PubMed Health⌕ Search

Biomedical subjects

H J Peter

Publications and source records attributed to H J Peter.

At least 19 recordsLinked to original sources
PubMed1992

Effect of human thyroid stimulating autoantibodies on the radioiodine uptake of the mouse thyroid gland.

Administration of sera from patients with active Graves' disease to nude mice bearing human thyroid xenografts provides the opportunity to compare directly the effects of TSAb on thyroid tissue of different species. The results presented in this paper, namely the fact that only one of 8 Graves' sera increased the RAIU of the nu/nu mouse thyroids modestly while all sera increased the RAIU in the transplanted human tissue considerable, clearly show a species specific effect of TSAb.

Animals↗
PubMed1992

Clonal analysis of human tumors with M27 beta, a highly informative polymorphic X chromosomal probe.

The clonality of human tumors can be studied by X inactivation/methylation analysis in female patients heterozygous for X-linked DNA polymorphisms. We present a detailed study on clonal tumor analysis with M27 beta, a highly informative probe detecting a polymorphic X chromosomal locus, DXS255. The polymorphism detected at this locus is due to variable numbers of tandem repeats. The rate of constitutional heterozygosity detected by M27 beta was 88%. Normal tissue from gastrointestinal mucosa and thyroid showed random, hence polyclonal, patterns. Nonrandom clonal X inactivation was detected in all 22 malignant neoplasms that had been shown to be clonal by other DNA markers, such as antigen receptor gene rearrangements or clonal loss of heterozygosity at 17p and other loci. 16/48 normal blood leukocyte samples (33%) showed considerably skewed X inactivation patterns. Comparison of blood leukocytes and normal tissue indicated that in a given individual, X inactivation patterns may be tissue specific. M27 beta was used to study the clonal composition of 13 benign thyroid nodules from 12 multinodular goiters with rapid recent growth, traditionally termed "adenomas." Nine of them were clonal, whereas four nodules and tissue from a case of Graves' goiter were not, indicating that some, but not all, such thyroid nodules may represent true clonal neoplasms. The M27 beta probe permits one to study the clonal composition by the X inactivation approach of a wide variety of solid tumors from most female patients. As a control, normal tissue homologous to the tumor type of interest is preferable to DNA from blood leukocytes, since the latter may show nonrandom X inactivation patterns in a fairly high proportion of cases. M27 beta may, therefore, be of limited use for the clonal analysis of neoplasms derived from hematopoietic cells.

Clone Cells↗
PubMed1992

Histomorphological and immunohistochemical evidence that human nodular goiters grow by episodic replication of multiple clusters of thyroid follicular cells.

This study was aimed at dissecting the cellular mechanisms that underly the growth of actively expanding human goiter nodules. Thirty-two nodules from different patients, all removed because of steady recent growth, were serially sectioned and screened for 1) histomorphological signs of cell proliferation and 2) in situ expression of the immunohistochemically stained p21ras protooncogene product. Bovine, porcine, and rat thyroid glands (the latter from both T4- and perchlorate-treated animals) were used as controls. In normal glands, only a few follicular cells contain substantial amounts of stainable p21ras. Some of these cells are unusually large, but do not proliferate. In contrast, all goiter nodules contain areas where the epithelial cells are morphologically grossly altered and heavily loaded with p21ras. Cells of this type are mostly clustered in large cohorts coating whole follicles or entire groups of follicles. Only a small fraction of these activated cells actually proliferates at any one point in time. Actively replicating cells are scattered in tiny foci all over the nodules. The earliest proliferating buds are solid, but soon begin to generate microfollicles that enlarge by adding new cells to the follicular epithelium. Regionally heterogeneous p21ras content in morphologically identical cells suggests that growth occurs in bursts and waves. We conclude that goiter nodules grow by episodic proliferation of heterogeneous cohorts of epithelial cells from which new follicles are generated. Only a tiny fraction of all goiter cells proliferate at any one point in time. The molecular mechanisms governing these growth processes are unknown.

