Relevance of increased serum thyroxine concentrations associated with normal serum triiodothyronine values in hypothyroid patients receiving thyroxine: a case for tissue thyrotoxicosis.

Fifteen patients receiving standard thyroxine replacement therapy (100-200 micrograms daily) for primary hypothyroidism and who had persistently raised free thyroxine concentrations in their serum were investigated to see whether the dose being given was too high. In addition to the usual thyroid hormone assays systolic time intervals (which indicate left ventricular contractility) were calculated as accurate reflectors of tissue thyroid activity. All patients showed the expected increased free and total thyroxine concentrations; but mean total and free concentrations of triiodothyronine were normal, while reverse triiodothyronine values were raised. Mean systolic time intervals were significantly reduced as compared with normal and fell within the thyrotoxic range. Seven patients subsequently had their doses of thyroxine reduced by 50 micrograms daily and were reinvestigated one month later. All showed significant falls in circulating thyroxine and triiodothyronine concentrations and an increase in mean systolic time intervals to the normal range. In patients receiving thyroxine replacement therapy for primary hypothyroidism a raised serum thyroxine concentration may indicate tissue thyrotoxicosis and should prompt a reduction of the thyroxine dose.     

Serum thyroxine and triiodothyronine radioimmunoassay values in the normal ferret

The European ferret, Mustela putorius furo, has become increasingly popular as an animal model in biomedical research. However, certain important normal clinical data have not been established for the ferret. In this study, serum thyroxine (T4) and 3,3',5-triiodothyronine (T3) values were obtained from ferrets by the use of commercial radioimmunoassays. Sera from 44 animals, 31 males (27 intact and 4 castrated) and 13 females (10 intact and 3 spayed) were assayed. Serum T4 values ranged from 1.01-8.29 micrograms/dl for males (mean = 3.24 +/- 1.65 micrograms/dl), and 0.71-3.43 micrograms/dl for females (mean = 1.87 +/- 0.79 micrograms/dl). Serum T4 values of adult female ferrets, juvenile ferrets (less than 1 year old) of either sex, and castrated males were similar to the normal T4 values of the cat, 1.20-3.80 micrograms/dl. Intact adult male ferrets had higher serum T4 values which were more comparable to those of the normal dog 1.52-3.60 micrograms/dl. Serum T3 values ranged from 0.45-0.78 ng/ml for males (mean = 0.58 +/- 0.09 ng/ml), and 0.29-0.73 ng/ml for females (mean = 0.53 +/- 0.13 ng/ml). These values are comparable to those of dogs and cats which are 0.50-1.50 ng/ml.     

Comparative neuropathogenesis and neurovirulence of attenuated flaviviruses in nonhuman primates

Based on previous preclinical evaluation in mice and monkeys, the chimeric TBEV/DEN4Delta30 virus, carrying the prM and E protein genes from a highly virulent Far Eastern strain of tick-borne encephalitis virus (TBEV) on the backbone of a nonneuroinvasive dengue type 4 virus (DEN4), has been identified as a promising live attenuated virus vaccine candidate against disease caused by TBEV. However, prior to use of this vaccine candidate in humans, its neurovirulence in nonhuman primates needed to be evaluated. In the present study, we compared the neuropathogeneses of the chimeric TBEV/DEN4Delta30 virus; Langat virus (LGTV), a former live TBEV vaccine; and yellow fever 17D virus vaccine (YF 17D) in rhesus monkeys inoculated intracerebrally. TBEV/DEN4Delta30 and YF 17D demonstrated remarkably similar spatiotemporal profiles of virus replication and virus-associated histopathology in the central nervous system (CNS) that were high in cerebral hemispheres but progressively decreased toward the spinal cord. In contrast, the neurovirulence of LGTV exhibited the reverse profile, progressing from the site of inoculation toward the cerebellum and spinal cord. Analysis of the spatiotemporal distribution of viral antigens in the CNS of monkeys revealed a prominent neurotropism associated with all three attenuated viruses. Nevertheless, TBEV/DEN4Delta30 virus exhibited higher neurovirulence in monkeys than either LGTV or YF 17D, suggesting insufficient attenuation. These results provide insight into the neuropathogenesis associated with attenuated flaviviruses that may guide the design of safe vaccines.     

Total and free thyroxine and triiodothyronine in blood serum of mammals

1. Blood samples were obtained from seven species of mammals: horses, cattle, sheep, goats, pigs, guinea pigs and rats for determination of total and free thyroxine and triiodothyronine. Total thyroxine in the order listed above in ng/ml was: 15, 60, 79, 185, 53, 45 and 79. Free thyroxine in pg/ml was: 5.9, 10.0, 19.2, 32.1, 21.7, 6.7 and 51.3. 2. Total triiodothyronine in pg/ml was: 677, 1290, 979, 3170, 760, 317 and 1747. Free triiodothyronine in pg/ml was: 3.22, 4.40, 2.60, 6.74, 2.74, 2.42 and 10.88. 3. Percent free thyroxine was high in rats and low in guinea pigs, while percent free triiodothyronine was high in guinea pigs and low in goats. 4. Free thyroxine and percent free thyroxine were higher in some groups of horses, particularly stallions, than in other groups.     

Rapid simultaneous radioimmunoassay for triiodothyronine and thyroxine in unextracted serum

A three hour radioimmunoassay for the simultaneous measurement of triiodothyronine and thyroxine in 25λ of unextracted serum has been developed. 8-anilino-1-napthalene sulfonic acid has been used to inhibit binding of the two hormones to thyroxine binding globulin. Comparisons of thyroxine with those obtained by competitive protein binding assay and triiodothyronine with those determined by our previously developed radioimmunoassay afford excellent agreement. The speed, accuracy, sensitivity and specificity of this assay renders it highly attractive for routine clinical determinations and for research applications as well.     

