Growth hormone replacement therapy in children with medulloblastoma: use and effect on tumor control.
Progress has been made in the treatment of medulloblastoma, the most common childhood malignant brain tumor: However, many long-term survivors will have posttherapy growth hormone insufficiency with resultant linear growth retardation. Growth hormone replacement therapy (GHRT) may significantly improve growth, but there is often reluctance to initiate GHRT because of concerns of an increased likelihood of tumor relapse. This study retrospectively reviewed the use of GHRT for survivors of medulloblastoma in 11 neuro-oncology centers in North America who received initial treatment for disease between 1980 and 1993 to determine its impact on disease control. A Landmark analysis was used to evaluate the relative risk of relapse in surviving patients. Five hundred forty-five consecutive patients less than 15 years of age at diagnosis were identified. Six-year progression-free survival (mean +/- SD) was 40% +/- 5% in children less than 3 years of age at diagnosis compared with 59% +/- 3% for older patients. Older patients with total or near-total resections (P = .003) and localized disease at diagnosis (P < .0001) had the highest likelihood of survival. One hundred seventy patients (33% +/- 3% of the cohort) received GHRT. GHRT use varied widely among institutions, ranging from 5% to 73%. GHRT was begun a mean of 3.9 years after diagnosis, later in children younger than 3 years at diagnosis (5.4 years). By Landmark analyses, for those surviving 2, 3, and 5 years after diagnosis, there was no evidence that GHRT increased the rate of disease relapse. This large retrospective review demonstrates that GHRT is underutilized in survivors of medulloblastoma and is used relatively late in the course of the illness. GHRT is not associated with an increased likelihood of disease relapse.


Adjuvant-Dependent Enhancement of HIV Env-Specific Antibody Responses in Infant Rhesus Macaques.
Toward the goal of developing an effective HIV vaccine that can be administered in infancy to protect against postnatal and lifelong sexual HIV transmission risks, the current pilot study was designed to compare the effect of novel adjuvants on the induction of HIV Env-specific antibody responses in infant macaques. Aligning our studies with the adjuvanted proteins evaluated in a prime-boost schedule with ALVAC in the ongoing HVTN (HIV Vaccine Trials Network) 702 efficacy trial, we selected the bivalent clade C Env immunogens gp120 C.1086 and gp120 TV1 in combination with the MF59 adjuvant. However, we hypothesized that the adjuvant system AS01, that is included in the pediatric RTS,S malaria vaccine, would promote Env-specific antibody responses superior to those of the oil-in-water MF59 emulsion adjuvant. In a second study arm, we compared two emulsions, glucopyranosyl lipid adjuvant formulated in a stable emulsion (GLA-SE) and 3M-052-SE, containing Toll-like receptor 4 (TLR4) and TLR7/TLR8 (TLR7/8) ligand, respectively. The latter adjuvant had been previously demonstrated to be especially effective in activating neonatal antigen-presenting cells. Our results demonstrate that different adjuvants drive quantitatively or qualitatively distinct responses to the bivalent Env vaccine. AS01 induced higher Env-specific plasma IgG antibody levels than the antigen in MF59 and promoted improved antibody function in infants, and 3M-052-SE outperformed GLA-SE by inducing the highest breadth and functionality of antibody responses. Thus, distinct adjuvants are likely to be required for maximizing vaccine-elicited immune responses in infants, particularly when immunization in infancy aims to elicit both perinatal and lifelong immunity against challenging pathogens such as HIV.IMPORTANCE Alum remains the adjuvant of choice for pediatric vaccines. Yet the distinct nature of the developing immune system in infants likely requires novel adjuvants targeted specifically at the pediatric population to reach maximal vaccine efficacy with an acceptable safety profile. The current study supports the idea that additional adjuvants for pediatric vaccines should be, and need to be, tested in infants for their potential to enhance immune responses. Using an infant macaque model, our results suggest that both AS01 and 3M-052-SE can significantly improve and better sustain HIV Env-specific antibody responses than alum. Despite the limited number of animals, the results revealed interesting differences that warrant further testing of promising novel adjuvant candidates in larger preclinical and clinical studies to define the mechanisms leading to adjuvant-improved antibody responses and to identify targets for adjuvant and vaccine optimization.


Pulmonary hepatic flow distribution in total cavopulmonary connections: extracardiac versus intracardiac.
Pulmonary arteriovenous malformations can occur after the Fontan procedure and are believed to be associated with disproportionate pulmonary distribution of hepatic venous effluent. We studied the effect of total cavopulmonary connection geometry and the effect of increased cardiac output on distribution of inferior vena caval return to the lungs. Ten patients undergoing the Fontan procedure, 5 with extracardiac and 5 with intracardiac configurations of the total cavopulmonary connection, previously analyzed for power loss were processed for calculating the distribution of inferior vena caval return to the lungs (second-order accuracy). One idealized total cavopulmonary connection was similarly analyzed under parametric variation of inferior vena caval offset and cardiac output flow split. Streaming of the inferior vena caval return in the idealized total cavopulmonary connection model was dependent on both inferior vena caval offset magnitude and cardiac output flow-split ratio. For patient-specific total cavopulmonary connections, preferential streaming of the inferior vena caval return was directly proportional to the cardiac output flow-split ratio in the intracardiac total cavopulmonary connections (P < .0001). Preferential streaming in extracardiac total cavopulmonary connections correlated to the inferior vena caval offset (P < .05) and did not correlate to cardiac output flow split. Enhanced mixing in intracardiac total cavopulmonary connections is speculated to explain the contrasting results. Exercising tends to reduce streaming toward the left pulmonary artery in intracardiac total cavopulmonary connections, whereas for extracardiac total cavopulmonary connections, exercising tends to equalize the streaming. Extracardiac and intracardiac total cavopulmonary connections have inherently different streaming characteristics because of contrasting mixing characteristics caused by their geometric differences. Pulmonary artery diameters and inferior vena caval offsets might together determine hepatic flow streaming.


Procedures for calculating cessation lag.
Environmental regulations aimed at reducing cancer risks usually have the effect of reducing exposure to a carcinogen at the time the regulation is implemented. The reduction of cancer risk may occur shortly after the reduced exposure or after a considerable period of time. The time of risk reduction associated with exposure reduction will vary by compound. Some recommended measures of the economic benefits associated with environmental regulations are sensitive to the timing of the risk reductions and cannot be effectively addressed by the conventional dose-response procedures. This paper introduces the concept and methodologies for calculating cessation lag effects, with the specific goal of answering the following questions: (1) How many cancer cases are avoided at age t after cessation (or reduction) of exposure concentration? and (2) How long does the effect of an exposure last after exposure has terminated (or been reduced)? The proposed procedures do not require more information than what is required by the conventional dose-response procedures for which cumulative or an averaged lifetime exposure is used.


High performance liquid chromatography using UV detection for the simultaneous quantification of the new non-nucleoside reverse transcriptase inhibitor etravirine (TMC-125), and 4 protease inhibitors in human plasma.
Etravirine (TMC-125, ETV) is a second-generation non-nucleoside reverse transcriptase inhibitor (NNRTI) that demonstrates potent activity against NNRTI-resistant strains of human immunodeficiency virus type-1 (HIV-1). Thus, ETV has been used in combination with ritonavir-boosted protease inhibitor (PI) and integrase inhibitor for therapy-experienced HIV-1-infected patients. On the other hand, as ETV is a substrate and inducer of cytochrome P450 3A4 (CYP3A4), ETV may induce metabolism of PI and alter the concentrations of co-administered PIs. In order to ensure optimal drug efficacy and prevention of resistance, it is essential to monitor plasma concentrations of ETV and PIs. Here we describe the application of HPLC with UV detection for the simulataneous assay of ETV and 4 PIs, darunavir (DRV), atazanavir (ATV), ritonavir (RTV) and lopinavir (LPV). In this study, the calibration curve of each drug was linear with the average accuracy ranging from 93.6 to 110.9%. Both intra- and interday coefficients of variation for each drug were less than 11.6%. The mean recovery of all drugs ranged from 88.0 to 97.5%. The limit of quantification was 0.04, 0.04, 0.04, 0.05 and 0.07 microg/ml for ETV, DRV, ATV, RTV and LPV, respectively. These results demonstrate that our HPLC-UV method can be used for routine determination of plasma concentrations of ETV and 4 PIs in clinical settings.


Oral delivery of zoledronic acid by non-covalent conjugation with lysine-deoxycholic acid: In vitro characterization and in vivo anti-osteoporotic efficacy in ovariectomized rats.
We assessed the possibility of changing the route of administration of zoledronic acid to an oral dosage form and its therapeutic efficacy in an estrogen-deficient osteoporosis rat model. To enhance oral bioavailability, we formed an ionic complex by electrostatic conjugation of zoledronic acid with lysine-linked deoxycholic acid (Lys-DOCA, an oral absorption enhancer). After forming the complex, the characteristic crystalline features of pure zoledronic acid disappeared completely in the powder X-ray diffractogram and differential scanning calorimetry thermogram, indicating that zoledronic acid existed in an amorphous form in the complex. In vitro permeabilities of zoledronic acid/Lys-DOCA (1:1) (ZD1) and zoledronic acid/Lys-DOCA (1:2) (ZD2) complex across Caco-2 cell monolayers were 2.47- and 4.74-fold higher than that of zoledronic acid, respectively. Upon intra-jejunal administration to rats, the intestinal absorption of zoledronic acid was increased significantly and the resulting oral bioavailability of the ZD2 complex was determined to be 6.76±2.59% (0.548±0.161% for zoledronic acid). Ovariectomized (OVX) rats showed 122% increased bone mineral density versus the OVX control at 12weeks after treatment with once weekly oral administration of ZD2 complex (16μg/kg of zoledronic acid). Furthermore, rats treated with ZD2 complex orally showed significant improvement in the parameters of trabecular microarchitecture and bone strength: 149% higher bone volume fraction (BV/TV), 115% higher trabecular number (Tb.N), and 56% higher mean maximum load (Fmax) than in the OVX group. The trabecular microstructure and bone mechanical properties in the oral zoledronic acid group were not significantly changed compared with the OVX control. Thus, the oral ZD2 complex inhibited osteoporosis progression effectively by promoting osteogenesis and trabecular connectivity. The oral ZD2 complex would be expected to improve patient compliance by replacing the conventional injectable form and expand the indications, to include prophylaxis for osteoporosis and bone metastases.


