Bioresorbable Multilayer Photonic Cavities as Temporary Implants for Tether-Free Measurements of Regional Tissue Temperatures.
Objective and Impact Statement. Real-time monitoring of the temperatures of regional tissue microenvironments can serve as the diagnostic basis for treating various health conditions and diseases. Introduction. Traditional thermal sensors allow measurements at surfaces or at near-surface regions of the skin or of certain body cavities. Evaluations at depth require implanted devices connected to external readout electronics via physical interfaces that lead to risks for infection and movement constraints for the patient. Also, surgical extraction procedures after a period of need can introduce additional risks and costs. Methods. Here, we report a wireless, bioresorbable class of temperature sensor that exploits multilayer photonic cavities, for continuous optical measurements of regional, deep-tissue microenvironments over a timeframe of interest followed by complete clearance via natural body processes. Results. The designs decouple the influence of detection angle from temperature on the reflection spectra, to enable high accuracy in sensing, as supported by in vitro experiments and optical simulations. Studies with devices implanted into subcutaneous tissues of both awake, freely moving and asleep animal models illustrate the applicability of this technology for in vivo measurements. Conclusion. The results demonstrate the use of bioresorbable materials in advanced photonic structures with unique capabilities in tracking of thermal signatures of tissue microenvironments, with potential relevance to human healthcare.


Mechanisms of circumferential gyral convolution in primate brains.
Mammalian cerebral cortices are characterized by elaborate convolutions. Radial convolutions exhibit homology across primate species and generally are easily identified in individuals of the same species. In contrast, circumferential convolutions vary across species as well as individuals of the same species. However, systematic study of circumferential convolution patterns is lacking. To address this issue, we utilized structural MRI (sMRI) and diffusion MRI (dMRI) data from primate brains. We quantified cortical thickness and circumferential convolutions on gyral banks in relation to axonal pathways and density along the gray matter/white matter boundaries. Based on these observations, we performed a series of computational simulations. Results demonstrated that the interplay of heterogeneous cortex growth and mechanical forces along axons plays a vital role in the regulation of circumferential convolutions. In contrast, gyral geometry controls the complexity of circumferential convolutions. These findings offer insight into the mystery of circumferential convolutions in primate brains.


IkappaB kinase alpha kinase activity is required for self-renewal of ErbB2/Her2-transformed mammary tumor-initiating cells.
NF-kappaB is constitutively active in many solid tumors, including breast cancer. However, the role of NF-kappaB in breast carcinogenesis is unknown. Ikkalpha(AA/AA) "knockin" mice in which activation of IkappaB kinase alpha (IKKalpha) is prevented by replacement of activation loop serines with alanines exhibit delayed mammary gland growth during pregnancy, because IKKalpha activity is required for cyclin D1 induction and proliferation of lobuloalveolar epithelial cells. Given the role of cyclin D1 in breast and mammary cancer, we examined involvement of IKKalpha in mammary carcinogenesis induced by oncogenes or a chemical carcinogen, 7,12-dimethylbenz[a]anthracene (DMBA). The Ikkalpha(AA) mutation retarded tumor development in response to either 7,12-dimethylbenzaanthracene or the MMTV-c-neu (ErbB2/Her2) transgene but had no effect on MMTV-v-Ha-ras-induced cancer, although both oncogenes rely on cyclin D1. Strikingly, primary Ikkalpha(AA/AA)/MMTV-c-neu carcinoma cells exhibited diminished self-renewal capacity, resulting in the inability to establish secondary tumors. Ikkalpha(AA/AA)/MMTV-c-neu carcinoma cells underwent premature senescence when cultured under conditions used for propagation of mammary gland stem cells. Thus, IKKalpha is not only a regulator of mammary epithelial proliferation, but is also an important contributor to ErbB2-induced oncogenesis, providing signals that maintain mammary tumor-initiating cells. IKKalpha may represent a novel and specific target for treatment of ErbB2-positive breast cancer.


Preferred Fourth-Line Pharmacotherapy for Resistant Hypertension: Are We There Yet?
Resistant hypertension (RH) is defined as blood pressure (BP) that remains above target levels despite adherence to at least three different antihypertensive medications, typically including a diuretic. Epidemiological studies estimate that RH is increasing in prevalence, and is associated with detrimental health outcomes. The pathophysiology underlying RH is complex, involving multiple, overlapping contributors including activation of the renin-angiotensin aldosterone system and the sympathetic nervous system, volume overload, endothelial dysfunction, behavioural and lifestyle factors. Hypertension guidelines currently recommend specific pharmacotherapy for 1st, 2nd and 3rd-line treatment, however no specific fourth-line pharmacotherapy is provided for those with RH. Rather, five different antihypertensive drug classes are generally suggested as possible alternatives, including: mineralocorticoid receptor antagonists, α1-adrenergic antagonists, α2-adrenergic agonists, β-blockers, and peripheral vasodilators. Each of these drug classes vary in their efficacy, tolerability and safety profile. This review summarises the available data on each of these drug classes as a potential fourth-line drug and reveals a lack of robust clinical evidence for preferred use of most of these classes in the setting of RH. Moreover, there is a lack of direct comparative trials that could assist in identifying a preferred fourth-line pharmacologic approach and in providing evidence for hypertensive guidelines for adequate treatment of RH.


The contemporary approach to the care of Jehovah's witnesses.
Jehovah's Witnesses are widely known for their prohibition on the acceptance of blood transfusion. Such refusal serves as a potential obstacle to optimal therapeutic intervention among critically injured Jehovah's Witnesses. As such, care of these patients requires an aggressive and multidisciplinary approach to therapy. A review of the pertinent English language literature. Jehovah's Witnesses exercise the right of any adult with capacity to refuse medical treatment and often carry advance directive cards indicating their incontrovertible refusal of blood. Despite their belief regarding transfusion, Jehovah's Witnesses do not have a higher mortality rate after traumatic injury or surgery. Transfusion requirements are often overestimated. Increased morbidity and mortality is rarely observed in patients with a hemoglobin concentration >7 g/dL, and the acute hemoglobin threshold for cardiovascular collapse may be as low as 3 g/dL to 5 g/dL. There are many modalities to treat the Jehovah's Witness patient with acute blood loss. Treatment with recombinant human erythropoietin, albumin, and recombinant activated Factor VIIa have all been used with success. Autologous autotransfusion and isovolemic hemodilution can also be used to treat patients who refuse transfusion. Hemoglobin-based oxygen carriers may play a future role as intravascular volume expanders in lieu of transfusion of red blood cell concentrates. There are many treatment modalities available to assist in the care of Jehovah's Witness patients, especially since their beliefs on the intricacies of the Blood Ban appear to be in flux.


Cellular differentiation, bioactive and mechanical properties of experimental light-curing pulp protection materials.
Materials for pulp protection should have therapeutic properties in order to stimulate remineralization and pulp reparative processes. The aim of this study was to evaluate the mechanical properties, biocompatibility, cell differentiation and bioactivity of experimental light-curable resin-based materials containing bioactive micro-fillers. Four calcium-phosphosilicate micro-fillers were prepared and incorporated into a resin blend: 1) Bioglass 45S5 (BAG); 2) zinc-doped bioglass (BAG-Zn); 3) βTCP-modified calcium silicate (β-CS); 4) zinc-doped β-CS (β-CS-Zn). These experimental resins were tested for flexural strength (FS) and fracture toughness (FT) after 24h and 30-day storage in simulated body fluid (SBF). Cytotoxicity was evaluated using MTT assay, while bioactivity was evaluated using mineralization and gene expression assays (Runx-2 & ALP). The lowest FS and FT at 24h was attained with β-CS resin, while all the other tested materials exhibited a decrease in FS after prolonged storage in SBF. β-CS-Zn maintained a stable FT after 30-day SBF aging. Incorporation of bioactive micro-fillers had no negative effect on the biocompatibility of the experimental materials tested in this study. The inclusion of zinc-doped fillers significantly increased the cellular remineralization potential and expression of the osteogenic genes Runx2 and ALP (p<0.05). The innovative materials tested in this study, in particular those containing β-CS-Zn and BAG-Zn may promote cell differentiation and mineralization. Thus, these materials might represent suitable therapeutic pulp protection materials for minimally invasive and atraumatic restorative treatments.


Fatty liver and insulin resistance: not always linked.
One significant clinical symptom of familial hypobetalipoproteinemia [FHBL] due to defects in apolipoprotein B (apoB) is steatohepatosis. However, the increased hepatic fat content in apoB-related FHBL subjects was not associated with glucose intolerance, in contrast with what is the case in the metabolic syndrome. Meanwhile, in human subjects with similar apoB truncations, degree of obesity and insulin sensitivity, their liver triglyceride (TG) contents may vary considerably, suggesting that, in addition to defective apoB, other genes may affect the magnitude of hepatic TG accumulation. We hypothesized that genetic background affects the severity of hepatic steatosis and the expression of insulin sensitivity. To test the hypotheses, mouse apoB38.9-bearing congenies were bred under high, medium and low liver triglyceride (TG) backgrounds using "speed congenics" approach. These mice were fed on regular diet for 12 weeks. Their insulin sensitivity, serum and liver lipids were assessed. The highest liver fat strain [BALB/cByJ] accumulated significantly higher TG in the liver under apoB38.9 heterozygous condition, while the lowest liver fat strain [SWR/J] had the smallest liver TG change, suggesting that the genetic backgrounds affected the hepatic TG responses to the presence of the apoB38.9 mutation. Interestingly, only the low liver fat strain [SWR/J-apoB38.9] showed significant upward shifts of both glucose tolerance test (GTT) and insulin tolerance test (ITT) curves. Neither the glucose nor the insulin tolerance curves were altered in the two cognate congenics with higher liver fat content [BALB/cByJ and C57BL/6J]. Thus, hepatic TG contents and measures of glucose metabolism were dissociated from each other. It is tempting to conclude that hepatic TG per se may not be responsible for the insulin resistance seen in fatty liver. The genetic/molecular bases for the differences between SWR/J and the other two strains with respect to their glucose metabolic responses to increases in hepatic TG contents remain to be elucidated.


Atrial fibrillation in a primary care practice: prevalence and management.
Atrial fibrillation is a common serious cardiac arrhythmia. Knowing the prevalence of atrial fibrillation and documentation of medical management are important in the provision of primary care. This study sought to determine the prevalence of atrial fibrillation in a primary care population and to identify and quantify the treatments being used for stroke prevention in this group of patients. A prevalence study through chart audit was conducted in the family medicine practice at the Sunnybrook campus of the Sunnybrook and Women's College Health Sciences Centre. The main outcome measures were the prevalence of atrial fibrillation in our primary care practice and the use of warfarin for stroke prevention in this population. 261 patients in our practice have atrial fibrillation. The overall prevalence in our family practice unit is 3.9%. When considering patients aged 60 and over, the prevalence rises to 12.2%. 204 of our patients with atrial fibrillation (78.2%) are currently being treated with warfarin. Another 21 patients were previously treated and discontinued for a number of reasons. Of the 57 patients not currently treated with warfarin, 44 are treated with ASA, 2 with ticlopidine, and 11 are receiving no preventative treatment. The prevalence of atrial fibrillation in our practice is higher than the range of prevalence reported in the general literature. However, our coverage with warfarin treatment exceeds previous reports in the literature.


