Signs of Warning: Do Health Warning Messages on Sweets Affect the Neural Prefrontal Cortex Activity?
In the global attempt to combat rising obesity rates, the introduction of health warning messages on food products is discussed as one possible approach. However, the perception of graphical health warning messages in the food context and the possible impact that they may have, in particular at the neuronal level, have hardly been studied. Therefore, the aim of this explorative study was to examine consumers' reactions (measured as neuronal activity and subjective reporting) of two different types of graphical health warning messages on sweets compared to sweets without warning messages. One type used the red road traffic stop sign as graphical information ("Stop"), while the other one used shocking pictures ("Shock"), an approach similar to the images on cigarette packages. The neural response of 78 participants was examined with the neuroimaging technique functional near-infrared spectroscopy (fNIRS). Different hemodynamic responses in the orbitofrontal cortex (OFC), the frontopolar cortex (FOC), and the dorsolateral prefrontal cortex (dlPFC) were observed, regions which are associated with reward evaluation, social behavior consequences, and self-control. Further, the health warning messages were actively and emotionally remembered by the participants. These findings point to an interesting health information strategy, which should be explored and discussed further.


Prediction of acute toxicity of emerging contaminants on the water flea Daphnia magna by Ant Colony Optimization-Support Vector Machine QSTR models.
According to the European REACH Directive, the acute toxicity towards Daphnia magna should be assessed for any industrial chemical with a market volume of more than 1 t/a. Therefore, it is highly recommended to determine the toxicity at a certain confidence level, either experimentally or by applying reliable prediction models. To this end, a large dataset was compiled, with the experimental acute toxicity values (pLC50) of 1353 compounds in Daphnia magna after 48 h of exposure. A novel quantitative structure-toxicity relationship (QSTR) model was developed, using Ant Colony Optimization (ACO) to select the most relevant set of molecular descriptors, and Support Vector Machine (SVM) to correlate the selected descriptors with the toxicity data. The proposed model showed high performance (QLOO2 = 0.695, Rfitting2 = 0.920 and Rtest2 = 0.831) with low root mean square errors of 0.498 and 0.707 for the training and test set, respectively. It was found that, in addition to hydrophobicity, polarizability and summation of solute-hydrogen bond basicity affected toxicity positively, while minimum atom-type E-state of -OH influenced toxicity values in Daphnia magna inversely. The applicability domain of the proposed model was carefully studied, considering the effect of chemical structure and prediction error in terms of leverage values and standardized residuals. In addition, a new method was proposed to define the chemical space failure for a compound with unknown toxicity to avoid using these prediction results. The resulting ACO-SVM model was successfully applied on an additional evaluation set and the prediction results were found to be very accurate for those compounds that fall inside the defined applicability domain. In fact, compounds commonly found to be difficult to predict, such as quaternary ammonium compounds or organotin compounds were outside the applicability domain, while five representative homologues of LAS (non-ionic surfactants) were, on average, well predicted within one order of magnitude.


A statistical appraisal of disproportional versus proportional microbial source tracking libraries.
Library-based microbial source tracking (MST) can assist in reducing or eliminating fecal pollution in waters by predicting sources of fecal-associated bacteria. Library-based MST relies on an assembly of genetic or phenotypic "fingerprints" from pollution-indicative bacteria cultivated from known sources to compare with and identify fingerprints of unknown origin. The success of the library-based approach depends on how well each source candidate is represented in the library and which statistical algorithm or matching criterion is used to match unknowns. Because known source libraries are often built based on convenience or cost, some library sources may contain more representation than others. Depending on the statistical algorithm or matching criteria, predictions may become severely biased toward classifying unknowns into the library's dominant source category. We examined prediction bias for four of the most commonly used statistical matching algorithms in library-based MST when applied to disproportionately-represented known source libraries; maximum similarity (MS), average similarity (AS), discriminant analyses (DA), and k-means nearest neighbor (k-NN). MS was particularly sensitive to disproportionate source representation. AS and DA were more robust. k-NN provided a compromise between correct prediction and sensitivity to disproportional libraries including increased matching success and stability that should be considered when matching to disproportionally-represented libraries.


Human cervical cancer as a venereal disease.
The operation of venereal factors in human cervical cancer is suggested by demographic and epidemiological data. Recent evidence supporting the genital herpesvirus hypothesis is consistent with this notion. A controlled epidemiological investigation has been undertaken on the role of the male coital partner in cervical carcinogenesis. An answer is sought to the question, "Is the risk of developing cervical cancer increased among the wives of men who at some other time were married to other women who developed cervical cancer?" With one-quarter of the study completed, a total of 14 marital clusters have been identified in which 2 or more wives of the same men developed cervical carcinoma. The expected number of such clusters is estimated to be 4.


Quintuple-zeta quality coupled-cluster correlation energies with triple-zeta basis sets.
The explicitly-correlated coupled-cluster method CCSD(T)(R12) is extended to include F12 geminal basis functions that decay exponentially with the interelectronic distance and reproduce the form of the average Coulomb hole more accurately than linear-r(12). Equations derived using the Ansatz 2 strong orthogonality projector are presented. The convergence of the correlation energy with orbital basis set for the new CCSD(T)(F12) method is studied and found to be rapid, 98% of the basis set limit correlation energy is typically recovered using triple-zeta orbital basis sets. The performance for reaction enthalpies is assessed via a test set of 15 reactions involving 23 molecules. The title statement is found to hold equally true for total and relative correlation energies.


Tuberculous anal fistulas--prevalence and clinical features in an endemic area.
The aim of this study was to determine the prevalence of tuberculosis (TB) in anal fistulas at a referral hospital in Cape Town, and to document the clinical features and course of patients with tuberculous anal fistulas. This was a prospective study of all patients who underwent surgery for anal fistulas at the Colorectal Surgery Unit at Groote Schuur Hospital, Cape Town, from 2004 to 2006. Tissue was submitted for histopathological examination, Ziehl-Neelsen (ZN) staining and TB culture. The patients with proven TB were followed up until January 2008. During the 3-year study period, 117 operations were performed on 96 patients. TB was diagnosed in 7 of the 96 patients (7.3%). In 5 of these 7 cases, the diagnosis of TB could be proven on histological examination and ZN staining, while in 2 cases the diagnosis could only be made on TB culture. None of the 7 patients had systemic features suggestive of TB, and only 1 had evidence of TB on a chest radiograph, Five patients were HIV-negative, and 2 declined testing. After a median follow-up of 2 years, 5 of 7 patients had evidence of recurrent or persistent fistulas, despite having completed 6 months of TB treatment. At a referral hospital in an endemic area, TB was present in 7.3% of anal fistulas. Histopathological examination including ZN staining was inadequate to make the diagnosis in a third of these patients. Tissue from anal fistulas should therefore routinely be sent for TB culture as well as histopathological examination and ZN staining in areas where TB is prevalent.


Identification of flame retardants in polyurethane foam collected from baby products.
With the phase-out of PentaBDE in 2004, alternative flame retardants are being used in polyurethane foam to meet flammability standards. However, insufficient information is available on the identity of the flame retardants currently in use. Baby products containing polyurethane foam must meet California state furniture flammability standards, which likely affects the use of flame retardants in baby products throughout the U.S. However, it is unclear which products contain flame retardants and at what concentrations. In this study we surveyed baby products containing polyurethane foam to investigate how often flame retardants were used in these products. Information on when the products were purchased and whether they contained a label indicating that the product meets requirements for a California flammability standard were recorded. When possible, we identified the flame retardants being used and their concentrations in the foam. Foam samples collected from 101 commonly used baby products were analyzed. Eighty samples contained an identifiable flame retardant additive, and all but one of these was either chlorinated or brominated. The most common flame retardant detected was tris(1,3-dichloroisopropyl) phosphate (TDCPP; detection frequency 36%), followed by components typically found in the Firemaster550 commercial mixture (detection frequency 17%). Five samples contained PBDE congeners commonly associated with PentaBDE, suggesting products with PentaBDE are still in-use. Two chlorinated organophosphate flame retardants (OPFRs) not previously documented in the environment were also identified, one of which is commercially sold as V6 (detection frequency 15%) and contains tris(2-chloroethyl) phosphate (TCEP) as an impurity. As an addition to this study, we used a portable X-ray fluorescence (XRF) analyzer to estimate the bromine and chlorine content of the foam and investigate whether XRF is a useful method for predicting the presence of halogenated flame retardant additives in these products. A significant correlation was observed for bromine; however, there was no significant relationship observed for chlorine. To the authors knowledge, this is the first study to report on flame retardants in baby products. In addition, we have identified two chlorinated OPFRs not previously documented in the environment or in consumer products. Based on exposure estimates conducted by the Consumer Product Safety Commission (CPSC), we predict that infants may receive greater exposure to TDCPP from these products compared to the average child or adult from upholstered furniture, all of which are higher than acceptable daily intake levels of TDCPP set by the CPSC. Future studies are therefore warranted to specifically measure infants exposure to these flame retardants from intimate contact with these products and to determine if there are any associated health concerns.


Orofacial dermoid cysts in pediatric patients: a review of 8 cases.
The aim was to analyze the clinical characteristics, treatment and outcome of 8 orofacial dermoid cysts (DC) in pediatric patients. A retrospective observational study was made, reviewing the medical records with clinical diagnosis of dermoid cyst between 1987 and 2006 in the Children's Maxillofacial Surgery Department of the Hospital Universitario La Fe, Valencia, Spain. The following data were collected: sex, age, location, size and duration of the lesion, treatment, length of follow-up, and recurrence. Eight patients (3 girls and 5 boys) with a mean age of 2.7 years (range 0-12 years). Four DC were located in the oral area (3 sublingual and 1 lingual), one in the periorbital and three in the nasal areas. The size ranged from 0.8 cm to 4 cm. The mean duration of the lesion was 13.7 months (range 4 days to 2 years). All DC were diagnosed pathologically following surgical removal of the lesion. There were no recurrences. The appearance of DC in the maxillofacial region of pediatric patients is uncommon. The floor of the mouth is the most frequently affected area in the oral cavity. Treatment is surgical removal of the lesion. Recurrence is unusual.


