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Biomedical subjects

W Young

Publications and source records attributed to W Young.

At least 19 recordsLinked to original sources
PubMed1992

Ricin and lentil lectin-affinity chromatography reveals oligosaccharide heterogeneity of thyrotropin secreted by 12 human pituitary tumors.

Some patients with thyrotropin (TSH)-producing pituitary tumors are more hyperthyroid than others despite similar TSH levels in serum, suggesting that qualitatively different TSH molecules with differing bioactivities may be secreted by different tumors. We used ricin and lentil lectin-affinity chromatography to test whether the TSH oligosaccharides varied among 12 patients with TSH-producing tumors. We found that each tumor secreted heterogeneous isoforms of TSH that differed in their extents of exposed galactose (Gal) residues, and their degrees of sialylation and core fucosylation. These biochemical parameters also varied markedly for TSH secreted by different tumors. Isoforms appeared to reflect poor sialyltransferase activity in two tumors and efficient sialyltransferase in the remainder. TSH secreted by tumors was more fucosylated than TSH secreted by control euthyroid persons. There was an inverse relationship between the sialylation and fucosylation of tumor TSH. No simple relationship between TSH oligosaccharide structures and bioactivity was evident, although mixtures of isoforms having the least and most sialylated TSH seemed to be the most bioactive clinically. In three patients from whom serum and medium TSH were both available, TSH in serum was more sialylated than TSH secreted by the tumor in vitro, perhaps reflecting slow clearance of sialylated isoforms from the circulation. Core fucosylation of serum TSH was less than that of medium TSH. These data prove that human tumors secrete TSH with heterogeneous oligosaccharide structures.

Adult↗
PubMed1992

Fetal cortical cells survive in focal cerebral infarct after permanent occlusion of the middle cerebral artery in adult rats.

Fetal rat cortical cells have been shown previously to survive at the periphery of cerebral infarction. The present study was designed to examine the ability of fetal cells to survive at the edge of the central core of ischemia. In three groups of 8 adult Sprague-Dawley rats, fetal cortical cells from ED 16 were stereotactically transplanted at 3 h, 24 h, and 7 days after unilateral middle cerebral artery occlusion. In 6 rats, fetal cells were transplanted by using the same coordinates, without arterial occlusion, for control. In the ischemic groups, overall graft survival was 85%, and in the control group, all grafts survived. Graft survival was determined by light microscopy. No significant difference was found in the survival of grafts transplanted at different intervals after middle cerebral artery occlusion. It is concluded that fetal cortical cells can survive in cerebral tissue undergoing severe ischemic change.

Animals↗
PubMed1992

Pharmacologic strategies in the treatment of experimental spinal cord injury.

Remarkable advances have been made in pharmacologic treatments of acute and chronic spinal cord injury. The recent National Acute Spinal Cord Injury Study (NASCIS) showed that very high dose methylprednisolone given within 8 hr after injury improves neurologic recovery. The mechanism is believed to be inhibition of lipid peroxidation. Many other drugs have been claimed to be beneficial in animal studies, including other lipid peroxidation inhibitors, free radical scavengers, opiate receptor blockers, NMDA receptor blockers, calcium channel blockers, inhibitors of arachidonic acid metabolism, and protease inhibitors. In chronic spinal cord injury, much progress also has been made. Myelin was found to possess factors that inhibit axonal regeneration. Blocking these factors enhances spinal cord regeneration. Monosialic gangliosides (GM1) were recently found to improve neurologic recovery in spinal-cord-injured patients. Given as late as 48-72 hr after injury, the mechanism of action is not well understood. However, the GM1 results give hope that recovery mechanisms can be manipulated pharmacologically. Nonregenerative therapy for chronic spinal cord injury is also being developed. Several drugs, including 4-aminopyridine and baclofen, respectively blockers of potassium channels and GABA-B receptors, improve conduction in demyelinated axons. These drugs may be useful for identifying patients who might benefit from remyelination therapy. Finally, NASCIS has complicated acute spinal cord injury studies. To bring a drug to clinical trial, an investigator must now determine the optimal treatment dose, timing, and duration over a range of injury severities, in comparison and combination with methylprednisolone. This requirement has so increased the scale of drug testing that multicenter laboratory trials may be necessary.

