Brain Angiotensinergic Regulation of the Immune System: Implications for Cardiovascular and Neuroendocrine Responses.

OBJECTIVE: The Renin-Angiotensin-Aldosterone System (RAAS) plays a major role in the regulation of cardiovascular functions, water and electrolytic balance, and hormonal responses. We perform a review of the literature, aiming at providing the current concepts regarding the angiotensin interaction with the immune system in the brain and the related implications for cardiovascular and neuroendocrine responses. METHODS: Appropriate keywords and MeSH terms were identified and searched in Pubmed. Finally, references of original articles and reviews were examined. RESULTS: Angiotensin II (ANG II), beside stimulating aldosterone, vasopressin and CRH-ACTH release, sodium and water retention, thirst, and sympathetic nerve activity, exerts its effects on the immune system via the Angiotensin Type 1 Receptor (AT 1R) that is located in the brain, pituitary, adrenal gland, and kidney. Several actions are triggered by the binding of circulating ANG II to AT 1R into the circumventricular organs that lack the Blood-Brain-Barrier (BBB). Furthermore, the BBB becomes permeable during chronic hypertension thereby ANG II may also access brain nuclei controlling cardiovascular functions. Subfornical organ, organum vasculosum lamina terminalis, area postrema, paraventricular nucleus, septal nuclei, amygdala, nucleus of the solitary tract and retroventral lateral medulla oblongata are the brain structures that mediate the actions of ANG II since they are provided with a high concentration of AT 1R. ANG II induces also T-lymphocyte activation and vascular infiltration of leukocytes and, moreover, oxidative stress stimulating inflammatory responses via inhibition of endothelial progenitor cells and stimulation of inflammatory and microglial cells facilitating the development of hypertension. CONCLUSION: Besides the well-known mechanisms by which RAAS activation can lead to the development of hypertension, the interactions between ANG II and the immune system at the brain level can play a significant role.

Metformin: Up to Date.

BACKGROUND: Metformin is an oral hypoglycemic agent extensively used as first-line therapy for type 2 diabetes. It improves hyperglycemia by suppressing hepatic glucose production and increasing glucose uptake in muscles. Metformin improves insulin sensitivity and shows a beneficial effect on weight control. Besides its metabolic positive effects, Metformin has direct effects on inflammation and can have immunomodulatory and antineoplastic properties. AIM: The aim of this narrative review was to summarize the up-to-date evidence from the current literature about the metabolic and non-metabolic effects of Metformin. METHODS: We reviewed the current literature dealing with different effects and properties of Metformin and current recommendations about the use of this drug. We identified keywords and MeSH terms in Pubmed and the terms Metformin and type 2 diabetes, type 1 diabetes, pregnancy, heart failure, PCOS, etc, were searched, selecting only significant original articles and review in English, in particular of the last five years. CONCLUSION: Even if many new effective hypoglycemic agents have been launched in the market in the last few years, Metformin would always keep a place in the treatment of type 2 diabetes and its comorbidities because of its multiple positive effects and low cost.

Thyroid Disorders and Prognosis in Chronic Heart Failure: A Long-Term Follow-Up Study.

