Physeal growth arrest after tibial lengthening in achondroplasia: 23 children followed to skeletal maturity.
Bilateral tibial lengthening has become one of the standard treatments for upper segment-lower segment disproportion and to improve quality of life in achondroplasia. We determined the effect of tibial lengthening on the tibial physis and compared tibial growth that occurred at the physis with that in non-operated patients with achondroplasia. We performed a retrospective analysis of serial radiographs until skeletal maturity in 23 achondroplasia patients who underwent bilateral tibial lengthening before skeletal maturity (lengthening group L) and 12 achondroplasia patients of similar height and age who did not undergo tibial lengthening (control group C). The mean amount of lengthening of tibia in group L was 9.2 cm (lengthening percentage: 60%) and the mean age at the time of lengthening was 8.2 years. The mean duration of follow-up was 9.8 years. Skeletal maturity (fusion of physis) occurred at 15.2 years in group L and at 16.0 years in group C. The actual length of tibia (without distraction) at skeletal maturity was 238 mm in group L and 277 mm in group C (p = 0.03). The mean growth rates showed a decrease in group L relative to group C from about 2 years after surgery. Physeal closure was most pronounced on the anterolateral proximal tibial physis, with relative preservation of the distal physis. Our findings indicate that physeal growth rate can be disturbed after tibial lengthening in achondroplasia, and a close watch should be kept for such an occurrence-especially when lengthening of more than 50% is attempted.


Effects of benthos, temperature, and dose on the fate of hexabromocyclododecane in experimental coastal ecosystems.
The authors studied the fate of the brominated flame retardant hexabromocyclododecane (HBCDD) added in a particulate suspension to experimental ecosystems assembled from brackish (Baltic Sea) coastal bays. Two experiments examined how benthic macrofauna (over 21 d) and increased temperature (14 d) affected HBCDD concentrations and fractionation of α, β, and γ diastereomers in the water, sediment, and biota. A third experiment run over 3 seasons (231 d), studied the effect of HBCDD dose on the same endpoints. In all treatments of the 3 experiments, HBCDD partitioned mainly to the sediment, and this proportion increased with time. Presence of macrofauna tended to increase the HBCDD concentration in the sediment and decreased its concentration in the water. Increased temperature (+ 5°C) decreased the amount of HBCDD in sediment and water but not in the filter- and deposit-feeding infaunal bivalves (Macoma balthica). The partitioning between water, sediment, and biota was not concentration dependent. In all treatments, sediment became enriched in γ-HBCDD, M. balthica in α-HBCDD, and water in α- and β-HBCDD. Bioaccumulation of HBCDD in M. balthica was high in all experiments (log biota-sediment accumulation factor [BSAF] > 1.25), the α diastereomer contributing the most (log BSAF 2.1-5.2). There is a risk of trophic transfer of HBCDD from benthic to pelagic food webs, as well as secondary poisoning of marine consumers.


Determinants and importance of stress hyperglycaemia in non-diabetic patients with myocardial infarction.
Determinants of plasma glucose concentrations were studied in patients on admission to hospital with confirmed acute myocardial infarction but without previous glucose intolerance as evidenced by raised concentrations of glycosylated haemoglobin (HbAlc). Mortality in hospital increased significantly with increasing plasma concentrations of glucose in patients with both normal (p less than 0.0001, n = 311) and borderline (p less than 0.02, n = 70) concentrations of HbAlc. There was a weak relation between plasma glucose concentrations and infarct size as estimated by peak aspartate transaminase activity in both HbAlc groups (rs = 0.26, n = 101 and rs = 0.41, n = 35 respectively). A correlation was found between adrenaline and plasma glucose concentrations (r = 0.47, n = 27) and cortisol and plasma glucose concentrations (r = 0.75, n = 19), but the relation of plasma noradrenaline and plasma glucose suggested a threshold effect. Concentrations of adrenaline, but not those of noradrenaline or cortisol, correlated with infarct size as measured both by peak aspartate transaminase activity and cumulative release of creatine kinase MB isoenzyme. Multiple regression analysis showed that concentrations of cortisol, adrenaline, and noradrenaline (but not the concentration of HbAlc, infarct size, or age) are the main determinants of plasma glucose concentration measured in non-diabetic patients when admitted to hospital after acute myocardial infarction.


A theoretical study on hot charge-transfer states and dimensional effects of organic photocells based on an ideal diode model.
This paper discusses an ideal diode model with hot charge-transfer (CT) states to analyze the power conversion efficiency of an organic photocell. A free carrier generation mechanism via sunlight in an organic photocell consists of four microscopic processes: photon absorption, exciton dissociation, CT, and charge separation. The hot CT state effect has been actively investigated to understand the charge separation process. We previously reported a theoretical method to calculate the efficiency of the charge separation process via a hot CT state (T. Shimazaki et al., Phys. Chem. Chem. Phys., 2015, 17, 12538 and J. Chem. Phys., 2016, 144, 234906). In this paper, we integrate the simulation method into the ideal photocell diode model and calculate several properties such as short circuit current, open circuit voltage, and power conversion efficiency. Our results highlight that utilizing the dimensional (entropy) effect together with the hot CT state can play an essential role in developing more efficient organic photocell devices.


The EU Nitrates Directive: a European approach to combat water pollution from agriculture.
From 1991 onward, the European Union (EU) member states have had to comply with the Nitrates Directive. The aim of this directive is to sustainably protect ground and surface waters from pollution with nitrogen (nitrate) originating from agriculture. Agriculture is, on an EU level, the largest single source of nitrate (runoff, leaching) pollution, although households and industries also contribute to some extent. An important element in the directive is the reporting every 4 years on the monitoring of ground- and surface-water quality. Furthermore, all 15 member states are compelled to designate so-called Nitrate Vulnerable Zones (NVZs). These are regions where the nitrate concentrations in the groundwater amount to 50 mg/l or more. In addition to Codes of Good Agricultural Practice, valid on a countrywide basis and often consisting of voluntary-based measures, specific Action Programmes with mandatory measures have to be developed for the NVZs. The first reporting period ended in 1995. This paper describes the progress in member states" compliance with the Nitrates Directive during the second period (1996-1999), with a focus on the agricultural practices and action programmes. An evaluation of the member states' reports shows that good progress is being made on the farmers" awareness of the need to comply with EU regulations on the protection of the aquatic environment. Action programmes are valuable tools to enforce measures that lead to a reduction of the water pollution by agricultural activities. Regional projects show that significant improvements can be achieved (e.g., reduced fertiliser inputs) while maintaining crop yields and thus maintaining the economic potential of agriculture.


Studying the consumption and health outcomes of fiscal interventions (taxes and subsidies) on food and beverages in countries of different income classifications; a systematic review.
Governments use fiscal interventions (FIs) on food and beverages to encourage healthy food behaviour and positive health outcomes. The objective of this review was to study the behavioural and health outcomes of implemented food and beverage FIs in the form of taxes and subsidies in countries of different income classifications. The present systematic review was conducted in accordance with Cochrane protocols. The search was carried out on academic and grey literature in English, for studies conducted in different countries on implemented FIs on food and non-alcoholic beverages and health outcomes, with a special focus on the income of those countries. Eighteen studies met the inclusion criteria and 14 were from peer- reviewed journals. Thirteen studies came from high-income (HI) countries, four from upper middle-income (UMI) countries and only one came from a lower middle-income (LMI) country. There were no studies from lower-income (LI) countries. Of these 18 studies; nine focused on taxes, all of which were from HI countries. Evidence suggests that FIs on foods can influence consumption of taxed and subsidized foods and consequently have the potential to improve health. Although this review supports previous findings that FIs can have an impact on healthy food consumption, it also highlights the lack of evidence available from UMI, LMI and LI countries on such interventions. Therefore, evidence from HI countries may not be directly applicable to middle-income and LI countries. Similar research conducted in middle and low income countries will be beneficial in advocating policy makers on the effectiveness of FIs in countering the growing issues of non-communicable diseases in these countries.


Aging and epigenetic drift: a vicious cycle.
The term epigenetics refers to stable patterns of gene expression that are seen during differentiation or X chromosome inactivation and are not dependent on dynamic changes in coding DNA. These gene expression states are encoded in the epigenome - a collection of marks on DNA or on histone tails that are established during embryogenesis. Genome-wide studies in aging cells and tissues have uncovered stochastic DNA methylation drift (gradual increases or decreases at specific loci) that reflects imperfect maintenance of epigenetic marks. Drift creates epigenetic mosaicism in aging stem cells that could potentially restrict their plasticity and worsen phenotypes such as stem cell exhaustion and focal proliferative defects that can lead to cancer.


Spectral information in nonspeech contexts influences children's categorization of ambiguous speech sounds.
For both adults and children, acoustic context plays an important role in speech perception. For adults, both speech and nonspeech acoustic contexts influence perception of subsequent speech items, consistent with the argument that effects of context are due to domain-general auditory processes. However, prior research examining the effects of context on children's speech perception have focused on speech contexts; nonspeech contexts have not been explored previously. To better understand the developmental progression of children's use of contexts in speech perception and the mechanisms underlying that development, we created a novel experimental paradigm testing 5-year-old children's speech perception in several acoustic contexts. The results demonstrated that nonspeech context influences children's speech perception, consistent with claims that context effects arise from general auditory system properties rather than speech-specific mechanisms. This supports theoretical accounts of language development suggesting that domain-general processes play a role across the lifespan.


Assessment and use of drug information references in Utah pharmacies.
To determine which drug references Utah pharmacists use most frequently. To determine which types of drug information questions are most commonly asked, and whether Utah pharmacists have access to adequate references to respond to these questions. A 19-question survey was created using Qualtrics, LLC (Provo, Utah) software. An electronic survey link was sent to 1,431 pharmacists with a valid e-mail address listed in the Department of Professional Licensing database. Questions focused on available references in the participant's pharmacy, how current the references are, and the participant's use of the references. Surveys were analyzed for participants practicing in either community or hospital pharmacies in the state of Utah. A total of 147 responses were included in the analysis. Approximately 44% of respondents practiced in the community, and 56% practiced in a hospital setting. The most commonly used references by Utah pharmacists are Micromedex, Lexicomp, UpToDate, Clinical Pharmacology, and Drug Facts & Comparisons. Pharmacists in the community frequently receive questions related to adverse drug reactions, drug interactions, and over-the-counter medications. Pharmacists in the hospital frequently receive questions relating to dosage and administration, drug interactions, and adverse drug reactions. About 89% of community pharmacists and 96% of hospital pharmacists feel available references are adequate to answer the questions they receive. Utah pharmacists generally use large reference suites to answer drug information questions. The majority of pharmacists consider the references available to them to be adequate to answer the questions they receive.


