Efficacy of spray formulations containing binary mixtures of clove and eucalyptus oils against susceptible and pyrethroid/ malathion-resistant head lice (Anoplura: Pediculidae).
The control efficacy of clove, Eugenia caryophyllata, and eucalyptus, Eucalyptus globulus, essential oils and 15 formulations containing these essential oils alone (8, 12, and 15% sprays) and their binary mixtures (7:3, 5:5, and 3:7 by weight) against adult females of insecticide-susceptible KR-HL and dual malathion- and permethrin-resistant BR-HL strains of head louse, Pediculus humanus capitis (De Geer), was examined by using contact plus fumigant and human hair wig (placed over the head of mannequin) mortality bioassays. In contact plus fumigant mortality bioassay, essential oils from eucalyptus (0.225 mg/cm2) and clove (1.149 mg/cm2) were less effective than either d-phenothrin (0.0029 mg/cm2) or pyrethrum (0.0025 mg/cm2) based on 6-h median lethal concentration values. However, the efficacies of eucalyptus and clove oils were almost identical against females fromn both strains, despite high levels of resistance of the BR-HL females to d-phenothrin (resistance ratio, 667) and pyrethrum (resistance ratio, 754). In human hair wig mortality bioassay, eucalyptus oil spray treatment gave better control efficacy than either spray treatment with clove oil alone or their binary mixtures. Thus, eucalyptus applied as 8% sprays (15 or 20 ml) appears to provide effective protection against pediculosis even to insecticide-resistant head louse populations. Once the safety issues resolved, covering the treated hair and scalp with bath shower cap or hat would ensure the fumigant action of the essential oil.


Leptin.
The discovery of the adipose-derived hormone leptin has generated enormous interest in the interaction between peripheral signals and brain targets involved in the regulation of feeding and energy balance. Plasma leptin levels correlate with fat stores and respond to changes in energy balance. It was initially proposed that leptin serves a primary role as an anti-obesity hormone, but this role is commonly thwarted by leptin resistance. Leptin also serves as a mediator of the adaptation to fasting, and this role may be the primary function for which the molecule evolved. There is increasing evidence that leptin has systemic effects apart from those related to energy homeostasis, including regulation of neuroendocrine and immune function and a role in development.


Coronary heart disease and cortical thickness, gray matter and white matter lesion volumes on MRI.
Coronary heart disease (CHD) has been linked with cognitive decline and dementia in several studies. CHD is strongly associated with blood pressure, but it is not clear how blood pressure levels or changes in blood pressure over time affect the relation between CHD and dementia-related pathology. The aim of this study was to investigate relations between CHD and cortical thickness, gray matter volume and white matter lesion (WML) volume on MRI, considering CHD duration and blood pressure levels from midlife to three decades later. The study population included 69 elderly at risk of dementia who participated in the Cardiovascular Risk Factors, Aging and Dementia (CAIDE) study. CAIDE participants were examined in midlife, re-examined 21 years later, and then after additionally 7 years (in total up to 30 years follow-up). MRIs from the second re-examination were used to calculate cortical thickness, gray matter and WML volume. CHD diagnoses were obtained from the Finnish Hospital Discharge Register. Linear regression analyses were adjusted for age, sex, follow-up time and scanner type, and additionally total intracranial volume in GM volume analyses. Adding diabetes, cholesterol or smoking to the models did not influence the results. CHD was associated with lower thickness in multiple regions, and lower total gray matter volume, particularly in people with longer disease duration (>10 years). Associations between CHD, cortical thickness and gray matter volume were strongest in people with CHD and hypertension in midlife, and those with CHD and declining blood pressure after midlife. No association was found between CHD and WML volumes. Based on these results, long-term CHD seems to have detrimental effects on brain gray matter tissue, and these effects are influenced by blood pressure levels and their changes over time.


Arthroscopy in rheumatology: where have we been? Where might we go?
The aim of our manuscript is to illustrate the past, present and future role of rheumatologists performing arthroscopy. Doctors first began adapting endoscopes to inspect joints to assess synovial conditions that concern rheumatologists. Rheumatologists were among the pioneers developing arthroscopy. Students of the father of modern arthroscopy, Watanabe, included rheumatologists, who taught others once home. Rheumatologists assessed the intra-articular features of their common diseases in the 60s and 70s. Improvements in instrumentation and efforts by a few orthopaedists adapted a number of common joint surgical procedures for arthroscopy. Interest from rheumatologists in arthroscopy grew in the 90s with 'needle scopes' used in an office setting. Rheumatologists conducting the first prospective questioning arthroscopic debridement in OA and developing biological compounds reduced the call for arthroscopic interventions. The arthroscope has proven an excellent tool for viewing and sampling synovium, which continues to at several international centres. Some OA features-such as calcinosis-beg further arthroscopic investigation. A new generation of 'needle scopes' with far superior optics awaits future investigators.


An Arylazopyrazole-Based N-Heterocyclic Carbene as a Photoswitch on Gold Surfaces: Light-Switchable Wettability, Work Function, and Conductance.
A novel photoresponsive and fully conjugated N-heterocyclic carbene (NHC) has been synthesized that combines the excellent photophysical properties of arylazopyrazoles (AAPs) with an NHC that acts as a robust surface anchor (AAP-BIMe). The formation of self-assembled monolayers (SAMs) on gold was proven by ToF-SIMS and XPS, and the organic film displayed a very high stability at elevated temperatures. This stability was also reflected in a high desorption energy, which was determined by temperature-programmed SIMS measurements. E-/Z-AAP-BIMe@Au photoisomerization resulted in reversible alterations of the surface energy (i.e. wettability), the surface potential (i.e. work function), and the conductance (i.e. resistance). The effects could be explained by the difference in the dipole moment of the isomers. Furthermore, sequential application of a dummy ligand by microcontact printing and subsequent backfilling with AAP-BIMe allowed its patterning on gold. To the best of our knowledge, this is the first example of a photoswitchable NHC on a gold surface. These properties of AAP-BIMe@Au illustrate its suitability as a molecular switch for electronic devices.


Abortion services and providers in Canada in 2019: results of a national survey.
Since 2016, abortion care has undergone several important changes, particularly related to the provision of medical abortion using mifepristone. We aimed to document characteristics of the abortion care workforce in Canada after the update of clinical practice guidelines of mifepristone use for medical abortion. We conducted a national, web-based, anonymized, bilingual (English/French) survey. We collected demographics and clinical care characteristics of physicians and nurse practitioners who provided abortion care in 2019. Between July and December 2020, we distributed the survey through professional organizations, including The College of Family Physicians of Canada and The Society of Obstetricians and Gynaecologists of Canada. We present descriptive statistics. Overall, 465 respondents representing all 10 provinces and 3 territories in Canada completed the survey. Of these, 388 (83.4%), including 30 nurse practitioners, provided first-trimester medical abortion, of which 350 (99.4%) used mifepristone. Two hundred and nineteen (47.1%) respondents provided first-trimester surgical abortion, 109 (23.4%) provided second-trimester surgical abortion and 115 (24.7%) provided second- or third-trimester medical abortion. Half of respondents reported fewer than 5 years of experience with any abortion care. Respondents reported providing a total of 48 509 abortions in 2019, including 32 345 (66.7%) first-trimester surgical abortions and 13 429 (27.7%) first-trimester medical abortions. In Quebec, only 1918 (12.5%) of reported abortions were first-trimester medical abortions. Primary care providers provided 34 540 (71.2%) of the total abortions. First-trimester medical abortions represented 44.4% (n = 2334) of all abortions in rural areas, as opposed to 25.6% (n = 11 067) in urban areas. The increased availability of medical abortion facilitates abortion access, especially in primary care and rural settings, and where surgical abortion is not available. Rejuvenation of the workforce is a critical contributor to equitable access to abortion services.


The use of vascular endothelial growth factor functionalized agarose to guide pluripotent stem cell aggregates toward blood progenitor cells.
The developmental potential of pluripotent stem cells is influenced by their local cellular microenvironment. To better understand the role of vascular endothelial growth factor (VEGFA) in the embryonic cellular microenvironment, we synthesized an artificial stem cell niche wherein VEGFA was immobilized in an agarose hydrogel. Agarose was first modified with coumarin-protected thiols. Upon exposure to ultra-violet excitation, the coumarin groups were cleaved leaving reactive thiols to couple with maleimide-activated VEGFA. Mouse embryonic stem cells (ESC) aggregates were encapsulated in VEGFA immobilized agarose and cultured for 7 days as free-floating aggregates under serum-free conditions. Encapsulated aggregates were assessed for their capacity to give rise to blood progenitor cells. In the presence of bone morphogenetic protein-4 (BMP-4), cells exposed to immobilized VEGFA upregulated mesodermal markers, brachyury and VEGF receptor 2 (T+VEGFR2+) by day 4, and expressed CD34 and CD41 (CD34+CD41+) on day 7. It was found that immobilized VEGFA treatment was more efficient at inducing blood progenitors (including colony forming cells) on a per molecule basis than soluble VEGFA. This work demonstrates the use of functionalized hydrogels to guide encapsulated ESCs toward blood progenitor cells and introduces a tool capable of recapitulating aspects of the embryonic microenvironment.


Clone identification and clonal structure of the European aspen (Populus tremula).
The European aspen (Populus tremula) is thought to reproduce mostly asexually. Thus aspen forms clones, in which several ramets belong to one genetically defined genet. We compared the clonal structure of aspen in old-growth and managed forests in southern and northeastern Finland. Clones were identified using morphological characters and nine microsatellite loci originally developed for Populus tremuloides. There were more clones identified by microsatellites than morphotypes both in old-growth and managed forest. The average size of the clones was only 2.3 ramets and most clones (70%) consisted of just one ramet. The size of the clones showed no difference between managed and old-growth forests or between northeastern and southern Finland. The small size of the clones suggests that most of them are relatively young. Therefore, sexual reproduction may be more common than previously thought. There was an aggregated spatial genetic structure as measured by Moran's I (0-10 m) and by co-ancestry (rho(ij), 0-20 m). Low level of co-ancestry can be explained by relatively unrestricted gene flow, the important role of disturbance in reproduction, and/or local selection.


