Complications of Cushing's syndrome: state of the art

Cushing's syndrome is a serious endocrine disease caused by chronic, autonomous, and excessive secretion of cortisol. The syndrome is associated with increased mortality and impaired quality of life because of the occurrence of comorbidities. These clinical complications include metabolic syndrome, consisting of systemic arterial hypertension, visceral obesity, impairment of glucose metabolism, and dyslipidaemia; musculoskeletal disorders, such as myopathy, osteoporosis, and skeletal fractures; neuropsychiatric disorders, such as impairment of cognitive function, depression, or mania; impairment of reproductive and sexual function; and dermatological manifestations, mainly represented by acne, hirsutism, and alopecia. Hypertension in patients with Cushing's syndrome has a multifactorial pathogenesis and contributes to the increased risk for myocardial infarction, cardiac failure, or stroke, which are the most common causes of death; risks of these outcomes are exacerbated by a prothrombotic diathesis and hypokalaemia. Neuropsychiatric disorders can be responsible for suicide. Immune disorders are common; immunosuppression during active disease causes susceptibility to infections, possibly complicated by sepsis, an important cause of death, whereas immune rebound after disease remission can exacerbate underlying autoimmune diseases. Prompt treatment of cortisol excess and specific treatments of comorbidities are crucial to prevent serious clinical complications and reduce the mortality associated with Cushing's syndrome

Aspetti igienico-sanitari in ambito urbanistico: conflittualità nelle norme urbanistiche nazionali e locali in tema di sanità pubblica [Hygienic and sanitary aspects in urban planning: contradiction in national and local urban legislation regarding public health]

Nowadays, the majority of world population lives in urban areas and this portion is going to increase in the coming decades. The health impact of urban areas is well established and described in scientific literature. Italian health and hygiene legislation dealing with urban health is fragmented and not coordinated with the regulation about environment and city planning. The overlapping of legal competences between different authorities and the conflict of attribution between the Central State and Regional Governments deeply contributed to generate uncertainty. The authors here analyse the Italian regulatory framework and depict its lacks in terms of public health protection

The GH-IGF-SST system in hepatocellular carcinoma: biological and molecular pathogenetic mechanisms and therapeutic targets

Hepatocellular carcinoma (HCC) is the sixth most common malignancy worldwide. Different signalling pathways have been identified to be implicated in the pathogenesis of HCC; among these, GH, IGF and somatostatin (SST) pathways have emerged as some of the major pathways implicated in the development of HCC. Physiologically, GH-IGF-SST system plays a crucial role in liver growth and development since GH induces IGF1 and IGF2 secretion and the expression of their receptors, involved in hepatocytes cell proliferation, differentiation and metabolism. On the other hand, somatostatin receptors (SSTRs) are exclusively present on the biliary tract. Importantly, the GH-IGF-SST system components have been indicated as regulators of hepatocarcinogenesis. Reduction of GH binding affinity to GH receptor, decreased serum IGF1 and increased serum IGF2 production, overexpression of IGF1 receptor, loss of function of IGF2 receptor and appearance of SSTRs are frequently observed in human HCC. In particular, recently, many studies have evaluated the correlation between increased levels of IGF1 receptors and liver diseases and the oncogenic role of IGF2 and its involvement in angiogenesis, migration and, consequently, in tumour progression. SST directly or indirectly influences tumour growth and development through the inhibition of cell proliferation and secretion and induction of apoptosis, even though SST role in hepatocarcinogenesis is still opened to argument. This review addresses the present evidences suggesting a role of the GH-IGF-SST system in the development and progression of HCC, and describes the therapeutic perspectives, based on the targeting of GH-IGF-SST system, which have been hypothesised and experimented in HCC

Cardiac Pacemaker Battery Discharge After External Electrical Cardioversion for Broad QRS Complex Tachycardia

