PTEN-inhibition by zinc ions augments interleukin-2-mediated Akt phosphorylation.
Free zinc ions (Zn(2+)) participate in several signaling pathways. The aim of the present study was to investigate a potential involvement of Zn(2+) in the PI3K/Akt pathway of interleukin (IL)-2 signaling in T-cells. The IL-2 receptor triggers three major pathways, ERK1/2, JAK/STAT5, and PI3K/Akt. We have previously shown that an IL-2-mediated release of lysosomal Zn(2+) into the cytoplasm activates ERK1/2, but not STAT5. In the present study, Akt phosphorylation in response to IL-2 was abrogated by the Zn(2+) chelator N,N,N',N'-tetrakis-2(pyridyl-methyl)ethylenediamine, and was induced by treatment with Zn(2+) and the ionophore pyrithione. The latter were ineffective in cells that were treated with siRNA against the phosphatase and tensin homolog deleted on chromosome 10 (PTEN), a phosphatase that degrades the lipid second messenger PI(3,4,5)P3, which is produced by PI3K and leads to activation of Akt. Inhibition of recombinant PTEN by Zn(2+)in vitro yielded an IC50 of 0.59 nM. Considering a resting free cytoplasmic Zn(2+) level of 0.2 nM in the T-cell line CTLL-2, this seems ideally suited for dynamic regulation by cellular Zn(2+). Oxidation with H2O2 and supplementation with Zn(2+) led to similar changes in the CD spectrum of PTEN. Moreover, Zn(2+) partially prevented the oxidation of cysteines 71 and 124. Hence, we hypothesize that zinc signals affect the IL-2-dependent PI3K/Akt pathway by inhibiting the negative regulator PTEN through binding with a sub-nanomolar affinity to cysteine residues that are essential for its catalytic activity.


Walnut supplementation reverses the scopolamine-induced memory impairment by restoration of cholinergic function via mitigating oxidative stress in rats: a potential therapeutic intervention for age related neurodegenerative disorders.
The brain is highly susceptible to the damaging effects of oxidative reactive species. The free radicals which are produced as a consequence of aerobic respiration can cause cumulative oxygen damage which may lead to age-related neurodegeneration. Scopolamine, the anti-muscarinic agent, induces amnesia and oxidative stress similar to that observed in the older age. Studies suggest that antioxidants derived from plant products may provide protection against oxidative stress. Therefore, the present study was designed to investigate the attenuation of scopolamine-induced memory impairment and oxidative stress by walnut supplementation in rats. Rats in test group were administrated with walnut suspension (400 mg/kg/day) for four weeks. Both control and walnut-treated rats were then divided into saline and scopolamine-treated groups. Rats in the scopolamine group were injected with scopolamine (0.5 mg/kg dissolved in saline) five minutes before the start of each memory test. Memory was assessed by elevated plus maze (EPM), Morris water maze (MWM), and novel object recognition task (NOR) followed by estimation of regional acetylcholine levels and acetylcholinesterase activity. In the next phase, brain oxidative status was determined by assaying lipid peroxidation, and measuring superoxide dismutase (SOD), glutathione peroxidase (GPx) and catalase (CAT) activities. Results showed that scopolamine-treatment impaired memory function, caused cholinergic dysfunction, and induced oxidative stress in rats compared to that saline-treated controls. These impairments were significantly restored by pre-administration of walnut. This study demonstrates that antioxidant properties of walnut may provide augmented effects on cholinergic function by reducing oxidative stress and thus improving memory performance.


Genome-wide expression patterns in Saccharomyces cerevisiae: comparison of drug treatments and genetic alterations affecting biosynthesis of ergosterol.
Enzymes in the ergosterol-biosynthetic pathway are the targets of a number of antifungal agents including azoles, allylamines, and morpholines. In order to understand the response of Saccharomyces cerevisiae to perturbations in the ergosterol pathway, genome-wide transcript profiles following exposure to a number of antifungal agents targeting ergosterol biosynthesis (clotrimazole, fluconazole, itraconazole, ketoconazole, voriconazole, terbinafine, and amorolfine) were obtained. These profiles were compared to the transcript profiles of strains containing deletions of one of the late-stage ergosterol genes: ERG2, ERG5, or ERG6. A total of 234 genes were identified as responsive, including the majority of genes from the ergosterol pathway. Expression of several responsive genes, including ERG25, YER067W, and YNL300W, was also monitored by PCR over time following exposure to ketoconazole. The kinetics of transcriptional response support the conditions selected for the microarray experiment. In addition to ergosterol-biosynthetic genes, 36 mitochondrial genes and a number of other genes with roles related to ergosterol function were responsive, as were a number of genes responsive to oxidative stress. Transcriptional changes related to heme biosynthesis were observed in cells treated with chemical agents, suggesting an additional effect of exposure to these compounds. The expression profile in response to a novel imidazole, PNU-144248E, was also determined. The concordance of responsive genes suggests that this compound has the same mode of action as other azoles. Thus, genome-wide transcript profiles can be used to predict the mode of action of a chemical agent as well as to characterize expression changes in response to perturbation of a metabolic pathway.


Density dependence and population differentiation of genetic architecture in Impatiens capensis in natural environments.
We identified environment-dependent constraints on the evolution of plasticity to density under natural conditions in two natural populations of Impatiens capensis. We also examined the expression of population divergence in genetic variance-covariance matrices in these natural environments. Inbred lines, originally collected from a sunny site with high seedling densities and a woodland site with low seedling densities, were planted in both original sites at natural high densities and at low density. Morphological and life-history characters were measured. More genetic variation for plastic responses to density was expressed in the sun site than in the woodland site, so the evolutionary potential of plasticity was greater in the sun site. Strong genetic correlations between the same character expressed at different densities and correlations among different characters could constrain the evolution of plasticity in both sites. Genetically based trade-offs in meristem allocation to vegetative growth and reproduction were apparent only in the high-resource environment with no overhead canopy and no intraspecific competition. Therefore, genetic constraints on the evolution of plasticity depended on the site and density in which plants were grown, and correlated responses to selection on plastic characters are also expected to differ between sites and densities. Population differentiation in genetic variance-covariance matrices was detected, but matrix structural differences, as opposed to proportional differences, were detected between populations only in the sun site at natural high density. Thus, population divergence in genetic architecture can occur rapidly and on a fine spatial scale, but the expression of such divergence may depend on the environment.


Processive Recoding and Metazoan Evolution of Selenoprotein P: Up to 132 UGAs in Molluscs.
Selenoproteins typically contain a single selenocysteine, the 21st amino acid, encoded by a context-redefined UGA. However, human selenoprotein P (SelenoP) has a redox-functioning selenocysteine in its N-terminal domain and nine selenium transporter-functioning selenocysteines in its C-terminal domain. Here we show that diverse SelenoP genes are present across metazoa with highly variable numbers of Sec-UGAs, ranging from a single UGA in certain insects, to 9 in common spider, and up to 132 in bivalve molluscs. SelenoP genes were shaped by a dynamic evolutionary process linked to selenium usage. Gene evolution featured modular expansions of an ancestral multi-Sec domain, which led to particularly Sec-rich SelenoP proteins in many aquatic organisms. We focused on molluscs, and chose Pacific oyster Magallana gigas as experimental model. We show that oyster SelenoP mRNA with 46 UGAs is translated full-length in vivo. Ribosome profiling indicates that selenocysteine specification occurs with ∼5% efficiency at UGA1 and approaches 100% efficiency at distal 3' UGAs. We report genetic elements relevant to its expression, including a leader open reading frame and an RNA structure overlapping the initiation codon that modulates ribosome progression in a selenium-dependent manner. Unlike their mammalian counterparts, the two SECIS elements in oyster SelenoP (3'UTR recoding elements) do not show functional differentiation in vitro. Oysters can increase their tissue selenium level up to 50-fold upon supplementation, which also results in extensive changes in selenoprotein expression.


Activation of cytokine-producing and antitumor activities of natural killer cells and macrophages by engagement of Toll-like and NOD-like receptors.
Macrophages and natural killer (NK) cells are important antitumor effectors by virtue of their ability to produce cytokines, chemokines and interferons (IFNs) and to mediate tumor cytotoxicity. Little is known about the impact of Toll-like receptor (TLR) and nucleotide binding and oligomerization domain (NOD)-like receptor (NLR) pathways on NK cell functions, and the role of TLRs and NLRs in macrophage activation is incompletely understood. In this study, we examined the capacities of expressed TLRs and NLRs to elicit cytokine production in human NK cells and THP1 macrophages, and to activate NK cytotoxicity against the squamous cell carcinoma of head and neck cell line Tu167 and erythroleukemia K562 cells. We found that NK cells express high levels of NOD2, NLRP3, TLR3, TLR7, and TLR9, while NOD1 was expressed at low levels. All tested NLR and TLR agonists potentiated NK cytotoxicity against Tu167 cells, whereas only poly (I:C) increased NK cytotoxicity against K562 cells. Poly (I:C) and Escherichia coli RNA markedly up-regulated TNF-α and IFN-γ expression in the NK92 cell line and human CD56(+)CD3(-) primary NK cells. High levels of NOD2, TLR7 and TLR9 proteins were observed in human THP1 cells, followed by TLR3, NOD1, and NLRP3. Stimulation of NLRP3 with E. coli RNA led to the highest induction of TNF-α, IL-6, IL-12p40, RANTES and IFN-β, whereas TLR7, TLR3, TLR9, NOD1 and NOD2 agonists had lower effects. Our data reveal involvement of TLRs and NLRs in potentiation of antitumor cytotoxicity and cytokine-producing activities of human NK cells and macrophages.


