Spatial summation of peripheral Gabor patches.
Previous studies have specified the foveal pattern that is seen most efficiently, with the assumption that the waveform of the best pattern matches the impulse response of the most sensitive visual filter. We measured the threshold contrast for circular, collinear, and orthogonal Gabor stimuli of 6 Hz temporal frequency presented 7 deg above the fixation point. We found that the threshold contrast energy is minimal for a class of stimuli whose Fourier-spectra bandwidth is less than approximately 1 octave. These findings suggest that an energy algorithm might underlie spatial summation of peripheral Gabor patches. The different behavior of spatial summation in fovea and periphery might reflect the differences in pattern detectability across space in the central and peripheral visual fields. It is also possible that a coherent (cross-correlation) algorithm is employed in detection of foveal stimuli and that an incoherent (energy) algorithm is employed in detection of peripheral stimuli.


Employing TDMA Protocol in Neural Nanonetworks in Case of Neuron Specific Faults.
Many neurodegenerative diseases arise from the malfunctioning neurons in the pathway where the signal is carried. In this paper, we propose neuron specific TDMA/multiplexing and demultiplexing mechanisms to convey the spikes of a receptor neuron over a neighboring path in case of an irreversible path fault existing in its original path. The multiplexing mechanism depends on neural delay box (NDB) which is composed of a relay unit and a buffering unit. The relay unit can be realized as a nanoelectronic device. The buffering unit can be implemented either via neural delay lines as employed in optical switching systems or via nanoelectronic delay lines, i.e., delay flip flops. Demultiplexing is realized by a demultiplexer unit according to the time slot assignment information. Besides, we propose the use of neural interfaces in the NDBs and the demultiplexer unit for detecting and stimulating the generation of spikes. The objective of the proposed mechanisms is to substitute a malfunctioning path, increase the number of spikes delivered and correctly deliver the spikes to the intended part of the somatosensory cortex. The results demonstrate that significant performance improvement on the successively delivered number of spikes is achievable when delay lines are employed as neural buffers in NDBs.


Estimating uncertainty in geospatial modelling at multiple spatial resolutions: the pattern of delivery via caesarean section in Tanzania.
Visualising maternal and newborn health (MNH) outcomes at fine spatial resolutions is crucial to ensuring the most vulnerable women and children are not left behind in improving health. Disaggregated data on life-saving MNH interventions remain difficult to obtain, however, necessitating the use of Bayesian geostatistical models to map outcomes at small geographical areas. While these methods have improved model parameter estimates and precision among spatially correlated health outcomes and allowed for the quantification of uncertainty, few studies have examined the trade-off between higher spatial resolution modelling and how associated uncertainty propagates. Here, we explored the trade-off between model outcomes and associated uncertainty at increasing spatial resolutions by quantifying the posterior distribution of delivery via caesarean section (c-section) in Tanzania. Overall, in modelling delivery via c-section at multiple spatial resolutions, we demonstrated poverty to be negatively correlated across spatial resolutions, suggesting important disparities in obtaining life-saving obstetric surgery persist across sociodemographic factors. Lastly, we found that while uncertainty increased with higher spatial resolution input, model precision was best approximated at the highest spatial resolution, suggesting an important policy trade-off between identifying concealed spatial heterogeneities in health indicators.


Radiation dose estimates in dual-source computed tomography coronary angiography.
The purpose of this study was to quantify radiation dose parameters of dual-source CT coronary angiography. Eighty patients underwent contrast-enhanced, retrospectively ECG-gated dual-source CT coronary angiography with heart rate-adapted ECG pulsing using two algorithms: In 40 patients, the tube current was reduced to 20% (A(min1)) of the normal tube current (A(max)) outside the pulsing window; in 40 patients tube current was reduced to 4% (A(min2)) of A(max). Mean CTDI(vol) in the A(min1) group was 45.1 +/- 3.6 mGy; the mean CTDI(vol) in the A(min2) group was 39.1 +/- 3.2 mGy, with CTDI(vol) in the A(min2) group being significantly reduced when compared to the A(min1) group (P < 0.001). A significant negative correlation was found between CTDI(vol) and heart rate in group A(min1) (r = -0.82, P < 0.001), whereas no correlation was found between CTDI(vol) and heart rate in group A(min2) (r = -0.066). Using the conversion coefficient for the chest, dual-source CT coronary angiography resulted in an estimated mean effective dose of 8.8 mSv in the A(min1) group and 7.8 mSv in the A(min2). Radiation exposure of dual-source CT coronary angiography using an ECG-pulsing protocol reducing the tube current to 20% significantly decreases with increasing heart rates, despite using wider pulsing windows at higher heart rates. When using a protocol with reduced tube current of 4%, the radiation dose is significantly lower, irrespective of the heart rate.


Completing the Picture: Importance of Considering Participatory Mapping for REDD+ Measurement, Reporting and Verification (MRV).
Remote sensing has been widely used for mapping land cover and is considered key to monitoring changes in forest areas in the REDD+ Measurement, Reporting and Verification (MRV) system. But Remote Sensing as a desk study cannot capture the whole picture; it also requires ground checking. Therefore, complementing remote sensing analysis using participatory mapping can help provide information for an initial forest cover assessment, gain better understanding of how local land use might affect changes, and provide a way to engage local communities in REDD+. Our study looked at the potential of participatory mapping in providing complementary information for remotely sensed maps. The research sites were located in different ecological and socio-economic contexts in the provinces of Papua, West Kalimantan and Central Java, Indonesia. Twenty-one maps of land cover and land use were drawn with local community participation during focus group discussions in seven villages. These maps, covering a total of 270,000ha, were used to add information to maps developed using remote sensing, adding 39 land covers to the eight from our initial desk assessment. They also provided additional information on drivers of land use and land cover change, resource areas, territory claims and land status, which we were able to correlate to understand changes in forest cover. Incorporating participatory mapping in the REDD+ MRV protocol would help with initial remotely sensed land classifications, stratify an area for ground checks and measurement plots, and add other valuable social data not visible at the RS scale. Ultimately, it would provide a forum for local communities to discuss REDD+ activities and develop a better understanding of REDD+.


Molecular Polymorphism and Morphometrics of Species of the Heterodera avenae Group in Syria and Turkey.
Molecular characterization of the three most common cereal cyst nematode species of the Heterodera avenae group (H. avenae, H. filipjevi, and H. latipons), originating from various locations in major cereal-cultivating areas in Syria and Turkey, showed distinct restriction fragment patterns of the ITS-rDNA following PCR amplification and RFLP digestion with four endonucleases (Hae III, Hinf I, Ita I, and Pst I). Genetic dissimilarity within H. avenae group populations increased in comparison with H. avenae and other species; it was 0.164 with H. filipjevi and 0.354 with H. latipons populations. No intraspecific polymorphism was observed within H. latipons or H. filipjevi populations. Principal component analysis revealed contrasted correlations among 12 morphological parameters of cysts and juveniles of the three Heterodera species that separated them and distinguished differences within populations of H. latipons. Our results showed a clear separation of the three cyst nematode species on cereal using a conventional method for classification and molecular tests, and confirmed the congruence between genetics and morphological traits.


Evaluation of the association between fecal excretion of Mycobacterium avium subsp paratuberculosis and detection in colostrum and on teat skin surfaces of dairy cows.
To evaluate the association between fecal excretion of Mycobacterium avium subsp paratuberculosis (MAP) by dairy cows in the periparturient period and detection of MAP DNA in colostrum specimens and on teat skin surfaces. Cross-sectional study. 112 Holstein cows. Fecal specimens were collected within 48 to 72 hours prior to parturition, and colostrum and teat swab specimens were collected immediately after parturition. Detection of MAP in fecal specimens was performed via microbial culture, and detection of MAP DNA in colostrum and teat swab specimens was achieved via a PCR assay targeting the genetic element ISMAP02. Logistic regression was used to model the relationship between MAP fecal shedding status and detection of MAP DNA in colostrum or teat swab specimens. Population attributable fractions for the proportion of colostrum and teat swab specimens containing MAP DNA were also calculated. The odds of detecting MAP DNA in colostrum or teat swab specimens in cows with MAP-positive (vs negative) fecal specimens were 2.02 and 1.87 respectively. Population attributable fractions estimates suggested that withholding colostrum from MAP-positive cows could reduce the odds of exposing calves to MAP in colostrum by 18.2%. Not permitting natural suckling by calves could reduce the odds of exposing calves to MAP on the teat surfaces of MAP-positive cows by 19.5%. Results underscored the need for strict adherence to practices that limit contact of calves with adult cows from the time of birth and promote hygienic colostrum handling to avoid possible contamination with MAP during colostrum harvest, storage, or feeding.


A procedure for the computerized analysis of cleft palate speech transcription.
The phonetic symbols used by speech-language pathologists to transcribe speech contain underlying hexadecimal values used by computers to correctly display and process transcription data. This study aimed to develop a procedure to utilise these values as the basis for subsequent computerized analysis of cleft palate speech. A computer keyboard file and a modified font file were developed using symbols from the International Phonetic Alphabet and extensions to the International Phonetic Alphabet to improve the computerized storage of phonetic symbols used in cleft palate speech transcription. Computerized coding procedures were written to retrieve hexadecimal values of transcribed symbols and match these to their phonetic attributes as defined in the International Phonetic Alphabet and extensions to the International Phonetic Alphabet. Computerized procedures were subsequently developed to analyse transcription data based on these matched hexadecimal values and their associated phonetic attributes, with respect to cleft palate speech. This method will be a useful addition to existing computerized speech analysis tools.


Ibuprofen versus fosfomycin for uncomplicated urinary tract infection in women: randomised controlled trial.
Can treatment of the symptoms of uncomplicated urinary tract infection (UTI) with ibuprofen reduce the rate of antibiotic prescriptions without a significant increase in symptoms, recurrences, or complications? Women aged 18-65 with typical symptoms of UTI and without risk factors or complications were recruited in 42 German general practices and randomly assigned to treatment with a single dose of fosfomycin 3 g (n=246; 243 analysed) or ibuprofen 3 × 400 mg (n=248; 241 analysed) for three days (and the respective placebo dummies in both groups). In both groups additional antibiotic treatment was subsequently prescribed as necessary for persistent, worsening, or recurrent symptoms. The primary endpoints were the number of all courses of antibiotic treatment on days 0-28 (for UTI or other conditions) and burden of symptoms on days 0-7. The symptom score included dysuria, frequency/urgency, and low abdominal pain. The 248 women in the ibuprofen group received significantly fewer course of antibiotics, had a significantly higher total burden of symptoms, and more had pyelonephritis. Four serious adverse events occurred that lead to hospital referrals; one of these was potentially related to the trial drug. Results have to be interpreted carefully as they might apply to women with mild to moderate symptoms rather than to all those with an uncomplicated UTI. Two thirds of women with uncomplicated UTI treated symptomatically with ibuprofen recovered without any antibiotics. Initial symptomatic treatment is a possible approach to be discussed with women willing to avoid immediate antibiotics and to accept a somewhat higher burden of symptoms. German Federal Ministry of Education and Research (BMBF) No 01KG1105. Patient level data are available from the corresponding author. Patient consent was not obtained but the data are anonymised and risk of identification is low.Trial registration No ClinicalTrialGov Identifier NCT01488955.


