Non-communicable diseases in the Arab world.
According to the results of the Global Burden of Disease Study 2010, the burden of non-communicable diseases (cardiovascular disease, cancer, chronic lung diseases, and diabetes) in the Arab world has increased, with variations between countries of different income levels. Behavioural risk factors, including tobacco use, unhealthy diets, and physical inactivity are prevalent, and obesity in adults and children has reached an alarming level. Despite epidemiological evidence, the policy response to non-communicable diseases has been weak. So far, Arab governments have not placed a sufficiently high priority on addressing the high prevalence of non-communicable diseases, with variations in policies between countries and overall weak implementation. Cost-effective and evidence-based prevention and treatment interventions have already been identified. The implementation of these interventions, beginning with immediate action on salt reduction and stricter implementation of tobacco control measures, will address the rise in major risk factors. Implementation of an effective response to the non-communicable-disease crisis will need political commitment, multisectoral action, strengthened health systems, and continuous monitoring and assessment of progress. Arab governments should be held accountable for their UN commitments to address the crisis. Engagement in the global monitoring framework for non-communicable diseases should promote accountability for effective action. The human and economic burden leaves no room for inaction.


Related male Drosophila melanogaster reared together as larvae fight less and sire longer lived daughters.
Competition over access to reproductive opportunities can lead males to harm females. However, recent work has shown that, in Drosophila melanogaster, male competition and male harm of females are both reduced under conditions simulating male-specific population viscosity (i.e., in groups where males are related and reared with each other as larvae). Here, we seek to replicate these findings and investigate whether male population viscosity can have repercussions for the fitness of offspring in the next generation. We show that groups of unrelated-unfamiliar (i.e., unrelated individuals raised apart) males fight more intensely than groups of related-familiar males (i.e., full siblings raised together as larvae), supporting previous findings, and that exposure to a female is required to trigger these differential patterns of male-male competition. Importantly, we show that differences in male-male competition can be associated with transgenerational effects: the daughters of females exposed to unrelated-unfamiliar males suffered higher mortality than the daughters of females exposed to related-familiar males. Collectively, these results suggest that population structure (i.e., variation in the relatedness and/or larval familiarity of local male groups) can modulate male-male competition with important transgenerational consequences.


The impact of fathers' physical and psychosocial work conditions on attempted and completed suicide among their children.
Adverse employment experiences, particularly exposure to unemployment and the threat of unemployment, have been strongly associated with several adverse mental and physical health outcomes including suicide. However, virtually no research has been conducted on the trans-generational impact of parental working conditions on attempted or completed suicide among their children. We conducted a nested case control study based on a cohort, gathered in the western Canadian province of British Columbia, of male sawmill workers and a second cohort of their children. Physical and psychosocial work conditions to which fathers were exposed during the first 16 years of their children's lives, measured using the demand/control model, were linked to hospital suicide records (attempted and completed) among their children. Two hundred and fifty children in the cohort attempted or committed suicide between 1985 and 2001. Multivariate models, with partial control for father's mental health outcomes prior to their child's suicide demonstrate, 1) a strong association between low duration of father's employment at a study sawmill and attempted suicide for their male children, 2) elevated odds for attempted suicide among female children of fathers' employed in a sawmill job with low control and, 3) a strong association between fathers in jobs with low psychological demand and completed suicides among male children. Exposure of fathers to adverse psychosocial work conditions during the first 16 years of their children's life was associated with greater odds for attempted and completed suicide among their children.


Enterocele Presenting as Anterior Rectal Prolapse: Resolution with Vaginal Repair.
An enterocele is a pelvic hernia formed from the separation of endopelvic fascia, associated with the posterior or anterior vaginal fornix, and most commonly located in the posterior superior vaginal segment. Rectal prolapse is a debilitating condition in which the mucosa of the rectum protrudes circumferentially from the anus. Surgical repair is the recommended treatment for rectal prolapse, and though there are many different surgical options, there is no consensus on which approach is best. We present a case of anterior rectal prolapse due to enterocele which was treated by correction of enterocele with a vaginal approach and propose some clinical features and diagnostic techniques that may distinguish this entity from traditional rectal prolapse.


Rapid evolution of the sequences and gene repertoires of secreted proteins in bacteria.
Proteins secreted to the extracellular environment or to the periphery of the cell envelope, the secretome, play essential roles in foraging, antagonistic and mutualistic interactions. We hypothesize that arms races, genetic conflicts and varying selective pressures should lead to the rapid change of sequences and gene repertoires of the secretome. The analysis of 42 bacterial pan-genomes shows that secreted, and especially extracellular proteins, are predominantly encoded in the accessory genome, i.e. among genes not ubiquitous within the clade. Genes encoding outer membrane proteins might engage more frequently in intra-chromosomal gene conversion because they are more often in multi-genic families. The gene sequences encoding the secretome evolve faster than the rest of the genome and in particular at non-synonymous positions. Cell wall proteins in Firmicutes evolve particularly fast when compared with outer membrane proteins of Proteobacteria. Virulence factors are over-represented in the secretome, notably in outer membrane proteins, but cell localization explains more of the variance in substitution rates and gene repertoires than sequence homology to known virulence factors. Accordingly, the repertoires and sequences of the genes encoding the secretome change fast in the clades of obligatory and facultative pathogens and also in the clades of mutualists and free-living bacteria. Our study shows that cell localization shapes genome evolution. In agreement with our hypothesis, the repertoires and the sequences of genes encoding secreted proteins evolve fast. The particularly rapid change of extracellular proteins suggests that these public goods are key players in bacterial adaptation.


Aryl hydrocarbon receptors in the frog Xenopus laevis: two AhR1 paralogs exhibit low affinity for 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD).
2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) is a potent developmental toxicant in most vertebrates. However, frogs are relatively insensitive to TCDD toxicity, especially during early life stages. Toxicity of TCDD and related halogenated aromatic hydrocarbons is mediated by the aryl hydrocarbon receptor (AhR), and specific differences in properties of the AhR signaling pathway can underlie in TCDD toxicity in different species. This study investigated the role of AhR in frog TCDD insensitivity, using Xenopus laevis as a model system. X. laevis, a pseudotetraploid species, expresses two distinct AhR1 genes, AhR1alpha and AhR1beta. Sharing 86% amino acid identity, these likely represent distinct genes, both orthologous to mammalian AhR and paralogous to the AhR2 gene(s) in most fish. Both AhR1alpha and AhR1beta exhibit TCDD-dependent binding of cognate DNA sequences, but they bind TCDD with at least 20-fold lower affinity than the mouse AhR(b-1) protein, and they are similarly less responsive in TCDD-induced reporter gene induction in conjunction with the mouse CYP1A1 promoter. Furthermore, CYP1A6 and CYP1A7 induction by TCDD in cultured X. laevis A6 cells appears much less responsive than CYP1A induction in cell lines derived from more sensitive animals. Taken together, these data suggest that low affinity binding by X. laevis AhRs plays an important mechanistic role in the insensitivity of frogs to TCDD. An understanding of these molecular mechanisms should aid amphibian ecotoxicology and refine the use of frog embryos as a model [e.g. in FETAX (Frog Embryo Teratogenesis Assay-Xenopus)] for determining developmental toxicity of samples containing dioxin-like compounds.


Refined diagnostic criteria and classification of mast cell leukemia (MCL) and myelomastocytic leukemia (MML): a consensus proposal.
Mast cell leukemia (MCL), the leukemic manifestation of systemic mastocytosis (SM), is characterized by leukemic expansion of immature mast cells (MCs) in the bone marrow (BM) and other internal organs; and a poor prognosis. In a subset of patients, circulating MCs are detectable. A major differential diagnosis to MCL is myelomastocytic leukemia (MML). Although criteria for both MCL and MML have been published, several questions remain concerning terminologies and subvariants. To discuss open issues, the EU/US-consensus group and the European Competence Network on Mastocytosis (ECNM) launched a series of meetings and workshops in 2011-2013. Resulting discussions and outcomes are provided in this article. The group recommends that MML be recognized as a distinct condition defined by mastocytic differentiation in advanced myeloid neoplasms without evidence of SM. The group also proposes that MCL be divided into acute MCL and chronic MCL, based on the presence or absence of C-Findings. In addition, a primary (de novo) form of MCL should be separated from secondary MCL that typically develops in the presence of a known antecedent MC neoplasm, usually aggressive SM (ASM) or MC sarcoma. For MCL, an imminent prephase is also proposed. This prephase represents ASM with rapid progression and 5%-19% MCs in BM smears, which is generally accepted to be of prognostic significance. We recommend that this condition be termed ASM in transformation to MCL (ASM-t). The refined classification of MCL fits within and extends the current WHO classification; and should improve prognostication and patient selection in practice as well as in clinical trials.


Clinical Inquiry: Does caffeine intake during pregnancy affect birth weight?
No. Reducing caffeinated coffee consumption by 180 mg of caffeine (the equivalent of 2 cups) per day after 16 weeks' gestation doesn't affect birth weight. Consuming more than 300 mg of caffeine per day is associated with a clinically trivial, and statistically insignificant (less than 1 ounce), reduction in birth weight, compared with consuming no caffeine.


Peripartum cardiomyopathy: ten year experience at a tertiary care hospital in Pakistan.
There is very little literature regarding peripartum cardiomyopathy from the Asian countries. We conducted this study to determine demographic details, clinical presentations, complications and recovery of left ventricular (LV) systolic function in peripartum cardiomyopathy (PPCMP) patients of Pakistani origin. A ten year retrospective case series of PPCMP was conducted at the Aga Khan University Hospital. Patients were also followed up for six months after presentation, with special regard to improvement in the LV function. Total 45 patients were included, 25 (55.5%) primigravida and 8 (17.7%) gravida 2 and the remaining 12 (26.6%) were multigravida. Fourteen patients (31.1%) presented during pregnancy and 31 (68.8%) after delivery. All patients presented with CHF and three (6.6%) were complicated with ventricular tachycardia (VT) at presentation. LV systolic dysfunction was present in 39 (86.66%) patients and RV dysfunction in 15 (33.3%) patients. Two patients had LV clot and thromboembolic stroke occurred in another 4 patients. All patients received standard treatment except three patients who had asthma and could not be given beta blockers. Echocardiogram was repeated after 6 month and in 32 (71.1%) patients LV functions recovered to normal. RV function improved in all except 2 (4.4%) patients. All patients were discharged in stable condition. Significant numbers of PPCMP patients, who had severe LV dysfunction at presentation recovered their LV functions at six month follow up.


