Association of Multiple Biomarkers of Iron Metabolism and Type 2 Diabetes: The EPIC-InterAct Study.
Observational studies show an association between ferritin and type 2 diabetes (T2D), suggesting a role of high iron stores in T2D development. However, ferritin is influenced by factors other than iron stores, which is less the case for other biomarkers of iron metabolism. We investigated associations of ferritin, transferrin saturation (TSAT), serum iron, and transferrin with T2D incidence to clarify the role of iron in the pathogenesis of T2D. The European Prospective Investigation into Cancer and Nutrition-InterAct study includes 12,403 incident T2D cases and a representative subcohort of 16,154 individuals from a European cohort with 3.99 million person-years of follow-up. We studied the prospective association of ferritin, TSAT, serum iron, and transferrin with incident T2D in 11,052 cases and a random subcohort of 15,182 individuals and assessed whether these associations differed by subgroups of the population. Higher levels of ferritin and transferrin were associated with a higher risk of T2D (hazard ratio [HR] [95% CI] in men and women, respectively: 1.07 [1.01-1.12] and 1.12 [1.05-1.19] per 100 μg/L higher ferritin level; 1.11 [1.00-1.24] and 1.22 [1.12-1.33] per 0.5 g/L higher transferrin level) after adjustment for age, center, BMI, physical activity, smoking status, education, hs-CRP, alanine aminotransferase, and γ-glutamyl transferase. Elevated TSAT (≥45% vs. <45%) was associated with a lower risk of T2D in women (0.68 [0.54-0.86]) but was not statistically significantly associated in men (0.90 [0.75-1.08]). Serum iron was not associated with T2D. The association of ferritin with T2D was stronger among leaner individuals (Pinteraction < 0.01). The pattern of association of TSAT and transferrin with T2D suggests that the underlying relationship between iron stores and T2D is more complex than the simple link suggested by the association of ferritin with T2D.


Prevalence of heart failure in three general practices in north west London.
There is little recent information on the prevalence of heart failure in the United Kingdom. Assuming that patients with heart failure would be taking diuretic drugs all such patients were identified in three general practices in north west London. The practice records of these patients were examined to determine which patients had heart failure. Of the 30,204 patients served by the practices, 117 had heart failure, a prevalence of 3.9 per 1000 patients. The mean age of these patients was 74 years. The prevalence of heart failure among patients under 65 years of age was 0.6 per 1000 patients rising to 27.7 per 1000 among those aged 65 years and over. The aetiology of heart failure was considered to be coronary heart disease for 32% of patients, valve disease for 19%, hypertension for 6%, cor pulmonale for 4% and congenital heart disease for 2%. The aetiology for the remaining 37% of patients was unknown. Most patients were referred to hospital and only 20% had been treated solely by the general practitioner. An electrocardiogram and chest radiograph had been obtained for over 80% of patients but only 28% had an echocardiogram. Heart failure occurs primarily in elderly patients, and coronary heart disease is the dominant aetiological factor.


Development and validation of the self-management profile for type 2 diabetes (SMP-T2D).
This study evaluated the measurement properties of a newly developed instrument - the Self-Management Profile for Type 2 Diabetes (SMP-T2D). The 18-item SMP-T2D assesses 12 constructs: level and perceived ease of performance in five self-care domains (blood glucose monitoring, medication-taking, healthy eating, being physically active, and coping), and two global constructs (ease of weight management, confidence with ability to manage diabetes). Validation analyses were based on two studies involving 240 patients with T2D, Study 1 (Clinicaltrials.gov #NCT00637273) with SMP-T2D administration supplemented by SMP-T2D retest one week later, and Study 2 (Clinical trials.gov #NCT00877890) with SMP-T2D administration supplemented by 24-week SMP-T2D follow-up after medication change. Validation included clinical indicators and measures of patient reported quality of life, psychological well-being and treatment outcomes. All multi-item SMP-T2D measures showed acceptable internal consistency (alphas = 0.71 to 0.87); ten measures had test-retest reliability >0.75. Correlations among SMP-T2D measures and between SMP-T2D measures and validation measures, which were as hypothesized, provided evidence of convergent and discriminant validity. Scores for six SMP-T2D measures improved significantly during Study 2. Multiple regression analysis showed independent associations between change in SMP-T2D measures and change in trial outcomes from baseline to end-of-study. Two studies provide preliminary evidence regarding the reliability, validity and responsiveness of the SMP-T2D. Further research on the utility of the instrument is needed.


Abortion training in obstetrics and gynecology residency programs in the United States, 1991-1992.
According to a 1991-1992 survey of program directors of obstetrics and gynecology residency programs in the United States, the overall percentage of programs providing any training in first-trimester (70%) or second-trimester abortion (66%) has changed very little since 1985. However, the proportion of programs providing routine training in first-trimester abortion decreased from 23% in 1985 to 12% in 1991-1992, and the proportion providing routine training in second-trimester abortion declined from 21% to 7%. The majority of the programs that dropped routine abortion training continued to offer optional training, but residents in programs with optional training were less likely to receive training. More than 80% of programs in private, non-Catholic hospitals and public hospitals provided some form of abortion training in 1991-1992, but only 6% of programs in Catholic hospitals and no military programs did so. In 45% of programs offering abortion training, residents performed one or fewer abortions per week.


Infected puncture wounds in adults with diabetes: risk factors for osteomyelitis.
The purpose of this study was to investigate factors that contribute to the development of osteomyelitis of the foot after a puncture wound in patients with diabetes. Forty-five male and 21 female adults with diabetes that were admitted to the hospital for a foot infection precipitated by a puncture were included in the study. Twenty-two (33%) patients had osteomyelitis (O) based on either a positive bone culture or pathology report. Forty-four patients had soft tissue infections (ST). Age and duration of diabetes were similar in both groups. Patients with osteomyelitis received medical treatment later than patients with soft tissue infections. A significant difference was identified when comparing the time interval from the time of the injury until patients were hospitalized and until they had the puncture wound surgically debrided, and when comparing the interval from when patients first received initial professional medical evaluation until they were hospitalized and until they had the puncture wound surgically debrided. Patients with punctures involving the forefoot (FF) and patients that wore shoes (S) at the time of the injury were more likely to develop osteomyelitis than patients that had rearfoot (RF) injuries O: FF = 20, 90%, RF = 2, 10%, ST: FF = 30, 70%, RF = 13, 30%, p < 0.05) and patients that were barefoot (B) at the time of injury (O: S = 15, 88%, B = 2, 12%, ST: S = 21, 57%, B = 16, 43%, p < 0.05). Osteomyelitis is a common complication in patients with diabetes with a foot infection following a puncture wound.(ABSTRACT TRUNCATED AT 250 WORDS)


Activation of large ions in FT-ICR mass spectrometry.
The advent of soft ionization techniques, notably electrospray and laser desorption ionization methods, has enabled the extension of mass spectrometric methods to large molecules and molecular complexes. This both greatly extends the applications of mass spectrometry and makes the activation and dissociation of complex ions an integral part of these applications. This review emphasizes the most promising methods for activation and dissociation of complex ions and presents this discussion in the context of general knowledge of reaction kinetics and dynamics largely established for small ions. We then introduce the characteristic differences associated with the higher number of internal degrees of freedom and high density of states associated with molecular complexity. This is reflected primarily in the kinetics of unimolecular dissociation of complex ions, particularly their slow decay and the higher energy content required to induce decomposition--the kinetic shift (KS). The longer trapping time of Fourier transform ion cyclotron resonance mass spectrometry (FT-ICR MS) significantly reduces the KS, which presents several advantages over other methods for the investigation of dissociation of complex molecules. After discussing general principles of reaction dynamics related to collisional activation of ions, we describe conventional ways to achieve single- and multiple-collision activation in FT-ICR MS. Sustained off-resonance irradiation (SORI)--the simplest and most robust means of introducing the multiple collision activation process--is discussed in greatest detail. Details of implementation of this technique, required control of experimental parameters, limitations, and examples of very successful application of SORI-CID are described. The advantages of high mass resolving power and the ability to carry out several stages of mass selection and activation intrinsic to FT-ICR MS are demonstrated in several examples. Photodissociation of ions from small molecules can be effected using IR or UV/vis lasers and generally requires tuning lasers to specific wavelengths and/or utilizing high flux, multiphoton excitation to match energy levels in the ion. Photodissociation of complex ions is much easier to accomplish from the basic physics perspective. The quasi-continuum of vibrational states at room temperature makes it very easy to pump relatively large amounts of energy into complex ions and infrared multiphoton dissociation (IRMPD) is a powerful technique for characterizing large ions, particularly biologically relevant molecules. Since both SORI-CID and IRMPD are slow activation methods they have many common characteristics. They are also distinctly different because SORI-CID is intrinsically selective (only ions that have a cyclotron frequency close to the frequency of the excitation field are excited), whereas IRMPD is not (all ions that reside on the optical path of the laser are excited). There are advantages and disadvantages to each technique and in many applications they complement each other. In contrast with these slow activation methods, the less widely appreciated activation method of surface induced dissociation (SID) appears to offer unique advantages because excitation in SID occurs on a sub-picosecond time scale, instantaneously relative to the observation time of any mass spectrometer. Internal energy deposition is quite efficient and readily adjusted by altering the kinetic energy of the impacting ion. The shattering transition--instantaneous decomposition of the ion on the surface--observed at high collision energies enables access to dissociation channels that are not accessible using SORI-CID or IRMPD. Finally, we discuss some approaches for tailoring the surface to achieve particular aims in SID.


On-line classification of US Select beef carcasses for longissimus tenderness using visible and near-infrared reflectance spectroscopy.
The current experiment was conducted to evaluate the on-line application of visible and near-infrared spectroscopy (VISNIR) to US Select carcasses during commercial beef carcass grading procedures to predict tenderness of longissimus steaks after 14 days of refrigerated storage. A regression model was calibrated using 146 carcasses and tested against an additional 146 carcasses. Carcasses were segregated into VISNIR-based tenderness classes based on whether their VISNIR-predicted slice shear force value was less than (tender) or greater than (tough) the median predicted slice shear force value. Carcasses classified as tender by VISNIR had a lower mean SSF value, were less likely to have slice shear force values greater than 245 N, had higher trained sensory panel tenderness ratings, and were less likely to have trained sensory panel tenderness ratings below slightly tender than were carcasses classified as tough (P<0.001). This technology might be useful for identification of US Select carcasses that excel in longissimus tenderness.


