Role of positron emission tomography in the assessment of disease burden and risk of relapse in patients affected by giant cell arteritis.

Giant cell arteritis (GCA) is characterized by two subsets: cranial GCA and large-vessel GCA (LV-GCA); positron emission tomography (PET) is an essential tool in the diagnosis of LV-GCA. In this study, we aimed to investigate its potential prognostic value in the stratification of relapse risk. We retrospectively revised all the clinical records of patients who received a diagnosis of GCA at an immuno-rheumatology clinic of a University Hospital along 6 years and who underwent to a PET-CT examination at diagnosis. Clinical, laboratory, and imaging data were collected. Relapses were recorded. The study population included 19 patients (10 females, 52.6%; median age 74.0 [65.5-76.0] years), 12 with typical cranial GCA (63%) and 7 (37%) with LV-GCA. Based on PET findings, a diagnosis of aortitis was made in 15/19 patients, including 8/12 patients with a classical cranial GCA (58%). Along a median follow-up of 15 months [4.5-26.5], 4 relapses were observed. All relapsers were male; indeed, the difference in gender distribution was the only variable reaching statistical difference between relapsers and non-relapsers. Specifically, aortitis was not more frequent among relapsers. Our study confirms PET as a valid tool in the identification of LV-GCA with no cranial involvement. We failed to demonstrate a role for PET in the prognostic stratification of GCA, while male gender is suggested as a potential risk factor for GCA relapse.Key Points• A significant proportion of patients with GCA presents with non-cranial disease, the identification of which requires imaging studies, among which PET is particularly useful.• Aortitis might be detected also in patients with the classical, cranial GCA type but does not seem to have prognostic implications, at least in terms of relapse risk.• Male gender is suggested as a risk factor for relapse in GCA.

Role of molecular imaging in the management of patients affected by inflammatory bowel disease: State-of-the-art.

AIM: To present the current state-of-the art of molecular imaging in the management of patients affected by inflammatory bowel disease (IBD). METHODS: A systematic review of the literature was performed in order to find important original articles on the role of molecular imaging in the management of patients affected by IBD. The search was updated until February 2016 and limited to articles in English. RESULTS: Fifty-five original articles were included in this review, highlighting the role of single photon emission tomography and positron emission tomography. CONCLUSION: To date, molecular imaging represents a useful tool to detect active disease in IBD. However, the available data need to be validated in prospective multicenter studies on larger patient samples.

Thyroid Ultrasound and Other Imaging Procedures in the Pediatric Age.

The purpose of this review is to provide a reappraisal of the diagnostic imaging procedures for thyroid carcinoma in pediatric patients, including thyroid ultrasound (US), ultrasound-guided fine-needle aspiration biopsy (FNAB), scintigraphy, radiological techniques (CT, MR), and PET/CT. The most frequent indication for thyroid imaging is characterization of a palpable mass in the neck or thyroid gland. Thyroid US is a first-line examination for visualizing the thyroid gland as it provides anatomic and perfusion information; on the other hand, scintigraphy mostly provides functional information but combined with some anatomic information as well. CT and MRI have a supplemental role in these patients. Furthermore, with the introduction of PET/CT and the development of new imaging agents, nuclear medicine plays an important role in different phases of neoplastic disease in terms of both staging and evaluation of response to medical/surgical treatments.

The Value of Oro-Pharyngo-Esophageal Scintigraphy in the Management of Patients with Aspiration into the Tracheo-bronchial Tree and Consequent Dysphagia.

CONTEXT: Tracheo-bronchial aspiration is the most invalidating condition which can happen to patients affected by dysphagia, especially when caused by central neurologic disorders; the associated pneumonia episodes represent the most frequent cause of death in these patients. Oro-pharyngo-esophageal scintigraphy (OPES) allows both functional imaging and semiquantitative evaluation of the subsequent phases of swallowing. CASE REPORT: We evaluated by means of OPES a woman who had previously undergone high-dose external beam radiation therapy for a nasopharyngeal carcinoma, which determined tissue fibrosis and progressive dysphagia. CONCLUSION: In this patient with dysphagia, OPES was a simple, inexpensive, noninvasive, and reliable technique that allowed to show the presence of bolus aspiration and quantified tracheobronchial aspirate.

