Exhaled eicosanoids and biomarkers of oxidative stress in exacerbation of chronic obstructive pulmonary disease.
Eicosanoids and oxidants play an important role in inflammation, but their role in chronic obstructive pulmonary disease (COPD) is uncertain. In this study we hypothesized that levels of exhaled leukotrienes, prostaglandins and biomarkers of oxidative stress are increased in infectious exacerbations of COPD and that they decrease after antibiotic therapy. Cysteinyl-leukotrienes (LTs), leukotriene B(4) (LTB(4)), prostaglandin E(4), hydrogen peroxide (H(2)O(2)) and 8-isoprostane were measured in exhaled breath condensate (EBC) in 16 COPD patients with infectious exacerbations (mean age 64 ±12 years, 13 male) on day 1, during antibiotic therapy (days 2-4), 2-4 days after therapy and at a follow-up visit when stable (21-28 days after therapy). There was a significant fall in concentration of cys-LTs, LTB(4) and 8-isoprostane at visit 3 compared to day 1 (cys-LTs: 196.5 ±38.4 pg/ml vs. 50.1 ±8.2 pg/ml, p < 0.002; LTB(4): 153.6 ±25.5 pg/ml vs. 71.9 ±11.3 pg/ml, p < 0.05; 8-isoprostane: 121.4 ±14.6 pg/ml vs. 56.1 ±5.2 pg/ml, p < 0.03, respectively). Exhaled H(2)O(2) was higher on day 1 compared to that at visits 2 and 3 (0.74 ±0.046 µM vs. 0.52 ±0.028 µM and 0.35 ±0.029 µM, p < 0.01 and p < 0.01, respectively). Exhaled PGE(2) levels did not change during exacerbations of COPD. Exhaled eicosanoids and H(2)O(2) in EBC measured at the follow-up visit (stable COPD) were significantly higher compared to those from healthy subjects. We conclude that eicosanoids and oxidants are increased in infectious exacerbations of COPD. They are also elevated in the airways of stable COPD patients compared to healthy subjects.


Golden rule for buttressing vulnerable soluble proteins.
Local weaknesses in the structure of soluble proteins have received little attention. The structure may be inherently weak at sites where hydration of the protein backbone is locally hampered by formation of an intramolecular hydrogen bond which in turn is not fully stabilized through burial within a hydrophobic environment. The result is insufficient compensation for the thermodynamic cost of dehydrating the backbone polar groups. This work shows that these structural deficiencies, the unburied backbone hydrogen bonds, are compensated in natural proteins by disulfide bonds that are needed to maintain the structural integrity. Examination of all PDB-reported soluble structures reveals that, after suitable normalization, the number of disulfide bonds, X, correlates tightly with the number of unburied backbone hydrogen bonds, Y, beyond the baseline level Y = 20, revealing a simple balance relation: Y = 5X + 20. This equation introduces a 1:5 ratio associated with the buttressing of soluble proteins with structural deficiencies. The results are justified on thermodynamic grounds and have implications for biomolecular engineering as they introduce two constants of universal applicability determining the architecture of soluble proteins.


Management of stage III breast cancer.
Stage III breast cancer encompasses a heterogeneous group of patients. According to the American Joint Committee on Cancer (AJCC) these tumors include stage IIIA and stage IIIB disease, the first generally being operable but the second inoperable. Patients with inflammatory breast cancer are also included in stage IIIB disease, and these patients have the worst prognosis. Multidisciplinary therapy has become the treatment of choice for these patients. Primary or neoadjuvant chemotherapy, followed by locoregional therapy, either surgery, radiotherapy or both, is now an accepted strategy. Most patients achieve a response to chemotherapy, resulting in downstaging of the tumor, and 5-year-survival rates have improved from 10-20% with local therapy alone to 30-60% with the multidisciplinary approach. Although many prospective, mainly phase II trials have been performed in stage III breast cancer, the optimal treatment scheme still has to be established. The role of new therapeutic strategies such as high-dose chemotherapy with hematopoietic stem cell rescue and higher dose intensity regimens with hematopoietic growth factors is currently under investigation. This article will review the literature and discuss our own research in this area.


Solid-phase synthesis of fusaricidin/LI-F class of cyclic lipopeptides: Guanidinylation of resin-bound peptidyl amines.
Fusaricidins/LI-Fs and related cyclic lipopeptides represent an interesting new class of antibacterial peptides with the potential to meet the challenge of antibiotic resistance in bacteria. Our previous study (Bionda et al. ChemMedChem 2012, 7, 871-882) revealed the significance of the guanidinium group located at the termini of the lipidic tails of these cyclic lipopeptides for their antibacterial activities. Therefore, devising a synthetic strategy that will allow incorporation of guanidinium functionality into their structure is of particular practical importance. Since appropriately protected guanidino fatty acid building blocks are not commercially available, our strategy toward guanidinylated fusaricidin/LI-F analogs include solid-phase synthesis of a cyclic lipopeptide precursor possessing a lipidic tail with a terminal amino group followed by its conversion into corresponding guanidine. To find the optimal method for this conversion, we have examined commonly used guanidinylation reagents under the conditions compatible with standard solid-phase peptide synthesis. Described experimental results demonstrated superiority of N,N'-di-Boc-N″-triflylguanidine in solid-phase preparation of fusaricidin/LI-F class of cyclic lipopeptides. The triflylguanidine reagent gave a single monoguanidinylated product in excellent yield independently of the type of solid-support.


Loss of Integrity: Impairment of the Blood-brain Barrier in Heavy Metal-associated Ischemic Stroke.
Although stroke is one of the leading causes of death and disability worldwide, preventive or therapeutic options are still limited. Therefore, a better understanding of the pathophysiological characteristics of this life-threatening disease is urgently needed. The incidence and prevalence of ischemic stroke are increased by exposure to certain types of xenobiotics, including heavy metals, suggesting the possible toxicological contribution of these compounds to the onset or aggravation of stroke. Among the potential targets, we have focused on alterations to cerebral endothelial cells (CECs), which play important roles in maintaining the functional integrity of brain tissue.


Neuropsychiatric disorders following vascular brain injury.
Several neuropsychiatric disorders such as mood, anxiety and psychotic disorders occur following cerebrovascular lesions. Post-stroke depression is the most common of these disorders and, along with post-stroke anxiety, has been shown to inhibit physical and cognitive recovery. Antidepressants have been shown to effectively treat post-stroke depression and to have a positive impact on rehabilitation efforts in patients suffering from this disorder. Much less is known about the potential impact of psychiatric conditions on recovery after stroke. Controlled trials will be able to adequately determine the effectiveness of treatment for these disorders.


[The influence of urea, ammonia and nitrate as they affect growth and viability of Trichophyton verrucosum].
Six strains of Trichophyton verrucosum were used in a test to determine effects of urea and sodium nitrate on their growth. Despite having urease activity, the strains failed to utilize the urea and sodium nitrate for their growth. Moreover, the organisms were killed if large amounts of these nitrogen compounds and ammonia were added to the medium. These nitrogen compounds, distributed in cattle breeding soil, inhibited the growth of T. verrucosum. Thus, soil in cattle breeding environments does not seem to be a reservoir of this pathogen.


Moisture content, fatty acid profile and oxidative traits of aged beef subjected to different temperature-time combinations.
Temperature-time combinations (TTC) effects on beef fatty acid (FA) composition, moisture content and oxidative traits were investigated. TTC were designed so temperatures were constant over each time period, and there was at most one variation in temperature within a sample's combined (total) time period. Therefore, three temperatures (~ 3, 5 and 7 °C) and five time periods (6, 8, 10 and 12 d) resulted in 72 different TTC, which were compared to control samples held for 14 d at ~ 1 °C. It was found that moisture losses increased as TTC temperature and time periods increased. There were negligible effects of TTC on FA composition. Sample TBARS and vitamin E content did not respond to TTC. A positive relationship between beef vitamin E and long chain polyunsaturated FA contents was observed. We concluded that TTC could be applied to accelerate the rate of ageing for beef and achieve comparable yield, oxidative and FA characteristics compared to conventional ageing approaches.


Polar phase hydroformylation: the dramatic effect of water on mono- and dirhodium catalysts.
The addition of 30% water (by volume) to acetone creates a remarkably effective polar phase solvent system for a dicationic dirhodium tetraphosphine hydroformylation catalyst. The initial turnover frequency (TOF) increases by 265% (to 73 min-1) for the hydroformylation of 1-hexene relative to the initial TOF in pure acetone (20 min-1). The aldehyde linear to branched (L:B) ratio increases to 33:1, and alkene isomerization and hydrogenation side reactions are essentially eliminated. Comparisons with monometallic rhodium catalysts based on PPh3, Bisbi, Naphos, and Xantphos ligands demonstrate that this polar-phase bimetallic catalyst is one of the fastest and most selective hydroformylation systems known under these mild conditions (90 degrees C, 6.2 bar H2/CO). The monometallic catalysts also show rate enhancements (although considerably smaller) in water-acetone, but Rh-Xantphos does show a large increase of 115%, with considerably reduced alkene isomerization side reactions. The dramatic effect of water on the dirhodium catalyst system is believed to be due to simple inhibition of the fragmentation of the catalytically active species into inactive mono- and bimetallic complexes.


Standardized Minimal Residual Disease Detection by Next-Generation Sequencing in Multiple Myeloma.
Next-generation sequencing (NGS) has been applied to monitor minimal residual disease (MRD) in multiple myeloma (MM). Standardized DNA input and sequencing depth is essential for achieving a uniform sensitivity in NGS-based MRD study. Herein, the sensitivity of 10-5 was verified by a standardized experimental design based on triplicate measurements of 1 μg DNA input and 1 million sequencing reads using the LymphoTrack-MiSeq platform. MRD level was defined as the mean MRD burden of the triplicates. Two spike-in controls at concentrations of 0.001% tumor plasma cells (PC) for verifying the sensitivity of 10-5 and 0.01% (or 0.005%) for MRD normalization were systematically analyzed. The spike-in control of 0.001% MRD was consistently detected in all samples, confirming a sensitivity of 10-5. Moreover, this standardized NGS approach yielded MRD measurements concordant with serological response and comparable to allele-specific oligonucleotide (ASO) real-time quantitative (RQ)-PCR. Moreover, NGS showed an improved sensitivity and provided quantification of MRD for cases assigned "positive but not quantifiable" (PNQ) by ASO RQ-PCR, even without the use of patient-specific probes/primers. Issues regarding the specificity of myeloma-specific sequences as MRD target, optimal input for spike-in normalization, and interpretation of MRD from triplicates are discussed. Herein, the standardized LymphoTrack-MiSeq-based method is verified to carry a sensitivity of 10-5, hence an effective tool for MRD monitoring in MM. As only a small number of samples are tested here, further study with a larger number of patients is warranted.


