Learning support strategies for learners with neurodevelopmental disorders: Perspectives of recently qualified teachers.
Inclusive education envisages the improvement of the quality of education for all learners. This further implies that schools must adjust all systems of teaching and learning to accommodate all learners regardless of their diverse needs. The reduction of educational inequalities through inclusive practices is aimed at supporting the accomplishment of academic outcomes for all. Learners presenting with neurodevelopmental disorders (NDDs) place specific requirements on teachers, particularly when they find themselves in mainstream classrooms. This study focused on the learning support strategies used by recently qualified teachers in accommodating learners with NDDs in mainstream classrooms in the Gauteng province of South Africa. A qualitative approach was used to explore the support strategies used by recently qualified teachers in mainstream classrooms when dealing with learners with NDDs. Purposive sampling was used to select six recently qualified teachers from different mainstream classroom. Data were collected using semi-structured interviews, observations and critical incident reports. The findings revealed that teachers employ a variety of support strategies such as cooperative learning, peer learning, ability grouping, extensive visual aids and curriculum differentiation in an attempt to support learners. The support provided by the teachers was evident in their performance as learners with NDD were able to learn and understand the lessons irrespective for their barrier to learning. Contrary to literature findings that teachers do not support learners with diverse needs because of lack of skills, training and knowledge, this study revealed that recently qualified teachers employ a variety of support strategies to support learners with NDDs. However, it appeared that these support strategies were rather general teaching and learning strategies. More support strategies should be applied to help learners with NDD in the mainstream classroom.


Use of Scandinavian moist smokeless tobacco (snus) and the risk of atrial fibrillation.
Snus is a smokeless tobacco product, widely used among Swedish men and increasingly so elsewhere. There is debate as to whether snus is an acceptable "harm-reduction" tobacco product. Since snus use delivers a dose of nicotine equivalent to cigarettes, and has been implicated in cardiac arrhythmia because of associations with sudden cardiovascular death, a relation with atrial fibrillation is plausible and important to investigate. To assess the relation between use of snus and risk of atrial fibrillation, we carried out a pooled analysis of 7 prospective Swedish cohort studies. In total, 274,882 men, recruited between 1978 and 2004, were followed via the National Patient Register for atrial fibrillation. Primary analyses were restricted to 127,907 never-smokers. Relative risks were estimated using Cox proportional hazard regression. The prevalence of snus use was 25% among never-smokers. During follow-up, 3,069 cases of atrial fibrillation were identified. The pooled relative risk of atrial fibrillation was 1.07 (95% confidence interval = 0.97-1.19) in current snus users, compared with nonusers. Findings from this large national pooling project indicate that snus use is unlikely to confer any important increase in risk of atrial fibrillation.


The Residential Long-Term Care Role in Health Care Transitions.
The objective of the current study is to describe the activities long-term care facilities are undertaking to reduce hospital admissions and readmissions by working to improve health care transitions. The data were collected via an online survey from 888 nursing facilities (NFs) and 527 residential care facilities (RCFs) that completed the care integration module of the Ohio Biennial Survey of Long-Term Care. Questions focused on partnerships, current work, type of care model, and perceived barriers to reducing hospital readmissions. More than nine in 10 (93.1%) of NFs and 63.6% of RCFs reported being engaged in a program to reduce hospital admissions/readmissions. Evidence-based care models were utilized by two thirds of NFs and one third of RCFs. Financial barriers were the most frequently cited challenges faced by facilities. Long-term care settings are increasingly becoming transitional care stops for short-term stay residents. Ensuring that facilities are well versed in current transition research and practice is critical to improve system outcomes.


Heterogeneous landscapes promote population stability.
Habitat heterogeneity is often suggested as being important for the stability of populations, and promoted as a means to aid the conservation of species, but the evidence for such an assumption is poor. Here we show that heterogeneous landscapes that contain a variety of suitable habitat types are associated with more stable population dynamics for 35 British butterfly species from 166 sites. In addition, topographic heterogeneity may also promote stability. Our results were robust to different measures of population variability, differences in mean abundance among sites, and to the spatial scale (radius 1-5 km around the centres of sites) at which landscapes were analysed. Responses to landscape heterogeneity differed among species; for more mobile 'wider-countryside' species, habitat heterogeneity at larger landscape scales had the strongest effect on population dynamics. We suggest that heterogeneous landscapes offer a greater range of resources and microclimates, which can buffer populations against climatic variation and generate more stable population dynamics.


School-based early childhood education and age-28 well-being: effects by timing, dosage, and subgroups.
Advances in understanding the effects of early education have benefited public policy and developmental science. Although preschool has demonstrated positive effects on life-course outcomes, limitations in knowledge on program scale, subgroup differences, and dosage levels have hindered understanding. We report the effects of the Child-Parent Center Education Program on indicators of well-being up to 25 years later for more than 1400 participants. This established, publicly funded intervention begins in preschool and provides up to 6 years of service in inner-city Chicago schools. Relative to the comparison group receiving the usual services, program participation was independently linked to higher educational attainment, income, socioeconomic status (SES), and health insurance coverage, as well as lower rates of justice-system involvement and substance abuse. Evidence of enduring effects was strongest for preschool, especially for males and children of high school dropouts. The positive influence of four or more years of service was limited primarily to education and SES. Dosage within program components was mostly unrelated to outcomes. Findings demonstrate support for the enduring effects of sustained school-based early education to the end of the third decade of life.


Similar and yet so different: cash-for-care in six European countries' long-term care policies.
In response to increasing care needs, the reform or development of long-term care (LTC) systems has become a prominent policy issue in all European countries. Cash-for-care schemes-allowances instead of services provided to dependents-represent a key policy aimed at ensuring choice, fostering family care, developing care markets, and containing costs. A detailed analysis of policy documents and regulations, together with a systematic review of existing studies, was used to investigate the differences among six European countries (Austria, France, Germany, Italy, the Netherlands, and Sweden). The rationale and evolution of their various cash-for-care schemes within the framework of their LTC systems also were explored. While most of the literature present cash-for-care schemes as a common trend in the reforms that began in the 1990s and often treat them separately from the overarching LTC policies, this article argues that the policy context, timing, and specific regulation of the new schemes have created different visions of care and care work that in turn have given rise to distinct LTC configurations. A new typology of long-term care configurations is proposed based on the inclusiveness of the system, the role of cash-for-care schemes and their specific regulations, as well as the views of informal care and the care work that they require.


An analysis of mortality in the grower/finisher phase of swine production in the United States.
Over a 6-month period, the mean mortality risk (based on 393 operations participating in the United States National Animal Health Monitoring System 1995 National Swine Study, and representing operations with > or = 300 market hogs in 16 states), was 2.3 +/- 0.2% in the grower/finisher production phase (where figures after the +/- represent the standard error of the estimate). Mortality > or = 4% was experienced by 13.5 +/- 2.9% of grower/finisher operations, while 63.6 +/- 5.3% had < or = 2% mortality. To identify factors associated with > or = 4% mortality, stepwise logistic regression [Statistical Analysis Systems, 1989. SAS/STAT User's Guide, Version 6, 4th edn, Vol. 2. SAS Institute, Cary, NC, 794 pp.] was performed twice: once using operations with all mortality rates, and again excluding operations with between 2% and 4% mortality. Final models were run with SUDAAN [Shah, B.V., Barnwell, B.G., Bieler, G.S., 1996. SUDAAN User's Manual, Version 6.40, 2nd edn. Research Triangle Institute, Research Triangle Park, NC, 492 pp.] to take the sample design into account. In addition, SAS and SUDAAN logistic regression models were developed to analyze factors associated with > 2.3% mortality among grower/finisher pigs. Mean weaning age < or = 28 days entered all models as being associated with increased mortality in the grower/finisher unit. Not obtaining all grower/finisher pigs from farrowing units belonging to the operation was associated with > or = 4% mortality among grower/finisher swine. Not typically giving grower/finisher pigs antibiotics or other agents as disease-preventives or growth-promotants in the feed or water, and ranking producer organizations as very or extremely important sources of antibiotic information were associated with < or = 2.3% mortality in the grower/finisher phase.


Estimation of dry deposition of atmospheric mercury in Nevada by direct and indirect methods.
Atmospheric models and limited measurements indicate that dry deposition of atmospheric mercury is an important process by which mercury is input to ecosystems. To begin to fill the measurement data gap, multiple methods were used simultaneously during seasonal campaigns conducted in 2005 and 2006 to estimate dry deposition of atmospheric mercury at two Mercury Deposition Network (MDN) sites in rural Nevada and in Reno, Nevada. Gaseous elemental mercury (Hg0), reactive gaseous mercury (RGM), and particulate-bound mercury (Hgp) concentrations were measured using Tekran 2537A/1130/ 1135 systems. These speciated measurements were combined with on-site meteorological measurements to estimate depositional fluxes of RGM and Hgp using dry deposition models. Modeled fluxes were compared with more direct measurements obtained using polysulfone cation-exchange membranes and foliar surfaces. Dynamic flux chambers were used to measure soil mercury exchange. RGM concentrations were higher during warmer months at all sites, leading to seasonal variation in the modeled importance of RGM as a component of total depositional load. The ratio of dry to wet deposition was between 10 and 90%, and varied with season and with the methods used for dry deposition approximations. This work illustrates the variability of mercury dry deposition with location and time and highlights the need for direct dry deposition measurements.


