Adenoviral vectors targeted to CD40 enhance the efficacy of dendritic cell-based vaccination against human papillomavirus 16-induced tumor cells in a murine model.
Dendritic cells (DCs) represent a unique junction from which to initiate antigen-specific immunity. One of the most challenging obstacles for DC-based immunotherapy has been the means by which to convey tumor antigen-encoding genes to DCs. In this study, we show that adenoviral (or adenovirus, Ad) vectors targeted to CD40 by means of bispecific antibodies can enhance gene transfer to murine DCs. Moreover, we illustrate that this vector initiates phenotypic changes characteristic of DC maturation. To explore the in vivo potential of this strategy, we coupled this targeting approach with an Ad vector carrying the gene for a tumor antigen. In particular, the human papillomavirus (HPV) E7 antigen represents an attractive target for antigen-specific immunity of cervical cancer. Relative to DCs infected by untargeted Ad, DCs infected by AdE7 targeted to the receptor CD40 enhanced protection against HPV-16-induced tumor cells in a murine model. We have further established that this protection was both antigen specific and CD8+ T-cell dependent. Illustrating that Ad-modified DCs may be used in repeated vaccination, we report that preimmunization of animals with Ad infected DCs prior to E7 vaccination only moderately reduced vaccine efficacy. Finally, we have observed that CD40-targeted AdE7 can initiate partial therapeutic immunity in mice bearing established tumors. These findings suggest that gene-based vaccination of DCs with tumor antigens can elicit productive antitumoral immunity and that enhancements in gene transfer efficacy and/or DC maturation may facilitate this process.


The cyclic AMP receptor protein modulates quorum sensing, motility and multiple genes that affect intestinal colonization in Vibrio cholerae.
Vibrio cholerae is the causative agent of cholera, which continues to be a major public health concern in Asia, Africa and Latin America. The bacterium can persist outside the human host and alternates between planktonic and biofilm community lifestyles. Transition between the different lifestyles is mediated by multiple signal transduction pathways including quorum sensing. Expression of the Zn-metalloprotease haemagglutinin (HA)/protease is subject to a dual regulation which involves the quorum-sensing regulator HapR and the cAMP receptor protein. In a previous study, we observed that a mutant defective in the cAMP-receptor protein (CRP) expressed lower levels of HapR. To further investigate the role of CRP in modulating HapR and other signal transduction pathways, we performed global gene expression profiling of a Deltacrp mutant of El Tor biotype V. cholerae. Here we show that CRP is required for the biosynthesis of cholera autoinducer 1 (CAI-1) and affects the expression of multiple HapR-regulated genes. As expected, the Deltacrp mutant produced more cholera toxin and enhanced biofilm. Expression of flagellar genes, reported to be affected in DeltahapR mutants, was diminished in the Deltacrp mutant. However, an epistasis analysis indicated that cAMP-CRP affects motility by a mechanism independent of HapR. Inactivation of crp inhibited the expression of multiple genes reported to be strongly induced in vivo and to affect the ability of V. cholerae to colonize the small intestine and cause disease. These genes included ompU, ompT and ompW encoding outer-membrane proteins, the alternative sigma factor sigma(E) required for intestinal colonization, and genes involved in anaerobic energy metabolism. Our results indicate that CRP plays a crucial role in the V. cholerae life cycle by affecting quorum sensing and multiple genes required for survival of V. cholerae in the human host and the environment.


Effects of castration on the expression of the NGF and TrkA in the vas deferens and accessory male genital glands of the rat.
Nerve Growth Factor (NGF) is a member of the neurotrophin family. Neurotrophins exert their effects by binding to corresponding receptors, which are formed by the tyrosine protein kinases TrkA, TrkB, and TrkC, and the low affinity p75NTR receptor. The role of neurotrophins in the biology of male genital organs is far from clear. In particular, little is known about the influence of sex hormones on the expression of neurotrophins and their receptors. In the present study, using immunohistochemistry and real time RT-PCR, we investigated the expression of NGF and TrkA in the vas deferens and accessory male genital glands in normal and castrated rats.In normal rats, both NGF- and TrkA-immunoreactivities (IR) were localized in the epithelial layer of the vas deferens. NGF-IR was also found in the stroma and epithelium of the vesicular gland and prostate. TrkA-IR was distributed in the epithelial cells of vesicular and prostate glands. The nerves were weakly immunoreactive in all the examined organs. After castration the immunoreactivities increased. Real-time RT-PCR experiments indicated that NGF and TrkA mRNA levels increased significantly after castration. These results suggest that NGF and TrkA are expressed in the internal male genital organs of the rat and that their expression is downregulated by androgen hormones. We hypothesize NGF and TrkA play a role in the processes that regulate the involution of these organs under conditions of androgen deprivation.


Antigenic stimulation and the occurrence of multiple myeloma.
To evaluate whether potent or prolonged stimulation of the immune system increases the risk of multiple myeloma, the authors compared 698 myeloma cases which occurred between July 1, 1977 and June 30, 1981 in four geographic areas of the United States with 1,683 demographically similar controls from the same areas. Cases and controls were interviewed about past exposures which may have involved antigenic challenge. Although few positive associations emerged, those most consistent with the immune stimulation hypothesis were modest associations between myeloma and a history of rheumatic fever (relative risk (RR) = 1.74, 95% confidence interval (CI) = 1.09-2.77) and between myeloma and urinary tract infection (RR = 1.30, 95% CI = 1.00-1.69, when self-respondent cases were compared with controls). Little association was found between the risk of myeloma and the number of past viral illnesses, number of bacterial illnesses, or number of allergy desensitization injections. Myeloma risk was found to be inversely related to the number of diseases against which a subject reported having been immunized, perhaps because of differences in socioeconomic status between cases and controls. These findings provide little support for the immune system stimulation hypothesis of myeloma etiology, but because of the limitations of interview techniques for assessing antigen exposure, further studies using laboratory methods may be warranted.


Nocardioides baculatus sp. nov., a novel actinomycete isolated from the rhizosphere of Tagetes patula.
An aerobic, Gram-stain-positive, non-motile, dull-yellow, short rod-shaped actinomycete strain, designated G10T, was isolated from Tagetes patula (marigold) roots collected from Goyang in the Republic of Korea. The isolate showed best growth on Reasoner's 2A agar at 25 °C, pH 6.5.0 and with 0% NaCl (w/v). The strain was negative for oxidase activity and positive for catalase activity. On the basis of 16S RNA gene sequence similarity, strain G10T was affiliated to the genus Nocardioides and the closest species were Nocardioides glacieisoli HLT3-15T (98.8 %), Nocardioides zhouii HLT2-9T (98.8 %), Nocardioides ganghwensis JC2055T (98.7 %), Nocardioides cavernae YIM A1136T (98.6 %), Nocardioides flavus Y4T (98.5 %), Nocardioides oleivorans DSM 16090T (98.3 %), Nocardioides alpinus Cr7-14T (98.2 %), Nocardioides exalbidus DSM 22017T (98.1 %) and Nocardioides hwasunensis KCTC 19197T (98.1 %). Strain G10T formed a monophyletic cluster with N. glacieisoli HLT3-15T, N. zhouii HLT2-9T and N. hwasunensis KCTC 19197T in all phylogenetic trees. The cell-wall peptidoglycan of strain G10T contained ll-diaminopimelic acid as the diagnostic amino acid. The predominant fatty acids were iso-C16 : 0 and C17 : 1 ω8c. MK-8(H4) was the major isoprenoid quinone. The major polar lipids were diphosphatidylglycerol, phosphatidylglycerol and phosphatidylinositol. Average nucleotide identity and digital DNA-DNA hybridization values were 78.6-88.7 % and 21.5-36.2 %, respectively, with the type strains of related species of the genus Nocardioides, suggesting that strain G10T represents a novel species. The genome of strain G10T is 4 231 000 bp long with a DNA G+C content of 71.5 mol% and encodes 4071 predicted proteins, six rRNAs and 46 tRNAs. The genome of strain G10T comprises the biosynthetic gene cluster for T3PKS, terpene, NRPS-like fragment and RRE-containing element as secondary metabolites. The results of taxonomic, phylogenetic, biochemical, chemotaxonomic and genomic analysis clearly supported that strain G10T represent a novel species within the genus Nocardioides, for which the name Nocardioides baculatus sp. nov is proposed and the type strain is G10T (=KCTC 49626T=NBRC 114801T).


Recessive mutations in the CYP4V2 gene in East Asian and Middle Eastern patients with Bietti crystalline corneoretinal dystrophy.
Bietti crystalline corneoretinal dystrophy (BCD) is an autosomal recessively inherited disorder characterised by tiny yellowish glittering retinal crystals, choroidal sclerosis, and crystals in the peripheral cornea, associated with progressive night blindness. CYP4V2, encoding a member of cytochrome p450 (CYP450) protein family, was recently identified as the causative gene. We recruited 11 unrelated patients with BCD and characteristic clinical features; eight of Japanese, two of Middle Eastern, and one of Chinese ancestry. Genomic DNA was extracted from peripheral blood leucocytes, and all 11 exons and the flanking intron splice sites of the CYP4V2 gene were amplified and sequenced. A complete ophthalmological examination was performed. We found recessive mutations in the CYP4V2 gene in all of the 11 patients. Two novel mutations, L173W and Q450X, were identified in a Japanese patient and two unrelated patients from Middle Eastern countries, respectively. Each patient was a homozygote. A previously reported mutation IVS6-8_810delinsGC was identified in seven unrelated Japanese patients and the Chinese patient with BCD. All patients with BCD shared a characteristic fundus appearance with numerous intraretinal crystal deposits and atrophy of the retinal pigment epithelium. However, the clinical findings, including elecroretinograph recordings, indicated that there was considerable variation in the degree of visual dysfunction even among patients of similar ages carrying the same mutation. Defects in CYP4V2 are the main cause of BCD. The IVS6-8_810delinsGC mutant allele may be especially prevalent among patients with BCD in East Asian countries, resulting from a single founder. Variation of disease severity suggests that environmental or additional genetic factors influence the course of the retinal disease.


