Publications by authors named "Elisa Colombo"

78 Publications

SLC35F1 as a candidate gene for neurodevelopmental disorders resembling Rett syndrome.

Am J Med Genet A 2021 Apr 5. Epub 2021 Apr 5.

Child Neuropsychiatry Unit, Epilepsy Center, ASST Santi Paolo e Carlo, San Paolo Hospital, Department of Health Sciences, Università degli Studi di Milano, Milan, Italy.

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http://dx.doi.org/10.1002/ajmg.a.62203DOI Listing
April 2021

Renal perfusion with histidine-tryptophan-ketoglutarate compared with Ringer's solution in patients undergoing thoracoabdominal aortic open repair.

J Thorac Cardiovasc Surg 2021 Mar 4. Epub 2021 Mar 4.

Department of Vascular Surgery, Vita-Salute University School of Medicine, San Raffaele Scientific Institute, Milano, Italy.

Objective: The objective of this study was to compare the efficacy of renal perfusion with Custodiol (Dr Franz-Kohler Chemie GmbH, Bensheim, Germany) versus enriched Ringer's solution for renal protection in patients undergoing open thoracoabdominal aortic aneurysm (TAAA) repair.

Methods: Ninety consecutive patients scheduled for elective open TAAA repair were enrolled between 2015 and 2017 in a single-center, phase IV, prospective, parallel, randomized, double-blind trial (the CUstodiol versus RInger: whaT Is the Best Agent [CURITIBA] trial), and randomized to renal arteries perfusion with 4°C Custodiol (Dr Franz-Kohler Chemie GmbH, Bensheim, Germany; n = 45) or 4°C lactated Ringer's solution (n = 45). The incidence of acute kidney injury (AKI) in patients undergoing TAAA open surgery using Custodiol renal perfusion versus an enriched Ringer's solution was the primary end point.

Results: Ninety patients completed the study (45 patients in each group). The incidence of postoperative AKI was significantly lower in the Custodiol group (48.9% vs 75.6%; P = .02). In the multivariable model, only the use of Custodiol solution resulted as protective from the occurrence of any AKI (odds ratio, 0.230; 95% confidence interval, 0.086-0.614; P = .003), whereas TAAA type II extent was associated with the development of severe AKI (odds ratio, 4.277; 95% confidence interval, 1.239-14.762; P = .02). At 1-year follow-up, serum creatinine was not significantly different from the preoperative values in both groups.

Conclusions: The use of Custodiol during open TAAA repair was safe and resulted in significantly lower rates of postoperative AKI compared with Ringer's solution. These findings support safety and efficacy of Custodiol in this specific setting, which is currently off-label.
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http://dx.doi.org/10.1016/j.jtcvs.2021.02.090DOI Listing
March 2021

Insights into the Role of the Microbiota and of Short-Chain Fatty Acids in Rubinstein-Taybi Syndrome.

Int J Mol Sci 2021 Mar 31;22(7). Epub 2021 Mar 31.

Department of Health Sciences, Università degli Studi di Milano, 20142 Milan, Italy.

The short-chain fatty acid butyrate, produced by the gut microbiota, acts as a potent histone deacetylase (HDAC) inhibitor. We assessed possible ameliorative effects of butyrate, relative to other HDAC inhibitors, in in vitro and in vivo models of Rubinstein-Taybi syndrome (RSTS), a severe neurodevelopmental disorder caused by variants in the genes encoding the histone acetyltransferases CBP and p300. In RSTS cell lines, butyrate led to the patient-specific rescue of acetylation defects at subtoxic concentrations. Remarkably, we observed that the commensal gut microbiota composition in a cohort of RSTS patients is significantly depleted in butyrate-producing bacteria compared to healthy siblings. We demonstrate that the effects of butyrate and the differences in microbiota composition are conserved in a mutant for CBP, enabling future dissection of the gut-host interactions in an in vivo RSTS model. This study sheds light on microbiota composition in a chromatinopathy, paving the way for novel therapeutic interventions.
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http://dx.doi.org/10.3390/ijms22073621DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8037970PMC
March 2021

Pregnancy in a patient with Rothmund-Thomson type 2 syndrome.

Int J Gynaecol Obstet 2021 Mar 4. Epub 2021 Mar 4.

Cardiology Department, James Black Centre, King's College London, London, UK.

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http://dx.doi.org/10.1002/ijgo.13667DOI Listing
March 2021

Clinical and Imaging Characteristics of Spinal Dural Arteriovenous Fistulas and Spinal Epidural Arteriovenous Fistulas.

Neurosurgery 2021 02;88(3):666-673

Department of Neurosurgery, Mayo Clinic, Rochester, Minnesota; Department of Radiology, Mayo Clinic, Rochester, Minnesota.

Background: Spinal epidural arteriovenous fistulas (SEDAVFs) are an increasingly recognized form of spinal vascular malformation and are distinct from spinal dural arteriovenous fistulas (SDAVFs). Differentiating between these 2 entities is important as operative strategies often differ based on angioarchitecture.

Objective: To compare demographic, clinical, anatomic, and imaging findings of SDAVFs and SEDAVFs.

Methods: Consecutive patients diagnosed and/or treated for SDAVF or SEDAVF at our institution between January 2000 and November 2018 were included. Data were collected on demographics, clinical presentation, and imaging findings. All cross-sectional and angiographic imaging were reviewed. To compare continuous variables, t-test was used Chi-squared was used for categorical variables.

