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Biomedical subjects

W R Clark

Publications and source records attributed to W R Clark.

At least 19 recordsLinked to original sources
PubMed2005

Extracorporeal ultrafiltration for acute exacerbations of chronic heart failure: report from the Acute Dialysis Quality Initiative.

This report from a work group affiliated with the Acute Dialysis Quality Initiative is a critical assessment of the use of extracorporeal ultrafiltration (UF) in the management of acutely decompensated heart failure (HF). In addition to assessing UF in this setting, the report also provides background information on HF, including classification, pathophysiology, and the importance of concomitant renal failure. A summary of important results from clinical trials in this area is provided, along with a discussion of technical considerations. Finally, specific recommendations for future clinical evaluations are given.

Heart Failure↗
PubMed2004

A modified equivalent annulus model for the hollow fiber hemodialyzer.

Experimental approaches to optimize hollow fiber hemodialyzer design are expensive and time-consuming. Computer modeling is an effective way to study mass transfer in the hemodialyzer because a substantial reduction in experimental time and cost can be achieved. This paper presents a two-dimensional modified "equivalent annulus" model, which employs Navier-Stokes (N-S) equations to describe blood and dialysate flow, and Kedem-Katchalsky (K-K) equations to calculate transmembrane flow. N-S equations and K-K equations must be coupled together in the process of computing. The corresponding experiments were designed to validate this model, and experimental results agreed well with numerical results. The distribution of velocity, pressure and solute concentration were investigated in detail, presenting a clear insight into dialyzer mass transfer. This model can be applied to help optimize hemodialyzer design.

Algorithms↗
PubMed2004

Reflections on an unsolved problem of biology: the evolution of senescence and death.

The evolutionary theory of senescence is based largely on principles first outlined by Williams in 1957, and consists of two relatively independent parts. The first part builds on ideas first put forward by Medawar, Haldane and others, to explain how something as negative as senescence could have been positively selected in evolution, particularly since most animals in the wild do not reach an age where senescence is expressed. Williams proposed that the genes responsible for the negative effects of senecence (senescence effector genes) were fixed in evolution by a process he called antagonistic pleiotropy, wherein a subset of genes selected because they confer a reproductive advantage early in life may have harmful effects in the post-reproductive period; negative selection against these harmful effects fails because, as pointed out by Medawar, the force of natural selection declines with age. The evolutionary history of senescence-causing genes is seen as a nondirected accumulation of genes selected on a basis independent of senescence per se. In the second portion of his paper, Williams made a series of predictions about how the age of organisms at reproductive maturity, fecundity, lifespan and the timing of the onset of senescence would all interact in the life history of a species. These latter predictions, which do not depend at all on details of the mechanisms of selection of senescence effector genes, have been validated by numerous experiments over the past several decades. On the other hand, it has become increasingly evident that the senescence effector genes did not, as would be predicted by antagonistic pleiotropy, accumulate in a random, non-directed fashion in various species over evolutionary time. Rather, everything we know about these genes suggests they were present in eukaryotic founder cells shortly after, or even congruent with, the emergence of eukaryotes from their prokaryotic ancestors, and have been stringently conserved ever since. Complicated explanations of how so-called "death genes" may have evolved in eukaryotes are thus not required. It is suggested that the evolutionary theory of senescence should be focused on those evolutionary principles that have been validated experimentally, and that the notion of antagonistic pleiotropy--which cannot be experimentally validated--be dropped from our thinking about the evolution of senescence.

Aging↗
PubMed2002

Dialysis in acute renal failure: is more better?

An increasing body of evidence indicates therapy dose and intensity influence the outcome of dialyzed ARF patients. However, a number of unanswered questions remain on this issue. These questions need to be addressed in future prospective, controlled trials that assess the effect of dose and intensity on outcome both within and between the various ARF renal replacement therapies, with appropriate and clinically relevant control arms. Such investigations should provide guidelines ultimately for the dialytic management of critically ill patients with ARF.

Acute Kidney Injury↗
PubMed2001

Renal versus continuous versus intermittent therapies for removal of uremic toxins.

