Antimicrobial Mechanisms and Effectiveness of Graphene and Graphene-Functionalized Biomaterials. A Scope Review.
Bacterial infections represent nowadays the major reason of biomaterials implant failure, however, most of the available implantable materials do not hold antimicrobial properties, thus requiring antibiotic therapy once the infection occurs. The fast raising of antibiotic-resistant pathogens is making this approach as not more effective, leading to the only solution of device removal and causing devastating consequences for patients. Accordingly, there is a large research about alternative strategies based on the employment of materials holding intrinsic antibacterial properties in order to prevent infections. Between these new strategies, new technologies involving the use of carbon-based materials such as carbon nanotubes, fullerene, graphene and diamond-like carbon shown very promising results. In particular, graphene- and graphene-derived materials (GMs) demonstrated a broad range antibacterial activity toward bacteria, fungi and viruses. These antibacterial activities are attributed mainly to the direct physicochemical interaction between GMs and bacteria that cause a deadly deterioration of cellular components, principally proteins, lipids, and nucleic acids. In fact, GMs hold a high affinity to the membrane proteoglycans where they accumulate leading to membrane damages; similarly, after internalization they can interact with bacteria RNA/DNA hydrogen groups interrupting the replicative stage. Moreover, GMs can indirectly determine bacterial death by activating the inflammatory cascade due to active species generation after entering in the physiological environment. On the opposite, despite these bacteria-targeted activities, GMs have been successfully employed as pro-regenerative materials to favor tissue healing for different tissue engineering purposes. Taken into account these GMs biological properties, this review aims at explaining the antibacterial mechanisms underlying graphene as a promising material applicable in biomedical devices.


Cell permeant peptide analogues of the small heat shock protein, HSP20, reduce TGF-beta1-induced CTGF expression in keloid fibroblasts.
A growing body of evidence suggests the involvement of connective tissue growth factor (CTGF) in the development and maintenance of fibrosis and excessive scarring. As the expression of this protein requires an intact actin cytoskeleton, disruption of the cytoskeleton represents an attractive strategy to decrease CTGF expression and, consequently, excessive scarring. The small heat-shock-related protein (HSP20), when phosphorylated by cyclic nucleotide signaling cascades, displaces phospho-cofilin from the 14-3-3 scaffolding protein leading to activation of cofilin as an actin-depolymerizing protein. In the present study, we evaluated the effect of AZX100, a phosphopeptide analogue of HSP20, on transforming growth factor-beta-1 (TGF-beta1)-induced CTGF and collagen expression in human keloid fibroblasts. We also examined the effect of AZX100 on scar formation in vivo in dermal wounds in a Siberian hamster model. AZX100 decreased the expression of CTGF and type I collagen induced by TGF-beta1, endothelin, and lysophosphatidic acid. Treatment with AZX100 decreased stress fiber formation and altered the morphology of human dermal keloid fibroblasts. In vivo, AZX100 significantly improved collagen organization in a Siberian hamster scarring model. Taken together, these results suggest the potential use of AZX100 as a strategy to prevent excessive scarring and fibrotic disorders.


A new measurement of sequence conservation.
Understanding sequence conservation is important for the study of sequence evolution and for the identification of functional regions of the genome. Current studies often measure sequence conservation based on every position in contiguous regions. Therefore, a large number of functional regions that contain conserved segments separated by relatively long divergent segments are ignored. Our goal in this paper is to define a new measurement of sequence conservation such that both contiguously conserved regions and discontiguously conserved regions can be detected based on this new measurement. Here and in the following, conserved regions are those regions that share similarity higher than a pre-specified similarity threshold with their homologous regions in other species. That is, conserved regions are good candidates of functional regions and may not be always functional. Moreover, conserved regions may contain long and divergent segments. To identify both discontiguously and contiguously conserved regions, we proposed a new measurement of sequence conservation, which measures sequence similarity based only on the conserved segments within the regions. By defining conserved segments using the local alignment tool CHAOS, under the new measurement, we analyzed the conservation of 1642 experimentally verified human functional non-coding regions in the mouse genome. We found that the conservation in at least 11% of these functional regions could be missed by the current conservation analysis methods. We also found that 72% of the mouse homologous regions identified based on the new measurement are more similar to the human functional sequences than the aligned mouse sequences from the UCSC genome browser. We further compared BLAST and discontiguous MegaBLAST with our method. We found that our method picks up many more conserved segments than BLAST and discontiguous MegaBLAST in these regions. It is critical to have a new measurement of sequence conservation that is based only on the conserved segments in one region. Such a new measurement can aid the identification of better local "orthologous" regions. It will also shed light on the identification of new types of conserved functional regions in vertebrate genomes.


Stratified, randomized, double-blind comparison of intravenous ondansetron administered as a multiple-dose regimen versus two single-dose regimens in the prevention of cisplatin-induced nausea and vomiting.
This study compares the efficacy and safety of two single-dose regimens with the approved three-dose regimen of ondansetron in the prevention of cisplatin-induced emesis. This multicenter study was a stratified, randomized, double-blind, and parallel group design. Chemotherapy-naive inpatients were randomized to receive intravenous (IV) ondansetron (Zofran; Glaxo Inc, Research Triangle Park, NC) 0.15 mg/kg times three doses, every 4 hours or a single 8-mg or 32-mg dose followed by two saline doses that began 30 minutes before cisplatin administration. Cisplatin (high-dose > or = 100 mg/m2 or medium-dose 50 to 70 mg/m2) was given as a single infusion (< or = 3 hours). Patients were monitored for emetic episodes, adverse events, and laboratory safety parameters for 24 hours after cisplatin administration. A total of 699 patients (359 high-dose, 340 medium-dose) were enrolled. Of these, 618 were assessable for efficacy (15 ineligible, 66 protocol deviations). The 32-mg dose was superior to the 8-mg single dose with regard to total number of emetic episodes (high-dose, P = .015; medium-dose, P < .001), complete response (no emetic episodes: high-dose, 48% v 35%; P = .048; medium-dose, 73% v 50%; P = .001) and failure rate (> 5 emetic episodes, withdrawn or rescued: high-dose, 20% v 34%; P = .018; medium-dose, 9% v 23%; P = .005). The 32-mg single dose was also superior to the 0.15 mg/kg times three dose regimen with regard to total number of emetic episodes (medium-dose, P = .033) and failure rate (high-dose, 20% v 36%; P = .009; medium-dose, 9% v 22%; P = .011). Ondansetron was well tolerated. The most common adverse event was headache. An approximate 10-fold increase in the incidence of clinically significant transaminase elevations was observed in the high-dose versus medium-dose cisplatin strata (aspartate aminotransferase [AST], 6.5% v 0.7%; serum alanine aminotransferase [ALT], 5.0% v 0.3%). A 32-mg single dose of ondansetron is more effective than a single 8-mg dose and is at least as effective as the standard regimen of 0.15 mg/kg times three doses in the prevention of cisplatin-induced acute emesis.


Quit interest, quit attempt and recent cigarette smoking cessation in the US working population, 2010.
To determine the prevalence of cigarette smoking cessation and examine the association between cessation and various factors among workers in a nationally representative sample of US adults. Data were derived from the 2010 National Health Interview Survey. Prevalence rates were calculated for interest in quitting smoking, making an attempt to quit smoking, and successful smoking cessation (defined as smokers who had quit for 6-12 months). Logistic regression analyses were used to identify factors associated with cessation after adjustment for demographic characteristics (age group, race/ethnicity, educational level and marital status). Data were available for 17 524 adults who were employed in the 12 months prior to interview. The prevalence of quit interest, quit attempt and recent cessation was 65.2%, 53.8% and 6.8%, respectively. Quit interest was less likely among workers with long work hours, but more likely among workers with job insecurity, or frequent workplace skin and/or respiratory exposures. Quit attempt was more likely among workers with a hostile work environment but less likely among workers living in a home that permitted smoking or who smoked ≥11 cigarettes/day. Recent smoking cessation was less likely among workers with frequent exposure to others smoking at work or living in a home that permitted smoking, but more likely among workers with health insurance. Factors associated with cessation interest or attempt differed from those associated with successful cessation. Cessation success might be improved by reducing exposure to others smoking at work and home, and by improving access to health insurance.


Discrepancies between parent- and adolescent-perceived problem severity and influences on help seeking from mental health services.
Attitudinal and practical barriers prevent many young people who are experiencing mental health problems from seeking professional help. The influence of others can help young people to overcome barriers to help seeking. Understanding the relative influence of parents and others on the help-seeking decision and the extent of parent-child agreement on the severity of the young person's problems, may be helpful in facilitating intake processes in child and adolescent mental health services (CAMHS). One hundred and nineteen parent-child (14-18-years-old) dyads attending an initial appointment at a Sydney and regional CAMHS completed the parent and youth Strength and Difficulties Questionnaires (SDQs) prior to their assessment interview. Parents and children also answered three equivalent questions on sources of influence in their decision to access services. Ninety-four per cent of young people reported that others had influenced their decision to access help, with parents being the strongest influence. Higher levels of parental influence in the help-seeking process were related to greater disagreement between parent and child on the severity of the problems. Parent and child ratings of influence were related to the severity of externalizing problems. The findings are consistent with models that highlight help seeking as a social process involving high degrees of influence particularly from parents. Referral sources and clinicians need to be aware of the effects of discrepant views between parent and child regarding the presenting problem. To facilitate joint therapy it may be helpful for clinicians to address the level of influence involved in having the young person attend their first appointment with parents and children.


Innate control of actin nucleation determines two distinct migration behaviours in dendritic cells.
Dendritic cell (DC) migration in peripheral tissues serves two main functions: antigen sampling by immature DCs, and chemokine-guided migration towards lymphatic vessels (LVs) on maturation. These migratory events determine the efficiency of the adaptive immune response. Their regulation by the core cell locomotion machinery has not been determined. Here, we show that the migration of immature DCs depends on two main actin pools: a RhoA-mDia1-dependent actin pool located at their rear, which facilitates forward locomotion; and a Cdc42-Arp2/3-dependent actin pool present at their front, which limits migration but promotes antigen capture. Following TLR4-MyD88-induced maturation, Arp2/3-dependent actin enrichment at the cell front is markedly reduced. Consequently, mature DCs switch to a faster and more persistent mDia1-dependent locomotion mode that facilitates chemotactic migration to LVs and lymph nodes. Thus, the differential use of actin-nucleating machineries optimizes the migration of immature and mature DCs according to their specific function.


