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2.
Surg Infect (Larchmt) ; 25(5): 357-361, 2024 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-38709799

RESUMEN

Background: Tsukamurella species were first isolated in 1941. Since then, 48 cases of Tsukamurella bacteremia have been reported, a majority of which were immunosuppressed patients with central venous catheters.A case is described and previous cases of Tsukamurella bacteremia are reviewed. Patients and Methods: A 70-year-old total parenteral nutrition (TPN)-dependent female with recurrent enterocutaneous fistula (ECF), developed leukocytosis one week after a challenging ECF takedown. After starting broad-spectrum antibiotic agents, undergoing percutaneous drainage of intra-abdominal abscess, and subsequent repositioning of the drain, her leukocytosis resolved. Blood and peripherally inserted central catheter (PICC) cultures grew Tsukamurella spp. The patient was discharged to home with 14 days of daily 2 g ceftriaxone, with resolution of bacteremia. Conclusions: Tsukamurella spp. are a rare opportunistic pathogen predominantly affecting immunocompromised patients, with central venous catheters present in most cases. However, there have been few reported cases in immunocompetent individuals with predisposing conditions such as end-stage renal disease and uncontrolled diabetes mellitus.


Asunto(s)
Infecciones por Actinomycetales , Antibacterianos , Bacteriemia , Humanos , Anciano , Femenino , Bacteriemia/microbiología , Bacteriemia/tratamiento farmacológico , Antibacterianos/uso terapéutico , Infecciones por Actinomycetales/microbiología , Infecciones por Actinomycetales/tratamiento farmacológico , Fístula Intestinal/microbiología , Fístula Intestinal/cirugía , Huésped Inmunocomprometido
5.
Mol Genet Metab ; 132(1): 27-37, 2021 01.
Artículo en Inglés | MEDLINE | ID: mdl-33129689

RESUMEN

Pathogenic alterations in the DPM2 gene have been previously described in patients with hypotonia, progressive muscle weakness, absent psychomotor development, intractable seizures, and early death. We identified biallelic DPM2 variants in a 23-year-old male with truncal hypotonia, hypertonicity, congenital heart defects, intellectual disability, and generalized muscle wasting. His clinical presentation was much less severe than that of the three previously described patients. This is the second report on this ultra-rare disorder. Here we review the characteristics of previously reported individuals with a defect in the DPM complex while expanding the clinical phenotype of DPM2-Congenital Disorders of Glycosylation. In addition, we offer further insights into the pathomechanism of DPM2-CDG disorder by introducing glycomics and lipidomics analysis.


Asunto(s)
Trastornos Congénitos de Glicosilación/genética , Predisposición Genética a la Enfermedad , Discapacidad Intelectual/genética , Manosiltransferasas/genética , Adulto , Trastornos Congénitos de Glicosilación/diagnóstico , Trastornos Congénitos de Glicosilación/patología , Humanos , Discapacidad Intelectual/diagnóstico , Discapacidad Intelectual/patología , Masculino , Debilidad Muscular/diagnóstico , Debilidad Muscular/genética , Debilidad Muscular/patología , Mutación/genética , Fenotipo
6.
Mol Genet Metab ; 131(1-2): 135-146, 2020.
Artículo en Inglés | MEDLINE | ID: mdl-33342467

