Cost-effectiveness of insulin aspart versus human soluble insulin in type 2 diabetes in four European countries: subgroup analyses from the PREDICTIVE study.
To evaluate the long-term health economic outcomes associated with insulin aspart (IAsp) compared to human soluble insulin (HI) in type 2 diabetes patients on basal-bolus therapy in Sweden, Spain, Italy and Poland. A published computer simulation model of diabetes was used to predict life expectancy, quality-adjusted life expectancy and incidence of diabetes-related complications. Baseline cohort characteristics (age 61.6 years, duration of diabetes 13.2 years, 45.1% male, HbA(1c) 8.2%, BMI 29.8 kg/m(2)) and treatment effects were derived from the PREDICTIVE observational study. Country-specific complication costs were derived from published sources. The analyses were run over 35-year time horizons from third-party payer perspectives in Spain, Italy and Poland and from a societal perspective in Sweden. Future costs and clinical benefits were discounted at country-specific discount rates. Sensitivity analyses were performed. IAsp was associated with improvements in discounted life expectancy and quality-adjusted life expectancy, and a reduced incidence of most diabetes-related complications versus HI in all four settings. IAsp was associated with societal cost-savings in Sweden (SEK 2470), direct medical cost-savings in Sweden and Spain (SEK 8248 and euro 1382, respectively), but increased direct costs in Italy (euro 2235) and Poland (euro 743). IAsp was associated with improved quality-adjusted life expectancy in Sweden (0.077 QALYs), Spain (0.080 QALYs), Italy (0.120 QALYs) and Poland (0.003 QALYs). IAsp was dominant versus HI in both Sweden and Spain, would be considered cost-effective in Italy with an incremental cost-effectiveness ratio of euro 18,597 per QALY gained, but would not be considered cost-effective in Poland.


Safety of fenbendazole in common peafowl (Pavo cristatus).
The present study was undertaken to find out the safety levels of fenbendazole in common peafowl. This bird, raised on aviaries and zoos, can be severely parasitized with Ascaridia galli (enteric worms) and Syngamus trachea (gapeworm) along with other parasitic worms. Fenbendazole is a highly effective benzimidazole-class anthelmintic in animals. The objective of this work was to provide target animal safety data in young peafowl and to demonstrate reproductive safety in adult birds. During the experimental study, diets containing fenbendazole at 0, 100, 200 and 300 ppm were fed for 21 days (three times the normal treatment duration). Data for feed consumption, feed conversion rate, and body weights were recorded for each bird in each group. Drug concentrations in different tissues of birds were determined to correlate concentrations with clinical observations, clinical pathology, and histologic findings. There were no morbidities or mortalities after study day 21. Additionally, there were no statistically significant treatment-related differences among above mentioned parameters. Analysis of fenbendazole concentrations in kidney, liver, leg/thigh, and breast muscle and skin with associated fat revealed that, even at the highest dose level used and with no feed withdrawal, fenbendazole concentrations were relatively low in these tissues. These findings indicate that fenbendazole has a relatively wide margin of safety in young peafowl and that the proposed dose of 100 ppm in the feed for 7 consecutive days is well within the margin of safety. In the reproductive safety study, five breeder peafowl farms fed fendbendazole at 100ppm for 7 days and collected data on hatching percentage of peahen eggs before and after treatment. Reproductive performance in peahen was not adversely affected.


Burden and risk factors for Pseudomonas aeruginosa community-acquired pneumonia: a multinational point prevalence study of hospitalised patients.
Pseudomonas aeruginosa is a challenging bacterium to treat due to its intrinsic resistance to the antibiotics used most frequently in patients with community-acquired pneumonia (CAP). Data about the global burden and risk factors associated with P. aeruginosa-CAP are limited. We assessed the multinational burden and specific risk factors associated with P. aeruginosa-CAP.We enrolled 3193 patients in 54 countries with confirmed diagnosis of CAP who underwent microbiological testing at admission. Prevalence was calculated according to the identification of P. aeruginosa Logistic regression analysis was used to identify risk factors for antibiotic-susceptible and antibiotic-resistant P. aeruginosa-CAP.The prevalence of P. aeruginosa and antibiotic-resistant P. aeruginosa-CAP was 4.2% and 2.0%, respectively. The rate of P. aeruginosa CAP in patients with prior infection/colonisation due to P. aeruginosa and at least one of the three independently associated chronic lung diseases (i.e. tracheostomy, bronchiectasis and/or very severe chronic obstructive pulmonary disease) was 67%. In contrast, the rate of P. aeruginosa-CAP was 2% in patients without prior P. aeruginosa infection/colonisation and none of the selected chronic lung diseases.The multinational prevalence of P. aeruginosa-CAP is low. The risk factors identified in this study may guide healthcare professionals in deciding empirical antibiotic coverage for CAP patients.


Categorization of β-cell capacity in patients with obesity via OGTT using K-means clustering.
Insufficient insulin release plays a crucial role in the development of unhealthy status in patients with obesity; the present study aimed to classify these patients by the indices for insulin resistance and insulin release. After the indices from OGTT were assessed to achieve high differentiability and low redundancy in classifying patients, HOMA-IR and IGI30min were chosen to classify the patients using K-means clustering method. A total of 249 non-diabetic patients with obesity were classified into four groups. In Group 1, 19 patients were characteristic of high insulin resistance and high insulin release, as well as well-controlled glucose levels, the highest BMI, the youngest age, and the highest early phase release of insulin. In Group 2, 38 patients were unhealthiest in terms of high insulin resistance, reduced insulin release and IGT status. Group 3 consisted of 63 patients that were healthiest with low insulin resistance and high insulin release. In Group 4, 46 IGT patients and 14 IFG patients were identified among 129 patients that showed low insulin resistance, low insulin release, moderate obesity and older age. These concurrent impotent insulin release, older age, and moderate obesity indicated decreasing obesity with increasing age and reduced insulin release. The classification of patients with obesity using K-means clustering method by HOMA-IR and IGI30min provides more information about the development of obesity and unhealthy status. The patients with distinct insulin resistance and insulin release should be followed up, especially for those with reduced or even absent insulin response to glucose stimulation.


Efficacy and tolerability of aripiprazole: a 26-week switching study from oral antipsychotics.
To determine if the maintenance effectiveness and tolerability of aripiprazole demonstrated in a 12-week study were maintained in an extension phase (up to 26 weeks). This study was the extension of our switching study from other antipsychotics to aripiprazole in symptomatically stable patients with schizophrenia or schizoaffective disorder. All the patients were randomly assigned to the aripiprazole group or the non-aripiprazole group. The effectiveness analysis consisted of the comparison of the upper bound of the 95% confidence interval (CI) of the mean Clinical Global Impression-Improvement (CGI-I) score to 4 (no change) at the end of the study. At the baseline, the aripiprazole group (n=135) and the non-aripiprazole group (n=31) were comparable with respect to their mean ages, gender distribution, baseline Positive and Negative Syndrome Scale scores, and Clinical Global Impression-Severity (CGI-S) scores. The study showed that the mean CGI-I score was 2.92 (95% CI: 2.72-3.12) in the aripiprazole group and 2.81 (95% CI: 2.35-3.26) in the non-aripiprazole group at 26 weeks. In the aripiprazole group, the remission rates at 12 and 26 weeks were 74.8% and 72.6%, respectively, and 80.2% of the patients with remission at 12 weeks maintained their remission state until the end of the study. About one-fourth of the patients in the aripiprazole group reported one or more spontaneous treatment-emergent adverse events, such as insomnia, headache, and nausea. This study suggested that most clinically stable outpatients with schizophrenia maintain their remission states after being switched to aripiprazole, without serious symptom aggravation and adverse events over a course of 26 weeks.


Changing attitudes toward aging policy in the United States during the 1980s and 1990s: a cohort analysis.
This research assessed how the attitudes of Americans toward government programs that serve older people changed between the mid-1980s and late 1990s and how much of the shift was dueto intracohort change and how much was due to cohort replacement. Data come from three nationally representative cross-sectional samples, surveyed by telephone in 1986 (N = 1.209), 1990 (N = 1,500), and 1997 (N = 1,559). Attitudes of Americans have become less supportive of expanding entitlement programs for older people and more supportive of cutting their costs and benefits. Between 1986 and 1997, most cohorts, particularly older adults, grew more in favor of maintaining Social Security benefit levels but less in favor of expanding them. Young adults tended to be driving the societal shift in attitudes toward decreasing benefits. Intercohort change was more important than cohort replacement in this process. Analyses of change in 2 attitude domains between 1990 and 1997 revealed that the general population felt less strongly that older people are entitled to benefits and expressed greater opposition to the associated costs. However, young adults moderated their concerns about costs as they got older, although the young adults in the cohort replacing them had become more critical of the principle of entitlement. These findings enhance the understanding of the roles that historical conditions and aging play in shaping the attitudes of adult cohorts toward public programs for older citizens. Discrepant findings based on the intercohort change in younger age groups are reconciled by differentiating maturation effects from period effects on impressionable youth.


Genetic research and health disparities.
Alleviating health disparities in the United States is a goal with broad support. Medical research undertaken to achieve this goal typically adopts the well-established perspective that racial discrimination and poverty are the major contributors to unequal health status. However, the suggestion is increasingly made that genetic research also has a significant role to play in alleviating this problem, which likely overstates the importance of genetics as a factor in health disparities. Overemphasis on genetics as a major explanatory factor in health disparities could lead researchers to miss factors that contribute to disparities more substantially and may also reinforce racial stereotyping, which may contribute to disparities in the first place. Arguments that promote genetics research as a way to help alleviate health disparities are augmented by several factors, including research funding initiatives and the distinct demographic patterns of health disparities in the United States.


