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This book brings together in one volume fifteen Nobel Prize-winning discoveries that have had the greatest impact upon medical science and the practice of medicine during the 20th century and up to the present time. Its overall aim is to enlighten, entertain and stimulate. This is especially so for those who are involved in or contemplating a career in medical research. Anyone interested in the particulars of a specific award or Laureate can obtain detailed information on the topic by accessing the Nobel Foundation's website. In contrast, this book aims to provide a less formal and more personal view of the science and scientists involved, by having prominent academics write a chapter each about a Nobel Prize-winning discovery in their own areas of interest and expertise.

Tony Seed, Gilbert Thompson, Jackie Downs and John MacDermot at the book's launch in LondonThis book brings together in one volume fifteen Nobel Prize-winning discoveries that have had the greatest impact upon medical science and the practice of medicine during the 20th century and up to the present time. Its overall aim is to enlighten, entertain and stimulate. This is especially so for those who are involved in or contemplating a career in medical research.Anyone interested in the particulars of a specific award or Laureate can obtain detailed information on the topic by accessing the Nobel Foundation's website. In contrast, this book aims to provide a less formal and more personal view of the science and scientists involved, by having prominent academics write a chapter each about a Nobel Prize-winning discovery in their own areas of interest and expertise.Sample Chapter(s)Foreword (34 KB)Chapter 1: The Discovery of Insulin (2,401 KB)Contents:The Discovery of Insulin (Robert Tattersall)The Discovery of the Cure for Pernicious Anaemia, Vitamin B12 (A Victor Hoffbrand)The Discovery of Penicillin (Eric Sidebottom)The Introduction of Cardiac Catheterization (Tony Seed)The Discovery of the Structure of DNA (James Scott and Gilbert Thompson)The Interpretation of the Genetic Code (John MacDermot and Ellis Kempner)The Discovery of Neuropeptides and Radioimmunoassay of Peptide Hormones (Jaimini Cegla and Stephen Bloom)The Development of Computer-Assisted Tomography (Adrian M K Thomas)The Discovery of Prostaglandins (Rod Flower)The Antibody Problem and the Generation of Monoclonal Antibodies (Herman Waldmann and Celia P Milstein)The Discovery of the LDL Receptor and Its Role in Cholesterol Metabolism (Gilbert Thompson)The Invention of the Polymerase Chain Reaction and Use of Site-Directed Mutagenesis (Anne K Soutar)The Discovery of the Pathophysiological Role of Nitric Oxide in Blood Vessels (Keith M Channon)The Discovery of Helicobacter pylori (Chris Hawkey)The Discovery of RNA Interference - Gene Silencing by Double-Stranded RNA (Richard P Hull and Timothy J Aitman)Readership: Students, undergraduates, graduates, professionals and members of the general public interested in the impact of Nobel Prize-winning discoveries in medicine.

Familial hypercholesterolemia carries a marked increase in the risk of coronary heart disease (CHD), but there is considerable variation between individuals in susceptibility to CHD. To investigate the possible role of lipoprotein(a) as a risk factor for CHD, we studied the association between serum lipoprotein(a) levels, genetic types of apolipoprotein(a) (which influence lipoprotein(a) levels), and CHD in 115 patients with heterozygous familial hypercholesterolemia. The median lipoprotein(a) level in the 54 patients with CHD was 57 mg per deciliter, which is significantly higher than the corresponding value of 18 mg per deciliter in the 61 patients without CHD. According to discriminant-function analysis, the lipoprotein(a) level was the best discriminator between the two groups (as compared with all other lipid and lipoprotein levels, age, sex, and smoking status). Phenotyping for apolipoprotein(a) was performed in 109 patients. The frequencies of the apolipoprotein(a) phenotypes and alleles differed significantly between the patients with and those without CHD. The allele Lp S2 , which is associated with high lipoprotein(a) levels, was found more frequently among the patients with CHD (0.33 vs. 0.12). In contrast, the Lp S4 allele, which is associated with low lipoprotein(a) levels, was more frequent among those without CHD (0.27 vs. 0.15). We conclude that an elevated level of lipoprotein(a) is a strong risk factor for CHD in patients with familial hypercholesterolemia, and the increase in risk is independent of age, sex, smoking status, and serum levels of total cholesterol, triglyceride, or high-density lipoprotein cholesterol. The higher level of lipoprotein(a) observed in the patients with CHD is the result of genetic influence. (N Engl J Med 1990; 322:1494–9.) LIPOPROTEIN(a) was described over 25 years ago by Berg as a genetic trait found in human plasma. 1 Subsequent workers characterized its physicochemical properties and distribution in plasma, as well as the association of high levels of lipoprotein(a) with coronary heart disease (CHD), reviewed by Morrisett et al. 2 Angiographic studies suggest that the level of lipoprotein(a) in plasma is a risk factor for disease of both native coronary vessels and saphenous-vein bypass grafts, and that the risk associated with an elevated level is of the same order of magnitude as that associated with low-density lipoprotein (LDL) cholesterol. 3 , 4 Evidence that lipoprotein(a) and . . .