Adolescent↗
PubMed1991

Autonomous growth and function of cultured thyroid follicles from cats with spontaneous hyperthyroidism.

Spontaneous feline hyperthyroidism is a unique experimental model of toxic nodular goiter. To determine whether feline toxic goiter is caused by extrathyroidal stimulating factors or by the intrinsic autonomy of follicular cells, primary cultures of enzymatically dissociated follicles from 15 hyperthyroid cat goiters and from 3 normal cat thyroid glands were embedded in collagen gels. Growth and function in chemically defined media were assessed by autoradiography after double labeling with 3H-thymidine and 131I-Na. Iodine organification in follicles from normal glands was TSH dependent, but intense radioiodine organification occurred in follicles from hyperfunctioning goiters even in the absence of TSH. Similarly, twice as many follicular cells of hyperfunctioning thyroid tissue, maintained without TSH in the medium, were labeled after exposure to 3H-thymidine than in follicles from normal glands. The results strongly suggest that intrinsic alterations of cell function lead to autonomy of follicular growth and function and subsequently to the development of hyperplastic nodules, causing thyrotoxicosis. The reason for the focal nature of the disease remains an unresolved challenge. Further investigation using this model may further understanding of the growth of autonomous endocrine tumors.

Animals↗
PubMed1991

Comparison of FRTL-5 cell growth in vitro with that of xenotransplanted cells and the thyroid of the recipient mouse.

The present work was designed to compare in vitro cell growth kinetics with in vivo growth under conditions as similar as possible using labeling with [3H]thymidine. To this purpose, FRTL-5 cells were cultured as monolayers and as three-dimensional spheroids embedded in collagen gels and transplanted simultaneously into nude mice treated with perchlorate and a low iodine diet. The growth of the transplants was compared to that of the thyroids in host mice. In the intact thyroid, the fraction of [3H]thymidine-labeled follicular cells (FLC; 24-h labeling) increased sluggishly to a maximum of 10% after 3 weeks of goitrogen exposure, with a subsequent autoregulatory decrease to 3% at 7 weeks. A 4-fold higher FLC was found in six adenomas, indicating focal failure of growth-restraining mechanisms. In nonconfluent monolayer cultures the FLC was as high as 90%, even within large individual clusters where cells are in tight mutual contact. Solid, highly cellular grafts growing from transplanted monodispersed cells showed an average FLC of 20%, which is 5 times higher than the FLC in the identically stimulated mouse thyroid. In collagen-embedded cells, forming three-dimensional spheroids, the mean FLC decreased from 70% at 1 week in vitro (40% in vivo) to 20% at 3 weeks both in vitro and in vivo, suggesting effective auto-regulation of excessive growth in both conditions. However, these FLC were again much higher than the 3% FLC in simultaneously assessed host thyroids. The difference remained throughout the 45-day period studied. We conclude that FRTL-5 cells growing as monolayers and as three-dimensional spheroids in vitro or after xenotransplantation in vivo invariably show much higher proliferation rates under comparable environmental conditions than the normal follicular epithelium in the thyroids of host mice. The one exception is the confluent monolayer with near-zero growth, while densely packed three-dimensional transplants still grow intensively. Although growth-retarding cell to cell interactions are also clearly operative in growing FRTL-5 cells, they are less effective than those dampening the replication rate of the thyrocytes within the monolayer hull of normal follicles. A local failure of these mechanisms, allowing growth rates comparable to those of grafted FRTL-5 cells results in adenoma formation in normal thyroids. These observations call for caution in the transfer of in vitro growth studies with FRTL-5 cells to in vivo conditions prevailing in the normal thyroid.

Adenoma↗
PubMed1991

Thyroid cell lines in research on goitrogenesis.

Thyroid cell lines have contributed a lot to the understanding of goitrogenesis. The cell lines mostly used in thyroid research are briefly discussed, namely the rat thyroid cell lines FRTL and FRTL-5, the porcine thyroid cell lines PORTHOS and ARTHOS, The sheep thyroid cell lines OVNIS 5H and 6H, the cat thyroid cell lines PETCAT 1 to 4 and ROMCAT, and the human thyroid cell lines FTC-133 and HTh 74. Chinese hamster ovary (CHO) cells and COS-7 cells, stably transfected with TSH receptor cDNA and expressing a functional TSH receptor, are discussed as examples for non-thyroidal cells, transfected with thyroid genes.

