Role of the basolateral amygdala and NMDA receptors in higher-order conditioned fear.
Laboratory rats learn to fear relatively innocuous stimuli which signal the imminent arrival of an innate source of danger, typically brief but aversive foot shock. Much is now known about the neural substrates underlying the acquisition, consolidation and subsequent expression of this fear. Rats also learn to fear stimuli which signal learned sources of danger but relatively little is known about the neural substrates underlying this form of fear. Two Pavlovian conditioning paradigms used to study this form of fear are second-order conditioning and sensory preconditioning. In second-order conditioning, rats are first exposed to a signaling relationship between one stimulus, such as a tone, and aversive foot shock, and then to a signaling relationship between a second stimulus, such as a light, and the now dangerous tone. In sensory preconditioning, these phases are reversed: rats are first exposed to a signaling relationship between the light and the tone and then to a signaling relationship between the tone and the foot shock. In both paradigms, rats exhibit fear when tested with the light. In this review paper, we describe the evidence for higher-order forms of conditioning, the conditions which promote this learning and its contents. We compare and contrast the substrates of the learning underlying second-order and sensory preconditioning fear with those known to underlie the better studied first-order conditioned fear. We conclude with some comments as to the role of higher-order processes in anxiety disorders.


["Pharaoh" line culture of Japanese quail cells as a leukosis-free system for virus reproduction].
Contamination of Japanese quail, strain Pharaoh, cell culture with oncogenous and infectious avian viruses was studied. The susceptibility of the embryonal cell cultures of the Japanese quail, strain Pharaoh, to measles, parotitis and fixed rabies viruses was also determined. It was found that the sera of pubertal quails had no antibody to Rous sarcoma virus (RSV), strains Brian, RSV (RAV-1), Schmidt-Ruppin, Carr-Zilber, as well as to Marek's disease and Newcastle disease viruses. No reverse transcriptase activity was detected in the embryonal alantoic fluid of this avian species. The quails were less susceptible, as compared to the chicken, to Schmidt-Ruppin and Carr-Zilber strains of RSV. Measles, parotitis and fixed rabies viruses reproduced actively in the Japanese quail, Pharaoh strain, embryonal cell cultures. It is suggested that the embryonal cell cultures of this avian species can be used as a leukemia-free substrate for experimental studies and manufacturing of viral vaccines.


Predictors of obesity in Michigan Operating Engineers.
Blue collar workers are at risk for obesity. Little is known about obesity in Operating Engineers, a group of blue collar workers, who operate heavy earth-moving equipment in road building and construction. Therefore, 498 Operating Engineers in Michigan were recruited to participate in a cross-sectional survey to determine variables related to obesity in this group. Bivariate and multivariate analyses were conducted to determine personal, psychological, and behavioral factors predicting obesity. Approximately 45% of the Operating Engineers screened positive for obesity, and another 40% were overweight. Multivariate analysis revealed that younger age, male sex, higher numbers of self-reported co-morbidities, not smoking, and low physical activity levels were significantly associated with obesity among Operating Engineers. Operating Engineers are significantly at risk for obesity, and workplace interventions are needed to address this problem.


Alcohol drinking and lung cancer risk: an evaluation based on a systematic review of epidemiologic evidence among the Japanese population.
The relationship between alcohol consumption and risk of lung cancer is controversial. Based on a systematic review of epidemiologic evidence, we evaluated this association among the Japanese population, who may be more susceptible to alcohol-related diseases than Western populations. Original data were obtained from MEDLINE searches using PubMed or from searches of the Ichushi database, complemented with manual searches. The evaluation of associations was based on the strength of evidence and the magnitude of association, together with biological plausibility as previously evaluated by the International Agency for Research on Cancer. We identified seven cohort studies and two case-control studies. One cohort study demonstrated a strong positive association between alcohol drinking and the risk of female lung cancer, but the association almost disappeared after adjustment for smoking. The other eight studies showed a weak positive or no association. Although smoking is the best-established risk factor for lung cancer, only five cohort studies presented smoking-adjusted risks out of all nine identified. Furthermore, only two studies explicitly reported the risk estimate for ex-drinkers who may have quit alcohol drinking after the development or diagnosis of the disease and have an apparently higher risk. We conclude that the epidemiologic evidence on the association between alcohol drinking and lung cancer risk remains insufficient in terms of both the number and methodological quality of studies among the Japanese population.


Specificity of transposon Tn5 insertion.
Genetic mapping studies had shown that the bacterial transposon Tn5 can insert into many sites in a gene, but that some sites are preferred. To begin understanding Tn5's insertion specificity at the molecular level, we selected transpositions of Tn5 from the Escherichia coli chromosome to the plasmid pBR322 and analyzed the resultant pBR322::Tn5 plasmids by restriction endonuclease digestion and DNA sequencing. Seventy-five insertions in the tet gene were found at 28 sites including one major hotspot (with 21 insertions) and four lesser hotspots (with four to ten insertions each). All five hotspots are within the first 300 of the 1250-base pair (bp) tet gene. In contrast, 31 independent insertions in the amp gene were found in at least 27 distinct sites.--Tn5 generates 9 bp target sequence duplications when it transposes. Such transposon-induced duplications are generally taken to indicate that cleavages of complementary target DNA strands are made 9 bp apart during transposition. DNA sequence analysis indicated that GC base pairs occupy positions 1 and 9 in the duplications at each of the five hotspots examined, suggesting a GC-cutting preference during Tn5 transposition.


Mental health and quality of life in deaf pupils.
In the past decade, the living conditions of hearing impaired children have been changing due to new technologies and mainstreaming in schools. The majority of population-based studies in deaf pupils were conducted before these changes started to take place. The present study aimed to evaluate the current situation regarding aspects of mental health and, for the first time, quality of life in a representative sample of deaf pupils. The sample stems from a population of 145,000 pupils attending the first to ninth grades during the school years 2003-2005 in Upper Austria. From 186 children with bilateral hearing impairment of at least 40 dB registered at the centre for special education for children with sensory impairments, 99 with a performance IQ above 70 were included in the present study. Parents and teachers completed the strengths and difficulties questionnaire (SDQ), while parents and children were administered the inventory for the assessment of the quality of life in children and adolescents (ILC). Results indicated that deaf children scored significantly higher on the SDQ than their counterparts from normative samples according to both parent and teacher ratings. Differences were most marked with regard to conduct problems, emotional problems, and peer problems, and less marked for hyperactivity/inattention. While parents of deaf children had a generally positive view of their children's quality of life, deaf children provided a more complex picture, stressing areas of dissatisfaction. Mental health and quality of life were found to be unrelated to the child's degree of deafness.


A comparison of gene transcription profiles of domesticated and wild Atlantic salmon (Salmo salar L.) at early life stages, reared under controlled conditions.
Atlantic salmon have been subject to domestication for approximately ten generations, beginning in the early 1970s. This process of artificial selection will have created various genetic differences between wild and farmed stocks. Each year, hundreds of thousands of farmed fish escape into the wild. These escapees may interbreed with wild conspecifics raising concerns for both the fish-farming industry and fisheries managers. Thus, a better understanding of the interactions between domesticated and wild salmon is essential to the continued sustainability of the aquaculture industry and to the maintenance of healthy wild stocks. We compared the transcriptomes of a wild Norwegian Atlantic salmon population (Figgjo) and a Norwegian farmed strain (Mowi) at two life stages: yolk sac fry and post first-feeding fry. The analysis employed 44 k oligo-microarrays to analyse gene expression of 36 farmed, wild and hybrid (farmed dam x wild sire) individuals reared under identical hatchery conditions. Although some of the transcriptional differences detected overlapped between sampling points, our results highlighted the importance of studying various life stages. Compared to the wild population, the Mowi strain displayed up-regulation in mRNA translation-related and down regulation in nervous and immune system -related pathways in the sac fry, whereas up-regulation of digestive and endocrine activities, carbohydrate, energy, amino acid and lipid metabolism and down-regulation of environmental information processing and immune system pathways were evident in the feeding fry. Differentially regulated pathways that were common among life stages generally belonged to environmental information processing and immune system functional groups. In addition, we found indications of strong maternal effects, reinforcing the importance of including reciprocal hybrids in the analysis. In agreement with previous studies we showed that domestication has caused changes in the transcriptome of wild Atlantic salmon and that many of the affected pathways are life-stage specific We highlighted the importance of reciprocal hybrids to the deconvolution of maternal/paternal effects and our data support the view that the genetic architecture of the strains studied highly influences the genes differentially expressed between wild and domesticated fish.


Recent developments in heterocycle labeling with carbon isotopes.
Heterocycles play an essential role in modern pharmaceutical and agrochemical developments, representing a very common structural unit in marketed drugs. Over the 46 new drugs approved in 2017 by the FDA, 25 contain in their structure a heterocyclic core. The development of novel and straightforward labeling strategies for the effective insertion of carbon isotopes into heterocylic scaffolds is an inspiring and vibrant field of research. The use of carbon-11, carbon-13, and carbon-14 isotopes is well established in life science and particularly in pharmaceutical and agrochemical industry. Their introduction into small organic molecules represents a crucial step for the radiochemists. Because the labeling should occur in metabolically stable positions and in the shortest synthetic route, their incorporation into the heterocycles represents a viable solution. This review summarizes recent contributions to this area of research through the analysis of different industrial and academic cases.


Toxic hazard of leachates from furfurylated wood: comparison between two different aquatic organisms.
Environmental concern regarding the use of toxic preservatives such as chromated copper arsenate (CCA) has been put forward. In the European Union, United States, and Japan, CCA has been phased out for residential and water-contact applications. Ecotoxicological studies of wood treated with conventional preservatives were carried out in the late 1990s, and it was concluded that the main impact is to water and aquatic organisms. Today, alternatives to conventional preservation methods, marketed as "environmentally friendly" or "nontoxic," are emerging. Examples of such alternatives are modified wood, e.g., thermally modified, furfurylated, and acetylated wood. To date, not enough hazard characterization has been performed. In the present study, the Microtox assay with the marine bacterium Vibrio fischeri and the Daphtox procedure with the crustacean Daphnia magna were used as screening methods in an effect assessment. Both organisms were exposed to water leachates from furfurylated wood using two different leaching procedures. The results indicate that Microtox is more sensitive to the toxic components from furfurylated wood than Daphtox. Furthermore, the toxicity of treated Pinus radiata was higher than that of treated Pinus sylvestris. The toxicity did not diminish over the test period, as is the case for preservative-treated wood. The present study found that treatment conditions can influence the toxicity considerably, so toxicity studies should be included in the development of new treatment process. The present study also shows that using an intermediate vacuum-drying step, leading to a more efficient curing/polymerization, results in slightly less hydrophobic oligomers in the product, such that the leachates become less toxic to bacteria.


