Assessing the role of learning devices and geovisualisation tools for collective action in natural resource management: Experiences from Vietnam.
In northern Vietnam uplands the successive policy reforms that accompanied agricultural decollectivisation triggered very rapid changes in land use in the 1990s. From a centralized system of natural resource management, a multitude of individual strategies emerged which contributed to new production interactions among farming households, changes in landscape structures, and conflicting strategies among local stakeholders. Within this context of agrarian transition, learning devices can help local communities to collectively design their own course of action towards sustainable natural resource management. This paper presents a collaborative approach combining a number of participatory methods and geovisualisation tools (e.g., spatially explicit multi-agent models and role-playing games) with the shared goal to analyse and represent the interactions between: (i) decision-making processes by individual farmers based on the resource profiles of their farms; (ii) the institutions which regulate resource access and usage; and (iii) the biophysical and socioeconomic environment. This methodological pathway is illustrated by a case study in Bac Kan Province where it successfully led to a communication platform on natural resource management. In a context of rapid socioeconomic changes, learning devices and geovisualisation tools helped embed the participatory approach within a process of community development. The combination of different tools, each with its own advantages and constraints, proved highly relevant for supporting collective natural resource management.


Spontaneous Splenic Rupture Caused by Scrub Typhus.
Spontaneous rupture of the spleen is rarely described as a complication of scrub typhus infection. We report a previously healthy 74-year-old Thai female farmer who presented in Nakhon Ratchasima, Thailand, with a history of fever and malaise for 5 days, followed by abdominal pain for 1 day. An exploratory laparotomy was performed due to peritonitis. Operative findings revealed a ruptured spleen and hemoperitoneum. A splenectomy was performed afterward. Scrub typhus was confirmed by a 4-fold increase of IgM titer using an indirect immunofluorescence antibody assay and a positive result from the polymerase chain reaction targeting the 47- and 56-kDa genes in Orientia tsutsugamushi She responded well to intravenous chloramphenicol and defervesced within 24 hours without any complication.


Group parent training with immigrant chinese families: enhancing engagement and augmenting skills training.
Parent training (PT) is an evidence-based treatment for reducing and preventing child conduct problems and abusive parenting. However, questions have been raised about the dissemination of PT to culturally diverse families who hold different views on childrearing. Group PT was applied in two Chinese immigrant families illustrating strategies for addressing potential cultural barriers. The Incredible Years program builds in therapeutic process elements to address cultural concerns to enhance engagement. In addition, augmenting basic PT with additional skills training can help parents manage stressors common in immigrant families to facilitate uptake of new parenting skills. This implementation experience suggested that high-risk immigrant Chinese parents can be effectively engaged in group PT, even when they are not in treatment voluntarily.


Serologic examination of hepatitis B infection and immunization in HIV-positive youth and associated risks. The Pediatric AIDS Clinical Trials Group Protocol 220 Team.
This seroprevalence report examines serologic evidence of hepatitis B immunization or infection and associated demographic/behavioral factors in adolescent (aged 12-20) subjects enrolled in a nontherapeutic clinical trial at 43 Pediatric AIDS Clinical Trials Group (PACTG) clinical centers. Subjects (n = 94) infected with the human immunodeficiency virus (HIV) through sexual activity were categorized as hepatitis B virus (HBV)-immunized, HBV-infected, or nonimmune by hepatitis B serology performed on specimens collected within the subject's first 48 weeks on study (1993-1995). Sixteen percent of the 94 serologically classified subjects were immunized; 19% HBV-infected; 65% nonimmune. Of the three risk factor scores examined (sociodemographic, sexual, and substance abuse), substance use alone demonstrated a significant difference among groups (despite virtually no reported injecting drug behavior), with the sexual risk score exhibiting marginally significant differences. Logistic regression analysis (restricted to nonimmunized subjects) showed that male-male sexual activity raised the odds of HBV infection by a factor of 5.14 (95% confidence interval [CI]: 1.45-18. 23) relative to heterosexual activity; and that for every one point increase on the substance abuse risk scale the odds of infection increased 5% (95% CI: 0.99-1.10). The HBV infection rate in PACTG 220 HIV-positive females is twice United States population-based rates; the rate in PACTG 220 HIV-positive males is nearly seven times higher. Past immunization efforts in this population appear to have been based on sexual activity volume without regard to injecting-drug use in sex partners.


Exploring Provider Reactions to Decision Aid Distribution and Shared Decision Making: Lessons from Two Specialties.
A critical component of shared decision making (SDM) is the role played by health care providers in distributing decision aids (DAs) and initiating SDM conversations. Existing literature indicates that decisions about designing and implementing DAs must take provider perspectives into account. However, little is known about how differences in provider attitudes across specialties may impact DA implementation and how provider attitudes may shift after DA implementation. Group Health's Decision Aid Implementation project was carried out in six specialties using 12 video-based DAs for preference-sensitive conditions; this study focused on two of the six specialties. In-depth, qualitative interviews with specialty care providers in two specialties-orthopedics and cardiology-at two time points during DA implementation. Data were analyzed using a thematic analysis approach. We interviewed 19 care providers in orthopedics and cardiology. All respondents believed that providing patients with accurate information on their health conditions and treatment options was important and that most patients wanted an active role in decision making. However, respondents diverged in decision-making styles and views on the practicality and appropriateness of using the DAs and SDM. For example, cardiology specialists were ambivalent about DAs for coronary artery disease because many viewed DAs and SDM as unnecessary or inappropriate for this clinical condition. Provider attitudes towards DAs and SDM were generally stable over two years. Limitations include a lack of patient perspectives, social desirability bias, and possible selection bias. Successfully implementing DAs in clinical practice to promote SDM requires addressing individual provider attitudes, beliefs, and knowledge of SDM by specialty. During DA development and implementation, providers should be asked for input about the specific conditions and care processes that are most appropriate for SDM.


SNP technologies for drug discovery: a current review.
Single nucleotide polymorphisms (SNPs) are unique genetic differences between individuals that contribute in significant ways to the determination of human variation including physical characteristics like height and appearance as well as less obvious traits such as personality, behaviour and disease susceptibility. SNPs can also significantly influence responses to pharmacotherapy and whether drugs will produce adverse reactions. The development of new drugs can be made far cheaper and more rapid by selecting participants in drug trials based on their genetically determined response to drugs. Technology that can rapidly and inexpensively genotype thousands of samples for thousands of SNPs at a time is therefore in high demand. With the completion of the human genome project, about 12 million true SNPs have been identified to date. However, most have not yet been associated with disease susceptibility or drug response. Testing for the appropriate drug response SNPs in a patient requiring treatment would enable individualised therapy with the right drug and dose administered correctly the first time. Many pharmaceutical companies are also interested in identifying SNPs associated with polygenic traits so novel therapeutic targets can be discovered. This review focuses on technologies that can be used for genotyping known SNPs as well as for the discovery of novel SNPs associated with drug response.


Beyond resistance: social factors in the general public response to pandemic influenza.
Influencing the general public response to pandemics is a public health priority. There is a prevailing view, however, that the general public is resistant to communications on pandemic influenza and that behavioural responses to the 2009/10 H1N1 pandemic were not sufficient. Using qualitative methods, this paper investigates how members of the general public respond to pandemic influenza and the hygiene, social isolation and other measures proposed by public health. Going beyond the commonly deployed notion that the general public is resistant to public health communications, this paper examines how health individualism, gender and real world constraints enable and limit individual action. In-depth interviews (n = 57) and focus groups (ten focus groups; 59 individuals) were conducted with community samples in Melbourne, Sydney and Glasgow. Participants were selected according to maximum variation sampling using purposive criteria, including: 1) pregnancy in 2009/2010; 2) chronic illness; 3) aged 70 years and over; 4) no disclosed health problems. Verbatim transcripts were subjected to inductive, thematic analysis. Respondents did not express resistance to public health communications, but gave insight into how they interpreted and implemented guidance. An individualistic approach to pandemic risk predominated. The uptake of hygiene, social isolation and vaccine strategies was constrained by seeing oneself 'at risk' but not 'a risk' to others. Gender norms shape how members of the general public enact hygiene and social isolation. Other challenges pertained to over-reliance on perceived remoteness from risk, expectation of recovery from infection and practical constraints on the uptake of vaccination. Overall, respondents were engaged with public health advice regarding pandemic influenza, indicating that the idea of public resistance has limited explanatory power. Public communications are endorsed, but challenges persist. Individualistic approaches to pandemic risk inhibit acting for the benefit of others and may deepen divisions in the community according to health status. Public communications on pandemics are mediated by gender norms that may overburden women and limit the action of men. Social research on the public response to pandemics needs to focus on the social structures and real world settings and relationships that shape the action of individuals.


Memories from the polycomb group proteins.
The first genes composing the Polycomb group (PcG) were identified 50 years ago in Drosophila melanogaster as essential developmental functions that regulate the correct segmental expression of homeotic selector genes. In the past two decades, what was initially described as a large family of chromatin-associated proteins involved in the maintenance of transcriptional repression to maintain cellular memory of homeotic genes turned out to be a highly conserved and sophisticated network of epigenetic regulators that play key roles in multiple aspects of cell physiology and identity, including regulation of all developmental genes, cell differentiation, stem and somatic cell reprogramming and response to environmental stimuli. These myriad phenotypes further spread interest for the contribution that PcG proteins revealed in the pathogenesis and progression of cancer and other complex diseases. Recent novel insights have increasingly clarified the molecular regulatory mechanisms at the basis of PcG-mediated epigenetic silencing and opened new visions about PcG functions in cells. In this review, we focus on the multiple modes of action of the PcG complexes and describe their biological roles.


Cloning and characterization of Krct, a member of a novel subfamily of serine/threonine kinases.
Protein kinases frequently play key roles in the normal regulation of growth and development in eukaryotic organisms. As a consequence, aberrant expression or mutations in this family of molecules frequently result in transformation. Previously, we have conducted a screen to identify protein kinases that are expressed in the mouse during mammary gland development and in breast cancer cell lines. We now describe the molecular cloning, characterization and expression of Krct, a novel serine/threonine protein kinase unrelated to previously defined families of protein kinases. At the mRNA level, Krct is widely expressed throughout murine development and in adult tissues. Despite its ubiquitous expression, Krct is expressed preferentially within specific cellular compartments in multiple tissues, in particular within the testis and gastrointestinal tract. At the amino acid level, Krct is most closely related to four previously undescribed kinases in Saccharomyces cerevisiae, Arabidopsis thaliana and Caenorhabditis elegans. Together, these kinases appear to define a novel subfamily of serine/threonine protein kinases. Krct possesses an unusually long 5'-untranslated region containing multiple upstream initiation codons and, in this regard, is similar to many proto-oncogenes that regulate normal growth and differentiation. In addition, Krct is located on mouse chromosome 11 closely linked to the epidermal growth factor receptor and, therefore, is likely to be co-amplified in a variety of human tumors.


