Trichromatic red-green-blue camera used for the recovery of albedo and reflectance of rough-textured surfaces under different illumination conditions.
Photometric-stereo techniques are based on the fact that image intensity depends upon the orientation of the surface with regard to the source of the illumination and its spectral reflectance. They are of special interest when dealing with rough surfaces because they usually present shadowed regions where sudden illumination changes might be found. In the present work we introduce an extension of the four-source photometric-stereo algorithm to color images that is able to recover the surface spectral reflectance of objects captured with a red-green-blue (RGB) camera. This method allows image rendering, even for rough-textured surfaces, under different directions of the impinging illumination. In addition, the introduction of spectral recovery techniques applied to the albedo and spectral reflectance from rough surfaces offers the possibility of image rendering for scenes captured under sources of illumination differing in spectral distribution. Using albedo instead of RGB information helps to avoid any shadows or highlights that might falsify results. One of the advantages of this spectral-based photometric-stereo method is that it can recover not only the albedo values, but also the spectral reflectance spectrum of an object's surface on a pixel-by-pixel basis, as can be done with more complex hyperspectral imaging devices involving a camera coupled to an extensive set of narrowband filters.


Role of metabolic waste products in the control of cell proliferation and antibody production by mouse hybridoma cells.
In order to determine the factors limiting the proliferation and productivity of mouse hybridoma cells in batch/fed-batch cultures, we tested the influence of various environmental parameters on the growth of a model cell line VO 208. We observed that, among the major metabolic waste products, ammonium ions at concentrations superior to that present in the medium at the end of a batch culture do not exert a significant toxic effect on cell growth, whereas in contrast, lactic acid is cytotoxic at concentrations reached in cultures. Feeding of fructose instead of glucose during the stationary phase of the culture markedly prolongs the life span of the culture and enhances the antibody secretion accordingly. However, we failed to observe a satisfactory proliferation pattern in cultures grown in a glucose-free fructose-supplemented medium. We also noted that vitamin supply may be limiting in fed-batch cultures. It thus appears that thorough examination of the cell metabolic needs allows the designing of a culture regimen which significantly improves cell growth and secretion.


Pain and smoking study (PASS): A comparative effectiveness trial of smoking cessation counseling for veterans with chronic pain.
Smoking is associated with greater pain intensity and pain-related functional interference in people with chronic pain. Interventions that teach smokers with chronic pain how to apply adaptive coping strategies to promote both smoking cessation and pain self-management may be effective. The Pain and Smoking Study (PASS) is a randomized clinical trial of a telephone-delivered, cognitive behavioral intervention among Veterans with chronic pain who smoke cigarettes. PASS participants are randomized to a standard telephone counseling intervention that includes five sessions focusing on motivational interviewing, craving and relapse management, rewards, and nicotine replacement therapy versus the same components with the addition of a cognitive behavioral intervention for pain management. Participants are assessed at baseline, 6, and 12 months. The primary outcome is smoking cessation. The 371 participants are 88% male, a median age of 60 years old (range 24-82), and smoke a median of 15 cigarettes per day. Participants are mainly white (61%), unemployed (70%), 33% had a high school degree or less, and report their overall health as "Fair" (40%) to "Poor" (11%). Overall, pain was moderately high (mean pain intensity in past week = 5.2 (Standard Deviation (SD) = 1.6) and mean pain interference = 5.5 (SD = 2.2)). Pain-related anxiety was high (mean = 47.0 (SD = 22.2)) and self-efficacy was low (mean = 3.8 (SD = 1.6)). PASS utilizes an innovative smoking and pain intervention to promote smoking cessation among Veterans with chronic pain. Baseline characteristics reflect a socioeconomically vulnerable population with a high burden of mental health comorbidities.


The staphylococcal enterotoxins and their relatives.
In the article "The staphylococcal enterotoxins and their relatives" by Philippa Marrack and John Kappler (11 May, p. 705), figures 1, 2, and 3 were incorrectly printed. The color portions of figures 2 and 3 should have been included in figure 1. The correct figure 1 is printed below. See image in PDF file


Association of Left Ventricular Diastolic Dysfunction with Subclinical Coronary Atherosclerotic Disease Burden Using Coronary Artery Calcium Scoring.
Diastolic dysfunction is a common problem in patients with obesity, hypertension, diabetes, or coronary artery disease. The purpose of this study was to evaluate the association of left ventricular diastolic dysfunction with an abnormal coronary artery calcium score (CAC score). This study considered a cohort of patients ≥ 18 years of age with normal ejection fraction who were admitted to the hospital with chest pain. All patients underwent regadenoson myocardial perfusion stress imaging and had no evidence of ischemia or infarction. Patients then underwent cardiac CT for measurement of CAC score. Patients were excluded if they had prior history of coronary artery disease, ECG findings diagnostic of an acute coronary syndrome, an elevated troponin level, or hemodynamic instability. A total of 114 patients were included and 52 (45.6%) patients had echocardiographic evidence of diastolic dysfunction. Patients with diastolic dysfunction were more likely to have an abnormal calcium score (79.6% vs 20%; OR 15.10, 95% CI 5.70 to 43.85; p < 0.001). In multivariable analysis, the presence of diastolic dysfunction on echocardiogram was significantly associated with an abnormal calcium score (OR 13.82, 95% CI 5.57 to 37.37; p < 0.001) after adjusting for Framingham Risk Score or clinical risk factors (age, gender, diabetes mellitus, dyslipidemia, and obesity; OR 19.06,95% CI 4.66 to 107.97; p < 0.001). Our study demonstrates that left ventricular diastolic dysfunction is associated with an abnormal CAC score even after adjusting for Framingham Risk Score or clinical risk factors. Patients without known coronary artery disease that present with chest pain and have normal perfusion imaging with evidence of abnormal diastolic function on echocardiogram may warrant more thorough evaluation for coronary atherosclerotic disease with CAC score assessment.


Comparison of HIV-1 genotypic resistance test interpretation systems in predicting virological outcomes over time.
Several decision support systems have been developed to interpret HIV-1 drug resistance genotyping results. This study compares the ability of the most commonly used systems (ANRS, Rega, and Stanford's HIVdb) to predict virological outcome at 12, 24, and 48 weeks. Included were 3763 treatment-change episodes (TCEs) for which a HIV-1 genotype was available at the time of changing treatment with at least one follow-up viral load measurement. Genotypic susceptibility scores for the active regimens were calculated using scores defined by each interpretation system. Using logistic regression, we determined the association between the genotypic susceptibility score and proportion of TCEs having an undetectable viral load (<50 copies/ml) at 12 (8-16) weeks (2152 TCEs), 24 (16-32) weeks (2570 TCEs), and 48 (44-52) weeks (1083 TCEs). The Area under the ROC curve was calculated using a 10-fold cross-validation to compare the different interpretation systems regarding the sensitivity and specificity for predicting undetectable viral load. The mean genotypic susceptibility score of the systems was slightly smaller for HIVdb, with 1.92+/-1.17, compared to Rega and ANRS, with 2.22+/-1.09 and 2.23+/-1.05, respectively. However, similar odds ratio's were found for the association between each-unit increase in genotypic susceptibility score and undetectable viral load at week 12; 1.6 [95% confidence interval 1.5-1.7] for HIVdb, 1.7 [1.5-1.8] for ANRS, and 1.7 [1.9-1.6] for Rega. Odds ratio's increased over time, but remained comparable (odds ratio's ranging between 1.9-2.1 at 24 weeks and 1.9-2.2 at 48 weeks). The Area under the curve of the ROC did not differ between the systems at all time points; p = 0.60 at week 12, p = 0.71 at week 24, and p = 0.97 at week 48. Three commonly used HIV drug resistance interpretation systems ANRS, Rega and HIVdb predict virological response at 12, 24, and 48 weeks, after change of treatment to the same extent.


Temporal profile of fluorodeoxyglucose uptake in malignant lesions and normal organs over extended time periods in patients with lung carcinoma: implications for its utilization in assessing malignant lesions.
In this study, the fluorodeoxyglucose (FDG) uptake was prospectively investigated in tumors as well as the normal organs over 8 h in patients with non small cell lung carcinoma (NSCLC). The intent of this study was to collect positron emission tomography (PET) data with regard to the time course of FDG uptake in the primary and metastatic sites and the normal tissues over extended time periods (up to 8 h) after intravenous FDG injection in patients. Three patients (2 males, 1 female; mean age: 64 years; age range: 57-76 years) with the diagnosis of NSCLC underwent a series of whole body FDG-PET at several time points, beginning at 5 min and extending up to 8 h after the intravenous administration of FDG. We calculated the standardized uptake values (SUVmax) in the malignant lesions and all organs. SUVmax was calculated over contiguous slices and the highest value was considered for the analysis. Similar locations were used for the placement of regions of interest in subsequent images. Time activity curves (TACs) were generated utilizing these SUV values for each of these sites. The ratios of the SUVmax of the malignant lesions to those of normal organs (viz. lung and liver) at specific time points were also calculated and the TACs for these ratios were generated. The blood and plasma decay curves of (18)F activity over time were generated based on the counts obtained from blood sample analysis. The ratios of 18F activity of blood to plasma were also calculated and the TACs of this ratio were generated. The observed mean SUVmax at different time points (5 min, 1 h, 2 h, 4 h, 6 h and 8 h) in the organs and the lesions were as follows: 1) heart: 2.9, 2, 1.9, 1.6, 1.3, 1.5; 2) kidney: 3.3, 3.5, 2.6, 2.1, 2, 2; 3) liver: 3.9, 2.2, 1.9, 1.6, 1.5, 1.8; 4) lung: 0.6, 0.5, 0.4, 0.4, 0.4, 0.4, 0.4; 5) large bowel: 2.1, 1.4, 1.8, 1.4, 2, 2.2; 6) small bowel: 2.6, 1.6, 1.4, 1.2, 1.3, 1.5; 7) lung neoplasm: 3.7, 5.1, 6.1, 6.8, 6.9, 6.8; 8) mediastinal lesion 1: 6.8, 8.8, 13, 12.7, 13.8, 12.5; 9) mediastinal lesion 2: 5.5, 8.6, 10.7, 13.2, 11.7, 12.1; 10) adrenal metastasis (starting at 1 h): 3.3, 3.7, 4.7, 4.7, 4.7; 11) right iliac metastasis: 2.6, 2.6, 3.1, 3.5, 3.4. For the right iliac metastasis, we had SUVmax up to 6 h. The SUVmax ratios of malignant lesions to those of normal lung and liver and their TACs demonstrate initial rise followed by a delayed plateau. Increasing (18)F count ratios of blood to plasma with time was observed in 2 patients where these data were available. The results from this preliminary study indicate that while the tumor sites show increased uptake of FDG during the course of 8 h, surrounding normal tissues demonstrate declining or stable values with time. This would indicate increasing contrast between the lesion and the background and, therefore, possibly improved sensitivity of the test. While the high SUV at 5 min can be explained by the blood pool activity in the organs and the malignant lesions, the SUVmax values at the later times decreases or remains the same in normal organs. The observation on the different slopes of the curves among the various malignant lesions can be partly explained by the well known ''seed and soil'' theory in cancer biology. The finding of continued increases in the blood to plasma count ratios of (18)F activity is also noteworthy and most likely reflects GLUT-1 mediated glucose transport into red blood cells.