External electrical cardioversion or defibrillation may be necessary in patients with implanted cardiac pacemaker (PM) or implantable cardioverter defibrillator (ICD). Sudden discharge of high electrical energy employed in direct current (DC) transthoracic countershock may damage the PM/ICD system resulting in a series of possible device malfunctions. For this reason, when defibrillation or cardioversion must be attempted in a patient with a PM or ICD, some precautions should be taken, particularly in PM dependent patients, in order to prevent damage to the device. We report the case of a 76-year-old woman with a dual chamber PM implanted in the right subclavicular region, who received two consecutive transthoracic DC shocks to treat haemodynamically unstable broad QRS complex tachycardia after cardiac surgery performed with a standard sternotomic approach. Because of the sternal wound and thoracic drainage tubes together with the severe clinical compromise, the anterior paddle was positioned near the pulse generator. At the following PM test, a complete battery discharge was detected

Cardiac pacemaker battery discharge after external electrical cardioversion for broad QRS Complex Tachycardia

External electrical cardioversion or defibrillation may be necessary in patients with implanted cardiac pacemaker (PM) or implantable cardioverter defibrillator (ICD). Sudden discharge of high electrical energy employed in direct current (DC) transthoracic countershock may damage the PM/ICD system resulting in a series of possible device malfunctions. For this reason, when defibrillation or cardioversion must be attempted in a patient with a PM or ICD, some precautions should be taken, particularly in PM dependent patients, in order to prevent damage to the device. We report the case of a 76-year-old woman with a dual chamber PM implanted in the right subclavicular region, who received two consecutive transthoracic DC shocks to treat haemodynamically unstable broad QRS complex tachycardia after cardiac surgery performed with a standard sternotomic approach. Because of the sternal wound and thoracic drainage tubes together with the severe clinical compromise, the anterior paddle was positioned near the pulse generator. At the following PM test, a complete battery discharge was detected

Bone demineralization and vertebral fractures in endogenous cortisol excess: role of disease etiology and gonadal status

INTRODUCTION: The effects of endogenous cortisol (F) excess on bone mass and vertebral fractures have still not been thoroughly investigated. The aim of this cross-sectional case-control study was to investigate factors influencing bone demineralization and vertebral fractures in different conditions of F excess, i.e. Cushing's disease and adrenal and ectopic Cushing's syndrome. MATERIALS AND METHODS: Eighty consecutive patients and 80 controls were prospectively enrolled: 37 patients (21 females) with pituitary ACTH-secreting adenoma, 18 (14 females) with adrenocortical adenoma, 15 (11 females) with adrenal carcinoma of mixed secretion, and 10 (three females) with ectopic ACTH secretion. The groups had similar age. At diagnosis, bone mineral density (BMD) was determined by the dual-energy x-ray absorptiometry technique at the lumbar spine (L1-L4) and femoral neck; vertebral fractures were investigated by standard spinal radiographs. RESULTS: When comparing the groups with different etiology of F excess, the patients with ectopic ACTH secretion had higher F and lower BMD values than the other subgroups. Morning F (P = 0.03) and testosterone levels (P = 0.04) correlated with lumbar BMD. Vertebral fractures were found in 61 (76%) of the patients, were multiple in 52 (85%) of the cases, and clinically evident in 32 (52%). Only multiple fractures were more frequent in patients with ectopic ACTH hypersecretion (P < 0.05). Lumbar spine BMD was the best predictor of vertebral fractures (P < 0.01). Surprisingly, amenorrheic and eumenorrheic women had similar BMD values and fracture prevalence. CONCLUSION: A high prevalence (76%) of vertebral fracture was revealed, regardless of the etiology of the patients' hypercortisolism. The harmful effects of F excess at the spine were partly counterbalanced by the increased androgen production but were not affected by gonadal status in women

Cushing's syndrome: aftermath of the cure

Cushing's syndrome (CS) is a chronic and systemic disease caused by endogenous or exogenous hypercortisolism, associated with an increase of mortality rate due to the clinical consequences of glucocorticoid excess, especially cardiovascular diseases. After cure, usually obtained by the surgical removal of the tumor responsible for the disease, the normalization of cortisol secretion is not constantly followed by the recovery of the clinical complications developed during the active disease, and it is often followed by the development of novel clinical manifestations induced by the fall of cortisol levels. These evidences were mostly documented in patients with pituitary-dependent CS, after surgical resection of the pituitary tumor. Indeed, despite an improvement of the mortality rate, metabolic syndrome and the consequent cardiovascular risk have been found to partially persist after disease remission, strictly correlated to the insulin resistance. Skeletal diseases, mainly osteoporosis, improve after normalization of cortisol levels but require a long period of time or the use of specific treatment, mainly bisphosphonates, to reach the normalization of bone mass. A relevant improvement or resolution of mental disturbances has been described in patients cured from CS, although in several cases, cognitive decline persisted and psychological or psychiatric improvement was erratic, delayed, or incomplete. On the other hand, development or exacerbation of autoimmune disorders, mainly thyroid autoimmune diseases, was documented in predisposed patients with CS after disease remission. The totality of these complications persisting or occurring after successful treatment contribute to the impairment of quality of life registered in patients with CS after disease cure

