The role of fluid intake in the prevention of kidney stone disease: A systematic review over the last two decades.
The incidence of kidney stone disease (KSD) is rising worldwide; hence, more focus must be directed toward its etiology and risk factors. Increasing fluid intake is recommended as the most ideal prevention; yet, there is inconsistent evidence surrounding optimum volumes and types of fluid that affect stone formation. This review aimed to analyze the published literature on fluid intake and types of fluid consumed and their impact on KSD prevention. Papers were acquired from databases: MEDLINE, EMBASE, PubMed, CINAHL, and Cochrane Library. Included English language studies that involved adults consuming beverages along with a standardized diet in relation to KSD. Those failing to control dietary factors were excluded. After an initial search of 1099 papers, 9 (541 participants) were included in the final review. Six varieties of water and ten different types of juices were investigated. Higher fluid intake was associated with increased urine output and reduced stone formation. Water with high calcium content seemingly increased the rate of calcium oxalate (CaOx) stone formation. The relative supersaturation of CaOx in urine was decreased with grapefruit, apple, orange juices, and sodas, whereas cranberry juice increased it. Plum juice and the energy drink Gatorade had no effect on stone formation. Fluids low in calcium seem to reduce the risk of KSD. Certain varieties of fluid, such as grapefruit, apple, and orange juices reduce urine CaOx saturation, with a subsequent reduction in stone formation. Findings from this review could contribute to primary prevention for those at risk of KSD.


The amphioxus SoxB family: implications for the evolution of vertebrate placodes.
Cranial placodes are regions of thickened ectoderm that give rise to sense organs and ganglia in the vertebrate head. Homologous structures are proposed to exist in urochordates, but have not been found in cephalochordates, suggesting the first chordates lacked placodes. SoxB genes are expressed in discrete subsets of vertebrate placodes. To investigate how placodes arose and diversified in the vertebrate lineage we isolated the complete set of SoxB genes from amphioxus and analyzed their expression in embryos and larvae. We find that while amphioxus possesses a single SoxB2 gene, it has three SoxB1 paralogs. Like vertebrate SoxB1 genes, one of these paralogs is expressed in non-neural ectoderm destined to give rise to sensory cells. When considered in the context of other amphioxus placode marker orthologs, amphioxus SoxB1 expression suggests a diversity of sensory cell types utilizing distinct placode-type gene programs was present in the first chordates. Our data supports a model for placode evolution and diversification whereby the full complement of vertebrate placodes evolved by serial recruitment of distinct sensory cell specification programs to anterior pre-placodal ectoderm.


Gene function prediction from synthetic lethality networks via ranking on demand.
Synthetic lethal interactions represent pairs of genes whose individual mutations are not lethal, while the double mutation of both genes does incur lethality. Several studies have shown a correlation between functional similarity of genes and their distances in networks based on synthetic lethal interactions. However, there is a lack of algorithms for predicting gene function from synthetic lethality interaction networks. In this article, we present a novel technique called kernelROD for gene function prediction from synthetic lethal interaction networks based on kernel machines. We apply our novel algorithm to Gene Ontology functional annotation prediction in yeast. Our experiments show that our method leads to improved gene function prediction compared with state-of-the-art competitors and that combining genetic and congruence networks leads to a further improvement in prediction accuracy.


Sepsis modifies the contribution of different organs to whole-body protein synthesis in rats.
1. Protein synthesis rate was measured in the liver, muscle, intestine and whole body of septic rats and pair-fed controls by administration of a large dose of L-[U14C]valine. Sepsis was induced by intravenous injection of live bacteria, and protein synthesis measurements were carried out 48 h later. 2. Septic rats exhibited a reduction in food intake to between 10 and 50% of the normal level on the 2 days after infection. Animals lost body weight and the relative organ weight was increased in liver, unchanged in intestine and decreased in skeletal muscle. 3. The fractional protein synthesis rate of the whole body excluding liver was increased by 19% in septic rats in comparison with pair-fed controls, but the absolute protein synthesis rate was similar in the two groups because of the low protein content of the infected group. 4. The fractional protein synthesis was increased in whole intestine and liver but was decreased in skeletal muscle. In muscle and liver, the difference between infected and pair-fed animals was more pronounced for the absolute than for the fractional protein synthesis rate. In intestine, the fractional protein synthesis rate was similarly increased in whole intestine and the muscular layer of ileum. This suggests different regulation of protein synthesis in skeletal and smooth muscles. 5. The present investigation shows a complete redistribution of protein synthesis in sepsis. Liver represents about a third of the whole-body protein synthesis instead of 15% and becomes predominant over synthesis of muscle.


Hydrogen storage on volleyballene.
This study is devoted to the hydrogenation of the recently predicted volleyballene (Sc20C60) compound. The hydrogenation produces structures with 24 and 70 H atoms, respectively. Twelve of the 20 available Sc atoms and C5 rings are found as preferred sites for hydrogenation. DFT calculations attest a H2 uptake capacity of 4.20 wt% for the heavily hydrogenated structure (Sc20C60H70), and a corrected -0.11 eV/H2 adsorption energy value. Calculated entalphy (negative) and entropy (positive) values assure that the hydrogenation reaction of volleyballene can be achieved at ambient temperature. The heavily hydrogenated structure holds a 1.1 eV HOMO-LUMO gap value and it does not feature imaginary frequencies attesting its experimental convenience.


Mortality risk by functional status and health-related quality of life in patients with rheumatoid arthritis.
Patients with rheumatoid arthritis (RA) are at increased risk of death. Modern RA therapy has been shown to improve health status, but the relationship of such improvements to mortality risk is unknown. We assessed the relationship between health status and all-cause mortality in patients with RA, using the Health Assessment Questionnaire (HAQ) and the Medical Outcomes Study Short Form-36 questionnaire (SF-36) physical and mental component summary scores (PCS, MCS). Subjects (n = 10,319) were selected from the National Data Bank for Rheumatic Diseases, a prospective longitudinal observational US study with semiannual assessments of HAQ, PCS, and MCS. Risk of death up to 7 years through 2006 was obtained from the US National Death Index. Relationship of HAQ, PCS, and MCS to mortality was assessed using Cox regression models; prediction accuracy was compared using Harrell's concordance coefficient (C). Over 64,888 patient-years of followup, there were 1317 deaths. Poorer baseline health status was associated with greater mortality risk. Adjusting for age, sex, and baseline PCS and MCS, declines in PCS and HAQ were associated with higher risk of death. HAQ improvement was associated with reduced mortality risk from 6 months through 3 years; a similar relationship was not observed for PCS or MCS improvement. Controlling for baseline values, change in PCS or HAQ did not improve prediction accuracy. The HAQ and the SF-36 PCS are similarly and strongly associated with mortality risk in patients with RA. Change in these measures over time does not appear to add to predictive accuracy over baseline levels.


Conformation, protein-carbohydrate interactions and a novel subunit association in the refined structure of peanut lectin-lactose complex.
The structure of the complex of the tetrameric peanut lectin with lactose has been refined to an R-value of 16.4% using 2.25 angstroms resolution X-ray diffraction data. The subunit conformation in the structure is similar to that in other legume lectins except in the loops. It has been shown that in the tertiary structure of legume lectins, the short five-stranded sheet plays a major role in connecting the larger flat six-stranded and curved seven-stranded sheets. Furthermore, the loops that connect the strands at the two ends of the seven-stranded sheet curve toward and interact with each other to produce a second hydrophobic core in addition to the one between the two large sheets. The protein-lactose interactions involve the invariant features observed in other legume lectins in addition to those characteristic of peanut lectin. The "open" quaternary association in peanut lectin is stabilised by hydrophobic, hydrogen-bonded and water-mediated interactions. Contrary to the earlier belief, the structure of peanut lectin demonstrates that the variability in quaternary association in legume lectins, despite all of them having nearly the same tertiary structure, is not necessarily caused by covalently bound carbohydrate. An attempt has been made to provide a structural rationale for this variability, on the basis of buried surface areas during dimerisation. A total of 45 water molecules remain invariant when the hydration shells of the four subunits are compared. A majority of them appear to be involved in stabilising loops.


The burden and treatment of HIV in tuberculosis patients in Papua Province, Indonesia: a prospective observational study.
New diagnoses of tuberculosis (TB) present important opportunities to detect and treat HIV. Rates of HIV and TB in Indonesia's easternmost Papua Province exceed national figures, but data on co-infection rates and outcomes are lacking. We aimed to measure TB-HIV co-infection rates, examine longitudinal trends, compare management with World Health Organisation (WHO) recommendations, and document progress and outcome. Adults with newly-diagnosed smear-positive pulmonary TB managed at the Timika TB clinic, Papua Province, were offered voluntary counselling and testing for HIV in accordance with Indonesian National Guidelines, using a point-of-care antibody test. Positive tests were confirmed with 2 further rapid tests. Study participants were assessed using clinical, bacteriological, functional and radiological measures and followed up for 6 months. Of 162 participants, HIV status was determined in 138 (85.2%), of whom 18 (13.0%) were HIV+. Indigenous Papuans were significantly more likely to be HIV+ than Non-Papuans (Odds Ratio [OR] 4.42, 95% confidence interval [CI] 1.38-14.23). HIV prevalence among people with TB was significantly higher than during a 2003-4 survey at the same TB clinic, and substantially higher than the Indonesian national estimate of 3%. Compared with HIV- study participants, those with TB-HIV co-infection had significantly lower exercise tolerance (median difference in 6-minute walk test: 25 m, p = 0.04), haemoglobin (mean difference: 1.3 g/dL, p = 0.002), and likelihood of cavitary disease (OR 0.35, 95% CI 0.12-1.01), and increased occurrence of pleural effusion (OR 3.60, 95% CI 1.70-7.58), higher rates of hospitalisation or death (OR 11.80, 95% CI 1.82-76.43), but no difference in the likelihood of successful 6-month treatment outcome. Adherence to WHO guidelines was limited by the absence of integration of TB and HIV services, specifically, with no on-site ART prescriber available. Only six people had CD4+ T-cell counts recorded, 11 were prescribed co-trimoxazole and 4 received ART before, during or after TB treatment, despite ART being indicated in 14 according to 2006 WHO guidelines. TB-HIV co-infection in southern Papua, Indonesia, is a serious emerging problem especially among the Indigenous population, and has risen rapidly in the last 5 years. Major efforts are required to incorporate new WHO recommendations on TB-HIV management into national guidelines, and support their implementation in community settings.


