Prospective evaluation of zirconia based tooth- and implant-supported fixed dental prostheses: 3-year results.
This prospective clinical study compared the performance of implant-retained (study group) and tooth-retained (control) zirconia based fixed dental prostheses (FDPs) with at least 4 units. The null-hypothesis stated that complication rates in both groups are equally distributed. The study included patients in need of one 4- to 6-unit implant- or tooth-retained FDP each. All patients were examined 2 weeks after insertion (baseline) and then at 6 month intervals up to 3 years. At follow-up all restorations were examined for framework fracture, chipping, marginal integrity, surface roughness and biological complications. Kaplan-Meier estimation was used for data analysis. 20 patients received tooth-retained and 7 patients implant-retained FDPs. The study was halted early when differences in chipping rates reached a statistically significant level. One FDP in the study group was lost due to implant abutment failure. FDP related chipping rates were 71% in the study group (mean observation time 32 months) and 15% in the control (mean observation time 34 months). Unit (abutment crown/pontic) related chipping rates were 32% in the study group and 6% in the control. Chipping rates differed statistically significant (log-rank test, p<.05). However, all ceramic defects could be corrected by grinding and polishing. No framework fracture was detected. Within the study limitations, survival rates seem satisfactorily in both implant- and tooth retained long-span zirconia based FDPs. However, implant-supported FDPs seem more susceptible to veneering ceramic chippings. The high chipping rates found in this study discourage the use of long-span implant-retained FDPs with zirconia frameworks. The study was registered in ClinicalTrials.gov with the ID Number NCT02220764.


Is C7-T1 cervical disc replacement a viable technique: A case series.
Cervical disc replacement (CDR) surgery is well established for the treatment of disc degeneration from C3-C7, but there is little data regarding the safety and efficacy of CDR at the cervicothoracic junction, C7-T1. CDR is an appealing option, in terms of range of motion preservation, symptom relief, and absence of risk for nonunion. Currently, C7-T1 CDR is not approved by the Food and Drug Administration, and the existing literature is limited to two case reports that describe the results of a combined two patients. This series explores whether C7-T1 CDR is a reasonable treatment and alternative to fusion. We present a case series of seven consecutive patients who underwent CDR at C7-T1 by a single surgeon from January to December of 2019. There were five females and two males with an average age of 61.3 ± 6.4 years. Average follow up was 18.9 ± 2.5 months. The average postoperative NDI score was 22.6 % ± 14.0. We also recorded qualitative data regarding patient satisfaction and revision surgery status. There was one complication of disc subsidence following three months of complete pain resolution. The six other patients reported being very satisfied with their surgical outcome. These seven cases dramatically increase the volume of data in the literature on clinical outcomes and patient satisfaction following CDR at the cervicothoracic junction. Additionally, the heterogeneity of cases shows the effectiveness of this treatment in many real-world cases. A greater volume of cases with longer follow up will be necessary to better establish long-term clinical success.


Foreskin necrosis - Complication following self-circumcision.
Male circumcision (MC) seems to be practiced since ancient times by Muslims and Jewish, and it is considered as commandment. Attempts at self-circumcision for any reason are very rare in our country. This article aims to highlight another case of self-circumcision in a 30 year-old male, using a sharp vegetable knife. The reasons behind this act are various and the most common complications, especially in the use of sharp tools, in addition to bleeding or laceration of the penis, are infection, penile curvature, urethral injury or necrosis of the foreskin and penile tissues. To our knowledge, this is the first case report with necrotic foreskin as complication.


Catalytic degradation of "trinitrogen" by Fe-Ce-SiO2 /TiO2 aerogel.
The "trinitrogen" [ammonia nitrogen (NH4+ - N), nitrate nitrogen (NO3- - N), and nitrite nitrogen (NO2- - N)] from industrial or domestic wastewater can lead to eutrophication of water bodies. When ammonia nitrogen is converted into nitrate nitrogen, it will cause high nitrogen oxygen demand, which will also lead to hyperammonemia. High nitrite content in water bodies will increase the risk of human cancer. In this paper, Fe-Ce bimetallic-doped composites (Fe-Ce/SiO2 and Fe-Ce-SiO2/TiO2) were synthesized using SiO2 aerogel as a carrier for the adsorption and degradation of "three nitrogen."SiO2/TiO2 was prepared by dipping method, and Fe and Ce bimetals were loaded on the surface of SiO2/TiO2 material, and the effect of photo-Fenton oxidation on the degradation rate of three nitrogen under different materials was explored. The results showed that when the dosage of catalyst was 0.01 g, pH value was 11.0, and the concentration of H2O2 was 80 mmol/L, the photocatalytic efficiency was the best, and the degradation efficiency of three nitrogen remained above 70%.


Medicinal chemical and pharmacological aspects of imidazole-containing histamine H3 receptor antagonists.
The first antagonists known for the histamine H3 receptor were mono-substituted imidazole-containing compounds like thioperamide. Meanwhile numerous novel leads have been developed possessing improved affinities, selectivities, specificities, and pharmacokinetic properties. Scope and limitations of this promising class are discussed concerning their structure-activity relationships as well as pharmacological and potential therapeutic aspects.


Humoral immunity of BBIBP-CorV (Sinopharm) in kidney transplant recipients: Is it time to revise vaccination strategies.
The mortality of coronavirus disease 2019 (COVID-19) is high in transplant patients, and effective vaccination is aimed to reduce severe disease and mortality. We conducted a cross-sectional study to evaluate humoral and cellular response to two 4-μg doses of BBIBP-CorV vaccine in 100 kidney transplant recipients, using anti-spike IgG, total anti-receptor-binding domain, neutralizing antibody (Ab) level (enzyme-linked immunoassay), and interferon-gamma release assay (IGRA). Seroconversion was evaluated 85.84 ± 30.72 days after the second dose. Note that, 58% of all and 43.05% of infection-naïve participants have developed at least one of the tested antibodies. IGRA was positive in 30.7% of tested transplant recipients. Sixty percent of the participants had either humoral or cellular responses to COVID-19. Only age was independently linked to seropositivity of any degree after vaccination (p < .05). COVID-naïve patients older than 60 years developed significantly less neutralizing Abs. (p = .011). Six patients developed mild COVID infection more than a month after the second dose of the vaccine (54.5 ± 20.8 days). No vaccine-related adverse effects were reported, except self-limited mild to moderate fever and injection site pain. BBIBP-CorV vaccine can be used safely in kidney transplant recipients, although impaired cellular and humoral immunity necessitate adjustments in vaccination strategies, like higher (8-μg doses), fourth booster dose, or boost with different platform vaccine.


The mutagenic effect of 1,2-dichloroethane on Salmonella typhimurium. II. Activation by the isolated perfused rat liver.
In this investigation Salmonella typhimurium strain TA 1530 and TA 1535 were combined with isolated perfused rat liver. Samples of perfusate and bile produced were tested for mutagenicity after treatment with 1,2-dichloroethane (DCE), 1,2-dibromoethane (DBE) or 2-chloroethanol. The results are in good agreement with our previous experiments which indicate that both DEC and DBE are activated through conjugation with glutathione (GSH). Most GSH conjugates are normally excreted in bile. Following liver perfusion the bile was highly mutagenic after DCE and DBE treatments, while 2-chloroethanol did not have this effect. The highest mutagenic effect was seen 15--30 min after the addition of DCE or DBE. The production of mutagenic bile also occurred in mice treated in vivo with DCE. One possible metabolic endproduct of a GSH conjugate is the corresponding mercapturic acid. Thus synthetic N-acetyl-S-(2-chloroethyl)-L-cysteine was tested on TA 1535 and found to be as mutagenic as S-(2-chloroethyl)-L-cysteine in the concentration range 0.2--0.6 mumol/plate. Differences and similarities in the metabolism of DCE and vinyl chloride are discussed on the basis of these results.


Seasonal plasticity: how do butterfly wing pattern traits evolve environmental responsiveness?
Phenotypic plasticity in response to environmental cues is common in butterflies, and is a major driver of butterfly wing pattern diversity. The endocrine signal ecdysone has been revealed as a major modulator of plasticity in butterflies. External cues such as day length or temperature are translated internally into variation in ecdysone titers, which in turn lead to alternate phenotypes such as seasonal wing patterns. Here we review the evidence showing that ecdysone-mediated plasticity of different wing pattern features such as wing color and eyespot size can evolve independently. Recent studies show that ecdysone regulates gene expression in Drosophila melanogaster via a chromatin remodeling mechanism. We thus propose that environmentally responsive ecdysone titers in butterflies may also function via chromatin regulation to promote different seasonal phenotypes. We present a model of ecdysone response evolution that integrates both gene regulatory architecture and organismal development, and propose a set of testable mechanistic hypotheses for how plastic response profiles of specific genes can evolve.


Air Quality in Africa: Public Health Implications.
This review highlights the importance of air quality in the African urban development process. We address connections between air pollution and (a) rapid urbanization, (b) social problems, (c) health impacts, (d) climate change, (e) policies, and (f) new innovations. We acknowledge that air pollution levels in Africa can be extremely high and a serious health threat. The toxic content of the pollution could relate to region-specific sources such as low standards for vehicles and fuels, cooking with solid fuels, and burning household waste. We implore the pursuit of interdisciplinary research to create new approaches with relevant stakeholders. Moreover, successful air pollution research must regard conflicts, tensions, and synergies inherent to development processes in African municipalities, regions, and countries. This includes global relationships regarding climate change, trade, urban planning, and transportation. Incorporating aspects of local political situations (e.g., democracy) can also enhance greater political accountability and awareness about air pollution.


Effect of culture environment on gene expression and developmental characteristics in IVF-derived embryos.
It is generally accepted that mammalian preimplantation embryos are sensitive to their environment and that conditions of culture can affect future growth and developmental potential both pre- and postnatally. Evidence suggests that while culture conditions during bovine in vitro embryo production can impact somewhat on the developmental potential of the early embryo, the intrinsic quality of the oocyte is the key factor determining the proportion of oocytes developing to the blastocyst stage. In addition, evidence suggests that the period of post fertilization embryo culture is the most critical period affecting blastocyst quality assessed in terms of cryotolerance, gene expression pattern and ability to establish a pregnancy. This paper reviews the current literature, with emphasis on the bovine model, demonstrating evidence for an effect of post fertilization culture environment on embryo gene expression and quality.


