Pregnancy following treatment of symptomatic myomas with laparoscopic bipolar coagulation of uterine vessels.
Laparoscopic bipolar coagulation of uterine vessels (LBCUV) has been employed for women with symptomatic uterine myomas, but its effect on subsequent pregnancy has not been characterized. Four-hundred and twenty-three women entered the study between March 1999 and December 2001. Of these, 142 women (33.6%) were under the age of 40 years at the time of LBCUV, 36 of whom (36/142, 25.3%) were sexually active without contraception. In a prospective study of 142 patients (<40 years old) undergoing LBCUV for symptomatic myomas, 15 women became pregnant (17 total pregnancies) and were evaluated by physical and ultrasound examinations. The volume of the dominant myoma was 117.4 +/- 118.4 and 36.8 +/- 56.8 cm(3) before and after LBCUV respectively. Volume of the dominant myoma after pregnancy was 46.2 +/- 76.7 cm(3) (mean +/- SD). There was a significant difference in myoma volume before and after LBCUV (P = 0.002), but no significant difference in myoma volume when comparing post-partum size with post-LBCUV size (P = 0.269). Pregnancy outcomes included seven miscarriages in the first trimester and one premature rupture of membrane (PPROM). Although the other pregnancies were regarded as uncomplicated, only two women were delivered of normal neonates as the other seven pregnancies were terminated secondary to patient request. The pregnancy and term pregnancy rates in sexually active women without contraception were 41.6% (15/36) and 5.6% (2/36) respectively. Because a relatively high rate (7/17, 41.2%) of early miscarriages was observed, we recommend that this procedure be employed only for women who do not desire additional children.


Will Helicobacter pylori affect short-term rebleeding rate in peptic ulcer bleeding patients after successful endoscopic therapy?
Helicobacter pylori (H. pylori) can augment the pH-increasing effect of omeprazole in patients with peptic ulcer. A high intragastric pH may be helpful in preventing recurrent hemorrhage by stabilizing the blood clot at the ulcer base of bleeding peptic ulcer patients. Therefore, we hypothesized that omeprazole may reduce short-term rebleeding rate in these patients with H. pylori infection after initial hemostasis had been obtained. Between July 1996 and December 1998, 65 bleeding peptic ulcer patients (24 gastric ulcer, 41 duodenal ulcer) who had obtained initial hemostasis with endoscopic therapy were enrolled in this trial. Thirty (46.2%) of them were found to have H. pylori infection by a rapid urease test and pathological examination. For all studied patients, omeprazole was given 40 mg intravenously every 6 h for 3 days. Thereafter, omeprazole was given 20 mg per os (p.o.) once daily for 2 months. A pH meter was inserted in the fundus of each patient under fluoroscopic guidance after intravenous omeprazole had been administered. The occurrence of rebleeding episode was observed for 14 days. In patients with H. pylori infection, intragastric pH (median, 95% confidence interval [CI]: 6.54, 5.90-6.68) was higher than in those without H. pylori infection (6.05, 5.59-6.50, p < 0.001). However, the patients with rebleeding (2 vs 3), volume of blood transfusion (median, range: 1000 ml, 0-2250 vs 750, 0-2000), number of operations (0 vs 1), mortality caused by bleeding (0 vs 0), and hospital stay (median, range: 6 days, 3-14 vs 7, 5-16) were not statistically different from those without H. pylori infection. Omeprazole does increase intragastric pH in bleeding peptic ulcer patients with H. pylori infection. However, the presence of H. pylori infection does not affect the short-term rebleeding rate in these patients.


OCT-based elastography for large and small deformations.
We present two approaches to speckle tracking for optical coherence tomography (OCT)-based elastography, one appropriate for small speckle motions and the other for large, rapid speckle motions. Both approaches have certain advantages over traditional cross-correlation based motion algorithms. We apply our algorithms to quantifying the strain response of a mechanically inhomogeneous, bi-layered polyvinyl alcohol tissue phantom that is subjected to either small or large dynamic compressive forces while being imaged with a spectral domain OCT system. In both the small and large deformation scenarios, the algorithms performed well, clearly identifying the two mechanically disparate regions of the phantom. The stiffness ratio between the two regions was estimated to be the same for the two scenarios and both estimates agreed with the expected stiffness ratio based on earlier mechanical testing. No single numerical approach is appropriate for all cases and the experimental conditions dictate the proper choice of speckle shift algorithm for OCT-based elastography studies.


T cell receptor-mediated recognition of self-ligand induces signaling in immature thymocytes before negative selection.
Shaping of the T cell repertoire by selection during intrathymic maturation involves T cell receptor (TCR) recognition of major histocompatibility complex/self-antigen complexes. In this communication, we studied the ability of minor lymphocyte stimulating (Mls) determinants to act as self-tolerogens in the selection of the T cell repertoire. We demonstrate that unprimed T cells from normal as well as TCR transgenic mice form Mls-specific conjugates with antigen-presenting cells, and that this TCR-ligand interaction leads to elevation of intercellular Ca2+ ([Ca2+]i). Peripheral T cells from TCR transgenic mice expressing receptors specific for self-Mls antigen show no reactivities to Mlsa. However, a proportion of immature thymocytes from these mice show specific binding and strong [Ca2+]i elevation in response to self-antigen-presenting cells, although these thymocytes do not proliferate. This self-reactivity of thymocytes is inhibited by antibodies specific for TCR, CD4, CD8, class II molecules, lymphocyte function-associated antigen 1, and intercellular adhesion molecule 1. These results demonstrate for the first time that before thymic negative selection, immature T cells can specifically interact with cells bearing self-antigen, and suggest that the resulting TCR-dependent signal transduction events provide a basis for negative selection of self-reactive T cells.


Lilly Lecture 1994. The beta-cell in diabetes: from molecular genetics to clinical research.
Pancreatic insulin secretion rates can be accurately derived by mathematical deconvolution of peripheral C-peptide concentrations either by using individual C-peptide kinetic parameters obtained by analysis of the decay curve of biosynthetic human C-peptide or by using published group parameters with appropriate adjustments for age and degree of obesity. Since the cross-reactivity of proinsulin and related peptides is low (< 10%) in many C-peptide assays, this experimental approach avoids the spurious increase in insulin immunoreactivity resulting from cross-reactivity with proinsulin and related peptides in the insulin assay. Application of this technique has demonstrated that the phenotypic expression of beta-cell dysfunction differs in subjects with different genetic mechanisms of non-insulin-dependent diabetes mellitus (NIDDM). Subjects who have maturity-onset diabetes of the young (MODY) due to mutations in the glucokinase gene demonstrate different patterns of altered insulin secretion when compared with subjects who have mutations in the MODY1 gene on chromosome 20. Glucokinase mutations affect the ability of the beta-cell to detect and respond to small increases in glucose above the basal level. However, compensatory mechanisms operative in vivo, which include a priming effect of glucose on insulin secretion, limit the severity of the observed insulin secretory defect, resulting in a generally mild clinical course in these subjects. In contrast, mutations in the MODY1 gene are associated with an inability to increase insulin secretion as the plasma glucose concentration increases above 7-8 mmol/l and the normal priming effect of glucose on insulin secretion is lost. These characteristics of the dose-response relationships between glucose and insulin secretion result in a more severe degree of hyperglycemia than observed in subjects with glucokinase mutations, and these subjects more frequently need insulin treatment. These alterations are evident in prediabetic subjects with normal glucose levels who carry the MODY1 mutation, suggesting that defective beta-cell function is the primary pathogenetic defect in the diabetic syndrome in these subjects. Studies performed in the classic form of NIDDM demonstrate that subjects with mild glucose intolerance and normal fasting glucose concentrations and glycosylated hemoglobin levels consistently demonstrate defective beta-cell function. These results are consistent with studies in the Zucker diabetic fatty rat, an animal model of NIDDM in which prediabetic animals demonstrate extensive alterations in expression of multiple genes involved in the regulation of insulin secretion. It thus appears that abnormal beta-cell function is present at a relatively early stage in the evolution of NIDDM, even before the onset of overt hyperglycemia.


Molecular Epidemiology of Ralstonia solanacearum Species Complex Strains Causing Bacterial Wilt of Potato in Uganda.
Bacterial wilt (BW) caused by the Ralstonia solanacearum species complex (RSSC) is a serious threat to potato production in Uganda. However, little is known about the extent of the disease and the type of the pathogen strains involved. A nationwide survey was conducted to study BW prevalence and incidence in potato, and potato tuber and stem samples of potential alternative hosts were collected for pathogen isolation. DNA was extracted from pure cultures for genetic diversity studies. The pathogen was phylotyped by multiplex PCR; then, a subset of isolates was typed at sequevar level. Isolates of the same sequevar were then haplotyped using multilocus tandem repeat sequence typing (TRST) schemes. BW prevalence and incidence in potato farms were 81.4 and 1.7%, respectively. Three RSSC phylotypes were identified, with the majority of the strains belonging to Phylotype II (80%) followed by Phylotype I (18.5%) and III (1.5%). Phylotype I strains belonged to Sequevar 31, and Phylotype II strains belonged to Sequevar 1. Potato-associated Phylotype II Sequevar 1 strains were more diverse (27 TRST haplotypes) than nonpotato Phylotype I (5 TRST haplotypes). Mapping of TRST haplotypes revealed that three TRST haplotypes of Phylotype II Sequevar 1 strains play an important epidemiological role in BW of potato in Uganda being disseminated via latently infected seed.[Formula: see text]Copyright © 2019 The Author(s). This is an open access article distributed under the CC BY-NC-ND 4.0 International license.


