Cranioplasty in medieval Persia and the potential spread of this knowledge to Europe.

INTRODUCTION: Skull trepanation is an ancient and often religious act found in remains from around the world. However, cranioplasty for the surgical treatment of skull pathologies is a relatively recent phenomenon. In this paper, we focus on the account of skull injury and cranioplasty in medieval Persia. MATERIALS AND RESULTS: Herein, we describe and translate the over 500-year-old writings of the Persian physician Baha al-Dowleh Razi regarding cranioplasty in an excerpt from his book entitled Khulasat al-Tajarib (Summary of Experiences). This early writer detailed the methods and indications for cranioplasty including the use of xenographs. Additionally, we attempt to trace this early understanding of skull surgery and follow its possible spread to Europe. CONCLUSIONS: It is such early experiences and methods of cranial surgery on which we base our current understanding of neurosurgery.

Rabi Rashidi (Rashidi Quarters): a late thirteen to early fourteenth century Middle Eastern Medical School.

INTRODUCTION: Following the Mongolian invasion of the Middle East in the thirteenth century, a regional power called the Ilkhanid emerged and was ruled by the heirs of Temujin from Mongolia. Embracing present-day Iran, Iraq, Afghanistan, Azerbaijan, areas of Russia, Turkey, and Pakistan, and nearby Middle Eastern territories, the Ilkhanid state patronized medicine and various other professions. Centered in Tabriz (Tauris), a city in the northwest of present-day Iran, was a non-profit-making educational and medical complex founded by Grand Minister Rashid al-Din Fazlollah Hamadani. METHODS: This paper reviews the literature regarding the rise and fall of the thirteenth century university and the Rabi Rashidi, emphasizing the structure of its medical school. CONCLUSIONS: The background training of Rashid al-Din and his keen interest in science turned this complex, Rabi Rashidi (literally meaning the Rashidi Quarters), into a cosmopolitan university that freely trained medical scholars nationally and internationally. The possibility that Rashid al-Din was inspired by university developments in Europe is discussed.

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.

Analytic theories of allometric scaling.

During the 13 years since it was first advanced, the fractal network theory (FNT), an analytic theory of allometric scaling, has been subjected to a wide range of methodological, mathematical and empirical criticisms, not all of which have been answered satisfactorily. FNT presumes a two-variable power-law relationship between metabolic rate and body mass. This assumption has been widely accepted in the past, but a growing body of evidence during the past quarter century has raised questions about its general validity. There is now a need for alternative theories of metabolic scaling that are consistent with empirical observations over a broad range of biological applications. In this article, we briefly review the limitations of FNT, examine the evidence that the two-variable power-law assumption is invalid, and outline alternative perspectives. In particular, we discuss quantum metabolism (QM), an analytic theory based on molecular-cellular processes. QM predicts the large variations in scaling exponent that are found empirically and also predicts the temperature dependence of the proportionality constant, issues that have eluded models such as FNT that are based on macroscopic and network properties of organisms.

Diet as prophylaxis and treatment for venous thromboembolism?

