A new cognitive behavioural approach to the treatment of obesity.
While behavioural approaches to the management of obesity are often successful in achieving clinically significant weight loss, the weight lost is generally regained. The great majority of patients return to their pre-treatment weight within 3 years. There have been attempts to improve the long-term effectiveness of behavioural treatment but the results have been disappointing. In this paper we suggest that, among other factors, this is because of the neglect of the contribution of cognitive factors to weight regain, and because there is often ambiguity over the goals of treatment. We present a cognitive behavioural analysis of the processes involved in weight regain, and we describe a new cognitive behavioural treatment derived from it. This treatment is designed to minimise the problem of weight regain by addressing psychological obstacles to the acquisition of, and long-term adherence to, effective weight-control behaviour.


Effectiveness of exercise interventions in reducing pain symptoms among older adults with knee osteoarthritis: a review.
Knee osteoarthritis (OA) affects approximately one third of older adults in the United States. The pain accompanying its progression reduces quality of life and leads to activity restriction and physical disability. Evidence suggests that exercise represents a promising treatment for pain among older knee-OA patients. The article provides an overview of the extant research examining the effectiveness of exercise interventions in reducing pain symptoms among older adults with knee OA. Critical evaluation of the literature reveals that aerobic training, strength training, and combination aerobic and strength training result in improvements in pain. The magnitude of pain reduction accompanying exercise interventions varies considerably across studies, however. In addition, most trials have focused on short-term (<6 months) interventions, and the limited number of long-term (>6 months) trials have been plagued by high attrition and poor postintervention maintenance of treatment effects. Given the variability in the effectiveness of exercise interventions, future research is necessary to determine the individual differences that influence older OA patients' responsiveness to exercise interventions and identify more efficacious strategies for promoting the maintenance of long-term exercise.


Continuous behavioural 'switching' in human spermatozoa and its regulation by Ca2+-mobilising stimuli.
Human sperm show a variety of different behaviours (types of motility) that have different functional roles. Previous reports suggest that sperm may reversibly switch between these behaviours. We have recorded and analysed the behaviour of individual human sperm (180 cells in total), each cell monitored continuously for 3-3.5 min either under control conditions or in the presence of Ca2+-mobilising stimuli. Switching between different behaviours was assessed visually (1 s bins using four behaviour categories), and was verified by fractal dimension analysis of sperm head tracks. In the absence of stimuli, ~90% of cells showed at least one behavioural transition (mean rate under control conditions = 6.4 ± 0.8 transitions.min-1). Type 1 behaviour (progressive, activated-like motility) was most common, but the majority of cells (>70%) displayed at least three behaviour types. Treatment of sperm with Ca2+-mobilising agonists had negligible effects on the rate of switching but increased the time spent in type 2 and type 3 (hyperactivation-like) behaviours (P < 2*10-8; chi-square). Treatment with 4-aminopyridine under alkaline conditions (pHo = 8.5), a highly-potent Ca2+-mobilising stimulus, was the most effective in increasing the proportion of type 3 behaviour, biasing switching away from type 1 (P < 0.005) and dramatically extending the duration of type 3 events (P < 10-16). Other stimuli, including 300 nM progesterone and 1% human follicular fluid, had qualitatively similar effects but were less potent. We conclude that human sperm observed in vitro constitutively display a range of behaviours and regulation of motility by [Ca2+]i, at the level of the single cell, is achieved not by causing cells to adopt a 'new' behaviour but by changing the relative contributions of those behaviours.


Synaptonemal complex and recombination nodules in wild-type Drosophila melanogaster females.
Electron microscope serial section reconstruction analysis of all zygotene-pachytene nuclei of meiotic cells from three wild-type germaria (a subunit of the ovary containing the early meiotic stages arrayed in temporal developmental sequence) of Drosophila melanogaster females corroborates and extends earlier observations (Carpenter 1975a) on the nature and sequence of ultrastructural events occurring during the time of meiotic recombination. Emphasis has been placed on (1) the time of appearance and disappearance of the synaptonemal complex (SC) and the changes in its dimensions that accompany a cell's progression through pachytene, and (2) the appearance, disappearance, number and chromosomal locations of recombination nodules (Carpenter 1975b). For both the SC and the recombination nodule the availability of several developmental series has provided an estimate of the biological variability in the properties of these recombination-associated structures. The much more extensive data presented here substantiate the earlier hypothesis that recombination nodules occur at sites where reciprocal meiotic recombination will occur, has occurred, or is occurring. A second morphological type of recombination nodule is reported; it is suggested that the presence of the latter type of nodule may correlate with sites of gene conversion. The hypothesis that there may be two types of meiotic recombination processes is discussed.


Field-Tunable Interactions and Frustration in Underlayer-Mediated Artificial Spin Ice.
Artificial spin ice systems have opened experimental windows into a range of model magnetic systems through the control of interactions among nanomagnet moments. This control has previously been enabled by altering the nanomagnet size and the geometry of their placement. Here we demonstrate that the interactions in artificial spin ice can be further controlled by including a soft ferromagnetic underlayer below the moments. Such a substrate also breaks the symmetry in the array when magnetized, introducing a directional component to the correlations. Using spatially resolved magneto-optical Kerr effect microscopy to image the demagnetized ground states, we show that the correlation of the demagnetized states depends on the direction of the underlayer magnetization. Further, the relative interaction strength of nearest and next-nearest neighbors varies significantly with the array geometry. We exploit this feature to induce frustration in an inherently unfrustrated square lattice geometry, demonstrating new possibilities for effective geometries in two-dimensional nanomagnetic systems.


Functional gene expression differences between inbred alcohol-preferring and -non-preferring rats in five brain regions.
The objective of this study was to determine if there are innate differences in gene expression in selected CNS regions between inbred alcohol-preferring (iP) and -non-preferring (iNP) rats. Gene expression was determined in the nucleus accumbens (ACB), amygdala (AMYG), frontal cortex (FC), caudate-putamen (CPU), and hippocampus (HIPP) of alcohol-naïve adult male iP and iNP rats, using Affymetrix Rat Genome U34A microarrays (n = 6/strain). Using Linear Modeling for Microarray Analysis with a false discovery rate threshold of 0.1, there were 16 genes with differential expression in the ACB, 54 in the AMYG, 8 in the FC, 24 in the CPU, and 21 in the HIPP. When examining the main effect of strain across regions, 296 genes were differentially expressed. Although the relatively small number of genes found significant within individual regions precluded a powerful analysis for over-represented Gene Ontology categories, the much larger list resulting from the main effect of strain analysis produced 17 over-represented categories (P < .05), including axon guidance, gliogenesis, negative regulation of programmed cell death, regulation of programmed cell death, regulation of synapse structure function, and transmission of nerve impulse. Co-citation analysis and graphing of significant genes revealed a network involved in the neuropeptide Y (NPY) transmitter system. Correlation of all significant genes with those located within previously established rat alcohol QTLs revealed that of the total of 313 significant genes, 71 are located within such QTLs. The many regional and overall gene expression differences between the iP and iNP rat lines may contribute to the divergent alcohol drinking phenotypes of these rats.


Polarization selective electro-optic polymer waveguide devices by direct electron beam writing.
A novel technique for the fabrication of polarization selective electro-optic polymer waveguide devices with direct electron beam writing was described. Birefringence induced by the electric field poling in the electro-optic polymer film was erased in the electron beam exposed regions. The formed waveguides had stronger confinement for the light polarized along the poling direction. High fabrication resolution on the 100 nm scale or smaller could be achieved. Fabrication of polymer polarizer and polarization selective microring resonators with this technique was reported. The highest polarization extinction ratio was measured to be 21.4 dB.


Comparative effects of two different forms of selenium on oxidative stress biomarkers in healthy men: a randomized clinical trial.
Epidemiologic and laboratory studies indicate that dietary selenium protects against prostate cancer. Results from clinical trials suggest that selenium-enriched yeast (SY) but not selenomethionine (SeMet) may be effective at reducing prostate cancer risk. Our objectives were to directly compare for the first time the effects of SeMet and SY on prostate cancer relevant biomarkers in men. We performed a randomized double blind, placebo-controlled trial of SY (200 or 285 μg/day) and SeMet (200 μg/day) administered for 9 months in 69 healthy men. Primary endpoints included blood levels of selenium-containing compounds and oxidative stress biomarkers [urine 8-hydroxy-2'-deoxyguanosine (8-OHdG) and 8-iso-prostaglandin-F2α (8-iso-PGF2α) and blood glutathione (GSH)]. Secondary endpoints included plasma glucose and PSA levels. Compliance was high in all groups (>95%). Plasma selenium levels were increased 93%, 54%, and 86% after 9 months in SeMet and low- and high-dose SY groups, respectively, and returned to baseline levels after a 3-month washout (P < 0.05). Levels of 8-OHdG and 8-iso-PGF2α were decreased 34% and 28%, respectively, after 9 months in the high-dose SY group (P < 0.05). These decreases were greatest in individuals with low baseline plasma levels of selenium (<127 ng/mL). No changes in serum PSA or blood glucose and GSH were observed. Overall, we showed for the first time, reductions in biomarkers of oxidative stress following supplementation with SY but not SeMet in healthy men. These findings suggest that selenium-containing compounds other than SeMet may account for the decrease in oxidative stress.


The effectiveness of physiotherapy exercises in subacromial impingement syndrome: a systematic review and meta-analysis.
To evaluate the effectiveness of exercise in the treatment of people with subacromial impingement syndrome (SAIS). A systematic review and meta-analysis were conducted. Ten electronic databases were searched from the dates of their inception until August 2010. Included studies were randomized controlled trials investigating exercise in the management of SAIS. Outcomes were pain, strength, function, and quality of life. Data were summarized qualitatively using a best evidence synthesis. Treatment effect size and variance of individual studies were used to give an overall summary effect and data were converted to standardized mean difference with 95% confidence intervals (standardized mean difference (SMD) (CI)). Sixteen studies were included (n = 1162). There was strong evidence that exercise decreases pain and improves function at short-term follow-up. There was also moderate evidence that exercise results in short-term improvement in mental well-being and a long-term improvement in function for those with SAIS. The most common risk of bias across the studies was inadequately concealed treatment allocation. Six studies in the review were suitable for meta-analysis. Exercise had a small positive effect on strength of the rotator cuff in the short term (SMD -0.46 (-0.76, 0.16); P = 0.003) and a small positive effect on long-term function (SMD -0.31 (-0.57, 0.04); P = 0.02). Physiotherapy exercises are effective in the management of SAIS. However, heterogeneity of the exercise interventions, coupled with poor reporting of exercise protocols, prevented conclusions being drawn about which specific components of the exercise protocols (ie, type, intensity, frequency and duration) are associated with best outcomes.


