Lamin A/C is a risk biomarker in colorectal cancer.
A-type lamins are type V intermediate filament proteins encoded by the gene LMNA. Mutations in LMNA give rise to diverse degenerative diseases related to premature ageing. A-type lamins also influence the activity of the Retinoblastoma protein (pRb) and oncogenes such a beta-catenin. Consequently, it has been speculated that expression of A-type lamins may also influence tumour progression. An archive of colorectal cancer (CRC) and normal colon tissue was screened for expression of A-type lamins. We used the Cox proportional hazard ratio (HR) method to investigate patient survival. Using CRC cell lines we investigated the effects of lamin A expression on other genes by RT-PCR; on cell growth by FACS analysis; and on invasiveness by cell migration assays and siRNA knockdown of targeted genes. We found that lamin A is expressed in colonic stem cells and that patients with A-type lamin-expressing tumours have significantly worse prognosis than patients with A-type lamin negative tumours (HR = 1.85, p = 0.005). To understand this finding, we established a model system based upon expression of GFP-lamin A in CRC cells. We found that expression of GFP-lamin A in these cells did not affect cell proliferation but did promote greatly increased cell motility and invasiveness. The reason for this increased invasiveness was that expression of lamin A promoted up-regulation of the actin bundling protein T-plastin, leading to down regulation of the cell adhesion molecule E-cadherin. Expression of A-type lamins increases the risk of death from CRC because its presence gives rise to increased invasiveness and potentially a more stem cell-like phenotype. This report directly links A-type lamin expression to tumour progression and raises the profile of LMNA from one implicated in multiple but rare genetic conditions to a gene involved in one of the commonest diseases in the Western World.


Morphological changes in hippocampal cytoarchitecture as a function of spatial treatment in birds.
Maintaining cognitive processes comes with neurological costs. Thus, enhanced cognition and its underlying neural mechanisms should change in response to environmental pressures. Indeed, recent evidence suggests that variation in spatially based cognitive abilities is reflected in the morphology of the hippocampus (Hp), the region of the brain involved in spatial memory. Moreover, recent work on this region establishes a dynamic link between brain plasticity and cognitive experiences both across populations and within individuals. However, the mechanisms involved in neurological changes as a result of differential space use and the reversibility of such effects are unknown. Using a house sparrow (Passer domesticus) model, we experimentally manipulated the space available to birds, testing the hypothesis that reductions in dendritic branching is associated with reduced Hp volume and that such reductions in volume are reversible. We found that reduced spatial availability associated with captivity had a profound and significant reduction in sparrow hippocampal volumes, which was highly correlated with the total length of dendrites in the region. This result suggests that changes to the dendritic structure of neurons may, in part, explain volumetric reductions in region size associated with captivity. In addition, small changes in available space even within captivity produced significant changes in the spine structure on Hp dendrites. These reductions were reversible following increased spatial opportunities. Overall, these results are consistent with the hypothesis that reductions to the Hp in captivity, often assumed to reflect a deleterious process, may be adaptive and a consequence of the trade-off between cognitive and energetic demands. © 2016 Wiley Periodicals, Inc. Develop Neurobiol 77: 93-101, 2017.


Essential articles on collaborative care models for the treatment of psychiatric disorders in medical settings: a publication by the academy of psychosomatic medicine research and evidence-based practice committee.
Collaborative care interventions for psychiatric disorders combine several components integrated into the medical setting: (1) systematic psychiatric assessment, (2) use of a nonphysician care manager to perform longitudinal symptom monitoring, treatment interventions, and care coordination, and (3) specialist-provided stepped-care recommendations. Collaborative care interventions have now been evaluated in a wide spectrum of care settings and offer great promise as a way of increasing quality of patient care, improving health of populations, and reducing health care costs. A systematic search of PubMed/MEDLINE databases was performed for publications between January 1970 and May 2013 to identify articles describing collaborative care and related interventions. Identified articles were then evaluated independently by multiple reviewers for quality and importance; additional articles were identified by searching reference lists and through recommendations of senior content-matter experts. The articles considered to be both of high quality and most important were then placed into categories and annotated reviews performed. Over 600 articles were identified of which 67 were selected for annotated review. The results reported in these articles indicate that collaborative care interventions for psychiatric disorders have been consistently successful in improving key outcomes in both research and clinical intervention studies; cost analyses also suggest that this model is cost effective. Collaborative care models for psychiatric disorders are likely to serve an increasingly large role in health care given their effect on patient and population outcomes and their focus on integration of care.


Expanded validation of the EPIC bowel and urinary domains for use in women with gynecologic cancer undergoing postoperative radiotherapy.
Women with endometrial or cervical cancer at risk for recurrence receive postoperative radiation therapy (RT). A patient reported outcomes (PRO) instrument to assess bowel and urinary toxicities is the Expanded Prostate Cancer Index Composite (EPIC), which has been validated in men with prostate cancer. As this instrument specifically measures bowel toxicity and the degree to which this is a problem, it was used in NRG Oncology/RTOG 1203 to compare intensity modulated RT (IMRT) to standard RT. This paper reports on the expanded validation of EPIC for use in women receiving pelvic RT. In addition to the EPIC bowel domain, urinary toxicity (EPIC urinary domain), patient reported bowel toxicities (PRO-CTCAE) and quality of life (Functional Assessment of Cancer Therapy (FACT)) were completed before, during and after treatment. Sensitivity, reliability and concurrent validity were assessed. Mean bowel and urinary scores among 278 women enrolled were significantly worse during treatment and differed between groups. Acceptable to good reliability for bowel and urinary domain scores were obtained at all time points with the exception of one at baseline. Correlations between function and bother scores within the bowel and urinary domains were consistently stronger than those across domains. Correlations between bowel domain scores and PRO-CTCAE during treatment were stronger than those with the FACT. Correlations within and among the instruments indicate EPIC bowel and urinary domains are measuring conceptually discrete components of health. These EPIC domains are valid, reliable and sensitive instruments to measure PRO among women undergoing pelvic radiation.


Mutation in the AP4B1 gene cause hereditary spastic paraplegia type 47 (SPG47) .
We recently identified a new locus for spastic paraplegia type 47 (SPG47) in a consanguineous Arabic family with two affected siblings with progressive spastic paraparesis,intellectual disability, seizures, periventricular white matter changes and thin corpus callosum. Using exome sequencing, we now identified a novel AP4B1 frameshift mutation (c.664delC) in this family. This mutation was homozygous in both affected siblings and heterozygous in both parents. The mutant allele was absent in 316 Caucasian and 200 ethnically matched control chromosomes. We propose that AP4B1 mutations cause SPG47 and should be considered in early onset spastic paraplegia with intellectual disability.


Boiler briquette coal versus raw coal: Part I--Stack gas emissions.
Stack gas emissions were characterized for a steam-generating boiler commonly used in China. The boiler was tested when fired with a newly formulated boiler briquette coal (BB-coal) and when fired with conventional raw coal (R-coal). The stack gas emissions were analyzed to determine emission rates and emission factors and to develop chemical source profiles. A dilution source sampling system was used to collect PM on both Teflon membrane filters and quartz fiber filters. The Teflon filters were analyzed gravimetrically for PM10 and PM2.5 mass concentrations and by X-ray fluorescence (XRF) for trace elements. The quartz fiber filters were analyzed for organic carbon (OC) and elemental carbon (EC) using a thermal/optical reflectance technique. Sulfur dioxide was measured using the standard wet chemistry method. Carbon monoxide was measured using an Orsat combustion analyzer. The emission rates of the R-coal combustion (in kg/hr), determined using the measured stack gas concentrations and the stack gas emission rates, were 0.74 for PM10, 0.38 for PM2.5, 20.7 for SO2, and 6.8 for CO, while those of the BB-coal combustion were 0.95 for PM10, 0.30 for PM2.5, 7.5 for SO2, and 5.3 for CO. The fuel-mass-based emission factors (in g/kg) of the R-coal, determined using the emission rates and the fuel burn rates, were 1.68 for PM10, 0.87 for PM2.5, 46.7 for SO2, and 15 for CO, while those of the BB-coal were 2.51 for PM10, 0.79 for PM2.5, 19.9 for SO2, and 14 for CO. The task-based emission factors (in g/ton steam generated) of the R-coal, determined using the fuel-mass-based emission factors and the coal/steam conversion factors, were 0.23 for PM10, 0.12 for PM2.5, 6.4 for SO2, and 2.0 for CO, while those of the BB-coal were 0.30 for PM10, 0.094 for PM2.5, 2.4 for SO2, and 1.7 for CO. PM10 and PM2.5 elemental compositions are also presented for both types of coal tested in the study.


Low calcaneal bone mineral density and the risk of distal forearm fracture in women and men: a population-based case-control study.
We used dual X-ray absorptiometry (DXA) to measure calcaneal bone mineral density (BMD) and estimate the prevalence of osteoporosis in a population with distal forearm fracture and a normative cohort. Patients 20 to 80 years of age with distal forearm fracture treated at one emergency hospital during two consecutive years were invited to calcaneal BMD measurement; 270 women (81%) and 64 men (73%) participated. A DXA heel scanner estimated BMD (g/cm(2)) and T-scores. Osteoporosis was defined as T-score< or =-2.5 SD. Of the fracture cohort, 254 women aged 40-80 years and 27 men aged 60-80 years were compared with population-based control cohorts comprising 171 women in the age groups 50, 60, 70 and 80 years and 75 men in the age groups 60, 70, and 80 years. In the fracture population no woman below 40 years or man below 60 years of age had osteoporosis. In women aged 40-80 years the prevalence of osteoporosis in the distal forearm fracture cohort was 34% and in the population-based controls was 25%; the age-adjusted prevalence ratio (PR) was 1.32 (95% CI 1.00-1.76). In the subgroup of women aged 60-80 years the age-adjusted prevalence ratio of osteoporosis was 1.28 (95% CI 0.95-1.71). In men aged 60-80 years the prevalence of osteoporosis in the fracture cohort was 44% and in the population-based controls was 8% (PR 6.31, 95% CI 2.78-14.4). The age-adjusted odds ratio for fracture associated with a 1-SD reduction in calcaneal BMD was in women aged 40-80 years 1.4 (95% CI 1.1-1.8), in the subgroup of women aged 60-80 years 1.2 (95% CI 0.95-1.6), and in men aged 60-80 years 2.6 (95% CI 1.7-4.1). Among those aged 60-80 years the area under the ROC curve was in women 0.56 (95% CI 0.49-0.63) and in men 0.80 (95% CI 0.70-0.80). The age-adjusted prevalence of osteoporosis based on calcaneal BMD is higher in individuals with distal forearm fracture than in population-based controls. BMD impairment is associated with increased odds ratio for forearm fracture in both women and men but the differences between cases and controls are more pronounced in men than in women, which may have implications in fracture prevention.


