Charcot and Cholesterin.

We offer here an observation written in 1866 by Jean-Martin Charcot, accompanied by drawings made during the autopsy of a patient who died of "cerebral softening." Focusing mainly on French medical progress at the time, our survey of the state of knowledge of cerebrovascular pathology indicates that Charcot completely explained the pathophysiology of cerebral infarction, describing the ulceration of an atheromatous plaque at the intima of an artery, on which a clot aggregates, blocks the vessel, or releases embolus downstream, causing cerebral ischemia and parenchymal lesions. Using the term "cholestérine" (cholesterin), the name of cholesterol at the time, he identified the biological nature of atheromatous plaques, and made detailed drawings. This observation, included in the famous thesis of Ivan Poumeau, indicates that Charcot did not neglect cerebrovascular pathology, ischemic in this case, but also pathology caused by hemorrhaging, as in the thesis of Charles Bouchard. This interest, which we see clearly during his first decade at Hôpital de la Salpêtrière, gradually turned toward other neurological pathologies that ensured his fame as a founder of neurology more enduringly and overshadowed the conceptual advances he made in the vascular domain.

Discovery of the cellular and molecular basis of cholesterol control.

The cellular control of cholesterol metabolism mediated by lipoproteins was first appreciated in pioneering work published in a 1974 PNAS Classic by Michael Brown and Joseph Goldstein. We know from this paper that the LDL binds to a cell surface receptor and dampens the activity of a key enzyme in cholesterol biosynthesis and that a receptor deficiency is responsible for a major genetic cause of hypercholesterolemia and premature atherosclerosis.

[The contribution of Goldstein and Brown to the study of cholesterol metabolism]. / Rememorando la contribución de Goldstein y Brown al estudio del metabolismo del colesterol: a un cuarto de siglo del Premio Nobel de Medicina.

In December 1985, the Nobel Prize of Medicine was awarded to Drs. Joseph L. Goldstein and Michael S. Brown for their fundamental scientific work on the regulation of cholesterol metabolism mediated by the low density lipoprotein receptor pathway. This article briefly reviews the academic and research accomplishments of Drs. Brown and Goldstein as a tribute to these physician-scientists for their well-deserved award and enormous contribution to biomedical science worldwide.

The LDL receptor.

In this article, the history of the LDL receptor is recounted by its codiscoverers. Their early work on the LDL receptor explained a genetic cause of heart attacks and led to new ways of thinking about cholesterol metabolism. The LDL receptor discovery also introduced three general concepts to cell biology: receptor-mediated endocytosis, receptor recycling, and feedback regulation of receptors. The latter concept provides the mechanism by which statins selectively lower plasma LDL, reducing heart attacks and prolonging life.

Two findings of gallstones in archaeological mummies from Colombia.

Results involving the analysis of gallstones found in two pre-Hispanic Colombian mummies are presented. By applying SEM, X-ray diffraction (XRD), sectioning, and CT-scan Hounsfield Units, we were able to identify these choleliths as mainly formed by cholesterol. The number of reports on gallstones in archaeological human remains from South America is very small, making these two cases an important addition to what little is known about ancient gallstone disease on the continent.

Nikolai N. Anichkov and his theory of atherosclerosis.

Nikolai N. Anichkov (1885-1964) first demonstrated the role of cholesterol in the development of atherosclerosis. His classic experiments in 1913 paved the way to our current understanding of the role of cholesterol in cardiovascular disease. Anichkov's research is often cited among the greatest discoveries of the 20th century; however, little is known about Anichkov and his team. Herein, we give a detailed historical account of Anichkov's work, his personality, his research team, and their pioneering effort.

[Cholesterol and atherosclerosis. Historical considerations and treatment]. / Colesterol y aterosclerosis. Consideraciones históricas y tratamiento.

Cholesterol is a precursor of steroid hormones and an essential component of the cell membrane, however, altered regulation of the synthesis, absorption and excretion of cholesterol predispose to cardiovascular diseases of atherosclerotic origin. Despite, the recognition of historical events for 200 years, starting with Michel Chevreul naming «cholesterol¼; later on, Lobstein coining the term atherosclerosis and Marchand introducing it, Anichkov identifying cholesterol in atheromatous plaque, and Brown and Goldstein discovering LDL receptor; as well as the emerging of different drugs, such as fibrates, statins and cetrapibs this decade, promising to increase HDL and the most recent ezetimibe and anti-PCSK9 to inhibit the degradation of LDL receptor, however morbidity has not been reduced in cardiovascular disease.

Cholesterol in the year 2000.