A randomized placebo-controlled pilot study of the impact of healing touch on fatigue in breast cancer patients undergoing radiation therapy.
This is a pilot study investigating the effect of healing touch (HT) on fatigue in breast cancer patients undergoing radiation therapy (RT). This study presents the results of a within-subjects design randomized clinical trial where the treatment group was treated with HT, whereas the control group experienced sham therapy. The setting was a university RT clinic. The participants were breast cancer patients treated with lumpectomy or mastectomy, 21 to 75 years old with an Eastern Cooperative Oncology Group (ECOG) score of 0 to 2. The intervention was a 45-minute session of HT or sham therapy once a week during RT. Outcome measures included fatigue, quality of life (QOL), and anxiety/depression. A total of 70 patients were approached, with 41 completing the study. At completion, the HT participants tended to report higher levels of fatigue, statistically significant for interference ( : = .010) and usual fatigue ( : = .024). The control group tended to report greater reductions in fatigue relative to their own means than the HT group (Cohen's : = 0.30 to 0.49 vs 0.06 to 0.18, respectively). There were no statistically significant differences between the groups for QOL. Our enrollment and retention indicate that HT is feasible for women during RT. Our pilot findings do not support a beneficial effect of HT on fatigue or QOL. Future research may explore increasing dose and teasing out therapist effect.


Lean mass and fat mass have differing associations with bone microarchitecture assessed by high resolution peripheral quantitative computed tomography in men and women from the Hertfordshire Cohort Study.
Understanding the effects of muscle and fat on bone is increasingly important in the optimisation of bone health. We explored relationships between bone microarchitecture and body composition in older men and women from the Hertfordshire Cohort Study. 175 men and 167 women aged 72-81 years were studied. High resolution peripheral quantitative computed tomography (HRpQCT) images (voxel size 82 μm) were acquired from the non-dominant distal radius and tibia with a Scanco XtremeCT scanner. Standard morphological analysis was performed for assessment of macrostructure, densitometry, cortical porosity and trabecular microarchitecture. Body composition was assessed using dual energy X-ray absorptiometry (DXA) (Lunar Prodigy Advanced). Lean mass index (LMI) was calculated as lean mass divided by height squared and fat mass index (FMI) as fat mass divided by height squared. The mean (standard deviation) age in men and women was 76 (3) years. In univariate analyses, tibial cortical area (p<0.01), cortical thickness (p<0.05) and trabecular number (p<0.01) were positively associated with LMI and FMI in both men and women. After mutual adjustment, relationships between cortical area and thickness were only maintained with LMI [tibial cortical area, β (95% confidence interval (CI)): men 6.99 (3.97,10.01), women 3.59 (1.81,5.38)] whereas trabecular number and density were associated with FMI. Interactions by sex were found, including for the relationships of LMI with cortical area and FMI with trabecular area in both the radius and tibia (p<0.05). In conclusion, LMI and FMI appeared to show independent relationships with bone microarchitecture. Further studies are required to confirm the direction of causality and explore the mechanisms underlying these tissue-specific associations.


Prostaglandin endoperoxide synthase 2 (PTGS2) and prostaglandins F2α and E2 synthases (PGFS and PGES) expression and prostaglandin F2α and E2 secretion following oestrogen and/or progesterone stimulation of the feline endometrium.
Sex steroids in synergy with prostaglandins (PG) are involved in the regulation of cyclic ovarian function. In this study, we investigated the mRNA expression of three genes involved in arachidonic acid (AA) metabolism and hence PG production in domestic cats: PG-endoperoxide synthase (PTGS2), PGF(2α) synthase (PGFS) and PGE(2) synthase (PGES). Feline endometria (n = 16) were collected at oestrus and mid and late phases of pseudopregnancy. In addition, the effects of E(2) and/or P(4) on PG secretion and gene expression on endometrial explants were studied in an in vitro culture system. Expression levels of all examined genes were up-regulated at the mid phase of pseudopregnancy. The effects of E(2) and/or P(4) treatment on both PG secretion and expression of the genes were observed after 12 h of culture. Expression of PGES was significantly up-regulated by E(2) plus P(4) at oestrus and the mid phase of pseudopregnancy and was also up-regulated by a single treatment with P(4) at late pseudopregnancy (p < 0.05). Simultaneous incubation with E(2) and P(4) up-regulated PTGS2 gene expression at oestrus and mid-luteal phase (p < 0.05). Progesterone plus E(2) significantly increased PGE(2) secretion at oestrus and the mid phase of pseudopregnancy. However, treatment with E(2) and/or P(4) affected neither PGF(2α) secretion nor PGFS expression at any phase after 12 h of culture. The overall findings indicate that genes involved in PG synthesis are up-regulated at the mid phase of pseudopregnancy. An increase in PGE(2) secretion and up-regulation of PGES and PTGS2 are the main responses of the endometrium to treatment with E(2) and P(4) at oestrus and the mid phase of pseudopregnancy in the cat. These data support the hypothesis that ovarian sex steroids via endometrial PGE(2) are involved in endocrine homoeostasis, especially at oestrus and the mid, but not the late, phase of pseudopregnancy in cats.


Perlecan: a major IL-2-binding proteoglycan in murine spleen.
Although interleukin-2 (IL-2) is typically considered a soluble cytokine, our laboratory has shown that the availability of IL-2 in lymphoid tissues is regulated, in part, by an association with heparan sulfate glycosaminoglycan. Heparan sulfate is usually found in proteoglycan form, in which the heparan sulfate chains are covalently linked to a specific core protein. We now show that perlecan is one of the major IL-2-binding heparan sulfate proteoglycans in murine spleen. IL-2 binds perlecan via heparan sulfate chains, as enzymatic removal of heparan sulfate from splenic perlecan abolishes its ability to bind IL-2. Furthermore, we demonstrate that perlecan-bound IL-2 supports the proliferation of an IL-2-dependent cell line. Identification of perlecan as a major heparan sulfate proteoglycan that binds IL-2 has implications for both the localization and regulation of IL-2 in vivo.


[Correlations between cognition and function in Alzheimer's disease: based on the abbreviated Barcelona Test (a-BT)].
The objective is to establish the existence of possible correlations between cognitive measures using the a-BT, and functional measures in a population of normal to moderately severe demented subjects. A sample of 107 subjects (42 healthy controls, 19 subjects with mild cognitive impairment and 46 patients with probable Alzheimer's disease) were included in the present study. The instruments of the cognitive measure used was the abbreviated Barcelona Test (a-BT), a test of general cognitive function. Apart from that, the following functional scales, evaluating activities of daily living, were used: Rapid Disability Rating Scale-2 (RDRS-2), Blessed Dementia Rating Scale (BDRS), and Interview for Deterioration in Daily living in Dementia (IDDD). The statistical procedures were the correlations between cognitive and functional measures using Pearson's correlation coefficient. The correlations obtained between the cognitive and all functional measures were all highly significant (p < 0.0001) and consistently high, with correlations ranging between 0.72 and 0.80. Correlations between the a-BT and functional measures of more basic activities of daily living (RDRS-2, BDRS) were lower than those that included instrumental and some advanced activities of daily living (IDDD). The present paper establishes the existence of satisfactory correlations between the functional measures studied and the global scores of the a-BT. These correlations are applicable for groups of subjects with cognitive impairment that does not reach the threshold of a diagnosis of dementia as well as subjects suffering from Alzheimer's disease, at least up to moderately severe cases. The global score of the a-BT allows for some degree of prediction of the functional status of a subject with suspected Alzheimer's disease pathology evaluated.


Sexual activity increases the number of newborn cells in the accessory olfactory bulb of male rats.
In rodents, sexual behavior depends on the adequate detection of sexually relevant stimuli. The olfactory bulb (OB) is a region of the adult mammalian brain undergoing constant cell renewal by continuous integration of new granular and periglomerular neurons in the accessory (AOB) and main (MOB) olfactory bulbs. The proliferation, migration, survival, maturation, and integration of these new cells to the OB depend on the stimulus that the subjects received. We have previously shown that 15 days after females control (paced) the sexual interaction an increase in the number of cells is observed in the AOB. No changes are observed in the number of cells when females are not allowed to control the sexual interaction. In the present study we investigated if in male rats sexual behavior increases the number of new cells in the OB. Male rats were divided in five groups: (1) males that did not receive any sexual stimulation, (2) males that were exposed to female odors, (3) males that mated for 1 h and could not pace their sexual interaction, (4) males that paced their sexual interaction and ejaculated one time and (5) males that paced their sexual interaction and ejaculated three times. All males received three injections of the DNA synthesis marker bromodeoxyuridine at 1h intervals, starting 1 h before the beginning of the behavioral test. Fifteen days later, males were sacrificed and the brains were processed to identify new cells and to evaluate if they differentiated into neurons. The number of newborn cells increased in the granular cell layer (GrCL; also known as the internal cell layer) of the AOB in males that ejaculated one or three times controlling (paced) the rate of the sexual interaction. Some of these new cells were identified as neurons. In contrast, no significant differences were found in the mitral cell layer (also known as the external cell layer) and glomerular cell layer (GlCL) of the AOB. In addition, no significant differences were found between groups in the MOB in any of the layers analyzed. Our results indicate that sexual behavior in male rats increases neurogenesis in the GrCL of the AOB when they control the rate of the sexual interaction.