Current role of 111In-DTPA-octreotide scintigraphy in diagnosis of thymic masses.

AIMS AND BACKGROUND: Thymic tumors (thymomas and thymic carcinomas) represent 50% of all mediastinal tumors. Thymomas usually express high levels of somatostatin receptors, which enable in vivo imaging with 111In-DTPA-octreotide (OctreoScan®). The aim of this study was to further investigate the role of radionuclide techniques in the diagnosis, staging and follow-up of these tumors. METHODS: Eight patients (5 women, 3 men, age range 35-79 years; mean ± SD 56.1 ± 15.8 years) entered the study. In 4 patients, myasthenia gravis was the presenting symptom. 111In-DTPA-octreotide scan was performed within 3 weeks after contrast enhanced CT and/or MRI. Planar and tomographic images were acquired within 24 hours of the injection of 111 MBq OctreoScan. The scintigraphic results were defined in correlation with the histological findings. RESULTS: Histology revealed thymoma in 3 patients, thymic carcinoma in 1, insular carcinoma of presumably thymic origin in 1, thymic carcinoid in 1, and thymic hyperplasia in 2 patients. Two thymomas were at stage I, 1 thymoma and 1 thymic carcinoma at stage II, 1 insular carcinoma of presumably thymic origin at stage IV, and 1 thymic carcinoid at stage IV. OctreoScan consistently accumulated in primary and/or metastatic sites of thymic tumors while no radiotracer uptake was detected in the 2 patients with benign thymic hyperplasia. In 1 patient with a very large mediastinal mass (13 cm in largest diameter) and multiple metastatic deposits in the lungs, OctreoScan scintigraphy showed a large area of pathological uptake in the anterior mediastinum and a small area of focal uptake in the cervical-dorsal region of the right lung corresponding to a lymph node expressing somatostatin receptors. CONCLUSIONS: OctreoScan is avidly taken up by thymic tumors, enabling the diagnosis of these tumors and a better evaluation of their extension. It does not accumulate in thymic hyperplasia, thus allowing the differential diagnosis between these 2 pathological conditions. In patients affected by myasthenia gravis, OctreoScan scintigraphy can play an important role in characterizing thymic masses.

The diagnosis of GH deficiency in obese patients: a reappraisal with GHRH plus arginine testing after pharmacological blockade of lipolysis.

BACKGROUND: The diagnosis of GH deficiency (GHD) in obese patients is complicated by the reduced GH secretion associated with overweight. A GH response to GHRH+arginine lower than 4.2 microg/l is currently considered indicative of GHD in obesity. The aim of the study was to investigate the effect of acute pharmacological blockade of lipolysis on the GH response to GHRH+arginine in obese patients. PATIENTS AND METHODS: Two groups of patients were studied: 12 obese patients with proven GHD and 14 patients with essential obesity. On separate occasions, two tests were carried out in each patient: GHRH+arginine and GHRH+arginine preceded by acipimox. RESULTS: The mean GH peak after GHRH+arginine was significantly lower in hypopituitary patients than in subjects with essential obesity. Acipimox significantly increased the mean GH response in patients with essential obesity, but not in hypopituitary subjects. All hypopituitary patients and 7/14 patients with essential obesity displayed GH peaks lower than 4.2 microg/l after GHRH+arginine: the GH response to the test increased after acipimox pretreatment in five of these seven essentially obese subjects. After acipimox administration, free fatty acids (FFAs) significantly fell in both groups with comparable mean absolute decreases. All IGF1 values were normal in both groups of subjects. CONCLUSIONS: Our study has demonstrated that the acipimox-induced acute reduction of circulating FFA levels increases mean somatotropin response to GHRH+arginine in patients with essential obesity, whereas it has no effect in hypopituitary subjects. The current criterion for the diagnosis of GHD in obese patients may be misleading. Indeed, subjects affected by third degree obesity, like most of our patients, may be erroneously classified as really GH-deficient and started on an expensive unjustified treatment. It appears therefore that the current criteria for the diagnosis of GHD in obesity should be reconsidered in the light of further studies also taking into account different body mass index groups.

