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1.
Clin Infect Dis ; 61(12): 1831-4, 2015 Dec 15.
Artículo en Inglés | MEDLINE | ID: mdl-26405147

RESUMEN

Four anatomical patterns of hydrocephalus secondary to congenital Toxoplasma gondii infection were identified and characterized for infants enrolled in the National Collaborative Chicago-based Congenital Toxoplasmosis Study. Analysis of parasite serotype revealed that different anatomical patterns associate with Type-II vs Not-Exclusively Type-II strains (NE-II) (P = .035).


Asunto(s)
Genotipo , Hidrocefalia/patología , Hidrocefalia/parasitología , Toxoplasma/clasificación , Toxoplasma/genética , Toxoplasmosis Congénita/complicaciones , Estudios de Cohortes , Humanos , Serogrupo , Toxoplasma/aislamiento & purificación
2.
Infect Immun ; 82(7): 2670-9, 2014 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-24686056

RESUMEN

ALOX12 is a gene encoding arachidonate 12-lipoxygenase (12-LOX), a member of a nonheme lipoxygenase family of dioxygenases. ALOX12 catalyzes the addition of oxygen to arachidonic acid, producing 12-hydroperoxyeicosatetraenoic acid (12-HPETE), which can be reduced to the eicosanoid 12-HETE (12-hydroxyeicosatetraenoic acid). 12-HETE acts in diverse cellular processes, including catecholamine synthesis, vasoconstriction, neuronal function, and inflammation. Consistent with effects on these fundamental mechanisms, allelic variants of ALOX12 are associated with diseases including schizophrenia, atherosclerosis, and cancers, but the mechanisms have not been defined. Toxoplasma gondii is an apicomplexan parasite that causes morbidity and mortality and stimulates an innate and adaptive immune inflammatory reaction. Recently, it has been shown that a gene region known as Toxo1 is critical for susceptibility or resistance to T. gondii infection in rats. An orthologous gene region with ALOX12 centromeric is also present in humans. Here we report that the human ALOX12 gene has susceptibility alleles for human congenital toxoplasmosis (rs6502997 [P, <0.000309], rs312462 [P, <0.028499], rs6502998 [P, <0.029794], and rs434473 [P, <0.038516]). A human monocytic cell line was genetically engineered using lentivirus RNA interference to knock down ALOX12. In ALOX12 knockdown cells, ALOX12 RNA expression decreased and levels of the ALOX12 substrate, arachidonic acid, increased. ALOX12 knockdown attenuated the progression of T. gondii infection and resulted in greater parasite burdens but decreased consequent late cell death of the human monocytic cell line. These findings suggest that ALOX12 influences host responses to T. gondii infection in human cells. ALOX12 has been shown in other studies to be important in numerous diseases. Here we demonstrate the critical role ALOX12 plays in T. gondii infection in humans.


Asunto(s)
Araquidonato 12-Lipooxigenasa/metabolismo , Toxoplasmosis Congénita/genética , Alelos , Araquidonato 12-Lipooxigenasa/química , Araquidonato 12-Lipooxigenasa/genética , Ácido Araquidónico/metabolismo , Caspasa 1/genética , Caspasa 1/metabolismo , Línea Celular , Estudios de Cohortes , Citocinas/genética , Citocinas/metabolismo , Femenino , Técnicas de Silenciamiento del Gen , Variación Genética , Humanos , Masculino , Monocitos/metabolismo , Monocitos/parasitología , Plásmidos/genética , Interferencia de ARN , ARN Interferente Pequeño , Toxoplasmosis Congénita/inmunología , Toxoplasmosis Congénita/parasitología
3.
Med ; 4(4): 245-251.e3, 2023 04 14.
Artículo en Inglés | MEDLINE | ID: mdl-36905929

RESUMEN

BACKGROUND: Utrophin, a dystrophin homolog, is consistently upregulated in muscles of patients with Duchenne muscular dystrophy (DMD) and is believed to partially compensate for the lack of dystrophin in dystrophic muscle. Even though several animal studies support the idea that utrophin can modulate DMD disease severity, human clinical data are scarce. METHODS: We describe a patient with the largest reported in-frame deletion in the DMD gene, including exons 10-60 and thus encompassing the entire rod domain. FINDINGS: The patient presented with an unusually early and severe progressive weakness, initially suggesting congenital muscular dystrophy. Immunostaining of his muscle biopsy showed that the mutant protein was able to localize at the sarcolemma and stabilize the dystrophin-associated complex. Strikingly, utrophin protein was absent from the sarcolemmal membrane despite the upregulation of utrophin mRNA. CONCLUSIONS: Our results suggest that the internally deleted and dysfunctional dystrophin lacking the entire rod domain may exert a dominant-negative effect by preventing upregulated utrophin protein from reaching the sarcolemmal membrane and thus blocking its partial rescue of muscle function. This unique case may set a lower size limit for similar constructs in potential gene therapy approaches. FUNDING: This work was supported by a grant from MDA USA (MDA3896) and by grant number R01AR051999 from NIAMS/NIH to C.G.B.


