Acute actions of thyroid hormone on blood vessel biochemistry and physiology

Purpose of review Description of the progress about the vascular effects promoted by thyroid hormones. Recent findings Over the past few years, a number of studies have shown that in addition to genomic effects on blood vessels, thyroid hormones exert extranuclear nongenomic effects on vascular smooth muscle cells and endothelium. These nongenomic effects occur rapidly and do not involve thyroid hormone response elements-mediated transcriptional events. In this context, the genomic and nongenomic events promoted by thyroid hormones act in concert to control the vascular hemodynamic and regulate the cardiovascular function. Summary Considering the antiatherogenic property of thyroid hormones and the rapid effects produced by this molecule as a vasodilator, including that in the coronary bed, a better understanding of the molecular mechanisms involved in its action may contribute to the development of drugs that can be clinically used to increase the known benefits promoted by thyroid hormones in cardiovascular physiology.

Iodide Transport Defect: Functional Characterization of a Novel Mutation in the Na(+)/I(-) Symporter 5 `-Untranslated Region in a Patient with Congenital Hypothyroidism

Context: Iodide transport defect (ITD) is an autosomal recessive disorder caused by impaired Na(+)/I(-) symporter (NIS)-mediated active iodide accumulation into thyroid follicular cells. Clinical manifestations comprise a variable degree of congenital hypothyroidism and goiter, and low to absent radioiodide uptake, as determined by thyroid scintigraphy. Hereditary molecular defects in NIS have been shown to cause ITD. Objective: Our objective was to perform molecular studies on NIS in a patient with congenital hypothyroidism presenting a clinical ITD phenotype. Design: The genomic DNA encoding NIS was sequenced, and an in vitro functional study of a newly identified NIS mutation was performed. Results: The analysis revealed the presence of an undescribed homozygous C to T transition at nucleotide -54 (-54C>T) located in the 5`-untranslated region in the NIS sequence. Functional studies in vitro demonstrated that the mutation was associated with a substantial decrease in iodide uptake when transfected into Cos-7 cells. The mutation severely impaired NIS protein expression, although NIS mRNA levels remained similar to those in cells transfected with wild-type NIS, suggesting a translational deficiency elicited by the mutation. Polysome profile analysis demonstrated reduced levels of polyribosomes-associated mutant NIS mRNA, consistent with reduced translation efficiency. Conclusions: We described a novel mutation in the 5`-untranslated region of the NIS gene in a newborn with congenital hypothyroidism bearing a clinical ITD phenotype. Functional evaluation of the molecular mechanism responsible for impaired NIS-mediated iodide concentration in thyroid cells indicated that the identified mutation reduces NIS translation efficiency with a subsequent decrease in protein expression and function. (J Clin Endocrinol Metab 96: E1100-E1107, 2011)

Distribution of small Rho GTPases in the developing rat submandibular gland

During the rat submandibular gland (SMG) development, organogenesis and cytodifferentiation depend on the actin cytoskeleton, which is regulated by small Rho GTPases. These proteins link cell surface receptors to pathways that regulate cell motility, polarity, gene expression, vesicular trafficking, proliferation and apoptosis. The aim of this study was to evaluate, by immunohistochemistry, the distribution pattern of RhoA, RhoB, RhoC, Rac1 and Cdc42 during cytodifferentiation of the rat SMG and in male adults. All GTPases were found in epithelial and mesenchymal tissues throughout gland development. Rac1 appeared to be important for parenchyma expansion at the beginning of cytodifferentiation, while RhoC, Cdc42 and the inactive phosphorylated form of Rac1 seemed associated with lumen formation and cell polarization in terminal tubules. RhoA and RhoB labeling was evident throughout development. All GTPases were differentially expressed in the adult gland, suggesting that they play specific roles during differentiation and function of the rat SMG.