Clinical emergence of entecavir-resistant hepatitis B virus requires additional substitutions in virus already resistant to Lamivudine.
Entecavir (ETV) exhibits potent antiviral activity in patients chronically infected with wild-type or lamivudine (3TC)-resistant (3TC(r)) hepatitis B virus (HBV). Among the patients treated in phase II ETV clinical trials, two patients for whom previous therapies had failed exhibited virologic breakthrough while on ETV. Isolates from these patients (arbitrarily designated patients A and B) were analyzed genotypically for emergent substitutions in HBV reverse transcriptase (RT) and phenotypically for reduced susceptibility in cultures and in HBV polymerase assays. After 54 weeks of 3TC therapy, patient A (AI463901-A) received 0.5 mg of ETV for 52 weeks followed by a combination of ETV and 100 mg of 3TC for 89 weeks. Viral rebound occurred at 133 weeks after ETV was started. The 3TC(r) RT substitutions rtV173L, rtL180M, and rtM204V were present at study entry, and the additional substitutions rtI169T and rtM250V emerged during ETV-3TC combination treatment. Reduced ETV susceptibility in vitro required the rtM250V substitution in addition to the 3TC(r) substitutions. For liver transplant patient B (AI463015-B), previous famciclovir, ganciclovir, foscarnet, and 3TC therapies had failed, and RT changes rtS78S/T, rtV173L, rtL180M, rtT184S, and rtM204V were present at study entry. Viral rebound occurred after 76 weeks of therapy with ETV at 1.0 mg, with the emergence of rtT184G, rtI169T, and rtS202I substitutions within the preexisting 3TC(r) background. Reduced susceptibility in vitro was highest when both the rtT184G and the rtS202I changes were combined with the 3TC(r) substitutions. In summary, infrequent ETV resistance can emerge during prolonged therapy, with selection of additional RT substitutions within a 3TC(r) HBV background, leading to reduced ETV susceptibility and treatment failure.


[Fingerprints of Curcuma wenyujin by RP-HPLC].
To establish a mutual mode fingerprint of Curcuma wenyujin for quality control of C. wenyujin. Waters Symmetry C18 column was used; the mobile phase was methanol-water in a linear gradient elution with the flow rate of 1.0 mL/ min, the temperature of column was 30 degrees C; the detection wavelength was set at 215 nm. 10 batches of C. wenyujin from different places and different time were determined, 3 batches of C. phaeocaulis and 3 batches of C. kwangsiensis were determined in the same chromatographic conditions. 11 mutual peaks in the fingerprint of the 10 groups of C. wenyujin, and the S peak among them represented germacrone. Curcuma wenyujin's fingerprints have strong feature and specificity, which can be combined with assaying in the quality control of C. wenyujin.


[Change in survival of cells in the first 2 generations after irradiation and exposure to inhibitors of repair synthesis].
In experiments on asynchronous population of HeLa S3 cells a study was made of the possibility of assessing DNA lesions which remained unrepaired for a long period of time following gamma-irradiation: in generation "O" directly affected by radiation and in generation "I" following the irradiated one. The presence of DNA damages was estimated by the reduction in survival of exposed cells incubated with inhibitors of repair and replicative syntheses of DNA, namely, with arabinoside cytosine and hydroxyurea. A considerable enhancement of the radiation effect was noted with the inhibitors added 0-6 h after irradiation (generation "O"), and a marked increase in the cell death was registered with the preparations injected 24-30 h after exposure (generation "I"). It is assumed that minor residual lesions persist in the generation of cells, following the one directly affected by gamma-radiation, which have completed the first postirradiation mitosis.


Charge density effects on the aggregation properties of poly(p-phenylene-ethynylene)-based anionic polyelectrolytes.
This work shows that low charge density poly(p-phenylene-ethynylene)s (PPE-SO3Na-L and PPE-CO2Na-L), which feature sulfonate and carboxylate groups on every other phenyl ring, form aggregates in water, whereas high charge density poly(p-phenylene-ethynylene)s (PPE-SO3Na-H and PPE-CO2Na-H), which possess sulfonate or carboxylate groups on every phenyl ring, do not aggregate in water. The formation of aggregates of PPE-SO3Na-L and PPE-CO2Na-L is demonstrated by comparing the concentration and temperature dependence of their steady-state spectra in water to that in DMSO, in which the two polymers do not aggregate. For the weak polyelectrolytes PPE-CO2Na-H and PPE-CO2Na-L, the solution pH was changed to vary the charge density. In addition, the cationic surfactant, octadecyltrimethyl ammonium, is shown to dissociate the low charge density polymer aggregates and to form supramolecular complexes with each of the different polyelectrolytes. Fluorescence correlation spectroscopy was applied to provide insight into the sizes of aggregates under different solution conditions.


Environmental bisphenol A exposure triggers trained immunity-related pathways in monocytes.
Trained Immunity represents a novel revolutionary concept of the immunological response involving innate immune cells. Bisphenol A is a well-known endocrine disrupter, widely disseminated worldwide and accumulated in the human body. Due to the increased interest regarding the effects of plastic-derived compounds on the immune system, our purpose was to explore whether BPA was able to induce trained immunity in human primary monocytes in vitro using low environmental concentrations. We extracted BPA from the serum of 10 healthy individuals through a liquid-liquid extraction followed by a solid phase extraction and measured the concentration using an HPLC system coupled to a triple quadrupole mass spectrometer. In parallel, monocytes were isolated from whole blood and acutely stimulated or trained with BPA at three different concentrations (1 nM, 10 nM, 20 nM). Pro- and anti-inflammatory cytokines (IL-1β, TNF-α, IL-6, and IL-10) production were assessed after 24 hours of acute stimulation and after Lipopolysaccharide (LPS) rechallenge. A comprehensive overview of the metabolic changes after BPA acute stimulation and trained immunity induction was assessed through extracellular lactate measurements, Seahorse XFb metabolic flux analysis and ROS production. Monocytes primed with BPA showed increased pro- and anti-inflammatory cytokine responses upon restimulation, sustained by the modulation of the immunometabolic circuits. Moreover, we proved the non-toxic effect of BPA at each experimental concentration by performing an MTT assay. Additionally, correlation analysis were performed between pro- and anti-inflammatory cytokines production after LPS acute stimulation or BPA-mediated trained immunity and BPA serum concentrations showing a significant association between TNF-α and BPA circulating levels. Overall, this study pointed out for the first time the immunological effects of an environmental chemical and plastic-derived compound in the induction of trained immunity in a healthy cohort.


Comparative performance assessment in managed care: data envelopment analysis for health care managers.
In health care markets increasingly dominated by managed care, health care managers need sophisticated yet understandable comparative performance assessment methods. Ideally, these methods should provide targets for the managers to improve program or organization performance. This article reviews three comparative performance methodologies with a comprehensive explanation of data envelopment analysis (DEA). DEA is a form of linear programming that allows for the inclusion of multiple input and output/outcome performance variables from a virtually unlimited number of organizations, facilitating meaningful health service provider comparative assessments.


Efficacy and safety of aprotinin in paediatric cardiac surgery: A systematic review and meta-analysis.
The relicensing of aprotinin in Europe and Canada has stimulated discussions on its usefulness in paediatric cardiac surgery. To systematically evaluate the available evidence on the efficacy and safety of aprotinin in paediatric cardiac surgery. Systematic review of all randomised and observational studies comparing aprotinin with tranexamic acid, epsilon aminocaproic acid, placebo or no drug in paediatric cardiac surgery. Meta-analyses were performed on efficacy and safety outcomes. PubMed, Cochrane Central Register of Controlled Trials, Web of Science and Embase were searched from January 2000 to March 2021. Studies that enrolled children under 18 years undergoing cardiac surgery with cardiopulmonary bypass. Thirty-two studies enrolling a total of 63 894 paediatric cardiac procedures were included. Aprotinin significantly reduced total blood loss [mean difference -4.70 ml kg-1, 95% confidence interval (CI), -7.88 to -1.53; P = 0.004], postoperative transfusion requirements and the incidence of surgical re-exploration for bleeding [odds ratio (OR) 0.74, 95% CI, 0.56 to 0.97; P = 0.03]. Aprotinin had no effects on 30-day mortality (OR 1.02, 95% CI, 0.93 to 1.11; P = 0.73) and on other safety outcomes, except for the incidence of renal replacement therapy (RRT), which was significantly increased in patients given aprotinin (OR 1.29, 95% CI, 1.08 to 1.54; P = 0.006). Findings from observational and randomised controlled trials did not largely differ. A sub-group analysis in neonates showed that aprotinin significantly reduced packed red blood cell transfusions and the incidence of postoperative surgical re-exploration for bleeding and/or tamponade. When compared with lysine analogues, aprotinin was more effective at reducing bleeding and transfusion without increasing the risk of side effects. This meta-analysis suggests that aprotinin is effective and well tolerated in paediatric cardiac surgery. Given the large heterogeneity of the results and the risk of selection bias in observational studies, large randomised controlled trials are warranted.


Impact of magnetic resonance imaging in management of pediatric Crohn's disease.
Crohn's disease (CD) is a chronic illness and radiographic evaluation is frequently used. Consequently, pediatric patients with CD who are diagnosed in childhood are at risk for high levels of radiation exposure during their lifetimes. We sought to evaluate the impact of magnetic resonance enterography (MRE) in management of pediatric patients with known or suspected Crohn's disease. A retrospective review of patients with known or suspected CD who underwent MRE for new onset of symptoms was conducted. All demographic data, clinical history, and results of all radiographic, endoscopic, and pathology studies were recorded. Twenty-eight patients with known or suspected CD underwent 31 MRE examinations. MRE showed active disease in 16 (52%), fistula or abscess in seven (22%), and no evidence of active disease in eight (26%). Sixty-five per cent of patients underwent MRE with no other radiation-based imaging used. Surgical intervention was deemed necessary after the MRE in 16 per cent. In all cases, surgical findings were consistent with MRE results. Nearly 60 per cent of patients with CD are managed based on the findings of MRE without additional radiographic evaluation. Based on the results of this retrospective study, we propose a clinical pathway for use of MRE in patients with known or suspected CD with new onset of symptoms.