Persistent effect of IFNAR-1 genetic polymorphism on the long-term pathogenesis of chronic HBV infection.
Genetic polymorphism of IFNAR-1 plays a large role in determining the clearance or chronicity after hepatitis B virus (HBV) exposure. However, it is not clear whether type I interferon receptor-1 (IFNAR-1) variations continuously exert their effects to influence the final outcomes following HBV chronicity, including acute-on-chronic hepatitis B liver failure (ACLF-HBV), chronic hepatitis B (CHB), liver cirrhosis (LC), and hepatocellular carcinoma (HCC). Here we report that these four potential outcomes of chronic HBV infection are strongly associated with IFNAR-1 polymorphisms through a hospital-based case-control study of 663 cases. ACLF-HBV and HCC were each compared with CHB+LC. In comparison with the G/G genotype, the C/G and C/C genotypes at both single-nucleotide polymorphism (SNP) sites (rs1012335 and rs2257167) showed significant susceptibility to ACLF-HBV (the highest odds ratio [OR] reached 2.374; 95% CI = 1.488, 3.788; p < 0.001 for the C/G genotype at rs2257167), as well as HCC (OR = 2.475; 95% CI = 1.435, 4.426; p < 0.001 for the C/C genotype at rs1012335). The C allele at both loci was a susceptibility allele for ACLF-HBV and HCC, with the highest ORs reaching 1.653 (95% CI = 1.233, 2.216; p < 0.01 at rs1012335) in the ACLF-HBV group, and 1.659 (95% CI = 1.274, 2.159; p < 0.01 at rs1012335) in the HCC group. A strongly linked disequilibrium was also found within these two alleles (p < 0.001). Our research indicates that genetic polymorphisms of IFNAR-1 not only contribute to the determination of clearance or chronicity in the early stages of HBV exposure, but they also persistently influence pathogenesis over the long-term process of chronic HBV infection.


Peptide macrocyclization by a bifunctional endoprotease.
Proteases usually cleave peptides, but under some conditions, they can ligate them. Seeds of the common sunflower contain the 14-residue, backbone-macrocyclic peptide sunflower trypsin inhibitor 1 (SFTI-1) whose maturation from its precursor has a genetic requirement for asparaginyl endopeptidase (AEP). To provide more direct evidence, we developed an in situ assay and used (18)O-water to demonstrate that SFTI-1 is excised and simultaneously macrocyclized from its linear precursor. The reaction is inefficient in situ, but a newfound breakdown pathway can mask this inefficiency by reducing the internal disulfide bridge of any acyclic-SFTI to thiols before degrading it. To confirm AEP can directly perform the excision/ligation, we produced several recombinant plant AEPs in E. coli, and one from jack bean could catalyze both a typical cleavage reaction and cleavage-dependent, intramolecular transpeptidation to create SFTI-1. We propose that the evolution of ligating endoproteases enables plants like sunflower and jack bean to stabilize bioactive peptides.


The evolution of larval morphology and swimming performance in ascidians.
The complexity of organismal function challenges our ability to understand the evolution of animal locomotion. To meet this challenge, we used a combination of biomechanics, phylogenetic comparative analyses, and theoretical morphology to examine evolutionary changes in body shape and how those changes affected swimming performance in ascidian larvae. Results of phylogenetic comparative analyses suggest that coloniality evolved at least three times among ascidians and that colonial species have a convergent larval morphology characterized by a large trunk volume and shorter tail length in proportion to the trunk. To explore the functional significance of this evolutionary change, we first verified the accuracy of a mathematical model of swimming biomechanics in a solitary (C. intestinalis) and a colonial (D. occidentalis) species and then ran numerous simulations of the model that varied in tail length and trunk volume. The results of these simulations were used to construct landscapes of speed and cost of transport predictions within a trunk volume/tail length morphospace. Our results suggest that the reduction of proportionate tail length in colonial species resulted in improved energetic economy of swimming. The increase in the size of larvae with the origin of coloniality facilitated faster swimming with negligible energetic cost, but may have required a reduction in adult fecundity. Therefore, the evolution of ascidians appears to be influenced by a trade-off between the fecundity of the adult stage and the swimming performance of larvae.


Independent Emergence of the Plasmodium falciparum Kelch Propeller Domain Mutant Allele C580Y in Guyana.
Suspected artemisinin resistance in Plasmodium falciparum can be explored by examining polymorphisms in the Kelch (PfK13) propeller domain. Sequencing of PfK13 and other gene resistance markers was performed on 98 samples from Guyana. Five of these samples carried the C580Y allele in the PfK13 propeller domain, with flanking microsatellite profiles different from those observed in Southeast Asia. These molecular data demonstrate independent emergence of the C580Y K13 mutant allele in Guyana, where resistance alleles to previously used drugs are fixed. Therefore, in Guyana and neighboring countries, continued molecular surveillance and periodic assessment of the therapeutic efficacy of artemisinin-based combination therapy are warranted.


CNAReporter: a GenePattern pipeline for the generation of clinical reports of genomic alterations.
Genomic copy number alterations are widely associated with a broad range of human tumors and offer the potential to be used as a diagnostic tool. Especially in the emerging era of personalized medicine medical informatics tools that allow the fast visualization and analysis of genomic alterations of a patient's genomic profile for diagnostic and potential treatment purposes increasingly gain importance. We developed CNAReporter, a software tool that allows users to visualize SNP-specific data obtained from Affymetrix arrays and generate PDF-reports as output. We combined standard algorithms for the analysis of chromosomal alterations, utilizing the widely applied GenePattern framework. As an example, we show genome analyses of two patients with distinctly different CNA profiles using the tool. Glioma subtypes, characterized by different genomic alterations, are often treated differently but can be difficult to differentiate pathologically. CNAReporter offers a user-friendly way to visualize and analyse genomic changes of any given tumor genomic profile, thereby leading to an accurate diagnosis and patient-specific treatment.


Choosing Wisely in Critical Care: A National Survey of Critical Care Nurses.
To promote the use of appropriate testing, and decrease unnecessary treatments, the ABIM Foundation established the Choosing Wisely campaign in 2012. Initially targeting physicians, the campaign has evolved to encourage all providers to promote high-value care; however, information related to critical care nursing is limited. To assess nurses' reports of the use of Choosing Wisely recommendations in critical care settings. Responses from nurses were examined as part of a critical care survey of members of 4 societies in order to assess awareness and use of the Choosing Wisely recommendations. Of the 1651 acute and critical care nurses who were members of the American Association of Critical-Care Nurses and responded to the survey, 632 (38.3%) reported being familiar with the Choosing Wisely campaign. Of these respondents, 200 identified as advanced practice nurses. A total of 620 reported implementing the 5 Critical Care Society Collaborative recommendations, including reducing diagnostic testing (n = 311 [50.2%]), reducing the number of red blood cell transfusions (n = 530 [85.5%]), not using parenteral nutrition in adequately nourished patients (n = 293 [47.3%]), not using deep sedation in patients receiving mechanical ventilation (n = 499 [80.5%]), and offering comfort care for patients at high risk for death (n = 416 [67.1%]). Staff education, specific protocols, electronic medical record alerts, and order sets all raised nurses' awareness of the recommendations. Acute and critical care nurses are directly involved with measures to reduce unnecessary testing and treatments. Greater awareness and championing of the Choosing Wisely recommendations by acute and critical care nurses can help to promote high-value care for acute and critically ill patients.


From discrete particles to spherical aggregates: a simple approach to the self-assembly of Au colloids.
Here we demonstrate a simple, template-free approach to the formation of spherical gold aggregates through the reduction of HAuCl4 by NaBH4, in the presence of cysteine (Cys) as a capping agent. The resulting aggregates are quite stable in solution. The pH of the solution and the molar ratio of Au:Cys are two key empirical factors in the formation of such highly ordered aggregates. At slightly alkaline pH (7-10) and with Au:Cys ratios ranging from 1:0.5 to 1:2, spherical Au aggregates of 30-80 nm are formed. At lower Cys ratios (Au:Cys> or =1:0.5) very loosely linked aggregates are formed; however, at very high Cys ratios (Au:Cys< or =1:3), highly dispersed Au particles of 2-4 nm are obtained, which are virtually indistinguishable from the original colloidal form. Aggregate size is influenced markedly by component concentration; a 3-fold increase in standard levels resulted in Au spherical aggregates of a larger size, 200-500 nm. In addition, we used a combination of Cys and lysine (Lys) as a capping agent/cross-linker and found that the morphology of the Au colloid aggregates can be easily manipulated from a linear to a spherical form by adjusting the proportions of Cys and Lys in the capping agent/cross-linker mixture. The introduction of mercapto (SH)-containing organic acids reduced the cross-linking ability of Cys, especially in the case of long-chain acids. Complete disruption of the spherical aggregates highlights the importance of Cys per se. An explanation of this ordered self-assembly process is proposed, in the context of the known surface chemistry of Au colloids.


The relationship between the Patient-rated Ulnar Nerve Evaluation and the common impairment measures of grip strength, pinch strength, and sensation.
Prospective cohort study. Grip strength, pinch strength, and sensory threshold are common evaluations used on a daily basis. Identifying how these variables relate to function for patients allows these assessments to be used for screening to identify who may benefit from surgical intervention, and provides valuable information about what impairments patients think are important with respect to functional use of their upper extremity. Therapists can use this information to focus rehabilitation programs on the most important impairments. To evaluate the relationship between the Patient-rated Ulnar Nerve Evaluation (PRUNE) and impairment measures of grip strength, pinch strength, and one-point sensory threshold. Data was prospectively collected from 77 patients before surgery and during regular time points for 2 years following surgery. Patients completed the PRUNE, grip and pinch strength measures, and a one-point sensory threshold evaluation. Correlations between these variables were calculated at baseline, 2 years after surgery, and for change scores during the 2-year follow up. A multiple regression analysis was used to determine the contribution of the impairment variables for determining functional change. Grip strength showed moderate, statistically significant correlation with PRUNE scores at both baseline (r = -0.38) and at two years (r = -0.29). There was also a statistically significant correlation between one point sensory threshold for the small finger at two years (r = 0.36), but not at baseline. Change in grip strength (r = -0.28) and pinch strength (r = -0.30) both demonstrated significant correlations with PRUNE change scores. Overall, changes in grip strength, pinch strength, and sensation accounted for 20% of the variance in PRUNE changes. Since grip strength was most highly correlated with PRUNE scores at baseline and at two years, rehabilitation programs that target grip strengthening is supported. While neither grip nor pinch strength were significant contributors to the regression when used together, each showed significant contributions to PRUNE variability when used in the model independently. Therefore, a combination of grip and pinch strengthening may be important during rehabilitation for improving functional results in patients that undergo surgical intervention for cubital tunnel syndrome. 2b.