Angioleiomyoma of the lower extremity.
Angioleiomyomas are benign soft tissue lesions that should be included in the differential diagnosis of any pedal soft tissue mass. There should be an increased index of suspicion for angioleiomyoma, especially when a freely movable subcutaneous mass is encountered in a middle-aged female patient. Treatment of such masses should involve surgical excision to relieve the symptomatology and to obtain tissue for a definitive histologic analysis. If the mass recurs, then the possibility of leiomyosarcoma should be explored.


Selective inhibition of inducible nitric oxide synthase: effects on hemodynamics and regional blood flow in healthy and septic sheep.
To investigate the effects of S-ethylisothiourea (S-EITU) on hemodynamics, oxygen transport, and regional blood flow in healthy and septic sheep. Prospective, randomized, controlled experimental study with repeated measures. Investigational intensive care unit at a university medical center. Eleven healthy, female adult sheep of the Merino breed, divided into a control group (n = 5) and into a group treated with S-EITU (n = 6). All sheep were chronically instrumented. After a 5-day recovery period, they were randomly assigned to either control or S-EITU groups. While control sheep received only saline, S-EITU was administered in increasing doses of 1, 3, and 9 mg/kg/hr over 1 hr each (nonseptic phase). After 2 days of recovery, a continuous infusion of live Pseudomonas aeruginosa (2.5 x 106 colony-forming units/min) was started in all sheep and maintained for the remainder of the experiment. After 24 hrs of sepsis, the sheep again received their assigned treatment (septic phase). In both the nonseptic and septic phases, the sheep received colored microspheres through a left atrial catheter to allow analysis of regional blood flows. All animals were autopsied at the end of the experiments, and organ probes were removed for blood flow analyses. The administration of S-EITU caused a dose-dependent vasoconstriction in the nonseptic phase. After 24 hrs of Pseudomonas infusion, all sheep developed a hyperdynamic circulatory state, with increased cardiac indices and reduced arterial pressures and systemic vascular resistances. Oxygen extraction decreased significantly, preventing an increase in oxygen consumption, despite an increased oxygen delivery. The hyperdynamic circulation was dose dependently reversed by S-EITU, causing an increase in arterial pressure by peripheral vasoconstriction. Sheep in the control group showed a continuation of the hyperdynamic circulation. The effects of S-EITU on hemodynamics and regional blood flows were comparable under septic and nonseptic conditions. With the inducible form of nitric oxide synthase expressed under septic, but not under nonseptic conditions, S-EITU was expected to have vasoconstrictive properties only in the septic phase. It produced a comparable vasoconstriction during the nonseptic phase of the experiment. Thus, either S-EITU does not selectively block the inducible nitric oxide synthase in sheep, or other vasodilators besides nitric oxide play an important role in septic vasodilation.


Neuro biomarker levels measured with high-sensitivity digital ELISA differ between serum and plasma.
Aim: Digital ELISA-based assays for blood biomarkers of neurological disease are on the verge of clinical use. Here, we aimed to determine whether different preanalytical blood processing techniques influence results. Materials & methods: Concentrations of neurofilament light chain (NfL), Tau and amyloid beta (Aβ) were measured in human plasma and serum specimens using digital ELISA and compared between blood products. Measured levels of NfL were highly equivalant between serum and plasma in all analyses, however, measured levels of Tau and Aβ were consistently lower in serum relative to plasma. Conclusion: Tau and Aβ are likely lost during clotting in serum preparations, and should be assayed in plasma to get an accurate measure of circulating levels.


Association of tuberculin-boosted antibody responses with pathology and cell-mediated immunity in cattle vaccinated with Mycobacterium bovis BCG and infected with M. bovis.
Vaccine development and our understanding of the pathology of bovine tuberculosis in cattle would be greatly facilitated by definition of the immunological correlates of protection and/or pathology. In this study we analyzed humoral immune responses in Mycobacterium bovis BCG-vaccinated and control cattle (in particular, the relationship between the intradermal comparative tuberculin skin test and serum immunoglobulin G [IgG] responses) against a range of mycobacterial antigens (MPB59, MPB64, MPB70, MPB83, ESAT-6, CFP-10, Acr1, and PstS-1) by multiantigen print immunoassay and conventional enzyme-linked immunosorbent assay. Following M. bovis infection, the comparative tuberculin skin test strongly boosted IgG, IgG1, and IgG2 antibody responses, particularly against MPB83 and MPB70, in unvaccinated cattle but failed to boost these responses, or did so only weakly, in BCG-vaccinated calves. In addition, the skin test-induced increases in MPB83-specific IgG responses correlated positively with bacterial loads and ESAT-6-induced in vitro gamma interferon responses. In conclusion, both the negative correlation of skin test-enhanced MPB83-specific antibody responses with BCG-induced protection and their positive correlation with bacterial loads can serve as useful markers for vaccine efficacy after challenge.


Cytomegalovirus microRNA expression is tissue specific and is associated with persistence.
MicroRNAs (miRNAs) are a class of small noncoding RNAs involved in posttranscriptional regulation. miRNAs are utilized in organisms ranging from plants to higher mammals, and data have shown that DNA viruses also use this method for host and viral gene regulation. Here, we report the sequencing of the small RNAs in rat cytomegalovirus (RCMV)-infected fibroblasts and persistently infected salivary glands. We identified 24 unique miRNAs that mapped to hairpin structures found within the viral genome. While most miRNAs were detected in both samples, four were detected exclusively in the infected fibroblasts and two were specific for the infected salivary glands. The RCMV miRNAs are distributed across the viral genome on both the positive and negative strands, with clusters of miRNAs at a number of locations, including near viral genes r1 and r111. The RCMV miRNAs have a genomic positional orientation similar to that of the miRNAs described for mouse cytomegalovirus, but they do not share any substantial sequence conservation. Similar to other reported miRNAs, the RCMV miRNAs had considerable variation at their 3' and 5' ends. Interestingly, we found a number of specific examples of differential isoform usage between the fibroblast and salivary gland samples. We determined by real-time PCR that expression of the RCMV miRNA miR-r111.1-2 is highly expressed in the salivary glands and that miR-R87-1 is expressed in most tissues during the acute infection phase. Our study identified the miRNAs expressed by RCMV in vitro and in vivo and demonstrated that expression is tissue specific and associated with a stage of viral infection.


Soft tissue and cellular preservation in vertebrate skeletal elements from the Cretaceous to the present.
Soft tissues and cell-like microstructures derived from skeletal elements of a well-preserved Tyrannosaurus rex (MOR 1125) were represented by four components in fragments of demineralized cortical and/or medullary bone: flexible and fibrous bone matrix; transparent, hollow and pliable blood vessels; intravascular material, including in some cases, structures morphologically reminiscent of vertebrate red blood cells; and osteocytes with intracellular contents and flexible filipodia. The present study attempts to trace the occurrence of these four components in bone from specimens spanning multiple geological time periods and varied depositional environments. At least three of the four components persist in some skeletal elements of specimens dating to the Campanian. Fibrous bone matrix is more altered over time in morphology and less likely to persist than vessels and/or osteocytes. Vessels vary greatly in preservation, even within the same specimen, with some regions retaining pliability and other regions almost crystalline. Osteocytes also vary, with some retaining long filipodia and transparency, while others present with short and stubby filipodia and deeply pigmented nuclei, or are pigmented throughout with no nucleus visible. Alternative hypotheses are considered to explain the origin/source of observed materials. Finally, a two-part mechanism, involving first cross-linking of molecular components and subsequent mineralization, is proposed to explain the surprising presence of still-soft elements in fossil bone. These results suggest that present models of fossilization processes may be incomplete and that soft tissue elements may be more commonly preserved, even in older specimens, than previously thought. Additionally, in many cases, osteocytes with defined nuclei are preserved, and may represent an important source for informative molecular data.


Loss of hepatic chaperone-mediated autophagy accelerates proteostasis failure in aging.
Chaperone-mediated autophagy (CMA), a cellular process that contributes to protein quality control through targeting of a subset of cytosolic proteins to lysosomes for degradation, undergoes a functional decline with age. We have used a mouse model with liver-specific defective CMA to identify changes in proteostasis attributable to reduced CMA activity in this organ with age. We have found that other proteolytic systems compensate for CMA loss in young mice which helps to preserve proteostasis. However, these compensatory responses are not sufficient for protection against proteotoxicity induced by stress (oxidative stress, lipid challenges) or associated with aging. Livers from old mice with CMA blockage exhibit altered protein homeostasis, enhanced susceptibility to oxidative stress and hepatic dysfunction manifested by a diminished ability to metabolize drugs, and a worsening of the metabolic dysregulation identified in young mice. Our study reveals that while the regulatory function of CMA cannot be compensated for in young organisms, its contribution to protein homeostasis can be handled by other proteolytic systems. However, the decline in the compensatory ability identified with age explains the more severe consequences of CMA impairment in older organisms and the contribution of CMA malfunction to the gradual decline in proteostasis and stress resistance observed during aging.


Fabrication and characterization of mechanically competent 3D printed polycaprolactone-reduced graphene oxide scaffolds.
The ability to produce constructs with a high control over the bulk geometry and internal architecture has situated 3D printing as an attractive fabrication technique for scaffolds. Various designs and inks are actively investigated to prepare scaffolds for different tissues. In this work, we prepared 3D printed composite scaffolds comprising polycaprolactone (PCL) and various amounts of reduced graphene oxide (rGO) at 0.5, 1, and 3 wt.%. We employed a two-step fabrication process to ensure an even mixture and distribution of the rGO sheets within the PCL matrix. The inks were prepared by creating composite PCL-rGO films through solvent evaporation casting that were subsequently fed into the 3D printer for extrusion. The resultant scaffolds were seamlessly integrated, and 3D printed with high fidelity and consistency across all groups. This, together with the homogeneous dispersion of the rGO sheets within the polymer matrix, significantly improved the compressive strength and stiffness by 185% and 150%, respectively, at 0.5 wt.% rGO inclusion. The in vitro response of the scaffolds was assessed using human adipose-derived stem cells. All scaffolds were cytocompatible and supported cell growth and viability. These mechanically reinforced and biologically compatible 3D printed PCL-rGO scaffolds are a promising platform for regenerative engineering applications.


