Mobilization of the high-riding vertebral artery for C2 screw insertion.
The basic surgical steps in the Goel technique of atlantoaxial fixation involve exposure of the atlantoaxial articulation, denuding of the articular cartilage, stuffing of bone graft pieces within the articular cavity, and subsequent instrumentation. "High-riding" vertebral artery in relationship to the pedicle-facet of C2 has been widely recognized to be a factor that makes insertion of the C2 pedicle-facet screw difficult or impossible. In this video, a technique of exposure and mobilization of the high-riding vertebral artery to permit safe C2 screw insertion is shown. An alternative option in the presence of such a high-riding vertebral artery is to use either C2 laminar or inferior facetal screw insertion. The video can be found here: https://youtu.be/LjxxINmzph0.


Characterization of cDNAs species encoding the Tat protein of caprine arthritis encephalitis virus.
Two distinct species of caprine arthritis encephalitis virus (CAEV) tat cDNAs were isolated early after infection of a Himalayan tahr cell line. Sequence analyses predicted that one cDNA (pCEV/e1) represented a polycistronic transcript that encodes Tat and Rev as well as an N-terminally truncated transmembrane protein and a protein, designated X, whose function is unknown; whereas the other cDNA (pCEV/f1) encodes Tat and the env gene products. pCEV/e1 trans-activated a CAEV LTR-chloramphenicol acetyltransferase reporter gene in goat synovial membrane cells. This activity was shown to be encoded by the Tat open reading frame by analysis of a deletion mutant. Because the pCAEV/f1 insert was unstable in plasmid form, its Tat activity could not be convincingly demonstrated. The target sequences for Tat within the CAEV LTR were localized to the U3 region which, when placed in either orientation upstream of heterologous promoters, was able to confer responsiveness to Tat.


Base-Promoted (3 + 2) Cycloaddition of Trifluoroacetohydrazonoyl Chlorides with Imidates En Route to Trifluoromethyl-1,2,4-Triazoles.
A base-mediated (3 + 2) cycloaddition of trifluoroacetohydrazonoyl chlorides with imidates for the construction of 3-trifluoromethyl-1,2,4-triazoles has been described. This reaction is characterized by readily starting materials, simple reaction conditions, good yields, a broad substrate scope, and excellent regioselectivity. The utility of this protocol has been validated by the synthesis of a drug-like molecule.


A simple and highly repeatable viral plaque assay for enterovirus 71.
The classic plaque assay is a method for counting infectious viral particles, however its complexity limits its use in a variety of virological experiments. To simplify the operation and to improve the repeatability, we employed an improved plaque assay procedure based on Avicel to make the whole experiment easier and optimize the results on a model of Vero cells infection with Enterovirus 71(EV71). Clear plaques visible to the naked eyes can be formed on a 24-well plate or a 96-well plate without immunostaining. Following further improvement, this plaque assay procedure could be applied to other viruses, being both simple and repeatable.


Dysfunctional homologous recombination mediates genomic instability and progression in myeloma.
A prominent feature of most if not all cancers is a striking genetic instability, leading to ongoing accrual of mutational changes, some of which underlie tumor progression, including acquisition of invasiveness, drug resistance, and metastasis. Thus, the molecular basis for the generation of this genetic diversity in cancer cells has important implications in understanding cancer progression. Here we report that homologous recombination (HR) activity is elevated in multiple myeloma (MM) cells and leads to an increased rate of mutation and progressive accumulation of genetic variation over time. We demonstrate that the inhibition of HR activity in MM cells by small inhibitory RNA (siRNAs) targeting recombinase leads to significant reduction in the acquisition of new genetic changes in the genome and, conversely, the induction of HR activity leads to significant elevation in the number of new mutations over time and development of drug resistance in MM cells. These data identify dysregulated HR activity as a key mediator of DNA instability and progression of MM, with potential as a therapeutic target.


Effectiveness and tolerability of methotrexate monotherapy in Crohn's disease patients: a multicenter observational study.
Methotrexate monotherapy is recommended as a maintenance therapy for Crohn's disease (CD). However, long-term follow-up data are scarce. We aimed to examine the effectiveness and tolerability of methotrexate monotherapy in 94 CD patients from three inflammatory bowel disease Clinics in Korea. This was a multicenter retrospective observational study. Patients with active CD treated with methotrexate monotherapy were included. Clinical characteristics, laboratory indicators, endoscopy indices were evaluated at baseline, 6, 12, and 24 months. Independent factors associated with long-term clinical and endoscopic outcomes were determined. Methotrexate was administered orally (70.2%) or parenterally (29.8%). The mean methotrexate induction dose was 15.3 ± 0.4 mg/week, and the mean duration of therapy was 26.2 months. Of 76 patients who were treated for >6 months, the clinical remission rates were 76.3%, 74.6%, and 80.0% at 6, 12, and 24 months, respectively, by per-protocol analysis. The mean CRP levels were 7.5 ± 1.3, 5.3 ± 1.2, 3.8 ± 0.7, and 2.6 ± 0.5 mg/L at 0, 6, 12, and 24 months, respectively. Of 31 patients who underwent follow-up endoscopy after 27.5 months, the endoscopic remission rate was 38.7%. Baseline hemoglobin level <10 g/dL was a significant independent factor negatively associated with clinical remission at 6 [odds ratio (OR): 0.023, 95% confidence interval (CI): 0.003-0.206, p = 0.001] and 12 (OR: 0.079, 95% CI: 0.009-0.699, p = 0.023) months. Parenteral administration was a significant independent factor positively associated with clinical remission (OR: 11.231, 95% CI: 1.027-122.811, p = 0.047) and endoscopic remission (hazard ratio: 4.711, 95% CI: 1.398-15.874, p = 0.012) at 12 months. Methotrexate monotherapy was effective and tolerable as a maintenance therapy in CD patients.


[INFECTIOUS SYMBIOLOGY].
In the article new line of research--infectious symbiology that studies interaction of microsymbionts with the host in case of infection under the conditions of their biocommunicative interrelations is discussed. The presence of interrelation of intestinal microbiota with human homeostasis disorders postulates thesis that: human organism is superorganism including a lot of prokaryote species where microbiota normoflora representatives are the main complex of extra-corporeal physiological system acting as organism homeostasis regulator. When studying intermicrobial relations under microsymbiocenosis its system-forming factor has been identified that includes basic general functions of microorganisms--reproductive (growth/reproduction) and adaptive (biofilm formation and antilysozyme test). It has been shown that microbial interaction in dominant-associant vector providing microsymbiocenosis functioning is implemented via opposite (amplification/suppression) effect of reproductive and adaptive functions of microsymbionts of dominant-associant pair contributing self-non-self discrimination. Intermicrobial discrimination of self-non-self microsymbionts goes before signaling of adaptive immunity of the host promoting microbe elimination or persistence in the body depending on the result of identification. It has been noted that microbial factor fulfilling the role of organism homeostasis regulator performs synergistic functioning of dominant microflora with the host. When penetrating foreign associants (pathogens) into the organism host defense is implemented by means of induction of its adaptive immunity via cytokine reticulum. Key players of human intestinal microbiota are Bifidobacteria which along with induction of adaptive immunity and balance changes of pro- and anti-inflammatory cytokines of the host directly regulate microsymbiocenosis including system of hormones and neurotransmitters.


Identification and Prevention of Extubation Failure by Using an Automated Continuous Monitoring Alert Versus Standard Care.
Postextubation monitoring helps identify patients at risk of developing respiratory failure. This study aimed to evaluate the effect of our standard respiratory therapist (RT) assessment tool versus an automated continuous monitoring alert to initiate postextubation RT-driven care on the re-intubation rate. This was a single-center randomized clinical trial from March 2020 to September 2021 of adult subjects who received mechanical ventilation for > 24 h and underwent planned extubation in the ICU. The subjects were assigned to the standard RT assessment tool or an automated monitoring alert to identify the need for postextubation RT-driven care. The primary outcome was the need for re-intubation due to respiratory failure within 72 h. Secondary outcomes included re-intubation within 7 d, ICU and hospital lengths of stay, hospital mortality, ICU cost, and RT time associated with patient assessment and therapy provision. Of 234 randomized subjects, 32 were excluded from the primary analysis due to disruption in RT-driven care during the surge of patients with COVID-19, and 1 subject was excluded due to delay in the automated monitoring initiation. Analysis of the primary outcome included 85 subjects assigned to the standard RT assessment group and 116 assigned to the automated monitoring alert group to initiate RT-driven care. There was no significant difference between the study groups in re-intubation rate, median length of stay, mortality, or ICU costs. The RT time associated with patient assessment (P < .001) and therapy provided (P = .031) were significantly lower in the automated continuous monitoring alert group. In subjects who received mechanical ventilation for > 24 h, there were no significant outcome or cost differences between our standard RT assessment tool or an automated monitoring alert to initiate postextubation RT-driven care. Using an automated continuous monitoring alert to initiate RT-driven care saved RT time. (ClinicalTrials.gov registration NCT04231890).


Pancreatic lipase inhibitory activity of selected pharmaceutical agents.
Twenty-five structurally diverse compounds have been tested in vitro for their pancreatic lipase (PL) inhibitory activity. Despite the diversity of tested compounds, the relationship comprising structural attributes of the compounds could be established to correlate with the observed inhibitory activity. Compounds that exerted inhibitory action through surface activity were of different profile from the rest of compounds. When co-incubated with orlistat (OsT), important synergistic effects for some compounds (orphenadrine, gliclazide, cefuroxime and sulfacetamide) were revealed, while antagonistic effects were demonstrated for others (camphor sulfonic acid and dinitro salicylic acid). Docking studies for the most active molecules were performed and molecular interaction forces with the PL active site were identified. The results suggested co-binding of OsT along with the other inhibitor in the binding site in cases of synergistic effect but not in the case of antagonistic effect. These results were additionally supported by affinity capillary electrophoresis. In conclusion, synergistic lipase inhibitory activity between OsT and some other pharmaceutical compounds was demonstrated for the first time, which might help improve the pharmacological effect of OsT.


