An exaggerated trait in insects: The prothoracic skeleton of Stictocephala bisonia (Homoptera: Membracidae).
The prothoracic skeleton of Stictocephala bisonia was investigated in adults and fifth-instar nymphs on a gross morphological (SEM, maceration) and light microscopic level. In both nymphs and adults, the prothoracic skeleton consists of the pronotum, episternum, epimeron, precoxale, sternum, trochantin, and two endoskeletal characters (furcal arms and pleural apophyses). In nymphs, the entire pronotum is a single-layered outgrowth of the integument communicating with the body cavity and filled with hemolymph and fat body cells ("spine"); the dorsal and ventral processes and the suprahumeral bud are extensions of this single-layered integument. In adults, the pronotum is composed of (1) a proximal, single-layered part, and (2) a larger, distal, double-layered part ("posterior reduplication") with two cuticular layers separated by a thin lumen. The posterior reduplication is elevated above the body and forms hollow (air-filled) extensions (e.g., suprahumeral horns). Its two cuticular layers are connected through cuticular columns that appear on the external surface as pits. The lumen between these layers communicates with the body cavity and contains nerves and tracheae. In the lumen of newly eclosed adults, intercellular space, epidermal cells with long processes, and hemocytes with nonlipid granules are present. In the lumen of sclerotized adult pronota, the intercellular space has disappeared, together with definite cell boundaries. Several structures are associated with the external cuticle: two types of innervated sensilla trichodea that articulate in the center of external pits, sensilla campaniformia, sensilla coeloconica, and cuticular canals with exterior openings. The morphogenetic implications of pronotal construction, various aspects of adult prothoracic anatomy, and the value of glands and sensilla for an adaptive interpretation of the pronotum are discussed. J. Morphol. 238:157-178, 1998. © 1998 Wiley-Liss, Inc.


Circle to line interferometer optical system.
This study describes a technique and apparatus for converting the circular fringes of a Fabry-Perot interferometer into a linear pattern which can be detected with a conventional linear detector. The conversion from a circular ring pattern at the focus of the objective lens of the interferometer is accomplished using a segment of an internally reflecting cone to direct the light from a sector of the ring pattern onto the linear detector. Light is concentrated into a single sector by the use of a kaleidoscopic mirror system. The aberrations associated with the transformation are shown to be small for high resolution devices which have large F numbers. A laboratory demonstration of a linearly scanned Fabry-Perot interferometer with a 0.7 cm. spacing illustrates a spectrum taken over ten orders with very small aperture defects. These results imply that a high resolution interferometer using five orders and a CCD detector would have a sensitivity 87.5 x greater than is presently achieved with those used to observe the winds in the upper atmosphere.


Lack of association between epicardial fat volume and extent of coronary artery calcification, severity of coronary artery disease, or presence of myocardial perfusion abnormalities in a diverse, symptomatic patient population: results from the CORE320 multicenter study.
Epicardial fat may play a role in the pathogenesis of coronary artery disease (CAD). We explored the relationship of epicardial fat volume (EFV) with the presence and severity of CAD or myocardial perfusion abnormalities in a diverse, symptomatic patient population. Patients (n=380) with known or suspected CAD who underwent 320-detector row computed tomographic angiography, nuclear stress perfusion imaging, and clinically driven invasive coronary angiography for the CORE320 international study were included. EFV was defined as adipose tissue within the pericardial borders as assessed by computed tomography using semiautomatic software. We used linear and logistic regression models to assess the relationship of EFV with coronary calcium score, stenosis severity by quantitative coronary angiography, and myocardial perfusion abnormalities by single photon emission computed tomography (SPECT). Median EFV among patients (median age, 62.6 years) was 102 cm(3) (interquartile range: 53). A coronary calcium score of ≥1 was present in 83% of patients. Fifty-nine percent of patients had ≥1 coronary artery stenosis of ≥50% by quantitative coronary angiography, and 49% had abnormal myocardial perfusion results by SPECT. There were no significant associations between EFV and coronary artery calcium scanning, presence severity of ≥50% stenosis by quantitative coronary angiography, or abnormal myocardial perfusion by SPECT. In a diverse population of symptomatic patients referred for invasive coronary angiography, we did not find associations of EFV with the presence and severity of CAD or with myocardial perfusion abnormalities. The clinical significance of quantifying EFV remains uncertain but may relate to the pathophysiology of acute coronary events rather than the presence of atherosclerotic disease.


Effects of preparatory and action planning instructions on situation-specific and general fruit and snack intake.
Evidence to date suggests heterogeneity in the effects of implementation intentions on health behaviour, including diet. Additional variables and study designs may impact on their effectiveness. Preparatory action, such as making sure fruits are available for consumption, may be an important additional variable. Likewise, most implementation intention research has focused on changes in general intake, yet implementation intention instructions typically require participants to consider behaviour in specific situations. Little is known on how implementation intentions impact situation-specific intake. The present study sought to add to the evidence base by comparing (1) the effects of action planning instructions versus preparatory planning instructions on (2) both situation-specific (as formulated in the implementation intention instruction) and general intake of fruits and in-between meal snack intake frequency. Fruit intake was assessed in average pieces per day, whereas snacking intake was assessed as average frequency in days per week. Using non-probability sampling, 243 undergraduate students who intended to have a healthy diet were randomized to either a standard information control condition, an action planning condition, or a preparatory planning condition. Planning manipulations were based on previous work. Two weeks later, general and situation-specific intake was assessed again in 181 participants. Data were analysed using 2 (time) x 3 (conditions) analyses of variance. Results showed that both planning manipulations were successful in decreasing snack intake frequency in the specified situation, with larger effect sizes for the action planning condition than for the preparatory planning condition. No effects were found on general snack intake frequency or fruit intake. Future planning interventions should more explicitly compare changes in situational and general intake, as well as simultaneously assessed decreases in unhealthy intake and increases in healthy intake.


Bespoke human hypertrophic chondrocytic cell lines provide the osteoinductive signals required for vascularized bone formation.
Hypertrophic cartilage provides the morphological and biochemical template for orchestrating bone growth. To produce a bone-inductive material such as hypertrophic cartilage for clinical use, we have conditionally immortalized hypertrophic chondrocytic cells from human femur and expanded them in vitro through more than 145 divisions. The clonal cell lines generated by this process consistently express signals that induce both rat and human marrow cells to differentiate in vitro into osteoblastic cells. Further, implantation of the cell-free extracellular matrix from the immortalized chondrocytic cells causes vascularized bone to form in vivo in bony defects, but not in ectopic sites such as skeletal muscle. This study shows that molecular techniques can be used to generate bespoke human cell lines for bone tissue engineering. It also demonstrates that matrix material generated from human immortalized hypertrophic chondrocytic cells may provide an abundant, efficacious, and safer alternative to bone autograft--the currently preferred material for fracture repair.


Amyotrophic lateral sclerosis-associated SOD1 mutant proteins bind and aggregate with Bcl-2 in spinal cord mitochondria.
Familial amyotrophic lateral sclerosis (ALS)-linked mutations in the copper-zinc superoxide dismutase (SOD1) gene cause motor neuron death in about 3% of ALS cases. While the wild-type (wt) protein is anti-apoptotic, mutant SOD1 promotes apoptosis. We now demonstrate that both wt and mutant SOD1 bind the anti-apoptotic protein Bcl-2, providing evidence of a direct link between SOD1 and an apoptotic pathway. This interaction is evident in vitro and in vivo in mouse and human spinal cord. We also demonstrate that in mice and humans, Bcl-2 binds to high molecular weight SDS-resistant mutant SOD1 containing aggregates that are present in mitochondria from spinal cord but not liver. These findings provide new insights into the anti-apoptotic function of SOD1 and suggest that entrapment of Bcl-2 by large SOD1 aggregates may deplete motor neurons of this anti-apoptotic protein.


Effects of Home Visiting Program Implementation on Preventive Health Care Access and Utilization: Results from a Randomized Trial of Healthy Families Oregon.
Home visiting programs are an increasingly popular mechanism for providing a broad set of early prevention supports to high-risk families. A key intended outcome for these programs is to support maternal and child health by helping families increase access to and use of preventive health care services. For many community-based home visiting programs, however, there is less evidence of positive outcomes in the health care domain. The current study used a randomized trial conducted in a statewide early childhood home visiting program, Healthy Families Oregon (HFO), to examine program impacts on families' use of preventive health care services. The study recruited a large sample of participants (n = 1438 HFO families and n = 1289 controls) and utilized state agency health insurance and medical records as the primary data source. There were challenges in providing services in alignment with an intent-to-treat research design, leading to the need to take alternative approaches to analyzing effects of service receipt on outcomes. Results found that while there were no significant differences in health care access or utilization in the intent-to-treat models, positive outcomes were found when propensity score matching was used to limit the program sample to those who actually received services. Further, within the program group, children who were enrolled for longer had fewer gaps in health insurance coverage and received more well-baby visits and immunizations compared to those with less service. The role of the home visitor in helping families navigate the complexities of publicly funded health care is discussed. Investments in professional development strategies that can increase staff expertise in this area and improve family retention may be needed to more effectively achieve intended health outcomes.


Atmospheric carbon dioxide levels over phanerozoic time.
A new model has been constructed for calculating the level of atmospheric CO(2) during the past 570 million years. A series of successive steady states for CO(2) is used in order to calculate CO(2) level from a feedback function for the weathering of silicate minerals. Processes considered are: sedimentary burial of organic matter and carbonates; continental weathering of silicates, carbonates, and organic matter; and volcanic and metamorphic degassing of CO(2). Sediment burial rates are calculated with the use of an isotope mass-balance model and carbon isotopic data on ancient seawater. Weathering rates are calculated from estimates of past changes in continental land area, mean elevation, and river runoff combined with estimates of the effects of the evolution of vascular land plants. Past degassing rates are estimated from changes in the rate of generation of sea floor and the shift of carbonate deposition from platforms to the deep sea. The model results indicate that CO(2) levels were high during the Mesozoic and early Paleozoic and low during the Permo-Carboniferous and late Cenozoic. These results correspond to independently deduced Phanerozoic paleoclimates and support the notion that the atmospheric CO(2) greenhouse mechanism is a major control on climate over very long time scales.