Psychological stress experienced by health care personnel.
Health care personnel consider the challenge of their work to be the principal reason for job satisfaction. Problems of work organization and the small number of personnel cause quantitative overload that has been perceived as problematic by various professional groups in health care units. Role ambiguity and role conflicts are also experienced frequently. Social contacts between patients and personnel, as well as social contacts among the personnel themselves, are sometimes thought to be very problematic. The increase in violent behavior towards health care personnel is a central stressor of their work. The way that work characteristics and strain are experienced, however, is affected by the profession and, especially, by the workplace. Psychological stress reactions are relatively common among health care personnel. The effects of work reorganization, the clarification of responsibilities, increased supplementary training and professional supervision, and the application of directions for the prevention of violence on the stress and strain of health care professionals should be studied as a means to diminish stress and increase well-being and productivity.


Attitudes of the public to medical care: part 6. Pharmaceutical benefits.
People's attitudes in Dunedin and Auckland were surveyed regarding prescribing. A significant proportion favoured a prescription charge. With a choice between a free doctor and free medicine, there was preference for the former. No great dissatisfaction with the present system of prescription medicine was found.


CT Examinations for COVID-19: A Systematic Review of Protocols, Radiation Dose, and Numbers Needed to Diagnose and Predict.
Although chest CT has been discussed as a first-line test for coronavirus disease 2019 (COVID-19), little research has explored the implications of CT exposure in the population. To review chest CT protocols and radiation doses in COVID-19 publications and explore the number needed to diagnose (NND) and the number needed to predict (NNP) if CT is used as a first-line test. We searched nine highly cited radiology journals to identify studies discussing the CT-based diagnosis of COVID-19 pneumonia. Study-level information on the CT protocol and radiation dose was collected, and the doses were compared with each national diagnostic reference level (DRL). The NND and NNP, which depends on the test positive rate (TPR), were calculated, given a CT sensitivity of 94% (95% confidence interval [CI]: 91%-96%) and specificity of 37% (95% CI: 26%-50%), and applied to the early outbreak in Wuhan, New York, and Italy. From 86 studies, the CT protocol and radiation dose were reported in 81 (94.2%) and 17 studies (19.8%), respectively. Low-dose chest CT was used more than twice as often as standard-dose chest CT (39.5% vs.18.6%), while the remaining studies (44.2%) did not provide relevant information. The radiation doses were lower than the national DRLs in 15 of the 17 studies (88.2%) that reported doses. The NND was 3.2 scans (95% CI: 2.2-6.0). The NNPs at TPRs of 50%, 25%, 10%, and 5% were 2.2, 3.6, 8.0, 15.5 scans, respectively. In Wuhan, 35418 (TPR, 58%; 95% CI: 27710-56755) to 44840 (TPR, 38%; 95% CI: 35161-68164) individuals were estimated to have undergone CT examinations to diagnose 17365 patients. During the early surge in New York and Italy, daily NNDs changed up to 5.4 and 10.9 times, respectively, within 10 weeks. Low-dose CT protocols were described in less than half of COVID-19 publications, and radiation doses were frequently lacking. The number of populations involved in a first-line diagnostic CT test could vary dynamically according to daily TPR; therefore, caution is required in future planning.


The caries experience of 5-year-old children in Scotland, Wales and England in 2011-2012: reports of cross-sectional surveys using BASCD criteria.
This paper collates differences in methods and trends in caries prevalence in surveys of the oral health of young children undertaken in Scotland, Wales and England in 2011-12. For Wales and England this was the second survey carried out since changes were required in consent arrangements. In compliance with BASCD criteria representative samples were drawn within the geographies of primary care organisations across the UK, and within Local Authorities across England and Wales. Consent was sought in two ways; via opt-in parental consent in England and Wales and opt-out parental consent in Scotland. Children aged five were examined in England and those aged 5 to 6 were examined in Wales and Scotland. Examinations were conducted in schools by trained and calibrated examiners and caries was diagnosed at the dentinal threshold using visual criteria. In Scotland there is a continuing decline in caries prevalence in young school children. Comparison with the previous survey using positive consent in England and Wales shows a decline in caries in both England and Wales although decay levels remain higher in more deprived areas. International comparisons assist in interpreting data and trends even if there are some differences in approach. A trend line is more useful than a single data point for monitoring of oral health. This second survey using positive parental consent in England and Wales has enabled trend analysis for the first time since the consent arrangements changed.


Hydrogen-rich medium protects mouse embryonic fibroblasts from oxidative stress by activating LKB1-AMPK-FoxO1 signal pathway.
Persistent oxidative stress is recognized as a major cause of many pathological conditions as well as ageing. However, most clinical trials of dietary antioxidants have failed to produce successful outcomes in treating oxidative stress-induced diseases. Molecular hydrogen (H2) has recently received considerable attention as a therapeutic agent owing to its novel antioxidant properties, a selective scavenger of hydroxyl and peroxynitrite radicals. Beyond this, numerous reports support that H2 can modulate the activity of various cellular signal pathways. However, its effect on AMP-activated protein kinase (AMPK) signal pathway, a central regulator of energy hemostasis, has remained almost elusive. Here, we report that hydrogen-rich medium activated LKB1-AMPK signal pathway without ATP depletion, which in turn induced FoxO1-dependent transcription of manganese superoxide dismutase and catalase in mouse embryonic fibroblasts. Moreover, hydrogen-rich media effectively reduced the level of reactive oxygen species in cells treated with hydrogen peroxide and protected these cells from apoptosis in an AMPK-dependent manner. These results suggest that the LKB1-AMPK-FoxO1 signaling pathway is a critical mediator of the antioxidant properties of H2, further supporting the idea that H2 acts as a signaling molecule to serve various physiological functions.


Prevalence of hepatitis C virus and hepatitis G virus in patients with non-Hodgkin's lymphoma.
Hepatitis C virus (HCV) and hepatitis G virus (HGV) belong to the same family of flaviviridea. A causative role of HCV infection in the pathogenesis of non-Hodgkin's lymphoma (NHL) has been discussed widely. Little is known about the possible association between NHL and HGV discovered recently. In this study, anti-HCV and HGV-RNA prevalence were investigated in a group of 70 patients with NHL. The results were compared to a control group of 70 age- and sex-matched healthy subjects. One patient in each group (1.4%) was found to be anti-HCV-positive; the difference was not statistically significant (P > 0.05). Five subjects in the patient group (7.1%) were positive for HGV-RNA, while a single subject was positive in the control group (1.4%); the difference was not statistically significant (P > 0.05). Odds ratios for anti-HCV and HGV-RNA were 1 and 5.30, respectively. Our findings suggest that neither HCV nor HGV are causative or contributing factors in the aetiopathogenesis of NHL.


Biological nanoparticles carrying the Hmda-7 gene are effective in inhibiting pancreatic cancer in vitro and in vivo.
Pancreatic cancer is one of the most common malignancies of the digestive system, and remains a clinical challenge. This study aimed to assess the effects of bovine serum albumin (BSA) nanoparticles carrying the hMDA-7 gene (BSA-NP-hMDA-7) in the treatment of pancreatic cancer. BSA-NP-hMDA-7 was generated by nanotechnology and gene recombination technology. A total of 5 BXPC-3 or PANC-1 pancreatic cancer cell groups were examined, including Control, BSA-NPs, Empty vector, hMDA-7 plasmid, and hMDA-7 BSA-NPs groups, respectively. Proliferation and apoptosis of cultured cells were assessed by the MTT method and flow-cytometry, respectively. In addition, pancreatic cancer models were established with both cell lines in nude mice, and the expression profiles of hMDA-7 and VEGF in cancer tissues were measured by Western blot and immunohistochemistry. BSA-NP-hMDA-7 nanoparticles were successfully generated, and significantly inhibited the proliferation of BXPC-3 and PANC-1 cells; in addition, apoptosis rates were higher in both cell lines after treatment with BSA-NP-hMDA-7 (P<0.05). Nude mouse xenograft studies indicated that treatment with BSA-NP-hMDA-7 nanoparticles resulted in decreased tumor size. Moreover, the hMDA-7 protein was found in tumor tissues after hMDA-7 gene transfection, while BSA-NP-hMDA-7 significantly suppressed VEGF expression in tumor tissues. Similar results were obtained for both BXPC-3 and PANC-1 xenograft models. BSA nanoparticles carrying the hMDA-7 gene effectively transfected BXPC-3 and PANC-1 pancreatic cancer cells, causing reduced cell proliferation and enhanced apoptosis in vitro. In mouse xenografts, BSA-NP-hMDA-7 treatment decreased tumor size and reduced VEGF expression. These findings indicated that BSA-NP-hMDA-7 might exert anticancer effects via VEGF suppression.


First isolation of Mycobacterium saskatchewanense from medical devices.
Mycobacterium saskatchewanense is a species of pigmented slow-growing Non-Tuberculous Mycobacteria (NTM), positive for Mycobacterium avium complex (MAC) by AccuProbe system. MAC organisms have frequently been isolated from different medical devices. This is the first study reporting isolation of M. saskatchewanense from medical devices and highlights the importance of correctly identifying the NTMs that often colonize sanitary water. GenoType Mycobacterium CM CE-IVD kit (CM) was used as the first step of NTM strain identification, and all positive cultures were found to be components of MAC. Then, GenoType NTM-DR CE-IVD kit (NTM-DR) was used to differentiate the different species. Sub-culture on solid media were used for: (i) phenotypical confirmation by colony morphology and Matrix-Assisted Laser Desorption/Ionization-Time of Flight (MALDI-TOF) mass spectrometry; (ii) molecular confirmation by Next Generation Sequencing. All positive cultures were identified as M. intracellulare by CM and NTM-DR assays, whereas colony morphology showed bright yellow scotochromogenic growth. MALDI-TOF analyses identified the strains as M. saskatchewanense with a high score, and identification was confirmed by NGS analysis based on the hsp-65 region. This paper suggests that it is important to actively monitor NTM contamination in medical devices that use sanitary water, to prevent the possibility of patients becoming infected.