Uremic toxin removal by renal replacement therapies (RRTs) differs from the elimination of waste products by the native kidney in several ways. Specifically, uremic toxin removal by a RRT is achieved by a one-step membrane-based process, without the subsequent modifications that occur in the native kidney after a solute is filtered across the glomerular membrane. Another major difference relates to the continuous nature of native kidney function, which provides constant solute clearances and mass removal rates for a patient in steady state. This constancy of solute clearance, mass removal rate, and serum concentration does not exist for RRTs used in patients with end-stage renal disease (ESRD). The purpose of this review is first to compare solute removal by the native kidney with that by the various RRTs used for uremic patients. Subsequently, the therapy specificity of the relationship between solute clearance and mass removal rate is discussed, and the effective solute removal capabilities of different therapies compared.

Humans↗
PubMed2001

Determinants of haemodialyser performance and the potential effect on clinical outcome.

The performance of a dialyser is determined by several factors. Many of these factors relate to the dialyser membrane, including mean pore size, pore size distribution, wall thickness, surface area, and adsorptivity. In this article, several of these factors are reviewed. The potential impact of these factors on the clinical outcome of chronic haemodialysis patients is also discussed.

Diffusion↗
PubMed2000

Initial and superior experience with 30 minute TUMT.

Transurethral microwave thermotherapy (TUMT) is an evolving technique with different machines, protocols, intraprostatic temperatures, marketing claims, and clinical outcomes that can be confusing to the clinician. We report our initial and superior results with 30 Minute TUMT over previous treatment protocols in 16 patients. Patient discomfort and acceptance are greatly improved, with reduced analgesic requirements (11 vs. 24 mL of remifentanil), visual analogue pain scores of 0-2, and no power interruption required in any patients. All four patients in urinary retention are catheter-free 1 week after therapy. Post-treatment catheterization was required in only one patient who was voiding spontaneously before the procedure. Urinary flow rates and postvoid residuals improved in all patients. Prostatic cavities were found in all patients having prostate ultrasound 3 months after TUMT. 30 Minute TUMT is not simply a shortened 30-minute TUMT treatment. Rather it is a very different TUMT with an initial power of 80 W and initial urethral cooling water of 48 degrees F/8 degrees C. Mean maximum intraprostatic temperatures achieved are 154 degrees F/68 degrees C or 43 degrees F/24 degrees C greater than previous versions of microwave thermotherapy. 30 Minute TUMT s increased cooling and shorter times result in minimal discomfort and elimination of routine catheterization, but the initial 80-W energy and avoidance of power interruption provide higher intraprostatic temperatures and prostatic cavities in almost all patients in this office-based treatment.

Aged↗
PubMed1999

Dialyzer-dependent changes in solute and water permeability with bleach reprocessing.

The effects of bleach reprocessing on the performance of high-flux dialyzers have not been comprehensively characterized. We compared the effects of automated bleach/formaldehyde reprocessing on solute and hydraulic permeability for cellulose triacetate (CT190) and polysulfone (F80B) dialyzers using an in vitro model. Dialyzers were studied after initial blood exposure (R0) and after 1 (R1), 5 (R5), 10 (R10), and 15 (R15) reuse cycles. Ultrafiltration coefficient (K(uf)), serial clearances, and/or sieving coefficients (SCs) of urea, creatinine, vancomycin, inulin, myoglobin, and albumin were determined. Urea, creatinine, and vancomycin clearances and SCs did not significantly differ from R0 to R15 with either dialyzer. Inulin clearances and SC also did not significantly change from R0 to R15 for the CT190. However, these same values for the F80B significantly increased (P < 0.05). The inulin clearance and SC values for the CT190 dialyzer were significantly higher than those for the F80B at all stages except R15. Myoglobin clearances significantly increased over 15 reuses for both dialyzers (P < 0.01). However, CT190 myoglobin clearances were significantly higher at all stages (R0 = 37.7 +/- 9.7; R15 = 52.5 +/- 8.8 mL/min) than the F80B (R0 = negligible; R15 = 41.3 +/- 16.5 mL/min; P < 0.01). Albumin pre- and postdialysis SCs significantly increased for both dialyzers (P < 0.01). K(uf) for R0 and R15 were 52.3 +/- 3.3 and 52.6 +/- 7.6 mL/h/mm Hg for CT190 (P = not significant) and 48.8 +/- 4.4 and 87.3 +/- 7.0 mL/h/mm Hg for F80B (P < 0.0001). We conclude that bleach reprocessing significantly increases larger solute and hydraulic permeability of high-flux cellulosic and polysulfone dialyzers. This effect is more pronounced for the polysulfone membrane. Until 10 reuses or greater, the removal of solutes greater than 1,500 d is significantly compromised with the polysulfone dialyzer used in this study.