Differential gene expression analysis of iodide-treated rat thyroid follicular cell line PCCl3

The inhibitory effect of supraphysiological iodide concentrations on thyroid hormone synthesis (Wolff - Chaikoff effect) and on thyrocyte proliferation is largely known as iodine autoregulation. However, the molecular mechanisms by which iodide modulates thyroid function remain unclear. In this paper, we analyze the transcriptome profile of the rat follicular cell lineage PCCl3 under untreated and treated conditions with 10 (- 3) M sodium iodide (NaI). Serial analysis of gene expression (SAGE) revealed 84 transcripts differentially expressed in response to iodide (p <= 0.001). We also showed that iodide excess inhibits the expression of essential genes for thyroid differentiation: Tshr, Nis, Tg, and Tpo. Relative expression of 14 of 20 transcripts selected by SAGE was confirmed by real-time PCR. Considering the key role of iodide organification in thyroid physiology, we also observed that both the oxidized form of iodide and iodide per se are responsible for gene expression modulation in response to iodide excess. (c) 2008 Elsevier Inc. All rights reserved.

The importance of hormone receptor analysis in osteosarcoma cells growth submitted to treatment with estrogen in association with thyroid hormone

Bone tumor incidence in women peaks at age 50-60, coinciding with the menopause. That estrogen (E2) and triiodothyronine (T3) interact in bone metabolism has been well established. However, few data on the action of these hormones are available. Our purpose was to determine the role of E2 and T3 in the expression of bone activity markers, namely alkaline phosphatase (AP) and receptor activator of nuclear factor kappa B ligand (RANKL). Two osteosarcoma cell lines: MG-63 (which has both estrogen (ER) and thyroid hormone (TR) receptors) and SaOs-29 (ER receptors only) were treated with infraphysiological E2 associated with T3 at infraphysiological, physiological, and supraphysiological concentrations. Real-time RT-PCR was used for expression analysis. Our results show that, in MG-63 cells, infraphysiological E2 associated with supraphysiological T3 increases AP expression and decreases RANKL expression, while infraphysiological E2 associated with either physiological or supraphysiological T3 decreases both AP and RANKL expression. On the other hand, in SaOs-2 cells, the same hormone combinations had no significant effect on the markers` expression. Thus, the analysis of hormone receptors was shown to be crucial for the assessment of tumor potential growth in the face of hormonal changes. Special care should be provided to patients with T3 and E2 hormone receptors that may increase tumor growth. Copyright (C) 2007 John Wiley & Sons, Ltd.

Only subtle protein conformational adaptations are required for ligand binding to thyroid hormone receptors: Simulations using a novel multipoint steered molecular dynamics approach

Thyroid hormone receptors (TR) are hormone-dependent transcription regulators that play a major role in human health, development, and metabolic functions. The thyroid hormone resistance syndrome, diabetes, obesity, and some types of cancer are just a few examples of important diseases that are related to TR malfunctioning, particularly impaired hormone binding. Ligand binding to and dissociation from the receptor ultimately control gene transcription and, thus, detailed knowledge of binding and release mechanisms are fundamental for the comprehension of the receptor`s biological function and development of pharmaceuticals. In this work, we present the first computational study of ligand entry into the ligand binding domain (LBD) of a nuclear receptor. We report molecular dynamics simulations of ligand binding to TRs using a generalization of the steered molecular dynamics technique designed to perform single-molecule pulling simulations along arbitrarily nonlinear driving pathways. We show that only gentle protein movements and conformational adaptations are required for ligand entry into the LBDs and that the magnitude of the forces applied to assist ligand binding are of the order of the forces involved in ligand dissociation. Our simulations suggest an alternative view for the mechanisms ligand binding and dissociation of ligands from nuclear receptors in which ligands can simply diffuse through the protein surface to reach proper positioning within the binding pocket. The proposed picture indicates that the large-amplitude protein motions suggested by the apo- and holo-RXR alpha crystallographic structures are not required, reconciling conformational changes of LBDs required for ligand entry with other nuclear receptors apo-structures that resemble the ligand-bound LBDs.

Self-reported symptoms and motor tests via telemetry in a 36-month levodopa-carbidopa intestinal gel infusion trial