The impact of imprinting: Prader-Willi syndrome resulting from chromosome translocation, recombination, and nondisjunction.
Prader-Willi syndrome (PWS) is most often the result of a deletion of bands q11.2-q13 of the paternally derived chromosome 15, but it also occurs either because of maternal uniparental disomy (UPD) of this region or, rarely, from a methylation imprinting defect. A significant number of cases are due to structural rearrangements of the pericentromeric region of chromosome 15. We report two cases of PWS with UPD in which there was a meiosis I nondisjunction error involving an altered chromosome 15 produced by both a translocation event between the heteromorphic satellite regions of chromosomes 14 and 15 and recombination. In both cases, high-resolution banding of the long arm was normal, and FISH of probes D15S11, SNRPN, D15S10, and GABRB3 indicated no loss of this material. Chromosome heteromorphism analysis showed that each patient had maternal heterodisomy of the chromosome 15 short arm, whereas PCR of microsatellites demonstrated allele-specific maternal isodisomy and heterodisomy of the long arm. SNRPN gene methylation analysis revealed only a maternal imprint in both patients. We suggest that the chromosome structural rearrangements, combined with recombination in these patients, disrupted normal segregation of an imprinted region, resulting in uniparental disomy and PWS.


Algorithm for optimizing bipolar interconnection weights with applications in associative memories and multitarget classification.
An algorithm for optimizing a bipolar interconnection weight matrix with the Hopfield network is proposed. The effectiveness of this algorithm is demonstrated by computer simulation and optical implementation. In the optical implementation of the neural network the interconnection weights are biased to yield a nonnegative weight matrix. Moreover, a threshold subchannel is added so that the system can realize, in real time, the bipolar weighted summation in a single channel. Preliminary experimental results obtained from the applications in associative memories and multitarget classification with rotation invariance are shown.


Pheochromocytoma and Paraganglioma in Children and Adolescents: Experience of the French Society of Pediatric Oncology (SFCE).
The purpose of this work is to assess the clinical outcome of pediatric patients diagnosed with pheochromocytoma and paraganglioma (PPGL) detected in France since 2000. A retrospective multicenter study was conducted that included all patients younger than 18 years with PPGL diagnosed in France between 2000 and 2016. Patients were identified from 4 different sources: the National Registry of Childhood Solid Tumors, the French Pediatric Rare Tumors Database, the French registry of succinate dehydrogenase (SDH)-related hereditary paraganglioma, and the nationwide TenGen network. Among 113 eligible patients, 81 children with available data were enrolled (41 with adrenal and 40 with extra-adrenal PPGL). At diagnosis, 11 had synchronous metastases. After a median follow-up of 53 months, 27 patients experienced a new event (n = 7 second PPGL, n = 1 second paraganglioma [PGL], n = 8 local recurrences, n = 10 metastatic relapses, n = 1 new tumor) and 2 patients died of their disease. The 3- and 10-year event-free survival rates were 80% (71%-90%) and 39% (20%-57%),respectively, whereas the overall survival rate was 97% (93%-100%)at 3 and 10 years. A germline mutation in one PPGL-susceptibility gene was identified in 53 of the 68 (77%) patients who underwent genetic testing (SDHB [n = 25], VHL [n = 21], RET [n = 2], HIF2A [n = 2], SDHC [n = 1], SDHD [n = 1], NF1 [n = 1]). Incomplete resection and synchronous metastases were associated with higher risk of events (P = .011, P = .004), but presence of a germline mutation was not (P = .11). Most pediatric PPGLs are associated with germline mutations and require specific follow-up because of the high risk of tumor recurrence.


Mitochondria and MAPK cascades modulate endosulfan-induced germline apoptosis in Caenorhabditis elegans.
Endosulfan as a new member of persistent organic pollutants has been shown to induce apoptosis in various animal models. However, the mechanism underlying endosulfan-induced apoptosis has not been well elucidated thus far. Caenorhabditis elegans N2 wild type and mutant strains were used in the present study to clarify the roles of the mitochondria, the insulin/insulin-like growth factor-1 (IGF-1) signaling pathway, and mitogen-activated protein kinase (MAPK) cascades in α-endosulfan-induced apoptosis. Our results demonstrated a dose- and time-dependent increase of apoptosis in the meiotic zone of the gonad of C. elegans exposed to graded concentrations of endosulfan. The expression levels of sod-3, localized in the mitochondrial matrix, increased greatly after endosulfan exposure. A significant increase in germ cell apoptosis was observed in abnormal methyl viologen sensitivity-1 (mev-1(kn-1)) mutants (with abnormal mitochondrial respiratory chain complex II and higher ROS levels) compared to that in N2 at equal endosulfan concentrations. We found that the insulin/IGF-1 signaling pathway and its downstream Ras/ERK/MAPK did not participate in the endosulfan-induced apoptosis. However, the apoptosis in the loss-of-function strains of JNK and p38 MAPK signaling pathways was completely or mildly suppressed under endosulfan stress. The apoptotic effects of endosulfan were blocked in the mutants of jnk-1/JNK-MAPK, sek-1/MAP2K, and pmk-1/p38-MAPK, suggesting that these downstream genes play an essential role in endosulfan-induced germ cell apoptosis. In contrast, the mkk-4/MAP2K and nsy-1/MAP3K were only partially involved in the apoptosis induction. Our data provide evidence that endosulfan increases germ cell apoptosis, which is regulated by mitochondrial function, JNK and p38 MAPK cascades. These findings contribute to the understanding of the signal transduction pathways involved in endosulfan-induced apoptosis.


Endovascular repair of ascending aortic rupture: effectiveness of a fenestrated stent-graft.
To present a technique for endovascular treatment using a fenestrated stent-graft in a patient with ascending aortic rupture in the setting of methicillin-resistant Staphylococcus aureus infection. A 62-year-old woman had undergone mastectomy and radiotherapy twice for breast cancer and then coronary artery bypass grafting (CABG). She developed sternal osteomyelitis 5 years after the CABG. Sternectomy and negative-pressure wound drainage were performed, but the infection did not resolve. Ascending aortic rupture occurred 5 months after sternectomy. Endovascular therapy was considered the only effective means of achieving hemostasis. A custom-designed fenestrated stent-graft was deployed from the ascending aorta to the proximal descending aorta via a femoral artery approach without transient cardiac arrest. Bleeding completely stopped after surgery. The postoperative course was uneventful, and the inflammatory activity subsided on antibiotic therapy. At 7 months after surgery, the patient's recovery has been uneventful. Rupture of the ascending aorta associated with infection was successfully treated by stent-graft repair. The use of a custom-made, fenestrated stent-graft was an effective, lifesaving procedure for the management of this ascending aortic lesion.


BDNF and NT-4/5 exert neurotrophic influences on injured adult spinal motor neurons.
Adult motor neurons, like their immature antecedents, express the mRNA for the signaling receptor for brain-derived neurotrophic factor (BDNF) and for neurotrophin-4/5 (NT-4/5). However, while both BDNF and NT-4/5 support the survival of axotomized developing spinal motor neurons in vitro or in vivo, it is not known whether these factors continue to influence spinal motor neurons in adulthood. The present study tests if BDNF or NT-4/5 modulate the reactive responses of adult spinal motor neurons to nerve injury. We utilize sciatic nerve transection to axotomize the spinal motor neurons that form the retrodorsal lateral nucleus (RDLN) and show that, after axotomy, RDLN motor neurons lose ChAT immunoreactivity and also reexpress p75Ingfr, the low affinity receptor for all neurotrophin family members. Treatment with BDNF or NT-4/5 alters these effects of sciatic nerve transection. Both BDNF and NT-4/5 attenuate the loss of ChAT expression in axotomized RDLN motor neurons; thus, as compared to vehicle treatments, BDNF and NT-4/5 produce statistically significant increases in the optical density of ChAT immunostaining. Furthermore, BDNF and NT-4/5 also significantly increase the RDLN reexpression of p75Ingfr after sciatic nerve transection. Interestingly, essentially identical increases in RDLN ChAT and p75Ingfr immunostaining are produced by sciatic nerve crush injuries in the absence of exogenous neurotrophin treatment. These data show that treatment with exogenous BDNF and NT-4/5 changes the response of adult spinal motor neurons to sciatic nerve transection. Furthermore, these neurotrophins elicit reactive responses in axotomized motor neurons that mimic those produced by endogenous agents in regenerating crushed peripheral nerve.


Idiopathic membranous nephropathy: an autoimmune disease.
For more than 50 years researchers have debated the evidence for an autoimmune basis of human idiopathic membranous nephritis (MN). Work published in the past 2 years has substantially strengthened the belief that MN is indeed an autoimmune disease of the kidney. Autoantibodies of the IgG4 subclass to at least three podocyte membrane proteins including phospholipase A(2)-receptor, aldose reductase, and manganese superoxide dismutase have been detected by immunoblotting in sera as well as in acid eluates prepared from renal biopsy tissue of patients with this disease, using either whole tissue or microdissected glomeruli from frozen sections. In each case the podocyte antigen has been shown to co-localize with the subepithelial glomerular immune deposits in renal tissue of the same patients. It is not certain if any of these podocyte proteins is an inciting/primary autoantigen or whether they are secondary antigens recruited by intermolecular epitope-spreading, initiating from a yet-to-be-discovered autoantigen. Although it is clear that autoantibodies to podocyte membrane proteins are elicited in idiopathic MN and contribute to the formation of the subepithelial deposits, many questions remain concerning the triggers for their development and their contribution toward proteinuria and progression of the disease.


Energy-Performance Assessment of Oscillatory Neural Networks Based on VO 2 Devices for Future Edge AI Computing.
Oscillatory neural network (ONN) is an emerging neuromorphic architecture composed of oscillators that implement neurons and are coupled by synapses. ONNs exhibit rich dynamics and associative properties, which can be used to solve problems in the analog domain according to the paradigm let physics compute. For example, compact oscillators made of VO 2 material are good candidates for building low-power ONN architectures dedicated to AI applications at the edge, like pattern recognition. However, little is known about the ONN scalability and its performance when implemented in hardware. Before deploying ONN, it is necessary to assess its computation time, energy consumption, performance, and accuracy for a given application. Here, we consider a VO 2 -oscillator as an ONN building block and perform circuit-level simulations to evaluate the ONN performances at the architecture level. Notably, we investigate how the ONN computation time, energy, and memory capacity scale with the number of oscillators. It appears that the ONN energy grows linearly when scaling up the network, making it suitable for large-scale integration at the edge. Furthermore, we investigate the design knobs for minimizing the ONN energy. Assisted by technology computer-aided design (TCAD) simulations, we report on scaling down the dimensions of VO 2 devices in crossbar (CB) geometry to decrease the oscillator voltage and energy. We benchmark ONN versus state-of-the-art architectures and observe that the ONN paradigm is a competitive energy-efficient solution for scaled VO 2 devices oscillating above 100 MHz. Finally, we present how ONN can efficiently detect edges in images captured on low-power edge devices and compare the results with Sobel and Canny edge detectors.


