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Biomedical subjects

C J Duncan

Publications and source records attributed to C J Duncan.

At least 37 records · Page 2Linked to original sources
PubMed1996

Extracellular K+ and protection against cellular damage in the rat heart.

Rat hearts were perfused at 37 degrees C with three clearly-defined protocols: the Ca2+ paradox, the O2 paradox and with 20 mM caffeine. Each protocol involved an initial priming (stage 1) and a subsequent full activation (stage 2) of the damage system of the sarcolemma. Raising [K+]o from 5.4 to 6.5 mM in the Ca2+ paradox had no significant effect, but creatine kinase release was significantly inhibited (P < 0.001) at 7.5, 10.8 or 16.2 mM. Raising [K+]o to 16.2 mM only during stage 1 or only during stage 2 also inhibited creatine kinase release (P < 0.001); protection was greater than when 16.2 mM [K+]o was present throughout. [K+]o at 10.8 mM exacerbated creatine kinase release in the O2 paradox (P < 0.001) and also when present only during stage 1. However, significant protection was provided when [K+]o was raised only during stage 2 (P < 0.001). Creatine kinase release in the caffeine protocol was significantly inhibited (P < 0.001) at 10.8 mM [K+]o and when [K+]o was raised only during stage 1 or stage 2. It is concluded that raised [K+]o has two opposing effects: prevention of the activation of the membrane damage system and an exacerbation of damage via an increased Ca2+ influx.

Animals↗
PubMed1996

Whooping cough epidemics in London, 1701-1812: infection dynamics, seasonal forcing and the effects of malnutrition.

Time series analysis of the London Bills of Mortality, 1701-1812, reveals that whooping cough appeared as a lethal endemic disease after 1700 with epidemics of progressively increasing amplitude after 1720. The interepidemic period changed from 5 years (1720-1750) to 3 years (1750-1785) before returning to 5 years during 1785-1812. The epidemiology of whooping cough can be described by the mathematics of linearized dynamic systems and the interepidemic interval is determined by population size and susceptibility. The latter was governed by fluctuating levels of malnutrition, which were directly associated with oscillations in the wheat prices. It is suggested that the epidemics were driven in 1720-1785 by fluctuating seasonal temperatures which interacted with oscillations in wheat prices to produce an oscillation in susceptibility, but after 1785 the dynamics escaped from the pattern predicted by mathematical theory and the epidemics were apparently driven only by the wheat prices which generated a regular oscillation in susceptibility. The results emphasize the importance of an adequate nutritive level in combating whooping cough in the Third World today where it remains a lethal disease in children because of immunodeficiency linked to fluctuating and severe malnutrition which is often a consequence of crop cycles.

Agriculture↗
PubMed1996

The dynamics of scarlet fever epidemics in England and Wales in the 19th century.

There was a marked rise in scarlet fever mortality in England and Wales in the mid-nineteenth century and spectral analysis of the registration details, 1847-80, shows that the interepidemic interval was 5-6 years, but after 1880 the endemic level fell and the fatal epidemics disappeared. The dynamics of the scarlet fever epidemics can be represented by a linearized mathematical model and because the system is lightly damped, it could be driven by an oscillation in susceptibility. Epidemics were significantly correlated with dry conditions in spring/summer (P < 0.001), suggesting that these produced a low amplitude oscillation in susceptibility which drove the system. Epidemics also correlated (P < 0.001) with an oscillation in wheat prices but at a lag of 3 years, suggesting that malnutrition during pregnancy caused increased susceptibility in the subsequent children which interacted synergistically with seasonal dry conditions. Scarlet fever mortality was sharply reduced after 1880 in parallel with falling wheat prices suggesting that the remarkable period of high scarlet fever mortality (1840-80) was dependent on poor nutritive levels during that time.

Disease Outbreaks↗
PubMed1996

Membrane damage and the Ca(2+)-paradox in the perfused rat kidney.

