Publications by authors named "Maria Ruggiero"

53 Publications

Long-term follow-up of the DERIVO® Embolization Device (DED®) for intracranial aneurysms: the Italian Multicentric Registry.

J Neurosurg Sci 2021 Apr 21. Epub 2021 Apr 21.

Ospedale Maggiore Policlinico, Milan, Italy.

Background: The flow-diverter devices (FDDs) safety and effectiveness have been demonstrated by large series and meta-analyses. Due to the high occlusion rates and the acceptable morbidity rates of FDDs, the indications for their use are continuously expanding. We presented our Italian multicentric experience using the second generation of DERIVO® Embolization Device (DED®; Acandis, Pforzheim, Germany) to cure cerebral aneurysms, evaluating both middle and long-term safety and efficacy of this device.

Methods: Between July 2016 and September 2017 we collected 109 consecutive aneurysms in 108 patients treated using DED® during 109 endovascular procedures in 34 Italian centers (100/109 aneurysms were unruptured, 9/109 were ruptured). The collected data included patient demographics, aneurysm location and characteristics, baseline angiography, adverse event and serious adverse event information, morbidity and mortality rates, and pre- and post-treatment modified Rankin Scale scores. Midterm and long-term clinical, angiographic and cross-sectional CT/MR follow-up were recorded and collected until December 2018.

Results: In 2/109 cases, DED® placement was classified as technical failures. The overall mortality and morbidity rates were respectively 6.5% and 5.5%. Overall DERIVO® related mortality and morbidity rates were respectively 0% and 4.6% (5 out of 108 patients). Midterm neuroimaging follow-up showed the complete or nearly complete occlusion of the aneurysm in 90% cases, which became 93% at long-term follow-up. Aneurysmal sac shrinking was observed in 65% of assessable aneurysms.

Conclusions: Our multicentric experience using DED® for endovascular treatment of unruptured and ruptured aneurysms showed a high safety and efficacy profile, substantially equivalent or better compared to the other FDDs.
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http://dx.doi.org/10.23736/S0390-5616.21.05300-5DOI Listing
April 2021

De Novo Dural Arteriovenous Fistula on Draining Veins of Previously Treated Pial Arteriovenous Malformation: a Case Report.

J Stroke Cerebrovasc Dis 2021 Apr 17;30(7):105798. Epub 2021 Apr 17.

Department of Neuroradiology, AUSL Romagna, M. Bufalini Hospital, Cesena, Italy. Electronic address:

A 71-year-old man, with a pial micro-arteriovenous malformation (pAVM) draining into the confluence of the vein of Trolard and the vein of Labbé was surgically removed, sparing these cortical veins. 4-months MR and angiographic controls showed a de novo dural arteriovenous fistula (dAVF) draining into the previously spared cortical veins. It was removed using intraoperative motor evoked potentials (MEP). This is the first case of iatrogenic dAVF developing on the same draining vein of a previously treated pAVM. De novo dAVFs are generally iatrogenic. This case suggests that the unresected venous drainage of an AVM might be the substratum for neo-angiogenetic processes; moreover inflammation related to surgery might be the trigger factor for the development of the dAVF.
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http://dx.doi.org/10.1016/j.jstrokecerebrovasdis.2021.105798DOI Listing
April 2021

Biodegradable polyelectrolyte/magnetite capsules for MR imaging and magnetic targeting of tumors.

Nanotheranostics 2021 2;5(3):362-377. Epub 2021 Apr 2.

Molecular and Preclinical Imaging Centres, Department of Molecular Biotechnology and Health Sciences, University of Torino, 10126 Torino, Italy.

The tireless research for effective drug delivery approaches is prompted by poor target tissue penetration and limited selectivity against diseased cells. To overcome these issues, various nano- and micro-carriers have been developed so far, but some of them are characterized by slow degradation time, thus hampering repeated drug administrations. The aim of this study was to pursue a selective delivery of magnetic biodegradable polyelectrolyte capsules in a mouse breast cancer model, using an external magnetic field. Four different kinds of magnetic polyelectrolyte capsules were fabricated via layer-by-layer assembly of biodegradable polymers on calcium carbonate templates. Magnetite nanoparticles were embedded either into the capsules' shell (sample S) or both into the shell and the inner volume of the capsules (samples CS, where n is the number of nanoparticle loading cycles). Samples were first characterized in terms of their relaxometric and photosedimentometric properties. magnetic resonance imaging (MRI) experiments, carried out on RAW 264.7 cells, allowed the selection of two lead samples that proceeded for the testing on a mouse breast cancer model. In the set of experiments, an external magnet was applied for 1 hour following the intravenous injection of the capsules to improve their delivery to tumor, and MRI scans were acquired at different time points post administration. All samples were considered non-cytotoxic as they provided more than 76% viability of RAW 264.7 cells upon 2 h incubation. Sample S appeared to be the most efficient in terms of T-MRI contrast, but the less sensitive to external magnet navigation, since no difference in MRI signal with and without the magnet was observed. On the other side, sample CS was efficiently delivered to the tumor tissue, with a three-fold T-MRI contrast enhancement upon the external magnet application. The effective magnetic targeting of CS capsules was also confirmed by the reduction in T-MRI contrast in spleen if compared with the untreated with magnet mice values, and the presence of dense and clustered iron aggregates in tumor histology sections even 48 h after the magnetic targeting. The highlighted strategy of magnetic biodegradable polyelectrolyte capsules' design allows for the development of an efficient drug delivery system, which through an MRI-guided externally controlled navigation may lead to a significant improvement of the anticancer chemotherapy performance.
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http://dx.doi.org/10.7150/ntno.59458DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8040826PMC
April 2021

Incidence of hemorrhagic cerebrovascular disease due to vascular malformations during the COVID-19 national quarantine in Italy.

Clin Neurol Neurosurg 2021 03 19;202:106503. Epub 2021 Jan 19.

Neurosurgery Department, S. Anna University Hospital, Ferrara, Italy; Department of Morphology, Surgery and Experimental Medicine, University of Ferrara, Ferrara, Italy.