New Insights into the Implication of Mitochondrial Dysfunction in Tissue, Peripheral Blood Mononuclear Cells, and Platelets during Lung Diseases.
Lung diseases such as chronic obstructive pulmonary disease, asthma, pulmonary arterial hypertension, or idiopathic pulmonary fibrosis are major causes of morbidity and mortality. Complex, their physiopathology is multifactorial and includes lung mitochondrial dysfunction and enhanced reactive oxygen species (ROS) release, which deserves increased attention. Further, and importantly, circulating blood cells (peripheral blood mononuclear cells-(PBMCs) and platelets) likely participate in these systemic diseases. This review presents the data published so far and shows that circulating blood cells mitochondrial oxidative capacity are likely to be reduced in chronic obstructive pulmonary disease (COPD), but enhanced in asthma and pulmonary arterial hypertension in a context of increased oxidative stress. Besides such PBMCs or platelets bioenergetics modifications, mitochondrial DNA (mtDNA) changes have also been observed in patients. These new insights open exciting challenges to determine their role as biomarkers or potential guide to a new therapeutic approach in lung diseases.


Implications for the catalytic mechanism of the vanadium-containing enzyme chloroperoxidase from the fungus Curvularia inaequalis by X-ray structures of the native and peroxide form.
Implications for the catalytic mechanism of the vanadium-containing chloroperoxidase from the fungus Curvularia inaequalis have been obtained from the crystal structures of the native and peroxide forms of the enzyme. The X-ray structures have been solved by difference Fourier techniques using the atomic model of the azide chloroperoxidase complex. The 2.03 A crystal structure (R = 19.7%) of the native enzyme reveals the geometry of the intact catalytic vanadium center. The vanadium is coordinated by four non-protein oxygen atoms and one nitrogen (NE2) atom from histidine 496 in a trigonal bipyramidal fashion. Three oxygens are in the equatorial plane and the fourth oxygen and the nitrogen are at the apexes of the bipyramid. In the 2.24 A crystal structure (R = 17.7%) of the peroxide derivate the peroxide is bound to the vanadium in an eta2-fashion after the release of the apical oxygen ligand. The vanadium is coordinated also by 4 non-protein oxygen atoms and one nitrogen (NE2) from histidine 496. The coordination geometry around the vanadium is that of a distorted tetragonal pyramid with the two peroxide oxygens, one oxygen and the nitrogen in the basal plane and one oxygen in the apical position. A mechanism for the catalytic cycle has been proposed based on these X-ray structures and kinetic data.


Metastatic prostatic stromal sarcoma: A challenging diagnosis on fine-needle aspiration with broad differential diagnosis.
Prostatic stromal sarcomas (PSS) are rare solid organ mesenchymal sarcomas. PSS may pose difficult diagnostic challenges on fine needle aspiration biopsy. We report a 48-year-old man diagnosed with metastatic high grade prostatic stromal sarcoma by a CT-scan guided fine needle aspiration (FNA) biopsy of a right lower lung lobe nodule. We reviewed the literature on the epidemiologic, cyto-histological, and immunophenotypic findings and discussed the differential diagnosis for this rare entity.


Topical Review: Developmental Framework of Moderators of Family Conflict for Type 1 Diabetes Outcomes.
To present a developmental framework of family conflict in youth with type 1 diabetes (T1D) that aims to guide future research. Developmental and pediatric literature are reviewed to highlight family factors that may modify the degree to which diabetes-related family conflict is related to adolescent health outcomes. Developmental literature suggests that family conflict is not inherently bad; rather, conflict that arises under optimal conditions (moderate frequency, warm and accepting relationships) can be adaptive for adolescents. However, family conflict is consistently associated with poor disease outcomes in youth with T1D, with few researchers examining specific moderators of these associations. In this topical review, we highlight moderators of family conflict and developmental outcomes identified in adolescents without chronic illness (e.g., cultural factors, parent-child relationship quality, conflict characteristics) and how these moderators may operate for a pediatric chronic illness such as T1D. Incorporating conceptualizations of family conflict from mainstream developmental research has important implications for future research and intervention adaptations on family conflict in pediatric populations.


Why nurses are calling in sick: the impact of health-care restructuring.
Absenteeism among registered nurses is a major concern for employers; it is costly and results in decreased standards of care. Despite the international interest in and research on absenteeism, there is relatively little cumulative knowledge regarding its determinants. This quantitative, non-experimental study profiled the reasons for absenteeism in a random sample of 2,000 front-line nurses in the Canadian province of Saskatchewan. Absence was defined as time away from work excluding holidays, strike, or layoff. Major causes of absenteeism were identified, including minor ailment and fatigue related to work overload. A total of 450 respondents had seriously considered leaving the nursing profession, with 50.4% citing overwork and stress as the primary causes. Higher rates of absenteeism were found to be associated with lower job satisfaction, longer shifts, working in acute care, and working full-time. Moderate job dissatisfaction was found to be associated with longer shifts and working in acute care. In light of the current nursing shortage, strategies for reducing absenteeism and increasing job satisfaction are warranted.


Predicting metabolite-disease associations based on auto-encoder and non-negative matrix factorization.
Metabolism refers to a series of orderly chemical reactions used to maintain life activities in organisms. In healthy individuals, metabolism remains within a normal range. However, specific diseases can lead to abnormalities in the levels of certain metabolites, causing them to either increase or decrease. Detecting these deviations in metabolite levels can aid in diagnosing a disease. Traditional biological experiments often rely on a lot of manpower to do repeated experiments, which is time consuming and labor intensive. To address this issue, we develop a deep learning model based on the auto-encoder and non-negative matrix factorization named as MDA-AENMF to predict the potential associations between metabolites and diseases. We integrate a variety of similarity networks and then acquire the characteristics of both metabolites and diseases through three specific modules. First, we get the disease characteristics from the five-layer auto-encoder module. Later, in the non-negative matrix factorization module, we extract both the metabolite and disease characteristics. Furthermore, the graph attention auto-encoder module helps us obtain metabolite characteristics. After obtaining the features from three modules, these characteristics are merged into a single, comprehensive feature vector for each metabolite-disease pair. Finally, we send the corresponding feature vector and label to the multi-layer perceptron for training. The experiment demonstrates our area under the receiver operating characteristic curve of 0.975 and area under the precision-recall curve of 0.973 in 5-fold cross-validation, which are superior to those of existing state-of-the-art predictive methods. Through case studies, most of the new associations obtained by MDA-AENMF have been verified, further highlighting the reliability of MDA-AENMF in predicting the potential relationships between metabolites and diseases.


The value of 18F-FDG PET/contrast-enhanced CT in detection of tumor thrombus.
The differentiation between tumor and bland thromboses is important as the management differs. Retrospectively, we aim to evaluate the utility of FDG PET in detecting and differentiating tumor from bland thromboses and if FDG PET provides additional value to contrast-enhanced CT for tumor thrombus detection. Twenty-four sites of venous thromboembolism, detected on PET/CT, were retrospectively reviewed. Classification of type of thrombosis was based on histology and radiological follow-up. We evaluated the presence of contrast-enhanced CT findings that were suggestive of tumor thrombosis; sign of invasion, neovascularity, and enhancement. Metabolic activity by means of SUV(max) was measured by drawing ROI at the site of thrombosis. Mann-Whitney U test was used to compare the mean SUV(max) between thromboses and internal references. We used ROC analysis to identify the optimal cutoff value of SUV(max) for detection of tumor thrombosis. Twenty-four sites of venous thromboembolism were identified in 15 patients. All tumor thromboses demonstrated at least 1 positive sign on contrast-enhanced CT, whereas 33% of bland thromboses had the same finding. The difference between tumor and bland thrombus SUV(max) was statistically significant (P < 0.005). On ROC analysis, a cutoff of SUV(max) 2.25 (sensitivity, 78%; specificity, 100%) was suggested to differentiate tumor from bland thrombosis. PET/CT is able to differentiate tumor from bland thrombosis, with an optimal cutoff value of SUV(max) 2.25. The metabolic information increases the diagnostic accuracy of tumor thrombus and is a useful adjunct to the described features on contrast-enhanced CT.


[Ureteral lithotripsy with rigid ureteroscopy and pulsed dye laser].
Pulsed dye laser lithotripsy represents nowadays a new approach to ureteral stones. 27 patients were treated with a pulsed dye laser unit (Pulsolith TM) at our department from november 1989 to january 1990. 21 had a single stone and the remaining a multiple ureteral lithiasis. The pulsed dye laser operated at a wave length of 504 nm, energy ranged between 90 and 160 mj with pulse of 1,5 ms. A 320 theta diameter quartz fiber with Helium Neon red laser (to visualize the top of the fiber) introduced in a rigid 9.5 ureteroscope (Wolf) was used during the procedure. Spinal, peridural or general anesthesia was done in all patients and the time of the procedure ranged between 8-150 minutes. Fiber was inserted in a 4 Ch ureteral catheter which provided easier manipulation of the fiber. Complete fragmentation was achieved in 88.9% of the patients, and combined manoeuvres were requested in another 3.7%. Failures were 7.4%. Minimal lesions of the ureter, due to ureteroscope advancement subsided spontaneously after placement of double F catheter. Pulsed dye laser lithotripsy seems to be a safe and useful procedure for treatment of impacted ureteral calculi and seems to offer low morbidity in respect of ultrasonic or electrohydraulic procedures especially when the stone location does not permit an ESWL approach.


Low Florbetapir PET Uptake and Normal Aβ1-42 Cerebrospinal Fluid in an APP Ala713Thr Mutation Carrier.
According to the literature, the APP Ala713Thr mutation is associated with Alzheimer's disease and cerebral amyloid angiopathy. We describe a case of dementia clinically compatible with frontotemporal dementia in an APP Ala713Thr mutation carrier in which both [18F]Florbetapir PET uptake and Aβ1-42 cerebrospinal fluid levels were normal. Further evidences are required to establish if this association is only incidental.