Surgical management of oral submucous fibrosis in an edentulous patient: A procedural challenge.
Prosthetic rehabilitation of patients with oral submucous fibrosis (OSMF) offers a formidable challenge due to restricted mouth opening. Physiotherapy via interocclusal force application is the mainstay for surgical treatment. Herein, we report a case of a man with OSMF requiring construction of dentures. The main objective was to deliver intra-operative and post operative inter occlusal forces without fracturing the mandible and thus providing rehabilitation to the patient prosthetically. An edentulous male patient reported with grade IVA OSMF to our department to improve his mouth opening for denture construction. The patient was managed successfully using surgical sectioning of the fibrous bands. Inter occlusal force application for mouth opening during the operation and post operative physiotherapy were facilitated using custom-made occlusal splints. Satisfactory mouth opening was achieved, with good healing and no event of infection or fracture. Here, we propose an easy method to achieve adequate mouth opening in an edentulous patient of OSMF, with atrophic ridges; without the chances of fracture of either jaw.


Clinical Characteristics, Oral Anticoagulation Patterns, and Outcomes of Medicaid Patients With Atrial Fibrillation: Insights From the Outcomes Registry for Better Informed Treatment of Atrial Fibrillation (ORBIT-AF I) Registry.
Whereas insurance status has been previously associated with care patterns, little is currently known about the association between Medicaid insurance and the clinical characteristics, treatment, or outcomes of patients with atrial fibrillation (AF). We used data from adults with AF enrolled in the Outcomes Registry for Better Informed Treatment of AF (ORBIT-AF), a national outpatient registry conducted at 176 community, multispecialty sites. The primary outcome of interest was the proportion of patients prescribed any oral anticoagulation (OAC; warfarin or novel oral anticoagulants [NOAC]). Secondary outcomes of interest included the proportion of patients prescribed NOACs (dabigatran or rivaroxaban); time in therapeutic range (TTR) for warfarin users, all-cause mortality, stroke/systemic embolism, and major bleed. Of 10 133 patients, N=470 (4.6%) had Medicaid insurance. Medicaid patients were similarly likely to receive OAC at baseline (72.8% vs 76.3%; unadjusted P=0.079), but less likely to receive NOAC at baseline or follow-up (12.1% vs 16.3%; unadjusted P=0.019). After risk adjustment, Medicaid status was associated with lower use of OAC at baseline among patients with high stroke risk (odds ratio [OR]=0.68; 95% CI=0.49, 0.94), but was not associated with OAC use overall (OR=0.82; 95% CI=0.61, 1.09). Among warfarin users, median TTR was lower among Medicaid patients (60% vs 68%; P<0.0001; adjusted TTR difference, -2.9; 95% CI=-5.7, -0.2; P=0.04). Use of an NOAC over 2 years of follow-up was not statistically different by insurance. Compared with non-Medicaid patients, Medicaid patients had higher unadjusted rates of mortality, stroke/systemic embolism, and major bleeding; however, these differences were attenuated following adjustment for clinical characteristics. In a contemporary AF cohort, use of OAC overall and use of NOACs were not significantly lower among Medicaid patients relative to others. However, among warfarin users, Medicaid patients spent less time in therapeutic range compared with those with other forms of insurance.


Psychophysical estimates of the number of spectral-reflectance basis functions needed to reproduce natural scenes.
Theoretical analyses of spectral reflectances of natural surfaces suggest that their perceived colors can be well reproduced by approximations comprising combinations of three or four spectral basis functions. The aim of the present work was to assess psychophysically the number of basis functions necessary to reproduce entire natural outdoor scenes. Hyperspectral images of 20 such scenes were each subjected to a principal component analysis and then reproduced with a variable number of basis functions. The quality of the color approximation under daylight illumination was quantified theoretically in CIELAB space and psychophysically by spatial and temporal two-alternative forced-choice measurements in which the original and the approximated images were compared on a calibrated color monitor. Although five basis functions produced on average unit error in CIELAB space, original images were visually indistinguishable from their approximations only if there were at least eight basis functions. The combination of the spectral diversity of the natural world and the observed levels of color discrimination suggest that estimates of the minimum number of basis functions necessary to reproduce natural scenes may need to be revised upward.


Cross-Foster Rederivation Compared with Antibiotic Administration in the Drinking Water to Eradicate Bordetella pseudohinzii.
Bordetella pseudohinzii is a microbial agent of potential importance in mice and has confounded pulmonary research at our institution. The purpose of this study was to evaluate cross-foster rederivation and antibiotic administration in the drinking water as methods to eradicate B. pseudohinzii. To evaluate the efficacy of cross-foster rederivation, 29 litters representing 16 strains of mice were cross-fostered from cages positive for B. pseudohinzii to B. pseudohinzii-negative Crl:CD1-Elite surrogate dams. To evaluate antibiotic administration, sulfamethoxazole and trimethoprim (TMS; 0.66 and 0.13 mg/mL, respectively) and tetracycline (4.5 mg/mL) were administered in the drinking water. We assessed 3 antibiotic treatment groups with 12 B. pseudohinzii-positive cages per group (6 cages of CD1 and 6 cages of C57BL/6 mice): TMS for 4 wk, TMS for 6 wk, and tetracycline for 6 wk. Of the 29 litters that underwent cross-foster rederivation, 24 were negative for B. pseudohinzii. Five of the 12 cages treated with TMS for 4 wk and 1 of the 12 cages treated with TMS for 6 wk were negative for B. pseudohinzii at 2 wk after treatment. Three of the 12 cages treated with tetracycline were negative for B. pseudohinzii at 2 wk after treatment. Pearson χ2 analysis revealed significant association between the method of eradication (cross-foster rederivation compared with antibiotic administration) and B. pseudohinzii infection, and an odds-ratio estimate from a logistic regression demonstrated that cross-foster rederivation was more successful. Whereas antibiotic administration in the drinking water failed to eradicate B. pseudohinzii, cross-foster rederivation was successful and has been used to establish a B. pseudohinzii-negative barrier.


A highly active catalyst for Pd-catalyzed amination reactions: cross-coupling reactions using aryl mesylates and the highly selective monoarylation of primary amines using aryl chlorides.
A catalyst system based on a new biarylmonophosphine ligand (BrettPhos) that shows excellent reactivity for C-N cross-coupling reactions is reported. This catalyst system enables the use of aryl mesylates as a coupling partner in C-N bond-forming reactions. Additionally, the use of BrettPhos permits the highly selective monoarylation of an array of primary aliphatic amines and anilines at low catalyst loadings and with fast reaction times, including the first monoarylation of methylamine. Lastly, oxidative addition complexes of BrettPhos are included, which provide insight into the origin of reactivity for this system.


Chemical proteomic profiles of the BCR-ABL inhibitors imatinib, nilotinib, and dasatinib reveal novel kinase and nonkinase targets.
The BCR-ABL tyrosine kinase inhibitor imatinib represents the current frontline therapy in chronic myeloid leukemia. Because many patients develop imatinib resistance, 2 second-generation drugs, nilotinib and dasatinib, displaying increased potency against BCR-ABL were developed. To predict potential side effects and novel medical uses, we generated comprehensive drug-protein interaction profiles by chemical proteomics for all 3 drugs. Our studies yielded 4 major findings: (1) The interaction profiles of the 3 drugs displayed strong differences and only a small overlap covering the ABL kinases. (2) Dasatinib bound in excess of 30 Tyr and Ser/Thr kinases, including major regulators of the immune system, suggesting that dasatinib might have a particular impact on immune function. (3) Despite the high specificity of nilotinib, the receptor tyrosine kinase DDR1 was identified and validated as an additional major target. (4) The oxidoreductase NQO2 was bound and inhibited by imatinib and nilotinib at physiologically relevant drug concentrations, representing the first nonkinase target of these drugs.


Trafficking, acidification, and growth factor signaling.
Wnt and Notch signaling pathways play key roles in development and disease. Despite great progress, the mechanism of signal transduction of their receptor-ligand complexes still holds surprises. For example, in both pathways, endocytosis is required for downstream signaling, but the mechanism by which endocytosis permits signaling is still unknown. New evidence indicates that endocytosis is required for the receptor-ligand complex to reach an acidified vesicular compartment. In turn, enzymes responsible for acidification are essential for Notch and Wnt signaling and also directly interact with the receptors. These findings raise new questions concerning the mechanism by which low pH promotes signal transduction and may open new possibilities for therapeutic intervention through the targeting of acidifying enzymes.


Spectroelectrochemical and computational studies of tetrahydrocannabinol (THC) and carboxy-tetrahydrocannabinol (THC-COOH).
Rapid and accurate detection of tetrahydrocannabinol (THC) and its main secondary metabolite carboxy-tetrahydrocannabinol (THC-COOH) is important to ensure safe roadways and workplaces, particularly in regions of the world where cannabis use is legal. In this work, we seek to demonstrate the usefulness of electrochemical SERS (EC-SERS) for the rapid detection of both THC and THC-COOH, complemented by thorough ab initio calculations for both molecules. These results indicate that application of a voltage is essential for efficient SERS detection of cannabinoids at low concentrations in bodily fluids, allowing for the eventual development of sensitive and quantitative screening tools. To the best of our knowledge, this work represents the first EC-SERS study of both THC and THC-COOH.


Warm-up and muscular injury prevention. An update.
Musculotendinous injuries are responsible for a significant proportion of injuries incurred by athletes. Many of these injuries are preventable. Importantly, musculotendinous injuries have a high incidence of recurrence. Thus, muscle injury prevention is advocated by coaches and trainers. Yet, most of the recommendations for muscle injury prevention are attempted by athletes and taught by coaches without supporting scientific evidence. This paper reviews the mechanics of muscular injury, associated and predisposing factors, and methods of prevention with a review of the supporting research and rationale for these methods with an emphasis on warm-up, stretching and strengthening. Muscles that are capable of producing a greater force, a faster contraction speed and subjected to a greater stretch are more likely to become injured. Many factors have been associated with muscular injury. From current research, some conclusions and recommendations for muscle injury prevention can be made. Overall and muscular conditioning and nutrition are important. Proper training and balanced strengthening are key factors in prevention of musculotendinous injuries as well. Warm-up and stretching are essential to preventing muscle injuries by increasing the elasticity of muscles and smoothing muscular contractions. Improper or excessive stretching and warming up can, however, predispose to muscle injury. Much research is still needed in this important aspect of sports medicine.


