Combination Of Triiodothyronine Research Articles

Abstract 354: Combination of Triiodothyronine and Dexamethasone with Flexible Matrigel Substrate Improves Structural and Electrophysiological Maturation of Human iPSC-derived Cardiomyocytes

Human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) have promise for disease modeling and cell therapy, but electrophysiological immaturity (ie. large pacemaker currents, small I K1 ) and structural immaturity (ie. lack of t-tubules) remain major limitations. Here, we test whether the combination of triiodothyronine (T 3 ) and dexamethasone (Dex) with a soft Matrigel substrate improves hiPSC-CMs maturity. T 3 & Dex or vehicle were added to cardiac induction media for 14 days. Day 30 hiPSC-CMs were plated either on hard or soft Matrigel-coated substrate for 5 days and studied using confocal imaging and voltage clamp. T 3 & Dex treatment significantly increased the width and volume of hiPSC-CMs cultured on soft but not on hard substrate ( Fig.1 ). T 3 & Dex treated hiPSC-CMs exhibited organized subcellular Ca release ( Fig.2 ) and evidence of t-tubule development, possibly as a result of increased Bin-1 and Caveolin-3 membrane trafficking. The combination of T 3 & Dex and soft substrate increased Ca spark frequency and the amount of Ca released per spark ( Fig.3 ). T 3 & Dex treatment significantly accelerated Ca transient decay under field stimulation and increased sarcoplasmic reticulum Ca-ATPase activity. Compared to vehicle, T 3 & Dex treatment significantly improved electrophysiological maturity: Pacemaker current (I f ) density was 3-fold reduced (-2.7±0.35 vs. -6.2±1.3 pA/pF) and inward rectifier current (I K1 ) density was 4-fold increased (-19.3±2.2 vs. -4.4±0.5 pA/pF). Combining T 3 & Dex and soft Matrigel substrate enhances structural and functional maturation of hiPSC-CMs, which will increase the utility of hiPSC-CM for disease modeling and cell therapy.

Triiodothyronine accelerates and enhances the antipsychotic effect of risperidone in acute schizophrenia

In acute psychotic schizophrenia patients we investigated if the combination of triiodothyronine (T3) plus risperidone was more effective when compared to risperidone monotherapy. Thirty-two in-patients meeting the DSM-IV-TR diagnostic criteria for schizophrenia and without thyroid disease received risperidone (flexibly adjusted dose for tolerability) and were randomized to additionally receive either T3 (25 μg daily; risperidone plus T3 group) or placebo (risperidone plus placebo group). Treatment lasted until meeting the response to treatment criteria defined as score of ≤3 on the Clinical Global Impression Severity and Improvement scales. Acute psychotic episode symptom severity was evaluated using the Brief Psychiatric Rating Scale (BPRS) at treatment initiation and at the final study assessment. Fourteen patients were randomized to receive risperidone plus T3 and eighteen to receive risperidone plus placebo. The time until treatment response was shorter in the risperidone plus T3 group relative to the risperidone plus placebo group (25.5 ± 4.4 days vs 32.2 ± 8.2 days, respectively; p = 0.001). Moreover, there was a greater reduction of BPRS-total score (p = 0.01) in the risperidone plus T3 group relative to the risperidone plus placebo group. Treatment with T3 was associated with shorter time to treatment response (β = −0.440, p = 0.022) and with greater improvement in BPRS score (β = 0.240, p = 0.053), independent of patients' gender, age, baseline BPRS score and mean risperidone dose. The study confirms that addition of T3 to risperidone was associated with accelerated and enhanced treatment response in acutely psychotic schizophrenic patients.

The combination of triiodothyronine (T3) and sertraline is not superior to sertraline monotherapy in the treatment of major depressive disorder

ObjectiveTo determine whether the combination of triiodothyronine (T3) plus sertraline at treatment initiation confers greater antidepressant efficacy than sertraline plus placebo in patients with major depressive disorder. MethodEight-week, double blind, randomized placebo controlled clinical trial of 153 adult outpatients between 18 and 60 years of age, with DSM-IV defined major depressive disorder. Patients were treated with sertraline flexibly adjusted for tolerability and in a double blind fashion with placebo or T3 (25 μg/day in week 1 and increasing to 50 μg/day in week 2). Response was defined categorically as 50% reduction and total score less than 15 in 21-item Hamilton Rating Scale for Depression (HRSD-21) at week 8 and remission as HRSD-21 less than 8. ResultsThere was no difference between treatment groups at final assessment; 65% of placebo and 61.8% of T3 treated subjects achieved response and 50.6% of placebo and 40.8% of T3 treated patients achieved remission. The mean daily dose at final assessment of sertraline and T3, respectively was 144.7 mg (±48.7 mg) and 48.2 μg (±7 μg). Median time to response did not differ between treatment groups. Baseline thyroid function tests did not predict response to sertraline treatment or T3 augmentation. ConclusionsThese results do not support the routine use of T3 to enhance or accelerate onset of antidepressant response in patients with major depressive disorder (Clinical Trials.gov: NCT00208702).