The hematological and biochemical changes in rats exposed to britholite mineral.
The present study was to investigate the alteration of biochemical and hematological parameters on the rats exposed to natural radiation caused by britholite mineral (REE, Ca, Na)5 [(Si,P)O4]3(OH,F) within 15 days. Britholite was collected from Kuluncak mining area, Malatya, bearing radioactive 232Th isotope (average 2.68% ThO2), which is rare earth elements found high amounts. Britholite is toxic for the living animal and human and emits the radiation to natural surroundings about 0.8R/h due to its radioactive 232Th properties. In this study, animals were divided to two groups, one groups exposed to 232Th, the other group was served as control group. All animals were fed with same food and water during the experimental study (15 days). After 15 days, the hematologic and biochemical parameters (Na, K, Ca, P, Cl, Mg, glucose, cholesterol, HDL, LDL, albumin, Uric acid, AST, ALT, total protein, Fe, urea and creatine level and hormonal parameters (TSH, T3 and T4)) were analyzed The levels of serum triglyceride in the ionizing radiation group generated by 232Th isotope (p < 0.05) statistically significantly increased compared with control group value. Lymphocytes, TSH, T3 and T4 decreased in the ionizing radiation group generated by 232Th isotope while neutrophils increased in the ionizing radiation group generated by 232Th isotope. The rats exposed to ionizing radiation generated by 232Th isotope caused significant changes in the hematological and biochemical parameters and the most significantly alteration was observed in the thyroid hormonal levels, which might be due to high radiation doses within short time. These results should be kept in mind to maintain healthy life in people who lives in britholite mineral vicinity.


Specificity of neomycin analogues bound to the packaging region of human immunodeficiency virus type 1 RNA.
The packaging region of HIV-1 RNA contains a number of structural features which are important in the life cycle of the virus, making this segment of RNA a potential target for new types of AIDS-directed drugs. We studied the binding of three neomycin analogues (neo-guanidino, neo-acridine, and neo-neo) to a 171-mer RNA molecule from the packaging region of HIV-1 using quantitative footprinting and circular dichroism. Neo-guanidino produced footprinting patterns and effects on the CD similar to those observed for neomycin and paromomycin, indicating that all three compounds bind to the same regions of the 171-mer. Neo-guanidino binds to SL 1 where it joins the large internal loop, near a bulge in the stem of SL 1, and on SL 2. Neo-acridine, which has an acridine attached to neomycin, and neo-neo, which has two neomycins linked by a flexible tether, bind bivalently, and give very different footprinting and CD results from the other compounds. The neomycin portion of neo-acridine binds to the same sites as neomycin, while the attached acridine group appears to bind to a duplex region in the main stem of the folded 171-mer. Since the footprinting data for this analogue show few enhancements, bivalent binding of neo-acridine appears to stabilize the folded structure of RNA by effectively 'stapling' parts of the structure together. Neo-neo induces significant structural changes in RNA where neomycin binds. This may be related to the inability of both neomycins of neo-neo it find optimal binding sites adjacent to one another without changing RNA structure. The intensity of a strong negative CD band in the spectrum of psi-RNA at 208 nm is sensitive to drug-induced changes in RNA structure. Neo-guanidino and neo-neo (also neomycin and paromomycin), which change RNA structure, cause an increase in intensity while neo-acridine, which induces little distortion to RNA, causes a decrease in intensity. Molecular modeling analysis shows that C-5' of ribose of neo-acridine and neo-neo must be directed away from the binding pocket when these analogues are bivalently bound to RNA. This study showed how variations in the structure of aminoglycosides lead to different binding specificity to part of the packaging region of HIV-1. Such knowledge will be important in design of drugs to target this region.


Anti-biofilm efficacy of a lactoferrin/xylitol wound hydrogel used in combination with silver wound dressings.
With an epidemic increase in obesity combined with an ageing population, chronic wounds such as diabetic foot ulcers, pressure ulcers and venous leg ulcers are an increasing clinical concern. Recent studies have shown that bacterial biofilms are a major contributor to wound bioburden and interfere with the normal wound healing process; therefore, rational design of wound therapies should include analysis of anti-biofilm characteristics. Studies using the combined treatment of bacterial biofilms with the innate immune molecule lactoferrin and the rare sugar-alcohol xylitol have demonstrated an antimicrobial capacity against a clinical wound isolate. Studies presented here used a colony-drip-flow reactor biofilm model to assess the anti-biofilm efficacy of a lactoferrin/xylitol hydrogel used in combination with commercially available silver-based wound dressings. Log reductions in biofilm viability are compared with a commercially available wound hydrogel used in combination with the silver-based wound dressings. For both a single species biofilm and a dual species biofilm, the lactoferrin/xylitol hydrogel in combination with the silver wound dressing Acticoat™ had a statistically significant reduction in biofilm viability relative to the commercially available wound hydrogel. This study also demonstrated a statistical interaction between the lactoferrin/xylitol hydrogel and the silver wound dressing.


Calcium uptake by subcellular fractions of human umbilical artery.
Two different mechanisms for the active accumulation of Ca2+ by subcellular fractions of human umbilical artery are described. One, located in the mitochondrial fraction, was induced by exogenous ATP or respiratory substrates (ADP and succinate) and was inhibited by azide. The other, located in the microsomal fraction, was induced by ATP and potentiated by oxalate, but not inhibited by azide. Increasing ATP concentrations up to 4-5 mM increased microsomal Ca2+ accumulation, whereas increasing ATP concentration above 2-3 mM caused inhibition of mitochondrial Ca2+ uptake. Although changing pH from 7.4 to 7.2 had no effect on mitochondrial Ca2+ accumulation, it doubled microsomal uptake. Neither adenosine 3',5'-monophosphate nor guanosine 3',5'-monophosphate in the presence or absence of protein kinase and kinase modulator affected Ca2+ uptake by or phosphorylation of the subcellular fractions. Partially purified protein kinases from umbilical and beef skeletal muscle contained a component(s) distinguishable from the kinase on the basis of its heat stability that enhanced ATP-induced Ca2+ uptake by mitochondrial fractions from the umbilical artery. It is suggested that alterations in Ca2+ sequestration induced by changes in ATP concentration and intracellular pH in mitochondrial and microsomal fractions, respectively, could play a role in the control of arterial patency and closure with changes in PO2.


Furin cleavage of SARS-CoV-2 Spike promotes but is not essential for infection and cell-cell fusion.
Severe Acute Respiratory Syndrome coronavirus 2 (SARS-CoV-2) infects cells by binding to the host cell receptor ACE2 and undergoing virus-host membrane fusion. Fusion is triggered by the protease TMPRSS2, which processes the viral Spike (S) protein to reveal the fusion peptide. SARS-CoV-2 has evolved a multibasic site at the S1-S2 boundary, which is thought to be cleaved by furin in order to prime S protein for TMPRSS2 processing. Here we show that CRISPR-Cas9 knockout of furin reduces, but does not prevent, the production of infectious SARS-CoV-2 virus. Comparing S processing in furin knockout cells to multibasic site mutants reveals that while loss of furin substantially reduces S1-S2 cleavage it does not prevent it. SARS-CoV-2 S protein also mediates cell-cell fusion, potentially allowing virus to spread virion-independently. We show that loss of furin in either donor or acceptor cells reduces, but does not prevent, TMPRSS2-dependent cell-cell fusion, unlike mutation of the multibasic site that completely prevents syncytia formation. Our results show that while furin promotes both SARS-CoV-2 infectivity and cell-cell spread it is not essential, suggesting furin inhibitors may reduce but not abolish viral spread.


API5 confers cancer stem cell-like properties through the FGF2-NANOG axis.
Immune selection drives the evolution of tumor cells toward an immune-resistant and cancer stem cell (CSC)-like phenotype. We reported that apoptosis inhibitor-5 (API5) acts as an immune escape factor, which has a significant role in controlling immune resistance to antigen-specific T cells, but its functional association with CSC-like properties remains largely unknown. In this study, we demonstrated for the first time that API5 confers CSC-like properties, including NANOG expression, the frequency of CD44-positive cells and sphere-forming capacity. Critically, these CSC-like properties mediated by API5 are dependent on FGFR1 signaling, which is triggered by E2F1-dependent FGF2 expression. Furthermore, we uncovered the FGF2-NANOG molecular axis as a downstream component of API5 signaling that is conserved in cervical cancer patients. Finally, we found that the blockade of FGFR signaling is an effective strategy to control API5high human cancer. Thus, our findings reveal a crucial role of API5 in linking immune resistance and CSC-like properties, and provide the rationale for its therapeutic application for the treatment of API5+ refractory tumors.


Using the Value of Information to improve conservation decision making.
Conservation decisions are challenging, not only because they often involve difficult conflicts among outcomes that people value, but because our understanding of the natural world and our effects on it is fraught with uncertainty. Value of Information (VoI) methods provide an approach for understanding and managing uncertainty from the standpoint of the decision maker. These methods are commonly used in other fields (e.g. economics, public health) and are increasingly used in biodiversity conservation. This decision-analytical approach can identify the best management alternative to select where the effectiveness of interventions is uncertain, and can help to decide when to act and when to delay action until after further research. We review the use of VoI in the environmental domain, reflect on the need for greater uptake of VoI, particularly for strategic conservation planning, and suggest promising areas for new research. We also suggest common reporting standards as a means of increasing the leverage of this powerful tool. The environmental science, ecology and biodiversity categories of the Web of Knowledge were searched using the terms 'Value of Information,' 'Expected Value of Perfect Information,' and the abbreviation 'EVPI.' Google Scholar was searched with the same terms, and additionally the terms decision and biology, biodiversity conservation, fish, or ecology. We identified 1225 papers from these searches. Included studies were limited to those that showed an application of VoI in biodiversity conservation rather than simply describing the method. All examples of use of VOI were summarised regarding the application of VoI, the management objectives, the uncertainties, the models used, how the objectives were measured, and the type of VoI. While the use of VoI appears to be on the increase in biodiversity conservation, the reporting of results is highly variable, which can make it difficult to understand the decision context and which uncertainties were considered. Moreover, it was unclear if, and how, the papers informed management and policy interventions, which is why we suggest a range of reporting standards that would aid the use of VoI. The use of VoI in conservation settings is at an early stage. There are opportunities for broader applications, not only for species-focussed management problems, but also for setting local or global research priorities for biodiversity conservation, making funding decisions, or designing or improving protected area networks and management. The long-term benefits of applying VoI methods to biodiversity conservation include a more structured and decision-focused allocation of resources to research.