Results: A total of 169 patients were included. In total 47 patients had SEDAVFs and 122 patients had SDVAFs. Clinical presentation and magnetic resonance imaging (MRI) imaging findings were similar between the 2 groups. SEDAVF patients were significantly more likely to have an epidural venous pouch on gadolinium bolus MR angiography (MRA) (0.0% vs 92.1%, P < .0001). SEDAVFs were more commonly located in the lumbar and sacral spine than SDAVFs (85.1% vs 34.4%, P < .0001). When in the lumbar spine, SEDAVFs unlike SDAVFs were more likely to involve the most caudal segments (L4 and L5, P = .02).

Conclusion: SEDAVF share clinical and radiological findings similar to SDAVFS, including high T2 cord signal, cord enhancement, and perimedullary flow voids on conventional MRI. However, they have a characteristic appearance on spinal MRA and DSA with a pouch of epidural contrast. SEDAVFs are more commonly located in the lumbosacral spine.
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http://dx.doi.org/10.1093/neuros/nyaa492DOI Listing
February 2021

Interleukin-1 promotes autoimmune neuroinflammation by suppressing endothelial heme oxygenase-1 at the blood-brain barrier.

Acta Neuropathol 2020 10 11;140(4):549-567. Epub 2020 Jul 11.

Institute for Molecular Medicine, University Medical Center of the Johannes Gutenberg-University Mainz, Mainz, Germany.

The proinflammatory cytokine interleukin 1 (IL-1) is crucially involved in the pathogenesis of multiple sclerosis (MS) and its animal model experimental autoimmune encephalomyelitis (EAE). Herein, we studied the role of IL-1 signaling in blood-brain barrier (BBB) endothelial cells (ECs), astrocytes and microglia for EAE development, using mice with the conditional deletion of its signaling receptor IL-1R1. We found that IL-1 signaling in microglia and astrocytes is redundant for the development of EAE, whereas the IL-1R1 deletion in BBB-ECs markedly ameliorated disease severity. IL-1 signaling in BBB-ECs upregulated the expression of the adhesion molecules Vcam-1, Icam-1 and the chemokine receptor Darc, all of which have been previously shown to promote CNS-specific inflammation. In contrast, IL-1R1 signaling suppressed the expression of the stress-responsive heme catabolizing enzyme heme oxygenase-1 (HO-1) in BBB-ECs, promoting disease progression via a mechanism associated with deregulated expression of the IL-1-responsive genes Vcam1, Icam1 and Ackr1 (Darc). Mechanistically, our data emphasize a functional crosstalk of BBB-EC IL-1 signaling and HO-1, controlling the transcription of downstream proinflammatory genes promoting the pathogenesis of autoimmune neuroinflammation.
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http://dx.doi.org/10.1007/s00401-020-02187-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7498485PMC
October 2020

Expanding the phenotype associated to KMT2A variants: overlapping clinical signs between Wiedemann-Steiner and Rubinstein-Taybi syndromes.

Eur J Hum Genet 2021 Jan 8;29(1):88-98. Epub 2020 Jul 8.

Genetica Medica e Biologia Applicata, Dipartimento di Scienze della Salute, Università degli Studi di Milano, Milano, Italy.

Lysine-specific methyltransferase 2A (KMT2A) is responsible for methylation of histone H3 (K4H3me) and contributes to chromatin remodeling, acting as "writer" of the epigenetic machinery. Mutations in KMT2A were first reported in Wiedemann-Steiner syndrome (WDSTS). More recently, KMT2A variants have been described in probands with a specific clinical diagnosis comprised in the so-called chromatinopathies. Such conditions, including WDSTS, are a group of overlapping disorders caused by mutations in genes coding for the epigenetic machinery. Among them, Rubinstein-Taybi syndrome (RSTS) is mainly caused by heterozygous pathogenic variants in CREBBP or EP300. In this work, we used next generation sequencing (either by custom-made panel or by whole exome) to identify alternative causative genes in individuals with a RSTS-like phenotype negative to CREBBP and EP300 mutational screening. In six patients we identified different novel unreported variants in KMT2A gene. The identified variants are de novo in at least four out of six tested individuals and all of them display some typical RSTS phenotypic features but also WDSTS specific signs. This study reinforces the concept that germline variants affecting the epigenetic machinery lead to a shared molecular effect (alteration of the chromatin state) determining superimposable clinical conditions.
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http://dx.doi.org/10.1038/s41431-020-0679-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7852672PMC
January 2021

Increased Lipophilicity of Halogenated Ruthenium(II) Polypyridyl Complexes Leads to Decreased Phototoxicity in vitro when Used as Photosensitizers for Photodynamic Therapy.

Chembiochem 2020 Oct 7;21(20):2966-2973. Epub 2020 Jul 7.

Chimie ParisTech, PSL University, CNRS, Institute of Chemistry for Life and Health Sciences, Laboratory for Inorganic Chemical Biology, 75005, Paris, France.

In the fight against cancer, photodynamic therapy is generating great interest thanks to its ability to selectively kill cancer cells without harming healthy tissues. In this field, ruthenium(II) polypyridyl complexes, and more specifically, complexes with dipyrido[3,2-a:2',3'-c]phenazine (dppz) as a ligand are of particular interest due to their DNA-binding and photocleaving properties. However, ruthenium(II) polypyridyl complexes can sometimes suffer from low lipophilicity, which hampers cellular internalisation through passive diffusion. In this study, four new [Ru(dppz-X ) ] complexes (X=H, F, Cl, Br, I) were synthesized and their lipophilicity (logP), cytotoxicity and phototoxicity on cancerous and noncancerous cell lines were assessed. This study shows that, counterintuitively, the phototoxicity of these complexes decreases as their lipophilicity increases; this could be due solely to the atomic radius of the halogen substituents.
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http://dx.doi.org/10.1002/cbic.202000289DOI Listing
October 2020

Direct carotid puncture in acute ischaemic stroke intervention.

Stroke Vasc Neurol 2020;5(1):71-79. Epub 2020 Jan 29.