Regulation of Saccharomyces cerevisiae kinetochores by the type 1 phosphatase Glc7p.
We have investigated the role of protein phosphorylation in regulation of Saccharomyces cerevisiae kinetochores. By use of phosphatase inhibitors and a type 1 protein phosphatase mutant (glc7-10), we show that the microtubule binding activity, but not the centromeric DNA-binding activity, of the kinetochore complex is regulated by a balance between a protein kinase and the type 1 protein phosphatase (PP1) encoded by the GLC7 gene. glc7-10 mutant cells exhibit low kinetochore-microtubule binding activity in vitro and a high frequency of chromosome loss in vivo. Specifically, the Ndc10p component of the centromere DNA-binding CBF3 complex is altered by the glc7-10 mutation; Ndc10p is hyperphosphorylated in glc7-10 extracts. Furthermore, addition of recombinant Ndc10p reconstitutes the microtubule-binding activity of a glc7-10 extract to wild-type levels. Finally, the glc7-10-induced mitotic arrest is abolished in spindle checkpoint mutants, suggesting that defects in kinetochore-microtubule interactions caused by hyperphosphorylation of kinetochore proteins activate the spindle checkpoint.


Temporal Progress of Septoria Leaf Spot on Rabbiteye Blueberry (Vaccinium ashei).
Septoria leaf spot, caused by Septoria albopunctata, is an important disease on blueberry in the southeastern United States, yet its epidemiology is largely unknown. Disease severity and dissemination of pycnidiospores were monitored from 2002 to 2004 in a planting of susceptible Premier rabbiteye blueberry to characterize the temporal progress of the disease and determine the effect of inoculum dynamics and selected leaf attributes on disease development. Disease onset was observed between late April and mid-June, followed by a rapid increase in disease severity until mid- to late September; thereafter, disease severity decreased until the end of the season due to abscission of severely infected leaves. A logistic model was fitted to disease severity data using nonlinear regression, and parameter estimates were used to compare the effects of leaf position on the shoot and shoot location in the canopy on disease progress. Based on this model, the highest absolute rate of disease increase and the highest upper asymptote of disease severity were predicted for leaves in intermediate positions on the shoot and for shoots in the lower canopy. Data collected with funnel spore samplers showed that splash-dispersed pycnidiospores of S. albopunctata were available throughout most of the period from April through late October. Final disease severity on individual leaves was more strongly correlated with cumulative spore numbers throughout the entire season (from leaf emergence to the end of the assessment period in November) than with cumulative spore numbers during shorter periods around the time of leaf emergence; this suggests that infection is not limited to young, expanding leaves, but rather that leaves at all developmental stages can become infected by S. albopunctata seasonlong. Disease incidence on leaves of potted trap plants exposed to natural inoculum in the field during rain events in 2003 and 2004 was >70.0% irrespective of leaf developmental stage at the time of exposure. Taken together, the results of this study indicate that inoculum of S. albopunctata is present throughout most of the growing season and that infection can occur season-long on leaves of any age, giving rise to a polycyclic epidemic.


Nutrition and bone health in women after the menopause.
Osteoporosis affects one out of three postmenopausal women. Their remaining lifetime risk of fragility fractures exceeds that of breast cancer. The risk of osteoporosis and/or fragility fractures can be reduced through healthy lifestyle changes. These include adequate dietary intakes of calcium, vitamin D and protein, regular weight-bearing exercise, reduction in alcohol intake and smoking cessation. European guidance for the diagnosis and management of osteoporosis in postmenopausal women recommends a daily intake of at least 1000 mg/day for calcium, 800 IU/day for vitamin D and 1 g/kg body weight of protein for all women aged over 50 years. The development of programs that encourage lifestyle changes (in particular balanced nutrient intakes) are therefore essential for the reduction of osteoporosis risk.


Detecting change in comparison to peers in NHS prescribing data: a novel application of cumulative sum methodology.
The widely used OpenPrescribing.net service provides standard measures which compare prescribing of Clinical Commissioning Groups (CCGs) and English General Practices against that of their peers. Detecting changes in prescribing behaviour compared with peers can help identify missed opportunities for medicines optimisation. Automating the process of detecting these changes is necessary due to the volume of data, but challenging due to variation in prescribing volume for different measures and locations. We set out to develop and implement a method of detecting change on all individual prescribing measures, in order to notify CCGs and practices of such changes in a timely manner. We used the statistical process control method CUSUM to detect prescribing behaviour changes in relation to population trends for the individual standard measures on OpenPrescribing. Increases and decreases in percentile were detected separately, using a multiple of standard deviation as the threshold for detecting change. The algorithm was modified to continue re-triggering when trajectory persists. It was deployed, user-tested, and summary statistics generated on the number of alerts by CCG and practice. The algorithm detected changes in prescribing for 32 prespecified measures, across a wide range of CCG and practice sizes. Across the 209 English CCGs, a mean of 2.5 increase and 2.4 decrease alerts were triggered per CCG, per month. For the 7578 practices, a mean of 1.3 increase and 1.4 decrease alerts were triggered per practice, per month. The CUSUM method appears to effectively discriminate between random noise and sustained change in prescribing behaviour. This method aims to allow practices and CCGs to be informed of important changes quickly, with a view to improve their prescribing behaviour. The number of alerts triggered for CCGs and practices appears to be appropriate. Prescribing behaviour after users are alerted to changes will be monitored in order to assess the impact of these alerts.


Effects of land use, habitat characteristics, and small mammal community composition on Leptospira prevalence in northeast Madagascar.
Human activities can increase or decrease risks of acquiring a zoonotic disease, notably by affecting the composition and abundance of hosts. This study investigated the links between land use and infectious disease risk in northeast Madagascar, where human subsistence activities and population growth are encroaching on native habitats and the associated biota. We collected new data on pathogenic Leptospira, which are bacteria maintained in small mammal reservoirs. Transmission can occur through close contact, but most frequently through indirect contact with water contaminated by the urine of infected hosts. The probability of infection and prevalence was compared across a gradient of natural moist evergreen forest, nearby forest fragments, flooded rice and other types of agricultural fields, and in homes in a rural village. Using these data, we tested specific hypotheses for how land use alters ecological communities and influences disease transmission. The relative abundance and proportion of exotic species was highest in the anthropogenic habitats, while the relative abundance of native species was highest in the forested habitats. Prevalence of Leptospira was significantly higher in introduced compared to endemic species. Lastly, the probability of infection with Leptospira was highest in introduced small mammal species, and lower in forest fragments compared to other habitat types. Our results highlight how human land use affects the small mammal community composition and in turn disease dynamics. Introduced species likely transmit Leptospira to native species where they co-occur, and may displace the Leptospira species naturally occurring in Madagascar. The frequent spatial overlap of people and introduced species likely also has consequences for public health.


Investigation of the Blood Glucose Lowering Potential of the Jamaican Momordica charantia (Cerasee) Fruit in Sprague-Dawley Rats.
The Momordica charantia (MC) fruit has been documented to possess antidiabetic properties. However, these studies were not without controversy surrounding the blood glucose-lowering ability and the mechanism of action in diabetes therapy. In an effort to evaluate such claims in the Jamaican MC species known as cerasee, aqueous extracts of the unripe fruit were studied in normal and diabetic rats. Normal male Sprague-Dawley rats were divided into groups (n = 6) orally administered distilled water, 10% dimethyl sulfoxide (DMSO) solution, the aqueous extract (400 mg/kg body weight) and glibenclamide (15 mg/kg body weight), respectively prior to assessment of fasting blood glucose (FBG) concentration. The oral glucose tolerance test (OGTT) was conducted in normoglycaemic rats orally administered distilled water, 10% DMSO solution, glibenclamide (15 mg/kg body weight) or aqueous extracts of the fruit (200 and 400 mg/kg body weight). Blood glucose concentration was also monitored in streptozotocin-induced diabetic rats administered the aqueous extract (250 mg/kg body weight) or water vehicle after an overnight fast. The aqueous extracts showed no hypoglycaemic or antidiabetic activity. However, the administration of the aqueous extracts (200 and 400 mg/kg body weight) resulted in significant improvement in glucose tolerance of glucose-primed normoglycaemic rats during the OGTT. These data suggest that the glucose-lowering mechanism of the Jamaican MC fruit species likely involves altered glucose absorption across the gastrointestinal tract.


Release of 50 new, drug-like compounds and their computational target predictions for open source anti-tubercular drug discovery.
As a follow up to the antimycobacterial screening exercise and the release of GSK´s first Tres Cantos Antimycobacterial Set (TCAMS-TB), this paper presents the results of a second antitubercular screening effort of two hundred and fifty thousand compounds recently added to the GSK collection. The compounds were further prioritized based on not only antitubercular potency but also on physicochemical characteristics. The 50 most attractive compounds were then progressed for evaluation in three different predictive computational biology algorithms based on structural similarity or GSK historical biological assay data in order to determine their possible mechanisms of action. This effort has resulted in the identification of novel compounds and their hypothesized targets that will hopefully fuel future TB drug discovery and target validation programs alike.


Development and initial validation of the Asthma Severity Scoring System (ASSESS).
Tools for quantification of asthma severity are limited. We sought to develop a continuous measure of asthma severity, the Asthma Severity Scoring System (ASSESS), for adolescents and adults, incorporating domains of asthma control, lung function, medications, and exacerbations. Baseline and 36-month longitudinal data from participants in phase 3 of the Severe Asthma Research Program (NCT01606826) were used. Scale properties, responsiveness, and a minimally important difference were determined. External replication was performed in participants enrolled in the Severe Asthma Research Program phase 1/2. The utility of ASSESS for detecting treatment response was explored in participants undergoing corticosteroid responsiveness testing with intramuscular triamcinolone and participants receiving biologics. ASSESS scores ranged from 0 to 20 (8.78 ± 3.9; greater scores reflect worse severity) and differed among 5 phenotypic groups. Measurement properties were acceptable. ASSESS was responsive to changes in quality of life with a minimally important difference of 2, with good specificity for outcomes of asthma improvement and worsening but poor sensitivity. Replication analyses yielded similar results, with a 2-point decrease (improvement) associated with improvements in quality of life. Participants with a 2-point or greater decrease (improvement) in ASSESS scores also had greater improvement in lung function and asthma control after triamcinolone, but these differences were limited to phenotypic clusters 3, 4, and 5. Participants treated with biologics also had a 2-point or greater decrease (improvement) in ASSESS scores overall. The ASSESS tool is an objective measure that might be useful in epidemiologic and clinical research studies for quantification of treatment response in individual patients and phenotypic groups. However, validation studies are warranted.