Animals↗
PubMed1990

Generation of intercellular heterogeneity of growth and function in cloned rat thyroid cells (FRTL-5).

The most characteristic hallmarks of human nodular goiters are nodular growth and heterogeneity of structure and function between different areas of the same goiter. In search of the earliest detectable stage of thyroid heterogeneity we have observed doubling times, TSH dependency, and thyroglobulin production in colonies formed from individual FRTL-5 cells growing as monolayers in slide flasks. Single cells and the colonies derived thereof were followed on photographs taken daily until confluence. We observed that each cell had its individual stable multiplication rate throughout the observation period. This was true for all TSH doses tested (0.625-10 mU/ml). A wide range of doubling times (20 h to almost infinite) in the individual cells was observed. The mean growth velocity of subcloned cell lines was highly reproducible in consecutive passages, although a minority of cells escaped this rule. Cells with either high or low thyroglobulin content occurred in clusters, indicating again that specific traits tend to remain stable in the offspring. We conclude that a highly individual growth program, unrelated to mutation, appears to be switched on at the very moment a cell is generated and that this program is passed on to the majority of the offspring, with a minority of cells acquiring qualities differing from those of their sister cell. Therefore, goiter heterogeneity may be the in vivo amplification of a natural phenomenon occurring in all growing cells. Monoclonal adenomas in vivo and nontransformed immortal cell lines in vitro may represent the far end of the large spectrum of individual growth potency among normal thyrocytes.

Animals↗
PubMed1990

Intercellular propagation of individually programmed growth bursts in FRTL-5 cells. Implications for interpreting growth factor actions.

Five methods are commonly used to quantify FRTL-5 cells' and other thyrocytes' growth in vitro and the impact of growth inhibiting or stimulating maneuvers: Total cell count, mitotic index, DNA measurement, total [3H]thymidine incorporation, and the fraction of [3H]thymidine labeled cells. All of them assess cell growth as though all cells were homogeneous with an identical response to growth factors. We demonstrate here that this assumption is not valid. Rather, some intrinsically growth-prone cells appear to pass a growth signal to neighboring cells so that variably sized colonies of synchronized cells within each cluster growing from monodispersed cells are formed. This is true for FRTL-5 cells growing in vitro in monolayers and in three-dimensional, collagen embedded spheroids. The pattern is the same when cell suspensions or collagen-embedded spheroids are implanted onto nude mice. Patches with alternating high and low growth become particularly prominent in the large tumor-like organoids grown from monodispersed cells in nude mice. The pattern much reminds of similar observations in growing intact thyroids. Since there is no significant correlation between the fraction of [3H]thymidine labeled cells and the size of two- or three-dimensional clusters in any experiment, growth of signal-spreading cells is assumed to occur in leaps and bounds. Growth velocity in each subclone of a cell population depends on the mean interval between bursts of replications and on the number of cells synchronized by cell-to-cell diffusion of the growth signal emanating from one dividing cell. Thus, growth-promoting and growth-inhibiting factors may not only act on the mean interval between successive growth bursts, but they may also change cell-to-cell spreading of growth signals.

Animals↗
PubMed1990

Cold follicles in a multinodular human goiter arise partly from a failing iodide pump and partly from deficient iodine organification.

To investigate whether the common cold follicles in human multinodular goiters are the consequence of a functional defect of the apical membrane peroxidase, a failure of the iodide transport system, or both deficiencies, we studied iodide accumulation and iodine organification in 30 fragments of a large multinodular goiter transplanted to nude mice and labeled with 125I. Transplants were frozen to -80 C immediately after removal to avoid diffusion of inorganic iodide. Autoradiographic assessment of over 1000 cryosections (exposed either at -20 C or after thawing and washing out unbound iodide) showed two types of cold follicles, namely those that failed to accumulate iodide and, therefore, did not organify iodine, and those that readily accumulated iodide but failed to bind it, suggesting a failure of apical membrane peroxidase. The two types of pathogenetically different cold follicles coexisted in an apparently randomly intermingled fashion throughout the whole goiter.