Chiropractic in the yellow pages: a content analysis study.
This paper presents a content analysis of advertisements by chiropractors in the yellow pages. Information was gathered from 13 cities in the United States for the years 1985 and 1986. Results were categorized by size, number and content of the ads. Estimated expenditures for each city were calculated and a total cost for advertising for the entire chiropractic profession was estimated. Of the 5456 chiropractors listed in the yellow pages in this study, 14.7% bought additional space in the regular listing section, and 11.6% purchased large display advertisements. The remaining 73.7% listed only their name and telephone number. Of those who bought additional space, 10.8% advertised techniques, 11.6% symptoms, 14.7% injuries, 3% professional affiliations and 4% advertised free services. The average annual expenditure for the chiropractor was $2474.00. Future research needs to address the attitudes of the profession and patients toward advertising, and the cost-effectiveness of advertising. The value of the distribution of resources for advertising by chiropractors is questioned.


Total lymphoid irradiation and antigen-specific tolerance: future therapy for experimental myasthenia gravis?
Total lymphoid irradiation (TLI) is effective in the immunosuppressive treatment of human and experimental autoimmune disorders, including experimental autoimmune myasthenia gravis (EAMG). Under certain circumstances. TLI may facilitate the induction of specific tolerance to antigens present during or shortly after the TLI treatment. This study was designed to determine whether TLI could induce or enhance tolerance to acetylcholine receptor (AChR), the antigen in myasthenia gravis, or to other antigens. We presented the antigens in various potentially tolerogenic forms to rats that were first pre-treated with TLI, or controls treated with sham irradiation. Injection of deaggregated human gamma globulin (HGG), a classical tolerogen, was most effective; it produced antigen-specific tolerance, which was significantly enhanced by pre-treatment with TLI. Injection of HGG coupled to rat peritoneal cells induced a moderate degree of specific tolerance; in this case, pre-treatment with TLI added only nonspecific suppression. In contrast, AChR, either in solubilized form with no adjuvant, or coupled to syngeneic rat peritoneal cells, failed to induce tolerance, and actually primed the immune system, when given alone or in conjunction with TLI. Subsequent challenge with AChR resulted in an enhanced (secondary) anti-AChR antibody response. These results show that the nature of the antigen itself may predispose to tolerance or to immune stimulation. AChR appears to be highly immunogenic. However, if a tolerogenic fragment or form of AChR can be identified, its use in combination with TLI may result in specific tolerance. If such specific tolerance can be induced during an ongoing autoimmune reaction to AChR, it would be an effective treatment for myasthenia gravis.


The 2018 Physical Activity Guidelines for Americans: What's New? Implications for Clinicians and the Public.
Despite the widely publicized health benefits of physical activity, a large proportion of the world's population is insufficiently active or completely inactive. The 2018 edition of the Physical Activity Guidelines for Americans (PAGA18) was a mammoth feat that took over 2 years to complete and resulted in a 779-page report in early 2018, followed by the publication of the summary guidelines in the Journal of the American Medical Association. In this Viewpoint, the authors (1) summarize the key components of the PAGA18 with respect to adults, and (2) discuss the implications for the general public and health care practitioners. J Orthop Sports Phys Ther 2019;49(7):487-490. doi:10.2519/jospt.2019.0609.


Genome-wide identification and molecular evolution of NAC gene family in Dendrobium nobile.
NAC transcription factors are an important genes that regulate plant growth and development, and can regulate functions such as fruit ripening in plants. Based on genome data of Dendrobium nobile, the NAC gene family was identified and analyzed by bioinformatics methods. In this study, we identified 85 NAC genes in Dendrobium nobile genome, and systematically analyzed the NAC gene family. We found that they were distributed unevenly in the nineteen chromosomes. The amino acid length of D. nobile NAC gene family (DnoNACs) ranged from 80 to 1065, molecular weight ranged from 22.17 to 119.02 kD, and isoelectric point ranged from 4.61~9.26. Its promoter region contains multiple stress responsive elements, including light responsive, gibberellin-responsive, abscisic acid responsiveness, MeJA-responsiveness and drought-inducibility elements. Phylogenetic analysis indicates that the D. nobile NAC gene family is most closely related to Dendrobium catenatum and Dendrobium chrysotoxum. Analysis of SSR loci indicates that the fraction of mononucleotide repeats was the largest, as was the frequency of A/T. Non-coding RNA analysis showed that these 85 NAC genes contain 397 miRNAs. The collinearity analysis shows that 9 collinear locis were found on the chromosomes of D. nobile with Arabidopsis thaliana, and 75 collinear locis with D.chrysotoxum. QRT-PCR experiment under different salt concentration and temperature conditions verified the response mechanism of DnoNAC gene family under stress conditions. Most DnoNAC genes are sensitive to salt stress and temperature stress. The results of this study provide a reference for further understanding the function of NAC gene in D. nobile.


Why Are We Scientists? Drawing Inspiration From Rita Levi-Montalcini.
In 2007, drawing inspiration from her previous experiments on chick embryos, Rita Levi-Montalcini, at the age of 98, proposed a new project, and a research group, in which I was included, was formed at the European Brain Research Institute (EBRI). Looking back on this experience, I can say that Professor Levi-Montalcini's approach and the relationships she formed with my colleagues and me, contributed to my growth as a researcher. With her welcoming and warm-hearted disposition, she taught me how to consider other people's ideas without prejudice, to reason and not to exclude any hypothesis. I also learned from her how to overcome those difficulties that are so frequent in the research field, always keeping in mind the starting point and looking toward the objective, with a factual optimism. I was just a young researcher and deeply flattered that a Nobel Laureate, with an incredible career and extraordinary life, treated me as her equal. My experience with Professor Levi-Montalcini has also provided me with a reliable path to follow, and when I encounter difficulties and challenges, I ask myself what would she have done. This approach has always helped me to move forward. Indeed, I believe the best way to celebrate Rita Levi-Montalcini as a woman in neuroscience is to recount how her exceptional example is a constant reminder as to why I have chosen to be a scientist. I hope she will always continue to be a source of inspiration for scientists in the future.


The role of radical prostatectomy and definitive external beam radiotherapy in combined treatment for high-risk prostate cancer: a systematic review and meta-analysis.
The first-line treatment options for high-risk prostate cancer (PCa) are definitive external beam radiotherapy (EBRT) with or without androgen deprivation therapy (ADT) and radical prostatectomy (RP) with or without adjuvant therapies. However, few randomized trials have compared the survival outcomes of these two treatments. To systematically evaluate the survival outcomes of high-risk PCa patients treated with EBRT- or RP-based therapy, a comprehensive and up-to-date meta-analysis was performed. A systematic online search was conducted for randomized or observational studies that investigated biochemical relapse-free survival (bRFS), cancer-specific survival (CSS), and/or overall survival (OS), in relation to the use of RP or EBRT in patients with high-risk PCa. The summary hazard ratios (HRs) were estimated under the random effects models. We identified heterogeneity between studies using Q tests and measured it using I2 statistics. We evaluated publication bias using funnel plots and Egger's regression asymmetry tests. Seventeen studies (including one randomized controlled trial [RCT]) of low risk of bias were selected and up to 9504 patients were pooled. When comparing EBRT-based treatment with RP-based treatment, the pooled HRs for bRFS, CSS, and OS were 0.40 (95% confidence interval [CI]: 0.24-0.67), 1.36 (95% CI: 0.94-1.97), and 1.39 (95% CI: 1.18-1.62), respectively. Better OS for RP-based treatment and better bRFS for EBRT-based treatment have been identified, and there was no significant difference in CSS between the two treatments. RP-based treatment is recommended for high-risk PCa patients who value long-term survival, and EBRT-based treatment might be a promising alternative for elderly patients.


Actinobacterial Degradation of 2-Hydroxyisobutyric Acid Proceeds via Acetone and Formyl-CoA by Employing a Thiamine-Dependent Lyase Reaction.
The tertiary branched short-chain 2-hydroxyisobutyric acid (2-HIBA) has been associated with several metabolic diseases and lysine 2-hydroxyisobutyrylation seems to be a common eukaryotic as well as prokaryotic post-translational modification in proteins. In contrast, the underlying 2-HIBA metabolism has thus far only been detected in a few microorganisms, such as the betaproteobacterium Aquincola tertiaricarbonis L108 and the Bacillus group bacterium Kyrpidia tusciae DSM 2912. In these strains, 2-HIBA can be specifically activated to the corresponding CoA thioester by the 2-HIBA-CoA ligase (HCL) and is then isomerized to 3-hydroxybutyryl-CoA in a reversible and B12-dependent mutase reaction. Here, we demonstrate that the actinobacterial strain Actinomycetospora chiangmaiensis DSM 45062 degrades 2-HIBA and also its precursor 2-methylpropane-1,2-diol via acetone and formic acid by employing a thiamine pyrophosphate-dependent lyase. The corresponding gene is located directly upstream of hcl, which has previously been found only in operonic association with the 2-hydroxyisobutyryl-CoA mutase genes in other bacteria. Heterologous expression of the lyase gene from DSM 45062 in E. coli established a 2-hydroxyisobutyryl-CoA lyase activity in the latter. In line with this, analysis of the DSM 45062 proteome reveals a strong induction of the lyase-HCL gene cluster on 2-HIBA. Acetone is likely degraded via hydroxylation to acetol catalyzed by a MimABCD-related binuclear iron monooxygenase and formic acid appears to be oxidized to CO2 by selenium-dependent dehydrogenases. The presence of the lyase-HCL gene cluster in isoprene-degrading Rhodococcus strains and Pseudonocardia associated with tropical leafcutter ant species points to a role in degradation of biogenic short-chain ketones and highly branched organic compounds.


[Prevalence of tuberculosis and chronic non-specific lung diseases in the towns of the Far North].
In the settlements of the Far North there is a significant reservoir of tuberculosis infection that makes up 40% and 16% in the aborigines and migrants, respectively. The alarming epidemiological prognosis, as well as the developmental association and the coincidence of clinical and social groups at risk for specific and non-specific abnormalities make it expedient to maintain annual mass fluorographic examinations by using screenings to detect the groups to be studied with auxiliary techniques and to actively detect chronic non-specific respiratory diseases.