Defining Benchmarks in Liver Transplantation: A Multicenter Outcome Analysis Determining Best Achievable Results.
: This multicentric study of 17 high-volume centers presents 12 benchmark values for liver transplantation. Those values, mostly targeting markers of morbidity, were gathered from 2024 "low risk" cases, and may serve as reference to assess outcome of single or any groups of patients. To propose benchmark outcome values in liver transplantation, serving as reference for assessing individual patients or any other patient groups. Best achievable results in liver transplantation, that is, benchmarks, are unknown. Consequently, outcome comparisons within or across centers over time remain speculative. Out of 7492 liver transplantation performed in 17 international centers from 3 continents, we identified 2024 low risk adult cases with a laboratory model for end-stage liver disease score ≤20 points, a balance of risk score ≤9, and receiving a primary graft by donation after brain death. We chose clinically relevant endpoints covering intra- and postoperative course, with a focus on complications graded by severity including the complication comprehensive index (CCI). Respective benchmarks were derived from the median value in each center, and the 75 percentile was considered the benchmark cutoff. Benchmark cases represented 8% to 49% of cases per center. One-year patient-survival was 91.6% with 3.5% retransplantations. Eighty-two percent of patients developed at least 1 complication during 1-year follow-up. Biliary complications occurred in one-fifth of the patients up to 6 months after surgery. Benchmark cutoffs were ≤4 days for ICU stay, ≤18 days for hospital stay, ≤59% for patients with severe complications (≥ Grade III) and ≤42.1 for 1-year CCI. Comparisons with the next higher risk group (model for end stage liver disease 21-30) disclosed an increase in morbidity but within benchmark cutoffs for most, but not all indicators, while in patients receiving a second graft from 1 center (n = 50) outcome values were all outside of benchmark values. Despite excellent 1-year survival, morbidity in benchmark cases remains high with half of patients developing severe complications during 1-year follow-up. Benchmark cutoffs targeting morbidity parameters offer a valid tool to assess higher risk groups.


Sialic acids of young and old red blood cells in healthy subjects.
A quite simple method for obtaining young and old erythrocytes is presented. Mean corpuscular volume, glutamic oxaloacetic transaminase activity which is one of the best age parameters, and contents of total sialic acids in erythrocyte membranes were determined in whole erythrocyte population and in low (old) and high (young) density fractions separated by centrifugation of packed cells obtained from 23 healthy subjects. Glutamic oxaloacetic transaminase (GOT) activity, and contents of total sialic acids in erythrocyte membranes were significantly higher in young cells then in old ones, or in the whole population of erythrocytes. The presented results suggest that this method is simple for obtaining two different fractions of erythrocytes and that erythrocytes lose intact sialic acids together with their membrane during erythrocytes senescence.


Genomics for health in preconception and prenatal periods.
To review and report changes in genomic-based knowledge and care during the preconception and prenatal periods. Integrative review of relevant medical and nursing literature. Client education and counseling are needed to understand genomic information and provide guidance in interpreting this information and making decisions. The factors that influence decision-making about testing and acting on test results constitute a complex process that has not been well studied. Family history is an important tool for obtaining genomic information and can assist women and families in understanding risk preconceptionally and prenatally. Genomic research has enhanced understanding of the mechanisms of birth defects such as neural tube defect and will likely provide research opportunities to better understand complex perinatal outcomes such as preterm birth. Research, education, advocacy, and anticipatory guidance are needed as women and families obtain more genetic and genomic information before and during pregnancy. All nurses will be involved in helping patients use genetic and genomic information to understand risk and to develop strategies to modify risk, and in translating the expanding array of genomic information to improve birth outcomes.


Evaluation of modal noise in graded-index silica and plastic optical fiber links for radio over multimode fiber systems.
We have evaluated and compared modal noise induced in a graded-index silica multimode fiber (GI-MMF) link and a graded-index plastic optical fiber (GI-POF) link with the misaligned fiber connections. In radio over fiber (RoF) systems using these optical fibers, modal noise appears as unwanted amplitude modulation in the received signal, and results in degradation of the RoF transmission performance. In this work, we have evaluated the modal noise induced in GI-MMFs and GI-POFs with its same core diameter of 50 μm. Our results show that GI-POFs have an inherently higher tolerance to misaligned connection and less modal noise than GI-MMFs in terms of both the error-vector magnitude and the speckle pattern of the transmitted signals.


Interventions for Physician Burnout: A Systematic Review of Systematic Reviews.
Occupational burnout is a common syndrome among physicians, and several individual-directed and organization-directed interventions have been implemented to reduce it. Until now, several review studies have tried to identify and introduce the most appropriate interventions. The aim of this article was to systematically review systematic review studies of interventions for physician burnout to evaluate and summarize their results, and ultimately guide researchers to select appropriate interventions. A search was conducted to find review studies and systematic reviews in Cochrane Database of Systematic Reviews, Medline, Google Scholar, PubMed, and PsycINFO. Two reviewers independently selected and evaluated the studies based on inclusion criteria. Four of seven obtained review studies and systematic reviews met the inclusion criteria. These studies have reviewed individual-directed and organization-directed interventions intended to reduce burnout among medical students, interns, physicians, residents, and fellows. Various studies of the effectiveness of individual- and organization-directed interventions have obtained different results. This research has shown that reaching conclusions about effective interventions (individual- or organization-directed) for physician burnout is not easy and that a number of mediating or moderating variables probably influence the effectiveness of these interventions. Therefore, it is necessary to understand approaches and interventions for the prevention or reduction of physician burnout to fill the gaps in research. In addition, review studies are required to be more precise in choosing their criteria to find more accurate results.


Labels as features (not names) for infant categorization: a neurocomputational approach.
A substantial body of experimental evidence has demonstrated that labels have an impact on infant categorization processes. Yet little is known regarding the nature of the mechanisms by which this effect is achieved. We distinguish between two competing accounts: supervised name-based categorization and unsupervised feature-based categorization. We describe a neurocomputational model of infant visual categorization, based on self-organizing maps, that implements the unsupervised feature-based approach. The model successfully reproduces experiments demonstrating the impact of labeling on infant visual categorization reported in Plunkett, Hu, and Cohen (2008). It mimics infant behavior in both the familiarization and testing phases of the procedure, using a training regime that involves only single presentations of each stimulus and using just 24 participant networks per experiment. The model predicts that the observed behavior in infants is due to a transient form of learning that might lead to the emergence of hierarchically organized categorical structure and that the impact of labels on categorization is influenced by the perceived similarity and the sequence in which the objects are presented. The results suggest that early in development, say before 12 months old, labels need not act as invitations to form categories nor highlight the commonalities between objects, but they may play a more mundane but nevertheless powerful role as additional features that are processed in the same fashion as other features that characterize objects and object categories.


Amplification and propagation of pacemaker Ca2+ signals by cyclic ADP-ribose and the type 3 ryanodine receptor in T cells.
Ligation of the T-cell receptor/CD3 complex results in global Ca(2+) signals that are essential for T-cell activation. We have recently reported that these global Ca(2+) signals are preceded by localized pacemaker Ca(2+) signals. Here, we demonstrate for the first time for human T cells that an increase in signal frequency of subcellular pacemaker Ca(2+) signals at sites close to the plasma membrane, in the cytosol and in the nucleus depends on the type 3 ryanodine receptor (RyR) and its modulation by cyclic ADP-ribose. The spatial distribution of D-myo-inositol 1,4,5-trisphosphate receptors and RyRs indicates a concerted action of both of these receptors/Ca(2+) channels in the generation of initial pacemaker signals localized close to the plasma membrane. Inhibition or knockdown of RyRs resulted in significant decreases in (1) the frequency of initial pacemaker signals localized close to the plasma membrane, and (2) the frequency of localized pacemaker Ca(2+) signals in the inner cytosol. Moreover, upon microinjection of cyclic ADP-ribose or upon extracellular addition of its novel membrane-permeant mimic N-1-ethoxymethyl-substituted cyclic inosine diphosphoribose, similarly decreased Ca(2+) signals were observed in both type 3 RyR-knockdown cells and in control cells microinjected with the RyR antagonist Ruthenium Red. Taken together, our results show that, under physiological conditions in human T cells, RyRs play crucial roles in the local amplification and the spatiotemporal development of subcellular Ca(2+) pacemaker signals.


Estimating the location and spatial extent of a covert anthrax release.
Rapidly identifying the features of a covert release of an agent such as anthrax could help to inform the planning of public health mitigation strategies. Previous studies have sought to estimate the time and size of a bioterror attack based on the symptomatic onset dates of early cases. We extend the scope of these methods by proposing a method for characterizing the time, strength, and also the location of an aerosolized pathogen release. A back-calculation method is developed allowing the characterization of the release based on the data on the first few observed cases of the subsequent outbreak, meteorological data, population densities, and data on population travel patterns. We evaluate this method on small simulated anthrax outbreaks (about 25-35 cases) and show that it could date and localize a release after a few cases have been observed, although misspecifications of the spore dispersion model, or the within-host dynamics model, on which the method relies can bias the estimates. Our method could also provide an estimate of the outbreak's geographical extent and, as a consequence, could help to identify populations at risk and, therefore, requiring prophylactic treatment. Our analysis demonstrates that while estimates based on the first ten or 15 observed cases were more accurate and less sensitive to model misspecifications than those based on five cases, overall mortality is minimized by targeting prophylactic treatment early on the basis of estimates made using data on the first five cases. The method we propose could provide early estimates of the time, strength, and location of an aerosolized anthrax release and the geographical extent of the subsequent outbreak. In addition, estimates of release features could be used to parameterize more detailed models allowing the simulation of control strategies and intervention logistics.


