Publications by authors named "Laura Oliva"

25 Publications

  • Page 1 of 1

New-onset atrial fibrillation following percutaneous closure of patent foramen ovale: a systematic review and meta-analysis.

J Interv Card Electrophysiol 2021 Mar 8;60(2):165-174. Epub 2021 Jan 8.

Institute of Health Policy, Management and Evaluation (IHPME), University of Toronto, Toronto, Ontario, Canada.

Purpose: A patent foramen ovale (PFO), present in up to 25% of adults, is an embryologic remnant which allows for right to left shunting and has been implicated in cryptogenic stroke (Neill and Lin, Methodist Debakey Cardiovasc J. 13(3):152-159, 2017; Bass 2015). The current standard of care for selected patients with PFO and cryptogenic stroke is transcatheter closure, but the risk of post-closure, new-onset atrial fibrillation (AF) is unknown (Vaidya et al., Cardiovasc Diagn Ther. 8(6):739-753, 2018; Kjeld et al., Acta Radiol Open. 7(9):2058460118793922, 2018; Staubach et al., Catheter Cardiovasc Interv. 74(6):889-95, 2009). This systematic review and meta-analysis synthesized evidence on AF development post transcatheter PFO closure and predictors of AF development, and assessed existing knowledge gaps.

Methods: Randomized controlled trials and observational studies were selected according to the inclusion criteria of adults that underwent a transcatheter PFO closure without a history of AF. Studies were retrieved from electronic databases from inception until February 2019. A Freeman-Tukey arcsine transformation was performed for meta-analysis of AF incidence rate.

Results: From 765 studies, 45 were included in quantitative data synthesis. Study sample sizes ranged between 20 and 1887 individuals, and average patient age between 37 to 67 years across studies. The overall incidence rate was 0.013 person-years, and 0.014 person-years for the within 6 months follow-up subgroup. There was no consistency in reported predictors of AF development.

Conclusions: The incidence of AF post-PFO closure was low across studies, with a high level of between-study heterogeneity. Until a concerted effort is made to improve accurate AF diagnosis, it will be difficult to gauge the association between transcatheter PFO closure and incidence of AF.
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http://dx.doi.org/10.1007/s10840-020-00925-5DOI Listing
March 2021

Classification of general and personal semantic details in the Autobiographical Interview.

Neuropsychologia 2020 07 21;144:107501. Epub 2020 May 21.

Rotman Research Institute, Baycrest, Toronto, Ontario, Canada; Department of Psychology, University of Toronto, Ontario, Canada; Department of Medicine (Neurology), University of Toronto, Ontario, Canada. Electronic address:

The Autobiographical Interview (AI) separates internal (episodic) and external (non-episodic) details from transcribed protocols using an exhaustive and reliable scoring system. While the details comprising the internal composite are centered on elements of episodic memory, external details are more heterogeneous as they are meant to capture a variety of non-episodic utterances: general semantics, different types of personal semantics details, metacognitive statements, repetitions, and details about off topic events. Elevated external details are consistently observed in aging and in neurodegenerative diseases. In the present study, we augmented the AI scoring system to differentiate subtypes of external details to test whether the elevation of these details in aging and in frontotemporal lobar degeneration (including mixed frontotemporal/semantic dementia [FTD/SD] and progressive non-fluent aphasia [PNFA]) would be specific to general and personal semantics or would concern all subtypes. Specifically, we separated general semantic details from personal semantic details (including autobiographical facts, self-knowledge, and repeated events). With aging, external detail elevation was observed for general and personal semantic details but not for other types of external details. In frontotemporal lobar degeneration, patients with FTD/SD (but not PNFA) generated an excess of personal semantic details but not general semantic details. The increase in personal but not general semantic details in FTD/SD is consistent with prevalent impairment of general semantic memory in SD, and with the personalization of concepts in this condition. Under standard AI instructions, external details were intended to capture off-topic utterances and were not intended as a direct measure of semantic abilities. Future investigations concerned with semantic processing in aging and in dementia could modify standard instructions of the AI to directly probe semantic content.
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http://dx.doi.org/10.1016/j.neuropsychologia.2020.107501DOI Listing
July 2020

Analgesic effects of a capacitive-resistive monopolar radiofrequency in patients with myofascial chronic neck pain: a pilot randomized controlled trial.

Rev Assoc Med Bras (1992) 2019 Feb;65(2):156-164

Department of Physical Therapy, Occupational Therapy, Rehabilitation, and Physical Medicine. Rey Juan Carlos University, Madrid, Spain.

Background: To date, there is a lack of prior studies on the use of capacitive resistive monopolar radiofrequency (RF) to treat neck pain. The objective of this study was to investigate the immediate effect of capacitive resistive monopolar radiofrequency (RF=448 kHz), in comparison with a placebo, on (1) reducing neck pain intensity at myofascial trigger points (MTrP), (2) decreasing neck disability and (3) improving cervical range of motion (CROM).

