Publications by authors named "Martina Locatelli"

19 Publications

  • Page 1 of 1

Age-dependent effect of susceptibility factors on the risk of intracerebral haemorrhage: Multicenter Study on Cerebral Hemorrhage in Italy (MUCH-Italy).

J Neurol Neurosurg Psychiatry 2021 Oct 12;92(10):1068-1071. Epub 2021 Jul 12.

Dipartimento di Scienze Cliniche e Sperimentali, Clinica Neurologica, Università degli Studi di Brescia, Brescia, Italia.

Objective: To investigate the age-dependent impact of traditional stroke risk factors on the occurrence of intracerebral haemorrhage (ICH).

Methods: We performed a case-control analysis, comparing consecutive patients with ICH with age-matched and sex-matched stroke-free controls, enrolled in the setting of the Multicenter Study on Cerebral Hemorrhage in Italy (MUCH-Italy) between 2002 and 2014 by multivariable logistic regression model within subgroups stratified by age quartiles (Q1-Q4).

Results: We analysed 3492 patients and 3492 controls. The impact of untreated hypertension on the risk of ICH was higher in the lower than in the upper age quartile (OR 11.64, 95% CI 7.68 to 17.63 in Q1 vs OR 6.05, 95% CI 3.09 to 11.85 in Q4 with intermediate ORs in Q2 and Q3), while the opposite trend was observed for untreated hypercholesterolaemia (OR 0.63, 95% CI 0.45 to 0.97 in Q1 vs OR 0.36, 95% CI 0.26 to 0.56 in Q4 with intermediate ORs in Q2 and Q3). The effect of untreated diabetes and excessive alcohol intake was detected only in the older age group (OR 3.63, 95% CI 1.22 to 10.73, and OR 1.69, 95% CI 1.13 to 2.51, respectively).

Conclusions: Our findings provide evidence of age-dependent differences in the effects of susceptibility factors on the risk of ICH.
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http://dx.doi.org/10.1136/jnnp-2020-325648DOI Listing
October 2021

SARS-CoV-2 infection and acute ischemic stroke in Lombardy, Italy.

J Neurol 2021 May 24. Epub 2021 May 24.

Department of Neurology and Stroke Unit, Carlo Poma Hospital, ASST Mantova, Mantova, Italy.

Objective: To characterize patients with acute ischemic stroke related to SARS-CoV-2 infection and assess the classification performance of clinical and laboratory parameters in predicting in-hospital outcome of these patients.

Methods: In the setting of the STROKOVID study including patients with acute ischemic stroke consecutively admitted to the ten hub hospitals in Lombardy, Italy, between March 8 and April 30, 2020, we compared clinical features of patients with confirmed infection and non-infected patients by logistic regression models and survival analysis. Then, we trained and tested a random forest (RF) binary classifier for the prediction of in-hospital death among patients with COVID-19.

Results: Among 1013 patients, 160 (15.8%) had SARS-CoV-2 infection. Male sex (OR 1.53; 95% CI 1.06-2.27) and atrial fibrillation (OR 1.60; 95% CI 1.05-2.43) were independently associated with COVID-19 status. Patients with COVID-19 had increased stroke severity at admission [median NIHSS score, 9 (25th to75th percentile, 13) vs 6 (25th to75th percentile, 9)] and increased risk of in-hospital death (38.1% deaths vs 7.2%; HR 3.30; 95% CI 2.17-5.02). The RF model based on six clinical and laboratory parameters exhibited high cross-validated classification accuracy (0.86) and precision (0.87), good recall (0.72) and F1-score (0.79) in predicting in-hospital death.

Conclusions: Ischemic strokes in COVID-19 patients have distinctive risk factor profile and etiology, increased clinical severity and higher in-hospital mortality rate compared to non-COVID-19 patients. A simple model based on clinical and routine laboratory parameters may be useful in identifying ischemic stroke patients with SARS-CoV-2 infection who are unlikely to survive the acute phase.
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http://dx.doi.org/10.1007/s00415-021-10620-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8142879PMC
May 2021

Impact of SARS-CoV-2 on reperfusion therapies for acute ischemic stroke in Lombardy, Italy: the STROKOVID network.