Biospecimen Complexity-the Next Challenge for Cancer Research Biobanks?
Purpose: Biospecimens (e.g., tissues, bloods, fluids) are critical for translational cancer research to generate the necessary knowledge to guide implementation of precision medicine. Rising demand and the need for higher quality biospecimens are already evident.Experimental Design: The recent increase in requirement for biospecimen complexity in terms of linked biospecimen types, multiple preservation formats, and longitudinal data was explored by assessing trends in cancer research publications from 2000 to 2014.Results: A PubMed search shows that there has been an increase in both raw numbers and the relative proportion (adjusted for total numbers of articles in each period) of the subgroups of articles typically associated with the use of biospecimens and both dense treatment and/or outcomes data and multiple biospecimen formats.Conclusions: Increasing biospecimen complexity is a largely unrecognized and new pressure on cancer research biobanks. New approaches to cancer biospecimen resources are needed such as the implementation of more efficient and dynamic consent mechanisms, stronger participant involvement in biobank governance, development of requirements for registration of collections, and models to establish stock targets for biobanks. In particular, the latter two approaches would enable funders to establish a better balance between biospecimen supply and research demand, reduce expenditure on duplicate collections, and encourage increased efficiency of biobanks to respond to the research need for more complex cases. This in turn would also enable biobanks to focus more on quality and standardization that are surely factors in the even more important arena of research reproducibility. Clin Cancer Res; 23(4); 894-8. ©2016 AACR.


Thalamic resting-state functional networks: disruption in patients with mild traumatic brain injury.
To explore the neural correlates of the thalamus by using resting-state functional magnetic resonance (MR) imaging and to investigate whether thalamic resting-state networks (RSNs) are disrupted in patients with mild traumatic brain injury (MTBI). This HIPAA-compliant study was approved by the institutional review board, and written informed consent was obtained from 24 patients with MTBI and 17 healthy control subjects. The patients had varying degrees of symptoms, with a mean disease duration of 22 days. The resting-state functional MR imaging data were analyzed by using a standard seed-based whole-brain correlation method to characterize thalamic RSNs. Student t tests were used to perform comparisons. The association between thalamic RSNs and performance on neuropsychologic and neurobehavioral measures was also investigated in patients with MTBI by using Spearman rank correlation. A normal pattern of thalamic RSNs was demonstrated in healthy subjects. This pattern was characterized as representing relatively symmetric and restrictive functional thalamocortical connectivity, suggesting an inhibitory property of the thalamic neurons during the resting state. This pattern was disrupted, with significantly increased thalamic RSNs (P ≤ .005) and decreased symmetry (P = .03) in patients with MTBI compared with healthy control subjects. Increased functional thalamocortical redistributive connectivity was correlated with diminished neurocognitive functions and clinical symptoms in patients with MTBI. These findings of abnormal thalamic RSNs lend further support to the presumed subtle thalamic injury in patients with MTBI. Resting-state functional MR imaging can be used as an additional imaging modality for detection of thalamocortical connectivity abnormalities and for better understanding of the complex persistent postconcussive syndrome.


The effects of two polymorphisms on p21cip1 function and their association with Alzheimer's disease in a population of European descent.
With the exception of ApoE4, genome-wide association studies have failed to identify strong genetic risk factors for late-onset Alzheimer's disease, despite strong evidence of heritability, suggesting that many low penetrance genes may be involved. Additionally, the nature of the identified genetic risk factors and their relation to disease pathology is also largely obscure. Previous studies have found that a cancer-associated variant of the cell cycle inhibitor gene p21cip1 is associated with increased risk of Alzheimer's disease. The aim of this study was to confirm this association and to elucidate the effects of the variant on protein function and Alzheimer-type pathology. We examined the association of the p21cip1 variant with Alzheimer's disease and Parkinson's disease with dementia. The genotyping studies were performed on 719 participants of the Oxford Project to Investigate Memory and Ageing, 225 participants of a Parkinson's disease DNA bank, and 477 participants of the Human Random Control collection available from the European Collection of Cell Cultures. The post mortem studies were carried out on 190 participants. In the in-vitro study, human embryonic kidney cells were transfected with either the common or rare p21cip1 variant; and cytometry was used to assess cell cycle kinetics, p21cip1 protein expression and sub-cellular localisation. The variant was associated with an increased risk of Alzheimer's disease, and Parkinson's disease with dementia, relative to age matched controls. Furthermore, the variant was associated with an earlier age of onset of Alzheimer's disease, and a more severe phenotype, with a primary influence on the accumulation of tangle pathology. In the in-vitro study, we found that the SNPs reduced the cell cycle inhibitory and anti-apoptotic activity of p21cip1. The results suggest that the cancer-associated variant of p21cip1 may contribute to the loss of cell cycle control in neurons that may lead to Alzheimer-type neurodegeneration.


Structural basis for targeted DNA cytosine deamination and mutagenesis by APOBEC3A and APOBEC3B.
APOBEC-catalyzed cytosine-to-uracil deamination of single-stranded DNA (ssDNA) has beneficial functions in immunity and detrimental effects in cancer. APOBEC enzymes have intrinsic dinucleotide specificities that impart hallmark mutation signatures. Although numerous structures have been solved, mechanisms for global ssDNA recognition and local target-sequence selection remain unclear. Here we report crystal structures of human APOBEC3A and a chimera of human APOBEC3B and APOBEC3A bound to ssDNA at 3.1-Å and 1.7-Å resolution, respectively. These structures reveal a U-shaped DNA conformation, with the specificity-conferring -1 thymine flipped out and the target cytosine inserted deep into the zinc-coordinating active site pocket. The -1 thymine base fits into a groove between flexible loops and makes direct hydrogen bonds with the protein, accounting for the strong 5'-TC preference. These findings explain both conserved and unique properties among APOBEC family members, and they provide a basis for the rational design of inhibitors to impede the evolvability of viruses and tumors.


In vitro fermentation of linear and alpha-1,2-branched dextrans by the human fecal microbiota.
The role of structure and molecular weight in fermentation selectivity in linear α-1,6 dextrans and dextrans with α-1,2 branching was investigated. Fermentation by gut bacteria was determined in anaerobic, pH-controlled fecal batch cultures after 36 h. Inulin (1%, wt/vol), which is a known prebiotic, was used as a control. Samples were obtained at 0, 10, 24, and 36 h of fermentation for bacterial enumeration by fluorescent in situ hybridization and short-chain fatty acid analyses. The gas production of the substrate fermentation was investigated in non-pH-controlled, fecal batch culture tubes after 36 h. Linear and branched 1-kDa dextrans produced significant increases in Bifidobacterium populations. The degree of α-1,2 branching did not influence the Bifidobacterium populations; however, α-1,2 branching increased the dietary fiber content, implying a decrease in digestibility. Other measured bacteria were unaffected by the test substrates except for the Bacteroides-Prevotella group, the growth levels of which were increased on inulin and 6- and 70-kDa dextrans, and the Faecalibacterium prausnitzii group, the growth levels of which were decreased on inulin and 1-kDa dextrans. A considerable increase in short-chain fatty acid concentration was measured following the fermentation of all dextrans and inulin. Gas production rates were similar among all dextrans tested but were significantly slower than that for inulin. The linear 1-kDa dextran produced lower total gas and shorter time to attain maximal gas production compared to those of the 70-kDa dextran (branched) and inulin. These findings indicate that dextrans induce a selective effect on the gut flora, short-chain fatty acids, and gas production depending on their length.


Airway stents.
Stents and tubes to maintain the patency of the airways are commonly used for malignant obstruction and are occasionally employed in benign disease. Malignant airway obstruction usually results from direct involvement of bronchogenic carcinoma, or by extension of carcinomas occurring in the esophagus or the thyroid. External compression from lymph nodes or metastatic disease from other organs can also cause central airway obstruction. Most malignant airway lesions are surgically inoperable due to advanced disease stage and require multimodality palliation, including stent placement. As with any other medical device, stents have significantly evolved over the last 50 years and deserve an in-depth understanding of their true capabilities and complications. Not every silicone stent is created equal and the same holds for metallic stents. Herein, we present an overview of the topic as well as some of the more practical and controversial issues surrounding airway stents. We also try to dispel the myths surrounding stent removal and their supposed use only in central airways. At the end, we come to the long-held conclusion that stents should not be used as first line treatment of choice, but after ruling out the possibility of curative surgical resection or repair.


Diffraction efficiency analysis of a parallel-aligned nematic-liquid-crystal spatial light modulator.
An optically addressed parallel-aligned nematic-liquid-crystal spatial light modulator is developed for applications in optical information processing and interferometry. Its performance, including diffraction efficiency, is measured, and a theoretical analysis of diffraction efficiency is performed. A comparison between the experimental results and the theoretical analysis shows good agreement. The diffraction efficiency of near-sinusoidal gratings written on the device is of the order of 30%, which is close to theoretical maximum.


More Unnecessary Imaginary Worlds - Part 1: The Institute for Clinical and Economic Review's Evidence Report on Janus Kinase (JAK) Inhibitors in Rheumatoid Arthritis.
Previous commentaries in the Formulary Evaluation section of INNOVATIONS in Pharmacy have pointed to the lack of credibility in modeled claims for cost-effectiveness and associated recommendations for pricing by the Institute for Clinical and Economic Review (ICER). The principal objection to ICER reports has been that their modeled claims fail the standards of normal science: they are best seen as pseudoscience. The purpose of this latest commentary is to consider the recently released ICER evidence report for Janus Kinase (JAK) Inhibitors. As ICER continues, in the case of JAK Inhibitors, to apply its modeled cost utility framework with consequent recommendations for pricing adjustments, these recommendations also lack credibility. In contrast with previous ICER evidence reports, the present report adopts only a 12-month timeframe, one due, in large part, to ICER being unable to justify assumptions to drive its construction of imaginary worlds beyond 12 months. This commentary emphasizesagain, why the ICER methodology fails to meet the standards of normal science. Claims made by ICER for the competing JAK Inhibitor therapies lack credibility, are impossible to evaluate, let alone replicate across treatment settings. Even so, it is important to examine a number of key elements in the ICER invention of the 12-month JAK Inhibitor imaginary world. While this does not imply any degree of acceptance of the ICER methodology, one element that merits particular attention is thefailure of the ICER modeling to meet logically defensible measurement standards in its application of generic health related quality of life (HRQoL) ordinal metrics to create its QALY claims. The failure to meet the required standards of fundamental measurement means that the cost-per-QALY claims are invalid. This raises the issue of the application of Rasch Measurement Theory (RMT) in instrument development and the potential role of patient centric outcome (PCO) instruments that represent the patient voice in value claims. The case made here is that the ICER approach should be abandoned as an unnecessary distraction. If we are to meet standards for the discovery of new facts in therapy response then our focus must be on proposing credible, evaluable and replicable claims within disease states. Instruments, such as the Rheumatoid Arthritis Quality of Life (RAQoL)questionnaire that build on the common construct that QoL is the extent to which human needs are fulfilled should be the basis for value claims. HRQoL Instruments that are clinically focused and reflect the value calculus of providers and not patients in measuring response by symptoms and activity limitations are irrelevant. This puts to one side the belief that incremental cost-per-QALY models, the construction of imaginary worlds are, in any sense, a 'gold standard'; a meme embraced by the health technology assessment profession. Claims for incremental cost per QALY outcomes and recommendations for pricing and access driven by willingness to pay thresholds are irrelevant to formulary decisions.


