Spatial versus angular resolution for tractography-assisted planning of deep brain stimulation.
Given the restricted total scanning time for clinical neuroimaging, it is unclear whether clinical diffusion MRI protocols would benefit more from higher spatial resolution or higher angular resolution. In this work, we investigated the relative benefit of improving spatial or angular resolution in diffusion MRI to separate two parallel running white matter tracts that are targets for deep brain stimulation: the anterior thalamic radiation and the supero-lateral branch of the medial forebrain bundle. Both these tracts are situated in the ventral anterior limb of the internal capsule, and recent studies suggest that targeting a specific tract could improve treatment efficacy. Therefore, we scanned 19 healthy volunteers at 3T and 7T according to three diffusion MRI protocols with respectively standard clinical settings, increased spatial resolution of 1.4 mm, and increased angular resolution (64 additional gradient directions at b = 2200s/mm2). We performed probabilistic tractography for all protocols and quantified the separability of both tracts. The higher spatial resolution protocol improved separability by 41% with respect to the clinical standard, presumably due to decreased partial voluming. The higher angular resolution protocol resulted in increased apparent tract volumes and overlap, which is disadvantageous for application in precise treatment planning. We thus recommend to increase the spatial resolution for deep brain stimulation planning to 1.4 mm while maintaining angular resolution. This recommendation complements the general advice to aim for high angular resolution to resolve crossing fibers, confirming that the specific application and anatomical considerations are leading in clinical diffusion MRI protocol optimization.


Increasing treatment of ruptured cerebral aneurysms at high-volume centers in the United States.
Evidence of better outcomes in patients with aneurysmal subarachnoid hemorrhage treated at higher-volume centers might be expected to result in more of these patients being referred to such centers. The authors evaluated the US National Inpatient Sample for the years 2001 to 2008 for trends in patient admissions for the treatment of ruptured aneurysms at high- and low-volume centers. The authors determined the number of ruptured aneurysms treated with clipping or coiling annually at low-volume (≤ 20 patients/year) and high-volume (> 20 patients/year) centers and also counted the number of high- and low-volume centers performing each treatment. Hospitalizations for clipping or coiling ruptured aneurysms were identified by cross-matching International Classification of Diseases, 9th Revision, Clinical Modification (ICD-9-CM) codes for the diagnosis of a ruptured aneurysm (ICD-9-CM 430) with procedure codes for clipping (ICD-9-CM 39.51) or coiling (ICD-9-CM 39.52, 39.79, or 39.72) cerebral aneurysms. In 2001, 31% (435 of 1392) of the patients who underwent clipping and 0% (0 of 122 patients) of those who underwent coiling did so at high-volume centers, whereas in 2008 these numbers increased to 62% (627 of 1016) and 68% (917 of 1351) of patients, respectively. For clipping procedures, the number of low-volume centers significantly declined from 177 in 2001 to 85 in 2008, whereas the number of high-volume centers remained constant at 13-15. For coiling procedures, the number of low-volume centers decreased from 62 in 2001 to 54 in 2008, whereas the number of high-volume centers substantially increased from 0 in 2001 to 16 in 2005 and remained constant thereafter. The treatment of ruptured cerebral aneurysms increasingly occurs at high-volume centers in the US. This trend is favorable given that better outcomes are associated with the treatment of these lesions at high-volume centers.


A Bistable Switch in Virus Dynamics Can Explain the Differences in Disease Outcome Following SIV Infections in Rhesus Macaques.
Experimental studies have shown that the size and infectious-stage of viral inoculum influence disease outcomes in rhesus macaques infected with simian immunodeficiency virus. The possible contribution to disease outcome of antibody developed after transmission and/or present in the inoculum in free or bound form is not understood. In this study, we develop a mathematical model of virus-antibody immune complex formation and use it to predict their role in transmission and protection. The model exhibits a bistable switch between clearance and persistence states. We fitted it to temporal virus data and estimated the parameter values for free virus infectivity rate and antibody carrying capacity for which the model transitions between virus clearance and persistence when the initial conditions (in particular the ratio of immune complexes to free virus) vary. We used these results to quantify the minimum virus amount in the inoculum needed to establish persistent infections in the presence and absence of protective antibodies.


Effects of resistance training on self-reported disability in older adults with functional limitations or disability - a systematic review and meta-analysis.
Self-reported disability has a strong negative impact on older people's quality of life and is often associated with the need for assistance and health care services. Resistance training (RT) has been repeatedly shown to improve muscle function (e.g. strength) and functional capacity (e.g. gait speed, chair-rise) in older adults with functional limitations. Nevertheless, it is unclear whether such objectively assessed improvements translate into a reduction in self-reported disability. To assess: i) whether and to what extent RT interventions have an effect on self-reported disability in older adults (≥65 years) with functional limitations or disability; and ii) whether the effects on self-reported disability are associated with changes in objective measures of muscle strength and functional capacity across studies. PubMed, Embase, Web of Science, CINAHL and SPORTDiscus electronic databases were searched in June 2018. Randomized controlled trials reporting effects of RT on self-reported disability/function in ≥65 year-old adults with defined, functional limitations or self-reported disability were eligible. Data on self-reported disability/function were pooled by calculating adjusted standardized mean differences (SMD) using Hedges'g. Likewise, effect sizes for three secondary outcomes: knee extensor muscle strength; gait capacity; and lower body functional capacity were calculated and fit as covariates in separate meta-regressions with self-reported disability as the dependent factor. Fourteen RCTs were eligible for the primary meta-analysis on self-reported disability. The total number of participants was 651 (intervention n = 354; control n = 297). A significant moderate positive effect of RT was found (SMD: 0.59, 95% CI: 0.253 to 0.925, p = 0.001). Between-study heterogeneity was present (I2 statistic = 75,1%, p < 0.001). RT effects on objective measures of lower body functional capacity were significantly associated with effects on self-reported disability (Adj. R2 = 99%, p = 0.002, n = 12 studies), whereas no significant associations with gait capacity or knee extensor strength were found. This review provides evidence that RT has a moderate positive effect on self-reported disability/function in old people with or at risk for disability. The effects are strongly associated with effects on objective measures of lower body functional capacity.


Characterization of ligand binding by the human p55 tumour-necrosis-factor receptor. Involvement of individual cysteine-rich repeats.
Two soluble tumour-necrosis-factor-alpha(TNF)-binding proteins are derived from the extracellular domains of the p55 and p75 TNF receptors. They are considered to play a pivotal regulatory role in TNF-mediated inflammatory processes, including diseases such as rheumatoid arthritis, by competing with the cell surface receptors for TNF and lymphotoxin (LT, tumour-necrosis factor beta). The extracellular domains of the two receptors each contain four similar cysteine-rich repeats of about 40 amino acids, in common with several other cell surface proteins including the p75 nerve-growth-factor receptor and the CD40 and Fas antigens. The aim of this study was to characterize the involvement of the four cysteine-rich repeats of the human p55 TNF receptor in TNF and LT binding by both membrane-bound and soluble forms of the receptor. Individual repeats were systematically deleted by PCR mutagenesis and the variants transiently expressed in COS cells. Immunoprecipitated receptor variants exhibited the expected sizes on SDS/PAGE gels, and bound a panel of conformation-dependent anti-(TNF receptor) antibodies. Binding of TNF by the four soluble derivatives was compared with binding by the wild-type soluble receptor using a TNF-affinity column and a BIAcore Biosensor, by measurement of their ability to inhibit TNF cytotoxicity on WEHI cells, and 125I-TNF binding to U937 cells. delta 4, which lacks the fourth cysteine-rich repeat, bound TNF comparably with the full-length soluble receptor. TNF-binding affinity was unaltered by deletion of the fourth membrane-proximal cysteine-rich repeat, as determined by Scatchard analysis of the transmembrane derivatives. We conclude that the fourth cysteine-rich repeat is not required for TNF binding. In contrast, both the soluble and the transmembrane derivatives lacking any one of the first, second or third repeats failed to bind TNF. Although we cannot entirely exclude the possibility that this may be due to indirect conformational change, rather than the removal of essential epitopes, our results suggest that the first three repeats are each required for TNF binding by both the soluble and the cell-surface receptor.


Plasmodium vivax in the Democratic Republic of East Timor: Parasite prevalence and antifolate resistance-associated mutations.
In the Democratic Republic of East Timor, Plasmodium falciparum and Plasmodium vivax malaria coexist, but limited information is available about the latter species. Consequently, the prevalence of P. vivax and of its corresponding antifolate resistance-associated mutations in the pvdhfr and pvdhps genes was assessed here. Blood samples were collected from 650 individuals distributed among six districts, over two different periods, by either passive case detection (PCD) or active case detection (ACD). As expected, malaria was over-represented in the PCD sample (26% PCD vs 5% ACD), because the infection increases medical care seeking. Additionally, the relative frequency of P. vivax infections in symptomatic individuals (37%) was twice as high as the one in the asymptomatic sampling group (18%), suggesting that that this parasite is accounting for a significant proportion malaria-attributed morbidity. The frequency of specific sulfadoxine-pyrimethamine resistance-associated mutations genes was ascertained in P. vivax positive samples by PCR-RFLP. Although no mutants were detected in codons 383 and 553 of pvdhps, 48%, 76% and 82% of P. vivax-infected samples harbored the dhfr 33L, 58R and 117N mutations, respectively. Additionally, the frequency of parasites carrying both pvdhfr 58R and 117N mutant alleles accounted for a third of all genotypes analyzed, most likely due to inadvertent SP use in the past. In conclusion, evidence-based information is provided to promote optimized drug deployment and limit the evolution of resistance to antifolate resistance in P. vivax from East Timor.


Instructional immediacy in elearning.
Instructor immediacy has been positively associated with many desirable academic outcomes including increased student learning. This study extends existing understanding of instructional immediacy behaviours in elearning by describing postgraduate nursing students' reflections on their own experience. An exploratory, descriptive survey design was used to collect qualitative data. Participants were asked what behaviours or activities help to create rapport or a positive interpersonal connection (immediacy) between students and their online teacher(s). Thematic analysis of the data revealed three main themes: acknowledging and affirming student's personal and professional responsibilities; providing clear and timely information; and utilising rich media. These findings give lecturers insight into instructional strategies they may adopt to increase immediacy in elearning and hence improve student learning outcomes.


