Krystallenia I. Alexandraki

Inflammatory Process in Type 2 Diabetes

Abstract:u2002 Population‐based studies have shown strong relationship between inflammatory markers and metabolic disturbances, obesity, and atherosclerosis, whereas inflammation has been considered as a “common soil” between these clinical entities and type 2 diabetes (T2D). The accumulation of macrophages in adipose tissue (AT), the common origin of macrophages and adipocytes, the prevalent presence of peripheral mononuclear cells, and apoptotic β cells by themselves seem to be the sources of inflammation present in T2D, since they generate the mediators of the inflammatory processes, namely cytokines. The main cytokines involved in the pathogenesis of T2D are interleukin‐1β (IL‐1β), with an action similar to the one present in type 1 diabetes, tumor necrosis factor‐α (TNF‐α), and IL‐6, considered as the main regulators of inflammation, leptin, more recently introduced, and several others, such as monocyte chemoattractant protein‐1, resistin, adiponectin, with either deleterious or beneficial effects in diabetic pathogenesis. The characterization of these molecules targeted diabetes treatment beyond the classical interventions with lifestyle changes and pharmaceutical agents, and toward the determination of specific molecular pathways that lead to low grade chronic inflammatory state mainly due to an immune systems unbalance.

Inflammatory and endothelial markers in women with polycystic ovary syndrome

Backgroundu2002 Women with polycystic ovary syndrome (PCOS) carry a pattern of cardiovascular risk factors. Endothelial dysfunction and chronic inflammation are early findings in the atherosclerotic process. The purpose of the study was to investigate the coexistence of active inflammation markers and endothelial dysfunction in young women with PCOS, and their relationship with metabolic and hormonal abnormalities of the syndrome.

Cytokine Secretion in Long-standing Diabetes Mellitus Type 1 and 2: Associations with Low-grade Systemic Inflammation

Low-grade systemic chronic inflammation is a very well-known feature of diabetes mellitus (DM). The purpose of this study was the assessment of the proinflammatory cytokine secretion profile in long-standing diabetes along with the presence of features of systemic inflammation. Metabolic parameters and serum high-sensitivity C-reactive protein, interleukin-1β, interleukin-6, and tumor necrosis factor-α levels were determined in 20 patients with type 1 DM and 21 patients with type 2 DM and compared to 34 healthy subjects. The number of cytokine-secreting peripheral blood mononuclear cells (PBMCs), before and after mitogenic stimulation, was also determined in the same groups. Adverse lipid profile, higher levels of inflammatory markers, and higher count of cytokine-secreting cells were observed more prevalently in type 2 diabetics than in controls. After stimulation, the increase in number of cytokine-secreting cells was higher in controls. In conclusion, patients with DM have evidence of low-grade inflammation and abnormal PBMC function that could be related to long-term sequelae, the accelerated atherosclerotic process, and the susceptibility to infections.

The prevalence and characteristic features of cyclicity and variability in Cushing's disease

OBJECTIVEnCyclical Cushings syndrome may render the diagnosis and management of Cushings disease difficult. The aim of the present study was to investigate the prevalence of cyclicity and variability in patients with Cushings disease, and to identify putative distinctive features.nnnDESIGNnRetrospective case-note study.nnnMETHODSnWe analysed the case records of 201 patients with Cushings disease in a retrospective case-note study. Cyclicity was considered as the presence of at least one cycle, defined as a clinical and/or biochemical hypercortisolaemic peak followed by clinical and biochemical remission, followed by a new clinical and/or biochemical hypercortisolaemic peak. The fluctuations of mean serum cortisol levels, as assessed by a 5-point cortisol day curve, defined the variability.nnnRESULTSnThirty (14.9%; 26 females) patients had evidence of cyclicity/variability. Cycling patients were older but no difference in sex or paediatric distribution was revealed between cycling and non-cycling patients. The median number of cycles was two for each patient, and 4 years was the median intercyclic period. A trend to lower cure rate post-neurosurgery and lower adenoma identification was observed in cycling compared with non-cycling patients. In multivariate analysis, older patients, longer follow-up, female sex and no histological identification of the adenoma were associated with an increased risk of cyclic disease.nnnCONCLUSIONSnThis large population study reveals that cyclicity/variability is not an infrequent phenomenon in patients with Cushings disease, with a minimum prevalence of 15%. Physicians should be alert since it can lead to frequent problems in diagnosis and management, and no specific features can be used as markers.