The protective role of coastal marshes: a systematic review and meta-analysis.
Salt marshes lie between many human communities and the coast and have been presumed to protect these communities from coastal hazards by providing important ecosystem services. However, previous characterizations of these ecosystem services have typically been based on a small number of historical studies, and the consistency and extent to which marshes provide these services has not been investigated. Here, we review the current evidence for the specific processes of wave attenuation, shoreline stabilization and floodwater attenuation to determine if and under what conditions salt marshes offer these coastal protection services. We conducted a thorough search and synthesis of the literature with reference to these processes. Seventy-five publications met our selection criteria, and we conducted meta-analyses for publications with sufficient data available for quantitative analysis. We found that combined across all studies (n = 7), salt marsh vegetation had a significant positive effect on wave attenuation as measured by reductions in wave height per unit distance across marsh vegetation. Salt marsh vegetation also had a significant positive effect on shoreline stabilization as measured by accretion, lateral erosion reduction, and marsh surface elevation change (n = 30). Salt marsh characteristics that were positively correlated to both wave attenuation and shoreline stabilization were vegetation density, biomass production, and marsh size. Although we could not find studies quantitatively evaluating floodwater attenuation within salt marshes, there are several studies noting the negative effects of wetland alteration on water quantity regulation within coastal areas. Our results show that salt marshes have value for coastal hazard mitigation and climate change adaptation. Because we do not yet fully understand the magnitude of this value, we propose that decision makers employ natural systems to maximize the benefits and ecosystem services provided by salt marshes and exercise caution when making decisions that erode these services.


Evidence of bad recycling practices: BFRs in children's toys and food-contact articles.
Brominated flame retardants (BFRs) have been used intentionally in a wide range of plastics, but are now found in an even wider range of such materials (including children's toys and food contact articles) as a result of recycling practices that mix BFR-containing waste plastics with "virgin" materials. In this study Br was quantified in toy and food contact samples on the assumption that its concentration can be used as a metric for BFR contamination. Subsequently, compound specific determination of BFRs was performed to evaluate the validity of the aforementioned assumption, crucial to render rapid, inexpensive, in situ Br determination in non-laboratory environments (such as waste handling facilities) a viable option for sorting wastes according to their BFR content. We report semi-quantitative compound specific BFR concentrations to give an overview of the distribution of individual BFRs in the analyzed samples. Finally, we evaluated the correlations between waste electrical and electronic equipment (WEEE) related substances (Ca, Sb and rare earth elements (REEs)) and Br as a proxy for identifying poor sorting practices in different waste streams. 26 samples of toys, food-contact articles and WEEE were analyzed with a suite of different techniques in order to obtain comprehensive information about their elemental and molecular composition. The information obtained from principal component analysis about WEEE-related compounds provides new insights into the influence of sorting practices on the extent of products' contamination and bringing out polymer-related trends in the pollutants' signature. 61% of all samples were Br positive: of these samples, 45% had decaBDE concentrations exceeding the concentration limits for PBDEs and their main constituent polymer was - according to the REE signature of such samples - Acrylonitrile Butadiene Styrene (ABS), uses of which include copying equipment, laptops and computers. The ability to better track chemicals of concern and their trends in products is the main requirement for high-level management and control of material cycles to become non-toxic in the future as proposed in the EU's 7th Environmental Action Plan.


Safety of thimerosal-containing vaccines: a two-phased study of computerized health maintenance organization databases.
To assess the possible toxicity of thimerosal-containing vaccines (TCVs) among infants. A 2-phased retrospective cohort study was conducted using computerized health maintenance organization (HMO) databases. Phase I screened for associations between neurodevelopmental disorders and thimerosal exposure among 124 170 infants who were born during 1992 to 1999 at 2 HMOs (A and B). In phase II, the most common disorders associated with exposure in phase I were reevaluated among 16 717 children who were born during 1991 to 1997 in another HMO (C). Relative risks for neurodevelopmental disorders were calculated per increase of 12.5 micro g of estimated cumulative mercury exposure from TCVs in the first, third, and seventh months of life. In phase I at HMO A, cumulative exposure at 3 months resulted in a significant positive association with tics (relative risk [RR]: 1.89; 95% confidence interval [CI]: 1.05-3.38). At HMO B, increased risks of language delay were found for cumulative exposure at 3 months (RR: 1.13; 95% CI: 1.01-1.27) and 7 months (RR: 1.07; 95% CI: 1.01-1.13). In phase II at HMO C, no significant associations were found. In no analyses were significant increased risks found for autism or attention-deficit disorder. No consistent significant associations were found between TCVs and neurodevelopmental outcomes. Conflicting results were found at different HMOs for certain outcomes. For resolving the conflicting findings, studies with uniform neurodevelopmental assessments of children with a range of cumulative thimerosal exposures are needed.


A library of protein surface patches discriminates between native structures and decoys generated by structure prediction servers.
Protein surfaces serve as an interface with the molecular environment and are thus tightly bound to protein function. On the surface, geometric and chemical complementarity to other molecules provides interaction specificity for ligand binding, docking of bio-macromolecules, and enzymatic catalysis.As of today, there is no accepted general scheme to represent protein surfaces. Furthermore, most of the research on protein surface focuses on regions of specific interest such as interaction, ligand binding, and docking sites. We present a first step toward a general purpose representation of protein surfaces: a novel surface patch library that represents most surface patches (~98%) in a data set regardless of their functional roles. Surface patches, in this work, are small fractions of the protein surface. Using a measure of inter-patch distance, we clustered patches extracted from a data set of high quality, non-redundant, proteins. The surface patch library is the collection of all the cluster centroids; thus, each of the data set patches is close to one of the elements in the library.We demonstrate the biological significance of our method through the ability of the library to capture surface characteristics of native protein structures as opposed to those of decoy sets generated by state-of-the-art protein structure prediction methods. The patches of the decoys are significantly less compatible with the library than their corresponding native structures, allowing us to reliably distinguish native models from models generated by servers. This trend, however, does not extend to the decoys themselves, as their similarity to the native structures does not correlate with compatibility with the library. We expect that this high-quality, generic surface patch library will add a new perspective to the description of protein structures and improve our ability to predict them. In particular, we expect that it will help improve the prediction of surface features that are apparently neglected by current techniques.The surface patch libraries are publicly available at http://www.cs.bgu.ac.il/~keasar/patchLibrary.


Viral co-infections and paraproteins in HIV: effect on development of hematological malignancies.
The role of viral co-infections and paraproteins in the development of hematological malignancies (HMs) in HIV remains unclear. Using our large database of HIV+ patients, we investigated whether co-infection and paraproteinemia increase the risk of HM. Data on demographics, hepatitis B (HBV) and hepatitis C virus (HCV) co-infections, paraproteinemia, HIV characteristics, and biopsy proven malignant hematological disorders for HIV+ patients were collected over a 10-year period in a large urban hospital setting. We identified 10,293 HIV+ patients who were followed for a median duration of 53 months. Of the 10,293 patients with HIV, 229 (2.2 %) were diagnosed with a HM. Over 85 % of patients in both groups were tested; no significant difference in the prevalence of chronic HBV or HCV was noted between the HM positive (n = 229) and HM negative (n = 9992) patients. The serum protein electrophoresis test was performed for 1371 of the 10,221 patients. HM positive patients, compared to HM negative, were more likely to be tested for paraproteins (OR 3.3, 95 % CI 2.5-4.4) and more likely to have a discrete paraprotein band (OR 3.3, 95 % CI 1.2-8.9). Discrete paraproteins exclusively correlated with the development of plasma cell malignancies. Faint or oligoclonal protein bands were seen in high grade B cell lymphomas but did not show a significant correlation with HM development. Chronic hepatitis B or C infections did not correlate with the development of HM in HIV; however, viral influence on host gene transformation may have been impacted by anti-viral therapy limiting the duration of high viremic states.


Correctable visual impairment in an elderly Chinese population in Taiwan: the Shihpai Eye Study.
To investigate the prevalence and risk factors of correctable visual impairment and the quality of life of persons with correctable visual impairment in a metropolitan senior population. The study was a community-based, cross-sectional survey of vision and eye diseases among noninstitutionalized subjects aged 65 years and older in the Shihpai community of Taipei, Taiwan. The study consisted of a structured questionnaire followed by a comprehensive standardized ophthalmic examination included presenting and best corrected visual acuity, tonometry, slit lamp biomicroscopy, and direct and indirect ophthalmoscopy. A total of 1361 subjects (response rate, 66.6%) participated in both completion of the questionnaire and ophthalmic examination. The prevalence of correctable visual impairment (presenting visual acuity in the better eye <6/12 that improved to no impairment [>/=6/12] after refractive correction) was 9.55% (95% confidence interval [CI], 7.97%-11.13%). Under multiple logistic regression analysis, older age (>/=75 years; odds ratio [OR], 2.41; 95% CI, 1.56-3.70) and nonemmetropic eyes (myopia; OR, 6.80; 95% CI, 3.77-12.77 vs. hyperopia; OR, 2.13; 95% CI, 1.29-3.51) were significantly related to correctable visual impairment. A higher level of education (OR, 0.52; 95% CI, 0.32-0.83) and wearing distance eyeglasses during the eye examination (OR, 0.23; 95% CI, 0.12-0.43) were protective factors for correctable visual impairment. Subjects with correctable visual impairment scored significantly lower in the physical functioning dimension of the SF-36 questionnaire (P < 0.001). The results demonstrate that approximately 10% of the senior population in the Shihpai district has a correctable visual impairment. Thus, it is important to educate the public about the importance of regular examination and the possibility of improving visual acuity by wearing glasses.


Photoredox-catalyzed oxytrifluoromethylation of allenes: stereoselective synthesis of 2-trifluoromethylated allyl acetates.
We have developed novel oxytrifluoromethylation of aryl-substituted allenes by photoredox catalysis. The present photocatalytic system allows direct and stereoselective synthesis of 2-CF3-allyl acetates bearing tetrasubstituted CF3-alkene scaffolds in a single operation. The obtained CF3-allyl acetates can be applied to further functionalization as CF3-containing building blocks.


