Biomedical subjects
M E Morris
Publications and source records attributed to M E Morris.
Renal adaptation to altered dietary sulfate in rats.
Proximal tubular reabsorption is of primary importance in the regulation of the homeostasis of inorganic sulfate, an electrolyte that is necessary for biosynthetic and detoxification reactions. The objective of the present investigation was to determine the effect of dietary sulfate deprivation, produced by a diet low in methionine, on the renal transport of sulfate. Female Lewis rats were fed a diet containing negligible amounts of sulfate and cystine and low in methionine (0.37%) or a control diet (methionine 1.12%, cystine 0.07%) for 8 days to examine the urinary excretion rate and renal clearance of sulfate. The sulfate excretion rate was decreased by day 4 of the low methionine diet and remained low. Both the urinary excretion rates and renal clearance values were significantly decreased on day 8 (144 +/- 71 vs. 517 +/- 264 mumol/12 hr in controls, mean +/- S.D., n = 7, P < .005 and 0.38 +/- 0.19 vs. 1.07 +/- 0.61 ml min-1 kg-1 in controls, n = 5-6, P < .05, respectively), although the serum sulfate concentrations were unchanged. In vitro transport studies were performed in kidney cortex brush border membrane (BBM) and basolateral membrane vesicles isolated from rats fed either the low methionine or control diet for 7 to 9 days. The Vmax for BBM sodium/sulfate cotransport was increased in kidneys from animals that received the low methionine diet (1.1 +/- 0.10 vs. 0.75 +/- 0.08 nmol mg of protein-1 10 sec-1 in controls, n = 5, P < .001); there were no significant differences in the Km.(ABSTRACT TRUNCATED AT 250 WORDS)
Ifosfamide metabolite chloroacetaldehyde causes Fanconi syndrome in the perfused rat kidney.
Renal proximal tubule dysfunction has been reported in patients treated with the chemotherapeutic agent ifosfamide. The present study investigated whether ifosfamide or its metabolites acrolein and chloroacetaldehyde would impair function in the isolated perfused rat kidney. Renal function was monitored before and after these chemicals were added to a modified Krebs-Ringer-bicarbonate perfusion medium containing 6.6 g/dl albumin and a mixture of substrates. No functional changes were observed when ifosfamide (470 microM) or acrolein (470 microM) was added to the perfusate. Addition of chloroacetaldehyde (210 microM) resulted in significant decreases in the fractional reabsorption of sodium (from 92 to 32%), glucose (from 97 to 46%), inorganic phosphate (from 88 to 22%), and inorganic sulfate (from 94 to 86%). There were no changes in glomerular filtration rate. PAH clearance also significantly decreased from 4.1 to 0.7 ml/min per gram of kidney weight, indicating impairment of proximal tubule organic acid secretion. This impairment was associated with a significant decline in the extraction ratio for PAH, suggesting abnormal PAH uptake at the basolateral membrane. These results show that chloroacetaldehyde causes generalized renal proximal tubule dysfunction and that it may be the ifosfamide metabolite responsible for nephrotoxic side effects.
Influence of temperature on anoxic responses of neocortical pyramidal neurons.
Intracellular recordings were made in pyramidal neurons of layers II-III of rat fronto-parietal neocortical slices. The membrane and synaptic properties and effects of brief (4-6 min) anoxia-anoxic depolarization and synaptic depression--were recorded at temperatures between 26 and 37.5 degrees C. In normoxic conditions, both warming (> or = 35 degrees C) and cooling (< or = 32 degrees C) induced a reduction in the amplitude of early and late excitatory postsynaptic potentials and abolished inhibitory postsynaptic potentials. Excitatory postsynaptic potential latency decreased with warming and increased with cooling. Warming also induced spontaneous brief depolarizations, had a general slow depolarizing effect on resting membrane potential, and decreased input resistance. During oxygen deprivation, the steepness of the rising phase of the anoxic depolarization and the duration of the repolarization phase were augmented by warming above 36.5 degrees C (3.7 +/- 0.1 vs 1.9 +/- 0.1 mV/min and 8.75 +/- 0.98 vs 4.16 +/- 0.28 min, respectively). The peak amplitude of the anoxic depolarization increased in only one-third of trials (6.6 +/- 0.6 vs 4.3 +/- 0.4 mV). Warming potentiated the depressant effect of anoxia: at 36.5 degrees C early excitatory postsynaptic potential amplitude decreased to 32.3 +/- 5.2% of control compared with 58.3 +/- 1.2% at 33.5 degrees C, the late excitatory postsynaptic potential was abolished in < 2 min, and the recovery of the compound excitatory postsynaptic potential was prolonged (12.8 +/- 0.8 vs 7.8 +/- 0.3 min). Cooling reduced the amplitude of the anoxic depolarization and increased the input resistance.(ABSTRACT TRUNCATED AT 250 WORDS)
The pathogenesis of gait hypokinesia in Parkinson's disease.