Evaluating the convergent and discriminant validity of three versions of the frailty phenotype in heart failure: results from the FRAME-HF study.
Frailty is an important predictive measure of mortality and rehospitalisation in people with heart failure. To date, there are no frailty instruments validated for use in people with heart failure. The aim of this study was to evaluate the convergent and discriminant validity of three versions of the frailty phenotype in those with heart failure. A single site, prospective cohort study was undertaken among individuals with a confirmed diagnosis of heart failure. Frailty was assessed concurrently using three versions of the frailty phenotype: the original frailty phenotype and two modified versions; the Survey of Health, Ageing and Retirement in Europe frailty instrument (SHARE-FI) and the St Vincent's frailty instrument. Convergent and discriminant validity were assessed by reporting the correlations between each version and related heart failure subconstructs, and by evaluating the ability of each version to discriminate between normal and abnormal scores of other physical and psychosocial scales specific to heart failure-related subconstructs. The New York Heart Association classes were moderately correlated with the St Vincent's frailty instrument (r=0.47, P⩽0.001), SHARE-FI (r=0.42, P⩽0.001) and the frailty phenotype (r=0.42, P⩽0.001). The SHARE-FI and the St Vincent's frailty instrument were both able to discriminate consistently between normal and abnormal scores in three out of five of the physical and psychosocial subconstructs that were assessed. The SHARE-FI was also able to discriminate between inpatients and outpatients who were classified as frail. Both the SHARE-FI and the St Vincent's frailty instrument displayed good convergent and discriminant validity.


Pure red cell aplasia secondary to treatment with erythropoietin.
Pure red cell aplasia (PRCA) is a rare condition defined as severe anemia secondary to the virtual absence of red blood cell precursors in the bone marrow. In the setting of patients treated with rHuEPO, the disease is generated by epoetin-induced antibodies that neutralise all the exogenous rHuEPO and cross-react with endogenous erythropoietin. As a result, serum erythropoietin levels are undetectable and erythropoiesis becomes ineffective. Only 4 cases of PRCA associated with rh-EPO have been reported before 1998. Thereafter, a sharp increase in the incidence of this rare condition has been reported, mainly associated with epoetin alpha use outside the United States. A number of possible mechanisms leading to PRCA development have been identified. Among these, modification of drug formulation and down stream processing probably has had a major role. Indeed, in 1998 the formulation of epoetin alpha in Europe was modified because of the fear of the "mad cow" syndrome. However, differences in molecule structure and glycosylation among different epoetins can not be excluded. It should also be underlined that the rise in the incidence of PRCA cases has been coincident with a major shift from intravenous to subcutaneous administration of rHuEPO. The abrupt rise in the incidence of PRCA cases observed in the last few years, deserves particular attention; however, we have to balance its severity, but extreme rarity, with the high number of chronic kidney disease patients who die each year because of cardiovascular disease that could partially be reduced by anemia treatment.


'You just change the channel if you don't like what you're going to hear': gamblers' attitudes towards, and interactions with, social marketing campaigns.
To investigate how gamblers interact with, and respond to, downstream social marketing campaigns that focus on the risks and harms of problem gambling and/or encourage help seeking. Qualitative study of 100 gamblers with a range of gambling behaviours (from non-problem to problem gambling). We used a Social Constructivist approach. Our constant comparative method of data interpretation focused on how participants' experiences and interactions with gambling influenced their opinions towards, and interactions with social marketing campaigns. Three key themes emerged from the narratives. (i) Participants felt that campaigns were heavily skewed towards encouraging individuals to take personal responsibility for their gambling behaviours or were targeted towards those with severe gambling problems. (ii) Participants described the difficulty for campaigns to achieve 'cut through' because of the overwhelming volume of positive messages about the benefits of gambling that were given by the gambling industry. (iii) Some participants described that dominant discourses about personal responsibility prevented them from seeking help and reinforced perceptions of stigma. Social marketing campaigns have an important role to play in the prevention of gambling risk behaviours and the promotion of help seeking. Social marketers should explore how to more effectively target campaigns to different audience segments, understand the role of environmental factors in undermining the uptake of social marketing strategies and anticipate the potential unforeseen consequences of social marketing strategies.


Non-invasive stem cell tracking in hindlimb ischemia animal model using bio-orthogonal copper-free click chemistry.
Labeling of stem cells aims to distinguish transplanted cells from host cells, understand in vivo fate of transplanted cells, particularly important in stem cell therapy. Adipose-derived mesenchymal stem cells (ASCs) are considered as an emerging therapeutic option for tissue regeneration, but much remains to be understood regarding the in vivo evidence. In this study, a simple and efficient cell labeling method for labeling and tracking of stem cells was developed based on bio-orthogonal copper-free click chemistry, and it was applied in a mouse hindlimb ischemia model. The human ASCs were treated with tetra-acetylated N-azidoacetyl-d-mannosamine (Ac4ManNAz) to generate glycoprotein with unnatural azide groups on the cell surface, and the generated azide groups were fluorescently labeled by specific binding of dibenzylcyclooctyne-conjugated Cy5 (DBCO-Cy5). The safe and long-term labeling of the hASCs by this method was first investigated in vitro. Then the DBCO-Cy5-hASCs were transplanted into the hindlimb ischemia mice model, and we could monitor and track in vivo fate of the cells using optical imaging system. We could clearly observe the migration potent of the hASCs toward the ischemic lesion. This approach to design and tailor new method for labeling of stem cells may be useful to provide better understanding on the therapeutic effects of transplanted stem cells into the target diseases.


Soft tissue augmentation using in vitro differentiated adipocytes: a clinical pilot study.
Although various commercially available filler materials are now commonly used, their variable degrees of resorption require repeated percutaneous injections. To overcome these drawbacks, a new injectable in vitro differentiated adipocyte filler has been developed, and animal studies have demonstrated that implantation of the filler successfully enhances in vivo adipose tissue formation. This study was undertaken to evaluate the clinical efficacy of this method, particularly in soft tissue augmentation. Autologous adipose-derived stromal cells were isolated, cultured, and differentiated to adipocytes in vitro. The differentiated adipocytes were suspended in Dulbecco's modified Eagle medium and injected into the lesion requiring soft tissue augmentation. Eight patients were treated with this tissue-engineered filler. Long-term follow-up for longer than 1 year was possible in all patients. Two or 3 weeks after the injection, volume increment of subcutaneous tissue was observed around the injection area in the ensuing 1 to 5 weeks. Thereafter, additional volume augmentation was not found and the augmentation effect was well-maintained. All patients agreed on the clinical effectiveness of the procedure, and no complications occurred. The results obtained indicate that this method is well tolerated and may be an effective means of achieving soft tissue augmentation. The authors have indicated no significant interest with commercial supporters.


A simple high-yielding process for transient gene expression in CHO cells.
Here we describe a simplified method for transient gene expression (TGE) in suspension-adapted Chinese hamster ovary (CHO) cells using polyethylenimine (PEI) for DNA delivery. Both the transfection and production phases of the bioprocess were performed at a density of 4 × 10⁶ cells/mL at 31 °C. In addition, the amounts of both PEI and plasmid DNA were reduced up to 50% on a per cell basis compared to previously published protocols from this laboratory, resulting in higher cell viability after transfection and higher volumetric recombinant protein yields. In batch cultures of up to 14 days, reproducible recombinant antibody yields up to 300 mg/L were achieved at small scale (5 mL) and up to 250 mg/L at large scale (500 mL). The simplicity and improved yields are expected to increase the utility of CHO cells for the rapid production of recombinant proteins at larger scales by TGE.


Classification of cytochrome P450 inhibitors with respect to binding free energy and pIC50 using common molecular descriptors.
Virtual screening of chemical libraries following experimental assays of drug candidates is a common procedure in structure based drug discovery. However, the relationship between binding free energies and biological activities (pIC50) of drug candidates is still an unsolved issue that limits the efficiency and speed of drug development processes. In this study, the relationship between them is investigated based on a common molecular descriptor set for human cytochrome P450 enzymes (CYPs). CYPs play an important role in drug-drug interactions, drug metabolism, and toxicity. Therefore, in silico prediction of CYP inhibition by drug candidates is one of the major considerations in drug discovery. The combination of partial least-squares regression (PLSR) and a variety of classification algorithms were employed by considering this relationship as a classification problem. Our results indicate that PLSR with classification is a powerful tool to predict more than one output such as binding free energy and pIC50 simultaneously. PLSR with mixed-integer linear programming based hyperboxes predicts the binding free energy and pIC50 with a mean accuracy of 87.18% (min: 81.67% max: 97.05%) and 88.09% (min: 79.83% max: 92.90%), respectively, for the cytochrome p450 superfamily using the common 6 molecular descriptors with a 10-fold cross-validation.


Engineering ethics beyond engineers' ethics.
Engineering ethics is usually focused on engineers' ethics, engineers acting as individuals. Certainly, these professionals play a central role in the matter, but engineers are not a singularity inside engineering; they exist and operate as a part of a complex network of mutual relationships between many other people, organizations and groups. When engineering ethics and engineers' ethics are taken as one and the same thing the paradigm of the ethical engineer which prevails is that of the heroic engineer, a certain model of the ideal engineer: someone both quite individualistic and strong enough to deal with all the moral challenges that could arise. We argue that this is not the best approach, at least today in our interrelated world. We have achieved a high degree of independence from nature by means of technology. In exchange for this autonomy we have become increasingly tied up with very complex systems to which we constantly delegate new tasks and powers. Concerns about safety keep growing everywhere due to the fact that now we have a sensitive awareness of the huge amount of power we are both consuming and deploying, thus, new forms of dialogue and consensus have to be incorporated at different levels, in different forums and at different times. Within these democratic channels of participation not just the needs and interests, but also the responsibilities and mutual commitments of all parties should be taken into account.


Dietary lipid source alters murine macrophage/vascular smooth muscle cell interactions in vitro.
This study was conducted to compare the impact of dietary lipids on the ability of macrophages to modulate vascular smooth muscle cell (SMC) DNA synthesis in vitro. C57BL/6 female mice were fed six different diets (6 mice/diet) containing 10% fat from corn oil (CO), borage oil (BO), primrose oil (PO), fish-corn oil mix (FC, 9:1, w/w), fish-borage oil mix (FB, 1:3, w/w), or fish-primrose oil mix (FP, 1:3, w/w) for 2 wk. Peritoneal macrophages were isolated from these mice, stimulated with zymosan or vehicle, and subsequently co-cultured with naive mouse aortic SMC in the presence of 3H-thymidine to measure SMC DNA synthesis. In this co-culture system, macrophages were seeded on 25-mm culture inserts (upper chamber) and SMC were seeded on 35-mm culture dishes (lower chamber). The two cell types were separated by a semipermeable membrane with a 30-kD cut-off. When quiescent SMC were co-cultured with macrophages, only the PO and FP diet groups had significantly (P < 0.05) lower SMC DNA synthesis compared with the control CO group whose diet contained no gamma-linolenic acid (GLA) or (n-3) polyunsaturated fatty acids (PUFA). In contrast, when cycling SMC were co-cultured with diet-modulated macrophages, all dietary groups except for those fed FC had significantly lower (P < 0.05) SMC DNA synthesis relative to the CO group. Although the level of GLA in PO and BO diets was different (11.5 and 22.3 g/100 g fatty acids, respectively), these treatments exerted comparable inhibitory effects on SMC DNA synthesis. The FP treatment consistently exhibited the lowest SMC DNA synthetic profile among the six dietary groups irrespective of SMC growth conditions. These data suggest that BO and PO alone or in combination with fish oil influence macrophage/smooth muscle cell interactions in a manner consistent with favorable modulation of the atherogenic process.