Do college students drink more than they think? Use of a free-pour paradigm to determine how college students define standard drinks.
Much of what is known about college drinking comes from self-report survey data. Such surveys typically ask students to indicate how many drinks they consume within a given period of time. It is currently unclear whether college students and researchers use similar operational definitions of a single drink. This information is critical given the widespread reliance on survey data for assessing the correlates and consequences of college drinking. This study investigated whether college students define standard drink volumes in a way that is consistent with the operational definitions commonly used by researchers. Students (n = 106) were administered an alcohol survey and then asked to perform three tasks. The tasks involved free-pouring fluid into empty cups of different sizes and estimating the volume of a single beer, a shot of liquor, or the amount of liquor in a mixed drink. The volumes poured by students then were compared with standards used in a well-known nationwide survey (i.e., 12 oz of beer and 1.25 oz of liquor in a shot or mixed drink). In every cup size of every task, students overestimated how much fluid they should pour to create a standard drink. In all three tasks, the magnitude of the discrepancy increased with cup size. Collapsed across cup sizes, students overpoured shots by 26%, mixed drinks by 80%, and beer by 25%. When a more liberal serving size of liquor (1.5 oz) was used as the standard, the results of the mixed drink task remained unchanged. However, the volumes poured by students during the shot free-pour task differed from the standard in only one cup size. The data suggest that college students drink more alcohol than indicated by their survey responses, raising questions about the validity of widely used alcohol surveys. Efforts to educate students about the alcohol content of standard drinks should be enhanced.


Efficacy of a Brief Tobacco Intervention for Tobacco and Nicotine Containing Product Use in the US Air Force.
While effective Brief Tobacco Interventions (BTIs) are available for cigarette smoking and smokeless tobacco, given the changing prevalence of tobacco and nicotine containing products (TNCPs), there is a need for interventions targeting a broader range of TNCPs (eg, cigarettes, smokeless tobacco, electronic cigarettes, and hookah). The purpose of the current investigation was to evaluate the efficacy of a BTI, a 40-minute intervention designed to intervene on four TNCPs in a sample of US military personnel during an 11-week period of involuntary tobacco abstinence, for reducing intentions to use TNCPs and increasing perceptions of harm of TNCPs. The BTI was administered to 1055 Airmen enrolled in Technical Training in the US Air Force. Assessments of perceived harm and intentions to use nine TNCPs (cigarettes, smokeless tobacco, snus, cigars, cigarillos, pipe, e-cigarettes, roll your own cigarettes, and hookah), were assessed at pretest and posttest (immediately following the BTI). Significant increases in perceived harm were observed across all nine TNCPs (all P < .0001) for both users and nonusers. Intentions to use TNCPs were significantly reduced for most products but mainly among users. Results suggested that a BTI shows promise for impacting TNCP use in a military population. Further research should evaluate the behavioral outcomes (tobacco use) as a result of the intervention. Given that there are 220 000 new trainees in the military every year, the public health implications of an effective BTI targeting the most commonly used TNCPs for military trainees is considerable.


BiDots: Visual Exploration of Weighted Biclusters.
Discovering and analyzing biclusters, i.e., two sets of related entities with close relationships, is a critical task in many real-world applications, such as exploring entity co-occurrences in intelligence analysis, and studying gene expression in bio-informatics. While the output of biclustering techniques can offer some initial low-level insights, visual approaches are required on top of that due to the algorithmic output complexity. This paper proposes a visualization technique, called BiDots, that allows analysts to interactively explore biclusters over multiple domains. BiDots overcomes several limitations of existing bicluster visualizations by encoding biclusters in a more compact and cluster-driven manner. A set of handy interactions is incorporated to support flexible analysis of biclustering results. More importantly, BiDots addresses the cases of weighted biclusters, which has been underexploited in the literature. The design of BiDots is grounded by a set of analytical tasks derived from previous work. We demonstrate its usefulness and effectiveness for exploring computed biclusters with an investigative document analysis task, in which suspicious people and activities are identified from a text corpus.


An emerging mobile air pollution source: outdoor plastic liner manufacturing sites discharge VOCs into urban and rural areas.
The in situ manufacture of cured-in-place-pipe (CIPP) plastic liners in damaged sewer pipes is an emerging mobile source of anthropogenic air pollution. Evidence indicates volatile organic compounds (VOCs) can be released before, during, and after manufacture. The chemical composition of a popular uncured styrene-based CIPP resin was examined, along with the VOCs that remained in the new cured composite. The roles of curing temperature and heating time in waste discharged into the air were examined. Uncured resin contained approximately 39 wt% VOCs. Multiple hazardous air pollutants were present, however, 61 wt% of the uncured resin was not chemically identified. A substantial mass of VOCs (8.87 wt%) was emitted into the air during manufacture, and all cured composites contained about 3 wt% VOCs. Some VOCs were created during manufacture. Curing temperature (65.5-93.3 °C) and heating time (25-100 min) did not cause different composite VOC loadings. High styrene air concentrations inhibited the detection of other VOCs in air. It is estimated that tens of tons of VOCs may be emitted at a single CIPP manufacturing site. Regulators should consider monitoring, and potentially regulating, these growing mobile air pollution and volatile chemical product sources as they are operating in urban and rural areas often in close proximity to residential and commercial buildings.


Global sensitivity analysis of the regional atmospheric chemical mechanism: an application of random sampling-high dimensional model representation to urban oxidation chemistry.
Chemical mechanisms play a crucial part for the air quality modeling and pollution control decision-making. Parameters in a chemical mechanism have uncertainties, leading to the uncertainties of model predictions. A recently developed global sensitivity analysis (SA) method based on Random Sampling-High Dimensional Model Representation (RS-HDMR) was applied to the Regional Atmospheric Chemical Mechanism (RACM) within a zero-dimensional photochemical model to highlight the main uncertainty sources of atmospheric hydroxyl (OH) and hydroperoxyl (HO(2)) radicals. This global SA approach can be applied as a routine in zero-dimensional photochemical modeling to comprehensively assess model uncertainty and sensitivity under different conditions. It also highlights the parameters to which the model is most sensitive during periods when the model/measurement OH and HO(2) discrepancies are greatest. Uncertainties in 584 model parameters were assigned for measured constituents used to constrain the model, for photolysis and kinetic rate coefficients, and for product yields of the reactions. With simulations performed for the hourly field data of two typical days, modeled and measured OH and HO(2) generally agree better for polluted conditions than for cleaner conditions, except during morning rush hour. Sensitivity analysis shows that the modeled OH and HO(2) depend most critically on the reactions of xylenes and isoprene with OH, NO(2) with OH, NO with HO(2), and internal alkenes with O(3) and suggests that model/measurement discrepancies in OH and HO(2) would benefit from a closer examination of these reactions.


Status, quality and specific needs of Ebola virus diagnostic capacity and capability in laboratories of the two European preparedness laboratory networks EMERGE and EVD-LabNet.
From December 2013 to March 2016, West Africa experienced the largest Ebola virus (EBOV) outbreak to date, leading to a European-wide activation of laboratory preparedness and response. At the end of the outbreak, laboratories associated with the two European preparedness networks of expert laboratories EMERGE JA and EVD-LabNet were invited to participate in an assessment of the response of European laboratories to the EBOV outbreak, to identify learning points and training needs to strengthen future outbreak responses. Response aspects assessed included diagnostics, biorisk management and quality assurance. The overall coverage of EBOV diagnostics in the European Union/European Economic Area (EU/EEA) was found to be adequate although some points for quality improvement were identified. These included the need for relevant International Organization for Standardization (ISO) accreditation, the provision of EBOV external quality assessments (EQA) in periods where there is no emergency, facilitating access to controls and knowledge, biorisk management without compromising biosafety and a rapid public health response, and the need for both sustained and contingency funding for preparedness and response activities.


Rejuvenation: an integrated approach to regenerative medicine.
The word "rejuvenate" found in the Merriam-Webster dictionary is (1) to make young or youthful again: give new vigor to, and (2) to restore to an original or new state. Regenerative medicine is the process of creating living, functional tissues to repair or replace tissue or organ function lost due to age, disease, damage, or congenital defects. To accomplish this, approaches including transplantation, tissue engineering, cell therapy, and gene therapy are brought into action. These all use exogenously prepared materials to forcefully mend the failed organ. The adaptation of the materials in the host and their integration into the organ are all uncertain. It is a common sense that tissue injury in the younger is easily repaired and the acute injury is healed better and faster. Why does the elder have a diminished capacity of self-repairing, or why does chronic injury cause the loss of the self-repairing capacity? There must be some critical elements that are involved in the repair process, but are suppressed in the elder or under the chronic injury condition. Rejuvenation of the self-repair mechanism would be an ideal solution for functional recovery of the failed organ. To achieve this, it would involve renewal of the injury signaling, reestablishment of the communication and transportation system, recruitment of the materials for repairing, regeneration of the failed organ, and rehabilitation of the renewed organ. It thus would require a comprehensive understanding of developmental biology and a development of new approaches to activate the critical players to rejuvenate the self-repair mechanism in the elder or under chronic injury condition. Efforts focusing on rejuvenation would expect an alternative, if not a better, accomplishment in the regenerative medicine.


Pain assessment in profound cognitive impaired children using the Checklist Pain Behavior; is item reduction valid?
There are both commonalities and idiosyncratic features in the reaction of pain children with profound cognitive impairment (CI), and that there is no evidence to suggest that idiosyncratic behavior is more characteristic of this population than of any other population. The main objective of this study was to identify whether the 23-item version of the Checklist Pain Behavior could be reduced to 10 items. Previous research demonstrated that only these 10 items discriminated between absence and presence of pain. Second, we wanted to explore the underlying structure of these 10 selected items including its performance. Data of 477 observations in 73 children were used. All these children were video-taped while they were admitted to the Sophia Children's Hospital for surgery, twice before and five times after surgery. These video-tapes were scored by an independent observer. A visual analogue scale (VAS) by a researcher was used to assess the presence of pain. We tested whether the underlying structure was unidimensional, and whether it had differential qualities between pain and no pain, and to which degree. Using a modern psychometric method, i.e., Mokken scaling model, we unraveled the interdependency of the pain response in CI-children, in that the structure turned out to be unidimensional. In addition, these behaviors could be hierarchically ordered in terms of frequency of occurrences. Finally, these behaviors had to a high degree the potentialities to estimate the likelihood of occurrence of pain.


