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Biomedical subjects

J A Lee

Publications and source records attributed to J A Lee.

At least 19 recordsLinked to original sources
PubMed1992

Hepatic reinnervation following orthotopic liver transplantation in man.

We have studied changes in the pattern of intrinsic hepatic innervation in sequential liver biopsies from 16 patients who underwent orthotopic liver transplantation. Seventy-one needle biopsies were used, including specimens obtained at the time of transplantation (time zero) and up to 4 years post-transplantation; five transplant hepatectomy tissue blocks removed 3-32 months after transplantation were also assessed. Paraffin sections were immunostained with anti-PGP 9.5 and anti-S-100 to identify nerve fibres. All 'time zero' biopsies contained portal nerves and all but two showed staining of parenchymal fibres. After 1 week, no subsequent biopsies contained parenchymal fibres. The disappearance of portal fibres was less rapid and showed greater variability between patients, but they had all disappeared by 6 weeks and there was no positive staining between 6 and 60 weeks. Thereafter, a minority of biopsies showed innervation of a few small portal tracts. Samples from the porta hepatis, hepatectomy specimens, and needle biopsies containing large tracts showed persistence of major nerve trunks at all stages. Abnormally large nerve bundles were seen in some of these areas. The pattern of nerve staining showed no obvious relationship to the intensity of rejection changes. Our results suggest that there is a limited, delayed capacity for regeneration of portal, but not parenchymal, fibres in the transplanted human liver. The physiological significance of this long-term parenchymal denervation in transplanted livers remains to be determined.

Humans↗
PubMed1992

Stimulation of c-fos and c-jun gene expression and down-regulation of proenkephalin gene expression in C6 glioma cells by endothelin-1.

The linkage between the transmembrane signal transduction system utilized by endothelin and alterations in gene expression has been investigated in C6 glioma cells. Treatment of C6 cells with endothelin-1 caused a rapid and transient 5-fold increase in c-fos and c-jun mRNA levels, followed by a decrease at 4 h. Dose-response studies indicated that 1 nM endothelin-1 caused half-maximal induction of c-fos mRNA 0.5 h after treatment and that maximal induction was elicited with a concentration of 10 nM. Actinomycin D totally abolished the rapid increase in c-fos mRNA caused by endothelin, indicating that the effect is at the transcriptional level. Endothelin-1 caused a decrease in proenkephalin mRNA to 50% of control levels at 4 h after treatment and had no effect on histone H4 mRNA over a 24 h period that was examined. These data indicate that receptor binding of endothelin-1 leads to rapid changes in the expression of immediate-early response genes which may cause more prolonged changes in the expression of AP-1 and/or CREB target genes in the nervous system.

Animals↗
PubMed1992

Etiology, risk factors, epidemiology, and public health issues in melanoma and other cutaneous neoplasms.

The cytogenetic features of melanoma, including the contribution of specific genes, are beginning to be unraveled. Reproductive factors have been shown to have little relationship to melanoma. The puzzles over apparent systemic effects of exposure have persisted, however. Evidence was published that the history of reaction to sun exposure altered when a diagnosis of melanoma was made. An interesting suggestion was made that the classic melanoma risk factors are associated with promotion rather than initiation of the disease. There is further evidence that exposure decreases melanoma risk in people who tan well but increases it in those who do not. Also reviewed is the evidence that the ozone layer of the stratosphere began to decrease in thickness under the influence of the chlorofluorocarbon gasses.

Heliotherapy↗
PubMed1992

Disappearance of hepatic parenchymal nerves in human liver cirrhosis.

