Targeting immune checkpoints: New opportunity for mesothelioma treatment?
Malignant pleural mesothelioma is an aggressive cancer linked to asbestos exposure in most patients. Due to the long latency between exposure and presentation, incidence is expected to further increase in the next decade, despite the ban on asbestos import which occurred at the end of last century in industrialized countries. Platinum-based palliative chemotherapy is the only treatment with proven benefit on outcome, resulting in selected patients in a median overall survival of about 1 year. Therefore, there is room for therapeutic improvement using a new strategy to prolong survival. Dealing with cancer cell induced immunosuppression is a promising approach. Reactivating immune responses that are silenced by immune checkpoints recently gained a lot of interest. Checkpoint blockade has already shown promising preclinical and clinical results in several cancer types and is currently also being investigated in mesothelioma. Here, we discuss the expression patterns and mechanisms of action of CTLA-4 and PD-1 as the two most studied and of TIM-3 and LAG-3 as two interesting upcoming immune checkpoints. Furthermore, we review the clinical results of molecules blocking these immune checkpoints and point out their future opportunities with a special focus on mesothelioma.


Increased half-life of gammaglobulin after prolonged intravenous replacement therapy.
The half-life of total IgG and antibodies to cytomegalovirus and pneumococcal polysaccharide type III was consistently prolonged after a 9 month course of intravenous gammaglobulin treatment in three patients with 'primary' hypogammaglobulinaemia. The half-life of antibody to tetanus toxoid showed no consistent pattern. These data are at variance with the traditional dogma that IgG half-life is inversely related to serum IgG concentration. They suggest that patients on intravenous gammaglobulin therapy are likely to need less, rather than more, infusions when their serum IgG has risen to within the physiological range.


Melatonin-induced glycosaminoglycans augmentation in myocardium remote to infarction.
Elevated levels of collagen as well as transient increases of glycosaminoglycans (GAG) have been shown in the myocardium remote to the infarction. The aim of the study is to observe the effect of melatonin on the accumulation of collagen and GAG in the left ventricle wall, remote to the infarction. A second aim is to determine whether the effect of the pineal indole is mediated by the membrane melatonin receptors of heart fibroblasts. Rats with myocardial infarction induced by ligation of the left coronary artery were treated with melatonin at a dose of 60 μg/100 g b.w. or vehicle (2% ethanol in 0.9% NaCl). The results were compared with an untreated control. In the second part of the study, the fibroblasts from the non-infarcted part of myocardium were isolated and cultured. Melatonin at a range of concentrations from 10(-8) M to 10(-6) M was applied to the fibroblast cultures. In the final part of the study, the influence of luzindole (10(-6) M), the melatonin membrane receptor inhibitor, on melatonin-induced GAG augmentation was investigated. Both collagen and GAG content were measured in the experiment. Melatonin elevated GAG content in the myocardium remote to the infarcted heart. Collagen level was not changed by pineal indoleamine. Fibroblasts isolated from the myocardium varied in shape from fusiform to spindle-shaped. Moreover, the pineal hormone (10(-7)M and 10(-6)M) increased GAG accumulation in the fibroblast culture. Luzindole inhibited melatonin-induced elevation of GAG content at 10(-6)M. Melatonin increased GAG content in the myocardium remote to infarction. This effect was dependent on the direct influence of the pineal indole on the heart fibroblasts. The melatonin-induced GAG elevation is blocked by luzindole, the melatonin membrane receptors inhibitor, indicating a direct effect of this indole.


Ubiquinol decreases hemorrhagic shock/resuscitation-induced microvascular inflammation in rat mesenteric microcirculation.
Hemorrhagic shock (HS) is a leading cause of death in traumatic injury. Ischemia and hypoxia in HS and fluid resuscitation (FR) creates a condition that facilitates excessive generation of reactive oxygen species (ROS). This is a major factor causing increased leukocyte-endothelial cell adhesive interactions and inflammation in the microcirculation resulting in reperfusion tissue injury. The aim of this study was to determine if ubiquinol (coenzyme Q10) decreases microvascular inflammation following HS and FR. Intravital microscopy was used to measure leukocyte-endothelial cell adhesive interactions in the rat mesentery following 1-h of HS and 2-h post FR with or without ubiquinol. Hemorrhagic shock was induced by removing ~ 40% of anesthetized Sprague Dawley rats' blood volume to maintain a mean arterial blood pressure <50 mmHg for 1 h. Ubiquinol (1 mg/100 g body weight) was infused intravascularly in the ubiquinol group immediately after 1-h HS. The FR protocol included replacement of the shed blood and Lactate Ringer's in both the control and ubiquinol groups. We found that leukocyte adherence (2.3 ± 2.0), mast cell degranulation (1.02 ± 0.01), and ROS levels (159 ± 35%) in the ubiquinol group were significantly reduced compared to the control group (10.8 ± 2.3, 1.36 ± 0.03, and 343 ± 47%, respectively). In addition, vascular permeability in the control group (0.54 ± 0.11) was significantly greater than the ubiquinol group (0.34 ± 0.04). In conclusion, ubiquinol attenuates HS and FR-induced microvascular inflammation. These results suggest that ubiquinol provides protection to mesenteric microcirculation through its antioxidant properties.


Dietary orotic acid accentuates the hepatic response to phenobarbital in rats.
In rats treated with phenobarbital for 3 days and simultaneously fed a semisynthetic diet containing 1.0% orotic acid, the extent of the increases in liver microsomal phosphatidylcholine, phosphatidylethanolamine, total RNA, total protein, and cytochrome P-450 were significantly greater than they were in rats treated identically with phenobarbital but without dietary orotic acid. This is attributed primarily to the stimulation of hepatic phosphatidylcholine synthesis by dietary orotic acid. In the absence of phenobarbital, orotic acid was shown to cause some increase in liver smooth endoplasmic reticulum components, but not cytochrome P-450. Orotic acid also decreased the activity of microsomal phosphatidylethanolamine N-methyltransferase, which may have contributed to the increase in the microsomal content of phosphatidylethanolamine. The hypothesis is advanced that phospholipid availability is a limiting factor in the hepatic response to phenobarbital. When more phospholipid is available to provide the structural framework for biogenesis of endoplasmic reticulum, all of the hepatic actions of phenobarbital, including induction of cytochrome P-450, are amplified.


The use of the Kohn chlorazol black fixative-stain in an intestinal parasite survey in rural Costa Rica.
The Kohn one-solution chlorazol black (KCB) fixative-stain was used in the examination of stools from 162 children for intestinal parasites in rural, northern Costa Rica. Many more parasites were found by examining the stained smears than were seen on fresh smears. This was especially true of protozoan parasites. The advantages of the KCB technique are, as follows: (1) its simplicity; (2) the stability of the stain in solution and on slides; (3) the ability to use the stain with carbol-xylol in humid regions; and (4) the metachromatic qualities of the stain.


N+NO reaction on Rh(111) surfaces studied with fast near-edge X-ray absorption fine structure spectroscopy: role of NO dimer as an extrinsic precursor.
We studied the mechanism of the N+NO reaction on Rh(111) surfaces by means of fast near-edge X-ray absorption fine structure spectroscopy. This reaction is important as a basis of NOx reduction reactions on platinum-group metal surfaces. Atomic nitrogen layers on Rh(111) were titrated with NO at various temperatures. N2O is exclusively formed and desorbs into the gas phase below 350 K. The consumption rate of atomic nitrogen exhibits strange temperature dependence between 100 and 350 K; the reaction proceeds slower with increasing temperature. Reaction kinetics analyses and isotope-controlled experiments have revealed that the surface N atoms do not react with chemisorbed NO molecules but with NO dimers weakly bound on top of the chemisorbed layer, which play a role as an extrinsic precursor. The present results may support the possibility that NO dimers participate in various NO-related synthetic, biochemical, and surface reactions as an intermediate.


Three new species and the molecular phylogeny of Antipathozoanthus from the Indo-Pacific Ocean (Anthozoa, Hexacorallia, Zoantharia).
In this study, three new species of macrocnemic zoantharians (Hexacorallia, Zoantharia) are described from localities in the Indo-Pacific Ocean including the Red Sea, the Maldives, Palau, and southern Japan: Antipathozoanthus obscurussp. n., A. remengesauisp. n., and A. cavernussp. n. Although the genus Antipathozoanthus is currently restricted to species living on antipatharians, A. obscurussp. n. is not associated with any living substrate and instead is found on coral reef carbonate substrate within narrow caves or cracks. The two new species that have association with antipatharians, A. remengesauisp. n. and A. cavernussp. n., can be distinguished by their relative coenenchyme development and the antipatharian species that each uses as substrate. Additionally, all new species described in this study have unique nuclear internal transcribed spacer region of ribosomal DNA (ITS-rDNA) sequences. Our results indicate that more phylogenetic studies focusing on increasing the numbers of species examined within each of the genera of Parazoanthidae are required in order to better understand the evolutionary history of substrate specificity within the family Parazoanthidae.


Synergistic effects of RAD and Neoral in inhibition of host-vs.-graft and graft-vs.-host immune responses in rat small-bowel transplantation.
The combined effects of RAD and Neoral were tested in a rat orthotopic small-bowel transplantation model. Seven groups (n = 6) were involved in this study, and each one was included in three rejection models for the evaluation of host-vs.-graft disease (HVG) (LBN-F1 to LEW), graft-vs.-host disease (GVH) (LEW to LBN-F1), and combined HVG and GVH immune responses (BN to LEW). Both drugs were administered orally throughout the study. Low doses of RAD (1.0-2.5 mg/kg/day) combined with Neoral (2.0-5.0 mg/kg/day) produced strong synergistic effects in the prolongation of small-bowel graft survival in HVG (combination index, CI = 0.095, 0.1212), GVH (CI = 0.027, 0.020), and combined HVG and GVH immune responses (CI = 0.070, 0.301). The combination therapy of RAD and Neoral produces a strong synergistic effect toward the inhibition of HVG, GVH, and combined HVG and GVH immune responses in a rat small-bowel transplantation model.