Background: hemorrhagic cerebrovascular disease due to vascular malformations represents an emergency for neurosurgery and neuro-interventional departments. During the COVID-19 pandemic, a dramatic reduction in the number of hospitalizations for acute myocardial infarction or stroke and a larger time interval from symptom onset to first medical contact have been reported. This study aims to verify the hypothesis that there would also have been a reduction of admissions for hemorrhagic cerebrovascular disease during the Italian lockdown.

Material And Method: s A multicenter, observational survey was conducted to collect data on hospital admissions for hemorrhagic cerebrovascular disease due to vascular malformations throughout two-months (March 15th to May 15th); the years 2020 (COVID-19 Italian lockdown), 2019 and 2018 were compared. Cases were identified by ICD-9 codes 430, 431, 432.1, 432.9, 747.81 of each hospital database. The statistical significance of the difference between the event rate of one year versus the others was evaluated using Poisson Means test, assuming a constant population.

Results: During the 2020 lockdown, the total number of admissions for hemorrhagic cerebrovascular disease was 92 compared with 116 in 2019 and 95 in 2018. This difference was not significant. GCS upon admission was 3-8 in 44 % of cases in 2020 (41 patients), 39.7 % in 2019 (46 patients) and 28 % in 2018 (27 patients).

Conclusion: Reduction of admissions for hemorrhagic cerebrovascular disease due to vascular malformations during the COVID-19 lockdown was not confirmed. Nevertheless, some patients reached the emergency rooms only several days after symptoms onset, resulting in a worse clinical condition at admission.
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http://dx.doi.org/10.1016/j.clineuro.2021.106503DOI Listing
March 2021

Impact of COVID-19 pandemic on acute stroke care: facing an epidemiological paradox with a paradigm shift.

Neurol Sci 2021 Feb 21;42(2):399-406. Epub 2020 Nov 21.

Neurology Unit, "M. Bufalini" hospital, AUSL Romagna, Viale Giovanni Ghirotti, 286, 47521, Cesena, FC, Italy.

Background: During the coronavirus disease 2019 (COVID-19) outbreak, a decrease of stroke's hospital admissions and reperfusion therapy has been reported worldwide. This retrospective observational study assessed the volume of stroke cases managed in the Emergency Department (ED) and reperfusion therapies in an Italian stroke network with a high incidence of COVID-19, particularly to evaluate if the in-hospital rerouting and the switch from a drip-and-ship to a mothership model could assure an adequate volume of acute treatments.

Methods: We compared data from March 2020 with those from previous years and formulated five PICO questions regarding (1) incidence of stroke cases in the ED; (2) relation between stroke cases and COVID-19; (3) differences in the number of reperfusion therapies, (4) in the call-to-needle and door-to-needle times for intravenous thrombolysis, and (5) in the call-to-groin and door-to-groin times for thrombectomy.

Results: We found (1) a 28% decreased of confirmed stroke cases managed in the ED, (2) a negative correlation between stroke cases in ED and COVID-19 progression (r = - .390, p = .030), and (3) a similar number of treatments in March 2020 and March 2019. The adoption of the mothership model (4) did not delay alteplase infusion (median call-to-needle p = .126, median door-to-needle p = .142) but led to (5) a significant reduction in median call-to-groin (p = .018) and door-to-groin times (p = .010).

Conclusion: The "hospital avoidance" of stroke patients during the "stay-at-home" appeals needs to be considered for future public health campaigns. A prompt reorganization of the stroke network can guarantee optimal performances at times of crisis.
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http://dx.doi.org/10.1007/s10072-020-04914-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7680213PMC
February 2021

Direct thrombectomy for stroke in the presence of absolute exclusion criteria for thrombolysis.

J Neurol 2020 Dec 25;267(12):3731-3740. Epub 2020 Jul 25.

Azienda Ospedaliero-Univeristaria, Padua, Italy.

Background: Intravenous thrombolysis (IVT)-ineligible patients undergoing direct thrombectomy tended to have poorer functional outcome as compared with IVT-eligible patients undergoing bridging therapy. We aimed to assess radiological and functional outcomes in large vessel occlusion-related stroke patients receiving direct thrombectomy in the presence of absolute exclusion criteria for IVT vs relative exclusion criteria for IVT and vs non-exclusion criteria for IVT.

Methods: A cohort study on prospectively collected data from 2282 patients enrolled in the Italian Registry of Endovascular Treatment in Acute Stroke cohort for treatment with direct thrombectomy (n = 486, absolute exclusion criteria for IVT alone; n = 384, absolute in combination with relative exclusion criteria for IVT; n = 777, relative exclusion criteria for IVT alone; n = 635, non-exclusion criteria for IVT).

Results: After adjustment for unbalanced variables (model 1), ORs for 3-month death was higher in the presence of absolute exclusion criteria for IVT alone (vs relative exclusion criteria for IVT alone) (1.595, 95% CI 1.042-2.440) and in the presence of absolute exclusion criteria for IVT alone (vs non-exclusion criteria for IVT) (1.235, 95% CI 1.014-1.504). After adjustment for predefined variables (model 2: age, sex, pre-stroke mRS ≤ 1, NIHSS, occlusion in the anterior circulation, onset-to-groin time, and procedure time), ORs for 3-month death was higher in the presence of absolute exclusion criteria for IVT alone (vs relative exclusion criteria for IVT alone) (1.235, 95% CI 1.014-1.504) and in the presence of absolute exclusion criteria for IVT alone (vs non-exclusion criteria for IVT) (1.246, 95% CI 1.039-1.495). No significant difference was found between the groups as regards any type of intracerebral hemorrhage and parenchymal hematoma within 24 h, successful and complete recanalization after procedure, and modified Rankin Scale score 0-2 at 3 months. After adjustment for predefined variables of model 2, ORs for death were higher in the presence of recent administration of IV heparin (OR: 2.077), platelet count < 100,000/mm (OR: 4.798), bacterial endocarditis (OR: 15.069), neoplasm with increased hemorrhagic risk (OR: 6.046), and severe liver disease (OR: 6.124).

Conclusions: Radiological outcomes were similar after direct thrombectomy in patients with absolute, relative, and non- exclusion criteria for IVT, while an increase of fatal outcome was observed in the presence of some absolute exclusion criterion for IVT.
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http://dx.doi.org/10.1007/s00415-020-10098-wDOI Listing
December 2020

Endovascular Thrombectomy for Acute Ischemic Stroke Beyond 6 Hours From Onset: A Real-World Experience.

