Pietro Milone

Traumatic Brain Injury: Oxidative Stress and Neuroprotection

SIGNIFICANCE A vast amount of circumstantial evidence implicates high energy oxidants and oxidative stress as mediators of secondary damage associated with traumatic brain injury. The excessive production of reactive oxygen species due to excitotoxicity and exhaustion of the endogenous antioxidant system induces peroxidation of cellular and vascular structures, protein oxidation, cleavage of DNA, and inhibition of the mitochondrial electron transport chain. RECENT ADVANCES Different integrated responses exist in the brain to detect oxidative stress, which is controlled by several genes termed vitagens. Vitagens encode for cytoprotective heat shock proteins, and thioredoxin and sirtuins. CRITICAL ISSUES AND FUTURE DIRECTIONS This article discusses selected aspects of secondary brain injury after trauma and outlines key mechanisms associated with toxicity, oxidative stress, inflammation, and necrosis. Finally, this review discusses the role of different oxidants and presents potential clinically relevant molecular targets that could be harnessed to treat secondary injury associated with brain trauma.

Redox regulation of cellular stress response in multiple sclerosis

Multiple sclerosis (MS) is an autoimmune-mediated neurodegenerative disease with characteristic foci of inflammatory demyelination in the brain, spinal cord, and optic nerves. Recent studies have demonstrated not only that axonal damage and neuronal loss are significant pathologic components of MS, but that this neuronal damage is thought to cause the permanent neurologic disability often seen in MS patients. Emerging finding suggests that altered redox homeostasis and increased oxidative stress, primarily implicated in the pathogenesis of MS, are a trigger for activation of a brain stress response. Relevant to maintenance of redox homeostasis, integrated mechanisms controlled by vitagenes operate in brain in preserving neuronal survival during stressful conditions. Vitagenes encode for heat shock proteins (Hsp) Hsp32, Hsp70, the thioredoxin and the sirtuin protein systems. In the present study we assess stress response mechanisms in the CSF, plasma and lymphocytes of control patients compared to MS patients. We found that the levels of vitagenes Hsp72, Hsc70, HO-1, as well as oxidative stress markers carbonyls and hydroxynonenals were significantly higher in the blood and CSF of MS patients than in control patients. In addition, an increased expression of Trx and sirtuin 1, together with a decrease in the expression of TrxR were observed. Our data strongly support a pivotal role for redox homeostasis disruption in the pathogenesis of MS and, consistently with the notion that new therapies that prevent neurodegeneration through nonimmunomodulatory mechanisms can have a tremendous potential to work synergistically with current MS therapies, unravel important targets for new cytoprotective strategies.

Cellular stress response, sirtuins and UCP proteins in Alzheimer disease: role of vitagenes

Alzheimer’s Disease (AD) is a neurodegenerative disorder affecting up to one third of individuals reaching the age of 80. Different integrated responses exist in the brain to detect oxidative stress which is controlled by several genes termed Vitagenes. Vitagenes encode for cytoprotective heat shock proteins (Hsp), as well as thioredoxin, sirtuins and uncouple proteins (UCPs). In the present study we evaluate stress response mechanisms in plasma and lymphocytes of AD patients, as compared to controls, in order to provide evidence of an imbalance of oxidant/antioxidant mechanisms and oxidative damage in AD patients and the possible protective role of vitagenes.We found that the levels of Sirt-1 and Sirt-2 in AD lymphocytes were significantly higher than in control subjects. Interestingly, analysis of plasma showed in AD patients increased expression of Trx, a finding associated with reduced expression of UCP1, as compared to control group.This finding can open up new neuroprotective strategies, as molecules inducing this defense mechanisms can represent a therapeutic target to minimize the deleterious consequences associated to oxidative stress, such as in brain aging and neurodegenerative disorders.

Nevus vascularis mixtus (cutaneous vascular twin nevi) associated with intracranial vascular malformation of the Dyke–Davidoff–Masson type in two patients

