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Biomedical subjects

K C Hayes

Publications and source records attributed to K C Hayes.

At least 37 records · Page 2Linked to original sources
PubMed2000

Classifying incomplete spinal cord injury syndromes: algorithms based on the International Standards for Neurological and Functional Classification of Spinal Cord Injury Patients.

OBJECTIVE: To develop an objective and uniform means for classifying patients with incomplete spinal cord injury (SCI) according to SCI syndromes. DESIGN: Criteria for assigning the syndromes (defined by the International Standards for Neurological and Functional Classification of SCI Patients) were operationalized by means of sensory and motor scores and were incorporated into a set of six independent algorithms and two composite algorithms. SETTING: A regional SCI rehabilitation center in Canada. PATIENTS: SCI patients (n = 56) with incomplete injuries (American Spinal Injury Association classes B, C, D) and stable neurologic deficits. RESULTS: Individual algorithms allowed the highest classification rate but with some patients meeting the criteria for more than one syndrome. A composite, differential allocation algorithm, with selected thresholds at decision nodes, yielded a classification rate approximating that of the individual algorithms but without double classifications. CONCLUSIONS: The composite algorithm provided an objective and standardized means of assigning patients to syndromes based on clinically measurable sensory and motor scores. The thresholds used to implement criteria and the order of decision nodes greatly influenced the outcomes and may be adjusted to suit the needs of the classification, that is, embracing liberal or stringent criteria. Controversy remains about the interpretation of some syndromes, and many patients remain unclassifiable because of mixed clinical presentation.

Adult↗
PubMed2000

Absorption characteristics of sustained-release 4-aminopyridine (fampridine SR) in patients with chronic spinal cord injury.

Fampridine SR (4-aminopyridine) is a potassium channel-blocking drug currently being investigated for its therapeutic efficacy in ameliorating central conduction deficits due to demyelination in patients with spinal cord injury (SCI). The present open-label pharmacokinetic trial examined the absorption characteristics of a sustained-release form of the drug in 25 SCI subjects with chronic incomplete injuries. The overall group mean Cmax of 27.7 +/- 6.2 ng/mL occurred at a tmax of 3.4 +/- 1.4 hours. AUC0-12 was 210.5 +/- 49.5 ng/mL.h. For paraplegics, AUCtmax was 76.02 +/- 33.28 and for tetraplegics was significantly less at 51.25 +/- 20.36 (p = 0.037). A statistically significant difference in the initial rate and extent of absorption, but not in total 4-AP bioavailability over the 12-hour study period, was evident between tetraplegic patients, 0.60 +/- 0.23, and paraplegic patients, 0.39 +/- 0.14 (p = 0.02). There was a linear correlation (p < 0.05) between the neurological level of injury and Cmax/AUCtmax. These results confirm and extend previous observations of different rates of drug absorption among SCI patients with lesions above and below the sympathetic outflow (T6) and provide evidence of the absorption characteristics of this sustained-release form of 4-aminopyridine, which is helpful for optimal dosing.

4-Aminopyridine↗
PubMed1999

Quantitative sensory testing in patients with incomplete spinal cord injury.

OBJECTIVE: To examine the utility of quantitative sensory testing (QST) to characterize sensory dysfunction in patients with spinal cord injury (SCI). DESIGN: Perceptual thresholds to warm, cold, cold pain, and vibratory stimuli were investigated using a modified method of "limits." METHOD: Three QST trials were administered to six lower leg dermatomes, on two different days, to estimate the reliability of measurement. SETTING: Regional Spinal Cord Injury Rehabilitation Center in Ontario, Canada. SUBJECTS: Twenty-one SCI patients with incomplete neurologic deficits and 14 able-bodied controls of similar age. RESULTS: ANOVA revealed significantly (p < .05) reduced perceptual threshold values (hypoesthesia) for warm, cold, and vibratory sensation in the SCI group. There were no differences between group mean values for cold pain because of the inclusion of patients with hypoalgesia and hyperalgesia. Intraclass correlation coefficient estimates of reliability revealed large between-subject variability in the SCI patients associated with relatively small trial-to-trial variability within each day of testing, and appreciable between-day variances. CONCLUSIONS: With QST in SCI there is a need for repeated measurements across days to establish stable baseline measures or outcomes following intervention. QST is a useful adjunct to clinical examination for assessment of preserved sensation.

