Exploring sequence-function space of a poplar glutathione transferase using designed information-rich gene variants.
Exploring the vicinity around a locus of a protein in sequence space may identify homologs with enhanced properties, which could become valuable in biotechnical and other applications. A rational approach to this pursuit is the use of 'infologs', i.e. synthetic sequences with specific substitutions capturing maximal sequence information derived from the evolutionary history of the protein family. Ninety-five such infolog genes of poplar glutathione transferase were synthesized and expressed in Escherichia coli, and the catalytic activities of the proteins determined with alternative substrates. Sequence-activity relationships derived from the infologs were used to design a second set of 47 infologs in which 90% of the members exceeded wild-type properties. Two mutants, C2 (V55I/E95D/D108E/A160V) and G5 (F13L/C70A/G122E), were further functionally characterized. The activities of the infologs with the alternative substrates 1-chloro-2,4-dinitrobenzene and phenethyl isothiocyanate, subject to different chemistries, were positively correlated, indicating that the examined mutations were affecting the overall catalytic competence without major shift in substrate discrimination. By contrast, the enhanced protein expressivity observed in many of the mutants were not similarly correlated with the activities. In conclusion, small libraries of well-defined infologs can be used to systematically explore sequence space to optimize proteins in multidimensional functional space.


Nesfatin-1 suppresses peripheral arterial remodeling without elevating blood pressure in mice.
Nesfatin-1 is a novel anorexic peptide hormone that also exerts cardiovascular protective effects in rodent models. However, nesfatin-1 treatment at high doses also exerts vasopressor effects, which potentially limits its therapeutic application. Here, we evaluated the vasoprotective and vasopressor effects of nesfatin-1 at different doses in mouse models. Wild-type mice and those with the transgene nucleobindin-2, a precursor of nesfatin-1, were employed. Wild-type mice were randomly assigned to treatment with vehicle or nesfatin-1 at 0.2, 2.0 or 10 μg/kg/day (Nes-0.2, Nes-2, Nes-10, respectively). Subsequently, mice underwent femoral artery wire injury to induce arterial remodeling. After 4 weeks, injured arteries were collected for morphometric analysis. Compared with vehicle, nesfatin-1 treatments at 2.0 and 10 μg/kg/day decreased body weights and elevated plasma nesfatin-1 levels with no changes in systolic blood pressure. Furthermore, these treatments reduced neointimal hyperplasia without inducing undesirable remodeling in injured arteries. However, nesfatin-1 treatment at 0.2 μg/kg/day was insufficient to elevate plasma nesfatin-1 levels and showed no vascular effects. In nucleobindin-2-transgenic mice, blood pressure was slightly higher but neointimal area was lower than those observed in littermate controls. In cultured human vascular endothelial cells, nesfatin-1 concentration-dependently increased nitric oxide production. Additionally, nesfatin-1 increased AMP-activated protein kinase phosphorylation, which was abolished by inhibiting liver kinase B1. We thus demonstrated that nesfatin-1 treatment at appropriate doses suppressed arterial remodeling without affecting blood pressure. Our findings indicate that nesfatin-1 can be a therapeutic target for improved treatment of peripheral artery disease.


Application of antisense transformation of a barley chitinase in studies of arbuscule formation by a mycorrhizal fungus.
Barley (Hordeum vulgare L.) plants of two commercial cultivars were transformed with sense and antisense constructs of a chitinase class II gene in order to develop a transformation system for this gene in barley. Transformation of embryos with the two antisense constructs resulted in ten regenerated plants, while no plants could be obtained using the sense construct. The presence of the inserted construct could be confirmed for six of the plants by PCR analysis. This system was used to study the role of class II chitinase in the regulation of mycorrhizal symbiosis. The colonization of two of the antisense transformants by the arbuscular mycorrhizal fungus Glomus intraradices was investigated microscopically and by use of signature fatty acids. The arbuscular incidence increased in transformed barley, and one transformant supported higher extraradical mycelium biomass. It is concluded that antisense transformation of barley could be a useful tool in investigations on the symbiosis between barley and mycorrhizal fungi.


In vivo conditions to identify Prkci phosphorylation targets using the analog-sensitive kinase method in zebrafish.
Protein kinase C iota is required for various cell biological processes including epithelial tissue polarity and organ morphogenesis. To gain mechanistic insight into different roles of this kinase, it is essential to identify specific substrate proteins in their cellular context. The analog-sensitive kinase method provides a powerful tool for the identification of kinase substrates under in vivo conditions. However, it has remained a major challenge to establish screens based on this method in multicellular model organisms. Here, we report the methodology for in vivo conditions using the analog-sensitive kinase method in a genetically-tractable vertebrate model organism, the zebrafish. With this approach, kinase substrates can uniquely be labeled in the developing zebrafish embryo using bulky ATPγS analogs which results in the thiophosphorylation of substrates. The labeling of kinase substrates with a thiophosphoester epitope differs from phosphoesters that are generated by all other kinases and allows for an enrichment of thiophosphopeptides by immunoaffinity purification. This study provides the foundation for using the analog-sensitive kinase method in the context of complex vertebrate development, physiology, or disease.


Epithelial-mesenchymal transition induced by growth suppressor p12CDK2-AP1 promotes tumor cell local invasion but suppresses distant colony growth.
Epithelial-mesenchymal transition (EMT) has been considered essential for metastasis, a multistep process including local invasion, intravasation, extravasation, and proliferation at distant sites. However, controversy remains as to whether EMT truly happens and how important it is to metastasis. We studied the involvement of EMT in individual steps of metastasis and found that p12(CDK2-AP1), a down-stream effector of transforming growth factor beta, induced EMT of hamster cheek pouch carcinoma-1 cells by promoting the expression of Twist2. EMT cells have an increased invasive but decreased metastatic phenotype. When s.c. inoculated, both EMT and non-EMT cells established primary tumors, but only EMT cells invaded into the adjacent tissues and blood vessels; however, neither cells formed lung metastases. When i.v. inoculated, only non-EMT cells established lung metastases. Moreover, s.c. inoculation of a mixture of the two cell types resulted in intravasation of both cell types and formation of lung metastasis from non-EMT cells. Our results allowed us to propose a novel model for the role of EMT in cancer metastasis. We showed that EMT and non-EMT cells cooperate to complete the spontaneous metastasis process. We thus hypothesize that EMT cells are responsible for degrading the surrounding matrix to lead the way of invasion and intravasation. Non-EMT cells then enter the blood stream and reestablish colonies in the secondary sites.


Phase correction of light modulators.
A new and inexpensive holographic technique for measuring the phase errors of a two-dimensional spatial light modulator (SLM) is described, and experimental verification is provided. A new technique to correct spatial phase errors in any SLM is then detailed and experimentally demonstrated. This technique is employed for the Radio Shack liquid-crystal television SLM, and a shift-invariant correlator is obtained. Additional low-pass filtering techniques (appropriate for any SLM with a fixed pattern of modulating cells) are discussed that provide improved contrast and achieve proper correlations.


1,25-dihydroxyvitamin D-responsive element and glucocorticoid repression in the osteocalcin gene.
The active hormonal form of vitamin D3, 1,25-dihydroxyvitamin D3[1,25(OH), which regulates cellular replication and function in many tissues and has a role in bone and calcium homeostasis, acts through a hormone receptor homologous with other steroid and thyroid hormone receptors. A 1,25(OH)2D3-responsive element (VDRE), which is within the promoter for osteocalcin [a bone protein induced by 1,25(OH)2D3] is unresponsive to other steroid hormones, can function in a heterologous promoter, and contains a doubly palindromic DNA sequence (TTGGTGACTCACCGGGTGAAC; -513 to -493 bp), with nucleotide sequence homology to other hormone responsive elements. The potent glucocorticoid repression of 1,25(OH)2D3 induction and of basal activity of this promoter acts through a region between -196 and +34 bp, distinct from the VDRE.


Recurrent familial hydatidiform mole - a rare clinical problem.
Familial recurrent hydatidiform mole is a rare event; here we report an unusual case of a gravida 5 aged 29 years, with five recurrent hydatidiform moles and no normal pregnancy. After the fourth molar pregnancy, she developed persistent trophoblastic disease that required 7 cycles of single agent chemotherapy. Two years after the treatment, she presented with her fifth molar pregnancy. Her elder sister had seven hydatidiform moles from two different unrelated male partners. As this is familial, and recurrent, with no viable conceptions in both the sisters, it is likely to be biparental in origin. Unlike androgenetic moles, biparental moles arise due to a global inherited failure of maternal imprinting. It is an autosomal recessive defect in the female germ line. Genetic analysis is essential, although it is not available in all centers. Donor Oocyte IVF is the only option for women with biparental moles to have normal offspring.


Pseudomonas aeruginosa Infective Endocarditis Following Aortic Valve Implantation: A Note of Caution.
Transcatheter aortic valve implantation (TAVI) is an alternative treatment for severe aortic valve stenosis (AS) in patients with prohibitive risk for surgical aortic valve replacement (SAVR). Prosthetic valve endocarditis (PVE) is a rare complication of this relatively novel procedure and current guidelines do not include specific recommendations for its treatment. We report a case of PVE due to Pseudomonas aeruginosa after TAVI that required SAVR, with successful outcome. PVE usually occurs during the first year after TAVI and entails a high mortality risk because patients eligible for this min-imally invasive procedure are fragile (i.e. advanced age and/or severe comorbidities). Additionally, clinical presentation may be atypical or subtle and transesophageal echocardiogram (TEE) may not be conclusive, which delays diagnosis and treatment worsening the prognosis. This case highlights that open SAVR might be ultimately indicated as part of treatment for TAVI-PVE despite a high-risk surgery score.


Health human resources planning and the production of health: development of an extended analytical framework for needs-based health human resources planning.
Health human resources planning is generally based on estimating the effects of demographic change on the supply of and requirements for healthcare services. In this article, we develop and apply an extended analytical framework that incorporates explicitly population health needs, levels of service to respond to health needs, and provider productivity as additional variables in determining the future requirements for the levels and mix of healthcare providers. Because the model derives requirements for providers directly from the requirements for services, it can be applied to a wide range of different provider types and practice structures including the public health workforce. By identifying the separate determinants of provider requirements, the analytical framework avoids the "illusions of necessity" that have generated continuous increases in provider requirements. Moreover, the framework enables policy makers to evaluate the basis of, and justification for, increases in the numbers of provider and increases in education and training programs as a method of increasing supply. A broad range of policy instruments is identified for responding to gaps between estimated future requirements for care and the estimated future capacity of the healthcare workforce.


