Effects of Orally Administered Sodium D-thyroxine upon Pregnancy Progression in Euthyroid Rabbits and its Effect Upon the Newborn

Many authorities believe that prophylactic treatment of idiopathic hypercholesterolemia will prevent atherosclerosis and plaque formation which almost always precedes clinical arteriosclerosis and subsequent degenerative heart disease. There has been intensive research investigation initiated to provide a pharmacologic agent that will lower elevated serum cholesterol levels in mammals including humans. Several hypocholesterolemic drugs are being tested at the present time, one of the most promising is the dextro-rotary isomer of thyroxine. This study was conducted not only to determine the effects of orally administered dextrothyroxine on pregnancy progression, but also to provide information for further investigations concerning alterations related to hypercholesterolemic pregnant animals. Cardiovascular diseases are by far the leading cause of death in the Western World. Therefore, the need for safe and reliable drugs that might be employed in the prevention and/or treatment of cardiovascular alterations is abundantly clear. Presently, within the United States, three hypocholesterolemic agents are being tested in massive clinical trials: nicotinic acid, ethyl p-chlorophenosyisobutyrate1 and sodium D-thyroxine2, of which D-thyroxine is the most promising. Almost nothing is known concerning the alterations of D-thyroxine in relation to pregnancy progression or its effects involving newborn mammals and/or humans. The possibility of congenital cardiac anamolies must, however, be considered in the light of previous research investigations which indicate that cardiac hypertrophy may occur during D-thyroxine administration. It is hoped that these investigations coupled with the contemplative studies utilizing hypercholesterolemic animals may shed some light on possible cardiovascular alterations caused by D-thyroxine administration during pregnancy.

Effects of Orally Administered Allopurinol (Hyroxyprazolo 3,4-d pyrimidine) on Uric Acid, Selected Blood Lipid and Hemogram Parameters in Rabbits

Gout is one of the earliest disease entities to be described in medical writings. Hippocrates noted familial distribution patterns and described its classic symptomatology in the 5th century B.C. Empirical treatment employing colchicine was advocated by Alexander of Tralles in the 5th century A.D. A better understanding of the complex association between clinical manifestations of gout and uric acid, carbohydrate and lipid metabolism has made rational treatment possible only very recently. Ample experimental and clinical data now available show a definite association between disorders of purine metabolism resulting in hyperuricemia and frequent concomitant hyperlipidemia. A high incidence of both hypercholesterolemia and hypertriglyceridemia has been documented. Elevated serum lipids may explain, in part, clinical manifestations of atherosclerosis, occlusive peripheral and coronary arterial disease and vascular nephrosclerosis so common in approximately 800,000 individuals suffering from gout in the United States. Renal failure, ischemic and degenerative cardiovascular disease are the most common cause of: death in these patients. Therefore, the need for safe and reliable drugs that may be employed in the rational treatment of both gout, and associated cardiovascular alterations is abundantly clear. Allopurinol (hydroxypyrazolo(3,4-d)pyrimidine) (HPP) is by far the most promising drug now available for treatment of gout and related hyperuricemic disorders. It represents a new and rational approach to therapy by inhibiting an enzyme essential to uric acid biosynthesis. The correlation between gout and clinical manifestations of atherosclerosis associated with hypercholesterolemia and hypertriglyceridemia dictates that drugs used in treating hyperuricemic conditions should not elevate serum lipids. A further elevation of these parameters could increase the incidence of cardiovascular disease in highly susceptible gouty subjects. A possible causal relationship between therapeutic use of allopurinol and elevations· in blood lipid values (human subject) was reported for the first time by this station in April, 1969. A subsequent preliminary animal study indicated an apparent experimentally provoked hypercholesterolemic hyperlipemia in rabbits administered allopurinol. This study was initiated to examine the problem in greater detail

Evaluation of Orally Administered Sodium D-Thyroxine as a Teratogen in New Zealand White Rabbits