Lung Fluid Balance During Development

After completing this article, readers should be able to: 1. Describe the major driving forces for liquid formation in and liquid removal from the lumen of the fetal lung. 2. Delineate the role of a normal volume of liquid within the lumen of the fetal lung for normal lung growth during development. 3. Describe the effects of labor on Na,K-ATPase activity in lung epithelial cells and clearance of lung liquid after birth. 4. Explain the route by which most residual liquid drains from the lung. 5. List the conditions associated with preterm birth that may contribute to delayed removal of fetal lung liquid. Curious students of mammalian development recognized more than a century ago that the lungs are filled with liquid during fetal life, (1) but the origin of that liquid remained obscure until 1948, when an unexpected discovery by two French scientists dispelled the prevailing view that fetal lung liquid derived from intrauterine inhalation of amniotic fluid. In studies designed to explore the ontogeny of the pituitary-adrenal axis, tracheal ligation of fetal rabbits for 9 days resulted in fluid distention of the lungs. (2) This serendipitous finding, subsequently confirmed and embellished by others, (3)(4)(5) established that the fetal lung itself, rather than the amniotic sac, is the source of the liquid that fills the lung during development. This liquid forms a slowly expanding structural template that prevents collapse and promotes growth of the fetal lung. Subsequent studies, conducted mostly with sheep, showed that liquid in the lumen of the fetal lung forms as a result of chloride secretion in the respiratory epithelium, (6)(7) a process that can be inhibited by diuretics that block Na,K-2Cl cotransport. (8)(9) In vitro experiments using cultured explants of lung tissue and monolayers of epithelial cells harvested from human fetal lung have …

Triiodothyronine supplementation improves lipid parameters in central hypothyroidism: a randomized controlled trial ('4 T study')

A normal thyroid function is critical for regular metabolism, wellbeing and cognitive function. Hypercholesterolaemia and increased creatine kinase levels are typical findings in hypothyroidism. In central hypothyroidism replacement therapy is mainly depending on clinical information which hampers optimal dosing of thyroxin (T4). In a placebo controlled, randomized trial 36 patients with central hypothyroidism including TSH deficiency were studied following a double blind cross-over design. 29 patients (age: 52±2; f/m: 7/22; deficient pituitary axes: 3.6±0.1; mean±SEM) completed the study after treatment for three five-week periods: 'P', usual doses of T4 (1±0.05µg/kg bw); 'T', optimized T4 treatment (1.6µg/kg bw T4); 'C', combination of triiodothyronine (T3; 10% of 1.6µg/kg bw) and T4. Biochemical parameters and Achilles tendon reflex time (ART) were assessed at the end of each treatment period. Heart rate (65±2/min) and blood pressure (125/80mmHg) did not change significantly. However, after period P, patients had a higher BMI than during T and C (29.5±0.7 vs. 29.0±0.7 vs. 28.9±0.7kg/m2; p<0.03). Unfavourable lipid parameters were higher during P, but improved during T and more pronounced after C. Cholesterol: 226±7 vs. 198±9 vs. 194±7, p<0.001; triglycerides: 184±23 vs. 191±24 vs. 168±22, p<0.05; VLDL: 39±4 vs. 42±5 vs. 35±4, p<0.03; LDL: 135±7 vs. 116±5 vs. 114±6, p<0.001; HDL 52±2 vs. 47±3 vs. 45±3mg/dl, p<0.001. Creatine kinase was higher during P and than in T and C: 159±16 vs. 127±13 vs. 106±10 U/l; p<0.001. Prolonged ART in phase P (389±0.08) and T (380±0.9) normalized during C treatment (364±0.08 ms; p<0.01; normal range: 360±3 ms). In conclusion, thyroxin treatment with a dose of 1.6µg/kg bw and additional supplementation of T3 improves unfavourable lipid parameters in patients with central hypothyroidism. Additional, Achilles tendon reflex time and creatine kinase are reduced during combination treatment indicating deficiency of biological active thyroid hormone during 'usual dose' T4 treatment.

Hormonal modulation of Na(+) transport in rat fetal distal lung epithelial cells.