Methods: A randomized, double-blind, placebo-controlled trial (NCT02353195) was carried out. Patients with myofascial chronic neck pain (N=24) with active MTrP in one upper trapezius muscle were randomly divided into two groups: a radio-frequency group, which received eight sessions of a monopolar capacitive resistive radio-frequency application over the upper trapezius muscle, and a placebo group (PG), which received eight sessions of placebo radio-frequency over the same muscle. Visual analog scale (VAS), CROM and Neck Disability Index (NDI) were evaluated after the first session and after the eight sessions.

Results: The Wilcoxon test for VAS showed statistically significant differences between baseline, immediately after the first session and after eight sessions (p<.001). No significant differences for PG were found. No differences were observed between groups. NDI improved in both groups after eight sessions, but no differences were found between groups (p<.05). ANOVA for time factor showed statistically significant changes in the right cervical rotation in both groups (F=4.112; p=.026) after eight sessions.

Conclusions: Even though there were no differences between both groups, the monopolar capacitive, resistive RF could have a potential effect on pain intensity.
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http://dx.doi.org/10.1590/1806-9282.65.2.156DOI Listing
February 2019

Proteasome stress sensitizes malignant pleural mesothelioma cells to bortezomib-induced apoptosis.

Sci Rep 2017 12 15;7(1):17626. Epub 2017 Dec 15.

Department of Veterinary Sciences, University of Turin, Largo P. Braccini 2, 10095, Grugliasco, Turin, Italy.

Based on promising results in preclinical models, clinical trials have been performed to evaluate the efficacy of the first-in-class proteasome inhibitor bortezomib towards malignant pleural mesothelioma (MPM), an aggressive cancer arising from the mesothelium of the serous cavities following exposure to asbestos. Unexpectedly, only minimal therapeutic benefits were observed, thus implicating that MPM harbors inherent resistance mechanisms. Identifying the molecular bases of this primary resistance is crucial to develop novel pharmacologic strategies aimed at increasing the vulnerability of MPM to bortezomib. Therefore, we assessed a panel of four human MPM lines with different sensitivity to bortezomib, for functional proteasome activity and levels of free and polymerized ubiquitin. We found that highly sensitive MPM lines display lower proteasome activity than more bortezomib-resistant clones, suggesting that reduced proteasomal capacity might contribute to the intrinsic susceptibility of mesothelioma cells to proteasome inhibitors-induced apoptosis. Moreover, MPM equipped with fewer active proteasomes accumulated polyubiquitinated proteins, at the expense of free ubiquitin, a condition known as proteasome stress, which lowers the cellular apoptotic threshold and sensitizes mesothelioma cells to bortezomib-induced toxicity as shown herein. Taken together, our data suggest that an unfavorable load-versus-capacity balance represents a critical determinant of primary apoptotic sensitivity to bortezomib in MPM.
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http://dx.doi.org/10.1038/s41598-017-17977-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5732203PMC
December 2017

Hybrid metal/scaffold-jacket versus full-metal jackets in left anterior descending coronary artery diffuse disease: Differences in radiation exposure and fluoroscopic/procedural times.

Cardiovasc Revasc Med 2017 Dec 18;18(8):592-595. Epub 2017 May 18.

Section of Cardiovascular Diagnosis and Endoluminal Interventions, Rovigo General Hospital, Rovigo, Italy.

Background/purpose: Bioabsorbable vascular scaffolds (BVS) are made from a radiolucent material. Their multiple implantations on a single long diffused segment requires a specific technique with imaging magnification, which could cause an increase in dose delivered during percutaneous coronary intervention (PCI) procedure. We aimed to identify differences in radiation dose, fluoroscopy and procedural times in Hybrid DES+ multiple BVS (Absorb, Abbott Inc., USA) implantation (hybrid metal/scaffold jacket) versus multiple III generation Drug-eluting stents (DES) (full-metal jacket) in patients with long and diffuse coronary artery disease of the left anterior descending (LAD) coronary artery.

Methods/materials: Patients with long and diffuse LAD disease were enrolled in a registry from 1st February 2015 to 1st February 2017. Patients treated with hybrid DES/BVS (at least three) jacket (n=72 procedure) were compared with a 2:1 matched cohort of exclusive multiple overlapped DES (full-metal jacket) patients in the same period (n=114 procedures).

Results: Patients had similar baseline characteristics due to matching. Radiation exposure (6035.7±2846.8 vs 4251.1±1787.3cGy∗cm, p<0.0001, Δ=1784.5±1055.6), fluoroscopy time (16.2±4.5 vs 9.1±2.4, p<0.0001) and procedure time (64.2±18.5 vs 5 8.7±13.5, p=0.02) were higher in patients treated using hybrid metal/scaffold jacket compared that regular full-metal jacket.

Conclusion: The use of hybrid metal/scaffold jacket for the treatment of long and diffuse disease of LAD is associated with a higher fluoroscopy time and radiation exposure compared to full-metal jacket, quantifiable in approximately 35%.
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http://dx.doi.org/10.1016/j.carrev.2017.05.015DOI Listing
December 2017

The amyloidogenic light chain is a stressor that sensitizes plasma cells to proteasome inhibitor toxicity.