A membrane protein, EzrA, regulates assembly dynamics of FtsZ by interacting with the C-terminal tail of FtsZ.
FtsZ polymerizes to form a dynamic ring structure called the Z-ring at the midcell of bacteria. EzrA, a membrane protein, has been shown to prevent the formation of aberrant Z-rings in the low GC Gram-positive bacteria by inhibiting FtsZ assembly. In this study, we show that Bacillus subtilis (B. subtilis) EzrA inhibited the assembly and bundling of B. subtilis FtsZ. It increased the critical concentration of FtsZ assembly and depolymerized the preformed FtsZ polymers in vitro. We obtained evidence suggesting that B. subtilis EzrA forms complex with B. subtilis FtsZ in vitro. EzrA was found to bind to FtsZ at a single site with a dissociation constant of 4.3 +/- 0.6 microM. EzrA-FtsZ interaction has a significant electrostatic contribution as apparent from the effect of salt on their binding interactions. To elucidate the site of interaction between EzrA and FtsZ, we deleted 16 amino acid residues from the extreme C-terminal tail of B. subtilis FtsZ, which are conserved in FtsZ orthologues. EzrA did not inhibit the assembly of C-terminal truncated B. subtilis FtsZ. It also did not bind to the C-terminal truncated FtsZ detectably, suggesting that EzrA interacts with FtsZ through its conserved C-terminal tail residues. Further, a 17-residue synthetic peptide (365-382) of the C-terminal tail of FtsZ (CTP17) was used to probe the interaction of EzrA with the C-terminal tail of FtsZ. CTP17 bound to EzrA, inhibited the binding of EzrA to FtsZ, and surmounted the inhibitory effects of EzrA on the assembly of FtsZ in vitro. The data together showed that EzrA binds to the C-terminal tail of FtsZ. FtsA, a positive regulator of FtsZ assembly, is also known to interact with the C-terminal tail of FtsZ. The results indicated an interesting possibility that the assembly dynamics of FtsZ in the Z-ring is regulated by the competition between positive and negative regulators sharing the same binding site on FtsZ.


Exercise- and strategy-based physiotherapy-delivered intervention for preventing repeat falls in people with Parkinson's: the PDSAFE RCT.
People with Parkinson's disease are twice as likely to experience a fall as a healthy older person, often leading to debilitating effects on confidence, activity levels and quality of life. To estimate the effect of a physiotherapy programme for fall prevention among people with Parkinson's disease. A multicentre, pragmatic, investigator-masked, individually randomised controlled trial (RCT) with prespecified subgroup analyses. Recruitment from NHS hospitals and clinics and community and social services in eight English regions with home-based interventions. A total of 474 people with Parkinson's disease (i.e. Hoehn and Yahr scale stages 1-4) were recruited: 238 were assigned to a physiotherapy programme and 236 were assigned to usual care. Random allocation was 50 : 50. All participants received routine care; the usual-care group received an information digital versatile disc (DVD) and a single advice session at trial completion. The intervention group had an individually tailored, progressive, home-based fall avoidance strategy training programme with balance and strengthening exercises: PDSAFE. The primary outcome was the risk of repeat falling, collected by self-report monthly diaries between 0 and 6 months after randomisation. Secondary outcomes included near-falls, falls efficacy, freezing of gait (FoG), health-related quality of life, and measurements taken using the Mini-Balance Evaluation Systems Test (Mini-BESTest), the Chair Stand Test (CST), the Geriatric Depression Scale, the Physical Activity Scale for the Elderly and the Parkinson's Disease Questionnaire. PDSAFE is the largest RCT of falls management among people with Parkinson's disease: 541 patients were screened for eligibility. The average age was 72 years, and 266 out of 474 (56%) participants were men. Of the 474 randomised participants, 238 were randomised to the intervention group and 236 were randomised to the control group. No difference in repeat falling within 6 months of randomisation was found [PDSAFE group to control group odds ratio (OR) 1.21, 95% confidence interval (CI) 0.74 to 1.98; p = 0.447]. An analysis of secondary outcomes demonstrated better balance (Mini-BESTest: mean difference 0.95, 95% CI 0.24 to 1.67; p = 0.009), functional strength (CST: p = 0.041) and falls efficacy (Falls Efficacy Scale - International: mean difference 1.6, 95% CI -3.0 to -0.19; p = 0.026) with near-falling significantly reduced with PDSAFE (OR 0.67, 95% CI 0.53 to 0.86; p = 0.001) at 6 months. Prespecified subgroup analysis (i.e. disease severity and FoG) revealed a PDSAFE differing effect; the intervention may be of benefit for people with moderate disease but may increase falling for those in the more severe category, especially those with FoG. All participants were assessed at primary outcome; only 73% were assessed at 12 months owing to restricted funding. PDSAFE was not effective in reducing repeat falling across the range of people with Parkinson's disease in the trial. Secondary analysis demonstrated that other functional tasks and self-efficacy improved and demonstrated differential patterns of intervention impact in accordance with disease severity and FoG, which supports previous secondary research findings and merits further primary evaluation. Further trials of falls prevention on targeted groups of people with Parkinson's disease are recommended. Current Controlled Trials ISRCTN48152791. This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 23, No. 36. See the NIHR Journals Library website for further project information. Sarah E Lamb is funded by the NIHR Collaboration for Leadership in Applied Health Research and Care (CLAHRC) at Oxford Health NHS Foundation Trust, the NIHR Oxford Biomedical Research Centre at the Oxford University Hospitals NHS Foundation Trust and CLAHRC Oxford. Victoria A Goodwin is supported by the NIHR Collaborations for Leadership in Applied Health Research and Care in the South West Peninsula (PenCLAHRC). Lynn Rochester is supported by the NIHR Newcastle Biomedical Research Centre based at Newcastle upon Tyne Hospitals NHS Foundation Trust and Newcastle University. The research was also supported by the NIHR Newcastle Clinical Research Facility Infrastructure funding. Helen C Roberts is supported by CLAHRC Wessex and the NIHR Southampton Biomedical Research Centre.


Site-specific perturbations of alpha-synuclein fibril structure by the Parkinson's disease associated mutations A53T and E46K.
Parkinson's disease (PD) is pathologically characterized by the presence of Lewy bodies (LBs) in dopaminergic neurons of the substantia nigra. These intracellular inclusions are largely composed of misfolded α-synuclein (AS), a neuronal protein that is abundant in the vertebrate brain. Point mutations in AS are associated with rare, early-onset forms of PD, although aggregation of the wild-type (WT) protein is observed in the more common sporadic forms of the disease. Here, we employed multidimensional solid-state NMR experiments to assess A53T and E46K mutant fibrils, in comparison to our recent description of WT AS fibrils. We made de novo chemical shift assignments for the mutants, and used these chemical shifts to empirically determine secondary structures. We observe significant perturbations in secondary structure throughout the fibril core for the E46K fibril, while the A53T fibril exhibits more localized perturbations near the mutation site. Overall, these results demonstrate that the secondary structure of A53T has some small differences from the WT and the secondary structure of E46K has significant differences, which may alter the overall structural arrangement of the fibrils.


Island cells control temporal association memory.
Episodic memory requires associations of temporally discontiguous events. In the entorhinal-hippocampal network, temporal associations are driven by a direct pathway from layer III of the medial entorhinal cortex (MECIII) to the hippocampal CA1 region. However, the identification of neural circuits that regulate this association has remained unknown. In layer II of entorhinal cortex (ECII), we report clusters of excitatory neurons called island cells, which appear in a curvilinear matrix of bulblike structures, directly project to CA1, and activate interneurons that target the distal dendrites of CA1 pyramidal neurons. Island cells suppress the excitatory MECIII input through the feed-forward inhibition to control the strength and duration of temporal association in trace fear memory. Together, the two EC inputs compose a control circuit for temporal association memory.


Paget's disease of bone: diagnosis and management.
The main features of Paget's disease are described, together with the indications for medical treatment. A brief summary is given of the drugs available for treatment of Paget's disease with particular emphasis on sodium etidronate (EHDP, ethylidene-1-hydroxy-1, 1-diphosphonate). Sodium etidronate, given at doses between 5 and 20 mg per kilogram per day for 3-6 months, causes a progressive reduction in the biochemical abnormalities (raised plasma alkaline phosphatase and urinary hydroxyproline) and in the histological abnormalities of bone. Clinical symptoms also improve. The usual dose is 5 mg per kilogram body weight per day to be given for not longer than 6 months. Higher doses (10 and 20 mg per kilogram per day) may cause impairment of normal bone mineralisation and should be given for short periods only (1-3 months). Sodium etidronate also has a limited place in the treatment of certain disorders of ectopic calcification, notably heterotopic ossification after spinal cord injury or hip surgery. At the present time there is insufficient evidence to justify its use in the treatment of renal stones or in osteoporosis other than that due to immobilisation after spinal cord injury.


Phenotypic change from transformed to normal induced by benzoquinonoid ansamycins accompanies inactivation of p60src in rat kidney cells infected with Rous sarcoma virus.
Three benzenoid ansamycin antibiotics (herbimycin, macbecin, and geldanamycin) were found to reduce the intracellular phosphorylation of p60src at a permissive temperature (33 degrees C) in a rat kidney cell line infected with a temperature-sensitive mutant of Rous sarcoma virus. This effect was accompanied by morphological changes from the transformed to the normal phenotype. The filamentous staining pattern of actin fibers was observed in the cells treated with these antibiotics at 33 degrees C. Removal of the antibiotics allowed the cells to revert to the transformed morphology. Ansamitocin, another benzenoid ansamycin, and naphthalenoid ansamycins such as streptovaricin and rifamycins did not show this effect. Pulse-labeling of the antibiotic-treated cultures with 32Pi showed a marked reduction of 32P radioactivity incorporated into p60src. A parallel experiment with [35S]methionine showed that synthesis of p60src was slightly inhibited. The immune complex prepared by mixing the herbimycin-treated cell extracts with antibody against p60src was inactive in vitro in phosphorylating the complex itself. On the contrary, the immune complex derived from untreated cells was active in vitro even in the presence of the antibiotics. These results suggest that benzoquinonoid ansamycins have no direct effect on src kinase but destroy its intracellular environment, resulting in an irreversible alteration of p60src and loss of catalytic activity.


Mastering the intermediaries.
Almost every retailer looks to Google to refer customers, and it's rare to find a manufacturer whose products aren't sold on Amazon. But these and other big platforms can capture a disproportionate share of the value a company creates: Buy an app on iTunes, and Apple takes 30%. The author presents four strategies to help businesses reduce their dependence on powerful platforms. Exploit the platform's need to be comprehensive. American Airlines' strong coverage of key routes made its presence on the travel website Kayak indispensable to Kayak's value proposition. As a result, AA negotiated a better deal. Identify and discredit discrimination. Public complaints that eBay was giving search prominence to suppliers who advertised on the site forced a reversal of the policy. Create an alternative platform. When MovieTickets was on the verge of dominating phone and online ticketing, Regal Entertainment and two other large theater chains formed Fandango. Deal more directly. People ordering takeout through online platforms like Foodler and GrubHub have often already chosen their restaurant. Restaurants that deal directly can exit the platform.