To identify the fundamental deficit in gait hypokinesia in Parkinson's disease (PD) we conducted a series of experiments that compared PD subjects with age- and height-matched controls in their capacity to regulate either stride length, cadence (steps per minute) or both parameters to three conditions. In the first condition the spatial and temporal parameters of gait were documented for slow, normal and fast walking. The second condition compared parkinsonian gait with the walking pattern of elderly controls whilst controlling for two movement speeds: fast (control preferred) speed and slow (PD preferred) speed. In the third condition we examined the ability of PD subjects to regulate one parameter (e.g. stride length) when the other two parameters (e.g. velocity and cadence) were held at control values. A total of 34 PD subjects and 34 matched controls were tested using a footswitch stride analysis system that measured the spatial and temporal parameters of gait for a series of 10 m walking trials. Parkinsonian subjects exhibited marked gait hypokinesia in each of the experiments. Although they retained the capacity to vary their gait velocity in a similar manner to controls, their range of response was reduced. Within the lower velocity range, PD subjects could vary their speed of walking by adjusting cadence and, to a lesser extent, stride length. However, when the speed of walking was controlled, the stride length was found to be shorter and the cadence higher in PD subjects than in controls. Stride length could not be upgraded by internal control mechanisms in response to a fixed cadence set for age and height-matched velocity. In contrast, cadence was readily modulated by external cues and by internal control mechanisms when stride length was fixed to the values obtained for age- and height-matched controls. It was concluded that regulation of stride length is the fundamental problem in gait hypokinesia and the relative increase in cadence exhibited by PD subjects is a compensatory mechanism for the difficulty in regulating stride length. These findings are discussed in the context of the hypothesized role of the basal ganglia in generating internal cues for the maintenance of the gait sequence and in relation to the structuring of movement rehabilitation strategies.
Current status of the motor program.
Motor program theory has provided physical therapists with one approach to understanding how the brain controls movement. Analogous with computer programs that specify the operations of computer hardware, motor programs are thought to contain commands for muscles that allow movements to occur without the need for continuous peripheral feedback. A review of the physical therapy literature reveals many instances in which motor program theory has been used as a theoretical framework for clinical practice. Yet despite the contribution programming theory has made to the advancement of movement science, the motor program construct is currently under considerable threat. Keele's (1968) original definition no longer seems tenable, given the problems of program storage, motor equivalence, movement flexibility, and context-conditioned variability. The finding that researchers from different disciplines define the motor program in a variety of ways adds difficulty to the task of evaluating the efficacy of the model. A critical appraisal of programming theory and its use in physical therapy suggests that clinicians need to reconsider the usefulness of the motor program model as a basis for movement rehabilitation following brain damage and musculoskeletal disorders.
Ability to modulate walking cadence remains intact in Parkinson's disease.
Gait hypokinesia (slowness) is a characteristic feature of Parkinson's disease. It is not clear, however, whether the slowness is due to a problem in regulation of the timing of consecutive steps or the control of stride size. Examination of cadence control for slow to medium walking speeds has shown an increase in step frequency that was a compensation for reduced stride length. In this investigation the ability of Parkinsonian patients to modulate their cadence (steps per minute) at the fast walking speeds exhibited by age and height matched controls was examined. The findings indicated that cadence control remains unaffected throughout its entire range in Parkinson's disease and that gait hypokinesia is directly attributable to an inability to internally generate sufficiently large steps.