The term twin spotting refers to phenotypes characterized by the spatial and temporal co‐occurrence of two (or more) different nevi arranged in variable cutaneous patterns, and can be associated with extra‐cutaneous anomalies. Several examples of twin spotting have been described in humans including nevus vascularis mixtus, cutis tricolor, lesions of overgrowth, and deficient growth in Proteus and Elattoproteus syndromes, epidermolytic hyperkeratosis of Brocq, and the so‐called phacomatoses pigmentovascularis and pigmentokeratotica. We report on a 28‐year‐old man and a 15‐year‐old girl, who presented with a previously unrecognized association of paired cutaneous vascular nevi of the telangiectaticus and anemicus types (naevus vascularis mixtus) distributed in a mosaic pattern on the face (in both patients) and over the entire body (in the man) and a complex brain malformation (in both patients) consisting of cerebral hemiatrophy, hypoplasia of the cerebral vessels and homolateral hypertrophy of the skull and sinuses (known as Dyke–Davidoff–Masson malformation). Both patients had facial asymmetry and the young man had facial dysmorphism, seizures with EEG anomalies, hemiplegia, insulin‐dependent diabetes mellitus (IDDM), autoimmune thyroiditis, a large hepatic cavernous vascular malformation, and left Legg‐Calvé‐Perthes disease (LCPD) [LCPD‐like presentation]. Array‐CGH analysis and mutation analysis of the RASA1 gene were normal in both patients.

THYMIC CARCINOMA, SYSTEMIC LUPUS ERYTHEMATOSUS, AND HYPERTROPHIC PULMONARY OSTEOARTHROPATHY IN AN 11-YEAR-OLD BOY: A Novel Association

Thymic carcinoma is exceptionally rare in children and it has never previously been associated with autoimmune disorders. The authors report the case of an 11-year-old boy with thymic carcinoma, hypertrophic pulmonary osteoarthropathy, and an autoimmune disease that resembled systemic lupus erythematosus. To their knowledge, this is the first case of such complex clinical findings. The tumor was of high grade histologically and the boy died after 1 year, in spite of chemotherapy and radiotherapy. A review is presented of the available medical literature on thymic malignancy in childhood.

Imaging findings of mucopolysaccharidoses: a pictorial review

IntroductionMucopolysaccharidosis (MPS) represent a heterogeneous group of inheritable lysosomal storage diseases in which the accumulation of undegraded glycosaminoglycans (GAGs) leads to progressive damage of affected tissues. The typical symptoms include organomegaly, dysostosis multiplex, mental retardation and developmental delay. Definitive diagnosis is usually possible through enzymatic assays of the defective enzyme in cultured fibroblasts or leukocytes.Imaging findingsRadiological and neuroradiological findings are reported. The most important neuroradiological features include abnormal signal intensity in the white matter, dilatation of periventricular spaces, widening of cortical sulci, brain atrophy, enlargement of extraventricular spaces and spinal cord compression. With reference to the skeletal system, most important radiological findings include multiplex dysostosis, which is represented by several bone malformations found in the skull, hands, legs, arms and column. The abnormal storage of GAGs leads to liver and spleen enlargement; it also damages cartilage layers and synovial recesses in the joints.ConclusionThe aim of this pictorial essay is to describe the imaging findings of MPS, represented by skeletal and neurological features; skeletal X-ray and MR allow an assessment of the severity of disease, to plan medical and surgical therapy and to evaluate response to treatment.Teaching Points• To describe the imaging findings common to different types of MPS.• To describe multiplex dysostosis encountered in the axial and appendicular skeleton.• To evaluate neuroradiological features of MPS, including brain abnormal signal intensity and atrophy.• To evaluate important otorhinolaryngological problems, such as otitis media and airways obstruction.

Diffusion-weighted MRI in a liver protocol: Its role in focal lesion detection

AIM To evaluate the role of diffusion-weighted imaging (DWI) in the detection of focal liver lesions (FLLs), using a conventional magnetic resonance imaging (MRI) protocol. METHODS Fifty-two patients (22 males, average age 55.6 years, range: 25-82 years), studied using a 1.5 Tesla magnetic resonance scanner, were retrospectively analyzed; detection of FLLs was evaluated by considering the number of lesions observed with the following sequences: (1) respiratory-triggered diffusion-weighted single-shot echo-planar (DW SS-EP) sequences; (2) fat-suppressed fast spin-echo (fs-FSE) T2 weighted sequences; (3) steady-state free precession (SSFP) images; and (4) dynamic triphasic gadolinium-enhanced images, acquired with three-dimensional fast spoiled gradient-echo (3D FSPGR). Two radiologists independently reviewed the images: they were blinded to their respective reports. DW SS-EP sequences were compared to fs-FSE, SSFP and dynamic gadolinium-enhanced acquisitions using a t-test. Pairs were compared for the detection of: (1) all FLLs; (2) benign FLLs; (3) malignant FLLs; (4) metastases; and (5) hepatocellular carcinoma (HCC). RESULTS Interobserver agreement was very good (weighted κ = 0.926, CI = 0.880-0.971); on the consensus reading, 277 FLLs were detected. In the comparison with fs-FSE, DW SS-EP sequences had a significantly higher score in the detection of all FLLs, benign FLLs, malignant FLLs and metastases; no statistical difference was observed in the detection of hepatocellular carcinoma (HCCs). In the comparison with SSFP sequences, DW SS-EP had significantly higher scores (P < 0.05) in the detection of all lesions, benign lesions, malignant lesions, metastases and HCC. All FLLs were better detected by dynamic 3D FSGR enhanced acquisition, with P = 0.0023 for reader 1 and P = 0.0086 for reader 2 in the comparison with DW SS-EP sequences; with reference to benign FLLs, DW SS-EP showed lower values than 3D FSPGR enhanced acquisition (P < 0.05). No statistical differences were observed in the detection of malignant lesions and metastases; considering HCCs, a very slight difference was reported by reader 1 (P = 0.049), whereas no difference was found by reader 2 (P = 0.06). CONCLUSION In lesion detection, DWI had higher scores than T2 sequences; considering malignant FLLs, no statistical difference was observed between DWI and dynamic gadolinium images.

