Cardiovascular effects of L-glutamate and tetrodotoxin microinjected into the rostral and caudal ventrolateral medulla in normotensive and spontaneously hypertensive rats.
The purpose of this study was to compare the responsiveness of the rostral and caudal ventrolateral medulla in spontaneously hypertensive (SH) and normotensive Wistar-Kyoto (WKY) rats to microinjection of L-glutamate, and to estimate tonic output of these areas by microinjecting the neurotoxin tetrodotoxin. Rats were anesthetized with 1.25 g/kg urethane s.c., implanted with arterial (femoral) and venous (femoral) catheters, artificially ventilated and paralyzed with gallamine triethiodide (10 mg/kg). Using a ventral approach to the brainstem, the mean arterial pressure and heart rate responses to microinjection (30 nl) of L-glutamate (1, 10 and 100 mM) and tetrodotoxin (10 microM) into the rostral and caudal ventrolateral medulla were compared in SH (n = 7) and WKY (n = 7) groups. Microinjection of L-glutamate into the rostral ventrolateral medulla produced equivalent increases in mean arterial pressure (maximum +33 +/- 3 and +36 +/- 6 mm Hg, SH and WKY groups respectively) and minimal changes in heart rate. Similar administration of L-glutamate into the caudal ventrolateral medulla caused decreases in mean arterial pressure and heart rate; changes in mean arterial pressure were significantly greater in the SH group than in the WKY group (-52.3 +/- 2.9 mm Hg for SH, -22.6 +/- 2.6 mm Hg for WKY). Bilateral microinjection of tetrodotoxin into the caudal ventrolateral medulla produced significantly larger increases of mean arterial pressure in WKY rats (+8 +/- 4 vs +46 +/- 8 mm Hg for SH vs WKY). These data indicate that SH rats may have a lower tonic activity of neurons in the caudal ventrolateral medulla, resulting in a lower restraining influence on sympathetic outflow in the SH rat.


Bioengineering a Human Face Graft: The Matrix of Identity.
During the last decade, face allotransplantation has been shown to be a revolutionary reconstructive procedure for severe disfigurements. However, offer to patients remains limited due to lifelong immunosuppression. To move forward in the field, a new pathway in tissue engineering is proposed. Our previously reported technique of matrix production of a porcine auricular subunit graft has been translated to a human face model. 5 partial and 1 total face grafts were procured from human fresh cadavers. After arterial cannulation, the specimens were perfused using a combined detergent/polar solvent decellularization protocol. Preservation of vascular patency was assessed by imaging, cell and antigen removal by DNA quantification and histology. The main extracellular matrix proteins and associated cytokines were evaluated. Lip scaffolds were cultivated with dermal, muscle progenitor and endothelial cells, either on discs or in a bioreactor. Decellularization was successful in all facial grafts within 12 days revealing acellular scaffolds with full preservation of innate morphology. Imaging demonstrated a preservation of the entire vascular tree patency. Removal of cells and antigens was confirmed by reduction of DNA and antigen markers negativation. Microscopic evaluation revealed preservation of tissue structures as well as of major proteins. Seeded cells were viable and well distributed within all scaffolds. Complex acellular facial scaffolds were obtained, preserving simultaneously a cell-friendly extracellular matrix and a perfusable vascular tree. This step will enable further engineering of postmortem facial grafts, thereby offering new perspectives in composite tissue allotransplantation.


Civil society participation in the health system: the case of Brazil's Health Councils.
Brazil created Health Councils to bring together civil society groups, heath professionals, and government officials in the discussion of health policies and health system resource allocation. However, several studies have concluded that Health Councils are not very influential on healthcare policy. This study probes this issue further by providing a descriptive account of some of the challenges civil society face within Brazil's Health Councils. Forty semi-structured interviews with Health Council Members at the municipal, state and national levels were conducted in June and July of 2013 and May of 2014. The geographical location of the interviewees covered all five regions of Brazil (North, Northeast, Midwest, Southeast, South) for a total of 5 different municipal Health Councils, 8 different state Health Councils, and the national Health Council in Brasilia. Interview data was analyzed using a thematic approach. Health Councils are limited by a lack of legal authority, which limits their ability to hold the government accountable for its health service performance, and thus hinders their ability to fulfill their mandate. Equally important, their membership guidelines create a limited level of inclusivity that seems to benefit only well-organized civil society groups. There is a reported lack of support and recognition from the relevant government that negatively affects the degree to which Health Council deliberations are implemented. Other deficiencies include an insufficient amount of resources for Health Council operations, and a lack of training for Health Council members. Lastly, strong individual interests among Health Council members tend to influence how members participate in Health Council discussions. Brazil's Health Councils fall short in providing an effective forum through which civil society can actively participate in health policy and resource allocation decision-making processes. Restrictive membership guidelines, a lack of autonomy from the government, vulnerability to government manipulation, a lack of support and recognition from the government and insufficient training and operational budgets have made Health Council largely a forum for consultation. Our conclusions highlight, that among other issues, Health Councils need to have the legal authority to act independently to promote government accountability, membership guidelines need to be revised in order include members of marginalized groups, and better training of civil society representatives is required to help them make more informed decisions.


Hypoglycemic effects of turmeric (Curcuma longa L. rhizomes) on genetically diabetic KK-Ay mice.
The turmeric (Curcuma longa L. rhizomes) EtOH extract significantly suppressed an increase in blood glucose level in type 2 diabetic KK-A(y) mice. In an in vitro evaluation, the extract stimulated human adipocyte differentiation in a dose-dependent manner and showed human peroxisome proliferator-activated receptor (PPAR)-gamma ligand-binding activity in a GAL4-PPAR-gamma chimera assay. The main constituents of the extract were identified as curcumin, demethoxycurcumin, bisdemethoxycurcumin, and ar-turmerone, which had also PPAR-gamma ligand-binding activity. These results indicate that turmeric is a promising ingredient of functional food for the prevention and/or amelioration of type 2 diabetes and that curcumin, demethoxycurcumin, bisdemethoxycurcumin, and ar-turmerone mainly contribute to the effects via PPAR-gamma activation.


Impact of Adverse Childhood Events on the Psychosocial Functioning of Children Affected by Parental HIV in Rural China.
Introduction: Children affected by parental HIV are more likely than unaffected peers to experience trauma and are at-risk for negative psychological and social outcomes. This study aimed to examine the relationship between adverse childhood events and psychosocial functioning among children affected by parental HIV. Methods: A total of 790 children ages 6-17 from Henan, China were enrolled in a longitudinal, randomized controlled trial of a resilience-based psychosocial intervention. At baseline, children reported on numerous psychosocial factors, including trauma exposure, symptoms of anxiety and depression, and peer social functioning. We used linear regression analysis to test the direct effect of trauma exposure on peer social functioning. We then tested whether depression and anxiety symptoms served as two potential parallel mediators in the association between trauma exposure and peer social functioning. Results: Trauma exposure was significantly associated with poor peer social functioning (β = -0.10, p = 0.005) when controlling for key covariates. When depression and anxiety symptoms were added to the model, the association between trauma exposure and peer social functioning became nonsignificant. Instead, there were significant indirect effects from trauma exposure to peer social functioning via depression (β = -0.06, 95%CI[-0.09, -0.03]) and anxiety (β = -0.02, 95%CI[-0.04, -0.00]). Conclusion: This study is among the first to link trauma exposure to peer social functioning deficits for children affected by parental HIV and demonstrates that symptoms of anxiety and depression mediate this relationship. Findings underscore the need for comprehensive psychosocial support for children affected by HIV, including screening for trauma exposure and mental health disorders.


The Lived Experience of Sexuality Among Adults With Intellectual and Developmental Disabilities: A Scoping Review.
Sexuality is an important part of the human experience. However, little is known about the experience of sexuality from the perspective of adults with intellectual and developmental disabilities (IDD). To review evidence about the lived experience of sexuality among adults with IDD to inform future research and practice. We located articles using search terms summarized into three categories: intellectual disability, sexual activity, and feelings/opinions. Articles were indexed in the following electronic databases: CINAHL, Scopus, PubMed, and PsycINFO. Study Selection and Data Collection: Arksey and O'Malley's methodology was used to review scientific literature published between 2008 and 2018. The studies were in English, were located in peer-reviewed journals, and described the experience of sexuality from the perspective of people with IDD or observations of expressed sexuality. Seventeen articles met inclusion criteria. Four main themes emerged: intimate relationships, oppressed sexual activity, knowledge, and identity. Findings indicate that sexuality is a part of the lives of many adults with IDD, regardless of their engagement in sexual activity. Barriers to expression of sexuality exist for people with IDD. Some of these barriers are internal, although many are external. The results provide support for addressing sexuality among adults with IDD. What This Article Adds: This review provides evidence to support occupational therapy practitioners in including sexuality as a part of their holistic view of clients and as an area for advocacy.


Latent rheumatic, thyroid and phospholipid autoimmunity in hospitalized patients with COVID-19.
Autoimmune responses mediated by autoantibodies have been observed in SARS-CoV-2 infection. Herein, we evaluate the presence of rheumatic, thyroid and phospholipid autoantibodies in sera samples from 120 adult hospitalized patients with COVID-19 in comparison to pre-pandemic samples from 100 healthy individuals. In addition, to estimate the frequency of these autoantibodies in COVID-19, a meta-analysis of selected articles was conducted. Hospitalized patients with COVID-19 had latent autoimmunity characterized by a high frequency of anti-thyroid peroxidase antibodies, rheumatoid factor (RF), anti-cyclic citrullinated peptide third generation antibodies, antinuclear antibodies (ANAs), IgM anti-β2-glycoprotein I (β2GP1) and IgM anti-cardiolipin antibodies. The meta-analysis confirmed our results, with RF and ANAs being the most common autoantibodies. In addition, cluster analysis revealed that those patients with high frequency of RF, IgM anti-β2GP1 antibodies and ANAs had a longer hospital stay, required more vasopressors during hospitalization, and were more likely to develop critical disease. These data suggest that latent autoimmunity influences the severity of COVID-19, and support further post-COVID studies in order to evaluate the development of overt autoimmunity.


