody for vessel identification and the NB100-131B and NB100-132D3 antibodies for HIF-1alpha and HIF-2alpha, respectively. In a multifactorial analysis, results were correlated with tumour stage, recurrence rate and long-term survival. Microvessel density was higher across T and N stages (P<0.001) and associated with poor survival (hazard ratio (HR)=8.7, P<0.005) and decreased disease-free survival (HR=4.7, P<0.005). hypoxia-inducible factor-1alpha and -2alpha were expressed in >50% of rectal cancers (HIF-1alpha, 54%, 48/90; HIF-2alpha, 64%, 58/90). HIF-1alpha positivity was associated with both TNM stage (P<0.05) and vascular invasion (P<0.005). In contrast, no associations were demonstrated [corrected] between HIF-2alpha [corrected] and any pathological features or [corrected] outcome. The study showed an independent association between HIF-1alpha expression and advanced TNM stage with poor outcome. Our results indicate that HIF-1alpha, but not HIF-2alpha, might be used as a marker of prognosis, in addition to methods currently used, to enhance patient management.


Population health rankings as policy indicators and performance measures.
Population health rankings can be used by various actors for different purposes. This article examines those potential uses and concludes that the chief promise of population health rankings lies in 2 areas. The first is to help set agendas - stimulating awareness, motivation, and debate over means to improved health outcomes. The second is to help establish broad responsibility for population health and the need for multisectoral collaboration to improve outcomes. A new performance regime based on rankings will require more research to establish causal pathways and relative determinants of health, as well as stronger evidence about the effects of public and private interventions to guide investment strategies. Finally, leaders who develop and promote population health rankings must further develop the technical community needed to translate the response to the rankings into constructive public debate and policy development.


Comparison of Transversus Abdominis Plane Infiltration with Liposomal Bupivacaine versus Continuous Epidural Analgesia versus Intravenous Opioid Analgesia.
Epidural analgesia is considered the standard of care but cannot be provided to all patients Liposomal bupivacaine has been approved for field blocks such as transversus abdominis plane (TAP) blocks but has not been clinically compared against other modalities. In this retrospective propensity matched cohort study we thus tested the primary hypothesis that TAP infiltration are noninferior (not worse) to continuous epidural analgesia and superior (better) to intravenous opioid analgesia in patients recovering from major lower abdominal surgery. 318 patients were propensity matched on 18 potential factors among three groups (106 per group): 1) TAP infiltration with bupivacaine liposome; 2) continuous Epidural analgesia with plain bupivacaine; and; 3) intravenous patient-controlled analgesia (IV PCA). We claimed TAP noninferior (not worse) over Epidural if TAP was noninferior (not worse) on total morphine-equivalent opioid and time-weighted average pain score (10-point scale) within first 72 hours after surgery with noninferiority deltas of 1 (10-point scale) for pain and an increase less of 20% in the mean morphine equivalent opioid consumption. We claimed TAP or Epidural groups superior (better) over IV PCA if TAP or Epidural was superior on opioid consumption and at least noninferior on pain outcome. Multivariable linear regressions within the propensity-matched cohorts were used to model total morphine-equivalent opioid dose and time-weighted average pain score within first 72 hours after surgery; joint hypothesis framework was used for formal testing. TAP infiltration were noninferior to Epidural on both primary outcomes (p<0.001). TAP infiltration were noninferior to IV PCA on pain scores (p = 0.001) but we did not find superiority on opioid consumption (p = 0.37). We did not find noninferiority of Epidural over IV PCA on pain scores (P = 0.13) and nor did we find superiority on opioid consumption (P = 0.98). TAP infiltration with liposomal bupivacaine and continuous epidural analgesia were similar in terms of pain and opioid consumption, and not worse in pain compared with IV PCA. TAP infiltrations might be a reasonable alternative to epidural analgesia in abdominal surgical patients. A large randomized trial comparing these techniques is justified.


Chaos in balance: non-linear measures of postural control predict individual variations in visual illusions of motion.
Visually-induced illusions of self-motion (vection) can be compelling for some people, but they are subject to large individual variations in strength. Do these variations depend, at least in part, on the extent to which people rely on vision to maintain their postural stability? We investigated by comparing physical posture measures to subjective vection ratings. Using a Bertec balance plate in a brightly-lit room, we measured 13 participants' excursions of the centre of foot pressure (CoP) over a 60-second period with eyes open and with eyes closed during quiet stance. Subsequently, we collected vection strength ratings for large optic flow displays while seated, using both verbal ratings and online throttle measures. We also collected measures of postural sway (changes in anterior-posterior CoP) in response to the same visual motion stimuli while standing on the plate. The magnitude of standing sway in response to expanding optic flow (in comparison to blank fixation periods) was predictive of both verbal and throttle measures for seated vection. In addition, the ratio between eyes-open and eyes-closed CoP excursions during quiet stance (using the area of postural sway) significantly predicted seated vection for both measures. Interestingly, these relationships were weaker for contracting optic flow displays, though these produced both stronger vection and more sway. Next we used a non-linear analysis (recurrence quantification analysis, RQA) of the fluctuations in anterior-posterior position during quiet stance (both with eyes closed and eyes open); this was a much stronger predictor of seated vection for both expanding and contracting stimuli. Given the complex multisensory integration involved in postural control, our study adds to the growing evidence that non-linear measures drawn from complexity theory may provide a more informative measure of postural sway than the conventional linear measures.