Asunto(s)
Distrofina , Distrofia Muscular de Duchenne , Animales , Humanos , Distrofina/genética , Distrofina/metabolismo , Utrofina/genética , Utrofina/metabolismo , Utrofina/uso terapéutico , Distrofia Muscular de Duchenne/genética , Distrofia Muscular de Duchenne/patología , Músculos/metabolismo , Músculos/patología , Sarcolema/metabolismo , Sarcolema/patología
4.
Cardiol Res ; 14(6): 446-452, 2023 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-38187509

RESUMEN

Background: Rett syndrome (RTT) is a developmental encephalopathy disorder that is associated with a high incidence of sudden death presumably from cardiorespiratory etiologies. Electrocardiogram (ECG) abnormalities, such as prolonged heart-rate corrected QT (QTc) interval, are markers of cardiac repolarization and are associated with potentially lethal ventricular arrhythmias. This study investigates the cardiac repolarization characteristics of RTT patients, including QTc and T-wave morphology characteristics. Methods: A retrospective quantitative analysis on 110 RTT patients and 124 age and sex-matched healthy controls was conducted. Results: RTT patients had longer QTc, more abnormal T-wave morphology, and greater heterogeneity of cardiac repolarization parameters compared to controls. Even RTT patients without prolonged QTc had more abnormal ECG and T-wave characteristics than controls. Among RTT patients, MECP2 patients had prolonged QTc compared to CDKL5 and FOXG1 patients. A subset of five RTT patients who died had normal QTc, but more abnormal T-wave morphology than the remaining RTT patients. Conclusions: Cardiac repolarization abnormalities are present in RTT patients, even without long QTc. T-wave morphology is related to RTT genotype and may be predictive of mortality. These findings could be used to help the management and monitoring of RTT patients.

5.
Ann Child Neurol Soc ; 1(3): 228-238, 2023 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-38496825

RESUMEN

Objective: To determine the longitudinal distribution of hand function skills in individuals with classic Rett Syndrome (RTT), an X-linked dominant neurodevelopmental disorder, and correlate with MECP2 variants. Method: We conducted a longitudinal study of 946 girls and young women with typical RTT seen between 2006 and 2021 in the US Natural History Study (NHS) featuring a structured clinical evaluation to assess the level of hand function skills. The specific focus in this study was to assess longitudinal variation of hand skills from age 2 through age 18 years in relation to specific MECP2 variant groups. Results: Following the initial regression period, hand function continues to decline across the age spectrum in individuals with RTT. Specific differences are noted with steeper declines in hand function among those with milder variants (Group A: R133C, R294X, R306C, and C-terminal truncations) compared to groups composed of individuals with more severe variants. Conclusions: These temporal variations in hand use represent specific considerations which could influence the design of clinical trials that test therapies aiming to ameliorate specific functional limitations in individuals with RTT. Furthermore, the distinct impact of specific MECP2 variants on clinical severity, especially related to hand use, should be considered in such interventional trials.

6.
Clin Infect Dis ; 54(11): 1595-605, 2012 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-22499837

RESUMEN

BACKGROUND: Congenital toxoplasmosis is a severe, life-altering disease in the United States. A recently developed enzyme-linked immunosorbent assay (ELISA) distinguishes Toxoplasma gondii parasite types (II and not exclusively II [NE-II]) by detecting antibodies in human sera that recognize allelic peptide motifs of distinct parasite types. METHODS: ELISA determined parasite serotype for 193 congenitally infected infants and their mothers in the National Collaborative Chicago-based Congenital Toxoplasmosis Study (NCCCTS), 1981-2009. Associations of parasite serotype with demographics, manifestations at birth, and effects of treatment were determined. RESULTS: Serotypes II and NE-II occurred in the United States with similar proportions during 3 decades. For persons diagnosed before or at birth and treated in infancy, and persons diagnosed after 1 year of age who missed treatment in infancy, proportions were similar (P = .91). NE-II serotype was more common in hot, humid regions (P = .02) but was also present in other regions. NE-II serotype was associated with rural residence (P < .01), lower socioeconomic status (P < .001), and Hispanic ethnicity (P < .001). Prematurity (P = .03) and severe disease at birth (P < .01) were associated with NE-II serotype. Treatment with lower and higher doses of pyrimethamine with sulfadizine improved outcomes relative to those outcomes of persons in the literature who did not receive such treatment. CONCLUSIONS: Type II and NE-II parasites cause congenital toxoplasmosis in North America. NE-II serotype was more prevalent in certain demographics and associated with prematurity and severe disease at birth. Both type II and NE-II infections improved with treatment. CLINICAL TRIALS REGISTRATION: NCT00004317.


