Publications by authors named "Francesco Pisani"

239 Publications

A novel ALG14 missense variant in an alive child with myopathy, epilepsy, and progressive cerebral atrophy.

Am J Med Genet A 2021 Mar 10. Epub 2021 Mar 10.

IRCCS Istituto delle Scienze Neurologiche di Bologna, Programma di Neurogenetica, Bologna, Italy.

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http://dx.doi.org/10.1002/ajmg.a.62153DOI Listing
March 2021

Consensus protocol for EEG and amplitude-integrated EEG assessment and monitoring in neonates.

Clin Neurophysiol 2021 Apr 3;132(4):886-903. Epub 2021 Feb 3.

Child Neuropsychiatric Unit, Neuroscience Section, Department of Medicine and Surgery, University of Parma, Italy.

The aim of this work is to establish inclusive guidelines on electroencephalography (EEG) applicable to all neonatal intensive care units (NICUs). Guidelines on ideal EEG monitoring for neonates are available, but there are significant barriers to their implementation in many centres around the world. These include barriers due to limited resources regarding the availability of equipment and technical and interpretive round-the-clock personnel. On the other hand, despite its limitations, amplitude-integrated EEG (aEEG) (previously called Cerebral Function Monitor [CFM]) is a common alternative used in NICUs. The Italian Neonatal Seizure Collaborative Network (INNESCO), working with all national scientific societies interested in the field of neonatal clinical neurophysiology, performed a systematic literature review and promoted interdisciplinary discussions among experts (neonatologists, paediatric neurologists, neurophysiologists, technicians) between 2017 and 2020 with the aim of elaborating shared recommendations. A consensus statement on videoEEG (vEEG) and aEEG for the principal neonatal indications was established. The authors propose a flexible frame of recommendations based on the complementary use of vEEG and aEEG applicable to the various neonatal units with different levels of complexity according to local resources and specific patient features. Suggestions for promoting cooperation between neonatologists, paediatric neurologists, and neurophysiologists, organisational restructuring, and teleneurophysiology implementation are provided.
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http://dx.doi.org/10.1016/j.clinph.2021.01.012DOI Listing
April 2021

Management of Infants with Brief Resolved Unexplained Events (BRUE) and Apparent Life-Threatening Events (ALTE): A RAND/UCLA Appropriateness Approach.

Life (Basel) 2021 Feb 22;11(2). Epub 2021 Feb 22.

Pediatric Clinic, Department of Medicine and Surgery, University of Parma, 43126 Parma, Italy.

Unexpected events of breath, tone, and skin color change in infants are a cause of considerable distress to the caregiver and there is still debate on their appropriate management. The aim of this study is to survey the trend in prevention, decision-making, and management of brief resolved unexplained events (BRUE)/apparent life-threatening events (ALTE) and to develop a shared protocol among hospitals and primary care pediatricians regarding hospital admission criteria, work-up and post-discharge monitoring of patients with BRUE/ALTE. For the study purpose, a panel of 54 experts was selected to achieve consensus using the RAND/UCLA appropriateness method. Twelve scenarios were developed: one addressed to primary prevention of ALTE and BRUE, and 11 focused on hospital management of BRUE and ALTE. For each scenario, participants were asked to rank each option from '1' (extremely inappropriate) to '9' (extremely appropriate). Results derived from panel meeting and discussion showed several points of agreement but also disagreement with different opinion emerged and the need of focused education on some areas. However, by combining previous recommendations with expert opinion, the application of the RAND/UCLA appropriateness permitted us to drive pediatricians to reasoned and informed decisions in term of evaluation, treatment and follow-up of infants with BRUE/ALTE, reducing inappropriate exams and hospitalisation and highlighting priorities for educational interventions.
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http://dx.doi.org/10.3390/life11020171DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7926945PMC
February 2021

Ocular Motor Paroxysmal Events in Neonates and Infants: A Review of the Literature.

Pediatr Neurol 2021 Apr 8;117:4-9. Epub 2020 Jun 8.

Neonatal Intensive Care Unit, Department of Maternal and Child Health, University of Palermo, Palermo, Italy.

Background: Ocular paroxysmal events can accompany a variety of neurological disorders. Particularly in infants, ocular paroxysmal events often represent a diagnostic challenge. Distinguishing between epileptic and nonepileptic events or between physiological and pathologic paroxysmal events can be challenging at this age because the clinical evaluation and physical examination are often limited. Continuous polygraphic video-electroencephalography (EEG) monitoring can be helpful in these situations.

Methods: We review ocular paroxysmal events in newborns and infants. The aim is to improve clinical recognition of ocular paroxysmal events and provide a guide to further management. Using the PubMed database, we identified studies focused on all ocular motor paroxysmal events in neonates and infants.

Results: Fifty-eight articles were selected on the topic. We summarized and divided these studies into those describing nonepileptic and epileptic ocular paroxysmal events.

Conclusions: The diagnosis of ocular paroxysmal events can be difficult, but their recognition is important because of the variety of underlying etiologies. The distinction between epileptic versus nonepileptic ocular paroxysmal events often often requires polygraphic video-EEG to identify the epileptic events. For nonepileptic events, further testing can characterize pathologic ocular movements. To determine the etiology and prognosis of ocular paroxysmal events, a multimodal approach is required, including a thorough full history and clinical examination, polygraphic video-EEG monitoring, neuroimaging, and a careful follow-up plan.
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http://dx.doi.org/10.1016/j.pediatrneurol.2020.06.001DOI Listing
April 2021

Psychological and psychiatric impact of COVID-19 pandemic among children and adolescents.

Acta Biomed 2020 11 10;91(4):e2020149. Epub 2020 Nov 10.

Child Neuropsychiatric Unit, Department of Medicine and Surgery, University of Parma, Parma, Italy.