4-Aminopyridine↗
PubMed1992

The Second National Acute Spinal Cord Injury Study.

In 1990, the Second National Acute Spinal Cord Injury Study reported that high-dosage methylprednisolone improves neurologic recovery in spinal-injured humans. The study showed that patients who received the drug within 8 hr after injury improved, whereas those who received the drug later did not. The drug significantly increased recovery even in severely injured patients who were admitted with no motor or sensory function below the lesion, contradicting a long-held dogma that such patients would not recover. Some researchers, however, have questioned the stratification of the patient population, the use of summed neurologic change scores, and the absence of functional assessments. The stratification by injury severity and treatment time was planned a priori and based on objective criteria. Detailed analyses revealed no differences between groups attributable to stratification or randomization. While multivariate analyses of the summed neurologic scores were used, the conclusions were corroborated by other analytical approaches that did not rely on summed scores. For example, treatment with methylprednisolone more than doubled the probability that patients would convert from quadriplegia or paraplegia to quadriparesis or paraparesis, analgesia to hypalgesia, and anesthesia to hypesthesia. The treatment also significantly improved neurologic scores in lumbosacral segments, indicating that beneficial effects were not limited to segments close to the lesion site. The treatment did not significantly affect mortality or morbidity. The study strongly suggests that methylprednisolone has significant beneficial effects in human spinal cord injury, that these effects occur only when the drug is given within 8 hr, and that it helps even in patients with severe spinal cord injuries. These conclusions have important implications for spinal cord injury care and research.

Drug Administration Schedule↗
PubMed1992

Role of calcium in central nervous system injuries.

Calcium ions initiate and regulate responses of central nervous tissues to injury. Calcium ions entering injured cells will activate phospholipases, disrupt mitochondrial electron transport, and release free radicals. Neurons normally possess a large reservoir of substances to bind calcium, as well as calcium-activated proteins that protect phospholipids and free radical scavengers. However, calcium entry can initiate a stereotyped injury response. Injured cells release potassium and neurotransmitters that depolarize neighboring cells and cause further calcium entry. Free radical and phospholipase attack of membranes cause lipid peroxidation, generating more free radicals and releasing arachidonic acid. Cyclo-oxygenase and lipo-oxygenase convert arachidonic acid to prostaglandins and leukotrienes, eicosanoids that cause edema and vasoconstriction. Why have neurons, the longest-lived and most important cells of the body, evolved these elaborate autodestructive mechanisms? The calcium-activated injury response may serve a protective purpose. Potassium and neurotransmitter release spreads the calcium load over many cells. Membrane breakdown floods extracellular fluids with phosphates and phosphatides that bind calcium ions. Lowering extracellular calcium activity efficiently reduces the driving force for calcium entry into surviving cells. Edema and vasoconstriction resulting from eicosanoids slow calcium diffusion from blood and surrounding tissues, reducing the probability of "calcium paradox" when calcium returns. The tissue rapidly eliminates moribund cells that would otherwise consume precious metabolic resources. The possibility that the injury response may be protective has important therapeutic implications.

Animals↗
PubMed1991

Metaphyseal sclerosis in patients with chronic renal failure.

We reviewed radiographs of the hands and wrists of 33 patients with immature skeletons and chronic renal disease. Various radiographic manifestations of renal osteodystrophy were seen, including osteopenia in 23 patients (70%), subperiosteal resorption in 20 (61%), distal tuft resorption in 14 (42%), sclerosis of vertebral bodies in 2 (6%), and soft-tissue calcification in 1 (3%). We also noted that 13 patients (39%) exhibited metaphyseal sclerosis adjacent to the growth plates. Five of these 13 showed persistent sclerosis years after the growth plates had fused. None of the patients showed other radiographic changes of rickets, and there was no correlation between the serum calcium, phosphorus, or aluminum levels and the presence of metaphyseal sclerosis. Neither was there any association with the underlying cause of renal failure, method of treatment, presence of a transplant, or type of dialysis. We view this finding as another manifestation of renal osteodystrophy. The importance of distinguishing it from other sclerotic lesions is discussed.

