1,720,999 research outputs found
Somatic and germline mutations in NETs: Implications for their diagnosis and management
No full textIt is now understood that specific somatic and germline mutations may lead to the development of the neuroendocrine tumours (NETs). NETs usually occur as sporadic isolated tumours, although they also may present as part of complex familial endocrine cancer syndromes, such as multiple endocrine neoplasia type 1 (MEN1) and type 2 (MEN2), Von Hippel-Lindau (VHL) and neurofibromatosis syndromes, tuberous sclerosis, Carney triad and dyad, Reed syndrome and polycythaemia-paraganglioma syndromes. Only in MEN2 syndrome is there a specific genotype-phenotype correlation, although in both sporadic and syndromic NETs some gene mutations are associated with specific clinico-pathological features and prognosis. There have been several advances in our understanding of the NETs leading to earlier detection and targeted therapeutic treatment, but given the poor prognosis associated with metastatic NETs, it will be necessary to find new biomarkers for the prediction of malignant potential and to find novel therapeutic targets for NETs
Hypoadrenalism: Primary and secondary adrenal failure
No full textPrimary adrenal failure has a prevalence of around 1/20,000. In the past, the primary cause was tuberculosis, but in the developed world most cases are now due to autoimmune adrenal failure, diagnosed in its early stages by the presence of antibodies to the enzyme 21-hydroxylase (although these decrease over time). This may be associated with other auto-immune diseases such as Hashimoto’s thyroiditis, premature ovarian failure, hypoparathyroidism, pernicious anaemia and type 1 diabetes mellitus. There is some evidence that the actual tissue destruction is T-cell mediated. Other causes included metastatic adrenal infiltration, bilateral adrenal haemorrhage, lupus anti-coagulant, histoplasmosis and various genetic disorders (familial glucocorticoid deficiency, primary adrenal hypoplasia, adrenoleukodystrophy, etc.). The symptoms are often very nonspecific, including malaise, nausea and vomiting, but on examination the hypovolaemia is associated with skin pigmentation due to activation of melanotrophs by the high circulating of ACTH. Diagnosis is made by the association of low serum cortisol with high levels of ACTH, but more rapidly by the subnormal response of serum cortisol to Synacthen (ACTH 1-24). Plasma renin is elevated and aldosterone suppressed. Secondary adrenal failure is due to hypothalamic or pituitary dysfunction, and the symptoms and signs are often milder. Cortisol is low, as is plasma ACTH, but renin and aldosterone levels are normal. Treatment is with hydrocortisone, usually best in divided doses (typically 10, 5 and 5 mg daily), plus fludrocortisone once-daily in the case of primary adrenal failure. There are slow-release forms of hydrocortisone becoming available. Doses of hydrocortisone need to be increased during acute stress and an emergency pack of hydrocortisone should be available. Care must be taken to avoid under-replacement and consequent on-going fatigue, or over-replacement and the metabolic syndrome. Some patients may additionally benefit from DHEA
Stili di vita e prevenzione della malattie cronico-degenerative
No full textAlla base della maggior parte delle patologie croniche, quali le malattie cardiovascolari, i tumori ed il diabete, ci sono fattori di rischio intermedi ormai ben noti rappresentati da obesità, dislipidemia, iperglicemia e ipertensione, responsabili della maggior parte dei decessi soprattutto nei paesi industrializzati. La presenza di questi fattori di rischio intermedi si può spesso ricondurre a quattro stili di vita non corretti in termini di salute, quali l’abitudine al fumo di tabacco, un’alimentazione non sana, la sedentarietà e l’abuso di alcolici. Per questo agire in modo coordinato e integrato sui principali fattori di rischio modificabili diventa una priorità non solo dei programmi sanitari, ma anche di ogni medico, per migliorare la salute, la qualità della vita e il benessere del singolo e della società in generale
Sarcopenic obesity and the impact on bone health
No full textPurpose of review: Sarcopenic obesity is a newly identified pathological entity defined by an increase in body fat mass with an associated sarcopenia, characterized by loss of muscle mass, strength, and function. Recently, the concomitant presence of skeletal alteration with sarcopenic obesity has been described leading to a new clinical entity defined osteosarcopenic obesity (OSO). Many studies have tried to unravel the metabolic complex mechanism leading to this clinical entity in order to understand the pathophysiology of this complex condition with the aim of posing an early diagnosis to improve the therapeutic approaches. The purpose of this narrative review is to highlight and revise recent studies on this issue. Recent findings: Recent research in the field of OSO has highlighted the role of nutrition and physical activity in the development and management of these conditions. While molecular and cellular pathways remain partially understood, there is a growing focus on lifestyle interventions as key factors in reducing the impact of OSO. These studies emphasize the need for early diagnosis and appropriate therapeutic strategies to improve quality of life and decrease morbidity and mortality associated with OSO. Summary: Although the pathophysiological pathways underlying OSO are not fully understood, the clinical implications underscore the need for expanded research in this field. This research is crucial for enabling early diagnosis and implementing effective therapeutic interventions, with the goal of reducing morbidity and mortality and enhancing quality of life
Nutritional and metabolic aspects related to vulvodynia: What do we really know?