Frank vectorcardiogram in common ventricle: correlation with anatomic findings.
The influence on the Frank vectorcardiogram of anatomic features in common ventricle was analyzed by comparison of Frank vectorcardiograms in 51 patients who had common ventricle with those of 36 patients who had large ventricular septal defect, 14 of whom had levotransposition of the great arteries and 22 of whom had dextrotransposition. Frank vector loops in common ventricle differed from those in ventricular septal defect by the frequent occurrence of clockwise horizontal rotation, most common in patients with type C common ventricle (no outflow chamber). There was a statistically significant difference in the amplitude of early forces between patients with common ventricle and those with large ventricular septal defect. The degree of overlap of vectorcardiographic features between the two groups is sufficiently great that the vectorcardiogram has limited usefulness in establishing the diagnosis of common ventricle in any individual patient.


Conformation control through concurrent N-H⋯S and N-H⋯O[double bond, length as m-dash]C hydrogen bonding and hyperconjugation effects.
In addition to the classical N-H⋯O[double bond, length as m-dash]C non-covalent interaction, less conventional types of hydrogen bonding, such as N-H⋯S, may play a key role in determining the molecular structure. In this work, using theoretical calculations in combination with spectroscopic analysis in both gas phase and solution phase, we demonstrate that both these H-bonding modes exist simultaneously in low-energy conformers of capped derivatives of Attc, a thietane α-amino acid. 6-Membered ring inter-residue N-H⋯S interactions (C6γ), assisted by hyperconjugation between the thietane ring and the backbone, combine with 5-membered ring intra-residue backbone N-H⋯O[double bond, length as m-dash]C interactions (C5) to provide a C5-C6γ feature that stabilizes a planar geometry in the monomer unit. Two contiguous C5-C6γ features in the planar dimer implicate an unprecedented three-centre H-bond of the type C[double bond, length as m-dash]O⋯H(N)⋯SR2, while the trimer adopts two C5-C6γ features separated by a Ramachandran α-type backbone configuration. These low-energy conformers are fully characterized in the gas phase and support is presented for their existence in solution state.


Very low gene duplication rate in the yeast genome.
The gene duplication rate in the yeast genome is estimated without assuming the molecular clock model to be approximately 0.01 to 0.06 per gene per billion years; this rate is two orders of magnitude lower than a previous estimate based on the molecular clock model. This difference is explained by extensive concerted evolution via gene conversion between duplicated genes, which violates the assumption of the molecular clock in the analyses of duplicated genes. The average length of the period of concerted evolution and the gene conversion rate are estimated to be approximately 25 million years and approximately 28 times the mutation rate, respectively.


LncRNA RHPN1-AS1 promoted cell proliferation, invasion and migration in cervical cancer via the modulation of miR-299-3p/FGF2 axis.
This study aims to determine the biological function and underlying mechanisms of lncRNA RHPN1 antisense RNA1 (RHPN1-AS1) in cervical cancer cell proliferation, invasion and migration. Gene expression was analysed by quantitative real-time PCR; protein levels were determined by western blot assay; in vitro functional assays determined the cervical cancer cell progression; in vivo tumor growth of cervical cancer cell was determined in nude mice xenograft models. The results showed that RHPN1-AS1 was up-regulated in cervical cancer tissues and cell lines. In vitro functional assays demonstrated that RHPN1-AS1 overexpression promoted SiHa cell proliferation, invasion and migration; while RHPN1-AS1 knockdown showed the opposite effects. In vivo study showed that RHPN1-AS1 knockdown suppressed tumor growth in the nude mice. Further investigation showed that miR-299-3p was targeted and inversely regulated by RHPN1-AS1. In addition, miR-299-3p targeted the 3' untranslated region of fibroblast growth factor 2 (FGF2) to suppress its expression. The rescue experiments showed that the enhanced effects of RHPN1-AS1 overexpression on cell proliferation, growth, invasion and migration in SiHa cells were significantly attenuated by miR-299-3p overexpression or FGF2 inhibition. On the other hand, knockdown of miR-299-3p and overexpression of FGF2 both significantly increased cell proliferation, growth, invasion and migration in SiHa cells transfected with RHPN1-AS1 siRNA. In conclusion, our results revealed that RHPN1-AS1 promoted cervical cancer progression via targeting miR-299-3p/FGF2 axis. Our data suggested that RHPN1-AS1/miR-299-3p/FGF2 axis may be a promising target for cervical cancer treatment.


Effectiveness and safety of tofacitinib for the treatment of ulcerative colitis: A single-arm meta-analysis of observational studies.
Several observational studies on Tofacitinib (TOFA) in ulcerative colitis (UC) have been published over the last 2 years. To estimate effectiveness and safety of TOFA arising from real-world experience. PubMed Central/Medline and Embase were systematically searched for real-world observational studies on TOFA for the treatment of UC through November 2020. Seven studies comprising 759 patients met the inclusion criteria. The pooled estimate rates were 49% for clinical response, 40% for clinical remission, and 34% for corticosteroid-free clinical remission at induction, while the rates of endoscopic response and endoscopic remission were 37% and 19%, respectively. At maintenance, the pooled estimate rates of clinical response, clinical remission, and corticosteroid-free clinical remission were 36%, 35%, and 24%, respectively. The pooled estimate of incidence rate of adverse events was 53.0 per 100 person-years (PY), while the pooled estimate of incidence rate of withdrawal of TOFA due to adverse events was 9.3 per 100 PY, with a pooled rate of infections of 17.6 per 100 PY. Cumulative analysis of data from real-world studies confirmed the good efficacy of TOFA in UC shown by randomized controlled trials for both induction and maintenance, while the safety profile was consistent with previous reports.


Depolarizing GABA-activated Cl- channels in embryonic rat spinal and olfactory bulb cells.
1. We have compared the electrical properties of the Cl- channels activated by GABA in cells acutely dissociated from embryonic (E) spinal cord (SC) and olfactory bulb (OB) regions at E15 using different configurations of the patch-recording technique. By in situ analysis these cells express GABAA receptor mRNAs encoding a common set of subunits (alpha 2, beta 2, and beta 3). SC cells also express alpha 3, alpha 5 and gamma 2s transcripts. 2. Whole-cell recordings revealed current responses to GABA (0.5 microM to 1 mM) in 242 out of 294 cells. In both SC and OB cells, currents evoked by 2 microM GABA could be potentiated by diazepam (DZP) in a dose-dependent manner with an EC50 of approximately 50 nM in both SC and OB. The maximal effect was approximately 300%. Both SC and OB cells exhibited GABA-activated currents that were only partially sensitive to zinc even at high micromolar concentrations. The effect of DZP and the relatively modest sensitivity to zinc suggest the presence of gamma subunits in both preparations. 3. Spectral analysis of current responses in twenty-six cells showed that power spectra could be fitted by three exponential components (tau 1-3) in the cells of both areas. The tau of the longest-lasting component (tau 3) was significantly different in the cells of the two areas: approximately 50 ms in OB and 80-100 ms in SC. No statistically significant differences in the average inferred unitary conductance between the two cell types could be resolved. 4. Single-channel properties were examined directly using the cell-attached configuration. GABA-activated channels could be recorded in only 89 out of well-sealed 984 patches and most of them exhibited multiple channel activity. The mean open time in the response to 10 microM GABA was significantly shorter in OB cells (12 ms) compared to SC cells (25 ms) while the average conductance values were not significantly different between the two cell types. 5. On average, Cl- channels reversed polarity when the on-cell patch pipette potential was approximately -30 mV. Thus, in these embryonic neurons, micromolar GABA activates Cl- channels, which, when open, effectively depolarize cells by approximately 30 mV. 6. Cl- channels activated by GABA are open longer in embryonic SC cells than in OB cells. This statistically significant difference in native GABAA receptor Cl- channel properties correlates with, and may be related to differences in subunit mRNA expression.


Prophylactic Atropine Administration Prevents Vasovagal Response Induced by Cryoballoon Ablation in Patients with Atrial Fibrillation.
Cryoballoon (CB) ablation of pulmonary vein ostia often induces a vagal response. This prospective study was designed to assess the effectiveness of prophylactic intravenous administration of atropine on hemodynamic impairment induced by CB ablation in patients with atrial fibrillation. Twenty-five patients with paroxysmal atrial fibrillation undergoing CB ablation were prospectively enrolled and assigned to one of two groups. First 12 patients (trial group) were administered 1 mg of atropine before deflation of the CB, while the following 13 patients (control group) were given atropine only after the onset of the hemodynamic variation (decrease in heart rate and/or blood pressure). Treatment was considered effective when the hemodynamic variations were restored. In the trial group, three patients with transient hypotension did not require supportive care throughout the procedures, and one patient with hypotension required supportive care. In the control group, hypotension, bradycardia, and mixed bradycardia with hypotension requiring supportive care occurred in six, three, and three patients, respectively. Overall, the rate of marked vagal responses was significantly lower when prophylactic atropine was administrated (4/12 patients vs 12/13 patients, respectively; P < 0.01). Atropine is significantly effective in the prevention of all types of vasovagal responses induced by CB ablation in patients with atrial fibrillation.


Core Outcome Measures in Effectiveness Trials (COMET) initiative: protocol for an international Delphi study to achieve consensus on how to select outcome measurement instruments for outcomes included in a 'core outcome set'.
The Core Outcome Measures in Effectiveness Trials (COMET) initiative aims to facilitate the development and application of 'core outcome sets' (COS). A COS is an agreed minimum set of outcomes that should be measured and reported in all clinical trials of a specific disease or trial population. The overall aim of the Core Outcome Measurement Instrument Selection (COMIS) project is to develop a guideline on how to select outcome measurement instruments for outcomes included in a COS. As part of this project, we describe our current efforts to achieve a consensus on the methods for selecting outcome measurement instruments for outcomes to be included in a COS. A Delphi study is being performed by a panel of international experts representing diverse stakeholders with the intention that this will result in a guideline for outcome measurement instrument selection. Informed by a literature review, a Delphi questionnaire was developed to identify potentially relevant tasks on instrument selection. The Delphi study takes place in a series of rounds. In the first round, panelists were asked to rate the importance of different tasks in the selection of outcome measurement instruments. They were encouraged to justify their choices and to add other relevant tasks. Consensus was reached if at least 70% of the panelists considered a task 'highly recommended' or 'desirable' and if no opposing arguments were provided. These tasks will be included in the guideline. Tasks that at least 50% of the panelists considered 'not relevant' will be excluded from the guideline. Tasks that were indeterminate will be taken to the second round. All responses of the first round are currently being aggregated and will be fed back to panelists in the second round. A third round will only be performed if the results of the second round require it. Since the Delphi method allows a large group of international experts to participate, we consider it to be the preferred consensus-based method for our study. Based upon this consultation process, a guideline will be developed on instrument selection for outcomes to be included in a COS.