Geographical mapping of type 1 diabetes in children and adolescents in south east Sweden.
As earlier studies have shown space-time clusters at onset of type 1 diabetes in the south east region of Sweden we investigated if there also has been any geographical clusters of diabetes in this region. The place of residence (coordinates) at the time of diagnosis were geocoded in a geographical information system (GIS). All children diagnosed with type 1 diabetes up to 16 years of age at diagnosis between 1977-1995 were included. The population at risk was obtained directly from the population registry for the respective years and geographical area levels. South east region of Sweden containing 5 counties, 49 municipalities, and 525 parishes. A significant geographical variation in incidence rate were found between the municipalities (p<0.001) but not between the counties. The variation became somewhat weaker when excluding the six largest municipalities (p<0.02). In municipalities with increased risk (>35.1/100 000) the major contribution comes from children in age group 6-10 years of age at diagnosis. There were no obvious differences between the age groups in municipalities with decreased risk (<20.1/100 000). Boys and girls had about the same degree of geographical variation. Apart from chance, the most probable explanation for the geographical variation in the risk for children and adolescents to develop type 1 diabetes between the municipalities in the region is that local environmental factors play a part in the process leading to the disease.


High rates of injured motorcycle drivers in emergency rooms and the association with substance use in Porto Alegre, Brazil.
Although the fleet of motorcycles and the number of traffic accidents (TA) is increasing in the world, few studies have evaluated intoxication by alcohol and/or drugs in this group of drivers. This study aims to evaluate the prevalence of motorcycle riders among drivers who are victims of TA, and ascertain factors associated with drug and alcohol use. All TA victims admitted on a 24/7 routine between October and November 2008 to two trauma hospitals of Porto Alegre, Brazil were invited to participate, then submitted to an interview, breathalysed and had their saliva collected for drugs. Among the overall sample of drivers, 78.4% were motorcycle riders. Toxicological analysis yielded a 15.3% prevalence of marijuana use, 9.2% of cocaine use, 3.2% benzodiazepine use and 7% of alcohol use. Factors associated with alcohol or drug intoxication were the diagnosis of alcohol abuse or dependence and history of previous TA. The prevalence of motorcycle riders among drivers who are victims of TA was alarming. The association of alcohol abuse or dependency and intoxication justify the need for therapeutic interventions specifically targeted to the treatment of drug dependency, as well as public policies directed to prevention of injuries-particularly among recidivist motorcycle riders.


SIRT1 is a positive regulator of in vivo bone mass and a therapeutic target for osteoporosis.
Overexpression or pharmacological activation of SIRT1 has been shown to extend the lifespan of mice and protect against aging-related diseases. Here we show that pharmacological activation of SIRT1 protects in two models of osteoporosis. Ovariectomized female mice and aged male mice, models for post-menopausal and aging-related osteoporosis, respectively, show significant improvements in bone mass upon treatment with SIRT1 agonist, SRT1720. Further, we find that calorie restriction (CR) results in a two-fold upregulation of sirt1 mRNA expression in bone tissue that is associated with increased bone mass in CR mice. Reciprocally, SIRT1 whole-body knockout (KO) mice, as well as osteoblast and osteoclast specific KOs, show a low bone mass phenotype; though double knockout mice (containing SIRT1 deleted in both osteoblasts and osteoclasts) do not show a more severe phenotype. Altogether, these findings provide strong evidence that SIRT1 is a positive regulator of bone mass and a promising target for the development of novel therapeutics for osteoporosis.


Nigeria's triumph: dracunculiasis eradicated.
This report describes how Nigeria, a country that at one time had the highest number of cases of dracunculiasis (Guinea worm disease) in the world, reduced the number of cases from more than 653,000 in 1988 to zero in 2009, despite numerous challenges. Village-based volunteers formed the foundation of the program, which used health education, cloth filters, vector control, advocacy for safe water, voluntary isolation of patients, and monitored program interventions and cases reported monthly. Other factors in the program's success were strong governmental support, advocacy by a former head of state of Nigeria, technical and financial assistance by The Carter Center, the U.S. Centers for Disease Control and Prevention, the United Nations Children's Fund, the World Health Organization, and many other partners and donors. The estimated cost of the Nigerian program during 1988-2009 is $37.5 million, not including funding for water supply projects or salaries of Nigerian governmental workers.


The Impact of Post-Myocardial Infarction (MI) Depression on Cardiovascular-Related Hospitalizations.
Routine depression screening and subsequent treatment in post-myocardial infarction (MI) patients may lead to improved cardiac outcomes. However, screening for depression is not a standard of post-MI care. Though the American Heart Association (AHA) published an advisory recommending routine depression screening in post-MI patients, there is conflicting evidence on the benefit that routine depression screening has on cardiovascular outcomes. The purpose of this study is to compare the occurrence of cardiovascular-related readmissions in post-MI patients diagnosed with depression versus post-MI patients not diagnosed with depression. This retrospective cohort study analyzed the incidence of cardiovascular-related readmissions and mortality in adult post-MI patients diagnosed with depression within 1 year compared to those not diagnosed with depression within a year. Those diagnosed with depression were more likely to experience a subsequent cardiovascular-related hospitalization within 2 years of MI than those not diagnosed with depression (52.6% vs 28.7%; odds ratio [OR], 3.19; 95% CI 2.33-4.38). There was no difference between groups in the incidence of in-hospital mortality.


How Wide the Divide? - Theorizing 'Constructions' in Generative and Usage-Based Frameworks.
What is the nature and function of mental representations in cognitive science, and in human language in particular? How do they come into existence and interact, and how is the information attributed to them stored in and retrieved from the human mind? Some theories treat constructions as primitive entities used for structure-building, central in both production and comprehension, while other theories only admit construction-like entities as devices to map the structure into semantics or to relate them to specific morphophonological exponents. In this positional piece, we seek to elucidate areas of commonality across what have traditionally been divergent approaches to the role of constructions in language. Here we outline a robust specification of the differences in how chunks of structure containing information are treated in the two main approaches, and we seek to offer a path toward a more unified theoretical stance.


Therapeutic targeting of aldosterone: a novel approach to the treatment of glomerular disease.
Numerous studies have established a role for mineralocorticoids in the development of renal fibrosis. Originally, the research focus for mineralocorticoid-induced fibrosis was on the collecting duct, where 'classical' mineralocorticoid receptors (MRs) involved with electrolyte transport are present. Epithelial cells in this segment can, under selected circumstances, also respond to MR activation by initiating pro-fibrotic pathways. More recently, 'non-classical' MRs have been described in kidney cells not associated with electrolyte transport, including mesangial cells and podocytes within the glomerulus. Activation of MRs in these cells appears to lead to glomerular sclerosis. Mechanistically, aldosterone induces excess production of reactive oxygen species (ROS) and oxidative stress in glomerular cells through activation of NADPH oxidase. In mesangial cells, aldosterone also has pro-apoptotic, mitogenic and pro-fibrogenic effects, all of which potentially promote active remodelling and expansion of the mesangium. Although mitochondrial dysfunction seems to mediate the aldosterone-induced mesangial apoptosis, the ROS dependent epithelial growth factor receptor (EGFR) transactivation is probably responsible for aldosterone-induced mesangial mitosis and proliferation. In podocytes, mitochondrial dysfunction elicited by oxidative stress is an early event associated with aldosterone-induced podocyte injury. Both the p38 MAPK (p38 mitogen-activated protein kinase) signalling and the redox-sensitive glycogen synthase kinase (GSK)3β pathways are centrally implicated in aldosterone-induced podocyte death. Aldosterone-induced GSK3β over-activity could potentially cause hyperphosphorylation and over-activation of putative GSK3β substrates, including structural components of the mitochondrial permeability transition (MPT) pore, all of which lead to cell injury and death. Clinically, proteinuria significantly decreases when aldosterone inhibitors are included in the treatment of many glomerular diseases further supporting the view that mineralocorticoids are important players in glomerular pathology.


Psychometric properties of the Brazilian-Portuguese version of the Spence Children's Anxiety Scale (SCAS): self- and parent-report versions.
This study examined the psychometric properties of the Spence Children's Anxiety Scale (SCAS) self- and parent-report versions in a community (n=712) and a clinical (n=70) sample of Brazilian children and adolescents. Confirmatory factor analysis conducted in the community sample provided support to the original six correlated factors model of the SCAS. Moreover, the SCAS demonstrated good internal consistency, convergent and divergent validity, and a significant informant effect on the total score with higher anxiety levels in the self-report than in the parent-report version. Considering the clinical sample, we could demonstrate that the SCAS total scores have good discriminant validity differentiating: (a) anxious, community, and negative screening groups; and (b) children diagnosed with different severity levels of anxiety disorders. Our findings suggest that the SCAS (self- and parent-report versions) is suitable for assessing anxiety symptoms in Brazilian children and adolescents in community and clinical settings.


Myeloablative Unrelated Cord Blood Transplantation in Adolescents and Young Adults with Acute Leukemia.
Outcomes for adolescents and young adults (AYAs) with leukemia differ from other age groups and are still under-represented in clinical research. The aim of this study was to analyze outcomes of umbilical cord blood transplant (UCBT) in AYAs with acute leukemia reported to Eurocord/European Society for Blood and Marrow Transplantation. Patients (N = 504) had acute lymphoblastic (59%) or myeloid leukemia (41%), were aged 15 to 25 years, and received UCBT after myeloablative conditioning regimens between 2004 and 2016. The primary endpoint was 3-year overall survival (OS). Median follow-up was 3.9 years. Transplant was single in 58% and double UCBT in 42%. Three-year OS was 45% and leukemia free survival (LFS) was 41%. Cumulative incidence functions (CIFs) of nonrelapse mortality (NRM) and relapse were 31% and 28%, respectively. CIF of acute graft-versus-host disease (GVHD) grades II to IV at day 100 was 28%. Three-year CIF of chronic GVHD was 25%. In adjusted analysis, better disease status at UCBT (hazard ratio [HR], 2.74; P < .001) and more recent UCBT (HR, 1.43; P = .01) were associated with increased OS, and a similar effect of these factors was observed on LFS. Contrastingly, the use of antithymocyte globulin had a negative effect in LFS. The risk of acute GVHD grades II to IV increased with the use of double UCBT (HR, 1.65; P = .02) and decreased with more recent transplant period (HR, .65; P = .02) and antithymocyte globulin use (HR, .55; P = .01). Outcomes of AYA UCBT improved in more recent years, becoming comparable with pediatric results. Demonstrating the feasibility of UCBT in AYAs facilitates stem cell source selection and provides the basis for future prospective studies.


