Frameless single-isocenter intensity modulated stereotactic radiosurgery for simultaneous treatment of multiple intracranial metastases.
Stereotactic radiosurgery (SRS) is well accepted treatment for patients with intracranial metastases, but the role of frameless radiosurgery is not well defined. Here, we describe our clinical experience applying a novel single-isocenter technique to frameless intensity modulated stereotactic radiosurgery (IMRS) for simultaneous treatment of multiple intracranial metastases. Between 2006 and 2012, 100 consecutive patients received frameless IMRS for multiple intracranial metastases using a single, centrally-located isocenter. Among these, 29 patients were treated for progressive or recurrent intracranial disease. A total of 465 metastases (median, 4 per patient, range, 2-18) were treated to a median dose of 20 Gy (range, 15-50 Gy). Follow-up including clinical examination and magnetic resonance imaging (MRI) occurred every 3 months. Median follow-up for all patients was 4.3 months (range, 0.2-58.3 months), with 83 patients (83.0%) followed until their death. For the remaining 17 patients alive at the time of analysis, median follow-up was 9.2 months (range, 2.2-58.3 months). Overall survival at 6 months was 49.5% [95% confidence interval (CI), 35.3-63.6%]. Local control at 6 and 12 months was 88.9% (95% CI, 79.1-98.6%) and 81.5% (95% CI, 65.2-97.7%), respectively. Regional failure was observed in 39 patients (39%), and 25 patients (25%) received salvage therapy. Grade 3 or greater treatment-related toxicity was observed in 4 patients (4%) and included intracranial hemorrhage, seizure, and radionecrosis. Median total treatment time was 17.2 minutes (range, 2.8-55.3 minutes). Single-isocenter IMRS for multiple intracranial metastases can produce clinical outcomes comparable to those of conventional radiosurgery techniques.


The dangers of sexual enhancement supplements and counterfeit drugs to "treat" erectile dysfunction.
Counterfeit phosphodiesterase-5 inhibitors (PDE-5i) are an increasing problem. Already in widespread use, the market for PDE-5i is steadily growing as the population ages. Counterfeiters are taking advantage of this growing market by developing illicit and counterfeit PDE-5i products. Many factors are contributing to the rapid growth of the illicit market, such as the low risk of prosecution, potentially high financial reward, and ease of distribution via Internet pharmacies. Consumers of illicit PDE-5i often do not realize they are using counterfeit products and placing themselves at an unnecessary health risk. Others seek to bypass the legitimate healthcare system due to either embarrassment of the underlying condition or desire for cheaper alternatives. However, taking illicit PDE-5i may harm consumers directly, as many illicit products contain detrimental contaminants and inaccurate amounts of the active ingredient without the appropriate warnings. Bypassing the legitimate healthcare system also endangers consumers indirectly, as erectile dysfunction (ED) is often associated with other medical comorbidities that patients should be screened for. Furthermore, PDE-5i can have potentially dangerous interactions with other pharmaceuticals that are rarely warned against with counterfeit PDE-5i. This communication reviews the literature regarding counterfeit PDE-5i, and summarizes both the scope and dangers of the illicit PDE-5i market.


Propagation of light trapped within a set of lowest-order modes of graded-index multimode fiber undergoing bending.
We describe experimental results and a theoretical analysis for propagation in graded-index multimode fiber when diode laser light is launched into the lowest-order propagation modes and the fiber undergoes severe bending perturbations. Experimentally, near-field modal interference images and transmission loss measurements were obtained for different loop diameters. The data indicate that, when the fundamental mode is excited, the light remains in lowest-order modes even for small bend diameters. This is consistent with analysis which predicts that, in a parabolic-index multimode fiber subject to constant diameter bending, the light tends to oscillate between lowest-order modes and remains trapped therein rather than diffusing to high-order modes. Implications of these results for an intrusion-resistant communication system with graded-index multimode fiber are discussed.


Unique Mutational Spectrum of the GJB2 Gene and its Pathogenic Contribution to Deafness in Tuvinians (Southern Siberia, Russia): A High Prevalence of Rare Variant c.516G>C (p.Trp172Cys).
Mutations in the GJB2 gene are the main cause for nonsyndromic autosomal recessive deafness 1A (DFNB1A) in many populations. GJB2 mutational spectrum and pathogenic contribution are widely varying in different populations. Significant efforts have been made worldwide to define DFNB1A molecular epidemiology, but this issue still remains open for some populations. The main aim of study is to estimate the DFNB1A prevalence and GJB2 mutational spectrum in Tuvinians-an indigenous population of the Tyva Republic (Southern Siberia, Russia). Sanger sequencing was applied to analysis of coding (exon 2) and non-coding regions of GJB2 in a cohort of Tuvinian patients with hearing impairments (n = 220) and ethnically matched controls (n = 157). Diagnosis of DFNB1A was established for 22.3% patients (28.8% of familial vs 18.6% of sporadic cases). Our results support that patients with monoallelic GJB2 mutations (8.2%) are coincidental carriers. Recessive mutations p.Trp172Cys, c.-23+1G>A, c.235delC, c.299_300delAT, p.Val37Ile and several benign variants were found in examined patients. A striking finding was a high prevalence of rare variant p.Trp172Cys (c.516G>C) in Tuvinians accounting for 62.9% of all mutant GJB2 alleles and a carrier frequency of 3.8% in controls. All obtained data provide important targeted information for genetic counseling of affected Tuvinian families and enrich current information on variability of GJB2 worldwide.


Radiographic investigation of dystocia in the West African dwarf goat.
Lateral and ventrodorsal radiographs were obtained from 30 West African dwarf goats with dystocia. The pelvic size was estimated from the ventrodorsal radiographs as the product of the transverse and conjugate diameters of the pelvic inlet. Radiography clearly showed the number of fetuses present, their presentation and position. The posture was clearly defined in singletons but not in twins and triplets. The commonest abnormal fetal disposition was bilateral flexion of the forelimbs with the head in the pelvic canal. The major maternal abnormality was small pelvic area. Of 19 dead fetuses, 13 showed radiographic signs of intrauterine death including free intracavity gas, tissue emphysema, abnormal fetal disposition and overlapping cranial bones. It was concluded that radiography is useful during examination of goats with dystocia especially small sized goats that cannot be manipulated easily.


Interleukin-1 antagonism in type 1 diabetes of recent onset: two multicentre, randomised, double-blind, placebo-controlled trials.
Innate immunity contributes to the pathogenesis of autoimmune diseases, such as type 1 diabetes, but until now no randomised, controlled trials of blockade of the key innate immune mediator interleukin-1 have been done. We aimed to assess whether canakinumab, a human monoclonal anti-interleukin-1 antibody, or anakinra, a human interleukin-1 receptor antagonist, improved β-cell function in recent-onset type 1 diabetes. We did two randomised, placebo-controlled trials in two groups of patients with recent-onset type 1 diabetes and mixed-meal-tolerance-test-stimulated C peptide of at least 0·2 nM. Patients in the canakinumab trial were aged 6-45 years and those in the anakinra trial were aged 18-35 years. Patients in the canakinumab trial were enrolled at 12 sites in the USA and Canada and those in the anakinra trial were enrolled at 14 sites across Europe. Participants were randomly assigned by computer-generated blocked randomisation to subcutaneous injection of either 2 mg/kg (maximum 300 mg) canakinumab or placebo monthly for 12 months or 100 mg anakinra or placebo daily for 9 months. Participants and carers were masked to treatment assignment. The primary endpoint was baseline-adjusted 2-h area under curve C-peptide response to the mixed meal tolerance test at 12 months (canakinumab trial) and 9 months (anakinra trial). Analyses were by intention to treat. These studies are registered with ClinicalTrials.gov, numbers NCT00947427 and NCT00711503, and EudraCT number 2007-007146-34. Patients were enrolled in the canakinumab trial between Nov 12, 2010, and April 11, 2011, and in the anakinra trial between Jan 26, 2009, and May 25, 2011. 69 patients were randomly assigned to canakinumab (n=47) or placebo (n=22) monthly for 12 months and 69 were randomly assigned to anakinra (n=35) or placebo (n=34) daily for 9 months. No interim analyses were done. 45 canakinumab-treated and 21 placebo-treated patients in the canakinumab trial and 25 anakinra-treated and 26 placebo-treated patients in the anakinra trial were included in the primary analyses. The difference in C peptide area under curve between the canakinumab and placebo groups at 12 months was 0·01 nmol/L (95% CI -0·11 to 0·14; p=0·86), and between the anakinra and the placebo groups at 9 months was 0·02 nmol/L (-0·09 to 0·15; p=0·71). The number and severity of adverse events did not differ between groups in the canakinumab trial. In the anakinra trial, patients in the anakinra group had significantly higher grades of adverse events than the placebo group (p=0·018), which was mainly because of a higher number of injection site reactions in the anakinra group. Canakinumab and anakinra were safe but were not effective as single immunomodulatory drugs in recent-onset type 1 diabetes. Interleukin-1 blockade might be more effective in combination with treatments that target adaptive immunity in organ-specific autoimmune disorders. National Institutes of Health and Juvenile Diabetes Research Foundation.


Properties of monoclonal antibodies selected for probing the conformation of wild type and mutant forms of the P22 tailspike endorhamnosidase.
Eleven species of monoclonal antibodies directed against the trimeric P22 tailspike endorhamnosidase have been selected and characterized. Seven of these antibodies recognize the native tailspike, both isolated and assembled onto the virion, and prevent phage infection. Four antibodies react with denatured forms of the tailspike as well as with the plastic absorbed tailspike. Three of these latter prevent the tailspike from assembling onto the phage head. The antibodies have been tested against tailspike proteins carrying single amino acid substitutions at 15 different sites on the protein. Two of these mutations interfere with binding by a set of the monoclonals, indicating that they disrupt the epitopes for these antibodies. Since amino acid replacements corresponding to the temperature-sensitive folding mutations do not change the conformation of the native protein, these mutant proteins may be particularly useful for mapping epitopes. Amber fragments of the tailspike chain are recognized predominantly by the anti-denatured antibodies suggesting either that they are conformationally closer to folding intermediates than to the native tailspike or that the epitopes recognized by anti-native antibodies are carried by the C-terminal end of the native protein. Immunochemical detection by an anti-denatured antibody, after sucrose gradient sedimentation of a large 55-kDa amber fragment, indicates a monomeric rather than a trimeric state. This suggests that the missing C-terminal region is important for the trimerization reaction. Such N-terminal amber fragments may be useful models for studying with the monoclonal antibodies the nascent chain emerging from the ribosome.