Aged↗
PubMed1988

Autonomous growth, but not autonomous function, in embryonic human thyroids: a clue to understanding autonomous goiter growth?

Thyroid glands from six 8- to 10-week-old fetuses obtained at the time of legal abortion were cryopreserved in liquid nitrogen and transplanted into nude nu/nu mice. Histological and autoradiographic studies of the grafts labeled with [3H]thymidine and [125I]iodine showed proliferation and functional differentiation of the fetal thyroid tissue. Despite T4-mediated suppression of host TSH secretion, up to 36% of the follicular cell nuclei incorporated the thymidine label, reflecting autonomous proliferation, while iodine organification was almost entirely obliterated. Methimazole-induced TSH hypersecretion readily stimulated both growth and function of the transplanted tissue. Thus, during early development, the human thyroid largely depends on TSH for function, but not for growth. Similar findings were obtained in newborn mice, in whom 58% of the thyroid follicular cells proliferated autonomously, i.e. in the absence of TSH. The number of autonomously proliferating cells gradually declined with increasing age to about 1% in 60-day-old animals and, as reported previously, in xenotransplanted normal human thyroid tissue, whereas the number of autonomously proliferating cells was previously found to be several times higher in xenotransplanted human multinodular goiters. We, therefore, hypothesize that the rapidly and autonomously replicating cells that initiate nodule formation in human multinodular goiters reflect the persistence in the adult gland of cells with fetal growth potential.

Age Factors↗
PubMed1988

[Histopathogenesis of goiters].

The basic mechanisms acting in the transformation of a normal thyroid gland into a toxic or nontoxic goiter are summarized: 1) Any goiter arises from multiplication of follicular epithelial cells forming new follicles. 2) In the follicular epithelium there are cell families with much higher than average growth potential. 3) Cells of an individual follicle are not identical but heterogeneous. 4) Each follicular cell has a certain level of autonomy of growth and of function.

Cell Division↗
PubMed1988

Pathogenesis of nodular goiter and its implications for surgical management.

Despite sufficient iodine supply, goiter continues to be of considerable surgical significance in formerly endemic countries. It now appears that iodine deficiency and increased thyrotropin stimulation are not the only causes of goiter. Xenotransplantation of human thyroid tissue onto nude mice allowed study of the regulation of growth and function in human goiter tissue. Grafts of human thyroid tissue growing in nude mice could be shown to react to endogenous mouse thyrotropic stimulation and suppression. 131I autoradiographs of xenotransplanted goiter tissue showed as marked a heterogeneity as did the original goitrous tissue prior to transplantation. There was no firm correlation between the morphologic appearance of a follicle and its iodine metabolism. Scintigraphically "cold" and "hot" goiter tissue differed from each other quantitatively but not qualitatively; i.e., both "hot" and "cold" tissue were composed of metabolically active and nonactive follicles. Iodine organification was not completely suppressible by thyroxine treatment; this indicates autonomous functional activity. The distribution of proliferating tissue labeled by 3-H-thymidine did not parallel the distribution of functionally active tissue labelled by 131I. Thyroxine treatment did not completely inhibit 3-H-thymidine incorporation, indicating autonomous growth. Thus, our pathogenetic concept of goiter formation is based on three mainstays: (1) goiter heterogeneity, (2) autonomy of growth and function, and (3) dissociation of growth and function in human goiter tissue. Thus, the surgeon dealing with goiter ought to remove all pathologically altered tissue, i.e., nodular tissue, irrespective of its appearance on scintiscans.

Animals↗
PubMed1987

[Current TSH-sensitive assays simplify thyroid diagnosis].

