314 results on '"Ferreira, CR"'
Search Results
2. OUTCOMES, PROGNOSTIC FACTORS, PREDICTORS FOR TRANSFORMATION TO HIGH-GRADE B-CELL LYMPHOMA, AND THERAPEUTIC MANAGEMENT IN FOLLICULAR LYMPHOMA: REAL-WORLD EVIDENCE FROM A LARGE AND LONG-TERM LATIN-AMERICAN COHORT
- Author
-
Nogueira, DS, primary, Lage, LAPC, additional, Reichert, CO, additional, Culler, HF, additional, Freitas, FA, additional, Ferreira, CR, additional, Costa, RO, additional, Rocha, V, additional, Levy, D, additional, and Pereira, J, additional
- Published
- 2023
- Full Text
- View/download PDF
3. Ectopic calcification and hypophosphatemic rickets: natural history of ENPP1 and ABCC6 deficiencies
- Author
-
Ferreira CR, Kintzinger K, Hackbarth ME, Botschen U, Nitschke Y, Mughal MZ, Baujat G, Schnabel D, Yuen E, Gahl WA, Gafni RI, Liu Q, Huertas P, Khursigara G, and Rutsch F
- Subjects
General Economics, Econometrics and Finance - Published
- 2022
4. TRANSFORMED MYCOSIS FUNGOIDES RELAPSED AT CENTRAL NERVOUS SYSTEM AFTER ALLOGENEIC BONE MARROW TRANSPLANT
- Author
-
Santanna, PVH, primary, Cortez, AC, additional, Costa, AD, additional, Correa, APR, additional, Ferreira, CR, additional, Costa, FD, additional, Silveira, TB, additional, and Fischer, T, additional
- Published
- 2021
- Full Text
- View/download PDF
5. 22q11.2 Deletion Syndrome in Diverse Populations
- Author
-
Muthukumarasamy, P, Muenke, M, Linguraru, MG, Kruszka, P, Addissie, YA, McGinn, DE, Porras, AR, Biggs, E, Share, M, Crowley, TB, Kaplan, JD, Chung, BHY, Abdul-Rahman, OA, Uwineza, A, Mok, TKG, MAK, CCY, Mutesa, L, Moresco, A, Obregon, MG, Richieri-Costa, A, Zackai, EH, Summar, M, McDonald-McGinn, DM, Adeyemo, AA, Gil-da-Silva-Lopes, VL, Thong, MK, Siriseria, ND, Dissanayake, VHW, Paththinige, CS, Prabodha, LBL, Mishra, R, Shotelersuk, V, Ekure, EN, Sokunbi, OJ, Kalu, N, Ferreira, CR, Duncan, JM, Patil, SJ, and Jones, KL
- Subjects
Adult ,Heart Defects, Congenital ,Male ,Adolescent ,Learning Disabilities ,Chromosomes, Human, Pair 22 ,Infant, Newborn ,Black People ,Facies ,Infant ,Hispanic or Latino ,Article ,White People ,Phenotype ,Asian People ,Biometric Identification ,Child, Preschool ,Image Interpretation, Computer-Assisted ,DiGeorge Syndrome ,Humans ,Female ,Child ,human activities ,In Situ Hybridization, Fluorescence - Abstract
22q11.2 deletion syndrome (22q11.2 DS) is the most common microdeletion syndrome and is underdiagnosed in diverse populations. This syndrome has a variable phenotype and affects multiple systems, making early recognition imperative. In this study, individuals from diverse populations with 22q11.2 DS were evaluated clinically and by facial analysis technology. Clinical information from 106 individuals and images from 101 were collected from individuals with 22q11.2 DS from 11 countries; average age was 11.7 and 47% were male. Individuals were grouped into categories of African descent (African), Asian, and Latin American. We found that the phenotype of 22q11.2 DS varied across population groups. Only two findings, congenital heart disease and learning problems, were found in greater than 50% of participants. When comparing the clinical features of 22q11.2 DS in each population, the proportion of individuals within each clinical category was statistically different except for learning problems and ear anomalies (P 0.05). However, when Africans were removed from analysis, six additional clinical features were found to be independent of ethnicity (P ≥ 0.05). Using facial analysis technology, we compared 156 Caucasians, Africans, Asians, and Latin American individuals with 22q11.2 DS with 156 age and gender matched controls and found that sensitivity and specificity were greater than 96% for all populations. In summary, we present the varied findings from global populations with 22q11.2 DS and demonstrate how facial analysis technology can assist clinicians in making accurate 22q11.2 DS diagnoses. This work will assist in earlier detection and in increasing recognition of 22q11.2 DS throughout the world.
- Published
- 2017
6. Matrix-assisted laser desorption/ionization imaging mass spectrometry for the spatial location of feline oviductal proteins
- Author
-
Apparicio, M, primary, Santos, VG, additional, Rocha, DFO, additional, Ferreira, CR, additional, Macente, BI, additional, Magalhães, GM, additional, Alves, AE, additional, Motheo, TF, additional, Padilha-Nakaghi, LC, additional, Pires-Buttler, EA, additional, Luvoni, GC, additional, Eberlin, MN, additional, and Vicente, WRR, additional
- Published
- 2016
- Full Text
- View/download PDF
7. Matrix-assisted laser desorption/ionization imaging mass spectrometry for the spatial location of feline oviductal proteins.
- Author
-
Apparicio, M, Santos, VG, Rocha, DFO, Ferreira, CR, Macente, BI, Magalhães, GM, Alves, AE, Motheo, TF, Padilha‐Nakaghi, LC, Pires‐Buttler, EA, Luvoni, GC, Eberlin, MN, and Vicente, WRR
- Subjects
MASS spectrometry ,EMBRYOS ,LIQUID nitrogen ,INDIUM tin oxide ,INFUNDIBULUM (Brain) ,THYMOSIN - Abstract
Contents With the purpose of identifying factors involved in early stages of embryo development in the domestic cat, matrix-assisted laser desorption/ionization imaging mass spectrometry ( MALDI- IMS) was used for the first time to describe the spatial localization of proteins in the oviducts of queens. Oviducts were obtained from two 2 and 4 years old cross-bred queens, divided into three segments, snap-frozen in liquid nitrogen and then stored at −80°C until use. Next, they were sectioned in a cryostat, fixed on ITO ( indium tin oxide) conductive glass slides for MALDI- IMS and serial sections were collected on microscope slides for histology. As confirmed by histology, MALDI- IMS was able to show contrasting protein distributions in the oviductal infundibulum, ampulla and isthmus. Mass spectra were characterized by abundant ions of m/ z 1,259, 4,939, 4,960 and 10,626, which have been tentatively attributed to keratin, thymosin β10, thymosin β4 and S100, respectively. Keratin and thymosins are involved in the biological response to tissue damage. S100 proteins are calcium-modulated proteins implicated in a variety of cellular activities, including cell differentiation and regulation of cell motility. These results suggest that protein composition differs between segments of the cat oviduct, which corresponds to morphological changes within these sections. Further functional studies could elucidate the effects of these proteins on feline reproductive physiology. [ABSTRACT FROM AUTHOR]
- Published
- 2017
- Full Text
- View/download PDF
8. MALDI-MS Lipid Profiles of Oocytes Recovered by Ovum Pickup fromBos indicusand 1/2indicus×tauruswith High vs Low Oocyte Yields
- Author
-
Silva-Santos, KC, primary, Ferreira, CR, additional, Santos, GMG, additional, Eberlin, MN, additional, Siloto, LS, additional, Rosa, CO, additional, Marcantonio, TN, additional, and Seneda, MM, additional
- Published
- 2014
- Full Text
- View/download PDF
9. Chemical Composition of Lipids Present in Cat and Dog Oocyte by Matrix-Assisted Desorption Ionization Mass Spectrometry (MALDI- MS)
- Author
-
Apparicio, M, primary, Ferreira, CR, additional, Tata, A, additional, Santos, VG, additional, Alves, AE, additional, Mostachio, GQ, additional, Pires-Butler, EA, additional, Motheo, TF, additional, Padilha, LC, additional, Pilau, EJ, additional, Gozzo, FC, additional, Eberlin, MN, additional, Lo Turco, EG, additional, Luvoni, GC, additional, and Vicente, WRR, additional
- Published
- 2012
- Full Text
- View/download PDF
10. Comparison of Synthetic Oviductal Fluid and G1/G2 Medium under Low-1 Oxygen Atmosphere on Embryo Production and Pregnancy Rates in Nelore (Bos indicus) Cattle
- Author
-
Sanches, BV, primary, Pontes, JHF, additional, Basso, AC, additional, Ferreira, CR, additional, Perecin, F, additional, and Seneda, MM, additional
- Published
- 2012
- Full Text
- View/download PDF
11. MALDI- MS Lipid Profiles of Oocytes Recovered by Ovum Pickup from Bos indicus and 1/2 indicus × taurus with High vs Low Oocyte Yields.
- Author
-
Silva‐Santos, KC, Ferreira, CR, Santos, GMG, Eberlin, MN, Siloto, LS, Rosa, CO, Marcantonio, TN, and Seneda, MM
- Subjects
- *
MATRIX-assisted laser desorption-ionization , *OVUM , *LIPID analysis , *CATTLE reproduction , *ZEBUS , *ULTRASONIC imaging , *COMPARATIVE studies - Abstract
Contents The aim of the present study was to compare the lipid profile in oocytes of indicus and 1/2 indicus × taurus cows with high and low antral follicle count ( AFC)/oocyte yields. After an OPU procedure (D0), antral follicles ≥3 mm were counted by ultrasonography (D4, 19, 34, 49, 64), and cows were assigned to groups with either high AFC (≥30 follicles; indicus, NH group; 1/2 indicus × taurus, AH group) or low AFC (≤15 antral follicles; indicus, NL group; 1/2 indicus × taurus, AL group). The lipid profiles of the oocytes were determined by MALDI- MS. For GI, GII and GIII oocytes, the indicus samples tend to cluster separately from the 1/2 indicus × taurus samples. The lipid species [ PC ( P-38:5) + H]+ and/or [ PC ( P-36:2) + Na]+, [ PC (38:2) + H]+, [ PC (38:5) + Na]+ and [ TAG (60:8) + NH4]+ were more abundant in indicus ( NH and NL groups) than 1/2 indicus × taurus. The higher lipid content in the indicus oocytes likely reflects differences in the rate of lipid metabolism and may contribute to oocyte competence and embryo development. [ABSTRACT FROM AUTHOR]
- Published
- 2014
- Full Text
- View/download PDF
12. Comparison of Synthetic Oviductal Fluid and G1/G2 Medium under Low-1 Oxygen Atmosphere on Embryo Production and Pregnancy Rates in Nelore (Bos indicus) Cattle.