Metal slit array Fresnel lens for wavelength-scale optical coupling to nanophotonic waveguides.
We propose a novel metal slit array Fresnel lens for wavelength-scale optical coupling into a nanophotonic waveguide. Using the plasmonic waveguide structure in Fresnel lens form, a much wider beam acceptance angle and wavelength-scale working distance of the lens was realized compared to a conventional dielectric Fresnel lens. By applying the plasmon waveguide dispersion relation to a phased antenna array model, we also develop and analyze design rules and parameters for the suggested metal slit Fresnel lens. Numerical assessment of the suggested structure shows excellent coupling efficiency (up to 59%) of the 10 mum free-space Gaussian beam to the 0.36 mum Si waveguide within a working distance of a few mum.


Zebrafish aversion to infrasound in an open field test.
Aquatic species are capable of detecting infrasound (sub-20 Hz frequencies) which may be a source of anthropogenic pollution and have a detrimental impact on the environmental fitness of fish. Infrasound is generated by infrastructure, producing acoustic frequency peaks that are not discernible by humans. The presence of these frequencies may therefore impact the environmental wellbeing of aquatic laboratory animals, which are often housed in spaces adjacent to facilities producing infrasound. To investigate the potential impact of infrasound, we used wild-type zebrafish (Danio rerio) and exposed them to short periods of infrasound at either 5, 10, 15, or 20 Hz, or 0 Hz as a control group. A motion-tracking software system was used to monitor fish movement in an open field test and arena location, distance moved, and immobility were quantified. There was a significant effect of 15 Hz which caused the fish to spend more time away from the infrasound source. The 20 Hz group also spent significantly less time in the zone closest to the speaker. There were no differences in distance moved or immobility between infrasound and control groups. These findings demonstrate that 15 Hz infrasound has aversive effects on zebrafish, causing them to move away from the sound source. To enhance environmental enrichment and wellbeing of aquatic laboratory animals, sources of infrasound pollution should be investigated and mitigated.


Infant feeding and HIV positive mothers in the Capricorn District of Limpopo province.
HIV-positive mothers who practise infant feeding of their choice at Mankweng clinic in the Limpopo province are experiencing specific problems with various feeding methods. This study was undertaken with the aim to explore and describe the socioeconomic and cultural experiences of HIV-positive mothers who practise infant feeding of their choice. The research design was exploratory, descriptive, qualitative and contextual in nature. A phenomenological approach was adopted to focus on the lived experiences of HIV-positive mothers. The study sample was purposely selected. Ten HIV-positive mothers volunteered to participate in the study. Data were collected through in-depth unstructured interviews. All participants responded to an open-ended question: "Could you please tell me, in detail, your experience on infant feeding of your choice?" Interviews were conducted until saturation, as was reflected in repeating themes, was reached. The model of trustworthiness, as outlined in Guba and Lincoln (1985:301-318), to ensure credibility and dependability, was used in this study. The study adhered to the ethical standards as set by DENOSA (1998:2.3.2-2.3.4). Data were analysed according to Tesch's method, as outlined in Creswell (2003:192) and De Vos (1998:343). Literature control was performed to verify the results. Two main categories that emerged were guided by options for infant feeding; namely those that chose formula feeding for their babies and those participants who opted to breast-feed their babies. The study proposed to recommend guidelines for the development of relevent content for inclusion in health education programmes of registered midwives who, in turn, can use such information to educate mothers.


Confined Tamm plasmon lasers.
We demonstrate that confined Tamm plasmon modes can be advantageously exploited for the realization of new kind of metal/semiconductor lasers. Laser emission is demonstrated for Tamm structures with various diameters of the metallic disks which provide the confinement. A reduction of the threshold with the size is observed. The competition between the acceleration of the spontaneous emission and the increase of the losses leads to an optimal size, which is in good agreement with calculations.


Autoantibodies against the chemokine receptor 3 predict cardiovascular risk.
Chronic inflammation and autoimmunity contribute to cardiovascular (CV) disease. Recently, autoantibodies (aAbs) against the CXC-motif-chemokine receptor 3 (CXCR3), a G protein-coupled receptor with a key role in atherosclerosis, have been identified. The role of anti-CXCR3 aAbs for CV risk and disease is unclear. Anti-CXCR3 aAbs were quantified by a commercially available enzyme-linked immunosorbent assay in 5000 participants (availability: 97.1%) of the population-based Gutenberg Health Study with extensive clinical phenotyping. Regression analyses were carried out to identify determinants of anti-CXCR3 aAbs and relevance for clinical outcome (i.e. all-cause mortality, cardiac death, heart failure, and major adverse cardiac events comprising incident coronary artery disease, myocardial infarction, and cardiac death). Last, immunization with CXCR3 and passive transfer of aAbs were performed in ApoE(-/-) mice for preclinical validation. The analysis sample included 4195 individuals (48% female, mean age 55.5 ± 11 years) after exclusion of individuals with autoimmune disease, immunomodulatory medication, acute infection, and history of cancer. Independent of age, sex, renal function, and traditional CV risk factors, increasing concentrations of anti-CXCR3 aAbs translated into higher intima-media thickness, left ventricular mass, and N-terminal pro-B-type natriuretic peptide. Adjusted for age and sex, anti-CXCR3 aAbs above the 75th percentile predicted all-cause death [hazard ratio (HR) (95% confidence interval) 1.25 (1.02, 1.52), P = .029], driven by excess cardiac mortality [HR 2.51 (1.21, 5.22), P = .014]. A trend towards a higher risk for major adverse cardiac events [HR 1.42 (1.0, 2.0), P = .05] along with increased risk of incident heart failure [HR per standard deviation increase of anti-CXCR3 aAbs: 1.26 (1.02, 1.56), P = .03] may contribute to this observation. Targeted proteomics revealed a molecular signature of anti-CXCR3 aAbs reflecting immune cell activation and cytokine-cytokine receptor interactions associated with an ongoing T helper cell 1 response. Finally, ApoE(-/-) mice immunized against CXCR3 displayed increased anti-CXCR3 aAbs and exhibited a higher burden of atherosclerosis compared to non-immunized controls, correlating with concentrations of anti-CXCR3 aAbs in the passive transfer model. In individuals free of autoimmune disease, anti-CXCR3 aAbs were abundant, related to CV end-organ damage, and predicted all-cause death as well as cardiac morbidity and mortality in conjunction with the acceleration of experimental atherosclerosis.


Non-targeted 1H-NMR-metabolomics suggest the induction of master regulators of energy metabolism in the liver of vitamin E-deficient rats.
The essential function of vitamin E in vivo is not fully understood. Several studies addressed changes in the pattern of gene expression induced by vitamin E, but often did not investigate if these changes altered biochemical pathways and are eventually translated into biological function. We therefore used (1)H-NMR metabolomics to investigate the biochemical effects in the liver of rats caused by long-term feeding with diets deficient (dVE; α-tocopherol (αT), <1; γ-tocopherol (γT), <1; all values in mg kg(-1) diet), marginal (mVE; αT, 6; γT, 11), sufficient (sVE; αT, 12; γT, 24), or fortified with vitamin E (fVE; αT, 140; γT, 24). The concentrations of four polar hepatic metabolites were affected by the vitamin E content of the diet; glucose was lower and creatine, phosphocholine, and betaine were higher in deficient compared with rats receiving vitamin E. To achieve further biochemical insight, we investigated transcriptional changes in genes involved in the regulation of metabolic pathways related to these metabolites. Transcription of PGC1α, PPARα, and PPARγ, transcription factors controlling energy metabolism, was lower and that of the fatty acid translocase CD36 higher in animals fed vitamin E-deficient compared to those fed vitamin E-replete diets. Our data thus indicate that consumption of a vitamin E-deficient diet may alter hepatic energy metabolism in rats.


Gender-associated genes in filarial nematodes are important for reproduction and potential intervention targets.
A better understanding of reproductive processes in parasitic nematodes may lead to development of new anthelmintics and control strategies for combating disabling and disfiguring neglected tropical diseases such as lymphatic filariasis and onchocerciasis. Transcriptomatic analysis has provided important new insights into mechanisms of reproduction and development in other invertebrates. We have performed the first genome-wide analysis of gender-associated (GA) gene expression in a filarial nematode to improve understanding of key reproductive processes in these parasites. The Version 2 Filarial Microarray with 18,104 elements representing ∼85% of the filarial genome was used to identify GA gene transcripts in adult Brugia malayi worms. Approximately 19% of 14,293 genes were identified as GA genes. Many GA genes have potential Caenorhabditis elegans homologues annotated as germline-, oogenesis-, spermatogenesis-, and early embryogenesis- enriched. The potential C. elegans homologues of the filarial GA genes have a higher frequency of severe RNAi phenotypes (such as lethal and sterility) than other C. elegans genes. Molecular functions and biological processes associated with GA genes were gender-segregated. Peptidase, ligase, transferase, regulator activity for kinase and transcription, and rRNA and lipid binding were associated with female GA genes. In contrast, catalytic activity from kinase, ATP, and carbohydrate binding were associated with male GA genes. Cell cycle, transcription, translation, and biological regulation were increased in females, whereas metabolic processes of phosphate and carbohydrate metabolism, energy generation, and cell communication were increased in males. Significantly enriched pathways in females were associated with cell growth and protein synthesis, whereas metabolic pathways such as pentose phosphate and energy production pathways were enriched in males. There were also striking gender differences in environmental information processing and cell communication pathways. Many proteins encoded by GA genes are secreted by Brugia malayi, and these encode immunomodulatory molecules such as antioxidants and host cytokine mimics. Expression of many GA genes has been recently reported to be suppressed by tetracycline, which blocks reproduction in female Brugia malayi. Our localization of GA transcripts in filarial reproductive organs supports the hypothesis that these genes encode proteins involved in reproduction. Genome-wide expression profiling coupled with a robust bioinformatics analysis has greatly expanded our understanding of the molecular biology of reproduction in filarial nematodes. This study has highlighted key molecules and pathways associated with reproductive and other biological processes and identified numerous potential candidates for rational drug design to target reproductive processes.