Patients with apparently nonfunctioning adrenal incidentalomas may be at increased cardiovascular risk due to excessive cortisol secretion.

CONTEXTnAlthough adrenal incidentalomas (AIs) are associated with a high prevalence of cardiovascular risk (CVR) factors, it is not clear whether patients with nonfunctioning AI (NFAI) have increased CVR.nnnOBJECTIVEnOur objective was to investigate CVR in patients with NFAI.nnnDESIGN AND SETTINGnThis case-control study was performed in a tertiary general hospital.nnnSUBJECTSnSUBJECTS included 60 normotensive euglycemic patients with AI and 32 healthy controls (C) with normal adrenal imaging.nnnMAIN OUTCOME MEASURESnAll participants underwent adrenal imaging, biochemical and hormonal evaluation, and the following investigations: 1) measurement of carotid intima-media thickness (IMT) and flow-mediated dilatation, 2) 2-hour 75-gram oral glucose tolerance test and calculation of insulin resistance indices (homeostasis model assessment, quantitative insulin sensitivity check, and Matsuda indices), 3) iv ACTH stimulation test, 4) low-dose dexamethasone suppression test, and 5) NaCl (0.9%) post-dexamethasone saline infusion test.nnnRESULTSnBased on cutoffs obtained from controls, autonomous cortisol secretion was documented in 26 patients (cortisol-secreting AI [CSAI] group), whereas 34 exhibited adequate cortisol and aldosterone suppression (NFAI group). IMT measurements were higher and flow-mediated vasodilatation was lower in the CSAI group compared with both NFAI and C and in the NFAI group compared with C. The homeostasis model assessment index was higher and quantitative insulin sensitivity check index and Matsuda indices were lower in the CSAI and NFAI groups compared with C as well as in CSAI compared with the NFAI group. The area under the curve for cortisol after ACTH stimulation was higher in the CSAI group compared with the NFAI group and C and in the NFAI group compared with C. In the CSAI group, IMT correlated with cortisol, urinary free cortisol, and cortisol after a low-dose dexamethasone suppression test, whereas in the NFAI group, IMT correlated with area under the curve for cortisol after ACTH stimulation and urinary free cortisol.nnnCONCLUSIONSnPatients with CSAI without hypertension, diabetes, and/or dyslipidemia exhibit adverse metabolic and CVR factors. In addition, NFAIs are apparently associated with increased insulin resistance and endothelial dysfunction that correlate with subtle but not autonomous cortisol excess.

Gastroenteropancreatic neuroendocrine tumors: new insights in the diagnosis and therapy

Gastroenteropancreatic neuroendocrine tumors (GEP-NETs) are relatively rare and heterogenous malignancies. Recent advances in histopathological classification according to the anatomical site of origin, proliferation rate, and extend of the disease have created a valid and powerful tool for the prognostic stratification of GEP-NETs. Chromogranin A is still the best available marker used for the biochemical confirmation of these tumors, but new more sensitive markers are urgently required. Although scintigraphy with 111In-octreotide has widely been applied for the localization and staging of GEP-NETs, newer imaging modalities based on the functional characteristics of these tumors are evolving aiming not only to facilitate the diagnosis but also prognosis and evaluation of treatment. Somatostatin receptors are the primary therapeutic targets through somatostatin analogs and peptide receptor radionuclide therapy (PRRT) producing symptomatic, biochemical and to a lesser extent antiproliferative effects. Due to the relatively limited and erratic response to chemotherapy, new molecular targeted therapies exploiting some of the biological properties of GEP-NETs such as increased vascularity and inhibition of pathways involved in downstream signal transduction have evolved. Some of these therapies, the mTOR inhibitor everolimus and the tyrosine kinase inhibitor sunitinib, have been recently validated in phase III studies producing practice changing outcomes. In addition, two oral chemotherapeutic agents temozolomide and capecitabine, show promising effects and may replace streptozotocin-based regimens whereas combination therapies with the angiogenesis inhibitor bevacizumab are being investigated. Although progression free survival is used as a feasible primary end point due to the long survival of patients even in the presence of extensive disease prolongation of overall survival following the introduction of new therapies needs to be established.

