Robotic gastrectomy: the current state of the art.
Since the first laparoscopic gastrectomy for cancer was reported in 1994, minimally invasive surgery is enjoying its wide acceptance. Numerous procedures of this approach have developed, and many patients have benefited from its effectiveness, which has been recently demonstrated for early gastric cancer. However, since laparoscopic surgery is not exempt from some limitations, the robotic surgery system was introduced as a solution by the late 1990's. Many experienced surgeons have embraced this new emerging method that provides undoubted technical and minimally invasive advantages. To date, several studies have concentrated to this new system, and have compared it with open and laparoscopic approach. Most of them have reported satisfactory results concerning the post-operative short-term outcomes, but almost all believe that the role of robotic gastrectomy is still out of focus, especially because long-term outcomes that can prove robotic oncologic equivalency are lacking, and operative costs and time are higher in comparison to the open and laparoscopic ones. This article is a review about the current status of robotic surgery for the treatment of gastric cancer, especially, focusing on the technical aspects, comparisons to other approaches and future prospects.


Technology Creep and the Arms Race: ICBM Problem a Sleeper.
In three articles, Science will discuss how the creep of technology affects the arms race. The first two articles will deal with the most important current example: first, how ICBM modernization is giving both sides a destabilizing, first-strike capability, and second, how arms control seems to be dealing inadequately with this pressing problem. The third article will describe other cases of incremental technical improvements affecting arms control, such as antisatellite research and ballistic missile defense research, which are bringing both sides closer to the antiballistic missile capability they forswore in a 1972 treaty.


Defining minimal residual disease in acute myeloid leukemia: which platforms are ready for "prime time"?
The past 40 years have witnessed major advances in defining the cytogenetic aberrations, mutational landscape, epigenetic profiles, and expression changes underlying hematological malignancies. Although it has become apparent that acute myeloid leukemia (AML) is highly heterogeneous at the molecular level, the standard framework for risk stratification guiding transplant practice in this disease remains largely based on pretreatment assessment of cytogenetics and a limited panel of molecular genetic markers, coupled with morphological assessment of bone marrow (BM) blast percentage after induction. However, application of more objective methodology such as multiparameter flow cytometry (MFC) has highlighted the limitations of morphology for reliable determination of remission status. Moreover, there is a growing body of evidence that detection of subclinical levels of leukemia (ie, minimal residual disease, MRD) using MFC or molecular-based approaches provides powerful independent prognostic information. Consequently, there is increasing interest in the use of MRD detection to provide early end points in clinical trials and to inform patient management. However, implementation of MRD assessment into clinical practice remains a major challenge, hampered by differences in the assays and preferred analytical methods employed between routine laboratories. Although this should be addressed through adoption of standardized assays with external quality control, it is clear that the molecular heterogeneity of AML coupled with increasing understanding of its clonal architecture dictates that a "one size fits all" approach to MRD detection in this disease is not feasible. However, with the range of platforms now available, there is considerable scope to realistically track treatment response in every patient.


Enthacrynic and acid effects on inner wall pores in living monkeys.
The influence of the inner wall of Schlemm's canal on aqueous outflow facility remains poorly understood. We examined the relationship between inner wall pore characteristics and outflow facility in living primate eyes in which facility had been pharmacologically increased by ethacrynic acid (ECA) infusion and in contralateral control eyes. Outflow facility (two-level constant pressure perfusion) was measured in eight pairs of living monkey eyes before and after administration of a bolus dose of either 0.125 mM ECA or vehicle. After exsanguination, eyes were fixed in situ under constant-pressure conditions (mean fixation pressure approximately 19 mm Hg). The density and diameter of inner wall pores and the number and area of platelet aggregates on the inner wall of Schlemm's canal were measured by scanning electron microscopy. In ECA-treated eyes, outflow facility increased 63% (P < 0.0001), intracellular pore density decreased 46% (P = 0.0094), intracellular pore size increased 27% (P = 0.049), platelet aggregate density increased 158% (P < 0.0001), and area covered by platelets increased 210% (P = 0.012) relative to contralateral controls. Although the average density and size of intercellular pores were essentially unaffected by ECA, an increased density of large (> or = 1.90 microm) intercellular pores was seen in ECA-treated eyes. The density of intracellular pores increased with the duration of fixative perfusion. Other than a weak negative correlation between outflow facility and intracellular pore density in ECA-treated eyes (P = 0.052), facility was not correlated with inner wall pore features. Our data are most consistent with a scenario in which ECA promotes formation of large intercellular pores in the inner wall of Schlemm's canal, which are then masked by platelet aggregates. Masking of intercellular pores, combined with fixation-induced alteration of inner wall pore density, greatly complicates attempts to relate facility to inner wall structure and suggests that in vivo pore density is smaller than in fixed tissue. Additionally, facility-influencing effects of ECA on the juxtacanalicular tissue cannot be excluded.


Optical fiber photoacoustic-photothermal probe.
We describe the operation of an all-optical probe that provides an alternative means of implementing photoacoustic and photothermal investigative techniques, particularly those used in biomedical applications. The probe is based on a transparent, acoustically and thermally sensitive Fabry-Perot polymer film sensor mounted at the end of an optical fiber. We demonstrate the ability of the system to make photoacoustic and photothermal measurements simultaneously and evaluate its photothermal response, using a nonscattering liquid target of known and adjustable absorption coefficient. The acoustic and thermal noise floors were 2 kPa and 6 x 10(-3) degrees C , respectively, obtained over a 25-MHz measurement bandwidth and 30 signal averages.


Dimerization of complement factor H-related proteins modulates complement activation in vivo.
The complement system is a key component regulation influences susceptibility to age-related macular degeneration, meningitis, and kidney disease. Variation includes genomic rearrangements within the complement factor H-related (CFHR) locus. Elucidating the mechanism underlying these associations has been hindered by the lack of understanding of the biological role of CFHR proteins. Here we present unique structural data demonstrating that three of the CFHR proteins contain a shared dimerization motif and that this hitherto unrecognized structural property enables formation of both homodimers and heterodimers. Dimerization confers avidity for tissue-bound complement fragments and enables these proteins to efficiently compete with the physiological complement inhibitor, complement factor H (CFH), for ligand binding. Our data demonstrate that these CFHR proteins function as competitive antagonists of CFH to modulate complement activation in vivo and explain why variation in the CFHRs predisposes to disease.


Children talking: emerging perspectives and experiences of cigarette smoking.
Despite efforts to prevent the onset of smoking, the rate among older children remains high. In this article, the authors report on a longitudinal, qualitative study of 11 to 16-year-old children describing children's construction of what it means to be a smoker, the reasons given for children smoking, and their views of smoking behavior. Findings indicate that children adopt broad interpretations of what constitutes smoking behavior; although they strongly disapprove of children who smoke, they are less disapproving of older children or adult smokers and are increasingly tolerant of smoking behavior as they get older. Children's disapproval of smoking acts as a protective mechanism against smoking for younger participants. Participants' broad interpretation of what it means to be a cigarette smoker, their association of smoking with adulthood, and their increasing tolerance of and exposure to smoking behavior as they move into adolescence appears to increase susceptibility to becoming cigarette smokers.


A formative evaluation of the implementation of an upper limb stroke rehabilitation intervention in clinical practice: a qualitative interview study.
The Graded Repetitive Arm Supplementary Program (GRASP) is a hand and arm exercise programme designed to increase the intensity of exercise achieved in inpatient stroke rehabilitation. GRASP was shown to be effective in a randomised controlled trial in 2009 and has since experienced unusually rapid uptake into clinical practice. The aim of this study was to conduct a formative evaluation of the implementation of GRASP to inform the development and implementation of a similar intervention in the United Kingdom. Semi-structured interviews were conducted with therapists who were involved in implementing GRASP at their work site, or who had experience of using GRASP. Normalisation Process Theory (NPT), a sociological theory used to explore the processes of embedding innovations in practice, was used to develop an interview guide. Intervention components outlined within the GRASP Guideline Manual were used to develop prompts to explore how therapists use GRASP in practice. Interview transcripts were analysed using a coding frame based on implementation theory. Twenty interviews were conducted across eight sites in British Columbia Canada. Therapists identified informal networks and the free online availability of GRASP as key factors in finding out about the intervention. All therapists reported positive opinions about the value of GRASP. At all sites, therapists identified individuals who advocated for the use of GRASP, and in six of the eight sites this was the practice leader or senior therapist. Rehabilitation assistants were identified as instrumental in delivering GRASP in almost all sites as they were responsible for organising the GRASP equipment and assisting patients using GRASP. Almost all intervention components were found to be adapted to some degree when used in clinical practice; coverage was wider, the content adapted, and the dose, when monitored, was less. Although GRASP has translated into clinical practice, it is not always used in the way in which it was shown to be effective. This formative evaluation has informed the development of a novel intervention which aims to bridge this evidence-practice gap in upper limb rehabilitation after stroke.


Residual vision in a scotoma. A follow-up study of 'form' discrimination.
This study is a follow-up of a patient, D.B., who was reported (Weiskrantz et al., 1974) to be able to discriminate between simple visual forms within the scotoma caused by a lesion in calcarine cortex. Among other capacities, he was able to discriminate between lines of different orientation in the frontal plane. Given the reported deficits for form discrimination but a high sensitivity for orientation discrimination in primates without striate cortex, the question arises whether D.B.'s apparent 'form' discrimination arises from an ability to discriminate the orientations of components of the figures. It is shown in the first experiment, by using the optic disc as a control, that his ability to detect stimuli in his scotoma cannot be due to stray light falling upon the intact field. Next, his ability to discriminate orientations is confirmed, and an orientation threshold determined. A range of form discriminations is presented varying in degree of orientation cues of their components. It is confirmed that he can discriminate those forms originally studied, in which such differences are large, but not when orientation cues are small or minimal. Finally, his ability to compare two forms both projected within his scotoma is examined. Even when the components of the two forms have large orientation differences and are highly discriminable when presented successfully, D.B. appears to be unable to make a 'same-different' comparison when both are presented simultaneously. The evidence is interpreted against D.B.'s having a residual capacity for form discrimination.


