The wheat Phs-A1 pre-harvest sprouting resistance locus delays the rate of seed dormancy loss and maps 0.3 cM distal to the PM19 genes in UK germplasm.
The precocious germination of cereal grains before harvest, also known as pre-harvest sprouting, is an important source of yield and quality loss in cereal production. Pre-harvest sprouting is a complex grain defect and is becoming an increasing challenge due to changing climate patterns. Resistance to sprouting is multi-genic, although a significant proportion of the sprouting variation in modern wheat cultivars is controlled by a few major quantitative trait loci, including Phs-A1 in chromosome arm 4AL. Despite its importance, little is known about the physiological basis and the gene(s) underlying this important locus. In this study, we characterized Phs-A1 and show that it confers resistance to sprouting damage by affecting the rate of dormancy loss during dry seed after-ripening. We show Phs-A1 to be effective even when seeds develop at low temperature (13 °C). Comparative analysis of syntenic Phs-A1 intervals in wheat and Brachypodium uncovered ten orthologous genes, including the Plasma Membrane 19 genes (PM19-A1 and PM19-A2) previously proposed as the main candidates for this locus. However, high-resolution fine-mapping in two bi-parental UK mapping populations delimited Phs-A1 to an interval 0.3 cM distal to the PM19 genes. This study suggests the possibility that more than one causal gene underlies this major pre-harvest sprouting locus. The information and resources reported in this study will help test this hypothesis across a wider set of germplasm and will be of importance for breeding more sprouting resilient wheat varieties.


Gene therapy for Wiskott-Aldrich syndrome in a severely affected adult.
Until recently, hematopoietic stem cell transplantation was the only curative option for Wiskott-Aldrich syndrome (WAS). The first attempts at gene therapy for WAS using a ϒ-retroviral vector improved immunological parameters substantially but were complicated by acute leukemia as a result of insertional mutagenesis in a high proportion of patients. More recently, treatment of children with a state-of-the-art self-inactivating lentiviral vector (LV-w1.6 WASp) has resulted in significant clinical benefit without inducing selection of clones harboring integrations near oncogenes. Here, we describe a case of a presplenectomized 30-year-old patient with severe WAS manifesting as cutaneous vasculitis, inflammatory arthropathy, intermittent polyclonal lymphoproliferation, and significant chronic kidney disease and requiring long-term immunosuppressive treatment. Following reduced-intensity conditioning, there was rapid engraftment and expansion of a polyclonal pool of transgene-positive functional T cells and sustained gene marking in myeloid and B-cell lineages up to 20 months of observation. The patient was able to discontinue immunosuppression and exogenous immunoglobulin support, with improvement in vasculitic disease and proinflammatory markers. Autologous gene therapy using a lentiviral vector is a viable strategy for adult WAS patients with severe chronic disease complications and for whom an allogeneic procedure could present an unacceptable risk. This trial was registered at www.clinicaltrials.gov as #NCT01347242.


Uncoupling proteins in human heart.
Abnormal energetic activity in heart failure correlates inversely with plasma free-fatty-acid concentrations. However, the link between energetic and metabolic abnormalities is unknown. To investigate this association, we obtained blood samples from 39 patients undergoing coronary artery bypass graft surgery. Patients fasted overnight before samples were taken. When plasma free-fatty-acid concentrations were raised, cardiac mitochondrial uncoupling proteins (UCP) increased (isoform UCP2, p<0.0001; isoform UCP3, p=0.0036) and those of glucose transporter (GLUT4) protein decreased (cardiac, p=0.0001; skeletal muscle, p=0.0006). Consequently, energy deficiency in heart failure might result from increased mitochondrial UCPs (ie, less efficient ATP synthesis) and depleted GLUT4 (ie, reduced glucose uptake). New treatment to correct these energy defects would be to simultaneously lower plasma free fatty acids and provide an alternative energy source.


Theoretical models of carcinogenic particle deposition and clearance in children's lungs.
Deposition and clearance of carcinogenic particles in the lungs of subjects belonging to four different age groups (infants, children, adolescents, and adults) were theoretically investigated. The study is thought to contribute to the improvement of our knowledge concerning the behaviour of inhaled particles in lungs that may be attributed to different stages of development. Particle deposition and clearance were simulated by using a well established stochastic lung model, allowing the generation of nearly realistic scenarios. For the computation of particle deposition all main deposition forces were considered. Additionally, any influences on particle behaviour due to particle geometry were covered by using the aerodynamic diameter concept. Particle clearance was simulated by defining both a fast mucociliary clearance phase and a slow bronchial/alveolar clearance phase, the latter of which is based on previously published models and suggestions. As clearly provided by the modelling computations, lung deposition of particles with aerodynamic diameters ranging from 1 nm to 10 µm may significantly differ between the studied age groups. Whilst in infants and children most particles are accumulated in the extrathoracic region and in the upper bronchi, in adolescents and adults high percentages of inhaled particular substances may also reach the lower bronchi and alveoli. Although mucus velocities are significantly lower in young subjects compared to the older ones, fast clearance is more efficient in small lungs due to the shorter clearance paths that have to be passed. Slow clearance is commonly characterized by insignificant discrepancies between the age groups. From the study presented here it may be concluded that particle behaviour in infants' and children's lungs has to be regarded in a different light with respect to that in adolescents and adults. Although young subjects possess natural mechanisms of protecting their lungs from hazardous aerosols (e.g., expressed by breathing behaviour and lung size), they are much more sensitive to any particle exposure, since particle concentrations per lung tissue area may reach alarming values within a short period of inhalation.


Dietary intake of folate, but not vitamin B2 or B12, is associated with increased bone mineral density 5 years after the menopause: results from a 10-year follow-up study in early postmenopausal women.
Folate, vitamin B2 (riboflavin), and vitamin B12 may affect bone directly or through an effect on plasma homocysteine levels. Previously, a positive association has been found between plasma levels and bone mineral density (BMD) as well as risk of fracture. However, there are limited data on whether dietary intakes affect bone. Our aim was to investigate whether intake of folate, vitamin B2) and vitamin B12, as assessed by food records affects BMD and fracture risk. In a population-based cohort including 1,869 perimenopausal women from the Danish Osteoporosis Prevention Study, associations between intakes and BMD were assessed at baseline and after 5 years of follow-up. Moreover, associations between intakes and 5- and 10-year changes in BMD as well as risk of fracture were studied. Intakes of folate, vitamin B2, and vitamin B12 were 417 (range 290-494) microg/day, 2.70 (range 1.70-3.16) mg/day, and 4.98 (range 3.83-6.62) microg/day, respectively, i.e., slightly above the intakes recommended by the United Nations Food and Agriculture Organization. At year 5, but not at baseline, cross-sectional analyses showed positive correlations between daily intake from diet and from diet plus supplements of folate and BMD at the femoral neck (P < 0.01). However, no associations were found between intakes and changes in BMD. During 10 years of follow-up, 360 subjects sustained a fracture. Compared with 1,440 controls, logistic regression analyses revealed no difference in intakes between cases and controls. A high dietary intake of folate, but not vitamin B2 or B12, exerts positive effects on BMD; but further studies are needed to confirm this association.


Alterations in the rate of binge ethanol consumption: implications for preclinical studies in mice.
The rate at which alcohol (ethanol) is consumed has direct impact on its behavioral and subjective effects. For this reason, alterations in the pattern of ethanol consumption as a function of drinking history might be critical to the development and maintenance of alcoholism. Furthermore, because pharmacological interventions aimed at disrupting the motivation to consume ethanol are dependent on the brain/plasma concentrations present when an individual is most likely to engage in consumption of this substance, characterizing temporal drinking patterns might be useful to determine the timing of such treatments. The primary goal of the present study was to evaluate alterations in the timecourse of daily binge (drinking-in-the-dark; DID) ethanol consumption. We gave 14 daily 2 hour DID ethanol or water access sessions to male C57BL/6J (B6) mice using a state of the art volumetric drinking monitoring device. We then, primarily as a proof-of-principle, used the GABAB allosteric modulator GS39783 (GS) to determine how this compound influenced the timecourse of binge-like ethanol intake. The rate of ethanol consumption increased dramatically over sessions with the majority occurring in the first few minutes of the final session. Additionally, ethanol consumption occurring immediately following access was almost completely abolished in mice pre-treated with GS; an effect which was ethanol-specific only at this early time interval. These data characterize progressive alterations in the rate of ethanol intake using the DID model and suggest that careful consideration of prior ethanol history and timing of drug administration are warranted when interpreting results of pre-clinical drug administration studies.


Recreational value of an oasis in Oman.
Increasing demand for water to develop non-agricultural activities is causing water to be diverted to high-value uses at the expense of irrigation. However, agriculture provides a flow of amenities in the desert environment which are not either accounted or paid. Oases are spread all over the globe and are threatened for various reasons among which is the high pressure of demand for fresh water. This paper estimates the recreation use value of an oasis. The paper is based on the Misfat Al-Abryeen oasis in Oman, a man-made area of streams and woodland. The travel cost method is used through an on-site questionnaire distributed to 230 visitors. Around 75% of visitors to the oasis also visited other historical or ecological sites during the same day-trip. The econometric model is estimated using negative binomial regression with endogenous stratification. The average consumer surplus, or benefit, from visiting Misfat Al-Abryeen is estimated at US$ 104.74 per individual per trip. The total social benefit from this oasis is estimated at $366,590 per year. These results underscore the importance of the role played by irrigated agriculture in the provision of amenity services for the tourism sector in a desert environment. The sustainability of the irrigation activity depends on the recognition of the recreation role of oases and the transfer of part of these benefits to the farmers who maintain the irrigation system. The implementation of an entrance fee to the oasis might increase farmers' profit by 6-21%.