Adolescent↗
PubMed1991

Randomized double pulse stimulation for assessing stimulus frequency-dependent conduction in injured spinal and peripheral axons.

Injury compromises the ability of axons to conduct action potentials at high frequencies. To study stimulus frequency-dependent conduction in injured spinal and peripheral axons, we developed a new stimulation paradigm which applies trains of double pulses at 5 Hz and randomly varied interpulse intervals of 3, 4, 5, 8, 10, 30, 50, and 80 msec. In each double pulse, the first pulse was used to condition the response activated by the second test pulse. Responses elicited by double pulses with 80 msec intervals served as controls. The L5 dorsal root was stimulated to activate dorsal column and dorsal root compound action potentials in pentobarbital anesthetized rats. To injure the spinal cord, we compressed the cord stepwise (0.25 mm every 5 min) until action potential conduction across the compression site was abolished and then decompressed the spinal cord 10 min later. Before injury, conditioning pulses applied 3-80 msec before the test pulses did not alter dorsal column responses except for a slight amplitude augmentation at 20 msec interpulse intervals (mean +/- S. E., + 4.2 +/- 0.8%, P less than 0.02) compared to controls. Injury had 3 effects on the responses. First, it significantly reduced response amplitudes and increased response latencies at 3-5 msec interpulse intervals, i.e., responses activated with 3 msec intervals were 26.0 +/- 7.4% (P less than 0.002, paired t test, n = 6) smaller and had 108 +/- 45 microseconds (P less than 0.04) longer latency than control responses. Second, response amplitude increases at 20 msec interpulse intervals (9.0 +/- 0.7%, P less than 0.0001) significantly exceeded those observed before injury (P less than 0.02, paired t test). Third, injury accentuated response amplitude declines during the stimulus train, most prominently at 80 msec intervals. Spinal cord injury did not affect the dorsal root responses. L5 root compression injury depressed dorsal root action potentials at 3-5 msec interpulse intervals (36.9 +/- 8.4%, n = 4, P less than 0.0001) but had no other effect on the responses. Our data indicate that randomized double pulse evoked potentials are sensitive detectors of acute axonal dysfunction and can be used to quantify stimulus frequency-dependent conduction deficits in injured central and peripheral axons.

Action Potentials↗
PubMed1991

Basilar artery occlusion in rats.

The basilar artery is one of the three major sources of blood supply to the circle of Willis. To investigate the effects of basilar artery occlusion, we surgically exposed and coagulated the basilar artery in 25 rats. Basilar artery occlusion at any single point between the foramen magnum and the circle of Willis in 11 rats did not produce histologically detectable infarcts in the brain at 12-24 hours. Two-point occlusions of the basilar artery in 12 rats produced variable infarcts between the occlusion sites but no ischemic lesions elsewhere. After either single- or double-point occlusions, the proximal basilar artery refilled within 2-3 minutes. When the basilar artery was occluded above and below the origins of the anterior inferior cerebellar arteries, the artery segments between the occlusion points initially collapsed but refilled within 2-3 minutes in two rats. Basilar artery occlusions invariably suppressed cortical somatosensory evoked potentials by greater than 50%. Regardless of whether a brain stem infarct developed, somatosensory evoked potential amplitudes recovered to greater than baseline levels by 4 hours in seven of 17 rats and returned to baseline levels by 24 hours in every rat tested. We conclude that the occluded basilar artery receives extensive retrograde collateral blood flow and that somatosensory evoked potentials are exquisitely sensitive to basilar artery occlusion but are insensitive to whether brain stem infarcts develop.

Animals↗
PubMed1991

Absent splenic uptake of indium-111-oxine-labeled autologous leukocytes in functional asplenia.

An incidental finding of absent splenic uptake of autologous, indium-111-oxine-labeled leukocytes in an immunosuppressed renal transplant recipient was documented to be associated with functional asplenia based on absence of technetium-99m-sulfur colloid clearance by a morphologically normal spleen. The patient had recently suffered an episode of disseminated varicella infection that might have led to the development of functional asplenia.

