Oceans and society: feedbacks between ocean and human health.
The concentration of human population along coastlines has far-reaching effects on ocean and societal health. The oceans provide benefits to humans such as food, coastal protection and improved mental well-being, but can also impact negatively via natural disasters. At the same time, humans influence ocean health, for example, via coastal development or through environmental stewardship. Given the strong feedbacks between ocean and human health there is a need to promote desirable interactions, while minimising undesirable interactions. To this end, we articulate two scenarios for 2030. First, Business-as-Usual, named 'Command and (out of) Control', focuses on the anticipated future based on our current trajectory. Second, a more sustainable scenario called 'Living and Connecting', emphasises the development of interactions between oceans and society consistent with achieving the Sustainable Development Goals. We describe a potential pathway to achieving the 'Living and Connecting' scenario, centred on improving marine citizenship, achieving a more equitable distribution of power among stakeholders, and more equitable access to resources and opportunities. The constituent actions of this pathway can be categorised into four groups: (i) improved approaches to science and health communication that account for society's diverse values, beliefs and worldviews, (ii) a shift towards more trusted relationships among stakeholders to enable two-way knowledge exchange, (iii) economic incentives that encourage behavioural changes necessary for achieving desired sustainability outcomes, and (iv) stronger regulations that simultaneously focus on ocean and human health. We contend that these changes will provide improved outcomes for both oceans and society over the United Nations Decade of Ocean Science. The online version contains supplementary material available at 10.1007/s11160-021-09669-5.


Efficacy of 12-weeks velpatasvir plus sofosbuvir-based regimen in HCV-naive subjects with mild fibrosis: a meta-analysis.
In literature systematic data on treatment with the fixed-dose combination of sofosbuvir and velpatasvir for 12 weeks in anti-HCV/HCV RNA positive subjects with mild fibrosis and naïve to previous Interferon free regimen are scanty. A meta-analysis has been performed to evaluate the efficacy of velpatasvir plus sofosbuvir combination in these patients. All randomized or non-randomized studies, investigating the sustained virological response rate to sofosbuvir plus velpatasvir without ribavirin for 12 weeks in subjects naïve to previous DAA therapy and with fibrosis F0-F2 or F0-F3, were included in the meta-analysis. A total of 16 studies enrolling 4,907 subjects met the inclusion criteria and were included in this meta-analysis. The prevalence of SVR by sofosbuvir and velpatasvir was 98% (95% CI 96-99%) in the 4,907 subjects without cirrhosis. The prevalence of SVR was similar considering the 9 clinical studies and the 7 real-world studies (98%, CI 95%: 96-99% and 98%; CI 95%: 96-99%, respectively). Considering the 4 studies enrolling 1,371 subjects without advanced liver fibrosis the prevalence of SVR was also high [96% (95% CI: 94-98%)]. Data indicate a prevalence of SVR ranging to 95-100% according to the different HCV genotypes. Sofosbuvir plus velpatasvir therapeutic regimen was highly effective in HCV patients without advanced liver disease naïve to previous DAA regimen independently the different HCV genotypes.


[Patient reported outcomes: general principles of development and interpretability].
Direct measurement of how people are feeling and the extent to which they are functioning in daily activities (generally as patient reported outcomes) is critical to judging the benefit of health interventions in chronic conditions. Selection of an appropriate instrument will reflect a comprehensive understanding of the condition of interest and a thorough knowledge of the expected benefits and harms of the proposed intervention. We provide a brief discussion about different ways that health and health measurement have been defined, including the International Classification of Function, Disability and Health (ICF), Health Related Quality of Life (HRQOL) and cost-to-benefit analyses. We outline important properties (reliability, validity, and responsiveness) that a measurement instrument must demonstrate depending on the purpose of measurement, and provide insight as to how to interpret the results of studies that report patient reported outcomes.


First report of a subgroup 16SrII-D phytoplasma associated with Opuntia cylindrica fasciated disease in Oman.
Cacti are evergreen perennial succulent plants that are used as ornamental and hedge plants. The fruits and leaves are also used as forage in some areas (Dewir, 2016). Cactus species are susceptible to several pathogens, including phytoplasma. In March 2020, three cactus plants (Opuntia cylindrica) out of ten (30% incidence) exhibited phytoplasma symptoms, including stunted growth, fasciation in stems and cladodes, color changes of the tips of cladodes to purple, and having clusters of highly proliferating cladodes. The plants were located in the Botanic Garden at Sultan Qaboos University, Muscat, Oman (N:23º59'14"; E:58º16'34"). PCR assays were carried out on the DNA samples extracted from young cladodes of three each of symptomatic and asymptomatic plants using phytoplasma-universal 16S rRNA primers, P1/P7 in direct PCR followed by R16F2n/R16R2, P4/P7 in the nested PCR. Distilled water (DW) and Alfalfa witches' broom phytoplasma (AlfWB) were used as negative and positive controls in each assay, respectively. In addition, amplification of the partial translocase protein A (secA) gene in the symptomatic cactus samples was done using SecA-II-F1/SecA-II-R1 (targeting 2140 bp) followed by SecA-II-F1/SecAR4 (targeting 1510 bp) (Al-Subhi et al., 2018). All the symptomatic plants and the positive control were positive for both genes (16S and secA), but no amplification was observed from the asymptomatic samples and DW. Sequence analysis and similarity searches against BLASTn revealed that the phytoplasma 16S rRNA (MT327813) shared 100% sequence identity with that of 'Candidatus Phytoplasma aurantifolia' isolate CB04 (MT555412) from India. The secA gene sequence (MT331815) analysis showed 100% identity with Cicer arietinum phyllody (KX358585). The associated phytoplasma was designated as cactus fasciated phytoplasma (CFP). Phylogenetic trees based on CFP 16Sr rRNA,secA genes, and a combined phylogenetic tree showed clustering of the CFP with the 16SrII-D subgroup phytoplasmas. The association of the aster yellows and peanut witches'-broom phytoplasma groups with other cactus species has already been reported from Lebanon, Mexico, China, Italy and Egypt (Dewir, 2016). The 16SrII phytoplasma in association with O. cylindrica showing fasciated stem has been reported from Egypt (Omar et al., 2014). A series of diverse plant species in association with 16SrII-D phytoplasma has been reported from Oman (Al-Subhi et al., 2018). However, this is the first report of a cactus phytoplasma disease in Oman belonging to the 16SrII-D subgroup phytoplasmas. Some fasciated cactus species are attractive and therefore cultivated as new ornamental plants and transported around the world, which may pose a new threat to other economically important crops.


Palliative Care Development in the Asia Pacific Region: A Review of Assessment Indicators.
Organizations such as Asia Pacific Hospice Palliative Care Network functions to promote quality palliative care development through training and education, research collaboration and variety relevant projects and events for all in the Asia and Pacific region. To summarise and further compare existing development indicators used in Asia Pacific region for palliative care. The current review used Whittemore and Knafl 's framework for integrative reviews. PubMed, Embase, CINAHL and Google Scholar databases were searched for eligible studies. This review focused on palliative care development according to the domains and indicators identified by the World Health Organization Public Health Strategy and ATLANTES Palliative Care Research Group. Joanna Briggs Institute critical appraisal checklists were adopted to assess the methodological quality of included studies. Ten studies were included and two main findings were identified: 1) There was a strong evidence of educational preparation, use of medicines and service provision for palliative care development in Asia Pacific and 2) Professional activities and policy geared towards palliative care development were limited and had relative emphasis at a country-level in Asia Pacific. Palliative care development is largely influenced by policies and funding structures as well as by cultural views and beliefs of stakeholders. It is expected that individuals, stakeholders and practitioners in Asia Pacific might have differing views and cultural beliefs when compared to the European or western counterparts. The lack of details and documentation in the region and inadequate reporting measures impacts on the development of strong palliative care framework.


The lipid phosphatase SHIP2 controls insulin sensitivity.
Insulin is the primary hormone involved in glucose homeostasis, and impairment of insulin action and/or secretion has a critical role in the pathogenesis of diabetes mellitus. Type-II SH2-domain-containing inositol 5-phosphatase, or 'SHIP2', is a member of the inositol polyphosphate 5-phosphatase family. In vitro studies have shown that SHIP2, in response to stimulation by numerous growth factors and insulin, is closely linked to signalling events mediated by both phosphoinositide-3-OH kinase and Ras/mitogen-activated protein kinase. Here we report the generation of mice lacking the SHIP2 gene. Loss of SHIP2 leads to increased sensitivity to insulin, which is characterized by severe neonatal hypoglycaemia, deregulated expression of the genes involved in gluconeogenesis, and perinatal death. Adult mice that are heterozygous for the SHIP2 mutation have increased glucose tolerance and insulin sensitivity associated with an increased recruitment of the GLUT4 glucose transporter and increased glycogen synthesis in skeletal muscles. Our results show that SHIP2 is a potent negative regulator of insulin signalling and insulin sensitivity in vivo.


Bif-1 Interacts with Prohibitin-2 to Regulate Mitochondrial Inner Membrane during Cell Stress and Apoptosis.
Mitochondria are dynamic organelles that undergo fission and fusion. During cell stress, mitochondrial dynamics shift to fission, leading to mitochondrial fragmentation, membrane leakage, and apoptosis. Mitochondrial fragmentation requires the cleavage of both outer and inner membranes, but the mechanism of inner membrane cleavage is unclear. Bif-1 and prohibitin-2 may regulate mitochondrial dynamics. We used azide-induced ATP depletion to incite cell stress in mouse embryonic fibroblasts and renal proximal tubular cells, and renal ischemia-reperfusion to induce stress in mice. We also used knockout cells and mice to determine the role of Bif-1, and used multiple techniques to analyze the molecular interaction between Bif-1 and prohibitin-2. Upon cell stress, Bif-1 translocated to mitochondria to bind prohibitin-2, resulting in the disruption of prohibitin complex and proteolytic inactivation of the inner membrane fusion protein OPA1. Bif-1-deficiency inhibited prohibitin complex disruption, OPA1 proteolysis, mitochondrial fragmentation, and apoptosis. Domain deletion analysis indicated that Bif-1 interacted with prohibitin-2 via its C-terminus. Notably, mutation of Bif-1 at its C-terminal tryptophan-344 not only prevented Bif-1/prohibitin-2 interaction but also reduced prohibitin complex disruption, OPA1 proteolysis, mitochondrial fragmentation, and apoptosis, supporting a pathogenic role of Bif-1/prohibitin-2 interaction. In mice, Bif-1 bound prohibitin-2 during renal ischemia/reperfusion injury, and Bif-1-deficiency protected against OPA1 proteolysis, mitochondrial fragmentation, apoptosis and kidney injury. These findings suggest that during cell stress, Bif-1 regulates mitochondrial inner membrane by interacting with prohibitin-2 to disrupt prohibitin complexes and induce OPA1 proteolysis and inactivation.


