Spatially-explicit modeling of multi-scale drivers of aboveground forest biomass and water yield in watersheds of the Southeastern United States.
Understanding ecosystem processes and the influence of regional scale drivers can provide useful information for managing forest ecosystems. Examining more local scale drivers of forest biomass and water yield can also provide insights for identifying and better understanding the effects of climate change and management on forests. We used diverse multi-scale datasets, functional models and Geographically Weighted Regression (GWR) to model ecosystem processes at the watershed scale and to interpret the influence of ecological drivers across the Southeastern United States (SE US). Aboveground forest biomass (AGB) was determined from available geospatial datasets and water yield was estimated using the Water Supply and Stress Index (WaSSI) model at the watershed level. Our geostatistical model examined the spatial variation in these relationships between ecosystem processes, climate, biophysical, and forest management variables at the watershed level across the SE US. Ecological and management drivers at the watershed level were analyzed locally to identify whether drivers contribute positively or negatively to aboveground forest biomass and water yield ecosystem processes and thus identifying potential synergies and tradeoffs across the SE US region. Although AGB and water yield drivers varied geographically across the study area, they were generally significantly influenced by climate (rainfall and temperature), land-cover factor1 (Water and barren), land-cover factor2 (wetland and forest), organic matter content high, rock depth, available water content, stand age, elevation, and LAI drivers. These drivers were positively or negatively associated with biomass or water yield which significantly contributes to ecosystem interactions or tradeoff/synergies. Our study introduced a spatially-explicit modelling framework to analyze the effect of ecosystem drivers on forest ecosystem structure, function and provision of services. This integrated model approach facilitates multi-scale analyses of drivers and interactions at the local to regional scale.


Conducting, Self-Assembled, Nacre-Mimetic Polymer/Clay Nanocomposites.
We demonstrate electrically and ionically conducting nacre-mimetic nanocomposites prepared using self-assembly of synthetic nanoclay in combination with PSS and a poly(ionic liquid) polymer from aqueous dispersions. The resulting nacre-mimetics show high degrees of mesoscale order and combine high stiffness and high strength. In terms of conductivities, the resulting hybrids exceed simple additive behavior and display synergetic conductivities due to high levels of interfaces and anisotropic conductivity pathways. The approach highlights the integration of relevant functionalities into stiff and strong bioinspired materials, and shows that synergetic properties beyond mechanical performance can be realized in advanced multifunctional nanocomposites using nacre-inspired design principles.


Exploring the structure of social media application-based information-sharing clinical networks in a community in Japan using a social network analysis approach.
Currently, use of social networking services (SNSs) for interprofessional collaboration is increasing. However, few studies have reported on virtual interprofessional interactions in community healthcare services. Revealing such structural characteristics of the networks can provide insight into the functions of the interprofessional information-sharing network and lead to smoother collaboration. Thus, we aimed to explore the structure of SNS-based information-sharing clinical networks. Social network analysis (SNA). We selected a community in City X in Japan. We analysed SNS-based information-sharing clinical network data linked to patients receiving home medical care or care services between January and December 2018. A network was created for each patient to allow healthcare professionals to post and view messages on the web platform. In the SNA, healthcare professions registered in a patient group were represented as nodes, and message posting/viewing relationships were represented as links in the patient network. We investigated the structural characteristics of the target networks using several measures for SNA, including indegree centrality and outdegree centrality, which reflect the number of incoming and outgoing links to/from a node, respectively. Additionally, the professions forming the most central nodes were investigated based on their ranking to identify those with a central role in the networks. Finally, to compare the networks of nursing care levels 1-3 (lighter care requirement) and those with nursing care levels 4-5 (heavier care requirement), we analysed the structural differences in the networks and investigated the roles of healthcare professionals using centrality measures of nodes. Among 844 groups, 247 groups with any nursing care level data were available for analysis. Increasing nursing care level showed higher density, reciprocity and lower centralisation. Healthcare professions with high indegree centrality (physicians, care workers and physical therapists) differed from those with high outdegree centrality (home care workers, physical therapists, and registered dieticians). Visiting nurses and nurses in the clinic played a central role, but visiting nurses tended to have higher indegree and outdegree centrality, while nurses in the clinic had higher closeness and betweenness centrality in networks with heavier care requirement. The SNS-based information-sharing clinical network structure showed that different professions played some form of a central role. Associations between network structures and patient outcomes, cost effectiveness and other factors warrant further investigation.


Decoding the orientation of contrast edges from MEG evoked and induced responses.
Visual gamma oscillations have been proposed to subserve perceptual binding, but their strong modulation by diverse stimulus features confounds interpretations of their precise functional role. Overcoming this challenge necessitates a comprehensive account of the relationship between gamma responses and stimulus features. Here we used multivariate pattern analyses on human MEG data to characterize the relationships between gamma responses and one basic stimulus feature, the orientation of contrast edges. Our findings confirmed we could decode orientation information from induced responses in two dominant frequency bands at 24-32 Hz and 50-58 Hz. Decoding was higher for cardinal than oblique orientations, with similar results also obtained for evoked MEG responses. In contrast to multivariate analyses, orientation information was mostly absent in univariate signals: evoked and induced responses in early visual cortex were similar in all orientations, with only exception an inverse oblique effect observed in induced responses, such that cardinal orientations produced weaker oscillatory signals than oblique orientations. Taken together, our results showed multivariate methods are well suited for the analysis of gamma oscillations, with multivariate patterns robustly encoding orientation information and predominantly discriminating cardinal from oblique stimuli.


From stop to start: tandem gene arrangement, copy number and trans-splicing sites in the dinoflagellate Amphidinium carterae.
Dinoflagellate genomes present unique challenges including large size, modified DNA bases, lack of nucleosomes, and condensed chromosomes. EST sequencing has shown that many genes are found as many slightly different variants implying that many copies are present in the genome. As a preliminary survey of the genome our goal was to obtain genomic sequences for 47 genes from the dinoflagellate Amphidinium carterae. A PCR approach was used to avoid problems with large insert libraries. One primer set was oriented inward to amplify the genomic complement of the cDNA and a second primer set would amplify outward between tandem repeats of the same gene. Each gene was also tested for a spliced leader using cDNA as template. Almost all (14/15) of the highly expressed genes (i.e. those with high representation in the cDNA pool) were shown to be in tandem arrays with short intergenic spacers, and most were trans-spliced. Only two moderately expressed genes were found in tandem arrays. A polyadenylation signal was found in genomic copies containing the sequence AAAAG/C at the exact polyadenylation site and was conserved between species. Four genes were found to have a high intron density (>5 introns) while most either lacked introns, or had only one to three. Actin was selected for deeper sequencing of both genomic and cDNA copies. Two clusters of actin copies were found, separated from each other by many non-coding features such as intron size and sequence. One intron-rich gene was selected for genomic walking using inverse PCR, and was not shown to be in a tandem repeat. The first glimpse of dinoflagellate genome indicates two general categories of genes in dinoflagellates, a highly expressed tandem repeat class and an intron rich less expressed class. This combination of features appears to be unique among eukaryotes.


Polo-like kinase 3 is associated with improved overall survival in cholangiocarcinoma.
Cholangiocarcinomas (CCA) paradoxically express the death ligand TRAIL and thus, are dependent on effective survival signals to circumvent apoptosis. Hedgehog signalling exerts major survival signals in CCA by regulating serine/threonine kinase polo-like kinase (PLK)2. We here aimed to examine the role of PLK1/2/3 expression for CCA tumour biology. We employed CCA samples from 73 patients and human HUCCT-1/Mz-CHA1/KMCH-1 CCA cells. Immunohistochemistry for PLK1/2/3 was performed using tissue microarrays from representative tumour areas. PLK1/2/3-immunoreactive cancer cells were present in most of the CCA samples. However, only PLK1 and especially PLK3 were expressed in higher amounts within CCA cells as compared to normal liver. Given that fibroblast growth factor (FGF) can induce PLK3 expression and also is present in CCA, we examined the effect of FGF on PLK3 in vitro. Indeed, rhFGF rapidly increased PLK3 mRNA expression all three CCA cell lines giving an explanation for the abundant PLK3 presence in the tissue samples. Clinicopathologically, PLK3 expression was associated with decreased tumour cell migration and lymph/blood vessel infiltration whereas higher levels of PLK1 were correlated with larger tumour sizes. Moreover, strong PLK3 expression was associated with prolonged overall survival. The results suggest that PLK3 predominantly is expressed in CCA cells and that high PLK3 expression correlates with prolonged overall survival. These observations might have implications for prognosis prediction of human CCA as well as the potential therapeutic use of polo-like kinase inhibitors (i.e., PLK1/2 specifity).


Functional properties of pro region of Escherichia coli heat-stable enterotoxin.
Escherichia coli heat-stable enterotoxin Ip (STp) is synthesized as the 72-amino-acid residue precursor consisting of three regions: pre region (amino acid residues 1 to 19), pro region (amino acid residues 20 to 54), and mature ST (mST) region (amino acid residues 55 to 72). We examined the role of the pro sequence of STp in enterotoxigenicity of a strain by deleting the gene fragment encoding amino acids 22 to 57. This deletion caused a remarkable reduction of its enterotoxic activity of culture supernatant. In order to analyze the sequence responsible for the function of the pro region, two additional deletion mutants were made. The deletion of the sequence covering amino acids 29 to 38, which is conserved in all sequences of ST reported, brought about a significant reduction of enterotoxic activity but the deletion of the non-conserved sequence (amino acids 40 to 53) did not. This result shows that conserved sequence is mainly responsible for the function. Subsequently, to examine the mechanism of action of the pro region, plasmids carrying DNA sequences of hybrid proteins consisting of pre-pro-nuclease, pre-mST-nuclease, pre-pro-mST-nuclease and pre-pro-nuclease-mST were constructed. Amino acid sequence determination and SDS-polyacrylamide gel analysis revealed that these fusion proteins were cleaved between pre sequence and pro sequence during secretion and the cleaved fusion proteins were accumulated in periplasmic space. But the amount of hybrid protein accumulated in the periplasmic space varied among the strains. That is, the amount of the pre-pro-nuclease gene product that accumulated in the periplasmic space was the highest of all fusion gene products. These results indicate that the existence of the mST region strongly interferes with the translocation of the gene product into the periplasmic space and that the pro region functions to guide the mST region into the periplasmic space.