Fabrication of novel elastosomes for boosting the transdermal delivery of diacerein: statistical optimization, ex-vivo permeation, in-vivo skin deposition and pharmacokinetic assessment compared to oral formulation.
Diacerein (DCN) is a hydrophobic osteoarthritis (OA) drug with short half-life and low oral bioavailability. Furthermore, DCN oral administration is associated with diarrhea which represents obstacle against its oral use. Hence, this article aimed at developing elastosomes (edge activator (EA)-based vesicular nanocarriers) as a novel transdermal system for delivering DCN efficiently and avoiding its oral problems. For achieving this goal, elastosomes were prepared according to 41.21 full factorial design using different EAs in varying amounts. The prepared formulae were characterized regarding their entrapment efficiency percentage (EE%), particle size (PS), polydispersity index (PDI), zeta potential (ZP) and deformability index (DI). Desirability function was employed using Design-Expert® software to select the optimal elastosomes (E1) which showed EE% of 96.25 ± 2.19%, PS of 506.35 ± 44.61 nm, PDI of 0.46 ± 0.09, ZP of -38.65 ± 0.91 mV, and DI of 12.74 ± 2.63 g. In addition, E1 was compared to DCN-loaded bilosomes and both vesicles exhibited superior skin permeation potential and retention capacity compared to drug suspension. In-vivo histopathological study was performed which ensured the safety of E1 for topical application. Furthermore, the pharmacokinetic study conducted in albino rabbits demonstrated that there was no significant difference in the rate and extent of DCN absorption from topically applied E1 compared to oral suspension. Multiple level C in-vitro in-vivo correlation showed good correlation between in-vitro release and in-vivo drug performance for E1 and DCN oral suspension. Overall, results confirmed the admirable potential of E1 to be utilized as novel carrier for transdermal delivery of DCN and bypassing its oral side effects.


Neurogliaform cortical interneurons derive from cells in the preoptic area.
Delineating the basic cellular components of cortical inhibitory circuits remains a fundamental issue in order to understand their specific contributions to microcircuit function. It is still unclear how current classifications of cortical interneuron subtypes relate to biological processes such as their developmental specification. Here we identified the developmental trajectory of neurogliaform cells (NGCs), the main effectors of a powerful inhibitory motif recruited by long-range connections. Using in vivo genetic lineage-tracing in mice, we report that NGCs originate from a specific pool of 5-HT3AR-expressing Hmx3+ cells located in the preoptic area (POA). Hmx3-derived 5-HT3AR+ cortical interneurons (INs) expressed the transcription factors PROX1, NR2F2, the marker reelin but not VIP and exhibited the molecular, morphological and electrophysiological profile of NGCs. Overall, these results indicate that NGCs are a distinct class of INs with a unique developmental trajectory and open the possibility to study their specific functional contribution to cortical inhibitory microcircuit motifs.


[Pre- and perinatal oxygen transport in mammals: the embryonic hemoglobins of the domestic pig (Sus scrofa domestica)].
Pigs express two globin genes of beta-type, the epsilon- and chains during their embryonic stage. With the alpha- and epsilon-chains they form four embryonic hemoglobins. We describe here in detail the experimental procedures for sequencing the epsilon- and chains from the pig (Sus scrofa domestica) and we discuss the data with respect to their special functional properties. From the components Gower I and Heide I, we obtained all embryonic chains by chromatography on CM-Cellulose. The sequence of the tryptic peptides of the beta-type chains was established by automatic Edman-Begg degradation. They were aligned by comparison with the corresponding human chains. The epsilon-chains from man and pig differ in 20 positions, porcine and epsilon-chains only in 4 positions. Up to now these have only been found in pigs. A fetal hemoglobin (gamma-chains) was not observed. As a result of this work the sequences of all peptide chains of pig's hemoglobin are determined.


[Mendelian randomization and its application in periodontitis].
Mendelian randomization is a causal inference method using genetic variations as instrumental variables, which skillfully takes advantages of the distributive randomness and timing priority of genetic variation, effectively avoiding confounding biases and reverse causalities in traditional observational researches. It has become a research hotspot in recent years. As a complex inflammatory disease, periodontitis is associated with many factors, but the cognitions about these associations are mostly based on traditional observational studies, lacking strong evidences to infer the causality. In order to bring up new research ideas in the periodontal field, this article mainly reviewed Mendelian randomization and its research progress in periodontitis.


Rational design and directed evolution of a bacterial-type glutaminyl-tRNA synthetase precursor.
Protein biosynthesis requires aminoacyl-transfer RNA (tRNA) synthetases to provide aminoacyl-tRNA substrates for the ribosome. Most bacteria and all archaea lack a glutaminyl-tRNA synthetase (GlnRS); instead, Gln-tRNA(Gln) is produced via an indirect pathway: a glutamyl-tRNA synthetase (GluRS) first attaches glutamate (Glu) to tRNA(Gln), and an amidotransferase converts Glu-tRNA(Gln) to Gln-tRNA(Gln). The human pathogen Helicobacter pylori encodes two GluRS enzymes, with GluRS2 specifically aminoacylating Glu onto tRNA(Gln). It was proposed that GluRS2 is evolving into a bacterial-type GlnRS. Herein, we have combined rational design and directed evolution approaches to test this hypothesis. We show that, in contrast to wild-type (WT) GlnRS2, an engineered enzyme variant (M110) with seven amino acid changes is able to rescue growth of the temperature-sensitive Escherichia coli glnS strain UT172 at its non-permissive temperature. In vitro kinetic analyses reveal that WT GluRS2 selectively acylates Glu over Gln, whereas M110 acylates Gln 4-fold more efficiently than Glu. In addition, M110 hydrolyzes adenosine triphosphate 2.5-fold faster in the presence of Glu than Gln, suggesting that an editing activity has evolved in this variant to discriminate against Glu. These data imply that GluRS2 is a few steps away from evolving into a GlnRS and provides a paradigm for studying aminoacyl-tRNA synthetase evolution using directed engineering approaches.


Three-dimensional carbon nanotube scaffolds for long-term maintenance and expansion of human mesenchymal stem cells.
Expansion of mesenchymal stem cells (MSCs) and maintenance of their self-renewal capacity in vitro requires specialized robust cell culture systems. Conventional approaches using animal-derived or artificial matrices and a cocktail of growth factors have limitations such as consistency, scalability, pathogenicity, and loss of MSC phenotype. Herein, we report the use of all-carbon 3-D single- and multiwalled carbon nanotube scaffolds (SWCNTs and MWCNTs) as artificial matrices for long-term maintenance and expansion of human MSCs. Three-dimensional SWCNT and MWCNT scaffolds were fabricated using a novel radical initiated thermal cross-linking method that covalently cross-links CNTs to form 3-D macroporous all-carbon architectures. Adipose-derived human MSCs showed good cell viability, attachment, proliferation, and infiltration in MWCNT and SWCNT scaffolds comparable to poly(lactic-co-glycolic) acid (PLGA) scaffolds (baseline control). ADSCs retained stem cell phenotype after 30 days and satisfied the International Society for Cellular Therapy's (ISCT) minimal criteria for MSCs. Post expansion, (1) ADSCs showed in vitro adherence to tissue culture polystyrene (TCPS); (2) MSC surface antigen expression [CD14(-), CD19(-), CD34(-), CD45(-), CD73(+), CD90(+), CD105(+)]; and (3) trilineage differentiation into osteoblasts, adipocytes, and chondrocytes. Results show that cross-linked 3-D MWCNTs and SWCNTs scaffolds are suitable for ex vivo expansion and maintenance of MSCs for therapeutic applications. © 2016 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 105A: 1927-1939, 2017.


Optimal designs of staggered dean vortex micromixers.
A novel parallel laminar micromixer with a two-dimensional staggered Dean Vortex micromixer is optimized and fabricated in our study. Dean vortices induced by centrifugal forces in curved rectangular channels cause fluids to produce secondary flows. The split-and-recombination (SAR) structures of the flow channels and the impinging effects result in the reduction of the diffusion distance of two fluids. Three different designs of a curved channel micromixer are introduced to evaluate the mixing performance of the designed micromixer. Mixing performances are demonstrated by means of a pH indicator using an optical microscope and fluorescent particles via a confocal microscope at different flow rates corresponding to Reynolds numbers (Re) ranging from 0.5 to 50. The comparison between the experimental data and numerical results shows a very reasonable agreement. At a Re of 50, the mixing length at the sixth segment, corresponding to the downstream distance of 21.0 mm, can be achieved in a distance 4 times shorter than when the Re equals 1. An optimization of this micromixer is performed with two geometric parameters. These are the angle between the lines from the center to two intersections of two consecutive curved channels, θ, and the angle between two lines of the centers of three consecutive curved channels, ϕ. It can be found that the maximal mixing index is related to the maximal value of the sum of θ and ϕ, which is equal to 139.82°.


Pilot test of a single-session AIDS workshop for young Hispanic U.S. immigrants.
A multiple-session AIDS workshop poses a substantial burden on the provider and on the clients. Therefore, we developed and pilot-tested a single-session AIDS prevention workshop, using a before and after comparison in a one group design. Young Hispanic patients at an HIV testing clinic completed a baseline survey and were invited to attend a single-session 90-min AIDS prevention workshop. The goals of the workshop were to reinforce issues discussed in the individual HIV counseling session, and to encourage and practice condom carrying, negotiation and use. Forty-seven percent of the patients attended the workshop and evaluated it very positively. Sixty-eight percent of all patients completed a telephone interview 4 weeks later. The proportion of subjects who always carried condoms increased from 18% at baseline to 42% at 4-week follow-up (p < 0.0004). Stratified analyses showed that condom carrying increased significantly only in males and only in workshop attenders.