Purine 3':5'-cyclic nucleotides with the nucleobase in a syn orientation: cAMP, cGMP and cIMP.
Purine 3':5'-cyclic nucleotides are very well known for their role as the secondary messengers in hormone action and cellular signal transduction. Nonetheless, their solid-state conformational details still require investigation. Five crystals containing purine 3':5'-cyclic nucleotides have been obtained and structurally characterized, namely adenosine 3':5'-cyclic phosphate dihydrate, C10H12N5O6P·2H2O or cAMP·2H2O, (I), adenosine 3':5'-cyclic phosphate 0.3-hydrate, C10H12N5O6P·0.3H2O or cAMP·0.3H2O, (II), guanosine 3':5'-cyclic phosphate pentahydrate, C10H12N5O7P·5H2O or cGMP·5H2O, (III), sodium guanosine 3':5'-cyclic phosphate tetrahydrate, Na(+)·C10H11N5O7P(-)·4H2O or Na(cGMP)·4H2O, (IV), and sodium inosine 3':5'-cyclic phosphate tetrahydrate, Na(+)·C10H10N4O7P(-)·4H2O or Na(cIMP)·4H2O, (V). Most of the cyclic nucleotide zwitterions/anions [two from four cAMP present in total in (I) and (II), cGMP in (III), cGMP(-) in (IV) and cIMP(-) in (V)] are syn conformers about the N-glycosidic bond, and this nucleobase arrangement is accompanied by Crib-H...Npur hydrogen bonds (rib = ribose and pur = purine). The base orientation is tuned by the ribose pucker. An analysis of data obtained from the Cambridge Structural Database made in the context of syn-anti conformational preferences has revealed that among the syn conformers of various purine nucleotides, cyclic nucleotides and dinucleotides predominate significantly. The interactions stabilizing the syn conformation have been indicated. The inter-nucleotide contacts in (I)-(V) have been systematized in terms of the chemical groups involved. All five structures display three-dimensional hydrogen-bonded networks.


The role of metabolomics in personalized medicine for diabetes.
Metabolomics is rapidly evolving omics technology in personalized medicine, it offers a new avenue for identification of multiple novel metabolic mediators of impaired glucose tolerance and dysglycemia. Liquid chromatography-mass spectrometry, gas chromatography-mass spectrometry and nuclear magnetic resonance spectroscopy are most commonly used analytical methods in the field of metabolomics. Recent evidences showed that metabolomic profiles are link to the incidence of diabetes. In this review, an overview of metabolomics studies in diabetes revealed several diabetes-associated metabolites including 1,5-anhydroglycitol, branch chain amino acids, glucose, α-hydroxybutyric acid, 3-hydroundecanoyl-carnitine and phosphatidylcholine that could be potential biomarkers associated with diabetes. These identified metabolites can be used to develop personalized prognostics and diagnostic, and help in diabetes management.


The effect of chemical disinfectants on the color of a porcelain shade guide.
To evaluate the effect of long term utilization of chemical disinfectants on the color of porcelain shade guides. three chemical disinfectants were used in this study: Minuten spray, Lysol ICQuaternary Disinfectant Cleaner (QDC), and Lysol IC Ready to Use Disinfectant Cleaner (RDC). Simulation of disinfecting cycles for one year, two years, and three years were done on Vita 3D master shade guide. Color differences were determined by visual inspection and analyzing ΔE. ΔE values were significantly below the perceptible (ΔE=1) and the clinically acceptable (ΔE=3.7) thresholds. Simulated utilization of Minuten Spray, Lysol IC (QDC), and Lysol (RDC) disinfectants for up to three years didn't cause a clinically significant difference in the color of VITA Toothguide 3D-Master Shade Guide.


5-FdUrd-araC heterodinucleoside re-establishes sensitivity in 5-FdUrd- and AraC-resistant MCF-7 breast cancer cells overexpressing ErbB2.
ErbB2 overexpressing breast tumors have a poor prognosis and a high risk to develop chemoresistance to therapeutic treatment. "Chemoresistance" is a response of cells to toxic stress, and, although it is a common phenomenon, it is still poorly defined. However, a detailed understanding is required to target desensitized pathways and mechanisms for successful reactivation as part of a tailored therapy. To gain insight, which malfunctions contribute to chemoresistance, two mechanisms relevant for tissue homeostasis, the regulation of the cell cycle and of apoptosis, were investigated. Maternal MCF-7- and ErbB2-overexpressing MCF-7(erbB2) breast cancer cells were long term pretreated with 2'-deoxy-5-fluorodeoxyuridine (5-FdUrd) or 1-beta-d-arabinofuranosylcytosine (AraC) and the acquisition of drug-insensitivity was analyzed. A phosphate-conjugated heterodinucleoside consisting of one 5-FdUrd- and one AraC-moiety (5-fluoro-2'-desoxyuridylyl-(3'-->5')-Arabinocytidine) was utilized as a tool to assess the type of acquired resistances. ErbB2-overexpression disrupted proper cell cycle regulation and furthermore facilitated the development of an apoptosis-refractory phenotype upon exposure to 5-FdUrd. Experiments with dimer 5-FdUrd-araC in ErbB2-overexpressing MCF-7(erbB2) cells, and also with nucleoside 5-FdUrd in maternal MCF-7 cells, evidenced that the phenotypes of resistance to cell cycle inhibition and to apoptosis induction were differently affected. The expression profile of cyclin D1 (but not that of p53, p21, or p27) correlated with the proliferative phenotypes and nuclear accumulation of apoptosis inducing factor (but not activation of caspase 7) with apoptotic phenotypes. Dimer 5-FdUrd-araC overrode acquired chemoresistances, whereas combined application of 5-FdUrd and AraC exhibited significantly less activity. Dimer 5-FdUrd-araC remained active in MCF-7 clones most likely by circumventing the prerequisite of first-step phosphorylation. The acquisition of chemoresistance encompassed the affection of apoptosis- and cell-cycle regulation to, respectively, different extents. Thus, drug-induced cell cycle arrest and apoptosis induction are independent of each other.


Vasoconstrictors in spinal anesthesia with tetracaine--a comparison of epinephrine and phenylephrine.
A randomized double-blind study was conducted in 50 orthopedic patients to determine the effect of epinephrine and phenylephrine on the anesthetic properties of intrathecally administered tetracaine. Two doses of each vasoconstrictor agent were studied: 0.2 mg of epinephrine, 0.3 mg of epinephrine, 1 mg of phenylephrine, and 2 mg of phenylephrine. The results show that both vasoconstrictor agents in the doses used significantly prolong duration of sensory anesthesia and motor blockade produced by the subarachnoid administration of tetracaine. At equipotent doses no differences existed between the ability of epinephrine and phenylephrine to prolong the duration of spinal anesthesia produced by tetracaine.


[Analysis of characteristics and problems of international trade of Poria cocos in China].
Poria cocos is one of medical materials frequently used in China and well marketed at home and abroad. Based on the analysis of exports and imports data of P. cocos, we found that large proportions of P. cocos were exported, while only a small proportions of those were imported in China between 2011 and 2016. During periods of these six years, the annual exporting trade of P. cocos in quantity significantly decreased, but that in dollars tend to increase slightly and the unit-prices of P. cocos significantly increased. Statistically, the average annual export trade of P. cocos from 2011 to 2016 in quantity and dollars were 9 279.73 tons and 35.454 million dollars, respectively. And the average annual export in unit-price was 4.14 dollars per kilogram. In total, P. cocos came from 29 provinces and exported to 44 countries through 21 ports. More than 98% of total exports of P. cocos were flew to the markets of countries in Asia, of which Hong Kong was the major partner in import trade of P. cocos. Large amount of P. cocos came from Guangdong province and exported mainly through Shenzhen port. Except the exports, China also imports P. cocos from other countries, among which Korea was the major country exports largest amount of P. cocos to China. And most of P. cocos were imported by Jilin province and mainly through Changchun port. To improve the export kinetic, quality and profits of P. cocos, and thus enhance the international competitiveness of the industry of P. cocos, Chinese governments should emphasize the researches on the products of P. cocos, broaden the demand space of the high-end customers, stimulate the high-end market grow in high speed and accelerate the process of standardization in future.


Whole-body inflammation in trauma patients. An autopsy study.
In a review of autopsy specimens and reports in 35 trauma cases, we found signs of generalized inflammation and tissue damage with increases in organ weights in organs not primarily injured. These abnormalities occurred independent of the time of death and were also found in patients who died of brain injury alone. The most pronounced signs of inflammation and increases in organ weights were found when the adult respiratory distress syndrome, hypovolemic shock, or multiple organ failure were the causes of death. These findings are similar to those found in several organs of rabbits after four hours of complement activation in combination with 20 minutes of hypoxia. Therefore, the autopsy findings in this series of trauma patients might represent the morphologic features of adult respiratory distress syndrome and multiple organ failure in an early, preclinical stage.


Chronic kidney disease and cancer: a troubling connection.
Chronic kidney disease (CKD) and cancer are connected in a number of ways in both directions: cancer can cause CKD either directly or indirectly through the adverse effects of therapies; CKD may, conversely, be a risk factor for cancer; and both may be associated because they share common risk factors, often toxins. In this review, we briefly address the issue of paraneoplastic nephropathies as well as that of toxin-related cancers and CKD, including analgesic and aristolochic acid nephropathies. We then focus on the links between the various stages of CKD and cancer incidence, and critically examine major epidemiologic surveys in the field. Compared with the general population, kidney transplant recipients have a threefold to fourfold increase in overall cancer risk, and relative risks higher than 3 for about 20 specific tumors, most, but not all, of which are known or suspected to be caused by viral agents. After dialysis, cancer risk increases 10% to 80% according to studies, with relative risks significantly higher than in the general population, for about 10 cancer sites. There is emerging evidence for an excess risk of cancer in patients in early CKD stages.


Seroprevalence and Spatial Distribution of Hepatitis C Virus in Bahia, Brazil.
In Salvador, which is the capital of the Brazilian state of Bahia, it has been estimated that 1.5% of the general population is infected with hepatitis C virus (HCV); however, the circulation of HCV throughout the state remains unknown. The present retrospective study aimed to determine anti-HCV seroprevalence and describe the geographic distribution of hepatitis C in Bahia. Data from HCV serological tests submitted to the Bahia Central Laboratory of Public Health between 2004 and 2013 were analyzed. Serology for HCV was performed using the AxSYM anti-HCV enzymatic microparticle immunoassay and chemiluminescence immunoassay. A subgroup of samples with detectable HCV-RNA was genotyped using the linear array hepatitis C virus genotyping assay. A total of 247,837 samples were analyzed. The median age of the studied population was 31 years (interquartile range, 25-44 years), and the female:male ratio was 3.9:1. The global seroprevalence of HCV in Bahia was estimated to be 1.3% (3,230/247,837), corresponding to an infection rate of 21.2/100,000 inhabitants. The seroprevalence of HCV was higher among males and increased with age. The presence of anti-HCV antibodies was detected throughout all mesoregions of Bahia, and the municipality with the highest infection rate was Ipiaú (112.04 cases/100,000 inhabitants). Genotypes 1 and 3 were found to be the most prevalent, followed by genotypes 2, 4, and 5. Our results provide evidence of the widespread distribution of previous HCV infection throughout the state of Bahia.