Treatment of experimental adjuvant arthritis with a novel folate receptor-targeted folic acid-aminopterin conjugate.
Folate receptor (FR)-expressing macrophages have been shown to accumulate at sites of inflammation, where they promote development of inflammatory symptoms. To target such a macrophage population, we designed and evaluated the biologic activity of EC0746, a novel folic acid conjugate of the highly potent antifolate, aminopterin. Using a FR-positive subclone of murine macrophage-derived RAW264.7 cells and rat thioglycollate-elicited macrophages, we studied the effect of EC0746 on dihydrofolate reductase activity, cell proliferation, and cellular response towards bacterial lipopolysaccharide as well as IFNγ activation. The EC0746 anti-inflammatory activity, pharmacokinetics, and toxicity were also evaluated in normal rats or in rats with adjuvant-induced arthritis; that is, a FR-positive macrophage model that closely resembles rheumatoid arthritis in humans. EC0746 suppresses the proliferation of RAW264.7 cells and prevents the ability of nonproliferating rat macrophages to respond to inflammatory stimuli. In the macrophage-rich rat arthritis model, brief treatment with subcutaneously administered EC0746 is shown to mediate an FR-specific anti-inflammatory response that is more potent than either orally administered methotrexate or subcutaneously delivered etanercept. More importantly, EC0746 therapy is also shown to be ~40-fold less toxic than unmodified aminopterin, with fewer bone marrow and gastrointestinal problems. EC0746 is the first high FR-binding dihydrofolate reductase inhibitor that demonstrates FR-specific anti-inflammatory activities both in vitro and in vivo. Our data reveal that a relatively toxic anti-inflammatory drug, such as aminopterin, can be targeted with folic acid to inflammatory macrophages and thereby relieve inflammatory symptoms with greatly reduced toxicity.


[Changes in ten years of social inequalities in health among elderly Brazilians (1998-2008)].
To assess the changes in income-related inequalities in health conditions and in the use of health services among elderly Brazilians. Representative samples of the Brazilian population aged 60 years and more were analyzed between 1998 and 2008 (n = 27,872 and 41,198, respectively), derived from the Pesquisa Nacional por Amostra de Domicílios (National Household Sample Survey). The following variables were considered in this study: per capita monthly household income, self-rated health, physical functioning, medical consultations and hospitalizations in the previous 12 months and exclusive use of the Sistema Único de Saúde (Unified Health System). Data analysis was based on estimates of prevalence and prevalence ratios obtained with robust Poisson regression. In 1998 and 2008, the prevalence of poor self-rated health, mobility limitations and inability to perform activities of daily living (ADLs), adjusted for age and sex, showed strong gradients associated with per capita household income quintiles, with the lowest values being found among those in the lowest income quintile. The prevalence ratios adjusted for age and sex between the lowest quintile (poorest individuals) and highest quintile (richest individuals) of income remained stable for poor self-rated health (PR = 3.12 [95%CI 2.79;3.51] in 1998 and 2.98 [95%CI 2.69;3.29] in 2008), mobility limitations (PR = 1.54 [95%CI 1.44;1.65 and 1.69 [95%CI 1.60;1.78], respectively) and inability to perform ADLs (PR = 1.79 [95%CI 1.52;2.11] and 2.02 [95%CI 1.78;2.29], respectively). There was a reduction in income-related disparities when three or more medical consultations had been made and with the exclusive use of the Unified Health System. Inequalities were not observed for hospitalizations. Despite reductions in income-related inequalities among indicators of use of health services, the magnitude of disparities in health conditions has not decreased. Longitudinal studies are necessary to better understand the persistence of such inequalities among elderly Brazilians.


Risk for metabolic control problems in minority youth with diabetes.
We examined and quantified the degree of risk for poor glycemic control and hospitalizations for diabetic ketoacidosis (DKA) among black, Hispanic, and white children and adolescents with diabetes. We examined ethnic differences in metabolic control among 68 black, 145 Hispanic, and 44 white children and adolescents with type 1 diabetes (mean age 12.9 [range 1-21] years), who were primarily of low socioeconomic status. Clinical and demographic data were obtained by medical chart review. Glycohemoglobins were standardized and compared across ethnic groups. Odds ratios among the ethnic groups for poor glycemic control and hospitalizations for DKA were also calculated. The ethnic groups were not different with respect to age, BMI, insulin dose, or hospitalizations for DKA, but black children were older at the time of diagnosis than Hispanics (P < 0.05) and were less likely to have private health insurance than white and Hispanic children (P < 0.001). Black youths had higher glycohemoglobin levels than white and Hispanic youths (P < 0.001 after controlling for age at diagnosis). Black youths were also at greatest risk for poor glycemic control (OR = 3.9, relative to whites; OR = 2.5, relative to Hispanics). These results underscore and quantify the increased risk for glycemic control problems of lower-income, black children with diabetes. In the absence of effective intervention, these youths are likely to be overrepresented in the health care system as a result of increased health complications related to diabetes.


Real-Time Dissection of Distinct Dynamin-Dependent Endocytic Routes of Influenza A Virus by Quantum Dot-Based Single-Virus Tracking.
Entry is the first critical step for the infection of influenza A virus and of great significance for the research and development of antiflu drugs. Influenza A virus depends on exploitation of cellular endocytosis to enter its host cells, and its entry behaviors in distinct routes still need further investigation. With the aid of a single-virus tracking technique and quantum dots, we have realized real-time and multicolor visualization of the endocytic process of individual viruses and comprehensive dissection of two distinct dynamin-dependent endocytic pathways of influenza A virus, either dependent on clathrin or not. Based on the sequential progression of protein recruitment and viral motility, we have revealed the asynchronization in the recruitments of clathrin and dynamin during clathrin-dependent entry of the virus, with a large population of events for short-lived recruitments of these two proteins being abortive. In addition, the differentiated durations of dynamin recruitment and responses to inhibitors in these two routes have evidenced somewhat different roles of dynamin. Besides promoting membrane fission in both entry routes, dynamin also participates in the maturation of a clathrin-coated pit in the clathrin-dependent route. Collectively, the current study displays a dynamic and precise image of the entry process of influenza A virus and elucidates the mechanisms of distinct entry routes. This quantum dot-based single-virus tracking technique is proven to be well-suited for investigating the choreographed interactions between virus and cellular proteins.


National Institutes of Health Hematopoietic Cell Transplantation Late Effects Initiative: The Immune Dysregulation and Pathobiology Working Group Report.
Immune reconstitution after hematopoietic stem cell transplantation (HCT) beyond 1 year is not completely understood. Many transplant recipients who are free of graft-versus-host disease (GVHD) and not receiving any immunosuppression more than 1 year after transplantation seem to be able to mount appropriate immune responses to common pathogens and respond adequately to immunizations. However, 2 large registry studies over the last 2 decades seem to indicate that infection is a significant cause of late mortality in some patients, even in the absence of concomitant GVHD. Research on this topic is particularly challenging for several reasons. First, there are not enough long-term follow-up clinics able to measure even basic immune parameters late after HCT. Second, the correlation between laboratory measurements of immune function and infections is not well known. Third, accurate documentation of infectious episodes is notoriously difficult. Finally, it is unclear what measures can be implemented to improve the immune response in a clinically relevant way. A combination of long-term multicenter prospective studies that collect detailed infectious data and store samples as well as a national or multinational registry of clinically significant infections (eg, vaccine-preventable severe infections, opportunistic infections) could begin to address our knowledge gaps. Obtaining samples for laboratory evaluation of the immune system should be both calendar and eventdriven. Attention to detail and standardization of practices regarding prophylaxis, diagnosis, and definitions of infections would be of paramount importance to obtain clean reliable data. Laboratory studies should specifically address the neogenesis, maturation, and exhaustion of the adaptive immune system and, in particular, how these are influenced by persistent alloreactivity, inflammation, and viral infection. Ideally, some of these long-term prospective studies would collect information on long-term changes in the gut microbiome and their influence on immunity. Regarding enhancement of immune function, prospective measurement of the response to vaccines late after HCT in a variety of clinical settings should be undertaken to better understand the benefits as well as the limitations of immunizations. The role of intravenous immunoglobulin is still not well defined, and studies to address it should be encouraged.


Characterizing the dielectric properties of human mesenchymal stem cells and the effects of charged elastin-like polypeptide copolymer treatment.
HUMAN MESENCHYMAL STEM CELLS (HMSCS) HAVE THREE KEY PROPERTIES THAT MAKE THEM DESIRABLE FOR STEM CELL THERAPEUTICS: differentiation capacity, trophic activity, and ability to self-renew. However, current separation techniques are inefficient, time consuming, expensive, and, in some cases, alter hMSCs cellular function and viability. Dielectrophoresis (DEP) is a technique that uses alternating current electric fields to spatially separate biological cells based on the dielectric properties of their membrane and cytoplasm. This work implements the first steps toward the development of a continuous cell sorting microfluidic device by characterizing native hMSCs dielectric signatures and comparing them to hMSCs morphologically standardized with a polymer. A quadrapole Ti-Au electrode microdevice was used to observe hMSC DEP behaviors, and quantify frequency spectra and cross-over frequency of hMSCs from 0.010-35 MHz in dextrose buffer solutions (0.030 S/m and 0.10 S/m). This combined approach included a systematic parametric study to fit a core-shell model to the DEP spectra over the entire tested frequency range, adding robustness to the analysis technique. The membrane capacitance and permittivity were found to be 2.2 pF and 2.0 in 0.030 S/m and 4.5 pF and 4.1 in 0.10 S/m, respectively. Elastin-like polypeptide (ELP-) polyethyleneimine (PEI) copolymer was used to control hMSCs morphology to spheroidal cells and aggregates. Results demonstrated that ELP-PEI treatment controlled hMSCs morphology, increased experiment reproducibility, and concurrently increased hMSCs membrane permittivity to shift the cross-over frequency above 35 MHz. Therefore, ELP-PEI treatment may serve as a tool for the eventual determination of biosurface marker-dependent DEP signatures and hMSCs purification.