The key kinematic determinants of undulatory underwater swimming at maximal velocity.
The optimisation of undulatory underwater swimming is highly important in competitive swimming performance. Nineteen kinematic variables were identified from previous research undertaken to assess undulatory underwater swimming performance. The purpose of the present study was to determine which kinematic variables were key to the production of maximal undulatory underwater swimming velocity. Kinematic data at maximal undulatory underwater swimming velocity were collected from 17 skilled swimmers. A series of separate backward-elimination analysis of covariance models was produced with cycle frequency and cycle length as dependent variables (DVs) and participant as a fixed factor, as including cycle frequency and cycle length would explain 100% of the maximal swimming velocity variance. The covariates identified in the cycle-frequency and cycle-length models were used to form the saturated model for maximal swimming velocity. The final parsimonious model identified three covariates (maximal knee joint angular velocity, maximal ankle angular velocity and knee range of movement) as determinants of the variance in maximal swimming velocity (adjusted-r2 = 0.929). However, when participant was removed as a fixed factor there was a large reduction in explained variance (adjusted r2 = 0.397) and only maximal knee joint angular velocity continued to contribute significantly, highlighting its importance to the production of maximal swimming velocity. The reduction in explained variance suggests an emphasis on inter-individual differences in undulatory underwater swimming technique and/or anthropometry. Future research should examine the efficacy of other anthropometric, kinematic and coordination variables to better understand the production of maximal swimming velocity and consider the importance of individual undulatory underwater swimming techniques when interpreting the data.


Scavenging of soluble organic matter from the prebiotic oceans.
The existence of hot or cold "nutrient broth" or "primeval soup" is challenged on the basis of the recent geochemistry of soluble organic carbon in the oceans. Most of the dissolved organic carbon is recycled quickly by organisms, but the residual, biologically refractive, organic matter is efficiently scavenged from the oceans (residence time of 1000 to 3500 years) by nonbiologically mediated chemical and physical processes, such as adsorption on sinking minerals, polymerization and aggregation to humic type polymers or by aggregation to particulate matter through bubbling and sinking of this material to the ocean bottom. Since there is no reason to believe that such nonbiological scavenging was not operative in the prebiotic oceans as well, then the prolonged existence of "organic soup" is very doubtful. The question of the origin of life is thus assumed to be related to solid-liquid interfacial activity, and the answer may be associated with sediment-water interaction rather than with solution chemistry.


Coronaviruses: an RNA proofreading machine regulates replication fidelity and diversity.
In order to survive and propagate, RNA viruses must achieve a balance between the capacity for adaptation to new environmental conditions or host cells with the need to maintain an intact and replication competent genome. Several virus families in the order Nidovirales, such as the coronaviruses (CoVs) must achieve these objectives with the largest and most complex replicating RNA genomes known, up to 32 kb of positive-sense RNA. The CoVs encode sixteen nonstructural proteins (nsp 1-16) with known or predicted RNA synthesis and modification activities, and it has been proposed that they are also responsible for the evolution of large genomes. The CoVs, including murine hepatitis virus (MHV) and SARS-CoV, encode a 3'-to-5' exoribonuclease activity (ExoN) in nsp14. Genetic inactivation of ExoN activity in engineered SARS-CoV and MHV genomes by alanine substitution at conserved DE-D-D active site residues results in viable mutants that demonstrate 15- to 20-fold increases in mutation rates, up to 18 times greater than those tolerated for fidelity mutants of other RNA viruses. Thus nsp14-ExoN is essential for replication fidelity, and likely serves either as a direct mediator or regulator of a more complex RNA proofreading machine, a process previously unprecedented in RNA virus biology. Elucidation of the mechanisms of nsp14-mediated proofreading will have major implications for our understanding of the evolution of RNA viruses, and also will provide a robust model to investigate the balance between fidelity, diversity and pathogenesis. The discovery of a protein distinct from a viral RdRp that regulates replication fidelity also raises the possibility that RNA genome replication fidelity may be adaptable to differing replication environments and selective pressures, rather than being a fixed determinant.


Direct analysis of thymic function in children with Down's syndrome.
Down's syndrome (DS) is characterized by several immunological defects, especially regarding T cell compartment. DS is considered the best example of accelerated ageing in humans. Direct observations of the thymus have shown that in DS this organ undergoes severe histological and morphological changes. However, no data on its capacity to generate T cells are present in the literature. Here, using a new technology based upon real time PCR, we have investigated the capacity of the thymus to produce and release newly generated T lymphocytes (the so called "recent thymic emigrants", RTE) in children with DS. We studied 8 children affected by DS, aged 2-7 years, compared with 8 age- and sex-matched healthy controls. Flow cytometry was used to determine different lymphocytes subsets. Real time PCR with the Taqman system was used to quantify the amount of RTE, i.e. peripheral blood lymphocytes that express the T cell receptor rearrangement excision circles (TREC). In comparison with control children, those with DS had a significant lower number of TREC+ peripheral blood cells. Moreover, in DS children but not in controls, a strong negative correlation between age and the levels of TREC+ cells was found. The direct measure of thymic output indicates that the impairment of the organ results in a reduced production of newly generated T cells. This observation could suggest that cytokines able to modulate thymic function, such as interleukins, could be useful to improve the functionality of the organ and to treat the immunodeficiency present in DS subjects.


Distributed versus focal cortical stimulation to enhance motor function and motor map plasticity in a rodent model of ischemia.
Motor rehabilitation after cerebral ischemia can enhance motor performance and induce motor map reorganization. Electrical stimulation of the cortex (CS) during rehabilitative training (CS/RT) augments motor map plasticity and confers gains in motor function beyond those observed with motor rehabilitation alone. However, it is unclear how the distribution of electrical stimulation across the cortex accomplishes these changes. This study examined the behavioral and neurophysiological effects of delivering CS/RT through a distributed versus focal arrangement of electrical contacts. Adult male rats were given rehabilitative training on a skilled forelimb reaching task following induction of focal ischemic damage within motor cortex. Intracortical microstimulation was used to derive high-resolution maps of forelimb movement representations within motor cortex contralateral to the trained/impaired paw before and after rehabilitation. All animals that received rehabilitation showed greater increases in motor map area and reaching accuracy than animals that received no training. Animals with the distributed configuration performed significantly greater reaching accuracy than animals in both the CS/RT with focused contact arrangement and rehabilitative training alone (RT) conditions on days 3 to 4 and on day 6 through the remainder of the study (P < .05). However, both CS/RT groups exhibited larger motor maps than the RT condition (E1-CS/RT, 4.71 ± 0.66 mm(2); E2-CS/RT, 4.64 ± 0.46 mm(2); RT, 2.99 ± 0.28 mm(2)). The results indicate that although both focal and distributed forms of CS/RT promote motor map reorganization only the distributed form of CS/RT enhances motor performance with rehabilitation.


Resting-State Functional Connectivity Magnetic Resonance Imaging and Outcome After Acute Stroke.
Background and Purpose- Physiological effects of stroke are best assessed over entire brain networks rather than just focally at the site of structural damage. Resting-state functional magnetic resonance imaging can map functional-anatomic networks by analyzing spontaneously correlated low-frequency activity fluctuations across the brain, but its potential usefulness in predicting functional outcome after acute stroke remains unknown. We assessed the ability of resting-state functional magnetic resonance imaging to predict functional outcome after acute stroke. Methods- We scanned 37 consecutive reperfused stroke patients (age, 69±14 years; 14 females; 3-day National Institutes of Health Stroke Scale score, 6±5) on day 3 after symptom onset. After imaging preprocessing, we used a whole-brain mask to calculate the correlation coefficient matrices for every paired region using the Harvard-Oxford probabilistic atlas. To evaluate functional outcome, we applied the modified Rankin Scale at 90 days. We used region of interest analyses to explore the functional connectivity between regions and graph-computation analysis to detect differences in functional connectivity between patients with good functional outcome (modified Rankin Scale score ≤2) and those with poor outcome (modified Rankin Scale score >2). Results- Patients with good outcome had greater functional connectivity than patients with poor outcome. Although 3-day National Institutes of Health Stroke Scale score was the most accurate independent predictor of 90-day modified Rankin Scale (84.2%), adding functional connectivity increased accuracy to 94.7%. Preserved bilateral interhemispheric connectivity between the anterior inferior temporal gyrus and superior frontal gyrus and decreased connectivity between the caudate and anterior inferior temporal gyrus in the left hemisphere had the greatest impact in favoring good prognosis. Conclusions- These data suggest that information about functional connectivity from resting-state functional magnetic resonance imaging may help predict 90-day stroke outcome.


Chikungunya Virus Overcomes Polyamine Depletion by Mutation of nsP1 and the Opal Stop Codon To Confer Enhanced Replication and Fitness.
Polyamines, which are small positively charge molecules present in all cells, play important roles in the replication of DNA and RNA viruses. Chikungunya virus (CHIKV) relies on polyamines for translation of the viral genome upon viral entry, and pharmacological depletion of polyamines limits viral replication. However, the potential development of antiviral resistance necessitates a better understanding of how polyamines function and can be targeted via compounds that alter polyamine levels. We have isolated CHIKV that is resistant to polyamine depletion and contains two mutations in the nonstructural protein 1 (nsP1)-coding region in combination with a mutation to the opal stop codon preceding nsP4. These mutations, in addition to promoting viral replication in polyamine-depleted cells, confer enhanced viral replication in vitro and in vivo The nsP1 mutations enhance membrane binding and methyltransferase activities, while the stop codon mutation allows increased downstream translation. These mutations, when combined, enhance viral fitness, but individual mutants are attenuated in mosquitoes. Together, our results suggest that CHIKV can evolve resistance to polyamine depletion and that pharmaceuticals targeting the polyamine biosynthetic pathway may be best used in combination with other established antivirals to mitigate the development of resistance.IMPORTANCE Chikungunya virus is a mosquito-borne virus that has infected millions worldwide. Its expansion into the Americas and rapid adaptation to new mosquito hosts present a serious threat to human health, which we can combat with the development of antiviral therapies as well as understanding how these viruses will mutate when exposed to antiviral therapies. Targeting polyamines, small positively charged molecules in the cell, may be a potential strategy against RNA viruses, including chikungunya virus. Here, we have described a virus that is resistant to polyamine depletion and has increased fitness in cells and in full organisms. Mutations in viral genome capping machinery, membrane binding activity, and a stop codon arise, and their altered activities enhance replication in the absence of polyamines. These results highlight strategies by which chikungunya virus can overcome polyamine depletion and emphasize continued research on developing improved antiviral therapies.