PDMS-based microfluidics for proteomic analysis.
A microfluidic poly(dimethylsiloxane) (PDMS) microdevice was realized, combining on-line protein electrophoretic separation, selection, and digestion of a protein of interest for identification by mass spectrometry. The system includes eight integrated valves and one micropump dedicated to control the flow operations. Myoglobin was successfully isolated from bovine serum albumin (BSA), then selected using integrated valves and digested in a rotary micromixer. Proteolytic peptides were recovered from the micromixer for protein identification. Total analysis from sample injection to protein identification is performed under 30 minutes, with samples of tens of nanolitres. The paper shows that PDMS technology can be successfully used for integrating complex preparation protocols of proteic samples prior to MS analysis.


[The centenary of the Israel Medical Association].
On January 12th 1912, six Jewish physicians and one pharmacist assembled in Tel-Aviv to proclaim the founding of the Jaffa Hebrew Medical Society. One year later the Jewish doctors of Jerusalem established the "Society of Hebrew Speaking Physicians". On 28th December, 1918 a few weeks after the end of World War 1, both organizations merged into the Hebrew Medical Association which later became the Israel Medical Association (I.M.A.). The Association played a leading role in the advancement of medicine in the Holy Land and was instrumental in imposing the Hebrew medical terminology in the newly founded State of Israel.


3-Hydroxy-3-methylglutaryl coenzyme A reductase in isolated villous and crypt cells of the rat ileum.
The localization of 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMG-CoA reductase, E.C. 184.108.40.206) in the villous and crypt cells of the small intestine was accomplished after separating these cells from the mucosal layer by sequential dissociation in a "dual-buffer" system. Consistent separation was demonstrated by using the marker enzymes alkaline phosphatase, specific to the villous cell, and thymidine kinase, specific to the crypt cell. Cells obtained were 95-100% viable, and no relative difference in lability was observed, as evidenced by the equal distribution of acid phosphatase. This method of cell separation was an improvement over the "scraping" technique which damaged cells severely and produced villous preparations that contained little or no reductase activity. The HMG-CoA reductase specific activity in whole cell homogenates of the ileal villi was 0.47 and of the crypts was 0.27 nmol/min per mg of protein, considerably higher values than have been reported earlier. Also in comparison to the crypts, the villi incorporated 1.5-fold more [(14)C]-acetate into sterols, a ratio similar to that describing the distribution of HMG-CoA reductase in the two cell populations. These results unequivocally establish that the villi have higher HMG-CoA reductase activity than the crypts and confirm an earlier report from this laboratory that the villi are a major site of sterol synthesis. The sterol bio-synthetic capacity of the small intestine was highest in the ileum and decreased towards the jejunum. The HMG-CoA reductase specific activity of the ileum averaged 0.30 and that of the jejunum 0.10 nmol/min per mg of protein; however, the cholesterol content of the ileum was slightly lower than the jejunum. These results are discussed to suggest the possibility that the sterol content of the ileum may largely be due to in situ synthesis.


[Hemobilia as a sign of arterio-biliary fistula].
Hepatic artery aneurysms (HAA) are rare (20% of all visceral arteries). Most often, HAAs are asymptomatic and detected at autopsy. However, their ruptures and/or bleeding following pressure ulcers in visceral gastrointestinal organs are a significant clinical and diagnostic problem. We present 2 patients with obstructive jaundice and hemobilia. Diagnostics revealed aneurysm of the right hepatic artery with arterio-biliary fistula. Life-threatening hemobilia is a consequence of HAA rupture into biliary system. Endovascular approach is preferable for HAA without clinical manifestations. Awareness of this disease is important for early detection and active surgical intervention before possible complications.


Characterization of mycoplasma strains isolated from house musk shrews (Suncus murinus) and their infectivity in mice and rats.
Five mycoplasma strains isolated from house musk shrews (Suncus murinus) in the Central Institute for Experimental Animals were characterized and compared with three murine mycoplasma strains, Mycoplasma pulmonis m 53, M. arthritidis PG6, and M. neurolyticum Type A, and with reference strain G3-5 previously isolated from a house musk shrew. These isolates fermented glucose, but did not hydrolyze urea and arginine, passed through membrane filters of 450 nm pore size, were sensitive to digitonin, and formed minute (115 to 231 microns in diameter) colonies on agar medium. All the five unclassified house musk shrew mycoplasma strains and strain G3-5 used as a reference constituted a homogeneous group based on (i) their antigenic properties (determined using the metabolism inhibition test), (ii) their polypeptide profiles (determined using sodium dodecyl sulfate-polyacrylamide gel electrophoresis and the Western blotting assay), and (iii) their genomic properties (determined using DNA cleavage pattern analysis), but were quite distinct from the established murine mycoplasmas on the basis of these findings. In a survey of 56 house musk shrews aged 2 to 45 weeks in our colonies, mycoplasmas were isolated from the oral cavities of all animals examined. No gross or microscopic lesions were observed in the five animals from which the mycoplasma strains were isolated. In experimental infection, the mycoplasma was not infective for mice and rats. The results suggest that this group of mycoplasmas is a common inhabitant of house musk shrews.


Photoactive Hybrid Materials with Fractal Designs Produced via 3D Printing and Plasma Grafting Technologies.
The present paper partly aims at exploring the potential of fractal geometry for concrete applications in the field of materials science. It is more specifically a study about the conception of hybrid polymer-based materials with photocatalytic activity. The concept behind this work is to investigate the use of polymer fractal structures manufactured by 3D-printing technology, as a highly ordered substrate with an important surface area to immobilize catalyst nanoparticles, by means of plasma grafting technology. Two types of fractal units, fractal pyramids (fracmids) and fractal cones (fracones), have been described and the former has been extensively characterized on a geometrical aspect. Various complex superstructures have also been described using fractal units as building blocks. 3D structures based on the aforementioned theoretical models have been designed using computer-aided design (CAD). On the basis of CAD models, several structures have been 3D-printed with PLA using fused deposition modeling. PLA substrates have been successfully coated with nanoparticles of ZnO using a combination of core-shell synthesis and plasma grafting. Finally, the photocatalytic activity of a hybrid material has been assessed with a positive outcome, showing the relevance of the concept developed in this study.


Aluminum microstructures on anodic alumina for aluminum wiring boards.
The paper demonstrates simple methods for the fabrication of aluminum microstructures on the anodic oxide film of aluminum. The aluminum sheets were first engraved (patterned) either by laser beam or by embossing to form deep grooves on the surface. One side of the sheet was then anodized, blocking the other side by using polymer mask to form the anodic alumina. Because of the lower thickness at the bottom part of the grooves, the part was completely anodized before the complete oxidation of the other parts. Such selectively complete anodizing resulted in the patterns of metallic aluminum on anodic alumina. Using the technique, we fabricated microstructures such as line patterns and a simple wiring circuit-board-like structure on the anodic alumina. The aluminum microstructures fabricated by the techniques were embedded in anodic alumina/aluminum sheet, and this technique is promising for applications in electronic packaging and devices.


Surgical palliation in pancreatic cancer.
The prognosis of patients with pancreatic carcinoma is poor. At the time of diagnosis, approximately 80% of patients are found to have an unresectable tumour, because of local spread or metastatic disease. Therefore, most patients will undergo palliative treatment, which is aimed at the improvement of the quality of life and the prevention of symptoms. The most important symptoms which are associated with advanced pancreatic cancer are pain, obstructive jaundice and gastric outlet obstruction. Controversy remains on the question whether these symptoms should be treated surgically or non-surgically. This review describes the best evidence (if possible randomised controlled trials) in recent literature on the palliation of most important symptoms and focuses on surgical palliative treatment options.


Mental health outcomes and correlates in cancer patients entering survivorship after curative treatment.
Cancer survivors face numerous physical and mental health challenges after treatment completion. However, few studies have examined mental health in cancer survivors who received curative treatment during the transition out of active treatment and into survivorship. The current study describes the mental health outcomes and their correlates in cancer survivors treated with curative intent during the first year of survivorship. A total of 120 cancer survivors of any cancer type completed a survey that assessed depression, anxiety, death ideation, alcohol and substance use, and demographic characteristics. Data regarding cancer type and treatment were extracted from the medical record. Approximately 15% of the sample reported depressive symptoms. Fifteen percent also reported anxiety symptoms in the past two weeks. Ten percent of the sample reported experiencing death ideation since their treatment ended and 7.5% reported death ideation in the past two weeks. Younger age, previous psychiatric diagnosis, and current substance use were associated with depressive symptoms, anxiety symptoms, and death ideation. Cancer survivors entering survivorship after curative treatment experience an increased rate of depressive symptoms, anxiety symptoms, and death ideation. Younger cancer survivors and those with previous psychiatric diagnoses or substance use may be at particular risk for mental health problems during the first year of survivorship. Future research within both oncology and primary care should further examine modifiable risk factors for depression, anxiety, and death ideation in cancer survivors at the transition into survivorship after curative treatment to improve survivorship care.


Comparative assessment of acute and chronic ecotoxicity of water soluble fractions of diesel and biodiesel on Daphnia magna and Aliivibrio fischeri.
The widespread use of diesel as a transportation fuel and the introduction of biodiesel into the world energy matrix increase the likelihood of aquatic contamination with these fuels. In this case, it is important to know the environmental impacts caused by water-soluble fraction (WSF) of these fuels, since it is the portion that can result in long-term impacts and affect regions far away from the location of a spill. Therefore, we evaluated and compared the aquatic ecotoxicity of the WSF of biodiesel and diesel through acute ecotoxicity tests with the aquatic microcrustacean Daphnia magna and the marine bacteria Aliivibrio fischeri, as well as chronic ecotoxicity tests with D. magna. The WSF of diesel was 2.5-4 folds more toxic than the WSF of biodiesel in acute ecotoxicity tests. Similarly, a comparison of the chronic ecotoxicity demonstrated that the WSF of diesel was more toxic than the WSF of biodiesel. WSF of diesel causes chronic effects on reproduction, longevity and growth of D. magna (NOEC was 12.5, 12.5, 6.25%, respectively), while WSF of biodiesel did not present significantly different results compared to the control for any of the parameters evaluated in any of the dilutions tested (NOEC> 25%). To the best of our knowledge, this is the first study that compares the chronic ecotoxicity of WSF of diesel and biodiesel on D. magna.


