Friday, January 25, 2013

Catecholamines (epinephrine (adrenaline), norepinephrine (noradrenaline) and dopamine)


Amine
I. Catecholamines, derived from the amino acid tyrosine, produced by the adrenal glands, which are found on top of the kidneys. are epinephrine (adrenaline), norepinephrine (noradrenaline) and dopamine. The hormone are released into the blood during times of physical or emotional stress.

1. Catecholamine and dorsolateral prefrontal cortical networks
The symptoms of attention-deficit/hyperactivity disorder (ADHD) involve impairments in prefrontal cortical top-down regulation of attention and behavior. In the study of Catecholamine influences on dorsolateral prefrontal cortical networks, conducted by Yale University School of Medicine, indicated that the stimulant medications and atomoxetine appear to enhance PFC function by indirectly increasing these catecholamine actions through blockade of norepinephrine and/or dopamine transporters. In contrast, guanfacine mimics the enhancing effects of norepinephrine at postsynaptic α(2A)-receptors in the PFC, strengthening network connectivity. Stronger PFC regulation of attention, behavior, and emotion likely contributes to the therapeutic effects of these medications for the treatment of ADHD(1).

2. SRY regulation of catecholaminess and The male fight-flight response
According to the study by Brain and Gender, Prince Henry's Institute of Medical Research, The SRY gene, which is located on the Y chromosome and directs male development, may promote aggression and other traditionally male behavioural traits, resulting in the fight-or-flight reaction to stress(2).

3. Caffeine on the levels of brain serotonin and catecholamine
Caffeine, a stimulant, which can prompt lipolysis, has been applied on the therapy of obesity. In the study to measure  The brain neurotransmitters levels and body fat content  At 12-week of age, obese mice and their lean counterparts (+/?) were administered with caffeine (4 mg/d) in water for 4 weeks, showed that the obese mice without caffeine treatment had lower brain norepinephrine and epinephrine levels than the lean controls. And there had no difference between obese and lean mice in brain levels of serotonin, tryptophan, and 5-hydroxyindoleacetic acid. Caffeine treatment showed no effect on the food intake, but decreased the body fat content significantly in obese mice(3).

4. Dietary copper supplementation influences the catecholamine levels
In the study to investigate the effects of dietary Cu supplementation on the catecholamine levels in genetically obese mice, male obese (ob/ob) mice and their lean (+/?) counterparts, with either a control diet (4.0 mg/kg) or a Cu-supplemented diet (50 mg/kg) for 4 wk, researchers at the Taichung Veterans General Hospital, showed that catecholamine levels in ob/ob mice can be increased by dietary Cu supplementation. However, the interaction between Cu and sympathetic nervous activity in obesity was not elucidated in this study(4).

5. The effects of dietary protein source on serotonin and catecholamine synthesis rates
In the study of fed rats single meals, containing one of 5 proteins (zein, wheat gluten, soy protein isolate, casein, lactalbumin, 17% by weight) or no protein, and killed them 2.5 h later, 30 min after the injection of m-hydroxybenzylhydrazine, to allow serotonin and catecholamine synthesis rates to be measured in brain, showed that tryptophan concentrations and serotonin synthesis in brain neurons are remarkably sensitive to which protein is present in a meal. Conceivably, this relationship might inform the brain about the nutritional quality of the protein ingested(5).

6. The role of glucose, oxygen and epinephrine resuscitation
In the study of Cholinergic alterations and its further complications in learning and memory due to hypoxic insult in neonatal rats and the effect of glucose, oxygen and epinephrine resuscitation, showed that the reduction in acetylcholine metabolism is indicated by the down regulated choline acetyltransferase and up regulated acetylcholine esterase expression. These cholinergic disturbances were reversed to near control in glucose resuscitated hypoxic neonates. The adverse effects of immediate oxygenation and epinephrine administration are also reported. This has immense clinical significance in establishing a proper resuscitation for the management of neonatal hypoxia(6).

7. Endocrine regulation of neonatal hypoxia
In the study to assess and focus on changes in insulin and triiodothyronine concentration in serum, its receptors in the hearts of hypoxic neonatal rats and glucose, oxygen, and epinephrine resuscitated groups, found that the insulin concentration was significantly increased with a significant upregulation of receptors in hypoxic neonates. Triiodothyronine content and its receptors were significantly decreased in serum and the hearts of hypoxic neonates. The change in hormonal levels is an adaptive modification of the endocrine system to encounter the stress. The effectiveness of glucose resuscitation to hypoxic neonates was also reported(7).

8. Enhanced brain stem 5HT₂A receptor function under neonatal hypoxic insult
Molecular processes regulating brain stem serotonergic receptors play an important role in the control of respiration. In the study to evaluate the 5-HT(2A) receptor alterations in the brain stem of neonatal rats exposed to hypoxic insult and the effect of glucose, oxygen, and epinephrine resuscitation in ameliorating these alterations, found that Hypoxic stress increased the total 5-HT and 5-HT(2A) receptor number along with an up regulation of 5-HT Transporter and 5-HT(2A) receptor gene in the brain stem of neonates. These serotonergic alterations were reversed by glucose supplementation alone and along with oxygen to hypoxic neonates. The enhanced brain stem 5-HT(2A) receptors act as a modulator of ventilatory response to hypoxia, which can in turn result in pulmonary vasoconstriction and cognitive dysfunction. The adverse effects of 100% oxygenation and epinephrine administration to hypoxic neonates were also reported(8).

9. Catecholamine-releasing action in guinea-pig papillary muscles
In the study to  investigate wheather tetraethylammonium ion (TEA) prolongs the action potential (AP) was examined by standard microelectrode techniques in papillary muscles isolated from nonreserpinized and reserpinized guinea-pig hearts, showed that TEA modifies its intrinsic prolonging action of the AP by releasing norepinephrine from sympathetic nerve terminals; TEA prolongs the AP by reducing the time-independent outward current rather than the time-dependent outward current; and a TEA-sensitive current does not effectively contribute to the total ionic current at the time of Vmax(9).

10. The Effects of hypertension on cardiovascular responses to epinephrine
Cardiac beta-receptor responsiveness is diminished by both aging and hypertension. In the study to evaluate of14 young and 18 older normotensive men and women and in 10 young and 17 older hypertensive men and women by echocardiography cardiac responses to intravenous infusion of epinephrine and to assess the relative contribution of intrinsic cardiac and counterregulatory components to the overall respons, found that Epinephrine-induced increases in heart rate were similar in the four groups. Increases in stroke volume, ejection fraction, and cardiac index were similar in the two hypertensive and two young normotensive groups. In contrast, they were attenuated in the older normotensive group, resulting in higher left ventricular responses in older hypertensive than in normotensive subjects. Heart rate and left ventricular responses to epinephrine in the presence of ganglionic blockade did not differ between the two young groups. Increases in plasma norepinephrine due to epinephrine infusion were larger in hypertensive than in normotensive subjects(10).

11. Epinephrine, vasodilation and hemoconcentration in syncopal, healthy men and women
In the study to evaluate why healthy young people may become syncopal during standing, head up tilt (HUT) or lower body negative pressure (LBNP by measuring the hormonal indices of autonomic activity along with arterial pressure (AP), heart rate (HR), stroke volume (SV), cardiac output (CO), total peripheral resistance (TPR) and measures of plasma volume, found that the presyncopal decline in blood pressure in otherwise healthy young people resulted from declining peripheral resistance associated with plateauing norepinephrine and plasma renin activity, rising epinephrine and rising blood viscosity. The increased hemoconcentration probably reflects increased rate of venous pooling rather than rate of plasma filtration and, together with cardiovascular effects of imbalances in norepinephrine, epinephrine and plasma renin activity may provide afferent information leading to syncope(11).

12. Adrenal glands and the activation of glucogenesis during undernutrition
In adults, the adrenal glands are essential for the metabolic response to stress, but little is known about their role in fetal metabolism. In the study to investigate the effects of adrenalectomizing fetal sheep on glucose and oxygen metabolism in utero in fed conditions and after maternal fasting for 48 h near term, showed that the circulating concentrations of cortisol and total catecholamines, and the hepatic glycogen content and activities of key gluconeogenic enzymes, were also less in AX than intact fetuses in fasted animals. Insulin concentrations were also lower in AX than intact fetuses in both nutritional states. Maternal glucose utilization and its distribution between the fetal, uteroplacental, and nonuterine maternal tissues were unaffected by fetal AX in both nutritional states. Ovine fetal adrenal glands, therefore, have little effect on basal rates of fetal glucose and oxygen metabolism but are essential for activating fetal glucogenesis in response to maternal fasting. They may also be involved in regulating insulin sensitivity in utero(12).

13. Catecholamine concentrations in hyperthyroidism and hypothyroidism
In the study to measure the plasma epinephrine (E) and norepinephrine (NE) concentrations in patients with thyroid dysfunction, showed that hyperthyroidism is accompanied by normal plasma NE concentrations and that hypothyroidism is associated with significantly increased plasma NE concentrations, possible in an attempt to compensate for the lack of thyroid hormones(13).



Sources
(1) http://www.ncbi.nlm.nih.gov/pubmed/21489408
(2) http://www.ncbi.nlm.nih.gov/pubmed/22408002
(3) http://www.ncbi.nlm.nih.gov/pubmed/8039038
(4) http://www.ncbi.nlm.nih.gov/pubmed/8962796
(5) http://www.ncbi.nlm.nih.gov/pubmed/19454292
(6) http://www.ncbi.nlm.nih.gov/pubmed/21907834
(7) http://www.ncbi.nlm.nih.gov/pubmed/21846315
(8) http://www.ncbi.nlm.nih.gov/pubmed/21484469
(9) http://www.ncbi.nlm.nih.gov/pubmed/3785438
(10) http://www.ncbi.nlm.nih.gov/pubmed/17307999
(11) http://www.ncbi.nlm.nih.gov/pubmed/11695710
(12) http://www.ncbi.nlm.nih.gov/pubmed/20959526
(13) http://www.ncbi.nlm.nih.gov/pubmed/958003

A. Epinephrine
1. Epinephrine and thyroidism
In the study of measurement of the secretion rate of epinephrine in 6 euthyroid, 6 hyperthyroid, and 6 hypothyroid subjects infused at a constant rate for a one hour period with tritiated epinephrine (.01 muc/kg/min) (New England Nuclear Inc.), found that plasma secretion rates averaged 48 +/- 27 mug/kg/day in normal subjects, compared to 54 +/- 18 mu/kg/day in hyperthyroidism and 43 +/- 20 mug/kg/day in hypothyroidism. Likewise, the mean urinary secretion rate was 55 +/- 27 mug/kg/day in normal subjects compared to 60 +/- 22 mug/kg/day in hyperthyroidism and 50 +/- 28 mug/kg/day in hypothyroidism. There is no statistical difference between the values found in the three groups of subjects (plasma and urine). Therefore, these results would indicate that the signs and symptoms encountered in hyperthyroidism are not secondary to a high secretion rate of epinephrine(1).

2. Epinephrine-containing local anesthesia and cardiovascular disease
In the study to examine the safety of epinephrine-containing local anesthesia for use on patients with cardiovascular diseasein twenty-seven patients with cardiovascular disease, showed that Systolic blood pressure and heart rate increased by 4.1% and 5.1%, respectively, immediately after the lidocaine-epinephrine injection. Consequently, rate pressure product increased by 10.0%. Cardiac index increased by 14.2%, and total peripheral resistance decreased by approximately 10%. No patient complained of cardiac symptoms. There were no significant differences in hemodynamic responses related to the extent of the cardiac functional capacity(2).

3. Propranolol administration epinephrine-stimulated SSRBC adhesion in Sickle red blood cells (SSRBCs)  patients
Sickle red blood cells (SSRBCs) adhere to both endothelial cells (ECs) and the extracellular matrix. In the study to investigate whether systemically administered propranolol inhibits SSRBC adhesion and to document the safety of propranolol in SCD, indicated that Propranolol administration significantly reduced epinephrine-stimulated SSRBC adhesion in a dose dependent manner (p = 0.03), with maximum inhibition achieved at 40 mg. Adverse events were not severe, did not show dose dependence, and were likely unrelated to drug. No significant heart rate changes occurred. These results imply that β-blockers may have a role as antiadhesive therapy for SCD(3).