Setting clock speed in mammals: the CK1 epsilon tau mutation in mice accelerates circadian pacemakers by selectively destabilizing PERIOD proteins.
The intrinsic period of circadian clocks is their defining adaptive property. To identify the biochemical mechanisms whereby casein kinase1 (CK1) determines circadian period in mammals, we created mouse null and tau mutants of Ck1 epsilon. Circadian period lengthened in CK1epsilon-/-, whereas CK1epsilon(tau/tau) shortened circadian period of behavior in vivo and suprachiasmatic nucleus firing rates in vitro, by accelerating PERIOD-dependent molecular feedback loops. CK1epsilon(tau/tau) also accelerated molecular oscillations in peripheral tissues, revealing its global role in circadian pacemaking. CK1epsilon(tau) acted by promoting degradation of both nuclear and cytoplasmic PERIOD, but not CRYPTOCHROME, proteins. Together, these whole-animal and biochemical studies explain how tau, as a gain-of-function mutation, acts at a specific circadian phase to promote degradation of PERIOD proteins and thereby accelerate the mammalian clockwork in brain and periphery.


Model-specific tests on variance heterogeneity for detection of potentially interacting genetic loci.
Trait variances among genotype groups at a locus are expected to differ in the presence of an interaction between this locus and another locus or environment. A simple maximum test on variance heterogeneity can thus be used to identify potentially interacting single nucleotide polymorphisms (SNPs). We propose a multiple contrast test for variance heterogeneity that compares the mean of Levene residuals for each genotype group with their average as an alternative to a global Levene test. We applied this test to a Bogalusa Heart Study dataset to screen for potentially interacting SNPs across the whole genome that influence a number of quantitative traits. A user-friendly implementation of this method is available in the R statistical software package multcomp. We show that the proposed multiple contrast test of model-specific variance heterogeneity can be used to test for potential interactions between SNPs and unknown alleles, loci or covariates and provide valuable additional information compared with traditional tests. Although the test is statistically valid for severely unbalanced designs, care is needed in interpreting the results at loci with low allele frequencies.


Biochemical and spectroscopic characterization of overexpressed fuscoredoxin from Escherichia coli.
Fuscoredoxin is a unique iron containing protein of yet unknown function originally discovered in the sulfate reducers of the genus Desulfovibrio. It contains two iron-sulfur clusters: a cubane [4Fe-4S] and a mixed oxo- and sulfido-bridged 4Fe cluster of unprecedented structure. The recent determination of the genomic sequence of Escherichia coli (E. coli) has revealed a homologue of fuscoredoxin in this facultative microbe. The presence of this gene in E. coli raises interesting questions regarding the function of fuscoredoxin and whether this gene represents a structural homologue of the better-characterized Desulfovibrio proteins. In order to explore the latter, an overexpression system for the E. coli fuscoredoxin gene was devised. The gene was cloned from genomic DNA by use of the polymerase chain reaction into the expression vector pT7-7 and overexpressed in E. coli BL21(DE3) cells. After two chromatographic steps a good yield of recombinant protein was obtained (approximately 4 mg of pure protein per liter of culture). The purified protein exhibits an optical spectrum characteristic of the homologue from D. desulfuricans, indicating that cofactor assembly was accomplished. Iron analysis indicated that the protein contains circa 8 iron atoms/molecule which were shown by EPR and Mössbauer spectroscopies to be present as two multinuclear clusters, albeit with slightly altered spectroscopic features. A comparison of the primary sequences of fuscoredoxins is presented and differences on cluster coordination modes are discussed on the light of the spectroscopic data.


The influence of anxiety on visual attentional control in basketball free throw shooting.
The aim of this study was to test the predictions of attentional control theory using the quiet eye period as an objective measure of attentional control. Ten basketball players took free throws in two counterbalanced experimental conditions designed to manipulate the anxiety they experienced. Point of gaze was measured using an ASL Mobile Eye tracker and fixations including the quiet eye were determined using frame-by-frame analysis. The manipulation of anxiety resulted in significant reductions in the duration of the quiet eye period and free throw success rate, thus supporting the predictions of attentional control theory. Anxiety impaired goal-directed attentional control (quiet eye period) at the expense of stimulus-driven control (more fixations of shorter duration to various targets). The findings suggest that attentional control theory may be a useful theoretical framework for examining the relationship between anxiety and performance in visuomotor sport skills.


Overcoming the detectability costs of symmetrical coloration.
For camouflaged prey, enhanced conspicuousness due to bilaterally symmetrical coloration increases predation risk. The ubiquity of symmetrical body patterns in nature is therefore paradoxical, perhaps explicable through tight developmental constraints. Placing patterns that would be salient when symmetrical (e.g. high contrast markings) away from the axis of symmetry is one possible strategy to reduce the predation cost of symmetrical coloration. Artificial camouflaged prey with symmetrical patterns placed at different distances from the axis were used in both visual search tasks with humans and survival experiments with wild avian predators. Targets were less conspicuous when symmetrical patterning was placed outside a 'critical zone' near the midline. To assess whether real animals have evolved as predicted from these experiments, the saliency of features at different distances from the midline was measured in the cryptically coloured forewings of 36 lepidopteran species. Salience, both in absolute terms and relative to wing area, was greatest away from the axis of symmetry. Our work, therefore, demonstrates that prey morphologies may have evolved to exploit a loophole in the ability of mammalian and avian visual systems to spot symmetrical patterns.


N-methyl-D-aspartate receptor 1 in the caudate-putamen nucleus: ultrastructural localization and co-expression with sorcin, a 22,000 mol. wt calcium binding protein.
Entry of calcium through N-methyl-D-aspartate-type glutamate receptors in the caudate-putamen nucleus is essential for normal motor activity, but can produce cytotoxicity with continued stimulation and subsequent release of intracellular calcium. To determine potential functional sites for N-methyl-D-aspartate receptor activation in this region, we examined the ultrastructural localization of the R1 subunit of the N-methyl-D-aspartate receptor (NMDAR1) in rat brain. In addition, we comparatively examined the localization of NMDAR1 and sorcin, a 22,000 mol. wt calcium binding protein present in certain striatal neurons and involved in calcium-induced calcium release. NMDAR1-like immunoreactivity was seen at synaptic and non-synaptic sites on neuronal plasma membranes. Of 1514 NMDAR1-labeled profiles, 62% were dendrites and dendritic spines and the remainder were mainly unmyelinated axons and axon terminals. Sorcin-like immunoreactivity was present in 39% of the profiles that contained NMDAR1 labeling, most (533/595) of which were dendrites and dendritic spines. Of 1807 sorcin-labeled profiles, 42% were identified, however, as small processes including spine necks and unmyelinated axons or axon terminals. These profiles also occasionally contained NMDAR1 or showed synaptic or appositional contacts with other NMDAR1-immunoreactive neurons. The results of this study suggest that in the caudate-putamen nucleus, activation of NMDA receptors permits calcium influx at plasmalemmal sites mainly on dendrites where sorcin may play a role in calcium-induced calcium release. The presence of sorcin in some, but not all NMDA-containing neurons in the caudate-putamen nucleus has potential implications for the known differential vulnerability of certain striatal neurons to excitotoxins.


Renal physiology of pregnancy.
Pregnancy involves remarkable orchestration of physiologic changes. The kidneys are central players in the evolving hormonal milieu of pregnancy, responding and contributing to the changes in the environment for the pregnant woman and fetus. The functional impact of pregnancy on kidney physiology is widespread, involving practically all aspects of kidney function. The glomerular filtration rate increases 50% with subsequent decrease in serum creatinine, urea, and uric acid values. The threshold for thirst and antidiuretic hormone secretion are depressed, resulting in lower osmolality and serum sodium levels. Blood pressure drops approximately 10 mmHg by the second trimester despite a gain in intravascular volume of 30% to 50%. The drop in systemic vascular resistance is multifactorial, attributed in part to insensitivity to vasoactive hormones, and leads to activation of the renin-aldosterone-angiostensin system. A rise in serum aldosterone results in a net gain of approximately 1000 mg of sodium. A parallel rise in progesterone protects the pregnant woman from hypokalemia. The kidneys increase in length and volume, and physiologic hydronephrosis occurs in up to 80% of women. This review will provide an understanding of these important changes in kidney physiology during pregnancy, which is fundamental in caring for the pregnant patient.


Production of a high level of specific IgG4 antibody associated with resistance to albendazole treatment in HLA-DRB1*0901-positive patients with strongyloidiasis.
Strongyloidiasis, a human intestinal infection with Strongyloides stercoralis, is difficult to treat with drugs. The factors influencing this phenomenon remain unclear. To determine the host factors involved in response to treatment, 46 patients with strongyloidiasis were treated with albendazole, followed-up for 1 year, and separated into two groups: cured and non-cured. Serum levels of specific IgA, IgE, IgG, IgG1, and IgG4 antibodies were estimated using S. stercoralis antigen. Significantly higher titers of IgG4 antibody were observed in the non-cured group than in the cured group (P = 0.016). A total of 88 patients were typed for HLA-DRB1 alleles and analyzed for serum levels of antibody. The S. stercoralis-specific IgG4 antibody titers were significantly higher in the HLA-DRB1*0901-positive group than in the negative group (corrected P = 0.044). These results suggest that HLA-DRB1*0901 is a possible genetic marker for resistance to treatment of S. stercoralis that is associated with elevation of S. stercoralis-specific IgG4 antibody titer.