Organophosphorus pesticide quinalphos (Ekalux 25 E.C.) reduces sperm functional competence and decreases the fertilisation potential in Swiss albino mice.
Quinalphos (QP) is one of the most commonly used organophosphate pesticide for agriculture. In this study, adult Swiss albino male mice were orally administered with 0.25, 0.5 and 1.0 mg/kg of QP (Ekalux 25 E.C.) for ten consecutive days and the reproductive function was assessed at 35 and 70 days after QP treatment. At highest dose (1.0 mg/kg), QP exposure resulted in significant decrease in motility and increase in sperm head defects and DNA damage. Pharmacokinetic data showed a threefold increase in concentration of QP in the testis as compared to serum. QP was detectable in testes even after 24 hr of administration indicating slow clearance from tissue. In addition, high oestradiol, low testosterone level with a parallel increase in aromatase and cytochrome P450 transcript levels was observed. Significant decrease in fertilisation, lower blastocyst rate and poor blastocyst quality was observed when spermatozoa collected from QP exposed mice were subjected to in vitro fertilisation. In conclusion, exposure of QP to male mice decreases the sperm functional competence and fertilising ability, which appears to be mediated through elevated oxidative stress and altered steroidogenesis in testes.


Proteomic analysis of zebrafish (Danio rerio) embryos exposed to cyclosporine A.
Cyclosporine A, a potent immunosuppressive agent extensively used to prevent allograft rejections, is under scrutiny due to severe toxic effects. CsA therapy is often continued during pregnancy in conditions such as organ transplantations and autoimmune diseases. Herein, we investigated the effects of CsA on early morphogenesis of zebrafish and identified a spectrum of proteins whose expression was altered in the drug treated embryos. Time-lapse fluorescence imaging of germ-line double transgenic zebrafish embryos treated with CsA revealed severe blood regurgitation in heart chambers, absence of blood circulation in vessels, pericardial and yolk sac edema. We also observed lack of mature blood vessels and down-regulation of endothelial markers in CsA treated embryos. Proteomic analysis using 2D-DIGE followed by mass-spectrometry led to the identification of 37 proteins whose expression was significantly modulated in presence of the drug. These proteins were mostly associated with cytoskeletal/structural assembly, lipid-binding, stress response and metabolism. Furthermore, mRNA expression analysis of eight proteins and Western blotting of actin revealed consistency between the changes observed in protein expression and its corresponding mRNA levels. Our findings demonstrate that CsA administration during early morphogenesis in zebrafish modulates the expression of some proteins which are known to be involved in important physiological processes.


Pleural mesothelioma side populations have a precursor phenotype.
DyeCycleViolet was used to set up the side population (SP) functional assay aimed at identifying subpopulations of malignant pleural mesothelioma (MPM) tumor cells with chemoresistance phenotype associated with ABCG2 transporter activity. Self-renewal, chemoresistance and tumorigenicity were tested for SP and non-side population (NSP) cells. Tumors were characterized by mesothelin, calretinin, N-cadherin, D2-40 and Wilms tumor 1 (WT1) immunohistochemistry. Surface expression of mesenchymal stem cell markers CD90, CD73 and CD105 was investigated in SP and NSP cells. We identified SP cells with self-renewal properties and increased chemoresistance in MPM cell lines and tumor-derived primary cell cultures. Compared with the non-SP fraction (NSP), the SP fraction led to the development of tumors including cells with mesothelium precursor phenotype characterized by mesenchymal morphology, being WT1 negative but cytoplasmic D2-40 positive and having a tendency of increased tumorigenicity. The same phenotypic shift was observed in patients with relapsing tumors after chemotherapy. Furthermore, the SP cells were enriched in CD105(-)(/low) expressing cells, which were small sized and had increased tumorigenicity compared with CD105(high) cells. Taken together, our results support the hypothesis that MPM CD105(-)(/low), chemoresistant small sized SP cells may constitute the cellular pool out of which recurrence develops. Further characterization of mechanisms of chemoresistance and self-renewal should lead to targets specific for this subpopulation in MPM patients.


Olfactory lateralization in homing pigeons: a GPS study on birds released with unilateral olfactory inputs.
A large body of evidence has shown that pigeons rely on an olfactory-based navigational map when homing from unfamiliar locations. Previous studies on pigeons released with one nostril occluded highlighted an asymmetry in favour of the right nostril, particularly concerning the initial orientation performance of naïve birds. Nevertheless, all pigeons experiencing only unilateral olfactory input showed impaired homing, regardless of the side of the occluded nostril. So far this phenomenon has been documented only by observing the birds' vanishing bearings. In the present work we recorded the flight tracks of pigeons with previous homing experience equipped with a GPS data logger and released from an unfamiliar location with the right or the left nostril occluded. The analysis of the tracks revealed that the flight path of the birds with the right nostril occluded was more tortuous than that of unmanipulated controls. Moreover, the pigeons smelling with the left nostril interrupted their journey significantly more frequently and displayed more exploratory activity than the control birds, e.g. during flights around a stopover site. These data suggest a more important involvement of the right olfactory system in processing the olfactory information needed for the operation of the navigational map.


What is attention-deficit hyperactivity disorder (ADHD)?
Attention-deficit hyperactivity disorder (ADHD) is described as the most common neurobehavioral condition of childhood. We raise the concern that ADHD is not a disease per se but rather a group of symptoms representing a final common behavioral pathway for a gamut of emotional, psychological, and/or learning problems. Increasing numbers of children, especially boys, are diagnosed with ADHD and treated with stimulant medications according to a simplified approach. Methodical review of the literature, however, raised concerning issues. "Core" ADHD symptoms of inattentiveness, hyperactivity and impulsivity are not unique to ADHD. Rates of "comorbid" psychiatric and learning problems, including depression and anxiety, range from 12 to 60%, with significant symptom overlap with ADHD, difficulties in diagnosis, and evidence-based treatment methods that do not include stimulant medications. No neuropsychologic test result is pathognomic for ADHD, and structural and functional neuroimaging studies have not identified a unique etiology for ADHD. No genetic marker has been consistently identified, and heritability studies are confounded by familial environmental factors. The validity of the Conners' Rating Scale-Revised has been seriously questioned, and parent and teacher "ratings" of school children are frequently discrepant, suggesting that use of subjective informant data via scale or interview does not form an objective basis for diagnosis of ADHD. Empiric diagnostic trials of stimulant medication that produce a behavioral response have been shown not to distinguish between children with and without "ADHD." In summary, the working dogma that ADHD is a disease or neurobehavioral condition does not at this time hold up to scrutiny of evidence. Thorough evaluation of symptomatic children should be individualized, and include assessment of educational, psychologic, psychiatric, and family needs.


Land Use and Family Formation in the Settlement of the U.S. Great Plains.
In agricultural settings, environment shapes patterns of settlement and land use. Using the Great Plains of the United States during the period of its initial Euro-American settlement (1880-1940) as an analytical lens, this article explores whether the same environmental factors that determine settlement timing and land use-those that indicate suitability for crop-based agriculture-also shape initial family formation, resulting in fewer and smaller families in areas that are more conducive to livestock raising than to cropping. The connection between family size and agricultural land availability is now well known, but the role of the environment has not previously been explicitly tested. Descriptive analysis offers initial support for a distinctive pattern of family formation in the western Great Plains, where precipitation is too low to support intensive cropping. However, multivariate analysis using county-level data at 10-year intervals offers only partial support to the hypothesis that environmental characteristics produce these differences. Rather, this analysis has found that the region was also subject to the same long-term social and demographic changes sweeping the rest of the country during this period.


Somatic CALR mutations in myeloproliferative neoplasms with nonmutated JAK2.
Somatic mutations in the Janus kinase 2 gene (JAK2) occur in many myeloproliferative neoplasms, but the molecular pathogenesis of myeloproliferative neoplasms with nonmutated JAK2 is obscure, and the diagnosis of these neoplasms remains a challenge. We performed exome sequencing of samples obtained from 151 patients with myeloproliferative neoplasms. The mutation status of the gene encoding calreticulin (CALR) was assessed in an additional 1345 hematologic cancers, 1517 other cancers, and 550 controls. We established phylogenetic trees using hematopoietic colonies. We assessed calreticulin subcellular localization using immunofluorescence and flow cytometry. Exome sequencing identified 1498 mutations in 151 patients, with medians of 6.5, 6.5, and 13.0 mutations per patient in samples of polycythemia vera, essential thrombocythemia, and myelofibrosis, respectively. Somatic CALR mutations were found in 70 to 84% of samples of myeloproliferative neoplasms with nonmutated JAK2, in 8% of myelodysplasia samples, in occasional samples of other myeloid cancers, and in none of the other cancers. A total of 148 CALR mutations were identified with 19 distinct variants. Mutations were located in exon 9 and generated a +1 base-pair frameshift, which would result in a mutant protein with a novel C-terminal. Mutant calreticulin was observed in the endoplasmic reticulum without increased cell-surface or Golgi accumulation. Patients with myeloproliferative neoplasms carrying CALR mutations presented with higher platelet counts and lower hemoglobin levels than patients with mutated JAK2. Mutation of CALR was detected in hematopoietic stem and progenitor cells. Clonal analyses showed CALR mutations in the earliest phylogenetic node, a finding consistent with its role as an initiating mutation in some patients. Somatic mutations in the endoplasmic reticulum chaperone CALR were found in a majority of patients with myeloproliferative neoplasms with nonmutated JAK2. (Funded by the Kay Kendall Leukaemia Fund and others.).