Nail biting; etiology, consequences and management.
Nail biting (NB) is a common, but unresolved, problem in psychiatry, psychology, medicine and dentistry. While it seems that NB is a simple behavior that can be stopped easily, many of the children with NB have already tried to stop it, but they have not been successful. The frustrations due to failed attempt involve others such as parents and siblings. The present review aims at providing an overview of prevalence, co-morbidities, education and counseling, and management for NB. Overall, the reviewed literatures suggest that co-morbidities of psychiatric disorders and other stereotypic behaviors in clinical sample of children with NB is more than 80%, and more than half of the parents suffer from psychiatric disorders mainly depression. Treatment of NB, however, is not as easy as it seems. The management of NB is much more complicated than just focusing on stopping it. Nail biting cannot be managed without considering its co-morbidities, antecedents and consequences. It might be concluded form the reviewed literature that children with NB, parents, siblings, and teachers should be educated about what to do and what not to do about NB. Punishment is not effective. Moreover, clinical randomized controlled trials are required to make available evidence-based behavioral and pharmacologic treatment protocols.


Copper diethyldithiocarbamate as an inhibitor of tissue plasminogen activator synthesis in cultured human coronary endothelial cells.
Recent developments have shown that organic-inorganic hybrid molecules have the potential to provide useful tools for analyzing biological systems. In the case of fibrinolysis, which is the phenomenon whereby fibrin is degraded by plasmin that has been converted from plasminogen via tissue plasminogen activator (t-PA) secreted from vascular endothelial cells, we hypothesized that there may be organic-inorganic hybrid molecules that could be used to analyze the mechanisms by which endothelial fibrinolysis is regulated. In our present study, we found that a copper complex - copper diethyldithiocarbamate (Cu10) - reduces t-PA activity in a conditioned medium of cultured human coronary endothelial cells by inhibiting the t-PA synthesis without changing the synthesis of plasminogen activator inhibitor type 1, which is a t-PA inhibitor. Copper sulfate, the Cu10 ligand, and zinc/iron complexes with the same Cu10 ligand, did not exhibit such biological activity. These results indicate that Cu10 has the potential to provide a useful tool for finding alternative pathways that downregulate endothelial t-PA synthesis.


The Paf1 complex and P-TEFb have reciprocal and antagonist roles in maintaining multipotent neural crest progenitors.
Multipotent progenitor populations are necessary for generating diverse tissue types during embryogenesis. We show the RNA polymerase-associated factor 1 complex (Paf1C) is required to maintain multipotent progenitors of the neural crest (NC) lineage in zebrafish. Mutations affecting each Paf1C component result in near-identical NC phenotypes; alyron mutant embryos carrying a null mutation in paf1 were analyzed in detail. In the absence of zygotic paf1 function, definitive premigratory NC progenitors arise but fail to maintain expression of the sox10 specification gene. The mutant NC progenitors migrate aberrantly and fail to differentiate appropriately. Blood and germ cell progenitor development is affected similarly. Development of mutant NC could be rescued by additional loss of positive transcription elongation factor b (P-TEFb) activity, a key factor in promoting transcription elongation. Consistent with the interpretation that inhibiting/delaying expression of some genes is essential for maintaining progenitors, mutant embryos lacking the CDK9 kinase component of P-TEFb exhibit a surfeit of NC progenitors and their derivatives. We propose Paf1C and P-TEFb act antagonistically to regulate the timing of the expression of genes needed for NC development.


Improved production of clavulanic acid by reverse engineering and overexpression of the regulatory genes in an industrial Streptomyces clavuligerus strain.
Genomic analysis of the clavulanic acid (CA)-high-producing Streptomyces clavuligerus strains, OL13 and OR, developed through random mutagenesis revealed a frameshift mutation in the cas1 gene-encoding clavaminate synthase 1. Overexpression of the intact cas1 in S. clavuligerus OR enhanced the CA titer by approximately 25%, producing ~ 4.95 g/L of CA, over the OR strain in the flask culture. Moreover, overexpression of the pathway-specific positive regulatory genes, ccaR and claR, in the OR strain improved CA yield by approximately 43% (~ 5.66 g/L) in the flask. However, co-expression of the intact cas1 with ccaR-claR did not further improve CA production. In the 7 L fermenter culture, maximum CA production by the OR strain expressing the wild-type cas1 and ccaR-claR reached approximately 5.52 g/L and 6.01 g/L, respectively, demonstrating that reverse engineering or simple rational metabolic engineering is an efficient method for further improvement of industrial strains.


Proteolytic inactivation of alpha-1-proteinase inhibitor by a neutrophil metalloproteinase.
Human neutrophils triggered with phorbol myristate acetate or opsonized zymosan particles released a metalloproteinase (MP) capable of cleaving and inactivating alpha-1-proteinase inhibitor (alpha-1-PI). Sequence analysis of the amino acids in proteolyzed, native alpha-1-PI revealed a unique single cleavage site between Phe-352 and Leu-353. An analysis of the process regulating the enzyme's activity revealed that the neutrophil MP was released from cells in a latent form whose activation was tightly linked to the generation of hypochlorous acid. These results indicate that human neutrophils use chlorinated oxidants to activate a latent MP that is capable of proteolytically inactivating alpha-1-PI by cleaving the antiproteinase at a unique point in its inhibitory site region.


Mitochondrial genomes reveal an east to west cline of steppe ancestry in Corded Ware populations.
From around 4,000 to 2,000 BC the forest-steppe north-western Pontic region was occupied by people who shared a nomadic lifestyle, pastoral economy and barrow burial rituals. It has been shown that these groups, especially those associated with the Yamnaya culture, played an important role in shaping the gene pool of Bronze Age Europeans, which extends into present-day patterns of genetic variation in Europe. Although the genetic impact of these migrations from the forest-steppe Pontic region into central Europe have previously been addressed in several studies, the contribution of mitochondrial lineages to the people associated with the Corded Ware culture in the eastern part of the North European Plain remains contentious. In this study, we present mitochondrial genomes from 23 Late Eneolithic and Bronze Age individuals, including representatives of the north-western Pontic region and the Corded Ware culture from the eastern part of the North European Plain. We identified, for the first time in ancient populations, the rare mitochondrial haplogroup X4 in two Bronze Age Catacomb culture-associated individuals. Genetic similarity analyses show close maternal genetic affinities between populations associated with both eastern and Baltic Corded Ware culture, and the Yamnaya horizon, in contrast to larger genetic differentiation between populations associated with western Corded Ware culture and the Yamnaya horizon. This indicates that females with steppe ancestry contributed to the formation of populations associated with the eastern Corded Ware culture while more local people, likely of Neolithic farmer ancestry, contributed to the formation of populations associated with western Corded Ware culture.


Joint modelling of repeated measurements and event time: application to performance traits and survival of lambs bred in sub-humid tropics.
We considered the analysis of a study for Dorper, Red Maasai and crossbred lambs born over a period of 6 years at the Diani Estate, Kenya. The study was designed to compare survival and performance traits of genotypes with differing susceptibilities to helminthiasis. The available data include information on time to death and repeated measurements of body weight, packed cell volume (PCV) and faecal egg count (FEC) of the animals. In the paper, we consider joint modelling of the survival time and the repeated measurements. Such an approach allows to account for the possible association between the survival and repeated measurement processes. The advantages and limitations of the joint modelling are discussed and illustrated using the Diani Estate study data.


Arsenic level in toenails is associated with hearing loss in humans.
Arsenic (As) pollution in drinking water is a worldwide health risk for humans. We previously showed hearing loss in young people who live in areas of As-polluted drinking water and in young mice orally treated with As. In this study, we epidemiologically examined associations between As levels in toenails and hearing in 145 Bangladeshi aged 12-55 years in 2014. Levels of As in toenails, but not those in urine, were shown to be significantly correlated with hearing loss at 4 kHz [odds ratio (OR) = 4.27; 95% confidence interval (CI): 1.51, 12.05], 8 kHz (OR = 3.91; 95% CI: 1.47, 10.38) and 12 kHz (OR = 4.15; 95% CI: 1.55, 11.09) by multivariate analysis with adjustments for age, sex, smoking and BMI. Our experimental study further showed a significant association between As levels in inner ears and nails (r = 0.8113, p = 0.0014) in mice orally exposed to As, suggesting that As level in nails is a suitable index to assess As level in inner ears. Taken together, the results of our study suggest that As level in nails could be a convenient and non-invasive biomarker for As-mediated hearing loss in humans.


Red meat and chicken consumption and its association with high blood pressure and obesity in South Korean children and adolescents: a cross-sectional analysis of KSHES, 2011-2015.
The impact of meat consumption on high blood pressure (HBP) and obesity in children and adolescents is a subject of debate. The aim of this study was thus to evaluate the association between meat consumption and both HBP and obesity in this group. We performed a cross-sectional analysis using nationally representative samples of children and adolescents aged 9, 12, and 15 years old (n = 136,739) who were included in the Korea School Health Examination Survey (KSHES) for the 2011-2015 period. Multiple linear and logistic regression analysis was used to determine the factors influencing systolic blood pressure (SBP), diastolic blood pressure (DBP), and body mass index (BMI, kg/m2) levels, and to test the strength of these relationships. Adjusted for covariates, 6.3% of those subjects who consumed >5 servings of meat (including beef, pork, and chicken) per week were obese, compared with 9.1% of the subjects who consumed <1 serving of meat/wk (obesity adjusted odds ratio [OR]: 1.44; 95% confidence interval [CI]: 1.21-1.70; P ≤0.001). Those who consumed <1 serving of meat/wk had an HBP prevalence of 8.2%, compared with 7.2% for subjects who consumed >5 servings of meat/wk (systolic HBP adjusted OR: 1.30; 95% CI: 1.05-1.62; P ≤0.01, diastolic HBP adjusted OR: 1.25; 95% CI: 1.02-1.54; P <0.05). Obese subjects were estimated to have a higher SBP (β = 7.497, P < 0.001) and DBP (β = 4.123, P <0.001) than subjects who had no excess weight. Compared to subjects who consumed >5 servings of meat/wk, those who consumed <3 servings of meat/wk had a higher SBP (β = 0.574, P <0.001) and DBP (β = 0.376, P = 0.003) after adjusting for BMI. The intake of milk, fruit, and vegetables was not associated with either SBP or DBP (P >0.05). In contrast, BMI was significantly associated with milk, fruits, and vegetables (P <0.01). Among children and adolescents, a higher level of meat consumption was associated with lower SBP, DBP, and BMI, and greater height, suggesting that consuming an appropriate amount of meat is important for healthy growth at a young age.