[...]before undertaking screening it is important to first answer the question as to whether the results are likely to influence the future management of the person screened. Furthermore, the risk of CHD can be decreased by therapeutic reduction of LDL cholesterol concentrations. [...]LDL not only has all the criteria of a true risk factor but its presence in plasma is obligatory for other risk factors to exert their effects.

Patients with high plasma plasminogen activator inhibitor-1 (PAI-1) antigen levels are prone to develop thrombosis. Lowering PAI-1 levels may offer a therapeutic option and help to better understand PAI-1 metabolism. We examined the effect on plasma PAI-1 levels of LDL-apheresis using dextran sulphate (DS) columns in 12 patients (9 male, 3 female, 49 ± 10 years) with heterozygous familial hypercholesterolaemia and coronary artery disease. One plasma volume equivalent (2.3–4.0 l) was treated during each procedure (at flow rates of 23 ± 2 ml/min). Lipids and PAI-1 antigen levels were measured in plasma before and immediately after 19 aphereses (once in 7 patients, twice in 3 patients and three times in 2 patients) and also at 3 and 7 days post apheresis in five of these patients and in the column eluates from 8 of these patients. DS-apheresis reduced plasma cholesterol (50 ± 8%), triglyceride (45 ± 27%), apolipoprotein B (59 ± 10%) and PAI-1 antigen levels from 10.2 ± 5.2 to 6.0 ± 3.1 ng/ml ( P = 0.005). The PAI-I changes were independent of circadian variation. PAI-I bound to the DS-columns (3.51 ± 1.03 ng/ml filtered plasma) and the percent of filtered PAI-1 that was bound correlated inversely ( r = −0.81, P < 0.02) with basal PAI-1 levels indicating a high affinity saturable binding process. In four patients, plasma PAI-1 levels post-apheresis were higher than expected based on the amount of PAI-removed by the DS columns. The difference between the expected and actual PAI-1 level post apheresis, reflecting PAI-1 secretion or extracellular redistribution, correlated inversely with basal PAI-1 levels ( r = −0.83, P = 0.01). PAI-1 levels returned to baseline pre-apheresis values 7 days post apheresis. PAI-1 antigen may be removed from plasma without adverse effect, resulting temporarily in its extracellular redistribution and restoration to baseline levels over one week. PAI-1 redistribution particularly when baseline pre-apheresis values were low may reflect a homeostatic mechanism to maintain sufficient PAI-1 levels. Procedures that could selectively remove PAI-1 from plasma may offer a treatment option for those with very high plasma PAI-1 levels and thrombosis.

Genetic and pharmacological increases of HDL cholesterol need further evaluation

EDITOR-Van Heyningen suggests that a margarine containing plant stanol ester (Benecol) may not lower low density lipoprotein cholesterol concentration in people with a fat modified diet. 1 He presents no evidence of his own for this assertion but cites a study by Denke in which participants were given plant stanol in gelatin capsules. 2 However, he fails to cite a more recent study in which plant stanol esters were dissolved in margarine and fed to participants eating a diet which provided only 26% of energy as fat and about 150 mg of cholesterol daily. 3 Reductions in low density lipoprotein cholesterol concentration in the two test groups were 8.6% and 13.7% respectively compared with controls.