Reference limit of thyrotropin (TSH) and free thyroxine (FT4) in thyroperoxidase positive and negative subjects: a population based study.

BACKGROUND: Current reference values for thyroid function tests are based on data from different ethnicities and geographical areas. The aim of the present study was to determine reference intervals for thyrotropin (TSH) and free T4 (FT4), based on the criteria of the National Academy of Clinical Biochemistry (NACB) in an Iranian population. MATERIAL AND METHODS: This study was conducted within the framework of Tehran Thyroid Study (TTS), an ongoing prospective cohort of 5704 randomly selected individuals, age ≥ 20 yr. A total of 2199 individuals (43.3% male, 56.7% female), based on NACB criteria were included in this study. Reference limit analysis was performed for the negative thyroid peroxidase antibody (TPOAb) group. RESULTS: After applying all exclusion criteria except TPOAb positivity (10.5%), data of 2459 participants remained for analysis. Of these, 953 (43.3%) were males and 1246 (56.7%) were females; the mean ± SD age was 43.53 ± 14.16 yr. The mean ± SD and median+IQR for TSH were 1.77 mU/l ± 1.24 and 1.46 (0.93-2.23) mU/l, respectively. The 2.5th and 97.5th percentiles TSH were 0.32 mU/l and 5.06 mU/l respectively. The mean ± SD and median (IQR) for FT4 for all negative TPOAb subjects were 1.19 ± 0.16 and 1.18 (1.08-1.31) ng/dl respectively. CONCLUSION: Reference ranges for thyroid function tests need to be derived from national databases. This study determined age and sex specific TSH and FT4 reference ranges in a Tehranian population, which could eventually enable clinicians to classify patients more appropriately.

Biological activity of activating thyrotrophin receptor mutants: modulation by iodide.

Epidemiological studies have revealed a significantly higher incidence of toxic adenoma (TA) and toxic multi-nodular goitre (TMNG) in regions of iodine deficiency. Fifty to eighty percent of TA and TMNG are caused by activation of the cAMP pathway, mostly by mutations in the thyrotrophin receptor (TSHR). We aimed to investigate whether iodide could modulate the biological effects of activating TSHR mutations. We have applied an in vitro model of TA comprising FRTL-5 cells stably expressing activating TSHR. We have mimicked the in vivo situation by examining the effects of prolonged exposure to iodide on the proliferation and signal transduction etc. of these cells. We observed an iodide-induced 'inhibition of proliferation' which was significant from 10 mM in the presence of serum but from 1 mM in its absence. The inhibition of proliferation was significantly higher in the activating mutant expressing FRTL-5 compared with control Neo or wild-type TSHR, indicating that the effect was mediated via the cAMP cascade. The effect was neither due to hyper-tonicity nor was it the result of an increase in cell death either by apoptosis or necrosis. Prolonged exposure to iodide produces an increase in cells in the G2 and post-G2 phases, indicating that G2/M blockade contributes to the mechanism of inhibition. The mutant expressing FRTL-5 cells have increased proliferation when chronically exposed to TSH, and this is associated with a reduction in phosphorylated (p) CREB levels. This contrasts with the effect of iodide in which inhibition of proliferation is accompanied by an increase in pCREB. In conclusion, our studies indicate that the biological effects of activating TSHR mutations vary with the ambient iodide supply and could be masked in regions of high iodine intake.

The permeability of the capsule of autonomic ganglia to horseradish peroxidase.

Horseradish peroxidase (HRP) was applied to the capsules of various autonomic ganglia in vivo. The capsules of the inferior mesenteric ganglion and superior cervical ganglion of guinea-pigs and the inferior mesenteric ganglion of mice were readily penetrated by the enzyme. The capsule of the mouse superior cervical ganglion was apparently impermeable to HRP, while that of the guinea-pig lumbar sympathetic trunk was intermediate in permeability, being most readily penetrated by HRP around the blood vessels entering or leaving the ganglia. The results of retrograde transport experiments from the guinea-pig inferior mesenteric ganglion to spinal ganglia are considered in the light of the ready permeability of its capsule.

A morphological study of the uptake and orthograde axoplasmic transport of horseradish peroxidase by damaged autonomic neurons in vitro.

A preparation comprising the guinea-pig inferior mesenteric ganglion (IMG) and ligated hypogastric nerves was maintained in vitro in a twin-chamber apparatus. Horseradish peroxidase (HRP), added to the ganglion compartment, was taken up via coated pinocytotic vesicles into the neuronal perikarya, and subsequently accumulated in many polymorphic cytoplasmic organelles, but it did not enter the Golgi complex. After 24 h incubation, HRP was also localized in membrane-bounded organelles in the nonmyelinated axons of the hypogastric nerves in the ligated nerve compartment. HRP-labelled organelles accumulated in swollen nonmyelinated axons immediately proximal to the ligation along with other organelles known to undergo fast axoplasmic transport. It is suggested that HRP taken up by the neuronal perikarya subsequently underwent fast axoplasmic transport without passing through the Golgi complex. The organelles in which HRP was transported in an orthograde direction were very similar to those in which the enzyme is known to be transported retrogradely in the same neuronal system. The advantages of this in vitro system for studying the orthograde transport of exogenous protein are discussed.

The uptake of intravenous horseradish peroxidase by the guinea-pig inferior mesenteric ganglion.

The uptake of intravenously injected horseradish peroxidase (HRP) by the neuronal perikarya and SIF cells has been studied in the guinea-pig inferior mesenteric ganglion (IMG). The HRP rapidly penetrated the walls of the blood vessels within the ganglion and was taken up by neurons and SIF cells by means of coated pinocytotic vesicles. HRP reaction product was subsequently found within larger vesicles which were most prominent 6--9 hours after injection. Thirty hours after injection all the neurons and SIF cells within the IMG were free of peroxidase reaction product. The implications of these findings were considered in relation to retrograde axonal transport studies in autonomic neurons.