Vascular endothelial growth factor expression and signaling in the lens.
Previous studies have identified sequences encoding vascular endothelial growth factor (VEGF)-A and one of the VEGF receptors (VEGFR2, Flk-1, KDR) in lens fiber cells. The current study was undertaken to determine the distribution of VEGF-A protein in the lens, whether signaling through VEGF receptors occurs in lens cells, the pattern of VEGF-A expression during lens development, and the effect of hypoxia on VEGF-A expression. VEGF-A and VEGFR2 were localized using immunocytochemistry. VEGF-A and VEGFR2 protein were identified and quantified by Western blot analysis. Activated (tyrosine phosphorylated) VEGFR2 was detected by immunoprecipitation with an anti-phosphotyrosine antibody followed by Western blot analysis with antibody to VEGFR2. Levels of VEGF-A mRNA were measured by quantitative PCR. Suturing the lids of adult mouse or rabbit eyes for 3 days was used to induce lens hypoxia. VEGFR2 sequences were present in adult human lens epithelial cells, and VEGF-A transcripts were detected in chicken embryo, adult human, and mouse lens epithelial cells. VEGF-A protein localized to the ends of mouse embryo lens fiber cells at developmental stages when the fetal vasculature was forming. At later stages, VEGF-A was distributed uniformly throughout the cytoplasm of cortical fiber cells. VEGFR2 was present in mouse lens epithelial and fiber cells and was tyrosine phosphorylated at all stages examined. VEGF-A protein was barely detectable in lens epithelial cells during the first postnatal week, but increased as the capillaries of the anterior pupillary membrane regressed. VEGF-A levels were highest in adult lenses. Suturing the eyelid caused an increase in VEGF-A mRNA and protein in lens epithelial and fiber cells. VEGF-A secreted by lens cells may stimulate the formation of the fetal vasculature, but regression of these vessels is not likely to be caused by a reduction in VEGF-A production by the lens. An active VEGF-A signaling system of unknown function appears to be active in the lens. It is likely that VEGF-A expression is regulated by tissue hypoxia at all stages of lens development.


Multiple introductions boosted genetic diversity in the invasive range of black cherry (Prunus serotina; Rosaceae).
Black cherry (Prunus serotina) is a North American tree that is rapidly invading European forests. This species was introduced first as an ornamental plant, then it was massively planted by foresters in many countries, but its origins and the process of invasion remain poorly documented. Based on a genetic survey of both native and invasive ranges, the invasion history of black cherry was investigated by identifying putative source populations and then assessing the importance of multiple introductions on the maintenance of gene diversity. Genetic variability and structure of 23 populations from the invasive range and 22 populations from the native range were analysed using eight nuclear microsatellite loci and five chloroplast DNA regions. Chloroplast DNA diversity suggests there were multiple introductions from a single geographic region (the north-eastern United States). A low reduction of genetic diversity was observed in the invasive range for both nuclear and plastid genomes. High propagule pressure including both the size and number of introductions shaped the genetic structure in Europe and boosted genetic diversity. Populations from Denmark, The Netherlands, Belgium and Germany showed high genetic diversity and low differentiation among populations, supporting the hypothesis that numerous introduction events, including multiple individuals and exchanges between sites, have taken place during two centuries of plantation. This study postulates that the invasive black cherry has originated from east of the Appalachian Mountains (mainly the Allegheny plateau) and its invasiveness in north-western Europe is mainly due to multiple introductions containing high numbers of individuals.


The Role of Mitochondrial Dysfunction in Radiation-Induced Heart Disease: From Bench to Bedside.
Radiation is a key modality in the treatment of many cancers; however, it can also affect normal tissues adjacent to the tumor, leading to toxic effects. Radiation to the thoracic region, such as that received as part of treatment for breast and lung cancer, can result in incidental dose to the heart, leading to cardiac dysfunction, such as pericarditis, coronary artery disease, ischemic heart disease, conduction defects, and valvular dysfunction. The underlying mechanisms for these morbidities are currently being studied but are not entirely understood. There has been increasing focus on the role of radiation-induced mitochondrial dysfunction and the ensuing impact on various cardiac functions in both preclinical models and in humans. Cardiomyocyte mitochondria are critical to cardiac function, and mitochondria make up a substantial part of a cardiomyocyte's volume. Mitochondrial dysfunction can also alter other cell types in the heart. This review summarizes several factors related to radiation-induced mitochondrial dysfunction in cardiomyocytes and endothelial cells. These factors include mitochondrial DNA mutations, oxidative stress, alterations in various mitochondrial function-related transcription factors, and apoptosis. Through improved understanding of mitochondria-dependent mechanisms of radiation-induced heart dysfunction, potential therapeutic targets can be developed to assist in prevention and treatment of radiation-induced heart damage.


Variability in Patterns of Recurrence After Resection of Primary Retroperitoneal Sarcoma (RPS): A Report on 1007 Patients From the Multi-institutional Collaborative RPS Working Group.
Retroperitoneal sarcomas (RPS) are rare tumors composed of several well defined histologic subtypes. The aim of this study was to analyze patterns of recurrence and treatment variations in a large population of patients, treated at reference centers. All consecutive patients with primary RPS treated at 6 European and 2 North American institutions between January 2002 and December 2011 were included. Five, 8, and 10-year overall survival (OS) and crude cumulative incidence (CCI) of local recurrence (LR) and distant metastasis (DM) were calculated. Multivariate analyses for OS, CCI of LR, and DM were performed. In all, 1007 patients were included. Median follow-up was 58 months (first and third quartile range 36-90). The 5, 8, and 10-year OS were 67% [95% confidence interval (CI), 63, 70), 56% (95% CI, 52, 61), and 46% (95% CI, 40, 53). The 5, 8, and 10-year CCI of LR and DM were 25.9 (95% CI, 23.1, 29.1), 31.3 (95% CI, 27.8, 35.1), 35% (95% CI, 30.5, 40.1), and 21% (95% CI, 18.4, 23.8%), 21.6 (95% CI, 19.0, 24.6), and 21.6 (95% CI, 19.0, 24.6), respectively. Tumour size, histologic subtype, malignancy grade, multifocality, and completeness of resection were significant predictors of outcome. Patterns of recurrence varied depending on histologic subtype. Different treatment policies at participating institutions influenced LR of well differentiated liposarcoma without impacting OS, whereas discrepancies in adjuvant systemic therapies did not impact LR, DM, or OS of leiomyosarcoma. Reference centers are critical to outcomes of RPS patients, as the management strategy requires specific expertise. Histologic subtype predicts patterns of recurrence and should inform management decision. A prospective international registry is under preparation, to further define our understanding of this disease.


Gaps in Developmental Pediatrics training: A Canadian resident physician perspective.
This article was migrated. The article was marked as recommended. Introduction: Postgraduate medical training worldwide has recently experienced a transition to Competency-Based Medical Education (CBME). This provides a timely opportunity to critically evaluate the postgraduate medical curriculum, particularly from a trainee perspective. Studies reveal that Canadian residents and recent graduates in pediatrics and family medicine are uncomfortable with their proficiency in child development. However, little is known about residents' perceptions of their training, nor where specific needs lie. We therefore sought to identify gaps in developmental pediatrics training, with the goal of informing the development of a new CBME curriculum. Methods: An online cross sectional needs assessment survey was administered to current pediatrics and family medicine residents at our institution. A total of 63 residents participated, 43 pediatrics and 20 family medicine. Results: Four key themes emerged from analysis of survey results: 1. Residents agree that developmental pediatrics is relevant to future practice and competency; 2. Residents feel they lack competency in the assessment and management of patients with developmental issues; 3. Residents' feelings of insufficient and inadequate training increase over time; 4. Residents recommend changes to developmental pediatrics training. Conclusion: As we prepare to transition to CBME, curriculum should be purposefully developed to meet resident identified need and reflect appropriate competencies required for clinical practice.


Steric factors direct Baylis-Hillman and aldol reactions in titanium tetrachloride mediated coupling between alpha-keto esters and cyclohex-2-enone derivatives.
The titanium tetrachloride mediated reaction of alpha-keto esters with 5,5-dimethylcyclohex-2-enone provides the corresponding Baylis-Hillman adducts exclusively whereas a similar reaction of alpha-keto esters with cyclohex-2-enone furnishes the corresponding aldol adducts (with high syn-diasteroeselectivity) as the major product (along with the Baylis-Hillman adducts as the minor product), thus clearly demonstrating the role of the steric factors in directing the reaction pathway.


Droplet on demand system utilizing a computer controlled microvalve integrated into a stiff polymeric microfluidic device.
An integrated microvalve fabricated in a stiff polymeric (polycarbonate) device allows for formation of droplets and bubbles of arbitrary volumes and at arbitrary times of emission. Predesigned protocols of formation of sequences of volumes, intervals between the droplets and their chemical compositions can be practically and reproducibly realised and controlled from a personal computer. The design of the microvalve enables its utilization in chips made in a range of other materials, including plastics and glass and in devices operated both with positive and negative pressure providing a useful module for a range of applications of microfluidic droplet systems.


Enhancing predictions of antimicrobial resistance of pathogens by expanding the potential resistance gene repertoire using a pan-genome-based feature selection approach.
Predicting which pathogens might exhibit antimicrobial resistance (AMR) based on genomics data is one of the promising ways to swiftly and precisely identify AMR pathogens. Currently, the most widely used genomics approach is through identifying known AMR genes from genomic information in order to predict whether a pathogen might be resistant to certain antibiotic drugs. The list of known AMR genes, however, is still far from comprehensive and may result in inaccurate AMR pathogen predictions. We thus felt the need to expand the AMR gene set and proposed a pan-genome-based feature selection method to identify potential gene sets for AMR prediction purposes. By building pan-genome datasets and extracting gene presence/absence patterns from four bacterial species, each with more than 2000 strains, we showed that machine learning models built from pan-genome data can be very promising for predicting AMR pathogens. The gene set selected by the eXtreme Gradient Boosting (XGBoost) feature selection approach further improved prediction outcomes, and an incremental approach selecting subsets of XGBoost-selected features brought the machine learning model performance to the next level. Investigating selected gene sets revealed that on average about 50% of genes had no known function and very few of them were known AMR genes, indicating the potential of the selected gene sets to expand resistance gene repertoires. We demonstrated that a pan-genome-based feature selection approach is suitable for building machine learning models for predicting AMR pathogens. The extracted gene sets may provide future clues to expand our knowledge of known AMR genes and provide novel hypotheses for inferring bacterial AMR mechanisms.