The normal human liver receives a substantial autonomic innervation that is thought to subserve motor, metabolic, and sensory functions. In this study an antibody to a neural axoplasmic protein (PGP 9.5) was used to visualise autonomic nerves in tissue from normal, precirrhotic, and cirrhotic livers. Nerve fibres were readily identified in the parenchyma and portal tracts of normal livers, and in those where the histological diagnosis was non-specific reactive hepatitis or acute liver injury. In precirrhotic and cirrhotic livers nerves in portal tracts and fibrous septae remained prominent, but the parenchymal innervation was reduced in precirrhotic livers and was absent from regenerating nodules in established cirrhosis. The causes and functional consequences of this parenchymal denervation in cirrhosis remain to be established.

Antibodies, Monoclonal↗
PubMed1992

Changes in intracellular free calcium concentration during long exposures to simulated ischemia in isolated mammalian ventricular muscle.

Intracellular free calcium concentration ([Ca2+]i) was measured in isolated ferret ventricular papillary muscles during and after long exposures to ischemia. All experiments were performed at 37 degrees C, and the muscles were stimulated at 1 Hz. Ischemia was simulated by changing from superfusion with oxygenated Tyrode's solution to superfusion with water-saturated gas (95% N2-5% CO2), thus simultaneously stopping oxygenation and restricting the extracellular space. [Ca2+]i was measured with aequorin, which was microinjected into superficial cells of the preparation. Exposure to ischemia caused a complex series of changes in [Ca2+]i. In the first few minutes the changes in [Ca2+]i were variable; however, after approximately 5 minutes all preparations exhibited a progressive increase in amplitude and duration of the stimulated rise in [Ca2+]i (the calcium transient). The amplitude of the calcium transients peaked after approximately 18 minutes of ischemia, when they were 339% of the control value. After this peak, the calcium transients progressively failed to occur in response to stimulation and declined in amplitude; simultaneously, spontaneous oscillations of [Ca2+]i appeared and increased in size and frequency. The oscillations in turn then gradually became less frequent until a large, prolonged (5-10 minute) increase in [Ca2+]i occurred, after which [Ca2+]i returned to a low level. There were no further oscillations after this event, which was seen on average after 37 minutes of ischemia. A slowly progressive contracture often began to develop at about this time. A gradual rise in resting [Ca2+]i occurred during the remainder of the exposure to ischemia. When muscles were reperfused after long exposures to ischemia, there was a very large and prolonged increase in [Ca2+]i, which was usually associated with a contracture and failure of recovery of developed tension. The large increase in [Ca2+]i could be reduced by the inclusion of 3 mM nickel chloride in the reperfusing solution. Comparison between reperfusion with O2 gas versus reperfusion with anoxic Tyrode's solution indicated that reoxygenation was more beneficial to the muscle than resumption of bulk flow. These results reveal the complex spectrum of changes in [Ca2+]i that occur during ischemia and on reperfusion. These changes in [Ca2+]i are likely to play an important role in the generation of ischemic arrhythmias and muscle damage.

Animals↗
PubMed1992

Role of excitation-contraction coupling in muscle fatigue.

The force produced by muscles declines during prolonged activity and this decline arises largely from processes within the muscle. At a cellular level the reduced force could be caused by: (a) reduced intracellular calcium release during activity; (b) reduced sensitivity of the myofilaments to calcium; or (c) reduced maximal force development. Experiments involving intracellular calcium measurements in isolated single fibres show that all 3 of the above contribute to the decline of force during fatigue. Metabolic changes associated with fatigue are probably involved in each of the 3 factors. Thus the accumulation of phosphate and protons which occur during fatigue cause a reduction in calcium sensitivity and a decline in maximal force. The cause of the reduced intracellular calcium during contractions in fatigue is less clear. During prolonged tetani the conduction of the action potential in the T-tubules appears to fail leading to reduced intracellular calcium in the central part of the muscle fibre. However, during repeated tetani there is a uniform decline of intracellular calcium across the fibre and this remains one of the least understood processes which contribute to fatigue.

Action Potentials↗
PubMed1992

Molecular cloning and characterization of the major endothelin receptor subtype in porcine cerebellum.