Objective To investigate if a home environment test battery can be used to measure effects of Parkinson’s disease (PD) treatment intervention and disease progression. Background Seventy-seven patients diagnosed with advanced PD were recruited in an open longitudinal 36-month study at 10 clinics in Sweden and Norway; 40 of them were treated with levodopa-carbidopa intestinal gel (LCIG) and 37 patients were candidates for switching from oral PD treatment to LCIG. They utilized a mobile device test battery, consisting of self-assessments of symptoms and objective measures of motor function through a set of fine motor tests (tapping and spiral drawings), in their homes. Both the LCIG-naïve and LCIG-non-naïve patients used the test battery four times per day during week-long test periods. Methods Assessments The LCIG-naïve patients used the test battery at baseline (before LCIG), month 0 (first visit; at least 3 months after intraduodenal LCIG), and thereafter quarterly for the first year and biannually for the second and third years. The LCIG-non-naïve patients used the test battery from the first visit, i.e. month 0. Out of the 77 patients, only 65 utilized the test battery; 35 were LCIG-non-naïve and 30 LCIG-naïve. In 20 of the LCIG-naïve patients, assessments with the test battery were available during oral treatment and at least one test period after having started infusion treatment. Three LCIG-naïve patients did not use the test battery at baseline but had at least one test period of assessments thereafter. Hence, n=23 in the LCIG-naïve group. In total, symptom assessments in the full sample (including both patient groups) were collected during 379 test periods and 10079 test occasions. For 369 of these test periods, clinical assessments including UPDRS and PDQ-39 were performed in afternoons at the start of the test periods. The repeated measurements of the test battery were processed and summarized into scores representing patients’ symptom severities over a test period, using statistical methods. Six conceptual dimensions were defined; four subjectively-reported: ‘walking’, ‘satisfied’, ‘dyskinesia’, and ‘off’ and two objectively-measured: ‘tapping’ and ‘spiral’. In addition, an ‘overall test score’ (OTS) was defined to represent the global health condition of the patient during a test period. Statistical methods Change in the test battery scores over time, that is at baseline and follow-up test periods, was assessed with linear mixed-effects models with patient ID as a random effect and test period as a fixed effect of interest. The within-patient variability of OTS was assessed using intra-class correlation coefficient (ICC), for the two patient groups. Correlations between clinical rating scores and test battery scores were assessed using Spearman’s rank correlations (rho). Results In LCIG-naïve patients, mean OTS compared to baseline was significantly improved from the first test period on LCIG treatment until month 24. However, there were no significant changes in mean OTS scores of LCIG-non-naïve patients, except for worse mean OTS at month 36 (p<0.01, n=16). The mean scores of all subjectively-reported dimensions improved significantly throughout the course of the study, except ‘walking’ at month 36 (p=0.41, n=4). However, there were no significant differences in mean scores of objectively-measured dimensions between baseline and other test periods, except improved ‘tapping’ at month 6 and month 36, and ‘spiral’ at month 3 (p<0.05). The LCIG-naïve patients had a higher within-subject variability in their OTS scores (ICC=0.67) compared to LCIG-non-naïve patients (ICC=0.71). The OTS correlated adequately with total UPDRS (rho=0.59) and total PDQ-39 (rho=0.59). Conclusions In this 3-year follow-up study of advanced PD patients treated with LCIG we found that it is possible to monitor PD progression over time using a home environment test battery. The significant improvements in the mean OTS scores indicate that the test battery is able to measure functional improvement with LCIG sustained over at least 24 months.

Assessment of cognitive function in heart failure patients

Background
Research on the cognitive capacity of heart failure patients is limited, with a paucity of benchmark information available for this population. It is highly likely that cognitive deficits affect patients' understanding of disease and treatment requirements, as well as limiting their functional capacity and ability to implement treatment plans, and undertake self-care.

Aims
The purpose of this study was to establish a comprehensive neurocognitive profile of the heart failure patient through systematic neurocognitive assessment and to determine whether an association existed between severity of heart failure and cognitive abilities.

Methods
Thirty-eight patients were recruited from the heart failure patient databases of two metropolitan hospitals in Melbourne, Australia. Participants were individually assessed using four standardised, internationally recognised neuropsychological tests that examined current and premorbid intelligence, memory and executive functioning.

Results
Although there was no significant decline from premorbid general intellectual function, other specific areas of deficit, including impaired memory and executive functioning, were identified. There were no significant correlations between heart failure severity and the neurocognitive measures used.

Conclusion
The results support the need to recognise cognitive impairment in people with heart failure and to develop an abbreviated method of assessing cognitive function that can be easily implemented in the clinical setting. Identifying cognitive deficits in this population will be useful in guiding the content and nature of treatment plans to maximise adherence and minimise worsening of heart failure symptoms.