Cancer cell growth inhibitory effect of bee venom via increase of death receptor 3 expression and inactivation of NF-kappa B in NSCLC cells.
Our previous findings have demonstrated that bee venom (BV) has anti-cancer activity in several cancer cells. However, the effects of BV on lung cancer cell growth have not been reported. Cell viability was determined with trypan blue uptake, soft agar formation as well as DAPI and TUNEL assay. Cell death related protein expression was determined with Western blotting. An EMSA was used for nuclear factor kappaB (NF-κB) activity assay. BV (1-5 μg/mL) inhibited growth of lung cancer cells by induction of apoptosis in a dose dependent manner in lung cancer cell lines A549 and NCI-H460. Consistent with apoptotic cell death, expression of DR3 and DR6 was significantly increased. However, deletion of DRs by small interfering RNA significantly reversed BV induced cell growth inhibitory effects. Expression of pro-apoptotic proteins (caspase-3 and Bax) was concomitantly increased, but the NF-κB activity and expression of Bcl-2 were inhibited. A combination treatment of tumor necrosis factor (TNF)-like weak inducer of apoptosis, TNF-related apoptosis-inducing ligand, docetaxel and cisplatin, with BV synergistically inhibited both A549 and NCI-H460 lung cancer cell growth with further down regulation of NF-κB activity. These results show that BV induces apoptotic cell death in lung cancer cells through the enhancement of DR3 expression and inhibition of NF-κB pathway.


Cerebrospinal fluid biomarkers in human genetic transmissible spongiform encephalopathies.
The 14-3-3 protein test has been shown to support the clinical diagnosis of sporadic Creutzfeldt-Jakob disease (CJD) when associated with an adequate clinical context, and a high differential potential for the diagnosis of sporadic CJD has been attributed to other cerebrospinal fluid (CSF) proteins such as tau protein, S100b and neuron specific enolase (NSE). So far there has been only limited information available about biochemical markers in genetic transmissible spongiform encephalopathies (gTSE), although they represent 10-15% of human TSEs. In this study, we analyzed CSF of 174 patients with gTSEs for 14-3-3 (n = 166), tau protein (n = 78), S100b (n = 46) and NSE (n = 50). Levels of brain-derived proteins in CSF varied in different forms of gTSE. Biomarkers were found positive in the majority of gCJD (81%) and insert gTSE (69%), while they were negative in most cases of fatal familial insomnia (13%) and Gerstmann-Sträussler-Scheinker syndrome (10%). Disease duration and codon 129 genotype influence the findings in a different way than in sporadic CJD.


SARS-CoV-2 Infection among Medical Institution Faculty and Healthcare Workers in Tokyo, Japan.
Objective To consider effective measures against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in medical institutions, this study estimated the SARS-CoV-2 infection rate among healthcare workers (HCWs) in Tokyo, Japan, and determined the specific findings for mild coronavirus disease 2019 (COVID-19) cases. Methods This study analyzed the results of serologic tests to detect immunoglobulin G antibodies against SARS-CoV-2 and evaluated the demographic and clinical characteristics of the faculty and HCWs at a Tokyo medical institution in August 2020. The demographic and clinical characteristics of participants with antibody-positive results were compared to those of participants with antibody-negative results. Materials This study recruited 2,341 faculty and HCWs at a Tokyo medical institution, 21 of whom had a COVID-19 history. Results Of the 2,320 participants without a COVID-19 history, 20 (0.862%) had positive serologic test results. A fever and dysgeusia or dysosmia occurred with greater frequency among the participants with positive test results than in those with negative results [odds ratio (OR), 5.475; 95% confidence interval (CI), 1.960-15.293 and OR, 24.158; 95% CI, 2.693-216.720, respectively]. No significant difference was observed in the positivity rate between HCWs providing medical care for COVID-19 patients using adequate protection and other HCWs (OR, 2.514; 95% CI, 0.959-6.588). Conclusion To reduce the risk of COVID-19 spread in medical institutions, faculty and HCWs should follow standard and necessary transmission-based precautions, and those with a fever and dysgeusia or dysosmia should excuse themselves from work as soon as possible.


A new giant species of placented worm and the mechanism by which onychophorans weave their nets (Onychophora: Peripatidae).
Onychophorans, or velvet worms, are poorly known and rare animals. Here we report the discovery of a new species that is also the largest onychophoran found so far, a 22 cm long female from the Caribbean coastal forest of Costa Rica. Specimens were examined with Scanning Electron Microscopy; Peripatus solorzanoi sp. nov., is diagnosed as follows: primary papillae convex and conical with rounded bases, with more than 18 scale ranks. Apical section large, spherical, with a basal diameter of at least 20 ranks. Apical piece with 6-7 scale ranks. Outer blade 1 principal tooth, 1 accessory tooth, 1 vestigial accessory tooth (formula: 1/1/1); inner blade 1 principal tooth, 1 accessory tooth, 1 rudimentary accessory tooth, 9 to 10 denticles (formula: 1/1/1/9-10). Accessory tooth blunt in both blades. Four pads in the fourth and fifth oncopods; 4th. pad arched. The previously unknown mechanism by which onychophorans weave their adhesive is simple: muscular action produces a swinging movement of the adhesive-spelling organs; as a result, the streams cross in mid air, weaving the net. Like all onychophorans, P. solorzanoi is a rare species: active protection of the habitat of the largest onychophoran ever described, is considered urgent.


Periodic micro-structures in optical microfibers induced by Plateau-Rayleigh instability and its applications.
A periodic micro-structure on optical microfibers induced by Plateau-Rayleigh instability (PRI) was investigated and a potential application for long period gratings (LPGs) fabrication was given. The linear relation between the average periods of micro-structures and the diameters of optical microfibers was demonstrated first. By brushing a glass rod with a Teflon droplet suspended at the end tip along microfibers, a continuous film of Teflon was formed at once, then the film broke up into a series of periodic droplets due to PRI. Periodic Teflon nodes were left after the evaporation of the solvent. A LPG structure based on polymer was finally formed by this method on a microfiber with a diameter of 5.5 μm. An attenuation transmission dip of 15 dB around 1447 nm was achieved. Investigation of the strain and temperature response characteristics of the grating presented a strain sensitivity of -2.5 pm/με and a temperature sensitivity of -157 pm/°C. The technique proposed here provides a versatile technique for polymer-based LPGs fabrication. Benefiting from the high sensitivities, LPGs based on numerous polymers fabricated in this way could have potential applications in optical and biological sensing.


Bayesian inferences for beta semiparametric-mixed models to analyze longitudinal neuroimaging data.
Diffusion tensor imaging (DTI) is a quantitative magnetic resonance imaging technique that measures the three-dimensional diffusion of water molecules within tissue through the application of multiple diffusion gradients. This technique is rapidly increasing in popularity for studying white matter properties and structural connectivity in the living human brain. One of the major outcomes derived from the DTI process is known as fractional anisotropy, a continuous measure restricted on the interval (0,1). Motivated from a longitudinal DTI study of multiple sclerosis, we use a beta semiparametric-mixed regression model for the neuroimaging data. This work extends the generalized additive model methodology with beta distribution family and random effects. We describe two estimation methods with penalized splines, which are formalized under a Bayesian inferential perspective. The first one is carried out by Markov chain Monte Carlo (MCMC) simulations while the second one uses a relatively new technique called integrated nested Laplace approximation (INLA). Simulations and the neuroimaging data analysis show that the estimates obtained from both approaches are stable and similar, while the INLA method provides an efficient alternative to the computationally expensive MCMC method.


Planning and response to the influenza A (H1N1) pandemic: ethics, equity and justice.
This paper aims to highlight three ethical considerations related to influenza pandemic planning and response: ethical allocation of scarce resources; obligations and duties of healthcare workers to treat patients, and the balance between conflicting individual and community interests. Among these, perhaps the most challenging question facing bioethics is how to allocate scarce, life-saving resources given the devastating social and economic ramifications of a pandemic. In such situations, the identification of clear overall goals for pandemic planning is essential in making difficult choices. The dilemma between the duty to save patients and the right to protect the healthcare personnel's own life and health is a key issue. During the course of a pandemic, civil liberties may also be threatened, requiring limits on individual freedom to protect individuals as well as entire communities. Yet, individual liberty should be restricted with great care, and only when alternative approaches are not effective. Pandemic influenza planning and response should be a cooperative and shared responsibility that balances community and individual interests.


Induction and metabolite regulation of levanase synthesis in Bacillus subtilis.
Levanase expression in Bacillus subtilis was studied by using transcriptional and translational fusions. It was shown that the degradative products of levan or inulin and low concentrations of fructose were able to induce levanase expression. In the wild-type strain and in a constitutive overproducing sacL mutant, levanase synthesis was repressed by glucose or fructose. This catabolite repression was partially abolished in the derepressed alpha-amylase gra-26 mutant. The levanase gene (sacC) appears to be the distal gene of an operon transcribed from a fructose-inducible promoter. Deletion mapping experiments and primer extension analysis revealed a transcriptional start point located 2.7 kilobases upstream from the sacC gene. Two constitutive sacL mutations were shown to be closely linked by transformation to the sacC gene. The sacL6 and sacL8 mutations were mapped in the promoter-proximal region of the operon.


Generation of CD8+ T cell-mediated immunity against idiotype-negative lymphoma escapees.
We investigated the ability of CpG-oligodeoxynucleotide to generate an anti-tumor CD8+ T-cell immune response and to synergize with passive antibody therapy. For these studies, we generated an antibody against the idiotype on the A20 B-cell lymphoma line. This antibody caused the regression of established tumors, but ultimately the tumors relapsed. The escaping surface IgG-negative tumor cells were resistant to both antibody-dependent cellular cytotoxicity and signaling-induced cell death. Addition of intratumoral CpG to antibody therapy cured large established tumors and prevented the occurrence of tumor escapees. The failure of the combination therapy in mice deficient for CD8+ T cells demonstrates the critical role of CD8+ T cells in tumor eradication. When mice were inoculated with 2 tumors and treated systemically with antibody followed by intratumoral CpG in just one tumor, both tumors regressed, indicating that a systemic immune response was generated. Although antibody therapy can eliminate tumor cells bearing the target antigen, it frequently selects for antigen loss variants. However, when a poly-specific T-cell response was generated against the tumor by intratumoral CpG, even large established tumors were cured. Such an immune response can prevent the emergence of antibody selected tumor escapees and provide long-lasting tumor protection.