Effectiveness of a Healthy Lifestyle Program (HeLP) for low back pain: statistical analysis plan for a randomised controlled trial.
This paper describes the statistical analysis plan for a randomised controlled trial of a Healthy Lifestyle Program (HeLP) for low back pain targeting multiple health risks and behaviours, weight, physical activity, diet and smoking, to improve disability. We describe the methods for the main analyses and economic analysis of the trial. The trial is a two-arm pragmatic randomised controlled trial comparing the effect of the HeLP intervention to usual care on low back pain disability at 26 weeks. A total of 346 adults with low back pain were recruited from the Newcastle and Hunter region between September 2017 and November 2019 and randomised to either HeLP or usual care. HeLP is a 6-month intervention with participant outcomes measured at weeks 6, 12, 26 and 52 post randomisation. This statistical analysis plan describes data integrity, handling and preparation of data for analyses and methods for analyses. The primary endpoint for the trial is disability at 26 weeks using the 24-item self-report Roland Morris Disability Questionnaire. The primary analysis will follow the intention-to-treat principle using linear mixed regression models. The statistical analysis plan for this trial was produced to reduce outcome reporting bias arising from knowledge of the study findings. Any deviations will be described and justified in the final report. Australian New Zealand Clinical Trials Registry ACTRN12617001288314 . Registered on 6 September 2017.


Slipping through the bowel cancer screening programme.
Colorectal cancer is common and a leading cause of cancer death. Faecal occult blood screening has been shown to reduce mortality. The aim of this study was to identify patients in Gloucestershire with a new diagnosis of colorectal cancer who had previously been screened via the Bowel Cancer Screening Programme (BCSP). Between 2006 and 2009, 1030 patients were diagnosed with colorectal cancer. Of these 237 (23%) had been invited to be screened via the BCSP. Their clinical notes were analysed. Fifty-seven (24%) of the 237 patients had previously had a negative faecal occult blood result. Thirty-three (14%) had their cancer discovered as part of the BCSP. Seventy (30%) had already been diagnosed with colorectal cancer prior to invitation, 62 (26%) did not respond to the invitation, nine (4%) were registered outside Gloucestershire and had therefore not been invited, and three (3%) had died before the invitation. Of the 57 patients with a negative faecal occult blood test, 47 (83%) had colorectal cancer staged Dukes B or C, and 34 (60%) had a rectal or sigmoid cancer. Patients will present with colorectal cancer despite having been invited to participate in the BCSP, with many having received a negative faecal occult blood test. This could be considered a high false negative rate.


Gamma oscillation underlies hyperthermia-induced epileptiform-like spikes in immature rat hippocampal slices.
Recently a hyperthermic rat hippocampal slice model system has been used to investigate febrile seizure pathophysiology. Our previous data indicates that heating immature rat hippocampal slices from 34 to 41 degrees C in an interface chamber induced epileptiform-like population spikes accompanied by a spreading depression (SD). This may serve as an in vitro model of febrile seizures. In this study, we further investigate cellular mechanisms of hyperthermia-induced initial population spike activity. We hypothesized that GABA(A) receptor-mediated 30-100 Hz gamma oscillations underlie some aspects of the hyperthermic population spike activity. In 24 rat hippocampal slices, the hyperthermic population spike activity occurred at an average frequency of 45.9 +/- 14.9 Hz (Mean +/- SE, range = 21-79 Hz, n = 24), which does not differ significantly from the frequency of post-tetanic gamma oscillations (47.1 +/- 14.9 Hz, n = 34) in the same system. High intensity tetanic stimulation induces hippocampal neuronal discharges followed by a slow SD that has the magnitude and time course of the SD, which resembles hyperthermic responses. Both post-tetanic gamma oscillations and hyperthermic population spike activity can be blocked completely by a specific GABA(A) receptor blocker, bicuculline (5-20 microM). Bath-apply kynurenic acid (7 mM) blocks synaptic transmission, but fails to prevent hyperthermic population spikes, while intracellular diffusion of QX-314 (30 mM) abolishes spikes and produces a smooth depolarization in intracellular recording. These results suggest that the GABA(A) receptor-governed gamma oscillations underlie the hyperthermic population spike activity in immature hippocampal slices.


Bisphenol A exposure and behavioral problems among inner city children at 7-9 years of age.
Bisphenol A (BPA) is a ubiquitous endocrine disrupting compound. Several experimental and epidemiological studies suggest that gestational BPA exposure can lead to neurodevelopmental and behavioral problems in early-life, but results have been inconsistent. We previously reported that prenatal BPA exposure may affect child behavior and differently among boys and girls at ages 3-5 years. We investigated the association of prenatal and early childhood BPA exposure with behavioral outcomes in 7-9 year old minority children and hypothesized that we would observe the same sex-specific pattern observed at earlier ages. African-American and Dominican women enrolled in an inner-city prospective cohort study and their children were followed from mother's pregnancy through children's age 7-9 years. Women during the third trimester of pregnancy and children at ages 3 and 5 years provided spot urine samples. BPA exposure was categorized by tertiles of BPA urinary concentrations. The Child Behavioral Checklist (CBCL) was administered at ages 7 and 9 to assess multiple child behavior domains. Associations between behavior and prenatal (maternal) BPA concentrations and behavior and postnatal (child) BPA concentration were assessed via Poisson regression in models stratified by sex. These models accounted for potential confounders including prenatal or postnatal urinary BPA concentrations, child age at CBCL assessment, ethnicity, gestational age, maternal intelligence, maternal education and demoralization, quality of child's home environment, prenatal environmental tobacco smoke exposure, and prenatal mono-n-butyl phthalate concentration. The direction of the associations differed between boys and girls. Among boys (n=115), high prenatal BPA concentration (upper tertile vs. lower two tertiles) was associated with increased internalizing (β=0.41, p<0.0001) and externalizing composite scores (β=0.40, p<0.0001) and with their corresponding individual syndrome scales. There was a general decrease in scores among girls that was significant for the internalizing composite score (β=-0.17, p=0.04) (n=135). After accounting for possible selection bias, the results remained consistent for boys. Conversely, high postnatal BPA concentration was associated with increased behaviors on both the internalizing composite (β=0.30, p=0.0002) and externalizing composite scores (β=0.33, p<0.0001) and individual subscores in girls but fewer symptoms in boys. These results remained significant in girls after accounting for selection bias. These results suggest BPA exposure may affect childhood behavioral outcomes in a sex-specific manner and differently depending on timing of exposure.


Moderation of psychosocial risk factors through dysfunction of the hypothalamic-pituitary-adrenal stress axis in the onset of chronic widespread musculoskeletal pain: findings of a population-based prospective cohort study.
To test the hypothesis that abnormalities in the hypothalamic-pituitary-adrenal (HPA) stress-response system would act as an effect moderator between HPA function and the onset of chronic widespread pain (CWP). We conducted a population-based prospective cohort study. Current pain and psychosocial status were ascertained in 11,000 subjects. Of the 768 eligible subjects free of CWP but at future risk based on their psychosocial profile, 463 were randomly selected, and 267 (57.7%) consented to assessment of their HPA axis function. Diurnal function was measured by assessing levels of salivary cortisol in the morning (9:00 AM) and evening (10:00 PM). Serum cortisol levels were measured after an overnight low-dose (0.25 mg) dexamethasone suppression test and a potentially stressful clinical examination. All subjects were followed up 15 months later to identify cases of new-onset CWP. A total of 241 subjects (94.9%) completed the followup study, and 28 (11.6%) reported the new onset of CWP. High levels of cortisol post-dexamethasone (odds ratio [OR] 3.53, 95% confidence interval [95% CI] 1.17-10.65), low levels in morning saliva (OR 1.43, 95% CI 0.52-3.94), and high levels in evening saliva (OR 2.32, 95% CI 0.64-8.42) were all associated with CWP. These 3 factors were found to be independent and additive predictors of CWP (OR for all 3 factors 8.5, 95% CI 1.5-47.9) in analyses controlling for age, sex, depression, sleep disturbance, recent traumatic life events, and pain status. One or more of these 3 HPA factors identified 26 (92.9%) cases of new-onset CWP. Among a group of psychologically at-risk subjects, dysfunction of the HPA axis helps to distinguish those who will and will not develop new-onset CWP.


Conservation Status of the Australian Humpback Dolphin (Sousa sahulensis) Using the IUCN Red List Criteria.
Australian humpback dolphins (Sousa sahulensis) were recently described as a new species endemic to northern Australia and potentially southern New Guinea. We assessed the species conservation status against IUCN Red List Criteria using available information on their biology, ecology and threatening processes. Knowledge of population sizes and trends across the species range is lacking. Recent genetic studies indicate Australian humpback dolphins live in small and relatively isolated populations with limited gene flow among them. The available abundance estimates range from 14 to 207 individuals and no population studied to date is estimated to contain more than 104 mature individuals. The Potential Biological Removal method indicates populations are vulnerable to even low rates of anthropogenic mortality. Habitat degradation and loss is ongoing and expected to increase across the species range in Australia, and a continuing decline in the number of mature individuals is anticipated. Considering the available evidence and following a precautionary approach, we considered this species as Vulnerable under IUCN criterion C2a(i) because the total number of mature individuals is plausibly fewer than 10,000, an inferred continuing decline due to cumulative impacts, and each of the populations studied to date is estimated to contain fewer than 1000 mature individuals. Ongoing research efforts and recently developed research strategies and priorities will provide valuable information towards the future conservation and management of Australian humpback dolphins.


Pinning and wicking in regular pillar arrays.
Pinning and wicking of a liquid meniscus in a square array of pillars is investigated in numerical energy minimizations and compared to wetting experiments. Our combined study shows that criteria for spontaneous film formation, based on thermodynamic considerations as well as on simple geometric modelling of the meniscus shape, are insufficient to predict the onset of wicking. High aspect ratio pillars with a square cross-section may display a re-entrant pinning regime as the density of the pillars is increased, a behaviour that is captured by neither of the aforementioned models. Numerically computed energy landscapes for the advancing meniscus allow us to explain the re-entrant behaviour in terms of energy barriers between topologically different meniscus shapes. Our numerical results are validated by wicking experiments where for the material contact angle θ0 = 47° the re-entrant behaviour is present for square pillars and absent for pillars with circular cross section.