Protein-size molecularly imprinted polymer nanogels as synthetic antibodies, by localized polymerization with multi-initiators.
A new approach is proposed for the synthesis of molecularly imprinted polymers (MIPs) (synthetic antibodies) as soluble nanogels with sizes close to the size of real antibodies. To imprint a molecular memory in particles consisting of only a few polymer chains, an initiator carrying multiple iniferter moieties is used. This allows for the simultaneous initiation of several polymer chains, and yields molecularly imprinted nanogels (17 nm, molecular weight (MW) = 97 kDa) with good affinity and selectivity for the target.


A Protein-Based Encapsulation System with Calcium-Controlled Cargo Loading and Detachment.
Protein-based encapsulation systems have a wide spectrum of applications in targeted delivery of cargo molecules and for chemical transformations in confined spaces. By engineering affinity between cargo and container proteins it has been possible to enable the efficient and specific encapsulation of target molecules. Missing in current approaches is the ability to turn off the interaction after encapsulation to enable the cargo to freely diffuse in the lumen of the container. Separation between cargo and container is desirable in drug delivery applications and in the use of capsids as catalytic nanoparticles. We describe an encapsulation system based on the hepatitis B virus capsid in which an engineered high-affinity interaction between cargo and capsid proteins can be modulated by Ca2+ . Cargo proteins are loaded into capsids in the presence of Ca2+ , while ligand removal triggers unbinding inside the container. We observe that confinement leads to hindered rotation of cargo inside the capsid. Application of the designed container for catalysis was also demonstrated by encapsulation of an enzyme with β-glucosidase activity.


Gender gap in medicine: only one woman councilor in the Japan Surgical Society.
Japan ranks low in the global gender gap index. Academic promotion is difficult for women doctors, and the leaky pipeline of women doctors is evident in academic medicine. The Japan Surgical Society (JSS) has 2,874 (7.2% of total membership) female members as of April 2014. The total number of councilors in JSS has increased, but there is still only one female member on the Council. The fact that there are so few women in decision-making positions makes it challenging to fight for equality. The Japanese Association of Medical Science (JAMS) is an association with exclusive institutional membership comprising the major medical societies in Japan, and currently has a membership of 122 specialist medical societies. It is essential to have at least one female committee member in each committee of the JAMS, which would provide opportunities to establish career paths for women doctors, to make rules that suit the lifestyle of women doctors, and to improve work-life balance.


Signal transduction by vascular endothelial growth factor receptors.
VEGFs (vascular endothelial growth factors) control vascular development during embryogenesis and the function of blood vessels and lymphatic vessels in the adult. There are five related mammalian ligands, which act through three receptor tyrosine kinases. Signalling is modulated through neuropilins, which act as VEGF co-receptors. Heparan sulfate and integrins are also important modulators of VEGF signalling. Therapeutic agents that interfere with VEGF signalling have been developed with the aim of decreasing angiogenesis in diseases that involve tissue growth and inflammation, such as cancer. The present review will outline the current understanding and consequent biology of VEGF receptor signalling.


Linear regression analysis of Hospital Episode Statistics predicts a large increase in demand for elective hand surgery in England.
We integrated two factors, demographic population shifts and changes in prevalence of disease, to predict future trends in demand for hand surgery in England, to facilitate workforce planning. We analysed Hospital Episode Statistics data for Dupuytren's disease, carpal tunnel syndrome, cubital tunnel syndrome, and trigger finger from 1998 to 2011. Using linear regression, we estimated trends in both diagnosis and surgery until 2030. We integrated this regression with age specific population data from the Office for National Statistics in order to estimate how this will contribute to a change in workload over time. There has been a significant increase in both absolute numbers of diagnoses and surgery for all four conditions. Combined with future population data, we calculate that the total operative burden for these four conditions will increase from 87,582 in 2011 to 170,166 (95% confidence interval 144,517-195,353) in 2030. The prevalence of these diseases in the ageing population, and increasing prevalence of predisposing factors such as obesity and diabetes, may account for the predicted increase in workload. The most cost effective treatments must be sought, which requires high quality clinical trials. Our methodology can be applied to other sub-specialties to help anticipate the need for future service provision.


Evaluation of irinotecan in combination with 5-fluorouracil or etoposide in xenograft models of colon adenocarcinoma and rhabdomyosarcoma.
Irinotecan [7-ethyl-10-(4-[1-piperidino]-1-piperidino)-carbonyloxy-camptothec in] administered i.v. in two courses, each course consisting of administration every day for 5 days [(dx5)2] on days 1-5 and 8-12, has demonstrated significant activity against advanced human tumor xenografts derived from colon adenocarcinomas and several childhood cancers. To build on this therapy, we have evaluated the combination of irinotecan given on this schedule with 5-fluorouracil given on days 1, 7, and 14 with or without leucovorin [(dx5)3 i.v.] against colon tumors, or combined with etoposide administered (dx5)2 i.v. either 2 h before or 2 h after irinotecan for treatment of colon tumors and rhabdomyosarcomas. A combination of 5-fluorouracil at 75% and irinotecan at 50% of their respective maximum tolerated doses when administered as single agents on this schedule gave acceptable toxicity. Against colon adenocarcinoma xenografts, 5-fluorouracil did not enhance the response rate compared with that obtained with the optimum dose of irinotecan given as a single agent. Against GC3/TK- xenografts, which lack thymidine kinase and cannot salvage thymidine to circumvent the inhibition of thymidylate synthase, the addition of leucovorin to the combination increased the complete response rate from 10 to >90%, whereas the response rates for the optimal doses of irinotecan or 5-fluorouracil, as single agents, were 30 and <10%, respectively. Etoposide d x 5 i.v. for two or three courses or (d x 5)3 p.o. did not cause objective regression of any colon tumors. In contrast, three of five rhabdomyosarcoma lines demonstrated a high frequency of partial regressions or complete regressions when treated (d x 5)1 i.v. Repetitive courses [e.g., (d x 5)2 or (d x 5)3] i.v. or p.o. or by 4-h infusion d x3 i.v. were either equally effective or less effective. Irinotecan and etoposide were combined using the (d x 5)2 i.v. schedule for both drugs, in which irinotecan was given 2 h before or 2 h after the administration of etoposide. Each drug could be combined at only 38% of its respective maximum tolerated dose when administered as a single agent, indicating greater than additive toxicity. Toxicity was similar irrespective of the sequence of administration and was manifested by loss of weight (73% of the initial weight, nadir day 7), myelosuppression, and prolonged thrombocytopenia. The responses of colon carcinomas to the combination given in either sequence were similar to that achieved with irinotecan given alone at the same dose as used in the combination. Similarly, when etoposide was given before irinotecan, the responses of rhabdomyosarcomas were similar to those for irinotecan. However, in experiments in which etoposide was administered 2 h after each dose of irinotecan, there was significant antagonism of the antitumor activity of irinotecan.


CREB-binding protein regulates lung cancer growth by targeting MAPK and CPSF4 signaling pathway.
CBP (CREB-binding protein) is a transcriptional co-activator which possesses HAT (histone acetyltransferases) activity and participates in many biological processes, including embryonic development, growth control and homeostasis. However, its roles and the underlying mechanisms in the regulation of carcinogenesis and tumor development remain largely unknown. Here we investigated the molecular mechanisms and potential targets of CBP involved in tumor growth and survival in lung cancer cells. Elevated expression of CBP was detected in lung cancer cells and tumor tissues compared to the normal lung cells and tissues. Knockdown of CBP by siRNA or inhibition of its HAT activity using specific chemical inhibitor effectively suppressed cell proliferation, migration and colony formation and induced apoptosis in lung cancer cells by inhibiting MAPK and activating cytochrome C/caspase-dependent signaling pathways. Co-immunoprecipitation and immunofluorescence analyses revealed the co-localization and interaction between CBP and CPSF4 (cleavage and polyadenylation specific factor 4) proteins in lung cancer cells. Knockdown of CPSF4 inhibited hTERT transcription and cell growth induced by CBP, and vice versa, demonstrating the synergetic effect of CBP and CPSF4 in the regulation of lung cancer cell growth and survival. Moreover, we found that high expression of both CBP and CPSF4 predicted a poor prognosis in the patients with lung adenocarcinomas. Collectively, our results indicate that CBP regulates lung cancer growth by targeting MAPK and CPSF4 signaling pathways.


A Review of Computational Tools in microRNA Discovery.
Since microRNAs (miRNAs) were discovered, their impact on regulating various biological activities has been a surprising and exciting field. Knowing the entire repertoire of these small molecules is the first step to gain a better understanding of their function. High throughput discovery tools such as next-generation sequencing significantly increased the number of known miRNAs in different organisms in recent years. However, the process of being able to accurately identify miRNAs is still a complex and difficult task, requiring the integration of experimental approaches with computational methods. A number of prediction algorithms based on characteristics of miRNA molecules have been developed to identify new miRNA species. Different approaches have certain strengths and weaknesses and in this review, we aim to summarize several commonly used tools in metazoan miRNA discovery.


The history of anaesthetic equipment evaluation in the United Kingdom: lessons for developing future strategy.
Recent guidance published by the Association of Anaesthetists of Great Britain and Ireland encourages the purchase of equipment based on evidence of safety and performance. For many years, evidence of the safety and performance of anaesthetic equipment was published by various government departments and agencies. However, these schemes were gradually eroded over time such that many devices entered the market with little or no clinical evidence of their efficacy. This recently led to the Difficult Airway Society's issuing guidance to its members on how best to select new airway devices; guidance that was based on the available evidence. This article provides a short history of the evaluation of anaesthetic equipment in the United Kingdom.


Interactive effects of viral and bacterial production on marine bacterial diversity.
A general model of species diversity predicts that the latter is maximized when productivity and disturbance are balanced. Based on this model, we hypothesized that the response of bacterial diversity to the ratio of viral to bacterial production (VP/BP) would be dome-shaped. In order to test this hypothesis, we obtained data on changes in bacterial communities (determined by terminal restriction fragment length polymorphism of 16S rRNA gene) along a wide VP/BP gradient (more than two orders of magnitude), using seawater incubations from NW Mediterranean surface waters, i.e., control and treatments with additions of phosphate, viruses, or both. In December, one dominant Operational Taxonomic Unit accounted for the major fraction of total amplified DNA in the phosphate addition treatment (75±20%, ± S.D.), but its contribution was low in the phosphate and virus addition treatment (23±19%), indicating that viruses prevented the prevalence of taxa that were competitively superior in phosphate-replete conditions. In contrast, in February, the single taxon predominance in the community was held in the phosphate addition treatment even with addition of viruses. We observed statistically robust dome-shaped response patterns of bacterial diversity to VP/BP, with significantly high bacterial diversity at intermediate VP/BP. This was consistent with our model-based hypothesis, indicating that bacterial production and viral-induced mortality interactively affect bacterial diversity in seawater.