Botulinum toxin A as an adjunct to treatment in the management of the upper limb in children with spastic cerebral palsy (UPDATE).
Cerebral palsy (CP) is "a group of permanent disorders of the development of movement and posture causing activity limitation(s) that are attributed to non-progressive disturbance that occurred in the developing fetal or infant brain" (Rosenbaum 2007, p.9). The spastic motor type is the most common form of CP. Therapeutic management may include splinting/casting, passive stretching, facilitation of posture/movement, spasticity-reducing medication and surgery. Botulinum toxin-A (BoNT-A) is now used as an adjunct to these techniques in an attempt to reduce spasticity, improve range of movement and function. To assess the effectiveness of injections of BoNT-A or BoNT-A and occupational therapy in the treatment of the upper limb in children with CP. We searched the Cochrane Controlled Trials Register/CENTRAL (The Cochrane Library, Issue 3, 2008), MEDLINE (1966 to August Week 1 2008), EMBASE (1980 to 2008 Week 28) and CINAHL (1982 to August Week 1 2008). All randomised controlled trials (RCTs) comparing BoNT-A injection or BoNT-A injection and occupational therapy in the upper limb(s) with other types of treatment (including no treatment or placebo) in children with CP. Two authors using standardised forms extracted the data independently. Each trial was assessed for internal validity and rated for quality using the PEDro scale. Data were extracted and entered into RevMan 5.0.15. Ten trials met the inclusion criteria. PEDro quality ratings ranged from 6/10 to 10/10. Concentration of BoNT-A ranged from 50U/1.0ml to 200U/1.0ml saline with doses of 0.5U to 16U/kg body weight and total doses of 220 to 410 Units (Botox(R)).A combination of BoNT-A and occupational therapy is more effective than occupational therapy alone in reducing impairment, improving activity level outcomes and goal achievement, but not for improving quality of life or perceived self-competence. When compared with placebo or no treatment, there is moderate evidence that BoNT-A alone is not effective. This systematic review found high level evidence supporting the use of BoNT-A as an adjunct to managing the upper limb in children with spastic CP. BoNT-A should not be used in isolation but should be accompanied by planned occupational therapy.Further research is essential to identify children most likely to respond to BoNT-A injections, monitor longitudinal outcomes, determine timing and effect of repeated injections and the most effective dosage, dilution and volume schedules. The most effective adjunct therapies including frequency and intensity of delivery also requires investigation.


Clinical results of XMR-assisted percutaneous transforaminal endoscopic lumbar discectomy.
Although percutaneous endoscopic lumbar discectomy (PELD) has shown favorable outcomes in the majority of lumbar discectomy cases, there were also some failures. The most common cause of failure is the incomplete removal of disc fragments. The skin entry point for the guide-needle trajectory and the optimal placement of the working sleeve are largely blind, which might lead to the inadequate removal of disc fragments. The objective of this study was to present our early experiences with image-guided PELD using a specially designed fluoroscope with magnetic resonance imaging-equipped operative suite (XMR) for the treatment of lumbar disc herniation. This prospective study included 89 patients who had undergone PELD via the transforaminal approach using an XMR protocol. Pre- and postoperative examinations (at 12 weeks) included a detailed clinical history, visual analogue scale (VAS), Oswestry disability index (ODI), and radiological workups. The results were categorized as excellent, good, fair, and poor according to MacNab's criteria. At the final follow-up, the minimum follow-up time for the subjects was 2 years. The need for revision surgeries and postoperative complications were noted on follow-up. Postoperative mean ODI decreased from 67.4% to 5.61%. Mean VAS score for back and leg pain improved significantly from 4 to 2.3 and from 7.99 to 1.04, respectively. Four (4.49%) patients underwent a second-stage PELD after intraoperative XMR had shown remnant fragments after the first stage. As per MacNab's criteria, 76 patients (85.4%) showed excellent, 8 (8.89%) good, 3 (3.37%) fair, and 2 (2.25) poor results. Four (4.49%) patients had remnant disc fragments on XMR, which were removed during the same procedure. All of these patients had either highly migrated or sequestrated disc fragments preoperatively. Four (4.49%) other patients needed a second, open surgery due to symptomatic postoperative hematoma (n = 2) and recurrent disc herniation (n = 2). This prospective analysis indicates that XMR-assisted PELD provides a precise skin entry point. It also confirms that decompression occurs intraoperatively, which negates the need for a separate surgery and thus increases the success rate of PELD, particularly in highly migrated or sequestrated discs. However, further extensive experience is required to confirm the advantages and feasibility of PELD in terms of cost effectiveness.


Oscillatory activity and phase-amplitude coupling in the human medial frontal cortex during decision making.
Electroencephalogram oscillations recorded both within and over the medial frontal cortex have been linked to a range of cognitive functions, including positive and negative feedback processing. Medial frontal oscillatory characteristics during decision making remain largely unknown. Here, we examined oscillatory activity of the human medial frontal cortex recorded while subjects played a competitive decision-making game. Distinct patterns of power and cross-trial phase coherence in multiple frequency bands were observed during different decision-related processes (e.g., feedback anticipation vs. feedback processing). Decision and feedback processing were accompanied by a broadband increase in cross-trial phase coherence at around 220 msec, and dynamic fluctuations in power. Feedback anticipation was accompanied by a shift in the power spectrum from relatively lower (delta and theta) to higher (alpha and beta) power. Power and cross-trial phase coherence were greater following losses compared to wins in theta, alpha, and beta frequency bands, but were greater following wins compared to losses in the delta band. Finally, we found that oscillation power in alpha and beta frequency bands were synchronized with the phase of delta and theta oscillations ("phase-amplitude coupling"). This synchronization differed between losses and wins, suggesting that phase-amplitude coupling might reflect a mechanism of feedback valence coding in the medial frontal cortex. Our findings link medial frontal oscillations to decision making, with relations among activity in different frequency bands suggesting a phase-utilizing coding of feedback valence information.


Climate change considerations are fundamental to management of deep-sea resource extraction.
Climate change manifestation in the ocean, through warming, oxygen loss, increasing acidification, and changing particulate organic carbon flux (one metric of altered food supply), is projected to affect most deep-ocean ecosystems concomitantly with increasing direct human disturbance. Climate drivers will alter deep-sea biodiversity and associated ecosystem services, and may interact with disturbance from resource extraction activities or even climate geoengineering. We suggest that to ensure the effective management of increasing use of the deep ocean (e.g., for bottom fishing, oil and gas extraction, and deep-seabed mining), environmental management and developing regulations must consider climate change. Strategic planning, impact assessment and monitoring, spatial management, application of the precautionary approach, and full-cost accounting of extraction activities should embrace climate consciousness. Coupled climate and biological modeling approaches applied in the water and on the seafloor can help accomplish this goal. For example, Earth-System Model projections of climate-change parameters at the seafloor reveal heterogeneity in projected climate hazard and time of emergence (beyond natural variability) in regions targeted for deep-seabed mining. Models that combine climate-induced changes in ocean circulation with particle tracking predict altered transport of early life stages (larvae) under climate change. Habitat suitability models can help assess the consequences of altered larval dispersal, predict climate refugia, and identify vulnerable regions for multiple species under climate change. Engaging the deep observing community can support the necessary data provisioning to mainstream climate into the development of environmental management plans. To illustrate this approach, we focus on deep-seabed mining and the International Seabed Authority, whose mandates include regulation of all mineral-related activities in international waters and protecting the marine environment from the harmful effects of mining. However, achieving deep-ocean sustainability under the UN Sustainable Development Goals will require integration of climate consideration across all policy sectors.


Comparison of T Helper Cell Patterns in Primary Open-Angle Glaucoma and Normal-Pressure Glaucoma.
BACKGROUND HSP60-related immunological activities are found in normal-pressure glaucoma (NPG) patients, in whom an elevated intraocular pressure (IOP) found in primary open-angle glaucoma (POAG) is not observed. HSP60 was found in POAG and NPG patients, while anti-HSP60 level was mainly found to be higher in NPG patients. The purpose of this study was to compare the percentages of Th cells and levels of related cytokines, attempting to provide evidence to explain this discrepancy. MATERIAL AND METHODS Blood samples from POAG, NPG, and normal control (NC) groups were collected and peripheral blood monocytes were isolated and cultured with or without the stimulation of HSP60. Flow cytometry and enzyme-linked immunosorbent assay were used to assess the percentages of Th1, Th2, Th17, and Treg cells, as well as HSP60 antibody levels and related cytokine levels, before and after culture. RESULTS Significantly higher titers of anti-HSP60 were observed only in NPG patients. Comparable Th1 and Th2 cell frequencies, IL-4 level, and IFN-γ level were found in POAG and NPG patients, while higher Treg cell frequency was only found in POAG patients. After culturing with HSP60, increased Th2 frequencies and decreased Th1 frequencies were observed in the POAG, NPG, and NC groups, while increased Treg frequency was only identified in the POAG and NC groups. CONCLUSIONS Different Th cell patterns were observed among POAG, NPG, and NC groups. Lack of induction of Treg cells and imbalance of the pro-inflammatory and anti-inflammatory response patterns of Th cells exist in some NPG patients.