Stroke 2020 07 17;51(7):2051-2057. Epub 2020 Jun 17.

Stroke Unit and Neurosonology Lab (A.P.), Padua University Hospital.

Background And Purpose: To evaluate outcome and safety of endovascular treatment beyond 6 hours of onset of ischemic stroke due to large vessel occlusion in the anterior circulation, in routine clinical practice.

Methods: From the Italian Registry of Endovascular Thrombectomy, we extracted clinical and outcome data of patients treated for stroke of known onset beyond 6 hours. Additional inclusion criteria were prestroke modified Rankin Scale score ≤2 and ASPECTS score ≥6. Patients were selected on individual basis by a combination of CT perfusion mismatch (difference between total hypoperfusion and infarct core sizes) and CT collateral score. The primary outcome measure was the score on modified Rankin Scale at 90 days. Safety outcomes were 90-day mortality and the occurrence of symptomatic intracranial hemorrhage. Data were compared with those from patients treated within 6 hours.

Results: Out of 3057 patients, 327 were treated beyond 6 hours. Their mean age was 66.8±14.9 years, the median baseline National Institutes of Health Stroke Scale 16, and the median onset to groin puncture time 430 minutes. The most frequent site of occlusion was middle cerebral artery (45.1%). Functional independence (90-day modified Rankin Scale score, 0-2) was achieved by 41.3% of cases. Symptomatic intracranial hemorrhage occurred in 6.7% of patients, and 3-month case fatality rate was 17.1%. The probability of surviving with modified Rankin Scale score, 0-2 (odds ratio, 0.58 [95% CI, 0.43-0.77]) was significantly lower in patients treated beyond 6 hours as compared with patients treated earlier No differences were found regarding recanalization rates and safety outcomes between patients treated within and beyond 6 hours. There were no differences in outcome between people treated 6-12 hours from onset (278 patients) and those treated 12 to 24 hours from onset (49 patients).

Conclusions: This real-world study suggests that in patients with large vessel occlusion selected on the basis of CT perfusion and collateral circulation assessment, endovascular treatment beyond 6 hours is feasible and safe with no increase in symptomatic intracranial hemorrhage.
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http://dx.doi.org/10.1161/STROKEAHA.119.027974DOI Listing
July 2020

General Anesthesia Versus Conscious Sedation and Local Anesthesia During Thrombectomy for Acute Ischemic Stroke.

Stroke 2020 07 10;51(7):2036-2044. Epub 2020 Jun 10.

Interventional Neuroradiology Unit and Stroke Unit, Azienda Ospedaliera-Universitaria, Padova, Italy (F.C., C.B.).

Background And Purpose: As numerous questions remain about the best anesthetic strategy during thrombectomy, we assessed functional and radiological outcomes in stroke patients treated with thrombectomy in presence of general anesthesia (GA) versus conscious sedation (CS) and local anesthesia (LA).

Methods: We conducted a cohort study on prospectively collected data from 4429 patients enrolled in the Italian Registry of Endovascular Treatment in Acute Stroke.

Results: GA was used in 2013 patients, CS in 1285 patients, and LA in 1131 patients. The rates of 3-month modified Rankin Scale score of 0-1 were 32.7%, 33.7%, and 38.1% in the GA, CS, and LA groups: GA versus CS: odds ratios after adjustment for unbalanced variables (adjusted odds ratio [aOR]), 0.811 (95% CI, 0.602-1.091); and GA versus LA: aOR, 0.714 (95% CI, 0.515-0.990). The rates of modified Rankin Scale score of 0-2 were 42.5%, 46.6%, and 52.4% in the GA, CS, and LA groups: GA versus CS: aOR, 0.902 (95% CI, 0.689-1.180); and GA versus LA: aOR, 0.769 (95% CI, 0.566-0.998). The rates of 3-month death were 21.5%, 19.7%, and 14.8% in the GA, CS, and LA groups: GA versus CS: aOR, 0.872 (95% CI, 0.644-1.181); and GA versus LA: aOR, 1.235 (95% CI, 0.844-1.807). The rates of parenchymal hematoma were 9%, 12.6%, and 11.3% in the GA, CS, and LA groups: GA versus CS: aOR, 0.380 (95% CI, 0.262-0.551); and GA versus LA: aOR, 0.532 (95% CI, 0.337-0.838). After model of adjustment for predefined variables (age, sex, thrombolysis, National Institutes of Health Stroke Scale, onset-to-groin time, anterior large vessel occlusion, procedure time, prestroke modified Rankin Scale score of <1, antiplatelet, and anticoagulant), differences were found also between GA versus CS as regards modified Rankin Scale score of 0-2 (aOR, 0.659 [95% CI, 0.538-0.807]) and GA versus LA as regards death (aOR, 1.413 [95% CI, 1.095-1.823]).

Conclusions: GA during thrombectomy was associated with worse 3-month functional outcomes, especially when compared with LA. The inclusion of an LA arm in future randomized clinical trials of anesthesia strategy is recommended.
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http://dx.doi.org/10.1161/STROKEAHA.120.028963DOI Listing
July 2020

Periprocedural to 1-year safety and efficacy outcomes with the Pipeline Embolization Device with Shield technology for intracranial aneurysms: a prospective, post-market, multi-center study.

J Neurointerv Surg 2020 Nov 1;12(11):1107-1112. Epub 2020 Jun 1.

Interventional Neuroradiology. Radiology, Queen Elizabeth Hospital, Birmingham, Birmingham, UK.

Background: The first and second generations of the Pipeline Embolization Device (PED) have been widely adopted for the treatment of intracranial aneurysms (IAs) due to their high associated occlusion rates and low morbidity and mortality. The objective of this study was to evaluate the safety and effectiveness of the third- generation Pipeline Shield device (PED-Shield) for the treatment of IAs.

Methods: The SHIELD study was a prospective, single-arm, multicenter, post-market, observational study evaluating the PED-Shield device for the treatment of IAs. The primary efficacy endpoint was complete aneurysm occlusion without significant parent artery stenosis or retreatment at 1-year post-procedure and the primary safety endpoint was major stroke in the territory supplied by the treated artery or neurological death.