School placement and perceived quality of life in youth who are deaf or hard of hearing.
In the education of students who are deaf and hard of hearing (DHH), there is much debate about how placement affects educational outcomes and quality of life. This study examined the relationship between quality of life and educational placement that include and do not include other DHH youth. Participants included 221 DHH youth, ages 11-18 with bilateral hearing loss. Results showed that there were few differences in quality of life related to school placement (with age, gender, depression symptoms, and hearing level as covariates). For both participation and perceived stigma, there was an interaction between school placement and parent hearing status, with no single school placement showing the best results. DHH youth with hearing parents in schools specifically for DHH students scored lower than DHH with deaf parents in some domains (Participation and Perceived Stigma). When the DHH youth were compared with the general population, those in schools that included DHH students scored lower in some aspects of quality of life, particularly Self and Relationships. This study demonstrates that DHH students may not differ much in terms of quality of life across schools placements, but that there may be differences in subsets of DHH youth.


Neurology and psychiatry: waking up to opportunities of sleep. : State of the art and clinical/research priorities for the next decade.
In recent years, evidence has emerged for a bidirectional relationship between sleep and neurological and psychiatric disorders. First, sleep-wake disorders (SWDs) are very common and may be the first/main manifestation of underlying neurological and psychiatric disorders. Secondly, SWDs may represent an independent risk factor for neuropsychiatric morbidities. Thirdly, sleep-wake function (SWF) may influence the course and outcome of neurological and psychiatric disorders. This review summarizes the most important research and clinical findings in the fields of neuropsychiatric sleep and circadian research and medicine, and discusses the promise they bear for the next decade. The findings herein summarize discussions conducted in a workshop with 26 European experts in these fields, and formulate specific future priorities for clinical practice and translational research. More generally, the conclusion emerging from this workshop is the recognition of a tremendous opportunity offered by our knowledge of SWF and SWDs that has unfortunately not yet entered as an important key factor in clinical practice, particularly in Europe. Strengthening pre-graduate and postgraduate teaching, creating academic multidisciplinary sleep-wake centres and simplifying diagnostic approaches of SWDs coupled with targeted treatment strategies yield enormous clinical benefits for these diseases.


The efficacy of blueberry and grape seed extract combination on triple therapy for Helicobacter pylori eradication: a randomised controlled trial.
Helicobacter pylori is a major risk factor for gastritis, gastric ulcers and gastric cancer. Traditional therapy with proton pump inhibitor and antibiotics is regarded as optimal for H. pylori eradication whereas, the eradication rate is unsatisfactory. Studies have reported that cranberry may inhibit H. pylori adhesion to the human gastric mucus but lack of other berry extracts have been evaluated in clinical study. Thus, a 9-week add-on randomised controlled trial was conducted to explore the impact of blueberry and grape seed extract (BGE) combinations traditional therapy for H. pylori eradication. In results, we found that there was no significant difference of eradication rate between the berry extract group and placebo group in the intention-to-treat analysis and in the per-protocol analysis (94.64% versus 84.62%, p = 0.085). Diarrhoea, constipation and epigastric pain were observed increasing during ingestion of the berry extract in some cases. In conclusion, this study indicated that no significant difference existed between the BGE extract group and placebo group in eradication rate under triple therapy.


Adsorption of Polar and Nonpolar Molecules on Isolated Cationic C60 , C70 , and Their Aggregates.
Physisorption on graphite, graphene, nanotubes, and other graphitic structures has been the subject of numerous studies, partly driven by interest in the nature of order in two-dimensional systems, their phase transitions, and the use of graphitic scaffolds for reversible storage of hydrogen at high volumetric density and low mass. In contrast, physisorption on individual fullerenes or small aggregates of fullerenes has remained largely unexplored, last but not least, because of technical challenges. A summary of recent progress in identifying specific adsorption sites on positively charged C60 , C70 , and their aggregates is given in this Minireview. Adsorption energies and storage capacities for helium, hydrogen, methane, oxygen, nitrogen, water, and ammonia are determined. Mass spectrometric data reveal the formation of a commensurate phase in which all hollow sites of C60 or C70 are occupied. This phase is identified for all nonpolar molecules, including oxygen, which does not form a commensurate phase on planar graphite. The polar molecules, on the other hand, do not wet fullerenes and they do not form this commensurate phase. A hierarchy of other distinct adsorption sites are identified for nonpolar molecules, namely, groove sites for fullerene dimers and beyond, and dimple sites for fullerene trimers and beyond. Furthermore, evidence is presented for the preferential adsorption of hydrogen and methane in registered sites on fullerene dimers. The interpretation of experimental data that merely count the number of preferred adsorption sites is aided by molecular dynamics simulations, which utilize interaction potentials derived from ab initio calculations to determine adsorption energies.


Informed decision making in persons acquitted not guilty by reason of insanity.
Deciding to raise an insanity defense carries serious consequences. This is especially true for persons charged with minor offenses, for whom an acquittal not guilty by reason of insanity (NGRI) might lead to a longer period of incarceration than would conviction. Before raising an insanity defense, a defendant should be provided with information necessary to make an informed decision and should be competent to understand the consequences of the verdict. This study attempted, through retrospective review and concurrent evaluation, to determine the degree to which trial courts in Virginia attended to these important aspects of informed decision making before finding defendants charged with misdemeanors NGRI. The study also attempted to assess the degree to which defendants were competent and informed at the time of adjudication. In most instances, trial courts did not consider defendants' competence to make decisions regarding the insanity defense and did not consider whether defendants were informed about the consequences of a successful insanity defense at the time of adjudication. The average length of stay for these patients was (at least) 21 months; most would have been released earlier had they been committed civilly rather than committed as a result of insanity pleas. We stress the need to educate judges, attorneys and forensic evaluators to the importance of considering defendants competence to plead insanity and of providing information about the consequences of a successful plea. We also propose that laws be changed to recognize the importance of these elements in the decision making process regarding pleas of insanity.