PRIMA-1MET cytotoxic effect correlates with p53 protein reduction in TP53-mutated chronic lymphocytic leukemia cells.
TP53 gene defects represent the most unfavorable prognostic factor in chronic lymphocytic leukemia (CLL). Although recently introduced small-molecule B-cell receptor signalling inhibitors have revolutionized CLL treatment, data for ibrutinib still point to impaired prognosis for TP53-affected patients. Among cancer-associated TP53 mutations, missense substitutions predominate and typically result in a high mutated-p53 protein level. Therefore, rescuing the p53 tumor suppressor function through specific small molecules restoring p53 wild-type (wt) conformation represents an attractive therapeutic strategy for cancer patients with TP53 missense mutations. We tested the effect of mutated-p53 reactivating molecule PRIMA-1MET in 62 clinical CLL samples characterized for TP53 mutations and p53 protein level. At the subtle PRIMA-1MET concentrations (1-4 μM), most samples manifested concentration-dependent viability decrease and, conversely, apoptosis induction, with the response being similar in both the TP53-mutated and TP53-wt groups, as well as in the TP53-mutated samples with p53 protein stabilization and without it. PRIMA-1MET was able to reduce mutated p53 protein in a proportion of TP53-mutated CLL samples, and this reduction correlated with a significantly stronger viability decrease and apoptosis induction than samples with stable p53 levels. CLL cells are mostly sensitive to PRIMA-1MET apart from those with stable mutated p53.


Comparison of 3-Factor Versus 4-Factor Prothrombin Complex Concentrate With Regard to Warfarin Reversal, Blood Product Use, and Costs.
Prothrombin complex concentrates (PCCs) are drug products containing varying amounts of vitamin K-dependent coagulation factors II, VII, IX, and X. The evidence comparing 3-factor PCC (3-PCC) versus 4-factor PCC (4-PCC) for warfarin reversal is conflicting. It has been hypothesized that 3-PCC may be less effective than 4-PCC because of relatively lower factor VII content. The primary objective of this study was to compare international normalized ratio (INR) reversal between 3-PCC and 4-factor PCC (4-PCC) in warfarin-treated patients. The secondary objectives include comparing blood product use, total reversal costs, and cost-effectiveness between the groups. This was a retrospective cohort study conducted in 2 affiliated, academic institutions in the United States. Consecutive adult patients who received 3-PCC or 4-PCC for warfarin reversal were included. The primary outcome was adequate INR reversal defined as a final INR ≤1.5. Secondary outcomes were the utilization of plasma, red blood cells and platelets, reversal costs, and the cost-effectiveness ratio. There were 89 patients who were included in the overall cohort (3-PCC = 57, 4-PCC = 32). Adequate INR reversal occurred less commonly with 3-PCC (45.6%) compared with 4-PCC (87.5%) (P < 0.001). There was no significant difference in the proportion of patients who received plasma (32% vs. 28%, P = 0.813), red blood cells (37% vs. 47%, P = 0.377), or platelets (16% vs. 28%, P = 0.180) between the 3-PCC and 4-PCC groups, respectively. The median reversal cost of 3-PCC ($3663) was lower than 4-PCC ($5105) (P = 0.001). The cost-effective ratio favored 4-PCC ($5105/87.5% = $5834) compared with 3-PCC ($3663/45.6% = $8033). Four-PCC was more effective than 3-PCC with regard to INR reversal in patients taking warfarin, but blood product use was similar. Although 4-PCC is associated with increased reversal costs, it may be cost-effective in terms of INR reversal.


Immunohistochemistry of bone sialoprotein and osteopontin during reparative dentinogenesis in vivo.
To investigate the stage-specific and tissue expression of bone sialoprotein (BSP) and osteopontin (OPN) during reparative dentinogenesis in vivo. Direct pulp-capping with Ca(OH)2 developed a model used for the investigation of reparative dentinogenesis in the exposed dental pulp. In this model, standardized class V cavities were prepared close to the gingival margin on the buccal surface of each tooth. Animals were sacrificed 3, 7, and 10 days post-operation. Immunohistochemical staining determined the tissue-specific expression of BSP and OPN during the process. Odontoblast-like cells and reparative dentin reacted positively with BSP and OPN. The expression of BSP reached a peak at day 7, then gradually decreased, while the expression of OPN showed no significant difference between day 7 and day 10. BSP and OPN may play different roles in reparative dentinogenesis. BSP may serve as a nucleator of hydroxyapatite crystal formation.


Cytochrome P4501-inhibiting chemicals amplify aryl hydrocarbon receptor activation and IL-22 production in T helper 17 cells.
The aryl hydrocarbon receptor (AHR) controls interleukin 22 production by T helper 17 cells (Th17). IL-22 contributes to intestinal homeostasis but has also been implicated in chronic inflammatory disorders and colorectal cancer, highlighting the need for appropriate regulation of IL-22 production. Upon activation, the AHR induces expression of cytochrome P4501 (CYP1) enzymes which in turn play an important feedback role that curtails the duration of AHR signaling by metabolizing AHR ligands. Recently we described how agents that inhibit CYP1 function potentiate AHR signaling by disrupting metabolic clearance of the endogenous ligand 6-formylindolo[3,2-b]carbazole (FICZ). In the present study, we investigated the immune-modulating effects of environmental pollutants such as polycyclic aromatic hydrocarbons on Th17 differentiation and IL-22 production. Using Th17 cells deficient in CYP1 enzymes (Cyp1a1/1a2/1b1-/-) we show that these chemicals potentiate AHR activation through inhibition of CYP1 enzymes which leads to increases in intracellular AHR agonists. Our findings demonstrate that IL-22 production by Th17 cells is profoundly enhanced by impaired CYP1-function and strongly suggest that chemicals able to modify CYP1 function or expression may disrupt AHR-mediated immune regulation by altering the levels of endogenous AHR agonist(s).


Cigarette smoking, mental health and social support: data from a northwestern First Nation.
The prevalence of smoking is high in many Aboriginal Canadian communities; rates of 50% are not uncommon. Aboriginal Canadians suffer a severe burden of smoking-related disease. Research in other populations has linked depression and smoking. It is not known whether mental health or affective measures are related to smoking for any of Canada's First Nations, and this study sought to answer this question. Understanding relations between affect and smoking behaviour is requisite to mounting anti-smoking interventions. Smoking status and psychosocial measures including depression, mastery, affect balance and social support were obtained in a community-based chronic disease survey for a rural Interior Salishan First Nation in British Columbia (Plateau area). Persons surveyed were on-reserve residents (n=187), overweight (body mass index > or = 25 kg/m2), with mean age of 44.1 years (standard deviation 15.0). The prevalence of smoking was 48.1%. Adjusted for age, sex and body mass index, smokers relative to nonsmokers had higher (p<0.010) depression (mean 21.3 [CI 95%, 19.1-23.4] vs. 16.1 [14.1-18.0]) and negative affect (18.6 [14.9-22.3] vs. 11.0 [7.6-14.4]), and lower mastery (36.4 [35.5-37.3] vs. 38.1 [37.2-38.9]). A positive relationship between mastery and social support was greater for nonsmokers (p=0.046). Depression and negative affect are associated with smoking among overweight persons in a rural First Nation in British Columbia. Furthermore, smoking is inversely related to mastery, and this relation varies with social support. Longitudinal study is required to determine whether smoking influences mental health and mastery, or the reverse.


[Polymorphism of six Alu-insertions in residents of Morocco: comparative study in Arab and Berber populations and residents of Casablanca].
Alu elements are the largest family of short tandem interspersed elements (SINEs) in human who have arisen to a copy number with an excess of 500,000 copies per haploid human genome and mobilize through an RNAse polymerase III derived transcript in a process termed "retroposition." Several features make Alu insertions a powerful tool used in population genetic studies: the polymorphic nature of many Alu insertions, the stability of an Alu insertion event and, furthermore, the ancestral state of an Alu insertion is known to be the absence (complete and exact) of the Alu element at a particular locus and the presence of an Alu insertion at the site that forward mutational change. Here we report on the distribution of six polymorphic Alu insertions in a general Moroccan population and in the Arab and Berber populations from Morocco and their relationships with other populations previously studied. Our results show that there is a small difference between Arabs and Berbers and that the Arab population was closer to African populations than Berber population which is closest to Europeans.


High-performance biocomputing for simulating the spread of contagion over large contact networks.
Many important biological problems can be modeled as contagion diffusion processes over interaction networks. This article shows how the EpiSimdemics interaction-based simulation system can be applied to the general contagion diffusion problem. Two specific problems, computational epidemiology and human immune system modeling, are given as examples. We then show how the graphics processing unit (GPU) within each compute node of a cluster can effectively be used to speed-up the execution of these types of problems. We show that a single GPU can accelerate the EpiSimdemics computation kernel by a factor of 6 and the entire application by a factor of 3.3, compared to the execution time on a single core. When 8 CPU cores and 2 GPU devices are utilized, the speed-up of the computational kernel increases to 9.5. When combined with effective techniques for inter-node communication, excellent scalability can be achieved without significant loss of accuracy in the results. We show that interaction-based simulation systems can be used to model disparate and highly relevant problems in biology. We also show that offloading some of the work to GPUs in distributed interaction-based simulations can be an effective way to achieve increased intra-node efficiency.


Associations between sedentary behavior and negative emotions in adolescents during home confinement: Mediating role of social support and sleep quality.
Prolonged periods of sedentary behaviour, for instance, engendered by home confinement in Shenzhen city, has led to negative mental health consequences, especially in adolescents. Previous research suggests, in general, that sedentary behavior can increase negative emotions. However, the specific mechanism driving the relationship between sedentary behavior and negative emotions is still relatively unclear. Social support and sleep quality might partly explain the effect of sedentary behavior on negative emotions. Thus, the current study aimed to examine the associations between sedentary behavior and negative emotions, and to investigate if social support and sleep quality mediate such a relationship. During home confinement due to the COVID-19 Omicron variant outbreak, 1179 middle and high school students in Shenzhen were invited to voluntarily complete an e-questionnaire, including the 21-item Depression Anxiety Stress Scale (DASS-21), the short form of the International Physical Activity Questionnaire (IPAQ-SF), the Social Support Rating Scale (SSRS) and the Pittsburgh Sleep Quality Index (PSQI). Data from 1065 participants were included in the analysis. We observed significant sex-related and demografic-related differences in emotional (e.g., anxiety, stress and social support) and other outcome variables (e.g., sitting duration and PSQI score). Furthermore, sedentary behavior, social support, and sleep quality were associated with negative emotions (p < .01), even after controlling for sex, age, only-child case, body mass index, and metabolic equivalent level. In addition, social support and sleep quality partially mediated the association between sedentary behavior and negative emotions. The findings of the current study suggest that social support and sleep quality partially mediate the relationship between sedentary behavior and negative emotions in middle and high school students during home confinement in Shenzhen city.