Results: Of 205 subjects who consented across 21 sites, 204 subjects with 204 target aneurysms were ultimately treated (mean age 54.8±12.81 years, 81.4% [166/204] female). Technical success (ie, deployment of the PED-Shield) was achieved in 98.0% (200/204) of subjects with a mean number of 1.1±0.34 devices per subject and a single device used in 86.8% (177/204) of subjects. The primary effectiveness endpoint was met in 71.7% (143/200) of subjects while the primary safety endpoint occurred in six (2.9%) subjects, two (1.0%) of which led to neurological death.

Conclusions: The findings of the SHIELD study support the safety and effectiveness of the PED-Shield for IA treatment, evidenced by high occlusion rates and low rates of neurological complications in the study population. CLINICAL TRIAL REGISTRATION-URL: http://www.clinicaltrials.gov. Unique identifier: NCT02719522.
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http://dx.doi.org/10.1136/neurintsurg-2020-015943DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7569365PMC
November 2020

Flow diverters for ruptured posterior circulation perforator aneurysms: multicenter experience and literature review.

J Neurointerv Surg 2020 Jul 12;12(7):688-694. Epub 2020 Feb 12.

Neuroradiology, Maurizio Bufalini Hospital, Cesena, Emilia-Romagna, Italy.

Background: The management of ruptured posterior circulation perforator aneurysms (rPCPAs) remains unclear. We present our experience in treating rPCPAs with flow diverter stents (FDs) and evaluate their safety and efficacy at mid- to long-term follow-up. A diagnostic and therapeutic algorithm for rPCPAs is also proposed.

Methods: We retrospectively analyzed data from all consecutive patients with rPCPAs treated with FDs at our institutions between January 2013 and July 2019. Clinical presentations, time of treatments, intra- and perioperative complications, and clinical and angiographic outcomes were recorded, with a mid- to long-term follow-up. A systematic review of the literature on rPCPAs treated with FDs was also performed.

Results: Seven patients with seven rPCPAs were treated with FDs. All patients presented with an atypical subarachnoid hemorrhage distribution and a low to medium Hunt-Hess grade. In 29% of cases rPCPAs were identified on the initial angiogram. In 57% of cases, FDs were inserted within 2 days of the diagnosis. Immediate aneurysm occlusion was observed in 14% of the cases and in 71% at the first follow-up (mean 2.4 months). At mean follow-up of 33 months (range 3-72 months) one case of delayed ischemic complication occurred. Six patients had a modified Rankin Scale (mRS) score of 0 and one patient had an mRS score of 4 at the latest follow-up.

Conclusions: The best management for rPCPAs remains unclear, but FDs seem to have lower complication rates than other treatment options. Further studies with larger series are needed to confirm the role of FDs in rPCPA.
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http://dx.doi.org/10.1136/neurintsurg-2019-015558DOI Listing
July 2020

In vivo assessment of tumour associated macrophages in murine melanoma obtained by low-field relaxometry in the presence of iron oxide particles.

Biomaterials 2020 04 27;236:119805. Epub 2020 Jan 27.

Department of Molecular Biotechnology and Health Sciences, University of Torino, Via Nizza 52, Torino, Italy. Electronic address:

Tumour-associated macrophages (TAM) are forced by cancer cells to adopt an anti-inflammatory phenotype and secrete factors to promote tumour invasion thus being responsible for poor patient outcome. The aim of this study is to develop a clinically applicable, non-invasive method to obtain a quantitative TAM detection in tumour tissue. The method is based on longitudinal proton relaxation rate (R) measurements at low field (0.01-1 MHz) to assess the localization of ferumoxytol (clinical approved iron oxide particles) in TAM present in melanoma tumours, where R = 1/T. R at low magnetic fields appears highly dependent on the intra or extra cellular localization of the nanoparticles thus allowing an unambiguous TAM quantification. R profiles were acquired on a Fast Field-Cycling relaxometer equipped with a 40 mm wide bore magnet and an 11 mm solenoid detection coil placed around the anatomical region of interest. The R values measured 3 h and 24 h after the injection were significantly different. At 24 h R exhibited a behavior similar to "in vitro" ferumoxytol-labelled J774A.1 macrophages whereas at 3 h, when the ferumoxytol distribution was extracellular, R exhibited higher values similar to that of free ferumoxytol in solution. This finding clearly indicated the intracellular localization of ferumoxytol at 24 h, as confirmed by histological analysis (Pearls and CD68 assays). This information could be hardly achievable from measurements at a single magnetic field and opens new horizons for cell tracking applications using FFC-MRI.
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http://dx.doi.org/10.1016/j.biomaterials.2020.119805DOI Listing
April 2020

The low-profile Neuroform Atlas stent in the treatment of wide-necked intracranial aneurysms - immediate and midterm results: An Italian multicenter registry.

J Neuroradiol 2020 Nov 2;47(6):421-427. Epub 2019 Apr 2.

Neuroradiology Unit, Biomedical Sciences and of Morphologic and Functional Images, AOU Policlinico G. Martino, Messina, Italy.

Background And Purpose: Wide-necked brain aneurysms therapy remains a challenge for neurointerventionalists, mainly for the high recurrence rate. Low-profile stents make feasible the treatment of these aneurysms. In our multicenter series we analyzed clinical and angiographic results of Neuroform Atlas stent-assisted coiling.

Materials And Methods: From January 2016 to March 2017, 113 wide-necked aneurysms were discovered with CTA, MRA and DSA. The Atlas stent-assisted coiling procedures were performed under general anesthesia with sequential or jailing techniques. Six months follow-up DSA was performed to assess the recurrence rate through the modified Raymond-Roy occlusion scale (RROC). Moreover, patients were evaluated clinically to analyse the degree of disability according to the mRS. MRI was performed at 12 months evaluating both the cerebral tissue and the vessels.