J Neurol 2021 Mar 8. Epub 2021 Mar 8.

Department of Neurology and Stroke Unit, Carlo Poma Hospital, ASST Mantova, Mantua, Italy.

Whether and how SARS-CoV-2 outbreak affected in-hospital acute stroke care system is still matter of debate. In the setting of the STROKOVID network, a collaborative project between the ten centers designed as hubs for the treatment of acute stroke during SARS-CoV-2 outbreak in Lombardy, Italy, we retrospectively compared clinical features and process measures of patients with confirmed infection (COVID-19) and non-infected patients (non-COVID-19) who underwent reperfusion therapies for acute ischemic stroke. Between March 8 and April 30, 2020, 296 consecutive patients [median age, 74 years (interquartile range (IQR), 62-80.75); males, 154 (52.0%); 34 (11.5%) COVID-19] qualified for the analysis. Time from symptoms onset to treatment was longer in the COVID-19 group [230 (IQR 200.5-270) minutes vs. 190 (IQR 150-245) minutes; p = 0.007], especially in the first half of the study period. Patients with COVID-19 who underwent endovascular thrombectomy had more frequently absent collaterals or collaterals filling ≤ 50% of the occluded territory (50.0% vs. 16.6%; OR 5.05; 95% CI 1.82-13.80) and a lower rate of good/complete recanalization of the primary arterial occlusive lesion (55.6% vs. 81.0%; OR 0.29; 95% CI 0.10-0.80). Post-procedural intracranial hemorrhages were more frequent (35.3% vs. 19.5%; OR 2.24; 95% CI 1.04-4.83) and outcome was worse among COVID-19 patients (in-hospital death, 38.2% vs. 8.8%; OR 6.43; 95% CI 2.85-14.50). Our findings showed longer delays in the intra-hospital management of acute ischemic stroke in COVID-19 patients, especially in the early phase of the outbreak, that likely impacted patients outcome and should be the target of future interventions.
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http://dx.doi.org/10.1007/s00415-021-10497-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7937781PMC
March 2021

Spontaneous cervical artery dissection and fibromuscular dysplasia: Epidemiologic and biologic evidence of a mutual relationship.

Trends Cardiovasc Med 2021 Jan 30. Epub 2021 Jan 30.

Dipartimento di Scienze Cliniche e Sperimentali, Clinica Neurologica, Università degli Studi di Brescia, P.le Spedali Civili, 1, 25123 Brescia, Italia. Electronic address:

Cervical artery dissection (CeAD) is the most common cause of ischemic stroke in young and middle-aged adults. Over the last decade, a relation between CeAD and fibromuscular dysplasia (FMD), an idiopathic, segmental, non-atherosclerotic and non-inflammatory arterial disease, has been suggested based on a number of epidemiologic observations, while preliminary data support the idea that the two conditions may share common biologic mechanisms. In this article, we review the literature on the relation between CeAD and FMD, focus on the potential pathogenetic mechanisms common to the two conditions, summarize clinical features, management and outcome, and provide support to the hypothesis that the coexistence of the two diseases in one individual might be conceptualized as a distinct non-atherosclerotic non-inflammatory arteriopathy.
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http://dx.doi.org/10.1016/j.tcm.2021.01.006DOI Listing
January 2021

Clinical Features of Patients With Cervical Artery Dissection and Fibromuscular Dysplasia.

Stroke 2021 Mar 28;52(3):821-829. Epub 2021 Jan 28.

UO Neurologia, Ospedale Villa Sofia, Palermo, Italy (V.T.).

Background And Purpose: Observational studies have suggested a link between fibromuscular dysplasia and spontaneous cervical artery dissection (sCeAD). However, whether patients with coexistence of the two conditions have distinctive clinical characteristics has not been extensively investigated.

Methods: In a cohort of consecutive patients with first-ever sCeAD, enrolled in the setting of the multicenter IPSYS CeAD study (Italian Project on Stroke in Young Adults Cervical Artery Dissection) between January 2000 and June 2019, we compared demographic and clinical characteristics, risk factor profile, vascular pathology, and midterm outcome of patients with coexistent cerebrovascular fibromuscular dysplasia (cFMD; cFMD+) with those of patients without cFMD (cFMD-).

