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1.
J Clin Immunol ; 39(6): 592-595, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31267431

RESUMO

Mutations in Dedicator of cytokinesis 8 (DOCK8) are a rare cause of combined immunodeficiency associated with atopy, infectious susceptibility, and risk for malignancy. We describe a 22-year-old male with a diagnosis of B cell lymphoblastic leukemia followed by Epstein-Barr virus (EBV)-associated diffuse large B cell lymphoma (DLBCL) with compound heterozygous mutations in DOCK8 and normal intracellular DOCK8 protein expression. Here, B cell lymphoblastic leukemia followed by EBV-associated DLBCL led to the discovery of DOCK8 deficiency. For instances of high clinical suspicion despite normal DOCK8 protein expression, additional functional testing is critical to make a diagnosis. Understanding the spectrum of DOCK8 mutants and their phenotypes will improve our understanding of DOCK8 deficiency.

2.
PLoS One ; 13(12): e0208558, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30521607

RESUMO

Three-dimensional (3D) cell culture models bridge the gap between two-dimensional (2D) monolayer cultures and animal models. Physiologically relevant, 3D culture models have significantly advanced basic cell science and provide unique insights into host-pathogen interactions intrinsically linked to cell morphology. Toxoplasma gondii is an obligate intravacuolar parasite that chronically infects a large portion of the global human population. Our current understanding of Toxoplasma infection is largely based on 2D cell cultures, in which mammalian cells are grown on flat surfaces. However, 2D cell cultures may not recapitulate key conditions of in vivo infections as they introduce artificial pressures and tensions, which may subsequently alter infectious processes that are dependent on spatiality, e.g., invasion, replication and egress. In this study, we adapted a collagen-based 3D cell culture system to reproduce the 3D environment of T. gondii natural infections for investigation of the replication and egress of the parasite from the parasitophorous vacuole. Suspended in the 3D matrix, Toxoplasma-infected VERO cells have round morphology, as opposed to infected VERO cells in 2D monolayers. The doubling time of Toxoplasma in VERO cells within the matrix is comparable to that of parasites cultivated in VERO cell monolayers. In the absence of the pressure of flattened host cells grown in 2D cultures, the parasitophorous vacuole of T. gondii has a globular shape, with intravacuolar parasites distributed radially, forming 3D spherical 'rosette' structures. Parasites egress radially away from the ruptured host cell in 3D matrices, in contrast to Toxoplasma cultivated in 2D monolayer cultures, where the parasites escape perpendicularly from the flat surface below the host cells. These observations demonstrate the utility of collagen matrices for studying parasite modes of infection as these 3D assays more closely mimic in vivo conditions.

3.
J Exp Med ; 215(10): 2567-2585, 2018 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-30143481

RESUMO

Life-threatening pulmonary influenza can be caused by inborn errors of type I and III IFN immunity. We report a 5-yr-old child with severe pulmonary influenza at 2 yr. She is homozygous for a loss-of-function IRF9 allele. Her cells activate gamma-activated factor (GAF) STAT1 homodimers but not IFN-stimulated gene factor 3 (ISGF3) trimers (STAT1/STAT2/IRF9) in response to IFN-α2b. The transcriptome induced by IFN-α2b in the patient's cells is much narrower than that of control cells; however, induction of a subset of IFN-stimulated gene transcripts remains detectable. In vitro, the patient's cells do not control three respiratory viruses, influenza A virus (IAV), parainfluenza virus (PIV), and respiratory syncytial virus (RSV). These phenotypes are rescued by wild-type IRF9, whereas silencing IRF9 expression in control cells increases viral replication. However, the child has controlled various common viruses in vivo, including respiratory viruses other than IAV. Our findings show that human IRF9- and ISGF3-dependent type I and III IFN responsive pathways are essential for controlling IAV.