Neuronal activity in narcolepsy: identification of cataplexy-related cells in the medial medulla.
Narcolepsy is a neurological disorder characterized by sleepiness and episodes of cataplexy. Cataplexy is an abrupt loss of muscle tone, most often triggered by sudden, strong emotions. A subset of cells in the medial medulla of the narcoleptic dog discharged at high rates only in cataplexy and rapid eye movement (REM) sleep. These cells were noncholinergic and were localized to ventromedial and caudal portions of the nucleus magnocellularis. The localization and discharge pattern of these cells indicate that cataplexy results from a triggering in waking of the neurons responsible for the suppression of muscle tone in REM sleep. However, most medullary cells were inactive during cataplexy but were active during REM sleep. These data demonstrate that cataplexy is a distinct behavioral state, differing from other sleep and waking states in its pattern of brainstem neuronal activity.


Effects of betamethasone administration to the fetal sheep in late gestation on fetal cerebral blood flow.
Glucocorticoid administration to women at risk of preterm delivery to accelerate fetal lung maturation has become standard practice. Antenatal glucocorticoids decrease the incidence of intraventricular haemorrhage as well as accelerating fetal lung maturation. Little is known regarding side effects on fetal cerebral function. Cortisol and synthetic glucocorticoids such as betamethasone increase fetal blood pressure and femoral vascular resistance in sheep. We determined the effects of antenatal glucocorticoid administration on cerebral blood flow (CBF) in fetal sheep. Vehicle (n = 8) or betamethasone (n = 8) was infused over 48 h via the jugular vein of chronically instrumented fetal sheep at 128 days gestation (term 146 days). The betamethasone infusion rate was that previously shown to produce fetal plasma betamethasone concentrations similar to human umbilical vein concentrations during antenatal glucocorticoid therapy. Regional CBF was measured in 10 brain regions, using coloured microspheres, before and 24 and 48 h after onset of treatment, and during hypercapnic challenges performed before and 48 h after onset of betamethasone exposure. Betamethasone exposure decreased CBF in all brain regions measured except the hippocampus after 24 h of infusion (P < 0.05). The CBF decrease was most pronounced in the thalamus and hindbrain (45-50% decrease) and least pronounced in the cortical regions (35-40% decrease). It was mediated by an increase in cerebral vascular resistance (CVR, P < 0.05) and led to a decrease in oxygen delivery to subcortical and hindbrain structures of 30-40%, to 8.6 +/- 1.1 ml x (100 g)(-1) x min(-1), and 40-45 %, to 11.0 +/- 1.6 ml x 100 g(-1) x min(-1), respectively (P < 0.05). After 48 h of betamethasone treatment, the reduction in CBF was diminished to about 25-30 %, but was still significant in comparison to vehicle-treated fetuses in all brain regions except three of the five measured cortical regions (P < 0.05). CVR and oxygen delivery were unchanged in comparison to values at 24 h of treatment. The CBF increase in response to hypercapnia was diminished (P < 0.05). These observations demonstrate for the first time that glucocorticoids exert major vasoconstrictor effects on fetal CBF. This mechanism may protect the fetus against intraventricular haemorrhage both at rest and when the fetus is challenged. Betamethasone exposure decreased the hypercapnia-induced increase in CBF (P < 0.05) due to decreased cerebral vasodilatation (P < 0.05).


High Content Analysis of Human Pluripotent Stem Cell Derived Hepatocytes Reveals Drug Induced Steatosis and Phospholipidosis.
Hepatotoxicity is one of the most cited reasons for withdrawal of approved drugs from the market. The use of nonclinically relevant in vitro and in vivo testing systems contributes to the high attrition rates. Recent advances in differentiating human induced pluripotent stem cells (hiPSCs) into pure cultures of hepatocyte-like cells expressing functional drug metabolizing enzymes open up possibilities for novel, more relevant human cell based toxicity models. The present study aimed to investigate the use of hiPSC derived hepatocytes for conducting mechanistic toxicity testing by image based high content analysis (HCA). The hiPSC derived hepatocytes were exposed to drugs known to cause hepatotoxicity through steatosis and phospholipidosis, measuring several endpoints representing different mechanisms involved in drug induced hepatotoxicity. The hiPSC derived hepatocytes were benchmarked to the HepG2 cell line and generated robust HCA data with low imprecision between plates and batches. The different parameters measured were detected at subcytotoxic concentrations and the order of which the compounds were categorized (as severe, moderate, mild, or nontoxic) based on the degree of injury at isomolar concentration corresponded to previously published data. Taken together, the present study shows how hiPSC derived hepatocytes can be used as a platform for screening drug induced hepatotoxicity by HCA.


Sociocultural and economic dimensions of Rift Valley fever.
Health researchers have advocated for a cross-disciplinary approach to the study and prevention of infectious zoonotic diseases, such as Rift Valley Fever. It is believed that this approach can help bring out the social determinants and effects of the zoonotic diseases for the design of appropriate interventions and public health policy. A comprehensive literature review using a systematic search strategy was undertaken to explore the sociocultural and economic factors that influence the transmission and spread of Rift Valley Fever. Although the findings reveal a paucity of social research on Rift Valley Fever, they suggest that livestock sacrificial rituals, food preparation and consumption practices, gender roles, and inadequate resource base for public institutions are the key factors that influence the transmission. It is concluded that there is need for cross-disciplinary studies to increase the understanding of Rift Valley Fever and facilitate appropriate and timely response and mitigation measures.


Psychometric properties of the World Health Organization Quality Of Life Assessment-Brief in methadone patients: a validation study in northern Taiwan.
Quality of life (QOL) is an important outcome measure in the treatment of heroin addiction. The Taiwan version of the World Health Organization Quality of Life assessment (WHOQOL-BREF [TW]) has been developed and studied in various groups, but not specifically in a population of injection drug users. The aim of this study was to analyze the psychometric properties of the WHOQOL-BREF (TW) in a sample of injection drug users undergoing methadone maintenance treatment. A total of 553 participants were interviewed and completed the instrument. Item-response distributions, internal consistency, corrected item-domain correlation, criterion-related validity, and construct validity through confirmatory factor analysis were evaluated. The frequency distribution of the 4 domains of the WHOQOL-BREF (TW) showed no floor or ceiling effects. The instrument demonstrated adequate internal consistency (Cronbach's alpha coefficients were higher than 0.7 across the 4 domains) and all items had acceptable correlation with the corresponding domain scores (r = 0.32-0.73). Correlations (p < 0.01) of the 4 domains with the 2 benchmark items assessing overall QOL and general health were supportive of criterion-related validity. Confirmatory factor analysis yielded marginal goodness-of-fit between the 4-domain model and the sample data. The hypothesized WHOQOL-BREF measurement model was appropriate for the injection drug users after some adjustments. Despite different patterns found in the confirmatory factor analysis, the findings overall suggest that the WHOQOL-BREF (TW) is a reliable and valid measure of QOL among injection drug users and can be utilized in future treatment outcome studies. The factor structure provided by the study also helps to understand the QOL characteristics of the injection drug users in Taiwan. However, more research is needed to examine its test-retest reliability and sensitivity to changes due to treatment.


Effectiveness of human ultralente versus NPH insulin in providing basal insulin replacement for an insulin lispro multiple daily injection regimen. A double-blind randomized prospective trial. The Canadian Lispro Study Group.
To compare human ultralente (UL) insulin with human NPH insulin as basal insulin replacement in patients who use insulin lispro before meals. There were 178 patients with type 1 diabetes who were randomized to receive either human NPH or UL insulin once daily at bedtime in a 1-year double-blind clinical study. Eight-point blood glucose profiles were collected once monthly in the first 4 months, then every 2 months for the remainder of the study. Patients were also asked to perform premeal blood glucose measurements every day throughout the study. If before-supper blood glucose levels consistently exceeded 8 mmol/l despite optimal postprandial control with the lunch dose of insulin lispro, a second dose of basal insulin before breakfast was administered. For the group as a whole, insulin doses before meals and basal insulin doses were similar at baseline. At study's end, meal doses remained the same (30 +/- 1 U/day for UL., 29 +/- 1 U/day for NPH), while basal requirements were somewhat higher for the UL group than the NPH group: 30 +/- 1 U/day vs. 26 +/- 1 U/day, respectively (P < 0.05). The rates of severe hypoglycemia were similar for patients on NPH (0.05 +/- 0.03 per patient every 30 days) and for UL (0.07 +/- 0.04 per patient every 30 days) insulin. There was no significant difference for glycemic control between the NPH and UL groups overall (HbAlc at the end of the study: 7.6 +/- 0.1 vs. 7.7 +/- 0.1%, respectively), and by study's end a similar number of patients in the NPH and the UL groups needed to be switched to twice daily basal insulin (21 and 24%, respectively). Patients requiring twice-daily injections of basal insulin had a longer duration of diabetes (17.8 +/- 1.5 vs. 14.0 +/- 0.8 years, P < 0.05) and a highest baseline HbAlc (8.6 +/- 0.1 vs. 8.0 +/- 0.1%, P < 0.002) and were significantly older (38 +/- 2 vs. 34 +/- 1 years, P < 0.007). Patients who were switched to twice-daily NPH insulin had lower HbAlc levels at study's end compared with those switched to twice-daily UL insulin (7.7 +/- 0.2 vs. 8.2 +/- 0.3%), but this difference was not statistically significant. Distribution of hypoglycemia across the day was also similar in both groups. UL or NPH insulin, when used as the basal insulin for multiple injection regimens, results in similar glycemic control in patients using insulin lispro before meals. However, in patients who require a second injection of basal insulin, NPH insulin appears to provide lower prebreakfast and prelunch glucose levels compared with UL insulin.


