Paul S. Agutter

Metabolic scaling: consensus or controversy?

BackgroundThe relationship between body mass (M) and standard metabolic rate (B) among living organisms remains controversial, though it is widely accepted that in many cases B is approximately proportional to the three-quarters power of M.ResultsThe biological significance of the straight-line plots obtained over wide ranges of species when B is plotted against log M remains a matter of debate. In this article we review the values ascribed to the gradients of such graphs (typically 0.75, according to the majority view), and we assess various attempts to explain the allometric power-law phenomenon, placing emphasis on the most recent publications.ConclusionAlthough many of the models that have been advanced have significant attractions, none can be accepted without serious reservations, and the possibility that no one model can fit all cases has to be more seriously entertained.

Sulfur mustard toxicity: History, chemistry, pharmacokinetics, and pharmacodynamics

Sulfur mustard (SM) and similar bifunctional agents have been used as chemical weapons for almost 100 years. Victims of high-dose exposure, both combatants and civilians, may die within hours or weeks, but low-dose exposure causes both acute injury to the eyes, skin, respiratory tract and other parts of the body, and chronic sequelae in these organs are often debilitating and have a serious impact on quality of life. Ever since they were first used in warfare in 1917, SM and other mustard agents have been the subjects of intensive research, and their chemistry, pharmacokinetics and mechanisms of toxic action are now fairly well understood. In the present article we review this knowledge and relate the molecular-biological basis of SM toxicity, as far as it has been elucidated, to the pathological effects on exposure victims.

Mustard gas toxicity: the acute and chronic pathological effects

Ever since it was first used in armed conflict, mustard gas (sulfur mustard, MG) has been known to cause a wide range of acute and chronic injuries to exposure victims. The earliest descriptions of these injuries were published during and in the immediate aftermath of the First World War, and a further series of accounts followed the Second World War. More recently, MG has been deployed in warfare in the Middle East and this resulted in large numbers of victims, whose conditions have been studied in detail at hospitals in the region. In this review, we bring together the older and more recent clinical studies on MG toxicity and summarize what is now known about the acute and chronic effects of the agent on the eyes, skin, respiratory tract and other physiological systems. In the majority of patients, the most clinically serious long‐term consequences of MG poisoning are on the respiratory system, but the effects on the skin and other systems also have a significant impact on quality of life. Aspects of the management of these patients are discussed. Copyright

Random walks and cell size

For many years, it has been believed that diffusion is the principle motive force for distributing molecules within the cell. Yet, our current information about the cell makes this improbable. Furthermore, the argument that limitations responsible for the relative constancy of cell size--which seldom varies by more than a factor of 2, whereas organisms can vary in mass by up to 10(24)--are based on the limits of diffusion is questionable. This essay seeks to develop an alternative explanation based on transport of molecules along structural elements in the cytoplasm and nucleus. This mechanism can better account for cell size constancy, in light of modern biological knowledge of the complex microstructure of the cell, than simple diffusion.

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 theorys 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 metabolism, 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.

Functional dissection of nuclear envelope mRNA translocation system: Effects of phorbol ester and a monoclonal antibody recognizing cytoskeletal structures

Unidirectional transport of poly(A)-containing mRNA [poly(A)+ mRNA] through the nuclear envelope pore complex is thought to be an energy (ATP or GTP)-dependent process which involves a nuclear envelope nucleoside triphosphatase (NTPase). In the intact envelope, this enzyme is regulatable by poly(A) binding and by poly(A)-dependent phosphorylation/dephosphorylation of other components of the mRNA translocation system, which are as yet unidentified. Monoclonal antibodies (mAbs) were elicited against the poly(A) binding nuclear envelope fraction isolated from rat liver. The mAbs were screened for their modulatory effects on mRNA transport in vitro. One stable clone decreased the efflux of rapidly labeled RNA and of one specific mRNA (ovalbumin) from isolated nuclei. It increased the binding of poly(A) to the envelope and increased the maximal catalytic rate of the NTPase, but it did not alter the apparent Km of the enzyme or the extent of its stimulation by poly(A). The nuclear envelope-associated protein kinase that down-regulates the NTPase was inhibited by the antibody, while other protein kinases were not affected. Because both the NTPase and mRNA efflux were inhibited by the tumor promoter, 12-O-tetradecanoylphorbol 13-acetate, the sensitive kinase is probably protein kinase C. Protein kinase C was found to be associated with the isolated nuclear envelope. The antibody reacted with both a Mr 83,000 and a Mr 65,000 nuclear envelope polypeptide from rat liver and other tissues. By immunofluorescence microscopy in CV-1 cells, the antibody localized to the nuclear envelope and, in addition, to cytoplasmic filaments which show some superposition with the microfilament network.