Ethnic comparison of attitudes and beliefs about cigarette smoking.
To determine if hypothesized differences in attitudes and beliefs about cigarette smoking between Latino and non-Latino white smokers are independent of years of formal education and number of cigarettes smoked per day. Cross-sectional survey using a random digit dial telephone method. San Francisco census tracts with at least 10% Latinos in the 1990 Census. Three hundred twelve Latinos (198 men and 114 women) and 354 non-Latino whites (186 men and 168 women), 18 to 65 years of age, who were current cigarette smokers participated. Self-reports of cigarette smoking behavior, antecedents to smoking, reasons to quit smoking, and reasons to continue smoking were the measures. Latino smokers were younger (36.6 vs 39.6 years, p < .01), had fewer years of education (11.0 vs 14.3 years, p < .001), and smoked on average fewer cigarettes per day (9.7 vs 20.1, p < .001). Compared with whites, Latino smokers were less likely to report smoking "almost always or often" after 13 of 17 antecedents (each p < .001), and more likely to consider it important to quit for 12 of 15 reasons (each p < .001). In multivariate analyses after adjusting for gender, age, education, income, and number of cigarettes smoked per day, Latino ethnicity was a significant predictor of being less likely to smoke while talking on the telephone (odds ratio [OR] 0.41; 95% confidence interval [CI] 0.26, 0.64), drinking alcoholic beverages (OR 0.66; 95% CI 0.44, 0.99), after eating (OR 0.55; 95% CI 0.37, 0.81), or at a bar (OR 0.62; 95% CI 0.41, 0.94), and a significant predictor of being more likely to smoke at a party (OR 1.72; 95% CI 1.14, 2.60). Latino ethnicity was a significant predictor of considering quitting important because of being criticized by family (OR 1.93; 95% CI 1.26, 2.98), burning clothes (OR 1.57; 95% CI 1.02, 2.42), damaging children's health (OR 1.67; 95% CI 1.08, 2.57), bad breath (OR 2.07; 95% CI 1.40, 3.06), family pressure (OR 1.67; 95% CI 1.10, 2.60), and being a good example to children (OR 1.83; 95% CI 1.21, 2.76). Differences in attitudes and beliefs about cigarette smoking between Latinos and whites are independent of education and number of cigarettes smoked. We recommend that these ethnic differences be incorporated into smoking cessation interventions for Latino smokers.


Resolution of hypertension and proteinuria after preeclampsia.
To estimate the time required for hypertension and proteinuria to resolve after preeclampsia, and to estimate how this time to resolution correlates with the levels of blood pressure and proteinuria during preeclampsia and prolonging pregnancy after the development of preeclampsia. This is a historic prospective cohort study of 205 preeclamptic women who were admitted between 1990 and 1992 at the Erasmus MC Medical Centre, Rotterdam, The Netherlands. Data were collected at 1.5, 3, 6, 12, 18, and 24 months after delivery. Hypertension was defined as a blood pressure 140/90 mm Hg or higher or use of antihypertensive drugs. Proteinuria was defined as 0.3 g/d or more. Resolution of hypertension and proteinuria were analyzed with the Turnbull extension to the Kaplan-Meier procedure. Correlations were calculated with an accelerated failure time model. At 3 months postpartum, 39% of women still had hypertension, which decreased to 18% at 2 years postpartum. Resolution time increased by 60% (P<.001) for every 10-mm Hg increase in maximal systolic blood pressure, 40% (P=.044) for every 10-mm Hg increase in maximal diastolic blood pressure, and 3.6% (P=.001) for every 1-day increase in the diagnosis-to-delivery interval. At 3 months postpartum, 14% still had proteinuria, which decreased to 2% at 2 years postpartum. Resolution time increased by 16% (P=.001) for every 1-g/d increase in maximal proteinuria. Gestational age at onset of preeclampsia was not correlated with resolution time of hypertension and proteinuria. The severity of preeclampsia and the time interval between diagnosis and delivery are associated with postpartum time to resolution of hypertension and proteinuria. After preeclampsia, it can take up to 2 years for hypertension and proteinuria to resolve. Therefore, the authors suggest that further invasive diagnostic tests for underlying renal disease may be postponed until 2 years postpartum. III.


Black and brown widow spider bites in South Africa. A series of 45 cases.
Cases of black widow (Latrodectus indistinctus) and brown widow (L. geometricus) spider bites referred to the Tygerberg Pharmacology and Toxicology Consultation Centre from the summer of 1987/88 to the summer of 1991/92 were entered into this series. Of a total of 45 patients, 30 had been bitten by black and 15 by brown widow spiders. It was evident that black widow spider bites caused a more severe form of envenomation than brown widow bites, characterised by generalised muscle pain and cramps, abdominal muscle rigidity, profuse sweating, raised blood pressure and tachycardia. The symptoms and signs of brown widow bites were mild and tended to be restricted to the bite site and surrounding tissues. Conditions which should be considered in the differential diagnosis include cytotoxic spider bite, scorpion sting, snakebite, acute abdominal conditions, myocardial infarction, alcohol withdrawal and organophosphate poisoning. To prevent the development of complications, the administration of black widow spider antivenom is recommended in severe cases because untreated latrodectism could become protracted, without improvement, for several days.


Carotid sinus syncope treated by pacing. Analysis of persistent symptoms and role of atrioventricular sequential pacing.
Seventy patients have been paced for carotid sinus syndrome over four years. Twelve patients had persistent symptoms despite adequate ventricular pacing. Patients with persistent symptoms were found to have a significant vasodepressor response, a significant hypotensive response to ventricular pacing (pacemaker effect), and a severe hypotensive response to carotid sinus massage with introduction of ventricular pacing, which reproduced symptoms in all patients. A group of 14 asymptomatic paced carotid sinus patients was found to have a significantly lower vasodepressor response, pacemaker effect, and combined vasodepressor response plus pacemaker effect than the group with persistent symptoms. Atrioventricular sequential pacing was shown to eliminate the hypotensive effect of ventricular pacing and is considered to be the treatment of choice for patients with carotid sinus syndrome who have both cardioinhibitory and significant vasodepressor responses.


Quality changes of prerigor filleted Atlantic salmon (Salmo salar L.) packaged in modified atmosphere using CO2 emitter, traditional MAP, and vacuum.
Pieces of prerigor salmon fillets were packaged in modified atmosphere (60% CO(2) and 40% N(2)) and in vacuum. The MA packages had a gas to product volume ratio (g/p ratio) of 3/1 (traditional MAP) and 1/1 (packaged with a CO(2) emitter). All the samples were stored at 1.2 degrees C for 25 d. The MA packages had lower bacterial growth during storage compared to vacuum packages. The analyses of 16S rRNA at day 22 indicated a similar bacterial diversity, independent of packaging methods, dominated by Photobacterium phosphoreum. The results therefore suggest that CO(2) inhibited total bacterial count, including, P. phosphoreum. Negative odors and liquid losses were detected earlier for the vacuum-packaged samples (8 d) compared to the MA samples (15 d) and higher levels were detected at the end of the storage period. The breaking strength (firmness) tended to be lower for the MA packaged samples compared with the vacuum samples after 15 d of storage, whereas the redness (a* value) and the yellowness (b* value) were significantly higher for the MA samples. In conclusion, MA packaging preserved the quality better during storage than vacuum packaging. MA packaging with a CO(2) emitter and reduced g/p ratio gave similar or better results compared with traditional MAP, thus CO(2) emitters are well suited for reduction of volume of MA packaged farmed salmon fillet pieces.


Insect herbivory alters impact of atmospheric change on northern temperate forests.
Stimulation of forest productivity by elevated concentrations of CO2 is expected to partially offset continued increases in anthropogenic CO2 emissions. However, multiple factors can impair the capacity of forests to act as carbon sinks; prominent among these are tropospheric O3 and nutrient limitations(1,2). Herbivorous insects also influence carbon and nutrient dynamics in forest ecosystems, yet are often ignored in ecosystem models of forest productivity. Here we assess the effects of elevated levels of CO2 and O3 on insect-mediated canopy damage and organic matter deposition in aspen and birch stands at the Aspen FACE facility in northern Wisconsin, United States. Canopy damage was markedly higher in the elevated CO2 stands, as was the deposition of organic substrates and nitrogen. The opposite trends were apparent in the elevated O3 stands. Using a light-use efficiency model, we show that the negative impacts of herbivorous insects on net primary production more than doubled under elevated concentrations of CO2, but decreased under elevated concentrations of O3. We conclude that herbivorous insects may limit the capacity of forests to function as sinks for anthropogenic carbon emissions in a high CO2 world.


The emerging role of nanomaterials in immunological sensing - a brief review.
Nanomaterials are beginning to play an important role in the next generation of immunological assays and biosensors, with potential impacts both in research and clinical practice. In this brief review, we highlight two areas in which nanomaterials are already making new and important contributions in the past 5-10 years: firstly, in the improvement of assay and biosensor sensitivity for detection of low abundance proteins of immunological significance, and secondly, in the real-time and continuous monitoring of protein secretion from arrays of individual cells. We finish by challenging the immunology/sensing communities to work together to develop nanomaterials that can provide real-time, continuous, and sensitive molecular readouts in vivo, a lofty goal that will require significant collaborative effort.


Self-reported mindfulness and soldier health following a combat deployment.
Combat exposure has been linked to health-related challenges associated with postcombat adjustment, including mental health symptoms, behavior-related problems, physical pain, and functional impairment. Mindfulness, or acceptance of the present moment without reactivity or judgment, may be associated with better mental health following a combat deployment. This study examined whether self-reported mindfulness predicted soldier health outcomes over the course of the postdeployment period. U.S. soldiers (n = 627) were surveyed 4 months after a deployment to Afghanistan (T1) and again 3 months later (T2). Mindfulness was assessed using the nonreactivity to inner experience subscale of the Five-Facet Mindfulness Questionnaire. Hierarchical linear regressions examined how mindfulness (T1) moderated the impact of combat exposure (T1) on outcomes at T2. Controlling for rank, the interaction between combat exposure and mindfulness significantly predicted posttraumatic stress disorder (PTSD) symptoms, depression symptoms, risk-taking behaviors, pain symptoms, and functional impairment. The interaction term explained 1% to 2% of the variance in these health outcomes. Simple slopes analyses revealed that combat exposure was associated with more PTSD symptoms, depression symptoms, risk-taking behaviors, pain symptoms, and functional impairment when soldiers reported low levels of mindfulness. There was no effect for alcohol misuse, sleep difficulties, or aggressive behaviors. Nonreactivity to inner experience may mitigate the detrimental effects of high-levels of combat exposure on both mental and physical health outcomes. These findings indicate that mindfulness strategies such as nonreactivity may be particularly useful for employees facing potentially traumatic stressors in a high-risk occupational context. (PsycINFO Database Record (c) 2019 APA, all rights reserved).