Knowledge and practice of confidential data handling in the Welsh Deanery: a brief report.
Recent large-scale personal data loss incidents highlighted the need for public bodies to more securely handle confidential data. We surveyed trainees from all specialties in the Welsh Deanery for their knowledge and practice. All registered trainees were invited to participate in an online anonymised survey. There were 880 completed and non-duplicated responses (52.9% response rate). Responses were analysed using Microsoft Access. Over 40% (388/880 (44.1%)) did not use formal guidelines on storage or disposal of confidential data. The majority appeared to dispose of confidential paper documents securely, that is, using shredders and white shredder bags. However, there were significant numbers of unmarked responses. Clinical documents, such as theatre lists, were taken home by 281/880 (31.9%) of trainees. The majority secured their computers (569/871 (65.3%)) by either not keeping patient identifiable data on them or using encryption. However, 302/871 (34.7%) did not adequately secure their computers. The surgical and anaesthetic specialties were least aware of formal confidentiality guidelines (95/178 (53.4%)) and 52/102 (51.0%) respectively) and least secured their computers (106/178 (59.6%) and 63/102 (61.8%) respectively). Education is needed to improve knowledge and practice of confidential data handling. This may be delivered through workshops during induction programmes or as part of European Computer Driving Licence (ECDL) modules. Training is especially indicated for the surgical and anaesthetic specialties.


Interaction between urethane and cannabinoid CB1 receptor agonist and antagonist in penicillin-induced epileptiform activity.
Previous experimental studies have shown that various anesthetics alter the effects of cannabinoid agonists and antagonists on the cardiac response to different stimuli. Since no data have shown an interaction between urethane and cannabinoid signaling in epilepsy, we examined the suitability of urethane with regard to testing the effects of a cannabinoid CB1 receptor agonist and an antagonist on penicillin-induced epileptiform activity in rats. Permanent screw electrodes for electrocorticographic (ECoG) recordings, and a permanent cannula for administration of the substances to the brain ventricles, were placed into the cranium of rats. Epileptiform activity was induced by injection of penicillin through the cannula in conscious animal. The CB1 receptor agonist arachidonyl-2-chloroethylamide (ACEA; 7.5 μg) and the CB1 receptor antagonist [N-(piperidin-1-yl)-5-(4-iodophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3 carboxamide] (AM-251; 0.25 μg) were administered intracerebroventricularly 30 minutes after the penicillin application in urethane-anesthetized and conscious animals. Urethane completely eliminated spontaneous ictal events in ECoG recordings and reduced the frequency and total amount of epileptiform activity. It did not alter either the proconvulsant effects of AM-251 or the anticonvulsant effects of ACEA on penicillin-induced epileptiform activity. The electrophysiological evidence suggests that there is no possible interaction between urethane and cannabinoid CB1 receptors in this experimental model of epilepsy.


[Controlled ventilation in a patient with acute exacerbation of a chronic myeloic leucaemia. A case report (author's transl)].
High counts of myeloid cells lead to erroneous results of blood gas measurements due to high rate of metabolism. This in vitro metabolism simulates hypoxaemia in the common chemical analyses. Therefore problems in the correct interpretation of blood gas measurements during controlled ventilation may arise, demonstrated in our case report of a patient with chronic myeloid leucaemia in acute stage. Immediate blocking of blood oxydative phosphorylation in the sample withdrawn is necessary in order to determine actual values which are important for adequate artificial ventilation.


Theogallin-to-Gallic-Acid Ratio as a Potential Biomarker of Pu-Erh Teas.
There are two types of Pu-erh tea available on the world market: Raw and Ripe. It is not difficult to tell them apart if the Raw version is relatively young. Researchers have already developed various tools to identify Pu-erh teas. However, they are quite complicated and require advanced statistical analyses. In addition, they are characterized by different levels of accuracy. The aim of the work was to identify relationships or differences that would easily give specific results for identifying types of Pu-erh tea. The content of selected methylxanthines was determined by high-performance liquid chromatography (HPLC) on an Agilent 1200 chromatograph with a UV-VIS diode array detector. The total analysis time was 28 min. A combination of liquid chromatography and a triple quadrupole mass spectrophotometer was used to identify gallic acid and theogallin in the analyzed samples. A multivariate cluster analysis was used to compare the results for single samples, and its results were presented in horizontal hierarchical tree plots. The quantitative determination showed that theophylline is present only in Ripe Pu-erh teas. In addition, it was shown that the ratio of theogallin to gallic acid can be an effective tool to verify the authenticity of Pu-erh varieties.


Islet1 is a direct transcriptional target of the homeodomain transcription factor Shox2 and rescues the Shox2-mediated bradycardia.
The heart's rhythm is initiated and regulated by a group of specialized cells in the sinoatrial node (SAN), the primary pacemaker of the heart. Abnormalities in the development of the SAN can result in irregular heart rates (arrhythmias). Although several of the critical genes important for SAN formation have been identified, our understanding of the transcriptional network controlling SAN development remains at a relatively early stage. The homeodomain transcription factor Shox2 is involved in the specification and patterning of the SAN. While the Shox2 knockout in mice results in embryonic lethality due to severe cardiac defects including improper SAN development, Shox2 knockdown in zebrafish causes a reduced heart rate (bradycardia). In order to gain deeper insight into molecular pathways involving Shox2, we compared gene expression levels in right atria of wildtype and Shox2 (-/-) hearts using microarray experiments and identified the LIM homeodomain transcription factor Islet1 (Isl1) as one of its putative target genes. The downregulation of Isl1 expression in Shox2 (-/-) hearts was confirmed and the affected region narrowed down to the SAN by whole-mount in situ hybridization. Using luciferase reporter assays and EMSA studies, we identified two specific SHOX2 binding sites within intron 2 of the ISL1 locus. We also provide functional evidence for Isl1 as a transcriptional target of Shox2 by rescuing the Shox2-mediated bradycardia phenotype with Isl1 using zebrafish as a model system. Our findings demonstrate a novel epistatic relationship between Shox2 and Isl1 in the heart with important developmental consequences for SAN formation and heart beat.


An archaeal chromosomal autonomously replicating sequence element from an extreme halophile, Halobacterium sp. strain NRC-1.
We report on the identification and first cloning of an autonomously replicating sequence element from the chromosome of an archaeon, the extreme halophile Halobacterium strain NRC-1. The putative replication origin was identified by association with the orc7 gene and replication ability in the host strain, demonstrated by cloning into a nonreplicating plasmid. Deletion analysis showed that sequences located up to 750 bp upstream of the orc7 gene translational start, plus the orc7 gene and 50 bp downstream, are sufficient to endow the plasmid with replication ability, as judged by expression of a plasmid-encoded mevinolin resistance selectable marker and plasmid recovery after transformation. Sequences located proximal to the two other chromosomally carried haloarchaeal orc genes (orc6 and orc8) are not able to promote efficient autonomous replication. Located within the 750-bp region upstream of orc7 is a nearly perfect inverted repeat of 31 bp, which flanks an extremely AT-rich (44%) stretch of 189 bp. The replication ability of the plasmid was lost when one copy of the inverted repeat was deleted. Additionally, the inverted repeat structure near orc7 homologs in the genomic sequences of two other halophiles, Haloarcula marismortui and Haloferax volcanii, is highly conserved. Our results indicate that, in halophilic archaea, a chromosomal origin of replication is physically linked to orc7 homologs and that this element is sufficient to promote autonomous replication. We discuss the finding of a functional haloarchaeal origin in relation to the large number of orc1-cdc6 homologs identified in the genomes of all haloarchaea to date.


Automated cot-side tracking of functional brain age in preterm infants.
A major challenge in the care of preterm infants is the early identification of compromised neurological development. While several measures are routinely used to track anatomical growth, there is a striking lack of reliable and objective tools for tracking maturation of early brain function; a cornerstone of lifelong neurological health. We present a cot-side method for measuring the functional maturity of the newborn brain based on routinely available neurological monitoring with electroencephalography (EEG). We used a dataset of 177 EEG recordings from 65 preterm infants to train a multivariable prediction of functional brain age (FBA) from EEG. The FBA was validated on an independent set of 99 EEG recordings from 42 preterm infants. The difference between FBA and postmenstrual age (PMA) was evaluated as a predictor for neurodevelopmental outcome. The FBA correlated strongly with the PMA of an infant, with a median prediction error of less than 1 week. Moreover, individual babies follow well-defined individual trajectories. The accuracy of the FBA applied to the validation set was statistically equivalent to the training set accuracy. In a subgroup of infants with repeated EEG recordings, a persistently negative predicted age difference was associated with poor neurodevelopmental outcome. The FBA enables the tracking of functional neurodevelopment in preterm infants. This establishes proof of principle for growth charts for brain function, a new tool to assist clinical management and identify infants who will benefit most from early intervention.


The p55 tumour necrosis factor receptor TNFR1 contains a trans-Golgi network localization signal in the C-terminal region of its cytoplasmic tail.
It has been reported in some human cells that, in addition to a plasma membrane localization, members of the tumour necrosis factor receptor superfamily may be localized to the Golgi complex. We have shown by immunofluorescence and immunoelectron microscopy that the p55 tumour necrosis factor receptor, TNFR1, is principally localized to the trans-Golgi network in the human breast carcinoma cell line, MCF7. Chimaeras consisting of the extracellular and transmembrane domains of CD8 together with the cytoplasmic tail of TNFR1 were targeted to the trans-Golgi network in stably transfected rat fibroblastic cells. Deletions in the cytoplasmic tails of these chimaeras demonstrated the requirement for the C-terminal sequence of 23 amino acids for this targeting. The 23 amino acid sequence is mostly outside the death domain and contains both an acid patch and a dileucine motif. Interaction of this sequence with membrane traffic adaptor proteins may play an important role in controlling the responses of cells to tumour necrosis factor, since binding of signalling adaptor proteins has only been demonstrated for plasma membrane, and not Golgi-localized, TNFR1.