Pharmacokinetics and tissue distribution of five major triterpenoids after oral administration of Rhizoma Alismatis extract to rats using ultra high-performance liquid chromatography-tandem mass spectrometry.
Rhizoma Alismatis (RA) was wildly used for treatment of dysuria, pyelonephritis, hyperlipidemia, enteritis diarrhea, diabetes, inflammation, and cancer. Triterpenoids are the major active components of RA, and its extract is mainly composed of alisol A (ALA), alisol B (ALB), alisol C 23-acetate (ALC-23A), alisol A 24-acetate (ALA-24A), and alisol B 23-acetate (ALB-23A). In this study, a simple, reliable, and sensitive ultra high-performance liquid chromatography with triple quadrupole mass spectrometry (UHPLC-MS/MS) method was created and validated for the quantification of the five major triterpenoids in rat plasma and various tissues biosamples (including intestine, stomach, liver, kidney, fat, muscle, brain, heart, lung, spleen, and testes). The plasma and tissues biosamples were pretreated by direct precipitation deproteinization method with acetonitrile. 17α-Hydroxyprogesterone was used as internal standard (IS). The chromatography was performed on a Phenomenex C8 column (30×2.00mm, 1.8μm) at room temperature with gradient elution. Compounds were quantified by selected multi-reactions monitoring (SRM) scanning with positive electric spray ionization mode. The linearity of detection for each triterpene was respectively from 1 to 1000ng/mL for ALC-23A and ALA, from 4 to 4000ng/mL for ALA-24A, from 10 to 10,000ng/mL for ALB, and from 2 to 2000ng/mL for ALB-23B (r>0.99) with low quantification limits of 1-10ng/mL for all analytes. All of the other validation parameters were also in an acceptable range. The validated UHPLC-MS/MS method subsequently applied for the pharmacokinetic and tissue distribution studies of RA extract. After orally given 100mg/kg of RA extract, ALA was the most exposed component, followed by ALB and ALA-24A. Whereas significant gender difference was observed for ALB, ALA, and ALA-24A between female and male rats. The AUC(0-∞) of ALA, ALB, and ALA-24A in female rats were approximately 2-5 fold larger than that in male rats. These triterpenoids also displayed approximately 1.5-2 times longer half-life (t1/2) in female rats. Appearant Km, Vmax and Clint of ALA, ALB, and ALA-24A were calculated by substrate depletion approach, rat P450 CYP3A2 plays an important role in the metabolism of ALA, ALB, and ALA-24A, which is an important factor leading to the different exprosures of ALA, ALB, and ALA-24A between the male rats and the female rats. Furthermore, results from tissue distribution in male rats showed that the main tissue depots of five triterpenoids were the stomach/intestine, followed by the liver, brain, and fat. However, ALA was still measured in the kidney after a long elimination time. ALB and ALB-23B exhibited lower elimination rate in the testis. These results provide a fundamental support for further pharmacological development and clinical safety application of RA.


Integrating oral health throughout cancer care.
Oral health is often not a priority during cancer treatment; however, patients with cancer are at increased risk for oral complications during and after treatment. This article focuses on the importance of oral health care before, during, and after cancer treatment using the head, eyes, ears, nose, oral cavity, and throat, or HEENOT, approach. AT A GLANCE: Oral health is linked to overall health, and healthcare providers must be cognizant of the oral-systemic connection with patients undergoing cancer treatment, which may cause acute and chronic oral health problems. Oral assessment, prevention, early recognition, and treatment of oral problems must be incorporated into cancer care, particularly with the aid of an interprofessional team to meet patients' oral care needs. The head, eyes, ears, nose, oral cavity, and throat, or HEENOT, approach integrates oral care into patients' history taking, physical examination, and plan of cancer care. .


The African disability scooter: efficiency testing in paediatric amputees in Malawi.
The African Disability Scooter (ADS) was developed for lower limb amputees, to improve mobility and provide access to different terrains. The aim of this study was to test the efficiency of the ADS in Africa over different terrains. Eight subjects with a mean age of 12 years participated. Energy expenditure and speed were calculated over different terrains using the ADS, a prosthetic limb, and crutches. Repeated testing was completed on different days to assess learning effect. Speed was significantly faster with the ADS on a level surface compared to crutch walking. This difference was maintained when using the scooter on rough terrain. Oxygen cost was halved with the scooter on level ground compared to crutch walking. There were no significant differences in oxygen consumption or heart rate. There were significant differences in oxygen cost and speed between days using the scooter over level ground, suggesting the presence of a learning effect. This study demonstrates that the ADS is faster and more energy efficient than crutch walking in young individuals with amputations, and should be considered as an alternative to a prosthesis where this is not available. The presence of a learning effect suggests supervision and training is required when the scooter is first issued. Implications for Rehabilitation The African Disability Scooter: is faster than crutch walking in amputees; is more energy efficient than walking with crutches; supervised use is needed when learning to use the device; is a good alternative/adjunct for mobility.


An overview of economic issues in computer-assisted total joint arthroplasty.
Computer-assisted techniques have been successfully used in many surgical procedures. More recently, computer-assisted surgery has been used to improve the accuracy and reproducibility of implant alignment in total hip and knee arthroplasty procedures. However, the impact of computer-assisted surgery on long-term clinical outcomes and implant survivorship in total joint arthroplasty has yet to be documented. The adoption of computer-assisted surgical systems for use in total joint arthroplasty will be heavily influenced by the economic impact on the various stakeholders in the health-care system. Currently, there are mixed financial incentives for surgeons, hospitals, and payers to adopt and use computer-assisted surgical techniques for total joint arthroplasty. Careful consideration of the impact of computer-assisted surgery on surgeon and hospital productivity as well as the financial contribution of this technology to hospital profit margins would provide valuable insight into the adoption and widespread use of computer-assisted surgery.


Treatment patterns and comparative effectiveness in elderly diffuse large B-cell lymphoma patients: a surveillance, epidemiology, and end results-medicare analysis.
The incidence of diffuse large B-cell lymphoma (DLBCL) occurs disproportionately in elderly patients. We evaluated real-world treatment patterns and outcomes in elderly DLBCL patients in the U.S. A retrospective cohort analysis of 9,333 DLBCL patients from the linked Surveillance, Epidemiology, and End Results (SEER)-Medicare database was conducted. Patients were diagnosed between January 1, 2000, and December 31, 2007; were aged >66 years, and were continuously enrolled in Medicare Part A and B in the year prior to diagnosis. Within 3 months of diagnosis, 4,565 (49%) received rituximab plus chemotherapy (R+chemo), 2,181 (23%) received chemotherapy only, and 467 (5%) received rituximab monotherapy (R-mono). Cox proportional hazards regression assessed overall survival between R+chemo versus chemotherapy only and R-mono versus no treatment. Overall, 23% of patients received no treatment, and the proportion was higher among those aged >80 years (33%). Patients receiving R+chemo were younger and more likely white compared with those receiving chemotherapy only. Patients receiving R-mono were older and more likely female compared with those not treated. In multivariate analysis, patients receiving chemotherapy only had a twofold increased mortality risk versus R+chemo, and this was confirmed in a subanalysis of patients aged >80 years. A 91% higher mortality risk was noted with receipt of fewer than six cycles versus six cycles of chemotherapy or chemoimmunotherapy. Patients receiving R-mono had a 69% decreased mortality risk compared with patients who were not treated. This real-world analysis of elderly DLBCL patients confirmed that 23% do not receive treatment. Overall survival is higher for patients receiving R+chemo and R-mono relative to chemotherapy only and no treatment, respectively. Suboptimal durations of therapy with curative intent (fewer than six cycles) were associated with poorer outcomes.


The role of cherries in exercise and health.
Recently, cherries and cherry products have received growing attention within the literature with regard to their application in both exercise and clinical paradigms. Reported to be high in anti-inflammatory and anti-oxidative capacity, cherries and their constituents are proposed to provide a similar but natural alternative akin to over-the-counter non-steroidal anti-inflammatory drugs (NSAIDs) or analgesics. Within exercise paradigms, concern has been raised with regard to the use of products, which inhibit such inflammatory or oxidative actions, because of the possibility of the blunting of physiological training adaptations. Despite this, numerous scenarios exist both within exercise and clinical populations where a goal of optimal recovery time is more important than physiological adaptation. This review critically evaluates and discusses the use of cherries as a supplementation strategy to enhance recovery of muscle function, inhibit exercise-induced inflammation, oxidative stress, and pain primarily; furthermore, the potential application of cherries to clinical populations is discussed.


Do women with polycystic ovary syndrome really have predisposition to atherosclerosis?
The elastic properties of the aorta were studied in 28 women with polycystic ovary syndrome (PCOS) and in 26 regularly menstruating healthy women. In PCOS and control groups, systolic and diastolic blood pressure, aortic systolic diameter, aortic diastolic diameter, aortic distensibility, aortic stiffness index, and aortic elastic modulus were similar. It is likely that PCOS does not have any innate adverse effects on the cardiovascular system if its undesirable metabolic consequences are successfully controlled.


Combination of DXA and BIS body composition measurements is highly correlated with physical function-an approach to improve muscle mass assessment.
Fluid volume estimates may help predict functional status and thereby improve sarcopenia diagnosis. Bioimpedance-derived fluid volume, combined with DXA, improves identification of jump power over traditional measures. DXA-measured lean mass should be corrected for fluid distribution in older populations; this may be a surrogate of muscle quality. Sarcopenia, the age-related loss of muscle mass and function, negatively impacts functional status, quality of life, and mortality. We aimed to determine if bioimpedance spectroscopy (BIS)-derived estimates of body water compartments can be used in conjunction with dual-energy X-ray absorptiometry (DXA) measures to aid in the prediction of functional status and thereby, ultimately, improve the diagnosis of sarcopenia. Participants (≥ 70 years) had physical and muscle function tests, DXA, and BIS performed. Using a BMI correction method, intracellular water (ICWc), extracellular water (ECWc), and ECWc to ICWc (E/Ic) ratio was estimated from standard BIS measures. Jump power was assessed using jump mechanography. The traditional measure used to diagnose sarcopenia, DXA-derived appendicular lean mass (ALM) corrected for height (ALM/ht2), was the least predictive measure explaining jump power variability (r2 = 0.31, p < 0.0001). The best measure for explaining jump power was a novel variable combining DXA ALM and BIS-derived E/Ic ratio (ALM/(E/Ic); r2 = 0.70, p < 0.0001). ALM/(E/Ic) and ICWc had the highest correlation with jump power and grip strength, specifically jump power (r = 0.84 and r = 0.80, respectively; p < 0.0001). The creation of a novel variable (ALM/(E/Ic)) improved the ability of DXA to predict jump power in an older population. ALM/(E/Ic) substantially outperformed traditional lean mass measures of sarcopenia and could well be an improved diagnostic approach to predict functional status. DXA-measured ALM should be corrected for fluid distribution, i.e., ALM/(E/Ic); this correction may be considered a surrogate of muscle quality.