Characterization of silicone elastomer vaginal rings containing HIV microbicide TMC120 by Raman spectroscopy.
Silicone elastomer vaginal rings are currently being pursued as a controlled-release strategy for delivering microbicidal substances for the prevention of heterosexual transmission of HIV. Although it is well established that the distribution of drugs in delivery systems influences the release characteristics, in practice the distribution is often difficult to quantify in-situ. Therefore, the aim of this work was to determine whether Raman spectroscopy might provide a rapid, non-contact means of measuring the concentrations of the lead candidate HIV microbicide TMC120 in a silicone elastomer reservoir-type vaginal ring. Vaginal rings loaded with TMC120 were manufactured and sectioned before either Raman mapping an entire ring cross-section (100 microm resolution) or running line scans at appropriate time intervals up to 30 h after manufacture. The results demonstrated that detectable amounts of TMC120, above the silicone elastomer saturation concentration, could be detected up to 1 mm into the sheath, presumably as a consequence of permeation and subsequent reprecipitation. The extent of permeation was found to be similar in rings manufactured at 25 and 80 degrees C.


Anti-Jagged Immunotherapy Inhibits MDSCs and Overcomes Tumor-Induced Tolerance.
Myeloid-derived suppressor cells (MDSC) are a major obstacle to promising forms of cancer immunotherapy, but tools to broadly limit their immunoregulatory effects remain lacking. In this study, we assessed the therapeutic effect of the humanized anti-Jagged1/2-blocking antibody CTX014 on MDSC-mediated T-cell suppression in tumor-bearing mice. CTX014 decreased tumor growth, affected the accumulation and tolerogenic activity of MDSCs in tumors, and inhibited the expression of immunosuppressive factors arginase I and iNOS. Consequently, anti-Jagged therapy overcame tumor-induced T-cell tolerance, increased the infiltration of reactive CD8+ T cells into tumors, and enhanced the efficacy of T-cell-based immunotherapy. Depletion of MDSC-like cells restored tumor growth in mice treated with anti-Jagged, whereas coinjection of MDSC-like cells from anti-Jagged-treated mice with cancer cells delayed tumor growth. Jagged1/2 was induced in MDSCs by tumor-derived factors via NFkB-p65 signaling, and conditional deletion of NFkB-p65 blocked MDSC function. Collectively, our results offer a preclinical proof of concept for the use of anti-Jagged1/2 to reprogram MDSC-mediated T-cell suppression in tumors, with implications to broadly improve the efficacy of cancer therapy. Cancer Res; 77(20); 5628-38. ©2017 AACR.


Subretinal Drusenoid Deposits and the Loss of Rod Function in Intermediate Age-Related Macular Degeneration.
To compare static rod function obtained with and without photobleach in control and intermediate age-related macular degeneration (iAMD) participants with and without subretinal drusenoid deposits (SDD). In this cross-sectional study, retinal sensitivities within the central 24° retina were obtained twice using a dark-adapted chromatic perimeter, both with 505- and 625-nm stimuli. Tests were performed after 30 minutes of dark-adaptation either with or without a preceding photobleach. Multimodal imaging was performed to grade AMD and SDD status, and other retinal changes considered being risk factors for progression to late AMD. The sensitivity difference between both stimuli was used to assess rod function. The average point wise sensitivity difference (PWSD) was compared among the study groups. Twenty-nine control subjects and 20 iAMD without SDD and 17 iAMD with SDD cases were recruited. The average PWSD of the SDD group was significantly reduced (more with photobleach) compared with that of the control (P < 0.001) and no-SDD groups (P < 0.001), but only within the central 8°. The average PWSD of the non-SDD group was also reduced compared with the control group but only for measurements with photobleach (P = 0.020). There was no difference in average PWSD between the presence and absence of hyperreflective foci and/or nascent geographic atrophy in iAMD eyes without SDD (P = 0.60) or with SDD (P = 0.12). iAMD eyes with SDD are associated with worse static rod function compared with eyes without SDD. The greatest abnormality in rods is observed within the central 8° and when tested with a preceding photobleach.


Characterizing mineral dusts and other aerosols from the Middle East--Part 1: ambient sampling.
The purpose of the Enhanced Particulate Matter Surveillance Program was to provide scientifically founded information on the chemical and physical properties of dust collected over a period of approximately 1 year in Djibouti, Afghanistan (Bagram, Khowst), Qatar, United Arab Emirates, Iraq (Balad, Baghdad, Tallil, Tikrit, Taji, Al Asad), and Kuwait (northern, central, coastal, and southern regions). Three collocated low-volume particulate samplers, one each for the total suspended particulate matter, < 10 micro m in aerodynamic diameter (PM(10)) particulate matter, and < 2.5 micro m in aerodynamic diameter (PM(2.5)) particulate matter, were deployed at each of the 15 sites, operating on a '1 in 6' day sampling schedule. Trace-element analysis was performed to measure levels of potentially harmful metals, while major-element and ion-chemistry analyses provided an estimate of mineral components. Scanning electron microscopy with energy dispersive spectroscopy was used to analyze the chemical composition of small individual particles. Secondary electron images provided information on particle size and shape. This study shows the three main air pollutant types to be geological dust, smoke from burn pits, and heavy metal condensates (possibly from metals smelting and battery manufacturing facilities). Non-dust storm events resulted in elevated trace metal concentrations in Baghdad, Balad, and Taji in Iraq. Scanning-electron-microscopy secondary electron images of individual particles revealed no evidence of freshly fractured quartz grains. In all instances, quartz grains had rounded edges and mineral grains were generally coated by clay minerals and iron oxides.


Disparities in Vulnerability to Severe Complications from COVID-19 in the United States.
This paper provides the first nationally representative estimates of vulnerability to severe complications from COVID-19 overall and across race-ethnicity and socioeconomic status. We use the Panel Study of Income Dynamics (PSID) to examine the prevalence of specific health conditions associated with complications from COVID-19 and to calculate, for each individual, an index of the risk of severe complications from respiratory infections developed by DeCaprio et al. (2020). We show large disparities across race-ethnicity and socioeconomic status in the prevalence of conditions which are associated with the risk of severe complications from COVID-19. Moreover, we show that these disparities emerge early in life, prior to age 65, leading to higher vulnerability to such complications. While vulnerability is highest among older adults regardless of their race-ethnicity or socioeconomic status, our results suggest particular attention should also be given to the risk of adverse outcomes in midlife for non-Hispanic Blacks, adults with a high school degree or less, and low-income Americans.


Either of the major H2A genes but not an evolutionarily conserved H2A.F/Z variant of Tetrahymena thermophila can function as the sole H2A gene in the yeast Saccharomyces cerevisiae.
H2A.F/Z histones are conserved variants that diverged from major H2A proteins early in evolution, suggesting they perform an important function distinct from major H2A proteins. Antisera specific for hv1, the H2A.F/Z variant of the ciliated protozoan Tetrahymena thermophila, cross-react with proteins from Saccharomyces cerevisiae. However, no H2A.F/Z variant has been reported in this budding yeast species. We sought to distinguish among three explanations for these observations: (i) that S. cerevisiae has an undiscovered H2A.F/Z variant, (ii) that the major S. cerevisiae H2A proteins are functionally equivalent to H2A.F/Z variants, or (iii) that the conserved epitope is found on a non-H2A molecule. Repeated attempts to clone an S. cerevisiae hv1 homolog only resulted in the cloning of the known H2A genes yHTA1 and yHTA2. To test for functional relatedness, we attempted to rescue strains lacking the yeast H2A genes with either the Tetrahymena major H2A genes (tHTA1 or tHTA2) or the gene (tHTA3) encoding hv1. Although they differ considerably in sequence from the yeast H2A genes, the major Tetrahymena H2A genes can provide the essential functions of H2A in yeast cells, the first such case of trans-species complementation of histone function. The Tetrahymena H2A genes confer a cold-sensitive phenotype. Although expressed at high levels and transported to the nucleus, hv1 cannot replace yeast H2A proteins. Proteins from S. cerevisiae strains lacking yeast H2A genes fail to cross-react with anti-hv1 antibodies. These studies make it likely that S. cerevisiae differs from most other eukaryotes in that it does not have an H2A.F/Z homolog. A hypothesis is presented relating the absence of H2A.F/Z in S. cerevisiae to its function in other organisms.


Bumble bee fauna of Palouse Prairie: survey of native bee pollinators in a fragmented ecosystem.
Bumble bees, Bombus Latreille (Hymenoptera: Apidae:), are dominant pollinators in the northern hemisphere, providing important pollination services for commercial crops and innumerable wild plants. Nationwide declines in several bumble bee species and habitat losses in multiple ecosystems have raised concerns about conservation of this important group. In many regions, such as the Palouse Prairie, relatively little is known about bumble bee communities, despite their critical ecosystem functions. Pitfall trap surveys for ground beetles in Palouse prairie remnants conducted in 2002-2003 contained considerable by-catch of bumble bees. The effects of landscape context, remnant features, year, and season on bumble bee community composition were examined. Additionally, bees captured in 2002-2003 were compared with historic records for the region to assess changes in the presence of individual species. Ten species of bumble bee were captured, representing the majority of the species historically known from the region. Few detectable differences in bumble bee abundances were found among remnants. Community composition differed appreciably, however, based on season, landscape context, and elevation, resulting in different bee assemblages between western, low-lying remnants and eastern, higherelevation remnants. The results suggest that conservation of the still species-rich bumble bee fauna should take into account variability among prairie remnants, and further work is required to adequately explain bumble bee habitat associations on the Palouse.


Is LSD toxic?
LSD (lysergic acid diethylamide) was discovered almost 75 years ago, and has been the object of episodic controversy since then. While initially explored as an adjunctive psychiatric treatment, its recreational use by the general public has persisted and on occasion has been associated with adverse outcomes, particularly when the drug is taken under suboptimal conditions. LSD's potential to cause psychological disturbance (bad trips) has been long understood, and has rarely been associated with accidental deaths and suicide. From a physiological perspective, however, LSD is known to be non-toxic and medically safe when taken at standard dosages (50-200μg). The scientific literature, along with recent media reports, have unfortunately implicated "LSD toxicity" in five cases of sudden death. On close examination, however, two of these fatalities were associated with ingestion of massive overdoses, two were evidently in individuals with psychological agitation after taking standard doses of LSD who were then placed in maximal physical restraint positions (hogtied) by police, following which they suffered fatal cardiovascular collapse, and one case of extreme hyperthermia leading to death that was likely caused by a drug substituted for LSD with strong effects on central nervous system temperature regulation (e.g. 25i-NBOMe). Given the renewed interest in the therapeutic potential of LSD and other psychedelic drugs, it is important that an accurate understanding be established of the true causes of such fatalities that had been erroneously attributed to LSD toxicity, including massive overdoses, excessive physical restraints, and psychoactive drugs other than LSD.


