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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
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↗
PubMed1998

Fas (CD95)-dependent cell-mediated immunity to Listeria monocytogenes.

Two distinct and complementary pathways, one mediated by perforin and the other dependent upon CD95 (Fas), effect cell-mediated cytotoxicity. We examined the relative roles of these pathways in host defenses against the intracellular bacterial pathogen Listeria monocytogenes by using murine listeriosis as a model system. Mice which lacked both perforin and Fas (P0L0) were generated, and their responses to primary and secondary listeriosis were compared to those of wild-type (WT), Fas-deficient (L0), and perforin knockout (P0) mice. Relative to WT mice during primary listeriosis, P0 mice exhibited a reduced capacity to clear the infection from their spleens but not their livers whereas L0 mice had elevated bacterial titers in their livers and a modestly increased titer in their spleens. In contrast, bacterial titers in P0L0 mice were increased approximately 50- to 560-fold in their spleens and 230- to 1, 000-fold in their livers; eventual clearance of listeriae from both organs was significantly delayed. Furthermore, the resistance of P0L0 mice to secondary listeriosis was significantly reduced in their spleens and livers compared to that of WT, P0, or L0 mice. In vitro experiments indicated that immune cytotoxic T lymphocytes (CTL) lysed L. monocytogenes-infected hepatocytes primarily via a Fas-dependent, perforin-independent mechanism. The absence of Fas severely abrogated the lysis of infected hepatocytes by immune CD8(+) CTL. Taken together, these results provide the first evidence for Fas-dependent CTL-mediated lysis of L. monocytogenes-infected hepatocytes and demonstrate complementary roles for Fas and perforin in host defenses against an intracellular bacterial pathogen.

Animals↗
PubMed1998

Seroprevalence of antibodies against Toxoplasma gondii in free-ranging mammals in Iowa.

Serum samples from raccoons (Procyon lotor), striped skunks (Mephitis mephitis), Virginia opossums (Didelphis virginiana), and free-ranging house cats trapped in Iowa between 1984 and 1988 were tested for antibodies against Toxoplasma gondii using the modified direct agglutination test (MAT). Antibody titers > or = 1:32 were considered indicative of infection. Prevalence rates by species were estimated for raccoons at 134/885 (15%), skunks at 38/81 (47%), opossums at 12/53 (23%), and cats at 16/20 (80%).

Age Distribution↗
PubMed1998

Renal replacement therapy in acute renal failure: solute removal mechanisms and dose quantification.

Based on numerous studies demonstrating a direct relationship between survival and delivered hemodialysis (HD) dose in end-stage renal disease (ESRD), quantification of delivered HD is now routinely performed in this setting. Recently, investigators have also begun applying kinetic modeling principles to quantify delivered dialysis dose in patients with acute renal failure (ARF). One purpose of this article is to review these ARF studies. However, a broader objective is to provide an overview of the solute removal capabilities of both intermittent and continuous therapies used in ARF. To achieve this goal, the dialytic removal mechanisms for solutes over a wide molecular weight spectrum are discussed.

Acute Kidney Injury↗
PubMed1997

The role of renal replacement therapy quantification in acute renal failure.

The recognition that both morbidity and mortality are inversely related to delivered hemodialysis (HD) dose in end-stage renal disease (ESRD) patients has substantially changed clinical practices in the United States. A number of quantification techniques, which differ greatly in complexity and sophistication, are now used in ESRD patients. Investigators recently have attempted to extrapolate some of these ESRD quantification methods to the acute renal failure (ARF) setting. This review focuses on these recent attempts. Both patient-related and renal replacement therapy (RRT)-related differences in ESRD and ARF are discussed. In addition, the potential pitfalls of extrapolating certain ESRD quantification methods to RRT in ARF are discussed. Prescription considerations for both intermittent HD (IHD) and continuous RRT (CRRT) are presented. The optimal technique for RRT quantification in ARF remains to be determined.

Humans↗