Lactate dehydrogenase (LDH) leaks from the perfused rat kidney under the artificial conditions of a Ca(2+)-paradox protocol, namely Ca(2+)-repletion following a 20 minute period of Ca(2+)-depletion. LDH leakage was markedly suppressed by perfusion at 25 degrees C or with 0.1 mM dibucaine or 2 mM lidocaine. Lidocaine inhibited leakage only during Ca(2+)-depletion. Lowering the perfusion rate significantly reduced LDH escape. No LDH loss occurred if the osmotic pressure of the perfusion fluid was raised by 420 mOsm during either Ca(2+)-depletion or Ca(2+)-repletion. Amiloride (2 mM) significantly reduced LDH leakage to 43%. Reduction of the pH of the perfusion fluid to 6.8 significantly inhibited LDH loss, and at pH 6.4 this leakage was almost completely suppressed. LDH loss was equally suppressed at pH 6.4 only during Ca(2+)-depletion, whereas pH 6.4 was markedly less effective when perfused only during Ca(2+)-repletion. Ouabain (5 x 10(-6) M) had only a limited effect in exacerbating LDH leakage. Raising [K+]o significantly protected against LDH leakage, which fell to 36% at 16 mM [K+]. These features correspond with the Ca(2+)-paradox of the perfused rat heart an it is suggested that: (i) a Ca(2+)-paradox can be produced in the rat kidney; (ii) a similar mechanism governs the release of cytosolic proteins in these two preparations; and (iii) the damage mechanism of the plasmalemma is a transmembrane oxidoreductase-diaphorase molecular complex which generates H+ when activated by Ca(2+)-depletion.

Amiloride↗
PubMed1996

Protective effect of lidocaine on cell damage in the perfused rat heart.

The effect of lidocaine (2 mM) on cell damage in the perfused rat heart is compared in three experimental protocols: the Ca(2+)-paradox, the O2-paradox and perfusion with caffeine. Lidocaine protected against creatine kinase (CK) release when perfused throughout or only during the priming stage in all three protocols. Lidocaine also protects against CK release in the Ca(2+)-paradox when present only during Ca(2+)-reperfusion. Lidocaine protects against myofilament damage in the Ca(2+)-paradox but not in the O2-paradox and caffeine protocols, even though CK release is inhibited. Analysis of these different effects of lidocaine on the priming and full activation stages in the three protocols suggests the sequence of the underlying biochemical events of the two separate damage pathways associated with the release of cytosolic proteins and the degradation of the myofilament apparatus.

Animals↗
PubMed1996

The protective effect of lowered temperature on the oxygen paradox in the rat heart.

The isolated rat heart was completely protected against creatine kinase (CK) release in the standard Ca2+ or O2 paradoxes when perfused at 28 degrees C instead of 37 degrees C, as previously reported. Hearts subjected to the O2 paradox at 28 degrees C recovered normal contractile activity, and electron microscopy revealed normal, undamaged ultrastructure. The mitochondria remained contracted and showed no signs of Ca2+ uptake following a rise in Ca2+ concentration in the cytosol that would be expected following the prolonged period of anoxia. It is concluded that the rise in [Ca2+]i that results from a perturbation of Ca2+ homeostasis during anoxic perfusion in the O2 paradox is not sufficient to cause either CK release or myofilament degradation which follow only on reoxygenation in the second phase of the paradox. Since both the Ca2+ and O2 paradoxes are completely protected when the first stage is carried out at 28 degrees C, it is concluded that the initial activation of the sequence of damage events is prevented at this temperature.

Animals↗
PubMed1995

Infant mortality and famine: a study in historical epidemiology in northern England.

OBJECTIVE: To examine whether periodic variations in annual infant mortality were associated with malnutrition and the poor quality of the food supply available to the community. DESIGN: Retrospective study of historical epidemiology of infant mortality by time series analysis and family reconstitution of parish registers of burials and baptisms. SETTING: Penrith, Cumbria, England, 1557-1812. SUBJECTS: A total of 17,500 births during 1557-1812. RESULTS: This community in the Eden Valley, Cumbria, close to the Scottish borders, was living under marginal conditions with high mortality and low fertility. Clear oscillations in infant mortality synchronise with the oscillations in the wheat price index which is regarded as a measure of the availability of food to the community, and to pregnant and nursing mothers in particular. Input-output analysis showed that the relationship between the wheat price index (input) and infant mortality (output) was highly significant (p < 0.001). Events during the famine of 1623 have been analysed in detail: high wheat prices during pregnancy caused subsequent severe infant mortality but did not have indirect effects on the subsequent mortality of the surviving children over the age of 1 year. Non-stationary oscillations in neonatal and post neonatal mortality were strongly coherent (p < 0.001) with the wheat price index throughout the period. CONCLUSIONS: Infant mortality is particularly sensitive to famine and also to the quality of the food supply available to pregnant and nursing mothers. The lags between neonatal and post-neonatal mortalities and wheat prices, together with the analysis of the famine of 1623, support the hypothesis that neonatal mortality was related to malnutrition in pregnancy whereas post-neonatal mortality was primarily directly dependent on exogenous causes in the first year of life.