Trans-palmitoleic acid, metabolic risk factors, and new-onset diabetes in U.S. adults: a cohort study.
Palmitoleic acid (cis-16:1n-7), which is produced by endogenous fat synthesis, has been linked to both beneficial and deleterious metabolic effects, potentially confounded by diverse determinants and tissue sources of endogenous production. Trans-palmitoleate (trans-16:1n-7) represents a distinctly exogenous source of 16:1n-7, unconfounded by endogenous synthesis or its determinants, that may be uniquely informative. To investigate whether circulating trans-palmitoleate is independently related to lower metabolic risk and incident type 2 diabetes. Prospective cohort study from 1992 to 2006. Four U.S. communities. 3736 adults in the Cardiovascular Health Study. Anthropometric characteristics and levels of plasma phospholipid fatty acids, blood lipids, inflammatory markers, and glucose-insulin measured at baseline in 1992 and dietary habits measured 3 years earlier. Multivariate-adjusted models were used to investigate how demographic, clinical, and lifestyle factors independently related to plasma phospholipid trans-palmitoleate; how trans-palmitoleate related to major metabolic risk factors; and how trans-palmitoleate related to new-onset diabetes (304 incident cases). Findings were validated for metabolic risk factors in an independent cohort of 327 women. In multivariate analyses, whole-fat dairy consumption was most strongly associated with higher trans-palmitoleate levels. Higher trans-palmitoleate levels were associated with slightly lower adiposity and, independently, with higher high-density lipoprotein cholesterol levels (1.9% across quintiles; P = 0.040), lower triglyceride levels (-19.0%; P < 0.001), a lower total cholesterol-HDL cholesterol ratio (-4.7%; P < 0.001), lower C-reactive protein levels (-13.8%; P = 0.05), and lower insulin resistance (-16.7%, P < 0.001). Trans-palmitoleate was also associated with a substantially lower incidence of diabetes, with multivariate hazard ratios of 0.41 (95% CI, 0.27 to 0.64) and 0.38 (CI, 0.24 to 0.62) in quintiles 4 and 5 versus quintile 1 (P for trend < 0.001). Findings were independent of estimated dairy consumption or other fatty acid dairy biomarkers. Protective associations with metabolic risk factors were confirmed in the validation cohort. Results could be affected by measurement error or residual confounding. Circulating trans-palmitoleate is associated with lower insulin resistance, presence of atherogenic dyslipidemia, and incident diabetes. Our findings may explain previously observed metabolic benefits of dairy consumption and support the need for detailed further experimental and clinical investigation. National Heart, Lung, and Blood Institute and National Institute of Diabetes and Digestive and Kidney Diseases of the National Institutes of Health.


Gene expression patterns in pancreatic tumors, cells and tissues.
Cancers of the pancreas originate from both the endocrine and exocrine elements of the organ, and represent a major cause of cancer-related death. This study provides a comprehensive assessment of gene expression for pancreatic tumors, the normal pancreas, and nonneoplastic pancreatic disease. DNA microarrays were used to assess the gene expression for surgically derived pancreatic adenocarcinomas, islet cell tumors, and mesenchymal tumors. The addition of normal pancreata, isolated islets, isolated pancreatic ducts, and pancreatic adenocarcinoma cell lines enhanced subsequent analysis by increasing the diversity in gene expression profiles obtained. Exocrine, endocrine, and mesenchymal tumors displayed unique gene expression profiles. Similarities in gene expression support the pancreatic duct as the origin of adenocarcinomas. In addition, genes highly expressed in other cancers and associated with specific signal transduction pathways were also found in pancreatic tumors. The scope of the present work was enhanced by the inclusion of publicly available datasets that encompass a wide spectrum of human tissues and enabled the identification of candidate genes that may serve diagnostic and therapeutic goals.


Recent advances in laser tweezers Raman spectroscopy (LTRS) for label-free analysis of single cells.
Laser tweezers Raman spectroscopy (LTRS), a technique that integrates optical tweezers with confocal Raman spectroscopy, is a variation of micro-Raman spectroscopy that enables the manipulation and biochemical analysis of single biological particles in suspension. This article provides an overview of the LTRS method, with an emphasis on highlighting recent advances over the past several years in the development of the technology and several new biological and biomedical applications that have been demonstrated. A perspective on the future developments of this powerful cytometric technology will also be presented.


Galectin-7 downregulation in lesional keratinocytes contributes to enhanced IL-17A signaling and skin pathology in psoriasis.
Psoriasis is a chronic inflammatory skin disease characterized by inflammatory cell infiltration, as well as hyperproliferation of keratinocytes in skin lesions, and is considered a metabolic syndrome. We found that the expression of galectin-7 is reduced in skin lesions of patients with psoriasis. IL-17A and TNF-α, 2 cytokines intimately involved in the development of psoriatic lesions, suppressed galectin-7 expression in human primary keratinocytes (HEKn cells) and the immortalized human keratinocyte cell line HaCaT. A galectin-7 knockdown in these cells elevated the production of IL-6 and IL-8 and enhanced ERK signaling when the cells were stimulated with IL-17A. Galectin-7 attenuated IL-17A-induced production of inflammatory mediators by keratinocytes via the microRNA-146a/ERK pathway. Moreover, galectin-7-deficient mice showed enhanced epidermal hyperplasia and skin inflammation in response to intradermal IL-23 injection. We identified fluvastatin as an inducer of galectin-7 expression by connectivity map analysis, confirmed this effect in keratinocytes, and demonstrated that fluvastatin attenuated IL-6 and IL-8 production induced by IL-17A. Thus, we validate a role of galectin-7 in the pathogenesis of psoriasis, in both epidermal hyperplasia and keratinocyte-mediated inflammatory responses, and formulate a rationale for the use of statins in the treatment of psoriasis.


Characterization and mapping of NBS-LRR resistance gene analogs in apricot (Prunus armeniaca L.).
Genomic DNA sequences sharing homology with the NBS-LRR (nucleotide binding site-leucine-rich repeat) resistance genes were isolated and cloned from apricot (Prunus armeniaca L.) using a PCR approach with degenerate primers designed from conserved regions of the NBS domain. Restriction digestion and sequence analyses of the amplified fragments led to the identification of 43 unique amino acid sequences grouped into six families of resistance gene analogs (RGAs). All of the RGAs identified belong to the Toll-Interleukin receptor (TIR) group of the plant disease resistance genes (R-genes). RGA-specific primers based on non-conserved regions of the NBS domain were developed from the consensus sequences of each RGA family. These primers were used to develop amplified fragment length polymorphism (AFLP)-RGA markers by means of an AFLP-modified procedure where one standard primer is substituted by an RGA-specific primer. Using this method, 27 polymorphic markers, six of which shared homology with the TIR class of the NBS-LRR R-genes, were obtained from 17 different primer combinations. Of these 27 markers, 16 mapped in an apricot genetic map previously constructed from the self-pollination of the cultivar Lito. The development of AFLP-RGA markers may prove to be useful for marker-assisted selection and map-based cloning of R-genes in apricot.


Intensive Glycemic Treatment During Type 1 Diabetes Pregnancy: A Story of (Mostly) Sweet Success!
Studies from Scotland and Canada confirm large increases in the incidence of pregnancies complicated by pregestational type 1 diabetes (T1D). With this increased antenatal workload comes more specialization and staff expertise, which may be important as diabetes technology use increases. While euglycemia remains elusive and obstetrical intervention (earlier delivery, increased operative deliveries) is increasing, there have been some notable successes in the past 5-10 years. These include a decline in the rates of congenital anomaly (Canada) and stillbirths (U.K.) and substantial reductions in both maternal hypoglycemia (both moderate and severe) across many countries. However, pregnant women with T1D still spend ∼30-45% of the time (8-11 h/day) hyperglycemic during the second and third trimesters. The duration of maternal hyperglycemia appears unchanged in routine clinical care over the past decade. This ongoing fetal exposure to maternal hyperglycemia likely explains the persistent rates of large for gestational age (LGA), neonatal hypoglycemia, and neonatal intensive care unit (NICU) admissions in T1D offspring. The Continuous Glucose Monitoring in Women With Type 1 Diabetes in Pregnancy Trial (CONCEPTT) found that pregnant women using real-time continuous glucose monitoring (CGM) spent 5% less time (1.2 h/day) hyperglycemic during the third trimester, with clinically relevant reductions in LGA, neonatal hypoglycemia, and NICU admissions. This article will review the progress in our understanding of the intensive glycemic treatment of T1D pregnancy, focusing in particular on the recent technological advances in CGM and automated insulin delivery. It suggests that even with advanced diabetes technology, optimal maternal dietary intake is needed to minimize the neonatal complications attributed to postprandial hyperglycemia.


Absolute lymphocyte count recovery after induction chemotherapy predicts superior survival in acute myelogenous leukemia.
Absolute lymphocyte count (ALC) recovery postautologous stem cell transplantation is an independent predictor for survival in acute myelogenous leukemia (AML). The role of ALC recovery after induction chemotherapy (IC) in AML is unknown. We hypothesize that ALC recovery after IC has a direct impact on survival. We have now evaluated the impact of ALC recovery after IC on overall survival (OS) and leukemia-free survival (LFS) in 103 consecutive, newly diagnosed AML patients treated with standard IC and consolidation chemotherapy (CC) from 1998 to 2002. ALC recovery was studied at days 15 (ALC-15), 21 (ALC-21), 28 (ALC-28) after IC and before the first CC (ALC-CC). Superior OS and LFS at each time point were observed with an ALC-15, ALC-21, ALC-28, and ALC-CC > or = 500 cells/microl. Patients with an ALC > or = 500 cells/microl at all time points vs those who did not have superior OS and LFS (not reached vs 13 months, P<0.0001; and not reached vs 11 months, P<0.0001, respectively). Multivariate analysis demonstrated ALC > or = 500 cells/microl at all time points to be an independent prognostic factor for survival. Our data suggest a critical role of lymphocyte (immune) recovery on survival after IC in AML.