Influence of Four Different Abutment Materials and the Adhesive Joint of Two-Piece Abutments on Cervical Implant Bone and Soft Tissue.
The main aim of this study was to evaluate the influence of four different abutment materials and the adhesive joint of two-piece abutments on the cervical implant bone and soft tissue. Sixty-four titanium implants (Camlog Conelog; 4.3 ± 9 mm) were placed bone level into the edentulous arches of four minipigs. Four different types of abutments were placed at implant exposure: zirconium dioxide, lithium disilicate, and titanium bonded to a titanium luting base with resin cement; one-piece titanium abutments served as the control. The animals were sacrificed 6 months after implant exposure, and the bone-to-implant contact (BIC) area, sulcus depth, the length of the junctional epithelium and the connective tissue, the biologic width, and first cervical BIC-implant shoulder distance were measured using histomorphometry and light and fluorescence microscopy. Overall, 14 implants were lost (22%). At exposure, the implant shoulder-bone distance was 0.6 ± 0.7 mm. Six months later, the bone loss was 2.1 ± 1.2 mm measured histomorphometrically. There was a significant difference between the two measurements (P ≤ .0001). No significant influence could be found between any of the abutment materials with regard to bone loss or soft tissue anatomy (P > .05), with the exception of zirconium dioxide and onepiece titanium abutments when measuring the length of the junctional epithelium (P ≤ .01). The maxilla provided significantly more soft tissue and less bone loss compared with the mandible (P ≤ .02). All tested abutment materials and techniques seem to be comparable with regard to soft tissue properties and the cervical bone level.


Help-seeking by male victims of domestic violence and abuse (DVA): a systematic review and qualitative evidence synthesis.
To understand help-seeking by male victims of domestic violence and abuse (DVA) and their experiences of support services by systematically identifying qualitative and mixed-method studies and thematically synthesising their findings. Systematic review and qualitative evidence synthesis. Searches were conducted in 12 databases and the grey literature with no language or date restrictions. Quality appraisal of the studies was carried out using the Critical Appraisal Skills Programme tool. Reviewers extracted first and second order constructs related to help-seeking, identified themes and combined them by interpretative thematic synthesis. DVA experienced by male victims and defined as any incident or pattern of incidents of controlling coercive or threatening behaviour, violence or abuse among people aged 18 or over who are or have been intimate partners or family members, regardless of gender or sexuality. Male victims of DVA. Any intervention which provides practical and/or psychological support to male victims of DVA including but not limited to DVA-specific services, primary healthcare and sexual health clinics. Qualitative data describing help-seeking experiences and interactions with support services of male victims of domestic violence RESULTS: We included twelve studies which were published between 2006 and 2017. We grouped nine themes described over two phases (a) barriers to help-seeking: fear of disclosure, challenge to masculinity, commitment to relationship, diminished confidence/despondency and invisibility/perception of services; and (b) experiences of interventions and support: initial contact, confidentiality, appropriate professional approaches and inappropriate professional approaches. The recent publication of the primary studies suggests a new interest in the needs of male DVA victims. We have confirmed previously identified barriers to help-seeking by male victims of DVA and provide new insight into barriers and facilitators to service provision. CRD42016039999.


Quantification of tumour response to radiotherapy.
In 1979, the World Health Organization (WHO) established criteria based on tumour volume change for classifying response to therapy as (i) progressive disease (PD), (ii) partial recovery (PR), and (iii) no change (NC). Typically, the tumour volume is reported from diameter measurements, using the calliper method. Alternatively, the Cavalieri method provides unbiased volume estimates of any structure without assumptions about its shape. In this study, we applied the Cavalieri method in combination with point counting to investigate the changes in tumour volume in four patients with high grade glioma, using 3D MRI. In particular, the volume of tumour within the enhancement boundary, the enhancing abnormality (EA), was estimated from T(1) weighted images, and the volume of the non-enhancing abnormality, (NEA) enhancing abnormality, was estimated from T(2) relaxation time and magnetic transfer ratio tissue characterization maps. We compared changes in tumour volume estimated by the Cavalieri method with those obtained using the calliper method. Absolute tumour volume differed significantly between the two methods. Analysis of relative change in tumour volume, based on the WHO criteria, provided a different classification using the calliper and Cavalieri methods. The benefit of the Cavalieri method over the calliper method in the estimation of tumour volume is justified by the following factors. First, Cavalieri volume estimates are mathematically unbiased. Second, the Cavalieri method is highly efficient under an appropriate sampling density (i.e. EA volume estimates can be obtained with a coefficient of error no higher than 5% in 2-3 min). Third, the source of variation of the volume estimates due to disagreements between observers, and within observer, is much greater in the positioning of the calliper diameters than in the identification of the tumour boundaries when applying the Cavalieri method. Additionally, the error prediction formula, available to estimate the coefficient of error of Cavalieri volume estimates from the data, allows us to establish more precise classification criteria against which to identify potentially clinical significant changes in tumour volume.


High Dietary Intake of Specific Fatty Acids Increases Risk of Flares in Patients With Ulcerative Colitis in Remission During Treatment With Aminosalicylates.
Dietary factors may have a significant role in relapse of disease among patients with ulcerative colitis (UC). However, the relationship between diet and UC is inadequately understood. We analyzed data from the diet's role in exacerbations of mesalamine maintenance study to determine whether dietary factors affect the risk of disease flares in patients with UC. We performed a prospective, multicenter, observational study of 412 patients, from 25 sites, with UC in remission during monotherapy with an aminosalicylate. Patients completed a validated food frequency questionnaire at enrollment and were followed for 12 months. We analyzed the relationship between diet and disease remission or flare for groups of macronutrients and micronutrients, and food groups previously associated with an increased risk of flare. Forty-five patients (11%) had a UC relapse within 1 year of study enrollment. When analyzed in tertiles, increasing intake of multiple fatty acids was associated with increasing odds of relapse. In multivariable logistic regression analysis, only myristic acid (odds ratio, 3.01; 95% confidence interval, 1.17-7.74) maintained this dose-response relationship. Other foods previously implicated in flares of UC, such as processed meat, alcohol, and foods high in sulfur, were not associated with an increased risk of flare. In a prospective study of more than 400 patients with UC undergoing treatment with aminosalicylates, we associated high dietary intake of specific fatty acids, including myristic acid (commonly found in palm oil, coconut oil, and dairy fats) with an increased risk of flare. These findings can help design interventional studies to evaluate dietary factors in UC.


Development and optimization of quantitative PCR for the diagnosis of invasive aspergillosis with bronchoalveolar lavage fluid.
The diagnosis of invasive pulmonary aspergillosis (IPA) remains challenging. Culture and histopathological examination of bronchoalveolar lavage (BAL) fluid are useful but have suboptimal sensitivity and in the case of culture may require several days for fungal growth to be evident. Detection of Aspergillus DNA in BAL fluid by quantitative PCR (qPCR) offers the potential for earlier diagnosis and higher sensitivity. It is important to adopt quality control measures in PCR assays to address false positives and negatives which can hinder accurate evaluation of diagnostic performance. BAL fluid from 94 episodes of pneumonia in 81 patients was analyzed. Thirteen episodes were categorized as proven or probable IPA using Mycoses Study Group criteria. The pellet and the supernatant fractions of the BAL were separately assayed. A successful extraction was confirmed with a human 18S rRNA gene qPCR. Inhibition in each qPCR was measured using an exogenous DNA based internal amplification control (IAC). The presence of DNA from pathogens in the Aspergillus genus was detected using qPCR targeting fungal 18S rRNA gene. Human 18S rRNA gene qPCR confirmed successful DNA extraction of all samples. IAC detected some degree of initial inhibition in 11 samples. When culture was used to diagnose IPA, the sensitivity and specificity were 84.5% and 100% respectively. Receiver-operating characteristic analysis of qPCR showed that a cutoff of 13 fg of Aspergillus genomic DNA generated a sensitivity, specificity, positive and negative predictive value of 77%, 88%, 50%, 96% respectively. BAL pellet and supernatant analyzed together resulted in sensitivity and specificity similar to BAL pellet alone. Some patients did not meet standard criteria for IPA, but had consistently high levels of Aspergillus DNA in BAL fluid by qPCR. The Aspergillus qPCR assay detected Aspergillus DNA in 76.9% of subjects with proven or probable IPA when the concentrated BAL fluid pellet fraction was used for diagnosis. There was no benefit from analyzing the BAL supernatant fraction. Use of both extraction and amplification controls provided optimal quality control for interpreting qPCR results and therefore may increase our understanding of the true potential of qPCR for the diagnosis of IPA.


Congenital high airway obstruction syndrome.
Congenital high airway obstruction syndrome (CHAOS) is a very rare fetal malformation caused by obstruction of fetal airway because of laryngeal or tracheal atresia, subglottic stenosis, laryngeal cyst or laryngeal web. The prenatal diagnosis is inferred from secondary changes such as enlarged, hyperechogenic lungs, ascites and/or hydrops, flattened or everted diaphragms, dilated distal airways and mediastinal compression. There are only few cases of long-term survival described in literature. We present the case of fetus with such secondary changes diagnosed during routine ultrasound evaluation in 20 weeks' gestation. There were no other abnormalities and the kariotype was normal. In 26 weeks' gestation fetal hydrops appeared and subsequent polyhydramnios occurred in 28 weeks' gestation. The patient was planned for EXIT procedure during labor in experienced in CHAOS cases center. In 29 weeks' gestation the premature rupture of membranes and regular uterine contractions occurred and we've performed cesarean section. A multidisciplinary team of neonatologists, laryngologists and pediatric surgeons made their efforts to save the newborn, but there was complete laryngeal atresia and tracheal agenesia and immediate tracheostomy was impossible. The most important about CHAOS are early diagnosis, detailed fetal assessment and an adequate postnatal intervention for establishing fetal airways.