Multi-path variational transition state theory for chemical reaction rates of complex polyatomic species: ethanol + OH reactions.
Complex molecules often have many structures (conformations) of the reactants and the transition states, and these structures may be connected by coupled-mode torsions and pseudorotations; some but not all structures may have hydrogen bonds in the transition state or reagents. A quantitative theory of the reaction rates of complex molecules must take account of these structures, their coupled-mode nature, their qualitatively different character, and the possibility of merging reaction paths at high temperature. We have recently developed a coupled-mode theory called multi-structural variational transition state theory (MS-VTST) and an extension, called multi-path variational transition state theory (MP-VTST), that includes a treatment of the differences in the multi-dimensional tunneling paths and their contributions to the reaction rate. The MP-VTST method was presented for unimolecular reactions in the original paper and has now been extended to bimolecular reactions. The MS-VTST and MP-VTST formulations of variational transition state theory include multi-faceted configuration-space dividing surfaces to define the variational transition state. They occupy an intermediate position between single-conformation variational transition state theory (VTST), which has been used successfully for small molecules, and ensemble-averaged variational transition state theory (EA-VTST), which has been used successfully for enzyme kinetics. The theories are illustrated and compared here by application to three thermal rate constants for reactions of ethanol with hydroxyl radical--reactions with 4, 6, and 14 saddle points.


Cyclosporin A drug interactions. Screening for inducers and inhibitors of cytochrome P-450 (cyclosporin A oxidase) in primary cultures of human hepatocytes and in liver microsomes.
In previous papers we demonstrated that cyclosporin A (CsA) was specifically oxidized in rabbit and human liver by cytochrome P-450IIIA. We therefore anticipated that any drug that is an inducer or an inhibitor of this cytochrome should lead to interaction with CsA when given in association with it. In order to confirm this hypothesis, primary cultures of human hepatocytes and human liver microsomes were used to "reproduce" in vitro clinically significant interactions observed between CsA and drugs known either as specific inducers (i.e., rifampicin) or as specific inhibitors (i.e., erythromycin) of P-450IIIA. Our results were in close agreement with the clinical reports. Human hepatocytes maintained in primary cultures for 72 hr in the presence of 50 microM rifampicin exhibited increased levels of P-450IIIA, determined by Western blot using specific antibodies, and concomitant increase in CsA oxidase activity, determined by HPLC analysis of extra and intracellular media. Conversely, these cultures exhibited erythromycin concentration-dependent decreases in CsA oxidase activity when incubated in the presence of 5, 20, and 100 microM erythromycin. In addition, a Lineweaver-Burk analysis of the erythromycin-mediated inhibition of CsA oxidase activity in human liver microsomes revealed competitive inhibition (with Ki of 75 microM) as expected, this macrolide being a specific substrate of P-450IIIA. Using this experimental approach, 59 molecules representative of 17 different therapeutic classes were screened for inducers and inhibitors of CsA oxidase activity. Our results allowed us to elucidate the molecular mechanism of previously observed, but unexplained, drug interactions involving CsA, and to detect drugs that should interfere with CsA metabolism as inducers or inhibitors. Drugs detected as potential inducers of CsA oxidase included: rifampicin, sulfadimidine, phenobarbital, phenytoin, phenylbutazone, dexamethasone, sulfinpyrazone, and carbamazepine. Drugs detected as potential competitive inhibitors included: triacetyloleandomycin, erythromycin, josamycin, midecamycin, ketoconazole, miconazole, midazolam, nifedipin, diltiazem, verapamil, nicardipine, ergotamine, dihydroergotamine, glibenclamide, bromocriptine, ethynylestradiol, progesterone, cortisol, prednisone, prednisolone, and methylprednisolone. Finally, cefoperazone, cefotaxime, ceftazidime, isoniazide, doxycycline, spiramycin, sulfamethoxazole, norfloxacin, pefloxacin, vancocin, trimethoprim, amphotericin B, valproic acid, quinidine, cimetidine, ranitidine, omeprazole, diclofenac, aspirin, paracetamol, debrisoquine, guanoxan, captopril, furosemide, acetazolamide, sparteine, gliclazide, and imipramine were found not to interfere with the hepatic metabolism of CsA.


Assessment with unenhanced MRI techniques of renal morphology and hemodynamic changes during acute kidney injury and chronic kidney disease in mice.
Changes in renal oxygenation and perfusion have been identified as common pathways to the development and progression of renal disease. Recently, the sensitivity of hemodynamic response imaging (HRI) was demonstrated; this is a functional magnetic resonance imaging (MRI) method combined with transient hypercapnia and hyperoxia for the evaluation of renal perfusion and vascular reactivity. The aim of this study was to utilize HRI for the noninvasive evaluation of changes in renal hemodynamics and morphology during acute, chronic and acute-on-chronic renal failures. Renal-HRI maps and true fast imaging with steady-state precession (True-FISP) images were used to evaluate renal perfusion, morphology and corticomedullary differentiation (CMD). MR images were acquired on two mouse models of kidney injury: adenine-induced chronic kidney disease (CKD) and rhabdomyolysis-induced acute kidney injury (AKI). Serum urea was measured from these mice in order to determine renal function. Renal-HRI maps revealed a blunted response to hypercapnia and hyperoxia with evolving kidney dysfunction in both models, reflecting hampered renal vascular reactivity and perfusion. True-FISP images showed a high sensitivity to renal morphological changes, with different patterns characterizing each model. Calculated data obtained from HRI and True-FISP during the evolution of renal failure and upon recovery, with and without protective intervention, closely correlated with the degree of renal impairment. This study suggests the potential combined usage of two noninvasive MRI methods, HRI and True-FISP, for the assessment of renal dysfunction without the potential risk associated with contrast-agents administration. HRI may also serve as a research tool in experimental settings, revealing the hemodynamic changes associated with kidney dysfunction.


Mediterranean diet and healthy ageing: a Sicilian perspective.
Traditional Mediterranean diet (MedDiet) is a common dietary pattern characterizing a lifestyle and culture proven to contribute to better health and quality of life in Mediterranean countries. By analyzing the diet of centenarians from the Sicani Mountains and eating habits of inhabitants of Palermo, it is reported that a close adherence to MedDiet is observed in the countryside, whereas in big towns this adherence is not so close. This has an effect on the rates of mortality at old age (and reciprocally longevity) that are lower in the countryside than in big towns. Concerning the health effects of the diet, the low content of animal protein and the low glycaemic index of the Sicilian MedDiet might directly modulate the insulin/IGF-1 and the mTOR pathways, known to be involved in ageing and longevity. In particular, the reduction of animal protein intake may significantly reduce serum IGF-1 concentrations and inhibit mTOR activity with a down-regulation of the signal that leads to the activation of FOXO3A and, consequently, to the transcription of homeostatic genes that favour longevity. The down-regulation of both IGF-1 and mTORC1 also induces an anti-inflammatory effect. In addition to the effects on sensing pathways, many single components of MedDiet are known to have positive effects on health, reducing inflammation, optimizing cholesterol and other important risk factors of age-related diseases. However, a key role is played by polyphenols represented in high amount in the Sicilian MedDiet (in particular in extra virgin olive oil) that can work as hormetins that provide an environmental chemical signature regulating stress resistance pathways such as nuclear factor erythroid 2-related factor 2.


Hierarchy of gene expression data is predictive of future breast cancer outcome.
We calculate measures of hierarchy in gene and tissue networks of breast cancer patients. We find that the likelihood of metastasis in the future is correlated with increased values of network hierarchy for expression networks of cancer-associated genes, due to the correlated expression of cancer-specific pathways. Conversely, future metastasis and quick relapse times are negatively correlated with the values of network hierarchy in the expression network of all genes, due to the dedifferentiation of gene pathways and circuits. These results suggest that the hierarchy of gene expression may be useful as an additional biomarker for breast cancer prognosis.


Evaluation of two dairy herd reproductive performance indicators that are adjusted for voluntary waiting period.
Overall reproductive performance of dairy herds is monitored by various indicators. Most of them do not consider all eligible animals and do not consider different management strategies at farm level. This problem can be alleviated by measuring the proportion of pregnant cows by specific intervals after their calving date or after a fixed time period, such as the voluntary waiting period. The aim of this study was to evaluate two reproductive performance indicators that consider the voluntary waiting period at the herd. The two indicators were: percentage of pregnant cows in the herd after the voluntary waiting period plus 30 days (PV30) and percentage of inseminated cows in the herd after the voluntary waiting period plus 30 days (IV30). We wanted to assess how PV30 and IV30 perform in a simulation of herds with different reproductive management and physiology and to compare them to indicators of reproductive performance that do not consider the herd voluntary waiting period. To evaluate the reproductive indicators we used the SimHerd-program, a stochastic simulation model, and 18 scenarios were simulated. The scenarios were designed by altering the reproductive management efficiency and the status of reproductive physiology of the herd. Logistic regression models, together with receiver operating characteristics (ROC), were used to examine how well the reproductive performance indicators could discriminate between herds of different levels of reproductive management efficiency or reproductive physiology. The logistic regression models with the ROC analysis showed that IV30 was the indicator that best discriminated between different levels of management efficiency followed by PV30, calving interval, 200-days not-in calf-rate (NotIC200), in calf rate at100-days (IC100) and a fertility index. For reproductive physiology the ROC analysis showed that the fertility index was the indicator that best discriminated between different levels, followed by PV30, NotIC200, IC100 and the calving interval. IV30 could not discriminate between the two levels. PV30 is the single best performance indicator for estimating the level of both herd management efficiency and reproductive physiology followed by NotIC200 and IC100. This indicates that PV30 could be a potential candidate for inclusion in dairy herd improvement schemes.


Bend performance-enhanced photonic crystal fibers with anisotropic numerical aperture.
Numerical calculations predict that particular birefringent photonic crystal fiber designs exhibit slightly better performance in a coiled configuration than non-birefringent step-index fiber designs with respect to higher order mode suppression for the realization of large mode area effectively single transverse mode fibers. The passive losses of the fundamental and first few higher order modes of a birefringent photonic crystal fiber design with a 41 microm diameter core incorporating stress applying parts (SAP) were calculated using an integrated electromechanical finite element method. Minimum higher order mode losses of up to 5.5 dB/m were predicted for fundamental mode losses of only 0.0014 dB/m. The bend performance of this PCF design was predicted to be relatively insensitive to manufacturing tolerances with respect to air hole size and device assembly tolerances with respect to coiling diameter based on the calculated dependence of the mode losses on these parameters. The positions and refractive index of the SAP render the numerical aperture of the core anisotropic allowing further tailoring of the bend performance by adjusting the angle between the coiling plane of the fiber and the orientation of the SAP within the cladding. Fundamental and higher-order mode losses are calculated for step-index fiber (SIF) designs with a 40 microm diameter core for comparison. The step-index fiber designs were predicted to exhibit slightly inferior bend loss mode discrimination and higher sensitivity to packaging configuration compared to the photonic crystal fiber designs presented.