Comparative Transcriptomic Analysis Reveals That Ethylene/H2O2-Mediated Hypersensitive Response and Programmed Cell Death Determine the Compatible Interaction of Sand Pear and Alternaria alternata.
A major restriction on sand pear (Pyrus pyrifolia) production is black spot disease caused by the necrotrophic fungus Alternaria alternata. However, the pear response mechanism to A. alternata is unknown at the molecular level. Here, host responses of a resistant cultivar Cuiguan (CG) and a susceptible cultivar Sucui1 (SC1) to A. alternata infection were investigated. We found that the primary necrotic lesion formed at 1 dpi and the expansion of lesions was aggressive in SC1. Data from transcriptomic profiles using RNA-Seq technology identified a large number of differentially expressed genes (DEGs) between CG and SC1 in the early phase of A. alternata infection. K-mean cluster and Mapman analysis revealed that genes involved in ethylene (ET) biosynthesis and ET signaling pathway, such as ACS, ACOs, and ERFs, and in hypersensitive response (HR) and programmed cell death (PCD) were significantly enriched and up-regulated in the susceptible cultivar SC1. Conversely, genes involved in response to hydrogen peroxide and superoxide were differentially up-regulated in the resistant cultivar CG after inoculation with the fungus. Furthermore, ET levels were highly accumulated in SC1, but not in CG. Higher activities of detoxifying enzymes such as catalases were detected in CG. Our results demonstrate that the ET-/H2O2-mediated PCD and detoxifying processes play a vital role in the interaction of pear and A. alternata.


Enhancement of the human mixed lymphocyte culture response by pretreating the stimulating cells with interferon.
The influence of interferon (IF) on the human mixed lymphocyte culture (MLC) reaction was examined. The presence of human IF in the MLCs but not pretreatment of the responding cell population with IF reduced the reaction. Pretreatment of the stimulating cells with human IF enhanced their MLC stimulatory capacities. This effect was observed with four different IF preparations of varying origin and purity, but not with a human mock or a mouse IF preparation.


Port implantation-related bloodstream infection caused by Wickerhamomyces myanmarensis: A case report.
Wickerhamomyces myanmarensis is a new opportunistic yeast previously named Pichai myanmarensis, which belongs to the order Saccharomycetales. Since its discovery, one environmental isolate of W. myanmarensis has been reported from Myanmar, and one clinical sample from Iran. We report a case of bloodstream infection related to an implantable venous access port. W. myanmarensis was isolated from patient's blood after chemotherapy, which was meant to control and heal T-cell lymphoblastic lymphoma. Broth dilution minimum inhibitory concentrations were performed according to the CLSI M27-A3 document. The patient recovered with intravenous voriconazole and was discharged with the recommended prescription of oral voriconazole as a maintenance drug. So far, only one case of W. myanmarensis fungemia has been reported in the world in 2019. This is the second case of bloodstream infection with this yeast from a patient undergoing chemotherapy in Iran.


A phase I study of irinotecan as a 3-week schedule in children with refractory or recurrent solid tumors.
A phase I study was performed to determine the maximum-tolerated dose (MTD) and safety profile of irinotecan (CPT-11) administered as a single intravenous infusion every 3 weeks in children with recurrent or refractory solid tumors. Eighty-one patients were enrolled, including 48 less heavily, and 33 heavily pretreated patients (cranial irradiation and/or high-dose chemotherapy). Children received CPT-11 as a 120-minute infusion at doses ranging from 200 to 720 mg/m2. The dose-limiting toxicities (DLT) on first cycle were determined in both cohorts. One hundred twenty-two cycles and 81 cycles were administered in less heavily, and heavily pretreated patients, respectively. The primary DLT was delayed diarrhea in less heavily pretreated patients, and neutropenia in heavily pretreated patients. MTD was 600 mg/m2 in both cohorts. Grade 3 to 4 neutropenia occurred in 33% and 38% of cycles in less heavily, and heavily pretreated patients, respectively. Grade 3 to 4 nonhematologic toxicities included nausea/vomiting (7% and 4% of cycles in less heavily, and heavily pretreated patients, respectively), asthenia (7% and 4% of cycles, respectively), and delayed diarrhea (6% and 2.5% of cycles, respectively). Four partial responses at 600 mg/m2 (high-grade glioma, neuroblastoma, medulloblastoma, and rhabdomyosarcoma) and 21 minor responses and stable diseases were observed. Pharmacokinetic analysis of CPT-11 and SN-38 was performed in 77 patients. The mean +/- standard deviation (SD) CPT-11 plasma clearance was 20.7 +/- 9.5 L/h/m2 (range, 5 to 54). The mean +/- SD SN-38 metabolic ratio was 1.5% +/- 1.1% (range, 0.15% to 5.55%). The recommended phase II dose of CPT-11 in a 3-week schedule is 600 mg/m2 in less heavily, and heavily pretreated children with solid tumors.


Comparison of SIV/SMM replication in CD4+ T cell and monocyte/macrophage cultures from rhesus macaques and sooty mangabeys.
Monocytes from SIV/SMM infected sooty mangabeys and rhesus macaques were incubated in vitro with live SIV/SMM. The reverse transcriptase (RT) activity in the supernatant fluids of the monocyte cultures of the former species was higher than the RT activity in the latter species. No differences were found in the supernatant fluid of similar cultures of CD4+ T cells from both these species. Autologous (but not allogeneic) CD8+ T cells from SIV infected mangabeys and rhesus macaques inhibited SIV replication in vitro. The suppression appeared more marked in monocytes from the mangabey species. These in vitro differences may relate to the clinically asymptomatic state of the sooty mangabeys and the disease-susceptible state of the rhesus macaques.


Antibody and T cell responses to Fusobacterium nucleatum and Treponema denticola in health and chronic periodontitis.
The characteristics of the T cell response to the members of oral flora are poorly understood. We characterized the antibody and T cell responses to FadA and Td92, adhesins from Fusobacterium nucleatum, an oral commensal, and Treponema denticola, a periodontal pathogen, respectively. Peripheral blood and saliva were obtained from healthy individuals and patients with untreated chronic periodontitis (CP, n = 11 paris) and after successful treatment of the disease (n = 9). The levels of antigen-specific antibody were measured by ELISA. In plasma, IgG1 was the most abundant isotype of Ab for both Ags, followed by IgA and then IgG4. The levels of FadA-specific salivary IgA (sIgA) were higher than Td92-specific sIgA and the FadA-specific IgA levels observed in plasma. However, the periodontal health status of the individuals did not affect the levels of FadA- or Td92-specific antibody. Even healthy individuals contained FadA- and Td92-specific CD4(+) T cells, as determined by the detection of intracytoplasmic CD154 after short-term in vitro stimulation of peripheral blood mononuclear cells (PBMCs) with the antigens. Patients with CP tended to possess increased numbers of FadA- and Td92-specific CD4(+) T cells but reduced numbers of Td92-specific Foxp3(+)CD4(+) Tregs than the healthy subjects. Both FadA and Td92 induced the production of IFNγ and IL-10 but inhibited the secretion of IL-4 by PBMCs. In conclusion, F. nucleatum induced Th3 (sIgA)- and Th1 (IFNγ and IgG1)-dominant immune responses, whereas T. denticola induced a Th1 (IFNγ and IgG1)-dominant response. This IFNγ-dominant cytokine response was impaired in CP patients, and the Td92-induced IFNγ levels were negatively associated with periodontal destruction in patients. These findings may provide new insights into the homeostatic interaction between the immune system and oral bacteria and the pathogenesis of periodontitis.


Regulation of sedimentation rate shapes the evolution of multicellularity in a close unicellular relative of animals.
Significant increases in sedimentation rate accompany the evolution of multicellularity. These increases should lead to rapid changes in ecological distribution, thereby affecting the costs and benefits of multicellularity and its likelihood to evolve. However, how genetic and cellular traits control this process, their likelihood of emergence over evolutionary timescales, and the variation in these traits as multicellularity evolves are still poorly understood. Here, using isolates of the ichthyosporean genus Sphaeroforma-close unicellular relatives of animals with brief transient multicellular life stages-we demonstrate that sedimentation rate is a highly variable and evolvable trait affected by at least 2 distinct physical mechanisms. First, we find extensive (>300×) variation in sedimentation rates for different Sphaeroforma species, mainly driven by size and density during the unicellular-to-multicellular life cycle transition. Second, using experimental evolution with sedimentation rate as a focal trait, we readily obtained, for the first time, fast settling and multicellular Sphaeroforma arctica isolates. Quantitative microscopy showed that increased sedimentation rates most often arose by incomplete cellular separation after cell division, leading to clonal "clumping" multicellular variants with increased size and density. Strikingly, density increases also arose by an acceleration of the nuclear doubling time relative to cell size. Similar size- and density-affecting phenotypes were observed in 4 additional species from the Sphaeroforma genus, suggesting that variation in these traits might be widespread in the marine habitat. By resequencing evolved isolates to high genomic coverage, we identified mutations in regulators of cytokinesis, plasma membrane remodeling, and chromatin condensation that may contribute to both clump formation and the increase in the nuclear number-to-volume ratio. Taken together, this study illustrates how extensive cellular control of density and size drive sedimentation rate variation, likely shaping the onset and further evolution of multicellularity.


Karyopherin alpha2: a control step of glucose-sensitive gene expression in hepatic cells.
Glucose is required for an efficient expression of the glucose transporter GLUT2 and other genes. We have shown previously that the intracytoplasmic loop of GLUT2 can divert a signal, resulting in the stimulation of glucose-sensitive gene transcription. In the present study, by interaction with the GLUT2 loop, we have cloned the rat karyopherin alpha2, a receptor involved in nuclear import. The specificity of the binding was restricted to GLUT2, and not GLUT1 or GLUT4, and to karyopherin alpha2, not alpha1. When rendered irreversible by a cross-linking agent, this transitory interaction was detected in vivo in hepatocytes. A role for karyopherin alpha2 in the transcription of two glucose-sensitive genes was investigated by transfection of native and inactive green fluorescent protein-karyopherin alpha2 in GLUT2-expressing hepatoma cells. The amount of inactive karyopherin alpha2 receptor reduced, in a dose-dependent manner, the GLUT2 and liver pyruvate kinase mRNA levels by competition with endogenous active receptor. In contrast, the overexpression of karyopherin alpha2 did not significantly stimulate GLUT2 and liver pyruvate kinase mRNA accumulation in green fluorescent protein-sorted cells. The present study suggests that, in concert with glucose metabolism, karyopherin alpha2 transmits a signal to the nucleus to regulate glucose-sensitive gene expression. The transitory tethering of karyopherin alpha2 to GLUT2 at the plasma membrane might indicate that the receptor can load the cargo to be imported locally.