Comprehensive Osteopathic Medical Licensing Examination-USA level 1 and level 2-cognitive evaluation preparation and outcomes.
The Comprehensive Osteopathic Medical Licensing Examination-USA (COMLEX-USA) assesses the competence of osteopathic physicians in training. It is designed to protect the public by setting minimum competence standards. All osteopathic medical students must pass COMLEX-USA Level 1, Level 2-Cognitive Evaluation, and Level 2-Performance Evaluation before being allowed to graduate from an osteopathic medical school. Residency training programs use COMLEX-USA scores as a major factor in deciding whom they will interview and admit into their programs. In addition, colleges of osteopathic medicine use student COMLEX-USA scores as an external assessment of their success in educating students. Because COMLEX-USA is a high-stakes examination series, it is important to understand predictive factors for performance. The authors review the literature on the relationship between COMLEX-USA scores and correlated student variables. Results from the Council on Osteopathic Student Government Presidents' survey on students' preparation methods and performance are also provided.


ACOG Practice Bulletin No. 191: Tubal Ectopic Pregnancy.
Ectopic pregnancy is defined as a pregnancy that occurs outside of the uterine cavity. The most common site of ectopic pregnancy is the fallopian tube. Most cases of tubal ectopic pregnancy that are detected early can be treated successfully either with minimally invasive surgery or with medical management using methotrexate. However, tubal ectopic pregnancy in an unstable patient is a medical emergency that requires prompt surgical intervention. The purpose of this document is to review information on the current understanding of tubal ectopic pregnancy and to provide guidelines for timely diagnosis and management that are consistent with the best available scientific evidence.


Oral lichen planus treated with tacrolimus 0.1%.
Oral lichen planus (OLP) is considered a chronic autoimmune inflammatory disease and its presence may be related to increased emotional stress. The clinical relevance of OLP is the possibility of developing a squamous cell carcinoma, the etiology of which is still unknown. The aim of this study is to treat OLP lesions resistant to conventional treatment with corticosteroids, using topical tacrolimus 0.1% (Protopic(®)) twice a day for a period of eight weeks. Fifteen patients were selected who had filled out a history form and a visual analog scale for pain before and after treatment. All patients underwent an initial biopsy to diagnose the disease and another at the end of the treatment period to evaluate the effect of the medication on the infiltrate. A weekly check was carried out, observing the clinical appearance, pain symptoms and occurrence of side effects which, where present, were mild and transient. The results showed twelve patients (80%) with total or nearly total remission of pain symptoms and lesions, two patients (13.33%) showed clearer lesions and only one patient (6.67%) had no change in clinical symptoms or pain. Histopathological analysis showed OLP had a moderate or strong regression in twelve patients (80%) and an absent or mild regression in three patients (20%). Based on these results, it was concluded that tacrolimus 0.1% (Protopic(®)) is a safe and effective medication that improves the clinical appearance of the lesion, reduces pain as well as the histopathological features of OLP.


Fronto-parietal areas necessary for a multisensory representation of peripersonal space in humans: an rTMS study.
A network of brain regions including the ventral premotor cortex (vPMc) and the posterior parietal cortex (PPc) is consistently recruited during processing of multisensory stimuli within peripersonal space (PPS). However, to date, information on the causal role of these fronto-parietal areas in multisensory PPS representation is lacking. Using low-frequency repetitive TMS (rTMS; 1 Hz), we induced transient virtual lesions to the left vPMc, PPc, and visual cortex (V1, control site) and tested whether rTMS affected audio-tactile interaction in the PPS around the hand. Subjects performed a timed response task to a tactile stimulus on their right (contralateral to rTMS) hand while concurrent task-irrelevant sounds were presented either close to the hand or 1 m far from the hand. When no rTMS was delivered, a sound close to the hand reduced RT-to-tactile targets as compared with when a far sound was presented. This space-dependent, auditory modulation of tactile perception was specific to a hand-centered reference frame. Such a specific form of multisensory interaction near the hand can be taken as a behavioral hallmark of PPS representation. Crucially, virtual lesions to vPMc and PPc, but not to V1, eliminated the speeding effect due to near sounds, showing a disruption of audio-tactile interactions around the hand. These findings indicate that multisensory interaction around the hand depends on the functions of vPMc and PPc, thus pointing to the necessity of this human fronto-parietal network in multisensory representation of PPS.


High-affinity single-domain binding proteins with a binary-code interface.
High degrees of sequence and conformation complexity found in natural protein interaction interfaces are generally considered essential for achieving tight and specific interactions. However, it has been demonstrated that specific antibodies can be built by using an interface with a binary code consisting of only Tyr and Ser. This surprising result might be attributed to yet undefined properties of the antibody scaffold that uniquely enhance its capacity for target binding. In this work we tested the generality of the binary-code interface by engineering binding proteins based on a single-domain scaffold. We show that Tyr/Ser binary-code interfaces consisting of only 15-20 positions within a fibronectin type III domain (FN3; 95 residues) are capable of producing specific binding proteins (termed "monobodies") with a low-nanomolar K(d). A 2.35-A x-ray crystal structure of a monobody in complex with its target, maltose-binding protein, and mutation analysis revealed dominant contributions of Tyr residues to binding as well as striking molecular mimicry of a maltose-binding protein substrate, beta-cyclodextrin, by the Tyr/Ser binary interface. This work suggests that an interaction interface with low chemical diversity but with significant conformational diversity is generally sufficient for tight and specific molecular recognition, providing fundamental insights into factors governing protein-protein interactions.


The value of testicular 'mapping' in men with non-obstructive azoospermia.
As the field of assisted reproduction has advanced, many previously untreatable men are now biological fathers. Although finding sperm in men with obstructive azoospermia is not difficult, locating and retrieving spermatozoa in men with non-obstructive azoospermia remains a clinical challenge, largely because sperm production in these men can be patchy or focal in nature. In response to this challenge, strategies such as fine-needle aspiration (FNA) mapping have been developed to find spermatozoa. This review discusses the history, evolution and current clinical utility and findings with FNA mapping for male infertility). Review of the current literature in the English language on FNA (diagnostic or therapeutic) with a keyword focuses on sperm detection, retrieval, safety and complications. FNA was described in human medicine over 100 years ago. Testis FNA was described 45 years ago and FNA 'mapping' of spermatozoa was described in 1997. This comparative review of the literature on sperm detection and complication rates with FNA and open testis biopsy or microdissection procedures suggests that FNA is highly informative, minimally invasive and is associated with fewer complications than other commonly used approaches to sperm detection in non-obstructive azoospermic patients. FNA mapping has gained considerable traction as an informative, 'testis sparing' technique for sperm detection in non-obstructive azoospermia. With knowledge of sperm presence and location prior to sperm retrieval, FNA maps can help clinicians tailor sperm retrieval to optimize time, effort and extent of procedures needed to procure spermatozoa in these difficult cases.


Reliability of readings of magnetic resonance imaging features of lumbar spinal stenosis.
A reliability assessment of standardized magnetic resonance imaging (MRI) interpretations and measurements. To determine the intra- and inter-reader reliability of MRI features of lumbar spinal stenosis (SPS), including severity of central, subarticular, and foraminal stenoses, grading of nerve root impingement, and measurements of cross-sectional area of the spinal canal and thecal sac. MRI is commonly used to assess patients with spinal stenosis. Although a number of studies have evaluated the reliability of certain MRI characteristics, comprehensive evaluation of the reliability of MRI readings in spinal stenosis is lacking. Fifty-eight randomly selected MR images from patients with SPS enrolled in the Spine Patient Outcomes Research Trial were evaluated. Qualitative ratings of imaging features were performed according to defined criteria by 4 independent readers (3 radiologists and 1 orthopedic surgeon). A sample of 20 MRIs was reevaluated by each reader at least 1 month later. Weighted kappa statistics were used to characterize intra- and inter-reader reliability for qualitative rating data. Separate quantitative measurements were performed by 2 other radiologists. Intraclass correlation coefficients and summaries of measurement error were used to characterize reliability for quantitative measurements. Intra-reader reliability was higher than inter-reader reliability for all features. Inter-reader reliability in assessing central stenosis was substantial, with an overall kappa of 0.73 (95% CI 0.69-0.77). Foraminal stenosis and nerve root impingement showed moderate to substantial agreement with overall kappa of 0.58 (95% CI 0.53-0.63) and 0.51 (95% CI 0.42-0.59), respectively. Subarticular zone stenosis yielded the poorest agreement (overall kappa 0.49; 95% CI 0.42-0.55) and showed marked variability in agreement between reader pairs. Quantitative measures showed inter-reader intraclass correlation coefficients ranging from 0.58 to 0.90. The mean absolute difference between readers in measured thecal sac area was 128 mm (13%). The imaging characteristics of spinal stenosis assessed in this study showed moderate to substantial reliability; future studies should assess whether these findings have prognostic significance in SPS patients.


Microbial species delineation using whole genome sequences.
Increased sequencing of microbial genomes has revealed that prevailing prokaryotic species assignments can be inconsistent with whole genome information for a significant number of species. The long-standing need for a systematic and scalable species assignment technique can be met by the genome-wide Average Nucleotide Identity (gANI) metric, which is widely acknowledged as a robust measure of genomic relatedness. In this work, we demonstrate that the combination of gANI and the alignment fraction (AF) between two genomes accurately reflects their genomic relatedness. We introduce an efficient implementation of AF,gANI and discuss its successful application to 86.5M genome pairs between 13,151 prokaryotic genomes assigned to 3032 species. Subsequently, by comparing the genome clusters obtained from complete linkage clustering of these pairs to existing taxonomy, we observed that nearly 18% of all prokaryotic species suffer from anomalies in species definition. Our results can be used to explore central questions such as whether microorganisms form a continuum of genetic diversity or distinct species represented by distinct genetic signatures. We propose that this precise and objective AF,gANI-based species definition: the MiSI (Microbial Species Identifier) method, be used to address previous inconsistencies in species classification and as the primary guide for new taxonomic species assignment, supplemented by the traditional polyphasic approach, as required.