No full textObjectives: Vulvodynia is an emerging health problem, still insufficiently studied, that causes a significant reduction in quality of life in many women and individuals assigned female sex at birth. Little is known about the effects of diet and metabolic disorders on this condition. The objective of this study was to review currently available evidence on the diet and the nutritional and metabolic status of patients affected by vulvodynia. Methods: Published articles were systematically searched in the PubMed, Scopus, and Web of Science databases. Results: The few available studies that reported data on patients' body mass index (BMI) described a BMI within the normal range in most patients affected by vulvodynia, showing no difference or a slightly lower BMI with respect to control individuals. Data on the relationship between metabolic diseases and vulvodynia are lacking. Regarding nutrition, the few available data do not support the prescription of a low-oxalate diet in women with vulvodynia. To date, studies on other dietary behaviors are also lacking. Conclusions: This review emphasizes-for the first time, to our knowledge-the lack of data and the importance of conducting prospective studies investigating the nutritional and metabolic aspects related to the onset, maintenance, and therapy of vulvodynia
Fixing the broken clock in adrenal disorders: focus on glucocorticoids and chronotherapy
Full text linkThe circadian rhythm derives from the integration of many signals that shape the expression of clock-related genes in a 24-hour cycle. Biological tasks, including cell proliferation, differentiation, energy storage and immune regulation, are preferentially confined to specific periods. A gating system, supervised by the central and peripheral clocks, coordinates the endogenous and exogenous signals and prepares for transition to activities confined to periods of light or darkness. The fluctuations of cortisol and its receptor are crucial in modulating these signals. Glucocorticoids and the autonomous nervous system act as a bridge between the suprachiasmatic master clock and almost all peripheral clocks. Additional peripheral synchronizing mechanisms including metabolic fluxes and cytokines stabilize the network. The pacemaker is amplified by peaks and troughs in cortisol and their response to food, activity, and inflammation. However, when the glucocorticoid exposure pattern becomes chronically flattened at high (as in Cushing's syndrome) or low (as in adrenal insufficiency) levels, the system fails. While endocrinologists are well aware of cortisol rhythm, too little attention has been given to interventions aimed at restoring physiological cortisol fluctuations in adrenal disorders. However, acting on glucocorticoid levels may not be the only way to restore clock-related activities. First, a counterregulatory mechanism on the glucocorticoid receptor itself controls signal transduction, and second, melatonin and/or metabolically active drugs and nutrients could also be used to modulate the clock. All these aspects are described herein, providing some insights into the emerging role of chronopharmacology, focusing on glucocorticoid excess and deficiency disorders
Non-canonical effects of ACTH: insights into adrenal insufficiency
Full text linkIntroduction: Adrenocorticotropic hormone (ACTH) is produced from proopiomelanocortin, which is predominantly synthetized in the corticotroph and melanotroph cells of the anterior and intermediate lobes of the pituitary gland and the arcuate nucleus of the hypothalamus. Although ACTH clearly has an effect on adrenal homeostasis and maintenance of steroid hormone production, it also has extra-adrenal effects that require further elucidation.
Methods: We comprehensively reviewed English language articles, regardless of whether they reported the presence or absence of adrenal and extra-adrenal ACTH effects.
Results: In the present review, we provide an overview on the current knowledge on adrenal and extra-adrenal effects of ACTH. In the section on adrenal ACTH effects, we focused on corticosteroid rhythmicity and effects on steroidogenesis, mineralocorticoids
and adrenal growth. In the section on extra-adrenal effects, we have analyzed the effects of ACTH on the osteoarticular and reproductive systems, adipocytes, immune system, brain and skin. Finally, we focused on adrenal insufficiency.