The impact of Wii Fit intervention on dynamic balance control in children with probable Developmental Coordination Disorder and balance problems.
The aim of this study was to examine differences in the performance of children with probable Developmental Coordination Disorder (p-DCD) and balance problems (BP) and typical developing children (TD) on a Wii Fit task and to measure the effect on balance skills after a Wii Fit intervention. Twenty-eight children with BP and 20 TD-children participated in the study. Motor performance was assessed with the Movement Assessment Battery for Children (MABC2), three subtests of the Bruininks Oseretsky Test (BOT2): Bilateral Coordination, Balance and Running Speed & Agility, and a Wii Fit ski slalom test. The TD children and half of the children in the BP group were tested before and after a 6weeks non-intervention period. All children with BP received 6weeks of Wii Fit intervention (with games other than the ski game) and were tested before and afterwards. Children with BP were less proficient than TD children in playing the Wii Fit ski slalom game. Training with the Wii Fit improved their motor performance. The improvement was significantly larger after intervention than after a period of non-intervention. Therefore the change cannot solely be attributed to spontaneous development or test-retest effect. Nearly all children enjoyed participation during the 6weeks of intervention. Our study shows that Wii Fit intervention is effective and is potentially a method to support treatment of (dynamic) balance control problems in children.


Deep generative modeling for single-cell transcriptomics.
Single-cell transcriptome measurements can reveal unexplored biological diversity, but they suffer from technical noise and bias that must be modeled to account for the resulting uncertainty in downstream analyses. Here we introduce single-cell variational inference (scVI), a ready-to-use scalable framework for the probabilistic representation and analysis of gene expression in single cells ( https://github.com/YosefLab/scVI ). scVI uses stochastic optimization and deep neural networks to aggregate information across similar cells and genes and to approximate the distributions that underlie observed expression values, while accounting for batch effects and limited sensitivity. We used scVI for a range of fundamental analysis tasks including batch correction, visualization, clustering, and differential expression, and achieved high accuracy for each task.


The role of erbB-2 and its ligands in growth control of malignant breast epithelium.
A wealth of recently derived information has strongly implicated the protooncogene erbB-2 (also termed HER-2 or neu) and its protein product as critically involved in human breast cancer as well as other important epithelial malignancies. Because of its substantial homology with the EGF receptor, erbB-2 has long been assumed to encode a growth factor receptor, although until recently definitive identification of ligand(s) has remained elusive. Both in a mutated form and when overexpressed in a non-mutated form, erbB-2 is capable of inducing malignant transformation of many target cells including immortalized breast epithelium. We have recently identified and purified a 30 kDa size growth factor secreted by some human breast cancer cells. The factor is related to transforming growth factor-alpha (TGF-alpha) in its ability to bind to the epidermal growth factor (EGF) receptor (though with about 10 fold lower apparent affinity), its ability to phosphorylate EGF receptor and its ability to induce cloning of normal rat kidney (NRK) fibroblasts. However, it is distinct from TGF-alpha as determined by peptide mapping and its ability to induce activation of erbB-2. TGF-alpha and EGF are incapable of directly inducing phosphorylation of erbB-2. However, in a variety of spontaneously occurring tumor cells as well as cell lines transfected with erbB-2 prepared in our laboratory, 30 kDa glycoprotein (gp30) is capable of inducing direct phosphorylation of erbB-2. The ability to induce phosphorylation of erbB-2 is not inhibited by an anti-EGF receptor blocking antibody. In cells that overexpress erbB-2, the gp30 low concentrations is stimulatory of both standard mitogenesis assays and in clonogenic assays. At higher concentrations, the ligand is growth inhibitory in both of these assays. Because of the ability of gp30 to compete for binding with antibodies directed against erbB-2 which inhibit growth, the gp30 ligand is capable of reversing antibody-induced inhibition of growth. In addition, the gp30 ligand can overcome inhibitory effects seen in cells which overexpress erbB-2 which are induced by extracellular domain fragments of the erbB-2 receptor, once again suggesting a specific pathway of action for the gp30 ligand mediated for interaction with erbB-2.(ABSTRACT TRUNCATED AT 400 WORDS)


Combining information across frequency regions in fundamental frequency discrimination.
Sensitivity to fundamental frequency (F0) differences was measured for two complex tones, A and B, which had the same F0 but were filtered into two different frequency regions. Tones were presented either alone or together. A signal-detection analysis was used to predict effects of combining F0 information across frequency regions. For 400-ms tones containing only unresolved harmonics, the first experiment showed that performance (in terms of d(')) for the combined presentation was better than for the isolated tones but was not optimal (assuming independent channels and noises) and was independent of the relative timing of pulses in the envelopes of tones A and B (varied by changing the starting phase of components of tone B relative to those of tone A). The nonoptimal performance was shown not to be due to peripheral masking (experiment II), or to listeners paying attention mainly to one frequency region (experiment III), nor was it specific to conditions where all harmonics were unresolved (experiment IV). In contrast, optimal performance in F0 discrimination for combined presentation was observed for 50-ms tones (experiment V). The results may reflect the limited ability of the human auditory system to integrate information simultaneously in the time and the frequency domains.


Probing Structural Perturbation in a Bent Molecular Crystal with Synchrotron Infrared Microspectroscopy and Periodic Density Functional Theory Calculations.
The range of unit cell orientations generated at the kink of a bent single crystal poses unsurmountable challenges with diffraction analysis and limits the insight into the molecular-scale mechanism of bending. On a plastically bent crystal of hexachlorobenzene, it is demonstrated here that spatially resolved microfocus infrared spectroscopy using synchrotron radiation can be applied in conjunction with periodic density functional theory calculations to predict spectral changes or to extract information on structural changes that occur as a consequence of bending. The approach reproduces well the observed trends, such as the wall effects, and provides estimations of the vibrational shifts, unit cell deformations, and intramolecular parameters. Generally, expansion of the lattice induces red-shift while compression induces larger blue-shift of the characteristic ν(C-C) and ν(C-Cl) modes. Uniform or non-uniform expansion or contraction of the unit cell of 0.1 Å results in shifts of several cm-1, whereas deformation of the cell of 0.5° at the unique angle causes shifts of <0.5 cm-1. Since this approach does not include parameters related to the actual stimulus by which the deformation has been induced, it can be generalized and applied to other mechanically, photochemically, or thermally bent crystals.


Sexual and Reproductive Health Research and Research Capacity Strengthening in Africa: Perspectives from the region.
Developing the capacity to effectively carry out public health research is an integral part of health systems at both the national and global levels and strengthening research capacity is recognized as an approach to better health and development in low- and middle-income countries (LMICs). Especially fields such as sexual and reproductive health (SRH) would require inter-disciplinary teams of researchers equipped with a range of methodologies to achieve this. In November 2013, as part of the International Family Planning Conference in Addis Ababa, Ethiopia, a group of African researchers came together to discuss the gaps and strategies to improve sexual and reproductive health research and research capacity strengthening in Africa. This commentary summarizes the three broad areas where the issues and proposed solutions have concentrated around: 1) Addressing research gaps that are most relevant to policies and programmes in SRH, 2) Carrying out high quality and collaborative research, and 3) Translating research findings into SRH policies and programmes. Even though the focus of the discussions was Africa, the issues and proposed solutions can also be applied to other regions facing a high burden of disease with limited resources. The time is now and these can be achieved through synergistic commitment of African and global researchers, funders and organizations.


Yet1p and Yet3p, the yeast homologs of BAP29 and BAP31, interact with the endoplasmic reticulum translocation apparatus and are required for inositol prototrophy.
The mammalian B-cell receptor-associated proteins of 29 and 31 kDa (BAP29 and BAP31) are conserved integral membrane proteins that have reported roles in endoplasmic reticulum (ER) quality control, ER export of secretory cargo, and programmed cell death. In this study we investigated the yeast homologs of BAP29 and BAP31, known as Yet1p and Yet3p, to gain insight on cellular function. We found that Yet1p forms a complex with Yet3p (Yet complex) and that complex assembly was important for subunit stability and proper ER localization. The Yet complex was not efficiently packaged into ER-derived COPII vesicles and therefore does not appear to act as an ER export receptor. Instead, a fraction of the Yet complex was detected in association with the ER translocation apparatus (Sec complex). Specific mutations in the Sec complex or Yet complex influenced these interactions. Moreover, associations between the Yet complex and Sec complex were increased by ER stress and diminished when protein translocation substrates were depleted. Surprisingly, yet1Delta and yet3Delta mutant strains displayed inositol starvation-related growth defects. In accord with the biochemical data, these growth defects were exacerbated by a combination of certain mutations in the Sec complex with yet1Delta or yet3Delta mutations. We propose a model for the Yet-Sec complex interaction that places Yet1p and Yet3p at the translocation pore to manage biogenesis of specific transmembrane secretory proteins.


FOXD1 mutations are related to repeated implantation failure, intra-uterine growth restriction and preeclampsia.
Human reproductive disorders consist of frequently occurring dysfunctions including a broad range of phenotypes affecting fertility and women's health during pregnancy. Several female-related diseases have been associated with hypofertility/infertility phenotypes, such as recurrent pregnancy loss (RPL). Other occurring diseases may be life-threatening for the mother and foetus, such as preeclampsia (PE) and intra-uterine growth restriction (IUGR). FOXD1 was defined as a major molecule involved in embryo implantation in mice and humans by regulating endometrial/placental genes. FOXD1 mutations in human species have been functionally linked to RPL's origin. FOXD1 gene mutation screening, in 158 patients affected by PE, IUGR, RPL and repeated implantation failure (RIF), by direct sequencing and bioinformatics analysis. Plasmid constructs including FOXD1 mutations were used to perform in vitro gene reporter assays. Nine non-synonymous sequence variants were identified. Functional experiments revealed that p.His267Tyr and p.Arg57del led to disturbances of promoter transcriptional activity (C3 and PlGF genes). The FOXD1 p.Ala356Gly and p.Ile364Met deleterious mutations (previously found in RPL patients) have been identified in the present work in women suffering PE and IUGR. Our results argue in favour of FOXD1 mutations' central role in RPL, RIF, IUGR and PE pathogenesis via C3 and PlGF regulation and they describe, for the first time, a functional link between FOXD1 and implantation/placental diseases. FOXD1 could therefore be used in clinical environments as a molecular biomarker for these diseases in the near future.