The methodology and clinical application of sensitive TSH assays are discussed. The new immunometric assays not only distinguish between normal and elevated, but also between normal and suppressed TSH values. Therefore, after clinical examination of the patient, serum TSH measurement by a sensitive assay may be used as a first line test whenever hypo- or hyperthyroidism is suspected. Normal TSH indicates euthyroidism and obviates the need for further thyroid function testing. In patients with elevated or suppressed TSH values, free T4 and (if TSH is suppressed and free T4 normal) free T3 are measured to discriminate between overt and subclinical hypo- or hyperthyroidism. Testing with TRH continues to be useful in some more complex cases, when the above-mentioned tests are not conclusive.

Diagnosis, Differential↗
PubMed1987

Naturally occurring clones of cells with high intrinsic proliferation potential within the follicular epithelium of mouse thyroids.

The proliferation pattern of some scattered clones of naturally occurring follicular cells with an exceedingly high intrinsic growth potential was investigated in the mouse thyroid gland. In particular, evidence was sought to demonstrate that the high propensity to replicate is a stable trait transmitted from the progenitor cells to their offspring. We hypothesize that these cell clones are at the origin of the multiple adenomas that invariably arise in chronically stimulated thyroid. Growth stimulation was induced either by hemithyroidectomy or by methimazole feeding. In a first series of experiments, involving hemithyroidectomized animals, [3H]thymidine was administered continuously for 3 weeks by means of osmotic minipumps, so that all cells entering the mitotic cycle during that time were labeled. Hemithyroidectomy led to a 3-fold increase of the fraction of labeled cells in the remaining lobe. The increase was prevented by thyroxine treatment in thyroid-stimulating hormone-suppressing doses. Autoradiographs of contiguous serial sections across whole follicles showed that roughly 75% of the labeled cells were clustered in groups of 3 or more, rather than being randomly distributed. In a second set of experiments, glands stimulated by methimazole-induced thyroid-stimulating hormone hypersecretion were pulse-labeled by a single i.p. injection of [3H]thymidine. Animals were sacrificed either 2 h or 3 weeks after the administration of the label. The thyroids were excised and the fate of labeled thyroid cells was analyzed autoradiographically. In the 2-h exposure, about 95% of all labeled follicular cells were single and the remaining 5% were in pairs. In contrast, about 50% of all labeled cells were clustered in groups of 3 to 12 cells 3 weeks after the pulse labeling. The number of silver grains per nucleus was compared to that of the identically exposed controls. The intensity of label per cell appeared to be decreased in proportion to the size of the labeled clusters, indicating that clusters had generated several subsequent generations of cells. The results support previously produced evidence that highly growth-prone cells naturally occur within the normal thyroid and demonstrate, in addition, that their high intrinsic growth rate is a stable, inheritable trait. Cells which replicate at a rate faster than that of the average epithelial cell have a tendency to overgrow during goitrogenesis. They may be at the very origin of the nodules and adenomas commonly found in experimentally produced and naturally occurring goiters.

Animals↗
PubMed1987

Autonomy of growth and of iodine metabolism in hyperthyroid feline goiters transplanted onto nude mice.

Hyperthyroidism caused by nodular goiters is a common disease of aging cats. Growth and iodine metabolism were studied by autoradiography in normal and hyperfunctioning thyroid tissue obtained from cats injected with 125I before surgery, and in xenografts, grown in nude mice, after double-labeling with 131I and [3H]thymidine. Hyperthyroid cat goiters contain single or multiple hyperplastic nodules, consisting of highly cellular tissue with an iodine metabolism exceeding that of the surrounding normal tissue. Xenografts of hyperplastic hot tissue in thyroxine-treated nude mice retain their original histologic pattern and continue to accumulate radioiodine intensely. Autoradiographs assessed for [3H]thymidine incorporation reveal autonomously proliferating follicular cells within the hyperplastic foci but not within the normal tissue. Administration of sera from donor cats into host mice fails to stimulate the xenografts. Neither hyperfunction nor growth of toxic cat goiters depends on extrathyroidal stimulators. The basic lesion appears to be an excessive intrinsic growth capacity of some thyroid cells.

Animals↗