In vitro reconstitution of T cell receptor-mediated segregation of the CD45 phosphatase.
T cell signaling initiates upon the binding of peptide-loaded MHC (pMHC) on an antigen-presenting cell to the T cell receptor (TCR) on a T cell. TCR phosphorylation in response to pMHC binding is accompanied by segregation of the transmembrane phosphatase CD45 away from TCR-pMHC complexes. The kinetic segregation hypothesis proposes that CD45 exclusion shifts the local kinase-phosphatase balance to favor TCR phosphorylation. Spatial partitioning may arise from the size difference between the large CD45 extracellular domain and the smaller TCR-pMHC complex, although parsing potential contributions of extracellular protein size, actin activity, and lipid domains is difficult in living cells. Here, we reconstitute segregation of CD45 from bound receptor-ligand pairs using purified proteins on model membranes. Using a model receptor-ligand pair (FRB-FKBP), we first test physical and computational predictions for protein organization at membrane interfaces. We then show that the TCR-pMHC interaction causes partial exclusion of CD45. Comparing two developmentally regulated isoforms of CD45, the larger RABC variant is excluded more rapidly and efficiently (∼50%) than the smaller R0 isoform (∼20%), suggesting that CD45 isotypes could regulate signaling thresholds in different T cell subtypes. Similar to the sensitivity of T cell signaling, TCR-pMHC interactions with Kds of ≤15 µM were needed to exclude CD45. We further show that the coreceptor PD-1 with its ligand PD-L1, immunotherapy targets that inhibit T cell signaling, also exclude CD45. These results demonstrate that the binding energies of physiological receptor-ligand pairs on the T cell are sufficient to create spatial organization at membrane-membrane interfaces.


SMA-EUROPE workshop report: Opportunities and challenges in developing clinical trials for spinal muscular atrophy in Europe.
Spinal muscular atrophy (SMA) is the most common lethal recessive disease in childhood, and there is currently no effective treatment to halt disease progression. The translation of scientific advances into effective therapies is hampered by major roadblocks in clinical trials, including the complex regulatory environment in Europe, variations in standards of care, patient ascertainment and enrolment, a narrow therapeutic window and a lack of biomarkers of efficacy. In this context, SMA-Europe organized its first international workshop in July 2012 in Rome, gathering 34 scientists, clinicians and representatives of patient organizations to establish recommendations for improving clinical trials for SMAa.


Identification of a sequence in the PEPCK gene that mediates a negative effect of insulin on transcription.
Phosphoenolpyruvate carboxykinase (PEPCK) governs the rate-limiting step in gluconeogenesis. Glucocorticoids and adenosine 3',5'-monophosphate (cAMP) increase PEPCK gene transcription and gluconeogenesis, whereas insulin has the opposite effect. Insulin is dominant, since it prevents cAMP and glucocorticoid-stimulated transcription. Glucocorticoid and cAMP response elements have been located in the PEPCK gene and now a 15-base pair insulin-responsive sequence (IRS) is described. Evidence for a binding activity that recognizes this sequence is presented.


Health Benefits Associated With Three Helping Behaviors: Evidence for Incident Cardiovascular Disease.
The purpose of this study was to investigate the association between three helping behaviors and incident cardiovascular disease (CVD; heart attack, stroke; fatal and nonfatal), with an exploration of gender differences. The study is framed within the caregiving system model. Helping others is argued to be an evolved characteristic of humans that yields beneficial health effects. Data were taken from the 2004-2014 waves of the Health and Retirement Study. The three forms of helping others considered were formal volunteering, informal helping, and caregiving for a parent or spouse. Cox proportional hazards models were estimated for gender-stratified samples. Women who volunteered showed a lower risk of incident CVD compared to women who did not volunteer. Men who informally helped others in the community exhibited a lower risk of incident CVD compared to men who did not provide this form of help. Caregiving status was generally not associated with incident CVD for women or men. The results demonstrated that specific types of prosocial behavior may be beneficial for women and men. However, tests for effect differences showed that gender did not moderate the relationships between these helping behaviors and CVD risk.


Extended incision in open-approach rhinoplasty for asians.
The purpose of this study was to introduce an extended incision in open-approach rhinoplasty for obtaining greater satisfaction in aesthetic rhinoplasty for Asians. This incision is the same as for the usual open rhinoplasty incision, but it is extended along the caudal border of the footplates of the medial crura onto the floor of the nasal vestibule to access the footplates of the medial crura more easily. This simple extended incision enabled the authors to achieve further tip projection because the pressure of the skin flap on the tip was reduced. By approximating the lateral curves of the medial crural footplates, the width and the length of the columella were narrowed and lengthened, respectively. The columella was also advanced caudally; thus, the shape of the nostrils could also be elongated. In addition, a cartilage graft or an implant insertion for alar base augmentation could be performed through this extended incision without an additional incision. Another advantage was that in correction of caudal septal deviation, displaced septal cartilage could be repositioned by suturing to the periosteum or soft tissue around the anterior nasal spine without drilling into it through an intraoral incision. Fifty-one consecutive patients who underwent this extended open-approach rhinoplasty between August of 1999 and September of 2000 were included in this study. A total of 40 patients had an adequate follow-up time of over 6 months. Patient satisfaction and postoperative complications were recorded. The majority of the patients (35 of 40) were satisfied with the results of the procedure. Two patients had complications of nostril-scar contracture requiring close follow-up. There were no cases of implant extrusion, displacement, or infection. No patients experienced transcolumellar or extended-incision scarring. Although further studies and longer follow-up are needed to determine the value of this incision, the authors believe that the addition of the extended incision in open-approach rhinoplasty is safe and reliable for effecting better results for Asians.


ISAG/IUIS-VIC Comparative MHC Nomenclature Committee report, 2005.
Nomenclature for Major Histocompatibility Complex (MHC) genes and alleles in species other than humans and mice has historically been overseen either informally by groups generating sequences, or by formal nomenclature committees set up by the International Society for Animal Genetics (ISAG). The suggestion for a Comparative MHC Nomenclature Committee was made at the ISAG meeting held in Göttingen, Germany (2002), and the committee met for the first time at the Institute for Animal Health, Compton, UK in January 2003. To publicize its activity and extend its scope, the committee organized a workshop at the International Veterinary Immunology Symposium (IVIS) in Quebec (2004) where it was decided to affiliate with the Veterinary Immunology Committee (VIC) of the International Union of Immunological Societies (IUIS). The goals of the committee are to establish a common framework and guidelines for MHC nomenclature in any species; to demonstrate this in the form of a database that will ensure that in the future, researchers can easily access a source of validated MHC sequences for any species; to facilitate discussion on this area between existing groups and nomenclature committees. A further meeting of the committee was held in September 2005 in Glasgow, UK. This was attended by most of the existing committee members with some additional invited participants (Table 1). The aims of this meeting were to facilitate the inclusion of new species onto the database, to discuss extension, improvement and funding of the database, and to address a number of nomenclature issues raised at the previous workshop.


Laboratory-developed L1 sequencing and type-specific, real-time polymerase chain reaction for the detection and typing of human papillomaviruses in formalin-fixed, paraffin-embedded tissues.
The detection and typing of high-risk and low-risk human papillomavirus (HPV) in archival formalin-fixed, paraffin-embedded tissues by nucleic acid amplification testing is an important adjunct to immunohistochemical staining in evaluation of squamous cell proliferations of the oropharynx, larynx, and anal canal. To evaluate semiautomated, xylene-free extraction from formalin-fixed, paraffin-embedded tissues combined with laboratory-developed HPV L1 sequencing and type-specific HPV 6, 11, 16, and 18 real-time polymerase chain reaction for identification and typing of HPV in the clinical laboratory. We evaluated the adequacy of extraction using β-globin amplification and compared L1 sequencing and real-time polymerase chain reaction methods for typing accuracy using 68 formalin-fixed, paraffin-embedded tissues, including 56 anorectal biopsy or surgical resection specimens and 12 laryngeal papilloma specimens from patients with recurrent respiratory papillomatosis. Adequate DNA was obtained from 68 of 68 specimens analyzed and all were HPV positive. In 47 cases where L1 sequencing demonstrated that the predominant HPV type was 6, 11, 16, or 18, type-specific, real-time polymerase chain reaction provided concordant results. Sequencing revealed additional low-risk (HPV 40) and high-risk HPV types (HPV 31, 33, 56, and 58) in anorectal specimens, whereas HPV 6 or 11 were the types found in laryngeal papillomas. Both L1 sequencing and type-specific, real-time polymerase chain reaction are suitable methods for routine HPV testing of formalin-fixed, paraffin-embedded tissues in a clinical laboratory setting.


Association of the actin-binding protein transgelin with lymph node metastasis in human colorectal cancer.
Metastatic dissemination of primary tumors is responsible for 90% of colorectal cancer (CRC) deaths. The presence of positive lymph nodes, which separates stage I/II from stage III CRC, is a particularly key factor in patient management. Here, we describe results of a quantitative proteomic survey to identify molecular correlates of node status. Laser capture microdissection and two-dimensional difference gel electrophoresis were used to establish expression profiles for 980 discrete protein features in 24 human CRC specimens. Protein abundances were determined with a median technical coefficient of variation of 10%, which provided an ability to detect small differences between cancer subtypes. Transgelin, a 23-kDa actin-binding protein, emerged as a top-ranked candidate biomarker of node status. The area under the receiver operating characteristic curve for transgelin in predicting node status was 0.868 (P = .002). Significantly increased frequency of moderate- and high-level transgelin expression in node-positive CRC was also seen using semiquantitative immunohistochemistry to analyze 94 independent CRC specimens on tissue microarrays (P = .036). Follow-up studies in CRC cell lines demonstrated roles for transgelin in promoting invasion, survival, and resistance to anoikis. Transgelin localizes to the nucleus of CRC cells, and its sequence and properties suggest that it may participate in regulation of the transcriptional program associated with the epithelial-to-mesenchymal transition.


