164 results on '"Hernandez RJ"'
Search Results
2. Chiral Self-assembled Solid Microspheres: optical control and photonics applications
- Author
-
CIPPARRONE G, MAZZULLA A, HERNANDEZ RJ, and BARTOLINO R
- Published
- 2012
3. Self-organized chiral microspheres
- Author
-
MAZZULLA A, CIPPARRONE G, HERNANDEZ RJ, and BARTOLINO R
- Published
- 2012
4. SELF-ORGANIZED CHIRAL MICRODROPLETS
- Author
-
Mazzulla A., Cipparrone G., Hernandez RJ, Pane A., and Bartolino R.
- Published
- 2011
5. Isostatic and Quasi-Isostatic Methods for Determining the Permeability of Organic Vapors Through Barrier Membranes
- Author
-
Baner, AL, primary, Hernandez, RJ, additional, Jayaraman, K, additional, and Giacin, JR, additional
- Full Text
- View/download PDF
6. The use of mechanical analyses, scanning electron microscopy and ultrasonic imaging to study the effects of high‐pressure processing on multilayer films
- Author
-
Caner, C, primary, Hernandez, RJ, additional, Pascall, MA, additional, and Riemer, J, additional
- Published
- 2003
- Full Text
- View/download PDF
7. Ultrasound diagnosis of neonatal congenital dislocation of the hip. A decision analysis assessment
- Author
-
Hernandez, RJ, primary, Cornell, RG, additional, and Hensinger, RN, additional
- Published
- 1994
- Full Text
- View/download PDF
8. Unexpected MRI findings in clinically suspected Legg-Calvé-Perthes disease.
- Author
-
Lobert PF, Dillman JR, Strouse PJ, Hernandez RJ, Lobert, Philip F, Dillman, Jonathan R, Strouse, Peter J, and Hernandez, Ramiro J
- Abstract
Background: In the setting of clinically suspected Legg-Calvé-Perthes (LCP) disease and negative/equivocal radiographs, contrast-enhanced MRI can be performed to confirm the diagnosis.Objective: To determine the frequency of unexpected causes of hip pain as identified by MRI in children with clinically suspected LCP disease and negative/equivocal radiographs.Materials and Methods: All pediatric contrast-enhanced MRI examinations of the pelvis and hips performed between January 2000 and February 2009 to evaluate for possible LCP disease in the setting of negative/equivocal radiographs were identified. MRI examinations performed to evaluate for secondary avascular necrosis were excluded. Imaging reports were retrospectively reviewed for unexpected clinically important causes of hip pain.Results: Thirty-six pediatric patients underwent contrast-enhanced MRI examinations for clinically suspected LCP disease in the setting of negative/equivocal radiographs. Twenty-two (61%) imaging studies were normal, while four (11%) imaging studies demonstrated findings consistent with LCP disease. Ten (28%) imaging studies revealed unexpected clinically important causes of hip pain, including nonspecific unilateral joint effusion and synovitis (n=7, juvenile chronic arthritis was eventually diagnosed in 3 patients), sacral fracture (n=1), apophyseal injury (n=1), and femoral head subluxation (n=1).Conclusion: MRI frequently reveals unexpected clinically important causes of hip pain in children with suspected LCP disease and negative/equivocal radiographs. [ABSTRACT FROM AUTHOR]- Published
- 2011
- Full Text
- View/download PDF
9. The mystery of skeletal muscle hypertrophy.
- Author
-
Hernandez RJ and Kravitz L
- Published
- 2003
10. Size and skeletal maturation of the hand in children with hypothyroidism and hypopituitarism
- Author
-
Hernandez, RJ, primary, Poznanski, AW, additional, and Hopwood, NJ, additional
- Published
- 1979
- Full Text
- View/download PDF
11. Capacity of the colon in children
- Author
-
Hernandez, RJ, primary, Gutowski, D, additional, and Guire, KE, additional
- Published
- 1979
- Full Text
- View/download PDF
12. Pulmonary lymphangiectasis in Noonan syndrome
- Author
-
Hernandez, RJ, primary, Stern, AM, additional, and Rosenthal, A, additional
- Published
- 1980
- Full Text
- View/download PDF
13. Incidence of growth lines in psychosocial dwarfs and idiopathic hypopituitarism
- Author
-
Hernandez, RJ, primary, Poznanski, AK, additional, Hopwood, NJ, additional, and Kelch, RP, additional
- Published
- 1978
- Full Text
- View/download PDF
14. CT determination of femoral torsion
- Author
-
Hernandez, RJ, primary, Tachdjian, MO, additional, Poznanski, AK, additional, and Dias, LS, additional
- Published
- 1981
- Full Text
- View/download PDF
15. Hip CT in congenital dislocation: appearance of tight iliopsoas tendon and pulvinar hypertrophy
- Author
-
Hernandez, RJ, primary, Tachdjian, MO, additional, and Dias, LS, additional
- Published
- 1982
- Full Text
- View/download PDF
16. Comparative evaluation of the pulmonary arteries in patients with right ventricular outflow tract obstructive lesions
- Author
-
Hernandez, RJ, primary, Bank, ER, additional, Shaffer, EM, additional, Snider, AR, additional, and Rosenthal, A, additional
- Published
- 1987
- Full Text
- View/download PDF
17. Comparison of the behavioral effects of gamma-hydroxybutyric acid (GHB) and its 4-methyl-substituted analog, gamma-hydroxyvaleric acid (GHV)
- Author
-
Carter LP, Chen W, Wu H, Mehta AK, Hernandez RJ, Ticku MK, Coop A, Koek W, and France CP
- Abstract
Gamma-hydroxybutyrate (GHB), a metabolite of GABA, is a drug of abuse and a therapeutic. The illicit use of GHB precursors and analogs reportedly has increased worldwide. Gamma-hydroxyvaleric (GHV) is a 4-methyl-substituted analog of GHB that reportedly is abused and is marketed as a dietary supplement and replacement for GHB. The purpose of these studies was to compare the pharmacological and behavioral profiles of GHV and GHB. In radioligand binding studies, GHV completely displaced [(3)H]NCS-382 with approximately 2-fold lower affinity than GHB and did not markedly displace [(3)H]GABA from GABA(B) receptors at a 20-fold larger concentration. In drug discrimination procedures, GHV did not share discriminative stimulus effects with GHB or baclofen. GHV shared other behavioral effects with GHB, such as sedation, catalepsy, and ataxia, although larger doses of GHV were required to produce these effects. Lethality (50%) was observed after the largest dose of GHV (5600mg/kg), a dose that produced less-than-maximal catalepsy and ataxia. To the extent that large doses of GHV might be taken to in an attempt to produce GHB-like effects (e.g., hypnosis) GHV toxicity may pose a greater public health concern than GHB. [ABSTRACT FROM AUTHOR]
- Published
- 2005
- Full Text
- View/download PDF
18. Lentiviral Vector Gene Therapy Protects XCGD Mice From Acute Staphylococcus aureus Pneumonia and Inflammatory Response
- Author
-
Bernhard Gentner, Chiara Bovolenta, Clelia Di Serio, Maddalena Migliavacca, Raisa Jofra Hernandez, Alice Rossi, Alessandra Bragonzi, Serena Ranucci, Francesca Sanvito, Aleksandar Pramov, Chiara Brombin, Giada Farinelli, Alessandro Aiuti, Farinelli, G, Hernandez, Rj, Rossi, A, Ranucci, S, Sanvito, F, Migliavacca, M, Brombin, Chiara, Pramov, A, DI SERIO, Mariaclelia, Bovolenta, C, Gentner, B, Bragonzi, A, and Aiuti, Alessandro
- Subjects
0301 basic medicine ,Staphylococcus aureus ,Chemokine ,Genetic enhancement ,Genetic Vectors ,Inflammation ,Granulomatous Disease, Chronic ,medicine.disease_cause ,Viral vector ,Proinflammatory cytokine ,Mice ,03 medical and health sciences ,Chronic granulomatous disease ,Pneumonia, Staphylococcal ,Drug Discovery ,Genetics ,medicine ,Animals ,Humans ,Vector (molecular biology) ,Molecular Biology ,Cells, Cultured ,Pharmacology ,Membrane Glycoproteins ,biology ,Lentivirus ,Hematopoietic Stem Cell Transplantation ,NADPH Oxidases ,Genetic Therapy ,Hematopoietic Stem Cells ,medicine.disease ,Bacterial Load ,3. Good health ,Disease Models, Animal ,030104 developmental biology ,NADPH Oxidase 2 ,Immunology ,biology.protein ,Cytokines ,Molecular Medicine ,Original Article ,Chemokines ,medicine.symptom - Abstract
Chronic granulomatous disease (CGD) is a primary immunodeficiency due to a deficiency in one of the subunits of the nicotinamide adenine dinucleotide phosphate (NADPH) oxidase complex. CGD patients are characterized by an increased susceptibility to bacterial and fungal infections, and to granuloma formation due to the excessive inflammatory responses. Several gene therapy approaches with lentiviral vectors have been proposed but there is a lack of in vivo data on the ability to control infections and inflammation. We set up a mouse model of acute infection that closely mimic the airway infection in CGD patients. It involved an intratracheal injection of a methicillin-sensitive reference strain of S. aureus . Gene therapy, with hematopoietic stem cells transduced with regulated lentiviral vectors, restored the functional activity of NADPH oxidase complex (with 20–98% of dihydrorhodamine positive granulocytes and monocytes) and saved mice from death caused by S. aureus , significantly reducing the bacterial load and lung damage, similarly to WT mice even at low vector copy number. When challenged, gene therapy-treated XCGD mice showed correction of proinflammatory cytokines and chemokine imbalance at levels that were comparable to WT. Examined together, our results support the clinical development of gene therapy protocols using lentiviral vectors for the protection against infections and inflammation.