CT Imaging of early hepatocellular carcinoma and the natural outcome of hypoattenuating nodular lesions in chronic liver disease.
The Liver Cancer Study Group of Japan has designated early hepatocellular carcinoma (HCC) a clinically early-stage HCC corresponding to a high-grade dysplastic nodule as proposed by the International Working Party. The majority of resected early HCCs were demonstrated as having hypo- or isoattenuation in the arterial and delayed phases of dynamic CT. Only 5% of early HCCs were hyperattenuated on dynamic CT, whereas 94% of advanced small HCC were hyperattenuated. CT arterial portography (CTAP) showed that 66% of early HCCs were hypo- and 34% were isoattenuated. CT hepatic arteriography (CTHA) demonstrated that 55% of them were hypo-, 30% were iso- and the remaining 15% were hyperattenuated. These findings suggest that most early HCCs receive equal or decreased blood supply from both portal and arterial blood flow compared with surrounding hepatic parenchyma. In contrast, 97% of small advanced HCCs were hypoattenuated on CTAP, and 93% were hyperattenuated on CTHA. For nodule-in-nodule type HCC, the central portion of the lesion was hyperattenuating and the peripheral portion was hypoattenuating in the arterial phase of dynamic CT, and both areas became hypoattenuated in the delayed phase. Sixty hypoattenuating nodular lesions in chronic liver disease were followed periodically with helical CT. Thirty-six (60%) of them developed to the hyperattenuating type (attenuation conversion), 21 were unchanged, and 3 disappeared spontaneously. The hyper-in-hypo-attenuating lesions showed rapid progression to entirely enhanced lesions, i.e. overt HCC. Dynamic CT is recommended as one of the low-invasive imaging modalities to follow the hypoattenuating nodules and to determine the optimal treatment with careful attention being given to intratumoral attenuation conversion.


Public health application of predictive modeling: an example from farm vehicle crashes.
The goal of predictive modelling is to identify the likelihood of future events, such as the predictive modelling used in climate science to forecast weather patterns and significant weather occurrences. In public health, increasingly sophisticated predictive models are used to predict health events in patients and to screen high risk individuals, such as for cardiovascular disease and breast cancer. Although causal modelling is frequently used in epidemiology to identify risk factors, predictive modelling provides highly useful information for individual risk prediction and for informing courses of treatment. Such predictive knowledge is often of great utility to physicians, counsellors, health education specialists, policymakers or other professionals, who may then advice course correction or interventions to prevent adverse health outcomes from occurring. In this manuscript, we use an example dataset that documents farm vehicle crashes and conventional statistical methods to forecast the risk of an injury or death in a farm vehicle crash for a specific individual or a scenario. Using data from 7094 farm crashes that occurred between 2005 and 2010 in nine mid-western states, we demonstrate and discuss predictive model fitting approaches, model validation techniques using external datasets, and the calculation and interpretation of predicted probabilities. We then developed two automated risk prediction tools using readily available software packages. We discuss best practices and common limitations associated with predictive models built from observational datasets. Predictive analysis offers tools that could aid the decision making of policymakers, physicians, and environmental health practitioners to improve public health.


Functional Priorities in Persons with Spinal Cord Injury: Using Discrete Choice Experiments To Determine Preferences.
Major goals of rehabilitation and health interventions in people with spinal cord injury (SCI) are to improve functional independence, increase social participation, and enhance quality of life (QOL). Determining functional areas perceived by consumers as most important can assist in research prioritization, planning for delivery of health services, and policy development. Five high priority areas of functioning for the SCI population (arm/hand use, walking, bladder/bowel control, sexual function, and relief of pain) were chosen to determine the preferences for these five attributes. A discrete choice experiment was conducted involving 151 persons with SCI sampled from Australia and the United States of America. Consistent with prior research, arm/hand function had the highest preference, with odds ratios of subjects being 44-76% more likely to choose arm/hand function over the other four functions. Preference for normal arm/hand function was found to be significantly more preferred by the group with paraplegia compared with those with tetraplegia; that is, retaining and not trading off existing arm/hand function for other improved functions. There were no significant differences found in preferences between bladder/bowel function and walking or elimination of pain, although walking was preferred in earlier (≤ 10) post-injury years and pain amelioration became more important with a longer duration (>10 years) post-injury. Sexual function had the lowest preference when traded against the other four functions. Understanding the functional preferences of persons with SCI will help to inform future research design, as well as enabling successful translation of research into practice and health policy, meeting the needs of people with SCI.


Pollen-mediated gene flow from transgenic safflower (Carthamus tinctorius L.) intended for plant molecular farming to conventional safflower.
Field experiments were conducted in Chile and western Canada to measure short-distance (0 to 100 m) outcrossing from transgenic safflower (Carthamus tinctorius L.) intended for plant molecular farming to non-transgenic commodity safflower of the same variety. The transgenic safflower used as the pollen source was transformed with a construct for seed-specific expression of a high-value protein and constitutive expression of a gene conferring resistance to the broad-spectrum herbicide glufosinate. Progeny of non-transgenic plants grown in plots adjacent to the transgenic pollen source were screened for glufosinate resistance to measure outcrossing frequency. Outcrossing frequency differed among locations: values closest to the transgenic pollen source (0 to 3 m) ranged from 0.48 to 1.67% and rapidly declined to between 0.0024 to 0.03% at distances of 50 to 100 m. At each location, outcrossing frequency was spatially heterogeneous, indicating insects or wind moved pollen asymmetrically. A power analysis assuming a binomial distribution and a range of alpha values (type 1 error) was conducted to estimate an upper and lower confidence interval for the probable transgenic seed frequency in each sample. This facilitated interpretation when large numbers of seeds were screened from the outcrossing experiments and no transgenic seeds were found. This study should aid regulators and the plant molecular farming industry in developing confinement strategies to mitigate pollen mediated gene flow from transgenic to non-transgenic safflower.


Identification of ability to form biofilm in Candida parapsilosis and Staphylococcus epidermidis by Raman spectroscopy.
Aim: Finding rapid, reliable diagnostic methods is a big challenge in clinical microbiology. Raman spectroscopy is an optical method used for multiple applications in scientific fields including microbiology. This work reports its potential in identifying biofilm positive strains of Candida parapsilosis and Staphylococcus epidermidis. Materials & methods: We tested 54 S. epidermidis strains (23 biofilm positive, 31 negative) and 51 C. parapsilosis strains (27 biofilm positive, 24 negative) from colonies on Mueller-Hinton agar plates, using Raman spectroscopy. Results: The accuracy was 98.9% for C. parapsilosis and 96.1% for S. epidermidis. Conclusion: The method showed great potential for identifying biofilm positive bacterial and yeast strains. We suggest that Raman spectroscopy might become a useful aid in clinical diagnostics.


Synovial Fluid Cell Count for Diagnosis of Chronic Periprosthetic Hip Infection.
There is a paucity of data regarding the threshold of synovial fluid white blood-cell (WBC) count and polymorphonuclear cell (neutrophil) percentage of the WBC count (PMN%) for the diagnosis of chronic periprosthetic joint infection (PJI) after total hip arthroplasty. Despite this, many organizations have provided guidelines for the diagnosis of PJI that include synovial fluid WBC count and PMN%. We attempted to define a threshold for synovial fluid WBC count and PMN% for the diagnosis of chronic PJI of the hip using a uniform definition of PJI and to investigate any variations in the calculated thresholds among institutions. From 4 academic institutions, we formed a cohort of 453 patients with hip synovial fluid cell count analysis as part of the work-up for revision total hip arthroplasty. Using the definition of PJI from the Musculoskeletal Infection Society (MSIS), 374 joints were diagnosed as aseptic and 79, as septic. Intraoperative aspirations were performed as routine practice, regardless of the suspicion for infection, in 327 (72%) of the patients. Using receiver operating characteristic curves, the optimal threshold values for synovial WBC count and PMN% were identified. For the diagnosis of chronic PJI of the hip, the threshold for the overall cohort was 3,966 cells/μL for WBC count and 80% for PMN%. Despite the high predictive accuracy for the cohort, there was notable institutional variation in fluid WBC count and PMN%. Furthermore, the rate of PJI was 14% (4 of 28) for patients with a WBC count of 3,000 to 5,000 cells/μL compared with 91% (20 of 22) for patients with a WBC count of >50,000 cells/μL. Similarly, the rate of PJI was 29% (14 of 49) for patients with a PMN% of 75% to 85% compared with 69% (33 of 48) for patients with a PMN% of >95%. Using the MSIS criteria, the optimal synovial fluid WBC count and PMN% to diagnose chronic PJI in the hip is closer to thresholds for the knee than those previously reported for the hip. This study validates the diagnostic utility of synovial fluid analysis for the diagnosis of periprosthetic hip infection; however, we also identified a clinically important "gray area" around the threshold for which the presence of PJI may be unclear. Diagnostic Level III. See Instructions for Authors for a complete description of levels of evidence.


Systematic study of interdependent relationship on gold nanorod synthesis assisted by electron microscopy image analysis.
Here, we systematically investigated the independent, multiple, and synergic effects of three major components, namely, ascorbic acid (AA), seed, and silver ions (Ag+), on the characteristics of gold nanorods (GNRs), i.e., longitudinal localized surface plasmon resonance (LSPR) peak position, shape, size, and monodispersity. To quantitatively assess the shape and dimensions of GNRs, we used an automated transmission electron microscopy image analysis method using a MATLAB-based code developed in-house and the concept of solidity, which is the ratio between the area of a GNR and the area of its convex hull. The solidity of a straight GNR is close to 1, while it decreases for both dumbbell- and dogbone-shaped GNRs. We found that the LSPR peak position, shape, and monodispersity of the GNRs all altered simultaneously with changes in the amounts of individual components. For example, as the amount of AA increased, both the LSPR peak and solidity decreased, while the polydispersity increased. In contrast, as the amount of seeds increased, both the LSPR and solidity increased, while the monodispersity improved. More importantly, we found that the influence of each component can actually change depending on the composition of the GNR growth solution. For instance, the LSPR peak position red-shifted as the amount of AA increased when the seed content was low, whereas it blue-shifted when the seed content was high.