Animals↗
PubMed1999

Effect of membrane composition and structure on solute removal and biocompatibility in hemodialysis.

Effect of membrane composition and structure on solute removal and biocompatibility in hemodialysis. Significant changes in extracorporeal membranes have occurred over the past five decades in which hemodialysis (HD) has been available as a therapy for both acute renal failure (ARF) and end-stage renal disease (ESRD). For cellulosic membranes, these changes have included a reduction in thickness, hydroxyl group substitution, and an increase in pore size. These modifications have resulted in enhanced efficiency of small solute removal, a broader spectrum of overall solute removal, and an attenuation of complement activation in comparison to the thick, unsubstituted cellulosic membranes of low permeability used in the early days of HD therapy. Synthetic membranes, originally developed specifically for use in high-flux HD and hemofiltration, have also evolved during this same time period. In fact, the initially clear distinction between low-flux regenerated cellulosic and high-flux synthetic membranes has become blurred, as membrane formulators have developed products designed to appeal to enthusiasts for both membrane formats. The purpose of this review is to characterize both the solute removal and biocompatibility characteristics of dialysis membranes according to their composition (that is, polymeric makeup) and structure. In this regard, the manner in which membrane biocompatibility interacts with flux is highlighted.

Biocompatible Materials↗
PubMed1999

A role for perforin in downregulating T-cell responses during chronic viral infection.

Cytotoxic T cells secrete perforin to kill virus-infected cells. In this study we show that perforin also plays a role in immune regulation. Perforin-deficient (perf -/-) mice chronically infected with lymphocytic choriomeningitis virus (LCMV) contained greater numbers of antiviral T cells compared to persistently infected +/+ mice. The enhanced expansion was seen in both CD4 and CD8 T cells, but the most striking difference was in the numbers of LCMV-specific CD8 T cells present in infected perf -/- mice. Persistent LCMV infection of +/+ mice results in both deletion and anergy of antigen-specific CD8 T cells, and our results show that this peripheral "exhaustion" of activated CD8 T cells occurred less efficiently in perf -/- mice. This excessive accumulation of activated CD8 T cells resulted in immune-mediated damage in persistently infected perf -/- mice; approximately 50% of these mice died within 2 to 4 weeks, and mortality was fully reversed by in vivo depletion of CD8 T cells. This finding highlights an interesting dichotomy between the role of perforin in viral clearance and immunopathology; perforin-deficient CD8 T cells were unable to clear the LCMV infection but were capable of causing immune-mediated damage. Finally, this study shows that perforin also plays a role in regulating T-cell-mediated autoimmunity. Mice that were deficient in both perforin and Fas exhibited a striking acceleration of the spontaneous lymphoproliferative disease seen in Fas-deficient (lpr) mice. Taken together, these results show that the perforin-mediated pathway is involved in downregulating T-cell responses during chronic viral infection and autoimmunity and that perforin and Fas act independently as negative regulators of activated T cells.

Animals↗
PubMed1999

Effect of gender on the pharmacokinetics of ofloxacin.

STUDY OBJECTIVES: To assess the influence of gender on the pharmacokinetics of ofloxacin. DESIGN: Open-label study. SETTING: Academic medical center. PATIENTS: Five healthy men and seven healthy women volunteers. INTERVENTIONS: Subjects received a single oral dose of ofloxacin 400 mg, and serial blood samples were collected for 24 hours. Plasma concentrations of ofloxacin were determined by high-performance liquid chromatography and pharmacokinetic parameters were determined. Statistical comparisons between genders were made with the Wilcoxon rank sum test. MEASUREMENTS AND MAIN RESULTS: Median volume of distribution at steady state/systemic bioavailability (V(ss)/F) was significantly smaller in women than in men, although when normalized for total body weight there were no differences. Except for terminal elimination half-life, which was 10% shorter in women, no other pharmacokinetic values were significantly different between genders. Median peak concentrations, although not statistically different, were 28% higher in women. CONCLUSION: Ofloxacin V(ss)/F values were smaller in women than in men, explained by gender-related differences in weight.