The use of diagnostic coding in chiropractic practice.
Diagnostic coding has several potential benefits, including improving the feasibility of data collection for research and clinical audits and providing a common language to improve interdisciplinary collaboration. The primary aim of this study was to determine the views and perspectives of chiropractors about diagnostic coding and explore the use of it in a chiropractic setting. A secondary aim was to compare the diagnostic coding undertaken by chiropractors and an independent coder. A codin exercise based on the International Classification of Primary Care version 2, PLUS extension (ICPC-2 PLUS) provided the 14 chiropractors with some experience in diagnostic coding, followed by an interview on the topic. The interviews were analysed thematically. The participating chiropractors and an independent coder applied ICPC-2 PLUS terms to the diagnoses of 10 patients. Then the level of agreement between the chiropractors and the coder was determined and Cohen's Kappa was used to determine the agreement beyond that expected by chance. From the interviews the three emerging themes were: 1) Advantages and disadvantages of using a clinical coding system in chiropractic practice, 2) ICPC-2 PLUS terminology issues for chiropractic practice and 3) Implementation of a coding system into chiropractic practice. The participating chiropractors did not uniformly support or condemn the idea of using diagnostic coding. However there was a strong agreement that the terminology in ICPC-2 PLUS would not be applicable or desirable for all practice types. In the coding exercise the chiropractors in total coded 202 diagnoses for 135 patients. The overall percentage agreement between the chiropractors and the coder was 52% (17% expected by chance) with a Kappa score of 0.4 (95% CI 0.3-0.7). Agreement was lower for more detailed coding (percentage agreement 35%; Kappa score of 0.3 (95% CI 0.2-0.5)). It appears that implementation of diagnostic coding would be possible in the majority of the chiropractic practices that participated in this study. However for those chiropractors who do not focus on symptoms in their approach to clinical care, it could be challenging to use the ICPC-2 PLUS coding system, since ICPC-2 PLUS is a symptom-based classification.


Spawning activity of the Australian lungfish Neoceratodus forsteri in an impoundment.
This study assessed the spawning activity of the threatened Australian lungfish Neoceratodus forsteri by measuring egg densities within the artificial habitat of a large impoundment (Lake Wivenhoe, Australia). Eggs were sampled (August to November 2009) from multiple locations across the impoundment, but occurred at highest densities in water shallower than 40 cm along shorelines with a dense cover of submerged terrestrial vegetation. The numbers of eggs declined over the study period and all samples were dominated by early developmental stages and high proportions of unviable eggs. The quality of the littoral spawning habitats declined over the study as flooded terrestrial grasses decomposed and filamentous algae coverage increased. Water temperatures at the spawning site exhibited extreme variations, ranging over 20·4° C in water shallower than 5 cm. Dissolved oxygen concentrations regularly declined to <1 mg l⁻¹ at 40 and 80 cm water depth. Spawning habitats utilised by N. forsteri within impoundments expose embryos to increased risk of desiccation or excessive submergence through water-level variations, and extremes in temperature and dissolved oxygen concentration that present numerous challenges for successful spawning and recruitment of N. forsteri in large impoundment environments.


Towards more ecologically realistic scenarios of plant uptake modelling for chemicals: PAHs in a small forest.
The importance of plants in the accumulation of organic contaminants from air and soil was recognized to the point that even regulatory predictive approaches now include a vegetation compartment or sub-compartment. However, it has recently been shown that many of such approaches lack ecological realism to properly evaluate the dynamic of air/plant/soil exchange, especially when environmental conditions are subject to sudden variations of meteorological or ecological parameters. This paper focuses on the development of a fully dynamic scenario in which the variability of concentrations of selected chemicals in air and plant leaves was studied weekly and related to the corresponding meteorological and ecological parameters, to the evaluate their influence. To develop scenarios for modelling purposes, two different sampling campaigns were performed to measure temporal variability of: 1) polycyclic aromatic hydrocarbon (PAH) concentrations in air of a clearing and a forest site, as well as in leaves of two broadleaf species and 2) two important leaf and canopy traits, specific leaf area (SLA) and leaf area index (LAI). The aim was to evaluate in detail how the variability of meteorological and ecological parameters (SLA and LAI) can influence the uptake/release of organic contaminants by plants and therefore air concentrations. A principal component analysis demonstrated how both meteorological and ecological parameters jointly influence PAH air concentrations. SLA, LAI, as well as leaf density were showed to change over time and among species and to be directly proportional to leaf/canopy uptake rate. While hazelnut had the higher leaf uptake rate, maple became the most important species when considering the canopy uptake rate due to its higher LAI. Other species specific traits, such as the seasonal variation in production of new leaves and the timing of bud burst, were also shown to influence the uptake rate of PAHs by vegetation.


Developmental Dynamic Analysis of the Excreted Microbiome of Chickens Using Next-Generation Sequencing.
Poultry contamination can be largely attributed to the presence of chicken feces during the production process. Fecal contamination is often found in raw chicken products sold for human consumption. Quantitative analysis of the fecal microbial community of chickens using next-generation sequencing techniques is the focus of this study. Fecal samples were collected from 30 broiler chickens at two time points: days 1 and 35 of development. 454 pyrosequencing was conducted on 16S rRNA extracted from each sample, and microbial population dynamics were investigated using various automated bioinformatics pipelines. Diversity of the microbial community at the genus level increased during the 5-week growth period. Despite this growth, only a few dominant bacteria groups (over 80%) were identified in each fecal sample, with most groups being unique and only a few were shared between samples. Population analysis at the genus level showed that microbial diversity increased with chicken growth and development. Classification and phylogenetic analysis of highly represented microbes (over 1%) clearly showed high levels of sequence similarity between groups such as Firmicutes and Proteobacteria. These results suggest that the chicken fecal excreted microbiome is a dynamic system with a differentiated population structure that harbors a highly restricted number of higher taxa.


Intrusive memories to traumatic footage: the neural basis of their encoding and involuntary recall.
A hallmark symptom after psychological trauma is the presence of intrusive memories. It is unclear why only some moments of trauma become intrusive, and how these memories involuntarily return to mind. Understanding the neural mechanisms involved in the encoding and involuntary recall of intrusive memories may elucidate these questions. Participants (n = 35) underwent functional magnetic resonance imaging (fMRI) while being exposed to traumatic film footage. After film viewing, participants indicated within the scanner, while undergoing fMRI, if they experienced an intrusive memory of the film. Further intrusive memories in daily life were recorded for 7 days. After 7 days, participants completed a recognition memory test. Intrusive memory encoding was captured by comparing activity at the time of viewing 'Intrusive scenes' (scenes recalled involuntarily), 'Control scenes' (scenes never recalled involuntarily) and 'Potential scenes' (scenes recalled involuntarily by others but not that individual). Signal change associated with intrusive memory involuntary recall was modelled using finite impulse response basis functions. We found a widespread pattern of increased activation for Intrusive v. both Potential and Control scenes at encoding. The left inferior frontal gyrus and middle temporal gyrus showed increased activity in Intrusive scenes compared with Potential scenes, but not in Intrusive scenes compared with Control scenes. This pattern of activation persisted when taking recognition memory performance into account. Intrusive memory involuntary recall was characterized by activity in frontal regions, notably the left inferior frontal gyrus. The left inferior frontal gyrus may be implicated in both the encoding and involuntary recall of intrusive memories.


A randomized effectiveness trial of a clinical informatics consult service: impact on evidence-based decision-making and knowledge implementation.
To determine the effectiveness of providing synthesized research evidence to inform patient care practices via an evidence based informatics program, the Clinical Informatics Consult Service (CICS). Consults were randomly assigned to one of two conditions: CICS Provided, in which clinicians received synthesized information from the biomedical literature addressing the consult question or No CICS Provided, in which no information was provided. Outcomes were measured via online post-consult forms that assessed consult purpose, actual and potential impact, satisfaction, time spent searching, and other variables. Two hundred twenty six consults were made during the 19-month study period. Clinicians primarily made requests in order to update themselves (65.0%, 147/226) and were satisfied with the service results (Mean 4.52 of possible 5.0, SD 0.94). Intention to treat (ITT) analyses showed that consults in the CICS Provided condition had a greater actual and potential impact on clinical actions and clinician satisfaction than No CICS consults. Evidence provided by the service primarily impacted the use of a new or different treatment (OR 8.19 95% CI 1.04-64.00). Reasons for no or little impact included a lack of evidence addressing the issue or that the clinician was already implementing the practices indicated by the evidence. Clinical decision-making, particularly regarding treatment issues, was statistically significantly impacted by the service. Programs such as the CICS may provide an effective tool for facilitating the integration of research evidence into the management of complex patient care and may foster clinicians' engagement with the biomedical literature.


Entomotoxicology in burnt bodies: a case of maternal filicide-suicide by fire.
One of the most common methods of maternal filicide is by fire. In this case study, a 40-year-old female and her children were found completely burned in a burnt out car. All bodies showed a degree of destruction by fire consisting to a level 3 of the Crow-Glassman Scale (CGS) and early stage of insect activity. Toxicological analyses were performed on soft tissues and body fluids still available. The results were positive for diazepam and its metabolites only for children with blood concentrations consistent with therapeutic doses of benzodiazepines. Home video surveillance cameras confirmed sedation prior to death recording the mother while administering some drops of sedative drugs in a soft drink to the children just a couple of hours before setting fire to the car. Based on autopsy findings, all victims were still alive at the time of fire. The cause of death was determined as carbon monoxide poisoning and fatal thermal injuries by fire. This case study has a special focus on the entomotoxicology and the potential role of insects in death investigations of burnt bodies, supposed to be an inadequate substratum for insect colonization. It demonstrates that in burnt bodies, arthropod colonization can be quite immediate after fire is extinguished. Toxicological analyses performed on larvae actively feeding on the children's bodies were positive for diazepam and its metabolites in small amount compared with blood concentrations, whereas the larvae collected from the mother's body were totally negative. These data, according to the autopsy findings and the toxicological results from the victim's blood and tissues, supported the suspect of a non-lethal sedation prior to death, which is a common behaviour in maternal filicide.


