Effectiveness of nutritional countermeasures in microgravity and its ground-based analogues to ameliorate musculoskeletal and cardiopulmonary deconditioning-A Systematic Review.
A systematic review was performed to evaluate the effectiveness of nutrition as a standalone countermeasure to ameliorate the physiological adaptations of the musculoskeletal and cardiopulmonary systems associated with prolonged exposure to microgravity. A search strategy was developed to find all astronaut or human space flight bed rest simulation studies that compared individual nutritional countermeasures with non-intervention control groups. This systematic review followed the guidelines of the Cochrane Handbook for Systematic Reviews and tools created by the Aerospace Medicine Systematic Review Group for data extraction, quality assessment of studies and effect size. To ensure adequate reporting this systematic review followed the guidelines of the Preferred Reporting Items for Systematic Review and Meta-Analyses. A structured search was performed to screen for relevant articles. The initial search yielded 4031 studies of which 10 studies were eligible for final inclusion. Overall, the effect of nutritional countermeasure interventions on the investigated outcomes revealed that only one outcome was in favor of the intervention group, whereas six outcomes were in favor of the control group, and 43 outcomes showed no meaningful effect of nutritional countermeasure interventions at all. The main findings of this study were: (1) the heterogeneity of reported outcomes across studies, (2) the inconsistency of the methodology of the included studies (3) an absence of meaningful effects of standalone nutritional countermeasure interventions on musculoskeletal and cardiovascular outcomes, with a tendency towards detrimental effects on specific muscle outcomes associated with power in the lower extremities. This systematic review highlights the limited amount of studies investigating the effect of nutrition as a standalone countermeasure on operationally relevant outcome parameters. Therefore, based on the data available from the included studies in this systematic review, it cannot be expected that nutrition alone will be effective in maintaining musculoskeletal and cardiopulmonary integrity during space flight and bed rest.


Cytoplasmic and nuclear leptin expression in lacrimal gland tumours: a pilot study.
To investigate leptin expression and distribution in the tissue of lacrimal gland epithelial tumours, and leptin concentration in the tears secreted by these tumours. Clinical records and microscopic slides of six pleomorphic adenoma (PA), three adenoid cystic carcinoma (ACC), and one chronic sclerosing dacryoadenitis (CSD) cases were reviewed. Normal-appearing gland tissue adjacent to tumours from patients with PA served as controls. Tissue leptin expression and distribution were assessed using leptin immunohistochemistry staining. Preoperative and postoperative leptin concentrations in tears were measured in the tumour-affected eye in two patients with PA, two with ACC and one with CSD, and in the contralateral eye in one patient with ACC and one with CSD. Moderate cytoplasmic staining was observed in all tumour-adjacent morphologically normal tissue, PA, ACC and CSD tissues. ACC tissues revealed moderate nuclear staining in tumour cells, whereas other tissues did not reveal leptin nuclear staining (p=0.012). Leptin in tears was not detected in the eyes of patients with PA preoperatively and postoperatively. However, leptin was detected in tears of patients with ACC and CSD preoperatively, and its concentration markedly decreased at 1 month postoperatively. Leptin was not detected in any sample from the contralateral eyes of patients for which such samples were available. The leptin concentration in tears was greater in patients with ACC than in those with PA. Leptin nuclear staining was only observed in the ACC tissue. Further investigations should be conducted to identify the cause and significance of these findings.


Energy Harvesting Hybrid Acoustic-Optical Underwater Wireless Sensor Networks Localization.
Underwater wireless technologies demand to transmit at higher data rate for ocean exploration. Currently, large coverage is achieved by acoustic sensor networks with low data rate, high cost, high latency, high power consumption, and negative impact on marine mammals. Meanwhile, optical communication for underwater networks has the advantage of the higher data rate albeit for limited communication distances. Moreover, energy consumption is another major problem for underwater sensor networks, due to limited battery power and difficulty in replacing or recharging the battery of a sensor node. The ultimate solution to this problem is to add energy harvesting capability to the acoustic-optical sensor nodes. Localization of underwater sensor networks is of utmost importance because the data collected from underwater sensor nodes is useful only if the location of the nodes is known. Therefore, a novel localization technique for energy harvesting hybrid acoustic-optical underwater wireless sensor networks (AO-UWSNs) is proposed. AO-UWSN employs optical communication for higher data rate at a short transmission distance and employs acoustic communication for low data rate and long transmission distance. A hybrid received signal strength (RSS) based localization technique is proposed to localize the nodes in AO-UWSNs. The proposed technique combines the noisy RSS based measurements from acoustic communication and optical communication and estimates the final locations of acoustic-optical sensor nodes. A weighted multiple observations paradigm is proposed for hybrid estimated distances to suppress the noisy observations and give more importance to the accurate observations. Furthermore, the closed form solution for Cramer-Rao lower bound (CRLB) is derived for localization accuracy of the proposed technique.


Evaluation of the effect of non-surgical periodontal treatment on oral health-related quality of life: estimation of minimal important differences 1 year after treatment.
To evaluate an individually tailored oral health educational programme on patient-reported outcome compared with a standard oral health educational programme, assess change over time and determine minimal important differences (MID) in change scores for two different oral health related quality of life (OHRQoL) instrument after non-surgical periodontal treatment (NSPT). In a randomized controlled trial evaluating two educational programmes, patients (n = 87) with chronic periodontitis completed a questionnaire at baseline and after 12 months. OHRQoL was assessed with the General Oral Health Assessment Index (GOHAI) and the UK oral health-related quality-of-life measure (OHQoL-UK). In addition, patients' global rating of oral health and socio-demographic variables were recorded. The MID was estimated with anchor-based and distributions-based methods. There were no differences between the two educational groups. The OHRQoL was significantly improved after treatment. The MID was approximately five for OHQoL-UK with a moderate ES, and three for GOHAI with a Small ES, and 46-50% of the patients showed improvements beyond the MID. Both oral health educational groups reported higher scores in OHRQoL after NSPT resulting in more positive well-being (OHQoL-UK) and less frequent oral problems (GOHAI). OHQoL-UK gave a greater effect size and mean change scores but both instruments were associated with the participants' self-rated change in oral health. The changes were meaningful for the patients supported by the estimated MID.


Comparison of Gait Parameters for Predicting Cognitive Decline: The Mayo Clinic Study of Aging.
Previous studies reported that slower gait speed might predict cognitive impairment and dementing illnesses, supporting the role of gait speed as a possible subclinical marker of cognitive impairment. However, the predictive value of other gait parameters for cognitive decline is unclear. To investigate and compare the association with, and prediction of, specific gait parameters for cognition in a population-based sample. The analysis included 3,426 cognitively normal participants enrolled in the Mayo Clinic Study of Aging. At baseline and every 15 months (mean follow-up = 1.93 years), participants had a study coordinator evaluation, neurological examination, and a neuropsychological assessment using nine tests that covered four domains. Gait parameters were assessed with the GAITRite® instrument. General linear mixed effects models were used to compute the annualized rate of change in cognitive domain z-scores, controlling for age, sex, education, depression, comorbidities, body mass index, APOE ɛ4 allele, and visit number, and excluding individuals with a history of stroke, alcoholism, Parkinson's disease, subdural hematoma, and normal pressure hydrocephalus. Spatial (stride length), temporal (ambulatory time, gait speed, step count, cadence, double support time), and spatiotemporal (cadence) gait parameters, and greater intraindividual variability in stride length, swing time, and stance time were associated with a significant decline in global cognition and in specific domains including memory, executive function, visuospatial, and language. Spatial, temporal, and spatiotemporal measures of gait and greater variability of gait parameters were associated with and predictive of both global- and domain-specific cognitive decline.


Oil, Gas and Conflict: A Mathematical Model for the Resource Curse.
Oil and natural gas are highly valuable natural resources, but many countries with large untapped reserves suffer from poor economic and social-welfare performance. This conundrum is known as the resource curse. The resource curse is a result of poor governance and wealth distribution structures that allow the elite to monopolize resources for self-gain. When rival social groups compete for natural resources, civil unrest soon follows. While conceptually easy to follow, there have been few formal attempts to study this phenomenon. Thus, we develop a mathematical model that captures the basic elements and dynamics of this dilemma. We show that when resources are monopolized by the elite, increased exportation leads to decreased domestic production. This is due to under-provision of the resource-embedded energy and industrial infrastructure. Decreased domestic production then lowers the marginal return on productive activities, and insurgency emerges. The resultant conflict further displaces human, built, and natural capital. It forces the economy into a vicious downward spiral. Our numerical results highlight the importance of governance reform and productivity growth in reducing oil-and-gas-related conflicts, and thus identify potential points of intervention to break the downward spiral.


Service user involvement in radiotherapy and oncology education; the patient perspective.
The Health & Care Professions Council (HCPC) recently mandated the integration of the service-user voice into all aspects of allied healthcare education in the UK. However, the potential benefits and harms of this integration to service users are largely unknown. This study aimed to determine service user perspectives on relaying their personal experience of the cancer treatment pathway to students in an undergraduate Radiotherapy and Oncology programme. A qualitative study was conducted where seven patients led educational sessions with students and were interviewed (1:1) 1 week later using an iterative semi-structured format. Unanimously, the primary motivation for participation was the opportunity for patients to tell their unique story to positively influence the future behaviour and understanding of student healthcare professionals. Patients experiencing significant cancer-related psychological trauma reported reacting more emotionally to the experience but also reported particularly positive benefits from their participation, including therapeutic healing. Findings highlight the array of benefits to service users associated with teaching in allied healthcare education. Post traumatic growth (PTG) may also potentially occur through this type of intervention in certain participants and this warrants further investigation in future studies.