Ligand-displacement-based two-photon fluorogenic probe for visualizing mercapto biomolecules in live cells, Drosophila brains and zebrafish.
Investigating the change in expression level of mercapto biomolecules (GSH/Cys/Hcy) necessitates a rapid detection method for a series of physiological and pathological processes. Herein, we present a ligand-displacement-based two-photon fluorogenic probe based on an Fe(iii) complex, TPFeS, which is a GSH/Cys/Hcy rapid detection fluorogenic probe for in vitro analysis and live cell/tissue/in vivo imaging. The "in situ" probe is non-fluorescent and was prepared from a 1 : 2 ratio of Fe(iii) and TPS, a novel two-photon (TP) fluorophore with excellent one-photon (OP) and TP properties under physiological conditions, as a fluorescent ligand. This probe shows a rapid and remarkable fluorescence restoration (OFF-ON) property due to the ligand-displacement reaction of mercapto biomolecules in a recyclable manner in vitro. A significant two-photon action cross-section, good selectivity for biothiols, low cytotoxicity, and insensitivity to pH over the biologically relevant pH range allowed the direct visualization of mercapto biomolecules at different levels between normal/drug-treated live cells, as well as in Drosophila brain tissues/zebrafish based on the use of two-photon fluorescence microscopy.


Avian maternal response to chick distress.
The extent to which an animal is affected by the pain or distress of a conspecific will depend on its capacity for empathy. Empathy most probably evolved to facilitate parental care, so the current study assessed whether birds responded to an aversive stimulus directed at their chicks. Domestic hens were exposed to two replicates of the following conditions in a counterbalanced order: control (C; hen and chicks undisturbed), air puff to chicks (APC; air puff directed at chicks at 30 s intervals), air puff to hen (APH; air puff directed at hen at 30 s intervals) and control with noise (CN; noise of air puff at 30 s intervals). During each test, the hens' behaviour and physiology were measured throughout a 10 min pre-treatment and a 10 min treatment period. Hens responded to APH and APC treatments with increased alertness, decreased preening behaviour and a reduction in eye temperature. No such changes occurred during any control period. Increased heart rate and maternal vocalization occurred exclusively during the APC treatment, even though chicks produced few distress vocalizations. The pronounced and specific reaction observed indicates that adult female birds possess at least one of the essential underpinning attributes of empathy.


Implicit bias and its relation to health disparities: a teaching program and survey of medical students.
The varying treatment of different patients by the same physician are referred to as within provider disparities. These differences can contribute to health disparities and are thought to be the result of implicit bias due to unintentional, unconscious assumptions. The purpose is to describe an educational intervention addressing both health disparities and physician implicit bias and the results of a subsequent survey exploring medical students' attitudes and beliefs toward subconscious bias and health disparities. A single session within a larger required course was devoted to health disparities and the physician's potential to contribute to health disparities through implicit bias. Following the session the students were anonymously surveyed on their Implicit Association Test (IAT) results, their attitudes and experiences regarding the fairness of the health care system, and the potential impact of their own implicit bias. The students were categorized based on whether they disagreed ("deniers") or agreed ("accepters") with the statement "Unconscious bias might affect some of my clinical decisions or behaviors." Data analysis focused specifically on factors associated with this perspective. The survey response rate was at least 69%. Of the responders, 22% were "deniers" and 77% were "accepters." Demographics between the two groups were not significantly different. Deniers were significantly more likely than accepters to report IAT results with implicit preferences toward self, to believe the IAT is invalid, and to believe that doctors and the health system provide equal care to all and were less likely to report having directly observed inequitable care. The recognition of bias cannot be taught in a single session. Our experience supports the value of teaching medical students to recognize their own implicit biases and develop skills to overcome them in each patient encounter, and in making this instruction part of the compulsory, longitudinal undergraduate medical curriculum.


Taking a community-based participatory research approach in the development of methods to measure a community health worker community advocacy intervention.
Public health advocacy is by necessity responsive to shifting sociopolitical climates, and thus a challenge of advocacy research is that the intervention must by definition be adaptive. Moving beyond the classification of advocacy efforts to measurable indicators and outcomes of policy, therefore, requires a dynamic research approach. The purposes of this article are to (1) describe use of the CBPR approach in the development and measurement of a community health worker (CHW) intervention designed to engage community members in public health advocacy and (2) provide a model for application of this approach in advocacy interventions addressing community-level systems and environmental change. The Kingdon three streams model of policy change provided a theoretical framework for the intervention. Research and community partners collaboratively identified and documented intervention data. We describe five research methods used to monitor and measure CHW advocacy activities that both emerged from and influenced intervention activities. Encounter forms provided a longitudinal perspective of how CHWs engaged in advocacy activities in the three streams. Strategy maps defined desired advocacy outcomes and health benefits. Technical assistance notes identified and documented intermediate outcomes. Focus group and interview data reflected CHW efforts to engage community members in advocacy and the development of community leaders. APPLICATION OF LESSONS LEARNED: We provide a model for application of key principles of CPBR that are vital to effectively capturing the overarching and nuanced aspects of public health advocacy work in dynamic political and organizational environments.


Camouflage and interception: how pathogens evade detection by intracellular nucleic acid sensors.
Intracellular DNA and RNA sensors play a vital part in the innate immune response to viruses and other intracellular pathogens, causing the secretion of type I interferons, cytokines and chemokines from infected cells. Pathogen RNA can be detected by retinoic-acid inducible gene I-like receptors in the cytosol, whereas cytosolic DNA is recognized by DNA sensors such as cyclic GMP-AMP synthase (cGAS). The resulting local immune response, which is initiated within hours of infection, is able to eliminate many pathogens before they are able to establish an infection in the host. For this reason, all viruses, and some intracellular bacteria and protozoa, need to evade detection by nucleic acid sensors. Immune evasion strategies include the sequestration and modification of nucleic acids, and the inhibition or degradation of host factors involved in innate immune signalling. Large DNA viruses, such as herpesviruses, often use multiple viral proteins to inhibit signalling cascades at several different points; for instance herpes simplex virus 1 targets both DNA sensors cGAS and interferon-γ-inducible protein 16, as well as the adaptor protein STING (stimulator of interferon genes) and other signalling factors in the pathway. Viruses with a small genome encode only a few immunomodulatory proteins, but these are often multifunctional, such as the NS1 protein from influenza A virus, which inhibits RNA sensing in multiple ways. Intracellular bacteria and protozoa can also be detected by nucleic acid sensors. However, as the type I interferon response is not always beneficial for the host under these circumstances, some bacteria subvert, rather than evade, these signalling cascades for their own gain.


Model medication management process in Australian nursing homes using business process modeling.
One of the reasons for end user avoidance or rejection to use health information systems is poor alignment of the system with healthcare workflow, likely causing by system designers' lack of thorough understanding about healthcare process. Therefore, understanding the healthcare workflow is the essential first step for the design of optimal technologies that will enable care staff to complete the intended tasks faster and better. The often use of multiple or "high risk" medicines by older people in nursing homes has the potential to increase medication error rate. To facilitate the design of information systems with most potential to improve patient safety, this study aims to understand medication management process in nursing homes using business process modeling method. The paper presents study design and preliminary findings from interviewing two registered nurses, who were team leaders in two nursing homes. Although there were subtle differences in medication management between the two homes, major medication management activities were similar. Further field observation will be conducted. Based on the data collected from observations, an as-is process model for medication management will be developed.


The Effect of Language Barriers at Discharge on Pediatric Adenotonsillectomy Outcomes and Healthcare Contact.
Effective delivery of discharge instructions and access to postoperative care play a critical role in outcomes after pediatric surgery. Previous studies in the pediatric emergency department suggest that caregivers with language barriers have less comprehension of discharge instructions despite use of interpretation services. However, the impact of language barriers during discharge on surgical outcomes in a pediatric surgical setting has not been studied. This study examined the effect of parental language during discharge on number and mode of healthcare contact following pediatric adenotonsillectomy. A retrospective cohort study was conducted on children who underwent adenotonsillectomy at a tertiary care pediatric academic medical center from July 1, 2016 to June 1, 2018. Data were collected on consecutive patients with non-English-speaking caregivers and a systematic sampling of patients with English-speaking caregiver. Surgery-related complications and healthcare contacts within 90 days after discharge were collected. Two-tailed t tests, χ2 tests, and logistic regression were performed to assess the association between parental primary language and incidence of healthcare contact after surgery. A total of 136 patients were included: 85 English-speaking and 51 non-English-speaking. The groups were comparable in age, sex, and comorbidities. The non-English group had more patients with public insurance (86% vs. 56%; P < .001). Number of encounters and types of complications following discharge were similar, but the non-English group was more likely to utilize the emergency department compared to phone calls (OR, 9.3; 95% CI, 2.3-38.2), even after adjustment for insurance type (OR, 7.9; 95% CI, 1.6-39.4). Language barriers at discharge following pediatric otolaryngology surgery is associated with a meaningful difference in how patients utilized medical care. Interventions to improve comprehension and access may help reduce preventable emergency department visits and healthcare costs.