Diagnostic classification of schizophrenia by neural network analysis of blood-based gene expression signatures.
Gene expression profiling with microarray technology suggests that peripheral blood cells might be a surrogate for postmortem brain tissue in studies of schizophrenia. The development of an accessible peripheral biomarker would substantially help in the diagnosis of this disease. We used a bioinformatics approach to examine whether the gene expression signature in whole blood contains enough information to make a specific diagnosis of schizophrenia. Unpaired t-tests of gene expression datasets from 52 antipsychotics-free schizophrenia patients and 49 normal controls identified 792 differentially expressed probes. Functional profiling with DAVID revealed that eleven of these genes were previously reported to be associated with schizophrenia, and 73 of them were expressed in the brain tissue. We analyzed the datasets with one of the supervised classifiers, artificial neural networks (ANNs). The samples were subdivided into training and testing sets. Quality filtering and stepwise forward selection identified 14 probes as predictors of the diagnosis. ANNs were then trained with the selected probes as the input and the training set for known diagnosis as the output. The constructed model achieved 91.2% diagnostic accuracy in the training set and 87.9% accuracy in the hold-out testing set. On the other hand, hierarchical clustering, a standard but unsupervised classifier, failed to separate patients and controls. These results suggest analysis of a blood-based gene expression signature with the supervised classifier, ANNs, might be a diagnostic tool for schizophrenia.


A lower dosage levonorgestrel and testosterone combination effectively suppresses spermatogenesis and circulating gonadotropin levels with fewer metabolic effects than higher dosage combinations.
Studies using exogenous high-dosage testosterone (T) or a combination regimen of physiologic T plus high-dosage levonorgestrel (LNG) administration in normal men have shown that oligoazoospermia (<3 million/mL) or azoospermia can be achieved in the majority of the men. However, these hormonal regimens have been associated with significant weight gain and suppression of serum high-density lipoprotein (HDL) cholesterol levels. We hypothesized that a combination of physiologic exogenous testosterone and lower dosage LNG would result in uniform severe oligoazoospermia or azoospermia in normal men but would cause fewer adverse metabolic side effects. We conducted a randomized, placebo-controlled, single-blind trial comparing 6 months of T enanthate (100 mg IM, weekly) plus LNG, 125 microg by mouth, daily (LNG 125; n = 18) or LNG, 250 microg by mouth, daily (LNG 250; n = 18) and compared these regimens with our previous study of the same dosage of T enanthate combined with placebo LNG (LNG 0; n = 18) or with 500 mg of LNG (LNG= 500; n = 18). All three combination regimens of T enanthate and LNG suppressed spermatogenesis more rapidly and resulted in significantly more uniform severe oligoazoospermia (<1 million/mL) than the T-alone regimen. Severe oligoazoospermia was achieved in 89% of the LNG 125, 89% of the LNG 250, and 78% of the LNG 500 groups, respectively, versus 56% of the men in LNG 0 (P < 0.05 for the combination groups vs. LNG 0), but there were no significant differences between the combination regimens (P = NS). All four groups gained significant weight compared with their baselines, although the gain tended to be greater as the dosage of LNG increased (2.0+/-0.9, 2.9+/-1.1, 3.6+/-1.0, and 5.4+/-1.0 kg gained, compared with baseline in the LNG 0, 125, 250, and 500 groups respectively; P < 0.05 compared with baseline). Serum levels of HDL cholesterol decreased in all of the groups, but the effect was larger as the dosage of LNG increased (4+/-4% vs. 13+/-4%, 20+/-3%, and 22+/-4% decrease in HDL levels from baseline in the LNG 0, LNG 125, LNG 250, and LNG 500 groups respectively; P = 0.06 for LNG 125 compared with LNG 0, and P < 0.05 for LNG 250 and LNG 500 compared with LNG 0). We conclude that 1) the combination of physiologic exogenous T enanthate and LNG suppresses spermatogenesis more effectively than T enanthate alone and that 2) the combination regimen of T enanthate plus lower dosage LNG suppresses sperm production comparably to T enanthate plus higher dosage LNG, while causing less weight gain and HDL cholesterol suppression. A combination regimen of physiologic testosterone plus a low dosage of levonorgestrel offers great promise as a safe and effective male contraceptive regimen.


Cost Effectiveness of Once-Weekly Semaglutide Versus Once-Weekly Dulaglutide in the Treatment of Type 2 Diabetes in Canada.
The aim of this study was to assess the cost effectiveness of semaglutide versus dulaglutide, as an add-on to metformin monotherapy, for the treatment of type 2 diabetes (T2D), from a Canadian societal perspective. The Swedish Institute for Health Economics Cohort Model of T2D was used to assess the cost effectiveness of once-weekly semaglutide (0.5 or 1.0 mg) versus once-weekly dulaglutide (0.75 or 1.5 mg) over a 40-year time horizon. Using data from the SUSTAIN 7 trial, which demonstrated comparatively greater reductions in glycated hemoglobin (HbA1c), body mass index and systolic blood pressure with semaglutide, compared with dulaglutide, a deterministic base-case and scenario simulation were conducted. The robustness of the results was evaluated with probabilistic sensitivity analyses and 15 deterministic sensitivity analyses. The base-case analysis indicated that semaglutide is a dominant treatment option, compared with dulaglutide. Semaglutide was associated with lower total costs (Canadian dollars [CAN$]) versus dulaglutide for both low-dose (CAN$113,287 vs. CAN$113,690; cost-saving: CAN$403) and high-dose (CAN$112,983 vs. CAN$113,695; cost-saving: CAN$711) comparisons. Semaglutide resulted in increased quality-adjusted life-years (QALYs) and QALY gains, compared with dulaglutide, for both low-dose (11.10 vs. 11.07 QALYs; + 0.04 QALYs) and high-dose (11.12 vs. 11.07 QALYs; + 0.05 QALYs) comparisons. The probabilistic sensitivity analysis showed that for 66-73% of iterations, semaglutide was either dominant or was considered cost effective at a willingness-to-pay threshold of CAN$50,000. From a Canadian societal perspective, semaglutide may be a cost-effective treatment option versus dulaglutide in patients with T2D who are inadequately controlled on metformin monotherapy.


A time- and space-resolved nuclear receptor atlas in mouse liver.
The functional versatility of the liver is paramount for organismal homeostasis. Adult liver functions are controlled by a tightly regulated transcription factor network including nuclear receptors (NRs), which orchestrate many aspects of hepatic physiology. NRs are transcription factors sensitive to extracellular cues such as hormones, lipids, xenobiotics, etc. and are modulated by intracellular signaling pathways. While liver functional zonation and adaptability to fluctuating conditions rely on a sophisticated cellular architecture, a comprehensive knowledge of NR functions within liver cell populations is still lacking. As a step toward the accurate mapping of NR functions in the liver, we characterized their levels of expression in the whole liver from C57Bl6/J male mice as a function of time and diet. Nr1d1 (Rev-erba), Nr1d2 (Rev-erbb), Nr1c2 (Pparb/d), and Nr1f3 (Rorg) exhibited a robust cyclical expression in ad libitum-fed mice which was, like most cyclically expressed NRs, reinforced upon time-restricted feeding. In a few instances, cyclical expression was lost or gained as a function of the feeding regimen. NR isoform expression was explored in purified hepatocytes, cholangiocytes, Kupffer cells, hepatic stellate cells, and liver sinusoidal cells. The expression of some NR isoforms, such as Nr1h4 (Fxra) and Nr1b1 (Rara) isoforms, was markedly restricted to a few cell types. Leveraging liver single-cell RNAseq studies yielded a zonation pattern of NRs in hepatocytes, liver sinusoidal cells, and stellate cells, establishing a link between NR subtissular localization and liver functional specialization. In summary, we provide here an up-to-date compendium of NR expression in mouse liver in space and time.


Cell lineage and cell cycling analyses of the 4d micromere using live imaging in the marine annelid Platynereis dumerilii.
Cell lineage, cell cycle, and cell fate are tightly associated in developmental processes, but in vivo studies at single-cell resolution showing the intricacies of these associations are rare due to technical limitations. In this study on the marine annelid Platynereis dumerilii, we investigated the lineage of the 4d micromere, using high-resolution long-term live imaging complemented with a live-cell cycle reporter. 4d is the origin of mesodermal lineages and the germline in many spiralians. We traced lineages at single-cell resolution within 4d and demonstrate that embryonic segmental mesoderm forms via teloblastic divisions, as in clitellate annelids. We also identified the precise cellular origins of the larval mesodermal posterior growth zone. We found that differentially-fated progeny of 4d (germline, segmental mesoderm, growth zone) display significantly different cell cycling. This work has evolutionary implications, sets up the foundation for functional studies in annelid stem cells, and presents newly established techniques for live imaging marine embryos.


HCV RNA viral load is independent from CD4 cell count and plasma HIV RNA viral load in immunocompetent HIV-HCV co-infected patients: a 3-years follow-up study.
HCV RNA viral load is an important predictor of sustained virological response and, recently, a significant correlation with liver fibrosis was described. We investigated on possible influence of clinical and viro-immunological variables on HCV viral load in HIV-HCV co-infected patients over a study time of three years (2009-2012). We retrospectively enrolled 98 adult patients with a diagnosis of chronic HIV infection in 2009, a diagnosis of chronic HCV infection with a detectable plasma HCV RNA in 2009 and 2012, HCV therapy-naïve or with failed and stopped antiviral treatment before June 2008. The following variables were recorded: age, gender, HCV genotype, IL28B rs12979860 CC genotype, HCV treatment status, advanced liver fibrosis diagnosis, antiretroviral therapy, CD4+ cell count, HCV viral load, HIV RNA (plasma HIV-1 RNA levels were measured from blood samples every three months at least). The correlation was established using linear regression analysis, analysis of variance and Fisher's exact test. Comparisons between groups were performed using Fisher's exact test, the independent samples t-test and the t-test for paired data, as appropriate, for continuous variables. A mixed mode (ME) maximum likelihood linear regression model was constructed to evaluate the dependence of HCV viral load. HCV RNA levels did not change significantly from 2009 to 2012 (from 3924650 ± 5320177 IU/ml to 3085128 ± 3372347 IU/ml, p = 0.13); the CD4+ count increased significantly (from a mean of 576 to a mean of 654, p = 0.003). Using linear regression, a positive correlation was observed for HCV load and genotype 1 (p = 0.002), nonresponder status (p = 0.04) and with interleukin 28B CC allele (p = 0.05). Other studied covariates failed to reach a significant correlation. The HCV RNA load, a known pretreatment predictor of response to antiviral therapy, was independent of the two main parameters of HIV disease, plasma HIV RNA and CD4 cell count, over an observation time of 3 years in patients with recovered or spontaneously maintained immunocompetence.