Programmed cell death 1 ligand 1 (PD-L1) expression is associated with poor prognosis of malignant pleural mesothelioma patients with good performance status.
Malignant pleural mesothelioma (MPM) is often associated with a poor prognosis and options for the treatment of this disease are few. To date, the important role of the immune microenvironment in modifying the disease natural history is well established. The programmed cell death pathway (PD-1/PD-L1) limits the T lymphocyte activation in peripheral tissues when an inflammatory response occurs, and controls the tumour immune escape. PD-L1 is broadly expressed in several malignant tumours and associated with poor clinical outcomes. Thus, the aim of our study is to investigate the potential role of PD-L1 expression in MPM prognosis. Biopsy samples from 198 patients diagnosed with MPM were examined by immunohistochemistry (IHC) and reverse transcription-polymerase chain reaction (RT-PCR) to evaluate PD-L1 protein and gene expression. For PD-L1 protein expression we consider at least 5% membranous staining as positive. Gene expression levels were calculated with ΔΔCt method. Positive expression of PD-L1 by IHC was correlated with worse overall survival (OS; p=0.0225) in MPM patients. PD-L1 positive status was correlated with worse OS in the subgroup of patients with ECOG score <2 (p=0.0004, n=129) and these data were confirmed by multivariate analysis. No significant correlation was found between PD-L1 gene expression and OS. Our results show that PD-L1 evaluated by IHC assay may be a prognostic biomarker for MPM patients with good performance status.


Validation of the continuous glucose monitoring sensor in preterm infants.
Recent studies have highlighted the need for improved methods of monitoring glucose control in intensive care to reduce hyperglycaemia, without increasing the risk of hypoglycaemia. Continuous glucose monitoring is increasingly used in children with diabetes, but there are little data regarding its use in the preterm infant, particularly at extremes of glucose levels and over prolonged periods. This study aimed to assess the accuracy of the continuous glucose monitoring sensor (CGMS) across the glucose profile, and to determine whether there was any deterioration over a 7 day period. Prospectively collected CGMS data from the NIRTURE Trial was compared with the data obtained simultaneously using point of care glucose monitors. An international multicentre randomised controlled trial. One hundred and eighty-eight very low birth weight control infants. Optimal accuracy, performance goals (American Diabetes Association consensus), Bland Altman, Error Grid analyses and accuracy. The mean (SD) duration of CGMS recordings was 156.18 (29) h (6.5 days), with a total of 5207 paired glucose levels. CGMS data correlated well with point of care devices (r=0.94), with minimal bias. It met the Clarke Error Grid and Consensus Grid criteria for clinical significance. Accuracy of single readings to detect set thresholds of hypoglycaemia, or hyperglycaemia was poor. There was no deterioration over time from insertion. CGMS can provide information on trends in glucose control, and guidance on the need for blood glucose assessment. This highlights the potential use of CGMS in optimising glucose control in preterm infants.


A 5-year longitudinal study of the clinical effectiveness of ITI solid-screw implants in the treatment of mandibular edentulism.
The aim of this longitudinal study was to gain 5-year clinical documentation of the 1-stage surgical technique in connection with ITI solid-screw implants used in the edentulous mandible. One hundred patients with totally edentulous mandibles were treated with bar-retained overdentures supported by a total of 340 consecutively placed ITI solid-screw implants. The patients were followed at annual intervals for at least 5 years to evaluate implant success, longitudinal reactions of the peri-implant hard and soft tissues, and incidences of biologic and mechanical complications. During the trial period, a total of 4 implants failed, all prior to loading, and 51 implants were lost to follow-up, resulting in a cumulative survival rate of 98.8% after 5 years of functional service. The success analysis included additional strictly defined events (either "first occurrence of marginal bone loss > or = 4 mm" or "first occurrence of pocket depth > or = 4 mm" and "first occurrence of crevicular fluid flow rate > or = 2.5 mm) and resulted in a cumulative 5-year success rate of 95.7%. The median marginal bone loss experienced between implant placement and prosthetic treatment was 0.5 mm, followed by an annual bone level change of 0.1 mm for the functional period of 5 years. The increasing incidence of remarkable plaque deposits from 19% to 50% represented the difficulties of the patients in maintaining a high level of oral hygiene, particularly for the lingual surfaces. Sulcus Bleeding Index, probing depth, attachment level, and crevicular fluid flow rate were used to describe the health of the peri-implant soft tissues and remained almost within acceptable standards. Survival and success rates of implants, amount of marginal bone loss, and periodontal indices of peri-implant soft tissues were consistent with those reported in the literature regarding implants with the submerged healing concept. With a cumulative survival rate of 98.8%, a cumulative success rate of 95.7%, and a median marginal bone loss of 0.5 mm during the healing period, followed by an annual rate of 0.1 mm after loading, non-submerged ITI solid-screw implants confirm the good clinical outcome of implant-supported treatment concepts for the rehabilitation of totally edentulous patients in a medium-term perspective.


Development of a simplified dual-pump dual-broadband coherent anti-Stokes Raman scattering system.
A dual-pump dual-broadband coherent anti-Stokes Raman scattering (CARS) setup for simultaneous pure rotational and vibrational CARS is further developed by reducing the experimental efforts due to the use of only one detection system. With this system dual-pump CARS for probing ro-vibrational transitions of N(2)/CO/H(2) and dual-broadband CARS for pure rotational transitions of N(2)/O(2)/CO/CO(2) are applicable simultaneously. In this work the improvements to the setup and the data evaluation are described. First simultaneous temperature and concentration results from cell measurements and from a partially premixed propane flame are presented. Interference effects due to smeared vibrational CARS are investigated. It is shown that with similar experimental effort to a conventional dual-pump CARS setup considerably more information can be gained.


Morphologically defined subgenera of Plasmodium from avian hosts: test of monophyly by phylogenetic analysis of two mitochondrial genes.
Malaria parasites in the genus Plasmodium are now placed within 11 subgenera based on morphology under the light microscope, life-history traits, and host taxon. The phylogenetic significance of these characters, however, is problematic because the observed variation could be homoplasious. Using Plasmodium infections found in 2632 birds of many avian families collected in the USA, and several samples from other locations, we compared identifications to subgenus based on morphology in blood smears with a 2-gene molecular phylogeny (the first for avian Plasmodium) to determine if the 5 avian Plasmodium subgenera represent monophyletic groups. Phylogenetic trees recovered by parsimony, likelihood, and Bayesian methods presented nearly identical topologies. The analysis allowed testing the hypothesis of monophyly for the subgenera. Monophyly of the subgenera Haemamoeba, Huffia, and Bennettinia was supported by the analysis. The distinctive morphology of Haemamoeba species appears to have evolved once. Most samples identified to Novyella also fell within a monophyletic clade with the exception of 2 samples that fell basal to all other avian Plasmodium. Samples of the subgenus Giovannolaia did not form a monophyletic group. Thus, the characters used by parasitologists for over a century to define subgenera of Plasmodium vary in their phylogenetic significance.


A comparative performance analysis of stand-alone, off-grid solar-powered sodium hypochlorite generators.
Sodium hypochlorite (NaClO) is a chemical commodity widely employed as a disinfection agent in water treatment applications. Its production commonly follows electrochemical routes in an undivided reactor. Powering the process with photovoltaic (PV) electricity holds the potential to install stand-alone, independent generators and reduce the NaClO production cost. This study reports the comparative assessment of autonomous, solar-powered sodium hypochlorite generators employing different photovoltaic (PV) technologies: silicon hetero-junction (SHJ) and multi-junction (MJ) solar cells. For Si hetero-junctions, the series connection of either four or five SHJ (4SHJ and 5SHJ, respectively) cells was implemented to obtain the reaction potential required. MJ cells were illuminated by a novel planar solar concentrator that guarantees solar tracking with minimal linear displacements. The three solar-hypochlorite generators were tested under real atmospheric conditions, demonstrating solar-to-chemical conversion efficiencies (SCE) of 9.8% for 4SHJ, 14.2% for 5SHJ and 25.1% for MJ solar cells, respectively. Simulations based on weather databases allowed us to assess efficiencies throughout the entire model year and resulted in specific sodium hypochlorite yearly production rates between 7.2-28 gNaClO cm-2 (referred to the PV surface), depending on the considered PV technology, location, and deployment of electronics converters. The economic viability and competitiveness of solar hypochlorite generators have been investigated and compared with an analog disinfection system deploying ultraviolet lamps. Our study demonstrates the feasibility of off-grid, solar-hypochlorite generators, and points towards the implementation of SHJ solar cells as a reliable technology for stand-alone solar-chemical devices.


Systematic approach to determination of maximum achievable capture capacity via leaching and carbonation processes for alkaline steelmaking wastes in a rotating packed bed.
Accelerated carbonation of basic oxygen furnace slag (BOFS) coupled with cold-rolling wastewater (CRW) was performed in a rotating packed bed (RPB) as a promising process for both CO2 fixation and wastewater treatment. The maximum achievable capture capacity (MACC) via leaching and carbonation processes for BOFS in an RPB was systematically determined throughout this study. The leaching behavior of various metal ions from the BOFS into the CRW was investigated by a kinetic model. In addition, quantitative X-ray diffraction (QXRD) using the Rietveld method was carried out to determine the process chemistry of carbonation of BOFS with CRW in an RPB. According to the QXRD results, the major mineral phases reacting with CO2 in BOFS were Ca(OH)2, Ca2(HSiO4)(OH), CaSiO3, and Ca2Fe1.04Al0.986O5. Meanwhile, the carbonation product was identified as calcite according to the observations of SEM, XEDS, and mappings. Furthermore, the MACC of the lab-scale RPB process was determined by balancing the carbonation conversion and energy consumption. In that case, the overall energy consumption, including grinding, pumping, stirring, and rotating processes, was estimated to be 707 kWh/t-CO2. It was thus concluded that CO2 capture by accelerated carbonation of BOFS could be effectively and efficiently performed by coutilizing with CRW in an RPB.