Evidence for the formation of multiple types of acetaldehyde-haemoglobin adducts.
Acetaldehyde readily reacted with red blood cells and isolated haemoglobin to form adducts. We examined acetaldehyde-haemoglobin reaction products, isolated from red blood cells incubated with acetaldehyde (AcH), for the presence of stable peptide-specific acetaldehyde adducts. Red blood cell incubations were with 20, 50, and 200 mM acetaldehyde for 3, 24 and 48 hr. Peptide-specific [14C]acetaldehyde modifications of Hb from each incubation were identified by tryptic peptide mapping procedures. Nine peptides had modifications and six were found in incubations with 20 mM acetaldehyde. Two of the peptides were acetaldehyde modifications of the Hb alpha- and beta-chain N-termini. Stability studies indicated that the remaining seven [14C]AcH-modified peptides did not result, as can occur under certain conditions, from the transfer of AcH on the N-termini of Hb to N-termini formed after trypsin digestion. An analysis of the relative amounts of [14C]AcH-peptide adducts indicated that at least two of the seven peptides had reactivities for AcH different than the N-termini of Hb; that is, at least two modified peptides differ from imidazolidine-type adducts formed on the N-termini. The presence of multiple modifications with different sensitivities for AcH adduct formation may be useful in developing markers of alcohol consumption.


Impact of early use of long-acting injectable antipsychotics on psychotic relapses and hospitalizations in first-episode psychosis.
Early relapse is frequent in the first-episode psychosis (FEP), often because of poor adherence to medication. Previous studies have shown positive impacts of long-acting injectable antipsychotics (LAI-AP) on relapse rates, while others have discerned no differences. This study describes the impact of early LAI-AP utilization on relapse and rehospitalization rates in FEP. A three-year, longitudinal, prospective, naturalistic study of all admissions of psychosis patients for early intervention services was conducted. Four hundred sixteen patients were subdivided into four groups according to the route of antipsychotic administration. Patients who received LAI-AP as their first treatment modality were more likely to exhibit poor prognostic factors at baseline. However, their relapse rate over time was similar to those with good prognostic factors at baseline who only received oral antipsychotics (OAP). Patients who were initially prescribed OAP and eventually switched to LAI-AP were more likely to relapse and to be rehospitalized, even if they manifested better functioning at baseline than those started on LAI-AP. Patients with poor prognosis in the early stage of their disease seem to benefit from early prescription of LAI-AP which can reduce and delay relapses and rehospitalizations. Because they are often still at school or at work at the time of their first episode of psychosis, relapse prevention seems particularly relevant to avoid functional deterioration.


Probing many-body dynamics on a 51-atom quantum simulator.
Controllable, coherent many-body systems can provide insights into the fundamental properties of quantum matter, enable the realization of new quantum phases and could ultimately lead to computational systems that outperform existing computers based on classical approaches. Here we demonstrate a method for creating controlled many-body quantum matter that combines deterministically prepared, reconfigurable arrays of individually trapped cold atoms with strong, coherent interactions enabled by excitation to Rydberg states. We realize a programmable Ising-type quantum spin model with tunable interactions and system sizes of up to 51 qubits. Within this model, we observe phase transitions into spatially ordered states that break various discrete symmetries, verify the high-fidelity preparation of these states and investigate the dynamics across the phase transition in large arrays of atoms. In particular, we observe robust many-body dynamics corresponding to persistent oscillations of the order after a rapid quantum quench that results from a sudden transition across the phase boundary. Our method provides a way of exploring many-body phenomena on a programmable quantum simulator and could enable realizations of new quantum algorithms.


Mpp4 is required for proper localization of plasma membrane calcium ATPases and maintenance of calcium homeostasis at the rod photoreceptor synaptic terminals.
Membrane palmitoylated protein 4 (Mpp4) is a member of the membrane-associated guanylate kinase family. We show that Mpp4 localizes specifically to the plasma membrane of photoreceptor synaptic terminals. Plasma membrane Ca(2+) ATPases (PMCAs), the Ca(2+) extrusion pumps, interact with an Mpp4-dependent presynaptic membrane protein complex that includes Veli3 and PSD95. In mice lacking Mpp4, PMCAs were lost from rod photoreceptor presynaptic membranes. Synaptic ribbons were enlarged, a phenomenon known to correlate with higher Ca(2+). SERCA2 (sarcoplasmic-endoplasmic reticulum Ca(2+) ATPase, type 2), which pumps cytosolic Ca(2+) into intracellular Ca(2+) stores and localizes next to the ribbons, was increased. The distribution of IP(3)RII (InsP(3) receptor, type 2), which releases Ca(2+) from the stores, was shifted away from the synaptic terminals. Synaptic transmission to second-order neurons was maintained but was reduced in amplitude. These data suggest that loss of Mpp4 disrupts a Ca(2+) extrusion mechanism at the presynaptic membranes, with ensuing adaptive responses by the photoreceptor to restore Ca(2+) homeostasis. We propose that Mpp4 organizes a presynaptic protein complex that includes PMCAs and has a role in modulating Ca(2+) homeostasis and synaptic transmission in rod photoreceptors.


Averaging over depth during optical mapping of unipolar stimulation.
Numerical simulations have predicted the distribution of transmembrane potential during electrical stimulation of cardiac tissue. When comparing these predictions to measurements obtained using optical mapping techniques, the optical signal should not be compared to the transmembrane potential calculated at the surface of the tissue, but instead to the transmembrane potential averaged over depth. In this paper, the bidomain model is used to calculate the transmembrane potential in a three-dimensional slab of cardiac tissue, stimulated by a unipolar electrode on the tissue surface. For an optical decay constant of 0.3 mm and an electrode radius of 1 mm, the surface transmembrane potential is more than a factor of three larger than the transmembrane potential averaged over depth. Our results suggest that optical mapping underestimates the surface transmembrane potential during electrical stimulation.


Surgical interventions for the early management of Bell's palsy.
Bell's palsy is an acute paralysis of one side of the face of unknown aetiology. Bell's palsy should only be used as a diagnosis in the absence of all other pathology. As the proposed pathophysiology is swelling and entrapment of the nerve, some surgeons suggest surgical decompression of the nerve as a possible management option. The objective of this review was to assess the effectiveness of surgery in the management of Bell's palsy and to compare this to outcomes of medical management. We searched the Cochrane Neuromuscular Disease Group Specialized Register (23 November 2010). We also searched the Cochrane Central Register of Controlled Trials (CENTRAL) (23 November in The Cochrane Library, Issue 4 2010). We adapted this strategy to search MEDLINE (January 1966 to November 2010) and EMBASE (January 1980 to November 2010). We included all randomised or quasi-randomised controlled trials involving any surgical intervention for Bell's palsy. Two review authors independently assessed whether trials identified from the search strategy were eligible for inclusion. Two review authors assessed trial quality and extracted data independently. Two trials with a total of 69 participants met the inclusion criteria. The first study considered the treatment of 403 patients but only included 44 in their surgical study. These were randomised into a surgical and non surgical group. The second study had 25 participants which they randomly allocated into surgical or control groups.The nerves of all the surgical group participants in both studies were decompressed using a retroauricular approach. The primary outcome was recovery of facial palsy at 12 months. The first study showed that both the operated and non operated groups had comparable facial nerve recovery at nine months. This study did not statistically compare the groups but the scores and size of the groups suggested that statistically significant differences are unlikely. The second study reported no statistically significant differences between their operated and control groups. One operated patient in the first study had 20 dB sensorineural hearing loss and persistent vertigo. There is only very low quality evidence from randomised controlled trials and this is insufficient to decide whether surgical intervention is beneficial or harmful in the management of Bell's palsy.Further research into the role of surgical intervention is unlikely to be performed because spontaneous recovery occurs in most cases.


[Effect of self-foot reflexology massage on depression, stress responses and immune functions of middle aged women].
This study was aimed to identify the effects of a self-foot reflexology massage on depression, stress responses and functions of the immune system of middle-aged women. This study was a one group pretest-posttest experimental design and the data was collected from August 1st, 2004 to May 31st, 2005. The subjects consisted of 46 middle-aged women (40 - 64 years) who were recruited from the Community Health Center in Busan city. Subjects were not treated for 4 weeks, subsequently they were trained in self foot reflexology massage for 2 weeks, and then they did their own daily for 6 weeks (2 days at the research center, 5 days at home). The outcome variables were measured 4 times, at baseline, pre training, after training, and after the intervention. The collected data was analyzed using repeated measure ANOVA by the SPSS/WIN program. There was a statistically significant difference in depression, perceived stress, systolic blood pressure, natural-killer cells and Ig G. However, there was not a statistically significant difference in diastolic blood pressure, pulse or serum cortisol. These results suggest that a self-foot reflexology massage could be utilized as an effective nursing intervention to reduce depression and stress responses, and to strengthen immune systems in middle-aged women.


Racial differences in access to the kidney transplant waiting list for children and adolescents with end-stage renal disease.
Renal transplantation is the treatment of choice for pediatric patients with end-stage renal disease (ESRD). Black patients wait longer for kidney transplants than do white patients. To determine whether the increased time to transplantation for black pediatric patients is attributable not only to a shortage of suitable donor organs, but also to racial differences in the time from a child's first treatment for ESRD until activation on the cadaveric kidney transplant waitlist. National longitudinal cohort study. US Medicare-eligible, pediatric ESRD population. Children and adolescents </=19 years old at the time of their first dialysis for ESRD between 1988 and 1993, followed through 1996. Patients who received living donor renal transplants were excluded from study. Time from first dialysis for ESRD until activation on the kidney transplant waiting list, relative hazard of activation on the waiting list for black compared with white pediatric patients. Comparisons of the time from first dialysis for ESRD to waitlisting among the 2162 white (60.7%) and 1122 black (31.5%) patients studied using survival analysis revealed that blacks were less likely to be waitlisted at any given time in follow-up. In multivariate analysis, even after controlling for patient age, gender, socioeconomic status, geographic region, incident year of renal failure, and cause of ESRD, blacks were 12% less likely to be waitlisted than were whites at any point in time (relative hazard:. 88: 95% confidence interval:.79-.97). Racial disparities in access to the renal transplant waiting list exist in pediatrics. Whether these disparities are attributable to differences in time of presentation to a nephrologist, physician bias in identification of transplant candidates, or patient preferences warrants further study.