Comparing the effects of two different educational methods on clinical skills of emergency intermediate technician: A quasi-experimental research.
Assessing the clinical skills of prehospital Intermediate technician is considered to be one of the priorities in dealing with diseases, which may provide an appropriate reflection of the training programs. The purpose of this study was to compare the two methods of clinical skills training of emergency intermediate technician. This quasi-experiment was carried out on Kerman's emergency medical technicians in 2017. Operational and clinical skills, such as cardiopulmonary resuscitation (CPR), triage, familiarity with the equipment, and proper patient transportation methods, were taught in both electronic and traditional methods on two groups, each consisting of 30 intermediate technicians. Finally, the personnel's satisfaction level with the two teaching methods was compared and analyzed using IBM SPSS Statistics for Windows, Version 22.0. Armonk, NY: IBM Corp. There was no significant difference between the theoretical test scores in both the electronic and traditional methods in all the participants (triage, pulmonary resuscitation, familiarity with equipment, and patient transportation). Furthermore, there were significant differences between the practical test scores in both the electronic and traditional methods, in all the participants except triage. There was a significant difference between learners' satisfaction in both electronic and traditional methods in two areas of teaching and course difficulty in CPR, equipment usage, and methods of transportation. According to the results obtained by the present study, the electronic educational systems due to their inclusive and interactive nature are recommended to be employed in courses that have more theoretical aspects such as triage. The traditional method is suggested in teaching practical courses such as CPR that need more practical and clinical skills.


Site-Specific Incorporation of a Cu2+ Spin Label into Proteins for Measuring Distances by Pulsed Dipolar Electron Spin Resonance Spectroscopy.
Pulsed dipolar electron spin resonance spectroscopy (PDS) is a powerful tool for measuring distances in solution-state macromolecules. Paramagnetic metal ions, such as Cu2+, are used as spin probes because they can report on metalloprotein features and can be spectroscopically distinguished from traditional nitroxide (NO)-based labels. Here, we demonstrate site-specific incorporation of Cu2+ into non-metalloproteins through the use of a genetically encodable non-natural amino acid, 3-pyrazolyltyrosine (PyTyr). We first incorporate PyTyr in cyan fluorescent protein to measure Cu2+-to-NO distances and examine the effects of solvent conditions on Cu2+ binding and protein aggregation. We then apply the method to characterize the complex formed by the histidine kinase CheA and its target response regulator CheY. The X-ray structure of CheY-PyTyr confirms Cu labeling at PyTyr but also reveals a secondary Cu site. Cu2+-to-NO and Cu2+-to-Cu2+ PDS measurements of CheY-PyTyr with nitroxide-labeled CheA provide new insights into the conformational landscape of the phosphotransfer complex and have implications for kinase regulation.


A case of acute lymphoblastic leukemia mimicking juvenile idiopathic arthritis.
Patients with leukemia can be presented with monoarthritis without any hematologic abnormalities. These patients may be misdiagnosed with juvenile idiopathic arthritis (JIA), and the main treatment can also be delayed. An 11-year-old girl was admitted to our pediatric rheumatology outpatient clinic with a 4-week history of swelling in the left ankle. JIA was considered as a preliminary diagnosis after the antinuclear antibody was found to be positive, and non-steroidal anti-inflammatory drug was started. Diffuse bony edema was observed in the talus, navicular, cuboid, and cuneiform bones in magnetic resonance imaging of the left ankle. Despite the treatments, the patient's joint pain increased. There were no abnormalities in repeated peripheral blood smears. On week 3 of follow-up, after bicytopenia was revealed in complete blood count, bone marrow biopsy was performed, and she was diagnosed with precursor B cell acute lymphoblastic leukemia. We presented this case to emphasize that malignancies must be evaluated in the differential diagnosis of patients with arthritis.


Properties of angiotensin-converting enzyme in intact cerebral microvessels.
Angiotensin-converting enzyme (ACE) was studied in preparations of microvessels isolated from rabbit cerebral cortex. Activity was determined by measuring the degradation of hippuryl-histidyl-leucine (Hip-His-Leu) by the intact microvessels in a physiological salt solution at pH 7.4. ACE activity was dependent on both substrate and chloride ion concentration and was inhibited by captopril in a manner similar to that observed previously with tissue homogenates. Angiotensin I was rapidly degraded by the intact microvessels, even in the presence of 10(-6)M captopril. An advantage of the methodology employed was the ability to pretreat the microvessels and then assess the effect of pretreatment by transfer to a postincubation assay system. Pretreatment with a hyperosmolar urea solution did not change ACE activity or cause release of ACE from the microvessels, although lactic dehydrogenase and lysosomal enzymes were released. Pretreatment with captopril caused a lag in the subsequent degradation of Hip-His-Leu, presumably reflecting dissociation of inhibitor from the cell-associated enzyme. ACE activity was unaffected by hypoxic or anoxic incubation conditions. The ability to measure ACE activity of the microvessels in vitro provides a unique opportunity to study the properties of the enzyme in intact cerebrovascular endothelial cells.


Computerized prompts for cancer screening in a community health center.
We describe the implementation and subsequent use of a computerized health maintenance tracking system in a large, urban, North Carolina community health center (Lincoln Community Health Center) as part of a larger study designed to increase rates of mammography, Papanicolaou tests, and smoking cessation in low-income African-Americans. Clinicians from the Lincoln Community Health Center were involved in the design and implementation of the computer system. At each office visit, clinicians received a computerized encounter form indicating needed screening tests, counseling, and immunizations for each randomly selected study patient (n = 1318). Initial clinician compliance rates with filling out the form were 95 percent (mammography), 82 percent (Papanicolaou test), 77 percent (clinician breast examination), and 55 percent (smoking cessation). Cumulative compliance leveled off at 21 months to 65 percent, 57 percent, 53 percent, and 38 percent, respectively, despite multiple reminder strategies. When surveyed, most clinicians thought it was a good reminder system but said they did not always complete the form because of time demands. Costs of adapting and implementing the system were $23,332.08 ($17.70 per study). Per-patient costs would have been reduced further if more patients had been included in the project. State-of-the-art computer prompting systems can be useful in a community health center; however, even with prompting, clinicians still only addressed health maintenance with their patients about 50 percent of the time. Additional interventions will be needed, particularly in low-income populations, to meet the Healthy People 2000 goals in health promotion.


First Report of Dieback on Euonymus fortunei Caused by Cylindrocladiella parva in Germany.
In August 2011, a severe shoot dieback was observed on several hundred plants of 1-year-old Euonymus fortunei cv. Emerald 'n Gold in a nursery in Lower Saxony and on a cemetery in Berlin. Single shoots or the whole plant were affected. Chocolate brown lesions around the shoots spread primarily acropetally to be followed by wilting of the shoot tip, reddish discoloration, dropping of leaves, and finally plant death. Two fungal isolates, JKI 2187 and JKI 1288, forming white mycelium on 2% malt extract agar (MEA) were obtained from symptomatic shoots. Both were identified by their morphology as Cylindrocladiella parva (P.J. Anderson) Boesewinkel (syn. Cylindrocladium parvum). After incubation for one week at 25°C in the dark, the reverse side of the colony became buff to ochreous and this was associated with development of long chains of chlamydospores. Microsclerotia and fruiting bodies were not observed. Morphological characteristics were determined on synthetic nutrient agar (SNA) after 7 days at 25°C under near-ultraviolet light. The conidiophores were penicillately branched. The stipe extensions were thick-walled with clavate to naviculate vesicles. Conidia measured 12.7 to 17.1 (14.9) × 2.2 to 3.3 (2.7) μm. The molecular studies confirmed the morphological identification. Genomic DNA was isolated from the mycelia. The rDNA internal transcribed spacer (ITS) region was amplified with the primers ITS1 and ITS4 and a part of the β-tubulin gene with the primers Bt2a and Bt2b (2). The sequences generated in this study were compared with sequences obtained from GenBank. A BLAST analysis showed that the ITS sequence had a 99% similarity with that of C. parva GenBank Accession No. AY793454 and the β-tubulin gene had a 100% similarity with AY793489. So far, pathogenicity of C. parva has been demonstrated for only a few plant species. Its pathogenicity was confirmed on grapevine (Vitis vinifera) in New Zealand (3), on common oak (Quercus robur) in Italy (4), and on eucalyptus in South Africa (1). To fulfill Koch's postulates for the pathogen on E. fortunei, the isolate JKI 2188 of C. parva was inoculated on 40 two-year-old plants of cv. Emerald 'n Gold. The leaves around one node were removed on five shoots per plant. After wounding the nodes with a needle, colonized agar plugs were placed on them. The plugs were covered with moist cellulose swabs and sealed with Parafilm. To act as negative controls, 20 plants were treated with sterile agar plugs. All the plants were incubated in a growth chamber at 21/16°C (day/night), with a day length of 12 h and a relative humidity of 90 to 100%. Seven weeks after inoculation, all inoculated plants showed symptoms identical to those of the diseased plants from which C. parva was originally isolated. The negative controls remained healthy. The strains reisolated were identical to the original isolates. To our knowledge, this is the first report of C. parva as a pathogen of Euonymus. Since 2011, there were no further reports of this disease. At present, the disease is not of economic importance. References: (1) P. W. Crous et al. Plant Pathol. 42:302, 1993. (2) N. L. Glass and G. C. Donaldson. Appl. Environ. Microbiol. 61:1323, 1995. (3) E. E. Jones et al. Plant Dis 96: 144, 2012. (4) L. Scattolin and L. Monteccio. Plant Dis. 91:771, 2007.


Context-dependent interactive effects of non-lethal predation on larvae impact adult longevity and body composition.
Predation impacts development, behavior and morphology of prey species thereby shaping their abundances, distribution and community structure. Non-lethal threat of predation, specifically, can have a strong influence on prey lifehistory characteristics. While investigations often focus on the impact of predation threat on prey in isolation, tests of its interactive effects with food availability and resource competition on prey survival and fitness can improve understanding of costs, benefits and trade-offs of anti-predator strategies. This study, involving Aedes aegypti mosquitoes as a model organism, investigates both simple and interactive effects of predation threat during the larval stage on survival, size at and time to maturity, stored teneral reserves of glycogen, protein and lipid in adults, and adult longevity. Our results show that development times of mosquito larvae were increased (by 14.84% in males and by 97.63% in females), and size of eclosing adults decreased (by 62.30% in males and by 58.33% in females) when exposed to lowered nutrition and elevated intraspecific competition, but that predation had no detectable effect on these simple traits. Teneral reserves of glycogen, protein and lipid and adult longevity were positively correlated with adult body size. Non-lethal predation threat had significant interactive effects with nutrition and larval competition on teneral reserves in males and adult longevity in males and females. The sexes responded differently to conditions encountered as larvae, with the larval environment affecting development and adult characteristics more acutely for females than for males. The outcome of this study shows how threat of predation on juveniles can have long-lasting effects on adults that are likely to impact mosquito population dynamics and that may impact disease transmission.