Parasitic contaminants in food.
There is a wide variety of food products that may be contaminated with one or more parasites and consequently enabling transmission to human beings. The prevalence of specific parasites in food supplies varies between countries and regions. Sources of food-borne products contaminated with parasites are pigs, cattle, fish, crabs, crayfish, snails, frogs, snakes and aquatic plants. One of the major factors influencing the prevalence of parasitic infections in the population is the habit, and traditional popularity of eating raw or inadequately cooked foods. The parasites that may be acquired by eating these foods are nematodes, trematodes, cestodes and protozoa. The major genera of parasites are Trichinella, Gnathostoma, Angiostrongylus, Anisakis, Paragonimus, Clonorchis, Opisthorchis, Fasciola, Fasciolopsis, Echinostoma, Taenia, Spirometra and Toxoplasma. These food-borne parasitic infections are public health problems worldwide. The contamination of food affects many including humans, livestock industry, agriculture, and food manufacturing and processing. Unsafe foods must be condemned and destroyed. Today there is increasing travel hence there is the risk of humans' acquiring food-borne parasitic infections through eating native food often raw. Moreover, the consumption of imported livestock and foods, especially from endemic areas of food-borne parasitic zoonoses, can be the cause of infection. Awareness should be heightened wherever and whenever raw or inadequately cooked food are consumed.


Scintillation camera quality control, Part I: Establishing the quality control program.
This is the first article in a four-part series on scintillation camera quality control. This series of articles will include both theory and practical knowledge on setting up a quality control program, acceptance testing and quality control for planar, SPECT and special imaging procedures. On completion of this article the reader should be able to: (a) discuss the purpose of a quality control program; (b) know how to establish the performance criteria for a scintillation camera; (c) know how to design a quality control program; (d) be able to set up the schedule for the quality control program; (e) understand the economics of quality control; and (f) justify the expenditure of the institution's resources on quality control.


Association of genetic polymorphisms of EGFR with glioma in a Chinese population.
Several studies indicated that genetic polymorphisms in the epidermal growth factor receptor (EGFR) gene were associated with glioma risk. However, the relationship between EGFR genetic polymorphisms and glioma remains unclear in the Chinese population. We designed a case-control study by selecting 300 histologically confirmed adult glioma patients and 300 cancer-free controls to analyze the distribution of EGFR genotype. Two single-nucleotide polymorphisms, rs730437 and rs1468727, were genotyped by using the polymerase chain reaction-restriction fragment length polymorphism method. We found that the CC genotype of rs1468727 was more common in the glioma group than in the control group (p=0.021). We also found that the C allele frequency was higher in the glioma group than that in the control group (p=0.005; odds ratio [OR]=1.38, 95% confidence interval [CI]: 1.101-1.740). For rs730437, we found both the AA genotype (p=0.011) and A allele frequency (p=0.003; OR=0.703; 95% CI: 0.558-0.886) were significantly lower in the glioma patients than in the control subjects, respectively. Haplotype analysis showed that the A T haplotype frequency was higher in the control group than in the glioma group (p=0.005; OR=0.722; 95% CI: 0.575-0.908). However, the CC haplotype frequency was higher in the glioma group than in the control group (p=0.003; OR=1.423; 95% CI: 1.129-1.793). Our study indicates that polymorphisms in the EGFR gene are associated with glioma susceptibility in the Chinese population.


The upper airway and sleep apnoea in the Prader-Willi syndrome.
Obesity, short stature, hypotonia and excessive daytime sleepiness are characteristic features of the Prader-Willi syndrome. Excessive daytime sleepiness has been attributed to obstructive sleep apnoea (OSA). To investigate the role of anatomical factors in OSA in the Prader-Willi syndrome, clinical and ENT assessment, radiology of the upper airway and polysomnography including sleep oximetry were done in 14 subjects. Excessive daytime sleepiness was present in eight of 14 subjects as determined by a mean sleep latency to non-rapid eye movement stage I-II of < 5 min and/or self-rating sleepiness score > 9 (Epworth Sleepiness scale). Seven subjects were snorers or mouth breathers and dental abnormalities were present in 11. Sleep apnoea, as determined by a combined apnoea-hypopnoea index of more than 10 respiratory events per hour was present in 12 of 14 subjects. On clinical assessment, the nasopharynx, oropharynx and hypopharynx were small in one subject. No subject had redundant pharyngeal mucosa or an enlarged tongue. However, radiological studies performed in the awake supine posture showed a slight reduction in the cross-sectional area in nine subjects at the oropharyngeal level and in four subjects at the nasopharyngeal level as compared with normal control subjects. Sleep apnoea and minor radiological evidence of narrowing of the upper airway are common in the Prader-Willi syndrome, although clinical otolaryngological examination is often unremarkable. Excessive daytime sleepiness occurs in approximately 50% of all patients with Prader-Willi syndrome. Although obstructive sleep apnoea is one important factor related to sleepiness, an additional central disturbance of sleep mechanisms is present.


Safety and antioxidant effects of a modest soy protein intervention in hemodialysis patients.
Antioxidant/anti-inflammatory effects of isoflavone-containing soy protein could partly explain why hemodialysis patients in Japan tend to outlive U.S. hemodialysis patients. However, a safety concern is that dialysis patients do not clear isoflavones well. A low-dose intervention with high isoflavone soy protein (25 g protein, four times a week for 4 weeks) was tested in 17 U.S. hemodialysis patients (eight given soy protein, nine given whey protein as a control). Soy protein intake produced no harmful effects based on a typical battery of blood safety tests. Post-treatment isoflavone levels, though high, were similar to those reported after a single 20-g soy protein intake by dialysis patients. In addition, intake of soy, but not whey, reduced plasma values for oxidized low-density lipoprotein, a risk factor for cardiovascular disease, which is a common mortality cause in hemodialysis patients. Three other measures of oxidant stress and/or inflammation were unchanged by the modest high isoflavone soy protein intervention. In conclusion, in hemodialysis patients, a fairly short, low intake level intervention with high isoflavone soy protein produced no obvious harm, and produced one potentially beneficial effect. This justifies tests of higher-dose, longer interventions with soy protein in hemodialysis patients.


Aridity and land use negatively influence a dominant species' upper critical thermal limits.
Understanding the physiological tolerances of ectotherms, such as thermal limits, is important in predicting biotic responses to climate change. However, it is even more important to examine these impacts alongside those from other landscape changes: such as the reduction of native vegetation cover, landscape fragmentation and changes in land use intensity (LUI). Here, we integrate the observed thermal limits of the dominant and ubiquitous meat ant Iridomyrmex purpureus across climate (aridity), land cover and land use gradients spanning 270 km in length and 840 m in altitude across northern New South Wales, Australia. Meat ants were chosen for study as they are ecosystem engineers and changes in their populations may result in a cascade of changes in the populations of other species. When we assessed critical thermal maximum temperatures (CTmax) of meat ants in relation to the environmental gradients we found little influence of climate (aridity) but that CTmax decreased as LUI increased. We found no overall correlation between CTmax and CTmin. We did however find that tolerance to warming was lower for ants sampled from more arid locations. Our findings suggest that as LUI and aridification increase, the physiological resilience of I. purpureus will decline. A reduction in physiological resilience may lead to a reduction in the ecosystem service provision that these populations provide throughout their distribution.


Effect of muscle strength on gait in hemodialysis patients with and without diabetes.
There is minimal data on the gait of hemodialysis (HD) patients with and without diabetes. This investigation examined spatiotemporal parameters of gait in HD patients with and without diabetes compared with age-matched, sex-matched, and BMI-matched controls. The effect of muscle weakness on gait in HD patients was also examined. Eighteen HD patients and 18 age-matched, sex-matched, and BMI-matched controls completed two walking trials along a 7.9 m long pressure sensitive pathway. The HD participants were divided into groups based on their diabetic status (eight patients without diabetes and 10 with diabetes). Spatiotemporal markers of gait, including variability metrics, were determined. Knee strength was quantified only in the HD groups. Overall HD patients had a worse gait compared with controls (P<0.01). Furthermore, HD patients with diabetes had an elevated gait variability compared with those without diabetes, even after controlling for muscle strength (P<0.05). Further research is warranted to explore whether increases in lower extremity strength lead to improvements in gait in this population.


A library for the twenty-first century: the Galter Health Sciences Library's renovation and expansion project.
A renovation and expansion project at the Galter Health Sciences Library of Northwestern University strikes a balance between traditional and future libraries, library ambiance and high technology, old and new. When guided by a vision of future building use, renovation projects can succeed in meeting many institutional goals as a viable alternative to new library buildings. Issues addressed include planning considerations, architectural history, library design, building features, information technology considerations, and ideal library space design when new construction is not possible.


How Could Peers in Online Health Community Help Improve Health Behavior.
Human behavior is the largest source of variance in health-related outcomes, and the increasingly popular online health communities (OHC) can be used to promote healthy behavior and outcomes. We explored how the social influence (social integration, descriptive norms and social support) exerted by online social relationships does affect the health behavior of users. Based on an OHC, we considered the effect of three types of social relationships (friendship, mutual support group and competing group) in the OHC. We found that social integration, descriptive norms and social support (information and emotional support) from the OHC had a positive effect on dietary and exercise behavior. Comparing the effects of different social relationships, we found that the stronger social relationship-friendship-had a stronger effect on health behavior than the mutual support group and competing group. Emotional support had a stronger effect on health behavior than informational support. We also found that the effects of social integration and informational support became stronger as membership duration increased, but the effects of the descriptive norms and emotional support became smaller. This study extended the research on health behavior to the online social environment and explored how the social influence exerted by various social relationships in an OHC affected health behavior. The results could be used for guiding users to make use of online social relationships for changing and maintaining healthy behavior, and helping healthcare websites improve their services.


[The grating acuity of children in preschool age].
To study the developmental trend of the binocular grating acuity of preschool children. Binocular grating acuities in 599 children from 2 months to 72 months old (18 groups) were measured using the closed-circuit operant preferential looking system (COPLs). The children included in the investigation were required to be a normal term birth, development and normal eyes, and cycloplegic refraction error within specific limits. The system's reliabilities and measurable rates were also evaluated. The difference of the vision acuities obtained by the same tester on different days has no statistic significance. The measurable rates reached 90% in most age groups. The grating acuity of the children included in the study developed rapidly during first year, and then it reached to a slower development period from 30 to 36-months, the grating acuity stabilized after 3 years old. The COPL system is a practical devise to assess the grating visual acuity of infants and preschool children and it can be used to investigate the vision developmental trend including speed, age of its maturation and the top-acuity of the development.