Microvesicular caspase-1 mediates lymphocyte apoptosis in sepsis.
Immune dysregulation during sepsis is poorly understood, however, lymphocyte apoptosis has been shown to correlate with poor outcomes in septic patients. The inflammasome, a molecular complex which includes caspase-1, is essential to the innate immune response to infection and also important in sepsis induced apoptosis. Our group has recently demonstrated that endotoxin-stimulated monocytes release microvesicles (MVs) containing caspase-1 that are capable of inducing apoptosis. We sought to determine if MVs containing caspase-1 are being released into the blood during human sepsis and induce apoptosis.. Single-center cohort study. 50 critically ill patients were screened within 24 hours of admission to the intensive care unit and classified as either a septic or a critically ill control. Circulatory MVs were isolated and analyzed for the presence of caspase-1 and the ability to induce lymphocyte apoptosis. Patients remaining in the ICU for 48 hours had repeated measurement of caspase-1 activity on ICU day 3. Septic patients had higher microvesicular caspase-1 activity 0.05 (0.04, 0.07) AFU versus 0.0 AFU (0, 0.02) (p<0.001) on day 1 and this persisted on day 3, 0.12 (0.1, 0.2) versus 0.02 (0, 0.1) (p<0.001). MVs isolated from septic patients on day 1 were able to induce apoptosis in healthy donor lymphocytes compared with critically ill control patients (17.8±9.2% versus 4.3±2.6% apoptotic cells, p<0.001) and depletion of MVs greatly diminished this apoptotic signal. Inhibition of caspase-1 or the disruption of MV integrity abolished the ability to induce apoptosis. These findings suggest that microvesicular caspase-1 is important in the host response to sepsis, at least in part, via its ability to induce lymphocyte apoptosis. The ability of microvesicles to induce apoptosis requires active caspase-1 and intact microvesicles.


New vaccine adoption in lower-middle-income countries.
Lower-middle-income countries (LMICs) are lagging behind both high-income and low-income countries in new vaccine adoption. Our study involved the following objectives: (1) understand the decision-making processes of LMICs on new vaccine adoption, (2) identify the factors influencing LMIC decisions, (3) obtain the views of vaccine manufacturers about LMIC markets for new vaccines, and (4) make recommendations concerning how to speed up and improve decision making, including proposing mechanisms for implementation of the recommendations. Collect and analyse qualitative data from participants in decision making in 15 case study countries [12 LMICs and three upper-middle-income countries (UMICs)] and multinational and developing country vaccine manufacturers. Interviews of actors in decision making indicate that the aspects deemed most important for adoption are: World Health Organization (WHO) recommendations, the existence of local epidemiological data and a set of factors comprising affordability, cost-effectiveness and overall cost of the new vaccine for the programme. National Immunization Technical Advisory Groups (NITAG) have a key role in advising decision-makers, although their resources and capacity vary. Country decision-makers and manufacturers both see advantages in pooled procurement mechanisms for vaccine purchasing. Recommendations for countries and the international community involve assisting with making epidemiological data and vaccine market information accessible to countries, building and reinforcing related analysis capacity, and assisting with purchasing mechanisms and practices such as pooled procurement.


Cross-Sectional Psychological and Demographic Associations of Zika Knowledge and Conspiracy Beliefs Before and After Local Zika Transmission.
Perceptions of infectious diseases are important predictors of whether people engage in disease-specific preventive behaviors. Having accurate beliefs about a given infectious disease has been found to be a necessary condition for engaging in appropriate preventive behaviors during an infectious disease outbreak, while endorsing conspiracy beliefs can inhibit preventive behaviors. Despite their seemingly opposing natures, knowledge and conspiracy beliefs may share some of the same psychological motivations, including a relationship with perceived risk and self-efficacy (i.e., control). The 2015-2016 Zika epidemic provided an opportunity to explore this. The current research provides some exploratory tests of this topic derived from two studies with similar measures, but different primary outcomes: one study that included knowledge of Zika as a key outcome and one that included conspiracy beliefs about Zika as a key outcome. Both studies involved cross-sectional data collections that occurred during the same two periods of the Zika outbreak: one data collection prior to the first cases of local Zika transmission in the United States (March-May 2016) and one just after the first cases of local transmission (July-August). Using ordinal logistic and linear regression analyses of data from two time points in both studies, the authors show an increase in relationship strength between greater perceived risk and self-efficacy with both increased knowledge and increased conspiracy beliefs after local Zika transmission in the United States. Although these results highlight that similar psychological motivations may lead to Zika knowledge and conspiracy beliefs, there was a divergence in demographic association.


Megadontia, striae periodicity and patterns of enamel secretion in Plio-Pleistocene fossil hominins.
Early hominins formed large and thick-enamelled cheek-teeth within relatively short growth periods as compared with modern humans. To understand better the developmental basis of this process, we measured daily enamel increments, or cross striations, in 17 molars of Plio-Pleistocene hominins representing seven different species, including specimens attributed to early Homo. Our results show considerable variation across species, although all specimens conformed to the known pattern characterised by greater values in outer than inner enamel, and greater cuspal than cervical values. We then compared our results with the megadontia index, which represents tooth size in relation to body mass, for each species to assess the effect of daily growth rates on tooth size. Our results indicate that larger toothed (megadont) taxa display higher rates or faster forming enamel than smaller toothed hominins. By forming enamel quickly, large tooth crowns were able to develop within the constraints of shorter growth periods. Besides daily increments, many animals express long-period markings (striae of Retzius) in their enamel. We report periodicity values (number of cross striations between adjacent striae) in 14 new specimens of Australopithecus afarensis, Paranthropus aethiopicus, Paranthropus boisei, Homo habilis, Homo rudolfensis and Homo erectus, and show that long-period striae express a strong association with male and average male-female body mass. Our results for Plio-Pleistocene hominins show that the biological rhythms that give rise to long-period striae are encompassed within the range of variation known for modern humans, but show a lower mean and modal value of 7 days in australopithecines. In our sample of early Homo, mean and modal periodicity values were 8 days, and therefore similar to modern humans. These new data on daily rates of enamel formation and periodicity provide a better framework to interpret surface manifestations of internal growth markings on fossil hominin tooth crowns. Importantly, our data on early hominin cross striation variation may now contribute towards solving difficult taxonomic diagnoses where much may depend on fragmentary molar remains and enamel structure.


The effect of motivational interviewing-based intervention using self-determination theory on promotion of physical activity among women in reproductive age: A randomized clinical trial.
Physical activity (PA) prevents chronic diseases. Self-determination theory (SDT) provides a useful framework to understand the nature of motivational interviewing (MI). This study aimed to determine the effect of MI-based intervention using SDT on the promotion of PA among women in reproductive age. Seventy women in reproductive age were selected by clustering sampling method for this randomized controlled trial. The questionnaire included the variables of physical fitness test, SDT, and global physical activity questionnaire (GPAQ). The validity of the questionnaires was approved using content validity ratio (CVR) and index (CVI). The reliability and internal consistency of the questionnaires and measures was approved using test-retest method and Cronbach's alpha test, respectively. The intervention group (n=35) received four MI sessions through theory and one standard education session about PA. The control group (n=35) received a standard education session about PA. Four months after the intervention, an increase in the mean scores of total PA (p<0.001, ES=4.77), physical fitness tests including flexibility (p<0.001, ES=1.59), muscular endurance (p<0.001, ES=2.0), cardiorespiratory endurance (p<0.001, ES=0.51), and a decrease in mean scores of agility test (p<0.001, ES= - 0.51) and sedentary behavior (p<0.01, ES=- 0.74) was observed in the intervention group compared to the control group. The intervention group reported an increase in the scores of intrinsic motivation (p<0.001, ES=3.34), identified regulation (p<0.001, ES= 1.28), perceptions of competence (p<0.001, ES=0.81) and autonomy (p<0.001, ES=2.01), enjoyment (p<0.001, ES=0.98) and health motives (p<0.01, ES=0.19), health care climate (p<0.001, ES=4.6), and a decreased score of external regulation (p<0.01, ES=-0.55) and amotivation (p<0.01, ES= -0.56) over time, compared to the control group. MI-based intervention using SDT was effective on the promotion of PA. The Trial was registered at the Iranian Registry of Clinical Trial (http://www.irct.ir) with the Irct ID: IRCT2015101924592N1.


Burkholderia pseudomallei kynB plays a role in AQ production, biofilm formation, bacterial swarming and persistence.
Kynurenine formamidase (KynB) forms part of the kynurenine pathway which metabolises tryptophan to anthranilate. This metabolite can be used for downstream production of 2-alkyl-4-quinolone (AQ) signalling molecules that control virulence in Pseudomonas aeruginosa. Here we investigate the role of kynB in the production of AQs and virulence-associated phenotypes of Burkholderia pseudomallei K96243, the causative agent of melioidosis. Deletion of kynB resulted in reduced AQ production, increased biofilm formation, decreased swarming and increased tolerance to ciprofloxacin. Addition of exogenous anthranilic acid restored the biofilm phenotype, but not the persister phenotype. This study suggests the kynurenine pathway is a critical source of anthranilate and signalling molecules that may regulate B. pseudomallei virulence.


Blood biomarkers for the diagnosis of acute cerebrovascular diseases: a prospective cohort study.
The diagnosis of stroke or TIA in the emergency department is difficult, though important for early treatment. Circulating biomarkers might improve upon clinical assessment at admission. We recruited symptomatic patients with suspected stroke or TIA and drew blood soon after admission. Each patient was assessed with the Face Arm Speech Test (FAST). We measured a panel of 15 circulating inflammatory, thrombotic, cardiac, and cerebral tissue damage biomarkers. Improvement in diagnostic performance was assessed by adding biomarkers to the FAST in logistic regression models to predict a final diagnosis of stroke or TIA (verified by expert review and imaging). 405 patients had suspected stroke: 285 with TIA or stroke (230 definite or probable ischemic stroke, 40 TIA, 15 hemorrhagic stroke) and 120 with other diagnoses. Only the markers t-PA and NT-proBNP were associated positively and significantly (p < 0.01) with a diagnosis of TIA or stroke. The FAST had a sensitivity of 82% (95% CI 78-87) and specificity of 38% (95% CI 29-46) for the diagnosis of TIA or stroke. No biomarker individually improved the sensitivity or specificity of the FAST. A model containing the FAST, age, systolic blood pressure, NT-proBNP and t-PA had a better sensitivity (88%, p < 0.006) and a better specificity (48%, p = 0.04) than the FAST test alone. No single blood marker improved the diagnostic performance of a validated clinical stroke scale. Panels of biomarkers may marginally improve diagnosis, but their practicability is uncertain, and requires further study.