Expression of meningococcal epitopes in LamB of Escherichia coli and the stimulation of serosubtype-specific antibody responses.
The class 1 outer membrane protein (OMP), a major variable surface antigen of Neisseria meningitidis, is a component of novel meningococcal vaccines currently in field trials. Serological variants of the protein are also used to serosubtype meningococci. Most of the amino acid changes that give rise to antigenic variants of the protein occur in two variable regions (VR1 and VR2) that are thought to form loops on the cell surface. The polymerase chain reaction (PCR) was used to amplify the nucleotide sequences encoding VR1 and VR2 from the chromosomal DNA of N. meningitidis strain M1080. These were cloned in frame into the lamB gene of the Escherichia coli expression vector pAJC264. Whole-cell enzyme-linked immunosorbent assays (ELISAs), using monoclonal antibodies, and SDS-PAGE confirmed that, upon induction, strains of E. coli carrying these constructs expressed hybrid LamB proteins containing the N. meningitidis surface loops. These strains were used to immunize rabbits and the resultant polyclonal antisera reacted specifically with the class 1 OMP of reference strain M1080 (P1.7). Immunogold labelling of meningococcal cells and whole-cell dot-blot analyses with these antisera showed that the variable epitopes were exposed on the cell surface and confirmed that this approach could be used to obtain serosubtype-specific antisera. The binding profiles of the antisera were determined from their reactions with overlapping synthetic peptides and their reactivity compared with that of relevant serosubtype-specific monoclonal antibodies. This approach was used successfully to raise antisera against two other class 1 OMP VR2s. A fourth antiserum raised against a VR2, including the P1.1 epitope, was not subtype specific.


Liaisons dangereuses: cross-border gene flow and dispersal of insecticide resistance-associated genes in the mosquito Aedes aegypti from Brazil and French Guiana.
In recent years, South America has suffered the burden of continuous high impact outbreaks of dengue, chikungunya and Zika. Aedes aegypti is the main mosquito vector of these arboviruses and its control is the only solution to reduce transmission. In order to improve vector control it is essential to study mosquito population genetics in order to better estimate the population structures and the geneflow among them. We have analysed microsatellites and knockdown resistance (kdr) mutations from a trans-border region in Amazonia between the state of Amapá (Brazil) and French Guiana (overseas territory of France), to provide further knowledge on these issues. These two countries have followed distinct vector control policies since last century. For population genetic analyses we evaluated variability in 13 well-established microsatellites loci in Ae. aegypti from French Guiana (Saint Georges and Cayenne) and Brazil (Oiapoque and Macapá). The occurrence and frequency of kdr mutations in these same populations were accessed by TaqMan genotype assays for the sites 1016 (Val/Ile) and 1534 (Phe/Cys). We have detected high levels of gene flow between the closest cross-border samples of Saint-Georges and Oiapoque. These results suggest one common origin of re-colonisation for the populations of French Guiana and Oiapoque in Brazil, and a different source for Macapá, more similar to the other northern Brazilian populations. Genotyping of the kdr mutations revealed distinct patterns for Cayenne and Macapá associated with their different insecticide use history, and an admixture zone between these two patterns in Saint Georges and Oiapoque, in accordance with population genetic results. The present study highlights the need for regional-local vector surveillance and transnational collaboration between neighboring countries to assess the impact of implemented vector control strategies, promote timely actions and develop preparedness plans.


A multiancestral genome-wide exome array study of Alzheimer disease, frontotemporal dementia, and progressive supranuclear palsy.
Previous studies have indicated a heritable component of the etiology of neurodegenerative diseases such as Alzheimer disease (AD), frontotemporal dementia (FTD), and progressive supranuclear palsy (PSP). However, few have examined the contribution of low-frequency coding variants on a genome-wide level. To identify low-frequency coding variants that affect susceptibility to AD, FTD, and PSP. We used the Illumina HumanExome BeadChip array to genotype a large number of variants (most of which are low-frequency coding variants) in a cohort of patients with neurodegenerative disease (224 with AD, 168 with FTD, and 48 with PSP) and in 224 control individuals without dementia enrolled between 2005-2012 from multiple centers participating in the Genetic Investigation in Frontotemporal Dementia and Alzheimer's Disease (GIFT) Study. An additional multiancestral replication cohort of 240 patients with AD and 240 controls without dementia was used to validate suggestive findings. Variant-level association testing and gene-based testing were performed. Statistical association of genetic variants with clinical diagnosis of AD, FTD, and PSP. Genetic variants typed by the exome array explained 44%, 53%, and 57% of the total phenotypic variance of AD, FTD, and PSP, respectively. An association with the known AD gene ABCA7 was replicated in several ancestries (discovery P=.0049, European P=.041, African American P=.043, and Asian P=.027), suggesting that exonic variants within this gene modify AD susceptibility. In addition, 2 suggestive candidate genes, DYSF (P=5.53×10(-5)) and PAXIP1 (P=2.26×10(-4)), were highlighted in patients with AD and differentially expressed in AD brain. Corroborating evidence from other exome array studies and gene expression data points toward potential involvement of these genes in the pathogenesis of AD. Low-frequency coding variants with intermediate effect size may account for a significant fraction of the genetic susceptibility to AD and FTD. Furthermore, we found evidence that coding variants in the known susceptibility gene ABCA7, as well as candidate genes DYSF and PAXIP1, confer risk for AD.


Genome-wide chromatin maps derived from limited numbers of hematopoietic progenitors.
Current methods for whole-genome mapping of protein-DNA interactions, performed by coupling chromatin immunoprecipitation with high-throughput sequencing (ChIP-seq), require large amounts of starting materials, which precludes their application to rare cell types. Here we combine a high-sensitivity ChIP assay with a new library preparation procedure to map histone modifications in as few as 10,000 cells. We used the technique to characterize mouse hematopoietic progenitors and thereby gain insight into their developmental program.


The return of increased blood pressure after discontinuation of antihypertensive treatment is associated with an impaired post-ischemic skin blood flow response.
To assess the post-ischemic skin blood flow response after withdrawal of antihypertensive therapy in hypertensive patients with normal blood pressure during treatment. Twenty hypertensive patients (group A) with a normal clinic blood pressure (<140/ 90 mmHg) receiving antihypertensive treatment (any monotherapy; one pill per day for at least 6 months) had their treatment discontinued. Before medication withdrawal and 2, 4, 12 and 24 weeks thereafter, the following measurements were made: clinic blood pressure, home blood pressure (three times per week, morning and evening) and skin blood flow response to a 5 min forearm arterial occlusion (using laser Doppler flowmetry). The patients were asked to perform an ambulatory blood pressure recording at any time if home blood pressure was > or =160/95 mmHg on two consecutive days, and treatment was initiated again, after determination of the skin hyperemic response, if daytime ambulatory blood pressure was > or =140/90 mmHg. The same studies were performed in 20 additional hypertensive individuals in whom antihypertensive treatment was not withdrawn (group B). The allocation of patients to groups A and B was random. The data fom 18 patients in group A who adhered strictly to the procedure were available for analysis. Seven of them had to start treatment again within the first 4 weeks of follow-up; four additional patients started treatment again during the next 8 weeks (group A1). The seven other patients remained untreated (group A2). The skin hyperemic response decreased significantly in patients in group A1 and returned to baseline values at the end of the study, when there were again receiving antihypertensive treatment. In patients in group A2 a significant attenuation of the hyperemic response was also observed. This impaired response was present even at the end of the 6 month follow-up, at which time the patients were still untreated but exhibited a significantly greater blood pressure than before drug discontinuation. The hyperemic response of patients who did not stop treatment (group B) did not change during the course of the study. Our findings show a decrease in the postischemic skin blood flow response after withdrawal of antihypertensive treatment in hypertensive patients. This impaired response may be due to the development of endothelial dysfunction, vascular remodeling, or both, and might contribute to the return of blood pressure to hypertensive values after withdrawal of antihypertensive therapy.


A purified membrane protein from Akkermansia muciniphila or the pasteurized bacterium improves metabolism in obese and diabetic mice.
Obesity and type 2 diabetes are associated with low-grade inflammation and specific changes in gut microbiota composition. We previously demonstrated that administration of Akkermansia muciniphila to mice prevents the development of obesity and associated complications. However, the underlying mechanisms of this protective effect remain unclear. Moreover, the sensitivity of A. muciniphila to oxygen and the presence of animal-derived compounds in its growth medium currently limit the development of translational approaches for human medicine. We have addressed these issues here by showing that A. muciniphila retains its efficacy when grown on a synthetic medium compatible with human administration. Unexpectedly, we discovered that pasteurization of A. muciniphila enhanced its capacity to reduce fat mass development, insulin resistance and dyslipidemia in mice. These improvements were notably associated with a modulation of the host urinary metabolomics profile and intestinal energy absorption. We demonstrated that Amuc_1100, a specific protein isolated from the outer membrane of A. muciniphila, interacts with Toll-like receptor 2, is stable at temperatures used for pasteurization, improves the gut barrier and partly recapitulates the beneficial effects of the bacterium. Finally, we showed that administration of live or pasteurized A. muciniphila grown on the synthetic medium is safe in humans. These findings provide support for the use of different preparations of A. muciniphila as therapeutic options to target human obesity and associated disorders.


Dynamically reconfigurable optical packet switch (DROPS).
A novel Dynamically Reconfigurable Optical Packet Switch (DROPS) that combines both spectral and spatial switching capabilities is proposed and experimentally demonstrated for the first time. Compared with an Arrayed Waveguide Grating Router (AWGR), the added spatial switching capability provided by the microelectromechanical systems (MEMS) enables dynamically reconfigurable routing that is not possible with an AWGR alone. This methodology has several advantages over an AWGR including scalability, additional degrees of freedom in routing a packet from an ingress port to an egress port and more flexibility in path or line card recovery. The experimental demonstration implemented with 10-Gb/s packets shows that the added spatial switching does not degrade the bit-error-rate performance, indicating the promising potential of DROPS as a versatile and ultra-high capacity switch for optical packet-switched networks.