Climate change and postglacial human dispersals in southeast Asia.
Modern humans have been living in Island Southeast Asia (ISEA) for at least 50,000 years. Largely because of the influence of linguistic studies, however, which have a shallow time depth, the attention of archaeologists and geneticists has usually been focused on the last 6,000 years--in particular, on a proposed Neolithic dispersal from China and Taiwan. Here we use complete mitochondrial DNA (mtDNA) genome sequencing to spotlight some earlier processes that clearly had a major role in the demographic history of the region but have hitherto been unrecognized. We show that haplogroup E, an important component of mtDNA diversity in the region, evolved in situ over the last 35,000 years and expanded dramatically throughout ISEA around the beginning of the Holocene, at the time when the ancient continent of Sundaland was being broken up into the present-day archipelago by rising sea levels. It reached Taiwan and Near Oceania more recently, within the last approximately 8,000 years. This suggests that global warming and sea-level rises at the end of the Ice Age, 15,000-7,000 years ago, were the main forces shaping modern human diversity in the region.


Bone mineral density and metabolism in children with congenital hypothyroidism after prolonged L-thyroxine therapy.
The effect of long-term L-thyroxine (LT4) replacement therapy on bone mineral density and on biochemical markers of bone turnover were studied in children with congenital hypothyroidism (CH). Forty-four children and adolescents (mean age 8.5 +/- 3.5 years) with primary CH who began LT4 replacement therapy within the first month of life were studied. Bone mineral density (BMD) of the lumbar vertebrae and the upper femoral bone was measured by dual energy X-ray absorptiometry. Serum osteocalcin (OC) and bone alkaline phosphatase were measured as markers of bone formation and urinary deoxypyridinoline was taken as a marker of bone resorption. Bone mineral densities of CH children were not different from those in age-matched controls. The biochemical markers of bone turnover were normal except for the serum OC levels which were found to be higher than in controls and positively correlated with the free thyroid hormone levels (for FT4 r = 0.42, p = 0.02). Eight CH children demonstrated low BMD values (below -1 SDS) at -2 +/- 0.7 SDS for the lumbar spine and -1.6 +/- 0.5 SDS for the femoral site. These eight children showed lower mean weight (p < 0.05) and their dietary calcium intake tended to be less (p <0.06) than that seen in the normal BMD group. In conclusion, our results show that LT4 replacement therapy for 8 years is not detrimental to the skeletal mineralization of CH children. As in a healthy population, weight and current intake of calcium seem to be major determinants of bone density. Dietary recommendations, especially when calcium intake is below the recommended dietary allowance, may have to be reconsidered.


Novel Neonatal Variants of the Carbamoyl Phosphate Synthetase 1 Deficiency: Two Case Reports and Review of Literature.
Carbamoyl phosphate synthetase I (CPS1) deficiency (CPS1D), is a rare autosomal recessive disorder, characterized by life-threatening hyperammonemia. In this study, we presented the detailed clinical features and genetic analysis of two patients with neonatal-onset CPS1D carrying two compound heterozygous variants of c.1631C > T (p.T544M)/c.1981G > T (p.G661C), and c.2896G > T (p.E966X)/c622-3C > G in CPS1 gene, individually. Out of them, three variants are novel, unreported including a missense (c.1981G > T, p.G661C), a nonsense (c.2896G > T, p.E966X), and a splicing change of c.622-3C > G. We reviewed all available publications regarding CPS1 mutations, and in total 264 different variants have been reported, with majority of 157 (59.5%) missense, followed by 35 (13.2%) small deletions. This study expanded the mutational spectrum of CPS1. Moreover, our cases and review further support the idea that most (≥90%) of the mutations were "private" and only ∼10% recurred in unrelated families.


SPARKLE (Subtypes of Ischaemic Stroke Classification System), incorporating measurement of carotid plaque burden: a new validated tool for the classification of ischemic stroke subtypes.
Previous classification systems of acute ischemic stroke (Causative Classification System, CCS, of acute ischemic stroke, Trial of Org 10172 in Acute Stroke Treatment, TOAST) established the diagnosis of large artery disease (LAD) based on the presence or absence of carotid stenosis. However, carotid plaque burden is a stronger predictor of cardiovascular risk than stenosis. Our objective was to update definitions of ischemic stroke subtypes to improve the detection of LAD and to assess the validity and reliability of a new classification system: SPARKLE (Subtypes of Ischaemic Stroke Classification System). In a retrospective review of clinical research data, we compared three stroke subtype classifications: CCS, TOAST and SPARKLE. We analyzed a random sample of 275 patients presenting with minor stroke or transient ischemic attack (TIA) in an Urgent TIA Clinic in London, Ont., Canada, between 2002 and 2012. There was substantial overall agreement between SPARKLE and CCS (κ = 0.75), with significant differences in the rate of detection of LAD, cardioembolic and undetermined causes of stroke or TIA. The inter-rater reliability of SPARKLE was substantial (κ = 0.76) and the intra-rater reliability was excellent (κ = 0.91). SPARKLE is a valid and reliable classification system, providing advantages compared to CCS and TOAST. The incorporation of plaque burden into the classification of LAD increases the proportion of cases attributable to LAD and reduces the proportion classified as being of 'undetermined' etiology.


The intracellular phosphorylation of (-)-2'-deoxy-3'-thiacytidine (3TC) and the incorporation of 3TC 5'-monophosphate into DNA by HIV-1 reverse transcriptase and human DNA polymerase gamma.
(-)-2'-deoxy-3'-thiacytidine (3TC) has been shown to be a potent, selective inhibitor of HIV replication in vitro, which requires phosphorylation to its 5'-triphosphate for antiviral activity. The intracellular concentration of 3TC 5'-triphosphate in phytohaemagglutinin (PHA)-stimulated peripheral blood lymphocytes (PBL) shows a linear dependence on the extracellular concentration of 3TC up to an extracellular 3TC concentration of 10 microM. At this extracellular concentration of 3TC, the resulting intracellular concentration of 3TC 5'-triphosphate is 5 microM. This value is similar to the inhibition constant (Ki) values for the competitive inhibition of human immunodeficiency virus type 1 (HIV-1) reverse transcriptase and human DNA polymerases (10-16 microM) by 3TC 5'-triphosphate. Since the concentration of 3TC producing 90% inhibition (IC90) of HIV replication in PBLs has been reported to be 76 nM, the antiviral activity of 3TC requires intracellular concentrations of 3TC 5'-triphosphate, which would result in very little inhibition of reverse transcriptase if its sole mode of action was competitive inhibition. This apparent discrepency may be explained by the ability of 3TC 5'-triphosphate to act as a substrate for reverse transcriptase. Primer extension assays have shown that 3TC 5'-triphosphate is a substrate for HIV-1 reverse transcriptase and DNA polymerase gamma, resulting in the incorporation of 3TC 5'-monophosphate into DNA. In the case of DNA polymerase gamma, the product of this reaction (i.e. double-stranded DNA with 3TC 5'-monophosphate incorporated at the 3'-terminus of the primer strand) is also a substrate for the 3'-5' exonuclease activity of this enzyme. This may explain the low levels of mitochondrial toxicity observed with 3TC.


Lower extremity muscle function after strength or power training in older adults.
It is unclear whether strength training (ST) or power training (PT) is the more effective intervention at improving muscle strength and power and physical function in older adults. The authors compared the effects of lower extremity PT with those of ST on muscle strength and power in 45 older adults (74.8 +/- 5.7 yr) with self-reported difficulty in common daily activities. Participants were randomized to 1 of 3 treatment groups: PT, ST, or wait-list control. PT and ST trained 3 times/wk for 12 wk using knee-extension (KE) and leg-press (LP) machines at approximately 70% of 1-repetition maximum (1RM). For PT, the concentric phase of the KE and LP was completed "as fast as possible," whereas for ST the concentric phase was 2-3 s. Both PT and ST paused briefly at the midpoint of the movement and completed the eccentric phase of the movement in 2-3 s. PT and ST groups showed significant improvements in KE and LP 1RM compared with the control group. Maximum KE and LP power increased approximately twofold in PT compared with ST. At 12 wk, compared with control, maximum KE and LP power were significantly increased for the PT group but not for the ST group. In older adults with compromised function, PT leads to similar increases in strength and larger increases in power than ST.


Peroxiredoxin-1 protects estrogen receptor α from oxidative stress-induced suppression and is a protein biomarker of favorable prognosis in breast cancer.
Peroxiredoxin-1 (PRDX1) is a multifunctional protein, acting as a hydrogen peroxide (H2O2) scavenger, molecular chaperone and immune modulator. Although differential PRDX1 expression has been described in many tumors, the potential role of PRDX1 in breast cancer remains highly ambiguous. Using a comprehensive antibody-based proteomics approach, we interrogated PRDX1 protein as a putative biomarker in estrogen receptor (ER)-positive breast cancer. An anti-PRDX1 antibody was validated in breast cancer cell lines using immunoblotting, immunohistochemistry and reverse phase protein array (RPPA) technology. PRDX1 protein expression was evaluated in two independent breast cancer cohorts, represented on a screening RPPA (n = 712) and a validation tissue microarray (n = 498). In vitro assays were performed exploring the functional contribution of PRDX1, with oxidative stress conditions mimicked via treatment with H2O2, peroxynitrite, or adenanthin, a PRDX1/2 inhibitor. In ER-positive cases, high PRDX1 protein expression is a biomarker of improved prognosis across both cohorts. In the validation cohort, high PRDX1 expression was an independent predictor of improved relapse-free survival (hazard ratio (HR) = 0.62, 95% confidence interval (CI) = 0.40 to 0.96, P = 0.032), breast cancer-specific survival (HR = 0.44, 95% CI = 0.24 to 0.79, P = 0.006) and overall survival (HR = 0.61, 95% CI = 0.44 to 0.85, P = 0.004). RPPA screening of cancer signaling proteins showed that ERα protein was upregulated in PRDX1 high tumors. Exogenous H2O2 treatment decreased ERα protein levels in ER-positive cells. PRDX1 knockdown further sensitized cells to H2O2- and peroxynitrite-mediated effects, whilst PRDX1 overexpression protected against this response. Inhibition of PRDX1/2 antioxidant activity with adenanthin dramatically reduced ERα levels in breast cancer cells. PRDX1 is shown to be an independent predictor of improved outcomes in ER-positive breast cancer. Through its antioxidant function, PRDX1 may prevent oxidative stress-mediated ERα loss, thereby potentially contributing to maintenance of an ER-positive phenotype in mammary tumors. These results for the first time imply a close connection between biological activity of PRDX1 and regulation of estrogen-mediated signaling in breast cancer.