Computational identification of conserved microRNAs and their putative targets in the Hypericum perforatum L. flower transcriptome.
MicroRNAs (miRNAs) have recently emerged as important regulators of gene expression in plants. Many miRNA families and their targets have been extensively studied in model species and major crops. We have characterized mature miRNAs along with their precursors and potential targets in Hypericum to generate a comprehensive list of conserved miRNA families and to investigate the regulatory role of selected miRNAs in biological processes that occur in the flower. St. John's wort (Hypericum perforatum L., 2n = 4x = 32), a medicinal plant that produces pharmaceutically important metabolites with therapeutic activities, was chosen because it is regarded as an attractive model system for the study of apomixis. A computational in silico prediction of structure, in combination with an in vitro validation, allowed us to identify 7 pre-miRNAs, including miR156, miR166, miR390, miR394, miR396, and miR414. We demonstrated that H. perforatum flowers share highly conserved miRNAs and that these miRNAs potentially target dozens of genes with a wide range of molecular functions, including metabolism, response to stress, flower development, and plant reproduction. Our analysis paves the way toward identifying flower-specific miRNAs that may differentiate the sexual and apomictic reproductive pathways.


A gene expression signature-based approach reveals the mechanisms of action of the Chinese herbal medicine berberine.
Berberine (BBR), a traditional Chinese herbal medicine, was shown to display anticancer activity. In this study, we attempted to provide a global view of the molecular pathways associated with its anticancer effect through a gene expression-based chemical approach. BBR-induced differentially expressed genes obtained from the Gene Expression Omnibus (GEO) at the National Center for Biotechnology Information (NCBI) were analyzed using the Connectivity Map (CMAP) database to compare similarities of gene expression profiles between BBR and CMAP compounds. Candidate compounds were further analyzed using the Search Tool for Interactions of Chemicals (STITCH) database to explore chemical-protein interactions. Results showed that BBR may inhibit protein synthesis, histone deacetylase (HDAC), or AKT/mammalian target of rapamycin (mTOR) pathways. Further analyses demonstrated that BBR inhibited global protein synthesis and basal AKT activity, and induced endoplasmic reticulum (ER) stress and autophagy, which was associated with activation of AMP-activated protein kinase (AMPK). However, BBR did not alter mTOR or HDAC activities. Interestingly, BBR induced the acetylation of α-tubulin, a substrate of HDAC6. In addition, the combination of BBR and SAHA, a pan-HDAC inhibitor, synergistically inhibited cell proliferation and induced cell cycle arrest. Our results provide novel insights into the mechanisms of action of BBR in cancer therapy.


Nonalcoholic fatty liver disease: diagnosis and management.
Nonalcoholic fatty liver disease is characterized by excessive fat accumulation in the liver (hepatic steatosis). Nonalcoholic steatohepatitis is characterized by steatosis, liver cell injury, and inflammation. The mechanism of nonalcoholic fatty liver disease is unknown but involves the development of insulin resistance, steatosis, inflammatory cytokines, and oxidative stress. Nonalcoholic fatty liver disease is associated with physical inactivity, obesity, and metabolic syndrome. Screening is not recommended in the general population. The diagnosis is usually made after an incidental discovery of unexplained elevation of liver enzyme levels or when steatosis is noted on imaging (e.g., ultrasonography). Patients are often asymptomatic and the physical examination is often unremarkable. No single laboratory test is diagnostic, but tests of liver function, tests for metabolic syndrome, and tests to exclude other causes of abnormal liver enzyme levels are routinely performed. Imaging studies, such as ultrasonography, computed tomography, and magnetic resonance imaging, can assess hepatic fat, measure liver and spleen size, and exclude other diseases. Liver biopsy remains the criterion standard for the diagnosis of nonalcoholic steatohepatitis. Noninvasive tests are available and may reduce the need for liver biopsy. A healthy diet, weight loss, and exercise are first-line therapeutic measures to reduce insulin resistance. There is insufficient evidence to support bariatric surgery, metformin, thiazolidinediones, bile acids, or antioxidant supplements for the treatment of nonalcoholic fatty liver disease. The long-term prognosis is not associated with an increased risk of all-cause mortality, cardiovascular disease, cancer, or liver disease.


Ischemia-modified albumin and total antioxidant status in patients with slow coronary flow: a pilot observational study.
Slow coronary flow (SCF) is defined as late opacification in the epicardial coronary arteries without significant stenosis. The underlying mechanism of SCF is similar to coronary atherosclerosis. Free radical damage may be responsible for the pathology. In this study, we aimed to investigate ischemia-modified albumin (IMA) levels and differences with regard to total antioxidant status (TAS) between patients with normal coronary arteries and patients with SCF without significant stenosis. Thirty patients who were diagnosed with SCF using coronary angiography were included in this cross-sectional observational study (13 male; mean age, 56±10 years). The control group consisted of 30 patients who had normal coronary arteries as shown by coronary angiography (13 male; mean age, 53±11 years). In this study, we assessed serum IMA levels, albumin-adjusted IMA and TAS. The Student t-test was used to compare serum IMA levels and TAS between the two groups. Pearson's correlation test was used to explore the relationship between TAS and serum IMA levels. Serum IMA levels and albumin-adjusted IMA were similar in both groups (p=0.432, p=0.349). The mean value of TAS was significantly lower in the SCF group compared to control group (p=0.011). The TAS was negatively correlated with the levels of IMA and albumin-adjusted IMA in the SCF group (r=-0.457, p=0.011; r=-0.509, p=0.004). This study shows that serum IMA levels and albumin-adjusted IMA were similar between the groups, however the mean value of TAS was significantly lower in the SCF group compared to control group and negatively correlated with IMA. These results are important in terms of understanding the pathophysiological basis of SCF.


First Report of Leaf Disease on Cinnamomum subavenium Caused by Colletotrichum fioriniae in China.
Cinnamomum subavenium Miq. (Lauraceae) is a subtropical arbor plant widely distributed in southwest China. It has a long history of cultivation and has been widely used in traditional Chinese medicine, food flavors, and industrial materials. In August 2010, a serious leaf disease was observed on wild Cinnamomum subavenium growing in Gutianshan Nature Reserve, Zhejiang, China. Lesions were approximately 1.0 cm in diameter and the margin of the lesions was light to dark brown and the middle was gray to pale yellowish. Necrotic lesions were surface disinfected with 1% sodium hypochlorite for 1 min and 70% ethanol for 3 min, and isolations were made from lesion edges onto potato dextrose agar (PDA). Three plants were tested and a fungus was consistently isolated from lesions. Colonies of this fungus on PDA were at first gray becoming pinkish gray with age, with salmon pink conidial masses, and the reverse of the colony was pink. The growth rate was 10.82 to 11.95 mm per day (average = 11.58 ± 0.25, n = 6) on PDA at 25°C. Conidia were oblong or cylindrical with acute ends, occasionally guttulate, hyaline, 7.5 to 14.5 × 2.5 to 4.3 μm (average = 11.25 ± 0.5 × 3.4 ± 0.4, n = 30). These characteristics matched the description of Colletotrichum fioriniae (Marcelino & Gouli) R.G. Shivas & Y.P. Tan (2). DNA was extracted from one isolate and the rDNA-internal transcribed spacer (ITS) region was amplified and sequenced using primers ITS1 and ITS4 (1). The ITS sequence of the isolate (GenBank Accession No. JN208890) shared 100% identity to the holotype of C. fioriniae (Accession No. EF464594). The pathogenicity of C. fioriniae on Cinnamomum subavenium was confirmed through inoculation. Three freshly harvested, healthy leaves were washed under running tap water, immersed in 5% sodium hypochlorite for 3 min and 70% ethanol for 1 min, rinsed three times in sterilized water, and finally dried with sterilized tissue paper. Plant leaves were inoculated with a concentration of 2.5 × 106 spores/ml. Sterilized water was used for controls. All the leaves inoculated with C. fioriniae were symptomatic with round to elliptical lesions with a brown margin 14 days postinoculation. The fungus, reisolated from symptomatic leaf tissue, had the same morphological and cultural characteristics of C. fioriniae. Although C. gloeosporioides has been reported from several species in the genus Cinnamomum ( http://nt.ars-grin.gov/fungaldatabases/ ), to our knowledge, this is the first report of leaf disease on Cinnamomum subavenium caused by a Colletotrichum species. References: (1) H. Prihastuti et al. Fungal Divers. 39:89, 2009. (2) R. G. Shivas and Y. P. Tan. Fungal Divers. 39:111, 2009.


Flow control techniques for Onyx embolization of intracranial dural arteriovenous fistulae.
Experience of flow control techniques during endovascular treatment of intracranial dural arteriovenous fistulas (DAVFs) using the Onyx liquid embolic system is reported, with an emphasis on high flow shunts. Data were evaluated in patients with DAVFs treated endovascularly with Onyx. Adjunctive techniques with coils, acrylics and balloon assistance were utilized to reduce the rate of flow with transarterial and transvenous approaches. The following types of adjunctive techniques were used in 58 patients who underwent a total of 84 embolization sessions with Onyx: transvenous coiling with transvenous or transarterial Onyx embolization in 36 patients, transarterial coiling with transarterial Onyx embolization in eight patients, arterial or venous balloon assisted technique with transarterial or transvenous Onyx embolization in 11 patients, transarterial high concentration acrylics with transarterial Onyx embolization in one patient and staged transarterial or transvenous coiling and Onyx embolization in two patients. Complete obliteration of the fistulae was achieved in 41 patients (70.7%) and 27 patients (65.9%) with high flow fistulae after endovascular treatment alone. Periprocedural complications were encountered in 16 patients, and 13 complications were associated with the adjunctive techniques. There were four neurologic and two non-neurologic clinical sequelae. Distal Onyx migration occurred in four, microcatheter retention in three and cranial neuropathy in three patients. There was one instance each of cerebellar hemorrhage, thromboembolism, coil stretching and retention, and dissection. 56 survivors experienced complete resolution or significant improvement of their symptoms on follow-up. Flow control techniques are safe and effective adjunctive methods in primary endovascular Onyx embolization of high flow DAVFs.