RESUMEN

Phosphoglucomutase 1 deficiency is a congenital disorder of glycosylation (CDG) with multiorgan involvement affecting carbohydrate metabolism, N-glycosylation and energy production. The metabolic management consists of dietary D-galactose supplementation that ameliorates hypoglycemia, hepatic dysfunction, endocrine anomalies and growth delay. Previous studies suggest that D-galactose administration in juvenile patients leads to more significant and long-lasting effects, stressing the urge of neonatal diagnosis (0-6 months of age). Here, we detail the early clinical presentation of PGM1-CDG in eleven infantile patients, and applied the modified Beutler test for screening of PGM1-CDG in neonatal dried blood spots (DBSs). All eleven infants presented episodic hypoglycemia and elevated transaminases, along with cleft palate and growth delay (10/11), muscle involvement (8/11), neurologic involvement (5/11), cardiac defects (2/11). Standard dietary measures for suspected lactose intolerance in four patients prior to diagnosis led to worsening of hypoglycemia, hepatic failure and recurrent diarrhea, which resolved upon D-galactose supplementation. To investigate possible differences in early vs. late clinical presentation, we performed the first systematic literature review for PGM1-CDG, which highlighted respiratory and gastrointestinal symptoms as significantly more diagnosed in neonatal age. The modified Butler-test successfully identified PGM1-CDG in DBSs from seven patients, including for the first time Guthrie cards from newborn screening, confirming the possibility of future inclusion of PGM1-CDG in neonatal screening programs. In conclusion, severe infantile morbidity of PGM1-CDG due to delayed diagnosis could be prevented by raising awareness on its early presentation and by inclusion in newborn screening programs, enabling early treatments and galactose-based metabolic management.


Asunto(s)
Trastornos Congénitos de Glicosilación/genética , Enfermedad del Almacenamiento de Glucógeno/sangre , Hipoglucemia/genética , Fosfoglucomutasa/sangre , Fisura del Paladar/sangre , Fisura del Paladar/complicaciones , Fisura del Paladar/genética , Trastornos Congénitos de Glicosilación/sangre , Trastornos Congénitos de Glicosilación/complicaciones , Trastornos Congénitos de Glicosilación/enzimología , Pruebas con Sangre Seca , Femenino , Enfermedad del Almacenamiento de Glucógeno/enzimología , Enfermedad del Almacenamiento de Glucógeno/genética , Humanos , Hipoglucemia/sangre , Hipoglucemia/complicaciones , Lactante , Recién Nacido , Masculino , Tamizaje Neonatal , Fenotipo , Fosfoglucomutasa/genética
7.
J Trauma Acute Care Surg ; 89(6): 1233-1238, 2020 12.
Artículo en Inglés | MEDLINE | ID: mdl-32890346

RESUMEN

BACKGROUND: Penetrating neck trauma (PNT) continues to present a diagnostic dilemma. Practice guidelines advocate the use of computed tomography angiography (CTA) for suspected vascular or aerodigestive injuries in all neck zones. There is also an evolving evidence of "no-zone" approach where the decision to obtain a CTA is guided by physical examination findings and clinical presentation. The aim of this systematic review was to examine existing literature on the diagnostic accuracy of CTA as an integral component of the no-zone approach in stable patients with PNT. METHODS: We performed a systematic review using an electronic search of three databases (PubMed, Medline, Cochrane Review) from 2000 to 2017. RESULTS: A total of 5 prospective and 8 retrospective studies were included. The sensitivity of CTA ranged from 83% to 100%; specificity, from 61% to 100%; positive predictive value, from 30% to 100%; and negative predictive value, from 90% to 100%. Three studies reported high sensitivity and specificity for the detection of vascular injuries but low specificity for aerodigestive tract injuries. When stratified by clinical presentation, CTA had a sensitivity of 89.5% to 100% and specificity of 61% to 100% in stable patients presenting with soft signs (SSs). In a combined group of stable patients with either hard signs (HSs) or SSs, the sensitivity of CTA was 94.4% to 100% and the specificity was 96.7% to 100%. Among patients presenting with HSs, the sensitivity of CTA was 78.6% to 90% and the specificity was 100%. CONCLUSIONS: This is the first systematic review to examine the role of CTA in PNT. In combination with physical examination, CTA demonstrated a reliable high sensitivity and specificity for detecting injuries in PNT in stable patients with SSs of injury and select patients with HSs of injury. These results support the management of PNT using no-zone approach based on physical examination and the use of CTA in stable patients. LEVEL OF EVIDENCE: Systematic review, level IV.