Background: COVID-19 outbreak and the unprecedent measures imposed by the government, including quarantine and social distancing, cause psychological distress in children and adolescents.

Methods: we review literature about mental health effects of COVID-19 pandemic by using the keywords "COVID-19", "coronavirus", "pandemic", "mental health", "psych*", "adolescent" and "child".

Results: early evidence show high prevalence of anxiety and depressive symptoms in children and adolescents, due to the pandemic itself, to social isolation and to parents' stress. High grade students, females and low-income families are at higher risk to develop psychiatric symptoms. Psychological distress can be reduced by maintaining contact with peers through social networks and by accurate updates provided by the government through the mass media. Online resources such as information about mental health education and preventive measure, video-counselling, telemedicine and telepsychiatry services, can be useful to reduce the psychosocial effects of the novel coronavirus.

Conclusion: there is urgent need to plan new strategies for early psychological interventions in order to reduce the impact of COVID-19 pandemic on children and adolescents mental health status.
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http://dx.doi.org/10.23750/abm.v91i4.10870DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7927507PMC
November 2020

Deep Learning for EEG Seizure Detection in Preterm Infants.

Int J Neural Syst 2021 Jan 30:2150008. Epub 2021 Jan 30.

Irish Centre for Maternal and Child Health Research (INFANT), Department of Electrical and Electronic Engineering, University College Cork, Cork, Ireland.

EEG is the gold standard for seizure detection in the newborn infant, but EEG interpretation in the preterm group is particularly challenging; trained experts are scarce and the task of interpreting EEG in real-time is arduous. Preterm infants are reported to have a higher incidence of seizures compared to term infants. Preterm EEG morphology differs from that of term infants, which implies that seizure detection algorithms trained on term EEG may not be appropriate. The task of developing preterm specific algorithms becomes extra-challenging given the limited amount of annotated preterm EEG data available. This paper explores novel deep learning (DL) architectures for the task of neonatal seizure detection in preterm infants. The study tests and compares several approaches to address the problem: training on data from full-term infants; training on data from preterm infants; training on age-specific preterm data and transfer learning. The system performance is assessed on a large database of continuous EEG recordings of 575[Formula: see text]h in duration. It is shown that the accuracy of a validated term-trained EEG seizure detection algorithm, based on a support vector machine classifier, when tested on preterm infants falls well short of the performance achieved for full-term infants. An AUC of 88.3% was obtained when tested on preterm EEG as compared to 96.6% obtained when tested on term EEG. When re-trained on preterm EEG, the performance marginally increases to 89.7%. An alternative DL approach shows a more stable trend when tested on the preterm cohort, starting with an AUC of 93.3% for the term-trained algorithm and reaching 95.0% by transfer learning from the term model using available preterm data. The proposed DL approach avoids time-consuming explicit feature engineering and leverages the existence of the term seizure detection model, resulting in accurate predictions with a minimum amount of annotated preterm data.
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http://dx.doi.org/10.1142/S0129065721500088DOI Listing
January 2021

Seizures in the neonate: A review of etiologies and outcomes.

Seizure 2021 Feb 4;85:48-56. Epub 2021 Jan 4.

Department of Neuropediatrics, University Children's Hospital Zurich, Switzerland. Electronic address:

Neonatal seizures occur in their majority in close temporal relation to an acute brain injury or systemic insult, and are accordingly defined as acute symptomatic or provoked seizures. However less frequently, unprovoked seizures may also present in the neonatal period as secondary to structural brain abnormalities, thus corresponding to structural epilepsies, or to genetic conditions, thus corresponding to genetic epilepsies. Unprovoked neonatal seizures should be thus considered as the clinical manifestation of early onset structural or genetic epilepsies that often have the characteristics of early onset epileptic encephalopathies. In this review, we address the conundrum of neonatal seizures including acute symptomatic, remote symptomatic, provoked, and unprovoked seizures, evolving to post-neonatal epilepsies, and neonatal onset epilepsies. The different clinical scenarios involving neonatal seizures, each with their distinct post-neonatal evolution are presented. The structural and functional impact of neonatal seizures on brain development and the concept of secondary epileptogenesis, with or without a following latent period after the acute seizures, are addressed. Finally, we underline the need for an early differential diagnosis between an acute symptomatic seizure and an unprovoked seizure, since it is associated with fundamental differences in clinical evolution. These are crucial aspects for neonatal management, counselling and prognostication. In view of the above aspects, we provide an outlook on future strategies and potential lines of research in this field.
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http://dx.doi.org/10.1016/j.seizure.2020.12.023DOI Listing
February 2021

Che-1/AATF-induced transcriptionally active chromatin promotes cell proliferation in multiple myeloma.

Blood Adv 2020 11;4(22):5616-5630

SAFU Laboratory.

Multiple myeloma (MM) is a hematologic malignancy produced by a clonal expansion of plasma cells and characterized by abnormal production and secretion of monoclonal antibodies. This pathology exhibits an enormous heterogeneity resulting not only from genetic alterations but also from several epigenetic dysregulations. Here we provide evidence that Che-1/AATF (Che-1), an interactor of RNA polymerase II, promotes MM proliferation by affecting chromatin structure and sustaining global gene expression. We found that Che-1 depletion leads to a reduction of "active chromatin" by inducing a global decrease of histone acetylation. In this context, Che-1 directly interacts with histones and displaces histone deacetylase class I members from them. Strikingly, transgenic mice expressing human Che-1 in plasma cells develop MM with clinical features resembling those observed in the human disease. Finally, Che-1 downregulation decreases BRD4 chromatin accumulation to further sensitize MM cells to bromodomain and external domain inhibitors. These findings identify Che-1 as a promising target for MM therapy, alone or in combination with bromodomain and external domain inhibitors.
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http://dx.doi.org/10.1182/bloodadvances.2020002566DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7686885PMC
November 2020

Acute symptomatic neonatal seizures, brain injury, and long-term outcome: The role of neuroprotective strategies.