Blood 2017 04 27;129(15):2132-2142. Epub 2017 Jan 27.

Unit of Age Related Diseases, Division of Genetics and Cell Biology.

Systemic light chain (AL) amyloidosis is caused by the clonal production of an unstable immunoglobulin light chain (LC), which affects organ function systemically. Although pathogenic LCs have been characterized biochemically, little is known about the biology of amyloidogenic plasma cells (PCs). Intrigued by the unique response rates of AL amyloidosis patients to the first-in-class proteasome inhibitor (PI) bortezomib, we purified and investigated patient-derived AL PCs, in comparison with primary multiple myeloma (MM) PCs, the prototypical PI-responsive cells. Functional, biochemical, and morphological characterization revealed an unprecedented intrinsic sensitivity of AL PCs to PIs, even higher than that of MM PCs, associated with distinctive organellar features and expression patterns indicative of cellular stress. These consisted of expanded endoplasmic reticulum (ER), perinuclear mitochondria, and a higher abundance of stress-related transcripts, and were consistent with reduced autophagic control of organelle homeostasis. To test whether PI sensitivity stems from AL LC production, we engineered PC lines that can be induced to express amyloidogenic and nonamyloidogenic LCs, and found that AL LC expression alters cell growth and proteostasis and confers PI sensitivity. Our study discloses amyloidogenic LC production as an intrinsic PC stressor, and identifies stress-responsive pathways as novel potential therapeutic targets. Moreover, we contribute a cellular disease model to dissect the biology of AL PCs.
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http://dx.doi.org/10.1182/blood-2016-08-730978DOI Listing
April 2017

Impact of Operators' Height on Individual Radiation Exposure Measurements During Catheter-Based Cardiovascular Interventions.

J Interv Cardiol 2016 Feb 5;29(1):83-8. Epub 2016 Jan 5.

Cardiovascular Diagnosis and Endoluminal Interventions Unit, Rovigo General Hospital, Viale tre Martiri, Rovigo, Italy.

Aim: This study is aimed to evaluate the impact of an operators' height on personal radiation exposure measurements during cardiovascular interventional procedures. Based upon both clinical data and phantom simulation, a new approach for monitoring an individual's exposure is proposed.

Methods: The clinical component of this study was composed of the operators and staff in a single center full service cardiovascular laboratory being divided into 2 groups based upon their height: group A included all individuals whose height was <165 cm; group B included the individuals >165 cm. All operators wore a standard TLD dosimeter at all times with doses recorded for 12 months. To support these clinical findings, a second investigation was performed utilizing a phantom. Measurements were obtained at 100 and 135 cm from the radiation source during simulation of different cardiovascular interventional procedures.

Results: The radiation dose measured from the personal dosimeters identified that Group A, operators <165 cm, had significantly higher doses than those recorded in Group B, operators >165 cm, when compared among individuals performing similar tasks (physicians, technicians, and nurses): 4.55 ± 4.0 (Group A) versus 1.95 ± 1.0 (Group B) mSv (P < 0.01). During procedure simulation with the phantom, the doses measured were similarly significantly higher if measured at 100 cm than at 135 cm from the radiation source.

Conclusion: This study suggests that the height from radiation source does impact the measured dose from an operator worn personal TLD. This was operator specific, consistent thought-out multiple procedures, and confined with phantom measurements.
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http://dx.doi.org/10.1111/joic.12263DOI Listing
February 2016

A plastic SQSTM1/p62-dependent autophagic reserve maintains proteostasis and determines proteasome inhibitor susceptibility in multiple myeloma cells.

Autophagy 2015 ;11(7):1161-78

a San Raffaele Scientific Institute; Division of Genetics and Cell Biology ; Milan , Italy.

Multiple myeloma (MM) is the paradigmatic proteasome inhibitor (PI) responsive cancer, but many patients fail to respond. An attractive target to enhance sensitivity is (macro)autophagy, recently found essential to bone marrow plasma cells, the normal counterpart of MM. Here, integrating proteomics with hypothesis-driven strategies, we identified the autophagic cargo receptor and adapter protein, SQSTM1/p62 as an essential component of an autophagic reserve that not only synergizes with the proteasome to maintain proteostasis, but also mediates a plastic adaptive response to PIs, and faithfully reports on inherent PI sensitivity. Lentiviral engineering revealed that SQSTM1 is essential for MM cell survival and affords specific PI protection. Under basal conditions, SQSTM1-dependent autophagy alleviates the degradative burden on the proteasome by constitutively disposing of substantial amounts of ubiquitinated proteins. Indeed, its inhibition or stimulation greatly sensitized to, or protected from, PI-induced protein aggregation and cell death. Moreover, under proteasome stress, myeloma cells selectively enhanced SQSTM1 de novo expression and reset its vast endogenous interactome, diverting SQSTM1 from signaling partners to maximize its association with ubiquitinated proteins. Saturation of such autophagic reserve, as indicated by intracellular accumulation of undigested SQSTM1-positive aggregates, specifically discriminated patient-derived myelomas inherently susceptible to PIs from primarily resistant ones. These aggregates correlated with accumulation of the endoplasmic reticulum, which comparative proteomics identified as the main cell compartment targeted by autophagy in MM. Altogether, the data integrate autophagy into our previously established proteasome load-versus-capacity model, and reveal SQSTM1 aggregation as a faithful marker of defective proteostasis, defining a novel prognostic and therapeutic framework for MM.
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http://dx.doi.org/10.1080/15548627.2015.1052928DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4590585PMC
April 2016

