Nutrient patterns and their relationship with general and central obesity in US adults.
Despite growing evidence on the associations between nutrient patterns and obesity, very few studies have examined the association between patterns of nutrient intake and obesity. To identify major nutrient patterns in U.S. adults and investigate their association with general and central obesity. National Health and Nutrition Examination Survey (NHANES) participants from 2005 to 2012 were included. General obesity was defined as body mass index ≥30 kg/m2, and central obesity as a waist circumference >102 cm for men and >88 cm for women. Intakes of 60 nutrients were calculated. Factor analysis was applied to derive the major nutrient patterns. Statistical analyses accounted for the survey design and sample weights. Overall 24,182 eligible individuals including 8155 with general obesity and 11730 with central obesity were included. Three nutrient patterns explaining 50.8% of the variance in dietary nutrients consumption, were identified. The odds of all types of obesity increased across quarters of the first nutrient patterns (mostly representative of saturated/mono-unsaturated fatty acids), such that the fourth quarter was associated with odds ratio of 1.31 (95%CI: 1.13-1.51) for general obesity and 1.47 (95%CI: 1.30-1.66) for central obesity, relative to the first quarter. The second nutrient patterns (mostly representative of micro nutrients and vitamins) was associated with lower odds of general [0.32 (95%CI: 0.61-0.77]) or central obesity [0.31 (95%CI: 0.62-0.78). Nutrient patterns may have deleterious or protective effects on the risk of general and central obesity, with implication for food-based strategies to prevent and control obesity. This article is protected by copyright. All rights reserved.


[Structured assessment important for remote consultations].
Telephone counselling in medical care has been used for many years, but there are several challenges and pitfalls. The counselling nurse must rely on what the patient tells him or her, and the description of symptoms may be biased by the patients' worries or thoughts. Furthermore, communication difficulties due to insufficient structure in the conversation may also cause problems. The same goes for situations where a nurse seeks counselling from the doctor. To reduce the risks of errors in these situations, the nurse must have good knowledge and skills in the evaluation of the patient's condition and vital functions, use a standardized model of examining and/or questioning and a structured way of communicating. By using the same instruments for clinical evaluation and communication, different care givers will also increase the patient safety when patients are transferred between them.


Gd-enhanced MR images of substrates other than water.
This communication reports the dramatic relaxation enhancements that can be obtained upon the interaction of substrates like lactate, trifluorolactate and inorganic phosphate with the paramagnetic GdDO3A agent. This occurs thanks to the formation of kinetically labile ternary complexes in which the substrate nuclei are in close proximity to the paramagnetic center. It is demonstrated that heteronuclear (13)C, (19)F and (31)P-MR images can be obtained from phantoms containing the substrate in the millimolar concentration range.


Bioactive oligopeptides in dermatology: Part I.
Short sequence amino acids or oligopeptides represent a relatively new and promising area of dermatology. Oligopeptides are defined as peptide sequences ranging from 2 to 20 amino acids. This class of proteins includes potent biologically active compounds, which can modulate various cellular and molecular processes. The medical potential of short sequence peptides was initially characterized many decades ago with the identification of biological mediators such as angiotensin, vasopressin, oxytocin and bradykinin. However, the role of oligopeptides in affecting biological activity within the skin has only recently been explored. Currently, the dermatologic use of protein peptide fragments is a rapidly growing field of research. Recent studies suggest that treatment with various biologically active peptides can result in favourable clinical outcomes such as for the treatment of hyperpigmentation disorders with tyrosinase inhibitors and the use of collagen synthesis modulators to diminish skin laxity. In this review, we explore the roles of biologically active short sequence peptides as potential therapeutics through the modulation of collagen, elastin and melanin synthesis.


Antioxidants for the treatment of mild cognitive impairment.
The isolated deficit in recent memory frequently associated with decline to Alzheimer's disease (AD) is defined as mild cognitive impairment (MCI). The observed progression of MCI to AD suggests a common pathogenesis between these two clinical syndromes, and several neuroimaging, neuropsychological and biological methods are applied with the purpose of identifying subjects at risk of AD. Among these methods, the evaluation of a condition of oxidative stress is gaining increasing attention. Since oxidative stress seems to be involved in the earliest phases of AD, and MCI may be considered as a prodromal phase of dementia, it is an attractive issue to focus therapeutic interventions on the early phase of the disease.


Studies of mechanosensation using the fly.
Mechanosensation requires the transduction of mechanical stimuli into neuronal impulses. It encompasses not only the sense of touch but also proprioception and hearing. In contrast to sight, smell and taste, relatively little is known about the molecular machinery of mechanosensation. It is already clear, however, that important aspects are conserved across phyla, from Caenorhabditis elegans to humans. Drosophila melanogaster is well placed to make a significant contribution to this field. Its advantages include a sequenced genome allied with powerful genetic techniques, and the ability to conduct electrophysiological recording from mechanoreceptor neurons. For human geneticists, it is expected that Drosophila studies will provide a source of candidate genes whose human homologues can be examined for roles in mechanosensory development, function and disease.


Spatio-temporal variation of fish taxonomic composition in a South-East Asian flood-pulse system.
The Tonle Sap Lake (TSL) is a flood-pulse system. It is the largest natural lake in South-East Asia and constitutes one of the largest fisheries over the world, supporting the livelihood of million peoples. Nonetheless, the Mekong River Basin is changing rapidly due to accelerating water infrastructure development (hydropower, irrigation, flood control, and water supply) and climate change, bringing considerable modifications to the annual flood-pulse of the TSL. Such modifications are expected to have strong impacts on fish biodiversity and abundance. This paper aims to characterize the spatio-temporal variations of fish taxonomic composition and to highlights the underlying determinants of these variations. For this purpose, we used data collected from a community catch monitoring program conducted at six sites during 141 weeks, covering two full hydrological cycles. For each week, we estimated beta diversity as the total variance of the site-by-species community matrix and partitioned it into Local Contribution to Beta Diversity (LCBD) and Species Contribution to Beta Diversity (SCBD). We then performed multiple linear regressions to determine whether species richness, species abundances and water level explained the temporal variation in the contribution of site and species to beta diversity. Our results indicate strong temporal variation of beta diversity due to differential contributions of sites and species to the spatial variation of fish taxonomic composition. We further found that the direction, the shape and the relative effect of species richness, abundances and water level on temporal variation in LCBD and SCBD values greatly varied among sites, thus suggesting spatial variation in the processes leading to temporal variation in community composition. Overall, our results suggest that fish taxonomic composition is not homogeneously distributed over space and time and is likely to be impacted in the future if the flood-pulse dynamic of the system is altered by human activities.


[Fuchs heterochromic cyclitis: current concepts].
The clinical features of Fuchs' heterochromic cyclitis (F.H.C.) were described thoroughly by him in 1906. Supplementary data was then supplied by Amsler and Verrey with respect to the vascular characteristics of this disease. Fuchs' disease is not a frequent affection and accounts for no more than 1-2% of the total cases of uveitis. The diagnosis is very difficult to establish at an early stage of the disease. Incomplete or atypical forms are frequent and differential diagnosis is difficult from other cases of cyclitis and/or intermediate uveitis. Furthermore, heterochromia is recognized with difficulty in brown-eyed people. The time of onset of the 3 main symptoms (cataract, heterochromia and cyclitis) varies considerably and the possibility that each of the symptoms follows an individual course at least for a certain period, cannot be excluded. Paraclinical and biological methods for investigating the disease are still limited. However immunological techniques have established the frequent incidence of immune complexes in the aqueous, while some anomalies in the vascular system have been detected on fluoroangiography of the iris. A congenital predisposition to this disease may explain the fact that F.H.C. is generally unilateral. Additionally it might explain Amsler's findings. The way to establish a link both in time and space between all these findings (so as to build up a unique theory which could explain different symptoms) is still unknown, but the so-called sympathetic theory and its theoretical consequences could be rejected permanently in the future.


Lectins as probes to Pneumocystis carinii surface glycocomplexes.
The binding characteristics of a panel of commercially available FITC-conjugated lectins to Pneumocystis carinii (Pc) were assessed by fluorescence microscopy and flow cytometry. Rat Pc obtained from infected lung homogenates were incubated with FITC-conjugated lectins in a series of concentrations, counterstained with propidium iodide, and analyzed for percent fluorescence and fluorescence intensity. All organisms bound concanavalin A and Wisteria floribunda agglutinin, 2 representatives of the glucose/mannose-binding group. From the lectin group specific for N-acetylglucosamine, Pc reacted more strongly with wheat germ agglutinin than with Solanum tuberosum agglutinin or Griffonia simplicifolia II lectin. Pneumocystis treated with lectins specific for N-acetyl-D-galactosamine and galactose exhibited much variation; the cells reacted moderately well to soybean agglutinin and less to Bauhinia purpurea, Maclura pomifera and Dolichos biflorus agglutinins and Griffonia simplicifolia I lectin. Arachis hypogaea agglutinin, Viscum album agglutinin and Griffonia simplicifolia I-beta 4 lectin had not effect. The organisms reacted weakly with Ulex europeus I agglutinin which is specific for fucose and did not react with Limax flavus lectin, which is specific for sialic acid. Competitive inhibition studies using relevant carbohydrates were performed to indicate that the positive reactions were specific. These studies should help to elucidate the mechanisms of attachment and pathogenesis of this organism.


Modifying surface structure to tune surface properties of vertically aligned carbon nanotube films.
We report a simple etching process to modify surface of vertically aligned carbon nanotube (VACNT) arrays for their applications in superhydrophobic surface, field emission display, and sun energy conversion, etc. At a high temperature (700-800 degrees C), very low concentration water vapor in presence with Ar and hydrogen flow can be a weak oxidant, and mildly etch nanotube tips without damaging their walls. This process can be performed right after the CNT growth process. Surface of nanotube arrays becomes multi-tiered nanotube patterns with open-ended nanotubes standing straightly. Surface morphology of nanotube arrays can be tuned by changing the etching time. Water droplets on a modified nanotube surface show a large contact angle and sliding angle, which make the etched nanotube film suitable for application such as small amount liquid transport. Light absorption measurement indicated that surface roughness has no effect to improve the light absorption, indicating a different mechanism from other black material. The surface modified nanotube arrays have much increased field enhancement factor in our field emission test, showing the better field emission ability of the nanotube arrays with open tips.