Role of electronic factors in binding and reduction of azo dyes by hepatic microsomes.
The factors which regulate the binding and reduction of azo dyes by rat liver microsomes have been investigated. Azo dyes having both electron-donating and -withdrawing substituents were reduced more readily both enzymically and chemically (dithionite) than those containing electron-donating substituents alone, which is consistent with less negative oxidation-reduction potentials of the former. A linear correlation between Vmax and Km was seen for substrates having only electron-donating substituents, suggesting a possible inverse relation between binding affinity and rate of reduction. This relationship was not apparent for substrates having both electron-donating and -withdrawing substituents. A lower Km was seen with substrates having a greater number of heteroatoms bearing nonbonding electrons in either electron-donating or -withdrawing groups. Furthermore, more basic dyes, which have a higher density of nonbonding electrons, showed an inverse correlation with both Vmax and Km. The requirement of nonbonding electrons was also observed with the binding of the fully reduced amine metabolites to microsomal cytochrome P-450. Type II binding spectra were observed for both aniline and 4-chloroaniline, but not with aniline derivatives bearing electron-withdrawing substituents such as methyl anthranilate and methyl-4-aminobenzoate. Electron-withdrawing substituents increase delocalization of nonbonding electrons on the amino residue; consequently, these are no longer available for binding to the enzyme. The binding constant of the reduced metabolite, aniline (36 microM), relative to the Km values of substrate azo dyes (range 0.31-1.73 microM) implies that the more weakly bound amine metabolites are readily released from the binding/catalytic site.(ABSTRACT TRUNCATED AT 250 WORDS)


Mephedrone: use, subjective effects and health risks.
To assess the patterns of use, subjective effect profile and dependence liability of mephedrone, supported by corroborative urine toxicology. Cross-sectional structured telephone interview. UK-based drug users associated with the dance music scene. A total of 100 mephedrone users, recruited through their involvement with the dance music scene. Assessment of pattern of use, acute and after effects, DSM dependence criteria and gas chromatography-mass spectrometry urinalysis. Mephedrone consumption results in typical stimulant-related subjective effects: euphoria, increased concentration, talkativeness, urge to move, empathy, jaw clenching, reduced appetite and insomnia. Thirty per cent of the sample potentially met criteria for DSM-IV dependence and there was evidence of a strong compulsion to use the drug (47% had used the drug for 2 or more consecutive days). Self-reported recent consumption of mephedrone was confirmed by toxicological analysis in all of the 14 participants who submitted a urine sample. Mephedrone has a high abuse and health risk liability, with increased tolerance, impaired control and a compulsion to use, the predominant reported dependence symptoms.


Osteogenic Melanoma With Desmin Expression.
Osteogenic differentiation is rarely seen in melanomas, when it occurs it is mainly in acral lesions. We report a case of an osteogenic melanoma in a 49-year-old woman who presented with a pigmented lesion in the subungueal region of her left hallux. The lesion was ulcerated and infiltrated until the deep dermis without bone involvement. The tumor was composed of pleomorphic atypical epithelioid and fusiform cells disposed in nests or cords, with vesicular nuclei and prominent central nucleoli. Focal lentiginous proliferation of large atypical melanocytes was present along the dermoepidermal junction. Areas of osteoid matrix focally mineralized were disposed in trabeculae, and there were islands of neoplastic cells. Immunohistochemistry revealed strong expression of S-100 protein and, unexpectedly, of desmin. Focal expression of Melan-A, microphthalmia transcription factor, and HMB-45 is also revealed. Mutations in BRAF and NRAS genes were not present. The patient was submitted to an amputation of the left hallux with negative sentinel lymph node. The importance of recognizing osteogenic melanoma is based on difficulties for histologic recognition and its differentials diagnosis.


Extract of Rhus verniciflua stokes protects the diet-induced hyperlipidemia in mice.
Rhus verniciflua stokes (RVS) is a popular medicinal plant in oriental medicines which is commonly used to resolve extravasated blood. To elucidate the molecular mechanism of the role of RVS extracts on the regulation of lipid and cholesterol biosynthesis, we investigated whether RVS extract protect the hyperlipidemia in western diet-induced C57BL6/J mice. Mice fed a western diet and additionally RVS extracts was administered orally at a dose of 0.1 or 1 g/kg/day for 2 weeks respectively. Group with higher dose of RVS extract showed a significantly decreased body weight compared with western diet fed mice groups. And total cholesterol, LDL-cholesterol levels and fatty liver formation were also improved especially in group of mice fed western diet supplemented high dose RVS extracts. Next, synthesis of hepatic bile acids were significantly increased in RVS extract fed groups. Furthermore, RVS extracts significantly increase promoter activity of Cyp7a1 via up-regulate the transcriptional expression level of LXRα. Our data suggest that RVS extracts could be a potent therapeutic ingredient for prevent a hyperlipidemia via increase of bile acids biosynthesis.


The eastern part of the Fertile Crescent concealed an unexpected route of olive (Olea europaea L.) differentiation.
Olive is considered a native plant of the eastern side of the Mediterranean basin, from where it should have spread westward along the Mediterranean shores, while little is known about its diffusion in the eastern direction. Genetic diversity levels and population genetic structure of a wide set of olive ecotypes and varieties collected from several provinces of Iran, representing a high percentage of the entire olive resources present in the area, was screened with 49 chloroplast and ten nuclear simple sequence repeat markers, and coupled with archaeo-botanical and historical data on Mediterranean olive varieties. Approximate Bayesian Computation was applied to define the demographic history of olives including Iranian germplasm, and species distribution modelling was performed to understand the impact of the Late Quaternary on olive distribution. The results of the present study demonstrated that: (1) the climatic conditions of the last glacial maximum had an important role on the actual olive distribution, (2) all Iranian olive samples had the same maternal inheritance as Mediterranean cultivars, and (3) the nuclear gene flow from the Mediterranean basin to the Iranian plateau was almost absent, as well as the contribution of subspecies cuspidata to the diversity of Iranian olives. Based on this evidence, a new scenario for the origin and distribution of this important fruit crop has been traced. The evaluation of olive trees growing in the eastern part of the Levant highlighted a new perspective on the spread and distribution of olive, suggesting two routes of olive differentiation, one westward, spreading along the Mediterranean basin, and another moving towards the east and reaching the Iranian plateau before its domestication.


Targeting stroke treatment to the individual.
Stroke motor rehabilitation is typically generic rather than being tailored to the individual and yet individuals may require different rehabilitation strategies according to the brain regions and networks damaged by the stroke and the impact of the lesion on remote locations and networks. Training may be targeted at facilitating neuroplasticity of these networks and towards utilizing the residual architecture that may be accessed in therapy. Careful analysis of the impact of the lesion on brain networks as well as knowledge of viable brain networks, via in vivo neuroimaging technologies has potential to guide rehabilitation clinicians in individualized stroke rehabilitation. More studies are needed, which combine knowledge of the integrity of brain regions and networks with measures of motor deficit and/or effectiveness of learning-based interventions to inform the direction for individualized therapy.


Mental illness and Irish people: stereotypes, determinants and changing perspectives.
The causes of psychological illness in Irish people have been identified with colonial rule and the catastrophic conditions deriving from famine in the nineteenth century. In particular, the scourge of unremitting emigration, resulting from famine, has formed a background against which speculative theories of inferiority, alienation and mental illness have been constructed. In particular, the long standing idea that Irish people exhibit higher rates of schizophrenia, both in Ireland and abroad, is discussed. Contemporary studies which suggest that these elevated rates do not correspond to international diagnostic criteria for schizophrenia are introduced. Rather, these enhanced rates may reflect a malaise which resembles schizophrenia but which is really a product of historical dispossession. The importance of these factors is underscored by the previous neglect of Irish people, considered as an ethnic minority, as well as the particular distaste which many Irish people display towards such a notion.


The heterodimerization domains of MLL-FYRN and FYRC--are potential target structures in t(4;11) leukemia.
The chromosomal translocation t(4;11)(q21;q23) is a frequent genetic aberration of the mixed lineage leukemia (MLL) gene, predominantly associated with high-risk acute lymphoblastic leukemia (ALL) in pediatric patients. Previous studies demonstrated that mice transplanted with hematopoietic cells expressing the AF4-MLL fusion protein develop proB ALL. The AF4-MLL oncoprotein becomes activated by Taspase1-mediated hydrolysis, which subsequently leads to a heterodimer of the cleavage products AF4-MLL·N and MLL·C. This protein-protein interaction is due to the FYRN and FYRC interaction domains present in both protein fragments. Heterodimerization subsequently induces high-molecular-weight protein complex formation that is protected against SIAH1/2-mediated polyubiquitinylation. Here, we attempted to selectively block this initial heterodimerization step, aiming to prevent the oncogenic activation of the AF4-MLL multiprotein complex. The minimal interaction interface was experimentally defined first in a bacterial two-hybrid system, and then in mammalian cells by using a biosensor assay. Expression of the FYRC domain, or smaller portions thereof, resulted in the inhibition of heterodimer formation, and blocked AF4-MLL multiprotein complex formation with subsequent destruction of the AF4-MLL oncoprotein. Thus, it is in principle possible to specifically target the AF4-MLL protein. This knowledge can now be exploited to design inhibitory decoys in order to destroy the AF4-MLL oncoprotein.


Selective autophagy regulates heat stress memory in Arabidopsis by NBR1-mediated targeting of HSP90.1 and ROF1.
In nature, plants are constantly exposed to many transient, but recurring, stresses. Thus, to complete their life cycles, plants require a dynamic balance between capacities to recover following cessation of stress and maintenance of stress memory. Recently, we uncovered a new functional role for macroautophagy/autophagy in regulating recovery from heat stress (HS) and resetting cellular memory of HS in Arabidopsis thaliana. Here, we demonstrated that NBR1 (next to BRCA1 gene 1) plays a crucial role as a receptor for selective autophagy during recovery from HS. Immunoblot analysis and confocal microscopy revealed that levels of the NBR1 protein, NBR1-labeled puncta, and NBR1 activity are all higher during the HS recovery phase than before. Co-immunoprecipitation analysis of proteins interacting with NBR1 and comparative proteomic analysis of an nbr1-null mutant and wild-type plants identified 58 proteins as potential novel targets of NBR1. Cellular, biochemical and functional genetic studies confirmed that NBR1 interacts with HSP90.1 (heat shock protein 90.1) and ROF1 (rotamase FKBP 1), a member of the FKBP family, and mediates their degradation by autophagy, which represses the response to HS by attenuating the expression of HSP genes regulated by the HSFA2 transcription factor. Accordingly, loss-of-function mutation of NBR1 resulted in a stronger HS memory phenotype. Together, our results provide new insights into the mechanistic principles by which autophagy regulates plant response to recurrent HS.Abbreviations: AIM: Atg8-interacting motif; ATG: autophagy-related; BiFC: bimolecular fluorescence complementation; ConA: concanamycinA; CoIP: co-immunoprecipitation; DMSO: dimethyl sulfoxide; FKBP: FK506-binding protein; FBPASE: fructose 1,6-bisphosphatase; GFP: green fluorescent protein; HS: heat stress; HSF: heat shock factor; HSFA2: heat shock factor A2; HSP: heat shock protein; HSP90: heat shock protein 90; LC-MS/MS: Liquid chromatography-tandem mass spectrometry; 3-MA: 3-methyladenine; NBR1: next-to-BRCA1; PQC: protein quality control; RFP: red fluorescent protein; ROF1: rotamase FKBP1; TF: transcription factor; TUB: tubulin; UBA: ubiquitin-associated; YFP: yellow fluorescent protein.