Whole Genome Analysis of the Red-Crowned Crane Provides Insight into Avian Longevity.
The red-crowned crane (Grus japonensis) is an endangered, large-bodied crane native to East Asia. It is a traditional symbol of longevity and its long lifespan has been confirmed both in captivity and in the wild. Lifespan in birds is known to be positively correlated with body size and negatively correlated with metabolic rate, though the genetic mechanisms for the red-crowned crane's long lifespan have not previously been investigated. Using whole genome sequencing and comparative evolutionary analyses against the grey-crowned crane and other avian genomes, including the long-lived common ostrich, we identified redcrowned crane candidate genes with known associations with longevity. Among these are positively selected genes in metabolism and immunity pathways (NDUFA5, NDUFA8, NUDT12, SOD3, CTH , RPA1, PHAX, HNMT , HS2ST1 , PPCDC , PSTK CD8B, GP9, IL-9R, and PTPRC). Our analyses provide genetic evidence for low metabolic rate and longevity, accompanied by possible convergent adaptation signatures among distantly related large and long-lived birds. Finally, we identified low genetic diversity in the red-crowned crane, consistent with its listing as an endangered species, and this genome should provide a useful genetic resource for future conservation studies of this rare and iconic species.


CovaDOTS: In Silico Chemistry-Driven Tool to Design Covalent Inhibitors Using a Linking Strategy.
We recently reported an integrated fragment-based optimization strategy called DOTS (Diversity Oriented Target-focused Synthesis) that combines automated virtual screening (VS) with semirobotized organic synthesis coupled to in vitro evaluation. The molecular modeling part consists of hit-to-lead chemistry, based on the growing paradigm. Here, we have extended the applicability of the DOTS strategy by adding new functionalities, allowing a generic chemistry-driven linking approach with a particular emphasis on covalent drugs. Indeed, the covalent mode of action can be described as a specific case of linking, where suitable linkers are sought to fuse a bound organic compound with a nucleophilic protein side chain. The proof of concept is established using three retrospective study cases in which known noncovalent inhibitors have been converted to covalent inhibitors. Our method is able to automatically design reference covalent inhibitors (and/or analogs) from an initial activated substructure and predict their binding mode. More importantly, the reference compounds are ranked high among several hundred putative adducts, demonstrating the utility of the approach to design covalent inhibitors.


Happenstance and regulatory culture: the evolution of innovative community mental health services in Oxfordshire in the late twentieth century.
This paper uses co-produced historical material to explore the evolution of two innovative mental healthcare institutions that emerged in Oxfordshire in the 1960s. We highlight how the trajectories of both institutions were driven by chance events occurring within social environments, rather than emerging out of evidence or policy initiatives. Both institutions found a role for spontaneity and an openness to chance in the way they worked. We argue that this kind of institutional history would be unlikely today; the paper develops and uses the concept of regulatory culture to explain why. We suggest that the role of regulatory culture has been neglected in the history of psychiatry.


microRNA-mediated regulation of mTOR complex components facilitates discrimination between activation and anergy in CD4 T cells.
T cell receptor (TCR) signals can elicit full activation with acquisition of effector functions or a state of anergy. Here, we ask whether microRNAs affect the interpretation of TCR signaling. We find that Dicer-deficient CD4 T cells fail to correctly discriminate between activating and anergy-inducing stimuli and produce IL-2 in the absence of co-stimulation. Excess IL-2 production by Dicer-deficient CD4 T cells was sufficient to override anergy induction in WT T cells and to restore inducible Foxp3 expression in Il2-deficient CD4 T cells. Phosphorylation of Akt on S473 and of S6 ribosomal protein was increased and sustained in Dicer-deficient CD4 T cells, indicating elevated mTOR activity. The mTOR components Mtor and Rictor were posttranscriptionally deregulated, and the microRNAs Let-7 and miR-16 targeted the Mtor and Rictor mRNAs. Remarkably, returning Mtor and Rictor to normal levels by deleting one allele of Mtor and one allele of Rictor was sufficient to reduce Akt S473 phosphorylation and to reduce co-stimulation-independent IL-2 production in Dicer-deficient CD4 T cells. These results show that microRNAs regulate the expression of mTOR components in T cells, and that this regulation is critical for the modulation of mTOR activity. Hence, microRNAs contribute to the discrimination between T cell activation and anergy.


Quantifying fenbendazole and its metabolites in self-medicating wild red grouse Lagopus lagopus scoticus using an HPLC-MS-MS approach.
On red grouse estates in the UK the nematode parasite Trichostrongylus tenuis is often controlled by application of grit medicated with the anthelmintic fenbendazole (FBZ). To date, assessment of the efficacy has been inhibited by the inability to quantify uptake of FBZ by the birds. We have developed a simple and sensitive HPLC-MS-MS method for detecting and quantifying FBZ and its metabolites from a 300 mg sample of red grouse liver. This method could be used to improve the efficacy of medicated grit treatment by allowing the identification of conditions and application methods that optimize the uptake of FBZ. With the necessary modifications, our method will also be applicable to other wildlife species where self-medication is used for parasite control.


Analysis of the complete mitochondrial genome sequences of the soybean rust pathogens phakopsora pachyrhizi and p. meibomiae.
The mitochondrial (mt) genomes of two soybean rust pathogens, Phakopsora pachyrhizi and P. meibomiae, have been sequenced. The mt genome of P. pachyrhizi is a circular 31 825-bp molecule with a mean GC content of 34.6%, while P. meibomiae possesses a 32 520-bp circular molecule with a mean GC content of 34.9%. Both mt genomes contain the genes encoding ATP synthase subunits 6, 8 and 9 (atp6, atp8 and atp9), cytochrome oxidase subunits I, II and III (cox1, cox2 and cox3), apocytochrome b (cob), reduced nicotinamide adenine dinucleotide ubiquinone oxidoreductase subunits (nad1, nad2, nad3, nad4, nad4L, nad5 and nad6), the large and small mt ribosomal RNA genes, one ORF coding for a ribosomal protein (rps3), and a set of 24 tRNA genes that recognize codons for all amino acids. The order of the protein-coding genes and tRNA is identical in the two Phakopsora species, and all genes are transcribed from the same DNA strand clockwise. Introns were identified in the cox1, cob and mnl genes of both species, with three of the introns having ORFs with motifs similar to the LAGLIDADG endonucleases of other fungi. Phylogenetic analysis of the 14 shared protein-coding genes agrees with commonly accepted fungal taxonomy.


Secondary structures and intramolecular interactions in fragments of the B-loops of naturally occurring analogs of epidermal growth factor.
Structures of naturally occurring analogs of the B-loop fragment of human epidermal growth factor-like (hEGF-like) polypeptides were examined by molecular dynamics simulation in order to predict their secondary structures, to find structural similarity and to detect any weakly polar aromatic-aromatic (pi-pi) or amide-aromatic (N-pi) interactions which stabilize the structures. NPT molecular dynamics simulations (1 ns) were performed by the GRO-MACS package with SPC/E water using a weak temperature and pressure coupling method. During the sampling time, the structures of all peptides showed a characteristic secondary structure with a turn and bend at residues 4-7, and a beta-sheet, beta-bridge and random coil at the N- and C-terminal regions. Though the peptide chains were flexible, the stabilization effect of the N-pi interactions was indicated in some cases by the angles and distances between the centroids of aromatic planes of the side-chains and the H-atom of peptide bonds and the planes of the aromatic side-chains, respectively. Pi-pi interactions occurred less frequently because of the flexibility of the short peptide chain.


Dominant De Novo Mutations in GJA1 Cause Erythrokeratodermia Variabilis et Progressiva, without Features of Oculodentodigital Dysplasia.
Genetic investigation of inherited skin disorders has informed the understanding of skin self-renewal, differentiation, and barrier function. Erythrokeratodermia variabilis et progressiva (EKVP) is a rare, inherited skin disease that is characterized by transient figurate patches of erythema, localized or generalized scaling, and frequent palmoplantar keratoderma. By using exome sequencing, we show that de novo missense mutations in GJA1 (gap junction protein alpha 1) cause EKVP. The severe, progressive skin disease in EKVP subjects with GJA1 mutations is distinct from limited cutaneous findings rarely found in the systemic disorder oculodentodigital dysplasia, also caused by dominant GJA1 mutations. GJA1 encodes connexin 43 (Cx43), the most widely expressed gap junction protein. We show that the GJA1 mutations in EKVP subjects lead to disruption of Cx43 membrane localization and aggregation within the Golgi. These findings reveal a critical role for Cx43 in epidermal homeostasis, and they provide evidence of organ-specific pathobiology resulting from different mutations within GJA1.


ASE suppression in a high energy Titanium sapphire amplifier.
The energy required to generate ultrashort pulses with petawatt peak power from a Ti:sapphire laser system is a few tens of joules. To achieve this, the final amplifier must have a gain region of around 5 cm diameter that is uniformly pumped at high fluence. The high level of amplified spontaneous emission (ASE) in such an amplifier will seriously degrade its performance unless care is taken to minimise the transverse gain and the internal reflections from the crystal edges. In developing the amplifiers for the Astra Gemini laser system, we have combined the techniques of beam homogenisation and double-pass pumping of a lightly-doped crystal with a new index-matched absorber liquid. Our results demonstrate that this combined approach successfully overcomes the problem of gain depletion by ASE in a high-energy Ti:sapphire amplifier.


Is birth weight a risk factor for ischemic heart disease in later life?
An inverse association between birth weight and ischemic heart disease (IHD) has been seen in observational studies. We wanted to determine the strength and consistency of the association between birth weight and subsequent IHD. We conducted a systematic review of observational studies. Seventeen published studies of birth weight and subsequent IHD were identified that included a total of 144,794 singletons. Relative risk estimates for the association between birth weight and IHD were available from 16 of these studies. Additional data from 2 unpublished studies of 3801 persons were also included. In total, the analyses included data from 18 studies on 4210 nonfatal and 3308 fatal IHD events in 147,009 persons. The mean weighted estimate for the association between birth weight and the combined outcome of nonfatal and fatal IHD was 0.84 (95% CI: 0.81, 0.88) per kilogram of birth weight (P<0.0001). No significant heterogeneity was observed between estimates in different studies (P=0.09), nor was there evidence of publication bias (P=0.3, Begg test). Neither restricting the analysis to fatal IHD events nor adjusting for socioeconomic status had any appreciable effect on the findings. These findings are consistent with a 1 kg higher birth weight being associated with a 10-20% lower risk of subsequent IHD. However, even if causal, interventions to increase birth weight are unlikely to reduce the incidence of IHD materially. Further studies are needed to determine whether the observed association reflects a stronger underlying association with a related exposure or is due (at least in part) to residual confounding.