Sodium D-thyroxine was evaluated for possible embryotoxic and/or teratogenic effects following oral administration in New Zealand White rabbits. All animals utilized were alert, active and apparently disease-free virgin does weighing three and one-half to four kilograms. Rabbits were individually housed in stainless steel batteries and maintained on a commercially available palletized diet and mineral supplement. Feed and water were provided ad libitum in animal quarters air conditioned to minimize environmental temperature fluctuations. Following a 14-day post-delivery observation period does were bred to New Zealand White bucks and randomly allocated to one of two experimental groups or the control group each containing 10 animals. A pure sodium salt sample of the dextro isomer of thyroxine (NaD-T4) was supplied for experimental use as a fine, cream-colored powder. The hormone was dissolved in an alkaline, hot ethanol media to produce solutions suitable for oral administration. Control animals received 0.5 ml. of diluent each day of pregnancy. Animals in Experimental Group I received 2.0 mg.· of NaD-T4 in 0.5 ml. of diluent each day of pregnancy. Does in Experimental Group II received 0.5 ml. of diluent during the first 15 days of gestation and 2.0 mg. of NaD-T4 in 0.5 ml. diluent daily the last 15 days of pregnancy. Unanesthetized pregnant does were sacrificed on day 29 of their gestation periods by massive air embolism induced by cardiac puncture. Data were obtained from 59 control, 63 Experimental I, and 56 Experimental II fetuses following post-mortem cesarean delivery. Increased doe lethality did not occur in experimental animal groups at the 2.0 mg. p.o. daily dosage level employed. Macroscopic uterine pathology was not observed in either control or experimental does. Intrauterine mortality rates were similar in control and Experimental II animal groups. An increase of over 20% in intrauterine mortality was noted in Experimental I group does. Observed discrepancies in embryotoxicity, at the same daily p.o. dosage level, are attributed to chronic fetal exposure during a more susceptible developmental stage. In every case, non-viable Experimental I and II fetuses were undergoing sterile intrauterine autolysis of approximately 24-48 hour duration when delivered on day 29. All rabbit fetuses were critically examined for embryotoxic and/or teratogenic effects following cesarean delivery. Fetuses were examined externally, internally, and roentgenologically for over 100 primary pantasomatous and merosomatous terata. Exhaustive examination of every fetus obtained in the study failed to uncover a single anomaly. Organ weight data including wet/dry heart, wet liver and wet right kidney and lung weights were obtained from fetuses judged viable following cesarean delivery. Results of statistical analysis indicated highly significant treatment effects (fetal organ weight increases) in both Experimental I and II animal groups. Absolute increases were greater in Experimental I doe fetuses who were exposed to the drug daily. No histopathology was observed in placental tissue or maternal heart sections obtained from each control and experimental doe. All fetal liver, kidney and lung tissue sections were judged normal. Increased liver, kidney and lung weights observed in fetuses obtained from does medicated with sodium dextrothyroxine were not associated with microscopic alterations or histopathology

An improved predictive recognition model for Cys2-His2 zinc finger proteins

Cys2-His2 zinc finger proteins (ZFPs) are the largest family of transcription factors in higher metazoans. They also represent the most diverse family with regards to the composition of their recognition sequences. Although there are a number of ZFPs with characterized DNA-binding preferences, the specificity of the vast majority of ZFPs is unknown and cannot be directly inferred by homology due to the diversity of recognition residues present within individual fingers. Given the large number of unique zinc fingers and assemblies present across eukaryotes, a comprehensive predictive recognition model that could accurately estimate the DNA-binding specificity of any ZFP based on its amino acid sequence would have great utility. Toward this goal, we have used the DNA-binding specificities of 678 two-finger modules from both natural and artificial sources to construct a random forest-based predictive model for ZFP recognition. We find that our recognition model outperforms previously described determinant-based recognition models for ZFPs, and can successfully estimate the specificity of naturally occurring ZFPs with previously defined specificities