Asunto(s)
Toxoplasma/clasificación , Toxoplasma/patogenicidad , Toxoplasmosis Congénita/epidemiología , Toxoplasmosis Congénita/parasitología , Adolescente , Alelos , Anticuerpos Antiprotozoarios/sangre , Niño , Preescolar , Ensayo de Inmunoadsorción Enzimática , Femenino , Humanos , Lactante , Recién Nacido , Masculino , Embarazo , Prevalencia , Serotipificación , Toxoplasmosis Congénita/patología , Estados Unidos/epidemiología , Virulencia
7.
J Neurodev Disord ; 14(1): 31, 2022 05 14.
Artículo en Inglés | MEDLINE | ID: mdl-35568815

RESUMEN

BACKGROUND: Rett syndrome (RTT) is a neurodevelopmental disorder most often related to a pathogenic variant in the X-linked MECP2 gene. Internalizing behaviors appear to be common, but standard methods of diagnosing anxiety are not readily applied in this population which typically has cognitive impairment and limited expressive language. This study aims to describe the frequency of anxiety-like behavior and anxiolytic treatments along with associated clinical features in individuals with RTT. METHODS: Parental reports and medication logs provided data from 1380 females with RTT participating in two iterations of the multicenter U.S. RTT Natural History Study (RNHS) from 2006 to 2019. RESULTS: Most participants with RTT (77.5%) had at least occasional anxious or nervous behavior. Anxiety was reported to be the most troublesome concern for 2.6%, and within the top 3 concerns for 10.0%, of participants in the second iteration. Parents directly reported treatment for anxious or nervous behavior in 16.6% of participants in the second iteration with most reporting good control of the behavior (71.6%). In the medication logs of both RNHS iterations, the indication of anxiety was listed for a similar number of participants (15% and 14.5%, respectively). Increased use of anxiolytics and selective serotonin reuptake inhibitors (SSRIs) was related to more frequent anxiety-like behaviors (P < 0.001), older age (P < 0.001), and mild MECP2 variants (P = 0.002). CONCLUSION: Anxiety-like behavior is frequent at all ages and is a significant parental concern in RTT. Older individuals and those with mild MECP2 variants are more likely to be treated with medications. Better diagnosis and treatment of anxiety in RTT should be a goal of both future studies and clinical care. TRIAL REGISTRATION: NCT00299312 and NCT02738281.


Asunto(s)
Ansiolíticos , Síndrome de Rett , Ansiolíticos/uso terapéutico , Ansiedad/tratamiento farmacológico , Ansiedad/epidemiología , Femenino , Humanos , Síndrome de Rett/complicaciones , Síndrome de Rett/tratamiento farmacológico , Síndrome de Rett/epidemiología
9.
PLoS Negl Trop Dis ; 11(6): e0005670, 2017 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-28650970

RESUMEN

BACKGROUND: Congenital toxoplasmosis is a serious but preventable and treatable disease. Gestational screening facilitates early detection and treatment of primary acquisition. Thus, fetal infection can be promptly diagnosed and treated and outcomes can be improved. METHODS: We tested 180 sera with the Toxoplasma ICT IgG-IgM point-of-care (POC) test. Sera were from 116 chronically infected persons (48 serotype II; 14 serotype I-III; 25 serotype I-IIIa; 28 serotype Atypical, haplogroup 12; 1 not typed). These represent strains of parasites infecting mothers of congenitally infected children in the U.S. 51 seronegative samples and 13 samples from recently infected persons known to be IgG/IgM positive within the prior 2.7 months also were tested. Interpretation was confirmed by two blinded observers. A comparison of costs for POC vs. commercial laboratory testing methods was performed. RESULTS: We found that this new Toxoplasma ICT IgG-IgM POC test was highly sensitive (100%) and specific (100%) for distinguishing IgG/IgM-positive from negative sera. Use of such reliable POC tests can be cost-saving and benefit patients. CONCLUSIONS: Our work demonstrates that the Toxoplasma ICT IgG-IgM test can function reliably as a point-of-care test to diagnose Toxoplasma gondii infection in the U.S. This provides an opportunity to improve maternal-fetal care by using approaches, diagnostic tools, and medicines already available. This infection has serious, lifelong consequences for infected persons and their families. From the present study, it appears a simple, low-cost POC test is now available to help prevent morbidity/disability, decrease cost, and make gestational screening feasible. It also offers new options for improved prenatal care in low- and middle-income countries.