Frequency-dependent circuits anchored in the dorsal and ventral left anterior insula.
The hub role of the right anterior insula (AI) has been emphasized in cognitive neurosciences and been demonstrated to be frequency-dependently organized. However, the functional organization of left AI (LAI) has not been systematically investigated. Here we used 100 unrelated datasets from the Human Connectome Project to study the frequency-dependent organization of LAI along slow 6 to slow 1 bands. The broadband functional connectivity of LAI was similar to previous findings. In slow 6-slow 3 bands, both dorsal and ventral seeds in LAI were correlated to the salience network (SN) and language network (LN) and anti-correlated to the default mode network (DMN). However, these seeds were only correlated to the LAI in slow 2-slow 1 bands. These findings indicate that broadband and narrow band functional connections reflect different functional organizations of the LAI. Furthermore, the dorsal seed had a stronger connection with the LN and anti-correlation with DMN while the ventral seed had a stronger connection within the SN in slow 6-slow 3 bands. In slow 2-slow 1 bands, both seeds had stronger connections with themselves. These observations indicate distinctive functional organizations for the two parts of LAI. Significant frequency effect and frequency by seed interaction were also found, suggesting different frequency characteristics of these two seeds. The functional integration and functional segregation of LDAI and LVAI were further supported by their cognitive associations. The frequency- and seed-dependent functional organizations of LAI may enlighten future clinical and cognitive investigations.


FTIR-based spectroscopic analysis in the identification of clinically aggressive prostate cancer.
Fourier transform infrared (FTIR) spectroscopy is a vibrational spectroscopic technique that uses infrared radiation to vibrate molecular bonds within the sample that absorbs it. As different samples contain different molecular bonds or different configurations of molecular bonds, FTIR allows us to obtain chemical information on molecules within the sample. Fourier transform infrared microspectroscopy in conjunction with a principal component-discriminant function analysis (PC-DFA) algorithm was applied to the grading of prostate cancer (CaP) tissue specimens. The PC-DFA algorithm is used alongside the established diagnostic measures of Gleason grading and the tumour/node/metastasis system. Principal component-discriminant function analysis improved the sensitivity and specificity of a three-band Gleason score criterion diagnosis previously reported by attaining an overall sensitivity of 92.3% and specificity of 99.4%. For the first time, we present the use of a two-band criterion showing an association of FTIR-based spectral characteristics with clinically aggressive behaviour in CaP manifest as local and/or distal spread. This paper shows the potential for the use of spectroscopic analysis for the evaluation of the biopotential of CaP in an accurate and reproducible manner.


Mycobacterium tuberculosis programs mesenchymal stem cells to establish dormancy and persistence.
Tuberculosis (TB) remains a major infectious disease worldwide. TB treatment displays a biphasic bacterial clearance, in which the majority of bacteria clear within the first month of treatment, but residual bacteria remain nonresponsive to treatment and eventually may become resistant. Here, we have shown that Mycobacterium tuberculosis was taken up by mesenchymal stem cells (MSCs), where it established dormancy and became highly nonresponsive to isoniazid, a major constituent of directly observed treatment short course (DOTS). Dormant M. tuberculosis induced quiescence in MSCs and promoted their long-term survival. Unlike macrophages, where M. tuberculosis resides in early-phagosomal compartments, in MSCs the majority of bacilli were found in the cytosol, where they promoted rapid lipid synthesis, hiding within lipid droplets. Inhibition of lipid synthesis prevented dormancy and sensitized the organisms to isoniazid. Thus, we have established that M. tuberculosis gains dormancy in MSCs, which serve as a long-term natural reservoir of dormant M. tuberculosis. Interestingly, in the murine model of TB, induction of autophagy eliminated M. tuberculosis from MSCs, and consequently, the addition of rapamycin to an isoniazid treatment regimen successfully attained sterile clearance and prevented disease reactivation.


Blood-brain barrier penetration and in vivo activity of an NGF conjugate.
Nerve growth factor (NGF) is essential for the survival of both peripheral ganglion cells and central cholinergic neurons of the basal forebrain. The accelerated loss of central cholinergic neurons during Alzheimer's disease may be a determinant of dementia in these patients and may therefore suggest a therapeutic role for NGF. However, NGF does not significantly penetrate the blood-brain barrier, which makes its clinical utility dependent on invasive neurosurgical procedures. When conjugated to an antibody to the transferrin receptor, however, NGF crossed the blood-brain barrier after peripheral injection. This conjugated NGF increased the survival of both cholinergic and noncholinergic neurons of the medial septal nucleus that had been transplanted into the anterior chamber of the rat eye. This approach may prove useful for the treatment of Alzheimer's disease and other neurological disorders that are amenable to treatment by proteins that do not readily cross the blood-brain barrier.


Course of Disease and Clinical Outcome of Infective Endocarditis in HIV-infected Individuals: A Systematic Review and Meta-analysis.
Infective endocarditis (IE) causes substantial morbidity and mortality if untreated. The clinical course of IE might be different in HIV-positive patients as a result of immune dysfunction. This systematic review investigates the clinical course of IE in HIV-positive compared to HIV-negative patients. A systematic search was performed in PubMed, EMBASE, and Cochrane Library and registered in PROSPERO (CRD42016048649). All articles from 1996 and onward addressing the clinical outcome of HIV-positive adults suffering from IE were reviewed and included based on predefined inclusion and exclusion criteria. A meta-analysis was performed for the outcome mortality. Twenty-three articles were included of which eight included HIVpositive patients only, and 15 compared HIV-positive to HIV-negative patients. Two studies included patients on antiretroviral therapy (ART). HIV and intravenous drug use (IVDU) were closely related. Mortality was higher in HIV-positive patients with a CD4 count below 200 cells/μl than in HIV-positive patients with a higher CD4 count, while mortality was similar for HIV-positive compared to HIV-negative patients (risk ratio = 0.86 [95% confidence interval: 0.53-1.40]). No difference was found in length of hospital stay or rehospitalization. Clinical outcomes were strongly related to the right- or left-sided endocarditis. The clinical course of IE is not different for patients with and without HIV. Clinical outcomes were mainly associated with other factors, such as IVDU and side of cardiac involvement, rather than HIV status.


Using inotropic and vasodilating agents in pediatric patients with cardiac disease.
Inotropic and vasodilating agents are traditionally used with diuretics to manage heart failure in children with congenital heart disease. This article reviews the developmental aspects of cardiovascular physiology and the rational use of therapeutic agents for acutely ill surgical and medical pediatric patients with cardiac disease. By understanding the actions and indications for inotropic support and afterload reduction, the critical care nurse can intelligently administer these agents and evaluate their effects.


Soluble HLA-G and HLA-E Levels in Bone Marrow Plasma Samples Are Related to Disease Stage in Neuroblastoma Patients.
The role of nonclassical HLA-class Ib molecules HLA-G and HLA-E in the progression of Neuroblastoma (NB), the most common pediatric extracranial solid tumor, has been characterized in the last years. Since BM infiltration by NB cells is an adverse prognostic factor, we have here analyzed for the first time the concentration of soluble (s)HLA-G and HLA-E in bone marrow (BM) plasma samples from NB patients at diagnosis and healthy donors. sHLA-G and sHLA-E are present in BM plasma samples, and their levels were similar between NB patients and controls, thus suggesting that these molecules are physiologically released by resident or stromal BM cell populations. This hypothesis was supported by the finding that sHLA-G and sHLA-E levels did not correlate with BM infiltration and other adverse prognostic factors (MYCN amplification and age at diagnosis). In contrast, BM plasma levels of both molecules were higher in patients with metastatic disease than in patients with localized NB, thus suggesting that concentration of these molecules might be correlated with disease progression. The prognostic role of sHLA-G and sHLA-E concentration in the BM plasma for NB patients will be evaluated in future studies, by analyzing the clinical outcome of the same NB patients at follow-up.


A novel autoantibody against fibronectin leucine-rich transmembrane protein 2 expressed on the endothelial cell surface identified by retroviral vector system in systemic lupus erythematosus.
Anti-endothelial cell antibodies (AECAs) are thought to be critical for vasculitides in collagen diseases, but most were directed against molecules localized within the cell and not expressed on the cell surface. To clarify the pathogenic roles of AECAs, we constructed a retroviral vector system for identification of autoantigens expressed on the endothelial cell surface. AECA activity in sera from patients with collagen diseases was measured with flow cytometry by using human umbilical vein endothelial cells (HUVECs). A cDNA library of HUVECs was retrovirally transfected into a rat myeloma cell line, from which AECA-positive clones were sorted with flow cytometry. cDNA of the cells was analyzed to identify an autoantigen, and then the clinical characteristics and the functional significance of the autoantibody were evaluated. Two distinct AECA-positive clones were isolated by using serum immunoglobulin G (IgG) from a patient with systemic lupus erythematosus (SLE). Both clones were identical to cDNA of fibronectin leucine-rich transmembrane protein 2 (FLRT2). HUVECs expressed FLRT2 and the prototype AECA IgG bound specifically to FLRT2-transfected cells. Anti-FLRT2 antibody activity accounted for 21.4% of AECAs in SLE. Furthermore, anti-FLRT2 antibody induced complement-dependent cytotoxicity against FLRT2-expressing cells. We identified the membrane protein FLRT2 as a novel autoantigen of AECAs in SLE patients by using the retroviral vector system. Anti-FLRT2 antibody has the potential to induce direct endothelial cell cytotoxicity in about 10% of SLE patients and could be a novel molecular target for intervention. Identification of such a cell-surface target for AECAs may reveal a comprehensive mechanism of vascular injury in collagen diseases.