Regulatory and DNA repair genes contribute to the desiccation resistance of Sinorhizobium meliloti Rm1021.
Sinorhizobium meliloti can form a nitrogen-fixing symbiotic relationship with alfalfa after bacteria in the soil infect emerging root hairs of the growing plant. To be successful at this, the bacteria must be able to survive in the soil between periods of active plant growth, including when conditions are dry. The ability of S. meliloti to withstand desiccation has been known for years, but genes that contribute to this phenotype have not been identified. Transposon mutagenesis was used in combination with novel screening techniques to identify four desiccation-sensitive mutants of S. meliloti Rm1021. DNA sequencing of the transposon insertion sites identified three genes with regulatory functions (relA, rpoE2, and hpr) and a DNA repair gene (uvrC). Various phenotypes of the mutants were determined, including their behavior on several indicator media and in symbiosis. All of the mutants formed an effective symbiosis with alfalfa. To test the hypothesis that UvrC-related excision repair was important in desiccation resistance, uvrA, uvrB, and uvrC deletion mutants were also constructed. These strains were sensitive to DNA damage induced by UV light and 4-NQO and were also desiccation sensitive. These data indicate that uvr gene-mediated DNA repair and the regulation of stress-induced pathways are important for desiccation resistance.


Evidence of a new phosphoryl transfer system in nucleotide metabolism.
Crude rat liver extract showed AMP-AMP phosphotransferase activity which, on purification, was ascribed to a novel interaction between adenylate kinase, also known as myokinase (EC 22.214.171.124), and adenosine kinase (EC 22.214.171.124). The activity was duplicated using the same enzymes purified from recombinant sources. The reaction requires physical contact between myokinase and adenosine kinase, and the net reaction is aided by the presence of adenosine deaminase (EC 184.108.40.206), which fills the gap in the energy balance of the phosphoryl transfer and shifts the equilibrium towards ADP and inosine synthesis. The proposed mechanism involves the association of adenosine kinase and myokinase through non-covalent, transient interactions that induce slight conformational changes in the active site of myokinase, bringing two already bound molecules of AMP together for phosphoryl transfer to form ADP. The proposed mechanism suggests a physiological role for the enzymes and for the AMP-AMP phosphotransferase reaction under conditions of extreme energy drain (such as hypoxia or temporary anoxia, as in cancer tissues) when the enzymes cannot display their conventional activity because of substrate deficiency.


Sexually dimorphic regulation of hepatic isoforms of human cytochrome p450 by growth hormone.
Sex differences in drug metabolism have been reported in numerous species, including humans. In rats and mice, sex-dependent differences in circulating growth hormone profiles are responsible for the differential expression of multiple sex-dependent isoforms of cytochrome P450, which is the basis for the sexual dimorphism in drug metabolism. In contrast, very little is known about sex differences in human isoforms of cytochrome P450 and their regulation by growth hormone. In this study, we have examined the effects of physiologic-like exposure doses to dexamethasone and/or pulsatile (masculine) or constant (feminine) human growth hormone on expression levels of CYP3A4, 1A2, 2D6, and 2E1 and the glucocorticoid and growth hormone receptors in hepatocyte cultures obtained from men and women donors. We report that growth hormone can regulate expression of CYP3A4, 1A2, and 2D6. The masculine-like pulsatile growth hormone profile suppresses dexamethasone-induced CYP3A4, 1A2, and 2D6, whereas the feminine-like constant profile is permissive allowing isoform expression to be equal to or greater than glucocorticoid induction alone. There are intrinsic sexual differences in hepatocytes of men and women resulting in different levels of responsiveness of CYP3A4, 1A2, and hormone receptor expression to the same sexually dimorphic growth hormone profiles. Last, although real, the sexually dimorphic effects of growth hormone on human cytochrome P450 expression are not as dramatic as those observed in rats and could easily be overlooked by the heterogeneous backgrounds of human populations.


Genome-wide meta-analysis of copy number variations with alcohol dependence.
Genetic association studies and meta-analyses of alcohol dependence (AD) have reported AD-associated single nucleotide polymorphisms (SNPs). These SNPs collectively account for a small portion of estimated heritability in AD. Recent genome-wide copy number variation (CNV) studies have identified CNVs associated with AD and substance dependence, suggesting that a portion of the missing heritability is explained by CNV. We applied PennCNV and QuantiSNP CNV calling algorithms to identify consensus CNVs in five AD cohorts of European and African origins. After rigorous quality control, genome-wide meta-analyses of CNVs were carried out in 3243 well-diagnosed AD cases and 2802 controls. We identified nine CNV regions, including a deletion in chromosome 5q21.3 with a suggestive association with AD (OR=2.15 (1.41-3.29) and P=3.8 × 10-4) and eight nominally significant CNV regions. All regions were replicated with consistent effect sizes across studies and populations. Pathway and gene-drug interaction enrichment analyses based on the resulting genes indicated the mitogen-activated protein kinase signaling pathway and the recombinant insulin and hyaluronidase drugs, which were relevant to AD biology or treatment. To our knowledge, this is the first genome-wide meta-analysis of CNVs with addiction. Further investigation of the AD-associated CNV regions will provide better understanding of the AD genetic mechanism.


Dynamic and structural evidence of mesoscopic aggregation in phosphonium ionic liquids.
Mesoscopic aggregation in aprotic ionic liquids due to the microphase separation of polar and non-polar components is expected to correlate strongly with the physicochemical properties of ionic liquids and therefore their potential applications. The most commonly cited experimental evidence of such aggregation is the observation of a low-q pre-peak in the x-ray and neutron scattering profiles, attributed to the polarity alternation of polar and apolar phases. In this work, a homologous series of phosphonium ionic liquids with the bis(trifluoromethylsulfonyl)imide anion and systematically varying alkyl chain lengths on the phosphonium cation are investigated by small and wide-angle x-ray scattering, dynamic-mechanical spectroscopy, and broadband dielectric spectroscopy. A comparison of the real space correlation distance corresponding to the pre-peak and the presence or absence of the slow sub-α dielectric relaxation previously associated with the motion of mesoscale aggregates reveals a disruption of mesoscale aggregates with increasing symmetry of the quaternary phosphonium cation. These findings contribute to the broader understanding of the interplay of molecular structures, mesoscale aggregation, and physicochemical properties in aprotic ionic liquids.


Switching or Discontinuing Disease-Modifying Therapies for Multiple Sclerosis.
This article reviews the reasons for discontinuation or switching of multiple sclerosis disease-modifying therapy as well as procedures that might mitigate risk to the patient under such circumstances. Recent review of the literature, as well as the author's extensive clinical experience, indicate that the discontinuation of multiple sclerosis disease-modifying therapies occurs for many reasons. Often one medication is stopped at the recommendation of the physician in order to switch to another medication. However, often the decision to discontinue medication is made by the patient. Unfortunately, in still other situations, treatment is stopped because of circumstances beyond the control of either patient or physician (eg, a loss of insurance coverage). Currently available data do not permit a conclusion about whether it is ever safe to discontinue disease-modifying therapy in a stable patient without the expectation of return of disease activity. Clinicians must help patients avoid unnecessary and undesirable cessation of disease-modifying therapy. While switches of therapy are often necessary, steps to minimize both adverse events and the risk of recurrent disease should be undertaken. Whether disease-modifying therapy can ever be purposely discontinued without incurring a significant risk of disease recurrence remains to be determined.


Developmentally regulated expression and localization of fibroblast growth factor receptors in the human muscle.
Fibroblast growth factors (FGFs) are believed to play a key role in tissue differentiation and maturation. Thus, the expression of the four members of the high-affinity tyrosine kinase FGF receptor family (FGFRs) and of the low-affinity heparan sulphate proteoglycan binding sites, syndecan-1 and perlecan, was studied in the human skeletal muscle during development. Northern blot analysis demonstrated a developmentally regulated expression of the mRNAs for FGFR-1, FGFR-3, FGFR-4, whereas only traces of FGFR-2 mRNA were found. Each receptor type had a different developmental pattern, suggesting an independent regulation. Signal for FGFR-3 was retained only in the adult muscle. Among the low-affinity FGF binding sites, perlecan was absent, whereas RNA transcript for syndecan-1 peaked at week 13 of gestation, after which a significant decrease was observed. Immunohistochemistry for FGFRs revealed that their localization changed with muscle maturation. At early embryonic stages, FGFR-3 and FGFR-4 had a scattered distribution in the tissue, and FGFR-1 was found on myotube and myofiber plasma membranes. At later stages, FGFR-1 positivity decreased and was found in a few areas of the muscle, FGFR-3 was concentrated in the nuclei of some, but not all, muscle fibers, and FGFR-4 maintained an association with plasma membrane. In adult tissue, weak positivity for FGFR-3 and FGFR-4 was observed in the connective tissue only. When immunocytochemistry was performed on human fetal myoblasts in culture, confocal microscope analysis revealed a nonhomogeneous cell membrane distribution of FGFRs. Taken together, the data strongly suggest that developmentally regulated expression and cell distribution of FGFRs play a role during muscle maturation.


Microsatellite markers for the Triticum timopheevi-derived leaf rust resistance gene Lr18 on wheat 5BL chromosome.
Leaf rust, caused by Puccinia triticina, is a common wheat disease worldwide. Developing resistant cultivars through deploying new or pyramiding resistance genes in a suitable line, is the most effective approach to control this disease. However, to stack genes in a genotype, efficient and reliable markers are required. In the present study, F2 plants and their corresponding F3 families from a cross between the resistant line; Thatcher (Tc) Lr18, and the susceptible cultivar 'Boolani' were used to map rust resistance gene, Lr18 using SSR markers on chromosome 5BL of hexaploid wheat. The P. triticina pathotype no 15 was used to inoculate plants. Out of 20 primers tested, eight showed polymorphism between the two parents and were subsequently genotyped in the entire F2 population. The markers Xgpw7425 and Xwmc75 flanked the locus at a distance of 0.3 and 1.2 cM, respectively. Analysis of 81 genotypes from different backgrounds with these two markers confirmed their usefulness in screening absence or presence of Lr18. Therefore, these markers can be used for gene postulation and marker-assisted selection (MAS) of this gene in wheat breeding programs in future.