Self-Reported Differences in Personality, Emotion Control, and Presence Between Pre-Military and Non-Military Groups in a Pilot Study Using the Stress Resilience in Virtual Environments (STRIVE) System.

Stud Health Technol Inform 2014 ;196:182-4

University of Southern California, Institute for Creative Technologies.

Mental health disorders are the signature wounds of war resulting from extended U.S. Military conflicts in the Middle East [1]. In an effort to abate the number of Service Members that develop mental health disorders in these conflicts, USC-ICT has created the Stress Resilience in Virtual Environments (STRIVE) project, a set of highly realistic virtual reality combat scenarios and resilience-building sessions designed for pre-deployed military personnel. This short-paper looks at self-reported differences in personality, emotion control, and presence between two different groups, pre-military and non-military, of pilot subjects that tested a prototype of the first four modules of STRIVE.
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April 2017

Autophagy in plasma cell pathophysiology.

Front Immunol 2014 12;5:103. Epub 2014 Mar 12.

Division of Genetics and Cell Biology, San Raffaele Scientific Institute , Milan , Italy ; Università Vita-Salute San Raffaele , Milan , Italy ; Bone Pathophysiology Program (BoNetwork), Division of Genetics and Cell Biology, San Raffaele Scientific Institute , Milan , Italy.

Plasma cells (PCs) are the effectors responsible for antibody (Ab)-mediated immunity. They differentiate from B lymphocytes through a complete remodeling of their original structure and function. Stress is a constitutive element of PC differentiation. Macroautophagy, conventionally referred to as autophagy, is a conserved lysosomal recycling strategy that integrates cellular metabolism and enables adaptation to stress. In metazoa, autophagy plays diverse roles in cell differentiation. Recently, a number of autophagic functions have been recognized in innate and adaptive immunity, including clearance of intracellular pathogens, inflammasome regulation, lymphocyte ontogenesis, and antigen presentation. We identified a previously unrecognized role played by autophagy in PC differentiation and activity. Following B cell activation, autophagy moderates the expression of the transcriptional repressor Blimp-1 and immunoglobulins through a selective negative control exerted on the size of the endoplasmic reticulum and its stress signaling response, including the essential PC transcription factor, XBP-1. This containment of PC differentiation and function, i.e., Ab production, is essential to optimize energy metabolism and viability. As a result, autophagy sustains Ab responses in vivo. Moreover, autophagy is an essential intrinsic determinant of long-lived PCs in their as yet poorly understood bone marrow niche. In this essay, we discuss these findings in the context of the established biological functions of autophagy, and their manifold implications for adaptive immunity and PC diseases, in primis multiple myeloma.
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http://dx.doi.org/10.3389/fimmu.2014.00103DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3950468PMC
June 2014

Pathophysiology of paradoxical embolism: evaluation of the role of interatrial septum anatomy based on the intracardiac echocardiography assessment of patients with right-to-left shunting.

Cardiol Young 2015 Jan 8;25(1):47-55. Epub 2013 Oct 8.

1Section of Adult Congenital and Adult Heart Disease,Cardiovascular Diagnosis and Endoluminal Interventions,Rovigo General Hospital,Rovigo,Italy.

Background: Detailed anatomic variants of the interatrial septum in patients with right-to-left shunt and contribution of specific anatomies to the risk of ischaemic recurrences has not yet been comprehensively classified.

Objective: To report a classification of the anatomic variants of the interatrial septum as observed by intracardiac echocardiography and its correlation with clinical and functional characteristics.

Methods: We retrospectively reviewed the medical and instrumental data of 520 consecutive patients (mean age 44±15. 5 years, 355 women) who had over a 10-year period undergone intracardiac echocardiography and right-to-left shunt catheter-based closure. The four main features used to analyse were: (a) diameter of the oval fossa, (b) presence and length of the channel, (c) presence and degree of atrial septal aneurysm, and (d) rim thickness. The presence of Eustachian valve was also tabulated.