Extrasynaptic effects of GABA (gamma-aminobutyric acid) agonists on myelinated axons of peripheral nerve.
Effects of the inhibitory neurotransmitter, GABA (gamma-aminobutyric acid) on the excitability of myelinated fibers of isolated amphibian sciatic nerves and their dorsal and ventral spinal roots have been compared with those of a GABAA agonist, THIP (4,5,6,7-tetrahydroisoxazolo[5,4-c]pyridin-3-ol), and the GABAB agonist baclofen. Graded, prolonged increases in the amplitude of A-fiber half-maximal compound action potentials of Rana ballenderi sciatic nerves were evoked by GABA (Rmax = 49%, EC50 = 0.1 mM); responses to THIP were smaller (Rmax = 34%, EC50 = 1.1 mM) and with a different, distinctly biphasic recovery phase. In studies of Rana catesbeiana nerves and their attached spinal roots, excitability increases produced in fibers of the ventral roots by GABA were smaller than those of the dorsal roots. Peak changes evoked by THIP in both roots were similar to the effects of GABA on the ventral root; however, THIP's ventral root response showed much less sensitivity and was followed by a rapid recovery phase, undershoot, and secondary, prolonged enhancement. Bicuculline methiodide antagonized agonist-induced increases, and revealed the presence of significant decreases in excitability of the ventral root fibers at concentrations of GABA or THIP < 3 mM. Baclofen evoked inconsistent changes in the excitability of whole nerve and root fibers; small increases occurred with lower doses and secondary, delayed decreases with higher doses. The high concentration (> or = 0.1 mM) of the active isomer needed to cause a small response suggests a limited contribution and (or) presence of GABAB receptors.(ABSTRACT TRUNCATED AT 250 WORDS)
Incidence and characterization of secondary myelodysplastic syndrome and acute myelogenous leukemia following high-dose chemoradiotherapy and autologous stem-cell transplantation for lymphoid malignancies.
PURPOSE: To analyze the risk of developing myelodysplastic syndrome (MDS) or acute myelogenous leukemia (AML) following autologous bone marrow transplantation (ABMT) or peripheral stem-cell transplantation (PSCT) and to determine the impact on failure-free survival (FFS). PATIENTS AND METHODS: Patients underwent ABMT or PSCT for the treatment of Hodgkin's disease (HD) and non-Hodgkin's lymphoma (NHL) at the University of Nebraska Medical Center. For those patients who went on to develop MDS/AML, controls were selected and a case-control-within-a-cohort study undertaken. RESULTS: Twelve patients developed MDS or AML a median of 44 months following ABMT/PSCT. The cumulative incidence (P = .42) and the conditional probability (P = .32) of MDS/AML were not statistically different between HD and NHL patients. Age greater than 40 years at the time of transplant (P = .05) and receipt of a total-body irradiation (TBI)-containing regimen (P = .06) were predictive for developing MDS/AML in patients with NHL. CONCLUSION: There is an increased risk of MDS/AML following ABMT/PSCT for lymphoid malignancies. NHL patients age > or = 40 years at the time of transplant and who received TBI are at greatest risk.
Nonlinear pharmacokinetics and protein binding of tiaprofenic acid in female Lewis rats.
Explore the source record for details and available documents.
Tiaprofenic acid inhibits the renal reabsorption of sulfate in rats.