Vascular access devices in leukemia: a retrospective review amongst patients treated at the Ottawa Hospital with induction chemotherapy for acute leukemia.
Patients with acute leukemia require reliable central vascular access to ensure delivery of intravenous therapy. Peripherally inserted central catheters (PICCs) and Hickman(®) catheters are two commonly inserted central vascular catheters (CVCs), providing access to the central vascular space. While there have been reports describing individual center experiences, no one has compared the two devices, retrospectively or prospectively. We analyzed patients diagnosed with acute leukemia between September 1996 and April 2009, who had a PICC or Hickman®, received induction chemotherapy and survived at least 20 days. Prior to 1 January 2007, PICCs were inserted by palpation (PICC-palp) and Hickman(®) catheters were inserted surgically (H-Surg). After this date, PICCs were inserted by ultrasound (PICC-U/S) and Hickman(") catheters were inserted by interventional radiology (H-IR). Fifty-five patients had a Hickman(®) catheter (18 H-Surg, 37 H-IR) and 92 patients had a PICC (69 PICC-palp, 23 PICC-U/S). Significant improvements from H-Surg to H-IR catheters include the reduction in exit-site inflammation and infection (27.8% to 5.4%) and in bacteremic episodes (72.2% to 27.0%). Compared to PICC-U/S, H-IR had fewer cases of thrombophlebitis (0.0% vs. 8.7%); H-IR also required fewer instillations of a thrombolytic agent than the PICC-U/S (8.1% vs. 69.6%). Both CVCs have shown improvements from pre- to post-2007 insertion methods. Our data suggest that there were fewer complications with post-2007 Hickman(®) catheters compared to PICCs, suggesting that Hickman® catheters provide a more reliable central vascular access in these patients.


Association of HTRA1 and CFH gene polymorphisms with age-related macular degeneration in Ningbo, China.
Age-related macular degeneration (AMD) is one of the major causes of blindness, and the incidence of this disease has been increasing in recent years. To investigate the association between the single nucleotide polymorphisms (SNPs) of the high temperature requirement factor A-1 (HTRA1) and complement factor H (CFH) genes and susceptibility to AMD in Ningbo, China. Ninety-eight patients with AMD and seventy-three controls were recruited at the Sixth Hospital of Ningbo from August 2017 to April 2019 in China. Genomic DNA was extracted from the venous blood provided by the hospital, and the genotypes of the AMD susceptibility genes CFH and HTAR1 were detected by polymerase chain reaction and sequenced directly. The SNPs rs11200638 on the HTRA1 gene and rs3753394 on the CFH gene were selected for genotype and association analysis. The correlations between the different genotypes of HTRA1 and CFH and AMD were analysed by the Chi-squared test. All the genotypes adhered to the Hardy-Weinberg equilibrium. There were three genotypes (AA, AG and GG) in HTRA1 (rs11200638). The differences in genotypes and allele frequency between the AMD group and the control group were statistically significant (P < 0.05). The A allele was a risk allele (OR: 4.19, 95% Cl: 2.28 ~ 7.70, P < 0.05), with a frequency of 61.7% in patients versus 43.8% in controls. However, the rs3753394 SNP in CFH was not associated with AMD in our study (P > 0.05). The rs11200638 SNP of the HTRA1 gene is associated with AMD, and the AA genotype is a risk factor for AMD in the Ningbo population. There is no significant correlation between the rs3753394 SNP of the CFH gene and AMD.


Regulation of norepinephrine levels in synaptic clefts of dog vascular tissue.
The overflow of endogenous norepinephrine (NE) from superfused dog pulmonary artery and saphenous vein in response to electrical stimulation and the content of NE remaining in the tissue after stimulation were measured using liquid chromatography with electrochemical detection. Overflow of NE was 0.15-0.22 and 0.14 to 0.30 ng/min in pulmonary artery and saphenous vein, respectively, during stimulation. Release of NE (measured in the presence of cocaine and corticosterone to block removal of NE from the synaptic cleft) was greater in the pulmonary artery (0.50-0.87 ng/min) than in saphenous vein (0.39-0.51 ng/min). NE overflow decreased after the first 4 min of continuous stimulation in saphenous vein but not in pulmonary artery. As only 2.26% of the NE content of vein overflowed during stimulation, depletion of NE or deterioration of the preparation seemed unlikely. Presynaptic alpha- or beta-receptor blockade did not change the pattern of NE overflow. Thus in the saphenous vein, but not in the pulmonary artery, removal of NE from the synaptic cleft appears to be facilitated during electric stimulation. This suggests the existence of a new mechanism, possibly related to enhanced catechol methyltransferase activity, which regulates NE levels in the synaptic cleft in saphenous vein but not in pulmonary artery.


Sweet DREAMs for Hippo.
The Hippo pathway coordinates organ size and cell proliferation. The retinoblastoma family of proteins regulates progression through the G0/G1 phase of the cell cycle. Disruption of either pathway contributes to cancer formation. Three recent studies in Genes & Development reveal how cellular proliferation is coordinated between these pathways. Here we discuss the implications of these studies and the new questions that they raise.


Effects of diabetes on cardiac contractile proteins in rabbits and reversal with insulin.
In rats, chronic diabetes is associated with depressed cardiac myosin ATPase activity and a shift from the predominant V1 isoenzyme to V3, correlating with depressed contractility. Rabbit myocardium consists mostly of the V3 isoenzyme, and therefore a switch to even more V3 isoenzyme in diabetes might not be possible and therefore not explain the mechanical abnormalities observed. To explore this, rabbits were made diabetic with 140-150 mg/kg of alloxan, and their hearts were studied 3 days, 1 mo, 3 mo, and 6 mo later. Ca2+-myosin-ATPase activity was decreased in the diabetic rabbit at 1, 3, and 6 mo, correlating with increased percent V3. Actin-activated Mg2+-ATPase activity was not significantly decreased in diabetics, but myofibrillar ATPase activity was decreased in 6-mo diabetic animals. When 3- to 4-mo diabetic animals were administered insulin for 3-4 additional months, myosin-ATPase activity and isoenzyme distribution normalized. These results correlate well with mechanical changes in papillary muscle from these same hearts. They suggest that in rabbit, as in rat, changes in cardiac contractile function are at least partially mediated by changes in myosin isoenzyme composition and are reversible with insulin.


Route to Stable Lead-Free Double Perovskites with the Electronic Structure of CH3NH3PbI3: A Case for Mixed-Cation [Cs/CH3NH3/CH(NH2)2]2InBiBr6.
During the past year, halide double perovskites attracted attention as potential lead-free alternatives to Pb-based halide perovskites. However, none of the compounds discovered so far can match the optoelectronic properties of MAPbI3 (MA = CH3NH3). Here we argue that, from the electronic structure viewpoint, the only option to make Pb-free double perovskites retaining the remarkable properties of MAPbI3 is to combine In and Bi as B+ and B3+ cations, respectively. While inorganic double perovskites such as Cs2InBiX6 were found to be unstable due to In+ oxidizing into In3+, we show that the +1 oxidation state of In becomes progressively more stable as the A-site cation changes from K to Cs. Hence, we propose the use of MA and FA [FA = CH(NH2)2] to stabilize A2InBiBr6 double perovskites. We show that the optoelectronic properties of MA2InBiBr6 are remarkably similar to those of MAPbI3 and explore the mixed-cation (Cs/MA/FA)2InBiBr6 halide double perovskites.


[The results of ulnar nerve decompression in Guyon's canal syndrome].
The aim of the study was to evaluate a group of patients treated for Guyon's canal syndrome with analysis of the cause for and outcome of surgery. The group comprised 13 patients operated on for compressive neuropathies of the ulnar nerve in the canal of Guyon in the period from 2007 to 2010. The clinical parameters evaluated were the adduction strength of the fifth digit, degree of interosseous primus muscle hypotrophy and degree of hypoesthesia in the area innervated by the ulnar nerve. EMG parameters included motor and sensory nerve conduction through Guyon's canal. Patients' subjective evaluations of the treatment outcomes were also recorded. The results were not compared with a control group. Post-operative improvements in all clinical and EMG parameters were significant (p=0.02-0.003). All but one patient (90%) reported an improved subjective condition after surgery; on the other hand, pre-operative severe impairment of motor nerve conduction highly affected the post-operative motor function. Guyon's canal syndrome accounted for 0.8% of all compressive neuropathies of the upper extremity in our patients. Ulnar nerve compression at the wrist is a relatively rare condition amongst the compressive neuropathies of the upper extremity, and literature data concerning this disease are very few. Although many causes of ulnar nerve compression at the wrist have been reported, only one of our patients had ganglion. We conclude that the majority of cases can be diagnosed as a "neuritis" due to chronic microtrauma produced by pressure of a hypertrophic palmar ligament. Syndrome of Guyon's canal can easily be treated by surgery. As in other compression syndromes, the sooner a surgical decompression is performed, the better outcomes are achieved.