Metabolic Modeling Elucidates the Transactions in the Rumen Microbiome and the Shifts Upon Virome Interactions.
The complex microbial ecosystem within the bovine rumen plays a crucial role in host nutrition, health, and environmental impact. However, little is known about the interactions between the functional entities within the system, which dictates the community structure and functional dynamics and host physiology. With the advancements in high-throughput sequencing and mathematical modeling, in silico genome-scale metabolic analysis promises to expand our understanding of the metabolic interplay in the community. In an attempt to understand the interactions between microbial species and the phages inside rumen, a genome-scale metabolic modeling approach was utilized by using key members in the rumen microbiome (a bacteroidete, a firmicute, and an archaeon) and the viral phages associated with them. Individual microbial host models were integrated into a community model using multi-level mathematical frameworks. An elaborate and heuristics-based computational procedure was employed to predict previously unknown interactions involving the transfer of fatty acids, vitamins, coenzymes, amino acids, and sugars among the community members. While some of these interactions could be inferred by the available multi-omic datasets, our proposed method provides a systemic understanding of why the interactions occur and how these affect the dynamics in a complex microbial ecosystem. To elucidate the functional role of the virome on the microbiome, local alignment search was used to identify the metabolic functions of the viruses associated with the hosts. The incorporation of these functions demonstrated the role of viral auxiliary metabolic genes in relaxing the metabolic bottlenecks in the microbial hosts and complementing the inter-species interactions. Finally, a comparative statistical analysis of different biologically significant community fitness criteria identified the variation in flux space and robustness of metabolic capacities of the community members. Our elucidation of metabolite exchange among the three members of the rumen microbiome shows how their genomic differences and interactions with the viral strains shape up a highly sophisticated metabolic interplay and explains how such interactions across kingdoms can cause metabolic and compositional shifts in the community and affect the health, nutrition, and pathophysiology of the ruminant animal.


Patients with temporomandibular disorders have increased fatigability of the cervical extensor muscles.
To determine whether patients with myogenous and mixed temporomandibular disorders (TMD) have greater fatigability of the cervical extensor muscles while performing a neck extensor muscle endurance test (NEMET) when compared with healthy controls. A total of 151 individuals participated in this study. Of these 47 were healthy controls, 57 patients had myogenous TMD, and 47 patients had mixed TMD. All patients performed the NEMET. The patients were instructed to maintain a prone lying position with the neck unsupported as long as possible, stopping at signs of fatigue or any discomfort. Electromyographic activity of the cervical extensor muscles during the NEMET and the holding time were collected for all patients and were compared across groups. A 1-way analysis of variance was used to evaluate the differences in holding time between patients with TMD and healthy controls. A mixed model analysis was used to evaluate the differences in normalized median frequency at different times (fatigue index) for the cervical extensor muscles while performing the NEMET between patients with TMD and controls. There were statistically significant differences (P<0.05) in the slopes of the normalized median frequency between patients with TMD and healthy controls at 10, 30, 40, 50, 60, 70, 80, 90, and 100 seconds of the NEMET. Holding time was significantly reduced in both patients with myogenous TMD and mixed TMD when compared with healthy controls (P<0.05). These results highlight the fact that alterations of endurance capacity of the extensor cervical muscles could be implicated in the neck-shoulder disturbances presented in patients with TMD.


Evaluating morphometric and metabolic markers of body condition in a small cetacean, the harbor porpoise (Phocoena phocoena).
Mammalian body condition is an important individual fitness metric as it affects both survival and reproductive success. The ability to accurately measure condition has key implications for predicting individual and population health, and therefore monitoring the population-level effects of changing environments. No consensus currently exists on the best measure to quantitatively estimate body condition in many species, including cetaceans. Here, two measures of body condition were investigated in the harbor porpoise (Phocoena phocoena). First, the most informative morphometric body condition index was identified. The mass/length2 ratio was the most appropriate morphometric index of 10 indices tested, explaining 50% of the variation in condition in stranded, male porpoises with different causes of death and across age classes (n = 291). Mass/length2 was then used to evaluate a second measure, blubber cortisol concentration, as a metabolic condition marker. Cortisol is the main glucocorticoid hormone involved in the regulation of lipolysis and overall energy balance in mammals, and concentrations could provide information on physiological state. Blubber cortisol concentrations did not significantly vary around the girth (n = 20), but there was significant vertical stratification through the blubber depth with highest concentrations in the innermost layer. Concentrations in the dorsal, outermost layer were representative of concentrations through the full blubber depth, showed variation by sex and age class, and were negatively correlated with mass/length2. Using this species as a model for live cetaceans from which standard morphometric measurements cannot be taken, but from which blubber biopsy samples are routinely collected, cortisol concentrations in the dorsal, outermost blubber layer could potentially be used as a biomarker of condition in free-ranging animals.


Contributions of intracellular and extracellular Ca2+ pools to activation of myosin phosphorylation and stress in swine carotid media.
Contractile agonists can mobilize Ca2+ from both intracellular and extracellular stores in smooth muscle. This study addresses the role of Ca2+ mobilization as it relates to the complex manner by which Ca2+ regulates the contractile system in smooth muscle. In swine carotid media, both histamine and phenylephrine produced initial rapid increases in myosin phosphorylation and stress. Stress was sustained for the duration of the stimulus while myosin phosphorylation slowly declined to steady-state levels. Removal of extracellular Ca2+ or elimination of cellular Ca2+ influx did not dramatically reduce the initial rapid increase in myosin phosphorylation produced by either agonist but reduced steady-state levels of myosin phosphorylation to basal values. Initial rapid increases in stress were seen, but stress was not maintained. Following depletion of Ca2+ from sarcoplasmic reticulum, muscle activation by Ca2+ influx in the presence of phenylephrine occurred without an initial transient in myosin phosphorylation, and stress developed slowly. Steady-state levels of myosin phosphorylation and stress were not different from control values. Similar results were obtained with histamine, although a small transient in myosin phosphorylation was also seen. These results are consistent with the hypothesis that the role of the sarcoplasmic reticulum in vascular smooth muscle is to provide high myoplasmic Ca2+ concentrations causing extensive myosin phosphorylation and rapid crossbridge cycling leading to rapid stress development. In the presence of extracellular Ca2+, control levels of agonist-induced steady-state stress and myosin phosphorylation could be produced without an initial phosphorylation transient when intracellular Ca2+ pools were depleted, suggesting that the sarcoplasmic reticulum is not required for the regulation of steady-state myoplasmic [Ca2+] during "latch".


Exercise training in normobaric hypoxia in endurance runners. III. Muscular adjustments of selected gene transcripts.
We hypothesized that specific muscular transcript level adaptations participate in the improvement of endurance performances following intermittent hypoxia training in endurance-trained subjects. Fifteen male high-level, long-distance runners integrated a modified living low-training high program comprising two weekly controlled training sessions performed at the second ventilatory threshold for 6 wk into their normal training schedule. The athletes were randomly assigned to either a normoxic (Nor) (inspired O2 fraction = 20.9%, n = 6) or a hypoxic group exercising under normobaric hypoxia (Hyp) (inspired O2 fraction = 14.5%, n = 9). Oxygen uptake and speed at second ventilatory threshold, maximal oxygen uptake (VO2 max), and time to exhaustion (Tlim) at constant load at VO2 max velocity in normoxia and muscular levels of selected mRNAs in biopsies were determined before and after training. VO2 max (+5%) and Tlim (+35%) increased specifically in the Hyp group. At the molecular level, mRNA concentrations of the hypoxia-inducible factor 1alpha (+104%), glucose transporter-4 (+32%), phosphofructokinase (+32%), peroxisome proliferator-activated receptor gamma coactivator 1alpha (+60%), citrate synthase (+28%), cytochrome oxidase 1 (+74%) and 4 (+36%), carbonic anhydrase-3 (+74%), and manganese superoxide dismutase (+44%) were significantly augmented in muscle after exercise training in Hyp only. Significant correlations were noted between muscular mRNA levels of monocarboxylate transporter-1, carbonic anhydrase-3, glucose transporter-4, and Tlim only in the group of athletes who trained in hypoxia (P < 0.05). Accordingly, the addition of short hypoxic stress to the regular endurance training protocol induces transcriptional adaptations in skeletal muscle of athletic subjects. Expressional adaptations involving redox regulation and glucose uptake are being recognized as a potential molecular pathway, resulting in improved endurance performance in hypoxia-trained subjects.


Unique Motifs and Length of Hairpin in Oleosin Target the Cytosolic Side of Endoplasmic Reticulum and Budding Lipid Droplet.
Plant cytosolic lipid droplets (LDs) are covered with a layer of phospholipids and oleosin and were extensively studied before those in mammals and yeast. Oleosin has short amphipathic N- and C-terminal peptides flanking a conserved 72-residue hydrophobic hairpin, which penetrates and stabilizes the LD Oleosin is synthesized on endoplasmic reticulum (ER) and extracts ER-budding LDs to cytosol. To delineate the mechanism of oleosin targeting ER-LD, we have expressed modified-oleosin genes in Physcomitrella patens for transient expression and tobacco (Nicotiana tabacum) BY2 cells for stable transformation. The results have identified oleosin motifs for targeting ER-LD and oleosin as the sole molecule responsible for budding-LD entering cytosol. Both the N-terminal and C-terminal peptides are not required for the targeting. The hairpin, including its entire length, initial N-portion residues, and hairpin-loop of three Pro and one Ser residues, as well as the absence of an N-terminal ER-targeting peptide, are necessary for oleosin targeting ER and moving onto budding LDs and extracting them to cytosol. In a reverse approach, eliminations of these necessities allow the modified oleosin to enter the ER lumen and extract budding LDs to the ER lumen. Modified oleosin with an added vacuole signal peptide transports the ER-luminal LDs to vacuoles. The overall findings define the mechanism of oleosin targeting ER-LDs and extracting budding LDs to the cytosol as well as reveal potential applications.