Chondroitin sulfate and sulfated hyaluronan-containing collagen coatings of titanium implants influence peri-implant bone formation in a minipig model.
An improved osseous integration of dental implants in patients with lower bone quality is of particular interest. The aim of this study was to evaluate the effect of artificial extracellular matrix implant coatings on early bone formation. The coatings contained collagen (coll) in conjunction with either chondroitin sulfate (CS) or sulfated hyaluronan (sHya). Thirty-six screw-type, grit-blasted, and acid-etched titanium implants were inserted in the mandible of 6 minipigs. Three surface states were tested: (1) uncoated control (2) coll/CS (3) coll/sHya. After healing periods of 4 and 8 weeks, bone implant contact (BIC), bone volume density (BVD) as well as osteoid related parameters were measured. After 4 weeks, control implants showed a BIC of 44% which was comparable to coll/CS coated implants (48%) and significantly higher compared to coll/sHya coatings (37%, p = 0.012). This difference leveled out after 8 weeks. No significant differences could be detected for BVD values after 4 weeks and all surfaces showed reduced BVD values after 8 weeks. However, at that time, BVD around both, coll/CS (30%, p = 0.029), and coll/sHya (32%, p = 0.015), coatings was significantly higher compared to controls (22%). The osteoid implant contact (OIC) showed no significant differences after 4 weeks. After 8 weeks OIC for controls was comparable to coll/CS, the latter being significantly higher compared to coll/sHya (0.9% vs. 0.4%, p = 0.012). There were no significant differences in osteoid volume density. In summary, implant surface coatings by the chosen organic components of the extracellular matrix showed a certain potential to influence osseointegration in vivo.


Far-field mapping of the longitudinal magnetic and electric optical fields.
In this Letter, we demonstrate the experimental mapping of the longitudinal magnetic and electric optical fields with a standard scanning microscope that involves a high-numerical-aperture far-field objective. The imaging concept relies upon the insertion of an azimuthal or a radial polarizer within the detection path of the microscope that acts as an optical electromagnetic filter aimed at transmitting selectively to the detector the signal from the magnetic or electric longitudinal fields present in the detection volume, respectively. The resulting system is thus versatile, noninvasive, and of high resolution, and shows high detection efficiencies. Magnetic optical properties of physical and biological micro- and nano-structures may thus be revealed with a far-field microscope.


An alternative approach to implementing patient-reported outcome measures.
Obtaining patients' views of their health and outcomes of interventions utilising patient-reported outcome measures (PROMs) is a well-established method, but there is still uncertainty about the impact of PROMs on services and patient care. Studies are now needed of alternative ways of implementing PROMs. This paper describes a case study of the introduction of a new PROM to assess musculoskeletal (MSK) problems, known as the Musculoskeletal Health Questionnaire (MSK-HQ). Following an invitation from the Arthritis Research UK (ARUK), 11 groups and organisations agreed to become 'partners' in piloting the MSK-HQ. Twenty-nine interviews and a focus group were carried out with key informants from the partners. Interviews were supplemented with some documentary evidence of partners' meetings. Data were coded and analysed with NVivo software V.10. Analysis was carried out via a framework method. Participants reported positive evidence that the MSK-HQ is feasible and practical for use in patient care with content that helped health professionals identify and address patients' main presenting problems. Although mediated and reported through health professionals' judgments, the questionnaire was also seen as very relevant and acceptable to a wide spectrum of patients.There was also broad support for the view that whilst the MSK-HQ is relevant to individual patient care, it could also, when aggregated, reflect the experiences of patients as a group and be used as evidence for third parties concerned with the provision and commissioning of services.The main difficulties revealed by the case study were in the form of logistics and sustainability. It was recognised that electronic systems would be more effective for administration and data processing but they were not feasible to develop and implement within reasonable timelines and available budgets. A sustainable approach to using the PROM required significant long-term commitment of budget, a coherent system, and active support from diverse organisations. The current study supports the view that a bottom-up approach is a promising method to generate PROM-related insights that are relevant to patients and health professionals. The partnership approach to developing and using PROMs may have wider relevance and potential as a model of implementation.


Human periosteum-derived cells maintain phenotypic stability and chondrogenic potential throughout expansion regardless of donor age.
To assess the in vitro chondrogenic potential of adult human periosteum-derived cells (PDCs) with regard to the number of cell passages and the age of the donor. Cells were enzymatically released from the periosteum of the proximal tibia obtained from adult human donors and expanded in monolayer. PDCs were harvested at multiple passages for total RNA extraction and semiquantitative reverse transcription-polymerase chain reaction (RT-PCR) gene expression analysis. For the chondrogenesis assay, cells were plated in micromass and treated with transforming growth factor beta1 (TGFbeta1) in a chemically defined medium. At different time points, micromasses were either harvested for RT-PCR analysis for cartilage and bone markers or fixed, paraffin-embedded, and stained for cartilage matrix, and immunostained for type II collagen. At the first 2 passages, human PDCs from young donors formed chondrogenic nodules. This spontaneous chondrogenic activity was lost upon passaging, and it was not observed in donors older than 30 years. Using a panel of marker genes, PDCs were shown to be phenotypically stable during cell expansion. Regardless of donor age or cell passage, chondrogenesis could be induced consistently by combining micromass culture and TGFbeta1 treatment. Histochemical and immunohistochemical analyses demonstrated the hyaline-like cartilage phenotype of the tissue generated in vitro. Other TGFbeta superfamily members, such as growth differentiation factor 5/cartilage-derived morphogenetic protein 1, and bone morphogenetic proteins 2, 4, and 7, were poorly chondrogenic under the same culture conditions. Adult human PDCs have the potential to differentiate toward the chondrocytic lineage in vitro, retaining this property even after extensive subculture. Human PDCs are easily accessible, expandable, and maintain their chondrogenic potential, and are therefore promising progenitor cells for use in the repair of joint surface defects.


Effects of platelet-rich plasma, adipose-derived stem cells, and stromal vascular fraction on the survival of human transplanted adipose tissue.
Traditional adipose tissue transplantation has unpredictable viability and poor absorption rates. Recent studies have reported that treatment with platelet-rich plasma (PRP), adipose-derived stem cells (ASCs), and stromal vascular fraction (SVF) are related to increased survival of grafted adipose tissue. This study was the first simultaneous comparison of graft survival in combination with PRP, ASCs, and SVF. Adipose tissues were mixed with each other, injected subcutaneously into the back of nude mice, and evaluated at 4, 8, and 12 weeks. Human adipocytes were grossly maintained in the ASCs and SVF mixtures. Survival of the adipose tissues with PRP was observed at 4 weeks and with SVF at 8 and 12 weeks. At 12 weeks, volume reduction in the ASCs and SVF mixtures were 36.9% and 32.1%, respectively, which were significantly different from that of the control group without adjuvant treatment, 51.0%. Neovascular structures were rarely observed in any of the groups. Our results suggest that the technique of adding ASCs or SVF to transplanted adipose tissue might be more effective than the conventional grafting method. An autologous adipose tissue graft in combination with ASCs or SVF may potentially contribute to stabilization of engraftment.


Coupling metabolite flux to transcriptomics: insights into the molecular mechanisms underlying primary productivity by the hydrothermal vent tubeworm Ridgeia piscesae.
Deep-sea hydrothermal vents host highly productive ecosystems. Many of these communities are dominated by vestimentiferan tubeworms that house endosymbiotic chemoautotrophic bacteria that provide the hosts with their primary nutritional needs. Rates of carbon fixation by these symbioses are also among the highest recorded. Despite the breadth of physiological and biochemical research on these associations, the underlying molecular mechanisms that regulate host and symbiont metabolite flux and carbon fixation are largely unknown. Here we present metabolite flux and transcriptomics data from shipboard high-pressure respirometry experiments in which we maintained Ridgeia piscesae tubeworms at conditions comparable to those in situ. Host trophosome was used for cDNA library construction and sequencing. Of the 19,132 clones sequenced, 10,684 represented unique expressed sequence tags (ESTs). The highest proportions of genes are involved with translation, ribosomal structure and biogenesis, cellular processing, and signal transduction. There was moderate representation of genes involved in metabolite exchange and acid-base regulation. These data represent the first concomitant surveys of metabolite flux rates and gene expression for a chemoautotrophic symbiosis during net autotrophy, and they suggest that-in the case of Ridgeia piscesae-host-symbiont interactions such as cell cycle regulation may play a significant role in maintaining physiological poise during high productivity.


Open-label trial with artemether-lumefantrine against uncomplicated Plasmodium falciparum malaria three years after its broad introduction in Jimma Zone, Ethiopia.
In Jimma Zone, Ethiopia, the first-line treatment of uncomplicated falciparum malaria has been changed from sulphadoxine-pyrimethamine (SP) to artemether-lumefantrine (AL) in 2006. The objective of this study was to assess the effectiveness of AL in Jimma Zone two to three years after its broad introduction. An open-label, single-arm, 42-day study of AL against falciparum malaria was conducted in four areas with moderate transmission in Jimma Zone between November 2008 and January 2009 and between August and December 2009. Patients (one-81 years) with uncomplicated Plasmodium falciparum mono-infection were consecutively enrolled. Follow-up visits were at day 2, 3, 7, 28 and 42 or any other day if symptoms reoccurred. Primary and secondary endpoints were PCR-corrected and uncorrected cure rates (molecular differentiation between recrudescence and re-infection) on days 28 and 42. Other secondary endpoints were gametocytaemia at day 7 and day 28, parasitaemia at day 2 and 3, and re-infection rates at day 28 and day 42. Of 348 enrolled patients, 313 and 301 completed follow-up at day 28 and at day 42, respectively. No early treatment failure occurred. For per protocol analysis, PCR-uncorrected cure rates at day 28 and 42 were 99.1% (95% CI 98.0-100.0) and 91.1% (95% CI 87.9-94.3), respectively. PCR-corrected cure rates at day 28 and 42 were 99.4% (95% CI 98.5-100.0) and 94.7% (95% CI 92.2-97.2), respectively. PCR-corrected cure rate at day 42 for children ≤ 5 years was 90.6% (95% CI 82.4-98.7) only. Adverse events were in general mild to moderate. Incidence of new infections was 3.4% during 42 days, no new infections with Plasmodium vivax were observed. Microscopically detected gametocytaemia was reduced by 80% between day 0 and day 7. In general, AL was effective and well tolerated in Jimma Zone, Ethiopia. However, the PCR-corrected recrudescence rate per-protocol at day 42 for children ≤ 5 years was 9.4%. Therefore, further development should be monitored on a regular basis as recommended by WHO.