Preoperative Laboratory Investigations: Rates and Variability Prior to Low-risk Surgical Procedures.
Increasing attention has been focused on low-value healthcare services. Through Choosing Wisely campaigns, routine laboratory testing before low-risk surgery has been discouraged in the absence of clinical indications. The authors investigated rates, determinants, and institutional variation in laboratory testing before low-risk procedures. Patients who underwent ophthalmologic surgeries or predefined low-risk surgeries in Ontario, Canada, between April 1, 2008, and March 31, 2013, were identified from population-based administrative databases. Preoperative blood work was defined as a complete blood count, prothrombin time, partial thromboplastin, or basic metabolic panel within 60 days before an index procedure. Adjusted associations between patient and institutional factors and preoperative testing were assessed with hierarchical multivariable logistic regression. Institutional variation was characterized using the median odds ratio. The cohort included 906,902 patients who underwent 1,330,466 procedures (57.1% ophthalmologic and 42.9% low-risk surgery) at 119 institutions. Preoperative blood work preceded 400,058 (30.1%) procedures. The unadjusted institutional rate of preoperative blood work varied widely (0.0 to 98.1%). In regression modeling, significant predictors of preoperative testing included atrial fibrillation (adjusted odds ratio [AOR], 2.58; 95% CI, 2.51 to 2.66), preoperative medical consultation (AOR, 1.68; 95% CI, 1.65 to 1.71), previous mitral valve replacement (AOR, 2.33; 95% CI, 2.10 to 2.58), and liver disease (AOR, 1.69; 95% CI, 1.55 to 1.84). The median odds ratio for interinstitutional variation was 2.43. Results of this study suggest that testing is associated with a range of clinical covariates. However, an association was similarly identified with preoperative consultation, and significant variation between institutions exists across the jurisdiction.


Characterization of NDM-5-positive extensively resistant Escherichia coli isolates from dairy cows.
The aim of this study was to investigate the prevalence of blaNDM-5 gene in Escherichia coli isolates from dairy cows and to characterize the molecular traits of the blaNDM-5-positive isolates. A total of 169 cows were sampled (169 feces and 169 raw milk samples) in three dairy farms in Jiangsu Province and 203 E. coli isolates were recovered. Among these strains, three isolates carried blaNDM-5 gene, including one co-harboring mcr-1, which belonged to sequence type 446 and the other two belonged to ST2. Susceptibility testing revealed that the three blaNDM-5-positive isolates showed extensive resistance to antimicrobials. The blaNDM-5 gene was located on a ∼46-kb IncX3 transferrable pNDM-MGR194-like plasmid in all three isolates, while mcr-1 was located on a ∼260-kb IncHI2 plasmid pXGE1mcr. Competition experiments revealed that acquisition of blaNDM-5 or mcr-1-bearing plasmid can incur fitness cost of bacterial host, however, plasmid stability testing showed that both blaNDM-5 and mcr-1-carrying plasmid maintained stable in the hosts after ten passages without antimicrobial selection. Whole genome sequencing revealed that the mcr-1 gene coexisted with multiple resistance genes in pXGE1mcr and the backbone of this plasmid was similar to that of previously reported mcr-1-positive plasmid pHNSHP45-2. Moreover, pXGE1mcr could be conjugated into clinical NDM-5-positive E. coli isolates in vitro, thereby generating strains that approached pan-resistance. Active surveillance efforts are imperative to monitor the prevalence of blaNDM-5 and mcr-1 in carbapenem-resistant Enterobacteriaceae from dairy farms throughout China.


Indoor and Outdoor Air Pollution- related Health Problem in Ethiopia: Review of Related Literature.
The health effects of air pollution are generally global problems, but they have, since recently become issues of particular concern for developing countries. This review assessed the situation of air pollution and related health effects in the context of Ethiopia. The materials reviewed in this publication are published scientific papers from online search engines, unpublished government reports and academic theses/dissertations. In addition, interview data obtained from authorities and experts involved in the management of air quality were analyzed, interpreted and reported in the article. Review of the few studies conducted in Ethiopia showed that average concentrations of PM2.5 reached as high as 280 µg/m3 for 24-hour measurements (range: 2,417-12,739 µg/m3). Indoor carbon monoxide (CO) levels were universally higher than regulatory limits for the United States and were found to be much higher among households using traditional stoves and solid biomass fuels. The use of traditional stoves and solid biomass fuels was reported in >95% of the households considered. High average levels of NO2 (97 ppb) were reported in a large longitudinal study. The ambient PM10 level was below the WHO guideline values in the majority of the samples. About 50% of the on-road CO samples taken from traffic roads in Addis Ababa were found to be less than the guideline values while the number of motor vehicles in Ethiopia is reported to be increasing by more than 9% per annum. There is a very limited air quality monitoring capacity in the country. The co-ordination between stakeholders in this regard is also inadequate. The limited evidence available on health effects of air pollution indicates that the prevalence of acute respiratory illness among children living in households using crude biomass fuels is significantly higher than the national average figures. The limited evidence reviewed and reported in this article indicates high levels of indoor air pollution and trends of worsening outdoor air pollution. This tentative conclusion carries with it the urgent need for more evidence-based research and capacity building in the areas of indoor and outdoor air pollution.


Origin of stem cells in organogenesis.
The development of individual organs in animal embryos involves the formation of tissue-specific stem cells that sustain cell renewal of their own tissue for the lifetime of the organism. Although details of their origin are not always known, tissue-specific stem cells usually share the expression of key transcription factors with cells of the embryonic rudiment from which they arise, and are probably in a similar developmental state. On the other hand, the isolation of pluripotent stem cells from the postnatal organism has encouraged the formulation of models of embryonic and postnatal development that are at variance with the conventional ones. Possible explanations for the existence of such cells, and the issue of whether they also exist in vivo, are discussed.


Effect of Alcohol Consumption on Recovery From Eccentric Exercise Induced Muscle Damage in Females.
This study was designed to investigate the effects of alcohol consumption on recovery of muscle force when consumed immediately postexercise in young females. Eight young women completed 300 maximal eccentric actions of the quadriceps femoris muscle on an isokinetic dynamometer on two occasions in a randomized, cross-over design after which an alcoholic beverage (0.88g ethanol/kg body weight) or an iso-caloric placebo was consumed. Maximal isokinetic (concentric and eccentric) torque and isometric tension produced across the knee were measured in both the exercised and control leg predamage, 36 hr post, and 60 hr post damage. Venous blood creatine kinase (CK) activity and muscle soreness ratings were taken before damage and once per day to 60 hr post damage. Significant differences were observed between the exercised and control leg for maximal concentric, and eccentric torque and isometric tension (p < .05). A near significant Treatment × Time interaction was observed for isometric tension (p = .077), but not for concentric or eccentric torque. No main effects of treatment (alcohol) or interactions with Time × Leg or Leg × Treatment were observed. Perceived muscle soreness during box stepping and squatting showed significant time effects (p < .05), and CK activity did not significantly change. Our results indicate that the consumption of 0.88g ethanol/kg body weight following eccentric exercise-induced muscle damage does not affect recovery in the days following damage in females.


Activation of Wnt/β-catenin signaling is involved in hair growth-promoting effect of 655-nm red light and LED in in vitro culture model.
Activation of the Wnt/β-catenin signaling pathway plays an important role in hair follicle morphogenesis and hair growth. Recently, low-level laser therapy (LLLT) was evaluated for stimulating hair growth in numerous clinical studies, in which 655-nm red light was found to be most effective and practical for stimulating hair growth. We evaluated whether 655-nm red light + light-emitting diode (LED) could promote human hair growth by activating Wnt/β-catenin signaling. An in vitro culture of human hair follicles (HFs) was irradiated with different intensities of 655-nm red light + LED, 21 h7 (an inhibitor of β-catenin), or both. Immunofluorescence staining was performed to assess the expression of β-catenin, GSK3β, p-GSK3β, and Lef1 in the Wnt/β-catenin signaling. The 655-nm red light + LED not only enhanced hair shaft elongation, but also reduced catagen transition in human hair follicle organ culture, with the greatest effectiveness observed at 5 min (0.839 J/cm2). Additionally, 655-nm red light + LED enhanced the expression of β-catenin, p-GSK3β, and Lef1, signaling molecules of the Wnt/β-catenin pathway, in the hair matrix. Activation of Wnt/β-catenin signaling is involved in hair growth-promoting effect of 655-nm red light and LED in vitro and therefore may serve as an alternative therapeutic option for alopecia.


Hybridoma antibody-based competitive ELISA in Schistosoma japonicum infection.
A competitive enzyme-linked immunosorbent assay (ELISA) has been developed and compared with the circumoval precipitin test (COPT) for diagnosis of schistosomiasis japonica using Philippine sera. The assay is based on the inhibition, by sera, of the binding of a penicillinase-conjugated hybridoma-derived antibody, I. 134, to a crude Schistosoma japonicum adult worm extract. A change in pH subsequent to addition of the substrate is used as the indicator system. Development of the color change in this assay is relatively slow, a fact which presumably facilitates detection of inhibition by serum. Relative to the COPT, no false positive reactions were obtained and the false negative rate was less than 10%. A wide range of inhibitory titers was obtained using sera in the competitive ELISA similar to that found in a competitive radioimmunoassay using 125I-labeled I. 134. The competitive ELISA will be of more general application for diagnosis of schistosomiasis japonica than the competitive RIA using hybridoma antibodies, and will provide more precise quantitative information than is obtainable in the COPT.