Mutations in the glucocerebrosidase gene are associated with early-onset Parkinson disease.
To evaluate the frequency of glucocerebrosidase (GBA) mutations in cases and controls enrolled in the Genetic Epidemiology of Parkinson's Disease (GEPD) study. We sequenced all exons of the GBA gene in 278 Parkinson disease (PD) cases and 179 controls enrolled in GEPD, with a wide range of age at onset (AAO), and that included a subset of 178 Jewish cases and 85 Jewish controls. Cases and controls were recruited without knowledge of family history of PD, and cases were oversampled in the AAO < 50 years category. 13.7% of PD cases (38/278) carried GBA mutations, compared with 4.5% of controls (8/179) (odds ratio [OR] 3.4, 95% CI 1.5 to 7.4). The frequency of GBA mutations was 22.2% in 90 cases with AAO < or = 50 years, compared with 9.7% in 185 cases with AAO > 50 years (OR 2.7, 95% CI 1.3 to 5.3). Adjusting for age at the time of evaluation, sex, family history of PD, and Jewish ancestry, GBA carriers had a 1.7-year-earlier AAO of PD (95% CI 0.5 to 3.3, p < 0.04) than noncarriers. The average AAO of PD was 2.5 years earlier in carriers with an AAO < or = 50 years compared with noncarriers (95% CI 0.6 to 4.5, p < 0.01) and this was not seen in the AAO > 50 years group. The frequency of GBA mutations was higher in a subset of 178 cases that reported four Jewish grandparents (16.9%) than in cases who did not report Jewish ancestry (8.0%) (p < 0.01). Nine different GBA mutations were identified in PD cases, including 84insGG, E326K, T369M, N370S, D409H, R496H, L444P, RecNciI, and a novel mutation, P175P. This study suggests that the Glucocerebrosidase gene may be a susceptibility gene for Parkinson disease and that Glucocerebrosidase mutations may modify age at onset.


In6S7 nanoparticle-embedded and sulfur and nitrogen co-doped microporous carbons derived from In(tdc)2 metal-organic framework.
Indium sulfide nanoparticle (NP)-embedded microporous carbons co-doped with S- and N-dopants are easily prepared by a direct carbonization of the as-prepared In(iii)-based metal-organic framework (In-MOF), [Et2NH2][In(tdc)2]·DEF, containing ditopic S-containing 2,5-thiophenedicarboxylate (tdc2-) bridging linkers as a potential source of S-dopant. The charge on the anionic framework of [In(tdc)2]- is balanced by Et2NH2+, which is also a potential N-dopant. Simultaneous embedding of In-based NPs, S-, and N-co-doping is achieved in a simple single step carbonization of In-MOF. Three porous carbon materials (PCMs), PCM-700, PCM-800, and PCM-900, are obtained from the carbonization of In-MOF at 700, 800, and 900 °C, respectively. The gas sorption analysis indicates them as good CO2 sorbents. The photocatalytic degradation of methyl orange by PCMs under visible light irradiation is also effectively operable owing to the photocatalytically active semiconducting indium sulfide NP with a small bandgap. The main component of indium sulfide NPs is revealed as In6S7 based on the powder X-ray diffraction pattern. Small amounts of metallic In and In2S3 are also observed. The specific capacitances of PCMs are also estimated from the galvanostatic charge/discharge curves. PCM-900 exhibits the highest gravimetric specific capacitance of 99.0 F g-1 at a current density of 0.05 A g-1.


A high density recombination map of the pig reveals a correlation between sex-specific recombination and GC content.
The availability of a high-density SNP genotyping chip and a reference genome sequence of the pig (Sus scrofa) enabled the construction of a high-density linkage map. A high-density linkage map is an essential tool for further fine-mapping of quantitative trait loci (QTL) for a variety of traits in the pig and for a better understanding of mechanisms underlying genome evolution. Four different pig pedigrees were genotyped using the Illumina PorcineSNP60 BeadChip. Recombination maps for the autosomes were computed for each individual pedigree using a common set of markers. The resulting genetic maps comprised 38,599 SNPs, including 928 SNPs not positioned on a chromosome in the current assembly of the pig genome (build 10.2). The total genetic length varied according to the pedigree, from 1797 to 2149 cM. Female maps were longer than male maps, with a notable exception for SSC1 where male maps are characterized by a higher recombination rate than females in the region between 91-250 Mb. The recombination rates varied among chromosomes and along individual chromosomes, regions with high recombination rates tending to cluster close to the chromosome ends, irrespective of the position of the centromere. Correlations between main sequence features and recombination rates were investigated and significant correlations were obtained for all the studied motifs. Regions characterized by high recombination rates were enriched for specific GC-rich sequence motifs as compared to low recombinant regions. These correlations were higher in females than in males, and females were found to be more recombinant than males at regions where the GC content was greater than 0.4. The analysis of the recombination rate along the pig genome highlighted that the regions exhibiting higher levels of recombination tend to cluster around the ends of the chromosomes irrespective of the location of the centromere. Major sex-differences in recombination were observed: females had a higher recombination rate within GC-rich regions and exhibited a stronger correlation between recombination rates and specific sequence features.


Spinal Infections Among Patients With Long-Term Central Venous Catheters for Home Parenteral Nutrition.
Spinal infections are a rare yet serious metastatic complication of bacteremia among patients with long-term central venous catheters (CVCs) for which clinicians must remain vigilant. We performed a retrospective review of all cases of spinal infection occurring in the context of a CVC for long-term parenteral nutrition (PN) managed in our department between January 2010 and October 2013, a cohort of 310 patients over this time period. Six patients were identified (mean age, 65 years; 5 male). One hundred percent of patients presented with spinal pain (5/6 cervical, 1/6 thoracic). Organisms were cultured from the CVC in 5 of 6 patients. In all cases, the white blood cell count was normal, and in 5 of 6, C-reactive protein was normal. All diagnoses were confirmed on magnetic resonance imaging (MRI), and in 3 of 6 cases, an MRI was repeated (on the advice of neurosurgical colleagues) to confirm resolution of changes after a period of antimicrobial therapy. There was no clear correlation between duration of PN or number of days following CVC insertion and onset of infection. The CVC was replaced in 4 of 6 patients at the time of diagnosis, delayed removal in 1 of 6, and salvaged in the remaining case. Although rare, a high index of suspicion is needed in patients receiving long-term PN who present with spinal pain. Peripheral inflammatory markers may not be elevated. MRI should be performed and patients should be treated with antibiotics alongside involvement of local microbiology and neurosurgical teams. Multidisciplinary discussion on CVC salvage in these cases is important, especially in cases of challenging vascular anatomy.


Reproductive and gynecologic surgical experience in diethylstilbestrol-exposed daughters.
Information on reproductive history, gynecologic operations, and examinations was analyzed for 338 diethylstilbestrol (DES)-exposed and 298 unexposed women whose mothers participated in an evaluation of DES use in pregnancy 28 years ago. A history of infrequent menses (less often than every 36 days) was reported more commonly by the exposed women (32%) than by the unexposed women (15%) and the mean duration of menstrual flow was also less. A greater number of exposed women than unexposed women experienced primary infertility (53 versus 19). The reasons for these differences are not currently known. Comparison of the outcomes of first pregnancies showed a higher proportion of premature births, spontaneous abortions, and ectopic pregnancies in the exposed women (P less than 0.001). The difference in the occurrence of ectopic pregnancies was statistically significant (8 versus 0; P less than 0.005). An adverse pregnancy outcome was more likely in DES-exposed women with cervicovaginal ridges. However, when the outcome of all pregnancies were considered, 81% of the exposed women had at least one living child. More exposed women than unexposed women had gynecologic surgical procedures, which may, in part, be due to the increased medical surveillance of the exposed group. The spectrum of diseases at operation in both groups was similar. Adnexal masses and pelvic inflammatory disease were more commonly reported among the exposed women while the occurrence of endometriosis in both groups was similar. For the exposed women who had been examined at the Chicago Lying-In Hospital over a 4-year period, epithelial changes in the vagina had disappeared in 32% and cervicovaginal ridges had disappeared in 57%.


Finished genome of the fungal wheat pathogen Mycosphaerella graminicola reveals dispensome structure, chromosome plasticity, and stealth pathogenesis.
The plant-pathogenic fungus Mycosphaerella graminicola (asexual stage: Septoria tritici) causes septoria tritici blotch, a disease that greatly reduces the yield and quality of wheat. This disease is economically important in most wheat-growing areas worldwide and threatens global food production. Control of the disease has been hampered by a limited understanding of the genetic and biochemical bases of pathogenicity, including mechanisms of infection and of resistance in the host. Unlike most other plant pathogens, M. graminicola has a long latent period during which it evades host defenses. Although this type of stealth pathogenicity occurs commonly in Mycosphaerella and other Dothideomycetes, the largest class of plant-pathogenic fungi, its genetic basis is not known. To address this problem, the genome of M. graminicola was sequenced completely. The finished genome contains 21 chromosomes, eight of which could be lost with no visible effect on the fungus and thus are dispensable. This eight-chromosome dispensome is dynamic in field and progeny isolates, is different from the core genome in gene and repeat content, and appears to have originated by ancient horizontal transfer from an unknown donor. Synteny plots of the M. graminicola chromosomes versus those of the only other sequenced Dothideomycete, Stagonospora nodorum, revealed conservation of gene content but not order or orientation, suggesting a high rate of intra-chromosomal rearrangement in one or both species. This observed "mesosynteny" is very different from synteny seen between other organisms. A surprising feature of the M. graminicola genome compared to other sequenced plant pathogens was that it contained very few genes for enzymes that break down plant cell walls, which was more similar to endophytes than to pathogens. The stealth pathogenesis of M. graminicola probably involves degradation of proteins rather than carbohydrates to evade host defenses during the biotrophic stage of infection and may have evolved from endophytic ancestors.


Regulation of osteopontin and related proteins in rat CC531 colorectal cancer cells.
Colorectal cancer accounts for 11% of all cancers and is the second most frequent cause of cancer-related death, with the majority of deaths attributable to hepatic metastasis. The main aim of the study was to investigate changes which occur in CC531 rat colon adenocarcinoma cells and are instrumental to the metastatic phenotype after homing to the liver. RT-PCR and Western blotting were used to detect the expression of certain proteins, transcription factors and enzymes, which are intimately linked to colorectal metastasis. These included osteopontin (OPN), bone sialoprotein ll (BSP ll), Runx2, Hoxc8, matrix metalloprotease-7 (MMP-7) and matrix-metalloprotease-9 (MMP-9). Subsequently, in order to detect the role of the hepatocytes in these changes seen in tumor cells, two models of co-culturing hepatocytes with CC531 cells were established. OPN, Runx2 and MMP-7 were found to be highly expressed in CC531 metastases explanted from the liver, but showed subsequent down-regulation and/or disappearance in cell culture. The inverse regulation of Hoxc8, OPN and Runx2 suggests that these genes may be regulated in a feed-back loop manner. MMP-9 mRNA and active MMP-7 protein were expressed in tumor cells themselves. The presence of hepatocytes was insufficient to induce induction of OPN and Runx2 in tumor cells in vitro, so was the addition of OPN or TGF-beta1. Whereas TGF-beta1 induced over-expression of OPN and Runx2 in hepatocytes, it did not exert the same effect on hepatocytes co-cultured with CC531 cells, indicating that this response was abrogated by CC531 cells.