Concordance of PCR and antibody results from HIV testing of injecting drug users.
Standard HIV-1 testing relies on the enzyme immunoassay (EIA) for detecting antibodies specific to HIV-1. This technique may misclassify persons as HIV-1-negative in instances where testing follows infection but precedes development of antibody to HIV-1. To evaluate the occurrence of HIV infection in the absence of positive antibody, polymerase chain reaction (PCR) for viral DNA in the blood has been applied. Research comparing these two testing techniques has generally focused on populations of homosexual and bisexual men. This study compares PCR and antibody testing of 337 injecting drug users recruited from street settings in San Francisco. Of 286 HIV-1 antibody-negative samples, 3 (1.0%) were PCR-positive. Of 49 HIV-1 antibody-positive samples, 1 (2.0%) was PCR-negative. Two samples were antibody-indeterminate and PCR-negative. This yielded an overall concordance of 331/335 (98.8%), excluding the indeterminate results. These results suggest that current antibody methodology is adequate. However, misclassification among recently infected individuals may occur, which is of concern in high-incidence groups.


A standardised method for use of the Leksell GammaPlan Inverse Planning module for metastases.
The aim of this investigation was to develop a standardised method for using the inverse planning module in Leksell GammaPlan. Leksell GammaPlan version 10 and higher contains an inverse planning module, consisting of functions to automatically fill a target volume with shots and subsequently optimise their resulting dosimetry. A standardised method for using the inverse planning module was developed for metastases, using the following optimisation parameter weightings: {coverage 0.9, selectivity 0.1, gradient index (GI) 0.2, }. 25 plans produced using these parameters were compared to manually produced clinical plans. Additionally, the 25 plans were manually adjusted to match the coverage of the clinical plans, and comparison of the PCI, GI and BOT was made. The average parameters for plans produced using the optimisation module were; coverage 98.7%; Paddick conformity index (PCI) 0.85; GI 2.75, compared to coverage 99.5%; PCI 0.83; GI 2.70 for manual clinical plans with BOT 21% shorter than clinical plans on average. The average parameters for the plans produced by the optimisation module after manual adjustment to match the coverage of the clinical plans were: coverage 99.5, PCI 0.83, GI 2.73 with BOT 16% shorter than clinical plans on average. The standardised method for using the optimisation module has potential for shortening treatment times and planning times.


Meteoroid Impacts as a Source of Bennu's Particle Ejection Events.
Asteroid (101955) Bennu, a near-Earth object with a primitive carbonaceous chondrite-like composition, was observed by the Origins, Spectral Interpretation, Resource Identification, and Security-Regolith Explorer (OSIRIS-REx) spacecraft to undergo multiple particle ejection events near perihelion between December 2018 and February 2019. The three largest events observed during this period, which all occurred 3.5 to 6 hr after local noon, placed numerous particles <10 cm on temporary orbits around Bennu. Here we examine whether these events could have been produced by sporadic meteoroid impacts using the National Aeronautics and Space Administration's (NASA) Meteoroid Engineering Model 3.0. Most projectiles that impact Bennu come from nearly isotropic or Jupiter-family comets and have evolved toward the Sun by Poynting-Robertson drag. We find that 7,000-J impacts on Bennu occur with a biweekly cadence near perihelion, with a preference to strike in the late afternoon (~6 pm local time). This timing matches observations. Crater scaling laws also indicate that these impact energies can reproduce the sizes and masses of the largest observed particles, provided the surface has the cohesive properties of weak, porous materials. Bennu's ejection events could be caused by the same kinds of meteoroid impacts that created the Moon's asymmetric debris cloud observed by the Lunar Atmosphere and Dust Environment Explorer (LADEE). Our findings also suggest that fewer ejection events should take place as Bennu moves further away from the Sun, a result that can be tested with future observations.


CXCL12-induced neurotoxicity critically depends on NMDA receptor-gated and L-type Ca2+ channels upstream of p38 MAPK.
The chemokine receptor CXCR4 (CD184) and its natural ligand CXCL12 contribute to many physiological processes, including decisions about cell death and survival in the central nervous system. In addition, CXCR4 is a co-receptor for human immunodeficiency virus (HIV)-1 and mediates the neurotoxicity of the viral envelope protein gp120. However, we previously observed that CXCL12 also causes toxicity in cerebrocortical neurons but the cellular mechanism remained incompletely defined. Primary neuronal-glial cerebrocortical cell cultures from rat were exposed to a neurotoxicity-inducing CXCL12 concentration for different times and the activity of the stress-associated mitogen-activated protein kinase p38 (p38 MAPK) was assessed using an in vitro kinase assay. Neurotoxicity of CXCL12 and cellular localization of p38 MAPK was analyzed by immunofluorescence microscopy. Pharmacological inhibition of NMDA-type glutamate receptor-gated ion channels (NMDAR) of L-type Ca2+ channels was employed during 12- and 24-h exposure to neurotoxic amounts of CXCL12 to study the effects on active p38 MAPK and neuronal survival by Western blotting and microscopy, respectively. Neurotoxicity of CXCL12 was also assessed during pharmacological inhibition of p38 MAPK. Here, we show that a neurotoxic amount of CXCL12 triggers a significant increase of endogenous p38 MAPK activity in cerebrocortical cells. Immunofluorescence and Western blotting experiments with mixed neuronal-glial and neuron-depleted glial cerebrocortical cells revealed that the majority of active/phosphorylated p38 MAPK was located in neurons. Blockade of NMDAR-gated ion channels or L-type Ca2+ channels both abrogated an increase of active p38 MAPK and toxicity of CXCL12 in cerebrocortical neurons. Inhibition of L-type Ca2+ channels with nimodipine kept the active kinase at levels not significantly different from baseline while blocking NMDAR with MK-801 strongly reduced phosphorylated p38 MAPK below baseline. Finally, we confirmed that directly blocking p38 MAPK also abrogated neurotoxicity of CXCL12. Our findings link CXCL12-induced neuronal death to the regulation of NMDAR-gated ion channels and L-type Ca2+ channels upstream of p38 MAPK activation.


Building up strain in colloidal metal nanoparticle catalysts.
The focus on surface lattice strain in nanostructures as a fundamental research topic has gained momentum in recent years as scientists investigated its significant impact on the surface electronic structure and catalytic properties of nanomaterials. Researchers have begun to tell a more complete story of catalysis from a perspective which brings this concept to the forefront of the discussion. The nano-'realm' makes the effects of surface lattice strain, which acts on the same spatial scales, more pronounced due to a higher ratio of surface to bulk atoms. This is especially evident in the field of metal nanoparticle catalysis, where displacement of atoms on surfaces can significantly alter the sorption properties of molecules. In part, the concept of strain-engineering for catalysis opened up due to the achievements that were made in the synthesis of a more sophisticated nanoparticle library from an ever-expanding set of methodologies. Developing synthesis methods for metal nanoparticles with well-defined and strained architectures is a worthy goal that, if reached, will have considerable impact in the search for catalysts. In this review, we summarize the recent accomplishments in the area of surface lattice-strained metal nanoparticle synthesis, framing the discussion from the important perspective of surface lattice strain effects in catalysis.


Communication: Pressure fluctuations in isotropic solids and fluids.
Comparing isotropic solids and fluids at either imposed volume or pressure, we investigate various correlations of the instantaneous pressure and its ideal and excess contributions. Focusing on the compression modulus K, it is emphasized that the stress fluctuation representation of the elastic moduli may be obtained directly (without a microscopic displacement field) by comparing the stress fluctuations in conjugated ensembles. This is made manifest by computing the Rowlinson stress fluctuation expression K(row) of the compression modulus for NPT-ensembles. It is shown theoretically and numerically that K(row∣P) = P(id)(2 - P(id)∕K) with P(id) being the ideal pressure contribution.


Effect of sodium nitrate loading on electrolyte transport by the renal tubule.
Effects of sodium nitrate were compared with sodium chloride loading on transport of electrolytes by the nephron. Maximal levels of free water clearance/clomerular filtration rate (CH2O/GFR) averaged 8.4% with nitrate loading and 14.4% with saline loading. Since ethacrynic acid and chlorothiazide exert their major natriuretic effect in the distal nephron, the increment in Na ad Cl reabsorbed beyond the proximal tubule. The administration of these agents resulted in an increase in fractional sodium excretion (CNa/GFR) of 21.1%, urinary sodium excretion (UNaV) of 1,126 mueq/min, and urinary chloride excretion (UClV) of 848 mueq/min during nitrate loading compared with an increase in CNa/GFR of 37.6%, UNaV of 2,362 mueq/min, and UClV of 2,397 mueq/min during saline loading. The smaller diuretic-induced increment in Na and Cl excretion in the nitrate studies suggests, as do the hydrated studies, that less Cl and Na are reabsorbed in the distal nephron during nitrate than saline loading. At every level of UNaV, fractional bicarbonate reabsorption was higher, urine pH was lower, and urinary potassium excretion (UKV) was higher in the nitrate studies. Thus, compared with saline loading, sodium nitrate decreases chloride and sodium reabsorption in the distal nephron. The higher hydrogen and potassium secretion in the nitrate studies may be consequent to the decreased ability of the distal nephron to reabsorb chloride.


The economic value of informal caregiving.
This study explores the current market value of the care provided by unpaid family members and friends to ill and disabled adults. Using large, national data sets we estimate that the national economic value of informal caregiving was $196 billion in 1997. This figure dwarfs national spending for formal home health care ($32 billion) and nursing home care ($83 billion). Estimates for five states also are presented. This study broadens the issue of informal caregiving from the micro level, where individual caregivers attempt to cope with the stresses and responsibilities of caregiving, to the macro level of the health care system, which must find more effective ways to support family caregivers.