The PKCÁ-D294G mutant found in pituitary and thyroid tumors fails to transduce extracellular signals

Protein kinase C (PKC) is a key regulator of cell proliferation, differentiation, and apoptosis and is one of the drug targets of anticancer therapy. Recently, a single point mutation (D294G) in PKCα has been found in pituitary and thyroid tumors with more invasive phenotype. Although the PKCα-D294G mutant is implicated in the progression of endocrine tumors, no apparent biochemical/cell biological abnormalities underlying tumorigenesis with this mutant have been found. We report here that the PKCα-D294G mutant is unable to bind to cellular membranes tightly despite the fact that it translocates to the membrane as efficiently as the wild-type PKCα upon treatment of phorbol ester. The impaired membrane binding is associated with this mutant's inability to transduce several antitumorigenic signals as it fails to mediate phorbol ester–stimulated translocation of myristoylated alanine–rich protein kinase C substrate (MARCKS), to activate mitogen-activated protein kinase and to augment melatonin-stimulated neurite outgrowth. Thus, the PKCα-D294G is a loss-of-function mutation. We propose that the wild-type PKCα may play important antitumorigenic roles in the progression of endocrine tumors. Therefore, developing selective activators instead of inhibitors of PKCα might provide effective pharmacological interventions for the treatment of certain endocrine tumors.

Effect of deer velvet on sexual function in men and their partners: a double-blind, placebo-controlled study

The use of alternative medicines and herbal remedies is an increasing trend in Western societies. For years, people have taken products made of deer velvet for their alleged beneficial effects on sexual function. There has been no scientific investigation of the effects of deer velvet powder on the sexual functioning of human males. This study investigated sexual function in men during a 12-week double-blind, placebo-controlled trial of deer velvet. Thirty-two volunteer male participants, aged 45–65 years, and their partners, were randomly assigned to either the deer velvet or placebo study group. The males took capsules containing ground deer velvet or placebo everyday for 12 weeks. Two sexual function questionnaires (the International Index of Erectile Function and the Brief Index of Sexual Function for Women) used at pre- and posttreatment assessed changes in sexual functioning in males and their partners. Blood tests at baseline, and end of study, determined levels of sex-related hormones in male participants. There were no significant differences in the sexual behavior of the men taking deer velvet compared with the men taking placebo capsules. There were no significant hormone changes from baseline to the end of the study in either group of men. We conclude that in normal males there was no advantage in taking deer velvet to enhance sexual function. All alternative health products or nutritional supplements should be subjected to randomized placebo-controlled trials to determine efficacy.

Ultraviolet vision in birds: what is its function?

Although UV vision was first demonstrated in birds in the early 1970s, its function is still unknown. Here we review the evidence for UV vision in birds, discuss the special properties of UV light, lay out in detail hypotheses for the function of UV vision in birds and discuss their plausibility. The main hypotheses are that UV vision functions: (i) in orientation, (ii) in foraging and (iii) in signalling. The first receives support from studies of homing pigeons, but it would be unwise to conclude that orientation is UV's primary function in all birds. It is especially important to test the signalling hypothesis because bird plumage often reflects UV and tests of theories of sexual selection have virtually always assumed that birds perceive plumage ''colours'' as humans do. A priori this assumption is unlikely to be correct, for unlike humans, birds see in the UV, have at least four types of cones and have a system of oil droplets which filters light entering individual cones.

The effects of treating male hypogonadism on couples' sexual desire and function

Introduction: Hypogonadism is a common endocrine condition characterized by low levels of testosterone (T) and marked by numerous symptoms, one of which is low sexual desire. Studies comparing T delivery systems have suggested that hypogonadal men’s partners may be at risk from exposure to T gels. Little other mention is found of the impact of hypogonadism and its treatment on a man’s partner and the couple’s sexual function.

Aim: To assess sexual desire and sexual function in hypogonadal men and their woman partners before and after treatment with T replacement therapy.

Methods: Twenty-one hypogonadal men and 18 partners were recruited from a   tertiary endocrine clinic, and were compared with a control group of 20 eugonadal age-matched men and their partners. All men had baseline blood tests to confirm their status as hypogonadal or eugonadal, and hypogonadal men repeated tests at 3-month intervals. All participants completed the Sexual Desire Inventory (SDI) and sexual function questionnaires at baseline and at 3-month intervals until the hypogonadal men attained normal T levels.