- Author
-
Sanches, BV, Pontes, JHF, Basso, AC, Ferreira, CR, Perecin, F, and Seneda, MM
- Subjects
PREGNANCY in animals ,TUBAL pregnancy ,CATTLE embryos ,AMINO acids ,BLASTOCYST ,PHYSIOLOGICAL effects of oxygen ,CELL culture - Abstract
Contents In this work, we evaluated whether embryo development and pregnancy rates would be affected by culturing bovine Bos indicus embryos in Synthetic Oviductal Fluid with amino acids (SOFaa) or G1/G2 sequential medium under a low-oxygen atmosphere. Using Ovum Pick Up, we obtained 1,538 oocytes, divided into G1/G2 (n = 783) and SOFaa (n = 755). No difference was observed for blastocyst development among the groups (27.8% ± 14.6 and 34.9% ± 20.0 for G1/G2 and SOFaa respectively, p > 0.05). Transferring the embryos (n = 450) from both groups to recipients resulted in similar pregnancy rates for the G1/G2 (38.4% n = 78/203) compared to the SOFaa (39.7% n = 98/247). Our findings confirm that Bos indicus embryos cultured in SOFaa and G1/G2 under low-oxygen atmosphere have similar in vitro (blastocyst rate) and in vivo (pregnancy rate) developmental capacity. However, embryos cultured in G1/G2 medium have higher cleavage than those cultured in SOFaa medium. [ABSTRACT FROM AUTHOR]
- Published
- 2013
- Full Text
- View/download PDF
13. L'Homme-Bus
- Author
-
Ferreira, Cristina, Maugué, Ludovic, and Maulini, Sandrine
- Subjects
Psychiatrie ,privation de liberté à des fins d'assistance ,Internements administratifs ,Histoire Suisse - Abstract
Le 10 janvier 1986, un jeune homme est escorté par la police à l’hôpital psychiatrique de Cery situé dans la périphérie de Lausanne. Connu pour arpenter la ville au volant de charrettes transformées en trolleybus, l’Homme-bus se trouve au centre des attentions médiatiques. Explorant des sources archivistiques, journalistiques et littéraires, ce livre situe ce cas singulier dans un contexte marqué par des controverses intenses sur la psychiatrie (1960-1980). Droits de l’homme et lois d’internement, psychiatrie punitive en URSS, fermeture des asiles en Italie, activisme des associations militantes en Suisse romande : ce moment historique est reconstitué à partir des débats sur la privation de liberté à des fins d’assistance de l’Homme-bus.
- Published
- 2020
- Full Text
- View/download PDF
14. Germline mutations in a G protein identify signaling cross-talk in T cells.
- Author
-
Ham H, Jing H, Lamborn IT, Kober MM, Koval A, Berchiche YA, Anderson DE, Druey KM, Mandl JN, Isidor B, Ferreira CR, Freeman AF, Ganesan S, Karsak M, Mustillo PJ, Teo J, Zolkipli-Cunningham Z, Chatron N, Lecoquierre F, Oler AJ, Schmid JP, Kuhns DB, Xu X, Hauck F, Al-Herz W, Wagner M, Terhal PA, Muurinen M, Barlogis V, Cruz P, Danielson J, Stewart H, Loid P, Rading S, Keren B, Pfundt R, Zarember KA, Vill K, Potocki L, Olivier KN, Lesca G, Faivre L, Wong M, Puel A, Chou J, Tusseau M, Moutsopoulos NM, Matthews HF, Simons C, Taft RJ, Soldatos A, Masle-Farquhar E, Pittaluga S, Brink R, Fink DL, Kong HH, Kabat J, Kim WS, Bierhals T, Meguro K, Hsu AP, Gu J, Stoddard J, Banos-Pinero B, Slack M, Trivellin G, Mazel B, Soomann M, Li S, Watts VJ, Stratakis CA, Rodriguez-Quevedo MF, Bruel AL, Lipsanen-Nyman M, Saultier P, Jain R, Lehalle D, Torres D, Sullivan KE, Barbarot S, Neu A, Duffourd Y, Similuk M, McWalter K, Blanc P, Bézieau S, Jin T, Geha RS, Casanova JL, Makitie OM, Kubisch C, Edery P, Christodoulou J, Germain RN, Goodnow CC, Sakmar TP, Billadeau DD, Küry S, Katanaev VL, Zhang Y, Lenardo MJ, and Su HC
- Subjects
- Humans, Proto-Oncogene Proteins c-akt metabolism, Cell Movement, MAP Kinase Signaling System, Cell Proliferation, ras Proteins metabolism, ras Proteins genetics, Phosphatidylinositol 3-Kinases metabolism, Phosphatidylinositol 3-Kinases genetics, Germ-Line Mutation, T-Lymphocytes immunology, T-Lymphocytes metabolism, Signal Transduction, Receptors, Antigen, T-Cell metabolism
- Abstract
Humans with monogenic inborn errors responsible for extreme disease phenotypes can reveal essential physiological pathways. We investigated germline mutations in GNAI2 , which encodes G
αi2 , a key component in heterotrimeric G protein signal transduction usually thought to regulate adenylyl cyclase-mediated cyclic adenosine monophosphate (cAMP) production. Patients with activating Gαi2 mutations had clinical presentations that included impaired immunity. Mutant Gαi2 impaired cell migration and augmented responses to T cell receptor (TCR) stimulation. We found that mutant Gαi2 influenced TCR signaling by sequestering the guanosine triphosphatase (GTPase)-activating protein RASA2, thereby promoting RAS activation and increasing downstream extracellular signal-regulated kinase (ERK)/mitogen-activated protein kinase (MAPK) and phosphatidylinositol 3-kinase (PI3K)-AKT S6 signaling to drive cellular growth and proliferation.- Published
- 2024
- Full Text
- View/download PDF
15. Quantitative correlation of ENPP1 pathogenic variants with disease phenotype.
- Author
-
Ansh AJ, Stabach PR, Ciccone C, Cao W, De La Cruz EM, Sabbagh Y, Carpenter TO, Ferreira CR, and Braddock DT
- Subjects
- Humans, Female, Genetic Variation, Male, Mutation genetics, Pyrophosphatases genetics, Phosphoric Diester Hydrolases genetics, Phosphoric Diester Hydrolases metabolism, Phenotype
- Abstract
Ectonucleotide pyrophosphatase/phosphodiesterase 1 (ENPP1) codes for a type 2 transmembrane glycoprotein which hydrolyzes extracellular phosphoanhydrides into bio-active molecules that regulate, inter alia, ectopic mineralization, bone formation, vascular endothelial proliferation, and the innate immune response. The clinical phenotypes produced by ENPP1 deficiency are disparate, ranging from life-threatening arterial calcifications to cutaneous hypopigmentation. To investigate associations between disease phenotype and enzyme activity we quantified the enzyme velocities of 29 unique ENPP1 pathogenic variants in 41 patients enrolled in an NIH study along with 33 other variants reported in literature. We correlated the relative enzyme velocities with the presenting clinical diagnoses, performing the catalytic velocity measurements simultaneously in triplicate using a high-throughput assay to reduce experimental variation. We found that ENPP1 variants associated with autosomal dominant phenotypes reduced enzyme velocities by 50 % or more, whereas variants associated with insulin resistance had non-significant effects on enzyme velocity. In Cole disease the catalytic velocities of ENPP1 variants associated with AD forms trended to lower values than those associated with autosomal recessive forms - 8-32 % vs. 33 % of WT, respectively. Additionally, ENPP1 variants leading to life-threatening vascular calcifications in GACI patients had widely variable enzyme activities, ranging from no significant differences compared to WT to the complete abolishment of enzyme velocity. Finally, disease severity in GACI did not correlate with the mean enzyme velocity of the variants present in affected compound heterozygotes but did correlate with the more severely damaging variant. In summary, correlation of ENPP1 enzyme velocity with disease phenotypes demonstrate that enzyme velocities below 50 % of WT levels are likely to occur in the context of autosomal dominant disease (due to a monoallelic variant), and that disease severity in GACI infants correlates with the more severely damaging ENPP1 variant in compound heterozygotes, not the mean velocity of the pathogenic variants present., Competing Interests: Declaration of competing interest DTB is an inventor on patents owned by Yale University for therapeutics treating ENPP1 deficiency and is an equity holder and receives research and consulting support from Inozyme Pharma, Inc. TOC is an advisor and has received consulting support from Inozyme Pharma. Y.S. is an employee of Inozyme Pharma., (Copyright © 2024 Elsevier Inc. All rights reserved.)
- Published
- 2024
- Full Text
- View/download PDF
16. Commentary on: The use of burosumab to treat autosomal-recessive hypophosphatemic rickets type 2: rationale and a first clinical experience.
- Author
-
Rutsch F, Salusky IB, and Ferreira CR
- Published
- 2024
- Full Text
- View/download PDF
17. Relevance of the Iron Distribution in Natural Smectite Clays for the Thermal Stability of PMMA-Clay Nanocomposites.
- Author
-
Ferreira CR, Santilli CV, Briois V, and Pulcinelli SH
- Abstract
Polymer-clay nanocomposites have greater thermal stability compared to the pristine polymer matrix. This can be attributed to the physical barrier provided by the inclusion of 2D clay nanoparticles (especially of the smectite group), together with radical trapping related to the distribution of specific 3d atoms in the inorganic phase. To elucidate the relevance of the Fe
3+ distribution in this synergic effect, the iron atoms present in octahedral sheets of natural nontronite clay (Non, 5.6 wt % Fe) or in maghemite (M) nanoparticles (γ-Fe2 O3 ) were incorporated in a poly(methyl methacrylate) (PMMA) matrix. Na-laponite (Lap) clay was used to evaluate the contribution of the diffusion barrier effect to the increased thermal stability of a PMMA-Lap nanocomposite, as evidenced by the upshift of the thermogravimetric (TGA) curve compared to that for PMMA. The contribution of radical trapping to the thermal stability of the PMMA-Non nanocomposite was evidenced by a significant shift of the Fe K-edge rising edge position by -4.5 eV after iron reduction by heating in N2 , while similar treatment of pristine nontronite did not lead to a significant rising edge shift in the X-ray absorption spectra (XAS). This downshift demonstrated the reduction of Fe3+ to Fe0 , induced by the sequestration of radicals formed by PMMA depolymerization. Raman spectroscopy analysis evidenced the formation of graphitic char deposits above 400 °C, further improving the thermal stability of PMMA-Non by providing an additional physical barrier to mass transport. A fourth contribution of well-dispersed iron was the abstraction of carbon from the char by the iron carburization reaction, which hindered CO2 formation by oxidative coking. In contrast, no relevant contribution of graphitic layer deposition was observed for the PMMA-M-Lap nanocomposite, where its improved thermal stability was only due to the combined contributions of the gas diffusion barrier effect and radical trapping by iron atoms. The maghemite effectively captured the radicals confined by the clay sheets, resulting in significant stabilization of the nanocomposite, with a shift of the mass loss of the PMMA-M-Lap nanocomposite compared to PMMA-Lap., Competing Interests: The authors declare no competing financial interest., (© 2024 The Authors. Published by American Chemical Society.)- Published
- 2024
- Full Text
- View/download PDF
18. Inherited phosphate and pyrophosphate disorders: New insights and novel therapies changing the oral health landscape.