Genital Ureaplasmas in nonhuman primates.

Ureaplasmas were isolated from the genital tracts of four of 22 (18.4%) male chimpanzees and eight of 23 (34.8%) female chimpanzees. Twenty-nine female rhesus monkeys, 38 female baboons, one gibbon, and black ape and one Java monkey were shown to be free of genital Ureaplasmas. The rate of reproductive failure among the chimpanzees was high and it is suggested that Ureaplasma may be responsible in part. The chimpanzee may serve as a useful model for human Ureaplasma genital infections.     

Serum triiodothyronine and thyroxine levels in children with celiac disease]

The study was aimed at determining relationship between thyroid function and the type and degree of malabsorption. Serum triiodothyronine (T3) and thyroxine (T4) levels were determined in children with celiac disease and the secondary malabsorption. Hundred fifty five children aged between 6 months and 7 years were followed up 3 years. Coeliac disease was diagnosed with classic Interlaken criteria. All children were divided into three groups: group I--57 children aged between 6 months and 3 years with suspected celiac disease; group II--55 children aged between 2.5 and 6 years after gluten-free diet therapy; group III--52 children aged between 3 and 7 years after gluten provocation test. Serum T3 and T4 levels for each group were compared with those in children with normal gut mucous membrane. Blood serum T3 and T4 were assayed with OPIDI kit (manufactured in Swierk). Serum T4 levels were significantly lower in children with mucous membrane atrophy in comparison with dystrophic children and normal gut mucous membrane. Both serum T3 and T4 were significantly lowered in the youngest children upto 12 months of life with mucous membranes atrophy. Serum T3 and T4 concentrations were below the normal values in 4 youngest children. Blood serum T3 and T4 levels did not depend on the morphology of the intestinal villi in children treated with gluten-free diet (some children did not observe the diet and had atrophic lesions to the mucous membrane of the small intestine). Blood serum T3 level was relatively increased in children of group II with mucous membrane regeneration; in comparison with the value determined in the period of active disease.     

Sociophysiology of well-being in nonhuman primates.

Knowledge of neuroendocrine responsiveness can provide insights into the social and physical conditions that promote well-being in captive primates. Activity and reactivity of stress response systems provide information regarding the degree to which animals are prepared for motoric expression, the kinds of situations that lead to mobilization of resources, and susceptibility to common clinical disorders. Social relationships can alter activity and reactivity of stress response systems. In some instances, social relationships can influence well-being by increasing or decreasing stress responsiveness. Other types of social relationships can influence well-being by altering homeostatic processes that regulate activity and reactivity of neuroendocrine systems. When the breadth of social and physiologic processes is considered, sociophysiologic contributions to well-being are more pervasive than has hitherto been considered.     

Impact of infections and normal flora in nonhuman primates on drug development

Preclinical safety studies that are required for the marketing approval of a pharmaceutical include single and repeat dose studies in rodent and nonrodent species. The use of nonhuman primates (NHPs), primarily macaques, as the nonrodent species has increased in recent years, in part due to the increase in development of biopharmaceuticals and immunomodulatory agents. Depending on the source of the macaques, they may vary in genetic background, normal flora, and/or the incidence of preexisting pathogens and inflammatory conditions. As the use of alternative sources of macaques rises to meet the increased demand for these animals in biomedical research, the toxicologic pathologist should be well versed in NHP pathology to adequately assess potential drug-related effects in the context of these variations. Such knowledge is particularly important in studies involving immunomodulatory drugs as the toxicologic pathologist should anticipate which type(s) of infections are most likely to arise depending on which arm of the immune system is modulated. The purpose of this review is to discuss the immunosuppressive (e.g., simian type D retrovirus, simian immunodeficiency virus) and opportunistic viruses (e.g., cytomegalovirus, adenovirus, simian virus 40, rhesus rhadinovirus, and lymphocryptovirus), primary and opportunistic bacteria (e.g., Campylobacter spp., Shigella flexneri, Yersinia enterocolitica, Moraxella catarrhalis, Mycobacterium avium complex, enteropathogenic Escherichia coli), and parasites (e.g., Plasmodium spp., Schistosoma spp., Strongyloides fulleborni) that have had the most profound impact on the interpretation of drug safety studies and/or that may reemerge as alternative sources of NHPs are used for drug safety studies.     

Presence of triiodothyronine, no detectable thyroxine and reverse triiodothyronine in human milk.

Thyroxine (T4), triiodothyronine (T3) and reverse triodothyronine (rT3) concentrations in human milk were measured by radioimmunoassay in 114 samples obtained from 1 week to 8 months postpartum. Several assay systems applied for the determination of serum thyroid hormone concentration were proved to be unsuitable for human milk, and the method of separating free and antibody-bound hormone by polyethylene glycol was also inappropriate for milk specimens, which tended to give a falsely high value. The binding of finity of T4 to milk was lower than that to serum protein, on which 8-anilino-1-naphthalene sulfonic acid showed no remarkable effect. In spite of the high sensitivity of 100 pg/tub in T4 assay system, no immunoassayable T4 was detected in all samples with or without ethanol extraction and trypsin hydrolysates of milk. In contrast, T3 was present in a measurable amount in most of the samples, the mean +/- SD value of which was 10 +/- 9 ng/100 ml, and those in colostrum were significantly higher than those in matured milk (P less than 0.01), whereas rT3 was not detectable in 76 samples tested. These results indicate that permeability of thyroid hormones through the mammary gland is different between T4 and T3 as well as in placental transport, and human milk can not be a source of thyroxine supply for the breast-fed infant.