Diabetic neuropathy.
The global epidemic of prediabetes and diabetes has led to a corresponding epidemic of complications of these disorders. The most prevalent complication is neuropathy, of which distal symmetric polyneuropathy (for the purpose of this Primer, referred to as diabetic neuropathy) is very common. Diabetic neuropathy is a loss of sensory function beginning distally in the lower extremities that is also characterized by pain and substantial morbidity. Over time, at least 50% of individuals with diabetes develop diabetic neuropathy. Glucose control effectively halts the progression of diabetic neuropathy in patients with type 1 diabetes mellitus, but the effects are more modest in those with type 2 diabetes mellitus. These findings have led to new efforts to understand the aetiology of diabetic neuropathy, along with new 2017 recommendations on approaches to prevent and treat this disorder that are specific for each type of diabetes. In parallel, new guidelines for the treatment of painful diabetic neuropathy using distinct classes of drugs, with an emphasis on avoiding opioid use, have been issued. Although our understanding of the complexities of diabetic neuropathy has substantially evolved over the past decade, the distinct mechanisms underlying neuropathy in type 1 and type 2 diabetes remains unknown. Future discoveries on disease pathogenesis will be crucial to successfully address all aspects of diabetic neuropathy, from prevention to treatment.


Gene expression microarray data analysis demystified.
The increasing use of gene expression microarrays, and depositing of the resulting data into public repositories, means that more investigators are interested in using the technology either directly or through meta analysis of the publicly available data. The tools available for data analysis have generally been developed for use by experts in the field, making them difficult to use by the general research community. For those interested in entering the field, especially those without a background in statistics, it is difficult to understand why experimental results can be so variable. The purpose of this review is to go through the workflow of a typical microarray experiment, to show that decisions made at each step, from choice of platform through statistical analysis methods to biological interpretation, are all sources of this variability.


Androgenetic alopecia in the female. Treatment with 2% topical minoxidil solution.
Women generally regard their hair loss as socially unacceptable and go to great measures to conceal their problem. In some cases, the negative self-image brought about by hair loss may be the basis of psychiatric illness. The purpose of this study was to evaluate a 2% topical minoxidil solution (Rogaine/Regaine, The Upjohn Co, Kalamazoo, Mich) for the treatment of female androgenetic alopecia. A 32-week, double-blind, placebo-controlled trial was conducted in 11 US centers. Three hundred eight women with androgenetic alopecia were enrolled. Two hundred fifty-six of these women completed the trial. A refined photographic technique was used to objectively determine the number of nonvellus hairs regrown. After 32 weeks of treatment, the number of nonvellus hairs in a 1-cm2 evaluation site was increased by an average of 23 hairs in the 2% minoxidil group and by an average of 11 hairs in the placebo group. The 95% confidence interval for the difference in mean hair count change between the treatment groups was 5.9 to 17.5 hairs. The investigators determined that 13% in the minoxidil-treated group had moderate growth and 50% had minimal growth. This compared with 6% and 33%, respectively, in the placebo-treated group. Similarly, 60% of the patients in the 2% minoxidil group reported that they had new hair growth (20% moderate, 40% minimal) compared with 40% (7% moderate, 33% minimal) of the patients in the placebo group. No evaluations of dense hair growth were reported for either treatment group. No clinically significant changes in vital signs were observed and no serious or unexpected medical events were reported. Topical minoxidil was significantly more effective than placebo in the treatment of female androgenetic alopecia.


Real-time phase-resolved optical coherence tomography and optical Doppler tomography.
We have developed a novel real-time phase-resolved optical coherence tomography (OCT) and optical Doppler tomography (ODT) system using optical Hilbert transformation. By combining circularly polarized reference and linearly polarized sample signals, in-phase and quadrature interference components are produced in separate channels and treated as the real and imaginary parts of a complex signal to obtain the phase information directly. Using a resonant scanner at an axial scanning speed of 4 kHz in the reference arm of the interferometer, both structure and blood flow velocity images with 200 axial scans can be acquired at 20 frames per second with high sensitivity and large dynamic range. Real-time videos of in vivo blood flow in the chick chorioallantoic membrane using this interferometer are presented.


End-of-life decision-making for patients admitted through the emergency department: hospital variability, patient demographics, and changes over time.
Early studies suggest that racial, economic, and hospital-based factors influence the do-not-attempt-resuscitation (DNAR) status of admitted patients, although it remains unknown how these factors apply to patients admitted through the emergency department (ED) and whether use is changing over time. The objective was to examine patient and hospital attributes associated with DNAR orders placed within 24 hours of admission through the ED and changes in DNAR use over time. This was a population-based, retrospective cross-sectional study of patients 65 years and older admitted to 367 acute care hospitals in California between 2002 and 2010; the subset of patients admitted through the ED formed the primary sample. The primary outcome was placement of a DNAR order within 24 hours of admission. Associations between DNAR order placement and hospital characteristics, patient demographics, and year were tested. Descriptive statistics are reported, and multivariable logistic regression models with generalized estimating equations (GEEs) were used to account for clustering within hospitals. There were 9,507,921 patients older than 65 years admitted to 367 California hospitals over the 9-year period, of whom 1,029,335 (10.8%) had DNAR orders placed within 24 hours of admission; 83% of DNAR orders were placed for patients admitted through the ED. Among patients over 65 years admitted through the ED (n = 6,396,910), DNAR orders were used less frequently at teaching hospitals (9.5% vs. 13.7%), for-profit hospitals (8.6% vs. 14.6% nonprofit), nonrural hospitals (12.0% vs. 26.2%), and large hospitals (11.1% vs. 15.0% for hospitals in the smallest quartile for bed size; all p < 0.0001). In regression modeling adjusted for clustering and patient demographics, these trends persisted for all hospital types, except teaching hospitals. Decreased DNAR frequency was associated with race (African American odds ratio [OR] = 0.59, 95% confidence interval [CI] = 0.51 to 0.67; Asian OR = 0.70, 95% CI = 0.59 to 0.82; reference = white), ethnicity (Hispanic OR = 0.61, 95% CI = 0.55 to 0.68), sex (male OR = 0.90, 95% CI = 0.88 to 0.92), and MediCal insurance (OR = 0.70, 95% CI = 0.57 to 0.85). Statewide rates of DNAR steadily increased from 12.2% in 2002 to 14.3% in 2010, although this trend occurred primarily among white and Asian patients. While statewide rates of DNAR use have increased over time among patients admitted through the ED, there is variable penetrance of this practice by hospital types, patient race, and patient ethnicity. These patterns may suggest barriers to end-of-life discussions, differences in hospital case mix, and variation in cultural or institutional beliefs and practices.


Disruption of the peroxisomal citrate synthase CshA affects cell growth and multicellular development in Dictyostelium discoideum.
Non-mitochondrial citrate synthase catalyses citrate synthesis in the glyoxylate cycle in gluconeogenesis. Screening Dictyostelium discoideum mutants generated by insertional mutagenesis isolated a poor-growing mutant that displayed aberrant developmental morphology on bacterial lawns. Axenically grown mutants developed normally and formed mature fruiting bodies on buffered agar. The affected locus encoded a novel protein (CshA) that was homologous to glyoxysomal citrate synthase. cshA was expressed maximally during vegetative growth and gradually decreased through subsequent developmental stages. An in vitro citrate synthase assay revealed that cshA disruption resulted in a 50% reduction in enzyme activity, implicating CshA as an active citrate synthase. The amino-terminus of CshA was found to have an atypical mitochondrial targeting signal, instead containing a unique nonapeptide sequence (RINILANHL) that was homologous to the conserved peroxisomal targeting signal 2 (PTS2). CshA protein was shown to be localized in the peroxisomes, and the RINILANHL sequence only efficiently targeted the peroxisomal green fluorescent protein. The growth defect of cshA(-) cells was associated with the impairment of phagocytosis and fluid-phase endocytosis, independent from cytokinesis. Disrupted multicellular development on bacterial lawns resulted from the abnormal susceptibility to the environmental conditions, perhaps because of citrate insufficiency. Taken together, these results provide new insights into the function of peroxisomal citrate synthase in cell growth and multicellular development.


White matter injury in the preterm infant: pathology and mechanisms.
The human preterm brain is particularly susceptible to cerebral white matter injury (WMI) that disrupts the normal progression of developmental myelination. Advances in the care of preterm infants have resulted in a sustained reduction in the severity of WMI that has shifted from more severe focal necrotic lesions to milder diffuse WMI. Nevertheless, WMI remains a global health problem and the most common cause of chronic neurological morbidity from cerebral palsy and diverse neurobehavioral disabilities. Diffuse WMI involves maturation-dependent vulnerability of the oligodendrocyte (OL) lineage with selective degeneration of late oligodendrocyte progenitors (preOLs) triggered by oxidative stress and other insults. The magnitude and distribution of diffuse WMI are related to both the timing of appearance and regional distribution of susceptible preOLs. Diffuse WMI disrupts the normal progression of OL lineage maturation and myelination through aberrant mechanisms of regeneration and repair. PreOL degeneration is accompanied by early robust proliferation of OL progenitors that regenerate and augment the preOL pool available to generate myelinating OLs. However, newly generated preOLs fail to differentiate and initiate myelination along their normal developmental trajectory despite the presence of numerous intact-appearing axons. Disrupted preOL maturation is accompanied by diffuse gliosis and disturbances in the composition of the extracellular matrix and is mediated in part by inhibitory factors derived from reactive astrocytes. Signaling pathways implicated in disrupted myelination include those mediated by Notch, WNT-beta catenin, and hyaluronan. Hence, there exists a potentially broad but still poorly defined developmental window for interventions to promote white matter repair and myelination and potentially reverses the widespread disturbances in cerebral gray matter growth that accompanies WMI.


