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Neurologists are worried about bleeding and complications from lumbar punctures in patients who use antiplatelet agents, such as aspirin and clopidogrel. We evaluated the bleeding risks of performing lumbar punctures in patients who are using or have recently used antiplatelet agents by retrospective review of lumbar punctures performed at the Johns Hopkins Hospital between 2004 and 2018 in patients who were actively using or recently used aspirin or clopidogrel, or both. Patients were stratified into time groups based on when the lumbar puncture was done relative to the time the antiplatelet drug was discontinued: <1 week, 1-4 weeks, >4 weeks. We recorded red blood cell counts for the earliest and latest spinal fluid collections to determine the risk of traumatic bleeding; we also noted any complications. Antiplatelet medication use within 1 week of lumbar puncture was associated with a 3% incidence of bloody tap and 4% incidence of traumatic tap that cleared. In the group of patients who waited for a lumbar puncture at least 4 weeks after discontinuation of antiplatelet drug, there was a 5% incidence of bloody or traumatic tap. There was no difference in rates of bleeding between aspirin versus aspirin plus clopidogrel. The rate of hematoma complications was highest in the group of patients on aspirin at the time of the procedure (0.7%). Aspirin or clopidogrel, or both, did not meaningfully increase hemorrhagic complications in patients undergoing lumbar punctures, regardless of when the antiplatelet drug was discontinued relative to the time of the procedure.

Presents letters to the editor referencing articles and topics discussed in previous issues. "Reflections on GM," which dealt with the product management efforts of General Motors; "Sold for Less Than Retail," which assessed the declining activities of the retail industry in the U.S.; "The Coming Collision," which examined the investments in China.

Motivation: Metabolic flux analysis of biochemical reaction networks using isotope tracers requires software tools that can analyze the dynamics of isotopic isomer (isotopomer) accumulation in metabolites and reveal the underlying kinetic mechanisms of metabolism regulation. Since existing tools are restricted by the isotopic steady state and remain disconnected from the underlying kinetic mechanisms, we have recently developed a novel approach for the analysis of tracer-based metabolomic data that meets these requirements. The present contribution describes the last step of this development: implementation of (i) the algorithms for the determination of the kinetic parameters and respective metabolic fluxes consistent with the experimental data and (ii) statistical analysis of both fluxes and parameters, thereby lending it a practical application. Results: The C++ applications package for dynamic isotopomer distribution data analysis was supplemented by (i) five distinct methods for resolving a large system of differential equations; (ii) the ‘simulated annealing’ algorithm adopted to estimate the set of parameters and metabolic fluxes, which corresponds to the global minimum of the difference between the computed and measured isotopomer distributions; and (iii) the algorithms for statistical analysis of the estimated parameters and fluxes, which use the covariance matrix evaluation, as well as Monte Carlo simulations. An example of using this tool for the analysis of 13C distribution in the metabolites of glucose degradation pathways has demonstrated the evaluation of optimal set of parameters and fluxes consistent with the experimental pattern, their range and statistical significance, and also the advantages of using dynamic rather than the usual steady-state method of analysis. Availability: Software is available free from http://www.bq.ub.es/bioqint/selivanov.htm Contact: martacascante@ub.edu

Motivation: Addition of labeled substrates and the measurement of the subsequent distribution of the labels in isotopomers in reaction networks provide a unique method for assessing metabolic fluxes in whole cells. However, owing to insufficiency of information, attempts to quantify the fluxes often yield multiple possible sets of solutions that are consistent with a given experimental pattern of isotopomers. In the study of the pentose phosphate pathways, the need to consider isotope exchange reactions of transketolase (TK) and transaldolase (TA) (which in past analyses have often been ignored) magnifies this problem; but accounting for the interrelation between the fluxes known from biochemical studies and kinetic modeling solves it. The mathematical relationships between kinetic and equilibrium constants restrict the domain of estimated fluxes to the ones compatible not only with a given set of experimental data, but also with other biochemical information. Method: We present software that integrates kinetic modeling with isotopomer distribution analysis. It solves the ordinary differential equations for total concentrations (accounting for the kinetic mechanisms) as well as for all isotopomers in glycolysis and the pentose phosphate pathway (PPP). In the PPP the fluxes created in the TK and TA reactions are expressed through unitary rate constants. The algorithms that account for all the kinetic and equilbrium constant constraints are integrated with the previously developed algorithms, which have been further optimized. The most time-consuming calculations were programmed directly in assembly language; this gave an order of magnitude decrease in the computation time, thus allowing analysis of more complex systems. The software was developed as C-code linked to a program written in Mathematica (Wolfram Research, Champaign, IL), and also as a C++ program independent from Mathematica. Results: Implementing constraints imposed by kinetic and equilibrium constants in the isotopomer distribution analysis in the data from the cancer cells eliminated estimates of fluxes that were inconsistent with the kinetic mechanisms of TK and TA. Fluxes measured experimentally in cells can be used to estimate better the kinetics of TK and TA as they operate in situ. Thus, our approach of integrating various methods for in situ flux analysis opens up the possibility of designing new types of experiments to probe metabolic interrelationships, including the incorporation of additional biochemical information. Availability: Software is available freely at: http://www.bq.ub.es/bioqint/selivanov.htm Contact: martacascante@ub.edu

Motivation: Analysis of the conversion of 13C glucose within the metabolic network allows the evaluation of the biochemical fluxes in interconnecting metabolic pathways. Such analyses require solving hundreds of equations with respect to individual isotopomer concentrations, and this assumes applying special software even for constructing the equations. The algorithm, proposed by others could be improved. Method: A C-code linked to the program written in Mathematica (Wolfram Research Inc.), constructs and solves differential equations for all isotopomer concentrations, using the general enzyme characteristics (Km, equilibrium constant, etc.). This code uses innovative algorithm of determination for the isotopomers–products, thus essentially decreasing the computation time. Feasible metabolic fluxes are provided by the parameters of enzyme kinetics found from the data fitting. Results: The software effectively evaluates metabolic fluxes based on the measured isotopomer distribution, as was illustrated by the analysis of glycolysis and pentose phosphate cycle. The mechanism of transketolase and transaldolase catalysis was shown to induce a specific kind of isotopomer re-distribution, which, despite the significance of its effect, usually is not taken into account. Availability: The software could be freely downloaded from the site: http://bq.ub.es/bioqint/label_distribution/