Effect of mycophenolate mofetil on the white blood cell count and the frequency of infection in systemic lupus erythematosus.

Leukopenia is a common manifestation of SLE. Addition of immunosuppressive therapy in a SLE patient who is already leukopenic is a clinical concern. It could worsen leukopenia, increase the risk of infection, or both. The aim of this study was to analyze the immediate effect of mycophenolate mofetil on the white blood cell count and the rate of infection in SLE patients. Two hundred and forty-four patients within the Hopkins Lupus Cohort who were newly started on mycophenolate mofetil were included in the study. The white blood cell count and interval infection history on the day mycophenolate mofetil was started were compared with the white blood cell count and interval infection history at the next visit. The study was based on 244 patients who began taking mycophenolate mofetil in the cohort. The study population included 47 % African Americans, 44 % Caucasians, and 9 % other ethnicities. There was a slight but not statistically significant increase in the white blood cell count (6.63 vs. 7.01), after starting mycophenolate mofetil. Patients with a baseline white blood cell count \u3c3000/mm(3) did have a statistically significant increase in the white blood cell count after starting mycophenolate mofetil (2.57 vs. 5.13, P = 0.0047). We also found a statistically significant increase in the risk of bacterial infection (but not viral infection) after starting mycophenolate mofetil (4 vs. 9 %, P = 0.0036). Leukopenia does not worsen with mycophenolate mofetil. However, mycophenolate mofetil appears to slightly increase the rate of bacterial (but not viral) infection

Further cautions for the use of ventilatory-induced changes in arterial pressures to predict volume responsiveness

Variations in systemic arterial pressure with positive-pressure breathing are frequently used to guide fluid management in hemodynamically unstable patients. However, because of the complex physiology that determines the response, there are important limitations to their use. Two papers in a previous volume add pulmonary hypertension as limitations. Uncritical use of ventilatory-induced changes in arterial pressure can lead to excessive volume therapy and potential clinical harm, and they must be used with respect and thought

Reactive oxygen species: toxic molecules or spark of life?

Increases in reactive oxygen species (ROS) and tissue evidence of oxidative injury are common in patients with inflammatory processes or tissue injury. This has led to many clinical attempts to scavenge ROS and reduce oxidative injury. However, we live in an oxygen rich environment and ROS and their chemical reactions are part of the basic chemical processes of normal metabolism. Accordingly, organisms have evolved sophisticated mechanisms to control these reactive molecules. Recently, it has become increasingly evident that ROS also play a role in the regulation of many intracellular signaling pathways that are important for normal cell growth and inflammatory responses that are essential for host defense. Thus, simply trying to scavenge ROS is likely not possible and potentially harmful. The 'normal' level of ROS will also likely vary in different tissues and even in different parts of cells. In this paper, the terminology and basic chemistry of reactive species are reviewed. Examples and mechanisms of tissue injury by ROS as well as their positive role as signaling molecules are discussed. Hopefully, a better understanding of the nature of ROS will lead to better planned therapeutic attempts to manipulate the concentrations of these important molecules. We need to regulate ROS, not eradicate them

Mechanical Limits of Cardiac Output at Maximal Aerobic Exercise

This chapter uses an analytic approach to the factors limiting maximal aerobic exercise. A person’s maximal aerobic work is determined by their maximal oxygen consumption (VO2max). Cardiac output is the dominant determinant of VO2 and thus the primary determinant of population differences in VO2max. Furthermore, cardiac output is the product of heart rate and stroke volume and maximum heart rate is determined solely by a person’s age. Thus, maximum stroke volume is the major factor for physiological differences in aerobic performance. Stroke output must be matched by stroke volume return, which is determined by the mechanical properties of the systemic circulation. These are primarily the compliances of each vascular region and the resistances between them. I first discuss the physiological principles controlling cardiac output and venous return. Emphasis is placed on the importance of the distribution of blood flow between the parallel compliances of muscle and splanchnic beds as described by August Krogh in 1912. I then present observations from a computational modeling study on the mechanical factors that must change to reach known maximum cardiac outputs during aerobic exercise. A key element that comes out of the analysis is the role of the muscle pump in achieving high cardiac outputs