Retardation or acceleration of diabetes in NOD/Lt mice mediated by intrathymic administration of candidate beta-cell antigens.
A single injection of syngeneic islet cells into the thymus of 4-week-old NOD/Lt female mice strongly retards diabetogenesis. The present study used the intrathymic route of antigen administration to compare the relative efficacy of peptides/proteins derived from two major candidate pancreatic beta-cell autoantigens, insulin and GAD65, to modulate diabetogenesis. Intrathymic administration of insulin B chain or recombinant human GAD65 significantly suppressed diabetogenesis during a 20-week follow-up period, whereas no protection was mediated by either insulin A chain or a synthetic peptide (A2) derived from it. Quite unexpectedly, two GAD65-derived peptides near the COOH-terminus (p34 and p35) accelerated diabetes onset. Semiquantitative reverse transcription-polymerase chain reaction analysis was performed on cDNAs from isolated islets or whole pancreases of NOD/Lt females 4 weeks after intrathymic injections. Protection mediated by intrathymic administration with either intact islet cells or GAD65 were correlated with an upregulation of mRNA for T-helper 2 (Th2)-associated cytokines (interleukin [IL]-4, IL-10), concomitant with downregulation of Th1-associated interferon (IFN) transcripts (all normalized to T-cell receptor Cbeta transcripts) in islet-infiltrating lymphocytes. Protection mediated by the intrathymic administration of insulin B chain, however, correlated only with a modest upregulation of IL-4 and IL-10 transcript levels, and no diminution in IFN-gamma transcripts. In contrast, the diabetes-accelerating GAD65 p34 and p35 peptides were not associated with an immune deviation, expressing levels of IFN-gamma characteristic of islet-infiltrating lymphocytes in vehicle-injected NOD controls. Hence, Th1-to-Th2 immune deviation provides only a partial explanation for peptide immunotherapy of diabetes in NOD mice. The finding that certain peptides can accelerate rather than retard diabetogenesis as a function of route and age of administration adds a cautionary note to this type of therapy.


Quantum control mechanism analysis through field based Hamiltonian encoding: a laboratory implementable algorithm.
While closed-loop control of quantum dynamics in the laboratory is proving to be broadly successful, the control mechanisms induced by the fields are often left obscure. Hamiltonian encoding (HE) was originally introduced as a method for understanding mechanisms in quantum dynamics in the context of computational simulations, based on access to the system wavefunction. As a step towards laboratory implementation of HE, this paper addresses the issues raised by the use of observables rather than the wavefunction in HE. The goal of laboratory based HE is to obtain an understanding of control mechanism through a sequence of systematic control experiments, whose collective information can identify the underlying control mechanism defined as the set of significant amplitudes connecting the initial and final states. Mechanism is determined by means of observing the dynamics of special sequences of system Hamiltonians encoded through the control field. The proposed algorithm can handle complex systems, operates with no recourse to dynamical simulations, and functions with limited understanding of the system Hamiltonian. As with the closed-loop control experiments, the HE control mechanism identification algorithm performs a new experiment each time the dynamical outcome from an encoded Hamiltonian is called for. This paper presents the basic HE algorithm in the context of physical systems described by a finite dimensional Hilbert space. The method is simulated with simple models, and the extension to more complex systems is discussed.


Colonization of Pythium oligandrum in the tomato rhizosphere for biological control of bacterial wilt disease analyzed by real-time PCR and confocal laser-scanning microscopy.
It recently has been reported that the non-plant-pathogenic oomycete Pythium oligandrum suppresses bacterial wilt caused by Ralstonia solanacearum in tomato. As one approach to determine disease-suppressive mechanisms of action, we analyzed the colonization of P. oligandrum in rhizospheres of tomato using real-time polymerase chain reaction (PCR) and confocal laser-scanning microscopy. The real-time PCR specifically quantified P. oligandrum in the tomato rhizosphere that is reliable over a range of 0.1 pg to 1 ng of P. oligandrum DNA from 25 mg dry weight of soil. Rhizosphere populations of P. oligandrum from tomato grown for 3 weeks in both unsterilized and sterilized field soils similarly increased with the initial application of at least 5 x 10(5) oospores per plant. Confocal microscopic observation also showed that hyphal development was frequent on the root surface and some hyphae penetrated into root epidermis. However, rhizosphere population dynamics after transplanting into sterilized soil showed that the P. oligandrum population decreased with time after transplanting, particularly at the root tips, indicating that this biocontrol fungus is rhizosphere competent but does not actively spread along roots. Protection over the long term from root-infecting pathogens does not seem to involve direct competition. However, sparse rhizosphere colonization of P. oligandrum reduced the bacterial wilt as well as more extensive colonization, which did not reduce the rhizosphere population of R. solanacearum. These results suggest that competition for infection sites and nutrients in rhizosphere is not the primary biocontrol mechanism of bacterial wilt by P. oligandrum.


Age Is Not a Contraindication for Cartilage Surgery: A Critical Analysis of Standardized Outcomes at Long-term Follow-up.
Age is commonly accepted as a negative prognostic factor in cartilage surgery, and cutoff values of 30 to 40 years have been previously suggested as treatment indication. However, the lower outcome scores documented in older patients do not take in consideration the decreasing requirements of an aging joint. To analyze the real effect of age in terms of recovery with respect to the functional level expected for different age categories of patients treated for cartilage lesions. Cohort study; Level of evidence, 3. Patients with International Cartilage Repair Society (ICRS) grade 3-4 defects, involving femoral condyles or trochlea without osteoarthritis, were treated with arthroscopic matrix-assisted autologous chondrocyte transplantation; 157 patients were evaluated with IKDC subjective and Tegner scores before surgery and then after 2 and 10 years. Results were first evaluated by dividing patients into 2 age groups according to the generally approved cutoff value of 40 years. The analysis was then repeated after the scores of each patient were standardized according to the score achievable per the normative data in healthy patients for the corresponding sex and age category. A significant improvement in all scores was observed. IKDC subjective score improved from 38.9 ± 14.5 to 74.7 ± 21.8 at 10 years. When a cutoff value of 40 years was used, older patients reached a significantly worse IKDC subjective value at 10 years (65.8 ± 24.3 vs 77.2 ± 20.4, P = .007). However, different findings were obtained after the scores were standardized. Although optimal results were still found in younger patients (<30 years), patients older than 40 years also appeared to benefit from the treatment, and no significant differences were noted compared with the younger population. The benefit of cartilage treatments in patients with increasing age but without any sign of osteoarthritis was higher than previously reported in literature. In fact, when the decreasing functional level expected by an aging population was considered, standardized results showed an overall benefit after cartilage treatment in patients older than 40 years that was not significantly different from the outcome achieved in younger patients. Thus, age is not a strict contraindication as previously suggested, and future studies should consider standardization of data to prove the real age limit of cartilage treatments.


Systematic review and economic modelling of the effectiveness and cost-effectiveness of non-surgical treatments for women with stress urinary incontinence.
To assess the clinical effectiveness and cost-effectiveness of non-surgical treatments for women with stress urinary incontinence (SUI) through systematic review and economic modelling. The Cochrane Incontinence Group Specialised Register, electronic databases and the websites of relevant professional organisations and manufacturers, and the following databases: CINAHL, EMBASE, BIOSIS, Science Citation Index and Social Science Citation Index, Current Controlled Trials, ClinicalTrials.gov and the UKCRN Portfolio Database. The study comprised three distinct elements. (1) A survey of 188 women with SUI to identify outcomes of importance to them (activities of daily living; sex, hygiene and lifestyle issues; emotional health; and the availability of services). (2) A systematic review and meta-analysis of non-surgical treatments for SUI to find out which are most effective by comparing results of trials (direct pairwise comparisons) and by modelling results (mixed-treatment comparisons - MTCs). A total of 88 randomised controlled trials (RCTs) and quasi-RCTs reporting data from 9721 women were identified, considering five generic interventions [pelvic floor muscle training (PFMT), electrical stimulation (ES), vaginal cones (VCs), bladder training (BT) and serotonin-noradrenaline reuptake inhibitor (SNRI) medications], in many variations and combinations. Data were available for 37 interventions and 68 treatment comparisons by direct pairwise assessment. Mixed-treatment comparison models compared 14 interventions, using data from 55 trials (6608 women). (3) Economic modelling, using a Markov model, to find out which combinations of treatments (treatment pathways) are most cost-effective for SUI. Titles and abstracts identified were assessed by one reviewer and full-text copies of all potentially relevant reports independently assessed by two reviewers. Any disagreements were resolved by consensus or arbitration by a third person. Direct pairwise comparison and MTC analysis showed that the treatments were more effective than no treatment. Delivering PFMT in a more intense fashion, either through extra sessions or with biofeedback (BF), appeared to be the most effective treatment [PFMT extra sessions vs no treatment (NT) odds ratio (OR) 10.7, 95% credible interval (CrI) 5.03 to 26.2; PFMT + BF vs NT OR 12.3, 95% CrI 5.35 to 32.7]. Only when success was measured in terms of improvement was there evidence that basic PFMT was better than no treatment (PFMT basic vs NT OR 4.47, 95% CrI 2.03 to 11.9). Analysis of cost-effectiveness showed that for cure rates, the strategy using lifestyle changes and PFMT with extra sessions followed by tension-free vaginal tape (TVT) (lifestyle advice-PFMT extra sessions-TVT) had a probability of greater than 70% of being considered cost-effective for all threshold values for willingness to pay for a QALY up to 50,000 pounds. For improvement rates, lifestyle advice-PFMT extra sessions-TVT had a probability of greater than 50% of being considered cost-effective when society's willingness to pay for an additional QALY was more than 10,000 pounds. The results were most sensitive to changes in the long-term performance of PFMT and also in the relative effectiveness of basic PFMT and PFMT with extra sessions. Although a large number of studies were identified, few data were available for most comparisons and long-term data were sparse. Challenges for evidence synthesis were the lack of consensus on the most appropriate method for assessing incontinence and intervention protocols that were complex and varied considerably across studies. More intensive forms of PFMT appear worthwhile, but further research is required to define an optimal form of more intensive therapy that is feasible and efficient for the NHS to provide, along with further definitive evidence from large, well-designed studies.