Expert Rev Neurother 2021 Feb 6;21(2):189-203. Epub 2020 Dec 6.

Child Neurology Unit, Department of Paediatrics, Azienda USL-IRCCS Di Reggio Emilia , Reggio Emilia, Italy.

Introduction: Neonatal seizures are frequent but underdiagnosed manifestations of acute brain dysfunction and an important contributor to unfavorable outcomes. Etiology and severity of brain injury are the single strongest outcome determinants.

Areas Covered: The authors will discuss the prognostic role of acute symptomatic seizures versus brain injury and the main neuroprotective and neurorestorative strategies for full-term and preterm infants.

Expert Opinion: Prolonged acute symptomatic seizures likely contribute to long-term outcomes by independently adding further brain injury to initial insults. Correct timing and dosing of therapeutic interventions, depending on etiology and gestational ages, need careful evaluation. Although promising strategies are under study, the only standard of care is whole-body therapeutic hypothermia in full-term newborns with hypoxic-ischemic encephalopathy.
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http://dx.doi.org/10.1080/14737175.2021.1848547DOI Listing
February 2021

Orthogonal arrays of particle assembly are essential for normal aquaporin-4 expression level in the brain.

Glia 2021 Feb 18;69(2):473-488. Epub 2020 Sep 18.

Department of Biosciences, Biotechnologies and Biopharmaceutics, University of Bari Aldo Moro, Bari, Italy.

Astrocyte endfeet are endowed with aquaporin-4 (AQP4)-based assemblies called orthogonal arrays of particles (OAPs) whose function is still unclear. To investigate the function of OAPs and of AQP4 tetramers, we have generated a novel "OAP-null" mouse model selectively lacking the OAP forming M23-AQP4 isoform. We demonstrated that AQP4 transcript levels were not reduced by using qPCR. Blue native (BN)/SDS-PAGE and Western blot performed on OAP-null brain and primary astrocyte cultures showed the complete depletion of AQP4 assemblies, the selective expression of M1-AQP4-based tetramers, and a substantial reduction in AQP4 total expression level. Fluorescence quenching and super-resolution microscopy experiments showed that AQP4 tetramers were functionally expressed in astrocyte plasma membrane and their dimensions were reduced compared to wild-type assemblies. Finally, as shown by light and electron microscopy, OAP depletion resulted in a massive reduction in AQP4 expression and a loss of perivascular AQP4 staining at astrocyte endfeet, with only sparse labeling throughout the brain areas analyzed. Our study relies on the unique property of AQP4 to form OAPs, using a novel OAP-null mouse model for the first time, to show that (a) AQP4 assembly is essential for normal AQP4 expression level in the brain and (b) most of AQP4 is organized into OAPs under physiological conditions. Therefore, AQP4 tetramers cannot be used by astrocytes as an alternative to OAPs without affecting AQP4 expression levels, which is important in the physiological and pathological conditions in which OAP aggregation/disaggregation dynamics have been implicated.
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http://dx.doi.org/10.1002/glia.23909DOI Listing
February 2021

Nystagmus in Infantile Pompe Disease: a new feature?

Acta Biomed 2020 09 7;91(3):e2020083. Epub 2020 Sep 7.

Child Neuropsychiatry Unit, Mother and Child Department, University-Hospital of Parma, Parma, Italy.

We describe a 3 month-old female floppy infant with hypertrophic cardiomyopathy, serum enzyme levels, which were characterized by an aspartate aminotransferase level of 144 U/l, alanine transaminase 240 U/L and creatine kinase level of 543 U/l. On the basis of the clinical signs and laboratory results,  acid α-glucosidase activity was determined from dried blood spots resulting lower than the normal range (0.2 mmol/L/h: normal reference range: 1,86-21,9 mmol/L/h) and leading to a diagnosis of infantile Pompe disease. She also showed multi-directional nystagmus. Refractive errors, ptosis and strabismus are described in infantile Pompe Disease, while nystagmus is rarely reported before. Therefore with this paper we highlight an atypical ocular symptom, whose uncertain pathogenesis, to be taken into consideration, because by now, with increasing survival with ERT, new phenotypes of Pompe disease are taking shape.
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http://dx.doi.org/10.23750/abm.v91i3.8366DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7716971PMC
September 2020

Neuropsychological and behavioral disorders as presentation symptoms in two brothers with early-infantile Niemann-Pick type C.

Acta Biomed 2020 09 7;91(3):e2020075. Epub 2020 Sep 7.

Department of Pediatrics, Child Neurology Unit, Presidio Ospedaliero Provinciale Santa Maria Nuova Azienda USL-IRCCS di Reggio Emilia; Pediatric Neurophysiology Laboratory, Presidio Ospedaliero Provinciale Santa Maria Nuova Azienda USL-IRCCS di Reggio Emilia, Italy.

Background: Niemann-Pick disease type C (NPC) is a lysosomal storage disease caused by mutations in NPC1 or NPC2 genes.

Case Presentation: We present two brothers with the same compound heterozygous variants in exon 13 of the NPC1 gene (18q11.2), the first one (c.1955C> G, p. Ser652Trp), inherited from the mother, the second (c.2107T>A p.Phe703Ile) inherited from the father, associated to the classical biochemical phenotype of NPC. The two brothers presented unspecific neurologic symptoms with difference in age of onset: one presented dyspraxia and motor clumsiness at age 7 years, the other showed a systemic presentation with hepatosplenomegaly noted at the age of two months and neurological symptoms onset at age 4 with speech disturbance. Clinical evolution and neuroimaging data led to the final diagnosis. Systemic signs did not correlate with the onset of neurological symptoms. Miglustat therapy was started in both patients.

