Reconceptualizing John F. Kennedy's chronic low back pain.

When the medical records for John Fitzgerald Kennedy were made public, it became clear that the 35th President of the United States suffered greatly from a series of medical illnesses from the time he was a toddler until his assassination in November of 1963. Aside from having Addison disease, no condition seemed to cause him more distress than did his chronic low back pain. A number of surgical procedures to address the presumed structural cause of the pain resulted in little relief and increased disability. Later, a conservative program, including trigger point injections and exercises, provided modest benefit. Herein, the mechanisms underlying his pain are evaluated based on more contemporary pain research. This reconceptualizing of John Fitzgerald Kennedy's pain could serve as a model for other cases where the main cause of the pain is presumed to be located in the periphery.

[Igor' Vladimirovich Torgov. Corresponding member of the Russian Academy of Sciences. On his 95th birthday].

The late 1940s and the early 1950s were marked by an extraordinary rise in the interest of scientists worldwide (chemists, biologists, and physicians) in steroid hormones, one of the types of natural compounds later referred to as low-molecular bioregulators. The steroid compounds constructed on the basis of the cyclopentanoperhydrophenanthrene skeleton turned out to be the most universal of all known representatives of natural compounds, exhibiting a high regulatory activity in the broadest set of physiological processes. At the very beginning of study of this class of compounds, it was found that they are responsible for sexual development and maturation, reproduction, water-salt balance, and exchange of carbohydrates. The spectrum of their activities was extended ever further, and, nowadays, perhaps no known vital function of living organisms remains in which, in some way, steroids are not involved.

[History, presence and trends of steroid endocrinology]. / Historie, soucasnost a smerování steroidní endokrinologie.

The millstones achieved in the field of steroid endocrinology since thirties until present are outlined, including major goals obtained in the author's laboratory. After the brief historical survey the following chapters are devoted to steroid laboratory diagnostics, therapy and expected trends.

Steroid hydroxylations: a paradigm for cytochrome P450 catalyzed mammalian monooxygenation reactions.

The present article reviews the history of research on the hydroxylation of steroid hormones as catalyzed by enzymes present in mammalian tissues. The report describes how studies of steroid hormone synthesis have played a central role in the discovery of the monooxygenase functions of the cytochrome P450s. Studies of steroid hydroxylation reactions can be credited with showing that: (a) the adrenal mitochondrial enzyme catalyzing the 11beta-hydroxylation of deoxycorticosterone was the first mammalian enzyme shown by O18 studies to be an oxygenase; (b) the adrenal microsomal enzyme catalyzing the 21-hydroxylation of steroids was the first mammalian enzyme to show experimentally the proposed 1:1:1 stoichiometry (substrate:oxygen:reduced pyridine nucleotide) of a monooxygenase reaction; (c) application of the photochemical action spectrum technique for reversal of carbon monoxide inhibition of the 21-hydroxylation of 17alpha-OH progesterone was the first demonstration that cytochrome P450 was an oxygenase; (d) spectrophotometric studies of the binding of 17alpha-OH progesterone to bovine adrenal microsomal P450 revealed the first step in the cyclic reaction scheme of P450, as it catalyzes the "activation" of oxygen in a monooxygenase reaction; (e) purified adrenodoxin was shown to function as an electron transport component of the adrenal mitochondrial monooxygenase system required for the activity of the 11beta-hydroxylase reaction. Adrenodoxin was the first iron-sulfur protein isolated and purified from mammalian tissues and the first soluble protein identified as a reductase of a P450; (f) fractionation of adrenal mitochondrial P450 and incubation with adrenodoxin and a cytosolic (flavoprotein) fraction were the first demonstration of the reconstitution of a mammalian P450 monooxygenase reaction.

Fifty years with bile acids and steroids in health and disease.