Magnetic resonance cholangiopancreatography and contrast-enhanced magnetic resonance cholangiopancreatography versus endoscopic ultrasonography in the diagnosis of extrahepatic biliary pathology

PurposeThis study compared the diagnostic accuracy of magnetic resonance cholangiopancreatography (MRCP) and endoscopic ultrasonography (EUS) in evaluating the cause of extrahepatic bile duct dilatation.Materials and methodsForty-five patients (26 men, mean age 57 years) with extrahepatic biliary dilatation, as shown by transabdominal ultrasound, with or without elevated biliary and pancreatic serum indices, were prospectively studied with MRCP and EUS between September 2007 and October 2008. EUS and MRCP were performed within no more than 24 h of each other to reduce the possibility of changes due to stone migration. Image analysis was carried out in a double-blind fashion.ResultsMRCP had 88.9% diagnostic accuracy, 91.9% sensitivity and 75% specificity, with 94.4% positive predictive value and 66.7% negative predictive value. EUS had 93.3% diagnostic accuracy, 97.3% sensitivity and 75% specificity; the positive and negative predictive values were 94.7% and 85.7%, respectively.ConclusionsMRCP and EUS do not show significant statistical differences in diagnostic accuracy. MRCP is an accurate, noninvasive modality in the study of extrahepatic biliary pathology. EUS is especially reliable in patients with extrahepatic biliary obstruction caused by endoluminal sludge.RiassuntoObiettivoScopo di questo lavoro è stato confrontare l’accuratezza diagnostica della colangiopancreatografia con risonanza magnetica (CPRM) e dell’ecografia endoscopica (EUS) nel valutare la causa di dilatazione in pazienti con aumentato diametro della via biliare extra-epatica.Materiali e metodiQuarantacinque pazienti (età media 57 anni, 26 maschi) sono stati studiati da settembre 2007 a ottobre 2008 con CPRM e EUS. Sono stati inclusi nello studio pazienti con dilatazione della via biliare extra-epatica rilevata all’ecografia trans-addominale, con o senza innalzamento degli indici sierologici bilio-pancreatici. Lo studio è stato condotto in modalità prospettica ed in doppio cieco. Per ridurre al minimo possibili variazioni legate alla migrazione di calcoli, EUS e CPRM sono state eseguite con intervallo non superiore alle 24 ore.RisultatiLa CPRM ha dimostrato accuratezza diagnostica, sensibilità e specificità rispettivamente dell’88,9%, 91,9% e 75%, con valore predittivo positivo del 94,4% e valore predittivo negativo del 66,7%. La EUS ha evidenziato accuratezza diagnostica, sensibilità e specificità del 93,3%, 97,3% e 75%; valore predittivo positivo e negativo sono stati rispettivamente 94,7% e 85,7%.ConclusioniCPRM ed EUS non presentano differenze statisticamente significative nell’accuratezza diagnostica. La CPRM è metodica accurata non invasiva nella patologia biliare extraepatica; la EUS è particolarmente attendibile nei pazienti con ostruzione biliare extra-epatica da sludge.

Evaluation of the biliary and pancreatic system with 2D SSFSE, breathhold 3D FRFSE and respiratory-triggered 3D FRFSE sequences.

