Hormonal alteration of the response of the rat uterus to catecholamines

The influence of circulating ovarian hormones on the uterine response to catecholamines in the rat has been studied. Uterine smooth muscles from untreated ovariectomized rats, or from ovariectomized rats under the influence of progesterone, are relaxed by norepinephrine. This response is blocked by [beta]-adrenergic blocking drugs. Samples taken from estrogen-dominated rat uteri, on the other hand, are usually stimulated by norepinephrine, a response which can be prevented by [alpha]-adrenergic blocking agents.Thus, the response of the rat uterus to norepinephrine appears to depend on a balance between [alpha] and [beta] adrenergic receptors in the myometrium, and this balance is in turn regulated by the ovarian hormones.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/33402/1/0000803.pd

The effect of triethyltin on mitochondrial swelling

Triethyltin induces swelling of isolated rat liver mitochondria suspended in sucrose or KCl media. This effect is not seen with brain mitochondria. Triethyltin swelling is only minimally reduced by EDTA or amytal but is prevented by 2:4-dinitrophenol, cyanide or salicylate. The addition of adenosine tri- or diphosphate causes reversal of the swelling; this effect is potentiated by Mn2+ but not by Mg2+. The reversal of thyroxine-induced swelling by ATP is blocked by triethyltin, perhaps via an inhibition of the hydrolysis of adenosine triphosphate. The relationship between in vitro effects of triethyltin on mitochondria and the toxic actions of the drug in the whole animal are discussed.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/32366/1/0000441.pd

Inhibition of Na+K+-activated adenosine triphosphatase activity in rat brain by substituted phenothiazines

The effects of fifteen substituted phenothiazines and certain other drugs were studied on microsomal Na+K+-activated ATPase in rat brain to attempt to relate their central nervous system effects with their inhibition of enzyme activity. The mean control activity of the preparation was 14[middle dot]4 +/- 0[middle dot]2 [mu]moles Pi/mg protein/15 min at 37[deg] in the presence of Na+, K+, and Mg++; and 3[middle dot]3 +/- 0[middle dot]1 in the presence of Mg++ alone.Certain substitutions on the phenothiazine nucleus were noted to increase the inhibitory potency. At position 2 of the phenothiazine nucleus, a trifluoromethyl group was more potent than a chloro group which was in turn more potent than hydrogen. At position 10, a piperazine side chain was more inhibitory than an aliphatic amine substitution. The sulfoxide derivatives of promazine, chlorpromazine, and triflupromazine did not inhibit Na+K+-ATPase activity at concentrations as high as 5 x 10-4 M.Compounds which failed to influence Na+K+-ATPase activity at concentrations used in the phenothiazine studies were pentylenetetrazol, d-amphetamine, strychnine, [gamma]-aminobutyric acid, and pentobarbital.The evidence in this report suggests that, for substituted phenothiazines, there may be a correlation between inhibition of brain Na+K+-ATPase activity in vitro and certain central nervous system effects in vivo.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/33438/1/0000840.pd

A Framework For Detecting Noncoding Rare-Variant associations of Large-Scale Whole-Genome Sequencing Studies

Large-scale whole-genome sequencing studies have enabled analysis of noncoding rare-variant (RV) associations with complex human diseases and traits. Variant-set analysis is a powerful approach to study RV association. However, existing methods have limited ability in analyzing the noncoding genome. We propose a computationally efficient and robust noncoding RV association detection framework, STAARpipeline, to automatically annotate a whole-genome sequencing study and perform flexible noncoding RV association analysis, including gene-centric analysis and fixed window-based and dynamic window-based non-gene-centric analysis by incorporating variant functional annotations. In gene-centric analysis, STAARpipeline uses STAAR to group noncoding variants based on functional categories of genes and incorporate multiple functional annotations. In non-gene-centric analysis, STAARpipeline uses SCANG-STAAR to incorporate dynamic window sizes and multiple functional annotations. We apply STAARpipeline to identify noncoding RV sets associated with four lipid traits in 21,015 discovery samples from the Trans-Omics for Precision Medicine (TOPMed) program and replicate several of them in an additional 9,123 toPMed samples. We also analyze five non-lipid toPMed traits

Both “illness and temptation of the enemy”: melancholy, the medieval patient and the writings of King Duarte of Portugal (r. 1433–38)

Recent historians have rehabilitated King Duarte of Portugal, previously maligned and neglected, as an astute ruler and philosopher. There is still a tendency, however, to view Duarte as a depressive or a hypochondriac, due to his own description of his melancholy in his advice book, the Loyal Counselor. This paper reassesses Duarte's writings, drawing on key approaches in the history of medicine, such as narrative medicine and the history of the patient. It is important to take Duarte's views on his condition seriously, placing them in the medical and theological contexts of his time and avoiding modern retrospective diagnosis. Duarte's writings can be used to explore the impact of plague, doubt and death on the life of a well-educated and conscientious late-medieval ruler

New genetic loci link adipose and insulin biology to body fat distribution.

Body fat distribution is a heritable trait and a well-established predictor of adverse metabolic outcomes, independent of overall adiposity. To increase our understanding of the genetic basis of body fat distribution and its molecular links to cardiometabolic traits, here we conduct genome-wide association meta-analyses of traits related to waist and hip circumferences in up to 224,459 individuals. We identify 49 loci (33 new) associated with waist-to-hip ratio adjusted for body mass index (BMI), and an additional 19 loci newly associated with related waist and hip circumference measures (P < 5 × 10(-8)). In total, 20 of the 49 waist-to-hip ratio adjusted for BMI loci show significant sexual dimorphism, 19 of which display a stronger effect in women. The identified loci were enriched for genes expressed in adipose tissue and for putative regulatory elements in adipocytes. Pathway analyses implicated adipogenesis, angiogenesis, transcriptional regulation and insulin resistance as processes affecting fat distribution, providing insight into potential pathophysiological mechanisms

No. I Printed in USA

ABSTRACT Davis, Mary

human Pharmacology : Molecular to clinical

xvii+1001hlm.;27c