Neurologic Surgery, Mayo Clinic, Rochester, Minnesota, USA.

Endovascular intervention for acute ischaemic stroke care is mostly performed in older patients, often with unfavourable aortic and supra-aortic anatomy, as well as cardiovascular comorbidities. A significant subset of them may benefit from transcervical access as the initial approach for mechanical thrombectomy. In fact, direct carotid artery puncture in these cases has the advantage to bypass the anatomical obstacles and achieve faster reperfusion. Caution is advised when common carotid artery access is pursued in order to avoid adverse events, including haematoma formation, iatrogenic arterial dissection and sheath kinking. In spite of potential complications, direct carotid puncture in acute ischaemic stroke intervention overcomes challenging angioarchitecture and may reduce the rate of poor clinical outcomes associated with delayed revascularisation in certain cases.
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http://dx.doi.org/10.1136/svn-2019-000260DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7213516PMC
November 2020

Customised next-generation sequencing multigene panel to screen a large cohort of individuals with chromatin-related disorder.

J Med Genet 2020 11 13;57(11):760-768. Epub 2020 Mar 13.

Division of Medical Genetics, IRCCS Ospedale Casa Sollievo della Sofferenza, San Giovanni Rotondo, Italy

Background: The regulation of the chromatin state by epigenetic mechanisms plays a central role in gene expression, cell function, and maintenance of cell identity. Hereditary disorders of chromatin regulation are a group of conditions caused by abnormalities of the various components of the epigenetic machinery, namely writers, erasers, readers, and chromatin remodelers. Although neurological dysfunction is almost ubiquitous in these disorders, the constellation of additional features characterizing many of these genes and the emerging clinical overlap among them indicate the existence of a community of syndromes. The introduction of high-throughput next generation sequencing (NGS) methods for testing multiple genes simultaneously is a logical step for the implementation of diagnostics of these disorders.

Methods: We screened a heterogeneous cohort of 263 index patients by an NGS-targeted panel, containing 68 genes associated with more than 40 OMIM entries affecting chromatin function.

Results: This strategy allowed us to identify clinically relevant variants in 87 patients (32%), including 30 for which an alternative clinical diagnosis was proposed after sequencing analysis and clinical re-evaluation.

Conclusion: Our findings indicate that this approach is effective not only in disorders with locus heterogeneity, but also in order to anticipate unexpected misdiagnoses due to clinical overlap among cognate disorders. Finally, this work highlights the utility of a prompt diagnosis in such a clinically and genetically heterogeneous group of disorders that we propose to group under the umbrella term of chromatinopathies.
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http://dx.doi.org/10.1136/jmedgenet-2019-106724DOI Listing
November 2020

Clinical and angioarchitectural characteristics of spinal vascular malformations of the cervical spine.

J Neurosurg Spine 2020 Jan 17:1-8. Epub 2020 Jan 17.

Departments of1Neurosurgery and.

Objective: Vascular malformations of the cervical spine are exceedingly rare. To date there have been no large case series describing the clinical presentation and angioarchitectural characteristics of cervical spine vascular malformations. The authors report their institutional case series on cervical spine vascular malformations diagnosed and treated at their institution.

Methods: The authors retrospectively reviewed all patients with spinal vascular malformations from their institution from January 2001 to December 2018. Patients with vascular malformations of the cervical spine were included. Lesions were characterized by their angioarchitectural characteristics by an interventional neuroradiologist and endovascular neurosurgeon. Data were collected on clinical presentation, imaging findings, treatment outcomes, and long-term follow-up. Descriptive statistics are reported.

Results: Of a total of 213 patients with spinal vascular malformations, 27 (12.7%) had vascular malformations in the cervical spine. The mean patient age was 46.1 ± 21.9 years and 16 (59.3%) were male. The most common presentations were lower-extremity weakness (13 patients, 48.1%), tetraparesis (8 patients, 29.6%), and lower-extremity sensory dysfunction (7 patients, 25.9%). Nine patients (33.3%) presented with hemorrhage. Fifteen patients (55.6%) had modified Rankin Scale scores of 0-2 at the time of diagnosis. Regarding angioarchitectural characteristics, 8 patients (29.6%) had intramedullary arteriovenous malformations (AVMs), 5 (18.5%) had epidural arteriovenous fistulas (AVFs), 4 (14.8%) had paraspinal fistulas, 4 (14.8%) had mixed epidural/intradural fistulas, 3 (11.1%) had perimedullary AVMs, 2 (7.4%) had dural fistulas, and 1 patient (3.7%) had a perimedullary AVF.

Conclusions: This retrospective study of 27 patients with cervical spine vascular malformations is the largest series to date on these lesions. The authors found substantial angioarchitectural heterogeneity with the most common types being intramedullary AVMs followed by epidural AVFs, paraspinal fistulas, and mixed intradural/extradural fistulas. Angioarchitecture dictated the clinical presentation as intradural shunts were more likely to present with hemorrhage and acute onset myelopathy, while dural and extradural shunts presented as either incidental lesions or gradually progressive congestive myelopathy.
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http://dx.doi.org/10.3171/2019.11.SPINE19798DOI Listing
January 2020

Ablation of neuronal ADAM17 impairs oligodendrocyte differentiation and myelination.

Glia 2020 06 18;68(6):1148-1164. Epub 2019 Dec 18.

INSPE, Division of Neuroscience, IRCCS San Raffaele Scientific Institute, Milan, Italy.