Extrinsic curvature, geometric optics, and lamellar order on curved substrates.
When thermal energies are weak, two-dimensional lamellar structures confined on a curved substrate display complex patterns arising from the competition between layer bending and compression in the presence of geometric constraints. We present broad design principles to engineer the geometry of the underlying substrate so that a desired lamellar pattern can be obtained by self-assembly. Two distinct physical effects are identified as key factors that contribute to the interaction between the shape of the underlying surface and the resulting lamellar morphology. The first is a local ordering field for the direction of each individual layer, which tends to minimize its curvature with respect to the three-dimensional embedding. The second is a nonlocal effect controlled by the intrinsic geometry of the surface that forces the normals to the (nearly incompressible) layers to lie on geodesics, leading to caustic formation as in optics. As a result, different surface morphologies with predominantly positive or negative Gaussian curvature can act as converging or diverging lenses, respectively. By combining these ingredients, as one would with different optical elements, complex lamellar morphologies can be obtained. This smectic optometry enables the manipulation of lamellar configurations for the design of materials.


Symbiotic diversity, specificity and distribution of rhizobia in native legumes of the Core Cape Subregion (South Africa).
Rhizobial diversity and host preferences were assessed in 65 native Fynbos legumes of the papilionoid legume tribes Astragaleae, Crotalarieae, Genisteae, Indigofereae, Millettieae, Phaseoleae, Podalyrieae, Psoraleeae and Sesbanieae. Sequence analyses of chromosomal 16S rRNA, recA, atpD and symbiosis-related nodA, nifH genes in parallel with immunogold labelling assays identified the symbionts as alpha- (Azorhizobium, Bradyrhizobium, Ensifer, Mesorhizobium and Rhizobium) and beta-rhizobial (Burkholderia) lineages with the majority placed in the genera Mesorhizobium and Burkholderia showing a wide range of host interactions. Despite a degree of symbiotic promiscuity in the tribes Crotalarieae and Indigofereae nodulating with both alpha- and beta-rhizobia, Mesorhizobium symbionts appeared to exhibit a general host preference for the tribe Psoraleeae, whereas Burkholderia prevailed in the Podalyrieae. Although host genotype was the main factor determining rhizobial diversity, ecological factors such as soil acidity and site elevation were positively correlated with genetic variation within Mesorhizobium and Burkholderia, respectively, indicating an interplay of host and environmental factors on the distribution of Fynbos rhizobia.


Bilateral renal agenesis in an alpaca cria.
A 3-day-old male alpaca cria was presented for lack of vigor and failure to urinate since birth. Based on the history, laboratory data, ultrasonographs, surgical findings, and postmortem examination, the cria was diagnosed with bilateral renal agenesis and hypoplastic bladder, a congenital condition rarely seen in veterinary medicine.


Direct observation of nodes and twofold symmetry in FeSe superconductor.
We investigated the electron-pairing mechanism in an iron-based superconductor, iron selenide (FeSe), using scanning tunneling microscopy and spectroscopy. Tunneling conductance spectra of stoichiometric FeSe crystalline films in their superconducting state revealed evidence for a gap function with nodal lines. Electron pairing with twofold symmetry was demonstrated by direct imaging of quasiparticle excitations in the vicinity of magnetic vortex cores, Fe adatoms, and Se vacancies. The twofold pairing symmetry was further supported by the observation of striped electronic nanostructures in the slightly Se-doped samples. The anisotropy can be explained in terms of the orbital-dependent reconstruction of electronic structure in FeSe.


Characteristics of HIV antiretroviral treatments, access and adherence in an ethnically diverse sample of men who have sex with men.
Data regarding HIV antiretroviral treatment regimens, access to treatment and medical care, and adherence to medications were collected as part of the Seropositive Urban Men's Study, a formative study of HIV-positive men who have sex with men. Participants (N = 456) were recruited from AIDS service organizations, mainstream gay venues and public/commercial sex environments. The sample was 94% gay or bisexually-identified; 29% were African American, 24% Latino and 30% white. The majority (71%) indicated being on antiretroviral treatment, and most were taking a protease inhibitor/nucleoside reverse transcriptase inhibitor combination. African American men in New York City were less likely to be on treatment. Among those on treatment (n = 322), 51% reported at least one day in which they had missed a dose of their medication and the mean number of days in which a dose was missed (in the past 30 days) was 1.72. Multivariate analyses indicated that avoidant coping, frequency of drinking alcohol and difficulty in communicating with sex partners about HIV were related to days of missed doses, suggesting the need or desire to escape from the reality of life with HIV as a potential explanation for poor adherence.


Local perceptions of risk to livelihood in semi-arid Tanzania.
This paper examines variation in local perceptions of risk in semi-arid Tanzania, identifying factors that influence local perceptions of problems and testing the feasibility of risk mapping as a technique. Twelve villages in six districts were visited between February and April 2001. Villagers were asked about their worries and concerns in providing for themselves and their families using a risk questionnaire. The responses were grouped into 21 categories of problem and incidence and severity indices were calculated for each category. Most problems were associated with the availability of natural resources on which livelihoods depend but others related to human and social capital assets. In addition to environmental factors, livelihood strategy and gender both influenced people's perceptions of risk. Problems of irrigation and weather, for example, were important for agricultural communities while problems relating to livestock diseases, access to land and hunger were more important in pastoral communities. The risks cited by men and women generally reflected their traditional roles in society. Very broadly, the risks associated with natural capital tended to be seen as higher by men while women mentioned more problems relating to human and social capital. However, this was not always the case. Problems linked to finance, traditionally the concern of men, were ranked similarly by men and women. In projects designed to facilitate community management and control over common pool resources, the identification of common interests is particularly important. Risk mapping can provide a cost-effective way of gaining insights to help improve research design and to inform policy development.