BACKGROUND: Thyroid disorders may have a negative impact on the prognosis of patients affected by chronic heart failure (CHF). OBJECTIVE: The aim of the current study was to evaluate the prognostic role of all thyroid disorders over a long term follow-up in a single centre large sample of CHF outpatients. METHODS: In all patients, the function of the thyroid was evaluated at the enrolment and during the follow- up. On the basis of free triiodothyronine (T3), free thyroxine (fT4) and thyroid-stimulating hormone (TSH) serum levels, patients were classified into one of the following four categories: euthyroid subjects, patients affected by hypothyroidism, low T3 (LT3) syndrome and hyperthyroidism. During the follow-up, death for all causes was assessed as primary end-point, whereas time to the first hospitalization for heart failure worsening was the secondary end-point analyzed. RESULTS: Among 762 patients, 190 patients were affected by hypothyroidism (Hypo). LT3 syndrome was diagnosed in 15 patients and 59 patients were affected by hyperthyroidism (Hyper). During a long term follow-up (5.1±3.7 years), 303 patients died. Patients with Hypo showed an increased risk of death as well as of hospitalization due to heart failure worsening at univariate regression analysis. At multivariate regression analysis, Hypo remained associated with hospitalization after correction for age >75 years, ischemic aetiology, diabetes, therapy with ACE-inhibitors or ARBs, therapy with betablockers and with aldosterone antagonists, NYHA class 3, systolic arterial pressure <95 mmHg, left ventricular ejection fraction <30%, estimated glomerular filtration rate <60 ml/min, hyponatremia and NTproBNP> 1000 pg/ml. At multivariate analysis, the independent association with death was significant only for the subgroup of patients with TSH >10 mIU/L. LT3 was independently associated with both heart failure hospitalization and death, whereas Hyper was not associated with any of the two considered end-points. CONCLUSION: Hypo is associated with a worse prognosis over a long-term follow-up. The association with heart failure hospitalization is not dependent on the baseline TSH levels, whereas the association with death is significant only when TSH >10 mIU/L. Finally, Hyper does not have any association with a worse prognosis.

Focus on the Correlations between Alzheimer's Disease and Type 2 Diabetes.

BACKGROUND: In the last decades, both diabetes mellitus and Alzheimer's disease are constantly increasing. Affected individuals, therefore, represent an enormous problem for the society, governments and global organizations. These diseases are usually considered as independent conditions, but increasing evidence shows that there are links between these two disorders. METHODS: In this review, we analyzed common features present in Alzheimer's disease and diabetes mellitus, showing how these two diseases are strictly correlated to each other. RESULTS: Some pathogenetic factors are shared by Type 2 Diabetes and Alzheimer's Disease: chronic inflammation, oxidative stress, mitochondrial dysfunction, adiponectin deficiency, different expression of plasma cholinesterase activity and vascular damage could represent a possible explanation for the coexistence of these two conditions in many patients. CONCLUSION: A better understanding of this issue and an appropriate management of diabetes by means of physical activity, low fat diet, and drugs to achieve a good glycemic control, avoiding both hyperglycemia and hypoglycemia, can represent a way to prevent cognitive decline and Alzheimer's disease.

Vasopressin in Heart Failure.

BACKGROUND AND OBJECTIVE: The nonapeptide hypothalamic hormone vasopressin (VP), exerts important effects on cardiovascular system via its receptors V1, V2 and V3. Patients with congestive heart failure (CHF) present elevated plasma VP levels. Aim of this paper is to review the role of vasopressin in CHF. METHODS: We analyzed the best of published literature dealing with the role of VP in patients affected by CHF, identifying keywords and MeSH terms in Pubmed and then searching them. The last search was performed on August 2017. RESULTS: Scientific articles dealing with the relationship between VP and CHF show that circulating high VP levels found in CHF despite an exaggerated increase in circulatory blood volume can contribute to CHF exacerbation. In particular, the stimulation of V1R induces vascular constriction responsible for increased systemic vascular resistance and afterload, and, in addition, coronary vasoconstriction with consequent reduced coronary circulation and cardiac contractility, whereas the stimulation of V2R induces free water reabsorption and this is responsible of preload increase and congestion of pulmonary vascular bed with edema and hyponatremia, markers of advanced CHF. CONCLUSION: VP can play an important role among the derangements of the endocrine system in CHF even being a possible target in the treatment of this condition. Vaptans, antagonists of VP receptors, in fact, are able to increase urine output and plasma sodium levels without the increased risk of arrhythmic death induced by diuretics, even though, further studies are needed to establish a possible role of these drugs in the treatment of CHF.

Serum Testosterone and Cognitive Function in Ageing Male: Updating the Evidence.