Results: The combinations of interatrial septum anatomical features were classified into six main anatomical subgroups. Recurrent embolism, multiple ischaemic foci on brain magnetic resonance imaging, high grade shunt, and permanent shunt before transcatheter closure procedure were associated with type 2, type 4, and type 6. Type 4 anatomical subtype (OR 4.1, 1.5-8 [95% CI], p<0.001) and type 2+presence of Eustachian valve (OR 4.3, 1.6-9 [95% CI], p<0.001) were the strongest predictors of recurrent ischaemic events before transcatheter closure.

Conclusion: Our study showed that interatrial septum anatomy greatly differs among patients with right-to-left shunt, as well as the risk of ischaemic recurrences in different anatomies.
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http://dx.doi.org/10.1017/S1047951113001480DOI Listing
January 2015

MHC class II transactivator is an in vivo regulator of osteoclast differentiation and bone homeostasis co-opted from adaptive immunity.

J Bone Miner Res 2014 Feb;29(2):290-303

Division of Genetics and Cell Biology and BoNetwork, DiBiT, San Raffaele Scientific Institute, Milano, Italy; Università Vita-Salute San Raffaele, Milano, Italy.

The molecular networks controlling bone homeostasis are not fully understood. The common evolution of bone and adaptive immunity encourages the investigation of shared regulatory circuits. MHC Class II Transactivator (CIITA) is a master transcriptional co-activator believed to be exclusively dedicated for antigen presentation. CIITA is expressed in osteoclast precursors, and its expression is accentuated in osteoporotic mice. We thus asked whether CIITA plays a role in bone biology. To this aim, we fully characterized the bone phenotype of two mouse models of CIITA overexpression, respectively systemic and restricted to the monocyte-osteoclast lineage. Both CIITA-overexpressing mouse models revealed severe spontaneous osteoporosis, as assessed by micro-computed tomography and histomorphometry, associated with increased osteoclast numbers and enhanced in vivo bone resorption, whereas osteoblast numbers and in vivo bone-forming activity were unaffected. To understand the underlying cellular and molecular bases, we investigated ex vivo the differentiation of mutant bone marrow monocytes into osteoclasts and immune effectors, as well as osteoclastogenic signaling pathways. CIITA-overexpressing monocytes differentiated normally into effector macrophages or dendritic cells but showed enhanced osteoclastogenesis, whereas CIITA ablation suppressed osteoclast differentiation. Increased c-fms and receptor activator of NF-κB (RANK) signaling underlay enhanced osteoclast differentiation from CIITA-overexpressing precursors. Moreover, by extending selected phenotypic and cellular analyses to additional genetic mouse models, namely MHC Class II deficient mice and a transgenic mouse line lacking a specific CIITA promoter and re-expressing CIITA in the thymus, we excluded MHC Class II expression and T cells from contributing to the observed skeletal phenotype. Altogether, our study provides compelling genetic evidence that CIITA, the molecular switch of antigen presentation, plays a novel, unexpected function in skeletal homeostasis, independent of MHC Class II expression and T cells, by exerting a selective and intrinsic control of osteoclast differentiation and bone resorption in vivo.
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http://dx.doi.org/10.1002/jbmr.2090DOI Listing
February 2014

Plasma cells require autophagy for sustainable immunoglobulin production.

Nat Immunol 2013 Mar 27;14(3):298-305. Epub 2013 Jan 27.

Division of Genetics and Cell Biology, San Raffaele Scientific Institute, Milano, Italy.

The role of autophagy in plasma cells is unknown. Here we found notable autophagic activity in both differentiating and long-lived plasma cells and investigated its function through the use of mice with conditional deficiency in the essential autophagic molecule Atg5 in B cells. Atg5(-/-) differentiating plasma cells had a larger endoplasmic reticulum (ER) and more ER stress signaling than did their wild-type counterparts, which led to higher expression of the transcriptional repressor Blimp-1 and immunoglobulins and more antibody secretion. The enhanced immunoglobulin synthesis was associated with less intracellular ATP and more death of mutant plasma cells, which identified an unsuspected autophagy-dependent cytoprotective trade-off between immunoglobulin synthesis and viability. In vivo, mice with conditional deficiency in Atg5 in B cells had defective antibody responses, complete selection in the bone marrow for plasma cells that escaped Atg5 deletion and fewer antigen-specific long-lived bone marrow plasma cells than did wild-type mice, despite having normal germinal center responses. Thus, autophagy is specifically required for plasma cell homeostasis and long-lived humoral immunity.
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http://dx.doi.org/10.1038/ni.2524DOI Listing
March 2013

Pivotal Advance: Protein synthesis modulates responsiveness of differentiating and malignant plasma cells to proteasome inhibitors.

J Leukoc Biol 2012 Nov 8;92(5):921-31. Epub 2012 Jun 8.

Division of Genetics and Cell Biology, DiBiT, San Raffaele Scientific Institute, Milano, Italy.