The N-terminal region of Sgs1, which interacts with Top3, is required for complementation of MMS sensitivity and suppression of hyper-recombination in sgs1 disruptants.
The SGS1 gene of Saccharomyces (cerevisiae is a homologue of the genes affected in Bloom's syndrome, Werner's syndrome, and Rothmund-Thomson's syndrome. Disruption of the SGS1 gene is associated with high sensitivity to methyl methanesulfonate (MMS) and hydroxyurea (HU), and with hyper-recombination phenotypes, including interchromosomal recombination between heteroalleles. SGS1 encodes a protein which has a helicase domain similar to that of Escherichia coli RecQ. A comparison of amino acid sequences among helicases of the RecQ family reveals that Sgs1,WRN, and BLM share a conserved region adjacent to the C-terminal part of the helicase domain (C-terminal conserved region). In addition, Sgs1 contains two highly charged acidic regions in its N-terminal region and the HRDC (helicase and RNaseD C-terminal) domain at its C-terminal end. These regions were also found in BLM and WRN, and in Rqh1 from Schizosaccharomyces pombe. In this study, we demonstrate that the C-terminal conserved region, as well as the helicase motifs, of Sgs1 are essential for complementation of MMS sensitivity and suppression of hyper-recombination in sgs1 mutants. In contrast, the highly charged acidic regions, the HRDC domain, and the C-terminal 252 amino acids were dispensable for the complementation of these phenotypes. Surprisingly, the N-terminal 45 amino acids of Sgs1 were absolutely required for the suppression of the above phenotypes. Introduction of missense mutations into the region encoding amino acids 4-13 abolished the ability of Sgsl to complement MMS sensitivity and suppress hyper-recombination in sgs1 mutants, and also prevented its interaction with Top3, indicating that interaction with Top3 via the N-terminal region of Sgs1 is involved in the complementation of MMS sensitivity and the suppression of hyper-recombination.


Wnt signaling in cardiovascular physiology.
Wnt signaling pathways play a key role in cardiac development, angiogenesis, and cardiac hypertrophy; emerging evidence suggests that they are also involved in the pathophysiology of atherosclerosis. Specifically, an important role for Wnts has been described in the regulation of endothelial inflammation, vascular calcification, and mesenchymal stem cell differentiation. Wnt signaling also induces monocyte adhesion to endothelial cells and is crucial for the regulation of vascular smooth-muscle cell (VSMC) behavior. We discuss how the Wnt pathways are implicated in vascular biology and outline the role of Wnt signaling in atherosclerosis. Dissecting Wnt pathways involved in atherogenesis and cardiovascular disease may provide crucial insights into novel mechanisms with therapeutic potential for atherosclerosis.


Transfer to hospital in planned home births: a systematic review.
There is concern about the safety of homebirths, especially in women transferred to hospital during or after labour. The scope of transfer in planned home births has not been assessed in a systematic review. This review aimed to describe the proportions and indications for transfer from home to hospital during or after labour in planned home births. The databases Pubmed, Embase, Cinahl, Svemed+, and the Cochrane Library were searched using the MeSH term "home childbirth". Inclusion criteria were as follows: the study population was women who chose planned home birth at the onset of labour; the studies were from Western countries; the birth attendant was an authorised midwife or medical doctor; the studies were published in 1985 or later, with data not older than from 1980; and data on transfer from home to hospital were described. Of the 3366 titles identified, 83 full text articles were screened, and 15 met the inclusion criteria. Two of the authors independently extracted the data. Because of the heterogeneity and lack of robustness across the studies, there were considerable risks for bias if performing meta-analyses. A descriptive presentation of the findings was chosen. Fifteen studies were eligible for inclusion, containing data from 215,257 women. The total proportion of transfer from home to hospital varied from 9.9% to 31.9% across the studies. The most common indication for transfer was labour dystocia, occurring in 5.1% to 9.8% of all women planning for home births. Transfer for indication for foetal distress varied from 1.0% to 3.6%, postpartum haemorrhage from 0% to 0.2% and respiratory problems in the infant from 0.3% to 1.4%. The proportion of emergency transfers varied from 0% to 5.4%. Future studies should report indications for transfer from home to hospital and provide clear definitions of emergency transfers.


Oxygen Activation and Radical Transformations in Heme Proteins and Metalloporphyrins.
As a result of the adaptation of life to an aerobic environment, nature has evolved a panoply of metalloproteins for oxidative metabolism and protection against reactive oxygen species. Despite the diverse structures and functions of these proteins, they share common mechanistic grounds. An open-shell transition metal like iron or copper is employed to interact with O2 and its derived intermediates such as hydrogen peroxide to afford a variety of metal-oxygen intermediates. These reactive intermediates, including metal-superoxo, -(hydro)peroxo, and high-valent metal-oxo species, are the basis for the various biological functions of O2-utilizing metalloproteins. Collectively, these processes are called oxygen activation. Much of our understanding of the reactivity of these reactive intermediates has come from the study of heme-containing proteins and related metalloporphyrin compounds. These studies not only have deepened our understanding of various functions of heme proteins, such as O2 storage and transport, degradation of reactive oxygen species, redox signaling, and biological oxygenation, etc., but also have driven the development of bioinorganic chemistry and biomimetic catalysis. In this review, we survey the range of O2 activation processes mediated by heme proteins and model compounds with a focus on recent progress in the characterization and reactivity of important iron-oxygen intermediates. Representative reactions initiated by these reactive intermediates as well as some context from prior decades will also be presented. We will discuss the fundamental mechanistic features of these transformations and delineate the underlying structural and electronic factors that contribute to the spectrum of reactivities that has been observed in nature as well as those that have been invented using these paradigms. Given the recent developments in biocatalysis for non-natural chemistries and the renaissance of radical chemistry in organic synthesis, we envision that new enzymatic and synthetic transformations will emerge based on the radical processes mediated by metalloproteins and their synthetic analogs.


Evaluation of the effect of the herpes zoster vaccination programme 3 years after its introduction in England: a population-based study.
In 2013, a herpes zoster vaccination programme was introduced in England for adults aged 70 years with a phased catch-up programme for those aged 71-79 years. We aimed to evaluate the effect of the first 3 years of the vaccination programme on incidence of herpes zoster and postherpetic neuralgia in this population. In this population-based study, we extracted data from the Royal College of General Practitioners sentinel primary care network on consultations with patients aged 60-89 years for herpes zoster and postherpetic neuralgia occurring between Oct 1, 2005, and Sept 30, 2016, obtaining data from 164 practices. We identified individual data on herpes zoster vaccinations administered and consultations for herpes zoster and postherpetic neuralgia, and aggregated these data to estimate vaccine coverage and incidence of herpes zoster and postherpetic neuralgia consultations. We defined age cohorts to identify participants targeted in each year of the programme, and as part of the routine or catch-up programme. We modelled incidence according to age, region, gender, time period, and vaccine eligibility using multivariable Poisson regression with an offset for person-years. Our analysis included 3·36 million person-years of data, corresponding to an average of 310 001 patients aged 60-89 years who were registered at an RCGP practice each year. By Aug 31, 2016, uptake of the vaccine varied between 58% for the recently targeted cohorts and 72% for the first routine cohort. Across the first 3 years of vaccination for the three routine cohorts, incidence of herpes zoster fell by 35% (incidence rate ratio 0·65 [95% 0·60-0·72]) and of postherpetic neuralgia fell by 50% (0·50 [0·38-0·67]). The equivalent reduction for the four catch-up cohorts was 33% for herpes zoster (incidence rate ratio 0·67 [0·61-0·74]) and 38% for postherpetic neuralgia (0·62 [0·50-0·79]). These reductions are consistent with a vaccine effectiveness of about 62% against herpes zoster and 70-88% against postherpetic neuralgia. The herpes zoster vaccination programme in England has had a population impact equivalent to about 17 000 fewer episodes of herpes zoster and 3300 fewer episodes of postherpetic neuralgia among 5·5 million eligible individuals in the first 3 years of the programme. Communication of the public health impact of this programme will be important to reverse the recent trend of declining vaccine coverage. Public Health England.


Ca(2+)-dependent Cl- current in canine tracheal smooth muscle cells.
Our goal was to investigate the role of Ca2+ entry in regulating Cl- current (ICl) in smooth muscle cells from canine trachealis. When studies were done using the perforated patch configuration, depolarization elicited a dihydropyridine-sensitive Ca2+ current (ICa), followed in many cells by a sustained current. This sustained current reversed direction close to the Cl- equilibrium potential, consistent with its representing ICl. The ICl was also apparent as slowly deactivating tail currents seen upon repolarization to negative potentials. The Cl- channel blocker niflumic acid abolished both the sustained and tail currents, without affecting ICa. Several observations indicated that the ICl was dependent on Ca2+ entry. ICl was increased in magnitude when Ca2+ influx was augmented [by prolonging the depolarization or using BAY K 8644 or acetylcholine (ACh)] and decreased in magnitude when Ca2+ influx was reduced (using nifedipine). Based on these findings, we conclude that depolarization causes Ca2+ entry, with resultant elevation of cytosolic free Ca2+ concentration leading to activation of ICl (ICl(Ca)). We investigated whether Ca(2+)-induced Ca2+ release from the sarcoplasmic reticulum was involved in activation of ICl(Ca), by depleting intracellular stores of Ca2+ using cyclopiazonic acid to block the sarcoplasmic Ca(2+)-adenosinetriphosphatase and repeated stimulation with ACh. In such Ca(2+)-depleted cells, depolarization-mediated Ca2+ entry continued to activate ICl(Ca), suggesting that Ca(2+)-induced Ca2+ release was not required for its activation. We conclude that Ca2+ entry can activate Cl- channels in tracheal smooth muscle. This represents a positive-feedback system, which would promote excitation and contraction of airway muscle.