Prospective evaluation of fexapotide triflutate injection treatment of Grade Group 1 prostate cancer: 4-year results.
This study was undertaken to determine the safety and efficacy of fexapotide triflutate (FT) 2.5 mg and 15 mg for the treatment of Grade Group 1 prostate cancer. Prospective randomized transrectal intraprostatic single injection FT 2.5 mg (n = 49), FT 15 mg (n = 48) and control active surveillance (AS) (n = 49) groups were compared in 146 patients at 28 U.S. sites, with elective AS crossover (n = 18) to FT after first follow-up biopsy at 45 days. Patients were followed for 5 years including biopsies (baseline, 45 days, and 18, 36, and 54 months thereafter), and urological evaluations with PSA every 6 months. Patients with Gleason grade increase or who elected surgical or radiotherapeutic intervention exited the study and were cumulatively included in the data analysis. Percentage of normal biopsies in baseline focus quadrant, tumor grades, and volumes; and outcomes including Gleason grade in entire prostate as well as treated prostate lobe, interventions associated with Gleason grade increase and total incidence of interventions were assessed. Significantly improved long-term clinical outcomes were found after 4-year follow-up, with percentages of patients progressing to interventions with and without Gleason grade increase significantly reduced by FT single treatment. Results in the FT 15-mg group were superior to the FT 2.5-mg dose group. There were no drug-related serious adverse events (SAEs). FT showed statistically significant long-term efficacy in the treatment of Grade Group 1 patients regarding clinical and pathological progression. FT 15 mg showed superior results to FT 2.5 mg. There were no drug-related SAEs; FT injection was well tolerated.


Posterior Surgical Techniques for Cervical Spondylotic Myelopathy: WFNS Spine Committee Recommendations.
This study was conducted to determine and recommend the most up-to-date information on the indications, complications, and outcomes of posterior surgical treatments for cervical spondylotic myelopathy (CSM) on the basis of a literature review. A comprehensive literature search was performed, using the MEDLINE (PubMed), the Cochrane Register of Controlled Trials, and Web of Science databases, for peer-reviewed articles published in English during the last 10 years. Posterior techniques, which include laminectomy alone, laminectomy with fusion, and laminoplasty, are often used in patients with involvement of 3 or more levels. Posterior decompression for CSM is effective for improving patients' neurological function. Complications resulting from posterior cervical spine surgery include injury to the spinal cord and nerve roots, complications related to posterior screw fixation or instrumentation, C5 palsy, spring-back closure of lamina, and postlaminectomy kyphosis. It is necessary to consider multiple factors when deciding on the appropriate operation for a particular patient. Surgeons need to tailor preoperative discussions to ensure that patients are aware of these facts. Further research is needed on the cost-to-benefit analysis of various surgical approaches, the comparative efficacy of surgical approaches using various techniques, and long-term outcomes, as current knowledge is deficient in this regard.


Endotoxin treatment protects vitamin E-deficient rats from pulmonary O2 toxicity.
Endotoxin treatment in normal rats has a marked protective effect against O2 toxicity (J. Appl. Physiol.: Respirat. Environ. Exercise Physiol. 47: 577-581, 1979 and 51: 577-583, 1981), and endotoxin's protective action is associated with stimulation of the lung's enzymatic antioxidant defense system (superoxide dismutase, catalase, glutathione peroxidase, and glucose-6-phosphate dehydrogenase). Vitamin E-deficient animals are especially sensitive to hyperoxidant stresses, including pulmonary O2 toxicity. In these studies we tested whether endotoxin could reverse the increased susceptibility of vitamin E-deficient rats to hyperoxic challenge. We found that untreated vitamin E-deficient rats do succumb more readily to O2 toxicity [0/11 alive at 72 h in greater than 95% O2, lethal time for 50% of the animals (LT50) = 50 h] than rats fed a regular diet (4/14 alive, LT50 = 69 h). In contrast, 15 of 16 vitamin E-deficient rats treated with endotoxin survived the same O2 exposures (P less than 0.001) and showed significantly reduced pulmonary edema compared with the other groups. The endotoxin-treated vitamin E-deficient group was also the only one to demonstrate significant elevations of all the antioxidant enzymes during O2 exposure, suggesting that the antioxidant enzyme defenses of the lung have a more primary and important role in prevention of O2-induced lung injury than the lipid-associated antioxidant, vitamin E.


Melanin-covered nanoparticles for protection of bone marrow during radiation therapy of cancer.
Protection of bone marrow against radiotoxicity during radioimmunotherapy and in some cases external beam radiation therapy such as hemi-body irradiation would permit administration of significantly higher doses to tumors, resulting in increased efficacy and safety of treatment. Melanin, a naturally occurring pigment, possesses radioprotective properties. We hypothesized that melanin, which is insoluble, could be delivered to the bone marrow by intravenously administrated melanin-covered nanoparticles (MNs) because of the human body's "self-sieving" ability, protecting it against ionizing radiation. The synthesis of MNs was performed via enzymatic polymerization of 3,4-dihydroxyphenylalanine and/or 5-S-cysteinyl-3,4-dihydroxyphenylalanine on the surface of 20-nm plain silica nanoparticles. The biodistribution of radiolabeled MNs in mice was done at 3 and 24 h. Healthy CD-1 mice (Charles River Laboratories International, Inc., Wilmington, MA) or melanoma tumor-bearing nude mice were given MNs intravenously, 50 mg/kg of body weight, 3 h before either whole-body exposure to 125 cGy or treatment with 1 mCi of (188)Re-labeled 6D2 melanin-binding antibody. Polymerization of melanin precursors on the surface of silica nanoparticles resulted in formation of a 15-nm-thick melanin layer as confirmed by light scattering, transmission electron microscopy, and immunofluorescence. The biodistribution after intravenous administration showed than MN uptake in bone marrow was 0.3% and 0.2% of injected dose per gram at 3 and 24 h, respectively, whereas pre-injection with pluronic acid increased the uptake to 6% and 3% of injected dose per gram, respectively. Systemic MN administration reduced hematologic toxicity in mice treated with external radiation or radioimmunotherapy, whereas no tumor protection by MNs was observed. MNs or similar structures provide a novel approach to protection of bone marrow from ionizing radiation based on prevention of free radical formation by melanin.


Plasma signature of apoptotic microvesicles is associated with endothelial dysfunction and plaque rupture in acute coronary syndromes.
Circulating microvesicles (MV) are surrogate biomarkers of atherosclerosis. However, their role in acute coronary syndromes (ACS) has not been fully elucidated yet. We sought to examine the association of circulating apoptotic MVs with ACS pathophysiology. One hundred and fifty-three patients (n = 153) were included in the study; 49 patients with ST-elevation myocardial infarction (STEMI), 35 with non-STEMI (NSTEMI), 38 with unstable angina, 15 with stable coronary artery disease and 16 control individuals. Flow cytometry analysis was used to quantify circulating apoptotic/non-apoptotic (phospatidyloserine+/phospatidyloserine-) endothelial cell (EMV), red blood cell (RMV) and platelet (PMV) derived MV. Flow-mediated dilatation (FMD) of the brachial artery was assessed by ultrasound to estimate endothelial function. The inflammatory profile was assessed by serum C-reactive protein (hsCRP) levels. Apoptotic only (but not non-apoptotic) MV were increased in patients with ACS (EMV, P = 2.32 × 10-9; RMV, P = .0019; PMV, P = .01). Hierarchical clustering of the total population of ACS patients (n = 122) by circulating levels of phospatidyloserine+ EMV, RMV and PMV identified two discreet clusters of patients without any differences in traditional risk factors, but significant differences in brachial FMD (5.2% (2.5) vs. 4.1% (2.3), P < .05) that remained significant after adjustment for co-variates. The prevalence of STEMI, a surrogate for plaque rupture and vessel thrombotic occlusion, was significantly higher in the patient cluster with impaired endothelial function (60% vs 32%, P = .016, adjusted odds ratio for STEMI, 3.041, 95%CI, 1.160 to 7.968, p = .024). Our findings indicate that the circulating levels of apoptotic MV are increased in ACS patients and their plasma profiles associate with endothelial dysfunction and thrombotic complications in ACS patients.


Types of change strategies for limiting or reducing gambling behaviors and their perceived helpfulness: A factor analysis.
Gamblers engage with a broad range of resources and strategies to limit or reduce their gambling. However, there is limited research examining the uptake and helpfulness of the full range of strategies gamblers employ. The aim of this study was to compile a comprehensive inventory of change strategies and then group these using principal component analysis based on perceived helpfulness. We also aimed to determine whether there are differences in the helpfulness of strategies by demographic, gambling severity, and readiness indicators. The Change Strategies Questionnaire-Version 1 contained 99 strategies, and 489 gamblers (including 333 problem gamblers) identified the most frequently endorsed strategy as remind yourself of negative consequences of gambling (92%) and think about how money could be better spent (92%). Principal components analysis identified 15 strategy groupings: cognitive, well-being, consumption control, behavioral substitution, financial management, urge management, self-monitoring, information seeking, spiritual, avoidance, social support, exclusion, planning, feedback, and limit finances. There were differences in the helpfulness of strategies by age and gambling severity. Few strategies were correlated with confidence to manage an urge to gamble. Overall, change strategies were viewed as moderately helpful. The top five strategies were all used by at least 90% of gamblers, and these strategies were all cognitive in nature. This study provides important information for the development of interventions targeting gambling behavior. Furthermore, it suggests that interventions for problem gambling should target cognitive, feedback, planning, and urge management strategies. (PsycINFO Database Record


Etoposide Loaded SPION-PNIPAM Nanoparticles Improve the in vitro Therapeutic Outcome on Metastatic Prostate Cancer Cells via Enhanced Apoptosis.
Prostate cancer is among the leading causes of death worldwide because its metastatic form is a deadly disease. Therefore, the development of new chemotherapeutics is of immense importance. Nanoparticle technology seems to provide diverse options in this regard. Therefore, poly(N-isopropylacrylamide) (PNIPAM) coated superparamagnetic iron oxide nanoparticles (SPION) loaded with Etoposide were prepared in small sizes (57 nm) and with 3.5 % drug content to improve the efficiency of Etoposide in prostate cancer therapy. Sustained release of the drug was achieved, which found to be sensitive to low pH and high temperature. The anti-growth activity of SPION-PNIPAM-Etoposide formulation against metastatic prostate cancer cells (PC-3, LNCaP) were investigated by SRB assay, then, confirmed by ATP assay. Mode of cell death was evaluated by using flow cytometry analyses. A significant improvement of nanoformulated drug was observed at 5-10 μg/ml doses of the drug in both cell lines. More importantly, this formulation enhanced the cytotoxic effect of Etoposide on PC-3 cells, which is considered more resistant to Etoposide than LNCaP and reduced the IC50 value by 55 % reaching to 4.5 μg drug/ml, which is a very significant improvement in the literature. It was clearly shown that nanoformulated drug provided about 3-fold increases in caspase-dependent early apoptotic cells in PC-3 cells. The novel formulation seems to successfully cause cell death of especially PC-3 metastatic prostate cancer cells. It should therefore be taken into consideration for further animal studies as a novel potent anticancer agent.