SCORE Study report 3: study design and baseline characteristics.
To describe the baseline characteristics of the participants in the Standard Care versus COrticosteroid for REtinal Vein Occlusion (SCORE) Study and to compare with cohorts from other retinal vein occlusion trials. The design of the SCORE Study is also described. Two, multicenter, Phase III, randomized clinical trials, one involving participants with central retinal vein occlusion (CRVO) and one involving participants with branch retinal vein occlusion (BRVO). A total of 682 participants, including 271 with CRVO and 411 with BRVO. Demographic and study eye characteristics are summarized and compared between the CRVO and BRVO study participants. Baseline ophthalmic characteristics, including visual acuity and duration of macular edema before enrollment, and medical history characteristics, including diabetes mellitus and hypertension. In the CRVO trial, at baseline, mean visual acuity letter score was 51 ( approximately 20/100), mean optical coherence tomography (OCT)-measured central subfield thickness was 595 microns, mean area of retinal thickening in the macular grid on color photography was 12.3 disc areas (DA), and mean area of fluorescein leakage was 11.0 DA. In the BRVO trial, at baseline, mean visual acuity letter score was 57 ( approximately 20/80), mean OCT-measured central subfield thickness was 491 microns, mean area of retinal thickening in the macular grid on color photography was 7.5 DA, and the mean area of fluorescein leakage was 6.1 DA. Differences observed in baseline visual acuity, OCT-measured retinal thickness, area of retinal thickening on color photography, and area of fluorescein leakage support the evaluation of CRVO and BRVO in separate trials. The authors have no proprietary or commercial interest in any of the materials discussed in this article.


Trends in up-to-date status in colorectal cancer screening, North Carolina, 1998-2002.
Rates of colorectal cancer (CRC) screening are rising nationwide. Our purpose was to determine the proportion of North Carolina adults who were up-to-date with CRC screening in 1998-2002 and analyze trends by socio-demographic subgroups. We examined data from the North Carolina Behavioral Risk Factor Surveillance System. For 1998, 1999, 2001, and 2002, we determined the proportion of respondents 50 years old and older who were up-to-date, defined as a home fecal occult blood test (FOBT) in the past 12 months and/or a sigmoidoscopy or colonoscopy in the past five years. We examined trends in up-to-date status in all respondents and in selected socio-demographic subgroups. We also examined the characteristics of respondents who were up-to-date in 2001-2002. From 1998-2002, the percentage of respondents 50 years old or older who were up-to-date with CRC screening increased from 46.1% to 54.0% (test for trend, p < 0.0001). The proportion who were up-to-date increased among those 50-74 years old, those with a high school or college education, and those with incomes less than dollar 25,000. Proportions that were up-to-date did not significantly increase among African Americans and respondents with less than a high school education. In 2001-2002, we found low percentages that were up-to-date among adults 50-54 years old Hispanics, and the uninsured The proportion of North Carolina adults who are up-to-date with CRC screening is increasing but not across all socio-demographic groups. These results indicate that there are subgroups that need to be reached with screening programs. Efforts to educate the public and providers about CRC screening should continue.


The estrogen receptor variants β2 and β5 induce stem cell characteristics and chemotherapy resistance in prostate cancer through activation of hypoxic signaling.
Chemotherapy resistant prostate cancer is a major clinical problem. When the prostate cancer has become androgen deprivation resistant, one of the few treatment regimens left is chemotherapy. There is a strong connection between a cancer's stem cell like characteristics and drug resistance. By performing RNA-seq we observed several factors associated with stem cells being strongly up-regulated by the estrogen receptor β variants, β2 and β5. In addition, most of these factors were also up-regulated by hypoxia. One mechanism of chemotherapy resistance was expression of the hypoxia-regulated, drug transporter genes, where especially ABCG2 and MDR1 were shown to be expressed in recurrent prostate cancer and to cause chemotherapy resistance by efficiently transporting drugs like docetaxel out of the cells. Another mechanism was expression of the hypoxia-regulated Notch3 gene, which causes chemotherapy resistance in urothelial carcinoma, although the mechanism is unknown. It is well known that hypoxic signaling is involved in increasing chemotherapy resistance. Regulation of the hypoxic factors, HIF-1α and HIF-2α is very complex and extends far beyond hypoxia itself. We have recently shown that two of the estrogen receptor β variants, estrogen receptor β2 and β5, bind to and stabilize both HIF-1α and HIF-2α proteins leading to expression of HIF target genes. This study suggests that increased expression of the estrogen receptor β variants, β2 and β5, could be involved in development of a cancer's stem cell characteristics and chemotherapy resistance, indicating that targeting these factors could prevent or reverse chemotherapy resistance and cancer stem cell expansion.


Consistent divergence times and allele sharing measured from cross-species application of SNP chips developed for three domestic species.
Recent advances in technology facilitated development of large sets of genetic markers for many taxa, though most often model or domestic organisms. Cross-species application of genomic technologies may allow for rapid marker discovery in wild relatives of taxa with well-developed resources. We investigated returns from cross-species application of three commercially available SNP chips (the OvineSNP50, BovineSNP50 and EquineSNP50 BeadChips) as a function of divergence time between the domestic source species and wild target species. Across all three chips, we observed a consistent linear decrease in call rate (~1.5% per million years), while retention of polymorphisms showed an exponential decay. These results will allow researchers to predict the expected amplification rate and polymorphism of cross-species application for their taxa of interest, as well as provide a resource for estimating divergence times.


The effect of additional physiotherapy to hospital inpatients outside of regular business hours: a systematic review.
Provision of out of regular business hours (OBH) physiotherapy to hospital inpatients is widespread in the hospital setting. This systematic review evaluated the effect of additional OBH physiotherapy services on patient length of stay (LOS), pulmonary complications, discharge destination, discharge mobility status, quality of life, cost saving, adverse events, and mortality compared with physiotherapy only within regular business hours. A literature search was completed on databases with citation tracking using key words. Two reviewers completed data extraction and quality assessment independently by using modified scales for historical cohorts and case control studies as well as the PEDro scale for randomized controlled trials and quasi-randomised controlled trials. This search identified nine articles of low to medium quality. Four reported a significant reduction in LOS associated with additional OBH physiotherapy, with two articles reporting overall significance and two reporting only for specific subgroups. Two studies reported significant reduction in pulmonary complications for two different patient groups in an intensive care unit (ICU) with additional OBH physiotherapy. Three studies accounted for discharge destination and/or discharge mobility status with no significant difference reported. Quality of life, adverse events, and mortality were not reported in any studies. Cost savings were considered in three studies, with two reporting a cost saving. This systematic review was unable to conclude that the provision of additional OBH physiotherapy made significant improvement to patient outcomes for all subgroups of inpatients. One study in critical care reported that overnight physiotherapy decreased LOS and reduced pulmonary complications of patients in the ICU. However, the studies in the area of orthopaedics, neurology, postcardiac surgery, and rheumatology, which all considered additional daytime weekend physiotherapy intervention, did not provide strong evidence to indicate effective reduction in patient LOS or improving patient discharge mobility status or discharge destination. Investigation should continue in this area, but future trials should ensure factors such as random allocation, groups equal at baseline, blinded investigators, and proven intervention are included in the study design.


Non-invasive determination of murine placental and foetal functional parameters with multispectral optoacoustic tomography.
Despite the importance of placental function in embryonic development, it remains poorly understood and challenging to characterize, primarily due to the lack of non-invasive imaging tools capable of monitoring placental and foetal oxygenation and perfusion parameters during pregnancy. We developed an optoacoustic tomography approach for real-time imaging through entire ~4 cm cross-sections of pregnant mice. Functional changes in both maternal and embryo regions were studied at different gestation days when subjected to an oxygen breathing challenge and perfusion with indocyanine green. Structural phenotyping of the cross-sectional scans highlighted different internal organs, whereas multi-wavelength acquisitions enabled non-invasive label-free spectroscopic assessment of blood-oxygenation parameters in foeto-placental regions, rendering a strong correlation with the amount of oxygen administered. Likewise, the placental function in protecting the embryo from extrinsically administered agents was substantiated. The proposed methodology may potentially further serve as a probing mechanism to appraise embryo development during pregnancy in the clinical setting.


Intramedullary Lesion Length on Postoperative Magnetic Resonance Imaging is a Strong Predictor of ASIA Impairment Scale Grade Conversion Following Decompressive Surgery in Cervical Spinal Cord Injury.
Evidence indicates that, over time, patients with spinal cord injury (SCI) improve neurologically in various degrees. We sought to further investigate indicators of grade conversion in cervical SCI. To detect predictors of ASIA impairment scale (AIS) grade conversion in SCI following surgical decompression. In a retrospective study, demographics, clinical, imaging, and surgical data from 100 consecutive patients were assessed for predictors of AIS grade conversion. American Spinal Injury Association motor score was 17.1. AIS grade was A in 52%, B in 29%, and C in 19% of patients. Surgical decompression took place on an average of 17.6 h following trauma (≤12 h in 51 and >12 h in 49). Complete decompression was verified by magnetic resonance imaging (MRI) in 73 patients. Intramedullary lesion length (IMLL) on postoperative MRI measured 72.8 mm, and hemorrhage at the injury epicenter was noted in 71 patients. Grade conversion took place in 26.9% of AIS grade A patients, 65.5% of AIS grade B, and 78.9% of AIS grade C. AIS grade conversion had statistical relationship with injury severity score, admission AIS grade, extent of decompression, presence of intramedullary hemorrhage, American Spinal Injury Association motor score, and IMLL. A stepwise multiple logistic regression analysis indicated IMLL was the sole and strongest indicator of AIS grade conversion (odds ratio 0.950, 95% CI 0.931-0.969). For 1- and 10-mm increases in IMLL, the model indicates 4% and 40% decreases, respectively, in the odds of AIS grade conversion. Compared with other surrogates, IMLL remained as the only predictor of AIS grade conversion.


CCL20 and β-defensin-2 induce arrest of human Th17 cells on inflamed endothelium in vitro under flow conditions.
CCR6 is a chemokine receptor that is expressed at the cell surface of Th17 cells, an IL-17- and IL-22-secreting population of CD4(+) T cells with antipathogenic, as well as inflammatory, properties. In the current study, we have determined the involvement of CCR6 in human Th17 lymphocyte migration toward inflamed tissue by analyzing the capacity of its ligands to induce arrest of these cells onto inflamed endothelium in vitro under flow conditions. We show that polarized, in situ-differentiated, skin-derived Th17 clones activated via the TCR-CD3 complex produce CCL20 in addition to IL-17 and IL-22. The latter cytokines induce, in a synergic fashion, the production of human β-defensin (hBD)-2, but neither hBD-1 nor hBD-3, by epidermal keratinocytes. Both CCL20 and hBD-2 are capable of inducing the arrest of Th17 cells, but not Th1 or Th2 cells, on HUVEC in an CD54-dependent manner that is CCR6 specific and independent from the expression of CXCR4, reported to be an alternative receptor for hBD-2. In addition, Ag-specific activation induces a transient loss of CCR6 expression, both at the transcriptional and protein level, which occurs with slow kinetics and is not due to endogenous CCL20-mediated internalization of CCR6. Together, these results indicate that Ag-specific activation will initially contribute to CCR6-mediated Th17 cell trafficking toward and sequestration in inflamed tissue, but that it eventually results in a transitory state of nonresponsiveness to further stimulation of these cells with CCR6 ligands, thus permitting their subsequent migration out of the inflamed site.