Comparison of Varroa destructor and Worker Honeybee Microbiota Within Hives Indicates Shared Bacteria.
The ectoparasitic mite Varroa destructor is a major pest of the honeybee Apis mellifera. In a previous study, bacteria were found in the guts of mites collected from winter beehive debris and were identified using Sanger sequencing of their 16S rRNA genes. In this study, community comparison and diversity analyses were performed to examine the microbiota of honeybees and mites at the population level. The microbiota of the mites and honeybees in 26 colonies in seven apiaries in Czechia was studied. Between 10 and 50 Varroa females were collected from the bottom board, and 10 worker bees were removed from the peripheral comb of the same beehive. Both bees and mites were surface sterilized. Analysis of the 16S rRNA gene libraries revealed significant differences in the Varroa and honeybee microbiota. The Varroa microbiota was less diverse than was the honeybee microbiota, and the relative abundances of bacterial taxa in the mite and bee microbiota differed. The Varroa mites, but not the honeybees, were found to be inhabited by Diplorickettsia. The relative abundance of Arsenophonus, Morganella, Spiroplasma, Enterococcus, and Pseudomonas was higher in Varroa than in honeybees, and the Diplorickettsia symbiont detected in this study is specific to Varroa mites. The results demonstrated that there are shared bacteria between Varroa and honeybee populations but that these bacteria occur in different relative proportions in the honeybee and mite bacteriomes. These results support the suggestion of bacterial transfer via mites, although only some of the transferred bacteria may be harmful.


Discovery of clostrubin, an exceptional polyphenolic polyketide antibiotic from a strictly anaerobic bacterium.
Genome mining of the strictly anaerobic bacterium Clostridium beijerinckii, an industrial producer of solvents, revealed the presence of several cryptic gene clusters for secondary metabolite biosynthesis. To unearth its metabolic potential, a C. beijerinckii strain was cultured under various conditions, which led to the discovery of a deep purple pigment. This novel metabolite, named clostrubin (1), was isolated and its structure was fully elucidated. The pentacyclic polyphenol features a benzo[a]tetraphene ring topology that is unprecedented for natural products. Stable-isotope labeling experiments showed that 1 is an aromatic polyketide that folds in a noncanonical manner to form the unusual perifused ring system. In addition to being the first reported polyketide from an anaerobic bacterium, 1 is a potent antibiotic with pronounced activity against various pathogenic bacteria, such as MRSA, VRE, and mycobacteria, with minimum inhibitory concentrations (MIC) of 0.12-0.97 μM.


Prediction of the optimal set of contacts to fold the smallest knotted protein.
Knotted protein chains represent a new motif in protein folds. They have been linked to various diseases, and recent extensive analysis of the Protein Data Bank shows that they constitute 1.5% of all deposited protein structures. Despite thorough theoretical and experimental investigations, the role of knots in proteins still remains elusive. Nonetheless, it is believed that knots play an important role in mechanical and thermal stability of proteins. Here, we perform a comprehensive analysis of native, shadow-specific and non-native interactions which describe free energy landscape of the smallest knotted protein (PDB id 2efv). We show that the addition of shadow-specific contacts in the loop region greatly enhances folding kinetics, while the addition of shadow-specific contacts along the C-terminal region (H3 or H4) results in a new folding route with slower kinetics. By means of direct coupling analysis (DCA) we predict non-native contacts which also can accelerate kinetics. Next, we show that the length of the C-terminal knot tail is responsible for the shape of the free energy barrier, while the influence of the elongation of the N-terminus is not significant. Finally, we develop a concept of a minimal contact map sufficient for 2efv protein to fold and analyze properties of this protein using this map.


Bayesian analysis of correlated evolution of discrete characters by reversible-jump Markov chain Monte Carlo.
We describe a Bayesian method for investigating correlated evolution of discrete binary traits on phylogenetic trees. The method fits a continuous-time Markov model to a pair of traits, seeking the best fitting models that describe their joint evolution on a phylogeny. We employ the methodology of reversible-jump (RJ) Markov chain Monte Carlo to search among the large number of possible models, some of which conform to independent evolution of the two traits, others to correlated evolution. The RJ Markov chain visits these models in proportion to their posterior probabilities, thereby directly estimating the support for the hypothesis of correlated evolution. In addition, the RJ Markov chain simultaneously estimates the posterior distributions of the rate parameters of the model of trait evolution. These posterior distributions can be used to test among alternative evolutionary scenarios to explain the observed data. All results are integrated over a sample of phylogenetic trees to account for phylogenetic uncertainty. We implement the method in a program called RJ Discrete and illustrate it by analyzing the question of whether mating system and advertisement of estrus by females have coevolved in the Old World monkeys and great apes.


Predicting 3-Year Survival in Patients Receiving Maintenance Dialysis: An External Validation of iChoose Kidney in Ontario, Canada.
Many patients with end-stage kidney disease (ESKD) do not appreciate how their survival may differ if treated with a kidney transplant compared with dialysis. A risk calculator (iChoose Kidney) developed and validated in the United States provides individualized mortality estimates for different treatment options (dialysis vs living or deceased donor kidney transplantation). The calculator can be used with patients and families to help patients make more educated treatment decisions. To validate the iChoose Kidney risk calculator in Ontario, Canada. External validation study. We used several linked administrative health care databases from Ontario, Canada. We included 22 520 maintenance dialysis patients and 4505 kidney transplant recipients. Patients entered the cohort between 2004 and 2014. Three-year all-cause mortality. We assessed model discrimination using the C-statistic. We assessed model calibration by comparing the observed versus predicted mortality risk and by using smoothed calibration plots. We used multivariable logistic regression modeling to recalibrate model intercepts using a correction factor, when appropriate. In our final version of the iChoose Kidney model, we included the following variables: age (18-80 years), sex (male, female), race (white, black, other), time on dialysis (<6 months, 6-12 months, >12 months), and patient comorbidities (hypertension, diabetes, and/or cardiovascular disease). Over the 3-year follow-up period, 33.3% of dialysis patients and 6.2% of kidney transplant recipients died. The discriminatory ability was moderate (C-statistic for dialysis: 0.70, 95% confidence interval [CI]: 0.69-0.70, and C-statistic for transplant: 0.72, 95% CI: 0.69-0.75). The 3-year observed and predicted mortality estimates were comparable and even more so after we recalibrated the intercepts in 2 of our models (dialysis and deceased donor kidney transplantation). As done in the United States, we developed a Canadian Web site and an iOS application called Dialysis vs. Kidney Transplant- Estimated Survival in Ontario. Missing data in our databases precluded the inclusion of all variables that were in the original iChoose Kidney (ie, patient ethnicity and low albumin). We were unable to perform all preplanned analyses due to the limited sample size. The original iChoose Kidney risk calculator was able to adequately predict mortality in this Canadian (Ontario) cohort of ESKD patients. After minor modifications, the predictive accuracy improved. The Dialysis vs. Kidney Transplant- Estimated Survival in Ontario risk calculator may be a valuable resource to help ESKD patients make an informed decision on pursuing kidney transplantation.


Interventions for attention problems after pediatric traumatic brain injury: what is the evidence?
To gain an understanding of the current state of the evidence for management of attention problems after traumatic brain injury (TBI) in children, determine gaps in the literature, and make recommendations for future research. TYPE: Focused systematic review. PubMed/Medline and PsychINFO databases were searched for relevant articles published in English during the last 20 years. Keywords included "attention" "attention deficit and disruptive behavior disorders," and "brain injuries." Studies were limited to children. Titles were examined first and eliminated based on lack of relevancy to attention problems after brain injury in children. This was followed by an abstract and full text review. Article quality was determined based on the US Preventative Services Task Force recommendations for evidence grading. Four pharmacologic and 10 cognitive therapy intervention studies were identified. These studies varied in level of evidence quality but were primarily nonrandomized or cohort studies. There are studies that demonstrate benefits of varying pharmacologic and cognitive therapies for the management of attention problems after TBI. However, there is a paucity of evidence available to definitively guide management of attention problems after pediatric TBI. Larger randomized, controlled trials and multicenter studies are needed to elucidate optimal treatment strategies in this population.


A crisis of protection and safe passage: violence experienced by migrants/refugees travelling along the Western Balkan corridor to Northern Europe.
Pushed by ongoing conflicts and pulled by the desire for a better life, over one million migrants/refugees transited Balkan countries and arrived in Europe during 2015 and early 2016. To curb this influx, European countries instituted restrictive migration policies often characterized by building of razor-wire border fences and border closures. Among migrants/refugees who received mental health care in Serbia while travelling through Balkan countries to Northern Europe, we assessed the prevalence and patterns of violent events experienced including physical trauma. A mixed methods study among migrants/refugees attending mobile mental health clinics run by Médecins sans Frontières (MSF) between July 2015 and June 2016, in Serbia - a main transit hub to European countries. Clinics were conducted according to MSF guidelines by experienced psychologists who were supported by cultural mediators. The main outcome measures were violent events and associated physical trauma. Of 992 migrants/refugees attending MSF mental health clinics, the majority (72%) were from Syria and Afghanistan and included vulnerable groups (14%) such as unaccompanied minors and pregnant women. The most frequent mental health symptoms/signs were anxiety (29%) and adjustment reactions (26%). Of the 992 migrants/refugees, 270 (27%) had experienced violent events during their journey. Signs of physical trauma due to acts of violence were seen in 223(22%) of the 992 individuals, 144 (65%) being perpetrated by State authorities and involving women (11%) and children (13%). Border closures along the Balkan route were associated with a dramatic decrease in registered migrants/refugee arrivals in Serbia. Conversely, among those that made it across the borders, an increasing linear trend in reported violent events was observed at MSF mental health clinics (X2 for linear trend, P <0 · 001). Qualitative evidence corroborated with quantitative findings. Nearly one-in-three migrants/refugees seen in MSF clinics experienced violent events including physical trauma along their journey. State authorities, including those in European countries were the perpetrators in over half of such events which were associated with border closures. There is "a crisis of protection and safe passage" which needs to change towards one of respect for the principles of international human rights and refugee law.