Macrophages and the hypoxic tumour microenvironment.
One characteristic of solid tumour tissue is the presence of large numbers of tumour-associated macrophages. These migrate down gradients of chemo-attractive agents to accumulate within hypoxic and / or necrotic areas where they are generally related to poor clinical prognosis. In this review we will discuss the molecular mechanisms that underlie recruitment of macrophages into tumours and their pro-tumourigenic activities with respect to stimulation of angiogenesis, lymphangiogenesis, tumour cell migration, metastasis and immuno-suppression. The potential of macrophage-related anticancer therapies will be discussed in the light of this phenotype.


Consensus report from the 10th Global Forum for Liver Magnetic Resonance Imaging: developments in HCC management.
The 10th Global Forum for Liver Magnetic Resonance Imaging (MRI) was held as a virtual 2-day meeting in October 2021, attended by delegates from North and South America, Asia, Australia, and Europe. Most delegates were radiologists with experience in liver MRI, with representation also from specialists in liver surgery, oncology, and hepatology. Presentations, discussions, and working groups at the Forum focused on the following themes: • Gadoxetic acid in clinical practice: Eastern and Western perspectives on current uses and challenges in hepatocellular carcinoma (HCC) screening/surveillance, diagnosis, and management • Economics and outcomes of HCC imaging • Radiomics, artificial intelligence (AI) and deep learning (DL) applications of MRI in HCC. These themes are the subject of the current manuscript. A second manuscript discusses multidisciplinary tumor board perspectives: how to approach early-, mid-, and late-stage HCC management from the perspectives of a liver surgeon, interventional radiologist, and oncologist (Taouli et al, 2023). Delegates voted on consensus statements that were developed by working groups on these meeting themes. A consensus was considered to be reached if at least 80% of the voting delegates agreed on the statements. CLINICAL RELEVANCE STATEMENT: This review highlights the clinical applications of gadoxetic acid-enhanced MRI for liver cancer screening and diagnosis, as well as its cost-effectiveness and the applications of radiomics and AI in patients with liver cancer. KEY POINTS: • Interpretation of gadoxetic acid-enhanced MRI differs slightly between Eastern and Western guidelines, reflecting different regional requirements for sensitivity vs specificity. • Emerging data are encouraging for the cost-effectiveness of gadoxetic acid-enhanced MRI in HCC screening and diagnosis, but more studies are required. • Radiomics and artificial intelligence are likely, in the future, to contribute to the detection, staging, assessment of treatment response and prediction of prognosis of HCC-reducing the burden on radiologists and other specialists and supporting timely and targeted treatment for patients.


Breathing solitary-pulse pairs in a linearly coupled system.
It is shown that pairs of solitary pulses (SPs) in a linearly coupled system with opposite group velocity dispersions form robust breathing bound states. The system can be realized by temporal-modulation coupling of SPs with different carrier frequencies propagating in the same medium, or by coupling of SPs in a dual-core waveguide. Broad SP pairs are produced in a virtually exact form by means of the variational approximation. Strong nonlinearity tends to destroy the periodic evolution of the SP pairs.


Tuscan Varieties of Sweet Cherry Are Rich Sources of Ursolic and Oleanolic Acid: Protein Modeling Coupled to Targeted Gene Expression and Metabolite Analyses.
The potential of six ancient Tuscan sweet cherry (Prunus avium L.) varieties as a source of health-promoting pentacyclic triterpenes is here evaluated by means of a targeted gene expression and metabolite analysis. By using a sequence homology criterion, we identify five oxidosqualene cyclase genes (OSCs) and three cytochrome P450s (CYP85s) that are putatively involved in the triterpene production pathway in sweet cherries. We performed 3D structure prediction and induced-fit docking using cation intermediates and reaction products for some OSCs to predict their function. We show that the Tuscan varieties have different amounts of ursolic and oleanolic acids and that these variations are related to different gene expression profiles. This study stresses the interest of valorizing ancient fruits as alternative sources of functional molecules with nutraceutical value. It also provides information on sweet cherry triterpene biosynthetic genes, which could be the object of follow-up functional studies.


Risks perception of electromagnetic fields in Taiwan: the influence of psychopathology and the degree of sensitivity to electromagnetic fields.
Little is known about the perceived health risks of electromagnetic fields (EMFs) and factors associated with risk perception in non-Western countries. Psychological conditions and risk perception have been postulated as factors that facilitate the attribution of health complaints to environmental factors. This study investigated people's perceived risks of EMFs and other environmental sources, as well as the relationships between risk perception, psychopathology, and the degree of self-reported sensitivity to EMFs. A total of 1,251 adults selected from a nationwide telephone interviewing system database responded to a telephone survey about the relationships between environmental sources and human health. The interview included questions assessing participants' psychiatric conditions and the presence and degree of sensitivity to EMFs. One hundred and seventy participants were self-identified as having sensitivity to EMFs, and 141 met the criteria for psychiatric conditions without EMF sensitivity. More than half of the survey respondents considered power lines and mobile phone base stations to affect people's health to a big extent. Higher sensitivity to EMFs, psychopathology, being female, being married, more years of education, and having a catastrophic illness had positive associations with perceived risks of EMF-related environmental sources as well as for all environmental sources combined. We observed no moderating effect of psychopathology on the association between degree of sensitivity to EMF and risk perception. Thus, psychopathology had influence on general people's risk perception without having influence on the relationship between people's degree of sensitivity to EMF and risk perception. The plausible explanations are discussed in the text.


Intergenerational effects of birth weight on glucose tolerance and reproductive performance.
Women who were themselves small-for-gestational age (SGA) are at a greater risk of adulthood diseases such as non-insulin-dependent diabetes mellitus (NIDDM), and twice at risk of having an SGA baby themselves. The aim of this study was to examine the intergenerational pig. Low (L) and normal (N) birth weight female piglets were followed throughout their first pregnancy (generation 1 (G1)). After they had given birth, the growth and development of the lightest (l) and heaviest (n) female piglet from each litter were monitored until approximately 5 months of age (generation 2 (G2)). A glucose tolerance test (GTT) was conducted on G1 pig at 6 months of age and again during late pregnancy; a GTT was also conducted on G2 pigs at 4 months of age. G1 L offspring exhibited impaired glucose metabolism in later life compared to their G1 N sibling but in the next generation a similar scenario was only observed between l and n offspring born to G1 L mothers. Despite G1 L mothers showing greater glucose intolerance in late pregnancy and a decreased litter size, average piglet birth weight was reduced and there was also a large variation in litter weight; this suggests that they were, to some extent, prioritising their nutrient intake towards themselves rather than promoting their reproductive performance. There were numerous relationships between body shape at birth and glucose curve characteristics in later life, which can, to some extent, be used to predict neonatal outcome. In conclusion, intergenerational effects are partly seen in the pig. It is likely that some of the intergenerational influences may be masked due to the pig being a litter-bearing species.


The experiences of people living with HIV/AIDS and of their direct informal caregivers in a resource-poor setting.
HIV/AIDS is a critical concern in South Africa, where extreme poverty and gender issues are major determinants of health. A comprehensive home-based care programme is needed to lessen the burden placed on the caregivers of those suffering from HIV/AIDS. The purpose of this study was to explore and describe the challenges faced by people who are living with HIV/AIDS and by their caregivers in resource-poor, remote South African villages. In-depth interviews were conducted with nine persons living with HIV/AIDS and their nine direct informal caregivers. Interviews explored the themes of physical, emotional and social wellbeing. Two focus groups, one involving community leaders and one with local health care providers, were conducted to build on themes emerging from the in-depth interviews. A thematic analysis of the transcripts was performed. This study sheds light on the needs of persons living with HIV/AIDS and the needs of their direct informal caregivers in a rural area of the Eastern Cape province of South Africa. These needs include: physical/medical, social, material, financial, physiological/emotional, gender issues, and instrumental. In developing home-based care programmes, it is vital to consider the perceived needs of persons living with HIV/AIDS and their direct informal caregivers. The results from this study serve as a basis for the development of a home-based care programme in one resource-poor setting of South Africa and could provide a model for such programmes in similar areas.


Identification of a transposon-like insertion in a Glu-1 allele of wheat.
The Glu-1 locus, present on the long arms of the group 1 chromosomes of wheat, codes for a group of storage protein polypeptides termed high molecular weight (HMW) subunits of glutenin. Hexaploid wheat varieties carry a 'silent' Glu-1y allele on chromosome 1A, no polypeptide being attributable to this locus. When two such alleles from different varieties were compared, one was found to contain an 8 kb insertion of DNA, termed Wis-2, interrupting the coding sequence. The insertion site is flanked by a 5 bp duplication. The two ends of Wis-2 contain similar sequences over 500 bp long and its termini contain almost the same short sequences but in opposite orientation. These terminal sequences are related to those of several 'retroposon'-type transposable elements found in other organisms.


Challenges and shifting paradigms in clinical trials in oncology: the case for immunological and targeted therapies.
The advent of immunotherapy has undoubtedly changed the current standard for cancer treatment. Immunotherapy offers the possibility of achieving excellent results-a new alternative for patients with advanced-stage or relapsed disease. Nowadays, the progress made in tumour biology has led to multiple advances in clinical and translational cancer research. Many oncogenic pathways responsible for tumour growth and metastases have been described and, consequently, multiple new cancer therapeutic agents have been developed and are under current investigation. Due to this rapid increase in knowledge and pharmaceutical development, traditional clinical trials designs have encountered major limitations. The pharmacological differences (in toxicity profiles and effectiveness patterns) between immunotherapy and chemotherapy have caused traditional clinical trials to evolve in order to meet this emerging need. This review focuses on the different options pertaining to clinical trial design that have arisen in the field of immuno-oncology, as well as the challenges of accurately interpreting traditional survival analyses within this novel area of cancer medicine.