BACKGROUND: Testosterone (T) deficit, either in prepubertal or postpubertal form of hypogonadism, seems to play a key role in impairing cognitive function, including memory, attention, language and visuospatial abilities, especially in elderly men. OBJECTIVE: Several studies have recently showed the association between low serum T levels and important cognitive dysfunctions in ageing male as well as in subjects suffering from Alzheimer's disease (AD), mild cognitive impairment (MCI) and even depression, suggesting that T could exert an active neuroprotective role. METHODS: By searching PubMed and recent patents (ranging from 2010 to 2015), we identified several observational and intervention studies dealing with T and cognitive function in adult and ageing men. Findings were reviewed, thoroughly examined and, finally, summarized herein. RESULTS: Although a large number of studies have been carried out so far, conclusive evidence cannot be drawn, in particular, for cognitive disorders in males. Conversely, T supplementation has been suggested for depressive syndrome in young and ageing men. To date, no clinical data have been carried out on cognitive dysfunctions employing the quoted patents in men. CONCLUSIONS: Studies aiming to evaluate the role of serum T and its supplementation in adult and ageing men with T deficiency syndrome need to be encouraged, given that subjects affected by overt hypogonadism, either in prepubertal (i.e. Klinefelter syndrome) or postpubertal forms (chemical castration in subjects affected by prostate cancer), often complain of cognitive dysfunction, and seem to considerably benefit from T replacement therapy.

Synaptic Inputs of Neural Afferent Pathways to Vasopressin- and Oxytocin-Secreting Neurons of Supraoptic and Paraventricular Hypothalamic Nuclei.

BACKGROUND: Magnocellular neurosecretory neurons of the hypothalamic supraoptic (SON) and paraventricular (PVN) nuclei synthesize vasopressin and oxytocin in response to signals generated by osmoreceptors and baroreceptors and, respectively, by receptors of the nipples and cervix. METHODS: We analyzed the literature identifying relevant articles dealing with synaptic inputs of neural afferent pathways to Vasopressin-and Oxytocin-secreting neurons of SON and PVN. RESULTS: This article focuses on the multisynaptic pathways involved in the regulation of Vasopressin and Oxytocin secretion. CONCLUSION: An updated topographic description of the afferent pathways involved in the regulation of VPergic and OTergic neurons and their synaptic inputs inducing the stimulus-secretion-coupling has been depicted.

False positive diagnosis on (131)iodine whole-body scintigraphy of differentiated thyroid cancers.

(131)Iodine is used both to ablate any residual thyroid tissue or metastatic disease and to obtain whole-body diagnostic images after total thyroidectomy for differentiated thyroid cancer (DTC). Even though whole-body scan is highly accurate in showing thyroid residues as well as metastases of DTC, false positive results can be found, possibly leading to diagnostic errors and unnecessary treatments. This paper reviews the physiological and pathological processes involved as well as the strategy to recognize and rule out false positive radioiodine images.

Mechanisms Explaining the Influence of Subclinical Hypothyroidism on the Onset and Progression of Chronic Heart Failure.

BACKGROUND: Subclinical hypothyroidism can be associated with the onset and progression of chronic heart failure. METHODS: We undertook a careful search of the literature aiming to review the possible pathogenetic mechanisms explaining the influence of subclinical hypothyroidism on the onset and progression of chronic heart failure. RESULTS: Thyroid hormones can influence the expression of genes involved in calcium handling and contractile properties of myocardiocytes. Subclinical hypothyroidism, therefore, can alter both cardiovascular morphology and function leading to changes in myocardiocytes shape and structure, and to alterations of both contractile and relaxing properties, impairing systolic as well as diastolic functions. Furthermore, it can favour dyslipidemia, endothelial dysfunction and diastolic hypertension, favouring atherogenesis and coronary heart disease, possibly evolving into chronic heart failure. Beside an influence on the onset of chronic heart failure, subclinical hypothyroidism can represent a risk factor for its progression, in particular hospitalization and mortality but the mechanisms involved need to be fully elucidated. CONCLUSIONS: Subclinical hypothyroidism can be associated with the onset of chronic heart failure, because it can favour two frequent conditions that can evolve in heart failure: coronary heart disease and hypertension; it can also alter both cardiovascular morphology and function leading to heart failure progression in patients already affected through mechanisms still not completely understood.

Selenium and Iodine in Autoimmune Thyroiditis.