4. Hormone Epinephrine and sickle cell disease (SCD).
The possible role of physiologic stress hormones in enhancing adhesion of sickle erythrocytes (SS RBCs) to endothelial cells (ECs) in sickle cell disease (SCD). In the study of Epinephrine acts through erythroid signaling pathways to activate sickle cell adhesion to endothelium via LW-alphavbeta3 interactions, found that up-regulation of intracellular cyclic adenosine monophosphate (cAMP)-dependent protein kinase A (PKA) by epinephrine significantly increased sickle but not normal erythrocyte adhesion to both primary and immortalized ECs. Inhibition of serine/threonine phosphatases also enhanced sickle erythrocyte adhesion at least partially through a PKA-dependent mechanism. Adhesion was mediated through LW (intercellular adhesion molecule-4 [ICAM-4], CD242) blood group glycoprotein, and immunoprecipitation studies showed that LW on sickle but not on normal erythrocytes undergoes increased PKA-dependent serine phosphorylation as a result of activation(4).

5. Low dose of intravenous (IV) epinephrine and monomorphic ventricular tachycardia (VT) in the setting of coronary artery disease
There is a report of three cases of sustained monomorphic ventricular tachycardia (VT) in the setting of coronary artery disease, resistant to beta-blockers in two patients and to amiodarone in all, successfully terminated by low doses of intravenous (IV) epinephrine. VT was the first manifestation of coronary artery disease in one patient, whereas the other two patients had a previous history of myocardial infarction and were recipients of an implantable cardioverter-defibrillator (ICD). One of these two patients experienced an arrhythmic storm. All had hemodynamic instability at the time of epinephrine administration(5).

6. Vitamin C and epinephrine
Vitamin C has several well-established roles in physiology including synthesis of collagen, carnitine and epinephrine, absorption of dietary iron, and mobilization of storage iron for erythropoeisis. Loss of several of these functions explains the pathology of scurvy, where defective collagen synthesis and anemia are major symptoms. Vitamin C deficiency is very common in dialysis patients and may arise from dialytic vitamin C clearance, restricted intake of vitamin C-rich foods, and increased vitamin C catabolism in vivo from inflammation. In the dialysis population, greater vitamin C intake may be needed for optimal health(6).

7. Epinephrine and cardiac arrest
Epinephrine is widely used in cardiopulmonary resuscitation for out-of-hospital cardiac arrest (OHCA). In the study to evaluate the association between epinephrine use before hospital arrival and short- and long-term mortality in patients with cardiac arrest, researchers at the Department of Health Services Management and Policy, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan, showed that among patients with OHCA in Japan, use of prehospital epinephrine was significantly associated with increased chance of return of spontaneous circulation before hospital arrival but decreased chance of survival and good functional outcomes 1 month after the event(7).

8. Epinephrine in the treatment of anaphylaxis
In the study to review recent literature that impacts the use of epinephrine in the therapy of anaphylaxis, found that the intramuscular route of administration for epinephrine is superior has now been recognized by the guidelines, and because the site of choice has been found to be the lateral aspect of the thigh, the needle used for injection must be long enough to penetrate the vastus lateralis muscle and  outdated EpiPens can usually be administered safely, and alternative routes of administration, which may be more acceptable to patients, may be on the horizon as a result of preliminary studies assessing the administration of sublingual epinephrine by wafer(8).

9. Local infiltration of epinephrine-containing lidocaine with bicarbonate reduces superficial bleeding and pain
In the study to determine whether skin infiltration with epinephrine-containing rather than plain lidocaine reduces superficial bleeding after catheter placement and whether adding epinephrine and/or sodium bicarbonate affected infiltration pain, showed that Local infiltration of epinephrine-containing lidocaine before epidural catheter insertion reduces superficial bleeding and the addition of bicarbonate decreases pain during skin infiltration(9).

10. Epinephrine and bronchospasm
there is a report of a 18-year-old female was admitted to hospital for an axillary abscess incision on a public holiday. The patient had a history of asthmatic episodes and an allergy to milk protein and 2 years previously an asthmatic attack had possibly been treated by mechanical ventilation. Retrospectively, this event turned out to be a cardiac arrest with mechanical ventilation for 24 h. During induction of anesthesia the patient suddenly developed massive bronchospasms and ventilation was impossible for minutes. Oxygen saturation fell below 80% over a period of 12 min with a lowest measurement of 13%. The patient was treated with epinephrine, prednisolone, antihistamine drugs, ß(2)-agonists, s-ketamine and methylxanthines and 15 min later the oxygen saturation returned to normal values, accoridng to the study by Charité-Universitätsmedizin Berlin, Campus Benjamin Franklin(10).

11. Epinephrine and Hypoglycemia
In the study of thirty-four subjects with type 1 diabetes (14 women, 20 men; 37 ± 2.1 years old; glycosylated hemoglobin [HbA1c], 7.6  ±  0.21%) performed self-monitoring of blood glucose (SMBG) for a month, followed by an inpatient hyperinsulinemic euglycemic and hypoglycemic clamp, showed that higher insulin sensitivity and lower epinephrine response during hypoglycemia are related to increased glucose variability (as quantified by the ADRR), irrespective of HbA1c and other patient characteristics. Lower epinephrine relates to risk for hypoglycemia as well(11). other study in determination of  whether real-time continuous glucose monitoring (CGM) with preset alarms at specific glucose levels would prove a useful tool to achieve avoidance of hypoglycemia and improve the counterregulatory response to hypoglycemia in adolescents with type 1 diabetes with hypoglycemia unawareness, indicated that a greater epinephrine response during hypoglycemia suggests that real-time CGM is a useful clinical tool to improve hypoglycemia unawareness in adolescents with type 1 diabetes(12).

13. Epinephrine and Asthma
In a double-blind study to compare the safety and efficacy of 0.1-, 0.3- and 0.5-mg doses of epinephrine hydrochloride in the initial treatment of an acute asthma attack, as epinephrine hydrochloride 1:1000 was injected subcutaneously in 45 emergency room patients suffering from an acute asthma attack, found that Arterial blood gases, heart rate and blood pressure were not significantly different for the three groups (p > 0.05) and suggested that a 0.5-mg subcantaneous dose represents optimal epinephrine dosing for the initial therapy of acute asthma(13). Other study indicated that Intravenous epinephrine is a potentially safe vital therapy for patients with life-threatening asthma(14).

14. Epinephrine and laryngotracheitis (croup)
Aerosolized racemic epinephrine, but not L-epinephrine, is commonly used in treating croup. In the study to compare the efficacy and adverse effects of nebulized racemic and L-epinephrine in the treatment of laryngotracheitis, found that patients in both groups showed significant transient reduction of the croup score and respiratory rate following the aerosol (P less than .001), but there were no differences between treatment groups when croup score, heart rate, blood pressure, and respiratory rate over time and concluded that L-epinephrine is at least as effective as racemic epinephrine in the treatment of laryngotracheitis and does not carry the risk of additional adverse effects. L-Epinephrine is also more readily available worldwide, is less expensive, and can be recommended for this purpose(15).

Sources
(1) http://www.ncbi.nlm.nih.gov/pubmed/1249180
(2) http://www.ncbi.nlm.nih.gov/pubmed/11740477
(3) http://www.ncbi.nlm.nih.gov/pubmed/23253664
(4) http://www.ncbi.nlm.nih.gov/pubmed/15308566
(5) http://www.ncbi.nlm.nih.gov/pubmed/23110246
(6) http://www.ncbi.nlm.nih.gov/pubmed/23106569
(7) http://www.ncbi.nlm.nih.gov/pubmed/22436956
(8) http://www.ncbi.nlm.nih.gov/pubmed/12865777
(9) http://www.ncbi.nlm.nih.gov/pubmed/17276670
(10) http://www.ncbi.nlm.nih.gov/pubmed/21918825
(11) http://www.ncbi.nlm.nih.gov/pubmed/21175266
(12) http://www.ncbi.nlm.nih.gov/pubmed/20929999
(13) http://www.ncbi.nlm.nih.gov/pubmed/7424927
(14) http://www.ncbi.nlm.nih.gov/pubmed/12712039
(15) http://www.ncbi.nlm.nih.gov/pubmed/1734400


B. Norepinephrine
1. Catecholamine metabolism in thyroid disease
In the same measuredment of the secretion rate of norepinephrine (NE) in 6 euthyroid subjects, 6 hyperthyroid and 6 hypothyroid patients, infused at a constant rate (0.1 microC/kg/min) for 1 h with tritiated norepinephrine (New England Nuclear Inc.), showed that the plasma NE secretion rate is normal in hyperthyroidism, and is significantly elevated in hypothyroidism thereby explaining the higher plasma NE concentrations seen in hypothyroidism(1).

2. High-dose norepinephrine treatment in critically ill patients
Critically ill patients with circulatory shock sometimes need rescue treatment with high doses of norepinephrine, a treatment that may be associated with a poor outcome because of excessive vasoconstriction. In a retrospective study to evaluate the outcome of treatment and its determinants in patients with circulatory shock who received high doses of norepinephrine in the intensive care unit and to identify indicators of futility for the treatment of 113 consecutive patients with circulatory shock who received 0.9 μg/kg per minute or greater of norepinephrine during at least 1 hour at any time in the intensive care unit, found that dose, and duration of norepinephrine administration did not have prognostic significance. Scores greater than 40 on the Acute Physiology and Chronic Health Evaluation II, bicarbonate levels less than 9.0 mEq/L, or receipt of an epinephrine dose of 0.25 μg/kg per minute or greater were associated with 100% mortality and concluded that although the cause of shock and treatment with norepinephrine were not predictive of death when high doses of the drug were deemed necessary, rescue treatment with high-dose norepinephrine is futile in patients with severe disease and metabolic acidemia(2).

3. Norepinephrine in Regulation of the Fear Network by Mediators of Stress
In the study of neural modulators, especially those activated during stress, such as norepinephrine (NE), regulate synaptic transmission and plasticity in the network, found that Norepinephrine (NE) inhibits synaptic transmission in both the subcortical and cortical input pathway but that sensory processing is biased toward the subcortical pathway. In addition binding of NE to β-adrenergic receptors further dissociates sensory processing in the LA. These findings suggest a network mechanism that shifts sensory balance toward the faster but more primitive subcortical input(3).

4. Norepinephrine transporter in humans with (S,S)-[11C]O-methyl reboxetine and PET
In a human studies with the PET radiotracer (S,S)-[(11)C]O-methyl reboxetine ([(11)C](S,S)-MRB), a ligand targeting the norepinephrine transporter (NET), found that The highest density of norepinephrine transporter (NET) was found in the MBR where the LC is located, followed by THL, whereas the lowest density was found in basal ganglia (lowest in CDT), consistent with the regional localization of NETs in the nonhuman primate brain. While all three doses of ATX were found to block most regions, no significant differences between doses were found for any region, although the average percent change across subjects of the MBR did correlate with ATX dose(4).

5. Atomoxetine and attention-deficit/hyperactivity disorder (ADHD)
Atomoxetine is a potent and selective norepinephrine transporter (NET) reuptake inhibitor acting as a nonstimulant for the treatment of attention-deficit/hyperactivity disorder (ADHD). In the study to determine if atomoxetine occupies NET in a dose-dependent fashion using (S,S)-[18F]FMeNER-D2 in nonhuman primate brain, found that after administration of atomoxetine, a dose-dependent occupancy from 38 to 82% was observed for various brain regions known to contain high densities of NET(5).

6. Norepinephrine and Cingulum
The midline and intralaminar thalamic nuclei (MITN), locus coeruleus (LC) and cingulate cortex contain nociceptive neurons. The MITN that project to cingulate cortex have a prominent innervation by norepinephrinergic axons primarily originating from the LC. Researchers at the Cingulum NeuroSciences Institute and SUNY Upstate Medical University,, found that  the LC may regulate nociceptive processing in the thalamus. The well established role of cingulate cortex in premotor functions and the projections of Pf and other MITN to the limbic striatum suggests a specific role in mediating motor outflow for the LC-innervated nuclei of the MITN(6).

7. Dopamine and the norepinephrine transporter
In the testing of the hypothesis that the norepinephrine transporter (NET) is involved in dopamine clearance in the hippocampus, found that  there is very little DAT in this area using ligand binding with radiolabelled RTI-55. Moreover, in contrast to raclopride (100 μM), a dopamine D2-autoreceptor antagonist, local administration of the α2-adrenoceptor antagonist idazoxan (100 μM) increased hippocampal dopamine. Taken together, our data demonstrate an interaction between dopamine and norepinephrine systems in the hippocampus. It is proposed that this interaction originates from a shared uptake mechanism at the NET level(7).