Auditory changes following firearm noise exposure, a review.
Firearms produce peak sound pressure levels (peak SPL) between ∼130 and 175 dB peak SPL, creating significant risk of noise-induced hearing loss (NIHL) in those exposed to firearm noise during occupational, recreational, and/or military operations. Noise-induced tinnitus and hearing loss are common in military service members, public safety officers, and hunters/shooters. Given the significant risk of NIHL due to firearm and other noise sources, there is an interest in, and demand for, interventions to prevent and/or treat NIHL in high-risk populations. However, research and clinical trial designs assessing NIHL prevention have varied due to inconsistent data from the literature, specifically with end point definitions, study protocols, and assessment methodologies. This article presents a scoping review of the literature pertaining to auditory changes following firearm noise exposure. Meta-analysis was not possible due to heterogeneity of the study designs. Recommendations regarding audiologic test approach and monitoring of populations at risk for NIHL are presented based on critical review of the existing literature.


Compassion focused therapy in a university counseling and psychological services center: A feasibility trial of a new standardized group manual.
Objectives: The feasibility and acceptability of a new Compassion Focused Therapy (CFT) group protocol were assessed in a university counseling and psychological services (CAPS) center. Outcome measures included mechanisms of change, compassion, and general psychiatric distress. Method: Eight transdiagnostic CFT groups composed of 75 clients met for 12 weekly sessions. Clients completed measures of fears of compassion, flows of compassion, self-reassurance, self-criticism, shame, and psychiatric distress at pre, mid, and post time points. Self-report feasibility and acceptability data were collected from therapists and clients, respectively. Significant and reliable change was assessed along with exploratory analysis of CFT mechanisms of change using correlational analysis. Results: Significant and reliable change was found for fears of self-compassion, fears of compassion from others, fears of compassion to others, self-compassion, compassion from others, self-reassurance, self-criticism, shame, and psychological distress. Improvements in fears and flows of compassion predicted improvements in self-reassurance, self-criticism, shame, and psychiatric distress. Conclusion: The new CFT group protocol appears to be feasible, acceptable, and effective in a transdiagnostic CAPS population. The identified mechanisms of change support the theory of CFT that transdiagnostic pathological constructs of self-criticism and shame can improve by decreasing fears and increasing flows of compassion.


Coordinate control of 3T3 cell proliferation by platelet-derived growth factor and plasma components.
DNA synthesis and cell division were measured in Swiss mouse 3T3 cells cultured in different concentrations of cell-free plasma-derived serum and increasing amounts of a platelet-derived growth factor. In plasma-derived serum alone, the cells were quiescent and they were arrested in the Go/G1 phase of the cell cycle. Addition of a platelet-derived growth factor to quiescent cells maintained in plasma-derived serum stimulated both DNA synthesis and cell division. When plasma components were present at high concentration (5%, vol/vol), the amount of platelet factor added to the cultures determined the number of cell doublings. Plasma-derived molecules were required for the platelet factor to stimulate DNA synthesis and cell division in the maximal number of cells. In addition, plasma components had to be present for recently divided cells to respond to the platelet factor. When 3T3 cells were cultured in excess platelet factor and limiting amounts of plasma-derived serum (0.5%, vol/vol), the cells underwent one doubling and then ceased to proliferate. Addition of fresh plasma-derived serum to these cells induced a second round of cell division. Plasma components and the platelet-derived growth factor acted in a coordinate fashion to regulate the proliferation of Swiss 3T3 cells.


A rapid, automated colorimetric assay for measuring antibody binding to cell surface antigens.
An automated, colorimetric procedure is described for detecting antibodies specific for cell surface antigens. The procedure entails (a) coating the wells of 96-well microplates with either protein A or anti-immunoglobulin antibodies and (b) preincubating either the microplate or target cells with the test antibody. Target cells which react with the test antibody bind to the wells of the microplate and bound cells are quantitated by staining with the dye Rose Bengal. A microplate spectrophotometer is used to measure absorbance in each well of the plate, providing a rapid, automated measure of antibody titre. The assay is simple to perform, uses readily available reagents and gives comparable sensitivity to rosetting assays. With these features, and the capacity for handling large numbers of trays quickly, this method has obvious advantages in screening for antibody activity in culture supernatants of hybridoma clones.


Lateral Hypothalamic Stimulation Reduces Hyperalgesia Through Spinally Descending Orexin-A Neurons in Neuropathic Pain.
No evidence to date shows that lateral hypothalamic (LH) stimulation produces orexin-A-mediated antinociception in the spinal cord dorsal horn (SCDH) in a model of neuropathic pain. We conducted experiments to examine the effect of orexin-A-mediated LH stimulation in female rats with chronic constriction injury (CCI) on thermal hyperalgesia. Rats receiving carbachol into the LH demonstrated antinociception on both the left CCI and right nonligated paws (p < .05). Rats were given carbachol in the LH followed by intrathecal injection of the orexin-1 (OX1) receptor antagonist SB-334867, which blocked LH-induced antinociception compared with control groups (p < .05) in the left paw, but not in the right paw. These findings support the hypothesis that LH stimulation produces antinociception in rats with thermal hyperalgesia from neuropathic pain via an orexin-A connection between the LH and the SCDH. Identification of this pathway may lead to studies using orexins to manage clinical pain.


New antimicrobial peptides against foodborne pathogens: From in silico design to experimental evidence.
Recently there has been growing interest in the discovery of new antimicrobial agents to increase safety and shelf-life of food products. Here, we developed an innovative approach by introducing the concept that mitochondrial targeting peptides (MTP) can interact and disrupt bacterial membranes, acting as antimicrobial agents. As proof-of-principle, we used a multidisciplinary strategy by combining in silico predictions, docking simulations and antimicrobial assays, to identify two peptides, MTP1 and MTP2, which were structurally and functionally characterized. Both compounds appeared effective against Listeria monocytogenes, one of the most important foodborne pathogens. Specifically, a significant bactericidal activity was evidenced with EC50 values of 16.8±1.2μM for MTP1 and 109±7.0μM for MTP2. Finally, NMR structure determinations suggested that MTP1 would be oriented into the membrane bilayer, while the molecular shape of MTP2 could indicate porin-mediated antimicrobial mechanisms, as predicted using molecular docking analysis. Therefore, MTPs represent alternative sources to design new potential bio-preservatives.


One-Pot Parallel Synthesis of Lipid Library via Thiolactone Ring Opening and Screening for Gene Delivery.
Efficient delivery of nucleic acids into cells is of great interest in the field of cell biology and gene therapy. Despite a lot of research, transfection efficiency and structural diversity of gene-delivery vectors are still limited. A better understanding of the structure-function relationship of gene delivery vectors is also essential for the design of novel and intelligent delivery vectors, efficient in "difficult-to-transfect" cells and in vivo clinical applications. Most of the existing strategies for the synthesis of gene-delivery vectors require multiple steps and lengthy procedures. Here, we demonstrate a facile, three-component one-pot synthesis of a combinatorial library of 288 structurally diverse lipid-like molecules termed "lipidoids" via a thiolactone ring opening reaction. This strategy introduces the possibility to synthesize lipidoids with hydrophobic tails containing both unsaturated bonds and reducible disulfide groups. The whole synthesis and purification are convenient, extremely fast, and can be accomplished within a few hours. Screening of the produced lipidoids using HEK293T cells without addition of helper lipids resulted in identification of highly stable liposomes demonstrating ∼95% transfection efficiency with low toxicity.


Correlation between H-ras p21TLeu61 protein content and tumorigenicity of NIH3T3 cells.
We have prepared a number of NIH3T3 clonal cell lines that contain an H-ras transforming gene with an A----T transversion at the 61st codon. The clonal lines contain 1 to 3 cell equivalents of the transforming oncogene and some lines look more morphologically transformed than others. Using Y13-238, a rat monoclonal antibody that recognizes H-ras p21 but not Ki- or N-ras in rodent cells, we found that the degree of morphological change is correlated with the relative amount of transforming protein in the selected clonal lines. Nude mice were injected with cells from lines containing different amounts of the transforming protein, ranging from approximately 1 to 10 times the level of normal H-ras protein present in NIH3T3 cells. Tumors arose in all mice that received cells containing the transforming protein. Their time of appearance (tumor latency) was correlated with the number of cells injected and the amount of transforming protein present in each clonal line; however, the subsequent rate of growth and ultimate size of the tumors were similar. Thus, it appears that the transforming protein has a significant effect on some early step in tumor development. Our results also show that relatively low amounts of transforming ras protein are sufficient to cause tumorigenicity in NIH3T3 cells and that higher amounts of the transforming protein cause proportionately faster responses.


[Loeffler's endocarditis and disseminated viral infection].
We report a case of Löffler's endocarditis in a 60-year-old woman with multiple lymphadenopathies, blood eosinophilia and acute heart failure. The eosinophilia developed over a six-month period to a maximum of 54.5% eosinophiles for 7600 X 10(9) leukocytes/l. Five weeks before death lymph node biopsy revealed Hodgkin's disease with mixed cellularity. Autopsy disclosed parietal endocarditis with endomyocardial fibrosis and mural thrombi, principally in the inflow tract of the left ventricle, lesions typical of the fibroplastic parietal endocarditis described by Löffler. Examination of the lymph nodes at autopsy showed a disseminated viral infection probably due to a virus of the herpes group, as was confirmed by electron microscopy. Since these findings disagree with the interpretation of the lymph node biopsy we think the diagnosis of Hodgkin's disease should be withdrawn. Löffler's endocarditis is discussed with reference to pathological features, differential diagnosis and lymph node changes in the patient.


Reproducibility of risk figures in 2nd-trimester maternal serum screening for down syndrome: comparison of 2 laboratories.
Analytical error affects 2nd-trimester maternal serum screening for Down syndrome risk estimation. We analyzed the between-laboratory reproducibility of risk estimates from 2 laboratories. Laboratory 1 used Bayer ACS180 immunoassays for alpha-fetoprotein (AFP) and human chorionic gonadotropin (hCG), Diagnostic Systems Laboratories (DSL) RIA for unconjugated estriol (uE3), and DSL enzyme immunoassay for inhibin-A (INH-A). Laboratory 2 used Beckman immunoassays for AFP, hCG, and uE3, and DSL enzyme immunoassay for INH-A. Analyte medians were separately established for each laboratory. We used the same computational algorithm for all risk calculations, and we used Monte Carlo methods for computer modeling. For 462 samples tested, risk figures from the 2 laboratories differed >2-fold for 44.7%, >5-fold for 7.1%, and >10-fold for 1.7%. Between-laboratory differences in analytes were greatest for uE3 and INH-A. The screen-positive rates were 9.3% for laboratory 1 and 11.5% for laboratory 2, with a significant difference in the patients identified as screen-positive vs screen-negative (McNemar test, P<0.001). Computer modeling confirmed the large between-laboratory risk differences. Differences in performance of assays and laboratory procedures can have a large effect on patient-specific risks. Screening laboratories should minimize test imprecision and ensure that each assay performs in a manner similar to that assumed in the risk computational algorithm.