Meta‐analysis of genetic variants associated with human exceptional longevity.
Despite evidence from family studies that there is a strong genetic influence upon exceptional longevity, relatively few genetic variants have been associated with this trait. One reason could be that many genes individually have such weak effects that they cannot meet standard thresholds of genome wide significance, but as a group in specific combinations of genetic variations, they can have a strong influence. Previously we reported that such genetic signatures of 281 genetic markers associated with about 130 genes can do a relatively good job of differentiating centenarians from non‐centenarians particularly if the centenarians are 106 years and older. This would support our hypothesis that the genetic influence upon exceptional longevity increases with older and older (and rarer) ages. We investigated this list of markers using similar genetic data from 5 studies of centenarians from the USA, Europe and Japan. The results from the meta‐analysis show that many of these variants are associated with survival to these extreme ages in other studies. Since many centenarians compress morbidity and disability towards the end of their lives, these results could point to biological pathways and therefore new therapeutics to increase years of healthy lives in the general population.


Diabetes is the main factor accounting for hypomagnesemia in obese subjects.
Type 2 diabetes (T2DM) and obesity are associated with magnesium deficiency. We aimed to determine whether the presence of type 2 diabetes and the degree of metabolic control are related to low serum magnesium levels in obese individuals. A) Case-control study: 200 obese subjects [50 with T2DM (cases) and 150 without diabetes (controls)] prospectively recruited. B) Interventional study: the effect of bariatric surgery on serum magnesium levels was examined in a subset of 120 obese subjects (40 with type 2 diabetes and 80 without diabetes). Type 2 diabetic patients showed lower serum magnesium levels [0.75±0.07 vs. 0.81±0.06 mmol/L; mean difference -0.06 (95% CI -0.09 to -0.04); p<0.001] than non-diabetic patients. Forty-eight percent of diabetic subjects, but only 15% of non-diabetic subjects showed a serum magnesium concentration lower than 0.75 mmol/L. Significant negative correlations between magnesium and fasting plasma glucose, HbA1c, HOMA-IR, and BMI were detected. Multiple linear regression analysis showed that fasting plasma glucose and HbA1c independently predicted serum magnesium. After bariatric surgery serum magnesium increased only in those patients in whom diabetes was resolved, but remain unchanged in those who not, without difference in loss weight between groups. Changes in serum magnesium negatively correlated with changes in fasting plasma glucose and HbA1c. Absolute changes in HbA1c independently predicted magnesium changes in the multiple linear regression analysis. Our results provide evidence that the presence of diabetes and the degree of metabolic control are essential in accounting for the lower levels of magnesium that exist in obese subjects.


Accidental ingestion of plastic from takeaway containers--food for thought.
Foreign body oesophageal obstruction is a medical emergency. It may be accidental, particularly in children, or deliberate, for example with suicide attempts. We present two cases illustrating accidental oesophageal foreign body impaction occurring after consumption of food that had been heated in a plastic container in a microwave oven, then cut and eaten directly from the softened container. To date, we are not aware of any similar reports. In view of potential complications, care needs to be taken when food is eaten directly from plastic takeaway containers.


Maternal and Fetal Outcomes of Pregnancies in Women with Atypical Hemolytic Uremic Syndrome.
Atypical HUS (aHUS) is a disorder most commonly caused by inherited defects of the alternative pathway of complement, or the proteins that regulate this pathway, and life-threatening episodes of aHUS can be provoked by pregnancy. We retrospectively and prospectively investigated 27 maternal and fetal pregnancy outcomes in 14 women with aHUS from the Vienna Thrombotic Microangiopathy Cohort. Seven pregnancies (26%) were complicated by pregnancy-associated aHUS (p-aHUS), of which three appeared to be provoked by infection, bleeding, and curettage, and three individuals were considered to have preeclampsia/HELLP syndrome before the definitive diagnosis of p-aHUS was made. Mutations in genes that encode the complement alternative pathway proteins or the molecules that regulate this pathway were detected in 71% of the women, with no relationship to pregnancy outcome. Twenty-one pregnancies (78%) resulted in a live birth, two preterm infants were stillborn, and four pregnancies resulted in early spontaneous abortions. Although short-term renal outcome was good in most women, long-term renal outcome was poor; among the 14 women, four had CKD stage 1-4, five had received a renal allograft, and three were dialysis-dependent at study end. We prospectively followed nine pregnancies of four women and treated six of these pregnancies with prophylactic plasma infusions (one pregnancy resulted in p-aHUS, one intrauterine fetal death occurred, and seven pregancies were uneventful). Our study emphasizes the frequency of successful pregnancies in women with aHUS. Close monitoring of such pregnancies for episodes of thrombotic microangiopathy is essential but, the best strategy to prevent these episodes remains unclear.


Isolation and cDNA cloning of ovarian cortical rod protein in kuruma prawn Marsupenaeus japonicus (Crustacea: Decapoda: Penaeidae).
Two cortical rod proteins having molecular weights of 28.6 kDa and 30.5 kDa were isolated from the mature ovary of Marsupenaeus japonicus using gel filtration and reversed-phase HPLC. Analysis of the N-terminal amino acid sequence of the 28.6 kDa molecule revealed that amino acid residues 1-21 corresponded to residues 9-29 of the 30.5 kDa molecule. Examination of homology using BLAST showed that 21 amino acids out of 29 residues of the 28.6 kDa molecule, and 14 out of 29 residues of the 30.5 kDa molecule were identical to that of the ovarian cortical rod proteins of Penaeus semisulcatus. Positive immunohistochemical reaction to antiserum raised against the 28.6 kDa protein was observed on cortical rods forming around the periphery of oocytes at the maturation stages. Western blotting analysis revealed that both the 28.6 kDa and 30.5 kDa molecules stained with the anti-28.6 kDa antiserum. Furthermore, the 28.6 kDa and 30.5 kDa proteins were both glycosylated, as evidenced by positive carbohydrate staining using Concanavalin A and production of positive PAS reaction. These results indicate that the cortical rods are comprised of the 28.6 kDa and 30.5 kDa molecules. We subsequently cloned two full-length cDNAs based on the N-terminal sequences of the 28.6 kDa and 30.5 kDa molecules. The open reading frame of 28.6 kDa and 30.5 kDa encoded 276 amino acid residues. Comparison analysis of the two cDNAs revealed that the location of the processing site and sequence of signal peptides differed, indicating that the two cDNAs are products of two separate genes and encode the 28.6 kDa molecule and 30.5 kDa molecule, respectively. Both proteins possessed one potential N-linked glycosylation site. It is considered that both molecules are components of the cortical rods, forming a jelly layer after fertilization.


Understanding the factors involved in determining the bioburdens of surgical masks.
Surgical site infection (SSI) continues to be one of the most common postoperative complications. In our previous study, surgical mask (SM) bioburden was identified to be a potential source of SSI. In the present study, we investigated the factors involved in SM bioburden. Bioburdens of the disposable SM (A: medical mask; B: medical surgical mask) and newly laundered cloth SM (C) were tested by immediately making an impression of the external surface of the mask on sterile culture media. SM microstructure was observed using a scanning electron microscope (SEM). Filtering efficiency and airflow resistance were evaluated with TSI Automated Filter Tester 8130 (TSI Incorporated) according to GB/19083-2010. Whether speaking during operation and washing the face pre-operatively affect SM bioburdens was also evaluated. Surgical procedures were performed in a dynamic operation room. Fifty cases of mask use were enrolled in this study. The bioburden of mask A was the highest. The bioburden of mask B was the lowest. Mask C possessed the lowest filtering efficiency and the highest airflow resistance. SM bioburden was higher in the speaking group. SM bioburden showed no significant difference after washing the face, despite the finding that washing could significantly reduce facial bioburden. Multiple factors influence SM bioburdens. Mask B showed the lowest bioburden and best protection effects. Mask C is not recommended to be used, especially considering that surgeons do not wash the cloth masks daily. Unnecessary talking during operation is not recommended, and washing the face before surgery is not strictly necessary.


Intake of Different Types of Fatty Acids in Infancy Is Not Associated with Growth, Adiposity, or Cardiometabolic Health up to 6 Years of Age.
Background: Studies in adults indicate that a lower saturated and higher unsaturated fat intake is associated with a lower risk of metabolic syndrome and cardiovascular diseases. However, studies on fat intake in relation to cardiometabolic health during childhood are scarce.Objective: We examined associations between dietary intake of fatty acids (FAs) at age 1 y and measures of growth, adiposity, and cardiometabolic health up to age 6 y.Methods: This study was conducted in 2927 children participating in the Generation R Study, a multiethnic, prospective, population-based cohort in the Netherlands. We measured children's total fat intake and intakes of saturated FAs (SFAs), monounsaturated FAs (MUFAs), and polyunsaturated FAs (PUFAs) at a median age of 12.9 mo (95% range: 12.2, 18.9 mo) with a food-frequency questionnaire. We repeatedly measured their height and weight up to age 6 y. At 6 y of age, we measured body fat percentage, diastolic and systolic blood pressure, and serum insulin, triacylglycerol, and HDL cholesterol. These outcomes were combined into a cardiometabolic risk factor score. We examined associations of FA intake with repeated measures of height, weight, and body mass index by using linear mixed models and with cardiometabolic outcomes by using linear regression models, adjusting for sociodemographic and lifestyle factors and taking into account macronutrient substitution effects.Results: In multivariable models, we observed no associations of a higher intake of total fat or SFAs, MUFAs, or PUFAs with growth, adiposity, or cardiometabolic health when fat was consumed at the expense of carbohydrates. In subsequent models, there were also no associations observed for higher MUFA or PUFA intakes at the expense of SFAs with any of the outcomes. Results did not differ by sex, ethnicity, age, or birth weight.Conclusion: The results of this study did not support our hypothesis that intake of different types of FAs was associated with adiposity or cardiometabolic health among children.