Herbal Immunomodulators - A Remedial Panacea for Designing and Developing Effective Drugs and Medicines: Current Scenario and Future Prospects.
Constant exposure to various stressors, such as immune pressure, rapidly increasing population, deleterious changes in the ecosystem, climate change, infection with emerging and re-emerging pathogens, and fast-paced lifestyle, is a critical factor in the globally increasing incidences of immunocompromising health conditions, as well as stress. Synthetic chemotherapeutic agents, which are widely available in the commercial market, may be highly efficacious, but most are immunosuppressive and exert many side effects. Herein, we comprehensively reviewed current literature from various scientific databases such as Bentham Science, PubMed, Scopus, Elsevier, Springer, etc. The inclusion/exclusion criteria based on literature with high importance was adopted to analyze and compile salient information from the authentic bibliographic sources. Undoubtedly, the pivotal characteristics of immunostimulants and immunomodulators in the maintenance of the health and productivity of humans, as well as animals, cannot be overlooked. Numerous herbs used in ethnoveterinary medicine can be successfully employed as adjuvant rehabilitators to negate the deleterious effects of chemotherapeutics. The sources of these medicinal remedies are part of long traditions in different regions of the world, such as Indian Ayurveda and Traditional Chinese Medicine, which have been developed through empirical experience. Traditional medicine employs a holistic approach to the prevention of disease, and traditional herbal medicines are a source of many components with a high therapeutic value that are used in modern allopathic medicine. Globally, many studies have been conducted on these herbs and have revealed unique active constituents that activate the innate immune system through the stimulation of macrophages and lymphocytes, and modulation of the cytokine profile, which leads to a state of alertness with a subsequent reduction in the incidence of infection. Immunomodulatory constituents with herbal origins are termed as phytochemicals, including flavonoids, glycosides, polysaccharides, terpenoids, essential oils, various bitters, and alkaloids; all these compounds exert vital, multidimensional effects. Efforts have focused on screening plant preparations to identify adjuvant immune properties; furthermore, several potent phytol adjuvants have been experimentally proven to downregulate inflammatory reactions in addition to enhance specific adaptive responses to vaccines. In summary, this review summarizes the current status and future prospects regarding the immunomodulatory potential of various herbs and plants and their promising utility for designing and developing effective drugs and medicines in safeguarding the health of humans, animals, and poultry.


ABA enhanced cold tolerance of wheat 'dn1' via increasing ROS scavenging system.
Abscisic acid (ABA) is an important plant hormone that plays significant roles in cold tolerance regulation. However, whether ABAimproves cold tolerance by increasing the activities of antioxidant enzymes in wheat remains unknown. In this study,the activities of antioxidant enzymes of the winter wheat variety 'dongnongdongmai 1' ('dn1')afterthe application of exogenous ABA under low temperature (0°C, -10°C, -20°C, and -25°C) were investigated. Results showed that cold stress significantly increased H2O2 and relative conductivity, whileABA significantly reduced this effect. ABA enhanced cold tolerance in both leaves and rhizomes at -10°C and -20 °Cby increasing CAT, SOD, POD, APX, GR, DHAR, and MDHAR. However, this tolerance was weakenedat -25°C with decreasing ASA, GSH, APX, DHAR, and MDHARthan at-10°C and -20°C.POD, GR, and DHARlevels peaked at -10°C, while CAT, SOD, GSH, APX, and MDHAR content in rhizomes peaked at -20°C. The rate of returning green was significantly increased after ABA treatment than in controls (93.5% vs 83.6 %). In 'dn1', rhizomes had a higher cold tolerance than leaves. Thereby, exogenous ABA could enhance cold tolerance byincreasing the activities of antioxidant enzymes.


The Surprise Question and Self-Rated Health Are Useful Screens for Frailty and Disability in Older Adults with Chronic Kidney Disease.
Background: Self-rated health (SRH) and the surprise question (SQ) capture perceptions of health and are independent risk factors for poor outcomes. Little is known about their association with physiologic and functional decline. Objective: Determine the association of SRH and SQ with frailty and functional status in older adults with chronic kidney disease (CKD) and their utility as screening tools. Design: Prospective cohort study. Setting/Subjects: Two hundred seventy-two adults, age ≥60 years, with advanced CKD seen in nephrology clinic. Measurements: Patients completed SRH and were evaluated for frailty (Fried criteria and Clinical Frailty Scale [CFS]) and functional status (Katz and Lawton indices of activities of daily living [ADLs] and instrumental ADLs [iADLs]). Providers completed the SQ. Correlations were evaluated using Spearman's rho. Results: Fifteen percent of patients were frail, 8% had ≥1 ADL deficit, and 29% had ≥1 iADL deficit. SRH and SQ were moderately correlated with frailty and iADLs. A SRH of excellent, very good, or good was predictive of nonfrail status (Fried negative predictive value [NPV]: 0.92; CFS NPV: 0.92) and preserved ADL function (NPV for ≥1 deficit: 0.96). A SQ response of 5, 4, or 3 (i.e., surprised) was predictive of nonfrail status and preserved ADL function (CFS NPV: 0.90; ADL ≥1 deficit NPV: 0.95). A SQ response of 1 or 2 had a positive predictive value of 0.64 for ≥1 iADL deficit. Conclusions: Subjective health measures may be useful screening tools for frailty and functional status.


The structures and properties of anionic tryptophan complexes.
The physicochemical properties of [Trpn-H]- and [TrpnCl]- (n = 1, 2) have been investigated in a combined computational and experimental infrared multiple dissociation (IRMPD) study. IRMPD spectra within the 850-1900 cm-1 region indicate that deprotonation is localized on the carboxylic acid moiety in [Trpn-H]- clusters. A combination of hydrogen bonding and higher order charge-quadrupole interactions appear to influence cluster geometries for all investigated systems. Calculated global minimum and low energy geometries of [TrpCl]- and [Trp2Cl]- clusters favour coordination of the halide by the indole NH. [Trp2-H]- and [Trp2Cl]- exhibit additional π-π interactions between the heterocyclic side chains.


Two Doses of Tranexamic Acid Reduce Blood Loss in Primary Posterior Lumbar Fusion Surgery: A Randomized-controlled Trial.
Tranexamic acid (TXA) has been widely used in hip and knee arthroplasty to reduce perioperative blood loss and blood transfusion, but the dosage and efficacy of TXA in posterior lumbar spinal surgery are not fully clear. The aim of this study was to investigate the efficacy and safety of TXA and to determine whether 2 doses of TXA could reduce the blood loss in primary single-segment or double-segment posterior lumbar fusion surgery. A total of 150 patients with lumbar degenerative disease undergoing posterior lumbar interbody fusion surgery between October 2017 and February 2019 were randomized to 3 groups. Group A was treated with 0.9% normal saline solution without TXA, group B was treated with a 15 mg/kg loading dose intravenous infusion 30 minutes before surgery, and group C was treated with a 15 mg/kg loading dose intravenous infusion 30 minutes before surgery; then, the same dose was administered again 3 hours later. The assessed outcomes were the operation time, the total blood loss, the hidden blood loss, postoperative drainage, blood transfusions, incidence of venous thromboembolism, and incision infection. The total blood loss, the hidden blood loss, and postoperative drainage were the lowest in group C. The amount of intraoperative blood loss was similar among the 3 groups. The hemoglobin and hematocrit values of the third postoperative day were the highest in group C. No significant differences in the incidence of complications and adverse events from TXA use were observed among the 3 groups. The use of TXA, the operation time, and the number of fusion segments were identified as risk factors related to total blood loss. Two doses of TXA significantly reduced the total blood loss, the hidden blood loss and postoperative drainage, and decreased hemoglobin and hematocrit drop in patients undergoing posterior lumbar fusion without increasing the risk of complications.


Spotlight on ramucirumab in the treatment of nonsmall cell lung cancer: design, development, and clinical activity.
The vascular endothelial growth factor (VEGF) and receptor is a therapeutic target because of the importance of this pathway in carcinogenesis. This pathway regulates and promotes angiogenesis as well as increases endothelial cell proliferation, permeability, and cancer survival. Ramucirumab is a new fully human monoclonal antibody that targets the VEGF receptor-2, an important key receptor implicated in angiogenesis. Ramucirumab has been approved for the treatment of second-line advanced or metastatic non-small cell lung cancer (NSCLC) in combination with the chemotherapy agent docetaxel. This was based on the result of the randomized trial REVEL of 1,253 patients with metastatic NSCLC previously treated with a platinum-based combination therapy. The authors observed a significant improvement in overall survival (OS) with an acceptable toxicities profile. In this study, patients were randomized to receive ramucirumab plus docetaxel or placebo with docetaxel. The combination of docetaxel and ramucirumab showed an improved OS (hazard ratio [HR]: 0.86; 95% CI: 0.75, 0.98). Median OS was 10.5 months in the ramucirumab arm versus 9.1 months in the placebo arm. Regarding side effects, the toxicity described on the ramucirumab arm were principally diarrhea, fatigue, and neutropenia. The most common (5%) adverse reactions of grade 3 and 4 in the ramucirumab arm were fatigue, neutropenia, febrile neutropenia, leukopenia, and hypertension. Adding ramucirumab to docetaxel improves QoL of patients, and does not impair symptoms or functioning. There are currently several trials in progress evaluating the effects of ramucirumab in combination with other drugs in patients with advanced NSCLC.


How do we probe ubiquitin's pathway heterogeneity?
We identify folding pathways for ubiquitin and assess its extent of transition state (TS) heterogeneity using a kinetically controlled ab initio algorithm that generates a coarse-grained description of torsional dynamics. The algorithm computes the time evolution of backbone-motion constraints, finds optimized conformations within such constraints, evaluates local solvent environments, and rescales accordingly the energetic contributions to determine the transition to the next set of torsional constraints. Native and nonnative structural features are found in the TS ensemble determined from a pool of 72 successful runs whose final folds are within 4-5 A RMSD from native. Certain nonnative features at the TS are shown to be necessary to create a large-scale context that overrides local propensities. Such misfolds undergo a subsequent rearrangement on the downhill side of the energy profile. The effects of tunable bi-histidine metal-binding sites, point mutations, negative Phi-value mutations, and denaturant on kinetics are predicted.


Seasonal correction factors for estimating radon exposure in dwellings in France.
Indoor radon concentrations are subject to seasonal variation with a maximum in winter and a minimum in summer. Procedures to correct for seasonal variation are necessary in order to get an unbiased estimate of the annual average radon concentration from data based on short-period radon measurements. To obtain correction factors, we apply the model developed by Pinel et al to the French database of indoor radon measurements (measurements performed as part of the indoor radon case-control study and of the national radon measurement campaign). For 6-month measurements, the correction factors vary from 0.87 to 1.17 and agree with those previously published. These results might be applicable when assessing indoor radon concentrations with regard to recommended action levels.


