Supraphysiological Levels (supraphysiological + level)

Distribution by Scientific Domains

Selected Abstracts

A novel therapeutic paradigm to treat congenital hypothyroidism

Sarah Mathai
Summary Objective, To determine the effectiveness of a novel therapeutic paradigm to treat congenital hypothyroidism (CH) incorporating variable initial doses of L-T4 based on the underlying aetiology and frequent monitoring, up to 2 years of age. Design, Retrospective cohort study. Patients, Infants with primary CH diagnosed by newborn screening. Measurements, Treatment with L-T4 suspension initiated at 10, 12 and 15 g/kg/day for dyshormonogenesis, ectopia and athyreosis, respectively. Serum TSH and free T4 (FT4) levels monitored weekly during the first 4 weeks, at 6 weeks, thereafter monthly during the first 2 years. Dose changes were made to keep FT4 level in upper half of the normal range. Results, Sixty-nine infants; 17 had dyshormonogenesis, 35 ectopia and 17 athyreosis. Seventy-eight percent of subjects normalized FT4 levels within 7 days of treatment and 100% within 14 days. TSH levels normalized in 26% of infants within 7 days and in 92% by 21 days. Supraphysiological levels of FT4 were noted in 28% of infants, for a maximum of 2 weeks. 48% infants needed one dose adjustment and 30% needed at least two in the first month. In 52 infants over the first 2 years, mean FT4 levels were consistently in the upper half of the normal range. Two or more dose adjustments every 3 months were made 57 times in the first year as compared to 19 times in the second year. Conclusions, A variable initial dose paradigm based on aetiology with frequent testing and using T4 suspension rapidly normalizes FT4 levels without producing persistent hyperthyroxinaemia. [source]

T lymphocyte rolling and recruitment into peripheral lymph nodes is regulated by a saturable density of L-selectin (CD62L)

Elena Galkina Dr.
Abstract L-selectin mediates tethering and rolling of lymphocytes in high endothelial venules (HEV) of lymph nodes (LN) and of leukocytes at inflammatory sites. We used transgenic mice expressing varying levels of wild-type or a non-cleavable mutant form of L-selectin on T cells to determine the relationship between L-selectin density, tethering and rolling, and migration into LN. T cells expressing supraphysiological levels of either wild-type or non-cleavable L-selectin showed rolling parameters similar to C57BL/6 T cells in hydrodynamic flow assays and during rolling in Peyer's patch HEV. In contrast, PMA- or antigen-activated T cells and L-selectin+/, T cells expressing subphysiological levels of L-selectin showed reduced numbers of rolling cells with increased rolling velocity. Short-term homing studies showed that elevated expression of L-selectin above physiological levels had no effect on T cell migration to LN; however, low L-selectin expression resulted in reduced T cell homing to LN. Thus, T lymphocyte migration into LN is regulated by the density of cell surface L-selectin. In addition, there is a saturable density of L-selectin required for optimal homing to PLN in C57BL/6 mice, the L-selectin level on circulating naive T cells promotes optimal homing, and increased expression above saturating levels promotes no further increase in T cell recruitment. [source]

Estrogen Receptor-, Inhibits Skeletal Growth and Has the Capacity to Mediate Growth Plate Fusion in Female Mice,

AS Chagin
Abstract To determine the long-term role of ER, in the regulation of longitudinal bone growth, appendicular and axial skeletal growth was followed and compared in female ER,,/,, ER,,/,, and ER,,/,,,/, mice. Our results show that ER, inhibits appendicular and axial skeletal growth and has the capacity to induce fusion of the growth plates. Introduction: Estrogen affects skeletal growth and promotes growth plate fusion in humans. In rodents, the growth plates do not fuse after sexual maturation, but prolonged treatment with supraphysiological levels of estradiol has the capacity to fuse the growth plates. It should be emphasized that the estrogen receptor (ER),,/, and the ER,,/,,,/,, but not the ER,,/,, mouse models have clearly increased serum levels of estradiol. Materials and Methods: The skeletal growth was monitored by X-ray and dynamic histomorphometry, and the growth plates were analyzed by quantitative histology, calcein double labeling, bromodeoxyuridine (BrdU) incorporation, and TUNEL assay in 4- and 18-month-old female ER,,/,, ER,,/,, and ER,,/,,,/, mice. Results: Young adult (4-month-old) ER,,/, mice demonstrated an increased axial- and appendicular-skeletal growth, supporting the notion that ER, inhibits skeletal growth in young adult female mice. Interestingly, the growth plates were consistently fused in the appendicular skeleton of 18-month-old female ER,,/, mice. This fusion of growth plates, caused by a prolonged exposure to supraphysiological levels of estradiol in female ER,,/, mice, must be mediated through ER, because old ER,,/,,,/, mice displayed unchanged, unfused growth plates. Conclusions: Our results confirm that ER, is a physiological inhibitor of appendicular- and axial-skeletal growth in young adult female mice. Furthermore, we made the novel observation that ER,, after prolonged supraphysiological estradiol exposure, has the capacity to mediate growth plate fusion in old female mice. [source]

Effects of oestradiol on gonadotrophin levels in normal and castrated men

Willem De Ronde
Summary Context, Testosterone inhibits gonadotrophin release in men either directly or after aromatization to oestradiol. We hypothesized that in males the androgen receptor-mediated effect of testosterone on LH release is negligible relative to that of oestradiol. Objective, To compare the effect of experimentally induced variations of plasma oestradiol levels on LH levels in normal (physiological testosterone levels) and castrated men (very low testosterone levels). Design, Prospective, open label, intervention. Subjects and interventions, We suppressed endogenous oestradiol in 10 young men with letrozole 25 mg once daily. In these men and in 10 young healthy castrated men, we restored plasma oestradiol levels with oestradiol patches (first week 100 ,g/day, second week 50 ,g/day, third week 25 ,g/day and fourth week no oestradiol patch). Measurements, The effect of the intervention on plasma levels of LH were monitored and compared between the groups. Results, With the intervention, the mean plasma oestradiol level in the two groups varied from supraphysiological to below the lower reference range. Levels of LH mirrored plasma oestradiol levels in both the groups, as did testosterone in the intact group. Despite similar oestradiol levels, mean levels of LH were significantly higher in the castrated group compared to the intact group for all doses of oestradiol, and supraphysiological levels of oestradiol were unable to suppress LH into the physiological range in the castrated group. Conclusions, Physiological plasma oestradiol levels have a substantial suppressive effect on LH in men. However, low-normal testosterone levels are a prerequisite for suppression of LH into the normal range. [source]