Screening of the Antimicrobial Activity against Drug Resistant Bacteria of Photorhabdus and Xenorhabdus Associated with Entomopathogenic Nematodes from Mae Wong National Park, Thailand.
Photorhabdus and Xenorhabdus are symbiotic with entomopathogenic nematodes (EPNs) of the genera Heterorhabditis and Steinernema, respectively. These bacteria produce several secondary metabolites including antimicrobial compounds. The objectives of this study were to isolate and identify EPNs and their symbiotic bacteria from Mae Wong National Park, Thailand and to evaluate the antibacterial activities of symbiont extracts against drug resistant bacteria. A total of 550 soil samples from 110 sites were collected between August 2014 and July 2015. A total of EPN isolates were obtained through baiting and White trap methods, which yielded 21 Heterorhabditis and 3 Steinernema isolates. Based on molecular identification and phylogenetic analysis, the most common species found in the present study was P. luminescens subsp. akhurstii associated with H. indica. Notably, two species of EPNs, H. zealandica and S. kushidai, and two species of symbiotic bacteria, X. japonica and P. temperata subsp. temperata represented new recorded organisms in Thailand. Furthermore, the association between P. temperata subsp. temperata and H. zealandica has not previously been reported worldwide. Disk diffusion, minimal inhibitory concentration, and minimal bactericidal concentration analyses demonstrated that the crude compound extracted by ethyl acetate from P. temperata subsp. temperata could inhibit the growth of up to 10 strains of drug resistant bacteria. Based on HPLC-MS analysis, compound classes in bacterial extracts were identified as GameXPeptide, xenoamicin, xenocoumacin, mevalagmapeptide phurealipids derivatives, and isopropylstilbene. Together, the results of this study provide evidence for the diversity of EPNs and their symbiotic bacteria in Mae Wong National Park, Thailand and demonstrate their novel associations. These findings also provide an important foundation for further research regarding the antimicrobial activity of Photorhabdus bacteria.


Mucocutaneous leishmaniasis masquerading as Wegener granulomatosis.
A 43-year-old Brazilian female presented in 2001 with nasal stuffiness and sinusitis. A biopsy was consistent with limited Wegener's granulomatosis although antineutrophil cytoplasmic antibodies were negative. Her nasal inflammation progressed despite trials of prednisone, methotrexate, and azathioprine. A septal perforation developed and a repeat biopsy showed granulomatous inflammation. In 2006 the patient was referred to Division of Rheumatology, University of California, Los Angeles. The nose was grossly erythematous and a magnetic resonance imaging revealed nasal destruction and sinusitis. Palatine biopsies showed chronic inflammation. Cyclophosphamide at 150 mg/d resulted in markedly improved mucocutaneous lesions. The patient developed a leg and arm rash in 2007. A skin biopsy was positive for Leishmania braziliensis. The cyclophosphamide was discontinued and amphotericin B was initiated with transient benefit. Remission was achieved with pentavalent antimony. Despite multiple nasopharyngeal biopsies, for a 6-year span, mucocutaneous leishmaniasis masqueraded as Wegener's granulomatosis. Cyclophosphamide not only resulted in clinical improvement, due to reduced inflammatory response, but also allowed widespread cutaneous dissemination.


Neuropeptide Y (NPY): a vasoconstrictor in the eye, brain and other tissues in the rabbit.
The effect of neuropeptide Y (NPY) on uveal vascular resistance was studied in rabbits by direct determination of uveal blood flow from a cannulated vortex vein. Regional blood flows, in the eye, the brain and several other tissues, were measured, with radioactive microspheres, during neuropeptide Y-infusion in rabbits with and without alpha-adrenoceptor blockade. Intravenous infusion of increasing doses of neuropeptide Y caused a dose-dependent increase in the total uveal vascular resistance. Maximal effect, a 70% increase, was achieved with 120 pmol kg-1 min-1. In the microsphere experiments, this dose rate was given i.v. over 10 minutes and blood flow determinations were made before and at 2 and 10 minutes after the start of the infusion. After 2 minutes of neuropeptide Y, there were marked blood flow reductions in the spleen, kidneys, adrenal glands, gastro-intestinal tract, choroid plexus and pineal and pituitary gland. The effect in the eye was small at 2 minutes, but at 10 minutes local blood flows in the choroid and the ciliary body were decreased by 50% and the iridal blood flow by 30%. Retinal blood flow was not affected by neuropeptide Y. At 10 minutes there were also significant blood flow reductions in the brain, tongue, masseter muscle and several glandular tissues. The effects of neuropeptide Y on local blood flow in rabbits that had been subjected to alpha-adrenoceptor blockade were very similar to the effects in the animals without alpha-adrenoceptor blockade. The results show that, in the rabbit, neuropeptide Y has marked effects on local blood flows in several tissues, including the eye, and suggest that neuropeptide Y may significantly contribute to the uveal vasoconstriction during sympathetic nerve stimulation.


Characterization of SCML1, a new gene in Xp22, with homology to developmental polycomb genes.
Using exon trapping, we have identified a new human gene in Xp22 encoding a 3-kb mRNA. Expression of this RNA is detectable in a range of tissues but is most pronounced in skeletal muscle and heart. The gene, designated "sex comb on midleg-like-1" (SCML1), maps 14 kb centromeric of marker DXS418, between DXS418 and DXS7994, and is transcribed from telomere to centromere. SCML1 spans 18 kb of genomic DNA, consists of six exons, and has a 624-bp open reading frame. The predicted 27-kDa SCML1 protein contains two domains that each have a high homology to two Drosophila transcriptional repressors of the polycomb group (PcG) genes and their homologues in mouse and human. PcG genes are known to be involved in the regulation of homeotic genes, and the mammalian homologues of the PcG genes repress the expression of Hox genes. SCML1 appears to be a new human member of this gene group and may play an important role in the control of embryonal development.


Radionuclide angiography.
RNA has clinical applications in virtually all forms of acquired heart disease and is also useful in the detection and quantitation of congenital left-to-right shunts. The method has achieved widespread acceptance for the qualitative and quantitative assessment of systolic ventricular function. It is also particularly well suited for identifying abnormal diastolic filling patterns typical of hypertrophic and ischemic heart diseases. To date, no single variable from any noninvasive or invasive procedure has been shown to have greater prognostic importance than the radionuclide exercise ejection fraction in patients with CAD.


Prognostic Factors and Multidisciplinary Postoperative Chemoradiotherapy for Clinical T4a Tongue Cancer.
The prognosis of patients with locally advanced squamous cell carcinoma (SCC) of the tongue is poor. Postoperative chemoradiotherapy (CRT) improves locoregional control and survival in high-risk patients. We investigated the prognostic factors for clinical T4a tongue SCC, and elucidated whether postoperative CRT has a benefit for patients with poor prognosis in terms of survival. We performed a retrospective analysis of 61 patients with stage T4a SCC of the tongue who underwent primary resection and neck dissection. The median follow-up was 53.8 months. Multivariate analysis revealed a 4.26× relative risk of death for patients with the involvement of ≥5 regional lymph nodes (pN ≥5) compared with those with pN 0-4 (p = 0.002). In Kaplan-Meier analysis, patients with pN ≥5 who received CRT had longer overall survival rates than those who did not (hazard ratio = 0.31; p = 0.041). pN ≥5 is the most powerful prognostic factor for clinical T4a SCC of the tongue. Postoperative CRT is recommended in patients with pN ≥5.


Challenges of non-clinical safety testing for biologics: A Report of the 9th BioSafe European Annual General Membership Meeting.
New challenges and other topics in non-clinical safety testing of biotherapeutics were presented and discussed at the nineth European BioSafe Annual General Membership meeting in November 2019. The session topics were selected by European BioSafe organization committee members based on recent company achievements, agency interactions and new data obtained in the non-clinical safety testing of biotherapeutics, for which data sharing would be of interest and considered as valuable information. The presented session topics ranged from strategies of in vitro testing, immunogenicity prediction, bioimaging, and developmental and reproductive toxicology (DART) assessments to first-in-human (FIH) dose prediction and bioanalytical challenges, reflecting the entire space of different areas of expertise and different molecular modalities. During the 9th meeting of the European BioSafe members, the following topics were presented and discussed in 6 main sessions (with 3 or 4 presentations per session) and in three small group breakout sessions: 1) DART assessment with biotherapeutics: what did we learn and where to go?; 2) Non-animal testing strategies; 3) Seeing is believing: new frontiers in imaging; 4) Predicting immunogenicity during early drug development: hope or despair?; 5) Challenges in FIH dose projections; and 6) Non-canonical biologics formats: challenges in bioanalytics, PKPD and biotransformation for complex biologics formats. Small group breakout sessions were organized for team discussion about 3 specific topics: 1) Testing of cellular immune function in vitro and in vivo; 2) MABEL approach (toxicology and pharmacokinetic perspective); and 3) mRNA treatments. This workshop report presents the sessions and discussions at the meeting.


Non-convulsive status epilepticus in the elderly.
Altered mental state is a very common presentation in the elderly admitted to the emergency department. It has been determined that about 16% of patients aged 60 or older with confusion of unknown origin have non-convulsive status epilepticus. The diagnosis of non-convulsive status epilepticus is difficult in the elderly because possible aetiologies of confusion may present with the same clinical picture. Non-convulsive status epilepticus in the elderly carries major morbidity and mortality, attributable primarily to aetiology, and treatment is complex, involving treatment of the aetiology and concomitant medical illnesses, whilst balancing the side effects and drug interactions of antiepileptic drugs.


miR-21 promotes cell migration and invasion of hepatocellular carcinoma by targeting KLF5.
Previous studies have reported that microRNAs regulate gene expression and transcription. miR-21 have been identified to play a role in many types of cancer. KLF5 functions as a tumor inhibitor in certain cancers. However, the role of KLF5 plays in hepatocellular carcinoma (HCC), especially concerning the relationship between miR-21 and the KLF5 gene remains to be determined. Reverse transcription-quantitative PCR (RT-qPCR), western blot analysis, as well as luciferase reporter and Transwell assays were used to determine the expression of miR-21 and KLF5 in Huh 7, SK-HEP-1, LO-2, and HCC tissues. In HCC cells and tissues, the upregulation of miR-21 was identified. HCC cell migratory and invasive abilities significantly increased because of miR-21 overexpression. KLF5 expression was inhibited by miR-21 by targeting its 3'-UTR. KLF5 overexpression alleviated the effect induced by miR-21 on the migratory and invasive ability of the Huh 7 cells. The results therefore show that, HCC cell migration and invasion is significantly suppressed by miR-21 via targeting KLF5. The newly identified miR-21/KLF5 axis provides a useful therapeutic biomarker for HCC treatment.