Pregnancy Experience: Nonclinical Studies and Pregnancy Outcomes in the Daclizumab Clinical Study Program.
Multiple sclerosis (MS) is more common in women and can occur during childbearing years; thus, information on outcomes following exposure to MS therapy during pregnancy is important. No formal studies of daclizumab have been conducted in pregnant women. Here, we report available nonclinical and clinical data on pregnancy outcomes from the daclizumab clinical study program. Reproductive and developmental toxicity studies were conducted in cynomolgus monkeys. Reports of pregnancies that occurred during the daclizumab clinical study program through March 9, 2015 were collated and summarized. In the event of pregnancy, daclizumab was discontinued and safety monitoring continued. Studies in cynomolgus monkeys showed no daclizumab-related effects on maternal well-being, embryo-fetal development, indirect fertility end points, and pre- and postnatal development and growth. Across the clinical study program, 38 pregnancies were reported in 36 daclizumab-exposed women (on treatment ≤6 months from last dose); 20 resulted in live births and four (11%) in spontaneous abortions or miscarriages. One congenital heart defect (complex transposition of great vessels) occurred in one live birth (considered unrelated to daclizumab); daclizumab had been discontinued and intramuscular interferon beta-1a and lisinopril were used at conception. Eight women had an elective termination, two had an ectopic pregnancy, and two were lost to follow-up; two pregnancy outcomes are pending. Six additional pregnancies occurred in five women >6 months after their last daclizumab dose; in one additional pregnancy, exposure was unknown. Spontaneous abortion rate in daclizumab-exposed women was consistent with early pregnancy loss in the general population (12%-26%). Data on pregnancies exposed to daclizumab do not suggest an increased risk of adverse fetal or maternal outcomes, although the numbers are too small for definitive conclusions. CLINICALTRIALS. NCT00390221, NCT01064401, NCT01462318, NCT00870740, NCT01051349, and NCT01797965. Biogen and AbbVie Biotherapeutics Inc.


Reactions of chlorine with inorganic and organic compounds during water treatment-Kinetics and mechanisms: a critical review.
Numerous inorganic and organic micropollutants can undergo reactions with chlorine. However, for certain compounds, the expected chlorine reactivity is low and only small modifications in the parent compound's structure are expected under typical water treatment conditions. To better understand/predict chlorine reactions with micropollutants, the kinetic and mechanistic information on chlorine reactivity available in literature was critically reviewed. For most micropollutants, HOCl is the major reactive chlorine species during chlorination processes. In the case of inorganic compounds, a fast reaction of ammonia, halides (Br(-) and I(-)), SO(3)(2-), CN(-), NO(2)(-), As(III) and Fe(II) with HOCl is reported (10(3)-10(9)M(-1)s(-1)) whereas low chlorine reaction rates with Mn(II) were shown in homogeneous systems. Chlorine reactivity usually results from an initial electrophilic attack of HOCl on inorganic compounds. In the case of organic compounds, second-order rate constants for chlorination vary over 10 orders of magnitude (i.e. <0.1-10(9)M(-1)s(-1)). Oxidation, addition and electrophilic substitution reactions with organic compounds are possible pathways. However, from a kinetic point of view, usually only electrophilic attack is significant. Chlorine reactivity limited to particular sites (mainly amines, reduced sulfur moieties or activated aromatic systems) is commonly observed during chlorination processes and small modifications in the parent compound's structure are expected for the primary attack. Linear structure-activity relationships can be used to make predictions/estimates of the reactivity of functional groups based on structural analogy. Furthermore, comparison of chlorine to ozone reactivity towards aromatic compounds (electrophilic attack) shows a good correlation, with chlorine rate constants being about four orders of magnitude smaller than those for ozone.


Does gastric lavage really push poisons beyond the pylorus? A systematic review of the evidence.
Classically, treatment of acute self-poisoning involves resuscitation and supportive care, followed by gastric emptying, administration of activated charcoal, and use of specific antidotes. Recently, however, the practice of gastric emptying has fallen out of favor in the West because physicians have recognized its complications and the lack of evidence for clinical benefit from its practice. Authoritative position statements have stated that forced emesis should not be used and that gastric lavage should be used in restricted settings. One commonly cited complication of gastric lavage is propulsion of poison beyond the pyloric sphincter into the small bowel. We have carried out a systematic search for studies addressing this issue and found only 2. The first, a randomized controlled trial of patients presenting to an emergency department, reported propulsion of poison into the small bowel and has been widely cited as showing evidence for such a complication. However, analysis of the data presented in this article shows no significant difference in the number of radio-opaque marker pellets present in the small bowel after gastric lavage, ipecac-induced forced emesis, or no intervention. The second, an observational study using human volunteers, showed significantly less poison in the small bowel after gastric lavage than after no intervention. In conclusion, it seems that no published data support the statement that gastric lavage forces poison into the small bowel.


The value of animal models for drug development in multiple sclerosis.
The rodent model for multiple sclerosis, experimental allergic (autoimmune) encephalomyelitis (EAE), has been used to dissect molecular mechanisms of the autoimmune inflammatory response, and hence to devise and test new therapies for multiple sclerosis. Clearly, artificial immunization against myelin may not necessarily reproduce all the pathogenetic mechanisms operating in the human disease, but most therapies tested in multiple sclerosis patients are nevertheless based on concepts derived from studies in EAE. Unfortunately, several treatments, though successful in pre-clinical EAE trials, were either less effective in patients, worsened disease or caused unexpected, severe adverse events, as we review here. These discrepancies must, at least in part, be due to genetic and environmental differences, but the precise underlying reasons are not yet clear. Our understanding of EAE pathogenesis is still incomplete and so, therefore, are any implications for drug development in these models. Here, we suggest some potential explanations based on new thinking about key pathogenic concepts and differences that may limit extrapolation from EAE to multiple sclerosis. To try to circumvent these rodent-human dissimilarities more systematically, we propose that pre-clinical trials should be started in humanized mouse models.


Observed Antibody Space: A Resource for Data Mining Next-Generation Sequencing of Antibody Repertoires.
Abs are immune system proteins that recognize noxious molecules for elimination. Their sequence diversity and binding versatility have made Abs the primary class of biopharmaceuticals. Recently, it has become possible to query their immense natural diversity using next-generation sequencing of Ig gene repertoires (Ig-seq). However, Ig-seq outputs are currently fragmented across repositories and tend to be presented as raw nucleotide reads, which means nontrivial effort is required to reuse the data for analysis. To address this issue, we have collected Ig-seq outputs from 55 studies, covering more than half a billion Ab sequences across diverse immune states, organisms (primarily human and mouse), and individuals. We have sorted, cleaned, annotated, translated, and numbered these sequences and make the data available via our Observed Antibody Space (OAS) resource at http://antibodymap.org The data within OAS will be regularly updated with newly released Ig-seq datasets. We believe OAS will facilitate data mining of immune repertoires for improved understanding of the immune system and development of better biotherapeutics.


Rapid estimation of nuclear magnetic resonance experiment time in low-concentration environmental samples.
Nuclear magnetic resonance (NMR) spectroscopy is an essential tool for studying environmental samples but is often hindered by low sensitivity, especially for the direct detection of nuclei such as(13) C. In very heterogeneous samples with NMR nuclei at low abundance, such as soils, sediments, and air particulates, it can take days to acquire a conventional(13) C spectrum. The present study describes a prescreening method that permits the rapid prediction of experimental run time in natural samples. The approach focuses the NMR chemical shift dispersion into a single spike, and, even in samples with extremely low carbon content, the spike can be observed in two to three minutes, or less. The intensity of the spike is directly proportional to the total concentration of nuclei of interest in the sample. Consequently, the spike intensity can be used as a powerful prescreening method that answers two key questions: (1) Will this sample produce a conventional NMR spectrum? (2) How much instrument time is required to record a spectrum with a specific signal-to-noise (S/N) ratio? The approach identifies samples to avoid (or pretreat) and permits additional NMR experiments to be performed on samples producing high-quality NMR data. Applications in solid- and liquid-state(13) C NMR are demonstrated, and it is shown that the technique is applicable to a range of nuclei.


The genetic component of Brugada syndrome.
Brugada syndrome (BrS) is a clinical entity first described in 1992. BrS is characterized by ST-segment elevations in the right precordial leads and susceptibility to ventricular arrhythmias and sudden cardiac death. It affects young subjects, predominantly males, with structurally normal hearts. The prevalence varies with ethnicity ranging from 1:2,000 to 1:100,000 in different parts of the world. Today, hundreds of variants in 17 genes have been associated with BrS of which mutations in SCN5A, coding for the cardiac voltage-gated sodium channel, accounts for the vast majority. Despite this, approximately 70% of BrS cases cannot be explained genetically with the current knowledge. Moreover, the monogenic role of some of the variants previously described as being associated with BrS has been questioned by their occurrence in about 4% (1:23) of the general population as found in NHLBI GO Exome Sequencing Project (ESP) currently including approximately 6500 individuals. If we add the variants described in the five newest identified genes associated with BrS, they appear at an even higher prevalence in the ESP (1:21). The current standard treatment of BrS is an implantable cardioverter-defibrillator (ICD). The risk stratification and indications for ICD treatment are based on the ECG and on the clinical and family history. In this review we discuss the genetic basis of BrS.


