• Total body irradiation causes long-term bone marrow suppression by selectively inducing HSC senescence.• The induction of HSC senescence is independent of telomere shortening and p16 Ink4a and Arf.Exposure to total body irradiation (TBI) induces not only acute hematopoietic radiation syndrome but also long-term or residual bone marrow (BM) injury. This residual BM injury is mainly attributed to permanent damage to hematopoietic stem cells (HSCs), including impaired self-renewal, decreased long-term repopulating capacity, and myeloid skewing. These HSC defects were associated with significant increases in production of reactive oxygen species (ROS), expression of p16 Ink4a (p16) and Arf mRNA, and senescenceassociated b-galacotosidase (SA-b-gal) activity, but not with telomere shortening or increased apoptosis, suggesting that TBI induces residual BM injury via induction of HSC premature senescence. This suggestion is supported by the finding that SA-b-gal 1 HSCenriched LSK cells showed more pronounced defects in clonogenic activity in vitro and long-term engraftment after transplantation than SA-b-gal -LSK cells isolated from irradiated mice. However, genetic deletion of p16 and/or Arf had no effect on TBI-induced residual BM suppression and HSC senescence, because HSCs from irradiated p16 and/or Arf knockout (KO) mice exhibited changes similar to those seen in HSCs from wild-type mice after exposure to TBI. These findings provide important new insights into the mechanism by which TBI causes long-term BM suppression (eg, via induction of premature senescence of HSCs in a p16-Arf-independent manner). (Blood. 2014;123(20):3105-3115)

To determine the implication of decreased T3 production during fasting, seven normal men were fasted for 80 hours on two occasions; they received 5 microgram of T3 every three hours durnig the second fast. The mean serum T3 concentration declined during the control fast from 120 to 73 ng per deciliter (P less than 0.01), but remained slightly above base-line values during the T3 fast. Mean serum T4 concentrations did not change, and mean serum rT3 concentrations increased, during both fasts. The peak serum TSH increment after TRH was 11.1 micromicron per milliliter before fasting, 8.9 (not significant) after the control fast and 2.2 (P less than 0.01) after the T3 fast. Urea excretion was 9.1 per cent higher during the T3 fast; there were no differences in the changes in blood glucose, plasma fatty acids or other substrates during the two fasts. Pretreatment with potassium iodide lowered serum T4 concentrations and increased the serum TSH response to TRH after fasting. We conclude that the decrease in serum T3 concentrations during fasting spares muscle protein. Fasting is accompanied by a lower set point of TSH secretion, which remains sensitive to changes in serum thyroid hormone concentrations.

Previous studies have demonstrated that short-term oral iodide administration, in doses ranging from 1500 micrograms to 250 mg/day, has an inhibitory effect on thyroid hormone secretion in normal men. As iodide intake in the USA may be as high as 800 micrograms/d, we investigated the effects of very low dose iodide supplementation on thyroid function. Thirty normal men aged 22-40 years were randomly assigned to receive 500, 1500, and 4500 micrograms iodide/day for 2 weeks. Blood was obtained on days 1 and 15 for measurement of serum T4, T3, T3-charcoal uptake, TSH, protein-bound iodide (PBI) and total iodide, and 24 h urine samples were collected on these days for measurement of urinary iodide excretion. TRH tests were performed before and at the end of the period of iodide administration. Serum inorganic iodide was calculated by subtracting the PBI from the serum total iodide. We found significant dose-related increases in serum total and inorganic iodide concentrations, as well as urinary iodide excretion. The mean serum T4 concentration and free T4 index values decreased significantly at the 1500 micrograms/day and 4500 micrograms/day doses. No changes in T3-charcoal uptake or serum T3 concentration occurred at any dose. Administration of 500 micrograms iodide/day resulted in a significant increase (P less than 0.005) in the serum TSH response to TRH, and the two larger iodide doses resulted in increases in both basal and TRH-stimulated serum TSH concentrations.(ABSTRACT TRUNCATED AT 250 WORDS)

Previous studies have characterized the pharmacology of propylthiouracil (PTU) in normal and hyperthyroid subjects, but there is little information available regarding PTU pharmacokinetics in pregnant hyperthyroid women. We investigated the serum PTU response to an oral dose of PTU in six hyperthyroid pregnant women both ante- and postpartum. The serum PTU profile during the third trimester of pregnancy was qualitatively similar to that in nonpregnant subjects, but serum PTU concentrations were consistently lower in the late third trimester compared with postpartum values. Cord serum PTU concentrations were consistently higher than simultaneously obtained maternal serum PTU concentrations, suggesting slower PTU clearance in the fetus. There was a significant inverse correlation (r = -0.92; P = 0.026) between the maternal serum PTU area under the curve in the third trimester and the cord serum free T4 index.