Assembly and use of new task rules in fronto-parietal cortex.
Severe capacity limits, closely associated with fluid intelligence, arise in learning and use of new task rules. We used fMRI to investigate these limits in a series of multirule tasks involving different stimuli, rules, and response keys. Data were analyzed both during presentation of instructions and during later task execution. Between tasks, we manipulated the number of rules specified in task instructions, and within tasks, we manipulated the number of rules operative in each trial block. Replicating previous results, rule failures were strongly predicted by fluid intelligence and increased with the number of operative rules. In fMRI data, analyses of the instruction period showed that the bilateral inferior frontal sulcus, intraparietal sulcus, and presupplementary motor area were phasically active with presentation of each new rule. In a broader range of frontal and parietal regions, baseline activity gradually increased as successive rules were instructed. During task performance, we observed contrasting fronto-parietal patterns of sustained (block-related) and transient (trial-related) activity. Block, but not trial, activity showed effects of task complexity. We suggest that, as a new task is learned, a fronto-parietal representation of relevant rules and facts is assembled for future control of behavior. Capacity limits in learning and executing new rules, and their association with fluid intelligence, may be mediated by this load-sensitive fronto-parietal network.


Steps that count! The development of a pedometer-based health promotion intervention in an employed, health insured South African population.
Physical activity (PA) has been identified as a central component in the promotion of health. PA programs can provide a low cost intervention opportunity, encouraging PA behavioral change while worksites have been shown to be an appropriate setting for implementing such health promotion programs. Along with these trends, there has been an emergence of the use of pedometers as a self-monitoring and motivational aid for PA.This study determines the effectiveness of a worksite health promotion program comprising of a 10-week, pedometer-based intervention ("Steps that Count!"), and individualized email-based feedback to effect PA behavioral change. The study is a randomized controlled trial in a worksite setting, using pedometers and individualized email-based feedback to increase steps per day (steps/d). Participant selection will be based on attendance at a corporate wellness event and information obtained, following the completion of a Health Risk Appraisal (HRA), in keeping with inclusion criteria for the study. All participants will, at week 1 (pre-intervention), be provided with a blinded pedometer to assess baseline levels of PA. Participants will be provided with feedback on pedometer data and identify strategies to improve daily PA towards current PA recommendations. Participants will thereafter be randomly assigned to the intervention group (INT) or control group (CTL). The INT will subsequently wear an un-blinded pedometer for 10 consecutive weeks.Individualized feedback messages based on average steps per day, derived from pedometer data (INT) and general supportive/motivational messages (INT+CTL), will be provided via bi-weekly e-mails; blinded pedometer-wear will be conducted at week 12 (post-intervention: INT+CTL). The purpose of this paper is to outline the rationale behind, and the development of, an intervention aimed at improving ambulatory PA through pedometer use, combined with regular, individualized, email-based feedback. Pedometer-measured PA and individualized feedback may be a practical and easily applied intervention.


Typologies of discrimination: Latinx youth's experiences in an emerging immigrant community.
Few studies examine how racial-ethnic peer discrimination experiences of Latinx youth vary across the race-ethnicity of the perpetrator. In a sample of 170 Latinx early adolescents (Mage = 12.86 years, range = 10.33-15.23; 51% female), we identified 4 latent profiles of youth: (a) relatively low likelihood of experiencing discrimination regardless of peers' racial-ethnic group (38%; low discrimination); (b) relatively high probability of experiencing discrimination from the majority outgroup peers (33%; outgroup); (c) relatively high likelihood of experiencing discrimination from ingroup peers (14%; ingroup); (d) the highest probability of discrimination experiences across the in- and outgroup (15%; high discrimination group). Overall, Latinx youth classified in a typology characterized by a higher likelihood of experiencing discrimination from both ingroup and outgroup peers also reported the worst internalizing and externalizing symptoms relative to those in the low discrimination typology. (PsycINFO Database Record (c) 2019 APA, all rights reserved).


Environmental trade-offs of direct air capture technologies in climate change mitigation toward 2100.
Direct air capture (DAC) is critical for achieving stringent climate targets, yet the environmental implications of its large-scale deployment have not been evaluated in this context. Performing a prospective life cycle assessment for two promising technologies in a series of climate change mitigation scenarios, we find that electricity sector decarbonization and DAC technology improvements are both indispensable to avoid environmental problem-shifting. Decarbonizing the electricity sector improves the sequestration efficiency, but also increases the terrestrial ecotoxicity and metal depletion levels per tonne of CO2 sequestered via DAC. These increases can be reduced by improvements in DAC material and energy use efficiencies. DAC exhibits regional environmental impact variations, highlighting the importance of smart siting related to energy system planning and integration. DAC deployment aids the achievement of long-term climate targets, its environmental and climate performance however depend on sectoral mitigation actions, and thus should not suggest a relaxation of sectoral decarbonization targets.


Suppressed transformation and induced differentiation of HER-2/neu-overexpressing breast cancer cells by emodin.
The amplification and overexpression of the HER-2/neu proto-oncogene, which encodes the tyrosine kinase receptor p185neu, have been observed frequently in tumors from human breast cancer patients and are correlated with poor prognosis. To explore the potential of chemotherapy directed at the tyrosine kinase of p185neu, we have found that emodin (3-methyl-1,6,8-trihydroxyanthraquinone), a tyrosine kinase inhibitor, suppresses autophosphorylation and transphosphorylation activities of HER-2/neu tyrosine kinase, resulting in tyrosine hypophosphorylation of p185neu in HER-2/neu-overexpressing breast cancer cells. Emodin, at a 40-microM concentration, which repressed tyrosine kinase of p185neu, efficiently inhibited both anchorage-dependent and anchorage-independent growth of HER-2/neu-overexpressing breast cancer cells. However, the inhibition was much less effective for those cells expressing basal levels of p185neu under the same conditions. Emodin also induced differentiation of HER-2/neu-overexpressing breast cancer cells by exhibiting a morphological maturation property of large lacy nuclei surrounded by sizable flat cytoplasm and by showing a measurable production of large lipid droplets, which is a marker of mature breast cells. Therefore, our results indicate that emodin inhibits HER-2/neu tyrosine kinase activity and preferentially suppresses growth and induces differentiation of HER-2/neu-overexpressing cancer cells. These results may have chemotherapeutic implications for using emodin to target HER-2/neu-overexpressing cancer cells.


Supervised injection facility use and all-cause mortality among people who inject drugs in Vancouver, Canada: A cohort study.
People who inject drugs (PWID) experience elevated rates of premature mortality. Although previous studies have demonstrated the role of supervised injection facilities (SIFs) in reducing various harms associated with injection drug use, including accidental overdose death, the possible impact of SIF use on all-cause mortality is unknown. Therefore, we examined the relationship between frequent SIF use and all-cause mortality among PWID in Vancouver, Canada. Data were derived from 2 prospective cohort studies of PWID in Vancouver, Canada, between December 2006 and June 2017. Every 6 months, participants completed questionnaires that elicited information regarding sociodemographic characteristics, substance use patterns, social-structural exposures, and use of health services including SIFs. These data were confidentially linked to the provincial vital statistics database to ascertain mortality rates and causes of death. We used multivariable extended Cox regression analyses to estimate the independent association between frequent (i.e., at least weekly) SIF use and all-cause mortality. Of 811 participants, 278 (34.3%) were women, and the median age was 39 years (IQR 33-46) at baseline. In total, 432 (53.3%) participants reported frequent SIF use at baseline, and 379 (46.7%) did not. At baseline, frequent SIF users were on average younger than nonfrequent users, and a higher proportion of frequent SIF users than nonfrequent users were unstably housed, resided in the Downtown Eastside neighbourhood, injected in public, had a recent non-fatal overdose, used prescription opioids at least daily, injected heroin at least daily, injected cocaine at least daily, and injected crystal methamphetamine at least daily. A lower proportion of frequent SIF users than nonfrequent users were HIV positive and enrolled in addiction treatment at baseline. The median duration of follow-up among study participants was 72 months (IQR 24-123). In total, 112 participants (13.8%) died during the study period, yielding a crude mortality rate of 22.7 (95% CI 18.7-27.4) deaths per 1,000 person-years. The median years of potential life lost per death was 34 (IQR 27-42) years. In a time-updated multivariable model, frequent SIF use was inversely associated with risk of all-cause mortality after adjusting for potential confounders, including age, sex, HIV seropositivity, unstable housing, at least daily cocaine injection, public injection, incarceration, enrolment in addiction treatment, and calendar year of interview (adjusted hazard ratio 0.46, 95% CI 0.26-0.80, p = 0.006). The main study limitations are the limited generalizability of findings due to non-random sampling, the potential for reporting biases due to reliance on some self-reported information, and the possibility that residual confounding influenced findings. We observed a high burden of premature mortality among a community-recruited cohort of PWID. Frequent SIF use was associated with a lower risk of death, independent of relevant confounders. These findings support efforts to enhance access to SIFs as a strategy to reduce mortality among PWID. Further analyses of individual-level data are needed to determine estimates of, and potential causal pathways underlying, associations between SIF use and specific causes of death.


Simultaneous viscosity and density measurement of small volumes of liquids using a vibrating microcantilever.
Many industrial and technological applications require precise determination of the viscosity and density of liquids. Such measurements can be time consuming and often require sampling substantial amounts of the liquid. These problems can partly be overcome with the use of microcantilevers but most existing methods depend on the specific geometry and properties of the cantilever, which renders simple, accurate measurement difficult. Here we present a new approach able to simultaneously quantify both the density and the viscosity of microliters of liquids. The method, based solely on the measurement of two characteristic frequencies of an immersed microcantilever, is completely independent of the choice of a cantilever. We derive analytical expressions for the liquid's density and viscosity and validate our approach with several simple liquids and different cantilevers. Application of our model to non-Newtonian fluids shows that the calculated viscosities are remarkably robust when compared to measurements obtained from a standard rheometer. However, the results become increasingly dependent on the cantilever geometry as the frequency-dependent nature of the liquid's viscosity becomes more significant.