Alveolar ridge reconstruction with a digitally customized bone block allograft.
Reduced alveolar ridge volume is an often consequence after tooth loss, compromising implant placement and prosthetic rehabilitation. The digital customization of bone block allografts (BBA) is an alternative that incorporates advantages such as intimate contact with the recipient bed, increasing graft stability and reduced surgical time. In addition, enamel matrix derivate (EMD) has attracted interest for its effect on osteogenic gene expression and cell adhesion; few studies have focused on the benefits of bone regeneration with EMD. The aim of this case report is to present the reconstruction of a severely atrophic alveolar ridge defect with a digitally customized bone block allograft (CBBA) in combination with EMD as an adjuvant for bone regeneration and soft tissue healing. Initially, the digital planning and manufacture of the BBA was performed based on an initial cone beam computed tomography (CBCT) scan. EMD was applied to the recipient site and to the CBBA before graft fixation. After 6 months, bone biopsies were obtained on re-entry surgery for prosthetically guided implant placement. Clinically, bone block showed good integration with the adjacent tissue and no signs of rejection or necrosis were found. On the histological evaluation, new bone was observed in intimate contact with the allograft and showed viable osteocytes and osteoblasts along its entire length. Residual allograft particles were observed to be highly osteoconductive. According to the clinical and histological results presented, the digital customization of the BBA allows an ideal graft fit to the recipient bed with excellent results in bone regeneration.


Mechanisms of neuronal polarity.
The mechanisms that permit neurons to establish axons and dendrites involve an interplay between a cell's genetic program and signals in its environment. Recent experiments have identified some of the important extracellular molecules that regulate dendritic development and have furthered our understanding of the endogenous cell biological mechanisms that underlie protein sorting. Some of the signaling pathways that allow extracellular cues to regulate neuronal morphogenesis are also being elucidated.


A spectroscopic investigation of hydrogen bond patterns in crystalline and amorphous phases in dihydropyridine calcium channel blockers.
To gain insight into the molecular structure of amorphous compounds by investigating hydrogen bonding patterns and strength in a series of structurally related compounds. Seven 1,4-dihydropyridine calcium channel blockers were evaluated. FT-Raman and FT-infrared spectra of the compounds in the crystalline and amorphous states were obtained. For crystalline compounds, the position of the NH vibration varied considerably. indicating that the strength of hydrogen bonding differs between the different compounds in agreement with published single crystal X-ray data. For the amorphous phases, the NH vibration occurred at approximately the same position for all compounds, suggesting a uniform average hydrogen bonding strength. Somewhat surprisingly, for some compounds, the average hydrogen bond strength in the amorphous state was found to be greater than in the crystalline compound, although for others, it was weaker as anticipated. Hydrogen bonding patterns (acceptor group) varied between the crystalline compounds, but were remarkably consistent in the amorphous compounds; thus the acceptor group in the amorphous phase is not necessarily the same as in the crystalline counterpart. Hydrogen bond patterns and strength within a group of chemically related amorphous compounds were found to be very similar, but were different from those in the equivalent group of crystalline substances.


The Selective Oral Immunomodulator Vidofludimus in Patients with Active Rheumatoid Arthritis: Safety Results from the COMPONENT Study.
The dihydroorotate dehydrogenase (DHODH) inhibitors leflunomide and teriflunomide are immunomodulatory agents approved to treat rheumatoid arthritis (RA) and multiple sclerosis, respectively, and are actively being investigated as therapeutic agents for other immune-related diseases; however, both structurally related compounds have a number of potentially serious adverse effects. Vidofludimus, a new selective second-generation DHODH inhibitor, is chemically distinct from leflunomide/teriflunomide and appears to exhibit a distinct safety profile. The aim of the COMPONENT study was to assess the efficacy, safety, and pharmacokinetics of vidofludimus in the treatment of patients with active RA on a background therapy of methotrexate. This report focuses solely on the safety results of the COMPONENT trial. Patients received once-daily oral vidofludimus (N = 122) or placebo (N = 119) along with their standard of care methotrexate treatment for 13 weeks. Efficacy endpoints were assessed. Safety parameters were monitored throughout treatment and at follow-up. Plasma concentrations of vidofludimus were measured. The primary efficacy endpoint, American College of Rheumatology 20 (ACR20) responder rate at 13 weeks, demonstrated numerical superiority in the treatment group compared with placebo; however, it did not reach statistical significance. Nonetheless, the COMPONENT study yielded important safety and pharmacokinetic data that could provide important information regarding the use of vidofludimus in other clinical trials, not only for RA but also for other autoimmune diseases. A safety profile for vidofludimus similar to placebo was obtained in this RA patient population. This includes similar rates of the adverse events of diarrhea, alopecia, neutropenia, and elevated liver enzymes, all of which are known drug-related adverse events reported for leflunomide and teriflunomide. A potential pharmacokinetic interaction between vidofludimus and methotrexate was observed. Vidofludimus demonstrated a positive safety profile, making it a promising candidate for the treatment of a variety of immune-related diseases. ClinicalTrials.gov identifier: NCT01010581.


Usefulness of the hyperventilation test in stable exertional angina pectoris in selecting medical therapy.
To assess the prevalence of abnormal coronary vasoconstriction in stable exertional angina and to evaluate whether the presence of increased coronary tone may have therapeutic implications, we studied 83 consecutive patients with typical exertional angina, positive response to exercise stress testing and documented coronary artery disease. Abnormal coronary vasoconstriction was induced by a hyperventilation test in 16 patients (group I) while the remaining 67 had a negative response (group II). No differences were observed between the 2 groups with regard to clinical, exercise and angiographic data. All group I patients and 16 patients in group II repeated hyperventilation and exercise tests after the administration of dihydropyridine-type calcium antagonists (7 patients nifedipine, 9 patients felodipine). After treatment 15 of 16 group I patients had a negative response to the hyperventilation test. The total exercise duration was significantly increased (278 +/- 183 vs 554 +/- 248 seconds; p less than 0.001) with higher values of rate pressure product at peak exercise (168 +/- 47 vs 235 +/- 67 mm Hg x beats/min/100; p less than 0.0025). In group II no significant differences were observed between pre- and posttreatment values for total exercise duration (244 +/- 210 vs 308 +/- 243 seconds) and rate pressure product at peak exercise (170 +/- 46 vs 188 +/- 56 mm Hg x beats/min/100). These data show that the hyperventilation test can be used to select a subset of patients with stable exertional angina and detectable abnormal coronary vasoconstriction who will improve their exercise tolerance with coronary vasodilator treatment.


Pharmacokinetic variability of long-acting stimulants in the treatment of children and adults with attention-deficit hyperactivity disorder.
Methylphenidate- and amfetamine-based stimulants are first-line pharmacotherapies for attention-deficit hyperactivity disorder, a common neurobehavioural disorder in children and adults. A number of long-acting stimulant formulations have been developed with the aim of providing once-daily dosing, employing various means to extend duration of action, including a transdermal delivery system, an osmotic-release oral system, capsules with a mixture of immediate- and delayed-release beads, and prodrug technology. Coefficients of variance of pharmacokinetic measures can estimate the levels of pharmacokinetic variability based on the measurable variance between different individuals receiving the same dose of stimulant (interindividual variability) and within the same individual over multiple administrations (intraindividual variability). Differences in formulation clearly impact pharmacokinetic profiles. Many medications exhibit wide interindividual variability in clinical response. Stimulants with low levels of inter- and intraindividual variability may be better suited to provide consistent levels of medication to patients. The pharmacokinetic profile of stimulants using pH-dependent bead technology can vary depending on food consumption or concomitant administration of medications that alter gastric pH. While delivery of methylphenidate with the transdermal delivery system would be unaffected by gastrointestinal factors, intersubject variability is nonetheless substantial. Unlike the beaded formulations and, to some extent (when considering total exposure) the osmotic-release formulation, systemic exposure to amfetamine with the prodrug stimulant lisdexamfetamine dimesylate appears largely unaffected by such factors, likely owing to its dependence on systemic enzymatic cleavage of the precursor molecule, which occurs primarily in the blood involving red blood cells. The high capacity but as yet unidentified enzymatic system for conversion of lisdexamfetamine dimesylate may contribute to its consistent pharmacokinetic profile. The reasons underlying observed differential responses to stimulants are likely to be multifactorial, including pharmacodynamic factors. While the use of stimulants with low inter- and intrapatient pharmacokinetic variability does not obviate the need to titrate stimulant doses, stimulants with low intraindividual variation in pharmacokinetic parameters may reduce the likelihood of patients falling into subtherapeutic drug concentrations or reaching drug concentrations at which the risk of adverse events increases. As such, clinicians are urged both to adjust stimulant doses based on therapeutic response and the risk for adverse events and to monitor patients for potential causes of pharmacokinetic variability.


In Acute Dengue Infection, High TIM-3 Expression May Contribute to the Impairment of IFNγ Production by Circulating Vδ2 T Cells.
γδ T cells are innate cells able to quickly eliminate pathogens or infected/tumoral cells by their antiviral and adjuvancy activities. The role of γδ T cells during Dengue Viral Infection (DENV) infection is not fully elucidated. Nevertheless, human primary γδ T cells have been shown to kill in vitro DENV-infected cells, thus highlighting their possible antiviral function. The aim of this work was to characterize the phenotype and function of Vδ2 T cells in DENV patients. Fifteen DENV patients were enrolled for this study and peripheral blood mononuclear cells (PBMC) were used to analyze Vδ2-T-cell frequency, differentiation profile, activation/exhaustion status, and functionality by multiparametric flow cytometry. Our data demonstrated that DENV infection was able to significantly reduce Vδ2-T-cell frequency and to increase their activation (CD38 and HLA-DR) and exhaustion markers (PD-1 and TIM-3). Furthermore, Vδ2 T cells showed a reduced capability to produce IFN-γ after phosphoantigenic stimulation that can be associated to TIM-3 expression. Several studies are needed to depict the possible clinical impact of γδ-T-cell impairment on disease severity and to define the antiviral and immunoregulatory activities of γδ T cells in the first phases of infection.