REG4 acts as a mitogenic, motility and pro-invasive factor for colon cancer cells.
REG4, the latest member of the regenerating gene family, is overexpressed in inflammatory bowel diseases and gastrointestinal carcinomas. To date, its pathophysiologic role has not been well established. Using HT-29 models, we previously identified REG4 as being overexpressed in colorectal tumor cells displaying a drug-resistance phenotype; some also displayed invasive properties. Thus, we investigated the potential functions of REG4 in biological processes involved in colorectal tumor progression such as cell proliferation, migration and invasion. Colon cancer cells secreting REG4 (HT29-5M21, HT29-5F7 and HT29/REG4-8) or not (HT-29, HT29/CT1 and Caco-2/TC7) were used to analyze the autocrine and paracrine effects of REG4. REG4 was continuously secreted into the culture medium of colon cancer cells. REG4 stimulated cell growth in a paracrine manner after 24 h of treatment. Notably, REG4 promoted migration and invasion of tumor cells in both an autocrine and paracrine manner, and these effects were significantly decreased by concomitant treatment with an anti-REG4 antibody. Using pharmacological inhibitors, we showed that PI3K/Akt, PKAs, PKCs and Rho-like GTPases, but not MAPK, are involved in REG4 invasion signals. In addition, REG4 expression was found to be increased in tissues harboring proliferation and migration properties such as the developing intestine and tissues from inflammatory bowel disease, hyperplastic polyps, adenoma and colorectal cancers. In various situations, REG4 expression was not confined to proliferating cells, regenerating cells or cells of the invasive front of metastatic tumors, suggesting that extracellular REG4 may act on epithelial cells in a paracrine manner. Altogether, our results indicate that REG4 is a multifunctional secreted protein which acts on colorectal cancer cells in an autocrine and paracrine manner. According to its biological functions and tissue expression, REG4 may play an important role in the development and progression of colorectal cancer, as well as in intestinal morphogenesis and epithelium restitution.


Analysis of rifapentine for preventive therapy in the Cornell mouse model of latent tuberculosis.
Rifapentine is a long-acting rifamycin which may be useful for intermittent drug therapy against tuberculosis. In this study we measured the efficacies of rifapentine-containing intermittent drug regimens for preventive therapy using the Cornell mouse model of latent tuberculosis. We infected groups of mice intravenously with Mycobacterium tuberculosis and then treated them with isoniazid and pyrazinamide for 12 weeks according to the Cornell latency development protocol. After a 4-week interval of no treatment, experimental preventive therapy was administered by esophageal gavage for 12 or 18 weeks. After equilibration and dexamethasone amplification treatment, mouse organs were analyzed by quantitative colony counts to measure the effectiveness of therapy. Our results showed that once-weekly isoniazid plus rifapentine combination therapy for 18 weeks was an effective preventive regimen with sterilizing potency and bacillary load reduction comparable to those of daily isoniazid therapy for 18 weeks. Monotherapy with rifapentine weekly or fortnightly or with rifampin twice weekly for up to 18 weeks did not offer advantages in reducing bacillary load or in sterilizing organs compared to the effects of a placebo. These results with the Cornell mouse model indicate that once-weekly, short-course preventive therapy with isoniazid plus rifapentine is effective and may warrant investigation in humans with latent tuberculosis infection.


Shifting global invasive potential of European plants with climate change.
Global climate change and invasions by nonnative species rank among the top concerns for agents of biological loss in coming decades. Although each of these themes has seen considerable attention in the modeling and forecasting communities, their joint effects remain little explored and poorly understood. We developed ecological niche models for 1804 species from the European flora, which we projected globally to identify areas of potential distribution, both at present and across 4 scenarios of future (2055) climates. As expected from previous studies, projections based on the CGCM1 climate model were more extreme than those based on the HadCM3 model, and projections based on the a2 emissions scenario were more extreme than those based on the b2 emissions scenario. However, less expected were the highly nonlinear and contrasting projected changes in distributional areas among continents: increases in distributional potential in Europe often corresponded with decreases on other continents, and species seeing expanding potential on one continent often saw contracting potential on others. In conclusion, global climate change will have complex effects on invasive potential of plant species. The shifts and changes identified in this study suggest strongly that biological communities will see dramatic reorganizations in coming decades owing to shifting invasive potential by nonnative species.


Cytomegalovirus infection in isolated lung transplantations.
The course of 52 isolated single and double lung transplant recipients who survived more than 2 weeks was reviewed to determine the incidence of cytomegalovirus (CMV) infection. In this group 22 patients were seromatched: 11 donor-recipient pairs were seronegative and 11 were seropositive. Of the remaining 30, 13 were donor-positive, recipient-negative and 17 were donor-negative, recipient positive. Diagnosis of CMV infection was made in the event of (1) seroconversion, (2) clinical symptoms consistent with CMV plus a fourfold rise in CMV titer, (3) isolation of CMV from tissue or body fluid by shell vial monoclonal antibody technique. CMV pneumonitis was diagnosed when shell vial culture from bronchoalveolar lavage fluid was positive in the appropriate clinical setting even if cytopathic changes were not yet present. Clinical CMV infection did not develop in any of the 22 seromatched pairs, and none of the seronegative pairs seroconverted. Of 17 recipient-positive, donor-negative pairs, CMV pneumonitis developed in two; one died. Of 13 recipient-negative, donor-positive pairs, seven seroconverted and pneumonitis developed in two but they did not die. The most recent 10 mismatched pairs received hyperimmune globulin prophylaxis, but this did not prevent the development of infection or clinical disease. Morbidity and mortality were greater in the seromismatched groups than in seromatched groups although this difference could not be directly related to CMV infection in most cases. Our experience suggests that both seronegative and seropositive recipients who receive a mismatched graft, but not the usual high-risk seropositive matched pairs, are at significant risk of clinical CMV disease after isolated single and double lung transplantation.


Probe-Sample Interaction-Independent Atomic Force Microscopy-Infrared Spectroscopy: Toward Robust Nanoscale Compositional Mapping.
Nanoscale topological imaging using atomic force microscopy (AFM) combined with infrared (IR) spectroscopy (AFM-IR) is a rapidly emerging modality to record correlated structural and chemical images. Although the expectation is that the spectral data faithfully represents the underlying chemical composition, the sample mechanical properties affect the recorded data (known as the probe-sample-interaction effect). Although experts in the field are aware of this effect, the contribution is not fully understood. Further, when the sample properties are not well-known or when AFM-IR experiments are conducted by nonexperts, there is a chance that these nonmolecular properties may affect analytical measurements in an uncertain manner. Techniques such as resonance-enhanced imaging and normalization of the IR signal using ratios might improve fidelity of recorded data, but they are not universally effective. Here, we provide a fully analytical model that relates cantilever response to the local sample expansion which opens several avenues. We demonstrate a new method for removing probe-sample-interaction effects in AFM-IR images by measuring the cantilever responsivity using a mechanically induced, out-of-plane sample vibration. This method is then applied to model polymers and mammary epithelial cells to show improvements in sensitivity, accuracy, and repeatability for measuring soft matter when compared to the current state of the art (resonance-enhanced operation). Understanding of the sample-dependent cantilever responsivity is an essential addition to AFM-IR imaging if the identification of chemical features at nanoscale resolutions is to be realized for arbitrary samples.


Tuning the mechanical properties of graphene oxide paper and its associated polymer nanocomposites by controlling cooperative intersheet hydrogen bonding.
The mechanical properties of pristine graphene oxide paper and paper-like films of polyvinyl alcohol (PVA)-graphene oxide nanocomposite are investigated in a joint experimental-theoretical and computational study. In combination, these studies reveal a delicate relationship between the stiffness of these papers and the water content in their lamellar structures. ReaxFF-based molecular dynamics (MD) simulations elucidate the role of water molecules in modifying the mechanical properties of both pristine and nanocomposite graphene oxide papers, as bridge-forming water molecules between adjacent layers in the paper structure enhance stress transfer by means of a cooperative hydrogen-bonding network. For graphene oxide paper at an optimal concentration of ~5 wt % water, the degree of cooperative hydrogen bonding within the network comprising adjacent nanosheets and water molecules was found to optimally enhance the modulus of the paper without saturating the gallery space. Introducing PVA chains into the gallery space further enhances the cooperativity of this hydrogen-bonding network, in a manner similar to that found in natural biomaterials, resulting in increased stiffness of the composite. No optimal water concentration could be found for the PVA-graphene oxide nanocomposite papers, as dehydration of these structures continually enhances stiffness until a final water content of ~7 wt % (additional water cannot be removed from the system even after 12 h of annealing).


A Case of Pancreatic Pseudocyst Complicated by Pseudoaneurysm.
Pancreatic pseudocyst is a complication that can arise in both acute and chronic pancreatitis. Overtime, this encapsulated enzyme-rich fluid collection may erode into surrounding vasculature and result in the formation of a pseudoaneurysm. Pseudoaneurysms can rupture into the gastrointestinal tract and present as upper, lower, and biliary bleeding. Evaluation of pancreatic pseudocysts involves computed tomography imaging or magnetic resonance imaging for both identification and monitoring. Esophagogastroduodenoscopy (EGD) and endoscopic ultrasound (EUS) can be done to further visualize the lesion. In the presence of gastrointestinal bleed, management involves the combination of interventional radiology and surgery.


Cause of acute tubular necrosis affects its prognosis. The Auriculin Anaritide Acute Renal Failure Study Group.
Acute tubular necrosis (ATN) is the most common type of acute renal failure in hospitalized patients and is associated with a high morbidity and mortality. The cause of ATN can be divided into nephrotoxic, ischemic, or mixed. To test the hypothesis that the cause of ATN affects its clinical outcome. The study compares clinical outcomes of patients enrolled in the placebo arm of a multicenter, randomized, double-blinded, placebo-controlled trial of anaritide (Auriculin, synthetic atrial natriuretic peptide, Scios, Mountain View, Calif) in patients with well-defined ATN. Patients were divided prospectively into groups according to the cause of ATN: pure nephrotoxic, pure ischemic, or mixed nephrotoxic and ischemic. Outcomes of interest were dialysis-free survival and all-cause mortality on day 14 and day 21. The causal groups were compared with respect to the prevalence of several comorbidities suspected of affecting the clinical outcomes. Mortality was 10% in the nephrotoxic group and 30% in the ischemic group on day 21. Dialysis-free survival was 66% in the nephrotoxic group and 41% in the ischemic group on day 21. Outcomes in the mixed and ischemic groups were similar. Compared with the nephrotoxic group, there was a significantly higher prevalence of cardiogenic shock, hypotension, sepsis, and respiratory failure and a tendency toward a higher prevalence of acute hepatic dysfunction in the ischemic group. Diabetes mellitus was more prevalent in the nephrotoxic group. Among patients with ischemic ATN, dialysis-free survival improved significantly and mortality tended to decline with advancing age. Among patients with ATN, those in whom renal ischemia was causative had significantly higher mortality and lower dialysis-free survival than those whose ATN was purely nephrotoxic in origin. This difference in clinical outcomes was associated with a higher prevalence of serious commorbidities in the ischemic ATN group. Advancing age was associated with improved dialysis-free survival and a tendency toward reduced mortality in patients with ischemic ATN.