Conclusions: We highlight the extreme phenotypic heterogeneity of NP-C in the presence of the same genetic variant and the unspecificity of neurologic signs at onset as previously reported. We report some positive effects of miglustat on disease progression assessed also with neuropsychological follow-up, with an age-dependent response.
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http://dx.doi.org/10.23750/abm.v91i3.9272DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7716979PMC
September 2020

Celiac disease and headache in children: a narrative state of the art.

Acta Biomed 2020 09 7;91(3):e2020056. Epub 2020 Sep 7.

Pediatric Clinic, Department of Clinical and Experimental Medicine, University Hospital "Policlinico-Vittorio Emanuele", Catania, Italy.

Celiac disease (CD) is one of the most important entity of the wide spectrum of gluten-related disorders (GRDs). It is well known that neurological manifestation can be present either at the onset of CD, or appear during the development of the pathology, and different can be the neurologic findings. Clinical features are very variable, ranging from typical manifestations of gastrointestinal involvement to neurologic symptom. The most frequent neurologic signs reported were headache, epileptic seizure, migraine, mental retardation, ataxia and attention deficit and hyperactive disorder. Headache either in form of migraine, or in non-specific form represents one of the main clinical presentation in CD. The aim of this work is to provide a narrative review of the pediatric literature focused on the cephalalgic features of children with CD evaluating the potential benefits of a gluten free diet (GFD).  Papers were identified by searching for related literature in Medline (PubMed) and Embase using the words "Celiac Disease" and "Headache" or "Migraine" by specifying "children"/"paediatric age" for reports published since 1972 till 31th October 2018. According to our inclusion criteria, a total of 25 papers has been evaluated. Although it is still controversial if headache is prevalent in CD children a correct compliance to a GFD seems to improve the neurological symptoms even if the underlying pathogenic relationship between CD and neurologic system involvement is still not fully understood.
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http://dx.doi.org/10.23750/abm.v91i3.8224DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7717030PMC
September 2020

Linking acute symptomatic neonatal seizures, brain injury and outcome in preterm infants.

Epilepsy Behav 2020 11 2;112:107406. Epub 2020 Sep 2.

Department of Pediatrics, Child Neurology Unit, Azienda USL-IRCCS di Reggio Emilia, Reggio Emilia, Italy. Electronic address:

Neonatal seizures (NS) are the most frequent sign of neurological dysfunction in newborn infants. With increased survival of preterm neonates, the current clinical focus has shifted from preventing death to improving long-term neurological outcome. In the context of acute symptomatic NS, the main negative prognostic factors include etiology, and severity of brain injury, but also prolonged seizures and especially status epilepticus. However, the reasons for the detrimental contribution of seizures to outcome are still unclear, and evidence has been collected both in favor of seizures being an epiphenomenon of brain injury and of independently contributing to further damage. In this narrative focused review, we will discuss both hypotheses, with special emphasis on data relating to preterm infants. We will also identify present controversies and possible future lines of research.
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http://dx.doi.org/10.1016/j.yebeh.2020.107406DOI Listing
November 2020

Paroxysmal movement disorder with response to carbamazepine in a patient with RHOBTB2 developmental and epileptic encephalopathy.

Parkinsonism Relat Disord 2020 07 1;76:54-55. Epub 2020 Jun 1.

Dipartimento Materno-Infantile, Struttura Complessa di Neuropsichiatria Infantile, Arcispedale Santa Maria Nuova, Azienda USL- IRCCS di Reggio Emilia, Reggio Emilia, Italy.

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http://dx.doi.org/10.1016/j.parkreldis.2020.05.031DOI Listing
July 2020

Follow-up and Management of Kidney Transplant Recipients During the COVID-19 Lockdown: The Experience of an Italian Transplant Center, Including Two Cases of COVID-19 Pneumonia.

Transplant Proc 2020 Nov 28;52(9):2614-2619. Epub 2020 Jun 28.

General and Transplant Surgery Department, DISCAB, University of L'Aquila, Coppito, L'Aquila, Italy.

Background: Coronavirus disease 2019 (COVID-19) is a new infectious disease that emerged in China in late 2019 and is now spreading around the world. Social distancing measures were needed to reduce transmission, and lockdown included restricted access to health care facilities. The impact of COVID-19 on transplant recipients is unknown, but considering their immunosuppression status and associated comorbidities, they should be considered a high-risk population.

Methods: A kidney transplant center in Central Italy implemented a strategy to maintain follow-up of kidney transplant recipients by phone and e-mail during lockdown. Telephone interviews were used to administer a clinical questionnaire to patients, and e-mail was used to receive the results of diagnostic tests conducted in outpatient settings.

Results: From March 17 to April 23, 2020, a total of 143 kidney transplant recipients were contacted. Twenty-eight patients needed in-hospital consultation for problems unrelated to COVID-19, 3 of whom needed hospitalization. Eleven patients were managed at home for mild urinary or respiratory diseases, and 1 was referred to the hematologist. We identified 2 suspected cases of COVID-19 infection, and the patients were referred to hospital care. Immunosuppressive therapy was modulated, and intravenous corticosteroids and potentially effective antiviral therapy were administered with a favorable outcome.

Conclusions: In the context of a lockdown, such as that occurring in response to COVID-19, we suggest implementing remote surveillance programs in kidney transplant recipients with the help of any available technology and offering medical consulting and logistic support as needed.
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http://dx.doi.org/10.1016/j.transproceed.2020.06.026DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7321021PMC
November 2020

Early-onset Dopamine Transporter Deficiency Syndrome: Long-term Follow-up.

Can J Neurol Sci 2021 Mar 10;48(2):285-286. Epub 2020 Jul 10.

Department of Pediatrics, Child Neurology Unit, AUSL-IRCCS di Reggio Emilia, Reggio Emilia, Italy.