Description of Amplimerlinius uramanatiensis sp. n. (Nematoda: Merliniidae) and observations on three other species of the genus from Iran.
A new species of the genus Amplimerlinius is described and illustrated from the rhizosphere of Vitis sp. from Kurdistan province in western Iran. A. uramanatiensis sp. n. is characterized by having seven to eight head annuli up to the end of the outer extension of the cephalic framework, 29-31 µm long stylet and cylindrical-clavate tail with a thin hyaline region (9-11 µm) and smooth terminus. Furthermore, A. paraglobigerus and A. macrurus were identified and intra-specific variability of A. globigerus was studied in detail, based on 21 populations collected from different regions of Iran. A key and diagnostic compendium to the species of the genus is provided.


The hemodynamics of adrenal veins with four-dimensional computed tomography using quantitative time-density curve: a study based on aldosteronism patients.
Present study quantitatively analyzed adrenal venous flow using four-dimensional computed tomography (4D CT). We reviewed 4D CT images of 55 patients [mean age, 52 years ± 11 (standard deviation); 23 females] who underwent adrenal venous sampling between August 2017 and February 2021. Time-density curves were referred for the adrenal venous enhancement. The clinical factors affecting hemodynamics were assessed using uni- and multivariate linear regression analyses. The right and left adrenal veins (RAV and LAV, respectively) were visualized in all cases. Mean peak enhancement values in RAV and LAV were 247 ± 67 and 292 ± 70 Hounsfield units (P < 0.01), and were reached at 44.43 ± 6.86 and 45.39 ± 7.53 s (P < 0.01), respectively. The body mass index (BMI), plasma renin activity and potassium were significant factors influencing the peak enhancement of RAV blood flow [standardized regression coefficients, - 0.327 (P = 0.017), - 0.346 (P = 0.013), 0.426 (P = 0.016), respectively]. A linear relationship between sex and the time-to-peak was observed for RAV [standardized regression coefficient, 0.348 (P = 0.046)]. RAV had a lower contrast effect than LAV and reached its peak faster. BMI, plasma renin activity, and potassium were associated with flow density in RAV. Sex independently influenced the time-to-peak.


Inverse molecular docking reveals a novel function of thymol: Inhibition of fat deposition induced by high-dose glucose in Caenorhabditis elegans.
As a natural product isolated from thyme oil in thyme, thymol (2-isopropyl-5-methylphenol) harbors antiviral, antioxidant, and other properties, and thus could be potentially used for the treatment of various diseases. However, the function of thymol has not been comprehensively studied. Here, we applied an inverse molecular docking approach to identify unappreciated functions of thymol. Potential targets of thymol in humans were identified by the server of DRAR-CPI, and targets of interest were then assessed by GO and KEGG pathway analysis. Subsequently, homologous proteins of these targets in Caenorhabditis elegans were identified by Blast tool, and their three-dimensional structures were achieved using Swiss-Model workspace. Interaction between thymol and the targeted proteins in worms was verified using AutoDock 4.0. Analyses of the targets revealed that thymol could be potentially involved in the glycolysis/gluconeogenesis and fatty acid degradation pathways. To verify the activity of thymol on lipid deposition in vivo, the C. elegans model was established. The lipid content of nematodes induced by high-dose glucose was determined by Oil Red O and Nile Red staining, and gene expression was assessed by qRT-PCR. The results showed that thymol might lead to the acceleration of β-oxidation by upregulating cpt-1, aco, fabp, and tph-1, causing the descent of lipid content in nematodes. Our findings indicated that thymol could be potentially used for the treatment of chronic metabolic diseases associated with increased fatty acid deposition.


[Mutagenesis and interchromosomal effect on crossing over in Drosophila].
The possibility of mutational consequences of interchromosomal effect on crossing-over was studied in Drosophila melanogaster females with four genotypes: (1) structurally normal (control); (2) heterozygous at In(1)-Muller-5 inversion (X chromosome); (3) heterozygous at In(3LR)CxD inversion (chromosome 3); and (4) heterozygous at both inversions. The mutational effect was determined through the loss of autosome 2 and formation of arm compounds C(2L) and C(2R). In females with recombinations, the rate of mutational events did not exceed that of the control. It was concluded that interchromosomal effect on crossing-over is of a regulatory character and disturbs neither recombination itself nor chromosome pairing. Coorientation X-3 leading to the appearance of intersexes in the progeny occurred in meiosis in females with two inversions.


Selecting Color-based Tracers and Classifying Sediment Sources in the Assessment of Sediment Dynamics Using Sediment Source Fingerprinting.
The use of sediment color as a fingerprint property to determine sediment sources is an emerging technique that can provide a rapid and inexpensive means of investigating sediment sources. The present study aims to test the feasibility of color fingerprint properties to apportion sediment sources within the South Tobacco Creek Watershed (74 km) in Manitoba, Canada. Suspended sediment from 2009 to 2011 at six monitoring stations and potential source samples along the main stem of the creek were collected. Reflectance spectra of sediments and source materials were quantified using a diffuse reflectance spectrometry, and 16 color coefficients were derived from several color space models. Canonical discriminant analysis was used to reclassify and downsize sediment source groups. After the linear additive test and stepwise discriminant function analysis, four color coefficients were chosen to fit the Stable Isotope Analysis in R model. Consistent with the conventional fingerprinting approach, the color fingerprint results demonstrated a switch in the dominant sediment source between the headwaters and the outlet of the watershed, with the main sources being topsoil in the upper reaches, whereas outcrop shale and stream bank materials dominated in the lower reaches. The color fingerprinting approach can be integrated with conventional fingerprints (e.g., geochemical and fallout radionuclide properties) to improve source discrimination, which is a key component for source ascription modeling. We concluded that the use of color fingerprints is a promising, cost-effective technique for sediment source fingerprinting.


Systematic Investigation of Lanthanoid Transition Heavy Metal Acetates as Electron Staining Reagents for Protein Molecules in Biological Transmission Electron Microscopy.
Cryo-electron microscopy, widely used for high-resolution protein structure determination, does not require staining. Yet negative staining with heavy metal salts such as uranyl acetate has been in persistent demand since the 1950s due to its image contrasting capabilities at room temperature with a common electron microscope. However, uranium compounds are nuclear fuel materials and are tightly controlled worldwide. Acetates of each lanthanoid series elements except promethium are prepared at the same concentration (2%(w/v)) and used as a model on horse spleen ferritin for electron microscopic analysis to systematically evaluate their effectiveness as electron staining reagents for the protein. Analysis shows that the triacetates of samarium and europium, followed by gadolinium and erbium, and then lanthanum and neodymium could function as electron staining reagents. Thulium-triacetate precipitates thin plate-like crystals and may be used for selecting better imaging fields. Of the 14 lanthanoid-triacetates examined, about half are viable alternatives to uranyl acetate as an electron staining reagent for ferritin, and there appears an optimal range in ionic sizes for promising lanthanoids. This is the first systematic investigation of lanthanoid transition heavy metal triacetates from the viewpoint of lanthanoid contraction, using density distribution histograms of electron micrographs as an indicator for comparison with uranyl acetate.


Comparative Study of Extracellular Proteolytic, Cellulolytic, and Hemicellulolytic Enzyme Activities and Biotransformation of Palm Kernel Cake Biomass by Lactic Acid Bacteria Isolated from Malaysian Foods.
Biotransformation via solid state fermentation (SSF) mediated by microorganisms is a promising approach to produce useful products from agricultural biomass. Lactic acid bacteria (LAB) that are commonly found in fermented foods have been shown to exhibit extracellular proteolytic, β-glucosidase, β-mannosidase, and β-mannanase activities. Therefore, extracellular proteolytic, cellulolytic, and hemicellulolytic enzyme activities of seven Lactobacillus plantarum strains (a prominent species of LAB) isolated from Malaysian foods were compared in this study. The biotransformation of palm kernel cake (PKC) biomass mediated by selected L. plantarum strains was subsequently conducted. The results obtained in this study exhibited the studied L. plantarum strains produced versatile multi extracellular hydrolytic enzyme activities that were active from acidic to alkaline pH conditions. The highest total score of extracellular hydrolytic enzyme activities were recorded by L. plantarum RI11, L. plantarum RG11, and L. plantarum RG14. Therefore, they were selected for the subsequent biotransformation of PKC biomass via SSF. The hydrolytic enzyme activities of treated PKC extract were compared for each sampling interval. The scanning electron microscopy analyses revealed the formation of extracellular matrices around L. plantarum strains attached to the surface of PKC biomass during SSF, inferring that the investigated L. plantarum strains have the capability to grow on PKC biomass and perform synergistic secretions of various extracellular proteolytic, cellulolytic, and hemicellulolytic enzymes that were essential for the effective biodegradation of PKC. The substantial growth of selected L. plamtraum strains on PKC during SSF revealed the promising application of selected L. plantarum strains as a biotransformation agent for cellulosic biomass.


Inflammatory Response Using Different Lipid Parenteral Nutrition Formulas in Children After Hematopoietic Stem Cell Transplantation.
Nutritional support is an integral part of the supportive care of hematopoietic stem cell transplantation (HSCT) patients. Omega-3 fatty acids (n-3 FA) emulsions in parenteral nutrition (PN) may modify the inflammatory response. The purpose of this study is to compare plasma cytokine levels in children after HSCT using an n-3 FA-containing lipid emulsion (LE) and a soybean oil-based formulation in PN. A randomized double-blind controlled trial was conducted on 14 children following HSCT. Children were randomized to receive either a fish oil or a soybean oil LE. Blood samples were drawn at baseline, on Day 10 and after completion of PN to analyze plasma interleukin 1 beta (IL-1β), 2 (IL-2), 6 (IL-6), 8 (IL-8), 10 (IL-10), and tumor necrosis factor alpha (TNF-α). After 10 days of PN, there were no significant changes in interleukins levels when comparing the two groups or time points (baseline vs. Day 10 of PN). In children requiring PN >21 days, IL-10 and TNF-α levels (P ≤ 0.05) were lower in the fish-oil-containing LE group. Fish oil- and soybean oil-supplemented PN administered for at least 10 days does not cause inflammatory changes. Prolonged PN based on fish oil LE may modulate the inflammatory response.


The Schooling Experience of Lesbian, Gay, and Bisexual Youth in lsrael: Falling Below and Rising Above as a Matter of Social Ecology.
Research on the schooling experience of lesbian, gay, and bisexual (LGB) youth in Israel and in other Western countries has been largely risk-focused, whereas extrinsic and intrinsic protective factors, which enable LGB adolescent students to cope with school homophobic bullying, are often overlooked. To address this shortcoming, the researchers conducted a qualitative study based on semistructured interviews with 20 LGB-identified secondary school students. The findings and implications emphasized the key role of adequate ecological protective factors for LGB youth in enhancing effective coping mechanisms in response to school homophobic bullying.