Development and validation of a gene expression oligo microarray for the gilthead sea bream (Sparus aurata).
Aquaculture represents the most sustainable alternative of seafood supply to substitute for the declining marine fisheries, but severe production bottlenecks remain to be solved. The application of genomic technologies offers much promise to rapidly increase our knowledge on biological processes in farmed species and overcome such bottlenecks. Here we present an integrated platform for mRNA expression profiling in the gilthead sea bream (Sparus aurata), a marine teleost of great importance for aquaculture. A public data base was constructed, consisting of 19,734 unique clusters (3,563 contigs and 16,171 singletons). Functional annotation was obtained for 8,021 clusters. Over 4,000 sequences were also associated with a GO entry. Two 60mer probes were designed for each gene and in-situ synthesized on glass slides using Agilent SurePrint technology. Platform reproducibility and accuracy were assessed on two early stages of sea bream development (one-day and four days old larvae). Correlation between technical replicates was always > 0.99, with strong positive correlation between paired probes. A two class SAM test identified 1,050 differentially expressed genes between the two developmental stages. Functional analysis suggested that down-regulated transcripts (407) in older larvae are mostly essential/housekeeping genes, whereas tissue-specific genes are up-regulated in parallel with the formation of key organs (eye, digestive system). Cross-validation of microarray data was carried out using quantitative qRT-PCR on 11 target genes, selected to reflect the whole range of fold-change and both up-regulated and down-regulated genes. A statistically significant positive correlation was obtained comparing expression levels for each target gene across all biological replicates. Good concordance between qRT-PCR and microarray data was observed between 2- and 7-fold change, while fold-change compression in the microarray was present for differences greater than 10-fold in the qRT-PCR. A highly reliable oligo-microarray platform was developed and validated for the gilthead sea bream despite the presently limited knowledge of the species transcriptome. Because of the flexible design this array will be able to accommodate additional probes as soon as novel unique transcripts are available.


Bacterial community composition associated with chironomid egg masses.
Chironomids (Diptera: Chironomidae) are the most widely distributed and often the most abundant insect in freshwater. They undergo a complete metamorphosis of four life stages, of which the egg, larva, and pupae are aquatic and the adult is terrestrial. Chironomid egg masses were found to be natural reservoirs of Vibrio cholerae and Aeromonas species. To expand the knowledge of the endogenous bacterial community associated with chironomid egg masses, denaturing gradient gel electrophoresis and clone analysis of 16S rRNA gene libraries were used in this study. Bacterial community composition associated with chironomid egg masses was found to be stable among different sampling periods. Cloned libraries of egg masses revealed that about 40% of the clones were related to bacteria known to degrade various toxicants. These findings were further supported when bacterial species that showed resistance to different toxic metals were isolated from egg masses and larval samples. Chironomids are found under a wide range of water conditions and are able to survive pollutants. However, little is known about their protective mechanisms under these conditions. Chironomid egg masses are inhabited by a stable endogenous bacterial community, which may potentially play a role in protecting chironomids from toxicants in polluted environments. Further study is needed to support this hypothesis.


First selection, then influence: Developmental differences in friendship dynamics regarding academic achievement.
This study concerns peer selection and influence dynamics in early adolescents' friendships regarding academic achievement. Using longitudinal social network analysis (RSiena), both selection and influence processes were investigated for students' average grades and their cluster-specific grades (i.e., language, exact, and social cluster). Data were derived from the SNARE (Social Network Analysis of Risk behavior in Early adolescence) study, using 6 waves (N = 601; Mage = 12.66, 48.9% boys at first wave). Results showed developmental differences between the first and second year of secondary school (seventh and eighth grade). Whereas selection processes were found in the first year on students' cluster-specific grades, influence processes were found in the second year, on both students' average and cluster-specific grades. These results suggest that students initially tend to select friends on the basis of similar cluster-based grades (first year), showing that similarity in achievement is attractive for friendships. Especially for low-achieving students, similar-achieving students were highly attractive as friends, whereas they were mostly avoided by high-achieving students. Influence processes on academic achievement take place later on (second year), when students know each other better, indicating that students' grades become more similar over time in response to their connectedness. Concluding, this study shows the importance of developmental differences and specific school subjects for understanding peer selection and influence processes in adolescents' academic achievement. (PsycINFO Database Record


Molecular cloning and characterization of novel glutamate-gated chloride channel subunits from Schistosoma mansoni.
Cys-loop ligand-gated ion channels (LGICs) mediate fast ionotropic neurotransmission. They are proven drug targets in nematodes and arthropods, but are poorly characterized in flatworms. In this study, we characterized the anion-selective, non-acetylcholine-gated Cys-loop LGICs from Schistosoma mansoni. Full-length cDNAs were obtained for SmGluCl-1 (Smp_096480), SmGluCl-2 (Smp_015630) and SmGluCl-3 (Smp_104890). A partial cDNA was retrieved for SmGluCl-4 (Smp_099500/Smp_176730). Phylogenetic analyses suggest that SmGluCl-1, SmGluCl-2, SmGluCl-3 and SmGluCl-4 belong to a novel clade of flatworm glutamate-gated chloride channels (GluCl) that includes putative genes from trematodes and cestodes. The flatworm GluCl clade was distinct from the nematode-arthropod and mollusc GluCl clades, and from all GABA receptors. We found no evidence of GABA receptors in S. mansoni. SmGluCl-1, SmGluCl-2 and SmGluCl-3 subunits were characterized by two-electrode voltage clamp (TEVC) in Xenopus oocytes, and shown to encode Cl⁻-permeable channels gated by glutamate. SmGluCl-2 and SmGluCl-3 produced functional homomers, while SmGluCl-1 formed heteromers with SmGluCl-2. Concentration-response relationships revealed that the sensitivity of SmGluCl receptors to L-glutamate is among the highest reported for GluCl receptors, with EC₅₀ values of 7-26 µM. Chloride selectivity was confirmed by current-voltage (I/V) relationships. SmGluCl receptors are insensitive to 1 µM ivermectin (IVM), indicating that they do not belong to the highly IVM-sensitive GluClα subtype group. SmGluCl receptors are also insensitive to 10 µM meclonazepam, a schistosomicidal benzodiazepine. These results provide the first molecular evidence showing the contribution of GluCl receptors to L-glutamate signaling in S. mansoni, an unprecedented finding in parasitic flatworms. Further work is needed to elucidate the roles of GluCl receptors in schistosomes and to explore their potential as drug targets.


Vesicles and vesicle fusion: coarse-grained simulations.
Biological cells are highly dynamic, and continually move material around their own volume and between their interior and exterior. Much of this transport encapsulates the material inside phospholipid vesicles that shuttle to and from, fusing with, and budding from, other membranes. A feature of vesicles that is crucial for this transport is their ability to fuse to target membranes and release their contents to the distal side. In industry, some personal care products contain vesicles to help transport reagents across the skin, and research on drug formulation shows that packaging active compounds inside vesicles delays their clearance from the blood stream. In this chapter, we survey the biological role and physicochemical properties of phospholipids, and describe progress in coarse-grained simulations of vesicles and vesicle fusion. Because coarse-grained simulations retain only those molecular details that are thought to influence the large-scale processes of interest, they act as a model embodying our current understanding. Comparing the predictions of these models with experiments reveals the importance of the retained microscopic details and also the deficiencies that can suggest missing details, thereby furthering our understanding of the complex dynamic world of vesicles.


Addressing the social determinants of health: a case study from the Mitanin (community health worker) programme in India.
The Mitanin Programme, a government community health worker (CHW) programme, was started in Chhattisgarh State of India in 2002. The CHWs (Mitanins) have consistently adopted roles that go beyond health programme-specific interventions to embrace community mobilization and action on local priorities. The aim of this research was to document how and why the Mitanins have been able to act on the social determinants of health, describing the catalysts and processes involved and the enabling programmatic and organizational factors. A qualitative comparative case study of successful action by Mitanin was conducted in two 'blocks', purposefully selected as positive exemplars in two districts of Chhattisgarh. One case focused on malnutrition and the other on gender-based violence. Data collection involved 17 in-depth interviews and 10 group interviews with the full range of stakeholders in both blocks, including community members and programme team. Thematic analysis was done using a broad conceptual framework that was further refined. Action on social determinants involved raising awareness on rights, mobilizing women's collectives, revitalizing local political structures and social action targeting both the community and government service providers. Through these processes, the Mitanins developed identities as agents of change and advocates for the community, both with respect to local cultural and gender norms and in ensuring accountability of service providers. The factors underpinning successful action on social determinants were identified as the significance of the original intent and vision of the programme, and how this was carried through into all aspects of programme design, the role of the Mitanins and their identification with village women, ongoing training and support, and the relative autonomy of the programme. Although the results are not narrowly generalizable and do not necessarily represent the situation of the Mitanin Programme as a whole, the explanatory framework may provide general lessons for programmes in similar contexts.


Outcomes of placing dental implants in patients taking oral bisphosphonates: a review of 115 cases.
In recent years, numerous cases of bisphosphonate-associated osteonecrosis of the jaw have been reported involving both intravenous and oral therapy regimens. The majority of these cases have involved intravenous bisphosphonates. Subsequently, drug manufacturers and the US Food and Drug Administration issued warnings about possible bisphosphonate-associated osteonecrosis of the jaw. The American Dental Association and the American Association of Oral and Maxillofacial Surgeons assembled expert panels to formulate treatment guidelines. Both panels differentiated between patients receiving bisphosphonates intravenously and those receiving the drugs orally. However, the recommendations were based on limited data, especially with regard to patients taking oral bisphosphonates. We wanted to ascertain the extent to which bisphosphonate-associated necrosis of the jaw has occurred in our dental implant patients. We also wanted to determine whether there was any indication that the bisphosphonate therapy affected the overall success of the implants as defined by Albrektsson and Zarb. We identified 1,319 female patients over the age of 40 who had received dental implants at Montefiore Medical Center between January 1998 and December 2006. A survey about bisphosphonate therapy was mailed to all 1,319 patients. Responses were received from 458 patients of whom 115 reported that they had taken oral bisphosphonates. None had received intravenous bisphosphonates. All 115 patients were contacted and informed about the risk of bisphosphonate-associated osteonecrosis of the jaw. Seventy-two patients returned to the clinic for follow-up clinical and radiological evaluation. A total of 468 implants were placed in the 115 patients who reported that they had received oral bisphosphonate therapy. There is no evidence of bisphosphonate-associated osteonecrosis of the jaw in any of the patients evaluated in the clinic and those contacted by phone or e-mail reported no symptoms. Of the 468 implants, all but 2 integrated fully and meet criteria for establishing implant success. Implant success rates were comparable for patients receiving oral bisphosphonate therapy and those not receiving oral bisphosphonate therapy. Guidelines for treatment of dental patients receiving intravenous bisphosphonate treatments should be different than for patients taking the oral formulations of these medications. In this study, oral bisphosphonate therapy did not appear to significantly affect implant success. Implant surgery on patients receiving bisphosphonate therapy did not result in bisphosphonate-associated osteonecrosis of the jaw. Nevertheless, sufficient evidence exists to suggest that all patients undergoing implant placement should be questioned about bisphosphonate therapy including the drug taken, the dosage, and length of treatment prior to surgery. For patients having a history of oral bisphosphonate treatment exceeding 3 years and those having concomitant treatment with prednisone, additional testing and alternate treatment options should be considered.