Recovery from mouse hepatitis virus infection depends on recruitment of CD8(+) cells rather than activation of intrahepatic CD4(+)alphabeta(-)TCR(inter) or NK-T cells.
Mouse hepatitis virus (MHV) provides an excellent animal model for the study of the immunopathological mechanisms involved in hepatic viral diseases. We previously generated an attenuated viral variant, YAC-MHV3, which induces a subclinical disease and recovery within 15 days. In contrast, the L2-MHV3 strain induces the development of a fulminant hepatitis, leading to death within 3 days. In this paper, we document intrahepatic and splenic T cell subpopulations involved in the hepatitis process and viral elimination identified in attenuated or pathogenic MHV3-infected C57BL/6 mice. Percentages of intrahepatic CD4(+) cells decreased in attenuated YAC-MHV3-infected mice, while they increased in mice infected with pathogenic L2-MHV3, compared with uninfected animals. Moreover, in YAC-MHV3-infected mice, the percentages of intrahepatic CD8(+) cells slightly decreased at 24 h pi, then increased until 15 days pi. In contrast, the CD4/CD8 ratios of splenic lymphoid subpopulations increased in the first days of infection and returned to normal values at 15 days pi. Intrahepatic NK1.1(+)alphabeta - TCR(inter) cells decreased in both virally infected groups of mice, while CD4(+)alphabeta - TCR(inter) LFA-1(high) cells increased in L2-MHV3-infected mice, in contrast with what was seen in YAC-MHV3-infected mice. However, these cells became anergic following Con A or PHA stimulation. Ex vivo studies showed that only the intrahepatic CD8(+) cells that were increased in YAC-MHV3-infected mice could be stimulated by lectins. In addition, in vitro viral infections revealed that L2-MHV3 viral infection led to an increase of intrahepatic CD4(+)alphabeta - TCR(inter) cells in the absence of CD8(+) cells only. These results indicate that the attenuated phenotype of the YAC-MHV3 virus is related to two different mechanisms: the first involves no increase of intrahepatic CD4(+)alphabeta - TCR(inter) or NK-T cells, while the second favors the recruitment and activation of CD8(+) cells in liver. The results are discussed in relation to the integrity of intrahepatic immune tolerance mechanisms and immune-mediated viral elimination.


Concise Review: Human Dermis as an Autologous Source of Stem Cells for Tissue Engineering and Regenerative Medicine.
The exciting potential for regenerating organs from autologous stem cells is on the near horizon, and adult dermis stem cells (DSCs) are particularly appealing because of the ease and relative minimal invasiveness of skin collection. A substantial number of reports have described DSCs and their potential for regenerating tissues from mesenchymal, ectodermal, and endodermal lineages; however, the exact niches of these stem cells in various skin types and their antigenic surface makeup are not yet clearly defined. The multilineage potential of DSCs appears to be similar, despite great variability in isolation and in vitro propagation methods. Despite this great potential, only limited amounts of tissues and clinical applications for organ regeneration have been developed from DSCs. This review summarizes the literature on DSCs regarding their niches and the specific markers they express. The concept of the niches and the differentiation capacity of cells residing in them along particular lineages is discussed. Furthermore, the advantages and disadvantages of widely used methods to demonstrate lineage differentiation are considered. In addition, safety considerations and the most recent advancements in the field of tissue engineering and regeneration using DSCs are discussed. This review concludes with thoughts on how to prospectively approach engineering of tissues and organ regeneration using DSCs. Our expectation is that implementation of the major points highlighted in this review will lead to major advancements in the fields of regenerative medicine and tissue engineering. Autologous dermis-derived stem cells are generating great excitement and efforts in the field of regenerative medicine and tissue engineering. The substantial impact of this review lies in its critical coverage of the available literature and in providing insight regarding niches, characteristics, and isolation methods of stem cells derived from the human dermis. Furthermore, it provides analysis of the current state-of-the-art regenerative approaches using human-derived dermal stem cells, with consideration of current guidelines, to assist translation toward therapeutic use.


Prognostic significance of night-time, early morning, and daytime blood pressures on the risk of cerebrovascular and cardiovascular mortality: the Ohasama Study.
To clarify whether high blood pressure (BP) at a particular time of day is associated with cerebrovascular and cardiovascular mortality risk. Cerebrovascular and cardiovascular mortality in 1360 individuals aged 40 years and older in Ohasama, Japan, was followed for an average of 10.6 years. We used 2-h moving averages of the BP (a total of 24 average BP measurements for two consecutive hours based on four BP readings taken every 30 min) to compare the predictive power of BP taken during a 24-h period given the same number of measurements. The associations between cerebrovascular and cardiovascular mortality risk and the 2-h moving averages of systolic blood pressure (2 h-SBP) recorded over 24 h were analysed using a Cox proportional hazards model after adjusting for possible confounding factors. The total cerebrovascular and cardiovascular mortality risk was significantly associated with elevated 2 h-SBP recorded during the night and early morning periods. Haemorrhagic stroke mortality was significantly associated with elevated daytime 2 h-SBP. Cerebral infarction mortality and heart disease mortality were significantly associated with elevated night-time 2 h-SBP. High BP at different times of day were associated with different subtypes of cerebrovascular and cardiovascular mortality risk.


Genetic correlations and maternal effect coefficients obtained from offspring-parent regression.
Additive genetic variances and covariances of quantitative characters are necessary to predict the evolutionary response of the mean phenotype vector in a population to natural or artificial selection. Standard formulas for estimating these parameters, from the resemblance between relatives in one or two characters at a time, are biased by natural selection on the parents and by maternal effects. We show how these biases can be removed using a multivariate analysis of offspring-parent regressions. A dynamic model of maternal effects demonstrates that, in addition to the phenotypic variance-covariance matrix of the characters, sufficient parameters for predicting the response of the mean phenotype vector to weak selection are the additive genetic variance-covariance matrix and a set of causal coefficients for maternal effects. These can be simultaneously estimated from offspring-parent regressions alone, in some cases just from the daughter-mother regressions, if all of the important selected and maternal characters have been measured and included in the analysis.


The Hirsch index - a play on numbers or a true appraisal of academic output?
Citation metrics have rapidly gained importance in today's landscape and are being increasingly utilized as a yardstick in making several important decisions regarding academic funding and appointments. The impact factor has traditionally been the metric most often employed in this regard. However, the emergence of the Hirsch index has provided an alternative to the impact factor. The h-index, despite its flaws, continues to gain acceptance and popularity in the medical community. Several medical journals have evaluated and endorsed the use of the h-index. However, it must be interpreted with all of its limitations in mind.


Retrospective, observation study: Quantitative and qualitative effect of ezetimibe and HMG-CoA reductase inhibitors on LDL-cholesterol: are there disappearance thresholds for small, dense LDL and IDL?
Lipid profiles were evaluated for 281 dyslipidemia patients treated with HMG-CoA reductase inhibitors (statins) for 2 years. The efficacy and safety of ezetimibe 10 mg/day one-year add-on therapy were also retrospectively evaluated. The results show that in 281 dyslipidemia patients with a mean low-density lipoprotein-cholesterol (LDL-C) level of 120 mg/dl or greater, ezetimibe 10 mg/day administration reduced LDL-C levels to 90 mg/dl or below. Patients who had been treated with one of six statins (pravastatin, simvastatin, fluvastatin, pitavastatin, atorvastatin, and rosuvastatin) for one year were given ezetimibe add-on therapy for one year, which reduced their LDL-C levels by 18% (pravastatin), 25% (simvastatin), 27% (fluvastatin), 30% (pitavastatin), 29% (atorvastatin), and 31% (rosuvastatin). Also, during the one-year add-on therapy, no severe adverse event was detected. An analysis of associations among lipids during a two-year lipid-lowering pharmacotherapy revealed correlations in a single patient. The correlation was between LDL-C and small, dense LDL as well as mid-band lipoprotein cholesterol. In conclusion, ezetimibe 10mg/day add-on therapy may be safe and effective for treating dislipidemia patients who have been treated with a statin. Moreover, this article discusses the disappearance thresholds for small, dense LDL and intermediate-density lipoprotein (IDL) by using the quantitative analysis of densitometric pattern based on genetic algorithm, which indicated that the major eight subspecies of lipoprotein (VLDL1, VLDL2, IDL1, IDL2, LDL1, LDL2, LDL3, HDL). The thershold for small dense LDL indicates the IDL1 plus IDL2 when LDL2 and LDL3 were not detectable, while the thershold for IDL indicates the LDL1 when IDL1, IDL2 and LDL3 were not detectable.


An optimal search filter for retrieving systematic reviews and meta-analyses.
Health-evidence.ca is an online registry of systematic reviews evaluating the effectiveness of public health interventions. Extensive searching of bibliographic databases is required to keep the registry up to date. However, search filters have been developed to assist in searching the extensive amount of published literature indexed. Search filters can be designed to find literature related to a certain subject (i.e. content-specific filter) or particular study designs (i.e. methodological filter). The objective of this paper is to describe the development and validation of the health-evidence.ca Systematic Review search filter and to compare its performance to other available systematic review filters. This analysis of search filters was conducted in MEDLINE, EMBASE, and CINAHL. The performance of thirty-one search filters in total was assessed. A validation data set of 219 articles indexed between January 2004 and December 2005 was used to evaluate performance on sensitivity, specificity, precision and the number needed to read for each filter. Nineteen of 31 search filters were effective in retrieving a high level of relevant articles (sensitivity scores greater than 85%). The majority achieved a high degree of sensitivity at the expense of precision and yielded large result sets. The main advantage of the health-evidence.ca Systematic Review search filter in comparison to the other filters was that it maintained the same level of sensitivity while reducing the number of articles that needed to be screened. The health-evidence.ca Systematic Review search filter is a useful tool for identifying published systematic reviews, with further screening to identify those evaluating the effectiveness of public health interventions. The filter that narrows the focus saves considerable time and resources during updates of this online resource, without sacrificing sensitivity.