Effect of Hypericum perforatum (St John's wort) in major depressive disorder: a randomized controlled trial.
Extracts of Hypericum perforatum (St John's wort) are widely used for the treatment of depression of varying severity. Their efficacy in major depressive disorder, however, has not been conclusively demonstrated. To test the efficacy and safety of a well-characterized H perforatum extract (LI-160) in major depressive disorder. Double-blind, randomized, placebo-controlled trial conducted in 12 academic and community psychiatric research clinics in the United States. Adult outpatients (n = 340) recruited between December 1998 and June 2000 with major depression and a baseline total score on the Hamilton Depression Scale (HAM-D) of at least 20. Patients were randomly assigned to receive H perforatum, placebo, or sertraline (as an active comparator) for 8 weeks. Based on clinical response, the daily dose of H perforatum could range from 900 to 1500 mg and that of sertraline from 50 to 100 mg. Responders at week 8 could continue blinded treatment for another 18 weeks. Change in the HAM-D total score from baseline to 8 weeks; rates of full response, determined by the HAM-D and Clinical Global Impressions (CGI) scores. On the 2 primary outcome measures, neither sertraline nor H perforatum was significantly different from placebo. The random regression parameter estimate for mean (SE) change in HAM-D total score from baseline to week 8 (with a greater decline indicating more improvement) was -9.20 (0.67) (95% confidence interval [CI], -10.51 to -7.89) for placebo vs -8.68 (0.68) (95% CI, -10.01 to -7.35) for H perforatum (P =.59) and -10.53 (0.72) (95% CI, -11.94 to -9.12) for sertraline (P =.18). Full response occurred in 31.9% of the placebo-treated patients vs 23.9% of the H perforatum-treated patients (P =.21) and 24.8% of sertraline-treated patients (P =.26). Sertraline was better than placebo on the CGI improvement scale (P =.02), which was a secondary measure in this study. Adverse-effect profiles for H perforatum and sertraline differed relative to placebo. This study fails to support the efficacy of H perforatum in moderately severe major depression. The result may be due to low assay sensitivity of the trial, but the complete absence of trends suggestive of efficacy for H perforatum is noteworthy.


Relative significance of mannose-sensitive hemagglutinin and toxin-coregulated pili in colonization of infant mice by Vibrio cholerae El Tor.
A previously described in-frame deletion in mshA--the gene encoding the structural subunit of the mannose-sensitive hemagglutinin pilus--has been introduced into the chromosome of three El Tor O1 strains of Vibrio cholerae. None of the deltamshA mutants showed significant attenuation or loss of colonization potential in the infant mouse cholera model. A second mutation, created by insertion of a kanamycin resistance cartridge into deltamshA, also failed to affect in vivo behavior. In contrast, strains carrying mutations in tcpA (encoding the monomer of the toxin-coregulated pilus [TCP]) were markedly attenuated and showed dramatically impaired colonization. This result was in line with those of previous studies. Protection tests performed with antibodies to TCP and to MshA showed that only the former were able to confer immunity against El Tor O1 challenge in this model. Studies with mutants constructed from two O139 strains similarly suggest that TCP but not mannose-sensitive hemagglutinin pili are critical for colonization by strains of this serogroup.


The impact of education and heart attack on smoking cessation among middle-aged adults.
Considerable evidence supports the premise that higher levels of education lead to enhanced health, including protective health behaviors. This paper focuses on how education affects one health behavior known to lead to enhanced health: the cessation of smoking. In particular, the authors examine the extent to which education influences the decision by middle-aged adults to quit smoking following a heart attack, a potentially life-threatening health event. We first hypothesize that middle-aged adults with more formal education will stop smoking more readily than people with less formal education following the experience of a heart attack. Second, we ask what other factors might underlie and explain that hypothesized effect. Using longitudinal data, the authors track changes in individual smoking behaviors after a heart attack among preretirement-age Americans. We control for documented correlates of smoking and heart attack plus other factors associated with education, heart attack, and smoking that may also influence whether a person quits smoking. In addition to confirming evidence on the education-health association as well as the documented connection between heart attack and smoking cessation, this study provides a surprising twist on those links: Our results show that the move to quit smoking following the experience of a heart attack among middle-aged adults is significantly and dramatically moderated by their level of educational attainment.


Mineralization of Polycyclic Aromatic Hydrocarbons by the White Rot Fungus Pleurotus ostreatus.
The white rot fungus Pleurotus ostreatus was able to mineralize to (sup14)CO(inf2) 7.0% of [(sup14)C]catechol, 3.0% of [(sup14)C]phenanthrene, 0.4% of [(sup14)C]pyrene, and 0.19% of [(sup14)C]benzo[a]pyrene by day 11 of incubation. It also mineralized [(sup14)C]anthracene (0.6%) much more slowly (35 days) and [(sup14)C]fluorene (0.19%) within 15 days. P. ostreatus did not mineralize fluoranthene. The activities of the enzymes considered to be part of the ligninolytic system, laccase and manganese-inhibited peroxidase, were observed during fungal growth in the presence of the various polycyclic aromatic hydrocarbons. Although activity of both enzymes was observed, no distinct correlation to polycyclic aromatic hydrocarbon degradation was found.


In vitro fibroblast and dermis fibroblast activation by laser irradiation at low energy. An electron microscopic study.
The effects of laser irradiations have been estimated both from the clinical point of view (rate of reduction of the ulcerated area) and in ultrastructural terms. The modification produced by laser in human fibroblasts in culture have also been investigated. Under our clinical and experimental conditions, laser stimulates the secretion of fibroblasts, both in vivo and in vitro, for reasons that are still the object of research. After irradiation the formation of periodic collagen fibrils is not observed, so that complete ' restitutio ad integrum' of the dermal matrix does not occur.


How universal is coverage and access to diagnosis and treatment for Chagas disease in Colombia? A health systems analysis.
Limited access to Chagas disease diagnosis and treatment is a major obstacle to reaching the 2020 World Health Organization milestones of delivering care to all infected and ill patients. Colombia has been identified as a health system in transition, reporting one of the highest levels of health insurance coverage in Latin America. We explore if and how this high level of coverage extends to those with Chagas disease, a traditionally marginalised population. Using a mixed methods approach, we calculate coverage for screening, diagnosis and treatment of Chagas. We then identify supply-side constraints both quantitatively and qualitatively. A review of official registries of tests and treatments for Chagas disease delivered between 2008 and 2014 is compared to estimates of infected people. Using the Flagship Framework, we explore barriers limiting access to care. Screening coverage is estimated at 1.2% of the population at risk. Aetiological treatment with either benznidazol or nifurtimox covered 0.3-0.4% of the infected population. Barriers to accessing screening, diagnosis and treatment are identified for each of the Flagship Framework's five dimensions of interest: financing, payment, regulation, organization and persuasion. The main challenges identified were: a lack of clarity in terms of financial responsibilities in a segmented health system, claims of limited resources for undertaking activities particularly in primary care, non-inclusion of confirmatory test(s) in the basic package of diagnosis and care, poor logistics in the distribution and supply chain of medicines, and lack of awareness of medical personnel. Very low screening coverage emerges as a key obstacle hindering access to care for Chagas disease. Findings suggest serious shortcomings in this health system for Chagas disease, despite the success of universal health insurance scale-up in Colombia. Whether these shortcomings exist in relation to other neglected tropical diseases needs investigating. We identify opportunities for improvement that can inform additional planned health reforms.


Preventability of early readmissions at a children's hospital.
To determine whether pediatric readmissions within 15 days of discharge were considered preventable. Retrospective chart review of 200 randomly selected readmissions (8% of all readmissions) occurring within 15 days of discharge from a freestanding children's hospital between January 1, 2007, and December 31, 2008. The degree of preventability was assessed independently for each case by 4 pediatricians using a 5-point Likert scale and was correlated with chronic conditions and reason for index admission with 3M's Clinical Risk Groups and All Patient-Refined Diagnostic-Related Groups, respectively. The rate of 15-day readmissions considered more likely preventable by the discharging hospital was 20.0% (1.7% of total admissions, 95% confidence interval 14.8%-26.4%). Reviewers failed to reach initial consensus in 62.5% of cases, although final consensus was achieved after the panel reviewed cases together. Consensus ratings served as the standard for the remainder of the study. Readmissions in children with malignancies were considered less preventable than those in children with other chronic illnesses (5.8% vs 25.8%, P = .003). Readmissions following surgical admissions were considered more likely preventable than those following medical admissions (38.9% vs 15.9%, P = .002). Central venous catheter infections and ventricular shunt malfunctions accounted for 8.5% of all readmissions reviewed. Although initial consensus about which readmissions were more likely preventable was difficult to achieve, the overall rate of preventable pediatric 15-day readmissions was low. Pediatric readmissions are unlikely to serve as a highly productive focus for cost savings or quality measurement.


Oligopeptide-modified poly(beta-amino ester)s-coated AdNuPARmE1A: Boosting the efficacy of intravenously administered therapeutic adenoviruses.
Oncolytic adenoviruses are used as agents for the treatment of cancer. However, their potential is limited due to the high seroprevalence of anti-adenovirus neutralizing antibodies (nAbs) within the population and the rapid liver sequestration when systemically administered. To overcome these challenges, we explored using nanoparticle formulation to boost the efficacy of systemic oncolytic adenovirus administration. Methods: Adenovirus were conjugated with PEGylated oligopeptide-modified poly(β-amino ester)s (OM-pBAEs). The resulting coated viral formulation was characterized in terms of surface charge, size, aggregation state and morphology and tested for anti-adenovirus nAbs evasion and activity in cancer cells. In vivo pharmacokinetics, biodistribution, tumor targeting, and immunogenicity studies were performed. The antitumor efficacy of the oncolytic adenovirus AdNuPARmE1A coated with OM-pBAEs (SAG101) in the presence of nAbs was evaluated in pancreatic ductal adenocarcinoma (PDAC) mouse models. Toxicity of the coated formulation was analyzed in vivo in immunocompetent mice. Results: OM-pBAEs conjugated to adenovirus and generated discrete nanoparticles with a neutral charge and an optimal size. The polymeric coating with the reporter AdGFPLuc (CPEG) showed enhanced transduction and evasion of antibody neutralization in vitro. Moreover, systemic intravenous administration of the formulation showed improved blood circulation and reduced liver sequestration, substantially avoiding activation of nAb production. OM-pBAEs coating of the oncolytic adenovirus AdNuPARmE1A (SAG101) improved its oncolytic activity in vitro and enhanced antitumor efficacy in PDAC mouse models. The coated formulation protected virions from neutralization by nAbs, as antitumor efficacy was preserved in their presence but was completely lost in mice that received the non-formulated AdNuPARmE1A. Finally, coated-AdNuPARmE1A showed reduced toxicity when high doses of the formulation were administered. Conclusions: The developed technology represents a promising improvement for future clinical cancer therapy using oncolytic adenoviruses.