The objectives of the current investigation were: (1) to examine the effects of the nonsteroidal anti-inflammatory drug, tiaprofenic acid (TA), on sulfate renal reabsorption, and (2) to determine if concomitant prostaglandin E2 (PGE2) could reverse these effects. In crossover studies, female Lewis rats (n = 9) received either TA (as an intravenous (i.v.) bolus injection of 15 mg/kg and constant infusion of 0.02 mg/min) or its vehicle for 6 h. A blood sample was obtained at 5 h and urine was collected between 4 and 6 h. At a steady-state TA serum concentration of approximately 190 micrograms/ml, the PGE2 urinary excretion rate was inhibited by > 90% with no change in glomerular filtration rate (GFR), as measured by creatinine clearance. TA administration resulted in a significant decrease in serum sulfate concentrations (0.65 +/- 0.22 vs 1.1 +/- 0.15 mM, mean +/- SD, p < 0.01) and increase in sulfate clearance ratio (0.32 +/- 0.14 vs 0.13 +/- 0.06, p < 0.01) when compared to the vehicle-treated period. There was also a significant decrease in the fraction of sulfate reabsorbed by the kidneys (0.68 +/- 0.14 vs 0.87 +/- 0.06 in the vehicle-treated period, p < 0.01). In a second crossover study, rats received either TA or TA plus PGE2. PGE2 was administered as an infusion (0.1 micrograms/min) beginning 210 min after the start of the TA infusion. An additional group of rats served as controls and received both vehicles.(ABSTRACT TRUNCATED AT 250 WORDS)
Additional sequence complexity in the muscle gene, unc-22, and its encoded protein, twitchin, of Caenorhabditis elegans.
Null mutations of the Caenorhabditis elegans unc-22 gene cause a pronounced body surface twitch associated with impaired movement and disruption of muscle structure. Partial sequence analysis of unc-22 has previously revealed that its encoded polypeptide, named twitchin, consists of a single protein kinase domain and multiple copies of both an immunoglobulin-like domain and a fibronectin type III-like domain. This paper reports additional DNA sequence information that has revealed the transcription start of unc-22, the N terminus of twitchin, and an explanation for the weak phenotype of a transposon insertion allele. These new data indicate that the unc-22 gene is 18 kb larger than previously reported and has a transcription unit of 38,308 bp. These data add 791 amino acids to the twitchin N terminus for a complete polypeptide size of 6,839 amino acids and a predicted molecular weight of 753,494. This new polypeptide sequence includes four additional copies of the above-mentioned immunoglobulin-like domains and also includes a glycine-rich sequence that might form a flexible hinge. The additional coding sequence reveals that the insertion of the Tc1 transposon, in the unc-22 allele, st139, should disrupt twitchin structure because it is located in an exon. However, cDNA sequencing has revealed that several cryptic splice donors and acceptors adjacent to the Tc1 insertion site are used to splice the transposon out of unc-22(st139) mRNA. One of these splicing events produces a near wild-type mRNA that deletes only six amino acids from twitchin, and this might explain the unusually mild phenotype associated with this mutation.
Changes in extracellular [K+] and [Ca2+] induced by anoxia in neonatal rabbit medulla.
Ion-selective microelectrodes were used to record levels of extracellular K+ and Ca2+ concentrations ([K+]o and [Ca2+]o, respectively) and the changes evoked by anoxia in the medulla of anesthetized ventilated newborn rabbits, 1-14 days of age. Resting levels of [K+]o showed significant decline with increasing age. The mean initial level of [K+]o was 6.5 +/- 0.3 mM for the 1st neonatal wk and 5.1 +/- 0.4 mM for the 2nd wk. Brief periods of N2 inhalation (1-3 min) induced reversible increases in [K+]o that were smaller with progression of maturity. The duration of the initial increase (phase I) in [K+]o was twofold greater during the 1st wk than the 2nd wk. At the maximal steady-state level of change (phase III), [K+]o increased by 1.8 +/- 0.2 mM during wk 1 and by 0.9 +/- 0.1 mM during wk 2. Large transient bursts of increase were frequently observed during both early and recovery phases of the sustained [K+]o accumulation. Resting levels of [Ca2+]o also showed age dependence. The mean values during early neonatal days 1-3, compared with days 7-10, were 3.7 +/- 0.3 and 2.4 +/- 0.6 mM, respectively. Anoxia evoked multiphasic decreases in [Ca2+]o that were largest in the youngest pups. Early transient falls of 0.5 +/- 0.1 mM occurred at times similar to those for the earliest increases of [K+]o and negative focal potentials; larger decreases (0.9 +/- 0.2 mM) were recorded after reoxygenation.(ABSTRACT TRUNCATED AT 250 WORDS)
Anoxic depression of excitatory and inhibitory postsynaptic potentials in rat neocortical slices.