Does Shyness Vary According to Attained Social Roles? Trends Across Age Groups in a Large British Sample.
The current study investigated (a) how a composite measure of shyness comprising introversion and neuroticism relates to other well-known constructs involving social fears, and (b) whether mean levels of shyness vary for men and women depending on the adoption of various social roles. Study 1 used a sample of 211 UK participants aged 17-70 (64% female; Mage = 47.90). Study 2 used data from a large cross-sectional data set with UK participants aged 17-70 (Ntarget = 552,663; 64% female; Mage = 34.19 years). Study 1 showed that shyness measured as a composite of introversion and neuroticism was highly correlated with other constructs involving social fears. Study 2 indicated that, controlling for various sociodemographic variables, females appeared to have higher levels, whereas males appeared to have lower levels of shyness. Males and females who were in employment had the lowest shyness levels, whereas those working in unskilled jobs had the highest levels and people working in sales the lowest levels of shyness. Participants in relationships had lower levels of shyness than those not in relationships, but parenthood was not associated with shyness. Mean levels of shyness are likely to vary according to adopted social roles, gender, and age.


Early intervention services in psychosis: from evidence to wide implementation.
Early intervention (EI) in psychosis is a comprehensive and evidence-based approach aimed at detection and treatment of psychotic symptoms in their early stages. This paper presents core features and noteworthy aspects of the evidence basis and limitations of EI, the importance of programme fidelity, challenges for its widespread dissemination and economic perspectives related to it. This paper is a narrative review about the evidence supporting EI and the challenges to its widespread dissemination. In spite of evidence of a wide range of benefits, widespread dissemination has been slow, and even currently implemented programmes might be threatened. This reflects in part the shortcomings of mental health care in general, such as low priority for funding, stigma and structural problems. Successful examples of advocacy, mobilization and destigmatization campaigns have overcome these difficulties. Funding for mental health in general and for EI services appears low relative to need. One key argument for better funding for EI can be found in its favourable cost-effectiveness, but not all stakeholders beyond mental health administrators are aware of this. Positive impacts of EI programmes on excess unemployment and tax forgone suggest that social affairs and labour ministries - and not only health ministries - could be more involved in governance of mental health issues; ministries of justice and education are other sector stakeholders than can benefit. Wider dissemination of EI services will probably benefit from better integration of potential funders, promotion of joint targets and shared financial or budgetary incentives.


Cationic lipid-mediated delivery of proteins enables efficient protein-based genome editing in vitro and in vivo.
Efficient intracellular delivery of proteins is needed to fully realize the potential of protein therapeutics. Current methods of protein delivery commonly suffer from low tolerance for serum, poor endosomal escape and limited in vivo efficacy. Here we report that common cationic lipid nucleic acid transfection reagents can potently deliver proteins that are fused to negatively supercharged proteins, that contain natural anionic domains or that natively bind to anionic nucleic acids. This approach mediates the potent delivery of nM concentrations of Cre recombinase, TALE- and Cas9-based transcription activators, and Cas9:sgRNA nuclease complexes into cultured human cells in media containing 10% serum. Delivery of unmodified Cas9:sgRNA complexes resulted in up to 80% genome modification with substantially higher specificity compared to DNA transfection. This approach also mediated efficient delivery of Cre recombinase and Cas9:sgRNA complexes into the mouse inner ear in vivo, achieving 90% Cre-mediated recombination and 20% Cas9-mediated genome modification in hair cells.


Regulation of autoimmunity and donor cell engraftment by recipient Lyt-2+ cells during the graft-versus-host reaction.
When lymphocytes from DBA/2 mice are transferred to (C57BL X DBA/2)F1 (BDF1) mice, the ensuing graft-vs.-host reaction (GVHR) causes an autoimmune illness resembling human SLE. To examine the role of recipient T cells in this process, BDF1 mice were depleted of L3T4+ or Lyt-2+ cells by thymectomy followed by treatment with mAbs to L3T4 or Lyt-2. This produced sustained depletion of these T cell subsets. Subsequent grafting with parental DBA/2 lymphocytes produced autoimmune disease in mice depleted of L3T4+ cells and controls but not in mice depleted of Lyt-2+ cells. Analysis of blood lymphocytes 4 wk after donor cell transfer demonstrated that BDF1 recipients depleted of Lyt-2+ cells were virtually repopulated with donor T lymphocytes, compared with less than or equal to 35% donor cell engraftment in all other groups. Thus, recipient Lyt-2+ cells influence both host cell engraftment and autoimmunity during the parent-into-F1 GVHR.


Solvation and hydrogen bonding in alanine- and glycine-containing dipeptides probed using solution- and solid-state NMR spectroscopy.
The NMR chemical shift is a sensitive reporter of peptide secondary structure and its solvation environment, and it is potentially rich with information about both backbone dihedral angles and hydrogen bonding. We report results from solution- and solid-state (13)C and (15)N NMR studies of four zwitterionic model dipeptides, L-alanyl-L-alanine, L-alanyl-glycine, glycyl-L-alanine, and glycyl-glycine, in which we attempt to isolate structural and environmental contributions to the chemical shift. We have mapped hydrogen-bonding patterns in the crystalline states of these dipeptides using the published crystal structures and correlated them with (13)C and (15)N magic angle spinning chemical shift data. To aid in the interpretation of the solvated chemical shifts, we performed ab initio quantum chemical calculations to determine the low-energy conformers and their chemical shifts. Assuming low energy barriers to interconversion between thermally accessible conformers, we compare the Boltzmann-averaged chemical shifts with the experimentally determined solvated-state shifts. The results allow us to correlate the observed differences in chemical shifts between the crystalline and solvated states to changes in conformation and hydrogen bonding that occur upon solvation.


Review: The risk of contracting anthrax from spore-contaminated soil - A military medical perspective.
Anthrax is an infectious disease of relevance for military forces. Although spores of Bacillus anthracis obiquitously occur in soil, reports on soil-borne transmission to humans are scarce. In this narrative review, the potential of soil-borne transmission of anthrax to humans is discussed based on pathogen-specific characteristics and reports on anthrax in the course of several centuries of warfare. In theory, anthrax foci can pose a potential risk of infection to animals and humans if sufficient amounts of virulent spores are present in the soil even after an extended period of time. In praxis, however, transmissions are usually due to contacts with animal products and reported events of soil-based transmissions are scarce. In the history of warfare, even in the trenches of World War I, reported anthrax cases due to soil-contaminated wounds are virtually absent. Both the perspectives and the experience of the Western hemisphere and of former Soviet Republics are presented. Based on the accessible data as provided in the review, the transmission risk of anthrax by infections of wounds due to spore-contaminated soil is considered as very low under the most circumstance. Active historic anthrax foci may, however, still pose a risk to the health of deployed soldiers.


Phase II Evaluation of Aggressive Dose De-Escalation for Adjuvant Chemoradiotherapy in Human Papillomavirus-Associated Oropharynx Squamous Cell Carcinoma.
The purpose of this study was to determine if dose de-escalation from 60 to 66 Gy to 30 to 36 Gy of adjuvant radiotherapy (RT) for selected patients with human papillomavirus-associated oropharyngeal squamous cell carcinoma could maintain historical rates for disease control while reducing toxicity and preserving swallow function and quality of life (QOL). MC1273 was a single-arm phase II trial testing an aggressive course of RT de-escalation after surgery. Eligibility criteria included patients with p16-positive oropharyngeal squamous cell carcinoma, smoking history of 10 pack-years or less, and negative margins. Cohort A (intermediate risk) received 30 Gy delivered in 1.5-Gy fractions twice per day over 2 weeks along with 15 mg/m2 docetaxel once per week. Cohort B included patients with extranodal extension who received the same treatment plus a simultaneous integrated boost to nodal levels with extranodal extension to 36 Gy in 1.8-Gy fractions twice per day. The primary end point was locoregional tumor control at 2 years. Secondary end points included 2-year progression-free survival, overall survival, toxicity, swallow function, and patient-reported QOL. Accrual was from September 2013 to June 2016 (N = 80; cohort A, n = 37; cohort B, n = 43). Median follow-up was 36 months, with a minimum follow-up of 25 months. The 2-year locoregional tumor control rate was 96.2%, with progression-free survival of 91.1% and overall survival of 98.7%. Rates of grade 3 or worse toxicity at pre-RT and 1 and 2 years post-RT were 2.5%, 0%, and 0%. Swallowing function improved slightly between pre-RT and 12 months post-RT, with one patient requiring temporary feeding tube placement. Aggressive RT de-escalation resulted in locoregional tumor control rates comparable to historical controls, low toxicity, and little decrement in swallowing function or QOL.


Fusion transcripts in normal human cortex increase with age and show distinct genomic features for single cells and tissues.
Fusion transcripts can contribute to diversity of molecular networks in the human cortex. In this study, we explored the occurrence of fusion transcripts in normal human cortex along with single neurons and astrocytes. We identified 1305 non-redundant fusion events from 388 transcriptomes representing 59 human cortices and 329 single cells. Our results indicate while the majority of fusion transcripts in human cortex are intra-chromosomal (85%), events found in single neurons and astrocytes were primarily inter-chromosomal (80%). The number of fusions in single neurons was significantly higher than that in single astrocytes (p < 0.05), indicating fusion as a possible contributor towards transcriptome diversity in neuronal cells. The identified fusions were largely private and 4 specific recurring events were found both in cortex and in single neurons but not in astrocytes. We found a significant increase in the number of fusion transcripts in human brain with increasing age both in single cells and whole cortex (p < 0.0005 and < 0.005, respectively). This is likely one of the many possible contributors for the inherent plasticity of the adult brain. The fusion transcripts in fetal brain were enriched for genes for long-term depression; while those in adult brain involved genes enriched for long-term potentiation pathways. Our findings demonstrate fusion transcripts are naturally occurring phenomenon spanning across the health-disease continuum, and likely contribute to the diverse molecular network of human brain.