Combretastatin A4-camptothecin micelles as combination therapy for effective anticancer activity.
Cancer is a major worldwide health problem, for which chemotherapy is a common treatment option. However drug toxicity and the development of resistance to chemotherapy are two main challenges associated with the traditional anticancer drugs. Combined pharmacological therapy based on different mechanisms might be an effective strategy in cancer treatment, and could exhibit a synergistic therapeutic efficacy. Herein, we aim to combine combretastatin A4 (CA4) and camptothecin (Cpt) chemically into a codrug through two hydrophilic linkers utilizing click chemistry to improve their water solubility and anticancer activity. The synthesized amphiphilic structure could self-assemble into a micelle structure as confirmed by atomic force microscopy (AFM) and dynamic light scattering (DLS), which showed a high stability and improved water solubility at pH 7.4, with a low critical micelle concentration (CMC) value of 0.9 mM. Moreover, in vitro hydrolysis was observed upon incubation of the hybrid compound with an esterase enzyme, which suggested a complete disassembly into the starting active drugs. Finally, cytotoxicity studies on HeLa cancer cells showed that the codrug demonstrated an enhanced (five fold) cytotoxicity as compared with the free drugs. In addition the combination index (CI) was <1, which suggests a synergistic activity for the codrug. Moreover, the tested concentrations of the codrug were not significantly cytotoxic to a noncancerous fibroblast cell line. The imaging of HeLa cells treated with FITC-loaded micelles showed a rapid internalization. In conclusion, the codrug of CA4 and Cpt might be a potential novel anticancer drug as it demonstrated a synergistic cytotoxic activity that might spare noncancerous cells.


Recent ecological selection on regulatory divergence is shaping clinal variation in senecio on Mount Etna.
The hybrid zone on Mount Etna (Sicily) between Senecio aethnensis and Senecio chrysanthemifolius (two morphologically and physiologically distinct species) is a classic example of an altitudinal cline. Hybridization at intermediate altitudes and gradients in phenotypic and life-history traits occur along altitudinal transects of the volcano. The cline is considered to be a good example of ecological selection with species differences arising by divergent selection opposing gene flow. However, the possibility that the cline formed from recent secondary contact following an allopatric phase is difficult to exclude. We demonstrate a recent split between S. aethnensis and S. chrysanthemifolius (as recent as ∼32,000 years ago) and sufficient gene flow (2Nm > 1) to have prevented divergence (implicating a role for diversifying selection in the maintenance of the cline). Differentially expressed genes between S. aethnensis and S. chrysanthemifolius exhibit significantly higher genetic divergence relative to "expression invariant" controls, suggesting that species differences may in part be mediated by divergent selection on differentially expressed genes involved with altitude-related adaptation. The recent split time and the absence of fixed differences between these two ecologically distinct species suggest the rapid evolution to an altitudinal cline involving selection on both sequence and expression variation.


Access to medicines and domestic compulsory licensing: learning from Canada and Thailand.
Within the array of measures for improving medicines access for the world's neediest populations, governments of many countries have turned to compulsory licensing, a statutory mechanism to enable third parties to manufacture a product or process still under patent. In this paper, we focus on a historic case example from Canada and the present example of Thailand's use of domestic compulsory licenses as a policy tool for ensuring public access to affordable medicines. The overarching objective is to draw out policy and legislative insights that may be of value for countries with pharmaceutical manufacturing capacity and which are considering better access to patented medicines for their populations under the current global intellectual property regime. From these cases, it is apparent that although compulsory licensing is not a novel remedy, even in a post-Trade Related Aspects of Intellectual Property Rights environment, it remains a powerful policy tool in improving access to medicines in a variety of domestic settings.


Women's information needs around urine testing for urinary tract infections: a qualitative study.
Urinary tract infection (UTI) is one of the commonest bacterial infections in general practice, with urine testing a frequent feature of its management. Urinary dipsticks are widely used, with urine culture the reference standard test. To avoid contamination, patients are advised to discard the first part of the urine stream, retaining the midstream part for the sample. This process, however, can be challenging both to explain and to perform. There is a lack of literature investigating women's perceptions and understanding of urine sampling. To explore women's understanding of urine collection, sample contamination, and how information from samples informed UTI management. Qualitative study embedded in a UK randomised controlled trial (RCT) of urinary collection devices (UCDs) among women attending primary care with a suspected UTI. Semi-structured telephone interviews were conducted with 29 women participating in the RCT. Interviews were transcribed and thematically analysed. Participants were not always aware about what midstream samples were and why they were preferable. They also lacked understanding about how urine samples may be contaminated, and sources of contamination. Participants experienced variability in the information received following analysis of their sample. Provision of clear information could help provide better urine samples, aiding the diagnosis of UTIs, presenting results with greater clarity, and creating less need for repeat samples. Sharing of information derived from uncontaminated samples may also support better UTI management, helping to reduce unnecessary prescribing and antibiotic resistance.


The nuclear receptors of Biomphalaria glabrata and Lottia gigantea: implications for developing new model organisms.
Nuclear receptors (NRs) are transcription regulators involved in an array of diverse physiological functions including key roles in endocrine and metabolic function. The aim of this study was to identify nuclear receptors in the fully sequenced genome of the gastropod snail, Biomphalaria glabrata, intermediate host for Schistosoma mansoni and compare these to known vertebrate NRs, with a view to assessing the snail's potential as a invertebrate model organism for endocrine function, both as a prospective new test organism and to elucidate the fundamental genetic and mechanistic causes of disease. For comparative purposes, the genome of a second gastropod, the owl limpet, Lottia gigantea was also investigated for nuclear receptors. Thirty-nine and thirty-three putative NRs were identified from the B. glabrata and L. gigantea genomes respectively, based on the presence of a conserved DNA-binding domain and/or ligand-binding domain. Nuclear receptor transcript expression was confirmed and sequences were subjected to a comparative phylogenetic analysis, which demonstrated that these molluscs have representatives of all the major NR subfamilies (1-6). Many of the identified NRs are conserved between vertebrates and invertebrates, however differences exist, most notably, the absence of receptors of Group 3C, which includes some of the vertebrate endocrine hormone targets. The mollusc genomes also contain NR homologues that are present in insects and nematodes but not in vertebrates, such as Group 1J (HR48/DAF12/HR96). The identification of many shared receptors between humans and molluscs indicates the potential for molluscs as model organisms; however the absence of several steroid hormone receptors indicates snail endocrine systems are fundamentally different.


Insights on the emergence of Mycobacterium tuberculosis from the analysis of Mycobacterium kansasii.
By phylogenetic analysis, Mycobacterium kansasii is closely related to Mycobacterium tuberculosis. Yet, although both organisms cause pulmonary disease, M. tuberculosis is a global health menace, whereas M. kansasii is an opportunistic pathogen. To illuminate the differences between these organisms, we have sequenced the genome of M. kansasii ATCC 12478 and its plasmid (pMK12478) and conducted side-by-side in vitro and in vivo investigations of these two organisms. The M. kansasii genome is 6,432,277 bp, more than 2 Mb longer than that of M. tuberculosis H37Rv, and the plasmid contains 144,951 bp. Pairwise comparisons reveal conserved and discordant genes and genomic regions. A notable example of genomic conservation is the virulence locus ESX-1, which is intact and functional in the low-virulence M. kansasii, potentially mediating phagosomal disruption. Differences between these organisms include a decreased predicted metabolic capacity, an increased proportion of toxin-antitoxin genes, and the acquisition of M. tuberculosis-specific genes in the pathogen since their common ancestor. Consistent with their distinct epidemiologic profiles, following infection of C57BL/6 mice, M. kansasii counts increased by less than 10-fold over 6 weeks, whereas M. tuberculosis counts increased by over 10,000-fold in just 3 weeks. Together, these data suggest that M. kansasii can serve as an image of the environmental ancestor of M. tuberculosis before its emergence as a professional pathogen, and can be used as a model organism to study the switch from an environmental opportunistic pathogen to a professional host-restricted pathogen.


Intestinal plasticity in response to nutrition and gastrointestinal surgery.
The plasticity of a material corresponds to its capacity to change its feature under the effect of an external action. Intestinal plasticity could be defined as the ability of the intestine to modify its size or thickness and intestinal cells to modulate their absorption and secretion functions in response to external or internal cues/signals. This review will focus on intestinal adaptation mechanisms in response to diet and nutritional status. These physiological mechanisms allow a fine and rapid adaptation of the gut to promote absorption of ingested food, but they can also lead to obesity in response to overnutrition. This plasticity could thus become a therapeutic target to treat not only undernutrition but also obesity. How the intestine adapts in response to 2 types of surgical remodeling of the digestive tract-extensive bowel resection leading to intestinal failure and surgical treatment of pathological obesity (ie, bariatric surgeries)-will also be reviewed.


Quantification of human body fat tissue percentage by MRI.
The MRI-based evaluation of the quantity and regional distribution of adipose tissue is one objective measure in the investigation of obesity. The aim of this article was to report a comprehensive and automatic analytical method for the determination of the volumes of subcutaneous fat tissue (SFT) and visceral fat tissue (VFT) in either the whole human body or selected slices or regions of interest. Using an MRI protocol in an examination position that was convenient for volunteers and patients with severe diseases, 22 healthy subjects were examined. The software platform was able to merge MRI scans of several body regions acquired in separate acquisitions. Through a cascade of image processing steps, SFT and VFT volumes were calculated. Whole-body SFT and VFT distributions, as well as fat distributions of defined body slices, were analysed in detail. Complete three-dimensional datasets were analysed in a reproducible manner with as few operator-dependent interventions as possible. In order to determine the SFT volume, the ARTIS (Adapted Rendering for Tissue Intensity Segmentation) algorithm was introduced. The advantage of the ARTIS algorithm was the delineation of SFT volumes in regions in which standard region grow techniques fail. Using the ARTIS algorithm, an automatic SFT volume detection was feasible. MRI data analysis was able to determine SFT and VFT volume percentages using new analytical strategies. With the techniques described, it was possible to detect changes in SFT and VFT percentages of the whole body and selected regions. The techniques presented in this study are likely to be of use in obesity-related investigations, as well as in the examination of longitudinal changes in weight during various medical conditions.