Phosphatidylserine synthase from bacteria.
This review summarizes the characteristics of two subclasses of phosphatidylserine synthases: subclass I of gram-negative bacteria and subclass II of gram-positive bacteria. Unlike other phospholipid biosynthetic enzymes, the phosphatidylserine synthases of gram-negative bacteria, the enzyme from Escherichia coli has been extensively examined and characterized, are associated with the ribosomal fraction of cell lysates. Enzymes from gram-positive bacteria are membrane-bound, and the structural gene of membrane-bound synthase of Bacillus subtilis has been cloned and used in our laboratory for replacement with the E. coli counterpart. This review discusses the possible regulatory mechanisms of phosphatidylethanolamine synthesis in E. coli, which are closely related to the subcellular localization and properties of phosphatidylserine synthase, and highlights the cross-feedback regulatory model which assumes two forms of phosphatidylserine synthase (only molecules bound with acidic phospholipids of the membrane are active in phosphatidylserine synthesis, whereas others in the cytoplasm are latent). In addition, considerations of the origin and evolution of the two vastly different subclasses of phosphatidylserine synthases of bacteria are also presented.


Outcome of bone marrow transplantation in acquired and inherited aplastic anaemia in the Republic of Ireland.
Severe Aplastic Anaemia (SAA) and Fanconi Anaemia (FA) are rare haematological disorders characterised by pancytopenia and bone marrow hypoplasia. We performed a retrospective study of all patients who underwent BMT for SAA and FA at St James's Hospital, Dublin, and at OLHSC, Crumlin, between 1985 and 2002. The medical records of 63 patients, 50 with acquired SAA and 13 with FA, were reviewed. The median age at the time of transplant was 14 years (range 3-43 years). The actuarial survival (OS) (n = 63) was 76% at 17 years. The transplant related mortality (TRM) was 22% (n = 14). The most common cause of death was infection (46%). The survival was significantly better in patients receiving their transplant after 1995 (p = 0.002). Outcome was superior in those receiving less than 20 red cell transfusions prior to transplant: OS 91% (< 20 Units) versus 62% (> or = 20 Units). These national results are comparable to those of published international series and support the use of BMT in the treatment of SAA and FA. The known adverse effect of prior transfusion was confirmed.


Studies on the inhibition of α-glucosidase by biflavonoids and their interaction mechanisms.
Biflavonoids are a kind of polyphenol compounds with numerous biological functions. However, the potential inhibitory activities of biflavonoids on α-glucosidase are yet unknown. Here, the inhibitory effects of two biflavonoids (amentoflavone and hinokiflavone) on α-glucosidase and their interaction mechanisms were explored using multispectral approaches and molecular docking. The results showed that the inhibitory activities of biflavonoids were much better compared with monoflavonoid (apigenin) and acarbose, and the order of inhibition ability was hinokiflavone > amentoflavone > apigenin > acarbose. These flavonoids were noncompetitive inhibitors of α-glucosidase and showed synergistic inhibition effects with acarbose. Additionally, they could statically quench the intrinsic fluorescence of α-glucosidase, and form the non-covalent complexes with enzyme primarily through hydrogen bonds and van der Waals forces. The binding of flavonoids changed the conformational structure of α-glucosidase, therefore impairing the enzyme activity. The findings suggested that biflavonoids could be considered as potential hypoglycemic functional foods in diabetes therapy.


Varying levels of protection against Plasmodium falciparium infection were conferred on non-users of long lasting insecticidal nets (LLINS) sleeping in rooms where different number of LLINS were hung in hyper endemic state of West Africa.
The use of Long Lasting Insecticidal Nets (LLINs) has greatly reduced the health and economic impact posed by malaria. This study evaluated the residual effect of LLINs on malaria parasite infections among non-LLIN users sleeping in rooms where nets were hung. This study was carried out at Federal University of Agriculture Abeokuta, Ogun State, Nigeria. A total of 259 students were systematically recruited into this study and were classified into two groups of LLINs users and non-users. The LLIN users were further classified according to the proportion of net usage and this includes; < 50%, exactly 50% and > 50% respectively. Finger prick blood samples were collected from the participants and microscopically analysed for the presence of parasites. Demographic characteristics were also recorded. A general prevalence of 40.5% positivity for malaria was recorded among the study population. A significantly high prevalence (p < 0.05) of malaria was recorded among non-users of LLINs compared to users (AOR 4.66, 95%CI 1.27-17.06). A significantly low prevalence of malaria parasite infection was recorded among non-users of LLINs occupying rooms where LLINs was hung compared with non-users from rooms where LLIN were not used. Furthermore, a reduction in prevalence of malaria and parasite densities was observed among non-users of LLINs (occupying rooms where LLINs was hung) as the proportion of LLIN usage increased in such rooms (p < 0.05). This study showed that some level of protection may be conferred on non-users of LLINs staying in rooms where LLINs are hung.


Cigarette Smoking, Alcohol Consumption and Overweight in Multiple Sclerosis: Disability Progression.
The rate at which disability progresses in multiple sclerosis (MS), and its severity, have been associated with modifiable lifestyle habits. To investigate the risk of disability progression in MS patients according to tobacco and alcohol consumption and to the presence of overweight. This was a follow-up of MS cases from a concluded case-control study (National Institute of Neurology and Neurosurgery, Mexico 2010-2013). The evolution in EDSS (Expanded Disability Scale Score) units was followed through a medical record review. Kaplan Meier statistics and multivariate Cox regression analysis were performed. Of 181 cases, 63.5% were women and 82.5% had relapsing remitting MS. Study duration was 19.95 ± 15.24 months. The disease progressed faster in daily smokers than in non-smokers (p = 0.0168). In overweight patients, disability progressed faster than in normal weight patients (p = 0.0249). Ex-consumers of alcohol had lower risk of progression than current consumers (HR = 0.33 CI 95% = 0.14-0.83, p = 0.019) and both daily and ex-smokers presented higher risk of progression than non-smokers (HR = 2.32 CI 95% = 1.14-4.72, p = 0.020 and HR = 3.56, CI 95% = 1.21-10.46, p = 0.021). Stratifying by gender, the effects of smoking and overweight were only found in men. Smoking is associated with rapid disability progression in MS. Our results suggest that cessation of tobacco and alcohol consumption could be clinically beneficial. Although there is association between overweight and disability progression in men, a further exploration of gender differences is necessary to corroborate this finding.


Insulin sensitivity of adipose tissue in vitro and the response to exogenous insulin in obese human subjects.
The effect of varying concentrations of insulin on 1-14C-glucose conversion to 14CO2 was measured in subcutaneous adipose tissue samples obtained from 16 obese human subjects (10 nondiabetic, 6 diabetic). An index of insulin sensitivity in vitro, Kins, was calculated as the concentration of insulin stimulating one-half maximal 14CO2 production. An index of insulin sensitivity in vivo, Kitt, was calculated as the rate constant for decrease in blood glucose after rapid intravenous administration of 0.05 U/kg insulin. There was, over-all, a significant correlation between Kins and Kitt, indicating that insulin sensitivity of 1-14C-glucose oxidation by adipose tissue in vitro reflects the general state of sensitivity of glucose metabolism to insulin in vivo in obese human subjects. The mean values for both Kins and Kitt in the nondiabetic subjects were significantly different from those in the diabetic subjects, indicating greater sensitivity to insulin in the former group. The nondiabetic group was also distinguished by a significantly greater plasma insulin:blood glucose ratio in the oral glucose tolerance test. These results support the view that tissue insulin sensitivity as well as pancreatic beta cell response play an important role in determining glucose tolerance in obesity.


Aflatoxin B1 promotes autophagy associated with oxidative stress-related PI3K/AKT/mTOR signaling pathway in mice testis.
Aflatoxin B1 (AFB1) is a hazard environmental pollutants and the most toxic one of all the aflatoxins. AFB1 can cause a serious impairment to testicular development and spermatogenesis, yet the underlying mechanisms remain inconclusive. Oxidative stress acts as a master mechanism of AFB1 toxicity, and can promote autophagy. Abnormal autophagy resulted in testicular damage and spermatogenesis disorders. The objective of this study was to explore the effect of AFB1 on autophagy in mice testis and its potential mechanisms. In this study, male mice were intragastrically administered with 0, 0.375, 0.75 or 1.5 mg/kg body weight AFB1 for 30 days. We found that AFB1 induced testicular damage, reduced serum testosterone level and impaired sperm quality accompanied with the elevation of oxidative stress and germ cell apoptosis. Interestingly, we observed increasing numbers of autophagosomes in AFB1-exposed mice testis. Meanwhile, AFB1 caused testis abnormal autophagy with the characterization of increased expressions of LC3, Beclin-1, Atg5 and p62. Furthermore, AFB1 downregulated the expressions of PI3K, p-AKT and p-mTOR in mice testis. Taken together, our data indicated AFB1 induced testicular damage and promoted autophagy, which were associated with oxidative stress-related PI3K/AKT/mTOR signaling pathway in mice testis.


Quality of life in patients with heart failure: ask the patients.
Heart failure (HF) is a progressive clinical condition that results in substantial impairment of quality of life (QOL). Helping patients maintain optimal QOL is essential. QOL reflects patients' subjective perceptions about the impact of a clinical condition and its treatment on daily life; however, definitions in the literature vary widely and few reflect the patient's perspective. The study explored how patients with HF define and perceive QOL. Qualitative data were obtained from 14 men and 6 women with HF (mean age 58 +/- 10 years) using semistructured open-ended interviews. The interviews were analyzed using content analysis. Patients with HF defined QOL as their ability to 1) perform desired physical and social activities to meet their and their family's needs; 2) maintain happiness; and 3) engage in fulfilling relationships with others. Patients perceived a variety of factors as positively or negatively affecting QOL: physical (symptoms and good or poor physical status), psychologic (mood and positive or negative perspective), economic (financial status), social (social support and ability for social activities), spiritual, and behavioral (self-care). Patients perceived that HF had a serious impact on QOL, but most evaluated their QOL as good nonetheless. Patients' definition of QOL reflected not only the impact of HF on their daily life but also their active pursuit of happiness. Patients' self-evaluation of QOL reflected the negative impact of HF and patients' altered expectations of what constituted good QOL.


Model carcinogen adsorption dynamics of DNA gel.
We have derived theoretical equations describing the adsorption of carcinogen to gels in an immersion medium containing carcinogens. The theory was developed for a cylindrical boundary condition under the assumption of a carcinogen diffusion-limited process combined with the "moving boundary picture (Furusawa et al., 2007)". The time course of the adsorbed carcinogen layer thickness and that of the carcinogen concentration in an immersion medium were expressed by a set of scaled variables, and the asymptotic behavior in the initial stage was derived. Experiments based on the theory were performed using a DNA gel sandwiched between a set of coverglasses in a medium containing acridine orange (AO). The boundary between the AO-adsorbed gel layer and AO-nonadsorbed gel layer was traced during the immersion. The time courses of the AO-adsorbed gel layer thickness and the AO concentration in the immersion medium were well explained by the theory, and the number ratio of the total AO molecules to the adsorption sites in the DNA gel was determined.