It's not all about price: factors associated with roll-your-own tobacco use among young people - a qualitative study.
Smoking prevalence in Ireland is falling in all age groups, but the prevalence of roll-your-own (RYO) tobacco use is rising among young people. This qualitative study aims to explore and understand the factors associated with young people's use of RYO products. Semi-structured individual and focus group interviews were conducted with young people aged 16-22 years. Participants were recruited from a higher education institution and youth organisations working with early school leavers across Dublin. In total, there were 62 participants in the study, consisting of 22 individual interviews and eight focus group interviews with 40 participants. Categoric and thematic data analysis was used to generate the findings. We identified two broad themes, incentivising and disincentivising factors. The lower cost of RYO products compared to pre-manufactured cigarettes was the most important incentive for users. However, other product characteristics, such as the artisanal factors associated with RYO products were also found. Social and environmental influences were apparent, in which certain groups and environments facilitated and normalised RYO practices. Amenities and facilities often provided smokers with normalised spaces which could be dedicated to the enactment of rolling practices and to the creation and maintenance of social bonds with other users. Disincentives included negative features related to the product itself, adverse health effects, and the effects of tobacco denormalisation. While the lower cost of RYO products is very important for young smokers, other product characteristics and influences also incentivise and disincentivise use. A more comprehensive understanding of the multi-dimensional appeal of these products will assist policymakers to target strategies to reduce the attractiveness to young smokers of these products.


Metarhizium anisopliae as a biological control agent against Hyalomma anatolicum (Acari: Ixodidae).
In the Sudan, ticks and Tick-borne Diseases (TBDs) with subsequent costs of control and treatment are causing substantial economic loss. Control of ticks is mainly by chemical insecticides. The rising environmental hazards and problem of resistance has motivated research on biological agents as alternative methods of control. The present study aims at controlling livestock ticks using fungi for their unique mode of action besides their ability to adhere to the cuticle, to germinate and penetrate enzymatically. The study was conducted to evaluate the fungus Metarhizium anisopliae for tick control as an alternative mean to chemical acaricides. Pathogenicity of the fungus was tested on different developmental stages of the tick Hyalomma anatolicum. The fungus induced high mortality to flat immature stages. It, also, affected reproductive potential of the females. Egg laid, hatching percent, fertility and moulting percent of immature stages were significantly (p < or = 0.05) reduced. It was, also, shown that the fungus had ability to adhere to the cuticle and penetrate the integument of the tick. Conidia of the fungus were isolated from their internal tissues. This phenomenon is important in considering fungi as bioinsecticides. Infection of eggs laid by treated engorged female ticks, with the fungus might demonstrate suggesting transovarian transmission. The use of M. anisopliae to control ticks is discussed.


Drug abuse, brain calcification and glutamate-induced neurodegeneration.
Positive and negative reinforcing systems are part of the mechanism of drug dependence. Drugs with abuse potential may change the manner of response to negative emotional stimuli, activate positive emotional reactions and possess primary reinforcing properties. Catecholaminergic and peptidergic processes are of importance in these mechanisms. Current research needs to understand the types of adaptations that underlie the particularly long-lived aspects of addiction. Presently, glutamate is candidate to play a role in the enduring effects of drugs of abuse. For example, it participates in the chronic pathological changes of corticostriatal terminals produced by methamphetamine. At the synaptic level, a link between over-activation of glutamate receptors, [C(a2+)](i) increase and neuronal damage has been clearly established leading to neurodegeneration. Thus, neurodegeneration can start after an acute over-stimulation whose immediate effects depend on a diversity of calcium-activated mechanisms. If sufficient, the initial insult results in calcification and activation of a chronic on-going process with a progressive loss of neurons. At present, long-term effects of drug dependence underlie an excitotoxicity process linked to a polysynaptic pathway that dynamically regulates synaptic glutamate. Retaliatory mechanisms include energy capability of the neurons, inhibitory systems and cytoplasmic calcium precipitation as part of the neuron-glia interactions. This paper presents an integrated view of these molecular and cellular mechanisms to help understand their relationship and interdependence in a chronic pathological process that suggest new targets for therapeutic intervention.


Clear cell carcinoma in a background of endometriosis. Case report of a finding in a midline abdominal scar 5 years after a total abdominal hysterectomy.
Endometriosis is considered a premalignant process whose association with carcinoma is well documented. We discuss a case of clear cell carcinoma with an unusual presentation in that it was located outside the abdominal cavity and was the only lesion noted clinically and radiologically. The histopathologic diagnostic criteria will be reviewed, as will the association of carcinomas with endometriosis. Furthermore, we will review the current literature of extraovarian clear cell carcinoma associated with endometriosis with regard to clinical outcome. A 42-year-old Hispanic woman presented to the Fine Needle Aspiration (FNA) Clinic at Parkland Hospital, Dallas, Texas, in August 2005 secondary to a growing area of firmness associated with her midline abdominal hysterectomy scar. A single mass anterior to the abdominal wall was identified radiologically. The FNA sample was reported as highly atypical cells suspicious for adenocarcinoma. Excision of this mass revealed a clear cell carcinoma in a background of endometriosis. Clear cell carcinoma is one of the most prevalent carcinomas associated with endometriosis, whether identified in the ovary or extraovarian site. This case is perplexing because the mass was a solitary lesion and the patient never had documented endometriosis. The unusual presentation may make survival difficult to predict.


Synthetic Fc peptide-mediated regulation of the immune response. I. Characterization of the immunomodulating properties of a synthetic 23-amino acid peptide derived from the sequence of the CH3 domain of human IgG1.
A synthetic 23-amino acid peptide derived from the CH3 domain of human IgG1 was found to be a potent adjuvant as well as a polyclonal activator. The Fc peptide was found to enhance human and murine humoral, and T cell-mediated immune responses. Moreover, in vivo administration of Fc peptide enhanced murine natural killer cell activity. The synthetic Fc peptide was found to be more potent, on a molar basis, than native Fc fragments in inducing polyclonal antibody production and potentiating immune responses.


pH and peptide supply can radically alter bacterial populations and short-chain fatty acid ratios within microbial communities from the human colon.
The effects of changes in the gut environment upon the human colonic microbiota are poorly understood. The response of human fecal microbial communities from two donors to alterations in pH (5.5 or 6.5) and peptides (0.6 or 0.1%) was studied here in anaerobic continuous cultures supplied with a mixed carbohydrate source. Final butyrate concentrations were markedly higher at pH 5.5 (0.6% peptide mean, 24.9 mM; 0.1% peptide mean, 13.8 mM) than at pH 6.5 (0.6% peptide mean, 5.3 mM; 0.1% peptide mean, 7.6 mM). At pH 5.5 and 0.6% peptide input, a high butyrate production coincided with decreasing acetate concentrations. The highest propionate concentrations (mean, 20.6 mM) occurred at pH 6.5 and 0.6% peptide input. In parallel, major bacterial groups were monitored by using fluorescence in situ hybridization with a panel of specific 16S rRNA probes. Bacteroides levels increased from ca. 20 to 75% of total eubacteria after a shift from pH 5.5 to 6.5, at 0.6% peptide, coinciding with high propionate formation. Conversely, populations of the butyrate-producing Roseburia group were highest (11 to 19%) at pH 5.5 but fell at pH 6.5, a finding that correlates with butyrate formation. When tested in batch culture, three Bacteroides species grew well at pH 6.7 but poorly at pH 5.5, which is consistent with the behavior observed for the mixed community. Two Roseburia isolates grew equally well at pH 6.7 and 5.5. These findings suggest that a lowering of pH resulting from substrate fermentation in the colon may boost butyrate production and populations of butyrate-producing bacteria, while at the same time curtailing the growth of Bacteroides spp.


Improvement of ventricular function in systolic heart failure patients with oral L-citrulline supplementation.
The utility of L-arginine and L-citrulline in treatment of arterial hypertension by increasing vascular oxide nitric availability has been demonstrated. Photoplethysmography, a simple and low-cost optical technique, makes it possible to assess vascular function and to detect changes in blood flow, pulse and swelling of the microvascular tissular space. The aim of the study was to evaluate the effect of L-citrulline supplementation on functional class, ejection fraction and peripheral blood flow in patients with systolic heart failure. Thirty-five stable outpatients attending the Heart Failure Clinic at the INCMNSZ underwent clinical evaluation, radioisotopic ventriculography and photoplethysmography before and at the end of 4 months. They were randomized into two groups: experimental group, with oral L-citrulline supplementation (3 g/day, n = 20) and control group, without supplementation (n = 15). In the experimental group the left ventricular ejection fraction (LVEF) increased 20.3% at rest and 12.7% with stress, as well as the right ventricular ejection fraction at rest of 15.10% and 14.88% with stress. In addition, functional class improved in 35%, and the maximum amplitude time/total time (MAT/TT) index decreased 23.1%. These changes were statistically significant compared with the control group. Citrulline supplementation significantly improved the LVEF, the endothelial function (MAT/TT index) and functional class. Citrulline can be an important co-adjuvant in the treatment of stable and stable systolic heart failure patients.


Likert scales, levels of measurement and the "laws" of statistics.
Reviewers of research reports frequently criticize the choice of statistical methods. While some of these criticisms are well-founded, frequently the use of various parametric methods such as analysis of variance, regression, correlation are faulted because: (a) the sample size is too small, (b) the data may not be normally distributed, or (c) The data are from Likert scales, which are ordinal, so parametric statistics cannot be used. In this paper, I dissect these arguments, and show that many studies, dating back to the 1930s consistently show that parametric statistics are robust with respect to violations of these assumptions. Hence, challenges like those above are unfounded, and parametric methods can be utilized without concern for "getting the wrong answer".


Law enforcement attitudes toward overdose prevention and response.
Law enforcement is often the first to respond to medical emergencies in the community, including overdose. Due to the nature of their job, officers have also witnessed first-hand the changing demographic of drug users and devastating effects on their community associated with the epidemic of nonmedical prescription opioid use in the United States. Despite this seminal role, little data exist on law enforcement attitudes toward overdose prevention and response. We conducted key informant interviews as part of a 12-week Rapid Assessment and Response (RAR) process that aimed to better understand and prevent nonmedical prescription opioid use and overdose deaths in locations in Connecticut and Rhode Island experiencing overdose "outbreaks." Interviews with 13 law enforcement officials across three study sites were analyzed to uncover themes on overdose prevention and naloxone. Findings indicated support for law enforcement involvement in overdose prevention. Hesitancy around naloxone administration by laypersons was evident. Interview themes highlighted officers' feelings of futility and frustration with their current overdose response options, the lack of accessible local drug treatment, the cycle of addiction, and the pervasiveness of easily accessible prescription opioid medications in their communities. Overdose prevention and response, which for some officers included law enforcement-administered naloxone, were viewed as components of community policing and good police-community relations. Emerging trends, such as existing law enforcement medical interventions and Good Samaritan Laws, suggest the need for broader law enforcement engagement around this pressing public health crisis, even in suburban and small town locations, to promote public safety.