Myelin, one of the most important adaptations of vertebrates, is essential to ensure efficient propagation of the electric impulse in the nervous system and to maintain neuronal integrity. In the central nervous system (CNS), the development of oligodendrocytes and the process of myelination are regulated by the coordinated action of several positive and negative cell-extrinsic factors. We and others previously showed that secretases regulate the activity of proteins essential for myelination. We now report that the neuronal α-secretase ADAM17 controls oligodendrocyte differentiation and myelin formation in the CNS. Ablation of Adam17 in neurons impairs in vivo and in vitro oligodendrocyte differentiation, delays myelin formation throughout development and results in hypomyelination. Furthermore, we show that this developmental defect is, in part, the result of altered Notch/Jagged 1 signaling. Surprisingly, in vivo conditional loss of Adam17 in immature oligodendrocytes has no effect on myelin formation. Collectively, our data indicate that the neuronal α-secretase ADAM17 is required for proper CNS myelination. Further, our studies confirm that secretases are important post-translational regulators of myelination although the mechanisms controlling CNS and peripheral nervous system (PNS) myelination are distinct.
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http://dx.doi.org/10.1002/glia.23765DOI Listing
June 2020

Clinical Reasoning: 63-Year-old woman with thoracic cavernous malformation and delayed worsening myelopathy.

Neurology 2019 12;93(24):1075-1078

From the Departments of Neurosurgery (E.C., G.L., B.D.E.) and Neurology (R.D.B.), Mayo Clinic, Rochester, MN.

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http://dx.doi.org/10.1212/WNL.0000000000008635DOI Listing
December 2019

Is There an Association Between Oxytocin Levels in Plasma and Pregnant Women's Mental Health?

J Am Psychiatr Nurses Assoc 2019 Nov 29:1078390319890400. Epub 2019 Nov 29.

Massimiliano Buoli, MD, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy.

Mood and anxiety disorders are prevalent in women during peripartum. Purpose of the present article was to study the relationship between oxytocin (OT) plasma levels and affective symptoms in women during the third trimester of pregnancy. Thirty-four pregnant women (13 with an affective disorder, 9 with preeclampsia, and 12 controls) were evaluated through the Edinburgh Postnatal Depression Scale (EPDS), the State/Trait Anxiety Inventory Form Y (STAI-Y), and the Prenatal Attachment Inventory (PAI). A blood sample was collected from all participants, and OT plasma levels have been compared between diagnostic groups. The total sample has been divided into two groups, according to OT median plasma levels, and compared using (a) χ tests for qualitative variables and (b) a multivariate analysis of covariance for quantitative ones. No statistically significant difference was found among the diagnostic groups in terms of OT plasma levels ( = 0.49, = .62). Women with lower OT plasma levels, independent from the presence of preeclampsia or an affective disorder, showed worse EPDS and STAI-S total scores than individuals with higher hormone levels ( = 5.93, = .02 and = 7.57, = .01, respectively). OT may play a role in the etiology of anxious/depressive symptoms during perinatal period independent from a medical or psychiatric diagnosis. This result has a clear effect on the quality of the relationship of patients with mental health professionals, including nurses, and higher levels of this hormone, in the light of its anxiolytic and antidepressive effect, may make easier medical and nursing procedures.
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http://dx.doi.org/10.1177/1078390319890400DOI Listing
November 2019

Teaching NeuroImages: Rete-like middle cerebral artery.

Neurology 2019 11;93(20):e1919-e1920

From the Departments of Neurosurgery (E.C.), Radiology (W.B.), and Neurology (J.K., G.L.), Mayo Clinic, Rochester, MN.

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http://dx.doi.org/10.1212/WNL.0000000000008480DOI Listing
November 2019

Phenotypic Overlap of Roberts and Baller-Gerold Syndromes in Two Patients With Craniosynostosis, Limb Reductions, and Mutations.

Front Pediatr 2019 28;7:210. Epub 2019 May 28.

Laboratorio di Citogenetica e Genetica Molecolare Umana, Istituto Auxologico Italiano, IRCCS, Milan, Italy.

Baller-Gerold (BGS, MIM#218600) and Roberts (RBS, MIM#268300) syndromes are rare autosomal recessive disorders caused, respectively, by biallelic alterations in (MIM603780) and (MIM609353) genes. Common features are severe growth retardation, limbs shortening and craniofacial abnormalities which may include craniosynostosis. We aimed at unveiling the genetic lesions underpinning the phenotype of two unrelated children with a presumptive BGS diagnosis: patient 1 is a Turkish girl with short stature, microcephaly, craniosynostosis, seizures, intellectual disability, midface hemangioma, bilateral radial and thumb aplasia, tibial hypoplasia, and pes equinovarus. Patient 2 is an Iranian girl born to consanguineous parents with craniosynostosis, micrognathism, bilateral radial aplasia, thumbs, and foot deformity in the context of developmental delay. Upon negative test, whole exome sequencing (WES) analysis performed on the two trios led to the identification of two different homozygous inactivating variants: a previously described c.1131+1G>A transition in patient 1 and an unreported deletion, c.417del, in patient 2, thus turning the diagnosis into Roberts syndrome. The occurrence of a Baller-Gerold phenotype in two unrelated patients that were ultimately diagnosed with RBS demonstrates the strength of WES in redefining the nosological landscape of rare congenital malformation syndromes, a premise to yield optimized patients management and family counseling.
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http://dx.doi.org/10.3389/fped.2019.00210DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6546804PMC
May 2019

Exploring by whole exome sequencing patients with initial diagnosis of Rubinstein-Taybi syndrome: the interconnections of epigenetic machinery disorders.

Hum Genet 2019 Mar 26;138(3):257-269. Epub 2019 Feb 26.

Genetica Medica, Dipartimento di Scienze della Salute, Università degli Studi di Milano, Milan, Italy.