8. Norepinephrine stimulate the release of corticotropin-releasing factor-41 from the rat hypothalamus?
In the study the effects of the two putative neurotransmitters acetylcholine and norepinephrine on immunoreactive CRF-41 release from incubated rat hypothalami, found that there is an evidence for a stimulatory role of acetylcholine and norepinephrine on CRF-41 release, and consequently on hypothalamo-pituitary-adrenal axis in the rat, through actions at a hypothalamic level. The stimulatory effect of acetylcholine is mediated principally through muscarinic receptors and that of norepinephrine through beta-adrenoceptors(8).

9. Relationship between locus coeruleus discharge rates and rates of norepinephrine release within neocortex
In the study to examine the relationship between discharge rates of locus coeruleus noradrenergic neurons and rates of norepinephrine release, found that  In general, neither activation nor suppression of locus coeruleus neuronal discharge rates appeared to alter the relationship between discharge activity and norepinephrine efflux during subsequent epochs. The one exception to this was observed during recovery from relatively high-magnitude locus coeruleus activation. In two out of three cases in which locus coeruleus discharge rates were increased greater than 450%, a recovery of norepinephrine concentrations to basal levels occurred more quickly than the recovery of locus coeruleus neuronal discharge rates to basal levels. Although limited, these latter observations suggest that dysregulation of norepinephrine release may occur following sustained activation of locus coeruleus at the highest rates examined, which may mimic those associated with intense arousal or stress.(9).

10. Norepinephrine facilitates inhibitory transmission in substantia gelatinosa of adult rat spinal cord
. The activation of descending norepinephrine-containing fibers from the brain stem inhibits nociceptive transmission at the spinal level.In the study to evaluate  the descending noradrenergic pathways exert the analgesic effect, found that norepinephrine enhances inhibitory synaptic transmission in the substantia gelatinosa through activation of presynaptic alpha1 receptors, thus providing a mechanism underlying the clinical use of alpha1 agonists with local anesthetics in spinal anesthesia(10).

11. Olanzapine and dopamine and norepinephrine release in rat prefrontal cortex, nucleus accumbens and striatum
The in vivo effects of olanzapine on the extracellular monoamine levels in rat prefrontal cortex (Pfc), nucleus accumbens (Acb) and striatum (Cpu) were investigated by means of microdialysis. In the study of the effect of Sequential doses of olanzapine at 0.5, 3 and 10 mg/kg (s.c.) dose-dependently in the extracellular dopamine (DA) and norepinephrine (NE) levels in all three brain areas, found that in the case of sequential dosing olanzapine more effectively enhances DA and NE release in the Pfc than in the subcortical areas, which may have an impact on its atypical antipsychotic actions(11).

12. Actions of norepinephrine in the cerebral cortex and thalamus
Norepinephrine (NE) has potent and long-lasting ionic effects on cortical and thalamic neurons. In the study by Yale University School of Medicine, indicated that  In cortical pyramidal cells, activation of beta-adrenergic receptors results in an enhanced excitability and responsiveness to depolarizing inputs. This enhanced excitability is expressed as a reduction in spike frequency adaptation and is mediated by a marked suppression of a slow Ca(++)-activated potassium current known as IAHP. In the thalamus, application of NE results in the suppression of ongoing rhythmic burst activity and a switch to the single spike firing mode of action potential generation. This effect is mediated through an alpha 1-adrenergic suppression of a resting leak potassium current, IKL, and through a beta-adrenoceptor-mediated enhancement of the hyperpolarization activated cation current Ih(12).

13. Peripheral hormone epinephrine (EPI) and brainstem nuclei
The peripheral hormone epinephrine (EPI) is known to modulate memory for arousing experiences. In the study to test the hypothesis of the actions of EPI on the LC suggest that its mnemonic properties may also be mediated by influencing NE output in the HIPP, dialysate levels of NE were collected from the HIPP of male rats given an i.p. injection of saline that was followed 100 min later by i.p. EPI (0.3 mg/kg). NE levels sampled 20 min after EPI injection were significantly larger than baseline and continued to show significant peaks for 60 min found that the mnemonic effects of EPI reported in a wide range of learning conditions may not be mediated solely by NE release in the amygdala, but may also involve coactivation of the HIPP NE system, according to the study by The University of Virginia(13).

14. Norepinephrine and Cerebellum
Presynaptic modulation of synaptic transmission is the primary function of central nicotinic acetylcholine receptors (nAChRs) in developing and adult brain. nAChR activation regulates release of various neurotransmitters, including norepinephrine (NA). In the study of to determine whether nAChRs modulate NA release in developing cerebellum. In vitro experiments using cerebellar slices examined the effects of nAChR stimulation on release of radiolabeled NA ([3H]NA), showed that these data support recent findings of a possible functional role of nAChRs in regulating cerebellar ontogeny, and provides further support for the role of NA as a neurotrophic factor during development(14).


Sources
(1) http://www.ncbi.nlm.nih.gov/pubmed/874048
(2) http://www.ncbi.nlm.nih.gov/pubmed/23283085
(3) http://www.ncbi.nlm.nih.gov/pubmed/21647395
(4) http://www.ncbi.nlm.nih.gov/pubmed/17707807
(5) http://www.ncbi.nlm.nih.gov/pubmed/16896954
(6) http://www.ncbi.nlm.nih.gov/pubmed/18317800
(7) http://www.ncbi.nlm.nih.gov/pubmed/21669025
(8) http://www.ncbi.nlm.nih.gov/pubmed/2970959
(9) http://www.ncbi.nlm.nih.gov/pubmed/10501450
(10) http://www.ncbi.nlm.nih.gov/pubmed/10691235
(11) http://www.ncbi.nlm.nih.gov/pubmed/9551772
(12) http://www.ncbi.nlm.nih.gov/pubmed/1726028
(13) http://www.ncbi.nlm.nih.gov/pubmed/15219710
(14) http://www.ncbi.nlm.nih.gov/pubmed/12603820


C. Dopamine
1. Acetylcholine-dopamine and CNS disorders
The substantia nigra pars compacta and ventral tegmental area of midbrain dopaminergic nuclei and their respective forebrain and cortical target areas are well established as serving a critical role in mediating voluntary motor control, as evidenced in Parkinson's disease, and incentive-motivated behaviors and cognitive functions, as exhibited in drug addiction and schizophrenia, respectively. According to the study by The University of Memphis, acetylcholine may be as important in regulating dopaminergic transmission. Midbrain dopaminergic cell tonic and phasic activity is closely dependent upon projections from hindbrain pedunculopontine and the laterodorsal tegmental nuclei, which comprises the only known cholinergic inputs to these neurons(1). Other study indicated that combinatorial signaling through dopamine and serotonin (DA and 5-HT) receptors can regulate the brain region- and cell-type specific pMeCP2 in the CNS(1a).

2. The effects of Dopamine and dobutamine on heart rate
In the study of twenty patients with symptomatic CHF (systolic dysfunction) were enrolled. After recording one-hour baseline electrocardiographs (ECGs), patients were randomly selected for either dopamine (4 micrograms/kg/minute, Group A) or dobutamine (4 micrograms/kg/minute, Group B) treatment for three days, conducted by Taichung Veterans General Hospital, found that Dopamine and dobutamine have comparable therapeutic effects in patients with CHF, but low-dose dopamine more favorably affects cardiac autonomic function(2).

3. Dopamine and blood pressure and cerebral hemodynamics
In a Standard meta-analytic techniques, including random and fixed effects models used to calculate combined effect size correlations and significance levels showed that Dopamine administration increases mean and systolic blood pressure in hypotensive preterm infants, and is more effective than dobutamine, colloid or hydrocortisone alone. Dopamine administration is associated with increased CBF, with greater increases in CBF in hypotensive than in normotensive preterm infants. Dopamine is not associated with a greater incidence of adverse effects than other therapies used to treat hypotension(3).

4. Dopamine in schizophrenia and Parkinson's disease
The neurotransmitter dopamine (DA) and the dopaminergic neurones play an important role in schizophrenia and Parkinson's disease (PD). According to the study byUniversity of Southampton, Royal South Hants Hospital, A decrease in DA in the substantia nigra of the brain has been implicated as the cause of PD. By contrast, it is argued that a functional excess of DA or oversensitivity of certain DA receptors is one of the causal factors in schizophrenia(4).

5. Dopamine and Attention deficit hyperactivity disorder
Through neuromodulatory influences over fronto-striato-cerebellar circuits, dopamine and noradrenaline play important roles in high-level executive functions often reported to be impaired in attention-deficit/hyperactivity disorder (ADHD). According to the study by University of Cambridge, Cambridge, United Kingdom, Medications used in the treatment of ADHD (including methylphenidate, dextroamphetamine and atomoxetine) act to increase brain catecholamine levels. However, the precise prefrontal cortical and subcortical mechanisms by which these agents exert their therapeutic effects remain to be fully specified(5).

6.  Dopamine  and restless legs syndrome
Restless legs syndrome (RLS) is a common neurological disorder causing considerable impairment to daily living. In a study to assess the reporting quality of published RCTs according to the Consolidated Standards of Reporting Trials (CONSORT) statement and to synthesize the study results in terms of efficacy and tolerability to inform the clinical management of RLS, showed that
DAs were significantly more efficacious in the treatment of RLS compared with placebo(6).

7. Dopamine  receptors and cognitive and motor function
According to the study by, Columbia University College of Physicians & Surgeons, repeated administration of this methamphetamine (5 mg/kg administered three times at 2-h intervals) leads to a transition from horizontal hyperlocomotion to excessive orofacial stereotypy (taffy pulling) only in wild type and D3 mutants. In both genotypes, this transition is accompanied by a change in the relative ratios of striatal neuronal activation in two neurochemically distinct compartments, with striosomal neuronal activation exceeding that of the striatal matrix during stereotypy. Both the stereotypic response to METH and the associated predominant activation of neurons located in striosomes require D2-receptor expression. These studies indicate a differential requirement for D1- and D2-like receptor activation in mediating the effects of METH on cognitive and motor function(7). Other indicated that the 'D3 Dopamine Receptor Hypothesis' suggests D3 antagonists could prevent sensitization, and may interrupt the development of psychosis when administered during the prodromal phase of psychotic illness(7a).

8.  Dopaminergic neurotransmission and behavioral changes
Dehydration is a powerful stimulus causing disequilibrium in homeostasis of water and electrolytes resulting from depletion in total body water. In the study of desert animals allows improved understanding about water balance and resistance to dehydration and associated behavioral changes, including those related to voluntary movements, showed that dehydration is able to increase dopaminergic neurotransmission, which might be involved in generating hyperactivity in this desert animal(8).

9. Dopamine and motivation
Dopamine (DA) D2 receptors expressed in DA neurons (D2 autoreceptors) exert a negative feedback regulation that reduces DA neuron firing, DA synthesis and DA release. According to the mice study by Consejo Nacional de Investigaciones Científicas y Técnicas, midbrain DA neurons from mice deficient in D2 autoreceptors (Drd2(loxP/loxP); Dat(+/IRES-cre), referred to as autoDrd2KO mice) lacked DA-mediated somatodendritic synaptic responses and inhibition of DA release. AutoDrd2KO mice displayed elevated DA synthesis and release, hyperlocomotion and supersensitivity to the psychomotor effects of cocaine. The mice also exhibited increased place preference for cocaine and enhanced motivation for food reward. Our results highlight the importance of D2 autoreceptors in the regulation of DA neurotransmission and demonstrate that D2 autoreceptors are important for normal motor function, food-seeking behavior, and sensitivity to the locomotor and rewarding properties of cocaine(9).

10. Dopimine in punishment and reward
In the study of Variations of extracellular dopamine (DA(ext)) levels in prefrontal cortex were assessed by in vivo microdialysis, found that a benzodiazepine-sensitive activation of mesoprefrontal DA neurones is induced by exposure to novel stressful surroundings and by food availability and consumption. The fact that cortical DA(ext) levels remained unchanged in rats that exerted complete control upon negative stimuli indicates that an activation of the mesoprefrontal DA system is not required for punishment-induced behavioural blockade(10).

11. Dopamine and the inhibition of prolactin production
Transcription of the prolactin gene is dynamically controlled by positive and negative hormone signals that target the regulatory promoter region. According to the study by University of Toronto, dopamine D2 receptor activation and inhibition of MAPK (ERK1/2) signaling lead to rapid deacetylation of histones at the genomic prolactin promoter. Recruitment of specific HDAC/ corepressor complexes may be an important mechanism for repression of target gene transcription by Gi/o-coupled receptors(11).