- Author
-
Foster BL, Boyce AM, Millán JL, Kramer K, Ferreira CR, Somerman MJ, and Wright JT
- Abstract
Background: Mineral metabolism is critical for proper development of hard tissues of the skeleton and dentition. The dentoalveolar complex includes the following 4 mineralized tissues: enamel, dentin, cementum, and alveolar bone. Developmental processes of these tissues are affected by inherited disorders that disrupt phosphate and pyrophosphate homeostasis, although manifestations are distinct from those in the skeleton., Types of Studies Reviewed: The authors discuss original data from experiments and comparative analyses and review articles describing effects of inherited phosphate and pyrophosphate disorders on dental tissues. A particular emphasis is placed on how new therapeutic approaches for these conditions may affect oral health and dental treatments of affected patients., Results: Disorders of phosphate and pyrophosphate metabolism can lead to reduced mineralization (hypomineralization) or inappropriate (ectopic) calcification of soft tissues. Disruptions in phosphate levels in X-linked hypophosphatemia and hyperphosphatemic familial tumoral calcinosis and disruptions in pyrophosphate levels in hypophosphatasia and generalized arterial calcification of infancy contribute to dental mineralization defects. Traditionally, there have been few options to ameliorate dental health problems arising from these conditions. New antibody and enzyme replacement therapies bring possibilities to improve oral health in affected patients., Practical Implications: Research over the past 2 decades has exponentially expanded the understanding of mineral metabolism, and has led to novel treatments for mineralization disorders. Newly implemented and emerging therapeutic strategies affect the dentoalveolar complex and interact with aspects of oral health care that must be considered for dental treatment, clinical trial design, and coordination of multidisciplinary care teams., Competing Interests: Disclosures None of the authors reported any disclosures., (Copyright © 2024 American Dental Association. Published by Elsevier Inc. All rights reserved.)
- Published
- 2024
- Full Text
- View/download PDF
19. Ocular findings in Jansen metaphyseal chondrodysplasia.
- Author
-
Obiezu F, Magone De Quadros Costa MT, Huryn LA, Pan K, Almpani K, Ninan A, Roszko KL, Weinstein LS, Gafni RI, Ferreira CR, Lee J, Collins MT, and Jha S
- Abstract
Jansen metaphyseal chondrodysplasia (JMC) is an ultra-rare disorder caused by germline heterozygous PTHR1 variants resulting in constitutive activation of parathyroid hormone type 1 receptor. A description of ocular manifestations of the disease is lacking. Six patients with JMC underwent a detailed ophthalmic evaluation, spectral-domain optical coherence tomography (OCT), visual field testing, and craniofacial CT scans. Five of 6 patients had good visual acuity. All patients had widely spaced eyes; 5/6 had downslanted palpebral fissures. One patient had proptosis, and another had bilateral ptosis. Two patients had incomplete closure of the eyelids (lagophthalmos), one had a history of progressive right facial nerve palsy with profuse epiphora, while the second had advanced optic nerve atrophy with corresponding retinal nerve fiber layer (RNFL) thinning on OCT and significant bilateral optic canal narrowing on CT scan. Additionally, this patient also had central visual field defects and abnormal color vision. A third patient had normal visual acuity, subtle temporal pallor of the optic nerve head, normal average RNFL, but decreased temporal RNFL and retinal ganglion cell layer analysis (GCA) on OCT. GCA was decreased in 4/6 patients indicating a subclinical optic nerve atrophic process. None of the patients had glaucoma or high myopia. These data represent the first comprehensive report of ophthalmic findings in JMC. Patients with JMC have significant eye findings associated with optic canal narrowing due to extensive skull base dysplastic bone overgrowth that appear to be more prevalent and pronounced with age. Progressive optic neuropathy from optic canal narrowing may be a feature of JMC, and OCT GCA can serve as a useful biomarker for progression in the setting of optic canal narrowing. We suggest that patients with JMC should undergo regular ophthalmic examination including color vision, OCT, visual field testing, orbital, and craniofacial imaging., Competing Interests: No conflicting relationship exists for any author., (Published by Oxford University Press on behalf of the American Society for Bone and Mineral Research 2024.)
- Published
- 2024
- Full Text
- View/download PDF
20. EXTENSIVE SUBRETINAL FIBROSIS ASSOCIATED WITH PSEUDOXANTHOMA ELASTICUM.
- Author
-
Oyeniran E, Wiley H, Bellur S, Sen HN, Ferreira CR, Chew EY, and Kodati S
- Subjects
- Humans, Female, Middle Aged, Retinal Diseases etiology, Retinal Diseases diagnosis, Fluorescein Angiography, Tomography, Optical Coherence, Male, Retina pathology, Pseudoxanthoma Elasticum complications, Pseudoxanthoma Elasticum diagnosis, Fibrosis
- Abstract
Purpose: The purpose of this study was to report an unusual case of pseudoxanthoma elasticum presenting with an inflammatory phenotype associated with atypical and rapidly progressive subretinal fibrosis., Methods: This was an observational case report., Results: A patient with a history of pseudoxanthoma elasticum presented with rapidly progressive subretinal fibrosis, particularly in the left eye, over the course of one year. The patient was noted at presentation to have intraocular inflammation, outer retinal attenuation, multifocal choroiditis-like lesions, and intraretinal fluid (in the absence of obvious clinical or angiographic signs of exudative choroidal neovascular membranes). An ocular inflammatory phenotype was diagnosed, and the patient was treated with a combination of local steroids and systemic corticosteroids/immunomodulatory agents. After initiation of these agents, the patient demonstrated functional and structural improvement, with partial outer retinal reconstitution, decreased intraretinal fluid, and lack of further progression of subretinal fibrosis., Conclusion: This report describes an inflammatory phenotype of pseudoxanthoma elasticum associated with severe and atypical subretinal fibrosis. This case expands upon the currently known spectrum of inflammatory phenotypes associated with pseudoxanthoma elasticum. Treatment with corticosteroids or immunomodulatory treatment should be considered in similar cases.
- Published
- 2024
- Full Text
- View/download PDF
21. Impact of Extraction Methods and Transportation Conditions on Lipid Profiles of Bovine Oocytes.
- Author
-
de Lima CB, Milazzotto MP, Vireque AA, Joaquim DC, Sobreira TJP, and Ferreira CR
- Subjects
- Animals, Cattle, Female, Lipidomics methods, Specimen Handling methods, Lipid Metabolism physiology, Oocytes metabolism, Lipids analysis, Lipids isolation & purification
- Abstract
Lipids play numerous pivotal physiological roles in mammalian reproduction, being indispensable for oocyte competence acquisition and post-fertilization embryonic development. Profiling lipids in minute samples, such as oocytes, presents challenges but has been accomplished through mass spectrometry technologies like Multiple Reaction Monitoring (MRM) profiling. With the dual objectives of simplifying workflow and examining the influence of preanalytical conditions, we assessed whether transportation at room temperature affects the lipid profile of bovine oocytes. To this end, samples were prepared using either monophasic (methanol only) or biphasic liquid extraction protocols (Bligh & Dyer method) and transported either on dry ice or at room temperature inside sealed-vacuum packages to prevent lipid oxidation. Subsequently, employing a comprehensive method, we screened a list of 316 MRMs from 10 different lipid subclasses in oocyte lipid extracts. Principal Component Analysis (PCA) revealed similar lipid profiles concerning temperature during transportation, whereas clear differentiation among samples was observed based on the lipid extraction method. Univariate analysis indicated that the one-phase methanol extraction resulted in higher relative abundances of phospholipids, except for phosphatidylserines. Conversely, the Bligh & Dyer extraction favored the detection of neutral intracellular lipids (triacylglycerols, free fatty acids, cholesteryl esters, and acyl-carnitines). Consequently, lipid recovery was directly correlated with the polarity of lipid class and the extraction method. Regarding transportation temperature, phosphatidylethanolamine, triacylglycerol, and free fatty acids exhibited lower abundances when samples were transported at room temperature. Based on multivariate and univariate analyses, we conclude that if samples undergo the same lipid extraction protocol and are transported in the same batch at room temperature inside vacuum-sealed bags, it is feasible to analyze lipid extracts of bovine oocytes and still obtain informative lipid profiling results., (© 2024. The Author(s), under exclusive licence to Society for Reproductive Investigation.)
- Published
- 2024
- Full Text
- View/download PDF
22. Implementation of multiomic mass spectrometry approaches for the evaluation of human health following environmental exposure.
- Author
-
Ferreira CR, Lima Gomes PCF, Robison KM, Cooper BR, and Shannahan JH
- Subjects
- Humans, Proteomics methods, Biomarkers, Genomics methods, Mass Spectrometry methods, Environmental Exposure analysis, Metabolomics methods
- Abstract
Omics analyses collectively refer to the possibility of profiling genetic variants, RNA, epigenetic markers, proteins, lipids, and metabolites. The most common analytical approaches used for detecting molecules present within biofluids related to metabolism are vibrational spectroscopy techniques, represented by infrared, Raman, and nuclear magnetic resonance (NMR) spectroscopies and mass spectrometry (MS). Omics-based assessments utilizing MS are rapidly expanding and being applied to various scientific disciplines and clinical settings. Most of the omics instruments are operated by specialists in dedicated laboratories; however, the development of miniature portable omics has made the technology more available to users for field applications. Variations in molecular information gained from omics approaches are useful for evaluating human health following environmental exposure and the development and progression of numerous diseases. As MS technology develops so do statistical and machine learning methods for the detection of molecular deviations from personalized metabolism, which are correlated to altered health conditions, and they are intended to provide a multi-disciplinary overview for researchers interested in adding multiomic analysis to their current efforts. This includes an introduction to mass spectrometry-based omics technologies, current state-of-the-art capabilities and their respective strengths and limitations for surveying molecular information. Furthermore, we describe how knowledge gained from these assessments can be applied to personalized medicine and diagnostic strategies.
- Published
- 2024
- Full Text
- View/download PDF
23. Pilot study to evaluate the safety and effectiveness of etidronate treatment for arterial calcification due to deficiency of CD73 (ACDC).