Use of force spectroscopy to investigate the adhesion of living adherent cells.
The use of force spectroscopy to study the adhesion of living fibroblasts to their culture substrate was investigated. Both primary fibroblasts (PEMF) and a continuous cell line (3T3) were studied on quartz surfaces. Using a fibronectin-coated AFM cantilever, it was possible to detach a large proportion of the 3T3 cells from the quartz surfaces. Their adhesion to the quartz surface and the effects of topography on this adhesion could be quantified. Three parameters characteristic of the adhesion were measured: the maximum force of detachment, the work of adhesion, and the distance of detachment. Few PEMF cells were detached under the same experimental conditions. The potential and limitations of this method in measuring cell/surface interactions for adherent cells are discussed.


Mmp14 is required for matrisome homeostasis and circadian rhythm in fibroblasts.
The circadian clock in tendon regulates the daily rhythmic synthesis of collagen-I and the appearance and disappearance of small-diameter collagen fibrils in the extracellular matrix. How the fibrils are assembled and removed is not fully understood. Here, we first showed that the collagenase, membrane type I-matrix metalloproteinase (MT1-MMP, encoded by Mmp14), is regulated by the circadian clock in postnatal mouse tendon. Next, we generated tamoxifen-induced Col1a2-Cre-ERT2::Mmp14 KO mice (Mmp14 conditional knockout (CKO)). The CKO mice developed hind limb dorsiflexion and thickened tendons, which accumulated narrow-diameter collagen fibrils causing ultrastructural disorganization. Mass spectrometry of control tendons identified 1195 proteins of which 212 showed time-dependent abundance. In Mmp14 CKO mice 19 proteins had reversed temporal abundance and 176 proteins lost time dependency. Among these, the collagen crosslinking enzymes lysyl oxidase-like 1 (LOXL1) and lysyl hydroxylase 1 (LH1; encoded by Plod2) were elevated and had lost time-dependent regulation. High-pressure chromatography confirmed elevated levels of hydroxylysine aldehyde (pyridinoline) crosslinking of collagen in CKO tendons. As a result, collagen-I was refractory to extraction. We also showed that CRISPR-Cas9 deletion of Mmp14 from cultured fibroblasts resulted in loss of circadian clock rhythmicity of period 2 (PER2), and recombinant MT1-MMP was highly effective at cleaving soluble collagen-I but less effective at cleaving collagen pre-assembled into fibrils. In conclusion, our study shows that circadian clock-regulated Mmp14 controls the rhythmic synthesis of small diameter collagen fibrils, regulates collagen crosslinking, and its absence disrupts the circadian clock and matrisome in tendon fibroblasts.


Pressure transduction and fluid evacuation during conventional negative pressure wound therapy of the open abdomen and NPWT using a protective disc over the intestines.
Negative pressure wound therapy (NPWT) has gained acceptance among surgeons, for the treatment of open abdomen, since very high closure rates have been reported with this method, compared to other kinds of wound management for the open abdomen. However, the method has occasionally been associated with increased development of fistulae. We have previously shown that NPWT induces ischemia in the underlying small intestines close to the vacuum source, and that a protective disc placed between the intestines and the vacuum source prevents the induction of ischemia. In this study we compare pressure transduction and fluid evacuation of the open abdomen with conventional NPWT and NPWT with a protective disc. Six pigs underwent midline incision and the application of conventional NPWT and NPWT with a protective disc between the intestines and the vacuum source. The pressure transduction was measured centrally beneath the dressing, and at the anterior abdominal wall, before and after the application of topical negative pressures of -50, -70 and -120 mmHg. The drainage of fluid from the abdomen was measured, with and without the protective disc. Abdominal drainage was significantly better (p < 0. 001) using NPWT with the protective disc at -120 mmHg (439 ± 25 ml vs. 239 ± 31 ml), at -70 mmHg (341 ± 27 ml vs. 166 ± 9 ml) and at -50 mmHg (350 ± 50 ml vs. 151 ± 21 ml) than with conventional NPWT. The pressure transduction was more even at all pressure levels using NPWT with the protective disc than with conventional NPWT. The drainage of the open abdomen was significantly more effective when using NWPT with the protective disc than with conventional NWPT. This is believed to be due to the more even and effective pressure transduction in the open abdomen using a protective disc in combination with NPWT.


Polymer-surfactant vesicular complexes in aqueous medium.
The introduction of ionic single-tailed surfactants to aqueous solutions of EO(18)BO(10) [EO = poly(ethylene oxide), BO = poly(1,2-butylene oxide), subscripts denote the number of repeating units] leads to the formation of vesicles, as probed by laser scanning confocal microscopy. Dynamic light scattering showed that the dimensions of these aggregates at early stages of development do not depend on the sign of the surfactant head group charge. Small-angle X-ray scattering (SAXS) analysis indicated the coexistence of smaller micelles of different sizes and varying polymer content in solution. In strong contrast to the dramatic increase of size of dispersed particles induced by surfactants in dilute solution, the d-spacing of corresponding mesophases reduces monotonically upon increasing surfactant loading. This effect points to the suppression of vesicles as a consequence of increasing ionic strength in concentrated solutions. Maximum enhancements of storage modulus and thermal stability of hybrid gels take place at different compositions, indicating a delicate balance between the number and size of polymer-poor aggregates (population increases with surfactant loading) and the number and size of polymer-surfactant complexes (number and size decrease in high surfactant concentrations).


Impact of Cardiac Resynchronization Therapy on Heart Transplant-Free Survival in Pediatric and Congenital Heart Disease Patients.
Cardiac resynchronization therapy (CRT) studies in pediatric or congenital heart disease patients have shown an improvement in ejection fraction and heart failure symptoms. However, a survival benefit of CRT in this population has not been established. This study aimed to evaluate the impact of CRT upon heart transplant-free survival in pediatric and congenital heart disease patients, using a propensity score-matched (PSM) analysis. This single-center study compared CRT patients (implant date, 2004-2017) and controls, matched by 1:1 PSM using 21 comprehensive baseline indices for risk stratification. CRT patients were <21 years of age or had congenital heart disease, had systemic ventricular ejection fraction <45%, symptomatic heart failure, and had significant electrical dyssynchrony, all before CRT implant. Controls were screened from nonselective imaging and ECG databases. Controls were retrospectively enrolled when they achieved the same inclusion criteria at an outpatient clinical encounter, within the same time period. Of 133 patients who received CRT during the study period, 84 met all study inclusion criteria. One hundred thirty-three controls met all criteria at an outpatient encounter. Following PSM, 63 matched CRT-control pairs were identified with no significant difference between groups across all baseline indices. Heart transplant or death occurred in 12 (19%) PSM-CRT subjects and 37 (59%) PSM-controls with a median follow-up of 2.7 years (quartiles, 0.8-6.1 years). CRT was associated with markedly reduced risk of heart transplant or death (hazard ratio, 0.24 [95% CI, 0.12-0.46]; P<0.001). There was no CRT procedural mortality and 1 system infection at 54 months post-implant. In pediatric and congenital heart disease patients with symptomatic systolic heart failure and electrical dyssynchrony, CRT was associated with improved heart transplant-free survival. Visual Overview: A visual overview is available for this article.


In Vitro Studies to Define the Cell-Surface and Intracellular Targets of Polyarginine-Conjugated Sodium Borocaptate as a Potential Delivery Agent for Boron Neutron Capture Therapy.
Boron neutron capture therapy (BNCT) requires pharmaceutical innovations and molecular-based evidence of effectiveness to become a standard cancer therapeutic in the future. Recently, in Japan, 4-borono-L-phenylalanine (BPA) was approved as a boron agent for BNCT against head and neck (H&N) cancers. H&N cancer appears to be a suitable target for BPA-BNCT, because the expression levels of L-type amino acid transporter 1 (LAT1), one of the amino acid transporters responsible for BPA uptake, are elevated in most cases of H&N cancer. However, in other types of cancer including malignant brain tumors, LAT1 is not always highly expressed. To expand the possibility of BNCT for these cases, we previously developed poly-arginine peptide (polyR)-conjugated mercaptoundecahydrododecaborate (BSH). PolyR confers the cell membrane permeability and tumor selectivity of BSH. However, the molecular determinants for the properties are not fully understood. In this present study, we have identified the cluster of differentiation 44 (CD44) protein and translational machinery proteins as a major cell surface target and intracellular targets of BSH-polyR, respectively. CD44, also known as a stem cell-associated maker in various types of cancer, is required for the cellular uptake of polyR-conjugated molecules. We showed that BSH-polyR was predominantly delivered to a CD44High cell population of cancer cells. Once delivered, BSH-polyR interacted with the translational machinery components, including the initiation factors, termination factors, and poly(A)-biding protein (PABP). As a proof of principle, we performed BSH-polyR-based BNCT against glioma stem-like cells and revealed that BSH-polyR successfully induced BNCT-dependent cell death specifically in CD44High cells. Bioinformatics analysis indicated that BSH-polyR would be suitable for certain types of malignant tumors. Our results shed light on the biochemical properties of BSH-polyR, which may further contribute to the therapeutic optimization of BSH-BNCT in the future.


Cell death: a program to regenerate.
Recent studies in Drosophila, Hydra, planarians, zebrafish, mice, indicate that cell death can open paths to regeneration in adult animals. Indeed injury can induce cell death, itself triggering regeneration following an immediate instructive mechanism, whereby the dying cells release signals that induce cellular responses over short and/or long-range distances. Cell death can also provoke a sustained derepressing response through the elimination of cells that suppress regeneration in homeostatic conditions. Whether common properties support what we name "regenerative cell death," is currently unclear. As key parameters, we review here the injury proapoptotic signals, the signals released by the dying cells, the cellular responses, and their respective timing. ROS appears as a common signal triggering cell death through MAPK and/or JNK pathway activation. But the modes of ROS production vary, from a brief pulse upon wounding, to repeated waves as observed in the zebrafish fin where ROS supports two peaks of cell death. Indeed regenerative cell death can be restricted to the injury phase, as in Hydra, Drosophila, or biphasic, immediate, and delayed, as in planarians and zebrafish. The dying cells release in a caspase-dependent manner a variety of signaling molecules, cytokines, growth factors, but also prostaglandins or ATP as recorded in Drosophila, Hydra, mice, and zebrafish, respectively. Interestingly, the ROS-producing cells often resist to cell death, implying a complex paracrine mode of signaling to launch regeneration, involving ROS-producing cells, ROS-sensing cells that release signaling molecules upon caspase activation, and effector cells that respond to these signals by proliferating, migrating, and/or differentiating.