Factors associated with progression to death in patients with Lassa fever in Nigeria: an observational study.
Lassa fever is endemic in several west African countries. Case-fatality rates ranging from 21% to 69% have been reported. The pathophysiology of the disease in humans and determinants of mortality remain poorly understood. We aimed to determine host protein biomarkers capable of determining disease outcome. In this observational study, we analysed left-over blood samples from patients who tested positive for Lassa fever at Irrua Specialist Teaching Hospital, Nigeria, between January, 2014, and April, 2017. We measured viral load, concentrations of clinical chemistry parameters, and levels of 62 circulating proteins involved in inflammation, immune response, and haemostasis. Patients with a known outcome (survival or death) and at least 200 μL of good-quality diagnostic sample were included in logistic regression modelling to assess the correlation of parameters with Lassa fever outcome. Individuals who gave consent could further be enrolled into a longitudinal analysis to assess the association of parameters with Lassa fever outcome over time. Participants were divided into two datasets for the statistical analysis: a primary dataset (samples taken between Jan 1, 2014, and April 1, 2016), and a secondary dataset (samples taken between April 1, 2016, and April 1, 2017). Biomarkers were ranked by area under the receiver operating characteristic curve (AUC) from highest (most predictive) to lowest (least predictive). Of 554 patients who tested positive for Lassa fever during the study period, 201 (131 in the primary dataset and 70 in the secondary dataset) were included in the biomarker analysis, of whom 74 (49 in the primary dataset and 25 in the secondary dataset) had died and 127 (82 in the primary dataset and 45 in the secondary dataset) had survived. Cycle threshold values (indicating viral load) and levels of 18 host proteins at the time of admission to hospital were significantly correlated with fatal outcome. The best predictors of outcome in both datasets were plasminogen activator inhibitor-1 (PAI-1; AUC 0·878 in the primary dataset and 0·876 in the secondary dataset), soluble thrombomodulin (TM; 0·839 in the primary dataset and 0·875 in the secondary dataset), and soluble tumour necrosis factor receptor superfamily member 1A (TNF-R1; 0·807 in the primary dataset and 0·851 in the secondary dataset), all of which had higher prediction accuracy than viral load (0·774 in the primary dataset and 0·837 in the secondary dataset). Longitudinal analysis (150 patients, of whom 36 died) showed that of the biomarkers that were predictive at admission, PAI-1 levels consistently decreased to normal levels in survivors but not in those who died. The identification of PAI-1 and soluble TM as markers of fatal Lassa fever at admission, and of PAI-1 as a marker of fatal Lassa fever over time, suggests that dysregulated coagulation and fibrinolysis and endothelial damage have roles in the pathophysiology of Lassa fever, providing a mechanistic explanation for the association of Lassa fever with oedema and bleeding. These novel markers might aid in clinical risk stratification and disease monitoring. German Research Foundation, Leibniz Association, and US National Institutes of Health.


Activation of Frataxin Protein Expression by Antisense Oligonucleotides Targeting the Mutant Expanded Repeat.
Friedreich's Ataxia (FA) is an inherited neurologic disorder caused by an expanded GAA repeat within intron 1 of the frataxin (FXN) gene that reduces expression of FXN protein. Agents that increase expression of FXN have the potential to alleviate the disease. We previously reported that duplex RNAs (dsRNAs) and antisense oligonucleotides (ASOs) complementary to the GAA repeat could enhance expression of FXN protein. We now explore the potential of a diverse group of chemically modified dsRNAs and ASOs to define the breadth of repeat-targeted synthetic nucleic acids as a platform for therapeutic development for FA. ASOs and dsRNAs can activate FXN protein expression in FA patient-derived cell lines that possess varied numbers of GAA repeats. Increased FXN protein expression was achieved by ASOs incorporating diverse chemical modifications with low nanomolar potencies, suggesting substantial flexibility in choosing compounds for further chemical optimization and animal studies. Our data encourage further development of ASOs as agents to treat FA.


Prematurity and low birth weight as potential mediators of higher stillbirth risk in mixed black/white race couples.
Although births of multiracial and multiethnic infants are becoming more common in the United States, little is known about birth outcomes and risks for adverse events. We evaluated risk of fetal death for mixed race couples compared with same race couples and examined the role of prematurity and low birth weight as potential mediating risk factors. We performed a retrospective cohort analysis using data from the 1998-2002 California Birth Cohort to evaluate the odds of fetal death, low birth weight, and prematurity for couples with a mother and father who were categorized as either being of same or different racial groups. Risk of prematurity (birth prior to 37 weeks gestation) and low birth weight (<2500 g) were also tested to see if the model could explain variations among groups. The analysis included approximately 1.6 million live births and 1749 stillbirths. In the unadjusted model, compared with two white parents, black/black and black/white couples had a significantly higher risk of fetal death. When all demographic, social, biological, genetic, congenital, and procedural risk factors except gestational age and birth weight were included, the odds ratios (OR) were all still significant. Black/black couples had the highest level of risk (OR 2.11, CI 1.77-2.51), followed by black mother/white father couples (OR 2.01, CI 1.16-3.48), and white mother/black father couples (OR 1.84, CI 1.33-2.54). Virtually all of the higher risk of fetal death was explainable by higher rates of low birth weight and prematurity. Mixed race black and white couples face higher odds of prematurity and low birth weight, which appear to contribute to the substantially higher demonstrated risk for stillbirth. There are likely additional unmeasured factors that influence birth outcomes for mixed race couples.


Neutralization of local toxicity induced by vipera russelli phospholipase A2 by lipophilic derivative of ascorbic acid.
L-ascorbic acid upon condensation with palmitic acid in the presence of sulphuric acid results in L-ascorbic acid-6-palmitate (AP). The effect of L-ascorbic acid derivative, AP on the pharmacological activities of purified basic multi-toxic PLA2 enzyme, VRV-PL-VIIIa from Vipera russelli snake venom along with in vitro activities is described. AP inhibited VRV-PL-VIIIa enzyme activity in a concentration dependent manner with IC50 value of 48.85 μM and the inhibition is found to be independent of substrate and calcium concentration. Upon investigating the in vivo pharmacological activities, it has been found that AP inhibited VRV-PL-VIIIa induced mouse paw edematogenic activity in a dose dependant manner. Intramuscular co-injection of AP with VRV-PL-VIIIa (1:10 w:w) neutralized the VRV-PL-VIIIa induced myotoxocity. Sections of mouse thigh muscle showed normal intact musculature with normal levels of serum creatine kinase and lactate dehydrogenase. Histopathological studies showed that administration of VRV-PL-VIIIa (i.p) along with AP mixture inhibited VRV-PL-VIIIa induced lung haemorrhage in mouse indicated that enzyme activity is responsible for all these observed pathological and pharmacological activities. The biophysical interaction studies showed that AP interacted directly with the enzyme and decreased the relative intrinsic fluorescence intensity. CD spectral analysis showed an apparent shift in the far UV-CD spectra of VRV-PL-VIIIa with AP. Docking study also confirmed the interaction of AP with enzyme directly. These results demonstrate that AP neutralizes VRV-PL-VIIIa induced pharmacological activities by inhibiting the enzyme with direct interactions. This compound along with other inhibitors of snake venom hydrolytic enzymes might be of use to neutralize local toxicity of V. russelli venom where antivenoms have failed.


Neobulgarones A approximately F from cultures of Neobulgaria pura, new inhibitors of appressorium formation of Magnaporthe grisea.
Six new dimeric anthraquinone derivatives, neobulgarones A (3a), B (3b), C (4a), D (4b), E (5a) and F (5b), were isolated from the mycelia of the ascomycete Neobulgaria pura together with the monomeric carviolin (1) and 1-O-methylemodin (2). All new compounds inhibited the formation of appressoria in germinating conidia of Magnaporthe grisea on inductive (hydrophobic) surface. The compounds exhibited moderate cytotoxic, but no antifungal, antibacterial, or phytotoxic activities.


Stereotactic radiosurgery for treatment of radiation-induced meningiomas: a multiinstitutional study.
Radiation-induced meningiomas (RIMs) are associated with aggressive clinical behavior. Stereotactic radiosurgery (SRS) is sometimes considered for selected RIMs. The authors investigated the effectiveness and safety of SRS for the management of RIMs. From 12 institutions participating in the International Radiosurgery Research Foundation, the authors pooled patients who had prior cranial irradiation and were subsequently clinically diagnosed with WHO grade I meningiomas that were managed with SRS. Fifty-two patients underwent 60 SRS procedures for histologically confirmed or radiologically suspected WHO grade I RIMs. The median ages at initial cranial radiation therapy and SRS for RIM were 5.5 years and 39 years, respectively. The most common reasons for cranial radiation therapy were leukemia (21%) and medulloblastoma (17%). There were 39 multiple RIMs (35%), the mean target volume was 8.61 ± 7.80 cm3, and the median prescription dose was 14 Gy. The median imaging follow-up duration was 48 months (range 4-195 months). RIM progressed in 9 patients (17%) at a median duration of 30 months (range 3-45 months) after SRS. Progression-free survival at 5 years post-SRS was 83%. Treatment volume ≥ 5 cm3 predicted progression (HR 8.226, 95% CI 1.028-65.857, p = 0.047). Seven patients (14%) developed new neurological symptoms or experienced SRS-related complications or T2 signal change from 1 to 72 months after SRS. SRS is associated with durable local control of RIMs in the majority of patients and has an acceptable safety profile. SRS can be considered for patients and tumors that are deemed suboptimal, poor surgical candidates, and those whose tumor again progresses after removal.


Engineered bacteria combined with doxorubicin nanoparticles suppress angiogenesis and metastasis in murine melanoma models.
Methods capable of distributing antitumour therapeutics uniformly throughout an entire tumour and that can suppress metastasis at the same time, would be of great significance in improving cancer treatment. Bacteria-mediated synergistic therapies have been explored for better specificity, temporal and spatial controllability, as well for providing regulation of the immune microenvironment, in order to provide improved cancer treatment. To achieve this goal, here we developed an engineered bacteria delivery system (GDOX@HSEc) using synthetic biology and interfacial chemistry technologies. The engineered bacteria were concurrently modified to express heparin sulfatase 1 (HSulf-1) inside (HSEc), to attach doxorubicin-loaded glycogen nanoparticles (GDOX NPs) on their surface. Here we demonstrate that HSEc can actively target and colonise tumour sites resulting in HSulf-1 overexpression, thereby suppressing angiogenesis and metastasis. Simultaneously, the GDOX NPs were able to penetrate into tumour cells, leading to intracellular DNA damage. Our results confirmed that a combination of biotherapy and chemotherapy using GDOX@HSEc resulted in significant melanoma suppression in murine models, with reduced side effects. This study provides a powerful platform for the simultaneous delivery of biomacromolecules and chemotherapeutic drugs to tumours, representing an innovative strategy potentially more effective in treating solid tumours. STATEMENT OF SIGNIFICANCE: An original engineered bacteria-based system (GDOX@HSEc) was developed using synthetic biology and interfacial chemistry technologies to concurrently produce naturally occurring heparin sulfatase 1 (HSulf-1) inside and anchor doxorubicin-loaded glycogen nanoparticles on the surface. GDOX@HSEc allowed for combined local delivery of chemotherapeutic agents along with the enzymes and immunostimulatory bacterial adjuvants, which resulted in a synergistic action in the inhibition of tumour growth and metastasis. The study provides a potential therapeutic approach that allows therapeutic agents to be distributed in a spatiotemporally controllable manner in tumours for combinatorial enhanced therapy.