- Author
-
Ferrante EA, Cudrici CD, Rashidi M, Fu YP, Huffstutler R, Carney K, Chen MY, St Hilaire C, Smith K, Bagheri H, Katz JD, Ferreira CR, Gahl WA, Boehm M, and Brofferio A
- Subjects
- Humans, Pilot Projects, Male, Female, Middle Aged, Treatment Outcome, Time Factors, Ankle Brachial Index, Adult, Bone Density Conservation Agents therapeutic use, Bone Density Conservation Agents adverse effects, Disease Progression, Peripheral Arterial Disease drug therapy, Peripheral Arterial Disease diagnosis, Peripheral Arterial Disease physiopathology, Aged, Lower Extremity blood supply, Computed Tomography Angiography, Genetic Predisposition to Disease, Regional Blood Flow, Vascular Calcification drug therapy, Vascular Calcification diagnostic imaging, Etidronic Acid therapeutic use, Etidronic Acid adverse effects, 5'-Nucleotidase genetics, 5'-Nucleotidase deficiency, GPI-Linked Proteins blood
- Abstract
Background: Arterial calcification due to deficiency of CD73 (ACDC; OMIM 211800) is a rare genetic disease resulting in calcium deposits in arteries and small joints causing claudication, resting pain, severe joint pain, and deformities. Currently, there are no standard treatments for ACDC. Our previous work identified etidronate as a potential targeted ACDC treatment, using in vitro and in vivo disease models with patient-derived cells. In this study, we test the safety and effectiveness of etidronate in attenuating the progression of lower-extremity arterial calcification and vascular blood flow based on the computed tomography (CT) calcium score and ankle-brachial index (ABI)., Methods: Seven adult patients with a confirmed genetic diagnosis of ACDC were enrolled in an open-label, nonrandomized, single-arm pilot study for etidronate treatment. They took etidronate daily for 14 days every 3 months and were examined at the NIH Clinical Center bi-annually for 3 years. They received a baseline evaluation as well as yearly follow up after treatment. Study visits included imaging studies, exercise tolerance tests with ABIs, clinical blood and urine testing, and full dental exams., Results: Etidronate treatment appeared to have slowed the progression of further vascular calcification in lower extremities as measured by CT but did not have an effect in reversing vascular and/or periarticular joint calcifications in our small ACDC cohort., Conclusions: Etidronate was found to be safe and well tolerated by our patients and, despite the small sample size, appeared to show an effect in slowing the progression of calcification in our ACDC patient cohort. (ClinicalTrials.gov Identifier NCT01585402) ., Competing Interests: Declaration of conflicting interestsThe authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
- Published
- 2024
- Full Text
- View/download PDF
24. CIAO1 and MMS19 deficiency: A lethal neurodegenerative phenotype caused by cytosolic Fe-S cluster protein assembly disorders.
- Author
-
van Karnebeek CDM, Tarailo-Graovac M, Leen R, Meinsma R, Correard S, Jansen-Meijer J, Prykhozhij SV, Pena IA, Ban K, Schock S, Saxena V, Pras-Raves ML, Drögemöller BI, Grootemaat AE, van der Wel NN, Dobritzsch D, Roseboom W, Schomakers BV, Jaspers YRJ, Zoetekouw L, Roelofsen J, Ferreira CR, van der Lee R, Ross CJ, Kochan J, McIntyre RL, van Klinken JB, van Weeghel M, Kramer G, Weschke B, Labrune P, Willemsen MA, Riva D, Garavaglia B, Moeschler JB, Filiano JJ, Ekker M, Berman JN, Dyment D, Vaz FM, Wasserman WW, Houtkooper RH, and van Kuilenburg ABP
- Subjects
- Animals, Humans, Male, Female, Phenotype, Fibroblasts metabolism, Fibroblasts pathology, Cytosol metabolism, Neurodegenerative Diseases genetics, Neurodegenerative Diseases metabolism, Neurodegenerative Diseases pathology, Microcephaly genetics, Microcephaly pathology, Infant, Metallochaperones, Zebrafish, Iron-Sulfur Proteins genetics, Iron-Sulfur Proteins metabolism
- Abstract
Purpose: The functionality of many cellular proteins depends on cofactors; yet, they have only been implicated in a minority of Mendelian diseases. Here, we describe the first 2 inherited disorders of the cytosolic iron-sulfur protein assembly system., Methods: Genetic testing via genome sequencing was applied to identify the underlying disease cause in 3 patients with microcephaly, congenital brain malformations, progressive developmental and neurologic impairments, recurrent infections, and a fatal outcome. Studies in patient-derived skin fibroblasts and zebrafish models were performed to investigate the biochemical and cellular consequences., Results: Metabolic analysis showed elevated uracil and thymine levels in body fluids but no pathogenic variants in DPYD, encoding dihydropyrimidine dehydrogenase. Genome sequencing identified compound heterozygosity in 2 patients for missense variants in CIAO1, encoding cytosolic iron-sulfur assembly component 1, and homozygosity for an in-frame 3-nucleotide deletion in MMS19, encoding the MMS19 homolog, cytosolic iron-sulfur assembly component, in the third patient. Profound alterations in the proteome, metabolome, and lipidome were observed in patient-derived fibroblasts. We confirmed the detrimental effect of deficiencies in CIAO1 and MMS19 in zebrafish models., Conclusion: A general failure of cytosolic and nuclear iron-sulfur protein maturation caused pleiotropic effects. The critical function of the cytosolic iron-sulfur protein assembly machinery for antiviral host defense may well explain the recurrent severe infections occurring in our patients., Competing Interests: Conflict of Interest The authors declare no conflicts of interest., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)
- Published
- 2024
- Full Text
- View/download PDF
25. Clinical and biochemical footprints of congenital disorders of glycosylation: Proposed nosology.
- Author
-
Ng BG, Freeze HH, Himmelreich N, Blau N, and Ferreira CR
- Subjects
- Humans, Glycosylation, Congenital Disorders of Glycosylation genetics, Congenital Disorders of Glycosylation metabolism, Congenital Disorders of Glycosylation diagnosis, Congenital Disorders of Glycosylation classification, Congenital Disorders of Glycosylation pathology
- Abstract
We have identified 200 congenital disorders of glycosylation (CDG) caused by 189 different gene defects and have proposed a classification system for CDG based on the mode of action. This classification includes 8 categories: 1. Disorders of monosaccharide synthesis and interconversion, 2. Disorders of nucleotide sugar synthesis and transport, 3. Disorders of N-linked protein glycosylation, 4. Disorders of O-linked protein glycosylation, 5. Disorders of lipid glycosylation, 6. Disorders of vesicular trafficking, 7. Disorders of multiple glycosylation pathways and 8. Disorders of glycoprotein/glycan degradation. Additionally, using information from IEMbase, we have described the clinical involvement of 19 organs and systems, as well as essential laboratory investigations for each type of CDG. Neurological, dysmorphic, skeletal, and ocular manifestations were the most prevalent, occurring in 81%, 56%, 53%, and 46% of CDG, respectively. This was followed by digestive, cardiovascular, dermatological, endocrine, and hematological symptoms (17-34%). Immunological, genitourinary, respiratory, psychiatric, and renal symptoms were less frequently reported (8-12%), with hair and dental abnormalities present in only 4-7% of CDG. The information provided in this study, including our proposed classification system for CDG, may be beneficial for healthcare providers caring for individuals with metabolic conditions associated with CDG., Competing Interests: Declaration of competing interest None of the authors have any COIs., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)
- Published
- 2024
- Full Text
- View/download PDF
26. ENPP1 in Blood and Bone: Skeletal and Soft Tissue Diseases Induced by ENPP1 Deficiency.
- Author
-
Ferreira CR, Carpenter TO, and Braddock DT
- Subjects
- Adult, Humans, Middle Aged, Pyrophosphatases genetics, Pyrophosphatases metabolism, Phosphoric Diester Hydrolases genetics, Phosphoric Diester Hydrolases metabolism, Vascular Calcification drug therapy, Vascular Calcification genetics
- Abstract
The enzyme ectonucleotide pyrophosphatase/phosphodiesterase 1 ( ENPP1 ) codes for a type 2 transmembrane glycoprotein that hydrolyzes extracellular ATP to generate pyrophosphate (PP
i ) and adenosine monophosphate, thereby contributing to downstream purinergic signaling pathways. The clinical phenotypes induced by ENPP1 deficiency are seemingly contradictory and include early-onset osteoporosis in middle-aged adults and life-threatening vascular calcifications in the large arteries of infants with generalized arterial calcification of infancy. The progressive overmineralization of soft tissue and concurrent undermineralization of skeleton also occur in the general medical population, where it is referred to as paradoxical mineralization to highlight the confusing pathophysiology. This review summarizes the clinical presentation and pathophysiology of paradoxical mineralization unveiled by ENPP1 deficiency and the bench-to-bedside development of a novel ENPP1 biologics designed to treat mineralization disorders in the rare disease and general medical population.- Published
- 2024
- Full Text
- View/download PDF
27. Rumen-protected methionine supplementation alters lipid profile of preimplantation embryo and endometrial tissue of Holstein cows.
- Author
-
Stella SL, Guadagnin AR, Velasco-Acosta DA, Ferreira CR, Rubessa M, Wheeler MB, Luchini D, and Cardoso FC
- Abstract
Our objective is to evaluate the effects of feeding rumen-protected Met (RPM) throughout the transition period and early lactation on the lipid profile of the preimplantation embryos and the endometrial tissue of Holstein cows. Treatments consisted of feeding a total mixed ration with top-dressed RPM (Smartamine
® M, Adisseo, Alpharetta, GA, United States; MET; n = 11; RPM at a rate of 0.08% of DM: Lys:Met = 2.8:1) or not (CON; n = 9, Lys:Met = 3.5:1). Endometrial biopsies were performed at 15, 30, and 73 days in milk (DIM). Prior to the endometrial biopsy at 73 DIM, preimplantation embryos were harvested via flushing. Endometrial lipid profiles were analyzed using multiple reaction monitoring-profiling and lipid profiles of embryos were acquired using matrix assisted laser desorption/ionization mass spectrometry. Relative intensities levels were used for principal component analysis. Embryos from cows in MET had greater concentration of polyunsaturated lipids than embryos from cows in CON. The endometrial tissue samples from cows in MET had lesser concentrations of unsaturated and monounsaturated lipids at 15 DIM, and greater concentration of saturated, unsaturated (specifically diacylglycerol), and monounsaturated (primarily ceramides) lipids at 30 DIM than the endometrial tissue samples from cows in CON. In conclusion, feeding RPM during the transition period and early lactation altered specific lipid classes and lipid unsaturation level of preimplantation embryos and endometrial tissue., Competing Interests: DL from Adisseo had input in the experimental design and had no influence in performing the experiment and analyzing the data. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Stella, Guadagnin, Velasco-Acosta, Ferreira, Rubessa, Wheeler, Luchini and Cardoso.)- Published
- 2024
- Full Text
- View/download PDF
28. Effect of lipid extraction and room temperature transportation of bovine oocytes determined by MRM profiling.
- Author
-
de Lima CB, Milazzotto MP, Vireque AA, Joaquim DC, Sobreira TJP, and Ferreira CR
- Abstract
Lipids play many important physiological roles in mammalian reproduction, being essential for the acquisition of oocyte competence and post-fertilization embryonic development. Lipid profiling in samples of minute size, such as oocytes, is challenging but has been achieved by mass spectrometry technologies such as multiple reaction monitoring (MRM) profiling. With the goals of further simplifying sample workflow and investigating the influence of pre-analytical conditions, we have evaluated how different extraction methods and transportation of lipid extracts in vacuum and at room temperature impacted the lipid profile of bovine oocytes. Using a comprehensive method, 316 MRMs associated with lipids of 10 different classes were screened in oocyte lipid extracts prepared by 2 extraction methods (one-step methanol addition or Bligh and Dyer) and transporting them in dry ice or at room temperature inside vacuum packages. No changes in the multivariate analysis (PCA) were noticeable due to transportation temperature, while lipid profiles were more affected by the lipid extraction protocol. Sample extraction using pure methanol favored the detection of phospholipids uniformly, while Bligh and Dyer favored the detection of neutral intracellular lipids. Triacylglycerol lipids and free fatty acids yielded decreased abundances when samples were transported at room temperature. We conclude that if samples are submitted to the same lipid extraction protocol and same transportation batch at room temperature coupled with vacuum conditions it is possible to analyze lipid extracts of bovine oocytes and still obtain informative lipid profiling results., Competing Interests: DECLARATIONS CONFLICT OF INTERESTS The authors have no conflict of interest to disclose.