Cervical compensatory alignment changes following correction of adult thoracic deformity: a multicenter experience in 57 patients with a 2-year follow-up.
OBJECT Alignment changes in the cervical spine that occur following surgical correction for thoracic deformity remain poorly understood. The purpose of this study was to evaluate such changes in a cohort of adults with thoracic deformity treated surgically. METHODS The authors conducted a multicenter retrospective analysis of consecutive patients with thoracic deformity. Inclusion criteria for this study were as follows: corrective osteotomy for thoracic deformity, upper-most instrumented vertebra (UIV) between T-1 and T-4, lower-most instrumented vertebra (LIV) at or above L-5 (LIV ≥ L-5) or at the ilium (LIV-ilium), and a minimum radiographic follow-up of 2 years. Sagittal radiographic parameters were assessed preoperatively as well as at 3 months and 2 years postoperatively, including the C-7 sagittal vertical axis (SVA), C2-7 cervical lordosis (CL), C2-7 SVA, T-1 slope (T1S), T1S minus CL (T1S-CL), T2-12 thoracic kyphosis (TK), apical TK, lumbar lordosis (LL), pelvic incidence (PI), PI-LL, pelvic tilt (PT), and sacral slope (SS). RESULTS Fifty-seven patients with a mean age of 49.1 ± 14.6 years met the study inclusion criteria. The preoperative prevalence of increased CL (CL > 15°) was 48.9%. Both 3-month and 2-year apical TK improved from baseline (p < 0.05, statistically significant). At the 2-year follow-up, only the C2-7 SVA increased significantly from baseline (p = 0.01), whereas LL decreased from baseline (p < 0.01). The prevalence of increased CL was 35.3% at 3 months and 47.8% at 2 years, which did not represent a significant change. Postoperative cervical alignment changes were not significantly different from preoperative values regardless of the LIV (LIV ≥ L-5 or LIV-ilium, p > 0.05 for both). In a subset of patients with a maximum TK ≥ 60° (35 patients) and 3-column osteotomy (38 patients), no significant postoperative cervical changes were seen. CONCLUSION Increased CL is common in adult spinal deformity patients with thoracic deformities and, unlike after lumbar corrective surgery, does not appear to normalize after thoracic corrective surgery. Cervical sagittal malalignment (C2-7 SVA) also increases postoperatively. Surgeons should be aware that spontaneous cervical alignment normalization might not occur following thoracic deformity correction.


Trends in Ischaemic Heart Disease in Australia, 2001-2015: A Comparison of Urban and Rural Populations.
Ischaemic heart disease (IHD) is a major source of disease burden worldwide. Recent trends show incidence is declining but it is unclear whether the trends are similar in urban and rural populations. This study examines the trends of IHD events (i.e. hospitalisations and deaths) in New South Wales, Australia by rurality. This was a retrospective analysis of linked administrative data for hospitalisation and death records across NSW between 2001 and 2015. Participants were NSW residents aged 15-105 years who died or were hospitalised with a principal diagnosis of IHD. The main outcome measures were annual age-standardised mortality and hospitalisations for IHD by calendar year and rurality. Between 2001 and 2015, age-standardised annual IHD hospitalisations declined in urban areas from 587 to 260 and in rural areas from 766 to 395 per 100,000 people. The annual decline in hospitalisations was greater in urban than rural areas, with Annual Percentage Change (APC) of -5.6% (95% CI, -6.1%, -5.0%) and -4.5% (95% CI, -5.0%, -4.0%), respectively (p=0.012). Ischaemic heart disease mortality declined at a similar rate in urban and rural regions (APC -7.6% and -6.7% per annum, p=0.28). Absolute inequalities in IHD deaths persisted until 2015 when there were 49 (urban) and 70 (rural) IHD deaths per 100,000 people. Ischaemic heart disease hospitalisations and mortality have declined considerably between 2001 and 2015 in both rural and urban areas, yet inequalities persist, suggesting more intensive preventive efforts are required to further reduce the burden of IHD in rural populations.


Fatigue and physical activity in older women after myocardial infarction.
Within 6 years of a myocardial infarction (MI) more women (35%) than men (18%) will have another MI. Participation in physical activity is one of the most effective methods to reduce cardiac risks; however, few older women participate. One of the most frequently reported barriers to physical activity is fatigue. The specific aims of this study were to (1) describe factors related to fatigue in older women after MI and (2) examine the relationship of fatigue to physical activity in older women after MI. This descriptive correlational study examined the effects of age, body mass index, comorbidities, sleep, beta-blocker medication, depression, and social support on fatigue and physical activity in women (N = 84), ages 65 to 88 years old, 6 to 12 months post-MI. All women had their height and weight measured and completed (1) a health form on comorbidities, physical activity, and medication history; (2) the Geriatric Depression Scale; (3) the Epworth Sleepiness Scale; (4) the Revised Piper Fatigue Scale; and (5) the Social Provisions Scale. The majority (67%) of the women reported fatigue that they perceived as different from fatigue before their MI. Moderately strong correlations were noted among depression, sleep, and fatigue, and multivariate analysis indicated that depression and sleep significantly accounted for 32.7% of the variance in fatigue. Although only 61% of the women reported participating in physical activity for exercise, most were meeting minimal kilocalories per week for secondary prevention. Fatigue was not significantly associated with participation in physical activity. Describing correlates to fatigue and older women's participation in physical activity after MI are important to develop interventions targeted at increasing women's participation in physical activity, thus decreasing their risk for recurrent MIs.


Mechanisms of Selective Attention in Generalized Anxiety Disorder.
A well-established literature has identified different selective attentional orienting mechanisms underlying anxiety-related attentional bias, such as engagement and disengagement of attention. These mechanisms are thought to contribute to the onset and maintenance of anxiety disorders. However, conclusions to date have relied heavily on experimental work from subclinical samples. We therefore investigated individuals with diagnosed generalized anxiety disorder (GAD), healthy volunteers, and individuals with high trait anxiety (but not meeting GAD diagnostic criteria). Across two experiments we found faster disengagement from negative (angry and fearful) faces in GAD groups, an effect opposite to that expected on the basis of the subclinical literature. Together these data challenge current assumptions that we can generalize, to those with GAD, the pattern of selective attentional orienting to threat found in subclinical groups. We suggest a decisive two-stage experiment identifying stimuli of primary salience in GAD, then using these to reexamine orienting mechanisms across groups.


Patients' and clinicians' research priorities.
If research addresses the questions of relevance to patients and clinicians, decision-makers will be better equipped to design and deliver health services which meet their needs. To this end, a number of initiatives have engaged patients and clinicians in setting research agendas. This paper aimed to scope the research literature addressing such efforts. A systematic search strategy combined electronic searches of bibliographic databases with handsearching and contacting key authors. Two researchers, initially working independently, described the relevant reports. Over 250 studies addressed patients' or clinicians' priorities for research and outcomes for assessment. This literature described different routes for patients and clinicians to contribute to research agendas. Two-thirds of the studies addressing patients' or clinicians' research questions were applicable across health care, with the remainder focussed on specific health conditions. The 27 formal studies of patient involvement revealed a literature that has grown in the last decade. Although only nine studies engaged patients and clinicians in identifying research questions together, they show that methods have advanced over time, with all of them engaging participants directly and repeatedly in facilitated debate and most employing formal decision-making procedures. A sizeable literature is available to inform priorities for research and the methods for setting research agendas with patients and clinicians. We recommend that research funders and researchers draw on this literature to provide relevant research for health service decision-makers.


High-throughput monitoring of plant nuclear DNA contents via flow cytometry.
Interest in measuring the nuclear holoploid genome sizes of higher plants reflects not just the status of the nucleus as a defining characteristic of eukaryotic organisms. Higher plants also attract interest in that they display an unusually large range of genome sizes, current measurements indicating an almost 2,500-fold difference between the smallest and the largest. Scientists would like to learn more about the significance of nuclear genome sizes, in terms of molecular and cytological mechanisms regulating the interaction of the nucleus with the cytoplasm and regulating the observed increases and decreases of genome sizes observed within and across families, genera, and species. We would like to understand their adaptive significance through charting their distribution within populations and ecosystems. Further, since genome size values are only available for a small minority of the ∼650,000 species of angiosperms (known and yet undiscovered), we would like to systematically survey plant genome sizes globally before their extinction as a consequence of anthropogenic change. Flow cytometry is accepted as the method of choice for genome size measurements, these measurements being based on fluorescent staining of the nuclear DNA. Flow cytometry offers exceptional ease of use, accompanied by high accuracy and reproducibility and low cost. This chapter provides a general discussion of flow cytometric methods for measuring plant genome sizes, and detailed methods for carrying out these analyses.


Early effects of hormone replacement therapy on bone.
Estrogen replacement is currently the preferred therapy for postmenopausal osteoporosis, although its mechanism of action remains poorly understood. Its primary action on bone is generally considered to be antiresorptive, but there is evidence in animals to suggest a stimulatory effect on bone formation. We have now attempted to detect a similar effect in humans by administering hormone replacement therapy (estradiol valerate 2 mg/day and dydrogesterone 5 mg/day given in a continuous, combined manner) to ten postmenopausal women. We carried out histomorphometric analyses of transiliac bone biopsies after quadruple tetracycline labeling, which was commenced before and continued during the first 4 weeks of hormone replacement therapy. Biochemical markers of bone turnover suggested that bone resorption decreased, but no significant effects on histomorphometric parameters of bone formation were detected. We conclude that hormone replacement therapy at the dose given does not stimulate bone formation in the iliac crest as assessed by histomorphometry.


Gene conversion rapidly generates major histocompatibility complex diversity in recently founded bird populations.
Population bottlenecks can restrict variation at functional genes, reducing the ability of populations to adapt to new and changing environments. Understanding how populations generate adaptive genetic variation following bottlenecks is therefore central to evolutionary biology. Genes of the major histocompatibility complex (MHC) are ideal models for studying adaptive genetic variation due to their central role in pathogen recognition. While de novo MHC sequence variation is generated by point mutation, gene conversion can generate new haplotypes by transferring sections of DNA within and across duplicated MHC loci. However, the extent to which gene conversion generates new MHC haplotypes in wild populations is poorly understood. We developed a 454 sequencing protocol to screen MHC class I exon 3 variation across all 13 island populations of Berthelot's pipit (Anthus berthelotii). We reveal that just 11-15 MHC haplotypes were retained when the Berthelot's pipit dispersed across its island range in the North Atlantic ca. 75,000 years ago. Since then, at least 26 new haplotypes have been generated in situ across populations. We show that most of these haplotypes were generated by gene conversion across divergent lineages, and that the rate of gene conversion exceeded that of point mutation by an order of magnitude. Gene conversion resulted in significantly more changes at nucleotide sites directly involved with pathogen recognition, indicating selection for functional variants. We suggest that the creation of new variants by gene conversion is the predominant mechanism generating MHC variation in genetically depauperate populations, thus allowing them to respond to pathogenic challenges.


