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P C Malone

Publications and source records attributed to P C Malone.

16 recordsLinked to original sources
PubMed2006

The aetiology of deep venous thrombosis.

Most ideas about the pathogenesis of deep venous thrombosis (DVT) are dominated by a 'consensus model' first articulated around 1962. This model invokes 'Virchow's triad' and attributes thrombogenesis in veins to some combination of 'hypercoagulability', 'stasis' and 'intimal injury'. This arose as a by-product of studies on the mechanisms of haemostasis and bleeding diatheses that were at best only indirectly relevant to thrombosis, and there are reasons for doubting the causal significance of 'hypercoagulability' and 'stasis' in the aetiology of DVT. Proponents of the consensus model make little reference to a substantial literature, mostly historical, that: (a) emphasizes the significance of the venous valve pockets (VVP) and blood rheology in DVT pathogenesis; and (b) describes morphological features specific to venous thrombi that a valid aetiological model must explain. This literature provides the basis for an alternative hypothesis of DVT aetiology, published some 30 years ago, which has been experimentally corroborated and is compatible with recent cell and molecular biological studies of the venous endothelium. We review this alternative hypothesis, considering its potential value for future research on DVT and embolism, and its significance for clinical practice.

Blood Coagulation Disorders↗
PubMed2000

Diffusion theory in biology: a relic of mechanistic materialism.

Diffusion theory explains in physical terms how materials move through a medium, e.g. water or a biological fluid. There are strong and widely acknowledged grounds for doubting the applicability of this theory in biology, although it continues to be accepted almost uncritically and taught as a basis of both biology and medicine. Our principal aim is to explore how this situation arose and has been allowed to continue seemingly unchallenged for more than 150 years. The main shortcomings of diffusion theory will be briefly reviewed to show that the entrenchment of this theory in the corpus of biological knowledge needs to be explained, especially as there are equally valid historical grounds for presuming that bulk fluid movement powered by the energy of cell metabolism plays a prominent note in the transport of molecules in the living body. First, the theory's evolution, notably from its origins in connection with the mechanistic materialist philosophy of mid nineteenth century physiology, is discussed. Following this, the entrenchment of the theory in twentieth century biology is analyzed in relation to three situations: the mechanism of oxygen transport between air and mammalian tissues; the structure and function of cell membranes; and the nature of the intermediary metalbolism, with its implicit presumptions about the intracellular organization and the movement of molecules within it. In our final section, we consider several historically based alternatives to diffusion theory, all of which have their precursors in nineteenth and twentieth century philosophy of science.

Biology↗
PubMed1996

Exchange of aspartate and alanine. Mechanism for development of a proton-motive force in bacteria.

We examined the idea that aspartate metabolism by Lactobacillus subsp. M3 is organized as a proton-motive metabolic cycle by using reconstitution to monitor the activity of the carrier, termed AspT, expected to carry out the electrogenic exchange of precursor (aspartate) and product (alanine). Membranes of Lactobacillus subsp. M3 were extracted with 1.25% octyl glucoside in the presence of 0. 4% Escherichia coli phospholipid and 20% glycerol. The extracts were then used to prepare proteoliposomes loaded with either aspartate or alanine. Aspartate-loaded proteoliposomes accumulated external [3H]aspartate by exchange with internal substrate; this homologous self-exchange (Kt = 0.4 mm) was insensitive to potassium or proton ionophores and was unaffected by the presence or absence of Na+, K+, or Mg2+. Alanine-loaded proteoliposomes also took up [3H]aspartate in a heterologous antiport reaction that was stimulated or inhibited by an inside-positive or inside-negative membrane potential, respectively. Several lines of evidence suggest that these homologous and heterologous exchange reactions were catalyzed by the same functional unit. Thus, [3H]aspartate taken up by AspT during self-exchange was released by a delayed addition of alanine. In addition, the spontaneous loss of AspT activity that occurs when a detergent extract is held at 37 degrees C prior to reconstitution was prevented by the presence of either aspartate (KD(aspartate) = 0.3 mm) or alanine (KD(alanine) > or = 10 mm), indicating that both substrates interact directly with AspT. These findings are consistent with operation of a proton-motive metabolic cycle during aspartate metabolism by Lactobacillus subsp. M3.

Adenosine Triphosphate↗
PubMed1995

Intracellular transport mechanisms: a critique of diffusion theory.

It is argued that Brownian motion makes a less significant contribution to the movements of molecules and particles inside cells than is commonly believed, and that the numbers of similar molecules and particles within any near-homogeneous subcompartment of the cell internum are insufficient to justify the statistical assumptions implicit in the derivation of the diffusion equation. For these reasons, it is contended that, contrary to accepted opinion, diffusion theory cannot provide an explanation for intracellular transport at the molecular level. Although attempts have been made to adapt diffusion theory to complex media, the conclusion is that none satisfactorily overcomes the problem of applying the theory to cell biology. However, the heuristic influence of the theory on cellular biophysics and physiology is noted, and possible alternative frameworks for interpreting the valuable experimental data obtained from such studies are outlined.