Immunoregulatory effects of very low density lipoprotein from healthy individuals and metabolic syndrome patients on glial cells.
Epidemiological studies have reported that elderly patients with metabolic syndrome (MetS) are significantly more likely to develop neuronal degenerative diseases than those without MetS. Our previous study showed that patients with MetS had significantly higher levels of negatively charged very low density lipoproteins (VLDLs) in the plasma than healthy controls. Highly electronegative VLDL is a key risk factor for endothelial dysfunction and atrial fibrillation. However, the impact of negatively charged VLDL in brain immunity remains unclear. In this study, VLDLs were isolated from normal healthy (nVLDL) individuals or patients with MetS (metVLDL). Primary astroglia and microglia mixed cell cultures as well as microglial-enriched cultures were used to test the effects of VLDLs. Microglia/astroglia activation as evidenced by their morphological changes and production of pro-inflammatory factors, such as tumor necrosis factor-α (TNF-α) and prostaglandin E2 (PGE2), were assessed by immunofluorescence staining and ELISA, respectively. Our results showed that metVLDLs mainly act on the microglia, and not the astroglia, with low concentration (0.05-0.5 μg/mL) inducing cell morphological changes and decreased cellular processes in the microglia. However, nVLDL treatment at these concentrations had no effects on microglia and astroglia. Most importantly, TNF-α and PGE2 levels significantly increased in the microglia treated with metVLDL via a dose-dependent manner. Together, our data indicate that metVLDLs can contribute to MetS-associated brain disorders through microglia activation and neuroinflammation.


The Importance of a Standardized Screening Tool to Identify Thromboembolic Risk Factors in Pediatric Lower Extremity Arthroscopy Patients.
Deep vein thrombosis and pulmonary embolism are major complications that can occur in common orthopaedic procedures such as knee arthroscopy. The purpose of this study is to determine the incidence of venous thromboembolism (VTE) risk factors in adolescent patients undergoing elective lower extremity arthroscopy. A second objective is to determine whether a targeted, standardized screening tool is both cost- and clinically effective in the identification of VTE risk factors in adolescents. A standardized VTE screening tool was prospectively administered to all elective arthroscopic procedures in a pediatric sports medicine practice. A comparison cohort that did not complete the screening tool was isolated through a retrospective chart review identifying VTE risk factors. The incidence and cost between the two cohorts were compared. Of 332 subjects who did not receive a targeted screening (TS) tool, 103 risk factors were noted. One pulmonary embolism case was identified with a total incidence of 0.15% over 3 years. With TS, we identified 325 subjects with 134 identifiable risk factors. Six patients (1.8%) were noted to be very high risk, requiring consultation with hematology. No VTEs were reported. When compared with the retrospective review, TS identified 30% more risk factors. A significant increase in the identification of family history of blood clots (P < 0.001), history of previous blood clot (P = 0.059), recurrent miscarriages in the family (P = 0.010), and smoking exposure (P = 0.062) was found. Additionally, the total cost of screening was less than the cost of prophylaxis treatment with no screening ($20.98 versus $23.51 per person, respectively). Risk factors for VTE may be present in 32.5% of elective adolescent arthroscopic patients. A TS model for VTE identified 30% more risk factors, especially a significant family history, and was shown to be a cost-effective way to safely implement a VTE prevention program. Level II.


A 76-year-old man with recurrent Clostridium difficile-associated diarrhea: review of C. difficile infection.
Clostridium difficile infection (CDI) is a common and increasingly severe nosocomial infectious disease. The case of Mr S, a 76-year-old man with multiple recurrences of CDI, illustrates the difficulties in treating recurrent disease and the way it complicates the management of other medical conditions. Risk factors for CDI include antimicrobial use, hospital admission, advancing age, and severe underlying disease. A clinical diagnosis of CDI is usually confirmed by identifying C. difficile toxins in a stool sample. Evidence supports metronidazole, 500 mg every 6 hours for 10 to 14 days, as the treatment of choice for mild to moderately severe CDI. Oral vancomycin, 125 mg every 6 hours for 10 to 14 days, is recommended for severe CDI, for which it is more effective than metronidazole. Recurrent CDI occurs in more than 20% of patients when metronidazole or vancomycin treatment is discontinued. Few studies have evaluated treatment options for recurrent CDI, but a prolonged, tapering, and pulse-dosed regimen of oral vancomycin is commonly used. Careful attention to antimicrobial stewardship and infection control practices is essential to curb this nosocomial, iatrogenic disease.


Quantifying He fluxes from the mantle using multi-tracer data assimilation.
A global, coarse-resolution ocean model previously fitted to geostrophic shear estimates and to data of 10 hydrographic parameters and tracers has been used to simulate the 3He and 4He distributions resulting from the release of mantle helium from mid-ocean ridges. The model is in very good agreement with 14C and chlorofluorocarbon data and has realistic global ocean overturning strength as well as water mass formation and transport rates. It is found that previously published global mantle 3He fluxes are too high by a factor of about 2. In the model, optimal agreement of modelled δ3He with data is achieved for a global flux of 450 ± 50 mol 3He yr-1 The formulation of He source strengths proportional to ridge spreading rates appears compatible with data. A model/data misfit analysis shows significant and large-scale δ3He underestimation in the southwestern Pacific centred over the Lau Backarc Basin (approx. 179° W/20° S). These misfits disappear in a set-up with 30 of the 450 mol yr-1 global total 3He flux released in the Lau Basin over a depth range between 1250 and 2500 m. Such He flux contributions are missing in present mantle He source compilations. Hydrothermal fluxes of other trace elements and isotopes (TEI) can be calculated from He fluxes on the basis of TEI : He ratios measured close to the sources.This article is part of the themed issue 'Biological and climatic impacts of ocean trace element chemistry'.


Longitudinal changes in intake and food sources of calcium from childhood to young adulthood: the bogalusa heart study.
To examine changes in calcium intake and food sources of calcium from childhood to young adulthood in a longitudinal sample. Information on food and nutrient intake was derived from a single 24-hour dietary recall collected on children who participated in a cross-sectional survey at age 10 and again in young adulthood. A cohort of 237 young adults who participated in the 1989-1991 young adult survey (ages 19 to 28 years) also participated in one of three cross-sectional surveys from 1973 to 1978 at 10 years of age. Repeated measures analysis of variance was applied to examine the longitudinal changes in intake of calcium and food sources from childhood to young adulthood. Total calcium intake at age 10 was not significantly different than total calcium intake of those same individuals when they were young adults. Gender and ethnic differences were observed within the two age groups. In both childhood (age 10 years) and young adulthood, African-American females had significantly lower total calcium intake than Euro-American males. However, this ethnic difference in total calcium intake did not exist after adjusting for energy intake. Calcium intake per 1000 kcal was significantly lower in females than males at age 10, but not in young adulthood. A large percentage of 10-year-olds did not meet the RDA or AI for calcium intake (54% and 88%, respectively), and this was also shown when they were young adults (77% and 75%, respectively). More effective nutrition educational efforts are needed to emphasize the importance of adequate calcium intake and the major food sources of calcium, beginning early in childhood and continuing into young adulthood.


Hypertonic stress induces rapid and widespread protein damage in C. elegans.
Proteostasis is defined as the homeostatic mechanisms that maintain the function of all cytoplasmic proteins. We recently demonstrated that the capacity of the proteostasis network is a critical factor that defines the limits of cellular and organismal survival in hypertonic environments. The current studies were performed to determine the extent of protein damage induced by cellular water loss. Using worm strains expressing fluorescently tagged foreign and endogenous proteins and proteins with temperature-sensitive point mutations, we demonstrate that hypertonic stress causes aggregation and misfolding of diverse proteins in multiple cell types. Protein damage is rapid. Aggregation of a polyglutamine yellow fluorescent protein reporter is observable with <1 h of hypertonic stress, and aggregate volume doubles approximately every 10 min. Aggregate formation is irreversible and occurs after as little as 10 min of exposure to hypertonic conditions. To determine whether endogenous proteins are aggregated by hypertonic stress, we quantified the relative amount of total cellular protein present in detergent-insoluble extracts. Exposure for 4 h to 400 mM or 500 mM NaCl induced a 55-120% increase in endogenous protein aggregation. Inhibition of insulin signaling or acclimation to mild hypertonic stress increased survival under extreme hypertonic conditions and prevented aggregation of endogenous proteins. Our results demonstrate that hypertonic stress causes widespread and dramatic protein damage and that cells have a significant capacity to remodel the network of proteins that function to maintain proteostasis. These findings have important implications for understanding how cells cope with hypertonic stress and other protein-damaging stressors.


The Use of Selfie Camera Traps to Estimate Home Range and Movement Patterns of Small Mammals in a Fragmented Landscape.
The use of camera traps to track individual mammals to estimate home range and movement patterns, has not been previously applied to small mammal species. Our aim was to evaluate the use of camera trapping, using the selfie trap method, to record movements of small mammals within and between fragments of habitat. In a fragmented landscape, 164 cameras were set up across four survey areas, with cameras left to record continuously for 28 nights. Live trapping was performed prior to ear mark animals to facilitate individual identification on camera. Four small mammal species (sugar glider; Petaurus breviceps; brown antechinus; Antechinus stuartii, bush rat; Rattus fuscipes, and brown rat; Rattus norvigecus) were recorded on camera (N = 284 individuals). The maximum distance travelled by an individual sugar glider was 14.66 km, antechinus 4.24 km; bush rat 1.90 km and brown rat 1.28 km. Movements of both female and male sugar gliders in linear fragments were recorded at much higher rates than in larger patches of forest sampled in grids. Short term core homes ranges (50% KDE) of 34 sugar gliders ranged from 0.3 ha to 4.2 ha. Sugar glider core home ranges were on average 1.2 ha (±0.17) for females and 2.4 ha (±0.28) for males. The selfie trap is an efficient camera trapping method for estimating home ranges and movements due to its ability to obtain high recapture rates for multiple species and individuals. In our study landscape, linear strips of habitat were readily utilised by all small mammals, highlighting their importance as wildlife corridors in a fragmented landscape.


Kinetic analysis of cytokines, chemokines, chemokine receptors and adhesion molecules in murine ocular toxoplasmosis.
To investigate the molecules possibly influencing the recruitment and migration of leucocytes in murine ocular toxoplasmosis, the kinetics of the messenger RNA expression levels of cytokines, chemokines, chemokine receptors and adhesion molecules in the retina were analysed. Retina and brain were obtained sequentially from Toxoplasma gondii Fukaya strain-infected wild-type (WT) C57BL/6 and interferon gamma (IFN-γ) knockout (GKO) mice of the same background. The mRNA expression levels of these molecules were analysed by real-time PCR assay. In the retina of WT mice the expression levels of IFN-γ, interleukin 17A, CCL3, CCL4, CCL5, CXCL1, CXCL2, CXCL10, CCR5, CCR7, CXCR2, CXCR3 and intracellular adhesion molecule 1 increased, reaching peaks approximately 14-28 days after infection. The expression levels of CXCR4 and CXCR5 were absent and very low, respectively, during the infection. In the brain of WT mice, the kinetic patterns of these expression levels tended to be the same as in the retina except CXCR4. On the other hand, in GKO mice these molecules, except CXCL1, CXCL2 and CXCR2, remained at basal levels. In murine ocular toxoplasmosis, cytokines, chemokines, chemokine receptors and adhesion molecules were involved in the pathogenesis, and IFN-γ played a pivotal role.