England↗
PubMed1995

The action of phenazine methosulphate in causing cellular damage in the isolated mouse soleus muscle preparation.

Exposure of the isolated mouse soleus preparation to 1.0 mM phenazine methosulphate (PMS) caused (i) a slow and modest release of creatine kinase (CK) that was exacerbated by removal of extracellular Ca2+, (ii) a specific type of ultrastructural damage, namely a characteristic spacing of the myofibrils, (iii) swelling of the mitochondria, indicating a modest rise in [Ca2+]i, and (iv) swelling of the sarcoplasmic reticulum (SR). It is suggested that PMS (i) activates a sarcolemma oxidoreductase which synergistically interacts with raised [Ca2+]i to cause modest CK efflux and (ii) activates an oxidoreductase on the SR, thereby generating electrons which directly modify the integrity and organisation of the contractile apparatus.

Animals↗
PubMed1994

Modelling the different smallpox epidemics in England.

Time series analysis has revealed two different patterns of smallpox epidemics in Britain in the seventeenth and eighteenth centuries: in large conurbations (exemplified by London) the disease was endemic whereas medium-sized rural towns (exemplified by Penrith, Cumbria) suffered from 5 year epidemics with no cases of smallpox in the inter-epidemic years. The oscillations (epidemics) persisted for over 150 years and it is suggested that both systems were pumped up by regular fluctuations in susceptibility (delta beta). Modelling suggests that: (i) the natural frequency of oscillations in large cities is two years and the system is pumped up by a 1 year, seasonal input; (ii) it takes five years to build up a pool of susceptibles in medium-sized towns by new births and epidemics are then triggered by a 5 year input. The equations represent a system that has two components, a basic linear element with the remainder of the system being nonlinear; modelling a progressive increase in delta beta in London illustrates theoretically how a predominantly linear response changes to a nonlinear response and ultimately to chaos. A variation in susceptibility is a theoretical condition for inducing chaos; the undriven system cannot become chaotic. Modelling populations of progressively increasing size/density and applying a 1 year or 5 year sinusoidal oscillation in delta beta illustrates the fundamental distinction in the response of medium-sized rural towns and large cities.

Child↗
PubMed1994

Ultrastructural changes in rat kidney mitochondria in response to the oxygen- or calcium-paradox.

Isolated, perfused rat kidney released lactate dehydrogenase in response to the protocol of a standard oxygen-paradox or calcium-paradox. The results are comparable to those found with rat heart. The mitochondria of the proximal tubule cells at the end of the calcium-paradox were swollen, had mitochondrial bars and were subdivided with internal septa; after the oxygen-paradox they exhibited, in addition, many myelin figures. Such ultrastructural changes were characteristic of the mitochondria of skeletal and cardiac muscles damaged by a rise in [Ca2+]i. It is concluded (i) that typical calcium- and oxygen-paradoxes can be produced in kidney, (ii) that these are associated with a rise in [Ca2+]i and (iii) the proximal tubules, in particular, are damaged.

Animals↗
PubMed1994

Are oxygen radicals implicated in the calcium paradox of the rat heart?

No reduction in creatine kinase (CK) release during standard Ca2+ paradox in the Langendorff-perfused rat heart was afforded by anoxic perfusion, nor by addition of the radical scavengers superoxide dismutase (150,000 U/L), catalase (150,000 U/L), mannitol (15 or 50 mM), dimethylthiourea (DMTU, 10 mM), the antioxidant vitamin E (0.25 or 0.75 mM), or the iron chelator desferrioxamine (0.8 mM). Even under mild Ca(2+)-paradox conditions, achieved by (a) reducing the duration of the Ca(2+)-free period, (b) increasing [Ca2+]0 during the "Ca(2+)-free" period, or (c) reperfusing with 0.1 mM Ca2+, no protection was achieved by mannitol, DMTU, or desferrioxamine. Perfusion with N2 did not cause a reduction in CK release caused by caffeine or dinitrophenol or Ca2+ paradox. We conclude that no evidence supports the hypothesis that oxygen radicals are implicated in release of CK in Ca2+ paradox.