World Federation of Societies of Biological Psychiatry (WFSBP) guidelines for the biological treatment of Alzheimer's disease and other dementias.
To define a practice guideline for biological treatment of dementia and to make transparent the development of the guideline connecting the original data with the resulting recommendations. This guideline includes pharmacologic treatment considerations for patients with Alzheimer's disease, vascular dementia, DLB, and fronto-temporal dementia. Studies were selected that represent double-blind placebo-controlled trials of at least 3 months duration in patients with a diagnosis of dementia according to accepted international diagnostic criteria (for example the NINCDS/ADRDA or NINDS/AIREN criteria). Moreover, to be included studies had to fulfill a restrictive set of methodological criteria. Original studies and not meta-analyses determined the evaluation and the development of recommendations. Antidementia pharmaceuticals neither cure nor arrest the disease. A modest effect of improvement of symptoms compared with placebo can be observed. Antidementia pharmaceuticals show different efficacy and side effect profiles. The type of dementia, the individual symptom constellation and the tolerability should determine what medication should be used. There are hints that combination therapy of drugs with different therapeutic mechanisms might improve the efficacy. In treating neuropsychiatric symptoms (NPS), psychosocial intervention should be the treatment of first choice. Pharmaceuticals can only be recommended when psychosocial interventions is not adequate. However, even then the side effects of pharmaceuticals limit their use. Depending on the diagnostic entity and the pathology treated different anti-dementia drugs can be recommended to improve symptoms. In the management of NPS, side effects limit the use of medications even when psychosocial interventions have failed. Thus, there is an urgent need to develop more efficacious medications for the treatment of dementia.


Piezoelectric coupling in a field-effect transistor with a nanohybrid channel of ZnO nanorods grown vertically on graphene.
Piezoelectric coupling phenomena in a graphene field-effect transistor (GFET) with a nano-hybrid channel of chemical-vapor-deposited Gr (CVD Gr) and vertically aligned ZnO nanorods (NRs) under mechanical pressurization were investigated. Transfer characteristics of the hybrid channel GFET clearly indicated that the piezoelectric effect of ZnO NRs under static or dynamic pressure modulated the channel conductivity (σ) and caused a positive shift of 0.25% per kPa in the Dirac point. However, the GFET without ZnO NRs showed no change in either σ or the Dirac point. Analysis of the Dirac point shifts indicated transfer of electrons from the CVD Gr to ZnO NRs due to modulation of their interfacial barrier height under pressure. High responsiveness of the hybrid channel device with fast response and recovery times was evident in the time-dependent behavior at a small gate bias. In addition, the hybrid channel FET could be gated by mechanical pressurization only. Therefore, a piezoelectric-coupled hybrid channel GFET can be used as a pressure-sensing device with low power consumption and a fast response time. Hybridization of piezoelectric 1D nanomaterials with a 2D semiconducting channel in FETs enables a new design for future nanodevices.


Microbial community dynamics in uranium contaminated subsurface sediments under biostimulated conditions with high nitrate and nickel pressure.
The subsurface at the Oak Ridge Field Research Center represents an extreme and diverse geochemical environment that places different stresses on the endogenous microbial communities, including low pH, elevated nitrate concentrations, and the occurrence of heavy metals and radionuclides, including hexavalent uranium [U(VI)]. The in situ immobilization of U(VI) in the aquifer can be achieved through microbial reduction to relatively insoluble U(IV). However, a high redox potential due to the presence of nitrate and the toxicity of heavy metals will impede this process. Our aim is to test biostimulation of the endogenous microbial communities to improve nitrate reduction and subsequent U(VI) reduction under conditions of elevated heavy metals. Column experiments were used to test the possibility of using biostimulation via the addition of ethanol as a carbon source to improve nitrate reduction in the presence of elevated aqueous nickel. We subsequently analyzed the composition of the microbial communities that became established and their potential for U(VI) reduction and its in situ immobilization. Phylogenetic analysis revealed that the microbial population changed from heavy metal sensitive members of the actinobacteria, alpha- and gamma-proteobacteria to a community dominated by heavy metal resistant (nickel, cadmium, zinc, and cobalt resistant), nitrate reducing beta- and gamma-proteobacteria, and sulfate reducing Clostridiaceae. Coincidentally, synchrotron X-ray absorption spectroscopy analyses indicated that the resulting redox conditions favored U(VI) reduction transformation to insoluble U(IV) species associated with soil minerals and biomass. This study shows that the necessary genetic information to adapt to the implemented nickel stress resides in the endogenous microbial population present at the Oak Ridge FRC site, which changed from a community generally found under oligotrophic conditions to a community able to withstand the stress imposed by heavy metals, while efficiently reducing nitrate as electron donor. Once nitrate was reduced efficient reduction and in situ immobilization of uranium was observed. This study provides evidence that stimulating the metabolism of the endogenous bacterial population at the Oak Ridge FRC site by adding ethanol, a suitable carbon source, results in efficient nitrate reduction under conditions of elevated nickel, and a decrease of the redox potential such that sulfate and iron reducing bacteria are able to thrive and create conditions favorable for the reduction and in situ immobilization of uranium. Since we have found that the remediation potential resides within the endogenous microbial community, we believe it will be feasible to conduct field tests. Biostimulation of endogenous bacteria provides an efficient tool for the successful in situ remediation of mixed-waste sites, particularly those co-contaminated with heavy metals, nitrate and radionuclides, as found in the United States and other countries as environmental legacies of the nuclear age.


Experience teaches plants to learn faster and forget slower in environments where it matters.
The nervous system of animals serves the acquisition, memorization and recollection of information. Like animals, plants also acquire a huge amount of information from their environment, yet their capacity to memorize and organize learned behavioral responses has not been demonstrated. In Mimosa pudica-the sensitive plant-the defensive leaf-folding behaviour in response to repeated physical disturbance exhibits clear habituation, suggesting some elementary form of learning. Applying the theory and the analytical methods usually employed in animal learning research, we show that leaf-folding habituation is more pronounced and persistent for plants growing in energetically costly environments. Astonishingly, Mimosa can display the learned response even when left undisturbed in a more favourable environment for a month. This relatively long-lasting learned behavioural change as a result of previous experience matches the persistence of habituation effects observed in many animals.


Effects of osmotic changes on the chemoreceptor cell of rat carotid body.
The carotid body plays a crucial role in cardiorespiratory regulation. In the present study we investigated the effect of osmotic changes on cytoplasmic calcium concentration ([Ca(2+)](c)) and pH (pH(i)) of isolated chemoreceptor cells of the rat carotid body. In CO(2)/HCO(3)(-)-buffered medium, reduction of osmolality from the control level of 300 mosmol kg(-1) to 250-285 mosmol kg(-1) resulted in a rise in [Ca(2+)](c), as measured with Indo-1, whereas elevation of osmolality to 350 mosmol kg(-1) had no effect. The Ca(2+) response required extracellular Ca(2+) and was reduced by application of the L-type Ca(2+) channel antagonist nifedipine (10 microM). The hyposmosis-induced Ca(2+) response could be prevented by application of niflumic acid (300 microM), an inhibitor of the swelling-activated Cl(-) channel. In whole-cell patch-clamp experiments niflumic acid abolished the swelling-activated Cl(-) current but only slightly depressed the Ca(2+) current. The inhibition of Ca(2+) current by niflumic acid does not account for its action in preventing of hyposmosis-induced Ca(2+) response, which seems to be initiated by Cl(-)-mediated depolarisation. Withdrawal of CO(2)/HCO(3)(-) also prevented the Ca(2+) response. Reduction of the osmotic concentration by 50 mosmol kg(-1) induced a small but sustained decrease in pH(i), while elevation by 50 mosmol kg(-1) had an inverse effect, as measured fluorimetrically with carboxy SNARF-1. Our conclusion is that in the rat chemoreceptor cell the activation of Cl(-) channels, e.g. by hyposmotic challenge, induces depolarisation, which, in turn, activates voltage-gated Ca(2+) channels.


HbA1c in type 2 diabetes diagnostic criteria: addressing the right questions to move the field forwards.
This commentary aims to move the debate regarding the adoption of HbA(1c) for diagnosis of type 2 diabetes forwards by highlighting the need to avoid addressing irrelevant questions, in particular, comparison of individuals diagnosed with different diagnostic criteria. Instead, we provide a list of important future questions, including whether adoption of HbA(1c) as the primary diagnostic test improves uptake of diabetes screening, with resultant earlier diagnosis and improvement in outcomes.


Kinship of long-term associates in the highly social sperm whale.
The evolution of stable social groups can be promoted by both indirect and direct fitness benefits. Sperm whales (Physeter macrocephalus) are highly social, with a hierarchical social structure based around core groups of adult females and subadults, a rare level of complexity among mammals. We combined long-term satellite tracking (ranging from 11 to 607 days) of 51 individual sperm whales with genetic kinship analysis to assess the pattern of kin associations within and among coherent social units. Unlike findings for other species with similar social structure, we find no consistent correlation between kinship and association apart from close associations between two pairs of first-order relatives. A third pair of first-order relatives did not associate, and overall, the mean relatedness was the same within as among social groups. However, social behaviour can also be promoted by ecological factors such as resource dispersion. We assessed putative foraging behaviour during travel from the satellite-tracking data, which suggested that prey resources were dispersed and unpredictable, a condition that could promote living in groups.


How well do postpartum blood loss and common definitions of postpartum hemorrhage correlate with postpartum anemia and fall in hemoglobin?
We aimed to better understand how well postpartum blood loss and common postpartum hemorrhage (PPH) definitions (i.e. blood loss ≥500ml = PPH, ≥1000ml = "severe" PPH) correlate with postpartum anemia and fall in hemoglobin. Secondary analysis of data from three randomized trials that objectively measured postpartum blood loss and pre- and post-delivery hemoglobin among vaginal deliveries: one trial included 1056 home-births in Pakistan and two multi-country hospital-based trials included 1279 women diagnosed with PPH. We calculated Spearman's correlation coefficients (rs) for blood loss with hemoglobin drop and postpartum hemoglobin, and we compared PPH blood loss markers (≥500ml, ≥1000ml) with large hemoglobin drops (≥2 g/dL) and the threshold for moderate postpartum anemia (<10g/dL). In the Pakistan study and the multi-country trials, blood loss was weakly correlated with hemoglobin drop (Pakistan: rs = -0.220, multi-country trials: rs = -0.271) and postpartum hemoglobin (Pakistan: rs = -0.220, multi-country trials: rs = -0.316). In both the Pakistan and multi-country trials, hemoglobin drop ≥2 g/dL occurred in less than half of women with 500-999 ml blood loss (55/175 [31%] and 302/725 [42%], respectively) and was more common among women who bled ≥1000ml (19/28 [68%] and 347/554 [63%], respectively). Similarly, in the Pakistan and multi-country trials, postpartum anemia <10 g/dL was less frequent among women who bled 500-999 ml (55/175 [31%] and 390/725 [54%], respectively) and more frequent among women with ≥1000ml blood loss (20/28 [71%] and 416/554 [75%], respectively). Postpartum morbidity as measured by hemoglobin markers was common for women with blood loss ≥1000ml and relatively infrequent among women with blood loss 500-999ml. These findings reinforce the importance of severe PPH as the preferred outcome to be used in research. The weak correlation between blood loss and hemoglobin markers also suggests that this relationship is not straightforward and should be carefully interpreted.