A Fungal Secretome Adapted for Stress Enabled a Radical Wood Decay Mechanism.
Brown rot fungi release massive amounts of carbon from forest deadwood, particularly at high latitudes. These fungi degrade wood by generating small reactive oxygen species (ROS) to loosen lignocellulose, to then selectively remove carbohydrates. The ROS mechanism has long been considered the key adaptation defining brown rot wood decomposition, but recently, we found preliminary evidence that fungal glycoside hydrolases (GHs) implicated in early cell wall loosening might have been adapted to tolerate ROS stress and to synergize with ROS to loosen woody lignocellulose. In the current study, we found more specifically that side chain hemicellulases that help in the early deconstruction of the lignocellulosic complex are significantly more tolerant of ROS in the brown rot fungus Rhodonia placenta than in a white rot fungus (Trametes versicolor) and a soft rot fungus (Trichoderma reesei). Using proteomics to understand the extent of tolerance, we found that significant oxidation of secreted R. placenta proteins exposed to ROS was less than half of the oxidation observed for T. versicolor or T. reesei. The principal oxidative modifications observed in all cases were monooxidation and dioxidation/trioxidation (mainly in methionine and tryptophan residues), some of which were critical for enzyme activity. At the peptide level, we found that GHs in R. placenta were the least ROS affected among our tested fungi. These results confirm and describe underlying mechanisms of tolerance in early-secreted brown rot fungal hemicellulases. These enzymatic adaptations may have been as important as nonenzymatic ROS pathway adaptations in brown rot fungal evolution. IMPORTANCE Brown rot fungi play a critical role in carbon recycling and are of industrial interest. These fungi typically use reactive oxygen species (ROS) to indiscriminately "loosen" wood cell walls at the outset of decay. Brown rot fungi avoid oxidative stress associated with this ROS step by delaying the expression/secretion of many carbohydrate-active enzymes, but there are exceptions, notably some side chain hemicellulases, implicated in loosening lignocellulose. In this study, we provide enzyme activity and secretomic evidence that these enzymes in the brown rot model Rhodonia placenta are more ROS tolerant than the white and soft rot isolates tested. For R. placenta, and perhaps all brown rot lineages, these ROS tolerance adaptions may have played a long-overshadowed role in enabling brown rot.


Topographic correlation of infarct area on CT perfusion with functional outcome in acute ischemic stroke.
The role of CT perfusion (CTP) in the management of patients with acute ischemic stroke (AIS) remains a matter of debate. The primary aim of this study was to evaluate the correlation between the areas of infarction and penumbra on CTP scans and functional outcome in patients with AIS. This was a retrospective review of 100 consecutively treated patients with acute anterior circulation ischemic stroke who underwent CT angiography (CTA) and CTP at admission between February 2011 and October 2014. On CTP, the volume of ischemic core and penumbra was measured using the Alberta Stroke Program Early CT Score (ASPECTS). CTA findings were also noted, including the site of occlusion and regional leptomeningeal collateral (rLMC) score. Functional outcome was defined by modified Rankin Scale (mRS) score obtained at discharge. Associations of CTP and CTA parameters with mRS scores at discharge were assessed using multivariable proportional odds logistic regression models. The median age was 67 years (range 19-95 years), and the median NIH Stroke Scale score was 16 (range 2-35). In a multivariable analysis adjusting for potential confounding variables, having an infarct on CTP scans in the following regions was associated with a worse mRS score at discharge: insula ribbon (p = 0.043), perisylvian fissure (p < 0.001), motor strip (p = 0.007), M2 (p < 0.001), and M5 (p = 0.023). A worse mRS score at discharge was more common in patients with a greater volume of infarct core (p = 0.024) and less common in patients with a greater rLMC score (p = 0.004). The results of this study provide evidence that several CTP parameters are independent predictors of functional outcome in patients with AIS and have potential to identify those patients most likely to benefit from reperfusion therapy in the treatment of AIS.


A conjunctive lipidomic approach reveals plasma ethanolamine plasmalogens and fatty acids as early diagnostic biomarkers for colorectal cancer patients.
Background: Colorectal cancer (CRC) represents a third leading cause of cancer-related death worldwide. The reliable diagnostic biomarkers for detecting CRC at early stage is critical for decreasing the mortality.Method: A conjunctive lipidomic approach was employed to investigate the differences in plasma lipid profiles of CRC patients (n = 101) and healthy volunteers (n = 52). Based on UHPLC-Q-TOF MS and UHPLC-QQQ MS platforms, a total of 236 lipids were structurally detected. Multivariate data analysis was conducted for biomarkers discovery.Results: A total of 11 lipid species, including 1 Glycerophosphoethanolamine (PE), 3 ethanolamine plasmalogens (PlsEtn), 1 plasmanyl glycerophosphatidylethanolamine (PE-O), 3 fatty acids (FFA), 1 Fatty acid ester of hydroxyl fatty acid (FAHFA) and 2 Diacylglycerophosphates (PA) were identified to distinguish the CRC patients at early stage from healthy controls. In addition, these potential lipid biomarkers achieved an estimated AUC=0.981 in a validation set for univariate ROC analysis.Conclusion: By combining Q-TOF MS and QQQ MS analysis, the 11 lipids exhibited good performance in differentiating early-stage CRC and healthy control. This study also demonstrated that lipidomics is a powerful tool in discovering new potential biomarkers for cancer diagnosis.


[Hematological studies of pigs vaccinated against Aujeszky's disease].
Hematological investigations within a period of six months were carried out on 4 groups of pigs vaccinated with different doses of living Aujeszky MK-25 vaccine. The pigs from groups I and II were vaccinated with a normal dose of 2 cm3, the pigs from group III--with 10 doses, whereas those from group IV--with a hundredfold dose. A clearly pronounced immunohemolytic anemia was proved, accompanied by leucocytopenia with an increased percentage of segmental-nuclear leucocytes and monocytes during the period of immunity build-up with pigs vaccinated with a high dose of vaccine (from groups III and IV). In the case of vaccination with increased doses a strongly pronounced immunogenic process was observed.


Plasmodium falciparum and helminth coinfection in a semi urban population of pregnant women in Uganda.
Helminth infections and malaria are widespread in the tropics. Recent studies suggest helminth infections may increase susceptibility to Plasmodium falciparum infection. If confirmed, this increased susceptibility could be particularly important during pregnancy-induced immunosuppression. To evaluate the geographical distribution of P. falciparum-helminth coinfection and the associations between P. falciparum infection and infection with various parasite species in pregnant women in Entebbe, Uganda. A cross-sectional study was conducted at baseline during a trial of antihelminthic drugs during pregnancy. Helminth and P. falciparum infections were quantified in 2,507 asymptomatic women. Subjects' socioeconomic and demographic characteristics and geographical details were recorded. Hookworm and Mansonella perstans infections were associated with P. falciparum infection, but the effect of hookworm infection was seen only in the absence of M. perstans infection. The odds ratio [OR] for P. falciparum infection, adjusted for age, tribe, socioeconomic status, HIV infection status, and location was as follows: for individuals infected with hookworm but not M. perstans, 1.53 (95% confidence interval [CI], 1.09-2.14); for individuals infected with M. perstans but not hookworm, 2.33 (95% CI, 1.47-3.69); for individuals infected with both hookworm and M. perstans, 1.85 (CI, 1.24-2.76). No association was observed between infection with Schistosoma mansoni, Trichuris, or Strongyloides species and P. falciparum infection. Hookworm-P. falciparum coinfection and M. perstans-P. falciparum coinfection among pregnant women in Entebbe is more common than would be expected by chance. Further studies are needed to elucidate the mechanism of this association. A helminth-induced increase in susceptibility to P. falciparum could have important consequences for pregnancy outcome and responses to P. falciparum infection in infancy.


Determination of the dose characteristics in the near area of a new type of 192Ir-HDR afterloading source with a pinpoint ionization chamber.
Since the company MDS Nordion Haan GmbH introduced the new afterloading radiation unit GammaMed plus in 1998, new HDR Ir-192 sources with a diameter of 0.9 mm (formerly 1.1 mm) and a length of 4.5 mm (formerly 5.5 mm) have been used. With this equipment it is possible to treat peripheral vessels for prophylaxis of restenosis after percutaneous transluminal angioplasty (PTA). In this case a good knowledge of the dose characteristics in the near area is the prerequisite for safe application. In this study, the dose characteristics for this source type is investigated at close range by means of an ionization chamber. For the description of the dose characteristics, the radial dose distribution and the anisotropy function are used. The measurements were carried out using an ionization chamber, the so-called PinPoint chamber (Type PTW 31006, PTW Freiburg, Germany). The radial dose distribution was examined in the area of 0.26 to 12 cm. The anisotropy function was examined in the range from 0.5 to 5 cm (distance from the effective site of measurement to the source axis). The radial dose function was compared with the correction function k(as,w) (r), published in the German standard DIN 6809 part 2 (1991 Beuth Verlag, Berlin, Germany). In the area up to 4 cm (distance source-axis to measuring point) the deviation maximized up to 2%. The deviation climbs with greater distance from the source with results around 3%. The anisotropy function was compared with that used in the treatment planning system Abacus 3.0 of the same manufacturer. In the close range between 0.5 and 1 cm, there were some major variations (up to 10%) from the anisotropy function used in the planning system. The fault reduces itself with greater distance to under 2%. In view of the results presented in this paper further measurements of the anisotropy function in the close range from 0 to 1.5 cm from the source axis should be made. It can be seen that the function used in the planning system supplies results that are too high in comparison with the results of other authors. This concerns primarily the area of very small and very big angles.


The (Ca2+ + Mg2+)-stimulated ATPase of the rat parotid endoplasmic reticulum.
A membrane fraction enriched in endoplasmic reticulum was prepared from rat parotid glands by using sucrose-gradient centrifugation. The fraction showed a 10-fold increase in specific activity of NADPH: cytochrome c reductase activity over that of tissue homogenates and minimal contamination with plasma membranes or mitochondria. The endoplasmic reticulum fraction possessed both Mg2+ -stimulated ATPase as well as Ca2+, Mg2+-ATPase [( Ca2+ + Mg2+)-stimulated ATPase]activity. The Ca2+, Mg2+-ATPase required 2-5 mM-Mg2+ for optimal activity and was stimulated by submicromolar concentrations of free Ca2+. The Km for free Ca2+ was 0.55 microM and the average Vmax. was 60 nmol/min per mg of protein. The Km for ATP was 0.11 mM. Other nucleotides, such as GTP, CTP or ADP, could not substitute for ATP in supporting the Ca2+-activated nucleotidase activity. Increasing the K+ concentration from 0 to 100 mM caused a 2-fold activation of the Ca2+, Mg2+-ATPase. Trifluoperazine, W7 [N-(6-aminohexyl)-5-chloronaphthalene-1-sulphonamide] and vanadate inhibited the enzyme. The concentration of trifluoperazine and vanadate required for 50% inhibition of the ATPase were 52 microM and 28 microM respectively. Calmodulin, cyclic AMP, cyclic AMP-dependent protein kinase and inositol 1,4,5-trisphosphate had no effect on the ATPase. The properties of the Ca2+, Mg2+ -ATPase were distinct from those of the Mg2+-ATPase, but comparable with those reported for the parotid endoplasmic-reticulum Ca2+-transport system [Kanagasuntheram & Teo (1982) Biochem. J. 208, 789-794]. The results suggest that the Ca2+, Mg2+-ATPase is responsible for driving the ATP-dependent Ca2+ accumulation by this membrane.