Endothelin receptors (ETRs) display subtype heterogeneity and are widely distributed throughout the tissues of the periphery and central nervous system. In order to gain further insight into the potential molecular differences of ETRs, we initiated molecular cloning of ETR genes by screening for the appearance of 125I-ET-1 binding activity in COS cells transfected with pools of a porcine cerebellum cDNA expression library. Two independent clones (pPCETR 1.1 and pPCETR 5.6) were identified and isolated by repeated rounds of pool enrichment and COS cell expression. DNA sequence analysis of pPCET 1.1 and pPCET 5.6 indicated that both clones have the same nucleotide sequence; the deduced amino acid sequence indicated that the porcine cerebellum ETR is 443 residues in length and consists of seven potential transmembrane domains, with homology to members of the GTP-binding protein-coupled receptor superfamily. Northern analysis indicated a single mRNA species of about 5 kilobases, which is expressed significantly in cerebellum, lung, kidney, and pituitary. Expression of functional receptor was demonstrated by endothelin-1 (ET-1)-mediated Ca2+ mobilization in COS cells transfected with pPCETR 1.1 (COS/ETR 1.1) and ET-1-mediated electrophysiological responses in Xenopus oocytes injected with RNA derived from pPCETR 1.1. Quantitative comparison of saturation binding of 125I-ET-1 to either porcine cerebellum or COS/ETR 1.1 membranes indicated an identical apparent dissociation constant. The relative efficacy of ET-related peptides to compete for binding of 125I-ET-1 to receptor from porcine cerebellum and COS/ETR 1.1 indicated that both preparations encode a nonselective or ETBR subtype. Chemical cross-linking of 125I-ET-1 to receptor derived from cerebellum or COS/ETR 1 revealed two bands, with apparent molecular masses of 47 and 35 kDa. These data demonstrate that the pPCETR 1.1 encodes the major ETR subtype in the porcine cerebellum.

Amino Acid Sequence↗
PubMed1991

Uraemia: is urea more important than we think?

Urea is accumulated as an osmolyte by some groups of animals even though it impairs protein function. These organisms can withstand high internal urea concentrations because they also accumulate other low-molecular-weight osmolytes, the methylamines, which can offset the effects of urea on proteins. Methylamines have also been found in the medulla of the mammalian kidney (where urea concentrations are high) and in the plasma of human subjects with chronic renal failure. These findings suggest that previous investigations of the potential contribution of urea to the syndrome of uraemia may have been confounded because of the presence of variable concentrations of protective substances. That naturally occurring methylamines or related substances may prove to have a useful therapeutic role in uraemia is also possible.

Animals↗
PubMed1991

Indications of future decreasing trends in skin-melanoma mortality among whites in the United States.

Trends in skin melanoma death rates during a 35-year period, 1950-84, were analyzed according to age, sex, and birth cohort for whites in the United States. In contrast to upward trends observed for older men and women (i.e., over 40), downward trends were noted for younger age groups. The risk of dying from skin melanoma appears to have peaked for male cohorts born during the 1950s and for female cohorts born during the 1930s. Assuming no future environmental or lifestyle changes, the upward trend in age-adjusted mortality rates, which averaged 2 to 3% per annum since 1950, is projected to discontinue and bend downward by the second decade of the 21st century. Skin melanoma incidence data, which was limited to a series of 12 years (1973-84) and inadequate for cohort analyses, were included to demonstrate that trends in age-specific rates were comparable with those observed for mortality during the overlapping time period. Incidence trends according to anatomical site are also described. These results indicate that baseline data necessary for assessing the potential effects on this disease from future depletions of the ozone layer, and predicted increases of solar ultra-violet radiation exposure, would be improved with the inclusion of cohort data and age-specific trend analyses.

Age Factors↗
PubMed1991

Nuclear magnetic resonance studies of blood plasma and urine from subjects with chronic renal failure: identification of trimethylamine-N-oxide.