Results: A total of 1283 sCeAD patients (mean age, 47.8±11.4 years; women, 545 [42.5%]) qualified for the analysis, of whom 103 (8.0%) were diagnosed with cFMD+. In multivariable analysis, history of migraine (odds ratio, 1.78 [95% CI, 1.13-2.79]), the presence of intracranial aneurysms (odds ratio, 8.71 [95% CI, 4.06-18.68]), and the occurrence of minor traumas before the event (odds ratio, 0.48 [95% CI, 0.26-0.89]) were associated with cFMD. After a median follow-up of 34.0 months (25th to 75th percentile, 60.0), 39 (3.3%) patients had recurrent sCeAD events. cFMD+ and history of migraine predicted independently the risk of recurrent sCeAD (hazard ratio, 3.40 [95% CI, 1.58-7.31] and 2.07 [95% CI, 1.06-4.03], respectively) in multivariable Cox proportional hazards analysis.

Conclusions: Risk factor profile of sCeAD patients with cFMD differs from that of patients without cFMD. cFMD and migraine are independent predictors of midterm risk of sCeAD recurrence.
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http://dx.doi.org/10.1161/STROKEAHA.120.031579DOI Listing
March 2021

Clinical characteristics and outcomes of inpatients with neurologic disease and COVID-19 in Brescia, Lombardy, Italy.

Neurology 2020 08 22;95(7):e910-e920. Epub 2020 May 22.

From the Neurology Unit (A.B., A. Pilotto, I.L., M.G., E.B., S.B., M.C., S.C.P., V.C., A.I., M. Locatelli, S.M., B.R., L.R., A.S., F.S.d.C., N.Z., B.B., A. Pezzini, A. Padovani), Department of Clinical and Experimental Sciences, University of Brescia; Neurology Unit (A.B., A. Pilotto, C.A., A.A., S.C., E.C., M.F., S. Gipponi, P.L., L.P., R.R., L.R., I.V., B.B., A. Pezzini, A. Padovani), Vascular Neurology Unit (E.P., A.C., I.D., M.G., N.G., R.S., V.V., M.M.), and Neurophysiology Unit (S. Gazzina, U.L.), Department of Neurological and Vision Sciences, ASST Spedali Civili, Brescia; Neurology Unit (M.B.), University of Bologna; Department of Neuroimmunology and Neuromuscular Diseases (L.B.) and Neurology (M. Leonardi), Public Health and Disability Unit, Foundation IRCCS Neurological Institute Carlo Besta, Milan; and Neurology Unit (P.I.), Fondazione Poliambulanza Hospital, Brescia, Italy.

Objective: To report clinical and laboratory characteristics, treatment, and clinical outcomes of patients admitted for neurologic diseases with and without coronavirus disease 2019 (COVID-19).

Methods: In this retrospective, single-center cohort study, we included all adult inpatients with confirmed COVID-19 admitted to a neuro-COVID unit beginning February 21, 2020, who had been discharged or died by April 5, 2020. Demographic, clinical, treatment, and laboratory data were extracted from medical records and compared (false discovery rate corrected) to those of neurologic patients without COVID-19 admitted in the same period.