A crossover comparison of progression of chronic renal failure: Ketoacids versus amino acids

A crossover comparison of progression of chronic renal failure: Ketoacids versus amino acids. Rates of progression of chronic renal failure were compared in patients receiving alternately an amino acid supplement (AA) and a ketoacid supplement (KA) to a very low protein (0.3 g/kg), low phosphorus (7 to 9 mg/kg) diet. The first supplement was randomly chosen. Bias due to carryover effects was minimized by delaying the regression analysis until one month after starting or changing supplements. In order to minimize possible bias caused by initiating the two supplements at differing levels of severity, a multiple crossover design was used (ABA, BAB, ABAB, or BABA) with at least four GFR's in each treatment period (except for three GFR's in one instance). Sixteen patients completed the protocol; five dropped out. Average starting GFR's were nearly identical for the two supplements (15.4 and 15.9 ml/min). For each patient, mean progression on KA was compared with mean progression on AA. Thirteen out of 16 patients progressed more slowly on KA than AA. On the average, progression on KA was significantly slower (95% confidence limits = -0.36 to 0.09 ml/min/month) than on AA (-0.91 to -0.41 ml/min/month; P = 0.024). There was no significant difference in estimated protein intake, phosphate excretion, or mean arterial pressure between KA and AA periods. Serum triglyceride concentration was significantly lower on KA (P = 0.0026). 17-hydroxycorticosteroid excretion was also lower (P = 0.031). We conclude that KA slow progression, relative to AA, independently of protein or phosphorus intake, in patients on this regimen

Progressions of Conceptual Models of Cardiovascular Physiology and their Relationship to Expertise

The application of scientific principles in diverse science domains is widely regarded as a hallmark of expertise. However, in medicine, the role of basic science knowledge is the subject of considerable controversy. In this paper, w e present a study that examines students' and experts* understanding of complex biomedical concepts related to cardiovascular physiology. In the experiment, subjects were presented with questions and problems pertaining to cardiac output, venous return, and the mechanical properties of the cardiovascular system. The results indicated a progression of conceptual models as a function of expertise, which was evident in predictive accuracy, and the explanation and application of these concepts. The study also documented and characterized the etiology of significant misconceptions that impeded subjects' ability to reason about the cardiovascular and circulatory system. Certain conceptual errors were evident even in the responses of physicians. The scope of application of basic science principles is not as evident in the practice of medicine, as in the applied physical domains. Students and medical practitioners do not experience the same kinds of epistemic challenges to counter their naive intuitions

Parameter estimation in Cox models with missing failure indicators and the OPPERA study

In a prospective cohort study, examining all participants for incidence of the condition of interest may be prohibitively expensive. For example, the "gold standard" for diagnosing temporomandibular disorder (TMD) is a physical examination by a trained clinician. In large studies, examining all participants in this manner is infeasible. Instead, it is common to use questionnaires to screen for incidence of TMD and perform the "gold standard" examination only on participants who screen positively. Unfortunately, some participants may leave the study before receiving the "gold standard" examination. Within the framework of survival analysis, this results in missing failure indicators. Motivated by the Orofacial Pain: Prospective Evaluation and Risk Assessment (OPPERA) study, a large cohort study of TMD, we propose a method for parameter estimation in survival models with missing failure indicators. We estimate the probability of being an incident case for those lacking a "gold standard" examination using logistic regression. These estimated probabilities are used to generate multiple imputations of case status for each missing examination that are combined with observed data in appropriate regression models. The variance introduced by the procedure is estimated using multiple imputation. The method can be used to estimate both regression coefficients in Cox proportional hazard models as well as incidence rates using Poisson regression. We simulate data with missing failure indicators and show that our method performs as well as or better than competing methods. Finally, we apply the proposed method to data from the OPPERA study.Comment: Version 4: 23 pages, 0 figure