Review of models used in economic analyses of new oral treatments for type 2 diabetes mellitus.
Economic models are considered to be important, as they help evaluate the long-term impact of diabetes treatment. To date, it appears that no article has reviewed and critically appraised the cost-effectiveness models developed to evaluate new oral treatments [glucagon-like peptide-1 (GLP-1) receptor agonists and dipeptidyl peptidase-4 (DPP-4) inhibitors] for type 2 diabetes mellitus (T2DM). This study aimed to provide insight into the utilization of cost-effectiveness modelling methods. The focus of our study was aimed at the applicability of these models, particularly around the major assumptions related to the clinical parameters (glycated haemoglobin [A1c], systolic blood pressure [SBP], lipids and weight) used in the models, and subsequent clinical outcomes. MEDLINE and EMBASE were searched from 1 January 2004 to 14 February 2013 in order to identify published cost-effectiveness evaluations for the treatment of T2DM by new oral treatments (GLP-1 receptor agonists and DPP-4 inhibitors). Once identified, the articles were reviewed and grouped together according to the type of model. The following data were captured for each study: comparators; country; evaluation and key cost drivers; time horizon; perspective; discounting rates; currency/year; cost-effectiveness threshold, sensitivity analysis; and cost-effectiveness analysis curves. A total of 15 studies were identified in our review. Nearly all of the models utilized a health care payer perspective and provided a lifetime horizon. The CORE Diabetes Model, UK Prospective Diabetes Study (UKPDS) Outcomes Model, Cardiff Diabetes Model, Centers for Disease Control and Prevention (CDC) Diabetes Cost-Effectiveness Group Model and Diabetes Mellitus Model were cited. With the exception of two studies, all of the studies made significant assumptions surrounding the impact of GLP-1 receptor agonists or DPP-4 inhibitors on clinical parameters and subsequent short- and long-term outcomes. Moreover, often the differences in the clinical parameters were relatively small (e.g. 1 or 2 mmHg in blood pressure) and would not be considered by many as clinically important. Yet, the impact of these small clinical changes often resulted in large lifetime changes in health outcomes in the models. In particular, many studies assumed that changes in weight associated with the therapies would equate to improved outcomes, despite limited evidence for this assumption. Although the new oral treatments were regarded as cost effective in most studies based upon the studies reviewed, the validity of these projections, particularly for the longer time frames, is questionable. Indeed, although most of these studies have been conducted in the last 5 years, recent trial evidence has already questioned the validity of most of these studies. It is clear that a number of changes are required in the evaluation of diabetes therapies. First and foremost, the basic models need to be updated to include contemporary important clinical trial data assessing hard clinical outcomes in patients with diabetes. Second, there should be less emphasis on 40-year or lifetime costs and consequences of the therapies and a greater focus on short-term (5-year) and intermediate-term (10-year) outcomes. Practice is continually evolving, and the probability that these models would provide any valid predictions beyond 10 years is remote. Third, all modellers should immediately remove the basic assumption that small clinically inconsequential changes in A1c, SBP, lipids and weight result in major clinical improvements in patients. Future models should aim to include all relevant treatment outcomes, whether these relate to effects on underlying diabetes and its complications or to short- or long-term side effects of treatment. We need to explore why cost-saving interventions could benefit further from adding patient characteristics, which may be able to better predict the use of lower-cost alternatives. Moreover, the vast array of different clinical, cost and utility data used in the different models reviewed makes it apparent that a uniform methodology should be developed for diabetes economic models. In this manner, future models could be run using the same data, which would allow for more acceptable comparability between studies.


Converting Plasmonic Light Scattering to Confined Light Absorption and Creating Plexcitons by Coupling a Gold Nano-pyramid Array onto a Silica-Gold Film.
This report presents a facile microfabrication-compatible approach to fabricate a large area of plasmonic nano-pyramid array-based antennas and demonstrates effective light management by tailoring the architecture. First, a long-range ordered gold nano-pyramid array is fabricated, which exhibits strong light scattering. The maximum electric field enhancement (|E|/|E 0 |) of 271 is achieved at the corner but decays rapidly away from the pyramid bottom. After the gold nanopyramid array is coupled to a gold film, strong light scattering is converted into strong light absorption due to the excitation of a spectrally tunable plasmonic gap mode, where an intense electric field enhancement of 233 and a strong magnetic field enhancement (|H|/|H 0 |) of 25 are simultaneously excited for a 10 nm silica gap. The electric field decays much slower away from the pyramid bottom while the magnetic field keeps almost constant. In addition, both experiments and finite-difference time-domain (FDTD) simulation have confirmed that strong plasmon-exciton coupling between the plasmonic gap mode and the J-aggregates can take place when the quantum emitters such as J-aggregates are embedded in the gap, creating plexcitons. This can overcome the problems of high energy loss and weak nonlinearity, which are typically associated with surface plasmon polariton (SPP) supported on plasmonic metallic nanostructures. The coherent plasmon-exciton coupling (plexciton) generated by the film-coupled nano-pyramid nanostructure is expected to find promising applications in light-emitting devices, photodetectors, photovoltaics and photoelectrochemical cells.


N-acetyl Cysteine Administration Is Associated With Increased Cerebral Glucose Metabolism in Patients With Multiple Sclerosis: An Exploratory Study.
Background: Multiple Sclerosis (MS) is an autoimmune disease marked by progressive neurocognitive injury. Treatment options affording neuroprotective effects remain largely experimental. The purpose of this proof of concept study was to explore the effects of N-acetyl-cysteine (NAC) on cerebral glucose metabolism (CMRGlu) and symptoms in patients with multiple sclerosis (MS). Methods: Twenty-four patients with MS were randomized to either NAC plus standard of care, or standard of care only (waitlist control). The experimental group received NAC intravenously once per week and orally the other 6 days. Patients in both groups were evaluated at baseline and after 2 months (of receiving the NAC or waitlist control period) with an integrated Position Emission Tomography (PET)/ Magnetic Resonance Imaging (MRI) scanner, using 18F Fluorodeoxyglucose (FDG) to measure cerebral glucose metabolism. Following imaging evaluation at 2 months, subjects initially attributed to the standard of care arm were eligible for treatment with NAC. Clinical and symptom questionnaires were also completed initially and after 2 months. Results: The FDG PET data showed significantly increased cerebral glucose metabolism in several brain regions including the caudate, inferior frontal gyrus, lateral temporal gyrus, and middle temporal gyrus (p < 0.05) in the MS group treated with NAC, as compared to the control group. Self-reported scores related to cognition and attention were also significantly improved in the NAC group as compared to the control group. Conclusions: The results of this study suggest that NAC positively affects cerebral glucose metabolism in MS patients, which is associated with qualitative, patient reported improvements in cognition and attention. Larger scale studies may help to determine the clinical impact of NAC on measures of functioning over the course of illness, as well as the most effective dosage and dosage regimen.


Embryonic timing, axial stem cells, chromatin dynamics, and the Hox clock.
Collinear regulation of Hox genes in space and time has been an outstanding question ever since the initial work of Ed Lewis in 1978. Here we discuss recent advances in our understanding of this phenomenon in relation to novel concepts associated with large-scale regulation and chromatin structure during the development of both axial and limb patterns. We further discuss how this sequential transcriptional activation marks embryonic stem cell-like axial progenitors in mammals and, consequently, how a temporal genetic system is further translated into spatial coordinates via the fate of these progenitors. In this context, we argue the benefit and necessity of implementing this unique mechanism as well as the difficulty in evolving an alternative strategy to deliver this critical positional information.


Using features of a Creole language to reconstruct population history and cultural evolution: tracing the English origins of Sranan.
Creole languages are formed in conditions where speakers from distinct languages are brought together without a shared first language, typically under the domination of speakers from one of the languages and particularly in the context of the transatlantic slave trade and European colonialism. One such Creole in Suriname, Sranan, developed around the mid-seventeenth century, primarily out of contact between varieties of English from England, spoken by the dominant group, and multiple West African languages. The vast majority of the basic words in Sranan come from the language of the dominant group, English. Here, we compare linguistic features of modern-day Sranan with those of English as spoken in 313 localities across England. By way of testing proposed hypotheses for the origin of English words in Sranan, we find that 80% of the studied features of Sranan can be explained by similarity to regional dialect features at two distinct input locations within England, a cluster of locations near the port of Bristol and another cluster near Essex in eastern England. Our new hypothesis is supported by the geographical distribution of specific regional dialect features, such as post-vocalic rhoticity and word-initial 'h', and by phylogenetic analysis of these features, which shows evidence favouring input from at least two English dialects in the formation of Sranan. In addition to explicating the dialect features most prominent in the linguistic evolution of Sranan, our historical analyses also provide supporting evidence for two distinct hypotheses about the likely geographical origins of the English speakers whose language was an input to Sranan. The emergence as a likely input to Sranan of the speech forms of a cluster near Bristol is consistent with historical records, indicating that most of the indentured servants going to the Americas between 1654 and 1666 were from Bristol and nearby counties, and that of the cluster near Essex is consistent with documents showing that many of the governors and important planters came from the southeast of England (including London) (Smith 1987 The Genesis of the Creole Languages of Surinam; Smith 2009 In The handbook of pidgin and creole studies, pp. 98-129).This article is part of the theme issue 'Bridging cultural gaps: interdisciplinary studies in human cultural evolution'.


2006 AAHA canine vaccine guidelines.
In 2005, AAHA's Canine Vaccine Task Force met to reexamine and revise guidelines on the use of vaccines in dogs. The results of the Task Force's work are summarized and tabulated in this article and are published in their entirety on the AAHA website (www.aahanet.org). The 2006 AAHA Canine Vaccine Guidelines contain information on new technological developments in vaccines, an introduction to conditionally licensed vaccines, and detailed recommendations on the use of available vaccines. Perhaps the most noteworthy addition to the guidelines is a separate set of recommendations created for shelter facilities. Vaccines are classified as core (universally recommended), noncore (optional), or not recommended. The Task Force recognizes that vaccination decisions must always be made on an individual basis, based on risk and lifestyle factors.