Models for solid‐state transport: messenger RNA movement from nucleus to cytoplasm.

This paper explores the idea that mRNAs are transported between their transcription and processing sites in the nucleus, and their translation and degradation sites in the cytoplasm, by a ‘solid‐state’ process. The underlying assumption is that negligible quantities of mRNA and of mRNA precursors are in solution in vivo. Therefore, mRNA transport cannot be considered as movement in the aqueous phase of the cell. The main lines of experimental evidence supporting this ‘solid‐state’ concept are summarized and related controversies are outlined. Three possible models for a solid‐state transport mechanism are discussed: a direct transfer model, with receptors organized analogously to the components of a multienzyme complex; a motor‐driven model, analogous to synaptic vesicle transport in axons; and an assembly‐driven model which assumes net movement along a fibril resulting from differential activities at the poles. Qualitative evaluation indicates that each of these models has characteristic advantages and disadvantages. The possibility that other nucleocytoplasmic transport processes might operate by solid‐state mechanisms is briefly discussed.

Leonardo da Vinci's studies of the heart

Leonardo da Vincis detailed drawings are justly celebrated; however, less well known are his accounts of the structures and functions of the organs. In this paper, we focus on his illustrations of the heart, his conjectures about heart and blood vessel function, his experiments on model systems to test those conjectures, and his unprecedented conclusions about the way in which the cardiovascular system operates. In particular, da Vinci seems to have been the first to recognize that the heart is a muscle and that systole is the active phase of the pump. He also seems to have understood the functions of the auricles and pulmonary veins, identified the relationship between the cardiac cycle and the pulse, and explained the hemodynamic mechanism of valve opening and closure. He also described anatomical variations and changes in structure and function that occurred with age. We outline da Vincis varied career and suggest ways in which his personality, experience, skills and intellectual heritage contributed to these advances in understanding. We also consider his influence on later studies in anatomy and physiology.

A historical perspective: Infection from cadaveric dissection from the 18th to 20th centuries

Today, the study of human anatomy utilizing the ultimate study guide, the cadaver, is relatively safe. In the past, however, human dissection was dangerous. Prior to the germ theory, antibiotics, and the use of gloves, cadavers were often life threatening to dissectors including both the teacher and the student. Medical students who graduated in the United States before 1880 were unlikely to practice antisepsis in the dissecting room. In the present article, we review human cadaveric dissection in Europe and the United States primarily from the 1700s to the early 1900s in regard to its potential for transmission of infection to the dissector. A brief account of the infectious hazards of human cadavers in general and those of cadavers used for dissection in particular is given. Clin. Anat. 2013.

The role of the renin--angiotensin system in the pathogenesis of intracranial aneurysms.

Introduction: Recent work has begun to elucidate the pathogenesis of intracranial aneurysms (IA) and has shown that many genes are involved in the risk for this condition. There has also been increasing research interest in the renin—angiotensin system (RAS) in the brain and its involvement in a range of cardiovascular and neurological disorders. The possibility that the RAS is implicated in the pathogenesis of IA merits further investigation. The aim of this article is to review the literature on the pathogenesis of IA and the pathophysiological significance of the brain RAS, and to identify directions for research into their association. Methods and results : A survey of the literature in these fields shows that although factors contributing to systemic hypertension predispose to IA, a large number of genes involved in endothelial cell adhesion, smooth muscle activity, extracellular matrix dynamics and the inflammatory and immune responses are also implicated. The brain RAS has a significant role in regulating blood pressure and in maintaining cerebrovascular autoregulation, but angiotensin II receptors are also involved in the maintenance of endothelial cell and vascular smooth muscle function and in the inflammatory response in the brain. Conclusions: There is strong, albeit largely circumstantial, evidence in the literature for a relationship between the brain RAS and the formation of IA. Research on the association between polymorphisms in RAS-related genes and the incidence of unruptured and ruptured IA is indicated.