Evolution of immunoglobulin V genes: evidence indicating that recently duplicated human V kappa sequences have diverged by gene conversion.
We have analyzed several closely related members of the gene family encoding the variable regions of human immunoglobulin kappa light chains (V kappa genes). Two of these genes differ at a single nucleotide out of 940 bases sequenced, and are believed to be alleles of a locus called HK 101. This substitution results in an amino acid replacement in the first complementarity-determining region of the kappa chain. We also compared the structures of two nonallelic human V kappa loci (HK 101 and HK 137) and found a high degree of sequence homology over a region at least 13.5 kb long. This long block of homology indicates that these two loci arose from a recent gene duplication. The DNA sequences of these two nonallelic V kappa genes exhibit a very unusual distribution of nucleotide substitutions. Seven of the ten substitutions found among 940 bases are clustered in a 39 base stretch encoding the first complementarity-determining region and the second framework region of the protein. We suggest that this cluster of substitutions was generated by a gene conversion in which a small segment of one gene was replaced with the homologous segment from another V kappa gene.


Magnesium status and supplementation influence vitamin D status and metabolism: results from a randomized trial.
Previous in vitro and in vivo studies indicate that enzymes that synthesize and metabolize vitamin D are magnesium dependent. Recent observational studies found that magnesium intake significantly interacted with vitamin D in relation to vitamin D status and risk of mortality. According to NHANES, 79% of US adults do not meet their Recommended Dietary Allowance of magnesium. The aim of this study was to test the hypothesis that magnesium supplementation differentially affects vitamin D metabolism dependent on baseline 25-hydroxyvitamin D [25(OH)D] concentration. The study included 180 participants aged 40-85 y and is a National Cancer Institute independently funded ancillary study, nested within the Personalized Prevention of Colorectal Cancer Trial (PPCCT), which enrolled 250 participants. The PPCCT is a double-blind 2 × 2 factorial randomized controlled trial conducted in the Vanderbilt University Medical Center. Doses for both magnesium and placebo were customized based on baseline dietary intakes. Subjects were randomly assigned to treatments using a permuted-block randomization algorithm. Changes in plasma 25-hydroxyvitamin D3 [25(OH)D3], 25-hydroxyvitamin D2 [25(OH)D2], 1,25-dihydroxyvitamin D3, 1,25-dihydroxyvitamin D2, and 24,25-dihydroxyvitamin D3 [24,25(OH)2D3] were measured by liquid chromatography-mass spectrometry. The relations between magnesium treatment and plasma concentrations of 25(OH)D3, 25(OH)D2, and 24,25(OH)2D3 were significantly different dependent on the baseline concentrations of 25(OH)D, and significant interactions persisted after Bonferroni corrections. Magnesium supplementation increased the 25(OH)D3 concentration when baseline 25(OH)D concentrations were close to 30 ng/mL, but decreased it when baseline 25(OH)D was higher (from ∼30 to 50 ng/mL). Magnesium treatment significantly affected 24,25(OH)2D3 concentration when baseline 25(OH)D concentration was 50 ng/mL but not 30 ng/mL. On the other hand, magnesium treatment increased 25(OH)D2 as baseline 25(OH)D increased. Our findings suggest that optimal magnesium status may be important for optimizing 25(OH)D status. This trial was registered at clinicaltrials.gov as NCT03265483.


Modeling Therapy Resistance in BRCA1/2-Mutant Cancers.
Although PARP inhibitors target BRCA1- or BRCA2-mutant tumor cells, drug resistance is a problem. PARP inhibitor resistance is sometimes associated with the presence of secondary or "revertant" mutations in BRCA1 or BRCA2 Whether secondary mutant tumor cells are selected for in a Darwinian fashion by treatment is unclear. Furthermore, how PARP inhibitor resistance might be therapeutically targeted is also poorly understood. Using CRISPR mutagenesis, we generated isogenic tumor cell models with secondary BRCA1 or BRCA2 mutations. Using these in heterogeneous in vitro culture or in vivo xenograft experiments in which the clonal composition of tumor cell populations in response to therapy was monitored, we established that PARP inhibitor or platinum salt exposure selects for secondary mutant clones in a Darwinian fashion, with the periodicity of PARP inhibitor administration and the pretreatment frequency of secondary mutant tumor cells influencing the eventual clonal composition of the tumor cell population. In xenograft studies, the presence of secondary mutant cells in tumors impaired the therapeutic effect of a clinical PARP inhibitor. However, we found that both PARP inhibitor-sensitive and PARP inhibitor-resistant BRCA2 mutant tumor cells were sensitive to AZD-1775, a WEE1 kinase inhibitor. In mice carrying heterogeneous tumors, AZD-1775 delivered a greater therapeutic benefit than olaparib treatment. This suggests that despite the restoration of some BRCA1 or BRCA2 gene function in "revertant" tumor cells, vulnerabilities still exist that could be therapeutically exploited. Mol Cancer Ther; 16(9); 2022-34. ©2017 AACR.


Correlations of Acute Cerebral Hemorrhage Complicated with Stress Ulcer Bleeding with Acute Physiology and Chronic Health Evaluation (APACHE) II Score, Endothelin (ET), Tumor Necrosis Factor-alpha (TNF-α), and Blood Lipids.
BACKGROUND This study investigated the correlations between acute cerebral hemorrhage complicated with stress ulcer bleeding and corresponding indexes, including the Acute Physiology and Chronic Health Evaluation (APACHE) II score, vascular endothelin-1 (ET-1), tumor necrosis factor-alpha (TNF-α), and blood lipid factors. MATERIAL AND METHODS A total of 53 patients with acute cerebral hemorrhage complicated with stress ulcer bleeding were selected as the observation group and 50 patients with simple acute cerebral hemorrhage were selected as the control group. The APACHE II score and the levels of ET-1, TNF-α, and blood lipid factors, including total cholesterol (TC), triglyceride (TG), high-density lipoprotein-cholesterol (HDL-C), low-density lipoprotein-cholesterol (LDL-C), and malondialdehyde (MDA), were detected and the correlations of were analyzed between the 2 groups of patients. RESULTS The blood lipid index TG, APACHE II score, ET-1, TNF-a, renal function indexes [blood urea nitrogen (BUN) and creatinine (Cr)], mortality rate, hemoglobin, and MDA in the observation group were significantly higher than those in the control group, while HDL-C in the observation group was obviously lower than in the control group (p<0.05). The APACHEII score had positive correlations with TG and TNF-α (r=0.8960, r=0.8563, respectively), while it was negatively correlated with TC, HDL-C, LDL-C, and ET-1 (r=-0.909, r=-0.9292, r=-0.8543, and r=-0.8899, respectively) (p<0.001 in all comparisons). APACHEII score, BUN, and Cr were all risk factors. CONCLUSIONS Stress ulcer in patients with acute cerebral hemorrhage is associated with blood lipid changes and inflammation, which provides clues for the diagnosis and treatment of acute cerebral hemorrhage.


High-throughput amplicon sequencing of rRNA genes requires a copy number correction to accurately reflect the effects of management practices on soil nematode community structure.
Nematodes are abundant consumers in grassland soils, but more sensitive and specific methods of enumeration are needed to improve our understanding of how different nematode species affect, and are affected by, ecosystem processes. High-throughput amplicon sequencing is used to enumerate microbial and invertebrate communities at a high level of taxonomic resolution, but the method requires validation against traditional specimen-based morphological identifications. To investigate the consistency between these approaches, we enumerated nematodes from a 25-year field experiment using both morphological and molecular identification techniques in order to determine the long-term effects of annual burning and nitrogen enrichment on soil nematode communities. Family-level frequencies based on amplicon sequencing were not initially consistent with specimen-based counts, but correction for differences in rRNA gene copy number using a genetic algorithm improved quantitative accuracy. Multivariate analysis of corrected sequence-based abundances of nematode families was consistent with, but not identical to, analysis of specimen-based counts. In both cases, herbivores, fungivores and predator/omnivores generally were more abundant in burned than nonburned plots, while bacterivores generally were more abundant in nonburned or nitrogen-enriched plots. Discriminate analysis of sequence-based abundances identified putative indicator species representing each trophic group. We conclude that high-throughput amplicon sequencing can be a valuable method for characterizing nematode communities at high taxonomic resolution as long as rRNA gene copy number variation is accounted for and accurate sequence databases are available.


Development and further characterization of a small subclass of rat olfactory receptor neurons that shows immunoreactivity for the HSP70 heat shock protein.
We previously described a rat olfactory receptor neuron (ORN) subpopulation [the 2A4(+) ORNs] that shows uniquely strong reactivity with antibodies to the 70-kD heat shock protein (HSP70) family of molecular chaperones (Carr et al. [1994] J. Comp. Neurol. 348:150-160). The 2A4(+)ORNs are dispersed through zones II-IV of the olfactory epithelium (OE), and their axons project to only two or three glomeruli that are located consistently in each olfactory bulb (OB). To date, the 2A4(+)ORN subpopulation is the only cell population to show such distinct HSP70 immunoreactivity as well as the most discrete ORN subpopulation to be so labeled. The present report shows that 2A4(+)ORN neurons first appear between postnatal days 7 (P7) and P10. Initially, low cell numbers rise to a density of 0.1 2A4(+)ORNs/mm OE length by P14, plateau at 0.9 2A4(+)ORNs/mm by P49, then fall to adult values of 0.4 cells/mm. Autoradiographic birthdating indicates that almost all of these early appearing 2A4(+)ORNs are generated postnatally, in contrast to the prenatal generation of all ORN subpopulations characterized to date by their expression of olfactory receptor protein mRNAs. A developmentally related increase in the mean depth of 2A4(+)ORNs within the OE also occurs. In the OB, initial 2A4(+)axonal projections are to only two or three glomeruli, as in adults. Slight but significant rostral shifts in (+)glomerular location occur with development. The 2A4(+)ORN immunoreactivity was found to be due to expression of HSP70, the dominant stress-inducible member of the HSP70 family, rather than constitutively expressed HSC70. In addition, despite their presence in rat OE, no 2A4(+)ORNs were found in mice, gerbils, guinea pigs, or hamsters.