Amyloid peptide inhibits ATP release from human erythrocytes.

The oxygen required to meet metabolic needs of all tissues is delivered by the erythrocyte, a small, flexible cell, which, in mammals, is devoid of a nucleus and mitochondria. Despite its simple appearance, this cell has an important role in its own distribution, enabling the delivery of oxygen to precisely meet localized metabolic need. When an erythrocyte enters in a hypoxic area, a signalling pathway is activated within the cell resulting in the release of ATP in amounts adequate to activate purinergic receptors on vascular endothelium, which trigger secretion of nitric oxide and other factors resulting in vasodilatation. Among other mechanisms, binding of deoxyhemoglobin to the cytoplasmic domain of the anion-exchange protein band 3 is probably involved in this pathway. The present study investigates the effect of amyloid beta peptide exposure on this molecular mechanism. We report that deoxygenated human erythrocytes fail to release ATP following 24 h exposure to amyloid beta peptide. Concurrently, amyloid beta peptide induces caspase 3 activation. Preincubation of amyloid beta peptide treated erythrocytes with a specific inhibitor of caspase 3 prevents amyloid-induced caspase 3 activation and restores the erythrocyte's ability to release ATP under deoxygenated conditions. Since the activity of red cell phosphofructokinase, a key step in glycolytic flux, is not modified within the red cell following amyloid peptide exposure, it is likely that ATP release reduction is not dependent on glycolytic flux alterations. It has also been suggested that the heterotrimeric G protein, Gi, and adenylyl cyclase are downstream critical components of the pathway responsible for ATP release. We show that cAMP synthesis and ATP release are not failed in amyloid-peptide-treated erythrocytes in response to incubation with mastoparan 7 or forskolin plus 3-isobutyl-1-methyl xanthine, agents that stimulate cAMP synthesis. In conclusion, these results indicate that amyloid beta peptide inhibits ATP release from deoxygenated erythrocytes by activating red cell caspase 3, suggesting a pathophysiologic role for vascular amyloid peptide in Alzheimer's disease.

Mitochondrial oxygen consumption inhibition importance for TMT-dependent cell death in undifferentiated PC12 cells.

The evolving role of mitochondria as a target for different death-inducing noxae prompted us to investigate trimethyltin (TMT)-dependent effects on mitochondrial functionality. For this purpose, we used a homogeneous cell culture model represented by undifferentiated PC12 cells. Mitochondria isolated from PC12 cells treated with TMT for 6, 12 and 24h, showed a time-dependent inhibition of ADP-stimulated oxygen consumption using succinate or glutamate/malate as substrate. Using a fluorescent assay, the effect of TMT on mitochondrial membrane potential (delta Psi) in PC12 cells was also determined. After 24h in culture, a strong loss of mitochondrial membrane potential (delta Psi) was observed in TMT-treated cells. Collapse of mitochondrial membrane potential correlated with an increased expression of bax/bcl-2 ratio, as evaluated by polymerase chain reaction. Western blotting and spectrophotometric analysis showed that cytochrome c release and activation of caspase 3 were concurrently induced. Our findings suggest that inhibition of mitochondrial respiration represents the early toxic event for cell death in PC12 due to trimethyltin.

Fragment 31-35 of beta-amyloid peptide induces neurodegeneration in rat cerebellar granule cells via bax gene expression and caspase-3 activation. A crucial role for the redox state of methionine-35 residue.