Moving the Needle Toward Fair Compensation in Pediatric Nephrology.
Remuneration issues are a substantial threat to the long-term stability of the pediatric nephrology workforce. It is uncertain whether the pediatric nephrology workforce will meet the growing needs of children with kidney disease without a substantial overhaul of the current reimbursement policies. In contrast to adult nephrology, the majority of pediatric nephrologists practice in an academic setting affiliated with a university and/or children's hospital. The pediatric nephrology service line is crucial to maintaining the financial health and wellness of a comprehensive children's hospital. However, in the current fee-for-service system, the clinical care for children with kidney disease is neither sufficiently valued, nor appropriately compensated. Current compensation models derived from the relative value unit (RVU) system contribute to the structural biases inherent in the current inequitable payment system. The perceived negative financial compensation is a significant driver of waning trainee interest in the field which is one of the least attractive specialties for students, with a significant proportion of training spots going unfilled each year and relatively stagnant growth rate as compared to the other pediatric subspecialties. This article reviews the current state of financial compensation issues plaguing the pediatric nephrology subspecialty. We further outline strategies for pediatric nephrologists, hospital administrators, and policy-makers to improve the landscape of financial reimbursement to pediatric subspecialists. A physician compensation model is proposed which aligns clinical activity with alternate metrics for current non-RVU producing activities that harmonizes hospital and personal mission statements.


Perioperative platelet reactivity and the effects of clonidine.
Increased postoperative platelet reactivity may contribute to arterial thrombotic complications following surgery. alpha 2 Agonists, which are being used increasingly to blunt the stress response of surgery, increase platelet aggregation in vitro. We compared perioperative changes in platelet reactivity in 21 patients receiving either clonidine or placebo. Patients undergoing major abdominal surgery were randomized to receive oral and transdermal clonidine (n = 11) or placebo (n = 10). All patients received similar perioperative management, including preoperative sedation, general anesthesia without neuraxial opioids, or local anesthetics and postoperative patient-controlled intravenous morphine. Blood was obtained for measurement of clonidine level, fibrinogen concentration, platelet count, and platelet reactivity (impedance aggregometry and dense granule release) before induction and 24, 48, and 72 h postoperatively. Thirteen of the 21 patients had biopsy-proven cancer at surgery, 5 of 11 received clonidine and 8 of 10 received placebo (NS). Clonidine levels were therapeutic (1-2 ng/ml) throughout the study period. Clonidine administration had no effect on platelet count or platelet reactivity. Therefore, the groups were combined for further analysis. In this group (n = 21), compared to preoperative values, fibrinogen levels rose maximally (36%) at 72 h postoperatively and platelet counts decreased 22% at 48 h. Platelet reactivity (aggregation and degranulation) to collagen, adenosine diphosphate, arachidonic acid, and ristocetin, increased at 24, 48, and 72 h postoperatively. Thrombin-induced (supramaximal stimulus) dense granule release did not change from preoperative values. These data indicate that major abdominal surgery causes increased platelet reactivity postoperatively but does not effect maximal degranulation. This increased platelet reactivity occurs within 48 h of surgery, coinciding with the peak incidence of postoperative arterial thrombotic complications. Clonidine administration has no effect on surgically induced changes in platelet reactivity. In this surgical patient population, the use of clonidine should not increase the risk of platelet-induced perioperative arterial thrombosis.


Development and characterization of a novel biodegradable and antioxidant film based on marine seaweed sulfated polysaccharide.
This research aims to produce an antioxidant and biodegradable polysaccharide film by using macroalgae agar and sulfated polysaccharide. Agar and sulfated polysaccharide (fucoidan) were extracted from Gracilaria corticata and Sargassum angustifolium macroalgae. Five treatments were conducted: (A) agar film (1%, W:V), (C) chitosan film (1%, W:V + 1% acetic acid), (AC) agar:chitosan composite (50:50, V:V), (ACF) AC film with fucoidan (0.5%, W:V), and (ACFA) ACF film with citric acid (30% of the dry weight of film) as a cross-linking agent. Then, 0.75% (V:V) of glycerol was added to all films. The physical, mechanical, antioxidant, color variations, microstructure (SEM), and Fourier transform infrared (FT-IR) spectroscopy were investigated. Based on the results, modifying the agar film with chitosan improved the mechanical strength, humidity, and solubility in the AC composite film (p < .05). Further, adding sulfated polysaccharide and citric acid cross-linking agent to the agar-chitosan composite led to a significant decrease in solubility, humidity, and permeability to water vapor in ACFA films (p < .05), indicating strong cross-linking and reduction in film pores based on the SEM pictures and FTIR results. However, the physical and mechanical properties of the agar-based film obtained from Gracilaria algae can be improved by adding chitosan and citric acid cross-linking agent, and the addition of fucoidan obtained from Sargassum algae has improved its antioxidant properties. This biodegradable film can be a good candidate for preserving perishable products.


Effects of carbon tetrachloride, menadione, and paraquat on the urinary excretion of malondialdehyde, formaldehyde, acetaldehyde, and acetone in rats.
Excretions of the lipid peroxidation products, formaldehyde (FA), acetaldehyde (ACT), malondialdehyde (MDA), and acetone (ACON), were simultaneously identified and quantitated in the urine of female Sprague-Dawley rats by gas chromatography-mass spectroscopy (GC-MS) and high pressure liquid chromatography (HPLC) following the acute administration of carbon tetrachloride, a model alkylating agent that does not induce glutathione depletion, and the redox cycling compounds paraquat and menadione. All three xenobiotics are well-known inducers of oxidative stress. Oxidative stress was induced by oral administration of single doses of 2.5 mL of carbon tetrachloride/kg, 60 mg menadione/kg, and 75 mg paraquat/kg. These doses are approximately 50% of the LD50's for the three xenobiotics. Urinary excretion of FA, ACT, MDA, and ACON increased relative to control animals following treatment with all xenobiotics. Over the 48 hours of the study, the greatest increases in the excretion of MDA, FA, ACT, and ACON occurred after paraquat administration, with increases of approximately 2.7-, 2.6-, 4.3-, and 11.0-fold, respectively. This technique may have wide-spread applicability as an effective biomarker for investigating altered lipid metabolism in disease states and exposure to environmental pollutants/xenobiotics.


Visible light-mediated C (sp3)-H bond functionalization inside an all-organic nanocavity.
Ultrafast C-H bond activation and functionalization in confinement using visible light will enable engineering chemical reactions with extraordinary speed and selectivity. To provide a transition metal-free route, here we demonstrate C-H bond activation reactions on poly-aromatic hydrocarbons (PAH) in all-organic cationic nanocage ExBox4+ for the first time. Visible light excitation in the host-guest charge transfer (CT) state allows the formation of oxidized photoproducts with high selectivity. Mechanistic understanding of this CT-mediated photoreaction using femtosecond broadband transient absorption revealed a few ∼100 ps timescale for C-H bond breaking on the attached -CH3 group via sequential electron transfer and proton transfer steps. We envision that our photosensitizer-free method will open up new avenues to pursue organic reactions using cavities that could serve both as photoredox catalysts and hosts for reactive reaction intermediates.


The effect of mannitol on renal function after cardiopulmonary bypass in patients with established renal dysfunction.
The usefulness of mannitol in the priming fluid for cardiopulmonary bypass is uncertain in patients with normal renal function, and has not been studied in patients with established renal dysfunction. We studied 50 patients with serum creatinine between 130 and 250 micromol.l(-1) having cardiac surgery. Patients were randomised to receive mannitol 0.5 g.kg(-1), or an equivalent volume of Hartmann's solution, in the bypass prime. There were no differences between the groups in plasma creatinine or change in creatinine from baseline, urine output, or fluid balance over the first three postoperative days. We conclude that mannitol has no effect on routine measures of renal function during cardiac surgery in patients with established renal dysfunction.


Delphinidin-3-glucoside protects against oxidized low-density lipoprotein-induced mitochondrial dysfunction in vascular endothelial cells via the sodium-dependent glucose transporter SGLT1.
Delphinidin-3-glucoside (Dp) is a member of a family of bioactive compounds known as anthocyanins that occur naturally in pigmented plants and are known to ameliorate oxidative stress. Previous studies have showed that Dp decreased oxidative stress in vascular endothelial cells, however, the underlying mechanisms remain largely unknown. In the present study, we showed that pretreatment with Dp significantly suppressed oxidized low-density lipoprotein (oxLDL)-induced cell proliferation inhibition and apoptosis in primary human umbilical vein endothelial cells (HUVECs). Also, Dp pretreatment attenuated oxLDL-induced mitochondrial dysfunction via decreased reactive oxygen species (ROS) and superoxide anion generation, thereby repressing mitochondrial membrane potential and closing mitochondrial permeability transition pore. Furthermore, in vitro and in vivo data showed that Dp was transported into endothelial cells in a temperature, concentration, and time-dependent manner via the sodium-dependent glucose transporter (SGLT1). Suppression of SGLT1 by its substrate glucose, its inhibitor phlorizin or SGLT1 siRNA blocked Dp transportation. Repression of SGLT1 significantly inhibited Dp function of ameliorating mitochondrial dysfunction induced by pro-apoptotic factors (Apoptosis-inducing factor, Cytochrome c, Caspase-3 and Bax/Bcl-2 ratio). Taken together, our data indicate that Dp protects VECs via the SGLT1-ROS-mitochodria pathway. This new insight may help to elucidate the molecular mechanisms underlying the vascular protection afforded by Dp, and anthocyanins in general, in the context of prevention of endothelial dysfunction and atherosclerosis.


The relationship between echocardiographic features of mitral valve and elastic properties of aortic wall and Beighton hypermobility score in patients with mitral valve prolapse.
The present study was designed to investigate the incidence of benign joint hypermobility syndrome (BJHMS) in mitral valve prolapse (MVP) and the correlation between the echocardiographic features of the mitral valve and elastic properties of the aortic wall and Beighton hypermobility score (BHS) in patients with MVP and BJHMS. Fourty-six patients with nonrheumatic, uncomplicated, and isolated mitral anterior leaflet prolapse (7 men and 39 women, mean age; 26.1 +/- 5.9) and 25 healthy subjects (3 men and 22 women, mean age, 25.4 +/- 4.3) were studied. Patients were divided into two groups according to their BHS (group I, MVP+BJHMS; group II, MVP-BJHMS). Individuals with accompanying cardiac or systemic disease were excluded. Echocardiographic examination was performed in all subjects. The presence of BJHMS was evaluated according to Beighton's criteria. The incidence of BJHMS in patients with MVP was found to be significantly higher than that of controls (45.6%, (21/46) vs 12% (3/25), P < 0.0001). Group I (MVP + BJHMS) had significantly increased anterior mitral leaflet thickness (AMLT, 3.4 +/- 0.4 vs 3.1 +/- 0.3; P < 0.005), maximal leaflet displacement (MLD, 2.4 +/- 0.4 vs 1.7 +/- 0.4; P < 0.005), and degree of mitral regurgitation (DMR, 17.1 +/- 7.2 vs 11.2 +/- 4.4; P < 0.01) compared to group II. However, the index of aortic stiffness (IAOS) was found to be lower (17.6 +/- 6.9 vs 23.9 +/- 7.6; P < 0.005) and aortic distensibility (AOD) to be higher (0.0035 +/- 0.007 vs 0.0024 +/- 0.005; P < 0.005) in group I. There was a significant correlation between AMLT, MLD and DMR, and BHS (r = 0.57/P = 0.007, r = 0.55/P < 0.009, r = 0.51/P < 0.01, respectively). In addition, AOD correlated positively with BHS (r = 0.53/P < 0.005), but the index of aortic stiffness correlated inversely with BHS (r = -0.49/P < 0.007). The incidence of BJHMS in patients with MVP was more frequent than the normal population and there was a significant correlation between the severity of BJHMS (according to BHS) and echocardiographic features of the mitral leaflets and elastic properties of the aortic wall.