Reflection impulsivity in binge drinking: behavioural and volumetric correlates.
The degree to which an individual accumulates evidence prior to making a decision, also known as reflection impulsivity, can be affected in psychiatric disorders. Here, we study decisional impulsivity in binge drinkers, a group at elevated risk for developing alcohol use disorders, comparing two tasks assessing reflection impulsivity and a delay discounting task, hypothesizing impairments in both subtypes of impulsivity. We also assess volumetric correlates of reflection impulsivity focusing on regions previously implicated in functional magnetic resonance imaging studies. Sixty binge drinkers and healthy volunteers were tested using two different information-gathering paradigms: the beads task and the Information Sampling Task (IST). The beads task was analysed using a behavioural approach and a Bayesian model of decision making. Delay discounting was assessed using the Monetary Choice Questionnaire. Regression analyses of primary outcomes were conducted with voxel-based morphometry analyses. Binge drinkers sought less evidence prior to decision in the beads task compared with healthy volunteers in both the behavioural and computational modelling analysis. There were no group differences in the IST or delay discounting task. Greater impulsivity as indexed by lower evidence accumulation in the beads task was associated with smaller dorsolateral prefrontal cortex and inferior parietal volumes. In contrast, greater impulsivity as indexed by lower evidence accumulation in the IST was associated with greater dorsal cingulate and precuneus volumes. Binge drinking is characterized by impaired reflection impulsivity suggesting a deficit in deciding on the basis of future outcomes that are more difficult to represent. These findings emphasize the role of possible therapeutic interventions targeting decision-making deficits.


The performance of resurfacing implants for focal cartilage defects depends on the degenerative condition of the opposing cartilage.
Non-degradable resurfacing implants are being developed for treatment of focal cartilage defects. Performance of these implants has been investigated opposing intact cartilage. This study investigates whether implants would perform equally well when the opposing cartilage is fibrillated. Human osteochondral strips (~2x1x1 cm) with a smooth (n = 9) or fibrillated (n = 17) cartilage surface were obtained from human tibial plateaus excised during total knee arthroscopy. A custom-made pin-on-plate sliding indenter was used to apply simultaneous compression (0.75-3 MPa) and movement (4 mm/s over 6 mm). Either metal implants, polycarbonate-urethane or healthy porcine osteochondral plugs with a diameter of 6 mm were used as indenter. Cartilage roughness of the osteochondral strips was significantly higher for the fibrillated than the smooth group prior to sliding-indentation. Roughness of the indenters was not significantly altered by sliding indentation using either smooth or fibrillated cartilage. For all but one sample, sliding of smooth cartilage against any of the indenter surfaces did not cause damage. However, samples with fibrillated cartilage showed varied responses from seemingly unaffected to severe tissue wear as quantified by analysis of Indian ink staining and histology. This study demonstrates that the opposing cartilage quality is relevant for the clinical success of implanting an artificial implant in a focal cartilage defect. Therefore it is essential to test the efficacy of newly developed implants against arthritic joint surfaces, and care should be taken when interpreting in vivo studies in which implants are inserted in healthy joints.


Post-transcriptional regulation of satellite cell quiescence by TTP-mediated mRNA decay.
Skeletal muscle satellite cells in their niche are quiescent and upon muscle injury, exit quiescence, proliferate to repair muscle tissue, and self-renew to replenish the satellite cell population. To understand the mechanisms involved in maintaining satellite cell quiescence, we identified gene transcripts that were differentially expressed during satellite cell activation following muscle injury. Transcripts encoding RNA binding proteins were among the most significantly changed and included the mRNA decay factor Tristetraprolin. Tristetraprolin promotes the decay of MyoD mRNA, which encodes a transcriptional regulator of myogenic commitment, via binding to the MyoD mRNA 3' untranslated region. Upon satellite cell activation, p38α/β MAPK phosphorylates MAPKAP2 and inactivates Tristetraprolin, stabilizing MyoD mRNA. Satellite cell specific knockdown of Tristetraprolin precociously activates satellite cells in vivo, enabling MyoD accumulation, differentiation and cell fusion into myofibers. Regulation of mRNAs by Tristetraprolin appears to function as one of several critical post-transcriptional regulatory mechanisms controlling satellite cell homeostasis.


Comparison of tai chi vs. strength training for fall prevention among female cancer survivors: study protocol for the GET FIT trial.
Women with cancer are significantly more likely to fall than women without cancer placing them at higher risk of fall-related fractures, other injuries and disability. Currently, no evidence-based fall prevention strategies exist that specifically target female cancer survivors. The purpose of the GET FIT (Group Exercise Training for Functional Improvement after Treatment) trial is to compare the efficacy of two distinct types of exercise, tai chi versus strength training, to prevent falls in women who have completed treatment for cancer. The specific aims of this study are to: 1) Determine and compare the efficacy of both tai chi training and strength training to reduce falls in older female cancer survivors, 2) Determine the mechanism(s) by which tai chi and strength training each reduces falls and, 3) Determine whether or not the benefits of each intervention last after structured training stops. We will conduct a three-group, single-blind, parallel design, randomized controlled trial in women, aged 50-75 years old, who have completed chemotherapy for cancer comparing 1) tai chi 2) strength training and 3) a placebo control group of seated stretching exercise. Women will participate in supervised study programs twice per week for six months and will be followed for an additional six months after formal training stops. The primary outcome in this study is falls, which will be prospectively tracked by monthly self-report. Secondary outcomes are maximal leg strength measured by isokinetic dynamometry, postural stability measured by computerized dynamic posturography and physical function measured by the Physical Performance Battery, all measured at baseline, 3, 6 and 12 months. The sample for this trial (N=429, assuming 25% attrition) will provide adequate statistical power to detect at least a 47% reduction in the fall rate over 1 year by being in either of the 2 exercise groups versus the control group. The GET FIT trial will provide important new knowledge about preventing falls using accessible and implementable exercise interventions for women following chemotherapy for cancer. ClinicalTrials.gov NCT01635413.


Nanodiamond modified copolymer scaffolds affects tumour progression of early neoplastic oral keratinocytes.
This study aimed to evaluate the tumorigenic potential of functionalising poly(LLA-co-CL) scaffolds. The copolymer scaffolds were functionalised with nanodiamonds (nDP) or with nDP and physisorbed BMP-2 (nDP-PHY) to enhance osteoinductivity. Culturing early neoplastic dysplastic keratinocytes (DOK(Luc)) on nDP modified scaffolds reduced significantly their subsequent sphere formation ability and decreased significantly the cells' proliferation in the supra-basal layers of in vitro 3D oral neoplastic mucosa (3D-OT) when compared to DOK(Luc) previously cultured on nDP-PHY scaffolds. Using an in vivo non-invasive environmentally-induced oral carcinogenesis model, nDP scaffolds were observed to reduce bioluminescence intensity of tumours formed by DOK(Luc) + carcinoma associated fibroblasts (CAF). nDP modification was also found to promote differentiation of DOK(Luc) both in vitro in 3D-OT and in vivo in xenografts formed by DOK(Luc) alone. The nDP-PHY scaffold had the highest number of invasive tumours formed by DOK(Luc) + CAF outside the scaffold area compared to the nDP and control scaffolds. In conclusion, in vitro and in vivo results presented here demonstrate that nDP modified copolymer scaffolds are able to decrease the tumorigenic potential of DOK(Luc), while confirming concerns for the therapeutic use of BMP-2 for reconstruction of bone defects in oral cancer patients due to its tumour promoting capabilities.


ARHGEF9 disruption in a female patient is associated with X linked mental retardation and sensory hyperarousal.
We identified a female patient with mental retardation and sensory hyperarousal. She has a de novo paracentric inversion of one X chromosome with completely skewed inactivation of the normal X chromosome. We aimed to identify whether a single gene or gene region caused her cognitive and behavioural impairment and that of others. Fluorescent in situ hybridisation (FISH) showed that the centromeric breakpoint disrupts a single gene: ARHGEF9 (CDC42 guanine nucleotide exchange factor (GEF) 9). We also found that the levels of the ARHGEF9 transcript from the patient are 10-fold less than those found in control samples. ARHGEF9 encodes a RhoGEF family protein: collybistin (hPEM), which is highly expressed in the brain. Collybistin can regulate actin cytoskeletal dynamics and may also modulate GABAergic and glycinergic neurotransmission through binding of a scaffolding protein, gephyrin, at the synapse. This potential dual role may explain both the mental retardation and hyperarousal observed in our patient.


Using a 'peer assessment questionnaire' in primary medical care.
Periodic assessment of clinician performance or 'revalidation' is being actively considered to reassure the public that doctors are 'up to date and fit to practice'. There is, therefore, increasing interest in how to assess individual clinician performance in a valid and reliable way. The use of peer assessment questionnaires is one of the methods being considered and investigated by the General Medical Council in the UK. To test the feasibility of using a peer assessment questionnaire in a primary care setting, and consider the related issues of validity and reliability and compare the results to previous studies. Cross-sectional survey in a volunteer sample. General practice in the UK. GPs who volunteered to take part in an evaluation of a pilot appraisal implementation scheme were recruited by appraisers. These volunteers (GP subjects) chose 15 colleagues to complete a 'peer assessment' questionnaire that asked peers to make judgements about their clinical skills and other characteristics, such as 'compassion', 'integrity' and 'responsibility'. Of the 207 practitioners that agreed to be appraised, 113 completed the optional task of implementing the peer questionnaire. Of the 1271 raters, 1189 provided data about their roles and 33.6% of these were GPs. The data revealed significant levels of items where peers were 'unable to evaluate' the issues posed in the questionnaire (ranging from 13.7-1.8%). These rates differed from those obtained in studies based in the US where mean scores were slightly higher. Although the overall results are broadly similar to those previously obtained, there are sufficient differences to suggest that there are contextual issues influencing the interpretation of the items and therefore the scoring process. The volunteer sample in this study found no major obstacles to the implementation of the peer assessment questionnaire. While it is not possible to generalise from this selected volunteer sample, the use of peer assessment questionnaires appears feasible and may be acceptable to clinical practitioners. However, concern remains about the validity of such instruments and that their development did not fully consider issues of procedural justice or whether the overall purpose of the tools was to be formative, summative, or both.