Lateral-shearing, delay-dithering Mach-Zehnder interferometer for spatial coherence measurement.
An image-shearing interferometer of Mach-Zehnder type with corner cubes is introduced for the purpose of measuring spatial coherence at the output of inhomogeneous optical sources, such as multimode fibers (MMFs). One arm of the interferometer is modulated in optical delay to produce dynamic interference fringes. Fringe visibility and the two individual intensities are measured nearly simultaneously to allow direct calculation of the modulus of the complex degree of coherence as a function of the lateral shear between the two interferometer arms. Spatial degree of coherence is measured for a step-index MMF pumped with monochromatic and broadband optical sources.


Targeting Colon Luminal Lipid Peroxidation Limits Colon Carcinogenesis Associated with Red Meat Consumption.
Red meat is probably carcinogenic to humans (WHO/IARC class 2A), in part through heme iron-induced lipoperoxidation. Here, we investigated whether red meat promotes carcinogenesis in rodents and modulates associated biomarkers in volunteers, speculating that an antioxidant marinade could suppress these effects via limitation of the heme induced lipid peroxidation. We gave marinated or non-marinated beef with various degrees of cooking to azoxymethane-initiated rats, Min mice, and human volunteers (crossover study). Mucin-depleted foci were scored in rats, adenoma in Min mice. Biomarkers of lipoperoxidation were measured in the feces and urine of rats, mice, and volunteers. The organoleptic properties of marinated meat were tested. Fresh beef increased colon carcinogenesis and lipoperoxidation in rats and mice and lipoperoxidation in humans. Without an adverse organoleptic effect on meat, marinade normalized peroxidation biomarkers in rat and mouse feces, reduced peroxidation in human feces and reduced the number of Mucin-depleted foci in rats and adenoma in female Min mice. This could lead to protective strategies to decrease the colorectal cancer burden associated with red meat consumption. Cancer Prev Res; 11(9); 569-80. ©2018 AACR.


Will European agricultural policy for school fruit and vegetables improve public health? A review of school fruit and vegetable programmes.
For the first time, public health, particularly obesity, is being seen as a driver of EU agricultural policy. In 2007, European Ministers of Agriculture were asked to back new proposals for school fruit and vegetable programmes as part of agricultural reforms. In 2008, the European Commission conducted an impact assessment to assess the potential impact of this new proposal on health, agricultural markets, social equality and regional cohesion. A systematic review of the effectiveness of interventions to promote fruit and/or vegetable consumption in children in schools, to inform the EC policy development process. School schemes are effective at increasing both intake and knowledge. Of the 30 studies included, 70% increased fruits and vegetables (FV) intake, with none decreasing intake. Twenty-three studies had follow-up periods >1 year and provide some evidence that FV schemes can have long-term impacts on consumption. Only one study led to both increased fruit and vegetable intake and reduction in weight. One study showed that school fruit and vegetable schemes can also help to reduce inequalities in diet. Effective school programmes have used a range of approaches and been organized in ways which vary nationally depending on differences in food supply chain and education systems. EU agriculture policy for school fruits and vegetables schemes should be an effective approach with both public health and agricultural benefits. Aiming to increase FV intake amongst a new generation of consumers, it will support a range of EU policies including obesity and health inequalities.


Contribution of Breast Cancer to Overall Mortality for US Women.
Breast cancer simulation models must take changing mortality rates into account to evaluate the potential impact of cancer control interventions. We estimated mortality rates due to breast cancer and all other causes combined to determine their impact on overall mortality by year, age, and birth cohort. Based on mortality rates from publicly available datasets, an age-period-cohort model was used to estimate the proportion of deaths due to breast cancer for US women aged 0 to 119 years, with birth years 1900 to 2000. Breast cancer mortality was calculated as all-cause mortality multiplied by the proportion of deaths due to breast cancer; other-cause mortality was the difference between all-cause and breast cancer mortality. Breast cancer and other-cause mortality rates were higher for older ages and birth cohorts. The percent of deaths due to breast cancer increased across birth cohorts from 1900 to 1940 then decreased. Among 50-year-old women, in the 1920 birth cohort, 52 (9.9%) of 100,000 deaths (95% CI, 9.8% to 10.1%) were attributed to breast cancer whereas 476 of 100,000 were due to other causes; in the 1960 birth cohort, 22 (8.5%) of 100,000 deaths (95% CI, 8.3% to 8.7%) were attributed to breast cancer with 242 of 100,000 deaths due to other causes. The percentage of all deaths due to breast cancer was highest (4.1% to 12.9%) for women in their 40s and 50s for all birth cohorts. This study offers evidence that advances in breast cancer screening and treatment have reduced breast cancer mortality for women across the age spectrum, and provides estimates of age-, year- and birth cohort-specific competing mortality rates for simulation models. Other-cause mortality estimates are important in these models because most women die from causes other than breast cancer.


Stability studies of testosterone and epitestosterone glucuronides in urine.
The stability of testosterone glucuronide (TG), epitestosterone glucuronide (EG) and the T/E ratio in urine has been studied. Samples were analyzed by gas chromatography coupled to mass spectrometry (GC/MS). Urine samples were submitted to a solid-liquid cleanup followed by extraction of unconjugated testosterone (T) and epitestosterone (E) with tert-butyl methyl ether (free fraction). The remaining aqueous phase was hydrolyzed with beta-glucuronidase and extracted at alkaline pH with n-pentane. Analytes were analyzed by GC/MS as their enol-trimethylsilyl (TMS) derivatives. The urine for stability testing was obtained from an excretion study after the administration of T to healthy volunteers. The homogeneity of the sample was verified before starting the stability study. The stability of TG and EG was evaluated at different storage conditions. For long-term stability testing, analyte concentration in urine stored at 4 degrees C and -20 degrees C was determined at different time intervals for 22 months. For short-term stability testing, analyte concentration was evaluated in urine stored at 37 degrees C for 3 and 7 days. The effect of repeated freezing (at -20 degrees C) and thawing (at room temperature) was studied for up to three cycles. Data obtained in this work demonstrated the stability of TG, EG and the T/E ratio in sterilized urine samples stored at 4 and -20 degrees C for 22 months and after going through repeated freeze/thaw cycles. Decreases in concentration were observed after 7 days of storage at 37 degrees C due to the partial cleavage of the glucuronide conjugates; however, the T/E ratio was not affected. These results show the feasibility of preparing reference materials containing TG and EG to be used for quality control purposes.