Exercise as an augmentation strategy for treatment of major depression.
The use of augmentation strategies among patients with major depression is increasing because rates of complete remission with standard antidepressant monotherapy are quite low. Clinical and neurobiological data suggest that exercise may be a good candidate for use as an augmentation treatment for depression. This pilot study examined the use of exercise to augment antidepressant medication in patients with major depression. Seventeen patients with incomplete remission of depressive symptoms began a 12-week exercise program while continuing their antidepressant medication (unchanged in type or dose). Individual exercise prescriptions were calculated based on an exercise dose consistent with currently recommended public health guidelines. The exercise consisted of both supervised and home-based sessions. The 17-item Hamilton Rating Scale for Depression (HRSD17) and the Inventory of Depressive Symptomatology-Self-Report (IDS-SR30) were used to assess symptoms of depression on a weekly basis. Intent-to-treat analyses yielded significant decreases on both the HRSD17 (5.8 points, p < 0.008) and IDS-SR30 (13.9 points, p < 0.002). For patients who completed the study (n = 8), HRSD17 scores decreased by 10.4 points and IDS-SR30 scores decreased by 18.8 points. This study provides preliminary evidence for exercise as an effective augmentation treatment for antidepressant medication. This is a lower-cost augmentation strategy that has numerous health benefits and may further reduce depressive symptoms in partial responders to antidepressant treatment. Practical tips on how practitioners can use exercise to enhance antidepressant treatment are discussed. Longer-term use of exercise is also likely to confer additional health benefits for this population.


Blueberry inhibits invasion and angiogenesis in 7,12-dimethylbenz[a]anthracene (DMBA)-induced oral squamous cell carcinogenesis in hamsters via suppression of TGF-β and NF-κB signaling pathways.
Aberrant activation of oncogenic signaling pathways plays a pivotal role in tumor initiation and progression. The purpose of the present study was to investigate the chemopreventive and therapeutic efficacy of blueberry in the hamster buccal pouch (HBP) carcinogenesis model based on its ability to target TGF-β, PI3K/Akt, MAPK and NF-κB signaling and its impact on invasion and angiogenesis. Squamous cell carcinomas were induced in the HBP by 7,12-dimethylbenz[a]anthracene (DMBA). The effect of blueberry on the oncogenic signaling pathways and downstream events was analyzed by quantitative real-time PCR and immunoblotting. Experiments with the ECV304 cell line were performed to explore the mechanism by which blueberry regulates angiogenesis. Blueberry supplementation inhibited the development and progression of HBP carcinomas by abrogating TGF-β and PI3K/Akt pathways. Although blueberry failed to influence MAPK, it suppressed NF-κB activation by preventing nuclear translocation of NF-κB p65. Blueberry also modulated the expression of the oncomiR miR-21 and the tumor suppressor let-7. Collectively, these changes induced a shift to an anti-invasive and anti-angiogenic phenotype as evidenced by downregulating matrix metalloproteinases and vascular endothelial growth factor. Blueberry also inhibited angiogenesis in ECV304 cells by suppressing migration and tube formation. The results of the present study suggest that targeting oncogenic signaling pathways that influence acquisition of cancer hallmarks is an effective strategy for chemointervention. Identification of modulatory effects on phosphorylation, intracellular localization of oncogenic transcription factors and microRNAs unraveled by the present study as key mechanisms of action of blueberry is critical from a therapeutic perspective.


PORTEC-4a: international randomized trial of molecular profile-based adjuvant treatment for women with high-intermediate risk endometrial cancer.
Vaginal brachytherapy is currently recommended as adjuvant treatment in patients with high-intermediate risk endometrial cancer to maximize local control and has only mild side effects and no or limited impact on quality of life. However, there is still considerable overtreatment and also some undertreatment, which may be reduced by tailoring adjuvant treatment to the patients' risk of recurrence based on molecular tumor characteristics. To compare the rates of vaginal recurrence in women with high-intermediate risk endometrial cancer, treated after surgery with molecular-integrated risk profile-based recommendations for either observation, vaginal brachytherapy or external pelvic beam radiotherapy or with standard adjuvant vaginal brachytherapy STUDY HYPOTHESIS: Adjuvant treatment based on a molecular-integrated risk profile provides similar local control and recurrence-free survival as current standard adjuvant brachytherapy in patients with high-intermediate risk endometrial cancer, while sparing many patients the morbidity of adjuvant treatment and reducing healthcare costs. A multicenter, international phase III randomized trial (2:1) of molecular-integrated risk profile-based adjuvant treatment (experimental arm) or adjuvant vaginal brachytherapy (standard arm). Women aged 18 years and over with a histological diagnosis of high-intermediate risk endometrioid endometrial cancer after total abdominal or laparoscopic hysterectomy and bilateral salpingo-oophorectomy. High-intermediate risk factors are defined as: (i) International Federation of Gynecology and Obstetrics stage IA (with invasion) and grade 3; (ii) stage IB grade 1 or 2 with age ≥60 and/or lymph-vascular space invasion; (iii) stage IB, grade 3 without lymph-vascular space invasion; or (iv) stage II (microscopic and grade 1). The primary endpoint is vaginal recurrence. Secondary endpoints are recurrence-free and overall survival; pelvic and distant recurrence; 5-year vaginal control (including treatment for relapse); adverse events and patient-reported symptoms and quality of life; and endometrial cancer-related healthcare costs. 500 eligible and evaluable patients. Estimated date for completing accrual will be late 2021. Estimated date for presentation of (first) results is expected in 2023. The trial is registered at clinicaltrials.gov (NCT03469674) and ISRCTN (11659025).


How to do (or not to do) … translation of national health accounts data to evidence for policy making in a low resourced setting.
For more than a decade, the Organization for Economic Co-operation and Development (OECD), the World Health Organization (WHO) and the World Bank have promoted the international standardization of National Health Accounts (NHA) for reporting global statistics on public, private and donor health expenditure and improve the quality of evidence-based decision-making at country level. A 2010-2012 World Bank review of NHA activity in 50 countries found structural and technical constraints (rather than cost) were key impediments to institutionalizing NHA in many low- and middle-income countries (LMICs). Pilot projects focused resources on data production, neglecting longer-term capacity building for analysing the data, developing ownership among local stakeholders and establishing routine production, utilization and dissemination of NHA data. Hence, genuine institutionalization of NHA in most LMICs has been slow to materialize. International manuals focus on the production of NHA data and do not include practical, incremental and low-cost strategies to guide countries in translating the data into evidence for policy-making. The main aim of this article is to recommend strategies for bridging this divide between production and utilization of NHA data in low-resource settings. The article begins by discussing the origins and purpose of NHA, including factors currently undermining their uptake. The focus then turns to the development and application of strategies to assist LMICs in 'unlocking' the hidden value of their NHA. The article draws on the example of Fiji, a country currently attempting to integrate their NHA data into policy formulation, despite minimal resources, training and familiarity with economic analysis of health systems. Simple, low cost recommendations such as embedding health finance indicators in planning documents, a user-friendly NHA guide for evaluating local health priorities, and sharing NHA data for collaborative research have helped translate NHA from raw data to evidence for policymaking.


The effects of 1-pentyne hydrogenation on the atomic structures of size-selected Au(N) and Pd(N) (N = 923 and 2057) nanoclusters.
We report an investigation into the effects of the vapour-phase hydrogenation of 1-pentyne on the atomic structures of size-selected Au and Pd nanoclusters supported on amorphous carbon films. We use aberration-corrected high-angle annular dark field (HAADF) scanning transmission electron microscopy (STEM) to image populations of the nanoclusters at atomic resolution, both before and after the reaction, and we assign their atomic structures by comparison with multi-slice image simulations over a full range of cluster orientations. Gold nanoclusters consisting of 923 ± 20 and 2057 ± 45 atoms are found to be robust, exhibiting high structural stability. However, a significant portion of Pd923±26 nanoclusters that appear amorphous prior to treatment are found to exhibit high symmetry structures post-reaction, which is interpreted as the reduction of oxidised Pd nanoclusters under the reaction conditions.


PSC, AIH and overlap syndrome in inflammatory bowel disease.
Primary sclerosing cholangitis (PSC) is a progressive, cholestatic disorder characterised by chronic inflammation and stricture formation of the biliary tree. Symptoms include pruritus, fatigue and in advanced cases ascending cholangitis, cirrhosis and end-stage hepatic failure. Patients are at an increased risk of malignancy arising from the bile ducts, gallbladder, liver and colon. The majority (>80%) of Northern European patients with PSC also have inflammatory bowel disease (IBD), usually ulcerative colitis (UC). IBD commonly presents before the onset of PSC, although the opposite can occur and the onset of both conditions can be separated by many years. The colitis associated with PSC is characteristically mild although frequently involves the whole colon. Despite the majority of patients having relatively inactive colonic disease, paradoxically the risk of colorectal malignancy is substantially increased. Patients may also develop dominant, stenotic lesions of the biliary tree which may be difficult to differentiate from cholangiocarcinoma and the coexistence of IBD may influence the development of this complication. Ursodeoxycholic acid may offer a chemoprotective effect against colorectal malignancy and improve liver biochemical indices. Evidence of any beneficial effect on histological progression of hepatobiliary disease is less clear. High doses (∼25-30 mg/kg/d) may be harmful and should be avoided. Autoimmune hepatitis (AIH) is less common in patients with IBD than PSC, however, an association has been observed. A small subgroup may have an overlap syndrome between AIH and PSC and management should be individualised dependant on liver histology, serum immunoglobulin levels, autoantibodies, degree of biochemical cholestasis and cholangiography.


Phase transition and hysteresis in an ensemble of stochastic spiking neurons.
An ensemble of stochastic nonleaky integrate-and-fire neurons with global, delayed, and excitatory coupling and a small refractory period is analyzed. Simulations with adiabatic changes of the coupling strength indicate the presence of a phase transition accompanied by a hysteresis around a critical coupling strength. Below the critical coupling production of spikes in the ensemble is governed by the stochastic dynamics, whereas for coupling greater than the critical value, the stochastic dynamics loses its influence and the units organize into several clusters with self-sustained activity. All units within one cluster spike in unison, and the clusters themselves are phase-locked. Theoretical analysis leads to upper and lower bounds for the average interspike interval of the ensemble valid for all possible coupling strengths. The bounds allow calculating the limit behavior for large ensembles and characterize the phase transition analytically. These results may be extensible to pulse-coupled oscillators.