A case of pembrolizumab-induced severe DKA and hypothyroidism in a patient with metastatic melanoma.
Immune checkpoint inhibitors (ICIs) have revolutionised cancer therapy and improved outcomes for patients with advanced disease. Pembrolizumab, a monoclonal antibody that acts as a programmed cell death 1 (PD-1(PDCD1)) inhibitor, has been approved for the treatment of advanced melanoma and other solid tumours. Immune-related adverse events (irAEs) including endocrinopathies have been well described with this and other PD-1 inhibitors. While hypothyroidism and hyperthyroidism, and less commonly hypophysitis, are the most common endocrinopathies occurring in patients treated with pembrolizumab, the incidence of type 1 diabetes mellitus (T1DM) was low in clinical trials. We report a case of pembrolizumab-induced primary hypothyroidism and T1DM presenting with severe diabetic ketoacidosis (DKA). A 52-year-old male patient was treated with pembrolizumab for metastatic melanoma. He presented to the emergency department with a 1-day history of nausea and vomiting 2 weeks after his seventh dose of pembrolizumab, having complained of polyuria and polydipsia for 2 months before presentation. He had been diagnosed with thyroid peroxidase (TPO) antibody-negative hypothyroidism, requiring thyroxine replacement, shortly after his fifth dose. Testing revealed a severe DKA (pH: 6.99, glucose: 38.6 mmol/L, capillary ketones: 4.9 and anion gap: 34.7). He was treated in the intensive care unit as per the institutional protocol, and subsequently transitioned to subcutaneous basal-bolus insulin. After his diabetes and thyroid stabilised, pembrolizumab was recommenced to treat his advanced melanoma given his excellent response. This case highlights the importance of blood glucose monitoring as an integral part of cancer treatment protocols composed of pembrolizumab and other ICIs. Learning points: The incidence of T1DM with pembrolizumab treatment is being increasingly recognised and reported, and DKA is a common initial presentation. Physicians should counsel patients about this potential irAE and educate them about the symptoms of hyperglycaemia and DKA. The ESMO guidelines recommend regular monitoring of blood glucose in patients treated with ICIs, a recommendation needs to be incorporated into cancer treatment protocols for pembrolizumab and other ICIs in order to detect hyperglycaemia early and prevent DKA.


Total synthesis of all (-)-Agelastatin alkaloids.
The pyrrole-imidazole family of marine alkaloids, derived from linear clathrodin-like precursors, constitutes a diverse array of structurally complex natural products. The bioactive agelastatins are members of this family that possess a tetracyclic molecular framework incorporating C4-C8 and C7-N12 bond connectivities. We provide a hypothesis for the formation of the unique agelastatin architecture that maximally exploits the intrinsic chemistry of plausible biosynthetic precursors. We report the concise enantioselective total syntheses of all known agelastatin alkaloids including the first total syntheses of agelastatins C, D, E, and F. Our gram-scale chemical synthesis of agelastatin A was inspired by our hypothesis for the biogenesis of the cyclopentane C-ring and required the development of new transformations including an imidazolone-forming annulation reaction and a carbohydroxylative trapping of imidazolones.


Speckle variance optical coherence tomography of the rodent spinal cord: in vivo feasibility.
Optical coherence tomography (OCT) has the combined advantage of high temporal (µsec) and spatial (<10µm) resolution. These features make it an attractive tool to study the dynamic relationship between neural activity and the surrounding blood vessels in the spinal cord, a topic that is poorly understood. Here we present work that aims to optimize an in vivo OCT imaging model of the rodent spinal cord. In this study we image the microvascular networks of both rats and mice using speckle variance OCT. This is the first report of depth resolved imaging of the in vivo spinal cord using an entirely endogenous contrast mechanism.


Swimming, but not vitamin E, ameliorates prothrombotic state and hypofibrinolysis in a rat model of nonalcoholic fatty liver disease.
Nonalcoholic fatty liver disease (NAFLD) is associated with a systemic procoagulant hypofibrinolysis state that is considered as a risk factor for microangiopathy and peripheral vascular diseases. Swimming exercise ameliorates the metabolic dysfunction in type 2 diabetes. Vitamin E is a natural antioxidant that reduces the risk of endothelial dysfunction in metabolic syndrome. The aim of the present study is to investigate the effect of combined swimming exercise with vitamin E on coagulation as well as blood fibrinolysis markers in rats with NAFLD. Eighty male rats were divided into control, control+vitamin E, control+exercise, high-fat diet (HFD), HFD+vitamin E, HFD+exercise, and HFD+vitamin E+exercise groups. Glucose, insulin, homeostatic model assessment for insulin resistance (HOMA-IR), triglycerides, cholesterol, low-density lipoprotein (LDL) and high-density lipoprotein (HDL), alanine transaminase (ALT) and aspartate transaminase (AST), intercellular adhesion molecule (ICAM-1), vascular cell adhesion molecule (VCAM-1), endothelin-1, von Willebrand factor (vWF), fibrinogen, plasminogen activator inhibitor (PAI-1), fibrin degradation products (FDP), platelet count and aggregation, bleeding and clotting times, activated partial thromboplastin time (aPTT), and prothrombin time (PT) were determined. HFD increased lipid profile, insulin, glucose, HOMA-IR, liver enzymes, adhesion molecules, endothelin-1, vWF, platelet aggregation, fibrinogen, FDP, and PAI-1, and decreased clotting and bleeding times and HDL. Although exercise reduced lipid profile, glucose, insulin, HOMA-IR, vWF, platelet aggregation, fibrinogen, FDP, and PAI-1 and increased PT, aPTT, bleeding and clotting times, and HDL, vitamin E had no effect. Exercise, but not vitamin E, ameliorated the HFD-induced prothrombotic state and enhanced fibrinolytic activity.


Disruption in the balance between goal-directed behavior and habit learning in obsessive-compulsive disorder.
Obsessive-compulsive disorder (OCD) is characterized by repetitive, ritualistic behaviors and thought patterns. Although patients with OCD report that these compulsive behaviors are unproductive and often senseless, they are unable to desist. This study investigated whether the urge to perform compulsive acts is mediated by a disruption in the balance between flexible, goal-directed action control and habitual behavior. A total of 21 patients with OCD and 30 healthy comparison subjects participated in a set of tasks designed to assess relative goal-directed versus habitual behavioral control. In the training stage, participants were asked to respond to different pictured stimuli in order to gain rewarding outcomes. In the subsequent (instructed) outcome devaluation test and in a novel "slips-of-action" test, the authors assessed whether participants were able to flexibly adjust their behavior to changes in the desirability of the outcomes. The authors also used a questionnaire to test explicit knowledge of the relationships between stimuli, responses, and outcomes. Patients with OCD showed no deficit in their ability to use feedback to respond appropriately to stimuli in the training stage. However, their knowledge of the outcomes of these responses was impaired relative to healthy comparison subjects, and patients were more prone to slips of action, indicating a deficit in goal-directed control and an overreliance on habits. This study provides the first experimental evidence for selective impairment in flexible and goal-directed behavioral control in patients with OCD. The impairment forces patients with OCD to rely instead on habits that can be triggered by stimuli regardless of the desirability of the consequences. Goal-directed actions are supported by orbitofronto-striatal circuitry, and the study findings are thus in line with findings from research that implicate dysfunction in this circuitry in the neuropathology of OCD.


Clinical and metabolic correction of pompe disease by enzyme therapy in acid maltase-deficient quail.
Pompe disease is a fatal genetic muscle disorder caused by a deficiency of acid alpha-glucosidase (GAA), a glycogen degrading lysosomal enzyme. GAA-deficient (AMD) Japanese quails exhibit progressive myopathy and cannot lift their wings, fly, or right themselves from the supine position (flip test). Six 4-wk-old acid maltase-deficient quails, with the clinical symptoms listed, were intravenously injected with 14 or 4.2 mg/kg of precursor form of recombinant human GAA or buffer alone every 2-3 d for 18 d (seven injections). On day 18, both high dose-treated birds (14 mg/kg) scored positive flip tests and flapped their wings, and one bird flew up more than 100 cm. GAA activity increased in most of the tissues examined. In heart and liver, glycogen levels dropped to normal and histopathology was normal. In pectoralis muscle, morphology was essentially normal, except for increased glycogen granules. In sharp contrast, sham-treated quail muscle had markedly increased glycogen granules, multi-vesicular autophagosomes, and inter- and intrafascicular fatty infiltrations. Low dose-treated birds (4.2 mg/kg) improved less biochemically and histopathologically than high dose birds, indicating a dose-dependent response. Additional experiment with intermediate doses and extended treatment (four birds, 5.7-9 mg/kg for 45 d) halted the progression of the disease. Our data is the first to show that an exogenous protein can target to muscle and produce muscle improvement. These data also suggest enzyme replacement with recombinant human GAA is a promising therapy for human Pompe disease.


Predatory potential of Chrysoperla carnea and Cryptolaemus montrouzieri larvae on different stages of the mealybug, Phenacoccus solenopsis: a threat to cotton in South Asia.
The outbreaks of mealybug, Phenacoccus solenopsis Tinsley (Homoptera: Pseudococcidae), have created problems to cotton crops in South Asia in the recent years. To control this menace, predatory potential of Chrysoperla carnea and Cryptolaemus montrouzieri larvae were investigated under laboratory conditions (27 ± 5° C and 65 ± 5% RH). The experiments were conducted in no choice (only first, second, or third instar larvae of mealybug were offered at a time) and choice (first, second, and third instar larvae were offered simultaneously) feeding tests. Both predators had high consumption rates, with C. montrouzeiri being the most voracious feeder. In the no choice feeding tests, third instar larvae of C. montrouzeiri devoured the highest mean number of first instar P. solenopsis (439.38) In the choice feeding tests, a similar number of first instar nymphs (410) were consumed. In both feeding tests, C. carnea devoured relatively fewer numbers of P. solenopsis than C. montrouzeiri. Manly's preference index suggested that the both predators preferred first instar nymphs of P. solenopsis over second or third instar nymphs. Furthermore, studies on developmental rate and fecundity revealed that first instar nymphs of P. solenopsis significantly reduced development time but increased the fecundity of both predators.