Rubinstein-Taybi syndrome (RSTS) is an autosomal-dominant neurodevelopmental disease affecting 1:125,000 newborns characterized by intellectual disability, growth retardation, facial dysmorphisms and skeletal abnormalities. RSTS is caused by mutations in genes encoding for writers of the epigenetic machinery: CREBBP (~ 60%) or its homologous EP300 (~ 10%). No causative mutation is identified in up to 30% of patients. We performed whole-exome sequencing (WES) on eight RSTS-like individuals who had normal high-resolution array CGH testing and were CREBBP- and EP300-mutation -negative, to identify the molecular cause. In four cases, we identified putatively causal variants in three genes (ASXL1, KMT2D and KMT2A) encoding members of the epigenetic machinery known to be associated with the Bohring-Opitz, Kabuki and Wiedemann-Steiner syndromes. Each variant is novel, de novo, fulfills the ACMG criteria and is predicted to result in loss-of-function leading to haploinsufficiency of the epi-gene. In two of the remaining cases, homozygous/compound heterozygous variants in XYLT2 and PLCB4 genes, respectively, associated with spondyloocular and auriculocondylar 2 syndromes and in the latter an additional candidate variant in XRN2, a gene yet unrelated to any disease, were detected, but their pathogenicity remains uncertain. These results underscore the broad clinical spectrum of Mendelian disorders of the epigenetic apparatus and the high rate of WES disclosure of the genetic basis in cases which may pose a challenge for phenotype encompassing distinct syndromes. The overlapping features of distinct intellectual disability syndromes reflect common pathogenic molecular mechanisms affecting the complex regulation of balance between open and closed chromatin.
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http://dx.doi.org/10.1007/s00439-019-01985-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6736609PMC
March 2019

Pet Grief: Tools to Assess Owners' Bereavement and Veterinary Communication Skills.

Animals (Basel) 2019 Feb 21;9(2). Epub 2019 Feb 21.

Department of Philosophy, Sociology, Education and Applied Psychology (FISPPA), University of Padova, 35131 Padua, Italy.

In Italy, there are still very few studies on the psychological impact of losing a pet. The need to fill this gap springs from the fact that pet loss counseling services are increasingly being activated. The aim of this study is the Italian adaptation of instruments for veterinary counseling services. The survey instruments adapted were: Pet Bereavement Questionnaire (PBQ) to describe the individual experience of pet-grief; Regret of Bereaved Family Members (RBFM) to assess the family regret; Shared Decision-Making Questionnaire (SDM-Q-9) for decision making in end of life; Consultation and Relational Empathy Measure (CARE) to assess the veterinarian relational empathy during clinical encounters. All the instruments obtained good internal reliability, and the results of the confirmative factor analysis of all the Italian versions were in accordance with the original ones. The correlational analysis among the variables evidenced the following aspects: the more the owner feels involved by the veterinarian in the decision making process the more the veterinarian is perceived by the owner as empathetic; when the veterinarian is perceived as empathic and the decision making is shared the owners' pet bereavement distress and regrets are reduced; negative dimensions of bereavement (grief, guilt, anger, intrusive thoughts and decisional regrets) are strictly linked to each other, therefore if one dimension increases or decreases the others do too. The path analysis suggests that developing a veterinary relationship-centered care practice may be beneficial for pet owners facing end-of-life issues and the death of their companion animals since it showed that shared-decision making strategies and empathic communication may reduce negative dimensions of bereavement that may complicate grief. Interestingly, adopting shared decision-making strategies may contribute to be perceived as more empathic. These aspects may be taken into consideration in end-of -life communication training in veterinary medicine.
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http://dx.doi.org/10.3390/ani9020067DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6406392PMC
February 2019

Hemorrhagic burden in poor-grade aneurysmal subarachnoid hemorrhage: a volumetric analysis of different bleeding distributions.

Acta Neurochir (Wien) 2019 04 21;161(4):791-797. Epub 2019 Feb 21.

Department of Neuroradiology, Interventional Neuroradiology Division, IRCCS San Raffaele Scientific Institute, Vita-Salute San Raffaele University, Via Olgettina 60, 20132, Milan, Italy.

Background: Volumetric assessment of aneurysmal bleeding has been evaluated in few studies and emerged as a promising outcome predictor. There is a lack of studies evaluating its impact in the poor-grade population.

Methods: Retrospective review of 63 consecutive poor-grade aneurysmal subarachnoid hemorrhage (aSAH) patients, defined as grade IV and V according to the World Federation of Neurological Surgeons (WFNS) classifications. Global intracranial bleeding volume was calculated with its subarachnoid, intracerebral (ICH), and intraventricular (IVH) portions by means of analytical software. Univariate and multivariate analyses were performed in order to identify independent predictors of outcome. Good outcome was defined as modified Rankin Scale (mRS) 0-2 and mortality as mRS 6. The cutoff values of bleeding volumes were derived by receiver operating curve (ROC) analysis.

Results: Mean follow-up was of 12.5 (± 1.5) months. Thirty (47.7%) patients achieved good outcome, whereas 19 (30.2) patients out of 63 died. Global intracranial bleeding resulted as an independent predictor of good outcome (cutoff 24 mL). Furthermore, ICH relative percentage of global volume (10% of total) and pure SAH (64% of total) emerged respectively as independent predictors of worsened and improved outcome. Global bleeding volume (cutoff 51 mL) along with global cerebral edema showed to independently predict mortality in the examined poor-grade aSAH population.

Conclusions: Volumetric assessment of aneurysmal bleeding has the potential for identifying cutoff values that independently predict outcome. Further insights into the relative importance of different bleeding volumes may be implicated in better tailoring the management of this dismal aSAH population.
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http://dx.doi.org/10.1007/s00701-019-03846-zDOI Listing
April 2019

Influence of age and spectral power distribution on mesopic visual sensitivity.