A clinical study of 57 children with fetal anticonvulsant syndromes.
Anticonvulsants taken in pregnancy are associated with an increased risk of malformations and developmental delay in the children. To evaluate the pattern of abnormalities associated with prenatal anticonvulsant exposure further, we undertook a clinical study of 57 children with fetal anticonvulsant syndromes. Fifty two children were ascertained through the Fetal Anticonvulsant Syndrome Association and five were referred to the Aberdeen Medical Genetics Service. Pregnancy and medical history were obtained through a standardised questionnaire and interview and the children were examined. Thirty four (60%) were exposed in utero to valproate alone, four (7%) to carbamazepine alone, four (7%) to phenytoin alone, and 15 (26%) to more than one anticonvulsant. Forty six (81%) reported behavioural problems, 22 (39%) with hyperactivity or poor concentration of whom four (7%) had a diagnosis of attention deficit and hyperactivity disorder. Thirty four (60%) reported two or more autistic features, of whom four had a diagnosis of autism and two of Asperger's syndrome. Forty four (77%) had learning difficulties, 46 (81%) had speech delay, 34 (60%) had gross motor delay, and 24 (42%) had fine motor delay. Nineteen (33%) had glue ear and 40 (70%) had joint laxity involving all sizes of joints. Of 46 who had formal ophthalmic evaluation, 16 (34%) had myopia. Speech delay, joint laxity, glue ear, and myopia are common in the fetal anticonvulsant syndromes and autistic features and hyperactivity form part of the behavioural phenotype.


Impact of Pre-Pregnancy BMI on B Vitamin and Inflammatory Status in Early Pregnancy: An Observational Cohort Study.
Maternal nutrition and inflammation have been suggested as mediators in the development of various adverse pregnancy outcomes associated with maternal obesity. We have investigated the relation between pre-pregnancy BMI, B vitamin status, and inflammatory markers in a group of healthy pregnant women. Cobalamin, folate, pyridoxal 5'-phosphate, and riboflavin; and the metabolic markers homocysteine, methylmalonic acid, and 3-hydroxykynurenine/xanthurenic acid ratio (HK/XA); and markers of cellular inflammation, neopterin and kynurenine/tryptophan ratio (KTR) were determined in pregnancy week 18 and related to pre-pregnancy body mass index (BMI), in 2797 women from the Norwegian Mother and Child Cohort Study (MoBa). Pre-pregnancy BMI was inversely related to folate, cobalamin, pyridoxal 5'-phosphate (PLP), and riboflavin (p < 0.001), and associated with increased neopterin and KTR levels (p < 0.001). Inflammation seemed to be an independent predictor of low vitamin B6 status, as verified by low PLP and high HK/XA ratio. A high pre-pregnancy BMI is a risk factor for low B vitamin status and increased cellular inflammation. As an optimal micronutrient status is vital for normal fetal development, the observed lower B vitamin levels may contribute to adverse pregnancy outcomes associated with maternal obesity and B vitamin status should be assessed in women with high BMI before they get pregnant.


Evaluation of pre-symptomatic nitisinone treatment on long-term outcomes in Tyrosinemia type 1 patients: a systematic review.
Tyrosinemia type 1 (TYR1) is a rare autosomal recessive disorder of amino acid metabolism that is fatal without treatment. With medication (nitisinone) and dietary restrictions outcomes are improved. We conducted a systematic review to investigate if treatment with nitisinone following screening provides better long-term outcomes than treatment with nitisinone following symptomatic detection. We searched Web of Science, Medline, Pre-Medline, and Embase up to 23rd September 2016 for journal articles comparing clinical outcomes of TYR1 patients receiving earlier versus later nitisinone treatment. Two reviewers independently screened titles and abstracts, assessed full texts, and appraised study quality. Data extraction was performed by a single reviewer and checked by a second. We included seven articles out of 470 unique records identified by our search. The seven articles included four studies (three cohort studies and one cross-sectional study). Study sample sizes ranged from 17 to 148. There is consistent evidence that nitisinone is an effective treatment for TYR1, and some evidence that earlier treatment with nitisinone and dietary restrictions within the first one or 2 months of life is associated with reduced need for liver transplantation, lower rates of renal dysfunction, fewer neurological crises, and fewer, shorter hospital admissions compared to later treatment. However, study quality was moderate to weak, with high risk of confounding and applicability concerns to the screening context. We conducted post hoc analyses to address these issues. Results suggested an association between earlier treatment and fewer liver transplants (earlier treatment: 0% of 10-24 patients; later treatment: 25-60% of 4-15 patients), but no impact on neurological crises. We found no effect of treatment timing on mortality in either the primary or post hoc analyses. Post hoc analyses of other health-related outcomes were not possible because of sample size or reporting. There is some evidence from observational studies that earlier treatment with nitisinone might be beneficial but this is subject to bias. The applicability of our findings to the screening context or clinical practice is limited as not all early-treated patients were identified by screening and late-treated groups included patients born prior to the availability of nitisinone.


Mixed Reality in Visceral Surgery: Development of a Suitable Workflow and Evaluation of Intraoperative Use-cases.
The paper evaluates the application of a mixed reality (MR) headmounted display (HMD) for the visualization of anatomical structures in complex visceral-surgical interventions. A workflow was developed and technical feasibility was evaluated. Medical images are still not seamlessly integrated into surgical interventions and, thus, remain separated from the surgical procedure.Surgeons need to cognitively relate 2-dimensional sectional images to the 3-dimensional (3D) during the actual intervention. MR applications simulate 3D images and reduce the offset between working space and visualization allowing for improved spatial-visual approximation of patient and image. The surgeon's field of vision was superimposed with a 3D-model of the patient's relevant liver structures displayed on a MR-HMD. This set-up was evaluated during open hepatic surgery. A suitable workflow for segmenting image masks and texture mapping of tumors, hepatic artery, portal vein, and the hepatic veins was developed. The 3D model was positioned above the surgical site. Anatomical reassurance was possible simply by looking up. Positioning in the room was stable without drift and minimal jittering. Users reported satisfactory comfort wearing the device without significant impairment of movement. MR technology has a high potential to improve the surgeon's action and perception in open visceral surgery by displaying 3D anatomical models close to the surgical site. Superimposing anatomical structures directly onto the organs within the surgical site remains challenging, as the abdominal organs undergo major deformations due to manipulation, respiratory motion, and the interaction with the surgical instruments during the intervention. A further application scenario would be intraoperative ultrasound examination displaying the image directly next to the transducer. Displays and sensor-technologies as well as biomechanical modeling and object-recognition algorithms will facilitate the application of MR-HMD in surgery in the near future.


Calibration method for multiangle lidar measurements.
A new method based on a two-angle approach is developed to determine the lidar solution constant from scanning elastic lidar data, hence providing a relative calibration for each lidar scan. Once the solution constant is determined, the vertical profiles of atmospheric extinction can be calculated. With this calibration method a minimization technique is used that replaces the linear regression used in a known two-angle approach that requires only local atmospheric homogeneity over a restricted altitude calibration range rather than overall horizontal homogeneity. Lidar signals from at least one pair of elevation angles are used, averaged in time when the system is operated in a permanent two-angle mode, or an arbitrary number of signal pairs is used, when a two-dimensional lidar scan is being processed. The method is tested extensively with synthetic data. The calibration method is a robust tool for determining the solution constant to the lidar equation and for obtaining vertical profiles of atmospheric extinction.


Proliferative neural stem cells have high endogenous ROS levels that regulate self-renewal and neurogenesis in a PI3K/Akt-dependant manner.
The majority of research on reactive oxygen species (ROS) has focused on their cellular toxicities. Stem cells generally have been thought to maintain low levels of ROS as a protection against these processes. However, recent studies suggest that ROS can also play roles as second messengers, activating normal cellular processes. Here, we investigated ROS function in primary brain-derived neural progenitors. Somewhat surprisingly, we found that proliferative, self-renewing multipotent neural progenitors with the phenotypic characteristics of neural stem cells (NSC) maintained a high ROS status and were highly responsive to ROS stimulation. ROS-mediated enhancements in self-renewal and neurogenesis were dependent on PI3K/Akt signaling. Pharmacological or genetic manipulations that diminished cellular ROS levels also interfered with normal NSC and/or multipotent progenitor function both in vitro and in vivo. This study has identified a redox-mediated regulatory mechanism of NSC function that may have significant implications for brain injury, disease, and repair.


Intra-Annual Variation in Responses by Flying Southern Pine Beetles (Coleoptera: Curculionidae: Scolytinae) to Pheromone Component endo-Brevicomin.
The southern pine beetle Dendroctonus frontalis Zimmermann (Coleoptera: Curculionidae: Scolytinae) is attracted to an aggregation pheromone that includes the multifunctional pheromone component endo-brevicomin. The effect of endo-brevicomin on attractive lures varies from strong enhancement to reduction of beetle attraction depending upon release rate, lure component spacing, and proximity of beetle infestations. Anecdotal observations have further suggested that the effects of endo-brevicomin vary during the year. We investigated this possibility under nonoutbreak conditions in southwestern Mississippi where for two-and-a-half years we monitored traps baited with frontalin and the host odor alpha-pinene either (a) alone, or with an endo-brevicomin release device either (b) located directly on the trap, or (c) displaced 6 m away. The endo-brevicomin devices in our tests increased D. frontalis catches during all times of year, and 6 m displacement of the endo-brevicomin release device from the trap did not significantly alter responses except during the spring flight peak when displacement increased catches. Our data suggest that flying D. frontalis have a stronger tendency to avoid the immediate proximity of a release point of endo-brevicomin during their springtime dispersal flight when catches are greatest. Catches of Thanasimus dubius (F.) (Coleoptera: Cleridae), a major predator of D. frontalis, were not altered by endo-brevicomin, and ratios of D. frontalis to T. dubius changed over the course of the year. We discuss the possible effects of intra-annual variation in D. frontalis response to endo-brevicomin both on beetle attack behavior and use of endo-brevicomin as a lure adjuvant in D. frontalis population monitoring.


Modulation of asymmetric cell division as a mechanism to boost CD8+ T cell memory.
Asymmetric partitioning of fate determinants is a mechanism that contributes to T cell differentiation. However, it remains unclear whether the ability of T cells to divide asymmetrically is influenced by their differentiation state, as well as whether enforcing asymmetric cell division (ACD) rates would have an impact on T cell differentiation and memory formation. Using the murine LCMV infection model, we established a correlation between cell stemness and the ability of CD8+ T cells to undergo ACD. Transient mTOR inhibition was proven to increase ACD rates in naïve and memory cells and to install this ability in exhausted CD8+ T cells. Functionally, enforced ACD correlated with increased memory potential, leading to more efficient recall response and viral control upon acute or chronic LCMV infection. Moreover, transient mTOR inhibition also increased ACD rates in human CD8+ T cells. Transcriptional profiling revealed that progenies emerging from enforced ACD exhibited more pronounced early memory signatures, which functionally endowed these cells with better survival in the absence of antigen exposure and more robust homing to secondary lymphoid organs, providing critical access to survival niches. Our data provide important insights into how ACD can improve long-term survival and function of T cells and open new perspectives for vaccination and adoptive T cell transfer therapies.