Case Report: Onset of Type 1 Diabetes Mellitus in a Patient With Ulcerative Colitis and Sjogren's Syndrome Under Euthyroid Hashimoto's Thyroiditis.
Type 1 diabetes mellitus (T1DM) is often complicated with some other autoimmune disorders. The complication of various autoimmune disorders is known as autoimmune polyglandular syndrome (APS). Once autoimmune thyroid disease develops, various autoimmune diseases can also occur. Such phenomena are classified as APS types 3A to 3D. In this report, we show the onset of T1DM in a patient with ulcerative colitis (UC) and Sjogren's syndrome. The most important and interesting point in this case is that, if we did not check her thyroid-associated antibodies, we could not have diagnosed her as APS. From the data of this case, we assumed that the patient suffered from APS type 3A, 3B, and 3D variants. This case pointed out very clearly the importance of testing for thyroid-associated antibodies under various autoimmune disease conditions even if the thyroid hormone levels are euthyroid. Moreover, based on the strong linkage between inflammatory bowel disease and T1DM and the compatibility with both T1DM and APS type 3, we think it is possible that Hashimoto's disease is present under complicated conditions together with UC and T1DM. It would be important to repeatedly check for thyroid-associated antibodies even in euthyroid patients, especially under various autoimmune disease conditions.


Doxycycline concentrations in lung tissue, bronchial wall, and bronchial secretions.
Doxycycline levels were measured in 44 patients undergoing lung surgery; 44 determinations were made on serum, 37 on resected lung tissue, 11 on bronchial wall, and 8 on bronchial secretions. The concentrations in lung tissue were, with few exceptions, higher than the serum concentrations, while those in homogenized bronchial wall specimens were slightly lower than the serum readings. All these concentrations were on average considerably higher than the minimum inhibitory concentrations for the pneumococcus and Haemophilus influenzae. The comparatively low bronchial secretion concentrations were accounted for by the surgical circumstances. All patients had been intensively trated pre-operatively, and showed no florid mucosal inflammation at the time of the operation: as inflammation subsides, so the antibiotic concentration in the bronchial secretion declines rapidly. The lung and bronchial wall tissue levels indicate that doxycycline has great promise in the treatment of pulmonary and bronchial disorders.


Gaze-Evoked Deformations in Optic Nerve Head Drusen: Repetitive Shearing as a Potential Factor in the Visual and Vascular Complications.
To determine if ocular ductions deform intrapapillary and peripapillary tissues in optic nerve head drusen (ONHD) and to compare these deformations with healthy eyes and eyes with other optic neuropathies. Observational case series. Twenty patients with ONHD. Axial rasters of the optic nerve from a spectral-domain OCT device (Cirrus 5000; Carl Zeiss Meditec, Inc, Dublin, CA) were used to analyze the shape of the peripapillary basement membrane (ppBM) layer in 20 confirmed cases of ONHD. We compared registered images obtained from 2 eye positions: 10° to 15° in adduction and 30° to 40° in abduction. Geometric morphometrics was used to analyze the shape of the ppBM layer defined by placing 10 equidistant landmarks extending 2500 μm on both sides of the basement membrane opening. We also adapted an image strain tracking technique to measure regional intrapapillary strains in 6 patients. Using manually placed nodes on the reference image (in adduction), an iterative, block-matching algorithm is used to determine local displacements between the reference and its paired image in abduction. Displacement vectors were used to calculate the mean shear and effective strain (percent change). Peripapillary shape deformations, intrapapillary shear strains, and effective strains. We found a statistically significant difference in the shape of the ppBM layer between abduction and adduction (P < 0.01). The deformation was characterized by a relative posterior displacement temporally in adduction that reversed in abduction. Strain tracking in all 6 patients showed substantial gaze-induced shearing and effective strains. Mean effective strains were 7.5% outside the drusen. Shear and effective strains were significantly larger outside versus within the drusen (P < 0.003 and P < 0.01, respectively). This study demonstrates that horizontal ocular ductions induce significant shearing deformations of the peripapillary retina and prelaminar intrapapillary tissues. We also found that the deformations in healthy persons are similar in magnitude to ONHD. Based on these findings, we speculate that patients with intrapapillary calcifications exposed to the long-term effects of repetitive shearing (induced by ocular ductions) may contribute to the progressive axonal loss and vascular complications associated with ONHD.


Discovery of Small Molecules for Repressing Cap-Independent Translation of Human Vascular Endothelial Growth Factor (hVEGF) as Novel Antitumor Agents.
Angiogenesis is important in tumorigenesis and tumor progression. Human vascular endothelial growth factor (hVEGF) is an angiogenic growth factor that plays a crucial role in tumor progression. The G-rich region within the 5'-untranslated regions (5'-UTR) of hVEGF-A mRNA can form a "switchable" RNA G-quadruplex structure that is essential for a cap-independent translation initiation. We screened our small-molecule library for binders of this G-tract. One novel quinazoline derivative, compound 1, showed a significant specific interaction with the G-tract and destabilized the G-quadruplex structure. The results of cellular experiments revealed that compound 1 down-regulated hVEGF-A translation and significantly impeded tumor cells migration. We also found that compound 1 exhibited tumor-inhibiting activity in MCF-7 xenograft tumors, which might be related to its ability to reduce hVEGF expression. These findings present a new strategy of hVEGF-A translational control in which small molecules interact with G-quadruplex structure in the 5'UTR.


Charge of a macroscopic particle in a plasma sheath.
Charging of a macroscopic body levitating in a rf plasma sheath is studied experimentally and theoretically. The nonlinear charge vs size dependence is obtained. The observed nonlinearity is explained on the basis of an approach taking into account different plasma conditions for the levitation positions of different particles. The importance of suprathermal electrons' contribution to the charging process is demonstrated.


Artificial insemination and in-vitro fertilization using donor spermatozoa: a report on 15 years of experience.
Donor insemination (DI) using cryopreserved semen commenced at The Royal Women's Hospital in 1976. Over the next 15 years we performed 5953 treatment cycles to achieve 816 pregnancies (13.7% per cycle) and 706 live births. In-vitro fertilization (IVF) using donor spermatozoa commenced in 1986. Over the next 5 years we performed 303 treatment cycles for 185 couples. Including subsequent transfer of cryopreserved embryos, a total of 33% of couples achieved a successful pregnancy by IVF. Statistical analysis indicated that, for DI pregnancies, the most important semen variable was the percentage post-thaw motility, whilst for normal fertilization in IVF it was the pre-freeze motility. These results may be explained by the compensatory effects of post-thaw processing of spermatozoa for IVF, but not for DI in our clinic.


Retinal Injury Activates Complement Expression in Müller Cells Leading to Neuroinflammation and Photoreceptor Cell Death.
Retinal detachment (RD) is a neurodegenerative blinding disease caused by plethora of clinical conditions. RD is characterized by the physical separation of retina from the underlying retinal pigment epithelium (RPE), eventually leading to photoreceptor cell death, inflammation, and vision loss. Albeit the activation of complement plays a critical role in the pathogenesis of RD, the retinal cellular source for complement production remains elusive. Here, using C3 tdTomato reporter mice we show that retinal injury upregulates C3 expression, specifically in Müller cells. Activation of the complement cascade results in the generation of proinflammatory cleaved products, C3a and C5a, that bind C3aR and C5aR1, respectively. Our flow cytometry data show that retinal injury significantly upregulated C3aR and C5aR1 in microglia and resulted in the infiltration of peripheral immune cells. Loss of C3, C5, C3aR or C5aR1 reduced photoreceptor cell death and infiltration of microglia and peripheral immune cells into the sub-retinal space. These results indicate that C3/C3aR and C5/C5aR1 play a crucial role in eliciting photoreceptor degeneration and inflammatory responses in RD.


Perioperative fluid prescription, complications and outcomes in major elective open gastrointestinal surgery.
Perioperative fluid therapy and associated outcomes of patients undergoing major elective open gastrointestinal surgery are poorly understood. This study measured perioperative fluid therapy, complication rates and outcomes for major elective open gastrointestinal surgery in a tertiary care hospital. We obtained demographic data, operative details, fluid prescription, complications and outcomes in 100 patients. Patients were elderly and had multiple comorbidities. Median delivered intraoperative fluid volume was 4.2 litres, followed by 6.3 litres over the subsequent 24 hours. Perioperative fluid prescription was associated with a positive fluid balance. Complications occurred in 57% of patients with 32% experiencing at least one major complication. Serious complications were substantially more frequent in patients having non-colorectal operations. The most common adverse events were pulmonary oedema (21%), ileus (18%), serious sepsis (17%), pneumonia (17%), arrhythmias (14%), delirium (14%) and wound healing problems (infections 13%, anastomotic leaks 12%). Mortality at 30 days was 2%. This study provides planning data for future interventional studies.


Structure prediction of partial-length protein sequences.
Protein structure information is essential to understand protein function. Computational methods to accurately predict protein structure from the sequence have primarily been evaluated on protein sequences representing full-length native proteins. Here, we demonstrate that top-performing structure prediction methods can accurately predict the partial structures of proteins encoded by sequences that contain approximately 50% or more of the full-length protein sequence. We hypothesize that structure prediction may be useful for predicting functions of proteins whose corresponding genes are mapped expressed sequence tags (ESTs) that encode partial-length amino acid sequences. Additionally, we identify a confidence score representing the quality of a predicted structure as a useful means of predicting the likelihood that an arbitrary polypeptide sequence represents a portion of a foldable protein sequence ("foldability"). This work has ramifications for the prediction of protein structure with limited or noisy sequence information, as well as genome annotation.