Using Principles of Complex Adaptive Systems to Implement Secondary Prevention of Coronary Heart Disease in Primary Care.
Primary care practice. To test whether the principles of complex adaptive systems are applicable to implementation of team-based primary care. We used complex adaptive system principles to implement team-based care in a private, five-clinic primary care practice. We compared randomly selected samples of patients with coronary heart disease (CHD) and diabetes before system implementation (March 1, 2009, to February 28, 2010) and after system implementation (December 1, 2011, to March 31, 2013). Rates of patients meeting the composite goals for CHD (blood pressure < 140/90 mmHg, low-density lipoprotein cholesterol level < 100 mg/dL, tobacco-free, and using aspirin unless contraindicated) and diabetes (CHD goal plus hemoglobin A1c concentration < 8%) before and after the intervention. We also measured provider and patient satisfaction with preventive services. The proportion of patients with CHD who met the composite goal increased from 40.3% to 59.9% (p < 0.0001) because documented aspirin use increased (65.2%-97.5%, p < 0.0001) and attainment of the cholesterol goal increased (77.0%-83.9%, p = 0.0041). The proportion of diabetic patients meeting the composite goal rose from 24.5% to 45.4% (p < 0.0001) because aspirin use increased (58.6%-97.6%, p < 0.0001). Increased percentages of patients meeting the CHD and diabetes composite goals were not significantly different (p = 0.2319). Provider satisfaction with preventive services delivery increased significantly (p = 0.0017). Patient satisfaction improved but not significantly. Principles of complex adaptive systems can be used to implement team-based care systems for patients with CHD and possibly diabetic patients.


Assimilation and transport of organic bound tritium in an irrigated pine forest.
The speciation of radioactive tritium (T) in a naturally-established subtropical loblolly pine forest that has been irrigated with highly-contaminated pond water for the last 20 years is reported. This irrigation project was created to limit the underground transport of a tritium-rich plume which also contains low levels of toxic organics, metals and radionuclides such as carbon-14 (14C) from a nearby low-level waste burial ground. The levels of tritiated water (HTO) in the wood cores were not influenced by recent irrigation activities. However, the tritium levels in the last 20 years of tree growth were more than 3-fold higher than that of tritium in the older growth. This was due to recent irrigation with organic-bound tritium (OBT)-rich water and subsequent accumulation of high levels tritium as OBT relative to tissue HTO. High levels of pond irrigation water OBT resulted from biogenic processes that converted HTO to OBT. Data for 14C that were acquired for some of the forest materials indicated that the processes controlling the movement and accumulation of 14C in this system are somewhat different than that of tritium. Spectroscopic characterization of tree core tissue of <20 years in age found no explanation for the unusually wide dark growth rings. It was concluded that the trees were over-irrigated based on results from other published studies with wood from severely-flooded areas. Although HTO is indeed toxic to biota, OBT represents a relatively greater hazard to biota because it can be bioaccumulated and retained for long periods of time in living tissues.


Activation of Nrf2 and Hypoxic Adaptive Response Contribute to Neuroprotection Elicited by Phenylhydroxamic Acid Selective HDAC6 Inhibitors.
Activation of HIF-1α and Nrf2 is a primary component of cellular response to oxidative stress, and activation of HIF-1α and Nrf2 provides neuroprotection in models of neurodegenerative disorders, including ischemic stroke, Alzheimer's and Parkinson's diseases. Screening a library of CNS-targeted drugs using novel reporters for HIF-1α and Nrf2 elevation in neuronal cells revealed histone deacetylase (HDAC) inhibitors as potential activators of these pathways. We report the identification of phenylhydroxamates as single agents exhibiting tripartite inhibition of HDAC6, inhibition of HIF-1 prolyl hydroxylase (PHD), and activation of Nrf2. Two superior tripartite agents, ING-6 and ING-66, showed neuroprotection against various cellular insults, associated with stabilization of both Nrf2 and HIF-1, and expression of their respective target genes in vitro and in vivo. Discovery of the innate ability of phenylhydroxamate HDAC inhibitors to activate Nrf2 and HIF provides a novel route to multifunctional neuroprotective agents and cautions against HDAC6 selective inhibitors as chemical probes of specific HDAC isoform function.


Methods used by the United States National Institute for Occupational Safety and Health to monitor crystalline silica.
The National Institute for Occupational Safety and Health (NIOSH) in the United States has four methods for monitoring the concentration of crystalline silica dust. They all employ a cyclone for size-selective sampling in the field, but differ primarily in that the laboratory measurement is based on either infrared spectroscopy, X-ray diffraction, or colorimetry. The limits of detection for these methods are similar, but their accuracy is poor, particularly at low filter loadings near the current recommended exposure limit (50 mu g center dot m-3). Advances in analytical instrumentation have improved measurement precision. Correction techniques to account for X-ray absorption in samples loaded with nonsilica dust have eliminated one source of bias. Direct analysis on collection filters is a convenient technique that should decrease sample manipulation errors, but it has not been shown to improve precision or accuracy significantly.


Properties of a conductive cellular chloride pathway in the skin of the toad (Bufo bufo).
Two types of chloride current response to a step-wise hyperpolarization of the toad skin is demonstrated: (1) An "instantaneous" response observed immediately upon voltage change, and (2) a subsequent slow response, the time course of which is sigmoidal. The slow response is due to an increase of a transcellular conductance which is specific to chloride ions. The time constant of the conductance increase is dependent on the amplitude of the transepithelial voltage displacement, the smallest time constants are obtained for the highest amplitudes and are in the order of 30 s. The voltage dependences of the steady-state conductance and the steady-state chloride current reveal that the chloride pathway has maximum conductance for V approximately -80 mV (outside of the skin being negative) and approaches a non-conducting safe for V greater than 0 mV. This strong outward going rectification is a steady-state phenomenon: In skins hyperpolarized for a few minutes, the "instantaneous" I-V curves show that the chloride pathway in the conducting state allows a large inward chloride current (outward chloride flux) to pass in the voltage range 40 mV greater than V greater than 0 mV. Calculations based on a three-compartment model indicate that the strong steady-state chloride current rectification cannot be obtained if only the intracellular chloride concentration and the membrane potentials are allowed to vary ("Goldman-rectification"). It is suggested, therefore, that the premeability of the chloride pathway varies reversibly with the transepithelial potential difference. The variable which controls the chloride permeability may be a membrane potential or the concentration of an intracellular ion.


Extracellular aromatic biosurfactant produced by Tsukamurella pseudospumae and T. spumae during growth on n-hexadecane.
Biosurfactants are surface-active agents produced by microorganisms and show increasing significance in various industrial applications. A great variety of these secondary metabolites are described to occur within actinomycetes, amongst trehalose lipids and oligosaccharide lipids produced by the family Tsukamurellaceae. This study reports on the production of not yet described compounds with surface active behavior by non-pathogenic Tsukamurella pseudospumae and Tsukamurella spumae during growth on hydrophobic carbon sources. Extracts of the purified compounds differ in terms of structure and performance properties to other biosurfactants described within their family. Infrared and nuclear magnetic resonance spectroscopic analysis revealed the presence of aromatic moieties within the surfactant produced, which to date is only known to occur within phenolic glycolipids of some mycobateria.


Structural model of a putrescine-cadaverine permease from Trypanosoma cruzi predicts residues vital for transport and ligand binding.
The TcPOT1.1 gene from Trypanosoma cruzi encodes a high affinity putrescine-cadaverine transporter belonging to the APC (amino acid/polyamine/organocation) transporter superfamily. No experimental three-dimensional structure exists for any eukaryotic member of the APC family, and thus the structural determinants critical for function of these permeases are unknown. To elucidate the key residues involved in putrescine translocation and recognition by this APC family member, a homology model of TcPOT1.1 was constructed on the basis of the atomic co-ordinates of the Escherichia coli AdiC arginine/agmatine antiporter crystal structure. The TcPOT1.1 homology model consisted of 12 transmembrane helices with the first ten helices organized in two V-shaped antiparallel domains with discontinuities in the helical structures of transmembrane spans 1 and 6. The model suggests that Trp241 and a Glu247-Arg403 salt bridge participate in a gating system and that Asn245, Tyr148 and Tyr400 contribute to the putrescine-binding pocket. To test the validity of the model, 26 site-directed mutants were created and tested for their ability to transport putrescine and to localize to the parasite cell surface. These results support the robustness of the TcPOT1.1 homology model and reveal the importance of specific aromatic residues in the TcPOT1.1 putrescine-binding pocket.


Protein C, antithrombin, and venous thromboembolism incidence: a prospective population-based study.
Although deficiencies of protein C and antithrombin, 2 natural plasma anticoagulants, are known risk factors for venous thrombosis, population-based prospective incidence data on these associations are lacking. Venous thromboembolic events have been identified in adults in 2 longitudinal cohort studies, the Atherosclerosis Risk in Communities (ARIC) Study and the Cardiovascular Health Study (CHS). Incidence was examined in relation to prediagnostic plasma levels of protein C (ARIC Study only) and antithrombin. Over a mean of 8.1 years of follow-up, there were 130 incident venous thromboembolic events that were not due to cancer in the ARIC Study. The age-adjusted incidence was elevated 3.36-fold (95% CI 1.24 to 9.11) in the 1.1% of subjects with protein C values <2.0 mg/L compared with subjects with higher values. In contrast, in the ARIC Study and the CHS, there was no association between low plasma antithrombin and venous thromboembolism. In conclusion, in this population-based study, a low protein C, but not antithrombin, level has been determined to be associated with an increased incidence of venous thromboembolism. Attributable risk estimates suggest that low protein C levels account for approximately 2.5% of venous thromboembolic events in the ARIC population.


Comparative effectiveness of HIV testing and treatment in highly endemic regions.
Universal testing and treatment holds promise for reducing the burden of human immunodeficiency virus (HIV) in sub-Saharan Africa, but linkage from testing to treatment sites and retention in care are inadequate. We developed a simulation of the HIV epidemic and HIV disease progression in South Africa to compare the outcomes of the present HIV treatment campaign (status quo) with 4 HIV testing and treating strategies that increase access to antiretroviral therapy: (1) universal testing and treatment without changes in linkage to care and loss to follow-up; (2) universal testing and treatment with improved linkage to care; (3) universal testing and treatment with reduced loss to follow-up; and (4) comprehensive HIV care with universal testing and treatment, improved linkage to care, and reduced loss to follow-up. The main outcome measures were survival benefits, new HIV infections, and HIV prevalence. Compared with the status quo strategy, universal testing and treatment (1) was associated with a mean (95% uncertainty bounds) life expectancy gain of 12.0 months (11.3-12.2 months), and 35.3% (32.7%-37.5%) fewer HIV infections over a 10-year time horizon. Improved linkage to care (2), prevention of loss to follow-up (3), and comprehensive HIV care (4) provided substantial additional benefits: life expectancy gains compared with the status quo strategy were 16.1, 18.6, and 22.2 months, and new infections were 55.5%, 51.4%, and 73.2% lower, respectively. In sensitivity analysis, comprehensive HIV care reduced new infections by 69.7% to 76.7% under a broad set of assumptions. Universal testing and treatment with current levels of linkage to care and loss to follow-up could substantially reduce the HIV death toll and new HIV infections. However, increasing linkage to care and preventing loss to follow-up provides nearly twice the benefits of universal testing and treatment alone.