Administration, Oral↗
PubMed1999

Quantifying the effect of changes in the hemodialysis prescription on effective solute removal with a mathematical model.

One potential benefit of chronic hemodialysis (HD) regimens of longer duration or greater frequency than typical three-times-weekly schedules is enhanced solute removal over a relatively wide molecular weight spectrum of uremic toxins. This study assesses the effect of variations in HD frequency (F: per week), duration (T: min per treatment), and blood/dialysate flow rates (QB/QD: ml/min) on steady-state concentration profiles of five surrogates: urea (U), creatinine (Cr), vancomycin (V), inulin (I), and beta2-microglobulin (beta2M). The regimens assessed for an anephric 70-kg patient were: A (standard): F = 3, T = 240, QB = 350, QD = 600; B (daily/short-time): F = 7, T = 100, QB = 350, QD = 600; C/D/E (low-flow/long-time): F = 3/5/7, T = 480, QB = 300, QD = 100. HD was simulated with a variable-volume double-pool model, which was solved by numerical integration (Runge-Kutta method). Endogenous generation rates (G) for U, Cr, and beta2M were 6.25, 1.0, and 0.17 mg/min, respectively; constant infusion rates for V and I of 0.2 and 0.3 mg/min, respectively, were used to simulate middle molecule (MM) G values. Intercompartment clearances of 600, 275, 125, 90, and 40 ml/min were used for U, Cr, V, I, and beta2M, respectively, For each solute/regimen combination, the equivalent renal clearance (EKR: ml/min) was calculated as a dimensionless value normalized to the regimen A EKR, which was 13.4, 10.8, 6.6, 3.7, and 4.8 ml/min for U, Cr, V, I, and beta2M, respectively. For regimens B, C, D, and E, respectively, these normalized EKR values were U: 1.04, 0.96, 1.58, and 2.22; Cr: 1.03, 1.08, 1.80, and 2.55; V: 1.06, 1.32, 2.21, and 3.12; I: 1.05, 1.54, 2.57, and 3.62; beta2M: 1.00, 1.27, 1.73, and 2.19. The extent of post-HD rebound (%) was highest for regimens A and B, ranging from 16% (urea) to 50% (inulin), and lowest for regimen E, ranging from 6% (urea) to 28% (beta2M). The following conclusions can be made: (1) Relative to a standard three-times-weekly HD regimen of approximately the same total (weekly) treatment duration, a daily/short-time regimen results in modest (3 to 6%) increases in effective small solute and MM removal. (2) Relative to a standard three-times-weekly HD regimen, a three-times-weekly low-flow/long-time regimen results in comparable effective small solute removal and progressive increases in MM and beta2M removal. A daily low-flow/long-time regimen substantially increases the effective removal of all solutes.

Body Fluid Compartments↗
PubMed1999

CRRT efficiency and efficacy in relation to solute size.

Removal of blood solutes in patients with decreased or absent glomerular filtration is the prime objective of continuous renal replacement therapies (CRRTs). However, because these blood solutes are of different molecular weights, factors such as the porosity and hydrophobicity of the filter membranes and the extracorporeal flow rates determine the CRRT that is the most effective filtration system. This article discusses both small and large solute removal, the interaction of convection and diffusion, and the potential for CRRTs to remove particular inflammatory mediators of acute renal failure.

Hemofiltration↗
PubMed1998

The regulation of CD95 ligand expression and function in CTL.