Results: One hundred seventy-three patients were included in this study, of whom 56 were positive and 117 were negative for COVID-19. Patients with COVID-19 were older (77.0 years, interquartile range [IQR] 67.0-83.8 years vs 70.1 years, IQR 52.9-78.6 years, = 0.006), had a different distribution regarding admission diagnoses, including cerebrovascular disorders (n = 43, 76.8% vs n = 68, 58.1%), and had a higher quick Sequential Organ Failure Assessment (qSOFA) score on admission (0.9, IQR 0.7-1.1 vs 0.5, IQR 0.4-0.6, = 0.006). In-hospital mortality rates (n = 21, 37.5% vs n = 5, 4.3%, < 0.001) and incident delirium (n = 15, 26.8% vs n = 9, 7.7%, = 0.003) were significantly higher in the COVID-19 group. Patients with COVID-19 and without COVID with stroke had similar baseline characteristics, but patients with COVID-19 had higher modified Rankin Scale scores at discharge (5.0, IQR 2.0-6.0 vs 2.0, IQR 1.0-3.0, < 0.001), with a significantly lower number of patients with a good outcome (n = 11, 25.6% vs n = 48, 70.6%, < 0.001). In patients with COVID-19, multivariable regressions showed increasing odds of in-hospital death associated with higher qSOFA scores (odds ratio [OR] 4.47, 95% confidence interval [CI] 1.21-16.5, = 0.025), lower platelet count (OR 0.98, 95% CI 0.97-0.99, = 0.005), and higher lactate dehydrogenase (OR 1.01, 95% CI 1.00-1.03, = 0.009) on admission.

Conclusions: Patients with COVID-19 admitted with neurologic disease, including stroke, have a significantly higher in-hospital mortality and incident delirium and higher disability than patients without COVID-19.
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http://dx.doi.org/10.1212/WNL.0000000000009848DOI Listing
August 2020

Long-term outcome of cervical artery dissection : IPSYS CeAD: study protocol, rationale, and baseline data of an Italian multicenter research collaboration.

Neurol Sci 2020 Nov 12;41(11):3265-3272. Epub 2020 May 12.

UO Neurologia, Ospedale Villa Sofia, Palermo, Italy.

Long-term consequences of cervical artery dissection (CeAD), a major cause of ischemic stroke in young people, have been poorly investigated. The Italian Project on Stroke at Young Age - Cervical Artery Dissection (IPSYS CeAD) project is a multicenter, hospital-based, consecutively recruiting, observational, cohort study aimed to address clinically important questions about long-term outcome of CeAD patients, which are not covered by other large-scale registries. Patients with radiologically diagnosed CeAD were consecutively included in the registry. Baseline demographic and clinical variables, as well as information on risk factors, were systematically collected for each eligible patient. Follow-up evaluations were conducted between 3 and 6 months after the initial event (t) and then annually (t at 1 year, t at 2 years , and so on), in order to assess outcome events (long-term recurrent CeAD, any fatal/nonfatal ischemic stroke, transient ischemic attack (TIA), or other arterial thrombotic event, and death from any cause). Between 2000 and 2019, data from 1530 patients (age at diagnosis, 47.2 ± 11.5 years; women, 660 [43.1%]) have been collected at 39 Italian neurological centers. Dissection involved a single vessel in 1308 (85.5%) cases and caused brain ischemia in 1303 (85.1%) (190 TIA/1113 ischemic stroke). Longitudinal data are available for 1414 (92.4%) patients (median follow-up time in patients who did not experience recurrent events, 36.0 months [25th to 75th percentile, 63.0]). The collaborative IPSYS CeAD effort will provide novel information on the long-term outcome of CeAD patients. This could allow for tailored treatment approaches based on patients' individual characteristics.
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http://dx.doi.org/10.1007/s10072-020-04464-9DOI Listing
November 2020

Pathophysiological Mechanisms and Potential Therapeutic Targets in Cerebral Autosomal Dominant Arteriopathy With Subcortical Infarcts and Leukoencephalopathy (CADASIL).

Front Pharmacol 2020 13;11:321. Epub 2020 Mar 13.

Department of Clinical and Experimental Sciences, Neurology Clinic, University of Brescia, Brescia, Italy.

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), is a hereditary small-vessels angiopathy caused by mutations in the NOTCH 3 gene, located on chromosome 19, usually affecting middle-ages adults, whose clinical manifestations include migraine with aura, recurrent strokes, mood disorders, and cognitive impairment leading to dementia and disability. In this review, we provide an overview of the current knowledge on the pathogenic mechanisms underlying the disease, focus on the corresponding therapeutic targets, and discuss the most promising treatment strategies currently under investigations. The hypothesis that CADASIL is an appropriate model to explore the pathogenesis of sporadic cerebral small vessel disease is also reviewed.
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http://dx.doi.org/10.3389/fphar.2020.00321DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7082755PMC
March 2020

Use of enteroscopy for the detection of malignant and premalignant lesions of the small bowel in complicated celiac disease: a meta-analysis.