Polypharmacology of Small-Molecule Modulators of the 5-Lipoxygenase Activating Protein (FLAP) Observed via a High-throughput Lipidomics Platform.
Leukotrienes (LTs) and related species are proinflammatory lipid mediators derived from arachidonic acid (AA) that have pathological roles in autoimmune and inflammatory conditions, cardiovascular diseases, and cancer. 5-Lipoxygenase activating protein (FLAP) plays a critical accessory role in the conversion of AA to LTA4, and its subsequent conversion to LTC4 by LTC4 synthase. Pharmacological inhibition of FLAP results in a loss of LT production by preventing the biosynthesis of both LTB4 and LTC4, making it an attractive target for the treatment of inflammatory diseases in which LTs likely play a role. Small-molecule (SM) drugs often exhibit polypharmacology through various pathways, which may explain the differential therapeutic efficacies of compounds sharing structural similarity. We have profiled a series of SM FLAP modulators for their selectivity across enzymes of AA cascade in human whole blood (HWB), using a recently developed LC/MS (liquid chromatography-mass spectrometry)-based high-throughput lipidomics platform that monitors 122 eicosanoids in multiplex. Highly efficient data acquisition coupled with fast and accurate data analysis allowed facile compound profiling from ex vivo study samples. This platform allowed us to quantitatively map the effects of those SMs on the entire AA cascade, demonstrating its potential to discriminate structurally related compounds.


A procedure to determine the individually comfortable position of visual displays relative to the eyes.
In an intervention phase, 38 operators used four different imposed screen positions (near versus distant, high versus low) for a full working day to experience the advantages and disadvantages. Screens at about 66 cm induced more reported strain than screens at about 98 cm. When operators later freely selected their individually most comfortable screen position, individually different changes due to the intervention were observed: some subjects changed to shorter, others to longer viewing distances, some operators adjusted the screen lower, others higher. These effects were confirmed in repeated tests. Thus, trying out different screen positions appears useful for arranging the VDU workstation to the individually most comfortable screen location relative to the eyes.


Rational Redesign of Inhibitors of Furin/kexin Processing Proteases.
Furin/kexin processing proteases catalyze the proteolysis of large protein precursors involved in many biological processes, such as zymogen activation, peptide hormone synthesis, viral protein processing and receptor maturation, making them potential targets for therapeutic agents. Herein, homology modeling and weighted evolutionary tracing were combined to investigate the interactionmechanism of furin/kex2 with eglin C mutants. The model structures showed that there were many acidic residues in the furin (kex2) binding interface, contributing to specificity for multiple basic residues of their corresponding substrates or inhibitors. Besides, some rational explanations were presented for the different inhibitor/substrate specificity of the furin/kexin members by combining the model structures with results of evolutionary tracing. Based on these analyses,an attempt was made to rationally redesign the eglin C by interface engineering with heterogeneous self-consistent ensemble optimization to improve its inhibitory specificity on furin/kex2. With the model complex structures of furin/kex2 and eglin C variants as structural templates, the P(1), P(2) and P(4) of eglin C were redesigned, respectively. The design results show that both furin and kex2 favored basic residues at P(1), P(2) and P(4) in eglin C, in good agreement with the experimental data. The detection of many specific residues in S' part of furin/kexin sequences made possible designing inhibitors with high specific binding to furin and kex2, respectively. As for furin, the best inhibitor designed was eglin C-P(2)'Glu-P(3)'Asp-P(4)'Arg (only these three positions were shown), while the best eglin C variant for kex2 designed was P(2)'Arg-P(3)'Arg-P(4)'Glu. The structures show that furin and kex2 form distinct interactions with these two eglin C variants. Herein, a strategy was proposed that combine homology modeling, evolutionary tracing and rational interface redesign to investigate enzyme-inhibitor interactions and inhibitor engineering. This computational design gives some rational guidance to further experimental inhibitor engineering.


Memory and PTPIP51--a new protein in hippocampus and cerebellum.
Previously the expression of Protein Tyrosine Phosphatase Interacting Protein 51 (PTPIP51) in mouse brain was reported. Here, we investigated PTPIP51 mRNA and protein in two of the brain regions namely the hippocampus and the cerebellum of mouse brains. On a cellular level both the protein and the mRNA were related to the pyramidal cells of the hippocampal formation, the granular cells of the dentate gyrus and the cells of the adjacent strata. In the cerebellum PTPIP51 was traced in Purkinje cells, the cells of the molecular layer and the granular layer. On a subcellular level only partial co-localization was seen for the endoplasmic reticulum, but not with mitochondria. In addition the interactome of PTPIP51 was analysed. In hippocampal cells a strong interaction with PTP1B and vesicle-associated membrane protein-associated protein B (VAPB) was detected. A somewhat differing interaction profile was found in the cerebellum, where high interaction levels were found for 14-3-3, diacylglycerol kinase α (DGKα), NFκB and PTP1B. These interaction partners represent specific signalling pathways linked to building memory. PTPIP51 can be associated with nerve growth factor signalling, dendritic and axonal growth, synaptogenesis, and all processes needed for memory formation. Moreover, in HT-22 mouse hippocampal cells PTPIP51 expression was induced by administrating the fibroblast growth factor 1 (FGF-1), which is known to take part in learning/memory processes. Knocking down p38-MAPK also led to an up-regulation of PTPIP51 probably resembling a compensative mechanism. Thus, a possible connection to the processing of memories can be anticipated. Differences in the interaction profile in both regions may be attributed to the actual/local differences in memory formation.


[Treatment of hydronephrosis caused by obstruction of the pyeloureteral junction diagnosed before birth].
From 1981 to 1987, the authors observed 69 patients with ureteropelvic junction obstruction diagnosed by antenatal ultrasound, representing a total of 77 pathological renal units. Seventy renal units were treated by ureteropelvic resection, one renal unit returned to normal without treatment. There were 3 primary nephrectomies and 3 secondary nephrectomies for non-improvement after percutaneous nephrostomy. An early antenatal surgical management of ureteropelvic obstruction after antenatal ultrasound diagnosis does not seem to give better results than when diagnosis is made at a later stage. The interest of the antenatal diagnosis is not as important as for other uropathies such as urecterocele, mega-ureter or posterior urethral valves.


[The clinical characteristics of involuntary movements in childhood].
The basal ganglia play important roles in the pathophysiology of various types of involuntary movement disorders, such as chorea, ballism, athetosis, dystonia, tremor and tics. These involuntary movements when occur in the childhood show the specific ages of onset and the courses. For example postural dystonia occurs in childhood but action dystonia tend to occur in later ages. Postural tremor occurs after the second decades but resting tremor does not occur in childhood. Furthermore drug induced dystonia but not levodopa induced dyskinesia occurs in childhood. The age dependent clinical features observed in these involuntary movements are thought to be due to the specific developmental processes of the pathway in the basal ganglia and its efferent projections, which are involved in the pathophysiology in the each disorder. For example, the dopamine activity is known to be increased in the striatum before ten years of age which decreases, rapidly during the first decade and further decreases in the next decade with the moderate degree till adult level. The direct pathway, which is predominant in the ventral area in the basal ganglia, matures earlier than the indirect pathway, which is predominant in the dorsal area. In this paper the pathophysiologies of the hereditary progressive dystonia with marked diurnal fluctuation, juvenile parkinsonism, idiopathic torsion dystonia, chorea, ballismus and tics, all of which occur in the childhood, are discussed from the view point of the age dependent specificities of the involved pathways in the basal ganglia and their projections during development.


Acute ST Elevation Myocardial Infarction in Patients With Immune Thrombocytopenia Purpura: A Case Report.
Acute myocardial infarction (AMI) in patients with immune thrombocytopenic purpura (ITP) is rare. We describe a case of AMI in patient with ITP. An 81-year-old woman presented with acute inferoposterior MI with low platelet count on admission (34,000/µl). Coronary angiography revealed significant mid right coronary artery (RCA) stenosis with thrombus, subsequently underwent successful percutaneous coronary intervention (PCI). In some patients with immune thrombocytopenia purpura and acute myocardial infarction, percutaneous coronary intervention is a therapeutic option.


Catecholamines and their blockade in congestive heart failure.
The hemodynamic effects of sympathetic nervous system stimulation and the benefits of catecholamine blockade in patients with congestive heart failure (CHF) are discussed. Prolonged stimulation of the sympathetic nervous system promotes disease progression in patients with CHF. The level of circulating norepinephrine is the factor most closely correlated with prognosis. Long-term catecholamine stimulation of beta-receptors in the myocardium reduces the ability of catecholamines to improve cardiac contractility. CHF patients have higher vascular resistance (afterload) than healthy persons, increasing the strain on the heart. Also, beta 1-adrenergic activity stimulates renin release, which is deleterious in CHF. Clinical trials suggest that long-term (greater than one month), carefully dose-adjusted therapy with beta-blockers improves symptoms, ventricular ejection fraction, exercise time, and quality of life in patients with CHF, but it is unclear whether beta-blockers reduce mortality. Some patients cannot tolerate even the lowest starting dosages of beta-blockers, and withdrawal of these agents may result in clinical and hemodynamic deterioration. Carvedilol, which has beta-blocking, alpha-blocking, and antioxidant properties, is associated with a reduction in hospitalizations and symptoms and improvements in ejection fraction it also appears to reduce mortality, although confirmatory studies are needed. Initiation of carvedilol therapy can cause symptomatic and hemodynamic worsening in the short term, and some patients cannot tolerate it. Adrenergic blocking agents are important components of therapy for CHF. Carvedilol may prove useful in reducing symptoms and improving survival in these patients.


Fluorescent cytochemical detection of sialidase activity using 5-bromo-4-chloroindol-3-yl-alpha- D- N-acetylneuraminic acid as the substrate.
A novel fluorescent cytochemical method for sialidase activity was developed using 5-bromo-4-chloroindol-3-yl-alpha- D- N-acetylneuraminic acid (X-Neu5Ac) as the substrate. Intact nuclei were isolated from porcine liver and incubated at 37 degrees C for 3 h with 1 mM X-Neu5Ac at pH 4.8. The nuclei were stained with blue color that was derived from the oxidized compound of the reaction product X (5-bromo-4-chloro-3-hydroxyindole). A specific sialidase inhibitor, 2,3-dehydro-2-deoxy- N-acetylneuraminic acid, suppressed the staining in a dose-dependent manner. Despite the specificity of the cytochemical reaction, the staining was too weak to analyze the staining distribution and pattern of individual nuclei. To attain more sensitive detection of sialidase activity, the nuclei were incubated with X-Neu5Ac in the presence of Fast Red Violet LB. Individual nuclei of porcine liver were clearly stained with fluorescence that was produced by the conjugated compound of product X with Fast Red Violet LB. This fluorescent cytochemical method was also employed successfully for detection of sialidase activity of intact GOTO neuroblastoma cells in culture. The present method should provide a useful tool for investigating the localization and stage-specific expression of sialidase activity in tissues and cells.