Systemic effect of intrathecal methotrexate during the initial phase of treatment of childhood acute lymphoblastic leukemia. The European Organization for Research and Treatment of Cancer Children's Leukemia Cooperative Group.
The in vivo response to prephase corticosteroid therapy for 1 week has been described as a major prognostic factor in childhood acute lymphoblastic leukemia (ALL). Patients with less than 1,000 blasts/microL at day 8 are considered responders and have a better prognosis. This prephase therapy is usually considered as an evaluation of glucocorticoid sensitivity. In fact, it also includes one intrathecal (IT) injection of methotrexate (MTX). In this study, we try to clarify the influence of this injection of IT MTX on the response to the prephase therapy. This retrospective study analyzed the response to prephase therapy in 1,044 children with ALL entered onto the European Organization for Research and Treatment of Cancer (EORTC) trial 58881 of the Children's Leukemia Cooperative Group (CLCG). Analysis was restricted to 732 cases with an initial blast count greater than 1,000/microL. The following variables were tested to analyze response to prephase therapy: age, sex, evaluated risk factor (RF), blast count on day 0, actual dose of prednisolone administered, immunophenotype (T v non-T), and day of IT MTX. For statistical analysis, the variable day of IT MTX (D) was stratified into three groups: group 1 if D less than 2, group 2 if D > or = 2 but < or = 6, and group 3 if D greater than 6. All variables tested had a significant influence on response to the prephase therapy. This was especially true for IT MTX: 90.4% responders in group 1, 76.9% in group 2, and 70% in group 3 (P < .001). Immunophenotype was also a major predictor of response to the prephase: 88% responders in B-lineage ALL versus 56.2% in T-lineage ALL. IT MTX had a significant influence in B-lineage ALL (96% responders in group 1, 90% in group 2, and 79% in group 3; P < .001), whereas the influence could not be detected in T-lineage ALL. These results clearly demonstrate a therapeutic systemic effect of low doses of IT MTX in childhood ALL, and response to prephase therapy should not be considered as an in vivo test for cortico-sensitivity only. Earlier use of IT MTX leads to a higher percentage of responders.


Congenital cardiac anomalies in relation to water contamination, Santa Clara County, California, 1981-1983.
In November 1981, a leak of solvents from an underground storage tank was detected at an electronics manufacturing plant in Santa Clara County, California. Solvents (predominantly 1,1,1-trichloroethene, or methyl chloroform) were found in a nearby well which supplied drinking water to the surrounding community. Residents were concerned about a possible relation between adverse reproductive outcomes and consumption of contaminated water. To address this concern, the California Department of Health Services conducted two epidemiologic studies: one of these, reported here, is a county-wide study of cardiac anomalies. This study, which looked at major cardiac anomalies among births throughout Santa Clara County in 1981-1983, found an increased prevalence in the service area of the water company which operated the contaminated well. During the potentially exposed time period (January 1981 through August 1982), 12 babies with major cardiac anomalies were born to residents of this area. This represents an excess of six cases over the number expected based on the prevalence in the remainder of the county (relative risk = 2.2, 95 per cent confidence interval 1.2-4.0). No excess was observed in the unexposed time period (September 1982 through December 1983). However, the temporal distribution of major cardiac cases born during the exposed time period suggests that the solvent leak is an unlikely explanation for this excess.


Detection and viability of Lactococcus lactis throughout cheese ripening.
Recent evidences highlighted the presence of Lactococcus lactis during late cheese ripening. For this reason, the role of this microorganism, well known as dairy starter, should be reconsidered throughout cheese manufacturing and ripening. Thus, the main objective of this study was to develop a RT-qPCR protocol for the detection, quantification and determination of the viability of L. lactis in ripened cheese samples by direct analysis of microbial nucleic acids. Standard curves were constructed for the specific quantification of L. lactis in cheese matrices and good results in terms of selectivity, correlation coefficient and efficiency were obtained. Thirty-three ripened cheeses were analyzed and, on the basis of RNA analysis, twelve samples showed 106 to 108 CFU of L. lactis per gram of product, thirteen from 103 to 105 CFU/g, and in eight cheeses, L. lactis was not detected. Traditional plating on M17 medium led to loads ranging from 105 to 109 CFU/g, including the cheese samples where no L. lactis was found by RT-qPCR. From these cheeses, none of the colonies isolated on M17 medium was identified as L. lactis species. These data could be interpreted as a lack of selectivity of M17 medium where colony growth is not always related to lactococcal species. At the same time, the absence or low abundance of L. lactis isolates on M17 medium from cheese where L. lactis was detected by RT-qPCR support the hypothesis that L. lactis starter populations are mainly present in viable but not culturable state during ripening and, for this reason, culture-dependent methods have to be supplemented with direct analysis of cheese.


Optimise inlet condition and design parameters of a new sewer overflow screening device using numerical model.
After heavy rainfall, sewer overflow spills to receiving water bodies cause serious concern for the environment, aesthetics and public health. To overcome these problems this study investigated a new self-cleansing sewer overflow screening device. The device has a sewer overflow chamber, a rectangular tank and a slotted ogee weir to capture the gross pollutants. To design an efficient screening device a numerical computational fluid dynamic (CFD) model was used. A plausibility check of the CFD model was done using a one-dimensional analytical model. Results showed that an inlet parallel to the weir ensured better self-cleansing than an inlet perpendicular to the weir. Perforations should be at the bottom of the weir to get increased velocity and shear stress to create a favourable self-cleaning effect of the screening device. Increasing inlet length from 0.3 to 1.5 m reduced wave reflection up to 10%, which increased flow uniformity downstream and improved self-cleansing effect. The orientation of the ogee weir with the rectangular tank was found most uniform with a 1:3 (horizontal:vertical) slope. These results will help to maximise functional efficiency of the new sewer overflow screening device. Otherwise it would be too expensive to alter after installation and at times difficult to customise accordingly to existing urban drainage systems.


Investigations into the relationship between phospholipids and brain acetylcholine.
The effect of a phospholipid mixture extracted from the bovine cerebral cortex and of pure phosphatidylserine (PS), phosphatidylethanolamine (PE) and phosphatidylcholine (PC) on ACh output from the cerebral cortex was investigated in rats anaesthetized with urethane. All the phospholipids were administered after sonication. ACh was determined by bioassay. The following results were obtained: after i.p. administration of 100 mg/kg of the phospholipid mixture a marked increase in ACh output I asting approximately 30 min was observed. The i.v. administration of PS caused a dose-dependent increase in ACh. At the dose of 150 mg/kg a 3-fold increase over the spontaneous ACh output was found. PE was less active than PS and PC showed no effect on ACh output. The possibility that PS and PE might increase ACh output through a mechanism facilitating Ca penetration is discussed.


[Clinical-pharmacological and pharmacokinetic studies with naproxen].
d-2-(6'-Methoxy-2'-naphthyl)-propionic acid (naproxen) is bound in blood to a high degree to plasma protein. After oral application naproxen is absorbed rapidly and completely. The mean biological half-life in man is fourteen hours. This gives us the possibility of controlling the symptoms of disease with two daily doses. In man, 99% of naproxen is excreted in the urine, either unchanged or glucuronized and as its 6-des-methyl metabolite. There is a linear increase of plasma levels with daily doses of up to 500 mg. Higher naproxen doses do not produce higher blood levels but lead to a faster excretion. This probably depends in part on a saturation of the binding sites in plasma. Differences in affinity of some compounds for binding sites in plasma are responsible for a potential interaction between naproxen and other agents, such as warfarin, acetyl salicylic acid (ASA) and sulfonylureas. These interactions are discussed. In a double-blind trial the influence of naproxen and ASA on the gastric mucosa of healthy volunteers has been compared. The results of gastroscopic findings as well as laboratory tests are reported.


[Further improving the result of multi-modality treatment for gastric cancer by optimizing scheme and measures].
The incidence of gastric cancer has declined worldwide in the past decades. However, due to the large number of population in mainland of China, the absolute number of newly-diagnosed patients in this developing country is still very high. Most of the major clinical centers have established multi-disciplinary team, but the strategy in treating this life-threatening disease still needs to be optimized, including the precise preoperative staging by various techniques, perioperative chemotherapy for locally advanced diseases, role of minimally invasive surgical approaches in treating patients with different stages, translational research to fill the gap between clinical trials and basic research, as well as the individualized treatment for gastric cancer. We believe that the biological behaviors and molecular events of gastric cancer in eastern countries are different from that of Western countries, so the clinical evidences derived from Eastern countries need to be strengthened to enrich the unmet demands in the clinical practice in China.


Genetics of Reproductive Aging from Gonadal Dysgenesis through Menopause.
Reproduction is essential for the survival of the species and is influenced by external factors such as smoking and exposure to chemotherapy as well as chronic disorders such as obesity and autoimmunity. Reproductive senescence, such as menopause, is also dependent on multiple intrinsic genetic factors. Reproductive aging is not isolated from an overall aging process, and several studies strongly support the link between the early age of menopause and mortality. The extreme form of reproductive aging is primary ovarian insufficiency (POI) with prevalence ranging from 1 to 5% of the female population. POI has been shown to have long-term consequences on overall health. POI and age of menopause have a significant hereditary component. The population-based genome-wide association studies have identified 44 genomic loci to associate with age of menopause, and 29 of 44 loci harbor DNA damage response genes. Recent application of whole exome sequencing on carefully selected families with POI has also revealed a significant contribution of DNA damage response genes. The inability to repair the DNA damage in both somatic and germ cells might be a predisposing factor for the link between reproductive and overall aging in a subset of individuals with POI. The aim of this review is to characterize recent advances in the genetics of POI and its link with overall health.


Disability discrimination in healthcare services and employment.
This article discusses the meaning and philosophical basis of disability discrimination in health care. It focuses on aspects of language that influence discourse about disability and affect the experiences of people with disabilities. Reference is made to the experiences of those who have an autism spectrum condition, with a specific focus on three NHS employees with Asperger syndrome, in relation to disability discrimination. The implications for nurses and nursing are discussed. Recommendations are made for awareness raising and training.


Bacterial expression of the scFv fragment of a recombinant antibody specific for Burkholderia pseudomallei exotoxin.
The scFv antibody towards the Burkholderia pseudomallei exotoxin was previously constructed by phage display and exhibited good specificity towards the exotoxin. We report here the optimization of the scFv expression in an E. coli expression system. Four different E. coli strains (ER2537, TG1, HB2151, and XL1-Blue) were examined for optimal expression of the scFv protein. Two types of carbon source (i.e. 0.2% glucose and 0.2% glycerol) were also tested for their ability to induce the scFv expression. Cells that carried the scFv construct were grown at 30 degrees C and induced with 0.05 mM IPTG. The expression was then monitored by SDS-PAGE, Western blotting, and indirect ELISA. The Western blot profile showed different levels of the scFv expression among the host strains; XL1-Blue exhibited the highest level of the scFv protein expression. Glycerol at a concentration of 0.2% (v/v) significantly increased the scFv protein expression level when compared to 0.2% (w/v) glucose. Further optimization demonstrated that the scFv protein expression in XL1-Blue was the most optimal with a glycerol concentration as low as 0.05%. However, by indirect ELISA, only the scFv protein that was expressed in 0.2% (v/v) glycerol exhibited high specificity towards the Burkholderia pseudomallei exotoxin.