Negative refraction, gain and nonlinear effects in hyperbolic metamaterials.
The negative refraction and evanescent-wave canalization effects supported by a layered metamaterial structure obtained by alternating dielectric and plasmonic layers is theoretically analyzed. By using a transmission-line analysis, we formulate a way to rapidly analyze the negative refraction operation for given available materials over a broad range of frequencies and design parameters, and we apply it to broaden the bandwidth of negative refraction. Our analytical model is also applied to explore the possibility of employing active layers for loss compensation. Nonlinear dielectrics can also be considered within this approach, and they are explored in order to add tunability to the optical response, realizing positive-to-zero-to-negative refraction at the same frequency, as a function of the input intensity. Our findings may lead to a better physical understanding and improvement of the performance of negative refraction and subwavelength imaging in layered metamaterials, paving the way towards the design of gain-assisted hyperlenses and tunable nonlinear imaging devices.


Prefrontal Responses to Odors in Individuals With Autism Spectrum Disorders: Functional NIRS Measurement Combined With a Fragrance Pulse Ejection System.
Individuals with autism spectrum disorders (ASD) are impaired not only in social competencies but also in sensory perception, particularly olfaction. The olfactory ability of individuals with ASD has been examined in several psychophysical studies, but the results have been highly variable, which might be primarily due to methodological difficulties in the control of odor stimuli (e.g., the problem of lingering scents). In addition, the neural correlates of olfactory specificities in individuals with ASD remain largely unknown. To date, only one study has investigated this issue using functional magnetic resonance imaging (fMRI). The present study utilized a sophisticated method-a pulse ejection system-to present well-controlled odor stimuli to participants with ASD using an ASD-friendly application. With this advantageous system, we examined their odor detection, identification, and evaluation abilities and measured their brain activity evoked by odors using functional near-infrared spectroscopy (fNIRS). As the odor detection threshold (DT) of participants with ASD was highly variable, these participants were divided into two groups according to their DT: an ASD-Low DT group and an ASD-High DT group. Behavioral results showed that the ASD-High DT group had a significantly higher DT than the typically developing (control) group and the ASD-Low DT group, indicating their insensitivity to the tested odors. In addition, while there was no significant difference in the odor identification ability between groups, there was some discrepancy between the groups' evaluations of odor pleasantness. The brain data identified, for the first time, that neural activity in the right dorsolateral prefrontal cortex (DLPFC) was significantly weaker in the ASD-High DT group than in the control group. Moreover, the strength of activity in the right DLPFC was negatively correlated with the DT. These findings suggest that participants with ASD have impairments in the higher-order function of olfactory processing, such as olfactory working memory and/or attention.


Large T and small T antigens of Merkel cell polyomavirus.
Merkel cell polyomavirus (MCV) is the etiological agent of Merkel cell carcinoma (MCC), a rare and highly lethal human skin cancer. A natural component of skin flora, MCV becomes tumorigenic only after integration into the host DNA together with specific mutations to the viral genome. Research on MCV large T (LT) and small T (sT) antigens, the only viral products expressed in MCC, shows that these major oncoproteins not only possess biochemical functions found in common with other polyomavirus T antigens, but also demonstrate new cellular targets not described in previous polyomavirus models. This review provides a map of the relevant functional motifs and domains in MCV T antigens that have been identified, highlighting their roles in tumorigenesis.


Activation of type 1 cannabinoid receptor (CB1R) promotes neurogenesis in murine subventricular zone cell cultures.
The endocannabinoid system has been implicated in the modulation of adult neurogenesis. Here, we describe the effect of type 1 cannabinoid receptor (CB1R) activation on self-renewal, proliferation and neuronal differentiation in mouse neonatal subventricular zone (SVZ) stem/progenitor cell cultures. Expression of CB1R was detected in SVZ-derived immature cells (Nestin-positive), neurons and astrocytes. Stimulation of the CB1R by (R)-(+)-Methanandamide (R-m-AEA) increased self-renewal of SVZ cells, as assessed by counting the number of secondary neurospheres and the number of Sox2+/+ cell pairs, an effect blocked by Notch pathway inhibition. Moreover, R-m-AEA treatment for 48 h, increased proliferation as assessed by BrdU incorporation assay, an effect mediated by activation of MAPK-ERK and AKT pathways. Surprisingly, stimulation of CB1R by R-m-AEA also promoted neuronal differentiation (without affecting glial differentiation), at 7 days, as shown by counting the number of NeuN-positive neurons in the cultures. Moreover, by monitoring intracellular calcium concentrations ([Ca(2+)]i) in single cells following KCl and histamine stimuli, a method that allows the functional evaluation of neuronal differentiation, we observed an increase in neuronal-like cells. This proneurogenic effect was blocked when SVZ cells were co-incubated with R-m-AEA and the CB1R antagonist AM 251, for 7 days, thus indicating that this effect involves CB1R activation. In accordance with an effect on neuronal differentiation and maturation, R-m-AEA also increased neurite growth, as evaluated by quantifying and measuring the number of MAP2-positive processes. Taken together, these results demonstrate that CB1R activation induces proliferation, self-renewal and neuronal differentiation from mouse neonatal SVZ cell cultures.


Family meal patterns: associations with sociodemographic characteristics and improved dietary intake among adolescents.
To examine family meal patterns and associations with sociodemographic characteristics and dietary intake in adolescents. A population-based cross-sectional study design was employed. Adolescents completed the Project EAT (Eating Among Teens) survey and the Youth and Adolescent Food Frequency Questionnaire within their schools. Subjects/setting The study population included 4,746 middle and high school students from Minneapolis/St. Paul public schools with diverse racial and socioeconomic backgrounds. Statistical analyses Associations were examined using cross tabulations, log-linear modeling, and linear regressions. There was a wide distribution in the frequency of family meals during the previous week: never (14.0%), 1 or 2 times (19.1%), 3 to 6 times (40.1%), and 7 or more times (24.8%). Sociodemographic characteristics associated with more frequent family meals included gender (boys), school level (middle school), race (Asian American), mother's employment status (not employed), and socioeconomic status (high). Frequency of family meals was positively associated with intake of fruits, vegetables, grains, and calcium-rich foods and negatively associated with soft drink consumption. Positive associations were also seen between frequency of family meals and energy; protein (percentage of total calories); calcium; iron; folate; fiber; and vitamins A, C, E, and B-6. Family meals appear to play an important role in promoting positive dietary intake among adolescents. Feasible ways to increase the frequency of family meals should be explored with adolescents and their families.


A method for proficiency testing of small peer groups in the College of American Pathologists Coagulation Surveys.
To develop a grading scheme for the proficiency testing of small peer groups of fewer than 10 members for the prothrombin time (PT) and activated partial thromboplastin time (APTT). A modified target value for small peer groups was derived based on the assumption that measurement variability in the PT and APTT is more greatly influenced by variations in reagents than in instruments. Criteria for grading were established by statistical simulation to achieve misclassification errors of less than 5% for both incorrectly passing and failing participants. College of American Pathologists Coagulation Survey data were analyzed to determine the number of additional laboratories graded using the proposed scheme, as well as the failure rates among participants in the small peer groups. The modified target value for small peer groups is a weighted average between the mean of the peer group and the mean of all participants using the same reagent (reagent group). Peer groups with as few as 4 members can be graded provided that specific criteria are satisfied: there must be at least 5 peer groups for the same reagent, at least 3 of these 5 peer groups must have more than 3 members, and the coefficient of variation for the reagent group must be less than 10%. This proposed grading scheme decreased the number of ungraded laboratories by 44% to 46% for the PT and 42% to 55% for the APTT. The percentage of failing grades among participants in the small peer groups ranged from 1.3% to 4.1% for the PT and 1.4% to 7.2% for the APTT. These failure rates were 2.8- to 13.0-fold higher than the failure rates in large peer groups (P < or = .05). The proposed small peer group grading scheme can improve the effectiveness of College of American Pathologists proficiency testing for the PT and APTT and may also be generally applicable to other test methods and analytes.


Use of myocardial performance index in pediatric patients with idiopathic pulmonary arterial hypertension.
The myocardial performance index (MPI) correlates with clinical status in adults with idiopathic pulmonary arterial (PA) hypertension (IPAH). This pediatric study used MPI to assess response to bosentan therapy. The study included 12 children with IPAH and 12 healthy control subjects. MPI was correlated with catheterization data at initiation of bosentan and at a median follow-up of 9 months. Therapy responders were defined by a greater than 20% decrease in mean PA pressure. Right ventricular MPI for patients with IPAH was 0.64 +/- 0.30 versus 0.28 +/- 0.03 in control subjects (P < .01). It had a strong correlation with mean PA pressure (R = 0.94; P < .001). Right ventricular MPI decreased significantly in responders (range 20%-44%, mean 25%) with a 5% increase in nonresponders. Right ventricular MPI in pediatric IPAH correlates with mean PA pressure and response to therapy. This study suggests that this noninvasive Doppler index may be useful to follow up children with IPAH, particularly when tricuspid regurgitation data are insufficient.


Association of gout with brain reserve and vulnerability to neurodegenerative disease.
Studies of neurodegenerative disease risk in gout are contradictory. Relationships with neuroimaging markers of brain structure, which may offer insights, are uncertain. Here we investigated associations between gout, brain structure, and neurodegenerative disease incidence. Gout patients had smaller global and regional brain volumes and markers of higher brain iron, using both observational and genetic approaches. Participants with gout also had higher incidence of all-cause dementia, Parkinson's disease, and probable essential tremor. Risks were strongly time dependent, whereby associations with incident dementia were highest in the first 3 years after gout diagnosis. These findings suggest gout is causally related to several measures of brain structure. Lower brain reserve amongst gout patients may explain their higher vulnerability to multiple neurodegenerative diseases. Motor and cognitive impairments may affect gout patients, particularly in early years after diagnosis.


The Evolution of Egg Trading in Simultaneous Hermaphrodites.
Egg trading-whereby simultaneous hermaphrodites exchange each other's eggs for fertilization-constitutes one of the few rigorously documented and most widely cited examples of direct reciprocity among unrelated individuals. Yet how egg trading may initially invade a population of nontrading simultaneous hermaphrodites is still unresolved. Here, we address this question with an analytical model that considers mate encounter rates and costs of egg production in a population that may include traders (who provide eggs for fertilization only if their partners also have eggs to reciprocate), providers (who provide eggs regardless of whether their partners have eggs to reciprocate), and withholders (cheaters who mate only in the male role and just use their eggs to elicit egg release from traders). Our results indicate that a combination of intermediate mate encounter rates, sufficiently high costs of egg production, and a sufficiently high probability that traders detect withholders (in which case eggs are not provided) is conducive to the evolution of egg trading. Under these conditions, traders can invade-and resist invasion from-providers and withholders alike. The prediction that egg trading evolves only under these specific conditions is consistent with the rare occurrence of this mating system among simultaneous hermaphrodites.