Addition of rosiglitazone to glimepirid and metformin combination therapy in type 2 diabetes.
The study was planned to determine the efficacy and safety of adding rosiglitazone to a combination of glimepiride and metformin therapy with insufficiently controlled type 2 diabetes. This was an open-label study with a follow-up period of 26 weeks. Thirty patients were taking 3 mg glimepiride two times and 850 mg metformin two times per day. Patients were told to take one rosiglitazone 4 mg tablet before breakfast additionally. The primary efficacy measure was the mean change in HbA1c from baseline to the end of the study. Secondary efficacy parameters included the mean changes from baseline to the end of the study in fasting plasma glucose (FPG) and insulin levels, as well as total cholesterol, HDL-C, LDL-C, triglycerides, alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels. Mean HbA1c levels decreased significantly from 7.54 +/- 0.9% to 6.57 +/- 0.7% (p < 0.001) at 26th week. FPG levels fell from 169.39 +/- 37.8 mg/dl to 135.69 +/- 28.0 mg/dl (p < 0.001), respectively. Insulin levels decreased from 19.60 +/- 9.8 U/L to 14.66 +/- 11.6 U/L (p = 0.026) at 26th week. No one experienced elevations of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels greater than 2.5 times the upper limit of the reference range. This study confirms that the addition of rosiglitazone (4 mg/day) to sulphonylurea and metformin treatment for patients with type 2 diabetes improves glycemic control, is safe, and generally well tolerated.


Across-shelf transport of bivalve larvae: can the interface between a coastal current and inshore waters act as an ecological barrier to larval dispersal?
Using an integrated physical and biological approach, we examined across-shelf advection and exchange and the associated transport of bivalve larvae in the presence of a strong coastal current separated from the coast by a stratified inshore environment. We tested the hypothesis that the interface of the coastal current and inshore waters can act as an ecological barrier to across-shelf transport of larvae but can be overcome by wind- or tidally-induced transport. Our study region in the Gulf of Maine encompasses a coastal current that diverges from the coast as it moves downshelf. The region inshore of this current is home to several species that exhibit limited recruitment in spite of extensive upshelf larval sources. Analysis of surface water temperatures and wind velocities revealed episodic decreases in temperature along the coast correlated with alongshelf (but not upwelling) winds, indicating wind-forced onshore movement of the cold coastal current. Such wind-driven onshore migrations are more common along the northern portion of the study region where the coastal current is near the coast, tidal currents are strong, and wind directions are more conducive to onshore migration, but rarer further south where the interface between inshore waters and the coastal current is further offshore and suitable wind events are less common. The distribution of bivalve larvae was consistent with the physical measurements. There was little across-shelf variation in larval abundance where the current abuts the coast, indicating strong across-shelf exchange of larvae, but strong across-shelf variation in larval density where the stratified inshore waters separate the current from the coast, indicating weak across-shelf transport of larvae. Our results suggest that the interface between the coastal current and inshore waters may constitute a major ecological barrier to larval dispersal in the southern part of the region that may only be overcome by rare, strong wind-forced events.


Development of a cross-over randomized trial method to determine the acceptability and safety of novel ready-to-use therapeutic foods.
To develop a method for determining the acceptability and safety of ready-to-use therapeutic foods (RUTF) before clinical trialing. Acceptability was defined using a combination of three consumption, nine safety, and six preference criteria. These were used to compare a soy/maize/sorghum RUTF (SMS-RUTFh), designed for the rehabilitation of human immunodeficiency virus/tuberculosis (HIV/TB) wasted adults, with a peanut-butter/milk-powder paste (P-RUTF; brand: Plumpy'nut) designed for pediatric treatment. A cross-over, randomized, controlled trial was conducted in Kenya. Ten days of repeated measures of product intake by 41 HIV/TB patients, >18 y old, body mass index (BMI) 18-24 kg · m(-2), 250 g were offered daily under direct observation as a replacement lunch meal. Consumption, comorbidity, and preferences were recorded. The study arms had similar age, sex, marital status, initial BMI, and middle upper-arm circumference. No carryover effect or serious adverse events were found. SMS-RUTFh energy intake was not statistically different from the control, when adjusted for BMI on day 1, and the presence of throat sores. General preference, taste, and sweetness scores were higher for SMS-RUTFh compared to the control (P < 0.05). Most consumption, safety, and preference criteria for SMS-RUTFh were satisfied except for the average number of days of nausea (0.16 versus 0.09 d) and vomiting (0.04 versus 0.02 d), which occurred with a higher frequency (P < 0.05). SMS-RUTFh appears to be acceptable and can be safely clinically trialed, if close monitoring of vomiting and nausea is included. The method reported here is a useful and feasible approach for testing the acceptability of ready-to-use foods in low income countries.


Patient-reported 1-year outcome not affected by body mass index in 3,327 total knee arthroplasty patients.
Background and purpose - Patient-reported outcome (PRO) in total knee arthroplasty (TKA) patients with high body mass index (BMI) is controversial. We compared pain, function, quality of life, general health, and satisfaction among different BMI categories preoperatively and 1 year after primary TKA. Patients and methods - 4,318 patients were operated with a TKA for knee osteoarthritis in the Region of Skane in 2013-2015. In all, 3,327 patients (77%) had complete PRO data and information on BMI and were included. Preoperatively the patients filled in the Knee injury and Osteoarthritis Outcome Score (KOOS) and EQ-VAS (general health). 1 year postoperatively the same questionnaires were filled in together with a question asking whether they were satisfied with the surgery. Information on age, sex, BMI, and ASA grade were obtained from the Swedish Knee Arthroplasty Register. Each patient was classified as Outcome Measures in Rheumatology- Osteoarthritis Research Society International (OMERACT-OARSI) responder or not based on a combination of absolute and relative changes in scores. Welch's t-test and a chi-square test were used in the statistical analysis. Results - Both preoperatively and 1 year postoperatively the obese patients reported somewhat worse scores than the normal weight and overweight. The differences were small with 1 exception, the KOOS sport- and recreation function postoperatively, where normal-weight and overweight patients reported fewer problems than obese patients with a BMI over 35 (40 and 39 points vs. 31 points, p < 0.001). Similar proportions of patients were satisfied and categorized as OMERACT-OARSI responders in the different BMI categories. Interpretation - The degree of improvement in PROs 1 year after TKA surgery does not seem to be affected by BMI.


Incidence, predisposing factors, management and survival following cardiac arrest due to subarachnoid haemorrhage: a review of the literature.
The prevalence of cardiac arrest among patients with subarachnoid haemorrhage [SAH], and the prevalence of SAH as the cause following out-of-hospital cardiac arrest [OHCA] or in-hospital cardiac arrest [IHCA] is unknown. In addition it is unclear whether cardiopulmonary resuscitation [CPR] and post-resuscitation care management differs, and to what extent this will lead to meaningful survival following cardiac arrest [CA] due to SAH. We reviewed the literature in order to describe; 1.The prevalence and predisposing factors of CA among patients with SAH 2.The prevalence of SAH as the cause of OHCA or IHCA and factors characterising CPR 3.The survival and management of SAH patients with CA. The following sources, PubMed, CinAHL and The Cochrane DataBase were searched using the following Medical Subheadings [MeSH]; 1. OHCA, IHCA, heart arrest and 2. subarachnoid haemorrhage. Articles containing relevant data based on the abstract were reviewed in order to find results relevant to the proposed research questions. Manuscripts in other languages than English, animal studies, reviews and case reports were excluded. A total of 119 publications were screened for relevance and 13 papers were included. The prevalence of cardiac or respiratory arrest among all patients with SAH is between 3-11%, these patients commonly have a severe SAH with coma, large bleeds and evidence of raised intracerebral pressure on computed tomography scans compared to those who did not experience a CA. The prevalence of patients with SAH as the cause of the arrest among OHCA cases vary between 4 to 8% among those who die before hospital admission, and between 4 to 18% among those who are admitted. The prevalence of SAH as the cause following IHCA is low, around 0.5% according to one recent study. In patients with OHCA survival to hospital discharge is poor with 0 to 2% surviving. The initial rhythm is commonly asystole or pulseless electrical tachycardia. In IHCA the survival rate is variable with 0-27% surviving. All survivors experience brief cardiac arrests with short latencies to ROSC. Cardiac arrest is a fairly common complication following severe SAH and these patients are encountered both in the pre-hospital and in-hospital setting. Survival is possible if the arrest occurs in the hospital and the latency to ROSC is short. In OHCA the outcome seems to be uniformly poor despite initially successful resuscitation.


Ageing induced vascular smooth muscle cell senescence in atherosclerosis.
Atherosclerosis is a disease of ageing in that its incidence and prevalence increase with age. However, atherosclerosis is also associated with biological ageing, manifest by a number of typical hallmarks of ageing in the atherosclerotic plaque. Thus, accelerated biological ageing may be superimposed on the effects of chronological ageing in atherosclerosis. Tissue ageing is seen in all cells that comprise the plaque, but particularly in vascular smooth muscle cells (VSMCs). Hallmarks of ageing include evidence of cell senescence, DNA damage (including telomere attrition), mitochondrial dysfunction, a pro-inflammatory secretory phenotype, defects in proteostasis, epigenetic changes, deregulated nutrient sensing, and exhaustion of progenitor cells. In this model, initial damage to DNA (genomic, telomeric, mitochondrial and epigenetic changes) results in a number of cellular responses (cellular senescence, deregulated nutrient sensing and defects in proteostasis). Ultimately, ongoing damage and attempts at repair by continued proliferation overwhelm reparative capacity, causing loss of specialised cell functions, cell death and inflammation. This review summarises the evidence for accelerated biological ageing in atherosclerosis, the functional consequences of cell ageing on cells comprising the plaque, and the causal role that VSMC senescence plays in atherogenesis.