DNA Capture and Enrichment: A Culture-Independent Approach for Characterizing the Genomic Diversity of Pathogenic Leptospira Species.
Because they are difficult to culture, obtaining genomic information from Leptospira spp. is challenging, hindering the overall understanding of leptospirosis. We designed and validated a culture-independent DNA capture and enrichment system for obtaining Leptospira genomic information from complex human and animal samples. It can be utilized with a variety of complex sample types and diverse species as it was designed using the pan-genome of all known pathogenic Leptospira spp. This system significantly increases the proportion of Leptospira DNA contained within DNA extracts obtained from complex samples, oftentimes reaching >95% even when some estimated starting proportions were <1%. Sequencing enriched extracts results in genomic coverage similar to sequenced isolates, thereby enabling enriched complex extracts to be analyzed together with whole genome sequences from isolates, which facilitates robust species identification and high-resolution genotyping. The system is flexible and can be readily updated when new genomic information becomes available. Implementation of this DNA capture and enrichment system will improve efforts to obtain genomic data from unculturable Leptospira-positive human and animal samples. This, in turn, will lead to a better understanding of the overall genomic diversity and gene content of Leptospira spp. that cause leptospirosis, aiding epidemiology and the development of improved diagnostics and vaccines.


Neurochemical basis for the photic control of circadian rhythms and seasonal reproductive cycles: role for acetylcholine.
A pharmacological approach was used to examine the role of acetylcholine in the photic control of circadian rhythms and seasonal reproductive cycles. The experimental protocol was designed to determine whether the administration of carbachol, a cholinergic agonist, could mimic the effects of brief light pulses on gonadal function and/or the circadian rhythm of wheel-running activity in golden hamsters. Intraventricular injections of carbachol, administered singularly at discrete phase points throughout the circadian cycle, induced phase-dependent shifts in the free-running rhythm of activity similar to those caused by a brief light exposure. Injections of carbachol once every 23.33 hr for 9 weeks entrained the activity rhythm and stimulated the neuroendocrine-gonadal axis in a manner similar to that observed after the presentation of 1-hr light pulses at this frequency. In contrast, the administration of carbachol once every 24 hr did not consistently provide an entraining signal for the activity rhythm and did not stimulate reproductive function. Importantly, the effects of carbachol on the seasonal reproductive response were correlated with the timing of the injections relative to the activity rhythm. These findings suggest that acetylcholine may play an important role in the mechanism by which light regulates circadian rhythms and seasonal reproductive cycles.


The emergence of cost effective battery storage.
Energy storage will be key to overcoming the intermittency and variability of renewable energy sources. Here, we propose a metric for the cost of energy storage and for identifying optimally sized storage systems. The levelized cost of energy storage is the minimum price per kWh that a potential investor requires in order to break even over the entire lifetime of the storage facility. We forecast the dynamics of this cost metric in the context of lithium-ion batteries and demonstrate its usefulness in identifying an optimally sized battery charged by an incumbent solar PV system. Applying the model to residential solar customers in Germany, we find that behind-the-meter storage is economically viable because of the large difference between retail rates and current feed-in tariffs. In contrast, investment incentives for battery systems in California derive principally from a state-level subsidy program.


Antilymphocyte antibodies in systemic lupus erythematosus. Effect on lymphocyte surface characteristics.
Antilymphocyte antibodies in SLE bind to normal lymphocytes and are not always associated with lymphocytotoxic activity. Detection of these antibodies on the surface of normal lymphocytes by immunofluorescent techniques is enhanced by short incubation periods, reduced temperature, and metabolic inhibition. The same effects occur in SLE blood and may influence the enumeration of B lymphocytes as determined by surface immunoglobulin. The percent of T lymphocytes forming sheep erythrocyte rosettes is not affected by these antibodies.


Editorial policies and background in editing Macedonian Medical Review and BANTAO journal.
Even in as small a country as R. Macedonia with limited resources allocated for science, there are many journals trying to establish good editorial practices and policies in publishing the scientific work achieved. Among the currently existing medical journals Macedonian Medical Review (MMR), ISSN 0025-1097, deserves to be elaborated as the oldest journal with continuous publication since its first appearance as the journal of the Macedonian Medical Association (MMA). Since its first issue, published in 1946, there has been an opus of some 4500 peer-reviewed published papers in more than 210 issues and some 80 supplements from various congresses and meetings. In this regard, great respect should be paid not only to the editorial boards, but also to the collaborators who have contributed to its successful continuity in all previous years. In line with the needs for further development of the journal and possibilities for access to world databases, the Editorial Board of MMR has made every effort to improve and modernize its work as well as the technical quality of the journal. Hence, MMA has signed a contract with De Gruyter Open as leading publisher of Open Access academic content for further improvement and promotion of the journal and facilitation of the Medline application, so we do hope for the further success of the journal. BANTAO Journal is published on behalf of the Balkan Cities Association of Nephrology, Dialysis, Transplantation and Artificial Organs (BANTAO), ISSN 1312-2517. The first issue was published in 2003, ten years after BANTAO was born. Its appearance was an extremely important event in the existence of BANTAO. The first official editor of the journal was Dimitar Nenov, Varna (2003-2005), followed by Ali Basci (Izmir, Turkey) and Goce Spasovski (Skopje, Macedonia) as editor-in-chief since 2009. Over the years, the Journal has been included in the EBSCO, DOAJ and SCOPUS/SCIMAGO databases. The journal is published biannually. Until now, 345 papers have been published in the past 11 years, in 21 regular issues and 3 supplements. It may be said that the journal is the "glue" between the nephrologists from the Balkan cities, reflecting the high quality research and scientific potential of Balkan nephrologists. The entire process of submitting and reviewing the manuscripts is electronically done and after their acceptance they are freely available (open access journal) on the website of the association and the journal: www.bantao.org. In this regard, the current President of BANTAO has already signed a contract with De Gruyter Open as leading publisher of Open Access academic content for further improvement and promotion of the journal and Medline application for the further success of the journal.


Risk for asthma in offspring of asthmatic mothers versus fathers: a meta-analysis.
Many human epidemiologic studies demonstrate that maternal asthma confers greater risk of asthma to offspring than does paternal disease. However, a handful have shown the opposite. Given this disparity, a meta-analysis is necessary to determine the veracity and magnitude of the "maternal effect." We screened the medical literature from 1966 to 2009 and performed a meta-analysis to compare the effect of maternal asthma vs. paternal asthma on offspring asthma susceptibility. Aggregating data from 33 studies, the odds ratio for asthma in children of asthmatic mothers compared with non-asthmatic mothers was significantly increased at 3.04 (95% confidence interval: 2.59-3.56). The corresponding odds ratio for asthma in children of asthmatic fathers was increased at 2.44 (2.14-2.79). When comparing the odds ratios, maternal asthma conferred greater risk of disease than did paternal asthma (3.04 vs. 2.44, p = 0.037). When analyzing the studies in which asthma was diagnosed by a physician the odds ratios were attenuated and no significant differences were observed (2.85 vs. 2.48, N = 18, p = 0.37). Similarly, no significant differences were observed between maternal and paternal odds ratios when analyzing the studies in which the patient population was 5 years or older (3.15 vs. 2.60, p = 0.14). However, in all cases the trend remained the same, that maternal asthma was a greater risk factor for asthma than paternal. The results show that maternal asthma increases offspring disease risk to a greater extent than paternal disease.


Women's stereotype threat-based performance motivation and prepotent inhibitory ability.
According to the mere effort account of performance, stereotype threat motivates disproval of the negative performance stereotype, which in turn potentiates the overproduction of prepotent responses. In mathematics (maths), prepotent responding facilitates solve type question (e.g., equations) performance, but reduces comparison type question (e.g., estimations) performance. Problematically, the mere effort account indexes performance motivation as task performance. Also, this account posits that performance reduction on non-prepotent tasks derives from the overproduction of prepotent responses, as opposed to failed inhibition of prepotent responses associated with the alternative, namely, the working memory interference perspective. We investigated motivational and prepotent responding as applied to stereotype threat. In Experiment 1, a maths question selection task indexed motivation (independently of performance). Stereotype threat led female test takers to select more solve than comparison maths questions, in accord with the mere effort account. In Experiment 2, higher inhibitory ability protected overall maths performance following stereotype threat, but it did not protect non-prepotentiated comparison question performance (inconsistent with the working memory interference perspective). The results support the mere effort account.


Synthesis of myo-inositol 1,3,4,5,6-pentakisphosphate from inositol phosphates generated by receptor activation.
myo-[3H]Inositol 1,3,4,5,6-pentakisphosphate can be made from myo-[3H]inositol 1,4,5-trisphosphate in a rat brain homogenate or soluble fraction. Although D-myo-inositol 3,4,5,6-tetrakisphosphate can be phosphorylated by a soluble rat brain enzyme to give myo-inositol 1,3,4,5,6-pentakisphosphate, it is not an intermediate in the pathway from myo-inositol 1,4,5-trisphosphate. The intermediates in the above pathway are myo-inositol 1,3,4,5-tetrakisphosphate, myo-inositol 1,3,4-trisphosphate and myo-inositol 1,3,4,6-tetrakisphosphate [Shears, Parry, Tang, Irvine, Michell & Kirk (1987) Biochem. J. 246, 139-147; Balla, Guillemette, Baukal & Catt (1987) J. Biol. Chem. 262, 9952-9955], and it is catalysed by soluble kinase activities of similar anion-exchange mobility and Mr value. Compounds with chromatographic and chemical properties consistent with the structures myo-inositol 1,3,4,5-tetrakisphosphate, myo-inositol 1,3,4,6-tetrakisphosphate and myo-inositol 3,4,5,6-tetrakisphosphate are present in avian erythrocytes, human 1321 N1 astrocytoma cells and primary-cultured murine bone-marrow-derived macrophages. The amounts of these inositol tetrakisphosphates rise upon muscarinic cholinergic stimulation of the astrocytoma cells or stimulation of macrophages with platelet-activating factor.