Efficacy and Safety of Human Retinal Progenitor Cells.
We assessed the long-term efficacy and safety of human retinal progenitor cells (hRPC) using established rodent models. Efficacy of hRPC was tested initially in Royal College of Surgeons (RCS) dystrophic rats immunosuppressed with cyclosporine/dexamethasone. Due to adverse effects of dexamethasone, this drug was omitted from a subsequent dose-ranging study, where different hRPC doses were tested for their ability to preserve visual function (measured by optokinetic head tracking) and retinal structure in RCS rats at 3 to 6 months after grafting. Safety of hRPC was assessed by subretinal transplantation into wild type (WT) rats and NIH-III nude mice, with analysis at 3 to 6 and 9 months after grafting, respectively. The optimal dose of hRPC for preserving visual function/retinal structure in dystrophic rats was 50,000 to 100,000 cells. Human retinal progenitor cells integrated/survived in dystrophic and WT rat retina up to 6 months after grafting and expressed nestin, vimentin, GFAP, and βIII tubulin. Vision and retinal structure remained normal in WT rats injected with hRPC and there was no evidence of tumors. A comparison between dexamethasone-treated and untreated dystrophic rats at 3 months after grafting revealed an unexpected reduction in the baseline visual acuity of dexamethasone-treated animals. Human retinal progenitor cells appear safe and efficacious in the preclinical models used here. Human retinal progenitor cells could be deployed during early stages of retinal degeneration or in regions of intact retina, without adverse effects on visual function. The ability of dexamethasone to reduce baseline visual acuity in RCS dystrophic rats has important implications for the interpretation of preclinical and clinical cell transplant studies.


De novo Nanopore read quality improvement using deep learning.
Long read sequencing technologies such as Oxford Nanopore can greatly decrease the complexity of de novo genome assembly and large structural variation identification. Currently Nanopore reads have high error rates, and the errors often cluster into low-quality segments within the reads. The limited sensitivity of existing read-based error correction methods can cause large-scale mis-assemblies in the assembled genomes, motivating further innovation in this area. Here we developed a Convolutional Neural Network (CNN) based method, called MiniScrub, for identification and subsequent "scrubbing" (removal) of low-quality Nanopore read segments to minimize their interference in downstream assembly process. MiniScrub first generates read-to-read overlaps via MiniMap2, then encodes the overlaps into images, and finally builds CNN models to predict low-quality segments. Applying MiniScrub to real world control datasets under several different parameters, we show that it robustly improves read quality, and improves read error correction in the metagenome setting. Compared to raw reads, de novo genome assembly with scrubbed reads produces many fewer mis-assemblies and large indel errors. MiniScrub is able to robustly improve read quality of Oxford Nanopore reads, especially in the metagenome setting, making it useful for downstream applications such as de novo assembly. We propose MiniScrub as a tool for preprocessing Nanopore reads for downstream analyses. MiniScrub is open-source software and is available at https://bitbucket.org/berkeleylab/jgi-miniscrub .


Overview of animal models of obesity.
The focus of this overview is on the animal models of obesity most commonly utilized in research. The models include monogenic models in the leptin pathway, polygenic diet-dependent models, and, in particular for their historical perspective, surgical and chemical models of obesity. However, there are far too many models to consider all of them comprehensively, especially those caused by selective molecular genetic approaches modifying one or more genes in specific populations of cells. Further, the generation and use of inducible transgenic animals (induced knock-out or knock-in) is not covered, even though they often carry significant advantages compared to traditional transgenic animals, e.g., influences of the genetic modification during the development of the animals can be minimized. The number of these animal models is simply too large to be covered in this unit.


Potentiated homeopathic drug Arsenicum Album 30C inhibits intracellular reactive oxygen species generation and up-regulates expression of arsenic resistance gene in arsenite-exposed bacteria Escherichia coli.
To examine if potentiated homeopathic drug Arsenicum Album 30C (Ars Alb 30C) can reduce sodium arsenite-induced toxicity in Escherichia coli. E. coli were exposed to low arsenite insult after they grew up to log phase in standard Luria-Bertani medium. E. coli were treated with 1 or 2 mmol/L sodium arsenite alone (control), or Ars Alb 30C was added to the medium of a subset of sodium arsenite-treated bacteria (drug-treated), or homeopathically agitated alcohol was added to the medium containing a subset of sodium arsenite-treated bacteria (placebo-treated). A sub-set of untreated E. coli served as the negative control. Glucose uptake, specific activities of hexokinase, lipid peroxidase (LPO), superoxide dismutase (SOD) and catalase, intra- and extra-cellular sodium arsenite content, cell growth, cell membrane potential, DNA damage, intracellular reactive oxygen species (ROS), adenosine triphosphate (ATP) and free glutathione content and expressions of arsB and ptsG gene in normal control, sodium arsenite-treated, drug-treated and placebo-treated E. coli were analyzed. Treatments were blinded and randomized. In sodium arsenite-treated E. coli, glucose uptake, intracellular ROS, LPO and DNA damage increased along with decrease in the specific activities of hexokinase, SOD and catalase, intracellular ATP and free glutathione contents and cell membrane potential and growth, and there were increases in expression levels of arsB gene and ptsG gene. Ars Alb 30C administration reduced arsenic toxicity in E. coli by inhibiting generation of ROS and increasing tolerance to arsenite toxicity and cell growth. Ars Alb 30C ameliorated arsenic toxicity and DNA damage, validating efficacy of ultra-highly diluted remedies used in homeopathy.


Hospital survey on patient safety culture: psychometric analysis on a Scottish sample.
To investigate the psychometric properties of the Hospital Survey on Patient Safety Culture on a Scottish NHS data set. The data were collected from 1969 clinical staff (estimated 22% response rate) from one acute hospital from each of seven Scottish Health boards. Using a split-half validation technique, the data were randomly split; an exploratory factor analysis was conducted on the calibration data set, and confirmatory factor analyses were conducted on the validation data set to investigate and check the original US model fit in a Scottish sample. Following the split-half validation technique, exploratory factor analysis results showed a 10-factor optimal measurement model. The confirmatory factor analyses were then performed to compare the model fit of two competing models (10-factor alternative model vs 12-factor original model). An S-B scaled χ(2) square difference test demonstrated that the original 12-factor model performed significantly better in a Scottish sample. Furthermore, reliability analyses of each component yielded satisfactory results. The mean scores on the climate dimensions in the Scottish sample were comparable with those found in other European countries. This study provided evidence that the original 12-factor structure of the Hospital Survey on Patient Safety Culture scale has been replicated in this Scottish sample. Therefore, no modifications are required to the original 12-factor model, which is suggested for use, since it would allow researchers the possibility of cross-national comparisons.


Australian Aboriginal and Torres Strait Islander Collections of Genetic Heritage: The Legal, Ethical and Practical Considerations of a Dynamic Consent Approach to Decision Making.
Dynamic Consent (DC) is both a model and a specific web-based tool that enables clear, granular communication and recording of participant consent choices over time. The DC model enables individuals to know and to decide how personal research information is being used and provides a way in which to exercise legal rights provided in privacy and data protection law. The DC tool is flexible and responsive, enabling legal and ethical requirements in research data sharing to be met and for online health information to be maintained. DC has been used in rare diseases and genomics, to enable people to control and express their preferences regarding their own data. However, DC has never been explored in relationship to historical collections of bioscientific and genetic heritage or to contexts involving Aboriginal and Torres Strait Islander people (First Peoples of Australia). In response to the growing interest by First Peoples throughout Australia in genetic and genomic research, and the increasing number of invitations from researchers to participate in community health and wellbeing projects, this article examines the legal and ethical attributes and challenges of DC in these contexts. It also explores opportunities for including First Peoples' cultural perspectives, governance, and leadership as a method for defining (or redefining) DC on cultural terms that engage best practice research and data analysis as well as respect for meaningful and longitudinal individual and family participation.


Diversity protects plant communities against generalist molluscan herbivores.
Wildflower strips are used to increase natural enemies of crop pests and to conserve insect diversity on farmland. Mollusks, especially slugs, can affect the vegetation development in these strips considerably. Although recent theoretical work suggests that more diverse plant communities will exhibit greater resistance against herbivore pressure, empirical studies are scarce. We conducted a semi-natural experiment in wildflower strips, manipulating trophic structure (reduction in herbivorous mollusks and reduction in major predators) and plant diversity (2, 6, 12, 20 and 24 sown species). This design allowed us to assess the effect of plant diversity, biomass and composition on mollusks, and vice versa, the effect of mollusc abundance on vegetation. Seven species of mollusks were found in the strips, with the slugs Arion lusitanicus, Deroceras reticulatum and Deroceras panormitanum being most frequent. We found a negative relationship between plant diversity and mollusk abundance, which was due predominantly to a decrease in the agricultural pest species A. lusitanicus. These results are consistent with the hypothesis that plant diversity can reduce the impact of herbivores. However, plant identity also had an effect on mollusks, and accounted for a much larger fraction of the variation in mollusk communities than biodiversity effects. While overall plant diversity decreased during the 3 years of the study, in the final year the highest plant diversity was found in the plots where mollusk populations were experimentally reduced. We conclude that selective feeding by generalist herbivores leads to changes in plant community composition and hence reduced plant diversity. Our results highlight the importance of plant biodiversity as protection against generalist herbivores, which if abundant can in the long term negatively impact plant diversity, driving the system along a "low plant diversity - high mollusk abundance" trajectory.