Influence of parity and litter size on gestation length in beagle dogs.
This study was conducted to investigate the effects of parity and litter size on gestation length in beagle bitches. The mean duration of the initial elevation (>2 ng/mL) in progesterone concentrations after the onset of proestrus was shorter (P < 0.05) in bitches without (nulliparous) whelping experience than in bitches with (multiparous) whelping experience (6.9 d versus 8.0 d). When calculated as the interval between the day of initial elevation in progesterone concentrations and the day of whelping, the gestation length in the nulliparous bitches was noted to be similar to that in the multiparous bitches (64.3 d versus 64.2 d). No significant correlation between gestation length and litter size was observed in any of the bitches. Our results indicate that the gestation length in beagle bitches is not affected by parity or litter size.


Corynebacterium Species Rarely Cause Orthopedic Infections.
Corynebacterium spp. are rarely considered pathogens, but data on Corynebacterium spp. as a cause of orthopedic infections are sparse. Therefore, we asked how often Corynebacterium spp. caused an infection in a defined cohort of orthopedic patients with a positive culture. In addition, we aimed to determine the species variety and the susceptibility of isolated strains to define potential treatment strategies. We retrospectively assessed all bone and joint samples that were collected between 2006 and 2015 from an orthopedic ward and that were positive for Corynebacterium spp. by culture. The isolates were considered relevant to an infection if the same Corynebacterium sp. was present in at least two samples. We found 97 orthopedic cases with isolation of Corynebacterium spp. (128 positive samples). These were mainly Corynebacterium tuberculostearicum (n = 26), Corynebacterium amycolatum (n = 17), Corynebacterium striatum (n = 13), and Corynebacterium afermentans (n = 11). Compared to the species found in a cohort of patients with positive blood cultures hospitalized in nonorthopedic wards, we found significantly more C. striatum- and C. tuberculostearicum-positive cases but no C. jeikeium-positive cases in our orthopedic cohort. Only 16 out of 66 cases (24.2%) with an available diagnostic set of at least two samples had an infection. Antibiotic susceptibility testing (AST) showed various susceptibility results for all antibiotics except vancomycin and linezolid, to which 100% of the isolates were susceptible. The rates of susceptibility of corynebacteria isolated from orthopedic samples and of isolates from blood cultures were comparable. In conclusion, our study results confirmed that a Corynebacterium sp. is most often isolated as a contaminant in a cohort of orthopedic patients. AST is necessary to define the optimal treatment in orthopedic infections.


Glycolipid-peptide vaccination induces liver-resident memory CD8+ T cells that protect against rodent malaria.
Liver resident-memory CD8+ T cells (TRM cells) can kill liver-stage Plasmodium-infected cells and prevent malaria, but simple vaccines for generating this important immune population are lacking. Here, we report the development of a fully synthetic self-adjuvanting glycolipid-peptide conjugate vaccine designed to efficiently induce liver TRM cells. Upon cleavage in vivo, the glycolipid-peptide conjugate vaccine releases an MHC I-restricted peptide epitope (to stimulate Plasmodium-specific CD8+ T cells) and an adjuvant component, the NKT cell agonist α-galactosylceramide (α-GalCer). A single dose of this vaccine in mice induced substantial numbers of intrahepatic malaria-specific CD8+ T cells expressing canonical markers of liver TRM cells (CD69, CXCR6, and CD101), and these cells could be further increased in number upon vaccine boosting. We show that modifications to the peptide, such as addition of proteasomal-cleavage sequences or epitope-flanking sequences, or the use of alternative conjugation methods to link the peptide to the glycolipid improved liver TRM cell generation and led to the development of a vaccine able to induce sterile protection in C57BL/6 mice against Plasmodium berghei sporozoite challenge after a single dose. Furthermore, this vaccine induced endogenous liver TRM cells that were long-lived (half-life of ~425 days) and were able to maintain >90% sterile protection to day 200. Our findings describe an ideal synthetic vaccine platform for generating large numbers of liver TRM cells for effective control of liver-stage malaria and, potentially, a variety of other hepatotropic infections.


Production of Linnocuicina 819, a bacteriocin produced by Listeria innocua.
We studied the reciprocal antagonistic properties of 14 Listeria strains. Listeria innocua 29-CCM-A 819 (CIP 8011) produces a bacteriocin named Linnocuicina 819. This substance is mainly released in the exponential phase of growth and was isolated from the supernatant of TPB cultures. Thermal resistance and sensitivity to proteolytic enzymes was assayed. Linnocuicina 819 has a bactericidal mode of action producing a lytic effect.


[Protective effect of tanshinones against liver injury in mice loaded with restraint stress].
To observe the protective effects of tanshinones (tanshinone IIA, tanshinone I, cryptotanshinone and dihydrotanshinone) against liver injury in mice loaded with restraint stress. The liver injury model was established under 12 h restraint stress in mice 5 days after tanshinones treatment. The hepatoprotective effects were evaluated by assessing alanine aminotransferase (ALT) levels in plasma. The contents of vitamin C, GSH and malondialdehyde (MDA) in liver were performed by HPLC and TBARS methods, respectively. Oxygen radical absorbance capacity (ORAC) assay was used to measure the antioxidant capacity. Tanshinones decreased ALT and MDA levels, and increased ORAC, vitamin C and GSH levels in liver tissues as compared with restraint stress control. Tanshinones also significantly inhibited oxidation in vitro. Among four tanshinones, dihydrotanshinone was more effective than others both in vivo and in vitro test. Tanshinones possesses potent antioxidant activity in vitro and in vivo, and protected against liver injury induced by restraint stress. The active mechanisms may be related to their antioxidant capability.


S-phase fraction is a prognostic factor in stage I breast carcinoma.
The prognostic significance of cell proliferation, estimated as cytometric S-phase fraction (SPF), was investigated in node-negative breast cancer patients with small tumors (T1, NO). The 219 stage I patients originated from two series and were diagnosed either from 1978 to 1981 or from 1981 to 1985. The tumors were analyzed for estrogen receptors (ERs) by isoelectric focusing and for cellular DNA content by static cytofluorometry or flow cytometry. A high SPF correlated with the absence of ERs and abnormal DNA content, and was less often found in tumors smaller than 11 mm compared with those with a diameter between 11 and 20 mm. Among the variables age, tumor size, DNA ploidy, ER status, and SPF, only SPF showed a significant association with distant recurrence and breast cancer survival in systemically untreated patients. The relative recurrence rate for patients with an SPF of 10% or greater was three times that for patients with lower SPFs. Estimated 8-year breast cancer survival rates for the same groups were 72% and 91%, respectively. This study suggests that cytometric SPF has prognostic significance in stage I breast carcinoma.


Bismuthπ arene versus bismuthhalide coordination in heterocyclic diorganobismuth(iii) compounds with transannular N→Bi interaction.
New diorganobismuth(iii) bromides of type [RN(CH2C6H4)2]BiBr [R = C6H5CH2 (1), C6H5CH2CH2 (2), and CH3OCH2CH2 (3)], based on the heterocyclic butterfly-like tetrahydro-dibenzo[c,f][1,5]azabismocine framework, were prepared starting from the corresponding RN(CH2C6H4Br-2)2 in a succession of reactions including ortho-lithiation and treatment of the dilithio derivative with BiBr3 in a 1 : 1 molar ratio. Further exchange reactions between bromides and appropriate metal halides or ammonium fluoride resulted in the formation of [RN(CH2C6H4)2]BiX [X = Cl and I for R = C6H5CH2 (4 and 5) and C6H5CH2CH2 (6 and 7) and X = F (8), Cl (9), and I (10) for R = CH3OCH2CH2]. All ten compounds were structurally characterized in solution by NMR and in the solid state by single-crystal X-ray diffraction. Strong transannular N→Bi interactions were observed in all the investigated diorganobismuth(iii) halides, thus giving rise to hypervalent 10-Bi-4 species in 1, 2, 4-7 and 12-Bi-5 species in 3, 8-10, where the oxygen atom in the pendant arm is intramolecularly coordinated to bismuth. The molecules are associated in dimeric units by strong Biπ arene interactions in 3, 4, and 10 (approx. 3.50 Å) and by BiX interactions in 1, 5, and 7. Bromide 1, chloride 4, and iodide 5 are isostructural, but stronger polarization of the Bi-Cl bond favors Biπ arene interaction in 4 over Bihalide interactions, as observed in 1 and 5. In the isostructural series [RN(CH2C6H4)2]BiX (R = CH3OCH2CH2), Bioxygen interactions compensate the electron deficiency at bismuth in fluoride 8 and chloride 9, whereas the coordination sphere of bismuth is completed by a combination of Biπ arene and Bihalide interactions in bromide 3 and only by Biπ arene interactions in iodide 10. Moreover, weak Hπ arene and HX intermolecular interactions, mainly of dispersion type, contribute to supramolecular networks in all three series of compounds.


Clinical and laboratory evaluation of four methods of assessing free thyroxine status in thyroid clinic patients.
The clinical value of four laboratory methods of assessing free thyroxine status was compared in 82 consecutive patients newly referred to a thyroid clinic with suspected thyroid dysfunction. The methods of determining free thyroxine used were: (1) free thyroxine index using a thyroid hormone uptake test (FTI (THUT)); (2) a free thyroxine index using thyroxine binding globulin (FTI (TBG)); (3) a kinetic radioimmunoassay (Immophase); and (4) an equilibrium dialysis method. The definitive thyroid status was evaluated by a combination of clinical assessment (including Wayne index), routine tests of thyroid function (total T4, T3, TSH, and TRH tests where appropriate), and by therapeutic trial in one case. The diagnostic efficiency of the tests was markedly dependent upon the method of determining the reference range for euthyroid patients. Best efficiency for each test was achieved using an amended range after excluding outliners. Test efficiency was then 97.6% for FTI (THUT) and the kinetic RIA and 96.8% for FTI (TBG). Misclassification by one or more of these tests occurred in only four patients (mild hypothyroid, euthyroid on phenytoin, euthyroid on oral contraceptive and valium, T3 hyperthyroid). In contrast, free T4 by equilibrium dialysis was much less efficient (86.6%) and was technically the most complex. Overall the kinetic T4 RIA provided similar diagnostic information to the indirect indices. However, further studies of cost benefit in settings other than a thyroid clinic are required to assess whether this method might replace total T4 and/or FTI as a first-line test of thyroid function.