Inactivation of ATP citrate lyase by Cucurbitacin B: A bioactive compound from cucumber, inhibits prostate cancer growth.
Prostate cancer, a leading cause of cancer-related deaths in males, is well recognized as having late disease on-set (mostly at age 60-70) and showing slow/latent disease development, and strategies to prevent cancer formation in late manhood may have significant health impacts. Cucurbitacin B (CuB) is a naturally occurring compound that is found abundantly in cucumbers and other vegetables, and it is known to exert anti-cancer activities (primarily via apoptosis-induction) in several human cancers. However, its chemopreventive potential for prostate cancer has not yet been investigated. Here, we reported that CuB significantly and specifically inhibited prostate cancer cell growth with low IC50 (~0.3 μM; PC-3 and LNCaP), accompanied by marked apoptosis (Caspase 3/7 activation, PARP cleavage, increase of Annexin V-Alexa Fluor 488 (Alexa488)+ cells and accumulation of Sub-G0/G1 population), whereas normal human prostate epithelial cells (PrEC) were CuB-insensitive. Using a chemopreventive model, pre-treatment of mice with CuB (2 weeks before PC-3 prostate cancer cell implantation) significantly reduced the rate of in vivo tumor-formation. A 79% reduction in tumor size (accompanied by marked in situ apoptosis) was observed in the CuB-treated group (with no noticeable toxicity) vs. controls at day 31. Strikingly, mechanistic investigations demonstrated that CuB drove dose-dependent inhibition of ATP citrate lyase phosphorylation (ACLY; an important enzyme for cancer metabolism) both in vitro and in the CuB-chemopreventive mouse model. Importantly, ACLY over-expression abrogated CuB's apoptotic effects in prostate cancer cells, confirming ACLY as a direct target of CuB. Thus, CuB harbors potent chemopreventive activity for prostate cancer, and we revealed a novel anti-tumor mechanism of CuB via inhibition of ACYL signaling in human cancer.


Band offsets at semiconductor-oxide interfaces from hybrid density-functional calculations.
Band offsets at semiconductor-oxide interfaces are determined through a scheme based on hybrid density functionals, which incorporate a fraction alpha of Hartree-Fock exchange. For each bulk component, the fraction alpha is tuned to reproduce the experimental band gap, and the conduction and valence band edges are then located with respect to a reference level. The lineup of the bulk reference levels is determined through an interface calculation, and shown to be almost independent of the fraction alpha. Application of this scheme to the Si-SiO2, SiC-SiO2, and Si-HfO2 interfaces yields excellent agreement with experiment.


The UK Northern region genetic register for familial adenomatous polyposis coli: use of age of onset, congenital hypertrophy of the retinal pigment epithelium, and DNA markers in risk calculations.
A polyposis register has been established in the Northern Region of England. A total of 48 families with 71 living affected subjects has been identified during the first three years of operation, a prevalence of 2.29 x 10(-5). Indirect ophthalmoscopy identifies the majority of gene carriers by showing multiple areas of congenital hypertrophy of the retinal pigment epithelium (CHRPE). The absence of this sign in families limits its value where a relative with CHRPE has not been identified. Combining eye examination with data on age of onset and linked DNA markers is highly effective in carrier exclusion; 38% of 528 first, second, and third degree relatives had their carrier risk reduced to less than 1 in 1000. Even with such assurance many subjects will request continued bowel screening at a reduced frequency. Little interest has been shown in prenatal diagnosis. The principal value of a genetic register with domiciliary nurse visiting is the reduction in early mortality among unrecognised gene carriers.


Managing the adverse effects of nonsteroidal anti-inflammatory drugs.
Conventional medical treatment for rheumatoid arthritis and osteoarthritis includes the use of NSAIDs (traditional and selective inhibitors of cyclooxygenase [COX]-2), because they provide unmistakable and significant health benefits in the treatment of pain and inflammation. However, they are associated with an increased risk of serious gastrointestinal (GI) and cardiovascular (CV) adverse events. Both beneficial and adverse effects are due to the same mechanism of action, which is inhibition of COX-dependent prostanoids. Since CV and GI risk are related to drug exposure, a reduction in the administered dose is recommended. However, this strategy will not eliminate the hazard owing to a possible contribution of individual genetic background. Further studies will be necessary to develop genetic and/or biochemical markers predictive of the CV and GI risk of NSAIDs.


Curcumin as therapeutics for the treatment of head and neck squamous cell carcinoma by activating SIRT1.
SIRT1 is one of seven mammalian homologs of Sir2 that catalyzes NAD(+)-dependent protein deacetylation. The aim of the present study is to explore the effect of SIRT1 small molecule activator on the anticancer activity and the underlying mechanism. We examined the anticancer activity of a novel oral agent, curcumin, which is the principal active ingredient of the traditional Chinese herb Curcuma Longa. Treatment of FaDu and Cal27 cells with curcumin inhibited growth and induced apoptosis. Mechanistic studies showed that anticancer activity of curcumin is associated with decrease in migration of HNSCC and associated angiogenesis through activating of intrinsic apoptotic pathway (caspase-9) and extrinsic apoptotic pathway (caspase-8). Our data demonstrating that anticancer activity of curcumin is linked to the activation of the ATM/CHK2 pathway and the inhibition of nuclear factor-κB. Finally, increasing SIRT1 through small molecule activator curcumin has shown beneficial effects in xenograft mouse model, indicating that SIRT1 may represent an attractive therapeutic target. Our studies provide the preclinical rationale for novel therapeutics targeting SIRT1 in HNSCC.


Chronic, recurring ligament instability in the lateral ankle.
According to the literature, chronic ankle instability occurs after acute rupture of the lateral ankle ligaments in 10-20 % of the cases. The etiology of the instability are ligamentous damage and functional neuromuscular disorder of the peroneal muscles. The standards of diagnostics are the history with the frequency of inversion trauma per period and the interval from the primary trauma, the clinical examination and radiological stress tests. Newer diagnostic methods, up to now not well established in clinical routine, include stabilometry, cybex-measurements of the pronator muscles, the evaluation of peroneal reaction time on a tilting platform and dynamic pedography. Conservative management of chronic ankle instability consists of wearing ankle braces and rehabilitation programs concerned with peroneal muscle strengthening and coordination training. The indication for surgical reconstruction of the ankle ligaments are a well-documented mechanical instability with the neuromuscular reflexes intact and a failed physiotherapeutic training program. The surgical procedure should be selected according to a priority list: 1. anatomical repair, eventually augmented with periosteum from the fibula, 2. Watson-Jones tenodesis, and 3. Chrisman-Snook tenodesis to treat a concomittant subtalar instability.


Pain and trauma in negative pressure wound therapy: a review.
Negative pressure wound therapy (NPWT) is considered an effective wound treatment, but there are a number of issues that need to be addressed for improvements to be made. This review aimed to explore the literature relating to the pain and skin trauma that may be experienced during NPWT. A literature search was carried out using the following databases: Academic Search Complete, CINAHL, PsychINFO, MEDLINE and PsyARTICLES. A total of 30 articles were reviewed. Studies reported varying levels of pain in patients undergoing NPWT, with certain treatment factors affecting the level of pain, such as the NPWT system and the dressing/filler used. Similarly, although there is much less research exploring NPWT-related trauma, findings suggest that dressing and filler type may impact on whether trauma occurs. However, further research needs to consider the different stages of NPWT and how pain and trauma can be minimised during the whole procedure. As both pain and skin trauma impact on the patient's well-being and on wound healing, it is essential that research further explores the factors that may affect the experience of pain and trauma, so as to inform developments in wound care.


An apparatus for pulsed ESR and DNP experiments using optically excited triplet states down to liquid helium temperatures.
In standard Dynamic Nuclear Polarization (DNP) electron spins are polarized at low temperatures in a strong magnetic field and this polarization is transferred to the nuclear spins by means of a microwave field. To obtain high nuclear polarizations cryogenic equipment reaching temperatures of 1 K or below and superconducting magnets delivering several Tesla are required. This equipment strongly limits applications in nuclear and particle physics where beams of particles interact with the polarized nuclei, as well as in neutron scattering science. The problem can be solved using short-lived optically excited triplet states delivering the electron spin. The spin is polarized in the optical excitation process and both the cryogenic equipment and magnet can be simplified significantly. A versatile apparatus is described that allows to perform pulsed dynamic nuclear polarization experiments at X-band using short-lived optically excited triplet sates. The efficient (4)He flow cryostat that cools the sample to temperatures between 4 K and 300 K has an optical access with a coupling stage for a fiber transporting the light from a dedicated laser system. It is further designed to be operated on a neutron beam. A combined pulse ESR/DNP spectrometer has been developed to observe and characterize the triplet states and to perform pulse DNP experiments. The ESR probe is based on a dielectric ring resonator of 7 mm inner diameter that can accommodate cubic samples of 5mm length needed for neutron experiments. NMR measurements can be performed during DNP with a coil integrated in the cavity. With the presented apparatus a proton polarization of 0.5 has been achieved at 0.3 T.


Case finding for dementia during acute hospital admissions: a mixed-methods study exploring the impacts on patient care after discharge and costs for the English National Health Service.
Between 2012 and 2017 dementia case finding was routinely carried out on people aged 75 years and over with unplanned admissions to acute hospitals across England. The assumption was that this would lead to better planning of care and treatment for patients with dementia following discharge from hospital. However, little is known about the experiences of patients and carers or the impacts on other health services. This study explored the impact of dementia case finding on older people and their families and on their use of services. Thematic content analysis was conducted on qualitative interview data and costs associated with service use were estimated. Measures included the Mini-Mental State Examination, the EuroQol quality of life scale and a modified Client Service Receipt Inventory. Four counties in the East of England. People aged ≥75 years who had been identified by case finding during an unplanned hospital admission as warranting further investigation of possible dementia and their family carers. We carried out 28 interviews, including 19 joint patient-carer(s), 5 patient only and 4 family carer interviews. Most patients and carers were unaware that memory assessments had taken place, with many families not being informed or involved in the process. Participants had a variety of views on memory testing in hospital and had concerns about how hospitals carried out assessments and communicated results. Overall, case finding did not lead to general practitioner (GP) follow-up after discharge home or lead to referral for further investigation. Few services were initiated because of dementia case finding in hospital. This study shows that dementia case finding may not lead to increased GP follow-up or service provision for patients after discharge from hospital. There is a need for a more evidence-based approach to the initiation of mandatory initiatives such as case finding that inevitably consume stretched human and financial resources.