3D carbon nanofiber microelectrode arrays fabricated by plasma-assisted pyrolysis to enhance sensitivity and stability of real-time dopamine detection.
In this paper, we have fabricated 3D carbon nanofiber microelectrode arrays (MEAs) with highly reproducible and rich chemical surface areas for fast scan cyclic voltammetry (FSCV). Carbon nanofibers are created from negative photoresist by a new process called dual O2 plasma-assisted pyrolysis. The proposed approach significantly improves film adhesion and increases surface reactivity. We showcase our sensor's compatibility with FSCV analysis by demonstrating highly sensitive and stable FSCV dopamine measurements on a prototype 4-channel array. We envision with proper surface fuctionalization the 3D carbon nanofiber MEA enable sensitive and reliable detection of multiple neurotransmitters simultaneously.


Finite element scaling analysis of human craniofacial growth.
The study of form change is central to traditional cephalometric research. Unfortunately, traditional cephalometric studies operate within systems of measurement that are based on registration and orientation. Measurements produced in registered systems are insufficient for the craniofacial biologist who is interested in locating morphological differences between forms. In this article we apply a registration-free method called finite element scaling analysis in a study of the form change occurring during growth of the normal human craniofacial complex. The method provides form change data that can be summarized at various morphological levels. Twenty normal male individuals are used to analyze the form change that occurs from age 4 to ages 5, 7, 8, 9, 10, 12, 13, and 15 years. The magnitude and direction of growth expressed as shape and size change specific to craniofacial landmarks are presented. Although exceptions occur, our analysis shows that localized size change is, on the average, greater than localized shape change. The relation between size and shape change during growth shows allometry (shape change increasing during growth along with size change) but at a lesser magnitude and slower rate. We conclude that although shape change occurs throughout ontogeny, the magnitude and rate of shape change in relation to size change diminishes as age increases. This analysis represents new insights into the understanding of human craniofacial growth at various levels of morphological integration.


Thermal dimensional instabilities of beryllium mirrors.
A method for evaluating the thermal dimensional stability and homogeneity of beryllium mirrors is described. Thermal dimensional instabilities are shown to be highly dependent on crystalline anisotropy. An x-ray quality control technique is discussed which can be used to predict optical performance under changes in ambient temperature.


Hyperleptinemia as a robust risk factor of coronary artery disease and metabolic syndrome in type 2 diabetic patients.
Leptin has been linked to adiposity, insulin resistance, and coronary artery disease (CAD). We examined whether the leptin concentrations are associated with the risk of CAD and metabolic syndrome (MS). The plasma leptin concentrations were measured in 556 diabetic patients (341 men and 215 women). The odds ratio (OR) of CAD and MS were increased on moving from the lowest quartile (Q1) of leptin concentration to the highest quartile (Q4) and remained significant after adjusting for age, sex, BMI, concentrations of total cholesterol, triglyceride, or high-sensitivity C-reactive protein (hsCRP), and treatment modalities for hyperglycemia. The frequency of CAD was highest in the insulin resistant group (Q4 of homeostasis model assessment-insulin resistance index [HOMA-IR]) at Q4 of leptin concentration (34.5%), compared with that of Q4 of leptin (26.4%) or HOMA-IR (21.9%). In multivariate analysis, plasma leptin concentration was identified as the most significantly independent predictor for CAD (OR 10.24, 95% CI 3.01 to 45.05). Other variables with associated with CAD were age, sex, hypertension, low-HDL cholesterolemia, and hsCRP. In conclusion, hyperleptinemia might be an independent risk factor for CAD and MS in diabetic subjects. And the simultaneous measurement of insulin resistance and leptin concentration might be helpful for screening subjects with a high-risk of CAD.


Vaccinia virus gene B1R encodes a 34-kDa serine/threonine protein kinase that localizes in cytoplasmic factories and is packaged into virions.
Vaccinia virus open reading frame B1R was expressed in E. coli and shown to encode a serine/threonine protein kinase which phosphorylated casein and calf thymus histones in vitro. A polyclonal rabbit antiserum was raised against a TrpE-B1R bacterial fusion protein and used to characterize the B1R gene product. Immunoprecipitation and immunoblotting analyses detected a 34-kDa polypeptide that was synthesized early during vaccinia virus infection and which was apparently stable since it was easily detectable 18 hr postinfection. Immunofluorescence demonstrated that this protein localizes in cytoplasmic virus factories, the sites of virus DNA replication. Immunoblotting of vaccinia virions showed that the enzyme is packaged into virus particles.


Exploring the use of internal and externalcontrols for assessing microarray technical performance.
The maturing of gene expression microarray technology and interest in the use of microarray-based applications for clinical and diagnostic applications calls for quantitative measures of quality. This manuscript presents a retrospective study characterizing several approaches to assess technical performance of microarray data measured on the Affymetrix GeneChip platform, including whole-array metrics and information from a standard mixture of external spike-in and endogenous internal controls. Spike-in controls were found to carry the same information about technical performance as whole-array metrics and endogenous "housekeeping" genes. These results support the use of spike-in controls as general tools for performance assessment across time, experimenters and array batches, suggesting that they have potential for comparison of microarray data generated across species using different technologies. A layered PCA modeling methodology that uses data from a number of classes of controls (spike-in hybridization, spike-in polyA+, internal RNA degradation, endogenous or "housekeeping genes") was used for the assessment of microarray data quality. The controls provide information on multiple stages of the experimental protocol (e.g., hybridization, RNA amplification). External spike-in, hybridization and RNA labeling controls provide information related to both assay and hybridization performance whereas internal endogenous controls provide quality information on the biological sample. We find that the variance of the data generated from the external and internal controls carries critical information about technical performance; the PCA dissection of this variance is consistent with whole-array quality assessment based on a number of quality assurance/quality control (QA/QC) metrics. These results provide support for the use of both external and internal RNA control data to assess the technical quality of microarray experiments. The observed consistency amongst the information carried by internal and external controls and whole-array quality measures offers promise for rationally-designed control standards for routine performance monitoring of multiplexed measurement platforms.


[MicroRNAs: circulating biomarkers in type 2 Diabetes Mellitus and physical exercise].
MicroRNAs are small, non-coding molecules with a crucial function in the cell´s biologic regulation. Circulating levels of miRNAs may be useful biomarkers in metabolic diseases such as type 2 Diabetes Mellitus (DM2), which alters the circulating concentrations of several types of miRNA. Specific serum profiles of these molecules have been identified in high-risk patients before the development of DM2 and its chronic complications. Most importantly, these profiles can be modified with physical exercise, which is crucial in the treatment of metabolic diseases. Acute physical activity alone can induce changes in tissue specific miRNAs, and responses are different in aerobic or non-aerobic training. Muscle and cardiovascular miRNAs, which may play an important role in the adap tation to exercise, are predominantly altered. Even further, there is a correlation between serum levels of miRNAs and fitness, suggesting a role for chronic exercise in their regulation. Thus, miRNAs are molecules of growing importance in exercise physiology, and may be involved in the mechanisms behind the beneficial effects of physical activity for patients with metabolic diseases.


Systematic review: an evaluation of major commercial weight loss programs in the United States.
Each year millions of Americans enroll in commercial and self-help weight loss programs. Health care providers and their obese patients know little about these programs because of the absence of systematic reviews. To describe the components, costs, and efficacy of the major commercial and organized self-help weight loss programs in the United States that provide structured in-person or online counseling. Review of company Web sites, telephone discussion with company representatives, and search of the MEDLINE database. Randomized trials at least 12 weeks in duration that enrolled only adults and assessed interventions as they are usually provided to the public, or case series that met these criteria, stated the number of enrollees, and included a follow-up evaluation that lasted 1 year or longer. Data were extracted on study design, attrition, weight loss, duration of follow-up, and maintenance of weight loss. We found studies of eDiets.com, Health Management Resources, Take Off Pounds Sensibly, OPTIFAST, and Weight Watchers. Of 3 randomized, controlled trials of Weight Watchers, the largest reported a loss of 3.2% of initial weight at 2 years. One randomized trial and several case series of medically supervised very-low-calorie diet programs found that patients who completed treatment lost approximately 15% to 25% of initial weight. These programs were associated with high costs, high attrition rates, and a high probability of regaining 50% or more of lost weight in 1 to 2 years. Commercial interventions available over the Internet and organized self-help programs produced minimal weight loss. Because many studies did not control for high attrition rates, the reported results are probably a best-case scenario. With the exception of 1 trial of Weight Watchers, the evidence to support the use of the major commercial and self-help weight loss programs is suboptimal. Controlled trials are needed to assess the efficacy and cost-effectiveness of these interventions.


Genomics-enabled analysis of the emergent disease cotton bacterial blight.
Cotton bacterial blight (CBB), an important disease of (Gossypium hirsutum) in the early 20th century, had been controlled by resistant germplasm for over half a century. Recently, CBB re-emerged as an agronomic problem in the United States. Here, we report analysis of cotton variety planting statistics that indicate a steady increase in the percentage of susceptible cotton varieties grown each year since 2009. Phylogenetic analysis revealed that strains from the current outbreak cluster with race 18 Xanthomonas citri pv. malvacearum (Xcm) strains. Illumina based draft genomes were generated for thirteen Xcm isolates and analyzed along with 4 previously published Xcm genomes. These genomes encode 24 conserved and nine variable type three effectors. Strains in the race 18 clade contain 3 to 5 more effectors than other Xcm strains. SMRT sequencing of two geographically and temporally diverse strains of Xcm yielded circular chromosomes and accompanying plasmids. These genomes encode eight and thirteen distinct transcription activator-like effector genes. RNA-sequencing revealed 52 genes induced within two cotton cultivars by both tested Xcm strains. This gene list includes a homeologous pair of genes, with homology to the known susceptibility gene, MLO. In contrast, the two strains of Xcm induce different clade III SWEET sugar transporters. Subsequent genome wide analysis revealed patterns in the overall expression of homeologous gene pairs in cotton after inoculation by Xcm. These data reveal important insights into the Xcm-G. hirsutum disease complex and strategies for future development of resistant cultivars.