Critical assessment of quantum mechanics based energy restraints in protein crystal structure refinement.
A critical evaluation of the performance of X-ray refinement protocols using various energy functions is presented using the bovine pancreatic trypsin inhibitor (BPTI) protein. The four potential energy functions we explored include: (1) fully quantum mechanical calculations; (2) one based on an incomplete molecular mechanics (MM) energy function employed in the Crystallography and NMR System (CNS) with empirical parameters developed by Engh and Huber (EH), which lacks electrostatic and attractive van der Waals terms; (3) one based on a complete MM energy function (AMBER ff99 parameter set); and (4) the same as 3, with the addition of a Generalized Born (GB) implicit solvation term. The R, R (free), real space R values of the refined structures and deviations from the original experimental structure were used to assess the relative performance. It was found that at 1 Angstrom resolution the physically based energy functions 1, 3, and 4 performed better than energy function 2, which we attribute to the better representation of key interactions, particularly electrostatics. The observed departures from the experimental structure were similar for the refinements with physically based energy functions and were smaller than the structure refined with EH. A test refinement was also performed with the reflections truncated at a high-resolution cutoff of 2.5 Angstrom and with random perturbations introduced into the initial coordinates, which showed that low-resolution refinements with physically based energy functions held the structure closer to the experimental structure solved at 1 Angstrom resolution than the EH-based refinements.


Intracellular signalling: the language of the chloroplast.
Chloroplasts emit signals that modulate nuclear gene expression, thereby ensuring the proper assembly of the photosynthetic apparatus. Recent studies have provided major new insights into one of these signalling mechanisms, and identified the chlorophyll precursor Mg-protoporphyrin IX as a key signalling molecule.


Survey of furan in foods and coffees from five European Union countries.
Canned and jarred baby foods (74), canned and jarred adult foods (63) and 70 coffees sold in Belgium, Italy, Portugal, Spain and The Netherlands were analysed for their furan content using a validated automated headspace GC-MS procedure. Seven balsamic vinegars from Italy and Spain were also analysed. All 74 baby food samples contained detectable furan, with an average level of 37 ng/g. A total of 54 of 63 canned and jarred foods contained detectable furan with an average level of 24 ng/g. Levels of furan in coffee as consumed were very variable and reflected different preparation methods and coffee strengths. Over 50% of Italian samples contained more than 200 ng/g, whereas over 20% of Belgian coffees contained less than 21 ng/g furan. Some brews made from fine grained coffee contained much more furan than did brews made from normal or coarse grained coffee. Although furan was low in most instant coffees, two Italian products "instant espresso" and "instant mocha" contained about 150 ng/g furan. Balsamic vinegars from Spain contained 159-662 ng/g of furan; however, other samples from Spain and Italy contained only 6-25 ng/g.


Pop-up COVID-19 vaccination clinics for vulnerable groups in the Midlands.
Roma, travellers and the homeless suffer from a higher risk of both COVID-19 infection and severe disease relative to the general population. The purpose of this project was to ensure as many members as possible from vulnerable groups in the Midlands availed of COVID-19 vaccines. Following on from successful testing of vulnerable populations in the Midlands of Ireland in March/April 2021, a collaboration of HSE Midland's Department of Public Health, Safetynet Primary Care and the HSE Midlands Traveller Health Unit (MTHU) operated pop-up vaccination clinics in June/July 2021, targeting the same populations. Clinics delivered the first dose of the Pfizer/BioNTech COVID-19 vaccine, registering clients for second doses in Community Vaccination Centres (CVCs). Thirteen clinics were hosted between 8 June 2021 and 20 July 2021, resulting in 890 first-dose Pfizer vaccinations delivered to vulnerable populations. Trust established months prior with our grassroots testing service resulted in strong vaccine uptake, with the quality service provided seeding further demand over time. This service integrated into the national system and allowed individuals to receive their second doses within the community.


Sequential cerebral blood flow changes in short-term cerebral ischemia in gerbils.
Using quantitative autoradiography, we studied sequential changes in regional cerebral blood flow during and after 2 minutes of bilateral common carotid artery occlusions in 18 gerbils. Occlusion (n = 4) led to severe ischemia in the forebrain (regional cerebral blood flow less than 5% of control [n = 4]) and midbrain (regional cerebral blood flow less than 10% of control), but was morphologically nonlethal. Reperfusion of the brain was complete, and regional cerebral blood flow was not different from control 1 minute after ischemia (n = 4), but hypoperfusion (regional cerebral blood flow 30-50% of control) occurred at 5 minutes (n = 3) and was pronounced at 1 hour (n = 4); at this stage blood flow was inhomogeneous. Hypoperfusion had disappeared at 4 hours (n = 3). Our results indicate that the well-documented sequence of cerebral blood flow changes (i.e., ischemia, initial recovery of blood flow, and delayed hypoperfusion) takes place even after nonlethal cerebral ischemia.


[Role of Treg/Th17 balance in the pathogenesis of cytomegalovirus infection].
To investigate the role of Treg/Th17 balance in the immune-regulated mechanism of cytomegalovirus (CMV) infection. According to the diagnostic criteria of the CMV infection, the patients with CMV infection were divided into the activate infection group and the latent infection group, and the normal children were recruited as control group. The percents of Treg and Th17 in peripheral blood were detected by flow cytometry to calculate Treg/Th17 ratio. ELISA and RT-PCR were performed to determine the levels of the related factors of Treg (IL-10, Foxp3) and Th17 (TGF-β, IL-17, IL-6, IL-23, ROR-γt), respectively. Compared with the control group, the proportion of Treg in peripheral blood was reduced, Th17 increased, so Treg/Th17 ratio went down after CMV infection (P<0.05). By comparison between two groups of CMV infection, Treg/Th17 ratio and Treg related factors of the activate infection group decreased significantly (P<0.05), but Th17 related factors were up-regulated significantly (P<0.05). Treg/Th17 balance takes part in the immune-regulated mechanism of CMV infection, and may be related to virus latent-active state.


Organization, distribution, and stability of endogenous ecotropic murine leukemia virus DNA sequences in chromosomes of Mus musculus.
The endogenous ecotropic murine leukemia virus DNA content and integration sites were characterized for 54 inbred strains and substrains of mice by restriction enzyme digestion, Southern blotting, and hybridization with an ecotropic murine leukemia virus DNA-specific probe. More than 75% of these strains carried endogenous ecotropic proviruses which were located in at least 29 distinct integration sites in chromosomes of Mus musculus. Fourteen of these proviruses have been assigned specific locus designations. Most, but not all, of the endogenous ecotropic proviruses were structurally indistinguishable by this analysis from the prototype AKR ecotropic virus, and the distribution of these proviruses followed known relationships among the inbred strains and substrains of mice. These results suggest that, in general, viral DNA integration preceded the establishment of inbred mouse strains and that these integrations are relatively stable.


RirA, an iron-responsive regulator in the symbiotic bacterium Rhizobium leguminosarum.
Mutations in a Rhizobium leguminosarum gene, rirA (rhizobial iron regulator), caused high-level, constitutive expression of at least eight operons whose transcription is normally Fe-responsive and whose products are involved in the synthesis or uptake of siderophores, or in the uptake of haem or of other iron sources. Close homologues of RirA exist in other rhizobia and in the pathogen Brucella; many other bacteria have deduced proteins with more limited sequence similarity. None of these homologues had been implicated in Fe-mediated gene regulation. Transcription of rirA itself is about twofold higher in cells grown in Fe-replete than in Fe-deficient growth media. Mutations in rirA reduced growth rates in Fe-replete and -depleted medium, but did not appear to affect symbiotic N(2) fixation.


The morphological basis for binocular and ON/OFF convergence in tree shrew striate cortex.
We used retrograde and anterograde transport methods and single-cell reconstructions to examine the projection from layer IV to supragranular layers in the tree shrew's striate cortex. We found that neurons in the ON and OFF subdivisions of layer IV (IVa and IVb, respectively) have overlapping terminal fields throughout layers II and III. Despite their overlap, these projections are organized in a highly stratified, mirror-symmetric fashion that respects the vertical position of neurons within each sublayer. Neurons in the middle of layer IV (lower IVa and upper IVb) project to layers IIIa/b, II, and I; neurons located at the edges of layer IV (upper IVa and lower IVb) project to the lower half of layer IIIc; and neurons in the middle of IVa and the middle of IVb project to upper IIIc. The stratified nature of the projections from layer IV to layer III is reminiscent of the pattern of ipsilateral and contralateral eye inputs to layer IV. Inputs from the ipsilateral eye are limited to the edges of layer IV (upper IVa and lower IVb), while those from the contralateral eye terminate throughout the depth of IVa and IVb. Thus, cells near the edges of layer IV should receive strong input from both eyes, while those in the middle of layer IV should receive mostly contralateral input. Taken together, these results suggest that the projections from layer IV to layer III bring together the information conveyed by the ON and OFF pathways, but do so in a way that matches the ocular dominance characteristics for each pathway.