Results: In all the procedures it was feasible to navigate the Neuroform Atlas to the goal vessel and deploy the stent across the aneurysmal neck. Intra-procedural complications account for the 6.2% (7/113). The immediate occlusion rate was RROC 1 in 88%, 2 in 9% and 3 in 3% of cases. The 6 months clinical data showed mRS Score 0-1 in 96.5% of patients; 3 patients died of complications related to SAH. The 12 months follow-up showed RROC of 1 in 82%, 2 in 13% and 3 in 5% of cases. No aneurysm has been retreated.

Conclusions: In our multicenter experience the Neuroform Atlas stent assisted-coiling has shown to be a safe and effective technique for the treatment of wide-necked intracranial aneurysms with encouraging clinical and angiographic results.
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http://dx.doi.org/10.1016/j.neurad.2019.03.005DOI Listing
November 2020

Exploring the tumour extracellular matrix by in vivo Fast Field Cycling relaxometry after the administration of a Gadolinium-based MRI contrast agent.

Magn Reson Chem 2019 08 19;57(10):845-851. Epub 2019 Feb 19.

Department of Molecular Biotechnology and Health Sciences, University of Torino, Torino, Italy.

H Fast Field Cycling NMR (FFC-NMR) relaxometry is proposed as a powerful method to investigate tumour stroma in vivo upon the administration of a Gd-based contrast agent. To perform this study, an FFC-NMR equipment endowed with a wide bore magnet was used for the acquisition of Nuclear Magnetic Resonance Dispersion profiles on healthy muscle and tumour tissue in living mice. At magnetic field strengths < of ca. 1 MHz, the differences in the relaxation rates of the intra and extracellular compartment become of the same order of magnitude of the exchange rate across the cellular membranes. Under this condition, the water exchange rate between the two compartments yields to a biexponential magnetization recovery that can be analysed by fitting the experimental data with the two-Site eXchange (2SX) model. Using this model, it was possible to obtain, for the two compartments, both relaxation properties and water kinetic constants for water exchange across cell membranes. The method allowed us to determine the effect of the "matrix" on the water proton relaxation times and, in turn, to get some insights of the composition of this compartment, till now, largely unknown.
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http://dx.doi.org/10.1002/mrc.4837DOI Listing
August 2019

Evidence for the Role of Intracellular Water Lifetime as a Tumour Biomarker Obtained by In Vivo Field-Cycling Relaxometry.

Angew Chem Int Ed Engl 2018 06 14;57(25):7468-7472. Epub 2018 Apr 14.

Department Molecular Biotechnology and Health Sciences, University of Torino, via Nizza 52, Torino, Italy.

It was established through in vivo T measurements at low magnetic fields that tumour cells display proton T values that are markedly longer than those shown by healthy tissue. Moreover, it has been found that the elongation of T parallels the aggressiveness of the investigated tumour. The T lengthening is associated with an enhanced water exchange rate across the transcytolemmal membrane through an overexpression/upregulation of GLUT1 and Na /K ATPase transporters. It follows that the intracellular water lifetime represents a hallmark of tumour cells that can be easily monitored by measuring T at different magnetic field strengths ranging from 0.2 to 200 mT.
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http://dx.doi.org/10.1002/anie.201713318DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6175164PMC
June 2018

SORL1 Variants in Familial Alzheimer's Disease.

J Alzheimers Dis 2018 ;61(4):1275-1281

Secugen S.L. Madrid, Spain.

The SORL1 gene encodes a protein involved in the amyloidogenic process, and its variants have been associated with Alzheimer's disease (AD) physiopathology. We screened for SORL1 variants in 124 familial (44 early- and 80 late-onset) dementia of Alzheimer type (DAT) cases. Nine potentially pathogenic changes (three not previously reported and six rare variants) were found in nine probands (7%). After screening the control population and siblings (presence in at least 1/200 controls and/or absence of segregation pattern), a causal relationship with the disease was considered unlikely in six variants and uncertain in one. The change Trp848Ter and a splice-site variant remained likely correlated with the disease. SORL1 mutations are present in 7% of our familial DAT cohort, though in most cases cannot be considered the direct cause of the disease.
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http://dx.doi.org/10.3233/JAD-170590DOI Listing
January 2019

Clonal expansion behind a marine diatom bloom.

ISME J 2018 02 21;12(2):463-472. Epub 2017 Nov 21.

Department of Integrative Marine Ecology, Stazione Zoologica Anton Dohrn, Villa Comunale, Napoli, Italy.

Genetic diversity is what selection acts on, thus shaping the adaptive potential of populations. We studied micro-evolutionary patterns of the key planktonic diatom Pseudo-nitzschia multistriata at a long-term sampling site over 2 consecutive years by genotyping isolates with 22 microsatellite markers. We show that both sex and vegetative growth interplay in shaping intraspecific diversity. We document a brief but massive demographic and clonal expansion driven by strains of the same mating type. The analysis of an extended data set (6 years) indicates that the genetic fingerprint of P. multistriata changed over time with a nonlinear pattern, with intermittent periods of weak and strong diversification related to the temporary predominance of clonal expansions over sexual recombination. These dynamics, rarely documented for phytoplankton, contribute to the understanding of bloom formation and of the mechanisms that drive microevolution in diatoms.
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http://dx.doi.org/10.1038/ismej.2017.181DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5776461PMC
February 2018

Italian COnsensus in Neuroradiological Anesthesia (ICONA).

Minerva Anestesiol 2017 Sep 11;83(9):956-971. Epub 2017 May 11.

Unit of Anesthesia and Intensive Care, Department of Surgical Sciences, University of Turin, Turin, Italy.