[Epidemiology of screening-targeted cancers according to new data of the Czech National Cancer Registry].
The Czech Society for Oncology has developed an information system which combines the population-based Czech National Cancer Registry with clinical databases in order to cover the main areas of health care assessment - monitoring of the population burden, prediction of the number of cancer patients, diagnostic and treatment results. The presented data demonstrate a high cancer burden within the Czech population - each year there are approximately 8,000 new cases of colorectal cancer, 6,500 new cases of breast cancer, and 1,000 new cases of cervical cancer. And each year, about 4,000 people die from colorectal cancer, around 2,000 women die from breast cancer, and approximately 400 women die from cervical cancer in the Czech Republic. Population-based screening programmes focus on all of the above-mentioned groups of malignant tumours; therefore, it is essential to monitor epidemiological trends in order to assess the screening impact. Despite the high incidence rates of all three cancer types, the trend in mortality rates has been stable or has even decreased in the long term, which has inevitably led to a significant increase in the total prevalence of cancer patients. In 2011, the prevalence of colorectal cancer, breast cancer and cervical cancer amounted to 51,064 people, 67,261 women and 17,398 women, respectively. When compared with the year 2001, there was a 59%, 69% and 25% increase in the prevalence of colorectal cancer, breast cancer, and cervical cancer, respectively. Undoubtedly, taking care of high numbers of cancer patients will continue to require significant financial resources in the near future. As the epidemiological burden is still on the increase, preventive programmes need to be further promoted, including secondary prevention, which is provided through organised screening programmes. Although effective methods exist for timely diagnosis of all three of the above-mentioned cancer types, the epidemiological situation in the Czech Republic is being steadily worsened by a relatively high proportion of primary cancers being diagnosed too late. Each year, more than 50% of new colorectal cancer cases are diagnosed in clinical stage III or higher; in cervical cancer, this proportion is nearly 35%. By contrast, the well-promoted breast cancer screening programme has led to more than 75% of new cases of breast cancer being diagnosed in stages I or II, when the chance of successful treatment is significantly higher.


Rapid and highly-specific generation of targeted DNA sequencing libraries enabled by linking capture probes with universal primers.
Targeted Next Generation Sequencing (NGS) is being adopted increasingly broadly in many research, commercial and clinical settings. Currently used target capture methods, however, typically require complex and lengthy (sometimes multi-day) workflows that complicates their use in certain applications. In addition, small panels for high sequencing depth applications such as liquid biopsy typically have low on-target rates, resulting in unnecessarily high sequencing cost. We have developed a novel targeted sequencing library preparation method, named Linked Target Capture (LTC), which replaces typical multi-day target capture workflows with a single-day, combined 'target-capture-PCR' workflow. This approach uses physically linked capture probes and PCR primers and is expected to work with panel sizes from 100 bp to >10 Mbp. It reduces the time and complexity of the capture workflow, eliminates long hybridization and wash steps and enables rapid library construction and target capture. High on-target read fractions are achievable due to repeated sequence selection in the target-capture-PCR step, thus lowering sequencing cost. We have demonstrated this technology on sample types including cell-free DNA (cfDNA) and formalin-fixed, paraffin-embedded (FFPE) derived DNA, capturing a 35-gene pan-cancer panel, and therein detecting single nucleotide variants, copy number variants, insertions, deletions and gene fusions. With the integration of unique molecular identifiers (UMIs), variants as low as 0.25% abundance were detected, limited by input mass and sequencing depth. Additionally, sequencing libraries were prepared in less than eight hours from extracted DNA to loaded sequencer, demonstrating that LTC holds promise as a broadly applicable tool for rapid, cost-effective and high performance targeted sequencing.


Exploring Flow, Factors, and Outcomes of Temporal Event Sequences with the Outflow Visualization.
Event sequence data is common in many domains, ranging from electronic medical records (EMRs) to sports events. Moreover, such sequences often result in measurable outcomes (e.g., life or death, win or loss). Collections of event sequences can be aggregated together to form event progression pathways. These pathways can then be connected with outcomes to model how alternative chains of events may lead to different results. This paper describes the Outflow visualization technique, designed to (1) aggregate multiple event sequences, (2) display the aggregate pathways through different event states with timing and cardinality, (3) summarize the pathways' corresponding outcomes, and (4) allow users to explore external factors that correlate with specific pathway state transitions. Results from a user study with twelve participants show that users were able to learn how to use Outflow easily with limited training and perform a range of tasks both accurately and rapidly.


Incidence of splayleg pigs in Nebraska litter size selection lines.
Genetic parameters for the splayleg (SL) condition were estimated from 37,673 records of pigs from six lines derived from a Large White-Land-race base population. Random selection for 22 generations was practiced in Lines C1 and C2. Line C2 was derived from C1 at Generation 8. Selection lines were as follows: 1) Line I, selected 11 generations for an index of ovulation rate and embryonic survival followed by 11 generations of selection for litter size; 2) Line IOL, derived from Line I at Generation 8 and which underwent eight generations of two-stage selection for ovulation rate and number of fully formed pigs per litter followed by four generations of litter size selection; 3) Line COL, derived from Line C1 at Generation 8 and selected eight generations in two stages for ovulation rate and number of fully formed pigs followed by four generations of litter size selection; and 4) Line T, selected 12 generations for increased testis size. From logistic models, it was found that boars were 224% more likely to have SL than gilts (P < 0.01). Decreases in birth weight, dam age at puberty, dam nipple number, and dam embryonic survival, and increases in dam litter size and inbreeding increased the odds of SL (P < 0.05). Direct and maternal heritabilities of SL were 0.07 and 0.16, respectively, and the correlation between direct and maternal effects was -0.24. Correlations between direct genetic effects for SL and number born alive, nipple number, birth weight, age at puberty, and embryonic survival were -0.19, -0.36, 0.23, -0.19, and -0.32, respectively. Except for the correlation of 0.32 between maternal effects for SL and direct effects for number of live pigs, correlations of SL maternal genetic effects with direct genetic effects of other traits were less than 0.11. Annual direct genetic trends (%) for SL in I, IOL, COL, T, C1, and C2 were -0.003 +/- 0.003, 0.121 +/- 0.012, -0.273 +/-0.009, 0.243 +/-0.014, -0.274 +/-0.004, and 0.086 +/-0.008, respectively; annual maternal genetic trends (%) were 0.106 +/-0.004, 0.508 +/-0.019, 0.383 +/-0.015, 0.527 +/-0.024, 0.188 +/-0.005, and 0.113 +/-0.012, respectively. Annual genetic maternal trend in Line I after Generation 12 was 0.339 +/-0.014. Maternal breeding value for SL is expected to increase as a correlated response to selection for increased litter size and increased size of testes.


Business school teams up with clinical innovators: An opportunity for health system transformation.
Healthcare represents one of the largest sectors in the economy with the health spending on average accounting for about 9% of GDP in OECD countries. Canada was projected in 2018 to spend about 11% of its GDP on healthcare with an expected health expenditure growth of 4.2%. Addressing this issue asks for a redesign of health delivery system and associated cultural shift allowing for incorporation of industry and business best practices. To make this redesign happen, system transformation requires seeking out new institutional mechanisms, partnerships, and forums where industry leaders in business and healthcare can develop a top-down approach with a shared vision, shared best practices, and support coming from a bottom-up approach through pilots and scaling-up initiatives. In this article, we describe one successful partnership initiative-Telfer Health Transformation Exchange at the Telfer School of Management at the University of Ottawa.


Multiscale modeling of brain dynamics: from single neurons and networks to mathematical tools.
The extreme complexity of the brain naturally requires mathematical modeling approaches on a large variety of scales; the spectrum ranges from single neuron dynamics over the behavior of groups of neurons to neuronal network activity. Thus, the connection between the microscopic scale (single neuron activity) to macroscopic behavior (emergent behavior of the collective dynamics) and vice versa is a key to understand the brain in its complexity. In this work, we attempt a review of a wide range of approaches, ranging from the modeling of single neuron dynamics to machine learning. The models include biophysical as well as data-driven phenomenological models. The discussed models include Hodgkin-Huxley, FitzHugh-Nagumo, coupled oscillators (Kuramoto oscillators, Rössler oscillators, and the Hindmarsh-Rose neuron), Integrate and Fire, networks of neurons, and neural field equations. In addition to the mathematical models, important mathematical methods in multiscale modeling and reconstruction of the causal connectivity are sketched. The methods include linear and nonlinear tools from statistics, data analysis, and time series analysis up to differential equations, dynamical systems, and bifurcation theory, including Granger causal connectivity analysis, phase synchronization connectivity analysis, principal component analysis (PCA), independent component analysis (ICA), and manifold learning algorithms such as ISOMAP, and diffusion maps and equation-free techniques. WIREs Syst Biol Med 2016, 8:438-458. doi: 10.1002/wsbm.1348 For further resources related to this article, please visit the WIREs website.


The mid-term effect of left ventricular assist devices on renal functions.
In this study, we aimed to investigate the mid-term effects of left ventricular assist devices on kidney functions. Between January 2015 and December 2017, a total of 61 patients (53 males, 8 females; mean age 46.4±11.2 years; range, 20 to 67 years) who underwent left ventricular assist device implantation were retrospectively analyzed. Glomerular filtration rate was evaluated preoperatively and at 24 and 48 h, at one week, and at one, three, and six months postoperatively. According to the preoperative glomerular filtration rates, the patients were divided into three groups: glomerular filtration rates ?60 mL/min/1.73 m2 ( Group 1 ), g lomerular f iltration rates 61-90 mL/min/1.73 m2 (Group 2), and glomerular filtration rates >90 mL/min/1.73 m2 (Group 3). In all groups, the glomerular filtration rate significantly increased at one week and one month postoperatively, compared to preoperative values (p<0.001 and p<0.01, respectively). However, the glomerular filtration values at six months significantly decreased, compared to the values at one week and one month postoperatively (p<0.001 and p<0.001, respectively). The most significant drop to preoperative values was observed in Group 3 (p=0.02) at three months and it dropped below the preoperative level at six months (p<0.001). Our study results suggest that left ventricular assist devices can significantly increase the glomerular filtration rate in short-term, irrespective of baseline values. However, this improvement may recede later, particularly in patients with normal renal functions, and it may even disappear following the third postoperative month.