Antiplatelet drug therapy moderates immune-mediated liver disease and inhibits viral clearance in mice infected with a replication-deficient adenovirus.
Treatment with a low dose of combined aspirin and clopidogrel, two antiplatelet drugs widely used in humans, markedly reduced the homing of virus-specific cytotoxic T lymphocytes and virus-nonspecific inflammatory leukocytes to the liver of mice acutely infected with a hepatotropic, replication-deficient, lacZ-expressing adenovirus (RAd35). Consequently, aspirin/clopidogrel-induced platelet dysfunction greatly diminished liver disease severity and inhibited viral clearance. Along with the finding that aspirin/clopidogrel caused neither bleeding nor anemia, our results suggest that antiplatelet drugs may be considered to limit excessive liver immunopathology and/or to facilitate the persistence of hepatotropic viral vectors utilized in gene therapy.


Phosphine-Catalyzed [3 + 2] Annulation of 2-Hydroxy-1,4-naphthaquinones and Allenoate: An Allene-Alkene [3 + 2] Annulation Mechanism Involving Consecutive γ-Addition-Aldol Reaction.
A diastereoselective construction of biologically important tetrahydrocyclopenta[ b]naphthalene derivatives has been achieved via a phosphine-catalyzed [3 + 2] annulation of 2-hydroxy-1,4-naphthaquinone derivatives and allenoate. Various tetrahydrocyclopenta[ b]naphthalene derivatives containing contiguous quaternary carbon centers are obtained in good yields with excellent diastereoselectivities. The asymmetric version gave the chiral product in up to 57% ee under catalysis of Kwon chiral phosphine. The reaction undergoes a reaction mechanism involving consecutive γ-addition-aldol reaction.


Spasticity treatment in Norwegian hospitals.
Spasticity is a frequent complication of diseases of and injuries to the central nervous system. Early treatment prevents further loss of function and spasticity-related complications. Basic spasticity treatment begins in the primary healthcare service and includes physiotherapy, occupational therapy and oral spasmolytics, while treatment with botulinum toxin and baclofen pump is carried out by the specialist healthcare services. The objective of the study was to obtain an overview of the availability and organisation of these specialised forms of spasticity treatment in Norway. We conducted a survey in which a digital questionnaire was sent to hospitals that offer spasticity treatment. A total of 30 of 47 hospital departments/outpatient clinics (hereafter referred to as 'hospital units') distributed across all Norwegian health regions responded to the questionnaire. Spasticity treatment with botulinum toxin and baclofen pump was available in all of the health regions. Median time from first referral was 10 weeks (interquartile range 7 weeks). A total of 14 of 30 hospital units expressed a need for more treatment days to cover the local demand. Of the 30 hospital units, 23 had interdisciplinary teams with doctors, physiotherapists, occupational therapists and/or nurses. For treatment with botulinum toxin, ultrasound was used as guidance in 22 of 26 hospital units, EMG was used in 15 units and electrical muscle stimulation was used in 11 units. The study suggests that there may be a need for improvements to specialised spasticity treatment in Norway to ensure good patient care pathways, interdisciplinary assessments, and safe and efficient performance of the practical interventions.


Isolation and in vitro translation of mRNA from inflorescences of Parietaria judaica.
The aqueous extract of inflorescences of Parietaria judaica contains an allergen homologous to the major pollen allergen Par o I (14 kD), as shown by radio-allergosorbent test (RAST) inhibition and immunoblot analysis. Poly(A)+ RNA was obtained from inflorescences and was shown to be able to code in vitro for a protein homologous to Par o I with respect to sodium dodecylsulphate polyacrylamide gel electrophoretic mobility and to antigenic specificity as defined by the binding, in affinity chromatography, to solid-phase IgG of rabbit anti-Par o I antisera, and in RAST inhibition, to IgE antibodies of human reaginic serum pool.


Sciatic neuropathy: clinical and prognostic features in 73 patients.
We examined the clinical features of patients with sciatic neuropathy and the factors that influence prognosis. Of 92 consecutive patients referred for EMG evaluation of sciatic neuropathy, 73 fulfilled strict inclusion and exclusion criteria and had adequate clinical and electrophysiologic information. The etiologies included hip arthroplasty (21.9%), acute external compression (13.7%), infarction (9.6%), gunshot wound (9.6%), hip fracture/dislocation (9.6%), femur fracture (4.1%), contusion (4.1%), and uncertain (16.4%). We used life table analysis to determine outcome and to identify prognostic factors in patients with acute or subacute onset. Moderate or better recovery (improvement to grade 2 or by two of six clinical grades) occurred in most patients (30% by 1 year, 50% by 2 years, 75% by 3 years). A subgroup experienced excellent improvement (by three of six grades, or to grade 2) less frequently (33% by 2 and 3 years). Of the nine factors tested, two predicted an earlier or better recovery: a recordable compound muscle action potential of the extensor digitorum brevis (p < 0.025), and an initial absence of paralysis of muscles controlling ankle plantar flexion and dorsiflexion (p < 0.05). Thus, good but incomplete recovery occurs over 2 to 3 years in most patients with sciatic neuropathy, particularly in those without severe motor axonal loss.


[Iron deficiency and anemia in female athletes--causes and risks].
Iron deficiency is probably the most common nutrient deficiency in the western world. Low levels of iron in the body are caused by several mechanisms, and become symptomatic with the onset of iron deficiency anemia. Athletes are a special group with additional reasons for iron or blood loss, such as plasma expansion, increase perspiration, 'foot strike hemolysis, and occasionally--malnutrition. Female athletes have yet another source of blood loss--menstruation. However, the most common cause for low hemoglobin levels in an athlete is dilutional pseudoanemia, which is caused by exercise-induced fluid retention. Athletes are more sensitive to the effects of anemia and iron deficiency, as exercise performance depends on maximal oxygen carrying capacity to the active muscle, and efficient oxygen utilization. Iron deficiency without anemia can also reduce athletic performance. Diagnosis is ultimately made by a blood count and red blood cell parameters, with ferritin serving as an index of body iron stores. Treatment requires iron supplements, as it is nearly impossible to refill the iron stores through diet alone.


Ayahuasca in adolescence: a preliminary psychiatric assessment.
Ayahuasca is believed to be harmless for those (including adolescents) drinking it within a religious setting. Nevertheless controlled studies on the mental/ psychiatric status of ritual hallucinogenic ayahuasca concoction consumers are still lacking. In this study, 40 adolescents from a Brazilian ayahuasca sect were compared with 40 controls matched on sex, age, and educational background for psychiatric symptomatology. Screening scales for depression, anxiety, alcohol consumption patterns (abuse), attentional problems, and body dysmorphic disorders were used. It was found that, compared to controls, considerable lower frequencies of positive scoring for anxiety, body dismorphism, and attentional problems were detected among ayahuasca-using adolescents despite overall similar psychopathological profiles displayed by both study groups. Low frequencies of psychiatric symptoms detected among adolescents consuming ayahuasca within a religious context may reflect a protective effect due to their religious affiliation. However further studies on the possible interference of other variables in the outcome are necessary.


Spontaneous intracranial hypotension with isolated cortical vein thrombosis and subarachnoid haemorrhage.
Spontaneous intracranial hypotension (SIH) associated with subarachnoid haemorrhage (SAH) has never been reported. Here, we report on a case of a 33-year-old woman with SIH, who developed simple partial sensory seizures 3 weeks later. Neuroimaging studies, including brain computed tomography and angiography, were initially normal, but revealed an isolated cortical venous thrombosis at 3 weeks. One week later, brain magnetic resonance imaging showed SAH around the thrombosed cortical vein. We postulate that the decline in the venous blood flow velocity due to SIH may have resulted in cortical venous thrombosis, which in turn led to rupture of the vessel wall and SAH in this patient.


Metalloproteinases stimulate ErbB-dependent ERK signaling in human skin organ culture.
To investigate the role of ERK signaling in human skin responses to wounding, organ cultures of human skin were maintained for 0.5-24 h in the presence of various inhibitors, followed by measurement of ERK phosphorylation or mRNA levels. The MEK inhibitor PD98059 produced near-complete (97-98%) inhibition of ERK phosphorylation, whereas inhibition of c-Fos, c-Jun, HB-EGF, AR, and VEGF mRNA by this compound was incomplete (41-65%). PD98059 was significantly more effective than either PD158780 or BB2516 as an inhibitor of ERK phosphorylation and of the rapid rise in c-Fos and c-Jun mRNA expression. In contrast, all three compounds inhibited the more delayed rise in HB-EGF mRNA to the same extent. Exogenous epidermal growth factor abrogated the inhibition of ERK phosphorylation caused by BB2516. These data indicate that one or more metalloproteinases activate ErbB signaling in skin organ culture, that ErbB signaling plays an important but not exclusive role in the activation of ERK, and that non-ERK pathways contribute to gene expression in this system. Because metalloproteinase-mediated cleavage of the HB-EGF transmembrane precursor is known to be ERK-dependent, our data suggest that ERK activation resulting from initial trauma leads to metalloproteinase-mediated cleavage of HB-EGF, thereby triggering the ErbB signaling cascade.


C3 convertase of human complement: enhanced formation and stability of the enzyme generated with nickel instead of magnesium.
We demonstrate that nickel++ (Ni) can replace Mg in the formation of the C3b,Bb enzyme, and that Ni is more efficient in enzyme formation than Mg. C3b-bearing sheep erythrocytes (EC3b) were used to measure radiolabeled Factor B uptake and C3 convertase activity. Up to nine times more Factor B was specifically bound to EC3b in the presence of Ni than in the presence of Mg under identical conditions. To form one effective hemolytic site (1 Z) per EC3b cell with Ni, three times less Factor B, 12 times less Factor D, and 66 times less metal ion were required than when using Mg. The C3b,Bb formed with Ni (C3b,Bb(Ni)) had a 5 to 10 times longer half-life at different temperatures than the enzyme formed with Mg (C3b,Bb(Mg)). Native properdin stabilized C3b,Bb(Ni) to the same extent as C3b,Bb(Mg) (four to five times) and Factor H accelerated similarly the decay of both enzymes. Ni could also replace Mg in the formation of the C4b,2a enzyme. C4b,2a formation was measured by using C1 and C4b-bearing sheep erythrocytes (EAC1,4b) and native C2. To form 1 Z per EAC1,4b cell with Ni, two times less C2 and 60 times less metal ion were required than when using Mg. The half-life of the C4b,2a formed with Ni was two times longer than that formed with Mg. Decay of both C3b,Bb and C4b,2a enzymes formed either with Mg or with Ni was unaffected by EDTA. These results show that Ni is more efficient than Mg in the generation of both enzymes and suggest that Ni binds to the Mg-binding sites of the enzymes with a higher affinity than Mg.