Fine tuning Exo2, a small molecule inhibitor of secretion and retrograde trafficking pathways in mammalian cells.
The small molecule 4-hydroxy-3-methoxybenzaldehyde (5,6,7,8-tetrahydro[1]benzothieno[2,3-d]pyrimidin-4-yl)hydrazone (Exo2) stimulates morphological changes at the mammalian Golgi and trans-Golgi network that are virtually indistinguishable from those induced by brefeldin A. Both brefeldin A and Exo2 protect cells from intoxication by Shiga(-like) toxins by acting on other targets that operate at the early endosome, but do so at the cost of high toxicity to target cells. The advantage of Exo2 is that it is much more amenable to chemical modification and here we report a range of Exo2 analogues produced by modifying the tetrahydrobenzothienopyrimidine core, the vanillin moiety and the hydrazone bond that links these two. These compounds were examined for the morphological changes they stimulated at the Golgi stack, the trans-Golgi network and the transferrin receptor-positive early endosomes and this activity correlated with their inherent toxicity towards the protein manufacturing ability of the cell and their protective effect against toxin challenge. We have developed derivatives that can separate organelle morphology, target specificity, innate toxicity and toxin protection. Our results provide unique compounds with low toxicity and enhanced specificity to unpick the complexity of membrane trafficking networks.


Mental health, wellness, and childhood overweight/obesity.
Childhood obesity is a growing concern, and while progress has been made to understand the association between multiple biological factors (i.e., genetics, nutrition, exercise etc.), little is known about the relationship between mental health and childhood obesity. In this paper, we offer a review of current evidence about the association between mental health and childhood obesity. A systematic literature search of peer-reviewed, English-language studies published between January 2000 and January 2011 was undertaken and resulted in 759 unique records, of which 345 full-text articles were retrieved and 131 articles were included. A theoretical model is proposed to organize the paper and reflect the current state of the literature and includes psychological factors (i.e., depression and anxiety, self-esteem, body dissatisfaction, eating disordered symptoms, and emotional problems); psychosocial mediating variables (i.e., weight-based teasing and concern about weight and shape), and wellness factors (i.e., quality of life and resiliency/protective factors). We conclude with a number of recommendations to support the creation of solutions to the rise in childhood obesity rates that do not further marginalize overweight and obese children and youth and that can potentially improve the well-being of all children and youth regardless of their weight status.


Epidemiological parameters of White Spot Syndrome Virus infections in Litopenaeus vannamei and L. setiferus.
An experimental protocol based on a mathematical epidemiology model was developed to study the transmission, virulence, and recovery rates of White Spot Syndrome Virus (WSSV). Two modes of transmission were compared for WSSV in Litopenaeus vannamei. We compared transmission by ingestion of infected cadavers to transmission by cohabitation with infected animals. In addition, we compared the ingestion transmission of WSSV in L. vannamei and in L. setiferus. Finally, we compared the virulence and recovery rates of WSSV in L. vannamei and L. setiferus. The transmission rate of WSSV to L. vannamei by cohabitation was 0.01. The transmission rate by ingestion of infected cadavers was over an order of magnitude larger at 0.46, suggesting that cohabitation is a much less important mode of transmission for WSSV. A statistically significant difference was detected between the estimates of ingestion transmission of L. vannamei (0.46) and those of L. setiferus (0.84), yet no differences in the virulence or recovery rates were detected between hosts. The overall estimated virulence rate was 0.34, and the overall estimated recovery rate from a WSSV infection was 0.007 for both species. According to epidemiological theory the threshold density of hosts necessary for an epidemic to occur is directly related to the virulence and recovery rates and inversely related to the transmission rate. Therefore, the epidemic threshold density may be lower for ingestion transmission than cohabitation transmission and lower for L. setiferus than for L. vannamei.


Simulating pesticide transport from a sloped tropical soil to an adjacent stream.
Preferential flow from stream banks is an important component of pesticide transport in the mountainous areas of northern Thailand. Models can help evaluate and interpret field data and help identify the most important transport processes. We developed a simple model to simulate the loss of pesticides from a sloped litchi (Litchi chinensis Sonn.) orchard to an adjacent stream. The water regime was modeled with a two-domain reservoir model, which accounts for rapid preferential flow simultaneously with slow flow processes in the soil matrix. Preferential flow is triggered when the topsoil matrix is saturated or the infiltration capacity exceeded. In addition, close to matrix saturation, rainfall events induce water release to the fractures and lead to desorption of pesticides from fracture walls and outflow to the stream. Pesticides undergo first order degradation and equilibrium sorption to soil matrix and fracture walls. The model was able to reproduce the dynamics of the discharge reasonably well (model efficiency [EF] = 0.56). The cumulative pesticide mass (EF = 0.91) and the pesticide concentration in the stream were slightly underestimated, but the deviation from measurement data is acceptable. Shape and timing of the simulated concentration peaks occurred in the same pattern as observed data. While the effect of surface runoff and preferential interflow on pesticide mass transport could not be absolutely clarified, according to our simulations, most concentration peaks in the stream are caused by preferential interflow pointing to the important role of this flow path in the hilly areas of northern Thailand.


Effect of Open- vs Closed-Cell Stent Design on Periprocedural Outcomes and Restenosis After Carotid Artery Stenting: A Systematic Review and Comprehensive Meta-analysis.
To compare periprocedural complications and in-stent restenosis rates associated with open- vs closed-cell stent designs used in carotid artery stenting (CAS). A systematic search was conducted to identify all randomized and observational studies published in English up to October 31, 2017, that compared open- vs closed-cell stent designs in CAS. Identified studies were included if they reported the following outcomes: stroke, transient ischemic attack (TIA), myocardial infarction (MI), hemodynamic depression, new ischemic lesions detected on imaging, and death within 30 days, as well as the incidence of in-stent restenosis. A random-effects model meta-analysis was employed. Model results are reported as the odds ratio (OR) and 95% confidence interval (CI). The I2 statistic was used to assess heterogeneity. Thirty-three studies (2 randomized trials) comprising 20, 291 patients (mean age 71.3±3.0 years; 74.6% men) were included. Patients in the open-cell stent group had a statistically significant lower risk of restenosis ⩾40% (OR 0.42, 95% CI 0.19 to 0.92; I2=0%) and ⩾70% (OR 0.23, 95% CI 0.10 to 0.52; I2=0%) at a mean follow-up of 24 months. No statistically significant differences were identified for periprocedural stroke, TIA, new ischemic lesions, MI, hemodynamic depression, or death within 30 days after CAS. Sensitivity analysis of the 2 randomized controlled trials only did not point to any significant differences either. Use of open-cell stent design in CAS is associated with a decreased risk for restenosis when compared to the closed-cell stent, without significant differences in periprocedural outcomes.


Stigma Associated with Classical Congenital Adrenal Hyperplasia in Women's Sexual Lives.
The risk of intersex-related stigma often serves as social indication for "corrective" genital surgery, but has not been comprehensively documented. In preparation for the development of an intersex-specific stigma assessment tool, this qualitative project aimed to explore stigma in girls and women with classical congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency. As part of a comprehensive follow-up project, 62 adult women with classical CAH (age range 18-51 years) took part in an open-ended retrospective interview focusing on the impact of CAH and its treatment on various aspects of girls' and women's lives. Deductive qualitative content analysis (Patton, 2014) of de-identified transcripts involved categorization of three types of stigma: experienced, anticipated, and internalized. Two-fifths of the participants reported CAH-related stigma in romantic/sexual situations. Stigma enactment by romantic partners occurred in reaction to both genital and non-genital sex-atypical features of CAH and sometimes included explicit questioning of the women's true gender. Stigma anticipation by the women and their related avoidance of nudity, genital exposure, and romantic involvement altogether were frequent. Internalization of stigma occurred as well. In conclusion, the data suggest that many women with CAH experience, anticipate, and/or internalize intersex-related stigma in the context of their romantic/sexual lives.


Thermotolerance capacities of native and exotic coastal plants will lead to changes in species composition under increased heat waves.
With an increase in the frequency and intensity of extreme heat events, plants are likely to reach their thermal limits and show slower growth or increased mortality. We investigated differences amongst coastal native and invasive shrubs and grasses to investigate if particular species might be more at risk in the future. Using an ecologically relevant experimental set of heat waves over a month, we assessed changes in biomass and photosynthetic efficiency in a laboratory setting using 25 coastal Australian species divided into native and exotic shrubs, and native and exotic grasses. We also compared three C3 and three C4 grasses within the native and exotic groups. Overall, native shrubs suffered higher mortality, lower growth and increased photosynthetic stress. There was some evidence that C3 grasses, had lower growth with heat waves, compared to C4 species although, in general, grasses showed evidence of photosynthetic acclimation over the month. Increases in leaf abscission suggest that part of the acclimation process was to develop new, thermally tolerant leaves. Our results indicate that in the future we would expect an increase in exotic shrubs and grasses occupying spaces in coastal plant communities that arise from native mortality following extreme heat events. Management of these coastal communities will need to focus strongly on maintaining a diverse native shrub composition that can resist climate-based disturbances (such as wildfire), as well as controlling the extent and biomass of exotic species, if coastal communities are to remain healthy and diverse in a changing climate.


Regional variation of tibialis anterior tendon mechanics is lost following denervation.
Denervation or inactivity is known to decrease the mass and alter the phenotype of muscle. The mechanical response of tendon to inactivity that has been determined experimentally differs from what is reported by patients. We investigated the hypothesis that this difference was the result of artifacts of the testing process and did not represent what occurred in vivo. To test this hypothesis, a novel approach was used to determine the mechanical properties of the tibialis anterior (TA) tendon by optically measuring the end-to-end mechanical strains as well as the local strains at specific regions of excised TA tendon units. When the end-to-end strain of normal TA tendon is determined, stress-strain response curves show considerably more extensibility than when strain is measured across only the midsection of the tendon (mid-tendon). The strain experienced by the region close to the muscle (muscle tendon) is five times greater than the strain in either the mid-tendon or near the bone (bone-tendon). Five weeks of denervation decreased muscle mass by 67%; increased tendon mass by 10%; and changed the entire shape of the nonlinear response curve, including a loss in regional variation in strain, a 3.9-fold increase in end-to-end tangent modulus, and a 70% reduction in the toe region, as a result of a drastic reduction of the extensibility in the muscle-tendon region. The stress-strain response in the mid-tendon region of a normal TA tendon is therefore not indicative of its overall ability to deform in vivo as it transmits forces from muscle to bone.