A significant upward shift in plant species optimum elevation during the 20th century.
Spatial fingerprints of climate change on biotic communities are usually associated with changes in the distribution of species at their latitudinal or altitudinal extremes. By comparing the altitudinal distribution of 171 forest plant species between 1905 and 1985 and 1986 and 2005 along the entire elevation range (0 to 2600 meters above sea level) in west Europe, we show that climate warming has resulted in a significant upward shift in species optimum elevation averaging 29 meters per decade. The shift is larger for species restricted to mountain habitats and for grassy species, which are characterized by faster population turnover. Our study shows that climate change affects the spatial core of the distributional range of plant species, in addition to their distributional margins, as previously reported.


Epinephrine enhances neurogenic vasoconstriction in the rat perfused kidney.
Epinephrine has been implicated in the genesis of some forms of hypertension. We have investigated the effects of epinephrine on vasoconstrictor responses evoked by adrenergic stimuli in the isolated perfused rat kidney. Low concentrations of epinephrine (2.5 - 5 X 10(-9) M) increased the amplitude of vasoconstrictor responses evoked by electrical stimulation of the renal adrenergic nerves. These concentrations of epinephrine had no effect on the basal perfusion pressure of the kidney or on the amplitude of vasoconstrictor responses evoked by exogenous norepinephrine. The potentiating effect of epinephrine persisted after infusion of the amine had ceased. Kidneys that had been perfused with 3H-epinephrine accumulated radioactivity, which could then be released by renal nerve stimulation. Cocaine (3 X 10(-5) M) reduced the renal accumulation of 3H-epinephrine and abolished both the persistent potentiating effect of the amine and the release of radioactivity evoked by subsequent nerve stimulation. The potentiating effect of epinephrine infusion was abolished by the beta 2-selective adrenergic receptor antagonist ICI 118,551 (3 X 10(-8) M), but not by the beta 1-selective adrenergic receptor antagonist atenolol (10(-6) M). These results indicate that concentrations of epinephrine that can be achieved during acute stress can enhance the amplitude of neurogenic vasoconstrictor responses. This effect appears to be mediated via a prejunctional beta 2-adrenergic receptor. The persistent nature of this effect may be due to the neuronal accumulation and subsequent release of epinephrine.


Glutamate receptor subunit 2 Serine 880 phosphorylation modulates synaptic transmission and mediates plasticity in CA1 pyramidal cells.
The cytoplasmic C termini of AMPA receptor subunits contain PDZ (postsynaptic density 95/Discs large/zona occludens 1) ligand domains that can control their synaptic trafficking during plasticity. The glutamate receptor subunit 2 (GluR2) PDZ ligand domain can be phosphorylated at serine 880 (S880), and this disrupts interactions with GRIP/ABP (glutamate receptor-interacting protein/AMPA-binding protein) but not with PICK1 (PKC-interacting protein 1). Here, the impact of GluR2 S880 phosphorylation on synaptic transmission and plasticity was explored by expressing, in hippocampal slice cultures, GluR2 subunits containing point mutations that mimic or prevent phosphorylation at this residue. Our results indicate that mimicking GluR2 S880 phosphorylation excludes these receptors from synapses, depresses transmission, and partially occludes long-term depression (LTD). Conversely, mutations that prevent phosphorylation reduce LTD. Disruption of the interaction between GluR2 and GRIP/ABP by S880 phosphorylation may thus facilitate removal of synaptic AMPA receptors and mediate some forms of activity-dependent synaptic depression.


Center of excellence for mobile sensor data-to-knowledge (MD2K).
Mobile sensor data-to-knowledge (MD2K) was chosen as one of 11 Big Data Centers of Excellence by the National Institutes of Health, as part of its Big Data-to-Knowledge initiative. MD2K is developing innovative tools to streamline the collection, integration, management, visualization, analysis, and interpretation of health data generated by mobile and wearable sensors. The goal of the big data solutions being developed by MD2K is to reliably quantify physical, biological, behavioral, social, and environmental factors that contribute to health and disease risk. The research conducted by MD2K is targeted at improving health through early detection of adverse health events and by facilitating prevention. MD2K will make its tools, software, and training materials widely available and will also organize workshops and seminars to encourage their use by researchers and clinicians.