Neuroprotective effect of asiatic acid in rat model of focal embolic stroke.
Asiatic acid (AA) is a pleiotropic neuroprotective agent that has been shown to attenuate infarct volume in mouse and rat models of focal ischemia and has a long clinically relevant therapeutic time-window. Because in a future trial AA would be administered with tissue-plasminogen activator (t-PA), the only approved acute stroke therapy, we sought to determine the effect of AA when co-administered with t-PA in a rat focal embolic stroke model. Male rats were treated with AA (75 mg/kg) alone, low-dose t-PA (2.5 mg/kg) alone, or a combination of AA and low-dose t-PA at 3 h after inducing embolic stroke. AA significantly reduced infarct volume whereas low-dose t-PA alone did not reduce infarct volume compared with vehicle. Significantly, combination treatment further enhanced reduction of infarct volume versus AA alone. Treatment with AA reduced cytochrome c (CytoC) and apoptosis-inducing factor (AIF) release from brain mitochondria after ischemia. AA was also neuroprotective against L-glutamate-induced toxicity in primary cortical neurons. In summary, combination treatment with AA and low-dose t-PA at 3 h after embolic stroke reduces infarct volume, improves neurological outcome, and provides neuroprotection. The neuroprotective effects of AA were partially associated with reduction of AIF and CytoC release.


Capture resonance of the asteroid 1685 toro by the Earth.
The asteroid 1685 Toro has its perihelion inside the Earth's orbit and a period which is 8/ 5 of that of the Earth. A calculation of Toro's orbit covering 200 years shows that this asteroid at present is captured in resonance with the Earth. The capture is due to the gravitational interaction at close encounters between the bodies.


Orphanin-FQ/nociceptin (OFQ/N) modulates the activity of suprachiasmatic nucleus neurons.
Neurons in the suprachiasmatic nucleus (SCN) constitute the principal circadian pacemaker of mammals. In situ hybridization studies revealed expression of orphanin-FQ/nociceptin (OFQ/N) receptor (NOR) mRNA in the SCN, whereas no expression of mRNA for preproOFQ/N (ppOFQ/N) was detected. The presence of OFQ/N peptide in the SCN was demonstrated by radioimmunoassay. SCN neurons (88%) responded dose-dependently to OFQ/N with an outward current (EC50 = 22.3 nM) that was reduced in amplitude by membrane hyperpolarization and reversed polarity near the theoretical potassium equilibrium potential. [Phe1psi(Ch2-NH)Gly2]OFQ/N(1-13)NH2 (3 microM), a putative NOR antagonist, activated a small outward current and significantly reduced the amplitude of the OFQ/N-stimulated current. OFQ/N reduced the NMDA receptor-mediated increase in intracellular Ca2+. When injected unilaterally into the SCN of Syrian hamsters housed in constant darkness, OFQ/N (1-50 pmol) failed to alter the timing of the hamsters' wheel-running activity. However, injection of OFQ/N (0.1-50 pmol) before a brief exposure to light during the midsubjective night significantly attenuated the light-induced phase advances of the activity rhythm. These data are consistent with the interpretation that OFQ/N acting at specific receptors modulates the activity of SCN neurons and, thereby, the response of the circadian clock to light.


Integrated analysis of CANVAS 1 and 2: phase 3, multicenter, randomized, double-blind studies to evaluate the safety and efficacy of ceftaroline versus vancomycin plus aztreonam in complicated skin and skin-structure infection.
Methicillin-resistant Staphylococcus aureus (MRSA) is a common cause of complicated skin and skin-structure infection (cSSSI). Increasing antimicrobial resistance in cSSSI has led to a need for new safe and effective therapies. Ceftaroline was evaluated as treatment for cSSSI in 2 identical phase 3 clinical trials, the pooled analysis of which is presented here. The primary objective of each trial was to determine the noninferiority of the clinical cure rate achieved with ceftaroline monotherapy, compared with that achieved with vancomycin plus aztreonam combination therapy, in the clinically evaluable (CE) and modified intent-to-treat (MITT) patient populations. Adult patients with cSSSI requiring intravenous therapy received ceftaroline (600 mg every 12 h) or vancomycin plus aztreonam (1 g each every 12 h) for 5-14 days. Of 1378 patients enrolled in both trials, 693 received ceftaroline and 685 received vancomycin plus aztreonam. Baseline characteristics of the treatment groups were comparable. Clinical cure rates were similar for ceftaroline and vancomycin plus aztreonam in the CE (91.6% vs 92.7%) and MITT (85.9% vs 85.5%) populations, respectively, as well as in patients infected with MRSA (93.4% vs 94.3%). The rates of adverse events, discontinuations because of an adverse event, serious adverse events, and death also were similar between treatment groups. Ceftaroline achieved high clinical cure rates, was efficacious against cSSSI caused by MRSA and other common cSSSI pathogens, and was well tolerated, with a safety profile consistent with the cephalosporin class. Ceftaroline has the potential to provide a monotherapy alternative for the treatment of cSSSI. ClinicalTrials.gov identifiers: NCT00424190 for CANVAS 1 and NCT00423657 for CANVAS 2.


Endoderm patterning by the notochord: development of the hypochord in Xenopus.
The patterning and differentiation of the vertebrate endoderm requires signaling from adjacent tissues. In this report, we demonstrate that signals from the notochord are critical for the development of the hypochord, which is a transient, endodermally derived structure that lies immediately ventral to the notochord in the amphibian and fish embryo. It appears likely that the hypochord is required for the formation of the dorsal aorta in these organisms. We show that removal of the notochord during early neurulation leads to the complete failure of hypochord development and to the elimination of expression of the hypochord marker, VEGF. Removal of the notochord during late neurulation, however, does not interfere with hypochord formation. These results suggest that signals arising in the notochord instruct cells in the underlying endoderm to take on a hypochord fate during early neural stages, and that the hypochord does not depend on further notochord signals for maintenance. In reciprocal experiments, when the endoderm receives excess notochord signaling, a significantly enlarged hypochord develops. Overall, these results demonstrate that, in addition to patterning neural and mesodermal tissues, the notochord plays an important role in patterning of the endoderm.


Diversity comparison of Pareto front approximations in many-objective optimization.
Diversity assessment of Pareto front approximations is an important issue in the stochastic multiobjective optimization community. Most of the diversity indicators in the literature were designed to work for any number of objectives of Pareto front approximations in principle, but in practice many of these indicators are infeasible or not workable when the number of objectives is large. In this paper, we propose a diversity comparison indicator (DCI) to assess the diversity of Pareto front approximations in many-objective optimization. DCI evaluates relative quality of different Pareto front approximations rather than provides an absolute measure of distribution for a single approximation. In DCI, all the concerned approximations are put into a grid environment so that there are some hyperboxes containing one or more solutions. The proposed indicator only considers the contribution of different approximations to nonempty hyperboxes. Therefore, the computational cost does not increase exponentially with the number of objectives. In fact, the implementation of DCI is of quadratic time complexity, which is fully independent of the number of divisions used in grid. Systematic experiments are conducted using three groups of artificial Pareto front approximations and seven groups of real Pareto front approximations with different numbers of objectives to verify the effectiveness of DCI. Moreover, a comparison with two diversity indicators used widely in many-objective optimization is made analytically and empirically. Finally, a parametric investigation reveals interesting insights of the division number in grid and also offers some suggested settings to the users with different preferences.


Tissue-engineered intervertebral discs: MRI results and histology in the rodent spine.
Tissue-engineered intervertebral discs (TE-IVDs) represent a new experimental approach for the treatment of degenerative disc disease. Compared with mechanical implants, TE-IVDs may better mimic the properties of native discs. The authors conducted a study to evaluate the outcome of TE-IVDs implanted into the rat-tail spine using radiological parameters and histology. Tissue-engineered intervertebral discs consist of a distinct nucleus pulposus (NP) and anulus fibrosus (AF) that are engineered in vitro from sheep IVD chondrocytes. In 10 athymic rats a discectomy in the caudal spine was performed. The discs were replaced with TE-IVDs. Animals were kept alive for 8 months and were killed for histological evaluation. At 1, 5, and 8 months, MR images were obtained; T1-weighted sequences were used for disc height measurements, and T2-weighted sequences were used for morphological analysis. Quantitative T2 relaxation time analysis was used to assess the water content and T1ρ-relaxation time to assess the proteoglycan content of TE-IVDs. Disc height of the transplanted segments remained constant between 68% and 74% of healthy discs. Examination of TE-IVDs on MR images revealed morphology similar to that of native discs. T2-relaxation time did not differ between implanted and healthy discs, indicating similar water content of the NP tissue. The size of the NP decreased in TE-IVDs. Proteoglycan content in the NP was lower than it was in control discs. Ossification of the implanted segment was not observed. Histological examination revealed an AF consisting of an organized parallel-aligned fiber structure. The NP matrix appeared amorphous and contained cells that resembled chondrocytes. The TE-IVDs remained viable over 8 months in vivo and maintained a structure similar to that of native discs. Tissue-engineered intervertebral discs should be explored further as an option for the potential treatment of degenerative disc disease.


Fluctuations in the open time of synaptic channels: an application to noise analysis based on charge.
Synaptic channels are stochastic devices. Even recording from large ensembles of channels, the fluctuations, described by Markov transition matrices, can be used to extract single channel properties. Here we study fluctuations in the open time of channels, which is proportional to the charge flowing through the channel. We use the results to implement a novel type of noise analysis that uses the charge rather than the current to extract fundamental channel parameters. We show in simulations that this charge based noise analysis is more robust if the synapse is located on the dendrites and thus subject to cable filtering. However, we also demonstrate that when multiple synapses are distributed on the dendrites, noise analysis breaks down. We finally discuss applications of our results to other biological processes.