The autonomic nervous system and hypertension.
Physiological studies have long documented the key role played by the autonomic nervous system in modulating cardiovascular functions and in controlling blood pressure values, both at rest and in response to environmental stimuli. Experimental and clinical investigations have tested the hypothesis that the origin, progression, and outcome of human hypertension are related to dysfunctional autonomic cardiovascular control and especially to abnormal activation of the sympathetic division. Here, we review the recent literature on the adrenergic and vagal abnormalities that have been reported in essential hypertension, with emphasis on their role as promoters and as amplifiers of the high blood pressure state. We also discuss the possible mechanisms underlying these abnormalities and their importance in the development and progression of the structural and functional cardiovascular damage that characterizes hypertension. Finally, we examine the modifications of sympathetic and vagal cardiovascular influences induced by current nonpharmacological and pharmacological interventions aimed at correcting elevations in blood pressure and restoring the normotensive state.


Plumbagin induces cell cycle arrest and autophagy and suppresses epithelial to mesenchymal transition involving PI3K/Akt/mTOR-mediated pathway in human pancreatic cancer cells.
Plumbagin (PLB), an active naphthoquinone compound, has shown potent anticancer effects in preclinical studies; however, the effect and underlying mechanism of PLB for the treatment of pancreatic cancer is unclear. This study aimed to examine the pancreatic cancer cell killing effect of PLB and investigate the underlying mechanism in human pancreatic cancer PANC-1 and BxPC-3 cells. The results showed that PLB exhibited potent inducing effects on cell cycle arrest in PANC-1 and BxPC-3 cells via the modulation of cell cycle regulators including CDK1/CDC2, cyclin B1, cyclin D1, p21 Waf1/Cip1, p27 Kip1, and p53. PLB treatment concentration- and time-dependently increased the percentage of autophagic cells and significantly increased the expression level of phosphatase and tensin homolog, beclin 1, and the ratio of LC3-II over LC3-I in both PANC-1 and BxPC-3 cells. PLB induced inhibition of phosphatidylinositol 3-kinase (PI3K)/protein kinase B/mammalian target of rapamycin and p38 mitogen-activated protein kinase (p38 MAPK) pathways and activation of 5'-AMP-dependent kinase as indicated by their altered phosphorylation, contributing to the proautophagic activities of PLB in both cell lines. Furthermore, SB202190, a selective inhibitor of p38 MAPK, and wortmannin, a potent, irreversible, and selective PI3K inhibitor, remarkably enhanced PLB-induced autophagy in PANC-1 and BxPC-3 cells, indicating the roles of PI3K and p38 MAPK mediated signaling pathways in PLB-induced autophagic cell death in both cell lines. In addition, PLB significantly inhibited epithelial to mesenchymal transition phenotype in both cell lines with an increase in the expression level of E-cadherin and a decrease in N-cadherin. Moreover, PLB treatment significantly suppressed the expression of Sirt1 in both cell lines. These findings show that PLB promotes cell cycle arrest and autophagy but inhibits epithelial to mesenchymal transition phenotype in pancreatic cancer cells with the involvement of PI3K/protein kinase B/mammalian target of rapamycin and p38 MAPK mediated pathways.


[3H]Org 43553, the first low-molecular-weight agonistic and allosteric radioligand for the human luteinizing hormone receptor.
The luteinizing hormone (LH) receptor plays a pivotal role in reproduction. The high-molecular-weight (HMW) human chorionic gonadotropin (hCG) and LH are the endogenous ligands of this receptor and bind to its large N terminus. The present study characterizes the binding of a new low-molecular-weight (LMW) radioligand, [(3)H]5-amino-2-methylsulfanyl-4-[3-(2-morpholin-4-yl-acetylamino)-phenyl]-thieno[2,3-d]pyrimidine-6-carboxylic acid tert-butylamide (Org 43553), at the LH receptor. Equilibrium saturation and displacement assays were developed and optimized. Specific binding of [(3)H]Org 43553 to CHO-K1 cell membranes expressing the human LH receptor and a cAMP response element-luciferase reporter gene was saturable with a K(D) value of 2.4 +/- 0.4 nM and a B(max) value of 1.6 +/- 0.2 pmol/mg protein. Affinities of five LMW analogs of Org 43553 were determined. All displaced the radioligand competitively, with K(i) values ranging from 3.3 to 100 nM. Finally, the potency of these compounds in a cAMP-induced luciferase assay was also determined. There was a high correlation between affinity and potency (r = 0.99; P < 0.0001) of these compounds. In the search for LMW ligands, which bind allosterically to the seven-transmembrane domain of the LH receptor, a HMW radioligand (e.g., (125)I-hCG) is not suitable as it is not displaced by a LMW compound. Therefore, [(3)H]Org 43553, a new radioligand with good binding properties, allows screening for new LMW ligands that mimic the action of the endogenous hormone at the LH receptor.


Prediction of human intestinal absorption of the prodrug temocapril by in situ single-pass perfusion using rat intestine with modified hydrolase activity.
Intestinal absorption of temocapril, a prodrug of temocaprilat, was evaluated in an in situ rat jejunal perfusion model under various conditions of luminal pH and in the presence and absence of carboxylesterase-mediated hydrolysis. Temocapril was more easily taken up by mucosal cells at a luminal pH of 5.4 than at pH 6.4 or 7.4 and was extensively hydrolyzed to temocaprilat in mucosal cells. The hydrolysis was limited by the intrinsic clearance and the influx rate at luminal perfusate pHs of 5.4 and 7.4, respectively. Temocaprilat, derived from temocapril, was transported into both mesenteric vein and jejunal lumen according to pH partition theory. The net absorption of both temocapril and temocaprilat was highest at a luminal perfusate pH of 5.4. When both the luminal and venous fluid were at pH 7.4, temocaprilat was transported approximately 3-fold faster into the lumen than into the vein, due presumably to the greater surface area of the brush border membrane because of the presence of microvilli. Under carboxylesterase-inhibited conditions, the hydrolysis of temocapril was inhibited by only 50%. It is postulated that serine esterases located on the membranes of the epithelial cells were responsible for the residual hydrolysis. We have confirmed that temocapril is most easily absorbed in the proximal intestine after meals, due to prolongation of the gastric emptying time, the lower intraluminal pH caused by secretion of bile acid, and the interaction between serine esterases and the digesta.


Does the evidence referenced in NICE guidelines reflect a primary care population?
Guidelines are a common and important tool in providing high-quality health care. The National Institute for Health and Clinical Excellence (NICE) guidelines are now being used to set standards for assessing the quality of care in UK general practice, and so the evidence behind them needs to be relevant to primary care. To assess the extent to which guideline recommendations aimed at primary care are based on research conducted in a primary care setting. Purposeful selection of a sample of NICE guidelines for conditions commonly seen in general practice, with identification of the evidence underpinning recommendations that are relevant to primary care. Three recent NICE guidelines were selected: chronic obstructive pulmonary disease (COPD), hypertension, and respiratory tract infection in adults and children. Publications referenced as evidence for each individual primary care relevant recommendation were classified as to whether or not they were based in primary care relevant settings. In the three guidelines assessed, 160 studies were used to derive the 115 recommendations that were relevant to, or aimed at primary care. A wide variation was found in the proportion of studies that recruited patients from a setting relevant to primary care (range 26% to 80%). In this sample of three NICE guidelines, a significant proportion of studies underlying the primary care relevant recommendations were derived from studies that were not conducted in that setting. In producing guidelines for a primary care audience, the guideline development groups should include explicit information about the setting of studies underpinning the recommendations.


Negative pressure dressings and the impact on pain management on thoracic incisions in patients undergoing oesophagectomy: a pilot study.
Pain control is recognised as a crucial post-operative measure for patients undergoing oesophagectomy with a thoracotomy incision for oesophageal cancer, where ineffective breathing due to pain is directly correlated with increased morbidity. The analgesic benefits of negative pressure wound therapy (NPWT) appear to be a relatively new and emerging finding. This pilot study aims to investigate the effects of NPWT on post-operative pain control and determine the feasibility of a larger trial. Ten consecutive patients undergoing oesophagectomy were prospectively enrolled to have a PREVENA Incision Management System placed over a closed thoracotomy wound. This dressing was changed at post-operative day 5 and removed after day 10. Post-operative morbidity was recorded and analgesia was prescribed by the Acute Pain Service who were blinded to the study aims. Analgesia requirements were recorded in oral morphine equivalents (OME) and compared to 30 patients that had previously undergone oesophagectomy via thoracotomy. One patient was withdrawn from the study and there was no significant differences in patient demographics. The study group had less average daily analgesia requirements and reduced overall reported pain. Patients in the study group were less likely to develop pneumonia (44% and 57%) and less likely to require re-operation for complications of their surgery (0% and 10%). This pilot study shows reduced post-operative analgesia requirements and reduced morbidity when using NPWT over a closed thoracotomy wound, and affirms the feasibility of a future randomized control trial.


An in vivo ultrasonic model of liver parenchyma.
Several ultrasonic tissue characterization features are known to discriminate pathological from normal tissue in vivo. Previously, the authors developed an in vivo attenuation- and backscatter estimation method with each frequency dependent coefficient being reduced to a slope and intercept at central frequency. They derived expressions predicting the standard deviation (SD) of these features, assuming a commonly used ultrasonic model of liver parenchyma. In its application to in vivo data, the SD of the intercept features was unexpectedly high. Another feature, signal-to-noise ratio (SNR), showed a significant bias related to the window size. In this paper, the model is extended with the notion of inhomogeneous parenchyma background (IPB). IPB is shown to be present in normal liver parenchyma and is statistically described by a noise term with small amplitude and large correlation cell size. A method is presented to estimate the IPB characteristics. The expressions predicting SD are extended, and an expression is derived predicting the window size bias of the feature SNR. The accuracy and precision estimated from a large in vivo data set shows good agreement with the predictions with the extended model. It is concluded that IPB is a realistic and relevant phenomenon and should be part of the in vivo ultrasonic model of liver parenchyma.


A mobile system for the collection of clinical data and EEG signals by using the sana platform.
Nowadays, more than 450 millions of people around the world suffer from mental disorders. One of the main problems of that type of illnesses is the lack of early detection, generally due to the reduced number of professionals specialized in mental health, especially in low- and middle-income countries. This article aims at describing the process of construction of an m-Health system that supports the collection of clinical data, including EEG signals, in order to assist the initial assessment of neurologic problems. The system has been mainly developed by using low-cost technology, implemented under the open-source platform SANA, and integrating a non-professional EEG device for the acquisition of bioelectric signals of the brain. The functionalities of this application and its usefulness have been evaluated by a group of six experts who concluded that a) the system implements 100% of the functionalities described in the system design phase, and b) the usefulness of the system's functionalities is 96%.