12. Dopamine and sleep behaviour disorder (IRBD)
 In a prospective study, 20 patients with IRBD (mean age 70·55 years [SD 6·02]) underwent serial DAT imaging with (123)I-2β-carbomethoxy-3β-(4-iodophenyl)-N-(3-fluoropropyl)-nortropane ((123)I-FP-CIT) SPECT at baseline and again after 1·5 years and 3 years; 20 age-matched and sex-matched control participants (69·50 years [6·77]) underwent imaging at baseline and 3 years, showed that in patients with  sleep behaviour disorder (IRBD), serial (123)I-FP-CIT SPECT shows decline in striatal tracer uptake that reflects progressive nigrostriatal dopaminergic dysfunction. Serial (123)I-FP-CIT SPECT can be used to monitor the progression of nigrostriatal deficits in patients with IRBD, and could be useful in studies of potential disease-modifying compounds in these patients(12).

13. Dopamine in depression
According to the study by New York State Psychiatric Institute, clinical evidence includes alterations in depressive symptoms with aging (concomitant with possible changes in dopamine metabolism), potential dopaminergic involvement in several subtypes of depression, similarities between some of the symptoms of Parkinson's disease and those of depression (including psychomotor retardation and diminished motivation), and potential dopaminergic abnormalities in seasonal mood disorder. The biochemical evidence in patients with depression derives from studies of homovanillic acid, a dopamine metabolite, indicating diminished dopamine turnover(13).

14. Dopamine and Mood disorder
Dysfunction in the monoamine systems of serotonin (5-HT), norepinephrine (NE) and dopamine (DA) may causally be related to major depressive disorder (MDD). According to the study by University of Amsterdam,  monoamine depletion studies demonstrate decreased mood in subjects with a family history of MDD and in drug-free patients with MDD in remission, but do not decrease mood in healthy humans. Although depletion studies usefully investigate the etiological link of 5-HT and NE with MDD, they fail to demonstrate a causal relation. They presumably clarify a vulnerability trait to become depressed. Directions for further investigation of this vulnerability trait are proposed(14).

15. Dopamine in the regulation of cognition and attention
Dopamine (DA) acts as a key neurotransmitter in the brain.. In the early stages of Parkinson's disease (PD), alterations of executive functions also suggest a role for DA in regulating cognitive functions. Some other diseases, which can also involve DA dysfunction, such as schizophrenia or attention deficit hyperactivity disorder (ADHD) in children, as shown from the ameliorative action of dopaminergic antagonists and agonists, respectively, also show alteration of cognitive functions. According to the study by Université de La Méditerranée, a correlation exists between DA innervation and expression of cognitive capacities. Altering the dopaminergic transmission could, therefore, contribute to cognitive impairment(15).

16. Dopamine and working memory
There is accumulating evidence that training working memory (WM) leads to beneficial effects in tasks that were not trained. According to the study by Department of Neuroscience and Stockholm Brain Institute, Karolinska Institutet, variation in the dopamine transporter gene (DAT1) influences improvements in WM and fluid intelligence in preschool-age children following cognitive training. Our results emphasize the importance of the role of dopamine in determining cognitive plasticity(16).

17. Dopamine and learning
Individuals make choices and prioritize goals using complex processes that assign value to rewards and associated stimuli. According to the University of Michigan in rat study, dopamine acts selectively in a form of stimulus-reward learning in which incentive salience is assigned to reward cues. In individuals with a propensity for this form of learning, reward cues come to powerfully motivate and control behaviour. This work provides insight into the neurobiology of a form of stimulus-reward learning that confers increased susceptibility to disorders of impulse control(17).

18. Dopamine on cellular and humoral immune responses
In vitro and in vivo studies have demonstrated that apart from its hemodynamic action dopamine can modulate immune responses. According to the study by Institut für Anästhesiologie und Operative Intensivmedizin, Universitätsklinikum, dopamine reduces the synthesis of proinflammatory and induces the synthesis of anti-inflammatory mediators. Dopamine inhibits neurohormone synthesis, lymphocyte proliferation and platelet aggregation. It reduces the phagocytic activity of neutrophils and induces apoptosis. Particularly with regard to sepsis, where high serum dopamine levels are reached by enhanced endogenous production, exogenous application and impaired clearance, this immunomodulation may have a clinical impact(18).

19. Dopamine and Salience
What roles do mesolimbic and neostriatal dopamine systems play in reward? Do they mediate the hedonic impact of rewarding stimuli? Do they mediate hedonic reward learning and associative prediction? According to the study by University of Michigan,  instead that dopamine may be more important to incentive salience attributions to the neural representations of reward-related stimuli. Incentive salience, we suggest, is a distinct component of motivation and reward. In other words, dopamine systems are necessary for 'wanting' incentives, but not for 'liking' them or for learning new 'likes' and 'dislikes'(19).

20. Dopamine and human idea generation and creative drive
According to the study of FRONTOTEMPORAL AND DOPAMINERGIC CONTROL OF IDEA GENERATION AND CREATIVE DRIVE by Alice W. Flaherty , mesolimbic dopamine influences novelty seeking and creative drive. Dopamine agonists and antagonists have opposite effects on goal-directed behavior and hallucinations. Creative drive is not identical to skill—the latter depends more on neocortical association areas. However, drive correlates better with successful creative output than skill does(20).

21. Dopamine and  natriuresis (sodium loss) in the kidneys
Diuretic and natriuretic effects of renal dopamine (DA) are well established. In the study of male Wistar rats to determine the pattern of UDAV during volume expansion and to characterize the involvement of monoamine-oxidase (MAO) and aromatic amino-acid decarboxylase (AADC) , found that in C rats UDAV (ng/30 min/100g BWt) increased in the first 30 min expansion from 11.5 +/- 1.20 to 21.8 +/- 3.10 (p < 0.05) and decreased thereafter. IMAO showed a similar pattern but significantly higher than C at 30 min expansion (32.5 +/- 2.20, p < 0.05). IMAO greatly reduced MAO activity from 8.29 +/- 0.35 to 1.1 +/- 0.03 nmol/mg tissue/hour and significantly increased diuresis and natriuresis over controls. BNZ abolished the early UDAV peak to 3.2+/-0.72 (p < 0.01) and though, UDAV increased over C after 60 min expansion, natriuresis and diuresis were diminished by BNZ treatment. Results indicate that an increment in renal DA release into urine occurs early in expansion and in a peak-shaped way.(21).

22. Dopamine and obesity
According to the study by Institute for Translational Medicine and Therapeutics, University of Pennsylvania, chronic intake of high-fat (HF) diet is known to alter brain neurotransmitter systems that participate in the central regulation of food intake. Dopamine (DA) system changes in response to HF diet have been observed in the hypothalamus, important in the homeostatic control of food intake, as well as within the central reward circuitry [ventral tegmental area (VTA), nucleus accumbens (NAc), and pre-frontal cortex (PFC)], critical for coding the rewarding properties of palatable food and important in hedonically driven feeding behavior(22).

23. Dopamine and noradrenaline on cardiovascular function
In the study to assess the short-term haemodynamic effects of terminating dopamine and/or a combination of noradrenaline and nitroglycerin infusions in 21 patients in acute respiratory failure, found that off treatment, stroke index and cardiac index decreased significantly from 40.2 to 36.9 ml m-2 (P < 0.02) and from 3.80 to 3.42 litres m-2 (P < 0.02), respectively. Cardiac filling pressures decreased significantly and systemic vascular resistance increased, when infusions were stopped. As to heart rate, mean arterial pressure, mean pulmonary arterial pressure, right and left ventricular ejection fraction there were no significant changes between the data obtained during and off treatment. Although the haemodynamic status was significantly better during treatment with dopamine and/or noradrenaline-nitroglycerin in some respects, the overall beneficial effects of inotropic support were much less than anticipated(23).

24. Dopamine and Immunoregulatory
The neurotransmitter dopamine (DA) is an important molecule bridging the nervous and immune systems. According to the study by the Ohio State University, Columbus, DA through autocrine/paracrine manner modulates the functions of immune effector cells by acting through its receptors present in these cells. DA also has unique and opposite effects on T cell functions. Although DA activates naïve or resting T cells, but it inhibits activated T cells. In addition, changes in the expression of DA receptors and their signaling pathways especially in T cells are associated with altered immune functions in disorders like schizophrenia and Parkinson's disease. These results suggest an immunoregulatory role of DA(24).

25. Dopamine toxicity
Parkinson's disease (PD) is a common age-related neurodegenerative disorder. Dopamine neurotoxicity, mediated through oxidative stress, is implicated in disease pathogenesis. According to the study of using 6-hydroxydopamine hemiparkinsonian mouse model and transgenic DJ-1 knockout mice by the Felsenstein Medical Research Centre, Tel Aviv University, our experimental data point to a novel potential protective function of DJ-1, which could be used as a therapeutic tool(25).

Sources
(1) http://www.ncbi.nlm.nih.gov/pubmed/20370804
(1a) http://www.ncbi.nlm.nih.gov/pubmed/21956448
(2) http://www.ncbi.nlm.nih.gov/pubmed/9614778
(3) http://www.ncbi.nlm.nih.gov/pubmed/21273985
(4) http://www.ncbi.nlm.nih.gov/pubmed/9849144
(5) http://www.ncbi.nlm.nih.gov/pubmed/21550021
(6) http://www.ncbi.nlm.nih.gov/pubmed/20206780
(7) http://www.ncbi.nlm.nih.gov/pubmed/15542707
(7a) http://www.ncbi.nlm.nih.gov/pubmed/11566480
(8) http://www.ncbi.nlm.nih.gov/pubmed/22847013
(9) http://www.ncbi.nlm.nih.gov/pubmed/21743470
(10) http://www.ncbi.nlm.nih.gov/pubmed/11420078
(11) http://www.ncbi.nlm.nih.gov/pubmed/15731170
(12) http://www.ncbi.nlm.nih.gov/pubmed/21802993
(13) http://www.ncbi.nlm.nih.gov/pubmed/8099801
(14) http://www.ncbi.nlm.nih.gov/pubmed/17389902
(15) http://www.ncbi.nlm.nih.gov/pubmed/12126656
(16) http://www.ncbi.nlm.nih.gov/pubmed/22103304
(17) http://www.ncbi.nlm.nih.gov/pubmed/21150898
(18) http://www.ncbi.nlm.nih.gov/pubmed/15997388
(19) http://www.ncbi.nlm.nih.gov/pubmed/9858756
(20) http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2571074/
(21) http://www.ncbi.nlm.nih.gov/pubmed/20228026
(22) http://www.ncbi.nlm.nih.gov/pubmed/22220805
(23) http://www.ncbi.nlm.nih.gov/pubmed/8174529
(24) http://www.ncbi.nlm.nih.gov/pubmed/19896530
(25) http://www.ncbi.nlm.nih.gov/pubmed/22887838

Tuesday, January 1, 2013

Thyroid hormone

 Thyroid hormone (triiodothyronine (T3) and thyroxine (T4)), produced by the thyroid gland, plays an important role in regulation of metabolism, including directly boosts energy metabolism and triggers rapid protein synthesis and regulates mitochondrial gene transcription, etc. Iodine is necessary for the production of T3 and T4, deficiency of Iodine can lead to enlarge thyroid grand and goitre.

1. Excessive iodine intake (or deficiency) and goitre 
In the study to investigate the associations between intakes of iodine and water chemicals and the thyroid gland status of schoolchildren living in the coastal city of Port Sudan, researchers at 1 Sudan Atomic Energy Commission, Khartoum, found that the coastal city of Port Sudan is a goitre-endemic area. In contrast to other Sudanese cities in which endemic goitre is related to iodine deficiency, goitre in Port Sudan is associated with iodine excess. Water chemicals seemed to have no effects on thyroid status(1)

2.  Thyroid hormones and lipid metabolism
Thyroid hormone (T3) and its receptor (TR) have the diverse effects on the lipid metabolism and hypothyroidism causes hypercholesterolaemia characterized by increased levels of low-density ripoproteins (LDL). In the study by Hamamatsu University School of Medicine, researchers described that the existence of the complex cross-talks in the lipid metabolism between TR and other nuclear hormone receptors including peroxisome proliferator -activated receptors (PPARs), liver X receptor alpha (LXRalpha) and farnesoid X receptors (FXRs). Understanding for the function of TRs and other nuclear factors may provide the new approach to the control of hypercholesterolaemia(2).

3. Thyroid hormones and Carbohydrate metabolism
 In the study to evaluate Carbohydrate metabolism in nine patients with subacute thyroiditis before treatment and after recovery, showed that Glucose area during oral glucose tolerance test was significantly correlated with the elevated thyroxine (r = 0.8, p less than 0.01), and triidothyronine (r = 0.66, p less than 0.05). The results indicated the importance of follow-up study of glucose tolerance in subacute thyroiditis as well as similarity of carbohydrate metabolism abnormalities in hyperthyroidism(3).