1. The effects of brief anoxia (4-6 min replacement of O2 by N2) on synaptic potentials evoked from layer IV and/or the white matter were studied in pyramidal neurons of layers II-III from rat neocortical slices. 2. The early and late components of excitatory postsynaptic potentials (EPSPs) showed differential sensitivity to anoxia: within 2 min the late EPSP (lEPSP) disappeared, whereas the amplitude of the early EPSP (eEPSP) decreased by 70% at 5 min of anoxia. Recovery was complete within 4-11 min. 3. Both fast and slow inhibitory postsynaptic potentials (IPSPs) were extremely sensitive to lack of O2 and were abolished earlier than the lEPSP evoked by the same stimulus. As well, recovery of the IPSPs was always more delayed than that of the EPSPs. 4. A transient increase in excitability during early anoxia and/or midrecovery, manifested as enhanced probability of spiking in 25% of neurons, is attributed to the higher sensitivity of IPSPs compared with EPSPs. 5. The anoxic-induced depression of the lEPSP and IPSPs, which are generated close to the soma, is not due to depolarization-induced occlusion; however, occlusion may cause an attenuation of the eEPSP at dendritic sites. 6. The depression of the EPSPs is not a result of a decreased transmembrane Na+ gradient after inactivation of Na-K-adenosine triphosphatase (Na-K-ATPase). Although ouabain induced a depolarization similar to that of anoxia, it did not affect EPSP amplitude.(ABSTRACT TRUNCATED AT 250 WORDS)
Processing procedures for recovering enteric viruses from wastewater sludges.
A powdered beef extract specially formulated for recovering viruses from environmental samples and designated as beef extract V was evaluated using indigenous and viral seeded wastewater sludge samples. When beef extract V was used to process activated and aerobically digested sludge solids, virus recoveries were shown to be similar to other methods that used commercially available supplemented beef extract. When used to process other sludge solids (primary and activated without primary clarification), cytotoxicity resulted in the BGM cell line used for virus assay. When these sludge solids were processed with the supplemented commercially marketed beef extract cell toxicity did not occur. Metal concentrations in the processed sewage sludge eluates were analyzed, but based on the levels observed they could not be shown as the source of the cytotoxicity. This did not exclude possible synergistic cytotoxic effects or organometal complexes. The commercially marketed beef extract was supplemented with either a floccing aid (FeCl3), a filter aid (Celite) or a floc prepared from paste beef extract. The paste beef floc supplement proved to be the most useful and reliable method for processing for viruses from wastewater sludge solids.
Influence of NSAID-induced inhibition of renal prostaglandin synthesis on inorganic sulfate clearance in rats.
The objective of the present investigation was to examine the influence of inhibition of renal prostaglandin synthesis on the renal clearance of inorganic sulfate, an electrolyte involved in the biotransformation of both exogenous and endogenous substrates. Homeostasis of inorganic sulfate is maintained predominantly by renal reabsorption in the proximal tubule. Using a crossover study design, the renal clearance of sulfate was assessed in conscious female Lewis rats during control periods and following the infusion of two structurally dissimilar nonsteroidal anti-inflammatory drugs, ibuprofen (IBU) and indomethacin (INDO). Animals were infused with IBU or INDO to achieve steady state concentrations of 59 +/- 8 micrograms/ml (mean +/- SD) of IBU and 22 +/- 3 micrograms/ml of INDO. At these serum concentrations, IBU and INDO produced greater than 80% decrease in the urinary excretion of prostaglandin (PG) E2. Treatment with either IBU or INDO significantly increased the renal clearance of sulfate, but did not alter the glomerular filtration rate as assessed by creatinine clearance. The role of prostaglandins in the effects of IBU and INDO on sulfate homeostasis was investigated by examining the influence of concomitant intraarterial PGE2 administration (infusion of 0.1 micrograms/min) on nonsteroidal anti-inflammatory drug-induced alterations in sulfate renal clearance. Although PGE2 alone did not significantly alter the renal clearance of inorganic sulfate or that of creatinine, the PGE2 infusion abolished the effects of IBU on sulfate renal clearance. Concomitant PGE2 administration also significantly increased the sulfate reabsorption rate in INDO-treated animals; other parameters were not significantly changed, although the fractional reabsorption of sulfate tended to increase (P = 0.17). The reason for the less pronounced effect on PGE2 on the INDO-sulfate interaction is as yet unknown, but may be partly due to additional mechanisms involved in the INDO-induced alterations in sulfate clearance. The results of these studies suggest that prostaglandin inhibition represents one mechanism whereby IBU can alter the renal clearance of inorganic sulfate.