Non Coding RNAs: A New Avenue for the Self-Tailoring of Blood Cancer Treatment.
Hematological malignancies, accounting for about 10% of all deaths for cancer, include various forms of leukemia, lymphoma and myeloma. At present, hematological malignancies are analyzed and classified on the basis of morphologic characteristics, cell surface markers, cytogenetic aberrations and molecular markers. Unfortunately, in most cases, standard criteria are not sufficient for both an early diagnosis and a complete classification. The latter issue hampers an optimal therapeutic choice for these patients that often display heterogeneous clinical outcomes or responses to therapy. This heterogeneity has determined a need for improved methods of analysis and novel markers for diagnosis and classification of these malignancies. Non coding RNAs act as master regulators of numerous biological processes including epigenetic response, apoptosis and cell cycle. The recent advances in cancer research have led to a spreading out in the clinical use of genomic information; in fact, several studies are investigating the prominent role of both miRNAs and lncRNAs in hematopoietic differentiation and proliferation, as well as in the development of various hematological malignancies. These investigations are mainly aimed at researching new therapeutic opportunities that could boost a reduced risk of adverse events in normal tissues. Moreover, not less important, there is also a growing interest in determining how ncRNAs are associated with clinical features. In this review we focus on the aberrant ncRNAs expression in the most common forms of blood cancers, each of which exhibits a unique signature in comparison to normal counterparts. In addition to their regulatory role and in virtue of the well known ncRNAs' capacity of modulating signal and pathway networks, herein we discuss both miRNAs' and lncRNAs' potential as new powerful biomarkers for efficient diagnosis and prediction of response for patients with hematological malignancies.


Early Glasgow Outcome Scale scores predict long-term functional outcome in patients with severe traumatic brain injury.
Patients sustaining severe traumatic brain injury (TBI) have variable long-term outcomes. We examined the association between Glasgow Outcome Scale (GOS) assessed at 3 months and long-term outcomes at 12 months after TBI. We studied 159 patients with severe, closed traumatic brain injuries (Glasgow Coma Scale [GCS] <or= 8) who were treated at an academic medical center and survived for a minimum of 3 months after TBI. Demographics and admission clinical data and GOS at 3 and 12 months were analyzed. Multivariate logistic regression was used to asses the relationship between 3-month GOS, demographics, and clinical data and a poor outcome, defined as GOS 1-3 assessed at 12 months after injury. The patient population was predominantly male (77%), with a median age of 30 years and a median admission GCS of 6. The logistic regression model showed that the GOS at 3 months was the best predictor of 12-month outcomes (odds ratio = 15.22, p < 0.001). The presence of prolonged hypotension, diffuse axonal injury (DAI), and fixed and dilated pupils on admission were also significant independent predictors of poor 12-month outcome (for all, p <or= 0.047). The adjusted logistic model showed a steep gradient of long-term recovery potential depending upon GOS at 3 months, ranging from an 89.4% chance of poor outcome for patients with a GOS of 2, to a 0.11% chance of poor outcome for those with a GOS of 5. The 3-month GOS is a powerful independent predictor of long-term outcome for patients with severe TBI. Prolonged hypotension, DAI, and the presence of fixed and dilated pupils were also independent predictors of poor outcome.


Arterial stiffness and insulin resistance.
Insulin resistance is associated with increased cardiovascular morbidity and mortality. The mechanism(s) underlying this association are poorly understood. Increased arterial stiffness is the main cause of the most prevalent form of hypertension, systolic hypertension. Hypertension is also commonly observed in individuals with insulin resistance. In cross-sectional epidemiological studies such as the Atherosclerosis Risk in Communities study, hyperinsulinemia was independently associated with increased arterial stiffness. Recent mechanistic studies performed in humans in vivo have suggested that increased stiffness could be yet another facet of insulin resistance. Insulin, at physiological concentrations, acutely diminishes wave reflection in the aorta in vivo. This action of insulin precedes any changes in peripheral blood flow, vascular resistance, ejection duration or heart rate, and therefore implies that insulin acutely diminishes stiffness in arteries greater than those controlling peripheral vascular resistance. This effect is blunted in insulin-resistant conditions such as obesity and type 1 diabetes. These data suggest that the inability of insulin to normally diminish arterial stiffness could provide a mechanistic link between insulin resistance and systolic hypertension.


Development of anti-bovine TNF-alpha mAb and ELISA for quantitating TNF-alpha in milk after intramammary injection of endotoxin.
Murine mAb reactive with recombinant bovine tumor necrosis factor-alpha (r-boTNF-alpha) were produced. An ELISA using murine mAb and rabbit polyclonal antibodies, each reactive with r-boTNF-alpha to sandwich bovine TNF-alpha was developed. Secretion of TNF-alpha in quarter milk increased 1 h after injection of 0.1 mg (four cows) or 0.5 mg (four cows) Escherichia coli lipopolysaccharide (LPS) into a mammary quarter, peaked 1 to 5 h later, and returned to control levels in 24 h. There were no differences in body temperature, SCC, TNF-alpha, and blood leukocyte responses between 0.1 and 0.5 mg of LPS. To determine effects of repeated injections of LPS into the same udder, a second injection of 0.1 mg of LPS into the same quarter (two cows) 24 h after the first injection produced a strongly attenuated TNF-alpha response. However, a normal TNF-alpha response was observed when LPS was injected into a contralateral quarter (two cows) 24 h after the first LPS injection. Leukocyte counts in blood decreased and body temperature increased substantially after each injection of LPS. Quarter milk SCC increased 200-fold 8 to 12 h after the LPS injections. It would appear that these changes were not regulated by TNF-alpha secretion because the changes were also similar after the second injection of LPS into the same mammary quarter.


Modulation of rosR expression and exopolysaccharide production in Rhizobium leguminosarum bv. trifolii by phosphate and clover root exudates.
The acidic exopolysaccharide (EPS) secreted in large amounts by the symbiotic nitrogen-fixing bacterium Rhizobium leguminosarum bv. trifolii is required for the establishment of an effective symbiosis with the host plant Trifolium spp. EPS biosynthesis in rhizobia is a very complex process regulated at both transcriptional and post-transcriptional levels and influenced by various nutritional and environmental conditions. The R. leguminosarum bv. trifolii rosR gene encodes a transcriptional regulator with a C(2)H(2) type zinc-finger motif involved in positive regulation of EPS synthesis. In silico sequence analysis of the 450-bp long rosR upstream region revealed the presence of several inverted repeats (IR1 to IR6) and motifs with significant identity to consensus sequences recognized by PhoB and LysR-type proteins associated with phosphate- and flavonoid-dependent gene regulation in R. leguminosarum. Using a set of sequentially truncated rosR-lacZ transcriptional fusions, the role of the individual motifs and the effect of phosphate and clover root exudates on rosR expression were established. In addition, the significance of IR4 inverted repeats in the repression, and P2-10 hexamer in the activation of rosR transcription, respectively, was found. The expression of rosR increased in the presence of phosphate (0.1-20 mM) and clover root exudates (10 μM). PHO boxes and the LysR motif located upstream of the rosR translation start site were engaged in the regulation of rosR transcription. The synthesis of EPS and biofilm formation decreased at high phosphate concentrations, but increased in the presence of clover root exudates, indicating a complex regulation of these processes.


Long-acting beta2-agonists as an inhaled corticosteroid-sparing agent for chronic asthma in adults and children.
The addition of a long acting beta agonist (LABA) to inhaled corticosteroid (ICS) therapy can improve asthma symptoms and reduce exacerbations. The addition of LABA may also have an ICS-sparing effect and permit a reduction in ICS maintenance dose. To determine the efficacy of adding LABA to maintenance ICS therapy in reducing the requirement for ICS while maintaining control of chronic asthma. We searched the Cochrane Airways Group trials register and reference lists of articles. Date of last search: November 2004 Parallel RCTs that compared reduced dose ICS in combination with LABA vs ICS alone in asthmatics requiring daily ICS. Trial quality was assessed and data were extracted independently by two reviewers. Study authors were contacted for confirmation. Trials were analysed according to the following ICS dose comparisons: a fixed moderate/high dose or a reduced/tapering dose of the same ICS. 19 publications describing 10 trials of adults were included in the review. Studies that compared reduced dose (mean 60% reduction) ICS/LABA combination to a fixed moderate/high dose ICS found no significant difference in severe exacerbations requiring oral corticosteroids (RR 1.0, 95%CI 0.76 to 1.32), withdrawal due to worsening asthma (RR 0.82, 95%CI 0.5 to 1.35) or airway inflammation. There were also significant improvements in FEV1 (change from baseline WMD 0.10, 95%CI 0.07 to 0.12), morning & evening PEF and percent rescue free days with LABA. Two studies provided outcomes for a reduced/tapering ICS dose comparison. More participants receiving the LABA/reduced ICS combination achieved a reduction in ICS dose reaching significance in one study. A significant reduction of 253 mcg BDP was achieved in one study. In adults with asthma, using moderate to high maintenance doses of ICS, the addition of LABA has an ICS-sparing effect. The addition ofLABA permits more participants on minimum maintenance ICS to reduce ICS. The precise magnitude of the ICS dose reduction requires further study.


Monophasic-Quadripulse Theta Burst Magnetic Stimulation for Motor Palsy Functional Evaluation After Intracerebral Hemorrhage.
Transcranial magnetic stimulation (TMS) is commonly employed for diagnostic and therapeutic purposes to enhance recovery following brain injury, such as stroke or intracerebral hemorrhage (ICH). Single-pulse TMS, most commonly used for diagnostic purposes and with motor evoked potential (MEP) recordings, is not suitable for clinical use in patients with severe motor paresis. To overcome this problem, we developed a quadripulse theta burst transcranial magnetic stimulation (QTS) device that combines the output from 16 stimulators to deliver a train of 16 monophasic magnetic pulses through a single coil. High-frequency theta rhythm magnetic bursts (bursts of four monophasic pulses, at 500 Hz, i.e., with a 2-ms interpulse interval, repeated at 5 Hz) were generated via a set of 16 separate magnetic stimulators connected to a specially designed combination module. No adverse effects or electroencephalogram (EEGs) abnormalities were identified during or after the recordings. MEP amplification in the QTS during four-burst theta rhythm stimulations produced four independent MEPs 20 ms after each burst onset maximizing the final third or fourth burst, which exhibited significantly greater amplitude than those resulting from a single burst or pulse. Motor functional palsy grades after ICH and QTS-MEP parameters and resting motor threshold (RMT) and amplitudes were significantly correlated (r = -0.83/-0.81 and 0.89/0.87; R2 = 0.69/0.66 and 0.79/0.76, p < 0.001; anterior/posterior-stimulus polarity, respectively). In conclusion, QTS-MEPs enabled a linear functional evaluation in patients with various degrees of motor paresis. However, the benefits, safety, and limitations of this device should be further explored in future studies.