- Published
- 2023
- Full Text
- View/download PDF
29. Clinical and biochemical footprints of inherited metabolic disease. XVI. Hematological abnormalities.
- Author
-
Dunlea E, Crushell E, Cotter M, Blau N, and Ferreira CR
- Subjects
- Humans, Metabolic Diseases genetics, Anemia
- Abstract
Many classical inherited metabolic diseases (IMDs) are associated with significant hematological complications such as anemia or thrombosis. While these may not be the prominent presenting feature of these conditions, management of these issues is important for optimal outcomes in people with IMDs. Some disorders that are included in the nosology of inherited metabolic disorders, such as inherited disorders of red cell energy metabolism, have purely hematological features, and have typically been cared for by a hematologist. In the 16th issue of the Footprints series, we identified 265 IMDs associated with hematological abnormalities. We review the major hematological manifestations of IMDs, suggest further investigation of hematological findings, and discuss treatment options available for specific hematological complications of IMDs., Competing Interests: Declaration of Competing Interest None., (Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)
- Published
- 2023
- Full Text
- View/download PDF
30. Imipramine Treatment Alters Sphingomyelin, Cholesterol, and Glycerophospholipid Metabolism in Isolated Macrophage Lysosomes.
- Author
-
Albright JM, Sydor MJ, Shannahan J, Ferreira CR, and Holian A
- Subjects
- Humans, Cholesterol metabolism, Macrophages metabolism, Lysosomes metabolism, Inflammation metabolism, Lipid Metabolism, Glycerophospholipids metabolism, Sphingomyelins metabolism, Imipramine pharmacology
- Abstract
Lysosomes are degradative organelles that facilitate the removal and recycling of potentially cytotoxic materials and mediate a variety of other cellular processes, such as nutrient sensing, intracellular signaling, and lipid metabolism. Due to these central roles, lysosome dysfunction can lead to deleterious outcomes, including the accumulation of cytotoxic material, inflammation, and cell death. We previously reported that cationic amphiphilic drugs, such as imipramine, alter pH and lipid metabolism within macrophage lysosomes. Therefore, the ability for imipramine to induce changes to the lipid content of isolated macrophage lysosomes was investigated, focusing on sphingomyelin, cholesterol, and glycerophospholipid metabolism as these lipid classes have important roles in inflammation and disease. The lysosomes were isolated from control and imipramine-treated macrophages using density gradient ultracentrifugation, and mass spectrometry was used to measure the changes in their lipid composition. An unsupervised hierarchical cluster analysis revealed a clear differentiation between the imipramine-treated and control lysosomes. There was a significant overall increase in the abundance of specific lipids mostly composed of cholesterol esters, sphingomyelins, and phosphatidylcholines, while lysophosphatidylcholines and ceramides were overall decreased. These results support the conclusion that imipramine's ability to change the lysosomal pH inhibits multiple pH-sensitive enzymes in macrophage lysosomes.
- Published
- 2023
- Full Text
- View/download PDF
31. Deep phenotyping of the neuroimaging and skeletal features in KBG syndrome: a study of 53 patients and review of the literature.
- Author
-
Peluso F, Caraffi SG, Contrò G, Valeri L, Napoli M, Carboni G, Seth A, Zuntini R, Coccia E, Astrea G, Bisgaard AM, Ivanovski I, Maitz S, Brischoux-Boucher E, Carter MT, Dentici ML, Devriendt K, Bellini M, Digilio MC, Doja A, Dyment DA, Farholt S, Ferreira CR, Wolfe LA, Gahl WA, Gnazzo M, Goel H, Grønborg SW, Hammer T, Iughetti L, Kleefstra T, Koolen DA, Lepri FR, Lemire G, Louro P, McCullagh G, Madeo SF, Milone A, Milone R, Nielsen JEK, Novelli A, Ockeloen CW, Pascarella R, Pippucci T, Ricca I, Robertson SP, Sawyer S, Falkenberg Smeland M, Stegmann S, Stumpel CT, Goel A, Taylor JM, Barbuti D, Soresina A, Bedeschi MF, Battini R, Cavalli A, Fusco C, Iascone M, Van Maldergem L, Venkateswaran S, Zuffardi O, Vergano S, Garavelli L, and Bayat A
- Subjects
- Humans, Facies, Phenotype, Repressor Proteins genetics, Transcription Factors, Neuroimaging, Intellectual Disability diagnosis, Intellectual Disability genetics, Abnormalities, Multiple diagnosis, Abnormalities, Multiple genetics, Bone Diseases, Developmental diagnostic imaging, Bone Diseases, Developmental genetics, Tooth Abnormalities diagnostic imaging, Tooth Abnormalities genetics
- Abstract
Background: KBG syndrome is caused by haploinsufficiency of ANKRD11 and is characterised by macrodontia of upper central incisors, distinctive facial features, short stature, skeletal anomalies, developmental delay, brain malformations and seizures. The central nervous system (CNS) and skeletal features remain poorly defined., Methods: CNS and/or skeletal imaging were collected from molecularly confirmed individuals with KBG syndrome through an international network. We evaluated the original imaging and compared our results with data in the literature., Results: We identified 53 individuals, 44 with CNS and 40 with skeletal imaging. Common CNS findings included incomplete hippocampal inversion and posterior fossa malformations; these were significantly more common than previously reported (63.4% and 65.9% vs 1.1% and 24.7%, respectively). Additional features included patulous internal auditory canal, never described before in KBG syndrome, and the recurrence of ventriculomegaly, encephalic cysts, empty sella and low-lying conus medullaris. We found no correlation between these structural anomalies and epilepsy or intellectual disability. Prevalent skeletal findings comprised abnormalities of the spine including scoliosis, coccygeal anomalies and cervical ribs. Hand X-rays revealed frequent abnormalities of carpal bone morphology and maturation, including a greater delay in ossification compared with metacarpal/phalanx bones., Conclusion: This cohort enabled us to describe the prevalence of very heterogeneous neuroradiological and skeletal anomalies in KBG syndrome. Knowledge of the spectrum of such anomalies will aid diagnostic accuracy, improve patient care and provide a reference for future research on the effects of ANKRD11 variants in skeletal and brain development., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)
- Published
- 2023
- Full Text
- View/download PDF
32. Annexin A5 stabilizes matrix vesicle-biomimetic lipid membranes: unravelling a new role of annexins in calcification.
- Author
-
Ferreira CR, Cruz MAE, Bolean M, Andrilli LHDS, Millan JL, Ramos AP, Bottini M, and Ciancaglini P
- Subjects
- Annexin A5 chemistry, Annexin A5 metabolism, Phosphatidylserines chemistry, Phosphatidylserines metabolism, Biomimetics, Proteomics, Calcium metabolism, Annexins, Liposomes
- Abstract
Matrix vesicles are a special class of extracellular vesicles thought to actively contribute to both physiologic and pathologic mineralization. Proteomic studies have shown that matrix vesicles possess high amounts of annexin A5, suggesting that the protein might have multiple roles at the sites of calcification. Currently, Annexin A5 is thought to promote the nucleation of apatitic minerals close to the inner leaflet of the matrix vesicles' membrane enriched in phosphatidylserine and Ca
2+ . Herein, we aimed at unravelling a possible additional role of annexin A5 by investigating the ability of annexin A5 to adsorb on matrix-vesicle biomimetic liposomes and Langmuir monolayers made of dipalmitoylphosphatidylserine (DPPS) and dipalmitoylphosphatidylcholine (DPPC) in the absence and in the presence of Ca2+ . Differential scanning calorimetry and dynamic light scattering measurements showed that Ca2+ at concentrations in the 0.5-2.0 mM range induced the aggregation of liposomes probably due to the formation of DPPS-enriched domains. However, annexin A5 avoided the aggregation of liposomes at Ca2+ concentrations lower than 1.0 mM. Surface pressure versus surface area isotherms showed that the adsorption of annexin A5 on the monolayers made of a mixture of DPPC and DPPS led to a reduction in the area of excess compared to the theoretical values, which confirmed that the protein favored attractive interactions among the membrane lipids. The stabilization of the lipid membranes by annexin A5 was also validated by recording the changes with time of the surface pressure. Finally, fluorescence microscopy images of lipid monolayers revealed the formation of spherical lipid-condensed domains that became unshaped and larger in the presence of annexin A5. Our data support the model that annexin A5 in matrix vesicles is recruited at the membrane sites enriched in phosphatidylserine and Ca2+ not only to contribute to the intraluminal mineral formation but also to stabilize the vesicles' membrane and prevent its premature rupture., (© 2023. The Author(s).)- Published
- 2023
- Full Text
- View/download PDF
33. Clinical and biochemical footprints of inherited metabolic diseases. XIII. Respiratory manifestations.
- Author
-
Rossi A, Basilicata S, Borrelli M, Ferreira CR, Blau N, and Santamaria F
- Subjects
- Humans, Diagnosis, Differential, Metabolic Diseases complications, Respiratory Tract Diseases etiology
- Abstract
At any age, respiratory manifestations are a major cause of increased morbidity and mortality of inherited metabolic diseases (IMDs). Type and severity are extremely variable, this depending on the type of the underlying disorder. Symptoms and signs originating from upper or lower airways and/or thoracic wall and/or respiratory muscles involvement can occur either at presentation or in the late clinical course. Acute respiratory symptoms can trigger metabolic decompensation which, in turn, makes airway symptoms worse, creating a vicious circle. We have identified 181 IMDs associated with various types of respiratory symptoms which were classified into seven groups according to the type of clinical manifestations affecting the respiratory system: (i) respiratory failure, (ii) restrictive lung disease, (iii) interstitial lung disease, (iv) lower airway disease, (v) upper airway obstruction, (vi) apnea, and (vii) other. We also provided a list of investigations to be performed based on the respiratory phenotypes and indicated the therapeutic strategies currently available for IMD-associated airway disease. This represents the thirteenth issue in a series of educational summaries providing a comprehensive and updated list of metabolic differential diagnoses according to system involvement., Competing Interests: Declaration of Competing Interest None., (Copyright © 2023. Published by Elsevier Inc.)