Lentiviral vector delivery of parkin prevents dopaminergic degeneration in an alpha-synuclein rat model of Parkinson's disease.
Parkinson's disease (PD) is characterized by a progressive loss of midbrain dopamine neurons and the presence of cytoplasmic inclusions called Lewy bodies. Mutations in several genes including alpha-synuclein and parkin have been linked to familial PD. The loss of parkin's E3-ligase activity leads to dopaminergic neuronal degeneration in early-onset autosomal recessive juvenile parkinsonism, suggesting a key role of parkin for dopamine neuron survival. To evaluate the potential neuroprotective role of parkin in the pathogenesis of PD, we tested whether overexpression of wild-type rat parkin could protect against the toxicity of mutated human A30P alpha-synuclein in a rat lentiviral model of PD. Animals overexpressing parkin showed significant reductions in alpha-synuclein-induced neuropathology, including preservation of tyrosine hydroxylase-positive cell bodies in the substantia nigra and sparing of tyrosine hydroxylase-positive nerve terminals in the striatum. The parkin-mediated neuroprotection was associated with an increase in hyperphosphorylated alpha-synuclein inclusions, suggesting a key role for parkin in the genesis of Lewy bodies. These results indicate that parkin gene therapy may represent a promising candidate treatment for PD.


The effect of early environmental manipulation on locomotor sensitivity and methamphetamine conditioned place preference reward.
Early life stress leads to several effects on neurological development, affecting health and well-being later in life. Instances of child abuse and neglect are associated with higher rates of depression, risk taking behavior, and an increased risk of drug abuse later in life. This study used repeated neonatal separation of rat pups as a model of early life stress. Rat pups were either handled and weighed as controls or separated for 180 min per day during postnatal days 2-8. In adulthood, male and female rats were tested for methamphetamine conditioned place preference reward and methamphetamine induced locomotor activity. Tissue samples were collected and mRNA was quantified for the norepinephrine transporter in the prefrontal cortex and the dopamine transporter in the nucleus accumbens. Results indicated rats given methamphetamine formed a conditioned place preference, but there was no effect of early separation or sex. Separated males showed heightened methamphetamine-induced locomotor activity, but there was no effect of early separation for females. Overall females were more active than males in response to both saline and methamphetamine. No differences in mRNA levels were observed across any conditions. These results suggest early neonatal separation affects methamphetamine-induced locomotor activity in a sex-dependent manner but has no effects on methamphetamine conditioned place preference.


Borrelia burgdorferi tissue morphologies and imaging methodologies.
This manuscript offers an image presentation of diverse forms of Borrelia burgdorferi spirochetes which are not spiral or corkscrew shaped. Explanations are offered to justify the legitimacy of tissue forms of Borrelia which may confuse the inexperienced microscopic examiner and which may lead to the misdiagnosis of non-spiral forms as artifacts. Images from the author's personal collection of Borrelia burgdorferi images and a few select images of Borrelia burgdorferi from the peer-reviewed published literature are presented. A commentary justifying each of the image profiles and a survey of the imaging modalities utilized provides the reader with a frame of reference. Regularly spiraled Borrelia are rarely seen in solid tissues. A variety of straightened, undulating, and clipped-off profiles are demonstrated, and the structural basis for each image is explained. Tissue examination is a diagnostic tool and a quality control for judging the eradication or the persistence of borreliosis following attempts to eradicate the infection with antibiotic therapy. The presence or absence of chronic Lyme borreliosis may be objectively adjudicated by tissue examinations which demonstrate or which fail to show pathogenic microbes in patients who have received a full course of antibiotics.


Human resources for primary health care in sub-Saharan Africa: progress or stagnation?
The World Health Organization defines a "critical shortage" of health workers as being fewer than 2.28 health workers per 1000 population and failing to attain 80% coverage for deliveries by skilled birth attendants. We aimed to quantify the number of health workers in five African countries and the proportion of these currently working in primary health care facilities, to compare this to estimates of numbers needed and to assess how the situation has changed in recent years. This study is a review of published and unpublished "grey" literature on human resources for health in five disparate countries: Mali, Sudan, Uganda, Botswana and South Africa. Health worker density has increased steadily since 2000 in South Africa and Botswana which already meet WHO targets but has not significantly increased since 2004 in Sudan, Mali and Uganda which have a critical shortage of health workers. In all five countries, a minority of doctors, nurses and midwives are working in primary health care, and shortages of qualified staff are greatest in rural areas. In Uganda, shortages are greater in primary health care settings than at higher levels. In Mali, few community health centres have a midwife or a doctor. Even South Africa has a shortage of doctors in primary health care in poorer districts. Although most countries recognize village health workers, traditional healers and traditional birth attendants, there are insufficient data on their numbers. There is an "inverse primary health care law" in the countries studied: staffing is inversely related to poverty and level of need, and health worker density is not increasing in the lowest income countries. Unless there is money to recruit and retain staff in these areas, training programmes will not improve health worker density because the trained staff will simply leave to work elsewhere. Information systems need to be improved in a way that informs policy on the health workforce. It may be possible to use existing resources more cost-effectively by involving skilled staff to supervise and support lower level health care workers who currently provide the front line of primary health care in most of Africa.


Impaired food transportation in Parkinson's disease related to lingual bradykinesia.
This study aimed to analyze quantitatively videofluoroscopic (VF) images of patients with Parkinson's disease (PD), to evaluate if the predicted factors of the oral phase of swallowing deteriorated with PD progression, and to demonstrate a relationship between the abnormal movements of the tongue and food transportation. Thirty PD patients were recruited and divided into mild/moderate (Hoehn & Yahr stages II and III) and advanced (stages IV and V) groups. They underwent measurement of tongue strength and VF using 5 ml of barium gelatin jelly as a test food. We measured the speed of bolus movement and the range of tongue and mandible movements during oropharyngeal transit time. The maximum tongue pressure of the mild/moderate group was significantly larger than that of advanced group (p = 0.047). The oropharyngeal transit time of the mild/moderate group was significantly shorter than that of the advanced group (p = 0.045). There was a significant negative correlation between the speed of tongue movement and the oropharyngeal transit time (p = 0.003, R = -0.527). Prolonged mealtimes and the ejection of insufficiently masticated food from the oral cavity into oropharynx were associated with PD progression. These results indicate the importance of the oral phase of swallowing in PD patients.


In vivo imaging of functional microvasculature within tissue beds of oral and nasal cavities by swept-source optical coherence tomography with a forward/side-viewing probe.
We report three-dimensional (3D) imaging of microcirculation within human cavity tissues in vivo using a high-speed swept-source optical coherence tomography (SS-OCT) at 1300 nm with a modified probe interface. Volumetric structural OCT images of the inner tissues of oral and nasal cavities are acquired with a field of view of 2 mm × 2 mm. Two types of disposable and detachable probe attachments are devised and applied to the port of the imaging probe of OCT system, enabling forward and side imaging scans for selective and easy access to specific cavity tissue sites. Blood perfusion is mapped with OCT-based microangiography from 3D structural OCT images, in which a novel vessel extraction algorithm is used to decouple dynamic light scattering signals, due to moving blood cells, from the background scattering signals due to static tissue elements. Characteristic tissue anatomy and microvessel architectures of various cavity tissue regions of a healthy human volunteer are identified with the 3D OCT images and the corresponding 3D vascular perfusion maps at a level approaching capillary resolution. The initial finding suggests that the proposed method may be engineered into a promising tool for evaluating and monitoring tissue microcirculation and its alteration within a wide-range of cavity tissues in the patients with various pathological conditions.


Nephritogenicity of anti-proteoglycan antibodies in experimental murine lupus nephritis.
Cross-reactivity between anti-DNA antibodies and heparan sulfate (HS)/heparan sulfate-proteoglycan (HS-PG) of glomerular basement membrane has been previously reported. Conceivably, this determines the final outcome of glomerular injury in lupus nephritis. We investigated the status of glomerular injury in NZB/NZW F1 mice after the administration of rabbit anti-HS-PG antibody (experiment group). The controls received normal rabbit IgG only. All experimental animals became proteinuric 2 weeks after the administration of anti-HS-PG. The animals of the older age group (16 weeks) had significant hematuria as well. Their glomeruli exhibited hypercellularity with a heavy influx of polymorphonuclear leukocytes and monocytes into their capillaries, and some of them exhibited crescentic changes. Electron-dense deposits were present in subepithelial, subendothelial, and mesangial regions of the glomeruli. The control group had normocellular glomeruli with a few mesangial deposits. Mouse IgG and C3 displayed a granular pattern of immunofluorescence in the experimental group. Anti-rabbit IgG titers in the serum were higher in the control group, which lower in the renal glomerular eluates. No significant differences were observed in the concentrations of anti-dsDNA and -ssDNA either in the sera or in the eluates. There was also no difference between the control and experimental group in terms of antibody synthesis by the splenic lymphocytes and their proliferation subsequent to antigenic challenge. Data suggest that administration of anti-HS-PG accentuates the glomerular injury during the natural course of lupus nephritis in (NZB/NZW F1 mice; seemingly these two antibodies (anti-HS-PG and -DNA) do not competitively inhibit the binding of the other to the same anionic sites of glomerular basement membrane enriched with heparan sulfate in vivo.