Diversification of EPR signatures in Site Directed Spin Labeling using a β-phosphorylated nitroxide.
Site Directed Spin Labeling (SDSL) combined with EPR spectroscopy is a very powerful approach to investigate structural transitions in proteins in particular flexible or even disordered ones. Conventional spin labels are based on nitroxide derivatives leading to classical 3-line spectra whose spectral shapes are indicative of the environment of the labels and thus constitute good reporters of structural modifications. However, the similarity of these spectral shapes precludes probing two regions of a protein or two partner proteins simultaneously. To overcome the limitation due to the weak diversity of nitroxide label EPR spectral shapes, we designed a new spin label based on a β-phosphorylated nitroxide giving 6-line spectra. This paper describes the synthesis of this new spin label, its grafting at four different positions of a model disordered protein able to undergo an induced α-helical folding and its characterization by EPR spectroscopy. For comparative purposes, a classical nitroxide has been grafted at the same positions of the model protein. The ability of the new label to report on structural transitions was evaluated by analyzing the spectral shape modifications induced either by the presence of a secondary structure stabilizer (trifluoroethanol) or by the presence of a partner protein. Taken together the results demonstrate that the new phosphorylated label gives a very distinguishable signature which is able to report from subtle to larger structural transitions, as efficiently as the classical spin label. As a complementary approach, molecular dynamics (MD) calculations were performed to gain further insights into the binding process between the labeled NTAIL and PXD. MD calculations revealed that the new label does not disturb the interaction between the two partner proteins and reinforced the conclusion on its ability to probe different local environments in a protein. Taken together this study represents an important step forward in the extension of the panoply of SDSL-EPR approaches.


Repeated and preemptive palliative radiotherapy of symptomatic hepatomegaly in a patient with advanced myelofibrosis.
Patients with advanced myelofibrosis often suffer from symptomatic extramedullary hematopoiesis in spleen and/or liver. In case of drug-refractory disease splenomegaly is treated surgically, whereas hepatomegaly is palliated by radiotherapy (RT). A 56-year-old man with advanced and drug-refractory myelofibrosis suffered from extensive hepatomegaly with severe upper abdominal pain, satiety, weight loss, and fatigue 1.5 years after splenectomy. The patient was treated periodically with fractionated RT to the liver in order to obtain symptom control and to prevent severe symptom recurrence. After 2 Gy fractionated RT to a treatment field encompassing nearly the whole liver, symptoms improved and liver size decreased without severe side effects. This treatment regimen was successfully conducted 3 times in trimonthly intervals. Because symptoms recurred periodically, we then continued RT on a preemptive basis in monthly intervals and with single-dose irradiation. The patient responded well to 1 Gy preemptive single-dose RT to the liver, but not to 0.5 Gy single-dose partial liver irradiation. RT is effective in palliation of hepatomegaly in advanced myelofibrosis. Even preemptive RT can benefit selected patients with advanced disease and periodical recurrence of symptoms.


"Culture" and the intergenerational transmission of poverty: the prevention paradox.
Many U.S. policymakers support changing the "culture" of poor parents to encourage marriage, work, and religion as a means to end the intergenerational transmission of poverty. In this article Jens Ludwig and Susan Mayer review and evaluate research on how parental work, marriage, and religion affect children's socioeconomic status as adults, as well as on the likelihood that changing these indicators of parental behavior will reduce poverty in the next generation. They conclude that even if policymakers were able to ensure that all children had married, working, and religious parents, the result would be a far smaller reduction in poverty among the children's generation than many people believe. The explanation for this "poverty-prevention paradox," say Ludwig and Mayer, is that the poverty rate in the children's generation depends not only on how many poor children grow up to be poor adults, but also on how many nonpoor children grow up to be poor adults. Reducing the chances that poor children become poor adults will dramatically lower future poverty rates only if most poor adults begin life as poor children. But most poor adults grow up as nonpoor children in the type of "pro-social" households that policymakers are pushing to attain. Moreover, little good evidence supports the idea that such parental behaviors as marriage, work, and religious adherence have strong causal effects on children's long-term economic success. The authors argue that encouraging positive social behaviors in the parents of poor children is a worthwhile goal in its own right. But they stress that policymakers should recognize the limits of this strategy for reducing poverty among future generations. There may be no substitute for a system of social insurance and income transfers for those children who do wind up poor as adults.


Language Control in Bilinguals: Monitoring and Response Selection.
Language control refers to the cognitive mechanism that allows bilinguals to correctly speak in one language avoiding interference from the nontarget language. Bilinguals achieve this feat by engaging brain areas closely related to cognitive control. However, 2 questions still await resolution: whether this network is differently engaged when controlling nonlinguistic representations, and whether this network is differently engaged when control is exerted upon a restricted set of lexical representations that were previously used (i.e., local control) as opposed to control of the entire language system (i.e., global control). In the present event-related functional magnetic resonance imaging study, we investigated these 2 questions by employing linguistic and nonlinguistic blocked switching tasks in the same bilingual participants. We first report that the left prefrontal cortex is driven similarly for control of linguistic and nonlinguistic representations, suggesting its domain-general role in the implementation of response selection. Second, we propose that language control in bilinguals is hierarchically organized with the dorsal anterior cingulate cortex/presupplementary motor area acting as the supervisory attentional system, recruited for increased monitoring demands such as local control in the second language. On the other hand, prefrontal, inferior parietal areas and the caudate would act as the response selection system, tailored for language selection for both local and global control.


Prefrontal cortex in the rat: projections to subcortical autonomic, motor, and limbic centers.
This paper describes the quantitative areal and laminar distribution of identified neuron populations projecting from areas of prefrontal cortex (PFC) to subcortical autonomic, motor, and limbic sites in the rat. Injections of the retrograde pathway tracer wheat germ agglutinin conjugated with horseradish peroxidase (WGA-HRP) were made into dorsal/ventral striatum (DS/VS), basolateral amygdala (BLA), mediodorsal thalamus (MD), lateral hypothalamus (LH), mediolateral septum, dorsolateral periaqueductal gray, dorsal raphe, ventral tegmental area, parabrachial nucleus, nucleus tractus solitarius, rostral/caudal ventrolateral medulla, or thoracic spinal cord (SC). High-resolution flat-map density distributions of retrogradely labelled neurons indicated that specific PFC regions were differentially involved in the projections studied, with medial (m)PFC divided into dorsal and ventral sectors. The percentages that WGA-HRP retrogradely labelled neurons composed of the projection neurons in individual layers of infralimbic (IL; area 25) prelimbic (PL; area 32), and dorsal anterior cingulate (ACd; area 24b) cortices were calculated. Among layer 5 pyramidal cells, approximately 27.4% in IL/PL/ACd cortices projected to LH, 22.9% in IL/ventral PL to VS, 18.3% in ACd/dorsal PL to DS, and 8.1% in areas IL/PL to BLA; and 37% of layer 6 pyramidal cells in IL/PL/ACd projected to MD. Data for other projection pathways are given. Multiple dual retrograde fluorescent tracing studies indicated that moderate populations (<9%) of layer 5 mPFC neurons projected to LH/VS, LH/SC, or VS/BLA. The data provide new quantitative information concerning the density and distribution of neurons involved in identified projection pathways from defined areas of the rat PFC to specific subcortical targets involved in dynamic goal-directed behavior.


Abdominal obesity and coronary heart disease in Thai men.
To determine the association of four simple anthropometric indices with coronary heart disease (CHD) in Thai men, and to determine the optimal cut-off points for each index in the prediction of CHD. This is a cohort study with 17 years of follow-up. A total of 2536 male employees from the Electricity Generating Authority of Thailand 35 to 59 years of age at baseline were included in the study. Height, weight, waist circumference, and hip circumference were measured to generate BMI, waist circumference (WC), waist-to-hip ratio (WHR), and waist-to-height ratio (WHtR). Cox regression models were used to estimate hazard ratios by thirds of each index. Receiver operating characteristic curves were used to assess discrimination of CHD. WHtR was most strongly associated with CHD events in Thai men. The age-adjusted hazard ratio for those in the highest, compared with the lowest, third was 2.89 (1.37, 6.11). Although WHtR had the largest area under the receiver operating characteristic curve (AUC) with the optimal cut-off estimated to be 0.51 (sensitivity, 55%; specificity, 61%), no statistically significant difference (p>0.10) was found between the AUC for WHtR and that for the other three indices. WHtR is, marginally, the best of the four indices considered to predict CHD events in Thai men.


Association of lysophosphatidic acids with cerebrospinal fluid biomarkers and progression to Alzheimer's disease.
Lysophosphatidic acids (LPAs) are bioactive signaling phospholipids that have been implicated in Alzheimer's disease (AD). It is largely unknown whether LPAs are associated with AD pathology and progression from mild cognitive impairment (MCI) to AD. The current study was performed on cerebrospinal fluid (CSF) and plasma samples of 182 MCI patients from two independent cohorts. We profiled LPA-derived metabolites using liquid chromatography-mass spectrometry. We evaluated the association of LPAs with CSF biomarkers of AD, Aβ-42, p-tau, and total tau levels overall and stratified by APOE genotype and with MCI to AD progression. Five LPAs (C16:0, C16:1, C22:4, C22:6, and isomer-LPA C22:5) showed significant positive association with CSF biomarkers of AD, Aβ-42, p-tau, and total tau, while LPA C14:0 and C20:1 associated only with Aβ-42 and alkyl-LPA C18:1, and LPA C20:1 associated with tau pathology biomarkers. Association of cyclic-LPA C16:0 and two LPAs (C20:4, C22:4) with Aβ-42 levels was found only in APOE ε4 carriers. Furthermore, LPA C16:0 and C16:1 also showed association with MCI to AD dementia progression, but results did not replicate in an independent cohort. Our findings provide evidence that LPAs may contribute to early AD pathogenesis. Future studies are needed to determine whether LPAs play a role in upstream of AD pathology or are downstream markers of neurodegeneration.