School and Teacher Factors That Promote Adolescents' Bystander Responses to Social Exclusion.
Schools may be one important context where adolescents learn and shape the behaviors necessary for promoting global inclusivity in adulthood. Given the importance of bystanders in halting bullying and peer aggression, the focus of this study is on both moral judgments regarding one type of bullying, social exclusion, and factors that are associated with bystander intervention. The study includes 896 adolescents, who were 6th (N = 450, M age = 11.73), and 9th (N = 446, M age = 14.82) graders, approximately evenly divided by gender. Participants were primarily European-American (63.3%). Results revealed that girls and participants who perceived better relationships between students and teachers were more likely to judge exclusion to be wrong. Further, ethnic minority participants, those who were more anxious about being rejected by their teachers and reported more teacher discrimination were less likely to judge exclusion as wrong. Participants who reported more positive student-teacher relationships, perceptions of a more positive school social environment and more prior experiences of teacher discrimination were more likely to report that they would seek help for the victim. On the other hand, participants who reported being more angry about teacher rejection, experiencing either peer or teacher discrimination, and perceiving they are excluded from opportunities at school were less likely to intervene to come to the aid of a peer who is being excluded. The results document the complex interplay of school and teacher factors in shaping adolescents' bystander responses to social exclusion. Our findings suggest that positive school climate can promote intentions to intervene. However, findings indicate that adolescents who are marginalized in their school environments, and who report experiences of rejection, exclusion or discrimination are not willing or likely to intervene to prevent others from experiencing exclusion.


Expression, purification and crystallization of a lyssavirus matrix (M) protein.
The matrix (M) proteins of lyssaviruses (family Rhabdoviridae) are crucial to viral morphogenesis as well as in modulating replication and transcription of the viral genome. To date, no high-resolution structural information has been obtained for full-length rhabdovirus M. Here, the cloning, expression and purification of the matrix proteins from three lyssaviruses, Lagos bat virus (LAG), Mokola virus and Thailand dog virus, are described. Crystals have been obtained for the full-length M protein from Lagos bat virus (LAG M). Successful crystallization depended on a number of factors, in particular the addition of an N-terminal SUMO fusion tag to increase protein solubility. Diffraction data have been recorded from crystals of native and selenomethionine-labelled LAG M to 2.75 and 3.0 A resolution, respectively. Preliminary analysis indicates that these crystals belong to space group P6(1)22 or P6(5)22, with unit-cell parameters a = b = 56.9-57.2, c = 187.9-188.6 A, consistent with the presence of one molecule per asymmetric unit, and structure determination is currently in progress.


Exome sequencing links mutations in PARN and RTEL1 with familial pulmonary fibrosis and telomere shortening.
Idiopathic pulmonary fibrosis (IPF) is an age-related disease featuring progressive lung scarring. To elucidate the molecular basis of IPF, we performed exome sequencing of familial kindreds with pulmonary fibrosis. Gene burden analysis comparing 78 European cases and 2,816 controls implicated PARN, an exoribonuclease with no previous connection to telomere biology or disease, with five new heterozygous damaging mutations in unrelated cases and none in controls (P = 1.3 × 10(-8)); mutations were shared by all affected relatives (odds in favor of linkage = 4,096:1). RTEL1, an established locus for dyskeratosis congenita, harbored significantly more new damaging and missense variants at conserved residues in cases than in controls (P = 1.6 × 10(-6)). PARN and RTEL1 mutation carriers had shortened leukocyte telomere lengths, and we observed epigenetic inheritance of short telomeres in family members. Together, these genes explain ~7% of familial pulmonary fibrosis and strengthen the link between lung fibrosis and telomere dysfunction.


The β3-adrenoceptor mediates the inhibitory effects of β-adrenoceptor agonists via the urothelium in pig bladder dome.
Relaxation of detrusor muscle via β-adrenoceptors may contribute to urine storage during bladder filling. Thus there is increasing interest in β-adrenoceptor agonists as a potential treatment for detrusor overactivity. The role of the urothelium in bladder responses to β-adrenoceptor agonists is not yet clear, although we have shown that these agonists have a greater inhibitory effect on detrusor contraction when the urothelium is intact. The aim was to determine which β-adrenoceptor subtype is involved in this effect. Paired strips of pig bladder dome mucosa-intact and mucosa-denuded, were mounted in tissue baths. Relaxation responses were obtained to β-adrenoceptor agonists (isoprenaline, dobutamine, salbutamol or BRL37344) in carbachol pre-contracted tissues. Inhibitory effects were studied by obtaining concentration-response curves (CRCs) to carbachol in the presence and absence of β-adrenoceptor agonists. The inhibitory effects of isoprenaline were also studied following incubation with β-adrenoceptor antagonists (propranolol, CGP20712, ICI-118, 551 or SR 59230A; non selected, β(1), β(2) and β(3) selective respectively). isoprenaline, dobutamine, salbutamol and BRL37344 all relaxed carbachol pre-contracted tissues and responses were similar in intact and denuded strips. In inhibition experiments, β-adrenoceptor agonists caused rightward shifts of carbachol CRCs. In intact strips the shift was greater with isoprenaline and BRL37344, but not with dobutamine or salbutamol. This increased shift was still observed in tissues pre-incubated with propranolo, CGP20712 and ICI-118, 551, but not with SR 59230A. β(3)-adrenoceptors are involved in mediating inhibitory effects of β-adrenoceptor agonists on detrusor contractions via the urothelium in pig bladder dome.


The future of outcomes measurement: item banking, tailored short-forms, and computerized adaptive assessment.
The use of item banks and computerized adaptive testing (CAT) begins with clear definitions of important outcomes, and references those definitions to specific questions gathered into large and well-studied pools, or "banks" of items. Items can be selected from the bank to form customized short scales, or can be administered in a sequence and length determined by a computer programmed for precision and clinical relevance. Although far from perfect, such item banks can form a common definition and understanding of human symptoms and functional problems such as fatigue, pain, depression, mobility, social function, sensory function, and many other health concepts that we can only measure by asking people directly. The support of the National Institutes of Health (NIH), as witnessed by its cooperative agreement with measurement experts through the NIH Roadmap Initiative known as PROMIS (www.nihpromis.org), is a big step in that direction. Our approach to item banking and CAT is practical; as focused on application as it is on science or theory. From a practical perspective, we frequently must decide whether to re-write and retest an item, add more items to fill gaps (often at the ceiling of the measure), re-test a bank after some modifications, or split up a bank into units that are more unidimensional, yet less clinically relevant or complete. These decisions are not easy, and yet they are rarely unforgiving. We encourage people to build practical tools that are capable of producing multiple short form measures and CAT administrations from common banks, and to further our understanding of these banks with various clinical populations and ages, so that with time the scores that emerge from these many activities begin to have not only a common metric and range, but a shared meaning and understanding across users. In this paper, we provide an overview of item banking and CAT, discuss our approach to item banking and its byproducts, describe testing options, discuss an example of CAT for fatigue, and discuss models for long term sustainability of an entity such as PROMIS. Some barriers to success include limitations in the methods themselves, controversies and disagreements across approaches, and end-user reluctance to move away from the familiar.


Molecular basis of severe gynecomastia associated with aromatase expression in a fibrolamellar hepatocellular carcinoma.
This report represents the first study in the literature linking development of severe gynecomastia, in a 17 1/2-yr-old boy, to high levels of aromatase expression in a large fibrolamellar hepatocellular carcinoma, which gave rise to extremely elevated serum levels of estrone (1200 pg/mL) and estradiol-17 beta (312 pg/mL) that suppressed FSH and LH (1.3 and 2.8 IU/L, respectively), and consequently testosterone (1.53 ng/mL). After removal of a 1.5-kg hepatocellular carcinoma, gynecomastia partially regressed, and essentially, normal hormone levels were restored (estradiol-17 beta, < 50 pg/mL; estrone, 74 pg/mL; testosterone, 6.85 ng/mL; and FSH/LH, 6.3/3.7 mIU/mL). Conversion of C19 steroids to estrogens occurs in a number of human tissues and is catalyzed by aromatase P450 (P450arom), the product of the CYP19 gene in a number of human tissues. Tissue-specific promoters are used to regulate P450arom gene transcription in adult human tissues, e.g. promoters I.4 and I.3 in adipose fibroblasts, and promoter II in the gonads. Human fetal liver uses promoter I.4 to express markedly high levels of P450arom, whereas hepatic P450arom expression normally becomes undetectable in postnatal life. Using immunohistochemistry, diffuse intracytoplasmic aromatase expression was detected in the liver cancer cells from this severely feminized boy. Northern analysis indicated the presence of P450arom transcripts in total RNA from the hepatocellular cancer but not in the adjacent liver nor in disease-free adult liver samples. Promoter use for aromatase expression was determined by a specific RT-PCR method. Promoters I.3 and II were used for P450arom gene expression in the hepatocellular cancer tissue. Because aromatase is not expressed in the disease-free adult liver, the presence of extremely high levels of aromatase expression in this fibrolamellar hepatocellular carcinoma tissue is intriguing, particularly because there is preferential use of the proximally located P450arom promoters I.3 and II by the tumor, instead of the much more distally located fetal liver-type promoter I.4.


Extent of tibiofemoral osteoarthritis before knee arthroplasty: multicenter data from the osteoarthritis initiative.
Knee arthroplasty traditionally is recommended for persons with substantial disability and disabling pain attributable to moderate or severe osteoarthritis (OA). Pain and functional status after arthroplasty may be influenced by the extent of knee OA before surgery and recent evidence suggests persons with less severe knee OA before undergoing TKA have greater pain levels and worse function than persons with more severe knee OA. We determined the proportion of patients undergoing knee arthroplasty who had less than moderate knee OA before surgery and who had either a radiographically normal medial or lateral joint space before surgery. One hundred sixteen persons in the Osteoarthritis Initiative underwent knee arthroplasty during a 3-year period. Ninety-seven of the 116 patients (84%) had radiographs available less than 1 year before surgery and were included. We used Z-tests to determine whether the proportion of patients with a modified Kellgren-Lawrence (KL) grade of 3 or higher differed from literature-based estimates. In addition, we described the proportion of patients with medial and lateral joint space narrowing. The proportion of patients with a modified KL grade of 3 or higher was 0.81 (95% CI, 0.73-0.89) and was less than the 0.95 estimated population proportion. Of the patients who underwent knee arthroplasty, 85% (82 of 97 knee arthroplasties) had at least one tibiofemoral joint compartment that had no joint space narrowing. One in six patients with OA who underwent knee arthroplasty had a KL grade of 2 or lower. Variation in the extent of tibiofemoral OA in patients preparing for joint arthroplasty is greater than previously described. A greater percentage of patients undergoing knee arthroplasty may be at risk for increased pain and poorer function than previously assumed after surgery because of less severe knee OA before surgery. Level I, diagnostic study. See Guidelines for Authors for a complete description of levels of evidence.