- Published
- 2016
19. Ex vivo gene therapy with lentiviral vectors rescues adenosine deaminase (ADA)–deficient mice and corrects their immune and metabolic defects
- Author
-
Filippo Carlucci, Luca Biasco, Claudio Doglioni, Antonella Tabucchi, Claudio Bordignon, Maurilio Ponzoni, Alessandro Aiuti, Antonia Follenzi, Raisa Jofra Hernandez, Alessandra Mortellaro, Luigi Naldini, Francesca Sanvito, Clelia Di Serio, Matteo M. Guerrini, Maria Grazia Roncarolo, Mortellaro, A, Hernandez, Rj, Guerrini, Mm, Carlucci, F, Tabucchi, A, Ponzoni, Maurilio, Sanvito, F, Doglioni, Claudio, DI SERIO, Mariaclelia, Biasco, L, Follenzi, A, Naldini, Luigi, Bordignon, Claudio, Roncarolo, MARIA GRAZIA, and Aiuti, Alessandro
- Subjects
Adenosine Deaminase ,Genetic enhancement ,Genetic Vectors ,Immunology ,Mice, Transgenic ,Lymphocyte Activation ,Biochemistry ,Viral vector ,Mice ,Adenosine deaminase ,Immune system ,medicine ,Animals ,Lymphocyte Count ,Bone Marrow Transplantation ,Mice, Knockout ,B-Lymphocytes ,Severe combined immunodeficiency ,biology ,Lentivirus ,Gene Transfer Techniques ,Cell Biology ,Hematology ,Flow Cytometry ,medicine.disease ,Adenosine deaminase deficiency ,Killer Cells, Natural ,Transplantation ,medicine.anatomical_structure ,Antibody Formation ,biology.protein ,Bone marrow ,Spleen - Abstract
Adenosine deaminase (ADA) deficiency is caused by a purine metabolic dysfunction, leading to severe combined immunodeficiency (SCID) and multiple organ damage. To investigate the efficacy of ex vivo gene therapy with self-inactivating lentiviral vectors (LVs) in correcting this complex phenotype, we used an ADA(-/-) mouse model characterized by early postnatal lethality. LV-mediated ADA gene transfer into bone marrow cells combined with low-dose irradiation rescued mice from lethality and restored their growth, as did transplantation of wild-type bone marrow. Mixed chimerism with multilineage engraftment of transduced cells was detected in the long term in animals that underwent transplantation. ADA activity was normalized in lymphocytes and partially corrected in red blood cells (RBCs), resulting in full metabolic detoxification and prevention of severe pulmonary insufficiency. Moreover, gene therapy restored normal lymphoid differentiation and immune functions, including antigen-specific antibody production. Similar degrees of detoxification and immune reconstitution were obtained in mice treated early after birth or after 1 month of enzyme-replacement therapy, mimicking 2 potential applications for ADA-SCID. Overall, this study demonstrates the efficacy of LV gene transfer in correcting both the immunological and metabolic phenotypes of ADA-SCID and supports the future clinical use of this approach. Adenosine deaminase (ADA) deficiency is caused by a purine metabolic dysfunction, leading to severe combined immunodeficiency (SCID) and multiple organ damage. To investigate the efficacy of ex vivo gene therapy with self-inactivating lentiviral vectors (LVs) in correcting this complex phenotype, we used an ADA(-/-) mouse model characterized by early postnatal lethality. LV-mediated ADA gene transfer into bone marrow cells combined with low-dose irradiation rescued mice from lethality and restored their growth, as did transplantation of wild-type bone marrow. Mixed chimerism with multilineage engraftment of transduced cells was detected in the long term in animals that underwent transplantation. ADA activity was normalized in lymphocytes and partially corrected in red blood cells (RBCs), resulting in full metabolic detoxification and prevention of severe pulmonary insufficiency. Moreover, gene therapy restored normal lymphoid differentiation and immune functions, including antigen-specific antibody production. Similar degrees of detoxification and immune reconstitution were obtained in mice treated early after birth or after 1 month of enzyme-replacement therapy, mimicking 2 potential applications for ADA-SCID. Overall, this study demonstrates the efficacy of LV gene transfer in correcting both the immunological and metabolic phenotypes of ADA-SCID and supports the future clinical use of this approach.
- Published
- 2006
20. IL-3 or IL-7 Increases ex Vivo Gene Transfer Efficiency in ADA-SCID BM CD34+ Cells while Maintaining in Vivo Lymphoid Potential
- Author
-
Nicole Carballido-Perrig, Maria Grazia Roncarolo, Grazia Andolfi, Alessandro Aiuti, Augusto Colombo, Claudio Bordignon, Daniela Superchi, Raisa Jofra Hernandez, Cristina Mocchetti, José M. Carballido, Francesca Ficara, Sara Deola, Ficara, F, Superchi, Db, Hernandez, Rj, Mocchetti, C, Carballido Perrig, N, Andolfi, G, Deola, S, Colombo, A, Bordignon, Claudio, Carballido, Jm, Roncarolo, MARIA GRAZIA, and Aiuti, Alessandro
- Subjects
Adenosine Deaminase ,Genetic enhancement ,T cell ,Antigens, CD34 ,Bone Marrow Cells ,Mice, SCID ,Biology ,Mice ,Transduction, Genetic ,In vivo ,Drug Discovery ,Genetics ,medicine ,Animals ,Humans ,Lymphocytes ,Progenitor cell ,Molecular Biology ,Cells, Cultured ,B cell ,Cell Proliferation ,Interleukin 3 ,Pharmacology ,Interleukin-7 ,Gene Transfer Techniques ,Cell Differentiation ,Genetic Therapy ,Fetal Blood ,Molecular biology ,medicine.anatomical_structure ,Immunology ,Molecular Medicine ,Interleukin-3 ,Severe Combined Immunodeficiency ,Bone marrow ,Ex vivo ,Stem Cell Transplantation - Abstract
To improve maintenance and gene transfer of human lymphoid progenitors for clinical use in gene therapy of adenosine deaminase (ADA)-deficient SCID we investigated several gene transfer protocols using various stem cell-enriched sources. The lymphoid differentiation potential was measured by an in vitro clonal assay for B/NK cells and in the in vivo SCID-hu mouse model. Ex vivo culture with the cytokines TPO, FLT3-ligand, and SCF (T/F/S) plus IL-3 or IL-7 substantially increased the yield of transduced bone marrow (BM) CD34(+) cells purified from ADA-SCID patients or healthy donors, compared to T/F/S alone. Moreover, the use of IL-3 or IL-7 significantly improved the maintenance of in vitro B cell progenitors from ADA-SCID BM cells and allowed the efficient transduction of B and NK cell progenitors. Under these optimized conditions transduced CD34(+) cells were efficiently engrafted into SCID-hu mice and gave rise to B and T cell progeny, demonstrating the maintenance of in vivo lymphoid reconstitution capacity. The protocol based on the T/F/S + IL-3 combination was included in a gene therapy clinical trial for ADA-SCID, resulting in long-term engraftment of stem/progenitor cells. Remarkably, gene-corrected BM CD34(+) cells obtained from one patient 4 and 11 months after gene therapy were capable of repopulating the lymphoid compartment of SCID-hu hosts.
- Published
- 2004
21. Preclinical Safety and Efficacy of Human CD34(+) Cells Transduced With Lentiviral Vector for the Treatment of Wiskott-Aldrich Syndrome
- Author
-
Maria G. Roncarolo, Robbert G. M. Bredius, Maria Carmina Castiello, Marita Bosticardo, Anna Villa, Monica Salomoni, Marco Ranzani, Mariana Loperfido, Elisa Vicenzi, Anna Ripamonti, Raisa Jofra Hernandez, Luca Biasco, Christof von Kalle, Samantha Scaramuzza, Fabrizio Benedicenti, Alessandra Biffi, Manfred Schmidt, Alessandro Aiuti, Elena Draghici, Luigi Naldini, Eugenio Montini, Andrea Finocchi, Cynthia C. Bartholomae, Marina Radrizzani, Scaramuzza, S1, Biasco, L, Ripamonti, A, Castiello, Mc, Loperfido, M, Draghici, E, Hernandez, Rj, Benedicenti, F, Radrizzani, M, Salomoni, M, Ranzani, M, Bartholomae, Cc, Vicenzi, E, Finocchi, A, Bredius, R, Bosticardo, M, Schmidt, M, von Kalle, C, Montini, E, Biffi, A, Roncarolo, MARIA GRAZIA, Naldini, Luigi, Villa, A, and Aiuti, A.
- Subjects
Wiskott–Aldrich syndrome ,Genetic enhancement ,Knockout ,Genetic Vectors ,CD34 ,Bone Marrow Cells ,Biology ,Viral vector ,03 medical and health sciences ,Mice ,Transduction ,0302 clinical medicine ,Genetic ,Drug Discovery ,medicine ,Genetics ,Animals ,Progenitor cell ,Antigens ,Molecular Biology ,030304 developmental biology ,Interleukin 3 ,Bone Marrow Transplantation ,Pharmacology ,0303 health sciences ,Antigens, CD34 ,Lentivirus ,Mice, Knockout ,Wiskott-Aldrich Syndrome ,Transduction, Genetic ,medicine.disease ,3. Good health ,Haematopoiesis ,medicine.anatomical_structure ,Settore MED/03 - Genetica Medica ,030220 oncology & carcinogenesis ,Immunology ,Molecular Medicine ,Original Article ,Bone marrow - Abstract
"Gene therapy with ex vivo-transduced hematopoietic stem/progenitor cells may represent a valid therapeutic option for monogenic immunohematological disorders such as Wiskott-Aldrich syndrome (WAS), a primary immunodeficiency associated with thrombocytopenia. We evaluated the preclinical safety and efficacy of human CD34+ cells transduced with lentiviral vectors (LV) encoding WAS protein (WASp). We first set up and validated a transduction protocol for CD34+ cells derived from bone marrow (BM) or mobilized peripheral blood (MPB) using a clinical grade, highly purified LV. Robust transduction of progenitor cells was obtained in normal donors and WAS patients' cells, without evidence of toxicity. To study biodistribution of human cells and exclude vector release in vivo, LV-transduced CD34+ cells were transplanted in immunodeficient mice, showing a normal engraftment and differentiation ability towards transduced lymphoid and myeloid cells in hematopoietic tissues. Vector mobilization to host cells and transmission to germline cells of the LV were excluded by different molecular assays. Analysis of vector integrations showed polyclonal integration patterns in vitro and in human engrafted cells in vivo. In summary, this work establishes the preclinical safety and efficacy of human CD34+ cells gene therapy for the treatment of WAS."
