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Biomedical subjects

C J Duncan

Publications and source records attributed to C J Duncan.

At least 55 records · Page 3Linked to original sources
PubMed1993

Cellular damage in the rat heart caused by caffeine or dinitrophenol.

1. Langendorff-perfusion of rat hearts with either 10 mM caffeine or 1 mM 2,4-dinitrophenol (DNP) caused severe ultrastructural damage to the myofilaments and mitochondria that was similar to that found in a standard Ca(2+)-paradox. 2. This damage occurred in the presence and absence of extracellular Ca2+. 3. Creatine kinase (CK) release (indicative of sarcolemma breakdown) was not recorded unless the caffeine- or DNP-perfusion was preceded by Ca(2+)0-depletion. 4. It is concluded that: (i) the pathways leading to damage to the myofilaments and sarcolemma are independent; (ii) the CK release mechanism requires dual activation of Ca(2+)0-depletion plus a rise in [Ca2+]i; and (iii) current theories concerning the mechanisms underlying the genesis of the Ca(2+)-paradox are incorrect or incomplete.

2,4-Dinitrophenol↗
PubMed1993

The dynamics of smallpox epidemics in Britain, 1550-1800.

Time-series analysis, a valuable tool in studying population dynamics, has been used to determine the periodicity of smallpox epidemics during the seventeenth and eighteenth centuries in two contrasting representative situations: 1) London, a large city where smallpox was endemic, and 2) Penrith, a small rural town. The interepidemic period was found to be two years in London and five years in Penrith. Equations governing the dynamics of epidemics predict 1) a two-year periodicity and 2) that oscillatory epidemics die out quickly. It is suggested that epidemics were maintained by a periodic variation in susceptibility linked either to a five-year cycle of malnutrition or to an annual cycle. Computer modeling shows how the very different patterns of epidemics are related to population size and to the magnitude of the oscillation in susceptibility.

Disease Outbreaks↗
PubMed1990

Biochemical events associated with rapid cellular damage during the oxygen- and calcium-paradoxes of the mammalian heart.

The O2- and Ca2(+)-paradoxes have a number of features in common and it is suggested that release of cytosolic proteins in both paradoxes is initiated by the activation of a sarcolemma NAD(P)H dehydrogenase which can generate a transmembrane flow of H+ and e- and also oxygen radicals or redox cycling which damage ion channels and membrane proteins (phase I). Entry of Ca2+ through the damaged ion channels then exacerbates the damage by further activating this system, either directly or indirectly, and the redox cycling and/or oxygen radicals cause further damage to integral and cytoskeletal proteins of the sarcolemma resulting in microdamage to the integrity of the membrane (phase II) and the consequent release or exocytosis of cytoplasmic proteins and, under specialised conditions, the blebbing of the sarcolemma. The system may be primed either by removal of extracellular Ca2+ or by raising [Ca2+]i by a variety of measures, these two actions being synergistic. The system is initially activated in the Ca2(+)-paradox by the membrane perturbation associated with removal of extracellular Ca2+; prolonged anoxia in the metabolically active cardiac muscle causes a depletion of the ATP supply, particularly in the absence of glucose, and hence a rise in [Ca2+]i in phase I of the oxygen paradox with the consequent activation of the NAD(P)H oxidase at the sarcolemma. Oxygen radicals are probably generated in both paradoxes and may have a partial role in the genesis of damage, but are not essential in the Ca2(+)-paradox which continues under anoxia. Massive entry of Ca2+ also activates an intracellularly localised dehydrogenase (probably at the SR) which produces myofilament damage by redox cycling.

Animals↗
PubMed1990

Progress toward an internal control system for fragile-X induction by 5-fluorodeoxyuridine in whole-blood cultures.