Stable amorphous solid dispersion of flubendazole with high loading via electrospinning.
In this work, an important step is taken towards the bioavailability improvement of poorly water-soluble drugs, such as flubendazole (Flu), posing a challenge in the current development of many novel oral-administrable therapeutics. Solvent electrospinning of a solution of the drug and poly (2-ethyl-2-oxazoline) (PEtOx) is demonstrated to be a viable strategy to produce stable nanofibrous amorphous solid dispersions (ASDs) with ultrahigh drug-loadings (up to 55 wt% Flu) and long-term stability (at least one year). Importantly, at such high drug loadings, the concentration of the polymer in the electrospinning solution has to be lowered below the concentration where it can be spun in absence of the drug as the interactions between the polymer and the drug result in increased solution viscosity. A combination of experimental analysis and molecular dynamics simulations revealed that this formulation strategy provides strong, dominant and highly stable hydrogen bonds between the polymer and the drug, which is crucial to obtain the high drug-loadings and to preserve the long-term amorphous character of the ASDs upon storage. In vitro drug release studies confirm the remarkable potential of this electrospinning formulation strategy by significantly increased drug solubility values and dissolution rates (respectively tripled and quadrupled compared to the crystalline drug), even after storing the formulation for one year.


Parental factors in early childhood are associated with approximal caries experience in young adults-A longitudinal study.
To test the hypothesis that parental factors in early childhood influence approximal caries experience in young adults. A cohort of 494 individuals was followed longitudinally from 1 to 20 years of age. Data were retrieved from parental interviews and questionnaires when the child was 1 and 3 years of age. At age 20, the participants underwent bitewing radiographic examination. Based on the number of approximal caries lesions (Da), stratified into initial (Di ) or manifest caries (Dm ) and approximal fillings (Fa), the participants were divided into two main groups: those with: (a) 0 Dim Fa (n = 244) and (b) >0 Dim Fa (n = 250). A subgroup was also created (≥8 Dim Fa; n = 33). Toothbrushing with fluoride toothpaste at 3 years of age less than twice a day (OR 1.6, 95% CI 1.0-2.6) and the participants' mothers' self-estimation of their oral health care as "less than optimal" were important risk factors for developing caries (>0 Dim Fa OR 2.0, 95% CI 1.3-3.1). An interaction effect between toothbrushing at 3 years of age less than twice a day and consumption of caries risk products > 3 times a day further increased the caries experience in young adults (≥8 Dim Fa OR 8.3, 95% CI 1.8-37.8) together with maternal anxiety about dental treatment (OR 7.4 95% CI 1.6-34.6). Parental factors in early childhood are associated with caries experience at 20 years of age.


Effects of a Proteasome Inhibitor on Cardiomyocytes in a Pressure-Overload Hypertrophy Rat Model: An Animal Study.
The ubiquitin-proteasome system (UPS) is an important pathway of proteolysis in pathologic hypertrophic cardiomyocytes. We hypothesize that MG132, a proteasome inhibitor, might prevent hypertrophic cardiomyopathy (CMP) by blocking the UPS. Nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) and androgen receptor (AR) have been reported to be mediators of CMP and heart failure. This study drew upon pathophysiologic studies and the analysis of NF-κB and AR to assess the cardioprotective effects of MG132 in a left ventricular hypertrophy (LVH) rat model. We constructed a transverse aortic constriction (TAC)-induced LVH rat model with 3 groups: sham (TAC-sham, n=10), control (TAC-cont, n=10), and MG132 administration (TAC-MG132, n=10). MG-132 (0.1 mg/kg) was injected for 4 weeks in the TAC-MG132 group. Pathophysiologic evaluations were performed and the expression of AR and NF-κB was measured in the left ventricle. Fibrosis was prevalent in the pathologic examination of the TAC-cont model, and it was reduced in the TAC-MG132 group, although not significantly. Less expression of AR, but not NF-κB, was found in the TAC-MG132 group than in the TAC-cont group (p<0.05). MG-132 was found to suppress AR in the TAC-CMP model by blocking the UPS, which reduced fibrosis. However, NF-κB expression levels were not related to UPS function.


Tuberculosis Case Finding With Combined Rapid Point-of-Care Assays (Xpert MTB/RIF and Determine TB LAM) in HIV-Positive Individuals Starting Antiretroviral Therapy in Mozambique.
Tuberculosis is a major health concern in several countries, and effective diagnostic algorithms for use in human immunodeficiency virus (HIV)-positive patients are urgently needed. At prescription of antiretroviral therapy, all patients in 3 Mozambican health centers were screened for tuberculosis, with a combined approach: World Health Organization (WHO) 4-symptom screening (fever, cough, night sweats, and weight loss), a rapid test detecting mycobacterial lipoarabinomannan in urine (Determine TB LAM), and a molecular assay performed on a sputum sample (Xpert MTB/RIF; repeated if first result was negative). Patients with positive LAM or Xpert MTB/RIF results were referred for tuberculosis treatment. Among 972 patients with a complete diagnostic algorithm (58.5% female; median CD4 cell count, 278/μL; WHO HIV stage I, 66.8%), 98 (10.1%) tested positive with Xpert (90, 9.3%) or LAM (34, 3.5%) assays. Compared with a single-test Xpert strategy, dual Xpert tests improved case finding by 21.6%, LAM testing alone improved it by 13.5%, and dual Xpert tests plus LAM testing improved it by 32.4%. Rifampicin resistance in Xpert-positive patients was infrequent (2.5%). Among patients with positive results, 22 of 98 (22.4%) had no symptoms at WHO 4-symptom screening. Patients with tuberculosis diagnosed had significantly lower CD4 cell counts and hemoglobin levels, more advanced WHO stage, and higher HIV RNA levels. Fifteen (15.3%) did not start tuberculosis treatment, mostly owing to rapidly deteriorating clinical conditions or logistical constraints. The median interval between start of the diagnostic algorithm and start of tuberculosis treatment was 7 days. The prevalence of tuberculosis among Mozambican HIV-positive patients starting antiretroviral therapy was 10%, with limited rifampicin resistance. Use of combined point-of-care tests increased case finding, with a short time to treatment. Interventions are needed to remove logistical barriers and prevent presentation in very advanced HIV/tuberculosis disease.


Evaluation of a collaborative project to develop sustainable healthcare education in eight UK medical schools.
Environmental change poses pressing challenges to public health and calls for profound and far-reaching changes to policy and practice across communities and health systems. Medical schools can act as a seedbed where knowledge, skills and innovation to address environmental challenges can be developed through innovative and collaborative approaches. The objectives of this study were to (1) explore drivers and challenges of collaboration for educational development between and within medical schools; (2) evaluate the effectiveness of a range of pedagogies for sustainable healthcare education; and (3) identify effective strategies to facilitate the renewal of medical curricula to address evolving health challenges. Participatory action research. Medical school teams participated in a nine-month collaborative project, including a one-day seminar to learn about sustainable healthcare education and develop a project plan. After the seminar, teams were supported to develop, deliver and evaluate new teaching at their medical school. New teaching was introduced at seven medical schools. A variety of pedagogies were represented. Collaboration between schools motivated and informed participants. The main challenges faced related to time pressures. Educators and students commented that new teaching was enjoyable and effective at improving knowledge and skills. Collaborative working supported educators to develop and implement new teaching sessions rapidly and effectively. Collaboration can help to build educators' confidence and capacity in a new area of education development. Different forms of collaboration may be appropriate for different circumstances and at different stages of education development.


Postoperative pain, edema and trismus following third molar surgery - A comparitive study between submucosal and intravenous dexamethasone.
Third molar surgey always needs primary intervention as it can lead to various complications and pathologies. Considering other ways for postoperative anesthesia it was infered that submucosal group which showed simple injection technique and direct surgical site administration is more beneficial. It was noticed as a patient comfort method which can be the preferred as the drug of choice over intravenous route of dexamethasone injection. Impaction of third molar is a common affliction and surgical removal is the only treatment option. The post-operative sequelae following the third molar surgery are pain, edema and trismus. The use of corticosteroids is to counteract it via various routes. Still, controversy exists in the literature regarding the administration of corticosteroids over the routes and time of administration. The purpose of this study was to compare the postoperative pain, edema and trismus following third molar surgery while using preoperative intravenous and submucosal routes of dexamethasone, in terms of pain, facial swelling, and trismus. This study consisted of 64 patients presented with mesioangular impacted mandibular third molar for surgical removal. Preoperative measurements of edema, trismus were analyzed. Postoperative pain was estimated using visual analogue scale. Edema was assessed by the extra oral facial measurements. Trismus was measured by recording the interincisal opening in millimeters. Dexamethasone was administered intravenously or submucosally according to the choice of operating surgeon and were divided into 2 groups. Mean and standard deviation calculated for continuous variables. Changes in parameters was analysed using t test and Mann-Whitney U test. Here, submucosal group were reported with increased pain on the second postoperative day. On seventh postoperative day mean value turns to 0.7 ± 1 for submucosal and 0.6 ± 1.2 for intravenous group. On overall observation, intravenous group expressed statistically significant (P < 0.01) reduction in pain compared to the submucosal group during immediate and second postoperative days. Analyzing the previous studies, and from the experience of the present one, it could be reasonably found out that administration of submucosal dexamethasone is beneficial for overall patient compliance.


p53, cancer and the immune response.
The importance of cancer-cell-autonomous functions of the tumour suppressor p53 (encoded by TP53) has been established in many studies, but it is now clear that the p53 status of the cancer cell also has a profound impact on the immune response. Loss or mutation of p53 in cancers can affect the recruitment and activity of myeloid and T cells, allowing immune evasion and promoting cancer progression. p53 can also function in immune cells, resulting in various outcomes that can impede or support tumour development. Understanding the role of p53 in tumour and immune cells will help in the development of therapeutic approaches that can harness the differential p53 status of cancers compared with most normal tissue.


Transient pseudo-hypertriglyceridemia: a useful biochemical marker of fructose-1,6-bisphosphatase deficiency.
Fructose-1,6-bisphosphatase (FBP) deficiency is an autosomal-recessive disorder of gluconeogenesis resulting from mutations within the FBP1 gene. During periods of trivial illness, individuals with FBP deficiency may develop ketotic hypoglycemia, metabolic acidosis, lactic acidemia, and an increased anion gap. Although detection of urinary excretion of glycerol by urine organic acid analysis has been previously described, the presence of transient pseudo-hypertriglyceridemia in serum during metabolic decompensation has not been reported before. This study describes four consanguineous Pakistani families, in which four patients were diagnosed with FBP deficiency. All showed transient pseudo-hypertriglyceridemia during the acute phase of metabolic decompensation, which resolved in a metabolically stable phase. Mutations in the FBP1 gene have been described from various ethnicities, but there is very limited literature available for the Pakistani population. This study also describes one novel mutation in the FBP1 gene which seems to be prevalent in Pakistani-Indian patients. As a result of this study, transient pseudo-hypertriglyceridemia should be added to glyceroluria, ketotic hypoglycemia, metabolic acidosis, and lactic acidosis as a useful biochemical marker of FBP deficiency.