Intracellular Ca2+, inositol 1,4,5-trisphosphate and additional signalling in the stimulation by platelet-activating factor of prostaglandin E2 formation in P388D1 macrophage-like cells.
In the P388D1 macrophage-like cell line, phospholipase A2 activity and prostaglandin production are stimulated by platelet-activating factor (PAF) and bacterial lipopolysaccharide (LPS). We have investigated the role of Ins(1,4,5)P3 and Ca2+ in signal transduction of PAF-induced prostaglandin E2 (PGE2) formation in these cells. The role of Ca2+ in the activation mechanism was studied by fluorescence imaging of intracellular Ca2+ in individual adherent cells and by determining the PGE2 production in the same population of cells. This new approach enabled us to correlate directly events on the single-cell level with a physiologically relevant response of the cell population. Priming the cells with LPS was required for PAF to stimulate PGE2 formation, yet LPS affected neither the intracellular free Ca2+ concentration ([Ca2+]i) nor the PAF-induced rise in [Ca2+]i. In addition, basal and PAF-stimulated Ins(1,4,5)P3 levels were not affected by LPS priming. However, the Ca2+ transient, the release of Ins(1,4,5)P3 and the formation of PGE2 induced by PAF were inhibited in cells pretreated with pertussis toxin. Buffering the [Ca2+]i with intracellular BAPTA [bis-(o-aminophenoxy)ethane-NNN'N'-tetra-acetic acid] blocked the PAF-stimulated rise in [Ca2+]i and PGE2 formation. Removal of extracellular Ca2+ during PAF stimulation prevented the influx of Ca2+, but did not affect the initial [Ca2+]i transient, nor did it inhibit PGE2 formation. Under the same conditions, ionomycin stimulated an identical [Ca2+]i transient, but, in contrast with PAF stimulation, no PGE2 formation was observed. PGE2 production could be rescued by prompt subsequent addition of PAF, which caused no further [Ca2+]i change on its own. These results show that the transient initial rise in [Ca2+]i, produced either by PAF via the formation of Ins(1,4,5)P3 or directly by ionomycin, is necessary, but not sufficient for the formation of PGE2 in LPS-primed P388D1 cells. Furthermore, we have demonstrated for the first time that PAF triggers a second signal that is not mediated by a change in [Ca2+]i. However, both signals are required to induce PGE2 formation.


Viscosity mechanisms in accretion disks
The self-sustained turbulence that develops in magnetized accretion disks is suppressed in the weakly ionized, quiescent disks of close binary stars. Because accretion still proceeds during quiescence, another viscosity mechanism operates in these systems. An anticorrelation of the recurrence times of SU UMa dwarf novae with their mass ratio supports spiral waves or shockwaves tidally induced by the companion star as the main process responsible for accretion in the quiescent disks. Other weakly ionized gaseous disks in systems lacking a massive companion must rely on yet another transport mechanism, or they could be essentially passive.


Gene expression centroids that link with low intrinsic aerobic exercise capacity and complex disease risk.
A strong link exists between low aerobic exercise capacity and complex metabolic diseases. To probe this linkage, we utilized rat models of low and high intrinsic aerobic endurance running capacity that differ also in the risk for metabolic syndrome. We investigated in skeletal muscle gene-phenotype relationships that connect aerobic endurance capacity with metabolic disease risk factors. The study compared 12 high capacity runners (HCRs) and 12 low capacity runners (LCRs) from generation 18 of selection that differed by 615% for maximal treadmill endurance running capacity. On average, LCRs were heavier and had increased blood glucose, insulin, and triglycerides compared with HCRs. HCRs were higher for resting metabolic rate, voluntary activity, serum high density lipoproteins, muscle capillarity, and mitochondrial area. Bioinformatic analysis of skeletal muscle gene expression data revealed that many genes up-regulated in HCRs were related to oxidative energy metabolism. Seven mean mRNA expression centroids, including oxidative phosphorylation and fatty acid metabolism, correlated significantly with several exercise capacity and disease risk phenotypes. These expression-phenotype correlations, together with diminished skeletal muscle capillarity and mitochondrial area in LCR rats, support the general hypothesis that an inherited intrinsic aerobic capacity can underlie disease risks.


A Commensal Bacterium Promotes Virulence of an Opportunistic Pathogen via Cross-Respiration.
Bacteria rarely inhabit infection sites alone, instead residing in diverse, multispecies communities. Despite this fact, bacterial pathogenesis studies primarily focus on monoculture infections, overlooking how community interactions influence the course of disease. In this study, we used global mutant fitness profiling (transposon sequencing [Tn-seq]) to determine the genetic requirements for the pathogenic bacterium Aggregatibacter actinomycetemcomitans to cause disease when coinfecting with the commensal bacterium Streptococcus gordonii Our results show that S. gordonii extensively alters A. actinomycetemcomitans requirements for virulence factors and biosynthetic pathways during infection. In addition, we discovered that the presence of S. gordonii enhances the bioavailability of oxygen during infection, allowing A. actinomycetemcomitans to shift from a primarily fermentative to a respiratory metabolism that enhances its growth yields and persistence. Mechanistically, respiratory metabolism enhances the fitness of A. actinomycetemcomitans in vivo by increasing ATP yields via central metabolism and creating a proton motive force. Our results reveal that, similar to cross-feeding, where one species provides another species with a nutrient, commensal bacteria can also provide electron acceptors that promote the respiratory growth and fitness of pathogens in vivo, an interaction that we term cross-respiration. Commensal bacteria can enhance the virulence of pathogens in mixed-species infections. However, knowledge of the mechanisms underlying this clinically relevant phenomenon is lacking. To bridge this gap, we comprehensively determined the genes a pathogen needs to establish coinfection with a commensal. Our findings show that the metabolism of the pathogen is low-energy-yielding in monoinfection, but in coinfection, the commensal improves the fitness of the pathogen by increasing the bioavailability of oxygen, thereby shifting the pathogen toward a high-energy-yielding metabolism. Similar to cross-feeding, this interaction, which we term cross-respiration, illustrates that commensal bacteria can provide electron acceptors that enhance the virulence of pathogens during infection.


Spontaneous regression of herniated lumbar discs: Report of one illustrative case and review of the literature.
Lumbar disc herniation (LDH) is a common disease that induces back pain and radicular pain. The most efficient method for the treatment of lumbar disc herniation is still controversial. Spontaneous regression of LDH has been recognized with the advancement of radiological diagnostic tools and can explain the reason of spontaneous relief of symptoms without treatment. The proposed hypotheses are; dehydration, retraction of the disc to the hernia in the annulus fibrosis, enzymatic catabolism and phagocytosis. In this study, the case of a patient with huge lumbar disc hernia regressing by itself has been presented and the potential mechanisms of disc regression have been discussed.


Passage of glucose through the cell membrane of capillary endothelium.
The mechanisms of glucose passage through the cell membrane of vascular endothelium were studied in vitro with a preparation of pure blood capillaries isolated from the rete mirabile of the eel swimbladder. In countertransport experiments, no competition for a common carrier could be detected between D-glucose and 3-O-methylglucose or between D-glucose and L-glucose. In the endothelial cells, inward and outward fluxes of labeled sugars were not changed when studied against concentration gradients of corresponding unlabeled sugars. The distribution of 3-O-methylglucose-14C and L-glucose-14C at equilibrium between intracellular and extracellular water was not modified by reducing their specific activity in the medium over a wide range. The addition to the medium of phlorizin 10-5 or 10-7 M, 3-O-methylglucose 60 mM, or L-glucose 60 mM did not reduce the rate of glucose utilization by the capillary tissue. The temperature coefficient for glucose uptake between 27 and 37 degrees C averaged 1.4. Insulin had no effect on the initial rate of 3-O-methylglucose-14C entry into cellular water. It is concluded that in the eel capillaries the mechanism of glucose passage into the vascular endothelial cell is compatible with the kinetics of free diffusion.


S-acylation mediates Mungbean yellow mosaic virus AC4 localization to the plasma membrane and in turns gene silencing suppression.
RNA silencing plays a critical role in plant resistance against viruses. To counteract host defense, plant viruses encode viral suppressors of RNA silencing (VSRs) that interfere with the cellular silencing machinery through various mechanisms not always well understood. We examined the role of Mungbean yellow mosaic virus (MYMV) AC4 and showed that it is essential for infectivity but not for virus replication. It acts as a determinant of pathogenicity and counteracts virus induced gene silencing by strongly suppressing the systemic phase of silencing whereas it does not interfere with local production of siRNA. We demonstrate the ability of AC4 to bind native 21-25 nt siRNAs in vitro by electrophoretic mobility shift assay. While most of the known VSRs have cytoplasmic localization, we observed that despite its hydrophilic nature and the absence of trans-membrane domain, MYMV AC4 specifically accumulates to the plasma membrane (PM). We show that AC4 binds to PM via S-palmitoylation, a process of post-translational modification regulating membrane-protein interactions, not known for plant viral protein before. When localized to the PM, AC4 strongly suppresses systemic silencing whereas its delocalization impairs VSR activity of the protein. We also show that AC4 interacts with the receptor-like kinase (RLK) BARELY ANY MERISTEM 1 (BAM1), a positive regulator of the cell-to-cell movement of RNAi. The absolute requirement of PM localization for direct silencing suppression activity of AC4 is novel and intriguing. We discuss a possible model of action: palmitoylated AC4 anchors to the PM by means of palmitate to acquire the optimal conformation to bind siRNAs, hinder their systemic movement and hence suppress the spread of the PTGS signal in the plant.


Effects of Low-Load Motor Control Exercises and a High-Load Lifting Exercise on Lumbar Multifidus Thickness: A Randomized Controlled Trial.
Randomized controlled trial. The aim of this study was to compare the effects of low-load motor control (LMC) exercises and a high-load lifting (HLL) exercise, on lumbar multifidus (LM) thickness on either side of the spine and whether the effects were affected by pain intensity or change in pain intensity. There is evidence that patients with low back pain (LBP) may have a decreased size of the LM muscles with an asymmetry between sides in the lower back. It has also been shown that LMC training can affect this asymmetry. It is, however, not known whether a high-load exercise has the same effect. Sixty-five participants diagnosed with nociceptive mechanical LBP were included and randomized into LMC exercises or a HLL exercise, the deadlift. The LM thickness was measured using rehabilitative ultrasound imaging (RUSI), at baseline and after a 2-month training period. There were no differences between interventions regarding effect on LM muscle thickness. However, the analysis showed a significant effect for asymmetry. The thickness of the LM muscle on the small side increased significantly compared with the large side in both intervention groups, without influence of pain at baseline, or change in pain intensity. At baseline, there was a difference in thickness of the LM muscles between sides. It seems that exercises focusing on spinal alignment may increase the thickness of the LM muscles on the small side, irrespective of exercise load. The increase in LM thickness does not appear to be mediated by either current pain intensity or the magnitude of change in pain intensity. 2.