Brain and CSF magnesium concentrations during magnesium deficit in animals and humans: neurological symptoms.
Magnesium is an essential cofactor for many enzymatic reactions, especially those involved in energy metabolism. Deficits of magnesium are prevalent due to inadequate intake or malabsorption and due to the renal loss of magnesium that occurs in certain disease states (alcoholism, diabetes) and with drug therapy (diuretics, aminoglycosides, cisplatin, digoxin, cyclosporin, amphotericin B). Protracted deficits of magnesium in humans and animals result in neurological disturbances, including hyperexcitability, convulsions and various psychiatric symptoms ranging from apathy to psychosis, some of which can be reversed with magnesium supplementation, others requiring correction of the dysregulation mechanism. Although the role of magnesium in neuronal function is not completely understood, a lowering of CSF or brain magnesium can induce epileptiform activity and there is an association between decreased CSF magnesium and the development of seizures. CSF concentrations of magnesium are normally higher than magnesium plasma ultrafiltrate (diffusible) concentrations due to the active transport of magnesium across the blood-brain barrier. Under conditions of magnesium deficiency, CSF concentrations decline, although this decline lags behind and is less pronounced than the changes observed in plasma magnesium concentrations. Decreases in CSF magnesium concentrations correlate with the alterations observed in extracellular brain magnesium concentrations in animals following the dietary deprivation of magnesium. CSF magnesium concentrations can readily be repleted following magnesium supplementation, although high dose magnesium therapy, such as that used in the treatment of convulsions in eclampsia, will only increase CSF magnesium concentrations to a very limited degree (approximately 11-18 per cent) above physiological concentrations. Greater increases in CSF magnesium may occur in neonates since neonatal swine, following treatment with magnesium, have CSF magnesium concentrations that are similar to their plasma concentrations. There has been a recent resurgence of interest in magnesium deficiency and its neurological consequences due to the finding that magnesium, at physiological concentrations, blocks N-methyl-D-aspartate (NMDA) receptors in neurones. NMDA receptors are normally activated by glutamate and/or aspartate which represent the principal neurotransmitters for excitatory synaptic transmission in vertebrate CNS. Magnesium deficiency produces epileptiform activity in the CNS which can be blocked by NMDA receptor antagonists. Other mechanisms, including alterations in Na+/K(+)-ATPase activity, cAMP/cGMP concentrations and calcium currents in pre- and postsynaptic membranes, may also be at least partially responsible for the neuronal effects associated with low brain magnesium. Further studies are necessary to increase our understanding of the neurological implications of magnesium deficit in the central nervous system.
Electrogoniometric feedback: its effect on genu recurvatum in stroke.
The purpose of this study was to determine the effect of combining electrogoniometric feedback with contemporary physical therapy procedures for treatment of genu recurvatum following stroke. Twenty-six patients suffering knee hyperextension resulting from cerebrovascular disorders were allocated to either a control group or an experimental group. Both groups received treatment for knee hyperextension during two consecutive phases. During phase I the control group received physical therapy and the experimental group received electrogoniometric feedback as an adjunct to physical therapy. In phase II both groups received physical therapy alone. Each phase lasted four weeks, during which time patients were treated 45 minutes daily, five days every week. Subjects in the experimental group showed greater reduction in knee hyperextension. This was particularly evident in phase II when the difference between groups for reduction in knee hyperextension reached statistical significance (U = 40, p = 0.011). These results suggest that the addition of electrogoniometric feedback to standard physical therapy enhanced the effectiveness of treatment for genu recurvatum in stroke.