Alzheimer's disease and heparan sulfate proteoglycan.
Alzheimer's disease (AD) is a debilitating neurodegenerative disorder. Cardinal histopathologic changes of AD are neurofibrillary tangles (NFTs) and deposits of beta-amyloid protein (A-beta) in the form of neuritic plaques (NPs). Several different mutations found in patients with familial AD have been demonstrated to increase A-beta production, resulting in a common pathological cascade of beta-amyloidosis in the brain. Heparan sulfate proteoglycan (HSPG) has been co-localized with both A-beta in the NPs and NFTs. The proteoglycans are a family of complex macromolecules consisting of a protein core to which glycosaminoglycan (GAG) chains are covalently attached. HSPG has been shown to bind to A-beta, accelerate its fibril formation, and maintain its fibril stability. In AD and other neurodegenerative disorders, tau becomes hyperphosphorylated hence it is unable to bind to microtubules which results in the production of paired helical filaments, a building unit of NFTs. It has been shown in vitro that sulfated GAGs induce the formation of paired helical-like filaments under physiological conditions from tau. Furthermore, an interaction between HSPG and apolipoprotein E (a potent risk factor of AD) has been shown to be involved in neurodegeneration. Thus, substantial evidence exists to underscore important roles of HSPG in the etiology of AD.


Preparation, Properties, and Bioapplications of Block Copolymer Nanopatterns.
Block copolymer (BCP) self-assembly has emerged as a feasible method for large-scale fabrication with remarkable precision - features that are not common for most of the nanofabrication techniques. In this review, recent advancements in the molecular design of BCP along with state-of-the-art processing methodologies based on microphase separation alone or its combination with different lithography methods are presented. Furthermore, the bioapplications of the generated nanopatterns in the development of protein arrays, cell-selective surfaces, and antibacterial coatings are explored. Finally, the current challenges in the field are outlined and the potential breakthroughs that can be achieved by adopting BCP approaches already applied in the fabrication of electronic devices are discussed.


Long-term effects of physical training on aerobic capacity: controlled study of former elite athletes.
We studied 15-yr changes in physical training, subcutaneous fat, and maximal oxygen consumption (VO2 max) in male former elite athletes (27 long-distance runners and 9 bobsledders) and in a control group of 23 normal men. In 1973, elite athletes all trained vigorously, whereas in 1988 there was a great interindividual variation in physical training. In the lowest tertile of runners' training activity in 1988 (n = 9), the rate of decline in VO2max during the 15 yr was 1.11 +/- 0.15 (SE) ml.kg-1.min-1.yr-1, or 16% per decade, whereas the most active quintile of runners (n = 5) tended to increase VO2max (NS). The remaining 13 runners showed a rate of decline in VO2max of 0.54 +/- 0.14 ml.kg-1.min-1.yr-1, or 7% per decade. The rates of decline were 0.22 +/- 0.12 and 0.56 +/- 0.10 ml.kg-1.min-1.yr-1, or 5 and 11% per decade, in bobsledders and controls, respectively. When normalized for lean body mass instead of body weight, VO2max showed a reduced variability in the rate of decline, with values ranging from 0.00 +/- 0.27 (most active runners) to 0.69 +/- 0.15 ml.kg lean body mass-1.min-1.yr-1 (least active runners). In multiple linear regression analysis, 15-yr changes in mileage, running pace, and truncal fat together explained 51% of variance in the 15-yr change of VO2max normalized for body weight in runners and 41% in all study men. In runners, change in truncal fat was dependent on changes in both mileage and running pace. In the presence of physical training and anthropometric variables in the regression equation, the 15-yr decrease in maximum heart rate was only modestly predictive of the change in VO2max.(ABSTRACT TRUNCATED AT 250 WORDS)


Prognostic significance of morphologic parameters in renal cell carcinoma.
The prognostic significance of morphologic parameters was evaluated in 103 patients with renal cell carcinoma diagnosed during 1961--1974. Pathologic material was classified as to pathologic stage, tumor size, cell arrangement, cell type and nuclear grade. Four nuclear grades (1--4) were defined in order of increasing nuclear size, irregularity and nucleolar prominence. Nuclear grade was more effective than each of the other parameters in predicting development of distant metastasis following nephrectomy. Among 45 patients who presented in Stage I, tumors classified as nuclear grade 1 did not metastasize for at least 5 years, whereas 50% of the higher grade tumors did so. Moreover, among Stage I tumors there was a significant difference in subsequent metastatic rate between nuclear grades 1 and 2. There was an apparent positive relationship between cell type and metastatic rate; clear cell tumors were less aggressive than predominantly granular cell tumors (metastatic rate 38% versus 71%). This relationship in part a function of the nuclear grade: only 5% of grade 3 and 4 tumors consisted of clear cells, whereas such high grades were seen in 57% of granular cell tumors. The size of the primary correlated well with the stage at the time of surgery. However, with the exception of extremely large and small tumors, the size was not useful in predicting the subsequent course of patients treated for Stage I tumors. Nuclear grade was the most significant prognostic criterion for the outcome of Stage I renal cell carcinoma.


The association between health-related quality of life and disease progression in idiopathic pulmonary fibrosis: a prospective cohort study.
Background and objective: Generally, a disease-specific health-related quality of life (HRQOL) measurement is more useful than generic measures in assessing perceived physical and mental health characteristic of a particular disease. The idiopathic pulmonary fibrosis (IPF)-specific version of St. George's Respiratory Questionnaire (SGRQ-I) has been recently developed for patients with IPF. We proposed to evaluate associations between the SGRQ-I and other clinical indices, as well as its prognostic value in patients with IPF. Methods: Fifty-two patients with IPF were recruited in this prospective cohort study. HRQOL was assessed using the SGRQ-I and the Medical Outcomes Study 36-item Short Form, dyspnea using the modified Medical Research Council (mMRC) dyspnea scale, and psychological status using the Hospital Anxiety and Depression Scale (HADS). We then evaluated the relationship between the SGRQ-I and other clinical measures, as well as one-year clinical deterioration defined as a hospital admission due to respiratory exacerbation or all-cause death. Results: Stepwise multiple-regression analyses revealed that the mMRC dyspnea scale, the HADS anxiety or depression, and minimum oxygen saturation during a six-minute walk test significantly contributed to the Total and three components of the SGRQ-I. In multivariate Cox proportional-hazards analyses, the Total score of SGRQ-I predicted clinical deterioration independent of forced vital capacity, the six-minute walk distance, or partial pressure of arterial oxygen on room air. Conclusions: The SGRQ-I is a multidisciplinary instrument representing physical, functional and psychological impairments in patients with IPF. The SGRQ-I is a significant predictor of short-term disease progression independent of physiological measurements. (Sarcoidosis Vasc Diffuse Lung Dis 2017; 34: 226-235).


Functional analysis of inappropriate mealtime behaviors.
The purpose of the current investigation was to apply the functional analysis described by Iwata, Dorsey, Slifer, Bauman, and Richman (1982/1994) to the inappropriate mealtime behaviors of 15 children who had been referred to an intensive program for the assessment and treatment of severe feeding disorders. During Study 1, we conducted descriptive assessments of children and parents during meals. The results of Study 1 showed that parents used the following consequences for inappropriate mealtime behaviors: coaxing and reprimanding, allowing the child to periodically take a break from or avoid eating, and giving the child preferred food or toys following inappropriate behavior. The effects of these consequences were tested systematically in Study 2 when we conducted analogue functional analyses with the children. During alternating meals, one of the consequences typically used by parents consistently followed inappropriate child behavior. Results indicated that these consequences actually worsened behavior for 10 of the 15 children (67%). These results suggested that the analogue functional analysis described by Iwata et al. may be useful in identifying the environmental events that play a role in feeding disorders.


Effect of MRI acquisition acceleration via compressed sensing and parallel imaging on brain volumetry.
To investigate the effect of compressed SENSE (CS), an acceleration technique combining parallel imaging and compressed sensing, on potential bias and precision of brain volumetry and evaluate it in the context of normative brain volumetry. In total, 171 scans from scan-rescan experiments on three healthy subjects were analyzed. Each subject received 3D-T1-weighted brain MRI scans at increasing degrees of acceleration (CS-factor = 1/4/8/12/16/20/32). Single-scan acquisition times ranged from 00:41 min (CS-factor = 32) to 21:52 min (CS-factor = 1). Brain segmentation and volumetry was performed using two different software tools: md.brain, a proprietary software based on voxel-based morphometry, and FreeSurfer, an open-source software based on surface-based morphometry. Four sub-volumes were analyzed: brain parenchyma (BP), total gray matter, total white matter, and cerebrospinal fluid (CSF). Coefficient of variation (CoV) of the repeated measurements as a measure of intra-subject reliability was calculated. Intraclass correlation coefficient (ICC) with regard to increasing CS-factor was calculated as another measure of reliability. Noise-to-contrast ratio as a measure of image quality was calculated for each dataset to analyze the association between acceleration factor, noise and volumetric brain measurements. For all sub-volumes, there is a systematic bias proportional to the CS-factor which is dependent on the utilized software and subvolume. Measured volumes deviated significantly from the reference standard (CS-factor = 1), e.g. ranging from 1 to 13% for BP. The CS-induced systematic bias is driven by increased image noise. Except for CSF, reliability of brain volumetry remains high, demonstrated by low CoV (< 1% for CS-factor up to 20) and good to excellent ICC for CS-factor up to 12. CS-acceleration has a systematic biasing effect on volumetric brain measurements.


RC1339/APRc from Rickettsia conorii is a novel aspartic protease with properties of retropepsin-like enzymes.
Members of the species Rickettsia are obligate intracellular, gram-negative, arthropod-borne pathogens of humans and other mammals. The life-threatening character of diseases caused by many Rickettsia species and the lack of reliable protective vaccine against rickettsioses strengthens the importance of identifying new protein factors for the potential development of innovative therapeutic tools. Herein, we report the identification and characterization of a novel membrane-embedded retropepsin-like homologue, highly conserved in 55 Rickettsia genomes. Using R. conorii gene homologue RC1339 as our working model, we demonstrate that, despite the low overall sequence similarity to retropepsins, the gene product of rc1339 APRc (for Aspartic Protease from Rickettsia conorii) is an active enzyme with features highly reminiscent of this family of aspartic proteases, such as autolytic activity impaired by mutation of the catalytic aspartate, accumulation in the dimeric form, optimal activity at pH 6, and inhibition by specific HIV-1 protease inhibitors. Moreover, specificity preferences determined by a high-throughput profiling approach confirmed common preferences between this novel rickettsial enzyme and other aspartic proteases, both retropepsins and pepsin-like. This is the first report on a retropepsin-like protease in gram-negative intracellular bacteria such as Rickettsia, contributing to the analysis of the evolutionary relationships between the two types of aspartic proteases. Additionally, we have also shown that APRc is transcribed and translated in R. conorii and R. rickettsii and is integrated into the outer membrane of both species. Finally, we demonstrated that APRc is sufficient to catalyze the in vitro processing of two conserved high molecular weight autotransporter adhesin/invasion proteins, Sca5/OmpB and Sca0/OmpA, thereby suggesting the participation of this enzyme in a relevant proteolytic pathway in rickettsial life-cycle. As a novel bona fide member of the retropepsin family of aspartic proteases, APRc emerges as an intriguing target for therapeutic intervention against fatal rickettsioses.