Piperine-mediated inhibition of glucuronidation activity in isolated epithelial cells of the guinea-pig small intestine: evidence that piperine lowers the endogeneous UDP-glucuronic acid content.
Piperine (1-peperoyl piperidine), a major component of the Piper species was reported recently by us to inhibit the activities of rat hepatic monooxygenases and UDP-glucuronyltransferase. This study explores further the basis of inhibition of glucuronidation. The effect of piperine on the rate of glucuronidation of 3-hydroxybenzo(a) pyrene and UDP-glucuronic acid content in the intact isolated epithelial cells of the guinea-pig small intestine was studied. The cells offered a fairly good system to study the modulation of glucuronidation activity. Glucuronidation of 3-hydroxybenzo(a) pyrene was dependent on the time of incubation, cellular protein and substrate concentration. From the kinetics of glucuronidation of 3-hydroxybenzo(a)pyrene in the isolated cell preparation the Vmax of 0.5 nmol of BP-3-glucuronide formed per min/mg of protein and Km of 25 microM were observed. The endogeneous concentration of UDP-glucuronic acid observed was 1.6 to 2.3 nmol/mg of cellular protein. Piperine caused a concentration-related decrease in UDP-glucuronic acid content and the rate of glucuronidation in the cells. It required much lower concentrations of piperine than D-galactosamine to diminish the endogeneous level of UDP-glucuronic acid. Rate of glucuronidation of 3-hydroxybenzo (a) pyrene was dependent on the endogeneous level of UDP-glucuronic acid. At 50 microM piperine, the rate of glucuronidation was reduced to about 50% of the basal rate. Piperine caused noncompetitive inhibition of hepatic microsomal UDP-glucuronyltransferase with Ki of 70 microM. The studies demonstrate that piperine modifies the rate of glucuronidation by lowering the endogeneous UDP-glucuronic acid content and also by inhibiting the transferase activity.


Formation of a spirodiazaselenurane and its corresponding azaselenonium derivatives from the oxidation of 2,2'-selenobis(benzamide). Structure, properties and glutathione peroxidase activity.
The oxidation of 2,2'-selenobis(benzamide) with N-chlorosuccinimide or hydrogen peroxide afforded the corresponding stable azaselenonium chloride and hydroxide, respectively. Both structures were characterized by spectroscopic and X-ray crystallographic methods. Each contains a covalent N-Se bond, as well as a noncovalent interaction between the selenium atom and the carbonyl oxygen atom of the other amide moiety. The treatment of the azaselenonium chloride with an excess of potassium hydride in DMSO-d(6) afforded the corresponding spirodiazaselenurane species, which proved hydrolytically unstable, but was characterized by NMR spectroscopy. The azaselenonium chloride displayed significant glutathione peroxidase-like catalytic activity in an assay with benzyl thiol and either hydrogen peroxide or tert-butyl hydroperoxide.


A meta-analysis of behavior therapy for Tourette Syndrome.
Individual randomized controlled trials (RCTs) of habit reversal training and a Comprehensive Behavioral Intervention for Tics (collectively referred to as behavior therapy, BT) have demonstrated efficacy in reducing tic severity for individuals with Tourette Syndrome and Chronic Tic Disorders (collectively referred to as TS), with no examination of treatment moderators. The present meta-analysis synthesized the treatment effect sizes (ES) of BT relative to comparison conditions, and examined moderators of treatment. A comprehensive literature search identified eight RCTs that met inclusion criteria, and produced a total sample of 438 participants. A random effects meta-analysis found a medium to large ES for BT relative to comparison conditions. Participant mean age, average number of therapy sessions, and the percentage of participants with co-occurring attention deficit hyperactivity disorder (ADHD) were found to moderate treatment effects. Participants receiving BT were more likely to exhibit a treatment response compared to control interventions, and identified a number needed to treat (NNT) of three. Sensitivity analyses failed to identify publication bias. Overall, BT trials yield medium to large effects for TS that are comparable to treatment effects identified by meta-analyses of antipsychotic medication RCTs. Larger treatment effects may be observed among BT trials with older participants, more therapeutic contact, and less co-occurring ADHD.


Identification of a putative GH-releasing factor (GRF) batch as predominantly ovine CRF with a small quantity of human GRF.
The existence of discordant results regarding the effects of intracerebroventricular (icv) administration of GRF on GH secretion prompted a reexamination of the central actions of GRF and a detailed chemical characterization of the peptide designated as hpGRF-44-NH2. The icv injection of 10 micrograms rat (r) GRF to freely-moving rats caused an acute stimulation of GH release, whereas 10 micrograms of the putative hpGRF peptide icv continued to suppress spontaneous GH secretion. Through a series of biochemical and immunologic studies we demonstrate that peptide hpGRF-44-NH2, code number 92-81-5G-41-47, is predominantly ovine (o) CRF and also contains a small amount (3-5%) human (h) GRF-44-NH2. We conclude that the major effect of icv administered GRF, at high doses, is to stimulate GH release and that the central actions previously attributed to the hpGRF peptide are, in fact, due to the oCRF component of this compound.


Combinations of cyclophilin inhibitor NIM811 with hepatitis C Virus NS3-4A Protease or NS5B polymerase inhibitors enhance antiviral activity and suppress the emergence of resistance.
Chronic hepatitis C virus (HCV) infection remains a major global health burden while current interferon-based therapy is suboptimal. Efforts to develop more effective antiviral agents mainly focus on two viral targets: NS3-4A protease and NS5B polymerase. However, resistant mutants against these viral specific inhibitors emerge quickly both in vitro and in patients, particularly in the case of monotherapy. An alternative and complementary strategy is to target host factors such as cyclophilins that are also essential for viral replication. Future HCV therapies will most likely be combinations of multiple drugs of different mechanisms to maximize antiviral activity and to suppress the emergence of resistance. Here, the effects of combining a host cyclophilin inhibitor NIM811 with other viral specific inhibitors were investigated in vitro using HCV replicon. All of the combinations led to more pronounced antiviral effects than any single agent, with no significant increase of cytotoxicity. Moreover, the combination of NIM811 with a nucleoside (NM107) or a non-nucleoside (thiophene-2-carboxylic acid) polymerase inhibitor was synergistic, while the combination with a protease inhibitor (BILN2061) was additive. Resistant clones were selected in vitro with these inhibitors. Interestingly, it was much more difficult to develop resistance against NIM811 than viral specific inhibitors. No cross-resistance was observed among these inhibitors. Most notably, NIM811 was highly effective in blocking the emergence of resistance when used in combination with viral protease or polymerase inhibitors. Taken together, these results illustrate the significant advantages of combining inhibitors targeting both viral and host factors as key components of future HCV therapies.


A Well-Tempered Hybrid Method for Solving Challenging Time-Dependent Density Functional Theory (TDDFT) Systems.
The time-dependent Hartree-Fock (TDHF) and time-dependent density functional theory (TDDFT) equations allow one to probe electronic resonances of a system quickly and inexpensively. However, the iterative solution of the eigenvalue problem can be challenging or impossible to converge, using standard methods such as the Davidson algorithm for spectrally dense regions in the interior of the spectrum, as are common in X-ray absorption spectroscopy (XAS). More robust solvers, such as the generalized preconditioned locally harmonic residual (GPLHR) method, can alleviate this problem, but at the expense of higher average computational cost. A hybrid method is proposed which adapts to the problem in order to maximize computational performance while providing the superior convergence of GPLHR. In addition, a modification to the GPLHR algorithm is proposed to adaptively choose the shift parameter to enforce a convergence of states above a predefined energy threshold.


Anaesthesia system with eliminated spill valve adjustment and without lung rupture risk.
A new anaesthesia system is presented. Apart from the inclusion of an inflating valve which is influenced by bag compression, the components are those commonly used in any absorption circuit, but arranged in a new sequence. The anaesthesia system is characterized by its use of a spill valve with a fixed low opening pressure, thus eliminating the commonly haphazard adjustment of this valve. The magnitude of the fresh gas flow does not influence the pressure in the bag during its compression, thereby introducing the "closed system" bag feeling, otherwise excluded with semi-closed and high flow systems. For the same reason, dangerous pressures cannot arise in the lung, as its peak pressure is defined by the volume inflated from the bag, and is controllable by the anaesthetist. Dumping of expired air in preference to fresh gas makes gas expenses optimally low with any semi-closed inflow. The permanent low pressure inside the carbon dioxide absorber makes it easier to produce a tightly closed system and also makes more economical use of expensive gases. Disclosure of disconnection by a steadily rotating volumeter pointer may add to safety, the same feature apparently also being helpful in teaching proper mask technique.


The antenatal diagnosis of fetal abnormalities: a 10 year audit of influencing factors.
During the 10 years 1984-1993, a total of 438 fetuses and children with a congenital abnormality, identified antenatally or in the first year of life, were registered from the North Tees Health District with the Northern Region Congenital Abnormality Survey (NorCAS). This represented an abnormality rate of 2% of all births. In total, 252 structural abnormalities (57.5%) were detected by antenatal ultrasound examination. In spite of a targeted education programme, identification of cardiac lesions remained poor. The detection of structural abnormality by antenatal scan rose from 52% in 1984 to 85% in 1993, due mainly to improvements in image quality and resolution of ultrasound equipment. Also important was audit, based both on review of images and feedback from a comprehensive central register (NorCAS).


The rate of cocaine administration alters gene regulation and behavioral plasticity: implications for addiction.
The rapid delivery of drugs of abuse to the brain is thought to promote addiction, but why this occurs is unknown. In the present study, we characterized the influence of rate of intravenous cocaine infusion (5-100 sec) on three effects thought to contribute to its addiction liability: its ability to block dopamine (DA) uptake, to activate immediate early gene expression, and to produce psychomotor sensitization. Rapid infusions potentiated the ability of cocaine to block DA reuptake, to induce c-fos and arc mRNA expression, especially in mesocorticolimbic regions, and to produce psychomotor sensitization. Thus, the rate at which cocaine is delivered influences both its neurobiological impact and its ability to induce a form of drug experience-dependent plasticity implicated in addiction. We propose that rapidly delivered cocaine may be more addictive, in part, because this more readily induces forms of neurobehavioral plasticity that lead to the compulsive pursuit of drugs.