Force-transmitting structures in the digital pads of the tree frog Hyla cinerea: a functional interpretation.
The morphology of the digital pads of tree frogs is adapted towards attachment, allowing these animals to attach to various substrates and to explore their arboreal habitat. Previous descriptions and functional interpretations of the pad morphology mostly focussed on the surface of the ventral epidermis, and little is known about the internal pad morphology and its functional relevance in attachment. In this study, we combine histology and synchrotron micro-computer-tomography to obtain a comprehensive 3-D morphological characterisation of the digital pads (in particular of the internal structures involved in the transmission of attachment forces from the ventral pad surface towards the phalanges) of the tree frog Hyla cinerea. A collagenous septum runs from the distal tip of the distal phalanx to the ventral cutis and compartmentalises the subcutaneous pad volume into a distal lymph space and a proximal space, which contains mucus glands opening via long ducts to the ventral pad surface. A collagen layer connects the ventral basement membrane via interphalangeal ligaments with the middle phalanx. The collagen fibres forming this layer curve around the transverse pad-axis and form laterally separated ridges below the gland space. The topological optimisation of a shear-loaded pad model using finite element analysis (FEA) shows that the curved collagen fibres are oriented along the trajectories of the maximum principal stresses, and the optimisation also results in ridge-formation, suggesting that the collagen layer is adapted towards a high stiffness during shear loading. We also show that the collagen layer is strong, with an estimated tensile strength of 2.0-6.5 N. Together with longitudinally skewed tonofibrils in the superficial epidermis, these features support our hypothesis that the digital pads of tree frogs are primarily adapted towards the generation and transmission of friction rather than adhesion forces. Moreover, we generate (based on a simplified FEA model and predictions from analytical models) the hypothesis that dorsodistal pulling on the collagen septum facilitates proximal peeling of the pad and that the septum is an adaptation towards detachment rather than attachment. Lastly, by using immunohistochemistry, we (re-)discovered bundles of smooth muscle fibres in the digital pads of tree frogs. We hypothesise that these fibres allow the control of (i) contact stresses at the pad-substrate interface and peeling, (ii) mucus secretion, (iii) shock-absorbing properties of the pad, and (iv) the macroscopic contact geometry of the ventral pad surface. Further work is needed to conclude on the role of the muscular structures in tree frog attachment. Overall, our study contributes to the functional understanding of tree frog attachment, hence offering novel perspectives on the ecology, phylogeny and evolution of anurans, as well as the design of tree-frog-inspired adhesives for technological applications.


Benchmarking the quality of schizophrenia pharmacotherapy: a comparison of the Department of Veterans Affairs and the private sector.
Comparing quality of care between large health care systems is important for health systems management. This study used measures of the quality of pharmacotherapy for patients with schizophrenia and compared these measures across a sample of patients from the Department of Veterans Affairs (VA) and the private sector. A random sample of all patients diagnosed with schizophrenia in the VA during fiscal year (FY) 2000 was identified using administrative data. In the private sector, a sample of patients diagnosed with schizophrenia in 2000 was identified using MEDSTAT's MarketScan database. For both groups, use of antipsychotic medications was studied and measures of the quality of pharmacotherapy were constructed, including whether patients were prescribed any antipsychotic medication, one of the newer atypical antipsychotics, and whether dosing adhered to established treatment recommendations. These measures were compared across the two groups using logistic regression models, controlling for age, gender, and comorbid diagnoses. Most patients with a diagnosis of schizophrenia (82% in the VA and 73% in the private sector) received an antipsychotic medication, usually one of the newer atypical drugs. Patients in the VA were more likely to be dosed above treatment recommendations, and less likely to be dosed below treatment recommendations. Overall, differences in proportion schizophrenia patients dosed according to recommendations were not statistically different across the two systems (60% in the VA, 58% in the private sector). Differences between the two systems were mixed, with the VA outperforming the private sector with respect to some measures and doing worse on others. Although the VA and the private sector were comparable with respect to the quality measures used in this study, there is room for improvement in both systems. Treatment recommendations are based on the best available clinical evidence of effectiveness and safety. Quality of care might be improved with better adherence to these recommendations. Relatively low rates of adherence to treatment recommendations may be due to lack of awareness of these recommendations among prescribing physicians, or a belief that the recommendations are inadequate. To the extent that low rates of adherence to treatment recommendations are caused by a lack of awareness among physicians, policies should be developed to disseminate this information and encourage the appropriate use of these medications. Further research is needed to understand physician prescribing decisions for these medications. To the extent that physicians feel treatment recommendations for these drugs are inadequate, further research is needed to refine the recommendations.


A Comparative Evaluation of a Labial Approach with a Conventional Palatal Approach for Endodontic Access in Primary Maxillary Incisors: A Pilot Study.
A straight-line access provides an uninterrupted path for a successful endodontic procedure and traditionally a palatal approach was used to achieve the same. A labial access opening may provide a straight-line access to the root canal more consistently than the conventional palatal access opening in primary maxillary incisors; its advantages being improved visibility and direct access to the root canal. This study was designed to compare and evaluate the time taken for pulpectomy in primary maxillary incisors with conventional palatal access and labial access as well as time taken for the postendodontic restoration. A cohort study was conducted wherein pulpectomy was performed on primary maxillary anterior teeth with labial endodontic access (group I-40 teeth) and palatal endodontic access (group II-40 teeth). Each group was further subdivided into two subgroups of 20 teeth each, requiring postendodontic composite restoration and requiring postendodontic strip crown restoration. Time taken for pulpectomy with both methods and for postendodontic restoration was evaluated. The mean time (in seconds) taken for pulpectomy and postendodontic composite restoration was significantly less with a labial access than a palatal access (p = 0.000). Although the time required for postendodontic strip crown restoration was less with a labial access compared with a palatal access, this difference was not statistically significant (p = 0.907). From the results of this study, it can be suggested that labial endodontic access may be routinely used for pulp therapy of primary anterior teeth. A labial endodontic access for primary anterior teeth provides a straight-line access and improves operator convenience and patient compliance when compared with a palatal access. Winnier J, Suresh R. A Comparative Evaluation of a Labial Approach with a Conventional Palatal Approach for Endodontic Access in Primary Maxillary Incisors: A Pilot Study. Int J Clin Pediatr Dent 2020;13(1):53-56.


Early onset of hypertension and serum electrolyte changes as potential predictive factors of activity in advanced HCC patients treated with sorafenib: results from a retrospective analysis of the HCC-AVR group.
Hypertension (HTN) is frequently associated with the use of angiogenesis inhibitors targeting the vascular endothelial growth factor pathway and appears to be a generalized effect of this class of agent. We investigated the phenomenon in 61 patients with advanced hepatocellular carcinoma (HCC) receiving sorafenib. Blood pressure and plasma electrolytes were measured on days 1 and 15 of the treatment. Patients with sorafenib-induced HTN had a better outcome than those without HTN (disease control rate: 63.4% vs. 17.2% (p=0.001); progression-free survival 6.0 months (95% CI 3.2-10.1) vs. 2.5 months (95% CI 1.9-2.6) (p<0.001) and overall survival 14.6 months (95% CI9.7-19.0) vs. 3.9 months (95% CI 3.1-8.7) (p=0.003). Sodium levels were generally higher on day 15 than at baseline (+2.38, p<0.0001) in the group of responders (+4.95, p <0.0001) compared to patients who progressed (PD) (+0.28, p=0.607). In contrast, potassium was lower on day 14 (-0.30, p=0.0008) in the responder group (-0.58, p=0.003) than in those with progressive disease (-0.06, p=0.500). The early onset of hypertension is associated with improved clinical outcome in HCC patients treated with sorafenib. Our data are suggestive of an activation of the renin-angiotensin system in patients with advanced disease who developed HTN during sorafenib treatment.


[Clinical relevance of proximal tubal occlusion--diagnosis and therapy].
Clinical examination of potential tubal disease is an essential part of the investigation of infertility. Proximal tubal occlusion accounts for 10-25% of tubal factor infertility. Authors review the history, methods and value of the relevant diagnostic and therapeutic procedures of proximal tubal occlusion, as well as determine the exact role of hysteroscopic selective tubal cannulation in the work-up process. Upon the relevant literature and the authors' data, the mentioned procedure is recommended in the assessment of the infertile females in order to avoid unnecessary in vitro fertilization procedures.


Immunologic variables in acute mania of bipolar disorder.
Macrophages, lymphocytes and their products, may be involved in the pathophysiology of psychiatric disorders. The cell-mediated immune activation response of manic patients during pre-medication and medication stages remains unclear. The purpose of this case-control study was to investigate the plasma levels of immunologic variables, including interleukin (IL)-1 receptor antagonist (IL-1RA), soluble CD 4 (sCD4) and sCD8, and TH1 (interferon [IFN]-gamma and IL-2) and TH2 (IL-4 and IL-10) cytokines in patients with pre-medicated, medicated bipolar mania. The study subjects, aged 16-44 years, were physically healthy patients with Young Mania Rating Scale (YMRS) scores > or =26, and normal controls, aged 19-40 years, were matched for sex. The immune variables were measured in acute mania and in consequent remission (YMRS scores < or =12) among bipolar patients. The plasma levels of IL-1RA, sCD4, and sCD8 were found significantly increased in pre-medicated acute manic patients as compared to normal controls. But only IL-1RA and sCD8 were found different in remitted bipolar patients as compared to normal controls. For TH1 cytokines, culture supernatant level of IFN-gamma was found significantly lower in manic patients of both acute and remission stages as compared to normal controls. No significant difference was found in IL-2 level in pre-medicated acute manic patients compared to controls. For TH2 cytokines, no significant differences in IL-4 and IL-10 levels were observed. We showed that cell-mediated immune response was activated in patients with bipolar disorder during the pre-medication, medication, and the remission stages. Our study findings suggest that the immune-modulation in patients with bipolar disorder may be abnormal.


The acute phase protein alpha1-acid glycoprotein: a model for altered glycosylation during diseases.
Glycosylation is one of the most important post-translational modifications of proteins, and has been widely acknowledged as one of the most important ways to modulate both protein function and lifespan. The acute phase proteins are a major group of serum proteins whose concentration is altered during various pathophysiological conditions. The aim of this paper is to review the structure and functions of the alpha1-acid glycoprotein (AGP). AGP belongs to the subfamily of immunocalins, a group of binding proteins that also have immunomodulatory functions. One of the most interesting features of AGP is that its glycosylation microheterogeneity can be modified during diseases. This aspect is particularly remarkable, since both the immunomodulatory and the binding properties of AGP strongly depend on its carbohydrate composition. For these reasons, AGP can be considered an outstanding model for the study of glycan pattern modification during diseases. This review is focused on the most recent studies on the occurrence of different glycoforms in plasma and tissues and how the appearance of different oligosaccharide patterns during systemic inflammation or diseases can influence AGP's biological functions. The first part of the review will describe the structure of AGP and the several biological functions identified so far for this protein. The second part will be devoted to the post-translational modifications of the oligosaccharides micro-heterogeneity of AGP caused by pathological states. A critical evaluation of the impact of different AGP glycoforms on both its transport and anti-inflammatory features, and how the modifications of the glycan pattern can be utilized in clinical biochemistry, is also discussed.