Crystalline desoxyribonuclease; isolation and general properties; spectrophotometric method for the measurement of desoxyribonuclease activity.
A crystalline enzyme capable of digesting thymus nucleic acid (desoxyribonucleic acid) has been isolated from fresh beef pancreas. The enzyme called "desoxyribonuclease" is a protein of the albumin type. Its molecular weight is about 60,000 and its isoelectric point is near pH 5.0. It contains about 8 per cent tyrosine and 2 per cent tryptophane. It is readily denatured by heat. The denaturation is reversible if heated in dilute acid at pH about 3.0. The digestion of thymus nucleic acid by crystalline desoxyribonuclease is accompanied by a gradual increase in the specific absorption of ultraviolet light by the acid. The spectrophotometric measurement of the rate of increase in the light absorption can be conveniently used as a general method for estimating desoxyribonuclease activity. Details are given of the method for isolation of crystalline desoxyribonuclease and of the spectrophotometric procedure for the measurement of desoxyribonuclease activity.


Cell Migration Research Based on Organ-on-Chip-Related Approaches.
Microfluidic devices have been widely used for cell migration research over the last two decades, owing to their attractive features in cellular microenvironment control and quantitative single-cell migration analysis. However, the majority of the microfluidic cell migration studies have focused on single cell types and have configured microenvironments that are greatly simplified compared with the in-vivo conditions they aspire to model. In addition, although cell migration is considered an important target for disease diagnosis and therapeutics, very few microfluidic cell migration studies involved clinical samples from patients. Therefore, more sophisticated microfluidic systems are required to model the complex in-vivo microenvironment at the tissue or organ level for cell migration studies and to explore cell migration-related clinical applications. Research in this direction that employs organ-on-chip-related approaches for cell migration analysis has been increasingly reported in recent years. In this paper, we briefly introduce the general background of cell migration and organ-on-chip research, followed by a detailed review of specific cell migration studies using organ-on-chip-related approaches, and conclude by discussing our perspectives of the challenges, opportunities and future directions.


Unintentional embolization of a guide wire in the inferior vena cava during central venous catheter insertion successfully retrieved percutaneously 9 months later.
Central venous catheters are routinely positioned for hemodynamic monitoring and fluid administration in patients undergoing cardiac surgery, and many well-known complications associated with this manoeuver have been described. Metalic guide wire embolization is a rare complication potentially associated with nonmechanical and mechanical adverse events. The case we report is peculiar as an almost fully endothelialized guide wire was successfully retrieved 9 months after its unintentional embolization in the inferior vena cava.


Viral interference between low pathogenic avian influenza H9N2 and avian infectious bronchitis viruses in vitro and in ovo.
Low pathogenic avian influenza (LPAI) H9N2 and infectious bronchitis virus (IBV) are important pathogens of poultry, causing important economic losses for the sector. Replication interference between these two viruses was described using cell cultures (CC) and embryonated chicken eggs (ECE). Chicken embryo lung (CEL) and ECE were simultaneously or sequentially infected with IBV vaccine strain (H120) and LPAIV-H9N2 (A/Ck/TUN/145/2012) to evaluate viral interactionsin vitro and in ovo, respectively. Real-time RT-PCR was developed to specifically quantify both AIV and IBV genomes as well as viral gene copy numbers during mixed infections. The amount of IL-1 beta, in supernatants of co-infected cell cultures, was determined using an ELISA assay. Quantitative results of AIV and IBV co-infection showed that interferences between the two viruses yielded decreased viral growth. However, in the case of super-infection, the second virus, either AIV or IBV, induced a decrease in the growth of the first inoculated virus. It appears that either AIV or IBV has a negative impact on the other virus growth when they are inoculated simultaneously or sequentially. The ELISA results showed that higher level of secreted IL-1beta varies, depending on the viral interference conditions between both viruses, during mixed infections.


A systematic review of economic evaluations of conservative treatments for chronic lower extremity musculoskeletal complaints.
The aim was to appraise and synthesize studies evaluating the clinical and cost effectiveness of conservative interventions for chronic lower extremity musculoskeletal (MSK) conditions and describe their characteristics, including the type of economic evaluation, primary outcomes and which conditions. The search strategy related to economic evaluations of lower limb MSK conditions that used conservative therapies. Eight electronic databases were searched (CENTRAL, MEDLINE, PubMed, EMBASE, CINAHL, PEDro, NHSEED and Proquest), as were the reference lists from included articles. The quality of articles was appraised using a modified version of the economic evaluations' reporting checklist (economic) and The Cochrane Collaboration's tool for assessing risk of bias (clinical). Twenty-six studies were eligible and included in the review. Economic evaluations of conservative interventions for OA or pain affecting the knee/hip (n = 25; 93%) were most common. The main approaches adopted were cost-utility analysis (n = 17; 68%) or cost-effectiveness analysis (n = 5; 19%). Two studies involved interventions including footwear/foot orthoses; for heel pain (n = 1; 4%) and overuse injuries (n = 1; 4%). Fifty per cent of economic evaluations adopted the EQ-5D-3L as the primary outcome measure for quality of life and quality-adjusted life year calculations. Economic evaluations have been conducted largely for exercise-based interventions for MSK conditions of the hip and knee. Few economic evaluations have been conducted for other clinically important lower limb MSK conditions. A matrix presentation of costs mapped with outcomes indicated increasing costs with either no difference or improvements in clinical effectiveness. The majority of economic evaluations were of good reporting quality, as were the accompanying clinical studies.


Tibia shaft fractures: costly burden of nonunions.
Tibia shaft fractures (TSF) are common for men and women and cause substantial morbidity, healthcare use, and costs. The impact of nonunions on healthcare use and costs is poorly described. Our goal was to investigate patient characteristics and healthcare use and costs associated with TSF in patients with and without nonunion. We retrospectively analyzed medical claims in large U.S. managed care claims databases (Thomson Reuters MarketScan®, 16 million lives). We studied patients ≥ 18 years old with a TSF diagnosis (ICD-9 codes: 823.20, 823.22, 823.30, 823.32) in 2006 with continuous pharmaceutical and medical benefit enrollment 1 year prior and 2 years post-fracture. Nonunion was defined by ICD-9 code 733.82 (after the TSF date). Among the 853 patients with TSF, 99 (12%) had nonunion. Patients with nonunion had more comorbidities (30 vs. 21, pre-fracture) and were more likely to have their TSF open (87% vs. 70%) than those without nonunion. Patients with nonunion were more likely to have additional fractures during the 2-year follow-up (of lower limb [88.9% vs. 69.5%, P < 0.001], spine or trunk [16.2% vs. 7.2%, P = 0.002], and skull [5.1% vs. 1.3%, P = 0.008]) than those without nonunion. Nonunion patients were more likely to use various types of surgical care, inpatient care (tibia and non-tibia related: 65% vs. 40%, P < 0.001) and outpatient physical therapy (tibia-related: 60% vs. 42%, P < 0.001) than those without nonunion. All categories of care (except emergency room costs) were more expensive in nonunion patients than in those without nonunion: median total care cost $25,556 vs. $11,686, P < 0.001. Nonunion patients were much more likely to be prescribed pain medications (99% vs. 92%, P = 0.009), especially strong opioids (90% vs. 76.4%, P = 0.002) and had longer length of opioid therapy (5.4 months vs. 2.8 months, P < 0.001) than patients without nonunion. Tibia fracture patterns in men differed from those in women. Nonunions in TSF's are associated with substantial healthcare resource use, common use of strong opioids, and high per-patient costs. Open fractures are associated with higher likelihood of nonunion than closed ones. Effective screening of nonunion risk may decrease this morbidity and subsequent healthcare resource use and costs.


Response of resistance arteries to reduced PO2 and vasodilators during hypertension and elevated salt intake.
This study assessed vasodilator responses in skeletal muscle resistance arteries (100-250 microns) from rats with chronic (4-8 wk) reduced renal mass (RRM) hypertension and normotensive sham-operated controls on a high (4% NaCl; HSSHAM)- or low (0.4% NaCl; LSSHAM)-salt diet. Arteries from RRM hypertensive rats [normal and high-salt diet (HSRRM)] and a separate group of spontaneously hypertensive rats exhibited an impaired dilation in response to reduced PO2 compared with those of their normotensive controls. Prostacyclin release, assessed by radio-immunoassay for 6-ketoprostaglandin F1 alpha, increased significantly in response to reduced PO2, but was unaffected by hypertension or salt intake. Dilator responses to acetylcholine and the prostacyclin analog iloprost were significantly reduced in both HSRRM and HSSHAM compared with LSSHAM rats. Dilation in response to direct activation of adenylate cyclase with forskolin or guanylate cyclase with the nitric oxide donor sodium nitroprusside was not significantly different in HSRRM, HSSHAM, and LSSHAM rats. These results indicate that hypoxic dilation is impaired in skeletal muscle resistance arteries of hypertensive rats and that chronic high-salt diet alone leads to impaired vasodilator responses in resistance arteries of normotensive animals, possibly via abnormalities in membrane function or G protein signaling rather than impaired second-messenger function.


CIRCAMULTISEPTAN ASPECT OF SUDDEN DEATH: COMPETING SOCIO-ECOLOGICAL SYNCHRONIZERS: ALCOHOL AND MAGNETICS?
In order to investigate infradian aspects of sudden death, the daily incidence of 70,531 cases recorded in response to a call for an ambulance during 3 years (1979-1981) in Moscow, Russia, were re-analysed, focusing on multiseptans (components with periods of 7 days and/or multiples thereof). Apart from a prominent yearly and half-yearly variation in the daily incidence of sudden death, least squares spectra revealed the presence of about-weekly and two-weekly components. The about 15.2-day variation was validated by nonlinear least squares and shown to differ in period length from that found in the local index of geomagnetic activity, K. This result suggests that apart from any geomagnetic influence on sudden death, changes in lifestyle (such as alcohol consumption) associated with the twice-a-month salary schedule may affect the occurrence of sudden death. Such a component is not prominently seen for the incidence of other cardiovascular conditions recorded in the same database. The weekly pattern of sudden death, peaking on Saturdays, also differs from those of other cardiovascular conditions, characterized by a higher daily incidence on Mondays. The possibility to now record events in cardioverter-defibrillators offers an opportunity to explore broad chronomes of potentially lethal arrhythmia that may lead to a better understanding of underlying triggers, so that novel countermeasures may be designed and implemented.