Management of the penetrating atherosclerotic ulcer in the descending thoracic aorta.
Penetrating atherosclerotic ulcers present with an insidious onset with a reported mortality of 9%, varying across populations. With vast arrays of risk factors and potentially ominous complications, it is vital to efficiently provide optimum strategies for management. There exists controversy in the literature regarding management, especially for Type B penetrating atherosclerotic ulcers; the decision-making framework encompasses numerous factors in considerations for medical management versus invasive intervention and choice of endovascular versus open repair in the latter. The concomitant presence of intramural haematoma adds further complexity to the already intricate decision-making for management. We performed searches through PubMed and SCOPUS analysing studies reporting outcomes for management strategies for penetrating atherosclerotic ulcers treatment, focusing on Type B, further seeking to analyse studies reporting their experiences of PAU patients with concomitant intramural haematoma. Our review highlights the ambiguity and controversy existing in the literature, comprising studies burdened by their inherent hindering limitations of their single-centre retrospective experiences. Endovascular therapy has come to the forefront of penetrating atherosclerotic ulcers management, often considered first line therapy. In the case of penetrating atherosclerotic ulcers alongside intramural haematoma, there have been reports of potential hybrid surgical approaches to management. Studies further show misdiagnosis of penetrating atherosclerotic ulcers in earlier data sets further complicates management. However, it is clear we must progress on the journey towards precision medicine, allowing delivery of optimum care to our patients.


Melanoma and skin cancer: evaluation of a health education programme for secondary schools.
The effectiveness of an education package for secondary schools about the sun and skin cancer was assessed using questionnaires. A variety of teaching methods was used, including pamphlets, workbooks, and a video. The effect of this material was assessed by asking pupils to complete questionnaires immediately after receiving the package (July), and after the summer holiday (September). Five-hundred and forty-three children from seven schools were recruited into the study. Results of the questionnaire demonstrated a significant difference in knowledge (P < 0.001) and reported attitude (P < 0.001) compared with a control group. There was no significant difference in behaviour of the taught groups compared with the control group. The only significant activity associated with increased knowledge was wearing a sunscreen (P < 0.005). In contrast, in terms of attitude, those who covered up in the sun (P < 0.0001), wore a sunscreen (P < 0.004), and sat in the shade (P < 0.02), had significantly better attitudes than those who did not behave in this way. This project is a first attempt to assess health education in schools, and reports changes in knowledge, attitudes, and some aspects of behaviour. Adolescents are a group who are difficult to influence, but our study has produced some useful information about how these children respond to such teaching measures.


Estimating the financial losses due to bovine fasciolosis in Switzerland.
In dairy cattle in Switzerland, the prevalence of infection with Fasciola hepatica is over 16 per cent. Previous studies have suggested that even subclinical infections with liver fluke may induce significant reductions in the performance of cattle. The financial losses attributable to F hepatica were estimated using a simple spreadsheet model to sum the individual losses that have been suggested in the literature. Because there is substantial variability in these production losses, Monte Carlo sampling techniques were used to model this variability. Each cost item and each data item related to the prevalence of F hepatica was assigned a mathematical distribution which took account of the variability of the experimental data and/or the sample size of the data. A total of 10,000 simulations were undertaken, with each item randomly varied through its mathematical distribution on each simulation. The results suggest that the median financial loss due to bovine fasciolosis in Switzerland is approximately 52 million, with probable 95 per cent confidence limits ranging from 22 million to 92 million per annum, which represents a median loss of 299 per infected animal. Most of the losses arise from reduced milk yield and reduced fertility, and smaller losses are due to reduced meat production and the condemnation of livers.


Investigating the "steric gate" of human immunodeficiency virus type 1 (HIV-1) reverse transcriptase by targeted insertion of unnatural amino acids.
To investigate how structural changes in the amino acid side chain affect nucleotide substrate selection in human immunodeficiency virus type 1 (HIV-1) reverse transcriptase (RT), a variety of non-natural tyrosine analogues were substituted for Tyr115 of p66 RT. RT variants containing meta-Tyr, nor-Tyr, aminomethyl-Phe, and 1- and 2-naphthyl-Tyr were produced in an Escherichia coli coupled transcription/translation system. Mutant p66 subunits were reconstituted with wild-type (WT) p51 RT and purified by affinity chromatography. Each modified enzyme retained DNA polymerase activity following this procedure. Aminomethyl-Phe115 RT incorporated dCTP more efficiently than the WT and was resistant to the chain terminator (-)-beta-2',3'-dideoxy-3'-thiacytidine triphosphate (3TCTP) when examined in a steady-state fidelity assay. However, 2-naphthyl-Tyr115 RT inefficiently incorporated dCTP at low concentrations and was kinetically slower with all dCTP analogues tested. Models of RT containing these side chains suggest that the aminomethyl-Phe115 substitution provides new hydrogen bonds through the minor groove to the incoming dNTP and the template residue of the terminal base pair. These hydrogen bonds likely contribute to the increased efficiency of dCTP incorporation. In contrast, models of HIV-1 RT containing 2-naphthyl-Tyr115 reveal significant steric clashes with Pro157 of the p66 palm subdomain, necessitating rearrangement of the active site.


High placement of noncemented acetabular components in revision total hip arthroplasty. A concise follow-up, at a minimum of fifteen years, of a previous report.
We previously reported the average ten-year results associated with the use of porous-coated noncemented acetabular shells that were placed at a high hip center at the time of revision total hip arthroplasty in thirty-four patients (thirty-six hips) with severe acetabular bone loss. We now report the average 16.8-year results for twenty-one patients (twenty-three hips). Of the original cohort of forty-four patients (forty-six hips), thirty-nine patients (forty-one hips; 89%) retained the shell. Two shells (4.3%) were revised because of aseptic loosening, and three (6.5%) were revised because of infection. Six femoral components were revised because of femoral osteolysis, and seven were revised because of aseptic loosening without osteolysis. On the basis of our results after an average duration of follow-up of 16.8 years, we believe that the placement of an uncemented acetabular component at a high hip center continues to be an excellent technique for revision total hip arthroplasty in selected patients with severe acetabular bone loss.


Promoter hypomethylation of RAR-related orphan receptor α 1 is correlated with unfavorable clinicopathological features in patients with colorectal cancer.
Retinoic acid receptor-related orphan receptor α (RORA) is a tumor-specific differentially methylated region. RORA mRNA expression is frequently downregulated in colorectal cancer (CRC) due to promoter methylation, and this methylation is correlated with the development of CRC. Here we investigated the correlation between the methylation status of the RORA promoter region and clinical CRC stages. The methylation status of RORA isoform 1 (RORA1) and isoform 4 (RORA4) promoters was investigated in 43 paired CRC specimens and adjacent normal tissues by quantitative DNA methylation analysis using the Sequenom MassARRAY system and bisulfite sequencing. The relationship between the methylation status of the RORA1 promoter and the CRC pathological stage was analyzed. RORA1 expression was evaluated using quantitative PCR. Sixteen of 43 CRC specimens (37%) and three CRC cell lines (Caco2, HT29, and HCT116) showed increased levels of methylation in the RORA1 promoter region compared with adjacent normal tissues, whereas no methylation was observed in the RORA4 promoter. Quantitative PCR showed downregulation of RORA1 expression both in CRC samples and cell lines. Furthermore, the RORA1 promoter hypomethylation status showed a significant correlation with unfavorable CRC stages (stages III and IV) compared with favorable stages (stages I and II, p = 0.014). Hypomethylation of the RORA1 promoter may have important clinical implications in unfavorable CRC development, and therefore, the methylation status of the RORA1 promoter may constitute a useful biomarker to determine an indication for postoperative therapy such as adjuvant chemotherapy in highly advanced CRC patients.


Health beliefs and behavior: the practicalities of "looking after yourself" in an Australian aboriginal community.
Recently, social determinants of health frameworks are receiving some criticism in that they do not engage with questions related to individual subjectivity and agency as they relate to health decision-making behavior. This article examines the different ways in which people living in a remote Arnhem Land community in the Northern Territory of Australia, take responsibility for their own health and the extent to which they are able to prevent illness. A number of related sub-questions are explored relating to how people perceive their health and their role in health care in their community, including their engagement with the health clinic, traditional medicines, and the influence of sorcery on ill health and sickness.


Occurrence and distribution of pharmaceuticals in raw, finished, and drinking water from seven large river basins in China.
The occurrence of pharmaceuticals in the drinking water is a growing concern in China. In this study, we determined the concentration and distribution of 59 selected pharmaceuticals in raw, finished, and tap water samples from 79 drinking water treatment plants (DWTPs) in 15 cities, encompassing seven large river basins in China, using solid-phase extraction pretreatment and ultra-high-performance liquid chromatography-tandem mass spectrometry analysis. Forty-seven pharmaceuticals were detected in raw water samples, with detection rates of 1.27-96.20% and average concentrations of 0.09-128.87 ng/L. Forty-three pharmaceuticals were detected in finished water samples, with detection rates of 1.27-96.20% and average concentrations of 0.07-59.17 ng/L. Forty-two pharmaceuticals were detected in tap water samples, with detection rates of 1.27-94.94% and average concentrations of 0.07-58.43 ng/L. Purification methods implemented by DWTPs are capable of removing some pharmaceuticals from water treatment systems; however, low concentrations of pharmaceuticals were detected in drinking water, raising concerns about the possible human health implications of long-term exposure to low-dose pharmaceuticals. The detection and quantification of pharmaceuticals in municipal water samples presented in this study represent the most extensive analysis of commonly used pharmaceuticals and personal care products located in Chinese river basins.