Implementation and evaluation of a rehabilitation concept in a patient suffering from Scleredema Adultorum Buschke: a case report.
Scleredema Adultorum Buschke is a disorder manifesting indurations of the skin mostly followed by musculoskeletal impairment. Data regarding this fact are seldom found and documentation of functional outcome of physical therapies and modalities related to Scleredema Adultorum Buschke is fragmentary. The aim of this case report is to demonstrate and to document an effective concept of rehabilitation in a patient suffering from Scleredema Adultorum Buschke. A treatment plan was developed containing therapeutic ultrasound, manual lymphatic drainage, and physiotherapy. Assessments were performed at baseline and after therapy. Treatment by physical therapies of presented patient resulted in an improved functionality. Five out of eight Short Form-36 questionaire sections increased in terms of enhanced general health and level of activity. Musculoskeletal impairment in a patient suffering from Scleredema Adultorum Buschke can be reduced by a multimodal concept of rehabilitation. Implications for Rehabilitation Rehabilitation professional should suspect scleredema in patients with diffuse skin thickening where hands and feet are spared Essential reactivating physical activity should be supported by skin softening physical modalities irrespective of etiology or primary therapy. There is a need for functional outcome measures and documentation in the rehabilitation of Scleredema Adultorum Buschke.


Competency-based medical education in two Sub-Saharan African medical schools.
Relatively little has been written on Medical Education in Sub-Saharan Africa, although there are over 170 medical schools in the region. A number of initiatives have been started to support medical education in the region to improve quality and quantity of medical graduates. These initiatives have led to curricular changes in the region, one of which is the introduction of Competency-Based Medical Education (CBME). This paper presents two medical schools, Makerere University College of Health Sciences and College of Medicine, University of Ibadan, which successfully implemented CBME. The processes of curriculum revision are described and common themes are highlighted. Both schools used similar processes in developing their CBME curricula, with early and significant stakeholder involvement. Competencies were determined taking into consideration each country's health and education systems. Final competency domains were similar between the two schools. Both schools established medical education departments to support their new curricula. New teaching methodologies and assessment methods were needed to support CBME, requiring investments in faculty training. Both schools received external funding to support CBME development and implementation. CBME has emerged as an important change in medical education in Sub-Saharan Africa with schools adopting it as an approach to transformative medical education. Makerere University and the University of Ibadan have successfully adopted CBME and show that CBME can be implemented even for the low-resourced countries in Africa, supported by external investments to address the human resources gap.


Development and outcomes of an online-onsite hybrid dental admissions enhancement pilot program.
The University of Missouri-Kansas City (UMKC) School of Dentistry has piloted two years of an Admissions Enhancement Program (AEP) with students from underrepresented minority groups and/or economically disadvantaged areas of Missouri interested in applying to dental school. The AEP utilizes an innovative online-onsite hybrid format to elevate students' foundational knowledge in biology, chemistry, organic chemistry, and quantitative reasoning. The online component includes interaction with UMKC instructors using tablet technology and Wimba virtual classroom sessions. The onsite component engages students in academic and professional development, enrichment activities targeting skills training, experience in dental labs and clinics, and mentoring in preparing the dental school application, essay writing, and interviewing. Results to date indicate overall program satisfaction among AEP participants and a dental school acceptance rate of 73.7 percent (14/19 students). Participants reported the mock interviews and essay-writing portions contributed to their becoming competitive candidates for the admission process, and the online material enhanced their preparation for the Dental Admission Test (DAT). Pre- and post-AEP data show participant DAT Academic Average scores increased by two points. The school will continue to monitor program participants in subsequent years.


Postnatal bacterial succession and functional establishment of hindgut in supplemental feeding and grazing goats.
The objectives of this study were 1) to investigate the age-related changes in functional achievement (establishment of fermentation capacity and enzyme activities) and bacterial succession (selected functional bacterial species) in the cecum and colon and 2) to assess the effect of feeding system (supplemental vs. grazing, Sup vs. G) on hindgut development in small ruminants. A total of 44 Liuyang black goat kids were randomly slaughtered at 0, 7, and 14 d of age (nonrumination period), 28 and 42 d of age (transition period), and 56 and 70 d of age (rumination period). Intestinal contents were sampled to determine VFA, activities of amylase, carboxymethylcellulase (CMCase), and xylanase, as well as abundances of total bacteria and selected functional bacterial species (genus Prevotella, cellulolytic and amylolytic bacteria) with quantitative PCR targeting the 16S rRNA subunit genes. Total VFA concentration (P < 0.01) and enzyme activities (P < 0.05) in hindgut contents were greater and total bacterial 16S rRNA gene copy numbers (P = 0.003) in the cecum were lower for Sup vs. G. Furthermore, irrespective of feeding system, hindgut total VFA concentrations and total bacterial 16S rRNA gene copy numbers increased with age (P < 0.01), with the greatest increase rate observed from 14 to 28 d. Amylase fluctuated with age, whereas CMCase and xylanase activities in Sup kids increased (P < 0.05) as age increased. The proportions of 16S rRNA copy numbers associated with the genus Prevotella and P. ruminicola increased (P < 0.05) with age, but those of cellulolytic bacteria and Ruminobacter amylophilus were detected only after 28 d of birth. The bacterial succession, fermentation capacity, and starch-degrading capacity in the hindgut of both groups were achieved at 1 mo, whereas fiber-degrading capacity in Sup kids was established at 2 mo of age; and supplemental feeding surpassed the grazing system in shaping hindgut development.


Characterization of somatically acquired ecotropic and mink cell focus-forming viruses in lymphomas of AKXD recombinant inbred mice.
The DNA of lymphomas from 12 AKXD recombinant inbred mouse strains was analyzed to determine the presence of somatically acquired ecotropic and mink cell focus-forming proviruses. Mink cell focus-forming proviruses were associated primarily with T-cell lymphomas, whereas ecotropic proviruses were associated with lymphomas of B-cell and myeloid lineages. A model based on the results is proposed to explain the variation in lymphoma types observed in different AKXD strains.


[EXPERIMENTAL STUDY ON CHITOSAN/ALLOGENEIC BONE POWDER COMPOSITE POROUS SCAFFOLD TO REPAIR BONE DEFECTS IN RATS].
To explore the feasibility of chitosan/allogeneic bone powder composite porous scaffold as scaffold material of bone tissue engineering in repairing bone defect. The composite porous scaffolds were prepared with chitosan and decalcified allogeneic bone powder at a ratio of 1 : 5 by vacuum freeze-drying technique. Chitosan scaffold served as control. Ethanol alternative method was used to measure its porosity, and scanning electron microscopy (SEM) to measure pore size. The hole of 3.5 mm in diameter was made on the bilateral femoral condyles of 40 adult Sprague Dawley rats. The composite porous scaffolds and chitosan scaffolds were implanted into the hole of the left femoral condyle (experimental group) and the hole of the right femoral condyle (control group), respectively. At 2, 4, 8, and 12 weeks after implantation, the tissues were harvested for gross observation, histological observation, and immunohistochemical staining. The composite porous scaffold prepared by vacuum freeze-drying technique had yellowish color, and brittle and easily broken texture; pore size was mostly 200-300 μm; and the porosity was 76.8% ± 1.1%, showing no significant difference when compared with the porosity of pure chitosan scaffold (78.4% ± 1.4%) (t = -2.10, P = 0.09). The gross observation and histological observation showed that the defect area was filled with new bone with time, and new bone of the experimental group was significantly more than that of the control group. At 4, 8, and 12 weeks after implantation, the bone forming area of the experimental group was significantly larger than that of the control group (P < 0.05). The immunohistochemical staining results showed that osteoprotegerin (OPG) positive expression was found in the experimental group at different time points, and the positive expression level was significantly higher than that in the control group (P < 0.05). Chitosan/allogeneic bone powder composite porous scaffold has suitable porosity and good osteogenic activity, so it is a good material for repairing bone defect, and its bone forming volume and bone formation rate are better than those of pure chitosan scaffold.


[Diagnostic value of cytologic examination of urine sediment in patients with non-neoplastic diseases].
The results are presented of urine sediment cytological examination of all patients treated in the Department of Urology for non-neoplastic diseases from March 01, 1989 to October 01, 1991. Out of the total number of 936 newly admitted patients in 88 cases the urine cytological examination demonstrated dysplastic cells which accounted for 9.4%, while in 11 cases cells suspected of malignancy were found which accounted for 1.2%. These patients are under constant urological control.


Bile Acid Receptors and Gastrointestinal Functions.
Bile acids modulate several gastrointestinal functions including electrolyte secretion and absorption, gastric emptying, and small intestinal and colonic motility. High concentrations of bile acids lead to diarrhea and are implicated in the development of esophageal, gastric and colonic cancer. Alterations in bile acid homeostasis are also implicated in the pathophysiology of irritable bowel syndrome (IBS) and inflammatory bowel disease (IBD). Our understanding of the mechanisms underlying these effects of bile acids on gut functions has been greatly enhanced by the discovery of bile acid receptors, including the nuclear receptors: farnesoid X receptor (FXR), vitamin D receptor (VDR), pregnane X receptor (PXR), and constitutive androstane receptor (CAR); and the G protein-coupled receptors: Takeda G protein-coupled receptor (TGR5), sphingosine-1-phosphate receptor 2 (S1PR2), and muscarinic acetylcholine receptor M3 (M3R).. For example, various studies provided evidence demonstrating the anti-inflammatory effects FXR and TGR5 activation in models of intestinal inflammation. In addition, TGR5 activation in enteric neurons was recently shown to increase colonic motility, which may lead to bile acid-induced diarrhea. Interestingly, TGR5 induces the secretion of glucagon-like peptide-1 (GLP-1) from L-cells to enhance insulin secretion and modulate glucose metabolism. Because of the importance of these receptors, agonists of TGR5 and intestine-specific FXR agonists are currently being tested as an option for the treatment of diabetes mellitus and primary bile acid diarrhea, respectively. This review summarizes current knowledge of the functional roles of bile acid receptors in the gastrointestinal tract.