Conclusions: The role of ACTH in maintaining the function of the hypothalamic–pituitary–adrenal axis is well known. Conversely, if we broaden our vision and analyze its role as a potential treatment strategy in other conditions, it will be evident in the literature that
researchers seem to have abandoned this aspect in studies conducted several years ago.
We believe it is worth re-evaluating the role of ACTH considering its noncanonical effects on the adrenal gland itself and on extra-adrenal organs and tissues; however, this would not have been possible without the recent advances in the pertinent technologies
The immune system in Cushing's syndrome
No full textCushing's syndrome (CS), or chronic hypercortisolism, induces a variety of alterations in the immune system, often leading to severe clinical complications such as sepsis and opportunistic infections. Prolonged exposure to high levels of glucocorticoids (GC), changes in the circadian rhythm, and the comorbidities associated therewith all combine to cause profound changes in the immune profile of affected patients. While traditionally associated with generalized immune suppression, such changes actually comprise a much more complex scenario, sharing traits with chronic inflammatory disorders. Persistently increased levels of interleukin-1 (IL-1), interleukin-6 (IL-6), and tumor necrosis factor alpha (TNFα) and adipose tissue infiltration by immune cells lead to a chronic, nonresolving, inflammatory state. The combination of low-grade inflammation and selectively impaired immune response is thought to play a major role in the pathogenesis of clinical complications of CS, including diabetes, lipodystrophy, visceral adiposity, atherosclerosis, osteoporosis, and cognitive impairment. This dysregulation also explains rebound phenomena when CS is treated, involving new clinical complications sustained by an excessive immune response and autoimmunity. The aim of this review is to summarize the available evidence on the immune system in chronic hypercortisolism, while describing the main mechanisms of immune derangement and their role in the increased mortality and morbidity seen in this complex disease. A better understanding of immune system alterations in CS could help improve risk stratification, offer novel biomarkers, and provide the basis for more tailored therapies and post-remission follow-up
The spectrum of haemostatic abnormalities in glucocorticoid excess and defect
No full textGlucocorticoids (GCs) target several components of the integrated system that preserves vascular integrity and free blood flow. Cohort studies on Cushing's syndrome (CS) have revealed increased thromboembolism, but the pathogenesis remains unclear. Lessons from epidemiological data and post-treatment normalisation time suggest a bimodal action with a rapid and reversible effect on coagulation factors and an indirect sustained effect on the vessel wall. The redundancy of the steps that are potentially involved requires a systematic comparison of data from patients with endogenous or exogenous hypercortisolism in the context of either inflammatory or non-inflammatory disorders. A predominant alteration in the intrinsic pathway that includes a remarkable rise in factor VIII and von Willebrand factor (vWF) levels and a reduction in activated partial thromboplastin time appears in the majority of studies on endogenous CS. There may also be a rise in platelets, thromboxane B2, thrombin-antithrombin complexes and fibrinogen (FBG) levels and, above all, impaired fibrinolytic capacity. The increased activation of coagulation inhibitors seems to be compensatory in order to counteract disseminated coagulation, but there remains a net change towards an increased risk of venous thromboembolism (VTE). Conversely, GC administered in the presence of inflammation lowers vWF and FBG, but fibrinolytic activity is also reduced. As a result, the overall risk of VTE is increased in long-term users. Finally, no studies have assessed haemostatic abnormalities in patients with Addison's disease, although these may present as a consequence of bilateral adrenal haemorrhage, especially in the presence of antiphospholipid antibodies or anticoagulant treatments. The present review aimed to provide a comprehensive overview of the complex alterations produced by GCs in order to develop better screening and prevention strategies against bleeding and thrombosis
Molecular pathology of well-differentiated gastro-entero-pancreatic neuroendocrine tumors
No full textWell differentiated neuroendocrine tumors (NETs) arising in the gastrointestinal and pancreaticobiliary system are the most common neuroendocrine neoplasms. Studies of the molecular basis of these lesions have identified genetic mutations that predispose to familial endocrine neoplasia syndromes and occur both as germline events and in sporadic tumors. The mutations often involve epigenetic regulators rather than the oncogenes and tumor suppressors that are affected in other malignancies. Somatic copy number alterations and miRNAs have also been implicated in the development and progression of some of these tumors. The molecular profiles differ by location, but many are shared by tumors in other sites, including those outside the gastroenteropancreatic system. The approach to therapy relies on both the neuroendocrine nature of these tumors and the identification of specific alterations that can serve as targets for precision oncologic approaches
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