DDB2 Genetic Risk Factor for Ocular Squamous Cell Carcinoma Identified in Three Additional Horse Breeds.
Squamous cell carcinoma (SCC) is the most common cancer affecting the equine eye. A missense variant within the gene damage-specific DNA binding protein 2 (DDB2 c.1013C>T, p.Thr338Met) was previously identified as a causal recessive genetic risk factor for the development of ocular SCC within Haflingers, Belgian Draft horses, and Rocky Mountain Horses, but not in the Appaloosa or Arabian breeds. This study aimed to evaluate three cases of ocular SCC in additional breeds and determine if DNA testing for the DDB2 variant in warmblood horses and Connemara ponies is warranted. Histopathology confirmed ocular SCC in all three cases and DNA testing confirmed each horse was homozygous for the DDB2 risk factor. The DDB2 risk allele frequency was estimated to be 0.0043 for Holsteiners (N = 115), 0.014 for Belgian Warmbloods (N = 71), and 0.22 for Connemara Ponies (N = 86). Taken together these data support using DNA testing for DDB2 in Connemara Ponies to assist in mate selection and clinical management. Given the low observed allele frequencies in both the Holsteiner and Belgian Warmblood breeds and that the case under investigation was a warmblood cross-bred, evaluating additional SCC affected warmbloods is warranted to fully determine the importance of DDB2 genotyping as a risk factor in warmblood breeds.


Definitive but not primitive hematopoiesis is impaired in jumonji mutant mice.
A novel gene, jumonji was identified by a mouse gene trap strategy. The jumonji gene encodes a protein containing a putative DNA binding domain. The mice homozygous for jumonji gene with a BALB/cA genetic background show hypoplasia of the fetal liver and embryonic lethality, suggesting impaired hematopoiesis. In the peripheral blood of jumonji mutant embryos, the number of fetal liver-derived definitive erythrocytes, but not yolk sac-derived primitive erythrocytes, showed a marked reduction, suggesting that jumonji mutants die of anemia. The defects of definitive erythrocytes in jumonji mutants seemed to be caused by a decrease in the numbers of multiple hematopoietic progenitors including colony-forming unit-spleen (CFU-S) in the fetal liver. However, hematopoietic stem cells (HSCs) in the fetal liver of jumonji mutants could reconstitute the hematopoietic system of lethally irradiated recipients. In the fetal liver, the jumonji gene is expressed in fibroblastic cells and endothelial cells, but not in Lin-/c-Kit+/Sca-1(+) cells known to include HSCs. These results suggest that an environmental defect induce the impaired hematopoiesis in the fetal liver of jumonji mutant embryos.


Interactive visualization of public health indicators to support policymaking: An exploratory study.
The purpose of this study is to examine the use of interactive visualizations to represent data/information related to social determinants of health and public health indicators, and to investigate the benefits of such visualizations for health policymaking. The study developed a prototype for an online interactive visualization tool that represents the social determinants of health. The study participants explored and used the tool. The tool was evaluated using the informal user experience evaluation method. This method involves the prospective users of a tool to use and play with it and their feedback to be collected through interviews. Using visualizations to represent and interact with health indicators has advantages over traditional representation techniques that do not allow users to interact with the information. Communicating healthcare indicators to policymakers is a complex task because of the complexity of the indicators, diversity of audiences, and different audience needs. This complexity can lead to information misinterpretation, which occurs when users of the health data ignore or do not know why, where, and how the data has been produced, or where and how it can be used. Public health policymaking is a complex process, and data is only one element among others needed in this complex process. Researchers and healthcare organizations should conduct a strategic evaluation to assess the usability of interactive visualizations and decision support tools before investing in these tools. Such evaluation should take into consideration the cost, ease of use, learnability, and efficiency of those tools, and the factors that influence policymaking.


Relation of black race between high density lipoprotein cholesterol content, high density lipoprotein particles and coronary events (from the Dallas Heart Study).
Therapies targeting high-density lipoprotein cholesterol content (HDL-C) have not improved coronary heart disease (CHD) outcomes. High-density lipoprotein particle concentration (HDL-P) may better predict CHD. However, the impact of race/ethnicity on the relations between HDL-P and subclinical atherosclerosis and incident CHD events has not been described. Participants from the Dallas Heart Study (DHS), a multiethnic, probability-based, population cohort of Dallas County adults, underwent the following baseline measurements: HDL-C, HDL-P by nuclear magnetic resonance imaging, and coronary artery calcium by electron-beam computed tomography. Participants were followed for a median of 9.3 years for incident CHD events (composite of first myocardial infarction, stroke, coronary revascularization, or cardiovascular death). The study comprised 1,977 participants free of CHD (51% women, 46% black). In adjusted models, HDL-C was not associated with prevalent coronary artery calcium (p = 0.13) or incident CHD overall (hazard ratio [HR] per 1 SD 0.89, 95% confidence interval [CI] 0.76 to 1.05). However, HDL-C was inversely associated with incident CHD among nonblack (adjusted HR per 1 SD 0.67, 95% CI 0.46 to 0.97) but not black participants (HR 0.94, 95% CI 0.78 to 1.13, pinteraction = 0.05). Conversely, HDL-P, adjusted for risk factors and HDL-C, was inversely associated with prevalent coronary artery calcium (p = 0.009) and with incident CHD overall (adjusted HR per 1 SD 0.73, 95% CI 0.62 to 0.86), with no interaction by black race/ethnicity (pinteraction = 0.57). In conclusion, in contrast to HDL-C, the inverse relation between HDL-P and incident CHD events is consistent across ethnicities. These findings suggest that HDL-P is superior to HDL-C in predicting prevalent atherosclerosis as well as incident CHD events across a diverse population and should be considered as a therapeutic target.


Is the relationship between body length and body mass consistent across habitats? A case study on Niphargus (Crustacea: Amphipoda).
Body size is one of the main characteristics of any organism and influences various aspects of individual's biology. In animal ecology, it represents a key functional trait that can be quantified using different measures and is often used as a proxy for different organismal functions. The way we quantify body size is critical in any study using this measure alone or to scale other organismal traits. It is especially important in groups that act as model systems across different fields of biological research. One of such groups are amphipods, which are at focus in many ecological studies where appropriate quantification of body size is needed. Here, we explored the relationship between body length and body mass in the largest freshwater amphipod genus Niphargus, and evaluated whether the two measures lead to different conclusions in a putative ecological study of species coexistence. We selected 16 species inhabiting two different subterranean habitats, cave lakes and cave streams. The relationship between log-transformed body mass and body length was linear in all species, but body mass increased steeper among species from cave lakes than from cave streams, reflecting the stouter body shape of the former. In the simulated ecological study, the comparisons of the two measures showed that they may yield different results: in 10 % of cases, body length detected differences between species when body mass did not and vice versa (13 %). Usage of body length or body mass can thus lead to different conclusions. We recommend avoiding direct transformations between body length and body mass in ecological studies. Whenever needed, such transformations should be done with caution using habitat-specific body mass - body length ratios.


Lyme disease--part II: clinical features and treatment.
Lyme disease (LD) is the most common vector-borne disease in the United States. Generally presenting with a characteristic rash, myalgia, and fatigue, LD can progress to chronic arthritis, central nervous system manifestations, and cardiac abnormalities, if left untreated. The number of cases continues to rise each year. Early diagnosis and proper therapy are required to halt disease progression to late chronic stages. By adhering to simple guidelines, many potential cases of LD can be prevented. In this article, the second in a 2-part series on LD, we discuss clinical features and treatment.


Racial/ethnic subgroup differences in outcomes and acceptability of an Internet-delivered intervention for substance use disorders.
The Therapeutic Education System (TES), an Internet version of the Community Reinforcement Approach plus prize-based motivational incentives, is one of few empirically supported technology-based interventions. To date, however, there has not been a study exploring differences in substance use outcomes or acceptability of TES among racial/ethnic subgroups. This study uses data from a multisite (N = 10) effectiveness study of TES to explore whether race/ethnicity subgroups (White [n = 267], Black/African American [n = 112], and Hispanic/Latino [n = 55])moderate the effect of TES. Generalized linear mixed models were used to test whether abstinence, retention, social functioning, coping, craving, or acceptability differed by racial/ethnic subgroup. Findings demonstrated that race/ethnicity did not moderate the effect of TES versus TAU on abstinence, retention, social functioning, or craving. A three-way interaction (treatment, race/ethnicity, and abstinence status at study entry) showed that TES was associated with greater coping scores among nonabstinent White participants (p = .008) and among abstinent Black participants (p < .001). Acceptability of the TES intervention, although high overall, was significantly different by race/ethnicity subgroup with White participants reporting lower acceptability of TES compared to Black (p = .006) and Hispanic/Latino (p = .008) participants. TES appears to be a good candidate treatment among a diverse population of treatment-seeking individuals with substance use disorders.


Viable adenovirus vaccine prototypes: high-level production of a papillomavirus capsid antigen from the major late transcriptional unit.
Safe, effective, orally delivered, live adenovirus vaccines have been in use for three decades. Recombinant derivatives of the live adenovirus vaccines may prove an economical alternative to current vaccines for a variety of diseases. To explore that possibility, we constructed a series of recombinants that express the major capsid protein (L1) of canine oral papillomavirus (COPV), a model for mucosal human papillomavirus (HPV) infection. Vaccination with virus-like particles (VLPs) composed of recombinant HPV L1 completely prevents persistent HPV infection [Koutsky, L. A., Ault, K. A., Wheeler, C. M., Brown, D. R., Barr, E., Alvarez, F. B., Chiacchierini, L. M. & Jansen, K. U. (2002) N. Engl. J. Med. 347, 1645-1651], suggesting that L1 expressed from recombinant adenoviruses might provide protective immunity. In our recombinants, COPV L1 is incorporated into adenovirus late region 5 (Ad L5) and is expressed as a member of the adenoviral major late transcriptional unit (MLTU). COPV L1 production by the most prolific recombinant is comparable to that of the most abundant adenoviral protein, hexon. COPV L1 production by recombinants is influenced by Ad L5 gene order, the specific mRNA processing signals associated with COPV L1, and the state of a putative splicing inhibitor in the COPV L1 gene. Recombinant COPV L1 protein assembles into VLPs that react with an antibody specific for conformational epitopes on native COPV L1 protein that correlate with protection in vivo. The designs of these recombinants can be applied directly to the production of recombinants appropriate for assessing immunogenicity and protective efficacy in animal models and in human trials.