The fate of syndesmotic screws.
A standard protocol for the management of syndesmosis injuries has yet to be established. Debate persists regarding number of screws, screw diameter, number of cortices purchased, and the need for and timing of screw removal. The purpose of this study was to identify factors related to screw fixation that may lead to the ultimate failure of syndesmosis fixation defined as a loss of reduction of the syndesmosis, screw breakage, screw loosening, or widening of the medial clear space. A retrospective assessment of 137 consecutive patients who underwent open reduction and internal fixation of the distal tibiofibular joint at a single institution from 2004 to 2008 was performed. Clinical and radiographic data were recorded regarding problems with questionable clinical significance (number of syndesmotic screws, number of cortices, screw diameter, screw location, hardware failure) and loss of syndesmosis reduction. A series of Fisher's exact tests were used to evaluate outcomes. A p value of 0.05 defined as significant. The 3.5-mm diameter screws were statistically more likely to break than 4- or 4.5-mm screws, but there was no difference in frequency of loss of reduction of the syndesmosis as a function of screw diameter; however, a power study revealed an n value of 1656 would be required to show a significant difference. Screw diameter may have an effect on screw breakage but clinical significance of hardware failure itself is unknown including whether or not it results in a loss of reduction or failure of syndesmotic fixation.


Hemodynamic effects of bufalin in the anesthetized dog.
Studies in Lichstein's laboratory suggest that the endogenous digitalislike substance implicated in low renin hypertension might be a steroidal dienolide derivative. If this is true, the bufadienolides should block potassium vasodilation and enhance norepinephrine vasoconstriction, constrict blood vessels, raise blood pressure, and produce natriuresis and diuresis. We have therefore examined these parameters while infusing bufalin (aglycone), a bufadienolide, intrabrachially and intravenously in the anesthetized dog. Intrabrachial infusion of 5-25 micrograms/min with brachial arterial blood flow held constant at 100 ml/min produced a dose-dependent increase in perfusion pressure with rapid onset and offset, a progressive decrease in the vasodilator response to intrabrachial injection of 1 ml iso-osmotic potassium chloride solution (but not to acetylcholine), and an increase in the vasoconstrictor response to intrabrachial injection of 0.1 microgram norepinephrine. Intravenous infusion at 5-50 micrograms/min produced a dose-dependent increase in systemic arterial blood pressure, rate of change of ventricular pressure (dP/dt), and after the highest dose, cardiac irregularities. Natriuresis and diuresis were not observed. Thus, bufalin does in fact have some of the physiological properties required to be considered a candidate for the digitalislike substance found in low renin hypertension.


Are numbers special? The comparison systems of the human brain investigated by fMRI.
Many studies have suggested that the intraparietal sulcus (IPS), particularly in the dominant hemisphere, is crucially involved in numerical comparisons. However, this parietal structure has been found to be involved in other tasks that require spatial processing or visuospatial attention as well. fMRI was used to investigate three different magnitude comparisons in an event-related-block design: (a) Which digit is larger in numerical value (e.g., 2 or 5)? (b) Which digit is brighter (e.g., 3 or 3)? (c) Which digit is physically larger (e.g., 3 or 3)? Results indicate a widespread cortical network including a bilateral activation of the intraparietal sulci for all different comparisons. However, by computing contrasts of brain activation between the respective comparison conditions and applying a cortical distance effect as an additional criterion, number-specific activation was revealed in left IPS and right temporal regions. These results indicate that there are both commonalities and differences in the spatial layout of the brain systems for numerical and physical comparisons and that especially the left IPS, while involved in magnitude comparison in general, plays a special role in number comparison.


Presumed Arterial Gas Embolism After Breath-Hold Diving in Shallow Water.
Dive-related injuries are relatively common, but almost exclusively occur in recreational or scuba diving. We report 2 children with acute central nervous system complications after breath-hold diving. A 12-year-old boy presented with unilateral leg weakness and paresthesia after diving beneath the water surface for a distance of ∼25 m. After ascent, he suddenly felt extreme thoracic pain that resolved spontaneously. Neurologic examination revealed right leg weakness and sensory deficits with a sensory level at T5. Spinal MRI revealed a nonenhancing T2-hyperintense lesion in the central cord at the level of T1/T2 suggesting a spinal cord edema. A few weeks later, a 13-year-old girl was admitted with acute dizziness, personality changes, confusion, and headache. Thirty minutes before, she had practiced diving beneath the water surface for a distance of ∼25 m. After stepping out, she felt sudden severe thoracic pain and lost consciousness. Shortly later she reported headache and vertigo, and numbness of the complete left side of her body. Neurologic examination revealed reduced sensibility to all modalities, a positive Romberg test, and vertigo. Cerebral MRI revealed no pathologic findings. Both children experienced a strikingly similar clinical course. The chronology of events strongly suggests that both patients were suffering from arterial gas embolism. This condition has been reported for the first time to occur in children after breath-hold diving beneath the water surface without glossopharyngeal insufflation.


Mouse DNA polymerase alpha. Subunit structure and identification of a species with associated exonuclease.
Two species of alpha-polymerase with very similar catalytic properties have been purified to near homogeneity from a soluble protein fraction of mouse myeloma. Sedimentation analysis in 0.5 M salt-containing glycerol gradients indicated that both species had a native Mr of about 190,000. Each species contained nonidentical subunits with apparent molecular weights of about 47,000 and 54,000. Subunits of Mr = approximately 50,000 had been found previously in calf thymus alpha-polymerase (Holmes, A. M., Hesslewood, I. P., and Johnston, I. R. (1974) Eur. J. Biochem. 43, 487-499; (1976) Eur. J. Biochem. 62, 229-235). Tryptic peptide mapping failed to reveal primary structure homology between the subunits of the two enzymes. Thus, the two alpha-polymerases are clearly different species. These two enzymes are further distinguished by the fact that one of them has associated exonuclease activities. One activity degraded single-stranded DNA to mononucleotides in the 3' leads to 5' direction and acted distributively. The other exonuclease activity also degraded single-stranded DNA to mononucleotides, but this degradation was in the 5' leads to 3' direction in a processive fashion. Both exonuclease activities co-migrated with the polymerase activity during the final purification step of polyacrylamide gradient gel electrophoresis, which yielded the essentially homogenous alpha-polymerase, and also during sedimentation of the purified enzyme through a high salt glycerol gradient.


Tubular p53 regulates multiple genes to mediate AKI.
A pathogenic role of p53 in AKI was suggested a decade ago but remains controversial. Indeed, recent work indicates that inhibition of p53 protects against ischemic AKI in rats but exacerbates AKI in mice. One intriguing possibility is that p53 has cell type-specific roles in AKI. To determine the role of tubular p53, we generated two conditional gene knockout mouse models, in which p53 is specifically ablated from proximal tubules or other tubular segments, including distal tubules, loops of Henle, and medullary collecting ducts. Proximal tubule p53 knockout (PT-p53-KO) mice were resistant to ischemic and cisplatin nephrotoxic AKI, which was indicated by the analysis of renal function, histology, apoptosis, and inflammation. However, other tubular p53 knockout (OT-p53-KO) mice were sensitive to AKI. Mechanistically, AKI associated with the upregulation of several known p53 target genes, including Bax, p53-upregulated modulator of apoptosis-α, p21, and Siva, and this association was attenuated in PT-p53-KO mice. In global expression analysis, ischemic AKI induced 371 genes in wild-type kidney cortical tissues, but the induction of 31 of these genes was abrogated in PT-p53-KO tissues. These 31 genes included regulators of cell death, metabolism, signal transduction, oxidative stress, and mitochondria. These results suggest that p53 in proximal tubular cells promotes AKI, whereas p53 in other tubular cells does not.


Structural Barriers to Antiretroviral Therapy Among Sex Workers Living with HIV: Findings of a Longitudinal Study in Vancouver, Canada.
In light of limited data on structural determinants of access and retention in antiretroviral therapy (ART) among sex workers, we examined structural correlates of ART use among sex workers living with HIV over time. Longitudinal data were drawn from a cohort of 646 female sex workers in Vancouver, Canada (2010-2012) and linked pharmacy records on ART dispensation. We used logistic regression with generalized estimating equations (GEE) to examine correlates of gaps in ART use (i.e., treatment interruptions or delayed ART initiation), among HIV seropositive participants (n = 74). Over a 2.5-year period, 37.8 % of participants experienced gaps in ART use (i.e., no ART dispensed in a 6-month period). In a multivariable GEE model, younger age, migration/mobility, incarceration, and non-injection drug use independently correlated with gaps in ART use. In spite of successes scaling-up ART in British Columbia, younger, mobile, or incarcerated sex workers face persistent gaps in access and retention irrespective of drug use. Community-based, tailored interventions to scale-up entry and retention in ART for sex workers should be further explored in this setting.


Maternal or infant antiretroviral drugs to reduce HIV-1 transmission.
We evaluated the efficacy of a maternal triple-drug antiretroviral regimen or infant nevirapine prophylaxis for 28 weeks during breast-feeding to reduce postnatal transmission of human immunodeficiency virus type 1 (HIV-1) in Malawi. We randomly assigned 2369 HIV-1-positive, breast-feeding mothers with a CD4+ lymphocyte count of at least 250 cells per cubic millimeter and their infants to receive a maternal antiretroviral regimen, infant nevirapine, or no extended postnatal antiretroviral regimen (control group). All mothers and infants received perinatal prophylaxis with single-dose nevirapine and 1 week of zidovudine plus lamivudine. We used the Kaplan-Meier method to estimate the cumulative risk of HIV-1 transmission or death by 28 weeks among infants who were HIV-1-negative 2 weeks after birth. Rates were compared with the use of the log-rank test. Among mother-infant pairs, 5.0% of infants were HIV-1-positive at 2 weeks of life. The estimated risk of HIV-1 transmission between 2 and 28 weeks was higher in the control group (5.7%) than in either the maternal-regimen group (2.9%, P=0.009) or the infant-regimen group (1.7%, P<0.001). The estimated risk of infant HIV-1 infection or death between 2 and 28 weeks was 7.0% in the control group, 4.1% in the maternal-regimen group (P=0.02), and 2.6% in the infant-regimen group (P<0.001). The proportion of women with neutropenia was higher among those receiving the antiretroviral regimen (6.2%) than among those in either the nevirapine group (2.6%) or the control group (2.3%). Among infants receiving nevirapine, 1.9% had a hypersensitivity reaction. The use of either a maternal antiretroviral regimen or infant nevirapine for 28 weeks was effective in reducing HIV-1 transmission during breast-feeding. (ClinicalTrials.gov number, NCT00164736.)