Spectral broadening and temporal compression of ∼ 100 fs pulses in air-filled hollow core capillary fibers.
We experimentally study the spectral broadening of intense, ∼ 100 femtosecond laser pulses at 785 nm coupled into different kinds of hollow core capillary fibers, all filled with air at ambient pressure. Differently from observations in other gases, the spectra are broadened with a strong red-shift due to highly efficient intrapulse Raman scattering. Numerical simulations show that such spectra can be explained only by increasing the Raman fraction of the third order nonlinearity close to 100%. Experimentally, these broadened and red-shifted pulses do not generally allow for straightforward compression using, for example, standard chirped mirrors. However, using special hollow fibers that are internally coated with silver and polymer we obtain pulse durations in the sub-20 fs regime with energies up to 300 μJ.


Psychosis secondary to traumatic brain injury.
Traumatic brain injury (TBI) can result in serious and disabling neuropsychiatric disorders. The authors report a case of a 51-year old male, admitted to the psychiatric ward for acute psychosis and suicidal ideation, probably associated with TBI. After a temporal head trauma he initiated auditory/verbal hallucinations and subsequently developed paranoid delusions. The electroencephalography showed slow bilateral temporal activity and the neuropsychological testing showed several impairments. The patient improved with olanzapine at a dosage of 20 mg daily. This case shows the difficulty of differential diagnosis between schizophrenia and psychotic disorder due to traumatic brain injury. The authors conducted a revision of literature about the diagnosis, epidemiology, clinical aspects, laboratory and structural investigations and the treatment of this condition. Based on this revision work, the authors sketch some recommendations about the work-up that should be done when faced with this diagnostic hypothesis.


Breast cancer stage, surgery, and survival statistics for Idaho's National Breast and Cervical Cancer Early Detection Program population, 2004-2012.
The National Breast and Cervical Cancer Early Detection Program (NBCCEDP) provides access to breast and cervical cancer screening for low-income, uninsured, and underinsured women in all states and US territories. In Idaho, a rural state with very low breast and cervical cancer screening rates, this program is called Women's Health Check (WHC). The program has been operating continuously since 1997 and served 4,719 enrollees in 2013. The objective of this study was to assess whether disparities existed in cause-specific survival (a net survival measure representing survival of a specified cause of death in the absence of other causes of death) between women screened by WHC and outside WHC and to determine how type of surgery or survival varies with stage at diagnosis. WHC data were linked to Idaho's central cancer registry to compare stage distribution, type of surgery, and cause-specific survival between women with WHC-linked breast cancer and a comparison group of women whose records did not link to the WHC database (nonlinked breast cancer). WHC-linked breast cancer was significantly more likely to be diagnosed at a later stage of disease than nonlinked breast cancer. Because of differences in stage distribution between WHC-linked and nonlinked breast cancers, overall age-standardized, cause-specific breast cancer survival proportions diverged over time, with a 5.1 percentage-point deficit in survival among WHC-linked cases at 5 years of follow-up (83.9% vs 89.0%). Differences in type of surgery and cause-specific survival were attenuated when controlling for stage. This study suggests that disparities may exist for Idaho WHC enrollees in the timely diagnosis of breast cancer. To our knowledge, this is the first study to publish comparisons of cause-specific breast cancer survival between NBCCEDP-linked and nonlinked cases.


Stability of Mina v2 for Robot-Assisted Balance and Locomotion.
The assessment of the risk of falling during robot-assisted locomotion is critical for gait control and operator safety, but has not yet been addressed through a systematic and quantitative approach. In this study, the balance stability of Mina v2, a recently developed powered lower-limb robotic exoskeleton, is evaluated using an algorithmic framework based on center of mass (COM)- and joint-space dynamics. The equivalent mechanical model of the combined human-exoskeleton system in the sagittal plane is established and used for balance stability analysis. The properties of the Linear Linkage Actuator, which is custom-designed for Mina v2, are analyzed to obtain mathematical models of torque-velocity limits, and are implemented as constraint functions in the optimization formulation. For given feet configurations of the robotic exoskeleton during flat ground walking, the algorithm evaluates the maximum allowable COM velocity perturbations along the fore-aft directions at each COM position of the system. The resulting velocity extrema form the contact-specific balance stability boundaries (BSBs) of the combined system in the COM state space, which represent the thresholds between balanced and unbalanced states for given contact configurations. The BSBs are obtained for the operation of Mina v2 without crutches, thus quantifying Mina v2's capability of maintaining balance through the support of the leg(s). Stability boundaries in single and double leg supports are used to analyze the robot's stability performance during flat ground walking experiments, and provide design and control implications for future development of crutch-less robotic exoskeletons.


Physical theory of the orientation of astral mitotic spindles.
A physical theory was developed for mitotic spindle orientation. This is important because spindle position is known to determine the placement of the cleavage furrow separating the offspring of a mitosis. The theory is based on an equation for the force exerted on spindle poles by the interaction of astral microtubules with the cell surface. Expected spindle placements are positions of stable equilibrium where the net force and torque resulting from the action of the astral microtubules on the spindle poles is zero. The theory provides a novel physical explanation of cleavage patterns in the early embryo.


Cueing training in the home improves gait-related mobility in Parkinson's disease: the RESCUE trial.
Gait and mobility problems are difficult to treat in people with Parkinson's disease. The Rehabilitation in Parkinson's Disease: Strategies for Cueing (RESCUE) trial investigated the effects of a home physiotherapy programme based on rhythmical cueing on gait and gait-related activity. A single-blind randomised crossover trial was set up, including 153 patients with Parkinson's disease aged between 41 and 80 years and in Hoehn and Yahr stage II-IV. Subjects allocated to early intervention (n = 76) received a 3-week home cueing programme using a prototype cueing device, followed by 3 weeks without training. Patients allocated to late intervention (n = 77) underwent the same intervention and control period in reverse order. After the initial 6 weeks, both groups had a 6-week follow-up without training. Posture and gait scores (PG scores) measured at 3, 6 and 12 weeks by blinded testers were the primary outcome measure. Secondary outcomes included specific measures on gait, freezing and balance, functional activities, quality of life and carer strain. Small but significant improvements were found after intervention of 4.2% on the PG scores (p = 0.005). Severity of freezing was reduced by 5.5% in freezers only (p = 0.007). Gait speed (p = 0.005), step length (p<0.001) and timed balance tests (p = 0.003) improved in the full cohort. Other than a greater confidence to carry out functional activities (Falls Efficacy Scale, p = 0.04), no carry-over effects were observed in functional and quality of life domains. Effects of intervention had reduced considerably at 6-week follow-up. Cueing training in the home has specific effects on gait, freezing and balance. The decline in effectiveness of intervention effects underscores the need for permanent cueing devices and follow-up treatment. Cueing training may be a useful therapeutic adjunct to the overall management of gait disturbance in Parkinson's disease.


A comprehensive catalogue of somatic mutations from a human cancer genome.
All cancers carry somatic mutations. A subset of these somatic alterations, termed driver mutations, confer selective growth advantage and are implicated in cancer development, whereas the remainder are passengers. Here we have sequenced the genomes of a malignant melanoma and a lymphoblastoid cell line from the same person, providing the first comprehensive catalogue of somatic mutations from an individual cancer. The catalogue provides remarkable insights into the forces that have shaped this cancer genome. The dominant mutational signature reflects DNA damage due to ultraviolet light exposure, a known risk factor for malignant melanoma, whereas the uneven distribution of mutations across the genome, with a lower prevalence in gene footprints, indicates that DNA repair has been preferentially deployed towards transcribed regions. The results illustrate the power of a cancer genome sequence to reveal traces of the DNA damage, repair, mutation and selection processes that were operative years before the cancer became symptomatic.


Are venous thromboembolic events associated with subsequent breast and colorectal carcinoma diagnoses in the elderly? A case-control study of Medicare beneficiaries.
Multiple epidemiologic studies have reported associations between venous thromboembolic events and subsequent cancer diagnoses, but the published results have not suggested clear cancer screening approaches. Using data from the National Cancer Institute's Surveillance, Epidemiology, and End Results-Medicare Program, the authors identified patients who were diagnosed with breast and colorectal carcinoma (n = 7166 patients) and compared them with a noncancer control group (n = 126,668 patients) according to their history of hospitalization for deep vein thrombosis (DVT) or pulmonary embolism (PE) in Medicare claims files over the previous 24 months. Using logistic regression analysis, the authors calculated the odds of receiving a diagnosis of breast carcinoma or colorectal carcinoma in the 24 months after admission for DVT or PE. Patients who were hospitalized for DVT or PE had nearly 3.0 times the odds of being diagnosed with colorectal carcinoma (odds ratio [OR], 2.83; 95% confidence interval [95% CI], 1.92-4.17) and > 1.5 times the odds of being diagnosed with breast carcinoma (OR, 1.78; 95% CI, 1.05-3.02) in the subsequent 24 months. Because hospitalization for DVT or PE is associated with an increased risk of a breast or colorectal carcinoma diagnosis in the subsequent 2 years, physicians should be vigilant in assessing the cancer screening status of patients with new DVT and/or PE to be certain that they are up to date with recommended breast and colorectal screening guidelines.


Stochastic dynamics of genetic networks: modelling and parameter identification.
Identification of regulatory networks is typically based on deterministic models of gene expression. Increasing experimental evidence suggests that the gene regulation process is intrinsically random. To ensure accurate and thorough processing of the experimental data, stochasticity must be explicitly accounted for both at the modelling stage and in the design of the identification algorithms. We propose a model of gene expression in prokaryotes where transcription is described as a probabilistic event, whereas protein synthesis and degradation are captured by first-order deterministic kinetics. Based on this model and assuming that the network of interactions is known, a method for estimating unknown parameters, such as synthesis and binding rates, from the outcomes of multiple time-course experiments is introduced. The method accounts naturally for sparse, irregularly sampled and noisy data and is applicable to gene networks of arbitrary size. The performance of the method is evaluated on a model of nutrient stress response in Escherichia coli.