Cholesterol and its metabolites, e.g., steroid hormones and bile acids, constitute a class of compounds of great biological importance. Their chemistry, biochemistry, and regulation in the body have been intensely studied for more than two centuries. The author has studied aspects of the biochemistry and clinical chemistry of steroids and bile acids for more than 50 years, and this paper, which is an extended version of the Schroepfer Medal Award lecture, reviews and discusses part of this work. Development and application of analytical methods based on chromatography and mass spectrometry (MS) have been a central part of many projects, aiming at detailed characterization and quantification of metabolic profiles of steroids and bile acids under different conditions. In present terminology, much of the work may be termed steroidomics and cholanoidomics. Topics discussed are bile acids in human bile and feces, bile acid production, bacterial dehydroxylation of bile acids and steroids during the enterohepatic circulation, profiles of steroid sulfates in plasma of humans and other primates, development of neutral and ion-exchanging lipophilic derivatives of Sephadex for sample preparation and group separation of steroid and bile acid conjugates, profiles of steroids and bile acids in human urine under different conditions, hydroxylation of bile acids in liver disease, effects of alcohol-induced redox changes on steroid synthesis and metabolism, alcohol-induced changes of bile acid biosynthesis, compartmentation of bile acid synthesis studied with 3H-labeled ethanol, formation and metabolism of sulfated metabolites of progesterone in human pregnancy, abnormal patterns of these in patients with intrahepatic cholestasis of pregnancy corrected by ursodeoxycholic acid, inherited and acquired defects of bile acid biosynthesis and their treatment, conjugation of bile acids and steroids with N-acetylglucosamine, sulfate-glucuronide double conjugates of hydroxycholesterols, extrahepatic 7alpha-hydroxylation and 3-dehydrogenation of hydroxycholesterols, and extrahepatic formation of C27 bile acids. The final part discusses analysis of free and sulfated steroids in brain tissue by capillary liquid chromatography-electrospray MS and suggests a need for reevaluation of the function of steroid sulfates in rat brain.

The rise and fall of the British Drug Houses, Ltd.

Steroid research at BDH began in earnest in 1946-1948, when Hartley and Petrow joined the company. With the need to find new progestational agents to replace ethisterone and progesterone, the company began work. They were the first to discover the vital importance of 6-methylation in enhancing the hormonal effects of steroid hormones. Their progestational studies led them to work on antifertility agents and the development of ovulation inhibitors, the mini-pill, and preliminary studies on the postcoital pill. Their search for new steroids additionally resulted in synthesis for biological evaluation of new corticoids, anabolic agents, estrogens, and mineralocorticoids. In 1968 the company, then known as The BDH Group Ltd., was incorporated into the Glaxo Group and company research terminated.

Between basic and applied research: Ciba's involvement in steroids in the 1950s and 1960s.

Through its collaboration with the ETH in Zurich (Ruzicka's group) and later on with the University of Basel (Reichstein's group). Ciba became involved very early in steroid chemistry. The main task of the chemists consisted at that time of the synthesis of natural hormones and their derivatives. Cholesterol served for several years as the preferred starting material, and efficient procedures were developed for its degradation to suitable intermediates. Total syntheses of estrogenic substances were pursued independently. Up to the mid-1950s the search for alternative starting materials, like hecogenin were intensively investigated. In a later period, collaboration with various companies in the United States and in Europe stimulated Ciba's involvement in the corticoids, especially the dermatocorticoids (Locorten, Sicorten, Miracortene/Ultravate). In line with Ciba's traditionally strong engagement in process development, during the period described in this report a major effort, was directed towards the isolation and synthesis of aldosterone, the most active natural mineralocorticoid. In connection with its partial synthesis, new intramolecular radical reactions (e.g., the lead(IV) acetate and the hypoiodite reaction) were discovered and studied. Although, from the commercial point of view, aldosterone did not meet our expectations, the application of these new reactions to the synthesis of 19-norsteroids opened for Ciba the road to progestins and related compounds.