BACKGROUND: Both prophylaxis and treatment of venous thromboembolism (VTE: deep venous thrombosis (DVT) and pulmonary emboli (PE)) with anticoagulants are associated with significant risks of major and fatal hemorrhage. Anticoagulation treatment of VTE has been the standard of care in the USA since before 1962 when the U.S. Food and Drug Administration began requiring randomized controlled clinical trials (RCTs) showing efficacy, so efficacy trials were never required for FDA approval. In clinical trials of 'high VTE risk' surgical patients before the 1980s, anticoagulant prophylaxis was clearly beneficial (fatal pulmonary emboli (FPE) without anticoagulants = 0.99%, FPE with anticoagulants = 0.31%). However, observational studies and RCTs of 'high VTE risk' surgical patients from the 1980s until 2010 show that FPE deaths without anticoagulants are about one-fourth the rate that occurs during prophylaxis with anticoagulants (FPE without anticoagulants = 0.023%, FPE while receiving anticoagulant prophylaxis = 0.10%). Additionally, an FPE rate of about 0.012% (35/28,400) in patients receiving prophylactic anticoagulants can be attributed to 'rebound hypercoagulation' in the two months after stopping anticoagulants. Alternatives to anticoagulant prophylaxis should be explored. METHODS AND FINDINGS: The literature concerning dietary influences on VTE incidence was reviewed. Hypotheses concerning the etiology of VTE were critiqued in relationship to the rationale for dietary versus anticoagulant approaches to prophylaxis and treatment.Epidemiological evidence suggests that a diet with ample fruits and vegetables and little meat may substantially reduce the risk of VTE; vegetarian, vegan, or Mediterranean diets favorably affect serum markers of hemostasis and inflammation. The valve cusp hypoxia hypothesis of DVT/VTE etiology is consistent with the development of VTE being affected directly or indirectly by diet. However, it is less consistent with the rationale of using anticoagulants as VTE prophylaxis. For both prophylaxis and treatment of VTE, we propose RCTs comparing standard anticoagulation with low VTE risk diets, and we discuss the statistical considerations for an example of such a trial. CONCLUSIONS: Because of (a) the risks of biochemical anticoagulation as anti-VTE prophylaxis or treatment, (b) the lack of placebo-controlled efficacy data supporting anticoagulant treatment of VTE, (c) dramatically reduced hospital-acquired FPE incidence in surgical patients without anticoagulant prophylaxis from 1980 - 2010 relative to the 1960s and 1970s, and (d) evidence that VTE incidence and outcomes may be influenced by diet, randomized controlled non-inferiority clinical trials are proposed to compare standard anticoagulant treatment with potentially low VTE risk diets. We call upon the U. S. National Institutes of Health and the U.K. National Institute for Health and Clinical Excellence to design and fund those trials.

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.

Editorial: hypotheses about protein folding--the proteomic code and wonderfolds.

Theoretical biology journals can contribute in many ways to the progress of knowledge. They are particularly well-placed to encourage dialogue and debate about hypotheses addressing problematical areas of research. An online journal provides an especially useful forum for such debate because of the option of posting comments within days of the publication of a contentious article.

The flux-summation theorem and the 'evolution of dominance'.

The flux-summation theorem (FST) is a central principle of metabolic control analysis. It describes how the control of flux through any metabolic pathway of arbitrary complexity is distributed among the component reaction steps. Two issues concerning the FST are discussed in this paper. First, it has been suggested that the theorem could, in principle, be inapplicable under certain conditions, i.e. the sum of the control coefficients of all the enzymes supporting a pathway could exceed unity. Such conditions have not been found in any species so far studied, so in practice the FST is always applicable. I argue that applicability of the FST is a precondition for phenotypic robustness and therefore for survival. Second, the FST provides a basis for explaining dominance that renders Fisher's 'modifier genes' hypothesis otiose. Some recent misunderstandings of metabolic control analysis have led to the claim that this explanation is flawed and therefore that Fisher's hypothesis can and should be reinstated. Here, these suggestions are refuted.

Cardiovascular Disease Death Before Age 65 in 168 Countries Correlated Statistically with Biometrics, Socioeconomic Status, Tobacco, Gender, Exercise, Macronutrients, and Vitamin K.