Effects of resveratrol on memory performance, hippocampus connectivity and microstructure in older adults - A randomized controlled trial.
The polyphenol resveratrol has been suggested to exert beneficial effects on memory and the aging hippocampus due to calorie-restriction mimicking effects. However, the evidence based on human interventional studies is scarce. We therefore aimed to determine the effects of resveratrol on memory performance, and to identify potential underlying mechanisms using a broad array of blood-based biomarkers as well as hippocampus connectivity and microstructure assessed with ultra-high field magnetic resonance imaging (UHF-MRI). In this double-blind, randomized controlled trial, 60 elderly participants (60-79 years) with a wide body-mass index (BMI) range of 21-37 kg/m2 were randomized to receive either resveratrol (200 mg/day) or placebo for 26 weeks (registered at ClinicalTrials.gov: NCT02621554). Baseline and follow-up assessments included the California Verbal Learning Task (CVLT, main outcome), the ModBent task, anthropometry, markers of glucose and lipid metabolism, inflammation and neurotrophins derived from fasting blood, multimodal neuroimaging at 3 and 7 T, and questionnaires to assess confounding factors. Multivariate repeated-measures ANOVA did not detect significant time by group effects for CVLT performance. There was a trend for preserved pattern recognition memory after resveratrol, while performance decreased in the placebo group (n.s., p = 0.07). Further exploratory analyses showed increases in both groups over time in body fat, cholesterol, fasting glucose, interleukin 6, high sensitive C-reactive protein, tumor necrosis factor alpha and in mean diffusivity of the subiculum and presubiculum, as well as decreases in physical activity, brain-derived neurotrophic factor and insulin-like growth factor 1 at follow-up, which were partly more pronounced after resveratrol. This interventional study failed to show significant improvements in verbal memory after 6 months of resveratrol in healthy elderly with a wide BMI range. A non-significant trend emerged for positive effects on pattern recognition memory, while possible confounding effects of unfavorable changes in lifestyle behavior, neurotrophins and inflammatory markers occurred. Our findings also indicate the feasibility to detect (un)healthy aging-related changes in measures of hippocampus microstructure after 6 months using 7T diffusion MRI. More studies incorporating a longer duration and larger sample size are needed to determine if resveratrol enhances memory performance in healthy older adults.


Daily fluid turnover during preseason training in U.S. college football.
The authors measured 24-h fluid-turnover (FTO) rate during 6 d of preseason training in U.S. college football players. Players, training (T, n = 9, full gear and contact drills) and reference (R, n = 4, conditioning without gear or contact), ingested a deuterium oxide (D(2)O) dose and provided urine samples every 24 h for analysis of D(2)O. During one approximately 2.3-h practice (wet-bulb globe temperature 24.6 degrees C), body-mass change, urine production, and voluntary fluid intake were measured to calculate gross sweat loss (GSL). Average FTO was 10.3 +/- 2.2 L/d for T and 7.0 +/- 1.0 L/d for R. GSL was 3.4 +/- 1.5 L for T and 1.7 +/- 1.3 for R (P > 0.05). By Day 6, body mass decreased significantly in T (-2.4 +/- 1.3 kg, P < 0.05) but not in R (0.38 +/- 0.95 kg). With preseason training under moderate environmental stress, football players had high FTO and sweat rates, which might have contributed to a loss of body mass during preseason football training.


Lexical learning and lexical processing in children with developmental language impairments.
Lexical skills are a crucial component of language comprehension and production. This paper reviews evidence for lexical-level deficits in children and young people with developmental language impairment (LI). Across a range of tasks, LI is associated with reduced vocabulary knowledge in terms of both breadth and depth and difficulty with learning and retaining new words; evidence is emerging from on-line tasks to suggest that low levels of language skill are associated with differences in lexical competition in spoken word recognition. The role of lexical deficits in understanding the nature of LI is also discussed.


Engaging health systems to increase colorectal cancer screening: community-clinical outreach in underserved areas of Wisconsin.
Colorectal cancer is the fourth most commonly diagnosed cancer and the second leading cause of cancer-related death in Wisconsin. Incidence and mortality rates for colorectal cancer vary by age, race/ethnicity, geography, and socioeconomic status. From 2010 through 2012, the Wisconsin Comprehensive Cancer Control Program awarded grants to 5 regional health systems for the purpose of planning and implementing events to increase colorectal cancer screening rates in underserved communities. Grantees were chosen for their ability to engage community partners in reaching underserved groups including African American, Hispanic/Latino, Hmong, rural, and uninsured populations in their service areas. Grantees identified target populations for proposed screening events, designated institutional planning teams, engaged appropriate local partner organizations, and created plans for follow-up. All grantees implemented 1 or more colorectal cancer screening events within 6 months of receiving their awards. Events were conducted in 2 phases. Participating health systems organized 36 screening events and distributed 633 individual test kits; 506 kits were returned, of which 57 (9%) tested positive for colorectal abnormalities. Of attendees who received screening, 63% were uninsured or underinsured, 55% had no previous screening, 46% were of a racial/ethnic minority group, 22% had a family history of cancer, and 13% were rural residents. This project strengthened partnerships between health systems and local organizations. An effective strategy for improving colorectal cancer screening rates, particularly among underserved populations, is to award health systems grants for implementing community-based screening events in conjunction with community partners.


Autophagic processes increase during senescence in cultured sheep neurons and astrocytes.
A possible response to aging is autophagy, a self-digestion process in which portions of cytoplasm are encapsulated by double-membrane-bound structures and delivered to lysosome for degradation. A previous work of our group showed that astrocytes under starving conditions are characterized by a higher upregulation of the marker of autophagy LC3 II than neurons. Aim of the present work was to evaluate LC3 II expression in an aging model consisting in fetal sheep neurons and astrocytes at 10, 20 and 30 days of culture. Such model has been validated by a remarkable activity of β-galactosidase, commonly used to reveal cell aging. LC3 II immunoreactivity in neurons and astrocytes progressively increased with time but differences were observed on the basis of cell density. Indeed, LC3 II immunoreactivity is higher in clusters of neurons and astrocytes and this may be due to the fact that cell-cell contact would represent a second stress in addition to aging itself. Both cell types displayed a reduction in LC3 II signal in nuclei, and a corresponding strengthening in the cytoplasm with time. This may be due to the need of aged cells to remove damaged cytoplasmic components through autophagic processes. Such variation in LC3 II localization could be caused by migration from the nucleus to cytoplasm as well as possible de novo intracytoplasmic production. The present work based on sheep neural cells in vitro may represent a helpful tool in the studies on aging processes in which autophagy plays a remarkable role.


[Type III procollagen N-peptide and hyaluronate in serum and dialysate of CAPD patients].
Long-term CAPD may develop peritoneal fibrosis, which is thought to be related to permanent loss of ultrafiltration capacity and sclerosing peritonitis. In CAPD patients, we examined the serum (P-) and effluent (D-) levels of type III procollagen N-peptide (P III P) and hyaluronate (HA), which are expected to change concomitantly with a local increase in submesothelial extracellular matrix of the peritoneum. We selected 40 CAPD patients (age: 46.3 +/- 11.3 years, time on CAPD: 33.6 +/- 26.2 months), who were not suffering from chronic liver disease, any inflammatory disease, nor peritonitis during the previous month. P-P III P, P-HA, D-P III P, and D-HA were measured by PET (values after 4-hour dwelling). D/P ratios (P III P 0.330 +/- 0.137, HA 5.68 +/- 6.44) suggested that their source was from the peritoneum. Although neither P-P III P nor log P-HA value had a significant correlation with age nor time on CAPD, both had significantly positive correlations (p = 0.0009, 0.0005, respectively) with time on total dialysis (including hemodialysis). D-P III P did not have a significant correlation with age nor time on total dialysis but had a significantly positive correlation (p = 0.0098) with D/P-creatinine. Although log D-HA had significantly positive correlations with time on CAPD and time on total dialysis (p = 0.0007, 0.0051, respectively), time on CAPD was first entered (F = 16.5) and time on total dialysis was removed (F to enter: 4) by stepwise regression analysis. In conclusion, a local increase in extracellular matrix of the peritoneum in CAPD patients, indicated by increases in P III P and HA in the effluent, may be related to higher peritoneal permeability and a longer duration of PD.


Ratiometric fluorescent pH-sensitive polymers for high-throughput monitoring of extracellular pH.
Extracellular pH has a strong effect on cell metabolism and growth. Precisely detecting extracellular pH with high throughput is critical for cell metabolism research and fermentation applications. In this research, a series of ratiometric fluorescent pH sensitive polymers are developed and the ps-pH-neutral is characterized as the best one for exculsive detection of extracellular pH. Poly(N-(2-hydroxypropyl)methacrylamide) (PHPMA) is used as the host polymer to increase the water solubility of the pH sensitive polymer without introducing cell toxicity. The fluorescent emission spectra from the polymeric sensor under excitation at the isosbestic point 455 nm possess two fluorescence peaks at 475 nm and 505 nm, which have different responding trends to pH. This enables the polymer to detect pH using fluorescent maxima at 475 nm and 505 nm (I475nm /I505nm ) ratiometrically. The cell impermeability ensures the sensor can solely detect the environmental pH. The sensor is tested to detect the extracellular pH of bacteria or eukaryotic cells in high throughput assays using a microplate reader. Results showed that the pH sensor can be used for high throughput detection of extracellular pH with high repeatability and low photobleaching effect.


Recombinant human betacellulin promotes the neogenesis of beta-cells and ameliorates glucose intolerance in mice with diabetes induced by selective alloxan perfusion.
Betacellulin (BTC), a member of the epidermal growth factor family, is expressed predominantly in the human pancreas and induces the differentiation of a pancreatic acinar cell line (AR42J) into insulin-secreting cells, suggesting that BTC has a physiologically important role in the endocrine pancreas. In this study, we examined the in vivo effect of recombinant human BTC (rhBTC) on glucose intolerance and pancreatic morphology using a new mouse model with glucose intolerance induced by selective alloxan perfusion. RhBTC (1 microg/g body wt) or saline was injected subcutaneously every day from the day after alloxan treatment. The intraperitoneal glucose tolerance test revealed no difference between rhBTC-treated and rhBTC-untreated glucose-intolerant mice at 2-4 weeks. However, glucose tolerance was significantly improved and body weight was significantly increased in rhBTC-treated mice compared with untreated mice at 8 weeks. Islet-like cell clusters, consisting mainly of beta-cells, were increased in the pancreas and were localized in contact with the ductal lining cells and sometimes with acinar cells. In conclusion, administration of rhBTC improved glucose tolerance in this mouse model by increasing beta-cell volume, primarily through accelerated neogenesis from ductal lining cells.