- Published
- 2013
22. ADA-deficient SCID is associated with a specific microenvironment and bone phenotype characterized by RANKL/OPG imbalance and osteoblast insufficiency
- Author
-
Anna Villa, Maria Grazia Roncarolo, Emanuela Mrak, Filippo Carlucci, Maria Célia Cervi, Elena Zacchi, Alessandro Rubinacci, Eyal Grunebaum, Chaim M. Roifman, Aisha V. Sauer, Francesco Cavani, Alessandro Aiuti, Alessandro Ambrosi, Miriam Casiraghi, Raisa Jofra Hernandez, Sauer, Av, Mrak, E, Hernandez, Rj, Zacchi, E, Cavani, F, Casiraghi, M, Grunebaum, E, Roifman, Cm, Cervi, Mc, Ambrosi, Alessandro, Carlucci, F, Roncarolo, MARIA GRAZIA, Villa, A, Rubinacci, A, and Aiuti, Alessandro
- Subjects
Male ,Adenosine Deaminase ,Genetic enhancement ,Biochemistry ,SEVERE COMBINED IMMUNODEFICIENCY ,Osteogenesis ,Bone cell ,DYSPLASIA ,Mice, Knockout ,PRECURSORS ,Mice, Inbred BALB C ,biology ,Hematopoietic Stem Cell Transplantation ,Osteoblast ,Hematology ,medicine.anatomical_structure ,RANKL ,Female ,medicine.medical_specialty ,Immunology ,ADA SCID RANKL OPG immunodeficiency bone mice ,Bone and Bones ,ENZYME-REPLACEMENT ,Osteoprotegerin ,Internal medicine ,medicine ,Animals ,Humans ,Transplantation, Homologous ,HEMATOPOIETIC STEM-CELLS ,MARROW-TRANSPLANTATION ,ADENOSINE-DEAMINASE DEFICIENCY ,GENE-THERAPY ,IMMUNE-SYSTEM ,MICE ,Settore MED/38 - Pediatria Generale e Specialistica ,Severe combined immunodeficiency ,Osteoblasts ,RANK Ligand ,Cell Biology ,Genetic Therapy ,medicine.disease ,Hematopoietic Stem Cells ,Adenosine deaminase deficiency ,Hematopoiesis ,Endocrinology ,biology.protein ,Bone marrow - Abstract
Adenosine deaminase (ADA) deficiency is a disorder of the purine metabolism leading to combined immunodeficiency and systemic alterations, including skeletal abnormalities. We report that ADA deficiency in mice causes a specific bone phenotype characterized by alterations of structural properties and impaired mechanical competence. These alterations are the combined result of an imbalanced receptor activator of nuclear factor-κB ligand (RANKL)/osteoprotegerin axis, causing decreased osteoclastogenesis and an intrinsic defect of osteoblast function with subsequent low bone formation. In vitro, osteoblasts lacking ADA displayed an altered transcriptional profile and growth reduction. Furthermore, the bone marrow microenvironment of ADA-deficient mice showed a reduced capacity to support in vitro and in vivo hematopoiesis. Treatment of ADA-deficient neonatal mice with enzyme replacement therapy, bone marrow transplantation, or gene therapy resulted in full recovery of the altered bone parameters. Remarkably, untreated ADA–severe combined immunodeficiency patients showed a similar imbalance in RANKL/osteoprotegerin levels alongside severe growth retardation. Gene therapy with ADA-transduced hematopoietic stem cells increased serum RANKL levels and children's growth. Our results indicate that the ADA metabolism represents a crucial modulatory factor of bone cell activities and remodeling. The trials were registered at www.clinicaltrials.gov as #NCT00598481 and #NCT00599781.
- Published
- 2009
23. Efficacy of Gene Therapy for Wiskott-Aldrich Syndrome Using a WAS Promoter/cDNA-Containing Lentiviral Vector and Nonlethal Irradiation
- Author
-
Loëc Dupré, Sara Trifari, Luigi Naldini, Samantha Scaramuzza, Raisa Jofra Hernandez, Maria Grazia Roncarolo, Francesco Marangoni, Alessandro Aiuti, Dupre, L, Marangoni, F, Scaramuzza, S, Trifari, S, Hernandez, Rj, Aiuti, Alessandro, Naldini, Luigi, and Roncarolo, MARIA GRAZIA
- Subjects
DNA, Complementary ,Wiskott–Aldrich syndrome ,T cell ,Genetic enhancement ,T-Lymphocytes ,Blotting, Western ,Genetic Vectors ,macromolecular substances ,Biology ,Transplantation, Autologous ,Viral vector ,Mice ,Transduction, Genetic ,medicine ,Genetics ,Animals ,Humans ,Fluorescent Antibody Technique, Indirect ,Promoter Regions, Genetic ,Molecular Biology ,Cell Proliferation ,B-Lymphocytes ,Reverse Transcriptase Polymerase Chain Reaction ,Lentivirus ,Hematopoietic Stem Cell Transplantation ,Genetic Therapy ,medicine.disease ,Virology ,Actins ,Wiskott-Aldrich Syndrome ,Transplantation ,Mice, Inbred C57BL ,Haematopoiesis ,medicine.anatomical_structure ,Primary immunodeficiency ,Cancer research ,Interleukin-2 ,Molecular Medicine ,Stem cell ,Wiskott-Aldrich Syndrome Protein - Abstract
Wiskott-Aldrich syndrome (WAS) is a life-threatening X-linked primary immunodeficiency characterized by infections, hemorrhages, autoimmune disorders, and lymphomas. Transplantation of genetically corrected autologous hematopoietic stem cells (HSCs) could represent an alternative treatment to allogeneic HSC transplantation, the latter being often associated with severe complications. We used WAS(-/-) mice to test the efficacy of a gene therapy approach based on nonlethal irradiation followed by transplantation of WAS(-/-) HSCs transduced with lentiviral vectors encoding the WAS protein (WASP) from either the ubiquitous PGK promoter or the tissue-specific WAS promoter. The procedure resulted in significant levels of engraftment of WASP-expressing T cells, B cells, platelets, and myeloid cells. T cells harbored one or two vector copies and displayed partial to full correction of T cell receptor-driven interleukin- 2 production and proliferation. In addition, polymerization of F-actin and localization of WASP at the site of the immunological synapse were restored. The treatment was well tolerated and no pathology was detected by systematic blood analysis and autopsy. The efficacy of WAS gene transfer into HSCs, using the WAS promoter-containing lentiviral vector, combined with nonlethal irradiation provides a strong rationale for the development of gene therapy for WAS patients. Wiskott-Aldrich syndrome (WAS) is a life-threatening X-linked primary immunodeficiency characterized by infections, hemorrhages, autoimmune disorders, and lymphomas. Transplantation of genetically corrected autologous hematopoietic stem cells (HSCs) could represent an alternative treatment to allogeneic HSC transplantation, the latter being often associated with severe complications. We used WAS-/- mice to test the efficacy of a gene therapy approach based on nonlethal irradiation followed by transplantation of WAS-/- HSCs transduced with lentiviral vectors encoding the WAS protein (WASP) from either the ubiquitous PGK promoter or the tissue- specific WAS promoter. The procedure resulted in significant levels of engraftment of WASP-expressing T cells, B cells, platelets, and myeloid cells. T cells harbored one or two vector copies and displayed partial to full correction of T cell receptor-driven interleukin-2 production and proliferation. In addition, polymerization of F-actin and localization of WASP at the site of the immunological synapse were restored. The treatment was well tolerated and no pathology was detected by systematic blood analysis and autopsy. The efficacy of WAS gene transfer into HSCs, using the WAS promoter-containing lentiviral vector, combined with nonlethal irradiation provides a strong rationale for the development of gene therapy for WAS patients
- Published
- 2006
24. Optical frequency filtering for Raman beams.
- Author
-
Ramírez-Meléndez G, López-Vázquez A, Ochoa HG, Jiménez L, Hernandez RJ, and Gomez E
- Abstract
We present an optical filter that is appropriate for use with Raman beams in atomic interferometry. This is a filter that lets the light of the two frequencies of the Raman pair go through and rejects spurious frequencies that may be close to the atomic resonance and cause decoherence. We characterized the filter's performance optically and also by shining the light into atoms in a Ramsey sequence, to look for decoherence effects from photon scattering. We found that it is safe to use tapered amplifiers in single and double pass for light amplification in the Raman beams since the pedestal of emission has a negligible effect, which can be further reduced by the use of the filter we present., (© 2024 Author(s). Published under an exclusive license by AIP Publishing.)
- Published
- 2024
- Full Text
- View/download PDF
25. A GLB1 transgene with enhanced therapeutic potential for the preclinical development of ex-vivo gene therapy to treat mucopolysaccharidosis type IVB.