We have used 1H-, 13C- and 14N-NMR spectroscopy to investigate the constituents of plasma and urine in 16 patients with chronic renal failure (CRF). Resonances not previously observed in spectra of plasma from healthy volunteers were seen in CRF plasma, including those for trimethylamine-N-oxide (TMAO) and dimethylamine (DMA). A possible analogy with the plasma of elasmobranch fishes, in which TMAO stabilizes proteins in the presence of very high urea concentrations, is noted. The intensity of the TMAO resonance for CRF subjects was correlated with the plasma concentration of urea (R = 0.55) and creatinine (R = 0.74), suggesting that the presence of TMAO is closely related to the degree of renal failure. When normal subjects ate a meal of TMAO-containing fish, TMAO appeared rapidly in the plasma and in the urine. Thus TMAO is efficiently cleared by the healthy kidney. Differences in the interaction of lactate with plasma proteins were detected by NMR, suggesting that uraemia impairs their transport roles.

Adult↗
PubMed1991

Okadaic acid, a protein phosphatase inhibitor, increases the calcium transients in isolated ferret ventricular muscle.

Okadaic acid is a protein phosphatase inhibitor which has been found to produce a marked positive inotropic effect in isolated cardiac muscle. Using aequorin-injected ferret papillary muscles, we demonstrate that the increase in tension seen with okadaic acid is accompanied by a simultaneous increase in the amplitude of the calcium transients. By comparison with the effects of changing the extracellular calcium concentration, it is shown that the increase in calcium transient amplitude can account for the inotropic effect of okadaic acid.

Animals↗
PubMed1991

Changes in tetanic and resting [Ca2+]i during fatigue and recovery of single muscle fibres from Xenopus laevis.

1. Single muscle fibres were dissected from the toe muscles of Xenopus laevis and microinjected with Fura-2 to measure myoplasmic calcium concentration ([Ca2+]i). Injected fibres were illuminated at 340 and 380 nm and the ratio of the resulting fluorescence at 505 nm (the Fura-2 ratio) was taken as a measure of [Ca2+]i. Fibres were fatigued at 21 degrees C by repeated tetani until developed tension had fallen to 50% of control. 2. Tetanic tension declined monotonically during fatiguing stimulation, whereas the tetanic Fura-2 ratio first increased and then declined. At the 10th tetanus, tension was 87% of control whereas the Fura-2 ratio was 106% of control. At the end of fatiguing stimulation, where tension was around 50% of control, the tetanic Fura-2 ratio was reduced to 71%. The rate of decline of both tension and the Fura-2 ratio after a tetanus slowed during fatigue. During recovery, the tension and the tetanic Fura-2 ratio recovered in parallel. 3. The resting Fura-2 ratio increased throughout fatigue reaching 237% of control when tension had declined to 50%. There was a rapid phase of recovery, complete within 1 min, by which time the resting Fura-2 ratio was 198% of control. Subsequent recovery was slower and took 20-30 min to reach a stable level which was 121% of control. 4. The resting Fura-2 ratio towards the end of fatiguing stimulation was greater than the tetanic Fura-2 ratio in the early part of recovery although there was no detectable increase of resting tension during fatiguing stimulation. This observation suggests that the Ca2+ sensitivity of the contractile proteins was reduced at the end of fatiguing stimulation. 5. Plots of the tetanic tension against tetanic Fura-2 ratios throughout fatiguing stimulation and recovery also suggested that Ca2+ sensitivity was reduced during fatiguing stimulation when compared to recovery. 6. The increases in resting [Ca2+]i caused by raised [K+]o (from 2.5 to 10 mM) and/or by application of 15% CO2 were much less than those produced by fatiguing stimulation. Much of the elevated [Ca2+]i in fatigue could be reversed by application of dantrolene (25 microM). 7. The results suggest that both reduced tetanic [Ca2+]i and reduced Ca2+ sensitivity contribute to the decline of tension during fatigue.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1991

Video absorbtiometry in diagnostic cytology: description of a new technique and a preliminary statistical evaluation.