The dual targeting of insulin and insulin-like growth factor 1 receptor enhances the mTOR inhibitor-mediated antitumor efficacy in hepatocellular carcinoma

Deregulation of mTOR and IGF pathways is frequent in hepatocellular carcinoma (HCC), thus mTOR and IGF1R represent suitable therapeutic targets in HCC. The aim of this study was to evaluate the effects of mTOR inhibitors (mTORi) and OSI-906, blocker of IGF1R/IR, on HCC cell proliferation, viability, migration and invasion, and alpha-fetoprotein (α-FP) secretion. In HepG2 and HuH-7 we evaluated, the expression of mTOR and IGF pathway components; the effects of Sirolimus, Everolimus, Temsirolimus and OSI-906 on cell proliferation; the effects of Sirolimus, OSI-906, and their combination, on cell secretion, proliferation, viability, cell cycle, apoptosis, invasion and migration. Moreover, intracellular mechanisms underlying these cell functions were evaluated in both cell lines. Our results show that HepG2 and HuH-7 present with the same mRNA expression profile with high levels of IGF2. OSI-906 inhibited cell proliferation at high concentration, while mTORi suppressed cell proliferation in a dose-time dependent manner in both cell lines. The co-treatment showed an additive inhibitory effect on cell proliferation and viability. This effect was not related to induction of apoptosis, but to G0/G1 phase block. Moreover, the co-treatment prevented the Sirolimus-induced AKT activation as escape mechanism. Both agents demonstrated to be differently effective in inhibiting α-FP secretion. Sirolimus, OSI-906, and their combination, blocked cell migration and invasion in HuH-7. These findings indicate that, co-targeting of IGF1R/IR and mTOR pathways could be a novel therapeutic approach in the management of HCC, in order to maximize antitumoral effect and to prevent the early development of resistance mechanisms

The role of mTOR inhibitors in the inhibition of growth and cortisol secretion in human adrenocortical carcinoma cells

Patients with adrenocortical carcinoma (ACC) need new treatment options. The aim of this study was to evaluate the effects of the mTOR inhibitors sirolimus and temsirolimus on human ACC cell growth and cortisol production. In H295, HAC15, and SW13 cells, we have evaluated mTOR, IGF2, and IGF1 receptor expressions; the effects of sirolimus and temsirolimus on cell growth; and the effects of sirolimus on apoptosis, cell cycle, and cortisol production. Moreover, the effects of sirolimus on basal and IGF2-stimulated H295 cell colony growth and on basal and IGF1-stimulated phospho-AKT, phospho-S6K1, and phospho-ERK in H295 and SW13 were studied. Finally, we have evaluated the effects of combination treatment of sirolimus with an IGF2-neutralizing antibody. We have found that H295 and HAC15 expressed IGF2 at a >1800-fold higher level than SW13. mTOR inhibitors suppressed cell growth in a dose-/time-dependent manner in all cell lines. SW13 were the most sensitive to these effects. Sirolimus inhibited H295 colony surviving fraction and size. These effects were not antagonized by IGF2, suggesting the involvement of other autocrine regulators of mTOR pathways. In H295, sirolimus activated escape pathways. The blocking of endogenously produced IGF2 increased the antiproliferative effects of sirolimus on H295. Cortisol production by H295 and HAC15 was inhibited by sirolimus. The current study demonstrates that mTOR inhibitors inhibit the proliferation and cortisol production in ACC cells. Different ACC cells have different sensitivity to the mTOR inhibitors. mTOR could be a target for the treatment of human ACCs, but variable responses might be expected. In selected cases of ACC, the combined targeting of mTOR and IGF2 could have greater effects than mTOR inhibitors alone