Feasibility and efficacy of a physical activity intervention among pregnant women: the behaviors affecting baby and you (B.A.B.Y.) study.
Physical activity during pregnancy is associated with reduced risk of adverse maternal and fetal outcomes. However, the majority of pregnant women are inactive and interventions designed to increase exercise during pregnancy are sparse. We evaluated the feasibility and preliminary efficacy of an exercise intervention among a diverse sample of pregnant women. The B.A.B.Y. (Behaviors Affecting Baby and You) Study is conducted at a large tertiary care facility in Western Massachusetts. We randomized 110 prenatal care patients (60% Hispanic) to an individually tailored 12-week exercise intervention arm (n = 58) or to a health and wellness control arm (n = 52) at mean = 11.9 weeks gestation. Physical activity was assessed via the Pregnancy Physical Activity Questionnaire (PPAQ). After the 12-week intervention, the exercise arm experienced a smaller decrease (-1.0 MET-hrs/wk) in total activity vs. the control arm (-10.0 MET-hrs/wk; P = .03), and a higher increase in sports/exercise (0.9 MET-hrs/wk) vs. the control arm (-0.01 MET-hrs/wk; P = .02). Intervention participants (95%) reported being satisfied with the amount of information received and 86% reported finding the study materials interesting and useful. Findings support the feasibility and preliminary efficacy of a tailored exercise intervention in increasing exercise in a diverse sample of pregnant women.


Characteristics, satisfaction, and perceptions of patients receiving ambulatory healthcare from osteopathic physicians: a comparative national survey.
A national telephone survey was conducted in 1998 using random-digit dialing and the first Osteopathic Survey of Healthcare in America (OSTEOSURV-I) instrument to determine patients' satisfaction with their healthcare, as well as their perceptions of osteopathic medicine. Of the 1106 respondents, 243 (22.0%) had received medical care from an osteopathic physician, and another 307 (27.8%) claimed to be aware of osteopathic physicians. Patients of osteopathic physicians reported the highest levels of satisfaction in 8 of the 11 elements studied when compared with patients of allopathic physicians, chiropractors, and nonphysician clinicians other than chiropractors. Respondents perceived osteopathic manipulative treatment (OMT) to be beneficial for musculoskeletal disorders (P < .001). In addition, respondents perceived that healthcare services provided by osteopathic physicians were similar to those provided by allopathic physicians (P < .001), but not to those provided by chiropractors (P = .01). A total of 97.9% of current patients of osteopathic physicians agreed with the statement that osteopathic physicians practiced in their local community, compared with 80.6% of former patients of osteopathic physicians and 67.8% of patients who had never visited osteopathic physicians (P < .001). In general, the most favorable perceptions of osteopathic medicine were reported by current patients of osteopathic physicians, followed by former patients of such physicians. The least favorable perceptions came from patients who had never been patients of osteopathic physicians. The perception that OMT should be covered by health insurance was significantly associated with the use of osteopathic physicians (odds ratio, 3.2; 95% confidence interval, 1.5 to 6.7, among patients who had ever been to an osteopathic physician). The results of our survey suggest that greater access to osteopathic services, including OMT, is desirable and that promotional efforts aimed at encouraging the use of osteopathic medical services among the general population are warranted.


[A new mechanism of tumor resistance to the immune system, based on tryptophan breakdown by indoleamine 2,3-dioxygenase].
T lymphocytes represent the main effectors of the immune response that can lead to tumor rejection, which represents the aim of various approaches of immunotherapy that are currently tested. However, in many cases, tumor cells appear to resist immune rejection. We have recently uncovered a new mechanism of tumoral immune resistance based on the expression by tumor cells of indoleamine 2,3-dioxygenase (IDO), an enzyme that rapidly degrades tryptophan, an amino acid that is crucial to sustain proliferation of T lymphocytes. We showed that most human tumors constitutively express IDO. We also observed that expression of IDO by immunogenic mouse tumor cells, prevents their rejection by pre-immunized mice. This effect is accompanied by a lack of accumulation of specific T cells at the tumor site, and can be partly reverted by systemic treatment of mice with an inhibitor of IDO, in the absence of noticeable toxicity. These results suggest that the efficacy of therapeutic vaccination of cancer patients might be improved by concomitant administration of an IDO inhibitor.


The upper respiratory tract: mucous membrane irritation.
Despite the widespread recognition that mucosal irritation is a cardinal feature of "sick-building syndrome," few data exist on the cause, natural history, or pathophysiology of upper respiratory mucous membrane irritation. The baseline prevalence of nasal symptoms among building occupants is often 20%, but in some studies it is as high as 50 to 60%. New techniques of nasal challenge and analysis of cells and mediators in nasal lavage fluid have proved useful in the assessment of rhinitis caused by antigens, cold air, and viruses, and these techniques are now being applied to the study the response to irritants. Human inhalation challenge studies have recently demonstrated a spectrum of sensitivity to environmental tobacco smoke, but the basis for this difference requires additional investigation. Animal and in vitro studies indicate that the chemosensitive neurons and airway epithelium may be critical targets for irritants that participate in the induction of inflammation. New research methods are needed, particularly to evaluate complaints of nasal congestion, drying, and irritation. Techniques should be developed that may be useful for field studies, where the health effects of a complex mixture are being assessed in a specific indoor environment. There exists a group of individuals who report a variety of symptoms on exposure to low levels of common volatile organic mixtures such as perfume, cigarette smoke, and cleaning agents. Some of these individuals report having occupied "sick buildings" during the time their symptoms began. Research is needed to understand the basis of their complaints, their etiology, and treatment.


Thermally activated motion of a contact line over defects.
At the nanometer scale, the motion of a contact line separating a dry from a wet region is limited by the presence of surface heterogeneities that pin it. Here we revisit the seminal model proposed by Joanny and de Gennes to include the influence of thermal noise and viscosity using a Langevin model with two degrees of freedom: the average position of the contact line and its distortion. We identify the conditions under which the dynamics in a velocity-driven experiment can in fact be described by a constant forcing at small scale. We then relate the asymptotic properties of the relation between force and contact line velocity to the properties of the defects. In particular, we show that Kramers' approximation misses the strong asymmetry between advancing and receding directions. Finally, we show how to use the model to fit experimental data and extract the salient features of the surface energy landscape.


Albinterferon Alfa-2b was not inferior to pegylated interferon-α in a randomized trial of patients with chronic hepatitis C virus genotype 2 or 3.
A phase 3 active-controlled study was conducted to assess the efficacy/safety of albinterferon alfa-2b (albIFN), a novel, long-acting, genetic fusion polypeptide of recombinant human albumin and interferon alfa-2b, in patients with chronic hepatitis C virus (HCV) genotype 2/3. In all, 933 patients were randomized to open-label subcutaneous treatment with pegylated interferon-alfa-2a (Peg-IFNalfa-2a) 180 μg/wk, or albIFN 900 or 1200 μg every 2 weeks for 24 weeks, each administered with oral ribavirin 800 mg/day. The primary end point of the study was sustained virologic response (SVR) (HCV-RNA level, <15 IU/mL at week 48). During the study, the data monitoring committee recommended dose modification for all patients receiving albIFN 1200 μg to 900 μg, impacting 38% of this treatment arm. By intention-to-treat analysis, SVR rates were 84.8% (95% confidence interval, 80.4%-88.6%), 79.8% (95% confidence interval, 74.9%-84.1%), and 80.0% (95% confidence interval, 75.1%-84.3%) with Peg-IFNalfa-2a, and albIFN 900 and 1200 μg, respectively. The primary hypothesis of noninferiority of SVR was established for albIFN 900 μg (P = .009) and 1200 μg (P = .006). Independent positive predictors of SVR by multivariate regression analysis were pretreatment HCV-RNA level less than 400,000 IU/mL, age younger than 45 years, body mass index less than 30 kg/m(2), genotype 2, normal γ-glutamyl transpeptidase and increased alanine aminotransferase levels at baseline, fibrosis stage F0-F2, no steatosis, and Asian geographic region (Peg-IFNalfa-2a only). The 3 treatment groups showed similar rates of serious (7%-8%) and severe (13%-16%) adverse events, and discontinuations owing to adverse events (3.6%-5.5%). Albinterferon alfa-2b 900 μg every 2 weeks provides an alternative efficacious treatment option in patients with chronic HCV genotype 2 or 3.


A novel heterozygous deletion in the EVC2 gene causes Weyers acrofacial dysostosis.
Weyers acrofacial dysostosis (MIM 193530) is an autosomal dominant disorder clinically characterized by mild short stature, postaxial polydactyly, nail dystrophy and dysplastic teeth. Ellis-van Creveld syndrome (EvC, MIM 225500) is an autosomal recessive disorder with a similar, but more severe phenotype. Mutations in the EVC have been identified in both syndromes. However, the EVC mutations only occur in a small proportion of EvC patients. Recently, mutations in a new gene, EVC2, were found to be associated with other EvC cases. The EVC and EVC2 are located close to each other in a head-to-head configuration and may be functionally related. In this study, we report identification of a novel heterozygous deletion in the EVC2 that is responsible for autosomal dominant Weyers acrofacial dysostosis in a large Chinese family. This constitutes the first report of Weyers acrofacial dysostosis caused by this gene. Hence, the spectrum of malformation syndromes due to EVC2 mutations is further extended. Our data provides conclusive evidence that Weyers acrofacial dysostosis and EvC syndrome are allelic and genetically heterogeneous conditions.


Plakoglobin rescues adhesive defects induced by ectodomain truncation of the desmosomal cadherin desmoglein 1: implications for exfoliative toxin-mediated skin blistering.
Desmoglein 1 (Dsg1) is a desmosomal cadherin that is essential to epidermal integrity. In the blistering diseases bullous impetigo and staphylococcal scalded-skin syndrome, pathogenesis depends on cleavage of Dsg1 by a bacterial protease, exfoliative toxin A, which removes residues 1 to 381 of the Dsg1 ectodomain. However, the cellular responses to Dsg1 cleavage that precipitate keratinocyte separation to induce blister formation are unknown. Here, we show that ectodomain-deleted Dsg1 (Δ381-Dsg1) mimics the toxin-cleaved cadherin, disrupts desmosomes, and reduces the mechanical integrity of keratinocyte sheets. In addition, we demonstrate that truncated Dsg1 remains associated with its catenin partner, plakoglobin, and causes a reduction in the levels of endogenous desmosomal cadherins in a dose-dependent manner, leading us to hypothesize that plakoglobin sequestration by truncated Dsg1 destabilizes other cadherins. Accordingly, a triple-point mutant of the ectodomain-deleted cadherin, which is uncoupled from plakoglobin, does not impair adhesion, indicating that this interaction is essential to the pathogenic potential of truncated Dsg1. Moreover, we demonstrate that increasing plakoglobin levels rescues cadherin expression, desmosome organization, and functional adhesion in cells expressing Δ381-Dsg1 or treated with exfoliative toxin A. Finally, we report that histone deacetylase inhibition up-regulates desmosomal cadherins and prevents the loss of adhesion induced by Dsg1 truncation. These findings further our understanding of the mechanism of exfoliative toxin-induced pathology and suggest novel strategies to suppress blistering in bulbous impetigo and staphylococcal scalded-skin syndrome.