Hyperexcitability of bladder afferent neurons associated with reduction of Kv1.4 α-subunit in rats with spinal cord injury.
To clarify the functional and molecular mechanisms inducing hyperexcitability of C-fiber bladder afferent pathways after spinal cord injury we examined changes in the electrophysiological properties of bladder afferent neurons, focusing especially on voltage-gated K channels. Freshly dissociated L6-S1 dorsal root ganglion neurons were prepared from female spinal intact and spinal transected (T9-T10 transection) Sprague Dawley® rats. Whole cell patch clamp recordings were performed on individual bladder afferent neurons. Kv1.2 and Kv1.4 α-subunit expression levels were also evaluated by immunohistochemical and real-time polymerase chain reaction methods. Capsaicin sensitive bladder afferent neurons from spinal transected rats showed increased cell excitability, as evidenced by lower spike activation thresholds and a tonic firing pattern. The peak density of transient A-type K+ currents in capsaicin sensitive bladder afferent neurons from spinal transected rats was significantly less than that from spinal intact rats. Also, the KA current inactivation curve was displaced to more hyperpolarized levels after spinal transection. The protein and mRNA expression of Kv1.4 α-subunits, which can form transient A-type K+ channels, was decreased in bladder afferent neurons after spinal transection. Results indicate that the excitability of capsaicin sensitive C-fiber bladder afferent neurons is increased in association with reductions in transient A-type K+ current density and Kv1.4 α-subunit expression in injured rats. Thus, the Kv1.4 α-subunit could be a molecular target for treating overactive bladder due to neurogenic detrusor overactivity.


Analytic design of multiple-axis, multifocal diffractive lenses.
In this Letter, we introduce an analytic procedure for designing diffractive lenses using the combination of wavefronts aberrated by Zernike polynomials. We show how to design amplitude-only, phase-only, continuous, and binary lenses providing equivalent results. As an example we apply it to the design of a multiple-axis, multifocal lens. The number of foci and their positions can be easily controlled. Theoretical predictions have been experimentally confirmed. The main advantage of this procedure is that, because it is simple and intuitive, it can be used successfully for the design of complex lenses.


Cerebral responses to change in spatial location of unattended sounds.
The neural basis of spatial processing in the auditory cortex has been controversial. Human fMRI studies suggest that a part of the planum temporale (PT) is involved in auditory spatial processing, but it was recently argued that this region is active only when the task requires voluntary spatial localization. If this is the case, then this region cannot harbor an ongoing spatial representation of the acoustic environment. In contrast, we show in three fMRI experiments that a region in the human medial PT is sensitive to background auditory spatial changes, even when subjects are not engaged in a spatial localization task, and in fact attend the visual modality. During such times, this area responded to rare location shifts, and even more so when spatial variation increased, consistent with spatially selective adaptation. Thus, acoustic space is represented in the human PT even when sound processing is not required by the ongoing task.


Occupation- and Activity-Based Interventions to Improve Performance of Instrumental Activities of Daily Living and Rest and Sleep for Children and Youth Ages 5-21: A Systematic Review.
Practitioners seek evidence from intervention effectiveness studies to provide best-practice services for children. To examine the effectiveness of occupation- and activity-based interventions to improve instrumental activities of daily living (IADLs) and sleep outcomes for children and youth ages 5-21 yr. MEDLINE, PsycINFO, CINAHL, ERIC, OTseeker, and Cochrane Database of Systematic Reviews. The American Occupational Therapy Association research methodologist conducted the first review of literature published from 2000 to 2017. The results were exported, and we completed the subsequent stages of review. Only peer-reviewed Level I, II, and III evidence was reviewed. Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines and the Cochrane risk-of-bias guidelines were used to compile evidence and risk-of-bias tables. We reviewed 96 articles; 28 studies met the inclusion criteria for IADL and rest-sleep outcomes. Analysis resulted in several themes: rest-sleep, health management (nutrition-dietary, physical activity-fitness, wellness), and the IADLs of driving, communication management, and safety. Strong evidence exists for interventions embedded in school programming to improve physical activity and fitness and for sleep preparation activities to maximize quality of rest and sleep. Moderate-strength evidence exists for interactive education and skills training interventions to improve health routines, dietary behaviors, and IADL participation and performance. Use of skills-focused training in activity- and occupation-based interventions was supported. Service provision in the context of natural environments, including school settings and with parental or caregiver participation, is recommended for children and youth ages 5-21 yr with varied abilities and diagnoses. Occupational therapy practitioners can confidently examine their current practices and choose activity- and occupation-based interventions and methods of service delivery that are supported by evidence.


Factors Affecting Soybean Root Colonization by Calonectria ilicicola and Development of Red Crown Rot Following Delayed Planting.
Field studies were conducted in 1994, 1995, and 1996 to determine the effects of planting date, cultivar susceptibility, and soil pathogen population on soybean root colonization by Calonectria ilicicola and subsequent development of red crown rot. Early season colonization of roots was important for red crown rot symptom development. Symptom development in the more susceptible cultivar, Sharkey, was reduced following delayed planting and remained low in the less susceptible cultivar, Cajun, regardless of planting date. Taproot colonization was positively correlated with inoculum density during all three growing seasons but was strongest in 1994. Also, lateral root colonization correlated positively with inoculum density in 1994, the only year in which foliar symptoms were detected. A substantial decrease in inoculum density in 1995, along with reduced soybean root colonization, were attributed to high soil temperatures and probably low rainfall recorded during that summer. The effect of soybean plant age on root colonization was examined by exposing plants to the pathogen at different ages. Soybean plants were most susceptible to C. ilicicola during the first week after seedling emergence. By the second week, susceptibility was reduced by nearly half, and it remained near that level for the next several weeks.


A comparison of methods to assess the antimicrobial activity of nanoparticle combinations on bacterial cells.
Bacterial cell quantification after exposure to antimicrobial compounds varies widely throughout industry and healthcare. Numerous methods are employed to quantify these antimicrobial effects. With increasing demand for new preventative methods for disease control, we aimed to compare and assess common analytical methods used to determine antimicrobial effects of novel nanoparticle combinations on two different pathogens. Plate counts of total viable cells, flow cytometry (LIVE/DEAD BacLight viability assay) and qPCR (viability qPCR) were used to assess the antimicrobial activity of engineered nanoparticle combinations (NPCs) on Gram-positive (Staphylococcus aureus) and Gram-negative (Pseudomonas aeruginosa) bacteria at different concentrations (0.05, 0.10 and 0.25 w/v%). Results were analysed using linear models to assess the effectiveness of different treatments. Strong antimicrobial effects of the three NPCs (AMNP0-2) on both pathogens could be quantified using the plate count method and flow cytometry. The plate count method showed a high log reduction (>8-log) for bacteria exposed to high NPC concentrations. We found similar antimicrobial results using the flow cytometry live/dead assay. Viability qPCR analysis of antimicrobial activity could not be quantified due to interference of NPCs with qPCR amplification. Flow cytometry was determined to be the best method to measure antimicrobial activity of the novel NPCs due to high-throughput, rapid and quantifiable results.


Comparing identified and statistically significant lipids and polar metabolites in 15-year old serum and dried blood spot samples for longitudinal studies.
The use of dried blood spots (DBS) has many advantages over traditional plasma and serum samples such as the smaller blood volume required, storage at room temperature, and ability to sample in remote locations. However, understanding the robustness of different analytes in DBS samples is essential, especially in older samples collected for longitudinal studies. Here we analyzed the stability of polar metabolites and lipids in DBS samples collected in 2000-2001 and stored at room temperature. The identified and statistically significant molecules were then compared to matched serum samples stored at -80°C to determine if the DBS samples could be effectively used in a longitudinal study following metabolic disease. A total of 400 polar metabolites and lipids were identified in the serum and DBS samples using gas chromatograph/mass spectrometry (GC/MS), liquid chromatography (LC)/MS, and LC/ion mobility spectrometry-MS (LC/IMS-MS). The identified polar metabolites overlapped well between the sample types, though only one statistically significant metabolite was conserved in a case-control study of older diabetic males with low amounts of high-density lipoproteins and high body mass indices, triacylglycerides and glucose levels when compared to non-diabetic patients with normal levels, indicating that degradation in the DBS samples affects polar metabolite quantitation. Differences in the lipid identifications indicated that some oxidation occurs in the DBS samples. However, 36 statistically significant lipids correlated in both sample types. The difference in the number of statistically significant polar metabolites and lipids indicated that the lipids did not degrade to as great of a degree as the polar metabolites in the DBS samples and lipid quantitation was still possible. Copyright © 2016 John Wiley & Sons, Ltd.


Cellular and network mechanisms of slow oscillatory activity (<1 Hz) and wave propagations in a cortical network model.
Slow oscillatory activity (<1 Hz) is observed in vivo in the cortex during slow-wave sleep or under anesthesia and in vitro when the bath solution is chosen to more closely mimic cerebrospinal fluid. Here we present a biophysical network model for the slow oscillations observed in vitro that reproduces the single neuron behaviors and collective network firing patterns in control as well as under pharmacological manipulations. The membrane potential of a neuron oscillates slowly (at <1 Hz) between a down state and an up state; the up state is maintained by strong recurrent excitation balanced by inhibition, and the transition to the down state is due to a slow adaptation current (Na(+)-dependent K(+) current). Consistent with in vivo data, the input resistance of a model neuron, on average, is the largest at the end of the down state and the smallest during the initial phase of the up state. An activity wave is initiated by spontaneous spike discharges in a minority of neurons, and propagates across the network at a speed of 3-8 mm/s in control and 20-50 mm/s with inhibition block. Our work suggests that long-range excitatory patchy connections contribute significantly to this wave propagation. Finally, we show with this model that various known physiological effects of neuromodulation can switch the network to tonic firing, thus simulating a transition to the waking state.