Targeted inactivation of p27kip1 is sufficient for large and small intestinal tumorigenesis in the mouse, which can be augmented by a Western-style high-risk diet.
Mice with a targeted inactivation of both alleles of the cyclin-dependent kinase inhibitor p27(kip1) developed both small and large intestinal adenomas when fed a control AIN-76A diet. A Western-style diet that is high in fat and phosphate and low in calcium and vitamin D was also able to initiate adenoma formation in wild-type mice. The combination of p27(kip1) inactivation and the Western-style diet was additive in terms of tumor incidence, frequency and size, and in reducing the life span of the mice. The genetic and dietary combination also resulted in development of adenocarcinoma. Tumor formation was linked to a disruption in homeostasis of the intestinal mucosa, involving increased cell proliferation and decreased apoptosis. There was also decreased goblet cell differentiation as assessed by alcian blue staining and expression of the Muc2 gene, especially in mice fed the Western-style diet, although this differentiation lineage was still present as indicated by expression and staining for intestinal trefoil factor. The inactivation of p27(kip1) and the consequent disruption of normal colonic cell maturation in the mucosa were associated with modestly elevated c-myc, cdk4, and cyclin D1 expression. These data establish a fundamental role for p27(kip1) in maintenance of intestinal cell homeostasis and in suppressing tumor formation. The data also emphasize the critical role that dietary factors can have in both tumor initiation and progression through interaction with pathways that normally maintain intestinal homeostasis.


Reconfigurable beams with arbitrary polarization and shape distributions at a given plane.
Methods for generating beams with arbitrary polarization based on the use of liquid crystal displays have recently attracted interest from a wide range of sources. In this paper we present a technique for generating beams with arbitrary polarization and shape distributions at a given plane using a Mach-Zehnder setup. The transverse components of the incident beam are processed independently by means of spatial light modulators placed in each path of the interferometer. The modulators display computer generated holograms designed to dynamically encode any amplitude value and polarization state for each point of the wavefront in a given plane. The steps required to design such beams are described in detail. Several beams performing different polarization and intensity landscapes have been experimentally implemented. The results obtained demonstrate the capability of the proposed technique to tailor the amplitude and polarization of the beam simultaneously.


MmpL3 is a lipid transporter that binds trehalose monomycolate and phosphatidylethanolamine.
The cell envelope of Mycobacterium tuberculosis is notable for the abundance of mycolic acids (MAs), essential to mycobacterial viability, and of other species-specific lipids. The mycobacterial cell envelope is extremely hydrophobic, which contributes to virulence and antibiotic resistance. However, exactly how fatty acids and lipidic elements are transported across the cell envelope for cell-wall biosynthesis is unclear. Mycobacterial membrane protein Large 3 (MmpL3) is essential and required for transport of trehalose monomycolates (TMMs), precursors of MA-containing trehalose dimycolates (TDM) and mycolyl arabinogalactan peptidoglycan, but the exact function of MmpL3 remains elusive. Here, we report a crystal structure of Mycobacterium smegmatis MmpL3 at a resolution of 2.59 Å, revealing a monomeric molecule that is structurally distinct from all known bacterial membrane proteins. A previously unknown MmpL3 ligand, phosphatidylethanolamine (PE), was discovered inside this transporter. We also show, via native mass spectrometry, that MmpL3 specifically binds both TMM and PE, but not TDM, in the micromolar range. These observations provide insight into the function of MmpL3 and suggest a possible role for this protein in shuttling a variety of lipids to strengthen the mycobacterial cell wall.


Intraoperative Cardiac Arrest: Immediate Treatment and Diagnostic Evaluation.
Although perioperative cardiac arrest during anesthetic care in infants and children is a rare event, its consequences can be devastating. Risk factors associated with perioperative cardiac arrest include cardiac surgery, younger age, presence of comorbid conditions and emergency surgery. Although medication-related etiologies formerly predominated, the elimination of halothane from anesthetic care has resulted in a shift in etiology to hemodynamic events related to blood loss or hyperkalemia associated with the rapid administration of blood products. Rarely, cardiac arrest can be sudden and unexpected without an obvious pre-existing etiology in an otherwise apparently healthy patient. We present a 16-month-old child who experienced a sudden cardiac arrest following anesthetic induction for a routine urologic procedure. The potential etiology of cardiac arrest during anesthesia is reviewed, keys to resuscitation discussed, and an outline for the investigative work-up presented.


Some recent statistical analyses of two long-term studies of exposure to ionizing radiation.
Two long-term studies of cancer mortality in population exposed to high doses of ionizing radiation are described briefly. Statistical analysis plays a key role in establishing to what extent it is appropriate to generalize from the experience of these populations to that of other populations who have been exposed, usually at lower doses. Two examples of recent analyses are given. First, a detailed comparison of the cancer mortality experience in the two studies has been carried out; this has shown a high level of agreement between them. In the second example the relation between the radiogenic risk and the baseline age-specific cancer risk in the two populations has been studied. Results are again in good agreement and show that for a group of epithelial tumours of non-sex-specific sites exposure to radiation multiplies the baseline risk.


Agile multicasting based on cascaded χ(2) nonlinearities in a step-chirped periodically poled lithium niobate.
We experimentally demonstrate the possibility of agile multicasting for wavelength division multiplexing (WDM) networks, of a single-channel to two and seven channels over the C band, also extendable to S and L bands. This is based on cascaded χ(2) nonlinear mixing processes, namely, second-harmonic generation (SHG)-sum-frequency generation (SFG) and difference-frequency generation (DFG) in a 20-mm-long step-chirped periodically poled lithium niobate crystal, specially designed and fabricated for a 28-nm-wide SH-SF bandwidth centered at around 1.55 μm. The multiple idlers are simultaneously tuned by detuning the pump wavelengths within the broad SH-SF bandwidth. By selectively tuning the pump wavelengths over less than 10 and 6 nm, respectively, multicasting into two and seven idlers is successfully achieved across ~70 WDM channels within the 50 GHz International Telecommunication Union grid spacing.


Methodology for developing competency standards for dietitians in Australia.
Competency standards document the knowledge, skills, and attitudes required for competent performance. This study develops competency standards for dietitians in order to substantiate an approach to competency standard development. Focus groups explored the current and emerging purpose, role, and function of the profession, which were used to draft competency standards. Consensus was then sought using two rounds of a Delphi survey. Seven focus groups were conducted with 28 participants (15 employers/practitioners, 5 academics, 8 new graduates). Eighty-two of 110 invited experts participated in round one and 67 experts completed round two. Four major functions of dietitians were identified: being a professional, influencing the health of individuals, groups, communities, and populations through evidence-based nutrition practice, and working collaboratively in teams. Overall there was a high level of consensus on the standards: 93% achieved agreement by participants in round one and all revised standards achieved consensus on round 2. The methodology provides a framework for other professions wishing to embark on competency standard review or development.


Establishing Global School Feeding Program Targets: How Many Poor Children Globally Should Be Prioritized, and What Would Be the Cost of Implementation?
The creation of Human Capital is dependent upon good health and education throughout the first 8,000 days of life, but there is currently under-investment in health and nutrition after the first 1,000 days. Working with governments and partners, the UN World Food Program is leading a global scale up of investment in school health, and has undertaken a strategic analysis to explore the scale and cost of meeting the needs of the most disadvantaged school age children and adolescents in low and middle-income countries globally. Of the 663 million school children enrolled in school, 328 million live where the current coverage of school meals is inadequate (<80%), of these, 251 million live in countries where there are significant nutrition deficits (>20% anemia and stunting), and of these an estimated 73 million children in 60 countries are also living in extreme poverty (<USD 1.97 per day). 62.7 million of these children are in Africa, and more than 66% live in low income countries, with a substantial minority in pockets of poverty in middle-income countries. The estimated overall financial requirement for school feeding is USD 4.7 billion, increasing to USD 5.8 billion annually if other essential school health interventions are included in the package. The DCP3 (Vol 8) school feeding edition and the global coverage numbers were launched in Tunis, 2018 by the WFP Executive Director, David Beasley. These estimates continue to inform the development of WFP's global strategy for school feeding.


Evidence for major gene inheritance of Alzheimer disease in families of patients with and without apolipoprotein E epsilon 4.
Apolipoprotein E (APOE) genotype is the single most important determinant to the common form of Alzheimer disease (AD) yet identified. Several studies show that family history of AD is not entirely accounted for by APOE genotype. Also, there is evidence for an interaction between APOE genotype and gender. We carried out a complex segregation analysis in 636 nuclear families of consecutively ascertained and rigorously diagnosed probands in the Multi-Institutional Research in Alzheimer Genetic Epidemiology study in order to derive models of disease transmission which account for the influences of APOE genotype of the proband and gender. In the total group of families, models postulating sporadic occurrence, no major gene effect, random environmental transmission, and Mendelian inheritance were rejected. Transmission of AD in families of probands with at least one epsilon 4 allele best fit a dominant model. Moreover, single gene inheritance best explained clustering of the disorder in families of probands lacking epsilon 4, but a more complex genetic model or multiple genetic models may ultimately account for risk in this group of families. Our results also suggest that susceptibility to AD differs between men and women regardless of the proband's APOE status. Assuming a dominant model, AD appears to be completely penetrant in women, whereas only 62%-65% of men with predisposing genotypes develop AD. However, parameter estimates from the arbitrary major gene model suggests that AD is expressed dominantly in women and additively in men. These observations, taken together with epidemiologic data, are consistent with the hypothesis of an interaction between genes and other biological factors affecting disease susceptibility.