Genome-wide association analyses identify new susceptibility loci for oral cavity and pharyngeal cancer

We conducted a genome-wide association study of oral cavity and pharyngeal cancer in 6,034 cases and 6,585 controls from Europe, North America and South America. We detected eight significantly associated loci (P < 5 x 10(-8)), seven of which are new for these cancer sites. Oral and pharyngeal cancers combined were associated with loci at 6p21.32 (rs3828805, HLA-DQB1), 10q26.13 (rs201982221, LHPP) and 11p15.4 (rs1453414, OR52N2-TRIM5). Oral cancer was associated with two new regions, 2p23.3 (rs6547741, GPN1) and 9q34.12 (rs928674, LAMC3), and with known cancer-related loci-9p21.3 (rs8181047, CDKN2B-AS1) and 5p15.33 (rs10462706, CLPTM1L). Oropharyngeal cancer associations were limited to the human leukocyte antigen (HLA) region, and classical HLA allele imputation showed a protective association with the class II haplotype HLA-DRB1*1301-HLA-DQA1*0103-HLA-DQB1*0603 (odds ratio (OR) = 0.59, P = 2.7 x 10(-9)). Stratified analyses on a subgroup of oropharyngeal cases with information available on human papillomavirus (HPV) status indicated that this association was considerably stronger in HPV-positive (OR = 0.23, P = 1.6 x 10(-6)) than in HPV-negative (OR = 0.75, P = 0.16) cancers

Shared heritability and functional enrichment across six solid cancers

Correction: Nature Communications 10 (2019): art. 4386 DOI: 10.1038/s41467-019-12095-8Quantifying the genetic correlation between cancers can provide important insights into the mechanisms driving cancer etiology. Using genome-wide association study summary statistics across six cancer types based on a total of 296,215 cases and 301,319 controls of European ancestry, here we estimate the pair-wise genetic correlations between breast, colorectal, head/neck, lung, ovary and prostate cancer, and between cancers and 38 other diseases. We observed statistically significant genetic correlations between lung and head/neck cancer (r(g) = 0.57, p = 4.6 x 10(-8)), breast and ovarian cancer (r(g) = 0.24, p = 7 x 10(-5)), breast and lung cancer (r(g) = 0.18, p = 1.5 x 10(-6)) and breast and colorectal cancer (r(g) = 0.15, p = 1.1 x 10(-4)). We also found that multiple cancers are genetically correlated with non-cancer traits including smoking, psychiatric diseases and metabolic characteristics. Functional enrichment analysis revealed a significant excess contribution of conserved and regulatory regions to cancer heritability. Our comprehensive analysis of cross-cancer heritability suggests that solid tumors arising across tissues share in part a common germline genetic basis.Peer reviewe

Shared heritability and functional enrichment across six solid cancers

Quantifying the genetic correlation between cancers can provide important insights into the mechanisms driving cancer etiology. Using genome-wide association study summary statistics across six cancer types based on a total of 296,215 cases and 301,319 controls of European ancestry, here we estimate the pair-wise genetic correlations between breast, colorectal, head/neck, lung, ovary and prostate cancer, and between cancers and 38 other diseases. We observed statistically significant genetic correlations between lung and head/neck cancer (r(g) = 0.57, p = 4.6 x 10(-8)), breast and ovarian cancer (r(g) = 0.24, p = 7 x 10(-5)), breast and lung cancer (r(g) = 0.18, p = 1.5 x 10(-6)) and breast and colorectal cancer (r(g) = 0.15, p = 1.1 x 10(-4)). We also found that multiple cancers are genetically correlated with non-cancer traits including smoking, psychiatric diseases and metabolic characteristics. Functional enrichment analysis revealed a significant excess contribution of conserved and regulatory regions to cancer heritability. Our comprehensive analysis of cross-cancer heritability suggests that solid tumors arising across tissues share in part a common germline genetic basis

Anatomy and physiology: laboratory manual

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