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http://dx.doi.org/10.1017/cjn.2020.144DOI Listing
March 2021

Front-Line Therapy for Elderly Chronic Lymphocytic Leukemia Patients: Bendamustine Plus Rituximab or Chlorambucil Plus Rituximab? Real-Life Retrospective Multicenter Study in the Lazio Region.

Front Oncol 2020 10;10:848. Epub 2020 Jun 10.

Institute of Hematology, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Rome, Italy.

Previous studies investigated the efficacy and the safety of bendamustine (B) vs. chlorambucil (Chl) associated with rituximab (R) in fludarabine-ineligible patients with treated and untreated chronic lymphocytic leukemia (CLL). We conducted a retrospective multicenter study in the Lazio region to further evaluate and compare the efficacy and the toxicity of Chl-R and B-R regimen in CLL patients over the age of 65. We enrolled 192 untreated CLL patients: 111 treated with B-R and 81 with Chl-R. The overall response rates (ORR; 93.6% in B-R and 86.5% in Chl-R) were not statistically different between the two groups, such as progression-free survival (PFS), time to retreatment (TTR), and overall survival (OS). The B-R group showed a higher hematological ( = 0.007) and extra-hematological ( = 0.008) toxicity. When comparing the toxicities according to age, we noted that the extra-hematological toxicity was higher in patients over the age of 75 who were treated with B-R than those treated with Chl-R ( = 0.03). This retrospective study confirms the feasibility of B-R and Chl-R in elderly untreated CLL patients. Currently, patients who are over 75 and unfit are usually treated with Chl-R. This scheme allows achieving the same ORR, PFS, TTR, and OS when compared with B-R because of hematological and extra-hematological toxicities due to B, in which a greater dose reduction has been shown in comparison to Chl.
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http://dx.doi.org/10.3389/fonc.2020.00848DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7298101PMC
June 2020

Targeted re-sequencing in malformations of cortical development: genotype-phenotype correlations.

Seizure 2020 Aug 3;80:145-152. Epub 2020 Jun 3.

Unit of Medical Genetics, IRCCS Istituto Giannina Gaslini, Genoa, Italy; Department of Neurosciences, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health (DINOGMI), University of Genoa, Italy.

Purpose: Malformations of cortical development (MCD) are a phenotypically and genetically heterogeneous group of disorders, for which the diagnostic rate of genetic testing in a clinical setting remains to be clarified. In this study we aimed to assess the diagnostic rate of germline and pathogenic variants using a custom panel in a heterogeneous group of subjects with MCD and explore genotype-phenotype correlations.

Methods: A total of 84 subjects with different MCD were enrolled. Genomic DNA was isolated from peripheral blood. Fifty-nine tartget genes were assessed using a custom next-generation sequencing (NGS) panel.

Results: Genetic causes were identified in one-fourth of our cohort (21.4 %). Overall, we identified 19 pathogenic or likely pathogenic single-nucleotide variants in 11 genes among 18 subjects, including PAFAH1B1 (LIS1) (n = 3), TUBA1A (n = 3), DYNC1H1 (n = 3), ACTG1 (n = 2), TUBB2B (n = 1), TUBB3 (n = 1), DCX (n = 1), FLNA (n = 1), LAMA2 (n = 1), POMGNT2 (n = 1) and VLDLR (n = 1). The diagnostic yield was higher in patients with lissencephaly/pachygyria (60 %) (p = 0.001), cobblestone malformation (50 %), and subcortical band heterotopia (SBH) (40 %). Furthermore, five out of six subjects with suspect tubulinopathies on imaging harboured pathogenic variants in tubulin genes. Overall, germline pathogenic variants were more likely to be identified if MCD were diffuse (p = 0.002) and associated with other central nervous system malformations (p = 0.029). Moderate to severe intellectual disability was also more commonly associated with pathogenic variants (p = 0.044).

Conclusion: Customized gene panels may support the diagnostic work-up for some specific MCD, especially when these are diffuse, bilateral and associated with other brain malformations.
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http://dx.doi.org/10.1016/j.seizure.2020.05.023DOI Listing
August 2020

Transplant Patients' Isolation and Social Distancing Because of COVID-19: Analysis of the Resilient Capacities of the Transplant in the Management of the Coronavirus Emergency.

Transplant Proc 2020 Nov 30;52(9):2626-2630. Epub 2020 May 30.

U.O.C. Chirurgia Generale e dei Trapianti d'Organo, L'Aquila, Italy.

Background: One of the peculiar aspects of the transplant patient's life is that, in the post-surgery phase, the patient lives in an "isolation" condition, having to pay particular attention to the living environment and preferring a limited social life given that the immunosuppressive treatment entails immunodepression in the patient. With coronavirus disease 2019 (COVID)-19, as in a post-surgery situation, social isolation is being implemented.

Materials And Methods: The study started on March 17, 2020, and ended on April 24, 2020. Consulting/phone interviews were made. The phone questionnaire, submitted to 71 patients, consisted of a set of 15 questions that investigated structure and psychological resistance. Eight patients have been monitored exclusively for the psychological aspect through a more articulate supporting path.

Results: In essence, from the overall analysis of the data derived from the study of the positioning of patients based on the stage of renal function, the bands related to the development of psychopathological aspects, and the use of positive personal resources, it emerges that patients in stage V kidney failure are in the first bracket as regards the development of psychopathological aspects (absence of these experiences) and in the third bracket as regards the good use of positive resources to deal with isolation. Therefore, it can be deduced that, although with data that can be expanded, a serious or medium-serious situation from an organic point of view in this socio-health emergency situation is well addressed by the transplanted patient.

Conclusion: Transplant patients have faced the measure of social distancing adequately and in adherence to the treatment thanks to the phone assistance of all the medical-surgical and psychological team.
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http://dx.doi.org/10.1016/j.transproceed.2020.05.031DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7260500PMC
November 2020

Antidepressant effect of vagal nerve stimulation in epilepsy patients: a systematic review.

