Renal clearance and protein binding of melphalan in patients with cancer

Summary The renal clearance of melphalan and the fraction unbound in plasma were determined after intravenous infusion of 5 mg/m² over 5 min in nine patients with cancer to obtain information regarding the mechanism of renal handling of melphalan. Four of the patients underwent bone marrow transplantation and also received an IV dose of 220 mg/m². Total melphalan clearance after the 5 mg/m² dose ranged from 66.0 to 272 ml/min per m²; the percentage of the dose excreted unchanged in urine, from 2.5% to 92.8%; renal clearance, from 4.1 to 188 ml/min per m²; the fraction unbound in plasma, from 0.0598 to 0.460; and t_1/2, from 39.4 to 84.3 min. Unbound melphalan clearance and renal clearance calculated from the unbound fraction in plasma for each patient ranged from 441 to 3356 ml/min per m² and 15 to 961 ml/min per m² respectively and were not related to serum albumin, serum creatinine or creatinine clearance. The percentage of the dose exctreted and melphalan renal clearance were not related to urine flow. There was evidence of active secretion of melphalan in the kidney an possible reabsorption. There were no significant paired differences in melphalan disposition between the high- and low-dose studies. Highly variable renal clearance involving active secretion may contribute in part to large interpatient differences in the total plasma clearance of melphalan in patients with cancer.This study was supported by a grant from The Queen Elizabeth Hospital Research Foundation     

Mode and speed specificity of eccentric and concentric exercise training

This research was supported by a Duke University Research Council Grant. The purpose of this study was to examine mode and speed specificity of strength training by comparing concentric and eccentric isokinetic exercise of the quadriceps. Forty-eight healthy men (mean age = 23.9 years) were randomly assigned to one of three groups: concentric training (C), eccentric training (E), or control (K). Average force (in Newtons) of 3 concentric and of 3 eccentric quadriceps contractions on the KIN-COM(R) dynamometer at 60, 120, and 180 degrees /sec was evaluated prior to and following a 6 week period during which only the C and E groups trained. Training sessions (3/week) included 4 submaximal and 1 maximal warm-up followed by 10 maximal effort isokinetic contractions of the quadriceps at 120 degrees /sec for each leg. Group C subjects trained concentrically only while Group E subjects trained eccentrically only. A t-test for independent means showed no significant right/left differences. ANOVA and Scheffe's F-tests were then used to assess the differences in training effects among the 3 groups for the left leg only. Results showed that although Group C increased slightly in both concentric and eccentric force at all speeds, the gains were significant only for concentric force at 180 degrees /sec. Group E showed significant gains (p < 0.05) in eccentric force at all speeds but not in concentric force. The K group had no significant change in concentric or eccentric force at any speed. We conclude that the eccentric mode of isokinetic exercise has highly specific strength training effects while the concentric mode has less specific training effects. In addition, speed of exercise does not appear to have specific training effects. J Orthop Sports Phys Ther 1989;11(2):70-75.     

An electrophysiological investigation of the relationship between conceptual fluency and familiarity

Brain potentials associated with the manipulation of conceptual fluency in a recognition memory paradigm were recorded. Enhanced fluency was associated with attenuation of the N400 and an increased rate of subjects' endorsing both studied and non-studied items as having been studied ("old" responses) in the recognition test. Differences were also found in latencies previously associated with post-retrieval processing, such that in the setting of enhanced fluency (1) non-studied items were associated with a positive wave from 800 to 1600 ms and (2) items endorsed as "new" were more positive than those endorsed as "old" from 1200 to 1600 ms. The effects on the N400 may be related to the impact of fluency on familiarity, whereas later processing may be involved in the attribution of fluency to prior experience.     

Evidence for two types of sodium conductance in axons perfused with sodium fluoride solution