Electrocardiographic effects of rivastigmine.
The electrocardiographic (ECG) effects of rivastigmine treatment were assessed in mild to moderately severe Alzheimer's disease (AD) by analysis of four 26-week, double-blind, multicenter, placebo-controlled, phase III clinical trials. Of an initial 2791 patients, 77% completed treatment. Seventy-one percent required at least one concomitant medication for conditions other than AD, with 34% requiring cardiovascular medications. Safety assessments included ECGs, adverse events, vital signs, and clinical laboratory parameters. Pooled 12-lead ECG data were analyzed by an independent cardiologist blinded to treatment group and clinical information. Heart rate, PR, QRS, and QTc intervals did not differ significantly between treatment and placebo groups. Percentage change from baseline for PR, QRS, and QTc intervals was also no different. In conclusion, rivastigmine appears not to produce adverse effects on cardiac function assessed by ECG.


Comparing costs and health care resource utilization between nmHSPC and mHSPC patients: a retrospective claims analysis.
BACKGROUND: Prostate cancer is common among men in the United States, and hormone sensitive-prostate cancer (HSPC) is the predominant etiology. However, there is a paucity of evidence documenting the financial impact of metastatic disease within this etiology. OBJECTIVE: To estimate the differences in health care resource utilization (HCRU) and costs for patients with nonmetastatic HSPC (nmHSPC) and metastatic HSPC (mHSPC) and their payers. METHODS: We conducted a retrospective cohort analysis using claims data from the IBM MarketScan databases from January 2016 to December 2019. HSPC was defined as having at least 1 inpatient services or 2 outpatient services claims with a prostate cancer diagnosis and a claim for androgen deprivation therapy use within 6 months of the initial diagnostic claim. Metastatic patients had a secondary diagnosis code of metastasis with their initial diagnostic claim. We compared mean 12-month HCRU, patient out-of-pocket (OOP), and payer costs between patients with nmHSPC and mHSPC using multivariable linear regression. RESULTS: 4,329 patients met the study inclusion criteria, 600 of which had mHSPC. Patients with mHSPC had more outpatient prescription fills (10.91 additional fills; 95% CI = 8.09-13.99) and outpatient services visits (10.61 additional visits; 95% CI = 8.38-13.04) but similar other HCRU. The overall 12-month costs of patients with mHSPC were significantly greater than patients with nmHSPC for patient OOP ($1,244; 95% CI = $1,004-$1,513) and payers ($113,725; 95% CI = $91,494-$141,127). CONCLUSIONS: Compared with patients with nmHSPC, individuals with mHSPC incur greater HCRU and significant personal and overall financial burden. DISCLOSURES: This study had no outside funding support. The authors have nothing to disclose.


Genetic code expansion and photocross-linking identify different β-arrestin binding modes to the angiotensin II type 1 receptor.
The angiotensin II (AngII) type 1 receptor (AT1R) is a member of the G protein-coupled receptor (GPCR) family and binds β-arrestins (β-arrs), which regulate AT1R signaling and trafficking. These processes can be biased by different ligands or mutations in the AGTR1 gene. As for many GPCRs, the exact details for AT1R-β-arr interactions driven by AngII or β-arr-biased ligands remain largely unknown. Here, we used the amber-suppression technology to site-specifically introduce the unnatural amino acid (UAA) p-azido-l-phenylalanine (azF) into the intracellular loops (ICLs) and the C-tail of AT1R. Our goal was to generate competent photoreactive receptors that can be cross-linked to β-arrs in cells. We performed UV-mediated photolysis of 25 different azF-labeled AT1Rs to cross-link β-arr1 to AngII-bound receptors, enabling us to map important contact sites in the C-tail and in the ICL2 and ICL3 of the receptor. The extent of AT1R-β-arr1 cross-linking among azF-labeled receptors differed, revealing variability in β-arr's contact mode with the different AT1R domains. Moreover, the signature of ligated AT1R-β-arr complexes from a subset of azF-labeled receptors also differed between AngII and β-arr-biased ligand stimulation of receptors and between azF-labeled AT1R bearing and that lacking a bias signaling mutation. These observations further implied distinct interaction modalities of the AT1R-β-arr1 complex in biased signaling conditions. Our findings demonstrate that this photocross-linking approach is useful for understanding GPCR-β-arr complexes in different activation states and could be extended to study other protein-protein interactions in cells.


Effects of heat, cold, acid and bile salt adaptations on the stress tolerance and protein expression of kefir-isolated probiotic Lactobacillus kefiranofaciens M1.
Lactobacillus kefiranofaciens M1 is a probiotic strain isolated from Taiwanese kefir grains. The present study evaluated the effects of heat, cold, acid and bile salt adaptations on the stress tolerance of L. kefiranofaciens M1. The regulation of protein expression of L. kefiranofaciens M1 under these adaptation conditions was also investigated. The results showed that adaptation of L. kefiranofaciens M1 to heat, cold, acid and bile salts induced homologous tolerance and cross-protection against heterologous challenge. The extent of induced tolerance varied depending on the type and condition of stress. Proteomic analysis revealed that 27 proteins exhibited differences in expression between non-adapted and stress-adapted L. kefiranofaciens M1 cells. Among these proteins, three proteins involved in carbohydrate metabolism (triosephosphate isomerase, enolase and NAD-dependent glycerol-3-phosphate dehydrogenase), two proteins involved in pH homeostasis (ATP synthase subunits AtpA and AtpB), two stress response proteins (chaperones DnaK and GroEL) and one translation-related protein (30S ribosomal protein S2) were up-regulated by three of the four adaptation treatments examined. The increased synthesis of these stress proteins might play a critical protective role in the cellular defense against heat, cold, acid and bile salt stresses.


Preparation of SERS active filter paper for filtration and detection of pesticides residue from complex sample.
The selectivity is needed mostly in SERS sensing because analytes of interest are commonly present in a complex mixture containing particles and impurities, which hinder the interactions between the laser and analyte being detected. In this manuscript, we describe our efforts developing a simple and instant. method to prepare a filter paper SERS sensor. Colloidal Ag nanoparticles were immobilized on one side of filter paper via an in-situ growth method. The fabrication process of the sensor could be finished in several minutes, and no special facility needed. The filter paper SERS sensor demonstrated a spectra uniformity with a 7.0 % point-by-point signal deviation. And the filter function of the sensor could effectively filter out interferences from samples in 1 min, that allowing the direct detection of thiram in ketchup by SERS with detection limit of 93 ppb. Furthermore, we used a Quick Easy Cheap Effective Rugged and Safe (QuEChERS) sample preparation method to detect malachite green (MG) in soil with a sensitivity as low as 0.01 ppm without any sample pre-treatment or purification. A SERS filter paper may open a new avenue for rapid testing of food quality during manufacturing as well as fast detection of potential contaminants in a myriad of substrates.


Does spasticity affect the postural stability and quality of life of children with cerebral palsy?
Cerebral palsy is a unique physical disability that primarily affects children's gross motor functions and postural control. Cerebral palsy has a direct impact on children's daily activities and quality of life. This study aims to determine the relationship between spasticity, motor function, postural stability, and the quality life of children with cerebral palsy. Forty-five children (age range 4-6 years) diagnosed with spasticity from cerebral palsy participated in this study. Spasticity was evaluated by the modified Ashwarth scale; the children's functions were evaluated by gross motor functional measures, postural stability was evaluated by biodex balance system, and quality of life was measured with the pediatric quality of life inventory. There was a strong positive correlation between the degree of spasticity and quality of life. Additionally, there was a significantly strong association between spasticity and gross motor function. In contrast, there was no correlation between spasticity and postural stability indices. Moreover, there was a strong positive correlation between quality of life and gross motor function. Lastly, there was no association between quality of life and the postural stability index. The findings highlight the impact of spasticity on motor function and the quality of life of a cohort of children with cerebral palsy. These findings may determine therapeutic interventions and priorities to plan physical therapy programs. Such measures may overcome the main cause of disorders that delay and undermine the daily routines of the affected children.


Tip60-mediated acetylation activates transcription independent apoptotic activity of Abl.
The proto-oncogene, c-Abl encodes a ubiquitously expressed tyrosine kinase that critically governs the cell death response induced by genotoxic agents such as ionizing radiation and cisplatin. The catalytic function of Abl, which is essential for executing DNA damage response (DDR), is normally tightly regulated but upregulated several folds upon IR exposure due to ATM-mediated phosphorylation on S465. However, the mechanism/s leading to activation of Abl's apoptotic activity is currently unknown. We investigated the role of acetyl modification in regulating apoptotic activity of Abl and the results showed that DNA strand break-inducing agents, ionizing radiation and bleomycin induced Abl acetylation. Using mass spectrophotometry and site-specific acetyl antibody, we identified Abl K921, located in the DNA binding domain, and conforming to one of the lysine residue in the consensus acetylation motif (KXXK--X3-5--SGS) is acetylated following DNA damage. We further observed that the S465 phosphorylated Abl is acetyl modified during DNA damage. Signifying the modification, cells expressing the non acetylatable K921R mutant displayed attenuated apoptosis compared to wild-type in response to IR or bleomycin treatment. WT-Abl induced apoptosis irrespective of new protein synthesis. Furthermore, upon γ-irradiation K921R-Abl displayed reduced chromatin binding compared to wild type. Finally, loss of Abl K921 acetylation in Tip60-knocked down cells and co-precipitation of Abl with Tip60 in DNA damaged cells identified Tip60 as an Abl acetylase. Collective data showed that DNA damage-induced K921 Abl acetylation, mediated by Tip60, stimulates transcriptional-independent apoptotic activity and chromatin-associative property thereby defining a new regulatory mechanism governing Abl's DDR function.


Use of the DBD-FISH technique for detecting DNA breakage in response to high doses of X-rays.
The aim of this study was to generate a dose-response curve using the DNA breakage detection-fluorescent in situ hybridization (DBD-FISH) test as a biomarker of initial genetic effects induced by high doses of X-rays. A dose-response curve was obtained by measuring the ex vivo responses to increasing doses (0-50 Gy) of X-rays in the peripheral blood lymphocytes of ten healthy donors. The overall dose-response curve was constructed using integrated density (ID; area × fluorescence intensity) as a measure of genetic damage induced by irradiation. The correlation coefficient was high (r = 0.934, b(0) = 10.408, and b(1) = 0.094). One-way ANOVA with the Student-Newman-Keuls test for multiple comparisons showed significant differences among the average ln ID values according to dose. Our results suggest the usefulness of the DBD-FISH technique for measuring intrinsic individual cellular radio sensitivity ex vivo.