Gastrointest Endosc 2017 Aug 20;86(2):264-273.e1. Epub 2017 Apr 20.

Gastroenterology and Endoscopy Unit, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy.

Background And Aims: Enteroscopy (wireless or wired) is the reference standard for small-bowel (SB) diseases, and it has been applied to detect SB malignancies in complicated celiac disease (CD) with heterogeneous results. The aim of this meta-analysis was to obtain a diagnostic yield (DY) by pooling the data of studies that investigated the use of enteroscopy to detect SB adverse events in CD.

Methods: We performed an online search for studies estimating the DY of wireless and wired enteroscopy in predicting the presence of SB premalignant and/or malignant lesions. The DerSimonian and Laird random-effects method was used to pool the arcsine-transformed proportions of patients with the events. Three meta-analyses were performed considering the following events: the presence of a malignancy, premalignant damage (ulcerative jejunoileitis [UJ]), or the presence of a malignancy or UJ. A subgroup analysis was performed after extracting (if possible) patients with refractory CD (RCD).

Results: Of the 529 titles initially resulting from the search, 10 studies on capsule enteroscopy (CE) and 3 on double-balloon or push enteroscopy met the inclusion criteria. Overall, 439 and 76 patients were enrolled in these studies using CE and enteroscopy, respectively. Twelve tumors and 47 UJs were found by CE versus 8 tumors and 13 UJs detected by wired enteroscopy. For malignancies the CE yield was 1.9% (95% CI, .5%-3.8%) and wired enteroscopy yield 8.7% (95% CI, 0%-21.2%); similarly, for UJ the DYs were 8.4% (95% CI, 2.1%-17.7%) and 16.7% (95% CI, 8.7%-26.3%); for either UJ or neoplasia the DYs were 13.0% (95% CI, 5.6%-22.5%) and 27.7% (95% CI, 14.8%-42.6%). For RCD the DYs of all enteroscopic techniques were 1.8% (95% CI, 0%-7.7%) for neoplasia, 22.3% (95% CI, 8.2%-39.7%) for UJ, and 27.5% (95% CI, 13.1%-44.2%) for either.

Conclusions: Enteroscopy is a powerful and efficient diagnostic tool for the detection of SB malignancies in complicated CD.
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http://dx.doi.org/10.1016/j.gie.2017.04.006DOI Listing
August 2017

Enteroscopy and radiology for the management of celiac disease complications: Time for a pragmatic roadmap.

Dig Liver Dis 2016 Jun 2;48(6):578-86. Epub 2016 Mar 2.

Department of Pathophysiology and Transplantation, Università degli Studi di Milano, Milan, Italy. Electronic address:

Celiac disease is the most common autoimmune enteropathy in Western countries, and is usually associated with a good response to the gluten free diet and an excellent prognosis. However, a minority of patients develop complications of the disease, such as refractory celiac disease, ulcerative jejunoileitis and neoplastic complications such as adenocarcinoma of the small bowel and enteropathy associated T cell lymphoma. Neoplastic complications described in association with celiac disease have a high mortality rate, due to their aggressive behavior and to the usual advanced stage at the time of diagnosis. In recent years, the detection of small bowel lesions has dramatically improved thank to the availability of highly performing radiologic and endoscopic techniques. The diagnostic delay of malignant complications in patients with celiac disease may be improved by establishing a pragmatic flowchart for the identification and follow up of "at risk" patients. We performed a comprehensive review of the articles published on this issue in order to promote a roadmap to be applied when facing with celiac patients with suspected small bowel complications.
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http://dx.doi.org/10.1016/j.dld.2016.02.015DOI Listing
June 2016

Celiac Disease and Double-Balloon Enteroscopy: What Can We Achieve?: The Experience of 2 European Tertiary Referral Centers.