Asunto(s)
Angiografía por Tomografía Computarizada , Traumatismos del Cuello/diagnóstico por imagen , Heridas Penetrantes/diagnóstico por imagen , Humanos , Examen Físico
9.
Clin Transplant ; 34(7): e13991, 2020 07.
Artículo en Inglés | MEDLINE | ID: mdl-32446267

RESUMEN

The data on the outcomes of solid organ transplant recipients who have contracted coronavirus disease 2019 (COVID-19) are still emerging. Kidney transplant recipients are commonly prescribed renin-angiotensin-aldosterone system (AAS) inhibitors given the prevalence of hypertension, diabetes, and cardiovascular disease. As the angiotensin-converting enzyme 2 (ACE2) facilitates the entry of coronaviruses into target cells, there have been hypotheses that preexisting use of renin-angiotensin-aldosterone system (RAAS) inhibitors may increase the risk of developing severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Given the common use of RAAS inhibitors among solid organ transplant recipients, we sought to review the RAAS cascade, the mechanism of SARS-CoV-2 entry, and pertinent data related to the effect of RAAS inhibitors on ACE2 to guide management of solid organ transplant recipients during the COVID-19 pandemic. At present, there is no clear evidence to support the discontinuation of RAAS inhibitors in solid organ transplant recipients during the COVID-19 pandemic.


Asunto(s)
Antagonistas de Receptores de Angiotensina/uso terapéutico , Inhibidores de la Enzima Convertidora de Angiotensina/uso terapéutico , Betacoronavirus , Enfermedades Cardiovasculares/terapia , Infecciones por Coronavirus/complicaciones , Trasplante de Órganos , Neumonía Viral/complicaciones , COVID-19 , Enfermedades Cardiovasculares/complicaciones , Infecciones por Coronavirus/diagnóstico , Infecciones por Coronavirus/terapia , Humanos , Pandemias , Neumonía Viral/diagnóstico , Neumonía Viral/terapia , Sistema Renina-Angiotensina/fisiología , SARS-CoV-2
11.
Am J Hum Genet ; 104(5): 835-846, 2019 05 02.
Artículo en Inglés | MEDLINE | ID: mdl-30982613

RESUMEN

Phosphoglucomutase 1 (PGM1) encodes the metabolic enzyme that interconverts glucose-6-P and glucose-1-P. Mutations in PGM1 cause impairment in glycogen metabolism and glycosylation, the latter manifesting as a congenital disorder of glycosylation (CDG). This unique metabolic defect leads to abnormal N-glycan synthesis in the endoplasmic reticulum (ER) and the Golgi apparatus (GA). On the basis of the decreased galactosylation in glycan chains, galactose was administered to individuals with PGM1-CDG and was shown to markedly reverse most disease-related laboratory abnormalities. The disease and treatment mechanisms, however, have remained largely elusive. Here, we confirm the clinical benefit of galactose supplementation in PGM1-CDG-affected individuals and obtain significant insights into the functional and biochemical regulation of glycosylation. We report here that, by using tracer-based metabolomics, we found that galactose treatment of PGM1-CDG fibroblasts metabolically re-wires their sugar metabolism, and as such replenishes the depleted levels of galactose-1-P, as well as the levels of UDP-glucose and UDP-galactose, the nucleotide sugars that are required for ER- and GA-linked glycosylation, respectively. To this end, we further show that the galactose in UDP-galactose is incorporated into mature, de novo glycans. Our results also allude to the potential of monosaccharide therapy for several other CDG.


Asunto(s)
Trastornos Congénitos de Glicosilación/metabolismo , Fibroblastos/metabolismo , Galactosa/administración & dosificación , Fosfoglucomutasa/deficiencia , Uridina Difosfato Galactosa/metabolismo , Uridina Difosfato Glucosa/metabolismo , Células Cultivadas , Estudios de Cohortes , Trastornos Congénitos de Glicosilación/tratamiento farmacológico , Trastornos Congénitos de Glicosilación/patología , Fibroblastos/efectos de los fármacos , Fibroblastos/patología , Glicosilación , Humanos
12.
Obstet Gynecol ; 133(4): 780-782, 2019 04.
Artículo en Inglés | MEDLINE | ID: mdl-30870304