Factoring-in agglomeration of carbon nanotubes and nanofibers for better prediction of their toxicity versus asbestos.
Carbon nanotubes (CNT) and carbon nanofibers (CNF) are allotropes of carbon featuring fibrous morphology. The dimensions and high aspect ratio of CNT and CNF have prompted the comparison with naturally occurring asbestos fibers which are known to be extremely pathogenic. While the toxicity and hazardous outcomes elicited by airborne exposure to single-walled CNT or asbestos have been widely reported, very limited data are currently available describing adverse effects of respirable CNF. Here, we assessed pulmonary inflammation, fibrosis, oxidative stress markers and systemic immune responses to respirable CNF in comparison to single-walled CNT (SWCNT) and asbestos. Pulmonary inflammatory and fibrogenic responses to CNF, SWCNT and asbestos varied depending upon the agglomeration state of the particles/fibers. Foci of granulomatous lesions and collagen deposition were associated with dense particle-like SWCNT agglomerates, while no granuloma formation was found following exposure to fiber-like CNF or asbestos. The average thickness of the alveolar connective tissue--a marker of interstitial fibrosis--was increased 28 days post SWCNT, CNF or asbestos exposure. Exposure to SWCNT, CNF or asbestos resulted in oxidative stress evidenced by accumulations of 4-HNE and carbonylated proteins in the lung tissues. Additionally, local inflammatory and fibrogenic responses were accompanied by modified systemic immunity, as documented by decreased proliferation of splenic T cells ex vivo on day 28 post exposure. The accuracies of assessments of effective surface area for asbestos, SWCNT and CNF (based on geometrical analysis of their agglomeration) versus estimates of mass dose and number of particles were compared as predictors of toxicological outcomes. We provide evidence that effective surface area along with mass dose rather than specific surface area or particle number are significantly correlated with toxicological responses to carbonaceous fibrous nanoparticles. Therefore, they could be useful dose metrics for risk assessment and management.


Carbonic anhydrase catalyzes cyanamide hydration to urea: is it mimicking the physiological reaction?
The interaction of human carbonic anhydrase (hCA) isozymes I and II with cyanamide, a linear molecule isoelectronic with the main physiological substrate of the enzyme, CO(2), was investigated through spectroscopic, kinetic, and X-ray crystallographic studies. We show here that cyanamide is hydrated to urea in the presence of CAs, and that it also acts as a weak non-competitive inhibitor (K(I)=61+/-3 mM and 238+/-9 mM for hCA II and hCA I, respectively) towards the esterasic activity of these enzymes, as tested with 4-nitrophenyl acetate. Changes in the spectrum of the Co(II)-hCA II derivative observed in the presence of cyanamide suggest that it likely binds the metal ion within the CA active site, adding to the coordination sphere, not substituting the metal-bound solvent molecule. It thereafter undergoes a nucleophilic attack from the metal-bound hydroxide ion, forming urea which remains bound to the metal, as observed in the X-ray crystal structure of hCA II soaked in cyanamide solutions for several hours. The urea molecule is directly coordinated to the active site Zn(II) ion through a protonated nitrogen atom. Several hydrogen bonds involving active site residues Thr199 and Thr200 as well as three water molecules (Wat99, Wat122, and Wat123) further stabilize the urea-hCA II adduct. Kinetic studies in solution further proved that urea acts as a tight binding inhibitor of the two isozymes hCA I and hCA II, with very slow binding kinetics (k(on) = 2.5 x 10(-5)s(-1)M(-1)). A mechanism to explain the hydration process of cyanamide by CAs, as well as the tight binding of urea in the active site, is also proposed based on the hypothesis that urea is deprotonated when bound to the enzyme. Cyanamide is thus the first true suicide substrate of this enzyme for which binding has been documented by means of X-ray crystallographic and spectroscopic studies.


Chemistry of the fullerenes: the manifestation of strain in a class of continuous aromatic molecules.
Within the wr-orbital axis vector theory, the total rehybridization required for closure of the fullerenes is approximately conserved. This result allows the development of a structure-based index of strain in the fullerenes, and it is estimated that about 80 percent of the heat of formation of the carbon atoms in C60 may be attributed to a combination of v strain and steric inhibition of resonance. Application of this analysis to the geometries of structurally characterized organometallic derivatives of C60 and C70 shows that the reactivity exhibited by the fullerenes may be attributed to the relief of a combination of local and global strain energy. C60 is of ambiguous aromatic character with anomalous magnetic properties but with the reactivity of a continuous aromatic molecule, moderated only by the tremendous strain inherent in the spheroidal structure.


At a crossroads of cancer risk and aging: the role of telomeres.
The risk of overall cancer inevitably increases with advancing age. The cancer incidence rate is not constant within the human life span (it exponentially increases with advancing age). Aging itself is a complex biological process with a poorly understood mechanism of its regulation. The aging process, as evidenced from the survey of the chances for death for the large cohort of people of various age groups, manifests probably due to a progressive accumulation of diverse adverse changes that increase the risk of death. While an increase of cancer risk due to aging cannot be fully explained, the length of telomeres (biomarker of aging) appears to be important to predict this risk. Cellular senescence, which is believed to be associated with dysfunctional (shortened) telomeres, may contribute to the aging of a whole organism. Here, based on recent literature data, we investigate the possible link between telomere dysfunction associated cellular senescence and tumorigenesis.