Multiple thromboembolic events in fetofetal transfusion syndrome in triplets contributing to the understanding of pathogenesis of hydranencephaly in combination with polymicrogyria.
Over the last 180 years, several theories concerning the origin of hydranencephaly have been proposed with an emphasis on infectious, aplastic, and vascular etiologies. In this report, we present a case of triplets with fetofetal transfusion syndrome of which 2 fetuses (1 and 2) developed almost similar hydranencephaly, whereas the third exhibited the features of a fetus papyraceus (3). In the monochorial triamniotic placenta, multiple arteriovenous anastomoses were detected, representing a probable route for the transmission of thrombi originating from fetus 3 causing visceral lesions in fetus 2. Hydranencephaly was histologically characterized by necrosis, macrophage invasion, and endothelial proliferation. In addition, polymicrogyria was seen in fetuses 1 and 2. The combination of multiple visceral thromboembolic events and the death of fetus 3 approximately in the 11th week of gestation suggested a vascular thrombotic pathogenesis of hydranencephaly. Polymicrogyria can be considered as postmigratory laminar necrosis. Our findings contribute to the pathogenetic understanding of combined hydranencephaly and polymicrogyria.


Incorporating the latest pediatric nutrition support guidelines into clinical practice.
Optimal nutrition support in critically ill children is associated with improved outcomes and decreased mortality. Nutrition provision often competes with other care priorities in critically ill patients. The 2017 Guidelines for the Provision and Assessment of Nutrition Support Therapy in the Pediatric Critically Ill Patient supplement clinician knowledge and inform best practices for nutrition therapy in this vulnerable patient population.


Frequency response of optical beam deflection by ultrasound in water.
Acoustic waveforms create fluctuations in the index of refraction of the medium. An optical beam passing through the disturbance will be deflected or displaced from the original path. The acoustic wave can be detected by sending a laser through the disturbance and sensing the path changes of the beam with a position-sensitive photodetector. This paper presents a model of this interaction in water to predict the sensitivity and frequency response. The model demonstrates that the frequency response of the system is broadband, allowing detection from a few hundred hertz to 20 MHz. This technique has potential use for underwater acoustic sensing and ultrasonic inspection of materials.


Care Transition Experiences of Older Veterans and Their Caregivers.
This study's main objective was to examine care transition experiences of older veterans and their caregivers. Fifty patients age 65 years and older, discharged from a Veterans Affairs Medical Center hospital, completed the Care Transitions Measure-15 survey three to four weeks postdischarge. Seven patients and six caregivers participated in semistructured interviews. Overall, the quality of care transitions was rated as good; however, some items were indicated as problematic for veterans. Themes that emerged included agreeableness, frustration with complex information, caregiver education, and the timing and methods of information delivery. These findings have implications for all clinical staff working with veterans, and particularly for social workers facilitating care transitions for veterans and their caregivers.


Intracerebroventricular effects of histaminergic agents on morphine-induced anxiolysis in the elevated plus-maze in rats.
Some reports indicate that morphine can induce anxiolytic effects both in animal and in man. It has also been reported that histaminergic system can interfere with some pharmacological effects of morphine. The effects of histaminergic agents on morphine-induced anxiolysis in rats, using elevated plus-maze were investigated in the present study. Intraperitoneal injection of morphine (3, 6 and 9 mg/kg) induced antianxiety effects. Intracerebroventricular administration of histamine at the doses of (5, 10 and 20 microg/rat) also increased anxiety-related behaviours. Intracerebroventricular injection of pyrilamine, a H1 receptor antagonist (25, 50 and 100 microg/rat), increased anxiety whereas injection of ranitidine, a H2 receptor antagonist (5, 10 and 20 microg/rat) at the same site, decreased anxiety. Therefore, it seems that histamine induces anxiogenic response through activation of H2 receptors, while the response of H1 blocker may be due to release of histamine. We also evaluated the interactions between morphine and histaminergic agents. Our data show that histamine (10 microg/rat), pyrilamine (50 microg/rat) and ranitidine (5 microg/rat) did not alter the response induced by different doses of morphine (3, 6 and 9 mg/kg). Similarly, a single dose of morphine did not alter the response induced by different doses of histamine (5, 10 and 20 microg/rat), pyrilamine (25, 50 and 100 microg/rat) or ranitidine (5, 10 and 20 microg/rat). In conclusion, the histaminergic system plays an important role in the modulation of anxiety, although in our experiments, no interaction was found between the effects of histaminergic agents and morphine on anxiety-related indices in the elevated plus-maze. This may imply that morphine-induced anxiolysis probably is independent of the histaminergic system.


Cost-effectiveness analysis of escitalopram compared with paroxetine in treatment of generalized anxiety disorder in the United Kingdom.
Generalized anxiety disorder (GAD) is associated with substantial economic burden. To assess, from a societal perspective, the cost-effectiveness of escitalopram and paroxetine in the treatment of GAD in the UK. A decision analytic model with a 9 month time horizon was adapted to the UK setting. Model inputs included drug- and nondrug-specific probabilities from head-to-head trial data, published literature, and expert opinion. Main outcome measures were success (response after 12 wk of treatment and no relapse during the following 24 wk) and costs. Resource use was based on National Institute for Health and Clinical Excellence guidance for GAD patient management, and estimated unit costs came from standard national sources. Human capital approach was used to estimate costs of absence from work. The analysis was performed from the societal perspective. Escitalopram-treated patients were associated with 14.4% higher first-line treatment success and significantly lower discontinuation rates due to adverse events than were those treated with paroxetine. Treatment with escitalopram yielded lower expected costs with greater effectiveness compared with paroxetine. These clinical advantages led to less sick leave and resource use as a result of lower switch rates and use of secondary care. Total expected 9 month costs were 1408 pounds sterling (2560 US dollars) lower for escitalopram-treated patients than for paroxetine-treated patients. Sensitivity analyses on key parameters demonstrated robustness of the model. Escitalopram appears to be cost-effective compared with paroxetine in the treatment of GAD in the UK.


Effect of physical activity during teenage years, based on type of sport and duration of exercise, on bone mineral density of young, premenopausal Japanese women.
In this cross-sectional study, 91 healthy premenopausal women aged 20-39 years were investigated to determine the effect of physical activities during their teenage years on their current bone mineral densities (BMD). We measured whole-body BMD (WBMD), lumbar BMD (LBMD), and radial BMD (RBMD) with dual energy X-ray absorptiometry (DXA). Using a questionnaire, we asked the women about their physical activities during junior and senior high school and at present. We also asked about their current nutritional status and past and current milk intake. After adjusting for age, body mass index (BMI), current total calorie and calcium (Ca) intake, and milk intake when they were teenagers and at present, we determined that subjects who exercised during extracurricular activities at each of the three periods (during junior and senior high school and at present) had significantly higher WBMD and LBMD (P <0.01, respectively) than did those who did not exercise at those times. Subjects who played high-impact sports at each period had significantly higher WBMD and LBMD than did subjects who played low-impact sports (P <0.05, respectively). Subjects who had exercised regularly from their teenage years to the present had significantly higher BMD at all sites than BMD in other subjects after adjusting for the potential confounders described above (P <0.05, respectively). Our data suggest that continuous exercise beginning in junior high school, especially high-impact sports, may be associated with greater current bone mass. It is important to incorporate adequate exercise beginning in the teenage years to lower one's future risk for osteoporosis.


Fluctuation in cognitive engagement during reading: Evidence from concurrent recordings of postural and eye movements.
The present study utilized a novel methodological combination of eye tracking and postural movement recordings to study task-induced changes in cognitive engagement during expository text reading. Thirty-three participants read an expository text with a specific task in mind while their eye and postural movements were concurrently recorded, and after reading recalled the text from memory. The results showed that readers spent longer total fixation time and had better memory for task-relevant than irrelevant text information. During the course of reading, head-to-screen distance and the speed of head motion decreased more for relevant than irrelevant text segments. The results support the dynamic engagement hypothesis: there is task-induced fluctuation in cognitive engagement during reading. Moreover, the results suggest two types of engagement processes: transient and sustained engagement. The former refers to fast, momentary changes, whereas the latter refers to slower changes in the level of engagement observed across the reading task. The novel combination of eye and postural movement recordings proved to be useful in studying how readers embody the cognitive task demands during reading. (PsycINFO Database Record (c) 2018 APA, all rights reserved).


Tilted platforms: rental housing technology and the rise of urban big data oligopolies.
This article interprets emerging scholarship on rental housing platforms-particularly the most well-known and used short- and long-term rental housing platforms-and considers how the technological processes connecting both short-term and long-term rentals to the platform economy are transforming cities. It discusses potential policy approaches to more equitably distribute benefits and mitigate harms. We argue that information technology is not value-neutral. While rental housing platforms may empower data analysts and certain market participants, the same cannot be said for all users or society at large. First, user-generated online data frequently reproduce the systematic biases found in traditional sources of housing information. Evidence is growing that the information broadcasting potential of rental housing platforms may increase rather than mitigate sociospatial inequality. Second, technology platforms curate and shape information according to their creators' own financial and political interests. The question of which data-and people-are hidden or marginalized on these platforms is just as important as the question of which data are available. Finally, important differences in benefits and drawbacks exist between short-term and long-term rental housing platforms, but are underexplored in the literature: this article unpacks these differences and proposes policy recommendations. As rental housing technologies upend traditional market processes in favor of platform oligopolies, policymakers must reorient these processes toward the public good.Long-term and short-term rental platforms offer different market benefits and drawbacks, but the latter in particular requires proactive regulation to mitigate harm.At a minimum, policymakers must require that short-term rental platforms provide the information necessary for cities to enforce current, let alone new, housing regulations.Practitioners should be cautious inferring market conditions from rental housing platform data, due to difficult-to-measure sampling biases.