Activation of the JAK/STAT-1 signaling pathway by IFN-gamma can down-regulate functional expression of the MHC class I-related neonatal Fc receptor for IgG.
Expression of many MHC genes is enhanced at the transcriptional or posttranscriptional level following exposure to the cytokine IFN-gamma. However, in this study we found that IFN-gamma down-regulated the constitutive expression of the neonatal Fc receptor (FcRn), an MHC class I-related molecule that functions to transport maternal IgG and protect IgG and albumin from degradation. Epithelial cell, macrophage-like THP-1 cell, and freshly isolated human PBMC exposure to IFN-gamma resulted in a significant decrease of FcRn expression as assessed by real-time RT-PCR and Western blotting. The down-regulation of FcRn was not caused by apoptosis or the instability of FcRn mRNA. Chromatin immunoprecipitation and gel mobility shift assays showed that STAT-1 bound to an IFN-gamma activation site in the human FcRn promoter region. Luciferase expression from an FcRn promoter-luciferase reporter gene construct was not altered in JAK1- and STAT-1-deficient cells following exposure to IFN-gamma, whereas expression of JAK1 or STAT-1 protein restored the IFN-gamma inhibitory effect on luciferase activity. The repressive effect of IFN-gamma on the FcRn promoter was selectively reversed or blocked by mutations of the core nucleotides in the IFN-gamma activation site sequence and by overexpression of the STAT-1 inhibitor PIAS1 or the dominant negative phospho-STAT-1 mutations at Tyr-701 and/or Ser-727 residues. Furthermore, STAT-1 might down-regulate FcRn transcription through sequestering the transcriptional coactivator CREB binding protein/p300. Functionally, IFN-gamma stimulation dampened bidirectional transport of IgG across a polarized Calu-3 lung epithelial monolayer. Taken together, our results indicate that the JAK/STAT-1 signaling pathway was necessary and sufficient to mediate the down-regulation of FcRn gene expression by IFN-gamma.


Chemoattraction to dimethylsulfoniopropionate throughout the marine microbial food web.
Phytoplankton-produced dimethylsulfoniopropionate (DMSP) provides underwater and atmospheric foraging cues for several species of marine invertebrates, fish, birds, and mammals. However, its role in the chemical ecology of marine planktonic microbes is largely unknown, and there is evidence for contradictory functions. By using microfluidics and image analysis of swimming behavior, we observed attraction toward microscale pulses of DMSP and related compounds among several motile strains of phytoplankton, heterotrophic bacteria, and bacterivore and herbivore microzooplankton. Because microbial DMSP cycling is the main natural source of cloud-forming sulfur aerosols, our results highlight how adaptations to microscale chemical seascapes shape planktonic food webs, while potentially influencing climate at the global scale.


Engineered Coiled-Coil Protein for Delivery of Inverse Agonist for Osteoarthritis.
Osteoarthritis (OA) results from degenerative and abnormal function of joints, with localized biochemistry playing a critical role in its onset and progression. As high levels of all- trans retinoic acid (ATRA) in synovial fluid have been identified as a contributive factor to OA, the synthesis of de novo antagonists for retinoic acid receptors (RARs) has been exploited to interrupt the mechanism of ATRA action. BMS493, a pan-RAR inverse agonist, has been reported as an effective inhibitor of ATRA signaling pathway; however, it is unstable and rapidly degrades under physiological conditions. We employed an engineered cartilage oligomeric matrix protein coiled-coil (CccS) protein for the encapsulation, protection, and delivery of BMS493. In this study, we determine the binding affinity of CccS to BMS493 and the stimulator, ATRA, via competitive binding assay, in which ATRA exhibits approximately 5-fold superior association with CccS than BMS493. Interrogation of the structure of CccS indicates that ATRA causes about 10% loss in helicity, while BMS493 did not impact the structure. Furthermore, CccS self-assembles into nanofibers when bound to BMS493 or ATRA as expected, displaying 11-15 nm in diameter. Treatment of human articular chondrocytes in vitro reveals that CccS·BMS493 demonstrates a marked improvement in efficacy in reducing the mRNA levels of matrix metalloproteinase-13 (MMP-13), one of the main proteases responsible for the degradation of the extracellular cartilage matrix compared to BMS493 alone in the presence of ATRA, interleukin-1 beta (IL-1β), or IL-1 β together with ATRA. These results support the feasibility of utilizing coiled-coil proteins as drug delivery vehicles for compounds of relatively limited bioavailability for the potential treatment of OA.


Diet and specific microbial exposure trigger features of environmental enteropathy in a novel murine model.
Environmental enteropathy (EE) is a subclinical chronic inflammatory disease of the small intestine and has a profound impact on the persistence of childhood malnutrition worldwide. However, the aetiology of the disease remains unknown and no animal model exists to date, the creation of which would aid in understanding this complex disease. Here we demonstrate that early-life consumption of a moderately malnourished diet, in combination with iterative oral exposure to commensal Bacteroidales species and Escherichia coli, remodels the murine small intestine to resemble features of EE observed in humans. We further report the profound changes that malnutrition imparts on the small intestinal microbiota, metabolite and intraepithelial lymphocyte composition, along with the susceptibility to enteric infection. Our findings provide evidence indicating that both diet and microbes combine to contribute to the aetiology of EE, and describe a novel murine model that can be used to elucidate the mechanisms behind this understudied disease.


Three-Phase Morphology Evolution in Sequentially Solution-Processed Polymer Photodetector: Toward Low Dark Current and High Photodetectivity.
Sequentially solution-processed polymer photodetectors (SSP PPDs) based on poly(3-hexylthiophene-2,5-diyl) (P3HT)/[6,6]-phenyl C71-butyric acid methyl ester (PC71BM) are fabricated by depositing the top layers of PC71BM from an appropriate cosolvent of 2-chlorophenol (2-CP)/o-dichlorobenzene (ODCB) onto the predeposited bottom layers of P3HT. By adjusting the ratio of 2-CP/ODCB in the top PC71BM layers, the resulting SSP PPD shows a decreased dark current and an increased photocurrent, leading to a maximum detectivity of 1.23 × 1012 Jones at a wavelength of 550 nm. This value is 5.3-fold higher than that of the conventional bulk heterojunction PPD. Morphology studies reveal that the PC71BM partially penetrates the predeposited P3HT layer during the spin-coating process, resulting in an optimal three-phase morphology with one well-mixed interdiffusion P3HT/PC71BM phase in the middle of the bulk and two pure phases of P3HT and PC71BM at the two electrode sides. We show that the pure phases form high Schottky barriers (>2.0 eV) at the active layer/electrodes interface and efficiently block unfavorable reverse charge carrier injection by significantly decreasing the dark current. The interdiffussion phase enlarges the donor-acceptor interfacial area leading to a large photocurrent. We also reveal that the improved performance of SSP PPDs is also due to the enhanced optical absorption, improved P3HT crystallinity, increased charge carrier mobilities, and suppressed bimolecular recombination.


Locusts as model organisms in which to study immunogen-induced anorectic behaviour.
When injected into adult or nymphal Locusta that have been deprived of food for 2h, immunogens such as laminarin and bacterial LPS can induce an almost immediate dose-dependent state of anorexia for at least 1h. Such anorexia is a component of a medley of physiological and behavioural changes called collectively 'sickness behaviour' that occurs in a wide range of animals in response to infection or immune challenge. Sub-optimal amounts of injected laminarin allow some locusts to feed, but with a longer latency than in controls, although the length of the first meal is unaffected. The feeding behaviour of fifth instar nymphs is more sensitive to laminarin than that of adults, but both stages respond to amounts of immunogen that are lower than those required to activate the phenoloxidase cascade. Injection of adipokinetic hormone (AKH) before the period of food deprivation prevents the anorexigenic action of the laminarin in adults but not in nymphs. It is argued that the effect of the AKH may be indirect, through its lipid-mobilising action. The insecticide pymetrozine increases the latency to feed but also reduces the length of the first meal, and its anorexigenic activity is not affected by injection of AKH. The present data support the concept that laminarin-induced anorexia involves a central lack of motivation to eat, rather than a 'stop eating' signal. Others have shown that the mechanism of action of pymetrozine involves the serotonergic system and can be blocked by mianserin, so it is intriguing that in the present study injection of mianserin prior to that of laminarin modulates the anorexigenic effect of the immunogen. This suggests that biogenic amines are involved in the control of appetitive behaviour in locusts, as they are in vertebrates. The possible usefulness of the locust model in studying sickness-induced anorexia is discussed briefly.


Critical conditions for phytoplankton blooms.
We motivate and analyse a reaction-advection-diffusion model for the dynamics of a phytoplankton species. The reproductive rate of the phytoplankton is determined by the local light intensity. The light intensity decreases with depth due to absorption by water and phytoplankton. Phytoplankton is transported by turbulent diffusion in a water column of given depth. Furthermore, it might be sinking or buoyant depending on its specific density. Dimensional analysis allows the reduction of the full problem to a problem with four dimensionless parameters that is fully explored. We prove that the critical parameter regime for which a stationary phytoplankton bloom ceases to exist, can be analysed by a reduced linearized equation with particular boundary conditions. This problem is mapped exactly to a Bessel function problem, which is evaluated both numerically and by asymptotic expansions. A final transformation from dimensionless parameters back to laboratory parameters results in a complete set of predictions for the conditions that allow phytoplankton bloom development. Our results show that the conditions for phytoplankton bloom development can be captured by a critical depth, a compensation depth, and zero, one or two critical values of the vertical turbulent diffusion coefficient. These experimentally testable predictions take the form of similarity laws: every plankton-water-light-system characterized by the same dimensionless parameters will show the same dynamics.


An intervention for sensory difficulties in children with autism: a randomized trial.
This study evaluated a manualized intervention for sensory difficulties for children with autism, ages 4-8 years, using a randomized trial design. Diagnosis of autism was confirmed using gold standard measures. Results show that the children in the treatment group (n = 17) who received 30 sessions of the occupational therapy intervention scored significantly higher (p = 0.003, d = 1.2) on Goal Attainment Scales (primary outcome), and also scored significantly better on measures of caregiver assistance in self-care (p = 0.008 d = 0.9) and socialization (p = 0.04, d = 0.7) than the Usual Care control group (n = 15). The study shows high rigor in its measurement of treatment fidelity and use of a manualized protocol, and provides support for the use of this intervention for children with autism. Findings are discussed in terms of their implications for practice and future research.