Atten Percept Psychophys 2019 Feb;81(2):504-516

Departamento de Física Teórica, Atómica y Óptica, Universidad de Valladolid, P. Belén 7, 47011, Valladolid, Spain.

The ability of the human visual system to detect stimuli at low illumination levels provides awareness of potential risks. The influence of age and spectral power distribution on mesopic spectral sensitivity is analyzed. Two typical light sources are used, a high-pressure sodium lamp (HPS), with a higher content of long wavelengths, and a metal halide lamp (MH), with a higher content of short wavelengths. Two experiments were performed, using a two-channel Maxwellian-view optical system to measure contrast threshold under different experimental conditions. In Experiment 1, three age groups (young, middle-aged and old, n = 2 each), two retinal locations (on-axis and off-axis vision), four background luminances (0.01, 0.07, 0.45, and 3.2 cd/m), and two photometry systems (photopic and the MES2 systems) were considered. In Experiment 2, contrast threshold measurement was performed with two age groups (young and old, n = 11 each), one retinal location (off-axis vision), one background luminance (0.01 cd/m), and two photometry systems (photopic and the MES2 systems). In on-axis vision, neither age nor spectral power distribution have an effect on the contrast threshold. In off-axis vision, however, a significant interaction between age and spectral power distribution is obtained, albeit only at 0.01 cd/m with an MH lamp. Only at this lowest background luminance was the greater content of short wavelengths of this lamp responsible for higher rod stimulation in off-axis vision, with the subsequent improvement in detection performance in young subjects. However, the effect of diffused light inside the aged eye counteracted the benefits of increased rod sensitivity for the MH lamp.
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http://dx.doi.org/10.3758/s13414-018-1616-6DOI Listing
February 2019

Quantifying the effect of straylight on photopic contrast sensitivity.

J Opt Soc Am A Opt Image Sci Vis 2018 Jul;35(7):1124-1130

The visual performance of a reference group (RG) using diffuser filters was compared to a cataract-diagnosed group (CatG). Measurements of straylight (SL) parameter, photopic contrast sensitivity (CS), and visual acuity (VA) were carried out in both groups. Before the analysis, the performance of the instruments used for this purpose was tested. The RG was comprised of three healthy, young eyes (25-30 years old) while 59 subjects (aged 50-80 years old) with lens opacities were recruited for the CatG. Six diffuser conditions were tested in the RG. To discriminate between light scattering levels, SL measurements proved to be most sensitive, VA did not discriminate at all, while CS showed intermediate sensitivity. VA was not correlated with SL, while the correlation between CS and SL was significant (p<0.05) in both groups. Since the correlation in the RG was particularly strong, parameters of a linear regression model are presented. The behavior of CS as a function of SL was comparable to some extent between RG and CatG.
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http://dx.doi.org/10.1364/JOSAA.35.001124DOI Listing
July 2018

The pattern of color change in small mammal museum specimens: is it independent of storage histories given museum-specific conditions?

BMC Res Notes 2018 Jul 3;11(1):424. Epub 2018 Jul 3.

Programa de Investigaciones de Biodiversidad Argentina-PIDBA, Facultad de Ciencias Naturales e Instituto Miguel Lillo-FCNeIML, Universidad Nacional de Tucumán-UNT, Miguel Lillo 205, 4000, San Miguel de Tucumán, Tucumán, Argentina.

Objective: Determination of color and evaluating its variation form the basis for a broad range of research questions. For studies on taxonomy, systematics, etc., resorting to mammal specimens in museum collections has a number of advantages over using field specimens. However, if museum specimens are to be for studying color, they should accurately represent the color of live animals, or we should understand how they differ. Basically, this study addresses this question: How does coat color vary when dealing with specimens of Akodon budini (Budin's grass mouse, Thomas 1918), stored in one museum collection for different periods of time?

Results: We measured color values through a spectroradiometer and a diffuse illumination cabin and used the reflectance values in the form of CIELab tri-stimulus values, considering CIE standard illuminant A. We observed that there is a relationship between specimen storage antiquity and pelage color and it seems that it is general for at least a number of small mammals and this could indicate a universal phenomenon across several mammal species and across several storage conditions. Our results, as others, emphasize the importance of considering storage time, among other circumstances, in research studies using mammal skins and where color is of importance.
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http://dx.doi.org/10.1186/s13104-018-3544-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6029030PMC
July 2018

Insights into Mutation Effect in Three Poikiloderma with Neutropenia Patients by Transcript Analysis and Disease Evolution of Reported Patients with the Same Pathogenic Variants.

J Clin Immunol 2018 05 16;38(4):494-502. Epub 2018 May 16.

Laboratorio di Citogenetica Medica e Genetica Molecolare, Centro di Ricerche e Tecnologie Biomediche IRCCS-Istituto Auxologico Italiano, Via Ariosto 13, 20145, Milan, Italy.

Purpose: Poikiloderma with neutropenia (PN) is a genodermatosis currently described in 77 patients, all presenting with early-onset poikiloderma, neutropenia, and several additional signs. Biallelic loss-of-function mutations in USB1 gene are detected in all molecularly tested patients but genotype-phenotype correlation remains elusive. Cancer predisposition is recognized among PN features and pathogenic variants found in patients who developed early in life myelodysplasia (n = 12), acute myeloid leukemia (n = 2), and squamous cell carcinoma (n = 2) should be kept into account in management and follow-up of novel patients. This will hopefully allow achieving data clustered on specific mutations relevant to oncological surveillance of the carrier patients.

Methods: We describe the clinical features of three unreported PN patients and characterize their USB1 pathogenic variants by transcript analysis to get insights into the effect on the overall phenotype and disease evolution.