A Novel Thoracic Ultrasound Measurement After Congenital Diaphragmatic Hernia Repair Identifies Decreased Diaphragmatic Excursion Associated With Adverse Respiratory and Surgical Outcomes.
Background and Aim: Congenital diaphragmatic hernia (CDH) is a rare defect often associated with pulmonary hypoplasia and abnormal pulmonary vascular development. Even after successful hernia repair, pulmonary disease may persist into adulthood. Impaired diaphragmatic motility may lead to compromised respiratory function long after index repair. This study investigates whether a novel ultrasound measurement, the diaphragmatic excursion ratio, can be a simple and non-invasive method to evaluate routine diaphragmatic motion after CDH repair, and whether it correlates with adverse surgical and respiratory outcomes. Materials and Methods: A cross-sectional study was conducted in consecutive patients who presented at medium-term follow-up visit between December 2017 and December 2018 after CDH repair at single pediatric hospital. Transthoracic ultrasound was performed with craniocaudal diaphragmatic excursion measured bilaterally during routine breathing. Diaphragmatic excursion ratios (diaphragmatic excursion of repaired vs. unrepaired side) were calculated and retrospectively compared with clinical data including demographics, length of stay, respiratory adjuncts, oral feeding, and need for gastrostomy. Results: Thirty-eight patients (median age at ultrasound, 24 months, interquartile range 11-60) were evaluated. Nine patients underwent primary repair, 29 had non-primary repair (internal oblique muscle flap or mesh patch). Patients with a diaphragmatic excursion ratio below the median (0.54) had longer hospital stays (median 77 vs. 28 days, p = 0.0007) more ventilator days (median 16 vs. 9 days, p =0.004), and were more likely to have been discharged on oxygen (68 vs. 16%, p = 0.001). They were also less likely to be exclusively taking oral feeds at 1-year post-surgery (37 vs. 74%, p = 0.02) and more likely to require a gastrostomy tube in the first year of life (74 vs. 21%, p = 0.003). Conclusions: Transthoracic ultrasound after CDH repair is practical method to assess diaphragm motion, and decreased diaphragm excursion ratio is associated with worse respiratory outcomes, a longer length of stay, and dependence on gastrostomy tube feeding within 1 year. Further prospective studies may help validate this novel ultrasound measurement and offer prognostic value.


Comparing the effects of different individualized music interventions for elderly individuals with severe dementia.
Individuals with dementia often experience poor quality of life (QOL) due to behavioral and psychological symptoms of dementia (BPSD). Music therapy can reduce BPSD, but most studies have focused on patients with mild to moderate dementia. We hypothesized that music intervention would have beneficial effects compared with a no-music control condition, and that interactive music intervention would have stronger effects than passive music intervention. Thirty-nine individuals with severe Alzheimer's disease were randomly and blindly assigned to two music intervention groups (passive or interactive) and a no-music Control group. Music intervention involved individualized music. Short-term effects were evaluated via emotional response and stress levels measured with the autonomic nerve index and the Faces Scale. Long-term effects were evaluated by BPSD changes using the Behavioral Pathology in Alzheimer's Disease (BEHAVE-AD) Rating Scale. Passive and interactive music interventions caused short-term parasympathetic dominance. Interactive intervention caused the greatest improvement in emotional state. Greater long-term reduction in BPSD was observed following interactive intervention, compared with passive music intervention and a no-music control condition. Music intervention can reduce stress in individuals with severe dementia, with interactive interventions exhibiting the strongest beneficial effects. Since interactive music intervention can restore residual cognitive and emotional function, this approach may be useful for aiding severe dementia patients' relationships with others and improving QOL. The registration number of the trial and the name of the trial registry are UMIN000008801 and "Examination of Effective Nursing Intervention for Music Therapy for Severe Dementia Elderly Person" respectively.


Evaluation of CSF shunt function: value of functional examination with contrast material.
Functional positive-contrast shuntography includes a patency check of both limbs of the shunt and the shunt valve by fluoroscopy following the injection of an iodinated contrast agent (anatomic shuntogram) and an assessment of the adequacy of ventricular fluid drainage under physiologic conditions by using serial CT scans to assess the rate of iodine dissipation from the ventricular system (physiologic shuntogram). To demonstrate its efficacy and utility, 82 functional shuntograms were obtained in 55 patients. Fifty-one of the 82 studies were abnormal. Of these, 22 demonstrated patency of both the proximal and distal limbs with an accompanying slow dissipation of contrast material after injection (21 of 22 patients were adults). Eighteen of these 22 patients improved following the reduction of shunt drainage pressure. In the case of frank shunt obstruction, the site of obstruction was delineated clearly in all 29 cases. Correlation of clinical outcome with test results confirmed the utility of this technique, especially when applied to the shunted adult hydrocephalic patient whose response to the shunt had been inadequate. The technique described here allows the clinician to differentiate between physiologic and anatomic shunt failure and between shunt failure and normal shunt function. It also allows for precise localization of the shunt obstruction in anatomic shunt failure and for demonstration of physiologic shunt failure when shunt patency is demonstrated in the presence of the slow dissipation of intraventricular contrast medium.


Development and evaluation of small peptidomimetic ligands to protease-activated receptor-2 (PAR2) through the use of lipid tethering.
Protease-activated receptor-2 (PAR2) is a G-Protein Coupled Receptor (GPCR) activated by proteolytic cleavage to expose an attached, tethered ligand (SLIGRL). We evaluated the ability for lipid-tethered-peptidomimetics to activate PAR2 with in vitro physiological and Ca2+ signaling assays to determine minimal components necessary for potent, specific and full PAR2 activation. A known PAR2 activating compound containing a hexadecyl (Hdc) lipid via three polyethylene glycol (PEG) linkers (2at-LIGRL-PEG3-Hdc) provided a potent agonist starting point (physiological EC50 = 1.4 nM; 95% CI: 1.2-2.3 nM). In a set of truncated analogs, 2at-LIGR-PEG3-Hdc retained potency (EC50 = 2.1 nM; 1.3-3.4 nM) with improved selectivity for PAR2 over Mas1 related G-protein coupled receptor type C11, a GPCR that can be activated by the PAR2 peptide agonist, SLIGRL-NH2. 2at-LIG-PEG3-Hdc was the smallest full PAR2 agonist, albeit with a reduced EC50 (46 nM; 20-100 nM). 2at-LI-PEG3-Hdc retained specific activity for PAR2 with reduced EC50 (310 nM; 260-360 nM) but displayed partial PAR2 activation in both physiological and Ca2+ signaling assays. Further truncation (2at-L-PEG3-Hdc and 2at-PEG3-Hdc) eliminated in vitro activity. When used in vivo, full and partial PAR2 in vitro agonists evoked mechanical hypersensitivity at a 15 pmole dose while 2at-L-PEG3-Hdc lacked efficacy. Minimum peptidomimetic PAR2 agonists were developed with known heterocycle substitutes for Ser1 (isoxazole or aminothiazoyl) and cyclohexylalanine (Cha) as a substitute for Leu2. Both heterocycle-tetrapeptide and heterocycle-dipeptides displayed PAR2 specificity, however, only the heterocycle-tetrapeptides displayed full PAR2 agonism. Using the lipid-tethered-peptidomimetic approach we have developed novel structure activity relationships for PAR2 that allows for selective probing of PAR2 function across a broad range of physiological systems.


Parenting styles and emerging adult depressive symptoms in Cebu, the Philippines.
Incidence of depressive disorders and symptoms increases during the transition to adulthood. The parenting relationship is a potential target for interventions to reduce risk for depression in offspring during this time period, and a four-category typology of parenting styles (authoritative, permissive, authoritarian, and neglectful) has been found to correlate with offspring psychological functioning. The majority of studies, however, have examined this four-category parenting style typology in Western populations. We used the Cebu Longitudinal Health and Nutrition Survey (CLHNS) from the Philippines to assess associations between parenting styles reported by offspring at age 18 and depressive symptoms reported by offspring at age 21 ( N = 1,723). Using adjusted linear regression models, we found that authoritarian and neglectful mothering styles were positively associated with daughters' depressive symptoms, whereas authoritarian mothering was negatively associated with sons' depressive symptoms. Findings suggest both cross-cultural similarities and variability in positive parenting. Results may have implications for family-based depression prevention interventions in the Philippines.


Lactate clearance and survival following injury.
Previous reports cite optimization of O2 delivery (DO2) to 660 mL/min/m2, O2 consumption (VO2) to 170 mL/min/m2, and cardiac index (CI) of 4.5 L/min as predicting survival. We prospectively evaluated 76 consecutive patients with multiple trauma admitted directly to the ICU from the operating room or emergency department. Patients had serum lactate levels and oxygen transport measured on ICU admission and at 8, 16, 24, 36, and 48 hours. Patients were analyzed with respect to survival (S) versus nonsurvival (NS), lactate clearance to normal (< or = 2 mmol/L) by 24 and 48 hours, hemodynamic optimization as defined above, as well as Injury Severity Score (ISS), ICU stay (LOS), and admission blood pressure. All patients achieved non-flow-dependent VO2. There was no difference in CI, DO2, VO2, or ISS when S was compared with NS. All 27 patients whose lactate level normalized in 24 hours survived. If lactate levels cleared to normal between 24 and 48 hours, the survival rate was 75%. Only 3 of the 22 patients who did not clear their lactate level to normal by 48 hours survived. Ten of the 25 nonsurvivors (40%) achieved the above arbitrary optimization criteria. Fifteen of the survivors never achieved any of these criteria. Optimization alone does not predict survival. However, the time needed to normalize serum lactate levels is an important prognostic factor for survival in severely injured patients.


Designing the Model Human Cochlea: An Ambient Crossmodal Audio-Tactile Display.
We present a model human cochlea (MHC), a sensory substitution technique and system that translates auditory information into vibrotactile stimuli using an ambient, tactile display. The model is used in the current study to translate music into discrete vibration signals displayed along the back of the body using a chair form factor. Voice coils facilitate the direct translation of auditory information onto the multiple discrete vibrotactile channels, which increases the potential to identify sections of the music that would otherwise be masked by the combined signal. One of the central goals of this work has been to improve accessibility to the emotional information expressed in music for users who are deaf or hard of hearing. To this end, we present our prototype of the MHC, two models of sensory substitution to support the translation of existing and new music, and some of the design challenges encountered throughout the development process. Results of a series of experiments conducted to assess the effectiveness of the MHC are discussed, followed by an overview of future directions for this research.


HIV rapid diagnostic testing by lay providers in a key population-led health service programme in Thailand.
Introduction: Rapid diagnostic testing (RDT) for HIV has a quick turn-around time, which increases the proportion of people testing who receive their result. HIV RDT in Thailand has traditionally been performed only by medical technologists (MTs), which is a barrier to its being scaled up. We evaluated the performance of HIV RDT conducted by trained lay providers who were members of, or worked closely with, a group of men who have sex with men (MSM) and with transgender women (TG) communities, and compared it to tests conducted by MTs. Methods: Lay providers received a 3-day intensive training course on how to perform a finger-prick blood collection and an HIV RDT as part of the Key Population-led Health Services (KPLHS) programme among MSM and TG. All the samples were tested by lay providers using Alere Determine HIV 1/2. HIV-reactive samples were confirmed by DoubleCheckGold Ultra HIV 1&2 and SD Bioline HIV 1/2. All HIV-positive and 10% of HIV-negative samples were re-tested by MTs using Serodia HIV 1/2. Results: Of 1680 finger-prick blood samples collected and tested using HIV RDT by lay providers in six drop-in centres in Bangkok, Chiang Mai, Chonburi and Songkhla, 252 (15%) were HIV-positive. MTs re-tested these HIV-positive samples and 143 randomly selected HIV-negative samples with 100% concordant test results. Conclusion: Lay providers in Thailand can be trained and empowered to perform HIV RDT as they were found to achieve comparable results in sample testing with MTs. Based on the task-shifting concept, this rapid HIV testing performed by lay providers as part of the KPLHS programme has great potential to enhance HIV prevention and treatment programmes among key at-risk populations.