RESUMEN

BACKGROUND: Endometrial intraepithelial neoplasia is a precursor lesion to endometrial adenocarcinoma. Total hysterectomy is the preferred management, but systemic or locally acting progestin therapies are acceptable alternatives. The use of the etonogestrel subdermal implant for treatment of endometrial intraepithelial neoplasia has not been studied. CASE: A 36-year-old woman, G2P2002, with obesity presented with abnormal uterine bleeding. Her endometrial specimen demonstrated endometrial intraepithelial neoplasia. She declined both hysterectomy and conventional medical management. The etonogestrel implant was offered as an alternative to no treatment. After etonogestrel implant insertion, serial biopsies showed regression of endometrial intraepithelial neoplasia. Sixteen months after implant insertion, biopsy showed inactive and atrophic endometrium. CONCLUSION: The etonogestrel subdermal implant should be considered for further study for the treatment of endometrial intraepithelial neoplasia in women who decline surgical management.


Asunto(s)
Adenocarcinoma/tratamiento farmacológico , Adenocarcinoma/patología , Agentes Anticonceptivos Hormonales/administración & dosificación , Desogestrel/administración & dosificación , Implantes de Medicamentos , Neoplasias Endometriales/tratamiento farmacológico , Adulto , Biopsia con Aguja , Neoplasias Endometriales/patología , Endometriosis/tratamiento farmacológico , Endometriosis/patología , Femenino , Estudios de Seguimiento , Humanos , Inmunohistoquímica , Tejido Subcutáneo , Factores de Tiempo , Resultado del Tratamiento , Hemorragia Uterina/prevención & control
13.
J Trauma Acute Care Surg ; 86(1): 43-51, 2019 01.
Artículo en Inglés | MEDLINE | ID: mdl-30358768

RESUMEN

BACKGROUND: Despite increasing popularity of prehospital tourniquet use in civilians, few studies have evaluated the efficacy and safety of tourniquet use. Furthermore, previous studies in civilian populations have focused on blunt trauma patients. The objective of this study was to determine if prehospital tourniquet use in patients with major penetrating trauma is associated with differences in outcomes compared to a matched control group. METHODS: An 8-year retrospective analysis of adult patients with penetrating major extremity trauma amenable to tourniquet use (major vascular trauma, traumatic amputation and near-amputation) was performed at a Level I trauma center. Patients with prehospital tourniquet placement (TQ) were identified and compared to a matched group of patients without tourniquets (N-TQ). Univariate analysis was used to compare outcomes in the groups. RESULTS: A total of 204 patients were matched with 127 (62.3%) in the prehospital TQ group. No differences in patient demographics or injury severity existed between the two groups. Average time from tourniquet application to arrival in the emergency department (ED) was 22.5 ± 1.3 minutes. Patients in the TQ group had higher average systolic blood pressure on arrival in the ED (120 ± 2 vs. 112 ± 2, p = 0.003). The TQ group required less total PRBCs (2.0 ± 0.1 vs. 9.3 ± 0.6, p < 0.001) and FFP (1.4 ± 0.08 vs. 6.2 ± 0.4, p < 0.001). Tourniquets were not associated with nerve palsy (p = 0.330) or secondary infection (p = 0.43). Fasciotomy was significantly higher in the N-TQ group (12.6% vs. 31.4%, p < 0.0001) as was limb amputation (0.8% vs. 9.1%, p = 0.005). CONCLUSION: This study demonstrated that prehospital tourniquets could be safely used to control bleeding in major extremity penetrating trauma with no increased risk of major complications. Prehospital tourniquet use was also associated with increased systolic blood pressure on arrival to the ED, decreased blood product utilization and decreased incidence of limb related complications, which may lead to improved long-term outcomes and increased survival in trauma patients. LEVEL OF EVIDENCE: Therapeutic, level IV.