Digital eversion of a hollow structure: an application in virtual colonography.
A new methodology is presented for digital eversion of a hollow structure. The digital eversion is advantageous for better visualization of a larger portion of the inner surface with preservation of geometric relationship and without time-consuming navigation. Together with other techniques, digital eversion may help improve screening, diagnosis, surgical planning, and medical education. Two eversion algorithms are proposed and evaluated in numerical simulation to demonstrate the feasibility of the approach.


Modeling the effects of motivation on choice and learning in the basal ganglia.
Decision making relies on adequately evaluating the consequences of actions on the basis of past experience and the current physiological state. A key role in this process is played by the basal ganglia, where neural activity and plasticity are modulated by dopaminergic input from the midbrain. Internal physiological factors, such as hunger, scale signals encoded by dopaminergic neurons and thus they alter the motivation for taking actions and learning. However, to our knowledge, no formal mathematical formulation exists for how a physiological state affects learning and action selection in the basal ganglia. We developed a framework for modelling the effect of motivation on choice and learning. The framework defines the motivation to obtain a particular resource as the difference between the desired and the current level of this resource, and proposes how the utility of reinforcements depends on the motivation. To account for dopaminergic activity previously recorded in different physiological states, the paper argues that the prediction error encoded in the dopaminergic activity needs to be redefined as the difference between utility and expected utility, which depends on both the objective reinforcement and the motivation. We also demonstrate a possible mechanism by which the evaluation and learning of utility of actions can be implemented in the basal ganglia network. The presented theory brings together models of learning in the basal ganglia with the incentive salience theory in a single simple framework, and it provides a mechanistic insight into how decision processes and learning in the basal ganglia are modulated by the motivation. Moreover, this theory is also consistent with data on neural underpinnings of overeating and obesity, and makes further experimental predictions.


Honoring our helpers.
This special issue of the Journal of Radiology Case Reports honors the reviewers who donated their time and expertise throughout the year 2018 to the high quality and success of this journal.


First Report of Tomato spotted wilt virus on a New Host Leuzea carthamoides in Bulgaria and the World.
The Siberian plant Leuzea carthamoides or maral root was introduced to Europe as a medicinal crop. Tomato spotted wilt virus (TSWV), genus Tospovirus, family Bunyaviridae, caused a harmful outbreak on L. carthamoides in central Bulgaria near the town of Kazanluk in 2009. In 2011, TSWV was identified on young sprouts from the rootages of L. carthamoides in the same place near the town of Kazanluk, Bulgaria, by means of indicator (test) plants, double antibody sandwich (DAS)-ELISA, and reverse transcription (RT)-PCR. Disease symptoms were small yellow spots on the young leaves grown from the tested sprouts and distortions of the leaf lamina. The old leaves had large yellow spots and necrosis, without deformations. Most of those L. carthamoides plants with such symptoms died in the second and third year. The number of the plants in the plantations decreased 20 to 40% during the 3-year period and some of these losses were from the virus disease except the environment conditions. DAS-ELISA was carried out with polyclonal TSWV antiserum of LOEWE Biochemica, GmbH, Germany. We obtained positive extinction values ODλ 405nm 0.358 ± 0.091 compared to the negative 0.053 ± 0.016 and the positive control 0.510 at a confidential interval at P ≤ 0.05. TSWV symptoms were observed on the following indicator plants according to Antignus et al. (1) and DPV/412 (2): Chenopodium quinoa, Cucumis sativus, Datura stramonium, Nicotiana glutinosa, N. rustica, N. tabacum cv. Samsun NN, and Petunia hybrida. TSWV caused on C. quinoa and on cotyledons of C. sativus cv. Delikates local chlorotic lesions only. In this TSWV differed from CMV because CMV caused systemic mosaic symptoms. Local small necrotic lesions and no systemic symptoms were observed on P. hybrida. We noticed systemic symptoms caused from TSWV on D. stramonium, N. glutinosa, N. rustica, and N. tabacum cv. Samsun NN. The systemic symptoms were chlorotic spots, concentric ring spots, and line patterns proceeding to necrosis. RT-PCR, adapted by Mumford et al. (3), was carried out on samples of L. carthamoides. Oligonucleotide primer sequences were used in accordance with Mumford et al. (3). The DNA fragment was visualized by UV trans-illumination. A fragment of the TSWV genome with a length of 276 base pairs was found in three young L. carthamoides leaf samples taken from the sprouts (marker 100 bp). The PCR fragment was sequenced and deposited to NCBI with GenBank Accession No. KC918808. PCR master mix without RNA template was used as a negative control. L. carthamoides is a newly established TSWV host in the world. To our knowledge, this is the first report of TSWV in L. carthamoides identified by RT-PCR. References: (1) Y. Antignus et al. Phytoparasitica 25:319, 1997. (2) R. Kormelink. Descriptions of Plant Viruses, p. 412, 2005. (3) R. A. Mumford et al. J. Virol. Methods 57:109, 1996.


Management strategies following slightly out-of-range INRs: watchful waiting vs dose changes.
Patients' international normalized ratios (INRs) often fall slightly out of range. In these cases, the American College of Chest Physicians (ACCP) guidelines suggest maintaining the current warfarin dose and retesting the INR within the following 2 weeks (watchful waiting). We sought to determine whether watchful waiting or dose changes for slightly out-of-range INRs is more effective in obtaining in-range INRs at follow-up. INRs and management strategies of warfarin-treated patients within the Michigan Anticoagulation Quality Improvement Initiative registry were analyzed. Management strategies included watchful waiting or dose changes. INRs slightly out of range (target range 2.0-3.0) and their associated management were identified. Multilevel mixed-effects logistic regression was used to estimate the probability of the next INR being in range, adjusted for clustering due to multiple out-of-range INRs per patient. A total of 45 351 slightly out-of-range INRs (ranging 1.50-1.99 and 3.01-3.49) from 8288 patients were identified. The next INR was slightly less likely to be in range with watchful waiting than with a dose change (predicted probabilities 58.9% vs 60.0%, P = 0.024). Although a significant statistical difference was detected in the probabilities of the next INR being back in range when managed by a dose change compared with watchful waiting following a slightly out-of-range INR, the magnitude of the difference was small and unlikely to represent clinical importance. Our study supports the current guideline recommendations for watchful waiting in cases of slightly out-of-range INRs values.


Results of a Patient Survey Regarding COPD Knowledge, Treatment Experiences, and Practices With Inhalation Devices.
Successful inhalation therapy depends on the ability of patients with COPD to properly use devices. We explored subjects' COPD knowledge, including education they receive from health care providers, treatment experiences, and practices with inhalation devices. A multiple-choice online survey, developed by a steering committee of American Thoracic Society clinicians and scientists, was administered to subjects with COPD who were sourced from the Harris Poll Online panel. Of the 254 respondents (mean age 61.8 y; 49% males), most subjects (82%) claimed to understand their disease and available treatments, yet COPD symptoms and causes were well known to only 45% and 44% of subjects, respectively. Forty-three percent of subjects had ever used a pressurized metered-dose inhaler or dry-powder inhaler. Of the 54% of subjects who had ever used a small-volume nebulizer (SVN), 63% considered this device to be easy to use, 55% considered it to be fast-acting, 53% considered it to be convenient, and 38% considered it to be essential for treatment. Among subjects who had ever used them, SVNs were preferred by 54% over other devices. One third of subjects desired more extensive education during office visits; 25% felt the time was insufficient to cover questions, and 15% felt their concerns about COPD treatment(s) were ignored. Subjects believed physicians (32%), nurses (26%), and no single provider (28%) were primarily responsible for training and assessing proper inhalation technique. The survey showed differences between patients' beliefs and knowledge of COPD; the need for continuous education from health care providers, particularly on inhalation devices; and extensive use of pressurized metered-dose inhalers and dry-powder inhalers despite positive perceptions of SVNs.


Optimally splitting cases for training and testing high dimensional classifiers.
We consider the problem of designing a study to develop a predictive classifier from high dimensional data. A common study design is to split the sample into a training set and an independent test set, where the former is used to develop the classifier and the latter to evaluate its performance. In this paper we address the question of what proportion of the samples should be devoted to the training set. How does this proportion impact the mean squared error (MSE) of the prediction accuracy estimate? We develop a non-parametric algorithm for determining an optimal splitting proportion that can be applied with a specific dataset and classifier algorithm. We also perform a broad simulation study for the purpose of better understanding the factors that determine the best split proportions and to evaluate commonly used splitting strategies (1/2 training or 2/3 training) under a wide variety of conditions. These methods are based on a decomposition of the MSE into three intuitive component parts. By applying these approaches to a number of synthetic and real microarray datasets we show that for linear classifiers the optimal proportion depends on the overall number of samples available and the degree of differential expression between the classes. The optimal proportion was found to depend on the full dataset size (n) and classification accuracy - with higher accuracy and smaller n resulting in more assigned to the training set. The commonly used strategy of allocating 2/3rd of cases for training was close to optimal for reasonable sized datasets (n ≥ 100) with strong signals (i.e. 85% or greater full dataset accuracy). In general, we recommend use of our nonparametric resampling approach for determining the optimal split. This approach can be applied to any dataset, using any predictor development method, to determine the best split.


Evaluating the Impact of Binning 2D Scalar Fields.
The expressiveness principle for visualization design asserts that a visualization should encode all of the available data, and only the available data, implying that continuous data types should be visualized with a continuous encoding channel. And yet, in many domains binning continuous data is not only pervasive, but it is accepted as standard practice. Prior work provides no clear guidance for when encoding continuous data continuously is preferable to employing binning techniques or how this choice affects data interpretation and decision making. In this paper, we present a study aimed at better understanding the conditions in which the expressiveness principle can or should be violated for visualizing continuous data. We provided participants with visualizations employing either continuous or binned greyscale encodings of geospatial elevation data and compared participants' ability to complete a wide variety of tasks. For various tasks, the results indicate significant differences in decision making, confidence in responses, and task completion time between continuous and binned encodings of the data. In general, participants with continuous encodings were faster to complete many of the tasks, but never outperformed those with binned encodings, while performance accuracy with binned encodings was superior to continuous encodings in some tasks. These findings suggest that strict adherence to the expressiveness principle is not always advisable. We discuss both the implications and limitations of our results and outline various avenues for potential work needed to further improve guidelines for using continuous versus binned encodings for continuous data types.