Extra-Fortification of Zinc Upsets Vitellogenin Gene Expression and Antioxidant Status in Female of Clarias magur brooders.
The present experiment was designed to evaluate the effect of graded level of zinc on Vitellogenin gene (Vtg) expression and antioxidant enzymes in threatened catfish, Clarias magur (C. magur). One hundred and eighty female C. magur with an average weight of 145 ± 5 g were allocated in twelve cemented tanks with dimension 4.5 × 2 × 1 m for a period of 60 days. Fish were distributed in four groups with three replicates following the completely randomised design. The first group treated as control (C) fed with basal diet contained normal zinc level, and remaining groups were fed with basal diets having 50, 200 and 300 mg/kg zinc acetate and treated as T1, T2 and T3 respectively. To evaluate the effect of dietary zinc supplementation on Vtg gene expression, three sampling were carried out, I sampling (April, before starting the experimental trail), II sampling (May, after 1 month of feeding trail) and III sampling (June before breeding season). In the present study, a dose-dependent relationship between Vtg gene expression and zinc inclusion in the diet of threatened catfish, C. magur, was reported. Vtg gene expression increased in all groups from I sampling to II sampling but the highest Vtg gene expression was found in T1 group and the lowest in T3 group at II sampling. Vtg gene expression among the treatments differs significantly (P < 0.05) in each sampling. Accumulation of zinc was measured by Inductively Coupled Plasma Atomic Emission Spectroscopy (ICP-AES) in C. magur and it was reported that the significantly higher (P < 0.05) zinc was accumulated in the liver and ovary of T3 group as compared to other groups. The antioxidant enzyme activities (superoxide dismutase, SOD, catalase and GST) were also measured in different tissues (liver, gill and ovary) to evaluate the effect of extra-supplementation of zinc on the antioxidant status. In T3 group, SOD, catalase and GST activities were significantly higher than those in other groups. In the current study, serum glucose level was also measured and it was found in increasing trend with inclusion of zinc in the diet of C. magur. In the present study, it can be concluded that the zinc exhibits beneficial effect only up to 50 mg/kg. Thus, it is concluded that supplementation of zinc at 200 mg/kg or more disrupts Vtg gene expression and antioxidant status.


Butyribacter intestini gen. nov., sp. nov., a butyric acid-producing bacterium of the family Lachnospiraceae isolated from human faeces, and reclassification of Acetivibrio ethanolgignens as Acetanaerobacter ethanolgignens gen. nov., comb. nov.
A novel, non-motile, Gram-stain-positive, non-spore-forming, obligate anaerobic bacterium, designated strain TF01-11T, was isolated from human faeces. The isolate was characterized by phylogenetic and phenotypic properties, as well as by determination of its whole genome sequence. The growth temperature and pH ranges were 30-42 °C and 6.0-8.5, respectively. The end products of glucose fermentation were butyric acid and a small amount of acetic acid. The genome was estimated to be 3.61 Mbp with G + C content of 36.8 mol%. Genes related to biosynthesis of diaminopimelic acid, polar lipids, polyamines, teichoic and lipoteichoic acids were present. The predominant fatty acids were C16:0 (37.9%), C14:0 (16.4%), C13:0 OH/iso-C15:1H (11.1%) and C18:1ω9c (10.6%). Phylogenetic analyses based on 16S rRNA gene sequences demonstrated that the isolate was a member of family Lachnospiraceae, with the highest sequence similarity to the type strain of Roseburia intestinalis DSM 14610T (92.2%), followed by Acetivibrio ethanolgignens ATCC 33324T (92.0%). The average nucleotide identity (ANI) and average amino acid identity (AAI) values between strain TF01-11T and these closest relatives were less than 70.5% and 52.3%. Based on results of phenotypic characteristics and genotypic properties presented in this study, strain TF01-11T represents a novel species in a new genus, for which the name Butyribacter intestini gen. nov., sp. nov. is proposed. The type strain of the type species is TF01-11T (CGMCC 1.5203T = DSM 105140T). In addition, Acetivibrio ethanolgignens is proposed to be reclassified as Acetanaerobacter ethanolgignens gen. nov., comb. nov.


Cerebral microvessels and derived cells in tissue culture: II. Establishment, identification, and preliminary characterization of an endothelial cell line.
An endothelial cell line has been established from a primary culture of cerebral microvessels isolated from Swiss-Webster mice. The microvessels were isolated by a mechanical dispersion and filtration technique. The cells that emerged from these microvessels, maintained in organoid cultures, proliferated and formed plaques of a single or mixed cell type. The endothelial cell line, designated ME-2, was isolated from one such morphologically homogeneous cell plaque, using both cloning ring techniques and C6 glioma-conditioned medium. An endothelial specific antiserum was made in rabbits and was used immunocytochemically to confirm the cell type of origin of the ME-2 cell line. Not only did the cell type specific antiserum react exclusively with endothelial cells in vivo, but in the brain the antiserum localized preferentially to the luminal membrane of the endothelium. The ME-2 endothelial cells have retained several of their unique properties such as cytomorphology, growth characteristics, and cell type specific surface antigens throughout the life of the line (in one case 40 passages before senescence).


Growth activity of tumors at different intracranial structures: immunohistochemical study with bromodeoxyuridine.
To elucidate the environmental influence on the growth of a tumor, bromodeoxyuridine (BrdU) uptake in multiple tumor foci within the intracranial cavity was studied immunohistochemically with a monoclonal antibody. Walker 256 tumor implanted intracerebrally produced multifocal tumors presented as intraparenchymal solid tumor, tumor in the choroid plexus, and leptomeningeal dissemination. The BrdU-labeling indices, or the S-phase fractions (% of nuclei labeled by BrdU divided by the number of tumor cell nuclei scored; LI), of those tumors were 48.4 +/- 1.1, 59.1 +/- 1.3, and 27.9 +/- 5.9, respectively (mean +/- SEM). These differences in LI, or the tumor growth activity, are discussed in relation to the different environmental conditions in different host structures. These host structure-related modification of tumor growth would be important in evaluating the proliferative activity of tumors growing at various intracranial structures.


Nonlinear relationship between visceral adiposity index and lung function: a population-based study.
As one of the critical indicators of obesity, the interaction between visceral fat content and lung disease is the focus of current research. However, the exact relationship between Visceral adipose index (VAI) and lung function is not fully understood. The purpose of this study was to evaluate the relationship between VAI and lung function, METHODS: Our study included all participants from the baseline survey population in Xinjiang in the Natural Population Cohort Study in Northwest China. A field survey was conducted in rural areas of Moyu County, Xinjiang, China, between 35 and 74 years old from June to December 2018. We collected standard questionnaires and completed physical examinations, visceral fat tests, and lung function measurements. The study included 2367 participants with a mean VAI of 10.35 ± 4.35, with males having a significantly higher VAI than females: 13.17 ± 3.91 vs. 7.58 ± 2.65. The piecewise linear spline models indicated a significant threshold effect between lung function and VAI in the general population and the males population, showing an inverted U-shaped curve. But there was no significant association between VAI and lung function in females. FEV1% predicted and FVC% predicted increased with the increase of VAI (β 0.76; 95% CI 0.30, 1.21) and (β 0.50; 95% CI 0.06, 0.94) in males with VAI ≤ 14, while FEV1% predicted and FVC% predicted decreased with the increase of VAI (β - 1.17; 95% CI - 1.90, - 0.45) and (β - 1.36; 95% CI - 2.08, - 0.64) in males with VAI ≥ 15. The relationship between lung function and VAI in male participants showed an inverted U-shaped curve, with the turning point of VAI between 14 and 15. The association between visceral fat and lung function was more robust in males than in females.


Evaluation of gastro-oesophageal reflux disease in wheezy infants using 24-h oesophageal combined impedance and pH monitoring.
Gastro-oesophageal reflux disease (GERD) is incriminated as a cause of non-asthmatic infantile wheeze. To date, no diagnostic test is considered standard for GERD-related airway reflux diagnosis. Oesophageal combined multiple channel intraluminal impedance and pH (MII-pH) monitoring is proposed to be a sensitive tool for evaluation of all GERD including infantile wheeze. We aimed to determine the GERD prevalence amongst wheezy infants in the first year of life using combined MII-pH versus pH monitoring alone and evaluate the sensitivity and specificity of objective MII-pH monitoring parameters in GERD-associated infantile wheeze diagnosis compared to those of lipid-laden macrophage index (LLMI). Thirty-eight wheezy infants below 1year of age were evaluated for GERD using oesophageal combined MII-pH monitoring and LLMI. Totally, 60.5% of cases had abnormal MII-pH; only 7.9% of them had abnormal pH monitoring. LLMI was significantly higher in wheezy infants with abnormal MII-pH than infants with normal MII-pH monitoring (112±88 versus 70±48; P=0.036). The current definitions of abnormal MII-pH study, reflux index≥10% and distal reflux episodes≥100, had low sensitivity (23%) but high specificity (100% and 96%, respectively) in GERD-related aspiration diagnosis defined by LLMI≥100. Using ROC curves, bolus contact time≥2.4% and proximal reflux episodes≥46 had 61% and 54% sensitivity and 64% and 76% specificity, respectively, in GERD-related aspiration diagnosis. Combined MII-pH is superior to pH monitoring in reflux-associated infantile wheeze diagnosis. Objective data including proximal reflux episodes and bolus contact time should be combined with the current parameters used in reflux-associated infantile wheeze diagnosis.


Morphological colour adaptation during development in fish: involvement of growth hormone receptor 1.
Morphological background adaptation is both an endocrine and a nervous response, involving changes in the amount of chromatophores and pigment concentration. However, whether this adaptation takes place at early developmental stages is largely unknown. Somatolactin (Sl) is a pituitary hormone present in fish, which has been associated to skin pigmentation. Moreover, growth hormone receptor type 1 (Ghr1) has been suggested to be the Sl receptor and was associated with background adaptation in adults. In this context, the aim of this work was to evaluate the ontogeny of morphological adaptation to background and the participation of ghr1 in this process. We found in larval stages of the cichlid Cichlasoma dimerus that the number of head melanophores and pituitary cells immunoreactive to Sl was increased in individuals reared with black backgrounds compared with that in fish grown in white tanks. In larval stages of the medaka Oryzias latipes, a similar response was observed, which was altered by ghr1 biallelic mutations using CRISPR/Cas9. Interestingly, melanophore and leucophore numbers were highly associated. Furthermore, we found that somatic growth was reduced in ghr1 biallelic mutant O. latipes, establishing the dual function of this growth hormone receptor. Taken together, these results show that morphological background adaptation is present at early stages during development and that is dependent upon ghr1 during this period.