Genetic and environmental influences on adult human height across birth cohorts from 1886 to 1994.
Human height variation is determined by genetic and environmental factors, but it remains unclear whether their influences differ across birth-year cohorts. We conducted an individual-based pooled analysis of 40 twin cohorts including 143,390 complete twin pairs born 1886-1994. Although genetic variance showed a generally increasing trend across the birth-year cohorts, heritability estimates (0.69-0.84 in men and 0.53-0.78 in women) did not present any clear pattern of secular changes. Comparing geographic-cultural regions (Europe, North America and Australia, and East Asia), total height variance was greatest in North America and Australia and lowest in East Asia, but no clear pattern in the heritability estimates across the birth-year cohorts emerged. Our findings do not support the hypothesis that heritability of height is lower in populations with low living standards than in affluent populations, nor that heritability of height will increase within a population as living standards improve.


Oral quercetin supplementation and blood oxidative capacity in response to ultramarathon competition.
Previous research indicates that ultramarathon exercise can result in blood oxidative stress. The purpose of this investigation was to examine the efficacy of oral supplementation with quercetin, a naturally occurring compound with known antioxidant properties, as a potential countermeasure against blood oxidative stress during an ultramarathon competition. In double-blind fashion, 63 participants received either oral quercetin (250 mg, 4x/day; 1,000 mg/day total) or quercetin-free supplements 3 weeks before and during the 160-km Western States Endurance Run. Blood drawn before and immediately after (quercetin finishers n = 18, quercetin-free finishers n = 21) the event was analyzed for changes in blood redox status and oxidative damage. Results show that quercetin supplementation did not affect race performance. In response to the ultramarathon challenge, aqueous-phase antioxidant capacity (ferric-reducing ability of plasma) was similarly elevated in athletes in both quercetin and quercetin-free treatments and likely reflects significant increases in plasma urate levels. Alternatively, trolox-equivalent antioxidant capacity was not altered by exercise or quercetin. Accordingly, neither F2-isoprostances nor protein carbonyls were influenced by either exercise or quercetin supplementation. In the absence of postrace blood oxidative damage, these findings suggest that oral quercetin supplementation does not alter blood plasma lipid or aqueous-phase antioxidant capacity or oxidative damage during an ultramarathon challenge.


The volume and capacity of colonoscopy procedures performed at New York City hospitals in 2002.
Colorectal cancer is the second leading cause of cancer death in New York City. In March 2003, the New York City Department of Health and Mental Hygiene recommended colonoscopy every 10 years as the preferred screening test for adults aged 50 years and older in New York City. To screen all eligible adults in New York City would require that approximately 200,000 colonoscopy exams be performed annually. As part of this recommendation, we evaluated current colonoscopy capacity in New York City hospitals. We surveyed endoscopy suite nursing or administrative staff at all 66 adult acute care hospitals performing colonoscopy in New York City. Data on colonoscopy procedures performed in 2002 were collected between February and June 2003. All hospitals and two affiliated clinics responded. The number of hospital-based colonoscopy exams performed in 2002 was estimated to be 126,000. Of these, 53,600 (43%) were estimated to be for screening. Hospitals reported their maximum annual capacity to be 195,200, approximately 69,100 more than current practice. Reported barriers to performing more colonoscopy exams included inadequate suite time and space (31%), inadequate staffing (28%), and insufficient patient referrals (24%). In 2003, endoscopy suites at New York City hospitals performed approximately one quarter of the estimated citywide need of 200,000 screening colonoscopies. Procedures conducted in outpatient office settings were not assessed. Most endoscopy suites, particularly private hospitals, reported having the capacity to conduct additional procedures. Hospitals and endoscopy suites should prioritize the development of institutional measures to increase the number of persons receiving screening colonoscopy.


Methanocaldococcus jannaschii prolyl-tRNA synthetase charges tRNA(Pro) with cysteine.
Methanocaldococcus jannaschii prolyl-tRNA synthetase (ProRS) was previously reported to also catalyze the synthesis of cysteinyl-tRNA(Cys) (Cys-tRNA(Cys)) to make up for the absence of the canonical cysteinyl-tRNA synthetase in this organism (Stathopoulos, C., Li, T., Longman, R., Vothknecht, U. C., Becker, H., Ibba, M., and Söll, D. (2000) Science 287, 479-482; Lipman, R. S., Sowers, K. R., and Hou, Y. M. (2000) Biochemistry 39, 7792-7798). Here we show by acid urea gel electrophoresis that pure heterologously expressed recombinant M. jannaschii ProRS misaminoacylates M. jannaschii tRNA(Pro) with cysteine. The enzyme is unable to aminoacylate purified mature M. jannaschii tRNA(Cys) with cysteine in contrast to facile aminoacylation of the same tRNA with cysteine by Methanococcus maripaludis cysteinyl-tRNA synthetase. Although M. jannaschii ProRS catalyzes the synthesis of Cys-tRNA(Pro) readily, the enzyme is unable to edit this misaminoacylated tRNA. We discuss the implications of these results on the in vivo activity of the M. jannaschii ProRS and on the nature of the enzyme involved in the synthesis of Cys-tRNA(Cys) in M. jannaschii.


Occurrence of glyphosate and AMPA residues in soy-based infant formula sold in Brazil.
Glyphosate is an herbicide widely used in the world, being applied in several crops, among them soybeans. Recently, glyphosate and its metabolite aminomethylphosphonic acid (AMPA) have been identified as possible contributors to the emergence of various diseases such as autism, Parkinson's and Alzheimer's diseases, as well as cancer. The child population-consuming cereal-based foods is the most exposed to the effects of pesticides because of their developmental phase and they have a higher food intake per kilogram of body weight than adults. The presence of glyphosate and AMPA residues in soy-based infant formulas was evaluated during the years 2012-2017, totalising 105 analyses carried out on 10 commercial brands from different batches. Glyphosate and AMPA were determined by liquid chromatography with fluorescence detection after derivatisation reaction. The method was validated and showed accuracy and precision with a limit of quantification (LOQ) of 0.02 mg kg-1. Among those samples that contained levels above the LOQ, the variation of glyphosate residues was from 0.03 mg kg-1 to 1.08 mg kg-1 and for AMPA residues was from 0.02 mg kg-1 to 0.17 mg kg-1. This is the first scientific communication about glyphosate and AMPA contamination in soy-based infant formula in Brazil, The study was conducted under good laboratory practice (GLP) and supported by good scientific practice.


Cigarette advertising in magazines: the tobacco industry response to the Master Settlement Agreement and to public pressure.
The Master Settlement Agreement (MSA) of November 1998 prohibited participating tobacco companies from directly or indirectly targeting youth in marketing. Widely publicised information in May 2000 showed increased cigarette advertising in magazines with substantial youth readership and companies were pressed to change their practices. The responses of the tobacco industry to the MSA and to the public pressure are examined. Expenditures on cigarette advertisements in national magazines in the USA are compared for three periods: January to November 1998, December 1998 to June 2000, and July 2000 to November 2001. Magazines in which at least 15% of readers are youth under age 18 are focused upon. Regression models test for the significance of period differences after controlling for seasonal and long term patterns. Commercially maintained data on advertising in US magazines and on magazine readership by age. Monthly cigarette ad expenditures in magazines with 15%+ youth readership, and monthly proportion of ad expenditures in 15%+ youth magazines. Cigarette advertising expenditures in magazines with 15%+ youth readership increased dramatically after MSA implementation and fell dramatically after public pressure. The percentage allocation of expenditures to 15%+ magazines fell significantly in both periods. Results differ somewhat by company. The tobacco industry response to the MSA was at best modest, reducing proportional allocations of advertising to youth magazines but increasing the absolute amount of such advertising. The value of public pressure was seen in substantial reductions in both absolute and proportional spending on youth magazines, although not by all companies.


Hypoplastic left heart syndrome: natural history in a geographically defined population.
Advances in surgical treatment of hypoplastic left heart syndrome with the Norwood procedure and cardiac transplantation have made essential the understanding of the natural history of hypoplastic left heart syndrome. In a geographically defined population, we ascertained the prevalence of hypoplastic left heart syndrome in children born in Oregon from 1971 through 1986. Clinical and anatomic data were extracted from the charts of the 98 affected children and the survival rate was calculated. Hypoplastic left heart syndrome occurred in 0.162 per 1000 live births in Oregon during this period. No syndrome complex was prevalent and 84% were free of other congenital malformations. However, there was an increased occurrence of congenital heart defects in first-degree relatives of probands with hypoplastic left heart syndrome. Of the affected children 15 +/- 4% died on the first day of life, 70 +/- 5% died within the first week, and 91 +/- 3% died within 30 days. No secular change in survival occurred during the study. Palliation with the Norwood procedure was performed in 20 children. Although survival was significantly improved with this surgery (P = .01), the effect was observed principally through 30 days of life and only one of these children remains alive. Hypoplastic left heart syndrome is a lethal congenital heart defect in children and poses management and ethical dilemmas.


Stability studies of ZnO and AlN thin film acoustic wave devices in acid and alkali harsh environments.
Surface acoustic wave (SAW) devices based on piezoelectric thin-films such as ZnO and AlN are widely used in sensing, microfluidics and lab-on-a-chip applications. However, for many of these applications, the SAW devices will inevitably be used in acid or alkali harsh environments, which may cause their early failures. In this work, we investigated the behavior and degradation mechanisms of thin film based SAW devices in acid and alkali harsh environments. Results show that under the acid and alkali attacks, chemical reaction and corrosion of ZnO devices are very fast (usually within 45 s). During the corrosion, the crystalline orientation of the ZnO film is not changed, but its grain defects are significantly increased and the grain sizes are decreased. The velocity of ZnO-based SAW devices is decreased due to the formation of porous structures induced by the chemical reactions. Whereas an AlN thin-film based SAW device does not perform well in acid-alkali conditions, it might be able to maintain a normal performance without obvious degradation for more than ten hours in acid or alkali solutions. This work could provide guidance for the applications of both ZnO or AlN-based SAW devices in acid/alkali harsh environments.