- Author
-
Crippa S, Alberti G, Passerini L, Savoia EO, Mancino M, De Ponti G, Santi L, Berti M, Testa M, Hernandez RJ, Quaranta P, Ceriotti S, Visigalli I, Morrone A, Paoli A, Forni C, Scala S, Degano M, Staiano L, Gregori S, Aiuti A, and Bernardo ME
- Abstract
Mucopolysaccharidosis type IVB (MPSIVB) is a lysosomal storage disorder caused by β-galactosidase (β-GAL) deficiency characterized by severe skeletal and neurological alterations without approved treatments. To develop hematopoietic stem progenitor cell (HSPC) gene therapy (GT) for MPSIVB, we designed lentiviral vectors (LVs) encoding human β-GAL to achieve supraphysiological release of the therapeutic enzyme in human HSPCs and metabolic correction of diseased cells. Transduced HSPCs displayed proper colony formation, proliferation, and differentiation capacity, but their progeny failed to release the enzyme at supraphysiological levels. Therefore, we tested alternative LVs to overexpress an enhanced β-GAL deriving from murine (LV-enhGLB1) and human selectively mutated GLB1 sequences (LV-mutGLB1). Only human HSPCs transduced with LV-enhGLB1 overexpressed β-GAL in vitro and in vivo without evidence of overexpression-related toxicity. Their hematopoietic progeny efficiently released β-GAL, allowing the cross-correction of defective cells, including skeletal cells. We found that the low levels of human GLB1 mRNA in human hematopoietic cells and the improved stability of the enhanced β-GAL contribute to the increased efficacy of LV-enhGLB1. Importantly, the enhanced β-GAL enzyme showed physiological lysosomal trafficking in human cells and was not associated with increased immunogenicity in vitro . These results support the use of LV-enhGLB1 for further HSPC-GT development and future clinical translation to treat MPSIVB multisystem disease., Competing Interests: A.A., M.E.B., S.C., S.S., and P.Q. are inventors of an international patent application related to this work filed on 8th August 2023 (PCT/IB2023/057998)., (© 2024 The Authors.)
- Published
- 2024
- Full Text
- View/download PDF
26. Clostridial Myonecrosis: A Comprehensive Review of Toxin Pathophysiology and Management Strategies.
- Author
-
Hussain H, Fadel A, Garcia E, Hernandez RJ, Saadoon ZF, Naseer L, Casmartino E, Hamad M, Schnepp T, Sarfraz R, Angly S, and Jayakumar AR
- Abstract
Clostridial myonecrosis, commonly known as gas gangrene (GG), is a rapidly progressing and potentially fatal bacterial infection that primarily affects muscle and soft tissue. In the United States, the incidence of GG is roughly 1000 cases per year, while, in developing countries, the incidence is higher. This condition is most often caused by Clostridium perfringens , a Gram-positive, spore-forming anaerobic bacterium widely distributed in the environment, although other Clostridium species have also been reported to cause GG. The CP genome contains over 200 transport-related genes, including ABC transporters, which facilitate the uptake of sugars, amino acids, nucleotides, and ions from the host environment. There are two main subtypes of GG: traumatic GG, resulting from injuries that introduce Clostridium spores into deep tissue, where anaerobic conditions allow for bacterial growth and toxin production, and spontaneous GG, which is rarer and often occurs in immunocompromised patients. Clostridium species produce various toxins (e.g., alpha, theta, beta) that induce specific downstream signaling changes in cellular pathways, causing apoptosis or severe, fatal immunological conditions. For example, the Clostridium perfringens alpha toxin (CPA) targets the host cell's plasma membrane, hydrolyzing sphingomyelin and phosphatidylcholine, which triggers necrosis and apoptosis. The clinical manifestations of clostridial myonecrosis vary. Some patients experience the sudden onset of severe pain, swelling, and muscle tenderness, with the infection progressing rapidly to widespread tissue necrosis, systemic toxicity, and, if untreated, death. Other patients present with discharge, pain, and features of cellulitis. The diagnosis of GG primarily involves clinical evaluation, imaging studies such as X-rays, computer tomography (CT) scans, and culture. The treatment of GG involves surgical exploration, broad-spectrum antibiotics, antitoxin, and hyperbaric oxygen therapy, which is considered an adjunctive treatment to inhibit anaerobic bacterial growth and enhance the antibiotic efficacy. Early recognition and prompt, comprehensive treatment are critical to improving the outcomes for patients affected by this severe and life-threatening condition., Competing Interests: The authors declare no conflicts of interest.
- Published
- 2024
- Full Text
- View/download PDF
27. Linking Vascular Structure and Function: Image-Based Virtual Populations of the Retina.
- Author
-
Hernandez RJ, Madhusudhan S, Zheng Y, and El-Bouri WK
- Subjects
- Humans, Hemodynamics physiology, Blood Flow Velocity physiology, Male, Female, Adult, Macula Lutea blood supply, Macula Lutea diagnostic imaging, Blood Pressure physiology, Tomography, Optical Coherence methods, Retinal Vessels diagnostic imaging, Retinal Vessels physiology, Retinal Vessels anatomy & histology, Fluorescein Angiography methods, Regional Blood Flow physiology
- Abstract
Purpose: This study explored the relationship among microvascular parameters as delineated by optical coherence tomography angiography (OCTA) and retinal perfusion. Here, we introduce a versatile framework to examine the interplay between the retinal vascular structure and function by generating virtual vasculatures from central retinal vessels to macular capillaries. Also, we have developed a hemodynamics model that evaluates the associations between vascular morphology and retinal perfusion., Methods: The generation of the vasculature is based on the distribution of four clinical parameters pertaining to the dimension and blood pressure of the central retinal vessels, constructive constrained optimization, and Voronoi diagrams. Arterial and venous trees are generated in the temporal retina and connected through three layers of capillaries at different depths in the macula. The correlations between total retinal blood flow and macular flow fraction and vascular morphology are derived as Spearman rank coefficients, and uncertainty from input parameters is quantified., Results: A virtual cohort of 200 healthy vasculatures was generated. Means and standard deviations for retinal blood flow and macular flow fraction were 20.80 ± 7.86 µL/min and 15.04% ± 5.42%, respectively. Retinal blood flow was correlated with vessel area density, vessel diameter index, fractal dimension, and vessel caliber index. The macular flow fraction was not correlated with any morphological metrics., Conclusions: The proposed framework is able to reproduce vascular networks in the macula that are morphologically and functionally similar to real vasculature. The framework provides quantitative insights into how macular perfusion can be affected by changes in vascular morphology delineated on OCTA.
- Published
- 2024
- Full Text
- View/download PDF
28. In-hospital outcomes of septal myectomy vs. alcohol septal ablation for hypertrophic cardiomyopathy with outflow tract obstruction: An update and insights from the national inpatient sample from 2011 to 2019.
- Author
-
Inestroza K, Mijares-Rojas I, Matute-Martínez C, Ergui I, Albosta M, Vergara-Sanchez C, Dangl M, Hernandez RJ, Ebner B, Vincent LT, Maning J, Alfonso C, and Colombo R
- Subjects
- Humans, Treatment Outcome, Heart Septum surgery, Ethanol, Inpatients, Cardiomyopathy, Hypertrophic complications, Cardiomyopathy, Hypertrophic surgery
- Abstract
Septal Myectomy (SM) and Alcohol Septal Ablation (ASA) improve symptoms in patients with Hypertrophic Cardiomyopathy with outflow tract obstruction (oHCM). However, outcomes data in this population is predominantly from specialized centers. The National Inpatient Database was queried from 2011 to 2019 for relevant international classification of diseases (ICD)-9 and -10 diagnostic and procedural codes. We compared baseline characteristics and in-hospital outcomes of patients with oHCM who underwent SM vs ASA. A p-value < 0.001 was considered statistically significant. We identified 15,119 patients with oHCM who underwent septal reduction therapies, of whom 57.4% underwent SM, and 42.6% underwent ASA. Patients who underwent SM had higher all-cause mortality (OR: 1.8 (1.3-2.5)), post-procedure ischemic stroke (OR: 2.3 (1.7-3.2)), acute kidney injury (OR: 1.4 (1.2-1.7)), vascular complications (OR: 3.6 (2.3-5.3)), ventricular septal defect (OR: 4.4 (3.2-6.1)), cardiogenic shock (OR: 1.7 (1.3-2.3)), sepsis (OR: 3.2 (1.9-5.4)), and left bundle branch block (OR: 3.5 (3-4)), compared to ASA. Patients who underwent ASA had higher post-procedure complete heart block (OR: 1.3 (1.1-1.4)), right bundle branch block (OR: 6.3 (5-7.7)), ventricular tachycardia (OR: 2.2 (1.9-2.6)), supraventricular tachycardia (OR: 1.6 (1.4-2)), and more commonly required pacemaker insertion (OR: 1.4 (1.3-1.7)) (p < 0.001 for all) compared to SM. This nationwide analysis evidenced that patients undergoing SM had higher in-hospital mortality and periprocedural complications than ASA; however, those undergoing ASA had more post-procedure conduction abnormalities and pacemaker implantation. The implications of these findings warrant further investigation regarding patient selection strategies for these therapies., Competing Interests: Declaration of Conflicting InterestsThe author(s) 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
29. Tunable locking of calcite narrow frequency filters through modulation switching.
- Author
-
López-Vázquez A, Hernandez RJ, and Gomez E
- Abstract
Generating pairs of Raman beams for gravimetry with fiber phase modulators is quite convenient but generates additional frequencies that must be filtered. The frequency filtering could be achieved by using a long (dispersive) birefringent calcite crystal followed by a polarizer that blocks the transmission of certain laser frequencies, as has been shown before. Here, we present a method to tune such a filter to the desired frequency position. The correction signal for the feedback is obtained by comparing (subtracting) the transmission through the filter when sending light that has been phase modulated or not, taking advantage of the fiber modulator that is already installed in the system. The method allows for continuously alternating between using the modulator for monitoring the filter position and other uses, an important characteristic for the operation of a complete gravimetric sequence., (© 2023 Author(s). Published under an exclusive license by AIP Publishing.)