A Coordinated Wheeled Gas Pipeline Robot Chain System Based on Visible Light Relay Communication and Illuminance Assessment.
The gas pipeline requires regular inspection since the leakage brings damage to the stable gas supply. Compared to current detection methods such as destructive inspection, using pipeline robots has advantages including low cost and high efficiency. However, they have a limited inspection range in the complex pipe owing to restrictions by the cable friction or wireless signal attenuation. In our former study, to extend the inspection range, we proposed a robot chain system based on wireless relay communication (WRC). However, some drawbacks still remain such as imprecision of evaluation based on received signal strength indication (RSSI), large data error ratio, and loss of signals. In this article, we thus propose a new approach based on visible light relay communication (VLRC) and illuminance assessment. This method enables robots to communicate by the 'light signal relay', which has advantages in good communication quality, less attenuation, and high precision in the pipe. To ensure the stability of VLRC, the illuminance-based evaluation method is adopted due to higher stability than the wireless-based approach. As a preliminary evaluation, several tests about signal waveform, communication quality, and coordinated movement were conducted. The results indicate that the proposed system can extend the inspection range with less data error ratio and more stable communication.


Effect of ghrelin and thyrotropin-releasing hormone on prolactin secretion in normal women.
It is known that ghrelin stimulates the secretion of prolactin in women. The aim of this study was to examine the effect of exogenous thyrotropin-releasing hormone (TRH) on ghrelin-induced prolactin release. Ten healthy normally cycling women were studied in four menstrual cycles. The women were injected intravenously in late follicular phase (follicle size 16-17 mm) with a single dose of normal saline (cycle 1), ghrelin (1 microg/kg) (cycle 2), thyrotropin-releasing hormone (200 microg) (cycle 3), and ghrelin plus thyrotropin-releasing hormone (cycle 4). Blood samples in relation to saline or drugs injection (time 0) were taken at -15, 0, 15, 30, 45, 60, 75, 90, and 120 min. The prolactin and growth hormone responses were assessed. After ghrelin administration (cycles 2 and 4), plasma ghrelin, serum prolactin, and growth hormone levels increased rapidly, peaking at 15-30 min (p<0.001). The injection of thyrotropin-releasing hormone (cycle 3) stimulated prolactin secretion markedly (p<0.001), but reduced growth hormone levels significantly (p<0.05). Ghrelin induced a smaller prolactin increase than thyrotropin-releasing hormone (p<0.05). The combination of ghrelin and thyrotropin-releasing hormone induced a similar increase in prolactin levels as with thyrotropin-releasing hormone alone. No changes in growth hormone and prolactin levels were seen after saline injection. These results demonstrate that the stimulating effect of ghrelin on prolactin secretion is not additive with that of thyrotropin-releasing hormone.


Continental shelf-wide response of a fish assemblage to rapid warming of the sea.
Climate change affects marine biological processes from genetic to ecosystem levels [1-3]. Recent warming in the northeast Atlantic [4, 5] has caused distributional shifts in some fish species along latitudinal and depth gradients [6, 7], but such changes, as predicted by climate envelope models [8], may often be prevented because population movement requires availability of suitable habitat. We assessed the full impacts of warming on the commercially important European continental shelf fish assemblage using a data-driven Eulerian (grid-based) approach that accommodates spatial heterogeneity in ecological and environmental conditions. We analyzed local associations of species abundance and community diversity with climatic variables, assessing trends in 172 cells from records of >100 million individuals sampled over 1.2 million km(2) from 1980-2008. We demonstrate responses to warming in 72% of common species, with three times more species increasing in abundance than declining, and find these trends reflected in international commercial landings. Profound reorganization of the relative abundance of species in local communities occurred despite decadal stability in the presence-absence of species. Our analysis highlights the importance of focusing on changes in species abundance in established local communities to assess the full consequences of climate change for commercial fisheries and food security.


Cycloparaphenylenes and related nanohoops.
The first synthesis of a cyclic oligophenylene possessing a radial π system was reported in 2008. In the short period that has elapsed since, there has been an ever-increasing level of interest in molecules of this type, as evidenced by the volume of publications in this area. This interest has been driven by the highly unusual properties of these molecules in comparison to their linear oligoarene analogues, as well as the diverse array of potential applications for them. Notably, CPPs and related structures were proposed as viable templates for the bottom-up synthesis of single-walled carbon nanotubes (SWCNTs), a proposition which has recently been realised. This review gives a comprehensive and strictly chronological (by date of first online publication) treatment of literature reports from the inception of the field, with emphasis on both synthesis and properties of CPPs and related nanohoops. (The scope of this review is restricted to molecules possessing a radial π system consisting entirely of subunits which are aromatic in isolation, e.g. CPPs, but not cycloparaphenyleneacetylenes or cyclopolyacetylenes).


A new [2 + 1] mixed ligand concept based on [99(m)Tc(OH2)3(CO)3]+: a basic study.
Mixed ligand fac-tricarbonyl complexes of the general formula [M(L1)(L2)(CO)3](M = Re, 99(m)Tc, L1= imidazole, benzyl isocyanide, L2 = 1H-imidazole-4-carboxylic acid, pyridine-2,4-dicarboxylic acid, pyridine-2,5-dicarboxylic acid) have been prepared starting from the precursors [M(OH2)3(CO)3]+. The complexes can be obtained in good yield and purity in a two-step procedure by first attaching the bidentate ligand followed by addition of the monodentate. 99mTc compounds can also be prepared at the tracer level in one-pot procedures with L1 and L2 being concomitantly present. This [2 + 1] approach allows the labeling of bioactive molecules containing a monodentate or a bidentate donor site. Examples given in here are N-(tert-butoxycarbonyl)glycyl-N-(3-(imidazol-1-yl)propyl)phenylalaninamide, 5-((3-(imidazol-1-yl)propyl)aminomethyl)-2'-deoxyuridine and 4-(5-isonitrilpentyl)-1-(2-methoxyphenyl)-piperazine as L1 and N-((6-carboxypyridine-3-yl)methyl)glycylphenylalanine as L2. The corresponding second ligand can be used to influence the physico-chemical properties of the conjugate. The crystal structures of [99Tc(OH2)(imc)(CO)3], [Re(OH2)(2,4-dipic)(CO)3], [Re(bic)(2,4-dipic)(CO)3] and [Re(im)(2,5-dipic)(CO)3] are reported.


Hydrogen Permeation in X65 Steel under Cyclic Loading.
This experimental work analyzes the hydrogen embrittlement mechanism in quenched and tempered low-alloyed steels. Experimental tests were performed to study hydrogen diffusion under applied cyclic loading. The permeation curves were fitted by considering literature models in order to evaluate the role of trapping-both reversible and irreversible-on the diffusion mechanism. Under loading conditions, a marked shift to the right of the permeation curves was noticed mainly at values exceeding the tensile yield stress. In the presence of a relevant plastic strain, the curve changes due to the presence of irreversible traps, which efficiently subtract diffusible atomic hydrogen. A significant reduction in the apparent diffusion coefficient and a considerable increase in the number of traps were noticed as the maximum load exceeded the yield strength. Cyclic loading at a tensile stress slightly higher than the yield strength of the material increases the hydrogen entrapment phenomena. The tensile stress causes a marked and instant reduction in the concentration of mobile hydrogen within the metal lattice from 55% of the yield strength, and it increases significantly in the plastic field.


Clinically relevant effectiveness of focused extracorporeal shock wave therapy in the treatment of chronic plantar fasciitis: a randomized, controlled multicenter study.
The effectiveness of extracorporeal shock wave therapy in the treatment of plantar fasciitis is controversial. The objective of the present study was to test whether focused extracorporeal shock wave therapy is effective in relieving chronic heel pain diagnosed as plantar fasciitis. Two hundred and fifty subjects were enrolled in a prospective, multicenter, double-blind, randomized, and placebo-controlled U.S. Food and Drug Administration trial. Subjects were randomized to focused extracorporeal shock wave therapy (0.25 mJ/mm(2)) or placebo intervention, with three sessions of 2000 impulses in weekly intervals. Primary outcomes were both the percentage change of heel pain on the visual analog scale composite score (pain during first steps in the morning, pain with daily activities, and pain with a force meter) and the Roles and Maudsley score at twelve weeks after the last intervention compared with the scores at baseline. Two hundred and forty-six patients (98.4%) were available for intention-to-treat analysis at the twelve-week follow-up. With regard to the first primary end point, the visual analog scale composite score, there was a significant difference (p = 0.0027, one-sided) in the reduction of heel pain in the extracorporeal shock wave therapy group (69.2%) compared with the placebo therapy group (34.5%). Extracorporeal shock wave therapy was also significantly superior to the placebo therapy for the Roles and Maudsley score (p = 0.0006, one-sided). Temporary pain and swelling during and after treatment were the only device-related adverse events observed. The results of the present study provide proof of the clinically relevant effect size of focused extracorporeal shock wave therapy without local anesthesia in the treatment of recalcitrant plantar fasciitis, with success rates between 50% and 65%. Therapeutic Level I. See Instructions for Authors for a complete description of levels of evidence.


The discriminative stimulus and subjective effects of d-amphetamine, phenmetrazine and fenfluramine in humans.
The discriminative stimulus (DS) and subjective effects of d-amphetamine (AMP), phenmetrazine (PMT) and fenfluramine (FFL) were studied in a group of normal healthy adults. Subjects (N = 27) were trained to discriminate between placebo and 10 mg AMP (PO). Fourteen of the subjects (discriminators) reliably learned the discrimination, whereas the other 13 did not. Nearly all discriminators labelled AMP as a stimulant, and AMP, relative to placebo, increased ratings of drug liking and general activity level, and produced typical stimulant-like subjective effects, as measured by the Profile of Mood States, the Addiction Research Center Inventory, and a series of visual analog scales. The discrimination accuracy of discriminators increased as a function of hour after drug ingestion, as did analog ratings of how certain subjects were that their discrimination responses were correct. Discriminators were tested with doses of PMT (25 and 50 mg) and FFL (20 and 40 mg) to determine whether the DS properties of these drugs would substitute for those of AMP. Both doses of PMT consistently substituted for AMP, and PMT produced subjective effects very similar to those of AMP. Conversely, neither dose of FFL consistently substituted for AMP, and FFL produced essentially no subjective effects. These findings are consistent with results from discrimination studies with other species, and provide further evidence of the validity of this procedure for studying the DS properties of drugs in humans.