Adult↗
PubMed1999

Characterization of the bile acid profile in developing male and female hamsters in response to dietary cholesterol challenge.

The Syrian golden hamster is a frequently used model to study cholesterol and bile acid metabolism as well as cholesterol-induced cholelithiasis. However, diet-induced gallstones seem limited to young male hamsters of certain strains that develop depressed cholate/chenodeoxycholate bile acid ratios. To further elucidate gender and age specific aspects of cholesterol and bile acid metabolism, i.e. a possible age-related bile acid/gallstone relationship, plasma and biliary lipids and bile acid composition were analyzed in male and female hamsters under various physiological conditions of age and diet, the latter formulated with and without dietary cholesterol. During normal development (no cholesterol challenge) the percentage of cholic acid decreased while chenodeoxycholate increased, the shift being more pronounced in males. Furthermore, female hamsters had higher total plasma cholesterol than in males, while hepatic and biliary lipids did not differ. When challenged with excessive dietary cholesterol, female hamsters again developed significantly higher total plasma and hepatic cholesterol concentrations. Biliary lipids and cholesterol gallstone incidence revealed a significant gender effect with male hamsters developing a higher lithogenic index and more gallstones (cholesterol and pigment stones) than females. Female hamsters revealed a lower percentage of chenodeoxycholate and a higher percentage of cholate resulting in a more protective, higher cholate/cheno ratio (1.5 +/- 1.0) than in males (1.0 +/- 0.2). In summary, the bile acid pattern in developing and cholesterol-fed hamsters renders females less susceptible to gallstones, in part because they maintain more favorable biliary lipid and bile acid profiles, characterized by lower molar percentages of biliary cholesterol and chenodeoxycholate.

Animals↗
PubMed1999

Safety of <7500 RE (<25000 IU) vitamin A daily in adults with retinitis pigmentosa.

BACKGROUND: Vitamin A supplementation is being used successfully to treat some forms of cancer and the degenerative eye disease retinitis pigmentosa. The daily biological need for vitamin A is estimated to be 800 retinol equivalents (RE)/d (2667 IU/d) for adult women and 1000 RE/d (3300 IU/d) for adult men; doses > or = 7500 RE (> or = 25000 IU)/d are considered potentially toxic over the long term. OBJECTIVE: We assessed the safety in adults of long-term vitamin A supplementation with doses above the daily biological need but <7500 RE (<25000 IU)/d. DESIGN: Adults aged 18-54 y with retinitis pigmentosa but in generally good health (n = 146) were supplemented with 4500 RE (15000 IU) vitamin A/d for < or = 12 y (group A) and compared with a similar group (n = 149) that received 23 RE (75 IU)/d (trace group). Mean total consumption of vitamin A in group A was 5583 RE (18609 IU)/d (range: 4911-7296 RE/d, or 16369-24318 IU/d) and that in the trace group was 1053 RE (3511 IU)/d (range: 401-3192 RE/d, or 1338-10638 IU/d). RESULTS: Patients in group A showed an 8% increase in mean serum retinol concentration at 5 y and an 18% increase at 12 y (P < 0.001); no retinol value exceeded the upper normal limit (3.49 micromol/L, or 100 microg/dL). Mean serum retinyl esters were elevated approximately 1.7-fold at 5 y and remained relatively stable thereafter. No clinical symptoms or signs of liver toxicity attributable to vitamin A excess were detected. CONCLUSIONS: Prolonged daily consumption of <7500 RE (<25000 IU) vitamin A/d can be considered safe in this age group.

Adolescent↗
PubMed1998

The acute phase response in apolipoprotein A-1 knockout mice: apolipoprotein serum amyloid A and lipid distribution in plasma high density lipoproteins.