Dietary predictors of plasma total homocysteine in the Hordaland Homocysteine Study.
Established dietary predictors of plasma total homocysteine (tHcy) include folate, riboflavin, and vitamins B6 and B12, while information is scarce regarding other dietary components. The aim of this study was to examine the relation between a variety of food groups, food items and nutrients, and plasma tHcy in a large population-based study. The study population included 5812 men and women aged 47-49 and 71-74 years who completed a 169-item FFQ. tHcy was examined across quartiles of dietary components by multiple linear regression analyses adjusting for age, sex, energy intake, various risk factors for elevated tHcy, as well as for dietary and plasma B-vitamins. Among 4578 non-users of vitamin supplements, intake of vegetables, fruits, cereals, eggs, fish and milk, as well as chicken and non-processed meats were inversely associated with tHcy level. The estimated mean difference in tHcy per increasing quartile of intake ranged from - 0.11 (95 % CI - 0.21, - 0.01) micromol/l for milk to - 0.32 (95 % CI - 0.42, - 0.22) micromol/l for vegetables. Positive associations were found for sweets and cakes. Whole-grain bread was significantly inversely related to tHcy only after additional adjustment for dietary and plasma B-vitamins. The nutrients folate, vitamin B6, B12, and riboflavin were inversely related to tHcy. Complex carbohydrates were inversely, and fat positively associated with tHcy, also after adjustment for dietary and plasma B-vitamins. In conclusion, food items rich in B-vitamins and with a low content of fat and sugar were related to lower tHcy levels. Eggs, chicken, non-processed meat, fish and milk were inversely associated with tHcy.


[Estrogenic effects after 14-days administration of 0.06 mg ethinyl estradiol in postmenopausal women].
The effect of a 26 day oestrogen-gestogene sequence therapy on double endometrium thickness, uterus size, blood flow in the uterine blood vessels (pulsatility and resistance index), serum concentration of FSH, LH and SHBG and on vaginal cytology of postmenopausal women was tested double-blind in a placebo-controlled trial. Thirteen postmenopausal women received 0.06 mg ethinyloestradiol (EE2) over 14 days and then a 12 day combination treatment with 0.04 mg EE2 and 0.125 mg levonorgestrel. Eight women received placebo treatment over 26 days. In each group, half the women were less, and half were more than 10 years postmenopausal. The above parameters were unchanged in the placebo group. However, in the verum group, the double endometrium thickness increased from 2 mm to about 6 mm after a 7 day treatment with EE2 and after a further treatment week with EE2, increased another millimeter. There was no obvious difference in the treatment groups between women less than ten years after menopause or more than ten years after menopause. Blood flow in the uterine artery increased significantly (decrease in pulsatility and resistance index by about 50%). Again, there did not seem to be any obvious connection with the menopausal interval. FSH decreased after the first treatment week by about 50% and 65% after the second treatment week. There was no significant decrease in LH. SHBG increased by about a factor of 5. An oestrogen effect could be demonstrated in the vaginal cytology of all cases in the verum group.


What we think before a voluntary movement.
A central feature of voluntary movement is the sense of volition, but when this sense arises in the course of movement formulation and execution is not clear. Many studies have explored how the brain might be actively preparing movement before the sense of volition; however, because the timing of the sense of volition has depended on subjective and retrospective judgments, these findings are still regarded with a degree of scepticism. EEG events such as beta event-related desynchronization and movement-related cortical potentials are associated with the brain's programming of movement. Using an optimized EEG signal derived from multiple variables, we were able to make real-time predictions of movements in advance of their occurrence with a low false-positive rate. We asked participants what they were thinking at the time of prediction: Sometimes they were thinking about movement, and other times they were not. Our results indicate that the brain can be preparing to make voluntary movements while participants are thinking about something else.


Natural hypothalamic circuit dynamics underlying object memorization.
Brain signals that govern memory formation remain incompletely identified. The hypothalamus is implicated in memory disorders, but how its rapidly changing activity shapes memorization is unknown. During encounters with objects, hypothalamic melanin-concentrating hormone (MCH) neurons emit brief signals that reflect object novelty. Here we show that targeted optogenetic silencing of these signals, performed selectively during the initial object encounters (i.e. memory acquisition), prevents future recognition of the objects. We identify an upstream inhibitory microcircuit from hypothalamic GAD65 neurons to MCH neurons, which constrains the memory-promoting MCH cell bursts. Finally, we demonstrate that silencing the GAD65 cells during object memory acquisition improves future object recognition through MCH-receptor-dependent pathways. These results provide causal evidence that object-associated signals in genetically distinct but interconnected hypothalamic neurons differentially control whether the brain forms object memories. This gating of memory formation by hypothalamic activity establishes appropriate behavioral responses to novel and familiar objects.


Parents' employment and children's wellbeing.
Since modern welfare reform began in the 1980s, we have seen low-income parents leave the welfare rolls and join the workforce in large numbers. At the same time, the Earned Income Tax Credit has offered a monetary incentive for low-income parents to work. Thus, unlike some of the other two-generation mechanisms discussed in this issue of Future of Children, policies that encourage low-income parents to work are both widespread and well-entrenched in the United States. But parents' (and especially mothers') work, writes Carolyn Heinrich, is not unambiguously beneficial for their children. On the one hand, working parents can be positive role models for their children, and, of course, the income they earn can improve their children's lives in many ways. On the other hand, work can impair the developing bond between parents and young children, especially when the parents work long hours or evening and night shifts. The stress that parents bring home from their jobs can detract from their parenting skills, undermine the atmosphere in the home, and thereby introduce stress into children's lives. Unfortunately, it is low-income parents who are most likely to work in stressful, low-quality jobs that feature low pay, little autonomy, inflexible hours, and few or no benefits. And low-income children whose parents are working are more likely to be placed in inadequate child care or to go unsupervised. Two-generation approaches, Heinrich writes, could maximize the benefits and minimize the detriments of parents' work by expanding workplace flexibility, and especially by mandating enough paid leave so that mothers can breastfeed and form close bonds with their infants; by helping parents place their children in high-quality child care; and by helping low-income parents train for, find, and keep a well-paying job with benefits.


Effect of Live Poultry Market Interventions on Influenza A(H7N9) Virus, Guangdong, China.
Since March 2013, three waves of human infection with avian influenza A(H7N9) virus have been detected in China. To investigate virus transmission within and across epidemic waves, we used surveillance data and whole-genome analysis of viruses sampled in Guangdong during 2013-2015. We observed a geographic shift of human A(H7N9) infections from the second to the third waves. Live poultry market interventions were undertaken in epicenter cities; however, spatial phylogenetic analysis indicated that the third-wave outbreaks in central Guangdong most likely resulted from local virus persistence rather than introduction from elsewhere. Although the number of clinical cases in humans declined by 35% from the second to the third waves, the genetic diversity of third-wave viruses in Guangdong increased. Our results highlight the epidemic risk to a region reporting comparatively few A(H7N9) cases. Moreover, our results suggest that live-poultry market interventions cannot completely halt A(H7N9) virus persistence and dissemination.


Cultural connection and transformation: substance abuse treatment at Friendship House.
This research investigates the transformational experiences of Native Americans during the course of their retraditionalization and treatment for drug and alcohol dependence. Twelve graduates of the residential treatment program at Friendship House in San Francisco were interviewed about the kind and quality of their healing experiences in this particular program which provides a comprehensive matrix of Native American medicine as well as Western models of psychological treatment. The purpose of this study was to understand and document the experience of substance abuse recovery from the perspective of the Native Americans in treatment. Twelve themes emerged from the data analysis: feeling cared for; spiritual experience; insight; making a commitment; empowerment/self-esteem; releasing emotional pain; remorse; reconnecting to traditional values; forgiveness; relief; safety; and gratitude.


Molecular remodeling of ion channels, exchangers and pumps in atrial and ventricular myocytes in ischemic cardiomyopathy.
Existing molecular knowledge base of cardiovascular diseases is rudimentary because of lack of specific attribution to cell type and function. The aim of this study was to investigate cell-specific molecular remodeling in human atrial and ventricular myocytes associated with ischemic cardiomyopathy. Our strategy combines two technological innovations, laser-capture microdissection of identified cardiac cells in selected anatomical regions of the heart and splice microarray of a narrow catalog of the functionally most important genes regulating ion homeostasis. We focused on expression of a principal family of genes coding for ion channels, exchangers and pumps (CE&P genes) that are involved in electrical, mechanical and signaling functions of the heart and constitute the most utilized drug targets. We found that (1) CE&P genes remodel in a cell-specific manner: ischemic cardiomyopathy affected 63 CE&P genes in ventricular myocytes and 12 essentially different genes in atrial myocytes. (2) Only few of the identified CE&P genes were previously linked to human cardiac disfunctions. (3) The ischemia-affected CE&P genes include nuclear chloride channels, adrenoceptors, cyclic nucleotide-gated channels, auxiliary subunits of Na(+), K(+) and Ca(2+) channels, and cell-surface CE&Ps. (4) In both atrial and ventricular myocytes ischemic cardiomyopathy reduced expression of CACNG7 and induced overexpression of FXYD1, the gene crucial for Na(+) and K(+) homeostasis. Thus, our cell-specific molecular profiling defined new landmarks for correct molecular modeling of ischemic cardiomyopathy and development of underlying targeted therapies.


Scavenger function of resident autofluorescent perivascular macrophages and their contribution to the maintenance of the blood-retinal barrier.
The retina contains two distinct populations of monocyte-derived cells: perivascular macrophages, and microglia. The present study was undertaken to evaluate the presence and function in mouse and human retinas of a subtype of resident perivascular macrophages with scavenger function, different from microglia, in physiological conditions and during retinopathy. Perivascular macrophages were characterized by means of confocal microscopy, electron microscopy, and flow cytometry analyses. Two murine models of blood-retinal barrier breakdown and photoreceptor degeneration were used to analyze the role of these macrophages during retinopathy. The macrophages analyzed constituted a small population of resident perivascular cells different from microglia, since they were Iba-1 negative. Although these cells expressed F4/80 and CD11b antigens in common with microglia, they also expressed BM8 and MOMA-2 epitopes, which are macrophagic markers not expressed by microglia. Perivascular macrophages emitted autofluorescence due to cytoplasmic inclusions containing protein-bound oxidized lipids. They constitutively expressed the scavenger receptor class A and moved along blood vessels, providing an additional coating to thinner areas of the basement membrane. Moreover, they accumulated blood-borne horseradish peroxidase and acetylated low-density lipoprotein in healthy retinas. In addition, during blood-retinal barrier breakdown and photoreceptor degeneration, these cells migrated to the lesion site. All these morphologic and functional features are consistent with those described for brain Mato cells. Thus, this study showed the presence of autofluorescent perivascular macrophages, different from microglia, with a scavenger function that may contribute to the maintenance of the blood-retinal barrier in healthy conditions and that are also involved in retinopathy.