Neurol Sci 2020 Nov 10;41(11):3075-3084. Epub 2020 Jun 10.

Epilepsy Surgery Center, IRCCS NEUROMED, Via Atinense 18, 86170, Pozzilli (IS), Italy.

Background: Vagal nerve stimulation (VNS) is an effective palliative therapy in drug-resistant epileptic patients and is also approved as a therapy for treatment-resistant depression. Depression is a frequent comorbidity in epilepsy and it affects the quality of life of patients more than the seizure frequency itself. The aim of this systematic review is to analyze the available literature about the VNS effect on depressive symptoms in epileptic patients.

Material And Methods: A comprehensive search of PubMed, Medline, Scopus, and Google Scholar was performed, and results were included up to January 2020. All studies concerning depressive symptom assessment in epileptic patients treated with VNS were included.

Results: Nine studies were included because they fulfilled inclusion criteria. Six out of nine papers reported a positive effect of VNS on depressive symptoms. Eight out of nine studies did not find any correlation between seizure reduction and depressive symptom amelioration, as induced by VNS. Clinical scales for depression, drug regimens, and age of patients were broadly different among the examined studies.

Conclusions: Reviewed studies strongly suggest that VNS ameliorates depressive symptoms in drug-resistant epileptic patients and that the VNS effect on depression is uncorrelated to seizure response. However, more rigorous studies addressing this issue are encouraged.
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http://dx.doi.org/10.1007/s10072-020-04479-2DOI Listing
November 2020

Autozygosity-driven genetic diagnosis in consanguineous families from Italy and the Greater Middle East.

Hum Genet 2020 Nov 2;139(11):1429-1441. Epub 2020 Jun 2.

Medical Genetics Sant'Orsola, Malpighi University Hospital of Bologna, Via Massarenti 9, 40138, Bologna, Italy.

Autozygosity-driven exome analysis has been shown effective for identification of genes underlying recessive diseases especially in countries of the so-called Greater Middle East (GME), where high consanguinity unravels the phenotypic effects of recessive alleles and large family sizes facilitate homozygosity mapping. In Italy, as in most European countries, consanguinity is estimated low. Nonetheless, consanguineous Italian families are not uncommon in publications of genetic findings and are often key to new associations of genes with rare diseases. We collected 52 patients from 47 consanguineous families with suspected recessive diseases, 29 originated in GME countries and 18 of Italian descent. We performed autozygosity-driven exome analysis by detecting long runs of homozygosity (ROHs > 1.5 Mb) and by prioritizing candidate clinical variants within. We identified a pathogenic synonymous variant that had been previously missed in NARS2 and we increased an initial high diagnostic rate (47%) to 55% by matchmaking our candidate genes and including in the analysis shorter ROHs that may also happen to be autozygous. GME and Italian families contributed to diagnostic yield comparably. We found no significant difference either in the extension of the autozygous genome, or in the distribution of candidate clinical variants between GME and Italian families, while we showed that the average autozygous genome was larger and the mean number of candidate clinical variants was significantly higher (p = 0.003) in mutation-positive than in mutation-negative individuals, suggesting that these features influence the likelihood that the disease is autozygosity-related. We highlight the utility of autozygosity-driven genomic analysis also in countries and/or communities, where consanguinity is not widespread cultural tradition.
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http://dx.doi.org/10.1007/s00439-020-02187-7DOI Listing
November 2020

Analysis of Psychopathologic Elements as a Compliance Limitation: Team Work as a Therapeutic Response.

Transplant Proc 2020 Jun 18;52(5):1577-1580. Epub 2020 May 18.

Local Health Authority ASL 1 Avezzano Sulmona L'Aquila, Complex Operating Unit General Surgery and Organ Transplants, L'Aquila, Italy.

Introduction: The psychological evaluation of the patient, carried out through psychodiagnostic tests, clinical interviews, and a joint work with the medical-surgical team, provided useful information to assess the compliance of the kidney transplant recipient.

Methodology: Two hundred and forty-five visits were carried out between September 2018 and May 2019 in the General Surgery and Organ Transplant Department of the San Salvatore Hospital, L'Aquila. The visits consisted of clinical interviews, targeted psychodiagnostic evaluations, graphic-projective tests, and personality and cognitive structure evaluation tests. These assessments were key not only to defining the patient's personality picture but also to offering suitable psychological support to patients on waiting lists for transplantation, during hospitalization, and during follow-up visits from transplantation phases.

Results: From the analysis of the tests and from the clinical and support interviews, some of the patients presented forms of psycho-emotional immaturity that impaired the predisposition to compliance and ultimately the establishment of the therapeutic alliance. During 8 months, 18 compliance limit cases were observed, 5 patients were sent to mental health centers, and 13 psychological support courses were activated within the Regional Transplant Center-Abruzzo Region Molise Region. No structured psychological support courses were deemed necessary for 9 of these 13 cases, whereas 4 were sent to the mental health centers.

Conclusions: By assessing the complexity of each patient from a medical and a psychological point of view and by considering the high number of transplant surgeries currently occurring, it can be noted that compliance to therapy is strongly linked to the reliability of the relationships between patients and caregivers.
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http://dx.doi.org/10.1016/j.transproceed.2020.03.009DOI Listing
June 2020

Psychodiagnostic Examination of a Living Kidney Donor. Correlation Between the Scales Referred to the Paranoia of the Minnesota Multiphasic Personality Inventory-2: A Case Report.

Transplant Proc 2020 Jun 11;52(5):1623-1626. Epub 2020 May 11.

ASL 1 Avezzano Sulmona L'Aquila U.O.C. Chirurgia Generale e dei Trapianti d'Organo L'Aquila, Italia.