Response of malaria vectors to conventional insecticides in the southern districts of Odisha State, India.
Updating information on response (susceptible / resistant status) of vectors to the insecticides in use is essential to formulate and introduce appropriate resistance management strategy. Therefore, a study was undertaken in the 10 southern districts of Odisha State, which are endemic for Plasmodium falciparum malaria, to determine the insecticide susceptibility/ resistance status of Anopheles fluviatilis and An. culicifacies, the vectors of malaria. Mosquitoes were collected during September 2010 - February 2012 from 60 randomly selected villages in the 10 districts and blood-fed females were exposed to the diagnostic dosage of DDT (4.0%), malathion (5.0%) and deltamethrin (0.05%) for one hour. Mortality was recorded at 24 h after the exposure. The test mortality was corrected to the control mortality. An. fluviatilis was susceptible to the three insecticides tested while, An. culicifacies was resistant to DDT and malathion in all the 10 districts except in two, where its response against malathion was under 'verification required' category. Against deltamethrin, An. culicifacies was susceptible in two districts; while in the other eight districts its response was under 'verification required' category. Since An. fluviatilis the vector species primarily associated with transmission of malaria, was still susceptible to DDT, indoor residual spraying with DDT could be continued in the 10 districts. Also, in view of the large scale implementation of long lasting insecticidal nets and the signs of development of resistance in An. culicifacies to deltamethrin, response of the vectors to synthetic pyrethroids needs to be periodically monitored.


Predicting the pathological response to neoadjuvant chemoradiation using untargeted metabolomics in locally advanced rectal cancer.
The present study aimed to identify a panel of potential metabolite biomarkers to predict tumor response to neoadjuvant chemo-radiation therapy (NCRT) in locally advanced rectal cancer (LARC). Liquid chromatography-mass spectrometry (LC-MS)-based untargeted metabolomics was used to profile human serum samples (n = 106) from LARC patients treated with NCRT. The samples were collected from Fudan University Shanghai Cancer Center (FUSCC) from July 2014 to January 2016. Statistical methods, such as partial least squares (PLS) and Wilcoxon rank-sum test, were used to identify discriminative metabolites between NCRT-sensitive and NCRT-resistant patients according to their tumor regression grade (TRG). This trial is registered with Clinical Trials.gov, number NCT03149978. A panel of metabolites was selected as potential predictive biomarkers of pathological response to NCRT. A total of 4810 metabolic peaks were detected, and 57 significantly dysregulated peaks were identified. These 57 metabolic peaks were used to differentiate patients using PLS in a dataset containing NCRT-sensitive (n = 56) and NCRT-resistant (n = 49) patients. The combination of 57 metabolic peaks had AUC values of 0.88, 0.81 and 0.84 in the prediction models using PLS, random forest, and support vector machine, respectively, suggesting that metabolomics has the potential ability to predict responses to NCRT. Furthermore, 15 metabolite biomarkers were identified and used to construct a logistic regression model and explore dysregulated metabolic pathways using untargeted metabolic profiling and data mining approaches. A panel of metabolites has been identified to facilitate the prediction of tumor response to NCRT in LARC, which is promising for the generation of personalized treatment strategies for LARC patients.


Living in aged care: using spiritual reminiscence to enhance meaning in life for those with dementia.
Spiritual reminiscence is a way of telling a life story with emphasis on meaning. Spiritual reminiscence can identify meaning associated with joy, sadness, anger, guilt, or regret. Exploring these issues in older age can help people to reframe some of these events and come to new understanding of the meaning and purpose of their lives. A total of 113 older adults with dementia, living in aged-care facilities, participated in this study. They were allocated to small groups for spiritual reminiscence, to meet weekly over 6weeks or 6months. Quantitative data were gathered using a behavioural scale before and after each spiritual reminiscence session. Qualitative data included taped and transcribed reminiscence sessions, individual interviews, and observer journals. A facilitator led the small-group discussion based on spiritual reminiscence. New relationships were developed among group members that improved life for these people in aged care. This paper examines aspects of the qualitative data around the themes of 'meaning in life' and 'vulnerability and transcendence'. Spiritual reminiscence offers nursing staff a way of knowing those with dementia in a deeper and more meaningful way.


Population dynamics, distribution, and species diversity of fruit flies on cucurbits in Kashmir Valley, India.
Given the economic importance of cucurbits and the losses incurred by fruit fly infestation, the population dynamics of fruit flies in cucurbit crops and the influence of abiotic parameters, such as temperature, relative humidity, rainfall, and total sunshine hours per day on the fruit fly population were studied. The study was carried out at six locations; in district Srinagar the locations were Batmaloo, Shalimar, and Dal, while in district Budgam the locations were Chadoora, Narkara, and Bugam (Jammu and Kashmir, India). Various cucurbit crops, such as cucumber, bottle gourd, ridge gourd and bitter gourd, were selected for the study. With regard to locations, mean fruit fly population was highest (6.09, 4.55, 3.87, and 3.60 flies/trap/week) at Batamaloo and Chadoora (4.73, 3.93, 2.73, and 2.73 flies/trap/week) on cucumber, bottle gourd, ridge gourd, and bitter gourd, respectively. The population of fruit flies was significantly correlated with the minimum and maximum temperature. The maximum species diversity of fruit flies was 0.511, recorded in Chadoora. Bactrocera cucurbitae (Coquillett) (Diptera: Tephritidae) was the most predominant species in both Srinagar and Budgam, followed by B. dorsalis (Hendel) and B. tau (Walker), while B. scutellaris (Bezzi) was found only in Chadoora. Results of the present investigation may be utilized in developing a sustainable pest management strategy in the agroecological system.


Systemic delivery of bioactive glucagon-like peptide 1 after adenoviral-mediated gene transfer in the murine salivary gland.
An adenoviral (Ad) vector that expresses bioactive glucagon-like peptide 1 (GLP-1) was generated, and its effectiveness at modulating glucose homeostasis was evaluated after transduction of murine salivary glands. The construct was engineered with the signal sequence of mouse GH to direct the peptide into the secretory pathway, followed by a furin cleavage site and the GLP-1(7-37) sequence encoding an Ala to Gly substitution at position 8 to achieve resistance to degradation. When expressed in Neuro2A and COS7 cells, an active form of GLP-1 was specifically detected by RIA in the conditioned medium of transduced cells, showed resistance to degradation by dipeptidyl-peptidase IV, and induced the secretion of insulin from NIT1 pancreatic beta-cells in vitro. In vivo studies demonstrated that healthy mice transduced with Ad-GLP-1 in both submandibular glands had serum GLP-1 levels approximately 3 times higher than mice transduced with the control Ad-luciferase vector. In fasted animals, serum glucose levels were similar between Ad-GLP-1 and Ad-luciferase transduced mice in keeping with GLP-1's glucose-dependent action. However, when challenged with glucose, Ad-GLP-1 transduced mice cleared the glucose significantly faster than control mice. In an animal model of diabetes induced by alloxan, progression of hyperglycemia was significantly attenuated in mice given the Ad-GLP-1 vector compared with control mice. These studies demonstrate that the bioactive peptide hormone, GLP-1, normally secreted from endocrine cells in the gut through the regulated secretory pathway, can be engineered for secretion into the circulatory system from exocrine cells of the salivary gland to affect glucose homeostasis.


Lymphoma development and survival in refractory coeliac disease type II: Histological response as prognostic factor.
Refractory coeliac disease type II (RCDII) frequently transforms into an enteropathy-associated T-cell lymphoma (EATL) and therefore requires intensive treatment. Current evaluated treatment strategies for RCDII include cladribine (2-CdA) and autologous stem cell transplantation (auSCT). The purpose of this study was to evaluate long-term survival and define clear prognostic criteria for EATL development comparing two treatment strategies. A total of 45 patients were retrospectively analysed. All patients received 2-CdA, after which they were either closely monitored (monotherapy, n = 30) or a step-up approach was used including auSCT (step-up therapy, n = 15). Ten patients (22%) ultimately developed EATL; nine of these had received monotherapy. Absence of histological remission after monotherapy was associated with EATL development (p = 0.010). Overall, 20 patients (44%) died with a median survival of 84 months. Overall survival (OS) within the monotherapy group was significantly worse in those without histological remission compared to those with complete histological remission(p = 0.030). The monotherapy group who achieved complete histological remission showed comparable EATL occurrence and OS as compared to the step-up therapy group (p = 0.80 and p = 0.14 respectively). Histological response is an accurate parameter to evaluate the effect of 2-CdA therapy and this parameter should be leading in the decisions whether or not to perform a step-up treatment approach in RCDII.


Delayed linkage to HIV care among asylum seekers in Quebec, Canada.
Migrants represent an increasing proportion of people living with HIV in many developed countries. We aimed to describe the HIV care cascade and baseline genotypic resistance for newly diagnosed asylum seekers referred to the McGill University Health Centre (MUHC) in Montreal, Quebec, Canada. We conducted a retrospective cohort study of patients linked to the MUHC from June 1, 2017 to October 31, 2018. We calculated the median time (days; interquartile range (IQR)) from: 1) entry into Canada to immigration medical examination (IME) (i.e. HIV screening); 2) IME to patient notification of diagnosis; 3) notification to linkage to HIV care (defined as a CD4 or viral load (VL) measure); 4) linkage to HIV care to combination antiretroviral therapy (cART) prescription; and 5) cART prescription to viral suppression (defined as a VL < 20 copies/mL). We reviewed baseline genotypes and interpreted mutations using the Stanford University HIV Drug Resistance Database. We calculated the proportion with full resistance to > 1 antiretroviral. Overall, 43% (60/139) of asylum seekers were newly diagnosed in Canada. Among these, 62% were late presenters (CD4 < 350 cells/μl), 22% presented with advanced HIV (CD4 < 200 cells/μl), and 25% with high-level viremia (VL > 100,000 copies/ml). Median time from entry to IME: 27 days [IQR:13;55]; IME to notification: 28 days [IQR:21;49]; notification to linkage: 6 days [IQR:2;19]; linkage to cART prescription: 11 days [IQR:6;17]; and cART to viral suppression: 42 days [IQR:31;88]; 45% were linked to HIV care within 30 days. One-fifth (21%) had baseline resistance to at least one antiretroviral agent; the K103 N/S mutation was the most common mutation. While the majority of newly diagnosed asylum seekers were late presenters, only 45% were linked to care within 30 days. Once linked, care and viral suppression were rapid. Delays in screening and linkage to care present increased risk for onward transmission, and in the context of 21% baseline resistance, consideration of point-of-care testing and immediate referral at IME screening should be made.