IRE1 inhibition affects the expression of insulin-like growth factor binding protein genes and modifies its sensitivity to glucose deprivation in U87 glioma cells.
The aim of the present study was to investigate the effect of inhibition of endoplasmic reticulum stress signaling mediated by IRE1/ERN1 (inositol-requiring enzyme 1/endoplasmic reticulum to nucleus signaling 1) on the expression of genes encoding different groups of insulin-like growth binding proteins (IGFBP6 and IGFBP7) and CCN family (IGFBP8/CTGF/CCN2, IGFBP9/NOV/CCN3, IGFBP10/CYR61/CCN1, WISP1/CCN4, and WISP2/CCN5) and its sensitivity to glucose deprivation in U87 glioma cells. The expression of IGFBP6, IGFBP7, IGFBP8, IGFBP9, IGFBP10, WISP1, and WISP2 genes was studied by qPCR in control U87 glioma cells (wild-type) and its subline with IRE1 signaling enzyme loss of function upon glucose deprivation. The expression of IGFBP8, IGFBP9, and WISP2 genes was up-regulated in control glioma cells upon glucose deprivation with most significant changes for IGFBP9 gene. At the same time, the expression of IGFBP6, IGFBP10, and WISP1 genes was resistant to glucose deprivation in these glioma cells, but the IGFBP7 gene expression was down-regulated. The inhibition of both enzymatic activities (kinase and endoribonuclease) of IRE1 in glioma cells modified the sensitivity of most studied gene expressions to glucose deprivation condition: introduced sensitivity of IGFBP10 and WISP1 genes to glucose deprivation, enhanced the effect of this deprivation on IGFBP7 and IGFBP9 gene expressions, and reduced this effect on WISP2 gene and induced suppressive effect of glucose deprivation on the expression of IGFBP8 gene. Furthermore, the inhibition of IRE1 strongly affected the expression of all studied genes in glioma cells upon regular growing condition in gene specific manner: up-regulated the expression levels of IGFBP7, IGFBP8, IGFBP10, WISP1, and WISP2 genes and down-regulated the IGFBP6 and IGFBP9 genes. The data of this investigation demonstrate that the expression of IGFBP7, IGFBP8, IGFBP9, and WISP2 genes are sensitive to glucose deprivation in U87 glioma cells and that inhibition of IRE1 signaling enzyme function may significantly affect the expression of all studied genes in the presence of glucose as well as modify the effect of glucose deprivation on the expression of most studied genes. These data also show that proteins encoded by these genes may participate in the regulation of metabolic and proliferative processes via IGF/INS receptors and possibly other signaling pathways as well, via IRE1 signaling, which is a central mediator of the unfolded protein response and an important component of the tumor growth and metabolic diseases.


Relationship between left ventricular diastolic function at rest and exercise capacity in patients who have suffered a previous myocardial infarction.
To assess whether left ventricular (LV) diastolic function is a determinant of exercise capacity in patients who have suffered a previous myocardial infarction (MI), we investigated the relationship between maximum exercise duration and resting LV diastolic function in 65 MI patients. Each patient underwent both a symptom-limited exercise test and LV biplane angiography with simultaneous high-fidelity pressure measurements. LV relaxation was assessed by the time constants (T1/e and T1/2) of isovolumic pressure decay, and LV diastolic distensibility was assessed by the LV end-diastolic volume (V) index-pressure (P) ratio. The time constants of relaxation did not correlate with maximum exercise capacity (r = -0.19 for T1/e, NS; r = - 0.17 for T1/2, NS). LV diastolic distensibility also did not correlate with exercise capacity (r = - 0.08, NS). These results suggest that the resting LV diastolic dysfunction is unlikely to be the principal cause of exercise intolerance in MI patients without congestive heart failure.


[Male infertility update].
Exact etiological factors cannot be found in more than 70% of male infertility. Although the causes of some male infertility are known, the pathogenesis is not yet clear. Therefore, the diagnosis and treatment of male infertility are particularly complicated. Some breakthroughs have been made in the treatment of refractory male infertility since the development of ICSI in 1992. However, traditional treatment should also be taken into account for individual male infertility. The standardization of diagnosis and treatment and the improvement of the success rate and safety of assistant reproductive technology will be the dominant factors in the development of male infertility researches.


A Phosphorylation Switch on Lon Protease Regulates Bacterial Type III Secretion System in Host.
Most pathogenic bacteria deliver virulence factors into host cytosol through type III secretion systems (T3SS) to perturb host immune responses. The expression of T3SS is often repressed in rich medium but is specifically induced in the host environment. The molecular mechanisms underlying host-specific induction of T3SS expression is not completely understood. Here we demonstrate in Xanthomonas citri that host-induced phosphorylation of the ATP-dependent protease Lon stabilizes HrpG, the master regulator of T3SS, conferring bacterial virulence. Ser/Thr/Tyr phosphoproteome analysis revealed that phosphorylation of Lon at serine 654 occurs in the citrus host. In rich medium, Lon represses T3SS by degradation of HrpG via recognition of its N terminus. Genetic and biochemical data indicate that phosphorylation at serine 654 deactivates Lon proteolytic activity and attenuates HrpG proteolysis. Substitution of alanine for Lon serine 654 resulted in repression of T3SS gene expression in the citrus host through robust degradation of HrpG and reduced bacterial virulence. Our work reveals a novel mechanism for distinct regulation of bacterial T3SS in different environments. Additionally, our data provide new insight into the role of protein posttranslational modification in the regulation of bacterial virulence.IMPORTANCE Type III secretion systems (T3SS) are an essential virulence trait of many bacterial pathogens because of their indispensable role in the delivery of virulence factors. However, expression of T3SS in the noninfection stage is energy consuming. Here, we established a model to explain the differential regulation of T3SS in host and nonhost environments. When Xanthomonas cells are grown in rich medium, the T3SS regulator HrpG is targeted by Lon protease for proteolysis. The degradation of HrpG leads to downregulated expression of HrpX and the hrp/hrc genes. When Xanthomonas cells infect the host, specific plant stimuli can be perceived and induce Lon phosphorylation at serine 654. Phosphorylation on Lon attenuates its proteolytic activity and protects HrpG from degradation. Consequently, enhanced stability of HrpG activates HrpX and turns on bacterial T3SS in the host. Our work provides a novel molecular mechanism underlying host-dependent activation of bacterial T3SS.


Making a diagnosis in severe cutaneous drug hypersensitivity reactions.
Severe cutaneous adverse reactions (SCAR) are relatively uncommon but can be life-threatening. This review focuses on the nonanaphylactic (non-IgE-mediated) phenotypes of drug hypersensitivity, with specific reference to diagnosis and management of acute generalized exanthematous pustulosis (AGEP), drug reaction with eosinophilia and systemic symptoms (DRESS), Stevens-Johnson syndrome (SJS), and toxic epidermal necrolysis (TEN). Here, we review recent guidelines on optimal supportive care as well as publications of interventional treatment for SJS/TEN, including various immunomodulating therapies, and management strategies for severe ocular disease with the use of amniotic membrane transplantation. In DRESS, long-term autoimmune sequelae are increasingly recognized and modify strategies for treatment of the acute episode. If the causative drug is not apparent from careful inspection of the drug exposure history, in-vitro diagnostics, HLA testing and skin testing before drug challenge testing may be considered and we present an algorithm for investigation of complex cases. Careful phenotypic analysis of the increasingly complex recognized patterns of SCAR facilitates the enhancement in our understanding of T-cell mediated drug hypersensitivity and allows the improvement of in-vitro diagnostic testing to minimize patient exposure to test substances in all but a very limited number of cases, thereby enhancing safety.


Congenital hypotonia: clinical and developmental assessment.
Identifying the underlying cause of congenital hypotonia remains difficult, despite advances in diagnostic laboratory and imaging techniques. Clinical evaluation strategies and standardized developmental tests can assist in differentiating hypotonia resulting from primary involvement of the upper motoneuron (central hypotonia) versus that involving the lower motoneuron and motor unit (peripheral hypotonia). This is especially important in infants with idiopathic hypotonia. This review outlines and describes the components of the clinical assessment: detailed infant and family history, clinical techniques and characteristics for differentiating hypotonia of central versus peripheral origin, and clinical evaluation (muscle tone, primitive reflexes, deep tendon reflexes, etc). Recent research that has contributed to the differential diagnosis of congenital hypotonia is reviewed and directions for future research are provided. Ideally, the assessment of infants with congenital hypotonia is best accomplished by an interdisciplinary team of developmental specialists including pediatricians, medical geneticists, child neurologists, and physical or occupational therapists.


What influences parental decisions about antibiotic use with their children: A qualitative study in rural Australia.
Inappropriate use of antibiotics can promote bacterial resistance, which is a growing public health concern. As children are amongst the highest recipients of antibiotics, understanding the drivers of parental decisions towards their children's antibiotic use is imperative for the development of strategies to assist parents in making more informed decisions. This is particularly relevant to the decisions of parents living in resource-limited settings. This study explored the perspectives and practices of parents living in a rural setting about the use of antibiotics in their children. Three focus group interviews were conducted with 10 parents of children under 12yrs, living in rural and remote areas of the Northern Territory, Australia. A focus group guide was developed to facilitate discussions, which was informed by the Theory of Planned Behaviour. Transcripts were analysed abductively using thematic analysis. Four themes emerged explaining factors that contributed to parent decisions about their children's antibiotic use: 1) Parental knowledge, attitudes and decision making; 2) Perceptions of antimicrobial resistance; 3) Healthcare challenges; 4) Behaviours with antibiotics. While parents demonstrated accurate knowledge of the indications for antibiotic use, their decisions about the need for antibiotics were often driven by fear of serious illness. This fear was exacerbated by resource limitations associated with living in a resource-limited setting. Additional drivers of parental decision making included what parents have read or heard from both medical and non-medical networks, underscoring the importance of Social Norms in predicting behavioural intentions. Mothers living in remote areas experiencing reduced access to health services may make decisions about antibiotic use out of fear and based on the advice of their personal network when they perceive their child is vulnerable to a health threat. Findings from this study provide guidance for future research in the prediction of antibiotic use behaviours and for context-specific interventions.