Gender dependent importance of IRAK-1 in dextran sulfate sodium induced colitis.
Toll-like receptor (TLR) signaling is important for the induction of pro-inflammatory cytokines and interferon (IFN)-inducible genes in response to bacterial and viral challenge. Interleukin-1 receptor-associated kinase-1 (IRAK-1) is a signaling kinase situated downstream of the adapter protein myeloid differentiation factor 88 (MyD88) in the TLR intracellular signaling cascade and is required for normal signal transduction through this pathway. We investigated the importance of IRAK-1 in intestinal inflammation by using the dextran sulfate sodium (DSS)-colitis model. We show that IRAK-1 deficient mice are protected against systemic signs of inflammation, i.e., weight loss and spleen enlargement compared to wild-type controls irrespective of gender. However, IRAK-1(-/y) males but not IRAK-1(-/-) females display significant protection against colitis and thymic atrophy compared to wild-type mice. Our results indicate a gender specific effect of IRAK-1 in the DSS-induced colitis, an interesting finding since the Irak-1 gene is located on the X-chromosome and several inflammatory diseases have a gender dependent incidence.


Protein tyrosine kinase 6 directly phosphorylates AKT and promotes AKT activation in response to epidermal growth factor.
Protein tyrosine kinase 6 (PTK6) is a nonmyristoylated Src-related intracellular tyrosine kinase. Although not expressed in the normal mammary gland, PTK6 is expressed in a majority of human breast tumors examined, and it has been linked to ErbB receptor signaling and AKT activation. Here we demonstrate that AKT is a direct substrate of PTK6 and that AKT tyrosine residues 315 and 326 are phosphorylated by PTK6. Association of PTK6 with AKT occurs through the SH3 domain of PTK6 and is enhanced through SH2 domain-mediated interactions following tyrosine phosphorylation of AKT. Using Src, Yes, and Fyn null mouse embryonic fibroblasts (SYF cells), we show that PTK6 phosphorylates AKT in a Src family kinase-independent manner. Introduction of PTK6 into SYF cells sensitized these cells to physiological levels of epidermal growth factor (EGF) and increased AKT activation. Stable introduction of active PTK6 into SYF cells also resulted in increased proliferation. Knockdown of PTK6 in the BPH-1 human prostate epithelial cell line led to decreased AKT activation in response to EGF. Our data indicate that in addition to promoting growth factor receptor-mediated activation of AKT, PTK6 can directly activate AKT to promote oncogenic signaling.


Processing of emotion words by patients with autism spectrum disorders: evidence from reaction times and EEG.
This study investigated processing of emotion words in autism spectrum disorders (ASD) using reaction times and event-related potentials (ERP). Adults with (n = 21) and without (n = 20) ASD performed a lexical decision task on emotion and neutral words while their brain activity was recorded. Both groups showed faster responses to emotion words compared to neutral, suggesting intact early processing of emotion in ASD. In the ERPs, the control group showed a typical late positive component (LPC) at 400-600 ms for emotion words compared to neutral, while the ASD group showed no LPC. The between-group difference in LPC amplitude was significant, suggesting that emotion words were processed differently by individuals with ASD, although their behavioral performance was similar to that of typical individuals.


Feasibility of Patient Navigation-Based Smoking Cessation Program in Cancer Patients.
Continued smoking after a cancer diagnosis is causally associated with increased risks of all-cause and cancer-specific mortality, and of smoking-related second primary cancers. Patient navigation provides individualized assistance to address barriers to smoking cessation treatment and represents a promising bridge to smoking cessation in persons with cancer who smoke cigarettes. We conducted a single-arm interventional cohort study of current smokers identified through prospective health record screening and recruited from Penn State Cancer Institute outpatient clinics. Consented participants received two telephone intervention sessions and gain-framed messaging-based smoking cessation educational materials designed for persons with cancer. The primary study outcome was the feasibility of the patient navigation-based intervention; the secondary outcome was the engagement in smoking cessation treatment at the two-month follow-up. Of 1168 unique screened Cancer Institute patients, 134 (11.5%) were identified as current cigarette smokers. Among 67 patients approached at outpatient clinics, 24 (35.8%) were interested in participating, 12 (17.9%) were enrolled, eight (11.9%) completed the intervention sessions and study assessments, and six engaged in smoking cessation treatment. The participants expressed satisfaction with the intervention sessions (median = 8.5, scale 0-10). The low recruitment rates preclude patient navigation as a feasible method for connecting cancer patients to smoking cessation treatment resources.


Preparation and Characterisation of Sustainable Wood Plastic Composites Extracted from Municipal Solid Waste.
Municipal solid waste (MSW) contains plastic waste that can be used as a sustainable green substitute to reduce oil footprints, CO2 emissions, and environmental pollution. This study aims to recycle plastic waste by manufacturing wood-plastic composites and to improve its mechanical properties by using additives, coupling agents, and lubricants. These composites are prepared by mixing 40-70% of wood flour with 20-25% of a polymer matrix. Wood was degraded at 220 °C, and then the composites were processed at 50 °C. The manufacturing process carried out in the study involved wood waste meshing, drying, shredding, drying, trimming, filling, blending, compounding, and extrusion moulding. The compounding of composites was accomplished in twin-screw extruders. Once the mixture was uniformly mixed, its final shape was given by a two-step extrusion moulding. Previously, researchers aimed at enhancing the mechanical properties of the composites, but our research focus was to improve their durability for different industrial applications. The results suggest that the impact strength is 17 MPa with 50% of wood powder ratio while the maximum value for the tensile strength is 32.5 MPa. About 50% of an increase in wood powder resulted in 8.1% bending strength increase from 26.1 to 32.8 MPa. Reducing the plastic matrix and the wood-particles water swelling ratio resulted in better mechanical properties. The wood species also affected the mechanical properties with their excellent dimensional stability and less variability. A high proportion of wood fibre tends to increase its steady-state torque and viscosity. The mechanical properties against different wood-flour proportions indicate that composite materials exhibit superior water swelling behaviour and extrusion quality.


[Total knee and hip prosthesis: variables associated with costs].
The elevated prevalence of osteoarthritis in Western countries, the high costs of hip and knee arthroplasty, and the wide variations in the clinical practice have generated considerable interest in comparing the associated costs before and after surgery. To determine the influence of a number of variables on the costs of total knee and hip arthroplasty surgery during the hospital stay and during the one-year post-discharge. A prospective multi-center study was performed in 15 hospitals from three Spanish regions. Relationships between the independent variables and the costs of hospital stay and postdischarge follow-up were analyzed by using multilevel models in which the "hospital" variable was used to group cases. Independent variables were: age, sex, body mass index, preoperative quality of life (SF-12, EQ-5 and Womac questionnaires), surgery (hip/knee), Charlson Index, general and local complications, number of beds and economic-institutional dependency of the hospital, the autonomous region to which it belongs, and the presence of a caregiver. The cost of hospital stay, excluding the cost of the prosthesis, was 4,734 Euros, and the post-discharge cost was 554 Euros. With regard to hospital stay costs, the variance among hospitals explained 44-46% of the total variance among the patients. With regard to the post-discharge costs, the variability among hospitals explained 7-9% of the variance among the patients. There is considerable potential for reducing the hospital stay costs of these patients, given that more than 44% of the observed variability was not determined by the clinical conditions of the patients but rather by the behavior of the hospitals.


Wastewater treatment plant performance analysis using artificial intelligence - an ensemble approach.
In the present study, three different artificial intelligence based non-linear models, i.e. feed forward neural network (FFNN), adaptive neuro fuzzy inference system (ANFIS), support vector machine (SVM) approaches and a classical multi-linear regression (MLR) method were applied for predicting the performance of Nicosia wastewater treatment plant (NWWTP), in terms of effluent biological oxygen demand (BODeff), chemical oxygen demand (CODeff) and total nitrogen (TNeff). The daily data were used to develop single and ensemble models to improve the prediction ability of the methods. The obtained results of single models proved that, ANFIS model provides effective outcomes in comparison with single models. In the ensemble modeling, simple averaging ensemble, weighted averaging ensemble and neural network ensemble techniques were proposed subsequently to improve the performance of the single models. The results showed that in prediction of BODeff, the ensemble models of simple averaging ensemble (SAE), weighted averaging ensemble (WAE) and neural network ensemble (NNE), increased the performance efficiency of artificial intelligence (AI) modeling up to 14%, 20% and 24% at verification phase, respectively, and less than or equal to 5% for both CODeff and TNeff in calibration phase. This shows that NNE model is more robust and reliable ensemble method for predicting the NWWTP performance due to its non-linear averaging kernel.


Rethinking cancer initiation: The role of large-scale mutational events.
Cancer initiation is revisited in light of recent discoveries in cancer pathogenesis. Of note is the detection of mutated cancer genes in benign conditions. More significantly, somatic clones, which harbor mutations in cancer genes, arise in normal tissues from early development through adulthood, but seldom do they transform into cancer. Further, clustered mutational events-kataegis, chromothripsis and chromoplexy-are widespread in cancer, generating point mutations and chromosomal rearrangements in a single cellular catastrophe. These observations are contrary to the prevailing somatic mutation theory, which states that a cancer is caused by the gradual accumulation of mutations over time. A different perspective is proposed within the framework of Waddington's epigenetic landscape wherein tumorigenesis is viewed primarily as a disruption of cell development. Cell types are defined by their specific gene-expression profiles, determined by the gene regulatory network, and can be regarded as attractor states of the network dynamics: they represent specific, self-stabilizing patterns of gene activities across the genome. However, large-scale mutational events reshape the landscape topology, creating abnormal "unphysiological" attractors. This is the crux of the process of initiation. Initiation primes the cell for conversion into a tumor phenotype by oncogenes and tumor suppressor genes, which drive cell proliferation and clonal diversification. This view of tumorigenesis calls for a different approach to therapy.