Prior exercise and postprandial substrate extraction across the human leg.
Prior exercise decreases postprandial plasma triacylglycerol (TG) concentrations, possibly through changes to skeletal muscle TG extraction. We measured postprandial substrate extraction across the leg in eight normolipidemic men aged 21-46 yr. On the afternoon preceding one trial, subjects ran for 2 h at 64 +/- 1% of maximal oxygen uptake (exercise); before the control trial, subjects had refrained from exercise. Samples of femoral arterial and venous blood were obtained, and leg blood flow was measured in the fasting state and for 6 h after a meal (1.2 g fat, 1.2 g carbohydrate/kg body mass). Prior exercise increased time averaged postprandial TG clearance across the leg (total TG: control, 0.079 +/- 0.014 ml.100 ml tissue(-1).min(-1) ; exercise, 0.158 +/- 0.023 ml.100 ml tissue(-1).min(-1), P <0.01), particularly in the chylomicron fraction, so that absolute TG uptake was maintained despite lower plasma TG concentrations (control, 1.53 +/- 0.13 mmol/l; exercise, 1.01 +/- 0.16 mmol/l, P < 0.001). Prior exercise increased postprandial leg blood flow and glucose uptake (both P < 0.05). Mechanisms other than increased leg TG uptake must account for the effect of prior exercise on postprandial lipemia.


Identification of Immunodominant Responses to the Plasmodium falciparum Antigens PfUIS3, PfLSA1 and PfLSAP2 in Multiple Strains of Mice.
Malaria, caused by the Plasmodium parasite, remains a serious global public health concern. A vaccine could have a substantial impact on eliminating this disease, alongside other preventative measures. We recently described the development of three novel, viral vectored vaccines expressing either of the antigens PfUIS3, PfLSA1 and PfLSAP2. Each vaccination regimen provided high levels of protection against chimeric parasite challenge in a mouse model, largely dependent on CD8+ T cells. In this study we aimed to further characterize the induced cellular immune response to these vaccines. We utilized both the IFNγ enzyme-linked immunosorbent spot assay and intracellular cytokine staining to achieve this aim. We identified immunodominant peptide responses for CD4+ and CD8+ T cells for each of the antigens in BALB/c, C57BL/6 and HLA-A2 transgenic mice, creating a useful tool for researchers for subsequent study of these antigens. We also compared these immunodominant peptides with those generated from epitope prediction software, and found that only a small proportion of the large number of epitopes predicted by the software were identifiable experimentally. Furthermore, we characterized the polyfunctionality of the induced CD8+ T cell responses. These findings contribute to our understanding of the immunological mechanisms underlying these protective vaccines, and provide a useful basis for the assessment of these and related vaccines as clinical constructs.


The effect of zinc supplementation on ghrelin-immunoreactive cells and lipid parameters in gastrointestinal tissue of streptozotocin-induced female diabetic rats.
Zinc is an essential nutrient with a wide range of functions and closely involved in a variety of enzymatic processes of importance in glucose, protein and lipid metabolism. Ghrelin is the endogenous ligand of the G protein coupled growth hormone secretagogue receptor. The regulatory mechanism that explain the biosynthesis and secretion of ghrelin in the gastrointestinal tract has not been clarified. This study was undertaken to examine the effect of zinc supplementation on the streptozotocin (STZ)-induced diabetic rats, which exhibits ghrelin production and secretion, and lipid metabolism on the gastrointestinal tract. The animals were divided into four groups. Group I: Non-diabetic untreated animals. Group II: Zinc-treated non-diabetic rats. Group III: STZ-induced diabetic untreated animals. Group IV: Zinc-treated diabetic animals. Zinc sulfate was given to some of the experimental animals by gavage at a dose of 100 mg/kg body weight every day for 60 days. In the zinc-treated diabetic group, the blood glucose levels decreased and body weight increased as compared to the diabetic untreated group. Zinc supplementation to STZ-diabetic rats revealed the protective effect of zinc on lipids parameters such as total lipid, cholesterol, HDL-cholesterol and atherogenic index. There is no statistically change in ghrelin-immunoreactive cells in gastrointestinal tissue. But, it has found that zinc supplementation caused a significant reduction in densities of ghrelin-producing cells of fundic mucosa of zinc-treated diabetic animals as compared to untreated, non-diabetic controls. Zinc supplementation may contribute to prevent some complications of diabetic rats, biochemically.


Analysis of the role of flagellar activity in virulence gene expression in Vibrio cholerae.
Expression of virulence factors and motility of VIBRIO: cholerae are intimately linked by an as yet uncharacterized mechanism. Several lines of evidence indicate that the activity of the flagellum of V. cholerae might have an impact on virulence gene regulation, as alterations of the motility phenotype, either by mutation or by inhibitory drugs, result in varied levels of virulence factor production. The Na(+)-driven polar flagella of some VIBRIO: species are proposed to act as mechanosensors, sensing media viscosity. It has been suggested that the V. cholerae flagellum might act as a 'voltmeter', responding to changes in membrane potential, or might sense some environmental conditions that lead to the repression of virulence factors in V. cholerae. To test these hypotheses, beta-galactosidase levels of several types of non-motile mutant derivatives of a V. cholerae toxT::lacZ reporter strain were analysed following changes in media viscosity, membrane potential and other environmental conditions. Like the parental strain, the non-motile strain showed increased toxT::lacZ expression in high-viscosity media, suggesting that the sensing of media viscosity does not occur via the flagella. Other molecules that might be able to detect changes in media viscosity could include mechanosensitive (MS) ion channels found in the bacterial membrane. However, a V. cholerae derivative strain mutated in two putative MS channels still showed increased toxT::lacZ expression in high-viscosity media, indicating that these putative ion channels of V. cholerae are not involved in the viscosity effect and suggesting an as yet uncharacterized mechanism for sensing of media viscosity. The flagellum does not appear to act as a voltmeter, as beta-galactosidase activities of the non-flagellate derivative strain were found to be similar to those of the parental strain after artificially changing the sodium membrane bioenergetics. Similarly, several environmental conditions known to reduce toxin expression were equally effective in reducing toxT::lacZ expression in the motile or non-motile strains. In conclusion, the flagellum of V. cholerae does not act as a mechanosensor, voltmeter or signal transducer for environmental conditions. Thus, alternative mechanisms for the detection of these conditions must exist that likely do not involve the ToxR molecule, as the sensing of all of the tested parameters occurred when the TcpP/H proteins alone activated the toxT::lacZ reporter gene.


Urinary pH is highly associated with tumor recurrence during intravesical mitomycin C therapy for nonmuscle invasive bladder tumor.
In recent years some reports have suggested without any significant evidence that mitomycin C instillation would be more effective with urinary alkalinization. We investigated the association between urinary pH and the efficiency of mitomycin C instillation. We identified 130 patients treated with transurethral resection of a bladder tumor and adjuvant intravesical mitomycin C instillation between 1985 and 2008 at Keio University Hospital. Urinary pH was determined in 124 of the 130 patients just before mitomycin C administration during the scheduled instillation period. These 124 patients were assigned to groups according to urinary pH in increments of 0.5 and the association between urinary pH and clinicopathological characteristics was evaluated. Mean±SD urinary pH was 5.77±0.05 (range 5.00 to 7.66) during the scheduled instillation period. Urinary pH was 5.00 to 5.49, 5.50 to 5.99, 6.00 to 6.49, 6.50 to 6.99 and 7.00 in 39, 46, 25, 7 and 7 patients, respectively. Patients were further divided into 2 groups by urinary pH using a cutoff of 5.5, including 39 with pH less than 5.5 and 85 with pH 5.5 or more. Age, gender, tumor grade, primary/recurrent disease, pathological stage and the presence or absence of concomitant carcinoma in situ were not significantly difference between the 2 groups. Multivariate analysis revealed that categorical urinary pH was an independent risk factor for tumor recurrence (HR 1.75, p=0.032). Three and 5-year recurrence-free rates were 64.2% and 52.9% in patients with pH 5.5 or greater, and 41.9% and 38.4% in those with pH less than 5.5, respectively (p=0.046). Multivariate analysis showed that the HR of urinary pH for tumor recurrence was 1.84 and 2.54 at the 5.4 and 5.2 cutoffs, respectively. Results suggest that urinary pH more than 5.5 is associated with a decreased risk of tumor recurrence in patients treated with intravesical mitomycin C for nonmuscle invasive bladder cancer. Monitoring urinary pH during mitomycin C adjuvant treatment and modifying pH for urine alkalization may improve the therapeutic efficacy of mitomycin C instillation.


Pre-treatment predictors and in-treatment factors associated with change in avoidant and dependent personality disorder traits among patients with social phobia.
We examined changes in avoidant and dependent personality disorder dimensions, and pre-treatment and in-treatment factors associated with such changes in 77 patients, randomized to medication-free residential cognitive (CT) or residential interpersonal therapy for social phobia. Personality disorders and personality dimensions according to the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV) were assessed at pre-treatment and at one-year post-treatment. Both treatments were associated with a decrease in avoidant and dependent personality dimensions; dependent dimension decreased more in CT. Changes in cognitive factors predicted changes in both personality dimensions, whereas changes in symptoms or interpersonal factors did not. Change in the cognitive factor estimated cost was the most powerful predictor in the avoidant dimension, as it was the only predictor that remained significant in the forward regression analyses. Change in the cognitive factor estimated cost, and treatment were the most powerful predictors of change in the dependent dimension. Pre-treatment use of anxiolytics predicted larger changes in both PD dimensions.


Schwann cells generated from neonatal skin-derived precursors or neonatal peripheral nerve improve functional recovery after acute transplantation into the partially injured cervical spinal cord of the rat.
The transplantation of Schwann cells (SCs) holds considerable promise as a therapy for spinal cord injury, but the optimal source of these cells and the best timing for intervention remains debatable. Previously, we demonstrated that delayed transplantation of SCs generated from neonatal mouse skin-derived precursors (SKP-SCs) promoted repair and functional recovery in rats with thoracic contusions. Here, we conducted two experiments using neonatal rat cells and an incomplete cervical injury model to examine the efficacy of acute SKP-SC transplantation versus media control (Experiment 1) and versus nerve-derived SC or dermal fibroblast (Fibro) transplantation (Experiment 2). Despite limited graft survival, by 10 weeks after injury, rats that received SCs from either source showed improved functional recovery compared with media- or fibroblast-treated animals. Compared with media treatment, SKP-SC-transplanted rats showed enhanced rubrospinal tract (RST) sparing/plasticity in the gray matter (GM) rostral to injury, particularly in the absence of immunosuppression. The functional benefits of SC transplantations over fibroblast treatment correlated with the enhanced preservation of host tissue, reduced RST atrophy, and/or increased RST sparing/plasticity in the GM. In summary, our results indicate that: (1) early transplantation of neonatal SCs generated from skin or nerve promotes repair and functional recovery after incomplete cervical crush injury; (2) either of these cell types is preferable to Fibros for these purposes; and (3) age-matched SCs from these two sources do not differ in terms of their reparative effects or functional efficacy after transplantation into the injured cervical spinal cord.