Antimicrobial biosynthetic potential and genetic diversity of endophytic actinomycetes associated with medicinal plants.
Endophytic actinomycetes are one of the primary groups that share symbiotic relationships with medicinal plants and are key reservoir of biologically active compounds. In this study, six selective medicinal plants were targeted for the first time for endophytic actinomycetes isolation from Gibbon Wild Life Sanctuary, Assam, India, during winter and summer and 76 isolates were obtained. The isolates were found to be prevalent in roots followed by stem and leaves. 16S rRNA gene sequence analysis revealed 16 genera, including rare genera, Verrucosispora, Isoptericola and Kytococcus, which have never been previously reported as endophytic. The genus Streptomyces (66%) was dominant in both seasons. Shannon's diversity index showed that Azadirachta indica (1.49), Rauwolfia serpentina (1.43) and Emblica officinalis (1.24) were relatively good habitat for endophytic actinomycetes. Antimicrobial strains showed prevalence of polyketide synthase (PKS) type-II (85%) followed by PKS type-I (14%) encoded in the genomes. Expression studies showed 12-fold upregulation of PKSII gene in seventh day of incubation for Streptomyces antibioticus (EAAG90). Our results emphasize that the actinomycetes assemblages within plant tissue exhibited biosynthetic systems encoding for important biologically active compounds.


Three-dimensional nanofabrication of polystyrene by focused ion beam.
Focused ion beam micromachining provides a maskless and resistless technique for prototyping of structures from thermoplastic polymers, an example being the production of polystyrene microcantilevers with potential applications as micro/nanoelectromechanical systems sensors and actuators. The applicability of FIB technology is, however, often restricted by the damage created by high energy gallium ion bombardment and local beam heating, which can affect the desired properties and limit the minimum achievable size of the fabricated structure. To investigate the ion-induced damage and determine the limitations of the technique for polymer nanofabrication, we have exposed thin polystyrene film to the ion beam at varying ion doses, ion energies and specimen temperatures. Ion doses ranging from 10(16) to 10(18) ions cm(-2) show significant gallium implantation, redeposition of sputtered material and chemical degradation in the polymer. Raman results show that the local heating in polymer during milling is severe at room temperature, damaging the aromatic carbon bonding (C = C) in particular. These observations are supported by the results of a beam heating model and Monte Carlo simulations. The chemical degradation caused by local beam heating is found to be significantly reduced by cooling the specimen to -25°C during milling. This is consistent with observations that reversible and repeatable thermal actuation of a fabricated polystyrene-platinum microcantilever is only observed when the cantilever is prepared at low temperature milling. Using this cooling approach, polymer structures can be fabricated with dimensions as low as 200 nm and still retain a sufficient volume of material unaffected by the ion beam.


Arrays of stochastic oscillators: Nonlocal coupling, clustering, and wave formation.
We consider an array of units each of which can be in one of three states. Unidirectional transitions between these states are governed by Markovian rate processes. The interactions between units occur through a dependence of the transition rates of a unit on the states of the units with which it interacts. This coupling is nonlocal, that is, it is neither an all-to-all interaction (referred to as global coupling), nor is it a nearest neighbor interaction (referred to as local coupling). The coupling is chosen so as to disfavor the crowding of interacting units in the same state. As a result, there is no global synchronization. Instead, the resultant spatiotemporal configuration is one of clusters that move at a constant speed and that can be interpreted as traveling waves. We develop a mean field theory to describe the cluster formation and analyze this model analytically. The predictions of the model are compared favorably with the results obtained by direct numerical simulations.


Minimally Invasive Sacroiliac Joint Fusion: A Lateral Approach Using Triangular Titanium Implants and Navigation.
Minimally invasive sacroiliac (SI) joint fusion is indicated for low back pain from the SI joint that is due to degenerative sacroiliitis and/or sacroiliac joint disruption. This technique is safe and effective in relieving pain uncontrolled by nonoperative management1-4. There is some controversy, but there continues to be increasing evidence of effectiveness. This procedure is performed, with the patient under general anesthesia and in the prone position, using fluoroscopy or 3-dimensional (3D) navigation such as cone-beam computed tomographic (CT) imaging. After navigation setup, a navigated probe is used to approximate the desired location of each implant and trajectory. These positions are marked on the skin, and the skin is incised. A 3 to 5-cm lateral incision is made. The gluteal fascia is bluntly dissected to the outer table of the ilium. A guide pin is passed across the SI joint and into the center of the sacrum lateral to the neural foramina, which is confirmed with imaging. This is then drilled and broached. Triangular titanium rods are placed. Typically, 3 implants are placed, 2 in S1 and 1 in S2. Multiplanar postplacement imaging of the pelvis is obtained. The wound is irrigated and closed in layers. Nonsurgical alternatives have been reported to include pharmacological therapies, such as nonsteroidal anti-inflammatory drugs, therapeutic SI joint blocks5, and physical therapy, such as core stabilization, orthotics (SI belts), and radiofrequency ablation1,2,6-8. The surgical alternative is an open anterior or posterior approach with SI joint arthrodesis. The anterior approach differs by the resection of the SI joint cartilage, the use of a plate or screws across the joint for stabilization, and the packing of bone graft to facilitate fusion9. These are more morbid and have a much longer recovery. Conservative management for SI joint pain is inadequate for all patients. Having 3 of 5 positive physical examination maneuvers7, having confirmatory diagnostic block(s)10, and ruling out the hip or spine as the pain generator provide a success rate of >80%. These patients have early and sustained clinically important and significantly improved outcomes across varying measures compared with conservative treatment1-4,11,12. Patients can expect to experience decreased pain, reduced disability, increased daily function, and improved quality of life soon after the procedure is performed. These patients typically have an improvement of ≥50% in the Oswestry Disability Index score and a clinically significant decrease in visual analog pain scores13. The procedure appears durable through at least 5 years14. Complete pain relief is rare, but clinically important improvement is typical. Proper setup of the navigation system or fluoroscopy is needed to ensure accurate starting points.For 3D navigation, use a reference pin in the contralateral posterior superior iliac spine.Although navigation is used, radiographic images are made periodically to confirm proper placement of guide pins and implants. Images provide the greatest benefit when establishing navigation, after guide-pin placement when an outlet view allows for evaluation of pin depth, and after implant placement to confirm proper placement.Blood loss is generally low, but care should be taken to avoid vascular injury. Although rare, improper placement has led to injury of the superior gluteal artery15 and iliac artery16. This can be avoided by staying in bone.Proper placement of the implant is imperative in this procedure. There is the potential for nerve injury with improper placement of the implant: an L5 nerve injury if the implant is too ventral or an S1 or S2 nerve injury if the implant is too deep and into the foramen. Revision surgery is commonly due to nerve root impingement and/or malpositioning.Preoperative 3D imaging is indicated when it is necessary to rule out differential diagnoses that mimic SI joint pain. This enables the surgeon to rule out intrapelvic pathology, assess sacral bone density17, and identify dysmorphic sacra or transitional vertebrae.


The effect of dopamine on the comprehension of spectrally-shifted noise-vocoded speech: a pilot study.
Objectives: Cochlear implantation has proven beneficial in restoring hearing. However, success is variable, and there is a need for a simple post-implantation therapy that could significantly increase implantation success. Dopamine has a general role in learning and in assigning value to environmental stimuli. We tested the effect of dopamine in the comprehension of spectrally-shifted noise-vocoded (SSNV) speech, which simulates, in hearing individuals, the signal delivered by a cochlear implant (CI).Design and study sample: Thirty-five participants (age = 38.0 ± 10.1 SD) recruited from the general population were divided into three groups. We tested SSNV speech comprehension in two experimental sessions. In one session, a metabolic precursor of dopamine (L-DOPA) was administered to participants in two of the groups; a placebo was administered in the other session.Results: A single dose of L-DOPA interacted with training to improve perception of SSNV speech, but did not significantly accelerate learning.Conclusions: These findings are a first step in exploring the use of dopamine to enhance speech understanding in CI patients. Replications of these results using SSNV in individuals with normal hearing, and also in CI users, are needed to determine whether these effects can translate into benefits in everyday language comprehension.


Expression and regulation of Nkd-1, an intracellular component of Wnt signalling pathway in the chick embryo.
The Wnt family of secreted signalling molecules control a wide range of developmental processes in all metazoans. The intracellular response to Wnt signalling depends on the choice of signalling cascade activated in the responding cell. Cells can activate either the canonical pathway that modulates gene expression to control cellular differentiation and proliferation, or the non-canonical pathway that controls cell polarity and movement. Recent work has identified the protein Naked Cuticle to act as an intracellular switch to promote the non-canonical pathway at the expense of the canonical pathway. We have cloned chick Naked Cuticle-1 (cNkd-1) and show that it is expressed in a dynamic manner during early embryogenesis. We show that it is expressed in the somites and in particular regions where cells are undergoing movement. Lastly, we show that the expression of cNkd-1 is regulated by Wnt expression originating from the neural tube. This study provides evidence that non-canonical Wnt signalling plays a part in somite development.


Dissection of overlapping functions within the adenovirus type 5 E1A gene.
The adenovirus E1A gene encodes multiple, overlapping mRNAs whose products function both to regulate mRNA levels during the lytic cycle of the virus and to facilitate transformation of non-permissive cells. To assign specific functions to the E1A gene products, two adenovirus type 5 variants have been constructed. Mutants dl347 and 348 carry cloned segments corresponding to the E1A 12 and 13S mRNAs, respectively, in place of the normal E1A gene. The variants produced the predicted E1A-specific mRNAs and polypeptides. Both viruses grew efficiently in HeLa cells. Although the 13S mRNA products were more effective, the products of either mRNA species could stimulate the accumulation of mRNAs from additional transcription units. Both viruses could induce the formation of transformed foci in an established rat cell line. Neither virus could transform primary rat embryo cells at normal frequency, and the dl347 foci which were induced were incomplete or abortive transformants. Thus, functions encoded by both 12S and 13S mRNAs are required for efficient and complete transformation of primary rat cells.