Behavioral and Psychological Symptoms of Dementia as a Means of Communication: Considerations for Reducing Stigma and Promoting Person-Centered Care.
Dementia has rapidly become a major global health crisis. As the aging population continues to increase, the burden increases commensurately on both individual and societal levels. The behavioral and psychological symptoms of dementia (BPSD) are a prominent clinical feature of Alzheimer's disease and related dementias (ADRD). BPSD represent a myriad of manifestations that can create significant challenges for persons living with dementia and their care providers. As such, BPSD can result in detriments to social interaction with others, resulting in harm to the psychosocial health of the person with dementia. While brain deterioration can contribute to BPSD as the disease progresses, it may be confounded by language and communication difficulties associated with ADRD. Indeed, when a person with dementia cannot effectively communicate their needs, including basic needs such as hunger or toileting, nor symptoms of pain or discomfort, it may manifest as BPSD. In this way, a person with dementia may be attempting to communicate with what little resources are available to them in the form of emotional expression. Failing to recognize unmet needs compromises care and can reduce quality of life. Moreover, failing to fulfill said needs can also deteriorate communication and social bonds with loved ones and caregivers. The aim of this review is to bring the differential of unmet needs to the forefront of BPSD interpretation for both formal and informal caregivers. The overarching goal is to provide evidence to reframe the approach with which caregivers view the manifestations of BPSD to ensure quality of care for persons with dementia. Understanding that BPSD may, in fact, be attempts to communicate unmet needs in persons with dementia may facilitate clinical care decisions, promote quality of life, reduce stigma, and foster positive communications.


Characterization of the human T cell receptor alpha-chain repertoire and demonstration of a genetic influence on V alpha usage.
Despite considerable knowledge of the determinants and profile of the T cell receptor (TCR) beta-chain repertoire, very little is known about the repertoire of the V alpha and J alpha segments of the TCR in man or mouse. We have used the anchored polymerase chain reaction (PCR) to analyze the human TCR alpha-chain repertoire at the mRNA level in peripheral blood lymphocytes. We find marked differences in the usage of individual V alpha segments. The V alpha repertoire is determined both by differences in the use of individual V alpha gene segments at the time of gene rearrangement and by genetic influences on the selection of the expressed V alpha repertoire, presumably during thymic maturation. Analysis of the J alpha repertoire shows non-random usage of individual J alpha segments but no obvious relationship to chromosomal position. We also report three new V alpha segments, three new J alpha segments and possible allelic variation in V alpha gene segments. Two unusual TCR alpha transcripts are described which add new information on the nature of TCR alpha transcript assembly.


Dendritic orientation and laminar architecture in the rabbit auditory thalamus.
A laminar organization composed of the dendritic fields of principal neurons and afferent axonal arbors has been proposed as the anatomical substrate for the frequency map at several levels of the mammalian central auditory system, including the inferior colliculus and medial geniculate body (MGB). In contrast to the auditory thalamus in most mammals, the ventral division of the rabbit medial geniculate body (MGV) has cellular laminae visible in routine Nissl stains, allowing a direct comparison of the laminar organization with the dendritic architecture and frequency organization. In total 30 presumptive relay neurons in the MGV were labeled with the juxtacellular recording method, and their dendritic arbors were fully reconstructed from serial sections with the aid of a computer microscope. The spatial organization of MGV dendritic fields was analyzed using the dendritic prism, dendritic stick, and fan-in projection methods. Quantitative spatial analyses revealed that, for MGV neurons in the central pars lateralis subdivision, the major axis of the dendritic fields (approximately 29 degrees relative to the horizontal plane) was closely aligned with that of the Nissl laminae (approximately 25 degrees). Both were oriented orthogonally to the tonotopic axis. In contrast, cells in the pars ovoidea had their major axis of orientation parallel to the anteroposterior axis of the brain. Although a bitufted dendritic field was the norm, it was not uncommon for MGV neurons to have pronounced spatial asymmetries in their dendritic fields. A model is presented that incorporates cellular laminae and oriented dendritic growth to form frequency-related slabs within the MGV.


Changes in contrast sensitivity induced by defocus and their possible relations to emmetropization in the chicken.
To test whether the level of contrast adaptation (CA) relates to refractive development in the chicken. (CA refers to a spatial frequency-selective increase of suprathreshold contrast sensitivity after exposure to low-contrast patterns). CA was determined in individual chicks by comparing their optomotor gain in response to drifting low-contrast stripe patterns before and after treatment with spectacle lenses. The amount of CA was compared with the loss of contrast predicted from defocus at the tested spatial frequency. The reversion of CA and recovery from deprivation myopia were studied while the retinal image features were controlled by forcing the animals to watch spatially filtered digital video clips. CA was induced by wearing positive and negative lenses for 1.5 hours, both without and with cycloplegia, but was less pronounced in the case of positive lenses when accommodation was intact. The amount of CA at a tested spatial frequency was predicted from the loss of contrast calculated from the modulation transfer function for a defocused optical system. Watching low-pass-filtered video clips induced deprivation myopia and inhibited recovery from it. It also prevented the reversal of CA that was previously induced by deprivation. Both recovery from deprivation myopia and recovery from CA occurred with sharp video clips, although less so than with normal visual exposure. CA changes with retinal image sharpness and occurs even when accommodation is intact. Because CA correlates with myopia induced by frosted occluders, negative lenses, and low-pass-filtered video clips, and its reversal correlates with recovery from myopia, it is possible that shifts in CA may represent a signal related to refractive error development.


Novel methods of instruction in ACL injury prevention programs, a systematic review.
Anterior cruciate ligament (ACL) injury prevention programs have been successful in the short term. Motor learning strategies with an internal focus (IF) to body movements have traditionally been utilized, but may be less suitable than an external focus (EF) for the acquisition and control of complex motor skills required for sport. To investigate the available literature and provide an overview of the effect of IF and EF instructions on jump landing technique. Systematic searches were conducted in PubMed (1966 to May 2014), CINAHL (1981 to May 2014) and PsycInfo (1989 to May 2014). A priori defined inclusion criteria were: (i) full text; (ii) published in English, German or Dutch; (iii) healthy adult subjects (mean age ≥18 years); (iv) jump and landing performance tested and (v) study used comparison between an EF and IF. Performance (jump height and distance) and technique (kinematics and kinetics) were the primary outcome variables of interest. Nine papers were included. Significant better motor performance and movement technique was found with an EF compared to an IF. Considering the beneficial results in the included studies when utilizing an EF, it is suggested to implement these strategies into ACL injury prevention programs.


Age-Dependent Modulation of Songbird Summer Feather Molt by Temporal and Functional Constraints.
Time constraints influence various ecological, life-history, and demographic properties of individuals and populations of many species throughout the annual cycle. Feather molt is a timely undertaking that is considered among the three most energy-demanding processes in the life cycle of birds. To deal with time pressure, passerines may shorten their molt duration, using three non-mutually exclusive mechanisms: (1) replacing only part of the plumage, (2) increasing the speed of molt, and (3) postponing the renewal of some or all the plumage to a later season (i.e., from the summer to the overwintering period). We used a comparative approach by measuring 12,349 individuals from 134 passerine species to explore how feather molt of juvenile and adult passerines is evolutionarily modulated under time constraints. The results indicate that breeding at northern latitudes and long-distance migration limit the time available for molt and that the consequences of time constraints were age dependent. While the duration of adult summer molt decreased, the extent, rather than the duration, of juvenile molt declined under time constraints. This study highlights the importance of considering time constraints in order to enhance the understanding of selective forces that shape life-history processes and their consequences throughout the annual routine.


Strengthening primary health care: achieving health gains in a remote region of Australia.
To evaluate the impact of a comprehensive primary health care service model on key health performance indicators in a remote region of Australia. A cross-sectional 6-year retrospective evaluation of the results of a health service partnership between an Aboriginal community controlled health service, a hospital and a community health service in north-west Western Australia. Integration of health promotion, health assessments and chronic disease management with an acute primary health care service as a result of the formal partnership. Cross-sectional data on use and outcomes of health care from 1 July 2006 to 30 June 2012 are reported in accordance with national key performance indicators. There were increases in occasions of service (from 21 218 to 33 753), most notably in primary health care services provided to very remote outlying communities (from 863 to 11 338). Health assessment uptake increased from 13% of the eligible population to 61%, leading to 73% of those identified with diabetes being placed on a care plan. Quality-of-care indicators (glycated haemoglobin checks and proportion of people with diabetics receiving antihypertensives) showed improvements over the 6-year study period, and there was also a downward trend in mortality. This study demonstrates that strengthening primary health care services by addressing key enablers and sustainability requirements can translate into population health gains consistent with the goals underpinning the National Health Care Reform and Closing the Gap policies, and may potentially reduce health inequity for remote-living Aboriginal Australians.


The relationship between body mass index and the risk of development of Dupuytren's disease: a Mendelian randomization study.
We performed Mendelian randomization analyses of body mass index and waist-hip ratio adjusted for body mass index in Dupuytren's disease using summary statistics from genome-wide association study meta-analyses. We found that adiposity is causally protective against Dupuytren's disease, with the inverse-variance weighted Mendelian randomization analysis estimating that a 1 standard deviation increase in body mass index (equivalent to 4.8 kg/m2) leads to 28% (95% confidence interval: 18-37%) lower relative odds of developing Dupuytren's disease, and a 1 standard deviation increase in waist-hip ratio adjusted for body mass index (equivalent to a waist-hip ratio of 0.09) leads to 26% (95% confidence interval: 6-42%) lower relative odds of developing Dupuytren's disease. We conclude from this study that regardless of the well-established negative health effects of obesity, the raised body mass index is associated with a lower risk of Dupuytren's disease and may be causally protective for the development of the disease.