Outcomes of Rescue Endovascular Treatment of Emergent Large Vessel Occlusion in Patients With Underlying Intracranial Atherosclerosis: Insights From STAR.
Background Some emergent large vessel occlusions (ELVOs) are refractory to reperfusion because of underlying intracranial atherosclerosis (ICAS), often requiring rescue therapy (RT) with balloon angioplasty, stenting, or both. In this study, we investigate the safety, efficacy, and long-term outcomes of RT in the setting of mechanical thrombectomy for ICAS-related ELVO. Methods and Results We queried the databases of 10 thrombectomy-capable centers in North America and Europe included in STAR (Stroke Thrombectomy and Aneurysm Registry). Patients with ELVO who underwent ICAS-related RT were included. A matched sample was produced for variables of age, admission National Institute of Health Stroke Scale, Alberta Stroke Program Early CT Score, onset to groin puncture time, occlusion site, and final recanalization. Out of 3025 patients with MT, 182 (6%) patients required RT because of underlying ICAS. Balloon angioplasty was performed on 122 patients, and 117 patients had intracranial stenting. In the matched analysis, 141 patients who received RT matched to a similar number of controls. The number of thrombectomy passes was higher (3 versus 1, P<0.001), and procedural time was longer in the RT group (52 minutes versus 36 minutes, P=0.004). There was a higher rate of symptomatic hemorrhagic transformation in the RT group (7.8% versus 4.3%, P=0.211), however, the difference was not significant. There was no difference in 90-day modified Rankin scale of 0 to 2 (44% versus 47.5%, P=0.543) between patients in the RT and control groups. Conclusions In patients with ELVO with underlying ICAS requiring RT, despite longer procedure time and a more thrombectomy passes, the 90 days favorable outcomes were comparable with patients with embolic ELVO.


Flaws in the application and interpretation of statistical analyses in systematic reviews of therapeutic interventions were common: a cross-sectional analysis.
The objective of the study was to investigate the application and interpretation of statistical analyses in a cross-section of systematic reviews (SRs) of therapeutic interventions, without restriction by journal, clinical condition, or specialty. We evaluated a random sample of SRs assembled previously, which were indexed in MEDLINE® during February 2014, focused on a treatment or prevention question, and reported at least one meta-analysis. The reported statistical methods used in each SR were extracted from articles and online appendices by one author, with a 20% random sample extracted in duplicate. We evaluated 110 SRs; 78/110 (71%) were non-Cochrane SRs and 55/110 (50%) investigated a pharmacological intervention. The SRs presented a median of 13 (interquartile range: 5-27) meta-analytic effects. When considering the index (primary or first reported) meta-analysis of each SR, just over half (62/110 [56%]) used the random-effects model, but few (5/62 [8%]) interpreted the meta-analytic effect correctly (as the average of the intervention effects across all studies). A statistical test for funnel plot asymmetry was reported in 17/110 (15%) SRs; however, in only 4/17 (24%) did the test include the recommended number of at least 10 studies of varying size. Subgroup analyses accompanied 42/110 (38%) index meta-analyses, but findings were not interpreted with respect to a test for interaction in 29/42 (69%) cases, and the issue of potential confounding in the subgroup analyses was not raised in any SR. There is scope for improvement in the application and interpretation of statistical analyses in SRs of therapeutic interventions. The involvement of statisticians on the SR team and establishment of partnerships between researchers with specialist expertise in SR methods and journal editors may help overcome these shortcomings.


pH dependence of the inwardly rectifying potassium channel, Kir5.1, and localization in renal tubular epithelia.
The physiological role of the inwardly rectifying potassium channel, Kir5.1, is poorly understood, as is the molecular identity of many renal potassium channels. In this study we have used Kir5.1-specific antibodies to reveal abundant expression of Kir5.1 in renal tubular epithelial cells, where Kir4.1 is also expressed. Moreover, we also show that Kir5.1/Kir4.1 heteromeric channel activity is extremely sensitive to inhibition by intracellular acidification and that this novel property is conferred predominantly by the Kir5.1 subunit. These findings suggest that Kir5.1/Kir4.1 heteromeric channels are likely to exist in vivo and implicate an important and novel functional role for the Kir5.1 subunit.


Polycyclic aromatic hydrocarbon sampling in wastewaters using semipermeable membrane devices: accuracy of time-weighted average concentration estimations of truly dissolved compounds.
Semipermeable membrane devices (SPMDs) previously spiked with performance reference compounds were exposed in wastewater. After 6 days of exposure, 13 polycyclic aromatic hydrocarbons (PAHs) were quantified in SPMDs. Exchange rate constants and time-weighted average (TWA) concentrations of SPMD-available PAHs in water were calculated. The bias of using SPMDs to estimate an actual TWA concentration if the concentration in water fluctuates, as can be expected in wastewater, was studied with numerical simulations. The bias increased with the exchange rate constant. However, most exchange rate constants evaluated in SPMDs exposed in wastewater were small enough for SPMDs to estimate a TWA concentration of PAHs even when the water concentration varied. TWA-SPMD-available concentrations were always below total dissolved (operationally defined as 0.7 microm) concentrations, indicating that part of the dissolved PAHs was not available for sampling. In situ partitioning coefficients K(DOC) were computed and found to be slightly higher than data from the literature. This confirms that only truly dissolved PAHs should be sampled by SPMDs in wastewater.


Constructing sexual health: gay men and 'risk' in the context of a public sex environment.
This article outlines the importance of conceptualizing 'sexual health' as a pluralistic and context-bound phenomenon. It explores gay men's sexual decision making in the particular context of public parks. Twenty gay men from Glasgow, Scotland, took part in semi-structured, in-depth interviews. Interpretative Phenomenological Analysis (IPA) was employed to analyse transcripts for recurrent themes-these represent shared understandings across participants. Risk reduction, danger and safety figured frequently in men's accounts of sex and sexual decision making. However, the risks men reported related more directly to the threat of attack or arrest rather than the avoidance of sexually transmitted infections. Indeed, danger itself was occasionally something to be sought and enjoyed. Given these findings, we discuss the appropriateness of traditional health psychological approaches to understanding sexual health. It is hoped that this approach can highlight some issues that a true psychology of sexual health must address in order to represent sexual decision making more accurately and to be useful with respect to both service provision and theoretical development.


The Kanizsa triangle illusion in foraging ants.
The Kanizsa triangle, wherein three Pac-Man configurations symmetrically face inwards, is a well-known illusion. By exposing foraging ants (Lasius niger) to Kanizsa-shaped honeydew solutions, we studied the origin of this illusion. More specifically, we examined whether foraging ants showed different movement reactions to local honeydew patterns formed by nestmates. This novel phenomenon could serve as an abstract model of the Kanizsa triangle illusion under the assumption that such an illusion could arise through the sum of each agent's limited global cognitions, because each agent could not perceive the entire subjective contours. Even a subjective consciousness consists of some parts which have no identical perception and could be an illusion. We succeeded in inducing foragers to move along the sides of a Kanizsa triangle when Pac-Man-shaped inducers were introduced. Furthermore, foragers appeared to form Y-shaped trajectories when dot-shaped or inverse Kanizsa inducers were used. Based on our findings, we propose an agent-based ant model that compares modelled behaviour with experimental phenomena. Our abstract model could be used to explain such cognitive phenomena for bottom-up processes, because ants cannot perceive the given subjective contours, instead simply move along the edges.


Interleukin 6 Accelerates Mortality by Promoting the Progression of the Systemic Lupus Erythematosus-Like Disease of BXSB.Yaa Mice.
IL6 is a multifunctional cytokine that drives terminal B cell differentiation and secretion of immunoglobulins. IL6 also cooperates with IL21 to promote differentiation of CD4+ T follicular helper cells (TFH). Elevated serum levels of IL6 correlate with disease flares in patients with systemic lupus erythematosus (SLE). We previously reported that IL21 produced by TFH plays a critical role in the development of the SLE-like disease of BXSB.Yaa mice. To examine the possible contributions of IL6 to disease, we compared disease parameters in IL6-deficient and IL6-competent BXSB.Yaa mice. We report that survival of IL6-deficient BXSB.Yaa mice was significantly prolonged in association with significant reductions in a variety of autoimmune manifestations. Moreover, B cells stimulated by co-engagement of TLR7 and B cell receptor (BCR) produced high levels of IL6 that was further augmented by stimulation with Type I interferon (IFN1). Importantly, the frequencies of TFH and serum levels of IL21 were significantly reduced in IL6-deficient mice. These findings suggest that high-level production of IL6 by B cells induced by integrated signaling from the IFN1 receptor, TLR7 and BCR promotes the differentiation of IL21-secreting TFH in a signaling sequence that drives the lethal autoimmune disease of BXSB.Yaa mice.


More Than 7 Years of Hindsight: Revisiting the FDA's 2008 Guidance on Cardiovascular Outcomes Trials for Type 2 Diabetes Medications.
IN BRIEF Concerns raised about the cardiovascular safety of type 2 diabetes medications such as rosiglitazone prompted the U.S. Food and Drug Administration to issue draft guidance in 2008 that, in practice, has required large cardiovascular outcomes trials (CVOTs) for all new type 2 diabetes therapies. After more than 7 years and six completed and published trials to date, this is an opportune time to consider whether these studies, as currently designed and conducted, accurately assess the long-term benefit/risk profile of new therapies and whether they represent an optimal use of limited health care resources. This article presents and contextualizes opinions on CVOTs from 10 thought leaders in diabetes. It is intended to inform an exploration of the costs, medical ethics, and effectiveness of using large-scale CVOTs to assess the safety of new diabetes therapies.