Alcohol and aldehyde dehydrogenase polymorphisms and a new strategy for prevention and screening for cancer in the upper aerodigestive tract in East Asians.
The ethanol in alcoholic beverages and the acetaldehyde associated with alcohol consumption are Group 1 human carcinogens (WHO, International Agency for Research on Cancer). The combination of alcohol consumption, tobacco smoking, the inactive heterozygous aldehyde dehydrogenase-2 genotype (ALDH2*1/*2) and the less-active homozygous alcohol dehydrogenase-1B genotype (ADH1B*1/*1) increases the risk of squamous cell carcinoma (SCC) in the upper aerodigestive tract (UADT) in a multiplicative fashion in East Asians. In addition to being exposed to locally high levels of ethanol, the UADT is exposed to a very high concentration of acetaldehyde from a variety of sources, including that as an ingredient of alcoholic beverages per se and that found in tobacco smoke; acetaldehyde is also produced by salivary microorganisms and mucosal enzymes and is present as blood acetaldehyde. The inefficient degradation of acetaldehyde by weakly expressed ALDH2 in the UADT may be cri! tical to the local accumulation of acetaldehyde, especially in ALDH2*1/*2 carriers. ADH1B*1/*1 carriers tend to experience less intense alcohol flushing and are highly susceptible to heavy drinking and alcoholism. Heavy drinking by persons with the less-active ADH1B*1/*1 leads to longer exposure of the UADT to salivary ethanol and acetaldehyde. The ALDH2*1/*2 genotype is a very strong predictor of synchronous and metachronous multiple SCCs in the UADT. High red cell mean corpuscular volume (MCV), esophageal dysplasia, and melanosis in the UADT, all of which are frequently found in ALDH2*1/*2 drinkers, are useful for identifying high-risk individuals. We invented a simple flushing questionnaire that enables prediction of the ALDH2 phenotype. New health appraisal models that include ALDH2 genotype, the simple flushing questionnaire, or MCV are powerful tools for devising a new strategy for prevention and screening for UADT cancer in East Asians.


Male dominance rarely skews the frequency distribution of Y chromosome haplotypes in human populations.
A central tenet of evolutionary social science holds that behaviors, such as those associated with social dominance, produce fitness effects that are subject to cultural selection. However, evidence for such selection is inconclusive because it is based on short-term statistical associations between behavior and fertility. Here, we show that the evolutionary effects of dominance at the population level can be detected using noncoding regions of DNA. Highly variable polymorphisms on the nonrecombining portion of the Y chromosome can be used to trace lines of descent from a common male ancestor. Thus, it is possible to test for the persistence of differential fertility among patrilines. We examine haplotype distributions defined by 12 short tandem repeats in a sample of 1269 men from 41 Indonesian communities and test for departures from neutral mutation-drift equilibrium based on the Ewens sampling formula. Our tests reject the neutral model in only 5 communities. Analysis and simulations show that we have sufficient power to detect such departures under varying demographic conditions, including founder effects, bottlenecks, and migration, and at varying levels of social dominance. We conclude that patrilines seldom are dominant for more than a few generations, and thus traits or behaviors that are strictly paternally inherited are unlikely to be under strong cultural selection.


Sacubitril/Valsartan in Advanced Heart Failure With Reduced Ejection Fraction: Rationale and Design of the LIFE Trial.
The PARADIGM-HF (Prospective Comparison of Angiotensin II Receptor Blocker Neprilysin Inhibitor With Angiotensin-Converting Enzyme Inhibitor to Determine Impact on Global Mortality and Morbidity in Heart Failure) trial reported that sacubitril/valsartan (S/V), an angiotensin receptor-neprilysin inhibitor, significantly reduced mortality and heart failure (HF) hospitalization in HF patients with a reduced ejection fraction (HFrEF). However, fewer than 1% of patients in the PARADIGM-HF study had New York Heart Association (NYHA) functional class IV symptoms. Accordingly, data that informed the use of S/V among patients with advanced HF were limited. The LIFE (LCZ696 in Hospitalized Advanced Heart Failure) study was a 24-week prospective, multicenter, double-blinded, double-dummy, active comparator trial that compared the safety, efficacy, and tolerability of S/V with those of valsartan in patients with advanced HFrEF. The trial planned to randomize 400 patients ≥18 years of age with advanced HF, defined as an EF ≤35%, New York Heart Association functional class IV symptoms, elevated natriuretic peptide concentration (B-type natriuretic peptide [BNP] ≥250 pg/ml or N-terminal pro-B-type natriuretic peptide [NT-proBNP] ≥800 pg/ml), and ≥1 objective finding of advanced HF. Following a 3- to 7-day open label run-in period with S/V (24 mg/26 mg twice daily), patients were randomized 1:1 to S/V titrated to 97 mg/103 mg twice daily versus 160 mg of V twice daily. The primary endpoint was the proportional change from baseline in the area under the curve for NT-proBNP levels measured through week 24. Secondary and tertiary endpoints included clinical outcomes and safety and tolerability. Because of the COVID-19 pandemic, enrollment in the LIFE trial was stopped prematurely to ensure patient safety and data integrity. The primary analysis consists of the first 335 randomized patients whose clinical follow-up examination results were not severely impacted by COVID-19. (Entresto [LCZ696] in Advanced Heart Failure [LIFE STUDY] [HFN-LIFE]; NCT02816736).


Impact of selection bias on the utilization of adjuvant therapy for pancreas adenocarcinoma.
Improved outcomes have been associated with the use of adjuvant therapy after resection of pancreas adenocarcinoma. However, the frequency with which patients receive adjuvant therapy and the factors impacting its use remain largely undefined. We hypothesized that nonutilization of adjuvant therapy was primarily associated with patient comorbidity and onset of postoperative complications. A prospectively maintained database was reviewed to identify patients who underwent potentially curative resection of histologically confirmed pancreas adenocarcinoma at our institution from January 1996 to May 2007. Clinicopathological data and postoperative treatment history were collected to identify variables associated with receipt of adjuvant therapy. Of 119 patients, 33% did not receive adjuvant therapy. The frequency with which patients underwent adjuvant therapy did not change over time. On multivariate analysis, patient age 70 years or greater, major postoperative complications, distal pancreatectomy, absence of nodal metastases, and absence of perineural invasion were associated with decreased utilization of adjuvant therapy. One-third of patients in this contemporary dataset of patients did not go on to receive adjuvant therapy. The likelihood of receiving adjuvant treatment is negatively impacted by the course of postoperative recovery. Moreover, the fact that adjuvant therapy was undertaken less often for older patients and patients with favorable pathological features highlights the selection bias impacting the decision to pursue postoperative therapy for this disease. This selective utilization of postoperative therapy for patients with adverse oncological characteristics is likely to bias any retrospective analysis attempting to measure the efficacy of adjuvant treatment for pancreas adenocarcinoma.


Sedation practice in six acute hospitals - a snapshot survey.
The number of UK hospital patients receiving procedural sedation remains unknown. Our trainee research network recorded all procedural sedation given over a 48-h period at six acute hospitals in the South West of England. Three hundred and sixty patients aged between 1 and 96 years old were sedated. Most sedation occurred in endoscopy units (56.4%), operating theatres (30.3%) and cardiology departments (7.2%). Sedation was administered in 82.8% of cases by consultants, and in only 5.6% of cases by nurses. The most frequent sedative combination was midazolam and fentanyl, with median (IQR [range]) doses of 2 (2-3 [1-10]) mg and 50 (50-100 [10-300]) μg used, respectively. We tested a methodology that could be used in a UK-wide denominator survey to describe sedation practice across the NHS. A national audit collecting serious adverse outcomes of sedation (severe harm or death) could then identify hotspots of sedation risk (clinical areas, patient groups, procedures and sedation techniques) where consistent application of current and improved standards might reduce harm.


Integrated PET/CT fusion imaging and endoscopic ultrasound in the pre-operative staging and evaluation of esophageal cancer.
Accurate staging of esophageal cancer (ECA) is critical in determining appropriate therapy. Endoscopic ultrasound (EUS), computed tomography (CT) and positron emission tomography (PET) scanning can be used, but limited data exists regarding the use of combined PET/CT fusion imaging and EUS in ECA staging. The objective of this study is to evaluate the role of integrated PET/CT imaging and EUS in the staging of ECA. Identification of patients diagnosed with ECA from 2004 to 2007 that underwent staging PET/CT and EUS. Data regarding tumor detection, lymph node identification, presence of metastatic disease, and affect on patient management were collected and compared between PET/CT and EUS. Eighty-one patients (65 male, 16 female) were identified with mean age of 63.5 years who underwent EUS and PET/CT to stage known ECA. PET/CT identified the primary tumor in 74/81 (91.4%) of cases, compared to 81/81 (100%) with EUS. Locoregional adenopathy was seen by PET/CT in 29/81 (35.8%) of cases, compared to 49/81 (60.5%) by EUS (p = 0.0001). PET/CT identified celiac axis adenopathy in 8/81 (9.9%) of cases, compared to 11/81 (13.6%) with EUS (p = 0.5050). PET/CT identified 17/81 (21.0%) of patients with distant metastases who subsequently did not undergo attempt at curative surgical resection. In ECA, EUS is superior to PET/CT for T staging and in identifying locoregional nodes, while PET/CT provides M staging. EUS and integrated PET/CT appear to independently affect treatment decisions, indicating complimentary and necessary roles in the staging of ECA.