Influence of particle size distribution on reflected and transmitted light from clouds.
The light reflected and transmitted from clouds with various drop size distributions is calculated by a Monte Carlo technique. Six different models are used for the drop size distribution: isotropic, Rayleigh, haze continental, haze maritime, cumulus, and nimbostratus. The scattering function for each model is calculated from the Mie theory. In general, the reflected and transmitted radiances for the isotropic and Rayleigh models tend to be similar, as are those for the various haze and cloud models. The reflected radiance is less for the haze and cloud models than for the isotropic and Rayleigh models/except for an angle of incidence near the horizon when it is larger around the incident beam direction. The transmitted radiance is always much larger for the haze and cloud models near the incident direction; at distant angles it is less for small and moderate optical thicknesses and greater for large optical thicknesses (all comparisons to isotropic and Rayleigh models). The downward flux, cloud albedo, and ean optical path are discussed. The angular spread of the beam as a function of optical thickness is shown for the nimbostratus model.


Hormonal regulation of hepatic organic anion transporting polypeptides.
Organic anion transporting polypeptides (Oatp) mediate the transport of a wide variety of amphipathic organic substrates. Rat Oatp1b2 and human OATP1B3 are members of a liver-specific subfamily of Oatps/OATPs. We investigated whether prolactin (PRL) and growth hormone (GH) regulated Oatp1b2 and OATP1B3 gene expression via signal transducers and activators of transcription 5 (Stat5). Binding sites for Stat5 transcription factors were located in the promoters of Oatp1b2 and OATP1B3 at -209 to -201 (5'-TTCTGGGAA-3') and -170 to -162 (5'-TTCTGAGAA-3'), respectively. In primary hepatocytes from female and male rats treated with PRL or GH, Oatp1b2 mRNA measured by real-time polymerase chain reaction was significantly induced 2-fold. HepG2 cells were transiently transfected with expression vectors containing Oatp1b2 or OATP1B3 promoter fragments, cDNAs for Stat5a, and the receptors for PRL (PRLR(L)) or GH (GHR), and treated with PRL or GH. PRL and GH induction of Oatp1b2 and OATP1B3 promoter activity required cotransfection of Stat5a and PRLR(L) or GHR. Mutation of the Stat5 binding site in both promoters eliminated hormonal induction. In DNA binding assays, HepG2 cells transfected with cDNAs for Stat5a and PRLR(L) were treated with PRL, and nuclear extracts were probed with a (32)P-labeled oligomer corresponding to -177 to -157 of the OATP1B3 promoter. PRL enhanced the binding of Stat5a to the OATP1B3 promoter and DNA-protein binding was inhibited in competition assays by excess OATP1B3 and Stat5 consensus oligomers but not by mutant Stat5 oligomers. These findings indicate that PRL and GH can regulate Oatp1b2 and OATP1B3 gene expression via the Stat5 signal-transduction pathway.


THE ROLE OF LOCATION IN EVALUATING RACIAL WAGE DISPARITY.
A standard object of empirical analysis in labor economics is a modified Mincer wage function in which an individual's log wage is specified to be a function of education, experience, and an indicator variable identifying race. We analyze this approach in a context in which individuals live and work in different locations (and thus face different housing prices and wages). Our model provides a justification for the traditional approach, but with the important caveat that the regression should include location-specific fixed effects. Empirical analyses of men in U.S. labor markets demonstrate that failure to condition on location causes us to (i) overstate the decline in black-white wage disparity over the past 60 years, and (ii) understate racial and ethnic wage gaps that remain after taking into account measured cognitive skill differences that emerge when workers are young.


Chaperones Skp and SurA dynamically expand unfolded OmpX and synergistically disassemble oligomeric aggregates.
Periplasmic chaperones 17-kilodalton protein (Skp) and survival factor A (SurA) are essential players in outer membrane protein (OMP) biogenesis. They prevent unfolded OMPs from misfolding during their passage through the periplasmic space and aid in the disassembly of OMP aggregates under cellular stress conditions. However, functionally important links between interaction mechanisms, structural dynamics, and energetics that underpin both Skp and SurA associations with OMPs have remained largely unresolved. Here, using single-molecule fluorescence spectroscopy, we dissect the conformational dynamics and thermodynamics of Skp and SurA binding to unfolded OmpX and explore their disaggregase activities. We show that both chaperones expand unfolded OmpX distinctly and induce microsecond chain reconfigurations in the client OMP structure. We further reveal that Skp and SurA bind their substrate in a fine-tuned thermodynamic process via enthalpy-entropy compensation. Finally, we observed synergistic activity of both chaperones in the disaggregation of oligomeric OmpX aggregates. Our findings provide an intimate view into the multifaceted functionalities of Skp and SurA and the fine-tuned balance between conformational flexibility and underlying energetics in aiding chaperone action during OMP biogenesis.


The contextualized self: how team-member exchange leads to coworker identification and helping OCB.
This article develops the argument that team-member exchange (TMX) relationships operate at both between- and within-group levels of analysis to influence an employee's sense of identification with coworkers in the group and their helping organizational citizenship behavior (OCB) directed at coworkers. Specifically, we propose that relatively higher quality TMX relationships of an employee as compared with other members of the group influence an employee's sense of positive uniqueness, whereas higher average level of TMX quality in the group creates a greater sense of belonging. Multilevel modeling analysis of field data from 236 bank managers and their subordinates supports the hypotheses and demonstrates 3 key findings. First, team members identify more with their coworkers when they have high relative TMX quality compared with other group members and are also embedded in groups with higher average TMX. Second, identification with coworkers is positively related to helping OCB directed toward team members. Finally, identification with coworkers mediates the interactive effect of relative TMX quality and group average TMX quality on helping. When TMX group relations allow individuals to feel a valued part of the group, but still unique, they engage in higher levels of helping. Overall moderated mediation analysis demonstrates that the mediated relationship linking relative TMX quality with helping OCB via identification with coworkers is stronger when group average TMX is high, but not present when group average TMX is low. We discuss theoretical and practical implications and recommend future research on multilevel conceptualizations of TMX.


Learning to reason: a journey of professional socialisation.
One of the key attributes that health professional students and new graduates develop during professional socialisation is clinical reasoning ability. Clinical reasoning is a complex skill that is essential for professional practice. There is limited research specifically addressing how physiotherapists learn to reason in the workplace. The research reported in this paper addressed this gap by investigating how experienced physiotherapists learned to reason in daily practice. This learning journey was examined in the context of professional socialisation. A hermeneutic phenomenological research study was conducted using multiple methods of data collection including observation, written reflective exercises and repeated, semi-structured interviews. Data were analysed using phenomenological and hermeneutic strategies involving in-depth, iterative reading and interpretation to identify themes in the data. Twelve physiotherapists with clinical and supervisory experience were recruited from the areas of cardiopulmonary, musculoskeletal and neurological physiotherapy to participate in this study. Participants' learning journeys were diverse, although certain episodes of learning were common or similar. Role models, mentors and colleagues were found to be influential in the development of reasoning. An important implication for the professional socialisation of physiotherapists and other health professionals and for those involved in practice development is the need to recognise and enhance the role of practice communities in the explicit learning of clinical reasoning skills.


Recurrent Infective Endocarditis with Mycotic Aneurysm - Imaging Modalities for the Detection of an Infective Focus.
Staphylococcus aureus bacteremia (SAB) and infective endocarditis (IE) are infections associated with considerable morbidity, requiring prompt accurate diagnosis and treatment. We present a case of a 58-year-old male patient with four episodes of recurrent symptomatic SAB treated for IE, but without positive findings on transthoracic echocardiography, transesophageal echocardiography, and fluorodeoxyglucose-positron emission tomography (FDG-PET). On the last admission, FDG-PET showed increased uptake in the right atrial appendage, and white blood cell single-photon emission computerized tomography (WBC-SPECT) was able to identify the infective focus as IE of the aortic valve. CT of the thorax also identified an associated mycotic aneurysm of the right coronary sinus. He was subsequently treated with mechanical aortic prosthesis and right coronary sinus plasty, and his symptoms did not recur till 2 years postcardiothoracic surgery. This case report demonstrates the emergence of nuclear cardiovascular imaging modalities in the diagnostic workup of IE and the utility of FDG-PET and WBC-SPECT in the identification of the infective focus. Patients with possible IE from the modified Duke criteria should be considered for FDG-PET or WBC-SPECT to enhance sensitivity. Peripheral mycotic aneurysms are a common complication of left-sided IE, which can present late into the disease process, and aortic imaging should be considered in patients with recurrent endocarditis to identify this.


Discovery and Optimization of Materials Using Evolutionary Approaches.
Materials science is undergoing a revolution, generating valuable new materials such as flexible solar panels, biomaterials and printable tissues, new catalysts, polymers, and porous materials with unprecedented properties. However, the number of potentially accessible materials is immense. Artificial evolutionary methods such as genetic algorithms, which explore large, complex search spaces very efficiently, can be applied to the identification and optimization of novel materials more rapidly than by physical experiments alone. Machine learning models can augment experimental measurements of materials fitness to accelerate identification of useful and novel materials in vast materials composition or property spaces. This review discusses the problems of large materials spaces, the types of evolutionary algorithms employed to identify or optimize materials, and how materials can be represented mathematically as genomes, describes fitness landscapes and mutation operators commonly employed in materials evolution, and provides a comprehensive summary of published research on the use of evolutionary methods to generate new catalysts, phosphors, and a range of other materials. The review identifies the potential for evolutionary methods to revolutionize a wide range of manufacturing, medical, and materials based industries.


Exploring the Benefit of Yoga Programs in Carceral Settings.
This article presents a perspective on the value of yoga and mindfulness programming in carceral settings. The authors explore this topic through interviews with two formerly incarcerated people who participated in yoga programming while incarcerated and who went on to become yoga instructors themselves. Also examined are the potential effects of yoga programming for people who are incarcerated, for those working within carceral settings, and on carceral environments generally. We share recommendations for implementing yoga programming in carceral institutions and discuss policy implications. The stories of both interviewees reflect the value and potential positive effects of yoga programming within criminal justice settings and suggest the need for sustained programming and ongoing empirical evaluation.