Calibration of life history traits with epiphyseal closure, dental eruption and bone histology in captive and wild red deer.
The study of skeletochronology and bone tissue as a record of information on ontogenetic stages and events is widely used for improving the knowledge about life histories (LHs) of extinct and extant vertebrates. Compared with dinosaurs and extant reptiles, mammalian bone histology has received little attention. Here, we calibrate for the first time bone and dental age with histological bone characteristics and LH stages in ontogenetic series of red deer. We rely on known LHs of different aged individuals of captive Cervus elaphus hippelaphus from Austria to correlate epiphyseal closure, dental eruption pattern, bone growth marks and bone tissue patterns in femora and tibiae, and of wild Cervus elaphus hispanicus from Spain. Our data show that females (of both subspecies) attain skeletal maturity earlier than males. At this moment, epiphyseal closure (in femora and tibiae) and dental eruption are complete and long bones start to deposit an external fundamental system. The results also show that the attainment of reproductive maturity in red deer occurs slightly before skeletal maturity.


Theranostic gold in a gold cage nanoparticle for photothermal ablation and photoacoustic imaging of skin and oral infections.
Biofilms are structured communities of microbial cells embedded in a self-produced matrix of extracellular polymeric substances. Biofilms are associated with many health issues in humans, including chronic wound infections and tooth decay. Current antimicrobials are often incapable of disrupting the polymeric biofilm matrix and reaching the bacteria within. Alternative approaches are needed. Here, we describe a unique structure of dextran coated gold in a gold cage nanoparticle that enables photoacoustic and photothermal properties for biofilm detection and treatment. Activation of these nanoparticles with a near infrared laser can selectively detect and kill biofilm bacteria with precise spatial control and in a short timeframe. We observe a strong biocidal effect against both Streptococcus mutans and Staphylococcus aureus biofilms in mouse models of oral plaque and wound infections respectively. These effects were over 100 times greater than that seen with chlorhexidine, a conventional antimicrobial agent. Moreover, this approach did not adversely affect surrounding tissues. We conclude that photothermal ablation using theranostic nanoparticles is a rapid, precise, and non-toxic method to detect and treat biofilm-associated infections.


Detection and localization of a lectin on Actinomyces viscosus T14V by monoclonal antibodies.
A cell-associated lectin activity that mediates lactose-inhibitable adherence of Actinomyces viscosus T14V has been localized to a specific population of fimbriae by the use of monoclonal antibodies. Nine monoclonal antibodies were produced that reacted with only 1 of 2 immunoelectrophoretically distinct fimbrial components on T14V. The fibrillar morphology of this component was revealed by the immunoelectronmicroscopic examination of bacteria incubated with the monoclonal antibodies. The lectin activity associated with these structures was detected when isolated fimbriae were cross-linked with monoclonal antibodies to form immune complexes with agglutination activity for neuraminidase-treated human erythrocytes, a reaction that was inhibited by lactose. Although the 9 monoclonal antibodies differed in their fine specificities, they reacted only with strains of A. viscosus and A. naeslundii that exhibited lactose-inhibitable adherence. These findings indicate that the lectin activity common to these bacteria resides on fimbriae that are antigenically related to those of T14V.


Separable bilayer microfiltration device for viable label-free enrichment of circulating tumour cells.
The analysis of circulating tumour cells (CTCs) in cancer patients could provide important information for therapeutic management. Enrichment of viable CTCs could permit performance of functional analyses on CTCs to broaden understanding of metastatic disease. However, this has not been widely accomplished. Addressing this challenge, we present a separable bilayer (SB) microfilter for viable size-based CTC capture. Unlike other single-layer CTC microfilters, the precise gap between the two layers and the architecture of pore alignment result in drastic reduction in mechanical stress on CTCs, capturing them viably. Using multiple cancer cell lines spiked in healthy donor blood, the SB microfilter demonstrated high capture efficiency (78-83%), high retention of cell viability (71-74%), high tumour cell enrichment against leukocytes (1.7-2 × 10(3)), and widespread ability to establish cultures post-capture (100% of cell lines tested). In a metastatic mouse model, SB microfilters successfully enriched viable mouse CTCs from 0.4-0.6 mL whole mouse blood samples and established in vitro cultures for further genetic and functional analysis. Our preliminary studies reflect the efficacy of the SB microfilter device to efficiently and reliably enrich viable CTCs in animal model studies, constituting an exciting technology for new insights in cancer research.


Suppression of the rice fatty-acid desaturase gene OsSSI2 enhances resistance to blast and leaf blight diseases in rice.
Fatty acids and their derivatives play important signaling roles in plant defense responses. It has been shown that suppressing a gene for stearoyl acyl carrier protein fatty-acid desaturase (SACPD) enhances the resistance of Arabidopsis (SSI2) and soybean to multiple pathogens. In this study, we present functional analyses of a rice homolog of SSI2 (OsSSI2) in disease resistance of rice plants. A transposon insertion mutation (Osssi2-Tos17) and RNAi-mediated knockdown of OsSSI2 (OsSSI2-kd) reduced the oleic acid (18:1) level and increased that of stearic acid (18:0), indicating that OsSSI2 is responsible for fatty-acid desaturase activity. These plants displayed spontaneous lesion formation in leaf blades, retarded growth, slight increase in endogenous free salicylic acid (SA) levels, and SA/benzothiadiazole (BTH)-specific inducible genes, including WRKY45, a key regulator of SA/BTH-induced resistance, in rice. Moreover, the OsSSI2-kd plants showed markedly enhanced resistance to the blast fungus Magnaporthe grisea and leaf-blight bacteria Xanthomonas oryzae pv. oryzae. These results suggest that OsSSI2 is involved in the negative regulation of defense responses in rice, as are its Arabidopsis and soybean counterparts. Microarray analyses identified 406 genes that were differentially expressed (>or=2-fold) in OsSSI2-kd rice plants compared with wild-type rice and, of these, approximately 39% were BTH responsive. Taken together, our results suggest that induction of SA-responsive genes, including WRKY45, is likely responsible for enhanced disease resistance in OsSSI2-kd rice plants.


Bioresorbable vascular scaffold implantation in acute coronary syndromes: clinical evidence, tips and tricks.
Percutaneous coronary intervention (PCI) with a drug-eluting stent (DES) is routine treatment for patients with acute coronary syndromes (ACS). However, permanent metallic caging of the vessel has several shortcomings, such as side branch jailing and impossibility of late lumen enlargement. Moreover, DES PCI is affected by vasomotion impairment. In ACS a high thrombus burden and vasospasm lead to a higher risk of acute and late acquired stent malapposition than in stable patients. This increases the risk of acute, late and very late stent thrombosis. In this challenging clinical setting, the implantation of bioresorbable vascular scaffolds (BVS) could represent an appealing therapeutic option. Temporary vessel scaffolding has proved to have several advantages over metallic stent delivery, such as framework reabsorption, late lumen enlargement, side branch patency, and recovery of physiological reactivity to vasoactive stimuli. In the thrombotic environment of ACS, BVS implantation has the benefit of capping the thrombus and the vulnerable plaque. Bioresorbable vascular scaffolds also seems to reduce the incidence of angina during follow-up. Acute coronary syndromes patients may therefore benefit more from temporary polymeric caging than from permanent stent platform implantation. The aim of this review is to update the available knowledge concerning the use of BVS in ACS patients, by analyzing the potential pitfalls in this challenging clinical setting and presenting tricks to overcome these limitations.


Generation of ammonia from non-urea sources in a faecal incubation system.
1. A 25% faecal suspension in sodium chloride solution, incubated anaerobically at 37 degrees C for 48 h, showed excellent survival of all the main groups of faecal bacteria. 2. All faecal incubation systems studied generated large amounts of ammonia, particularly those in which bacterial counts fell during incubation. As normal faeces contain negligible amounts of urea this ammonia must have been generated from sources other than urea. 3. Ammonia was also generated by faeces delivered by sodium chloride enema, and by ileostomy fluid, indicating that the phenomenon is not confined to distal colonic contents. 4. Ammonia generation by incubated faeces was inhibited by prior autoclaving of the sample, but not by sterilization with gamma-irradiation. 5. Generation of ammonia by incubated stool was accompanied by release of large amounts of organic anion and a fall in pH. 6. These observations are interpreted as evidence that ammonia generated within the colon in situ is not derived exclusively from urea, but also from bacterial deamination of amino acids, peptides and proteins. Simultaneously bacterial activity generates large amounts of organacid. The presence of living bacteria is not essential for ammonia generation, provided that bacterial enzymes are present. 7. Bacterial generation of organic solute in faeces which have left the body is sufficiently rapid to cast serious doubts on the validity of faecal centrifugation, or other time-consuming techniques involving lengthy handling of faeces, as methods of obtaining extracellular faecal fluid for measurements of organic constituents or ammonia.


Investment in new technology research can save future health care dollars.
To perform a cost analysis of the emerging technology of lymphatic mapping for patients with malignant melanoma. A retrospective, computer-aided chart and financial cost and charge review of consecutive patients with the diagnosis of melanoma registered at a cancer center from December, 1995 to March, 1996. 73 consecutive patients with the diagnosis of Stage 1 and 2 melanoma (cutaneous disease only) had nodal staging of their disease with either a sentinel node (SLN) biopsy or an elective complete node dissection (ELND). This was determined largely by patient choice and the protocol in operation at the time of the presentation of the patient to the clinic. There were no deaths in the series. Patient morbidity endpoints included rates of infection, incidence of extremity lymphedema, development of a seroma in the regional nodal basin wound and wound healing. Clinical outcome was measured by the ability to obtain complete nodal staging information with the new lymphatic mapping technology, and recurrence rates in the nodal basin after a negative SLN biopsy. Total charges, direct costs and total costs were calculated from all hospital, OR, pathology and lab charges. Professional fees were included in the analysis. Group 1 patients (50) had melanomas greater than 0.76 mm in thickness treated with a wide local excision (WLE), lymphatic mapping and SLN biopsy under general anesthesia. Five patients (Group 2) had their procedure performed under a straight local anesthesia. Group 3 patients (18) had nodal staging performed with an elective node dissection. In Groups 1 and 2, if the SLN was positive for micrometastases, the patients were taken back to the OR for a complete node dissection. The total charges per patient were $13,835, $6,853 and $19,285, respectively. Significant dollar savings were achieved if the nodal staging could be accomplished with the lymphatic mapping technology (p = 0.001). Morbidity was significantly less in Groups 1 and 2 compared to Group 3. After a mean follow-up of three years, only one patient has recurred in a SLN negative basin. With 38,300 new cases of melanoma diagnosed each year in the United States, a projected savings of $172 million per year (general anesthesia) and $350 million per year (local anesthesia) could be realized if this new mapping technology could be incorporated into the care of the melanoma patient. Patient morbidity is minimized, nodal staging is complete and patients return to work sooner. Recently approved adjuvant therapy can be applied in a selective fashion, treating only those patients in which a documented benefit has been obtained, saving the health care system more dollars. Initial investment in defining the technology was minimal.