Priorities in oral health care in non-EME countries.
This paper describes the prevailing problems pertaining to oral care in non-established market economy (non-EME) countries. The current situation with large numbers of untreated cases of oral diseases, the inequality in delivery systems and the virtual non-existence of an adequate community oriented prevention calls for action. What is needed is a turn towards an oral care system that meets the principles of primary health care (PHC). This implies an oral health care system which makes use of the existing health care infrastructures and which applies an appropriate technology with emphasis on community oriented prevention directed to all at an affordable price. Four components of oral care are proposed as priorities in basic oral care, aiming to achieve the objectives of the PHC philosophy. These four components are: emergency care; exposure to fluoride; oral health education (OHE); atraumatic restorative treatment (ART). These components should be available for all. The exact content and extent of each component in various countries depends on local existing supporting conditions and on the level of development as well as on specific perceived needs of the population. Therefore, small-scale demonstration projects containing one or more of the described components should firstly be launched in various countries to evaluate the acceptability, effectiveness and sustainability of the proposed basic oral care programme.


Transradial approach for mechanical thrombectomy in anterior circulation large-vessel occlusion.
OBJECTIVE The goals of this study were to describe the authors' recent institutional experience with the transradial approach to anterior circulation large-vessel occlusions (LVOs) in acute ischemic stroke patients and to report its technical feasibility. METHODS The authors reviewed their institutional database to identify patients who underwent mechanical thrombectomy via a transradial approach over the 2 previous years, encompassing their experience using modern techniques including stent retrievers. RESULTS Eleven patients were identified. In 8 (72%) of these patients the right radial artery was chosen as the primary access site. In the remaining patients, transfemoral access was initially attempted. Revascularization (modified Treatment in Cerebral Ischemia [mTICI] score ≥ 2b) was achieved in 10 (91%) of 11 cases. The average time to first pass with the stent retriever was 64 minutes. No access-related complications occurred. CONCLUSIONS Transradial access for mechanical thrombectomy in anterior circulation LVOs is safe and feasible. Further comparative studies are needed to determine criteria for selecting the transradial approach in this setting.


Multiple activities of a cloned cell line mediating natural killer cell function.
A special class of immunologic cells can lyse or damage a variety of target cells, notably malignant cells in vitro. These cells have been called natural killer (NK) cells because lysis does not require deliberate immunization by tumor cells. Although these cells can be distinguished from conventional T cells, B cells, and phagocytic cells, they have been difficult to define. We describe a representative cloned cell line that was obtained by cloning Ig -Ly-5+ cells from spleen. This clone, Cl.Ly-1-2-NK-1+/11, displays Thy-1, Ly-5, Qat-4, Qat-5 and NK-1 cell surface antigens and lyses the NK-sensitive YAC-1 lymphoma cells, but does not lyse RL-12 cells, an NK-resistant lymphoma. In addition, this clone lysed the P815 mastocytoma, EL4 lymphoma, and lipopolysaccharide-activated B lymphocyte targets. This cloned population therefore combined information for a unique display of cell surface antigens and specialized function similar to "activated" NK cells. Because this cloned population forms conjugates with susceptible but not resistant target cells, it may prove useful to identify the structure of cell surface molecules that recognize foreign cells. Finally, cells of this clone also specificity lysed target cells coated by antibodies to determinants on the target cell surface, demonstrating that a single cloned cell population can mediate two specialized immunologic functions: antibody-dependent cellular cytotoxicity and NK cell lysis.


Ganglioside metabolism in a transgenic mouse model of Alzheimer's disease: expression of Chol-1α antigens in the brain.
The accumulation of Aβ (amyloid β-protein) is one of the major pathological hallmarks in AD (Alzheimer's disease). Gangliosides, sialic acid-containing glycosphingolipids enriched in the nervous system and frequently used as biomarkers associated with the biochemical pathology of neurological disorders, have been suggested to be involved in the initial aggregation of Aβ. In the present study, we have examined ganglioside metabolism in the brain of a double-Tg (transgenic) mouse model of AD that co-expresses mouse/human chimaeric APP (amyloid precursor protein) with the Swedish mutation and human presenilin-1 with a deletion of exon 9. Although accumulation of Aβ was confirmed in the double-Tg mouse brains and sera, no statistically significant change was detected in the concentration and composition of major ganglio-N-tetraosyl-series gangliosides in the double-Tg brain. Most interestingly, Chol-1α antigens (cholinergic neuron-specific gangliosides), such as GT1aα and GQ1bα, which are minor species in the brain, were found to be increased in the double-Tg mouse brain. We interpret that the occurrence of these gangliosides may represent evidence for generation of cholinergic neurons in the AD brain, as a result of compensatory neurogenesis activated by the presence of Aβ.


Examining change in emotional-social intelligence, caring, and leadership in health professions students.
To describe and compare the development of emotional-social intelligence (ESI), caring, and leadership of nursing and physical therapy students from the beginning of their professional education until after their first clinical experiences. At the beginning of their first professional year, 73 nursing students and 60 physical therapy students completed three self-report questionnaires: the BarOn Emotional Quotient Inventory Short (EQ-i:S) for ESI, the Caring Ability Inventory, and the Self-Assessment Leadership Instrument (SALI). For each instrument, higher scores represent higher levels of ESI, caring, or leadership, respectively. The students completed the questionnaires again after finishing their first clinical experiences. A two-way ANOVA with repeated measures (group vs time) revealed a significant interaction for the total score of the EQ-i:S. At both time periods, scores on the SALI were lower for the nursing students compared to the physical therapy students. There were no other significant time or group effects. Nursing and physical therapy students had little change in ESI, leadership, and caring between the start of their academic programs and completion of their first clinical affiliations.


Polymerization characteristics of colored compomers cured with different LED units.
Incomplete polymerization of a resin material used for dental restoration affects the properties of the restoration. We evaluated the structural and mechanical properties of three different colored compomers cured with three different LED units to observe the characteristic changes occurring in different matches. Polytetrafluoroethylene molds (5 mm in diameter and 2 mm in thickness) were used to prepare disk-shaped sample specimens. Nine sample groups (each of five specimens) were prepared, three each of different compomer resin colors (gold, berry, and silver). Samples were cured using three different LED units (Optima, VALO, and Demi Ultra), according to the manufacturers' instructions. Microstructural properties of samples were characterized by determining the degree of curing using Fourier-transform infrared spectroscopy and by analyzing sample morphology under a scanning electron microscope. The Vickers hardness, compressive strength, and elastic modulus of the samples were measured to investigate their mechanical properties. The degrees of curing decreased in the order of silver > berry > gold for all curing units. Conversely, gold compomers exhibited poorer mechanical values than the berry and silver counterparts. The Optima 10 unit yielded slightly higher degrees of curing than the other devices, followed by Demi Ultra and VALO light-curing units, respectively. The resin color affected the structural and mechanical properties of the compomers, possibly as a result of the complex interactions and relationships between the irradiation light and resin material, such as light absorbance and reflectance; thus, depending on the color as well as the curing protocol.


Environment and past land use together predict functional diversity in a temperate forest.
Environment and human land use both shape forest composition. Abiotic conditions sift tree species from a regional pool via functional traits that influence species' suitability to the local environment. In addition, human land use can modify species distributions and change functional diversity of forests. However, it is unclear how environment and land use simultaneously shape functional diversity of tree communities. Land-use legacies are especially prominent in temperate forest landscapes that have been extensively modified by humans in the last few centuries. Across a 900-ha temperate deciduous forest in the northeastern United States, comprising a mosaic of different-aged stands due to past human land use, we used four key functional traits-maximum height, rooting depth, wood density, and seed mass-to examine how multiple environmental and land-use variables influenced species distributions and functional diversity. We sampled ~40,000 trees >8 cm DBH within 485 plots totaling 137 ha. Species within plots were more functionally similar than expected by chance when we estimated functional diversity using all traits together (multi-trait), and to a lesser degree, with each trait separately. Multi-trait functional diversity was most strongly correlated with distance from the perennial stream, elevation, slope, and forest age. Environmental and land-use predictors varied in their correlation with functional diversities of the four individual traits. Landscape-wide change in abundances of individual species also correlated with both environment and land-use variables, but magnitudes of trait-environment interactions were generally stronger than trait interactions with land use. These findings can be applied for restoration and assisted regeneration of human-modified temperate forests by using traits to predict which tree species would establish well in relation to land-use history, topography, and soil conditions.


Molecularly imprinted electrospun nanofibers for adsorption of 2,4-dinitrotoluene in water.
The detection and adsorption of nitroaromatic compounds such as 2,4-dinitrotoluene (DNT) is of great importance, but the selective detection of trace DNT in water remains a challenge. Here, we report molecularly imprinted polymer (MIP) nanofibers fabricated by electrospinning using DNT as a template molecule and poly(allylamine) as a functional macromer. The physical and chemical properties of the nanofibers were characterized by Fourier transform infrared (FTIR) spectroscopy, X-ray photoelectron spectroscopy (XPS), and scanning electron microscopy (SEM), and the DNT adsorption and selectivity properties were also studied by high performance liquid chromatography (HPLC). The results show that the nanofibers prepared using 20 wt% poly(ethylene terephthalate) (PET) in solvent had a good morphology and an optimal ratio of poly(allylamine) and DNT, and the imprinted nanofibers showed specific adsorption of DNT, in accordance with the Freundlich isotherm model and Scatchard analysis. Furthermore, the imprinted nanofibers showed remarkable stability and reusability, losing only 3% of their performance after eight cycles. Thus, the imprinted nanofibers fabricated by this strategy could be used for trace DNT extraction, separation, and further construction of sensors in the near future.


Hippo/Mst1 stimulates transcription of the proapoptotic mediator NOXA in a FoxO1-dependent manner.
The proapoptotic protein Noxa, a member of the BH3-only Bcl-2 protein family, can effectively induce apoptosis in cancer cells, although the relevant regulatory pathways have been obscure. Previous studies of the cytotoxic effects of α-tocopheryl succinate (α-TOS) on cancer cells identified a mechanism whereby α-TOS caused apoptosis requiring the Noxa-Bak axis. In the present study, ab initio analysis revealed a conserved FoxO-binding site (DBE; DAF-16 binding element) in the NOXA promoter, and specific affinity of FoxO proteins to this DBE was confirmed by fluorescence anisotropy. FoxO1 and FoxO3a proteins accumulated in the nucleus of α-TOS-treated cells, and the drug-induced specific FoxO1 association with the NOXA promoter and its activation were validated by chromatin immunoprecipitation. Using siRNA knockdown, a specific role for the FoxO1 protein in activating NOXA transcription in cancer cells was identified. Furthermore, the proapoptotic kinase Hippo/Mst1 was found to be strongly activated by α-TOS, and inhibiting Hippo/Mst1 by specific siRNA prevented phosphorylation of FoxO1 and its nuclear translocation, thereby reducing levels of NOXA transcription and apoptosis in cancer cells exposed to α-TOS. Thus, we have demonstrated that anticancer drugs, exemplified by α-TOS, induce apoptosis by a mechanism involving the Hippo/Mst1-FoxO1-Noxa pathway. We propose that activation of this pathway provides a new paradigm for developing targeted cancer treatments.