Prognosis-Based Shoulder Hemiarthroplasty After Resection of Proximal Humeral Malignancy.
After wide excision of proximal humeral bony malignancy, prognosis-based reconstruction was performed at Taipei Veterans General Hospital. Bone prosthesis composite (BPC) was carried out among patients with a favored prognosis, while cement-spacer prosthesis composite (CSPC) was preserved for patients with poor prognosis. The aim of our study is to compare the clinical outcomes between the BPC and CSPC reconstruction procedures. From January 2000 to December 2014, we retrospectively reviewed the clinical outcomes of 34 patients who underwent shoulder hemiarthroplasty following wide excision of a malignant lesion of the proximal humerus, 15 of whom were treated with a BPC reconstruction and 19 cases were treated with a CSPC reconstruction. The mean postoperative follow-up was 51.9 months for the BPC group and 29.0 months for the CSPC group. At the end of the study, four patients (two in the BPC group and two in the CSPC group) developed local recurrence. Thirteen patients (1 in the BPC group and 12 in the CSPC group) had died of disease progression. The postoperative visual analogue scale score of BPC and CSPC groups was similar (P = 0.262). Functional outcome, measured using the Musculoskeletal Tumor Society score and shoulder range of motion, favored the BPC procedure (P < 0.001). The CSPC procedure, however, had less complication rate, required less operative time, and had a lower volume of intraoperative blood loss than the BPC procedure (P < 0.001). Although functional outcomes are expected to be more favorable with a BPC procedure, the CSPC procedure continues to be a safe and cost-effective shoulder hemiarthroplasty procedure for patients with low-demanding activities and when a poor disease prognosis is expected.


Dual 8-plate technique is not as effective as ablation for epiphysiodesis about the knee.
Lower extremity length inequality can be problematic in children and is often addressed surgically. Several techniques have traditionally been utilized for epiphysiodesis, the goal being physeal ablation. Recently, 8-plates, initially developed for hemiepiphysiodesis, have been extended to epiphysiodesis by placing the plates on both medial and lateral sides of the physis. No prior studies have compared 8-plates with physeal ablation techniques. Between January 2003 and August 2009, 27 patients underwent epiphysiodesis surgery using either physeal ablation or 8-plate technique. Sixteen patients had physeal ablation and 11 had dual 8-plates. A retrospective chart review sought demographic data, outcomes, and complications. Radiographs were reviewed to measure pretreatment and posttreatment limb lengths. The median improvement in limb length discrepancy was 15.5 mm in the physeal ablation group and 4 mm in the 8-plate group (P<0.001). This difference was maintained following linear regression factoring out the effect of time (10.78 mm for ablation vs. 5.62 mm for 8-plates; P=0.016). There was no statistically significant difference in complication rate between the groups (P=0.112). Our study demonstrated physeal ablation to be a significantly superior treatment compared with dual 8-plates for epiphysiodesis. Despite theoretical advantages of 8-plates to perform epiphysiodesis about the knee, this study does not recommend the use of medial and lateral 8-plates to effect epiphysiodesis. Therapeutic III.


[Histological and autoradiographic studies of the objective characterization of the degree of dysplasia in the urothelium].
282 biopsy specimens of tumorous and tumor-free urinary bladders have been examined by histological and autoradiographical means. There is no recommendation unified on an international scale for the histological classification of intra-urothelial cell and nucleus abnormities . The classification into three degrees of dysplasia is proposed. The exact characterization of urothelium requires additional objective methods. The increase of the average labeling index parallel to the increasing degree of dysplasia has been proved autoradiographically. Moreover, the change of proliferation pattern with the increasing degree of dysplasia points to the loss of physiological regeneration.


Enhancement of the anti-tumor activity of S-1 by low-dose cisplatin in mice bearing the sarcoma-180 model.
The combination of S-1, consisting of 1 mol/l tegafur, 0.4 mol/l 5-chloro-2,4-dihydroxypyridine and 1 mol/l potassium oxonate, plus low-dose cisplatin has showed promising anti-tumor activities in experimental and clinical studies. The aim of this study was to investigate the mechanism of this combination chemotherapy. Mice bearing sarcoma-180 cells were divided into groups of seven animals each - Group A: no treatment; Group B: 5-fluorouracil (5-FU) 10 mg/kg continuous i.p. infusion; Group C: S-1 10 mg/kg p.o.; Group D: cisplatin 0.2 mg/kg i.p.; Group E: B+D; Group F: C+D. Treatments were given for 5 consecutive days, and then anti-tumor activity, the concentration of 5-FU, the thymidylate synthase inhibition rate (TSIR) and the level of 5-FU incorporated into RNA (F-RNA) in tumor tissue were evaluated. Anti-tumor activity in Group F was higher than in any other group. A significantly higher concentration of 5-FU in tumor was detected in the S-1-treated groups (C and F) than in the 5-FU-treated groups (B and E). No differences in TSIR were observed between the groups treated with 5-FU or S-1 with or without cisplatin; however, the F-RNA level in Group F was about 1.24 times significantly higher than that in Group C. Group F showed the highest anti-tumor activity, with increasing intratumoral levels of 5-FU and F-RNA, but not that of TSIR. These results suggested that the superior anti-tumor activity obtained by S-1+cisplatin might be associated with an incorporation of 5-FU into RNA.


[Peripheral nerve injury during laparoscopic procedures].
Laparoscopic approach predominates in almost all surgical procedures. In comparison with classical surgery the laparoscopic procedures are more considerable for most tissues. Nevertheless, after learning of laparoscopic surgical techniques, iatrogenic peripheral nerve lesions still occure. The authors present a review of the most frequent laparoscopic operations and occurrence of peripheral nerve injuries in particular procedures. They try to point to the situations leading to iatrogenic lesions, to identify different causes of nerve damage and to deduce necessary preventive measures.


Polymer micronetworks with shape-memory as future platform to explore shape-dependent biological effects.
Polymer micronetworks allowing stimuli-induced, predefined, and spatially directed shape shifts. The temperature-induced on-demand switching of shape is introduced as a function of polyester carriers. With their adjustable -switching temperature, micronetworks may serve as a model system to explore static and dynamic shape effects in biological systems.


Dichloromaleic anhydride.
Although molecules of the title compound, 3,4-dichloro-2,5-dihydrofuran-2,5-dione (dichloromaleic anhydride, C(4)Cl(2)O(3)), (I), possess approximate non-crystallographic C(2v) symmetry, the two chlorine substituents deviate from the ring plane. Their deviations are in the same direction, but with values of 0.0356 (17) and 0.0167 (17) A, they differ significantly in magnitude. The closest intermolecular contact is of 2.888 (2) A between a carbonyl O atom and the C atom of a carbonyl group, with the O.C direction orthogonal to the C=O bond [O5.C2(i)=O2(i) 93.6 (2) degrees; symmetry code: (i) $3 \over 2$ - x, -(1/2) + y, z]. These contacts form infinite chains of molecules running parallel to the crystallographic b direction.


Intact protein analysis for site-directed mutagenesis overexpression products: plasmid-encoded R67 dihydrofolate reductase.
Mass spectrometry is currently the method of choice for the analysis of recombinant protein expression products. By combining proteolytic digestion with peptide mapping and tandem mass spectrometry techniques, verification of site-directed mutagenesis products can be obtained. The proteolytic digestion step converts a purified recombinant protein into a mixture that must be reseparated, thus greatly increasing the analysis time associated with the confirmation of site-directed mutagenesis products. Ion/ion reaction chemistry combined with quadrupole ion trap mass spectrometry provides a fast and efficient way to analyze intact proteins for the correct site-directed mutagenesis products, without heavy reliance on the proteolytic digestion step. Analysis of a series of protein variants (I68M, I68Q, Y69F, and Q67Y) from plasmid-encoded R67 dihydrofolate reductase using ion/ion reaction chemistry confirmed the presence of the correct site-directed mutagenesis products. For the I68M mutant, ion/ion separations detected the presence of extensive degradation from the N-terminal end of the protein. In the case of the Q67Y mutant, a mixture of Q67Y and Q67C species was detected by employing tandem mass spectrometry combined with ion/ion reactions. The ion/ion reaction technique was also performed on a partially purified lysate of the Q67Y/C mixture and successfully screened for the presence of both components in a complex mixture. The ion/ion reaction approach achieved the same results as the proteolytic-digestion-based methodology in a much shorter analysis time.


Significance of immunohistochemically detected c-erbB-2 protein expression in stage III breast cancer, with reference to nuclear deformity, DNA content and prognosis.
The significance of c-erbB-2 protein expression was immunohistochemically investigated in 32 patients with stage III breast cancer with regard to area, shape factor and DNA content of cancer cell nuclei. Thirty-one percent of the tumors showed c-erbB-2-positive cell membrane staining (10 out of 32 cases), and the cancer cells of the c-erbB-2-positive tumors had larger and more irregular nuclei with an increased DNA content. All patients with c-erbB-2 protein-positive tumors died of the disease within six years of their mastectomy. It can be concluded that positive immunohistochemical staining of c-erbB-2 protein indicates an aggressive biological behavior of the cancer cells as well as a poor prognosis in patients with stage III breast cancer.


Is population's cardiorespiratory fitness really declining?
Cardiorespiratory fitness (CRF) is defined as the capacity of the cardiovascular and pulmonary systems to meet the oxygen demands of the body during physical work. Poor CRF is connected with a higher risk for the development of various noninfectious diseases such as cardiovascular disease or malignancies. The standard test for the assessment of CRF is exercise testing with the measurement of maximal oxygen consumption (VO2 max). Standard VO2 max values for adult men and women in the Czech Republic have been available since the 1970s without being updated. According to experts, these standard values are now unusable for contemporary CRF measurements of the population in the Czech Republic. The Fitness Registry and the Importance of Exercise: a National Database (FRIEND) - 4,494 patients (1,717 men) defined new standard values for bicycle ergometry CRF for the population in the United States of America. The aim of the study was the statistical comparison of VO2 max values (reference standards) in the 1970s population in the Czech Republic with the new reference standards of the FRIEND registry. All analyses were performed using IBM SPSS statistics and all tests with a p-value of less than 0.05 were considered statistically significant. VO2 max norms for women in the Czech population were higher in all age categories with statistically significant differences in the categories 30-39, 40-49 and 50-59 (p < 0.001). In the male population aged 20-29 years, VO2 max was significantly higher in the FRIEND registry (p < 0.001) in contrast to the other age categories, 30-39, 40-49 and 50-59, which were significantly higher in the Czech population (p < 0.001). Czech VO2 max population norms from the 1970s are (with the exception of age category 20-29 years) higher than values from the recent FRIEND registry.