151 endoprosthetic reconstructions for patients with primary tumors involving bone.
As part of the UCLA limb salvage program, 151 patients received 151 endoprostheses for primary tumors involving bone. Follow-up of all patients was to death (56), revision (21), or a minimum two years for the 74 additional survivors (range: 24-114 months; mean: 52 months). Endoprosthetic replacements were of the distal femur (81), proximal femur (19), proximal humerus (13), proximal tibia (11), scapula (11), total femur (8), total humerus (4), intercalary prostheses (2), and one each of the distal humerus and the pelvis. There were three soft tissue sarcomas, five benign bone lesions, and 143 primary malignant tumors of bone. MSTS function was good-excellent in 78%. There were 64 local complications in 55 patients (36%). Mechanical failure occurred in 24 patients (15.9%), local recurrence occurred in ten (6.6%), minor wound healing problems in nine (5.9%), and infection in eight (5.3%). Few systemic complications were reported. Function appeared to be location dependent. All of the 29 patients with benign or low grade malignant tumors (parosteal, IA, IB) have survived. Of the 116 patients with stage IIA and IIB disease, 59% survived three years, and a Kaplan-Meier analysis projects that 56% are expected to survive at five years. Only 17 (11%) of these 151 endoprostheses have been revised; an additional four (3%) eventually came to amputation. The Kaplan-Meier analysis revealed that 91% of the prostheses survived three years and 83% survived five years. The Cox Proportional Hazards model revealed that for patients with stage IIA and IIB disease, the risk of death is four times the risk of the need for revision at five years. Although endoprosthetic reconstructions have their own unique complications, they have proven durable in this series of patients. Local problems usually can be managed without amputation, and patient satisfaction is high.


Lady in Red: Hormonal Predictors of Women's Clothing Choices.
Recent evidence supports the idea that women use red clothing as a courtship tactic, and results from one study further suggested that women were more likely to wear red on days of high fertility in their menstrual cycles. Subsequent studies provided mixed support for the cycle-phase effect, although all such studies relied on counting methods of cycle-phase estimation and used between-subjects designs. By comparison, in the study reported here, we employed frequent hormone sampling to more accurately assess ovulatory timing and used a within-subjects design. We found that women were more likely to wear red during the fertile window than on other cycle days. Furthermore, within-subjects fluctuations in the ratio of estradiol to progesterone statistically mediated the within-subjects shifts in red-clothing choices. Our results appear to represent the first direct demonstration of specific hormone measurements predicting observable changes in women's courtship-related behaviors. We also demonstrate the advantages of hormonal determination of ovulatory timing for tests of cycle-phase shifts in psychology or behavior.


Using a modified intervention mapping approach to develop and refine a single-session motivational intervention for methamphetamine-using men who have sex with men.
There is an ongoing need for the development and adaptation of behavioral interventions to address behaviors related to acquisition and transmission of infectious diseases and for preventing the onset of chronic diseases. This paper describes the application of an established systematic approach to the development of a behavioral intervention to reduce sexual risk behaviors for HIV among men who have sex with men and who use methamphetamine. The approach includes six steps: (1) a needs assessment; (2) preparing matrices of proximal program objectives; (3) selecting theory-based methods and practical strategies; (4) producing program components and materials; (5) planning for program adoption, implementation, and sustainability; and (6) planning for evaluation. The focus of this article is on the intervention development process; therefore the article does not describe steps 5 and 6. Overall the process worked well, although it had to be adapted to fit the sequence of events associated with a funded research project. This project demonstrates that systematic approaches to intervention development can be applied even in research projects where some of the steps occur during the proposal writing process rather than during the actual project. However, intervention developers must remain flexible and be prepared to adapt the process to the situation. This includes being ready to make choices regarding intervention efficacy versus feasibility and being willing to select the best intervention that is likely to be delivered with available resources rather than an ideal intervention that may not be practical.


Monochorionic-diamniotic twins discordant in gender from a naturally conceived pregnancy through postzygotic sex chromosome loss in a 47,XXY zygote.
It is generally believed that monochorionic-diamniotic twin pregnancies result from one fertilized oocyte with both siblings having the same genotype and phenotype. In rare instances, due to somatic mutations or chromosome aberrations, the karyotypes and phenotypes of the two twins can differ. We report cytogenetic, molecular genetic and clinical examinations in monochorionic-diamniotic twins discordant in gender. The monochorionic-diamniotic status of the twins was diagnosed by ultrasound and histologic examination of the placenta. Prenatal chromosome examination performed on amniocytes revealed a normal female karyotype in one and a 46,XX(26)/46,XY(3) karyotype in the other twin. Molecular examinations confirmed monozygosity despite discordant sex. Based on the cytogenetic and molecular results of lymphocytes and placental cells, the only explanation for gender discordance was that the conceptus originally had a 47,XXY chromosome complement. A 47,XXY zygote appears to have undergone a twinning process. A postzygotic loss of the X chromosome in some cells and the Y chromosome in other cells, either before or after twinning, resulted in 46,XX/46,XY mosaicism in both monozygotic (MZ) twins. The sex discordance of the MZ twins can be explained by different proportions of the 46,XX and 46,XY cell lines in the gonads and other tissues.


Important functional role of residue x of the presenilin GxGD protease active site motif for APP substrate cleavage specificity and substrate selectivity of γ-secretase.
γ-Secretase plays a central role in the generation of the Alzheimer disease-causing amyloid β-peptide (Aβ) from the β-amyloid precursor protein (APP) and is thus a major Alzheimer's disease drug target. As several other γ-secretase substrates including Notch1 and CD44 have crucial signaling functions, an understanding of the mechanism of substrate recognition and cleavage is key for the development of APP selective γ-secretase-targeting drugs. The γ-secretase active site domain in its catalytic subunit presenilin (PS) 1 has been implicated in substrate recognition/docking and cleavage. Highly critical in this process is its GxGD active site motif, whose invariant glycine residues cannot be replaced without causing severe functional losses in substrate selection and/or cleavage efficiency. Here, we have investigated the contribution of the less well characterized residue x of the motif (L383 in PS1) to this function. Extensive mutational analysis showed that processing of APP was overall well-tolerated over a wide range of hydrophobic and hydrophilic mutations. Interestingly, however, most L383 mutants gave rise to reduced levels of Aβ37-39 species, and several increased the pathogenic Aβ42/43 species. Several of the Aβ42/43 -increasing mutants severely impaired the cleavages of Notch1 and CD44 substrates, which were not affected by any other L383 mutation. Our data thus establish an important, but compared with the glycine residues of the motif, overall less critical functional role for L383. We suggest that L383 and the flanking glycine residues form a spatial arrangement in PS1 that is critical for docking and/or cleavage of different γ-secretase substrates.


TOR signaling.
The mammalian target of rapamycin, mTOR, is a protein Ser-Thr kinase that functions as a central element in a signaling pathway involved in the control of cell growth and proliferation. The activity of mTOR is controlled not only by amino acids, but also by hormones and growth factors that activate the protein kinase Akt. The signaling pathway downstream of Akt leading to mTOR involves the protein products of the genes mutated in tuberous sclerosis, TSC1 and TSC2, and the small guanosine triphosphatase, Rheb. In cells, mTOR is found in a complex with two other proteins, raptor and mLST8. In this review, we describe recent progress in understanding the control of the mTOR signaling pathway and the role of mTOR-interacting proteins.


Liver transplantation for childhood hepatic malignancy: a review of the United Network for Organ Sharing (UNOS) database.
Orthotopic liver transplantation (OLT) is the only treatment option for unresectable hepatoblastoma (HB) and hepatocellular carcinoma (HCC) in children. Aggregated outcomes of OLT for these hepatic malignancies have not been evaluated in the United Network for Organ Sharing national database. The purpose of this study was to evaluate graft and patient survival in pediatric OLT recipients with HB and HCC. Data from the United Network for Organ Sharing Standard Transplant and Research Files were analyzed and included pediatric (<18 years) OLT recipients with HB or HCC from 1987 to 2004. The effects of diagnosis on pretransplant variables were evaluated using analysis of variance methods or chi2 tests, as appropriate. Actuarial survival and effect of diagnosis on survival were determined using Kaplan-Meier methods and log-rank tests. Since 1987, 152 OLTs have been performed in 135 pediatric patients for HB and 43 OLTs in 41 pediatric patients for HCC. Respective 1-, 5-, and 10-year patient survival after OLT was 79%, 69%, and 66% for HB and 86%, 63%, and 58% for HCC (P = .73). The primary cause of death for both groups was metastatic or recurrent disease, accounting for 54% of deaths in the HB group and 86% in the HCC group (P = .338). Patients with hepatoblastoma were younger (mean age, 2.9 +/- 2.5 vs 10.4 +/- 4.8 years for the HCC group; P < .001) and more likely to receive a living donor organ (16% vs 4%, P = .03). A greater proportion of the patients with HB had previous abdominal surgery than patients with HCC (63% HB vs 37% HCC, P = .04). Pretransplant medical condition and transplant era were associated with graft and patient survival on univariate and multivariate analysis (all P < .05). Orthotopic liver transplantation remains a viable option for pediatric patients with unresectable primary hepatic malignancies and results in good long-term survival. Pretransplant medical condition is an important predictor of outcome. Thus, in conjunction with better chemotherapy regimens, earlier evaluation for OLT in patients with unresectable HB and HCC may result in yet further improved long-term survival.


Enhanced ultraviolet emission of MgZnO/ZnO multiple quantum wells light-emitting diode by p-type MgZnO electron blocking layer.
We report on the effect of a p-type MgZnO electron blocking layer (EBL) on the optical and electrical properties of MgZnO/ZnO multiple quantum wells (MQWs) light-emitting diodes (LEDs). The p-type Mg(0.15)Zn(0.85)O EBL was introduced between the MQWs and p-type Mg(0.1)Zn(0.9)O layers. The p-type Mg(0.15)Zn(0.85)O EBL increased the ultraviolet emission by 111.2% at 60 mA and decreased the broad deep-level emission from ZnO LEDs. The calculated band structures and carrier distribution in ZnO LEDs show that p-type Mg(0.15)Zn(0.85)O EBL effectively suppresses the electron overflow from MQWs to p-type Mg(0.1)Zn(0.9)O and increases the hole concentration in the MQWs.