A previously unsuspected, considerable proportion of newly synthesized polypeptides are hydrolyzed rapidly by proteasomes, possibly competing with endogenous substrates and altering proteostasis. In view of the anti-cancer effects of PIs, we set out to achieve a quantitative assessment of proteasome workload in cells hallmarked by different PI sensitivity, namely, a panel of MM cells, and in a dynamic model of plasma cell differentiation, a process that confers exquisite PI sensitivity. Our results suggest that protein synthesis is a key determinant of proteasomal proteolytic burden and PI sensitivity. In different MM cells and in differentiating plasma cells, the average proteolytic work accomplished per proteasome ranges over different orders of magnitude, an unexpected degree of variability, with increased workload invariably associated to increased PI sensitivity. The unfavorable load-versus-capacity balance found in highly PI-sensitive MM lines is accounted for by a decreased total number of immunoproteasomes/cell coupled to enhanced generation of RDPs. Moreover, indicative of cause-effect relationships, attenuating general protein synthesis by the otherwise toxic agent CHX reduces PI sensitivity in activated B and in MM cells. Our data support the view that in plasma cells protein synthesis contributes to determine PI sensitivity by saturating the proteasomal degradative capacity. Quantitating protein synthesis and proteasome workload may thus prove crucial to design novel negative proteostasis regulators against cancer.
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http://dx.doi.org/10.1189/jlb.1011497DOI Listing
November 2012

Anatomo-functional characterization of interatrial septum for catheter-based interventions.

Am J Cardiovasc Dis 2011 10;1(3):227-35. Epub 2011 Aug 10.

Section of Congenital Heart Disease Interventions, Cardiovascular Diagnosis and Endoluminal, Interventions Unit, Rovigo General Hospital Rovigo, Italy.

Secundum Atrial septal defect (ASD) and Patent foramen ovale (PFO) is becoming the most popular field of interest for catheter-based interventions. While there is a common agreement about the management of ASD patients, there is no complete agreement on which is the best management of PFO patients. In PFO patients, the real challenge for the clinician, beside secondary prevention of recurrent stroke, is to understand which the higher risk patients to refer for treatment are and which is the proper device to use. In this setting, the anatomo-functional characterization of interatrial septum seems to be of paramount importance for both ASD and PFO, not only for the device selection but also for therapeutic decision-making. In the present review the author overviews the main anatomic a functional characteristics of interatrial septum, obtained with the current available diagnostic tools, such as transcranial Doppler, transthoracic and transesophageal echocardiography and intracardiac echocardiography, and discusses the impact of such characteristics on catheter based closure.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3253514PMC
October 2012

The proteasome load versus capacity balance determines apoptotic sensitivity of multiple myeloma cells to proteasome inhibition.

Blood 2009 Mar 22;113(13):3040-9. Epub 2009 Jan 22.

Division of Genetics and Cell Biology, San Raffaele Scientific Institute, Milano, Italy.

Proteasome inhibitors (PIs) are effective against multiple myeloma (MM), but the mechanisms of action and bases of individual susceptibility remain unclear. Recent work linked PI sensitivity to protein synthesis and proteasome activity, raising the question whether different levels of proteasome expression and workload underlie PI sensitivity in MM cells (MMCs). Exploiting human MM lines characterized by differential PI sensitivity, we report that highly sensitive MMCs express lower proteasome levels and higher proteasomal workload than relatively PI-resistant MMCs, resulting in the accumulation of polyubiquitinated proteins at the expense of free ubiquitin (proteasome stress). Manipulating proteasome expression or workload alters apoptotic sensitivity to PI, demonstrating a cause-effect relationship between proteasome stress and apoptotic responses in MMCs. Intracellular immunostaining in primary, patient-derived MMCs reveals that polyubiquitinated proteins hallmark neoplastic plasma cells, in positive correlation with immunoglobulin (Ig) content, both intra- and interpatient. Moreover, overall proteasome activity of primary MMCs inversely correlates with apoptotic sensitivity to PI. Altogether, our data indicate that the balance between proteasome workload and degradative capacity represents a critical determinant of apoptotic sensitivity of MMCs to PI, potentially providing a framework for identifying indicators of responsiveness and designing novel combination therapies.
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http://dx.doi.org/10.1182/blood-2008-08-172734DOI Listing
March 2009

Education, and obtaining of informed consent, using multimedia before adults with congenitally malformed hearts are submitted to transcatheter interventions.

Cardiol Young 2009 Feb 23;19(1):60-3. Epub 2008 Dec 23.

Section of Adult Congenital and Structural Heart Disease, Cardiovascular Diagnosis and Endoluminal Interventions, Rovigo General Hospital, Rovigo, Italy.

Background: Multimedia programmes relating to education and consents may be useful for decreasing anxiety during catheter-based repair in patients with congenitally malformed hearts.

Objective: Our study was aimed at evaluating the impact of multimedia protocols for education of a population of consecutive patients with congenitally malformed hearts prior to transcatheter repair.