The role of 3-canal biomechanics in angular motion transduction by the human vestibular labyrinth.
The present work examines the role of the complex geometry of the human vestibular membranous labyrinth in the process of angular motion transduction by the semicircular canals. A morphologically descriptive mathematical model was constructed to address the biomechanical origins of temporal signal processing and directional coding in determining the inputs to the brain. The geometrical model was developed based on shrinkage-corrected temporal bone sections using a segmentation/data-fitting procedure. Endolymph fluid dynamics within the 3-canal labyrinth was modeled using an asymptotic form of the Navier-Stokes equations and solved to estimate endolymph and cupulae volume displacements. The geometrical model was manipulated to study the role of major morphological features on directional and temporal coding. Anatomical results show that the bony osseous canals provide reasonable estimates of the orientation of the delicate membranous canals--the two differed by only 3.48 +/- 1.89 degrees . Biomechanical results show that the maximal response directions are distinct from the anatomical canal planes, but can be closely approximated by fitting a flat plane to the centerline of the canal of interest and weighting each location along the centerline with the inverse of the cross-sectional area squared. Vector cross-products of these maximal response directions, in turn, determine the null planes and prime directions that transmit the direction of angular motion to the brain as three independent directional channels associated with the nerve bundles. Finally, parameter studies indicate that changes in canal cross-sectional area and shape only moderately affect canal temporal and directional coding, while three-canal orientation is critical to directional coding.


Dimorphic sperm and the unlikely route to fertilisation in the yellow seahorse.
Uniquely among vertebrates, seahorses and pipefishes (Family Syngnathidae) incubate their eggs within a male brood pouch. This has contributed to a widespread, but poorly founded belief, that the eggs are fertilised using spermatozoa that are deposited directly into the brood pouch via an internal sperm duct. Anatomical dissections showed, however, not only that direct sperm deposition into the pouch is physically impossible, but that spermatozoa must somehow travel a significant distance (>4 mm) outside the body of the male, to reach and fertilise eggs in the pouch. Observations of courtship and mating behaviour also revealed that the pouch closes immediately after mating, and that sperm transfer must occur within a time window of no more than 6 s. In addition to this, the yellow seahorse produces extraordinarily low quantities of dimorphic spermatozoa, but is nevertheless highly fertile and can produce broods that exceed 100 embryos. The entire fertilisation process in seahorses is therefore uniquely efficient among vertebrates, yet paradoxically involves several steps that would seem to complicate, and even appear to prevent, the interaction of the gametes. Although we are still unable to describe the exact fertilisation mechanism, we speculate that spermatozoa are ejaculated into a mixture of ovarian fluid and eggs, while the male and female are in close contact. Thereafter, this mixture must enter the pouch, whereupon the spermatozoa encounter seawater. These observations also support the view, indirectly inferred in previous publications, that sperm competition in seahorses is not only non-existent but impossible.


Mid-term and long-term safety and efficacy of bioresorbable vascular scaffolds versus metallic everolimus-eluting stents in coronary artery disease: A weighted meta-analysis of seven randomised controlled trials including 5577 patients.
Mid- and long-term safety and efficacy of the Absorb bioresorbable vascular scaffold (BVS) have been studied in randomised trials; however, most were not individually powered for clinical endpoints. We performed a weighted meta-analysis comparing mid- and long-term outcomes in patients treated with the BVS compared with the Xience metallic stent. Randomised trials comparing the BVS and Xience were identified by searching MEDLINE, EMBASE and conference abstracts. Seven trials were included (BVS n = 3258, Xience n = 2319) with follow-up between 1-3 years. The primary outcome of target lesion failure occurred more frequently in BVS compared with Xience [OR 1.34; 95% CI 1.11-1.62, p = 0.003]. Overall definite or probable device thrombosis occurred more frequently with the BVS [OR 2.86; 95% CI 1.88-4.36, p < 0.001] and this extended beyond 1 year of follow-up [OR 4.13; 95% CI 1.99-8.57, p < 0.001]. Clinically indicated or ischaemia driven target lesion revascularisation [OR 1.43; 95% CI 1.11-1.83, p = 0.005] and myocardial infarction (all MI) [OR 1.64; 95% CI 1.20-2.23, p = 0.002] were more frequently seen in the BVS compared with Xience. Rates of target vessel failure [OR 1.15; 95% CI 0.91-1.46, p = 0.25] and cardiac death [OR 0.91; 95% CI 0.57-1.46, p = 0.71] were not significantly different between BVS and Xience. This meta-analysis shows a higher rate of target lesion failure and an almost threefold higher rate of device thrombosis in BVS compared with Xience, which extends beyond the first year. Device thrombosis did not lead to an overall increased (cardiac) mortality.


Malnutrition Affects the Outcomes of Patients with Low-Output Heart Failure and Congestion.
This study aimed to investigate the relationship between malnutrition and outcomes in patients with decompensated severe systolic heart failure (HF) focusing on clinical presentations and medication use. This study prospectively enrolled 108 patients admitted for severe systolic HF with a left ventricular (LV) ejection fraction < 35%, low cardiac output, and high LV filling pressure. Five patients died during the index hospitalization, and the remaining 103 patients were followed up for 2 years. The primary endpoints were HF rehospitalization and all-cause mortality. Nutritional risk index (NRI) was calculated as (1.519 × serum albumin, g/L) + (41.7 × body weight/ideal body weight). Forty-four patients reached the study endpoints. An NRI ≤ 93 predicted events. The NRI ≤ 93 group had higher pulmonary artery systolic pressure, more edema over dependent parts, longer hospital stay, and more primary endpoints compared to the NRI > 93 group. The NRI ≤ 93 group received fewer evidence-based medications and more loop diuretics compared to the NRI > 93 group. NRI was an independent predictor of cardiovascular events [hazard ratio 0.902; 95% confidence interval (CI) 0.814-0.982 per 1 point increase; p = 0.012]. Low NRI was associated with a significantly higher use of loop diuretics [odds ratio (OR) 2.75; 95% CI 1.046-5.647; p = 0.004] and significantly lower use of beta blockers (OR 0.541; 95% CI 0.319-0.988; p = 0.002). Malnutrition assessed using the NRI was associated with cardiovascular events in the patients with severe systolic HF with low cardiac output and high LV filling pressure. Low NRI was associated with more diuretic and less beta blocker use.


Involvement of Substance P in the Analgesic Effect of Low-Level Laser Therapy in a Mouse Model of Chronic Widespread Muscle Pain.
Low-level laser therapy (LLLT) is widely used in pain control in the field of physical medicine and rehabilitation and is effective for fibromyalgia pain. However, its analgesic mechanism remains unknown. A possible mechanism for the effect of LLLT on fibromyalgia pain is via the antinociceptive signaling of substance P in muscle nociceptors, although the neuropeptide has been known as a neurotransmitter to facilitate pain signals in the spinal cord. To establish an animal model of LLLT in chronic muscle pain and to determine the role of substance P in LLLT analgesia. We employed the acid-induced chronic muscle pain model, a fibromyalgia model proposed and developed by Sluka et al., and determined the optimal LLLT dosage. LLLT with 685 nm at 8 J/cm2 was effective to reduce mechanical hyperalgesia in the chronic muscle pain model. The analgesic effect was abolished by pretreatment of NK1 receptor antagonist RP-67580. Likewise, LLLT showed no analgesic effect on Tac1-/- mice, in which the gene encoding substance P was deleted. Besides, pretreatment with the TRPV1 receptor antagonist capsazepine, but not the ASIC3 antagonist APETx2, blocked the LLLT analgesic effect. LLLT analgesia is mediated by the antinociceptive signaling of intramuscular substance P and is associated with TRPV1 activation in a mouse model of fibromyalgia or chronic muscle pain. The study results could provide new insight regarding the effect of LLLT in other types of chronic pain.


Effects of Parental Education on Screen Time, Sleep Disturbances, and Psychosocial Adaptation Among Asian Preschoolers: A Randomized Controlled Study.
A recent increase in screen time during early childhood has adversely affected the sleep and psychosocial health of children; however, limited information is available regarding effective interventions to reduce the screen time among them. This study aimed to investigate the effect of a parental educational program on screen use, sleep quality, and psychosocial adaptation among preschoolers. A clustered randomized controlled study with a parallel-group design was conducted. Preschoolers with a screen time of ≥2 h/day and their parents were recruited. In total, 14 kindergartens containing 129 parent-child dyads were randomly allocated to either the experimental group (receiving parental education, N = 63 dyads) or the control group (daily activities, N = 66 dyads). Data were collected before and after the intervention. A screen time questionnaire, the Children's Sleep Habits Questionnaire, and the Pediatric Symptom checklist-17 were provided to the participants. A linear mixed-model analysis was performed to examine the efficacy of the intervention. After the intervention, the screen time of children in the experimental group was significantly reduced (effect size: 0.83, p < .001), and they presented improved sleep quality (effect size: 0.57, p = .01) and attention score (effect size: 0.77, p = .02) for psychosocial adaptation. Parental education is an effective intervention for reducing screen time and improving sleep quality and attention among preschoolers. Healthcare professionals should consider implementing parental educational programs to reduce screen time, and thus improve the sleep quality and psychosocial health of preschoolers.


Leishmania major-specific, CD4+, major histocompatibility complex class II-restricted T cells derived in vitro from lymphoid tissues of naive mice.
Several studies indicate that the outcome of experimental murine cutaneous leishmaniasis caused by Leishmania major (Lm) is determined by immunological events occurring shortly after infection. These events lead to outgrowth of either protective CD4+ T cells in the C57BL/6 mouse, which cures, or exacerbative cells in the BALB/c mouse, which succumbs to disease. Potential factors influencing the outgrowth of protective or exacerbative T cells include antigen-presenting cells (APC), cytokines, and parasite antigens. An in vitro system, in which one could precisely control the factors shaping early events in the T cell response to Lm, would be very useful. To this end, we have examined the in vitro response of naive lymphocytes to Lm promastigotes. The data presented here show that Lm-specific CD4+ T cell receptor alpha/beta + T cells can be generated in vitro from spleen and lymph node cell populations of naive mice. Furthermore, they can be obtained from the CD44low (unprimed) population of T lymphocytes, indicating that in vitro priming occurs. The ability to generate these T cells is dependent on the presence of live parasites and is not due to a parasite-derived nonspecific T cell mitogen. Restimulation, as assayed by proliferation, requires APC bearing syngeneic I-A. Optimal restimulation of the in vitro derived T cells is achieved only when live promastigotes are used. The T cells do not proliferate in response to a frozen-and-thawed lysate of promastigotes, yet they exhibit mild reactivity to lysates prepared from heat-shocked promastigotes. Furthermore, they do not recognize two predominant antigens on the promastigote surface, lipophosphoglycan and gp63. T cells derived in vitro with Lm show crossreactivity with live L. donovani, less crossreactivity with live L. mexicana, and no crossreactivity with live Bacillus-Calmette-Guerin or live Brugia malayi microfilariae. Finally, these early T cells, whether derived from healing C57BL/6 or nonhealing BALB/c mice, produce interleukin 2 (IL-2), IL-4, and interferon gamma.