Homeopathic and integrative treatment for feline hyperthyroidism--four cases (2006-2010).
Hyperthyroidism is a frequent veterinary problem, particularly in elderly cats. Homeopathic treatment and other integrative modalities were provided for four hyperthyroid cats whose owners did not want conventional treatment. Symptomatic homeopathic treatment with Thyroidinum was helpful in one cat. All cats were prescribed an appropriate individualized homeopathic remedy. All four cats showed resolution of clinical signs; three attained normal thyroid hormone levels. Three cats later received acupuncture and/or herbal medicines; two cats later received symptomatic homeopathic remedies. Two cats are thriving after over 3.5 and 4.25 years of treatment; two were euthanized for unrelated problems after 3 and 4 years of treatment. Homeopathic and complementary therapies avoid the potential side effects of methimazole and surgical thyroidectomy, they are less costly than radioactive iodine treatment, and they provide an option for clients who decline conventional therapies.


Ultrasonography of the urinary tract in 29 female Saanen goats.
The left and right kidneys, ureters, urinary bladder and urethra of 29 female clinically healthy Saanen goats were examined via transcutaneous and transrectal ultrasonography. In order to establish reference values the examinations were performed using a 5.0 MHz linear transducer to scan the right caudal costal part of the abdominal wall, right and left dorsal flanks and right and left inguinal regions of standing goats. A 5.0 MHz intracavity probe was used for transrectal ultrasonographic examination of the urinary bladder and urethra. The kidneys were examined in longitudinal and cross section and assessed subjectively. They could usually be seen from the 12th intercostal space on the right side and dorsal right flank. The right kidney was 8.0 ± 0.67 cm long and the left was 8.4 ± 0.64 cm long. The ureters could not be visualized in any of the goats. The length of the urinary bladder was 5.1 ± 1.38 cm, and its largest cross-sectional diameter was 2.6 ± 1.01 cm. The urethra was seen in 23 goats and appeared as echogenic lines with no visible lumen. The transition from the neck of the bladder to the internal urethral orifice extended beyond the brim of the pelvis in only one goat.


Future of therapy for rectal cancer.
Since 2004, the standard of care for patients with cT3 and/or N+ rectal cancer has been preoperative chemoradiation followed by surgery and postoperative adjuvant chemotherapy. A number of advances have occurred and are defining the future of rectal cancer therapy. Among these are short course radiation, the impact of postoperative adjuvant chemotherapy, selective radiation and selective surgery, and new chemoradiation regimens with novel agents. This review will examine these developments and assess their impact on the future therapy of rectal cancer.


Role of Nrf2, HO-1 and GSH in Neuroblastoma Cell Resistance to Bortezomib.
The activation of Nrf2 has been demonstrated to play a crucial role in cancer cell resistance to different anticancer therapies. The inhibition of proteasome activity has been proposed as a chemosensitizing therapy but the activation of Nrf2 could reduce its efficacy. Using the highly chemoresistant neuroblastoma cells HTLA-230, here we show that the strong reduction in proteasome activity, obtained by using low concentration of bortezomib (BTZ, 2.5 nM), fails in reducing cell viability. BTZ treatment favours the binding of Nrf2 to the ARE sequences in the promoter regions of target genes such as heme oxygenase 1 (HO-1), the modulatory subunit of γ-glutamylcysteine ligase (GCLM) and the transporter for cysteine (x-CT), enabling their transcription. GSH level is also increased after BTZ treatment. The up-regulation of Nrf2 target genes is responsible for cell resistance since HO-1 silencing and GSH depletion synergistically decrease BTZ-treated cell viability. Moreover, cell exposure to all-trans-Retinoic acid (ATRA, 3 μM) reduces the binding of Nrf2 to the ARE sequences, decreases HO-1 induction and lowers GSH level increasing the efficacy of bortezomib. These data suggest the role of Nrf2, HO-1 and GSH as molecular targets to improve the efficacy of low doses of bortezomib in the treatment of malignant neuroblastoma.


Integration of machine learning and mechanistic models accurately predicts variation in cell density of glioblastoma using multiparametric MRI.
Glioblastoma (GBM) is a heterogeneous and lethal brain cancer. These tumors are followed using magnetic resonance imaging (MRI), which is unable to precisely identify tumor cell invasion, impairing effective surgery and radiation planning. We present a novel hybrid model, based on multiparametric intensities, which combines machine learning (ML) with a mechanistic model of tumor growth to provide spatially resolved tumor cell density predictions. The ML component is an imaging data-driven graph-based semi-supervised learning model and we use the Proliferation-Invasion (PI) mechanistic tumor growth model. We thus refer to the hybrid model as the ML-PI model. The hybrid model was trained using 82 image-localized biopsies from 18 primary GBM patients with pre-operative MRI using a leave-one-patient-out cross validation framework. A Relief algorithm was developed to quantify relative contributions from the data sources. The ML-PI model statistically significantly outperformed (p < 0.001) both individual models, ML and PI, achieving a mean absolute predicted error (MAPE) of 0.106 ± 0.125 versus 0.199 ± 0.186 (ML) and 0.227 ± 0.215 (PI), respectively. Associated Pearson correlation coefficients for ML-PI, ML, and PI were 0.838, 0.518, and 0.437, respectively. The Relief algorithm showed the PI model had the greatest contribution to the result, emphasizing the importance of the hybrid model in achieving the high accuracy.


Preliminary observations on the response of Chironex fleckeri (Cnidaria: Cubozoa: Chirodropida) to different colors of light.
Cubozoans are well known for their attraction to light and light-colored objects. Two highly venomous types are a public safety concern in Australian waters and elsewhere: Chironex fleckeri, long considered the world's deadliest animal and colloquially called the box jellyfish; and the irukandjis, a group of at least 10 species that cause various degrees of debilitating illness. We were asked by the tourism industry whether there might be a color of light that box jellyfish and irukandjis are not attracted to, such that nighttime diving activities might pose less risk of being stung. Our preliminary trials with Chironex fleckeri indicated a marked positive response to lights of white, red, yellow, green, orange, and blue. All colors elicited a strong and directed attraction to light; however, medusae slowed down their pulsation rate, streamed out their tentacles, and performed a series of figure-eight patterns back and forth through the lighted area when exposed to blue light, which we interpreted as feeding behavior. This compares curiously with a report subsequent to our testing, in which the small, mangrove-inhabiting cubomedusa Tripedalia cystophora and the beach-dwelling Chiropsella bronzie demonstrate a peak sensitivity to blue-green light in the region of 500 nm, and that the former is behaviorally attracted to blue and green light, but ignores red. This leaves open the possibility that Irukandji species, which are more closely related to Tripedalia than to Chironex, may be blind to red.


Newborn screening for homocystinuria.
Homocystinuria is a rare inherited disorder due to a deficiency in cystathionine beta synthase. Individuals with this condition appear normal at birth but develop serious complications in childhood. Diagnosis and treatment started sufficiently early in life can effectively prevent or reduce the severity of these complications. To determine if newborn population screening for the diagnosis of homocystinuria due to cystathionine beta synthase deficiency leads to clinical benefit compared to later clinical diagnosis. We searched the Cochrane Cystic Fibrosis and Genetic Disorders Group's Inborn Errors of Metabolism Trials Register.Date of the most recent search of the Inborn Errors of Metabolism Register: 27 June 2011. Randomised controlled trials and controlled clinical trials assessing the use of any neonatal screening test to diagnose infants with homocystinuria before the condition becomes clinically evident. Eligible studies compare a screened population versus a non-screened population. No studies were identified for inclusion in the review. No studies were identified for inclusion in the review. We were unable to identify eligible studies for inclusion in this review and hence it is not possible to draw any conclusions based on controlled studies; however, we are aware of uncontrolled case-series which support the efficacy of newborn screening for homocystinuria and its early treatment. Any future randomised controlled trial would need to be both multicentre and long term in order to provide robust evidence for or against screening and to allow a cost effectiveness analysis to be undertaken.


Ozanimod Induction and Maintenance Treatment for Ulcerative Colitis.
Ozanimod (RPC1063) is an oral agonist of the sphingosine-1-phosphate receptor subtypes 1 and 5 that induces peripheral lymphocyte sequestration, potentially decreasing the number of activated lymphocytes circulating to the gastrointestinal tract. We conducted a double-blind, placebo-controlled phase 2 trial of ozanimod in 197 adults with moderate-to-severe ulcerative colitis. Patients were randomly assigned, in a 1:1:1 ratio, to receive ozanimod at a dose of 0.5 mg or 1 mg or placebo daily for up to 32 weeks. The Mayo Clinic score was used to measure disease activity on a scale from 0 to 12, with higher scores indicating more severe disease; subscores range from 0 to 3, with higher scores indicating more severe disease. The primary outcome was clinical remission (Mayo Clinic score ≤2, with no subscore >1) at 8 weeks. The primary outcome occurred in 16% of the patients who received 1 mg of ozanimod and in 14% of those who received 0.5 mg of ozanimod, as compared with 6% of those who received placebo (P=0.048 and P=0.14, respectively, for the comparison of the two doses of ozanimod with placebo). Differences in the primary outcome between the group that received 0.5 mg of ozanimod and the placebo group were not significant; therefore, the hierarchical testing plan deemed the analyses of secondary outcomes exploratory. Clinical response (decrease in Mayo Clinic score of ≥3 points and ≥30% and decrease in rectal-bleeding subscore of ≥1 point or a subscore ≤1) at 8 weeks occurred in 57% of those receiving 1 mg of ozanimod and 54% of those receiving 0.5 mg, as compared with 37% of those receiving placebo. At week 32, the rate of clinical remission was 21% in the group that received 1 mg of ozanimod, 26% in the group that received 0.5 mg of ozanimod, and 6% in the group that received placebo; the rate of clinical response was 51%, 35%, and 20%, respectively. At week 8, absolute lymphocyte counts declined 49% from baseline in the group that received 1 mg of ozanimod and 32% from baseline in the group that received 0.5 mg. The most common adverse events overall were anemia and headache. In this preliminary trial, ozanimod at a daily dose of 1 mg resulted in a slightly higher rate of clinical remission of ulcerative colitis than placebo. The trial was not large enough or of sufficiently long duration to establish clinical efficacy or assess safety. (Funded by Receptos; TOUCHSTONE ClinicalTrials.gov number, NCT01647516.).