Severe Hemorrhagic Shock Leads to a Delayed Fracture Healing and Decreased Bone Callus Strength in a Mouse Model.
Multiple trauma is frequently associated with hemorrhagic shock and fractures of the extremities. Clinically, the rate of impaired fracture healing (delayed healing and nonunion) seems to be increased in patients with multiple injuries compared with patients with isolated fractures. As the underlying pathogenesis remains poorly understood, we aimed to analyze the biomechanical properties during fracture healing in a murine model. The aim of this study was to determine whether fracture healing after severe hemorrhagic shock results in (1) delayed bridging as determined by macroscopic and radiographic assessment, (2) altered conditions of callus components as determined by µCT, and (3) decreased maximum bending moment measured by a three-point-bending test compared with ordinary fracture healing. Male C57BL/6NCrl mice were randomly assigned to five groups and four different times (five to 10 mice per group and time). Only the right femur from each mouse was used for analysis: the trauma hemorrhage (TH) group received a pressure-controlled hemorrhagic shock via catheter; the osteotomy (Fx) group underwent osteotomy and implantation of an external fixator on the right femur; the combined trauma (THFx) group received hemorrhagic shock and an external fixator with osteotomy; the sham group underwent implantation of a catheter and external fixator but had no blood loss or osteotomy, and the control group underwent no interventions. After 2, 3, 4, or 6 weeks, five to 10 animals of each group were sacrificed. Bones were analyzed macroscopically and via radiographs, µCT, and three-point-bending test. Statistical significance was set at a probability less than 0.05. Comparisons were performed using the Mann-Whitney U or the Kruskal-Wallis test. In the Fx group, the osteotomy gap was stable and bridged after 2 weeks in contrast to some bones in the THFx group where stable bridging did not occur. No difference was observed between the groups. µCT analysis showed reduced density of bone including callus (THFx: 1.17 g/cm3; interquartile range [IQR], 0.04 g/cm3; Fx: 1.22 g/cm3; IQR, 0.04 g/cm3; p = 0.002; difference of medians [DM], -0.048; 95% CI, -0.073 to -0.029) and increased share of callus per volume of bone mass (%) after 2 weeks in the THFx group compared with the Fx group (THFx: 44.16%; IQR, 8.66%; Fx: 36.73%; IQR, 4.39%; p = 0.015; DM, 7.634; 95% CI, 2.018-10.577). The three-point-bending test established a decreased maximum bending moment in the THFx group compared with the Fx group 2 weeks after surgery (THFx: 7.10 Nmm; IQR, 11.25 Nmm; Fx: 11.25 Nmm; IQR, 5.70 Nmm; p = 0.026; DM, -5.043; 95% CI, -10.867 to -0.74). No differences were observed between the THFx and Fx groups after more than 2 weeks. In this in vivo mouse fracture model, we conclude that hemorrhagic shock retards fracture healing during the early phase of the facture healing process. A severe hemorrhagic shock in patients could result in initial delayed fracture healing and needs special attention. We plan to conduct a prospective, observational clinical research study to analyze if delayed fracture healing occurs in patients after severe blood loss.


Two-photon holography in a 3D photopolymer host-guest matrix.
We demonstrate for the first time two-photon induced holographic recording at an arbitrary point in three dimensional photopolymeric cube by overlapping two coherent pulses from a 200 femtosecond Ti: Sapphire tunable laser operating at 710 nm. Spatial overlap is achieved by a novel pupil division method. The polymer material is made of epoxy host, which is fully polymerized and filled with liquid photopolymerisable formulation comprising acrylate type monomer and two-photon photoinitiator. Measured diffraction efficiency is measured to be 3.5%.


A systematic review of low-level light therapy for treatment of diabetic foot ulcer.
Diabetes mellitus (DM) is a significant international health concern affecting more than 387 million individuals. A diabetic person has a 25% lifetime risk of developing a diabetic foot ulcer (DFU), leading to limb amputation in up to one in six DFU patients. Low-level light therapy (LLLT) uses low-power lasers or light-emitting diodes to alter cellular function and molecular pathways, and may be a promising treatment for DFU. The goal of this systematic review is to examine whether the clinical use of LLLT is effective in the healing of DFU at 12 and 20 weeks in comparison with the standard of care, and to provide evidence-based recommendation and future clinical guidelines for the treatment of DFU using LLLT. On September 30, 2015, we searched PubMed, EMBASE, CINAHL, and Web of Science databases using the following terms: "diabetic foot" AND "low level light therapy," OR "light emitting diode," OR "phototherapy," OR "laser." The relevant articles that met the following criteria were selected for inclusion: randomized control trials (RCTs) that investigated the use of LLLT for treatment of DFU. Four RCTs involving 131 participants were suitable for inclusion based upon our criteria. The clinical trials used sham irriadiation, low dose, or nontherapeutic LLLT as placebo or control in comparison to LLLT. The endpoints included ulcer size and time to complete healing with follow-up ranging from 2 to 16 weeks. Each article was assigned a level of evidence (LOE) and graded according to the Oxford Center for Evidence-based Medicine Levels of Evidence Grades of Recommendation criteria. Limitations of reviewed RCTs include a small sample size (N < 100), unclear allocation concealment, lack of screening phase to exclude rapid healers, unclear inclusion/exclusion criteria, short (<30 days) follow-up period, and unclear treatment settings (wavelength and treatment time). However, all reviewed RCTs demonstrated therapeutic outcomes with no adverse events using LLLT for treatment of DFU. This systematic review reports that LLLT has significant potential to become a portable, minimally invasive, easy-to-use, and cost effective modality for treatment of DFU. To enthusiastically recommend LLLT for treatment of DFU, additional studies with comparable laser parameters, screening period to exclude rapid healers, larger sample sizes and longer follow-up periods are required. We envision future stringent RCTs may validate LLLT for treatment of DFU. Systematic review registration number: PROSPERO CRD42015029825.


Risk factors, treatment, and outcomes associated with nonunion of the midshaft humerus fracture.
Charts of 28 patients with a diagnosis of delayed union or nonunion were reviewed. There were four delayed unions and 25 nonunions. Comorbidities, risk factors, treatments, and outcomes were evaluated. Comorbidities were common and included cardiovascular, pulmonary, and renal compromise, as well as endocrinopathies and rheumatologic disease. Consensus risk factors included: unstable fractures (comminuted or short oblique, 83% (24/29); advanced age, 57% (16/28); obesity, 35% (9/28); daily tobacco use, 38% (10/28); and multiple long bone fractures, 21% (6/29). Sixty-nine percent (20/29) of the fractures united; 21% (6/29) failed to heal. Healing outcome for 11% (3/29) could not be determined because of death or loss to follow-up. Patients presenting for primary treatment with any of the aforementioned risk factors should be cautioned regarding possible nonunion.


Overall Structures of Mycobacterium tuberculosis DNA Gyrase Reveal the Role of a Corynebacteriales GyrB-Specific Insert in ATPase Activity.
Despite sharing common features, previous studies have shown that gyrases from different species have been modified throughout evolution to modulate their properties. Here, we report two crystal structures of Mycobacterium tuberculosis DNA gyrase, an apo and AMPPNP-bound form at 2.6-Å and 3.3-Å resolution, respectively. These structures provide high-resolution structural data on the quaternary organization and interdomain connections of a gyrase (full-length GyrB-GyrA57)2 thus providing crucial inputs on this essential drug target. Together with small-angle X-ray scattering studies, they revealed an "extremely open" N-gate state, which persists even in the DNA-free gyrase-AMPPNP complex and an unexpected connection between the ATPase and cleavage core domains mediated by two Corynebacteriales-specific motifs, respectively the C-loop and DEEE-loop. We show that the C-loop participates in the stabilization of this open conformation, explaining why this gyrase has a lower ATPase activity. Our results image a conformational state which might be targeted for drug discovery.


Treatment of urinary schistosomiasis: methodological issues and research needs identified through a Cochrane systematic review.
Guidelines recommend praziquantel (PZQ) for the treatment and control of schistosomiasis, with no real alternative. Metrifonate was still widely used against Schistosoma haematobium in the 1990s, and then withdrawn. Experimental studies and clinical trials suggest that artemisinin compounds are active against S. haematobium. In a Cochrane systematic review assessing the efficacy and safety of drugs for treating urinary schistosomiasis, 24 randomized controlled trials (n=6315 individuals) met our inclusion criteria. These trials compared a variety of single agent and combination regimens with PZQ, metrifonate or artemisinin derivatives. The review confirmed that both the standard recommended doses of PZQ (single 40 mg/kg oral dose) and metrifonate (3x7.5-10 mg/kg oral doses administered fortnightly) are efficacious and safe in treating urinary schistosomiasis, but there is no study comparing these two regimens head-to-head. There is currently not enough evidence to evaluate artemisinin compounds. Most of the studies included in the Cochrane systematic review were insufficiently powered, lacked standardization in assessing and reporting outcomes, and had a number of methodological limitations. In this paper we discuss the implications of these findings with respect to public health and research methodology and propose priority research needs.


Benefit of adjuvant radiation therapy for localized prostate cancer with a positive surgical margin.
Positive surgical margins are common after radical prostatectomy, and the role of adjuvant therapy in such cases is controversial. We determined the benefit of postoperative external beam radiation therapy in patients with margin positive prostate cancer with respect to biochemical progression or cancer recurrence. To decrease confounding factors that may affect the likelihood of biochemical progression our study was limited to men with organ confined cancer and a single positive margin. We retrospectively evaluated the records of a nested matched cohort of 76 patients with pathological stage T2N0 prostate cancer and a single positive margin who underwent adjuvant radiation therapy within 3 months of radical prostatectomy. There was a positive margin at the prostatic apex in 35 cases, prostatic base in 18, posterior prostate in 11, urethra in 7, and prostatic apex and urethra in 5. These patients were matched 1:1 with 76 controls who did not receive adjuvant radiation therapy. Neither group received androgen deprivation therapy. Patients and controls were matched exactly for the margin positive site, age at surgery, preoperative serum prostate specific antigen, Gleason score and DNA ploidy. Biochemical relapse was defined as posttreatment PSA greater than 0.2 ng./ml. Overall there was significant estimated improvement plus or minus standard error in 5-year clinical and biochemical progression-free survival in 88%+/-5% versus 59%+/-11% of patients treated with adjuvant radiation therapy versus no radiation therapy (p = 0.005). No patient who received radiation therapy had local or distant recurrence, while 16% of controls had recurrence (p = 0.015). When stratified by site of margin positivity, the 5-year estimated clinical and biochemical progression-free rate in 18 cases and controls with a positive base margin was 95%+/-15% and 65%+/-13%, respectively (p = 0.02). The rate in 35 cases and cases with a positive apex margin was 95%+/-5% and 64%+/-15%, respectively (p = 0.07). Limited sample size precluded analysis of the other sites. Patients with localized prostate cancer and a singe positive surgical margin appear to have a lower rate of biochemical relapse at 5 years when adjuvant radiation therapy is administered. Definitive evidence of the beneficial effect of adjuvant radiation therapy for patients with involved surgical margins awaits conclusion of randomized clinical trials.