J Clin Gastroenterol 2016 Apr;50(4):313-7

*Department of Pathophysiology and Transplantation, Center for the Prevention and Diagnosis of Celiac Disease, Gastroenterology and Endoscopy Unit, Fondazione IRCCS Ca' Granda-Ospedale Maggiore Policlinico†Departments of Pathophysiology and Transplantation§Biomedical Surgical and Dental Sciences, Università degli Studi di Milano, Milan, Italy‡Gastroenterology and Liver Unit, Royal Hallamshire Hospital, Sheffield, UK.

Background: Indications to double-balloon enteroscopy (DBE) are not standardized in celiac disease (CD).

Goals: To evaluate the clinical usefulness of DBE in complicated CD.

Study: DBE findings in celiac patients with suspected small bowel (SB) complications were retrospectively evaluated in 2 tertiary referral centers (Milan and Sheffield). Demographic data of the studied cohort were compared with a database of 1000 noncomplicated CD patients.

Results: Twenty-four CD cases (12 males, P=0.01 vs. controls) were reviewed. Mean age at CD diagnosis (y±SD) was 37±20 versus 27±18 and at SB evaluation 47±15 versus 38±13 (P<0.01 compared with controls). Indications for DBE were refractory CD (#9), gastrointestinal symptoms (#6), severe iron-deficiency anemia (#6), and long standing poor dietary adherence (#3). Two jejunal adenocarcinomas and an ileal neuroendocrine tumor were detected in presence of iron-deficiency anemia. Three type I and 3 type II refractory CD patients showed jejunal ulcerations; 2 of type II presented small white raised patches. Patchy atrophy was observed in nonadherent patients and in 2 on a gluten-free diet for a short time. Therapy was planned in 33% of patients after DBE. No adverse events were detected at follow-up [21 mo (range, 0 to 60 mo)].

Conclusions: This is the largest international study on the outcomes of DBE in CD demonstrating its usefulness to exclude/confirm malignant or premalignant conditions, associated with even minor lesions. Studies are needed to understand the clinical relevance of the SB endoscopic features and to optimize DBE indications.
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http://dx.doi.org/10.1097/MCG.0000000000000424DOI Listing
April 2016

Enteroscopy for the early detection of small bowel tumours in at-risk celiac patients.

Dig Liver Dis 2014 May 15;46(5):400-4. Epub 2014 Jan 15.

Center for the Prevention and Diagnosis of Celiac Disease and Gastroenterology Unit II, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico and Università degli Studi di Milano, via F. Sforza 35, 20122 Milan, Italy.

Background: A subset of celiac patients shows a high risk for small bowel malignancies.

Aims: To select celiac patients considered at risk and evaluate the diagnostic yield of enteroscopy in this context.

Methods: Celiac patients were enrolled from a tertiary referral centre during the period June 2011-June 2013, based on the following criteria: (i) patients diagnosed when aged 50+ and with poor response to gluten-free dieting; (ii) low dietary compliance; (iii) alarm symptoms. The patients underwent small bowel capsule endoscopy and/or double-balloon enteroscopy. Control populations were represented by the 165 non-celiac patients undergoing capsule endoscopy for obscure gastrointestinal bleeding, and the 815,362-strong population of the Italian province of Varese as a registered cohort.

Results: Fifty-three patients (19% males, mean age 43.6±17.4 years) were evaluated. Two jejunal adenocarcinomas and one ileal neuro-endocrine tumour were diagnosed by enteroscopy (the diagnostic yield for malignancies in the selected population being 5.7%). In the non-celiac controls the detection rate of small bowel tumours by capsule endoscopy was 0.6% (P=0.04). When compared to the registered population, the relative risk for intestinal malignancy was 1282 (95% CI, 407-4033; P<0.0001).

Conclusions: Capsule endoscopy and double-balloon enteroscopy can be considered for early disease management of a subset of celiac patients.
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http://dx.doi.org/10.1016/j.dld.2013.12.009DOI Listing
May 2014

microRNA profiles in coeliac patients distinguish different clinical phenotypes and are modulated by gliadin peptides in primary duodenal fibroblasts.