Introduction: The study involves the psychodiagnostic evaluation of a 53-year-old female living kidney donor. The donation is in favor of the 56-year-old sister. The potential donor is separated, is currently unemployed, and holds a lower secondary education diploma.

Methodology: The psychodiagnostic evaluation of the donor was carried out by means of clinical-anamnestic interviews, followed by Graphic-Projective Tests. The MMPI-2 Personality Test was administered at a later stage.

Results: It was noted that the patient showed: an initial lack of collaboration to undergo the psychodiagnostic evaluation; limited cognitive aspects of flexibility, criticism, and judgment; a distinct emotive response, which manifested as closure, anxiety, and dependence on the other; and elements that resulted from MMPI-2. The analysis of the clinical interviews, of the tests and their correlations, shows the existence of a simple personality framework characterized by concrete thinking that seldom performs functions exceeding the limits by a tendency toward closure and introversion and by consistent mood tone. No elements of psychopathology were identified.

Conclusions: The psychodiagnostic evaluation resulted in excluding the subsistence of psychopathologies and allowed for a positive judgment of the suitability for donation. The evaluation also provided significant information on the limited capacity for therapeutic alliance and on the general attitude of closure and rejection of inputs coming from the external world. Patient monitoring is recommended in case of actual donation.
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http://dx.doi.org/10.1016/j.transproceed.2020.03.010DOI Listing
June 2020

Long-term follow-up in infantile-onset SCAR18: A case report.

J Clin Neurosci 2020 Jul 6;77:232-234. Epub 2020 May 6.

S.C. Neuropsichiatria Infantile, Arcispedale Santa Maria Nuova, AUSL - IRCCS di Reggio Emilia, Reggio Emilia, Italy; Laboratorio di Neurofisiologia dell'età evolutiva, S.C. Neuropsichiatria Infantile, Arcispedale Santa Maria Nuova, AUSL - IRCCS di Reggio Emilia, Reggio Emilia, Italy.

Autosomal recessive spinocerebellar ataxia type 18 (SCAR18) is caused by pathogenic variants in the Glutamate Receptor, Ionotropic, Delta-2 (GRID2) gene. We describe the long-term follow-up from 1 to 31 years of an Italian patient with congenital SCAR18 who is compound heterozygous for a maternally-inherited nonsense variant and a de novo microdeletion. To date, this is the longest follow-up in congenital SCAR18.
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http://dx.doi.org/10.1016/j.jocn.2020.05.008DOI Listing
July 2020

Neuromyelitis Optica Spectrum Disorder Attack Triggered by Herpes Zoster Infection.

Mult Scler Int 2020 25;2020:6151258. Epub 2020 Apr 25.

Unit of Neurosciences, Department of Medicine and Surgery, University of Parma, Italy.

Neuromyelitis optica spectrum disorder is a severe autoimmune disease of the central nervous system characterized by recurrent inflammatory events primarily involving the optic nerves and spinal cord. Recently, a triggering role of infectious events in the development of NMOSD has been suggested. Varicella zoster virus is the most common viral infection involved, though the linkage with anti-aquaporin-4 antibodies is so far unknown. We report, to the best of our knowledge, the first pediatric case report about NMOSD relapse triggered by herpes zoster infection. The strict temporal relationship between VZV infection and NMO attacks seems to be more than simply due to chance; however, further reports are needed to be confirmed.
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http://dx.doi.org/10.1155/2020/6151258DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7196994PMC
April 2020

Risk factors for neonatal seizures: A case-control study in the province of Parma, Italy.

Epilepsy Behav 2020 06 15;107:107075. Epub 2020 Apr 15.

Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Milano, Italy. Electronic address:

Purpose: The present study evaluated the risk factors for electroencephalographic (EEG)-confirmed seizures during the whole neonatal period in preterm and term neonates born in the province of Parma between January 2009 and December 2014.

Methods: We selected as cases the infants that presented EEG-confirmed neonatal seizures (NS). Two population controls for each case were matched by gestational age (GA), sex, hospital, and period of birth. Information on the mother, the pregnancy, the labor and delivery, and the neonates were taken from the Emilia-Romagna Certificate of Delivery Assistance database and from hospital charts and ICD-9-CM codes.

Results And Interpretation: In the 6-year period of this study, 22 patients were recorded with NS. The association between at least one pregnancy complication and at least one neonatal complication, a low Apgar score, the need for resuscitation at birth, intraventricular hemorrhages (IVH) grades II-IV for preterm, and acute perinatal asphyxia/hypoxic-ischemic encephalopathy (HIE) for term infants were all statistically significant among cases. Neonates presenting these risk factors are more prone to develop NS and have to be strictly monitored.
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http://dx.doi.org/10.1016/j.yebeh.2020.107075DOI Listing
June 2020

Paediatric-onset hereditary spastic paraplegias: a retrospective cohort study.

Dev Med Child Neurol 2020 09 10;62(9):1068-1074. Epub 2020 Apr 10.

Child Neurology Unit, Department of Paediatrics, Azienda USL-IRCCS di Reggio Emilia, Reggio Emilia, Italy.

Aim: To describe the clinical and neurogenetic spectrum of paediatric-onset hereditary spastic paraplegias (HSPs) diagnosed in our unit.

Method: We report on 47 patients (30 males, 17 females; mean [SD] age 12y 7mo [6y 2mo], range 4-34y) clinically diagnosed with an HSP at the Child Neurology Unit, IRCCS-ASMN (Reggio Emilia, Italy) between 1990 and 2018, who were genetically investigated by means of single-gene direct sequencing and/or next-generation sequencing technologies (targeted panels, whole-exome sequencing [WES]).