In plasma, the bulk of apoSAA, a positive acute phase reactant protein, is transported in high density lipoproteins (HDL), especially HDLH (apoA1-rich HDL). In this study we tested whether apoA1 deficiency would adversely affect apoSAA concentration and lipid distribution in mouse plasma lipoproteins. Acute phase response (APR) was induced in C57BL/6J (apoA1+/+) and apoA1-knockout mice (apoA1-/-) by a subcutaneous injection of silver nitrate. The APR increased cholesterol concentrations in LDL of apoA1-/- mice and apoA1+/+ mice in a like manner. In contrast to apoA1+/+ mice, concentrations of cholesterol, phospholipids and proteins in both HDLL (1.063<d<1.103 g/ml) and HDLH (1.103<d<1.21 g/ml) were significantly increased by the APR in apoA1-/- mice. Total concentration of plasma apoSAA and its distribution in lipoprotein fractions was similar in both APR groups. The bulk of plasma apoSAA was contained in HDL and not in VLDL or LDL even when the HDL concentration was low. In apoA1-/- mice, HDLL and HDLH contained more apoSAA than in apoA1+/+ mice. These results indicate that apoA1-/- mice are not deterred from mounting an apoSAA response similar to apoA1+/+ mice and that apoA1-rich HDL particles are not necessary for apoSAA transport in the plasma.

Acute-Phase Reaction↗
PubMed1998

Effect of vitamin A supplementation on rhodopsin mutants threonine-17 --> methionine and proline-347 --> serine in transgenic mice and in cell cultures.

A therapeutic effect of vitamin A supplementation on the course of photoreceptor degeneration, previously reported for patients with retinitis pigmentosa, was tested in two transgenic mouse models of this disease, each carrying a dominant rhodopsin mutation. The threonine-17 --> methionine (T17M) mutation is a class II rhodopsin mutation, characterized by a thermal instability/folding defect and minimal regeneration with the chromophore. The proline-347 --> serine (P347S) mutation belongs to class I, comprised of a smaller number of mutations that exhibit no recognized biochemical abnormality in vitro. In the present study, each of the two mouse models was fed a diet containing 2.5 mg of vitamin A palmitate (control) or 102.5 mg of vitamin A palmitate (high vitamin A) per kilogram of diet. Dark-adapted, full-field electroretinograms showed that the high vitamin A diet significantly reduced the rate of decline of a-wave and b-wave amplitudes in the T17M mice but had no significant effect on the decline of electroretinogram amplitude in the P347S mice. Correspondingly, histologic evaluation revealed that the treatment was associated with significantly longer photoreceptor inner and outer segments and a thicker outer nuclear layer in the T17M mice but had no effect on photoreceptor morphology in the P347S mice. In a separate series of experiments, the instability defect of the T17M mutant opsin expressed in vitro was partially alleviated by inclusion of 11-cis-retinal in the culture media. These results show that vitamin A supplementation slows the rate of photoreceptor degeneration caused by a class II rhodopsin mutation. Vitamin A supplementation may confer therapeutic benefit by stabilizing mutant opsins through increased availability of the chromophore.

Animals↗
PubMed1998

Sustained improvements in neurological function in spinal cord injured patients treated with oral 4-aminopyridine: three cases.

Preclinical trials of intravenously administered 4-Aminopyridine (4-AP) have demonstrated transient improvements in neurological function in patients with longstanding spinal cord injury (SCI). The present report describes three patients with SCI who responded favourably in preclinical trials and who were subsequently administered oral (capsule) 4-AP (10 mg b.i.d. or t.i.d.) over a 4 month interval. The three patients (two male: 1 female) all had incomplete tetraplegia (ASIA levels C and D) with the neurological level of the lesion between C5-C7. Following the administration of 4-AP the patients demonstrated marked and sustained reductions in upper (n = 1) or lower extremity (n = 2) spasticity. Other clinical benefits of 4-AP were reduced pain (n = 1), restored muscle strength (n = 3), improved sensation (n = 2), voluntary control of bowel function (n = 1), and sustained penile tumescence (n = 2). The patients exhibited improved hand function (n = 1), enhanced mobility in transfers and gait (n = 2), with improved energy and endurance. Only trivial side effects (transient light-headedness) were observed. In one case, the enhanced neurological function allowed the patient to stand with support for the first time post injury (16 years). The time course of therapeutic response to the initial dose matched the pharmacokinetic elimination profile derived from serum and urine analysis. There was no evidence of renal or hepatic toxicity with prolonged use. These results indicate a therapeutic benefit of oral 4-Aminopyridine in the management of various neurological deficits in a select group of SCI patients.