Effect of long-term orlistat treatment on serum levels of advanced glycation end-products in women with polycystic ovary syndrome

Backgroundu2002 Women with polycystic ovary syndrome (PCOS) exhibit elevated serum advanced glycation end‐products (AGE) compared with healthy subjects. Short‐term administration of orlistat has been shown to reduce the postmeal increase in serum AGE levels in women with PCOS and in controls.

Long-term follow-up of a large series of patients with type 1 gastric carcinoid tumors. Data from a multicenter study.

OBJECTIVEnTo study the clinical presentation, diagnostic approach, response to treatment, and the presence of other pathologies in patients with gastric carcinoid type 1 (GC 1) tumors.nnnDESIGN AND METHODSnRetrospective analysis of 111 patients from four institutions and a mean follow-up of 76 months.nnnRESULTSnThe main indications for gastroscopy were upper gastrointestinal tract symptoms. The mean number of lesions, maximum tumoral diameter, and percentage of cells expressing Ki-67 labeling index were 3.6±3.8, 8±12.1 mm and 1.9±2.4% respectively. Serum gastrin and chromogranin A (CgA) levels were elevated in 100/101 and 85/90 patients respectively. Conventional imaging studies demonstrated pathology in 9/111 patients. Scintigraphy with radiolabeled octreotide was positive in 6/60 without revealing any additional lesions. From the 59 patients who had been followed-up without any intervention, five developed tumor progression. Thirty-two patients were treated with long-acting somatostatin analogs (SSAs), leading to a significant reduction of gastrin and CgA levels, number of visible tumors, and CgA immune-reactive tumor cells in 28, 19, 27, and 23 treated patients respectively. Antrectomy and/or gastrectomy were initially performed in 20 patients and a complete response was achieved in 13 patients. The most common comorbidities were vitamin B12 deficiency, thyroiditis, and parathyroid adenomas.nnnCONCLUSIONSnMost GCs1 are grade 1 (82.7%) tumors presenting with stage I (73.9%) disease with no mortality after prolonged follow-up. Ocreoscan did not provide further information compared with conventional imaging techniques. Treatment with SSAs proved to be effective for the duration of administration.

MANAGEMENT OF ENDOCRINE DISEASE: Hyperandrogenism after menopause

Postmenopausal hyperandrogenism is a state of relative or absolute androgen excess originating from either the adrenals and/or the ovaries, clinically manifested as the appearance and/or increase in terminal hair growth or the development of symptoms/signs of virilization. In either settings, physicians need to evaluate such patients and exclude the presence of the relatively rare but potentially life-threatening underlying tumorous causes, particularly adrenal androgen-secreting tumors. It has been suggested that the rapidity of onset along with severity of symptom and the degree of androgen excess followed by relevant imaging studies may suffice to identify the source of excessive androgen secretion. However, up to date, there is no consensus regarding specific clinical and hormonal indices and/or imaging modalities required for diagnostic certainty. This is particularly relevant as the aging population is increasing and more cases of postmenopausal women with clinical/biochemical evidence of hyperandrogenism may become apparent. Furthermore, the long-term sequels of nontumorous hyperandrogenism in postmenopausal women in respect to cardiovascular morbidity and mortality still remain unsettled. This review delineates the etiology and pathophysiology of relative and absolute androgen excess in postmenopausal women. Also, it attempts to unravel distinctive clinical features along with specific hormonal cut-off levels and/or appropriate imaging modalities for the facilitation of the differential diagnosis and the identification of potential long-term sequels.

Somatostatin and dopamine receptor expression in neuroendocrine neoplasms: correlation of immunohistochemical findings with somatostatin receptor scintigraphy visual scores

The expression of somatostatin (sstr1‐5) and dopamine (DR) receptors in neuroendocrine neoplasms (NENs) facilitates diagnosis by tumour visualization with somatostatin receptor scintigraphy (SRS) and directs towards specific treatment with peptide receptor radionuclide therapy (PRRT) with radiolabelled somatostatin analogues.