Clinical review: checklists - translating evidence into practice.
Checklists are common tools used in many industries. Unfortunately, their adoption in the field of medicine has been limited to equipment operations or part of specific algorithms. Yet they have tremendous potential to improve patient outcomes by democratizing knowledge and helping ensure that all patients receive evidence-based best practices and safe high-quality care. Checklist adoption has been slowed by a variety of factors, including provider resistance, delays in knowledge dissemination and integration, limited methodology to guide development and maintenance, and lack of effective technical strategies to make them available and easy to use. In this article, we explore some of the principles and possible strategies to further develop and encourage the implementation of checklists into medical practice. We describe different types of checklists using examples and explore the benefits they offer to improve care. We suggest methods to create checklists and offer suggestions for how we might apply them, using some examples from our own experience, and finally, offer some possible directions for future research.


Improved full-length killer cell immunoglobulin-like receptor transcript discovery in Mauritian cynomolgus macaques.
Killer cell immunoglobulin-like receptors (KIRs) modulate disease progression of pathogens including HIV, malaria, and hepatitis C. Cynomolgus and rhesus macaques are widely used as nonhuman primate models to study human pathogens, and so, considerable effort has been put into characterizing their KIR genetics. However, previous studies have relied on cDNA cloning and Sanger sequencing that lack the throughput of current sequencing platforms. In this study, we present a high throughput, full-length allele discovery method utilizing Pacific Biosciences circular consensus sequencing (CCS). We also describe a new approach to Macaque Exome Sequencing (MES) and the development of the Rhexome1.0, an adapted target capture reagent that includes macaque-specific capture probe sets. By using sequence reads generated by whole genome sequencing (WGS) and MES to inform primer design, we were able to increase the sensitivity of KIR allele discovery. We demonstrate this increased sensitivity by defining nine novel alleles within a cohort of Mauritian cynomolgus macaques (MCM), a geographically isolated population with restricted KIR genetics that was thought to be completely characterized. Finally, we describe an approach to genotyping KIRs directly from sequence reads generated using WGS/MES reads. The findings presented here expand our understanding of KIR genetics in MCM by associating new genes with all eight KIR haplotypes and demonstrating the existence of at least one KIR3DS gene associated with every haplotype.


Secondary failure of nasal intermittent positive pressure ventilation using the Monnal D: effects of changing ventilator.
Some patients started on nasal intermittent positive pressure ventilation (NIPPV) with the Monnal D ventilator deteriorate after a period. The effects of changing them to the Nippy ventilator were investigated. The records of such patients were examined retrospectively. Comparisons were made between blood gas tensions and overnight oximetry records before NIPPV, 12 weeks after the initiation of NIPPV with the Monnal D, at the time of deterioration, and 12 weeks after initiation of treatment with the Nippy ventilator. Ten patients (seven women) were identified. Prior to starting NIPPV their mean (SD) age was 59.6 (8.39) years and their mean arterial oxygen and carbon dioxide tensions (PaO2 and PaCO2) while breathing air were 6.1 (1.79) and 9.6 (3.28) kPa, respectively. All were started on NIPPV with the Monnal D with improvements in symptoms, PaO2, PaCO2, and overnight oximetry after 12 weeks of treatment. After a mean interval of 118 (69.0) weeks all measures of ventilation had deteriorated and the patients were converted to the Nippy ventilator. Twelve weeks after initiation of treatment with the Nippy ventilator symptoms and overnight oximetry were improved again and the mean PaO2 and PaCO2 were 8.9 (1.27) and 6.9 (0.45) kPa, respectively. After a total mean period of 59 (26.9) weeks on the Nippy all but one of the patients have maintained this improvement. Support with NIPPV using the Monnal D ventilator may fail after an interval and changing to the Nippy ventilator can reverse this deterioration, probably because of its superior responsiveness to leaks and patient effort. The regular follow up of patients on long term NIPPV is necessary if secondary treatment failure is to be identified and effectively treated.


Central corneal thickness in children and adolescents with pediatric glaucoma and eye disorders at risk of developing glaucoma.
To investigate central corneal thickness (CCT) in children with glaucoma and at risk for glaucoma. The study included 139 children with glaucoma: 66 at risk for glaucoma (ie, aphakia, aniridia, or uveitis) and 66 normal children. CCT was measured by ultrasound pachymetry and intraocular pressure (IOP) by applanation. Analysis of variance was used to compare CCT between groups. Correlation analysis assessed associations between CCT and ocular factors including spherical equivalent, cup-to-disc ratio, glaucoma medications, and number of intraocular surgeries. CCT was significantly higher for 141 eyes with glaucoma (mean: 0.598 mm, P < .001) and 76 eyes at risk for glaucoma (mean: 0.604 mm, P = .001) than for 66 normal eyes (mean: 0.558 mm). No significant difference was observed between at-risk (P = .989) and glaucoma eyes. Eyes with aphakia (0.653 mm) and aniridia (0.639 mm) had the thickest CCT values. Thinnest CCT was found in anterior segment dysgenesis and uveitis (mean: 0.541 mm). A significant positive correlation between CCT and spherical equivalent was found for glaucoma (r = 0.413; P < .001) and at-risk (r = 0.412; P < .0003) eyes, and between CCT and intraocular surgery for at-risk eyes (P = .0066). A significant negative correlation was found between CCT and cup-to-disc ratio for glaucoma eyes (r = -0.223; P = .01). This is the largest series of CCT in pediatric glaucoma and related disorders. The data suggest caution in application of standard formulas for IOP-to-CCT correction when evaluating children with glaucoma because their mean CCT values extend far beyond values reported for normal eyes.


[Spectral properties of porcine plasminogen: study of the acidic transition (author's transl)].
The acidic transition of porcine plasminogen, prepared by affinity chromatography, was studied by non-destructive methods. These methods are based on the analysis of the behaviour of the tryptophyls under various conditions. The perturbation of the absorption and emission spectra by pH or temperature and the dynamic quenching of the intrinsic fluorescence are used to obtain information on structural changes which affect the environment of these residues. It is shown that by decreasing pH the fluorescence emission spectra are shifted toward the long wavelengths, with a broadening of the fluorescence band. The same effect can be obtained at constant pH by heating the protein solution. In order to analyze these phenomena, it is assumed that the fluorescence intensities at 355 nm and 328 nm reflect the proportion of the tryptophans which are exposed to the solvent, and buried, respectively. The plot of the ratio of the fluorescence intensities at these wavelengths versus pH or temperature leads to a titration curve showing an unmasking of tryptophans. The proportion of exposed tryptophans is measured by the dynamic fluorescence quenching technique and the data analyzed according to Lehrer. The plot of the fraction of exposed tryptophyls versus pH also shows the unmasking of these chromophores. Thermal perturbation of a solution of plaminogen at neutral pH induces a difference absorption spectrum whose amplitudes at the maxima are proportional to the number of exposed aromatic residues. The comparison with a solution of fully denatured plasminogen in 6 M guanidium chloride, where all the tryptophyls are exposed, shows that the percentage of exposure is equal to 59%. This number is significantly higher than the percentage found by the fluorescence quenching technique (20%), indicating that some tryptophyls are located in crevices, exposed to the solvent but not to the iodide. At acidic pH the absorption difference spectra induced by thermal perturbation are not classical, since they show an inversion and a new band between 300 nm and 305 nm. This band is mentioned in the literature as a minor band of tryptophan which appears when this chromophore is located in an asymmetric environment. On plotting the maximum amplitude of these spectra obtained at acidic pH versus temperature, we obtain a curve indicating that two types of antagonistic interactions are involved in the perturbation of the chromophores spectra. The spectrophotometric titration of plasminogen gives classical absorption difference spectra. By plotting the maximum amplitude at 292 nm versus pH, we obtain a titration curve with an apparent pK of 2.9 units. This pK is acidic which respect to the pK value of a normal carboxyl. This low value can be due to a positively charged group in the neighbourhood of a carboxyl, which interacts with one or more chromophores. When the carboxyl becomes protonated, this positively charged group is free and available to perturb the environment of some chromophores...


Possible role of reactive chlorine in microbial antagonism and organic matter chlorination in terrestrial environments.
Several studies have demonstrated that extensive formation of organically bound chlorine occurs both in soil and in decaying plant material. Previous studies suggest that enzymatic formation of reactive chlorine outside cells is a major source. However, the ecological role of microbial-induced extracellular chlorination processes remains unclear. In the present paper, we assess whether or not the literature supports the hypothesis that extracellular chlorination is involved in direct antagonism against competitors for the same resources. Our review shows that it is by no means rare that biotic processes create conditions that render biocidal concentrations of reactive chlorine compounds, which suggest that extracellular production of reactive chlorine may have an important role in antagonistic microbial interactions. To test the validity, we searched the UniprotPK database for microorganisms that are known to produce haloperoxidases. It appeared that many of the identified haloperoxidases from terrestrial environments are originating from organisms that are associated with living plants or decomposing plant material. The results of the in silico screening were supported by various field and laboratory studies on natural chlorination. Hence, the ability to produce reactive chlorine seems to be especially common in environments that are known for antibiotic-mediated competition for resources (interference competition). Yet, the ability to produce haloperoxidases is also recorded, for example, for plant endosymbionts and parasites, and there is little or no empirical evidence that suggests that these organisms are antagonistic.