The Psychological and HRQoL related Aftermaths of Extra Corporeal Membrane Oxygenation Treatment: A Cross-Sectional Study.
To assess symptoms of post-traumatic stress disorder, anxiety, depression and health related quality of life in a sample of adult patients treated with veno-arterial extracorporeal membrane oxygenation. This is a cross-sectional study. The population were all patients discharged (2008-2018) from a thoracic surgical intensive ward at a tertiary university hospital in Norway. A sample of 20 patients was recruited. Symptoms of post-traumatic stress disorder were assessed using Impact of Events Scale-Revised, while symptoms of depression and anxiety were assessed using Hospital Anxiety and Depression Scale. RAND 36-Item Short Form Health Survey was applied to measure health-related quality of life. Symptoms of post-traumatic stress disorder were reported by 40% of the participants. Twenty percent reported symptoms of depression and anxiety. Compared to the general population, participants reported poorer health-related quality of life on all domains, and significantly worse on the domains physical function, general health and social function. Patients in our study reported symptoms of post-traumatic stress disorder, anxiety, depression and impaired health-related quality of life following treatment with veno-arterial extra corporeal membrane oxygenation. Addressing possible emotional and psychological distress could represent a potential major improvement in health care provided to this group. Further research is needed to incorporate prophylactic methods, such as identifying vulnerable patients and implement corresponding interventions, into clinical practice.


Awareness of and subjective needs for post-discharge healthcare services among older adult patients.
Increasing patient awareness of post-discharge care resources is an effective strategy to reduce rehospitalization rates and medical costs. Therefore, the purpose of this study was to explore hospitalized older adult patients' awareness of and subjective demands for post-discharge healthcare services. A cross-sectional study design was conducted from November 2018 to May 2020. STROBE statement was completed. Participants were inpatients over 65 years of age in the general ward of a medical center in northern Taiwan. A questionnaire was used to collect data by face-to-face interviews. Two hundred and twelve participants were recruited. Home nursing care, home rehabilitation, home respiratory therapy, home services, assistive devices rental, and transportation were the main post-discharge healthcare services in this study. Overall, 83.5% of older adult patients were aware of and 55.7% of the older adult patients demanded at least one post-discharge healthcare services. Logistic regression results found that, patients experiencing moderate to severe disability and cognitive impairment, and those hospitalized in the past year had significantly higher demands for services. Developing post-discharge healthcare services for older adult patients provides continuous patient-centered services for assisting patients and their families in adapting to the transition period of the post-acute stage. Satisfying these demands is beneficial for older adult patients and their families, as well as for reducing readmissions and medical costs.


Identification of alpha 1-adrenoceptor subtypes in the human prostatic urethra.
To identify the alpha 1-adrenoceptor subtypes in the human prostatic urethra, we compared the potencies of various alpha 1-adrenoceptor agonists and antagonists in inhibiting [3H]tamsulosin binding to human prostatic urethral membranes with their potencies in inhibiting the binding of (+)-beta-([125I]iodo-4-hydroxyphenyl)ethylaminomethyl-tetralone ([125I]HEAT) to cloned human alpha 1a, alpha 1b and alpha 1d subtypes. The alpha 1A-selective antagonists 5-methylurapidil and (+)niguldipine showed higher affinities for both cloned alpha 1a and urethral alpha 1-adrenoceptors than for cloned alpha 1b- and alpha 1d-adrenoceptors. NS-49, (R)-3'-(2-amino-1-hydroxyethyl)-4'-fluoromethanesulfonanilide hydrochloride, recently characterized as an alpha 1A-selective agonist, also showed high affinity for the cloned alpha 1a subtype and urethral alpha 1-adrenoceptors. Prazosin showed lower affinity for alpha 1-adrenoceptors in the human prostatic urethra than for any of the three cloned alpha 1-adrenoceptors. Comparison of the affinities of alpha 1-adrenoceptor agonists and antagonists for human prostatic urethral alpha 1-adrenoceptors to their affinities for the three cloned alpha 1 subtypes indicated a close correlation between the affinities for human urethral alpha 1 and the cloned alpha 1a-adrenoceptors. However, prazosin did not conform to this pattern. These findings suggest that the predominant alpha 1-adrenoceptor in the human urethra is the alpha 1A subtype, and that an alpha 1L subtype which has been characterised by its low affinity for prazosin, may also be present.


Single-row vs. double-row refixation of the subscapularis tendon after primary anatomic shoulder arthroplasty.
The postoperative integrity of the subscapularis tendon after primary anatomical shoulder arthroplasty has a significant effect on postoperative results. A transosseus Single Row Refixation technique (SRR) has shown up to 30% of partial tears in literature, a modified Double Row Refixation technique (DRR) has biomechanically shown a significantly reduced tear rate, but is yet to be proven in a clinical setting. Thus, we compared the SRR to the DRR technique using clinical outcome parameters and ultrasound examination. 36 patients (40 shoulders; 20f, 16 m; øage: 66 years) were included in our retrospective cohort study. 20 shoulders were treated with the SRR technique (12f, 8 m; FU ø40.9 months) and 20 with the DRR technique (11f, 9 m; FU ø31.6 months). The SRR was performed with three to five transosseus mattress sutures. DRR consisted of two medial placed transosseus sutures and four laterally placed single tendon-to-tendon sutures. The postoperative subscapularis integrity was evaluated by ultrasound examination, the clinical outcome was assessed with the Constant-Murley Score (CS) and the American Shoulder and Elbow Surgeons Score (ASES). The subscapularis tendon was intact in 14 patients (70%) after SRR, whereas 18 patients (90%) treated with the DRR demonstrated a sonographically intact postoperative subscapularis tendon. The CS was 61.4 points in the SRR cohort and 67.3 points in the DRR cohort (p = 0.314). No significant differences were found in both cohorts preoperative (øSRR: 21.3 points; øDRR: 16.2 points, p = 0.720) and postoperative absolute ASES Scores (øSRR: 70.2 points; øDRR: 73.0 points, p = 0.792). However, the DRR cohort showed a statistical tendency to a higher postoperative ASES increase than the SRR cohort (øSRR-ASES increase: 48.9 points; øDRR-ASES increase: 56.8 points, p = 0.067). The results of this study show that application of the DRR technique can significantly reduce the total rate of postoperative subscapularis tears what effects a clinical tendency towards higher ASES improvements and a better range of motion compared to the SRR technique.


Investigation of structure-property relationships of polyisobutylene-based biomaterials: Morphology, thermal, quasi-static tensile and long-term dynamic fatigue behavior.
This study examines the morphology, thermal, quasi-static and long-term dynamic creep properties of one linear and three arborescent polyisobutylene-based block copolymers (L_SIBS31, D_IBS16, D_IBS27 and D_IBS33). Silicone rubber, a common biopolymer, was considered as a benchmark material for comparison. A unique hysteretic testing methodology of Stepwise Increasing Load Test (SILT) and Single Load Test (SLT) was used in this study to evaluate the long-term dynamic fatigue performance of these materials. Our experimental findings revealed that the molecular weight of polyisobutylene (PIB) and polystyrene (PS) arms [M(n)(PIB(arm)) and M(n)(PS(arm))], respectively had a profound influence on the nano-scaled phase separation, quasi-static tensile, thermal transition, and dynamic creep resistance behaviors of these PIB-based block copolymers. However, silicone rubber outperformed the PIB-based block copolymers in terms of dynamic creep properties due to its chemically crosslinked structure. This indicates a need for a material strategy to improve the dynamic fatigue and creep of this class of biopolymers to be considered as alternative to silicone rubber for biomedical devices.


Fluorescence assay for the detection of adherent Candida yeasts to target cells in microtest plates.
We describe an assay based on photometric analysis for the measurement of adherence of Candida species to epithelial target cells (Vero cell line). Adherent Candida cells were detected by staining the cells with the fluorescent dye Calcofluor white (CFW), which binds to chitin and glucan in the yeasts. The tests were performed on microtest plates, which were analysed automatically by fluorescence plate readers. The assay is based on the following steps: (i) coating of the microtest plates with target cells (e.g. Vero cells); (ii) infection with Candida: (iii) staining of Candida with CFW; (iv) rinsing to remove non-adherent Candida cells and unbound dye; (v) detection of adherent fluorescent Candida cells. The test was able to detect 4 x 10(4) cells ml-1. The standard deviation was +/- 8%. Day-to-day variation was +/- 10% at most. The adherence of strains of different Candida species was assayed by a standard procedure. The results confirmed the order of adherence, with C. albicans ranking first, followed by C. tropicalis, C. parapsilosis and C. glabrata.


The dynamics of prostate specific antigen during watchful waiting of prostate carcinoma: a study of 94 Japanese men.
For the moment, there is uncertainty about the usefulness of early treatment of localized prostate carcinoma, uncertainty about whether some patients with early cancer can be managed expectantly, and uncertainty about how such patients might be recognized. The authors studied serial values of prostate specific antigen (PSA) in 94 Japanese men with diagnosed prostate carcinoma and who were managed by watchful waiting. Their median follow-up duration was 32 months (range, 1.6-118). The authors used a log-linear model to fit the values of PSA over time, and then they used the Cox survival model to relate the intercept (PSA amplitude) and slope (relative velocity) to observed local or systemic outcomes that were independent of PSA. The authors found that the log-linear model fit the serial values of PSA during watchful waiting very well. Prostate specific antigen amplitude related significantly to T classification (P = 0.0006), but not to grade (P > 0.2), and the relative velocity related significantly to both T classification (P = 0.009) and to grade (P = 0.02). Although the T classification, histologic grade, and log(PSA) at diagnosis were associated significantly with time to outcome, the combination of amplitude and relative velocity provided more information. These 2 PSA parameters resulted in a higher model likelihood ratio, and their individual P values in the Cox model were 0.0005 and 0.005, respectively. With these two in the Cox model, T classification, grade, log(PSA), and PSA doubling time provided no further significant information. A log-linear model seems to fit serial measurements of PSA during watchful waiting, and preliminary results suggest that both the amplitude and the relative velocity relate closely to clinical outcomes.