Human Pluripotent Stem Cell-Derived Neurons Are Functionally Mature In Vitro and Integrate into the Mouse Striatum Following Transplantation.
Human pluripotent stem cells (hPSCs) are a powerful tool for modelling human development. In recent years, hPSCs have become central in cell-based therapies for neurodegenerative diseases given their potential to replace affected neurons. However, directing hPSCs into specific neuronal types is complex and requires an accurate protocol that mimics endogenous neuronal development. Here we describe step-by-step a fast feeder-free neuronal differentiation protocol to direct hPSCs to mature forebrain neurons in 37 days in vitro (DIV). The protocol is based upon a combination of specific morphogens, trophic and growth factors, ions, neurotransmitters and extracellular matrix elements. A human-induced PSC line (Ctr-Q33) and a human embryonic stem cell line (GEN-Q18) were used to reinforce the potential of the protocol. Neuronal activity was analysed by single-cell calcium imaging. At 8 DIV, we obtained a homogeneous population of hPSC-derived neuroectodermal progenitors which self-arranged in bi-dimensional neural tube-like structures. At 16 DIV, we generated hPSC-derived neural progenitor cells (NPCs) with mostly a subpallial identity along with a subpopulation of pallial NPCs. Terminal in vitro neuronal differentiation was confirmed by the expression of microtubule associated protein 2b (Map 2b) by almost 100% of hPSC-derived neurons and the expression of specific-striatal neuronal markers including GABA, CTIP2 and DARPP-32. HPSC-derived neurons showed mature and functional phenotypes as they expressed synaptic markers, voltage-gated ion channels and neurotransmitter receptors. Neurons displayed diverse spontaneous activity patterns that were classified into three major groups, namely "high", "intermediate" and "low" firing neurons. Finally, transplantation experiments showed that the NPCs survived and differentiated within mouse striatum for at least 3 months. NPCs integrated host environmental cues and differentiated into striatal medium-sized spiny neurons (MSNs), which successfully integrated into the endogenous circuitry without teratoma formation. Altogether, these findings demonstrate the potential of this robust human neuronal differentiation protocol, which will bring new opportunities for the study of human neurodevelopment and neurodegeneration, and will open new avenues in cell-based therapies, pharmacological studies and alternative in vitro toxicology.


Negative Perceptions and Long-Acting Reversible Contraceptive Choice in Adolescents and Young Adults: A Cross-Sectional Study.
Long-acting reversible contraceptives (LARCs) have high rates of safety, satisfaction, and continuation in adolescents and young adults (AYAs). Despite this, utilization of these methods by AYAs is low. The purpose of this study was to evaluate the negative personal perceptions or beliefs about birth control and LARCs and their association with contraceptive use in AYAs. We surveyed young people (14-24 years old) seeking care at a Title X-supported adolescent reproductive and sexual health clinic to assess negative perceptions of birth control methods, with an emphasis on LARCs. We used appropriate bivariate statistics to compare those endorsing 3 or fewer negative perceptions with those who had more than 3 and logistic regression to identify predictors of contraceptive choice. We recruited 345 participants; 337 (97.7%) completed the survey. Among respondents, the median age was 20 (range 14-24) years, and 7.04% of participants had ever been pregnant. The most commonly held negative perceptions were fear of device migration or breakage causing adverse health effects and concern about effect on future fertility. The number of negative perceptions endorsed did not differ significantly by age. However, a greater number of negative perceptions and younger age were clinical predictors of LARC nonuse. AYAs have negative perceptions about LARCs that are often inaccurate and may limit contraceptive acceptability and perceived options. Engaged and respectful dialogue with AYAs about their concerns and fears is essential to provide accurate and patient-centered contraceptive counseling and to ensure that young people can make informed contraceptive choices.


Opioid vs nonopioid prescribers: Variations in care for a standardized acute back pain case.
Opioid analgesics are effective and appropriate therapy for many types of acute pain. Epidemiologic evidence supports a direct relationship between increased opioid prescribing and increases in opioid use disorders and overdoses. To tailor our residency curriculum, we designed and fielded an unannounced standardized patient (USP) case involving a patient with acute back pain who is requesting Vicodin (5/325 mg). We describe residents' case management and examine whether their management decisions, including opioid prescribing, were related to their core clinical skills. Results are based on 50 (USP) visits with residents in 2 urban primary care clinics. Highly trained USPs portrayed a patient with acute lower back pain who was taking leftover Vicodin with effective pain relief but was running out. We describe how residents managed this case, using both USP report and chart review data, and compare summary clinical skills scores between those who prescribed Vicodin and those who did not. Of the 50 residents, 18 prescribed Vicodin (10-60 pills). Among those who did not prescribe (32/50), most (50%) prescribed ibuprofen. Eighty-three percent of the prescribers and 72% of nonprescribers ordered physical therapy (nonsignificant). Of the 18 prescribers, 13 documented checking the prescription monitoring database. Prescribers had significantly better communication scores than nonprescribers (relationship development: 80% vs. 58% well done, P = .029; patient education: 59% vs. 31% well done, P = .018). Assessment summary scores were also higher (60% vs. 46%) but not significantly (P = .060). Patient satisfaction and activation scores were higher in the prescribers than nonprescribers (71% vs. 39%, P = .004 and 48% vs. 26%, P = .034, respectively). Most Vicodin prescribers did not follow prescribing guidelines, and they demonstrated better communication and assessment skills than the nonprescribers. Results suggest the need to guide residents in using a systematic approach to prescribing opioids safely and to develop an acceptable alternative pain management plan when they decide against prescribing.


Bradykinin and its role in osteoarthritis.
Osteoarthritis (OA), the most common joint disorder, is a disease involving all the articular structures. It presents both degenerative and inflammatory aspects. Recently, the important role of Bradykinin (BK), a phlogistic mediator, has been proposed in the pathophysiology of OA. In our review, we summarized the currently available information on the mechanisms of action of BK in OA by linking its B2 receptors. Then, we analyzed the data about the effects of BK in synoviocytes and chondrocytes cultures. Furthermore, we described the action of B2 receptor antagonists (Icatibant and Fasitibant), presenting them as new promising symptom-anddisease- modifying agents in the treatment of OA. However, more in vitro, animal model and clinical studies, are needed to better understand the mechanisms of action as well as the efficacy and tolerability of the B2 receptor antagonists in OA.


Design, Implementation, and Assessment Approaches Within a Pharmacogenomics Course.
Objective. To design and implement a pharmacogenomics course that focuses on analysis and integration of pharmacogenomic data into clinical practice and to explore how participation in the course influences student self-confidence. Design. The Basic and Clinical Pharmacogenomics course content was divided into three modules: genetic-based didactic sessions, genomic techniques and self-genotype/phenotype laboratory exercise, and clinical-based case studies. Student learning assessment included knowledge- and application-based tests and performance on a group project. Assessment. Effectiveness of the course was evaluated using results of student performance on coded test questions, student perceptions on pre- and post-course self-assessments, performance on a group project, and course evaluation results. Student pharmacists successfully demonstrated competency in pharmacogenomics knowledge-based learning, demonstrated their abilities to apply learned skills in clinical-based scenarios, and reported improved confidence in analyzing patient-based genomic testing results. Conclusions. This course appears to have contributed to student learning and positively influenced student self-confidence in pharmacogenomics.


Angiotensin type 1 receptor A1166C polymorphism and systemic lupus erythematosus: correlation with cellular immunity and oxidative stress markers.
Angiotensin II, one of the rennin-angiotensin system components, is important in the cardiovascular hemodynamic and plays an important role in the development of cardiovascular disease in systemic lupus erythematosus (SLE) patients. The angiotensin II, through interaction with angiotensin II type 1 receptor (AGTR1), promotes proliferation, inflammation and fibrosis. The single nucleotide polymorphism of the AGTR1 (dbSNP: rs5186) gene can be associated with development and progression of SLE disease. The aims of this study were to compare the frequency of AGTR1 rs5186 in SLE patients with healthy individuals and to evaluate possible association between AGTR1 A1166C gene polymorphism and serum level of lipids, neopterin and malondialdehyde in SLE patients from a population of West Iran. One hundred SLE patients and 98 healthy subjects were studied. The AGTR1 A1166C polymorphism was detected by polymerase chain reaction- restriction fragment length polymorphism method and the serum lipid profile was obtained by enzymatic method. Neopterin and malondialdehyde were detected using high-performance liquid chromatography. We did not detect significant association between AGTR1 A1166C polymorphism and the risk of SLE. The levels of triglyceride (225 ± 118 mg/dl), neopterin (30 ± 24 nmol/l) and malondialdehyde (25 ± 9.6 nmol/l) in SLE patients were significantly higher than those in control subjects (139 ± 56 mg/dl, p = 0.03, 6.4 ± 2, p = 0.03, 9.4 ± 2.5 nmol/l, p = 0.01, respectively). Individuals with AGTR1 AC + CC genotype had higher levels of total cholesterol and malondialdehyde compared with those with AGTR1 AA genotype. SLE patients with either AGTR1 AA or AGTR1AC + CC genotype had significantly higher malondialdehyde or neopterin levels compared with the corresponding control subjects. In conclusion, although the present study did not find any association between AGTR1 A1166C polymorphism and the risk of SLE, the presence of this polymorphism was associated with higher levels of malondialdehyde and higher concentration of neopterin in patients.


Antibodies against CD20 (rituximab) for treating multiple sclerosis: US20100233121.
The application is in the field of medication and treatment for MS. It aims at identifying and characterizing the activity and potency of antibodies against CD20 (rituximab) for treating MS and at devising treatments and dosing protocols for various forms of MS. Various doses of antibody and different time points were assessed to devise treatments and dosing protocols for MS. Rituximab depletes peripheral B cells and reduces the level of B cells in the cerebrospinal fluid of patients with relapsing-remitting MS. Various treatments and dosing protocols are proposed for improving the signs, symptoms or other indicators of patients with relapsing-remitting MS and with primary progressive MS. Antibodies against CD20 and rituximab offer new opportunities to treat patients with MS. The application claims the use of antibodies against CD20 and rituximab for treating the various forms of MS. The application claims the administration of the antibodies at separate intervals, and alone or in combination with other drugs and treatments. It claims a manufacture product for the medication. It further claims the administration of antibodies against CD20 by gene therapy for treating MS.