Protein changes in macrophages induced by plasma from rats exposed to 35 GHz millimeter waves.
A macrophage assay and proteomic screening were used to investigate the biological activity of soluble factors in the plasma of millimeter wave-exposed rats. NR8383 rat macrophages were incubated for 24 h with 10% plasma from male Sprague-Dawley rats that had been exposed to sham conditions, or exposed to 42 °C environmental heat or 35 GHz millimeter waves at 75 mW/cm² until core temperature reached 41.0 °C. Two-dimensional polyacrylamide gel electrophoresis, image analysis, and Western blotting were used to analyze approximately 600 protein spots in the cell lysates for changes in protein abundance and levels of 3-nitrotyrosine, a marker of macrophage stimulation. Proteins of interest were identified using peptide mass fingerprinting. Compared to plasma from sham-exposed rats, plasma from environmental heat- or millimeter wave-exposed rats increased the expression of 11 proteins, and levels of 3-nitrotyrosine in seven proteins, in the NR8383 cells. These altered proteins are associated with inflammation, oxidative stress, and energy metabolism. Findings of this study indicate both environmental heat and 35 GHz millimeter wave exposure elicit the release of macrophage-activating mediators into the plasma of rats.


First Report of a Lasmenia sp. Causing Rachis Necrosis, Flower Abortion, Fruit Rot, and Leaf Spots on Rambutan in Puerto Rico.
Rambutan (Nephelium lappaceum L.) is a tropical fruit tree that has increased in importance for fruit growers in Puerto Rico. In 2008 and 2009, fruit rot and lesions on leaves and inflorescences were observed. A total of 276 diseased samples were collected from commercial orchards, orchards at the University of Puerto Rico, and the USDA-ARS in Mayaguez. Plant tissue was disinfested and plated on acidified potato dextrose agar (APDA). Besides other typical fungi associated with these tissue samples (2,3), 130 unknown isolates were identified as a Lasmenia sp. at the Fungal Biodiversity Centre (CBS), the Netherlands and the University of Puerto Rico using taxonomic keys (1,4). Sequencing of the rDNA with primers ITS 1 and ITS 4 and Lr5 and LR0R corresponding to the (internal transcribed spacer) ITS1-5.8S-ITS2 region and the partial region of the large ribosomal subunit (LSU), respectively, was completed. Five isolates (CBS 124122 to 124126) were deposited at the CBS. In APDA, colonies of a Lasmenia sp. were cream-colored with dark brown concentric rings and immersed, hyaline, branched, and septate mycelium. Acervuli were produced on APDA and plant tissue that was sampled from field and clean tissue that was inoculated with a Lasmenia sp. Conidia were 10 to 12 × 4 to 5 μm, light brown, thick walled, obclavate, aseptate, and the apex was obtuse with a scar at the base. Conidiophores were hyaline, septate, cylindrical, and sparingly branched. The conidiogenous cells were hyaline, cylindrical, and holoblastic. Pathogenicity tests were done on 12 healthy, superficially sterilized fruits under laboratory conditions, on four random leaves in each of six 6-month-old rambutan seedlings under greenhouse conditions, and on four flowers in six random inflorescences for each of six mature trees from an orchard. Tests were repeated. Either wounded or unwounded tissues were inoculated with a conidial suspension (2 to 4.5 × 106 conidia/ml) and 5-mm mycelial disks from each fungal isolate grown in APDA. After 5 days, a Lasmenia sp. produced necrotic spots on leaves, rachis necrosis and flower abortion, fruit rot, and water-soaked lesions on the fruit surface that spread to cause an aril (flesh) rot. Acervuli were produced on fruit spintems (hair-like appendages). Koch's postulates were fulfilled by reisolation of inoculated fungi from diseased tissue. A complete sequence for the ITS region for four isolates of a Lasmenia sp. was submitted to NCBI GenBank (Accession Nos. GU797405, GU797406, GU797407, and JF838336). Complete sequences of the LSU region for all five isolates were submitted to GenBank (Accession Nos. JF838337, JF838338, JF838339, JF838340, and JF838341). For both types of sequences, the identity was 100% between isolates. Although there is no DNA sequence data for the genus Lasmenia, a BLASTN search indicates a closer affinity to the Cryphonectriaceae (Diaporthales) (1). A Lasmenia sp. has been reported from Hawaii as causing fruit rot in rambutan (2). To our knowledge, this is the first report of a Lasmenia sp. causing rachis necrosis and flower abortion worldwide, and the first report of fruit rot and necrotic spots on leaves of rambutan in Puerto Rico. References: (1) M. N. Kamat et al. Rev. Mycol. 38:19, 1973. (2) K. A. Nishijima and P. A. Follett. Plant Dis. 86:71, 2002. (3) L. M. Serrato et al. Phytopathology (Abstr.) 100(suppl):S176, 2010. (4) B. C. Sutton. The Coelomycetes: Fungi Imperfecti with Pycnidia Acervuli and Stromata. CMI. Kew, Surrey, England, 1980.


Parallel kinetic resolution of tert-butyl (RS)-3-oxy-substituted cyclopent-1-ene-carboxylates for the asymmetric synthesis of 3-oxy-substituted cispentacin and transpentacin derivatives.
tert-Butyl (RS)-3-methoxy- and (RS)-3-tert-butyldiphenylsilyloxy-cyclopent-1-ene-carboxylates display excellent levels of enantiorecognition in mutual kinetic resolutions with both lithium (RS)-N-benzyl-N-(alpha-methylbenzyl)amide and lithium (RS)-N-3,4-dimethoxybenzyl-N-(alpha-methylbenzyl)amide. A 50 : 50 pseudoenantiomeric mixture of lithium (S)-N-benzyl-N-(alpha-methylbenzyl)amide and lithium (R)-N-3,4-dimethoxybenzyl-N-(alpha-methylbenzyl)amide allows for the efficient parallel kinetic resolution of the tert-butyl (RS)-3-oxy-substituted cyclopent-1-ene-carboxylates, affording differentially protected 3-oxy-substituted cispentacin derivatives in high yield and >98% de. Subsequent N-deprotection and hydrolysis provides access to 3-oxy-substituted cispentacin derivatives in good yield, and in >98% de and >98% ee, while stereoselective epimerisation and subsequent deprotection affords the corresponding transpentacin analogues in good yield, and in >98% de and >98% ee.


Reduced baroreflex sensitivity with volume loading in conscious dogs.
The Bainbridge reflex, i.e., the effect of rapid saline infusion (1.1 +/- 0.1 liters) on heart rate and arterial and atrial blood pressures, was examined in 12 intact conscious dogs; mean arterial blood pressure rose by 33 +/- 3 (SE) mm Hg, mean atrial pressure by 14 +/- 1 mm Hg, and heart rate by 75 +/- 9 beats/min. After beta-receptor blockade, heart rate rose slightly less (+49 +/- 5 beats/min, P = 0.05). Cholinergic blockade, combined cholinergic and beta-receptor, or beta-receptor blockade after vagotomy blocked the heart rate response to the infusion. The rise in heart rate in the face of an increase in arterial blood pressure with volume loading suggested that the arterial baroreceptor reflex was not responding appropriately to the increase in arterial blood pressure. In conscious dogs after denervation of the arterial baroreceptors, the increase in heart rate with volume loading was no greater than that in those dogs with their arterial baroreceptors intact, suggesting that the baroreceptor reflex was not restraining heart rate in the normal response to volume loading. The relationship between the pulse interval (PI) and the systolic arterial blood pressure (SAP) following an intravenous injection of methoxamine was used to evaluate the sensitivity of the baroreceptor reflex in intact conscious dogs. After a mild amount of volume loading, when atrial pressure was 8 +/- 2 mm Hg, the PI/SAP slope was significantly depressed from normal. When atrial pressure was elevated further to 28 +/- 1 mm Hg by volume loading, the slope was further depressed. Thus, arterial baroreflex sensitivity is reduced progressively as atrial pressure is raised by volume loading, an observation that explains how heart rate can rise strikingly in the face of an elevated arterial blood pressure.


Prenatal ultrasound in the prediction of bowel obstruction in infants with gastroschisis.
To assess the value of prenatal ultrasound in predicting bowel obstruction requiring surgery in fetuses with prenatal diagnosis of gastroschisis. The database of our center was searched for cases with an antenatal diagnosis of gastroschisis. The ultrasound images were reviewed blindly to assess the presence of intra- or extra-abdominal bowel dilatation. Details of surgical procedures were noted and the discharge letters were obtained. Pediatric follow-up was also obtained from pediatric surgeons, general practitioners or parents. In the 10-year period between November 1998 and September 2008 there were 62 cases with a prenatal diagnosis of gastroschisis. Postnatal outcome was not available for five cases, four pregnancies underwent termination and intrauterine fetal demise occurred in five cases. A final population of 48 liveborn infants was available for analysis. Intra-abdominal bowel dilatation was identified in 14 of these 48 fetuses (29.2%) and extra-abdominal bowel dilatation in 30 (62.5%) fetuses on prenatal ultrasound images. Eight fetuses (16.7%) had bowel obstruction. The relative risk of bowel obstruction with intra-abdominal bowel dilatation was 4.05 (95% CI, 1.12-14.70). On the other hand, the relative risk of bowel obstruction with extra-abdominal bowel dilatation was 1.0 (95% CI, 0.37-3.70). Four babies died, two of whom had intra- and one had extra-abdominal bowel dilatation. Intra-abdominal dilatation of the bowel on prenatal ultrasound examination appears to predict postnatal bowel obstruction and the need for surgical resection. Extra-abdominal bowel dilatation is observed frequently on prenatal ultrasound scans, but is not predictive of bowel obstruction.


A retrospective survey of perinatal risk factors of 104 living children with holoprosencephaly.
Holoprosencephaly (HPE) is a brain malformation resulting from a primary defect in development of the basal forebrain during early gestation. Prenatal genetic and environmental factors and birth outcomes were described in a population of 104 children with holoprosencephaly referred to three clinical centers from 1998 through 2002. The mean child age was 4 years. Of cases karyotyped, 9% presented with a chromosomal abnormality. This study of living children with holoprosencephaly, the majority of whom are cytogenetically normal, provides new information on the subsample of children with a less severe phenotype. Most children were born at term; about 51% were microcephalic at birth. Consistent with previous research, the association between HPE and maternal history of diabetes merits further investigation. Several findings have important implications for future research. Only 22% of the children in this study sample were diagnosed with holoprosencephaly prenatally. The vast majority of children (72%) were diagnosed with HPE between birth and 1 year of age. Also, 19% of the cases referred to the Carter Centers with HPE were not confirmed on scan review. When possible, future population-based epidemiological studies should emphasize mechanisms that identify children with HPE outside of the newborn period and confirm the diagnosis by review of MRI or high quality CT brain scan.