Fetal cortical surface atlas parcellation based on growth patterns.
Defining anatomically and functionally meaningful parcellation maps on cortical surface atlases is of great importance in surface-based neuroimaging analysis. The conventional cortical parcellation maps are typically defined based on anatomical cortical folding landmarks in adult surface atlases. However, they are not suitable for fetal brain studies, due to dramatic differences in brain size, shape, and properties between adults and fetuses. To address this issue, we propose a novel data-driven method for parcellation of fetal cortical surface atlases into distinct regions based on the dynamic "growth patterns" of cortical properties (e.g., surface area) from a population of fetuses. Our motivation is that the growth patterns of cortical properties indicate the underlying rapid changes of microstructures, which determine the molecular and functional principles of the cortex. Thus, growth patterns are well suitable for defining distinct cortical regions in development, structure, and function. To comprehensively capture the similarities of cortical growth patterns among vertices, we construct two complementary similarity matrices. One is directly based on the growth trajectories of vertices, and the other is based on the correlation profiles of vertices' growth trajectories in relation to a set of reference points. Then, we nonlinearly fuse these two similarity matrices into a single one, which can better capture both their common and complementary information than by simply averaging them. Finally, based on this fused similarity matrix, we perform spectral clustering to divide the fetal cortical surface atlases into distinct regions. By applying our method on 25 normal fetuses from 26 to 29 gestational weeks, we construct age-specific fetal cortical surface atlases equipped with biologically meaningful parcellation maps based on cortical growth patterns. Importantly, our generated parcellation maps reveal spatially contiguous, hierarchical and bilaterally relatively symmetric patterns of fetal cortical surface development.


A comparison of algorithms for inference and learning in probabilistic graphical models.
Research into methods for reasoning under uncertainty is currently one of the most exciting areas of artificial intelligence, largely because it has recently become possible to record, store, and process large amounts of data. While impressive achievements have been made in pattern classification problems such as handwritten character recognition, face detection, speaker identification, and prediction of gene function, it is even more exciting that researchers are on the verge of introducing systems that can perform large-scale combinatorial analyses of data, decomposing the data into interacting components. For example, computational methods for automatic scene analysis are now emerging in the computer vision community. These methods decompose an input image into its constituent objects, lighting conditions, motion patterns, etc. Two of the main challenges are finding effective representations and models in specific applications and finding efficient algorithms for inference and learning in these models. In this paper, we advocate the use of graph-based probability models and their associated inference and learning algorithms. We review exact techniques and various approximate, computationally efficient techniques, including iterated conditional modes, the expectation maximization (EM) algorithm, Gibbs sampling, the mean field method, variational techniques, structured variational techniques and the sum-product algorithm ("loopy" belief propagation). We describe how each technique can be applied in a vision model of multiple, occluding objects and contrast the behaviors and performances of the techniques using a unifying cost function, free energy.


Perceived versus actual distance to local physical-activity facilities: does it really matter?
Research in adults shows poor agreement between self-reported and objectively measured proximity to physical activity resources; however there is little such research in adolescents. This study assessed the level of agreement between self-reported and objective measures of distance to physical activity resources in adolescents; and whether perceived or actual distance was related to actual use and physical activity levels. 110 New Zealand high school students (12-18 years) were asked the time (in minutes) it would take them to walk from their home to the nearest physical activity resource, and whether they had used it in the previous month. The distance from participants' homes to the nearest resource was measured using GIS. Physical activity was assessed with accelerometers. Agreement was poor, with weighted Kappa Indices ranging from 0.1 to 0.4. The facilities used most frequently were schools (90%), public parks (76%), and playing fields (74%). Closer location was associated with higher use of some facilities only. Moderate-to-vigorous activity levels were not associated with self-reported or measured distance. Agreement between perceived and measured access is poor among adolescents. Further research is needed to understand how individual and social factors interact with environmental factors and whether improving awareness improves use.


Mortality among substance-using mothers in California: a 10-year prospective study.
To examine mortality rates and causes of death among a cohort of substance-using mothers and to identify risk factors that predict mortality. This is a prospective study of a cohort of 4447 substance-using mothers (pregnant or parenting) who were enrolled during 2000-02 in 40 drug abuse treatment programs across California. All mothers were assessed at baseline using the Addiction Severity Index. Mortality data were obtained from the National Death Index and causes of death were coded using ICD-10. Standardized mortality ratios (SMR) were calculated relative to women in the general population adjusted for age. Proportional hazard (Cox) regression was used to identify risk factors predicting death. At the end of 2010, 194 deaths were confirmed, corresponding to a crude mortality rate of 4.47 per 1000 person-years and SMR of 8.4 (95% confidence interval: 7.2-9.6). Drug overdose (28.8%), cardiovascular disease (10%), and alcohol or drug disorders (8.9%) were the leading causes of death. Baseline factors associated with higher mortality included older age, being white (relative to African American or Hispanic), heroin, alcohol, cocaine or marijuana (relative to methamphetamine) as the primary drug problem, drug injection and greater severity of employment, medical/health and psychiatric problems. Substance-using mothers have 8.4 times the mortality than that observed among US women of similar age. Greater severity of employment, medical/health and psychiatric problems contributed to the elevated mortality.


Alternative Design for Anterolateral Thigh Multi-Paddled Flaps: The 3-5 System.
BACKGROUND The design and harvest of the anterolateral thigh (ALT) multi-paddled flap is a critical step in reconstructive surgeries. However, limited perforator distribution patterns of traditional design methods have gradually emerged in clinical practice. The aim of this study was to investigate the effect of a new technique (the 3-5 system) on ALT multi-paddled flap design. MATERIAL AND METHODS A total of 151 ALT flaps were harvested from 149 patients over a 26-month period. Among them, 100 ALT flaps were examined preoperatively using a handheld Doppler device to localize vascular perforators. RESULTS By detecting perforator penetration points through the vastus lateral muscle (VLM) or the intermuscular septum and perforator entry points to the deep fascia, precise ALT flap perforator distribution patterns were found. Meanwhile, a 3-5 system was developed to design ALT flaps based on these findings. The remaining 51 ALT flaps from 49 patients during a 9-month period did not require the use of preoperative handheld Doppler. In addition, preoperative handheld Doppler and intraoperative findings demonstrated that all ALT flap penetration points through the VLM or intermuscular septum and the perforator entry point in the deep fascia were closely related based on 3 longitudinal lines and 5 horizontal lines. CONCLUSIONS ALT flaps were successfully harvested using a 3-5 system without the need for preoperative handheld Doppler analysis. Moreover, the 3-5 system is a simple and practical approach for preoperative ALT multi-paddled flap design.


Molecular fractionation with conjugated caps density matrix with pairwise interaction correction for protein energy calculation.
Pairwise interaction correction (PIC) is introduced to account for electron density polarization due to short-range interactions such as hydrogen bonding and close contact between molecular fragments in the molecular fractionation with conjugated caps density matrix (MFCC-DM) approach for energy calculation of protein and other polymers [Chen et al., J. Chem. Phys. 122, 184105 (2005)]. With this PIC, the accuracy of the calculated protein energy and other electronic properties are improved, and the MFCC approach can be applied to study real proteins with short-range structural complexity. In the present MFCC-DM-PIC approach, the short-range interresidual interactions are represented by a pair of small molecules (interacting units) which are made from the two residues that fall within a certain distance criterion. The density matrices of fragments, concaps, interacting units and pairs are calculated by conventional Hartree-Fock or density functional theory methods and are combined to construct the full density matrix which is finally employed to calculate the total energy, electron density, electrostatic potential, dipole moment, etc., of the protein. Numerical tests on seven conformationally varied peptides are presented to demonstrate the accuracy of the MFCC-DM-PIC method.


Cow's milk proteins in human milk.
Cow's milk proteins (CMPs) are among the best characterized food allergens. Cow's milk contains more than twenty five different proteins, but only whey proteins alpha-lactalbumin, beta-lactoglobulin, bovine serum albumin (BSA), and lactoferrin, as well as the four caseins, have been identified as allergens. Aim of this study was to investigate by proteomics techniques cow's milk allergens in human colostrum of term and preterm newborns' mothers, not previously detected, in order to understand if such allergens could be cause of sensitization during lactation. Term colostrum samples from 62 healthy mothers and preterm colostrum samples from 11 healthy mothers were collected for this purpose. The most relevant finding was the detection of the intact bovine alpha-S1-casein in both term and preterm colostrum. Using this method, which allows direct proteins identification, beta-lactoglobulin was not detected in any of colostrum samples. According to our results bovine alpha 1 casein that is considered a major cow's milk allergen is readily secreted in human milk: further investigations are needed in order to clarify if alpha-1-casein has a major role in sensitization or tolerance to cow's milk of exclusively breastfed predisposed infants.


Application of Virtual Three-Dimensional Models for Simultaneous Visualization of Intracardiac Anatomic Relationships in Double Outlet Right Ventricle.
Our goal was to construct three-dimensional (3D) virtual models to allow simultaneous visualization of the ventricles, ventricular septal defect (VSD) and great arteries in patients with complex intracardiac anatomy to aid in surgical planning. We also sought to correlate measurements from the source cardiac magnetic resonance (CMR) image dataset and the 3D model. Complicated ventriculo-arterial relationships in patients with complex conotruncal malformations make preoperative assessment of possible repair pathways difficult. Patients were chosen with double outlet right ventricle for the complexity of intracardiac anatomy and potential for better delineation of anatomic spatial relationships. Virtual 3D models were generated from CMR 3D datasets. Measurements were made on the source CMR as well as the 3D model for the following structures: aortic diameter in orthogonal planes, VSD diameter in orthogonal planes and long axis of right ventricle. A total of six patients were identified for inclusion. The path from the ventricles to each respective outflow tract and the location of the VSD with respect to each great vessel was visualized clearly in all patients. Measurements on the virtual model showed excellent correlation with the source CMR when all measurements were included by Pearson coefficient, r = 0.99 as well as for each individual structure. Construction of virtual 3D models in patients with complex conotruncal defects from 3D CMR datasets allows for simultaneous visualization of anatomic relationships relevant for surgical repair. The availability of these models may allow for a more informed preoperative evaluation in these patients.