Anesthetic management of patients undergoing endovascular procedures for treating intracranial aneurysms or cerebrovascular malformations must consider a number of specific challenges, in addition to those associated with anesthesia for other specialties. In addition to maintenance of physiological stability, manipulation of systemic and cerebral hemodynamic parameters may be required to treat any sudden unexpected catastrophic neurological events. A multidisciplinary group including neuro- and pediatric anesthesiologists, interventional neuroradiologists, neurosurgeons, and a clinical methodologist contributed to this document. This consensus working group from 21 Italian institutions identified open questions regarding the best practices for management of anesthesia during endovascular neuroradiological procedures for intracranial aneurysms and cerebrovascular malformations, and addressed these by formulating practical consensus statements. At the first meeting in November 2015, nine key areas were identified regarding choice of anesthetic, patient monitoring, hemodynamic targets, postoperative care, and the management of neuromuscular blockade, anticoagulant and/or antiplatelet therapy, and special considerations for pediatric patients. Nine subgroups were established and a medical librarian performed literature searches in the Cochrane and MEDLINE/PubMed databases for each group. Groups drafted literature summaries and provisional responses in the form of candidate consensus statements based on evidence, when possible, and clinical experience, when this was lacking. Final wording was agreed at a meeting in April 2016 and where possible evidence was graded using United States Preventive Services Task Force criteria. Consensus (defined as >90% agreement) was based on evidence, clinical experience, clinician preference, feasibility in the Italian healthcare system, and cost/benefit considerations.
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http://dx.doi.org/10.23736/S0375-9393.17.11753-0DOI Listing
September 2017

Ferritin Decorated PLGA/Paclitaxel Loaded Nanoparticles Endowed with an Enhanced Toxicity Toward MCF-7 Breast Tumor Cells.

Bioconjug Chem 2017 04 24;28(4):1283-1290. Epub 2017 Mar 24.

University of Turin , Department of Molecular Biotechnology and Health Sciences, via Nizza 52, 10126, Turin, Italy.

Polylactic and glycolic acid nanoparticles (PLGA-NPs), coated with L-ferritin, are exploited for the simultaneous delivery of paclitaxel and an amphiphilic Gd based MRI contrast agent into breast cancer cells (MCF7). L-ferritin has been covalently conjugated to the external surface of PLGA-NPs exploiting NHS activated carboxylic groups. The results confirmed that nanoparticles decorated with L-ferritin have many advantages with respect to both albumin-decorated and nondecorated particles. Ferritin moieties endow PLGA-NPs with targeting capability, exploiting SCARA5 receptors overexpressed by these tumor cells, that results in an increased paclitaxel cytotoxicity. Moreover, protein coating increased nanoparticle stability, thus reducing the fast and aspecific drug release before reaching the target. The theranostic potential of the nanoparticles has been demonstrated by evaluating the signal intensity enhancement on T-weighted MRI images of labeled MCF7 cells. The results were compared with that obtained with MDA cells used as negative control due to their lower SCARA5 expression.
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http://dx.doi.org/10.1021/acs.bioconjchem.7b00096DOI Listing
April 2017

Distribution, occurrence and biotoxin composition of the main shellfish toxin producing microalgae within European waters: A comparison of methods of analysis.

Harmful Algae 2016 05 5;55:112-120. Epub 2016 Mar 5.

Institute for Global Food Security, School of Biological Sciences, Queen's University, Stranmillis Road, Belfast BT9 5AG, UK. Electronic address:

Harmful algal blooms (HABs) are a natural global phenomena emerging in severity and extent. Incidents have many economic, ecological and human health impacts. Monitoring and providing early warning of toxic HABs are critical for protecting public health. Current monitoring programmes include measuring the number of toxic phytoplankton cells in the water and biotoxin levels in shellfish tissue. As these efforts are demanding and labour intensive, methods which improve the efficiency are essential. This study compares the utilisation of a multitoxin surface plasmon resonance (multitoxin SPR) biosensor with enzyme-linked immunosorbent assay (ELISA) and analytical methods such as high performance liquid chromatography with fluorescence detection (HPLC-FLD) and liquid chromatography-tandem mass spectrometry (LC-MS/MS) for toxic HAB monitoring efforts in Europe. Seawater samples (n=256) from European waters, collected 2009-2011, were analysed for biotoxins: saxitoxin and analogues, okadaic acid and dinophysistoxins 1/2 (DTX1/DTX2) and domoic acid responsible for paralytic shellfish poisoning (PSP), diarrheic shellfish poisoning (DSP) and amnesic shellfish poisoning (ASP), respectively. Biotoxins were detected mainly in samples from Spain and Ireland. France and Norway appeared to have the lowest number of toxic samples. Both the multitoxin SPR biosensor and the RNA microarray were more sensitive at detecting toxic HABs than standard light microscopy phytoplankton monitoring. Correlations between each of the detection methods were performed with the overall agreement, based on statistical 2×2 comparison tables, between each testing platform ranging between 32% and 74% for all three toxin families illustrating that one individual testing method may not be an ideal solution. An efficient early warning monitoring system for the detection of toxic HABs could therefore be achieved by combining both the multitoxin SPR biosensor and RNA microarray.
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http://dx.doi.org/10.1016/j.hal.2016.02.008DOI Listing
May 2016

Magnetic hyperthermia efficiency and (1)H-NMR relaxation properties of iron oxide/paclitaxel-loaded PLGA nanoparticles.

Nanotechnology 2016 Jul 6;27(28):285104. Epub 2016 Jun 6.

University of Torino, Department of Molecular Biotechnology and Health Sciences, via Nizza 52, Torino, Italy. SAET S.p.A via Torino, 213 10040 Leinì, Torino, Italy.

Magnetic iron oxide nanoparticles (Fe-NPs) can be exploited in biomedicine as agents for magnetic fluid hyperthermia (MFH) treatments and as contrast enhancers in magnetic resonance imaging. New, oleate-covered, iron oxide particles have been prepared either by co-precipitation or thermal decomposition methods and incorporated into poly(lactic-co-glycolic acid) nanoparticles (PLGA-Fe-NPs) to improve their biocompatibility and in vivo stability. Moreover, the PLGA-Fe-NPs have been loaded with paclitaxel to pursue an MFH-triggered drug release. Remarkably, it has been found that the nanoparticle formulations are characterized by peculiar (1)H nuclear magnetic relaxation dispersion (NMRD) profiles that directly correlate with their heating potential when exposed to an alternating magnetic field. By prolonging the magnetic field exposure to 30 min, a significant drug release was observed for PLGA-Fe-NPs in the case of the larger-sized magnetic nanoparticles. Furthermore, the immobilization of lipophilic Fe-NPs in PLGA-NPs also made it possible to maintain Néel relaxation as the dominant relaxation contribution in the presence of large iron oxide cores (diameters of 15-20 nm), with the advantage of preserving their efficiency when they are entrapped in the intracellular environment. The results reported herein show that NMRD profiles are a useful tool for anticipating the heating capabilities of Fe-NPs designed for MFH applications.
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http://dx.doi.org/10.1088/0957-4484/27/28/285104DOI Listing
July 2016

A Novel System for Single-Port Laparoscopic Surgery: Preliminary Experience.