[Effect of nutritional status during infancy and childhood on the risk of overweight and obesity in adulthood].
To examine the association between fetal nutritional status and overweight and obesity in their adulthood and to provide evidence for formulation of the strategy on preventing low birth weight. Using data from 2002 Nationwide Nutrition and Health Survey to set up a case-control method in order to compare body mass index(BMI), prevalence of overweight and obesity as well as to calculate odds ratio of overweight and obesity of case group compared with control group. Three case groups were selected from those who were born in 1959, 1960,1961 respectively, and the controls were those who were born in 1964. The health consequence of being famines on adulthood was evident in women. Means of BMI in women were significantly higher in three case groups than that in control group(P<0.01). After adjustment on geographic regions, the prevalence of overweight in women was significantly higher in three case groups than that in control group(P< 0.01). The prevalence rates of obesity were significantly higher in 1959, 1960 groups than 1964 group(P< 0.05). The odds ratios of overweight of women in three case groups were 28.9% (95% CI:1.063-1.565), 37.2% (95% CI:1. 136-1.658) and 35.2% (95% CI: 1. 103-1.657) respectively, all higher than that in the control group. The odds ratios of obesity of women born in 1959, 1960 groups were 46.5% (95% CI: 1.088-1.972) and 39.6% (95% CI: 1.039- 1.876) respectively, higher than that in the 1964 group. However, such differences were not found in men. Higher risks of overweight and obesity in women were caused by malnutrition during their fetal lives. A strategy on preventing low birth weight should be formulated by the government to prevent the chronic disease in adulthood.


Periostin and Discoidin Domain Receptor 1: New Biomarkers or Targets for Therapy of Renal Disease.
Chronic kidney disease (CKD) can be a life-threatening condition, which eventually requires renal replacement therapy through dialysis or transplantation. A lot of effort and resources have been invested the last years in the identification of novel markers of progression and targets for therapy, in order to achieve a more efficient prognosis, diagnosis, and treatment of renal diseases. Using experimental models of renal disease, we identified and studied two promising candidates: periostin, a matricellular protein with high expression in bone and dental tissues, and discoidin domain receptor 1 (DDR1), a transmembrane collagen receptor of the tyrosine kinase family. Both proteins are inactive in physiological conditions, while they are highly upregulated during development of renal disease and are primarily expressed at the sites of injury. Further studies demonstrated that both periostin and DDR1 are involved in the regulation of inflammation and fibrosis, two major processes implicated in the development of renal disease. Targeting of either protein by genetic deletion or pharmacogenetic inhibition via antisense oligonucleotides highly attenuates renal damage and preserves renal structure and function in several animal models. The scope of this review is to summarize the existing evidence supporting the role of periostin and DDR1 as novel biomarkers and therapeutic targets in CKD.


Myth: blood transfusion is effective for sickle cell anemia-associated priapism.
Priapism is a recognized complication of sickle cell anemia (SCA). When initial conventional treatments fail, simple or exchange blood transfusion has been advocated as a secondary intervention. However, recent literature suggests this may not be an effective therapy and may have significant neurologic sequelae. This paper reviews and summarizes the effectiveness and risks of blood transfusion compared with conventional priapism therapy. All relevant papers identified from a MEDLINE search were systematically examined for data related to the use of blood transfusion in the setting of priapism due to SCA. The effectiveness of conventional therapy was compared with transfusion therapy using the outcome of "time to detumescence" (TTD). In addition, papers documenting adverse neurologic sequela were reviewed and summarized. Forty-two case reports were identified containing complete information with regard to patient age and TTD. The mean TTD was 8.0 days with conventional therapy (n = 16) and 10.8 days with blood transfusion therapy (n = 26). Adverse neurologic sequelae from blood transfusion therapy was described in 9 cases, with long term outcomes ranging from complete resolution to severe residual deficits. The current literature does not support the contention that blood transfusion is an effective therapy in the treatment of priapism due to SCA, as defined by an acceleration of TTD. In fact, numerous reports suggest that serious neurologic sequelae may result from this treatment. We feel the routine use of this therapy cannot be recommended.


Vinylogy in orthoester hydrolysis: total syntheses of cyclophellitol, valienamine, gabosine K, valienone, gabosine G, 1-epi-streptol, streptol, and uvamalol A.
C7-cyclitols represent an important category of natural products possessing a broad spectrum of biological activities. As each member of these compounds is structurally unique, the usual practice is to synthesize them individually from appropriate polyhydroxylated chiral pools. We have observed an unusual vinylogy in acid mediated hydrolysis of enol ethers of myo-inositol 1,3,5-orthoesters giving a synthetically versatile polyhydroxylated cyclohexenal intermediate. We have exploited this unprecedented reaction for developing a general strategy for the rapid and efficient syntheses of several structurally diverse natural products of C7-cyclitol family. We have made an appropriately protected advanced intermediate 25 in five steps from the cheap and commercially available myo-inositol, and this common intermediate has been used to synthesize eight natural products in racemic form. We could synthesize (±)-cyclophellitol in seven steps, (±)-valienamine in five steps, (±)-gabosine I in five steps, (±)-gabosine G in six steps, (±)-gabosine K in three steps, (±)-streptol in six steps, (±)-1-epi-streptol in two steps, and (±)-uvamalol A in five steps from this intermediate.


Effects of different light conditions on transient expression and biomass in Nicotiana benthamiana leaves.
In the process of the production of recombinant proteins by using an Agrobacterium-mediated transient gene expression system, the effectiveness of the control of light conditions pre- and post-agroinfiltration on efficiency of transient expression is worth being evaluated. In this study, Nicotiana benthamiana plants were used as a bioreactor to investigate the effects of different light conditions pre- and post-agroinfiltration on the transient expression of green fluorescent protein (GFP). The results showed that the plants grown under light condition for 5 weeks had the highest level of transient expression among those grown for 4-8 weeks. In the pre-agroinfiltration, the level of transient expression of GFP was obviously decreased by the increase in light intensity or by the shortening of the photoperiod. Although the shortening of the photoperiod post-agroinfiltration also decreased the level of transient expression, moderate light intensity post-agroinfiltration was needed for higher level of transient expression efficiency. However, there was no strong correlation between the transient expression efficiency and plant growth. The results suggested that light condition was an important factor affecting the level of transient expression in plants. Hence, light conditions should be optimized to obtain higher productivity of recombinant protein from transient expression systems.


Identification of a glycolysis-related lncRNA prognostic signature for clear cell renal cell carcinoma.
The present study investigated the independent prognostic value of glycolysis-related long noncoding (lnc)RNAs in clear cell renal cell carcinoma (ccRCC). A coexpression analysis of glycolysis-related mRNAs-long noncoding RNAs (lncRNAs) in ccRCC from The Cancer Genome Atlas (TCGA) was carried out. Clinical samples were randomly divided into training and validation sets. Univariate Cox regression and least absolute shrinkage and selection operator (LASSO) regression analyses were performed to establish a glycolysis risk model with prognostic value for ccRCC, which was validated in the training and validation sets and in the whole cohort by Kaplan-Meier, univariate and multivariate Cox regression, and receiver operating characteristic (ROC) curve analyses. Principal component analysis (PCA) and functional annotation by gene set enrichment analysis (GSEA) were performed to evaluate the risk model. We identified 297 glycolysis-associated lncRNAs in ccRCC; of these, 7 were found to have prognostic value in ccRCC patients by Kaplan-Meier, univariate and multivariate Cox regression, and ROC curve analyses. The results of the GSEA suggested a close association between the 7-lncRNA signature and glycolysis-related biological processes and pathways. The seven identified glycolysis-related lncRNAs constitute an lncRNA signature with prognostic value for ccRCC and provide potential therapeutic targets for the treatment of ccRCC patients.


A systematic approach for detecting high-frequency restriction fragment length polymorphisms using large genomic probes.
Thirteen phage clones containing low-copy sequences were isolated from a human DNA library and tested for their ability to detect restriction fragment length polymorphisms (RFLPs). Reported are the RFLPs revealed with each clone, all found in frequencies useful for linkage studies. Cytological data are available for five of the 13 clones, with regional assignments made for three of the markers by in situ hybridization. It is concluded that phage clones containing large unique DNA inserts detect multiple RFLPs with high efficiency. An analysis of the relative efficiency of 20 restriction enzymes for detecting single nucleotide changes is discussed by comparing the observed data to those expected on the basis of recognition and potential site frequencies, as computed from the dinucleotide distribution. Finally, in an effort to facilitate linkage studies using polymorphic DNA sequences, experiments were made with pools of probes from various sources.


Serum magnesium and stable asthma: Is there a link?
Although magnesium is used through intravenous and inhalation route in the management of asthma, actual prevalence of hypomagnesemia in asthma is not known. We conducted this study: 1) to detect the prevalence of hypomagnesemia in stable asthma and 2) to assess the significance of hypomagnesemia in these patients. Prospective clinical study. Department of Respiratory Medicine, Calcutta National Medical College, Kolkata. Four months from January, 2007, to April, 2007. Fifty patients attending outpatients department of respiratory medicine with stable asthma were randomly selected. They were assessed clinically and their serum magnesium levels were measured. This was compared with the serum magnesium values of 45 nonasthmatic healthy controls. Out of 50 patients, 14 had hypomagnesemia. Possible relationship of hypomagnesemia with tachycardia, tachypnoea, severity of asthma, medication use, and previous and future exacerbations were analyzed. There was statistically significant association of hypomagnesemia with tachypnoea, severe asthma, use of long-acting β-agonist, inhaled corticosteroids, theophylline, use of ≥ 3 medications, previous and future exacerbations but not with tachycardia or use of short-acting β(2) -agonist or montelukast.