4. Insulin resistance in hyperthyroidism
Insulin-like growth factor binding-protein-1 (IGFBP-1) has a role in glucose homeostasis and is present at high concentrations in hyperthyroidism. In the study to investigate the relationship between IGFBP-1 concentration and glucose homeostasis in hyperthyroidism, showed that in hyperthyroidism thyroid hormones directly increase fasting IGFBP-1 concentration but acute regulation of IGFBP-1 by insulin is normal and that elevated fasting phosphorylated IGFBP-1 concentration is associated with insulin resistance(4).

5. Thyroid hormones (TH) and brain development
Thyroid hormones (TH) are essential for normal brain development. Even subclinical hypothyroidism experienced in utero can result in neuropsychological deficits in children despite normal thyroid status at birth, researchers summerized that epidemiological, preclinical and animal research has clearly identified the critical role of TH in brain development. Additional work is required to understand the impact of low level perturbations of the thyroid axis to evaluate the risk associated with environmental contaminants with thyroid action(5).

6. Thyroid autoimmunity (TA) and heigh of Children
In the study to assess the association between pancreatic and thyroid autoimmunity (TA) and determine impact of thyroid antibodies on statural growth in Seventy-two children with type 1 diabetes mellitus (TIDM) and no clinical evidence of thyroid disorders, showed that patients with TA had significantly higher prevalence of GADA and IA2A and significantly higher A1c vs. patients without TA. Our data suggest significant association between TA and height in children with T1DM. SDS was independently associated with diabetes duration and TSH(6).

7. Thyroid hormone and the cardiovascular system
Increased or reduced action of thyroid hormone on certain molecular pathways in the heart and vasculature causes relevant cardiovascular derangements. It is well established that overt hyperthyroidism induces a hyperdynamic cardiovascular state (high cardiac output with low systemic vascular resistance), which is associated with a faster heart rate, enhanced left ventricular (LV) systolic and diastolic function, and increased prevalence of supraventricular tachyarrhythmias - namely, atrial fibrillation - whereas overt hypothyroidism is characterized by the opposite changes.In the study of Effects of thyroid hormone on the cardiovascular system, researchers suggested that
administration of thyroid hormone or its analogue 3,5-diiodothyropropionic acid greatly benefits these patients, highlighting the potential role of thyroid hormone treatment in patients with acute and chronic cardiovascular disease(7).

8. Thyroid hormone and Delayed development
In the study to investigate the phenotype of TTR(Transthyretin (TTR) is a TH distributor protein in the circulatory system and is the only TH distributor protein synthesised in the central nervous system) null mice during development by The University of Melbourne, showed that TTR null mice also displayed a delayed suckling-to-weaning transition, decreased muscle mass, delayed growth and retarded longitudinal bone growth. In addition, ileums from postnatal day 0 (P0) TTR null mice displayed disordered architecture and contained fewer goblet cells than wild type. Protein concentrations in cerebrospinal fluid from P0 and P14 TTR null mice were higher than in age-matched wild type mice(8).

9. Thyroid disease in pregnancy
Thyroid diseases are common in women of childbearing age and it is well known that untreated thyroid disturbances result in an increased rate of adverse events, particularly miscarriage, preterm birth and gestational hypertension. According to the study by Division of Endocrinology, "V. Fazzi" Hospital, Lecce, overt dysfunctions (hyper- or hypothyroidism) have deleterious effects on pregnancy, subclinical disease, namely subclinical hypothyroidism, has still to be conclusively defined as a risk factor for adverse outcomes. Additionally, other conditions, such as isolated hypothyroxinemia and thyroid autoimmunity in euthyroidism, are still clouded with uncertainty regarding the need for substitutive treatment(9).

10. Thyroid disease in pregnancy and childhood
Thyroid function in pregnancy is characterised by a T4 surge at 12 weeks declining thereafter. Serum thyroid hormone concentrations fall in the second half of pregnancy. According to the study by Cardiff University School of Medicine, Fetal brain development depends on T4 transport into the fetus which in turn depends on sufficient maternal iodine supply. There is current concern that adequate iodisation is not present in large parts of Europe. There is increasing evidence that thyroid autoimmunity is associated with fetal loss but the mechanism is unclear and therapy requires carefully conducted studies. While hyperthyroidism in pregnancy is uncommon, effects on both mother and child are critical if untreated. Screening for thyroid function in early pregnancy and levothyroxine intervention therapy for maternal subclinical hypothyroidism should be considered but evidence is awaited. Screening for both thyroid dysfunction and thyroid antibodies ideally at a preconception clinic but certainly in early gestation is recommended(10).

11. Thyroid hormone stimulates protein synthesis
According to the study by North Shore-Long Island Jewish Health System, Thyroid hormones affect cardiac growth and phenotype; however, the mechanisms by which the hormones induce cardiomyocyte hypertrophy remain uncharacterized. Tri-iodo-L-thyronine (T3) treatment of cultured cardiomyocytes for 24 h resulted in a 41 +/- 5% (p < 0.001) increase in [(3)H]leucine incorporation into total cellular protein. This response was abrogated by the phosphatidylinositol 3-kinase (PI3K) inhibitor, wortmannin. Co-immunoprecipitation studies showed a direct interaction of cytosol-localized thyroid hormone receptor TRalpha1 and the p85alpha subunit of PI3K. T3 treatment rapidly increased PI3K activity by 52 +/- 3% (p < 0.005)(11).  

12. Thyroid hormone and skeletal growth
Understanding how bone growth is regulated by hormonal and mechanical factors during early growth periods is important for optimizing the attainment of peak bone mass to prevent or postpone the occurrence of fragility fractures later in life. According to the study by Musculoskeletal Disease Center, Loma Linda VA HealthCare System , there is an important period prior to puberty when the effects of GH are surprisingly small and TH plays a critical role in the regulation of skeletal growth. Daily administration of T3/T4 during days 5 to 14, the time when serum levels of T3 increase rapidly in mice, rescued the skeletal deficit in TH-deficient mice but not in mice lacking both TH and GH. However, treatment of double-mutant mice with both GH and T3/T4 rescued the bone density deficit. Increased body fat in the TH-deficient as well as TH/GH double-mutant mice was rescued by T3/T4 treatment during days 5 to 14(12).

13. Triiodothyronine stimulates glucose transport in bone cells
In the study to evaluate whether 3,3',5-triiodo-l-thyronine (T₃) stimulates the uptake of glucose in osteoblastic cells, PyMS (a cell line derived from rat bone) cells were kept in serum-free culture medium and treated with T₃, found that T₃ did not influence the cell number but slightly (1.3-fold) increased the protein content of the cell cultures.  2DG ([1-¹⁴C]-2-deoxy-D: -glucose)uptake was low in serum-deprived cell cultures and was increased by T₃ (up to 2.5-fold at 1 nmol l⁻¹ after 4 days) in a dose- and time-dependent manner. Triiodothyronine at 1 nmol l⁻¹ increased GLUT1 and GLUT3 abundance in membranes. Therefore, increased glucose uptake induced by T₃ in osteoblasts may be mediated by the known high-affinity glucose transporters GLUT1 and GLUT3(13).

14. Thyronamines and body temperature and heart rate
 The thyronamines which are decarboxylated thyroid hormones initiating physiological actions like lowering body temperature and heart rate, thereby acting in opposite direction to the classical thyroid hormones. So far it is believed that thyronamines function via the activation of a G-protein coupled receptor, TAAR1. The objective of this review is to summarise the recent findings in thyroid hormone synthesis and action and to discuss their implications for diagnosis of thyroid disease and for treatment of patients, according to the study by Institute of Experimental Pediatric Endocrinology, Charité Universitätsmedizin Berlin(14).

15. Effect of iodine deficiency and cold exposure on thyroxine 5'-deiodinase activity
In the study to measure the thyroxine 5'-deiodinase I (T(4)5'D-I) activity in thyroid, liver, and kidney and thyroxine 5'-deiodinase II (T(4)5'D-II) activity in brown adipose tissue (BAT) in rats on a low-iodine diet (LID)  and to test the possibility that increased deiodinase activity in these tissues might contribute to the maintenance of ther serum 3,5,3'-triiodothyronine (T3) level, found that  increased thyroxine (T4)-to-T3 conversion in the greatly enlarged thyroids of LID rats contributed to the maintenance of serum T3. T(4)5'D-II activity in BAT was markedly increased in LID rats and was further greatly increased on cold exposure(15).

16. Chemiluminescent and respiratory responses related to thyroid hormone-induced liver oxidative stress
In the study of Chemiluminescent and respiratory responses  in the liver of rats treated with 0.1 mg of triiodothyronine (T3)/kg for 1 to 7 days, showed that  the calorigenic response in the hyperthyroid state is accompanied by the development of an hepatic oxidative stress characterized by enhanced spontaneous chemiluminescence, enhanced NADPH-dependent microsomal respiration and a decreased antioxidant cellular activity(16).

17. Oxidative stress and thyroid hormones
The liver metabolizes the thyroid hormones and regulates their systemic endocrine effects so liver disease could affect thyroid hormone metabolism. In the study to investigate serum levels of oxidative stress and antioxidant in liver diseases as prognostic markers and know the importance of these antioxidants level in relation to thyroid hormones, researchers at the Ain Shams University, found that measurement of the total T(3), NO, MDA, GSH reduced and GSHPx as biomarkers for liver diseases might be a beneficial tool, helping in monitoring the state of liver disease patients.(17).

18. Radioiodine treatment and oxidative stress in thyroidectomised patients
Post-operative radioiodine treatment of differentiated thyroid cancer occupies a well determined place in the treatment policy of this disease. In the study to measure erythrocyte malondialdehyde (MDA) levels, as a marker of lipid peroxidation, erythrocyte reduced glutathione (GSH) levels and activities of GSH-Peroxidase and GSH-Reductase as antioxidants, showed that erythrocyte MDA levels were significantly higher, and erythrocyte GSH levels and activities of GSH-related enzymes were significantly lower in thyroidectomised patients after surgery than in healthy controls. Additionally, according to their thyroid hormone levels the patients had hypothyroidism at this time. In patients 2 days after radioiodine treatment both MDA and GSH levels and GSH-related enzyme activities were significantly increased when compared to their own initial levels(18).

19. Oxidant/antioxidant balance in patients with thyroid cancer
In the study to compare the antioxidant enzyme activities of superoxide dismutase (SOD), glutathione peroxidase (GSH-Px) and the levels of lipid peroxidation product malondialdehyde (MDA) in blood samples of thyroid cancer patients compared to healthy controls, found that tThe superoxide dismutase does not seem to change with thyroid cancer and thyroidectomy but both antioxidant glutathione peroxidase and lipid peroxidation product malondialdehyde do. These preliminary findings may point out oxidant/antioxidant imbalance associated with thyroid cancer.(19).

20. Metabolic parameters and thyroid hormones and the level of gastric peptides in children with autoimmune thyroid diseases
Overweight and diseases connected with it are increasing problems in children and adults. In the sudy by Medical University of Białystok, to analyze the relationship between lipid-carbohydrate metabolism parameters and thyroid hormones and the level of gastric peptides (ghrelin and obestatin) in young patients with Graves' disease, Hashimoto's thyroiditis and in children with simple goiter, showed that the disturbances in carbohydrate parameters in thyroid diseases have an essential effect on change of hormone-controlled appetite: ghrelin (in hyperthyroidism) and obestatin (in Subclinical hypothyroidism)(20).

21. Analysis of serum adiponectin, resistin and leptin levels in children and adolescents with autoimmune thyroid diseases
Leptin, adiponectin and resistin, mainly produced by adipocytes, play a major role in body weight regulation. In the study  to analyze the levels of leptin, adiponectin and resistin in children with untreated Graves' disease, subclinical hypothyroidism in Hashimoto's thyroiditis and in children with simple goiter, researchers at the Medical University of Białystok, showed that disturbances in thyroid hormones in thyroid diseases have an essential effect on the levels of adiponectin and resistin released by adipose tissue(21).

22. Serum antibodies against three eye muscle antigens and the connective tissue antigen collagen XIII in patients with Graves' disease
In the study cohort consisted of patients with Graves' hyperthyroidism with and without ophthalmopathy, controls patients with other thyroid or other autoimmune disorders and healthy subjects, by The University of Sydney, Nepean Hospital, found that prevalences of positive antibody tests to calsequestrin (75.0%) and collagen XIII (43.8%) were significantly greater in Graves' disease (GD) patients with ophthalmopathy than in healthy subjects, whereas modest significance was demonstrated with antibodies against Fp, but not G2s. Significantly greater serum levels of antibodies against calsequestrin, G2s, and collagen XIII, but not Fp, were found in GD patients with ophthalmopathy compared to control patients without eye disease and healthy subjects(22).