Anomalous mole-fraction effects in recombinant and native cyclic nucleotide-gated channels in rat olfactory receptor neurons.
Anomalous mole-fraction effects (AMFE) were studied, using the inside-out configuration of the patchclamp technique, in both recombinant wild-type alpha-homomeric rat olfactory adenosine 3',5'-cyclic monophosphate (cAMP)-gated channels (rOCNC1) expressed in human embryonic kidney cells (HEK 293) and native cyclic nucleotide-gated (CNG) channels in acutely isolated rat olfactory receptor neurons. Single-channel and macroscopic currents were activated by 200 microM and 500 microM cAMP, respectively. Macroscopic currents, measured with mixtures of Na(+)-NH(4)(+) or Cs(+)-Li(+) in the cytoplasmic bathing solution, displayed AMFE in the rOCNC1 channels at both positive and negative membrane potentials. The rOCNC1 single-channel conductance showed a distinct minimum (or maximum) in an 80% Na(+)-20% NH(4)(+) mixture (or a 60% Cs(+)-40% Li(+) mixture), but only at positive membrane potentials. Macroscopic measurements in native olfactory CNG channels with mixtures of Na(+)-NH(4)(+) indicated similar AMFE. These results suggest that both native CNG channels and recombinant alpha-homomeric channels allow several ions to be present simultaneously within the channel pore. They also further validate the dominant role of the alpha-subunit in permeation through these channels, provide the first evidence to suggest that rOCNC1 channels have multi-ion properties and further justify the use of the rOCNC1 channel as an effective model for structure-function studies of ion permeation and selectivity in olfactory CNG channels.


Description of a New Species of the Genus Tylopharynx (Nemata: Diplogasteroidea), T. clariamphida sp. n., with a Redescription of T. foetida (Bütschli, 1874) Goffart, 1930.
Tylopharynx clariamphida sp. n. is described from muddy sand collected in Anhui Province, China. It can be distinguished from T. foetida (Bütschli, 1874), the type and only species of the genus, by numerous characters: having 24 to 26 prominent and clearly separated longitudinal ridges, a higher lip region with no hint of a cephalic framework, more prominent amphidial foveae in lateral view, wider and more posteriorly located amphidial apertures, smaller basal knobs of stoma, longer metacorpus, more enlarged phasmids, shorter spicules with shorter digitate terminus, shorter reflexed part of testis, and thicker gubernaculum with more angular shape. For comparison, an expanded description is given for T. foetida from Belgium, and SEM photographs of both species are provided.


The Lrs4-Csm1 monopolin complex associates with kinetochores during anaphase and is required for accurate chromosome segregation.
Lrs4 and Csm1, components of the monopolin complex, localize to the rDNA where they regulate rDNA maintenance and segregation. During meiosis, the complex also associates with kinetochores to bring about sister kinetochore co-orientation, an essential aspect of meiosis I chromosome segregation. We show here that the Lrs4-Csm1 complex associates with kinetochores during mitosis. This kinetochore localization is observed during anaphase and depends on the on the Mitotic Exit Network, a signaling cascade essential for the completion of mitosis. Furthermore, we find that Lrs4 and Csm1 are important for chromosome segregation fidelity. Our results reveal a previously unanticipated function for Lrs4-Csm1 in mitotic chromosome segregation.


Brain MRI changes in phenylketonuria. Associations with dietary status.
Following the introduction 30 years ago of neonatal screening and early dietary treatment for phenylketonuria there has been a dramatic decrease in the severity of neurological dysfunction associated with this disorder. However, there is evidence that subtle neurological impairment remains common in early treated subjects and in the last 3 years there have been a number of reports of overt neurological impairment with white matter abnormalities on MRI. The frequency of white matter changes in phenylketonuria, and the relation of these changes to dietary management, have remained unclear. The present study examines MRI findings in 34 subjects aged 8-33 years. Twenty-five subjects had been detected by routine neonatal screening and nine had been missed in the screening programme. At the time of the investigation 16 of the early treated and two of the late treated subjects were still receiving a diet low in phenylalanine. All but two of the 34 subjects showed abnormalities on MRI. In the early diagnosed group it could be shown that the severity of MRI changes (graded 1-5) was significantly and independently associated with phenylalanine concentrations at the time of investigation and the time since dietary treatment had been withdrawn. These data are consistent with studies in animals showing that hyperphenylalaninaemia increases myelin turnover in a dose dependent manner. It is suggested that the effects of phenylalanine on myelin pose a lifelong hazard to the nervous system.


Graphene and nanowire transistors for cellular interfaces and electrical recording.
Nanowire field-effect transistors (NW-FETs) have been shown to be powerful building blocks for nanoscale bioelectronic interfaces with cells and tissue due to their excellent sensitivity and their capability to form strongly coupled interfaces with cell membranes. Graphene has also been shown to be an attractive building block for nanoscale electronic devices, although little is known about its interfaces with cells and tissue. Here we report the first studies of graphene field effect transistors (Gra-FETs) as well as combined Gra- and NW-FETs interfaced to electrogenic cells. Gra-FET conductance signals recorded from spontaneously beating embryonic chicken cardiomyocytes yield well-defined extracellular signals with signal-to-noise ratio routinely >4. The conductance signal amplitude was tuned by varying the Gra-FET working region through changes in water gate potential, V(wg). Signals recorded from cardiomyocytes for different V(wg) result in constant calibrated extracellular voltage, indicating a robust graphene/cell interface. Significantly, variations in V(wg) across the Dirac point demonstrate the expected signal polarity flip, thus allowing, for the first time, both n- and p-type recording to be achieved from the same Gra-FET simply by offsetting V(wg). In addition, comparisons of peak-to-peak recorded signal widths made as a function of Gra-FET device sizes and versus NW-FETs allowed an assessment of relative resolution in extracellular recording. Specifically, peak-to-peak widths increased with the area of Gra-FET devices, indicating an averaged signal from different points across the outer membrane of the beating cells. One-dimensional silicon NW- FETs incorporated side by side with the two-dimensional Gra-FET devices further highlighted limits in both temporal resolution and multiplexed measurements from the same cell for the different types of devices. The distinct and complementary capabilities of Gra- and NW-FETs could open up unique opportunities in the field of bioelectronics in the future.


The caracol tower at chichen itza: an ancient astronomical observatory?
Although our investigations reveal a number of significant astronomical events coinciding with many of the measured alignments presented in Table 1, not every alignment appears to have an astronomical match which we can recognize. It may be that only some of the sighting possibilities we have discussed were actually functional. Moreover, our search of significant astronomical events to match the alignments has included only those which seem of obvious functional importance to us: sun, moon, and planetary extremes and the setting positions of the brightest stars. We have emphasized those celestial bodies which are documented in the literature as having been of importance. Perhaps hitherto unrecognized constellations were sighted in the windows, perhaps fainter stars, the heliacal rising and setting times of which could have served to mark important dates in the calendar. While we propose no grand cosmic scheme for the astronomical design of the Caracol it can be inferred that the building, apart from being a monument related to Quetzalcoatl, was erected primarily for the purpose of embodying in its architecture certain significant astronomical event alignments, in the same sense that a modern astronomical ephemeris exhibits information of importance to us in the keeping of the current calendar. There are examples in the Mesoamerican historical literature of deliberate attempts to align buildings with astronomical directions of importance. For example, Maudslay (33) quotes Father Motolinia, who tells us that in Tenochtitlan the festival called Tlacaxipeualistli "took place when the sun stood in the middle of Huicholobos, which was at the equinox, and because it was a little out of the straight, Montezuma wished to pull it down and set it right." According to Maudslay, worshipers were probably facing east to watch the sun rise between the two oratories on the Great Temple of Tenochtitlan at the time of the equinox. The directions of the faces of the Lower and Upper platforms of the Caracol seem to have been laid out deliberately to point to horizon events involving the sun and the planet Venus. Of the lines taken through the windows, the Venus setting points seem most plausible to us in view of both the accuracy with which they fit the architecture and the historical evidence bearing upon the importance of Venus to the Mesoamerican people. A specific connection between the Venus calendar in the Dresden Codex and the sighting of the extreme positions of the planet along the horizon, however, is yet to be established. It is especially significant that alignments in both the base and the top of the tower relate to Venus. The solar equinox alignment in window I remains problematical, although the arrangement probably functioned as an approximate means of determining the first day of spring and the first day of autumn. Lines pointing to individual bright stars undoubtedly should be given lower value. If one is willing to carry the matching game to its ultimate completion, a stellar object can always be found which, although very obscure, will fit an alignment. In our consideration of the problem we have attempted to single out bright stars which appeared or disappeared on significant calendar dates. Other round structures resembling the Caracol exist in Mesoamerica (20), although there are comparatively few built by the Maya. Nearly all can be attributed to the cult of Quetzalcoatl (34). To our knowledge none have been carefully measured and analyzed for astronomical orientations. The ruined tower Q-152 at Mayapan bore distinct similarities to the Caracol, both in shape and structure. It probably contained only a single doorway which faced west. Both structures possessed circular corridors. A circular tower is still standing at Paalmul on the coast of Quintana Roo north of Tulum. Pollock (20, p. 115) states that it has a single room in the turret. A window similar to No. I in the Caracol faces northwest, the same direction as the base of the front of the structure. It may be astronomically significant that the Yucatecan towers fronted in approximately the same direction. Andrews (34) reports the existence of a curious circular building located at Puerto Rico, Campeche, near Xpujil. His crosssectional view of the tower bears a close resemblance to Ruppert's sketch (6, figure 293) of a horizontal section taken through the windows remaining at the top of the Caracol. Hartung (12) has suggested a possible astronomical use for the Puerto Rico tower, but no analysis of the orientation of its "windows," which are much smaller than those of the Caracol, has yet been conducted. Other circular buildings are reported at Ake (20, p. 113) and Isla Cozumel (35, p. 557). We hope that future investigations of the remains of Yucatecan towers will shed further light upon the significance and use of the Caracol as an astronomical observatory.


Does Changing Vertical Disparity Induce Horizontal Head Movement?
Theoretically, one can estimate the direction of an object that is relative to the head using vertical disparity if the distance from the head to the object is known. However, several reports describe vertical disparity as having little or no effect on the perception of visual direction. It has been suggested, however, that the visual processes involved in action are different from those involved in perception, and the effect of visual disparity on action has not been investigated in previous studies. This study investigated the influence of vertical disparity on the stability of head direction as a motor response to visual information. We presented a stimulus consisting of horizontal lines with vertical size-disparity oscillation, and examined whether the stimulus affected the subject's head movement. The results showed that the head movement in the condition of vertical size-disparity oscillation was not significantly different from that in the condition of no disparity oscillation. Our results suggest that, despite theoretical validity, vertical disparity is not used for controlling head movement.