Results: A Turkish boy is homozygous for the c.531delA deletion, a recurrent mutation in Turkey; an adult Italian male is compound heterozygous for two nonsense mutations, c.243G>A and c.541C>T, while an Italian boy is homozygous for the splicing c.683_693+1del variant. The identified mutations have already been reported in PN patients who developed hematologic or skin cancer. Aberrant mRNAs of all four mutated alleles could be identified confirming that transcripts of USB1 main isoform either carrying stop codons or mis-spliced may at least partially escape nonsense-mediated decay.

Conclusions: Our study addresses the need of gathering insights on genotype-phenotype correlations in newly described PN patients, by transcript analysis and information on disease evolution of reported patients with the same pathogenic variants.
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http://dx.doi.org/10.1007/s10875-018-0508-9DOI Listing
May 2018

Assessment of intrafamilial clinical variability of poikiloderma with neutropenia by a 10-year follow-up of three affected siblings.

Eur J Med Genet 2019 Jan 24;62(1):73-76. Epub 2018 May 24.

Medical Cytogenetics and Molecular Genetics Laboratory, Centro di Ricerche e Tecnologie Biomediche IRCCS, Istituto Auxologico Italiano, Milan, Italy.

Clericuzio-type poikiloderma with neutropenia is a well-defined nosological entity, but despite a remarkable number of clinical reports, no long term follow-up data has been presented to date regarding patients with this rare condition. Here we describe the results of clinical follow-up of three siblings, one male (Patient 1) and two females (Patients 2 and 3), subsequent to their first clinical and then molecular diagnosis of Clericuzio-type poikiloderma with neutropenia syndrome due to mutation of USB1gene. Patient 1 always expressed the most severe phenotype, while patients 2 and 3 showed an intermediate and mild phenotype, respectively, as observed since their first clinical evaluation. None of the patients developed skin cancer and/or myelodysplastic disorders considering the peripheral haematological findings. Lens opacity, never reported before, was found in two of the three patients. The long term follow-up observations confirm the stability over time of the pronounced intra-familial heterogeneity of clinical manifestations observed prior to and upon molecular diagnosis. We conclude that prolonged follow-up is an adjunct tool to monitor intra-familial variability of PN clinical spectrum which may favour surveillance of more serious complications of the disease among siblings, when a patient-specific clinical expressivity is present.
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http://dx.doi.org/10.1016/j.ejmg.2018.05.007DOI Listing
January 2019

Nest predation risk modifies nestlings' immune function depending on the level of threat.

J Exp Biol 2018 05 20;221(Pt 10). Epub 2018 May 20.

Groningen Institute for Evolutionary Life Sciences, University of Groningen, 9700 CC Groningen, The Netherlands.

Predation risk is thought to modify the physiology of prey mainly through the stress response. However, little is known about its potential effects on the immunity of animals, particularly in young individuals, despite the importance of overcoming wounding and pathogen aggression following a predator attack. We investigated the effect of four progressive levels of nest predation risk on several components of the immune system in common blackbird () nestlings by presenting them with four different calls during 1 h: non-predator calls, predator calls, parental alarm calls and conspecific distress calls to induce a null, moderate, high and extreme level of risk, respectively. Nest predation risk induced an increase in ovotransferrin, immunoglobulin and the number of lymphocytes and eosinophils. Thus, the perception of a potential predator per se could stimulate the mobilization of a nestling's immune function and enable the organism to rapidly respond to the immune stimuli imposed by a predator attack. Interestingly, only high and extreme levels of risk caused immunological changes, suggesting that different immunological parameters are modulated according to the perceived level of threat. We also found a mediator role of parasites (i.e. ) and the current health status of the individual, as only nestlings not parasitized or in good body condition were able to modify their immune system. This study highlights a previously unknown link between predation risk and immunity, emphasizing the complex relationship among different selective pressures (predation, parasitism) in developing organisms and accentuating the importance of studying predation from a physiological point of view.
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http://dx.doi.org/10.1242/jeb.170662DOI Listing
May 2018

Rothmund-Thomson Syndrome: Insights from New Patients on the Genetic Variability Underpinning Clinical Presentation and Cancer Outcome.

Int J Mol Sci 2018 Apr 6;19(4). Epub 2018 Apr 6.

Laboratory of Medical Cytogenetics and Molecular Genetics, IRCCS Istituto Auxologico Italiano, 20149 Milan, Italy.

Biallelic mutations in gene, a caretaker of the genome, cause Rothmund-Thomson type-II syndrome (RTS-II) and confer increased cancer risk if they damage the helicase domain. We describe five families exemplifying clinical and allelic heterogeneity of RTS-II, and report the effect of pathogenic variants by predictions and transcripts analyses. Complete phenotype of patients #39 and #42 whose affected siblings developed osteosarcoma correlates with their c.[1048_1049del], c.[1878+32_1878+55del] and c.[1568G>C;1573delT], c.[3021_3022del] variants which damage the helicase domain. Literature survey highlights enrichment of these variants affecting the helicase domain in patients with cancer outcome raising the issue of strict oncological surveillance. Conversely, patients #29 and #19 have a mild phenotype and carry, respectively, the unreported homozygous c.3265G>T and c.3054A>G variants, both sparing the helicase domain. Finally, despite matching several criteria for RTS clinical diagnosis, patient #38 is heterozygous for c.2412_2414del; no pathogenic CNVs out of those evidenced by high-resolution CGH-array, emerged as contributors to her phenotype.
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http://dx.doi.org/10.3390/ijms19041103DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5979380PMC
April 2018

Familial gastrointestinal stromal tumors, lentigines, and café-au-lait macules associated with germline c-kit mutation treated with imatinib.

Int J Dermatol 2017 Feb;56(2):195-201

Department of Surgery, Jawaharlal Institute of Postgraduate Medical Education & Research (JIPMER), Puducherry, India.