Phylogenetic relationships among the Chromatiaceae, their taxonomic reclassification and description of the new genera Allochromatium, Halochromatium, Isochromatium, Marichromatium, Thiococcus, Thiohalocapsa and Thermochromatium.
Sequences of the 16S rDNA from all available type strains of Chromatium species have been determined and were compared to those of other Chromatiaceae, a few selected Ectothiorhodospiraceae and Escherichia coli. The clear separation of Ectothiorhodospiraceae and Chromatiaceae is confirmed. Most significantly the sequence comparison revealed a genetic divergence between Chromatium species originated from freshwater sources and those of truly marine and halophilic nature. Major phylogenetic branches of the Chromatiaceae contain (i) marine and halophilic species, (ii) freshwater Chromatium species together with Thiocystis species and (iii) species of the genera Thiocapsa and Amoebobacter as recently reclassified [Guyoneaud, R. & 6 other authors (1988). Int J Syst Bacteriol 48, 957-964], namely Thiocapsa roseopersicina, Thiocapsa pendens (formerly Amoebobacter pendens), Thiocapsa rosea (formerly Amoebobacter roseus), Amoebobacter purpureus and Thiolamprovum pedioforme (formerly Amoebobacter pedioformis). The genetic relationships between the species and groups are not in congruence with the current classification of the Chromatiaceae and a reclassification is proposed on the basis of 16S rDNA sequence similarity supported by selected phenotypic properties. The proposed changes include the transfers of Chromatium minus and Chromatium violascens to Thiocystis minor comb. nov. and Thiocystis violascens comb. nov., of Chromatium vinosum, Chromatium minutissimum and Chromatium warmingii to the new genus Allochromatium as Allochromatium vinosum comb. nov., Allochromatium minutissimum comb. nov., and Allochromatium warmingii comb. nov., of Chromatium tepidum to the new genus Thermochromatium as Thermochromatium tepidum comb. nov., of Chromatium salexigens and Chromatium glycolicum to the new genus Halochromatium as Halochromatium salexigens comb. nov. and Halochromatium glycolicum comb. nov., of Chromatium gracile and Chromatium purpuratum to the new genus as Marichromatium gracile comb. nov. and Marichromatium purpuratum comb. nov., of Thiocapsa pfennigii to Thiococcus pfennigii gen. nom. rev., of Thiocapsa halophila to the new genus Thiohalocapsa as Thiohalocapsa halophila comb. nov., and of Chromatium buderi to the new genus Isochromatium as Isochromatium buderi comb. nov.


Testing for boosting at the Paralympic games: policies, results and future directions.
'Boosting' is defined as the intentional induction of autonomic dysreflexia (AD) by athletes with a spinal cord injury (SCI) at or above the level of T6 for the purpose of improving sports performance. Boosting has been shown to confer up to a 9.7% improvement in race time. Additionally, to compete in a hazardous dysreflexic state, whether intentional or unintentional, would present an extreme health risk to the athlete. For these reasons, the International Paralympic Committee strictly bans the practice of boosting, and has developed a protocol to test for its presence. Testing was performed at three major international Paralympic events. Education regarding the dangers of AD was provided to athletes and team staff. Testing was conducted on athletes from the relevant sport classes: Athletics (wheelchair racing classes T51/T52/T53) and Handcycling (H1). Key parameters included the athlete's demographics (gender, country of origin), classification and blood pressure measurements. An extremely elevated blood pressure was considered to be a proxy maker for AD, and a systolic blood pressure of ≥180 mm Hg was considered a positive test. A total of 78 tests for the presence of AD were performed during the three games combined. No athlete tested positive. The number of athletes tested, by classification, was: 6 in Athletics T51, 47 in Athletics T52, 9 in Athletics T53 and 16 in Handcycling H1. Of those tested, the average systolic and diastolic blood pressures were 135 mm Hg (range 98-178) and 82 mm Hg (range 44-112), respectively. All athletes were compliant with testing. No athletes were withdrawn from competition due to the presence of AD. Testing for the presence of AD in paralympic athletes with SCI prior to competition has been carried out for the first time at three major international paralympic competitions. There have been no positive tests thus far. Knowledge gained during these early testing experiences will be used to guide ongoing refinement of the testing protocol and the development of further educational initiatives.


Public health interventions for addressing childhood overweight: analysis of the business case.
We investigated the appropriateness of basing childhood obesity interventions on expectations of return on investment (ROI). We show that excess weight is indeed associated with greater medical expenditures even among children and adolescents. However, under current best practices, it is unlikely that interventions will be able to meet the level of effectiveness required at a low enough implementation cost to show positive ROI. The merits of childhood obesity interventions should be based on their ability to efficiently control weight and improve health compared with alternative uses for available resources. They should not be based on the potential for short-term financial savings.


Impact of Levodopa in Lung Functions in Patients with Parkinson Disease.
Parkinson's disease (PD) is the second-most common neurodegenerative disorder known primarily by its motor symptomatology. These motor manifestations are also hypothesised to affect the respiratory muscular function of PD patients contributing to restrictive pattern of ventilatory dysfunction. Previous reports attempting to detect these abnormalities through spirometric assessments have been inconclusive. Attempts at reversal of the restrictive abnormalities by levodopa therapy too, have yielded conflicting results. This study aims to classify spirometric abnormalities in asymptomatic PD patients after levopopa withdrawal and document changes after levodopa replacement. Thirty-six non-smoker PD patients without pre-existing respiratory abnormalities were enrolled. Their standard spirometric values- FEV1, FVC and FEV1/FVC, were noted before and after their morning levodopa dose. Nineteen patients had abnormal PFT values at baseline - 14 restrictive and 5 obstructive defects. Fourteen patients showed improvement in their pulmonary performances after dopamine administration with 6 showing complete reversibility. Statistically significant improvement in the post-levodopa FVC values was seen in patients with restrictive disorder (P value=0.04) but not for obstructive disorders. This pilot study characterised that 39% of PD patients had restrictive ventilatory defects prior to morning dopamine administration. Of these, 40% showed improvement after levodopa administration. Restrictive defects are common in PD patients which are evident on routine spirometric screening. These defects are reversible on levodopa administration.


A review of the assessment and prevalence of sedentarism in older adults, its physiology/health impact and non-exercise mobility counter-measures.
This literature review focuses on aspects of sedentary behaviour (SB) in elderly. Since it has been identified as a distinct health risk, independent of physical activity, SB is a significant issue. This is particularly true for an ageing population as evidence shows that older adults (aged ≥65 years) are the most sedentary age group (on average 8.5-9.6 h daily sitting time). Accurate SB assessment is important for understanding this habitual behaviour and its impact. However, SB measurement is challenging, regardless of the method used. Although negative associations of SB in elderly have been reported for several health outcomes, evidence is inconclusive, apart from the evidence on the adverse SB effect on the all-cause mortality rate. Generally, strategies have been proposed to counteract SB, of which breaking prolonged sedentary bouts with at least light-intensity physical activity seems to be the most promising. Overall, further research in elderly is required to increase the evidence and to either support or refute the current findings. Moreover, further research will help to develop informed SB guidelines for an optimal strategy to counteract SB and its health effects in older adults.


Sex selection and non-invasive prenatal testing: A review of current practices, evidence, and ethical issues.
Non-invasive prenatal testing (NIPT) can determine the sex of the fetus very accurately and very early in gestation. There are concerns that the ease, timing, and accuracy of NIPT sex determination will facilitate sex-selective termination of pregnancy (TOP). Here, we review current practices, the evidence for a link between NIPT and sex-selective TOP, and associated ethical issues. Sex-selective TOP, usually motivated by son preference, has had serious demographic consequences in countries such as India and China. Currently, ultrasound is the primary method by which parents determine the sex of the fetus. The diffusion of ultrasound technology has had a direct impact on the rates of sex-selective TOP. Although NIPT is currently more costly, it is feasible that increased uptake of this technology could have a similar effect. Partly because NIPT is a relatively recent development in prenatal screening, there is little data on the impact of NIPT on sex selection practices. Evidence that NIPT is playing a role in sex-selective TOP remains largely anecdotal. Further research is required to assess and quantify TOP resulting from NIPT sex determination. The use of these technologies for sex selection raises a number of ethical issues, in addition to practical demographic consequences.


Study of the oligosaccharide units from mucus glycoproteins of meconium from normal infants and from cases of cystic fibrosis with meconium ileus.
1. The mucus glycoproteins in meconium from normal infants and from infants having cystic fibrosis with meconium ileus have been studied. 2. Whereas normal meconium contained about 50% protein-bound carbohydrate, the meconium from cystic fibrosis contained only about 10%. 3. Glycopolypeptides were prepared from the mucus of glycoproteins. The oligosaccharide units from this material were released and fractionated. The fractions ranged widely in size and composition. 4. The fractions from cystic fibrosis specimens had a significantly higher content of fucose than those from normal specimens.


Pleistocene Mitochondrial Genomes Suggest a Single Major Dispersal of Non-Africans and a Late Glacial Population Turnover in Europe.
How modern humans dispersed into Eurasia and Australasia, including the number of separate expansions and their timings, is highly debated [1, 2]. Two categories of models are proposed for the dispersal of non-Africans: (1) single dispersal, i.e., a single major diffusion of modern humans across Eurasia and Australasia [3-5]; and (2) multiple dispersal, i.e., additional earlier population expansions that may have contributed to the genetic diversity of some present-day humans outside of Africa [6-9]. Many variants of these models focus largely on Asia and Australasia, neglecting human dispersal into Europe, thus explaining only a subset of the entire colonization process outside of Africa [3-5, 8, 9]. The genetic diversity of the first modern humans who spread into Europe during the Late Pleistocene and the impact of subsequent climatic events on their demography are largely unknown. Here we analyze 55 complete human mitochondrial genomes (mtDNAs) of hunter-gatherers spanning ∼35,000 years of European prehistory. We unexpectedly find mtDNA lineage M in individuals prior to the Last Glacial Maximum (LGM). This lineage is absent in contemporary Europeans, although it is found at high frequency in modern Asians, Australasians, and Native Americans. Dating the most recent common ancestor of each of the modern non-African mtDNA clades reveals their single, late, and rapid dispersal less than 55,000 years ago. Demographic modeling not only indicates an LGM genetic bottleneck, but also provides surprising evidence of a major population turnover in Europe around 14,500 years ago during the Late Glacial, a period of climatic instability at the end of the Pleistocene.