23. Serum levels of thyroid hormones in liver diseases
In the study to measure the concentrations of thyroid hormones and thyrotropin (TSH) in sera of clinically euthyroid patients with various liver diseases and compared with normal controls, found that the marked alterations of peripheral conversion of thyroxine (T4) to rT3 or T3 may be found only in a state of decompensated liver cirrhosis among the various liver diseases(23).

24. Thyroid hormones and TSH in chronic active hepatitis
The study of a  total and free circulating thyroid hormones, rT3, TBG and TSH behaviour on chronic liver disease in 11 subjects with cirrhosis of the liver with ascites(C.E.) and in 6 subjects with chronic active hepatitis (E.C.A.) in comparison with 15 healthy and euthyroid controls, indicated that serum T3,FT3,T4 and FT4 levels were decreased significantly and serum rT3 values increased significantly both in the subjects with C.E. and in patients with E.C.A. Moreover no significantly changes of TSH and TBG levels has been found in 3 groups studied. These data suggest that the alteration of circulating thyroid hormones in chronic liver disease, may represent a compensatory way of reducing the patient's metabolic requirements(24).

25. Transient Willis-Ekbom's disease (restless legs syndrome) during pregnancy
Willis-Ekbom's disease (WED), formerly called restless legs syndrome, is more common in pregnant than in non-pregnant women, implying that the physiological and biochemical changes during pregnancy influence its development. Researchers at the Faculdade de Medicina de Jundiaí, Rua Francisco Telles, found that during pregnancy, the activity of the thyroid axis is enhanced to meet the increased demand for thyroid hormones during this state. Dopamine is a neuroendocrine hormone that diminishes the levels of thyrotropin and consequently of thyroxine, and one of the roles of the dopaminergic system is to counteract the activity of thyroid hormones. When the activity of dopamine is not sufficient to modulate thyroid hormones, WED may occur(25).

26. Maternal hyperthyroidism and the pattern of expression of cardiac renin-angiotensin system components
Changes in perinatal environment can lead to physiological, morphological, or metabolic alterations in adult life. In the study to evaluate the effect of maternal hyperthyroidism on cardiac RAS components in pups during development, showed that Maternal hyperthyroidism is associated with alterations in fetal development and altered pattern of expression in RAS components, which in addition to cardiac hypertrophy observed on GD20 may represent an important predisposing factor to cardiovascular diseases in adult life(26).

27. Vitamin E management of oxidative damage-linked dysfunctions of hyperthyroid tissues
Thyroid hormones affect growth, development, and metabolism of vertebrates, and are considered the major regulators of their homeostasis and elevated circulating levels of thyroid hormones are associated with modifications in the whole organism (weight loss and increased metabolism and temperature) and in several body regions. Indeed, tachycardia, atrial arrhythmias, heart failure, muscle weakness and wasting, bone mass loss, and hepatobiliary complications are commonly found in hyperthyroid animals and humans. In the study of vitamin E and oxdative linked dysfunctions of huperthroid tissues, showed that vitamin E has a primary function to destroy peroxyl radicals, thus protecting polyunsaturated fatty acids biological membranes from oxidative damage. However, results are also available indicating that protective vitamin E effects against oxidative damage can be obtained even through different mechanisms(27).

28. Progesterone Therapy increases Free Thyroxine Levels
Thyroid hormones and progesterone both influence core temperature, metabolism and are crucial during pregnancy. In the study to discover whether progesterone therapy caused changes in thyroid physiology compared with placebo, researchers at the University of British Columbia and Vancouver Coastal Health Research Institute, found that progesterone caused a significant FreeT4 increase that was discovered during this randomized controlled VMS trial. The clinical importance of this increased FreeT4 level remains to be documented(28).

29.  Resistance to Thyroid Hormone and Episodes of Thyrotoxicosis
In the study of a 44-year-old Japanese woman with resistance to thyroid hormone, which was confirmed by the P453A mutation in the thyroid hormone receptor ß (TRß) gene, showed a slight elevation of the basal levels of thyroid hormones, which indicated that her pituitary resistance to thyroid hormone was mild. She experienced a slight exacerbation of hyperthyroxinemia concomitant with TSH suppression, showed that Mild pituitary resistance to thyroid hormone can be overcome by slight exacerbation of hyperthyroxinemia during mild thyrotoxicosis. When pituitary resistance is severe and TSH is not suppressed, thyrotoxicosis may be overlooked(29).

30. Thyroid hormone receptors in health and disease
Thyroid hormones (TH) play a key role in energy homeostasis throughout life. In the study conducted by Academic Medical Centre, University of Amsterdam, Amsterdam, The Netherlands, found that thyroid hormone has to be transported into the cell, where it can bind to the thyroid hormone receptor (TR) in the nucleus to exert its effect on cellular gene-transcription. Mutations in both the THRA and THRB gene have been described, each inducing a characteristic phenotype clearly showing the selective effect of an excess or shortage of thyroid hormone in specific TRα and TRβ regulated organs. Profound changes in thyroid hormone metabolism occur during a variety of non-thyroidal illnesses, each associated with reduced TR expression in a tissue-specific manner(30).

31. Osteoarthritis (OA), metabolic OA, and hormones
In the study to define a subtype of osteoarthritis (OA), metabolic OA, which is dependent on an unhealthy phenotype with  peer-reviewed research articles and reviews were reviewed and summarized. Only literature readily available online, either by download or by purchase order, was included, found that cartilage is a central tissue of joint health. Thus, the joint, more specifically the cartilage, may be considered a target of endocrine function in addition to the well-described traditional risk factors of disease initiation and progression such as long-term loading of the joint due to obesity. Metabolic syndrome affects a range of tissues and may in part be molecularly described as a dysregulation of cytokines, adipokines, and hormones (eg, estrogen and thyroid hormone)(31).

32. Thyrotropin secreting pituitary adenoma in a child
There is a report of a case of 11-year old boy with Type 1 Autoimmune Polyglandular Syndrome and thyrotropin secreting pituitary adenoma, which was diagnosed by elevated TSH and thyroid hormones levels and MRI signs of pituitary tumor and without clinical symptoms of hyperthyroidism. He underwent partial resection of the tumor via transnasal approach and subsequent radiation therapy. Consequently 1 year after XRT patient developed growth hormone deficiency, 3.5 years later patient became euthyroid, and 5.5 years after treatment - hypothyroid, acccording to the study in Russia with no author listed(32).

33. phytosterol-containing treatments and throid gland activity
In the study of the effect of supplementation of probiotics and phytosterols alone or in combination on serum and hepatic lipid profiles and thyroid hormones of hypercholesterolemic rats, researchers at the epartment of Food Science, Al-Balqa Applied University, found that the phytosterol-containing treatment. The phytosterol-containing treatments induced the increased activity of thyroid glands, as evident by elevated levels of serum total thyroxine, total triiodothyronine, and free triiodothyronine.(33).

34. Reduced cerebrospinal fluid level of thyroxine in patients with Alzheimer's disease
There is an association between thyroid hormones in the central nervous system and Alzheimer's disease (AD). In the study to determine thyroid hormone levels in serum and cerebrospinal fluid (CSF) in a well-defined homogeneous mono-center population, showed that  The CSF level of total T4 was decreased in patients with AD and other dementias compared to SMCI (both P=0.01) and healthy controls (both P=0.001), whereas CSF levels of TSH and total T3 were unchanged. In the total study population, CSF total T4 level correlated positively with MMSE score (r=0.26, P<0.05) and negatively with CSF total-tau (T-Tau) level (r=-0.23, P<0.05). Patients with AD as well as other dementias had signs of mild brain hypothyroidism, which could only to a small extent be detected in serum values(34).

35. Serum copper levels in benign and malignant thyroid diseases
In the study to examine the changes in serum copper (Cu) levels in benign and malignant thyroid disease in humans in 47 papillary thyroid cancer and 43 benign multinodular goitre patients who underwent total thyroidectomy and 37 healthy control subjects, showed that in our small groups serum Cu levels increased in malignant thyroid patients and decreased in the benign group(35).

36. THYROID DYSFUNCTION IN PREGNANT WOMEN
In the study to measure the levels of thyroid-stimulating hormone (TSH), free thyroxine (fT4), and thyroperoxidase antibodies (TPO-Ab) in 951 women at different gestational age of pregnancy (Trimester-specific reference ranges for TSH were used to classify pregnant women into five groups: 1) Overt hypothyroidism (OH); 2) Subclinical hypothyroidism (SCH); 3) Isolated hypothyroxinemia (IH); 4) Low TSH (isolated or associated with high fT4); and 5) Normal), found that 117 women (12.3%) had hypothyroidism and 25 (2.6%) had low TSH. The prevalence of both OH and SCH was higher in the high-risk group than in the low-risk group, but 17.9% of women with hypothyroidism were classified at low-risk. A family history of thyroid disorders and TPO-Ab positivity increased the risk of SCH. Using non-pregnant reference range for TSH, 10.6% of women were misclassificated(36).

37. Iodine and thyroid
Approximately about 13% of the world population is affected by diseases caused by iodine deficiency. Iodine is a trace element necessary for the synthesis of thyroid hormones which, since it cannot be formed by the organism, must be taken regularly with food. According to the study by Sociedade Portuguesa de Endocrinologia, Diabetes e Metabolismo, Salt is the best way for iodine supplementation. Cooking the food with iodized salt is a desirable practice because it guarantees the presence of this element. There are also other methods to provide iodine to the general population, such as adding iodine to drinking water or taking supplements of iodine. In pregnancy is recommended iodine supplementation, except in patients with known thyroid disorders. Iodine is an essential component of thyroid hormones (T4 and T3). Inadequate iodine intake leads to inadequate thyroid hormone production.  The most important consequences of iodine deficiency, in the general population are goiter and hypothyroidism, and in the severe cases, mental retardation, cretinism and increased neo-natal and infant mortality(37).

38. Thyroid hormone and cardiac and renal capillary density and glomerular morphology
In the study to analyze the cardiac and renal capillary density and glomerular morphology that result from a chronic excess or deficiency of thyroid hormones in rats, showed that the renal dysfunctions of thyroid disorders are not related to cortical or medullary microvascular rarefaction, and that the proteinuria of hyperthyroidism is not secondary to a deficit of podocytes. Finally, we propose that thyroid hormone or its analogues may be useful to increase capillarity in renal diseases associated with microvascular rarefaction(38).

39. Selenium and the thyroid gland
Accoring to the study by Department of Endocrinology and Metabolic diseases, Hôpital du Cluzeau, although very minor amounts of selenium appear sufficient for adequate activity of deiodinases, thus limiting the impact of its potential deficiency on synthesis of thyroid hormones, selenium status appears to have an impact on the development of thyroid pathologies. The value of selenium supplementation in autoimmune thyroid disorders has been emphasised. Most authors attribute the effect of supplementation on the immune system to regulation of the production of reactive oxygen species and their metabolites. In patients with Hashimoto's disease and in pregnant women with anti-TPO antibodies, selenium supplementation decreases anti-thyroid antibody levels and improves the ultrasound structure of the thyroid gland(39).

40. Thyroid diseases
The prevalence is about 2 % in women and 0.2 % in men. The most frequent causes are various forms of thyroid autonomy in elderly women and Graves' disease, which occurs mostly in younger women.Hypothyroidism is defined by a lack of thyroid hormones. It is a common endocrine disorder caused by autoimmune thyroiditis (Hashimoto thyroiditis), iodine deficiency or following surgery or radioiodine therapy. Thyroxine requirements depend on fat-free mass and are, therefore, somewhat higher in males who are more often undersubstituted. In pregnancy lower TSH-reference ranges have to be considered and thyroid function should be monitored throughout pregnancy to avoid harm to the foetus caused by maternal thyroid dysfunctions. If overtreated women more often feature fractures, whereas males more often develop atrial fibrillation, according to the study by Department of Internal Medicine III, Medical University Of Vienna(40).

41. Thyroid axis hormones and Fatigue in patients with coronary artery disease
In people with coronary artery disease, the association between endocrine measures and fatigue is not well understood. We evaluated possible associations of fatigue and exercise capacity with function of adrenal axis and thyroid axis. In the study by Behavioral Medicine Institute, Lithuanian University of Health Sciences in a sample of Sixty-five men and 18 women (mean age 55 years), showed that In coronary artery disease patients, increased thyroid hormone concentrations are associated with decreased physical fatigue and decreased exertion fatigue, and increased cortisol concentrations with decreased mental fatigue. Exercise capacity is not associated with endocrine factors(41).