Animals↗
PubMed1993

An hypothesis for the periodicity of smallpox epidemics as revealed by time series analysis.

Parish registers have been studied by time series analysis to detect smallpox epidemics in England during 1600-1800. Confirmatory evidence was provided by the seasonality of child mortality. A 5-year cycle in smallpox epidemics was detected in medium-sized, rural towns. Consideration of the mathematics of the dynamics of viral diseases suggests that the true interepidemic period where smallpox is endemic should be 2-3 years and it is concluded that, in the towns studied, the disease was not endemic but that the oscillations were established by 5-year cycles of periods of famine associated with high wheat prices. The cross-correlation function between the two cycles shows zero lag and the input-output function shows significant coherence. Another epidemic follows only when a sufficient density of susceptibles has been established by births, so that the cycles become phase-locked. It is predicted that smallpox (i) was endemic in London and other large cities, with 2-3 year epidemics, (ii) was epidemic with a 5-year oscillation in rural towns, (iii) did not reach epidemic proportions in scattered communities.

Birth Rate↗
PubMed1993

Does the protein kinase C pathway modulate sarcolemma damage and the release of cytosolic proteins in the rat heart?

1. The release of creatine kinase (CK) in the Langendorff-perfused rat heart during the Ca(2+)-paradox, was critically dependent on the duration and [Ca2+]o of the initial Ca(2+)-depletion phase. 2. When [Ca2+]i was raised by perfusion with caffeine or under N2, activation of the protein kinase C pathway (PKC) produced a small but significant release of CK. PKC stimulation is therefore able to substitute for the Cao(2+)-depletion of the Ca(2+)-paradox. 3. The PKC inhibitor, 1-(5-isoquinolinyl sulphonyl)-2-methyl piperazine, (2 x 10(-6) M) inhibited both the Ca(2+)-paradox and caffeine-induced release of CK. 4. It is concluded that the PKC pathway has a regulatory role for the damage system of the sarcolemma that is responsible for the release of cytosolic proteins.

1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine↗
PubMed1993

Biochemical pathways of cell damage during the oxygen paradox of the rat heart.

1. The standard O2-paradox has been studied in the Langendorff-perfused rat heart. 2. Perfusion of glucose-free saline under anoxia did not cause release of creatine kinase (CK) although, it is suggested, there was a progressive rise in [Ca2+]i. 3. Ca(2+)-depletion after anoxia caused CK release. 4. Prolonged anoxic perfusion (55 min) produced a markedly reduced release of CK on Ca(2+)-depletion because, it is suggested, of the reduction in substrates for the release mechanism. 5. No protection against the O2-paradox was found with oxygen radical scavengers and inhibitors. 6. Lowering [Ca2+]o during reoxygenation to 0.1 mM did not reduce CK release. 7. Neither 1 mM amiloride (Na+/H+ antiporter inhibitor) nor 2 x 10(-6) M 1-(5-isoquinolinesulphonyl) piperazine (protein kinase C inhibitor) reduced CK release, unlike their effects in the Ca(2+)-paradox. 8. An hypothesis for events in the O2-paradox in presented: anoxia causes a loss of Ca(2+)-homeostasis and a rise in [Ca2+]i thereby activating a transmembrane NAD(P) oxido-reductase/diaphorase (stage 1); the return of O2 synergistically activates this molecular complex and causes CK release (stage 2).

1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine↗
PubMed1993

Interaction of H2O2 and dithiothreitol and the genesis of cellular damage in the perfused rat heart.

1. H2O2 (0.3 mM) causes release of creatine kinase (CK) from the perfused rat heart, but only when activated by removal of extracellular Ca2+. 2. Dithiothreitol (DTT), 2 mM, provides partial protection against this damage induced by artificially-introduced O2 radicals. 3. Paradoxically, DTT triggers CK release by H2O2 in the presence of extracellular Ca2+. The interaction of these agents in stimulating and protecting against this damage to the sarcolemma is discussed.

Animals↗