Systolic and diastolic heart failure in the community.
The heart failure (HF) syndrome is heterogeneous. While it can be defined by ejection fraction (EF) and diastolic function, data on the characteristics of HF in the community are scarce, as most studies are retrospective, hospital-based, and rely on clinically indicated tests. Further, diastolic function is seldom systematically assessed based on standardized techniques. To prospectively measure EF, diastolic function, and brain natriuretic peptide (BNP) in community residents with HF. Echocardiographic measures of EF and diastolic function, measurement of blood levels of BNP, and 6-month mortality. Olmsted County residents with incident or prevalent HF (inpatients or outpatients) between September 10, 2003, and October 27, 2005, were prospectively recruited to undergo assessment of EF and diastolic function by echocardiography and measurement of BNP. A total of 556 study participants underwent echocardiography at HF diagnosis. Preserved EF (> or =50%) was present in 308 (55%) and was associated with older age, female sex, and no history of myocardial infarction (all P<.001). Isolated diastolic dysfunction (diastolic dysfunction with preserved EF) was present in 242 (44%) patients. For patients with reduced EF, moderate or severe diastolic dysfunction was more common than when EF was preserved (odds ratio, 1.67; 95% confidence interval [CI], 1.11-2.51; P = .01). Both low EF and diastolic dysfunction were independently related to higher levels of BNP. At 6 months, mortality was 16% for both preserved and reduced EF (age- and sex-adjusted hazard ratio, 0.85; 95% CI, 0.61-1.19; P = .33 for preserved vs reduced EF). In the community, more than half of patients with HF have preserved EF, and isolated diastolic dysfunction is present in more than 40% of cases. Ejection fraction and diastolic dysfunction are independently related to higher levels of BNP. Heart failure with preserved EF is associated with a high mortality rate, comparable to that of patients with reduced EF.


Principles, implementation, and application of biology-oriented synthesis (BIOS).
Biology-oriented synthesis (BIOS) represents an alternative approach for the generation of compound collections for biological applications. In BIOS, biologically relevant and prevalidated scaffold structures, such as core structures of natural products or known drugs, are employed as scaffolds for the generation of compound collections with focused diversity. In this review, we discuss the underlying concept of the BIOS approach, and its practical implementation in library design and synthesis. To highlight its relevance for chemical biology applications, we finally present examples in which compound collections generated under the BIOS principle have been used to elucidate biological questions.


Promoting smoking cessation in Bangladeshi and Pakistani male adults: design of a pilot cluster randomised controlled trial of trained community smoking cessation workers.
The prevalence of smoking is higher among Pakistani and Bangladeshi males than among the general population. Smokers who receive behavioural support and medication quadruple their chances of stopping smoking, but evidence suggests that these populations do not use National Health Service run stop smoking clinics as frequently as would be expected given their high prevalence of smoking. This study aims to tackle some of the main barriers to use of stop smoking services and adherence to treatment programmes by redesigning service delivery to be more acceptable to these adult male populations. The study compares the effectiveness of trained Pakistani and Bangladeshi smoking cessation workers operating in an outreach capacity ('clinic + outreach') with standard care ('clinic only') to improve access to and success of National Health Service smoking cessation services. This is a pilot cluster randomised controlled trial based in Birmingham, UK. Super output areas of Birmingham will be identified in which more than 10% of the population are of Pakistani and/or Bangladeshi origin. From these areas, 'natural geographical communities' will be identified. Sixteen aggregated agglomerations of super output areas will be identified, separating areas from each other using buffer regions in order to reduce potential contamination. These natural communities will be randomised to 'clinic + outreach' (intervention) or 'clinic only' (control) arms. The use of stop smoking services and the numbers of people quitting smoking (defined as prolonged self-reported abstinence at four weeks, three months and six months) will be assessed in each area. In addition, we will assess the impact of the intervention on adherence to smoking cessation treatments and patient satisfaction.


Declining physical activity and the socio-cultural context of the geography of industrial restructuring: a novel conceptual framework.
At the population level, the prevalence of physical activity has declined considerably in many developed countries in recent decades. There is some evidence that areas exhibiting the lowest activity levels are those which have undergone a particularly strong transition away from employment in physically demanding occupations. We propose that processes of deindustrialization may be causally linked to unexplained geographical disparities in levels of physical activity. While the sociocultural correlates of physical activity have been well studied, and prior conceptual frameworks have been developed to explain more general patterns of activity, none have explicitly attempted to identify the components of industrial change that may impact physical activity. In this work we review the current literature on sociocultural correlates of health behaviors before using a case study centered on the United Kingdom to present a novel framework that links industrial change to declining levels of physical activity. We developed a comprehensive model linking sociocultural correlates of physical activity to processes associated with industrial restructuring and discuss implication for policy and practice. A better understanding of sociocultural processes may help to ameliorate adverse health consequences of employment decline in communities that have experienced substantial losses of manual employment.


Switching of EBV cycles between latent and lytic states.
The EBV is a human gamma-herpesvirus that is associated with a variety of neoplasms. Upon primary infection, it transiently runs a short lytic program and then predominantly establishes latent infection. Only a small percentage of infected cells switch from the latent stage into the lytic cycle and produce progeny viruses. Although EBV in cancer cells is mostly in the latent state, the lytic cycle of the virus is also expected to play a pivotal role in development and maintenance of tumors because of its association with secretion of cytokines or growth factors. Moreover, if efficient artificial induction of lytic replication could somehow be achieved, development of oncolytic therapy for EBV-positive cancers would be conceivable. Thus, understanding the switching mechanism is of essential importance. Reactivation of the virus from latency is dependent on expression of the viral BZLF1 protein. The BZLF1 promoter (Zp) normally exhibits only low basal activity but is activated in response to chemical or biological inducers, such as 12-O-tetradecanoylphorbol-13-acetate, calcium ionophore, or histone deacetylase inhibitors. Transcription from the Zp is regulated by the balance between active and suppressive epigenetic histone marks, including histone acetylation, histone H3 Lysine 4 trimethylation and histone H3 lysine 27 trimethylation, being mediated by multiple transcription factors, such as myocyte enhancer factor 2, specificity protein 1, and zinc finger E-box binding homeobox. This review will focus on such molecular mechanisms by which the EBV lytic switch is controlled and discuss the physiological significance of the switching for oncogenesis.


Validity and Repeatability of Single-Sensor Loadsol Insoles during Landing.
Clinically feasible methods for quantifying landing kinetics could help identify patients at risk for secondary anterior cruciate ligament injuries. The purpose of this study was to evaluate the validity and between-day repeatability of the loadsol insole during a single-hop and bilateral stop-jump. Thirty healthy recreational athletes completed seven single-hops and seven stop-jumps while simultaneous loadsol (100 Hz) and force plate (1920 Hz) measurements were recorded. Peak impact force, loading rate, and impulse were computed for the dominant limb, and limb symmetry was calculated between limbs for each measure. All outcomes were compared between the loadsol and force plate using intraclass correlation coefficients (ICC) and Bland⁻Altman plots. Fifteen participants completed a second day of testing to assess between-day repeatability of the loadsol. Finally, an additional 14 participants completed the first day of testing only to assess the validity of the newest generation loadsol, which sampled at 200 Hz. At 100 Hz, validity ICC results were moderate to excellent (0.686⁻0.982), and repeatability ICC results were moderate to excellent (0.616⁻0.928). The 200 Hz loadsol demonstrated improved validity ICC (0.765⁻0.987). Bland⁻Altman plots revealed that the loadsol underestimated load measures. However, this bias was not observed for symmetry outcomes. The loadsol device is a valid and repeatable tool for evaluating kinetics during landing.


Promoting effects on reproduction increase population vulnerability of Daphnia magna.
Environmental risk assessment of chemicals is based on single species tests at the individual level with single compounds. However, the protection goal is the sustainability of a population, which faces several natural stressors and mixtures of chemicals in the environment. Therefore, experiments were undertaken to quantify the combined effects of chemicals with different modes of action on Daphnia magna populations. Populations continuously exposed to dispersogen A and at abundance equilibrium were treated with a 2-d pulse of p353-nonylphenol. In previous studies, dispersogen A was shown to act as a natural info-chemical, promoting the reproduction of daphnids (higher offspring quantity) coupled with reduced offspring fitness, whereas nonylphenol in pulsed-exposure caused size-selective mortality. Dispersogen A caused accelerated population growth to maximum abundance, shifted the population structure towards smaller individuals, and increased the population sensitivity to nonylphenol. The authors showed that a positive effect observed at the individual level can be transposed to a negative effect when monitored at the population level. So far, positive effects are not addressed in environmental risk assessment, and even in higher-tier testing, population structure is not quantified. Both factors indicate a potential mismatch between protection aim and risk assessment practice.


A comparison of polysomnography and the WatchPAT in the diagnosis of obstructive sleep apnea.
Our goal was to validate the WatchPAT in the diagnosis of obstructive sleep apnea. We conducted a prospective, blinded, nonrandomized clinical trial. Patients with suspected obstructive sleep apnea scheduled for an overnight level I polysomnogram were offered enrollment in a study to compare the WatchPAT (Itamar Ltd, Israel) device with polysomnography. Patients wore the WatchPAT device simultaneously while undergoing polysomnography during evaluation in the sleep lab. Thirty-seven patients participated in the study. They had a mean age of 50.1 years (range, 31-73 years) and mean body mass index of 34.6 kg/m(2) (range, 21.2-46.8 kg/m(2)). There was high correlation between the polysomnogram and WatchPAT apnea-hypopnea index (r = 0.9288; 95% confidence interval = 0.8579-0.9650, P < 0.0001). The lowest oxygen saturation also showed high correlation (r = 0.989; 95% confidence interval = 0.9773-0.9947, P < 0.0001). The overall polysomnogram and WatchPAT sleep times revealed a correlation of r = 0.5815 (P = 0.005). The WatchPAT showed a high correlation with the polysomnogram in apnea-hypopnea index, lowest oxygen saturation, and sleep time. It's use as a reliable tool in the diagnosis of Obstructive Sleep Apnea.