Asunto(s)
Transfusión Sanguínea/estadística & datos numéricos , Extremidades/lesiones , Hemorragia/terapia , Torniquetes/efectos adversos , Heridas Penetrantes/complicaciones , Adulto , Amputación Quirúrgica/efectos adversos , Amputación Quirúrgica/estadística & datos numéricos , Amputación Traumática/complicaciones , Presión Sanguínea/fisiología , Estudios de Casos y Controles , Servicios Médicos de Urgencia/normas , Servicio de Urgencia en Hospital/estadística & datos numéricos , Extremidades/irrigación sanguínea , Fasciotomía/estadística & datos numéricos , Femenino , Hemorragia/prevención & control , Humanos , Masculino , Persona de Mediana Edad , Evaluación de Resultado en la Atención de Salud , Estudios Retrospectivos , Factores de Tiempo , Torniquetes/estadística & datos numéricos , Centros Traumatológicos , Índices de Gravedad del Trauma , Lesiones del Sistema Vascular/complicaciones , Heridas Penetrantes/etnología , Heridas Penetrantes/terapia
14.
Am J Hum Genet ; 102(4): 685-695, 2018 04 05.
Artículo en Inglés | MEDLINE | ID: mdl-29576219

RESUMEN

Biogenesis of the mitochondrial oxidative phosphorylation system, which produces the bulk of ATP for almost all eukaryotic cells, depends on the translation of 13 mtDNA-encoded polypeptides by mitochondria-specific ribosomes in the mitochondrial matrix. These mitoribosomes are dual-origin ribonucleoprotein complexes, which contain mtDNA-encoded rRNAs and tRNAs and ∼80 nucleus-encoded proteins. An increasing number of gene mutations that impair mitoribosomal function and result in multiple OXPHOS deficiencies are being linked to human mitochondrial diseases. Using exome sequencing in two unrelated subjects presenting with sensorineural hearing impairment, mild developmental delay, hypoglycemia, and a combined OXPHOS deficiency, we identified mutations in the gene encoding the mitochondrial ribosomal protein S2, which has not previously been implicated in disease. Characterization of subjects' fibroblasts revealed a decrease in the steady-state amounts of mutant MRPS2, and this decrease was shown by complexome profiling to prevent the assembly of the small mitoribosomal subunit. In turn, mitochondrial translation was inhibited, resulting in a combined OXPHOS deficiency detectable in subjects' muscle and liver biopsies as well as in cultured skin fibroblasts. Reintroduction of wild-type MRPS2 restored mitochondrial translation and OXPHOS assembly. The combination of lactic acidemia, hypoglycemia, and sensorineural hearing loss, especially in the presence of a combined OXPHOS deficiency, should raise suspicion for a ribosomal-subunit-related mitochondrial defect, and clinical recognition could allow for a targeted diagnostic approach. The identification of MRPS2 as an additional gene related to mitochondrial disease further expands the genetic and phenotypic spectra of OXPHOS deficiencies caused by impaired mitochondrial translation.


Asunto(s)
Alelos , Pérdida Auditiva Sensorineural/genética , Hipoglucemia/genética , Enfermedades Mitocondriales/genética , Proteínas Mitocondriales/genética , Mutación/genética , Proteínas Ribosómicas/genética , Secuencia de Aminoácidos , Preescolar , Análisis Mutacional de ADN , ADN Mitocondrial/genética , Femenino , Fibroblastos/metabolismo , Pérdida Auditiva Sensorineural/complicaciones , Humanos , Hipoglucemia/complicaciones , Lactante , Recién Nacido , Masculino , Enfermedades Mitocondriales/complicaciones , Proteínas Mitocondriales/química , Fosforilación Oxidativa , Subunidades de Proteína/genética , ARN Ribosómico/genética , Proteínas Ribosómicas/química
15.
Genet Med ; 19(11): 1226-1235, 2017 11.
Artículo en Inglés | MEDLINE | ID: mdl-28617415