- Published
- 2023
- Full Text
- View/download PDF
30. Temperature, season, and latitude influence development-related phenotypes of Philippine Aedes aegypti (Linnaeus): Implications for dengue control amidst global warming.
- Author
-
Edillo F, Ymbong RR, Bolneo AA, Hernandez RJ, Fuentes BL, Cortes G, Cabrera J, Lazaro JE, and Sakuntabhai A
- Subjects
- Animals, Global Warming, Humans, Phenotype, Philippines epidemiology, Seasons, Temperature, Aedes, Dengue epidemiology
- Abstract
Background: Dengue is endemic in the Philippines. Aedes aegypti is the primary vector. This study aimed to determine the hatching behavior and viability of Ae. aegypti first-generation (F1) eggs when exposed to temperature and photoperiod regimes under laboratory conditions., Methods: Parental eggs were collected from selected highland and lowland sites in the Philippine big islands (Luzon, Visayas, and Mindanao) during the wet (2017-2018) and dry (2018) seasons. F1 egg cohorts were exposed separately in environmental chambers at 18, 25, and 38 °C with respective photoperiods for 6 weeks. Phenotypes (percent pharate larvae [PPL], hatch rates [HRs], and reproductive outputs [ROs]) were determined., Results: Results of multivariate analyses of variance (MANOVA) between seasons showed significant main effects of temperature, season, and big island on all phenotypes across all sites. Significant interaction effects between seasons on all phenotypes across sites were shown between or among (1) season and big island, (2) season and temperature, (3) big island and temperature, (4) season, big island, and temperature, (5) big island, altitude, and temperature, and (6) season, big island, altitude, and temperature. Factors associated with the big islands might include their ecology, available breeding sites, and day lengths due to latitudinal differences, although they were not measured in the field. MANOVA results within each season on all phenotypes across sites showed (1) significant main effects of big island and temperature, and (2) significant interaction effects between big island and temperature within the wet season and (3) between temperature and photoperiod within the dry season. PPL were highest at 18 °C and were formed even at 38 °C in both seasons. Pharate larvae might play an adaptive role in global warming, expanded distribution to highlands, and preponderance to transmit human diseases. HRs in both seasons were highest at 25 °C and lowest at 38 °C. ROs were highest at 25 °C in the wet season and at 18 °C in the dry season., Conclusions: Temperature and latitude of Philippine big islands influenced the development-related phenotypes of Ae. aegypti in both seasons. The two seasons influenced the phenotypes and their interaction effects with big island and/or temperature and/or altitude. Recommendations include year-round enhanced 4S control strategies for mosquito vectors and water pipeline installation in rural highlands., (© 2022. The Author(s).)
- Published
- 2022
- Full Text
- View/download PDF
31. Knee Injuries in the Elite American Football Player: A Descriptive Pictorial Imaging and Mechanism of Injury Review.
- Author
-
Hernandez RJ, Lamplot JD, Hammond KE, Joshi NB, Wong PK, Umpirrez M, Singer A, and Gonzalez FM
- Subjects
- Humans, Incidence, Football injuries, Knee Injuries diagnostic imaging
- Abstract
Abstract: Musculoskeletal injuries are common in American football, with an incidence ranging from approximately 10 to 35 per 1000 playing hours. Injuries occur more commonly in games than in practice. Although several studies have analyzed specific injury types in football, this review aims to describe the most common knee injuries sustained by American football players and to review the existing literature pertaining to the radiologic findings used in the diagnosis of these injuries., Competing Interests: The authors declare no conflict of interest., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)
- Published
- 2022
- Full Text
- View/download PDF
32. CT-guided versus MR-guided radiotherapy: Impact on gastrointestinal sparing in adrenal stereotactic body radiotherapy.
- Author
-
Rodriguez LL, Kotecha R, Tom MC, Chuong MD, Contreras JA, Romaguera T, Alvarez D, McCulloch J, Herrera R, Hernandez RJ, Mercado J, Mehta MP, Gutierrez AN, and Mittauer KE
- Subjects
- Humans, Organs at Risk, Radiotherapy Dosage, Radiotherapy Planning, Computer-Assisted, Tomography, X-Ray Computed, Radiosurgery, Radiotherapy, Image-Guided, Radiotherapy, Intensity-Modulated
- Abstract
Background and Purpose: To quantify the indication for adaptive, gated breath-hold (BH) MR-guided radiotherapy (MRgRT
BH ) versus BH or free-breathing (FB) CT-based image-guided radiotherapy (CT-IGRT) for the ablative treatment of adrenal malignancies., Materials and Methods: Twenty adrenal patients underwent adaptive IMRT MRgRTBH to a median dose of 50 Gy/5 fractions. Each patient was replanned for VMAT CT-IGRTBH and CT-IGRTFB on a c-arm linac. Only CT-IGRTFB used an ITV, summed from GTVs of all phases of the 4DCT respiratory evaluation. All used the same 5 mm GTV/ITV to PTV expansion. Metrics evaluated included: target volume and coverage, conformality, mean ipsilateral kidney and 0.5 cc gastrointestinal organ-at-risk (OAR) doses (D0.5cc ). Adaptive dose for MRgRTBH and predicted dose (i.e., initial plan re-calculated on anatomy of the day) was performed for CT-IGRTBH and MRgRTBH to assess frequency of OAR violations and coverage reductions for each fraction., Results: The more common VMAT CT-IGRTFB , with its significantly larger target volumes, proved inferior to MRgRTBH in mean PTV and ITV/GTV coverage, as well as small bowel D0.5cc . Conversely, VMAT CT-IGRTBH delivered a dosimetrically superior initial plan in terms of statistically significant (p ≤ 0.02) improvements in target coverage, conformality and D0.5cc to the large bowel, duodenum and mean ipsilateral kidney compared to IMRT MRgRTBH . However, non-adaptive CT-IGRTBH had a 71.8% frequency of predicted indications for adaptation and was 2.8 times more likely to experience a coverage reduction in PTV D95% than predicted for MRgRTBH ., Conclusion: Breath-hold VMAT radiotherapy provides superior target coverage and conformality over MRgRTBH , but the ability of MRgRTBH to safely provide ablative doses to adrenal lesions near mobile luminal OAR through adaptation and direct, real-time motion tracking is unmatched., (Copyright © 2021 The Authors. Published by Elsevier B.V. All rights reserved.)- Published
- 2022
- Full Text
- View/download PDF
33. Correction to: Experiences of early graduate medical students working in New York hospitals during the COVID-19 pandemic: a mixed methods study.
- Author
-
Pravder HD, Langdon-Embry L, Hernandez RJ, Berbari N, Shelov SP, and Kinzler WL
- Published
- 2021
- Full Text
- View/download PDF
34. Experiences of early graduate medical students working in New York hospitals during the COVID-19 pandemic: a mixed methods study.
- Author
-
Pravder HD, Langdon-Embry L, Hernandez RJ, Berbari N, Shelov SP, and Kinzler WL
- Subjects
- Adult, Cohort Studies, Delivery of Health Care organization & administration, Female, Focus Groups, Humans, Male, New York, SARS-CoV-2, Surveys and Questionnaires, COVID-19, Education, Medical, Graduate, Medical Staff, Hospital
- Abstract
Background: The coronavirus disease 2019 (COVID-19) pandemic presented the world with a sudden need for additional medical professionals. Senior medical students were identified as potential workers and many worldwide graduated early to serve as Junior Physicians in hospitals. The authors sought to identify factors that informed the decision to work, describe experiences in this capacity, and elucidate benefits for trainees., Methods: The investigators conducted a mixed-methods observational cohort study of early medical graduates eligible to work as Junior Physicians at two New York medical centers in April/May 2020 during an initial surge in COVID-19 hospitalizations. Graduates were surveyed, and a sample of Junior Physicians participated in a focus group. Survey responses of those who worked were compared to those who did not. Focus group responses were transcribed, coded, and thematically analyzed., Results: Fifty-nine graduates completed the study methods and 39 worked as Junior Physicians. Primary reasons for working included duty to help (39 [100%]), financial incentive (32 [82%]), desire to learn about pandemic response (25 [64%]), and educational incentive (24 [62%]). All had direct contact with COVID-19 patients, believed working was beneficial to their medical training, and were glad they worked. None contracted a symptomatic infection while working. Compared with non-Junior Physicians, Junior Physicians reported increased comfort levels in completing medical intern-level actions like transitions of care functions, such as writing transfer notes (P < 0.01), writing discharge orders (P = 0.01), and providing verbal sign out (P = 0.05), and they reported more comfort in managing COVID-19 patients. Sixteen themes emerged from the focus group and were placed into four categories: development of skills, patient care, safety, and wellness., Conclusions: Senior medical students chose to work as Junior Physicians for both personal and educational reasons. Experiences were beneficial to trainees and can inform future innovations in medical education.
- Published
- 2021
- Full Text
- View/download PDF
35. Conditioning Regimens in Long-Term Pre-Clinical Studies to Support Development of Ex Vivo Gene Therapy: Review of Nonproliferative and Proliferative Changes.
- Author
-
Chanut FJA, Sanvito F, Ferrari G, Visigalli I, Carriglio N, Hernandez RJ, Norata R, Doglioni C, Naldini L, and Cristofori P
- Subjects
- Animals, Busulfan, Cyclophosphamide, Genetic Therapy, Mice, Whole-Body Irradiation, Hematopoietic Stem Cell Transplantation, Transplantation Conditioning
- Abstract
Hematopoietic stem cell gene therapy has become a successful therapeutic strategy for some inherited genetic disorders. Pre-clinical toxicity studies performed to support the human clinical trials using viral-mediated gene transfer and autologous hematopoietic stem and progenitor cell (HSPC) transplantation are complex and the use of mouse models of human diseases makes interpretation of the results challenging. In addition, they rely on the use of conditioning agents that must induce enough myeloablation to allow engraftment of transduced and transplanted HSPC. Busulfan and total body irradiation (TBI) are the most commonly used conditioning regimens in the mouse. Lenticular degeneration and atrophy of reproductive organs are expected histopathological changes. Proliferative and nonproliferative lesions can be observed with different incidence and distribution across strains and mouse models of diseases. The occurrence of these lesions can interfere with the interpretation of pre-clinical toxicity and tumorigenicity studies performed to support the human clinical studies. As such, it is important to be aware of the background incidence of lesions induced by different conditioning regimens. We review the histopathology results from seven long-term studies, five using TBI and two using busulfan.