Selenium and iodine are essential for thyroid hormone synthesis and function. Selenium, in form of selenocysteine, is found either in the catalytic center of enzymes involved in the protection of the thyroid gland from free radicals originating during thyroid hormone synthesis, and in three different iodothyronine deiodinases catalyzing the activation and the inactivation of thyroid hormones. Iodine is an essential constituent of thyroid hormones and its deficiency causes different disorders that include goiter, hypothyroidism, reduced fertility and alteration in growth, physical and neurological development. These two micronutrients could be involved in the pathogenesis of autoimmune thyroid diseases, a spectrum of pathological conditions including Hashimoto's thryoiditis, post-partum thyroiditis, the so-called painless thyroiditis, Graves' disease and Graves' ophtalmopathy. Aim of this paper is to review the role played by selenium and iodine in autoimmune thyroiditis.

The association between diabetes and depression: a very disabling condition.

Rates of depression are significantly increased in diabetic patients, and even more in the elderly. About 20-30% of patients with diabetes suffer from clinically relevant depressive disorders, 10% of which being affected by the major depression disorder. Moreover, people with depression seem to be more prone to develop an associated diabetes mellitus, and depression can worsen glycemic control in diabetes, with higher risk to develop complications and adverse outcomes, whereas improving depressive symptoms is generally associated with a better glycemic control. Thus, the coexistence of depression and diabetes has a negative impact on both lifestyle and quality of life, with a reduction of physical activity and an increase in the request for medical care and prescriptions, possibly increasing the healthcare costs and the susceptibility to further diseases. These negative aspects are particularly evident in the elderly, with further decrease in the mobility, worsening of disability, frailty, geriatric syndromes and increased mortality. Healthcare providers should be aware of the possible coexistence of depression and diabetes and of the related consequences, to better manage the patients affected by these two pathological conditions.

Sevelamer carbonate markedly reduces levothyroxine absorption.

We report the case of a young woman affected by hypothyroidism due to Hashimoto's thyroiditis, previously well compensated with a full replacement therapy (150 mcg/day of levothyroxine), presenting a clinical picture of myxedema, with a TSH=650 mU/L. Two years earlier she had started a dialysis treatment because of a chronic renal failure and had been under treatment for the last 18 months with sevelamer carbonate, a phosphate binder. No improvement of clinical conditions nor reduction in TSH serum levels was observed even on increasing the dose of levothyroxine up to 300 mcg/day, whereas euthyroidism finally restored by administering the first morning dose of sevelamer carbonate at least 4 hours after levothyroxine administration. This case shows that sevelamer carbonate, in analogy with what has been already reported for sevelamer hydrochloride, can interfere with levothyroxine absorption leading to a condition of hypothyroidism in patients previously well compensated with a given replacement dose.

Amiodarone-induced SIADH: two cases report.

Amiodarone-induced SIADH is a rare but serious side effect of this drug. We report two cases of mild hyponatremia, observed in the last five years, and discuss the role played by age, sex and dose of amiodarone as well as the influence that this molecule may have on aquaporin-2 water channel expression in the renal collecting ducts.

Ectopic thyroid gland: description of a case and review of the literature.

The clinical occurrence of ectopic thyroid gland is an infrequently encountered condition, resulting from a developmental abnormality during the migration of the thyroid anlage from the floor of the primitive foregut to its final position in the neck. It can be found along the way of thyroid descent, in the midline, or laterally in the neck or even in the mediastinum or under the diaphragm. This condition is often asymptomatic, whereas symptoms could be related to ectopic thyroid size, to its relationships with surrounding organs or to diseases affecting the ectopic thyroid in the same way they involve orthotopic glands. Sometimes, a growing mass can lead to the clinical suspicion of a tumor disease. On the other hand, thyroid ectopy must be distinguished from metastasis of thyroid cancer. Scintigraphy and ultrasonography are the main diagnostic means for evaluating ectopic thyroid tissue, whereas fine needle aspiration could be useful in the presence of a nodular ectopic gland or when the coexistence of an orthotopic thyroid can arise the suspicion of a metastasis from a thyroid cancer. Surgical removal is indicated in symptomatic cases, whereas radioiodine ablation is reserved to recurrent disease. In this paper we report an emblematic case of ectopic thyroid gland and a review of the literature dealing with this condition.