Imaging diagnosis--cervical spine chondroma in a dog.
An extradural chondroma originating in the cervical spine was diagnosed in an 8-year-old, intact male Chow-Chow that presented acute cervical pain and chronic right thoracic limb lameness. Myelographic images were within normal limits. With magnetic resonance (MR) imaging, an extradural mass was identified at the level of the C4-C5 vertebrae. This mass was excised, and the histologic diagnosis was chondroma. Fifteen months after surgery, the dog was clinically normal, and no regrowth of the mass was identified on follow-up MR images. Spinal chondromas are rare tumors in the dog, but should be considered as a rule out for contrast-enhancing extradural vertebral masses.


Do glycemic marker levels vary by race? Differing results from a cross-sectional analysis of individuals with and without diagnosed diabetes.
It is well known that A1c varies by race. However, racial differences in other biomarkers of hyperglycemia are less well characterized. The objective of this study was to determine whether average levels of glycemic markers differ by race in adults with and without diagnosed diabetes, before and after accounting for postchallenge glucose. This cross-sectional study included 2692 middle-aged men and women (5.5% with diagnosed diabetes; 44% African-American; and 56% white) from the Coronary Artery Risk Development in Young Adults Study (2005-2006) who had fasting glucose, 2-hour postchallenge glucose, A1c, glycated albumin, fructosamine, and 1,5-anhydroglucitol (1,5-AG) measured. Multiple linear regression was used to evaluate racial differences in mean levels of each glycemic marker stratified by the diabetes status and adjusted for sociodemographics, cardiovascular factors, and postchallenge glucose. Among those with diagnosed diabetes, racial differences were not observed for any of the glycemic markers. In contrast, among those without diagnosed diabetes, African-Americans had higher mean levels than whites of A1c (β=0.19% points; 95% CI 0.14 to 0.24), glycated albumin (β=0.82% points; 95% CI 0.68 to 0.97), fructosamine (β=8.68 μmol/L; 95% CI 6.68 to 10.68), and 2-hour glucose (β=3.50 mg/dL; 95% CI 0.10 to 6.90) after multivariable adjustment, whereas there were no statistically significant racial difference in 1,5-AG. The racial differences observed for A1c, glycated albumin, and fructosamine persisted after further adjustment for fasting and 2-hour glucose and were of similar magnitude (SD units). Racial differences in glycemic marker levels were evident among middle-aged adults without diagnosed diabetes even after adjustment for postchallenge glucose. Whether these racial differences in biomarkers of hyperglycemia affect the risk of complications warrants additional study.


Major histocompatibility complex variation and evolution at a single, expressed DQA locus in two genera of elephants.
Genes of the vertebrate major histocompatibility complex (MHC) are crucial to defense against infectious disease, provide an important measure of functional genetic diversity, and have been implicated in mate choice and kin recognition. As a result, MHC loci have been characterized for a number of vertebrate species, especially mammals;however, elephants are a notable exception. Our study is the first to characterize patterns of genetic diversity and natural selection in the elephant MHC. We did so using DNA sequences from a single, expressed DQA locus in elephants.We characterized six alleles in 30 African elephants(Loxodonta africana) and four alleles in three Asian elephants (Elephas maximus). In addition, for two of the African alleles and three of the Asian alleles, we characterized complete coding sequences (exons 1-5) and nearly complete non-coding sequences (introns 2-4) for the class II DQA loci. Compared to DQA in other wild mammals, we found moderate polymorphism and allelic diversity and similar patterns of selection; patterns of non-synonymous and synonymous substitutions were consistent with balancing selection acting on the peptides involved in antigen binding in the second exon. In addition, balancing selection has led to strong trans-species allelism that has maintained multiple allelic lineages across both genera of extant elephants for at least 6 million years. We discuss our results in the context of MHC diversity in other mammals and patterns of evolution in elephants.


Electrophysiological evidence for age effects on sensory memory processing of tonal patterns.
In older adults, difficulties processing complex auditory scenes, such as speech comprehension in noisy environments, might be due to a specific impairment of temporal processing at early, automatic processing stages involving auditory sensory memory (ASM). Even though age effects on auditory temporal processing have been well-documented, there is a paucity of research on how ASM processing of more complex tone-patterns is altered by age. In the current study, age effects on ASM processing of temporal and frequency aspects of two-tone patterns were investigated using a passive listening protocol. The P1 component, the mismatch negativity (MMN) and the P3a component of event-related brain potentials (ERPs) to tone frequency and temporal pattern deviants were recorded in younger and older adults as a measure of auditory event detection, ASM processing, and attention switching, respectively. MMN was elicited with smaller amplitude to both frequency and temporal deviants in older adults. Furthermore, P3a was elicited only in the younger adults. In conclusion, the smaller MMN amplitude indicates that automatic processing of both frequency and temporal aspects of two-tone patterns is impaired in older adults. The failure to initiate an attention switch, suggested by the absence of P3a, indicates that impaired ASM processing of patterns may lead to less distractibility in older adults. Our results suggest age-related changes in ASM processing of patterns that cannot be explained by an inhibitory deficit.


Catalytic Determinants of Alkene Production by the Cytochrome P450 Peroxygenase OleTJE.
The Jeotgalicoccus sp. peroxygenase cytochrome P450 OleTJE (CYP152L1) is a hydrogen peroxide-driven oxidase that catalyzes oxidative decarboxylation of fatty acids, producing terminal alkenes with applications as fine chemicals and biofuels. Understanding mechanisms that favor decarboxylation over fatty acid hydroxylation in OleTJE could enable protein engineering to improve catalysis or to introduce decarboxylation activity into P450s with different substrate preferences. In this manuscript, we have focused on OleTJE active site residues Phe79, His85, and Arg245 to interrogate their roles in substrate binding and catalytic activity. His85 is a potential proton donor to reactive iron-oxo species during substrate decarboxylation. The H85Q mutant substitutes a glutamine found in several peroxygenases that favor fatty acid hydroxylation. H85Q OleTJE still favors alkene production, suggesting alternative protonation mechanisms. However, the mutant undergoes only minor substrate binding-induced heme iron spin state shift toward high spin by comparison with WT OleTJE, indicating the key role of His85 in this process. Phe79 interacts with His85, and Phe79 mutants showed diminished affinity for shorter chain (C10-C16) fatty acids and weak substrate-induced high spin conversion. F79A OleTJE is least affected in substrate oxidation, whereas the F79W/Y mutants exhibit lower stability and cysteine thiolate protonation on reduction. Finally, Arg245 is crucial for binding the substrate carboxylate, and R245E/L mutations severely compromise activity and heme content, although alkene products are formed from some substrates, including stearic acid (C18:0). The results identify crucial roles for the active site amino acid trio in determining OleTJE catalytic efficiency in alkene production and in regulating protein stability, heme iron coordination, and spin state.


A method for estimating the fibre length in fibre-PLA composites.
Wood pulp fibres are an important component of environmentally sound and renewable fibre-reinforced composite materials. The high aspect ratio of pulp fibres is an essential property with respect to the mechanical properties a given composite material can achieve. The length of pulp fibres is affected by composite processing operations. This thus emphasizes the importance of assessing the pulp fibre length and how this may be affected by a given process for manufacturing composites. In this work a new method for measuring the length distribution of fibres and fibre fragments has been developed. The method is based on; (i) dissolving the composites, (ii) preparing the fibres for image acquisition and (iii) image analysis of the resulting fibre structures. The image analysis part is relatively simple to implement and is based on images acquired with a desktop scanner and a new ImageJ plugin. The quantification of fibre length has demonstrated the fibre shortening effect because of an extrusion process and subsequent injection moulding. Fibres with original lengths of >1 mm where shortened to fibre fragments with length of <200 μm. The shortening seems to be affected by the number of times the fibres have passed through the extruder, the amount of chain extender and the fraction of fibres in the polymer matrix.


Effectiveness of novel herbal dentifrice in control of plaque, gingivitis, and halitosis - Randomized controlled trial.
Plaque is a common etiological factor for common oral conditions like gingivitis, periodontitis, dental caries and halitosis. We aimed to evaluate the efficacy of a novel herbal dentifrice in control of plaque, gingivitis, and halitosis in comparison to control dentifrice. We conducted a randomized controlled, single center, double-blinded parallel arm clinical trial. Participants were randomly distributed with commercially available herbal dentifrice or control dentifrice. Assessments of plaque, gingivitis, halitosis, unstimulated saliva pH were done at baseline and at one month by a trained and calibrated periodontist. All the participants were given new toothbrushes one week before the start of the study. They were asked to brush with the designated dentifrices for 2-4 min, twice daily for one month. A total of 79 participants were recruited for this study, out of which 75 participants completed the follow-up. Inter-group comparisons of all the variables at baseline showed no significant differences in the mean plaque index, gingival index, halitosis and pH between test and control groups respectively. Intra-group comparisons showed a significant decrease in mean plaque, gingival and halitosis at follow-up than at baseline in both test and control groups. No significant differences between test and control groups were seen in the mean plaque index (P = 0.792), gingival index (P = 0.292), halitosis (P = 0.266), pH (P = 0.742) at follow-up after adjusting the respective baseline scores. The novel herbal dentifrice could be a suitable alternative for the control of plaque, gingivitis, and halitosis.