1. Voltage clamp experiments were carried out on squid giant axons internally perfused with 300 mM-NaF + sucrose. K-free artificial sea-water, -0.3 to 3.5 degrees C, was used externally.2. Membrane currents were corrected for capacitative and leakage components, and the resulting Na current was converted to Na conductance, g(Na). An attempt was made to fit changes in g(Na) according to the Hodgkin-Huxley model, namely [Formula: see text].According to the model g(Na) is a constant, m(infinity) and h(infinity) are steady-state values which depend only on voltage, tau(m) (-1) and tau(h) (-1) are rate constants which also are functions only of voltage.3. Stepwise depolarizations from the holding potential (-67 to -83 mV) to a potential which varied from -10 to +63 mV resulted in an exponential decline of h from its initial level to a final, non-zero level. If the test depolarization was preceded by a positive prepulse (duration, 19-105 msec; voltage, -6 to 94 mV) the rate constant for h, tau(h) (-1), was increased roughly threefold with practically no change in the final level.4. The steady-state level of h was studied by using prepulses of varying amplitude followed by a test depolarization. In one such experiment a value of 0.34 was obtained for a 105 msec prepulse to -49 mV. The same value for the steady level of h was obtained from analysing a record taken at +52 mV. If the potential was switched from -49 to +52 mV there was a transient increase in g(Na) although h(infinity) had the same value at these two potentials.5. Recovery from depolarization was studied by repolarizing the fibre for varying lengths of time, then applying a test depolarization. If the first depolarization was strongly positive (for example, 70 mV), so that the steady level of h was large (0.39), the currents associated with the test pulse could not be fitted on the basis of an exponential increase in h during the recovery period. Rather, the results suggested that on repolarization h rapidly decreased initially, then slowly increased.6. These results can be explained by assuming that h is given by the sum of two components, h(1) and h(2). Changes are represented kinetically by h(1) right harpoon over left harpoon x right harpoon over left harpoon h(2), where x signifies the inactive state. The distribution is shifted to the left at negative potentials and to the right for positive ones. The resulting Na conductance is comprised of two types: the first type, g(Na)m(3)h(1), is similar to the Hodgkin-Huxley system and underlines the usual transient increase in g(Na) associated with depolarization; the second type, g(Na)m(3)h(2), is maintained with depolarization and gives rise to a steady level of g(Na).     

Tolerance in TCR/Cognate Antigen Double-Transgenic Mice Mediated by Incomplete Thymic Deletion and Peripheral Receptor Downregulation

Influenza nucleoprotein (NP)-specific T-cell receptor transgenic mice (F5) were crossed with transgenic mice expressing the cognate antigenic protein under the control of the H- 2K^b promoter. Double-transgenic mice show negative selection of thymocytes at the CD4⁺8⁺TCR¹⁰ to CD4⁺8⁺TCR^hi transition stage. A few CD8 T cells, however, escape clonal deletion, and in the peripheral lymphoid organs of these mice, they exhibit low levels of the transgenic receptor and upregulated levels of the CD44 memory marker. Such cells do not proliferate upon exposure to antigen stimulation in vivo or ex vivo, however, they can develop low but detectable levels of antigen-specific cytotoxic function after stimulation in vitro in the presence of IL-2.     

Huntington disease-linked locusD4S111 exposed as the α-l-iduronidase gene

-l-Iduronidase (IDUA) has been intensively studied due to its causative role in mucopolysaccharidosis type I (Hurler, Scheie and Hurler/Scheie syndromes). The recent cloning of a human IDUA cDNA has resulted in a reevaluation of the chromosomal location of this gene. Previously assigned to chromosome 22, IDUA now has been localized to 4p16.3, the region of chromosome 4 associated with Huntington's disease (HD). The existence of a battery of cloned DNA, physical map information, and genetic polymorphism data for this region has allowed the rapid fine mapping of IDUA within the terminal cytogenetic band of 4p. IDUA was found to be coincident with D4S111, an anonymous locus displaying a highly informative multiallele DNA polymorphism. This map location, 1.1×10⁶ bp from the telomere, makes IDUA the most distal cloned gene assigned to 4p. However, it falls within a segment of 4p16.3 that has been eliminated from the HD candidate region, excluding a role for IDUA in this disorder.     

A PCR Specific for Escherichia coli O157 Based on the rfb Locus Encoding O157 Lipopolysaccharide

A PCR was developed for the detection of Escherichia coli O157 based on the rfbE O-antigen synthesis genes. A 479-bp PCR product was amplified specifically from E. coli O157 in cell lysates containing 200 or 2 CFU following crude DNA extraction. The PCR detected <1 CFU of E. coli O157 per ml in raw milk following enrichment.     

The effects of orofacial sensory input on spontaneously occurring and apomorphine-induced rhythmical jaw movements in the anesthetized guinea pig

The effects of tonic mandibular loading (jaw depression) on spontaneously occurring and apomorphine (APO)-induced rhythmical jaw movements (RJMs) were examined in the anesthetized guinea pig. It was found that this type of perturbation significantly increased only the amplitude and burst duration of the masseter (jaw closer) EMG activity, whereas the frequency of RJMs was not changed. The data suggest that jaw closer muscle spindle or temporomandibular joint feedback does not strongly influence the activity of the neural networks responsible for determining the frequency of RJMs in the anesthetized guinea pig.     

Bicycle helmet ventilation and comfort angle dependence

Five modern bicycle helmets were studied to elucidate some of the variations in ventilation performance, using both a heated manikin headform and human subjects (n=7). Wind speed and head angle were varied to test their influence on the measured steady-state heat exchange (cooling power) in the skull section of the headform. The cooling power transmitted by the helmets varied from about 60% to over 90% of that of the nude headform, illustrating the range of present manufacturer designs. Angling the head forward by 30° was found to provide better cooling power to the skull (up to 25%) for three of the helmets and almost equal cooling power in the remaining two cases. Comparisons of skull ventilation at these angles with human subjects strongly supported the headform results.