Intercellular adhesion molecule 1 and selectin l play crucial roles in ulcerative colitis.
Ulcerative colitis (UC) is a chronic inflammatory bowel disease that primarily affects the mucosal layer of the colon (large intestine). However, the relationship between Intercellular Adhesion Molecule-1 (ICAM1), SELL and UC is unclear. The UC datasets, GSE87466 and GSE36807, were downloaded from the gene expression omnibus database. The R package limma was utilized to identify differentially expressed genes (DEGs). Weighted gene co-expression network analysis was conducted. The construction and analysis of protein-protein interaction network, functional enrichment analysis, gene set enrichment analysis, and comparative toxicogenomics database analysis were performed. TargetScan was employed to screen miRNAs regulating central DEGs. Western blot (WB) was used to verify. A total of 2118 DEGs were identified in our study. Gene ontology analysis indicated their enrichment primarily in immune system processes, cellular responses to chemical stimuli, responses to organic substances, responses to external stimuli, and immune responses. Kyoto Encyclopedia of Genes and Genomes analysis revealed that the target cells were mainly enriched in chemokine signaling pathways and TNF signaling pathways. Gene set enrichment analysis enrichment analysis showed significant enrichment in chemokine signaling pathways and cell adhesion molecules. In the Metascape enrichment project, gene ontology terms included regulation of cell activation and positive regulation of immune response. Through the construction and analysis of a protein-protein interaction network, we identified 11 core genes (ICAM1, SELL, CD44, CD40, CCR7, CXCL8, CD19, CCL4, CD274, IL7R, IL1B). We found that the core genes (ICAM1, SELL) were highly expressed in UC samples and lowly expressed in normal samples, suggesting their potential regulatory roles in UC. These core genes were associated with lymphoproliferative disorders, inflammation and necrosis. WB results confirmed the high expression of ICAM1 and SELL in UC. ICAM1 and SELL are highly expressed in UC, and the higher the ICAM1 and SELL genes, the worse the prognosis.


Effectiveness of Mindfulness- and Relaxation-Based eHealth Interventions for Patients with Medical Conditions: a Systematic Review and Synthesis.
This systematic review aims to summarize eHealth studies with mindfulness- and relaxation-based interventions for medical conditions and to determine whether eHealth interventions have positive effects on health. A comprehensive search of five databases was conducted for all available studies from 1990 to 2015. Studies were included if the intervention was mainly technology delivered and included a mindfulness- or relaxation-based intervention strategy and if patients with a medical condition were treated. Treatment effects were summarized for different outcomes. A total of 2383 records were identified, of which 17 studies with 1855 patients were included in this systematic review. These studies were conducted in patients with irritable bowel syndrome, chronic fatigue syndrome, cancer, chronic pain, surgery, and hypertension. All but one study were delivered online through a web-based platform; one study delivered the intervention with iPods. The studies indicate that mindfulness- and relaxation-based eHealth interventions can have positive effects on patients' general health and psychological well-being. No effects were found for stress or mindfulness. Only five studies reported economic analyses of eHealth interventions without any clear conclusion. There is some evidence that mindfulness- and relaxation-based eHealth interventions for medical conditions can have positive effects on health outcomes. Therefore, such interventions might be a useful addition to standard medical care. No app studies were retrieved, even though a vast number of smartphone apps exist which aim at increasing users' health. Therefore, more studies investigating those health apps are needed.


Virus-Induced Cytoplasmic Aggregates and Inclusions are Critical Cellular Regulatory and Antiviral Factors.
RNA granules, aggresomes, and autophagy are key players in the immune response to viral infections. They provide countermeasures that regulate translation and proteostasis in order to rewire cell signaling, prevent viral interference, and maintain cellular homeostasis. The formation of cellular aggregates and inclusions is one of the strategies to minimize viral infections and virus-induced cell damage and to promote cellular survival. However, viruses have developed several strategies to interfere with these cellular processes in order to achieve productive replication within the host cells. A review on how these mechanisms could function as modulators of cell signaling and antiviral factors will be instrumental in refining the current scientific knowledge and proposing means whereby cellular granules and aggregates could be induced or prevented to enhance the antiviral immune response in mammalian cells.


Wegener granulomatosis in a child: cutaneous findings as the presenting signs.
Wegener granulomatosis (WG) is a systemic disease that is particularly unusual in children. A limited form has been described without renal involvement. We report a 14-year-old girl in whom the disease started with acneiform nodular and papular lesions on the forehead. Later necrotic ulcers developed on her forehead, arms, and buttocks. The cutaneous lesions were associated with upper and lower respiratory tract involvement, low-grade fever and arthralgias. Subsequently clinical and laboratory evaluations (increased ESR; leukocytosis and presence of serum IgG antibodies cANCA = 1:160), with chest roentgenograms revealing pulmonary densities and parenchymal infiltration, suggested the diagnosis of WG. The histologic findings of a cutaneous biopsy specimen were ulceration of the epidermis with diffuse neutrophilic inflammatory infiltrate and a late-stage small vessel vasculitis in the dermis. Histopathology of the nasal mucosa was characterized by a granulomatous process with a dense lymphohistiocytic infiltrate with few giant cells, a finding that confirmed the diagnosis of WG. No renal involvement was present. One month of cyclophosphamide (125 mg/day) and prednisone (70 mg/day) therapy markedly improved the patient's clinical condition. At present, 1 year later, she is free from any signs of the disease. According to the literature, the frequency of cutaneous lesions in WG ranges from 16% to 46%. They are the presenting sign only in 6% of patients. Cutaneous lesions are even more uncommon in children. In particular, an "acneiform" presentation is a rare finding in WG.


DNA-binding small-ligand-immobilized surface plasmon resonance biosensor for detecting thymine-related single-nucleotide polymorphisms.
A surface plasmon resonance (SPR) biosensor that carries DNA-binding small ligands has been developed for the detection of single-nucleotide polymorphisms (SNPs). 3,5-Diaminopyrazine derivatives, with a hydrogen-bonding profile fully complementary to the thymine base, were utilized as recognition elements on the sensor surface, and a target single-stranded DNA sequence was hybridized with a DNA probe containing an abasic site to place this site opposite a nucleobase to be detected. In a continuous flow of sample solutions buffered to pH 6.4 (0.25 M NaCl), the 3,5-diaminopyrazine-based SPR sensor can detect an orphan nucleobase in the duplex with a clear selectivity for thymine over cytosine, guanine, and adenine (5'-GTT GGA GCT GXG GGC GTA GGC-3'/3'-CAA CCT CGA CNC CCG CAT CCG-5'; X=abasic site, N=target nucleobase G, C, A, or T). The SPR response was linear in the concentration range 10-100 nM. Allele discrimination is possible based on the combination of different binding surfaces in a flow cell of the SPR system, which is demonstrated for the analysis of the thymine/cytosine mutation present in 63-meric polymerase chain reaction (PCR) amplification products (Ha-ras gene, codon 12, antisense strand). Comparison with a bulk assay based on 3,5-diaminopyrazine/DNA binding shows that the immobilization of 3,5-diaminopyrazine derivatives on the SPR sensor allows more sensitive detection of the target DNA sequence, and binding selectivity can be tuned by controlling the salt concentration of sample solutions. These features of the DNA-binding small-molecule-immobilized SPR sensor are discussed as a basis for the design of SPR biosensors for SNP genotyping.


Postoperative infection rates in low risk patients undergoing percutaneous nephrolithotomy with and without antibiotic prophylaxis: a matched case control study.
Current guidelines recommend prophylactic antibiotic therapy for all patients undergoing percutaneous nephrolithotomy. We examined the effects of antibiotic prophylaxis in patients undergoing percutaneous nephrolithotomy with negative preoperative urine cultures. Of the 5,803 patients in the CROES (Clinical Research Office of the Endourological Society) Percutaneous Nephrolithotomy Global Study database, a group of 162 patients undergoing percutaneous nephrolithotomy with a negative baseline urine culture who did not receive antibiotic prophylaxis were matched on preoperative nephrostomy, the presence of staghorn calculi and diabetes status with an equal number of patients who received antibiotic prophylaxis. Comparisons were made between the 2 groups in terms of operative and postoperative outcomes, including the incidence of fever and other complications. Patients who received antibiotic prophylaxis had a lower mean (SD) age at 44.9 (14.2) vs 50.1 (14.4) years (p = 0.001). They were also more likely to be in the prone position during the procedure (71.6% vs 39.5%, p <0.001) but less likely to receive postoperative stenting (17.3% vs 32.7%, p = 0.002) than those who did not receive prophylaxis. The 2 groups were comparable in terms of all other baseline characteristics and operative factors. Patients who received antibiotic prophylaxis were less likely to experience fever (2.5% vs 7.4%, p = 0.040) and other postoperative complications (1.9% vs 22.0%, p <0.0001), and had a higher stone-free rate after percutaneous nephrolithotomy (86.3% vs 74.4%, p = 0.006). Antibiotic prophylaxis of patients undergoing percutaneous nephrolithotomy with a negative baseline urine culture is associated with a significant reduction in the rate of postoperative fever and other complications.


Cholinergic and β-adrenergic control of cardiovascular reflex responses to brief repeated asphyxia in term-equivalent fetal sheep.
The role of cholinergic and β-adrenergic activity in mediating fetal cardiovascular recovery from brief repeated episodes of asphyxia consistent with established labor, remains unclear. In this study, we tested the effect of cholinergic and β-adrenergic blockade on the fetal chemoreflex and fetal heart rate (FHR) overshoot responses during brief repeated asphyxia at rates consistent with early or active labor. Chronically instrumented fetal sheep at 0.85 of gestation received either i.v. atropine sulfate (cholinergic blockade, n=8) or vehicle (n=7) followed by 3 x 1-minute umbilical cord occlusions repeated every 5 minutes (1:5; consistent with early labor), or i.v. propranolol hydrochloride (β-adrenergic blockade, n=6) or vehicle (n=6) followed by 3 x 2-minute occlusions repeated every 5 minutes (2:5; consistent with active labor). In vehicle-controls, 1:5 occlusions were associated with rapid and sustained FHR decelerations followed by rapid return of FHR to baseline values after release of the occlusion. Cholinergic blockade abolished FHR decelerations during occlusions and caused FHR overshoot after release of the occlusion (P<0.05 vs. control 1:5). In vehicle-controls, 2:5 occlusions caused rapid and sustained FHR decelerations followed by FHR overshoot after release of the occlusion. β-adrenergic blockade was associated with greater reduction in FHR during occlusions and attenuated FHR overshoot (P<0.05 vs. control 2:5). These data demonstrate that the FHR overshoot pattern after asphyxia is mediated by a combination of attenuated parasympathetic activity and increased β-adrenergic stimulation of the fetal heart.