RESUMEN

PurposePhosphoglucomutase-1 deficiency is a subtype of congenital disorders of glycosylation (PGM1-CDG). Previous casereports in PGM1-CDG patients receiving oral D-galactose (D-gal) showed clinical improvement. So far no systematic in vitro and clinical studies have assessed safety and benefits of D-gal supplementation. In a prospective pilot study, we evaluated the effects of oral D-gal in nine patients.MethodsD-gal supplementation was increased to 1.5 g/kg/day (maximum 50 g/day) in three increments over 18 weeks. Laboratory studies were performed before and during treatment to monitor safety and effect on serum transferrin-glycosylation, coagulation, and liver and endocrine function. Additionally, the effect of D-gal on cellular glycosylation was characterized in vitro.ResultsEight patients were compliant with D-gal supplementation. No adverse effects were reported. Abnormal baseline results (alanine transaminase, aspartate transaminase, activated partial thromboplastin time) improved or normalized already using 1 g/kg/day D-gal. Antithrombin-III levels and transferrin-glycosylation showed significant improvement, and increase in galactosylation and whole glycan content. In vitro studies before treatment showed N-glycan hyposialylation, altered O-linked glycans, abnormal lipid-linked oligosaccharide profile, and abnormal nucleotide sugars in patient fibroblasts. Most cellular abnormalities improved or normalized following D-gal treatment. D-gal increased both UDP-Glc and UDP-Gal levels and improved lipid-linked oligosaccharide fractions in concert with improved glycosylation in PGM1-CDG.ConclusionOral D-gal supplementation is a safe and effective treatment for PGM1-CDG in this pilot study. Transferrin glycosylation and ATIII levels were useful trial end points. Larger, longer-duration trials are ongoing.


Asunto(s)
Galactosa/uso terapéutico , Enfermedad del Almacenamiento de Glucógeno/tratamiento farmacológico , Administración Oral , Adolescente , Coagulación Sanguínea , Glucemia/metabolismo , Niño , Preescolar , Creatina Quinasa/sangre , Relación Dosis-Respuesta a Droga , Femenino , Galactosa/administración & dosificación , Galactosa/efectos adversos , Glicoproteínas/metabolismo , Humanos , Lactante , Masculino , Fosfoglucomutasa/metabolismo , Proyectos Piloto , Estudios Prospectivos , Piel/citología , Piel/metabolismo , Transferrina/metabolismo , Adulto Joven
16.
J Clin Endocrinol Metab ; 102(4): 1375-1386, 2017 Apr 01.
Artículo en Inglés | MEDLINE | ID: mdl-28323990

RESUMEN

CONTEXT: TMEM165 deficiency is a severe multisystem disease that manifests with metabolic, endocrine, and skeletal involvement. It leads to one type of congenital disorders of glycosylation (CDG), a rapidly growing group of inherited diseases in which the glycosylation process is altered. Patients have decreased galactosylation by serum glycan analysis. There are >100 CDGs, but only specific types are treatable. OBJECTIVE: Galactose has been shown to be beneficial in other CDG types with abnormal galactosylation. The aim of this study was to characterize the effects of galactose supplementation on Golgi glycosylation in TMEM165-depleted HEK293 cells, as well as in 2 patients with TMEM165-CDG and in their cultured skin fibroblast cells. DESIGN AND SETTING: Glycosylation was assessed by mass spectrometry, western blot analysis, and transferrin isoelectrofocusing. PATIENTS AND INTERVENTIONS: Both unrelated patients with TMEM165-CDG with the same deep intronic homozygous mutation (c.792+182G>A) were allocated to receive d-galactose in a daily dose of 1 g/kg. RESULTS: We analyzed N-linked glycans and glycolipids in knockout TMEM165 HEK293 cells, revealing severe hypogalactosylation and GalNAc transfer defects. Although these defects were completely corrected by the addition of Mn2+, we demonstrated that the observed N-glycosylation defect could also be overcome by galactose supplementation. We then demonstrated that oral galactose supplementation in patients with TMEM165-deficient CDG improved biochemical and clinical parameters, including a substantial increase in the negatively charged transferrin isoforms, and a decrease in hypogalactosylated total N-glycan structures, endocrine function, and coagulation parameters. CONCLUSION: To our knowledge, this is the first description of abnormal glycosylation of lipids in the TMEM165 defect and the first report of successful dietary treatment in TMEM165 deficiency. We recommend the use of oral d-galactose therapy in TMEM165-CDG.