Electron-phonon scattering effect on the lattice thermal conductivity of silicon nanostructures.
Nanostructuring technology has been widely employed to reduce the thermal conductivity of thermoelectric materials because of the strong phonon-boundary scattering. Optimizing the carrier concentration can not only improve the electrical properties, but also affect the lattice thermal conductivity significantly due to the electron-phonon scattering. The lattice thermal conductivity of silicon nanostructures considering electron-phonon scattering is investigated for comparing the lattice thermal conductivity reductions resulting from nanostructuring technology and the carrier concentration optimization. We performed frequency-dependent simulations of thermal transport systematically in nanowires, solid thin films and nanoporous thin films by solving the phonon Boltzmann transport equation using the discrete ordinate method. All the phonon properties are based on the first-principles calculations. The results show that the lattice thermal conductivity reduction due to the electron-phonon scattering decreases as the feature size of nanostructures goes down and could be ignored at low feature sizes (50 nm for n-type nanowires and 20 nm for p-type nanowires and n-type solid thin films) or a high porosity (0.6 for n-type 500 nm-thick nanoporous thin films) even when the carrier concentration is as high as 1021 cm-3. Similarly, the size effect due to the phonon-boundary scattering also becomes less significant with the increase of carrier concentration. The findings provide a fundamental understanding of electron and phonon transports in nanostructures, which is important for the optimization of nanostructured thermoelectric materials.


Prevalence of stroke in Taiwan.
We investigated the prevalence of stroke in Taiwan in an epidemiologic study of stroke, diabetes, and cardiovascular disease that used a two-phase survey design. The study population was drawn by cluster sampling and consisted of both urban and rural communities from four regions of Taiwan. There were 8,705 people 36 years of age or older interviewed during the period of October 1 to December 31, 1986, and 143 cases of completed stroke were later identified by a neurologist. The point prevalence rate for people aged 36 or older in our study was 1,642/100,000 population (95% confidence interval 1,389-1,942/100,000). Prevalence rates differed significantly among the four study regions and between urban and rural communities; prevalence was greater in northern Taiwan and in urban communities. Percentages of the major types of stroke in 143 stroke survivors were as follows: cerebral infarction 67.1% (96 cases), cerebral hemorrhage 14.0% (20 cases), subarachnoid hemorrhage 4.2% (six cases), and unclassified 14.7% (21 cases). Of the stroke survivors, 67.1% were independent in activities of daily living, and 75.5% were independent in ambulation. Hypertension, heart disease, diabetes mellitus, and a family history of stroke were significantly more common in stroke survivors than in strokefree individuals.


Predicting the risk of chronic Kidney Disease in men and women in England and Wales: prospective derivation and external validation of the QKidney Scores.
Chronic Kidney Disease is a major cause of morbidity and interventions now exist which can reduce risk. We sought to develop and validate two new risk algorithms (the QKidney Scores) for estimating (a) the individual 5 year risk of moderate-severe CKD and (b) the individual 5 year risk of developing End Stage Kidney Failure in a primary care population. We conducted a prospective open cohort study using data from 368 QResearch general practices to develop the scores. We validated the scores using two separate sets of practices--188 separate QResearch practices and 364 practices contributing to the THIN database.We studied 775,091 women and 799,658 men aged 35-74 years in the QResearch derivation cohort, who contributed 4,068,643 and 4,121,926 person-years of observation respectively.We had two main outcomes (a) moderate-severe CKD (defined as the first evidence of CKD based on the earliest of any of the following: kidney transplant; kidney dialysis; diagnosis of nephropathy; persistent proteinuria; or glomerular filtration rate of < 45 mL/min) and (b) End Stage Kidney Failure.We derived separate risk equations for men and women. We calculated measures of calibration and discrimination using the two separate validation cohorts. Our final model for moderate-severe CKD included: age, ethnicity, deprivation, smoking, BMI, systolic blood pressure, diabetes, rheumatoid arthritis, cardiovascular disease, treated hypertension, congestive cardiac failure; peripheral vascular disease, NSAID use and family history of kidney disease. In addition, it included SLE and kidney stones in women. The final model for End Stage Kidney Failure was similar except it did not include NSAID use.Each risk prediction algorithms performed well across all measures in both validation cohorts. For the THIN cohort, the model to predict moderate-severe CKD explained 56.38% of the total variation in women and 57.49% for men. The D statistic values were high with values of 2.33 for women and 2.38 for men. The ROC statistic was 0.875 for women and 0.876 for men. These new algorithms have the potential to identify high risk patients who might benefit from more detailed assessment, closer monitoring or interventions to reduce their risk.


Maternal gaze to the infant face: Effects of infant age and facial configuration during mother-infant engagement in the first nine weeks.
Adult gaze plays an important role in early infant development, and infants are highly sensitive to its presence and direction. Little is known, however, about how adults look at infants while interacting with them. Using eye-tracking technology, this study investigated maternal gaze during naturalistic interactions, and how it was influenced by infant age, focusing on the transition from the first to the second month when social expressiveness emerges, and by infant facial configuration, focusing on the effect of cleft lip. Thirty infants (10 with a cleft lip), and their mothers, were seen at 1, 3, 5, 7, and 9 weeks. Mothers were asked to interact with their infants while wearing eye-tracking glasses. Fixation duration and count were calculated for general (infant face, body, and surrounding environment), and infant facial (eyes, mouth, other) areas. At all ages, mothers gazed almost exclusively towards their infant's face, but this was reduced in the presence of a cleft lip. Within the infant's face, the eyes attracted the greatest attention, for all mothers, at all ages. From the first to the second month, all mothers increased their visual attention towards their infant's mouth. Regardless of infant age, the presence of a cleft lip was associated with decreased maternal gaze to the infant's mouth. This study provides novel findings concerning maternal gaze to infant faces during naturalistic interactions. Maternal gaze changes with infant age, in line with established shifts in social development, and according to infant facial configuration. Decreased gaze to the mouth area associated with infant cleft lip might affect maternal responsiveness, and suggests new dimensions to target in supporting these mothers.


Design of a digital, ultra-broadband electro-optic switch for reconfigurable optical networks-on-chip.
We present a novel design for a noise-tolerant, ultra-broadband electro-optic switch, based on a Mach-Zehnder lattice (MZL) interferometer. We analyze the switch performance through rigorous optical simulations, for devices implemented in silicon-on-insulator with carrier-injection-based phase shifters. We show that such a MZL switch can be designed to have a step-like switching response, resulting in improved tolerance to drive-voltage noise and temperature variations as compared to a single-stage Mach-Zehnder switch. Furthermore, we show that degradation in switching crosstalk and insertion loss due to free-carrier absorption can be largely overcome by a MZL switch design. Finally, MZL switches can be designed for having an ultra-wide, temperature-insensitive optical bandwidth of more than 250 nm. The proposed device shows good potential as a broadband optical switch in reconfigurable optical networks-on-chip.


Protein tyrosine phosphorylation in the cyanobacterium Anabaena sp. strain PCC 7120.
Components of a protein tyrosine phosphorylation/dephosphorylation network were identified in the cyanobacterium Anabaena sp. strain PCC 7120. Three phosphotyrosine (P-Tyr) proteins of 27, 36, and 52 kDa were identified through their conspicuous immunoreactions with RC20H monoclonal antibodies specific for P-Tyr. These immunoreactions were outcompeted completely by free P-Tyr (5 mM) but not by phosphoserine or phosphothreonine. The P-Tyr content of the three major P-Tyr proteins and several minor proteins increased with their time of incubation in the presence of Mg-ATP and the protein phosphatase inhibitors sodium orthovanadate and sodium fluoride. Incubation of the same extracts with [gamma-32P]ATP but not [alpha-32P]ATP led to the phosphorylation of five polypeptides with molecular masses of 20, 27, 52, 85, and 100 kDa. Human placental protein tyrosine phosphatase 1B, with absolute specificity for P-Tyr, liberated significant quantities of 32Pi from four of the polypeptides, confirming that a portion of the protein-bound phosphate was present as 32P-Tyr. Alkaline phosphatase and the dual-specificity protein phosphatase IphP from the cyanobacterium Nostoc commune UTEX 584 also dephosphorylated these proteins and did so with greater apparent efficiency. Two of the polypeptides were partially purified, and phosphoamino analysis identified 32P-Tyr, [32P]phosphoserine, and [32P]phosphothreonine. Anabaena sp. strain PCC 7120 cell extracts contained a protein tyrosine phosphatase activity that was abolished in the presence of sodium orthovanadate and inhibited significantly by the sulfhydryl-modifying agents p-hydroxymercuriphenylsulfonic acid and p-hydroxymercuribenzoate as well as by heparin. In Anabaena sp. strain PCC 7120 the presence and/or phosphorylation status of P-Tyr proteins was influenced by incident photon flux density.


Diversity in lectins enables immune recognition and differentiation of wide spectrum of pathogens.
Carbohydrate-binding lectins play essential roles as pattern recognition receptors in innate immunity in both vertebrates and invertebrates. The carcinolectins 5 (CL5a and CL5b, the CL5 isoforms of horseshoe crab, Carcinoscorpius rotundicauda, with apparent sizes of 36 and 40 kDa, respectively) are prominent plasma lectins that bind all representative microbes and pathogen-associated molecular pattern molecules. Different cDNA isoforms of both CL5a and CL5b were isolated, leading to our speculation on their functional divergence. Characterization of CL5 isoforms bound to microbial cell surfaces demonstrates the diversity of these lectins. The resolution patterns of the isoforms that associate with fungus differ from those that associate with bacteria, suggesting the unique roles these lectins play in the recognition and differentiation of microbes. We postulate that different populations of plasma lectins act in collaboration in frontline innate immune defense against disparate pathogens. The functional diversity of lectins in invertebrates appears to evolutionarily compensate for the lack of acquired immunity.


