Stimulation of DNA repair synthesis of rat thymocytes by novobiocin and nalidixic acid in vitro without detectable DNA damage

Scheduled (SDS) and unscheduled (UDS) DNA synthesis as well as nucleoid sedimentation was investigated in vitro under the influence of novobiocin (NB) and nalidixic acid (NA) using intact thymic (T-cells) and splenic (S-cells) rat cells and cells which were exposed to X-rays, UV irradiation, methyl methanesulfonate (MMS), and DNA polymerase inhibitors. At concentrations of 56.25 (S-cells) and 225 g/ml (T-cells), respectively, NB inhibited SDS in a dose-dependent manner. Within a concentration range of 225–900 g NB/ml, UDS of S-cells decreased to values far below the tracer ([³H-methyl]-thymidine) incorporation of control cells, whereas UDS of T-cells increased by at least 200%. Within a concentration range of 450–1800 g/ml, NA enhanced SDS and UDS by about 30% in S-cells and by 100% in T-cells. The stimulating activity of NB and/or NA could be eliminated specifically by the DNA polymerase inhibitor 2',3'-dideoxythymidine. Enhanced nucleoid sedimentation was observed at NB concentrations 750 g/ml; S-cells revealed a higher sedimentation rate than T-cells. It is suggested that NB (and NA) influence DNA topology in a rather cell specific manner, stimulating UDS of T-cells by a DNA polymerase — dependent repair-like mechanism.     

Evaluation of LY163443, 1-[2-hydroxy-3-propyl-4-{[4-(1H-tetrazol-5-ylmethyl)phenoxy]methyl}phenyl]ethanone,as a pharmacologic antagonist of leukotrienes D4 and E4

Summary LY163443,1-[2-hydroxy-3-propyl-4-{[4-(1H-tetrazol-5-ylmethyl)-phenoxy]methyl}phenyl]ethanone, antagonized LTD₄-induced contractions of guinea pig ileum, trachea, and lung parenchyma. Tracheal contractions to LTE₄ were also inhibited by LY163443. The compound had minimal effect against ileal responses to LTC₄ and parenchymal contractions to LTB₄. Furthermore, LY163443.had little to no effect against contractions of isolated smooth muscles to histamine, bradykinin, PGF₂, carbachol, serotonin or U46619. LY163443, given by oral administration to guinea pigs, blocked LTD₄-induced increases in total pulmonary impedance (TPI). Similar responses elicited by histamine or U46619 were unaffected. Increases in TPI in response to i.v. administration of LTC₄ were antagonized by LY163443 given by the same route. Ovalbumin challenge also increased TPI in guinea pigs previously sensitized against this antigen. In such animals, pretreated with pyrilamine, propranolol, and indomethacin, oral administration of LY163443 blocked the increase in TPI caused by ovalbumin. Additionally, LTD₄ given intradermally to guinea pigs caused a vascular leakage which was suppressed by prior oral administration of LY163443. Finally, LY163443 relaxed isolated guinea pig trachea previously contracted with LTD₄, histamine, or carbachol. Relaxation of tissues contracted by these latter two agonists suggested some inherent airway smooth muscle relaxant properties of the molecule. This was further demonstrated by showing some bronchodilator activity in an in vivo setting. Thus, this pharmacologic profile indicates that LY163443, or a member of the same chemical family, warrants consideration as a possible therapeutic agent in the treatment of asthma and in diseases characterized by an overproduction of LTD₄ and LTE₄.Presented in part at the meeting of The Federation of American Societies for Experimental Biology, April 1985, Anaheim, California.     

Can Machine Learning Methods Produce Accurate and Easy-to-Use Preoperative Prediction Models of One-Year Improvements in Pain and Functioning After Knee Arthroplasty?