Alpha 2-adrenergic agonism enhances the growth hormone (GH) response to GH-releasing hormone through an inhibition of hypothalamic somatostatin release in normal men.
The purpose of this study was to investigate the precise mechanism by which central alpha 2-adrenergic pathways modulate GH secretion in humans. In 10 normal subjects we compared the pattern of clonidine-induced GH release to that elicited by GH-releasing hormone (GHRH) given at a time of presumably similar responsiveness of the somatotrope. We also evaluated the effect of stimulation by GHRH (either endogenous, by administration of clonidine, or exogenous) on the GH response to a further exogenous GHRH stimulation. In 2 experiments the administration of clonidine (0.150 mg, orally) at 0 or 60 min was followed by a GHRH [GRF-(1-29); 1 micrograms/kg, iv] challenge at 180 min. In other experiments subjects received on separate occasions placebo or clonidine at 0 min, followed by GHRH at 60 min and again at 180 min. In a further experiment the administration of clonidine at 0 min was followed by 2 GHRH challenges (60 and 180 min later). The administration of clonidine 60 or 120 min, but not 180 min, before the GHRH bolus significantly (P less than 0.01) increased the GH responses to this challenge compared to those elicited by GHRH when given after placebo in a period of a similar somatotrope responsiveness. These, in turn, were significantly (P less than 0.05) higher than those elicited by clonidine alone. The close relationship between pre-GHRH plasma GH values and GHRH-elicited GH peaks, not observed for clonidine, was lost after pretreatment with this drug. These data indicate that clonidine was able to disrupt the intrinsic hypothalamic-somatotroph rhythm, suggesting that alpha 2-adrenergic pathways have a major inhibitory effect on somatostatin release. Our data also indicate that GH responses to a GHRH bolus administered 120 min after a prior GHRH challenge are dependent on two parameters: the intrinsic hypothalamic-somatotroph rhythm at the time of the second GHRH bolus, and the magnitude of GH secretion elicited by the previous somatotroph stimulation. In summary, alpha 2-adrenergic agonism appears to act primarily in GH control by inhibiting the hypothalamic release of somatostatin, rather than by stimulating GHRH secretion.


"TOGETHER WE ARE UNBEATABLE": young sisters' narration of a sibling's cancer in personal blogs on the internet.
Siblings of children and young people diagnosed with cancer are commonly reluctant to talk about their experiences due to the circumstances of the illness situation. This article aims to bring voice to experience and inform practice by investigating what and how three young sisters narrate about their illness experiences in personal blogs on the Internet. A narrative methodology for the analysis of life storytelling was applied primarily to investigate the sister's coping strategies and support needs. The results show how the sisters constructed their own space for narration, with the main aims of expressing their feelings about the illness and seeking social support. The telling of their experiences along with encouraging comments from a supportive audience enabled a change in position from feeling neglected and silenced to being a recognized agent and caring sister. In addition, through their narrative coping the sisters went from powerless to powerful in their position in relation to cancer. The results highlight the need for siblings to be able to narrate experience in a supportive context, where the processing of their relationship with the ill sister/brother should be understood as an important element of their coping with cancer and death.


Increased platelet aggregates in patients with transient ischemic attacks.
In order to evaluate the pathogenetic importance of platelet aggregates in cerebrovascular disease, a platelet count ratio method was used to study 66 patients with transient ischemic attacks (TIAs). Thirty normal subjects and 22 patients without thromboembolic disorders were also included as controls. The mean platelet aggregate ratio of the TIA group was 0.75 +/- 0.03 SEM which was significantly lower than that of normal subjects (0.90 +/- 0.02) or patients controls (0.88 +/- 0.01) (P less than 0.01). Seventeen patients with TIA were then treated with aspirin (1,200 mg) and dipyridamole (200 mg) daily. The platelet aggregate ratios were normalized in 13 patients. Of four patients who did not respond to this regimen, one did respond to sulfinpyrazone. When sulfinpyrazone was discontinued, recurrence of symptoms was preceded by an increase in platelet aggregates. These findings suggest that platelet aggregates may play an important role in the pathogenesis of cerebrovascular insufficiency. The determination of platelet aggregates appears useful in selecting patients for antiplatelet therapy.


A Rare Cause of Haemorrhage in the Upper Gastrointestinal System: Bochdalek Hernia.
Diaphragmatic hernia originates from insufficient closure of the pericardioperitoneal canals and pleuroperitoneal membranes. It is seen in one in every 4000 births. The general finding in the newborn period is respiratory difficulty. Mortality is 40-50%. There may be other accompanying organ anomalies. Congenital diaphragmatic hernias diagnosed after the newborn period are known as late-presenting congenital diaphragmatic hernias. This group is seen at a level of 5-20% and poses difficulty in diagnosis. This report describes a case under observation and receiving treatment for gastrointestinal haemorrhage, diagnosed as Bochdalek hernia.


Force Fields for Macromolecular Assemblies Containing Diketopyrrolopyrrole and Thiophene.
Utilizing a force-matching procedure, we parametrize new force fields systematically for large conjugated systems. We model both conjugated polymers and molecular crystals that contain diketopyrrolopyrrole, thiophene, and thieno[3,2-b]thiophene units. These systems have recently been found to have low band gaps, which exhibit high efficiency for photovoltaic devices. The equilibrium structures, forces, and energies of the building block chromophores, diketopyrrolopyrrole, thiophene, and thieno[3,2-b]thiophene computed using our parameters are comparable to those computed using the reference electronic structure method. We assess the suitability of this new force field for electronic property calculations by comparing the electronic excitation properties computed along classical and ab initio molecular dynamics trajectories. For both trajectories, we find similar distributions of TDDFT-calculated excitation energies and oscillator strengths for the building block chromophore diketopyrrolopyrrole-thieno[3,2-b]thiophene. The structural, dynamic, and electronic properties of the macromolecular assemblies built upon these chromophores are characterized. For both polymers and molecular crystals, pronounced peaks around 0° or 180° are observed for the torsions between chromophores under ambient conditions. The high planarity in these systems can promote local ordering and π-π stacking, thereby potentially facilitating charge transport across these materials. For the model conducting polymers, we found that the fluctuations in the density of states per chain per monomer is negligibly small and does not vary significantly with chains comprising 20-40 monomers. Analysis of the electron-hole distributions and the transition density matrices indicates that the delocalized length is approximately 4-6 monomers, which is in good agreement with other theoretical and experimental studies of different conducting polymers. For the molecular crystals, our investigation of the characteristic time scale of the fluctuation in the excitonic couplings shows that a low-frequency vibration below 100 cm-1 is observed for the nearest neighbors. These observations are in line with previous studies on other molecular crystals, in which low-frequency vibrations are believed to be responsible for the large modulation of the excitonic coupling. Thus, our approach and the new force fields provide a direct route for studying the structure-property relations and the molecular level origins of the high efficiency of these classes of materials.


Secretin occupies a single protomer of the homodimeric secretin receptor complex: insights from photoaffinity labeling studies using dual sites of covalent attachment.
The secretin receptor, a prototypic family B G protein-coupled receptor, forms a constitutive homodimeric complex that is stable even in the presence of hormone. Recently, a model of this agonist-bound receptor was built based on high resolution structures reported for amino-terminal domains of other family members. Although this model provided the best solution for all extant data, including 10 photoaffinity labeling constraints, a new such constraint now obtained with a position 16 photolabile probe was inconsistent with this model. As the secretin receptor forms constitutive homodimers, we explored whether secretin might dock across both protomers of the complex, an observation that could also contribute to the negative cooperativity observed. To directly explore this, we prepared six secretin analogue probes that simultaneously incorporated two photolabile benzoylphenylalanines as sites of covalent attachment, in positions known to label distinct receptor subdomains. Each bifunctional probe was a full agonist that labeled the receptor specifically and saturably, with electrophoretic migration consistent with labeling a single protomer of the homodimeric secretin receptor. No band representing radiolabeled receptor dimer was observed with any bifunctional probe. The labeled monomeric receptor bands were cleaved with cyanogen bromide to demonstrate that both of the photolabile benzoylphenylalanines within a single probe had established covalent adducts with a single receptor in the complex. These data are consistent with a model of secretin occupying a single secretin receptor protomer within the homodimeric receptor complex. A new molecular model accommodating all constraints is now proposed.


The treatment of recurrent trichiasis with argon laser photocoagulation.
We report our experience with the use of Argon laser photocoagulation for the treatment of recurrent trichiasis. A total of 28 lids (of 21 patients) with aberrant lashes were treated in our study. Each lash was treated with a beam of 50-200 micron (spot size), 0.2 s (time), and 1-1.2 Watt (power). Neither infiltration nor topical anaesthesia was used. The mean follow-up time was 6.57 months. Successful treatment with no evidence of recurrence was achieved in 67.9% of lids after one to two laser sessions. The remaining 32.1% of the lids required three to four sessions to achieve no recurrence of the condition. There was a significant correlation between the number of aberrant lashes per lid and the number of required laser sessions. Complete healing of the treated areas occurred within six weeks after treatment, with no vascularisation or distortion of the lid margin. Argon laser treatment appears to be a safe and effective alternative to the other recognised methods of therapy in selected cases.


Trace metal concentrations in post-hatching cuttlefish Sepia officinalis and consequences of dissolved zinc exposure.
In this study, we investigated the changes of 13 trace metal and metalloid concentrations (i.e. Ag, As, Cd, Co, Cr, Cu, Fe, Mn, Ni, Pb, Se, V, Zn) and their subcellular fractionation in juvenile cuttlefish Sepia officinalis reared in controlled conditions between hatching and 2 months post-hatching. In parallel, metallothionein concentrations were determined. Our results highlighted contrasting changes of studied metals. Indeed, As and Fe concentrations measured in hatchlings suggested a maternal transfer of these elements in cuttlefish. The non-essential elements Ag and Cd presented the highest accumulation during our study, correlated with the digestive gland maturation. During the 6 first weeks of study, soluble fractions of most of essential trace metals (i.e. Co, Cr, Cu, Fe, Se, Zn) slowly increased consistently with the progressive needs of cuttlefish metabolism during this period. In order to determine for the first time in a cephalopod how metal concentrations and their subcellular distributions are impacted when the animals are trace metal-exposed, we studied previously described parameters in juveniles exposed to dissolved Zn at environmental (i.e. 50 μg l(-1)) and sublethal (i.e. 200 μg l(-1)) levels. Moreover, oxidative stress (i.e. glutathione S-transferase (GST), superoxide dismutase (SOD) and catalase activities, and lipid peroxidation (LPO)) was assessed in digestive gland and gills after 1 and 2 months exposures. Our results highlighted no or low ability of this stage of life to regulate dissolved Zn accumulation during the studied period, consistently with high sensitivity of this organism. Notably, Zn exposures caused a concentration-dependent Mn depletion in juvenile cuttlefish, and an increase of soluble fraction of Ag, Cd, Cu without accumulation modifications, suggesting substitution of these elements (i.e. Mn, Ag, Cd, Cu) by Zn. In parallel, metallothionein concentrations decreased in individuals most exposed to Zn. Finally, no perturbations in oxidative stress management were detected in gills, whereas modifications of GST, SOD and catalase activity levels were recorded in digestive gland, resulting in an increase of LPO content after a 6-week exposure to low Zn concentration. Altogether, these perturbations are consistent with previously described high sensitivity of juvenile cuttlefish towards Zn. Our results underlined the need to study deeply contamination impact on this animal at this stage of life.