A Significant Effect of Pemafibrate on Hepatic Steatosis and Fibrosis Indexes in Patients With Hypertriglyceridemia.
We previously reported that the selective peroxisome proliferator-activated receptor alpha modulator, pemafibrate, significantly reduced serum levels of aspartate aminotransferase (AST), alanine aminotransferase (ALT) and gamma-glutamyl transferase (GGT) and significantly increased serum albumin levels at 3, 6 and 12 months after the start of pemafibrate, with an improvement of atherogenic dyslipidemia, in patients with hypertriglyceridemia. We performed a post hoc analysis of our previous data obtained from patients with hypertriglyceridemia who had been prescribed pemafibrate continuously for 1 year or longer. We compared the indexes for hepatic steatosis (hepatic steatosis index (HSI)) and fibrosis (nonalcoholic fatty liver disease (NAFLD) fibrosis score (NFS), AST to platelet ratio index (APRI) and FIB-4 index) at baseline with the data at 1 year after the start of pemafibrate. Pemafibrate significantly reduced HSI at 1 year after the start of pemafibrate. NFS did not show a significant change after 1 year. However, APRI was significantly reduced by pemafibrate after 1 year. FIB-4 index significantly decreased in patients with baseline FIB-4 index ≥ 1.45 at 1 year after the start of pemafibrate. HSI at baseline tended to be negatively correlated with change in HSI after 1 year. There was no significant correlation between NFS at baseline and change in this score after 1 year. APRI and FIB-4 index at baseline were significantly and negatively correlated with changes in APRI and FIB-4 index at 1 year after the start of pemafibrate. The 1-year pemafibrate treatment improved hepatic steatosis and fibrosis indexes in patients with hypertriglyceridemia.


Identification of oxidized amino acid residues in the vicinity of the Mn(4)CaO(5) cluster of Photosystem II: implications for the identification of oxygen channels within the Photosystem.
As a light-driven water-plastoquinone oxidoreductase, Photosystem II produces molecular oxygen as an enzymatic product. Additionally, under a variety of stress conditions, reactive oxygen species are produced at or near the active site for oxygen evolution. In this study, Fourier-transform ion cyclotron resonance mass spectrometry was used to identify oxidized amino acid residues located in several core Photosystem II proteins (D1, D2, CP43, and CP47) isolated from spinach Photosystem II membranes. While the majority of these oxidized residues (81%) are located on the oxygenated solvent-exposed surface of the complex, several residues on the CP43 protein ((354)E, (355)T, (356)M, and (357)R) which are in close proximity (<15 Å) to the Mn(4)CaO(5) active site are also modified. These residues appear to be associated with putative oxygen/reactive oxygen species exit channel(s) in the photosystem. These results are discussed within the context of a number of computational studies which have identified putative oxygen channels within the photosystem.


Fermionic Reduced Density Low-Rank Matrix Completion, Noise Filtering, and Measurement Reduction in Quantum Simulations.
Fermionic reduced density matrices summarize the key observables in Fermionic systems. In electronic systems, the two-particle reduced density matrix (2-RDM) is sufficient to determine the energy and most physical observables of interest. Here, we consider the possibility of using matrix completion to reconstruct the two-particle reduced density matrix to chemical accuracy from partial information. We consider the case of noiseless matrix completion, where the partial information corresponds to a subset of the 2-RDM elements, as well as noisy completion, where the partial information corresponds to both a subset of elements and statistical noise in their values. Through experiments on a set of 24 molecular systems, we find that 2-RDM can be efficiently reconstructed from a reduced amount of information. In the case of noisy completion, this results in a multiple orders of magnitude reduction in the number of measurements needed to determine the 2-RDM with chemical accuracy. These techniques can be readily applied to both classical and quantum algorithms for quantum simulations.


Stereotactic body radiotherapy for very elderly patients (age, greater than or equal to 85 years) with stage I non-small cell lung cancer.
Stereotactic body radiotherapy (SBRT) for non-small cell lung cancer (NSCLC) is primarily a treatment option for medically inoperable patients, who are often elderly. However, few studies report the effects of SBRT in elderly patients. Thus, we retrospectively analyzed clinical outcomes and feasibility following treatment of very elderly patients (age ≥ 85 years) with stage Ι NSCLC and younger patients (age < 85 years) with SBRT in our institution. From January 2006 to December 2012, 81 patients (20 very elderly; median age, 80 years; age range 64-93 years) with stage Ι NSCLC received SBRT. Prescription doses of 48 Gy were delivered in 4 fractions over 2 weeks or doses of 60 Gy were delivered in 10 fractions over 3 weeks. Local control was achieved in 91.8% of all patients at 3 years (83.1% and 93.8% of very elderly and younger patients, respectively), and the 3-year overall survival (OS) rate was 69.4% (40.7% and 75.0% of very elderly and younger patients, respectively). OS rates were significantly shorter for the very elderly group than for the younger group, with a 3-year cause-specific survival (CSS) rate of 77.9% (50.4% and 81.6% of very elderly and younger patients, respectively) and a 3-year progression-free survival (PFS) rate of 59.5% (44.7% and 63.5% in very elderly and younger groups, respectively). Multivariate analysis revealed a significant correlation between T stage and OS. Grades 2 and 3 radiation pneumonitis (RP) occurred in 7 (8.6%) and 2 (2.5%) patients, respectively. Among patients of very elderly and younger groups, grade 2 RP occurred in 4 (20%) and 3 (4.9%) patients, and grade 3 occurred in 2 (10%) and 0 (0%) patients, respectively. No grade 4 or 5 toxicity was observed, RP was significantly more severe among very elderly patients. SBRT for stage Ι NSCLC was well tolerated and feasible in very elderly patients. The efficacy of SBRT was comparable to that achieved in younger patients, although very elderly patients experienced significantly more severe RP. Although this study cohort included only 20 very elderly patients, the present data suggest that decreasing volumes of normal lung tissues exposed to ≥ 20 Gy and mean lung doses reduces the risk of RP in very elderly patients. The present data warrant studies of larger very elderly cohorts.


Bioresponsive and near infrared photon co-enhanced cancer theranostic based on upconversion nanocapsules.
Developing nanotheranostics responsive to tumor microenvironments has attracted tremendous attention for on-demand cancer diagnosis and treatment. Herein, a facile Mn-doping strategy was adopted to transform mesoporous silica coated upconversion nanoparticles (UCNPs) to yolk-like upconversion nanostructures which possess a tumor-responsive biodegradation nature. The huge internal space of the innovated nanocarriers is suitable for doxorubicin (DOX) storage, besides, the Mn-doped shell is sensitive to the intratumoral acidity and reducibility, which enables shell biodegradation and further accelerates the breakage of Si-O-Si bonds within the silica framework. This tumor-responsive shell degradation is beneficial for realizing tumor-specific DOX release. Subsequently, polyoxometalate (POM) nanoclusters that can enhance photothermal conversion in response to the tumor reducibility and acidity were modified on the surface of the silica shell, thereby achieving NIR-enhanced shell degradation and also preventing premature DOX leakage. The as-produced thermal effect of the POM couples with the chemotherapy effect of the released DOX to perform a synergetic chemo-photothermal therapy. Additionally, the shell degradation brings size shrinkage to the nanocarriers, allowing faster nanoparticle diffusion and deeper tumor penetration, which is significant for improving theranostic outcomes. Also, the drastic decline of the red/green (R/G) ratio caused by the DOX release can be used to monitor the DOX release content through a fluorescence resonance energy transfer (FRET) method. The MRI effect caused by Mn release together with the MRI/CT/UCL imaging derived from Gd3+/Yb3+/Nd3+/Er3+ co-doped UCNPs under 808 nm laser excitation endow the nanosystem with multiple imaging capability, thus realizing imaging-guided cancer therapy.


Shared genetic etiology underlying late-onset Alzheimer's disease and posttraumatic stress syndrome.
Late-onset Alzheimer's disease (LOAD) manifests comorbid neuropsychiatric symptoms and posttraumatic stress disorder (PTSD) is associated with an increased risk for dementia in late life, suggesting the two disorders may share genetic etiologies. We performed genetic pleiotropy analysis using LOAD and PTSD genome-wide association study (GWAS) datasets from white and African-American populations, followed by functional-genomic analyses. We found an enrichment for LOAD across increasingly stringent levels of significance with the PTSD GWAS association (LOAD|PTSD) in the discovery and replication cohorts and a modest enrichment for the reverse conditional association (PTSD|LOAD). LOAD|PTSD association analysis identified and replicated the MS4A genes region. These genes showed similar expression pattern in brain regions affected in LOAD, and across-brain-tissue analysis identified a significant association for MS4A6A. The African-American samples showed moderate enrichment; however, no false discovery rate-significant associations. We demonstrated common genetic signatures for LOAD and PTSD and suggested immune response as a common pathway for these diseases.


Expression of three genes for elongation factor 1 alpha during morphogenesis of Mucor racemosus.
Three genes, TEF-1, -2, and -3, encode elongation factor 1 alpha in Mucor racemosus. Neutral and alkaline S1 nuclease analyses revealed that the genetic organization is unique for each of the genes. The number and size of the intervening sequences vary in these closely related genes, which suggests that complex genetic rearrangements gave rise to the elongation factor 1 alpha gene family. Nucleotide sequence data from restriction fragments isolated from the 5' and 3' ends of TEF-2 and -3 confirmed the presence of a second intervening sequence in these genes. These data along with S1 nuclease mapping revealed a region at the 3' end of the three genes which was predicted to be transcribed but untranslated. Unique oligonucleotides containing 19 bases were synthesized to hybridize to this unique trailer region in the elongation factor 1 alpha transcripts. These oligonucleotides were used as probes in standard Northern analysis of RNA purified from M. racemosus cells of several morphological types. It was determined that all three genes were expressed in the cell morphological types studied. However, the accumulated level of transcript derived from each gene varied considerably, with TEF-1 mRNA present in approximately twofold greater quantity than the TEF-3 transcript and up to sixfold greater quantity than TEF-2. The level of TEF-1 and -2 mRNA varied little among the cell morphological types studied, whereas TEF-3 mRNA was present in twofold greater quantity in sporangiospores than in either germlings or yeast cells which had been induced to undergo morphogenesis to hyphae. These data suggest that there is differential expression of the genes encoding elongation factor 1 alpha in M. racemosus. At least one gene, TEF-3, shows a morphology-specific pattern of transcript accumulation.