Regulation by ACTH of steroid hormone biosynthesis in the adrenal cortex.
In this article, current knowledge about the mechanism of action of ACTH will be reviewed. Emphasis will be placed on events which occur subsequent to binding of ACTH to its receptor, stimulation of adenylate cyclase, and activation of protein kinase. In the first part of the review, the acute action of ACTH will be discussed with emphasis on present hypotheses as to the roles of calcium, phospholipids, sterol carrier proteins, and a "labile protein" activator of cholesterol side-chain cleavage. The presumptive role of these factors to increase the binding of cholesterol to the mitochondrial cholesterol side-chain cleavage enzyme will be discussed in the light of the concept that such binding is the step in steroidogenesis which is activated during the acute response of the adrenal cell to ACTH. In the second part of the article, the long-term action of ACTH to increase the levels of steroidogenic enzymes will be reviewed. Recent evidence is indicative that ACTH causes induction of the synthesis of key steroidogenic enzymes present in both the mitochondria and the microsomes. This appears to result from transcription of genes specific for these various species of cytochrome P-450 and ancillary proteins, resulting in increased synthesis of specific forms of mRNA. Whereas the mitochondrial steroidogenic enzymes are synthesized on cytoplasmic polysomes as precursor forms of higher molecular weight, the microsomal proteins are synthesized as forms of similar molecular weight to the mature forms.


Lung homing of endothelial progenitor cells in humans with asthma after allergen challenge.
Increased bronchial vascularity is a feature of asthma that can contribute to airflow obstruction and progressive decline in lung function. Angiogenesis is associated with the lung homing and in situ differentiation of endothelial progenitor cells (EPC) in mouse models of asthma. We have previously shown that inhibiting allergen (Ag)-induced recruitment of EPC in sensitized mice attenuated increased bronchial vascularity and development of airway hyperresponsiveness. We investigated the accumulation of EPC and formation of new blood vessels in the lungs of human subjects with asthma after Ag inhalation challenge. Consenting patients with mild atopic asthma (n = 13) with FEV1 ≥ 70%, methacholine PC20 ≤ 16 mg/ml, and a dual response to Ag were recruited. Sputum levels of EPC were determined by multigating flow cytometry, and lung vascularity was enumerated by immunostaining with von Willebrand factor. Sputum levels of EPC were determined by multigating flow cytometry and lung vascularity was enumerated by immunostaining with von Willebrand factor. There was a significant increase in sputum EPC levels 24 hours post Ag but not diluent challenge. Similarly, a significant increase in the number and diameter of blood vessels in lung biopsy tissue 24 hours post Ag was observed. In vitro culture of EPC demonstrated the capacity of these cells to differentiate into mature endothelial cells and form tubelike vessel structures. In sputum supernatants, there was a significant increase in CXCR2 agonists, IL-8, and Gro-α 24 hours post Ag. Only Gro-α stimulated a significant EPC migrational response in vitro. Our data suggest that increased lung homing of EPC may promote bronchial vascularity in allergic asthmatic responses and that the recruitment of these progenitors maybe orchestrated by CXCR2 chemokines.


Self-Reported Sleep, Anxiety, and Cognitive Performance in a Sample of U.S. Military Active Duty and Veterans.
Unhealthy sleep can interfere with U.S. military service members affective and cognitive functioning, and increase accident and injury risks. This study examined the relationship between U.S. active duty and veterans' (n = 233) self-reported sleep (Pittsburgh Sleep Quality Index), anxiety (Zung Self-Rating Anxiety Scale), and cognitive performance (Automated Neuropsychological Assessment Metric). Statistical analyses included Pearson product moment correlations and multivariate analysis of variance, with Tukey-b post-hoc tests, with a p < 0.05 significance level. Higher education, abstinence from sleep aids, longer time in active duty service, and being on active duty were correlated with better sleep and lower anxiety. Greater sleep disturbance, poor sleep quality, and sleepiness-related daytime dysfunction were associated with greater anxiety and slower response times, and lower response accuracy. Statistically controlling for anxiety diminished the magnitude and significance of the correlations between sleep and cognitive performance, suggesting that reducing anxiety will improve sleep and diminish cognitive performance effects. These findings suggest the need for addressing both sleep and anxiety for those with diagnosed sleep disorders, as well as using a procedural systems approach to decrease anxiety during missions that demand outstanding cognitive performance.


Detection of attenuated wavy fibers in the myocardium of Newfoundlands without clinical or echocardiographic evidence of heart disease.
To determine whether attenuated wavy fibers may be found in the myocardium of Newfoundlands without clinical or echocardiographic evidence of heart disease. 15 Newfoundlands from a kennel with a known predisposition to dilated cardiomyopathy (DCM) and 32 dogs of other breeds that died suddenly or were euthanatized for reasons unrelated to heart disease and did not have gross postmortem evidence of heart disease. Echocardiography was performed on all Newfoundlands on a yearly basis. Necropsy specimens from all dogs were evaluated for attenuated wavy fibers (i.e., myocardial cells <6 microm in diameter with a wavy appearance). None of the Newfoundlands had clinical signs of heart disease, and results of echocardiographic examinations were within reference ranges. Seven Newfoundlands had histologic evidence of attenuated wavy fibers, whereas attenuated wavy fibers were not found in the remaining 8 Newfoundlands or in any of the 32 dogs of other breeds. Findings suggest that attenuated wavy fibers in dogs with a known predisposition for DCM may indicate an early stage of the disease. However, further studies on a larger number of dogs are needed to confirm this hypothesis.


The effects of vardenafil and pentoxifylline administration in an animal model of ischemic colitis.
Vardenafil enhances dilatation of vascular smooth muscle and inhibits platelet aggregation. The purpose of this study was to evaluate the clinical effects of vardenafil and pentoxifylline administration in an experimental model of ischemic colitis. Forty female Wistar albino rats weighing 250-300 g were randomized into five experimental groups (each with n = 8) as follows:1) a sham group subjected to a sham surgical procedure and administered only tap water; 2) a control group subjected to a standardized surgical procedure to induce ischemic colitis and administered only tap water; 3) and 4) treatment groups subjected to surgical induction of ischemic colitis followed by the postoperative administration of 5 mg/kg or 10 mg/kg vardenafil, respectively; and 5) a treatment group subjected to surgical induction of ischemic colitis followed by postoperative administration of pentoxifylline at 50 mg/kg/day per day as a single dose for a 3-day period. All animals were sacrificed at 72 h post-surgery and subjected to relaparotomy. We scored the macroscopically visible damage, measured the ischemic area and scored histopathology to determine the severity of ischemia. Tissue malondialdehyde levels were also quantified. The mean Gomella ischemic areas were 63.3 mm2 in the control group; 3.4 and 9.6 mm2 in the vardenafil 5 and vardenafil 10 groups, respectively; and 3.4 mm2 in the pentoxifylline group (p = 0.0001). The mean malondialdehyde values were 63.7 nmol/g in the control group; 25.3 and 25.6 nmol/g in the vardenafil 5 and vardenafil 10 groups, respectively; and 22.8 nmol/g in the pentoxifylline group (p = 0.0001). Our findings indicate that vardenafil and pentoxifylline are effective treatment options in an animal model of ischemic colitis. The positive clinical effects produced by these drugs are likely due to their influence on the hemodynamics associated with vascular smooth muscle and platelet functions.


Based on HLA-DR beta1* allele binding specificities, striking differences in distance and TCR Contacting Residue Orientation can be observed in modified protection-inducing malarial synthetic peptides.
An anti-malarial vaccine is urgently needed, especially against P. falciparum which causes 2 to 3 million deaths each year, mostly in Sub-Saharan African children. This vaccine should contain molecules from the parasite's different developmental stages due to the parasite's remarkable complexity and genetic variability. The first approach using synthetic peptides from different parasite stage molecules (the SPf66 malaria vaccine) conferred limited protective efficacy in Aotus monkeys and in large field-trials carried out in different parts of the world SPf66 contains red blood cell (RBC) binding merozoite peptides for which immune responses against them are genetically controlled by HLA-DR region. Therefore, a systematic search of conserved high activity binding peptides (HABP) was undertaken aimed at using them as immunogens. However, these peptides were poorly immunogenic and had poor protection-inducing capacity against experimental challenge with a P. falciparum strain highly infective for Aotus monkeys an experimental model with an immune system quite similar to humans. Modifications were thus made to key residues to render them immunogenic and protection-inducing. These native and modified HABPs' three-dimensional structure was determined by (1)H-NMR studies and their ability in forming stable Major Histocompatibility Class II - peptide (MHCII-peptide) complexes was correlated with their ability to bind in vitro to purified HLA-DR beta1* molecules. Our experimental data suggests a correlation between modified HABPs' three-dimensional structure, HLA-DR beta1* binding preferences and their protection-inducing capacity in monkeys. Furthermore, the data presented here indicates that a synthetic peptide vaccine's three-dimensional structural features dictate both HLA-DR beta1* allele binding preference (imposing genetic restriction on the immune response) and on these vaccines' protection-inducing value. Basic knowledge of a parasite's functionally active peptides, their 3D structure and their interaction for forming the MHC II- peptide-TCR complex will thus contribute towards designing fully effective multi-component, multi-stage subunit-based malarial vaccines.


Nanofluid optical property characterization: towards efficient direct absorption solar collectors.
Suspensions of nanoparticles (i.e., particles with diameters < 100 nm) in liquids, termed nanofluids, show remarkable thermal and optical property changes from the base liquid at low particle loadings. Recent studies also indicate that selected nanofluids may improve the efficiency of direct absorption solar thermal collectors. To determine the effectiveness of nanofluids in solar applications, their ability to convert light energy to thermal energy must be known. That is, their absorption of the solar spectrum must be established. Accordingly, this study compares model predictions to spectroscopic measurements of extinction coefficients over wavelengths that are important for solar energy (0.25 to 2.5 μm). A simple addition of the base fluid and nanoparticle extinction coefficients is applied as an approximation of the effective nanofluid extinction coefficient. Comparisons with measured extinction coefficients reveal that the approximation works well with water-based nanofluids containing graphite nanoparticles but less well with metallic nanoparticles and/or oil-based fluids. For the materials used in this study, over 95% of incoming sunlight can be absorbed (in a nanofluid thickness ≥10 cm) with extremely low nanoparticle volume fractions - less than 1 × 10-5, or 10 parts per million. Thus, nanofluids could be used to absorb sunlight with a negligible amount of viscosity and/or density (read: pumping power) increase.