4-Aminopyridine↗
PubMed1998

Randomized double-blind crossover trial of fampridine-SR (sustained release 4-aminopyridine) in patients with incomplete spinal cord injury.

A randomized double-blind dose-titration crossover trial of the safety and efficacy of oral fampridine-SR (sustained release 4-aminopyridine) was conducted on spinal cord injured (SCI) patients at two centers. Twenty-six patients (n = 26) with incomplete lesions completed the trial. These patients all had chronic (>2 years) and stable neurological deficits. They received fampridine-SR 12.5 and 17.5 mg b.i.d. over a 2-week treatment period, followed by a 1-week washout and 2 weeks of placebo, or vice versa. Patients reported significant benefit of fampridine-SR over placebo on patient satisfaction (McNemar's test, p2 < 0.05) and quality of life scores (p2 < 0.01). Sensory scores (p1 < 0.01), including both pin prick (p1 = 0.059) and light touch (p1 = 0.058), and motor scores (adjusted to reflect only paretic segments) (p1 < 0.01) all yielded evidence of benefit of fampridine-SR over placebo. The Ashworth scale of spasticity was significantly (p2 < 0.05) reduced when patients received fampridine-SR. There were no statistically significant benefits of the drug on measures of pain or bowel, bladder and sexual function, or functional independence. Side effects of lightheadedness and nausea were transient and trivial relative to efficacy, and approximately 30% of patients reported a wish to continue to use fampridine-SR. The clinical benefits most likely derive from the K+ channel blocking action of the drug. Potassium channel blockade enhances axonal conduction across demyelinated internodes and enhances neuroneuronal and neuromuscular transmission in preserved axons. These results provide the first evidence of therapeutic benefit of fampridine-SR in SCI patients.

4-Aminopyridine↗
PubMed1998

Myristic acid-rich fat raises plasma LDL by stimulating LDL production without affecting fractional clearance in gerbils fed a cholesterol-free diet.

The imbalance that develops between low-density lipoprotein (LDL) production and clearance during saturated fat consumption is responsible for expanding the circulating LDL pool. To assess the imbalance attributable to fatty acids alone, i.e., without the interaction of dietary cholesterol, the most fat-sensitive species available (the gerbil) was challenged with either a 12:0+14:0 rich-fat (high coconut, low safflower) or high 18:2 (high safflower, low coconut) fat for 4-5 wks. The plasma lipoprotein cholesterol profile, including lipoprotein composition, particle size and 125I-LDL turnover were measured. Although total plasma cholesterol (TC) was threefold higher with saturated fatty acid (SFA) feeding (230 vs. 70 mg/100 mL; 5.9 +/- 0.1 vs. 1.8 +/- 0.05 mmol/L, P < 0. 0001) and LDL cholesterol (LDL-C) was fivefold greater (10 vs. 54 mg/100 mL; 0.26 +/- 0.02 vs. 1.4 +/- 0.02 mmol/L, P < 0.001), the high-density lipoprotein (HDL2) fraction increased the most (27 vs. 79 mg/100 mL; 0.7 +/- 0.02 vs. 2.0 +/- 0.1 mmol/L, P < 0.05) with minimal HDL3 (NS) difference (16 vs. 26 mg/100 mL; 0.43 +/- 0.08 vs. 0. 7 +/- 0.05 mmol/L). Particle composition and size did not differ between groups. LDL kinetic analyses revealed that the fractional catabolic rate did not differ between gerbils with these extreme fat intakes, implicating overproduction and not reduced clearance as the primary consideration in LDL expansion. Thus SFA-induced cholesterolemia can be severe in the absence of dietary cholesterol with a greater impact on high-density lipoprotein than LDL and without an appreciable role attributed to LDL clearance (receptors).

Animals↗
PubMed1997

Saturated fatty acids and LDL receptor modulation in humans and monkeys.