The Arctic Alzheimer mutation facilitates early intraneuronal Abeta aggregation and senile plaque formation in transgenic mice.
The Arctic mutation (APP E693G) is unique, since it is located within the amyloid-beta (Abeta) sequence and leads to Alzheimer's disease (AD). Arctic Abeta peptides more easily form Abeta protofibrils in vitro, but little is known about the pathogenic mechanism of the Arctic mutation in vivo. Here, we analyzed APP transgenic mice with both the Swedish and Arctic mutations (tg-APPArcSwe) and transgenic mice with the Swedish mutation alone (tg-APPSwe). Intense intraneuronal Abeta-immunoreactive staining was present in young tg-APPArcSwe mice, but not in tg-APPSwe mice. Intracellular Abeta aggregates in tg-APPArcSwe were strongly stained by antibodies recognizing the N-terminus of Abeta, while those recognizing the C-terminus of Abeta stained weakly. The Abeta aggregates inside neurons increased with age and predated extracellular Abeta deposition in both tg-APPArcSwe and tg-APPSwe mice. Senile plaque deposition was markedly accelerated in tg-APPArcSwe mice, as compared to tg-APPSwe mice. We conclude that the Arctic mutation causes AD by facilitating amyloidosis through early accumulation of intracellular Abeta aggregates in association with a rapid onset of senile plaque deposition.


Relationship between Muscular Activity and Postural Control Changes after Proprioceptive Focal Stimulation (Equistasi®) in Middle-Moderate Parkinson's Disease Patients: An Explorative Study.
The aim of this study was to investigate the effects of Equistasi®, a wearable device, on the relationship between muscular activity and postural control changes in a sample of 25 Parkinson's disease (PD) subjects. Gait analysis was carried out through a six-cameras stereophotogrammetric system synchronized with two force plates, an eight-channel surface electromyographic system, recording the activity of four muscles bilaterally: Rectus femoris, tibialis anterior (TA), biceps femoris, and gastrocnemius lateralis (GL). The peak of the envelope (PoE) and its occurrence within the gait cycle (position of the peak of the envelope, PPoE) were calculated. Frequency-domain posturographic parameters were extracted while standing still on a force plate in eyes open and closed conditions for 60 s. After the treatment with Equistasi®, the mid-low (0.5-0.75) Hz and mid-high (0.75-1 Hz) components associated with the vestibular and somatosensory systems, PoE and PPoE, displayed a shift toward the values registered on the controls. Furthermore, a correlation was found between changes in proprioception (power spectrum frequencies during the Romberg Test) and the activity of GL, BF (PoE), and TA (PPoE). Results of this study could provide a quantitative estimation of the effects of a neurorehabilitation device on the peripheral and central nervous system in PD.


Comparing CESD-10, PHQ-9, and PROMIS depression instruments in individuals with multiple sclerosis.
This study evaluated psychometric properties of the Patient Health Questionnaire-9 (PHQ-9), the Center for Epidemiological Studies Depression Scale-10 (CESD-10), and the 8-item PROMIS Depression Short Form (PROMIS-D-8; 8b short form) in a sample of individuals living with multiple sclerosis (MS). Data were collected by a self-reported mailed survey of a community sample of people living with MS (n = 455). Factor structure, interitem reliability, convergent/discriminant validity and assignment to categories of depression severity were examined. A 1-factor, confirmatory factor analytic model had adequate fit for all instruments. Scores on the depression scales were more highly correlated with one another than with scores on measures of pain, sleep disturbance, and fatigue. The CESD-10 categorized about 37% of participants as having significant depressive symptoms. At least moderate depression was indicated for 24% of participants by PHQ-9. PROMIS-D-8 identified 19% of participants as having at least moderate depressive symptoms and about 7% having at least moderately severe depression. None of the examined scales had ceiling effects, but the PROMIS-D-8 had a floor effect. Overall, scores on all 3 scales demonstrated essential unidimensionality and had acceptable interitem reliability and convergent/discriminant validity. Researchers and clinicians can choose any of these scales to measure depressive symptoms in individuals living with MS. The PHQ-9 offers validated cutoff scores for diagnosing clinical depression. The PROMIS-D-8 measure minimizes the impact of somatic features on the assessment of depression and allows for flexible administration, including Computerize Adaptive Testing (CAT). The CESD-10 measures 2 aspects of depression, depressed mood and lack of positive affect, while still providing an interpretable total score.


Genetic ablation of the tumor suppressor menin causes lethality at mid-gestation with defects in multiple organs.
Patients suffering from multiple endocrine neoplasia type 1 (MEN1) are predisposed to multiple endocrine tumors. The MEN1 gene product, menin, is expressed in many embryonic, as well as adult tissues, and interacts with several proteins in vitro and in vivo. However, the biological function of menin remains largely unknown. Here we show that disruption of the Men1 gene in mice causes embryonic lethality at E11.5-E13.5. The Men1 null mutant embryos appeared smaller in size, frequently with body haemorrhages and oedemas, and a substantial proportion of them showed disclosure of the neural tube. Histological analysis revealed an abnormal development of the nervous system and heart hypotrophy in some Men1 null embryos. Furthermore, Men1 null livers generally displayed an altered organization of the epithelial and hematopoietic compartments associated with enhanced apoptosis. Chimerism analysis of embryos generated by injection of Men1 null ES cells, showed that cells lacking menin do not seem to have a general cell-autonomous defect. However, primary Men1 null embryonic fibroblasts entered senescence earlier than their wild-type counterparts. Despite normal proliferation ability, Men1 null ES cells exhibited a deficiency to form embryoid bodies, suggesting an impaired differentiation capacity in these cells. The present study demonstrates that menin plays an important role in the embryonic development of multiple organs in addition to its proposed role in tumor suppression.


Preliminary experience with 4K ultra-high definition endoscope: analysis of pros and cons in skull base surgery.
During the last two decades endoscopic skull base surgery observed a continuous technical and technological development 3D endoscopy and ultra High Definition (HD) endoscopy have provided great advances in terms of visualisation and spatial resolution. Ultra-high definition (UHD) 4K systems, recently introduced in the clinical practice, will shape next steps forward especially in skull base surgery field. Patients were operated on through transnasal transsphenoidal endoscopic approaches performed using Olympus NBI 4K UHD endoscope with a 4 mm 0° Ultra Telescope, 300 W xenon lamp (CLV-S400) predisposed for narrow band imaging (NBI) technology connected through a camera head to a high-quality control unit (OTV-S400 - VISERA 4K UHD) (Olympus Corporation, Tokyo, Japan). Two screens are used, one 31" Monitor - (LMD-X310S) and one main ultra-HD 55" screen optimised for UHD image reproduction (LMD-X550S). In selected cases, we used a navigation system (Stealthstation S7, Medtronic, Minneapolis, MN, US). We evaluated 22 pituitary adenomas (86.3% macroadenomas; 13.7% microadenomas). 50% were not functional (NF), 22.8% GH, 18.2% ACTH, 9% PRL-secreting. Three of 22 were recurrences. In 91% of cases we achieved total removal, while in 9% near total resection. A mean follow-up of 187 days and average length of hospitalisation was 3.09 ± 0.61 days. Surgical duration was 128.18± 30.74 minutes. We experienced only 1 case of intraoperative low flow fistula with no further complications. None of the cases required any post- or intraoperative blood transfusion. The visualisation and high resolution of the operative field provided a very detailed view of all anatomical structures and pathologies allowing an improvement in safety and efficacy of the surgical procedure. The operative time was similar to the standard 2D HD and 3D procedures and the physical strain was also comparable to others in terms of ergonomics and weight.


Computational aeroelastic modelling of airframes and turbomachinery: progress and challenges.
Computational analyses such as computational fluid dynamics and computational structural dynamics have made major advances towards maturity as engineering tools. Computational aeroelasticity (CAE) is the integration of these disciplines. As CAE matures, it also finds an increasing role in the design and analysis of aerospace vehicles. This paper presents a survey of the current state of CAE with a discussion of recent research, success and continuing challenges in its progressive integration into multidisciplinary aerospace design. It approaches CAE from the perspective of the two main areas of application: airframe and turbomachinery design. An overview will be presented of the different prediction methods used for each field of application. Differing levels of nonlinear modelling will be discussed with insight into accuracy versus complexity and computational requirements. Subjects will include current advanced methods (linear and nonlinear), nonlinear flow models, use of order reduction techniques and future trends in incorporating structural nonlinearity. Examples in which CAE is currently being integrated into the design of airframes and turbomachinery will be presented.


Time-resolved spatial parametric characterization of pulsed light beams.
New time-resolved spatial parameters are given that characterize the behavior of pulsed beams along with their propagation laws through first-order optical systems. The analytical conditions that should be fulfilled so that the intensity-moment formalism remains valid are investigated. Their physical meaning is also discussed, along with the implications for the evolution of the spatial profile of a pulsed beam.


Safety assessment of nicotinamide riboside, a form of vitamin B3.
Nicotinamide riboside (NR) is a naturally occurring form of vitamin B3 present in trace amounts in some foods. Like niacin, it has been shown to be a precursor in the biosynthesis of nicotinamide adenine dinucleotide (NAD+). The safety of Niagen™, a synthetic form of NR, was determined using a bacterial reverse mutagenesis assay (Ames), an in vitro chromosome aberration assay, an in vivo micronucleus assay, and acute, 14-day and 90-day rat toxicology studies. NR was not genotoxic. There was no mortality at an oral dose of 5000 mg/kg. Based on the results of a 14-day study, a 90-day study was performed comparing NR at 300, 1000, and 3000 mg/kg/day to an equimolar dose of nicotinamide at 1260 mg/kg/day as a positive control. Results from the study show that NR had a similar toxicity profile to nicotinamide at the highest dose tested. Target organs of toxicity were liver, kidney, ovaries, and testes. The lowest observed adverse effect level for NR was 1000 mg/kg/day, and the no observed adverse effect level was 300 mg/kg/day.


GDH-Dependent Glutamate Oxidation in the Brain Dictates Peripheral Energy Substrate Distribution.
Glucose, the main energy substrate used in the CNS, is continuously supplied by the periphery. Glutamate, the major excitatory neurotransmitter, is foreseen as a complementary energy contributor in the brain. In particular, astrocytes actively take up glutamate and may use it through oxidative glutamate dehydrogenase (GDH) activity. Here, we investigated the significance of glutamate as energy substrate for the brain. Upon glutamate exposure, astrocytes generated ATP in a GDH-dependent way. The observed lack of glutamate oxidation in brain-specific GDH null CnsGlud1(-/-) mice resulted in a central energy-deprivation state with increased ADP/ATP ratios and phospho-AMPK in the hypothalamus. This induced changes in the autonomous nervous system balance, with increased sympathetic activity promoting hepatic glucose production and mobilization of substrates reshaping peripheral energy stores. Our data reveal the importance of glutamate as necessary energy substrate for the brain and the role of central GDH in the regulation of whole-body energy homeostasis.