The natural history of autoimmune hepatitis presenting with jaundice.
Forty percent of patients with autoimmune hepatitis (AIH) present with acute jaundice/hepatitis. Such patients, when treated promptly, are thought to have a good prognosis. The objective of this study was to describe the natural history of AIH in patients presenting with jaundice/hepatitis and to determine whether the diagnosis could have been made earlier, before presentation. This study is a retrospective review of 2249 consecutive patients who presented with jaundice to the Jaundice Hotline clinic, Truro, Cornwall, UK, over 15 years (1998-2013) and includes a review of the laboratory data over a 23-year period (1990-2013). Of the 955 patients with hepatocellular jaundice, 47 (5%) had criterion-referenced AIH: 35 female and 12 male, the median age was 65 years (range 15-91 years); the bilirubin concentration was 139 μmol/l (range 23-634 μmol/l) and the alanine transaminase level was 687 IU/l (range 22-2519 IU/l). Among the patients, 23/46 (50%) were cirrhotic on biopsy; 11/47 (23%) died: median time from diagnosis to death, 5 months (range 1-59); median age, 72 years (range 59-91 years). All 8/11 patients who died of liver-related causes were cirrhotic. Weight loss (P=0.04) and presence of cirrhosis (P=0.004) and varices (P=0.015) were more common among those who died. Among patients who died from liver-related causes, 6/8 (75%) died less than 6 months from diagnosis. Cirrhosis at presentation and oesophageal varices were associated with early liver-related deaths (P=0.011, 0.002 respectively). Liver function test results were available in 33/47 (70%) patients before presentation. Among these patients, 16 (49%) had abnormal alanine transaminase levels previously, and eight (50%) were cirrhotic at presentation. AIH presenting as jaundice/hepatitis was mainly observed in older women: 50% of the patients were cirrhotic, and liver-related mortality was high. Some of these deaths were potentially preventable by earlier diagnosis, as the patients had abnormal liver function test results previously, which had not been investigated.


Improved growth of toddlers fed a milk containing synbiotics.
Bifidobacterium longum (BL999), Lactobacillus rhamonosus (LPR), prebiotics (inulin and fructo-oligosaccharides), and long-chain polyunsaturated fatty acids (LCPUFA) are believed to have health benefits. In a randomized, double-blind, controlled trial we compared growth and development of toddlers fed milk containing synbiotics (BL999, LPR, and prebiotics) and LCPUFA or a control milk. Three hundred and ninety three healthy, 12 month-old toddlers were fed approximately 400 mL/day for 12 months. Anthropometric measurements were taken at 12, 14, and 16 months. Toddlers' response to measles and hepatitis A vaccine was measured at 16 months, and Bayley scale for motor, cognitive, and behavioral functions made at 24 months. The primary outcome was weight gain between 12 and 16 months. Secondary outcomes were gain in length, head circumference, and body mass index, gastrointestinal tolerance (stool characteristics), stool bacterial counts, safety, anti-vaccine IgG, and neurodevelopment. Weight gain was greater in the synbiotics group (mean±SD, 7.57±4.13 g/day) compared with the control group (6.64±4.08 g/day). The difference of 0.93 g/day (with a 95% confidence interval of 0.12 to 1.75) is significant (p=0.025). The gain in the synbiotics group resulted in a change in z-score weight-for-age closer to WHO Child Growth Standard. There was a significant increase in lactobacilli and enterococci counts between 12 months and 16 months in the synbiotic group. We conclude that in healthy toddlers milk containing synbiotics and LCPUFA provides better growth and promotes favorable gut colonization, as shown by higher Lactobacillus counts.


Protease nexin 1 induces apoptosis of prostate tumor cells through inhibition of X-chromosome-linked inhibitor of apoptosis protein.
Protease nexin 1 (PN1) is an endogenous serine protease inhibitor (SERPIN), expressed at high levels in the prostate, and capable of inhibiting the proliferation of prostate cancer cells. We previously showed that PN1-uPA complexes inhibited Sonic Hedgehog (SHH) signalling through engagement of the LRP receptor. Here, we describe an alternative anti-proliferative mechanism through which PN1 expression leads to apoptosis. In prostate cancer cells, increased expression of PN1 led to substantial reduction of XIAP levels and apoptosis mediated through the uPAR, but not the LRP receptor. The alterations in XIAP were effected in two ways 1) via alteration in the NF-κB pathway, a pathway known to signal XIAP transcription and 2) by promoting XIAP instability. The AKT pathway is known to phosphorylate XIAP at serine 87 leading to protein stability and PN1 expression is shown to interfere with this process. As a result of both mechanisms, programmed cell death is substantially increased. Consistent with these observations, reduced PN1 protein correlated with elevated p65/XIAP expression and with higher Gleason scores in human prostate tissue arrays. Thus, PN1 expression appears to differentially down-regulate distinct oncogenic pathways depending upon the cell surface receptor engaged by its complexes and demonstrates a novel molecular mechanism by which the protein can promote tumor cell apoptosis.


Relationships and responsiveness in the psychological treatment of trauma: The tragedy of the APA Clinical Practice Guideline.
The therapeutic relationship and responsiveness/treatment adaptations rightfully occupy a prominent, evidence-based place in any guidelines for the psychological treatment of trauma. In this light, we critique the misguided efforts of the American Psychological Association's (APA, 2017) Clinical Practice Guideline on Posttraumatic Stress Disorder in Adults to advance a biomedical model for psychotherapy and thus focus almost exclusively on treatment methods for particular disorders. Instead, the research evidence, clinical expertise, and patient preferences and culture (the necessary triumvirate of evidence-based practice) should converge on distinctive psychological guidelines that emphasize the therapy relationship, treatment adaptations, and individual therapist effects, all of which independently account for patient improvement more than the particular treatment method. Meta-analytic findings and several trauma-specific studies illustrate the thesis. Efforts to promulgate guidelines without including the relationship and responsiveness are seriously incomplete and potentially misleading. The net result is an APA Guideline that proves empirically dubious, clinically suspect, and marginally useful; moreover, it squanders a vital opportunity to identify what actually heals the scourge of trauma. We conclude with recommendations for moving forward with future APA practice guidelines. (PsycINFO Database Record (c) 2019 APA, all rights reserved).


A threshold analysis of the cost-effectiveness of artemisinin-based combination therapies in sub-saharan Africa.
Artemisinin-based combination therapies (ACTs) are generally regarded as vital in addressing the growing problem posed by the development of antimalarial resistance across sub-Saharan Africa. However, the costs of the new ACTs are likely to be significantly higher than current therapies. Therefore, it is important to examine formally the cost-effectiveness of the more effective yet more expensive ACTs before advocating a switch in policy. Importantly, any such economic evaluation must consider the temporal dynamics of drug resistance, and not just focus on the static question of whether switching today would be cost-effective at current levels of resistance, particularly since the development of new antimalarials in the future is so uncertain. However, predicting the future changes in drug resistance is a major difficulty in accurately quantifying the relative costs and health outcomes associated with different drug therapies over time. Here, we use a simple decision tree model to estimate the incremental cost-effectiveness of using ACTs, compared with persisting with current therapies, over 5-, 10-, and 15-year periods. We describe the dynamics of drug resistance using a general logistic growth function, in which the starting frequency of resistance and maximum growth may be altered. However, rather than make assumptions about the absolute rate at which resistance to ACTs will progress, we allow the ratio of the growth rate of resistance to ACTs relative to that of current therapies to vary. Defining the growth rate of ACT resistance in this manner allows us to calculate the threshold ratio at which ACTs would no longer appear cost-effective, for any starting conditions of resistance to current therapies and ACTs, and over any time period. The influence of uncertainty in other decision tree parameters on the threshold ratio values is also quantified, using Monte Carlo simulation techniques. This analysis shows that ACTs are more than 95% likely to be cost-effective under most conditions, other than very low levels of initial resistance to sulfadoxine/pyrimethamine and a five-year time frame. These predictions are conservative in that 95% certainty is a stringent decision rule favoring the rejection of new policies. The importance of other variables not included in the analysis for the robustness of the findings are discussed (e.g., consideration of the entire population at risk for malaria, the affordability of ACTs in specific settings, and the growth of resistance modeled according to population genetic parameters).


Fortune favours the bold: an agent-based model reveals adaptive advantages of overconfidence in war.
Overconfidence has long been considered a cause of war. Like other decision-making biases, overconfidence seems detrimental because it increases the frequency and costs of fighting. However, evolutionary biologists have proposed that overconfidence may also confer adaptive advantages: increasing ambition, resolve, persistence, bluffing opponents, and winning net payoffs from risky opportunities despite occasional failures. We report the results of an agent-based model of inter-state conflict, which allows us to evaluate the performance of different strategies in competition with each other. Counter-intuitively, we find that overconfident states predominate in the population at the expense of unbiased or underconfident states. Overconfident states win because: (1) they are more likely to accumulate resources from frequent attempts at conquest; (2) they are more likely to gang up on weak states, forcing victims to split their defences; and (3) when the decision threshold for attacking requires an overwhelming asymmetry of power, unbiased and underconfident states shirk many conflicts they are actually likely to win. These "adaptive advantages" of overconfidence may, via selection effects, learning, or evolved psychology, have spread and become entrenched among modern states, organizations and decision-makers. This would help to explain the frequent association of overconfidence and war, even if it no longer brings benefits today.