- Published
- 2023
- Full Text
- View/download PDF
34. Clinical and biochemical footprints of inherited metabolic diseases. XV. Epilepsies.
- Author
-
Latzer IT, Blau N, Ferreira CR, and Pearl PL
- Subjects
- Infant, Newborn, Humans, Seizures complications, Electroencephalography, Spasms, Infantile diagnosis, Epilepsy diagnosis, Epilepsy genetics, Epilepsy complications, Metabolic Diseases complications, Epilepsies, Myoclonic
- Abstract
We provide a comprehensive overview of inherited metabolic disorders (IMDs) in which epilepsy is a prominent manifestation. Our unique database search has identified 256 IMDs associated with various types of epilepsies, which we classified according to the classic pathophysiology-based classification of IMDs, and according to selected seizure-related factors (neonatal seizures, infantile spasms, myoclonic seizures, and characteristic EEG patterns) and treatability for the underlying metabolic defect. Our findings indicate that inherited metabolic epilepsies are more likely to present in the neonatal period, with infantile spasms or myoclonic seizures. Additionally, the ∼20% of treatable inherited metabolic epilepsies found by our search were mainly associated with the IMD groups of "cofactor and mineral metabolism" and "Intermediary nutrient metabolism." The information provided by this study, including a comprehensive list of IMDs with epilepsy stratified according to age of onset, and seizure type and characteristics, along with an overview of the key clinical features and proposed diagnostic and therapeutic approaches, may benefit any epileptologist and healthcare provider caring for individuals with metabolic conditions., Competing Interests: Declaration of Competing Interest None, (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)
- Published
- 2023
- Full Text
- View/download PDF
35. Clinical and biochemical footprints of inherited metabolic diseases. XIV. Metabolic kidney diseases.
- Author
-
Schumann A, Schultheiss UT, Ferreira CR, and Blau N
- Subjects
- Humans, Kidney, Metabolism, Inborn Errors diagnosis, Metabolism, Inborn Errors genetics, Metabolic Diseases genetics, Metabolic Diseases diagnosis, Kidney Diseases, Hypertension
- Abstract
Kidney disease is a global health burden with high morbidity and mortality. Causes of kidney disease are numerous, extending from common disease groups like diabetes and arterial hypertension to rare conditions including inherited metabolic diseases (IMDs). Given its unique anatomy and function, the kidney is a target organ in about 10% of known IMDs, emphasizing the relevant contribution of IMDs to kidney disease. The pattern of injury affects all segments of the nephron including glomerular disease, proximal and distal tubular damage, kidney cyst formation, built-up of nephrocalcinosis and stones as well as severe malformations. We revised and updated the list of known metabolic etiologies associated with kidney involvement and found 190 relevant IMDs. This represents the 14th of a series of educational articles providing a comprehensive and revised list of metabolic differential diagnoses according to system involvement., Competing Interests: Declaration of Competing Interest None., (Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)
- Published
- 2023
- Full Text
- View/download PDF
36. Main autopsy findings of visceral involvement by fatal mpox in patients with AIDS: necrotising nodular pneumonia, nodular ulcerative colitis, and diffuse vasculopathy.
- Author
-
Duarte-Neto AN, Gonçalves AM, Eliodoro RHA, Martins WD, Claro IM, Valença IN, Paes VR, Teixeira R, Sztajnbok J, França E Silva ILA, Leite LAF, Malaque CMS, Borges LMS, Gonzalez MP, Barra LAC, Junior LCP, Mello CF, Queiroz W, Atomya AN, Fernezlian SM, Alves VAF, Leite KRM, Ferreira CR, Saldiva PHN, Mauad T, da Silva LFF, Faria NR, Mendes Corrêa MCJ, Sabino EC, Sotto MN, and Dolhnikoff M
- Subjects
- Humans, Autopsy, Colitis, Ulcerative, Acquired Immunodeficiency Syndrome complications, Mpox (monkeypox), Pneumonia
- Abstract
Competing Interests: We declare no competing interests. We would like to thank all health professionals from IIER who provided medical care to the patients, and all autopsy and pathology laboratory technicians from Departamento de Patologia-FMUSP, who collaborated in the analysis of the cases. We acknowledge support from the Medical Research Council–São Paulo Research Foundation CADDE partnership award (MR/S0195/1; FAPESP18/143890; 2013/17159‐2), Wellcome Trust and Royal Society (Sir Henry Dale Fellowship 204311/Z/16/Z), and the Bill & Melinda Gates Foundation (INV-034540; INV-034652; and INV‐002396), and Bolsa de produtividade em pesquisa: Conselho Nacional de Desenvolvimento Científico e Tecnológico 304987/2017-4 (MD).
- Published
- 2023
- Full Text
- View/download PDF
37. Identification of potential non-invasive biomarkers in diastrophic dysplasia.
- Author
-
Paganini C, Carroll RS, Gramegna Tota C, Schelhaas AJ, Leone A, Duker AL, O'Connell DA, Coghlan RF, Johnstone B, Ferreira CR, Peressini S, Albertini R, Forlino A, Bonafé L, Campos-Xavier AB, Superti-Furga A, Zankl A, Rossi A, and Bober MB
- Subjects
- Animals, Sulfate Transporters, Glycosaminoglycans, Biomarkers, Collagen metabolism, Sulfates metabolism, Anion Transport Proteins genetics, Achondroplasia
- Abstract
Diastrophic dysplasia (DTD) is a recessive chondrodysplasia caused by pathogenic variants in the SLC26A2 gene encoding for a cell membrane sulfate/chloride antiporter crucial for sulfate uptake and glycosaminoglycan (GAG) sulfation. Research on a DTD animal model has suggested possible pharmacological treatment approaches. In view of future clinical trials, the identification of non-invasive biomarkers is crucial to assess the efficacy of treatments. Urinary GAG composition has been analyzed in several metabolic disorders including mucopolysaccharidoses. Moreover, the N-terminal fragment of collagen X, known as collagen X marker (CXM), is considered a real-time marker of endochondral ossification and growth velocity and was studied in individuals with achondroplasia and osteogenesis imperfecta. In this work, urinary GAG sulfation and blood CXM levels were investigated as potential biomarkers for individuals affected by DTD. Chondroitin sulfate disaccharide analysis was performed on GAGs isolated from urine by HPLC after GAG digestion with chondroitinase ABC and ACII, while CXM was assessed in dried blood spots. Results from DTD patients were compared with an age-matched control population. Undersulfation of urinary GAGs was observed in DTD patients with some relationship to the clinical severity and underlying SLC26A2 variants. Lower than normal CXM levels were observed in most patients, even if the marker did not show a clear pattern in our small patient cohort because CXM values are highly dependent on age, gender and growth velocity. In summary, both non-invasive biomarkers are promising assays targeting various aspects of the disorder including overall metabolism of sulfated GAGs and endochondral ossification., Competing Interests: Declaration of competing interest R.F. Coghlan declares an interest as an inventor of the CXM ELISA assay and receives royalties on the technology; other Authors report no conflict of interest., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)
- Published
- 2023
- Full Text
- View/download PDF
38. Contribution of lipids to the organelle differential profile of in vitro-produced bovine embryos.
- Author
-
Annes K, Ferreira CR, Valente RS, Marsico TV, Tannura JH, da Silveira JC, Silva FH, Landim-Alvarenga FDC, Mesquista FS, and Sudano MJ
- Subjects
- Female, Pregnancy, Cattle, Animals, Lipid Droplets, Blastocyst, Ceramides, Endoplasmic Reticulum, Mitochondria
- Abstract
Each living organism is unique because of the lipid identity of its organelles. The diverse distribution of these molecules also contributes to the role of each organelle in cellular activity. The lipid profiles of whole embryos are well documented in the literature. However, this approach can often lead to the loss of relevant information at the subcellular and consequently, metabolic levels, hindering a deeper understanding of key physiological processes during preimplantation development. Therefore, we aimed to characterize four organelles in vitro-produced bovine embryos: lipid droplets (LD), endoplasmic reticulum (ER), mitochondria (MIT), and nuclear membrane (NUC), and evaluate the contribution of the lipid species to each organelle evaluated. Expanded blastocysts were subjected to cell organelle isolation. Thereafter, lipid extraction from cell organelles and lipid analysis using the Multiple Reaction Monitoring (MRM) profiling method were performed. The LD and ER displayed a greater number of lipids (Phosphatidylcholine - PC, Ceramide - Cer, and Sphingomielin - SM) with high signal-to-noise intensities. This result is due to the high rate of biosynthesis, lipid distribution, and ability to store and recycle lipid species of these organelles. The NUC had a more distinct lipid profile than the other three organelles, with high relative intensities of PC, SM, and triacylglycerols (TG), which is consistent with its high nuclear activity. MIT had an intermediate profile that was close to that of LD and ER, which aligns with its autonomous metabolism for some classes of phospholipids (PL). Our study revealed the lipid composition of each organelle studied, and the roles of these lipids could be associated with the characteristic organellar activity. Our findings highlight the lipid species and classes that are relevant for the homeostasis and function of each associated organelle and provide tentative biomarkers for the determination of in vitro embryonic development and quality., Competing Interests: Declaration of competing interest The authors declare no conflict of interest., (Copyright © 2023 Elsevier Inc. All rights reserved.)