Results: Complex forms prevailed slightly (n=26), autosomal dominant being the main inheritance pattern (n=11), followed by recessive (n=5) and X-linked (n=1). A definite genetic diagnosis was achieved in 17 patients. Spastic paraplegia 3A (n=4) was the most frequent cause of autosomal dominant HSP in our cohort, while no genetic variant prevailed in autosomal recessive forms and pathogenic/likely pathogenic variants were disclosed in a wide range of different genes.

Interpretation: We found wide phenotypic and genetic heterogeneity. With increasing accessibility to WES, a higher number of patients receive a diagnosis, allowing detection of variants in ultra-rare disease-causing genes and refining genotype-phenotype correlations.

What This Paper Adds: A genetic diagnosis of paediatric-onset hereditary spastic paraplegia was achieved in one-third of patients. Pathogenic/likely pathogenic variants in rare genes were found. Genotypic and phenotypic heterogeneity favours targeted panel/whole-exome sequencing for diagnosis.
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http://dx.doi.org/10.1111/dmcn.14547DOI Listing
September 2020

HLA-G14bp ins/del polymorphism and post-transplant weight gain in kidney transplantation: potential implications beyond tolerance.

BMC Nephrol 2020 03 30;21(1):109. Epub 2020 Mar 30.

General Surgery and Organ Transplantation, S. Salvatore Hospital, L'Aquila, Italy.

Background: Human leukocyte antigen (HLA)-G is a non-classical HLA molecule with immunomodulant and immunosuppressive functions, involved in transplantation tolerance. HLA-G14bp ins/del polymorphism in exon 8 has been associated with allograft rejection and kidney transplant outcome, with controversial results. We investigated associations of HLA-G14bp ins/del polymorphism on onset of some of the main post-transplant risk factors, like excess body weight, lipid abnormalities, increased fasting plasma glucose. Polymorphisms of cytokines with both immunosuppressive and metabolic effects were also assessed for comparisons and associated analysis.

Methods: The present study involved kidney transplant recipients (n = 173) in which body mass index, cholesterol, triglycerides, fasting plasma glucose were registered in the first years after transplantation and analyzed in association with genotypes. Presence of hypertension and smoking habits, demographic, transplant-related and therapeutic data of patients were also recorded. Polymerase chain reaction, sequence-specific primer amplification and Taqman allelic discrimination techniques were used for genotyping of HLA-G14bp ins/del, interleukin (IL)-10(-1082G > A,-819 T > C,-592A > C), transforming growth factor-β(+ 869 T > C,+915C > G), IL-6(-174G > C), tumor necrosis factor-α(-308G > A) and IL-18(-137G > C,-607C > A). Effects of genotypes on clinical markers at each time point (pre-transplant and 1 to 5 years after transplant) were analyzed using a repeated-measures general linear model analysis; adjustment for potential confounders was performed.

Results: Results showed that HLA-G14bp ins/ins was significantly associated with obesity, in particular after transplantation (3 years, p = 0.002, OR = 4.48, 95% CI:1.76-11.41). Post-transplant body mass index was significantly increased in HLA-G14bp ins/ins carriers (3 and 4 years, p = 0.033 and p = 0.044); effects of HLA-G14bp genotypes on post-transplant BMI were confirmed by using repeated-measures analysis and after controlling for confounding variables. Cytokine genotypes did not associate with the examined factors.

Conclusions: The study of transplanted patients allowed to evidence a potential relationship between post-transplant weight gain and HLA-G14bp ins/del polymorphism, previously involved in rejection for its immunosuppressive/tolerogenic activity. This novel association could widen the knowledge of the role and functions of HLA-G molecules in diseases and transplantation.
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http://dx.doi.org/10.1186/s12882-020-01752-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7104538PMC
March 2020

Evaluation of Plasma Levels of Soluble HLA-G and HLA-G Genotypes in Kidney Transplant Recipients.

Transplant Proc 2020 Jun 24;52(5):1559-1561. Epub 2020 Mar 24.

General Surgery and Organ Transplantation, S. Salvatore Hospital, L'Aquila, Italy; Department of Biotechnological and Applied Clinical Sciences, University of L'Aquila, Italy.

In the field of transplantation, expression of HLA-G, a nonclassical HLA molecule with immunosuppressive functions and limited gene polymorphism, is considered beneficial for graft acceptance; various studies have aimed to demonstrate this role in transplantation. Recently, in other clinical conditions, it has been observed that insulin resistance was associated with HLA-G14bpins/del polymorphism, the most studied regulatory polymorphism of this molecule. In the present study, plasma levels of the soluble form of HLA-G (sHLA-G) were analyzed in kidney transplant recipients (n = 103) with different HLA-G14bpins/del genotypes. In a group of 26 recipients, sHLA-G was detected before and after transplantation (1 year) to evaluate early variations. In 77 recipients, sHLA-G was detected after transplantation (3-24 years) and correlated with occurrence of long-term post-transplant morbidity (diabetes mellitus, hyperlipidemia, hypertension, obesity, etc.).

Methods: Levels of sHLA-G were measured in plasma with an enzyme-linked immunosorbent assay; HLA-G14bpins/del and HLA-G+3142C>G genotypes were assessed using direct polymerase chain reaction.

Results: Plasma levels of sHLA-G significantly decreased during the first year after transplantation (P = .019); no significant correlations were found with genotypes or early post-transplant events. Lower levels of sHLA-G were found in recipients with post-transplant diabetes mellitus or obesity carrying the HLA-G14bpins/ins (P = .006 and P = .003, respectively) or HLA-G+3142G/G genotypes.

Conclusions: A complex modulation of HLA-G, which includes both immunologic and metabolic effects, could affect the risk for long-term post-transplant morbidity in kidney transplant recipients. Associations of HLA-G, diabetes, and obesity deserve to be investigated by deeply exploring HLA-G regulatory variants.
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http://dx.doi.org/10.1016/j.transproceed.2020.02.044DOI Listing
June 2020