Gynecol Obstet Invest 2016 21;81(5):454-60. Epub 2016 May 21.

Division of Gynecology and Obstetrics, University of Pisa, Pisa, Italy.

Aims: To present preliminary data of single-access laparoscopic surgery with a new device for the treatment of benign adnexal pathologies.

Methods: Ten women with benign adnexal pathologies underwent salpingectomy (n = 4) and ovarian/para-ovarian cyst enucleation (n = 6) using a laparo-endoscopic single-port approach with an innovative advanced multiport reusable trocar inserted transumbilically through a small wound retractor. Trocar introduction time, operative time, estimated blood loss, conversion to standard laparoscopy, peri- and postoperative complications, hospital stay and Visual Analog Scale score (as assessment of pain and cosmesis) were analyzed.

Results: Port placement was successful in all patients. Mean trocar introduction time was 4.4 min (range 3.4-5.3 min) and no intra or postoperative complication occurred. The mean operating time was 50.0 ± 9.2 min and mean blood loss was 28.5 ± 8.8 ml. The mean hospital stay following surgery was 1.6 ± 0.5 days and convalescence was complete in 1 week. Neither scores for postoperative incisional pain nor cosmesis side effects have been observed in any subjects.

Conclusion: We concluded that adnexal single-port surgery performed with this innovative advanced surgical instrumentation is a feasible, safe, and effective technique that drastically reduces postoperative pain and does not compromise cosmetic appearance. The isolation of the operative field by means of the drape prevents the contamination of the port site that occurs frequently, and mainly in adnexal pathologies of uncertain etiology. In addition, the ease of insertion and the conformation of the new port access also make the procedure feasible in obese patients.
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http://dx.doi.org/10.1159/000443394DOI Listing
April 2017

Pseudo-nitzschia arctica sp. nov., a new cold-water cryptic Pseudo-nitzschia species within the P. pseudodelicatissima complex.

J Phycol 2016 Apr 8;52(2):184-99. Epub 2016 Mar 8.

Integrative Marine Ecology Department, Stazione Zoologica Anton Dohrn, Villa Comunale, Naples, 80121, Italy.

A new nontoxic Pseudo-nitzschia species belonging to the P. pseudodelicatissima complex, P. arctica, was isolated from different areas of the Arctic. The erection of P. arctica is mainly supported by molecular data, since the species shares identical ultrastructure with another species in the complex, P. fryxelliana, and represents a new case of crypticity within the genus. Despite their morphological similarity, the two species are not closely related in phylogenies based on LSU, ITS and rbcL. Interestingly, P. arctica is phylogenetically most closely related to P. granii and P. subcurvata, from which the species is, however, morphologically different. P. granii and P. subcurvata lack the central larger interspace which is one of the defining features of the P. pseudodelicatissima complex. The close genetic relationship between P. arctica and the two species P. granii and P. subcurvata is demonstrated by analysis of the secondary structure of ITS2 which revealed no compensatory base changes, two hemi-compensatory base changes, and two deletions in P. arctica with respect to the other two species. These findings emphasize that rates of morphological differentiation, molecular evolution and speciation are often incongruent for Pseudo-nitzschia species, resulting in a restricted phylogenetic value for taxonomic characters used to discriminate species. The description of a new cryptic species, widely distributed in the Arctic and potentially representing an endemic component of the Arctic diatom flora, reinforces the idea of the existence of noncosmopolitan Pseudo-nitzschia species and highlights the need for combined morphological and molecular analyses to assess the distributional patterns of phytoplankton species.
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http://dx.doi.org/10.1111/jpy.12395DOI Listing
April 2016

Interspecific plastidial recombination in the diatom genus Pseudo-nitzschia.

J Phycol 2015 Dec 23;51(6):1024-8. Epub 2015 Oct 23.

Integrative Marine Ecology Department, Stazione Zoologica Anton Dohrn, Villa Comunale, Naples, I-80121, Italy.

Plastids are usually uni-parentally inherited and genetic recombination between these organelles is seldom observed. The genus Pseudo-nitzschia, a globally relevant marine diatom, features bi-parental plastid inheritance in the course of sexual reproduction. This observation inspired the recombination detection we pursued in this paper over a ~1,400-nucleotide-long region of the plastidial rbcL, a marker used in both molecular taxonomy and phylogenetic studies in diatoms. Among all the rbcL-sequences available in web-databases for Pseudo-nitzschia, 42 haplotypes were identified and grouped in five clusters by Bayesian phylogeny. Signs of hybridization were evident in four of five clusters, at both intra- and interspecific levels, suggesting that, in diatoms, (i) plastidial recombination is not absent and (ii) hybridization can play a role in speciation of Pseudo-nitzschia spp.
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http://dx.doi.org/10.1111/jpy.12350DOI Listing
December 2015

A new hexapeptide from the leader peptide of rMnSOD enters cells through the oestrogen receptor to deliver therapeutic molecules.

Sci Rep 2016 Jan 4;6:18691. Epub 2016 Jan 4.

Laedhexa Biotechnologies Inc., QB3@953, San Francisco, CA, USA.

A 24-amino acid leader peptide of a new human recombinant manganese superoxide dismutase can enter cells and carry molecules. Here, we demonstrated that six of the 24 amino acids penetrate cells through a particular gate represented by a specific amino acid sequence of the oestrogen receptor (ER). We analysed the internalization of the synthetic hexapeptide and the cytotoxic activity of the hexapeptide conjugated to cisplatin on a cell line panel. In most cell lines, the hexapeptide delivered an amount of cisplatin that was 2 to 8 times greater than that released by cisplatin when the drug was used alone. This increased delivery increases the therapeutic index of cisplatin and reduces side effects caused by a high dosage or long-term treatment times. We may consider this hexapeptide a new molecular carrier to deliver molecules with therapeutic activity into ER(+) cells for diagnostic purposes and clinical or immune therapy.
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http://dx.doi.org/10.1038/srep18691DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4698655PMC
January 2016

Endometritis in Infertile Couples: The Role of Hysteroscopy and Bacterial Endotoxin.