Deep UV resonant Raman spectroscopy for photodamage characterization in cells.
We employed deep UV (DUV) Raman spectroscopy for characterization of molecular photodamage in cells. 244 nm light excitation Raman spectra were measured for HeLa cells exposed to the excitation light for different durations. In the spectra obtained with the shortest exposure duration (0.25 sec at 16 µW/µm(2) irradiation), characteristic resonant Raman bands of adenine and guanine at 1483 cm(-1) and tryptophan and tyrosine at 1618 cm(-1) were clearly visible. With increasing exposure duration (up to 12.5 sec), these biomolecular Raman bands diminished, while a photoproduct Raman band at 1611 cm(-1) grew. By exponential function fitting analyses, intensities of these characteristic three bands were correlated with sample exposure duration at different intensities of excitation light. We then suggest practical excitation conditions effective for DUV Raman observation of cells without photodamage-related spectral distortion.


Improving the efficiency and relevance of evidence-based recommendations in the era of whole-genome sequencing: an EGAPP methods update.
To provide an update on recent revisions to Evaluation of Genomic Applications in Practice and Prevention (EGAPP) methods designed to improve efficiency, and an assessment of the implications of whole genome sequencing for evidence-based recommendation development. Improvements to the EGAPP approach include automated searches for horizon scanning, a quantitative ranking process for topic prioritization, and the development of a staged evidence review and evaluation process. The staged process entails (i) triaging tests with minimal evidence of clinical validity, (ii) using and updating existing reviews, (iii) evaluating clinical validity prior to analytic validity or clinical utility, (iv) using decision modeling to assess potential clinical utility when direct evidence is not available. EGAPP experience to date suggests the following approaches will be critical for the development of evidence based recommendations in the whole genome sequencing era: (i) use of triage approaches and frameworks to improve efficiency, (ii) development of evidence thresholds that consider the value of further research, (iii) incorporation of patient preferences, and (iv) engagement of diverse stakeholders. The rapid advances in genomics present a significant challenge to traditional evidence based medicine, but also an opportunity for innovative approaches to recommendation development.


Dietary energy density in young children across Europe.
To describe energy density (ED; kcal g(-1)) of dietary intake of European children. From 16, 228 children who participated in the IDEFICS (Identification and prevention of Dietary- and lifestyle-induced health EFfects In Children and infantS) baseline examination, 8551 children with 24-h dietary recalls (24-HDR), with plausible reported energy intakes and complete covariate information were included in the present analysis. ED was calculated using two methods: (1) ED including solid foods (EDF) and (2) ED including solid foods and energy-containing beverages (EDF&B). Beverage energy was calculated in kcal per day. Dietary characteristics and body mass index (BMI) z-score of children aged 2 to <6 years and 6 to <10 years were compared between children with an overall EDF below the <25th percentile, between the 25th and 75th percentile as well as above the >75th percentile. Standardised regression coefficients were estimated to assess the association between dietary characteristics, BMI z-score and ED of the diet. Children with low EDF and EDF&B diets consumed less energy but higher quantity of food and beverages than children with high EDF and EDF&B diets. Consumption of caloric beverages decreased with increasing EDF&B of the diet owing to the relatively low ED of the beverages, in relation to solid foods. Generally, children with low EDF and EDF&B diets showed healthier food choices than peers with higher EDF and EDF&B diets. In this sample, EDF and EDF&B were not associated with BMI z-score. Health promotion strategies should proclaim lower ED diets by means of foods with high water and low fat content and mainly fruit and vegetable components. Excluding caloric beverages from EDF calculation is a useful method to avoid misinterpretation of true exposure to a high energy dense diet. We recommend excluding caloric beverages from EDF calculation when investigating the effect of ED on a certain (health) outcome.


Successful vaccination strategies that protect aged mice from lethal challenge from influenza virus and heterologous severe acute respiratory syndrome coronavirus.
Newly emerging viruses often circulate as a heterogeneous swarm in wild animal reservoirs prior to their emergence in humans, and their antigenic identities are often unknown until an outbreak situation. The newly emerging severe acute respiratory syndrome coronavirus (SARS-CoV) and reemerging influenza virus cause disproportionate disease in the aged, who are also notoriously difficult to successfully vaccinate, likely due to immunosenescence. To protect against future emerging strains, vaccine platforms should induce broad cross-reactive immunity that is sufficient to protect from homologous and heterologous challenge in all ages. From initial studies, we hypothesized that attenuated Venezuelan equine encephalitis virus (VEE) replicon particle (VRP) vaccine glycoproteins mediated vaccine failure in the aged. We then compared the efficacies of vaccines bearing attenuated (VRP(3014)) or wild-type VEE glycoproteins (VRP(3000)) in young and aged mice within novel models of severe SARS-CoV pathogenesis. Aged animals receiving VRP(3000)-based vaccines were protected from SARS-CoV disease, while animals receiving the VRP(3014)-based vaccines were not. The superior protection for the aged observed with VRP(3000)-based vaccines was confirmed in a lethal influenza virus challenge model. While the VRP(3000) vaccine's immune responses in the aged were sufficient to protect against lethal homologous and heterologous challenge, our data suggest that innate defects within the VRP(3014) platform mediate vaccine failure. Exploration into the mechanism(s) of successful vaccination in the immunosenescent should aid in the development of successful vaccine strategies for other viral diseases disproportionately affecting the elderly, like West Nile virus, influenza virus, norovirus, or other emerging viruses of the future.


Control of exciton fluxes in an excitonic integrated circuit.
Efficient signal communication uses photons. Signal processing, however, uses an optically inactive medium, electrons. Therefore, an interconnection between electronic signal processing and optical communication is required at the integrated circuit level. We demonstrated control of exciton fluxes in an excitonic integrated circuit. The circuit consists of three exciton optoelectronic transistors and performs operations with exciton fluxes, such as directional switching and merging. Photons transform into excitons at the circuit input, and the excitons transform into photons at the circuit output. The exciton flux from the input to the output is controlled by a pattern of the electrode voltages. The direct coupling of photons, used in communication, to excitons, used as the device-operation medium, may lead to the development of efficient exciton-based optoelectronic devices.


Contributions of symptomatic osteoarthritis and physical function to incident cardiovascular disease.
Osteoarthritis (OA) is associated with worsening physical function and a high prevalence of comorbid health conditions. In particular, cardiovascular disease (CVD) risk is higher in individuals with OA than the general population. Limitations in physical function may be one pathway to the development of CVD among individuals with OA. This study evaluated associations of symptomatic knee OA (sxKOA), baseline physical function and worsening of function over time with self-reported incident CVD in a community-based cohort. Our sample consisted of individuals from the Johnston County Osteoarthritis Project who did not report having CVD at baseline. Variables used to evaluate physical function were the Health Assessment Questionnaire (HAQ), time to complete 5 chair stands, and the 8-ft walk. Worsening function for these variables was defined based on previous literature and cutoffs from our sample. Logistic regression analyses examined associations of sxKOA, baseline function and worsening of function over time with self-reported incident CVD, unadjusted and adjusted for relevant demographic and clinical characteristics. Among 1709 participants included in these analyses, the mean age was 59.5 ± 9.5 years, 63.6% were women, 15% had sxKOA, and the follow up time was 5.9 ± 1.2 years. About a third of participants reported worsening HAQ score, about two-fifths had worsened chair stand time, half had worsened walking speed during the 8-ft walk, and 16% self-reported incident CVD. In unadjusted analyses, sxKOA, baseline function, and worsening function were all associated with self-reported incident CVD. In multivariable models including all of these variables, sxKOA was not associated with incident CVD, but worsening function was significantly associated with increased CVD risk, for all three functional measures: HAQ odds ratio (OR) = 2.49 (95% confidence interval (CI) 1.90-3.25), chair stands OR = 1.58 (95% CI 1.20-2.08), 8-ft walk OR = 1.53 (95%CI 1.15-2.04). These associations for worsening function remained in models additionally adjusted for demographic and clinical characteristics related to CVD risk. The association between symptomatic knee osteoarthritis and cardiovascular disease risk was explained by measures of physical function. This highlights the importance of physical activity and other strategies to prevent functional loss among individuals with symptomatic knee osteoarthritis.


Effect of work glove and type of muscle action on grip fatigue.
Fatigue plays a major role in limiting work performance. The objectives of this study were: (1) to determine the effect of wearing a work glove on handgrip fatigue; (2) to compare the effect of a sustained grip contraction of concentric versus eccentric nature, named in this study isometric and eccentric; and (3) to determine if there is a relationship between physiological muscle performance and subjective perceptional fatigue during isometric and eccentric gripping. The study had 2 x 2 repeated measures design. The two factors were: (1) glove condition (glove, no glove); and (2) type of contraction (eccentric and isometric). The measurements taken were: (1) time to limit of endurance (Tlim); (2) rate of perceived effort (RPE); (3) mean power frequency (MPF) derived from the electromyogram (EMG); and (4) the fatigue objective-subjective relationship (FOSR, which is the correlation coefficient between RPE and MPF). Twenty-one normal subjects maintained a handgrip of 60% of their maximal effort until exhaustion for each of the four conditions. During each trial EMG values were recorded every 5 s and RPE values were recorded every 10 s. The RPE was recorded as a subjective value selected from a 10-point Borg scale. The results showed that Tlim was greater for the no glove condition (p < 0.0005) and for the eccentric muscle action (p < 0.05). The FOSR was greatest for the glove condition (p < 0.03) and for the isometric muscle action (p < 0.013). The MPF decline showed no significant difference for any condition. These data indicate that glove condition and type of handgrip contraction have an effect on physiological fatigue and subjective perception of fatigue.