Attitudes of final-year dental students to bleaching of vital and non-vital teeth in Cardiff, Cork, and Malmö.
The aim of this study was to determine attitudes of final-year dental students in Cardiff, Cork and Malmö towards tooth whitening. Following receipt of ethical approval, pre-piloted questionnaires were distributed to final-year dental students in Cork, Cardiff, and Malmö as close as possible to graduation. The questionnaire sought information relating to various opinions and attitudes towards the use of bleaching techniques including safety of bleaching, confidence in the provision of bleaching, recommendations to patients, teaching received, awareness of restrictions on the use of bleaching products and management of simulated clinical scenarios. Eighty three per cent (n = 116) of questionnaires were returned. Cork dental students had the most didactic teaching (2-h vital, 1-h non-vital bleaching) compared to Cardiff or Malmö students (0 h each). More Cork students regarded bleaching as safe (76%, n = 28) than Cardiff (70%, n = 32) or Malmö (36%, n = 12) students. More than 50% of Cork students feel they know enough about bleaching to provide it in practice, significantly more than Cardiff (< 25%) or Malmö (< 25%) students. The majority of students would provide vital bleaching after qualification (100% (n = 37) Cork; 82% (n = 27) Malmö; 76% (n = 35) Cardiff). In simulated clinical scenarios, more Cork students would propose bleaching treatments (89%n = 33) than Malmö (64%n = 21) or Cardiff (48%n= 22) students. Variations exist in the attitudes and approaches of three European dental schools towards bleaching. Dental students need to be best prepared to meet the needs of their future patients.


A novel lipid hydroperoxide-derived cyclic covalent modification to histone H4.
Previous studies have established that 4-hydroxy-2-nonenal is a lipid hydroperoxide-derived aldehydic bifunctional electrophile that reacts with DNA and proteins. However, it has now been recognized that 4-oxo-2-nonenal is also a major product of lipid hydroperoxide decomposition. Furthermore, 4-oxo-2-nonenal is more reactive than 4-hydroxy-2-nonenal toward the DNA-bases 2'-deoxyguanosine, 2'-deoxyadenosine, and 2'-deoxycytidine and proteins. The formation of 4-oxo-2-nonenal can be induced through vitamin C-mediated or transition metal ion-mediated homolytic decomposition of polyunsaturated omega-3 lipid hydroperoxides such as 13(S)-hydroperoxyoctadecadienoic acid. We have discovered that synthetic 4-oxo-nonenal or 4-oxo-2-nonenal-generated from 13(S)-hydroperoxyoctadecadienoic acid recognizes the specific amino acid motifs of His75, Ala76, and Lys77 in bovine histone H4. Reaction of the histidine and lysine residues with 4-oxo-2-nonenal results in the formation of a novel cyclic structure within the protein. The cyclic structure incorporates the histidine imidazole ring and a newly formed pyrrole derived from the lysine. The cyclic imidazole-pyrrole derivative that is formed from the small Nalpha-acetyl-His-Ala-Lys peptide exists as a mixture of two atropisomers that inter-convert upon heating. Such lipid hydroperoxide-derived modifications could potentially modulate transcriptional activation in vivo. Furthermore, the ability to synthesize cyclic peptides using 4-oxo-2-nonenal will facilitate the preparation of novel structural analogs with potential biological activity.


Footboards: Indigenous and Novel Method of Screening for Diabetes Peripheral Neuropathy - A Pilot Study.
To validate the effectiveness of indigenously designed "footboard (FB)" in early diagnosis of diabetic peripheral neuropathy (PNP) by comparing it with Semmes-Weinstein monofilament (SWM) and vibration perception (VP). Two hundred and forty-four patients with diabetes were examined for PNP using SWM and 128 Hz tuning fork. The findings were compared with indigenously designed FBs with 1, 2, and 3 mm elevations. Out of 108 patients who did not have protective sensation as per SWM, only 10 (9.2%) felt 1 mm board bearings, and out of 72 patients who did not feel vibration, only 8 (11.1%) felt 1 mm board bearings. Out of 136 patients who had protective sensation, 128 (94.11%) felt 2 mm elevated board bearings, and out of 172 patients who had VP, only 152 patients (88.3%) felt 2 mm board bearings. With SWM as standard, the sensitivities and specificities, respectively, were 63% and 90% (1 mm board), and 94% and 60% (2 mm board). With VP, the sensitivities and specificities, respectively, were 59% and 90% (1 mm board), and 88% and 61% (2 mm board). FB, which simultaneously tests touch and pressure sensation, shows a high level of performance in detecting at-risk feet. FB may be simple, time-efficient, and inexpensive test for detection of neuropathy and needs further validation in a larger study.


Animal models for the study of Chlamydial infections of the urogenital tract.
Various experimental animal models have been used for the study of chlamydial infections of the urogenital tract. Experimental urethral and vaginal inoculation of guinea pigs with the guinea-pig inclusion conjunctivitis agent provoke urogenital infection. Direct inoculation of this agent into the uterine horns of guinea pigs induced an acute self-limiting salpingitis. In cats, urethritis and vaginitis have been produced with the feline keratoconjunctivitis agent. The results obtained by using the grivet monkey as an animal model for the study of chlamydial infections of the urogenital tract indicate that Chlamydia trachomatis is able to cause inflammation of the urethra, the spermatic cord, and the epididymis of male grivet monkeys. In female grivet monkeys, the organism can cause inflammation of the cervix, the endometrium, and the fallopian tubes. In some cases, tubal occlusion can be demonstrated several weeks after the inoculation.


Study of garlic extracts and fractions on cholesterol plasma levels and vascular reactivity in cholesterol-fed rats.
Garlic is known for its pharmacologic and nutritional properties. In previous studies, garlic elicited a reduction in plasma levels of lipids by inhibiting hepatic cholesterol synthesis. The aim of this study was to investigate in an in vivo model the effects of garlic extract and some fractions on cholesterol levels and vascular reactivity in cholesterol-fed rats. Rats were fed a cholesterol-enriched diet for 16 wk and were divided into 10 groups as follows: control and hypercholesterolemic diet groups, 4 groups fed frozen garlic fractions and 4 groups fed raw garlic fractions with different doses. Blood samples were obtained to analyze HDL and LDL cholesterol levels. After treatment, rats were killed. The heart, liver and kidneys were weighed; the aorta was isolated, mounted in organ chambers and vascular reactivity was tested. Plasma concentration of cholesterol was 58 mg/dL (100%) at the beginning of the study and increased to 102 mg/dL (153%; hypercholesterolemic group) at the end of the treatment. Plasma total cholesterol decreased in all groups treated with garlic; moreover, this effect was higher in rats fed raw garlic fractions and extracts. LDL decreased significantly with respect to the hypercholesterolemic group in all groups treated with garlic fractions and extracts (P: < 0.01); however, an increase in HDL was found in those treated with frozen fractions and extracts. The liver:body weight ratio decreased in all treated groups. The relaxing effect of acetylcholine (ACh) was enhanced in arteries contracted with noradrenaline (NE). These data suggest that garlic fractions could prevent diet-induced hypercholesterolemia and vascular alterations in the endothelium-dependent relaxation associated with atherosclerosis.


Nurses' experiences of being present with a patient receiving a diagnosis of cancer.
Nurses' experiences of being present with a patient receiving a diagnosis of cancer This paper reports the findings of a study which describes the experiences of nurses who were present with a patient when they received a diagnosis of cancer, cancer recurrence or prognosis of terminal cancer. Semi-structured interviews were conducted with six nurses who had experience of caring for patients with cancer in an acute surgical setting. Data were analysed using a phenomenological descriptive approach. Participants' descriptions revealed the following seven core themes: 'What if it was me?'; divergent feelings; being there; becoming closer; method of disclosure; time as an influence and learning by reflection. Possible implications for nursing practice and education are discussed and recommendations are made for future research.


Food allergy in Alergológica-2005.
Alergológica-2005 is a cross-sectional study carried out in Spain in 4991 new patients prospectively recruited in allergy clinics. To describe the characteristics of food allergic patients included in Alergológica-2005. Food allergy was diagnosed in 369 subjects (7.4%, 95% CI, 6.7%-8.1%). The most common offending foods were fruits (33.3% of cases), nuts (26%), shellfish (22%), egg (16%), milk (13.9%) and fish (9.8%). Rosaceae fruits and crustaceans elicited 23.6% and 18.7% of the reactions, respectively. Milk and egg were the most common foods in patients < 5 years of age, whereas fruits and nuts were the most prevalent foods in patients over 5 years. The most frequent manifestations included skin reactions (65.3%), oral allergy syndrome (33.6%), digestive symptoms (24.7%) and anaphylaxis (17.9%). The clinical presentation differed among foods. Prick-tests were carried out more frequently than serum immunoglobulin E (IgE) determinations (95.9% vs. 65%). Oral challenges were performed in 13% of patients, and 72.3% of these were open. Food allergy was diagnosed on the basis of medical history and positive IgE in 60.2% of the patients, ranging from 13.7% for milk to 75% for cereals. The self perception of patients' quality of life was lower than that of the 75% of Spanish reference population. Food allergy is diagnosed in 7.4% of the patients seen in allergy clinics across Spain, and has an important impact on the quality of life of patients. The foods involved in reactions change with age. The clinical presentation changes with the food, although the skin is the most frequently affected organ.


Descriptive and surveillance studies of suppliers to New York and New Jersey retail live-bird markets.
Low pathogenicity avian influenza virus (AIV) H7N2 has been isolated since 1994 from retail live-bird markets (LBMs) in the northeastern United States. This study examines the suppliers to the LBMs in New York and New Jersey. In 2001, 185 supplier premises in nine states were surveyed for the presence of AIV by virus isolation (VI) in embryonating chicken eggs. No H7 or H5 virus was isolated. In addition, 104 producer premises in two states were serologically negative for H7 and H5 AIV. Information on management practices was obtained via questionnaire for 191 premises in 12 states. The survey results suggest that current biosecurity practices at supplier premises could be improved, especially regarding movement of birds. The study supports the hypothesis that H7N2 AIV is primarily maintained within the LBMs and, if reintroduction from suppliers is occurring, it is likely reintroduced at a very low level or from suppliers not included in this study.