Phase I pharmacokinetic and pharmacodynamic evaluation of combined valproic acid/doxorubicin treatment in dogs with spontaneous cancer.
Histone deacetylase inhibitors (HDACi) are targeted anticancer agents with a well-documented ability to act synergistically with cytotoxic agents. We recently showed that the HDACi valproic acid sensitizes osteosarcoma cells to doxorubicin in vitro and in vivo. As there are no published reports on the clinical utility of HDACi in dogs with spontaneous cancers, we sought to determine a safe and biologically effective dose of valproic acid administered prior to a standard dose of doxorubicin. Twenty-one dogs were enrolled into eight cohorts in an accelerated dose-escalation trial consisting of pretreatment with oral valproic acid followed by doxorubicin on a three-week cycle. Blood and tumor tissue were collected for determination of serum valproic acid concentration and evaluation of pharmacodynamic effects by immunofluorescence cytochemistry and immunohistochemistry. Serum and complete blood counts were obtained for determination of changes in doxorubicin pharmacokinetics or hematologic effects. All doses of valproic acid were well tolerated. Serum valproic acid concentrations increased linearly with dose. Doxorubicin pharmacokinetics were comparable with those in dogs receiving doxorubicin alone. A positive correlation was detected between valproic acid dose and histone hyperacetylation in peripheral blood mononuclear cells. No potentiation of doxorubicin-induced myelosuppression was observed. Histone hyperacetylation was documented in tumor and peripheral blood mononuclear cells. Responses included 2 of 21 complete, 3 of 21 partial, 5 of 21 stable disease, and 11 of 21 progressive disease. Valproic acid can be administered to dogs at doses up to 240 mg/kg/day prior to a standard dose of doxorubicin. In addition, we have developed the pharmacokinetic/pharmacodynamic tools necessary for future studies of novel HDACi in the clinical setting of canine cancer.


The relationship between trained ratings and untrained listeners' judgments of global coherence in extended monologues.
Global coherence rating scales have been used by a number of researchers to examine spoken discourse in populations with and without acquired neurogenic communication disorders. The 4-point global coherence (GC) scale in the current study has demonstrated reliability and convergent validity. However, we have not yet established how a global coherence rating corresponds to functional communication. The current study explores the clinical meaningfulness of the 4-point GC rating scale. Survey questions and ratings were developed to examine discourse quality and functional coherence as perceived by untrained listeners. Ratings by untrained listeners were compared to trained discourse ratings using the established 4-point GC scale. Twelve discourse samples, scored by a trained rater, were selected for the current study from a previously collected set of discourse transcripts. Transcripts were extended monologues in response to one of four possible open-ended questions that were re-recorded by the trained rater to remove any distracting features of the original recordings, such as articulatory errors. Twenty-four untrained listeners rated the discourse samples using a short questionnaire that included questions for each sample about: topic maintenance, inclusion of unnecessary information, and the listener level of interest and attention. Questions for untrained listeners were based on operational definitions of global coherence and discourse quality respectively. These untrained ratings were compared to trained ratings of global coherence. Outcome measures were compared using non-parametric tests and a Spearman Rank Order test was also used to examine relationships among variables. Untrained listeners' ratings for topic maintenance and inclusion of unnecessary information were significantly different between trained low, medium, and high global coherence ratings. Topic maintenance and inclusion of unnecessary information were also both significantly correlated with global coherence. Untrained listeners' ratings of their level of interest and attention for a sample were significantly different between trained medium-high and low-high global coherence ratings. Interest and attention ratings were also significantly correlated with ratings of global coherence. Untrained raters did differentiate between levels of global coherence using ratings of topic maintenance, inclusion of unnecessary information, and their level of attention and interest. Global coherence was also significantly correlated with the untrained ratings. These findings provide preliminary external validity for the global coherence scale and support its clinical utility.


Visuospatial information in the retinotectal system of xenopus before correct image formation by the developing eye.
The retinotectal pathway of Xenopus laevis is a well-established experimental model for studying activity-dependent processes during visual system development. Such processes can be guided by stimulus-evoked activity patterns, which depend on the refractive characteristics of the eye. Previous work has shown that many animals are hyperopic at early developmental stages due to immature refractive properties. Whether this is also the case for Xenopus laevis is unknown. Here, we measure the focal length of the lens and the size of the eye of embryos at different stages and find that Xenopus laevis exhibits a similar shift from hyperopia to emmetropia. At early stages, immediately after innervation of the tectum by the optic nerve, Xenopus embryos are hyperopic. Soon afterwards the focal length of the lens decreases and the eye converges to a state of emmetropia. Despite being hyperopic we find that some visuospatial information is available to the young circuit. Calculations based on the optical properties of the eye show that even when the animals are hyperopic the blurred retinal image provides a crude spatial resolution. Furthermore, using whole-cell recordings in the optic tectum combined with visual stimulation through the intact eye, we show that tectal neurons in hyperopic embryos have spatially restricted glutamatergic receptive fields. Our data demonstrate that Xenopus laevis eyes undergo a process of developmental emmetropization, and suggest that despite an initial stage of suboptimal image formation there is potentially enough information to guide activity-dependent refinements of the retinotectal pathway from the onset of vision.


Adaptive decision rules for the acquisition of nature reserves.
Although reserve-design algorithms have shown promise for increasing the efficiency of conservation planning, recent work casts doubt on the usefulness of some of these approaches in practice. Using three data sets that vary widely in size and complexity, we compared various decision rules for acquiring reserve networks over multiyear periods. We explored three factors that are often important in real-world conservation efforts: uncertain availability of sites for acquisition, degradation of sites, and overall budget constraints. We evaluated the relative strengths and weaknesses of existing optimal and heuristic decision rules and developed a new set of adaptive decision rules that combine the strengths of existing optimal and heuristic approaches. All three of the new adaptive rules performed better than the existing rules we tested under virtually all scenarios of site availability, site degradation, and budget constraints. Moreover, the adaptive rules required no additional data beyond what was readily available and were relatively easy to compute.


Osteoarthritis and nutrition. From nutraceuticals to functional foods: a systematic review of the scientific evidence.
The scientific and medical community remains skeptical regarding the efficacy of nutrition for osteoarthritis despite their broad acceptation by patients. In this context, this paper systematically reviews human clinical trials evaluating the effects of nutritional compounds on osteoarthritis. We searched the Medline, Embase, and Biosis databases from their inception to September 2005 using the terms random, double-blind method, trial, study, placebo, and osteoarthritis. We selected all peer-reviewed articles reporting the results of randomised human clinical trials (RCTs) in osteoarthritis that investigated the effects of oral interventions based on natural molecules. Studies on glucosamine and chondroitin sulfate were excluded. The quality of the RCTs was assessed with an osteoarthritic-specific standardised set of 12 criteria and a validated instrument. A best-evidence synthesis was used to categorise the scientific evidence behind each nutritional compound as good, moderate, or limited. A summary of the most relevant in vitro and animal studies is used to shed light on the potential mechanisms of action. Inclusion criteria were met by 53 RCTs out of the 2,026 identified studies. Good evidence was found for avocado soybean unsaponifiables. Moderate evidence was found for methylsulfonylmethane and SKI306X, a cocktail of plant extracts. Limited evidence was found for the Chinese plant extract duhuo jisheng Wan, cetyl myristoleate, lipids from green-lipped mussels, and plant extracts from Harpagophytum procumbens. Overall, scientific evidence exists for some specific nutritional interventions to provide symptom relief to osteoarthritic patients. It remains to be investigated whether nutritional compounds can have structure-modifying effects.


The Role of Astrocyte Dysfunction in Parkinson's Disease Pathogenesis.
Astrocytes are the most populous glial subtype and are critical for brain function. Despite this, historically there have been few studies into the role that they may have in neurodegenerative diseases, such as Parkinson's disease (PD). Recently, however, several studies have determined that genes known to have a causative role in the development of PD are expressed in astrocytes and have important roles in astrocyte function. Here, we review these recent developments and discuss their impact on our understanding of the pathophysiology of PD, and the implications that this might have for its treatment.


Comparison of the survival between coronary artery bypass graft surgery versus percutaneous coronary intervention in patients with poor left ventricular function (ejection fraction <30%): a propensity-matched analysis.
Existing evidence comparing the outcomes of coronary artery bypass graft (CABG) surgery versus percutaneous coronary intervention (PCI) in patients with poor left ventricular function (LVF) is sparse and flawed. This is largely due to patients with poor LVF being underrepresented in major research trials and the outdated nature of some studies that do not consider drug-eluting stent PCI. Following strict inclusion criteria, 717 patients who underwent revascularization by CABG or PCI between 2002 and 2015 were enrolled. All patients had poor LVF (defined by ejection fraction <30%). By employing a propensity score analysis, 134 suitable matches (67 CABG and 67 PCI) were identified. Several outcomes were evaluated, in the matched population, using data extracted from national registry databases. CABG patients required a longer length of hospital stay post-revascularization compared to PCI in the propensity-matched population, 7 days (lower-upper quartile; 6-12) and 2 days (lower-upper quartile; 1-6), respectively (Mood's median test, P = 0.001). Stratified Cox-regression proportional-hazards analysis of the propensity-matched population found that PCI patients experienced a higher adjusted 8-year mortality rate (hazard ratio 3.291, 95% confidence interval 1.776-6.101; P < 0.001). This trend was consistent amongst urgent cases of revascularization: patients with 3 or more vessels with coronary artery disease and patients where complete revascularization was achieved. Although sub-analyses found no difference between survival distributions of on-pump versus off-pump CABG (log-rank P = 0.726), both modes of CABG were superior to PCI (stratified log-rank P = 0.002). Despite a longer length of hospital stay, patients with impaired LVF requiring intervention for coronary artery disease experienced a greater post-procedural survival benefit if they received CABG compared to PCI. We have demonstrated this at 30 days, 90 days, 1 year, 3 years, 5 years and 8 years following revascularization. At present, CABG remains a superior revascularization modality to PCI in patients with poor LVF.