The B-subunit of cholera toxin induces immunoregulatory cells and prevents diabetes in the NOD mouse.
The B-subunit of the cholera toxin molecule (CT-B) has T-cell immunomodulatory properties. Because the pathogenesis of diabetes in the nonobese diabetic (NOD) mouse model of IDDM is thought to be a T-cell-mediated process due to an imbalance of immunoregulatory and anti-islet effector cells, we examined the effect of CT-B administration on the development of diabetes in the NOD mouse and assessed whether this potential diabetes-sparing effect of CT-B is mediated by changes in immunoregulatory and/or anti-islet cytotoxic effector cell activity. The administration of either intravenous or intraperitoneal CT-B decreased the development of diabetes with no apparent drug toxicity. At 6 months of age, only 18% of CT-B vs. 75% of saline-treated animals had diabetes. Histopathological examination revealed less islet atrophy in CT-B-treated animals. The in vitro proliferative responses of mononuclear splenocytes and thymocytes to concanavalin A and lipolysaccharide and the proportion of B-cells and T-cell subsets were not altered by CT-B treatment. CT-B administration did not inhibit the primary immunization of mice to tetanus toxoid. The development of diabetes in irradiated NOD mice was slower in the animals injected with spleen cells (SC) from CT-B-treated than from saline-treated NOD mice, suggesting that CT-B decreases anti-islet effector cell activity. The injection of SC from CT-B-treated mice inhibited the adoptive transfer of diabetes by SC from diabetic mice into irradiated NOD mice, documenting that CT-B administration induces regulatory cell activity. In conclusion, CT-B administration prevents the development of diabetes in NOD mice by inhibiting the immune destruction of islets. This islet-sparing activity appears mediated, at least in part, by the induction of regulatory cells and, in turn, suppression of anti-islet effector cells, which is not associated with generalized immunosuppression or T- or B-cell depletion.


Cysticercosis of the central nervous system. II. Spinal cysticercosis.
The compromising of the spinal canal by cysticercus is considered infrequent, varying from 16 to 20% in relation to the brain involvement. In the spinal canal the cysticercus predominantly places in the subarachnoid space. Clinical signs in spinal cysticercosis can be caused by direct compression of the spinal cord/roots by cysticerci and by local or at distance inflammatory reactions (arachnoiditis). Another mechanism of lesion is degeneration of the spinal cord due to pachymeningitis or circulatory insufficiency. The most frequent clinical features are signs of spinal cord and/or cauda equina compression. The diagnosis of spinal cysticercosis is based on evidence of cerebral cysticercosis and on neuroradiological examinations (myelography and myelo-CT) that show signs of arachnoiditis and images of cysts in the subarachnoid space and sometimes, signs of intramedullary lesions, but the confirmation can only be made through immunological reactions in the CSF or during surgery. The clinical course of 10 patients with diagnosis of spinal cysticercosis observed among 182 patients submitted to surgical treatment due to this disease are analyzed. The clinical pictures in all cases were signs of spinal cord or roots compression. All but two presented previously signs of brain cysticercosis. Neuroradiological examinations showed signs of arachnoiditis in 4 patients, images of cysts in the subarachnoid space in 5, and signs of arachnoiditis and images of cysts in one. The 6 patients that presented intraspinal cysts were submitted to exeresis of the cysts and 2 patients with total blockage of the spinal canal underwent surgery for diagnosis. The 2 remaining patients with arachnoiditis and blockage of the spinal canal were clinically treated. All of the six patients submitted to cyst exeresis had initial improvement but 4 of them later developed arachnoiditis and recurrence of the clinical signs and only 2 remained well for long-term. The 2 non operated patients had no improvement of their clinical signs. Two patients died later due to complications of cerebral cysticercosis. Based on the experience acquired in the management of these patients we indicate surgical treatment for patients that present free cyst in subarachnoid space. For those who present arachnoiditis, surgery is indicated only when there is doubt in the diagnosis. Intramedullary cysts should also be surgically treated.


Cooperative regulation of vocal fold morphology and stress by the cricothyroid and thyroarytenoid muscles.
Voice is produced by vibrations of vocal folds that consist of multiple layers. The portion of the vocal fold tissue that vibrates varies depending primarily on laryngeal muscle activity. The effective depth of tissue vibration should significantly influence the vibrational behavior of the tissue and resulting voice quality. However, thus far, the effect of the activation of individual muscles on the effective depth is not well understood. In this study, a three-dimensional finite element analysis is performed to investigate the effect of the activation of two major laryngeal muscles, the cricothyroid (CT) and thyroarytenoid (TA) muscles, on vocal fold morphology and stress distribution in the tissue. Because structures that bear less stress can easily be deformed and involved in vibration, information on the morphology and stress distribution may provide a useful estimate of the effective depth. The results of the analyses indicate that the two muscles perform distinct roles, which allow cooperative control of the morphology and stress. When the CT muscle is activated, the tip region of the vocal folds becomes thinner and curves upward, resulting in the elevation of the stress magnitude all over the tissue to a certain degree that depends on the stiffness of each layer. On the other hand, the TA muscle acts to suppress the morphological change and controls the stress magnitude in a position-dependent manner. Thus, the present analyses demonstrate quantitative relationships between the two muscles in their cooperative regulation of vocal fold morphology and stress.


Free form fabricated features on CoCr implants with and without hydroxyapatite coating in vivo: a comparative study of bone contact and bone growth induction.
The current study evaluates the in vivo response to free form fabricated cobalt chromium (CoCr) implants with and without hydroxyapatite (HA) plasma sprayed coatings. The free form fabrication method allowed for integration of complicated pyramidal surface structures on the cylindrical implant. Implants were press fit into the tibial metaphysis of nine New Zealand white rabbits. Animals were sacrificed and implants were removed and embedded. Histological analysis, histomorphometry and electron microscopy studies were performed. Focused ion beam was used to prepare thin sections for high-resolution transmission electron microscopy examination. The fabricated features allowed for effective bone in-growth and firm fixation after 6 weeks. Transmission electron microscopy investigations revealed intimate bone-implant integration at the nanometre scale for the HA coated samples. In addition, histomorphometry revealed a significantly higher bone contact on HA coated implants compared to native CoCr implants. It is concluded that free form fabrication in combination with HA coating improves the early fixation in bone under experimental conditions.


Current evidence of oral anticoagulant reversal: A systematic review.
Approximately 4-6% of patients treated with oral anticoagulants (OAC) will suffer from major hemorrhage or be in need of urgent surgery necessitating anticoagulant reversal therapy. Several new oral anticoagulants and reversal agents have been introduced that make it difficult for physicians to stay updated on the current evidence of reversal management. This study aims to review the recent literature on oral anticoagulation reversal therapy and to present the current evidence in an easily approachable manner. A systematic literature search was conducted using PubMed and EMBASE to identify the latest publications on both vitamin K antagonist (VKA) and direct oral anticoagulant (DOAC) reversal strategies. All studies on humans who received any acute reversal management of VKA treatment were included, except case studies. Since only two studies on acute reversal of DOAC treatment have been published, clinical trials on healthy volunteers were also included. Twenty-one studies with a total of 4783 VKA treated patients, and 12 studies with a total of 529 DOAC treated patients were included. Elevated INR values due to VKA treatment could be reversed (INR≤1.5) in 63.1% (95% CI: 61.0-65.2) of study subjects after treatment with 4F-PCC, as compared with 12.2% (95% CI: 8.2-16.2) after treatment with fresh frozen plasma (FFP), (p<0.001). Thromboembolism occurred in 1.6% (95% CI: 1.2-2.1) of VKA-patients treated with 4F-PCC, and in 4.5% (95% CI: 2.3-6.7) of FFP-treated patients. To date, reversal of laboratory parameters has been demonstrated for two reversal agents specific to DOACs: idarucizumab for dabigatran reversal and andexanet-alfa for factor Xa-inhibitor reversal. This review supports the use of PCC for VKA reversal, specifically for 4F-PCC over FFP for laboratory reversal. There are no studies on clinical efficacy of non-specific agents for DOAC reversal and the evidence for laboratory reversal is not consistent.


White matter hyperintensities at critical crossroads for executive function and verbal abilities in small vessel disease.
The presence of white matter lesions in patients with cerebral small vessel disease (SVD) is among the main causes of cognitive decline. We investigated the relation between white matter hyperintensity (WMH) locations and executive and language abilities in 442 SVD patients without dementia with varying burden of WMH. We used Stroop Word Reading, Stroop Color Naming, Stroop Color-Word Naming, and Category Fluency as language measures with varying degrees of executive demands. The Symbol Digit Modalities Test (SDMT) was used as a control task, as it measures processing speed without requiring language use or verbal output. A voxel-based lesion-symptom mapping (VLSM) approach was used, corrected for age, sex, education, and lesion volume. VLSM analyses revealed statistically significant clusters for tests requiring language use, but not for SDMT. Worse scores on all tests were associated with WMH in forceps minor, thalamic radiations and caudate nuclei. In conclusion, an association was found between WMH in a core frontostriatal network and executive-verbal abilities in SVD, independent of lesion volume and processing speed. This circuitry underlying executive-language functioning might be of potential clinical importance for elderly with SVD. More detailed language testing is required in future research to elucidate the nature of language production difficulties in SVD.