Quantitative, highly sensitive liquid chromatography-tandem mass spectrometry method for detection of synthetic corticosteroids.
Measurements of serum or urine concentrations of synthetic glucocorticoids are useful for assessing suspected iatrogenic hypothalamic-pituitary-adrenal axis suppression and Cushing syndrome. We have developed a liquid chromatography-tandem mass spectrometry (LC-MS/MS) assay for the simultaneous quantitative analysis of beclomethasone dipropionate, betamethasone, budesonide, dexamethasone, fludrocortisone, flunisolide, fluorometholone, fluticasone propionate, megestrol acetate, methylprednisolone, prednisolone, prednisone, triamcinolone, and triamcinolone acetonide. Stable isotopes of cortisol-9,11,12,12-d(4) and triamcinolone-d(1) acetonide-d(6) were added as internal standards to calibrators, controls, and unknown samples. After acetonitrile precipitation, these samples were extracted with methylene chloride, and the extracts were washed and dried. Reconstituted extract (15 muL) was injected on a reversed-phase column and analyzed by LC-MS/MS in positive-ion mode. Assay precision, accuracy, linearity, and sample stability were determined by use of enriched samples. Clinical validation included analysis of 8 serum and 20 urine samples from patients with undetectable cortisol concentrations and analysis of different types of tablets. Functional assay sensitivity was as low as 0.6-1.6 nmol/L for all compounds except for triamcinolone (7.6 nmol/L). Interassay CVs were 3.0-20% for concentrations of 0.6-364 nmol/L for all analytes. Recoveries of all analytes (except triamcinolone in serum) were 82-138% at 19.2-693 nmol/L. All but one of the serum and urine samples from patients who were tested because of suppressed cortisol concentrations contained at least one synthetic steroid. Tablet analysis recovered 75% of the synthetic steroids in suspected drugs. LC-MS/MS allows simultaneous quantitative detection of various synthetic steroids in serum, plasma, urine, and tablets. This provides a valuable tool for evaluating the clinical effects of topical and systemic synthetic corticosteroids.


Highly optimized CO2 capture by inexpensive nanoporous covalent organic polymers and their amine composites.
Carbon dioxide (CO2) storage and utilization requires effective capture strategies that limit energy penalties. Polyethylenimine (PEI)-impregnated covalent organic polymers (COPs) with a high CO2 adsorption capacity are successfully prepared in this study. A low cost COP with a high specific surface area is suitable for PEI loading to achieve high CO2 adsorption, and the optimal PEI loading is 36 wt%. Though the adsorbed amount of CO2 on amine impregnated COPs slightly decreased with increasing adsorption temperature, CO2/N2 selectivity is significantly improved at higher temperatures. The adsorption of CO2 on the sorbent is very fast, and a sorption equilibrium (10% wt) was achieved within 5 min at 313 K under the flow of simulated flue gas streams. The CO2 capture efficiency of this sorbent is not affected under repetitive adsorption-desorption cycles. The highest CO2 capture capacity of 75 mg g(-1) at 0.15 bar is achieved under dry CO2 capture however it is enhanced to 100 mg g(-1) in the mixed gas flow containing humid 15% CO2. Sorbents were found to be thermally stable up to at least 200 °C. TGA and FTIR studies confirmed the loading of PEIs on COPs. This sorbent with high and fast CO2 sorption exhibits a very promising application in direct CO2 capture from flue gas.


Update on the epidemiology of Paget's disease of bone.
Paget's disease of bone (PDB) is characterized by rapid bone remodeling and the formation of bone that is structurally abnormal. Recent studies have confirmed that both genetic and environmental factors are important in its etiology. Epidemiological studies in Europe and North America have revealed that PDB shows an increasing frequency of occurrence with age and is more prevalent among men than women. There is marked geographic variation in the prevalence of PDB throughout western nations, with the highest rates reported during the 1970s in Britain. Recent studies of the secular trends in PDB suggest declining rates in both prevalence and severity at diagnosis. Thus, the overall age/sex standardized prevalence rate in Britain during the period 1993-1995 was found to be 2.5% among men and 1.6% among women > or = 55 years of age. Prevalence rates had fallen by approximately 50% in several of the centers studied, suggesting an environmental contribution to the etiology of this disorder. Similar findings have been reported from other European countries and New Zealand. Recent study of the incidence and clinical manifestations of PDB have emerged from large cohort studies in primary care record linkage resources, such as the General Practice Research Database. Over the period 1988-1999, the incidence rate of clinically diagnosed PDB was found to be 5 per 10,000 person-years among men and 3 per 10,000 person-years among women 75 years of age. The disorder was associated with an increased risk of back pain (RR, 2.1; 95% CI, 1.9-2.3); osteoarthritis (RR, 1.7; 95% CI, 1.5-1.9); and fracture (RR, 1.2; 95% CI, 1.0-1.5). Using life table methodology, the estimated proportion of patients dying within 5 years of follow-up was 32.7% among the cohort with PDB compared with 28.0% among control patients (p < 0.05).


Neural Correlates of Word Recognition: A Systematic Comparison of Natural Reading and Rapid Serial Visual Presentation.
Neural correlates of word recognition are commonly studied with (rapid) serial visual presentation (RSVP), a condition that eliminates three fundamental properties of natural reading: parafoveal preprocessing, saccade execution, and the fast changes in attentional processing load occurring from fixation to fixation. We combined eye-tracking and EEG to systematically investigate the impact of all three factors on brain-electric activity during reading. Participants read lists of words either actively with eye movements (eliciting fixation-related potentials) or maintained fixation while the text moved passively through foveal vision at a matched pace (RSVP-with-flankers paradigm, eliciting ERPs). The preview of the upcoming word was manipulated by changing the number of parafoveally visible letters. Processing load was varied by presenting words of varying lexical frequency. We found that all three factors have strong interactive effects on the brain's responses to words: Once a word was fixated, occipitotemporal N1 amplitude decreased monotonically with the amount of parafoveal information available during the preceding fixation; hence, the N1 component was markedly attenuated under reading conditions with preview. Importantly, this preview effect was substantially larger during active reading (with saccades) than during passive RSVP with flankers, suggesting that the execution of eye movements facilitates word recognition by increasing parafoveal preprocessing. Lastly, we found that the N1 component elicited by a word also reflects the lexical processing load imposed by the previously inspected word. Together, these results demonstrate that, under more natural conditions, words are recognized in a spatiotemporally distributed and interdependent manner across multiple eye fixations, a process that is mediated by active motor behavior.


Outcome of children with multiply relapsed B-cell acute lymphoblastic leukemia: a therapeutic advances in childhood leukemia & lymphoma study.
The survival of pediatric patients with multiply relapsed and/or refractory (R/R) B-cell acute lymphoblastic leukemia has historically been very poor; however, data are limited in the current era. We conducted a retrospective study to determine the outcome of multiply R/R childhood B-ALL treated at 24 TACL institutions between 2005 and 2013. Patient information, treatment, and response were collected. Prognostic factors influencing the complete remission (CR) rate and event-free survival (EFS) were analyzed. The analytic set included 578 salvage treatment attempts among 325 patients. CR rates (mean ± SE) were 51 ± 4% for patients with bone marrow R/R B-ALL who underwent a second salvage attempt, 37 ± 6% for a third attempt, and 31 ± 6% for the fourth through eighth attempts combined. For patients achieving a CR after their second, third, and fourth through eighth attempts, the 2 year EFS was 41 ± 6%, 13 ± 7%, and 27 ± 13% respectively. Our results showed slight improvement when compared to previous studies. This is the largest and most recent study to date that evaluates the outcome of this patient population. Our data will provide detailed reference for the evaluation of new agents being developed for childhood B-ALL.


Comprehensive Proteomic Analysis of Mesenchymal Stem Cell Exosomes Reveals Modulation of Angiogenesis via Nuclear Factor-KappaB Signaling.
Mesenchymal stem cells (MSC) are known to facilitate healing of ischemic tissue related diseases through proangiogenic secretory proteins. Recent studies further show that MSC derived exosomes function as paracrine effectors of angiogenesis, however, the identity of which components of the exosome proteome responsible for this effect remains elusive. To address this we used high-resolution isoelectric focusing coupled liquid chromatography tandem mass spectrometry, an unbiased high throughput proteomics approach to comprehensively characterize the proteinaceous contents of MSCs and MSC derived exosomes. We probed the proteome of MSCs and MSC derived exosomes from cells cultured under expansion conditions and under ischemic tissue simulated conditions to elucidate key angiogenic paracrine effectors present and potentially differentially expressed in these conditions. In total, 6,342 proteins were identified in MSCs and 1,927 proteins in MSC derived exosomes, representing to our knowledge the first time these proteomes have been probed comprehensively. Multilayered analyses identified several putative paracrine effectors of angiogenesis present in MSC exosomes and increased in expression in MSCs exposed to ischemic tissue-simulated conditions; these include platelet derived growth factor, epidermal growth factor, fibroblast growth factor, and most notably nuclear factor-kappaB (NFkB) signaling pathway proteins. NFkB signaling was identified as a key mediator of MSC exosome induced angiogenesis in endothelial cells by functional in vitro validation using a specific inhibitor. Collectively, the results of our proteomic analysis show that MSC derived exosomes contain a robust profile of angiogenic paracrine effectors, which have potential for the treatment of ischemic tissue-related diseases.


Exploring the adoption of telemedicine and virtual software for care of outpatients during and after COVID-19 pandemic.
As the novel coronavirus disease 2019 (COVID-19) continues to spread across countries, the need for innovative measures to provide high-quality patient care and manage its spread has become more imperative. Software-based systems such as medical software applications could provide valuable suggestion on health-related information to physicians towards improving quality of life, especially for outpatients (e.g., elderly, immunosuppressed, pregnant women). The use of telemedicine and virtual software offers promising potential in the fight against COVID-19. Accordingly, by means of expedited literature and document review, this paper provides implication on the opportunities, application, and challenges of telemedicine and existing virtual software currently adopted as suitable initiatives for reducing the spread of COVID-19. More importantly, findings present factors that impact adoption of telemedicine. The findings suggest that telemedicine and virtual software are capable of decreasing emergency room visits, safeguarding healthcare resources, and lessening the spread of COVID-19 by remotely treating patients during and after the COVID-19 pandemic.