Previous studies with CTL lines and CTL hybridomas have suggested that functional CD95 (APO-1/Fas)-ligand (CD95L) expression on effector CTLs is a consequence of specific CTL-target recognition and TCR triggering of newly transcribed CD95L. Such a control on the expression of CD95L could provide a double safeguard for killing only cognate target cells. Here the regulation of CD95L expression and function was tested in in vivo primed, alloreactive peritoneal exudate CTL (PEL) from perforin-deficient (P0) mice. CD95L-based, PEL-mediated cytotoxicity was blocked by brefeldin A, an inhibitor of intracellular protein transport, but not by the protein synthesis inhibitor emetine, the immunosuppressive drug cyclosporin A, or the DNA transcription inhibitor actinomycin D. CD95L mRNA transcripts in freshly isolated PEL were shown by RT-PCR; CD95L surface expression was evident by staining with Fas-Fc as well as CD95L Abs. Undiminished CD95L expression and cytocidal activity were found in PEL incubated for 48 h in culture, without adding Ag, mitogen, or cytokines. PEL expressed functional CD95L, yet exhibited target cell-specific killing, except when encountering high CD95-expressing cells. The results indicate that PEL use CD95L probably expressed in the Golgi and/or on the cell surface and do not require newly transcribed CD95L upon target cell conjugation. Hence the TCR-triggered recruitment of preformed CD95L, rather than its biosynthesis, controls CD95L-based specific lysis induced by CTL.

Animals↗
PubMed1998

Quantification of creatinine kinetic parameters in patients with acute renal failure.

BACKGROUND: Urea kinetic modeling (UKM) and creatinine (Cr) kinetic modeling (CKM) are used in the nutritional evaluation of end-stage renal disease (ESRD) patients. Both the UKM-derived normalized protein catabolic rate (nPCR) and the CKM-derived estimate of lean body mass (LBM) may also provide important information in critically ill acute renal failure (ARF) patients. Estimation of LBM may be particularly useful as previous data demonstrate that malnutrition adversely influences outcome in ARF patients. METHODS: Eleven critically ill ARF patients (age 52 +/- 21 years; mean +/- SD) treated with continuous venovenous hemofiltration (CVVH) were the study group. They were analyzed at steady state with a single-pool variable-volume model that determined the creatinine generation rate (GCr) by a methodology that we have previously described. RESULTS: The CVVH ultrafiltrate production rate was 913 +/- 49 ml/hr, yielding a blood Cr clearance of 15.2 +/- 0.9 ml/min and a steady state serum Cr of 3.4 +/- 1.7 mg/dl. Daily creatinine generation normalized to body wt (creatinine index: CI) was 6.3 +/- 0.8 and 10.6 +/- 3.0 mg/kg/day for females (N = 4) and males (N = 7), respectively (P < 0.05). Estimated mean LBM was 30.0 +/- 2.0 and 41.2 +/- 7.0 kg in females and males, respectively (P < 0.05), while the same parameter normalized to body wt was 0.50 +/- 0.05 and 0.52 +/- 0.10, respectively. These values are substantially lower than those previously reported for both normal and ESRD patients. Regression analysis demonstrated both GCr (r2 = 0.96; P < 0.001) and LBM (r2 = 0.96; P < 0.001) were significantly correlated with steady state serum Cr in a linear manner. However, no significant correlation (r2 = 0.06; P = 0.24) between nPCR and CI was observed. CONCLUSIONS: These data suggest critically ill ARF patients have severe somatic protein depletion. This malnourished state is likely due to deficits established prior to the development of ARF, such as those secondary to underlying chronic illnesses or prolonged hospitalization, and deficits related to acute hypercatabolism. Quantitative assessment of malnutrition in ARF patients with this CKM-based methodology may permit a better understanding of predisposing factors and, consequently, facilitate the development of interventions designed to prevent malnutrition in these patients.

Acute Kidney Injury↗
PubMed1998

Renal replacement therapy quantification in acute renal failure.

Recent results suggest that RRT delivery affects outcome in critically ill ARF patients. These data have generated interest in the use of RRT quantification methods, originally developed for ESRD patients, in ARF. However, the fundamental differences between ARF and ESRD, with respect to both patient and therapy characteristics, must be fully appreciated before making this extrapolation. These differences may render many of the simplified ESRD quantification formulae of little use in ARF. As is the case in ESRD, the use of clearance-based methods to compare disparate therapies is problematic in ARF. Although the optimal technique for RRT quantification in ARF remains to be defined, dialysate-side quantification may be the most rational approach for the future, as has been suggested for ESRD patients [43].

Acute Kidney Injury↗