FOR THE POPULATION GENETICIST, diabetes mellitus has long presented an enigma. Here is a relatively frequent disease, often interfering with reproduction by virtue of an onset during the reproductive or even pre-reproductive years, with a well-defined genetic basis, perhaps as simple in many families as a single recessive or incompletely recessive gene (cf. Allan, 1933; Pincus and White, 1933, 1934; Harris, 1950; Steinberg and Wilder, 1952; Lamy, Frezal and de Grouchy, 1957; Steinberg, 1959; Post, 1962a). If the considerable frequency of the disease is of relatively long duration in the history of our species, how can this be accounted for in the face of the obvious and strong genetic selection against the condition? If, on the other hand, this frequency is a relatively recent phenomenon, what changes in the environment are responsible for the increase? Current developments in the study of this disease suggest an explanation with important biological ramifications.

Diabetes mellitus: a "thrifty" genotype rendered detrimental by "progress"?

Plasminogen was prepared from human plasma by affinity chromatography on L-lysine-substituted Sepharose. Thirty milligrams of plasminogen, with a specific activity of 100 caseinolytic units (Committee on Thrombolytic Agents) per milligram of nitrogen, were obtained from 340 milliliters of plasma. This corresponds to over 200-fold purification from plasma. Disc-gel electrophoresis at pH 8.3 indicated seven distinct bands, all of which contained activity.

https://science.sciencemag.org/content/sci/170/3962/1095.full.pdf

Plasminogen: Purification from Human Plasma by Affinity Chromatography

"Sexual Behavior in the Human Female" was originally published in 1953, five years after the male volume. The material presented in this book was derived from personal interviews with nearly 6,000 women; from studies in sexual Anatomy, Physiology, Psychology, and Endocrinology. The book presents data on the incidence and frequency with which women participate in various types of sexual activity. The authors show how such factors as age, decade of birth, and religious adherence are reflected in patterns of sexual behavior. Some measure of the social significance of the various types of sexual behavior is provided. The authors make comparisons of female and male sexual activities, and investigate the factors which account for the similarities and differences between female and male patterns of behavior.

Sexual Behavior in the Human Female

Preclinical strategies that are used to identify potential drug candidates include target-based screening, phenotypic screening, modification of natural substances and biologic-based approaches. To investigate whether some strategies have been more successful than others in the discovery of new drugs, we analysed the discovery strategies and the molecular mechanism of action (MMOA) for new molecular entities and new biologics that were approved by the US Food and Drug Administration between 1999 and 2008. Out of the 259 agents that were approved, 75 were first-in-class drugs with new MMOAs, and out of these, 50 (67%) were small molecules and 25 (33%) were biologics. The results also show that the contribution of phenotypic screening to the discovery of first-in-class small-molecule drugs exceeded that of target-based approaches — with 28 and 17 of these drugs coming from the two approaches, respectively — in an era in which the major focus was on target-based approaches. We postulate that a target-centric approach for first-in-class drugs, without consideration of an optimal MMOA, may contribute to the current high attrition rates and low productivity in pharmaceutical research and development.

How were new medicines discovered

There is still an unresolved paradox with respect to the immunomodulating role of estrogens. On one side, we recognize inhibition of bone resorption and suppression of inflammation in several animal models of chronic inflammatory diseases. On the other hand, we realize the immunosupportive role of estrogens in trauma/sepsis and the proinflammatory effects in some chronic autoimmune diseases in humans. This review examines possible causes for this paradox. This review delineates how the effects of estrogens are dependent on criteria such as: 1) the immune stimulus (foreign antigens or autoantigens) and subsequent antigen-specific immune responses (e.g., T cell inhibited by estrogens vs. activation of B cell); 2) the cell types involved during different phases of the disease; 3) the target organ with its specific microenvironment; 4) timing of 17beta-estradiol administration in relation to the disease course (and the reproductive status of a woman); 5) the concentration of estrogens; 6) the variability in expression of estrogen receptor alpha and beta depending on the microenvironment and the cell type; and 7) intracellular metabolism of estrogens leading to important biologically active metabolites with quite different anti- and proinflammatory function. Also mentioned are systemic supersystems such as the hypothalamic-pituitary-adrenal axis, the sensory nervous system, and the sympathetic nervous system and how they are influenced by estrogens. This review reinforces the concept that estrogens have antiinflammatory but also proinflammatory roles depending on above-mentioned criteria. It also explains that a uniform concept as to the action of estrogens cannot be found for all inflammatory diseases due to the enormous variable responses of immune and repair systems.

/pdf/the-complex-role-of-estrogens-in-inflammation-29aw75ptuv.pdf

The complex role of estrogens in inflammation

1 A definite chronological sequence of events occurs in the eggs and follicles of rabbits after mating or after the injection of ovulation-inducing substances The follicle secretes secondary liquor folliculi, and there occurs a separation of the corona radiata from strands connecting it to the follicle cells The ovum goes through nuclear maturation with as climax the production of the first polar body by the 8th hour after copulation 2 Thyroxin injections cause indirectly the same effects as mating or pituitary injections but no ovulation occurs The thyroxin effect occurs later than the pituitary effect and is due to an initiation of atresia in the follicles 3 Explantation of ova results in typical maturation phenomena which are apparently unaffected by the presence of pituitary hormones or of thyroxin in the culture medium 4 It is concluded that maturation of the ovum can be obtained simply by isolating it from the normal follicular environment 5 Normal fertilization can be secured with eggs removed from the follicles

/pdf/the-comparative-behavior-of-mammalian-eggs-in-vivo-and-in-49xhq45032.pdf

The comparative behavior of mammalian eggs in vivo and in vitro : i. the activation of ovarian eggs.

printed. The editors have used a rather curious technique of organi¬ zation, introducing some apparently meaningless repetition. In this com¬ pendium, many authors are repre¬ sented by more than one published work. But throughout the two vol¬ umes, wherever the individual's work appears, the same biographical note is reprinted. Thus the identi¬ cal note on R. M. Waters appears on pages 540, 548, 645, and 708, all in volume one. Inclusion of both subject and name indices enhances the useful¬ ness of these books. They contain a matchless collection of material now for the first time easily acces¬ sible. The resident and practicing anesthesiologist will find the vol¬ umes both interesting and educa¬ tional. And they will prove invalu¬ able to the medical historian.

Gregory Pincus

Papers

The comparative behavior of mammalian eggs in vivo and in vitro : i. the activation of ovarian eggs.

The control of fertility

Genesis of the adrenocortical secretion

Fertility control with oral medication

The eggs of mammals