A Bayesian approach for stochastic white matter tractography.
White matter fiber bundles in the human brain can be located by tracing the local water diffusion in diffusion weighted magnetic resonance imaging (MRI) images. In this paper, a novel Bayesian modeling approach for white matter tractography is presented. The uncertainty associated with estimated white matter fiber paths is investigated, and a method for calculating the probability of a connection between two areas in the brain is introduced. The main merits of the presented methodology are its simple implementation and its ability to handle noise in a theoretically justified way. Theory for estimating global connectivity is also presented, as well as a theorem that facilitates the estimation of the parameters in a constrained tensor model of the local water diffusion profile.


[Trazodone in involuntary pathologic movements].
The authors report an experiment undertaken with trazodone in the treatment of different forms of pathological involuntary movements. Forty-five subjects were treated for two months; 15 were affected with L-DOPA + decarboxylase inhibitor induced dyskinesias, 9 with choreic or choreoathetosic syndromes, 6 with primary buccolingual dyskinesias, 4 with ticks, 9 with tremors--3 of whom had delirium tremens--and 1 case of Wilson's disease with severe postural dystonia. At the end of treatment there was a considerable improvement in 40 cases (88.9%), 17 of whom (37.8%) had a reduction of over 65% of symptoms. The results were good in all the groups considered; particularly interesting were those obtained in delirium tremens, alcoholic induced tremor, primary buccolingual dyskinesias, L-DOPA + decarboxylase inhibitor induced dyskinesias. Emphasis is placed on the efficacy of the drug in inhibiting postural dystonia in the one case of Wilson's disease. The good tolerance of the drug was confirmed.


Hybrid spin-exchange optical pumping of 3He.
We demonstrate spin-exchange optical pumping of 3He using a "hybrid" K-Rb vapor mixture. The Rb atoms absorb light from a standard laser at 795 nm, then collisionally polarize the potassium atoms. Spin-exchange collisions of K and 3He atoms then transfer the angular momentum to the 3He with much greater efficiency than Rb-3He. For a K-rich vapor, the efficiency of the hybrid spin-exchange collisions approaches 1/4, an order of magnitude greater than achieved by pure Rb pumping. We present the first measurements of actual photon efficiencies (polarized nuclei produced per absorbed photon), and show that a new parasitic absorption process limits the total efficiencies for both hybrid and pure Rb pumping.


Clinical and Epidemiological Characteristics of Pituitary Tumours using a Web-based Pituitary Tumour Registry in Oman.
From a recently instituted web-based pituitary tumour registry at Sultan Qaboos University Hospital, Oman, this study explores the results of comprehensive clinical evaluation, hormonal levels, radiological evidence of pituitary mass lesion using magnetic resonance (MRI) and the different treatment modalities. All patients who were diagnosed with pituitary mass tumours in our tertiary care endocrinology clinic between January 1998 and February 2006 were registered in the Oman pituitary tumour registry. Two physicians performed hospital chart review and data entry. A total of 160 entries were made into the pituitary tumour registry. The overall mean age of the cohort was 32 ±12 years (age range 8-73 years). The majority of registrations were female (n=114; 71%). There were 81 patients with non-functioning adenomas (50.6%), 59 with prolactinoma (36.9%) eight with acromegaly (5%), seven with craniopharyngioma (4.4%), four with Cushing's disease (2.5%) and one with sarcoidosis (0.6%). Sub-group analyses were done only for the subjects with the 3 most prevalent pituitary tumours (non-functioning adenomas, prolactinomas, and acromegaly). The most prevalent symptoms are amenorrhea-galactorrhea (n=55; 37%), headache (n=31; 21%) and fatigue (n=23; 16%). The most common treatment modality was medical (n=58; 39%), followed by observation (n=56; 38%), surgery (n=31; 21%) and surgery plus medical (n=3; 2%). None of the patients in this registry are recorded to have died. To our knowledge, this is the first pituitary tumour registry in the Arabian Gulf countries using a web-based programme. This tumour registry will enable us to characterize clinical and the epidemiological features of pituitary tumours in the Sultanate of Oman.


Host tolerance of homologous fascia lata in retinal detachment surgery.
The use of homologous fascia lata in ocular surgery has been frequently questioned in regard to its host tolerance. Our electron microscopic examination of homologous fascia lata grafts up to 19 years old, which had been implanted as scleral buckling elements, showed no gross or microscopic histologic changes. Late infection, migration, and erosion were virtually nonexistent in comparison with other series using synthetic buckling materials. Therefore, homologous fascia lata is ideally tolerated and the most perfect scleral buckling material currently available.


Parkinson plus syndrome: diagnosis using high field MR imaging of brain iron.
The distribution of iron in the brain was analyzed using high field strength (1.5 T) magnetic resonance (MR) imaging in 14 healthy control individuals and six patients with Parkinson plus syndromes (multisystem atrophy and progressive supranuclear palsy) who were unresponsive to antiparkinsonian therapy. The normal topographic distribution of iron in the brain as indicated by high field MR images coincided precisely with the distribution of iron in the brain as determined by Perls staining for ferric iron. In Parkinson plus syndromes, there were abnormally increased concentrations of iron (decreased T2 relaxation times) in the putamen, and less prominent increases in the caudate nucleus and lateral pars compacta of the substantia nigra. In high field strength MR images of normal patients, the decreased signal intensity in the globus pallidus is more prominent than that of the putamen. In MR images of patients with Parkinson plus syndromes, the decreased signal intensity of the putamen is more prominent than that of the globus pallidus.


Both miR-17-5p and miR-20a alleviate suppressive potential of myeloid-derived suppressor cells by modulating STAT3 expression.
Myeloid-derived suppressor cells (MDSCs) were one of the major components of the immune suppressive network. STAT3 has an important role in regulating the suppressive potential of MDSCs. In this study, we found that the expression of STAT3 could be modulated by both miR-17-5p and miR-20a. The transfection of miR-17-5p or miR-20a remarkably reduces the expression of reactive oxygen species and the production of H(2)O(2), which are regulated by STAT3. MDSCs transfected with miR-17-5p or miR-20a are less able to suppress Ag-specific CD4 and CD8 T cells. Importantly, both miR-17-5p and miR-20a alleviate the suppressive function of MDSCs in vivo. The expression of miR-17-5p and miR-20a in tumor-associated MDSCs was found to be lower than in Gr1(+)CD11b(+) cells isolated from the spleens of disease-free mice. Tumor-associated factor downregulates the expression of both miR-17-5p and miR-20a. The modulation of miR-17-5p and miR-20a expression may be important for the process by which patients with a tumor can overcome the immune tolerance mediated by MDSCs. Our results suggest that miR-17-5p and miR-20a could potentially be used for immunotherapy against diseases, especially cancer, by blocking STAT3 expression.


Innate Immune Cells' Contribution to Systemic Lupus Erythematosus.
Systemic lupus erythematosus (SLE) is a chronic autoimmune disease characterized by the presence of autoantibodies against nuclear antigens, immune complex deposition, and tissue damage in the kidneys, skin, heart and lung. Because of the pathogenic role of antinuclear antibodies and autoreactive T cells in SLE, extensive efforts have been made to demonstrate how B cells act as antibody-producing or as antigen-presenting cells that can prime autoreactive T cell activation. With the discovery of new innate immune cells and inflammatory mediators, innate immunity is emerging as a key player in disease pathologies. Recent work over the last decade has highlighted the importance of innate immune cells and molecules in promoting and potentiating SLE. In this review, we discuss recent evidence of the involvement of different innate immune cells and pathways in the pathogenesis of SLE. We also discuss new therapeutics targets directed against innate immune components as potential novel therapies in SLE.


Suppression of food intake and growth by amino acids in Drosophila: the role of pumpless, a fat body expressed gene with homology to vertebrate glycine cleavage system.
We have isolated a Drosophila mutant, named pumpless, which is defective in food intake and growth at the larval stage. pumpless larvae can initially feed normally upon hatching. However, during late first instar stage, they fail to pump the food from the pharynx into the esophagus and concurrently begin moving away from the food source. Although pumpless larvae do not feed, they do not show the typical physiologic response of starving animals, such as upregulating genes involved in gluconeogenesis or lipid breakdown. The pumpless gene is expressed specifically in the fat body and encodes a protein with homology to a vertebrate enzyme involved in glycine catabolism. Feeding wild-type larvae high levels of amino acids could phenocopy the feeding and growth defects of pumpless mutants. Our data suggest the existence of an amino acid-dependent signal arising from the fat body that induces cessation of feeding in the larva. This signaling system may also mediate growth transition from larval to the pupal stage during Drosophila development.


Micro- and nanocelluloses from non-wood waste sources; processes and use in industrial applications.
In addition to renewability and abundance, nanocellulose materials have tremendous (and variable) properties for different applications, ranging from bulk applications, such as paper and packaging reinforcement, to emerging high added-value applications, such as substrates for optoelectronics. Lignocellulosic biomass from agricultural and industrial waste sources is readily available and shows great promise as an inexpensive and sustainable raw material for nanocellulose production. However, the understanding of the potential of using non-wood based biowaste sources is not established and systematic comparisons of versatile agricultural and industrial waste sources can elucidate this complex topic. Here we present an overview of the most studied and most promising sources from agro-industrial waste, the processes to convert them into nanocellulose, some of the established and emerging applications, and discuss the advancements that are still needed for large-scale production. Sugarcane bagasse and oil palm empty fruit bunch have been the most researched waste-based sources for nanocellulose production and demonstrate the most promise due to availability and access. Industrial sources seem to have advantages over agricultural sources in collectability and ease of access. This work gives insight on the potential and the challenges of nanocellulose production from waste sources and discusses how the criteria set for nanocellulose materials in different applications can be met, thus opening new routes for circular economy.