Asunto(s)
Anticuerpos Antiprotozoarios/sangre , Inmunoensayo/métodos , Inmunoglobulina G/sangre , Inmunoglobulina M/sangre , Pruebas en el Punto de Atención/economía , Toxoplasma/inmunología , Toxoplasmosis/diagnóstico , Costos y Análisis de Costo , Países en Desarrollo , Pruebas Diagnósticas de Rutina/economía , Pruebas Diagnósticas de Rutina/métodos , Humanos , Inmunoensayo/economía , Sensibilidad y Especificidad , Estados Unidos
10.
Sci Rep ; 7(1): 11496, 2017 09 13.
Artículo en Inglés | MEDLINE | ID: mdl-28904337

RESUMEN

One third of humans are infected lifelong with the brain-dwelling, protozoan parasite, Toxoplasma gondii. Approximately fifteen million of these have congenital toxoplasmosis. Although neurobehavioral disease is associated with seropositivity, causality is unproven. To better understand what this parasite does to human brains, we performed a comprehensive systems analysis of the infected brain: We identified susceptibility genes for congenital toxoplasmosis in our cohort of infected humans and found these genes are expressed in human brain. Transcriptomic and quantitative proteomic analyses of infected human, primary, neuronal stem and monocytic cells revealed effects on neurodevelopment and plasticity in neural, immune, and endocrine networks. These findings were supported by identification of protein and miRNA biomarkers in sera of ill children reflecting brain damage and T. gondii infection. These data were deconvoluted using three systems biology approaches: "Orbital-deconvolution" elucidated upstream, regulatory pathways interconnecting human susceptibility genes, biomarkers, proteomes, and transcriptomes. "Cluster-deconvolution" revealed visual protein-protein interaction clusters involved in processes affecting brain functions and circuitry, including lipid metabolism, leukocyte migration and olfaction. Finally, "disease-deconvolution" identified associations between the parasite-brain interactions and epilepsy, movement disorders, Alzheimer's disease, and cancer. This "reconstruction-deconvolution" logic provides templates of progenitor cells' potentiating effects, and components affecting human brain parasitism and diseases.

11.
Pediatr Neurol ; 33(3): 208-10, 2005 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-16139737

RESUMEN

A previously healthy 3-year-old female presented with rapidly progressive neurologic deterioration. She was initially diagnosed with acute disseminated encephalomyelitis but was subsequently found to have late-onset Krabbe's disease.


Asunto(s)
Encefalomielitis Aguda Diseminada/diagnóstico , Leucodistrofia de Células Globoides/diagnóstico , Preescolar , Diagnóstico Diferencial , Femenino , Humanos
12.
Pediatr Neurol ; 27(5): 384-7, 2002 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-12504207

RESUMEN

Various paraneoplastic autoantibodies have been linked to discrete neurologic syndromes and tumors in adults, but little is known about their incidence in children. We report a cross-sectional study of known paraneoplastic antibodies in 59 children with opsoclonus-myoclonus-ataxia, 86% of whom were moderately or severely symptomatic, and 68% of whom had relapsed at the time of testing. This total number of patients includes 18 children with low-stage neuroblastoma (tested after tumor resection), six of whom had never been treated with immunosuppressants. All were seronegative for anti-Hu, anti-Ri, and anti-Yo, the three paraneoplastic antibodies most associated with opsoclonus-myoclonus or ataxia in adults. These data contrast with reports of anti-Hu-positive sera in children with high-stage tumors and suggest that anti-Hu, anti-Ri, and anti-Yo do not explain relapses in pediatric opsoclonus-myoclonus-ataxia. They underscore the need to search for unique autoantibodies, as well as cellular mechanisms of pediatric paraneoplastic disease.


Asunto(s)
Neoplasias Abdominales/sangre , Autoanticuerpos/sangre , Tamizaje Masivo/estadística & datos numéricos , Neuroblastoma/sangre , Síndromes Paraneoplásicos del Sistema Nervioso/sangre , Neoplasias Torácicas/sangre , Neoplasias Abdominales/diagnóstico , Neoplasias Abdominales/epidemiología , Edad de Inicio , Ataxia/sangre , Ataxia/diagnóstico , Ataxia/epidemiología , Preescolar , Comorbilidad , Estudios Transversales , Femenino , Humanos , Inmunoglobulina G/sangre , Lactante , Masculino , Neuroblastoma/diagnóstico , Neuroblastoma/epidemiología , Síndromes Paraneoplásicos del Sistema Nervioso/diagnóstico , Síndromes Paraneoplásicos del Sistema Nervioso/epidemiología , Recurrencia , Pruebas Serológicas , Distribución por Sexo , Neoplasias Torácicas/diagnóstico , Neoplasias Torácicas/epidemiología , Estados Unidos/epidemiología
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