42. Depression and thyroid axis function in coronary artery disease
In the study to examine the relationship between depression and thyroid axis function in patients with CAD, showed that The patients with CAD with depressive symptoms had a higher prevalence of cardiac failure (p = 0.04), higher NT-pro BNP concentrations (p = 0.02), and lower free triiodothyronine (T3) concentrations (p = 0.04) than patients with CAD but without depressive symptoms. They also showed a strong trend (p = 0.058) toward a higher incidence of the low T3 syndrome. Higher NT-pro BNP concentrations were related to lower total T3 concentrations (r = -0.294, p = 0.011) and to higher reverse T3 concentrations (r = 0.353, p = 0.002). In men, higher scores of depression were related to lower total T3 concentration (r = -0.289, p = 0.034) and to higher NT-pro BNP concentration (r = 0.380, p = 0.005)(42).

43. Kidney and thyroid dysfunction
Thyroid hormones influence renal development, kidney structure, renal hemodynamics, glomerular filtration rate, the function of many transport systems along the nephron, and sodium and water homeostasis. In the study by Service de néphrologie, hôpital de Pitié-Salpêtrière, showed that
latients with hypothyroidism can have clinically important reductions in GFR, so screening for hypothyroidism should be considered in patients with unexplained elevations in serum creatinine. patients with thyroid disorders are also at risk for immune-mediated glomerular diseases. Finally, patients with nephrotic syndrome, as well as acute and chronic kidney injury, have alterations in thyroid gland physiology that can impact thyroid function and the testing of thyroid function status(43).

44. Thyroid storm
Thyroid storm, also referred to as thyrotoxic crisis, a rare disorder with a sudden onset, rapid progression and high mortality due to hypermetabolic state induced by excessive release of thyroid hormones. There is a report of a case of thyroid storm which had a devastating course, including multiple organ failure (MOF), severe hypoglycemia, disseminated intravascular coagulation (DIC), and stroke. It was difficult to make a diagnosis of thyroid storm in the present patient, because she did not have a history of thyroid disease and her serum FT3 level was normal. Clinicians should be aware that thyroid storm can occur even when there is an almost normal level of thyroid hormones, and that intensive anticoagulation is required for patients with atrial fibrillation to prevent stroke after thyroid storm(44).

45. Hypothyroidism
Hypothyroidism is a clinical disorder commonly encountered by the primary care physician. Untreated hypothyroidism can contribute to hypertension, dyslipidemia, infertility, cognitive impairment, and neuromuscular dysfunction. Acording to the study by Dwight D. Eisenhower Army Medical Center, the prevalence increases with age, and is higher in females than in males. Hypothyroidism may occur as a result of primary gland failure or insufficient thyroid gland stimulation by the hypothalamus or pituitary gland. Autoimmune thyroid disease is the most common etiology of hypothyroidism in the United States. Clinical symptoms of hypothyroidism are nonspecific and may be subtle, especially in older persons. The best laboratory assessment of thyroid function is a serum thyroid-stimulating hormone test. There is no evidence that screening asymptomatic adults improves outcomes. In the majority of patients, alleviation of symptoms can be accomplished through oral administration of synthetic levothyroxine, and most patients will require lifelong therapy(45).

46. Hypothyroidism treatments
Hypothyroidism denotes deficient production of thyroid hormone by the thyroid gland and can be primary (abnormality in thyroid gland itself) or secondary/central (as a result of hypothalamic or pituitary disease), according to the study by Department of Endocrinology and Metabolism, All India Institute of Medical Sciences, treatment of hypothyroidism can be started with the full calculated dose for most young patients. However, treatment should be initiated at a low dose in elderly patients, patients with coronary artery disease and patients with long-standing severe hypothyroidism. In primary hypothyroidism, treatment is monitored with serum TSH, with a target of 0.5-2.0 mIU/L. In patients with central hypothyroidism, treatment is tailored according to free or total T4 levels, which should be maintained in the upper half of the normal range for age. In patients with persistently elevated TSH despite an apparently adequate replacement dose of LT4, poor compliance, malabsorption and the presence of drug interactions should be checked. Over-replacement is common in clinical practice and is associated with increased risk of atrial fibrillation and osteoporosis, and hence should be avoided(46).

47. Heart failure and thyroid dysfunction
In the study to review  the results of the prospective studies that evaluated the risk of HF in patients with overt and subclinical thyroid disease and discuss the mechanism of this dysfunction, showed that the outcome of this analysis suggests that patients with untreated overt thyroid dysfunction are at increased risk of HF. Moreover, persistent subclinical thyroid dysfunction is associated with the development of HF in patients with serum TSH <0.1 or > 10 mU/l. The timely recognition and effective treatment of cardiac symptoms in patients with thyroid dysfunction is mandatory because the prognosis of HF may be improved with the appropriate treatment of thyroid dysfunction(47).

48. Adiposopathy and thyroid disease
Adiposopathy, defined as functionally disturbed adipose tissue mainly composed of large adipocytes and induced by chronic excess of food intake, has been associated with immune, metabolic and endocrine derangements promoting inflammation and, eventually, cardiovascular disease. According to the study by Evgenidion Hospital, University of Athens Medical School, Athens, adiposopathy may positively influence thyrotropin-stimulating hormone, by raising leptin levels, and triggering autoimmunity. In this regard, it is hypothesized that the increased thyrotropin-stimulating hormone is independent of the negative regulation of the thyroid hormone, thereby constituting a secondary phenomenon and not a causal effect(48).

49. Hypothyroidism in pregnancy
Hypothyroidism belongs to the most common endocrinopathies affecting women of childbearing age. Accordin g to the study by Medical University of Silesia, Department of Internal Medicine and Clinical Pharmacology, the diagnosis of hypothyroidism in pregnant patients may be complicated by the fact that pregnancy has a considerable impact on thyroid homeostasis. Even overt hypothyroidism in these patients may be characterized by nonspecific signs or symptoms that are easily confused with complaints common to pregnancy itself. Unrecognised or untreated hypothyroidism during pregnancy is associated with adverse outcomes that can be ameliorated or prevented by adequate therapy with thyroxine(49).

50. Hormones in aging men
As men grow older, their levels of testosterone decline while the prevalence of ill-health increases. There is evidances in linking lower testosterone levels with cardiovascular disease and mortality in middle-aged and older men and the reduced sexual activity and frailty in aging men. According to the study by Dr. Yeap BB., during aging, the response of the pituitary-thyroid axis alters to manifest higher thyrotropin levels. The presences of subclinical hypo- and hyper-thyroidism predict adverse cardiovascular outcomes. Newer results indicate that in euthyroid older men, differences in free thyroxine levels within the normal range predict specific health outcomes including frailty. Clarification of the roles of endogenous testosterone and thyroxine in the genesis of ill-health during male aging offers the prospect of future intervention to preserve health and well-being in this growing population(50).

51. Thyroid hormone and cardiovascular functions
Thyroid hormone is well known for its direct effects in regulating cardiovascular function and metabolism. In the recent meta-analyses of population-based studies with long-term follow-up have clarified the risk of cardiovascular disorders in patients with subclinical thyroid dysfunction, researchers at the Inwendige Geneeskunde - Endocrinologie en Metabolisme, showed that treatment of patients with TSH levels between 0.1-0.4 mU/l or 4-10 mU/l should depend on other risk factors and patient age, with no treatment for persons with a TSH level of 4-10 mU/l who are older than 65 years(51).

52. Thyroid dysfunction are not associated with normocholesterolemia or hypercholesterolemia
In the study to assess in a clinically healthy, middle-aged population of employees the prevalence of thyroid function disorders and their relation to demographic variables and cardiovascular risk factors, found that the cardiovascular risk profile of subjects with mild subclinical hypothyroidism was not different from subjects with normal TSH levels. The prevalence of subclinical hypothyroidism was 0.8% in normocholesterolemic (cholesterol <5.2 mmol/l) and 1.4% in hypercholesterolemic subjects (n.s.). One woman each with the subclinical form of the disease developed hypothyroidism or hyperthyroidism after 21 and 11 months of follow-up, respectively. Subclinical hypothyroidism and subclinical hyperthyroidism were rarely observed in a target group for coronary heart disease prevention. Mild subclinical hypothyroidism was not associated with any adverse cardiovascular risk profile. These results argue against indiscriminate measurements of TSH concentrations in clinically healthy subjects either with normocholesterolemia or hypercholesterolemia(52).

53. Subclinical hypothyroidism treatment?
Subclinical thyroid dysfunction is characterized by normal levels of thyroid hormones but abnormal values of thyrotropin (TSH) in an asymptomatic individual. It is a common disorder with a prevalence of about 7 to 8% in women (most frequently in females over 50 years), and about 3% in men. In the study of Is there a need for treatment in subclinical hypo- and hyperthyroidism?, researchers indicated that most frequently, this disorder is caused by exogenous L-thyroxine treatment. The endogenous form of subclinical hyperthyroidism mainly caused by nodular goiter has a prevalence of up to 20% in patients with large goiters. In patients with subclinical hyperthyroidism, there is an increased risk for development of atrial fibrillation and for a decrease in bone mass in postmenopausal women. In the majority of patients measurable TSH levels can be detected before or after stimulation with TRH. This formally excludes overt hyperthyroidism in such patients. Frequently, there is no need for treatment but follow-up is important. However, in patients with subclinical hyperthyroidism associated with atrial fibrillation a therapy with antithyroid drugs, beta-blockers or radioiodine must be considered(53).

54. Thyroid function and postmenopause
The rate of thyroid cancer increases with age. The incidence of thyroid disease in a population of postmenopausal women is as follows: clinical thyroid disease, about 2.4%; subclinical thyroid disease, about 23.2%. Among the group with subclinical thyroid disease, 73.8% are hypothyroid and 26.2% are hyperthyroid. According to the Institute for Medical Research and Education (IMRE), Essen,  It is of importance that even mild thyroid failure can have a number of clinical effects such as depression, memory loss, cognitive impairment and a variety of neuromuscular complaints. Myocardial function has been found to be subtly impaired. There is also an increased cardiovascular risk, caused by increased serum total cholesterol and low-density lipoprotein cholesterol as well as reduced levels of high-density lipoprotein. These adverse effects can be improved or corrected by L-thyroxine replacement therapy(54).

55. Thyroid hormone levels and vegetative dysfunction and heart connective tissue dysplasia (HCTD)
Heart connective tissue dysplasia (HCTD) are known to be subject to infectious and inflammatory diseases due to peculiarities of their immune system. In the study of 181 patients with HCTD depending on thyroid hormone levels and vegetative dysfunction. indicated that HCTD was shown to be associated with a significant decrease of IgM levels and increase of circulating immune complexes. The IgG level in patients with mitral valve prolapse (MVP), anomalous chord localization, and combination of MPV and tricuspid valve prolapse was significantly higher than in the absence of HCTD(55).

56. Thyroid physiology and common diseases in pregnancy
Thyroid diseases are common during pregnancy and an adequate treatment is important to prevent adverse maternal and fetal outcomes, such as neurodevelopment complications in the fetus. According to the study by Artemisia Fetal-Maternal Medical Center, found that large-scale intervention trials are urgently needed to assess the efficacy of preconception or early pregnancy screening for thyroid disorders. Accurate interpretation of both antepartum and postpartum levels of thyroid hormones is important in preventing pregnancy-related complication secondary to thyroid dysfunction(56).

57. Subclinical hypothyroidism in pregnancy
In the study to evaluate the intellectual development of children of mothers who had M-SCH during the pregnancy for these children with 68 children were recruited, after excluding those age < 4 or age > 15, 44, found that IQ level and cognitive performance of children born to LT4-treated hypothyroid mothers is similar in those whose mothers have M-SCH during pregnancy compared with those whose mothers have normal serum TSH concentrations during pregnancy(57).

58. Thyroid disease in pregnancy and childhood
Thyroid function in pregnancy is characterised by a T4 surge at 12 weeks declining thereafter. Fetal brain development depends on T4 transport into the fetus which in turn depends on sufficient maternal iodine supply. In the study to measure free T4 using direct equilibrium dialysis, as well as total T4 and TSH in 287 pregnant women at 27 weeks' gestation, found that Increasing maternal TSH was related to better performance on tests of cognition and language at 12 months but not at later ages. At 60 months, there was inconsistent evidence that higher TSH was related to improved attention. We found no convincing evidence that maternal TH during the second half of pregnancy was related to impaired child neurodevelopment(58).