The T cell response to persistent herpes virus infections in common variable immunodeficiency.
We show that at least half of patients with common variable immunodeficiency (CVID) have circulating CD8(+) T cells specific for epitopes derived from cytomegalovirus (CMV) and/or the Epstein-Barr virus (EBV). Compared to healthy age-matched subjects, more CD8(+) T cells in CVID patients were committed to CMV. Despite previous reports of defects in antigen presentation and cellular immunity in CVID, specific CD4(+) and CD8(+) T cells produced interferon (IFN)-gamma after stimulation with CMV peptides, and peripheral blood mononuclear cells secreted perforin in response to these antigens. In CVID patients we found an association between a high percentage of circulating CD8(+) CD57(+) T cells containing perforin, CMV infection and a low CD4/CD8 ratio, suggesting that CMV may have a major role in the T cell abnormalities described previously in this disease. We also show preliminary evidence that CMV contributes to the previously unexplained severe enteropathy that occurs in about 5% of patients.


Occupational post-exposure prophylaxis (PEP) against human immunodeficiency virus (HIV) infection in a health district in Cameroon: assessment of the knowledge and practices of nurses.
Health care providers are at risk of acquiring human immunodeficiency virus (HIV) infection from occupational exposure, with nurses being the most vulnerable. There is no data on the awareness of post-exposure prophylaxis (PEP) among nurses in Cameroon. This study aimed to assess the knowledge, practices of nurses regarding PEP for HIV and their determinants in Cameroon. A cross-sectional study was conducted between April and July 2013, and involved 80 nurses in a rural health district in the North West Region of Cameroon. Data was collected using a structured questionnaire and analysed using the SPSS software version 20. In all, 73.7% of the participants had poor knowledge about PEP for HIV. Though many (83.8%) had heard about PEP, just 10 (12.5%) had received formal training on PEP for HIV. Only 24 (30%) and 20 (25%) knew the correct drug regimen and duration of treatment respectively. The majority (85%) considered themselves to be at risk of acquiring HIV at work, with 54 (67.5%) having experienced an exposure in the past, mainly while setting up intravenous lines (57.4%), recapping needles (37.0%) and during delivery (24.1%). Of those exposed, ten (18.9%) received PEP, which was started after 24 hours in 50%. In multivariable regression analyses, awareness of hospital policy [OR: 0.043 (0.005-0.404), p-value = 0.006] was associated with Good knowledge on PEP for HIV. The knowledge and practice of nurses on PEP for HIV in Cameroon is low. There is urgent need for training programmes and workshops to increase awareness, improve practice, and reduce the risk of HIV acquisition from work related activities among health care providers.


Comparative analysis of Tritrichomonas foetus (Riedmüller, 1928) cat genotype, T. foetus (Riedmüller, 1928) cattle genotype and Tritrichomonas suis (Davaine, 1875) at 10 DNA loci.
The parasitic protists in the genus Tritrichomonas cause significant disease in domestic cattle and cats. To assess the genetic diversity of feline and bovine isolates of Tritrichomonas foetus (Riedmüller, 1928) Wenrich and Emmerson, 1933, we used 10 different genetic regions, namely the protein coding genes of cysteine proteases 1, 2 and 4-9 (CP1, 2, 4-9) involved in the pathogenesis of the disease caused by the parasite. The cytosolic malate dehydrogenase 1 (MDH1) and internal transcribed spacer region 2 of the rDNA unit (ITS2) were included as additional markers. The gene sequences were compared with those of Tritrichomonas suis (Davaine, 1875) Morgan and Hawkins, 1948 and Tritrichomonas mobilensisCulberson et al., 1986. The study revealed 100% identity for all 10 genes among all feline isolates (=T. foetus cat genotype), 100% identity among all bovine isolates (=T. foetus cattle genotype) and a genetic distinctness of 1% between the cat and cattle genotypes of T. foetus. The cattle genotype of T. foetus was 100% identical to T. suis at nine loci (CP1, 2, 4-8, ITS2, MDH1). At CP9, three out of four T. suis isolates were identical to the T. foetus cattle genotype, while the T. suis isolate SUI-H3B sequence contained a single unique nucleotide substitution. Tritrichomonas mobilensis was 0.4% and 0.7% distinct from the cat and cattle genotypes of T. foetus, respectively. The genetic differences resulted in amino acid changes in the CP genes, most pronouncedly in CP2, potentially providing a platform for elucidation of genotype-specific host-pathogen interactions of T. foetus. On the basis of this data we judge T. suis and T. foetus to be subjective synonyms. For the first time, on objective nomenclatural grounds, the authority of T. suis is given to Davaine, 1875, rather than the commonly cited Gruby and Delafond, 1843. To maintain prevailing usage of T. foetus, we are suppressing the senior synomym T. suisDavaine, 1875 according to Article 23.9, because it has never been used as a valid name after 1899 and T. foetus is widely discussed as the cause of bovine trichomonosis. Thus bovine, feline and porcine isolates should all be given the name T. foetus. This promotes the stability of T. foetus for the veterinary and economically significant venereal parasite causing bovine trichomonosis.


Methods for exploring treatment effect heterogeneity in subgroup analysis: an application to global clinical trials.
Multi-country randomised clinical trials (MRCTs) are common in the medical literature, and their interpretation has been the subject of extensive recent discussion. In many MRCTs, an evaluation of treatment effect homogeneity across countries or regions is conducted. Subgroup analysis principles require a significant test of interaction in order to claim heterogeneity of treatment effect across subgroups, such as countries in an MRCT. As clinical trials are typically underpowered for tests of interaction, overly optimistic expectations of treatment effect homogeneity can lead researchers, regulators and other stakeholders to over-interpret apparent differences between subgroups even when heterogeneity tests are insignificant. In this paper, we consider some exploratory analysis tools to address this issue. We present three measures derived using the theory of order statistics, which can be used to understand the magnitude and the nature of the variation in treatment effects that can arise merely as an artefact of chance. These measures are not intended to replace a formal test of interaction but instead provide non-inferential visual aids, which allow comparison of the observed and expected differences between regions or other subgroups and are a useful supplement to a formal test of interaction. We discuss how our methodology differs from recently published methods addressing the same issue. A case study of our approach is presented using data from the Study of Platelet Inhibition and Patient Outcomes (PLATO), which was a large cardiovascular MRCT that has been the subject of controversy in the literature. An R package is available that implements the proposed methods.


Position emission tomography with or without computed tomography in the primary staging of Hodgkin's lymphoma.
In order to receive the most appropriate therapy, patients with Hodgkin's lymphoma (HL) must be accurately stratified into different prognostic staging groups. Computed tomography (CT) plays a pivotal role in the conventional staging. The aim of the present study was to investigate the value of positron emission tomography using 2-[18F]fluoro-2-deoxy-D-glucose (FDG-PET) and combined FDG-PET/CT for the staging of HL patients, and the impact on the choice of treatment. Ninety-nine consecutive, prospectively included patients had FDG-PET and CT in their staging work-up. Sixty-one of the 99 patients had combined FDG-PET/CT. A standard of reference for each nodal region and organ was determined using all available information including scan results, histology and a minimum of one year's clinical follow-up data. The lack of a satisfactory diagnostic gold standard limits the reliability of accuracy calculations. FDG-PET would have upstaged 19% of patients and downstaged 5% of patients, leading to a different treatment in 9% of patients. For FDG-PET/CT, the corresponding figures are 17%, 5%, and 7%. In nodal regions, the sensitivity of FDG-PET and FDG-PET/CT seemed higher than that of CT (92% and 92% vs. 83%). FDG-PET identified more false positive nodal sites than did CT and FDG-PET/CT (1.6% vs 0.7% and 0.5%). FDG-PET and FDG-PET/CT were highly sensitive for evaluating organs (86% and 73%) while CT detected 37% of involved organs. FDG-PET and FDG-PET/CT have a substantial potential impact on staging and choice of treatment and the methods tend to upstage rather than downstage patients. FDG-PET and FDG-PET/CT seem to have a higher diagnostic accuracy than CT in the staging of HL. However, care should be taken so patients with an excellent prognosis and at risk of over-treatment do not receive more intensive treatment because of these staging methods.


Reducing low-value care in endometriosis between limited evidence and unresolved issues: a proposal.
Quantification of benefits and harms of medical interventions should be based on high-quality evidence, which is not always the case in the endometriosis field. In many clinical circumstances, healthcare decisions in women with endometriosis are taken based on suboptimal evidence or on evidence of coexistence of benefits and harms that must be balanced. In these conditions, it is important to avoid or reduce the use of low-value care, i.e. interventions with defined harms and uncertain benefits, or whose effectiveness is comparable with less expensive alternatives. In particular, we suggest that: (i) non-surgical diagnosis based on symptoms, physical findings and transvaginal ultrasonography is possible in most women with symptomatic endometriosis. Thus, except in doubtful cases, laparoscopy should be intended for surgical treatment, not for diagnostic purposes: early diagnosis and diagnostic laparoscopy are not synonymous; (ii) future trials on new drugs for endometriosis should address those outcomes that are most important to patients, should be designed as superiority trials and should include a progestin or an estrogen-progestin as a comparator. Moreover, limitation of repetitive surgery for recurrent endometriosis is among the objectives of long-term medical treatment; (iii) indications for surgery should be the result of a balance between demonstrated benefits in terms of fertility enhancement and pain relief, specific risks associated with excision of different types of endometriotic lesions, cost-effectiveness and patient preference after detailed information; (iv) physicians, health professionals and policy makers should discriminate between screening for and diagnosis of endometriosis. Limited peritoneal foci, which are frequently observed also in asymptomatic women, regress or remain stable in about two thirds of cases. Therefore, the theoretical premises for a screening campaign are currently unclear; (v) physicians should develop the ability to effectively communicate quantitative information based on international guidelines and systematic literature reviews. This will assist a woman's understanding of the interaction between the evidence and her priorities, facilitating the transition towards value-based medicine.