Serotonin and cancer: what is the link?
Serotonin (5-hydroxytryptamine, 5-HT) is a biogenic monoamine that acts as a neurotransmitter in the central nervous system, local mediator in the gut and vasoactive agent in the blood. Serotonin exerts its multiple, sometimes opposing actions through interaction with a multiplicity of receptors coupled to various signalling pathways. In addition to its well-known functions, serotonin has been shown to be a mitogenic factor for a wide range of normal and tumoral cells. Serotonin exhibits a growth stimulatory effect in aggressive cancers and carcinoids more often through 5- HT1 and 5-HT2 receptors. In contrast, low doses of serotonin can inhibit tumour growth via the decrease of blood supply to the tumour, suggesting that the role of serotonin on tumour growth is concentration-dependent. Data are also available on serotonin involvement in cancer cell migration, metastatic processes and as a mediator of angiogenesis. Moreover, the progression of some tumours is accompanied by a dysregulation of the pattern of serotonin receptor expressions. Serum serotonin level was found to be suitable for prognosis evaluation of urothelial carcinoma in the urinary bladder, adenocarcinoma of the prostate and renal cell carcinoma. In some cases, antagonists of serotonin receptors, inhibitors of selective serotonin transporter and of serotonin synthesis have been successfully used to prevent cancer cell growth. This review revaluates serotonin involvement in several types of cancer and at different stages of their progression.


Lipid profiles of female and male Drosophila.
D. melanogaster is increasingly used as a lipid metabolism model, but the D. melanogaster metabolome is not well studied. A number of studies strongly suggest that lipid metabolism is linked to sexual behavior and gametogenesis. We determined the levels of 400 different lipids in the non-gonadal soma of D. melanogaster females and males. We found higher levels of saturated cholesterol esters and lysophosphatidylcholine in males, and higher levels of polyunsaturated cholesterol esters in females. We also determined the levels of these lipids in females and males without a germline to determine if the absence of gamete "sinks" for metabolic products, such as yolk and lipid deposits in eggs, altered somatic lipid profiles. We observed little change in lipid profiles between these samples. Overall lipid compositions are similar between the sexes, although there are differences in saturation states of two lipid classes, where saturated fatty acids were male-biased and polyunsaturated fatty acids were female-biased. The presence of a germline did not significantly influence lipid profiles, raising the possibility that germline-dependent changes in metabolic gene expression patterns serve a homeostatic purpose.


Workdays lost due to occupational injuries among young workers in Brazil.
The severity of non-fatal work-related injuries has seldom been examined among young workers. We estimated the extent and distribution of workdays lost due to non-fatal work injuries using compensation data. Data are from the Brazilian Institute of Social Insurance, for 2006. The study population is comprised of all insured workers of age 16-24. Descriptive statistics reflect workdays lost due to health-related disability, according to sex, age group, wage, and trade. Out of 4.8 million insured workers ages 16-24 years, we estimated 1,282,940 workdays lost. We observed a larger number of median workdays lost among males age 20-24 in retail and service trades (83 days) and among 16-19-year-old females in the agriculture/fish/forestry/cattle (142 days). Young workers experience a heavy burden of work-related injuries. Disability workdays may compromise school attendance and performance. Other potential impacts affect productivity and social insurance costs.


A perceptual and electropalatographic study of /integral/ in young people with Down's syndrome.
Speech production in young people with Down's syndrome has been found to be variable and inconsistent. Errors tend to be more in the production of sounds that typically develop later, for example, fricatives and affricates, rather than stops and nasals. It has been suggested that inconsistency in production is a result of a motor speech deficit. Late acquired fricatives such as /s/ and /integral/ are complex articulations, which may require more precise motor programming and may therefore show highly inconsistent productions. Other factors potentially affecting speech production in this population are abnormal palatal structure, hearing loss, and hypotonia. A group of 20 young people with Down's syndrome were recorded using Electropalatography (EPG), reading a wordlist containing the phrase 'a sheep'. The wordlist contained seven other phrases and was repeated 10 times. Eight typically developing, cognitively matched children and eight adults were also recorded producing the same data set. Articulatory (EPG pattern analysis) and perceptual analyses of the 10 productions of /integral/ were carried out. /integral/ production was found to be inconsistent in the young people with Down's syndrome, with more errors both in the auditory analysis and articulatory analysis than in the typical sample, which may be due to a motor programming or motor control problem. There were a greater number of errors in the EPG analysis than in the perceptual analysis. This suggests that some young people with DS were able to produce perceptually acceptable /integral/ with atypical EPG patterns. The use of typical, adult-modelled /integral/ EPG patterns in therapy may be inappropriate for some children with DS who present with atypical palatal structures.


The role of APC and beta-catenin in the aetiology of aggressive fibromatosis (desmoid tumors).
Aggressive fibromatosis (syn. desmoid tumor) is a sporadically occurring neoplastic proliferation of fibroblasts originating from musculoaponeurotic planes, forming invasively growing masses without the capability to metastasize. The choice of treatment remains surgical resection with or without radiotherapy, and is characterized by high recurrence rates. Better understanding of the aetiology of aggressive fibromatosis is needed to be able to develop new treatment strategies to cope with the high recurrence rates. Relevant studies were identified through a search of the electronic databases PubMed/ Medline. The following search terms were used: 'aggressive fibromatosis', 'desmoid tumor', 'adenomatous polyposis coli', 'APC', 'beta-catenin', 'Wnt', 'Wingless' and 'Wnt/Wingless'. Studies were selected for review on the basis of abstract reading. A hand search was performed by checking reference lists in selected articles. The neoplastic nature of aggressive fibromatosis and the role of the adenomatous polyposis coli (APC) and beta-catenin signaling cascade in driving the onset and progression of this disease are discussed. Mutations in either the APC or beta-catenin genes are likely to be a major driving force in the formation of these desmoid tumors. More research is needed to develop new treatment strategies.


Health-related quality of life following ambulatory surgery procedures: assessment by RAND-36.
Increasing numbers of elective surgical procedures are performed as day-cases. The impact of ambulatory surgery on health-related quality of life in the recovery period has seldom been described. We assessed health-related quality of life in 143 adult outpatients scheduled for arthroscopic procedures of the knee and shoulder joints, laparoscopic cholecystectomy and inguinal hernia repair using the RAND 36-Item Health Survey preoperatively and one week after patients had returned to work or comparable normal daily routines. Postoperatively all patient groups reported significant improvements in bodily pain and vitality. Physical functioning improved significantly in orthopedic and inguinal hernia patients. However, in the orthopedic groups, postoperative scores for physical health were still relatively lower compared to the general population reference values. Ambulatory surgery has a positive impact on health-related quality of life. Assessment of the recovery process is necessary for recognition of potential areas of improvement in care and postoperative rehabilitation.


Effects of passive mobilization on acute hemodynamic responses in mechanically ventilated patients.
To assess the effects of passive mobilization on acute hemodynamic responses in mechanically ventilated patients. This cross-sectional, quantitative, observational study enrolled patients who were admitted to the intensive care unit, sedated and mechanically ventilated. The infusion of sedative and analgesic drugs aimed to maintain a Ramsay scale sedation level of 4 to 6. Passive mobilization consisted of hip and knee flexion-extension movements for five minutes. After 10 minutes of rest, an additional five minutes of flexion-extension passive movements was performed for the shoulders. Hemodynamic assessments (heart rate and systolic, diastolic and mean blood pressure) were performed one minute before the mobilization protocol and one minute after each phase. The double product and myocardial oxygen consumption were calculated using appropriate formulas. A total of 13 patients (69.2% male, with a mean age of 69.1 ± 15.8 years) were admitted from June to December, 2011. Passive mobilization led to statistically significant increases in heart rate, double product and myocardial oxygen consumption. However, mean blood pressure was not significantly altered. Our results suggest that passive mobilization of mechanically ventilated and sedated patients is safe and provides beneficial effects on acute hemodynamic parameters, particularly heart rate, although mean blood pressure is not significantly altered.


Modulation of superoxide generation in in vivo lipopolysaccharide-primed rat alveolar macrophages by arachidonic acid and inhibitors of protein kinase C, phospholipase A2, protein serine-threonine phosphatase(s), protein tyrosine kinase(s) and phosphatase(s).
Ninety minutes after i.v. injection of Escherichia coli lipopolysaccharide (LPS) (1 mg/kg) into rats, phorbol 12-myristate 13-acetate (PMA)-stimulated superoxide anion (O2-) secretion was enhanced in suspensions of in vivo LPS-treated alveolar macrophages (AM phi) when compared with saline (SAL)-treated AM phi. The purpose of this investigation was to dissect the in vitro mechanism of PMA-stimulated O2- generation in both LPS and SAL-treated rat AM phi, with a panel of inhibitors of protein kinase C (PKC), protein serine-threonine phosphatase(s) (PSP), protein tyrosine kinase(s) (PTK) and phosphatase(s) (PTP), phospholipase A2 (PLA2), cyclooxygenase (CO) and 5-lipoxygenase (5-LO). The following agents blocked PMA-stimulated O2- generation in both LPS- and SAL-treated AM phi (expressed as percentage of control): 1) PKC inhibitors: staurosporine: 100 nM, 7.0% (LPS) and 5.6% (SAL); sphingosine: 10 microM, 21% (LPS) and 10.5% (SAL); 2) PTK inhibitor: genistein: 100 microM, 44% (LPS) and 31% (SAL); 3) PTP inhibitors: phenylarsine oxide, 10 microM, 12.1% (LPS) and 18% (SAL); diamide, 1000 microM, 10.1% (LPS) and 10.5% (SAL); and 4) PLA2 inhibitors: manoalide: 1 microM, 29.3% (LPS) and 5.2% (SAL); scalaradial: 1 microM, 7.7% (LPS) and 7.1% (SAL); and WAY 125,984: 10 microM, 17.1% (LPS) and 14.5% (SAL). In addition, it was observed that exogenously added arachidonic acid (AA)-stimulated O2- generation in a time- and dose-dependent manner in both LPS and SAL-treated AM phi. The following inhibitors enhanced or did not affect PMA-stimulated O2- generation in LPS- and SAL-treated AM phi (expressed as percentage of of control): 1) PSP inhibitors: okadaic acid: 0.5 microM, 117% (LPS) and 153% (SAL); calyculin A: 1 microM, 112% (LPS) and 101% (SAL); 2) CO and 5-LO inhibitors: indomethacin: 10 microM, 107% (LPS) and 90% (SAL); WY 50, 295: 1 microM, 99% (LPS) and 103% (SAL); and 3) the PTP inhibitor orthovanadate upon prolonged preincubation. In both in vivo LPS- or SAL-primed AM phi, PMA-stimulated O2- generation appears to be modulated by PKC, PLA2, AA, PTK, PTP and PSP. No modulatory role was evident for either CO or 5-LO metabolites. These findings might bear on the design of therapeutic approaches for the modulation of O2- release by AM phi in the early stages of sepsis and adult respiratory distress syndrome.