- Published
- 2023
- Full Text
- View/download PDF
39. Immunoexpression of Autophagy-Related Proteins in Salivary Gland Tumors: An Exploratory Study.
- Author
-
Pires EG, Ferreira CR, Cavalcante RB, de Aguiar MCF, Mesquita RA, Alves PM, and Nonaka CFW
- Subjects
- Humans, Autophagy-Related Proteins, Immunohistochemistry, Salivary Glands metabolism, Biomarkers, Tumor metabolism, Salivary Gland Neoplasms pathology, Adenoma, Pleomorphic pathology, Carcinoma, Adenoid Cystic pathology, Adenocarcinoma pathology, Carcinoma, Mucoepidermoid pathology
- Abstract
Background: Autophagy is a cellular survival mechanism involved in several human diseases, but its participation in the development of salivary gland tumors is not fully understood. This study investigated the immunoexpression of autophagy-related proteins (autophagy-related 7 [Atg7], microtubule-associated protein 1 light chain 3A [LC3A], microtubule-associated protein 1 light chain 3B [LC3B], protein p62 [p62], and phosphorylated mammalian target of rapamycin [p-mTOR]) in pleomorphic adenoma (PA), polymorphous adenocarcinoma (PAC), mucoepidermoid carcinoma (MEC), and adenoid cystic carcinoma (ACC) of salivary glands., Methods: Twenty PAs, 20 PACs, 20 MECs, and 14 ACCs were selected. The percentages of cytoplasmic and nuclear positivity for autophagy-related proteins in neoplastic cells were assessed and correlated with histopathological parameters., Results: Cytoplasmic immunoexpression of Atg7 was observed in all groups, with high median percentages of positivity. Regarding LC3A and LC3B, cytoplasmic immunoexpression was found in most PACs (95%) and in all cases of PA, MEC and ACC, with the highest percentages of positivity in PACs and PAs (p < 0.005). ACCs exhibited lower cytoplasmic immunoexpression of p-mTOR (p < 0.005) and lower nuclear expression of p62 (p < 0.05) when compared to PAs, PACs and MECs. Low nuclear immunoexpression of Atg7, LC3A and p-mTOR and absence of nuclear staining for LC3B were observed in all groups. Regarding histopathological parameters of PAs, MECs and ACCs, there were no significant differences in the expression of autophagy-related proteins. In all groups, positive correlations were observed between the immunoexpression of some autophagy-related proteins (p < 0.05)., Conclusions: The results suggest the participation of autophagy in the pathogenesis of PA, PAC, MEC, and ACC of salivary glands. Upregulation of autophagy and reduced nuclear translocation of p62 may contribute to the aggressive biological behavior of salivary gland ACC., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)
- Published
- 2023
- Full Text
- View/download PDF
40. Indolent NK-Cell Lymphoproliferative Disorder of the Gastrointestinal Tract - a Report of two Cases of a new Provisional Entity on the World Health Organization Classification of Hematolymphoid Tumors.
- Author
-
Alves de Castro JV, Costa FD, and Ferreira CR
- Subjects
- Humans, Gastrointestinal Tract pathology, World Health Organization, Neoplasms pathology, Lymphoproliferative Disorders diagnosis, Lymphoproliferative Disorders pathology, Lymphoma, T-Cell, Peripheral pathology
- Abstract
Indolent NK-cell lymphoproliferative disorder of the gastrointestinal tract is a new provisional entity listed in the structure of the forthcoming fifth edition of the World Health Organization (WHO) Classification of Hematolymphoid Tumors. It was first named as "NK-cell enteropathy" and "Lymphomatoid gastropathy" by two independent series a decade ago. Molecular or cytogenetic studies have lent support to the clonal/neoplastic nature of this entity. Herein we add two of such cases that still challenge pathologists and were previously diagnosed as aggressive lymphomas of NK/T derivation.
- Published
- 2023
- Full Text
- View/download PDF
41. Vascular stiffness and healthy arterial aging in older patients with optimal blood pressure.
- Author
-
Jiticovski AFM, Souza DF, Freitas EGB, Ferreira CR, Pereira CS, Galvão RDV, Santos WAM, Oliveira EP, and Ferreira Filho SR
- Subjects
- Humans, Aged, Blood Pressure physiology, Antihypertensive Agents therapeutic use, Pulse Wave Analysis, Aging, Vascular Stiffness physiology
- Abstract
Introduction: Pulse wave velocity is used to diagnose central arterial stiffness (CAS) and quantify healthy vascular aging (HVA)., Objective: To evaluate the CAS and HVA in elderly patients with systemic blood pressure levels classified as optimal/normal., Methods: A total of 102 patients without comorbidities and with systolic pressure (SP) < 120 mmHg and diastolic pressure (DP) < 80 mmHg were selected from the EVOPIU database (Pulse Wave Velocity of Elderly Individuals in an Urban area of Brazil). The carotid-femoral pulse wave velocity (c-fPWV) and the central and peripheral pressures were evaluated in all patients. The patients were divided into four groups: G1: (n = 19, with c-fPWV < 7.6 m/s, without medication), G2 (n = 26, c-fPWV ≥ 7.6 m/s; without medication), G3 (n = 25, c-fPWV < 7.6 m/s with antihypertensive medication), and G4 (n = 32, c-fPWV ≥ 7.6 m/s with antihypertensive medication)., Results: In our sample, 56.7% of patients had c-fPWV ≥ 7.6 m/s. The central systolic pressure in G1 [99 (10) mmHg] was lower than that found in the other three groups [vs. 112 (14) mmHg, 111 (15), 112 (20) mmHg; P < 0.05)]., Conclusion: Older people with optimal arterial blood pressure do not necessarily have HVA and could have c-fPWV values close to the limits established for CAS diagnosis.
- Published
- 2023
- Full Text
- View/download PDF
42. Step-by-Step Approach to Build Multiple Reaction Monitoring (MRM) Profiling Instrument Acquisition Methods for Class-based Lipid Exploratory Analysis by Mass Spectrometry.
- Author
-
Reis LG, Casey TM, Sobreira TJP, Cooper BR, and Ferreira CR
- Subjects
- Mass Spectrometry, Databases, Factual, Isomerism, Carbon, Fatty Acids
- Abstract
Multiple reaction monitoring (MRM) profiling is a strategy for the exploratory analysis of small molecules and lipids by direct sample injection, ie, without the use of chromatographic separation. It is based on instrument methods that comprise a list of ion transitions (MRMs), in which the precursor ion is the expected ionized m/z of the lipid at its species level, ie, the description of lipid class and number of carbon and double bonds in the fatty acid chain(s), and the product ion is a fragment expected for the lipid class or for the fatty acid neutral loss. The Lipid Maps database is expanding constantly, and therefore the MRM-profiling methods associated with this database need to be continuously updated. Here, we provide a comprehensive overview and the key references for the MRM-profiling methodology and workflow, followed by a step-by-step approach to build MRM-profiling instrument acquisition methods for class-based lipid exploratory analysis based on the Lipid Maps database. The detailed workflow includes (1) importing the list of lipids from the database; (2) for a given class, combining isomeric lipids described at full structural level into 1 entry to obtain the neutral mass at species level; (3) attributing the standard Lipid Maps abbreviated nomenclature for the lipid at its species level; (4) predicting the ionized precursor ions; and (5) adding the expected product ion. We also describe how to simulate the precursor ion for the suspect screening of modified lipids using lipid oxidation and their expected product ions as an example. After determining the MRMs, information about collision energy, dwell time, and other instrument parameters are added to finalize the acquisition method. As an example of final method output, we describe the format for Agilent MassHunter v.B.06 and provide the parameters in which optimization can be performed by lipid class using one or more lipid standards., Competing Interests: Conflict of Interest Disclosures: The authors declare no conflicts of interest., (Copyright © 2023 Association of Biomolecular Resource Facilities. All rights reserved.)
- Published
- 2023
- Full Text
- View/download PDF
43. Clinical and biochemical footprints of inherited metabolic diseases. XII. Immunological defects.
- Author
-
de Boer L, Cambi A, Verhagen LM, de Haas P, van Karnebeek CDM, Blau N, and Ferreira CR
- Subjects
- Humans, Glycosylation, Inflammation, Metabolic Diseases genetics
- Abstract
Immunological problems are increasingly acknowledged manifestations in many inherited metabolic diseases (IMDs), ranging from exaggerated inflammation, autoimmunity and abnormal cell counts to recurrent microbial infections. A subgroup of IMDs, the congenital disorders of glycosylation (CDG), includes CDG types that are even classified as primary immunodeficiencies. Here, we reviewed the list of metabolic disorders reported to be associated with various immunological defects and identified 171 IMDs accompanied by immunological manifestations. Most IMDs are accompanied by immune dysfunctions of which immunodeficiency and infections, innate immune defects, and autoimmunity are the most common abnormalities reported in 144/171 (84%), 44/171 (26%) and 33/171 (19%) of IMDs with immune system involvement, respectively, followed by autoinflammation 17/171 (10%). This article belongs to a series aiming at creating and maintaining a comprehensive list of clinical and metabolic differential diagnoses according to organ system involvement., (Published by Elsevier Inc.)
- Published
- 2023
- Full Text
- View/download PDF
44. Nosology of genetic skeletal disorders: 2023 revision.
- Author
-
Unger S, Ferreira CR, Mortier GR, Ali H, Bertola DR, Calder A, Cohn DH, Cormier-Daire V, Girisha KM, Hall C, Krakow D, Makitie O, Mundlos S, Nishimura G, Robertson SP, Savarirayan R, Sillence D, Simon M, Sutton VR, Warman ML, and Superti-Furga A
- Abstract
The "Nosology of genetic skeletal disorders" has undergone its 11th revision and now contains 771 entries associated with 552 genes reflecting advances in molecular delineation of new disorders thanks to advances in DNA sequencing technology. The most significant change as compared to previous versions is the adoption of the dyadic naming system, systematically associating a phenotypic entity with the gene it arises from. We consider this a significant step forward as dyadic naming is more informative and less prone to errors than the traditional use of list numberings and eponyms. Despite the adoption of dyadic naming, efforts have been made to maintain strong ties to the MIM catalog and its historical data. As with the previous versions, the list of disorders and genes in the Nosology may be useful in considering the differential diagnosis in the clinic, directing bioinformatic analysis of next-generation sequencing results, and providing a basis for novel advances in biology and medicine., (© 2023 The Authors. American Journal of Medical Genetics Part A published by Wiley Periodicals LLC. This article has been contributed to by U.S. Government employees and their work is in the public domain in the USA.)
- Published
- 2023
- Full Text
- View/download PDF
45. Comparison of two immunohistochemical staining protocols for ALK demonstrates non-inferiority of a 5A4 clone-based protocol versus an ALK01 clone-based protocol for the diagnosis of ALK + anaplastic large cell lymphoma.
- Author
-
Fernandez-Pol S, Ferreira CR, Manohar V, Sanches JA, Lage LAPC, Pereira J, Zerbini MCN, Gratzinger D, and Natkunam Y
- Subjects
- Humans, Antibodies, Laboratories, Receptor Protein-Tyrosine Kinases genetics, Staining and Labeling, Lymphoma, Large-Cell, Anaplastic diagnosis
- Abstract
Detection of ALK rearrangement and/or expression of the ALK protein is an essential component in the evaluation of many neoplasms. Variability has been reported in the ability of different antibody clones to detect ALK expression. The ALK01 clone is commonly used to detect ALK expression in ALK-positive anaplastic large cell lymphoma (ALK + ALCL). However, this clone has been shown to lack sensitivity when used for solid tumors. The aim of this study was to determine if our high-sensitivity 5A4-based immunohistochemistry protocol is non-inferior to our ALK01-based protocol for the detection of ALK expression in ALK + ALCL. To compare the two protocols, we stained tissue microarrays of 126 hematolymphoid neoplasms and an additional 21 primary cutaneous ALK-negative anaplastic large cell lymphomas with both protocols. All 28 ALK + ALCL samples that were positive for the ALK01 antibody were also positive for the 5A4 clone. Three cases on the tissue microarray that were negative with the ALK01 antibody were clearly positive with the 5A4 antibody. We subsequently stained whole tissue sections of these three cases with the ALK01 antibody and found that these three cases were indeed positive with the ALK01 protocol, suggesting that the absence of staining on the tissue microarray samples was due to a combination of sampling error as well as a dimmer signal with the ALK01 protocol. Our study demonstrates that our 5A4-based protocol is non-inferior to the ALK01 antibody for the diagnosis of ALK-positive anaplastic large cell lymphoma, thus allowing our laboratory to discontinue the use of the ALK01-based protocol., (© 2023. The Author(s).)