Pex19p contributes to peroxisome inheritance in the association of peroxisomes to Myo2p.
During budding of yeast cells peroxisomes are distributed over mother cell and bud, a process that involves the myosin motor protein Myo2p and the peroxisomal membrane protein Inp2p. Here, we show that Pex19p, a peroxin implicated in targeting and complex formation of peroxisomal membrane proteins, also plays a role in peroxisome partitioning. Binding studies revealed that Pex19p interacts with the cargo-binding domain of Myo2p. We identified mutations in Myo2p that specifically reduced binding to Pex19p, but not to Inp2p. The interaction between Myo2p and Pex19p was also reduced by a mutation that blocked Pex19p farnesylation. Microscopy revealed that the Pex19p-Myo2p interaction is important for peroxisome inheritance, because mutations that affect this interaction hamper peroxisome inheritance in vivo. Together these data suggest that both Inp2p and Pex19p are required for proper association of peroxisomes to Myo2p.


Toward an oligonucleotide therapy for Duchenne muscular dystrophy: a complex development challenge.
Antisense oligonucleotide (AO)-mediated exon skipping is a promising new therapy for Duchenne muscular dystrophy (DMD), recently demonstrating proof of principle for restoring the absent dystrophin protein in DMD patients. However, the range of AO chemistries available for exon skipping is limited; effective systemic dystrophin protein restoration has yet to be demonstrated and will be required for disease modification in patients; and the current approach is mutation-specific, necessitating the development of multiple AO drugs to treat all DMD patients. This is therefore a highly complex drug development challenge.


Clinical relevance of insulin-like growth factor-1 to cardiovascular risk markers.
Insulin-like growth factor-1 (IGF-1) is an anabolic hormone, the levels of which decline with age. The present study aimed to determine the impact of age-related declines in serum IGF-1 levels on various physiological processes. We retrospectively reviewed the medical records of patients whose serum IGF-1 levels were estimated in our department, and assessed the relationships between serum IGF-1 levels and various physiological parameters. A total of 427 patients with a mean (± standard deviation) age of 52.8 (± 17.1) years were included in the analysis. The levels of serum IGF-1 showed significant positive correlation with those of hemoglobin and hematocrit, and negative correlation with the presence of inflammatory and fibrin-related markers including C-reactive protein (CRP) and procalcitonin (PCT), and D-dimer and fibrin degradation products (FDP). These tendencies persisted after exclusion of patients with pituitary disease. In this study population of diverse diseases and backgrounds, a decline in serum IGF-1 levels with age was associated with an increase in inflammatory and fibrin-related markers. This may explain the correlation between low serum IGF-1 levels and an increased risk of cardiovascular events. Our findings suggest that serum IGF-1 is a clinically relevant marker of cardiovascular risk, particularly in males.


Novel application of a balloon-anchoring technique for the realignment of a prolapsed pipeline embolization device: a technical report.
Flow-diverting stents represent a substantial advancement in the treatment of cerebral aneurysms. They can, however, be associated with unique complications that may require management through adjunctive techniques. To present a technical report of a salvage technique used to realign a prolapsed Pipeline Embolization Device (PED) during the treatment of a giant internal carotid artery (ICA) aneurysm. A patient in his late 70s with an incidental giant supraclinoid ICA aneurysm presented for endovascular consideration. Treatment was planned using the PED. Following placement of the device there were two focal areas of incomplete expansion and balloon angioplasty was performed. This manipulation resulted in foreshortening of the distal aspect of the PED which caused the device to prolapse into the aneurysm. After multiple unsuccessful attempts to regain distal access, a salvage technique was attempted in which a balloon was inflated in the middle cerebral artery and, by applying traction, the PED was realigned with the parent artery. After the PED was realigned, direct distal catheter access was achieved and a second Pipeline device was deployed, successfully covering the aneurysm neck with resultant flow stasis. The patient had no postoperative issues and was discharged 2 days later without deficit. The balloon-anchoring technique was successfully used to realign a PED that had prolapsed into a giant ICA aneurysm. This maneuver prevented potentially disastrous complications and allowed the satisfactory completion of the aneurysm embolization. This represents a useful salvage technique that should be considered when encountering a prolapsed stent.


Electrostatics analysis of radiative absorption by sphere clusters in the Rayleigh limit: application to soot particles.
An analysis of radiative absorption and scattering by clusters of spheres in the Rayleigh limit is developed with an electrostatics analysis. This approach assumes that the largest dimension of the cluster is significantly smaller than the wavelength of the radiation. The electric field that is incident upon and scattered by the cluster can then be represented by the gradient of a potential that in turn satisfies Laplace's equation. An analytical solution for the potential that exactly satisfies the boundary conditions at the surfaces of the spheres is obtained with a coupled spherical harmonics method. The components of the polarizability tensor and the absorption, scattering, and depolarization factors are obtained from the solution. Calculations are performed on fractallike clusters of spheres, with refractive-index values that are characteristic of carbonaceous soot in the visible and the IR wavelengths. Results indicate that the absorption cross sections of fractal soot clusters can be significantly larger in the mid-IR wavelengths than what is predicted for Rayleigh-limit spheres that have the same total volume. The absorption cross section (relative to a sphere of the same volume) is dependent on the number of spheres in the aggregate for aggregates with up to approximately 100 primary spheres, and for larger aggregates the relative absorption becomes constant. The predicted spectral variation of soot absorption in the visible and the mid-IR wavelengths is shown to agree well with experimental measurements.


Calibration-free sensor for pressure and H2O concentration in headspace of sterile vial using tunable diode laser absorption spectroscopy.
Tunable diode laser absorption measurements of pressure and H2O concentration in the headspace of vials using a distributed-feedback (DFB) diode laser near 1.4 μm are reported. A H2O line located near 7161.41 cm(-1) is selected based on its strong absorption strength and isolation from interference of neighboring transitions. Direct absorption spectra of H2O are obtained for the measurement path as well as the reference path by scanning the laser wavelength. The pressure and H2O vapor concentration in the headspace of a vial are inferred from a differential absorption signal, which is the difference between the measured and the referenced absorbance spectra. This sensor is calibration-free and no purge gas is needed. The demonstrated capability would enable measurements of pressure and H2O concentration in the headspace of vials within 2.21% and 2.86%, respectively. A precision of 1.02 Torr and 390 ppm is found for the pressure and H2O concentration, respectively. A set of measurements for commercial freeze-dried products are also performed to illustrate the usefulness of this sensor.


Drug hypersensitivity reactions involving skin.
Immune reactions to drugs can cause a variety of diseases involving the skin, liver, kidney, lungs, and other organs. Beside immediate, IgE-mediated reactions of varying degrees (urticaria to anaphylactic shock), many drug hypersensitivity reactions appear delayed, namely hours to days after starting drug treatment, showing a variety of clinical manifestations from solely skin involvement to fulminant systemic diseases which may be fatal. Immunohistochemical and functional studies of drug-specific T cells in patients with delayed reactions confirmed a predominant role for T cells in the onset and maintenance of immune-mediated delayed drug hypersensitivity reactions (type IV reactions). In these reactions, drug-specific CD4+ and CD8+ T cells are stimulated by drugs through their T cell receptors (TCR). Drugs can stimulate T cells in two ways: they can act as haptens and bind covalently to larger protein structures (hapten-carrier model), inducing a specific immune response. In addition, they may accidentally bind in a labile, noncovalent way to a particular TCR of the whole TCR repertoire and possibly also major histocompatibility complex (MHC)-molecules - similar to their pharmacologic action. This seems to be sufficient to reactivate certain, probably in vivo preactivated T cells, if an additional interaction of the drug-stimulated TCR with MHC molecules occurs. The mechanism was named pharmacological interaction of a drug with (immune) receptor and thus termed the p-i concept. This new concept may explain the frequent skin symptoms in drug hypersensitivity to oral or parenteral drugs. Furthermore, the various clinical manifestations of T cell-mediated drug hypersensitivity may be explained by distinct T cell functions leading to different clinical phenotypes. These data allowed a subclassification of the delayed hypersensitivity reactions (type IV) into T cell reactions which, by releasing certain cytokines and chemokines, preferentially activate and recruit monocytes (type IVa), eosinophils (type IVb), or neutrophils (type IVd).


Associations between vitamin D receptor polymorphisms and breast cancer risk.
Many epidemiologic studies have investigated the association between vitamin D receptor (VDR) gene polymorphisms and breast cancer risk, but the results were inconsistent. We performed a meta-analysis of 31 studies on VDR polymorphisms, including FokI, BsmI, TaqI, and ApaI, and breast cancer risk published before May 2013. For FokI, the allele of f was found to be associated with increased risk of breast cancer compared with F (OR, 1.19; 95% CI, 1.03-1.36). Patients with ff genotype were at significantly higher risk of breast cancer compared with those with FF genotype (OR, 1.95; 95% CI, 1.66-2.29). In subgroup analysis by race, Fok1 polymorphism was significantly associated with breast cancer risk for Caucasian population (f vs. F: OR, 1.35; 95% CI, 1.14-1.59; ff vs. FF: OR, 2.18; 95% CI, 1.86-2.54; ff vs. FF + Ff: OR, 1.16; 95% CI, 1.03-1.30). For ApaI, aa genotype was associated with increased breast cancer risk in Asian population based on four studies (aa vs. Aa + AA, OR, 1.49; 95% CI, 1.12-1.98). No significant association was found between breast cancer risk and ApaI and TaqI polymorphism in different models and populations. Our updated meta-analysis showed that Fok1 polymorphism is associated with breast cancer risk both in general population and in Caucasian population. ApaI polymorphism might be associated with breast cancer risk in Asian population. Large well-designed epidemiological studies are necessary to clarify the risk identified in the current meta-analysis.


Neuroprotective effect of Scutellaria baicalensis on spinal cord injury in rats.
Inflammation has been known to play an important role in the pathogenesis after spinal cord injury (SCI). Microglia are activated after injury and produce a variety of proinflammatory factors such as tumor necrosis factor-alpha, interleukin-1beta, cyclooxygenase-2, and reactive oxygen species leading to apoptosis of neurons and oligodendrocytes. In this study, we examined the neuroprotective effects of total ethanol extract of Scutellaria baicalensis (EESB), after SCI. Using primary microglial cultures, EESB treatment significantly inhibited lipopolysaccharide-induced expression of such inflammatory mediators as tumor necrosis factor-alpha, IL-1beta, IL-6, cyclooxygenase-2, and inducible nitric oxide synthase. Furthermore, reactive oxygen species and nitric oxide production were significantly attenuated by EESB treatment. For in vivo study, rats that had received a moderate spinal cord contusion injury at T9 received EESB orally at a dose of 100 mg/kg. EESB inhibited expression of proinflammatory factors and protein carbonylation and nitration after SCI. EESB also inhibited microglial activation at 4 h after injury. Furthermore, EESB significantly inhibited apoptotic cell death of neurons and oligodendrocytes and improved functional recovery after SCI. Lesion cavity and myelin loss were also reduced following EESB treatment. Thus, our data suggest that EESB significantly improve functional recovery by inhibiting inflammation and oxidative stress after injury.