- Published
- 2021
- Full Text
- View/download PDF
36. The evaluation of comprehensive medication management for chronic diseases in primary care clinics, a Texas delivery system reform incentive payment program.
- Author
-
Chung TH, Hernandez RJ, Libaud-Moal A, Nguyen LK, Lal LS, Swint JM, Lansangan PJ, and Le YL
- Subjects
- Adolescent, Adult, Aged, Aged, 80 and over, Female, Health Care Reform, Health Services Research, Humans, Male, Middle Aged, Program Evaluation, Reimbursement, Incentive organization & administration, Retrospective Studies, Texas, Young Adult, Chronic Disease drug therapy, Medication Therapy Management organization & administration, Primary Health Care organization & administration
- Abstract
Background: The Institute of Medicine reported that more than 1.5 million preventable adverse drug events occur annually in the United States. Comprehensive Medication Management (CMM) is the medication review process to improve clinical outcomes, enhance patient adherence, reduce drug therapy problems and reduce health care costs. University of Texas (UT) Physicians implemented a CMM program in several community-based clinics. We evaluated the effectiveness of CMM to reduce drug therapy problems and achieve medical cost savings., Methods: This was a retrospective, observational study of CMM participants from October 2015 to September 2016. Program participants included patients aged 18 years or older who had taken more than 4 prescribed medications and were diagnosed with at least one of the following chronic diseases: hypertension, congestive heart failure, chronic obstructive pulmonary disease, asthma or diabetes. Under the CMM program, a clinical pharmacist reviewed patients' electronic health records and created action plans to resolve identified drug problems. As part of the evaluation of the clinical process, two independent physicians conducted peer review on the recommendations issued by the pharmacist in order to establish inter-rater reliability of drug therapy problems and potential consequent medical services. The drug therapy problems were identified and classified into four categories: indication, effectiveness, safety and/or compliance. The average cost of avoided medical services was obtained based on cost extrapolations from the literature, combined with hospital discharge data. Potential medical services avoided were linked to the average cost of those services to calculate the total cost savings of the program from the payers' perspective., Results: By reviewing electronic health records of 3280 patients, the pharmacist identified 301 drug therapy problems and resolved 49.8% of these problems with collaboration from the patient's primary care physician or care team. The most commonly identified drug problems were related to potentially adverse drug reactions or inappropriate drug dosage. The CMM program resulted in potential cost savings of $1,143,015., Conclusions: The CMM program resolved medication therapy problems among program participants and achieved significant health care cost savings.
- Published
- 2020
- Full Text
- View/download PDF
37. Bone marrow stromal cells from β-thalassemia patients have impaired hematopoietic supportive capacity.
- Author
-
Crippa S, Rossella V, Aprile A, Silvestri L, Rivis S, Scaramuzza S, Pirroni S, Avanzini MA, Basso-Ricci L, Hernandez RJ, Zecca M, Marktel S, Ciceri F, Aiuti A, Ferrari G, and Bernardo ME
- Subjects
- Animals, Bone Marrow Cells pathology, Coculture Techniques, Hematopoietic Stem Cells pathology, Humans, Mice, Stromal Cells metabolism, Stromal Cells pathology, beta-Thalassemia pathology, Bone Marrow Cells metabolism, Hematopoiesis, Hematopoietic Stem Cells metabolism, Oxidative Stress, beta-Thalassemia metabolism
- Abstract
Background: The human bone marrow (BM) niche contains a population of mesenchymal stromal cells (MSCs) that provide physical support and regulate hematopoietic stem cell (HSC) homeostasis. β-Thalassemia (BT) is a hereditary disorder characterized by altered hemoglobin beta-chain synthesis amenable to allogeneic HSC transplantation and HSC gene therapy. Iron overload (IO) is a common complication in BT patients affecting several organs. However, data on the BM stromal compartment are scarce., Methods: MSCs were isolated and characterized from BM aspirates of healthy donors (HDs) and BT patients. The state of IO was assessed and correlated with the presence of primitive MSCs in vitro and in vivo. Hematopoietic supportive capacity of MSCs was evaluated by transwell migration assay and 2D coculture of MSCs with human CD34+ HSCs. In vivo, the ability of MSCs to facilitate HSC engraftment was tested in a xenogenic transplant model, whereas the capacity to sustain human hematopoiesis was evaluated in humanized ossicle models., Results: We report that, despite iron chelation, BT BM contains high levels of iron and ferritin, indicative of iron accumulation in the BM niche. We found a pauperization of the most primitive MSC pool caused by increased ROS production in vitro which impaired MSC stemness properties. We confirmed a reduced frequency of primitive MSCs in vivo in BT patients. We also discovered a weakened antioxidative response and diminished expression of BM niche-associated genes in BT-MSCs. This caused a functional impairment in MSC hematopoietic supportive capacity in vitro and in cotransplantation models. In addition, BT-MSCs failed to form a proper BM niche in humanized ossicle models., Conclusion: Our results suggest an impairment in the mesenchymal compartment of BT BM niche and highlight the need for novel strategies to target the niche to reduce IO and oxidative stress before transplantation., Funding: This work was supported by the SR-TIGET Core grant from Fondazione Telethon and by Ricerca Corrente.
- Published
- 2019
- Full Text
- View/download PDF
38. Using the wax moth larva Galleria mellonella infection model to detect emerging bacterial pathogens.
- Author
-
Hernandez RJ, Hesse E, Dowling AJ, Coyle NM, Feil EJ, Gaze WH, and Vos M
- Abstract
Climate change, changing farming practices, social and demographic changes and rising levels of antibiotic resistance are likely to lead to future increases in opportunistic bacterial infections that are more difficult to treat. Uncovering the prevalence and identity of pathogenic bacteria in the environment is key to assessing transmission risks. We describe the first use of the Wax moth larva Galleria mellonella , a well-established model for the mammalian innate immune system, to selectively enrich and characterize pathogens from coastal environments in the South West of the UK. Whole-genome sequencing of highly virulent isolates revealed amongst others a Proteus mirabilis strain carrying the Salmonella SGI1 genomic island not reported from the UK before and the recently described species Vibrio injenensis hitherto only reported from human patients in Korea. Our novel method has the power to detect bacterial pathogens in the environment that potentially pose a serious risk to public health., Competing Interests: The authors declare that they have no competing interests.
- Published
- 2019
- Full Text
- View/download PDF
39. Mixed emulsion of liquid crystal microresonators: towards white laser systems.
- Author
-
Petriashvili G, De Santo MP, Hernandez RJ, Barberi R, and Cipparrone G
- Abstract
Microdroplet systems have attracted great interest because of their wide range of applications, easiness in processing and handling, feasibility in developing miniaturized devices with high performances and large flexibility. In this study, a stable emulsion based on different dye-doped chiral liquid crystal droplets has been engineered in order to achieve simultaneous omnidirectional lasing at different wavelengths. To obtain the mixed emulsion of dye doped Bragg onion-type microresonators the twofold action, as a surfactant and a droplet stabilizer, of the polyvinyl alcohol dissolved in water has been exploited. Multiple wavelengths lasing in all directions around the mixed emulsion is demonstrated. By water evaporation, a plastic sheet including different types of chiral droplets is also obtained, retaining all the emission characteristic of the precursor emulsion. A relevant feature is the large flexibility of the preparation method that enables an easy and full control of the lasing spectrum addressing white laser systems. However, the simplicity of the procedure based on a single-step process as well as the high stability of the mixed emulsion is a relevant result, envisaging strong potentiality for developing easy and friendly technologies useful in the field of identification, sensing, imaging, coating and lab-on-a-chip architectures.
- Published
- 2017
- Full Text
- View/download PDF
40. Impaired hypothalamic-pituitary-testicular axis activity, spermatogenesis, and sperm function promote infertility in males with lead poisoning.
- Author
-
Gandhi J, Hernandez RJ, Chen A, Smith NL, Sheynkin YR, Joshi G, and Khan SA
- Subjects
- Animals, Humans, Hypothalamo-Hypophyseal System drug effects, Infertility, Male chemically induced, Male, Hypothalamo-Hypophyseal System pathology, Infertility, Male pathology, Lead adverse effects, Lead Poisoning complications, Sperm Motility drug effects, Spermatogenesis drug effects, Testis drug effects
- Abstract
Lead poisoning is a stealthy threat to human physiological systems as chronic exposure can remain asymptomatic for long periods of time before symptoms manifest. We presently review the biophysical mechanisms of lead poisoning that contribute to male infertility. Environmental and occupational exposure of lead may adversely affect the hypothalamic-pituitary-testicular axis, impairing the induction of spermatogenesis. Dysfunction at the reproductive axis, namely testosterone suppression, is most susceptible and irreversible during pubertal development. Lead poisoning also appears to directly impair the process of spermatogenesis itself as well as sperm function. Spermatogenesis issues may manifest as low sperm count and stem from reproductive axis dysfunction or testicular degeneration. Generation of excessive reactive oxygen species due to lead-associated oxidative stress can potentially affect sperm viability, motility, DNA fragmentation, membrane lipid peroxidation, capacitation, hyperactivation, acrosome reaction, and chemotaxis for sperm-oocyte fusion, all of which can contribute to deter fertilization. Reproductive toxicity has been tested through cross-sectional analysis studies in humans as well as in vivo and in vitro studies in animals.