Fine-scale movement and habitat use of a prairie stream fish assemblage.
Measuring an organism's movement and habitat use is highly dependent on the spatial and temporal scale of the study, with most studies measuring distributions once a day or at less frequent intervals. Yet, to fully understand the rates of intra- and interspecific encounters among individuals, observations at finer spatial and temporal scales might be necessary. We used passive integrated transponder tags and antenna arrays to continuously monitor habitat use and vagility of three stream minnows; southern redbelly dace Chrosomus erythrogaster, central stoneroller Campostoma anomalum, and creek chub Semotilus atromaculatus, among and within pools of an intermittent stream. Most fish remained in the pool where they were caught and released, or returned after emigrating from the pool. Despite largely remaining within the release pool, distribution among four microhabitats differed significantly over six, 4-h time periods for all three species. Vagility, the summed distance moved among antennas, differed significantly among species. Individual vagility (m day-1) increased significantly with body length for stoneroller and chub, but not dace. Some individuals moved as much as 110 m day-1 within the pool, showcasing extensive movement at fine scales. Finally, we found no evidence that feeding activity changed as a result of differential habitat use over a 24-h period. Our findings indicate considerable variation in habitat use and movement occurs among species over a 24-h period. This suggests ecologists can broaden the interpretation of processes influencing community structure (e.g., resource partitioning, avoidance of predators) by quantifying species distributions across a range of spatial and temporal scales.


Modeling the underlying dynamics of the spread of crime.
The spread of crime is a complex, dynamic process that calls for a systems level approach. Here, we build and analyze a series of dynamical systems models of the spread of crime, imprisonment and recidivism, using only abstract transition parameters. To find the general patterns among these parameters--patterns that are independent of the underlying particulars--we compute analytic expressions for the equilibria and for the tipping points between high-crime and low-crime equilibria in these models. We use these expressions to examine, in particular, the effects of longer prison terms and of increased incarceration rates on the prevalence of crime, with a follow-up analysis on the effects of a Three-Strike Policy.


The effects of environmental pollutants on complex fish behaviour: integrating behavioural and physiological indicators of toxicity.
Environmental pollutants such as metals, pesticides, and other organics pose serious risks to many aquatic organisms. Accordingly, a great deal of previous research has characterized physiological mechanisms of toxicity in animals exposed to contaminants. In contrast, effects of contaminants on fish behaviour are less frequently studied. Because behaviour links physiological function with ecological processes, behavioural indicators of toxicity appear ideal for assessing the effects of aquatic pollutants on fish populations. Here we consider the many toxicants that disrupt complex fish behaviours, such as predator avoidance, reproductive, and social behaviours. Toxicant exposure often completely eliminates the performance of behaviours that are essential to fitness and survival in natural ecosystems, frequently after exposures of lesser magnitude than those causing significant mortality. Unfortunately, the behavioural toxicity of many xenobiotics is still unknown, warranting their future study. Physiological effects of toxicants in the literature include disruption of sensory, hormonal, neurological, and metabolic systems, which are likely to have profound implications for many fish behaviours. However, little toxicological research has sought to integrate the behavioural effects of toxicants with physiological processes. Those studies that take this multidisciplinary approach add important insight into possible mechanisms of behavioural alteration. The most commonly observed links with behavioural disruption include cholinesterase (ChE) inhibition, altered brain neurotransmitter levels, sensory deprivation, and impaired gonadal or thyroid hormone levels. Even less frequently studied are the implications of interrelated changes in behaviour and physiology caused by aquatic pollutants for fish populations. We conclude that future integrative, multidisciplinary research is clearly needed to increase the significance and usefulness of behavioural indicators for aquatic toxicology, and aim to highlight specific areas for consideration.


Neuraminidase inhibitors for preventing and treating influenza in healthy adults.
Neuraminidase inhibitors (NI) are recommended for use against influenza and its complications in interpandemic years and in a pandemic. To assess the effects of NIs in preventing or ameliorating influenza, its transmission and its complications in healthy adults and to estimate the frequency of adverse effects. We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library Issue 3, 2005), MEDLINE (2004 to September, Week 4 2005), EMBASE (2003 to June 2005) and contacted manufacturers, researchers in the field, and authors of studies evaluated in the review. Randomised or quasi-randomised placebo-controlled studies of NIs in healthy adults exposed to naturally occurring influenza. Two authors applied inclusion criteria, assessed trial quality and extracted data. We structured the comparisons into prophylaxis, treatment and adverse events with further subdivision by outcome and dose. We identified four prophylaxis, 13 treatment and four post-exposure prophylaxis (PEP) trials. In prophylaxis compared to placebo, NIs have no effect against influenza-like illnesses (ILI) (relative risk (RR) 1.28, 95% confidence interval (CI) 0.45 to 3.66 for oral oseltamivir 75 mg daily; RR 1.51, 95% CI 0.77 to 2.95 for inhaled zanamivir 10 mg daily). The efficacy of oral oseltamivir 75 mg daily against symptomatic influenza is 61% (RR 0.39, 95% CI 0.18 to 0.85), or 73% (RR 0.27, 95% CI 0.11 to 0.67) at 150 mg daily. Inhaled zanamivir 10 mg daily is 62% efficacious (RR 0.38, 95% CI 0.17 to 0.85). Neither NI has a significant effect on asymptomatic influenza. Oseltamivir induces nausea (odds ratio (OR) 1.79, 95% CI 1.10 to 2.93). Oseltamivir for PEP has an efficacy of 58.5% (15.6% to 79.6) for households and of 68% (34.9 to 84.2%) to 89% in contacts of index cases. Zanamivir has similar performance. The hazard ratios for time to alleviation of influenza symptoms were in favour of the treated group 1.33 (1.29 to 1.37) for zanamivir and 1.30 (1.13 to 1.50) for oseltamivir. Viral nasal titres were significantly diminished by both NIs. Oseltamivir 150 mg daily prevented lower respiratory tract complications (OR 0.32, 95% CI 0.18 to 0.57). We could find no comparative data on the effects of oseltamivir on avian influenza. Because of their low effectiveness, NIs should not be used in routine seasonal influenza control. In a serious epidemic or pandemic, NIs should be used with other public health measures. We are unsure of the generalisability of our conclusions from seasonal to pandemic or avian influenza.


Social class rank, essentialism, and punitive judgment.
Recent evidence suggests that perceptions of social class rank influence a variety of social cognitive tendencies, from patterns of causal attribution to moral judgment. In the present studies we tested the hypotheses that upper-class rank individuals would be more likely to endorse essentialist lay theories of social class categories (i.e., that social class is founded in genetically based, biological differences) than would lower-class rank individuals and that these beliefs would decrease support for restorative justice--which seeks to rehabilitate offenders, rather than punish unlawful action. Across studies, higher social class rank was associated with increased essentialism of social class categories (Studies 1, 2, and 4) and decreased support for restorative justice (Study 4). Moreover, manipulated essentialist beliefs decreased preferences for restorative justice (Study 3), and the association between social class rank and class-based essentialist theories was explained by the tendency to endorse beliefs in a just world (Study 2). Implications for how class-based essentialist beliefs potentially constrain social opportunity and mobility are discussed.


Deep mRNA sequencing analysis to capture the transcriptome landscape of zebrafish embryos and larvae.
Transcriptome analysis is a powerful tool to obtain large amount genome-scale gene expression profiles. Despite its extensive usage to diverse biological problems in the last decade, transcriptomic researches approaching the zebrafish embryonic development have been very limited. Several recent studies have made great progress in this direction, yet the large gap still exists, especially regarding to the transcriptome dynamics of embryonic stages from early gastrulation onwards. Here, we present a comprehensive analysis about the transcriptomes of 9 different stages covering 7 major periods (cleavage, blastula, gastrula, segmentation, pharyngula, hatching and early larval stage) in zebrafish development, by recruiting the RNA-sequencing technology. We detected the expression for at least 24,065 genes in at least one of the 9 stages. We identified 16,130 genes that were significantly differentially expressed between stages and were subsequently classified into six clusters. Each revealed gene cluster had distinct expression patterns and characteristic functional pathways, providing a framework for the understanding of the developmental transcriptome dynamics. Over 4000 genes were identified as preferentially expressed in one of the stages, which could be of high relevance to stage-specific developmental and molecular events. Among the 68 transcription factor families active during development, most had enhanced average expression levels and thus might be crucial for embryogenesis, whereas the inactivation of the other families was likely required by the activation of the zygotic genome. We discussed our RNA-seq data together with previous findings about the Wnt signaling pathway and some other genes with known functions, to show how our data could be used to advance our understanding about these developmental functional elements. Our study provides ample information for further study about the molecular and cellular mechanisms underlying vertebrate development.


The effect of whole-body vibration training on lean mass in postmenopausal women: a systematic review and meta-analysis.
The purpose of the present systematic review and meta-analysis was to evaluate published, randomized controlled trials that investigated the effects of whole-body vibration training (WBVT) on lean mass in postmenopausal women. The following electronic databases were searched from September to October 2015: PubMed, Web of Science, and Cochrane. Two different authors tabulated, independently, the selected indices in identical predetermined forms. The methodological quality of all randomized trial studies was evaluated according to the modified PEDro scale. In each trial, the effect size of the intervention was calculated by the difference between pre- and postintervention lean mass in WBVT postmenopausal women. For controlled trials, the effect size of the WBVT was also calculated by the difference in lean mass after the WBVT and in control participants. Of the 189 articles found from the database search and all duplicates removed, 5 articles were analyzed. The lean mass of 112 postmenopausal women who performed either WBVT or a control protocol was evaluated. The methodological quality of the trials was high, where the mean score was 8 out of a possible 10 points. No significant improvements in lean mass with WBVT were found in postmenopausal women. In addition, there was no significant difference in lean mass between WBVT and control postmenopausal women. This meta-analysis demonstrated that WBVT alone may not be a sufficient stimulus to increase lean mass in postmenopausal women. Thus, additional complimentary training methods with WBVT are needed to increase muscle size in women with lower hormonal responses.