PurposeThe authors compared biliary and pancreatic imaging obtained through 2D single-shot fast spin-echo (SSFSE), breath-hold 3D fast recovery fast spin-echo (FRFSE) and respiratory-triggered 3D FRFSE sequences.Materials and methodsA total of 106 magnetic resonance cholangiopancreatography (MRCP) examinations performed between December 2007 and September 2008 were evaluated with a comparison of 2D SSFSE (thin section and thick slab), breath-hold 3D FRFSE and respiratory-triggered 3D FRFSE sequences. The biliary tract was divided into seven segments: right hepatic duct, left hepatic duct, common hepatic duct, cystic duct, common bile duct, cystic duct junction and biliarypancreatic confluence. The main pancreatic duct was divided into three segments (head, body and tail). Visualisation of biliary variants was also compared. Two blinded radiologists evaluated segment visibility using a quantitative scale. The Student’s t test for paired samples was used for statistical analysis.ResultsCompared with 2D SSFSE, respiratory-triggered 3D FRFSE sequences showed better visibility of the right hepatic duct (p=0.0277), the cystic duct (p=0.0081), the cystic duct junction (p=0.0010), the biliary-pancreatic confluence (p=0.0334) and biliary variants (p=0.0198). In the comparison between breath-hold 3D FRFSE and 2D SSFSE, a significant statistical difference was found in visualisation of the cystic duct (p=0.027), the cystic duct junction (p=0.020), the biliary-pancreatic confluence (p=0.0338) and biliary variants (p=0.0311).ConclusionsThree-dimensional FRFSE offers a significant benefit over conventional 2D imaging.RiassuntoObiettivoScopo del nostro studio è stato confrontare l’imaging biliare e pancreatico mediante 2D single-shot fast spin-echo (SSFSE), 3D fast recovery fast spin-echo (FRFSE) breath-hold e 3D FRFSE triggerate.Materiali e metodiCentosei esami di colangiopancreatografia in risonanza magnetica (RM) — eseguiti tra dicembre 2007 e settembre 2008 — sono state analizzati confrontando SSFSE 2D (con spessore sottile e con slab), FRFSE 3D breath-hold e FRFSE 3D triggerate con il respiro. L’albero biliare è stato suddiviso in 7 segmenti: dotto destro, dotto sinistro, dotto epatico comune, dotto cistico, coledoco, inserzione cistico-coledocica e confluenza coledoco-pancreatica. Il dotto pancreatico è stato ripartito in 3 parti (testa, corpo e coda). È stata confrontata anche la visualizzazione di varianti biliari. Due radiologi in cieco hanno valutato la visibilità dei segmenti mediante una scala quantitativa; le analisi statistiche sono state effettuate mediante test t di Student per dati appaiati.RisultatiRispetto alle SSFSE 2D, FRFSE triggerate hanno evidenziato migliore visualizzazione dell’epatico destro (p=0,0277), del cistico (p=0,0081), della giunzione cistico-coledocica (p=0,0010) e delle varianti biliari (p=0,0198); nel confronto 3D FRFSE breath-hold versus SSFSE 2D, è stata rilevata differenza statisticamente significativa nella visualizzazione del cistico (p=0,027), del punto d’inserzione del cistico (p=0,020), della confluenza coledoco-pancreatica (p=0,0338) e delle varianti biliari (p=0,0311).ConclusioniFRFSE 3D rappresentano un importante valore aggiunto all’imaging convenzionale 2D.

MR imaging of ovarian masses: classification and differential diagnosis

AbstractObjectiveWe propose a Magnetic Resonance Imaging (MRI) guided approach to differential diagnosis of ovarian tumours based on morphological appearance.BackgroundCharacterization of ovarian lesions is of great importance in order to plan adequate therapeutic procedures, and may influence patient’s management. Optimal assessment of adnexal masses requires a multidisciplinary approach, based on physical examination, laboratory tests and imaging techniques. Primary ovarian tumours can be classified into three main categories according to tumour origin: epithelial, germ cell and sex cord-stromal tumours. Ovarian neoplasms may be benign, borderline or malignant. Using an imaging-guided approach based on morphological appearance, we classified adnexal masses into four main groups: unilocular cyst, multilocular cyst, cystic and solid, predominantly solid. We describe MR signal intensity features and enhancement behaviour of ovarian lesions using pathologically proven examples from our institution.ConclusionMRI is an essential problem-solving tool to determine the site of origin of a pelvic mass, to characterize an adnexal mass, and to detect local invasion. The main advantages of MRI are the high contrast resolution and lack of ionizing radiation exposure. Although different pathological conditions may show similar radiologic manifestations, radiologists should be aware of MRI features of ovarian lesions that may orientate differential diagnosis.Teaching Points• Diagnostic imaging plays a crucial role in detection, characterization and staging of adnexal masses. • Characterization of an ovarian lesion may influence patient’s management. • Different pathological conditions may have similar radiologic manifestations. • Non-neoplastic lesions should always be taken into consideration.