BackgroundApproximately 15%-20% of total knee arthroplasty (TKA) patients do not experience clinically meaningful improvements. We sought to compare the accuracy and parsimony of several machine learning strategies for developing predictive models of failing to experience minimal clinically important differences in patient-reported outcome measures (PROMs) 1 year after TKA.MethodsPatients (N = 587) in 3 large Veteran Health Administration facilities completed PROMs before and 1 year after TKA (92% follow-up). Preoperative PROMs and electronic health record data were used to develop and validate models to predict failing to experience at least a minimal clinically important difference in Knee Injury and Osteoarthritis Outcome Score (KOOS) Total, KOOS JR, and KOOS subscales (Pain, Symptoms, Activities of Daily Living, Quality of Life, and recreation). Several machine learning strategies were used for model development. Ten-fold cross-validation and bootstrapping were used to produce measures of overall accuracy (C-statistic, Brier Score). The sensitivity and specificity of various predicted probability cut-points were examined.ResultsThe most accurate models produced were for the Activities of Daily Living, Pain, Symptoms, and Quality of Life subscales of the KOOS (C-statistics 0.76, 0.72, 0.72, and 0.71, respectively). Strategies varied substantially in terms of the numbers of inputs required to achieve similar accuracy, with none being superior for all outcomes.ConclusionModels produced in this project provide estimates of patient-specific improvements in major outcomes 1 year after TKA. Integrating these models into clinical decision support, informed consent and shared decision making could improve patient selection, education, and satisfaction.Level of EvidenceLevel III, diagnostic study.     

Significance and clinical impact of routinely tested urinary ethyl glucuronide after liver transplantation – development of a risk score

Alcohol abuse after liver transplantation can seriously impact graft and patient survival. However, to date, there is no defined standard procedure to identify patients consuming alcohol after liver transplantation. The aim of this study was to analyze the diagnostic value and clinical impact of routinely measured urinary ethyl glucuronide (uEtG) – a metabolite of ethanol – in patients after liver transplantation. Data of 362 consecutive patients after liver transplantation who visited the University Hospital of Tuebingen for outpatient follow-up were analyzed. Forty-eight patients (13%) displayed positive uEtG results. The uEtG positive group contained significantly more patients with pretransplant alcoholic liver disease. However, two thirds of the uEtG positive patients had no history of pretransplant alcoholic liver disease. Several clinical parameters were significantly associated with positive uEtG. In order to enable a more cost-effective application of uEtG in the future, a clinical risk score was developed (specificity 0.95). In conclusion, routine testing for uEtG reveals a considerable percentage of patients practicing alcohol intake after liver transplantation. Application of our proposed risk score could help focusing uEtG testing on patients at risk.     

Novel approach to an early assessment of a patient’s potential for neurological remission after acute spinal cord injury: Analysis of hemoglobin concentration dynamics

Context/objective: Examining hemoglobin (Hb) dynamics with regard to the potential of neurological remission in patients with traumatic spinal cord injury (TSCI).Design: Prospective Clinical Observational Study.Setting: BG Trauma Centre Ludwigshafen, Department of Paraplegiology, Rhineland-Palatinate, Germany.Methods: From 2011 to 2017 a total of 80 patients with acute spinal injury were enrolled and divided into three groups: initial neurological impairment either with (G1; n = 33) or without subsequent neurological remission (G0; n = 35) and vertebral fractures without initial neurological impairment as control group (C; n = 12). Blood samples were taken for 3 months at 11 time-points after injury. Analyses were performed using routine diagnostics.Outcome measures: Multiple logistic regression was used to determine the prognostic value of Hb regarding neurological remission respecting clinical covariates.Results: Data showed elevated mean Hb concentrations in G1 from the third day to 1 month compared to G0, Hb levels were significantly higher in G1 after 3 days (P = 0.03, G1 > G0). The final multiple logistic regression model based on this data predicting the presence of neurological remission resulted in an AUC (area under the curve) of 80.5% (CI: 67.8%–93.2%) in the ROC (receiver operating characteristic) analysis.Conclusion: Elevated Hb concentrations are associated with a higher likelihood of neurological remission. Elevated concentrations of Hb in G1 compared to G0 over time might be linked to both a better initial oxygen supply response and a decreased ECM (extracellular matrix) degradation highlighting the role of Hb as a valuable biomarker for neural regeneration after TSCI.     

A pilot study of recombinant interferon beta (IFN-βser) in patients with recurrent glioma

Recombinant interferon beta (IFN-_ser) has been administered by intravenous bolus injection three times weekly at a dose of 90 × 10⁶ IU to 14, patients with recurrent malignant glioma in an ongoing study. The treatment period has ranged from 1 to 40 weeks. The most common adverse experiences were fever, chills, malaise, and headache. Fever, chills and headache were worse with the first two doses and were usually relieved with acetaminophen. All patients tolerated subsequent treatments without any difficulties. No neurologic or hematologic toxicities were observed. Of ten evaluable patients, five had progressive disease in 4 to 8 weeks; three had stable disease for 12 to 21 weeks; one has had a minor response for 13 weeks; and one has had a complete resolution of tumor for 150 + weeks. IFN-_ser appears to have activity in human glioma and is well tolerated at this dosage and schedule.