The amyloid beta-peptide (AbetaP) is the major protein component of brain senile plaques in Alzheimer's disease. The redox state of methionine-35 residue plays a critical role in peptide neurotoxic actions. We used the fragment 31-35 of AbetaP [AbetaP(31-35)], containing a single methionine-35 residue (Met-35), to investigate the relationship between the oxidative state of Met-35 and neurotoxic and pro-apoptotic actions induced by the peptide; in rat cerebellar granule cells (CGC), we compared the effects of AbetaP(31-35), in which the Met-35 is present in the reduced state, with those of a modified peptide with oxidized Met-35 [AbetaP(31-35)Met-35(OX)](,) as well as an AbetaP-derivative with Met-35 substituted by norleucine [AbetaP(31-35)Nle-35]. AbetaP(31-35) induced a time-dependent decrease in cell viability. AbetaP(31-35)Met-35(OX) was significantly less potent, but still induced a significant decrease in cell viability compared to control. No toxic effects were observed after treatment with AbetaP(31-35)Nle-35. AbetaP(31-35) induced a 2-fold increase in bax mRNA levels after 4h, whereas AbetaP(31-35)Met-35(OX) raised bax mRNA levels by 41% and AbetaP(31-35)Nle-35 had no effect. Finally, AbetaP(31-35) caused a 43% increase in caspase-3 activity after 24h; AbetaP(31-35)Met-35(OX) caused only a 18% increase, and AbetaP(31-35)Nle-35 had no effect. These findings suggest that AbetaP(31-35)-induced neurodegeneration in CGC is mediated by a selective early increase in bax mRNA levels followed by delayed caspase-3 activation; the redox state of the single Met-35 residue is crucial in the occurrence and extent of the above phenomena.

Abeta(31-35) and Abeta(25-35) fragments of amyloid beta-protein induce cellular death through apoptotic signals: Role of the redox state of methionine-35.

In order to clarify the basis of neuronal toxicity exerted by the shortest active peptides of amyloid beta-protein (Abeta), the toxic effects of Abeta(31-35) and Abeta(25-35) peptides on isolated rat brain mitochondria were investigated. The results show that exposure of isolated rat brain mitochondria to Abeta(31-35) and Abeta(25-35) peptides determines: (i) release of cytochrome c; (ii) mitochondrial swelling and (iii) a significant reduction in mitochondrial oxygen consumption. In contrast, the amplitude of these events resulted attenuated in isolated brain mitochondria exposed to the Abeta(31-35)Met35(OX) in which methionine-35 was oxidized to methionine sulfoxide. The Abeta peptide derivative with norleucine substituting Met-35, i.e., Abeta(31-35)Nle-35, had not effect on any of the biochemical parameters tested. We have further characterized the action of Abeta(31-35) and Abeta(25-35) peptides on neuronal cells. Taken together our result indicate that Abeta(31-35) and Abeta(25-35) peptides in non-aggregated form, i.e., predominantly monomeric, are strongly neurotoxic, having the ability to enter within the cells, determining mitochondrial damage with an evident trigger of apoptotic signals. Such a mechanism of toxicity seems to be dependent by the redox state of methionine-35.

Effect of nitric oxide on the transport and release of oxygen in fetal blood.

It is well known that nitric oxide (NO), the most important vasodilator agent, plays an important role in lowering vascular resistance in the human umbilical-placental circulation and that its deficiency is related to the pathogenesis of pre-eclamptic disorder. Besides it has recently been demonstrated that human hemoglobin (HbA) is able to transport nitric oxide, as S-nitrosohemoglobin (SNO-Hb), from the arterial to the venous blood. In the present study we examine the functional properties of the adult and fetal nitrosated hemoglobins to see if the double transport of oxygen and NO may influence the fetal oxygenation and the relation between maternal and fetal blood. Our results show that S-nitrosation significantly increases the oxygen affinity of the adult Hb (HbA) with respect to native protein (no-nitrosated) while the functional properties of HbF are less influenced. The oxygen affinity modification, found for SNO-HbA, was ascribed to the nitrosation of cysteine beta 93: really, the same residue is also present in the gamma chains of fetal hemoglobin, while the increase of affinity is less evidenced; hence, it is probable that the 39 aminoacidic substitutions between beta and gamma chains allay the effects of S-nitrosation. As regards the physiological modulators (protons, chloride ions, 2,3-diphosphoglyceric acid, and temperature), they influence the oxygen affinity of the two hemoglobins S-nitrosated, in equal mode with respect to the native forms determining the same variation on the oxygen affinity. Hence, our results evidence the fact that the NO release by SNO-HbA "in vivo" would be limited to regions of extremely low oxygen tension (such as hypoxic regions), while in fetus, SNO-HbF would unload nitric oxide and oxygen at pressure values close to normal.