Ifosfamide, carboplatin and etoposide in children with poor-risk relapsed Wilms' tumor: a Children's Cancer Group report.
The outcome of children with relapsed Wilms' tumor is poor, especially with poor-risk factors such as unfavorable histology, early recurrence, previous three-drug therapy, relapse not confined to lungs and abdominal relapse following abdominal radiotherapy. We report the overall response rate, progression-free survival and overall survival of 11 children with relapsed and poor-risk Wilms' tumor following ifosfamide/carboplatin/etoposide (ICE) chemotherapy. ICE therapy consisted of ifosfamide 1800 mg/m2/day (on day 0-4), carboplatin 400 mg/m2/day (on day 0-1) and etoposide 100 mg/m2/day (on day 0-4). The median age at diagnosis was 39 months (range from 13 months to 16 years) and the median time to relapse after initial diagnosis was 9 months (range 4-72 months). All but one patient had at least one poor prognostic feature, with eight patients showing three or four. After ICE chemotherapy the number of patients showing a complete response (CR) was three (27%) and a partial response (PR) was six (55%). The overall response rate (CR+PR) was 82%. Five of the six patients with a PR subsequently achieved a CR with further therapy. The 3-year event-free survival and overall survival were 63.6 +/- 14.5%. The response rate in children with relapsed and poor-risk Wilms' tumor is >80% with ICE re-induction chemotherapy followed by post-ICE therapy. The optimal approach for post-ICE consolidation therapy has yet to be determined.


Isolated popliteal vein entrapment by a fibrous band--a case report.
Popliteal vein entrapment is commonly associated with popliteal artery entrapment, whereas isolated popliteal vein entrapment is a less common entity. The authors present a case of isolated popliteal vein entrapment caused by a fibrous band.


An introduction to Turner syndrome.
Turner syndrome is a chromosomal condition affecting around 1 in 2,000 girls born in the UK. The severity of the problems experienced can be partly predicted by the child's karyotype but some are mediated by the social and other life experiences of the developing child. Management focuses on minimising the effects of the condition on the girls' lives and promoting their long term health and wellbeing. Nurses specialising in paediatric endocrinology have a valuable role in supporting the child and family and in educating families and colleagues with regard to the medical, psychosocial and educational needs of these children.


Assessment of the patient who is neurologically impaired.
Care of the patient with emergent neurologic trauma incorporates assessment, diagnosis, and treatment by a multidisciplinary team. Establishing intravenous access and determining fluid requirements necessitates an advanced knowledge of infusion support and of fluid and electrolyte balance. When these factors are addressed in a systematic, continuous manner throughout all phases of the trauma care continuum, the patient with emergent neurologic trauma has the best opportunity for restoration of optimal neurologic function.


Circulating metabolites and cardiovascular disease in Asians with chronic kidney disease.
Introduction Chronic kidney disease (CKD) is a growing public health problem, with significant burden of cardiovascular disease and mortality. The risk of cardiovascular disease in CKD is elevated beyond that predicted by traditional cardiovascular risk factors, suggesting that other factors may account for this increased risk. Through metabolic profiling, this study aimed to investigate the associations between serum metabolites associated with prevalent cardiovascular disease in Asian patients with CKD to provide insights into the complex interactions between metabolism, cardiovascular disease in CKD. Methods This was a single-center cross-sectional study of 1122 individuals from three ethnic cohorts in the population-based Singapore Epidemiology of Eye Disease (SEED) study (153 Chinese, 707 Malays, and 262 Indians) aged 40-80 years with CKD (estimated glomerular filtration rate <60 mL/min/1.73 m2). Nuclear magnetic resonance (NMR) spectroscopy was used to quantify 228 metabolites from participants' serum or plasma. Prevalent cardiovascular disease was defined as self-reported myocardial infarction, angina, or stroke. Multivariate logistic regression identified metabolites independently associated with cardiovascular disease in each ethnic cohort. Metabolites with the same direction of association in all three cohorts were selected and those significantly associated with cardiovascular disease after Bonferroni correction were meta-analyzed. Results Cardiovascular disease was present in 275 (24.5%). Participants with cardiovascular disease tend to be male, of older age, with hypertension, hyperlipidemia and diabetes; with lower systolic and diastolic blood pressure (BP), high-density lipoprotein (HDL)- and low-density lipoprotein (LDL)- cholesterol than those without cardiovascular disease. After adjusting for age, sex, systolic blood pressure, diabetes, total cholesterol and HDL-cholesterol, 10 lipoprotein subclass ratios and 6 other metabolites were significantly associated with prevalent cardiovascular disease in at least one cohort. Meta-analysis with Bonferroni correction for multiple comparisons found that lower tyrosine, leucine and valine concentrations and lower cholesteryl esters to total lipid ratio in intermediate-density lipoprotein (IDL) were associated with cardiovascular disease. Discussion/Conclusion In Chinese, Malay and Indian participants with CKD, prevalent cardiovascular disease was associated with tyrosine, leucine, valine and cholesteryl esters to total lipid ratios in IDL. Increased cardiovascular risk in CKD patients may be contributed by altered amino acid and lipoprotein metabolism. The presence of CKD and ethnic differences may affect interactions between metabolites in health and disease, and with greater understanding will allow us to better risk stratify patients, and also individualize care with consideration of ethnic disparities.


The use of intravenous buprenorphine for the treatment of opioid withdrawal in medically ill hospitalized patients.
The aim of this study was to assess the safety of buprenorphine administered intravenously for the treatment of opioid withdrawal in medically ill hospitalized patients. Data regarding demographic information, number of doses of buprenorphine, and measures of buprenorphine's effects were collected via chart reviews for 30 heroin-dependent patients who received buprenorphine intravenously during their hospitalization for an acute medical problem. No respiratory depression was observed, and no patients reported feeling "high." All patients reported that buprenorphine decreased withdrawal symptoms. Thus, intravenous administration of buprenorphine appears to be safe for the treatment of opioid withdrawal.


Transient global amnesia: definition and clinical phenomenology.
Based on personal observations and analysis of the most impressive literature, some considerations are made on transient global amnesia definition and clinical phenomenology.


Age-grading the biting midge Culicoides sonorensis using near-infrared spectroscopy.
Age-grading of insects is important in the control and monitoring of both insect populations and vector-borne diseases. Microscopy and morphological techniques exist to age-grade most blood-feeding flies, but these techniques are laborious, often destructive to the insects, and slow. Near-infrared spectroscopy (NIRS) can be automated and is a non-destructive technique for age-grading. We applied NIRS techniques to age-grade females of the biting midge, Culicoides sonorensis Wirth & Jones (Diptera: Ceratopogonidae), the vector of bluetongue and other arboviruses in North America. Female flies of five known age cohorts (1, 3, 6, 9 and 12 days post-emergence) from three laboratory colonies were used. The data indicate that NIRS can be used to differentiate age groups of C. sonorensis.


Augmenting PTSD treatment with physical activity: study protocol of the APPART study (Augmentation for PTSD with Physical Activity in a Randomized Trial).
New intensive trauma-focused treatment (TFT) programmes that incorporate physical activity have been developed for people with post-traumatic stress disorder (PTSD). However, the unique contribution of physical activity within these intensive TFT programmes has never been investigated in a controlled manner. This randomized controlled trial will investigate the effectiveness of physical activity added to an intensive TFT programme. In addition, the study aims to investigate the underlying mechanisms of the effects of physical activity on the change in PTSD symptoms. Individuals with PTSD (N = 120) will be randomly allocated to two conditions: a physical activity or a non-physical active control condition. All participants will receive the same intensive TFT lasting eight days within two consecutive weeks, in which daily prolonged exposure and EMDR therapy sessions, and psycho-education are combined. The amount of physical activity will differ per condition. While the physical activity condition induces daily physical activities with moderate intensity, in the non-physical active control condition no physical activity is prescribed; but instead, a controlled mixture of guided (creative) tasks is performed. The two primary outcome measures are change in PTSD symptoms from pre- to post-treatment and at six months follow-up, measured with the Clinician-Administered PTSD Scale (CAPS-5), and the PTSD Checklist for DSM-5 (PCL-5). Additionally, self-reported sleep problems, depressive symptoms, emotion regulation, dissociation symptoms and anxiety sensitivity will be measured as potential underlying mechanisms. This study will contribute to the research field of augmentation strategies for PTSD treatment by investigating the effectiveness of physical activity added to intensive TFT. This trial is registered in the Netherlands Trial Register (Trial NL9120).


Mediastinal node staging by positron emission tomography-computed tomography and selective endoscopic ultrasound with fine needle aspiration for patients with upper gastrointestinal cancer: Results from a regional centre.
To investigate the impact of endoscopic ultrasound-guided fine-needle aspiration (EUS-FNA) and positron emission tomography-computed tomography (PET-CT) in the nodal staging of upper gastrointestinal (GI) cancer in a tertiary referral centre. We performed a retrospective review of prospectively recorded data held on all patients with a diagnosis of upper GI cancer made between January 2009 and December 2015. Only those patients who had both a PET-CT and EUS with FNA sampling of a mediastinal node distant from the primary tumour were included. Using a positive EUS-FNA result as the gold standard for lymph node involvement, the sensitivity, specificity, positive and negative predictive values (PPV and NPV) and accuracy of PET-CT in the staging of mediastinal lymph nodes were calculated. The impact on therapeutic strategy of adding EUS-FNA to PET-CT was assessed. One hundred and twenty one patients were included. Sixty nine patients had a diagnosis of oesophageal adenocarcinoma (Thirty one of whom were junctional), forty eight had oesophageal squamous cell carcinoma and four had gastric adenocarcinoma. The FNA results were inadequate in eleven cases and the PET-CT findings were indeterminate in two cases, therefore thirteen patients (10.7%) were excluded from further analysis. There was concordance between PET-CT and EUS-FNA findings in seventy one of the remaining one hundred and eight patients (65.7%). The sensitivity, specificity, PPV and NPV values of PET-CT were 92.5%, 50%, 52.1% and 91.9% respectively. There was discordance between PET-CT and EUS-FNA findings in thirty seven out of one hundred and eight patients (34.3%). MDT discussion led to a radical treatment pathway in twenty seven of these cases, after the final tumour stage was altered as a direct consequence of the EUS-FNA findings. Of these patients, fourteen (51.9%) experienced clinical remission of a median of nine months (range three to forty two months). EUS-FNA leads to altered staging of upper GI cancer, resulting in more patients receiving radical treatment that would have been the case using PET-CT staging alone.