Breast cancer: variables affecting sentinel lymph node visualization at preoperative lymphoscintigraphy.
To compare patients with visualized sentinel lymph nodes (SLNs) and patients with nonvisualized SLNs, with a focus on variables affecting SLN visualization at preoperative lymphoscintigraphy and on nodal drainage basins as related to tumor location. One hundred thirty-six patients who had breast cancer underwent preoperative lymphoscintigraphy before SLN biopsy. Patients with visualized and nonvisualized SLNs were compared for age; tumor site, size, and histologic findings; injection guidance method; diagnostic biopsy type; interval between biopsy and lymphoscintigraphy; intraoperative identification method; and surgical identification rate. Visualized SLN drainage basins were noted. Ninety-nine patients had visualized and 37 had nonvisualized SLNs, without statistically significant differences in tumor site, size, and histologic findings; injection guidance method; diagnostic biopsy type; and interval between biopsy and lymphoscintigraphy. Ninety-nine (73%) of the 136 SLNs were visualized at lymphoscintigraphy; 30 (81%) of the 37 nonvisualized SLNS were identified at surgery. Of the seven SLNs not identified at surgery, five were mapped with radiocolloid only. Patients with nonvisualized SLNs were older than those with visualized SLNs. Eleven (46%) of 24 tumors with internal mammary drainage were in the outer part of the breast. Patients with and those without visualization differed in age, SLN identification at surgery, and surgical identification method. Nonvisualized status does not preclude axillary metastasis. In older patients with nonvisualized SLNs, blue dye may aid in SLN detection, as compared with isotope-only localization.


Endogenous triacylglycerol utilization by rat skeletal muscle during tetanic stimulation.
An isolated perfused rat hindquarter preparation was used to examine the utilization of endogenous triacylglycerol (TG) during 20 min of electrical stimulation. The sciatic nerve was stimulated with maximal tetanic trains at 0.5 Hz. The isometric tension generated by the gastrocnemius-plantaris-soleus muscle group was recorded, and muscle samples were taken pre- and poststimulation. Twenty minutes of stimulation significantly reduced endogenous TG from 6.78 +/- 0.84 to 4.64 +/- 0.64 mumol X g dry wt-1 (32%) in the red gastrocnemius muscle and from 7.70 +/- 0.61 to 6.66 +/- 0.80 mumol X g dry wt-1 (13.5%) in the plantaris muscle. Although TG content decreased by 16% in the soleus (28.2 +/- 5.0 to 23.8 +/- 4.4 mumol X g-1), the change was not significant. Stimulation had no effect on white gastrocnemius TG concentration (6.84 +/- 1.22 to 6.25 +/- 1.41 mumol X g-1). Thus oxidation of TG occurred primarily in muscles with a large proportion of fast-twitch oxidative-glycolytic fibers. Calculations from measurements of muscle energy stores and fuel uptake indicated that up to 62% of the aerobic energy was provided by endogenous TG. Carbohydrate oxidation contributed up to 28% and the remaining 10% may be accounted for by the oxidation of exogenous free fatty acids originating in the perfusate or from hindquarter adipose tissue. The magnitude of the fall in TG concentration in a given muscle was inversely related to the fall in glycogen concentration.


Higher physical activity is associated with lower aortic stiffness but not with central blood pressure: the ADDITION-Pro Study.
Physical activity is associated with reduced cardiovascular disease risk. However, improvements in conventional risk factors due to physical activity do not explain its full benefit. Therefore, we examined associations of objectively measured physical activity energy expenditure and intensity with central hemodynamics to provide new insight into the link between physical activity and cardiovascular disease. We analyzed data from 1816 Danes (median age: 66 years) without cardiovascular disease. Physical activity was estimated using combined accelerometry and heart rate monitoring. Aortic stiffness was assessed by applanation tonometry, as aortic pulse wave velocity, and central blood pressure was estimated from radial waveforms. Associations between physical activity energy expenditure and central hemodynamics were examined by linear regression. Furthermore, the consequence of substituting 1 hour sedentary behavior with 1 hour light or moderate-to-vigorous physical activity on central hemodynamics was examined. Median physical activity energy expenditure was 28.0 kJ/kg/d (IQR: 19.8; 38.7). A 10 kJ/kg/d higher energy expenditure was associated with 0.75% lower aortic pulse wave velocity (CI: -1.47; -0.03). Associations with central systolic blood pressure and central pulse pressure were not statistically significant. We observed no difference in central hemodynamics when substituting 1 hour sedentary behavior with 1 hour light or moderate-to-vigorous physical activity. In this relatively inactive population, higher physical activity energy expenditure was associated with lower aortic stiffness, while there was no statistically significant association between substitution of activity intensity and central hemodynamics. This suggests that lower aortic stiffness is one of a number of health benefits attributed to higher habitual physical activity.


The ventilated patient undergoing hydrotherapy: a case study.
The ascending peripheral neuropathy and paralysis that result from Guillain-Barre Syndrome's (GBS) demyelination of peripheral nerves is a challenge to health professionals; the patient requires support during the acute disease process and during the remyelination recovery period, often lasting months to years. The staff of a major metropolitan teaching hospital's critical care unit (CCU) and physiotherapy departments developed a hydrotherapy treatment programme for a ventilated patient with GBS. Through careful planning and appropriate preparation, it was found that hydrotherapy could successfully and safely be incorporated into a patient's treatment regimen. The benefits included improved range of movement due to the supportive nature of water, anecdotal increased strength, size and movement of remyelinating muscles and a psychological improvement. Although this patient has not recovered from GBS to be independent, hydrotherapy was a valuable part of the treatment regimen and it could be suggested the increase muscle strength lead to improved respiratory function and enabled weaning from ventilation, reducing intensive care length of stay and cost.


Comparison of operator and patient radiation exposure during fluoroscopy-guided vertebroplasty and kyphoplasty: a systematic review and meta-analysis.
Percutaneous vertebroplasty (PV) and balloon kyphoplasty (BK) are two minimally invasive techniques used to treat mechanical pain secondary to spinal compression fractures. A concern for both procedures is the radiation exposure incurred by both operators and patients. The authors conducted a systematic review of the available literature to examine differences in interventionalist radiation exposure between PV and BK and differences in patient radiation exposure between PV and BK. The authors conducted a search of the PubMed, Ovid Medline, Cochrane Reviews, Embase, and Web of Science databases according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Full-text articles in English describing one of the primary endpoints in ≥ 5 unique patients treated with PV or BK of the mobile spine were included. Estimates of mean operative time, radiation exposure, and fluoroscopy duration were reported as weighted averages. Additionally, annual occupational dose limits provided by the United States Nuclear Regulatory Commission (USNRC) were used to determine the number needed to harm (NNH). The meta-analysis included 27 articles. For PV, the mean fluoroscopy times were 4.9 ± 3.3 minutes per level without protective measures and 5.2 ± 3.4 minutes with protective measures. The mean operator radiation exposures per level in mrem were 4.6 ± 5.4 at the eye, 7.8 ± 8.7 at the neck, 22.7 ± 62.4 at the torso, and 49.2 ± 62.2 at the hand without protective equipment and 0.3 ± 0.1 at the torso and 95.5 ± 162.5 at the hand with protection. The mean fluoroscopy times per level for BK were 6.1 ± 2.5 minutes without protective measures and 6.0 ± 3.2 minutes with such measures. The mean exposures were 31.3 ± 39.3, 19.7 ± 4.6, 31.8 ± 34.2, and 174.4 ± 117.3 mrem at the eye, neck, torso, and hand, respectively, without protection, and 1, 9.2 ± 26.2, and 187.7 ± 100.4 mrem at the neck, torso, and hand, respectively, with protective equipment. For protected procedures, radiation to the hand was the limiting factor and the NNH estimates were 524 ± 891 and 266 ± 142 for PV and BK, respectively. Patient exposure as measured by flank-mounted dosimeters, entrance skin dose, and dose area product demonstrated lower exposure with PV than BK (p < 0.01). Operator radiation exposure is significantly decreased by the use of protective equipment. Radiation exposure to both the operator and patient is lower for PV than BK. NNH estimates suggest that radiation to the hand limits the number of procedures an operator can safely perform. In particular, radiation to the hand limits PV to 524 and BK to 266 procedures per year before surpassing the threshold set by the USNRC.


A primary role for Golgi positioning in directed secretion, cell polarity, and wound healing.
Peri-centrosomal positioning of the mammalian Golgi apparatus is known to involve microtubule-based motility, but its importance for cellular physiology is a major unanswered question. Here, we identify golgin-160 and GMAP210 as proteins required for centripetal motility of Golgi membranes. In the absence of either golgin, peri-centrosomal positioning of the Golgi apparatus was disrupted while the cytoskeleton remained intact. Although secretion persisted with normal kinetics, it was evenly distributed in response to wounding rather than directed to the wound edge. Strikingly, these cells also completely failed to polarize. Further, directionally persistent cell migration was inhibited such that wound closure was impaired. These findings not only reveal novel roles for golgin-160 and GMAP210 in conferring membrane motility but also indicate that Golgi positioning has an active role in directed secretion, cell polarity, and wound healing.


Transcriptomic analysis of the temporal host response to skin infestation with the ectoparasitic mite Psoroptes ovis.
Infestation of ovine skin with the ectoparasitic mite Psoroptes ovis results in a rapid cutaneous immune response, leading to the crusted skin lesions characteristic of sheep scab. Little is known regarding the mechanisms by which such a profound inflammatory response is instigated and to identify novel vaccine and drug targets a better understanding of the host-parasite relationship is essential. The main objective of this study was to perform a combined network and pathway analysis of the in vivo skin response to infestation with P. ovis to gain a clearer understanding of the mechanisms and signalling pathways involved. Infestation with P. ovis resulted in differential expression of 1,552 genes over a 24 hour time course. Clustering by peak gene expression enabled classification of genes into temporally related groupings. Network and pathway analysis of clusters identified key signalling pathways involved in the host response to infestation. The analysis implicated a number of genes with roles in allergy and inflammation, including pro-inflammatory cytokines (IL1A, IL1B, IL6, IL8 and TNF) and factors involved in immune cell activation and recruitment (SELE, SELL, SELP, ICAM1, CSF2, CSF3, CCL2 and CXCL2). The analysis also highlighted the influence of the transcription factors NF-kB and AP-1 in the early pro-inflammatory response, and demonstrated a bias towards a Th2 type immune response. This study has provided novel insights into the signalling mechanisms leading to the development of a pro-inflammatory response in sheep scab, whilst providing crucial information regarding the nature of mite factors that may trigger this response. It has enabled the elucidation of the temporal patterns by which the immune system is regulated following exposure to P. ovis, providing novel insights into the mechanisms underlying lesion development. This study has improved our existing knowledge of the host response to P. ovis, including the identification of key parallels between sheep scab and other inflammatory skin disorders and the identification of potential targets for disease control.