- Published
- 2023
- Full Text
- View/download PDF
46. Clinical and biochemical footprints of inherited metabolic disorders. XI. Gastrointestinal symptoms.
- Author
-
Salazar D, Kloke KM, Guerrero RB, Ferreira CR, and Blau N
- Subjects
- Humans, Gastrointestinal Diseases genetics, Gastrointestinal Diseases diagnosis, Metabolic Diseases genetics
- Abstract
Inherited metabolic disorders presenting with gastrointestinal (GI) symptoms are characterized by the dysfunction of the esophagus, stomach, small and large intestines, and pancreas. We have summarized associations of signs and symptoms in 339 inherited metabolic diseases presenting with GI symptoms. Feeding difficulties represent the most common abnormality reported for IMDs with GI involvement (37%) followed by intestinal problems (30%), vomiting (22%), stomach and pancreas involvement (8% each), and esophagus involvement (4%). This represents the eleventh of a series of articles attempting to create and maintain a comprehensive list of clinical and metabolic differential diagnoses according to system involvement., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)
- Published
- 2023
- Full Text
- View/download PDF
47. Biallelic variants in PIGN cause Fryns syndrome, multiple congenital anomalies-hypotonia-seizures syndrome, and neurologic phenotypes: A genotype-phenotype correlation study.
- Author
-
Loong L, Tardivo A, Knaus A, Hashim M, Pagnamenta AT, Alt K, Böhrer-Rabel H, Caro-Llopis A, Cole T, Distelmaier F, Edery P, Ferreira CR, Jezela-Stanek A, Kerr B, Kluger G, Krawitz PM, Kuhn M, Lemke JR, Lesca G, Lynch SA, Martinez F, Maxton C, Mierzewska H, Monfort S, Nicolai J, Orellana C, Pal DK, Płoski R, Quarrell OW, Rosello M, Rydzanicz M, Sabir A, Śmigiel R, Stegmann APA, Stewart H, Stumpel C, Szczepanik E, Tzschach A, Wolfe L, Taylor JC, Murakami Y, Kinoshita T, Bayat A, and Kini U
- Subjects
- Pregnancy, Female, Humans, Muscle Hypotonia genetics, Seizures genetics, Phenotype, Genetic Association Studies, Syndrome, Epilepsy genetics, Abnormalities, Multiple genetics, Hernia, Diaphragmatic genetics, Congenital Disorders of Glycosylation
- Abstract
Purpose: Biallelic PIGN variants have been described in Fryns syndrome, multiple congenital anomalies-hypotonia-seizure syndrome (MCAHS), and neurologic phenotypes. The full spectrum of clinical manifestations in relation to the genotypes is yet to be reported., Methods: Genotype and phenotype data were collated and analyzed for 61 biallelic PIGN cases: 21 new and 40 previously published cases. Functional analysis was performed for 2 recurrent variants (c.2679C>G p.Ser893Arg and c.932T>G p.Leu311Trp)., Results: Biallelic-truncating variants were detected in 16 patients-10 with Fryns syndrome, 1 with MCAHS1, 2 with Fryns syndrome/MCAHS1, and 3 with neurologic phenotype. There was an increased risk of prenatal or neonatal death within this group (6 deaths were in utero or within 2 months of life; 6 pregnancies were terminated). Incidence of polyhydramnios, congenital anomalies (eg, diaphragmatic hernia), and dysmorphism was significantly increased. Biallelic missense or mixed genotype were reported in the remaining 45 cases-32 showed a neurologic phenotype and 12 had MCAHS1. No cases of diaphragmatic hernia or abdominal wall defects were seen in this group except patient 1 in which we found the missense variant p.Ser893Arg to result in functionally null alleles, suggesting the possibility of an undescribed functionally important region in the final exon. For all genotypes, there was complete penetrance for developmental delay and near-complete penetrance for seizures and hypotonia in patients surviving the neonatal period., Conclusion: We have expanded the described spectrum of phenotypes and natural history associated with biallelic PIGN variants. Our study shows that biallelic-truncating variants usually result in the more severe Fryns syndrome phenotype, but neurologic problems, such as developmental delay, seizures, and hypotonia, present across all genotypes. Functional analysis should be considered when the genotypes do not correlate with the predicted phenotype because there may be other functionally important regions in PIGN that are yet to be discovered., Competing Interests: Conflict of Interest The authors declare no conflict of interest., (Copyright © 2022 American College of Medical Genetics and Genomics. All rights reserved.)
- Published
- 2023
- Full Text
- View/download PDF
48. Repeat expansions nested within tandem CNVs: a unique structural change in GLS exemplifies the diagnostic challenges of non-coding pathogenic variation.
- Author
-
Fazal S, Danzi MC, van Kuilenburg ABP, Reich S, Traschütz A, Bender B, Leen R, Toro C, Usdin K, Hayward B, Adams DR, van Karnebeek CDM, Ferreira CR, D'Sousa P, Network UD, Tekin M, Züchner S, and Synofzik M
- Subjects
- Humans, 5' Untranslated Regions, Ataxia diagnosis, Ataxia genetics, Glutaminase genetics
- Abstract
Glutaminase deficiency has recently been associated with ataxia and developmental delay due to repeat expansions in the 5'UTR of the glutaminase (GLS) gene. Patients with the described GLS repeat expansion may indeed remain undiagnosed due to the rarity of this variant, the challenge of its detection and the recency of its discovery. In this study, we combined advanced bioinformatics screening of ~3000 genomes and ~1500 exomes with optical genome mapping and long-read sequencing for confirmation studies. We identified two GLS families, previously intensely and unsuccessfully analyzed. One family carries an unusual and complex structural change involving a homozygous repeat expansion nested within a quadruplication event in the 5'UTR of GLS. Glutaminase deficiency and its metabolic consequences were validated by in-depth biochemical analysis. The identified GLS patients showed progressive early-onset ataxia, cognitive deficits, pyramidal tract damage and optic atrophy, thus demonstrating susceptibility of several specific neuron populations to glutaminase deficiency. This large-scale screening study demonstrates the ability of bioinformatics analysis-validated by latest state-of-the-art technologies (optical genome mapping and long-read sequencing)-to effectively flag complex repeat expansions using short-read datasets and thus facilitate diagnosis of ultra-rare disorders., (© The Author(s) 2022. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)
- Published
- 2023
- Full Text
- View/download PDF
49. Targeted Lipidomics Analysis of Adipose and Skeletal Muscle Tissues by Multiple Reaction Monitoring Profiling.
- Author
-
Chen X, Ferreira CR, and Kuang S
- Subjects
- Humans, Cholesterol Esters, Lipid Metabolism, Phosphatidylcholines metabolism, Muscle, Skeletal metabolism, Lipidomics, Obesity metabolism
- Abstract
Lipid homeostasis is critical for maintaining normal cellular functions including membrane structural integrity, cell metabolism, and signal transduction. Adipose tissue and skeletal muscle are two major tissues involved in lipid metabolism. Adipose tissue can store excessive lipids in the form of triacylglyceride (TG), which can be hydrolyzed to release free fatty acids (FFAs) under insufficient nutrition states. In the highly energy-demanding skeletal muscle, lipids serve as oxidative substrates for energy production but can cause muscle dysfunction when overloaded. Lipids undergo fascinating cycles of biogenesis and degradation depending on physiological demands, while dysregulation of lipid metabolism has been increasingly recognized as a hallmark of diseases such as obesity and insulin resistance. Thus, it is important to understand the diversity and dynamics of lipid composition in adipose tissue and skeletal muscle. Here, we describe the use of multiple reaction monitoring profiling, based on lipid class and fatty acyl chain specific fragmentation, to explore various classes of lipids in skeletal muscle and adipose tissues. We provide a detailed method for exploratory analysis of acylcarnitine (AC), ceramide (Cer), cholesteryl ester (CE), diacylglyceride (DG), FFA, phosphatidylcholine (PC), phosphatidylethanolamine (PE), phosphatidylglycerol (PG), phosphatidylinositol (PI), phosphatidylserine (PS), sphingomyelin (SM), and TG. Characterization of lipid composition within adipose tissue and skeletal muscle under different physiological situations will provide biomarkers and therapeutic targets for obesity-related diseases., (© 2023. Springer Science+Business Media, LLC, part of Springer Nature.)
- Published
- 2023
- Full Text
- View/download PDF
50. Estimation of ENPP1 deficiency genetic prevalence using a comprehensive literature review and population databases.
- Author
-
Chunn LM, Bissonnette J, Heinrich SV, Mercurio SA, Kiel MJ, Rutsch F, and Ferreira CR
- Subjects
- Animals, Female, Pregnancy, Humans, Prevalence, Asian People, Databases, Factual, Familial Hypophosphatemic Rickets, Rickets, Hypophosphatemic
- Abstract
Background: ENPP1 Deficiency-caused by biallelic variants in ENPP1-leads to widespread arterial calcification in early life (Generalized Arterial Calcification of Infancy, GACI) or hypophosphatemic rickets in later life (Autosomal Recessive Hypophosphatemic Rickets type 2, ARHR2). A prior study using the Exome Aggregation Consortium (ExAC)-a database of exomes obtained from approximately 60,000 individuals-estimated the genetic prevalence at approximately 1 in 200,000 pregnancies., Methods: We estimated the genetic prevalence of ENPP1 Deficiency by evaluating allele frequencies from a population database, assuming Hardy-Weinberg equilibrium. This estimate benefitted from a comprehensive literature review using Mastermind ( https://mastermind.genomenon.com/ ), which uncovered additional variants and supporting evidence, a larger population database with approximately 140,000 individuals, and improved interpretation of variants as per current clinical guidelines., Results: We estimate a genetic prevalence of approximately 1 in 64,000 pregnancies, thus more than tripling the prior estimate. In addition, the carrier frequency of ENPP1 variants was found to be highest in East Asian populations, albeit based on a small sample., Conclusion: These results indicate that a significant number of patients with ENPP1 Deficiency remain undiagnosed. Efforts to increase disease awareness as well as expand genetic testing, particularly in non-European populations are warranted, especially now that clinical trials for enzyme replacement therapy, which proved successful in animal models, are underway., (© 2022. The Author(s).)
- Published
- 2022
- Full Text
- View/download PDF
Catalog
Discovery Service for Jio Institute Digital Library
For full access to our library's resources, please sign in.