Estimation of ultrasonic attenuation in a bone using coded excitation.
This paper describes a novel approach to estimate broadband ultrasound attenuation (BUA) in a bone structure in human in vivo using coded excitation. BUA is an accepted indicator for assessment of osteoporosis. In the tested approach a coded acoustic signal is emitted and then the received echoes are compressed into brief, high amplitude pulses making use of matched filters and correlation receivers. In this way the acoustic peak pressure amplitude probing the tissue can be markedly decreased whereas the average transmitted intensity increases proportionally to the length of the code. This paper examines the properties of three different transmission schemes, based on Barker code, chirp and Golay code. The system designed is capable of generating 16 bits complementary Golay code (CGC), linear frequency modulated (LFM) chirp and 13-bit Barker code (BC) at 0.5 and 1 MHz center frequencies. Both in vivo data acquired from healthy heel bones and in vitro data obtained from human calcaneus were examined and the comparison between the results using coded excitation and two cycles sine burst is presented. It is shown that CGC system allows the effective range of frequencies employed in the measurement of broadband acoustic energy attenuation in the trabecular bone to be doubled in comparison to the standard 0.5 MHz pulse transmission. The algorithm used to calculate the pairs of Golay sequences of the different length, which provide the temporal side-lobe cancellation is also presented. Current efforts are focused on adapting the system developed for operation in pulse-echo mode; this would allow examination and diagnosis of bones with limited access such as hip bone.


Electrically tunable coherent optical absorption in graphene with ion gel.
We demonstrate electrical control over coherent optical absorption in a graphene-based Salisbury screen consisting of a single layer of graphene placed in close proximity to a gold back reflector. The screen was designed to enhance light absorption at a target wavelength of 3.2 μm by using a 600 nm-thick, nonabsorbing silica spacer layer. An ionic gel layer placed on top of the screen was used to electrically gate the charge density in the graphene layer. Spectroscopic reflectance measurements were performed in situ as a function of gate bias. The changes in the reflectance spectra were analyzed using a Fresnel based transfer matrix model in which graphene was treated as an infinitesimally thin sheet with a conductivity given by the Kubo formula. The analysis reveals that a careful choice of the ionic gel layer thickness can lead to optical absorption enhancements of up to 5.5 times for the Salisbury screen compared to a suspended sheet of graphene. In addition to these absorption enhancements, we demonstrate very large electrically induced changes in the optical absorption of graphene of ∼3.3% per volt, the highest attained so far in a device that features an atomically thick active layer. This is attributable in part to the more effective gating achieved with the ion gel over the conventional dielectric back gates and partially by achieving a desirable coherent absorption effect linked to the presence of the thin ion gel that boosts the absorption by 40%.


Molecular epidemiology of canine parvovirus type 2 in Vietnam from November 2016 to February 2018.
Canine parvovirus type 2 (CPV-2) was first identified in the late 1970s; it causes intestinal hemorrhage with severe bloody diarrhea in kennels and dog shelters worldwide. Since its emergence, CPV-2 has been replaced with new genetic variants (CPV-2a, CPV-2b, and CPV-2c). Currently, information about the genotype prevalence of CPV-2 in Vietnam is limited. In the present study, we investigated the genotype prevalence and distribution of CPV-2 in the three regions of Vietnam. Rectal swabs were collected from 260 dogs with suspected CPV-2 infection from northern, central, and southern Vietnam from November 2016 to February 2018. All samples were identified as parvovirus positive by real-time PCR, and further genotyping was performed using a SimpleProbe® real-time PCR assay. Of the 260 Vietnamese CPV-2 isolates, 6 isolates (2.31%) were identified as CPV-2a, 251 isolates (96.54%) were identified as CPV-2c and 3 isolates (1.15%) were untypable using the SimpleProbe® real-time PCR assay. In northern Vietnam, the percentages of CPV-2a and CPV-2c were 2.97% (3/101) and 97.3% (98/101), respectively. In central Vietnam, the percentages of CPV-2a and CPV-2c were 1.11% (1/90) and 98.89% (89/90), respectively. In southern Vietnam, the percentages of CPV-2a and CPV-2c were 3.03% (2/66) and 96.97% (64/66), respectively. CPV-2b was not observed in this study. The VP2 genes of CPV-2c in Vietnam are more genetically similar to those of CPV-2c strains in China and Taiwan than to those of prototype CPV-2c strains (FJ222821) or the first Vietnamese CPV-2c (AB120727). The present study provides evidence that CPV-2c is the most prevalent variant in Vietnam. Phylogenetic analysis demonstrated that the recent Vietnamese CPV-2c isolates share a common evolutionary origin with Asian CPV-2c strains.


Changing the Apoptosis Pathway through Evolutionary Protein Design.
One obstacle in de novo protein design is the vast sequence space that needs to be searched through to obtain functional proteins. We developed a new method using structural profiles created from evolutionarily related proteins to constrain the simulation search process, with functions specified by atomic-level ligand-protein binding interactions. The approach was applied to redesigning the BIR3 domain of the X-linked inhibitor of apoptosis protein (XIAP), whose primary function is to suppress the cell death by inhibiting caspase-9 activity; however, the function of the wild-type XIAP can be eliminated by the binding of Smac peptides. Isothermal calorimetry and luminescence assay reveal that the designed XIAP domains can bind strongly with the Smac peptides but do not significantly inhibit the caspase-9 proteolytic activity in vitro compared with the wild-type XIAP protein. Detailed mutation assay experiments suggest that the binding specificity in the designs is essentially determined by the interplay of structural profile and physical interactions, which demonstrates the potential to modify apoptosis pathways through computational design.


Survival of hydrogen sulfide oxidizing bacteria on corroded concrete surfaces of sewer systems.
The activity of hydrogen sulfide oxidizing bacteria within corroded concrete from a sewer manhole was investigated. The bacteria were exposed to hydrogen sulfide starvation for up till 18 months, upon which their hydrogen sulfide oxidizing activity was measured. It was tested whether the observed reduction in biological activity was caused by a biological lag phase or by decay of the bacteria. The results showed that the bacterial activity declined with approximately 40% pr. month during the first two months of hydrogen sulfide starvation. After 2-3 months of starvation, the activity stabilized. Even after 6 months of starvation, exposure to hydrogen sulfide for 6 hours a day on three successive days could restore the bacteriological activity to about 80% of the initial activity. After 12 months of starvation, the activity could, however, not be restored, and after 18 months the biological activity approached zero. The long-term survival aspect of concrete corroding bacteria has implications for predicting hydrogen sulfide corrosion in sewer systems subject to irregular hydrogen sulfide loadings, e.g. as they occur in temperate climates where hydrogen sulfide often is a summer-problem only.


Indications for breast MRI in the patient with newly diagnosed breast cancer.
Use of breast MRI in the preoperative evaluation of patients recently diagnosed with breast cancer has increased significantly over the past 10 years because of its well-documented high sensitivity for detecting otherwise occult breast cancer in the affected and contralateral breasts. However, published research reports on the impact of this improved cancer detection are limited. Equally important are growing concerns that the quality of breast MRI may vary significantly across practice sites, and therefore the published value of MRI may not be achieved for many patients. This article describes the peer-reviewed, published clinical research trials evaluating breast MRI in patients with newly diagnosed breast cancer on which the National Comprehensive Cancer Network (NCCN) practice guidelines are based. The current NCCN guidelines recommend that breast MRI be considered for patients with a newly diagnosed breast cancer to evaluate the extent of ipsilateral disease and to screen the contralateral breast, particularly for women at increased risk for mammographically occult disease. In addition, the guidelines indicate that breast MRI may be used for patients with axillary nodal adenocarcinoma to identify the primary malignancy. The guidelines stress the importance of having proper equipment, imaging technique, and provider training necessary to achieve high-quality breast MRI, and emphasize that MRI practice sites should have the ability to perform MRI-guided biopsy or needle localization. In addition to describing the data regarding use of breast MRI in women with newly diagnosed cancer, this article provides recommendations for the performance of high-quality breast MRI and suggestions for future research.


Isolation and characterization of Chinese hamster ovary cell mutants defective in assembly of peroxisomes.
We made use of autoradiographic screening to isolate two Chinese hamster ovary (CHO) cell mutants deficient in peroxisomal dihydroxyacetonephosphate acyltransferase, a key enzyme for the biosynthesis of ether glycerolipids such as plasmalogens. Morphological analysis revealed no evidence of peroxisome in these mutants. Catalase was as active as in the normal cells but was not sedimentable. Pulse-chase radiolabeling experiments and cell-free translation of RNA demonstrated that acyl-CoA oxidase, the first enzyme of the peroxisomal beta-oxidation system, was synthesized as the 75-kD form but was not converted to 53- and 22-kD mature components that were present in the wild-type CHO cells; rather, degradation was apparent. Peroxisomal thiolase was synthesized as in normal cells but remained as a larger, 44-kD precursor, whereas maturation to the 41-kD enzyme was detected in the wild-type cells. The peroxisomal 70-kD integral membrane protein was also equally synthesized, as in the wild-type cells, and was not degraded. These results suggest that assembly of the peroxisomes is defective in the mutants, whereas the synthesis of peroxisomal proteins appears to be normal. Cell-fusion studies revealed that the two mutants are recessive to the wild-type CHO cells and belong to different complementation groups. Thus, these mutants presumably contain different lesions in gene(s) encoding factor(s) required for peroxisome assembly.