Cholesterol research was one of the key areas of scientific investigation in the 20th century. Little was known about the structure of cholesterol until the pioneering research of A. Windaus and H. Wieland in the first part of the century. The structure of cholesterol was completely elucidated in 1932. With the development of isotopic tracers in the 1930s studies on cholesterol biosynthesis were initiated. In 1942 K. Bloch and D. Rittenberg showed that deuterium-labeled acetate was incorporated into the ring structure and side chain of cholesterol. Another important discovery from Bloch's laboratory was that squalene was a precursor of cholesterol. In 1956, the main elements of the biosynthetic pathway became known when isopentenyl pyrophosphate was discovered as a precursor. In 1966, J. Cornforth and G. Popjak predicted that there were 16234 possible stereochemical pathways by which mevalonate could be converted into squalene. They subsequently showed which of these pathways was correct. In the 1970s and 1980s K. Bloch was able to provide intriguing evidence for an evolutionary advantage of cholesterol over lanosterol or some of the intermediates in the conversion of lanosterol to cholesterol. The last quarter of the 20th century was when M. Brown and J. Goldstein showed that the low density lipoprotein receptor was a key regulator of cholesterol homeostasis. They have also demonstrated that cholesterol balance in the cell is transcriptionally regulated via the sterol regulatory element binding protein. In the later part of the 20th century drugs were developed that effectively lower plasma cholesterol and lessen the risk of atherosclerosis and cardiovascular disease.

Development of liposomal polyene antibiotics: an historical perspective.

PURPOSE: The purpose of this review article is to review the development of a number of liposomal polyene antibiotics. BACKGROUND: In the past thirty years, the increase in life-threatening pre-systemic and systemic fungal infections within cancer, diabetic and AIDS patients have reached alarming proportions. A number of antifungal agents have been developed to combat this problem. In particular, polyene antibiotics such as Amphotericin B (AmB) and Nystatin (Nys) have remained the most effective and widely used agents in the treatment of these infections. However, their administration is limited by dose-dependent toxicities. One such dose-limiting toxicity is renal toxicity. Polyene antibiotic-induced renal toxicity is believed to be mediated by the drug anchoring to cholesterol within the mammalian cell membrane, resulting in pore formation, abnormal electrolyte flux, decrease in adenosine triphosphate (ATP), and eventually a loss of cell viability. CONCLUSION: In the 1980s and 90s a number of promising lipid-based AmB and Nys formulations were developed to overcome these toxicities. This article will review the development of these liposomal polyene antibiotics.

From gallstones to genes: two hundred years of sterol research. A tribute to George J. Schroepfer Jr.

The origins of cholesterol research can be traced to prerevolutionary France. The discovery of cholesterol as a single substance, present in human gallstones, owes much to the scientists of l'Académie Française, including Lavoisier, who contributed so much to the emergence of chemistry as a modern scientific discipline. Since that time, cholesterol probably has been the most intensively scrutinized natural product of all time, and it has been the subject of Nobel Prizes for several who have studied its structure, biosynthesis, and regulation. The pace of research into cholesterol shows no sign of diminishing, and recent discoveries have led to the recognition that the regulation of cholesterol metabolism is intimately linked with that of other metabolic pathways. Details of these interactions are only just emerging, but it is becoming apparent that under some circumstances it is difficult to reconcile, in a conventional manner, changes in regulatory gene expression with corresponding changes in pathway carbon flux. The present review includes some of our studies on the roles of the transcription factors sterol regulatory element-binding protein, liver X-receptor alpha, and peroxisome proliferator activated receptor a in the coordination of cholesterol and fatty acid synthesis and describes how some of the results obtained can best be interpreted from a Metabolic Control Analysis perspective of the regulation of pathway carbon fluxes.

The history of corticosteroids.

The development from the discovery of the structure of cholesterol, the precursor of all steroids, to the first application of a topically effective steroid in 1952 took about 20 years. Thereafter the development of more potent topically effective steroids accelerated and the third generation of potent steroids with a topical activity of about 10 to 20 times that of hydrocortisone was already available about 10 years later. Today the newly developed non-fluorinated non-symmetric 16 alpha, 17 alpha-acetal derivate budesonide could perhaps be considered as the sixth generation.

Treatment and prevention of coronary heart disease by lowering serum cholesterol levels; from the pioneer work of C.D. de Langen to the third "Dutch Consensus on Cholesterol".