Classification of platelet concentrates (Platelet-Rich Plasma-PRP, Platelet-Rich Fibrin-PRF) for topical and infiltrative use in orthopedic and sports medicine: current consensus, clinical implications and perspectives.
Platelet concentrates for topical and infiltrative use - commonly termed Platetet-Rich Plasma (PRP) or Platelet-Rich Fibrin (PRF) - are used or tested as surgical adjuvants or regenerative medicine preparations in most medical fields, particularly in sports medicine and orthopaedic surgery. Even if these products offer interesting therapeutic perspectives, their clinical relevance is largely debated, as the literature on the topic is often confused and contradictory. The long history of these products was always associated with confusions, mostly related to the lack of consensual terminology, characterization and classification of the many products that were tested in the last 40 years. The current consensus is based on a simple classification system dividing the many products in 4 main families, based on their fibrin architecture and cell content: Pure Platelet-Rich Plasma (P-PRP), such as the PRGF-Endoret technique; Leukocyte- and Platelet-Rich Plasma (LPRP), such as Biomet GPS system; Pure Platelet-Rich Fibrin (P-PRF), such as Fibrinet; Leukocyte- and Platelet-Rich Fibrin (L-PRF), such as Intra-Spin L-PRF. The 4 main families of products present different biological signatures and mechanisms, and obvious differences for clinical applications. This classification serves as a basis for further investigations of the effects of these products. Perspectives of evolutions of this classification and terminology are also discussed, particularly concerning the impact of the cell content, preservation and activation on these products in sports medicine and orthopaedics.


Trunk Muscle Activation at the Initiation and Braking of Bilateral Shoulder Flexion Movements of Different Amplitudes.
The aim of this study was to investigate if trunk muscle activation patterns during rapid bilateral shoulder flexions are affected by movement amplitude. Eleven healthy males performed shoulder flexion movements starting from a position with arms along sides (0°) to either 45°, 90° or 180°. EMG was measured bilaterally from transversus abdominis (TrA), obliquus internus (OI) with intra-muscular electrodes, and from rectus abdominis (RA), erector spinae (ES) and deltoideus with surface electrodes. 3D kinematics was recorded and inverse dynamics was used to calculate the reactive linear forces and torque about the shoulders and the linear and angular impulses. The sequencing of trunk muscle onsets at the initiation of arm movements was the same across movement amplitudes with ES as the first muscle activated, followed by TrA, RA and OI. All arm movements induced a flexion angular impulse about the shoulders during acceleration that was reversed during deceleration. Increased movement amplitude led to shortened onset latencies of the abdominal muscles and increased level of activation in TrA and ES. The activation magnitude of TrA was similar in acceleration and deceleration where the other muscles were specific to acceleration or deceleration. The findings show that arm movements need to be standardized when used as a method to evaluate trunk muscle activation patterns and that inclusion of the deceleration of the arms in the analysis allow the study of the relationship between trunk muscle activation and direction of perturbing torque during one and the same arm movement.


Carbon dioxide chemoreception and hypoventilation syndromes with autonomic dysregulation.
Respiratory and autonomic disorders of infancy, childhood, and adulthood are a group of disorders that have varying presentation, combined with a range of severity of respiratory control and autonomic nervous system dysfunction. Within this group, congenital central hypoventilation syndrome and rapid onset obesity with hypothalamic dysfunction, hypoventilation, and autonomic dysregulation, exhibit the greatest respiratory control deficits, requiring supported ventilation as a mainstay of care. The discovery of the key role of the paired-like homeobox 2B gene in autonomic nervous system development, along with the identification of paired-like homeobox 2B gene mutations causing congenital central hypoventilation syndrome, has led to a fruitful dialog between basic scientists and physician-scientists, producing an explosion of knowledge regarding genotype-phenotype correlations in this disorder, as well as important animal models of chemosensory regulation deficit. Though the etiology of rapid onset obesity with hypothalamic dysfunction, hypoventilation, and autonomic dysregulation is still to be determined, recent studies have begun to carefully delineate the phenotype, suggesting that it too may provide fertile ground for research that both advances our knowledge and improves patient care.


Human muscle-derived stem/progenitor cells promote functional murine peripheral nerve regeneration.
Peripheral nerve injuries and neuropathies lead to profound functional deficits. Here, we have demonstrated that muscle-derived stem/progenitor cells (MDSPCs) isolated from adult human skeletal muscle (hMDSPCs) can adopt neuronal and glial phenotypes in vitro and ameliorate a critical-sized sciatic nerve injury and its associated defects in a murine model. Transplanted hMDSPCs surrounded the axonal growth cone, while hMDSPCs infiltrating the regenerating nerve differentiated into myelinating Schwann cells. Engraftment of hMDSPCs into the area of the damaged nerve promoted axonal regeneration, which led to functional recovery as measured by sustained gait improvement. Furthermore, no adverse effects were observed in these animals up to 18 months after transplantation. Following hMDSPC therapy, gastrocnemius muscles from mice exhibited substantially less muscle atrophy, an increase in muscle mass after denervation, and reorganization of motor endplates at the postsynaptic sites compared with those from PBS-treated mice. Evaluation of nerve defects in animals transplanted with vehicle-only or myoblast-like cells did not reveal histological or functional recovery. These data demonstrate the efficacy of hMDSPC-based therapy for peripheral nerve injury and suggest that hMDSPC transplantation has potential to be translated for use in human neuropathies.


Trends in incidence, treatment and survival of borderline ovarian tumors in the Netherlands: a nationwide analysis.
Background: Population-based data on borderline ovarian tumors (BOTs) are scarce and information regarding recent trends in incidence, treatment and survival is lacking. The purpose of this study was to analyze these trends in the Netherlands and to assess the risk of developing a subsequent invasive ovarian tumor. Material and methods: All consecutive patients diagnosed with BOTs between 1993 and 2016 (n = 7113) were identified from the Netherlands Cancer Registry (NCR). Annual age-adjusted incidence rates were calculated. Relative survival (RS) analyses and multivariable analyses estimating excess mortality were conducted. Patients with a subsequent invasive ovarian tumor were identified by the NCR. Results: Age-adjusted incidence increased from 2.1/100,000 person-years in 1993 to 4.2/100,000 in 2011, after 2011 the incidence declined. The proportion of bilateral tumors decreased over time from 16% in 1993-1998 to 11% in 2005-2010 and remained stable onwards. Survival improved over time (excess mortality ratioadjusted 2011-2016 versus 1993-1998: 0.25; 95%CI: 0.13-0.47). Five-year RS increased from 91% in 1993-1998 to 98% in 2011-2016 and 10-year RS from 88% in 1993-1998 to 96% in 2005-2010. Fewer patients were treated with chemotherapy (4.4% in 1993-1998 versus 0.7% in 2011-2016). During a median follow-up time of 8 years, 0.9% developed a subsequent invasive ovarian carcinoma. Conclusions: The incidence of BOTs increased over time from 1993 until 2010 but declined since 2011. This decline may be partly due to changes in the classification of gynecological tumors, as serous BOTs are now more often diagnosed as low grade serous ovarian cancers. Survival is high and has improved since 1993. The risk of a subsequent invasive ovarian carcinoma seems low.


Retinal dystrophy: development retarded by galactose feeding in spontaneously hypertensive rats.
Retinal photoreceptor cell dystrophies have been widely observed in humans and in animals, but pathogenetic mechanisms are known in only a few such disorders, and successful therapeutic intervention has been reported in fewer still. Spontaneously hypertensive albino rats develop a retinal photoreceptor cell dystrophy with onset late in the first year or early in the second year of life. Between 60 and 70 percent of the animals are affected. A substantial reduction in the prevalence and severity of the dystrophy occurred in such animals whose diet contained 30 percent (by weight) D-galactose. Neither an inhibitor of the enzyme aldose reductase, present in the diet, nor diabetes mellitus, induced by streptozotocin, had any statistically significant influence on the dystrophy. Ambient light and systolic blood pressure levels also did not seem to influence the course of the disorder. The mechanism by which galactose exerts its effect is unknown, but a mutant enzyme with an elevated Michaelis constant (Km) for galactose is plausible.


Effect of polyelectrolyte electron collection layer counteranion on the properties of polymer solar cells.
Polyviologen (PV) derivatives are known materials used for adjusting the work function (WF) of cathodes by reducing the electron injection/collection barrier at the cathode interface. To tune and improve device performance, we introduce different types of counteranions (CAs), such as bromide, tetrafluoroborate, and tetraphenylborate, to a PV derivative. The effective WF of the Al cathode is shown to depend on the size of the CA, indicating that a Schottky barrier can be modulated by the size of the CA. Through the increased size of the CA from bromide to tetraphenylborate, the effective WF of the Al cathode is gradually decreased, indicating a decreased Schottky barrier at the cathode interface. In addition, the change of the power conversion efficiency (PCE) and the short circuit current (Jsc) value show good correlation with the change of the WF of the cathode, signifying the typical transition from a Schottky to an Ohmic contact. The turn-on electric field of the electron-only device without PV was 0.21 MV/cm, which is dramatically higher than those of devices with PV-X (0.07 MV/cm for PV-Br, 0.06 MV/cm for PV-BF4, and 0.05 MV/cm for PV-BPh4) This is also coincident with a decrease in the Schottky barrier at the cathode interface. The device ITO/PEDOT/P3HT:PCBM/PV/Al, with a thin layer of PV derivative and tetraphenylborate CA as the cathode buffer layer, has the highest PCE of 4.02%, an open circuit voltage of 0.64 V, a Jsc of 11.6 mA/cm2, and a fill factor of 53.0%. Our results show that it is possible to improve the performance of polymer solar cells by choosing different types of CAs in PV derivatives without complicated synthesis and to refine the electron injection/collection barrier height at the cathode interface.