Discovering schizophrenia endophenotypes in randomly ascertained pedigrees.
Although case-control approaches are beginning to disentangle schizophrenia's complex polygenic burden, other methods will likely be necessary to fully identify and characterize risk genes. Endophenotypes, traits genetically correlated with an illness, can help characterize the impact of risk genes by providing genetically relevant traits that are more tractable than the behavioral symptoms that classify mental illness. Here, we present an analytic approach for discovering and empirically validating endophenotypes in extended pedigrees with very few affected individuals. Our approach indexes each family member's risk as a function of shared genetic kinship with an affected individual, often referred to as the coefficient of relatedness. To demonstrate the utility of this approach, we search for neurocognitive and neuroanatomic endophenotypes for schizophrenia in large unselected multigenerational pedigrees. A fixed-effects test within the variance component framework was performed on neurocognitive and cortical surface area traits in 1606 Mexican-American individuals from large, randomly ascertained extended pedigrees who participated in the Genetics of Brain Structure and Function study. As affecteds were excluded from analyses, results were not influenced by disease state or medication usage. Despite having sampled just 6 individuals with schizophrenia, our sample provided 233 individuals at various levels of genetic risk for the disorder. We identified three neurocognitive measures (digit-symbol substitution, facial memory, and emotion recognition) and six medial temporal and prefrontal cortical surfaces associated with liability for schizophrenia. With our novel analytic approach, one can discover and rank endophenotypes for schizophrenia, or any heritable disease, in randomly ascertained pedigrees.


Acetylcholine-Binding Protein Affinity Profiling of Neurotoxins in Snake Venoms with Parallel Toxin Identification.
Snakebite is considered a concerning issue and a neglected tropical disease. Three-finger toxins (3FTxs) in snake venoms primarily cause neurotoxic effects since they have high affinity for nicotinic acetylcholine receptors (nAChRs). Their small molecular size makes 3FTxs weakly immunogenic and therefore not appropriately targeted by current antivenoms. This study aims at presenting and applying an analytical method for investigating the therapeutic potential of the acetylcholine-binding protein (AChBP), an efficient nAChR mimic that can capture 3FTxs, for alternative treatment of elapid snakebites. In this analytical methodology, snake venom toxins were separated and characterised using high-performance liquid chromatography coupled with mass spectrometry (HPLC-MS) and high-throughput venomics. By subsequent nanofractionation analytics, binding profiling of toxins to the AChBP was achieved with a post-column plate reader-based fluorescence-enhancement ligand displacement bioassay. The integrated method was established and applied to profiling venoms of six elapid snakes (Naja mossambica, Ophiophagus hannah, Dendroaspis polylepis, Naja kaouthia, Naja haje and Bungarus multicinctus). The methodology demonstrated that the AChBP is able to effectively bind long-chain 3FTxs with relatively high affinity, but has low or no binding affinity towards short-chain 3FTxs, and as such provides an efficient analytical platform to investigate binding affinity of 3FTxs to the AChBP and mutants thereof and to rapidly identify bound toxins.


Repair strength of denture base resins using various methods.
The object of this study was to measure the repair strength of denture base resins repaired using, (a) standard heat activated polymerising resin, (b) a denture base resin especially formulated for microwave-activated polymerisation, and (c) an autopolymerising resin. Comparisons were made between conventional water bath and microwave curing and autopolymerised resin repairs, using transverse bend and impact tests. Repairs with the two heat-activated denture base resins were carried out using conventional dental flasking procedures, whereas autopolymerised resin repairs were carried out in open gypsum moulds. The results indicate that the transverse strength, and impact resistance of the resin specimens repaired with microwave irradiation were generally superior to specimens repaired by using a water bath curing cycle or the use of an autopolymerising resin.


The effect of pinealectomy and leptin hormone on the proliferation and apoptosis activation in Syrian hamster testis in different photoperiods.
The effects of pinealectomy and leptin hormone on proliferative and apoptotic processes in the epithelia of testicular seminiferous tubules of Syrian hamsters have been investigated. Proliferative and apoptotic processes were assessed semi-quantitatively by proliferating cell nuclear antigen (PCNA) and caspase-3 immune stainings. Animals used in the study were divided into four groups; control, pinealectomy (PinX), leptin-treated (10 microg/mL/day/kg body weight, intraperitoneally) and pinealectomy + leptin groups. Half of the hamsters in each group were exposed to short and the other half to long photoperiods for 8 weeks. In short photoperiod, PCNA activity especially in spermatogonia was significantly higher in the pinealectomy and leptin-treated groups compared with the control group. Histological score (HSCORE) value of PCNA in the PinX + leptin group was lower than those of PinX and leptin-treated groups. HSCORE value of caspase-3 in PinX and PinX + leptin groups was increased. In the long photoperiod, PCNA activation in the PinX group was significantly lower than the control group while the differences between the controls and other groups were not significant. The difference between the increases in caspase-3 activity in the PinX and control groups was significant. Thus, it was observed that photoperiods had no effect on the proliferation activity in the control groups. The inhibiting effect of short photoperiod on testis was not observed throughout 8 weeks. PinX eliminated the inhibiting effect of short photoperiod but did not alter the stimulating effect of long photoperiod. Leptin did not show any effect in long photoperiod but decreased proliferation by stimulating melatonin in short photoperiod.


Performance of silicon microdosimetry detectors in boron neutron capture therapy.
Reverse-biased silicon p-n junction arrays using Silicon-On-Insulator technology have been proposed as microdosimeters. The performance of such detectors in boron neutron capture therapy (BNCT) is discussed. This work provides the first reported measurements using boron-coated silicon diode arrays as microdosimeters in BNCT. Results are in good agreement with measurements with gas proportional counters. Various boron-coating options are investigated along with device orientation effects. Finally, a 235U coating is tested to simulate the behavior of the device in a heavy-ion therapy beam.


Genetic and environmental influences on eating behavior: the Swedish Young Male Twins Study.
Eating behavior may be implicated in the increasing prevalence of overweight and obesity, presumably in relation to easy access to energy-dense and highly palatable foods. The aim of the present study was to disentangle genetic and environmental influences on eating behavior in a population-based cohort of male twins. The study included 326 dizygotic and 456 monozygotic male twin pairs aged 23-29 y from Sweden. The revised 21-item version of the Three-Factor Eating Questionnaire (TFEQ-R21) was used to assess eating behavior. This validated instrument consists of 3 dimensions: cognitive restraint, emotional eating, and uncontrolled eating. Structural equation modeling was used to estimate the heritability of eating behavior. Cognitive restraint was the only TFEQ-R21 scale that significantly correlated with BMI (r = 0.39, P < 0.0001). The best-fitted models gave a heritability of 59% (95% CI: 52%, 66%) for cognitive restraint, 60% (95% CI: 52%, 67%) for emotional eating, and 45% (95% CI: 36%, 53%) for uncontrolled eating. These results show the great importance of genetic factors in the eating behavior of a large, unselected population of young adult male twins. Nonshared environmental factors were also important, whereas shared environmental factors did not contribute to eating behavior.


The estimation of age-related rates of infection from case notifications and serological data.
The paper describes a maximum-likelihood method for the estimation of age-related changes in the per capita rate of infection, from case notification records or serological data. The methods are applied to records of measles incidence in the UK and USA, for which the estimated rates of infection tend to rise to a maximum value at around 10 years of age and then to decline in the older age-classes. Longer-term and seasonal trends are analysed by reference to changes in the estimated average age at infection; a statistic derived from a knowledge of the age-specific rates of infection. Future data needs in the epidemiological study of directly transmitted viral and bacterial diseases are discussed with reference to the detection and interpretation of age-dependent rates of disease transmission.


The Casuarina glauca metallothionein I promoter in nodulated transgenic hairy roots of the actinorhizal plant Datisca glomerata.
The activity of the promoter of a metallothionein gene expressed in actinorhizal nodules of Casuarina glauca Sieber ex Spreng., CgMT1, has previously been analysed in Casaurinaceae and in tobacco (Nicotiana tabacum L.), Arabidopsis and rice. In all these plants, the promoter showed high activity in the root cortex and epidermis, making it a useful tool for the expression of transgenes. Therefore, its activity was now analysed in transgenic root systems of Datisca glomerata (C. Presl) Baill, an actinorhizal plant from a different phylogenetic group than C. glauca, using the same CgMT1::GUS fusion as in previous studies. However, in contrast with all other plant species examined previously, the CgMT1::GUS construct showed no activity at all in D. glomerata hairy roots: the expression pattern in nodules resembled that found in C. glauca nodules. This is probably due to the changed hormone balance in hairy roots since experiments on the CgMT1::GUS construct in transgenic Arabidopsis showed that CgMT1 promoter activity was repressed by auxin or cytokinin, respectively. Yet, in hairy roots of the model legume Lotus japonicus L. induced by the same Agrobacterium rhizogenes strain, the CgMT1 promoter was active in roots and not in nodules. These results indicate that although the expression of pRi T-DNA genes leads to changes in root hormone balance, these changes do not abolish the differences in phytohormone levels or sensitivity between plant species. Therefore, gene expression data obtained using transgenic hairy root systems have to be viewed with care, not only due to the disturbed hormone balance, but also because the effects of the pRI-T-DNA genes can differ between species.


Are Co-users of Alcohol and Marijuana More Willing to Experience Consequences From Drinking? A Longitudinal Examination Among First-Year College Students.
Alcohol and marijuana co-users are at heightened vulnerability for experiencing a variety of negative alcohol use outcomes including heavier alcohol use and driving under the influence. The current study explored willingness to experience negative consequences as a potential factor underlying the association between co-user status and negative consequences in an effort to guide future intervention work. From a longitudinal study of first-year college students, we examined willingness to experience consequences at Time 2 as a mediator of co-user status at Time 1 and experience of negative consequences at Time 3. First-year college student drinkers (n = 1,914) at a large university completed surveys in the fall and spring of their freshman year and the fall of their sophomore year. Alcohol and marijuana co-users reported higher willingness to experience consequences than alcohol-only users. Willingness to experience consequences partially explained the association between alcohol and marijuana couse and consequences. The current study was the first to compare co-users of alcohol and marijuana to alcohol-only users on willingness to experience consequences, and examine the role of willingness as a mediator between co-user status and consequences experienced. Co-users were more willing to experience adverse effects from drinking, in turn predicting more consequences. Intervention work targeting consequences may be less effective for co-users; thus, additional work is needed to identify other potential mechanisms for change for this at-risk group.