The oxygen-conserving potential of the diving response: A kinetic-based analysis.
We investigated the oxygen-conserving potential of the human diving response by comparing trained breath-hold divers (BHDs) to non-divers (NDs) during simulated dynamic breath-holding (BH). Changes in haemodynamics [heart rate (HR), stroke volume (SV), cardiac output (CO)] and peripheral muscle oxygenation [oxyhaemoglobin ([HbO2]), deoxyhaemoglobin ([HHb]), total haemoglobin ([tHb]), tissue saturation index (TSI)] and peripheral oxygen saturation (SpO2) were continuously recorded during simulated dynamic BH. BHDs showed a breaking point in HR kinetics at mid-BH immediately preceding a more pronounced drop in HR (-0.86 bpm.%-1) while HR kinetics in NDs steadily decreased throughout BH (-0.47 bpm.%-1). By contrast, SV remained unchanged during BH in both groups (all P > 0.05). Near-infrared spectroscopy (NIRS) results (mean ± SD) expressed as percentage changes from the initial values showed a lower [HHb] increase for BHDs than for NDs at the cessation of BH (+24.0 ± 10.1 vs. +39.2 ± 9.6%, respectively; P < 0.05). As a result, BHDs showed a [tHb] drop that NDs did not at the end of BH (-7.3 ± 3.2 vs. -3.0 ± 4.7%, respectively; P < 0.05). The most striking finding of the present study was that BHDs presented an increase in oxygen-conserving efficiency due to substantial shifts in both cardiac and peripheral haemodynamics during simulated BH. In addition, the kinetic-based approach we used provides further credence to the concept of an "oxygen-conserving breaking point" in the human diving response.


IRA balances and contributions: an overview of the EBRI IRA database.
NEW IRA DATABASE: The Employee Benefit Research Institute created the EBRI IRA Database in order to more closely examine retirement savings behavior. The EBRI IRA Database is able to link individuals within and across the data providers and will also be able to link the data with participants in 401(k) plans, allowing retirement funds to be tracked as they are generated, rolled over, and ultimately used. This Issue Brief is the first of a series of publications analyzing the EBRI IRA Database, and highlights the distribution of IRA owners by IRA type, average and median account balances, and contributions to IRAs. The data security techniques used by the data providers assure that EBRI has no ability to identify individuals so that all privacy is assured. IRA TYPES: In the EBRI IRA Database, IRAs are classified into four types: traditional (originating from contributions), rollovers from other retirement plans, Roth, and SEP/SIMPLE. The distribution of the IRA accounts is 33.6 percent traditional IRAs; 33.4 percent rollover IRAs (combined with the traditional IRAs, 67 percent); 23.4 percent Roth IRAs; the remaining 9.6 percent are SEPs and SIMPLEs. OWNERSHIP BY AGE AND GENDER: IRA owners were more likely to be male, especially those having a rollover or a SEP/SIMPLE IRA. Among all IRA participants in the database, nearly one-half (48.3 percent) were ages 45-64. Only 16.7 percent of those owning a traditional IRA were under age 45, compared with 46.5 percent for those with a Roth, 30.4 percent for rollovers, and 34.8 percent for those with a SEP or SIMPLE. AVERAGE AND MEDIAN BALANCES: The average and median IRA account balance in 2008 was $54,863 and $15,756, respectively, while the average and median IRA individual balance (all accounts from the same person combined) was $69,498 and $20,046, Individuals with a rollover balance had the highest average and median balance at $91,783 and $31,264. Roth owners had the lowest average and median balance at $14,056 and $7,319. The average and median individual IRA balance increased with age before leveling off for those age 70 or older. Averages--The average amount contributed to an IRA in the database was $3,665 in 2008. The average contribution was highest for accounts owned by those ages 65-69. More contributions were made to Roth accounts than to traditional (combined traditional and rollover) accounts. However, the average contribution to a traditional account was higher, at $3,798, compared with $3,580 to a Roth account. Yet, a higher overall amount was contributed to Roth IRAs ($3.4 billion for Roths compared with $2.3 billion for traditional accounts). By type--Focusing only on those owning traditional, rollover, or Roth IRAs, 12.1 percent of the accounts were contributed to, and 15.1 percent of the individuals owning these IRA types contributed to them in 2008. When combining the owners of traditional and rollover IRAs (which are considered the same type for contribution purposes), 7.2 percent contributed, while 29.5 percent of those owning a Roth IRA contributed to a Roth IRA. Maxing out--Of those individuals contributing, 42.4 percent contributed the maximum amount. Of those contributing to a traditional or rollover IRA, 43.4 percent maxed out, while 40.2 percent did so with a Roth IRA.


Balance confidence and functional mobility are independently associated with falls in people with Parkinson's disease.
The present study aimed to examine the association of falls with self-perceived balance confidence level, and balance and mobility performance in patients with Parkinson's disease (PD). Forty-nine healthy subjects and 71 subjects with PD completed the study. Among the PD patients, 33 (46%) were fallers and 38 were non-fallers. All subjects were tested with the activities-specific balance confidence scale (ABC), one-leg-stance test (OLS), and timed-up-and-go test (TUG). Results indicated that PD fallers had significantly lower ABC scores, shorter OLS times and longer times to complete TUG than PD non-fallers (P < 0.05). Having a high ABC score (>80) was significantly associated with a lower fall risk, after adjusting for age, gender, and duration of PD, and for depression [odds ratio (OR) = 0.06, P = 0.020]. For performance-based measures of balance and mobility, a longer TUG time (> or =16 s) was independently associated with increased risk of falling after controlling for relevant factors (OR = 3.86, P = 0.043); OLS time, however, was not significantly associated with falls. A lower self-perceived balance confidence level and a prolonged time to complete TUG were associated with increased risk of falling in patients with PD. Interventions to improve these modifiable risk factors could be useful in reducing future falls in the PD population and will require further study.


Molecular analysis of a major antigenic region of the 240-kD protein of Mi-2 autoantigen.
Anti-Mi-2 autoantibody is strongly associated with dermatomyositis and found in sera of 20% of patients. Mi-2 antigen contains at least eight components and previous evidence suggested that the 240-kD protein was the antigenic component for at least some sera. In this study, anti-M-2 patient sera were used to screen human thymocyte and HeLa cell lambda gt11 expression libraries, and two clones from each had plaques specifically reactive with anti-Mi-2 sera. Studies with affinity-purified antibody supported the identification of the clones. All of 44 anti-Mi-2 sera reacted with the plaques, but none of 44 control sera reacted significantly. The cDNAs were identical, and full sequencing of one revealed an open reading frame spanning a 1,054-bp insert. Rescreening the library with the cDNA yielded a 1,589-bp cDNA that continued the open reading frame. The Mi-2 cDNA hybridized to a single 7.5-8.0 kb mRNA of HeLa cells, by Northern blot. Rabbit antiserum directed at a portion of the cDNA product reacted with HeLa 240-kD Mi-2 protein. The sequence was notable for four potential zinc-fingers and several charged regions. The protein encoded by the cDNA produced in vitro reacted with only one of five of the Mi-2 sera. These findings indicate that the Mi-2 240 kD is a novel protein that is antigenic for all Mi-2 sera, and strongly suggests that a major common epitope is conformational in nature.


Reflectometric interference spectroscopy-based sensing for evaluating biodegradability of polymeric thin films.
Enzymatic degradation of poly(ε-caprolactone) (PCL) thin films was analyzed by reflectometric interference spectroscopy (RIfS)-based sensing system, and validated by attenuated total reflection infrared spectroscopy (ATR-IR) imaging. The degradation of the PCL thin film spin-coated on the silicon substrate on which 65-nm silicon nitride layer was deposited as an interference layer was easily monitored by shifting the peak bottom of reflectance spectra (Δλ) that is known to be proportional to the thickness of thin films. The Δλ values decreased with increasing the concentration of lipase from Pseudomonas cepacia, and the obtained sensorgrams were applied for kinetic analysis using a curve fitting software. ATR-IR spectra and imaging analysis on the surface of the PCL film revealed that carbonyl groups on the surface decreased with time, resulting from proceeding with the enzymatic hydrolysis, and importantly, extinction of the carbonyl group was declined with proportional to the decrease in the film thickness measured by the RIfS system. Consequently, the present RIfS-based label-free monitoring system can provide a simple and reliable way for evaluating biodegradability on synthetic materials. A RIfS-based sensing system in combination with ATR-IR measurements can be an analytical method for evaluation of biodegradability of polymeric thin films. This study demonstrates the utility of the RIfS-based sensing approach for analyzing the lipase-catalyzed degradation of PCL. Despite the RIfS is known as an inexpensive label-free detection method for biological interaction, the RIfS applications as monitoring methods for enzymatic degradation of biodegradable polymers had not been systematically explored. This study additionally demonstrated the capability of combined analysis of the biodegradation with ATR-IR spectra/imaging and RIfS measurements, which could be broadly applied towards evaluating biodegradability of various biodegradable polymers in environmental protection research.


Detecting awareness in patients with disorders of consciousness using a hybrid brain-computer interface.
The bedside detection of potential awareness in patients with disorders of consciousness (DOC) currently relies only on behavioral observations and tests; however, the misdiagnosis rates in this patient group are historically relatively high. In this study, we proposed a visual hybrid brain-computer interface (BCI) combining P300 and steady-state evoked potential (SSVEP) responses to detect awareness in severely brain injured patients. Four healthy subjects, seven DOC patients who were in a vegetative state (VS, n = 4) or minimally conscious state (MCS, n = 3), and one locked-in syndrome (LIS) patient attempted a command-following experiment. In each experimental trial, two photos were presented to each patient; one was the patient's own photo, and the other photo was unfamiliar. The patients were instructed to focus on their own or the unfamiliar photos. The BCI system determined which photo the patient focused on with both P300 and SSVEP detections. Four healthy subjects, one of the 4 VS, one of the 3 MCS, and the LIS patient were able to selectively attend to their own or the unfamiliar photos (classification accuracy, 66-100%). Two additional patients (one VS and one MCS) failed to attend the unfamiliar photo (50-52%) but achieved significant accuracies for their own photo (64-68%). All other patients failed to show any significant response to commands (46-55%). Through the hybrid BCI system, command following was detected in four healthy subjects, two of 7 DOC patients, and one LIS patient. We suggest that the hybrid BCI system could be used as a supportive bedside tool to detect awareness in patients with DOC.