Animals↗
PubMed1993

Heat conductance, diffusion theory and intracellular metabolic regulation.

Diffusion theory played a major role in the development of biology as an exact science. The question is raised, however, as to its relevance and applicability in the molecular interactions which occur in metabolism in the living cell. This review looks at diffusion theory from its inception and subsequent introduction into biology, its shortcomings with regard not only to whole-body physiology, but more pertinently at the intracellular level, with its failure to offer a rational basis for metabolic regulation in the internum of the cell. The conclusion is reached that although diffusion inevitably occurs within cells, its role is of little importance with regard to most metabolic activity. In comparison, perfusion of the internal surfaces of the cell by streaming of the fluid compartment of the cytoplasm seems to be the modus operandi which allows molecular interactions to occur at rates far beyond those that diffusion would permit, and at the same time offers a mechanism which permits sensitive control of metabolic activity.

Animals↗
PubMed1988

Might the aphorism "there is no indication in medicine for a pint of blood" lie behind some of the residual morbidity and mortality of surgery?

Reconsideration of, and some uncertainty about, the risks of whole blood transfusion are stimulating renewed debate around and about transfusion policy. This essay -- 1) considers probable risks of retreating in fright from the approach which has significantly reduced the morbidity and mortality of surgical operations over the last 100 years, so that we may balance them against the known and putative risks of transfusion. 2) questions the universality of the aphorism "There is no indication in medicine for a pint of blood" -- because it presumes and implies that everyone can "tolerate"/not be harmed by/minor blood loss, or minor hypovolaemia from any other cause, and leads surgeons and anaesthetists to aim at "minimising" the degree and duration of hypovolaemia during surgery rather than to prevent it entirely. 3) proposes that circulating volume deficiencies, including small ones, are intrinsically intolerable pathological events to be prevented by a "positive" policy aiming at normovolaemia throughout operative procedures by "priming" patients about to undergo major operations with volume expanders before surgery, minimising their intraoperative blood loss, giving non-blood plasma expanders until dilution threatens significant anaemia, and whole-blood transfusion as a last resort when it does. 4) proposes that averting "minor" short-lived circulating volume depletion might avert the residual "minor" morbidity and mortality caused by venous thrombosis, pulmonary embolism, bronchopneumonia, intestinal ileus, postoperative abdominal distension, wound and anastomotic dehiscence, fat embolism, (alone or in various combinations) and give us a greater (insight into and) control over fluid and electrolyte balance.

Blood Transfusion↗
PubMed1987

The physiology of intestinal oxygenation and the pathophysiology of intestinal ileus.

Intestinal Ileus is Gut Shock caused by Bowel Hypoxia. The morbidity and mortality of Intestinal Ileus has puzzled more than two generations of investigators because they have overlooked the fact that the gas which collects in obstructed small intestine is mostly (90+%) Nitrogen. For some strange reason a gut full of nitrogen has not been looked on as comparable to a lung full of nitrogen, even though the lung and gut have a common embryological origin. My proposal is that intestinal epithelium lining a nitrogen filled lumen becomes as oxygen starved as alveolar lining in a similar circumstance. Bowel hypoxia may be brought about either by failure of the intestine to "breathe out", having breathed in due to mechanical block, or gut paralysis, from any cause, of which one may be failure of blood borne oxygen transport to the bowel, Individually, or together, these may reduce or stop the flow of air and/or aerated intestinal contents along the lumen. Local (bowel) or general underperfusion +/- hypovolaemia +/- anaemia may be a particular cause of paresis or paralysis (aperistalsis) of intestinal muscle. The non-contracting gut then fails to transport the luminal current of fluid and air (oxygen), and adds lumenal to blood-borne oxygen deficiency. The intestinal mucosa utilises oxygen from the current of air churned along the bowel by normal peristalsis to mix with and dissolve in the luminal contents. Should this current be obstructed or the propulsive churning activity cease, oxygen will be "used up", the residual gas become almost entirely nitrogen, and the mucosa must necessarily become oxygen starved and suffocated. Hypoxic mucosa lives in a dangerous environment, at risk of autodigestion by self-produced proteolytic or other enzymes secreted into the lumen by exocrine glands, and it may rapidly become necrotic and gangrenous. Different presentations of Ileus are different degrees of the same Gut Shock due to different levels and durations of tissue hypoxia brought about by different mechanisms with that final common path, complicated by different degrees of autodigestive mucosal destruction, bowel wall oedema, and fluid exudation into the lumen comparable to that through BURNED skin. This idea is new only in so far as it has been put together in this way. Parts have been anticipated by other writers. No new ways of managing ileus are proposed, but it is suggested that existing empirical methods be rationalised and applied more widely and logically.

Acute Disease↗
PubMed1984

Experimental deep venous thrombogenesis by a non-invasive method.