Bonding of hybrid composite resin to the surface of gold-alloy used in porcelain-fused-to-metal restorations.
The aim of this study was to determine the bond strength of hybrid composite resin to the surface of a gold alloy used in porcelain-fused-to-metal restorations. The surface of the gold alloy was either ground with a sintered diamond burr, sandblasted with Al2O4 or ground with a silicon-carbide stone. The composite resin was bonded to the surface of the gold alloy with or without a commercial silane primer. Bond strength was tested with a three-point loading test, and the elemental composition of the surface of the gold alloy after various mechanical treatments was analysed by SEM/EDS method. Replicas of the fracture surface of the test specimens were examined by SEM to determine whether or not composite resin particles left on the surface had adhered after the loading test. The results showed that mechanical treatment of the surface of the gold alloy affects the bond strength of the composite resin (P < 0.001) but that silane treatment of the surface did not affect the bond strength (P = 0.217). SEM/EDS analysis showed evenly distributed aluminium on the surface of sandblasted gold alloy and silicon on the surface that had been ground with the silicon-carbide stone. This study suggests that sandblasting of the gold alloy surface considerably enhances the strength of its bond to hybrid composite resin.


Delivering problem-solving treatment in low-vision rehabilitation: A pilot feasibility study.
To explore the feasibility and preliminary effectiveness of Problem-Solving Treatment for Primary Care (PST-PC) delivered by low-vision rehabilitation (LVR) practitioners to adult clients with depressive symptoms. A single-group pre/postintervention study. Eighteen adult LVR clients with depressive symptoms (Patient Health Questionnaire-9 [PHQ-9] score of ≥5) received 6-8 weekly telephone sessions of PST-PC delivered by expertly trained practitioners (n = 14). Feasibility was determined via participating client and practitioner recruitment and intervention retention rates. Depressive symptoms (PHQ-9), health-related quality of life (HRQoL; Assessment of QoL Instrument-7D), and confidence in one's ability to cope using problem-solving strategies (Coping Self-Efficacy Scale) were assessed using pre/posttelephone assessments. Participating client recruitment and retention rates were 71% and 40%, respectively. Seventy percent of practitioners completed supervised training in PST-PC and demonstrated satisfactory levels of fidelity and competency. Postintervention, we observed a 53% improvement in depressive symptoms (p < .001), a 23% improvement in HRQoL (p = .001), and an 18% improvement in participants' confidence to use problem-focused coping strategies (p = .001). Telephone-PST-PC delivered by a trained LVR practitioner may be an effective intervention for clients of LVR services who exhibit depressive symptoms. A randomized controlled trial is now needed to confirm these preliminary findings and establish longer-term effectiveness. (PsycINFO Database Record


Safety Culture and Attitudes Among Spine Professionals: Results of an International Survey.
International survey. A positive safety culture has been linked to better surgical outcomes, less hospital costs and less patient harm and severity-adjusted mortality, making safety attitudes relevant for society and both patient and health care provider. The aim of the current study is to assess attitudes toward safety culture among spinal care professionals. An online survey was distributed to members of AOSpine International in 2016. The survey consisted out of 3 parts: (1) demographics, (2) the Safety Attitude Questionnaire (SAQ), and (3) expectations of responsibility for improving the safety culture. The SAQ measured job satisfaction, teamwork, and safety climate, perceptions of management, stress recognition, and working conditions. Multivariate logistic regression was performed to identify factors associated with safety attitudes. A total of 356 respondents replied. The SAQ showed that respondents in Africa have a significant lower score (odds ratio [OR] 0.19, P < .05) on working conditions, compared with spine professionals in Asia. Respondents in North America had the highest odds of having a higher score (OR 4.04, P < .05) compared with respondents in Asia. Gender, continent, occupation, tenure, and the number of employees in the clinic were not associated with the dimensions of safety culture (P > .05). The majority expected the surgeon to be mainly responsible for improving the safety culture in the operating room and at management level. There was a lot of variety among different respondents worldwide albeit respondents in Africa scored significantly lower on working conditions, compared with spine professionals in Asia and North America, suggesting that wealthier countries have better working conditions which may lead toward better safety attitudes. Closer collaboration between hospital management and clinicians seems to be a target for improvement in safety culture. Furthermore, to show clinical relevance in this field, studies correlating safety attitudes with outcomes after spine surgery are warranted.


Development of human gene reporter cell lines using rAAV mediated homologous recombination.
Understanding mechanisms of gene regulation has broad therapeutic implications for human disease. Here we describe a novel method for generating human cell lines that serve as reporters of transcriptional activity. This method exploits the ability of recombinant adeno-associated virus to mediate the insertion of exogenous DNA sequences into specific genomic loci through homologous recombination. To overcome the severe size limitation of the rAAV for carrying exogenous DNA, an enhanced green fluorescent protein (EGFP)-Luciferase fusion gene was used as both a selectable marker and gene expression reporter. EGFP was used for selection of correctly targeted alleles by taking advantage of known regulatory conditions that activate transcription of specific genes. Using this method, we describe the generation of primary human fibroblasts that express EGFP-Luciferase under the control of the c-Myc oncogene.


Rab5 GTPases are required for optimal TORC2 function.
Target of rapamycin complex-2 (TORC2), a conserved protein kinase complex, is an indispensable regulator of plasma membrane homeostasis. In budding yeast (Saccharomyces cerevisiae), the essential downstream effector of TORC2 is protein kinase Ypk1 and its paralog Ypk2. Muk1, a Rab5-specific guanine nucleotide exchange factor (GEF), was identified in our prior global screen for candidate Ypk1 targets. We confirm here that Muk1 is a substrate of Ypk1 and demonstrate that Ypk1-mediated phosphorylation stimulates Muk1 function in vivo. Strikingly, yeast lacking its two Rab5 GEFs (Muk1 and Vps9) or its three Rab5 paralogs (Vps21/Ypt51, Ypt52, and Ypt53) or overexpressing Msb3, a Rab5-directed GTPase-activating protein, all exhibit pronounced reduction in TORC2-mediated phosphorylation and activation of Ypk1. Vps21 coimmunoprecipitates with TORC2, and immuno-enriched TORC2 is less active in vitro in the absence of Rab5 GTPases. Thus, TORC2-dependent and Ypk1-mediated activation of Muk1 provides a control circuit for positive (self-reinforcing) up-regulation to sustain TORC2-Ypk1 signaling.


Insulin increases the potency of glycine at ionotropic glycine receptors.
The mechanisms by which insulin modulates neuronal plasticity and pain processes remain poorly understood. Here we report that insulin rapidly increases the function of glycine receptors in murine spinal neurons and recombinant human glycine receptors expressed in human embryonic kidney cells. Whole-cell patch-clamp recordings showed that insulin reversibly enhanced current evoked by exogenous glycine and increased the amplitude of spontaneous glycinergic miniature inhibitory postsynaptic currents recorded in cultured spinal neurons. Insulin (1 microM) also shifted the glycine concentration-response plot to the left and reduced the glycine EC(50) value from 52 to 31 microM. Currents evoked by a submaximal concentration of glycine were increased to approximately 140% of control. The glycine receptor alpha subunit was sufficient for the enhancement by insulin because currents from recombinant homomeric alpha(1) receptors and heteromeric alpha(1)beta receptors were both increased. Insulin acted at the insulin receptor via pathways dependent on tyrosine kinase and phosphatidylinositol 3 kinase because the insulin effect was eliminated by the insulin receptor antagonist, hydroxy-2-naphthalenylmethylphosphonic acid trisacetoxymethyl ester, the tyrosine kinase inhibitor lavendustin A, and the phosphatidylinositol 3 kinase antagonist wortmannin. Together, these results show that insulin has a novel regulatory action on the potency of glycine for ionotropic glycine receptors.


Prostaglandin and leukotriene receptors in pulmonary, vascular, and uterine smooth muscle.
Prostaglandins are currently used to maintain patency of the ductus arteriosus and to elicit uterine contractions. Prostaglandin synthesis inhibitors are used to promote closure of the ductus and their administration in pregnant animals has produced fetal pulmonary hypertension. Exposure of the human fetus to inhibitors of prostaglandin synthesis has been associated with persistent pulmonary hypertension. A case report of a child with primary hypertension supports the hypothesis that the balance of prostaglandin metabolites plays an important role in maintaining PVR. Leukotrienes have been identified in the sputum of allergic asthmatic patients, patients with cystic fibrosis and infants with persistent pulmonary hypertension. Leukotriene inhibition in rats and newborn lambs prevented and reversed HPV. Receptors for prostaglandins have been identified in smooth muscle preparations of the uterus and renal glomerulus. Further studies have characterized the binding sites in lung tissue, giving supportive evidence for the existence of receptor sites there. Specific receptor sites for LTC4 and LTD4 have been demonstrated in lung tissue. Temperature, pH, and the presence of cations and guanine nucleotides have been shown to affect the receptor density and affinity. Lewis et al demonstrated that the characteristics of the receptor for [3H]LTD4 in the human lung are identical in adult and fetal tissue. This leads to the need for further investigation of the receptors and the effects of the local environments in an attempt to explain the physiologic changes seen in the successful and unsuccessful transition from fetal to neonatal circulation.


Immunologic considerations of large volume radiotherapy.
There is clinical evidence that the immune response can increase or decrease cancer growth. 1) Cancer is increased in congenital immune deficiency states and in those given immuno-suppressants after renal transplantation; 2) there is a correlation between mononuclear cell infiltration and prognosis; 3) spontaneous regression occurs occasionally on an immunologic basis; 4) cancer specific antigens and antibodies can be demonstrated, and 5) immunotherapy can cause tumor regression. The cells that are responsible for the immune response are 1) families of thymic-derived lymphocytes, or T-cells, ("memory," "effector", "helper" or "suppressor" T-cells), and 2) bursal-derived lymphocytes, or B-cells, which on specific sensitization become either plasma cells that produce cytotoxic or blocking antibody or macrophages (A-cells) that process antigen, and may become "armed" with cytophilic antibody. The main effect of local radiotherapy is to destroy certain families of radiosensitive lymphocytes in the afferent, central and efferent components of the immune response. In Hodgkin's disease, extended field radiotherapy causes a prolonged decrease in the number of lymphocytes in the peripheral blood and a decrease in function of the cells, as determined by RNA and DNA synthesis after culture with mitogen, phytohemagglutinin. There is no correlation, however, with the values after treatment and recurrence of the disease. The effect of local radiotherapy to large volumes of tissues, on the incidence of new primary cancers, is uncertain but the majority of reports show that it is no effect.