Cytological specimens from 21 patients were examined using digital video microscopy. The staining characteristics of cells incubated with hydroquinone and the tetrazolium stain MTT were analysed using a novel procedure that is independent of morphological features and relies on characteristics of the frequency distribution of the localised (pixel) absorbances of the cellular images. The properties of the distribution of absorbances were assessed by a number of procedures. Comparisons were made of nine malignant and 12 non-malignant cytological samples, obtained mainly from pleural and peritoneal fluid. The data showed significant differences between the sets of samples which may be of value in cytological diagnosis. In the material examined all the malignant samples exhibited a positive skewness with the alpha-3 test (the mean alpha-3 value being greater than 0.5); this was true in only two of 12 non-malignant samples. This analytical technique, which is largely independent of morphology, magnification, and absolute absorbance values, seems to hold promise for the simplification and automation of cytological screening procedures.

Absorptiometry, Photon↗
PubMed1991

Cellular mechanisms of fatigue in skeletal muscle.

Prolonged activation of skeletal muscle leads to a decline of force production known as fatigue. In this review we outline the ionic and metabolic changes that occur in muscle during prolonged activity and focus on how these changes might lead to reduced force. We discuss two distinct types of fatigue: fatigue due to continuous high-frequency stimulation and fatigue due to repeated tetanic stimulation. The causes of force decline are considered under three categories: 1) reduced Ca2+ release from the sarcoplasmic reticulum, 2) reduced myofibrillar Ca2+ sensitivity, and 3) reduced maximum Ca(2+)-activated tension. Reduced Ca2+ release can be due to impaired action potential propagation in the T tubules, and this is a principal cause of the tension decline with continuous tetanic stimulation. Another type of failing Ca2+ release, which is homogeneous across the fibers, is prominent with repeated tetanic stimulation; the underlying mechanisms of this reduction are not fully understood, although several possibilities emerge. Changes in intracellular metabolites, particularly increased concentration of Pi and reduced pH, lead to reduced Ca2+ sensitivity and reduced maximum tension, which make an important contribution to the force decline, especially with repeated tetanic stimulation.

Actin Cytoskeleton↗
PubMed1991

EMD 53998 sensitizes the contractile proteins to calcium in intact ferret ventricular muscle.

EMD 53998 (a thiadiazinone) is an inotropic drug that produces a pronounced increase in the Ca2+ sensitivity of the contractile proteins in skinned cardiac fibers. The present study was undertaken to determine whether this effect on Ca2+ sensitivity could explain the increase in tension observed in intact ventricular muscle. The experiments were performed on isolated ferret papillary muscles that had been microinjected with aequorin to measure the intracellular Ca2+ concentration. Force and intracellular Ca2+ concentration were monitored before, during, and after application of EMD 53998. EMD 53998 (5 microM) increased developed tension by 230%; aequorin light transients increased by only 85%, and this increase was reduced and became insignificant in the presence of agents that prevent catecholamine release. When a similar increase in developed tension was produced by elevation of extracellular calcium, the aequorin light transients increased by 240%. Thus, EMD 53998 produces a substantial Ca2+ sensitization in intact ventricular muscle, and this can explain most of its inotropic effect. In addition, EMD 53998 caused a small prolongation of the time course of contraction and a small reduction of the time course of the aequorin light transient. A computer model is described that shows that both these effects can be explained by the effect of EMD 53998 on Ca2+ sensitivity. At much higher concentrations, EMD 53998 also caused an increase in resting tension. EMD 53998 is the first agent for which much of the inotropic effect in intact cardiac muscle can be accounted for by increased Ca2+ sensitivity of the contractile proteins. Inotropic agents with this mechanism of action cause increased force production with much less increase in the intracellular Ca2+ transients than conventional agents and, therefore, increase the energy efficiency of the myocardium and are less likely to cause Ca(2+)-activated arrhythmias.

Animals↗