Self-insertion of an odd urethral foreign body that led to Fournier's gangrene.
Self-inserted urethral foreign bodies (FBs) are rare. Neither reported case was the self-inflicted FB due to a lack of financial resources nor was either case complicated by Fournier's gangrene. We present a 54-year-old male who inserted a household pipe to relieve his urine retention. Unfortunately, the FB became stuck inside, perforated the urethra, and required perineal exploration. After it was removed, the urethra was closed over a 16F urethral catheter. The wound was complicated by severe infection and resulting Fournier's gangrene. This required an additional surgery for debridement and urine diversion. Retrospectively, it would have been better if the urethra had been left open with SP tube only. We are sharing a clinical lesson learned by the practicing urologist and surgeons. Conclusively, self-inserted FBs in the urethra may lead to a series of complications. Patients with limited financial resources need more attention and care because they may hurt themselves unintentionally.


Revisiting oxo-centered carbonyl-triruthenium clusters: investigating CO photorelease and some spectroscopic and electrochemical correlations.
We synthesized and characterized a series of oxo-centered carbonyl-triruthenium complexes with the general formula [Ru3O(CH3COO)6(L)2(CO)], where L = 2,6-dimethylpyrazine (dmpz) (1), isonicotinamide (adpy) (2), 4-acetylpyridine (acpy) (3), 3-methylpyridine (3-pic) (4), 4-methylpyridine (4-pic) (5), 4-tert-butylpyridine (4-tbpy) (6), 4-(dimethyl)aminopyridine (dmap) (7), or 4-aminopyridine (ampy) (8); we also investigated the photoreactivity of these complexes. Single-crystal X-ray diffraction helped to elucidate the structures of 1·H2O, 7·C2H4Cl2, and 8. The unit cell of 8 is composed of four cluster units; the hydrogen bonds between the amino groups of the terminal ligand of a neighboring molecule and the oxygen atoms of CO or acetate bridging ligands hold these cluster units together. The spectroscopic (NMR, UV-visible, and IR) and the electrochemical properties (cyclic voltammetry) of these complexes correlated with the ancillary ligands in terms of their σ-donating and π-accepting characteristics. The molecular orbital and the electronic localized description of the [Ru3O]-CO unit helped to rationalize the correlations. The photoreactivity of compounds 1-8 was investigated by laser excitation at 377 nm. Given the CO photorelease quantum yields, σ-donor ligands and aqueous medium (more polar) stabilized the charge-transfer excited state that culminated in CO photosubstitution, leading to higher Φ values.


Picosecond light scattering measurements of cataract microstructure.
A picosecond range-gated light scattering technique is used to measure the microstructure of cataracts in the living eye, with a resolution of the order of the wavelength of light. The cataract is illuminated with ultrashort pulses of light derived from a mode-locked Nd:glass laser. The pulses backscattered by the opacity are collected at several angles simultaneously by an array of fiber-optic light guides whose outputs are sequentially sampled by a multichannel picosecond Kerr shutter. This shutter transmits only that light which is scattered from the desired depth in the eye, while blocking from the detector any light scattered by foreground or background tissue and reducing multiple scattering effects. The size distribution of scatterers in the cataract is deduced from the angular distribution of scattering intensities by application of Mie theory. The results of experiments with suspensions of latex microspheres and with rabbit cataracts in vivo are presented. Cataract microstructure down to 0.5 microm has been measured in a rabbit eye and verified with electron microscopy.


Implications of new early Homo fossils from Ileret, east of Lake Turkana, Kenya.
Sites in eastern Africa have shed light on the emergence and early evolution of the genus Homo. The best known early hominin species, H. habilis and H. erectus, have often been interpreted as time-successive segments of a single anagenetic evolutionary lineage. The case for this was strengthened by the discovery of small early Pleistocene hominin crania from Dmanisi in Georgia that apparently provide evidence of morphological continuity between the two taxa. Here we describe two new cranial fossils from the Koobi Fora Formation, east of Lake Turkana in Kenya, that have bearing on the relationship between species of early Homo. A partial maxilla assigned to H. habilis reliably demonstrates that this species survived until later than previously recognized, making an anagenetic relationship with H. erectus unlikely. The discovery of a particularly small calvaria of H. erectus indicates that this taxon overlapped in size with H. habilis, and may have shown marked sexual dimorphism. The new fossils confirm the distinctiveness of H. habilis and H. erectus, independently of overall cranial size, and suggest that these two early taxa were living broadly sympatrically in the same lake basin for almost half a million years.


Ultrasound imaging velocimetry with interleaved images for improved pulsatile arterial flow measurements: a new correction method, experimental and in vivo validation.
Blood velocity measurements are important in physiological science and clinical diagnosis. Doppler ultrasound is the most commonly used method but can only measure one velocity component. Ultrasound imaging velocimetry (UIV) is a promising technique capable of measuring two velocity components; however, there is a limit on the maximum velocity that can be measured with conventional hardware which results from the way images are acquired by sweeping the ultrasound beam across the field of view. Interleaved UIV is an extension of UIV in which two image frames are acquired concurrently, allowing the effective interframe separation time to be reduced and therefore increasing the maximum velocity that can be measured. The sweeping of the ultrasound beam across the image results in a systematic error which must be corrected: in this work, we derived and implemented a new velocity correction method which accounts for acceleration of the scatterers. We then, for the first time, assessed the performance of interleaved UIV for measuring pulsatile arterial velocities by measuring flows in phantoms and in vivo and comparing the results with spectral Doppler ultrasound and transit-time flow probe data. The velocity and flow rate in the phantom agreed within 5-10% of peak velocity, and 2-9% of peak flow, respectively, and in vivo the velocity difference was 9% of peak velocity. The maximum velocity measured was 1.8 m s-1, the highest velocity reported with UIV. This will allow flows in diseased arteries to be investigated and so has the potential to increase diagnostic accuracy and enable new vascular research.


The two "rules of speciation" in species with young sex chromosomes.
The two "rules of speciation," Haldane's rule (HR) and the large-X effect (LXE), are thought to be caused by recessive species incompatibilities exposed in the phenotype due to the hemizygosity of X-linked genes in the heterogametic sex. Thus, the reports of HR and the LXE in species with recently evolved non- or partially degenerate Y-chromosomes, such as Silene latifolia and its relatives, were surprising. Here, I argue that rapid species-specific degeneration of Y-linked genes and associated adjustment of expression of X-linked gametologs (dosage compensation) may lead to rapid evolution of sex-linked species incompatibilities. This process is likely to be too slow in species with old degenerate Y-chromosomes (e.g., in mammals), but Y-degeneration in species with young gene-rich sex chromosomes may be fast enough to play a significant role in speciation. To illustrate this point, I report the analysis of Y-degeneration and the associated evolution of gene expression on the X-chromosome of S. latifolia and Silene dioica, a close relative that shares the same recently evolved sex chromosomes. Despite the recent (≤1MY) divergence of the two species, ~7% of Y-linked genes have undergone degeneration in one but not the other species. This species-specific degeneration appears to drive faster expression divergence of X-linked genes, which may account for HR and the LXE reported for these species. Furthermore, I suggest that "exposure" of autosomal or sex-linked recessive species incompatibilities in the haploid plant gametophyte may mimic the presence of HR in plants. Both haploid expression and species-specific Y-degeneration need to receive more attention if we are to understand the role of these processes in speciation.


The effect of overlaying titanium mesh with collagen membrane for ridge preservation.
The aim of this study was to determine the effect of overlaying titanium mesh (TM) with an adjunctive collagen membrane (CM) for preserving the buccal bone when used in association with immediate implant placement in dogs. Immediate implant placements were performed in the mesial sockets of the third premolars of five dogs. At one site the TM was attached to the fixture with the aid of its own stabilizers and then covered by a CM (CM group), while the contralateral site received only TM (TM group). Biopsy specimens were retrieved for histologic and histomorphometric analyses after 16 weeks. All samples exhibited pronounced buccal bone resorption, and a high rate of TM exposure was noted (in three and four cases of the five samples in each of the TM and CM groups, respectively). A dense fibrous tissue with little vascularity or cellularity had infiltrated through the pores of the TM irrespective of the presence of a CM. The distances between the fixture platform and the first bone-implant contact and the bone crest did not differ significantly between the TM and CM groups. Our study suggests that the additional use of a CM over TM does not offer added benefit for mucosal healing and buccal bone preservation.


Vocational rehabilitation for enhancing return-to-work in workers with traumatic upper limb injuries.
Traumatic upper limb injury is a leading cause of work-related disability. After return-to-work (RTW), many survivors of injuries are able to regain a quality of life (QoL) comparable with the normal population. Since RTW plays an important role in economic productivity and regaining health-related QoL, enhancing RTW in workers with traumatic limb injuries is the primary goal of rehabilitation. Vocational rehabilitation has been adapted in the field of occupational safety and health to enhance the number of injured people returning to the labour market, prevent illness, increase well-being, and reduce disability. To assess the effects of vocational rehabilitation programs in enhancing RTW of workers with traumatic upper limb injuries. We searched OSH UPDATE databases (CISDOC, HSELINE, International Bibliographic, NIOSHTIC, NIOSHTIC-2, RILOSH) (up to 10 December 2012), the Cochrane Central Register of Controlled Trials (CENTRAL) (2012, Issue 11), MEDLINE through PubMed (up to 15 November 2012), EMBASE (up to 28 November 2012), CINAHL (up to 5 May 2013), PsycINFO (up to 7 December 2012), and handsearched the reference lists of relevant review articles. We aimed to include all randomised controlled trials (RCTs) comparing vocational rehabilitation with an alternative (control) intervention such as standard rehabilitation, an incomplete form of the vocational rehabilitation intervention (such as with limited advice on RTW, referral information, or liaison with employer), or waiting-list controls. Two authors independently inspected abstracts and we obtained full papers when necessary. When the two authors disagreed about the inclusion of a study, we resolved disagreements by discussion. A third author arbitrated when necessary. Our search identified 332 citations. Based on assessments of their titles and abstracts, we decided to evaluate the full texts of 15 citations. In the end, none of these 15 citations met our inclusion criteria. There is currently no high-level evidence to support or refute the efficacy of vocational rehabilitation in enhancing RTW in workers with traumatic upper limb injuries. Since vocational rehabilitation has frequently been provided to injured people in occupational settings with the aim of decreasing work disability, enhancing RTW, increasing productivity, and containing the welfare cost, further high-quality RCTs assessing the efficacy of vocational rehabilitation for workers with traumatic upper limb injury are needed to fill this gap in knowledge.