Local-Level Genetic Diversity and Structure of Matsutake Mushroom (Tricholoma matsutake) Populations in Nagano Prefecture, Japan, Revealed by 15 Microsatellite Markers.
The annual yield of matsutake mushrooms (Tricholoma matsutake) has consistently decreased in Japan over the past few decades. We used 15 polymorphic and codominant simple sequence repeat (SSR) markers, developed using next-generation sequencing, to carry out genetic analyses of 10 populations in Nagano, Japan. Using the SSRs, we identified 223 genotypes, none of which was observed in more than one population. The mean expected heterozygosity and standardized allelic richness values were 0.67 and 4.05, respectively. Many alleles appeared in only one of the 10 populations; 34 of these private alleles were detected with a mean number per population of 3.4. The fixation index (FST) and standardized genetic differentiation (G'ST) values were 0.019 and 0.028, respectively. Analysis of molecular variance (AMOVA) showed that the contribution of among population, among genets within a population, and within genets variation to the total variation was 2.91%, 11.62%, and 85.47%, respectively, with genetic differentiation being detected for all sources. Twenty-eight of 45 pairwise FST values were significantly larger than zero, and no pattern of isolation by distance was detected among the 10 populations. Bayesian-based clustering did not show clear differences among populations. These results suggest that reestablishment of a colony would be best accomplished by transplantation within a field; if this is not possible, then transplantation from within several dozen kilometers will cause little damage to the original population genetic structure.


Electrochemical imination of sulfoxides using N-aminophthalimide.
[reaction: see text] A novel electrochemical sulfoxide imination process is described. Our approach starts with a highly selective nitrene transfer from N-aminophthalimide to a variety of sulfoxides. This oxidative treatment is followed by reductive N-N bond cleavage under the controlled current conditions, which leads to a range of parent NH sulfoximines. In addition to solving the challenging problem of removing the N-phthalimido group, the overall process avoids the use of toxic oxidants and metal additives.


Effects of intermittent suckling and creep feed intake on pig performance from birth to slaughter.
An experiment was conducted to determine if the improved creep feed intake observed during intermittent suckling (IS) is important for postweaning performance. Therefore, creep feed intake of litters was assessed, and within litters, eaters and noneaters were distinguished using chromic oxide as an indigestible marker. Batches of sows were suckled intermittently (IS, 7 batches; n = 31) or continuously (control, 7 batches; n = 31). In the IS group, litters were separated from the sow for a period of 12 h/d (0930 to 2130), beginning 11 d before weaning. Litters were weaned at 4 wk of age. Litters had free access to creep feed from 1 wk of age onward. Five days after weaning, the piglets were moved as a litter to weanling pens. At 8 wk of age, 2 barrows and 2 gilts were randomly chosen from each litter and moved to a finishing facility. Feed intake was improved by IS during the last 11 d of lactation (IS, 284 +/- 27 vs. control, 83 +/- 28 g/piglet; P < 0.001) and after weaning during the first (IS, 201 +/- 24 vs. control, 157 +/- 25 g x piglet(-1) x d(-1); P < 0.05) and second (IS, 667 +/- 33 vs. control, 570 +/- 35 g x piglet(-1) x d(-1); P < 0.05) wk. Thereafter, no differences were found to slaughter. Weaning BW was lower in IS litters (IS, 7.1 +/- 0.01 vs. control, 8.1 +/- 0.01 kg/piglet; P < 0.05), but 7 d after weaning BW was similar (IS, 8.5 +/- 0.2 vs. control, 8.7 +/- 0.2 kg/piglet; P = 0.18), and no differences were found to slaughter. The percentage of eaters within a litter was not increased by IS during lactation (IS, 23 +/- 4.5% vs. control, 19 +/- 4.1%; P = 0.15). Weaning BW did not differ between eaters and noneaters (eater, 7.7 +/- 0.1 vs. noneater, 7.5 +/- 0.08 kg/piglet; P = 0.63). From 1 until 4 wk after weaning, piglets that were eaters during lactation had heavier BW than noneaters (eater, 20.3 +/- 0.3 kg vs. noneater, 18.2 +/- 0.2 kg; P < 0.05). The influence of eating creep feed during lactation on BW and ADG and the influence of suckling treatment never showed an interaction. We conclude that IS increases ADFI during lactation on a litter level and improves ADG in the first week and ADFI in the first and second weeks after weaning. No long-term effects on ADFI or ADG were observed throughout the finishing period. In the current experiment, in which creep feed intake was low, the percentage of eaters within a litter was not increased, suggesting that creep feed intake of piglets that were already eating was stimulated by IS. Further, piglets that were eaters during lactation had heavier BW up to 4 wk after weaning.


Demonstration of organic anion transport in T lymphocytes. L-lactate and fluo-3 are target molecules.
In this paper, we describe for the first time the existence of organic anion transport in T lymphocytes, exemplified by the transmembrane transport of the anions L-lactate and the Ca2+ indicator fluo-3. The transport of either anion was found to be inhibitable by probenecid, a common blocker of organic anion transport. Transport of L-lactate was observed in long-term cultured T cell lines, as well as in freshly ex vivo isolated T cells, and occurred via a saturable, pH-dependent, and stereospecific process. L-Lactate uptake was dependent on the activation state of the T cells, because activation of T cells by Con A strongly enhanced accumulation of L-lactate from the medium. Because L-lactate may be transported bidirectionally through the T cell membrane in vivo, different physiologic roles of L-lactate transport are discussed. L-Lactate uptake may serve as an alternative source of energy in an inflamed, glucose-deficient tissue or may represent a prerequisite for the earlier-published immunoregulatory function of this molecule on T cells. On the other hand, release of L-lactate emerging from glycolysis could be necessary to avoid acidification of the cell. The fact that the Ca2+ indicator fluo-3 is also transported through the cellular membranes of long-term cultured T cells via organic anion transport has important implications for the determination of Ca2+ influx into T cells. Even though the transport of both molecules, L-lactate and fluo-3, represents organic anion transport, evidence is presented that confirms that the respective transport systems are different.


Antithrombotic therapy with Transcatheter aortic valve replacement.
Aortic valve replacement is a necessary management strategy for patients with severe aortic stenosis. The use of transaortic valve replacement (TAVR) has increased significantly over the last decade and now exceeds traditional surgical aortic valve replacement. Since the valve systems used in TAVR consist of bioprosthetic valve tissue encased in a metal stent frame, antithrombotic therapy recommendations cannot be extrapolated from prior data with differently constructed surgical bioprosthetic or mechanical valves. Data on the use of antithrombotic therapy with TAVR are a rapidly developing area of medicine. Choice of agents depends on several patient factors. Patients undergoing TAVR also have a relatively high incidence of subclinical valve thrombosis. The clinical impact of this phenomenon and the implications for antithrombotic therapy continue to evolve. It is critical for clinicians who treat patients undergoing TAVR to have a firm understanding of practice guidelines, the evolving evidence, and its implications for the use of antithrombotic therapy in these patients.


Sexual recombination and the power of natural selection.
Theory predicts that recombination will increase the effectiveness of natural selection. A Drosophila melanogaster model system was developed that increased experimental power with the use of high experimental replication, explicit tracking of individual genes, and high but natural levels of background selection. Each of 34 independent experiments traced the fate of a newly arisen mutation located within genome-wide, synthetic chromosomes that were propagated with or without recombination. An intrinsic advantage to recombination was demonstrated by the finding that the realized strength of selection on new mutations was markedly increased when recombination was present.


External Fixation Using a Locking Plate: A Reliable Way in Treating Distal Tibial Fractures.
The surgical treatment of distal tibial fractures is still challenging. The purpose of this study was to evaluate the clinical and radiographic results associated with the use of a precontoured distal femoral locking plate as an external fixator in treating distal tibial fractures. From August 2011 to October 2012, 28 patients with distal tibial fractures were consecutively enrolled in this study. There were 9 OTA 43.A1, 9 43.A2, and 10 43.A3, including 21 closed and 7 open fractures. The precontoured distal femoral locking plate was placed on the anteromedial aspect of the tibia as an external fixator. All patients were followed for an average of 16 months. The mean surgical duration was 38 (25-60) minutes. The mean time until fracture healing was 16.7 (12-24) weeks. At final follow-up, the mean American Orthopaedic Foot and Ankle Society score was 93 (88-100). There were no nonunions, deep infections, or implant fractures. Three patients had transient superficial pin site infection, but these did not change the clinical outcome. External fixation using a precontoured distal femoral locking plate is a reliable option in treating distal tibial fracture. The procedure is easy to perform, is less invasive, and the low profile plate can be concealed under stockings and can be conveniently removed.


The Association of Metabolomic Profiles of a Healthy Lifestyle with Heart Failure Risk in a Prospective Study.
Lifestyle has been linked to the incidence of heart failure, but the underlying biological mechanisms remain unclear. Using the metabolomic, lifestyle, and heart failure data of the UK Biobank, we identified and validated healthy lifestyle-related metabolites in a matched case-control and cohort study, respectively. We then evaluated the association of healthy lifestyle-related metabolites with heart failure (HF) risk and the added predictivity of these healthy lifestyle-associated metabolites for HF. Of 161 metabolites, 8 were identified to be significantly related to healthy lifestyle. Notably, omega-3 fatty acids and docosahexaenoic acid (DHA) positively associated with a healthy lifestyle score (HLS) and exhibited a negative association with heart failure risk. Conversely, creatinine negatively associated with a HLS, but was positively correlated with the risk of HF. Adding these three metabolites to the classical risk factor prediction model, the prediction accuracy of heart failure incidence can be improved as assessed by the C-statistic (increasing from 0.806 [95% CI, 0.796-0.816] to 0.844 [95% CI, 0.834-0.854], p-value < 0.001). A healthy lifestyle is associated with significant metabolic alterations, among which metabolites related to healthy lifestyle may be critical for the relationship between healthy lifestyle and HF. Healthy lifestyle-related metabolites might enhance HF prediction, but additional validation studies are necessary.


The experience of facilitators and participants of long term condition self-management group programmes: A qualitative synthesis.
Our aim was to systematically review the qualitative literature about the experiences of both facilitators and participants in a range of group-based programmes to support the self-management of long-term conditions. We searched 7 databases using the terms 'self-management', 'group' and 'qualitative'. Full text articles meeting the inclusion criteria were retrieved for review. A thematic synthesis approach was used to analyse the studies. 2126 articles were identified and 24 were included for review. Group participants valued being with similar others and perceived peer support benefits. Facilitators (HCP and lay) had limited group specific training, were uncertain of purpose and prioritised education and medical conformity over supportive group processes and the promotion of self-management agency and engagement. Overall, studies prioritised positive descriptions. Group programmes' medical self-management focus may reduce their ability to contribute to patient-valued outcomes. Further research is needed to explore this disconnect. This review supports broadening the scope of group-based programmes to foreground shared learning, social support and development of agency. It is of relevance to developers and facilitators of group self-management programmes and their ability to address the burden of long-term conditions.