Asunto(s)
Trastornos Congénitos de Glicosilación/dietoterapia , Trastornos Congénitos de Glicosilación/genética , Galactosa/farmacología , Galactosa/uso terapéutico , Glicosilación/efectos de los fármacos , Proteínas de la Membrana/genética , Adulto , Antiportadores , Proteínas de Transporte de Catión , Niño , Trastornos Congénitos de Glicosilación/patología , Suplementos Dietéticos , Fibroblastos/efectos de los fármacos , Fibroblastos/metabolismo , Fibroblastos/patología , Células HEK293 , Humanos , Masculino , Proteínas de la Membrana/deficiencia , Mutación , Resultado del Tratamiento
17.
Am J Hum Genet ; 100(2): 216-227, 2017 02 02.
Artículo en Inglés | MEDLINE | ID: mdl-28065471

RESUMEN

Defects of the V-type proton (H+) ATPase (V-ATPase) impair acidification and intracellular trafficking of membrane-enclosed compartments, including secretory granules, endosomes, and lysosomes. Whole-exome sequencing in five families affected by mild to severe cutis laxa, dysmorphic facial features, and cardiopulmonary involvement identified biallelic missense mutations in ATP6V1E1 and ATP6V1A, which encode the E1 and A subunits, respectively, of the V1 domain of the heteromultimeric V-ATPase complex. Structural modeling indicated that all substitutions affect critical residues and inter- or intrasubunit interactions. Furthermore, complexome profiling, a method combining blue-native gel electrophoresis and liquid chromatography tandem mass spectrometry, showed that they disturb either the assembly or the stability of the V-ATPase complex. Protein glycosylation was variably affected. Abnormal vesicular trafficking was evidenced by delayed retrograde transport after brefeldin A treatment and abnormal swelling and fragmentation of the Golgi apparatus. In addition to showing reduced and fragmented elastic fibers, the histopathological hallmark of cutis laxa, transmission electron microscopy of the dermis also showed pronounced changes in the structure and organization of the collagen fibers. Our findings expand the clinical and molecular spectrum of metabolic cutis laxa syndromes and further link defective extracellular matrix assembly to faulty protein processing and cellular trafficking caused by genetic defects in the V-ATPase complex.


Asunto(s)
Cutis Laxo/genética , Mutación Missense , ATPasas de Translocación de Protón Vacuolares/genética , Adolescente , Alelos , Secuencia de Aminoácidos , Estudios de Casos y Controles , Niño , Femenino , Fibroblastos/metabolismo , Regulación de la Expresión Génica , Estudio de Asociación del Genoma Completo , Glicosilación , Aparato de Golgi/metabolismo , Humanos , Lactante , Recién Nacido , Masculino , Linaje , Conformación Proteica , Transporte de Proteínas , Espectrometría de Masas en Tándem
18.
J Pediatr ; 175: 130-136.e8, 2016 08.
Artículo en Inglés | MEDLINE | ID: mdl-27206562

RESUMEN

OBJECTIVE: To define phenotypic groups and identify predictors of disease severity in patients with phosphoglucomutase-1 deficiency (PGM1-CDG). STUDY DESIGN: We evaluated 27 patients with PGM1-CDG who were divided into 3 phenotypic groups, and group assignment was validated by a scoring system, the Tulane PGM1-CDG Rating Scale (TPCRS). This scale evaluates measurable clinical features of PGM1-CDG. We examined the relationship between genotype, enzyme activity, and TPCRS score by using regression analysis. Associations between the most common clinical features and disease severity were evaluated by principal component analysis. RESULTS: We found a statistically significant stratification of the TPCRS scores among the phenotypic groups (P < .001). Regression analysis showed that there is no significant correlation between genotype, enzyme activity, and TPCRS score. Principal component analysis identified 5 variables that contributed to 54% variance in the cohort and are predictive of disease severity: congenital malformation, cardiac involvement, endocrine deficiency, myopathy, and growth. CONCLUSIONS: We established a scoring algorithm to reliably evaluate disease severity in patients with PGM1-CDG on the basis of their clinical history and presentation. We also identified 5 clinical features that are predictors of disease severity; 2 of these features can be evaluated by physical examination, without the need for specific diagnostic testing and thus allow for rapid assessment and initiation of therapy.