Methods: Between September, 2006, and May, 2008, we enrolled 100 consecutive patients, with a mean age of 45 +/- 19 years, of whom 69 were female, for catheter-based repair of their congenitally malformed hearts. In the first 50 patients, we used a written form for informed consent sent to the patients 15 days before the procedure, coupled with a personal interview of 30 minutes. In the subsequent 50 patients, we used multimedia protocol for education, comprising a booklet of 4 pages containing a simple and brief explanation of the intervention, and a digital film of 4 minutes showing the transcatheter procedure with a commentary provided by the referring physician, prior to obtaining the signature for informed consent. We then compared the scores for anxiety, the pre-operative heart rate, the frequency of vaso-vagal episodes, and the need for conscious sedation between the two groups.

Results: Patients who underwent preconditioning using the multimedia programme were significantly less anxious, and had significantly lower heart rates. Vaso-vagal episodes were also significantly less in this group, with no episodes compared to 14% in those providing standard informed consent. Conscious sedation was needed more frequently in those providing standard informed consent.

Conclusion: Our brief study suggests that a comprehensive multimedia programme of preparation increases the tolerability, and decrease the emotional state, of adults about to undergo catheter-based interventions for congenital cardiac disease.
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http://dx.doi.org/10.1017/S1047951108003417DOI Listing
February 2009

Dampening Ab responses using proteasome inhibitors following in vivo B cell activation.

Eur J Immunol 2008 Mar;38(3):658-67

Department of Veterinary Morphophysiology, University of Turin, Italy.

Upon encounter with Ag, B lymphocytes undergo terminal differentiation into plasma cells, highly specialized Ab secretors that mediate humoral immune responses. Profound changes adapt cellular morphology and proteome to the new secretory functions. Although a massive secretory activity is expected to require an efficient ubiquitin-proteasome degradation system, recent in vitro studies have surprisingly revealed that the proteasome function sharply decreases during plasma cell development, thereby limiting the proteolytic capacity. We challenged this paradigm in mouse models of B cell activation, and observed that following polyclonal activation, proteasome activity decreases more than previously reported in vitro. This decrease is linked to enhanced apoptosis after treatment with the potent anti-myeloma proteasome inhibitor PS-341. Accordingly, in vivo treatment with PS-341 decreases Ab titres in T-dependent and -independent mouse immunization models. This study provides the rationale for limiting the activity of Ab-secreting cells in vivo by impacting proteasome function.
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http://dx.doi.org/10.1002/eji.200737743DOI Listing
March 2008

Impact of intracardiac echocardiography on radiation exposure during adult congenital heart disease catheter-based interventions.

Int J Cardiovasc Imaging 2007 Apr 5;23(2):139-42. Epub 2006 Jul 5.

Interventional Cardiology Unit, Division of Cardiology, Department of Emergency, Rovigo General Hospital, Rovigo, Italy.

Background: Intracardiac echocardiography (ICE) is a widespread approach in many cardiovascular procedures in which it has the potential to reduce the fluoroscopy time and patients radiation exposure. We sought to assess the patient radiation exposure during transcatheter closure of interatrial communications with and without ICE-guidance.

Methods: In a prospective consecutive series of 25 consecutive patients who underwent transcatheter closure of interatrial communications between May and October 2005 with (15 patients) and without (10 patients) ICE-guidance in a single secondary care referral centre, we measured the dose-area product (DAP), the fluoroscopy dose-area product (FDAP), the total dose-area product (TDAP), and the mean procedural time.

Results: In patients underwent ICE-guided transcatheter closure procedure the mean fluoroscopy time, the mean DAP, mean FDAP, and mean TDAP resulted significantly lower than in control patients: 2.0 +/- 0.21 (range 1.6-2.2) versus 5.05 +/- 0.54 (range 4.2-5.8) minutes (P < 0.001) , 13.72 +/- 9.03 (range 11.36-14.63) versus 21.95 +/- 6.93 (range 20.90-23.93) Gycm2 (P < 0.001), 8.25 +/- 1.22 (range 6.60-9.50) versus 20.15 +/- 8.83 (range 18.90-20.93) Gycm2 (P < 0.001), and 29.33 +/- 1.51(range 27.16-31.00) versus 32.61 +/- 2.53 (range 29.20-35.55) Gycm2 (P < 0.01). On the contrary, the mean procedural time, was significantly higher in ICE-guided transcatheter closure patients: 30.2 +/- 2.45 (range 23-40) versus 24.5 +/- 2.45 (range 24-31) minutes (P = 0.03).

Conclusion: The radiation exposure during ICE-guided transcatheter closure of interatrial communications in this group of patients was quite lower than that reported in literature for such procedures and compared favourably with radiation exposure of patients in whom the intervention was performed without ICE guidance.
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http://dx.doi.org/10.1007/s10554-006-9125-4DOI Listing
April 2007

Immunomodulation of TGF-beta 1 in mdx mouse inhibits connective tissue proliferation in diaphragm but increases inflammatory response: implications for antifibrotic therapy.

J Neuroimmunol 2006 Jun 27;175(1-2):77-86. Epub 2006 Apr 27.

Department of Neuroimmunology and Neuromuscular Diseases, National Neurological Institute Carlo Besta, via Celoria 11, 20133 Milan, Italy.