Arrayed primer extension computing with variant mRNA splice forms. Multiple isoforms of CD44 in a human breast tumor.
The analysis of RNA splicing is important to understanding the diversity in protein sequences at specific disease loci, in the immune response, and across the proteome. The presence of each exon in a mature mRNA formed from a genomic sequence of n exons can be represented by a Boolean variable, enabling mRNA structure to be encoded by an n-bit binary number. The CD44 locus has been studied as an example of a variantly spliced RNA. Microarray methods can be used to address RNA splicing provided they exhibit high fidelity. Our previous work showed that the arrayed primer extension (APEX; single-nucleotide polymerase extension of microarrays of DNA primers) method gives high-fidelity, digital detection of nucleic acid sequences, and it has been used for the solution of Boolean computing problems. APEX was adapted to RNA analysis by the use of reverse transcriptase and arrays of primers specific to each exon in the CD44 locus. "Splicotypes" were readily assigned for a number of variant RNA templates. Because CD44 is known to be aberrantly spliced in a number of cancers, the RNA APEX method with a CD44 microarray was applied to samples from primary tumors of individual patients. Up to four different splicing forms of CD44 were detected, whereas there have been no previous reports of the presence of more than two CD44 isoforms within the same tissue.


Acetylcholine release from urinary bladder smooth muscles of non-insulin-dependent diabetic rats.
To investigate the mechanism of voiding dysfunction in non-insulin-dependent diabetes mellitus, we attempted to measure the acetylcholine (ACh) release using an in vivo microdialysis technique and measuring the detrusor pressure after electrical field stimulation (EFS) of the pelvic nerve. Eight- and 32-week-old female Goto-Kakizaki (GK) rats (non-insulin-dependent diabetes mellitus model) and age-matched female Wistar rats (controls) were used in this study. The pelvic nerve was exposed on a bipolar platinum electrode to EFS, and a cannula was inserted into the bladder to measure the detrusor pressure. The microdialysis probe was inserted into the bladder wall and was connected to a microinfusion syringe pump. Dialysate was constantly perfused, collected in a microtube, and then injected into the ACh assay system. Histological examinations were performed by staining with hematoxylin and eosin and S-100 immunohistochemical staining in bladder preparations of both GK and control rats. In 8-week-old rats, both detrusor pressures and amounts of ACh release of GK rats were not significantly different from those of control rats. In 32-week-old rats, both detrusor pressures and ACh releases were only significantly increased at 5 and 10 Hz of EFS. In the histological study, the number of nerve fibers or bundles of 32-week-old GK rats was significantly decreased as compared with control rats. The present data suggest that the decrease in EFS-induced ACh release in GK rats, which may be caused by the decreased number of nerve fibers, may contribute to the decrease in bladder contractions.


Recurrent embolotherapy in Dieulafoy's disease of the bronchus.
Dieulafoy's disease is a vascular anomaly characterized by the presence of a dysplastic artery that is related to an epithelial ulcer. The French surgeon Georges Dieulafoy first described it in 1898. Most frequently, it is a gastrointestinal condition, but occurrence in the bronchus has been reported in a few cases. The case of a 52-year-old man with massive hemoptysis, for which he underwent successful embolotherapy 10 years previously, is described. Over the next 10 years, he had several hospital admissions due to hemoptysis, and he underwent successful embolotherapy on each occasion. This case report underlines the importance of bronchial arteriography as the investigation of choice for massive hemoptysis.


Comparison of computational to human observer detection for evaluation of CT low dose iterative reconstruction.
Model observers were created and compared to human observers for the detection of low contrast targets in computed tomography (CT) images reconstructed with an advanced, knowledge-based, iterative image reconstruction method for low x-ray dose imaging. A 5-channel Laguerre-Gauss Hotelling Observer (CHO) was used with internal noise added to the decision variable (DV) and/or channel outputs (CO). Models were defined by parameters: (k1) DV-noise with standard deviation (std) proportional to DV std; (k2) DV-noise with constant std; (k3) CO-noise with constant std across channels; and (k4) CO-noise in each channel with std proportional to CO variance. Four-alternative forced choice (4AFC) human observer studies were performed on sub-images extracted from phantom images with and without a "pin" target. Model parameters were estimated using maximum likelihood comparison to human probability correct (PC) data. PC in human and all model observers increased with dose, contrast, and size, and was much higher for advanced iterative reconstruction (IMR) as compared to filtered back projection (FBP). Detection in IMR was better than FPB at 1/3 dose, suggesting significant dose savings. Model(k1,k2,k3,k4) gave the best overall fit to humans across independent variables (dose, size, contrast, and reconstruction) at fixed display window. However Model(k1) performed better when considering model complexity using the Akaike information criterion. Model(k1) fit the extraordinary detectability difference between IMR and FBP, despite the different noise quality. It is anticipated that the model observer will predict results from iterative reconstruction methods having similar noise characteristics, enabling rapid comparison of methods.


Brain angiotensin II, an important stress hormone: regulatory sites and therapeutic opportunities.
The presence of a brain Angiotensin II (Ang II) system, separated from and physiologically integrated with the peripheral, circulating renin-angiotensin system, is firmly established. Ang II is made in the brain and activates specific brain AT(1) receptors to regulate thirst and fluid metabolism. Some AT(1) receptors are located outside the blood-brain barrier and are sensitive to brain and circulating Ang II. Other AT(1) receptors, located inside the blood-brain barrier, respond to stimulation by Ang II of brain origin. AT(1) receptors in the subfornical organ, the hypothalamic paraventricular nucleus (PVN), and the median eminence are involved in the regulation of the stress response. In particular, AT(1) receptors in the PVN are under glucocorticoid control and regulate corticotrophin-releasing hormone (CRH) formation and release. In the PVN, restraint elicits a fast increase in AT(1) receptor mRNA expression. The expression of paraventricular AT(1) receptors is increased during repeated restraint and after 24 h of isolation stress, and their stimulation is essential for the hypothalamic-pituitary-adrenal axis activation, the hallmark of the stress response. Peripheral administration of an AT(1) receptor antagonist blocks peripheral and brain AT(1) receptors, prevents the sympathoadrenal and hormonal response to isolation stress, and prevents the gastric stress ulcers that are a characteristic consequence of cold-restraint stress. This evidence indicates that pharmacologic inhibition of the peripheral and brain Ang II system by AT(1) receptor blockade has a place in the prevention and treatment of stress-related disorders.


The role of lymph nodes in cervical cancer: incidence and identification of lymph node metastases-a literature review.
Correct identification of patients with lymph node metastasis from cervical cancer prior to treatment is of great importance, because it allows more tailored therapy. Patients may be spared unnecessary surgery or extended field radiotherapy if the nodal status can be predicted correctly. This review captures the existing knowledge on the identification of lymph node metastases in cervical cancer. The risk of nodal metastases increases per 2009 FIGO stage, with incidences in the pelvic region ranging from 2% (stage IA2) to 14-36% (IB), 38-51% (IIA) and 47% (IIB); and in the para-aortic region ranging from 2 to 5% (stage IB), 10-20% (IIA), 9% (IIB), 13-30% (III) and 50% (IV). In addition, age, tumor size, lymph vascular space invasion, parametrial invasion, depth of stromal invasion, histological type, and histological grade are reported to be independent prognostic factors for the risk of nodal metastases. Furthermore, biomarkers can contribute to predict a patient's nodal status, of which the squamous cell carcinoma antigen (SCC-Ag) is currently the most widely used in squamous cell cervical cancer. Still, pre-treatment lymph node assessment is primarily performed by imaging, of which diffusion-weighted magnetic resonance imaging has the highest sensitivity and 2-deoxy-2-[18F]fluoro-D-glucose positron emission computed tomography the highest specificity. Imaging results can be combined with clinical parameters in nomograms to increase the accuracy of predicting positives nodes. Despite all the progress regarding pre-treatment prediction of lymph node metastases in cervical cancer in recent years, prediction rates are not robust enough to safely abandon surgical staging of the pelvic or para-aortic region yet.


Applying gene regulatory network logic to the evolution of social behavior.
Animal behavior is ultimately the product of gene regulatory networks (GRNs) for brain development and neural networks for brain function. The GRN approach has advanced the fields of genomics and development, and we identify organizational similarities between networks of genes that build the brain and networks of neurons that encode brain function. In this perspective, we engage the analogy between developmental networks and neural networks, exploring the advantages of using GRN logic to study behavior. Applying the GRN approach to the brain and behavior provides a quantitative and manipulative framework for discovery. We illustrate features of this framework using the example of social behavior and the neural circuitry of aggression.


Synthesis of tertiary alpha-hydroxy acids by silylene transfer to alpha-keto esters.
Alpha-keto esters can be converted into alpha-hydroxy acids in a single flask involving metal-catalyzed silylene transfer, 6pi-electrocyclization, Ireland-Claisen rearrangement, and hydrolysis. This reaction sequence is stereoselective and tolerates alkyl- and aryl-substituted alpha-keto ester substrates as well as an alpha-imino ester.


FEMALE CONTROL OF SPERM TRANSFER AND INTRASPECIFIC VARIATION IN SPERM PRECEDENCE: ANTECEDENTS TO THE EVOLUTION OF A COURTSHIP FOOD GIFT.
Manipulation of ejaculates is believed to be an important avenue of female choice throughout the animal kingdom, but evidence of its importance to sexual selection remains scarce. In crickets, such manipulation is manifest in the premature removal of the externally attached spermatophore, which may afford females an important means of postcopulatory mate choice. We tested the hypothesis that premature spermatophore removal contributes significantly to intraspecific variation in sperm precedence by (1) experimentally manipulating spermatophore attachment durations of competing male Gryllodes sigillatus and (2) employing protein electrophoresis to determine the paternity of doubly mated females. The relative spermatophore attachment durations of competing males had a significant influence on male paternity, but the pattern of sperm precedence deviated significantly from the predictions of an ideal lottery. Instead, paternity data and morphological evidence accorded best with a model of partial sperm displacement derived here. Our model is similar to a displacement model of Parker et al. in that sperm of the second male mixes instantaneously with that of the first throughout the displacement process, but the novel feature of our model is that the number of sperm displaced is only a fraction of the number of sperm transferred by the second male. Regardless of the underlying mechanism, female G. sigillatus can clearly alter the paternity of their offspring through their spermatophore-removal behavior, and employ such cryptic choice in favoring larger males and those providing larger courtship food gifts. We discuss how female control of sperm transfer and intraspecific variation in sperm precedence may be important precursors to the evolution of gift giving in insects.