Prehistoric genomes reveal the genetic foundation and cost of horse domestication.
The domestication of the horse ∼ 5.5 kya and the emergence of mounted riding, chariotry, and cavalry dramatically transformed human civilization. However, the genetics underlying horse domestication are difficult to reconstruct, given the near extinction of wild horses. We therefore sequenced two ancient horse genomes from Taymyr, Russia (at 7.4- and 24.3-fold coverage), both predating the earliest archeological evidence of domestication. We compared these genomes with genomes of domesticated horses and the wild Przewalski's horse and found genetic structure within Eurasia in the Late Pleistocene, with the ancient population contributing significantly to the genetic variation of domesticated breeds. We furthermore identified a conservative set of 125 potential domestication targets using four complementary scans for genes that have undergone positive selection. One group of genes is involved in muscular and limb development, articular junctions, and the cardiac system, and may represent physiological adaptations to human utilization. A second group consists of genes with cognitive functions, including social behavior, learning capabilities, fear response, and agreeableness, which may have been key for taming horses. We also found that domestication is associated with inbreeding and an excess of deleterious mutations. This genetic load is in line with the "cost of domestication" hypothesis also reported for rice, tomatoes, and dogs, and it is generally attributed to the relaxation of purifying selection resulting from the strong demographic bottlenecks accompanying domestication. Our work demonstrates the power of ancient genomes to reconstruct the complex genetic changes that transformed wild animals into their domesticated forms, and the population context in which this process took place.


Speech and Safety in Tracheostomy Patients Receiving Mechanical Ventilation: A Systematic Review.
To synthesize evidence of the safety and effectiveness of phonation in patients with fenestrated tracheostomy tubes. PubMed, CINAHL, Scopus, Cochrane, and Web of Science databases were searched. The research question was, "Are fenestrated tracheostomy tubes a safe and effective option to facilitate early phonation in patients undergoing tracheostomy?" Studies of fenestrated tracheostomy tubes were assessed for risk of bias and quality of evidence. Data were abstracted, cross-checked for accuracy, and synthesized. Of the 160 studies identified, 13 met inclusion criteria, including 6 clinical studies (104 patients), 6 case reports (13 patients), and 1 nationwide clinician survey. The primary indications for a tracheostomy were chronic ventilator dependence (83%) and airway protection (17%). Indications for fenestrated tracheostomy included inaudible phonation and poor voice intelligibility. Patients with fenestrated tubes achieved robust voice outcomes. Complications included granulation tissue (6 patients [5%]), malpositioning (1 patient [0.9%]), decreased oxygen saturation (3 patients [2.6%]), increased blood pressure (1 patient [0.9%]), increased peak pressures (2 patients [1.7%]), and air leakage (1 patient [0.9%]); subcutaneous emphysema also occurred frequently. Patient-reported symptoms included shortness of breath (4 patients [3.4%]), anxiety (3 patients [2.6%]), and chest discomfort (1 patient [0.9%]). Fenestrated devices afford benefits for speech and decannulation but carry risks of granulation, aberrant airflow, and acclimation challenges. Findings highlight the need for continued innovation, education, and quality improvement around the use of fenestrated devices.


A systematic review of research on culturally relevant issues for Hispanics with diabetes.
The purpose of this review is to provide a description of current research on culturally relevant issues among Hispanics subgroups with diabetes throughout the United States. A search of 2655 abstracts was conducted using Medline, PubMed, and Psychlit. Sixty articles were identified, and 33 were reviewed. Most studies focused on Mexican Americans, and little is known about the unique and shared health beliefs of different Hispanics subgroups within the United States. Personal models of illness varied across groups and were influenced by levels of acculturation. Definitions and treatments for susto varied considerably: Puerto Ricans did not identify it as a cause of diabetes. Patients' thoughts about God and diabetes differed, and little is known about how these thoughts affect diabetes self-management. There is also limited research on Hispanics' use of curanderos (folk healers) for diabetes-related care, and only some participants reported using alternative treatments in conjunction with standard medical care. There is limited evidence that fatalistic thinking is unique to Hispanic culture, and its relationship to diabetes self-management remains unclear. More research is needed to determine how cultural factors influence Hispanics' approaches to diabetes self-management. Clinicians and educators would benefit from exploring cultural belief systems with patients, as they may enhance the patient-provider relationship and serve as tools in identifying appropriate treatment strategies.


Development of a risk model for predicting QTc interval prolongation in patients using QTc-prolonging drugs.
Background Numerous drugs prolong the QTc interval on the ECG and potentially increase the risk of cardiac arrhythmia. This risk is clinically relevant in patients with additional risk factors. Objective The objective was to develop and validate a risk model to predict QTc interval prolongation of eligible ECGs. Setting Spaarne Gasthuis (Haarlem/Hoofddorp, The Netherlands). Method A dataset was created from ECGs recorded in patients using one or more QTc prolonging drugs, in the period January 2013 and October 2016. In the development set, independent risk factors for QTc interval prolongation were determined using binary logistic regression. Risk scores were assigned based on the beta coefficient. In the risk-score validation set, the area under the ROC-curve, sensitivity and specificity were calculated. Main outcome measure QTc interval prolongation, defined as a QTc interval > 500 ms. Results In the development set 12,949 ECGs were included and in the risk-score validation set 6391 ECGs. The proportion of ECGs with a prolonged QTc interval in patients with no risk factors in the risk-score validation set was 2.7%, while in patients with a high risk score the proportion was 26.1%. The area under the ROC curve was 0.71 (95% CI 0.68-0.73). The sensitivity and specificity were 0.81 and 0.48, respectively. Conclusion A risk model was developed and validated for the prediction of QTc interval prolongation. This risk model can be implemented in a clinical decision support system, supporting the management of the risks involved with QTc interval prolonging drugs.


The Influence of Chronic Wound Extracts on Inflammatory Cytokine and Histatin Stability.
Chronic ulcers represent a major health burden in our society. Despite many available therapies, a large number of ulcers do not heal. Protein based therapies fail in part due to proteolytic activity in the chronic wound bed. The aim of this in vitro study was to determine whether typical inflammatory cytokines and human salivary histatins remain stable when incubated with chronic wound extracts. Furthermore we determined whether a short exposure of histatins or cytokines was sufficient to exert long term effects on fibroblast migration. Stability of human recombinant cytokines IL-6 and CXCL8, and histatin variants (Hst1, Hst2, cyclic Hst1, minimal active domain of Hst1) in the presence of chronic wound extracts isolated from non-healing ulcers, was monitored by capillary zone electrophoresis. Migration-stimulating activity was assessed using a dermal fibroblast wound healing scratch assay. Histatins and cytokines stayed stable in saline for > 24 h at 37°C, making them ideal as an off-the-shelf product. However, incubation with chronic wound extracts resulted in serious breakdown of Hst1 and Hst2 (~50% in 8 h) and to lesser extent cyclic Hst1 and the minimal active domain of Hst1 (~20% in 8 h). The cytokines IL-6 and CXCL8 were more stable in chronic wound extracts (~40% degradation in 96 h). An initial 8-hour pulse of histatins or cytokines during a 96-hour study period was sufficient to stimulate fibroblast migration equally well as a continuous 96-hour exposure, indicating that they may possibly be used as novel bioactive therapeutics, exerting their activity for up to four days after a single exposure.


Phylogenetic relationships of Thiomicrospira species and their identification in deep-sea hydrothermal vent samples by denaturing gradient gel electrophoresis of 16S rDNA fragments.
Denaturing gradient gel electrophoresis (DGGE) of PCR-amplified 16S rDNA fragments was used to explore the genetic diversity of hydrothermal vent microbial communities, specifically to determine the importance of sulfur-oxidizing bacteria therein. DGGE analysis of two different hydrothermal vent samples revealed one PCR band for one sample and three PCR bands for the other sample, which probably correspond to the dominant bacterial populations in these communities. Three of the four 16S rDNA fragments were sequenced. By comparison with 16S rRNA sequences of the Ribosomal Database Project, two of the DGGE-separated fragments were assigned to the genus Thiomicrospira. To identify these 'phylotypes' in more detail, a phylogenetic framework was created by determining the nearly complete 16S rRNA gene sequence (approx. 1500 nucleotides) from three described Thiomicrospira species, viz., Tms. crunogena, Tms. pelophila, Tms. denitrificans, and from a new isolate, Thiomicrospira sp. strain MA2-6. All Thiomicrospira species except Tms. denitrificans formed a monophyletic group within the gamma subdivision of the Proteobacteria. Tms. denitrificans was assigned as a member of the epsilon subdivision and was distantly affiliated with Thiovulum, another sulfur-oxidizing bacterium. Sequences of two dominant 16S rDNA fragments obtained by DGGE analysis fell into the gamma subdivision Thiomicrospira. The sequence of one fragment was in all comparable positions identical to the 16S rRNA sequence of Tms. crunogena. Identifying a dominant molecular isolate as Tms. crunogena indicates that this species is a dominant community member of hydrothermal vent sites. Another 'phylotype' represented a new Thiomicrospira species, phylogenetically in an intermediate position between Tms. crunogena and Tms. pelophila. The third 'phylotype' was identified as a Desulfovibrio, indicating that sulfate-reducing bacteria, as sources of sulfide, may complement sulfur- and sulfide-oxidizing bacteria ecologically in these sulfide-producing hydrothermal vents.


Histochemical detection of sugar residues in lizard teeth (Liolaemus gravenhorsti): a lectin-binding study.
The structural diversity of the many oligosaccharide chains of surface glycoconjugates renders them likely candidates for modulators of cell-interactions, cellular movements, differentiation, and cellular recognition. A selection of different lectins was used to investigate the appearance of cellular distribution and changes in sugar residues during tooth development in the polyphyodont lizard, Liolaemus gravenhorsti. Lectins from three groups were used: (1) N-acetylgalactosamine specificity: BS-1, PNA, RCA-120; (2) N-acetylglucosamine specificity: ECA; and (3) fucose specificity: UEA 1 and LTA.. Digital images were processed using Scion Image. Grayscale graphics in each image were obtained. The lectins used showed a strong, wide distribution of the L-fucose and N-acetylgalactosamine at the cell surface and in the cytoplasm of multinucleate odontoclast cell, while mononuclear odontoclast cells showed no binding, suggesting some roles that the residues sugar might play in the resorption of dentine or with multinucleation of odontoclast after the attachment to the dentine surface in this polyphyodont species. Further studies must be planned to determine the specific identities of these glycoconjugates,and to elucidate the roles played by these sugar residues in the complex processes related to odontogenesis in polyphyodont species.