Surface bound amine functional group density influences embryonic stem cell maintenance.
Gradient surfaces are highly effective tools to screen and optimize cell- surface interactions. Here, the response of embryonic stem (ES) cell colonies to plasma polymer gradient surfaces is investigated. Surface chemistry ranged from pure allylamine (AA) plasma polymer on one end of the gradient to pure octadiene (OD) plasma polymer on the other end. Optimal surface chemistry conditions for retention of pluripotency were identified. Expression of the stem cell markers alkaline phosphatase (AP) and Oct4 varied with the position of the ES cell colonies across the OD-AA plasma polymer gradient. Both markers were more strongly retained on the OD plasma polymer rich regions of the gradients. The observed variation of expression across the plasma polymer gradient increased with duration of stem cell culture. While maximum cell adhesion to the gradient substrate occurred at a nitrogen- to-carbon (N/C ratio) of approximately 0.1, Oct4 and AP expression was best retained at an N/C ratio < 0.04. Stem cell marker expression correlated with colony size and morphology: more compact, multilayered colonies with prominent F-actin staining arose as the N/C ratio decreased. Disruption of actin polymerization using Y-27632 ROCK inhibitor resulted in a collapse of the multilayer colony structure into monolayers with limited cell-cell contact. A corresponding decrease in expression of AP and Oct4 was observed. Oct4 expression along with 3D colony morphology was partially rescued on the OD plasma polymer rich regions of the gradient.


Fabry-Pérot cavity based on chirped sampled fiber Bragg gratings.
A novel kind of Fabry-Pérot (FP) structure based on chirped sampled fiber Bragg grating (CSFBG) is proposed and demonstrated. In this structure, the regular chirped FBG (CFBG) that functions as reflecting mirror in the FP cavity is replaced by CSFBG, which is realized by chirping the sampling periods of a sampled FBG having uniform local grating period. The realization of such CSFBG-FPs having diverse properties just needs a single uniform pitch phase mask and sub-micrometer precision moving stage. Compared with the conventional CFBG-FP, it becomes more flexible to design CSFBG-FPs of diverse functions, and the fabrication process gets simpler. As a demonstration, based on the same experimental facilities, FPs with uniform FSR (~73 pm) and chirped FSR (varying from 28 pm to 405 pm) are fabricated respectively, which shows good agreement with simulation results.


Tedizolid: a novel oxazolidinone with potent activity against multidrug-resistant gram-positive pathogens.
Tedizolid phosphate is a novel oxazolidinone prodrug (converted to the active form tedizolid by phosphatases in vivo) that has been developed and recently approved (June 2014) by the United States FDA for the treatment of acute bacterial skin and skin structure infections (ABSSSIs) caused by susceptible Gram-positive pathogens, including methicillin-resistant Staphylococcus aureus (MRSA). Tedizolid is an oxazolidinone, but differs from other oxazolidinones by possessing a modified side chain at the C-5 position of the oxazolidinone nucleus which confers activity against certain linezolid-resistant pathogens and has an optimized C- and D-ring system that improves potency through additional binding site interactions. The mechanism of action of tedizolid is similar to other oxazolidinones and occurs through inhibition of bacterial protein synthesis by binding to 23S ribosomal RNA (rRNA) of the 50S subunit of the ribosome. As with other oxazolidinones, the spontaneous frequency of resistance development to tedizolid is low. Tedizolid is four- to eightfold more potent in vivo than linezolid against all species of staphylococci, enterococci, and streptococci, including drug-resistant phenotypes such as MRSA and vancomycin-resistant enterococci (VRE) and linezolid-resistant phenotypes. Importantly, tedizolid demonstrates activity against linezolid-resistant bacterial strains harboring the horizontally transmissible cfr gene, in the absence of certain ribosomal mutations conferring reduced oxazolidinone susceptibility. With its half-life of approximately 12 h, tedizolid is dosed once daily. It demonstrates linear pharmacokinetics, has a high oral bioavailability of approximately 90 %, and is primarily excreted by the liver as an inactive, non-circulating sulphate conjugate. Tedizolid does not require dosage adjustment in patients with any degree of renal dysfunction or hepatic dysfunction. Studies in animals have demonstrated that the pharmacodynamic parameter most closely associated with the efficacy of tedizolid is fAUC(0-24h)/MIC. In non-neutropenic animals, a dose-response enhancement was observed with tedizolid and lower exposures were required compared to neutropenic cohorts. Two Phase III clinical trials have demonstrated non-inferiority of a once-daily tedizolid 200 mg dose for 6-10 days versus twice-daily 600 mg linezolid for the treatment of ABSSSIs. Both trials used the primary endpoint of early clinical response at 48-72 h; however, one trial compared oral formulations while the other initiated therapy with the parenteral formulation and allowed oral sequential therapy following initial clinical response. Throughout its development, tedizolid has demonstrated that it is well tolerated and animal studies have shown a lower propensity for neuropathies with long-term use than its predecessor linezolid. Data from the two completed Phase III clinical trials demonstrated that the studied tedizolid regimen (200 mg once daily for 6 days) had significantly less impact on hematologic parameters as well as significantly less gastrointestinal treatment-emergent adverse effects (TEAEs) than its comparator linezolid. As with linezolid, tedizolid is a weak, reversible MAO inhibitor; however, a murine head twitch model validated to assess serotonergic activity reported no increase in the number of head twitches with tedizolid even at doses that exceeded the C max in humans by up to 25-fold. Tyramine and pseudoephedrine challenge studies in humans have also reported no meaningful MAO-related interactions with tedizolid. With its enhanced in vitro activity against a broad-spectrum of Gram-positive aerobic bacteria, convenient once-daily dosing, a short 6-day course of therapy, availability of both oral and intravenous routes of administration, and an adverse effect profile that appears to be more favorable than linezolid, tedizolid is an attractive agent for use in both the hospital and community settings. Tedizolid is currently undergoing additional Phase III clinical trials for the treatment of hospital-acquired bacterial pneumonia (HABP) and ventilated nosocomial pneumonia (VNP).


Multisite randomized trial of behavioral interventions for women with co-occurring PTSD and substance use disorders.
The authors compared the effectiveness of the Seeking Safety group, cognitive-behavioral treatment for substance use disorder and posttraumatic stress disorder (PTSD), to an active comparison health education group (Women's Health Education [WHE]) within the National Institute on Drug Abuse's Clinical Trials Network. The authors randomized 353 women to receive 12 sessions of Seeking Safety (M = 6.2 sessions) or WHE (M = 6.0 sessions) with follow-up assessment 1 week and 3, 6, and 12 months posttreatment. Primary outcomes were the Clinician Administered PTSD Scale (CAPS), the PTSD Symptom Scale-Self Report (PSS-SR), and a substance use inventory (self-reported abstinence and percentage of days of use over 7 days). Intention-to-treat analysis showed large, clinically significant reductions in CAPS and PSS-SR symptoms (d = 1.94 and 1.12, respectively) but no reliable difference between conditions. Substance use outcomes were not significantly different over time between the two treatments and at follow-up showed no significant change from baseline. Study results do not favor Seeking Safety over WHE as an adjunct to substance use disorder treatment for women with PTSD and reflect considerable opportunity to improve clinical outcomes in community-based treatments for these co-occurring conditions.


Tumor-Associated Macrophages Can Contribute to Antitumor Activity through FcγR-Mediated Processing of Antibody-Drug Conjugates.
The primary mechanism of antibody-drug conjugates (ADC) is targeted delivery of a cytotoxic payload to tumor cells via cancer-associated membrane receptors. However, the tumor microenvironment likely plays a role in ADC penetration, distribution, and processing and thus impacts the overall antitumor activity. Here, we report on the potential contribution of Fc-FcγR interactions between ADCs and tumor-associated macrophages (TAM) to the preclinical antitumor activities of ADCs. In the CD30+ L-428 Hodgkin lymphoma model, anti-CD30-vcMMAE and a non-binding control (hIgG-vcMMAE) demonstrated similar antitumor activity as well as similar payload release in the tumors. IHC analysis revealed L-428 tumors contained highly abundant TAMs, which were confirmed to bind ADCs by IHC and flow cytometry. The infiltration of TAMs was further found to correlate with the antitumor activity of the non-binding hIgG-vcMMAE in five additional xenograft models. hIgG1V1-vcMMAE, bearing a mutation in the Fc region which ablates Fc gamma receptor (FcγR) binding, lost antitumor activity in three TAM-high xenograft models, suggesting Fc-FcγR interactions modulate the TAM-ADC interaction. Our results suggest that TAMs can contribute to ADC processing through FcγR interaction in preclinical tumor models and may represent an important additional mechanism for drug release from ADCs. Correlative studies in clinical trials will further shed light on whether TAMs play a role in patients' response to ADC therapies. Mol Cancer Ther; 16(7); 1347-54. ©2017 AACR.


Factors associated with active commuting to school by bicycle from Bogotá, Colombia: The FUPRECOL study.
Active commuting to school (ACS) can contribute to daily physical activity (PA) levels in children and adolescents. The aim of the study was to analyze the characteristics of active commuting to and from school by bicycle and to identify the factors associated with the use of bicycles for active commuting to school based in a sample of schoolchildren in Bogotá, Colombia. A cross-sectional study was conducted in 8,057 children and adolescents. A self-reported questionnaire was used to measure frequency and mode of commuting to school and the time it took them to get there. Weight, height, and waist circumference measurements were obtained using standardized methods, and mothers and fathers self-reported their highest level of educational attainment and household level. Multivariate analyses using unordered multinomial logistic regression models were conducted in the main analysis. 21.9 % of the sample reported commuting by bicycle and 7.9 % reported commuting for more than 120 min. The multivariate logistic regression showed that boys, aged 9-12 years, and those whose parents had achieved higher levels of education (university/postgraduate) were the factors most strongly associated with a use bicycles as a means of active commuting to and from school. The findings of this study suggest that it's necessary to promote ACS from childhood and to emphasize its use during the transition to adolescence and during adolescence itself in order to increase its continued use by students.