Role of central and peripheral chemoreceptors in vasopressin secretion control.

In this review, we analyzed the role played by central and peripheral chemoreceptors (CHRs) in vasopressin (AVP) secretion control. Central neural pathways subserving osmotic and non-osmotic control of AVP secretion are strictly correlated to brain areas participating in chemoreception mechanisms. Among the different brain areas involved in central chemoreception, the most important site has been localized in the retrotrapezoid nucleus of the rostral ventrolateral medulla. These central CHRs are able to detect very small pH/CO2 fluctuations, participating in brain blood flow regulation, acid-base balance and blood pressure control. Decreases in arterial pH and increases in arterial pCO2 stimulate AVP release by the Supraoptic and Paraventricular Nuclei. Carotid CHRs transduce low arterial O2 tension into increased action potential activity, leading to bradycardia and coronary vasodilatation via vagal stimulation, and systemic vasoconstriction via catecholaminergic stimulation. Stimulation of carotid CHRs by hypoxia increases neurohypophyseal blood flow and AVP release, an effect inhibited by CHRs denervation. Two renal CHRs have been identified: Type R1 CHRs do not have a resting discharge but are activated by renal ischemia and hypotension; Type R2 CHRs have a resting discharge and respond to backflow of urine into the renal pelvis. Signals arising from renal CHRs modulate the activity of hypothalamic AVPergic neurons: activation of R1 and R2 CHRs, following increased intrapelvic pressure with solutions of mannitol, NaCl and KCl, produces a significant increase of AVP secretion and the same effect has been obtained by the intrarenal infusion of bradykinin, which excites afferent renal nerves, as well as by the electrical stimulation of these nerves.

Parathyroid hormone determination in ultrasound-guided fine needle aspirates allows the differentiation between thyroid and parathyroid lesions: our experience and review of the literature.

In many cases, it is difficult or even impossible to distinguish parathyroid lesions from thyroid ones at ultrasound as well as at scintiscan and even at cytology, because they often share common features. The aim of this study was to evaluate the role of Parathyroid Hormone (PTH) determination in the aspirates in the differential diagnosis of parathyroid from thyroid lesions in an area of mild iodine deficiency and high prevalence of thyroid nodules. Forty-six consecutive patients were suspected to have one or more nodule(s) of parathyroid origin because of their position in the posterior aspect of thyroid lobes and/or their shape and echo-pattern at ultrasound examination. In 13 cases, there were also laboratory findings suggestive for primary hyperparathyroidism, with clinical evidence in 6 of these patients. A total of 55 lesions suspected to be of parathyroid origin were selected. After obtaining cytological preparations, the needle used to perform the fine-needle aspirate (FNA) was washed using 1 ml of normal saline. Intact PTH determination in the washout was done whereas the evaluation was performed directly in the aspirated fluid in case of cystic lesions. The values of PTH in the aspirates ranged from 6.7 to 16640 pg/ml. Sixteen patients underwent surgical intervention and the histological examination of the 23 operated lesions previously submitted to FNA-PTH showed 11 parathyroid adenomas, 5 hyperplasic parathyroid lesions and 7 benign thyroid nodules. A strong positive correlation between high levels of PTH in the aspirate and the histological findings of parathyroid lesions was found. A value over 245 pg/ml was constantly associated to the parathyroid lesions. Our results confirmed the high accuracy of FNA-PTH determination in differentiating parathyroid lesions from thyroid nodules and this is of special value in an area of mild iodine deficiency with a high prevalence of thyroid nodules.

Diffuse 131I lung uptake in bronchiectasis: a potential pitfall in the follow-up of differentiated thyroid carcinoma.