Allowable carbon emissions lowered by multiple climate targets.
Climate targets are designed to inform policies that would limit the magnitude and impacts of climate change caused by anthropogenic emissions of greenhouse gases and other substances. The target that is currently recognized by most world governments places a limit of two degrees Celsius on the global mean warming since preindustrial times. This would require large sustained reductions in carbon dioxide emissions during the twenty-first century and beyond. Such a global temperature target, however, is not sufficient to control many other quantities, such as transient sea level rise, ocean acidification and net primary production on land. Here, using an Earth system model of intermediate complexity (EMIC) in an observation-informed Bayesian approach, we show that allowable carbon emissions are substantially reduced when multiple climate targets are set. We take into account uncertainties in physical and carbon cycle model parameters, radiative efficiencies, climate sensitivity and carbon cycle feedbacks along with a large set of observational constraints. Within this framework, we explore a broad range of economically feasible greenhouse gas scenarios from the integrated assessment community to determine the likelihood of meeting a combination of specific global and regional targets under various assumptions. For any given likelihood of meeting a set of such targets, the allowable cumulative emissions are greatly reduced from those inferred from the temperature target alone. Therefore, temperature targets alone are unable to comprehensively limit the risks from anthropogenic emissions.


Caring for older adults with diabetes mellitus: characteristics of carers and their prime roles and responsibilities.
Expanding prevalence of diabetes has a major health impact on older people and the burden experienced by their informal carers. We report research which aimed to examine the burden on carers and highlight their input into diabetes care. Of 98 diabetes patients aged over 59 years, 89 regularly received help with day-to-day activities or looking after from someone else and, of these, 83 carers consented to interview. Patients and carers were administered questionnaires related to the management of diabetes and personal strain (including Diabetes Knowledge Questionnaire, EuroQol, Caregiver Strain Scale and General Health Questionnaire). A substantial unmet need of older people with diabetes mellitus, in relation to domestic activities and diabetes care, was highlighted. Patient and carer diabetes knowledge was low. Primary carers were generally female relatives from the same household, not in paid employment. Twenty-seven carers (33%) provided > or = 35 h of care work each week. Most carers experienced a moderate level of stress, but 11 (14%) regularly felt overwhelmed. Thirty-three carers (40%) said they had never received any information on diabetes from professionals. Help most frequently wanted was advice and support in relation to accessing community services and about finances, benefits and/or allowances. Both patient and carer diabetes education strategies are required. Instruction for carers in the basic care of patients with diabetes is also needed and should be targeted. As many as one in seven carers felt regularly overwhelmed and lacked adequate support. Finally, 26 carers (31%) were entitled to benefits which they did not claim.


Miscreant myeloproliferative disorder stem cells.
Myeloproliferative disorders (MPDs), typified by robust marrow and extramedullary hematopoiesis, have a propensity to progress to acute leukemia. Although the hematopoietic stem cell (HSC) origin of MPDs was suggested over 30 years ago, only recently the HSC-specific effects of MPD molecular mutations have been investigated. The pivotal role of BCR-ABL in chronic myeloid leukemia (CML) development provided the rationale for targeted therapy, which greatly reduced mortality rates. However, BCR-ABL inhibitor-resistant CML HSCs persist that may be a reservoir for relapse. This has provided the impetus for investigating molecular mechanisms governing the production of recalcitrant HSC. Comparatively little was known about the molecular events driving BCR-ABL-negative MPDs until seminal studies revealed that a large proportion of MPD patients harbor a JAK2-activating point mutation, JAK2V617F. Although JAK2 activation appears to be central to BCR-ABL-negative MPD pathogenesis, its effects may be cell type and context specific. Recent evidence suggests that acquired mutations misdirect differentiation and survival of the MPD-initiating stem cell resulting in the production of aberrant self-renewing progenitors that subvert the microenvironment leading to leukemia stem cell generation and leukemic transformation. Thus, combined therapies targeting aberrant molecular pathways may be required to redirect miscreant MPD stem cells.


Pyruvate uptake is increased in highly invasive ovarian cancer cells under anoikis conditions for anaplerosis, mitochondrial function, and migration.
Anoikis resistance, or the ability for cells to live detached from the extracellular matrix, is a property of epithelial cancers. The "Warburg effect," or the preference of cancer cells for glycolysis for their energy production even in the presence of oxygen, has been shown to be evident in various tumors. Since a cancer cell's metastatic ability depends on microenvironmental conditions (nutrients, stromal cells, and vascularization) and is highly variable for different organs, their cellular metabolic fluxes and nutrient demand may show considerable differences. Moreover, a cancer cell's metastatic ability, which is dependent on the stage of cancer, may further create metabolic alterations depending on its microenvironment. Although recent studies have aimed to elucidate cancer cell metabolism under detached conditions, the nutrient demand and metabolic activity of cancer cells under nonadherent conditions remain poorly understood. Additionally, less is known about metabolic alterations in ovarian cancer cells with varying invasive capability under anoikis conditions. We hypothesized that the metabolism of highly invasive ovarian cancer cells in detachment would differ from less invasive ovarian cancer cells and that ovarian cancer cells will have altered metabolism in detached vs. attached conditions. To assess these metabolic differences, we integrated a secretomics-based metabolic footprinting (MFP) approach with mitochondrial bioenergetics. Interestingly, MFP revealed higher pyruvate uptake and oxygen consumption in more invasive ovarian cancer cells than their less invasive counterparts. Furthermore, ATP production was higher in more invasive vs. less invasive ovarian cancer cells in detachment. We found that pyruvate has an effect on highly invasive ovarian cancer cells' migration ability. Our results are the first to demonstrate that higher mitochondrial activity is related to higher ovarian cancer invasiveness under detached conditions. Importantly, our results bring insights regarding the metabolism of cancer cells under nonadherent conditions and could lead to the development of therapies for modulating cancer cell invasiveness.


Stimulatory effect of CO2 on vagal bronchopulmonary C-fiber afferents during airway inflammation.
This study investigated 1) whether pulmonary C fibers are activated by a transient increase in the CO2 concentration of alveolar gas; and 2) if the CO2 sensitivity of these afferents is altered during airway inflammation. Single-unit pulmonary C-fiber activity was recorded in anesthetized, open-chest rats. Transient alveolar hypercapnia (HPC) was induced by administering a CO2-enriched gas mixture (25-30% CO2, 21% O2, balance N2) for five to eight breaths, which increased alveolar CO2 concentration progressively to near or above 13% for 3-5 s and lowered the arterial pH transiently to 7.10 +/- 0.05. Our results showed the following. 1) HPC evoked only a mild stimulation in a small fraction (4/47) of pulmonary C fibers, and there was no significant change in fiber activity (change in fiber activity = 0.22 +/- 0.16 imp/s; P > 0.1, n = 47). 2) In sharp contrast, after airway exposure to poly-L-lysine, a cationic protein known to induce mucosal injury, the same challenge of transient HPC activated 87.5% of the pulmonary C fibers tested and evoked a distinct stimulatory effect on these afferents (change in fiber activity = 6.59 +/- 1.78 imp/s; P < 0. 01, n = 8). 3) Similar potentiation of the C-fiber response to HPC was also observed after acute exposure to ozone (n = 6) and during a constant infusion of inflammatory mediators such as adenosine (n = 15) or prostaglandin E2 (n = 12). 4) The enhanced C-fiber sensitivity to CO2 after poly-L-lysine was completely abrogated by infusion of NaHCO3 (1.82 mmol.kg(-1).min(-1)) that prevented the reduction in pH during HPC (n = 6). In conclusion, only a small percentage (<10%) of the bronchopulmonary C fibers exhibit CO2 sensitivity under control conditions, but alveolar HPC exerts a consistent and pronounced stimulatory effect on the C-fiber endings during airway inflammation. This effect of CO2 is probably mediated through the action of hydrogen ions.


Attributable risk for laryngeal cancer in northern Italy.
Using data from a case-control study conducted between 1986 and 1992 in Northern Italy on 367 cases of laryngeal cancers (350 men and 17 women) and 1931 hospital controls (1373 men and 558 women), we estimated the relative risks (RR) and the population attributable risks (AR) for laryngeal cancer in relation to tobacco and alcohol consumption and a diet containing little fresh fruit and vegetables (low beta-carotene intake). In men, the RR and their 95% confidence interval (CI), derived from multiple logistic regression, including terms for center, age, and education, plus, simultaneously, tobacco, alcohol, and beta-carotene) were 3.3 (95% CI, 1.9 to 5.5) for ex- or moderate smokers (< 15 cigarettes/day) and 8.8 (95% CI, 5.2 to 14.8) for heavy current smokers compared to never smokers; the RR were 1.5 (95% CI, 1.0 to 2.2) for drinkers of 6 to < 8 alcoholic drinks/day and 2.2 (95% CI, 1.6 to 3.0) for drinkers of 8 or more drinks/day compared to teetotallers or moderate drinkers; with respect to carotene intake the RR were 1.4 (95% CI, 1.0 to 2.0) for the intermediate tertile and 1.8 (95% CI, 1.3 to 2.5) for the lowest tertile, as compared to the highest tertile of intake. AR were estimated assuming a multiplicative model: the single factor with the largest AR was smoking, which accounted for about 77% of laryngeal cancers in men; alcohol intake explained about 25% of cases, low beta-carotene intake accounted for about 18% of cases, and together the three factors were responsible for about 86% of laryngeal cancers in men.(ABSTRACT TRUNCATED AT 250 WORDS)


Mapping in structured populations by resample model averaging.
Highly recombinant populations derived from inbred lines, such as advanced intercross lines and heterogeneous stocks, can be used to map loci far more accurately than is possible with standard intercrosses. However, the varying degrees of relatedness that exist between individuals complicate analysis, potentially leading to many false positive signals. We describe a method to deal with these problems that does not require pedigree information and accounts for model uncertainty through model averaging. In our method, we select multiple quantitative trait loci (QTL) models using forward selection applied to resampled data sets obtained by nonparametric bootstrapping and subsampling. We provide model-averaged statistics about the probability of loci or of multilocus regions being included in model selection, and this leads to more accurate identification of QTL than by single-locus mapping. The generality of our approach means it can potentially be applied to any population of unknown structure.