Clin Sci (Lond) 2014 Mar;126(6):417-23

*Division of Pathology, Fondazione IRCCS Ca' Granda-Ospedale Maggiore Policlinico, Milan, Italy.

CD (coeliac disease) is a frequent autoimmune disorder of the small bowel, which is characterized by an immunological reaction against gluten and transglutaminase in genetically predisposed subjects. However, the molecular determinants underpinning CD pathogenesis are yet to be fully elucidated and little data are available about the involvement of miRNAs (microRNAs) in CD. In the present study, the duodenal mucosa miRNA expression was profiled in adult untreated CD presenting with a classic phenotype or iron-deficiency anaemia, treated patients with or without duodenal normalization, and non-CD subjects as controls. Deregulation of seven miRNAs (miR-31-5p, miR-192-3p, miR-194-5p, miR-551a, miR-551b-5p, miR-638 and miR-1290) was determined in a larger series of CD patients with different clinical phenotypes compared with non-CD subjects. These seven microRNAs were then analysed in duodenal fibroblasts obtained from CD patients and incubated with gliadin peptides (13- and 33-mer). The miRNA cluster miR-192/194, involved in matrix remodelling, was deregulated in CD according to the different clinical presentations, and miR-192-3p levels were modulated by gliadin peptides in vitro. In conclusion, the analysis of miRNAs deserves further consideration for its potential use in the treatment and management of CD.
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http://dx.doi.org/10.1042/CS20130248DOI Listing
March 2014

TMEM16A alternative splicing coordination in breast cancer.

Mol Cancer 2013 Jul 16;12:75. Epub 2013 Jul 16.

Human Molecular Genetics, International Centre for Genetic Engineering and Biotechnology, Trieste, Italy.

Background: TMEM16A, also known as Anoctamin-1, is a calcium-activated chloride channel gene overexpressed in many tumors. The role of TMEM16A in cancer is not completely understood and no data are available regarding the potential tumorigenic properties of the multiple isoforms generated by alternative splicing (AS).

Methods: We evaluated TMEM16A AS pattern, isoforms distribution and Splicing Coordination (SC), in normal tissues and breast cancers, through a semi-quantitative PCR-assay that amplifies transcripts across three AS exons, 6b, 13 and 15.

Results: In breast cancer, we did not observe an association either to AS of individual exons or to specific TMEM16A isoforms, and induced expression of the most common isoforms present in tumors in the HEK293 Flp-In Tet-ON system had no effect on cellular proliferation and migration. The analysis of splicing coordination, a mechanism that regulates AS of distant exons, showed a preferential association of exon 6b and 15 in several normal tissues and tumors: isoforms that predominantly include exon 6b tend to exclude exon 15 and vice versa. Interestingly, we found an increase in SC in breast tumors compared to matched normal tissues.

Conclusions: As the different TMEM16A isoforms do not affect proliferation or migration and do not associate with tumors, our results suggest that the resulting channel activities are not directly involved in cell growth and motility. Conversely, the observed increase in SC in breast tumors suggests that the maintenance of the regulatory mechanism that coordinates distant alternative spliced exons in multiple genes other than TMEM16A is necessary for cancer cell viability.
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http://dx.doi.org/10.1186/1476-4598-12-75DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3728142PMC
July 2013

Shear-wave elastography improves the specificity of breast US: the BE1 multinational study of 939 masses.

Radiology 2012 Feb;262(2):435-49

Magee-Womens Hospital, University of Pittsburgh School of Medicine, 300 Halket St, Pittsburgh, PA 15213, USA.

Purpose: To determine whether adding shear-wave (SW) elastographic features could improve accuracy of ultrasonographic (US) assessment of breast masses.