BACKGROUND: Nutrition researchers recently recognized that deficiency of vitamin K2 (menaquinone: MK-4-MK-13) is widespread and contributes to cardiovascular disease (CVD). The deficiency of vitamin K2 or vitamin K inhibition with warfarin leads to calcium deposition in the arterial blood vessels. METHODS: Using publicly available sources, we collected food commodity availability data and derived nutrient profiles including vitamin K2 for people from 168 countries. We also collected female and male cohort data on early death from CVD (ages 15-64 years), insufficient physical activity, tobacco, biometric CVD risk markers, socioeconomic risk factors for CVD, and gender. The outcome measures included (1) univariate correlations of early death from CVD with each risk factor, (2) a multiple regression-derived formula relating early death from CVD (dependent variable) to macronutrient profile, vitamin K1 and K2 and other risk factors (independent variables), (3) for each risk factor appearing in the multiple regression formula, the portion of CVD risk attributable to that factor, and (4) similar univariate and multivariate analyses of body mass index (BMI), fasting blood sugar (FBS) (simulated from diabetes prevalence), systolic blood pressure (SBP), and cholesterol/ HDL-C ratio (simulated from serum cholesterol) (dependent variables) and dietary and other risk factors (independent variables). RESULTS: Female and male cohorts in countries that have vitamin K2 < 5µg per 2000 kcal/day per capita (n = 70) had about 2.2 times the rate of early CVD deaths as people in countries with > 24 µg/day of vitamin K2 per 2000 kcal/day (n = 72). A multiple regression-derived formula relating early death from CVD to dietary nutrients and other risk factors accounted for about 50% of the variance between cohorts in early CVD death. The attributable risks of the variables in the CVD early death formula were: too much alcohol (0.38%), too little vitamin K2 (6.95%), tobacco (6.87%), high blood pressure (9.01%), air pollution (9.15%), early childhood death (3.64%), poverty (7.66%), and male gender (6.13%). CONCLUSIONS: Worldwide dietary vitamin K2 data derived from food commodities add much understanding to the analysis of CVD risk factors and the etiology of CVD. Vitamin K2 in food products should be systematically quantified. Public health programs should be considered to increase the intake of vitamin K2-containing fermented plant foods such as sauerkraut, miso, and natto.

Deep venous thrombosis: The valve cusp hypoxia thesis and its incompatibility with modern orthodoxy.

The valve cusp hypoxia thesis (VCHT) of the aetiology of deep venous thrombosis (DVT) was adumbrated in this journal in 1977 and fully articulated in 2008, the original hypothesis having been strongly corroborated by experiments published in 1981 and 1984. It presents a unitary account of the pathogenesis of venous thrombosis and embolism that is rooted in the pathophysiological tradition of Hunter, Virchow, Lister, Welch and Aschoff, a tradition traceable back to Harvey. In this paper we summarise the thesis in its mature form, consider its compatibility with recent advances in the DVT field, and ask why it has not yet been assimilated into the mainstream literature, which during the past half century has been dominated by a haematology-orientated 'consensus model'. We identify and discuss seven ways in which the VCHT is incompatible with these mainstream beliefs about the aetiology of venous thrombosis, drawing attention to: (1) the spurious nature of 'Virchow's triad'; (2) the crucial differences between 'venous thrombus' and 'clot'; the facts that (3) venous thrombi form in the valve pockets (VVPs), (4) DVT is not a primarily haematological condition, (5) the so-called 'thrombophilias' are not thrombogenic per se; (6) the conflict between the single unitary aetiology of DVT and the tacit assumption that the condition is 'multicausal'; (7) the inability of anticoagulants to prevent the initiation of venous thrombogenesis, though they do prevent the growth of thrombi to clinically significant size. In discussing point (7), we show that the VCHT indicates new approaches to mechanical prophylaxis against DVT. These approaches are then formulated as experimentally testable hypotheses, and we suggest methods for testing them preclinically using animal trials.

Stochastic description of the ligand-receptor interaction of biologically active substances at extremely low doses.

Signalling molecules can be effective at extraordinarily low concentrations (down to attomolar levels). To handle such cases, probabilistic methods have been used to describe the formal kinetics of action of biologically active substances in these low doses, although it has been necessary to review what is meant by such a term. The mean numbers of transformed/degraded molecules and their dispersions were calculated for the possible range of ligand-receptor binding schemes. We used both analytical equations and numerical simulations to calculate the coefficients of variation (ratio of standard deviation to mean) and demonstrated that the distribution of the coefficient is highly dependent on the reaction scheme. It may, therefore, be used as an additional factor for discriminating between cooperative and noncooperative models of ligand-receptor interaction over extreme ranges of ligand dilution. The relevance to signalling behaviour is discussed.

Metabolic scaling: consensus or controversy?