Efficiency-enhanced photon sieve using Gaussian/overlapping distribution of pinholes.
A class of photon sieve is introduced whose structure is based on the overlapping pinholes in the innermost zones. This kind of distribution is produced by, for example, a particular form of Gaussian function. The focusing property of the proposed model was examined theoretically and experimentally. It is shown that under He-Ne laser and white light illumination, the focal spot size of this novel structure has considerably smaller FWHM than a photon sieve with randomly distributed pinholes and a Fresnel zone plate. In addition, secondary maxima have been suppressed effectively.


Myosin II contributes to cell-scale actin network treadmilling through network disassembly.
Crawling locomotion of eukaryotic cells is achieved by a process dependent on the actin cytoskeleton: protrusion of the leading edge requires assembly of a network of actin filaments, which must be disassembled at the cell rear for sustained motility. Although ADF/cofilin proteins have been shown to contribute to actin disassembly, it is not clear how activity of these locally acting proteins could be coordinated over the distance scale of the whole cell. Here we show that non-muscle myosin II has a direct role in actin network disassembly in crawling cells. In fish keratocytes undergoing motility, myosin II is concentrated in regions at the rear with high rates of network disassembly. Activation of myosin II by ATP in detergent-extracted cytoskeletons results in rear-localized disassembly of the actin network. Inhibition of myosin II activity and stabilization of actin filaments synergistically impede cell motility, suggesting the existence of two disassembly pathways, one of which requires myosin II activity. Our results establish the importance of myosin II as an enzyme for actin network disassembly; we propose that gradual formation and reorganization of an actomyosin network provides an intrinsic destruction timer, enabling long-range coordination of actin network treadmilling in motile cells.


Office management of early pregnancy loss.
The management of early pregnancy loss used to be based largely in the hospital setting, but it has shifted to the outpatient setting, allowing women to remain under the care of their family physician throughout the miscarriage process. Up to 15 percent of recognized pregnancies end in miscarriage, and as many as 80 percent of miscarriages occur in the first trimester, with chromosomal abnormalities as the leading cause. In general, no interventions have been proven to prevent miscarriage; occasionally women can modify their risk factors or receive treatment for relevant medical conditions. Unless products of conception are seen, the diagnosis of miscarriage is made with ultrasonography and, when ultrasonography is not available or is nondiagnostic, with measurement of beta subunit of human chorionic gonadotropin levels. Management options for early pregnancy loss include expectant management, medical management with misoprostol, and uterine aspiration. Expectant management is highly effective for the treatment of incomplete abortion, whereas misoprostol and uterine aspiration are more effective for the management of anembryonic gestation and embryonic demise. Misoprostol in a dose of 800 mcg administered vaginally is effective and well-tolerated. Compared with dilation and curettage in the operating room, uterine aspiration is the preferred procedure for early pregnancy loss; aspiration is equally safe, quicker to perform, more cost-effective, and amenable to use in the primary care setting. All management options are equally safe; thus, patient preference should guide treatment choice.


Measurement of human gracilis muscle isometric forces as a function of knee angle, intraoperatively.
The goals of the present study were (1) to measure the previously unstudied isometric forces of activated human Gracilis (G) muscle as a function of knee joint angle and (2) to test whether length history effects are important also for human muscle. Experiments were conducted intraoperatively during anterior cruciate ligament (ACL) reconstruction surgery (n=8). Mean peak G muscle force, mean peak G tendon stress and mean optimal knee angle equals 178.5±270.3N, 24.4±20.6 MPa and 67.5±41.7 °, respectively. The substantial inter-subject variability found (e.g., peak G force ranges between 17.2 and 490.5 N) indicate that the contribution of the G muscle to knee flexion moment may vary considerably among subjects. Moreover, typical subject anthropometrics did not appear to provide a sound estimate of the peak G force: only a limited insignificant correlation was found between peak G force and subject mass as well as mid-thigh perimeter and no correlation was found between peak G force and thigh length. The functional joint range of motion for human G muscle was determined to be at least as wide as full knee extension to 120 ° of knee flexion. However; the portion of the knee angle-muscle force relationship operationalized is not unique but individual specific: our data suggest for most subjects that G muscle operates in both ascending and descending limbs of its length-force characteristics whereas, for the remainder of the subjects, its function is limited to the descending limb, exclusively. Previous activity of G muscle at high muscle length attained during collection of a complete set of knee angle-force data showed for the first time that such length history effects are important also for human muscles: a significant correlation was found between optimal knee angle and absolute value of % force change. Except for two of the subjects, G muscle force measured at low length was lower than that measured during collection of knee joint-force data (maximally by 42.3%).


Intestinal pseudo-obstruction in patients with systemic sclerosis: an analysis of the Nationwide Inpatient Sample.
Intestinal pseudo-obstruction is a rare gastrointestinal complication in patients with SSc without large studies examining its prevalence or outcomes. We aimed to compare outcomes in SSc patients with intestinal pseudo-obstruction to patients with intestinal pseudo-obstruction secondary to other causes, and SSc patients without intestinal pseudo-obstruction. This is a case-control study using the Healthcare Cost and Utilization Project Nationwide Inpatient Sample for the period 2002-2011. We included patients with the previously validated International Classification of Diseases-Clinical Modification-9 code 710.1 for SSc in combination with codes for intestinal pseudo-obstruction, and determined length of hospitalization and the risks for surgical procedures, use of total parenteral nutrition (TPN) and in-hospital mortality. A total of 193 610 SSc hospitalizations occurred in the USA between 2002 and 2011, of which 5.4% (n = 10 386) were associated with a concurrent intestinal pseudo-obstruction diagnosis (cases). In-hospital mortality was 7.3%. In multivariate analyses, cases were more likely to die during the inpatient stay and to receive TPN than patients with idiopathic intestinal pseudo-obstruction (control group 1), patients with intestinal pseudo-obstruction and diabetes (control group 2), and SSc patients without intestinal pseudo-obstruction (control group 3). Cases had longer in-hospital stay than control groups 2 and 3, and were less likely to undergo surgical procedures than control groups 1 and 2. Intestinal pseudo-obstruction is a rare cause of hospitalization in patients with SSc, but is associated with high in-hospital mortality in comparison with other SSc patients and those with intestinal pseudo-obstruction secondary to other causes.


MiR-score: a novel 6-microRNA signature that predicts survival outcomes in patients with malignant pleural mesothelioma.
Prognosis of malignant pleural mesothelioma (MPM) is poor, and predicting the outcomes of treatment is difficult. Here we investigate the potential of microRNA expression to estimate prognosis of MPM patients. Candidate microRNAs from microarray profiling of tumor samples from 8 long (median: 53.7 months) and 8 short (median: 6.4 months) survivors following extrapleural pneumonectomy (EPP) were validated by RT-qPCR in 48 additional EPP samples. Kaplan-Meier log ranking was used to further explore the association between microRNA expression and overall survival (OS). Binary logistic regression was used to construct a microRNA signature (miR-Score) that was able to predict an OS of ≥20 months. Performance of the miR-Score was evaluated by receiver operating characteristic (ROC) curve analysis and validated in a series of 43 tumor samples from patients who underwent palliative surgery [pleurectomy/decortication (P/D)]. The miR-Score, using expression data of six microRNAs (miR-21-5p, -23a-3p, -30e-5p, -221-3p, -222-3p, and -31-5p), enabled prediction of long survival with an accuracy of 92.3% for EPP and 71.9% for palliative P/D. Hazard ratios for score-negative patients were 4.12 (95% CI: 2.03-8.37) for EPP and 1.93 (95% CI: 1.01-3.69) for P/D. Importantly, adding the miR-Score to a set of clinical selection criteria (histology, age, gender) increased predictive accuracy in the independent validation set from 76.3% for clinical factors only to 87.3%. This study has identified a novel 6-microRNA signature (miR-Score) that can accurately predict prognosis of MPM patients.


Beech Fructification and Bank Vole Population Dynamics--Combined Analyses of Promoters of Human Puumala Virus Infections in Germany.
The transmission of wildlife zoonoses to humans depends, amongst others, on complex interactions of host population ecology and pathogen dynamics within host populations. In Europe, the Puumala virus (PUUV) causes nephropathia epidemica in humans. In this study we investigated complex interrelations within the epidemic system of PUUV and its rodent host, the bank vole (Myodes glareolus). We suggest that beech fructification and bank vole abundance are both decisive factors affecting human PUUV infections. While rodent host dynamics are expected to be directly linked to human PUUV infections, beech fructification is a rather indirect predictor by serving as food source for PUUV rodent hosts. Furthermore, we examined the dependence of bank vole abundance on beech fructification. We analysed a 12-year (2001-2012) time series of the parameters: beech fructification (as food resource for the PUUV host), bank vole abundance and human incidences from 7 Federal States of Germany. For the first time, we could show the direct interrelation between these three parameters involved in human PUUV epidemics and we were able to demonstrate on a large scale that human PUUV infections are highly correlated with bank vole abundance in the present year, as well as beech fructification in the previous year. By using beech fructification and bank vole abundance as predictors in one model we significantly improved the degree of explanation of human PUUV incidence. Federal State was included as random factor because human PUUV incidence varies considerably among states. Surprisingly, the effect of rodent abundance on human PUUV infections is less strong compared to the indirect effect of beech fructification. Our findings are useful to facilitate the development of predictive models for host population dynamics and the related PUUV infection risk for humans and can be used for plant protection and human health protection purposes.