The parameters affecting the success of irrigation and debridement with component retention in the treatment of acutely infected total knee arthroplasty.
The aims of our study were to evaluate the success rate of irrigation and debridement with component retention (IDCR) for acutely infected total knee arthroplasty (TKA) (< 4 weeks of symptom duration) and to analyze the factors affecting prognosis of IDCR. We retrospectively reviewed 28 knees treated by IDCR for acutely infected TKA from 2003 to 2012. We evaluated the success rate of IDCR. All variables were compared between the success and failure groups. Multivariable logistic regression analysis was also used to examine the relative contribution of these parameters to the success of IDCR. Seventeen knees (60.7%) were successfully treated. Between the success and failure groups, there were significant differences in the time from primary TKA to IDCR (p = 0.021), the preoperative erythrocyte sedimentation rate (ESR; p = 0.021), microorganism (p = 0.006), and polyethylene liner exchange (p = 0.017). Multivariable logistic regression analysis of parameters affecting the success of IDCR demonstrated that preoperative ESR (odds ratio [OR], 1.02; p = 0.041), microorganism (OR, 12.4; p = 0.006), and polyethylene liner exchange (OR, 0.07; p = 0.021) were significant parameters. The results show that 60.7% of the cases were successfully treated by IDCR for acutely infected TKA. The preoperative ESR, microorganism, and polyethylene liner exchange were factors that affected the success of IDCR in acutely infected TKA.


Cellular ATP depletion by LY309887 as a predictor of growth inhibition in human tumor cell lines.
The antifolate LY309887 is a specific glycinamide ribonucleotide formyltransferase inhibitor that blocks de novo purine synthesis and produces a depletion of purine nucleotides. The activity of LY309887 in six human tumor cell lines has been examined by growth inhibition and clonogenic assay after continuous exposure for three cell doubling times and by ATP depletion at 24 h. Three cell lines (CCRF-CEM, MCF7, and GC3) were sensitive to LY309887-induced growth inhibition (IC50: 5.6-8.1 nM), whereas the other cell lines (COR-L23, T-47D, and A549) were comparatively resistant (IC50: 36-55 nM). Sensitivity to LY309887 cytotoxicity was consistent with sensitivity to growth inhibition in four of five cell lines tested (MCF7/GC3: 0.01% survival and COR-L23/T-47D: 1-5% survival at 100 nM LY309887). LY309887-induced ATP depletion was measured by luciferase-based ATP assay and confirmed by high performance liquid chromatography measurements. There was a linear relationship between ATP depletion and growth inhibition when data were analyzed for all six cell lines (r2 = 0.93; P < 0.0001). Depletion of 24-h cellular ATP concentrations to < 1 mM was associated with both cell growth inhibition and cytotoxicity in all cell lines studied. In conclusion, cellular ATP depletion induced by LY309887 can be used to predict growth inhibition and cytotoxicity in human tumor cells.


Light curing time reduction: in vitro evaluation of new intensive light-emitting diode curing units.
The aim of the present in vitro study was to establish the minimum necessary curing time to bond stainless steel brackets (Mini Diamond Twin) using new, intensive, light-emitting diode (LED) curing units. Seventy-five bovine primary incisors were divided into five equal groups. A standard light curing adhesive (Transbond XT) was used to bond the stainless steel brackets using different lamps and curing times. Two groups were bonded using an intensive LED curing lamp (Ortholux LED) for 5 and 10 seconds. Two more groups were bonded using another intensive LED curing device (Ultra-Lume LED 5) also for 5 and 10 seconds. Finally, a high-output halogen lamp (Optilux 501) was used for 40 seconds to bond the final group, which served as a positive control. All teeth were fixed in hard acrylic and stored for 24 hours in water at 37 degrees C. Shear bond strength (SBS) was measured using an Instron testing machine. Weibull distribution and analysis of variance were used to test for significant differences. The SBS values obtained were significantly different between groups (P < 0.001). When used for 10 seconds, the intensive LED curing units achieved sufficient SBS, comparable with the control. In contrast, 5 seconds resulted in significantly lower SBS. The adhesive remnant index (ARI) was not significantly affected.A curing time of 10 seconds was found to be sufficient to bond metallic brackets to incisors using intensive LED curing units. These new, comparatively inexpensive, curing lamps seem to be an advantageous alternative to conventional halogen lamps for bonding orthodontic brackets.


Glypican-1 nanoliposomes for potentiating growth factor activity in therapeutic angiogenesis.
Therapeutic angiogenesis is a highly appealing concept for treating tissues that become ischemic due to vascular disease. A major barrier to the clinical translation of angiogenic therapies is that the patients that are in the greatest need of these treatments often have long term disease states and co-morbidities, such as diabetes and obesity, that make them resistant to angiogenic stimuli. In this study, we identified that human patients with type 2 diabetes have reduced levels of glypican-1 in the blood vessels of their skin. The lack of this key co-receptor in the tissue may make the application of exogenous angiogenic growth factors or cell therapies ineffective. We created a novel therapeutic enhancer for growth factor activity consisting of glypican-1 delivered in a nanoliposomal carrier (a "glypisome"). Here, we demonstrate that glypisomes enhance FGF-2 mediated endothelial cell proliferation, migration and tube formation. In addition, glypisomes enhance FGF-2 trafficking by increasing both uptake and endosomal processing. We encapsulated FGF-2 or FGF-2 with glypisomes in alginate beads and used these to deliver localized growth factor therapy in a murine hind limb ischemia model. Co-delivery of glypisomes with FGF-2 markedly increased the recovery of perfusion and vessel formation in ischemic hind limbs of wild type and diabetic mice in comparison to mice treated with FGF-2 alone. Together, our findings support that glypisomes are effective means for enhancing growth factor activity and may improve the response to local angiogenic growth factor therapies for ischemia.


Sharp Decline In Prostate Cancer Treatment Among Men In The General Population, But Not Among Diagnosed Men.
The indolent nature of many prostate cancers has heightened concerns that harms from treatment may outweigh those from the disease and has resulted in a growing consensus in favor of less aggressive screening and treatment. We sought to understand the population-level impact of this consensus on the treatment of prostate cancer. Using national Medicare data for the period 2007-12, we assessed treatment rates among men with newly diagnosed prostate cancer. We identified both population-based rates (which are sensitive to changes in diagnosis and treatment patterns) and rates among diagnosed men (which are sensitive only to changes in treatment patterns). We also assessed trends in treatment among men with a high risk of noncancer mortality, who are unlikely to benefit from treatment. Population-based treatment rates declined by 42 percent, while rates among diagnosed men declined by only 8 percent. Treatment rates among men with the highest noncancer mortality risk and regional variation were unchanged. These results suggest that decreasing rates of diagnosis, changing attitudes, and guidelines calling for reduced prostate-specific antigen screening, not changes in practice patterns among specialists treating diagnosed men, drove the decline in population-based treatment rates. Compared to policies that emphasize volume, those that emphasize value in specialty care have the potential to exert stronger effects on practice patterns.


Genetic dissection of differential signaling threshold requirements for the Wnt/beta-catenin pathway in vivo.
Contributions of null and hypomorphic alleles of Apc in mice produce both developmental and pathophysiological phenotypes. To ascribe the resulting genotype-to-phenotype relationship unambiguously to the Wnt/beta-catenin pathway, we challenged the allele combinations by genetically restricting intracellular beta-catenin expression in the corresponding compound mutant mice. Subsequent evaluation of the extent of resulting Tcf4-reporter activity in mouse embryo fibroblasts enabled genetic measurement of Wnt/beta-catenin signaling in the form of an allelic series of mouse mutants. Different permissive Wnt signaling thresholds appear to be required for the embryonic development of head structures, adult intestinal polyposis, hepatocellular carcinomas, liver zonation, and the development of natural killer cells. Furthermore, we identify a homozygous Apc allele combination with Wnt/beta-catenin signaling capacity similar to that in the germline of the Apc(min) mice, where somatic Apc loss-of-heterozygosity triggers intestinal polyposis, to distinguish whether co-morbidities in Apc(min) mice arise independently of intestinal tumorigenesis. Together, the present genotype-phenotype analysis suggests tissue-specific response levels for the Wnt/beta-catenin pathway that regulate both physiological and pathophysiological conditions.


Effect of increasing doses of Rosuvastatin and Atorvastatin on apolipoproteins, enzymes and lipid transfer proteins involved in lipoprotein metabolism and inflammatory parameters.
This paper contains detailed results of a sub-population of the prospective randomized RADAR (Rosuvastatin and Atorvastatin in different Dosages And Reverse cholesterol transport) study. Statin treatment results in substantially decreased incidence of cardiovascular events but the exact pathophysiological mechanism of their beneficial effect is yet unclear. We aimed to examine the effects of up-titrated doses of two widely used statins (atorvastatin (ATOR) and rosuvastatin (ROSU)) on parameters involved in lipoprotein metabolism, in patients with low high density lipoprotein cholesterol values (HDL-C). In this RADAR substudy, 80 patients, aged 40-80 years, with known cardiovascular disease and low HDL-C (<1.0 mmol/l), were randomized to receive, after an initial 6 week dietary run-in phase, either ATOR 20 mg (n = 41) or ROSU 10 mg (n = 39). The doses were up-titrated (in 6 week intervals) to 80 mg of ATOR or 40 mg of ROSU at 12 weeks. Serum lipoproteins and lipoprotein metabolism parameters were measured at baseline and at 6 and 18 weeks of follow up. Both statins significantly reduced total cholesterol (TChol) and non-HDL-C values with ROSU being more effective for the doses studied (p < 0.05). No statistically significant effect on HDL-C was observed for either statin. Apolipoproteins (apo) B, CI, CIII, AV and E were significantly reduced in both groups (p < 0.05), while the ratio of HDL particles containing both apoAI and apoAII (LpAI-AII) over HDL containing apoAI alone (LpAI) was changed for both statins with the decrease of LpAI being more prominent in the ATOR group (p = 0.028). Cholesterol ester transfer protein (CETP) mass and activity, phospholipid transfer protein (PLTP) activity and lipoprotein-associated phospholipase A2 (Lp-PLA2) mass and activity were all significantly reduced in both treatment groups over the follow-up period (p < 0.001). ATOR displayed a more prominent decrease of PLTP activity compared to ROSU (p = 0.043), while ROSU displayed a more prominent decrease of Lp-PLA2 activity compared to ATOR (p = 0.04). Both statins effectively reduced, in a dose-dependent way, high sensitivity C-reactive protein values over time, while no effect on the levels of circulating inter cellular adhesion molecule 1 (cICAM-1) was observed. The effects of statin treatment extend further and beyond a mere TChol and LDL cholesterol reduction, as demonstrated by the aforementioned alterations of lipoproteins, enzymes and lipid transfer proteins involved in lipoprotein metabolism and pro-atherogenic and inflammatory molecules. ROSU and ATOR displayed a similar pattern of effect on lipid metabolism with discrete differences in the magnitude of this effect in certain variables. Despite the limitations of small population size and lack of clinical end points, reported data provide an insight for the possible pathophysiological mechanisms implicated in the effect of increasing dosages of different statin treatments.