Dissociation, trauma, and the role of lived experience: toward a new conceptualization of voice hearing.
Voice hearing (VH) is often regarded as pathognomic for schizophrenia. The purpose of this article is to review and integrate historical, clinical, epidemiological, and phenomenological evidence in order to suggest that VH may be more appropriately understood as a dissociative rather than a psychotic phenomenon. First, we discuss the lifetime prevalence of VH in the general population, which is estimated to range between 1% and 16% for adult nonclinical populations and 2% and 41% in healthy adolescent samples. Second, we demonstrate how the ubiquity of VH phenomenology, including variables like voice location, content, and frequency, limits its diagnostic and prognostic utility for differentiating psychotic from trauma-spectrum and nonclinical populations. Finally, we report on the empirical associations between VH, measures of dissociation, and trauma particularly (though not exclusively) childhood sexual abuse. There are 2 main conclusions from this review. First, we argue that available evidence suggests that VH experiences, including those in the context of psychotic disorders, can be most appropriately understood as dissociated or disowned components of the self (or self-other relationships) that result from trauma, loss, or other interpersonal stressors. Second, we provide a rationale for clinicians to use psychotherapeutic methods for integrating life events as precipitating and/or maintaining factors for distressing voices. Potential mechanisms for the relationship between trauma, dissociation, VH, and clinical diagnosis are described, including the relevance of literature from the field of attachment in providing a diathesis for dissociation. Suggestions for future research are also discussed.


Dose-response characteristics of methylphenidate on locomotor behavior and on sensory evoked potentials recorded from the VTA, NAc, and PFC in freely behaving rats.
Methylphenidate (MPD) is a psychostimulant commonly prescribed for attention deficit/hyperactivity disorder. The mode of action of the brain circuitry responsible for initiating the animals' behavior in response to psychostimulants is not well understood. There is some evidence that psychostimulants activate the ventral tegmental area (VTA), nucleus accumbens (NAc), and prefrontal cortex (PFC). The present study was designed to investigate the acute dose-response of MPD (0.6, 2.5, and 10.0 mg/kg) on locomotor behavior and sensory evoked potentials recorded from the VTA, NAc, and PFC in freely behaving rats previously implanted with permanent electrodes. For locomotor behavior, adult male Wistar-Kyoto (WKY; n = 39) rats were given saline on experimental day 1 and either saline or an acute injection of MPD (0.6, 2.5, or 10.0 mg/kg, i.p.) on experimental day 2. Locomotor activity was recorded for 2-h post injection on both days using an automated, computerized activity monitoring system. Electrophysiological recordings were also performed in the adult male WKY rats (n = 10). Five to seven days after the rats had recovered from the implantation of electrodes, each rat was placed in a sound-insulated, electrophysiological test chamber where its sensory evoked field potentials were recorded before and after saline and 0.6, 2.5, and 10.0 mg/kg MPD injection. Time interval between injections was 90 min. Results showed an increase in locomotion with dose-response characteristics, while a dose-response decrease in amplitude of the components of sensory evoked field responses of the VTA, NAc, and PFC neurons. For example, the P3 component of the sensory evoked field response of the VTA decreased by 19.8% +/- 7.4% from baseline after treatment of 0.6 mg/kg MPD, 37.8% +/- 5.9% after 2.5 mg/kg MPD, and 56.5% +/- 3.9% after 10 mg/kg MPD. Greater attenuation from baseline was observed in the NAc and PFC. Differences in the intensity of MPD-induced attenuation were also found among these brain areas. These results suggest that an acute treatment of MPD produces electrophysiologically detectable alterations at the neuronal level, as well as observable, behavioral responses. The present study is the first to investigate the acute dose-response effects of MPD on behavior in terms of locomotor activity and in the brain involving the sensory inputs of VTA, NAc, and PFC neurons in intact, non-anesthetized, freely behaving rats previously implanted with permanent electrodes.


Vitamin E supplementation during the dry period in dairy cattle. Part I: adverse effect on incidence of mastitis postpartum in a double-blind randomized field trial.
A randomized, controlled field trial with dairy cows demonstrated an adverse effect of vitamin E supplementation during the dry period on mastitis incidence in early lactation. This study was conducted on farms with historically high rates of mastitis to investigate the benefit of vitamin E supplementation on udder health; however, the outcome showed an adverse effect. The aim of the study was to evaluate whether daily supplementation of 3,000 IU of vitamin E to dairy cows during the dry period could improve udder health in commercial herds with a high incidence of mastitis. On 5 dairy farms, dry cows were randomly divided into 2 experimental groups: a high and a low group. Both groups received a dry cow mineral mix providing 3,000 or 135 IU of vitamin E/cow per day, respectively, between dry-off and calving for a mean period of 8 wk. Providing 3,000 IU of vitamin E exceeds NRC standards, but this amount has been used in previous studies. The experiment, as well as the majority of the statistical analysis, were carried out blinded. Blood was sampled 3 times before calving and on calving day. Serum was analyzed for vitamin E and cholesterol. Vitamin E and the vitamin E:cholesterol ratio were analyzed as dependent variables in mixed models and Student's t-tests to study trends in time and differences between groups. Relative risk calculation and survival analysis were used to study the effect of supplementation on mastitis incidence in the first 3 mo of lactation. The results showed that vitamin E supplements increased both absolute vitamin E and the ratio of vitamin E to cholesterol in blood. In the high group, significantly more subclinical and clinical cases occurred, showing the same trend on all farms. In this study, an initial vitamin E level at dry off above 14.5 μmol/L was a risk factor for clinical mastitis, suggesting that the vitamin E status at the start of the dry period is important. It is recommended to work out exactly at what threshold vitamin E is harmful for udder health before new trials with high dosages of vitamin E are started. Additionally, further research is required to investigate the mechanism by which vitamin E affects udder health.


Big catch, little sharks: Insight into Peruvian small-scale longline fisheries.
Shark take, driven by vast demand for meat and fins, is increasing. We set out to gain insights into the impact of small-scale longline fisheries in Peru. Onboard observers were used to document catch from 145 longline fishing trips (1668 fishing days) originating from Ilo, southern Peru. Fishing effort is divided into two seasons: targeting dolphinfish (Coryphaena hippurus; December to February) and sharks (March to November). A total of 16,610 sharks were observed caught, with 11,166 identified to species level. Of these, 70.6% were blue sharks (Prionace glauca), 28.4% short-fin mako sharks (Isurus oxyrinchus), and 1% were other species (including thresher (Alopias vulpinus), hammerhead (Sphyrna zygaena), porbeagle (Lamnus nasus), and other Carcharhinidae species (Carcharhinus brachyurus, Carcharhinus falciformis, Galeorhinus galeus). Mean ± SD catch per unit effort of 33.6 ± 10.9 sharks per 1000 hooks was calculated for the shark season and 1.9 ± 3.1 sharks per 1000 hooks were caught in the dolphinfish season. An average of 83.7% of sharks caught (74.7% blue sharks; 93.3% mako sharks) were deemed sexually immature and under the legal minimum landing size, which for species exhibiting k-selected life history traits can result in susceptibility to over exploitation. As these growing fisheries operate along the entire Peruvian coast and may catch millions of sharks per annum, we conclude that their continued expansion, along with ineffective legislative approaches resulting in removal of immature individuals, has the potential to threaten the sustainability of the fishery, its target species, and ecosystem. There is a need for additional monitoring and research to inform novel management strategies for sharks while maintaining fisher livelihoods.


An after-hours pediatric walk-in clinic for an entire urban community: utilization and effectiveness of follow-up care.
A retrospective record review was used to examine utilization of a pediatric walk-in clinic available to an entire urban community and to evaluate the effectiveness of follow-up care for a sample of the users of this facility who receive their regular pediatric care at a local comprehensive child health center. Results indicate that this walk-in facility is used extensively for the care of nonemergency conditions. The findings did not, however, support the generally accepted belief that a disproportionate number of Medicaid-supported and minority children overuse emergency type facilities. Utilization did not differ by race or medical care financing. Only 35.6% of the children who were advised to make a follow-up visit to the health center actually did so. White children complied significantly more often than black children (48.0% vs 15.8%). A larger percentage of patients for whom follow-up was optional (48.5%) than for whom follow-up was recommended (35.6%) made a return visit. Noncompliance with recommendations concerning follow-up care of adult users of emergency type facilities is a well recognized problem; the present study demonstrates a similar problem among children.


How E. coli DNA polymerase I (Klenow fragment) distinguishes between deoxy- and dideoxynucleotides.
Deoxy- and dideoxynucleotides differ only in whether they have a hydroxyl substituent at C-3' of the ribose moiety, and yet the Klenow fragment DNA polymerase prefers the natural (dNTP) substrate by several thousandfold. We have used this preference in order to investigate how Klenow fragment interacts with the sugar portion of an incoming dNTP. We screened mutant derivatives of Klenow fragment so as to identify those amino acid residues that play important roles in distinguishing between dNTPs and ddNTPs. Substitution of Phe762 with Ala or Tyr caused a dramatic decrease in the discrimination against ddNTPs, while mutations in Tyr766 and Glu710 had a smaller effect, suggesting that these two side-chains play secondary roles in the selection of dNTPs over ddNTPs. In order to understand the interactions in the enzyme-DNA-dNTP ternary complex, pre-steady-state kinetic parameters for the incorporation of dNTPs and ddNTPs were determined for wild-type Klenow fragment and for mutant derivatives that showed changes in dNTP/ddNTP discrimination. From elemental effect measurements we infer that selection against dideoxynucleotides takes place in the transition state for the conformational change that precedes phosphoryl transfer. The crucial role of the Phe762 side-chain appears to be to constrain the dNTP molecule so that the 3'-OH can make an interaction with another group within the ternary complex. When Tyr is substituted at position 762, the same interactions can take place to position the dNTP, but specificity against the ddNTP is lost because the phenolic OH can compensate for the missing 3'-OH of the nucleotide. Substitution of the smaller Ala side-chain results in a loss in specificity because the dNTP is no longer appropriately constrained. Measurement of reaction rates as a function of magnesium ion concentration suggests that the interaction made with the dNTP 3'-OH may involve a metal ion and the Glu710 side-chain, the simplest scenario being that both the 3'-OH and the carboxylate of Glu710 are ligands to the same metal ion.