Dysfunction of the mTOR pathway is a risk factor for Alzheimer's disease.
The development of disease-modifying therapies for Alzheimer's disease is hampered by our lack of understanding of the early pathogenic mechanisms and the lack of early biomarkers and risk factors.We have documented the expression pattern of mTOR regulated genes in the frontal cortex of Alzheimer's disease patients. We have also examined the functional integrity of mTOR signaling in peripheral lymphocytes in Alzheimer's disease patients relative to healthy controls. In the brain mTOR is seen to control molecular functions related to cell cycle regulation, cell death and several metabolic pathways. These downstream elements of the mTOR signaling cascade are deregulated in the brain of Alzheimer's disease patients well before the development of pathology. This dysregulation of the mTOR downstream signaling cascade is not restricted to the brain but appears to be systemic and can be detected in peripheral lymphocytes as a reduced Rapamycin response. The dysfunction of the signaling pathways downstream of mTOR may represent a risk factor for Alzheimer's disease and is independent of the ApoE status of the patients.We have also identified the molecular substrates of the beneficial effects of Rapamycin on the nervous system. We believe that these results can further inform the development of clinical predictive tests for the risk of Alzheimer's disease in patients with mild cognitive impairment.


Fc gamma receptor 3B (FCGR3B-c.233C>A-rs5030738) polymorphism modifies the protective effect of malaria specific antibodies in Ghanaian children.
Immunoglobulin G (IgG) cross-linking with Fc gamma receptor IIIB (FcγRIIIB) triggers neutrophil degranulation, releasing reactive oxygen species with high levels associated with protection against malaria. The FCGR3B-c.233C>A polymorphism thought to influence the interaction between IgG and FcγRIIIB was recently associated with malaria. We studied the statistical interaction between glutamate rich protein antibodies and FCGR3B-c.233C>A genotypes on risk of malaria in a cohort of Ghanaian children. The absolute risk of malaria decreased more rapidly with increasing antibody levels for 233AA/AC individuals compared with 233CC children. This genotype related effect modification may significantly influence malaria sero-epidemiological and vaccine trial studies.


Intersectionality and underrepresentation among health care workforce: the case of Arab physicians in Israel.
An intersectionality approach that addresses the non-additive influences of social categories and power structures, such as gender and ethnicity, is used as a research paradigm to further understanding the complexity of health inequities. While most researchers adopt an intersectionality approach to study patients' health status, in this article we exemplify its usefulness and importance for studying underrepresentation in the health care workforce. Our research objectives were to examine gender patterns of underrepresentation in the medical profession among the Arab minority in Israel. We used both quantitative and qualitative methodologies. The quantitative data were obtained from the 2011 Labor Force Survey conducted by the Israeli Central Bureau of Statistics, which encompassed some 24,000 households. The qualitative data were obtained through ten semi-structured, in-depth interviews conducted during 2013 with Arab physicians and with six nurses working in Israeli hospitals. The findings indicate that with respect to physicians, the Arab minority in Israel is underrepresented in the medical field, and that this is due to Arab women's underrepresentation. Arab women's employment and educational patterns impact their underrepresentation in medicine. Women are expected to enter traditional gender roles and conform to patriarchal and collectivist values, which makes it difficult for them to study medicine. Using an intersectionality approach to study underrepresentation in medicine provides a foundation for action aimed at improving public health and reducing health disparities.


Mass-selective soft-landing of protein assemblies with controlled landing energies.
Selection and soft-landing of bionanoparticles in vacuum is potentially a preparative approach to separate heterogeneous mixtures for high-resolution structural study or to deposit homogeneous materials for nanotechnological applications. Soft-landing of intact protein assemblies however remains challenging, due to the difficulties of manipulating these heavy species in mass-selective devices and retaining their structure during the experiment. We have developed a tandem mass spectrometer with the capability for controlled ion soft-landing and ex situ visualization of the soft-landed particles by means of transmission electron microscopy. The deposition conditions can be controlled by adjusting the kinetic energies of the ions by applying accelerating or decelerating voltages to a set of ion-steering optics. To validate this approach, we have examined two cage-like protein complexes, GroEL and ferritin, and studied the effect of soft-landing conditions on the method's throughput and the preservation of protein structure. Separation, based on mass-to-charge ratio, of holo- and apo-ferritin complexes after electrospray ionization enabled us to soft-land independently the separated complexes on a grid suitable for downstream transmission electron microscopy analysis. Following negative staining, images of the soft-landed complexes reveal that their structural integrity is largely conserved, with the characteristic central cavity of apoferritin, and iron core of holoferritin, surviving the phase transition from liquid to gas, soft-landing, and dehydration in vacuum.


Position of the American Dietetic Association: nutrition and lifestyle for a healthy pregnancy outcome.
It is the position of the American Dietetic Association that women of child-bearing ages should maintain good nutritional status through a lifestyle that optimizes maternal health and reduces the risk of birth defects, suboptimal fetal growth and development, and chronic health problems in their children. The key components of a health-promoting lifestyle during pregnancy include appropriate weight gain; appropriate physical activity; consumption of a variety of foods in accordance with the Dietary Guidelines for Americans 2005; appropriate and timely vitamin and mineral supplementation; avoidance of alcohol, tobacco, and other harmful substances; and safe food handling. Pregnant women with inappropriate weight gain, hyperemesis, poor dietary patterns, phenylketonuria, certain chronic health problems, or a history of substance abuse should be referred to a registered dietitian for medical nutrition therapy. Prenatal weight gain within the Institute of Medicine recommended ranges has been associated with better pregnancy outcomes. Most pregnant women need 2,200 to 2,900 kcal a day, but prepregnancy body mass index, rate of weight gain, maternal age, and appetite must be considered when tailoring this recommendation to the individual. The consumption of more food to meet energy needs, and the increased absorption and efficiency of nutrient utilization that occurs in pregnancy, are generally adequate to meet the needs for most nutrients. However, vitamin and mineral supplementation is appropriate for some nutrients and situations. This position paper also includes recommendations pertaining to use of alcohol, tobacco, caffeine, and illicit drugs.


Effects of tadalafil on hemorrhagic cystitis and testicular dysfunction induced by cyclophosphamide in rats.
The protective and/or therapeutic potential of tadalafil (TDL) on cyclophosphamide (CP)-induced hemorrhagic cystitis (HC) and testicular dysfunction in rats was evaluated. The animals except from the control group were divided into four groups and treated with saline, or 1, 5 or 10 mg/kg TDL orally (CP, TDL1, TDL5 and TDL10 groups, respectively) before and after CP injection. Body and organ weights, sperm count, cGMP, nitric oxide (NO), IL-6 and IL-10 levels in serum and bladder tissue, and serum testosterone (T), LH and FSH levels were determined. The histological analysis of bladder and testis was performed and the number of apoptotic cells was determined. The CP group had decreased cGMP and NO levels in the bladder, serum T level (p < 0.05) and sperm count (p < 0.001) and higher IL-6 levels in serum and bladder (p < 0.01). Treatment with TDL resulted in increased cGMP (p < 0.001), NO (p < 0.05) and serum T (p < 0.05) levels. Histological analysis of the CP group showed severe HC in bladder and testicular damage. TDL-treated animals showed a dose-dependent improvement in all of these histological impairments. In conclusion, a selective inhibitor of phosphodiesterase-5 enzyme, TDL, showed a protective and/or therapeutic effect on CP-induced HC and testicular dysfunction in rats.


Metacognition in patients with anorexia nervosa, dieting and non-dieting women: a preliminary study.
To explore metacognition in women with anorexia nervosa (AN), dieting and non-dieting women. A cross-sectional study between groups design compared women with AN (n = 15), normal dieters (n = 17) and non-dieters (n = 18). A semi-structured interview was used to explore presence and content of explicit metacognitions and use of metacognitive control strategies. Explicit metacognitions and metacognitive control strategies were present in all three groups of women. There were group differences in amount and function of metacognitive activity and trends in the qualitative data suggested participants with AN believed that their thoughts were abnormal and uncontrollable. They used six metacognitive strategies more than control groups and were less successful at using thought re-appraisal and attending to body and others. Half of participants with AN reported using these strategies to deliberately make themselves feel worse. It is suggested that metacognitive activity may play a role in the maintenance of AN, particularly in reinforcing negative self-evaluations.


Contextual processing of abstract concepts reveals neural representations of nonlinguistic semantic content.
Concepts develop for many aspects of experience, including abstract internal states and abstract social activities that do not refer to concrete entities in the world. The current study assessed the hypothesis that, like concrete concepts, distributed neural patterns of relevant nonlinguistic semantic content represent the meanings of abstract concepts. In a novel neuroimaging paradigm, participants processed two abstract concepts (convince, arithmetic) and two concrete concepts (rolling, red) deeply and repeatedly during a concept-scene matching task that grounded each concept in typical contexts. Using a catch trial design, neural activity associated with each concept word was separated from neural activity associated with subsequent visual scenes to assess activations underlying the detailed semantics of each concept. We predicted that brain regions underlying mentalizing and social cognition (e.g., medial prefrontal cortex, superior temporal sulcus) would become active to represent semantic content central to convince, whereas brain regions underlying numerical cognition (e.g., bilateral intraparietal sulcus) would become active to represent semantic content central to arithmetic. The results supported these predictions, suggesting that the meanings of abstract concepts arise from distributed neural systems that represent concept-specific content.