Multi-level omics analysis in a murine model of dystrophin loss and therapeutic restoration.
Duchenne muscular dystrophy (DMD) is a classical monogenic disorder, a model disease for genomic studies and a priority candidate for regenerative medicine and gene therapy. Although the genetic cause of DMD is well known, the molecular pathogenesis of disease and the response to therapy are incompletely understood. Here, we describe analyses of protein, mRNA and microRNA expression in the tibialis anterior of the mdx mouse model of DMD. Notably, 3272 proteins were quantifiable and 525 identified as differentially expressed in mdx muscle (P < 0.01). Therapeutic restoration of dystrophin by exon skipping induced widespread shifts in protein and mRNA expression towards wild-type expression levels, whereas the miRNome was largely unaffected. Comparison analyses between datasets showed that protein and mRNA ratios were only weakly correlated (r = 0.405), and identified a multitude of differentially affected cellular pathways, upstream regulators and predicted miRNA-target interactions. This study provides fundamental new insights into gene expression and regulation in dystrophic muscle.


Prognostic value of telomere function in gastric cancers with and without microsatellite instability.
To identify molecular markers that may be useful in the selection of gastric cancer patients with different prognoses, we investigated telomere function in gastric cancers with and without microsatellite instability (MSI). We analyzed 83 gastric cancers and its paired-normal tissues to investigate MSI and telomere function. MSI was established using five polymorphic human repeat DNA markers. Telomere function was evaluated by determining telomerase activity, telomere length, and telomere-repeat factors 1 and 2 (TRF1 and TRF2) expression. Patients with high microsatellite instability (MSI-H) gastric cancers showed a significantly better prognosis than those affected by microsatellite stable or low microsatellite instability (MSS/MSI-L) tumors (P = 0.03). The lowest expression levels of TRF1 and TRF2 were associated with MSI-H gastric cancers (P = 0.008 and 0.006, respectively). Moreover, a clear trend toward a worse prognosis was found in the group of patients who had tumors with the shortest telomeres (P = 0.01). Cox multivariate analysis showed that MSI emerged as a protective prognostic factor; MSS/MSI-L tumors conferred a significantly poor prognosis in patients (relative risk = 4.862-fold greater than the MSI-H group) (P = 0.033). Telomere length of gastric tumors less than 2.86 kbp was a factor that led to a poor prognosis (relative risk = 4.420, with respect to tumors showing telomere length ≥ 2.86 kbp) (P = 0.002). We propose telomere status as a potential molecular marker with usefulness in the establishment of the prognosis of gastric cancers both for the mutator phenotype and for the suppressor pathway.


LDL, scavenger, and beta-VLDL receptors on aortic endothelial cells.
Primary and first passage aortic endothelial cells were shown to possess a high affinity receptor for beta-migrating very low density lipoproteins (beta-VLDL) distinct from the low density lipoprotein (LDL) receptor and scavenger receptor on these cells. In bovine aortic endothelial cells, 125I-rabbit beta-VLDL was taken up and degraded by a high affinity process that was competed for by unlabeled rabbit beta-VLDL and unlabeled postprandial VLDL from a fat-fed normal subject. However, unlabeled human or rabbit LDL, human LDL modified by malondialdehyde (MDA-LDL), or VLDL from a fasted normal human or a rabbit were not effective competitors for the degradation of 125I-rabbit beta-VLDL. In contrast to the receptor-mediated degradation of 125I-human or rabbit LDL and 125I-human-MDA-LDL, cell density did not affect the receptor-mediated degradation of 125I-rabbit beta-VLDL. Endothelial cells from a Watanabe heritable hyperlipidemic (WHHL) rabbit virtually did not degrade rabbit LDL, but degraded rabbit beta-VLDL at a rate equal to that seen in normal rabbit endothelial cells. It was concluded that the beta-VLDL receptor on endothelial cells is genetically distinct from the LDL receptor. Incubation of cells for 3 days with 100 micrograms/ml protein of unlabeled beta-VLDL caused an 88% increase in cellular cholesterol content, even though the beta-VLDL receptor activity was down-regulated by 60%. Endothelial cells and monocyte-macrophages are thus far the only cells known to possess the LDL receptor, the scavenger receptor, and the beta-VLDL receptor.


HLA-A2-restricted glypican-3 peptide-specific CTL clones induced by peptide vaccine show high avidity and antigen-specific killing activity against tumor cells.
Glypican-3 (GPC3) is an onco-fetal antigen that is overexpressed in human hepatocellular carcinoma (HCC), and is only expressed in the placenta and embryonic liver among normal tissues. Previously, we identified an HLA-A2-restricted GPC3(144-152) (FVGEFFTDV) peptide that can induce GPC3-reactive CTLs without inducing autoimmunity in HLA-A2 transgenic mice. In this study, we carried out a phase I clinical trial of HLA-A2-restricted GPC3(144-152) peptide vaccine in 14 patients with advanced HCC. Immunological responses were analyzed by ex vivo γ-interferon enzyme-linked immunospot assay. The frequency of GPC3(144-152) peptide-specific CTLs after vaccination (mean, 96; range, 5-441) was significantly larger than that before vaccination (mean, 6.5; range, 0-43) (P < 0.01). An increase in the GPC3(144-152) peptide-specific CTL frequency was observed in 12 (86%) of 14 patients after vaccination. Additionally, there was a significant correlation between the maximum value of GPC3(144-152) peptide-specific CTLs after vaccination and the dose of the peptide injected (P = 0.0166, r = 0.665). Moreover, we established several GPC3(144-152) peptide-specific CTL clones from PBMCs of patients vaccinated with GPC3(144-152) peptide by single cell sorting using Dextramer and CD107a antibody. These CTL clones had high avidity (the recognition efficiency showing 50% cytotoxicity was 10(-10) or 10(-11) M) and could recognize HCC cell lines expressing GPC3 in an HLA-class I-restricted manner. These results suggest that GPC3(144-152) peptide vaccine can induce high avidity CTLs capable of killing HCC cells expressing GPC3. This trial was registered with University Hospital Medical Information Network number 000001395.


Attention alters spatial resolution by modulating second-order processing.
Endogenous and exogenous visuospatial attention both alter spatial resolution, but they operate via distinct mechanisms. In texture segmentation tasks, exogenous attention inflexibly increases resolution even when detrimental for the task at hand and does so by modulating second-order processing. Endogenous attention is more flexible and modulates resolution to benefit performance according to task demands, but it is unknown whether it also operates at the second-order level. To answer this question, we measured performance on a second-order texture segmentation task while independently manipulating endogenous and exogenous attention. Observers discriminated a second-order texture target at several eccentricities. We found that endogenous attention improved performance uniformly across eccentricity, suggesting a flexible mechanism that can increase or decrease resolution based on task demands. In contrast, exogenous attention improved performance in the periphery but impaired it at central retinal locations, consistent with an inflexible resolution enhancement. Our results reveal that endogenous and exogenous attention both alter spatial resolution by differentially modulating second-order processing.


A high resolution electron impact spectrometer for chemical analysis of gases and vapors.
A commercial electron impact spectrometer operating at an excitation energy of 100 eV and capable of energy resolution of the order of 10 mV is described. The advantages of electron impact spectroscopy for chemical analysis are reviewed with regard to the high resolution achieved. Several aspects of high resolution spectra of H(2), N(2), CO, and air are examined. Some comparisons are made with other high resolution spectra to indicate the reliability and accuracy of the method and the facility with which the presence of specific elements may be determined.


Evaluation of extraction parameters in authentic hair reference material using statistical design of experiments.
Optimal methods for forensic hair analysis are often debated, especially regarding extraction parameters that include incubation time, temperature, and size of extracted hair particles. To assess hair pretreatment parameters for analysis of drugs of abuse, the statistical technique known as Design of Experiments (DoE) is useful. DoE evaluates both the individual roles and the combinatorial associations between multiple variables and overall drug extraction efficiency. Previous reports have focused on incorporated hair reference material (HRM), which is prepared in the lab at a specified drug concentration. In contrast, authentic HRM, which is prepared by diluting hair from drug users with blank hair to achieve specific drug concentrations, is an effective matrix for standardization of forensic hair testing, since the drug is incorporated into the hair matrix via uptake from systemic distribution. In the present study, extraction parameters for authentic HRM samples containing multiple drugs (diazepam, alprazolam, cocaine, methamphetamine, oxycodone, hydrocodone, and morphine) and metabolites (nordiazepam, cocaethylene, norcocaine, hydroxycocaine, and 6-monoacetylmorphine) were optimized based on recovery using a 23 full factorial DoE matrix. The factors evaluated included extraction solvent volume/sample weight ratio (12.5 or 25 μL/mg), particle size (pulverized or cut into 1 mm snippets), and extraction time (2 or 24 h) using solvent swelling. DoE analysis revealed significant differences in the optimal combinations of extraction parameters for maximum recovery. However, for the majority of drugs and metabolites, the most effective extraction method consisted of pulverizing hair prior to a 2-h extraction with a 12.5 μL/mg extraction solvent volume/sample weight ratio.


Clinical benefit of statin pretreatment in patients undergoing percutaneous coronary intervention: a collaborative patient-level meta-analysis of 13 randomized studies.
Previous studies suggested that statin pretreatment reduces cardiac events in patients undergoing percutaneous coronary intervention. However, most data were observational, and single randomized trials included limited numbers of patients. We performed a collaborative meta-analysis using individual patient data from 13 randomized studies in which 3341 patients received either high-dose statin (n=1692) or no statin/low-dose statin (n=1649) before percutaneous coronary intervention, with all patients receiving statin therapy after intervention. Occurrence of periprocedural myocardial infarction, defined as postintervention creatine kinase-MB increase ≥3 times the upper limit of normal, and 30-day major adverse cardiac events (death, myocardial infarction, target-vessel revascularization) was evaluated. Incidence of periprocedural myocardial infarction was 7.0% in the high-dose statin versus 11.9% in the control group, which corresponds to a 44% risk reduction in the active-treatment arm (odds ratio by fixed-effects model 0.56, 95% confidence interval, 0.44 to 0.71, P<0.00001). The rate of major adverse cardiac events at 30 days was significantly lower in the high-dose statin group (7.4% versus 12.6%, a 44% risk reduction; P<0.00001), and 1-month major adverse cardiac events, excluding periprocedural events, were also reduced (0.6% versus 1.4%; P=0.05). The benefit of high-dose statins was realized irrespective of clinical presentation (P for interaction=0.43) and was maintained across various subgroups but appeared greater in the subgroup with elevated baseline C-reactive protein levels (n=734; 68% risk reduction for periprocedural myocardial infarction versus 31% in those 1861 patients with normal CRP; P for quantitative interaction=0.025). High-dose statin pretreatment leads to a significant reduction in periprocedural myocardial infarction and 30-day adverse events in patients undergoing percutaneous coronary intervention. This strategy should be considered in all patients with planned percutaneous coronary intervention.