Molecular determinants archetypical to the phylum Nematoda.
Nematoda diverged from other animals between 600-1,200 million years ago and has become one of the most diverse animal phyla on earth. Most nematodes are free-living animals, but many are parasites of plants and animals including humans, posing major ecological and economical challenges around the world. We investigated phylum-specific molecular characteristics in Nematoda by exploring over 214,000 polypeptides from 32 nematode species including 27 parasites. Over 50,000 nematode protein families were identified based on primary sequence, including approximately 10% with members from at least three different species. Nearly 1,600 of the multi-species families did not share homology to Pfam domains, including a total of 758 restricted to Nematoda. Majority of the 462 families that were conserved among both free-living and parasitic species contained members from multiple nematode clades, yet approximately 90% of the 296 parasite-specific families originated only from a single clade. Features of these protein families were revealed through extrapolation of essential functions from observed RNAi phenotypes in C. elegans, bioinformatics-based functional annotations, identification of distant homology based on protein folds, and prediction of expression at accessible nematode surfaces. In addition, we identified a group of nematode-restricted sequence features in energy-generating electron transfer complexes as potential targets for new chemicals with minimal or no toxicity to the host. This study identified and characterized the molecular determinants that help in defining the phylum Nematoda, and therefore improved our understanding of nematode protein evolution and provided novel insights for the development of next generation parasite control strategies.


Performance enhancement of blue light-emitting diodes without an electron-blocking layer by using special designed p-type doped InGaN barriers.
In this study, the characteristics of the nitride-based blue light-emitting diode (LED) without an electron-blocking layer (EBL) are analyzed numerically. The emission spectra, carrier concentrations in the quantum wells (QWs), energy band diagrams, electrostatic fields, and internal quantum efficiency (IQE) are investigated. The simulation results indicate that the LED without an EBL has a better hole-injection efficiency and smaller electrostatic fields in its active region over the conventional LED with an AlGaN EBL. The simulation results also show that the LED without an EBL has severe efficiency droop. However, when the special designed p-type doped InGaN QW barriers are used, the efficiency droop is markedly improved and the electroluminescence (EL) emission intensity is greatly enhanced which is due to the improvement of the hole uniformity in the active region and small electron leakage.


Posterolateral Diskectomies for Treatment of Pediatric Spinal Deformities.
Retrospective. To investigate the indications, radiographic outcomes, and complications in children with spinal deformities treated with posterolateral diskectomy with posterior fusion (PLDF), and to compare them against those of patients treated with anteroposterior spinal fusion (APSF). A novel technique for treating large, rigid spinal deformities in children has been proposed, consisting of PLDF at the apex of the deformity using an all-posterior approach. We evaluated records of all patients 21 years or younger who underwent treatment for spinal deformity between 2010 and 2015 by one surgeon using PLDF (n = 56) or APSF (n = 21). The indications for PLDF were large, rigid curves (37 patients); focal curves with severe rotation (10 patients); or large curves with open triradiate cartilage (nine patients). PLDF patients had a mean (± standard deviation) of 3 ± 1 diskectomies and 14 ± 3 posterior spinal levels fused. Compared with the APSF group, the PLDF group had significantly greater major curve correction (86% vs. 57%, P = 0.006), less blood transfused (mean, 2.5 ± 2.6 vs. 4.0 ± 3.3 units, P = 0.038), and a lower rate of staged surgery (1.8% vs. 86%, P < 0.001). There were no significant differences between the PLDF and APSF groups in T1-S1 length gained (mean, 6.2 ± 3.4 vs. 6.6 ± 8.8 cm, respectively; P = 0.77) or in the rate of major complications (P = 0.557). PLDF is an effective alternative to APSF for treating children with severe spinal deformities. It is effective for treating large, rigid curves with severe rotation and may be useful for treating large curves in children with open triradiate cartilage. 4.


Triumph and adversity: Exploring the complexities of consumer storytelling in mental health nursing education.
Consumer participation in the education of health professionals is increasing, particularly in mental health nursing education and storytelling remains the most frequent approach to consumer involvement. The use of story has tended to be accepted as a legitimate educational tool with limited critique or consideration of its potential consequences presented within the academic literature. A qualitative exploratory research study was undertaken with mental health nurse academics (n = 34) and consumer educators and academics (n = 12), to investigate the perceptions and experiences of mental health nurses and consumers regarding the involvement of consumers in mental health nursing education. Data were analysed thematically. Story was a major theme to emerge from consumer participants and received some attention from nurse academics. Consumers and nurses both referred to the power of story to convey the human experience of mental illness diagnosis and service use; and the vulnerability that can result from storytelling. Consumers also described: story as expectation; preparation and support; and the politics of story. All participants supported the value of storytelling in mental health nursing education. Consumers had considered the complexities in far greater detail. The ongoing value of story as an educational technique requires further research. Equally important is considering a broader range of educational roles for mental health consumers.


Why does the number of dangerous species of scorpions increase? The particular case of the genus Leiurus Ehrenberg (Buthidae) in Africa.
The aim of this contribution is to bring some precise information on the reasons why the number of noxious scorpion species is constantly growing. This fact is directly associated with the zoological research on the domains generally defined as systematics and taxonomy. The classification of any zoological group is in most cases a source of problem for most biologists not directly involved with this almost confidential aspect of the zoological research. Much information has been gathered and published over two centuries on the classification but it is remains poorly accessible and too technical for non-experts. The exposed example could be taken from several groups of scorpions possessing infamous species, but the choice went to the genus Leiurus Ehrenberg, 1828 distributed from North Africa to the Middle East. Maybe this contribution will help to explain why so numerous cases of species misidentification are regularly present in the general literature devoted to scorpion venoms and incidents.


Common Molecular Alterations in Canine Oligodendroglioma and Human Malignant Gliomas and Potential Novel Therapeutic Targets.
Spontaneous canine (Canis lupus) oligodendroglioma (ODG) holds tremendous potential as an immunocompetent large animal model of human malignant gliomas (MG). However, the feasibility of utilizing this model in pre-clinical studies depends on a thorough understanding of the similarities and differences of the molecular pathways associated with gliomas between the two species. We have previously shown that canine ODG has an immune landscape and expression pattern of commonly described oncogenes similar to that of human MG. In the current study, we performed a comprehensive analysis of canine ODG RNAseq data from 4 dogs with ODG and 2 normal controls to identify highly dysregulated genes in canine tumors. We then evaluated the expression of these genes in human MG using Xena Browser, a publicly available database. STRING-database inquiry was used in order to determine the suggested protein associations of these differentially expressed genes as well as the dysregulated pathways commonly enriched by the protein products of these genes in both canine ODG and human MG. Our results revealed that 3,712 (23%) of the 15,895 differentially expressed genes demonstrated significant up- or downregulation (log2-fold change > 2.0). Of the 3,712 altered genes, ~50% were upregulated (n = 1858) and ~50% were downregulated (n = 1854). Most of these genes were also found to have altered expression in human MG. Protein association and pathway analysis revealed common pathways enriched by members of the up- and downregulated gene categories in both species. In summary, we demonstrate that a similar pattern of gene dysregulation characterizes both human MG and canine ODG and provide additional support for the use of the canine model in order to therapeutically target these common genes. The results of such therapeutic targeting in the canine model can serve to more accurately predict the efficacy of anti-glioma therapies in human patients.


Developmental trends in the facilitation of multisensory objects with distractors.
Sensory integration and the ability to discriminate target objects from distractors are critical to survival, yet the developmental trajectories of these abilities are unknown. This study investigated developmental changes in 9- (n = 18) and 11-year-old (n = 20) children, adolescents (n = 19) and adults (n = 22) using an audiovisual object discrimination task with uni- and multisensory distractors. Reaction times (RTs) were slower with visual/audiovisual distractors, and although all groups demonstrated facilitation of multisensory RTs in these conditions, children's and adolescents' responses corresponded to fewer race model violations than adults', suggesting protracted maturation of multisensory processes. Multisensory facilitation could not be explained by changes in RT variability, suggesting that tests of race model violations may still have theoretical value at least for familiar multisensory stimuli.


Comparative study on the antiviral activity of selected monoterpenes derived from essential oils.
Essential oils are complex natural mixtures, their main constituents, e.g. terpenes and phenylpropanoids, being responsible for their biological properties. Essential oils from eucalyptus, tea tree and thyme and their major monoterpene compounds alpha-terpinene, gamma-terpinene, alpha-pinene, p-cymene, terpinen-4-ol, alpha-terpineol, thymol, citral and 1,8-cineole were examined for their antiviral activity against herpes simplex virus type 1 (HSV-1) in vitro. These essential oils were able to reduce viral infectivity by >96%, the monoterpenes inhibited HSV by about >80%. The mode of antiviral action has been determined, only moderate antiviral effects were revealed by essential oils and monoterpenes when these drugs were added to host cells prior to infection or after entry of HSV into cells. However, both essential oils and monoterpenes exhibited high anti-HSV-1 activity by direct inactivation of free virus particles. All tested drugs interacted in a dose-dependent manner with herpesvirus particles thereby inactivating viral infection. Among the analysed compounds, monoterpene hydrocarbons were slightly superior to monoterpene alcohols in their antiviral activity, alpha-pinene and alpha-terpineol revealed the highest selectivity index. However, mixtures of different monoterpenes present in natural tea tree essential oil revealed a ten-fold higher selectivity index and a lower toxicity than its isolated single monoterpenes.


The auxin influx carrier LAX3 promotes lateral root emergence.
Lateral roots originate deep within the parental root from a small number of founder cells at the periphery of vascular tissues and must emerge through intervening layers of tissues. We describe how the hormone auxin, which originates from the developing lateral root, acts as a local inductive signal which re-programmes adjacent cells. Auxin induces the expression of a previously uncharacterized auxin influx carrier LAX3 in cortical and epidermal cells directly overlaying new primordia. Increased LAX3 activity reinforces the auxin-dependent induction of a selection of cell-wall-remodelling enzymes, which are likely to promote cell separation in advance of developing lateral root primordia.


The Factor Structure of the Forms of Self-Criticising/Attacking & Self-Reassuring Scale in Thirteen Distinct Populations.
There is considerable evidence that self-criticism plays a major role in the vulnerability to and recovery from psychopathology. Methods to measure this process, and its change over time, are therefore important for research in psychopathology and well-being. This study examined the factor structure of a widely used measure, the Forms of Self-Criticising/Attacking & Self-Reassuring Scale in thirteen nonclinical samples (N = 7510) from twelve different countries: Australia (N = 319), Canada (N = 383), Switzerland (N = 230), Israel (N = 476), Italy (N = 389), Japan (N = 264), the Netherlands (N = 360), Portugal (N = 764), Slovakia (N = 1326), Taiwan (N = 417), the United Kingdom 1 (N = 1570), the United Kingdom 2 (N = 883), and USA (N = 331). This study used more advanced analyses than prior reports: a bifactor item-response theory model, a two-tier item-response theory model, and a non-parametric item-response theory (Mokken) scale analysis. Although the original three-factor solution for the FSCRS (distinguishing between Inadequate-Self, Hated-Self, and Reassured-Self) had an acceptable fit, two-tier models, with two general factors (Self-criticism and Self-reassurance) demonstrated the best fit across all samples. This study provides preliminary evidence suggesting that this two-factor structure can be used in a range of nonclinical contexts across countries and cultures. Inadequate-Self and Hated-Self might not by distinct factors in nonclinical samples. Future work may benefit from distinguishing between self-correction versus shame-based self-criticism.