Bone mineral density is associated with left ventricular diastolic function in women.
Low bone mineral density (BMD) and left ventricular (LV) diastolic function are associated with heart failure. However, little is known about the association between BMD and LV diastolic function. BMD is independently related to LV diastolic function in women. We conducted a cross-sectional study of 432 women. Brachial-ankle pulse wave velocity (baPWV) and BMD measurements were performed. LV diastolic function and structure were assessed by echocardiographic examination. BaPWV and the percentage of LV diastolic dysfunction increased with progressive bone loss. Moreover, partial correlation analysis demonstrated that BMD at spine L2-4 and at femoral neck were correlated with baPWV and LV diastolic function parameters after adjusting covariates. Multivariate logistic regression analysis revealed that osteoporosis was independently associated with LV diastolic dysfunction in women. Osteoporosis is independently associated with LV diastolic dysfunction in women. A prospective study is needed to elucidate the effects of BMD on cardiac function in women.


Nodule excitability in an animal model of periventricular nodular heterotopia: c-fos activation in organotypic hippocampal slices.
Aberrations in brain development may lead to dysplastic structures such as periventricular nodules. Although these abnormal collections of neurons are often associated with difficult-to-control seizure activity, there is little consensus regarding the epileptogenicity of the nodules themselves. Because one common treatment option is surgical resection of suspected epileptic nodules, it is important to determine whether these structures in fact give rise, or essentially contribute, to epileptic activities. To study the excitability of aberrant nodules, we have examined c-fos activation in organotypic hippocampal slice cultures generated from an animal model of periventricular nodular heterotopia created by treating pregnant rats with methylazoxymethanol acetate. Using this preparation, we have also attempted to assess tissue excitability when the nodule is surgically removed from the culture. We then compared c-fos activation in this in vitro preparation to c-fos activation generated in an intact rat treated with kainic acid. Quantitative analysis of c-fos activation failed to show enhanced nodule excitability compared to neocortex or CA1 hippocampus. However, when we compared cultures with and without a nodule, presence of a nodule did affect the excitability of CA1 and cortex, at least as reflected in c-fos labeling. Surgical removal of the nodule did not result in a consistent decrease in excitability as reflected in the c-fos biomarker. Our results from the organotypic culture were generally consistent with our observations on excitability in the intact rat-as seen not only with c-fos but also in previous electrophysiologic studies. At least in this model, the nodule does not appear to be responsible for enhanced excitability (or, presumably, seizure initiation). Excitability is different in tissue that contains a nodule, suggesting altered network function, perhaps reflecting the abnormal developmental pattern that gave rise to the nodule.


Pain among children and adolescents: restrictions in daily living and triggering factors.
Pain among children and adolescents has been identified as an important public health problem. Most studies evaluating recurrent or chronic pain conditions among children have been limited to descriptions of pain intensity and duration. The effects of pain states and their impact on daily living have rarely been studied. The objective of this study was to investigate the impact of perceived pain on the daily lives and activities of children and adolescents. In addition, we sought to delineate self-perceived triggers of pain among children and adolescents. In this study, we (1) document the 3-month prevalence of painful conditions among children and adolescents, (2) delineate their features (location, intensity, frequency, and duration), (3) describe their consequences (restrictions and health care utilization), and (4) elucidate factors that contribute to the occurrence of pain episodes among young subjects. The study was conducted in 1 elementary school and 2 secondary schools in the district of Ostholstein, Germany. Children and adolescents, as well as their parents/guardians, were contacted through their school administrators. The teachers distributed an information leaflet, explaining the conduct and aim of the study, to the parents a few days before the official enrollment of the youths in the study. Parents of children in grades 1 to 4 of elementary school were asked to complete the pain questionnaire for their children at home, whereas children from grade 5 upward completed the questionnaire on their own during class, under the supervision of their teachers. The response rate was 80.3%. As previously stated, chronic pain was defined as any prolonged pain that lasted a minimum of 3 months or any pain that recurred throughout a minimal period of 3 months. The children and adolescents were surveyed with the Luebeck Pain-Screening Questionnaire, which was specifically designed for an epidemiologic study of the characteristics and consequences of pain among children and adolescents. The questionnaire evaluates the prevalence of pain in the preceding 3 months. The body area, frequency, intensity, and duration of pain are addressed by the questionnaire. In addition, the questionnaire inquires about the private and public consequences of pain among young subjects. Specifically, the questionnaire aims to delineate the self-perceived factors for the development and maintenance of pain and the impact of these conditions on daily life. Of the 749 children and adolescents, 622 (83%) had experienced pain during the preceding 3 months. A total of 30.8% of the children and adolescents stated that the pain had been present for >6 months. Headache (60.5%), abdominal pain (43.3%), limb pain (33.6%), and back pain (30.2) were the most prevalent pain types among the respondents. Children and adolescents with pain reported that their pain caused the following sequelae: sleep problems (53.6%), inability to pursue hobbies (53.3%), eating problems (51.1%), school absence (48.8%), and inability to meet friends (46.7%). The prevalence of restrictions in daily living attributable to pain increased with age. A total of 50.9% of children and adolescents with pain sought professional help for their conditions, and 51.5% reported the use of pain medications. The prevalence of doctor visits and medication use increased with age. Weather conditions (33%), illness (30.7%), and physical exertion (21.9%) were the most frequent self-perceived triggers for pain noted by the respondents. A total of 30.4% of study participants registered headache as the most bothersome pain, whereas 12.3% cited abdominal pain, 10.7% pain in the extremities, 8.9% back pain, and 3.9% sore throat as being most bothersome. A total of 35.2% of children and adolescents reported pain episodes occurring > or =1 time per week or even more often. Health care utilization because of pain differed among children and adolescents according to the location of pain. Children and adolescents with back pain (56.7%), limb pain (55.0%), and abdominal pain (53.3%) visited a doctor more often than did those with headache (32.5%). In contrast, children and adolescents with headache (59.2%) reported taking medication because of pain more often than did those with back pain (16.4%), limb pain (22.5%), and abdominal pain (38.0%). The prevalence of self-reported medication use and doctor visits because of pain increased significantly with age (chi2 test). The prevalence of self-reported medication use was significantly higher among girls than among boys of the same age, except between the ages of 4 and 9 years (chi2 test). The prevalence of restrictions in daily activities varied among children and adolescents with different pain locations; 51.1% of children and adolescents with abdominal pain and 43.0% with headache but only 19.4% with back pain reported having been absent from school because of pain. The prevalence of restrictions attributable to pain was significantly higher among girls than among boys of the same age, except between the ages of 4 and 9 years (chi2 test). The self-reported triggers for pain varied between girls and boys. Girls stated more often than boys that their pain was triggered by weather conditions (39% vs 25%), illness (eg, common cold or injury) (35.9% vs 23.9%), anger/disputes (20.9% vs 11.9%), family conditions (12.1% vs 5.2%), and sadness (11.9% vs 3.4%). In contrast, boys stated more often than girls that their pain was triggered by physical exertion (28% vs 17.2%). We used a logistic regression model to predict the likelihood of a child paying a visit to the doctor and/or using pain medication. Health care utilization was predicted by increasing age, greater intensity of pain, and longer duration of pain but not by the frequency of pain. We used a logistic regression model to predict restrictions in daily activities. Only the intensity of pain was predictive of the degree of restrictions in daily life attributable to pain; the duration of pain and the frequency of pain episodes had no bearing on the degree to which the daily lives of the children were restricted because of pain. More than two thirds of the respondents reported restrictions in daily living activities attributable to pain. However, 30 to 40% of children and adolescents with pain reported moderate effects of their pain on school attendance, participation in hobbies, maintenance of social contacts, appetite, and sleep, as well as increased utilization of health services because of their pain. Restrictions in daily activities in general and health care utilization because of pain increased with age. Girls > or =10 years of age reported more restrictions in daily living and used more medications for their pain than did boys of the same age. We found gender-specific differences in self-perceived triggers for pain. Pain intensity was the most robust variable for predicting functional impairment in > or =1 areas of daily life. Increasing age of the child and increasing intensity and duration of pain had effects in predicting health care utilization (visiting a doctor and/or taking medication), whereas restrictions in daily activities were predicted only by the intensity of pain. Our results underscore the relevance of pediatric pain for public health policy. Additional studies are necessary and may enhance our knowledge about pediatric pain, to enable parents, teachers, and health care professionals to assist young people with pain management, allowing the young people to intervene positively in their conditions before they become recurrent or persistent.


Biomechanical Comparison of Intramedullary Screw Versus Low-Profile Plate Fixation of a Jones Fracture.
Intramedullary screw fixation of fifth metatarsal Jones fractures often produces satisfactory results, however, nonunion and refracture rates are not negligible. The low-profile "hook" plate is an alternative fixation method that has been promoted to offer improved rotational control at the fracture site, but this remains to be proven. The purpose of this study was to document biomechanical performance differences between this type of plate and a contemporary solid, dual-pitch intramedullary screw in a cadaveric Jones fracture model. Simulated Jones fractures were created in 8 matched pairs of fresh-frozen cadaveric fifth metatarsals. One bone from each pair was stabilized using an intramedullary TriMed Jones Screw and the other using a TriMed Jones Fracture Plate (TriMed, Inc, Santa Clarita, CA). Controlled bending and torsional loads were applied. Bending stiffness and fracture site angulation, as well as torsional stiffness, peak torque, and fracture site rotation were quantified and compared. Intramedullary screw fixation demonstrated greater bending stiffness and less fracture site angulation than plate fixation during plantar-to-dorsal and lateral-to-medial bending. Torsional stiffness of screw-fixed metatarsals exceeded that of plate-fixed bones at initial loading; however, as rotation progressed, the plate resisted torque better than the screw. No difference in peak torque was demonstrable between fixation methods, but it was reached earlier in specimens fixed with screws and later in those fixed with plates as rotation progressed. In this cadaveric Jones fracture model, intramedullary screw fixation demonstrated bending stiffness and resistance to early torsional loading that was superior to that offered by plate fixation. Although low-profile "hook" plates offer an alternative for fixation of fifth metatarsal Jones fractures, intramedullary screw fixation may provide better resistance to bending and initiation of fracture site rotation. The influence of these mechanical characteristics on fracture healing is unknown, and further clinical investigation is warranted.