Honey and honey-based sugars partially affect reproductive trade-offs in parasitoids exhibiting different life-history and reproductive strategies.
Adult dietary regimes in insects may affect egg production, fecundity and ultimately fitness. This is especially relevant in parasitoid wasps where many species serve as important biological control agents of agricultural pests. Here, we tested the effect of honey and sugar diets on daily fecundity schedules, lifetime reproductive success and longevity in four species of parasitoid wasps when reared on their respective hosts. The parasitoid species were selected based on dichotomies in host usage strategies and reproductive traits. Gelis agilis and G. areator are idiobiont ecto-parasitoids that develop in non-growing hosts, feed on protein-rich host fluids to maximize reproduction as adults and produce small numbers of large eggs. Meteorus pulchricornis and Microplitis mediator are koinobiont endoparasitoids that develop inside the bodies of growing hosts, do not host-feed, and produce greater numbers of small eggs. Parasitoids were reared on diets of either pure honey (containing trace amounts of proteins), heated honey (with denatured proteins) and a honey-mimic containing sugars only. We hypothesized that the benefits of proteins in honey would enhance reproduction in the ectoparasitoids due to their high metabolic investment per egg, but not in the koinobionts. Pure honey diet resulted in higher lifetime fecundity in G. agilis compared with the honey-mimic, whereas in both koinobionts, reproductive success did not vary significantly with diet. Longevity was less affected by diet in all of the parasitoids, although there were variable trade-offs between host access and longevity in the four species. We argue that there are both trait-based and association-specific effects of supplementary nutrients in honey on reproductive investment and success in parasitoid wasps.


Climate change and health in Israel: adaptation policies for extreme weather events.
Climatic changes have increased the world-wide frequency of extreme weather events such as heat waves, cold spells, floods, storms and droughts. These extreme events potentially affect the health status of millions of people, increasing disease and death. Since mitigation of climate change is a long and complex process, emphasis has recently been placed on the measures required for adaptation. Although the principles underlying these measures are universal, preparedness plans and policies need to be tailored to local conditions. In this paper, we conducted a review of the literature on the possible health consequences of extreme weather events in Israel, where the conditions are characteristic of the Mediterranean region. Strong evidence indicates that the frequency and duration of several types of extreme weather events are increasing in the Mediterranean Basin, including Israel. We examined the public health policy implications for adaptation to climate change in the region, and proposed public health adaptation policy options. Preparedness for the public health impact of increased extreme weather events is still relatively limited and clear public health policies are urgently needed. These include improved early warning and monitoring systems, preparedness of the health system, educational programs and the living environment. Regional collaboration should be a priority.


Lesson Learned from Peer Volunteers in a Peer-Led Pain Management Program among Nursing Home Residents.
Chronic pain is common among older adults and is associated with adverse physical and psychological outcomes. Given the burden of pain and limited healthcare resources, devising innovative and cost-effective ways of managing chronic pain is of high priority. The aim of this paper is to explore the experiences and perceptions of peer volunteers (PVs) in a peer-led pain management program among nursing home residents in Hong Kong. Forty-six PVs were recruited and trained to lead a pain management program (PAP). The PAP consisted of one 1 hour session per week for 12 weeks. It included 20 min of physical exercises performed under the supervision of PVs, followed by 30 min of pain management education, including information on pain situations, the impacts of pain, the use of drugs and non-drug strategies for pain management, demonstrations, and return demonstrations of various non-drug pain management techniques. Quantitative data were collected from questionnaires (demographics, pain situation, and pain knowledge) for all PVs. Qualitative data (PVs' experiences in leading the PAP, their perceived benefits, barriers encountered, and recommendations for improving the PAP) were collected at week 12 (upon completion of the PAP). Data were analyzed using the Statistical Package for Social Sciences and content analysis for qualitative data. A total of 46 PVs were recruited (34 females, 74%), with a mean ± SD age of 61.0 ± 5.1 years. Thirty-one of them reported having chronic pain. Before the training, their self-rated pain knowledge was 40.0 ± 20.5 (maximum 100 points) while their actual pain knowledge score was 86.1 ± 10.6 (maximum 100 points). The PVs reported an improvement in their knowledge and skills after leading PAPs. No PVs reported having received any negative comments about their role in leading the PAP but mentioned that they had received feedback on how to improve the program. This study provides further evidence that peer-led pain management programs are feasible and can lead to positive experiences for the PVs. Peer support models are coming into wide use because they show promise in helping patients to manage chronic conditions. Peer volunteers will become important resources in elderly care. The barriers that were identified may lead to improvements in the design and planning of future PAPs.


Processing of the VP1/2A junction is not necessary for production of foot-and-mouth disease virus empty capsids and infectious viruses: characterization of "self-tagged" particles.
The foot-and-mouth disease virus (FMDV) capsid protein precursor, P1-2A, is cleaved by 3C(pro) to generate VP0, VP3, VP1, and the peptide 2A. The capsid proteins self-assemble into empty capsid particles or viruses which do not contain 2A. In a cell culture-adapted strain of FMDV (O1 Manisa [Lindholm]), three different amino acid substitutions (E83K, S134C, and K210E) were identified within the VP1 region of the P1-2A precursor compared to the field strain (wild type [wt]). Expression of the O1 Manisa P1-2A (wt or with the S134C substitution in VP1) plus 3C(pro), using a transient expression system, resulted in efficient capsid protein production and self-assembly of empty capsid particles. Removal of the 2A peptide from the capsid protein precursor had no effect on capsid protein processing or particle assembly. However, modification of E83K alone abrogated particle assembly with no apparent effect on protein processing. Interestingly, the K210E substitution, close to the VP1/2A junction, completely blocked processing by 3C(pro) at this cleavage site, but efficient assembly of "self-tagged" empty capsid particles, containing the uncleaved VP1-2A, was observed. These self-tagged particles behaved like the unmodified empty capsids in antigen enzyme-linked immunosorbent assays and integrin receptor binding assays. Furthermore, mutant viruses with uncleaved VP1-2A could be rescued in cells from full-length FMDV RNA transcripts encoding the K210E substitution in VP1. Thus, cleavage of the VP1/2A junction is not essential for virus viability. The production of such engineered self-tagged empty capsid particles may facilitate their purification for use as diagnostic reagents and vaccines.


Whole-tree sap flow is substantially diminished by leaf herbivory.
Ecohydrological models consider the relationship between tree size and structure (especially leaf area index) and water use but generally treat herbivory as a source of unwanted noise in the data. Little is known of how insect damage to leaves influences whole-plant water use in trees. Water use is driven by environmental demand and the total leaf area through which transpiration can occur, but the effects of insects are expected to be complex. Different kinds of insects could have different effects; for example, chewing insects reduce leaf area, whereas sucking and tissue mining insects reduce leaf function without reducing area. Further, plants respond to herbivory in a range of ways, such as by altering leaf production or abscising leaves. We examined the effect of insects on Eucalyptus blakelyi in a woodland near Canberra, Australia, using sap flow velocity as a measure of whole-plant water use. We applied insecticide to 16 trees matched to an untreated control group. After 6 months, we examined the effects on sap flow velocity and crown condition. There was a general increase in sap flow velocity as trees produced leaves over the growing season, but the increase in sap flow for trees without insecticide protection was half that of the protected trees (increase: 4.4 vs. 9.0 cm/h, respectively). This dramatic effect on sap flow was consistent with effects on crown condition. Unprotected trees had 20% less leaf mass per unit stem in the crown. In addition, unprotected trees had a 20% greater loss of leaf functional area from necrosis. It should be noted that these effects were detected in a year in which there was not an outbreak of the psyllids (Homoptera) that commonly cause severe leaf damage to this tree species. It is predicted that the effect in a psyllid outbreak year would be even more substantial. This result underscores the significant impact that insect herbivores can have on an ecological process of significance to the ecosystem, namely, the movement of water from the soil to the atmosphere.


Genetic and physiological studies of the CiaH-CiaR two-component signal-transducing system involved in cefotaxime resistance and competence of Streptococcus pneumoniae.
A mutation in the ciaH gene of Streptococcus pneumoniae induces cefotaxime resistance and transformation deficiency. ciaH encodes a putative sensor protein that belongs to the family of signal-transducing histidine kinases. This gene is adjacent to ciaR, which encodes a DNA-binding protein involved in the regulation of genes responding to environmental signals sensed by the histidine kinase. The authors have characterized a mutation that induces reversion of both cefotaxime resistance and transformation deficiency. It is a T/A deletion in the ciaR gene resulting in the synthesis of a truncated protein containing only 125 amino acids instead of 224. The ciaH mutation requires a functional CiaR protein for expression. Northern blot analysis, using ciaR-ciaH as a probe, revealed one mRNA from the wild-type strain, indicating that the two genes constitute an operon. Comparisons of Northern blots show that the operon is constitutively activated in the strain carrying only the ciaH mutation. In the wild-type strain the activation occurs when the Ca2+ concentration is very low, demonstrating that Ca2+ is the environmental signal. The pleiotropic effects caused by the ciaH mutation include sensitivity to antibiotics and toxins, the ability to form protoplasts and the susceptibility to lysis with deoxycholate. Null-mutants were constructed in both genes and the particular features of the ciaR null mutant determined. It is able to grow in choline-deprived medium, and competence development occurs in a phosphate-deprived competence medium (CH-maleate), suggesting that the CiaH-CiaR system regulates several pathways, including teiochoic acid synthesis.


Elevated serum dehydroepiandrosterone sulfate levels in practitioners of the Transcendental Meditation (TM) and TM-Sidhi programs.
Serum dehydroepiandrosterone sulfate (DHEA-S) levels were measured in 270 men and 153 women who were experienced practitioners of the Transcendental Meditation (TM) and TM-Sidhi programs, mental techniques practiced twice daily, sitting quietly with the eyes closed. These were compared according to sex and 5-year age grouping to 799 male and 453 female nonmeditators. The mean DHEA-S levels in the TM group were higher in all 11 of the age groups measured in women and in 6 of 7 5-year age groups over 40 in men. There were no systematic differences in younger men. Simple regression using TM-group data revealed that this effect was independent of diet, body mass index, and exercise. The mean TM-group levels measured in all women and in the older men were generally comparable to those of nonmeditator groups 5 to 10 years younger. These findings suggest that some characteristics of TM practitioners are modifying the age-related deterioration in DHEA-S secretion by the adrenal cortex.