Association between gestational weight gain and perinatal outcomes in women with chronic hypertension.
Gestational weight gain above or below the 2009 National Academy of Medicine guidelines has been associated with adverse maternal and neonatal outcomes. Although it has been well established that excess gestational weight gain is associated with the development of gestational hypertension and preeclampsia, the relationship between gestational weight gain and adverse perinatal outcomes among women with pregestational (chronic) hypertension is less clear. The objective of this study was to examine the relationship between gestational weight gain above and below National Academy of Medicine guidelines and perinatal outcomes in a large, population-based cohort of women with chronic hypertension. This is a population-based retrospective cohort study of women with chronic hypertension who had term, singleton, vertex births in the United States from 2012 through 2014. Prepregnancy body mass index was calculated using self-reported prepregnancy weight and height. Women were categorized into 4 groups based on gestational weight gain and prepregnancy body mass index: (1) weight gain less than, (2) weight gain within, (3) weight gain 1-19 lb in excess of, and (4) weight gain ≥20 lb in excess of the National Academy of Medicine guidelines. The χ2 tests and multivariable logistic regression analysis were used for statistical comparisons. Stratified analyses by body mass index category were additionally performed. In this large birth cohort, 101,259 women met criteria for inclusion. Compared to hypertensive women who had gestational weight gain within guidelines, hypertensive women with weight gain ≥20 lb over National Academy of Medicine guidelines were more likely to have eclampsia (adjusted odds ratio, 1.93; 95% confidence interval, 1.54-2.42) and cesarean delivery (adjusted odds ratio, 1.60; 95% confidence interval, 1.50-1.70). Excess weight gain ≥20 lb over National Academy of Medicine guidelines was also associated with increased odds of 5-minute Apgar <7 (adjusted odds ratio, 1.29; 95% confidence interval, 1.13-1.47), neonatal intensive care unit admission (adjusted odds ratio, 1.23; 95% confidence interval, 1.14-1.33), and large-for-gestational-age neonates (adjusted odds ratio, 2.41; 95% confidence interval, 2.27-2.56) as well as decreased odds of small-for-gestational-age status (adjusted odds ratio, 0.52; 95% confidence interval, 0.46-0.58). Weight gain 1-19 lb over guidelines was associated with similar fetal growth outcomes although with a smaller effect size. In contrast, weight gain less than National Academy of Medicine guidelines was not associated with adverse maternal outcomes but was associated with increased odds of small for gestational age (adjusted odds ratio, 1.31; 95% confidence interval, 1.21-1.52) and decreased odds of large-for-gestational-age status (adjusted odds ratio, 0.86; 95% confidence interval, 0.81-0.92). Analysis of maternal and neonatal outcomes stratified by body mass index demonstrated similar findings. Women with chronic hypertension who gain less weight than National Academy of Medicine guidelines experience increased odds of small-for-gestational-age neonates, whereas excess weight gain ≥20 lb over National Academy of Medicine guidelines is associated with cesarean delivery, eclampsia, 5-minute Apgar <7, neonatal intensive care unit admission, and large-for-gestational-age neonates.


Treatment of metastatic pancreatic cancer.
Pancreatic adenocarcinoma represents the fourth-leading cause of cancer-related mortality in the United States. The vast majority of patients are diagnosed at advanced stages of the disease when surgery is no longer an option. For these patients, systemic therapy remains the mainstay of care. Although single-agent gemcitabine has remained the standard of care since its approval in 1997, improvements in patient outcomes may potentially be realized by (1) applying pharmacokinetic principles to optimize drug delivery, such as the administration of gemcitabine at a "fixed-dose rate" infusion; (2) combining gemcitabine with other cytotoxic agents for which evidence of synergy exists, such as platinum compounds; and (3) integrating novel targeted agents such as bevacizumab, erlotinib, and cetuximab into treatment paradigms, based on an increasing understanding of the molecular pathways that govern pancreatic tumor growth and maintenance. This article provides the evidence to support each of these approaches and highlights future directions in the management of metastatic pancreatic cancer.


Studying the local character of Raman features of single-walled carbon nanotubes along a bundle using TERS.
Here, we show that the Raman intensity of the G-mode in tip-enhanced Raman spectroscopy (TERS) is strongly dependent on the height of the bundle. Moreover, using TERS we are able to position different single-walled carbon nanotubes along a bundle, by correlating the observed radial breathing mode (RBM) with the AFM topography at the measuring point. The frequency of the G- mode behaves differently in TERS as compared to far-field Raman. Using the RBM frequency, the diameters of the tubes were calculated and a very good agreement with the G--mode frequency was observed.


Dynamic simulation as an approach to understanding hurricane risk response: insights from the Stormview lab.
This article investigates the use of dynamic laboratory simulations as a tool for studying decisions to prepare for hurricane threats. A prototype web-based simulation named Stormview is described that allows individuals to experience the approach of a hurricane in a computer-based environment. In Stormview participants can gather storm information through various media, hear the opinions of neighbors, and indicate intentions to take protective action. We illustrate how the ability to exert experimental control over the information viewed by participants can be used to provide insights into decision making that would be difficult to gain from field studies, such as how preparedness decisions are affected by the nature of news coverage of prior storms, how a storm's movement is depicted in graphics, and the content of word-of-mouth communications. Data from an initial application involving a sample of Florida residents reveal a number of unexpected findings about hurricane risk response. Participants who viewed forecast graphics, which contained track lines depicting the most likely path of the storm, for example, had higher levels of preparation than those who saw graphics that showed only uncertainty cones-even among those living far from the predicted center path. Similarly, the participants who were most likely to express worry about an approaching storm and fastest to undertake preparatory action were those who, ironically, had never experienced one. Finally, external validity is evidenced by a close rank-order correspondence between patterns of information use revealed in the lab and that found in previous cross-sectional field studies.