Characterization of cryptic flagellin genes in Shigella boydii and Shigella dysenteriae.
Flagellin (fliC) genes of 12 Shigella boydii and five Shigella dysenteriae strains were characterized. Though these strains are nonmotile, the cryptic fliCSB gene, cloned from S. boydii strain C3, is functional for expression of flagellin. It consists of 1,704 bp, and encodes 568 amino acid residues (57,918 Da). The fliCSD gene from S. dysenteriae strain 16 consists of 1,650 bp encoding 549 amino acid residues (57,591 Da) and contains an IS1 element inserted in its 3' end. The two genes are composed of the 5'-constant, central variable and 3'-constant sequences, like other known fliC genes. The two genes share high homology in nucleotide and amino acid sequences with each other and also with the Escherichia coli fliCE gene, indicating that both genes are closely related to the fliCE gene. Comparison of the central variable sequences of six different fliC genes showed that the fliCSB and fliCSD genes share low homology in amino acid sequence with the other fliC genes, suggesting that they encode antigenic determinants intrinsic to respective subgroups. However, Southern blotting using as probes the central variable sequences of several fliC genes showed that four of 12 S. boydii strains have a fliC gene similar to that of Shigella flexneri, and that among five fliC genes from S. dysenteriae strains, one is similar to that of S. flexneri, two are similar to that of S. boydii, and only one is unique to S. dysenteriae. Some of these variant alleles were verified by immunoblotting with flagellins produced from cloned fliC genes. The presence of variant fliC alleles in S. boydii and S. dysenteriae indicates that subdivision into subgroups does not reflect the ancestral flagella H antigenic relationships. These data will be useful in considering the evolutionary divergence of the Shigella spp..


Vaccinia-T7 RNA polymerase expression system: evaluation for the expression cloning of plasma membrane transporters.
The vaccinia/T7 transient expression system, which results in rapid, high-level expression of proteins encoded by plasmids bearing T7 promoters, provides a powerful strategy for the expression cloning of membrane transporters. To test the feasibility of this approach, we introduced the rabbit Na+/glucose transporter by liposome-mediated transfection into vaccinia infected HeLa cells and determined the characteristics and sensitivity of induced [14C]alpha-methyl D-glucopyranoside uptake. We observed a rapid (4-12 h) expression of saturable (Kt = 342 microM) [14C]alpha-methyl D-glucopyranoside uptake following transfection, with substrate and inhibitor sensitivities of the native carrier, including Na+ and temperature dependence and appropriate phloridzin sensitivity (KI = 9.1 microM). The time-dependent increase in alpha-methyl D-glucopyranoside uptake coincided with a decline in endogenous Na+/D-aspartate transport. Maximal levels of expression achieved were nearly 10-fold higher than that reported for transient expression of Na+/glucose transporters in the COS cell system. Rate and dilution estimates demonstrates a sensitivity of detection of single clones diluted several thousand fold by nonspecific plasmid DNA. A further 3-fold increase in transport sensitivity was achieved after transfection of plasmid constructs bearing additional 5'-T7 stem-loop and 3'-T7 termination signals. When cell lines with low endogenous transport were coupled with substrates of high specific activity, as with measurements of induced [3H]gamma-aminobutyric acid uptake, we were able to detect expression from transporter bearing plasmids diluted as much as 10,000-fold by non-specific plasmid DNA.(ABSTRACT TRUNCATED AT 250 WORDS)


Considerations for the use of restricted, soaked grass hay diets to promote weight loss in the management of equine metabolic syndrome and obesity.
The addition of hay soaking to current nutritional advice for weight loss management for equine obesity lacks clinical evidence. Twelve overweight/obese horses and ponies were used to test the hypothesis that feeding soaked hay at 1.25% of body mass (BM) daily as dry matter (DM) before soaking would elicit weight losses within the target 0.5-1.0% of BM weekly. Six animals were used to evaluate the impact of nutrient-leaching on the digestibility and daily intakes of dietary energy and nutrients. Soaked hay DM was corrected in accordance with the 'insoluble' ADF content of fresh and soaked hays. The ADF-based method was validated using a test-soaking protocol. Animals fed soaked hay for 6 weeks lost 0.98 ± 0.10% of BM weekly. The most weight loss sensitive animal lost ~2% of BM weekly. Soaking hay did not alter DM gross energy concentrations, incurred losses of water soluble carbohydrates (WSC) and ash and increased acid detergent fibre (ADF) concentrations. Digestibilities of GE, DM, ash and WSC were unaltered but soaking increased uncorrected values for crude protein (+12%) and ADF (+13.5%) digestibility. Corrected DM provision was only 1% of BM daily, providing 64% of maintenance DE requirements, a 23.5% increase in the intended magnitude of energy restriction. Hay soaking leached nutrients, reduced DM and DE provision and was associated with accelerated weight losses over those expected had fresh-hay been fed to the same level. The ADF-based method will allow the predictive evaluation of individual hays to direct feeding management and prevent inadvertently severe DM and energy restriction.


VH1-46 is the dominant immunoglobulin heavy chain gene segment in rotavirus-specific memory B cells expressing the intestinal homing receptor alpha4beta7.
Memory B cells expressing the intestinal homing marker alpha4beta7 are important for protective immunity against human rotavirus (RV). It is not known whether the B cell repertoire of intestinal homing B cells differs from B cells of the systemic compartment. In this study, we analyzed the RV-specific VH and VL repertoire in human IgD- B cells expressing the intestinal homing marker alpha4beta7. The mean frequency of RV-specific B cells in the systemic compartment of healthy adult subjects was 0.6% (range, 0.2-1.2). The mean frequency of IgD- B cells that were both RV specific and alpha4beta7 was 0.04% (range, 0.01-0.1), and a mean of 10% (range, 1-32) of RV-specific peripheral blood human B cells exhibited an intestinal homing phenotype. We previously demonstrated that VH1-46 is the dominant Ab H chain gene segment in RV-specific systemic B cells from adults and infants. RV-specific systemic IgD- or intestinal homing IgD-/alpha4beta7+ B cells in the current study also used the gene segment VH1-46 at a high frequency, while randomly selected B cells with those phenotypes did not. These data show that VH1-46 is the immunodominant gene segment in human RV-specific effector B cells in both the systemic compartment and in intestinal homing lymphocytes. The mean replacement/silent mutation ratio of systemic compartment IgD- B cells was >2, consistent with a memory phenotype and antigenic selection. Interestingly, RV-specific intestinal homing IgD-/alpha4beta7+ B cells using the VH1-46 gene segment were not mutated, in contrast to systemic RV-specific IgD- B cells.


[Historical consideration of the widespread infection of the hepatitis C virus in Japan and use of a fishbone diagram to investigate the cause].
About 75% of Japanese liver cancer is caused by hepatitis C. Widespread infection of the virus resulted from inadequate medical knowledge, as well as the political, economic and administrative conditions of the time. We investigated the association between the widespread infection of the hepatitis C virus and the historical events. We used a fishbone diagram to investigate the cause of widespread infection of the hepatitis C virus and considered the issue from a historical standpoint. We found causes including treatment (medical care), transfusion (medicine), economy (expense) and people (infection route). These causes are explained in further detail below. 1) Treatment (medical care). The initial large-scale infection occurred following attempts to eradicate Schistosoma japonicum involving mass vaccination in schools and public health centers. 2) Transfusion (medicine). The use of non-heated fibrinogen for massive postpartum hemorrhage spread the virus further. In 1987, it resulted in a mass outbreak of hepatitis in Aomori Prefecture. 3) Economy (expense). Recognition of the benefit of disposable syringes was delayed. As a result, disposable syringes were too expensive to be widely available, and did not become low-priced. 4) People (infection route). The second wave of dissemination of the hepatitis C virus was stimulant abuse after World War II. Prior to the discovery of the hepatitis C virus, transmission resulted from repeated use of contaminated syringes. Although we initially thought that these four causes occurred independently on a historical chronology, associations between the causes were found when we investigated the problem with a fishbone diagram.


Cellular localization of serotonin 1A, 1B and uptake sites in cingulate cortex of the rat.
Experimental lesions followed by binding of [3H]8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT), [125I]cyanopindolol and [3H] paroxetine to cryostat sections and coverslip autoradiography were used to localize 5-HT1A, 5-HT1B and 5-HT uptake sites in rat posterior cingulate cortex. Ablations included: 1) undercutting for removal of all afferent axons; 2) destruction of the raphe nuclei; 3) cortical ibotenic acid injections for removal of neurons and 4) anterior thalamic and caudate nuclei injections of the immunotoxin OX7-saporin which destroys single classes of cortical projection neurons by retrograde axonal transport. Peak paroxetine binding was in layer Ia with low binding in layer Va and moderate amounts in other layers. Undercut lesions reduced binding only in layer Ia by 35%. Major loses were observed after raphe ablations with decreases of 40 to 72% across all layers. Cortical ibotenic acid injections did not alter paroxetine binding. Peak cyanopindolol binding was in layers Ia to Ic. Undercutting decreased binding significantly in layers Ia, Ib, III and IV, whereas after raphe lesions binding was decreased by 34 to 58% in layers Ia to IV. 5,7-Dihydroxytryptamine injection increased binding by 10 to 40% in layers Ib, II, III and IV. Cortical ibotenic acid injections reduced grain density in all layers with a range of 28 to 47%. Peak 8-OH-DPAT binding was in layer Vb. No change was observed after undercut lesions, whereas after cortical ibotenic acid injection, binding reductions of 44 to 75% were observed throughout all nine sublaminae. Thalamic OX7-saporin injections destroyed almost all layer VI neurons, which resulted in a 45% decrease in layer VI 8-OH-DPAT binding.(ABSTRACT TRUNCATED AT 250 WORDS)


A practical method for multimodal registration and assessment of whole-brain disease burden using PET, MRI, and optical imaging.
Many neurological diseases present with substantial genetic and phenotypic heterogeneity, making assessment of these diseases challenging. This has led to ineffective treatments, significant morbidity, and high mortality rates for patients with neurological diseases, including brain cancers and neurodegenerative disorders. Improved understanding of this heterogeneity is necessary if more effective treatments are to be developed. We describe a new method to measure phenotypic heterogeneity across the whole rodent brain at multiple spatial scales. The method involves co-registration and localized comparison of in vivo radiologic images (e.g. MRI, PET) with ex vivo optical reporter images (e.g. labeled cells, molecular targets, microvasculature) of optically cleared tissue slices. Ex vivo fluorescent images of optically cleared pathology slices are acquired with a preclinical in vivo optical imaging system across the entire rodent brain in under five minutes, making this methodology practical and feasible for most preclinical imaging labs. The methodology is applied in various examples demonstrating how it might be used to cross-validate and compare in vivo radiologic imaging with ex vivo optical imaging techniques for assessing hypoxia, microvasculature, and tumor growth.