Excitation wavelength independent visible color emission of carbon dots.
Carbon dots (CDs) usually emit a strong blue light and excitation wavelength dependent long wavelength lights. This significantly limits their applications because one has to use a series of different excitation light sources to get different colors and the long wavelength emissions are usually very weak. We found that one type of CDs synthesized from p-phenylenediamine could emit various long wavelength lights (green to red) independent of the excitation wavelength when dispersed in different solvents. The photoluminescence quantum yields of the same CDs were 10-35% in different solvents for different color emissions. Based on this solvent-color effect, we further mixed the same CDs with different polymers to form solid CD films for various color emissions, and these film emissions were also excitation wavelength independent. Multicolor LEDs were demonstrated with the same CDs in solution and solid film states for color displays.


Polyphenols inhibit indoleamine 3,5-dioxygenase-1 enzymatic activity--a role of immunomodulation in chemoprevention.
Metastasis is one of the cancer hallmarks described by Hanahan and Weinberg. Emerging evidence shows that it requires interplays between cancer cells and micro-environmental biofactors. Indoleamine 3,5-dioxygenase-1 (IDO-1) produced by cancer, local lymph nodes, and satellite cells have been demonstrated as one of the biofactors. Aberrant IDO-1 activity has partially contributed to immunosuppressive environment by repressing T lymphocyte and natural killer cell activities, and activating regulatory T cells (Treg, CD4+CD25+). Clinical investigations further show a negative correlation between the enzyme activity and prognosis in patients with various cancer types. The findings suggest a possible role of IDO-1 inhibitor in restoring host anti-tumor immunity and attenuating cancer metastasis. Data from preclinical and phase I/II clinical studies with IDO-1 inhibitors support this hypothesis. Polyphenols as antioxidants are shown to exhibit anticancer activities. However, the underlying mechanism has not been entirely characterized. We recently found that certain flavone molecules profoundly inhibit the enzymatic activity of IDO-1 but not mRNA expression in human neuronal stem cells (hNSC) confirmed by cell-based assay and qRT-PCR. To further the investigation, we studied additional anti-cancer phytochemicals including chalcone, flavonol, isoflavone, and diterpene. Here we summarize the results and show that the inhibitory sensitivity depends on the molecular structure in the following order: apigenin > wogonin > chrysin > biacalein ~ genistein > quercetin. Curcumin and isoliquiritigenin (a chalcone) exhibited toxicity to hNSCs. Although oridonin (a diterpene) showed a null toxicity toward hNSCs, it repressed the enzymatic function only marginally in contrast to its potent cytotoxicity in various cancer cell lines. While the mode of action of the enzyme-polyphenol complex awaits to be investigated, the sensitivity of enzyme inhibition was compared to the anti-proliferative activities toward three cancer cell lines. The IC50s obtained from both sets of the experiments indicate that they are in the vicinity of micromolar concentration with the enzyme inhibition slightly more active. These results suggest that attenuation of immune suppression via inhibition of IDO-1 enzyme activity may be one of the important mechanisms of polyphenols in chemoprevention or combinatorial cancer therapy.


A randomized controlled trial on effects of different hemostatic sponges in posterior spinal fusion surgeries.
Spinal fusion surgery is associated with significant blood loss, which may result in potential clinical complications, it is necessary to take safe and effective measures to reduce blood loss in surgery. We perform this study to assess the impact of three different hemostatic materials on perioperative blood loss. We performed a Randomized Controlled Trial research and recruited patients with lumbar disease into the study between November 2013 and March 2015. All the participants were randomly assigned to 3 groups using a simple equal probability randomization scheme: Group A (Stypro hemostatic sponge), Group B (Collagen hemostatic sponge) and Group C (gelatin sponge). We compared postoperative blood loss between these 3 groups. In our study, drainage volume in the first 24 h of patients in Group A and B is significantly smaller, as well as total postoperative volumes of drainage (p < 0.05) during their hospital stay. The drainage volumes in the second 24 h were similar in the 3 groups. We also found that the average drainage Hematocrit (HCT) reduced over time, the average HCT of drainage is 18.04% and 11.72% on the first day and on the second day respectively. Hemostatic collagen sponge demonstrated better hemostasis effects than gelatin sponge with lower volume of postoperative drainage volume and blood loss in posterior spinal fusion surgery. The trial registration number (TRN) of the study is ISRCTN29254316 and date of registration is 25/10/2016. Our trial was registered retrospectively.


A balanced level of profilin-1 promotes stemness and tumor-initiating potential of breast cancer cells.
Profilin-1 (Pfn1) is an important actin-regulatory protein that is downregulated in human breast cancer and when forcibly elevated, it suppresses the tumor-initiating ability of triple-negative breast cancer cells. In this study, we demonstrate that Pfn1 overexpression reduces the stem-like phenotype (a key biologic feature associated with higher tumor-initiating potential) of MDA-MB-231 (MDA-231) triple-negative breast cancer cells. Interestingly, the stem-like trait of MDA-231 cells is also attenuated upon depletion of Pfn1. A comparison of cancer stem cell gene (CSC) gene expression signatures between depleted and elevated conditions of Pfn1 further suggest that Pfn1 may be somehow involved in regulating the expression of a few CSC-related genes including MUC1, STAT3, FZD7, and ITGB1. Consistent with the reduced stem-like phenotype associated with loss-of-function of Pfn1, xenograft studies showed lower tumor-initiating frequency of Pfn1-depleted MDA-231 cells compared to their control counterparts. In MMTV:PyMT mouse model, homozygous but not heterozygous deletion of Pfn1 gene leads to severe genetic mosaicism and positive selection of Pfn1-proficient tumor cells further supporting the contention that a complete lack of Pfn1 is likely not conducive for efficient tumor initiation capability of breast cancer cells. In summary, these findings suggest that the maintenance of optimal stemness and tumor-initiating ability of breast cancer cells requires a balanced expression of Pfn1.


Resveratrol disrupts peroxynitrite-triggered mitochondrial apoptotic pathway: a role for Bcl-2.
Resveratrol (3,4',5-trihydroxystilbene) is a phytochemical believed to be partly responsible for the cardioprotective effects of red wine due to its numerous biological activities. Here, we studied biochemical pathways underlying peroxynitrite-mediated apoptosis in endothelial cells and potential mechanisms responsible for resveratrol cytoprotective action. Peroxynitrite triggered endothelial cell apoptosis through caspases-8, -9 and -3 activation implying both mitochondrial and death receptor apoptotic pathways. Resveratrol was able to prevent peroxynitrite-induced caspases-3 and -9 activation, but not caspase-8 activation. Additionally, peroxynitrite increased intracellular levels of Bax without affecting those of Bcl-2, increasing consequently the Bax/Bcl-2 ratio. This ratio decreased when cells where pre-incubated with 10 and 50 muM resveratrol, mainly due to resveratrol ability per se to increase Bcl-2 intracellular levels without affecting Bax intracellular levels. These results propose an additional mechanism whereby resveratrol may exert its cardioprotective effects and suggest a key role for Bcl-2 in the resveratrol anti-apoptotic action, especially in disrupting peroxynitrite-triggered mitochondrial pathway.


The Role of Angiogenesis-Inducing microRNAs in Vascular Tissue Engineering.
Angiogenesis is an important process in tissue repair and regeneration as blood vessels are integral to supply nutrients to a functioning tissue. In this review, the application of microRNAs (miRNAs) or anti-miRNAs that can induce angiogenesis to aid in blood vessel formation for vascular tissue engineering in ischemic diseases such as peripheral arterial disease and stroke, cardiac diseases, and skin and bone tissue engineering is discussed. Endothelial cells (ECs) form the endothelium of the blood vessel and are recognized as the primary cell type that drives angiogenesis and studied in the applications that were reviewed. Besides ECs, mesenchymal stem cells can also play a pivotal role in these applications, specifically, by secreting growth factors or cytokines for paracrine signaling and/or as constituent cells in the new blood vessel formed. In addition to delivering miRNAs or cells transfected/transduced with miRNAs for angiogenesis and vascular tissue engineering, the utilization of extracellular vesicles (EVs), such as exosomes, microvesicles, and EVs collectively, has been more recently explored. Proangiogenic miRNAs and anti-miRNAs contribute to angiogenesis by targeting the 3'-untranslated region of targets to upregulate proangiogenic factors such as vascular endothelial growth factor (VEGF), basic fibroblast growth factor, and hypoxia-inducible factor-1 and increase the transduction of VEGF signaling through the PI3K/AKT and Ras/Raf/MEK/ERK signaling pathways such as phosphatase and tensin homolog or regulating the signaling of other pathways important for angiogenesis such as the Notch signaling pathway and the pathway to produce nitric oxide. In conclusion, angiogenesis-inducing miRNAs and anti-miRNAs are promising tools for vascular tissue engineering for several applications; however, future work should emphasize optimizing the delivery and usage of these therapies as miRNAs can also be associated with the negative implications of cancer.


Missing laboratory test data in electronic general practice records: analysis of rheumatoid factor recording in the clinical practice research datalink.
To investigate whether information from the literature could be used to identify periods of practice data in an electronic healthcare database during which rheumatoid factor (RF) test results are likely to be missing-not-at-random (MNAR). RF tests recorded in the Clinical Practice Research Datalink (CPRD) were identified and defined as having a positive, negative or missing result. The proportion of positive test results was then calculated based on (i) complete-case analysis (ii) after restriction to tests from practice years with no missing test results and (iii) following multiple imputation of missing test results. The same three analyses were then carried out after excluding practice years with a proportion of positive tests incompatible with the missing completely at random (MCAR) assumption. We identified 127,969 RF test records, 30.4% of which did not have an associated test result. Among tests with results available, 19% were positive. Both multiple imputation of the 38,867 missing test results and restriction of the study population to the 491 practice years with complete data had little impact on the percentage of positive tests. Following exclusion of the 544 practice years in which data were likely to be MNAR the percentage of positive tests in all analyses decreased to ~7%. Recording of RF tests and RF test results in the CPRD is incomplete, with data likely to be MNAR in many practices. Exclusion of practice years with a high proportion of positive tests brought the distribution of positive tests in the study in line with the literature.