Anomaly Detection in Paleoclimate Records Using Permutation Entropy.
Permutation entropy techniques can be useful for identifying anomalies in paleoclimate data records, including noise, outliers, and post-processing issues. We demonstrate this using weighted and unweighted permutation entropy with water-isotope records containing data from a deep polar ice core. In one region of these isotope records, our previous calculations (See Garland et al. 2018) revealed an abrupt change in the complexity of the traces: specifically, in the amount of new information that appeared at every time step. We conjectured that this effect was due to noise introduced by an older laboratory instrument. In this paper, we validate that conjecture by reanalyzing a section of the ice core using a more advanced version of the laboratory instrument. The anomalous noise levels are absent from the permutation entropy traces of the new data. In other sections of the core, we show that permutation entropy techniques can be used to identify anomalies in the data that are not associated with climatic or glaciological processes, but rather effects occurring during field work, laboratory analysis, or data post-processing. These examples make it clear that permutation entropy is a useful forensic tool for identifying sections of data that require targeted reanalysis-and can even be useful for guiding that analysis.


The chick limb: embryology, genetics and teratology.
The chick embryo has a long history in investigations of vertebrate limb development because of the ease with which its limbs can be experimentally manipulated. Early studies elucidated the fundamental embryology of the limb and identified the key signalling regions that govern its development. The chick limb became a leading model for exploring the concept of positional information and understanding how patterns of differentiated cells and tissues develop in vertebrate embryos. When developmentally important molecules began to be identified, experiments in chick limbs were crucial for bridging embryology and molecular biology. The embryological mechanisms and molecular basis of limb development are largely conserved in mammals, including humans, and uncovering these molecular networks provides links to clinical genetics. We emphasise the important contributions of naturally occurring chick mutants to elucidating limb embryology and identifying novel developmentally important genes. In addition, we consider how the chick limb has been used to study mechanisms involved in teratogenesis with a focus on thalidomide. These studies on chick embryos have given insights into how limb defects can be caused by both genetic changes and chemical insults and therefore are of great medical significance.


Bimetallic structure fabricated by laser interference lithography for tuning surface plasmon resonance.
Tuning of surface plasmon resonance by gold and silver bimetallic thin film and bimetallic dot array is investigated. Laser interference lithography is applied to fabricate the nanostructures. A bimetallic dot structure is obtained by a lift-off procedure after gold and silver thin film deposition by an electron beam evaporator. Surface plasmon behaviors of these films and nanostructures are studied using UV-Vis spectroscopy. It is observed that for gold thin film on quartz substrate, the optical spectral peak is blue shifted when a silver thin film is coated over it. Compared to the plasmon band in single metal gold dot array, the bimetallic nanodot array shows a similar blue shift in its spectral peak. These shifts are both attributed to the interaction between gold and silver atoms. Electromagnetic interaction between gold and silver nanostructures is discussed using a simplified spring model.


Handsewn versus stapled anastomosis in penetrating colon injuries requiring resection: a multicenter study.
Although the use of stapling devices in elective colon surgery has been shown to be as safe as handsewn techniques, there have been concerns about their safety in emergency trauma surgery. The purpose of this study was to compare stapled with handsewn colonic anastomosis following penetrating trauma. This was a prospective multicenter study and included patients who underwent colon resection and anastomosis following penetrating trauma. Multivariate logistic regression analysis was used to identify independent risk factors for abdominal complications and compare outcomes between stapled and handsewn repairs. Two hundred seven patients underwent colon resection and primary anastomosis. In 128 patients (61.8%) the anastomosis was performed with handsewing and in the remaining 79 (38.2%) with stapling devices. There were no colon-related deaths and the overall incidence of colon-related abdominal complications was 22.7% (26.6% in the stapled group and 20.3% in the handsewn group, p = 0.30). The incidence of anastomotic leak was 6.3% in the stapled group and 7.8% in the handsewn group (p = 0.69). Multivariate analysis adjusting for blood transfusions, fecal contamination, and type of antibiotic prophylaxis showed that the adjusted odds ratio (OR) of complications in the stapled group was 0.83 (95% CI, 0.38-1.74, p = 0.63). In a second multivariate analysis adjusting for blood transfusions, hypotension, fecal contamination, Penetrating Abdominal Trauma Index, and preoperative delays the adjusted OR in the stapled group was 0.99 (95% CI, 0.46-2.11, p = 0.99). The results of this study suggest that the method of anastomosis following colon resection for penetrating trauma does not affect the incidence of abdominal complications and the choice should be surgeon's preference.


Female sex and oligoarthritis category are not risk factors for uveitis in Italian children with juvenile idiopathic arthritis.
To investigate the risk factors for chronic anterior uveitis in patients with juvenile idiopathic arthritis (JIA). The clinical charts of patients followed between January 1987 and December 2011 were reviewed to establish whether they had uveitis. Inclusion criteria were a diagnosis of JIA and a disease category of persistent oligoarthritis, extended oligoarthritis, rheumatoid factor-negative polyarthritis, psoriatic arthritis, or undifferentiated arthritis. Risk factors included sex, age at arthritis onset, disease category, and antinuclear antibody (ANA) status. The association of risk factors with occurrence of uveitis was evaluated by survival analysis, with first episode of uveitis as the event of interest, and Cox regression analysis. Of a total of 1189 patients, 278 (23.4%) had uveitis a median of 1.1 years after onset of arthritis. There was no difference in the cumulative probability of developing uveitis between males and females and between patients belonging to different JIA categories, whereas uveitis was strongly associated with age at arthritis onset ≤ 3.5 years and positive ANA. Patients possessing the latter 2 factors in combination had a greater probability of having uveitis than patients who had either of them alone. In our patients, the risk of uveitis was related to younger age at onset of arthritis and presence of ANA, but not to female sex and disease category. This finding suggests that the patients who require the most intensive ophthalmologic screening are those who have early-onset JIA and are ANA-positive, regardless of their sex or disease subtype.


Intermediates caught in the act: tracing insulin amyloid fibril formation in time by combined optical spectroscopy, light scattering, mass spectrometry and microscopy.
Interest in the topic of amyloid formation by peptides and proteins has increased dramatically in recent years, transforming it from a puzzling phenomenon associated with a small number of diseases into a major subject of study in disciplines ranging from material science to biology and medicine. The tendency of numerous (also non-pathogenic) proteins such as insulin to self-assemble into amyloid-like fibrils is well known. While fibrils are usually easily detected, the observation of transient intermediates is a big challenge in general. They are the key and the 'holy grail' for a molecular understanding of mechanisms in this context. Here we show that intermediates, i.e. oligomers, can be detected and their hydrodynamic radius RH as well as their overall conformation and structure can be monitored and the aggregation dynamics as well as structure formation can be detected in time with a suitable combination of experimental techniques. We have observed transient intermediates that resemble large oligomers held together in solution by non-covalent forces. The oligomers appear to convert into building blocks for mature fibrils with largely beta-sheet conformation resembling key players in a mechanism, which is termed 'nucleated conformation conversion' in the literature. Structural transformations of oligomers in time towards dominant beta-sheet conformations have been observed for the first time. The structures can even be observed in liquid phase AFM experiments. With this approach we have successfully shed new light into the aggregation and fibrilization process of insulin being possibly a model system for other amyloid systems.


Retinoids and synovial factor(s) stimulate the production of plasminogen activator by cultured human chondrocytes. A possible role for plasminogen activator in the resorption of cartilage in vitro.
Agents such as retinol, interleukin 1 and catabolin stimulate resorption of cultured cartilage. This process seems to be mediated by chondrocytes, but the mechanism by which breakdown occurs remains unknown. We have found that (10(-6)-10(-8) M) retinoic acid and (1 X 10(-6) M) retinol, in the presence or absence of a factor derived from cultured synovium (synovial factor), stimulate the degradation of fibrin by human chondrocytes in culture. Plasminogen was required for the enhancement of fibrinolysis, suggesting that the breakdown depended upon the production of plasminogen activators and subsequent liberation of plasmin. However, the chondrocytes did not release significant amounts of plasminogen activator, and the effects of the synovial factor and retinoids resulted from augmentation of the production or activity of enzymes which remained bound to the cell layer. The role of plasminogen in the resorption of cultured cartilage was also investigated. In the presence of plasminogen, (1 X 10(-8) M) retinoic acid or synovial factor stimulated the breakdown of cultured bovine nasal cartilage, but in the absence of plasminogen, the effect of synovial factor was abolished and that of retinoic acid reduced. However, in cultures containing both retinoic acid and synovial factor the resorption process was not affected by removal of plasminogen. Thus, the resorption of cartilage matrix in vitro may be partially mediated by plasminogen activators and plasmin.


Description of self-reported fluid intake and its effects on body weight, symptoms, quality of life and physical capacity in patients with stable chronic heart failure.
To describe the self-reported fluid intake and its effects on body weight, signs and symptoms of heart failure, quality of life, physical capacity and thirst, in patients with stabilised chronic heart failure. Patients with chronic heart failure are often recommended a fluid restriction of 1.5 l/day but there is no evidence in the literature for this recommendation and little is known about the fluid intake consequences. Crossover study. Chronic heart failure patients, clinically stabilised after an unstable state, were randomised to a 32-week cross-over study assessing the clinical importance of fluid prescription. In a secondary analysis of 63 patients, efficacy variables were analysed in relation to the self-reported median fluid intake of 19 ml/kg body weight/day. The mean fluid intake was 16 ml/kg/day in the below-median group and 24 ml/kg/day in the above-median group. No between-group differences were found in change in body weight, signs and symptoms, diuretic use, quality of life or physical capacity. However, the above-median group significantly decreased sense of thirst and difficulties to adhere to the fluid prescription compared with the below-median group. In clinically stabilised chronic heart failure patients on optimal pharmacological treatment, a larger fluid intake was associated with decreasing thirst without any measurable negative effects on signs and symptoms of heart failure, diuretic use or physical capacity. Thus, a more liberal fluid intake may be advisable in chronic heart failure patients who have been stabilised after an initial unstable clinical state. Nurses involved in the care for patients with heart failure known how troublesome thirst can be and how difficult it can be to follow a restricted fluid intake. This study indicates that it is possible to reassess and recommend a less strict fluid intake in stabilised patients with chronic heart failure.