Ethyl pyruvate ameliorates liver ischemia-reperfusion injury by decreasing hepatic necrosis and apoptosis.
Hepatic ischemia-reperfusion injury (I/R) occurs in the settings of transplantation, trauma, and elective liver resections. Reactive oxygen species (ROS) have been shown to play a major role in organ I/R injury. Pyruvate, a key intermediate in cellular metabolism, is an effective scavenger of ROS. The purpose of this study was to test the hypothesis that ethyl pyruvate (EP), a soluble pyruvate derivative, is effective in preventing hepatic I/R injury. Lewis rats underwent 60 minutes of partial warm hepatic ischemia. Three doses of EP dissolved in lactated Ringer's solution or lactated Ringer's solution (LR) alone were given by intravenous injection. Serum and tissue samples were obtained at 1 to 24 hours postreperfusion. Serum transaminases, degree of hepatic necrosis, and neutrophil infiltration were all significantly decreased in the EP-treated rats compared with control animals. The amount of hepatic lipid peroxidation was also significantly decreased in EP-treated animals. Both circulating levels and hepatic expression of inflammatory cytokines were significantly decreased in the EP-treated animals. Furthermore, EP inhibited activation of extracellular signal-regulated kinase, p38, and c-Jun N-terminal kinase mitogen-activated protein kinases, as well as nuclear factor-kappaB, signaling pathways involved in cytokine release. Treatment with EP also inhibited hepatic apoptosis. EP has a protective effect on hepatic I/R injury, mediated in part by decreasing lipid peroxidation, down-regulation of inflammatory mediators, and inhibition of apoptosis. Strategies using this additive to LR solution should be considered in clinical settings of ischemic liver injury to decrease organ damage.


[Transrectal ultrasound-guided prostatic biopsy: contribution of an ultrasound diagnostic unit after ten years of experience].
Although transrectal ultrasound-guided (TRUS) prostatic biopsy is the procedure of choice for the diagnosis of prostate cancer (PC), neither the ideal number of cores nor the number of repeated biopsies, nor the required diagnostic yield have been established. After our experience of ten years with TRUS biopsy we perform a review of the technique and its indications. PSA, ultrasound features, and pathologic data of 6000 patients undergoing modified sextant TRUS biopsy between 1994 to December 2002 were collected. 222 patients undergoing ten-core TRUS biopsy were included in an experimental group to study the role of the extended biopsy. The contribution of the extra cores to the diagnostic yield in the experimental group was studied to determine the effectiveness of the extended biopsy, using as a control group 552 patients undergoing sextant TRUS biopsy during 2002. Both groups were comparable for the study variables at the start of the study. The incidence of PC in the first biopsy in the group of 6000 patients was 39.1% (2345/6000). Patients with PSA between 4 and 10 ng/ml have an incidence of PC greater than 50% among prostates smaller than 20 cc, diminishing down to 8.9% in those greater than 50 cc. The percentage of PC among patients with negative digital rectal examination (DRE), normal TRUS, and PSA below 4 ng/ml was 16.7%. The diagnostic yield for PSA density lower than 0.11 ng/ml/cc was lower than 8%. The free/total PSA ratio shows a 13.7% incidence of PC with values higher than 0.24. Multivariate logistic regression analysis showed that the only non-significant parameter was free/total PSA. Sixty (27.15%) patients of the extended TRUS biopsy group had PC. Only 2.25% of the 221 patients benefited from the augmented number of biopsies. There were no significant differences in the figures of prostate cancer between groups. Only PSA and volume where significant in the multivariate logistic regression analysis; number of samples, PSA density and age lacked of influence in the detection of PC. The sextant biopsy model obtaining cores from the lateral horns of the prostate continues to be the reference for TRUS biopsy, and the extended biopsy is not applicable to all patients from the beginning do to the small increase in the diagnostic yield. Isolated PSA may not be the unique reference to indicate TRUS biopsy, being volume, in our experience, a definitive factor for the adjustment of high risk levels.


Rosuvastatin use improves measures of coagulation in patients with venous thrombosis.
Observational studies indicate that statins reduce the risk of recurrent venous thrombosis (VT). However, trials have not been performed and the mechanism is unknown. We aimed to determine whether statin therapy improves the coagulation profile in patients with prior VT. Randomized clinical trial (NCT01613794). Patients were randomized to rosuvastatin 20 mg/day for 4 weeks or no intervention. Blood was drawn at baseline and at end of study. The primary outcome was factor (F) VIII:C. In total, five coagulation factors were measured: FVIII:C, von Willebrand factor:Ag, FVII:C, FXI:C, and D-dimer. Among 247 randomized participants, mean age was 58 years, 62% were women and 49% had unprovoked VT. For all tested coagulation factors, mean levels were clearly decreased at end of study in rosuvastatin users, whereas they hardly differed in non-statin users. Results were most consistent for FVIII:C where mean FVIII:C levels were 7.2 IU/dL [95% CI (confidence interval) 2.9-11.5] lower in rosuvastatin users, while among non-users, no change in FVIII:C was observed (mean difference -0.1; 95% CI -3.0 to 2.9). The mean age and sex adjusted difference in FVIII:C change was -6.7 IU/dL (95% CI -12.0 to -1.4) in rosuvastatin users vs. non-users. Subgroup analyses revealed that the decrease in coagulation factors by rosuvastatin was more pronounced in participants with unprovoked VT and in those with cardiovascular risk factors. Rosuvastatin 20 mg/day substantially improved the coagulation profile among patients with prior VT. These results suggest that statin therapy might be beneficial in patients at risk of recurrent VT.


Subject-specific finite element analysis to characterize the influence of geometry and material properties in Achilles tendon rupture.
Achilles tendon injuries including rupture are one of the most frequent musculoskeletal injuries, but the mechanisms for these injuries are still not fully understood. Previous in vivo and experimental studies suggest that tendon rupture mainly occurs in the tendon mid-section and predominantly more in men than women due to reasons yet to be identified. Therefore we aimed to investigate possible mechanisms for tendon rupture using finite element (FE) analysis. Specifically, we have developed a framework for generating subject-specific FE models of human Achilles tendon. A total of ten 3D FE models of human Achilles tendon were generated. Subject-specific geometries were obtained using ultrasound images and a mesh morphing technique called Free Form Deformation. Tendon material properties were obtained by performing material optimization that compared and minimized difference in uniaxial tension experimental results with model predictions. Our results showed that both tendon geometry and material properties are highly subject-specific. This subject-specificity was also evident in our rupture predictions as the locations and loads of tendon ruptures were different in all specimens tested. A parametric study was performed to characterize the influence of geometries and material properties on tendon rupture. Our results showed that tendon rupture locations were dependent largely on geometry while rupture loads were more influenced by tendon material properties. Future work will investigate the role of microstructural properties of the tissue on tendon rupture and degeneration by using advanced material descriptions.


Clinical Implications of Brief Device-Detected Atrial Tachyarrhythmias in a Cardiac Rhythm Management Device Population: Results from the Registry of Atrial Tachycardia and Atrial Fibrillation Episodes.
The RATE Registry (Registry of Atrial Tachycardia and Atrial Fibrillation Episodes) is a prospective, outcomes-oriented registry designed to document the prevalence of atrial tachycardia and/or fibrillation (AT/AF) of any duration in patients with pacemakers and implantable cardioverter defibrillators (ICDs) and evaluate associations between rigorously adjudicated AT/AF and predefined clinical events, including stroke. The appropriate clinical response to brief episodes of AT/AF remains unclear. Rigorously adjudicated electrogram (EGM) data were correlated with adjudicated clinical events with logistic regression and Cox models. Long episodes of AT/AF were defined as episodes in which the onset and/or offset of AT/AF was not present within a single EGM recording. Short episodes of AT/AF were defined as episodes in which both the onset and offset of AT/AF were present within a single EGM recording. We enrolled 5379 patients with pacemakers (N=3141) or ICDs (N=2238) at 225 US sites (median follow-up 22.9 months). There were 359 deaths. There were 478 hospitalizations among 342 patients for clinical events. We adjudicated 37 531 EGMs; 50% of patients had at least one episode of AT/AF. Patients with clinical events were more likely than those without to have long AT/AF (31.9% vs. 22.1% for pacemaker patients and 28.7% vs. 20.2% for ICD patients; P<0.05 for both groups). Only short episodes of AT/AF were documented in 9% of pacemaker patients and 16% of ICD patients. Patients with clinical events were no more likely than those without to have short AT/AF (5.1% vs. 7.9% for pacemaker patients and 11.5% vs. 10.4% for ICD patients; P=0.21 and 0.66, respectively). In the RATE Registry, rigorously adjudicated short episodes of AT/AF, as defined, were not associated with increased risk of clinical events compared with patients without documented AT/AF. URL: http://www.clinicaltrials.gov. Unique identifier: NCT00837798.


Parallel self-consistent-field calculations via Chebyshev-filtered subspace acceleration.
Solving the Kohn-Sham eigenvalue problem constitutes the most computationally expensive part in self-consistent density functional theory (DFT) calculations. In a previous paper, we have proposed a nonlinear Chebyshev-filtered subspace iteration method, which avoids computing explicit eigenvectors except at the first self-consistent-field (SCF) iteration. The method may be viewed as an approach to solve the original nonlinear Kohn-Sham equation by a nonlinear subspace iteration technique, without emphasizing the intermediate linearized Kohn-Sham eigenvalue problems. It reaches self-consistency within a similar number of SCF iterations as eigensolver-based approaches. However, replacing the standard diagonalization at each SCF iteration by a Chebyshev subspace filtering step results in a significant speedup over methods based on standard diagonalization. Here, we discuss an approach for implementing this method in multi-processor, parallel environment. Numerical results are presented to show that the method enables to perform a class of highly challenging DFT calculations that were not feasible before.