M2-factor of coherent and partially coherent dark hollow beams propagating in turbulent atmosphere.
Analytical formula is derived for the M(2)-factor of coherent and partially coherent dark hollow beams (DHB) in turbulent atmosphere based on the extended Huygens-Fresnel integral and the second-order moments of the Wigner distribution function. Our numerical results show that the M(2)- factor of a DHB in turbulent atmosphere increases on propagation, which is much different from its invariant properties in free-space, and is mainly determined by the parameters of the beam and the atmosphere. The relative M(2)-factor of a DHB increases slower than that of Gaussian and flat-topped beams on propagation, which means a DHB is less affected by the atmospheric turbulence than Gaussian and flat-topped beams. Furthermore, the relative M(2)-factor of a DHB with lower coherence, longer wavelength and larger dark size is less affected by the atmospheric turbulence. Our results will be useful in long-distance free-space optical communications.


IkappaB kinase alpha-mediated derepression of SMRT potentiates acetylation of RelA/p65 by p300.
Over the last several years, significant progress has been made in identifying chromatin-regulated events that govern NF-kappaB transcription. Using either laminin attachment or tumor necrosis factor alpha as a physiological stimulus of NF-kappaB activation, we demonstrate that IkappaB kinase alpha (IKKalpha) is recruited to chromatin in distinct phases. In the initial phase, IKKalpha is responsible for derepressing the silencing mediator for retinoic acid and thyroid hormone receptor (SMRT)-histone deacetylase 3 (HDAC3) corepressor complex from the p50 homodimer. However, in the latter phase, chromatin-bound IKKalpha coordinates the simultaneous phosphorylation of RelA/p65(S536) and SMRT(S2410) as detected by chromatin immunoprecipitation (ChIP) assays. Although phosphorylated SMRT remains bound to the active p50-RelA/p65 heterodimer of NF-kappaB, derepression of SMRT is evidenced by the loss of chromatin-associated HDAC3 activity. ChIP and re-ChIP analysis demonstrates that phosphorylation of RelA/p65(S536) and SMRT(S2410) occurs prior to acetylation of RelA/p65 at K310. Moreover, IKKalpha-induced phosphorylation of RelA/p65(S536) displaces corepressor activity, allowing p300-mediated acetylation of RelA/p65. Introduction of nonphosphorylatable mutants of RelA/p65 and SMRT proteins or the inhibition of IKK activity results in active repression of NF-kappaB promoters by tethering the SMRT-HDAC3 complex. Similar to phosphorylation within the Rel homology domain of RelA/p65, which governs an exchange of HDAC1 for CBP/p300 acetyltransferases, we demonstrate that phosphorylation within the transactivation domain of RelA/p65(S536) displaces SMRT-HDAC3 repressor activity, allowing p300 to acetylate RelA/p65.


Sensitization to the behavioral effect of kainic acid in the mouse is mediated by nitric oxide.
Kainic acid (KA)-sensitive receptors are located on primary afferent C-fibers. Behavioral sensitization to each of four repeated injections of KA appears to involve activation of primary afferent C-fibers based on its susceptibility to capsaicin pretreatment. Hyperalgesia, thought to involve transmission along C-fibers, is sensitive to pharmacologic manipulation of nitric oxide (NO). We tested the hypothesis that KA activates C-fibers, either directly or indirectly, by a mechanism that involves NO. Pretreatment with N omega-nitro-L-arginine methyl ester (L-NAME), an inhibitor of NO synthesis, inhibited KA sensitization whereas D-NAME, the inactive isomer, failed to mimic this action. D-Arginine also inhibited sensitization to KA, whereas L-arginine, a NO precursor, was inactive when administered alone but reversed the inhibitory effect of L-NAME. Methylene blue, which inhibits guanylyl cyclase and NO synthase, attenuated KA sensitization, suggesting that cyclic GMP synthesis may also be involved in this phenomenon. Reduced hemoglobin, which sequesters NO in the extracellular space, attenuated KA sensitization, indicating that the effect of NO is brought about in structures adjacent to cells in which it is synthesized. This convergence of data is consistent with the mediation of behavioral sensitization to KA by NO. KA sensitization has been shown to involve an action of the NH2 terminus of substance P (SP) and NO may thus mobilize SP. Consistent with this, in the presence of SP(1-7), methylene blue was no longer able to inhibit sensitization to KA, suggesting that NO evokes, rather than results from, mobilization of SP.(ABSTRACT TRUNCATED AT 250 WORDS)


Peptidic termini play a significant role in TCR recognition.
TCR recognition of class I MHC is dependent on the composition of the antigenic peptide and the MHC. Single amino acid substitutions in either the MHC or the peptide may dramatically alter recognition. While the major interactions between TCR and the peptide/MHC complex appear to be focused on the complementarity-determining region (CDR)3, it is also clear from the cocrystal structure of class I MHC and TCR that the amino and carboxyl ends of the peptide may play a role through interactions with the CDR1. In this work we show that gp33 variants substituted at the peptidic termini at the putative CDR1 contact regions show improved recognition in B6 mice. The rank order of recognition is different using the P14 transgenic T cells, suggesting that one reason for improved recognition is a change in the TCR repertoire that recognizes the peptide. However, the affinity of the TCR by some of the peptide/MHC complex with increased recognition is improved, as shown by increased tetramer binding to P14 T cells. These substitutions at the termini of the peptide-binding cleft cause localized conformational changes as seen by changes in mAb binding and crystallographic structures. The different peptide structures also show different conformations in the center of the peptide, but these are shown to be energetically similar and thus most likely have no significance with respect to TCR recognition. Therefore, small conformational changes, localized to the CDR1 contact regions, may play a significant role in TCR recognition.


An ALE meta-analytic review of top-down and bottom-up processing of music in the brain.
A remarkable feature of the human brain is its ability to integrate information from the environment with internally generated content. The integration of top-down and bottom-up processes during complex multi-modal human activities, however, is yet to be fully understood. Music provides an excellent model for understanding this since music listening leads to the urge to move, and music making entails both playing and listening at the same time (i.e., audio-motor coupling). Here, we conducted activation likelihood estimation (ALE) meta-analyses of 130 neuroimaging studies of music perception, production and imagery, with 2660 foci, 139 experiments, and 2516 participants. We found that music perception and production rely on auditory cortices and sensorimotor cortices, while music imagery recruits distinct parietal regions. This indicates that the brain requires different structures to process similar information which is made available either by an interaction with the environment (i.e., bottom-up) or by internally generated content (i.e., top-down).


Hydroxytyrosol in the Prevention of the Metabolic Syndrome and Related Disorders.
Virgin olive oil (VOO) constitutes the main source of fat in the Mediterranean diet. VOO is rich in oleic acid, displaying health-promoting properties, but also contains minor bioactive components, especially phenolic compounds. Hydroxytyrosol (HT), the main polyphenol of olive oil, has been reported to be the most bioactive component. This review aims to compile the results of clinical, animal and cell culture studies evaluating the effects of HT on the features of Metabolic Syndrome (MetS) (body weight/adiposity, dyslipidemia, hypertension, and hyperglycemia/insulin resistance) and associated complications (oxidative stress and inflammation). HT was able to improve the lipid profile, glycaemia, and insulin sensitivity, and counteract oxidative and inflammatory processes. Experimental studies identified multiple molecular targets for HT conferring its beneficial effect on health in spite of its low bioavailability. However, rodent experiments and clinical trials with pure HT at biologically relevant concentrations are still lacking. Moreover, the roles of intestine and its gut microbiota have not been elucidated.


Suspected scaphoid injuries managed by MRI direct from the emergency department : a single-centre prospective cohort study.
To determine the role of early MRI in the management of suspected scaphoid fractures. A total of 337 consecutive patients presenting to an emergency department (ED) following wrist trauma over a 12-month period were prospectively included in this service evaluation project. MRI was not required in 62 patients with clear diagnoses, and 17 patients were not managed as per pathway, leaving a total of 258 patients with normal scaphoid series radiographs who were then referred directly from ED for an acute wrist MRI scan. Patient demographics, clinical details, outcomes, and complications were recorded at a minimum of a year following injury. The median time from injury to ED presentation was one day and the median number of positive clinical signs was two out of three (snuffbox tenderness, tubercle tenderness, pain on telescoping). Of 258 patients referred for acute MRI, 208 scans were performed as 50 patients either did not tolerate (five patients) or did not attend their scan (45 patients). MRI scans demonstrated scaphoid fracture (13%), fracture of another bone (22%), scaphoid contusion (6%), other contusion/ligamentous injury (20%), or solely degenerative pathology (10%). Only 29% of scans showed no abnormality. Almost 50% of those undergoing MRI (100 patients) were discharged by ED with advice, with only one re-presentation. Of the 27 undisplaced occult scaphoid fractures, despite prompt cast immobilization, two experienced delayed union which was successfully treated with surgery. The use of MRI direct from ED enables prompt diagnosis and the early discharge of a large proportion of patients with normal radiographs following wrist trauma. Cite this article: Bone Jt Open 2021;2(6):447-453.


Fatty acid profile, tocopherol, squalene and phytosterol content of brazil, pecan, pine, pistachio and cashew nuts.
Nuts contain bioactive constituents that elicit cardio-protective effects including phytosterols, tocopherols and squalene. The objective of the present study was to determine the total oil content, peroxide value, fatty acid composition and levels of tocopherols, squalene and phytosterols in oil extracted from freshly ground brazil, pecan, pine, pistachio and cashew nuts. The total oil content of the nuts ranged from 40.4 to 60.8% (w/w) while the peroxide values ranged from 0.14 to 0.22 mEq O2/kg oil. The most abundant monounsaturated fatty acid was oleic acid (C18:1), while linoleic acid (C18:2) was the most prevalent polyunsaturated fatty acid. The levels of total tocopherols ranged from 60.8 to 291.0 mg/g. Squalene ranged from 39.5 mg/g oil in the pine nut to 1377.8 mg/g oil in the brazil nut. beta-Sitosterol was the most prevalent phytosterol, ranging in concentration from 1325.4 to 4685.9 mg/g oil. In conclusion, the present data indicate that nuts are a good dietary source of unsaturated fatty acids, tocopherols, squalene and phytosterols.