It has been known for 40 years that dietary saturated fat (SAT FAT) increases plasma cholesterol, including LDL-C and HDL-C. In humans, where LDL-C is typically > 90 mg/dl this SAT FAT effect largely reflects changes in LDL-C pool size. The original human studies suggested that LDL-C expansion during SAT FAT consumption reflected reduced LDL clearance (LDL receptor activity) in hyperlipemics and increased LDL production rates in normolipemics (LDL-C < 100 mg/dl) . This dual explanation is supported by data from several animal models where specific saturated fatty acids (SFAs) have been the focus. However, the situation is complicated by the fact that polyunsaturated fatty acids (PUFAs) oppose SFAs, i.e. PUFAs decrease LDL-C and increase LDL receptor (LDLr) activity, so the effect of SAT FAT intake may represent the combined influence of increased SFAs and decreased PUFAs. In fact, careful scrutiny of primate data suggests a negligible effect of saturated fat on LDL clearance (and receptor activity) in the absence of dietary cholesterol when PUFA intake is adequate (5-10%en) and the lipoprotein profile is relatively normal (LDL-C < 90 mg/dl), i.e. normolipemic situations at the time of dietary intervention. In such cases increases in LDL-C due to SFAs (particularly 12:0+14:0) appear to reflect LDL overproduction associated with a shift in cholesterol from tissues to the plasma cholesteryl ester (CE) pool (both LDL-C and HDL-C) without altering whole-body cholesterol balance. The reason for this shift, which is accompanied by an increase in the plasma oleic/linoleic CE ratio, is unknown but may reflect a decreased rate of CE hydrolysis by the liver. When individuals or animals are rendered hyperlipemic by other factors (e.g. chronic caloric and dietary cholesterol excesses in humans or by cholesterol feeding in animals) specific SFAs (particularly 16:0) can contribute to decreased LDLr activity initiated by a primary factor, such as dietary cholesterol. However, LDLr down-regulation by dietary cholesterol greatly exceeds any contribution from SFAs.

Animals↗
PubMed1997

Oxygen costs using a reciprocating gait orthosis in a paraplegic (T9) patient with a bilateral below-knee amputation: case report.

The Reciprocating Gait Orthosis (RGO) is a useful aid to ambulation for patients with paraplegia. Its use has been described previously though not in conjunction with limb prostheses. We report here the energy costs of ambulation of a patient, disabled by paraplegia at T9 and bilateral below-knee amputations, walking at her preferred rate using an RGO while gas exchange was measured by the Douglas bag method. Oxygen uptake (VO2) rose from 0.198 1 min-1 at rest to 0.582 1 min-1 in the last minute of exercise, representing a VO2 of 14.3 ml kg-1 min-1. During the fourth minute of ambulation, energy consumption was 30.44 J kg-1 s-1 with an energy cost of 4.17 J kg-1 m-1 at a velocity of 0.13 m s-1, Ambulation with this combination of disability is possible with the aid of limb prostheses and an RGO though it is slow and the energy expenditure as consumption per second and cost per metre are high.

Adult↗
PubMed1997

Effects of 4-aminopyridine on motor evoked potentials in patients with spinal cord injury.

The potassium (K+) channel-blocking agent 4-aminopyridine (4-AP) is currently being investigated for its potential therapeutic value in patients with spinal cord injury (SCI). The present study was designed to test the hypothesis that 4-AP ameliorates central motor conduction deficits in individuals with SCI. Oral 4-AP (10 mg) was administered to 19 (n = 19) SCI subjects with stable neurological deficits. Their response to the drug was monitored using motor evoked potentials (MEPs) following transcranial magnetic stimulation of motor cortex and various measures of segmental or peripheral reflex activity (F-waves, H-reflex, and M-response) recorded from lower limb muscles. The mean MEP amplitude in the extensor digitorum brevis muscle (left) was significantly (p < .05) increased from x = .25 +/- .42 mV to x = .59 +/- 1.04 mV at 2 h after drug administration, and the cortical stimulation threshold was reduced (p < .05) by 5.8%. Similar results were obtained in all subjects exhibiting MEPs (n = 13) and in all muscles (n = 6) studied. These changes were maintained at 4 h postdrug. MEP latencies were reduced in all subjects who initially exhibited abnormally prolonged MEP latencies relative to control group (n = 13) values. F-wave, H-reflex, and M-response values (latency and amplitude) were not systematically altered by 4-AP, leading to the conclusion that it was central motor conduction that was enhanced. This interpretation was supported by observed reductions in central motor conduction time (CMCT) in the majority of SCI subjects from whom CMCT measurements were obtained, two of whom anecdotally reported improved motor control after 4-AP, and by increased MEP:M-wave amplitude ratios. The MEP:M-wave ratios indicated that the magnitude of the effect of 4-AP on motoneuron recruitment was not large, in absolute terms (<4% motoneuron pool), but was appreciable relative to the initial level of motoneuron recruitment. These results provide the first statistically significant, objective evidence of improved functioning of the neuromuscular system in chronically injured SCI subjects receiving 4-AP and suggest that the improvements are mediated through enhanced central conduction. The results further support the emerging view that pharmaceutical management of central conduction deficits may prove to be a useful therapeutic strategy for some patients with long-standing SCI.