Growth and puberty after treatment for acute lymphoblastic leukemia.
Over the last 20 years, after combining treatment of chemotherapy and radiotherapy, there has been an improvement in the survival rate of acute lymphoblastic leukemia patients, with a current cure rate of around 70%. Children with the disease have been enrolled into international treatment protocols designed to improve survival and minimize the serious irreversible late effects. Our oncology unit uses the international protocol: GBTLI LLA-85 and 90, with the drugs methotrexate, cytosine, arabinoside, dexamethasone, and radiotherapy. However, these treatments can cause gonadal damage and growth impairment. The authors analyzed 20 children off therapy in order to determine the role of the various doses of radiotherapy regarding endocrinological alterations. They were divided into 3 groups according to central nervous system prophylaxis: Group A underwent chemotherapy, group B underwent chemotherapy plus radiotherapy (18 Gy), and group C underwent chemotherapy plus radiotherapy (24 Gy). Serum concentrations of LH, FSH, GH, and testosterone were determined. Imaging studies included bone age, pelvic ultrasound and scrotum, and skull magnetic resonance imaging. Nine of the patients who received radiotherapy had decreased pituitary volume. There was a significant difference in the response to GH and loss of predicted final stature (Bayley-Pinneau) between the 2 irradiated groups and the group that was not irradiated, but there was no difference regarding the radiation doses used (18 or 24 Gy). The final predicted height (Bayley-Pinneau) was significantly less (P = 0.0071) in both groups treated with radiotherapy. Two girls had precocious puberty, and 1 boy with delayed puberty presented calcification of the epididymis. Radiotherapy was been responsible for late side effects, especially related to growth and puberty.


Aldosterone Does Not Predict Cardiovascular Events Following Acute Coronary Syndrome in Patients Initially Without Heart Failure.
Aldosterone may have adverse effects in the myocardium and vasculature. Treatment with an aldosterone antagonist reduces cardiovascular risk in patients with acute myocardial infarction complicated by heart failure (HF) and left ventricular systolic dysfunction. However, most patients with acute coronary syndrome do not have advanced HF. Among such patients, it is unknown whether aldosterone predicts cardiovascular risk. To address this question, we examined data from the dal-OUTCOMES trial that compared the cholesteryl ester transfer protein inhibitor dalcetrapib with placebo, beginning 4 to 12 weeks after an index acute coronary syndrome. Patients with New York Heart Association class II (with LVEF <40%), III, or IV HF were excluded. Aldosterone was measured at randomization in 4073 patients. The primary outcome was a composite of coronary heart disease death, nonfatal myocardial infarction, stroke, hospitalization for unstable angina, or resuscitated cardiac arrest. Hospitalization for HF was a secondary endpoint. Over a median follow-up of 37 months, the primary outcome occurred in 366 patients (9.0%), and hospitalization for HF occurred in 72 patients (1.8%). There was no association between aldosterone and either the time to first occurrence of a primary outcome (hazard ratio for doubling of aldosterone 0.92, 95% confidence interval 0.78-1.09, P=0.34) or hospitalization for HF (hazard ratio 1.38, 95% CI 0.96-1.99, P=0.08) in Cox regression models adjusted for covariates. In patients with recent acute coronary syndrome but without advanced HF, aldosterone does not predict major cardiovascular events. URL: http://www.clinicaltrials.gov. Unique identifier: NCT00658515.


Inhibition of polyamine synthesis induces p53 gene expression but not apoptosis.
The nuclear phosphoprotein p53 acts as a transcription factor and is involved in growth inhibition and apoptosis. The present study was designed to examine the effect of decreasing cellular polyamines on p53 gene expression and apoptosis in small intestinal epithelial (IEC-6) cells. Cells were grown in DMEM containing 5% dialyzed fetal bovine serum in the presence or absence of alpha-difluoromethylornithine (DFMO), a specific inhibitor of polyamine biosynthesis, for 4, 6, and 12 days. The cellular polyamines putrescine, spermidine, and spermine in DFMO-treated cells decreased dramatically at 4 days and remained depleted thereafter. Polyamine depletion by DFMO was accompanied by a significant increase in expression of the p53 gene. The p53 mRNA levels increased 4 days after exposure to DFMO, and the maximum increases occurred at 6 and 12 days after exposure. Increased levels of p53 mRNA in DFMO-treated cells were paralleled by increases in p53 protein. Polyamines given together with DFMO completely prevented increased expression of the p53 gene. Increased expression of the p53 gene in DFMO-treated cells was associated with a significant increase in G1 phase growth arrest. In contrast, no features of programmmed cell death were identified after polyamine depletion: no internucleosomal DNA fragmentation was observed, and no morphological features of apoptosis were evident in cells exposed to DFMO for 4, 6, and 12 days. These results indicate that 1) decreasing cellular polyamines increases expression of the p53 gene and 2) activation of p53 gene expression after polyamine depletion does not induce apoptosis in intestinal crypt cells. These findings suggest that increased expression of the p53 gene may play an important role in growth inhibition caused by polyamine depletion.


Delivery of viral vectors for gene therapy in intimal hyperplasia and restenosis in atherosclerotic swine.
Cardiovascular diseases including atherosclerosis are a major financial and health burden globally. Inflammation associated with atherosclerosis results in the development of plaques that can rupture causing thrombosis, stroke, or death. The most widely used treatment for the removal of atherosclerotic plaques is percutaneous transluminal coronary angioplasty (PTCA) with or without stenting. Although this is a safer and minimally invasive method, restenosis and intimal hyperplasia after interventional procedure remains a major hurdle and more refined approaches are needed. Studies in large animal models such as pigs have facilitated a greater understanding of the underlying mechanisms of the disease and provided novel targets for therapeutic intervention. In pre-clinical studies, viral vector gene therapy has emerged as a promising option for the reduction and/or prevention of restenosis and intimal hyperplasia. Although studies in animal models have generated promising results, clinical trials have yet to prove the clinical efficacy of gene therapy in coronary artery diseases. In this review, we examined and critically reviewed the most recent advances in viral vector gene therapy obtained from studies using porcine model of atherosclerosis.


Role of upper airway in ventilatory control in awake and sleeping dogs.
We examined the role of the upper airway in the regulation of the pattern of breathing in six adult dogs during wakefulness and sleep. The dogs breathed through a fenestrated endotracheal tube inserted through a tracheostomy. The tube was modified to allow airflow to be directed either through the nose or through the tracheostomy. When airflow was diverted from nose to tracheostomy there was an abrupt increase in the rate of expiratory airflow, resulting in prolongation of the end-expiratory pause but no change in overall expiratory duration or respiratory frequency. Furthermore, electromyogram recordings from implanted diaphragmatic and laryngeal muscle electrodes did not show any changes that could be interpreted as an attempt to delay expiratory airflow or increase end-expiratory lung volume. The effects of switching from nose to tracheostomy breathing could be reversed by adding a resistance to the endotracheal tube so as to approximate upper airway resistance. The findings indicate that under normal conditions in the adult dog upper airway receptors play little role in regulation of respiratory pattern and that the upper airway exerts little influence on the maintenance of end-expiratory lung volume.


Two approaches to integrating phenotype and clinical information.
Linkages between animal models of diseases and human data enable the development of translational research hypotheses. The objective of this study is to investigate two approaches to integrating phenotype and clinical information. On the one hand, we develop a terminology mapping between phenotypes from the Mammalian Phenotype Ontology (MPO) and Online Mendelian Inheritance in Man (OMIM) through the Unified Medical Language System (UMLS). On the other, we associate MPO phenotypes with OMIM manifestations through annotations made to orthologous genes. 1,469 MPO concepts (22%) were mapped successfully to some disease concept in the UMLS, of which 869 were present in OMIM. Among the 16,764 distinct MGI genes associated with human orthologs, 1,968 distinct genes were associated with both MPO and OMIM annotations. The UMLS is a valuable resource for linking phenotype terms to clinical terminologies, and these mappings between terminologies can help enrich gene annotation databases and unify phenotype representation.


Assessment of play and leisure: delineation of the problem.
This paper discusses current perspectives on play and leisure and proposes that if play and leisure are to be accepted as viable occupations, then (a) valid and reliable measures of play must be developed, (b) interventions must be examined for inclusion of the elements of play, and (c) the promotion of play and leisure must be an explicit goal of occupational therapy intervention. Existing tools used by occupational therapists to assess clients' play and leisure are evaluated for the aspects of play and leisure they address and the aspects they fail to address. An argument is presented for the need for an assessment of playfulness, rather than of play or leisure activities. A preliminary model for the development of such an assessment is proposed.


The human cytomegalovirus UL44 C clamp wraps around DNA.
Processivity factors tether the catalytic subunits of DNA polymerases to DNA so that continuous synthesis of long DNA strands is possible. The human cytomegalovirus DNA polymerase subunit UL44 forms a C clamp-shaped dimer intermediate in structure between monomeric herpes simplex virus UL42, which binds DNA directly via a basic surface, and the trimeric sliding clamp PCNA, which encircles DNA. To investigate how UL44 interacts with DNA, calculations were performed in which a 12 bp DNA oligonucleotide was docked to UL44. The calculations suggested that UL44 encircles DNA, which interacts with basic residues both within the cavity of the C clamp and in flexible loops of UL44 that complete the "circle." The results of mutational and crosslinking studies were consistent with this model. Thus, UL44 is a "hybrid" of UL42 and PCNA: its structure is intermediate between the two and its mode of interaction with DNA has elements of both.