[In-depth assessment of work-related stress in a major company undergoing restructuring].
An in-depth assessment of work-related stress was conducted in a major national telecommunications company undergoing major changes. The assessment was made on three homogeneous groups of workers and covered a large representative sample of the corresponding populations. To identify the main sources of stress for the three populations of workers, stimulate a discussion on the possible corrective actions, and assess the impact of the on-going organizational changes on workers' health. The assessment started with an analysis of the objective stress indicators listed in the INAIL (National Insurance Institute for Occupational Diseases and Accidents) Checklist. This was followed by a combination of qualitative and quantitative investigations on work context and tasks and on the subjective perceptions of workers, which were carried out by using: semi-structured interviews with management, field observations of work tasks, focus groups and questionnaires (GHQ-12, HSE Indicator Tool, ad-hoc questionnaire). The assessment allowed identification of the critical areas to be addressed with specific interventions: relationship with the company, work performance, work organization, and equipment. the investigation allowed to identification of specific practical actions (improvement of technological tools; professional development through training courses) as well as strategic actions ( re-establish relationship of trust with the company) so as to mitigate the workers' level of stress. Analysis of the results also showed that the three targeted populations differed in the degree of acceptance and understanding of the organizational changes.


Protein-protein interactions and metabolite channelling in the plant tricarboxylic acid cycle.
Protein complexes of sequential metabolic enzymes, often termed metabolons, may permit direct channelling of metabolites between the enzymes, providing increased control over metabolic pathway fluxes. Experimental evidence supporting their existence in vivo remains fragmentary. In the present study, we test binary interactions of the proteins constituting the plant tricarboxylic acid (TCA) cycle. We integrate (semi-)quantitative results from affinity purification-mass spectrometry, split-luciferase and yeast-two-hybrid assays to generate a single reliability score for assessing protein-protein interactions. By this approach, we identify 158 interactions including those between catalytic subunits of sequential enzymes and between subunits of enzymes mediating non-adjacent reactions. We reveal channelling of citrate and fumarate in isolated potato mitochondria by isotope dilution experiments. These results provide evidence for a functional TCA cycle metabolon in plants, which we discuss in the context of contemporary understanding of this pathway in other kingdoms.


Is there a relationship between primary school children's enjoyment of recess physical activities and health-related quality of life? A cross-sectional exploratory study.
Issue addressed An important strategy for increasing children's physical activity is to enhance children's opportunities for school recess physical activities, yet little is known about the influence of school recess physical activities on children's health-related quality of life (HRQOL). The purpose of the present study was to explore the relationship between Australian primary school children's enjoyment of recess physical activities and HRQOL. Methods The study consisted of children at two Australian primary schools (n=105) aged 8-12 years. The Lunchtime Enjoyment Activity and Play questionnaire was used to measure school children's enjoyment of school recess physical activities. The Pediatric Quality of Life Inventory 4.0 was used to measure children's HRQOL. Researchers applied linear regression modelling in STATA (ver. 13.0) to investigate the relationship between children's enjoyment of school recess physical activities and HRQOL. Results It was discovered that primary school children's enjoyment of more vigorous-type school recess physical activities and playing in a range of weather conditions was associated with children's improved HRQOL. Conclusion The findings from this study suggest that health providers and researchers should consider providing primary school children with opportunities and facilities for more vigorous-intensity school recess physical activities as a key strategy to enhance children's HRQOL. So what? Considering a social-ecological model framework of the key predictors of children's enjoyment of school recess physical activities may provide valuable insight for school health providers into the multiple levels of influence on children's HRQOL when developing school settings and activities for school recess.


Hemoparasites in a wild primate: Infection patterns suggest interaction of Plasmodium and Babesia in a lemur species.
Hemoparasites can cause serious morbidity in humans and animals and often involve wildlife reservoirs. Understanding patterns of hemoparasite infections in natural populations can therefore inform about emerging disease risks, especially in the light of climate change and human disruption of natural ecosystems. We investigated the effects of host age, sex, host group size and season on infection patterns of Plasmodium sp., Babesia sp. and filarial nematodes in a population of wild Malagasy primates, Verreaux's sifakas (Propithecus verreauxi), as well as the effects of these infections on hematological variables. We tested 45 blood samples from 36 individuals and identified two species of Plasmodium, one species of Babesia and two species of filarial nematodes. Plasmodium spp. and Babesia sp. infections showed opposite patterns of age-dependency, with babesiosis being prevalent among young animals, while older animals were infected with Plasmodium sp. In addition, Babesia sp. infection was a statistically significant negative predictor of Plasmodium sp. infection. These results suggest that Plasmodium and Babesia parasites may interact within the host, either through cross-immunity or via resource competition, so that Plasmodium infections can only establish after babesiosis has resolved. We found no effects of host sex, host group size and season on hemoparasite infections. Infections showed high prevalences and did not influence hematological variables. This preliminary evidence supports the impression that the hosts and parasites considered in this study appear to be well-adapted to each other, resulting in persistent infections with low pathogenic and probably low zoonotic potential. Our results illustrate the crucial role of biodiversity in host-parasite relationships, specifically how within-host pathogen diversity may regulate the abundance of parasites.


Innovative in cellulo method as an alternative to in vivo neurovirulence test for the characterization and quality control of human live Yellow Fever virus vaccines: A pilot study.
Live attenuated vaccines have proved to be mostly valuable in the prevention of infectious diseases in humans, especially in developing countries. The safety and potency of vaccine, and the consistency of vaccine batch-to-batch manufacturing, must be proven before being administrated to humans. For now, the tests used to control vaccine safety largely involve animal testing. For live viral vaccines, regulations require suppliers to demonstrate the absence of neurovirulence in animals, principally in non-human primates and mice. In a search to reduce the use of animals and embracing the 3Rs principles (Replacement, Reduction, Refinement in the use of laboratory animals), we developed a new Blood-Brain Barrier Minibrain (BBB-Minibrain) in cellulo device to evaluate the neuroinvasiveness/neurovirulence of live Yellow Fever virus (YFV) vaccines. A pilot study was performed using the features of two distinct YFV strains, with the ultimate goal of proposing a companion test to characterize YFV neurovirulence. Here, we demonstrate that the BBB-Minibrain model is a promising alternative to consider for future replacement of YFV vaccine in vivo neurovirulence testing (see graphical abstract).


[A myoelectric prosthesis for the forearm amputee].
The authors make a revision of the principles of action of the myoelectric prosthesis for the forearm amputees and describe their components. The indications and contra-indications (French law) are also referred. We can say as a conclusion that the great progress made in prosthesis in the last years were possible on account of synthetic materials and the use of electronics and miniaturised computers. However, their functional possibilities are remote when compared with the human hand. The high costs of this prosthesis are one limitation to its prescription.


A Survey of Phytophthora spp. in Midwest Nurseries, Greenhouses, and Landscapes.
A survey of nurseries, greenhouses, and landscapes was conducted from 2006 to 2008 in order to determine the prevalence and diversity of Phytophthora spp. From sites in Iowa, Michigan, Ohio, and, predominantly, Indiana, 121 Phytophthora isolates were obtained from 1,657 host samples spanning 32 host genera. Based on sequence of the internal transcribed spacer (ITS) region of the ribosomal DNA, 11 Phytophthora spp. and two hybrid species were identified. A majority of the isolates were P. citricola (35.9%) or P. citrophthora (27.4%). Six isolates were confirmed as hybrids (four of P. cactorum × hedraiandra and two of P. nicotianae × cactorum) by cloning and sequencing the ITS region. Three P. cactorum × hedraiandra isolates were obtained from the same site, from three Rhododendron spp., which are known hosts to the parental species. The fourth isolate, however, was recovered out of a different location in a Dicentra sp., which is not a known host to either parental species, suggesting an expansion of host range of the hybrid isolate as compared with either parental species.


Effect of electromagnetic fields on patients undergoing massive bone graft following bone tumor resection. A double blind study.
Massive bone allograft after tumor resection has been used for over 20 years. Many factors negatively influence the healing of the junction between the allograft and the host bone, resulting in a low healing rate and lengthy time to union. This study evaluated whether pulsing electromagnetic field stimulation could be advantageously used in these patients. A double blind prospective randomized study was designed. Eighty three host graft junctions in 47 patients were considered. The overall host graft junction healing rate was the same (67%) in both control and active stimulated patients. Although not statistically significant, a positive effect of pulsing electromagnetic fields was observed for those host graft junctions with a cortico-cortical contact between allograft and host bone. When adjuvant postoperative chemotherapy was not employed, a definite effect of pulsing electromagnetic field stimulation was observed: the healing time decreased from 9.4 months in the control group to 6.7 months in the active stimulated group (p < 0.001). This effect would have been lost if chemotherapy was employed. There was also no advantage in supplement with iliac crest autografts at the host graft junction site if chemotherapy was used. Factors that significantly influenced the host graft junction healing rate were: chemotherapy; type of allograft host bone contact; quality of host graft junction; and, in intercalary allografts, use of the osteosynthesis device. No difference was observed between control and active groups for patient survival or number of local or distal tumor recurrences.


Pretreatment with a grape seed proanthocyanidin extract downregulates proinflammatory cytokine expression in airway epithelial cells infected with respiratory syncytial virus.
Respiratory syncytial virus (RSV) infections are associated with significant morbidity and mortality. Inflammation is mediated by cytokine secretion from RSV‑infected airway epithelial cells. Grape seed proanthocyanidin extract (GSPE) exhibits potent antioxidant capacity, as well as anti‑bacterial, anti‑viral, anti‑carcinogenic, anti‑inflammatory and anti‑allergic actions. However, few studies have explored the anti‑inflammatory effects of GSPE on airway epithelial cells infected with RSV. Airway epithelial A549 cells were pretreated with GSPE and its effects on cytokine production during RSV infection were investigated. A549 cells were infected with RSV, with or without GSPE pretreatment, and cultured for 24, 48 and 72 h. The expression of interleukin (IL)‑1β, IL‑6 and IL‑8, were measured by reverse transcription‑quantitative polymerase chain reaction, ELISA and western blotting. RSV infection induced significant increases in proinflammatory cytokine expression. However, GSPE pretreatment decreased the mRNA and protein expression levels of IL‑1ß, IL‑6 and IL‑8. GSPE regulated the immune response by reducing the RSV‑induced transcription of proinflammatory cytokines in airway epithelial cells, suggesting that GSPE helps to prevent RSV‑induced airway disease.