Characterization of Pediococcus acidilactici PFC69 and Lactococcus lactis PFC77 Bacteriocins and Their Antimicrobial Activities in Tarhana Fermentation.
Tarhana is a traditional cereal product fermented by lactic acid bacteria (LAB) and yeast strains that has gained special interest recently as an infant nutrition. Tarhana contains wheat flour, yogurt, and various vegetables that might create a microbiological toxicological risk, especially for Bacillus cereus and Staphylococcus aureus. In this study, characterization of the metabolites responsible for antibacterial activity of Pediococcus acidilactici PFC69 and Lactococcus lactis PFC77 strains obtained from tarhana was performed, and antibacterial effects were detected against B. cereus ATCC 11778 and S. aureus ATCC 29213 during the fermentation. A total of 12,800 AU/mL antibacterial activity was observed for the supernatants of the PFC69 and PFC77 strains that were found to be stable at high temperature and in low pH conditions and sensitive to proteases, suggesting the antimicrobial metabolite is a bacteriocin. These bacteriocins were further purified and their molecular sizes were determined as 4.5 and 3.5 kDa, respectively. Importantly, inoculation of PFC69 and PFC77 to tarhana dough significantly decreased B. cereus ATCC 11778 and S. aureus ATCC 29213 amounts from the fifth day of fermentation compared to the control dough samples. P. acidilactici PFC69 and L. lactis PFC77 strains were concluded as bioprotective cultures for tarhana and these strains were offered for other cereal-based fermentations.


Extensive repertoire of membrane-bound and soluble dendritic cell-specific ICAM-3-grabbing nonintegrin 1 (DC-SIGN1) and DC-SIGN2 isoforms. Inter-individual variation in expression of DC-SIGN transcripts.
Expression in dendritic cells (DCs) of DC-SIGN, a type II membrane protein with a C-type lectin ectodomain, is thought to play an important role in establishing the initial contact between DCs and resting T cells. DC-SIGN is also a unique type of human immunodeficiency virus-1 (HIV-1) attachment factor and promotes efficient infection in trans of cells that express CD4 and chemokine receptors. We have identified another gene, designated here as DC-SIGN2, that exhibits high sequence homology with DC-SIGN. Here we demonstrate that alternative splicing of DC-SIGN1 (original version) and DC-SIGN2 pre-mRNA generates a large repertoire of DC-SIGN-like transcripts that are predicted to encode membrane-associated and soluble isoforms. The range of DC-SIGN1 mRNA expression was significantly broader than previously reported and included THP-1 monocytic cells, placenta, and peripheral blood mononuclear cells (PBMCs), and there was cell maturation/activation-induced differences in mRNA expression levels. Immunostaining of term placenta with a DC-SIGN1-specific antiserum showed that DC-SIGN1 is expressed on endothelial cells and CC chemokine receptor 5 (CCR5)-positive macrophage-like cells in the villi. DC-SIGN2 mRNA expression was high in the placenta and not detectable in PBMCs. In DCs, the expression of DC-SIGN2 transcripts was significantly lower than that of DC-SIGN1. Notably, there was significant inter-individual heterogeneity in the repertoire of DC-SIGN1 and DC-SIGN2 transcripts expressed. The genes for DC-SIGN1, DC-SIGN2, and CD23, another Type II lectin, colocalize to an approximately 85 kilobase pair region on chromosome 19p13.3, forming a cluster of related genes that undergo highly complex alternative splicing events. The molecular diversity of DC-SIGN-1 and -2 is reminiscent of that observed for certain other adhesive cell surface proteins involved in cell-cell connectivity. The generation of this large collection of polymorphic cell surface and soluble variants that exhibit inter-individual variation in expression levels has important implications for the pathogenesis of HIV-1 infection, as well as for the molecular code required to establish complex interactions between antigen-presenting cells and T cells, i.e. the immunological synapse.


Does clinician-reported lipid guideline adoption translate to guideline-adherent care? An evaluation of the Patient and Provider Assessment of Lipid Management (PALM) registry.
The 2013 American College of Cardiology (ACC)/American Heart Association (AHA) cholesterol guideline recommends statin treatment based on patients' predicted atherosclerotic cardiovascular disease (ASCVD) risk. Whether clinician-reported guideline adoption translates to implementation into practice is unknown. We aimed to compare clinician lipid management in hypothetical scenarios versus observed practice. The PALM Registry asked 774 clinicians how they would treat 4 hypothetical scenarios of primary prevention patients with: (1) diabetes; (2) high 10-year ASCVD risk (≥7.5%) with high low-density lipoprotein cholesterol (LDL-C; ≥130 mg/dL); (3) low 10-year ASCVD risk (<7.5%) with high LDL-C (130-189 mg/dL); or (4) primary and secondary prevention patients with persistently elevated LDL-C (≥130 mg/dL) despite high-intensity statin use. We assessed agreement between clinician survey responses and observed practice. In primary prevention scenarios, 85% of clinicians reported they would prescribe a statin to a diabetic patient and 93% to a high-risk/high LDL-C patient (both indicated by guidelines), while 40% would prescribe statins to a low-risk/high LDL-C patient. In clinical practice, statin prescription rates were 68% for diabetic patients, 40% for high-risk/high LDL-C patients, and 50% for low-risk/high LDL-C patients. Agreement between hypothetical and observed practice was 64%, 39%, and 52% for patients with diabetes, high-risk/high LDL-C, and low-risk/high LDL-C, respectively. Among patients with persistently high LDL-C despite high-intensity statin treatment, 55% of providers reported they would add a non-statin lipid-lowering medication, while only 22% of patients were so treated. While the majority of clinicians report adoption of the 2013 ACC/AHA guideline recommendations, observed lipid management decisions in practice are frequently discordant.


Purification and characterization of a membrane protein (gp45-70) that is a cofactor for cleavage of C3b and C4b.
Based on preliminary evidence indicating that a cell-associated protein of U937 (a human monocyte-like cell line) possessed cofactor activity and was not the C3b/C4b receptor, we sought to further characterize this protein. A sequential four-column purification procedure was devised that includes C3(H2O) affinity chromatography to isolate in reasonable yields and purity a cell-associated protein of U937 and several other human cell lines. Based on its pattern and Mr on SDS-PAGE, acidic pI, and ligand specificity, it is identical to a recently described C3(H2O) or C3b-binding membrane glycoprotein of human PBL and cell lines; having no presently identified function, it was termed gp45-70. After purifying this protein, we determined its functional capabilities and compared them to those of the other complement proteins with regulatory activity directed at components comprising the C3 convertases. This protein was the most efficient (50 times that of H) yet-described cofactor for the I-mediated first cleavage of C3b. It also was a cofactor for the first cleavage of C4b, but was not as efficient as C4bp. The second cleavage of C3b and C4b was not efficiently mediated. It had no ability to accelerate decay in the classical or alternative pathway C3 convertases. Based on this unique activity profile and ability to be surface labeled, we have renamed this molecule membrane cofactor protein (MCP). We suggest that this protein plays a major role in preventing autologous complement activation.


A global perspective on assisted reproductive technology fertility treatment: an 8-country fertility specialist survey.
Procedures that may optimize success in achieving live births from assisted reproductive technology (ART) continue to be examined. Not yet considered are the perspectives of fertility specialists regarding important developments in the fertility treatment field, current unmet needs, and anticipated future advances. In the current study, an 8-country survey of fertility specialists was conducted to provide a comprehensive, global depiction of fertility treatments across different regions. Fertility specialists from France, Germany, Italy, Spain, the United Kingdom (UK), the United States (US), China, and Japan were invited to participate in an online survey. Participants were eligible if they personally managed ≥25 patients/month who were experiencing difficulty conceiving, and if they had performed ART fertility treatment with ≥1 patient in the previous month. Quantitative questions addressed the number of patients seen, main infertility causes, number of cycles performed, ART procedure type, and ART outcomes. Qualitative questions covered diagnostic trends, unmet needs, important advances, and expected future developments. The number of fertility specialists who completed the survey included 29 in France, 33 in Germany, 23 in Italy, 38 in Spain, 34 in the UK, 91 in the US, 50 in China, and 65 in Japan. Patient volume increased over the prior 2 years according to 67 % (242/363) of the fertility specialists. As expected, ART outcomes all declined with age in all countries. ART outcomes varied by country, with the highest implantation, pregnancy, and live birth rates reported by fertility specialists in the US and China and the lowest rates reported in France and Italy. The most frequently reported unmet needs in fertility treatment were financial coverage, improved implantation rate, and egg donation. Most frequently named future advancements expected to change the fertility treatment field included improved embryo selection through imaging and/or metabolomics, improved embryo implantation rate, and use of preimplantation genetic diagnosis. This study, which follows a rigorous survey methodology, elucidates the current state of fertility specialists' practices and perspectives on the global fertility treatment field, which highlights differences and similarities among countries. This research may inform further studies and procedural developments that might better improve and standardize ART.


Identification of a synthetic peptide that mimics an HIV glycoprotein 120 envelope conformational determinant exposed following ligation of glycoprotein 120 by CD4.
CD4 ligation of HIV envelope gp120 results in conformational changes in gp120 that lead to exposure of the gp41 fusogenic domain and fusion with the host cell membrane. One determinant at or near the CD4-binding site exposed on gp120 subsequent to CD4 binding is defined by two human MAbs termed 17b and 48d. These MAbs do not block CD4 binding to gp120; rather, their binding to gp120 is upregulated following CD4 binding. To determine if synthetic peptide mimetopes could be found that reflect conformational determinants on the surface of gp120, synthetic gp120 peptides from 10 divergent HIV isolates were screened for their ability to bind to 17b and 48d in ELISAs. Although MAb 48d binds to HIV IIIB recombinant gp120 protein, in our studies 48d selectively bound only to the HIV Can0A V3 peptide and not to HIV IIIB V3 peptide, whereas MAb 17b bound none of the peptides tested. Monoclonal antibody 48d bound to the HIV Can0A V3 peptide both in solid-phase ELISA and in solution in a competitive ELISA, but could not bind to HIV Can0A V3 peptide bound to human T cells. The HIV Can0A V3 peptide induced anti-HIV antibodies in rhesus monkeys that neutralized the laboratory-adapted HIV MN strain but did not induce antibodies that neutralized HIV IIIB/LAI, HIV SF-2, or HIV RF isolates, or that neutralized HIV primary isolates. These data suggested that the primary sequence of the HIV Can0A V3 loop exists in a conformer that mimicks a non-V3 determinant of native gp120 exposed subsequent to CD4 binding on the surface of gp120 of laboratory-adapted HIV strains. Structural studies of the Can0A V3 peptide and/or the 48d MAb may provide important information regarding the nature of gp120 conformational changes that occur following gp120 ligation by CD4.