Isolated rat fetal distal lung epithelial (FDLE) cells were cultured (approximately 48 h) on permeable supports in medium devoid of hormones and growth factors whilst P(O2) was maintained at the level found in either the fetal (23 mmHg) or the postnatal (100 mmHg) alveolar regions. The cells became incorporated into epithelial layers that generated a basal short-circuit current (I(SC)) attributable to spontaneous Na(+) absorption. Cells at neonatal P(O2) generated larger currents than did cells at fetal P(O2), indicating that this Na(+) transport process is oxygen sensitive. Irrespective of P(O2), isoprenaline failed to elicit a discernible change in I(SC), demonstrating that beta-adrenoceptor agonists do not stimulate Na(+) transport under these conditions. However, isoprenaline did elicit cAMP accumulation in these cells, indicating that functionally coupled beta-adrenoceptors are present. Further experiments showed that isoprenaline did increase I(SC) in cells treated (24 h) with a combination of tri-iodothyronine (T(3), 10 nM) and dexamethasone (200 nM). Studies of basolaterally permeabilised cells showed that these hormones are essential for the isoprenaline-evoked increase in the apical membrane's Na(+) conductance (G(Na)), whereas isoprenaline-evoked changes in apical Cl(-) conductance (G(Cl)) can occur in both control and hormone-treated cells. Irrespective of their hormonal status, FDLE cells thus express beta-adrenoceptors that are functionally coupled to adenylate cyclase, and allow beta-adrenoceptor agonists to modulate the apical membrane's anion conductance. However, T(3) and dexamethasone are needed if these receptors are to exert control over G(Na). These hormones may thus play an important role in the functional maturation of the lung by allowing beta-adrenoceptor-mediated control over epithelial Na(+) channels in the apical plasma membrane.

Hormonal modulation of Na+ transport in rat fetal distal lung epithelial cells

Isolated rat fetal distal lung epithelial (FDLE) cells were cultured (≈48 h) on permeable supports in medium devoid of hormones and growth factors whilst PO2 was maintained at the level found in either the fetal (23 mmHg) or the postnatal (100 mmHg) alveolar regions. The cells became incorporated into epithelial layers that generated a basal short-circuit current (ISC) attributable to spontaneous Na+ absorption. Cells at neonatal PO2 generated larger currents than did cells at fetal PO2, indicating that this Na+ transport process is oxygen sensitive. Irrespective of PO2, isoprenaline failed to elicit a discernible change in ISC, demonstrating that β-adrenoceptor agonists do not stimulate Na+ transport under these conditions. However, isoprenaline did elicit cAMP accumulation in these cells, indicating that functionally coupled β-adrenoceptors are present. Further experiments showed that isoprenaline did increase ISC in cells treated (24 h) with a combination of tri-iodothyronine (T3, 10 nm) and dexamethasone (200 nm). Studies of basolaterally permeabilised cells showed that these hormones are essential for the isoprenaline-evoked increase in the apical membrane's Na+ conductance (GNa), whereas isoprenaline-evoked changes in apical Cl− conductance (GCl) can occur in both control and hormone-treated cells. Irrespective of their hormonal status, FDLE cells thus express β-adrenoceptors that are functionally coupled to adenylate cyclase, and allow β-adrenoceptor agonists to modulate the apical membrane's anion conductance. However, T3 and dexamethasone are needed if these receptors are to exert control over GNa. These hormones may thus play an important role in the functional maturation of the lung by allowing β-adrenoceptor-mediated control over epithelial Na+ channels in the apical plasma membrane.

Interaction of Cortisoi and Thyroid Hormone in the Larval Development of Pacific Threadfin

SYNOPSIS. We have conducted three hatchery-scale experiments designed to examine the actions and interactions of cortisoi and thyroid hormones in the development of a larval marine fish. Survival among controls varied significantly between the 3 replicate experiments. The threadfin (Polydactylus sexfilis) consistently responds to 1 hr posthatch immersion in a combination of triiodothyronine and cortisoi (T3 + F) with accelerated gut development and increased survival compared with untreated controls (C). Survival among larvae treated with T, or F separately was significantly improved over controls in one of the three experiments. The frequency of spinal deformities was reduced by cortisoi treatment, alone or in combination with T3. Growth did not vary with treatment, except that variance in larval length was reduced in (T, + F) vs. C in all 3 experiments. A hormoneinduced increase in uniformity could lead to reduced cannibalism, which is a problem in the culture of threadnns. These results suggest interactive hormonal regulation of developmental processes, working within the context of other biological variables.

Effects of triiodothyronine and carnitine therapy on myocardial dysfunction in diabetic rats.

Streptozocin-diabetic rats were treated with a combination of triiodothyronine and carnitine for 6 weeks. These compounds were used as they are known to correct the diabetes-induced depression of cardiac myosin ATPase and sarcoplasmic reticular (SR) calcium uptake, respectively. Myocardial performance, which was assessed using the working heart preparation, revealed a depression of function in untreated diabetics when compared with controls at most left atrial filling pressures. Hearts from diabetic rats treated with the combination exhibited depression at only the higher filling pressures as compared with untreated or treated controls. The results suggest that functional alterations occurring as a result of diabetes cannot be accounted for by the depression of cardiac myosin ATPase and SR calcium uptake alone.