The Effect of Vitamins on Glaucoma: A Systematic Review and Meta-Analysis.
The aim of is to determine the association of vitamins with glaucoma by performing a systematic review and meta-analyses. Studies on the relation of vitamins and glaucoma published up to December 2017 were identified in the PubMed and Embase database. Data on vitamins (method of assessment), glaucoma (type and method of assessment), study characteristics and quality were recorded. In case of multiple studies for one nutrient a meta-analysis was performed. A total of 629 articles were identified of which 36 were included in the systematic review. The meta-analysis included five of them (940 open-angle glaucoma (OAG) cases and 123,697 controls in total) and resulted in an odds ratio [95% confidence interval] (OR [95% CI]) of 0.58 [0.37-0.91] for dietary vitamin A, though heterogeneity was high (I² = 51%). After omitting studies that contributed significantly to the heterogeneity, the pooled OR [95% CI] was 0.45 [0.30-0.68] for dietary vitamin A on OAG (I² = 0%). For vitamin B1, C and E no significant association with OAG was found (OR [95% CI]: 0.84 [0.47-1.51]; 0.68 [0.38-1.22]; 0.95 [0.75-1.19]; respectively). However, after addressing heterogeneity, vitamin C showed a protective effect as well. Especially, foods high in these vitamins (e.g., dark green vegetables) were protective for OAG. Dietary intake of vitamin A and C showed a beneficial association with OAG; however, findings on blood levels of vitamins do not show a clear relation with OAG.


Complete modeling of subsurface microscopy system based on aplanatic solid immersion lens.
A general model of a subsurface microscopy system based on an aplanatic solid immersion lens (ASIL) is presented. This model is composed of three components: generation of incident light into the ASIL, interaction of the incident light with the sample, and imaging of the scattered light. Interaction of incident light with sample can be calculated numerically using electromagnetic scattering theory, while vector diffraction theory is used to treat the other two components. Examples of imaging small and extended scatterers are shown. For small scatterers, we show the differences between the actual resolution of the whole system and the resolution predicted by considering only one subsystem of the whole system. For extended scatterers, two types of illuminations-focusing light illumination and plane wave direct illumination-are used to image the scatterers, and observations are explained using interaction of the incident light with the sample.


A comparison of the genetic pathways involved in the pathogenesis of three types of colorectal cancer.
Patterns of allele loss (loss of heterozygosity, LOH) have been studied in order to investigate the genetic pathways involved in the pathogenesis of three types of colorectal cancer (CRC): sporadic CRC without replication errors (RER-) (32 cases); sporadic RER+ CRC (23 cases); and ulcerative colitis-associated CRC (UCACRC) (16 cases). Each tumour was assessed for allele loss at ten microsatellite markers which map close to known or putative tumour-suppressor genes: APC (5q21-q22); DCC (18q21.1); 1p35-p36; p16 (9p21); 22q; 8p; E-cadherin (16q22.1); beta-catenin (3p22-p21.3); RB1 (13q14.1-q14.2); and HLA. Overall, high frequencies of allele loss (> 30 per cent) were found near DCC (42 per cent), p16 (38 per cent), 22q (37 per cent), 1p35-p36 (34 per cent) and APC (31 per cent), and low frequencies (< 20 per cent) near RB1 (16 per cent) and E-cadherin (13 per cent). LOH near beta-catenin, HLA, and on 8p occurred at frequencies between 20 and 30 per cent. The overall frequency of allele loss did not differ among the three tumour groups, but some variation was seen at individual loci. There was a significantly higher frequency of LOH at 1p35-36 in RER+ tumours compared to RER- tumours. Allele loss at this site was also associated with a more advanced Dukes' stage at presentation. In addition, RER- tumours showed a higher frequency of allele loss at p16 than RER+ tumours. No significant difference existed at any locus between the frequency of LOH in sporadic CRC and in UCACRC. Pairwise analysis showed a negative association between LOH at APC and DCC, and between LOH at chromosome 22p and p53 overexpression. Thus, there may be specific differences between the mutation spectra of RER+ and RER- CRCs, but there are large degrees of overlap among the underlying genetic pathways of these cancers and UCACRCs.


Angiogenic co-operation of VEGF and stromal cell TP in endometrial carcinomas.
Vascular endothelial growth factor (VEGF) and thymidine phosphorylase (TP) are important angiogenic enzymes, inducing new blood vessel formation in many human malignancies. In this study, the immunohistochemical expression of the two molecules was analysed in a series of 121 endometrial carcinomas. VEGF was expressed exclusively in cancer cells, while TP expression was shown in cancer cells (TPcc) and in stromal cells (TPsc) of both fibroblastic and myometrial origin. In all cases, enzymatic detection was particularly evident at the invading tumour front. At this site, TPsc, but not VEGF, expression was associated with non-endometrioid-type carcinomas, high tumour grade, deep myometrial invasion, and advanced stage. VEGF, but not TP, expression was related to increased angiogenesis (p=0.01). Double stratification of the two factors, however, marked VEGF/TPsc co-expression as the most potent angiogenic phenotype (p=0.008), suggesting a synergistic function. Survival analysis revealed that VEGF and TPsc, whether expressed alone or in combination, define poor prognosis. In multivariate analysis, however, stage of disease (p<0.0001, t-ratio 4.4) and VEGF expression (p=0.01, t-ratio 2.4) were the most important prognostic variables. Furthermore, VEGF expression emerged as the only independent prognostic variable in stage I endometrial carcinomas (p=0.04, t-ratio 1.9). This was not shown for TP, probably because of its close association with histopathological parameters. In conclusion, VEGF is a major angiogenic factor in endometrial carcinomas and an independent prognostic factor in stage I endometrial disease. TP is not an effective contributor to the angiogenic process, but is associated with aggressive histological features. The two factors, when co-expressed, play a co-operative role in the induction of angiogenesis.


Non-Pathogenic Mopeia Virus Induces More Robust Activation of Plasmacytoid Dendritic Cells than Lassa Virus.
Lassa virus (LASV) causes a viral haemorrhagic fever in humans and is a major public health concern in West Africa. An efficient immune response to LASV appears to rely on type I interferon (IFN-I) production and T-cell activation. We evaluated the response of plasmacytoid dendritic cells (pDC) to LASV, as they are an important and early source of IFN-I. We compared the response of primary human pDCs to LASV and Mopeia virus (MOPV), which is very closely related to LASV, but non-pathogenic. We showed that pDCs are not productively infected by either MOPV or LASV, but produce IFN-I. However, the activation of pDCs was more robust in response to MOPV than LASV. In vivo, pDC activation may support the control of viral replication through IFN-I production, but also improve the induction of a global immune response. Therefore, pDC activation could play a role in the control of LASV infection.


A Cost-Effectiveness Model for Frail Older Persons: Development and Application to a Physiotherapy-Based Intervention.
The clinical importance of frailty is increasing. Existing economic evaluations of interventions to manage frailty have limited time horizons, but even in older populations there may be important longer-term differences in costs and outcomes. This paper reports on the development of a cost-effectiveness model to predict publicly funded health and aged care costs and quality-adjusted life years (QALYs) over the remaining lifetime of frail Australians and a model-based cost-utility analysis of a physiotherapy-based intervention for frail individuals. A cohort-based state transition (Markov) model was developed to predict costs and QALYs over the remaining lifetime of a frail population. Frailty is defined using the phenotypic definition of frailty, and the model comprises health states that describe frailty status, residential status, the experience of bone fractures and depression, and death. Model input parameters were estimated and calibrated using the Dynamic Analyses to Optimise Ageing dataset, supplemented with data from the published literature. The cost-effectiveness model was subject to a range of validation approaches, which did not negate the validity of the model. The evaluated physiotherapy-based frailty intervention has an expected incremental cost per QALY gained of Australian $8129 compared to usual care, but there is a probability of 0.3 that usual care is more effective and less costly than the intervention. Frailty reduces quality of life, is costly to manage and it's prevalence is increasing, but new approaches to managing frailty need to demonstrate value for money. The value of the reported cost-effectiveness model is illustrated through the estimation of all important costs and effects of a physiotherapy-based frailty intervention, which facilitates comparisons with funding decisions for other new technologies in Australia.


Two-year longitudinal survey reveals high genetic diversity of Schistosoma mansoni with adult worms surviving praziquantel treatment at the start of mass drug administration in Uganda.
A key component of schistosomiasis control is mass drug administration with praziquantel. While control interventions have been successful in several endemic regions, mass drug administration has been less effective in others. Here we focus on the impact of repeated praziquantel treatment on the population structure and genetic diversity of Schistosoma mansoni. We examined S. mansoni epidemiology, population genetics, and variation in praziquantel susceptibility in parasites isolated from children across three primary schools in a high endemicity region at the onset of the Ugandan National Control Programme. Children were sampled at 11 timepoints over two years, including one week and four weeks post-praziquantel treatment to evaluate short-term impacts on clearance and evidence of natural variation in susceptibility to praziquantel. Prevalence of S. mansoni was 85% at baseline. A total of 3576 miracidia larval parasites, isolated from 203 individual children, were genotyped at seven loci. Overall, genetic diversity was high and there was low genetic differentiation, indicating high rates of parasite gene flow. Schistosome siblings were found both pre-treatment and four weeks post-treatment, demonstrating adult worms surviving treatment and natural praziquantel susceptibility variation in these populations at the beginning of mass drug administration. However, we did not find evidence for selection on these parasites. While genetic diversity decreased in the short-term (four weeks post-treatment), diversity did not decrease over the entire period despite four rounds of mass treatment. Furthermore, within-host genetic diversity was affected by host age, host sex, infection intensity and recent praziquantel treatment. Our findings suggest that praziquantel treatments have short-term impacts on these parasite populations but impacts were transient and no long-term reduction in genetic diversity was observed. High gene flow reduces the likelihood of local adaptation, so even though parasites surviving treatment were observed, these were likely to be diluted at the beginning of the Ugandan National Control Programme. Together, these results suggest that MDA in isolation may be insufficient to reduce schistosome populations in regions with high genetic diversity and gene flow.