- Published
- 2017
- Full Text
- View/download PDF
41. Good Laboratory Practice Preclinical Safety Studies for GSK2696273 (MLV Vector-Based Ex Vivo Gene Therapy for Adenosine Deaminase Deficiency Severe Combined Immunodeficiency) in NSG Mice.
- Author
-
Carriglio N, Klapwijk J, Hernandez RJ, Vezzoli M, Chanut F, Lowe R, Draghici E, Nord M, Albertini P, Cristofori P, Richards J, Staton H, Appleby J, Aiuti A, and Sauer AV
- Subjects
- Adenosine Deaminase genetics, Agammaglobulinemia genetics, Animals, Drug Evaluation, Preclinical, Female, Gene Transfer Techniques, Humans, Male, Mice, Mice, Inbred NOD, Mice, SCID, Severe Combined Immunodeficiency genetics, Tissue Distribution, Adenosine Deaminase deficiency, Agammaglobulinemia therapy, Genetic Therapy, Genetic Vectors therapeutic use, Laboratories standards, Severe Combined Immunodeficiency therapy
- Abstract
GSK2696273 (autologous CD34+ cells transduced with retroviral vector that encodes for the human adenosine deaminase [ADA] enzyme) is a gamma-retroviral ex vivo gene therapy of bone marrow-derived CD34+ cells for the treatment of adenosine deaminase deficiency severe combined immunodeficiency (ADA-SCID). ADA-SCID is a severe monogenic disease characterized by immunologic and nonimmunologic symptoms. Bone-marrow transplant from a matched related donor is the treatment of choice, but it is available for only a small proportion of patients. Ex vivo gene therapy of patient bone-marrow CD34+ cells is an alternative treatment. In order to prepare for a marketing authorization application in the European Union, preclinical safety studies in mice were requested by the European Medicines Agency (EMA). A pilot study and a main biodistribution study were performed according to Good Laboratory Practice (GLP) at the San Raffaele Telethon Institute for Gene Therapy test facility. In the main study, human umbilical cord blood (UCB)-derived CD34+ cells were transduced with gamma-retroviral vector used in the production of GSK2696273. Groups of 10 male and 10 female NOD-SCID gamma (NSG) mice were injected intravenously with a single dose of transduced- or mock-transduced UCB CD34+ cells, and they were observed for 4 months. Engraftment and multilineage differentiation of blood cells was observed in the majority of animals in both groups. There was no significant difference in the level of chimerism between the two groups. In the gene therapy group, vector was detectable in lymphohemopoietic and nonlymphohemopoietic tissues, consistent with the presence of gene-modified human hematopoietic donor cells. Given the absence of relevant safety concerns in the data, the nonclinical studies and the clinical experience with GSK2696273 supported a successful application for market authorization in the European Union for the treatment of ADA-SCID patients, for whom no suitable human leukocyte antigen-matched related donor is available.
- Published
- 2017
- Full Text
- View/download PDF
42. Alterations in the brain adenosine metabolism cause behavioral and neurological impairment in ADA-deficient mice and patients.
- Author
-
Sauer AV, Hernandez RJ, Fumagalli F, Bianchi V, Poliani PL, Dallatomasina C, Riboni E, Politi LS, Tabucchi A, Carlucci F, Casiraghi M, Carriglio N, Cominelli M, Forcellini CA, Barzaghi F, Ferrua F, Minicucci F, Medaglini S, Leocani L, la Marca G, Notarangelo LD, Azzari C, Comi G, Baldoli C, Canale S, Sessa M, D'Adamo P, and Aiuti A
- Subjects
- Animals, Behavior, Behavior, Animal, Humans, Mice, Nervous System Diseases pathology, Adenosine metabolism, Adenosine Deaminase deficiency, Brain metabolism, Nervous System Diseases physiopathology
- Abstract
Adenosine Deaminase (ADA) deficiency is an autosomal recessive variant of severe combined immunodeficiency (SCID) caused by systemic accumulation of ADA substrates. Neurological and behavioral abnormalities observed in ADA-SCID patients surviving after stem cell transplantation or gene therapy represent an unresolved enigma in the field. We found significant neurological and cognitive alterations in untreated ADA-SCID patients as well as in two groups of patients after short- and long-term enzyme replacement therapy with PEG-ADA. These included motor dysfunction, EEG alterations, sensorineural hypoacusia, white matter and ventricular alterations in MRI as well as a low mental development index or IQ. Ada-deficient mice were significantly less active and showed anxiety-like behavior. Molecular and metabolic analyses showed that this phenotype coincides with metabolic alterations and aberrant adenosine receptor signaling. PEG-ADA treatment corrected metabolic adenosine-based alterations, but not cellular and signaling defects, indicating an intrinsic nature of the neurological and behavioral phenotype in ADA deficiency., Competing Interests: A.A. is the PI of a clinical trial of gene therapy for ADA-SCID sponsored by GSK, which has licensed the gene therapy from SR-TIGET. All other authors declare no competing financial interests.
- Published
- 2017
- Full Text
- View/download PDF
43. Light-induced rotations of chiral birefringent microparticles in optical tweezers.
- Author
-
Donato MG, Mazzulla A, Pagliusi P, Magazzù A, Hernandez RJ, Provenzano C, Gucciardi PG, Maragò OM, and Cipparrone G
- Abstract
We study the rotational dynamics of solid chiral and birefringent microparticles induced by elliptically polarized laser light in optical tweezers. We find that both reflection of left circularly polarized light and residual linear retardance affect the particle dynamics. The degree of ellipticity of laser light needed to induce rotations is found. The experimental results are compared with analytical calculations of the transfer of angular moment from elliptically polarized light to chiral birefringent particles.
- Published
- 2016
- Full Text
- View/download PDF
44. Overestimation and Underestimation Biases in Photon Mapping with Non-Constant Kernels.
- Author
-
Garcia Hernandez RJ, Ureña C, Poch J, and Sbert M
- Abstract
This paper presents an analysis of the overestimation bias in common used filtering kernels in the context of photon mapping density estimation. We use the joint distribution of order statistics to calculate the expected value of the estimators of irradiance, and show that the estimator provided by the cone filter is not consistent unless the slope is one (yielding the triangular kernel), and that the Epanechnikov and Silverman kernels are consistent. The Gaussian filter has two different estimation biases: the original normalization constant α underestimates radiance by 46.9 percent, and the use of the kth nearest photon reduces this underestimation slightly. We also show that a new normalization constant for the Gaussian filter together with discarding the contribution of the kth nearest photon in the Gaussian and cone filter estimators produces new, consistent estimators. The specialized differential filter also benefits from the new estimate.
- Published
- 2014
- Full Text
- View/download PDF
45. Dual-regulated lentiviral vector for gene therapy of X-linked chronic granulomatosis.
- Author
-
Chiriaco M, Farinelli G, Capo V, Zonari E, Scaramuzza S, Di Matteo G, Sergi LS, Migliavacca M, Hernandez RJ, Bombelli F, Giorda E, Kajaste-Rudnitski A, Trono D, Grez M, Rossi P, Finocchi A, Naldini L, Gentner B, and Aiuti A
- Subjects
- Animals, Antigens, CD34 metabolism, Cell Line, Cells, Cultured, Combined Modality Therapy, Disease Models, Animal, Genetic Vectors therapeutic use, Granulomatous Disease, Chronic pathology, Hematopoietic Stem Cells metabolism, Humans, Lentivirus genetics, Mice, Myeloid Cells metabolism, NADPH Oxidase 2, Genetic Therapy methods, Granulomatous Disease, Chronic therapy, Hematopoietic Stem Cell Transplantation methods, Hematopoietic Stem Cells virology, Membrane Glycoproteins metabolism, MicroRNAs genetics, NADPH Oxidases metabolism
- Abstract
Regulated transgene expression may improve the safety and efficacy of hematopoietic stem cell (HSC) gene therapy. Clinical trials for X-linked chronic granulomatous disease (X-CGD) employing gammaretroviral vectors were limited by insertional oncogenesis or lack of persistent engraftment. Our novel strategy, based on regulated lentiviral vectors (LV), targets gp91(phox) expression to the differentiated myeloid compartment while sparing HSC, to reduce the risk of genotoxicity and potential perturbation of reactive oxygen species levels. Targeting was obtained by a myeloid-specific promoter (MSP) and posttranscriptional, microRNA-mediated regulation. We optimized both components in human bone marrow (BM) HSC and their differentiated progeny in vitro and in a xenotransplantation model, and generated therapeutic gp91(phox) expressing LVs for CGD gene therapy. All vectors restored gp91(phox) expression and function in human X-CGD myeloid cell lines, primary monocytes, and differentiated myeloid cells. While unregulated LVs ectopically expressed gp91(phox) in CD34(+) cells, transcriptionally and posttranscriptionally regulated LVs substantially reduced this off-target expression. X-CGD mice transplanted with transduced HSC restored gp91(phox) expression, and MSP-driven vectors maintained regulation during BM development. Combining transcriptional (SP146.gp91-driven) and posttranscriptional (miR-126-restricted) targeting, we achieved high levels of myeloid-specific transgene expression, entirely sparing the CD34(+) HSC compartment. This dual-targeted LV construct represents a promising candidate for further clinical development.