Estimating the effect of a rifampicin resistant tuberculosis diagnosis by the Xpert MTB/RIF assay on two-year mortality.
Studies assessing patient-centred outcomes of novel rifampicin resistant tuberculosis (RR-TB) diagnostics are rare and mostly apply conventional methods which may not adequately address biases. Even though the Xpert MTB/RIF molecular assay was endorsed a decade ago for simultaneous diagnosis of tuberculosis and RR-TB, the impact of the assay on mortality among people with RR-TB has not yet been assessed. We analysed data of an observational prospective cohort study (EXIT-RIF) performed in South Africa. We applied a causal inference approach using inverse odds of sampling weights to rectify survivor bias and selection bias caused by differing screening guidelines. We also adjusted for confounding using a marginal structural model with inverse probability of treatment weights. We estimated the total effect of an RR-TB diagnosis made by the Xpert assay versus the pre-Xpert diagnostic algorithm (entailing a targeted Line Probe Assay (LPA) among TB-confirmed patients) on two-year mortality and we assessed mediation by RR-treatment initiation. Of the 749 patients diagnosed with RR-TB [247 (33%) by the pre-Xpert diagnostic algorithm and 502 (67%) by the Xpert assay], 42.7% died. Of these, 364 (48.6%) patients died in the pre-Xpert group and 200 (39.8%) in the Xpert group. People diagnosed with RR-TB by the Xpert assay had a higher odds of RR-TB treatment initiation compared to those diagnosed by the targeted LPA-based diagnostic process (OR 2.79; 95%CI 2.19-3.56). Receiving an RR-TB diagnosis by Xpert resulted in a 28% reduction in the odds of mortality within 2 years after presentation to the clinic (ORCI 0.72; 95%CI 0.53-0.99). Causal mediation analysis suggests that the higher rate of RR-TB treatment initiation in people diagnosed by the Xpert assay explains the effect of Xpert on 2-year mortality [natural indirect effect odds ratio 0.90 (95%CI 0.85-0.96). By using causal inference methods in combination with high quality observational data, we could demonstrate that the introduction of the Xpert assay caused a 28% reduction in 2-year odds of mortality of RR-TB. This finding highlights the need for advocacy for a worldwide roll-out of rapid molecular tests. Because the effect is mainly caused by increased RR-TB treatment initiation, health care systems should also ensure timely initiation of effective treatment upon an RR-TB diagnosis.


Immobilization of biocomponents for immune optical sensors.
Immobilisation of both human immunoglobulin(IgG) and antiimmunoglobulin (anti-IgG) was performed by means of polyelectrolyte self-assembly. This technique was compared with direct immobilisation of the immune components on bare gold and their covalent binding via glutaraldehyde as a bifunctional reagent. Additionally, the immune components were properly oriented during their immobilisation by using a predeposited layer of the protein A. Methods of the surface plasmon resonance (SPR) and planar interferometry were employed for monitoring the immobilisation as well as specific immune reaction. It was shown that in case of the use of polyelectrolyte self-assembly it is possible to achieve the sensitivity of the analysis up to 30 ng/ml for SPR and up to 1 ng/ml for planar interferometer based immune sensors.


[Current Approaches in Cancer Immunotherapy].
Methods of cancer immunotherapy have finally entered clinical medicine after years of preclinical research. Currently, there are several methods, which have proven to be very effective even in cases of incurable cancer. Antitumor monoclonal antibodies are among major therapeutic anti-cancer drugs and have been successfully used for many ears. Novel group of antibodies are immunomodulatory antibodies which can break tumor -specific immune tolerance and induce regression of tumors by nonspecific activation of immune system. Bispecific antibodies represent a novel class of anticancer agents which can induce expansion of T cells in vivo, blinatumomab is an example of such agents and is currently available for the treatment of acute B -cell leukemia. Cellular immunotherapy is also very effective, especially the use of Chimeric receptor modified T-cells for the therapy of B- cell lymphoproliferative diseases. Although it is a very complicated and expensive method, it is highly effective approach which can induce remission even in previously hopeless conditions. The goal of this article is to explain the basic principles of cancer immunotherapy and summarize the newest findings in this field.


Epigenetic regulation of cytokine production in human amnion and villous placenta.
The mechanisms of human preterm labour appear inextricably linked to cytokine biosynthesis by gestational tissues. In turn, cytokine production by gestational tissues has been shown to be regulated by epigenetic mechanisms. In this paper, we demonstrate that cytokine production in gestational tissues is regulated epigenetically in a tissue-specific manner. Furthermore, we show that treatment with a histone deacetylation inhibitor can partially abrogate LPS-stimulated TNFα production in villous placenta but not amnion. LPS treatment significantly (P < 0.05) increased the production of IL-1β (∼10-34-fold), TNFα (∼23->100-fold) and IL10 (∼6-10-fold) after 24 h of treatment in villous explants, as expected. There were no significant LPS effects on IL1Ra production. AZA treatment did not have any significant effect on any cytokines' production tested either alone or in combination with LPS. Interestingly, however, the stimulatory effects of LPS on TNFα production were partially mitigated (P < 0.05) by TSA treatment in villous explants. We suggest caution in the consideration of histone deacetylation inhibitors in pregnancy due to the different responses in gestational tissues.


Completion rates in health-related quality-of-life assessment: approach of the National Cancer Institute of Canada Clinical Trials Group.
The approach of the National Cancer Institute of Canada Clinical Trials Group to measuring compliance, that is, completion rates, for health-related quality of life questionnaires is presented. Completion rates can be measured at the institutional, patient, questionnaire and item levels for baseline, on-treatment and off-treatment follow-up study periods. Time windows are defined for each expected completion time. In seven completed clinical trials, completion rates were high with more than 93 per cent of patients completing questionnaires in the specified time windows at baseline and while on-treatment. The rate while on off-treatment follow-up is still acceptable at 85 per cent. The proportions of analysable questionnaires were 97.6 per cent, 82.0 per cent and 77.0 per cent respectively, at the three study periods. Item completion rates within questionnaires were high at 95.5 per cent or more. The variables most likely to influence baseline and on-treatment questionnaire completion rates were breast cancer, ovarian cancer, metastases and study centre size.


Clinical, Economic and Policy Implications of Drug Shortages in the European Union.
Drug shortages are an international problem, which seems to worsen. In this paper, the clinical, economic and policy implications of drug shortages are discussed, based on data available for the EU. Research on the clinical impact is scarce. Most data describe that patients will experience more side effects or need to postpone their treatment. However, more detailed research such as case studies and the number of patients affected are lacking. Information on the economic impact is described as an estimation of the time spent by hospital pharmacies. Other stakeholders are also burdened: manufacturers loose part of their profit, patients may pay more for the alternative treatment and society pays for additional health-care costs. However, no data are available. Again more detailed and objective research is necessary to know where the problem is situated and how solutions can be proposed. Policy implications are also rather scarce. However, once more detailed and objective research has been conducted, policy changes will follow. All stakeholders should be involved in the discussions, prior to the implementation of policy measures.


Comparison of eggshell surface microbial populations for in-line and off-line commercial egg processing facilities.
The objective of this project was to evaluate the aerobic plate counts (APC) of eggshells at in-line and off-line egg processing facilities at selected sites, throughout the processing procedure. Samples were collected from four sites in the processing plant and five time periods during the daily processing shift. Site 1 was from the conveyor system before the eggs passed through the washing system. Site 2 was after detergent wash but before sanitizer application. Site 3 was immediately after sanitizer treatment. Site 4 was immediately before packaging. Samples were collected from the sites at five equally spaced intervals beginning 15 min after the processing shift began and ending 15 min before the processing shift ended. At each sampling time, eggs were aseptically collected from each site and placed into sterile plastic bags containing 50 mL of PBS that was serially diluted immediately. The dilutions were plated on APC agar within 8 h of collection and were incubated at 37 C for 48 h. APC counts of in-line and off-line eggs were compared within time periods across sites. As the processing shift progressed, off-line APC counts were significantly higher than in-line counts at Site 1. At Site 2, off-line APC counts were significantly higher than in-line counts for Periods 2 through 5. At Site 3, off-line APC counts were significantly higher than in-line counts for Periods 2 through 5. Site 4 off-line counts were significantly higher than in-line counts at all time periods.


Biofilm Formation Plays a Role in the Formation of Multidrug-Resistant Escherichia coli Toward Nutrients in Microcosm Experiments.
In this study, microcosms were established to determine the effect of nitrogen (N) and phosphorus (P) on the multidrug resistance and biofilm-forming abilities of Escherichia coli. The expression of biofilm-formation-related genes was detected to establish correlations between genotype and phenotype. Different concentrations of N and P were added to make one control group and four treatment groups. The glass tube method was used to determine biofilm-forming capabilities. Real-time PCR was used to detect the mRNA abundance of six biofilm-formation-related genes in E. coli. No resistant strains were isolated from the control group; meanwhile, multidrug resistance rates were high in the treatment groups. Expression of the biofilm-associated genes luxS, flhD, fliA, motA, and fimH was detected in all treatment groups; however, there was no expression of mqsR. The expression of luxS, flhD, fliA, motA, and fimH significantly correlated with the concentration of N and P, as well as with the appearance and duration of multidrug resistance in different groups. Overall, the results of this study suggest that biofilm-forming ability plays a key role in the formation of multidrug resistance in E. coli after the addition of N and P to a microcosm.


Effect of excipients on acetaminophen metabolism and its implications for prevention of liver injury.
Acetaminophen poisoning is the most frequent cause of acute hepatic failure in the US. Toxicity requires reductive metabolism of acetaminophen, primarily via CYP2E1. Liquid acetaminophen preparations contain propylene glycol, a common excipient that has been shown to reduce hepatocellular injury in vitro and in rodents. Children are less susceptible to acetaminophen toxicity for unclear reasons. We conducted a pharmacokinetic single-blinded crossover study of 15 healthy adult volunteers comparing the CYP2E1 and conjugative metabolism of a 15 mg/kg dose of liquid versus solid preparations of acetaminophen. Measured AUC's for the CYP2E1 metabolites were 16-17% lower and extrapolated AUC's were 25-28% lower in the liquid formulation arm while there was no difference in conjugative metabolite production. The formation rate constants for reductive metabolites were equivalent between solid and liquid formulations indicating that enzyme inhibition was competitive. Propylene glycol, an established CYP2E1 competitive antagonist, was detected in the liquid formulation but not solid formulation arm. Since children tend to ingest liquid preparations, the protective effect of this excipient could explain their decreased susceptibility to acetaminophen toxicity. A less hepatotoxic formulation of acetaminophen could potentially be developed if co-formulated with a CYP2E1 inhibitor.