Isolation and expression of a pea vicilin cDNA in the yeast Saccharomyces cerevisiae.
A cDNA clone containing the complete coding sequence for vicilin from pea (Pisum sativum L.) was isolated. It specifies a 50,000-Mr protein that in pea is neither post-translationally processed nor glycosylated. The cDNA clone was expressed in yeast from a 2 micron plasmid by using the yeast phosphoglycerate kinase promoter and initiator codon. The resultant fusion protein, which contains the first 16 amino acid residues of phosphoglycerate kinase in addition to the vicilin sequence, was purified and subsequently characterized. It has slightly slower mobility on SDS/polyacrylamide-gel electrophoresis than standard pea vicilin and forms a mixture of multimers, some of which resemble the native protein.


Short Chain Fatty Acid Metabolism in Relation to Gut Microbiota and Genetic Variability.
It is widely accepted that the gut microbiota plays a significant role in modulating inflammatory and immune responses of their host. In recent years, the host-microbiota interface has gained relevance in understanding the development of many non-communicable chronic conditions, including cardiovascular disease, cancer, autoimmunity and neurodegeneration. Importantly, dietary fibre (DF) and associated compounds digested by the microbiota and their resulting metabolites, especially short-chain fatty acids (SCFA), were significantly associated with health beneficial effects, such as via proposed anti-inflammatory mechanisms. However, SCFA metabolic pathways are not fully understood. Major steps include production of SCFA by microbiota, uptake in the colonic epithelium, first-pass effects at the liver, followed by biodistribution and metabolism at the host's cellular level. As dietary patterns do not affect all individuals equally, the host genetic makeup may play a role in the metabolic fate of these metabolites, in addition to other factors that might influence the microbiota, such as age, birth through caesarean, medication intake, alcohol and tobacco consumption, pathogen exposure and physical activity. In this article, we review the metabolic pathways of DF, from intake to the intracellular metabolism of fibre-derived products, and identify possible sources of inter-individual variability related to genetic variation. Such variability may be indicative of the phenotypic flexibility in response to diet, and may be predictive of long-term adaptations to dietary factors, including maladaptation and tissue damage, which may develop into disease in individuals with specific predispositions, thus allowing for a better prediction of potential health effects following personalized intervention with DF.


Protein Microarray-Guided Development of a Highly Sensitive and Specific Dipstick Assay for Glanders Serodiagnostics.
Burkholderia mallei, the causative agent of glanders, is a clonal descendant of Burkholderia pseudomallei, the causative agent of melioidosis, which has lost its environmental reservoir and has a restricted host range. Despite limitations in terms of sensitivity and specificity, complement fixation is still the official diagnostic test for glanders. Therefore, new tools are needed for diagnostics and to study the B. mallei epidemiology. We recently developed a highly sensitive serodiagnostic microarray test for human melioidosis based on the multiplex detection of B. pseudomallei proteins. In this study, we modified our array tests by using anti-horse IgG conjugate and tested sera from B. mallei-infected horses (n = 30), negative controls (n = 39), and horses infected with other pathogens (n = 14). Our array results show a sensitivity of 96.7% (confidence interval [CI] 85.5 to 99.6%) and a specificity of 100.0% (CI, 95.4 to 100.0%). The reactivity pattern of the positive sera on our array test allowed us to identify a set of 12 highly reactive proteins of interest for glanders diagnosis. The B. mallei variants of the three best protein candidates were selected for the development of a novel dipstick assay. Our point-of-care test detected glanders cases in less than 15 min with a sensitivity of 90.0% (CI, 75.7 to 97.1%) and a specificity of 100.0% (CI, 95.4 to 100.0%). The microarray and dipstick can easily be adopted for the diagnosis of both B. mallei and B. pseudomallei infections in different animals. Future studies will show whether multiplex serological testing has the potential to differentiate between these pathogens.


The effects of Global Fund financing on health governance in Brazil.
The impact of donors, such as national government (bi-lateral), private sector, and individual financial (philanthropic) contributions, on domestic health policies of developing nations has been the subject of scholarly discourse. Little is known, however, about the impact of global financial initiatives, such as the Global Fund to Fight AIDS, Tuberculosis, and Malaria, on policies and health governance of countries receiving funding from such initiatives. This study employs a qualitative methodological design based on a single case study: Brazil. Analysis at national, inter-governmental and community levels is based on in-depth interviews with the Global Fund and the Brazilian Ministry of Health and civil societal activists. Primary research is complemented with information from printed media, reports, journal articles, and books, which were used to deepen our analysis while providing supporting evidence. Our analysis suggests that in Brazil, Global Fund financing has helped to positively transform health governance at three tiers of analysis: the national-level, inter-governmental-level, and community-level. At the national-level, Global Fund financing has helped to increased political attention and commitment to relatively neglected diseases, such as tuberculosis, while harmonizing intra-bureaucratic relationships; at the inter-governmental-level, Global Fund financing has motivated the National Tuberculosis Programme to strengthen its ties with state and municipal health departments, and non-governmental organisations (NGOs); while at the community-level, the Global Fund's financing of civil societal institutions has encouraged the emergence of new civic movements, participation, and the creation of new municipal participatory institutions designed to monitor the disbursement of funds for Global Fund grants. Global Fund financing can help deepen health governance at multiple levels. Future work will need to explore how the financing of civil society by the Global Fund and other donors influence policy agenda-setting and institutional innovations for increased civic participation in health governance and accountability to citizens.


Acetazolamide attenuates transvascular fluid flux in equine lungs during intense exercise.
During intense exercise in horses the transvascular fluid flux in the pulmonary circulation (Jv-a) represents 4% of cardiac output (Q). This fluid flux has been attributed to an increase in pulmonary transmural hydrostatic forces, increases in perfused microvascular surface area, and reversible alterations in capillary permeability under conditions of high flow and pressure. Erythrocyte fluid efflux, however, accounts for a significant fraction of Jv-a. In the lung the Jacobs-Stewart cycle occurs with diffusion of CO2 into alveolar space with possible accompanying chloride (Cl-) and water movement from the erythrocyte directly into the pulmonary interstitium. We hypothesised that inhibition of carbonic anhydrase in erythrocytes inhibits the Jacobs-Stewart cycle and attenuates Jv-a. Five horses were exercised on a treadmill until fatigue without (control) and with acetazolamide treatment (30 mg kg(-1) 30 min before exercise). Erythrocyte fluid efflux, plasma fluid flux across the lung and Jv-a were calculated using haemoglobin, haematocrit, plasma protein and Q. Fluid fluxes were used to calculate erythrocyte, plasma and whole blood Cl- fluxes across the lung. Cardiac output was not different between control and acetazolamide treatment. During exercise erythrocyte fluid efflux and Jv-a increased in control (9.3±3.3 and 11.0±4.4 l min(-1), respectively) and was higher than after acetazolamide treatment (3.8±1.6 and 1.2±1.2 l min(-1), respectively) (P<0.05). Plasma fluid flux did not change from rest in control and decreased after acetazolamide treatment (-4.5±1.5 l min(-1)) (P<0.05). Erythrocyte Cl- flux increased during exercise in control and after acetazolamide treatment (P<0.05). During exercise plasma Cl- flux across the lung did not change in control; however, it increased with acetazolamide treatment (P=0.0001). During exercise whole blood Cl- flux increased across the lung in control (P<0.05) but not after acetazolamide treatment. The results indicate that Jv-a in the lung is dependent on the Jacobs-Stewart cycle and mostly independent of transmural hydrostatic forces. It also appears that Jv-a is mediated by Cl- and water egress from erythrocytes directly into the interstitium without transit through plasma.


Enhancement of optical Kerr effect in quantum-cascade lasers with multiple resonance levels.
In this paper, we investigated the optical Kerr lensing effect in quantum-cascade lasers with multiple resonance levels. The Kerr refractive index n2 is obtained through the third-order susceptibility at the fundamental frequency chi(3)( omega; omega, omega,-omega). Resonant two-photon processes are found to have almost equal contributions to chi(3)( omega; omega, omega,-omega) as the single-photon processes, which result in the predicted enhancement of the positive nonlinear (Kerr) refractive index, and thus may enhance mode-locking of quantum-cascade lasers. Moreover, we also demonstrate an isospectral optimization strategy for further improving n2 through the band-structure design, in order to boost the multimode performance of quantum-cascade lasers. Simulation results show that the optimized stepwise multiple-quantum-well structure has n2 approximately 10-8 cm2/W, a twofold enhancement over the original flat quantum-well structure. This leads to a refractive-index change (delta)n of about 0.01, which is at the upper bound of those reported for typical Kerr medium. This stronger Kerr refractive index may be important for quantum-cascade lasers ultimately to demonstrate self-mode-locking.


Diabetes in Africa. Diabetes microvascular and macrovascular disease in Africa.
This review on the prevalence and characteristics of diabetes micro- and macrovascular disease in Africa is based on a bibliographical Medline search and diabetes conference proceedings of published data over the past decade. The prevalence of diabetic retinopathy varies from 16 to 77% depending on the duration of diabetes and glycaemic control, with severe retinopathy representing 15% of all cases. At diagnosis, 21-25% of type 2 patients and 9.5% of type 1 patients have retinopathy. The prevalence of nephropathy varies between 32-57% after a mean duration of diabetes of 5-10 years, and 5-28% within the first year following the diagnosis of diabetes. The prevalence of neuropathy varies widely depending on the methodology used. Macrovascular complications of diabetes are considered rare in Africa despite a high prevalence of hypertension. Coronary heart disease may affect 5-8% of type 2 diabetic patients and cardiomyopathy up to 50% of all patients. Lower extremity amputation varies from 1.5 to 7%, and about 12% of all hospitalized diabetic patients have foot ulceration. Neuropathy underlies diabetic foot more often than peripheral vascular disease. In conclusion, whereas microvascular complications of diabetes are highly prevalent and occur early during the course of disease, macrovascular disease is rare. Late diagnosis of diabetes, poor metabolic control and nonstandardized diagnostic procedures rather than genetic predisposition may account for this difference from other populations around the world.