Experimental deep venous thrombi were produced in the untraumatised leg veins of anaesthetised dogs. In place of trauma, the endothelium lining the valve pockets in femoral veins was damaged by hypoxaemia, and the pockets were then intermittently re-perfused with oxygenated blood. Histologically, the experimental thrombi resembled human valve pocket thrombi found at postmortem.

Animals↗
PubMed1981

The PO2 in venous valve pockets: its possible bearing on thrombogenesis.

The PO2 in the lumen and valve pockets of veins in 2 patients and 8 dogs was measured during streamline blood flow and in conditions of intermittent pulsatile flow. The blood within the valve pockets became rapidly hypoxic when undisturbed during streamline flow (i.e. when "static"), but the PO2 in the pockets rose to that of the lumenal blood when the column of venous blood was made to pulsate and so empty the valve pockets at short intervals. The observations suggest that the endothelium covering the valve cusps is entirely dependent on pocket or lumenal blood for its oxygen supply. The endothelium facing the pocket can therefore become hypoxic during non-pulsatile blood flow when that facing the lumen is adequately to oxygenated. Early thrombus formation was seen to develop on a valve cusp after only 2 h non-pulsatile flow. The demonstration that localized hypoxaemia occurs readily and can produce endothelial damage, in circumstances and situations where thrombi are commonly found to originate, is additional circumstantial evidence that hypoxia may trigger thrombogenesis.

Adult↗
PubMed1981

Cell, membrane, and diffusion-an essay in bio-theory.

The Cell Theory is criticised and an alternative version proposed. It is suggested that the notion of a sponge-like, spongioform, cell (7) might be preferable to the classical notion of a membrane-bound cell. This would allow consideration of the probability that cells behave like sponges and procure their material and metabolite requirements entrained in a convected flow of water past their internal membrane systems. I shall consider some deductive consequences of this alternative in a companion article (1). The Cell Theory, however, formulated on the basis of a membrane-bound cell, specifically excludes the possibility of convective flow in and out of cells. For that reason, the metaphysical and historical foundations of Cell Theory are re-examined, the cases for the physicochemical viewpoint as against the teleological viewpoint further discussed, and the relationship of them to the notions of 'cell', 'membrane', and 'diffusion' looked into all over again. It is concluded that there is more evidence, from light and electron microscopy, for a spongioform cell than for a balloon cell.

Cell Biology↗
PubMed1981

Concerning the oxygenation of tissues and cells.

The hypothesis that our tissues are oxygenated by 'pure' diffusion is rejected because diffusion is never 'pure' in living tissues-it is everywhere contaminated by the 'impurity' of convective or agitative 'flow'. The suggested alternative hypothesis is that tissue cells breathe by 'convection + diffusion' like all other aquatic organisms and that all aquatic respiration is identical. This change alters the interrelationship between Cell Theory, Membrane Theory, and Diffusion Theory: it also invalidates the premises of Krogh's tissue oxygenation model (Krogh's Cylinder), and his conclusions. The presumption that cell respiration is active (rather than passive, as is implicit in classical theory) has wideranging consequences: the following are only a few: -cells must work to procure oxygen, and - the ratio of work done to oxygen procured must depend on the oxygen content of the ECF. -since pO2 is only one of many factors determining oxygen content, it cannot be more than one of many factors determining the adequacy or efficiency of cell oxygenation: etc.

Cells↗
PubMed1978

The sequestration and margination of platelets and leucocytes in veins during conditions of hypokinetic and anaemic hypoxia: potential significance in clinical postoperative venous thrombosis.

Lesions apparently similar to the white part of natural and experimental thrombi were found in the veins of animals starved of oxygen by "hypokinetic" and "anaemic" means: in contrast to this, no comparable lesions were seen in animals exposed to "arterial" hypoxia. The interpretation of these observations, and their probable relevance to the conditions in which postoperative venous thrombi develop, is discussed.

Anemia↗
PubMedDate not supplied

A hypothesis concerning the aetiology of venous thrombosis.

The historical background against which a new hypothesis must be discussed is presented, and the main threads of thinking about thrombosis are isolated so far as they can be. The interplay between such ideas as pus, white thrombus, white blood corpuscles, platelets, fibrin, and red blood cells, is traced: the origins of our concepts of blood circulation, stasis and slow blood flow, and vessel wall damage, are likewise dug up. The new hypothesis rearranges concepts which are not themselves actually or entirely new: instead of postulating that reduced blood flow results in 'silting' of presumably lifeless blood cells, it proposes that slow flow is more likely to injure venous endothelium by metabolic deprivation: and, in place of 'passive' silting, it postulates attachment of white blood cells and platelets to the damaged endothelium by virtue of their phagocytic or reparative function/s. This implies that thrombi are likely to form wherever living blood cells pass through veins whose endothelium is dying or dead from impaired nutrition (or other cause). The death of endothelium may be widespread, as in the agonal state, or, very limited, as in venous valve pockets when stasis is prolonged. The hypothesis is novel in that it seeks to explain thrombogenesis in functional or physiological terms, rather than in terms of purely biochemical pathogenesis.

Blood Flow Velocity↗