Adult↗
PubMed1991

Methylprednisolone treatment of acute spinal cord injury: an introduction.

Contusion injuries of cat spinal cords rapidly block action potential conduction across the impact site. Ion-selective microelectrode measurements revealed large and immediate extracellular ionic derangements, sufficient to block conduction. As extracellular potassium recovers, evoked potentials often return but are lost again when white matter blood flow fall. The delayed decline of evoked potentials and blood flow suggest secondary injury processes that may respond to pharmacological therapy. High dose methylprednisolone (15-30 mg/kg) dramatically improved blood flow, extracellular ionic shifts, blood flow, and evoked potentials in cat spinal cords. Methylprednisolone also decreased tissue ionic shifts and improved locomotory recovery. In concomitant experiments, we showed that naloxone also prevented posttraumatic declines in blood flow and improved locomotory recovery. Examination of the spinal cords at 6-12 weeks after injury, revealed that many recovered animals had only 10% of spinal cord axons remaining. Other studies revealed that many axons surviving injury are demyelinated, suggesting that drugs that protect oligodendroglial cells may also have beneficial effects.

Acute Disease↗
PubMed1990

A randomized, controlled trial of methylprednisolone or naloxone in the treatment of acute spinal-cord injury. Results of the Second National Acute Spinal Cord Injury Study.

Studies in animals indicate that methylprednisolone and naloxone are both potentially beneficial in acute spinal-cord injury, but whether any treatment is clinically effective remains uncertain. We evaluated the efficacy and safety of methylprednisolone and naloxone in a multicenter randomized, double-blind, placebo-controlled trial in patients with acute spinal-cord injury, 95 percent of whom were treated within 14 hours of injury. Methylprednisolone was given to 162 patients as a bolus of 30 mg per kilogram of body weight, followed by infusion at 5.4 mg per kilogram per hour for 23 hours. Naloxone was given to 154 patients as a bolus of 5.4 mg per kilogram, followed by infusion at 4.0 mg per kilogram per hour for 23 hours. Placebos were given to 171 patients by bolus and infusion. Motor and sensory functions were assessed by systematic neurological examination on admission and six weeks and six months after injury. After six months the patients who were treated with methylprednisolone within eight hours of their injury had significant improvement as compared with those given placebo in motor function (neurologic change scores of 16.0 and 11.2, respectively; P = 0.03) and sensation to pinprick (change scores of 11.4 and 6.6; P = 0.02) and touch (change scores, 8.9 and 4.3; P = 0.03). Benefit from methylprednisolone was seen in patients whose injuries were initially evaluated as neurologically complete, as well as in those believed to have incomplete lesions. The patients treated with naloxone, or with methylprednisolone more than eight hours after their injury, did not differ in their neurologic outcomes from those given placebo. Mortality and major morbidity were similar in all three groups. We conclude that in patients with acute spinal-cord injury, treatment with methylprednisolone in the dose used in this study improves neurologic recovery when the medication is given in the first eight hours. We also conclude that treatment with naloxone in the dose used in this study does not improve neurologic recovery after acute spinal-cord injury.

Acute Disease↗
PubMed1990

Effect of pulsed electromagnetic fields on calcium tissue changes in focal ischaemia.

The effect of a pulsed electromagnetic field (PEMF) (parameters: 27.1 MHz, 585 W peak power, and 65 microseconds pulses, 400 times per second) on rats undergoing middle cerebral artery occlusion (MCAo) was investigated. Four groups of eight rats each underwent microsurgical MCAo. Two groups were treated with a PEMF generator for 2 h following the onset of ischemia and were sacrificed at 4 and 24 h following the MCAo respectively. The other two groups were also sacrificed at the same time intervals. Regional brain sodium, potassium, and calcium tissue contents were determined by atomic spectrophotometry. As distinct from results found in spinal cord contusion, no significant difference between the PEMF-treated groups and the non-treatment groups was found. PEMF treatment did not alter the 300% rise in calcium tissue dry weight content observed at 24 h following MCAo in the infarcted tissue. Regional brain water content was determined by the dry weight method. A regionally inconsistent reduction in brain water content was noted in the PEMF-treated rats.

Animals↗