Irreversible connective tissue proliferation in muscle is a pathological hallmark of Duchenne muscular dystrophy (DMD), a genetic degenerative muscle disease due to lack of the sarcolemmal protein dystrophin. Focal release of transforming growth factor-beta1 (TGF-beta1) is involved in fibrosis development. Murine muscular dystrophy (mdx) is genetically homologous to DMD and histopathological alterations comparable to those in DMD muscles occur in diaphragm of older mdx mice. To investigate the early development of fibrosis and TGF-beta1 involvement, we assessed diaphragms in 6-36-week-old mdx and C57/BL6 (control) mice for fibrosis, and used real-time PCR and ELISA to determine TGF-beta1 expression. Significantly greater fibrosis and TGF-beta1 expression were found in mdx from the 6th week. Mice treated with neutralizing antibody against TGF-beta1 had lower levels of TGF-beta1 protein, reduced fibrosis, unchanged muscles fiber degeneration/regeneration, but increased inflammatory cells (CD4+lymphocytes). These data demonstrate early and progressive fibrosis in mdx diaphragm accompanied by TGF-beta1 upregulation. Reduction of TGF-beta1 appears promising as a therapeutic approach to muscle fibrosis, but further studies are required to evaluate long term effects of TGF-beta1 immunomodulation on the immune system.
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http://dx.doi.org/10.1016/j.jneuroim.2006.03.005DOI Listing
June 2006

An improved technique for gaining radial artery access in endovascular interventions.

Cardiovasc Revasc Med 2006 Jan-Mar;7(1):46-7

Interventional Cardiology Unit, Division of Cardiology, Rovigo General Hospital, Italy.

We present a simple technique to avoid time loss and potential dangerous maneuvers for catheterization of the radial artery in endovascular interventions. If any difficulties are encountered when advancing the guide wire after the arterial puncture using standard transradial kits, we found it useful to routinely use a 60-mm polyethylene radial pressure line catheter like the Leader Cath (Vygon, Ecquen, France), which is more flexible and less traumatic than short catheters and are usually available in the standard hydrophilic transradial kit. With the 20-gauge needle within the arterial lumen, it is sufficient to advance the guide wire 3 or 4 cm, followed by the insertion of the radial pressure line catheter for administering a vasodilator cocktail. The contrast injection through the catheter is safer than through the needle, and visualization of the underling problems may avoid any time loss and complications. The standard sheath insertion is facilitated by the pressure line catheter that acts as a dilator. This technique, especially when performing coronary or peripheral interventions in which large introducers are needed, may avoid potentially dangerous vascular complications and improve the success rate.
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http://dx.doi.org/10.1016/j.carrev.2005.11.001DOI Listing
September 2006

Progressively impaired proteasomal capacity during terminal plasma cell differentiation.

EMBO J 2006 Mar 23;25(5):1104-13. Epub 2006 Feb 23.

Department of Biology and Technology, DiBiT, San Raffaele Scientific Institute, Milan, Italy.

After few days of intense immunoglobulin (Ig) secretion, most plasma cells undergo apoptosis, thus ending the humoral immune response. We asked whether intrinsic factors link plasma cell lifespan to Ig secretion. Here we show that in the late phases of plasmacytic differentiation, when antibody production becomes maximal, proteasomal activity decreases. The excessive load for the reduced proteolytic capacity correlates with accumulation of polyubiquitinated proteins, stabilization of endogenous proteasomal substrates (including Xbp1s, IkappaBalpha, and Bax), onset of apoptosis, and sensitization to proteasome inhibitors (PI). These events can be reproduced by expressing Ig-mu chain in nonlymphoid cells. Our results suggest that a developmental program links plasma cell death to protein production, and help explaining the peculiar sensitivity of normal and malignant plasma cells to PI.
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http://dx.doi.org/10.1038/sj.emboj.7601009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1409720PMC
March 2006

Muscle inflammation and MHC class I up-regulation in muscular dystrophy with lack of dysferlin: an immunopathological study.

J Neuroimmunol 2003 Sep;142(1-2):130-6

Department of Neuromuscular Diseases, Istituto Nazionale Neurologico Carlo Besta, via Celoria 11, 20133 Milan, Italy.

Muscle inflammation is characteristic of inflammatory myopathies but also occurs in muscular dystrophy with lack of the sarcolemmal protein dysferlin. We quantified inflammatory cells and major histocompatibility complex (MHC) expression in muscle from 10 patients with dysferlinopathy. Infiltrating cells were always present although numbers varied considerably; macrophages were more common than T cells, T cytotoxicity was absent, and MHC class I was overexpressed on muscle fibers. These findings differ from polymyositis (PM) but are closely similar to those in SJL/J mice (which lack dysferlin) and emphasize the relationship between absence of dysferlin and immune system abnormalities in muscle.
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http://dx.doi.org/10.1016/s0165-5728(03)00255-8DOI Listing
September 2003