Detection of osteomalacia in British Asians: a comparison of clinical score with biochemical measurements.
1. In a prospective study of 160 Asian outpatients, plasma calcium, phosphate, alkaline phosphatase, 25-hydroxyvitamin D and parathyroid hormone were compared with a clinical score to determine which measurements singly or in combination were most useful in the detection of osteomalacia. 2. Bone biopsies were performed in 45 of 48 patients considered to be at risk of osteomalacia. Of the 39 quantifiable bone biopsies, nine showed unequivocal osteomalacia, 13 were judged to be borderline and 17 biopsies were normal. 3. The clinical score was highly sensitive, identifying eight of nine patients with osteomalacia, but not specific, six of 17 normal patients having an abnormal score. 4. Plasma parathyroid hormone was the best single biochemical test for identifying osteomalacia. By using a discriminant function based on parathyroid hormone and alkaline phosphatase, it was possible to classify 96% cases correctly; a discriminant function utilizing calcium, phosphate and alkaline phosphatase was successful in 85% of cases. It was not possible to discriminate between histological groups on the basis of plasma 25-hydroxy-vitamin D values. 5. We confirm that the clinical score is a useful and inexpensive screening test for osteomalacia in British Asians. In those patients with an abnormal score we suggest that parathyroid hormone and alkaline phosphatase are measured. Where both parathyroid hormone and alkaline phosphatase are high, in the absence of hypercalcaemia, histological osteomalacia is extremely likely.


Assessment of insulin action and glucose effectiveness in diabetic and nondiabetic humans.
Insulin concentrations in humans continuously change and typically increase only when glucose also increases such as with eating. In this setting, it is not known whether the severity of hepatic and extrahepatic insulin resistance is comparable and whether the ability of glucose to regulate its own uptake and release is defective in non-insulin-dependent diabetes mellitus (NIDDM). To address this question, NIDDM and nondiabetic subjects were studied when glucose concentrations were clamped at either 5 mM (euglycemia) or varied so as to mimic the glucose concentrations observed in nondiabetic humans after food ingestion (hyperglycemia). Insulin was infused so as to simulate a "nondiabetic" postprandial profile. During euglycemia, insulin increased glucose disposal in nondiabetic but not diabetic subjects indicating marked extrahepatic resistance. In contrast, insulin-induced suppression of glucose release was only minimally less (P < 0.05) in diabetic than nondiabetic subjects (-1.06 +/- 0.09 vs. -1.47 +/- 0.21 nmol.kg-1 per 4 h). Hyperglycemia substantially enhanced disposal in both groups. Glucose effectiveness measured as the magnitude of enhancement of disposal (0.59 +/- 0.18 vs. 0.62 +/- 0.17 nmollkg-1 per 4 h) and suppression of release (-0.36 +/- 0.12 vs. -0.14 +/- 0.12 nmol.kg-1 per 4 h) did not differ in the diabetic and nondiabetic subjects. In conclusion, when assessed in the presence of a physiological insulin profile, people with NIDDM demonstrate: (a) profound extrahepatic insulin resistance, (b) modest hepatic insulin resistance, and (c) normal ability of glucose to stimulate its own uptake and suppress its own release.


Spatial Heterogeneity of Habitat Suitability for Rift Valley Fever Occurrence in Tanzania: An Ecological Niche Modelling Approach.
Despite the long history of Rift Valley fever (RVF) in Tanzania, extent of its suitable habitat in the country remains unclear. In this study we investigated potential effects of temperature, precipitation, elevation, soil type, livestock density, rainfall pattern, proximity to wild animals, protected areas and forest on the habitat suitability for RVF occurrence in Tanzania. Presence-only records of 193 RVF outbreak locations from 1930 to 2007 together with potential predictor variables were used to model and map the suitable habitats for RVF occurrence using ecological niche modelling. Ground-truthing of the model outputs was conducted by comparing the levels of RVF virus specific antibodies in cattle, sheep and goats sampled from locations in Tanzania that presented different predicted habitat suitability values. Habitat suitability values for RVF occurrence were higher in the northern and central-eastern regions of Tanzania than the rest of the regions in the country. Soil type and precipitation of the wettest quarter contributed equally to habitat suitability (32.4% each), followed by livestock density (25.9%) and rainfall pattern (9.3%). Ground-truthing of model outputs revealed that the odds of an animal being seropositive for RVFV when sampled from areas predicted to be most suitable for RVF occurrence were twice the odds of an animal sampled from areas least suitable for RVF occurrence (95% CI: 1.43, 2.76, p < 0.001). The regions in the northern and central-eastern Tanzania were more suitable for RVF occurrence than the rest of the regions in the country. The modelled suitable habitat is characterised by impermeable soils, moderate precipitation in the wettest quarter, high livestock density and a bimodal rainfall pattern. The findings of this study should provide guidance for the design of appropriate RVF surveillance, prevention and control strategies which target areas with these characteristics.


Anti-neoplastic effect of chicken anemia virus VP3 protein (apoptin) in Rous sarcoma virus-induced tumours in chicken.
The anti-neoplastic effect of chicken anemia virus VP3 protein (apoptin) was investigated in vitro in Rous sarcoma virus (RSV)-transformed chicken embryo fibroblast (CEF) cells and in RSV-induced tumours of specific-pathogen-free (SPF) chicks in vivo. The apoptin gene was cloned in the pVAX expression vector and in vitro expression of the recombinant vector pVAX-CAV-VP3 was confirmed. Two groups of SPF chicks, each containing ten chicks, were used. Chicks in groups I and II were inoculated with RSV at 1 day old. Group I served as the control, receiving pVAX vector without insert, and group II received recombinant vector pVAX-CAV-VP3 containing the apoptin gene, on day 10. An in vitro study confirmed that apoptin induced apoptosis in RSV-transformed CEF cells, which was demonstrated by observation of the characteristic changes of apoptosis using the indirect immunofluorescence technique and acridine orange/ethidium bromide staining. In vivo study also indicated that apoptin induced apoptosis and caused tumour regression by an intratumoral-delivery method. Apoptotic changes, such as nuclear condensation, fragmentation of the chromatin and formation of apoptic bodies in the tumour cells, were demonstrated by histopathology and acridine orange/ethidium bromide staining. No apoptotic changes were seen in the tumours of the control group. The results of the present study showed that apoptin had an anti-neoplastic effect in vivo and in vitro in RSV-induced tumours. The anti-neoplastic effect is due to apoptin-induced apoptosis. Further improvements in the dose, delivery method and delivery frequency of the apoptin-expressing recombinant vector could help to develop apoptin as an anti-neoplastic drug.


Monotherapy Administration of Sorafenib in Patients With Non-Small Cell Lung Cancer (MISSION) Trial: A Phase III, Multicenter, Placebo-Controlled Trial of Sorafenib in Patients with Relapsed or Refractory Predominantly Nonsquamous Non-Small-Cell Lung Cancer after 2 or 3 Previous Treatment Regimens.
Sorafenib monotherapy has shown benefits in phase II trials as third-/fourth-line treatment in patients with non-small-cell lung cancer (NSCLC). The phase III, multinational, double-blind, placebo-controlled Monotherapy admInistration of Sorafenib in patientS wIth nOn-small-cell luNg cancer (MISSION) trial randomized patients with advanced relapsed/refractory NSCLC, following two or three prior treatment regimens, to sorafenib 400 mg twice a day (n = 350) or matching placebo (n = 353) plus best supportive care. The primary end point was overall survival (OS); secondary end points included progression-free survival (PFS) and time to progression. Epidermal growth factor receptor and KRAS mutation status was analyzed in archival tumor and/or circulating tumor DNA from blood samples obtained during screening. Median OS was similar in the sorafenib and placebo groups (8.2 versus 8.3 mo; hazard ratio [HR], 0.99; 95% confidence interval [CI], 0.84-1.17; p = 0.47). Median PFS (2.8 versus 1.4 mo; HR, 0.61; 95% CI, 0.51-0.72; p < 0.0001), and time to progression (2.9 versus 1.4 mo; HR, 0.54; 95% CI, 0.45-0.65; p < 0.0001) were significantly greater with sorafenib than with placebo. Among the 89 patients with epidermal growth factor receptor mutations, OS (13.9 versus 6.5 mo; HR, 0.48; 95% CI, 0.30-0.76; p = 0.002) and PFS (2.7 versus 1.4 mo; HR, 0.27; 95% CI, 0.16-0.46; p < 0.001) were significantly higher with sorafenib than placebo. PFS was significantly longer with sorafenib than placebo in patients with either wild-type or mutated KRAS, but OS was similar. Common drug-related adverse events were rash/desquamation, diarrhea, and fatigue, consistent with the safety profile of sorafenib. Third-/fourth-line sorafenib therapy did not significantly increase OS in patients with relapsed/refractory NSCLC, despite significantly increasing PFS.


Breaking the Barrier of Cancer Through Liposome Loaded with Phytochemicals.
Currently, the most important cause of death is cancer. To treat the cancer there are a number of drugs existing in the market but no drug is found to be completely safe and effective. The toxicity of the drugs is the key problem in the cancer chemotherapy. However, plants and plant derived bioactive molecule have proved safe and effective in the treatment of cancers. Phytochemicals that are found in fruits, vegetables, herbs, and plant extract have been usually used for treating cancer. It has been established that several herbal drug have a strong anticancer activity. However, their poor bioavailability, solubility, and stability have severely restricted their use. These problems can be overcome by incorporating the herbal drug in nanolipolomal vesicles. In last few decades, researcher have used herbal drug loaded nanoliposome for the treatment and management of a variety of cancers. Presently, a number of liposomal formulations are on the market for the treatment of cancer and many more are in pipe line. This review discusses about the tumor microenvironment, targeting mechanism of bioactive phytochemicals to the tumor tissue, background of nanoliposome, and the potential therapeutic applications of different bioactive phytochemicals loaded nanoliposome in cancer therapy.