Asunto(s)
Enfermedad del Almacenamiento de Glucógeno/diagnóstico , Fenotipo , Índice de Severidad de la Enfermedad , Adolescente , Adulto , Algoritmos , Niño , Preescolar , Femenino , Marcadores Genéticos , Genotipo , Enfermedad del Almacenamiento de Glucógeno/enzimología , Enfermedad del Almacenamiento de Glucógeno/genética , Humanos , Masculino , Mutación , Fosfoglucomutasa/deficiencia , Fosfoglucomutasa/genética , Examen Físico , Análisis de Componente Principal , Análisis de Regresión , Adulto Joven
20.
Stem Cell Res Ther ; 5(6): 129, 2014 Nov 23.
Artículo en Inglés | MEDLINE | ID: mdl-25418536

RESUMEN

INTRODUCTION: Clinically, a good deal of injury from stroke results from ischemic-reperfusion. There is a loss of cerebral parenchyma and its associated cells, disruption of neuronal connections, compromise of the blood-brain barrier, and inflammation. We tested whether exogenously engrafted human neural stem cells could migrate rapidly and extensively to damaged regions, following transplantation into a neurogenic site where migration cues are already underway during stroke onset, then counteract a number of these pathological processes. METHODS: One day post-injury, we injected human neural stem cells (hNSCs) into the ipsilesional hippocampus of a mouse model of stroke with middle cerebral artery occlusion to induce focal ischemia followed by reperfusion (MCAO/R). The time frame for hNSC transplantation corresponded to upregulation of endogenous proinflammatory cytokines. We examined the effect of hNSC transplantation on pathological processes and behavioral dysfunction 48 hours post-injury. RESULTS: Twenty-four hours after transplantation, engrafted hNSCs had migrated extensively to the lesion, and infarct volume was reduced relative to MCAO/R controls. The behavioral deficits seen in MCAO/R controls were also significantly improved. Given this rapid response, we hypothesized that the mechanisms underlying therapeutic activity were anti-inflammatory rather than due to cell replacement. In support of this idea, in hNSC-transplanted mice we observed reduced microglial activation, decreased expression of proinflammatory factors (tumor necrosis factor-α, interleukin (IL)-6, IL-1ß, monocyte chemotactic protein-1, macrophage inflammatory protein-1α) and adhesion molecules (intercellular adhesion molecule-1, vascular cell adhesion molecule-1), and amelioration of blood-brain barrier damage. CONCLUSIONS: While long-term effects of engrafted hNSCs on the amelioration of ischemic stroke-induced behavioral dysfunction in a rodent model have been reported, our study is the first to show rapid, beneficial impacts on behavioral function (within 24 hours) upon early delivery of hNSCs into the hippocampus.


Asunto(s)
Células Madre Embrionarias/trasplante , Infarto de la Arteria Cerebral Media/terapia , Células-Madre Neurales/trasplante , Animales , Células Cultivadas , Quimiocina CCL2/genética , Quimiocina CCL2/metabolismo , Células Madre Embrionarias/metabolismo , Humanos , Inflamación/terapia , Interleucinas/genética , Interleucinas/metabolismo , Factores de Transcripción de Tipo Kruppel/genética , Factores de Transcripción de Tipo Kruppel/metabolismo , Masculino , Ratones , Ratones Endogámicos C57BL , Células-Madre Neurales/metabolismo , Factor de Necrosis Tumoral alfa/genética , Factor de Necrosis Tumoral alfa/metabolismo
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