Main Outcome Measures: Pre- and post-treatment SDI and sexual function questionnaires were compared once T normalization was achieved. Between- and within-group comparisons were carried out.

Results: Pretreatment hypogonadal men recorded lower levels of sexual desire and function than controls, but significantly improved once hypogonadism was corrected. Eugonadal controls recorded no significant changes in either sexual desire or function during the study. Partners of the hypogonadal men reported no changes on the SDI, but significant improvements in sexual function as their partners recovered.

Conclusion: SDI and sexual function measures reflect sexual changes that  accompany rising serum T levels during correction of male hypogonadism. Women partners reported more satisfaction, less pain, and improved sexual function following the men’s treatment. Treatments affecting one partner potentially have important effects on the other.

Cognitive function in adolescents with chronic fatigue syndrome

This thesis explored cognitive function in adolescents with chronic fatigue syndrome. Counter to what has been found in adults, adolescents with CFS performed as well as their peers on demanding tests of executive function, information processing, memory and attention. The results suggest that CFS might impact differently on the developing brain. The portfolio used a case study approach to examine the effectiveness and utility of Finn's Therapeutic Assessment model in four clients.

Cardiac structure and function in young endurance athletes and nonathletes

The purpose of this study was to examine, in male adolescents, the effects of long-term endurance training on cardiac structure and function, by adopting a cross-sectional comparison with a nonathletic control group. A total of 13 endurance-trained (EX) and seven untrained (CON) male adolescents (mean ± SE, age = 15.3 ± 0.3 and 15.2 ± 0.28 yrs, respectively) underwent echocardiography at rest to determine left ventricular enddiastolic dimension (LVD_d), left ventricular end-systolic dimension (LVD_s), left ventricular posterior wall thickness (LVPW), stroke volume (SV), and cardiac output (CO). On separate days, incremental exercise tests were conducted on a cycle ergometer to measure peak oxygen uptake (VO_2max) and anaerobic power. VO_2max was greater in the endurance group (54.4 ± 1.8 mL min^–1 kg^–1) than in the control group (45.8 ± 1.6 mL min^–1 kg^–1; p < 0.05). Mean exercise time was longer in EX (12.9 ± 0.7 min) than CON (10.4 ± 0.8 min; p < 0.05). No significant differences were noted between the two groups in resting heart rate, maximal heart rate, LVD_d, LVD_s, LVPW, SV, SV indexed, CO, and CO indexed, or in the anaerobic strength. These data provide evidence that endurance-trained adolescent males develop superior exercise performance before the cardiac remodeling that is evident in trained adult athletes.

Identification of an attractin-like pheromone in the mucus-secreting hypobranchial gland of the abalone Haliotis asinina linnaeus.

Pheromones are chemicals used to communicate between animals of the same species, and are thought to be used by most marine animals. With limited vision, abalone primarily sense their world chemically, and pheromones may play an important role in settlement, attraction, recognition, alarm, and reproduction. Despite this, there has been no detailed investigation into pheromone substances, both in their precise biochemical nature or pheromonal function. In this study, we investigated the presence of pheromonelike substances from the hypobranchial gland of the abalone Haliotis asinina using bioassays, immunohistochemistry, Western blotting, and reverse-phase high-performance liquid chromatography (RP-HPLC). The hypobranchial gland of many prosobranchial marine molluscs has been classified as a sex auxiliary gland releasing unknown substances during spawning. In our study, cephalic tentacle assays demonstrated that the cell extracts of the hypobranchial gland contain chemical cues that are sensed by conspecifics. An antibody against the sea slug “attractin” pheromone was used as a probe to localize a similar protein in the mucin-secreting cells of the epithelial lining the hypobranchial gland of both male and female abalone. The approximate molecular weight of this abalone attractin-like protein is 30 kDa in both males and females. Fractionation of hypobranchial gland extracts by C5 RP-HPLC could not selectively purify this protein, and no sex-specific differences were observed. We predict that the attractin-like protein could be one of a number of important proteins involved in maturation, aggregation, and/or spawning behavior of abalone. In future research, additional hypobranchial gland components will be tested further for these types of behavior.