Modulation of human uterine smooth muscle cell collagen contractility by thrombin, Y-27632, TNF alpha and indomethacin.
Preterm labour occurs in approximately 10% of pregnancies and is a major cause of infant morbidity and mortality. However, the pathways involved in regulating contractility in normal and preterm labour are not fully elucidated. Our aim was to utilise a human myometrial contractility model to investigate the effect of a number of uterine specific contractility agents in this system. Therefore, we investigated the contractile response of human primary uterine smooth muscle cells or immortalised myometrial smooth muscle cells cultured within collagen lattices, to known mediators of uterine contractility, which included thrombin, the ROCK-1 inhibitor Y-27632, tumour necrosis factor alpha (TNF alpha) and the non-steroidal anti-inflammatory indomethacin. Cell contractility was calculated over time, with the collagen gel contraction assay, utilising human primary uterine smooth muscle cells (hUtSMCs) and immortalised myometrial smooth muscle cells (hTERT-HM): a decrease in collagen gel area equated to an increase in contractility. RNA was isolated from collagen embedded cells and gene expression changes were analysed by real time fluorescence reverse transcription polymerase chain reaction. Scanning electron and fluorescence microscopy were employed to observe cell morphology and cell collagen gel interactions. Statistical analysis was performed using ANOVA followed by Tukey's post hoc tests. TNF alpha increased collagen contractility in comparison to the un-stimulated collagen embedded hUtSMC cells, which was inhibited by indomethacin, while indomethacin alone significantly inhibited contraction. Thrombin augmented the contractility of uterine smooth muscle cell and hTERT-HM collagen gels, this effect was inhibited by the thrombin specific inhibitor, hirudin. Y-27632 decreased both basal and thrombin-induced collagen contractility in the hTERT-HM embedded gels. mRNA expression of the thrombin receptor, F2R was up-regulated in hUtSMCs isolated from collagen gel lattices, following thrombin-stimulated contractility. TNF alpha and thrombin increased uterine smooth muscle cell collagen contractility while indomethacin had the opposite effect. Thrombin-induced collagen contractility resulted in F2R activation which may in part be mediated by the ROCK-1 pathway. This study established the in vitro human myometrial model as a viable method to assess the effects of a range of uterotonic or uterorelaxant agents on contractility, and also permits investigation of the complex regulatory pathways involved in mediating myometrial contractility at labour.


Leishmania infection and host-blood feeding preferences of phlebotomine sandflies and canine leishmaniasis in an endemic European area, the Algarve Region in Portugal.
The Algarve Region (AR) in southern Portugal, which is an international tourist destination, has been considered an endemic region of zoonotic leishmaniasis caused by Leishmania infantum since the 1980s. In the present study, phlebotomine and canine surveys were conducted to identify sandfly blood meal sources and to update the occurrence of Leishmania infection in vectors and dogs. Four sandfly species were captured: Phlebotomus perniciosus, Phlebotomus ariasi, Phlebotomus sergenti and Sergentomyia minuta. In one P. perniciosus female, L. infantum DNA was detected. Blood meal tests showed that this species had no host preferences and was an opportunistic feeder. An overall canine leishmaniasis (CanL) seroprevalence of 16.06% was found; the seroprevalence was 3.88% in dogs housed in kennels and 40.63% in dogs that attended veterinary clinics. The simultaneous occurrence of dogs and P. perniciosus infected with L. infantum in the AR indicates that the region continues to be an endemic area for CanL. Our results reinforce the need for the systematic spatial distribution of phlebotomine populations and their Leishmania infection rates and the need to simultaneously perform pathogen monitoring in both invertebrate and vertebrate hosts to investigate the transmission, distribution and spreading of Leishmania infection.


Real-Time External Labeling of Ghosted Views.
We present a new algorithm for calculating the external labeling of ghosted views of moderately complex 3D models. The algorithm uses multiple criteria decision making, based on fuzzy logic, to optimize positions of the labels associated with different parts of the input model. The proposed method can be used with various existing algorithms for creating ghosted views from 3D models. The method operates in real-time, which allows the user to acquire a good understanding of the structure of the input model by studying the model and its labels from different viewpoints. We have conducted a user study to evaluate label layouts produced by our algorithm and those created by humans. The results show that the proposed method can significantly improve user understanding of labeled ghosted views of complicated 3D models, and its label layouts are comparable with label layouts created by humans.


Effect of temperature on the morphology and kinetics of surface pattern formation in thin block copolymer films.
Hole formation and growth on the top layer of thin symmetric diblock copolymer films, forming an ordered lamellar structure parallel to the solid substrate (silicon wafer) within these films, is investigated as a function of time (t), temperature (T), and film thickness (l), using a high-throughput experimental technique. The kinetics of this surface pattern formation process is interpreted in terms of a first-order reaction model with a time-dependent rate constant determined uniquely by the short-time diffusive growth kinetics characteristic of this type of ordering process. On the basis of this model, we conclude that the average hole size, lambda(h), approaches a steady-state value, lambda(h)(t-->infinity) identical with lambda(h,infinity)(T), after long annealing times. The observed change in lambda(h,infinity)(T) with temperature is consistent with a reduction of the surface elasticity (Helfrich elastic constant) of the outer block copolymer layer with increasing temperature. We also find that the time constant, tau(T), characterizing the rate at which lambda(h)(t) approaches lambda(h,infinity)(T), first decreases and then increases with increasing temperature. This temperature variation of tau(T) is attributed to two basic competing effects that influence the rate of ordering in block copolymer materials: the reduction in molecular mobility at low temperatures associated with glass formation and a slowing of the rate of ordering due to fluctuation effects associated with an approach to the block copolymer film disordering temperature (T(d)) from below.


The use of biosimilars in paediatric inflammatory bowel disease.
After expiry of the patent of originator anti-tumor necrosis factor drug infliximab (Remicade), CT-P13 was in 2013 the first infliximab biosimilar to be approved by the European Medicine Agency (EMA) for the same indications as the reference drug, including paediatric inflammatory bowel disease (IBD). The approval was based on extrapolation, after extensive in-vitro studies and clinical experience in patients with ankylosing spondylitis and rheumatoid arthritis. The extrapolation of CT-P13 to IBD and to paediatric patients raised concerns among paediatric IBD specialists. Now, almost 4 years later, we can conclude that those concerns have been resolved. There are a growing number of postmarketing studies and real-life data, so far mostly in adults and some in children with IBD. These studies show reassuring comparable efficacy, safety and immunogenicity between CT-P13 and the reference Infliximab. In Europe, biosimilars are increasingly regularly prescribed drugs in paediatric IBD. Due to their lower cost, treatment expenses have gone down considerably (up to 30% or more in some countries) and patient access has improved. However, additional well designed studies to investigate long term follow-up of biosimilars in children are still needed. In addition, clinical studies addressing pharmacokinetics, pharmacodynamics and optimal use of infliximab (originator as well as biosimilar) are still desirable.


Presence of postsynaptic alpha 2-adrenoreceptors of predominantly extrasynaptic location in the vascular smooth muscle of the dog hind limb.
1. In the autoperfused hind limb of the dog prazosin (10 microgram/kg intravenously) markedly antagonized responses to lumbar sympathetic stimulation, whereas responses to injected noradrenaline were largely unaffected. 2. In beta-adrenoreceptor- and ganglion-blocked animals, the hind limb pressor responses to phenylephrine were antagonized to a greater degree by prazosin than responses to injected noradrenaline. 3. Rauwolscine, a selective alpha 2-adrenoreceptor-blocking agent, antagonized responses to the alpha 2-adrenoreceptor agonist guanabenz, but not those to phenylephrine. 4. Hind limb pressor responses to noradrenaline were significantly inhibited by rauwolscine and further reduced by prazosin. 5. These results demonstrate that in this vascular bed alpha 1- and alpha 2-adrenoreceptors are located postsynaptically. Furthermore the results suggest that neuronally released noradrenaline acts mainly upon alpha 1-adrenoreceptors, whereas exogenous noradrenaline acts upon alpha 1- and alpha 2-adrenoreceptors. 6. It is suggested that this selectivity of prazosin in blocking the vasoconstriction to neuronally-released noradrenaline may in part explain the effectiveness of this drug as an antihypertensive agent.


VIP and PACAP in the CNS: regulators of glial energy metabolism and modulators of glutamatergic signaling.
VIP neurons are a homogeneous population of intracortical bipolar cells. They receive excitatory synapses from afferent circuits to the cortex and exert effects on neurons, astrocytes, and capillaries. Effects on the two latter cell types imply that VIP neurons can translate incoming neuronal signals into local metabolic actions. Indeed, VIP tightly regulates glycogen metabolism in astrocytes. In this cell type VIP regulates the expression of a number of genes related to energy metabolism, such as glycogen synthase. These effects of VIP involve the transcription factor family C/EBP and result in the induction of at least seven new proteins by astrocytes. The actions of VIP on neurons appear to be of a modulatory nature: thus VIP enhances glutamate-mediated neurotransmission by potentiating the effects of glutamate on arachidonic acid formation and on the induction of c-fos and on BDNF expression. These effects indicate that VIP can actually increase the strength of glutamate-mediated neurotransmission.


Safety, immune and clinical responses in metastatic melanoma patients vaccinated with a long peptide derived from indoleamine 2,3-dioxygenase in combination with ipilimumab.
Indoleamine 2,3-dioxygenase (IDO) is an emerging new target in cancer therapy that can be targeted with active immunotherapy (e.g. through peptide vaccination). Furthermore, IDO has been identified as a key mechanism underlying resistance to treatment with the checkpoint blocking antibody ipilimumab (ipi). Ten patients with metastatic melanoma participated in a phase I first-in-human clinical study assessing safety of combining ipi with a 21-mer synthetic peptide vaccine from IDO denoted IDOlong. Secondary and tertiary end points included vaccine and clinical response. Treatment was generally safe and well tolerated. Vaccine related adverse reactions included grade I and II erythema, oedema and pruritus at the vaccination site, which were manageable with mild topical corticosteroids. One patient developed presumed ipi-induced colitis. It initially responded to high-dose parenteral corticosteroids but later relapsed while the patient was admitted to a local hospital, where he died after receiving suboptimal therapy. Vaccine-specific T-cell responses were detectable ex vivo in three patients. At first evaluation, five of the 10 treated patients were in stable disease, one of whom had an unconfirmed partial response. Treatment with IDOlong synthetic peptide vaccine in combination with ipi was generally safe and without augmented toxicity. The vaccine induced readily detectable T-cell responses in a subset of patients. Treatment showed signs of clinical activity, although not exceeding efficacy of ipi alone. Results should be confirmed in a larger study.