The cost-effectiveness of banning highly hazardous pesticides to prevent suicides due to pesticide self-ingestion across 14 countries: an economic modelling study.
Reducing suicides is a key Sustainable Development Goal target for improving global health. Highly hazardous pesticides are among the leading causes of death by suicide in low-income and middle-income countries. National bans of acutely toxic highly hazardous pesticides have led to substantial reductions in pesticide-attributable suicides across several countries. This study evaluated the cost-effectiveness of implementing national bans of highly hazardous pesticides to reduce the burden of pesticide suicides. A Markov model was developed to examine the costs and health effects of implementing a national ban of highly hazardous pesticides to prevent suicides due to pesticide self-poisoning, compared with a null comparator. We used WHO cost-effectiveness and strategic planning (WHO-CHOICE) methods to estimate pesticide-attributable suicide rates for 100 years from 2017. Country-specific costs were obtained from the WHO-CHOICE database and denominated in 2017 international dollars (I$), discounted at a 3% annual rate, and health effects were measured in healthy life-years gained (HLYGs). We used a demographic projection model beginning with the country population in the baseline year (2017), split by 1-year age group and sex. Country-specific data on overall suicide rates were obtained for 2017 by age and sex from the Global Burden of Disease Study 2017 Data Resources. The analysis involved 14 countries spanning low-income to high-income settings, and cost-effectiveness ratios were analysed at the country-specific level and aggregated according to country income group and the proportion of suicides due to pesticides. Banning highly hazardous pesticides across the 14 countries studied could result in about 28 000 (95% uncertainty interval [UI] 24 000-32 000) fewer suicide deaths each year at an annual cost of I$0·007 per capita (95% UI 0·006-0·008). In the population-standardised results for the base case analysis, national bans produced cost-effectiveness ratios of $94 per HLYG (95% UI 73-123) across low-income and lower-middle-income countries and $237 per HLYG (95% UI 191-303) across upper-middle-income and high-income countries. Bans were more cost-effective in countries where a high proportion of suicides are attributable to pesticide self-poisoning, reaching a cost-effectiveness ratio of $75 per HLYG (95% UI 58-99) in two countries with proportions of more than 30%. National bans of highly hazardous pesticides are a potentially cost-effective and affordable intervention for reducing suicide deaths in countries with a high burden of suicides attributable to pesticides. However, our study findings are limited by imperfect data and assumptions that could be improved upon by future studies. WHO.


Non-pharmacological interventions for people with dementia: A review of reviews.
Aged care services increasingly respond to the needs of people with dementia. Non-pharmacological approaches are preferable to reduce responsive behaviours, improve/maintain functional capacity and reduce emotional disorders. This rapid review of systematic reviews aimed to consolidate the evidence for non-pharmacological interventions and determine outcome effectiveness. Systematic review literature was comprehensively searched for non-pharmacological interventions for dementia in residential care. Quality ratings used adapted GRADE methodology, and ease of implementation assessed. Of 629 abstracts screened, 81 full-text articles were retrieved, 38 articles included. The strongest evidence for reducing responsive behaviours was music, sensory stimulation, simulated presence and validation therapies. Exercise and light therapy improved/maintained activities of daily living, while cognitive stimulation and reminiscence improved cognition. Strongest evidence for reducing emotional disorders was music, psychological interventions and reminiscence. Much evidence of varying quality exists, with resource-constrained residential care providers now able to make evidence-based decisions about non-pharmacological interventions.


Orientational dynamics of a triaxial ellipsoid in simple shear flow: Influence of inertia.
The motion of a single ellipsoidal particle in simple shear flow can provide valuable insights toward understanding suspension flows with nonspherical particles. Previously, extensive studies have been performed on the ellipsoidal particle with rotational symmetry, a so-called spheroid. The nearly prolate ellipsoid (one major and two minor axes of almost equal size) is known to perform quasiperiodic or even chaotic orbits in the absence of inertia. With small particle inertia, the particle is also known to drift toward this irregular motion. However, it is not previously understood what effects from fluid inertia could be, which is of highest importance for particles close to neutral buoyancy. Here, we find that fluid inertia is acting strongly to suppress the chaotic motion and only very weak fluid inertia is sufficient to stabilize a rotation around the middle axis. The mechanism responsible for this transition is believed to be centrifugal forces acting on fluid, which is dragged along with the rotational motion of the particle. With moderate fluid inertia, it is found that nearly prolate triaxial particles behave similarly to the perfectly spheroidal particles. Finally, we also are able to provide predictions about the stable rotational states for the general triaxial ellipsoid in simple shear with weak inertia.


Serum amino acids, biopterin and neopterin during long-term immunotherapy with interferon-alpha in high-risk melanoma patients.
Immunotherapy with interferon-alpha (IFN-alpha) induces neuropsychiatric side effects, most notably depression. One of the presumed pathophysiological mechanisms is an effect on tryptophan metabolism. As tryptophan is the precursor of serotonin, decreased availability of tryptophan to the central nervous system could result in serotonin deficiency. Tetrahydrobiopterin (BH((4))) is a cofactor for one of the enzymes synthesizing serotonin. We conducted an exploratory study into the serum concentrations of large neutral amino acids (AA), biopterin (BIOP) and neopterin (NEOP), of 67 patients with high-risk melanoma, who were either treated with two different doses of IFN-alpha or were part of an observation-only control group. We found evidence for IFN-alpha to decrease concentrations of all AA except phenylalanine. The decrease in tryptophan concentration was most prominent and consistent. These changes persisted throughout a year of maintenance treatment. Concentrations of NEOP rose sharply, whereas, those of BIOP did not change. Except for the increase in NEOP and the increase in the ratio between phenylalanine (PHE) and tyrosine (TYR), no support for derangement in BH((4)) metabolism was found. The increase in the ratio between PHE and TYR suggests inhibition of the enzyme phenylalanine hydroxylase. Patients with IFN-alpha induced anxiety and depression had higher pretreatment concentrations of NEOP. Changes in tryptophan metabolism may play a role in the pathophysiology of the neuropsychiatric side effects of IFN-alpha, and further research into the predictive potential of NEOP is warranted.


A silurian soft-bodied biota.
A new Silurian (Llandoverian) biota from Wisconsin with a significant soft-bodied and lightly sclerotized component is dominated by arthropods and worms. The fauna includes the earliest well-preserved xiphosure, a possible marine uniramian, three new arthropods of uncertain affinity, and possibly the first Paleozoic leech. This may be only the second locality to yield a conodont animal. Lack of a normal shelly fauna suggests an unusual environment. The discovery adds significantly to the few such exceptionally preserved faunas known from Lower Paleozoic rocks.


Designing therapeutic clinical trials for older and frail adults with cancer: U13 conference recommendations.
A majority of cancer diagnoses and deaths occur in patients age ≥ 65 years. With the aging of the US population, the number of older adults with cancer will grow. Although the coming wave of older patients with cancer was anticipated in the early 1980s, when the need for more research on the cancer-aging interface was recognized, many knowledge gaps remain when it comes to treating older and/or frailer patients with cancer. Relatively little is known about the best way to balance the risks and benefits of existing cancer therapies in older patients; however, these patients continue to be underrepresented in clinical trials. Furthermore, the available clinical trials often do not include end points pertinent to the older adult population, such as preservation of function, cognition, and independence. As part of its ongoing effort to advance research in the field of geriatric oncology, the Cancer and Aging Research Group held a conference in November 2012 in collaboration with the National Cancer Institute, the National Institute on Aging, and the Alliance for Clinical Trials in Oncology. The goal was to develop recommendations and establish research guidelines for the design and implementation of therapeutic clinical trials for older and/or frail adults. The conference sought to identify knowledge gaps in cancer clinical trials for older adults and propose clinical trial designs to fill these gaps. The ultimate goal of this conference series is to develop research that will lead to evidence-based care for older and/or frail adults with cancer.


Prenatal or early-life exposure to antibiotics and risk of childhood asthma: a systematic review.
The increasing prevalence of childhood asthma has been associated with low microbial exposure as described by the hygiene hypothesis. We sought to evaluate the evidence of association between antibiotic exposure during pregnancy or in the first year of life and risk of childhood asthma. PubMed was systematically searched for studies published between 1950 and July 1, 2010. Those that assessed associations between antibiotic exposure during pregnancy or in the first year of life and asthma at ages 0 to 18 years (for pregnancy exposures) or ages 3 to 18 years (for first-year-of-life exposures) were included. Validity was assessed according to study design, age at asthma diagnosis, adjustment for respiratory infections, and consultation rates. For exposure in the first year of life, the pooled odds ratio (OR) for all studies (N = 20) was 1.52 (95% confidence interval [CI]: 1.30-1.77). Retrospective studies had the highest pooled risk estimate for asthma (OR: 2.04 [95% CI: 1.83-2.27]; n = 8) compared with database and prospective studies (OR: 1.25 [95% CI: 1.08-1.45]; n = 12). Risk estimates for studies that adjusted for respiratory infections (pooled OR: 1.16 [95% CI: 1.08-1.25]; n = 5) or later asthma onset (pooled OR for asthma at or after 2 years: OR: 1.16 [95% CI: 1.06-1.25]; n = 3) were weaker but remained significant. For exposure during pregnancy (n = 3 studies), the pooled OR was 1.24 (95% CI: 1.02-1.50). Antibiotics seem to slightly increase the risk of childhood asthma. Reverse causality and protopathic bias seem to be possible confounders for this relationship.


Major Physical Health Conditions and Risk of Suicide.
Most individuals make healthcare visits before suicide, but many do not have a diagnosed mental health condition. This study seeks to investigate suicide risk among patients with a range of physical health conditions in a U.S. general population sample and whether risk persists after adjustment for mental health and substance use diagnoses. This study included 2,674 individuals who died by suicide between 2000 and 2013 along with 267,400 controls matched on year and location in a case-control study conducted in 2016 across eight Mental Health Research Network healthcare systems. A total of 19 physical health conditions were identified using diagnostic codes within the healthcare systems' Virtual Data Warehouse, including electronic health record and insurance claims data, during the year before index date. Seventeen physical health conditions were associated with increased suicide risk after adjustment for age and sex (p<0.001); nine associations persisted after additional adjustment for mental health and substance use diagnoses. Three conditions had a more than twofold increased suicide risk: traumatic brain injury (AOR=8.80, p<0.001); sleep disorders; and HIV/AIDS. Multimorbidity was present in 38% of cases versus 15.5% of controls, and represented nearly a twofold increased risk for suicide. Although several individual conditions, for example, traumatic brain injury, were associated with high risk of suicide, nearly all physical health conditions increased suicide risk, even after adjustment for potential confounders. In addition, having multiple physical health conditions increased suicide risk substantially. These data support suicide prevention based on the overall burden of physical health.