Effects of Qishe Pill, a compound traditional Chinese herbal medicine, on cervical radiculopathy: study protocol for a randomized controlled trial.
Neck pain is a common symptom in most patients suffering from cervical radiculopathy. However, some conservative treatments are limited by their modest effectiveness. On the other hand, surgical intervention for cervical disc disorders is indicated when symptoms are refractory to conservative treatments and neurological symptoms are progressive. Many patients use complementary and alternative medicine, including traditional Chinese medicine, to address their symptoms. The purpose of the present study is to examine the efficacy and safety of Qishe Pill, a compound traditional Chinese herbal medicine, for neck pain in patients with cervical radiculopathy. A multicenter, double-blind, randomized, placebo-controlled trial to evaluate the efficacy and safety of the Qishe Pill is proposed. The study will include 240 patients from five sites across China and diagnosed with cervical radiculopathy, according to the following inclusion criteria: age 18 to 65 with pain or stiffness in the neck for at least 2 weeks (neck disability index score 25 or more) and accompanying arm pain that radiates distally from the elbow. Qualified participants will be randomly allocated into two groups: Qishe Pill group and placebo group. The prescription of the trial medications (Qishe Pill/placebo) are 3.75 g each twice a day for 28 consecutive days. The primary outcome is pain severity. Secondary outcomes are functional status, patient satisfaction, and adverse events as reported in the trial. Qishe Pill is composed of processed Radix Astragali, Muscone, Szechuan Lovage Rhizome, Radix Stephaniae Tetrandrae, Ovientvine, and Calculus Bovis Artifactus. According to modern research and preparation standards, Qishe Pill is developed to improve on the various symptoms of cervical radiculopathy, especially for neck pain. As it has a potential benefit in treating patients with neck pain, we designed a double-blind, prospective, randomized-controlled trial and would like to publish the results and conclusions later. If Qishe Pill can alleviate neck pain without adverse effects, it may be a unique strategy for the treatment of cervical radiculopathy. This study is registered at ClinicalTrials.gov, NCT01274936.


Carbamates and ICH M7 classification: Making use of expert knowledge.
Carbamates are widely used in the chemical industry so understanding their toxicity is important to safety assessment. Carbamates have been associated with certain toxicities resulting in publication of structural alerts, including alerts for mutagenicity. Structural alerts for bacterial mutagenicity can be used in combination with statistical systems to enable ICH M7 classification, which allows assessment of the genotoxic risk posed by pharmaceutical impurities. This study tested a hypothetical bacterial mutagenicity alert for carbamates and examined the impact it would have on ICH M7 classifications using (Q)SAR predictions from the expert rule-based system Derek Nexus and the statistical-based system Sarah Nexus. Public datasets have a low prevalence of mutagenic carbamates, which highlighted that systems containing an alert for carbamates perform poorly for achieving correct ICH M7 classifications. Carbamates are commonly used as protecting groups and proprietary datasets containing such compounds were also found to have a low prevalence of mutagenic compounds. Expert review of the mutagenic compounds established that mutagenicity was often only observed under certain (non-standard) conditions and more generally that the Ames test may be a poor predictor for the risk of carcinogenicity posed by chemicals in this class. Overall a structural alert for the in vitro bacterial mutagenesis of carbamates does not benefit workflows for assigning ICH M7 classification to impurities.


Chordate betagamma-crystallins and the evolutionary developmental biology of the vertebrate lens.
Several animal lineages, including the vertebrates, have evolved sophisticated eyes with lenses that refract light to generate an image. The nearest invertebrate relatives of the vertebrates, such as the ascidians (sea squirts) and amphioxus, have only basic light detecting organs, leading to the widely-held view that the vertebrate lens is an innovation that evolved in early vertebrates. From an embryological perspective the lens is different from the rest of the eye, in that the eye is primarily of neural origin while the lens derives from a non-neural ectodermal placode which invaginates into the developing eye. How such an organ could have evolved has attracted much speculation. Recently, however, molecular developmental studies of sea squirts have started to suggest a possible evolutionary origin for the lens. First, studies of the Pax, Six, Eya and other gene families have indicated that sea squirts have areas of non-neural ectoderm homologous to placodes, suggesting an origin for the embryological characteristics of the lens. Second, the evolution and regulation of the betagamma-crystallins has been studied. These form one of the key crystallin gene families responsible for the transparency of the lens, and regulatory conservation between the betagamma-crystallin gene in the sea squirt Ciona intestinalis and the vertebrate visual system has been experimentally demonstrated. These data, together with knowledge of the morphological, physiological and gene expression similarities between the C. intestinalis ocellus and vertebrate retina, have led us to propose a hypothesis for the evolution of the vertebrate lens and integrated vertebrate eye via the co-option and combination of ancient gene regulatory networks; one controlling morphogenetic aspects of lens development and one controlling the expression of a gene family responsible for the biophysical properties of the lens, with the components of the retina having evolved from an ancestral photoreceptive organ derived from the anterior central nervous system.


Microsatellite instability and loss of heterozygosity of tumor suppressor genes in Bosnian patients with sporadic colorectal cancer.
Considering its frequency, high mortality rate as well as many etiological mysteries colorectal cancer is a challenge to contemporary science. In our study we analyzed RER + and RER--phenotypes and their relations with clinical-pathological characteristics of sporadic colorectal cancers. We also analyzed genetic alterations of tumor suppressor genes as well as their relation with microsatellite instability. The study was based on 54 tumor samples and 54 samples of the surrounding healthy tissue of patients with colorectal cancer. According to Amsterdam Criteria and Bethesda Criteria 35/54 or 64,81% belonged in the group of sporadic colorectal cancer. Mononucleotide marker Bat 25 showed instability in 48,57%; Bat 26 in 45,71% and Bat 40 in 29/35 82,86% of tumor samples. Considering dinucleotide markers, TP 53 showed instability in 54,29% and DS123 in 37,14% of tumor samples. Genetic alterations in tumor suppressor genes were found in tumor tissue: NM 23 in 54,29% samples, p53 in 51,43%, APC in 51,43%, DCC2 in 34,29%, RB1 in 22, 86% and DCC 1 in 28,57%. Our studies confirmed that genetic instability had an important role in the development of tumor type. Our results showed that mononucleotide marker Bat 40 might be used for an easy and fast screening procedure in Bosnian population, because it exhibited high percent of microsatellite instability and was in relation with RER+ phenotype. This investigation showed that different genetic alterations may occur during cancer development in each individual patient's tumor. These changes result in MMR inactivation, which causes RER+ phenotype. Our results suggest a connection between alteration in some tumor suppressor genes and MSI phenotype of sporadic colorectal cancer in Bosnian population.