4-Aminopyridine↗
PubMed1997

Neuropathology of human spinal cord injury sustained in sports-related activities.

The neuropathology of 20 cases of traumatic human spinal injury is described. Cases were classified as having "complete" or "incomplete" spinal cord injuries based upon the neuropathological findings. Special attention was directed to those cases with neuropathological evidence of continuity of long tract axons across the lesion but that were obtained from individuals with clinically complete sensory and motor loss. Clinical and neuropathological data were obtained from the Western Australian Spinal Cord Injury Database and were selected from those cases involving sports-related injuries. From the total of 20 cases of spinal injury, 6 exhibited neuropathologically and clinically complete cord injuries, 4 were neuropathologically incomplete yet clinically complete, and 4 were neuropathologically and clinically incomplete (one being motor complete yet sensory incomplete). The clinical/neuropathological correlation was indeterminate in 6 cases because of death at or shortly after the accident. The neuropathological findings varied with the severity of trauma and the length of survival. In those cases examined less than 3 months postinjury, there was typically swelling of the cord from vasogenic edema with petechial hemorrhage and myelomalacia. Central hemorrhagic necrosis was common as was hyperemia with free red cells present among disrupted tissue. Activated astrocytes and polymorphs or macrophages were observed and early stages of glial cell scar formation were evident. Wallerian degeneration was evident in motor tracts caudal to the level of insult and in sensory tracts rostral to the lesion. Cases examined 3-6 months postinjury often revealed multilocular cysts with gliotic walls often extending several millimeters above and below the primary locus of injury. In the "chronic" cases (i.e., those surviving more than 6 months), there was evidence of varying degrees of preserved long tract parenchyma, nerve root regeneration, and Schwann cell remyelination of long tract axons. The degree of sparing of long motor and sensory tract parenchyma generally correlated well with the clinical observations of residual function. In four cases, however, there was a residuum of motor or sensory tract axons that appeared to have been spared injury, but the clinical data reported chronically complete sensory and motor loss. The presence of clinically complete yet neuropathologically incomplete injury was more often associated with crush or flexion injuries than with extension or compression trauma. The preserved parenchyma in these types of lesion may provide the anatomical substrate for restorative intervention.

Accidental Falls↗
PubMed1997

Trans (elaidic) fatty acids adversely affect the lipoprotein profile relative to specific saturated fatty acids in humans.

Although dietary trans fatty acids can affect plasma lipoproteins negatively in humans, no direct comparison with specific saturated fatty acids has been reported, even though trans fatty acids were designed to replace saturates in foods and food processing. In this study, dietary trans 18:1 [elaidic acid at 5.5% energy (en)] was specifically exchanged for cis 18:1, 16:0 or 12:0 + 14:0 in 27 male and female subjects consuming moderate fat (31% en), low cholesterol (<225 mg/d) whole food diets during 4-wk diet periods in a crossover design. The trans-rich fat significantly elevated total cholesterol and LDL cholesterol relative to the 16:0-rich and 18:1-rich fats and uniquely depressed HDL cholesterol relative to all of the fats tested. Trans fatty acids also elevated lipoprotein (a) [Lp(a)] values relative to all dietary treatments. Furthermore, identical effects on lipoproteins were elicited by 16:0 and cis 18:1 in these subjects. The current results suggest that elaidic acid, one of the principal trans isomers produced during industrial hydrogenation of edible oils, adversely affects plasma lipoproteins. Thus, the negative effect of elaidic acid on the lipoprotein profile of humans appears to be unmatched by any other natural fatty acid(s).

Adult↗