BACKGROUND: Iodine-131 ((131)I) total-body scintigraphy is a commonly used post-thyroidectomy imaging procedure in the management of differentiated thyroid cancer (DTC), in particular in patients with an intermediate or high risk of persistent or recurrent disease, in combination with serum thyroglobulin (Tg) determinations and ultrasonography of the neck. It can show the persistence of residual thyroid tissue after thyroidectomy and local and distant metastases. Although this is a highly sensitive method for detecting normal and pathologic thyroid tissue, especially when performed after an ablative dose of (131)I, false-positive scans (i.e., uptake in the absence of residual thyroid tissue or metastases) can occur in different situations. PATIENT FINDINGS: We report a case of a 42-year-old woman with recurrent chest infections and bronchiectasis, who had a total thyroidectomy and (131)I treatment because of a papillary thyroid carcinoma. She presented with marked bilateral (131)I uptake in the lungs mimicking metastatic involvement of the lungs by thyroid cancer, but interpreted as nonspecific bilateral uptake by her bronchiectatic bronchial tree. SUMMARY: Our case, as well as others reported in the literature, calls attention to the fact that (131)I lung uptake may be related to chronic inflammatory lung disease, thus representing a potential diagnostic pitfall in patients with DTC. CONCLUSIONS: (131)I uptake should be interpreted on the bases of clinical context, imaging, and laboratory findings (serum Tg). Recognition of potential false-positive (131)I scans is critical to avoid unnecessary exposure to further radiation from repeated therapeutic doses of (131)I with possible side effects and even worsening of lung disease itself.

Vasopressin secretion control: central neural pathways, neurotransmitters and effects of drugs.

Vasopressin (AVP) secretion and release are regulated by a number of central nervous system sites that receive peripheral signals from the osmoreceptors and baroreceptors. Aim of this paper is to review anatomical pathways and neurotransmitters involved as well as drugs affecting AVP secretion.

Differentiated thyroid carcinoma and intestinal polyposis syndromes.

Familial Adenomatous Polyposis, Cowden's Syndrome, and Peutz-Jeghers Syndrome are well known as Intestinal Polyposis Syndromes, inherited conditions characterized by the development of polyps of the gastro-intestinal tract in association with extra-intestinal manifestations, in particular malignant tumors at different sites. Thyroid carcinoma is sometimes a part of the clinical picture of these syndromes. The aim of this paper is to review the literature dealing with the association between differentiated thyroid carcinomas and Intestinal Polyposis Syndromes in order to point out peculiar aspects, providing suggestions for the screening and the management of thyroid tumors in these patients.

Incidence and prevalence of hypothyroidism in patients affected by chronic heart failure: role of amiodarone.

BACKGROUND: It has been demonstrated that hypothyroidism can lead to significant hemodynamic alterations favoring the onset of chronic heart failure (CHF) as well as its progression. Furthermore, amiodarone, an iodine-containing antiarhythmic drug frequently used in CHF patients, is often the cause of primary hypothyroidism. AIM OF THE STUDY: To define the prevalence and incidence of hypothyroidism in a group of CHF outpatients in stable clinical conditions, with particular reference to the role of amiodarone therapy. RESULTS: Among the 422 enrolled patients (326 males, aged 65±12 years), 51 (12%) had a previous diagnosis of hypothyroidism while 21 (5%) were newly diagnosed at the enrolment. Then, the overall prevalence of hypothyroidism at the first evaluation was 17%and, as expected, it was significantly higher in females than males (33% vs 13%; p < 0.001). During follow-up (median 28 months) hypothyroidism occurred in further 19 patients (incidence rate: 26/1000/year) and it was mainly attributable to amiodarone therapy. Considering all together the hypothyroid patients, either those affected by thyroid failure at the enrolment than those developing hypothyroidism during the follow-up, levothyroxine therapy was continued or started in 69% of them; however, normal serum TSH values were obtained only in 76% of treated cases (mean levothyroxine dose: 69±44 mcg/day). In any case, in the group of patients affected by hypothyroidism a significantly greater occurrence of heart failure progression was observed. CONCLUSIONS: Hypothyroidism, especially the subclinical form, frequently occurs in patients affected by CHF receiving amiodarone therapy. Given the unfavorable impact of hypothyroidism on the progression and prognosis of CHF, and the opportunity to adequately manage thyroid failure by means of levothyroxine replacement therapy without the need to withdraw amiodarone, we recommend regular testing of thyroid function in CHF patients, in particular in those submitted to amiodarone therapy, in order to early diagnose a condition of hypothyroidism and titrate substitutive treatment.