Response to strict and liberalized specific carbohydrate diet in pediatric Crohn's disease.
To investigate the specific carbohydrate diet (SCD) as nutritional therapy for maintenance of remission in pediatric Crohn's disease (CD). Retrospective chart review was conducted in 11 pediatric patients with CD who initiated the SCD as therapy at time of diagnosis or flare. Two groups defined as SCD simple (diet alone, antibiotics or 5-ASA) or SCD with immunomodulators (corticosteroids and/or stable thiopurine dosing) were followed for one year and compared on disease characteristics, laboratory values and anthropometrics. The mean age at start of the SCD was 11.8 ± 3.0 years (range 6.6-17.6 years) with five patients starting the SCD within 5 wk of diagnosis. Three patients maintained a strict SCD diet for the study period and the mean time for liberalization was 7.7 ± 4.0 mo (range 1-12) for the remaining patients. In both groups, hematocrit, albumin and ESR values improved while on strict SCD and appeared stable after liberalization (P-value 0.006, 0.002, 0.002 respectively). The majority of children gained in weight and height percentile while on strict SCD, with small loss in weight percentile documented with liberalization. Disease control may be attainable with the SCD in pediatric CD. Further studies are needed to assess adherence, impact on mucosal healing and growth.


Association between first airborne cedar pollen level peak and pollinosis symptom onset: a web-based survey.
Cedar pollinosis in Japan affects nearly 25 % of Japanese citizens. To develop a treatment for cedar pollinosis, it is necessary to understand the relationship between the time of its occurrence and the amount of airborne cedar pollen. In the spring of 2009, we conducted daily Internet-based epidemiologic surveys, which included 1453 individuals. We examined the relationship between initial date of onset of pollinosis symptoms and daily amount of airborne cedar pollen to which subjects were exposed. Approximately 35.2 % of the subjects experienced the onset of pollinosis during a one-week interval in which the middle day coincided with the peak pollen count. The odds ratio for this one-week time interval was 4.03 (95 % confidence interval: 3.34-4.86). The predicted date of the cedar pollen peak can be used to determine the appropriate date for initiation of self-medication with anti-allergy drugs and thus avoid development of sustained and severe pollinosis.


High susceptibility to fatty liver disease in two-pore channel 2-deficient mice.
Endolysosomal organelles play a key role in trafficking, breakdown and receptor-mediated recycling of different macromolecules such as low-density lipoprotein (LDL)-cholesterol, epithelial growth factor (EGF) or transferrin. Here we examine the role of two-pore channel (TPC) 2, an endolysosomal cation channel, in these processes. Embryonic mouse fibroblasts and hepatocytes lacking TPC2 display a profound impairment of LDL-cholesterol and EGF/EGF-receptor trafficking. Mechanistically, both defects can be attributed to a dysfunction of the endolysosomal degradation pathway most likely on the level of late endosome to lysosome fusion. Importantly, endolysosomal acidification or lysosomal enzyme function are normal in TPC2-deficient cells. TPC2-deficient mice are highly susceptible to hepatic cholesterol overload and liver damage consistent with non-alcoholic fatty liver hepatitis. These findings indicate reduced metabolic reserve of hepatic cholesterol handling. Our results suggest that TPC2 plays a crucial role in trafficking in the endolysosomal degradation pathway and, thus, is potentially involved in the homoeostatic control of many macromolecules and cell metabolites.


Progressive changes in striatal dopaminergic markers, nigral volume, and rotational behavior following iron infusion into the rat substantia nigra.
Excess iron (Fe) within the substantia nigra zona compacta (SNc) has been implicated in the pathogenesis of Parkinson's disease (PD). We recently reported that intranigral Fe infusion into the rat substantia nigra (SN) induces dose-dependent SN neurodegeneration and associated reductions in striatal dopaminergic (DA) markers. The objective of the present study was to determine whether infused Fe is capable of inducing persistent/progressive neurodegenerative changes relevant to PD. Following unilateral infusions of vehicle, 1.25 or 2.10 nmol Fe into the rat SN, SNc neuronal loss, SN volume, striatal neurochemical markers, and apomorphine-induced rotational behavior were assessed at 2, 4, and 6 months. Semiquantitative analysis of thionine-stained SNc neurons demonstrated an initial modest neuronal loss which remained stable through 6 months postinfusion. Fe-induced SN atrophy was dose-dependent and progressive through 6 months. Striatal DA and homovanillic acid levels were progressively decreased at least through 4 months following 1.25 nmol Fe infusion; both doses of Fe induced significant reductions of both DA markers at 4 months with no recovery evident through 6 months. Apomorphine-induced rotational behavior progressively increased for both Fe infusion groups through the 6 months of testing. These data indicate that a single exposure of the SN to a modest amount of Fe can induce persistent/progressive changes occurring through a number of months postinfusion and further establishes intranigral Fe infusion as an animal model for PD.


Natriuretic peptide receptors, NPR-A and NPR-B, in cultured rabbit retinal pigment epithelium cells.
We tried to detect natriuretic peptide (NP) receptor (NPR-A and NPR-B) mRNAs in cultured rabbit retinal pigment epithelium (RPE) cells and examined the regulation of their expression in relation to subretinal fluid absorption or RPE cell proliferation. RPE cells from 2-4 passages were grown to confluence on microporous membranes and analyzed for levels of expression of receptor mRNAs by quantitative RT-PCR and Northern blotting. The expression of NPR-B mRNA was approximately tenfold higher than that of NPR-A mRNA. The expression of NPR-A mRNA was not affected by treatments that may change subretinal fluid transport, while that of NPR-B mRNA was inhibited by transmitters involved in light- and dark-adaptation such as dopamine and melatonin. Expression of NPR-B mRNA was also suppressed by platelet-derived growth factor and transforming growth factor-beta. Furthermore, atrial natriuretic peptide (ANP) and C-type natriuretic peptide (CNP), ligands for NPR-A and B, respectively, inhibited the proliferation of RPE cells, as analyzed by incorporation of [3H]thymidine. These findings suggest that ANP may be involved in constitutive absorption of subretinal fluid and that NPs form an important regulatory system of proliferation in RPE cells.


Dental amalgam as one of the risk factors in autoimmune diseases.
Experimental and clinical data published recently show that dental amalgam can give rise to undesirable immunological responses in susceptible individuals. In genetically susceptible strains of experimental animals, mercury and silver can induce autoimmune responses. Sera of patients sensitive to mercury were found to have a higher incidence of autoantibodies relative to controls. The aim of this study was to determine possible presence of antinuclear SSB/La autoantibodies after the in vitro stimulation of peripheral blood lymphocytes with HgCl2. Lymphocytes were obtained from patients with autoimmune thyroiditis and increased response to mercury in vitro. Mononuclear cells were cultivated for 6 days with 100 microl HgCl2 solution or with pure medium and the levels of antinuclear autoantibodies SSB/La were assayed by a commercial SSB/La ELISA kit. Increased production of SSB/La autoantibodies in the media following stimulation of peripheral blood lymphocytes with HgCl2 was found in all cases. Using the Student's paired test, the results were significant on the p=0.05 significance level. Results imply that, in some patients with thyroiditis, mercury from dental amalgam can stimulate the production of antinuclear antibodies. Dental amalgam may be a risk factor in some patients with autoimmune disease.


Local immune response against larvae of Rhipicephalus (Boophilus) microplus in Bos taurus indicus and Bos taurus taurus cattle.
Bos taurus indicus cattle are less susceptible to infestation with Rhipicephalus (Boophilus) microplus than Bos taurus taurus cattle but the immunological basis of this difference is not understood. We compared the dynamics of leukocyte infiltrations (T cell subsets, B cells, major histocompatibility complex (MHC) class II-expressing cells, granulocytes) in the skin near the mouthparts of larvae of R. microplus in B. t. indicus and B. t. taurus cattle. Previously naïve cattle were infested with 50,000 larvae (B. t. indicus) or 10,000 larvae (B. t. taurus) weekly for 6 weeks. One week after the last infestation all of the animals were infested with 20,000 larvae of R. microplus. Skin punch biopsies were taken from all animals on the day before the primary infestation and from sites of larval attachment on the day after the first, second, fourth and final infestations. Infiltrations with CD3(+), CD4(+), CD8(+) and gammadelta T cells followed the same pattern in both breeds, showing relatively little change during the first four weekly infestations, followed by substantial increases at 7 weeks post-primary infestation. There was a tendency for more of all cell types except granulocytes to be observed in the skin of B. t. indicus cattle but the differences between the two breeds were consistently significant only for gammadelta T cells. Granulocyte infiltrations increased more rapidly from the day after infestation and were higher in B. t. taurus cattle than in B. t. indicus. Granulocytes and MHC class II-expressing cells infiltrated the areas closest to the mouthparts of larvae. A large volume of granulocyte antigens was seen in the gut of attached, feeding larvae.


The Solanum demissum R8 late blight resistance gene is an Sw-5 homologue that has been deployed worldwide in late blight resistant varieties.
The potato late blight resistance gene R8 has been cloned. R8 is found in five late blight resistant varieties deployed in three different continents. R8 recognises Avr8 and is homologous to the NB-LRR protein Sw-5 from tomato. The broad spectrum late blight resistance gene R8 from Solanum demissum was cloned based on a previously published coarse map position on the lower arm of chromosome IX. Fine mapping in a recombinant population and bacterial artificial chromosome (BAC) library screening resulted in a BAC contig spanning 170 kb of the R8 haplotype. Sequencing revealed a cluster of at least ten R gene analogues (RGAs). The seven RGAs in the genetic window were subcloned for complementation analysis. Only one RGA provided late blight resistance and caused recognition of Avr8. From these results, it was concluded that the newly cloned resistance gene was indeed R8. R8 encodes a typical intracellular immune receptor with an N-terminal coiled coil, a central nucleotide binding site and 13 C-terminal leucine rich repeats. Phylogenetic analysis of a set of representative Solanaceae R proteins shows that R8 resides in a clearly distinct clade together with the Sw-5 tospovirus R protein from tomato. It was found that the R8 gene is present in late blight resistant potato varieties from Europe (Sarpo Mira), USA (Jacqueline Lee, Missaukee) and China (PB-06, S-60). Indeed, when tested under field conditions, R8 transgenic potato plants showed broad spectrum resistance to the current late blight population in the Netherlands, similar to Sarpo Mira.


Coordination-driven micellelization of block copolymers with gold(i) complexes induces remarkable phosphorescence enhancements with reversible mechanochromism.
The coordination-driven self-assembly of block copolymers with gold(i) complexes leads to the formation of spherical micelles with remarkable phosphorescence enhancements. The rising luminescence level increases unexpectedly with increasing the degree of polymerization of the noncoordinated block. Furthermore, one of the gold(i)-containing metallopolymers shows reversible mechanochromic luminescence.