Asymmetric fluoroallylboration of aldehydes.
Contrary to previous reports, the homologation of benzyloxydifluorovinyllithium with bulky chiral iodomethylboronates readily provides a series of chiral γ,γ-difluoroallylboronates. Asymmetric fluoroallylboration of aldehydes with a 2-phenylbornane-2,3-diol-derived reagent provides gem-difluorinated homoallyl alcohols in good yields and 77-95% ee. Preparation of a chiral α-pyrone in >99% ee has also been described.


[Preparation and identification of polyclonal antibody against small peptides of beta-tubulin of Toxoplasma gondii].
The amino acid sequences of beta-tubulin from Toxoplasma gondii stains (GT1 and ME49) and human were aligned by ClustalW2 software. Based on the alignment result, the C-terminal peptides of beta-tubulin of T. gondii were artificially synthesized. Rabbits were immunized with 0.5 mg synthesized peptides for five times at 2-week intervals. Serum samples were collected at the second week after the final immunization, and were analyzed for specific antibodies by ELISA. Finally, the specific-beta-tubulin polyclonal antibody was evaluated by Western blotting with the total protein of RH strain, ME49 strain, and PRU strain of T. gondii, respectively. The results showed that beta-tubulin of T. gondii stains (GT1 and ME49) shared 100% amino-acid sequence identity, and there was 98% amino acid homology between T. gondii and human. The main variable region was the C-terminus. After the fifth immunization, the titers of polyclonal antibody reached 1 : 52,800. Western blotting result indicated that the specific-beta-tubulin polyclonal antibody reacted with beta-tubulin in all the three strains (RH, ME49, and PRU), respectively.


Probabilistic risk and benefit assessment of nitrates and nitrites by integrating total diet study-based exogenous dietary exposure with endogenous nitrite formation using toxicokinetic modeling.
The impacts of dietary nitrates and nitrites on human health have been a controversial topic for many years. However, the risk and benefit assessment of nitrates and nitrites is complicated by the large variation in nitrate and nitrite intake among people and the endogenous nitrite formation in the body. This study conducted a probabilistic risk-benefit assessment of dietary nitrates and nitrites based on internal dose by integrating exogenous and endogenous exposures with human trial data on cardiovascular benefits. A total diet study was carried out to quantify the age-specific dietary intakes of nitrates and nitrites. A previously well-validated human toxicokinetic model was used to predict internal doses for different age groups. In addition, the integrated approach was applied to different populations from different countries/regions based on reported exposure estimates to conduct a comprehensive risk-benefit assessment of dietary nitrates and nitrites. The results demonstrated that vegetable consumption was the main contributor to the internal nitrate and nitrite levels in all age groups. Exposure to nitrates and nitrites exceeding acceptable daily intakes in a variety of foods showed cardiovascular benefits. The probabilistic risk assessment showed that the exposure to nitrates and nitrites did not pose an appreciable health and safety risk. Therefore, the present results suggest that dietary nitrates and nitrites have clear cardiovascular benefits that may outweigh potential risks. Our analysis contributes significantly to addressing the controversy regarding risks and benefits from dietary nitrates and nitrites, and our approach could be applied to other dietary constituents with the potential for both risks and benefits.


Daytime Sleepiness Is Associated with Lower Cognitive Scores: The Look AHEAD Study.
Daytime sleepiness is common in older adults and may result from poor nighttime sleep due to sleep disordered breathing, fragmented sleep, or other sleep disorders. Daytime sleepiness may be associated with cognition in older adults. We investigated the association between self-reported daytime sleepiness and cognitive function in the Look AHEAD clinical trial. Observational follow-up of a randomized clinical trial of an intensive lifestyle intervention. Clinic. Participants (n=1,778) aged 45-76 years at baseline with type 2 diabetes and overweight or obesity. Participants were randomized to an intensive lifestyle intervention for weight loss or a control condition of diabetes support and education. Participants provided self-reported levels of daytime sleepiness at baseline and years 12-13. Cognitive function was assessed with a neurocognitive battery at years 12-13 and 18-20. Participants who reported having frequent daytime sleepiness (often or always) performed significantly worse than others on the cognitive composite (-0.35; p-value=0.014) after controlling for covariates. When stratified by intervention arm, participants assigned to the intensive lifestyle intervention who reported often/always having daytime sleepiness performed worse on Digit Symbol Coding (-0.63; p-value=0.05) and Trail Making Part-B (-0.56; p-value=0.02) after controlling for covariates. Statistical interactions revealed associations between daytime sleepiness and the following covariates: race and ethnicity, APOE ε4 carrier status, baseline history of cardiovascular disease, and depression. Daytime sleepiness over ~13 years predicted poorer cognitive performance in older individuals who, by virtue of having diabetes and overweight/obesity, are at high risk for sleep disorders and cognitive impairment.


Custom RT-qPCR-array for glaucoma filtering surgery prognosis.
Excessive subconjunctival scarring is the main reason of failure of glaucoma filtration surgery. We analyzed conjunctival and systemic gene expression patterns after non penetrating deep sclerectomy (NPDS). To find expression patterns related to surgical failure and their correlation with the clinical outcomes. This study consisted of two consecutive stages. The first was a prospective analysis of wound-healing gene expression profile of six patients after NPDS. Conjunctival samples and peripheral blood samples were collected before and 15, 90,180, and 360 days after surgery. In the second stage, we conducted a retrospective analysis correlating the late conjunctival gene expression and the outcome of the NPDS for 11 patients. We developed a RT-qPCR Array for 88 key genes associated to wound healing. RT-qPCR Array analysis of conjunctiva samples showed statistically significant differences in 29/88 genes in the early stages after surgery, 20/88 genes between 90 and 180 days after surgery, and only 2/88 genes one year after surgery. In the blood samples, the most important changes occurred in 12/88 genes in the first 15 days after surgery. Correspondence analyses (COA) revealed significant differences between the expression of 20/88 genes in patients with surgical success and failure one year after surgery. Different expression patterns of mediators of the bleb wound healing were identified. Examination of such patterns might be used in surgery prognosis. RT-qPCR Array provides a powerful tool for investigation of differential gene expression wound healing after glaucoma surgery.


Wavelet phase synchronization and chaoticity.
It has been shown that the so-called "wavelet phase" (or "time-scale") synchronization of chaotic signals is actually synchronization of smoothed functions with reduced chaotic fluctuations. This fact is based on the representation of the wavelet transform with the Morlet wavelet as a solution of the Cauchy problem for a simple diffusion equation with initial condition in a form of harmonic function modulated by a given signal. The topological background of the resulting effect is discussed. It is argued that the wavelet phase synchronization provides information about the synchronization of an averaged motion described by bounding tori instead of the fine-level classical chaotic phase synchronization.


Comparison of the immediate effects of gaseous ozone and chlorhexidine gel on bacteria in cavitated carious lesions in children in vivo.
Clinical application of ozone gas has been shown to arrest the progression of dentinal caries in children. In this study, we compare the immediate effects of gaseous ozone and chlorhexidine gel on bacteria in cavitated carious lesions in children. Forty children, each with at least two open occlusal carious lesions, were enrolled in the study. Two teeth were chosen randomly. In one lesion, overlying soft biological material was removed, whilst the other lesion was not excavated. Cavities were rinsed with sterile water and dried with air. A standardised sample was taken from the mesial part of each lesion. Then, gaseous ozone (HealOzone) or 1% chlorhexidine gel (Corsodyl) was applied for 30 s on both lesions of 20 children each, and a second sample was taken from the distal part of each lesion. The anaerobic microbiota was cultivated; the number of colony forming units was calculated per milligram sample. The two-sided paired t test showed no significant (P > 0.05) differences in the reduction of total bacterial counts per milligram comparing samples before and after ozone or chlorhexidine application. The tests also showed no statistically significant difference whether the superficial decayed dentine had been removed before ozone or with chlorhexidine treatment or not. It can be concluded that gaseous ozone or chlorhexidine gel application for 30 s to deep occlusal carious cavities had no significant immediate antimicrobial effects whether the superficial decayed layers dentine were removed or not.


Surgical Algorithm and Results of Isolated Traumatic Axillary Nerve Injuries.
Axillary nerve injuries are common and typically occur during high-energy, traumatic events. The purpose of this study is to propose a treatment algorithm for acute isolated axillary nerve injuries and report the outcomes of surgically treated patients. A retrospective review identified 14 patients surgically treated for an isolated axillary nerve injury. Axillary nerve neurolysis was performed for all patients, and a triceps branch of the radial nerve was transferred to the axillary nerve in patients without evidence of deltoid function following intraoperative axillary nerve stimulation. Four patients were treated with neurolysis alone and 10 patients received a transfer. Pre- and postoperative deltoid strength, shoulder abduction, and the Disabilities of the Arm, Shoulder, and Hand (DASH) outcome score were evaluated. At most recent follow-up, both the neurolysis and nerve transfer groups had significant improvement in deltoid strength, with 86% achieving M4 or greater. Shoulder abduction improved from a mean of 63 to 127 degrees. This difference was significant in the nerve transfer group and when all patients were analyzed together. DASH scores significantly improved from a mean of 47 to 34 when all patients were analyzed together. No patients experienced a decrease in elbow extension strength following nerve transfer. In patients with preserved triceps strength, a triceps branch of the radial nerve can be coapted directly to the axillary nerve in the absence of deltoid contraction following electrical stimulation. Functional improvements were seen in patients treated with neurolysis alone and in combination with nerve transfer, supporting the use of intraoperative axillary nerve stimulation to guide treatment.


Dissociation between complete hippocampal context memory formation and context fear acquisition.
Rodents require a minimal time period to explore a context prior to footshock to display plateau-level context fear at test. To investigate whether this rapid fear plateau reflects complete memory formation within that short time-frame, we used the immediate-early gene product Arc as an indicator of hippocampal context memory formation-related activity. We found that hippocampal Arc expression continued to increase well past the minimal time required for plateau-level fear. This raises the possibility that context fear conditioning occurs more rapidly than complete memory formation. Thus, animals may be able to condition robustly to both complete and incomplete contextual representations.