How can inequalities in mortality be reduced? A quantitative analysis of 6 risk factors in 21 European populations.
Socioeconomic inequalities in mortality are one of the greatest challenges for health policy in all European countries, but the potential for reducing these inequalities is unclear. We therefore quantified the impact of equalizing the distribution of six risk factors for mortality: smoking, overweight, lack of physical exercise, lack of social participation, low income, and economic inactivity. We collected and harmonized data on mortality and risk factors by educational level for 21 European populations in the early 2000s. The impact of the risk factors on mortality in each educational group was determined using Population Attributable Fractions. We estimated the impact on inequalities in mortality of two scenarios: a theoretical upward levelling scenario in which inequalities in the risk factor were completely eliminated, and a more realistic best practice scenario, in which inequalities in the risk factor were reduced to those seen in the country with the smallest inequalities for that risk factor. In general, upward levelling of inequalities in smoking, low income and economic inactivity hold the greatest potential for reducing inequalities in mortality. While the importance of low income is similar across Europe, smoking is more important in the North and East, and overweight in the South. On the basis of best practice scenarios the potential for reducing inequalities in mortality is often smaller, but still substantial in many countries for smoking and physical inactivity. Theoretically, there is a great potential for reducing inequalities in mortality in most European countries, for example by equity-oriented tobacco control policies, income redistribution and employment policies. Although it is necessary to achieve substantial degrees of upward levelling to make a notable difference for inequalities in mortality, the existence of best practice countries with more favourable distributions for some of these risk factors suggests that this is feasible.


Geriatric assessment among older adults receiving intensive therapy for acute myeloid leukemia: Report of CALGB 361006 (Alliance).
To demonstrate feasibility of performing geriatric assessment (GA) in the National Clinical Trials Network (NCTN) and to explore the utility of GA to characterize treatment tolerance. We conducted a multisite companion study (CALGB 361006) to CALGB 11001, a phase 2 trial of adults ≥60 years old with newly diagnosed FLT3- mutated AML, testing the efficacy of adding sorafenib to intensive chemotherapy. On 361006, a GA was administered prior to induction and prior to post-remission therapy. The GA is divided into items requiring administration by a health care professional (HCP) and patient self-administered questionnaires. Feasibility outcomes were recruitment rate, time to GA completion, difficulty with GA administration, percent of patients requiring assistance, and satisfaction. Change in GA measures pre- and post-induction were compared using Wilcoxon signed rank test and McNemar's tests. The recruitment rate was 80% (N = 43, median age 68 years). Median completion time of the GA was 30 min; (10 and 21 min for HCP and patients, respectively). HCP reported no difficulty completing assessments (100%). Most patients completed questionnaires without assistance (77%), and were satisfied with the length (89%). Self-reported physical function, mental health, social activity and nutritional parameters worsened after induction. GA is feasible to administer in the setting of intensive induction for older adults with AML in the NCTN and provides evidence of the impact of induction therapy on physical and emotional health.


Characterization of the binding properties and retrograde axonal transport of a monoclonal antibody directed against the rat nerve growth factor receptor.
We have demonstrated in vitro and in vivo the specific binding of a monoclonal antibody to the rat nerve growth factor (NGF) receptor. Previous work had shown that this antibody, designated 192-IgG, does not compete with NGF for binding to the NGF receptor of PC12 cells, but instead interacts with the receptor to increase NGF binding to PC12 cells (Chandler, C. E., L. M. Parsons, M. Hosang, and E. M. Shooter, 1984, J. Biol. Chem., 259:6882-6889). In the present study, a solid-phase separation assay verified the specific formation of a ternary complex of 192-IgG, the NGF receptor, and NGF: 125I-labeled 192-IgG precipitated from solution only when incubated with both solubilized NGF receptor and NGF covalently linked to a solid phase (Sepharose 4B). Filtration assays using plasma membrane preparations of various tissues showed strict correlation of 125I-192-IgG and 125I-labeled NGF binding; only membranes obtained from superior cervical ganglion bound significant amounts of the monoclonal antibody and NGF. Injection of 125I-192-IgG into the rat anterior eye chamber led to accumulation of intact antibody molecules in the ipsilateral superior cervical ganglion, indicating retrograde axonal transport of 125I-192-IgG from the neuronal termini, located at the iris, to the cell bodies situated in the ganglion. The time course and saturation characteristics of 125I-192-IgG retrograde transport were very similar to those previously reported for 125I-NGF transport, indicating that 192-IgG can be internalized and transported by the same mechanisms as is NGF. Consistent with results of the in vitro binding assays, 192-IgG and NGF failed to compete for retrograde transport and were actually co-transported. Retrograde axonal transport of 192-IgG appears to be species specific, since 125I-192-IgG was transported in the rat, but not in mice, gerbils, hamsters, or guinea pigs. These results establish monoclonal antibody 192-IgG as a specific probe for the rat NGF receptor in vitro and in vivo.


Soft tissue sarcomas of the hand: functional reconstruction and outcome analysis.
Functional hand reconstruction following treatment of soft tissue sarcomas (STS) is a difficult surgical problem. Because survival rates between amputation and limb salvage do not differ, there is a trend toward reconstruction. Unlike amputation, hand salvage usually requires multiple complex operations in combination with adjuvant radiation or chemotherapy, prolonged rehabilitation, and carries a high complication rate. We investigated tumor recurrence, survival, and scored functional outcomes to determine if limb salvage is justified after hand STS resection. Patients treated for hand STS between years 1985 and 2005 were reviewed by two surgeons in three medical centers. All patients having functional reconstruction instead of amputation were reviewed. Patient demographics, tumor type and grade, resection extent, reconstruction procedure, timing, adjuvant therapy use, complications, tumor recurrence, survival, and functional outcome were recorded and analyzed. Five patients underwent functional reconstruction for hand STS. All patients underwent attempted curative resections, and four patients received neoadjuvant or postoperative radiation therapy. Three patients received adjuvant chemotherapy. Reconstructive techniques included three modified pollicizations, one free-tissue transfer, and one groin flap. All patients were alive and disease-free at a mean follow-up of 5 years (range 1.5-17 years). Three patients (60%) had local complications, requiring secondary surgeries. Two complications were related to radiation therapy. Hand function was evaluated using the Enneking Scoring System, and ranged from 17 to 28. The average Enneking score was 22.4, representing an average preservation of 74.6% of function. Because most patients retain excellent function and survival is unaffected, we advocate functional reconstruction despite high complication rates.


Reporting of conflicts of interest from drug trials in Cochrane reviews: cross sectional study.
To investigate the degree to which Cochrane reviews of drug interventions published in 2010 reported conflicts of interest from included trials and, among reviews that reported this information, where it was located in the review documents. Cross sectional study. Cochrane Database of Systematic Reviews. Systematic reviews of drug interventions published in 2010 in the Cochrane Database of Systematic Reviews, with review content classified as up to date in 2008 or later and with results from one or more randomised controlled trials. Of 151 included Cochrane reviews, 46 (30%, 95% confidence interval 24% to 38%) reported information on the funding sources of included trials, including 30 (20%, 14% to 27%) that reported information on trial funding for all included trials and 16 (11%, 7% to 17%) that reported for some, but not all, trials. Only 16 of the 151 Cochrane reviews (11%, 7% to 17%) provided any information on trial author-industry financial ties or trial author-industry employment. Information on trial funding and trial author-industry ties was reported in one to seven locations within each review, with no consistent reporting location observed. Most Cochrane reviews of drug trials published in 2010 did not provide information on trial funding sources or trial author-industry financial ties or employment. When this information was reported, location of reporting was inconsistent across reviews.


All trauma is not created equal: Redefining severe trauma for combat injuries.
Injury severity scores (ISS) and shock index (SI) are popular trauma scoring systems. We assessed ISS and SI in combat trauma to determine the optimal cut-off values for mortality and trauma outcomes. Retrospective analysis of the Department of Defense Trauma Registry, 2008-2016, was performed. Areas under receiver operating characteristic curves (AUROCs) were calculated for ISS and SI on mortality, massive volume transfusion (MVT), and emergent surgical procedure (ESP). Optimal cut-off values were defined using the Youden index (YI). 22,218 patients (97.1% male), median ages 25-29 years, ISS 9.4 ± 0.07, with 58.1% penetrating injury were studied. Overall mortality was 3.4%. AUROCs for ISS on mortality, MVT, and ESP were 0.882, 0.898, and 0.846, while AUROCs for SI were 0.727, 0.864, and 0.711 respectively. The optimal cut-off values for ISS on mortality, MVT, and ESP were 12.5 (YI = 0.634), 12.5 (YI = 0.666), and 12.5 (YI = 0.819), with optimal values for SI being 0.94 (YI = 0.402), 0.88 (YI = 0.608), and 0.81 (YI = 0.345) respectively. Classic values for severe ISS underrepresent combat injury while the SI values defined in this study are consistent with civilian data.


Competitor phenology as a social cue in breeding site selection.
Predicting habitat quality is a major challenge for animals selecting a breeding patch, because it affects reproductive success. Breeding site selection may be based on previous experience, or on social information from the density and success of competitors with an earlier phenology. Variation in animal breeding phenology is often correlated with variation in habitat quality. Generally, animals breed earlier in high-quality habitats that allow them to reach a nutritional threshold required for breeding earlier or avoid nest predation. In addition, habitat quality may affect phenological overlap between species and thereby interspecific competition. Therefore, we hypothesized that competitor breeding phenology can be used as social cue by settling migrants to locate high-quality breeding sites. To test this hypothesis, we experimentally advanced and delayed hatching phenology of two resident tit species on the level of study plots and studied male and female settlement patterns of migratory pied flycatchers Ficedula hypoleuca. The manipulations were assigned at random in two consecutive years, and treatments were swapped between years in sites that were used in both years. In both years, males settled in equal numbers across treatments, but later arriving females avoided pairing with males in delayed phenology plots. Moreover, male pairing probability declined strongly with arrival date on the breeding grounds. Our results demonstrate that competitor phenology may be used to assess habitat quality by settling migrants, but we cannot pinpoint the exact mechanism (e.g. resource quality, predation pressure or competition) that has given rise to this pattern. In addition, we show that opposing selection pressures for arrival timing may give rise to different social information availabilities between sexes. We discuss our findings in the context of climate warming, social information use and the evolution of protandry in migratory animals.