Design of a suspended germanium micro-antenna for efficient fiber-chip coupling in the long-wavelength mid-infrared range.
Recent developments of photonic integrated circuits for the mid-infrared band has opened up a new field of attractive applications for group IV photonics. Grating couplers, formed as diffractive structures on the chip surface, are key components for input and output coupling in integrated photonic platforms. While near-infrared optical fibers exhibit large mode field diameters compared to the wavelength, in the long-wave regime commercially available single-mode optical fibers have mode field diameters of the order of the operating wavelength. Consequently, an efficient fiber-chip surface coupler designed for the long-wave infrared range must radiate the power propagating in the waveguide with a higher radiation strength than a conventional grating coupler in the near-infrared range. In this article, we leverage the short electrical length required for long-wave infrared couplers to design a broadband all-dielectric micro-antenna for a suspended germanium platform at 7.67 µm. The design methodology is inspired by fundamental grating coupler equations, which remain valid even when the micro-antenna has only two or three diffractive elements. A simulated coupling efficiency of ~ 40% is achieved with a 1-dB bandwidth broader than 430 nm, which is almost twice the typical fractional bandwidth of a conventional grating coupler. In addition, the proposed design is markedly tolerant to fiber tilt misalignments of ±10°. This all-dielectric micro-antenna design paves the way for efficient fiber-chip coupling in long-wavelength mid-infrared integrated platforms.


A genomic study of the inter-ORF distances in Saccharomyces cerevisiae.
The genome of eukaryotic microbes is usually quite compacted. The yeast Saccharomyces cerevisiae is one of the best-known examples. Open reading frames (ORFs) occupy about 75% of the total DNA sequence. The existence of other, non-protein coding genes and other genetic elements leaves very little space for gene promoters and terminators. We have performed an in silico study of inter-ORF distances that shows that there is a minimum distance between two adjacent ORFs that depends on the relative orientation between them. Our analyses suggest that different kinds of promoters and terminators exist with regard to their length and ability to overlap each other. The experimental testing of some putative exceptions to the minimum length model in tandemly orientated ORF pairs suggests that, in those cases, defects in promoter or terminator functionality exist that provoke transcription of polycistronic mRNAs.


Monoclonal antibody immunohistochemistry. Applications in research and diagnosis.
Monoclonal antibodies have been applied as primary antibodies for the cellular and subcellular localisation of neuroactive substances. The application of monoclonal antibodies against neuropeptides and small molecular weight neurotransmitters allows the investigation of aspects of the anatomical organisation, sensitivity to drugs and pathological aspects of cells or neurones containing these substances. A new technique for the localisation of tissue antigens has been developed based on the in vitro radiolabelling of monoclonal antibodies during their biosynthesis. This radioimmunocytochemical technique promises to be a useful tool for quantitative immunohistochemistry as well as being suitable for the simultaneous localisation of two antigenic sites at light and electron microscopical level.


Modeling the climatic response to orbital variations.
According to the astronomical theory of climate, variations in the earth's orbit are the fundamental cause of the succession of Pleistocene ice ages. This article summarizes how the theory has evolved since the pioneer studies of James Croll and Milutin Milankovitch, reviews recent evidence that supports the theory, and argues that a major opportunity is at hand to investigate the physical mechanisms by which the climate system responds to orbital forcing. After a survey of the kinds of models that have been applied to this problem, a strategy is suggested for building simple, physically motivated models, and a time-dependent model is developed that simulates the history of planetary glaciation for the past 500,000 years. Ignoring anthropogenic and other possible sources of variation acting at frequencies higher than one cycle per 19,000 years, this model predicts that the long-term cooling trend which began some 6000 years ago will continue for the next 23,000 years.


The Eyewitness Community Survey: An Engaging Citizen Science Tool to Capture Reliable Data while Improving Community Participants' Environmental Health Knowledge and Attitudes.
Many youths and young adults have variable environmental health knowledge, limited understanding of their local environment's impact on their health, and poor environmentally friendly behaviors. We sought to develop and test a tool to reliably capture data, increase environmental health knowledge, and engage youths as citizen scientists to examine and take action on their community's challenges. The Eyewitness Community Survey (ECS) was developed through several iterations of co-design. Herein, we tested its performance. In Phase I, seven youths audited five 360° photographs. In Phase II, 27 participants works as pairs/trios and audited five locations, typically 7 days apart. Inter-rater and intra-rater reliability were determined. Changes in participants' knowledge, attitudes, behaviors, and self-efficacy were surveyed. Feedback was obtained via focus groups. Intra-rater reliability was in the substantial/near-perfect range, with Phase II having greater consistency. Inter-rater reliability was high, with 42% and 63% of Phase I and II Kappa, respectively, in the substantial/near-perfect range. Knowledge scores improved after making observations (p ≤ 0.032). Participants (85%) reported the tool to be easy/very easy to use, with 70% willing to use it again. Thus, the ECS is a mutually beneficial citizen science tool that rigorously captures environmental data and provides engaging experiential learning opportunities.


SOX6 Expression Is Sensitive for Peritoneal Epithelioid Malignant Mesothelioma, But Not Specific in the Differential Diagnosis With Tubo-ovarian Serous Neoplasia.
Primary peritoneal malignant mesothelioma (MM) can demonstrate morphologic overlap with low-grade and high-grade tubo-ovarian serous neoplasms; it is also biologically and prognostically distinct from benign mesothelial proliferations. Currently, there is no single biomarker that can definitively distinguish these neoplasms. Sex-determining region Y box 6 (SOX6) immunohistochemistry has been recently described to differentiate pleural epithelioid MM from lung adenocarcinoma, but it has not been evaluated in the peritoneum. SOX6 immunohistochemistry was performed on 43 peritoneal epithelioid MM, 7 peritoneal biphasic MM, 5 well-differentiated papillary mesotheliomas, 5 serous borderline tumors, 29 low-grade serous carcinomas (LGSCs), 20 high-grade serous carcinomas (HGSCs), and 25 cases of peritoneal reactive mesothelial hyperplasia. Quantitative SOX6 expression in epithelioid MM (median, 100% of tumor cells) was significantly greater than in LGSC/serous borderline tumor (median, 90%; P=0.004) and HGSC (median, 45%; P=0.0001). However, when SOX6 is expression is defined as ≥10% of tumor cells, there was no significant difference in the rate of SOX6 positivity between epithelioid MM (41/43, 95%), LGSC (28/29, 97%; P=1.0), and HGSC (17/20, 85%; P=0.16). Quantitative extent of SOX6 expression in epithelioid MM was significantly greater than in biphasic MM (median, 0%; P=0.0001), well-differentiated papillary mesothelioma (median, 20%; P=0.001), and reactive mesothelial hyperplasia (median, 20%; P=0.0001), but not significantly different from flat quiescent mesothelium (median, 90%; P=0.82). SOX6 immunohistochemistry is 95% sensitive for peritoneal epithelioid MM, but is also consistently expressed in LGSC and HGSC, negating its usefulness in this common differential diagnosis. SOX6 also shows variable expression across the spectrum of reactive, benign neoplastic, and malignant mesothelial lesions of the peritoneum, and does not appear to be diagnostically useful in distinguishing benign from malignant mesothelial proliferations.


A semi-analytical model for estimating total suspended matter in highly turbid waters.
Total suspended matter (TSM) is related to water quality. High TSM concentrations limit underwater light availability, thus affecting the primary productivity of aquatic ecosystems. Accurate estimation of TSM concentrations in various waters with remote sensing technology is particularly challenging, as the concentrations and optical properties vary greatly among different waters. In this research, a semi-analytical model was established for Hangzhou Bay and Lake Taihu for estimating TSM concentration. The model construction proceeded in two steps. 1) Two indices of the model were calculated by deriving absorption and backscattering coefficients of suspended matter (ap(λ) and bbp(λ)) from the reflectance signal using a semi-analytical method. 2) The two indices were then weighted to derive TSM. The performance of the proposed model was tested using in situ reflectance and Geostationary Ocean Color Imager (GOCI) data. The derived TSM based on in situ reflectance and GOCI images both corresponded well with the in situ TSM with low mean relative error (32%, 41%), root mean square error (20.1 mg/L, 43.1 mg/L), and normalized root mean square error (33%, 55%). The model was further used for the slightly turbid Xin'anjiang Reservoir to demonstrate its applicability to derive ap(λ) and bbp(λ) in other water types. The results indicated that the form Rrs -1(λ1) - Rrs -1(λ2) could minimize the effect of CDOM absorption in deriving ap(λ) from the total absorption. The model exploited the different relationships between TSM concentration and multiband reflectance, thus improving the performance and application range in deriving TSM.


Evolution of specialization and ecological character displacement of herbivores along a gradient of plant quality.
We study the combined evolutionary dynamics of herbivore specialization and ecological character displacement, taking into account foraging behavior of the herbivores, and a quality gradient of plant types. Herbivores can adapt by changing two adaptive traits: their level of specialization in feeding efficiency and their point of maximum feeding efficiency along the plant gradient. The number of herbivore phenotypes, their levels of specialization, and the amount of character displacement among them are the result of the evolutionary dynamics, which is driven by the underlying population dynamics, which in turn is driven by the underlying foraging behavior. Our analysis demonstrates broad conditions for the diversification of a herbivore population into many specialized phenotypes, for basically any foraging behavior focusing use on highest gains while also including errors. Our model predicts two characteristic phases in the adaptation of herbivore phenotypes: a fast character-displacement phase and a slow coevolutionary niche-shift phase. This two-phase pattern is expected to be of wide relevance in various consumer-resource systems. Bringing together ecological character displacement and the evolution of specialization in a single model, our study suggests that the foraging behavior of herbivorous arthropods is a key factor promoting specialist radiation.


Imposing structure on a Corsi-type task: evidence for hierarchical organisation based on spatial proximity in serial-spatial memory.
Structure was imposed on a tapping task by requiring participants to reproduce sequences of responses to icons organised in spatial clusters. A first experiment featured sequences either segregated or not segregated by clusters. Accuracy was higher for sequences segregated by clusters. Moreover, inter-response times were longer at cluster boundaries than within cluster boundaries. To rule out possible confounding effects of movement length, this temporal pattern was replicated in a second experiment requiring a single response indicating the next sequential step, following the presentation of a portion of a previously practised sequence. These results suggest that sequence reproduction can be sustained by a hierarchical representation based on spatial proximity and provide a first indication of the role of spatial structure in serial-spatial memory.