Materials And Methods: From September 2008 to September 2010, 958 women consented to repeat standard breast US supplemented by quantitative SW elastographic examination in this prospective multicenter institutional review board-approved, HIPAA-compliant protocol. B-mode Breast Imaging Reporting and Data System (BI-RADS) features and assessments were recorded. SW elastographic evaluation (mean, maximum, and minimum elasticity of stiffest portion of mass and surrounding tissue; lesion-to-fat elasticity ratio; ratio of SW elastographic-to-B-mode lesion diameter or area; SW elastographic lesion shape and homogeneity) was performed. Qualitative color SW elastographic stiffness was assessed independently. Nine hundred thirty-nine masses were analyzable; 102 BI-RADS category 2 masses were assumed to be benign; reference standard was available for 837 category 3 or higher lesions. Considering BI-RADS category 4a or higher as test positive for malignancy, effect of SW elastographic features on area under the receiver operating characteristic curve (AUC), sensitivity, and specificity after reclassifying category 3 and 4a masses was determined.

Results: Median participant age was 50 years; 289 of 939 (30.8%) masses were malignant (median mass size, 12 mm). B-mode BI-RADS AUC was 0.950; eight of 303 (2.6%) BI-RADS category 3 masses, 18 of 193 (9.3%) category 4a lesions, 41 of 97 (42%) category 4b lesions, 42 of 57 (74%) category 4c lesions, and 180 of 187 (96.3%) category 5 lesions were malignant. By using visual color stiffness to selectively upgrade category 3 and lack of stiffness to downgrade category 4a masses, specificity improved from 61.1% (397 of 650) to 78.5% (510 of 650) (P<.001); AUC increased to 0.962 (P=.005). Oval shape on SW elastographic images and quantitative maximum elasticity of 80 kPa (5.2 m/sec) or less improved specificity (69.4% [451 of 650] and 77.4% [503 of 650], P<.001 for both), without significant improvement in sensitivity or AUC.

Conclusion: Adding SW elastographic features to BI-RADS feature analysis improved specificity of breast US mass assessment without loss of sensitivity.
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http://dx.doi.org/10.1148/radiol.11110640DOI Listing
February 2012

Detection of liver metastases by pulse inversion harmonic imaging during Levovist late phase: comparison with conventional ultrasound and helical CT in 160 patients.

Eur Radiol 2003 Mar 26;13(3):475-83. Epub 2002 Sep 26.

Department of Radiology, Cattinara Hospital, University of Trieste, Strada di Fiume 447, 34149 Trieste, Italy.

The aim of this study was to evaluate capabilities of pulse inversion harmonic imaging (PIHI) with Levovist in detection of liver metastases compared with conventional ultrasound (US) and helical CT (HCT). One hundred sixty consecutive patients with known malignancies were evaluated by conventional US, PIHI 2 min (40 patients) or 4 min (120 patients) after Levovist injection and HCT. Conspicuity and number of the identified metastatic lesions were evaluated and assessed by statistical analysis (significance p<0.05). Mean diameter of the smallest identified metastases was computed for conventional US, PIHI and HCT. In cases where PIHI revealed more lesions suspicious for metastases than HCT, intraopertive US with surgical biopsy or 3-6-month US follow-up were performed to confirm diagnosis. Images were stored on magneto-optical disk and evaluated off-line by a dedicated software. Metastases conspicuity was significantly improved on PIHI if compared with conventional US ( p<0.05). In 49 patients all the employed imaging techniques did not reveal any lesion, whereas in the remaining 111 patients, 28 patients revealed more than five metastatic lesions and 83 patients presented from one to five metastatic lesions. In comparison with conventional US, PIHI revealed more metastases in 39/83 (47%), the same number in 44/83 (53%) and a lower number in 0/83 (0%) patients. In comparison with HCT, PIHI revealed more metastases in 10/83 (12%), the same number in 61/83 (74%) and a lower number in 12/83 (14%) patients. Average number +/- SD (standard deviation) of confirmed metastases for patients was 2.21+/-1.6 for conventional US, 3.1+/-2.44 for PIHI and 3.05+/-2.41 for HCT. The difference between PIHI and conventional US was statistically significant ( p<0.0001), whereas the difference between PIHI and HCT was not significant ( p=0.9). The smallest identified metastases presented 3-mm mean diameter on PIHI, 5-mm on HCT and 7-mm on conventional US. PIHI with Levovist is a reliable technique in metastases detection.
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http://dx.doi.org/10.1007/s00330-002-1670-1DOI Listing
March 2003
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