Background: Familial lentiginosis syndromes are characterized by a wide array of manifestations resulting from activation of molecular pathways which control growth, proliferation, and differentiation of a broad range of tissues. Familial gastrointestinal stromal tumors (GISTs) are often accompanied by additional features like hyperpigmentation, mastocytosis, and dysphagia. They have been described with mutations in c-kit (most commonly), platelet-derived growth factor receptor A, neurofibromatosis-1, and succinate dehydrogenase genes.

Materials And Methods: We report on molecular characterization and tumor histopathology of two siblings in whom lentigines and café-au-lait macules were present along with multifocal GIST. Immuhistochemical analysis of CD34 and CD117 was performed on GIST biopsy samples from both siblings, while c-kit mutational analysis was done by PCR and direct sequencing on DNA from peripheral blood leukocytes of all family members and from paraffin-embedded gastric biopsy specimens of affected siblings.

Results: Histopathology revealed positive expression of CD117 and CD34. Mutational analysis showed the germline c.1676T>C mutation in c-kit exon 11, (p.(Val559Ala)), in the peripheral blood of both siblings and a second exon 11 mutation, c.1669T>A (p.(Trp557Arg)) in the tumor biopsy of one of them. Initiation of imatinib treatment resulted in striking resolution of their hyperpigmentation and a stable gastrointestinal disease in one of them.

Conclusions: A c-kit mutational test in familial GISTs is indicated before initiation of imatinib therapy, as it can help predict tumor response to treatment.
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http://dx.doi.org/10.1111/ijd.13516DOI Listing
February 2017

Viable phenotype of ILNEB syndrome without nephrotic impairment in siblings heterozygous for unreported integrin alpha3 mutations.

Orphanet J Rare Dis 2016 10 7;11(1):136. Epub 2016 Oct 7.

Laboratorio di Citogenetica Medica e Genetica Molecolare, Centro di Ricerche e Tecnologie Biomediche IRCCS-Istituto Auxologico Italiano, Via Zucchi 18, 20095, Cusano Milanino, Italy.

Background: Integrin α3 (ITGA3) gene mutations are associated with Interstitial Lung disease, Nephrotic syndrome and Epidermolysis bullosa (ILNEB syndrome). To date only six patients are reported: all carried homozygous ITGA3 mutations and presented a dramatically severe phenotype leading to death before age 2 years, from multi-organ failure due to interstitial lung disease and congenital nephrotic syndrome. The involvement of skin and cutaneous adnexa was variable with sparse hair and nail dysplasia combined or not to skin lesions ranging from skin fragility to epidermolysis bullosa-like blistering.

Results: We report on two siblings of 13 and 9 years born to non-consanguineous healthy parents, who display growth delay, severe pulmonary fibrosis with fatigue, dyspnea on exertion and wheezing, atrophic skin with erythematosus lesions, rare eyelashes/eyebrows and pachyonychia. By exome sequencing, we identified two unreported ITGA3 missense mutations, c.373G>A (p.(G125R)) in exon 3 and c.821G>A (p.(R274Q)) in exon 6, affecting highly conserved residues in the integrin α3 extracellular N-terminal β-propeller domain. Homology modelling of α3β1 heterodimer fragment, encompassing the mutation sites, showed that G125 plays a pivotal structural role in the β-propeller, while R274 might prevent the interaction between integrin and urokinase complex.

Conclusion: We report a variant of ILNEB syndrome in two siblings differing from the previously reported patients in the lack of nephrotic impairment and survival beyond childhood. Our siblings are the first reported compound heterozygous for ITGA3 mutations; this state as well as the hypomorphic nature of their p.(R274Q) mutation likely account for their survival.
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http://dx.doi.org/10.1186/s13023-016-0514-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5054609PMC
October 2016

Pupil dynamics with periodic flashes: effect of age on mesopic adaptation.

J Opt Soc Am A Opt Image Sci Vis 2016 Aug;33(8):1546-52

The purpose of this study is to determine the pupillary dynamics with periodical flashes from a peripheral glare source, in similar conditions to night driving, while focusing on dependence with age. We measured two groups of people: youth and adults. Maximum pupil size decreases due to periodic flashes. Latency does not present significant differences. The reduction of pupil size is greater for older adults. The presence of a peripheral and periodic glare source modifies the pupil size. This leads to a reduction of retinal illuminance, which is greater for older adults.
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http://dx.doi.org/10.1364/JOSAA.33.001546DOI Listing
August 2016

Strawberry tannins inhibit IL-8 secretion in a cell model of gastric inflammation.

Pharmacol Res 2016 09 27;111:703-712. Epub 2016 Jul 27.

Department of Pharmacological and Biomolecular Sciences, Università degli Studi di Milano, Italy. Electronic address:

In the present study we chemically profiled tannin-enriched extracts from strawberries and tested their biological properties in a cell model of gastric inflammation. The chemical and biological features of strawberry tannins after in vitro simulated gastric digestion were investigated as well. The anti-inflammatory activities of pure strawberry tannins were assayed to get mechanistic insights. Tannin-enriched extracts from strawberries inhibit IL-8 secretion in TNFα-treated human gastric epithelial cells by dampening the NF-κB signaling. In vitro simulated gastric digestion slightly affected the chemical composition and the biological properties of strawberry tannins. By using pure compounds, we found that casuarictin may act as a pure NF-κB inhibitor while agrimoniin inhibits IL-8 secretion also acting on other biological targets; in our system procyanidin B1 prevents the TNFα-induced effects without interfering with the NF-κB pathway. We conclude that strawberry tannins, even after in vitro simulated gastric digestion, exert anti-inflammatory activities at nutritionally relevant concentrations.
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http://dx.doi.org/10.1016/j.phrs.2016.07.028DOI Listing
September 2016