Inhibition of renin angiotensin axis may be associated with reduced risk of developing venous thromboembolism in patients with atherosclerotic disease.
Arterial and venous thrombosis may share common pathophysiology involving the activation of platelets and inflammatory mediators. A growing body of evidence suggests prothrombotic effect of renin angiotensin system (RAS) including vascular inflammation and platelet activation. We hypothesized that the use of angiotensin converting enzyme inhibitors (ACEIs) or angiotensin receptor blockers (ARBs) plays a role in protecting against venous thromboembolism (VTE) in patients atherosclerosis. We conducted a retrospective study, reviewing 1,100 consecutive patients admitted to a teaching hospital with a diagnosis of either myocardial infarction or ischemic stroke from 2005 to 2010. Patients who had been treated with anticoagulation therapy before or after the first visit were excluded. The occurrence of VTE during the follow up period, risk factors for VTE on admission, and the use of ACEIs or ARBs during the follow up period were recorded. The mean age of the entire study population was 68.1 years. 52.0% of the patients were female and 76.5% were African American. 67.3% were on RAS inhibitors. The overall incidence of VTE was 9.7% (n = 107). Among the RAS inhibitor users, the incidence of VTE events was 9.0% (54/603) for the ACEI only users, 7.1% (8/113) for the ARB only users, and 0% (0/24) for the patients taking combination of ACEI and ARB. Among patients on RAS inhibitors, 8.4% (62/740) developed a VTE, compared with 12.5% (45/360) in the nonuser group [HR (hazard ratio), 0.58; 95% CI (confidence interval), 0.39-0.84; P<0.01]. Even after controlling for factors related to VTE (smoking, history of cancer, and immobilization, hormone use) and diabetes, the use of RAS inhibitors was still associated with a significantly lower risk of developing VTE (AHR, 0.59; 95% CI, 0.40-0.88; P = 0.01). The use of RAS inhibitors appears to be associated with a reduction in the risk of VTE.


FeCl3 catalysed 7-membered ring formation in a single pot: a new route to indole-fused oxepines/azepines and their cytotoxic activity.
Various oxepine and azepine fused N-heterocyclic derivatives were synthesized using a new and one-pot reaction of 2,3-dichloro quinoxaline/pyrazine with 2-(1H-indol-2-yl)phenol/aniline in the presence of 25 mol% FeCl3. The reaction proceeded via C-C bond followed by C-X (X = O or N) bond formation to construct the central 7-membered ring, affording the desired products in good yields. The structure assignment was confirmed by the single crystal X-ray analysis of a synthesized oxepine fused N-heterocycle derivative. Most of the synthesized compounds were found to be promising when tested for their anti-proliferative properties against cervical and breast cancer cell lines.


Realist synthesis: illustrating the method for implementation research.
Realist synthesis is an increasingly popular approach to the review and synthesis of evidence, which focuses on understanding the mechanisms by which an intervention works (or not). There are few published examples of realist synthesis. This paper therefore fills a gap by describing, in detail, the process used for a realist review and synthesis to answer the question 'what interventions and strategies are effective in enabling evidence-informed healthcare?' The strengths and challenges of conducting realist review are also considered. The realist approach involves identifying underlying causal mechanisms and exploring how they work under what conditions. The stages of this review included: defining the scope of the review (concept mining and framework formulation); searching for and scrutinising the evidence; extracting and synthesising the evidence; and developing the narrative, including hypotheses. Based on key terms and concepts related to various interventions to promote evidence-informed healthcare, we developed an outcome-focused theoretical framework. Questions were tailored for each of four theory/intervention areas within the theoretical framework and were used to guide development of a review and data extraction process. The search for literature within our first theory area, change agency, was executed and the screening procedure resulted in inclusion of 52 papers. Using the questions relevant to this theory area, data were extracted by one reviewer and validated by a second reviewer. Synthesis involved organisation of extracted data into evidence tables, theming and formulation of chains of inference, linking between the chains of inference, and hypothesis formulation. The narrative was developed around the hypotheses generated within the change agency theory area. Realist synthesis lends itself to the review of complex interventions because it accounts for context as well as outcomes in the process of systematically and transparently synthesising relevant literature. While realist synthesis demands flexible thinking and the ability to deal with complexity, the rewards include the potential for more pragmatic conclusions than alternative approaches to systematic reviewing. A separate publication will report the findings of the review.


Glomerular filtration rate determined by measuring serum clearance of a single dose of inulin and serum symmetric dimethylarginine concentration in clinically normal cheetahs (Acinonyx jubatus).
To establish a reference interval for glomerular filtration rate (GFR) determined by measuring serum clearance of a single IV dose of inulin in clinically normal cheetahs (Acinonyx jubatus) and compare serum symmetric dimethylarginine (SDMA) concentration in cheetahs with GFR. 33 cheetahs housed at 3 institutions. A single bolus of inulin (3,000 mg/m2) was administered IV, and 5 serial blood samples were collected and analyzed for serum inulin concentration with the anthrone technique. The GFR was estimated with a modified slope-intercept method for the slow component of the serum concentration-versus-time curve. Blood urea nitrogen and serum creatinine concentrations were measured in samples obtained immediately prior to inulin administration, and serum SDMA concentration was measured in stored samples. Mean ± SD measured GFR was 1.58 ± 0.39 mL/min/kg, and the calculated reference interval was 0.84 to 2.37 mL/min/kg. There were significant negative correlations between GFR and serum creatinine concentration (r = -0.499), BUN concentration (r = -0.592), and age (r = -0.463). Serum SDMA concentration was not significantly correlated with GFR (r = 0.385), BUN concentration (r = -0.281), or serum creatinine concentration (r = 0.165). A reference interval for GFR in clinically normal cheetahs was obtained. Further evaluation of animals with renal disease is needed to determine whether measuring serum clearance of a single IV dose of inulin is a reliable diagnostic test for early detection of renal disease in cheetahs.


HIV-1 exposed uninfected men who have sex with men have increased levels of salivary CC-chemokines associated with sexual behavior.
To determine whether soluble molecules with known anti-HIV-1 activity are increased in saliva of HIV-1 exposed uninfected individuals of discordant couples of men who have sex with men (MSM), and whether the levels of these molecules are associated with genetic polymorphisms, sexual behavior and/or HIV-1 neutralizing capacity. Saliva and PBMC were collected from exposed uninfected individuals (n=25), and low-risk controls (n=22). Levels of CCL2, CCL3, CCL4, CCL5 and CCL11 were detected by Luminex, and SLPI, LL-37, alpha-defensins and IgA2 were detected by ELISA. Single nucleotide polymorphisms (SNPs) were investigated using mass spectrometry or PCR-sequencing. HIV-1 neutralizing activity was assessed using PBMCbased neutralization assays. Self-reported questionnaires described sexual behavior. Exposed uninfected individuals had significantly higher levels of salivary CCL2, CCL4, CCL5 and CCL11 as compared with controls although genetic polymorphisms within the corresponding regions were equally distributed. IgA2 was also increased in exposed uninfected individuals, whereas neither CCL3, SLPI, LL-37 nor alpha-defensins differed between exposed uninfected individuals and controls. The HIV-1 neutralizing capacity of saliva was associated with higher levels of CC-chemokines (but not SLPI, LL-37, alpha-defensins or IgA2) in both exposed uninfected individuals and controls. The increased levels of CC-chemokines were associated with a higher frequency of unprotected oral sex and/or additional casual sex partners. HIV-1 exposed uninfected MSM had higher levels of salivary CC-chemokines compared with controls, this finding associated with sexual behavior rather than with genetic polymorphisms. The increased levels of CC-chemokines associated with HIV-1 neutralizing capacity in saliva.


Myocardial Steatosis Among Antiretroviral Therapy-Treated People With Human Immunodeficiency Virus Participating in the REPRIEVE Trial.
People with human immunodeficiency virus (PWH) face increased risks for heart failure and adverse heart failure outcomes. Myocardial steatosis predisposes to diastolic dysfunction, a heart failure precursor. We aimed to characterize myocardial steatosis and associated potential risk factors among a subset of the Randomized Trial to Prevent Vascular Events in HIV (REPRIEVE) participants. Eighty-two PWH without known heart failure successfully underwent cardiovascular magnetic resonance spectroscopy, yielding data on intramyocardial triglyceride (IMTG) content (a continuous marker for myocardial steatosis extent). Logistic regression models were applied to investigate associations between select clinical characteristics and odds of increased or markedly increased IMTG content. Median (Q1, Q3) IMTG content was 0.59% (0.28%, 1.15%). IMTG content was increased (> 0.5%) among 52% and markedly increased (> 1.5%) among 22% of participants. Parameters associated with increased IMTG content included age (P = .013), body mass index (BMI) ≥ 25 kg/m2 (P = .055), history of intravenous drug use (IVDU) (P = .033), and nadir CD4 count < 350 cells/mm³ (P = .055). Age and BMI ≥ 25 kg/m2 were additionally associated with increased odds of markedly increased IMTG content (P = .049 and P = .046, respectively). A substantial proportion of antiretroviral therapy-treated PWH exhibited myocardial steatosis. Age, BMI ≥ 25 kg/m2, low nadir CD4 count, and history of IVDU emerged as possible risk factors for myocardial steatosis in this group. NCT02344290; NCT03238755.


Caregivers' beliefs about dementia: findings from the IDEAL study.
Objective: Informal caregivers of people with dementia develop their own beliefs about the condition, referred to as Dementia Representations (DRs), as they try to make sense of the changes they are observing. The first aim of this study was to provide a profile of the types of DRs held by caregivers. The second aim was to examine the impact of caregivers' DRs on their well-being, satisfaction with life (SwL) and caregiving stress. Methods: Participants were 1264 informal caregivers of people in the mild-to-moderate stages of dementia from time-point 1 of the IDEAL cohort study. Measures: DRs were measured using questionnaire items covering: Identity, Cause, Control, and Timeline. Results: Almost half (49.2%) of caregivers used a diagnostic term to describe the person's condition, although 93.4% of caregivers stated they were aware of the diagnosis. Higher well-being, SwL, and lower caregiving stress were associated with the use of an identity term relating to specific symptoms of dementia, attributing the cause to ageing or not knowing the cause, and believing the condition would stay the same. Lower well-being, SwL, and higher caregiving stress were associated with believing there was little that could be done to control the effects of the condition. Conclusion: Healthcare professionals should assess and gain an understanding of caregivers' DRs in order to provide more tailored information and support.