Ni(ii)/Cu(ii)/Zn(ii) 5,5-diethylbarbiturate complexes with 1,10-phenanthroline and 2,2'-dipyridylamine: synthesis, structures, DNA/BSA binding, nuclease activity, molecular docking, cellular uptake, cytotoxicity and the mode of cell death.
New 5,5-diethylbarbiturate (barb) complexes of Ni(ii), Cu(ii) and Zn(ii) with 1,10-phenanthroline (phen) and 2,2'-dipyridylamine (dpya), namely [Ni(phen-κN,N')3]Cl(barb)·7H2O (), [Cu(barb-κN)(barb-κ(2)N,O)(phen-κN,N')]·H2O (), [Cu(barb-κN)2(phen-κN,N')] (), [Zn(barb-κN)2(phen-κN,N')]·H2O (), [Ni(barb-κ(2)N,O)(dpya-κN,N')2]Cl·2H2O (), [Cu(barb-κ(2)N,O)2(dpya-κN,N')]·2H2O () and [Zn(barb-κN)2(dpya-κN,N')] (), were synthesized and characterized by elemental analysis, UV-vis, FT-IR and ESI-MS. The structures of the complexes were determined by X-ray crystallography. Notably, and were fluorescent in MeOH : H2O at rt. The interaction of the complexes with fish sperm (FS) DNA and bovine serum albumin (BSA) was investigated in detail by various techniques. The complexes exhibited groove binding along with a partial intercalative interaction with DNA, while the hydrogen bonding and hydrophobic interactions played a major role in binding to BSA. It is noteworthy that exhibited the highest affinity towards DNA and BSA. Enzyme inhibition assay showed that show a preference for both A/T and G/C rich sequences in pUC19 DNA, while and display a binding specificity to the G/C and A/T rich regions, respectively. These findings were further supported by molecular docking. The cellular uptake studies suggested that was deposited mostly in the membrane fraction of the cells. Among the present complexes, exhibited a very strong cytotoxic effect on A549, MCF-7, HT-29 and DU-145 cancer cells, being more potent than cisplatin. Moreover, induces cell death through the apoptotic mode obtained by flow cytometry.


Polymorphism of structural forms of C-reactive protein.
C-reactive protein (CRP), as a classical member of acute phase reactants, plays a variety of physiological functions in vivo and in vitro. Here we show that CRP exists in different structural forms in solution and on phospholipid membranes. At least three types of CRP structures, i.e., the pentameric ring-like form, the small globulin-like form and the fibril-like structure, were observed by combination of size-exclusion chromatography and electron microscopy. The pentameric ring-like CRPs were discovered mostly on ligand containing membrane in a calcium-dependent manner. The globulin-like monomers found on negatively charged membrane in the absence of calcium exhibited structural stability. The fibril-like structures, that have not been reported before, were formed by face-to-face stacking of pentameric CRP in a number from several to hundreds. The freshly purified CRPs form short single-strand fibrils while those CRPs stored for more than several days form long and bundled fibrils. The different structural forms may convert to each other under certain conditions, which gives some hints as to the structural basis of multiple functions of CRP.


Regulation of the production of extracellular pectinase, cellulase, and protease in the soft rot bacterium Erwinia carotovora subsp. carotovora: evidence that aepH of E. carotovora subsp. carotovora 71 activates gene expression in E. carotovora subsp. carotovora, E. carotovora subsp. atroseptica, and Escherichia coli.
The production of pectolytic enzymes (pectate lyase [Pel] and polygalacturonase [Peh]), cellulase (Cel), and protease (Prt) is activated in the soft rot bacterium Erwinia carotovora subsp. carotovora by aepA (activator of extracellular protein production) and celery extract (Y. Liu, H. Murata, A. Chatterjee, and A. K. Chatterjee, Mol. Plant-Microbe Interact. 6:299-308, 1993). We recently isolated a new class of mutants of strain E. carotovora subsp. carotovora 71 which overproduces Pel, Peh, Cel, and Prt. From the overproducing strain AC5034, we identified an activator locus, designated aepH*, which stimulated Pel, Peh, Cel, and Prt production in E. carotovora subsp. carotovora 71 or its derivatives. The nucleotide sequence of the aepH* DNA segment revealed an open reading frame of 141 bp that could encode a small (5.45-kDa) highly basic (pI 11.7) protein of 47 amino acid residues. Analyses of deletions and MudI insertions indicated that the activator function required the 508-bp DNA segment which contains this open reading frame. The wild-type locus, aepH+, is localized within a DNA segment upstream of aepA. An AepH- strain constructed by exchanging aepH+ with aepH*::MudI was deficient in Pel, Peh, Cel, and Prt production; exoenzyme production was restored upon the introduction of a plasmid carrying aepH+ or aepH*. Plasmids carrying either aepH+ or aepH* activated the production of Pel-1, Peh-1, and Cel in Escherichia coli HB101 carrying the cognate genes. The aepH effect in E. coli was due to the activation of transcription, as indicated by assays of pel-1 and peh-1 mRNAs. The aepH+ and aepH* plasmids also stimulated Pel, Peh, Cel, and Prt production in other wild-type E. carotovora subsp. carotovora strains as well as in E. carotovora subsp. atroseptica. Although the stimulatory effect was generally more pronounced with aepH* than with aepH+, the extent of activation in the wild-type strains depended upon the bacterial strain and the growth medium. Southern blot hybridization revealed the presence of aepH homologs in E. carotovora subsp. carotovora and E. carotovora subsp. atroseptica, and provided physical evidence for linkage between aepA and aepH homologs in genomes of these bacteria. We conclude that aepH-mediated activation of exoprotein gene expression is a feature common to most strains of E. carotovora.


Matrix protein mutations contribute to inefficient induction of apoptosis leading to persistent infection of human neural cells by vesicular stomatitis virus.
In a model system to study factors involved in the establishment of a persistent viral infection that may lead to neurodegenerative diseases, Indiana and New Jersey variants of vesicular stomatitis virus (VSV) with different capacities to infect and persist in human neural cells were studied. Indiana matrix (M) protein mutants and the wild-type New Jersey strain persisted in the human neural cell line H4 for at least 120 days. The Indiana wild-type virus (HR) and a non-M mutant (TP6), both unable to persist, induced apoptosis more strongly than all the other variants tested, as indicated by higher levels of DNA fragmentation and caspase-3-like activity. Transfection of H4 cells with mRNA coding for the VSV M protein confirmed the importance of this protein in the induction of apoptosis. Furthermore, the pan-caspase inhibitor ZVAD-fmk maintained cell survival to about 80%, whereas inhibition of caspase-8, caspase-9, or both only partially protected the cells against death, consistent with the fact that anti-apoptotic molecules from the Bcl-2 family also protect cells from death only partially. These results suggest that VSV activates many pathways of cell death and that an inefficient induction of caspase-3-related apoptosis participates in the establishment of a persistent infection of human neural cells by less virulent VSV variants.


Learning to see, but not discriminate, visual forms is impaired in aging.
Despite the central role of learning in visual recognition, it is largely unknown whether visual form learning is maintained in older age. We examined whether training improved performance in both young and older adults at two key stages of visual recognition: integration of local elements and global form discrimination. We used a shape-discrimination task (concentric vs. radial patterns) in which young and older adults showed similar performance before training. Using a parametric stimulus space that allowed us to manipulate global features and background noise, we were able to distinguish integration and discrimination processes. We found that training improves global form discrimination in both young and older adults. However, learning to integrate local elements is impaired in older age, possibly because of reduced tolerance to external noise. These findings suggest that visual selection processes, rather than global feature representations, provide a fundamental limit for learning-dependent plasticity in the aging brain.


Supervisory control of multiple robots in dynamic tasking environments.
A military targeting environment was simulated to examine the effects of an intelligent route-planning agent RoboLeader, which could support dynamic robot re-tasking based on battlefield developments, on the performance of robotics operators. We manipulated the level of assistance (LOAs) provided by RoboLeader as well as the presence of a visualisation tool that provided feedback to the participants on their primary task (target encapsulation) performance. Results showed that the participants' primary task benefited from RoboLeader on all LOAs conditions compared to manual performance; however, visualisation had little effect. Frequent video gamers demonstrated significantly better situation awareness of the mission environment than did infrequent gamers. Those participants with higher spatial ability performed better on a secondary target detection task than did those with lower spatial ability. Finally, participants' workload assessments were significantly lower when they were assisted by RoboLeader than when they performed the target entrapment task manually. Practitioner Summary: This study demonstrated the utility of an intelligent agent for enhancing robotics operators' supervisory control performance as well as reducing their workload during a complex urban scenario involving moving targets. The results furthered the understanding of the interplay among level-of-autonomy, multitasking performance and individual differences in military tasking environments.


Synthesis of ortho-haloaminoarenes by aryne insertion of nitrogen-halide bonds.
A rapid and general access to ortho-haloaminoarenes has been developed by aryne insertion into N-chloramine, N-bromoamine, and N-iodoamine bonds via two complementary protocols harnessing fluoride-promoted 1,2-elimination of ortho-trimethylsilyl aryltriflates. Typically, electron-deficient N-chloramines effectively react with aryne intermediates generated at elevated temperature with CsF, while less stable N-haloamines are found more efficient under milder, TBAF-mediated aryne formation at room temperature. Both protocols demonstrate a good level of regioselectivity and functional group tolerance. Efforts to elucidate the mechanism of N-X insertion are also discussed. The practical value of this transformation is highlighted by rapid synthesis of novel analogues of the antipsychotic cariprazine.


Sources of mathematics self-efficacy: The interactive role of parental education and perceptions of teachers.
Using US National Education Longitudinal Study (NELS) data, we explore how parental education and primary students' perceptions of their teachers interact to impact students' self-efficacy in mathematics. Our results demonstrate that students tend to have higher self-efficacy if they perceive that their teacher promotes the importance of mathematics. This relationship holds regardless of parental education, though it is strongest for children of parents without a university education. Children of less educated parents also tend to have lower self-efficacy if they attend private schools, which typically have high average parental socio-economic status (SES). School type has no discernable impact on children of university-educated parents. These findings are highly relevant to the Canadian context, which is characterized by schools being stratified by SES and the high importance of STEM education for occupational outcomes.