The GET complex mediates insertion of tail-anchored proteins into the ER membrane.
Tail-anchored (TA) proteins, defined by the presence of a single C-terminal transmembrane domain (TMD), play critical roles throughout the secretory pathway and in mitochondria, yet the machinery responsible for their proper membrane insertion remains poorly characterized. Here we show that Get3, the yeast homolog of the TA-interacting factor Asna1/Trc40, specifically recognizes TMDs of TA proteins destined for the secretory pathway. Get3 recognition represents a key decision step, whose loss can lead to misinsertion of TA proteins into mitochondria. Get3-TA protein complexes are recruited for endoplasmic reticulum (ER) membrane insertion by the Get1/Get2 receptor. In vivo, the absence of Get1/Get2 leads to cytosolic aggregation of Get3-TA complexes and broad defects in TA protein biogenesis. In vitro reconstitution demonstrates that the Get proteins directly mediate insertion of newly synthesized TA proteins into ER membranes. Thus, the GET complex represents a critical mechanism for ensuring efficient and accurate targeting of TA proteins.


Does sleep promote false memories?
Memory is constructive in nature so that it may sometimes lead to the retrieval of distorted or illusory information. Sleep facilitates accurate declarative memory consolidation but might also promote such memory distortions. We examined the influence of sleep and lack of sleep on the cerebral correlates of accurate and false recollections using fMRI. After encoding lists of semantically related word associates, half of the participants were allowed to sleep, whereas the others were totally sleep deprived on the first postencoding night. During a subsequent retest fMRI session taking place 3 days later, participants made recognition memory judgments about the previously studied associates, critical theme words (which had not been previously presented during encoding), and new words unrelated to the studied items. Sleep, relative to sleep deprivation, enhanced accurate and false recollections. No significant difference was observed in brain responses to false or illusory recollection between sleep and sleep deprivation conditions. However, after sleep but not after sleep deprivation (exclusive masking), accurate and illusory recollections were both associated with responses in the hippocampus and retrosplenial cortex. The data suggest that sleep does not selectively enhance illusory memories but rather tends to promote systems-level consolidation in hippocampo-neocortical circuits of memories subsequently associated with both accurate and illusory recollections. We further observed that during encoding, hippocampal responses were selectively larger for items subsequently accurately retrieved than for material leading to illusory memories. The data indicate that the early organization of memory during encoding is a major factor influencing subsequent production of accurate or false memories.


Tip-enhanced Raman spectroscopy with silver-coated optical fiber probe in reflection mode for investigating multiwall carbon nanotubes.
We developed a tip-enhanced Raman spectrometer (TERS) with reflection mode. The instrument, with a scanning shear-force microscope (ShFM) and a side-illumination Raman spectroscope, can overcome the diffraction limit and has high sensitivity. A chemical method to fabricate optical fiber probes with Ag coating is proposed. The local electromagnetic responses of the silver-coated optical fiber probe are numerically analyzed by the finite-difference time-domain method, and the excitation wavelength is optimized to resonate with the localized surface plasmons (LSP) of the probe tip. The instrument is applied to investigate a single multiwall carbon nanotube. The experiment results indicate that our TERS instrument has a spatial resolution better than 70 nm, and the enhancement factor is about 5 x 10(3).


Change in emergency department providers' beliefs and practices after use of new protocols for suicidal patients.
The study examined changes in self-reported attitudes and practices related to suicide risk assessment among providers at emergency departments (EDs) during a three-phase quasi-experimental trial involving implementation of ED protocols for suicidal patients. A total of 1,289 of 1,828 (71% response rate) eligible providers at eight EDs completed a voluntary, anonymous survey at baseline, after introduction of universal suicide screening, and after introduction of suicide prevention resources (nurses) and a secondary risk assessment tool (physicians). Among participants, the median age was 40 years old, 64% were female, and there were no demographic differences across study phases; 68% were nurses, and 32% were attending physicians. Between phase 1 and phase 3, increasing proportions of nurses reported screening for suicide (36% and 95%, respectively, p<.001) and increasing proportions of physicians reported further assessment of suicide risk (63% and 80%, respectively, p<.01). Although increasing proportions of providers said universal screening would result in more psychiatric consultations, decreasing proportions said it would slow down clinical care. Increasing proportions of nurses reported often or almost always asking suicidal patients about firearm access (18%-69%, depending on the case), although these numbers remained low relative to ideal practice. Between 35% and 87% of physicians asked about firearms, depending on the case, and these percentages did not change significantly over the study phases. These findings support the feasibility of implementing universal screening for suicide in EDs, assuming adequate resources, but providers should be educated to ask suicidal patients about firearm access.


The response regulator SprE (RssB) modulates polyadenylation and mRNA stability in Escherichia coli.
In Escherichia coli, the adaptor protein SprE (RssB) controls the stability of the alternate sigma factor RpoS (sigma(38) and sigma(S)). When nutrients are abundant, SprE binds RpoS and delivers it to ClpXP for degradation, but when carbon sources are depleted, this process is inhibited. It also has been noted that overproduction of SprE is toxic. Here we show that null mutations in pcnB, encoding poly(A) polymerase I (PAP I), and in hfq, encoding the RNA chaperone Hfq, suppress this toxicity. Since PAP I, in conjunction with Hfq, is responsible for targeting RNAs, including mRNAs, for degradation by adding poly(A) tails onto their 3' ends, these data indicate that SprE helps modulate the polyadenylation pathway in E. coli. Indeed, in exponentially growing cells, sprE deletion mutants exhibit significantly reduced levels of polyadenylation and increased stability of specific mRNAs, similar to what is observed in a PAP I-deficient strain. In stationary phase, we show that SprE changes the intracellular localization of PAP I. Taken together, we propose that SprE plays a multifunctional role in controlling the transcriptome, regulating what is made via its effects on RpoS, and modulating what is degraded via its effects on polyadenylation and turnover of specific mRNAs.


Insulin suppresses endothelial secretion of C-type natriuretic peptide, a novel endothelium-derived relaxing peptide.
We have previously reported that C-type natriuretic peptide (CNP), the third member of the natriuretic peptide family, is produced in vascular endothelial cells (ECs) and acts as an endothelium-derived relaxing peptide. We further demonstrated the detection of the gene transcripts of CNP and atrial natriuretic peptide (ANP) B receptor, a specific receptor for CNP, in human blood vessels. We thus propose the existence of a vascular natriuretic peptide system (NPS). CNP secretion was also demonstrated to be stimulated by various growth factors and cytokines. To clarify the significance of vascular NPS in proliferative vascular complications associated with diabetes, hypertension, or atherosclerosis, in the present study we examined the effect of insulin on CNP secretion from cultured ECs. Insulin at a concentration in the physiological range (10(-10)-10(-7) mol/l) potently suppressed CNP secretion, whereas insulin at the same concentration did not suppress endothelin (ET) secretion from EC. IGF-I had no significant effect on CNP secretion. Insulin, therefore, can be a potent inhibitor of CNP secretion through the activation of insulin receptor. Since CNP has been shown to be a potent inhibitor of vascular smooth muscle cell proliferation, the present study suggests the possibility that attenuated activity of vascular NPS is associated with hyperinsulinemia, which might result in proliferative vascular lesions.


Differences in the effects of age on the development of entheseal changes among historical Japanese populations.
This study aims to determine the impacts of both age and physical activity on entheseal changes at sites of muscle and ligament attachment, and proposes that the influence of age on entheseal changes may depend on specific social systems. Entheseal markers of 193 individuals excavated from archaeological sites in Japan were examined, and archaeological evidence from those sites was used to determine the subsistence activities that those individuals engaged in. Fifteenth-century samples were either fishermen or Agehamashiki salt manufacturers, while samples from between the late 17(th) century and the 19(th) century were peasants, townspeople, or samurai. Nineteen entheses were examined using the scoring method of Hawkey and Merbs (1995) to clarify the degree to which age influenced entheseal severity of a given sample as well as the differences in the degree to which age influenced entheseal changes among samples. Results indicated that age influenced entheseal changes; however, the degree to which age influenced entheseal development was dependent on the characteristic physical activities associated with an individual's class and occupation. Furthermore, in certain groups, aging did not significantly impact entheseal changes. The degree to which age influenced entheseal changes was dependent on characteristic physical activities associated with an individual's class and occupation. This indicated that physical activities and lifestyle, along with age, were major factors that contributed to entheseal changes. Based on these results, it was concluded that entheseal changes could serve as a useful tool in the reconstruction of physical activities of past populations.


Identification and characterization of regions of the rice genome associated with broad-spectrum, quantitative disease resistance.
Much research has been devoted to understanding the biology of plant-pathogen interactions. The extensive genetic analysis of disease resistance in rice, coupled with the sequenced genome and genomic resources, provides the opportunity to seek convergent evidence implicating specific chromosomal segments and genes in the control of resistance. Published data on quantitative and qualitative disease resistance in rice were synthesized to evaluate the distributions of and associations among resistance loci. Quantitative trait loci (QTL) for resistance to multiple diseases and qualitative resistance loci (R genes) were clustered in the rice genome. R genes and their analogs of the nucleotide binding site-leucine-rich repeat class and genes identified on the basis of differential representation in disease-related EST libraries were significantly associated with QTL. Chromosomal segments associated with broad-spectrum quantitative disease resistance (BS-QDR) were identified. These segments contained numerous positional candidate genes identified on the basis of a range of criteria, and groups of genes belonging to two defense-associated biochemical pathways were found to underlie one BS-QDR region. Genetic dissection of disease QTL confidence intervals is needed to reduce the number of positional candidate genes for further functional analysis. This study provides a framework for future investigations of disease resistance in rice and related crop species.