Hyperthyroidism after primary hypothyroidism. Follow-up with serial thyroid biopsies.
Hyperthyroidism occurred following primary hypothyroidism in a 46-year-old man with serologically and histologically proved chronic lymphocytic thyroiditis. Repeated thyroid biopsy specimens revealed that histologic features compatible with chronic lymphocytic thyroiditis seen at the initial hypothyroid state subsequently underwent a remarkable resolution, with titers of circulating antithyroid antibodies being reduced in correspondence with the histologic improvement. This case shows that primary hypothyroidism in adults can spontaneously evolve into a hyperthyroid state, as has been suggested previously, and that the histologic abnormalities in chronic lymphocytic thyroiditis may not necessarily be irreversible.


Retroperitoneal fibrosis secondary to different etiologies (hemilaminectomy and hypothyroidism): reports of two cases.
Retroperitoneal fibrosis (RF) is a clinical entity characterized by the progressive proliferation of connective tissue that rarely forms a mass involving the periaortic area of the abdomen, which may be idiopathic as well as a result of an inflammatory process after aneurysmal dilatation of the aorta. This fibrotic tissue may cover both aorta and iliac arteries, reach the retroperitoneum and surrounding ureters, and cause serious obstructions and renal insufficiency in three-quarters of patients. Most of the patients are known to have atherosclerosis and local inflammation against the antigens of the plaques. A systemic autoimmune disease presenting with retroperitoneal fibrosis seems to be pronounced more frequently nowadays because of the elevated acute-phase reactant levels, positive autoantibodies, and concurrent autoimmune diseases affecting other organs in majority of the diagnosed patients. Ultrasonography, computed tomography, magnetic resonance imaging, positron emission tomography, and retroperitoneal biopsy are useful in diagnosing and assessing the full extent of the disease. Surgical interventions such as ureterolysis and aneurysm repair are frequently performed, but medical therapy including steroids and immunosuppressants is often needed because of the inflammatory and chronic-relapsing nature of the disease. In this paper, we described two cases diagnosed with RF secondary to hemilaminectomy and hypothyroidism, and we summarized the literature related to RF.


Topical anaesthesia and decongestion in rhinology.
Topical anaesthesia and decongestion of the sinonasal mucosa are used commonly in rhinology practice to facilitate nasal endoscopy, as well as debridement and biopsies. Topical agents used for sinonasal anaesthesia include lignocaine, tetracaine and cocaine. Unlike lignocaine and tetracaine, cocaine also has a decongestant effect. Phenylephrine, oxymetazoline, xylometazoline or adrenaline are usually added to lignocaine and tetracaine to provide decongestion. Several studies have been performed seeking to identify the optimal nasal preparation for nasal endoscopy in the clinic setting. However, there remains no clear consensus in the literature resulting in ongoing wide variation between anaesthetic-decongestant preparations used in clinical practice. Indeed, some authors have argued that no anaesthetic is required at all for flexible nasendoscopy despite the apparent consensus that nasal instrumentation is generally uncomfortable, inferred by the persistence of ongoing research in this area. This review provides a practical summary of local anaesthetic and decongestant pharmacology as it relates to rhinologic practice and summarises the literature to date, with the goal of identifying current gaps in the literature and guiding future research efforts.


A comprehensive faculty development model for nursing education.
Professional nursing education has undergone profound legislative changes requiring a university baccalaureate in nursing as entry to practice as a registered nurse (RN) in Ontario, Canada. Subsequent partnerships between colleges and universities were mandated by the ministry of post secondary education in order to maximize existing resources, such as faculty, and capitalize on the strenghts of both sectors. Faculty, in partnered collaborative undergraduate nursing programs, are challenged by the ever-evolving transition in conceptualization, development, and delivery of nursing education; consequently, the design, dissemination, and evaluation of effective faculty development programs is of paramount importance (Steinert, 2000). This paper focuses on the creation of the Comprehensive Faculty Development Model implemented by a collaborative BScN program partnership in south-western Ontario. It describes the model's contextual underpinnings, illustrates the component parts, explains their relationship, and provides an in-depth discussion of foundational concepts. The model was developed under the auspices of a collaborative faculty development committee with representation from all partners. Summaries of four research studies designed and implemented by members of the partnership provide a useful assessment of how faculty members experienced the inaugural BScN program; however, more study is needed in order to understand what approaches to faculty development are most effective and sustainable.


Contralateral brachial plexus neuropathy after arthroscopic shoulder surgery.
This case report presents a neurologic complication that occurred after shoulder arthroscopic surgery on the contralateral arm. This brachial plexus palsy has been documented as a reversible C7-T1 lesion, which was the consequence of the patient's unknown cervical rib and the applied lateral position during the operation. In this case, the recovery was almost complete within 3 months postoperatively; however, one should take care to prevent these complications with an appropriate positioning of patients with an anatomic variant.


Allosteric pluripotency: challenges and opportunities.
Allosteric pluripotency arises when the functional response of an allosteric receptor to an allosteric stimulus depends on additional allosteric modulators. Here, we discuss allosteric pluripotency as observed in the prototypical Protein Kinase A (PKA) as well as in other signaling systems, from typical multidomain signaling proteins to bacterial enzymes. We identify key drivers of pluripotent allostery and illustrate how hypothesizing allosteric pluripotency may solve apparent discrepancies currently present in the literature regarding the dual nature of known allosteric modulators. We also outline the implications of allosteric pluripotency for cellular signaling and allosteric drug design, and analyze the challenges and opportunities opened by the pluripotent nature of allostery.


Exercise-induced ischemia after successful percutaneous coronary intervention is related to distal coronary endothelial dysfunction.
As endothelial dysfunction can be responsible for myocardial ischemia even in the absence of significant coronary lesions, we aimed to assess the correlation between endothelium-dependent vasomotor function and inducible ischemia late after successful coronary angioplasty. In 30 patients without angiographic restenosis or coronary disease progression, coronary endothelial function was determined by acetylcholine infusion 6 months after elective single-vessel stenting of the left coronary artery. Acetylcholine-induced diameter changes were assessed in the proximal and distal segments of both the stented and the contralateral vessels by means of quantitative coronary angiography. A maximal workload ergometric test was also performed prior to endothelial function testing. Acetylcholine induced significant vasoconstrictive responses in the distal but not in the proximal segments of both the stented (-11 +/- 7% versus baseline; p < .01) and the contralateral vessels (-11 +/- 6%; p < .01), which were significantly correlated (R = .48; p < .05) and were completely reverted by nitroglycerine. Inducible ischemia was the only predictive factor for distal vasoconstriction in the stented vessel (p < .01) but not in the contralateral vessel (p = .06). Patients with minor signs of ischemia at the ergometric test showed a greater vasoconstriction than those with a completely normal test (-16 +/- 7% versus -7 +/- 6%; p< .01). Exercise-induced ischemia late after successful percutaneous coronary intervention is related to distal coronary endothelial dysfunction.


Laboratory bioassays to estimate the lethal and sublethal effects of various insecticides and fungicides on Deraeocoris brevis (Hemiptera: Miridae).
This laboratory bioassay focused on lethal and sublethal effects of five insecticides (chlorantraniliprole, cyantraniliprole, spinetoram, novaluron, and lambda-cyhalothrin) and two fungicide treatments (sulfur and a mixture of copper hydroxide and mancozeb) on the predatory mired bug, Deraeocoris brevis (Uhler) (Hemiptera: Miridae) using second instars and adult males and females. Formulated pesticides were tested using concentrations that were equivalent to the high label rate (1x) (high rate) and 1/10th of that amount (0.1x) (low rate) dissolved in 378.5 liters of water. Lambda-cyhalothrin was highly toxic to D. brevis nymphs and adults at both rates, whereas both rates of novaluron were highly toxic to nymphs. Cyantraniliprole, chlorantraniliprole, and novaluron were less toxic to adults, and chlorantraniliprole and spinetoram were less toxic to nymphs. Both rates of spinetoram caused significant mortality to adults. Fecundity of adult females was affected negatively by the high rates of either novaluron or spinetoram, whereas the fertility was affected only by the high rate of novaluron. The high rate of spinetoram reduced survival of nymphs. Adults treated with spinetoram had reduced longevity. Cyantraniliprole caused some mortality to nymphs and affected their survival. Both rates of sulfur were toxic to nymphs and affected emergence to adults. The mixture of copper hydroxide and mancozeb was less toxic to D. brevis. Neither adult longevity nor sex ratio was affected by the fungicides. The r values for D. brecis treated with lambda-cyhalothrin, novaluron, spinetoram, and sulfur were low, indicating that these products may have negative impact on population growth.


Adding online storytelling-based acceptance and commitment therapy to antidepressant treatment for primary care patients: a randomized clinical trial.
Depression is most often treated in primary care, where the prevailing treatment is antidepressant medication. Primary care patients with depression are less likely to be exposed to psychosocial interventions, despite evidence suggesting many of these treatments are effective. An example is acceptance and commitment therapy (ACT), a behavioral treatment for depression with a growing evidence base. A self-guided ACT intervention with a peer narrative (i.e. storytelling) format was developed with the intention of creating a treatment option for primary care patients that was more accessible than traditional psychotherapy. Titled LifeStories, the online program features videos of real individuals sharing coping skills for depression based on lived experiences and key ACT principles. A total of 93 primary care patients taking antidepressants were randomized to either continued antidepressant treatment alone or antidepressant treatment plus LifeStories for 4 weeks. There were no differences over time on depression severity and psychological inflexibility. However, LifeStories led to greater improvements in quality of life and increased patients' interest in additional treatment compared to antidepressant medication alone.Clinical trial pre-registration: ClinicalTrials.gov (NCT04757961).


A systematic comparison of supervised classifiers.
Pattern recognition has been employed in a myriad of industrial, commercial and academic applications. Many techniques have been devised to tackle such a diversity of applications. Despite the long tradition of pattern recognition research, there is no technique that yields the best classification in all scenarios. Therefore, as many techniques as possible should be considered in high accuracy applications. Typical related works either focus on the performance of a given algorithm or compare various classification methods. In many occasions, however, researchers who are not experts in the field of machine learning have to deal with practical classification tasks without an in-depth knowledge about the underlying parameters. Actually, the adequate choice of classifiers and parameters in such practical circumstances constitutes a long-standing problem and is one of the subjects of the current paper. We carried out a performance study of nine well-known classifiers implemented in the Weka framework and compared the influence of the parameter configurations on the accuracy. The default configuration of parameters in Weka was found to provide near optimal performance for most cases, not including methods such as the support vector machine (SVM). In addition, the k-nearest neighbor method frequently allowed the best accuracy. In certain conditions, it was possible to improve the quality of SVM by more than 20% with respect to their default parameter configuration.