Involving young people in cyberbullying research: The implementation and evaluation of a rights-based approach.
Cyberbullying is an international Public Health concern. Efforts to understand and address it can be enhanced by involving young people. This paper describes a rights-based collaboration with young people in a qualitative exploration of cyberbullying. It describes the establishment, implementation and evaluation of a Young Person's Advisory Group as well as identifying the impact on the research process and the young people involved. Sixteen postprimary school students met with researchers on five occasions in a youth centre. Sessions focused on building the young people's capacity to engage with the research, designing the qualitative study, interpreting study findings and evaluating the collaboration process. The Advisory Group highlighted a lack of understanding and appropriate action with regard to cyberbullying but believed that their involvement would ultimately help adults to understand their perspective. Evaluation findings indicate that members were supported to form as well as express their views on the design, conduct and interpretation of the research and that these views were acted upon by adult researchers. Their involvement helped to ensure that the research was relevant and reflective of the experiences, interests, values and norms of young people. Young people can contribute a unique perspective to the research process that is otherwise not accessible to adult researchers. The approach described in this study is a feasible and effective way of operationalizing young people's involvement in health research and could be adapted to explore other topics of relevance to young people.


Development and validation of an LC-MS/MS generic assay platform for small molecule drug bioanalysis.
We developed a generic high-performance liquid chromatography mass spectrometry approach for quantitation of small molecule compounds without availability of isotopically labelled standard. The assay utilized 50 μL of plasma and offers 8 potential internal standards (IS): acetaminophen, veliparib, busulfan, neratinib, erlotinib, abiraterone, bicalutamide, and paclitaxel. Preparation consisted of acetonitrile protein precipitation and aqueous dilution in a 96 well-plate format. Chromatographic separation was achieved with a Kinetex C18 reverse phase (2.6 μm, 2 mm x 50 mm) column and a gradient of 0.1 % formic acid in acetonitrile and water over an 8 min run time. Mass spectrometric detection was performed on an AB SCIEX4000QTRAP with electrospray, positive-mode ionization. Performance of the generic approach was evaluated with seven drugs (LMP744, olaparib, cabozantinib, triapine, ixabepilone, berzosertib, eribulin) for which validated assays were available. The 8 IS covered a range of polarity, size, and ionization; eluted over the range of chromatographic retention times; were quantitatively extracted; and suffered limited matrix effects. The generic approach proved to be linear for test drugs evaluated over at least 3 orders of magnitude starting at 1-10 ng/mL, with extension of assay ranges with analyte isotopologue MRM channels. At a bias of less than 16 % and precision within 15 %, the assay performance was acceptable. The generic approach has become a useful tool to further define the pharmacology of drugs studied in our laboratory and may be utilized as described, or as starting point to develop drug-specific assays with more extensive performance characterization.


Creating a culture of compassion: developing supportive care for people with cancer.
Receiving the 2003 Distinguished Merit Award from the European Oncology Nursing Society is a great moment in my professional career. It is also a time for reflection. We can easily become immersed in the specifics of our work and forget the larger picture. An opportunity such as this allows me to step back, reflect and review what I have accomplished. It also challenges me to think about the totality of cancer nursing and cancer care, look at where we have been and about where we should be going. At the heart of this lies the concept of supportive care. I would like to consider three pertinent areas. First, I will define what I consider the domain of supportive care in cancer to be. Second, I will look at what is needed to further supportive care for people with cancer. This involves building the discipline of more rigorous symptom assessment and documentation; better management of the symptoms and concerns that confront people with cancer; moving beyond the traditional framework of treatment and care, embracing a more integrated approach; addressing quality whilst at the same expediting the delivery of supportive care services. Third, I would like to consider the challenges to reform that this presents for cancer nursing and cancer nurses. A road map for change will be presented which highlights both the necessity to promote a supportive care culture whilst simultaneously building a dedicated infrastructure of staff and services. Nurses must play a key role in supportive care. Because of our unique clinical and research base, we are primed to assume leadership roles in both these spheres. Mutual valuing, partnership and shared working are the only means of delivering enhanced cancer care. We should grasp opportunities, confident that together we have the skills and knowledge to move forward. Today is yesterday's tomorrow. We cannot do anything about yesterday, but we can do something about today to ensure tomorrow is how we want it to be. We can become what we dream, let us live that dream outside and really drive forward the care we provide for people with cancer and their families.


Survey by TEDDY European Network of Excellence for Paediatric Clinical Research demonstrates potential for Europe-wide trials.
The European Network of Excellence for Paediatric Clinical Research, known as the TEDDY Network, carried out a survey to determine the capacity and competence of paediatric centres to perform research studies. A cross-sectional, web-based pilot survey was conducted from October 2016 to April 2017 with paediatric clinical research centres in 11 countries: Albania, Austria, Belgium, Denmark, Iceland, Ireland, Italy, Norway, Spain, Switzerland and the United Kingdom. All were registered with the TEDDY Network database. We approached 107 centres and 63 provided data on their experiences and expertise in paediatric clinical trials. Four groups of performance indicators were identified, referring to scientific experience, trial readiness, trial competence, regulatory issues, ethics and patients. Most centres were actively involved in paediatric clinical research: 53 centres (84.1%) had received funds for more than five paediatric studies in the last 5 years, and 42 (66.7%) had a specific clinical trial unit and dedicated study coordinators. We concluded that the European centres we studied had the capability and capacity to conduct paediatric trials, but there was still room for improvement, including enhanced collaboration. This pilot survey demonstrated that there is potential for performing paediatric trials across Europe, but improvements are possible.


Effects of short-term nocturnal and diurnal food deprivation on subsequent feeding in intact and VMH lesioned rats: relation to blood glucose level.
Ad lib feeding responses were studied in VMH lesioned rats, following 2 to 6 hours of food deprivation during the dark and the light phases of the diurnal cycle. The correlation between glucose level at the time of restoration of food and these feeding responses was examined. At night, VMH as well as intact rats increased their food intake significantly following 2 to 6 hours of food deprivation. In both groups, the responses were correlated with a decrease in blood glucose which was dependent on the duration of previous food deprivation. During the day, in normal rats, food deprivation did not induce a change either in subsequent food intake or in blood glucose level. On the contrary, VMH lesioned rats increased their food intake following diurnal food deprivation as they did at night. But, surprisingly, this increase was not associated with a fall of blood glucose.


Elevated gatifloxacin and reduced rifampicin concentrations in a single-dose interaction study amongst healthy volunteers.
Pharmacokinetic drug-drug interactions were investigated between the fluoroquinolone gatifloxacin and a fixed dose combination (FDC) of rifampicin, isoniazid and pyrazinamide. The single-dose pharmacokinetics of the four drugs was evaluated in an open-label three-way cross-over study amongst 22 healthy volunteers following administration of gatifloxacin, the FDC or the two products together. Modest but potentially important drug-drug interactions affecting gatifloxacin and rifampicin concentrations were detected. The elimination rate of gatifloxacin was reduced such that the AUC from 0 h to infinity was increased with a geometric mean ratio (GMR) [90% confidence interval (CI)] of 1.14 (1.10, 1.18). Conversely, the AUC from 0 h to infinity for rifampicin was reduced (GMR: 0.81, 90% CI: 0.81, 0.96) when rifampicin, isoniazid and pyrazinamide were given together with gatifloxacin. Studies in patients including pharmacokinetic evaluation at steady state, efficacy and toxicity are required to determine the importance of the interactions for use of the combination of gatifloxacin, rifampicin, isoniazid and pyrazinamide in the treatment of tuberculosis.


Detection of novel oxazolidinone and phenicol resistance gene optrA in enterococcal isolates from food animals and animal carcasses.
Altogether 7720 Enterococcus faecalis and 3939 E. faecium isolated from food animals and animal carcasses during 2003-2014 in Korea were investigated to determine if linezolid-resistant (LR) enterococci (≥8μg/ml) are present. Overall, 12 E. faecalis and 27 E. faecium recovered from chickens (n=32), pigs (n=6), and cattle (n=1) were resistant to linezolid and were further characterized using molecular methods Most LR isolates were also resistant to chloramphenicol (97.44%) and florfenicol (92.31%). Molecular analysis showed no mutations in the 23S ribosomal RNA and in the ribosomal protein L3. The optrA gene was found in 89.74% of the LR enterococci, including 12 E. faecalis and 23 E. faecium isolates. Among them, 30 optrA-positive isolates co-carried phenicol exporter gene fexA. Seven LR E. faecium isolates had Asn130Lys mutations in the ribosomal protein L4, of which six also carried optrA gene. None of the isolates carried the mutliresistance gene cfr. Transfer of optrA gene was observed in 16 of the 35 optrA-positive isolates by conjugation. Pulsed-field gel electrophoresis demonstrated that the vast majority of Enterococcus strains carrying optrA gene were genetically heterogeneous. Multi-locus sequence typing revealed eight novel Sequence types among E. faecalis and E. faecium strains. To our knowledge, this is the first report of optrA gene in isolates from cattle and animal carcasses. This is also the first report of optrA gene in Korea. Active surveillance of optrA in enterococci is urgently warranted.


Exploring the effectiveness of emotionally focused therapy for depressive symptoms and relationship distress among couples in Taiwan: A single-arm pragmatic trial.
This is the first study to explore the effectiveness of emotionally focused couple therapy (EFT) for depressive symptoms and relationship distress among couples in Taiwan. This one-arm pragmatic trial assessed the clinical outcomes of 17 couples using multilevel modeling to investigate changes in depressive symptoms and relationship distress throughout treatment. Over half of the participants were moderately depressed and moderately distressed at baseline. Multilevel models revealed decreased depressive symptoms over time, with a small increase toward the end of treatment. However, no significant changes were observed in relationship distress over time. The study was limited by the low "dose" of EFT (M = 7 sessions) received by participants and the small sample size (n = 17). A comprehensive discussion of the findings from a cultural perspective was provided. Future research is needed to further examine the effectiveness of EFT for couples in Taiwan and Asia.


Doppler ultrasound examination of the renal artery in healthy women, normotensive pregnant women and in pre-eclampsia.
A combination of real-time linear array ultrasound scanning and pulsed Doppler ultrasonography was used to record blood flow signals from the right renal artery in 17 healthy women, in 15 normotensive pregnant women and in I7 women with pre-eclampsia. The maximum blood velocity waveforms were analyzed for pulsatility index and systolic/diastolic ratio (S/D ratio). As compared with the two healthy groups, in pre-eclamptic women the pulsatility index was slightly lower (p < 0.05), and the systolic/diastolic ratio non-significantly different. These variables were unrelated to mean arterial pressure or the degree of proteinuria. A theory of renal arteriovenous shunts in pre-eclampsia is proposed. Doppler ultrasound examination of the renal artery would seem to be of limited value-for the purpose of monitoring renal vascular pathology in pre-eclampsia.