Detection of subclinical tubular injury after renal transplantation: comparison of urine protein analysis with allograft histopathology.
Tubulointerstitial injury due to rejection leads to tubular atrophy (TA)/interstitial fibrosis (IF) followed by deterioration of allograft function. This study investigated whether urinary tubular injury biomarkers can detect subclinical tubulitis found in protocol biopsies allowing for a noninvasive screening procedure. Four rigidly defined groups (stable transplants with normal tubular histology [n=24], stable transplants with subclinical tubulitis [n=38], patients with clinical tubulitis Ia/Ib [n=18], and patients with other clinical tubular pathologies [n=20]) were compared for differences in urinary intact/cleaved beta2-microglobulin (i/cbeta2m), retinol-binding protein (RBP), neutrophil-gelatinase-associated lipocalin (NGAL), and alpha1-microglobulin (alpha1m). Tubular proteinuria was present in 38% (RBP) to 79% (alpha1m) of patients in the stable transplant with normal tubular histology group. The stable transplant with subclinical tubulitis group had slightly higher levels of i/cbeta2m (P=0.11), RBP (P=0.17), alpha1m (P=0.09), and NGAL (P=0.06) than the stable transplant with normal tubular histology group with a substantial overlap. The clinical tubulitis Ia/Ib and the other clinical tubular pathology groups had significantly higher levels of RBP, NGAL, and alpha1m than stable transplants with normal tubular histology or stable transplants with subclinical tubulitis (P<0.002). None of the investigated biomarkers allow for clear differentiation between stable transplants with normal tubular histology and stable transplants with subclinical tubulitis. Therefore, the protocol allograft biopsy currently remains the preferred tool to screen for subclinical tubulitis. Further longitudinal studies should determine whether tubular proteinuria in stable transplants with normal tubular histology indicates a clear risk for early development of TA/IF.


Modeling Physiological Flow in Fontan Models With Four-Dimensional Flow Magnetic Resonance Imaging, Particle Image Velocimetry, and Arterial Spin Labeling.
The Fontan procedure is a successful palliation for single ventricle defect. Yet, a number of complications still occur in Fontan patients due to abnormal blood flow dynamics, necessitating improved flow analysis and treatment methods. Phase-contrast magnetic resonance imaging (MRI) has emerged as a suitable method for such flow analysis. However, limitations on altering physiological blood flow conditions in the patient while in the MRI bore inhibit experimental investigation of a variety of factors that contribute to impaired cardiovascular health in these patients. Furthermore, resolution and flow regime limitations in phase contrast (PC) MRI pose a challenge for accurate and consistent flow characterization. In this study, patient-specific physical models were created based on nine Fontan geometries and MRI experiments mimicking low- and high-flow conditions, as well as steady and pulsatile flow, were conducted. Additionally, a particle image velocimetry (PIV)-compatible Fontan model was created and flow was analyzed with PIV, arterial spin labeling (ASL), and four-dimensional (4D) flow MRI. Differences, though nonstatistically significant, were observed between flow conditions and between patient-specific models. Large between-model variation supported the need for further improvement for patient-specific modeling on each unique Fontan anatomical configuration. Furthermore, high-resolution PIV and flow-tracking ASL data provided flow information that was not obtainable with 4D flow MRI alone.


Pathophysiological role of microRNA-29 in pancreatic cancer stroma.
Dense fibrotic stroma associated with pancreatic ductal adenocarcinoma (PDAC) is a major obstacle for drug delivery to the tumor bed and plays a crucial role in pancreatic cancer progression. Current, anti-stromal therapies have failed to improve tumor response to chemotherapy and patient survival. Furthermore, recent studies show that stroma impedes tumor progression, and its complete ablation accelerates PDAC progression. In an effort to understand the molecular mechanisms associated with tumor-stromal interactions, using in vitro and in vivo models and PDAC patient biopsies, we show that the loss of miR-29 is a common phenomenon of activated pancreatic stellate cells (PSCs)/fibroblasts, the major stromal cells responsible for fibrotic stromal reaction. Loss of miR-29 is correlated with a significant increase in extracellular matrix (ECM) deposition, a major component in PDAC stroma. Our in vitro miR-29 gain/loss-of-function studies document the role of miR-29 in PSC-mediated ECM stromal protein accumulation. Overexpression of miR-29 in activated stellate cells reduced stromal deposition, cancer cell viability, and cancer growth in co-culture. Furthermore, the loss of miR-29 in TGF-β1 activated PSCs is SMAD3 dependent. These results provide insights into the mechanistic role of miR-29 in PDAC stroma and its potential use as a therapeutic agent to target PDAC.


The occurrence of Clostridium botulinum and Clostridium tetani in the soil of the United States.
Soil samples taken every fifty miles on four east-west transects across the United States were examined for C. botulinum and C. tetani, organisms that could inhibit the growth of C. botulinum type A, and for various soil properties. Type A strains were found mostly in the western part of the United States, in neutral to alkaline soil. Type B strains were more uniformly distributed, with a majority of them occurring east of the Mississippi River; none, however, were found in samples taken in the southermost transect. They were associated with soil of high organic content. Type C strains were found only in acid soil of the Gulf Coast, and type D strains in alkaline soil of some western states. Type E strains were mostly associated with damp to wet soil. Organisms inhibitory to type A strains were found in 4 of 21 samples of soil in which type A strains were demonstrated and in 7 of 20 samples in which they were not. Trypsin activation of culture fluids was necessary for the demonstration of most strains of types B, C, D, and E. C. tetani was demonstrated in 30 per cent of the soil samples. Its occurrence was not correlated with any particular soil type or climatic area.


Strategies to support self-management in osteoarthritis: five categories of interventions, including education.
This overview of successful strategies for supporting self-management in patients with osteoarthritis (OA) defines the concepts of self-management, self-management support (SMS), and self-management education (SME); describes five categories of SMS interventions; identifies common elements across SMS categories; and provides evidence for and examples of self-management tools that are useful in OA. SMS categories include SME, other skill-building and behavior-change interventions, supportive provider interactions, ongoing supportive follow-up, and environmental changes. Where available, relevant OA-specific SMS strategies are used to illustrate these categories.


The Underlying Nature of Epigenetic Variation: Origin, Establishment, and Regulatory Function of Plant Epialleles.
In plants, the gene expression and associated phenotypes can be modulated by dynamic changes in DNA methylation, occasionally being fixed in certain genomic loci and inherited stably as epialleles. Epiallelic variations in a population can occur as methylation changes at an individual cytosine position, methylation changes within a stretch of genomic regions, and chromatin changes in certain loci. Here, we focus on methylated regions, since it is unclear whether variations at individual methylated cytosines can serve any regulatory function, and the evidence for heritable chromatin changes independent of genetic changes is limited. While DNA methylation is known to affect and regulate wide arrays of plant phenotypes, most epialleles in the form of methylated regions have not been assigned any biological function. Here, we review how epialleles can be established in plants, serve a regulatory function, and are involved in adaptive processes. Recent studies suggest that most epialleles occur as byproducts of genetic variations, mainly from structural variants and Transposable Element (TE) activation. Nevertheless, epialleles that occur spontaneously independent of any genetic variations have also been described across different plant species. Here, we discuss how epialleles that are dependent and independent of genetic architecture are stabilized in the plant genome and how methylation can regulate a transcription relative to its genomic location.


[Analysis on TCM syndrome distribution laws in 319 patients with coronary heart disease].
To study TCM syndrome distribution laws in patients with coronary heart diseases (CHD) by epidemiological investigation. A clinical survey was carried out in 319 inpatients with CHD, whose diagnosis was confirmed by coronary arteriography, in the authors' hospital from January 2004 to December 2004. The TCM syndrome distribution laws were analyzed, and the relationship of coronary arteriographic picture with TCM syndrome elements, common symptoms, pulse and tongue figures, as well as the correlation between syndrome typing and blood-lipid levels were analyzed, too. Qi deficiency was the most popular syndrome in patients with CHD (87.1%), blood stasis syndrome and phlegm retention syndrome took the second place, accounting for 79.9% and 78.7% respectively. No significant difference was shown in comparison of tongue and pulse figures with the affected branches of coronary artery, the dark-pale tongue with white greasy fur and taut-slippery pulse being the dominance in patients. The blood-lipid levels in patients with various TCM syndrome types were similar, showing insignificant difference. The TCM pathogenesis of CHD takes qi deficiency as the core, blood stasis and phlegm retention as the important pathologic products.


Phosphate may promote CKD progression and attenuate renoprotective effect of ACE inhibition.
Phosphate may promote the onset and progression of chronic nephropathies. Here we evaluated the relationships between baseline serum phosphate levels, disease progression, and response to ACE inhibition in 331 patients with proteinuric nephropathies in the prospective Ramipril Efficacy In Nephropathy (REIN) trial. Independent of treatment, patients with phosphate levels in the highest two quartiles progressed significantly faster either to ESRD or to a composite endpoint of doubling of serum creatinine or ESRD compared with patients with phosphate levels below the median (P < 0.001). Results were similar when we analyzed phosphate as a continuous variable (P ≤ 0.004). The renoprotective effect of ramipril decreased as serum phosphate increased (P ≤ 0.008 for interaction); this modification of the treatment effect by phosphate persisted despite adjusting for potential confounders such as GFR and urinary protein. In summary, these data suggest that phosphate is an independent risk factor for progression of renal disease among patients with proteinuric CKD, and high levels of phosphate may even attenuate the renoprotective effect of ACE inhibitors. Future trials should test whether reducing serum phosphate improves renal outcomes and optimizes the renoprotective effect of ACE inhibition.


Structure of amorphous GeSe9 by neutron diffraction and first-principles molecular dynamics: Impact of trajectory sampling and size effects.
The structure of glassy GeSe9 was investigated by combining neutron diffraction with density-functional-theory-based first-principles molecular dynamics. In the simulations, three different models of N = 260 atoms were prepared by sampling three independent temporal trajectories, and the glass structures were found to be substantially different from those obtained for models in which smaller numbers of atoms or more rapid quench rates were employed. In particular, the overall network structure is based on Sen chains that are cross-linked by Ge(Se4)1/2 tetrahedra, where the latter are predominantly corner as opposed to edge sharing. The occurrence of a substantial proportion of Ge-Se-Se connections does not support a model in which the material is phase separated into Se-rich and GeSe2-rich domains. The appearance of a first-sharp diffraction peak in the Bhatia-Thornton concentration-concentration partial structure factor does, however, indicate a non-uniform distribution of the Ge-centered structural motifs on an intermediate length scale.


[Wing receptors of the American cockroach Periplaneta americana].
Wing receptors of the cockroach have been studied using staining technique with methylene blue in living animals. Five types of the receptors were found: trychoid hairs, bristles, complaniform sensillae, chordotonal organs and multiterminal neurons. The majority of the receptors is located at the lower surface of the wing, especially along its ribs. Together with primitive features in the structure (polyneuronal origin of hairs and bristles, poor content of chordotonal organs, absence of distinct groups of companiform sensillae), some specialization of wing receptors with respect to flight function is noted (concentration of proprioceptors along the main mechanical axis of the wing and formation of distinct rows by the companiform sensillae).