At Least Seven Distinct Rotavirus Genotype Constellations in Bats with Evidence of Reassortment and Zoonotic Transmissions.
Bats host many viruses pathogenic to humans, and increasing evidence suggests that rotavirus A (RVA) also belongs to this list. Rotaviruses cause diarrheal disease in many mammals and birds, and their segmented genomes allow them to reassort and increase their genetic diversity. Eighteen out of 2,142 bat fecal samples (0.8%) collected from Europe, Central America, and Africa were PCR-positive for RVA, and 11 of those were fully characterized using viral metagenomics. Upon contrasting their genomes with publicly available data, at least 7 distinct bat RVA genotype constellations (GCs) were identified, which included evidence of reassortments and 6 novel genotypes. Some of these constellations are spread across the world, whereas others appear to be geographically restricted. Our analyses also suggest that several unusual human and equine RVA strains might be of bat RVA origin, based on their phylogenetic clustering, despite various levels of nucleotide sequence identities between them. Although SA11 is one of the most widely used reference strains for RVA research and forms the backbone of a reverse genetics system, its origin remained enigmatic. Remarkably, the majority of the genotypes of SA11-like strains were shared with Gabonese bat RVAs, suggesting a potential common origin. Overall, our findings suggest an underexplored genetic diversity of RVAs in bats, which is likely only the tip of the iceberg. Increasing contact between humans and bat wildlife will further increase the zoonosis risk, which warrants closer attention to these viruses.IMPORTANCE The increased research on bat coronaviruses after severe acute respiratory syndrome coronavirus (SARS-CoV) and Middle East respiratory syndrome coronavirus (MERS-CoV) allowed the very rapid identification of SARS-CoV-2. This is an excellent example of the importance of knowing viruses harbored by wildlife in general, and bats in particular, for global preparedness against emerging viral pathogens. The current effort to characterize bat rotavirus strains from 3 continents sheds light on the vast genetic diversity of rotaviruses and also hints at a bat origin for several atypical rotaviruses in humans and animals, implying that zoonoses of bat rotaviruses might occur more frequently than currently realized.


Efficacy of a new attenuated duck parvovirosis vaccine in Muscovy ducks.
The efficacy of a new live attenuated parvovirosis vaccine was tested in conventional ducklings against Derzsy's disease by comparing two vaccination regimens. Ducklings were vaccinated with either one injection at 17 days of age or two injections at 1 and 17 days of age. Controls and vaccinated ducklings were challenged with a virulent Derzsy strain at 21 days of age (day 20). Weight was measured on days 20, 34 and 42/43. Surviving birds were necropsied on day 42/43. Protection rates were significantly higher in the groups vaccinated once (90 per cent, P=0.003) and twice (95 per cent, P<0.001) than in the control group (59 per cent). The bodyweight was significantly higher in both vaccinated groups than in the control group on day 34 (P=0.008 and P<0.001, respectively) and day 42/43 (P<0.001 for both groups). The growth was significantly higher in the group vaccinated twice than the group vaccinated once on day 34 (P=0.047) and day 42/43 (P=0.017). Both vaccination regimens provided a quick onset of immunity. The higher weight gain in the group vaccinated twice suggests that an early vaccination at hatchery followed by a second injection at 17 days of age is an optimal and practical schedule to prevent parvovirosis.


Effects of Contract-Relax, Static Stretching, and Isometric Contractions on Muscle-Tendon Mechanics.
Loading characteristics of stretching techniques likely influence the specific mechanisms responsible for acute increases in range of motion (ROM). Therefore, the effects of a version of contract-relax (CR) proprioceptive neuromuscular facilitation stretching, static stretching (SS), and maximal isometric contraction (Iso) interventions were studied in 17 healthy human volunteers. Passive ankle moment was recorded on an isokinetic dynamometer, with EMG recording from the triceps surae, simultaneous real-time motion analysis, and ultrasound-imaging-recorded gastrocnemius medialis muscle and Achilles tendon elongation. Subjects then performed each intervention randomly on separate days before reassessment. Significant increases in dorsiflexion ROM (2.5°-5.3°; P < 0.01) and reductions in whole muscle-tendon stiffness (10.1%-21.0%; P < 0.01) occurred under all conditions, with significantly greater changes detected following CR stretching (P < 0.05). Significant reductions in tendon stiffness were observed after CR stretching and Iso (17.7%-22.1%; P < 0.01) but not after SS (P > 0.05), whereas significant reductions in muscle stiffness occurred after CR stretching and SS (16.0%-20.5%; P < 0.01) but not after Iso (P > 0.05). Increases in peak passive moment (stretch tolerance) occurred after Iso (6.8%; P < 0.05), CR stretching (10.6%; P = 0.08), and SS (5.2%; P = 0.08); no difference in changes between conditions was found (P > 0.05). Significant correlations (rs = 0.69-0.82; P < 0.01) were observed between changes in peak passive moment and maximal ROM under all conditions. Although similar ROM increases occur after Iso and SS, changes in muscle and tendon stiffness are distinct. Concomitant reductions in muscle and tendon stiffness after CR stretching suggest a broader adaptive response that likely explains its superior efficacy in acutely increasing ROM. Although mechanical changes appear tissue-specific between interventions, similar increases in stretch tolerance after all interventions are strongly correlated with changes in ROM.


Association between hypouricemia and reduced kidney function: a cross-sectional population-based study in Japan.
Hypouricemia, conventionally defined as a serum uric acid level of ≤2 mg/dl, is considered a biochemical disorder with no clinical significance. However, individuals with renal hypouricemia have a high risk of urolithiasis and exercise-induced acute kidney injury, both of which are risk factors for reduced kidney function. To test the hypothesis that individuals with hypouricemia would be at a higher risk of reduced kidney function, we conducted a population-based cross-sectional study using data from the Specific Health Checkups and Guidance System in Japan. Logistic analysis was used to examine the relationship between hypouricemia and reduced kidney function, defined as estimated glomerular filtration rate <60 ml/min/1.73 m(2). Among 90,710 men (mean age, 63.8 years) and 136,935 women (63.7 years), 193 (0.2%) and 540 (0.4%) were identified as having hypouricemia, respectively. The prevalence of hypouricemia decreased with age in women (p for trend <0.001), but not in men (p for trend = 0.24). Hypouricemia was associated with reduced kidney function in men (odds ratio, 1.83; 95% confidence interval, 1.23-2.74), but not in women (0.61; 0.43-0.86), relative to the reference category (i.e., serum uric acid levels of 4.1-5.0 mg/dl) after adjusting for age, drinking, smoking, diabetes, hypertension, hypercholesterolemia, obesity, and history of renal failure. Sensitivity analyses stratified by diabetic status yielded similar results. This study is the first to provide evidence that hypouricemia is associated with reduced kidney function in men. Further research will be needed to determine the long-term prognosis of individuals with hypouricemia.


Low-field magnetic resonance imaging of bone marrow in the lumbar spine, pelvis, and femur in the adult dog.
The purpose of this study was to describe the appearance of normal bone marrow in seven adult dogs using low-field (0.3T) magnetic resonance (MR) imaging. The areas imaged included the lumbar spine, pelvis, and femur. T1-weighted, fast spin-echo T2-weighted, and short tau (T1) inversion recovery (STIR) sequences were obtained at all locations. Histopathology was performed on sections from the sixth lumbar vertebral body, the wing of the ilium, and the femur (head and neck, mid-diaphysis, and condyle) for evaluation of cellularity and fat content. The lumbar spine and pelvic marrow MR images were similar in all dogs. The lumbar vertebral bone marrow was uniform, intermediate signal intensity, and isointense to muscle on all sequences. There was variation between dogs in the bone marrow distribution with MR imaging of the femur. In the proximal and mid-diaphysis of the femur there was patchy high-signal intensity on T1- and T2-weighted images, and hypointense foci on the STIR images. The distal femoral metaphysis had a variable pattern ranging from intermediate-to-high signal on T1- and T2-weighted images and intermediate-to-low signal on STIR images. The femoral condyles were uniformly high signal on T1- and T2-weighted images and hypointense on STIR images. Histopathologically there was a normal variation in the bone marrow cellularity. The marrow was normocellular (25-75% cellularity) for all sites examined except the femoral condyles, which were hypocellular (<25% cellularity).


Soil TPH concentration estimation using vegetation indices in an oil polluted area of eastern China.
Assessing oil pollution using traditional field-based methods over large areas is difficult and expensive. Remote sensing technologies with good spatial and temporal coverage might provide an alternative for monitoring oil pollution by recording the spectral signals of plants growing in polluted soils. Total petroleum hydrocarbon concentrations of soils and the hyperspectral canopy reflectance were measured in wetlands dominated by reeds (Phragmites australis) around oil wells that have been producing oil for approximately 10 years in the Yellow River Delta, eastern China to evaluate the potential of vegetation indices and red edge parameters to estimate soil oil pollution. The detrimental effect of oil pollution on reed communities was confirmed by the evidence that the aboveground biomass decreased from 1076.5 g m(-2) to 5.3 g m(-2) with increasing total petroleum hydrocarbon concentrations ranging from 9.45 mg kg(-1) to 652 mg kg(-1). The modified chlorophyll absorption ratio index (MCARI) best estimated soil TPH concentration among 20 vegetation indices. The linear model involving MCARI had the highest coefficient of determination (R(2) = 0.73) and accuracy of prediction (RMSE = 104.2 mg kg(-1)). For other vegetation indices and red edge parameters, the R(2) and RMSE values ranged from 0.64 to 0.71 and from 120.2 mg kg(-1) to 106.8 mg kg(-1) respectively. The traditional broadband normalized difference vegetation index (NDVI), one of the broadband multispectral vegetation indices (BMVIs), produced a prediction (R(2) = 0.70 and RMSE = 110.1 mg kg(-1)) similar to that of MCARI. These results corroborated the potential of remote sensing for assessing soil oil pollution in large areas. Traditional BMVIs are still of great value in monitoring soil oil pollution when hyperspectral data are unavailable.