The history of the coronary care unit.
The first coronary care units were established in the early 1960s in an attempt to reduce mortality from acute myocardial infarction. Pioneering cardiologists recognized the threat of death due to malignant arrhythmias in the postinfarction setting, and developed techniques for successful external defibrillation. The ability to abort sudden death led to continuous monitoring of the cardiac rhythm and an organized system of cardiopulmonary resuscitation, incorporating external defibrillation with cardiac drugs and specialized equipment. Arrhythmia monitoring and cardiopulmonary resuscitation could be performed by trained nursing staff, which eliminated delays in treatment and significantly reduced mortality. These early triumphs in aborting sudden death led to the development of techniques to treat cardiogenic shock, limit infarct size and initiate prehospital coronary care, all of which laid the foundation for the current era of interventional cardiology.


An innovative path to improving cancer care in Indian country.
The Native American Cancer Survivors' Support Network is an innovative public health program designed to improve survival from cancer and the quality of life after a cancer diagnosis for American Indians, Alaska Natives, and Canadian Aboriginal patients and their loved ones. The Network, initiated in 1999, now has more than 300 survivors enrolled as members. This article briefly describes the process that led to its formation and preliminary findings, primarily for breast cancer survivors, of ongoing qualitative and quantitative research. Network data show patterns of cancer care that are partially responsible for poor survivorship outcomes.


Universal molecular structures in natural dissolved organic matter.
Natural dissolved organic matter (DOM) comprises a broad range of dissolved organic molecules in aquatic systems and is among the most complex molecular mixtures known. Here we show, by comparing detailed structural fingerprints of individual molecular formulae in DOM from a set of four marine and one freshwater environments, that a major component of DOM is molecularly indistinguishable in these diverse samples. Molecular conformity was not only apparent by the co-occurrence of thousands of identical molecular formulae, but also by identical structural features of those isomers that collectively represent a molecular formula. The presence of a large pool of compounds with identical structural features in DOM is likely the result of a cascade of degradation processes or common synthetic pathways that ultimately lead to the formation of a universal background, regardless of origin and history of the organic material. This novel insight impacts our understanding of long-term turnover of DOM as the underlying mechanisms are possibly universal.


Quinolinyl Nitrone RP19 Induces Neuroprotection after Transient Brain Ischemia.
There is a need to develop additional effective therapies for ischemic stroke. Nitrones, which were first developed as reactive oxygen species (ROS)-trapping compounds, have been proposed as neuroprotective agents for ischemic stroke, a ROS-related disorder. The previous reported ROS-trapping compound, quinolyl nitrone RP19, is here being assayed to induce neuroprotection to ischemia-reperfusion injury in three experimental ischemia models: (i) oxygen-glucose deprivation (OGD) on primary neuronal cultures; (ii) transient global cerebral ischemia in four-vessel occlusion model; and (iii) transient focal cerebral ischemia in middle cerebral artery occlusion (tMCAO) model. RP19 (50 μM) induced long-term neuroprotection at 5 days of recovery after OGD in primary neuronal cultures, evaluated by cell viability assay, and decreased both ROS formation and lipid peroxidation upon recovery after OGD. Furthermore, treatment of animals with RP19 at the onset of reperfusion after either global or focal ischemia, at the dose range that was demonstrated to be neuroprotective in neuronal cultures, decreased neuronal death and apoptosis induction, reduced the size of infarct, and improved the neurological deficit scores after 48 h or 5 days of reperfusion after ischemia. The molecule proposed, quinolyl nitrone RP19, induced substantial neuroprotection on experimental ischemia in neuronal cells, and against ischemic injury following transient brain ischemia in treated animals. This molecule may have potential therapeutic interest in ischemic stroke and to reduce the reoxygenation-induced injury after induced reperfusion.


Clinically approved heterocyclics act on a mitochondrial target and reduce stroke-induced pathology.
Substantial evidence indicates that mitochondria are a major checkpoint in several pathways leading to neuronal cell death, but discerning critical propagation stages from downstream consequences has been difficult. The mitochondrial permeability transition (mPT) may be critical in stroke-related injury. To address this hypothesis, identify potential therapeutics, and screen for new uses for established drugs with known toxicity, 1,040 FDA-approved drugs and other bioactive compounds were tested as potential mPT inhibitors. We report the identification of 28 structurally related drugs, including tricyclic antidepressants and antipsychotics, capable of delaying the mPT. Clinically achievable doses of one drug in this general structural class that inhibits mPT, promethazine, were protective in both in vitro and mouse models of stroke. Specifically, promethazine protected primary neuronal cultures subjected to oxygen-glucose deprivation and reduced infarct size and neurological impairment in mice subjected to middle cerebral artery occlusion/reperfusion. These results, in conjunction with new insights provided to older studies, (a) suggest a class of safe, tolerable drugs for stroke and neurodegeneration; (b) provide new tools for understanding mitochondrial roles in neuronal cell death; (c) demonstrate the clinical/experimental value of screening collections of bioactive compounds enriched in clinically available agents; and (d) provide discovery-based evidence that mPT is an essential, causative event in stroke-related injury.


High-density lipoprotein cholesterol and paraoxonase 1 (PON1) genetics and serum PON1 activity in prepubertal children in Spain.
Oxidative stress plays an important role in atherosclerosis. Paraoxonase 1 (PON1) is a high-density lipoprotein (HDL)-associated enzyme that inhibits low-density lipoprotein (LDL) oxidation and may play a protective role against coronary heart disease. The aim of this study was to analyze the relationship between HDL-cholesterol (HDL-C) and PON1 in a Spanish prepubertal population with high plasma HDL-C levels. The study population included 1,266 children between the ages of 6 and 8 years. Serum PON1 activity was measured by the hydrolysis of paraoxon. PON1 192Q/R and PON1 55L/M polymorphisms were analyzed by PCR and restriction analysis. The prevalence of the less common PON1 192R and PON 55M alleles in this population was 30% and 38%, respectively. No significant correlations between serum PON1 activity and lipid profile were observed. Multiple linear regression analysis showed that the PON1 192Q/R polymorphism accounts for 69% of PON1 activity in the children in the study, with the PON1 55L/M polymorphism accounting for an additional 5% of this variation in boys, and for an additional 3% together with HDL-C concentration in girls. PON1 192Q/R polymorphism is the main determinant of PON1 activity in the prepubertal population in this study, accounting for around 70% of serum PON1 activity. HDL-C concentration has a small contribution to serum PON1 activity in girls.


10 weeks of heavy strength training improves performance-related measurements in elite cyclists.
Elite cyclists have often a limited period of time available during their short preparation phase to focus on development of maximal strength; therefore, the purpose of the present study was to investigate the effect of 10-week heavy strength training on lean lower-body mass, leg strength, determinants of cycling performance and cycling performance in elite cyclists. Twelve cyclists performed heavy strength training and normal endurance training (E&S) while 8 other cyclists performed normal endurance training only (E). Following the intervention period E&S had a larger increase in maximal isometric half squat, mean power output during a 30-s Wingate sprint (P < 0.05) and a tendency towards larger improvement in power output at 4 mmol ∙ L-1 [la-] than E (P = 0.068). There were no significant difference between E&S and E in changes in 40-min all-out trial (4 ± 6% vs. -1 ± 6%, respectively, P = 0.13). These beneficial effects may encourage elite cyclists to perform heavy strength training and the short period of only 10 weeks should make it executable even in the compressed training and competition schedule of elite cyclists.


Microsatellite markers uncover cryptic species of Odontotermes (Termitoidae: Termitidae) from Peninsular Malaysia.
Termites from the genus Odontotermes are known to contain numerous species complexes that are difficult to tell apart morphologically or with mitochondrial DNA sequences. We developed markers for one such cryptic species complex, that is, Odontotermes srinakarinensis sp. nov. from Maxwell Hill Forest Reserve (Perak, Malaysia), and characterised them using a sample of 41 termite workers from three voucher samples from the same area. We then genotyped 150 termite individuals from 23 voucher samples/colonies of this species complex from several sites in Peninsular Malaysia. We analysed their population by constructing dendograms from the proportion of shared-alleles between individuals and genetic distances between colonies; additionally, we examined the Bayesian clustering pattern of their genotype data. All methods of analysis indicated that there were two distinct clusters within our data set. After the morphologies of specimens from each cluster were reexamined, we were able to separate the two species morphologically and found that a single diagnostic character found on the mandibles of its soldiers could be used to separate the two species quite accurately. The additional species in the clade was identified as Odontotermes denticulatus after it was matched to type specimens at the NHM London and Cambridge Museum of Zoology.


An Architecture for Translational Cancer Research As Exemplified by the German Cancer Consortium.
Networking of medical institutions by means of a capable data infrastructure has the potential to open up vast amounts of routine data to translational cancer research. However, the secondary use of information collected independently in several institutions is a challenging task of data integration. In this review, we discuss the requirements and common challenges involved in the establishment of such a platform. We present methods and tools from the field of medical informatics as solutions to semantic and technical heterogeneity, questions of data protection and record linkage, as well as issues of trust and data ownership. We also describe the architecture of an existing cancer research network as an exemplary application of these methods.


Functional diversification of acyl-coenzyme A oxidases in jasmonic acid biosynthesis and action.
The biosynthesis of jasmonic acid (JA) in plant peroxisomes requires the action of acyl-coenzyme A oxidase (ACX). Among the five expressed members (ACX1-5) of the ACX gene family in Arabidopsis (Arabidopsis thaliana), only ACX1 is known to serve a role in JA production. Here, we used transgenic promoter-reporter lines to show that ACX1 is highly expressed in mature and germinating pollen, stem epidermal cells, and other tissues in which jasmonate-signaled processes occur. Wound-induced JA accumulation was reduced in a mutant that is defective in ACX1 and was abolished in a mutant that is impaired in both ACX1 and its closely related paralog, ACX5. The severe JA deficiency in acx1/5 double mutants was accompanied by decreased resistance to the leaf-eating insect Trichoplusia ni. The double mutant also showed reduced pollen viability and fecundity. Treatment of acx1/5 plants with JA restored both protection against T. ni larvae and normal seed set. Unexpectedly, acx1/5 plants accumulated JA in response to infection by the necrotrophic fungal pathogen Alternaria brassicicola. In contrast to mutants that are impaired in jasmonate perception or early steps of the JA biosynthetic pathway, acx1/5 plants maintained resistance to A. brassicicola infection. These results indicate that ACX1/5-mediated JA synthesis is essential for resistance to chewing insects and male reproductive function and further suggest that other ACX isozymes contribute to JA production in response to A. brassicicola challenge. Thus, different types of biotic stress may induce JA synthesis via distinct enzymatic routes.