[Study of biocompatibility of polybutylcyanoacrylate nanoparticles].
To evaluate the biocompatibility of polybutylcyanoacrylate nanoparticles (PBCA-NP) manufactured by emulsion polymerization technique. MTT assay was performed for evaluation of the cytotoxicity of PBCA-NP (e.g. cell proliferation and hemolytic test) experiments of long-term subcutaneous implantation and implantation in the muscular tissues of PBCA-NP was conducted in rabbits to observe the inflammatory reactions due to the implantation. No obvious cytotoxicity or hemolytic reactions were observed (with the hemolytic rate at different concentrations of PBCA-NP(5%). Three months after PBCA-NP implantation, obvious lymphocyte infiltration was not observed in the tissues around the implants which underwent gradual degradation. PBCA-NP possesses good biocompatibility.


The role of estrogens in control of energy balance and glucose homeostasis.
Estrogens play a fundamental role in the physiology of the reproductive, cardiovascular, skeletal, and central nervous systems. In this report, we review the literature in both rodents and humans on the role of estrogens and their receptors in the control of energy homeostasis and glucose metabolism in health and metabolic diseases. Estrogen actions in hypothalamic nuclei differentially control food intake, energy expenditure, and white adipose tissue distribution. Estrogen actions in skeletal muscle, liver, adipose tissue, and immune cells are involved in insulin sensitivity as well as prevention of lipid accumulation and inflammation. Estrogen actions in pancreatic islet β-cells also regulate insulin secretion, nutrient homeostasis, and survival. Estrogen deficiency promotes metabolic dysfunction predisposing to obesity, the metabolic syndrome, and type 2 diabetes. We also discuss the effect of selective estrogen receptor modulators on metabolic disorders.


[Fibrinogens and their role in atherogenesis in diabetes mellitus].
In the recent years, measurement of blood level of fibrinogen has been treated very seriously and this parameter has been considered an individual cardiovascular risk factor. A correlation between serum fibrinogen and the frequency of acute myocardial or cerebral ischemia has been found in a large number of studies. A distinct association between a high fibrinogen level and vascular complications in diabetic patients has been revealed as well. Two types of fibrinogen--high molecular weight fibrinogen (HMWF) weighing 340 kD, and low molecular weight fibrinogen (LMWF), weighing 280 kD and lacking a certain part of A alpha-polypeptide chain, are known today. B. Lipinski created a technique to measure the content of LMWF in blood serum, which made it possible to study the role played by this protein in the clinical presentation of atherothrombosis in diabetic patients. This work presents the results of research into the role of LMWF in the clinical picture of atherothrombosis in patients with type 2 diabetes mellitus. According to the localization of the manifestation of arterial ischemia and the presence of diabetes, three groups ofpatients were formed. The study revealed significantly higher LMWF level in all the three groups compared to controls. The LMWF/total blood fibrinogen ratio was also elevated.


A crisis triage rating scale. Brief dispositional assessment of patients at risk for hospitalization.
The authors have developed a brief rating scale to expedite the rapid screening of emergency psychiatric patients who require hospital admission from those who are suitable for outpatient crisis intervention treatment. The interviewers used this scale to assess and score the patient rapidly on the basis of three factors: dangerousness, support system, and motivation or ability to cooperate. The authors report on and discuss the use of the scale in a preliminary study of 300 cases and in a prospective study of 122 patients who were followed for 6 months after they were evaluated. They found that those who scored below a median point on the scale required hospitalization and those who scored higher were suitable for crisis intervention as outpatients.


Nickel/Photoredox-Catalyzed Amidation via Alkylsilicates and Isocyanates.
A nickel/photoredox, dual-catalyzed amidation reaction between alkylsilicate reagents and alkyl/aryl isocyanates is reported. In contrast to the previously reported reductive coupling process, this protocol is characterized by mild reaction conditions and the absence of a stoichiometric reductant. A mechanistic hypothesis involving a nickel-isocyanate adduct is proposed based on literature precedent and further validation by experimental results.


Design and Implementation of IoT Data-Driven Intelligent Law Classroom Teaching System.
In this paper, we conduct in-depth research and analysis by building an IoT data-driven intelligent law classroom teaching system and implementing it in the actual teaching process. Firstly, the application requirements and main functions of the classroom interactive system are analysed and studied in depth; the overall design of the classroom interactive system based on wireless communication is carried out; and the classroom interactive system consisting of teacher's receiver, wireless receiver, student's handheld terminal, teacher's receiver upper computer software, student's handheld terminal upper computer software, and data management website is developed. Platform and communication part: middleware comprises multiple modules such as real-time memory event database, task management system, and event management system. The system uses USB communication, serial time-sharing communication, Zigbee wireless communication, WebSocket, and other technologies to realize data communication between several modules, and some key technologies are studied and improved in detail. Finally, the system is deployed to the actual experimental application scenario, and the software and hardware construction of the IoT innovation lab is completed. The lab equipment is officially put into use, the information platform is also in the trial run stage, and the system is tested in time during the operation stage to provide the basis for the improvement of the system functions. Use data to conduct an in-depth analysis of learning situations and learning process analysis, optimize the reasonable construction of a personalized learning environment, serve personalized learning, and achieve the most optimal learning effect. The secondary development of the Turing robot provides a personalized auxiliary Q&A system for teaching, allowing artificial intelligence-assisted teaching to be integrated into the curriculum. With the help of teaching law courses, the empirical study demonstrates that the personalized learning environment has significant advantages in improving teaching effectiveness.


Monitoring the health of the work environment with a daily assessment tool: the REAL - Relative Environment Assessment Lens - indicator.
Evidence shows that the health of the work environment impacts staff satisfaction, interdisciplinary communication, and patient outcomes. Utilising the American Association of Critical-Care Nurses' Healthy Work Environment standards, we developed a daily assessment tool. The Relative Environment Assessment Lens (REAL) Indicator was developed using a consensus-based method to evaluate the health of the work environment and to identify opportunities for improvement from the front-line staff. A visual scale using images that resemble emoticons was linked with a written description of feelings about their work environment that day, with the highest number corresponding to the most positive experience. Face validity was established by seeking staff feedback and goals were set. Over 10 months, results from the REAL Indicator in the cardiac catheterisation laboratory indicated an overall good work environment. The goal of 80% of the respondents reporting their work environment to be "Great", "Good", or "Satisfactory" was met each month. During the same time frame, this goal was met four times in the cardiovascular operating room. On average, 72.7% of cardiovascular operating room respondents reported their work environment to be "Satisfactory" or better. The REAL Indicator has become a valuable tool in assessing the specific issues of the clinical area and identifying opportunities for improvement. Given the feasibility of and positive response to this tool in the cardiac catheterisation laboratory, it has been adopted in other patient-care areas where staff and leaders believe that they need to understand the health of the environment in a more specific and frequent time frame.


Mixture model-based association analysis with case-control data in genome wide association studies.
Multilocus haplotype analysis of candidate variants with genome wide association studies (GWAS) data may provide evidence of association with disease, even when the individual loci themselves do not. Unfortunately, when a large number of candidate variants are investigated, identifying risk haplotypes can be very difficult. To meet the challenge, a number of approaches have been put forward in recent years. However, most of them are not directly linked to the disease-penetrances of haplotypes and thus may not be efficient. To fill this gap, we propose a mixture model-based approach for detecting risk haplotypes. Under the mixture model, haplotypes are clustered directly according to their estimated disease penetrances. A theoretical justification of the above model is provided. Furthermore, we introduce a hypothesis test for haplotype inheritance patterns which underpin this model. The performance of the proposed approach is evaluated by simulations and real data analysis. The results show that the proposed approach outperforms an existing multiple testing method.


[Conconi tests in children].
From 1990 to 1992 we carried out 158 Conconi-Tests on children aged from 7 to 15. Of these tests 128 were carried out on the 400 m-track, and further 30 were Conconi-Intervall-Tests (Probst-Test). The testing was done on the members of the Swiss Figure-Skating Team, on the best runners of the Volksbank Grand Prix St. Gallen 1991/92 and on the youngest girls and boys of the Athletic Club Brühl St. Gallen. 89 tests were performed on girls and 69 tests on boys. In 84% of all cases (133 tests) the results were open to unambiguous interpretation, and were determined by the anaerobic threshold, 14% (22 tests), however, could not be clearly interpreted or had to be done again, and in 2% of all cases (3 tests) the results delivered no analysable information. In the results we only considered the 133 tests where clear interpretation was possible (114 from 128 Conconi-Tests, i.e. 89%, and 19 from 30 Probst-Tests, i.e. 63%). Thus we achieved the first aim of our research, which was to investigate the feasibility of carrying out Conconi-Tests on children and analysing the subsequent results thereof (with very interesting threshold results). From this, it is hoped, that norm data can be established, on which the anaerobic threshold and the threshold pulse of children active in sports can be based. At this point it must be stated that the classical Conconi-Test was found to deliver data easily and clearly interpretable, while the Intervall-Test was less easily analyzable.(ABSTRACT TRUNCATED AT 250 WORDS)


Inhibitory effects of desmethylimipramine on the action of thyroxine on cardiac beta-receptors and myocardial phosphorylase.
The influence of chronic administration of desmethylimipramine (DMI) on the actions of thyroxine (T4) on rat heart was studied. Administration od DMI (10 mg/kg, i.p., twice daily) for 7 days did not alter the cardiac beta-adrenergic receptor density or the affinity for (-)[3H]dihydroalprenolol (3H-DHA) but diminished the activation of myocardial phosphorylase produced by isoproterenol. Chronic injections of T4 (500 microgram/rat) for 5 days caused an increase in the number of beta-adrenergic receptors in the heart and potentiated the stimulatory effect of isoproterenol on cardiac phosphorylase alpha activity. When DMI was administered concomitantly with T4, there was no increase in the density of myocardial beta-adrenergic receptors and the T4-induced potentiation of the activation of heart phosphorylase by isoproterenol was abolished. However, simultaneous treatment of the rats with DMI and TR4 did not diminish the positive chronotropic effect of T4. It was concluded that DMI, while not affecting the population of cardiac beta-adrenergic receptors by itself, prevents the increase in these receptors produced by T4 and obviates the T4-induced potentiation of phosphorylase activation by isoproterenol. That the tachycardia caused by T4 persists in hearts in which DMI has impeded the increase in myocardial beta-receptors suggests that the increase in heart rate is not dependent on cardiac beta-adrenergic receptor density.