In the beginning of this century a possible relation was observed between cholesterol-rich foods, blood cholesterol levels and atherosclerosis by "pioneers" in this field as Anitschkow and De Langen. In the second half of this century a definite link was established between serum cholesterol levels and development of coronary heart disease (CHD). In angiographic studies it has recently been shown that a decrease in total cholesterol as well as in low-density lipoprotein cholesterol level results in a retardation of the progression of vascular disease. Furthermore, clinical event intervention trials demonstrated that therapy with cholesterol synthesis inhibitors reduces not only cardiovascular and total mortality, but also other manifestations of CHD. These recent results prompted to revise, for the second time, the Dutch consensus text for lipid lowering therapy, with the following conclusions. Hypercholesterolaemia is treated with a low-saturated fat diet and normalisation of weight. For individuals, this might result in a reduction of the risk for myocardial infarction or death and for the population in a decrease of the mean serum cholesterol concentration and a reduction of the incidence of CHD. The indication for drug therapy is founded on the expected effectiveness to reduce the incidence of (new manifestations of) CHD, which is related to the level of the absolute risk of vascular disease. Treatment with cholesterol synthesis inhibitors must be considered in (a) patients with familial hypercholesterolaemia; (b) all patients with a history of myocardial infarction or other symptomatic vascular disease with a total cholesterol concentration above 5.0 mmol/l and a life expectancy of at least five years; (c) persons without known vascular disease with a combination of diabetes mellitus, hypertension, hypercholesterolaemia, cigarette smoking and high risk for development of CHD, rising from 25% per 10 years at the age of 40 years to 35-40% per 10 years at the age of 70 years, with a life expectancy of at least five years. If these guidelines are followed, the calculated cost-effectiveness is about Dfl. 40,000 per life year gained or less. The consensus committee judges this reasonable in comparison with other therapeutic interventions in the Netherlands. Thus by now, with regard to lipids and atherosclerosis, the definite link has been established between observational medicine and an effective treatment modality which is applicable in daily practise.

Social worlds, actor-networks and controversy: the case of cholesterol, dietary fat and heart disease.

Knowledge which links dietary fat and cholesterol to coronary heart disease (CHD) has been controversial for more than forty years. While policies advocating fat and cholesterol restriction are now deeply ingrained in affluent western societies, the scientific 'facts' on which they are supposedly based are highly contested. Applying concepts from actor-network theory and the symbolic interactionist social worlds approach, I argue that knowledge and dietary recommendations relating to cholesterol, fat and CHD are the outcome of complex social negotiations which can only be understood in their cultural, commercial and political contexts. Policies were framed in the 1960s before 'proof' of their efficacy was available. Since then, ambiguous experimental results have been shaped to support the policies. I argue that, despite its many attractive features, actor-network theory cannot adequately deal with protracted controversies. Social worlds theory provides a much more useful framework for investigating long debates in which the 'facts' remain elusive.

[Historical development of the cholesterol-atherosclerosis concept]. / Die historische Entwicklung des Cholesterin-Atherosklerose-Konzepts.

The development of the cholesterol hypothesis to the cholesterol theory, as related to atherogenesis, is followed in chronological sequence. The major milestones in terms of chemical pathology of the lesions, clinical observations on serum cholesterol levels in patients with coronary heart disease, lipoprotein research, epidemiological investigations and prevention of diseases due to atherosclerosis are described within three time periods: from the 19th till the beginning of the 20th century, the years between the two World Wars and the last 40 years. A total picture emerges which assigns to cholesterol and its lipoprotein carriers a key role in the origins and progression of atherosclerosis. These causal relationships have opened the way to the prevention of the disease, supported by intervention studies aimed at reduction of serum cholesterol levels.

Reconstructing long-term trends in municipal sewage discharge into a small lake in northern Manitoba, Canada.

Ross Lake lies within the City of Flin Flon (Manitoba, Canada), a mining community originally formed by the Hudson Bay Mining and Smelting Company (now Hudbay Minerals Inc.) in 1927. At the time of this investigation, a continuous effluent stream from Hudbay Minerals (approximately 80 years) and a discontinuous and unknown amount of raw and minimally treated municipal sewage (>20 years, likely ending in 1951) was discharged into the north basin of the lake. Maximum concentrations of fecal sterols, such as coprostanol and terrestrial phytosterols, such as: ß-sitosterol, campesterol, stigmastanol were measured in vertical sections of sediment cores, collected from Ross Lake, in the 15-16-cm section, which likely corresponds to the 1930s. Concentrations of coprostanol increased from <1 µg g(-1) in older sediments, to 252.3 µg g(-1) organic carbon at the peak. Observed changes in concentrations of sterols, in combination with radiometric dating and changes to sediment physicochemical characteristics, support the conclusion that sediments of a depth of less than 17.5-cm depth were deposited during the post-industrial era from approximately 1930 onwards. Ratios of coprostanol to cholesterol>1, peaking at 3.6 are consistent with anecdotal information that municipal sewage was discharged into Ross Lake during the early years of urbanization, prior to changes in treatment of sewage and discharge practices that began in 1951. Finally, historical concentrations of terrestrial phytosterols followed trends similar to those of coprostanol and cholesterol and may possibly be the result of an increase in the flux of terrestrial organic matter into Ross Lake as the result of regional deforestation due to logging and fire.