Tuning the Brake While Raising the Stake: Network Dynamics during Sequential Decision-Making.
When gathering valued goods, risk and reward are often coupled and escalate over time, for instance, during foraging, trading, or gambling. This escalating frame requires agents to continuously balance expectations of reward against those of risk. To address how the human brain dynamically computes these tradeoffs, we performed whole-brain fMRI while healthy young individuals engaged in a sequential gambling task. Participants were repeatedly confronted with the option to continue with throwing a die to accumulate monetary reward under escalating risk, or the alternative option to stop to bank the current balance. Within each gambling round, the accumulation of gains gradually increased reaction times for "continue" choices, indicating growing uncertainty in the decision to continue. Neural activity evoked by "continue" choices was associated with growing activity and connectivity of a cortico-subcortical "braking" network that positively scaled with the accumulated gains, including pre-supplementary motor area (pre-SMA), inferior frontal gyrus, caudate, and subthalamic nucleus (STN). The influence of the STN on continue-evoked activity in the pre-SMA was predicted by interindividual differences in risk-aversion attitudes expressed during the gambling task. Furthermore, activity in dorsal anterior cingulate cortex (ACC) reflected individual choice tendencies by showing increased activation when subjects made nondefault "continue" choices despite an increasing tendency to stop, but ACC activity did not change in proportion with subjective choice uncertainty. Together, the results implicate a key role of dorsal ACC, pre-SMA, inferior frontal gyrus, and STN in computing the trade-off between escalating reward and risk in sequential decision-making. Using a paradigm where subjects experienced increasing potential rewards coupled with increasing risk, this study addressed two unresolved questions in the field of decision-making: First, we investigated an "inhibitory" network of regions that has so far been investigated with externally cued action inhibition. In this study, we show that the dynamics in this network under increasingly risky decisions are predictive of subjects' risk attitudes. Second, we contribute to a currently ongoing debate about the anterior cingulate cortex's role in sequential foraging decisions by showing that its activity is related to making nondefault choices rather than to choice uncertainty.


Mental stress increases sympathetic nerve activity during sustained baroreceptor stimulation in humans.
Muscle sympathetic nerve activity (MSNA) in humans is regulated in part by arterial baroreceptors. However, although mental stress increases blood pressure, it also increases MSNA. This suggests that baroreceptor control of MSNA is altered during mental stress. In nine healthy men (age range, 20-26 years), we recorded heart rate, blood pressure, and efferent MSNA (peroneal nerve, microneurography) during a 4-minute mental arithmetic task performed both before and during infusion of phenylephrine sufficient to markedly suppress resting MSNA. Before phenylephrine, mental stress significantly increased mean blood pressure (p less than 0.01), heart rate (p less than 0.01), and MSNA (from 18.5 +/- 3.2 to 24.8 +/- 3.5 bursts/min, p less than 0.001). Phenylephrine infusion increased resting mean blood pressure (from 84.0 +/- 2.6 to 90.0 +/- 2.7 mm Hg, p less than 0.01) and decreased resting heart rate (from 65.6 +/- 1.7 to 55.6 +/- 2.0 beats/min, p less than 0.01). Resting MSNA decreased dramatically during phenylephrine (from 18.5 +/- 3.2 to 3.3 +/- 1.3 bursts/min, p less than 0.01). During phenylephrine, mental stress again significantly (p less than 0.01) increased mean blood pressure, heart rate, and MSNA (from 3.1 +/- 1.4 to 10.9 +/- 1.8 bursts/min). The magnitude of stress-induced increases in MSNA and heart rate were comparable before and during phenylephrine infusion despite the greater elevation in diastolic pressure during stress plus phenylephrine. The present study demonstrates that mental stress produces sympathoexcitatory and pressor responses even during sustained stimulation of arterial baroreceptors.


Topological structure and dynamics of three-dimensional active nematics.
Topological structures are effective descriptors of the nonequilibrium dynamics of diverse many-body systems. For example, motile, point-like topological defects capture the salient features of two-dimensional active liquid crystals composed of energy-consuming anisotropic units. We dispersed force-generating microtubule bundles in a passive colloidal liquid crystal to form a three-dimensional active nematic. Light-sheet microscopy revealed the temporal evolution of the millimeter-scale structure of these active nematics with single-bundle resolution. The primary topological excitations are extended, charge-neutral disclination loops that undergo complex dynamics and recombination events. Our work suggests a framework for analyzing the nonequilibrium dynamics of bulk anisotropic systems as diverse as driven complex fluids, active metamaterials, biological tissues, and collections of robots or organisms.


Femoroacetabular impingement surgery leads to early pain relief but minimal functional gains past 6 months: experience from the FIRST trial.
To understand the early outcomes after hip arthroscopy and better define the trajectory of improvement in a prospective cohort of patients who have undergone hip arthroscopic osteochondroplasty for femoroacetabular impingement (FAI) syndrome. Data were analyzed from the Femoroacetabular Impingement RandomiSed controlled Trial (FIRST) on the 108 study patients who underwent osteochondroplasty, with or without labral repair. Study outcomes included patient-reported pain (using a 100-point Visual Analogue Scale (VAS)), hip function (using the Hip Outcome Score (HOS) and International Hip Outcome Tool (iHOT-12)), and health-related quality of life (using the EuroQol 5 Dimensions (EQ-5D)) measured at baseline, 2 weeks, 3 months, 6 months, and 12 months post-operatively. There was a decrease in mean post-operative pain VAS scores from baseline. The first 2 weeks post-operative yielded the greatest reduction in pain with a mean (SD) VAS score of 37.8 (23.4), with score stabilization between 6 months (26.9 (26.9)) and 12 months (25.3 (27.6)). Mean HOS (activities of daily living) scores improved from baseline (59.7 (16.2)) starting at 6 weeks post-operative (64.1 (19.1)). The HOS (Sports) showed no improvement from baseline (41.2 (20.4)) until 3 months (49.1 (27.9)), and continued to improve at 6 months (64.1 (28.7)) and 12 months (68.6 (30.5)). The iHOT-12 scores showed functional improvement from baseline (31.3 (18.8)), as early as 6 weeks (44.9 (22.4)) up to and including 12 months (67.1 (29.7)). EQ-5D index scores showed modest steady improvement from 6 weeks to 12 months post-operative, while the EQ-5D VAS component similarly showed modest and steady improvements from 3 months onward. Results from this study highlight that hip arthroscopic osteochondroplasty with or without labral repair for FAI leads to early pain relief. While all scores improved from baseline, functional gains appear to plateau from 6 months onwards. These data can be used to inform decision-making about timelines for rehabilitation and return to sport, a knowledge gap in the current FAI literature. II.


Dietary transfatty acids and cancer risk.
This study assesses the association between dietary transfatty acid (TFA) intake and the risk of selected cancers. Mailed questionnaires were completed between 1994 and 1997 in eight Canadian provinces by 1182 incident, histologically confirmed cases of the stomach, 1727 of the colon, 1447 of the rectum, 628 of the pancreas, 3341 of the lung, 2362 of the breast, 442 of the ovary, 1799 of the prostate, 686 of the testis, 1345 of the kidney, 1029 of the bladder, 1009 of the brain, 1666 non-Hodgkin's lymphomas, 1069 leukemias, and 5039 population controls. Information on dietary habits and nutrition intake was obtained using a food frequency questionnaire, which provided data on eating habits 2 years before the study. Odds ratios (OR) and 95% confidenc530e intervals (CI) were derived by unconditional logistic regression to adjust for total energy intake and other potential confounding factors. Dietary TFA were positively associated with the risk of cancers of the colon (OR: 1.38 for the highest vs. the lowest quartile), breast in premenopause (OR: 1.60), and prostate (OR: 1.42). There were a borderline association for pancreas cancer (OR: 1.38; P=0.06). No significant association was observed for cancers of the stomach, rectum, lung, ovary, testis, kidney, bladder, brain, non-Hodgkin's lymphomas, and leukemia, although the ORs for the highest quartile were above unity for all neoplasms considered, except testis. Our findings add evidence that high TFA is associated with an increased risk of various cancers. Thus, a diet low in transfat may play a role in the prevention of several cancers.


A nuclear localization signal binding protein in the nucleolus.
We used functional wild-type and mutant synthetic nuclear localization signal peptides of SV-40 T antigen cross-linked to human serum albumin (peptide conjugates) to assay their binding to proteins of rat liver nuclei on Western blots. Proteins of 140 and 55 kD (p140 and p55) were exclusively recognized by wild-type peptide conjugates. Free wild-type peptides competed for the wild-type peptide conjugate binding to p140 and p55 whereas free mutant peptides, which differed by a single amino acid from the wild type, competed less efficiently. The two proteins were extractable from nuclei by either low or high ionic strength buffers. We purified p140 and raised polyclonal antibodies in chicken against the protein excised from polyacrylamide gels. The anti-p140 antibodies were monospecific as judged by their reactivity with a single nuclear protein band of 140 kD on Western blots of subcellular fractions of whole cells. Indirect immunofluorescence microscopy on fixed and permeabilized Buffalo rat liver (BRL) cells with anti-p140 antibodies exhibited a distinct punctate nucleolar staining. Rhodamine-labeled wild-type peptide conjugates also bound to nucleoli in a similar pattern on fixed and permeabilized BRL cells. Based on biochemical characterization, p140 is a novel nucleolar protein. It is possible that p140 shuttles between the nucleolus and the cytoplasm and functions as a nuclear import carrier.


CTLA-4 promotes Foxp3 induction and regulatory T cell accumulation in the intestinal lamina propria.
Thymic induction of CD4(+)Foxp3(+) regulatory T (Treg) cells relies on CD28 costimulation and high-affinity T-cell receptor (TCR) signals, whereas Foxp3 (forkhead box P3) induction on activated peripheral CD4(+) T cells is inhibited by these signals. Accordingly, the inhibitory molecule CTLA-4 (cytotoxic T-lymphocyte antigen 4) promoted, but was not essential for CD4(+) T-cell Foxp3 induction in vitro. We show that CTLA-4-deficient cells are equivalent to wild-type cells in the thymic induction of Foxp3 and maintenance of Foxp3 populations in the spleen and mesenteric lymph nodes, but their accumulation in the colon, where Treg cells specific for commensal bacteria accumulate, is impaired. In a T cell-transfer model of colitis, the two known CTLA-4 ligands, B7-1 and B7-2, had largely redundant roles in inducing inflammation and promoting Treg cell function. However, B7-2 proved more efficient than B7-1 in inducing Foxp3 in vitro and in vivo. Our data reveal an unappreciated role for CTLA-4 in establishing the Foxp3(+) compartment in the intestine.