Role of HbA1c in management of diabetes mellitus.
To represent that glycosylated hemoglobin (HbA1c) is not requested by the physicians in spite of its critical importance in the monitoring of glycemic control and prediction of complications due to diabetes. A cross-sectional study was conducted at the outpatient department of King Abdul-Aziz University Hospital, Jeddah, Kingdom of Saudi Arabia, between October 2002 and July 2003. Out of the 265 known patients with diabetes, 130 patients were included in the study, which had HbA1c levels registered in their medical records. Demographic features, smoking habit, presence of hypertension, hyperlipidemia were recorded. Detailed information on diabetes were recorded, which included duration, type (type I or type II) and pattern of treatment, degree of glycemic control (assessed by two-points blood sugar and HbA1c levels). Screening for microvascular complications was recorded. Only 130 (49%) of the patients with diabetes were included in the study. Poor control was detected in the majority of the patients with diabetes. There was a difference in the detection of poor glycemic control by both methods; HbA1c levels showed poor control in 77% of the patients and by the two-point blood sugar (2-PBS) methods in 69% of the patients. Only 70% of the patients with poor glycemic control by HbA1C showed poor control by 2-PBS (p=0.7). Poor control was detected in 45% of the patients using insulin by measuring HbA1c levels, and by measuring 2-PBS in 34% of the patients (p=0.005, p=0.16). A significant relation was found between HbA1c levels, retinopathy and nephropathy (p=0.02, p=0.05). Guidelines of the American Diabetic Association (ADA) regarding proper management of patients with diabetes should be followed to achieve the recommended outcome. Glycosylated hemoglobin levels should be checked every 3 months. Physicians and patients must be advised not to depend solely on 2-PBS results, especially for insulin dependent diabetics.


Inferior rectus rupture following blowout fracture.
Extra-ocular muscle rupture is uncommon, usually seen after penetrating trauma or surgery. It is a very rare cause of diplopia following blunt orbital trauma. A patient who presented with no inferior rectus function after blunt orbital trauma is described. Computed tomography (CT) scans demonstrated a large orbital floor fracture and suggested that the inferior rectus muscle was ruptured. This was confirmed at operation. Despite anatomical repair, there was no postoperative improvement in ocular motility. Traumatic rupture of the inferior rectus is rare. Forced duction and force generation testing and CT are important in diagnosing ocular motility defects following orbital trauma.


Multifunctional pH-sensitive magnetic nanoparticles for simultaneous imaging, sensing and targeted intracellular anticancer drug delivery.
A novel multifunctional magnetic nanocarrier was fabricated for synchronous cancer therapy and sensing. The nanocarrier, programed to display a response to environmental stimuli (pH value), was synthesized by coupling doxorubicin (DOX) to adipic dihydrazide-grafted gum arabic modified magnetic nanoparticles (ADH-GAMNP) via the hydrolytically degradable pH-sensitive hydrazone bond. The resultant nanocarrier, DOX-ADH-GAMNP, had a mean diameter of 13.8 nm and the amount of DOX coupled was about 6.52 mg g(-1). Also, it exhibited pH triggered release of DOX in an acidic environment (pH 5.0) but was relatively stable at physiological pH (pH 7.4). Furthermore, both GAMNP and DOX were found to possess fluorescence properties when excited in the near-infrared region due to the two-photon absorption mechanism. The coupling of DOX to GAMNP resulted in a reversible self-quenching of fluorescence through the fluorescence resonant energy transfer (FRET) between the donor GAMNP and acceptor DOX. The release of DOX from DOX-ADH-GAMNP when exposed to acidic media indicated the recovery of fluorescence from both GAMNP and DOX. The change in the fluorescence intensity of DOX-ADH-GAMNP on the release of DOX can act as a potential sensor to sense the delivery of the drug. The analysis of zeta potential and plasmon absorbance in different pH conditions also confirmed the pH sensitivity of the product. This multifunctional nanocarrier is a significant breakthrough in developing a drug delivery vehicle that combines drug targeting as well as sensing and therapy at the same time.


Bi-cultural dynamics for risk and protective factors for cardiometabolic health in an Alaska Native (Yup'ik) population.
Alaska Native people experience disparities in mortality from heart disease and stroke. This work attempts to better understand the relationships between socioeconomic, behavioral, and cardiometabolic risk factors among Yup'ik people of southwestern Alaska, with a focus on the role of the socioeconomic, and cultural components. Using a cross-sectional sample of 486 Yup'ik adults, we fitted a Partial Least Squares Path Model (PLS-PM) to assess the associations between components, including demographic factors [age and gender], socioeconomic factors [education, economic status, Yup'ik culture, and Western culture], behavioral factors [diet, cigarette smoking and smokeless tobacco use, and physical activity], and cardiometabolic risk factors [adiposity, triglyceride-HDL and LDL lipids, glycemia, and blood pressure]. We found relatively mild associations of education and economic status with cardiometabolic risk factors, in contrast with studies in other populations. The socioeconomic factor and participation in Yup'ik culture had potentially protective associations with adiposity, triglyceride-HDL lipids, and blood pressure, whereas participation in Western culture had a protective association with blood pressure. We also found a moderating effect of participation in Western culture on the relationships between Yup'ik culture participation and both blood pressure and LDL lipids, indicating a potentially beneficial additional effect of bi-culturalism. Our results suggest that reinforcing protective effects of both Yup'ik and Western cultures could be useful for interventions aimed at reducing cardiometabolic health disparities.


First-Line Therapy for Immune Thrombocytopenia.
Immune thrombocytopenia (ITP) is an autoimmune disease affecting blood platelets that causes thrombocytopenia and an increased risk of bleeding. First-line therapy is indicated for patients with bleeding complications or who are at increased risk of bleeding, and the decision to initiate therapy depends not only on the platelet count, but also on other endpoints including quality of life. The choice of first-line therapy depends primarily on how quickly a platelet count response is required, with intravenous immune globulin providing the more rapid response, followed by high-dose dexamethasone and prednisone. In this narrative review, we discuss key issues with first-line therapy in ITP including when to initiate therapy, treatment options and special considerations for children. Evidence-based guidelines are lacking for the emergency management of patients with ITP who present with significant bleeding; we provide our approach to this critical situation.


Pregnancy-associated plasma protein-A2 (PAPP-A2): tissue expression and biological consequences of gene knockout in mice.
Pregnancy-associated plasma protein-A2 (PAPP-A2) is a novel homolog of PAPP-A in the metzincin superfamily. However, compared with the accumulating data on PAPP-A, very little is known about PAPP-A2. In this study, we determined the tissue expression pattern of PAPP-A2 mRNA in wild-type (WT) mice and characterized the phenotype of mice with global PAPP-A2 deficiency. Tissues expressing PAPP-A2 in WT mice were more limited than those expressing PAPP-A. The highest PAPP-A2 mRNA expression was found in the placenta, with abundant expression in fetal, skeletal, and reproductive tissues. Heterozygous breeding produced the expected Mendelian distribution for the pappa2 gene and viable homozygous PAPP-A2 knockout (KO) mice that were normal size at birth. The most striking phenotype of the PAPP-A2 KO mouse was postnatal growth retardation. Male and female PAPP-A2 KO mice had 10 and 25-30% lower body weight, respectively, than WT littermates. Adult femur and body length were also reduced in PAPP-A2 KO mice, but without significant effects on bone mineral density. PAPP-A2 KO mice were fertile, but with compromised fecundity. PAPP-A expression was not altered to compensate for the loss of PAPP-A2 expression, and proteolysis of PAPP-A2's primary substrate, IGF-binding protein-5, was not altered in fibroblasts from PAPP-A2 KO embryos. In conclusion, tissue expression patterns and biological consequences of gene KO indicate distinct physiological roles for PAPP-A2 and PAPP-A in mice.


Exposure of Macrophages to Low-Dose Gadolinium-Based Contrast Medium: Impact on Oxidative Stress and Cytokines Production.
The toxicity of gadolinium-based contrast agents (GBCAs) has drawn a lot of attention. Nephrogenic systemic fibrosis (NSF), a lethal disease related to the use of GBCAs, is still not understood. Recently, gadolinium retention is found in brain tissues after repeated use of GBCAs in magnetic resonance imaging (MRI). However, most of the works investigating the toxicity of GBCAs are focusing on its high-concentration (0.5-10 mM) part, which is not reflective of the physiological conditions in human beings. Macrophages play a regulatory role in immune responses and are responsible for the fibrosis process. Their role in gadolinium retention and the pathogenesis of NSF, however, has seldom been investigated. This study aimed to evaluate the immune response generated by macrophages (RAW 264.7) exposing to low levels of GBCAs. The incubation concentration of GBCAs, including Omniscan®, Primovist®, Magnevist®, and Gadovist®, is proportional to the level of gadolinium uptake when detected via inductively coupled plasma mass spectrometry (ICP-MS) and imaged by MRI, whereas Primovist® treatment groups have highest gadolinium uptake among all of the tested concentrations. Low-concentration (2.5 μmol/L) Gd chloride or GBCAs exposure promoted the reactive production of oxygen species (ROS), nitrate/nitrite, prostaglandin E2 (PGE2), and suppressed the potential of mitochondrial membrane. There was higher ROS, nitrate/nitrite, and PGE2 production in the Primovist®, Omniscan®, and Magnevist® groups compared to the Gadovist® group. In face of lipopolysaccharide (LPS) stimulation, Primovist®, Omniscan®, and Magnevist® groups exhibited elevated nitrite/nitrate and suppressed IL-1β secretion and IL-6 and IL-10 secretion. Moreover, upon LPS stimulation, there is decreased TNF-α secretion 4 hours after Primovist® or Omiscan® exposure but the TNF-α secretion increased at 24 hours. Our data suggest that there is upregulated inflammation even in the presence of low levels of GBCAs, even similar to the physiological condition in murine macrophage. Further investigation of GBCAs on the human macrophage or in vivo animal study may clarify the role of macrophage on the pathogenesis of NSF and other GBCAs-related disease.