[Perception of abuse among medical students of the University of Chile].
Even though studying Medicine and perceiving abuse seem to be two opposite situations, recent investigations in Chile and abroad find that this is a frequent and pervasive combination. These studies also report the negative effects in the lives of students as well as the impact on the profession as a whole. To ascertain the perception of abusive situations in medical students during training at the University of Chile. Descriptive and cross sectional study in which a questionnaire was applied to all the students enrolled in 2nd, 3rd, 5th and 7th year during 2001 and 2002. Using short vignettes, they were asked if they had experienced verbal, psychological, physical and sexual abuse, at least once, during their training, by whom and the eventual effects derived from it. We obtained 757 questionnaires. Of the surveyed students, 91% reported having perceived at least one abusive episode during training. Teachers and fellow students were identified as the main offenders. Among the effects of such behavior, 32% mentioned that they considered dropping out of the career as a consequence of this experience. The perception of abuse in medical students is common and has adverse effects. Efforts should be made to draw attention to this problem to prevent it.


The use of mobile phone data to inform analysis of COVID-19 pandemic epidemiology.
The ongoing coronavirus disease 2019 (COVID-19) pandemic has heightened discussion of the use of mobile phone data in outbreak response. Mobile phone data have been proposed to monitor effectiveness of non-pharmaceutical interventions, to assess potential drivers of spatiotemporal spread, and to support contact tracing efforts. While these data may be an important part of COVID-19 response, their use must be considered alongside a careful understanding of the behaviors and populations they capture. Here, we review the different applications for mobile phone data in guiding and evaluating COVID-19 response, the relevance of these applications for infectious disease transmission and control, and potential sources and implications of selection bias in mobile phone data. We also discuss best practices and potential pitfalls for directly integrating the collection, analysis, and interpretation of these data into public health decision making.


Laboratory Rodent Diets Contain Toxic Levels of Environmental Contaminants: Implications for Regulatory Tests.
The quality of diets in rodent feeding trials is crucial. We describe the contamination with environmental pollutants of 13 laboratory rodent diets from 5 continents. Measurements were performed using accredited methodologies. All diets were contaminated with pesticides (1-6 out of 262 measured), heavy metals (2-3 out of 4, mostly lead and cadmium), PCDD/Fs (1-13 out of 17) and PCBs (5-15 out of 18). Out of 22 GMOs tested for, Roundup-tolerant GMOs were the most frequently detected, constituting up to 48% of the diet. The main pesticide detected was Roundup, with residues of glyphosate and AMPA in 9 of the 13 diets, up to 370 ppb. The levels correlated with the amount of Roundup-tolerant GMOs. Toxic effects of these pollutants on liver, neurodevelopment, and reproduction are documented. The sum of the hazard quotients of the pollutants in the diets (an estimator of risk with a threshold of 1) varied from 15.8 to 40.5. Thus the chronic consumption of these diets can be considered at risk. Efforts toward safer diets will improve the reliability of toxicity tests in biomedical research and regulatory toxicology.


Genomic organization and evolution of the CX3CR1/CCR8 chemokine receptor locus.
The chemokine receptors CCR8 and CX3CR1 are key players in adaptive immunity and are co-receptors for human immunodeficiency virus. We describe here the genomic organization and evolutionary history of both of these genes. CX3CR1 has three promoters that transcribe three separate exons that are spliced with a fourth exon containing the coding region. CCR8 has two promoters. One promoter produces a transcript of two spliced exons, and the other promoter transcribes an exon containing the coding region and lacks introns. We analyzed these promoters in the context of a luciferase reporter and identified several positive and negative regulatory elements. Identification of the genomic organization of these genes in mouse demonstrates a similar organization for CCR8, but mouse CX3CR1 lacks two of the human promoters and has an additional mouse-specific promoter that transcribes only the exon containing the coding region and therefore resembles the organization of the human and mouse CCR8 genes. We also identify two nontranscribed regions that are highly conserved between human and mouse CX3CR1 containing possible regulatory elements. Examination of the CX3CR1 and CCR8 genes and surrounding genomic regions indicates that these genes are the result of the duplication of an ancestral gene prior to the divergence of teleost fish. We characterize single nucleotide polymorphisms in the promoters of human CCR8 and CX3CR1 and establish linkage relationships between CX3CR1 promoter polymorphisms and two previously described CX3CR1 coding polymorphisms associated with human immunodeficiency virus disease progression and arteriosclerosis susceptibility.


Infant feeding among HIV-positive mothers and the general population mothers: comparison of two cross-sectional surveys in Eastern Uganda.
Infant feeding recommendations for HIV-positive mothers differ from recommendations to mothers of unknown HIV-status. The aim of this study was to compare feeding practices, including breastfeeding, between infants and young children of HIV-positive mothers and infants of mothers in the general population of Uganda. This study compares two cross-sectional surveys conducted in the end of 2003 and the beginning of 2005 in Eastern Uganda using analogous questionnaires. The first survey consisted of 727 randomly selected general-population mother-infant pairs with unknown HIV status. The second included 235 HIV-positive mothers affiliated to The Aids Support Organisation, TASO. In this article we compare early feeding practices, breastfeeding duration, feeding patterns with dietary information and socio-economic differences in the two groups of mothers. Pre-lacteal feeding was given to 150 (64%) infants of the HIV-positive mothers and 414 (57%) infants of general-population mothers. Exclusive breastfeeding of infants under the age of 6 months was more common in the general population than among the HIV-positive mothers (186 [45%] vs. 9 [24%] respectively according to 24-hour recall). Mixed feeding was the most common practice in both groups of mothers. Solid foods were introduced to more than half of the infants under 6 months old among the HIV-positive mothers and a quarter of the infants in the general population. Among the HIV-positive mothers with infants below 12 months of age, 24 of 90 (27%) had stopped breastfeeding, in contrast to 9 of 727 (1%) in the general population. The HIV-positive mothers were poorer and had less education than the general-population mothers. In many respects, HIV-positive mothers fed their infants less favourably than mothers in the general population, with potentially detrimental effects on both the child's nutrition and the risk of HIV transmission. Mixed feeding and pre-lacteal feeding were widespread. Breastfeeding duration was shorter among HIV-positive mothers. Higher educational level and being socio-economically better off were associated with more beneficial infant feeding practices.


Heterogeneity of neuromasts in a fish without lateral line canals: the pufferfish (Takifugu obscurus) model.
Fish detect water motion with their mechanosensory lateral line. The basic functional unit of the lateral line is the neuromast. In most fish species, neuromasts are located in lateral line canals (canal neuromasts) or on the skin (superficial neuromasts). In this paper, we describe the lateral line system of the pufferfish, Takifugu obscurus If threatened, this fish inflates its body by sucking water into the esophagus. Pufferfish lack a canal system but have neuromasts located directly on the skin or in open grooves. Each groove houses tall, medium and short neuromasts, based on the height of their pedestal. One or more medium neuromasts were always located between two tall neuromasts, and the short neuromasts were scattered between them. Tall neuromasts showed phasic responses to water jets, similar to the canal neuromasts of other fish species. In contrast, the medium and short neuromasts showed tonic responses to water jets. The response properties of nerve fibers that innervated the medium and short neuromasts were similar to those of the superficial neuromasts found in other fish species. Our results suggest that each groove of a pufferfish has two functional groups of neuromasts. This may allow pufferfish to extract spatial and temporal hydrodynamic information, despite the changes in body shape that occur during and after inflation. The short neuromasts at the bottom of a groove most likely supplement the medium neuromasts when the body is maximally inflated.


Genesis of anxiety, depression, and ongoing abdominal discomfort in ulcerative colitis-like colon inflammation.
Psychological disorders are prevalent in patients with inflammatory bowel disease; the underlying mechanisms remain unknown. We tested the hypothesis that ulcerative colitis-like inflammation induced by dextran sodium sulfate (DSS) exacerbates the ongoing spontaneous activity in colon-projecting afferent neurons that induces abdominal discomfort and anxiety, and depressive-like behaviors in rats. In this study, we used the conditioned place preference and standard tests for anxiety- and depression-like behaviors. DSS rats developed anxiety- and depression-like behaviors 10 to 20 days after the start of inflammation. Single-fiber recordings showed an increase in the frequency of spontaneous activity in L6-S1 dorsal root ganglion (DRG) roots. Prolonged desensitization of transient receptor potential vanilloid 1 (TRPV1)-expressing colonic afferents by resiniferatoxin (RTX) suppressed the spontaneous activity, as well as the anxiety- and depressive-like behaviors. Reduction in spontaneous activity in colon afferents by intracolonic administration of lidocaine produced robust conditioned place preference (CPP) in DSS rats, but not in control rats. Patch-clamp studies demonstrated a significant decrease in the resting membrane potential, lower rheobase, and sensitization of colon-projecting L6-S1 DRG neurons to generate trains of action potentials in response to current injection in DSS rats. DSS inflammation upregulated the mRNA levels of transient receptor potential ankyrin 1 and TRPV1 channels and downregulated that of Kv1.1 and Kv1.4 channels. Ulcerative colitis-like inflammation in rats induces anxiety- and depression-like behaviors, as well as ongoing abdominal discomfort by exacerbating the spontaneous activity in the colon-projecting afferent neurons. Alterations in the expression of voltage- and ligand-gated channels are associated with the induction of mood disorders following colon inflammation.


Soft Tissue Atrophy Related to Corticosteroid Injection: Review of the Literature and Implications for Hand Surgeons.
Corticosteroid injections (CIs) are frequently used by hand surgeons to treat a wide range of pathology including de Quervain tenosynovitis and lateral epicondylitis. Although generally viewed as a benign modality, and a way to potentially avoid or postpone surgical intervention, common complications from CI should be considered and discussed with patients before the procedure. One such complication is local soft tissue atrophy and hypopigmentation after injection. We discuss the incidence of soft tissue-related adverse effects from CI, the pathophysiology and influence of different steroid preparations on soft tissues, and potential treatment options once atrophy has occurred.