- Published
- 2014
- Full Text
- View/download PDF
46. Effects of full-scale beach renovation on fecal indicator levels in shoreline sand and water.
- Author
-
Hernandez RJ, Hernandez Y, Jimenez NH, Piggot AM, Klaus JS, Feng Z, Reniers A, and Solo-Gabriele HM
- Subjects
- Biofilms, Colony Count, Microbial, Enterococcus isolation & purification, Feces microbiology, Water Microbiology
- Abstract
Recolonization of enterococci, at a non-point source beach known to contain high background levels of bacteria, was studied after a full-scale beach renovation project. The renovation involved importation of new exogenous sand, in addition to infrastructure improvements. The study's objectives were to document changes in sand and water quality and to evaluate the relative contribution of different renovation activities towards these changes. These objectives were addressed: by measuring enterococci levels in the sand and fecal indicator bacteria levels (enterococci and fecal coliform) in the water, by documenting sediment characteristics (mineralogy and biofilm levels), and by estimating changes in observable enterococci loads. Analysis of enterococci levels on surface sand and within sediment depth cores were significantly higher prior to beach renovation (6.3-72 CFU/g for each sampling day) when compared to levels during and after beach renovation (0.8-12 CFU/g) (P < 0.01). During the renovation process, sand enterococci levels were frequently below detection limits (<0.1 CFU/g). For water, exceedances in the regulatory thresholds that would trigger a beach advisory decreased by 40% for enterococci and by 90% for fecal coliform. Factors that did not change significantly between pre- and post- renovation included the enterococci loads from animals (approx. 3 × 10(11) CFU per month). Factors that were observed to change between pre- and post- renovation activities included: the composition of the beach sand (64% versus 98% quartz, and a significant decrease in biofilm levels) and loads from direct stormwater inputs (reduction of 3 × 10(11) CFU per month). Overall, this study supports that beach renovation activities contributed to improved sand and water quality resulting in a 50% decrease of observable enterococci loads due to upgrades to the stormwater infrastructure. Of interest was that the change in the sand mineralogy also coincided with changes in biofilm levels. More work is needed to evaluate the relationships between beach sand mineralogy, biofilm characteristics, and the retention of fecal indicator bacteria in sand., (Copyright © 2013 Elsevier Ltd. All rights reserved.)
- Published
- 2014
- Full Text
- View/download PDF
47. Efficacy of a cartoon and photograph montage storybook in preparing children for voiding cystourethrogram.
- Author
-
Gebarski KS, Daley J, Gebarski MW, Keshavarzi N, Hernandez RJ, Ivanzic V, and Gebarski SS
- Subjects
- Adolescent, Child, Child, Preschool, Female, Humans, Male, Stress, Psychological etiology, Treatment Outcome, Urination, Urography adverse effects, Urography psychology, Books, Illustrated, Cartoons as Topic psychology, Narration, Patient Education as Topic methods, Stress, Psychological prevention & control, Stress, Psychological psychology
- Abstract
Background: Undergoing voiding cystourethrogram (VCUG) can be distressing for children., Objective: To assess the efficacy of a cartoon and photograph montage storybook in preparing children for VCUG., Materials and Methods: Outpatient children (ages 2-14 years) who had VCUGs between December 2011 and June 2012 were randomly assigned to two groups; one group received the storybook a week before the procedure. Parents and guardians were asked to complete an anonymous survey rating their child's tolerance of the exam from 1 to 5, worst to best, immediately after VCUG. The VCUG technologist also rated the child's tolerance., Results: Children prepared for VCUG with the storybook had less distress than those without. Results were analyzed by Cochran-Mantel-Haenszel and Cochran-Armitage Trend exact tests, a P value of both tests of 0.0092 indicating a statistically significant difference between the tolerance scores of children prepared with the storybook and those without. Effects of gender and history of VCUG were not statistically significant. Two-thirds of all children had no other source of information., Conclusion: The cartoon and photograph montage storybook format of preparing children for VCUG was effective in increasing their tolerance for the procedure. The storybook should be mailed out in advance because the majority of families did not pursue information on preparing their children for VCUG.
- Published
- 2013
- Full Text
- View/download PDF
48. Preclinical safety and efficacy of human CD34(+) cells transduced with lentiviral vector for the treatment of Wiskott-Aldrich syndrome.
- Author
-
Scaramuzza S, Biasco L, Ripamonti A, Castiello MC, Loperfido M, Draghici E, Hernandez RJ, Benedicenti F, Radrizzani M, Salomoni M, Ranzani M, Bartholomae CC, Vicenzi E, Finocchi A, Bredius R, Bosticardo M, Schmidt M, von Kalle C, Montini E, Biffi A, Roncarolo MG, Naldini L, Villa A, and Aiuti A
- Subjects
- Animals, Bone Marrow Cells immunology, Mice, Mice, Knockout, Antigens, CD34 immunology, Bone Marrow Cells cytology, Bone Marrow Transplantation, Genetic Vectors, Lentivirus genetics, Transduction, Genetic, Wiskott-Aldrich Syndrome therapy
- Abstract
Gene therapy with ex vivo-transduced hematopoietic stem/progenitor cells may represent a valid therapeutic option for monogenic immunohematological disorders such as Wiskott-Aldrich syndrome (WAS), a primary immunodeficiency associated with thrombocytopenia. We evaluated the preclinical safety and efficacy of human CD34(+) cells transduced with lentiviral vectors (LV) encoding WAS protein (WASp). We first set up and validated a transduction protocol for CD34(+) cells derived from bone marrow (BM) or mobilized peripheral blood (MPB) using a clinical grade, highly purified LV. Robust transduction of progenitor cells was obtained in normal donors and WAS patients' cells, without evidence of toxicity. To study biodistribution of human cells and exclude vector release in vivo, LV-transduced CD34(+) cells were transplanted in immunodeficient mice, showing a normal engraftment and differentiation ability towards transduced lymphoid and myeloid cells in hematopoietic tissues. Vector mobilization to host cells and transmission to germline cells of the LV were excluded by different molecular assays. Analysis of vector integrations showed polyclonal integration patterns in vitro and in human engrafted cells in vivo. In summary, this work establishes the preclinical safety and efficacy of human CD34(+) cells gene therapy for the treatment of WAS.
- Published
- 2013
- Full Text
- View/download PDF
49. Alterations in the adenosine metabolism and CD39/CD73 adenosinergic machinery cause loss of Treg cell function and autoimmunity in ADA-deficient SCID.
- Author
-
Sauer AV, Brigida I, Carriglio N, Hernandez RJ, Scaramuzza S, Clavenna D, Sanvito F, Poliani PL, Gagliani N, Carlucci F, Tabucchi A, Roncarolo MG, Traggiai E, Villa A, and Aiuti A
- Subjects
- 5'-Nucleotidase metabolism, Adenosine metabolism, Adenosine Deaminase deficiency, Adenosine Deaminase genetics, Adenosine Deaminase immunology, Adenosine Deaminase metabolism, Adenosine Deaminase therapeutic use, Adolescent, Adult, Agammaglobulinemia genetics, Agammaglobulinemia therapy, Animals, Antigens, CD metabolism, Apyrase metabolism, Autoantibodies immunology, Child, Child, Preschool, Female, Forkhead Transcription Factors immunology, Forkhead Transcription Factors metabolism, Genetic Therapy methods, Hematopoietic Stem Cell Transplantation methods, Humans, Hypothyroidism enzymology, Hypothyroidism genetics, Hypothyroidism immunology, Immunohistochemistry, Infant, Male, Mice, Mice, Knockout, Polyethylene Glycols chemistry, Severe Combined Immunodeficiency genetics, Severe Combined Immunodeficiency therapy, T-Lymphocytes, Regulatory metabolism, 5'-Nucleotidase immunology, Adenosine immunology, Agammaglobulinemia immunology, Antigens, CD immunology, Apyrase immunology, Severe Combined Immunodeficiency immunology, T-Lymphocytes, Regulatory immunology
- Abstract
Adenosine acts as anti-inflammatory mediator on the immune system and has been described in regulatory T cell (Treg)-mediated suppression. In the absence of adenosine deaminase (ADA), adenosine and other purine metabolites accumulate, leading to severe immunodeficiency with recurrent infections (ADA-SCID). Particularly ADA-deficient patients with late-onset forms and after enzyme replacement therapy (PEG-ADA) are known to manifest immune dysregulation. Herein we provide evidence that alterations in the purine metabolism interfere with Treg function, thereby contributing to autoimmune manifestations in ADA deficiency. Tregs isolated from PEG-ADA-treated patients are reduced in number and show decreased suppressive activity, whereas they are corrected after gene therapy. Untreated murine ADA(-/-) Tregs show alterations in the plasma membrane CD39/CD73 ectonucleotidase machinery and limited suppressive activity via extracellular adenosine. PEG-ADA-treated mice developed multiple autoantibodies and hypothyroidism in contrast to mice treated with bone marrow transplantation or gene therapy. Tregs isolated from PEG-ADA-treated mice lacked suppressive activity, suggesting that this treatment interferes with Treg functionality. The alterations in the CD39/CD73 adenosinergic machinery and loss of function in ADA-deficient Tregs provide new insights into a predisposition to autoimmunity and the underlying mechanisms causing defective peripheral tolerance in ADA-SCID.
- Published
- 2012
- Full Text
- View/download PDF
50. Chiral self-assembled solid microspheres: a novel multifunctional microphotonic device.
- Author
-
Cipparrone G, Mazzulla A, Pane A, Hernandez RJ, and Bartolino R
- Subjects
- Colloids chemistry, Emulsions, Equipment Design, Glass, Lasers, Light, Liquid Crystals, Materials Testing, Microscopy methods, Optics and Photonics methods, Photons, Polymers chemistry, Microspheres, Optical Tweezers
- Abstract
Solid chiral microspheres with unique and multifunctional optical properties are produced from cholesteric liquid crystal-water emulsions using photopolymerization processes. These self-organizing microspheres exhibit different internal configurations of helicoidal structures with radial, conical or cylindrical geometries, depending on the physicochemical characteristics of the precursor liquid crystal emulsion., (Copyright © 2011 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)
- Published
- 2011
- Full Text
- View/download PDF
Catalog
Discovery Service for Jio Institute Digital Library
For full access to our library's resources, please sign in.