We have been attempting to develop a consistently reliable internal control to assure the effectiveness of the 5-fluorodeoxyuridine (FUdR) fragile-X [fra(X)] induction system. We carried out a systematic study of whole-blood specimens cultured from 56 individuals from two different laboratories. An analysis of nearly 9,000 cells demonstrated: (1) the importance of establishing baseline levels of fragile sites in each laboratory, and (2) that a combination of common fragile sites (different for each laboratory) could serve as a consistently reliable indicator of the effectiveness of the FUdR fra(X) induction system. It was suggested that a non-FUdR culture(s) should be incorporated into a laboratory's fra(X)-screening protocol, so that if there are any doubts about the effectiveness of the FUdR system a comparison to background or spontaneously occurring fragile sites can be made within the laboratory. Repeat cultures are recommended where no increase in common fragile-site frequency is observed in the FUdR induction system, and where fra(X) was strongly suspected but not found. In addition, the necessity of using more than one fra(X) induction system in whole-blood cultures was demonstrated, including the effectiveness of an FUdR/excess thymidine double-induction system. Finally, 2 cases of apparent mosaicism for Klinefelter syndrome in fra(X) individuals were observed.

Blood Cells↗
PubMed1989

Mechanisms that produce rapid damage to myofilaments of amphibian skeletal muscle.

The system causing myofilament damage is separate from the phospholipase A2 pathway, Ca activation of which ultimately causes sarcolemma breakdown in muscle cells. Mitochondrial agents cause myofilament damage in saponin-skinned frog pectoris cutaneous muscle when [Ca] = 0. There are parallels with other systems that generate oxygen radicals. However, a variety of protectors against oxygen radicals, or anoxia, failed to protect; Ca-activated damage was not augmented by diethylthiocarbamate, nor was it accompanied by a respiratory burst. Thus, there is no firm evidence implicating oxygen radicals in myofilament damage. Thiol-oxidizing agents cause contraction damage in skinned muscle that resembles the quasirigor induced in myosin by N-ethylmaleimide. Activation of transmembrane dehydrogenases and electron flow produced damage and increased Ca sensitivity in skinned muscle, and it is suggested that this enzyme system may be implicated in characteristic damage to the myofilaments via redox cycling and modification of sulphydryl groups; its possible location on the sarcoplasmic reticulum is discussed.

Actin Cytoskeleton↗
PubMed1989

Cytotoxic effect of oxygen on the skeletal muscle of mouse diaphragm.

Incubation of the isolated mouse diaphragm with a high rate of oxygenation (10 ml s-1, 95% O2 + 5% CO2) causes a characteristic cellular damage with widely-separated myofibrils and swollen sarcotubular system within 10 min. This damage was ameliorated by inhibitors of the hydroxyl radical (.OH), desferrioxamine, dimethyl thiourea and 120 mM mannitol, and by incubation at 8 degrees C. It was not prevented either by inhibitors of the pathway leading to sarcolemma damage (nordihydroguaiaretic acid, alpha-tocopherol, butylated hydroxytoluene) nor by agents and treatments that inhibit the oxygen paradox of cardiac muscle (glucose, omission of extracellular calcium, incubation at 30 degrees C, superoxide dismutase and catalase). Nevertheless there are similarities between these two types of damage triggered by O2 and the possibility that in both an NAD(P)H oxidase is stimulated and cytotoxic oxygen radicals are generated is discussed.

Animals↗
PubMed1989

Cytotoxic action of the lysosomotropic agent L-leucine methyl ester on mammalian skeletal muscle. The role of the sarcoplasmic reticulum in producing myofilament damage.

Incubation in vitro of mouse or rat diaphragms or mouse soleus muscle with the lysosomotropic agent leucine methyl ester (10 mM) produced a slowly-developing swelling of the sarcoplasmic reticulum (SR), showing that this organelle is able to take up amino acid methyl esters and conforming with previous suggestions that the SR may serve some of the functions of the lysosomal system in muscle cells. Cellular damage followed, sometimes associated with the shrinkage of the SR, but experiments with inhibitors of lysosomal cathepsins suggest that acid hydrolases were not implicated in this damage. It is suggested that the system producing myofilament damage is located on the SR and that it may be directly activated by membrane perturbation.