The Fox genes of Branchiostoma floridae.
The Fox genes are united by encoding a fork head domain, a deoxyribonucleic acid (DNA)-binding domain of the winged-helix type that marks these genes as encoding transcription factors. Vertebrate Fox genes are classified into 23 subclasses named from FoxA to FoxS. We have surveyed the genome of the amphioxus Branchiostoma floridae, identifying 32 distinct Fox genes representing 21 of these 23 subclasses. The missing subclasses, FoxR and FoxS, are specific to vertebrates, and in addition, B. floridae has one further group, FoxAB, that is not found in vertebrates. Hence, we conclude B. floridae has maintained a high level of Fox gene diversity. Expressed sequence tag and complementary DNA sequence data support the expression of 23 genes. Several linkages between B. floridae Fox genes were noted, including some that have evolved relatively recently via tandem duplication in the amphioxus lineage and others that are more ancient.


Integrated Omics: Tools, Advances, and Future Approaches.
With the rapid adoption of high-throughput omic approaches to analyze biological samples such as genomics, transcriptomics, proteomics, and metabolomics, each analysis can generate tera- to peta-byte sized data files on a daily basis. These data file sizes, together with differences in nomenclature among these data types, make the integration of these multi-dimensional omics data into biologically meaningful context challenging. Variously named as integrated omics, multi-omics, poly-omics, trans-omics, pan-omics, or shortened to just 'omics', the challenges include differences in data cleaning, normalization, biomolecule identification, data dimensionality reduction, biological contextualization, statistical validation, data storage and handling, sharing, and data archiving. The ultimate goal is towards the holistic realization of a 'systems biology' understanding of the biological question in hand. Commonly used approaches in these efforts are currently limited by the 3 i's - integration, interpretation, and insights. Post integration, these very large datasets aim to yield unprecedented views of cellular systems at exquisite resolution for transformative insights into processes, events, and diseases through various computational and informatics frameworks. With the continued reduction in costs and processing time for sample analyses, and increasing types of omics datasets generated such as glycomics, lipidomics, microbiomics, and phenomics, an increasing number of scientists in this interdisciplinary domain of bioinformatics face these challenges. We discuss recent approaches, existing tools, and potential caveats in the integration of omics datasets for development of standardized analytical pipelines that could be adopted by the global omics research community.


Atypical developmental patterns of brain chemistry in children with autism spectrum disorder.
Autism spectrum disorder (ASD) is a neurodevelopmental disorder with symptoms emerging during early childhood. The pathophysiology underlying the disorder remains incompletely understood. To examine cross-sectional and longitudinal patterns of brain chemical concentrations in children with ASD or idiopathic developmental delay (DD) from 3 different age points, beginning early in the clinical course. Proton magnetic resonance spectroscopic imaging data were acquired longitudinally for children with ASD or DD, and primarily cross-sectionally for children with typical development (TD), at 3 to 4, 6 to 7, and 9 to 10 years of age. Recruitment, diagnostic assessments, and magnetic resonance imaging were performed at the University of Washington in Seattle. Seventy-three children (45 with ASD, 14 with DD, and 14 with TD) at 3 to 4 years of age; 69 children (35 with ASD, 14 with DD, and 20 with TD) at 6 to 7 years of age; and 77 children (29 with ASD, 15 with DD, and 33 with TD) at 9 to 10 years of age. Concentrations of N-acetylaspartate (NAA), choline (Cho), creatine (Cr), myo-inositol (mI), and glutamine plus glutamate (Glx) in cerebral gray matter (GM) and white matter (WM) at 3 to 4, 6 to 7, and 9 to 10 years of age, and calculation of rates of change of these chemicals between 3 and 10 years of age. At 3 to 4 years of age, the ASD group exhibited lower NAA, Cho, and Cr concentrations than did the TD group in both GM and WM, alterations that largely were not observed at 9 to 10 years of age. The DD group exhibited reduced GM and WM NAA concentrations at 3 to 4 years of age; GM NAA concentrations remained reduced at 9 to 10 years of age compared with the TD group. There were distinct differences between the ASD and DD groups in the rates of GM NAA, Cho, and Cr changes between 3 and 10 years of age. The GM chemical changes between 3 and 10 years of age differentiated the children with ASD from those with DD. Most notably, a dynamic reversal of GM NAA reductions was observed in the children with ASD. By contrast, persistent GM NAA reductions in the children with DD suggest a different, more static, underlying developmental process.


Brain and motor synchrony in children and adolescents with ASD-a fNIRS hyperscanning study.
Brain-to-brain synchrony has been proposed as an important mechanism underlying social interaction. While first findings indicate that it may be modulated in children with autism spectrum disorder (ASD), no study to date has investigated the influence of different interaction partners and task characteristics. Using functional near-infrared spectroscopy hyperscanning, we assessed brain-to-brain synchrony in 41 male typically developing (TD) children (8-18 years; control sample), as well as 18 children with ASD and age-matched TD children (matched sample), while performing cooperative and competitive tasks with their parents and an adult stranger. Dyads were instructed either to respond jointly in response to a target (cooperation) or to respond faster than the other player (competition). Wavelet coherence was calculated for oxy- and deoxyhemoglobin brain signals. In the control sample, a widespread enhanced coherence was observed for parent-child competition, and a more localized coherence for parent-child cooperation in the frontopolar cortex. While behaviorally, children with ASD showed a lower motor synchrony than children in the TD group, no significant group differences were observed on the neural level. In order to identify biomarkers for typical and atypical social interactions in the long run, more research is needed to investigate the neurobiological underpinnings of reduced synchrony in ASD.


Analysis of the Optimal Duration of Behavioral Observations Based on an Automated Continuous Monitoring System in Tree Swallows (Tachycineta bicolor): Is One Hour Good Enough?
Studies of animal behavior often rely on human observation, which introduces a number of limitations on sampling. Recent developments in automated logging of behaviors make it possible to circumvent some of these problems. Once verified for efficacy and accuracy, these automated systems can be used to determine optimal sampling regimes for behavioral studies. Here, we used a radio-frequency identification (RFID) system to quantify parental effort in a bi-parental songbird species: the tree swallow (Tachycineta bicolor). We found that the accuracy of the RFID monitoring system was similar to that of video-recorded behavioral observations for quantifying parental visits. Using RFID monitoring, we also quantified the optimum duration of sampling periods for male and female parental effort by looking at the relationship between nest visit rates estimated from sampling periods with different durations and the total visit numbers for the day. The optimum sampling duration (the shortest observation time that explained the most variation in total daily visits per unit time) was 1h for both sexes. These results show that RFID and other automated technologies can be used to quantify behavior when human observation is constrained, and the information from these monitoring technologies can be useful for evaluating the efficacy of human observation methods.


TGF-β3 modulates the inflammatory environment and reduces scar formation following vocal fold mucosal injury in rats.
Transforming growth factor (TGF)-β1 and TGF-β3 have been reported to exert differential effects on wound healing, and possibly even account for tissue-specific differences in scar formation. Scarring is particularly detrimental in the vocal fold mucosa (VFM), where destruction of the native extracellular matrix causes irreparable biomechanical changes and voice impairment. Here, in a series of in vitro and in vivo experiments, we identified differences in TGF-β1 and TGF-β3 transcription and immunolocalization to various cell subpopulations in naïve and injured rat VFM, compared with oral mucosa (which undergoes rapid healing with minimal scar) and skin (which typically heals with scar). Treatment of cultured human vocal fold fibroblasts with TGF-β3 resulted in less potent induction of profibrotic gene transcription, extracellular matrix synthesis and fibroblast-myofibroblast differentiation, compared with treatment with TGF-β1 and TGF-β2. Finally, delivery of exogenous TGF-β3 to rat VFM during the acute injury phase modulated the early inflammatory environment and reduced eventual scar formation. These experiments show that the TGF-β isoforms have distinct roles in VFM maintenance and repair, and that TGF-β3 redirects wound healing to improve VFM scar outcomes in vivo.


Evaluation of the perception of cultural competency assessment instrument for allied health students.
A growing effort is aimed at reducing health disparities influenced by culturally based misinterpretations between patients and health professionals. There are few validated instruments to assess students' self-efficacy of cultural understandings that are linked to pre and post testing of educational interventions. To evaluate the psychometric properties of an instrument that measures perception of self-efficacy with respect to cultural competency in allied health students. The Perception of Cultural Competency Assessment (POCCA) was developed and subsequently evaluated for reliability and validity in a convenience sample of 135 students of allied health programs. The POCCA demonstrated acceptable internal consistency (a = .92) and 2-week test-retest reliability of (R = .78). Four sub-scales were identified by factor analysis that accounted for 63% of total variance. The subscale a coefficients ranged from .61 to .89, and inter-item correlations varied from (R = .41-53). POCCA total scores following an educational intervention were significantly higher compared to pre-test values (p<.00001). While these findings provide support for POCCA, more refinement is warranted. The challenge remains to improve the test-retest reliability and to expand the sample to evaluate its effectiveness in a broader context.


Explaining survival differences between two consecutive studies with allogeneic stem cell transplantation in patients with chronic myeloid leukemia.
In the two consecutive German studies III and IIIA on chronic myeloid leukemia, between 1995 and 2004, 781 patients were randomized to receive either allogeneic hematopoietic stem cell transplantation with a related donor or continued drug treatment. Despite comparable transplantation protocols and most centers participating in both studies, the post-transplant survival probabilities for patients transplanted in first chronic phase were significantly higher in study IIIA (144 patients) than in study III (113 patients). Prior to the decision on a combined analysis of both studies, reasons for this discrepancy had to be investigated. The Cox proportional hazard cure model was used to identify prognostic factors for post-transplant survival. Donor-recipient matching for human leukocyte antigen, patient age, time between diagnosis and transplantation, and calendar time showed a significant influence on survival and/or the incidence of cure. Added as a further factor, affiliation to study IIIA had no significant impact any longer. Discrepancies in influential prognostic factors explained the different post-transplant survival probabilities between the studies. The significance of calendar time suggests a lack of consistency of transplantation practice over time. Accordingly, the prerequisite for a common assessment of overall survival in the two randomized transplantation arms was not met. Moreover, our analyses provide an independent validation of established prognostic factors and their cutoffs. The statistical approach in investigating and modeling potential prognostic factors for survival sets an example for the examination of studies with unexpected outcome differences in concurrent treatment arms.