JBRA Assist Reprod 2015 Feb 1;19(1):21-3. Epub 2015 Feb 1.

University of Siena, Gynecology and Obstetrics Department, Siena - Italy.

Objective: The role of endometritis on infertility is still controversial. The aim of our prospective controlled study was to select infertile couples and to analyze: hysteroscopic findings of endometritis, bacterial endotoxin level in the menstrual blood, histological pattern of endometrial biopsy and to determine the effect of antibiotic therapy on endometritis resolution.

Methods: 100 infertile couples of University Hospital waiting for in vitro fertilization program. We evaluated the incidence of endometritis in infertile population by hysteroscopy, endometrial biopsy and bacterial endotoxin levels in the menstrual samples. Moreover, we verified the effectiveness of antimicrobial treatment on the endometritis resolution by hysteroscopic control.

Results: Out of 100 women enrolled, 15 showed hysteroscopic evidence of endometritis and 12 of these patients presented higher bacterial endotoxin in the menstrual samples. The histological results were positive for endometritis in 9 cases, 1 woman had no adequate samples and 5 patients had negative result. After antibiotic therapy, 9 patients had a complete hysteroscopic endometritis resolution, 4 patients had an improvement and in 2 cases there was no endometrial change. Concerning histological findings after therapy, we had negative results in 12 patients and persistent inflammatory findings in 2 patients.

Conclusion: Our study demonstrated a high incidence of endometritis in infertile couples (15%). The endometrial biopsy was in agreement with the hysteroscopic findings in 60% of the cases, and the bacterial endotoxin level in the menstrual samples was higher in 12 patients with suspected endometritis, then its measurement can be helpful to confirm an endometrial infection but its influence must be confirmed with further researches. The antibiotic therapy can improve the hysteroscopic endometrial inflammatory aspect in over 80% of cases.
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http://dx.doi.org/10.5935/1518-0557.20150006DOI Listing
February 2015

Comparative cath-lab assessment of coronary stenosis by radiology technician, junior and senior interventional cardiologist in patients treated with coronary angioplasty.

Interv Med Appl Sci 2014 Mar 14;6(1):26-30. Epub 2014 Mar 14.

Cardiology Department, University of Foggia Foggia Italy.

Background: Exact quantification of plaque extension during coronary angioplasty (PCI) usually falls on interventional cardiologist (IC). Quantitative coronary stenosis assessment (QCA) may be possibly committed to the radiology technician (RT), who usually supports cath-lab nurse and IC during PCI. We therefore sought to investigate the reliability of QCA performed by RT in comparison with IC.

Methods: Forty-four consecutive patients with acute coronary syndrome underwent PCI; target coronary vessel size beneath target coronary lesion (S) and target coronary lesion length (L) were assessed by the RT, junior IC (JIC), and senior IC (SIC) and then compared. SIC evaluation, which determined the final stent selection for coronary stenting, was considered as a reference benchmark.

Results: RT performance with QCA support in assessing target vessel size and target lesion length was not significantly different from SIC (r = 0.46, p < 0.01; r = 0.64, p < 0.001, respectively) as well as JIC (r = 0.79, r = 0.75, p < 0.001, respectively). JIC performance was significantly better than RT in assessing target vessel size (p < 0.05), while not significant when assessing target lesion length.

Conclusions: RT may reliably assess target lesion by using adequate QCA software in the cath-lab in case of PCI; RT performance does not differ from SIC.
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http://dx.doi.org/10.1556/IMAS.6.2014.1.4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3955812PMC
March 2014

A quantitative relaxometric version of the ELISA test for the measurement of cell surface biomarkers.

Angew Chem Int Ed Engl 2014 Mar 24;53(13):3488-91. Epub 2014 Feb 24.

Department Molecular Biotechnology and Health Sciences, Institution University of Torino, Address via Nizza 52, Torino (Italy).

Quantitative measurement of marker expression in diseased cells is still a topic of considerable interest and different methodologies are currently under intense scrutiny. This work aims at developing an in vitro diagnostic method based on the release of paramagnetic species from relaxometrically "silent" liposomes operated by the action of a phospholipase A2 (PLA2) previously targeted to the epitope of interest. The released paramagnetic species causes an increase of the longitudinal water proton relaxation rate proportional to the number of PLA2 bound to the cell outer surface. The sensitivity of the herein proposed method, named R-ELISA, was attempted in the detection of folate receptor expression on human ovarian cancer cells by functionalizing PLA2 with folic acid. Receptor/cell number of 8.3×10(5) has been measured on IGROV-1 cells. The R-ELISA assay can detect nanomolar cell suspension receptor concentrations and has been validated by well-established spectrofluorimetric procedures.
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http://dx.doi.org/10.1002/anie.201310959DOI Listing
March 2014

Erythrophagocytosis in circulating blood of loggerhead turtles Caretta caretta: the pitting of Heinz bodies.

J Exp Zool A Ecol Genet Physiol 2014 Mar 19;321(3):144-50. Epub 2013 Nov 19.

Department of Biology, University of Naples Federico II, Naples, Italy.

In humans red blood cells live on average of 120 days. Senescent erythrocytes are removed from circulation by macrophages; this process, called erythrophagocytosis (EPC), takes place mainly in the liver but also in the bone marrow. We studied this process in loggerhead turtles Caretta caretta, inhabiting the Mediterranean Sea. Leukocytes of reptiles include heterophils, eosinophils, lymphocytes, basophils, thrombocytes, monocytes, and of these heterophils and monocytes represent the main phagocytic cells. The aim of this study was to investigate the blood of C. caretta specimens and to observe, in the blood smears, heterophils phagocytizing erythrocytes. The phagocytizing cells were also identified by cytochemical reactions. Furthermore some examples of tear-shaped erythrocytes (dacrocytes) were observed. A mechanism presuming a causative link between erythrophagocytosis and teardrop-erythrocyte detection have been proposed to explain this seemingly general pattern of all specimens both wild and housed.
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http://dx.doi.org/10.1002/jez.1844DOI Listing
March 2014