Animals↗
PubMed1989

Effects of anoxia on cellular damage in the incubated mouse diaphragm.

Satisfactory ultrastructural integrity of the mouse diaphragm was maintained in vitro in modified Krebs-henseleit saline for 3h when the rate of oxygenation was 2.8 ml sec-1 (95% O2 + 5% CO2). Hypoxic (O2 = 1.6-2.0 ml sec-1) or anoxic (95% N2 + 5% CO2) conditions triggered typical Ca-triggered myofilament damage, believed to be induced by a rise in [Ca]i. It was unaffected by omission of Ca from the saline, but the muscle was protected at 7.8 degrees C. 'High-O2' gassing (10 ml sec-1) also caused a characteristic, but different, damage with swollen sarcoplasmic reticulum and spacing of the myofibrils.

Animals↗
PubMed1989

Sarcolemma blebs and cell damage in mammalian skeletal muscle.

Plasma membrane blebs are an early sign of cellular damage in isolated cells. Phenazine methosulphate (PMS) triggers the production of conspicuous and characteristic sarcolemma blebs in mouse diaphragm skeletal muscle incubated in vitro and also causes severe myofilament damage. It is suggested that PMS activates transmembrane NAD(P)H dehydrogenases and, in turn, a modification of sulphydryl groups of the cytoskeleton, thereby permitting bleb formation in contracting cells.

Animals↗
PubMed1989

A model for the oxygen-paradox in mouse cardiac muscle.

1. Mouse ventricle strips provide a good model system for studying cellular damage in mammalian cardiac muscle. 2. Anoxia rapidly causes destruction of the myofilament apparatus that is characteristic of calcium-triggered damage in muscle cells, and it is suggested that anoxia promotes release of calcium from the mitochondria. 3. Oxygen exacerbates this damage which is independent of extracellular calcium; it is suggested that it initiates myofilament damage by activation at an intracellular site, probably the sarcoplasmic reticulum.

Animals↗
PubMed1989

Independent pathways causing cellular damage in mouse soleus muscle under hypoxia.

1. Mouse soleus muscle incubated in vitro released creatine kinase (CK) and underwent ultrastructural damage under hypoxic conditions. 2. Both events were exacerbated by contractile activity following field stimulation. 3. Ultrastructural damage preceded CK release. 4. Omission of extracellular Ca2+ protected against CK release whereas ultrastructural damage was unaffected. 5. Excessive contractile activity for 30 min under normoxic conditions caused myofilament damage, but this was not accompanied by CK release. 6. The results support the hypothesis that the pathways leading to myofilament breakdown and to CK release are separate and independent. 7. The results are discussed in relation to changes in the supply of high energy phosphates and consequently in the regulation of Ca2+-homeostasis under hypoxia. 8. Both pathways are believed to be triggered by rises in [Ca2+]i. 9. A high rate of oxygenation (10 ml sec-1) had no damaging effects, unlike its action on mouse diaphragm in vitro. 10. Since damage is exacerbated under N2, there is no evidence to support the view that O2 metabolites are necessarily implicated in cell damage in skeletal muscle.

Animals↗
PubMed1989

Cytotoxic effect of phenazine methosulphate on the isolated frog heart.

1. Perfusion of isolated frog hearts with phenazine methosulphate (PMS) at 0.3-1.0 mM caused a fall in amplitude and frequency of beat, and finally a cessation of contractile activity, together with widespread ultrastructural damage. 2. Sarcolemma blebs were a characteristic feature of the damage. 3. No protection was provided by mannitol (10-100 mM), superoxide dismutase, catalase or a pHo of 6.6. 4. Potassium ferricyanide (1-6 mM), an artificial electron acceptor, also caused ultrastructural damage. 5. Comparisons are made with the oxygen paradox of mammalian heart, and the possible role of Ca2+ fluxes and oxygen radicals in muscle damage are discussed.

Animals↗