Influence of lipid on the structure and phosphorylation of protein kinase C alpha substrate peptides.
The structure and phosphorylation of two protein kinase C (PKC) alpha substrate peptides were investigated in varying lipid systems using enzyme activity assays and circular dichroism (CD) spectroscopy. The alpha-peptide, which exhibits the typical PKC alpha substrate motif and is based on the pseudosubstrate region of PKCalpha, was phosphorylated to a similar extent in bovine brain phosphatidylserine vesicles or diheptanoylphosphatidylcholine (PC7) micelles (both with 5 mol % 1,2-dioleoyl-sn-glycerol), whereas neuromodulin (NM)-peptide, which does not exhibit this motif by virtue of its primary structure, was phosphorylated to a much lesser extent in the PC7 micellar system. CD spectra of the peptides indicated that NM-peptide underwent a dramatic structural change in the presence of dimyristoylphosphatidylserine (DMPS) vesicles, whereas spectra acquired in PC7 micelles were similar to those acquired in buffer alone. No significant structural change was observed in the alpha-peptide in the presence of either lipid. PKC activity assays conducted with a series of NM-peptides successively substituted with nitroxide spin labels at each residue position suggested that several residues distal to the phosphorylation site are necessary for substrate recognition. The effect of these substitutions is not consistent with the binding of the NM-peptide to PKC in an extended structure, but is consistent with the binding of this peptide in a helical conformation. Furthermore, the docking of a helical NM-peptide to the substrate binding site of PKC suggests that the interaction is energetically feasible. These results suggest that PKC may recognize some non-linear substrate motifs and that lipid binding may convert a protein into a better PKC substrate.


The role of industry in vascular surgery trainee education.
Vascular surgery is a specialty discipline highlighted by a lifelong learning process from which new endovascular devices and techniques will continue to emerge. Industry partnerships can provide a safe learning environment for trainees, with a focus on maximizing learning opportunities during fellowship or residency. Unlike other surgical specialties, vascular surgery empowers its trainees to become competent in both open and image-guided endovascular interventions, requiring two unique skill sets to become a contemporary vascular surgeon. Due to the rapid growth of technology and innovations, industry partnerships enhance and maximize the learning experience of the trainee by often providing the products, education, research support, and financial assistance. This can come in the form of innovative and educational activities, including simulation, exposure to thought leaders, attendance at conferences and workshops, and one-on-one assistance with cases. In this article, we review the role that industry can serve in vascular education to support budding vascular surgeons through exposure and repetition as they lay down the fundamentals of their careers.


Human Immunodeficiency Virus Infection and Hip and Knee Arthroplasty.
Modern management of human immunodeficiency virus (HIV) infection has afforded patients longevity while increasing the burden of arthroplasty procedures because of the increased risk of osteonecrosis, fragility fractures, and degenerative joint disease. Early publications on hip and knee arthroplasty in HIV-positive patients reported a high risk of complications, although some more recent publications demonstrated acceptable outcomes. Despite the widespread nature of the HIV pandemic, there is a paucity of literature addressing outcomes following joint arthroplasty in infected patients. We pooled available studies to obtain the best evidence regarding the safety of total hip and knee arthroplasty procedures in HIV-positive patients. The studies identified were heterogeneous, precluding a meta-analysis. However, we performed a review of the literature focusing on complications and outcomes. Twenty-one published English-language articles involving 6,516,186 joints were identified by a systematic review as suitable for inclusion in the study. The articles were analyzed for complication and prosthesis survivorship rates and relative risks. An overall complication rate of 3.3% was found across the 19 articles that provided such data. HIV-positive patients had a significantly elevated risk of periprosthetic joint infection, at 7.6%, compared with HIV-negative patients, at 3.3% (relative risk = 2.28, 95% confidence interval = 2.14 to 2.43). Eleven articles were suitable for analysis of prosthesis survivorship, and survivorship rates did not differ significantly between HIV-positive and negative patients. Total hip and total knee arthroplasty appear to be safe procedures with acceptable outcomes in HIV-positive patients. Therapeutic Level IV. See Instructions for Authors for a complete description of levels of evidence.


Electrospray ionization mass spectrometry analyses of nuclear membrane phospholipid loss after reperfusion of ischemic myocardium.
The role of nuclear membrane phospholipids as targets of phospholipases resulting in the generation of nuclear signaling messengers has received attention. In the present study, we have exploited the utility of electrospray ionization mass spectrometry to determine the phospholipid content of nuclei isolated from perfused hearts. Rat heart nuclei contained choline glycerophospholipids composed of palmitoyl and stearoyl residues at the sn-1 position with oleoyl, linoleoyl, and arachidonoyl residues at the sn-2 position. Diacyl molecular species were the predominant molecular subclass in the choline glycerophospholipids, with the balance of the molecular species being plasmalogens. In the ethanolamine glycerophospholipid pool from rat heart nuclei approximately 50% of the molecular species were plasmalogens, which were enriched with arachidonic acid at the sn-2 position. A 50% loss of myocytic nuclear choline and ethanolamine glycerophospholipids was observed in hearts rendered globally ischemic for 15 min followed by 90 min of reperfusion in comparisons with the content of these phospholipids in control perfused hearts. The loss of nuclear choline and ethanolamine glycerophospholipids during reperfusion of ischemic myocardium was partially reversed by the calcium-independent phospholipase A(2) (iPLA(2)) inhibitor bromoenol lactone (BEL), suggesting that the loss of nuclear phospholipids during ischemia/reperfusion is mediated, in part, by iPLA(2). Western blot analyses of isolated nuclei from ischemic hearts demonstrated that iPLA(2) is translocated to the nucleus after myocardial ischemia. Taken toghether, these studies have demonstrated that nuclear phospholipid mass decreases after myocardial ischemia by a mechanism that involves, at least in part, phospholipolysis mediated by iPLA2.


Body condition explains migratory performance of a long-distance migrant.
Body condition (i.e. relative mass after correcting for structural size) affects the behaviour of migrating birds, but how body condition affects migratory performance, timing and fitness is still largely unknown. Here, we studied the effects of relative body condition on individual departure decisions, wind selectivity, flight speed and timing of migration for a long-distance migratory shorebird, the red knot Calidris canutus rufa. By using automated VHF telemetry on a continental scale, we studied knots' migratory movements with unprecedented temporal resolution over a 3-year period. Knots with a higher relative body condition left the staging site later than birds in lower condition, yet still arrived earlier to their Arctic breeding grounds compared to knots in lower relative body condition. They accomplished this by selecting more favourable winds at departure, thereby flying faster and making shorter stops en route Individuals with a higher relative body condition in spring migrated south up to a month later than individuals in lower condition, suggesting that individuals in better condition were more likely to have bred successfully. Moreover, individuals with a lower relative body condition in spring had a lower probability of being detected in autumn, suggestive of increased mortality. The pressure to arrive early to the breeding grounds is considered to be an important constraint of migratory behaviour and this study highlights the important influence of body condition on migratory decisions, performance and potentially fitness of migrant birds.


Monoclonal antibody analysis of p53 expression in normal and transformed cells.
The cellular phosphoprotein p53 binds tightly and specifically to simian virus 40 T antigen and the 58,000-molecular-weight adenovirus E1b protein. Many human and murine tumor cell lines contain elevated levels of the p53 protein even in the absence of these associated viral proteins. Recently the cloned p53 gene, linked to strong viral promoters, has been shown to complement activated ras genes in transformation of primary rodent cell cultures. Overexpression of the p53 gene alone rescues some primary rodent cell cultures from senescence. We isolated three new monoclonal antibodies to the p53 protein, designated PAb242, PAb246, and PAb248, and mapped the epitopes they recognized on p53 in comparison with other previously isolated antibodies. At least five sterically separate epitopes were defined on murine p53. One of the antibodies, PAb246, recognizes an epitope on p53 that is unstable in the absence of bound simian virus 40 T antigen. This effect is demonstrable in vivo and in newly developed in vitro assays of T-p53 complex formation. Using the panel of anti-p53 antibodies and sensitive immunocytochemical methods, we found that p53 has a predominantly nuclear location in established but not transformed cells as well as in the vast majority of transformed cell lines. Several monoclonal antibodies to p53 showed cross-reactions with non-p53 components in immunocytochemical staining.


Exploring the Roles of Dietary Herbal Essential Oils in Aquaculture: A Review.
The aquaculture sector is one of the main activities contributing to food security for humanity around the globe. However, aquatic animals are susceptible to several farming stressors involved in deteriorated growth performance, reduced productivity, and eventually high mortality rates. In some countries still, antibiotics and chemotherapies are comprehensively applied to control biotic stressors. Aside from the apparent benefits, the continuous usage of antibiotics develops bacterial resistance, deteriorates bacterial populations, and accumulates these compounds in the aquatic environment. Alternatively, environmentally friendly additives were used to avoid the direct and indirect impacts on the aquatic ecosystem and human health. In aquaculture, medicinal herbs and extracts are extensively used and approved for their growth-promoting, anti-inflammatory, and antioxidative properties. Herbal essential oils contain many bioactive components with powerful antibacterial, antioxidative, and immunostimulant potentials, suggesting their application for aquatic animals. Essential oils can be provided via diet and can benefit aquatic animals by improving their well-being and health status. The use of essential oils in aquafeed has been studied in a variety of aquatic animals to determine their beneficial roles and optimum doses. The outputs illustrated that herbal essential oils are exciting alternatives to antibiotics with prominent growth promotion, antioxidative, and immunostimulant roles. Herein, we reviewed the beneficial roles of essential oils in aquaculture. This review also aims to describe trends in herbal essential oils use, mainly in commercial fish species, and to analyze different factors that affect essential oils' efficacy on the growth performance, antioxidative, and immune responses of finfish species.


The Role of Risk Proximity in the Beliefs and Behaviors Related to Mosquito-Borne Diseases: The Case of Chikungunya in French Guiana.
Human behaviors are increasingly recognized to play a key role in the spread of infectious diseases. Although a set of social and cognitive determinants has been consistently found to affect the adoption of health protective behaviors aiming to control and prevent a variety of infections, little is currently known about the ecological drivers of these behaviors in epidemic settings. In this article, we took advantage of the outbreak of chikungunya, a reemerging mosquito-borne disease, that occurred in French Guiana in 2014-15 to test empirically the assumption proposed by Zielinski-Gutierrez and Hayden that the proximity of the disease and perceptions of the natural environment may considerably shape public response to an emerging health threat. To achieve this, a cross-sectional survey was conducted among high school students of the region (N = 1462) at an early stage of the epidemic. Surprisingly, spatial analysis of the collected data leads to counterintuitive results as the participants who lived in the most affected area expressed less concern about the disease and practiced preventive behaviors less frequently than did other participants. These paradoxical results may be attributed to the possible activation of risk denial processes which have previously been observed in the risk perception literature, and described by several social and psychological defensiveness theories.