BACKGROUND: The 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. RESULTS: The 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. CONCLUSION: Although 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.

Directions in biomedical research: a plea for ideological pluralism.

Feinstein [A.R. Feinstein, Am. J. Med. 107 (1999) 461] complained that 'basic medical science' has overwhelmed 'pathophysiological medical science' during the past half century, and 'destroyed the bridge between bedside and bench'. We agree that a 'drastic reorientation' will be necessary to correct the overemphasis and imbalance. Re-examining the roots of his problem, we believe that a plea to restore a balance between the 'status' (esteem) of 'large research' and 'small research' in medical science brings back into question the decision of academic physiologists to invoke the framework of Physics in/of 1847 [P.F. Cranefield, J. Hist. Med. Allied Sci. 12 (1957) 407] (together with an absolutist 'Prime Mover'/Metaphysic which Einstein would delete from Physics in 1905). The current 'imbalance' arose when that Cartesian 'Prime Mover' was NOT deleted from the Biological frame. Feinstein felt that the 'privileged status' (esteem) in which fund-giving bodies hold 'Small' researches compared to 'Large' should be cancelled. Once Biology replaces its Cartesian absolutism with a relativist framework, redress will follow naturally when living-material has regained the status of cause as well as effect. Descartes' 'Great Watchmaker' is a Dead God in Biology: a non-metaphysical Biological Perspective would restore balance between 'large' and 'small' investigations. ('Pluralism' implies that no scientific perspective would be second-rate in a relativist framework.)

Leonardo da Vinci's studies of the heart.

Leonardo da Vinci's 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 Vinci's 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.

Hysterical paralysis and premature burial: a medieval Persian case, fear and fascination in the West, and modern practice.

Premature burial (taphophobia) is an ancient fear, but it became especially common in 18th and 19th century Europe and may have a modern-day counterpart. Examination of a well-documented case from medieval Persia reveals the importance of funeral practices in the risk of actual premature burial and sheds light on the question of why taphophobia became so prevalent in Europe during the early industrial revolution period. The medieval Persian case was attributed to hysterical paralysis (conversion). We discuss the relationship between hysterical paralysis and premature burial more generally and show that although understanding of conversion syndrome remains incomplete, modern knowledge and practices have limited the risk of any similar tragedy today.

Experimental Validation of Methods for Prophylaxis against Deep Venous Thrombosis: A Review and Proposal.

The experimental procedure by which the valve cusp hypoxia (VCH) hypothesis of the etiology of deep venous thrombosis (DVT) was confirmed lends itself to testing of methods of prophylaxis. Similar animal experiments could end the present exclusive reliance on statistical analysis of data from large patient cohorts to evaluate prophylactic regimes. The reduction of need for such (usually retrospective) analyses could enable rationally-based clinical trials of prophylactic methods to be conducted more rapidly, and the success of such trials would lead to decreased incidences of DVT-related mortality and morbidity. This paper reviews the VCH hypothesis ("VCH thesis", following its corroboration) and its implications for understanding DVT and its sequelae, and outlines the experimental protocol for testing prophylactic methods. The advantages and limitations of the protocol are briefly discussed.

Legacy of Avicenna and evidence-based medicine.

Although the term 'evidence-based medicine' (EBM) is of recent origin, its roots are generally agreed to lie in earlier times. Several writers have suggested that the 11th century CE physician and philosopher Avicenna (Ibn Sina) formulated an approach to EBM that broadly resembles modern-day principles and practice. The aim of this paper is to explore the origins and influence of Avicenna's version of EBM. A survey of the literature suggests that two influences on Avicenna's thought were crucial: the doctrine of Ijma; and Stoic logic, perhaps transmitted via the writings of Galen. In turn, Avicenna is known to have been a major influence on both medical practice and the development of logic in medieval Europe. Through this route, Avicennian logic (notably its inductive aspect) inspired the new style of thought associated with the scientific revolution, which later came to be reflected in 'scientific medicine', and may therefore have been an indirect source of EBM today.