59. Hereditary medullary thyroid carcinoma (HMTC)
In the study to investigate the role of germline inheritance of polymorphisms in CYP1A2*F, CYP1A1m1, GSTP1, NAT2 and TP53 genes in hereditary medullary thyroid carcinoma (HMTC) patients of 132 patients with HMTC, 88 first-degree relatives of HMTC patients and 575 control individuals, found that
the inheritance of specific genes determining the individual response to environmental toxins may contribute to the risk and phenotypic variability that exists in patients with HMTC(59).

60. Thyroid Nodule Size and Cancer
In the study to evaluate the association of nodule size upon cancer risk in a retrospective cohort analysis at an academic hospital with 4955 consecutive patients evaluated between 1995 and 2009, found that Increasing thyroid nodule size impacts cancer risk in a nonlinear fashion. A threshold is detected at 2.0 cm, beyond which cancer risk is unchanged. However, the risk of follicular carcinomas and other rare thyroid malignancies increases as nodules enlarge(60).

61. Analysis of patients with anaplastic thyroid cancer
In the study to to analyze the clinicopathologic characteristics of patients diagnosed with ATC expected to undergo curative thyroidectomy, with the goal of finding differences between patients surviving ≥6 months and <6 months, found that ATC showed female predominance. Patients initially presented with neck mass, and median age was 55 years. In patients with ATC who are expected to undergo curative thyroidectomy, surgery should actively be considered as primary therapy for patient survival when the size is <5 cm(61).

62. Treatment of patients with anaplastic thyroid cancer
Anaplastic thyroid cancer is known to have a poor prognosis due to its aggressive and rapid metastasis with median survival of less than 6 months. In a retrospectively reviewed medical records of 13 anaplastic thyroid cancer patients who received multidisciplinary treatment between 2006 and 2010, showed thatthe median patient age at diagnosis was 69 years, and six patients had stage IVc diseases. Eight patients received primary surgery followed by radiotherapy or concurrent chemoradiotherapy (CCRT). Five patients received weekly doxorubicin-based definitive CCRT, but only one patient's condition remained stable, while the rest experienced rapid disease progression. The median progression-free survival was 2.8 months (95% CI, 1.2-4.4 months), and the median overall survival was 3.8 months (95% CI, 3.0-4.6 months)(62).

63. Thyroid cancer and I-131 therapy
In the study in overview of the benefits of I-131 therapy for ablation, adjuvant treatment, and treatment of locoregional and/or metastasis of well-differentiated thyroid cancer and considers the risks of complications of I-131 therapy, showed that although there are never-ending controversies regarding I-131 therapy in well-differentiated thyroid cancer, the benefits and risks are becoming better understood. This in turn helps the treating physician and patient in making decisions regarding therapy(63).

64. Thyroid function in the nutritionally obese child and adolescent
In the study to evaluate the prevalence of disturbed thyroid hormone and TSH values in childhood obesity and the underlying pathophysiologic mechanisms linking obesity to thyroid function.l, showed that in the past 18 months, four studies demonstrated moderate elevation of TSH concentrations in 10-23% of obese children, which was associated with normal or slightly elevated thyroxine and triiodothyronine values. Two studies reported ultrasonographic hypoechogenicity of the thyroid in obese children with hyperthyrotropinemia, which was not caused by autoimmune thyroiditis; therefore, the authors hypothesized a link to chronic inflammation in obesity. Weight loss led to a normalization of elevated TSH levels in two studies. The adipokine leptin is the most promising link between obesity and hyperthyrotropinemia since leptin stimulates the hypothalamic-pituitary-thyroid(64).

65. Treating elevated thyroid stimulating hormone levels in obese children and adolescents?
In the differentiation to examine the prevalence of abnormal thyroid function tests among obese children and adolescents, and to study the effect of thyroid hormone supplementation on body weight, linear growth and lipid profiles in these children, showed that hyperthyrotropinemia is relatively common in obese children, but autoimmune thyroid disease accounts for a minority of the cases. TSH levels returned to normal in the majority of patients even without thyroid hormone administration. No beneficial effects on body weight, body mass index, linear growth and body lipids were found in treated subjects, suggesting that thyroid substitution is not necessary in most cases(65).

66. Thyroid disease in patients with vitiligo
In the study to summarize and critically appraise current evidence of the prevalence of thyroid diseases in vitiligo, found that There is an increased prevalence and an increased risk of (autoimmune) thyroid disease in patients with vitiligo compared with nonvitiligo. This risk seems to increase with age(66).

67. Thyroid antibodies and risk of preterm delivery
In a meta-analysis of prospective cohort studies to evaluate the associations between thyroid antibodies and risk of preterm delivery found that eleven prospective cohort studies involving 35 467 participants were included. The combined RR of preterm delivery for pregnant women with thyroid antibodies compared with the reference group was 1.41 (95% CI 1.08-1.84, P=0.011). Subgroup analysis yielded the combined RR of preterm delivery for pregnant women with TPO-Ab compared with the reference group was 1.69 (95% CI 1.19-2.41, P=0.003), whereas pregnant women with positive TG-Ab had no obvious risk of preterm delivery compared with the reference group (RR=0.88, 95% CI 0.60-1.29, P=0.513). Sensitivity analysis restricted to studies excluding women with thyroid dysfunction yielded similar results. Meta-regression analysis suggested that the status of exclusion or inclusion of women with thyroid dysfunction was the major source of heterogeneity in this meta-analysis(67).

68. Thyroid hormones in the skeleton
In the study to evaluate the cellular effects and molecular mechanisms of thyroid hormone action in the skeleton, showed that both thyroid hormone deficiency and excess are associated with an increased risk of fracture. Understanding the cellular and molecular basis of T3 action in skeletal cells will lead to the identification of new targets to regulate bone turnover and mineralization in the prevention and treatment of osteoporosis(68).



69. Skeletal responses to disruption of the hypothalamic-pituitary-thyroid axis
In the study to review the skeletal responses to disruption of the hypothalamic-pituitary-thyroid axis result from altered thyroid hormone (T(3)) action in bone of mice, showed that these mice must display opposing skeletal phenotypes if TSH has a major role in bone, whereas they would be similar if thyroid hormone actions predominate. Pax8(-/-) and hyt/hyt mice both displayed delayed ossification, reduced cortical bone, a trabecular bone remodeling defect, and reduced bone mineralization, thus indicating that the skeletal abnormalities of congenital hypothyroidism are independent of TSH. Treatment of primary osteoblasts and osteoclasts with TSH or a TSHR-stimulating antibody failed to induce a cAMP response. Furthermore, TSH did not affect the differentiation or function of osteoblasts or osteoclasts in vitro(69).

70. Congenital hypothyroidism (CH)
Congenital hypothyroidism (CH) is defined as thyroid hormone deficiency present at birth. According to the study by Department of Pediatrics, Dhahran Health Center, CH is classified into permanent and transient forms, which in turn can be divided into primary, secondary, or peripheral etiologies. Permanent CH refers to a persistent deficiency of thyroid hormone that requires life-long treatment. Transient CH refers to a temporary deficiency of thyroid hormone that is discovered at birth but recovers to normal in the first few months or years of life. Babies with CH who are not identified and treated promptly develop severe mental retardation. Most of the babies with CH do not manifest the typical known signs and symptoms of hypothyroidism, and this is most likely due to transplacental passage of some maternal thyroid hormone in addition to some residual neonatal thyroid function, as might be seen with thyroid hypoplasia, an ectopic gland, or mild dyshormonogenesis(70).










Sources
(1) http://www.ncbi.nlm.nih.gov/pubmed/23206325
(2) http://www.ncbi.nlm.nih.gov/pubmed/17154100
(3) http://www.ncbi.nlm.nih.gov/pubmed/7034290
(4) http://www.ncbi.nlm.nih.gov/pubmed/10671946 
(5) http://www.ncbi.nlm.nih.gov/pubmed/22138353
(6) http://www.ncbi.nlm.nih.gov/pubmed/23155700
(7) http://www.ncbi.nlm.nih.gov/pubmed/14749496
(8) http://www.ncbi.nlm.nih.gov/pubmed/23092911
(9) http://www.ncbi.nlm.nih.gov/pubmed/22115167
(10) http://www.ncbi.nlm.nih.gov/pubmed/15988403
(11) http://www.ncbi.nlm.nih.gov/pubmed/16717100
(12) http://www.ncbi.nlm.nih.gov/pubmed/22513648
(13) http://www.ncbi.nlm.nih.gov/pubmed/22258767
(14) http://www.ncbi.nlm.nih.gov/pubmed/21835056
(15) http://www.ncbi.nlm.nih.gov/pubmed/1996620
(16) http://www.ncbi.nlm.nih.gov/pubmed/3215552
(17) http://www.ncbi.nlm.nih.gov/pubmed/19818291
(18) http://www.ncbi.nlm.nih.gov/pubmed/9774495
(19) http://www.ncbi.nlm.nih.gov/pubmed/19030755
(20) http://www.ncbi.nlm.nih.gov/pubmed/20583539
(21) http://www.ncbi.nlm.nih.gov/pubmed/20583542
(22) http://www.ncbi.nlm.nih.gov/pubmed/17042681
(23) http://www.ncbi.nlm.nih.gov/pubmed/7357737
(24) http://www.ncbi.nlm.nih.gov/pubmed/6518098
(25) http://www.ncbi.nlm.nih.gov/pubmed/23257652
(26) http://www.ncbi.nlm.nih.gov/pubmed/23257210
(27) http://www.ncbi.nlm.nih.gov/pubmed/23255045
(28) http://www.ncbi.nlm.nih.gov/pubmed/23252963
(29) http://www.ncbi.nlm.nih.gov/pubmed/23240983
(30) http://www.ncbi.nlm.nih.gov/pubmed/23235186
(31) http://www.ncbi.nlm.nih.gov/pubmed/23232594
(32) http://www.ncbi.nlm.nih.gov/pubmed/23230697
(33) http://www.ncbi.nlm.nih.gov/pubmed/23182355
(34) http://www.ncbi.nlm.nih.gov/pubmed/23159010
(35) http://www.ncbi.nlm.nih.gov/pubmed/23173630
(36) http://www.ncbi.nlm.nih.gov/pubmed/23095459
(37) http://www.ncbi.nlm.nih.gov/pubmed/23069238
(38) http://www.ncbi.nlm.nih.gov/pubmed/23048210
(39) http://www.ncbi.nlm.nih.gov/pubmed/23046013
(40) http://www.ncbi.nlm.nih.gov/pubmed/23027459
(41) http://www.ncbi.nlm.nih.gov/pubmed/23023678
(42) http://www.ncbi.nlm.nih.gov/pubmed/16649727
(43) http://www.ncbi.nlm.nih.gov/pubmed/23022287
(44) http://www.ncbi.nlm.nih.gov/pubmed/22975553
(45) http://www.ncbi.nlm.nih.gov/pubmed/22962987
(46) http://www.ncbi.nlm.nih.gov/pubmed/22191793
(47) http://www.ncbi.nlm.nih.gov/pubmed/22956554
(48) http://www.ncbi.nlm.nih.gov/pubmed/22894634
(49) http://www.ncbi.nlm.nih.gov/pubmed/22891567
(50) http://www.ncbi.nlm.nih.gov/pubmed/22884846
(51) http://www.ncbi.nlm.nih.gov/pubmed/23218037
(52) http://www.ncbi.nlm.nih.gov/pubmed/10880781
(53) http://www.ncbi.nlm.nih.gov/pubmed/10434773
(54) http://www.ncbi.nlm.nih.gov/pubmed/12724022
(55) http://www.ncbi.nlm.nih.gov/pubmed/23285764
(56) http://www.ncbi.nlm.nih.gov/pubmed/22419883
(57) http://www.ncbi.nlm.nih.gov/pubmed/21943136
(58) http://www.ncbi.nlm.nih.gov/pubmed/22132346
(59) http://www.ncbi.nlm.nih.gov/pubmed/23278115
(60) http://www.ncbi.nlm.nih.gov/pubmed/23275525
(61) http://www.ncbi.nlm.nih.gov/pubmed/22977757
(62) http://www.ncbi.nlm.nih.gov/pubmed/22318823
(63) http://www.ncbi.nlm.nih.gov/pubmed/20001720
(64) http://www.ncbi.nlm.nih.gov/pubmed/21430532
(65) http://www.ncbi.nlm.nih.gov/pubmed/17907328
(66) http://www.ncbi.nlm.nih.gov/pubmed/22860695
(67) http://www.ncbi.nlm.nih.gov/pubmed/22826476
(68) http://www.ncbi.nlm.nih.gov/pubmed/22634735
(69) http://www.ncbi.nlm.nih.gov/pubmed/17932107
(70) http://www.ncbi.nlm.nih.gov/pubmed/22570946