4.
Artigo em Inglês | MEDLINE | ID: mdl-28758344

RESUMO

AIM: To characterize the inpatient care received by individuals experiencing early psychotic episodes in an inner city hospital. METHOD: Medical records of patients admitted between April 01, 2013, and March 31, 2015, to a psychiatric ward at an inner city hospital were retrospectively examined. Included in the study are patients who were 25 years of age or younger and were hospitalized for psychotic symptoms. Demographics and health service use were summarized using descriptive statistics. RESULTS: A total of 73 inpatients (mean age = 22; males =78%; Caucasian = 41%) met the study inclusion criteria with a combined total of 102 care episodes and an average length of stay of 32.6 days. Monitoring of vital signs (VS) and mental status examinations (MSE) were performed in most care episodes although these were not performed regularly (daily VS checks-31%; MSE every nursing shift-18.6%). In 49% of the care episodes, patients were discharged on long-acting injectable antipsychotics. Even when indicated, not all care episodes had follow-up appointments (82.8%) in the community. The use of seclusion was higher in the wards (32%) than in the emergency department (21%), whereas the use of restraints was higher in the emergency department (16%) than in the wards (<1%). CONCLUSIONS: There is wide variation in the rate at which various clinical care processes are performed and in the provision of inpatient care to younger adults experiencing episodes of early psychosis. Consistent standards of care are needed to reduce variations and improve treatment outcomes and experiences.

5.
Genetics ; 203(1): 283-98, 2016 05.
Artigo em Inglês | MEDLINE | ID: mdl-26920761

RESUMO

In Toxoplasma gondii, an intracellular parasite of humans and other animals, host mitochondrial association (HMA) is driven by a gene family that encodes multiple mitochondrial association factor 1 (MAF1) proteins. However, the importance of MAF1 gene duplication in the evolution of HMA is not understood, nor is the impact of HMA on parasite biology. Here we used within- and between-species comparative analysis to determine that the MAF1 locus is duplicated in T. gondii and its nearest extant relative Hammondia hammondi, but not another close relative, Neospora caninum Using cross-species complementation, we determined that the MAF1 locus harbors multiple distinct paralogs that differ in their ability to mediate HMA, and that only T. gondii and H. hammondi harbor HMA(+) paralogs. Additionally, we found that exogenous expression of an HMA(+) paralog in T. gondii strains that do not normally exhibit HMA provides a competitive advantage over their wild-type counterparts during a mouse infection. These data indicate that HMA likely evolved by neofunctionalization of a duplicate MAF1 copy in the common ancestor of T. gondii and H. hammondi, and that the neofunctionalized gene duplicate is selectively advantageous.


Assuntos
Duplicação Gênica , Interações Hospedeiro-Parasita/genética , Proteínas de Protozoários/genética , Toxoplasma/genética , Toxoplasmose/parasitologia , Animais , Gatos , Dosagem de Genes , Regulação da Expressão Gênica , Camundongos , Camundongos Knockout , Família Multigênica , Transcrição Genética
6.
J Biol Rhythms ; 28(3): 201-7, 2013 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-23735499

RESUMO

A1 adenosine receptor (A1AR) activation within the central nervous system induces torpor, but in obligate hibernators such as the arctic ground squirrel (AGS; Urocitellus parryii), A1AR stimulation induces torpor only during the hibernation season, suggesting a seasonal increase in sensitivity to A1AR signaling. The purpose of this research was to investigate the relationship between body temperature (Tb) and sensitivity to an adenosine A1 receptor agonist in AGS. We tested the hypothesis that increased sensitivity in A1AR signaling would lead to lower Tb in euthermic animals during the hibernation season when compared with the summer season. We further predicted that if a decrease in euthermic Tb reflects increased sensitivity to A1AR activation, then it should likewise predict spontaneous torpor. We used subcutaneous IPTT-300 transponders to monitor Tb in AGS housed under constant ambient conditions (12:12 L:D, 18 °C) for up to 16 months. These animals displayed an obvious rhythm in euthermic Tb that cycled with a period of approximately 8 months. Synchrony in the Tb rhythm within the group was lost after several months of constant L:D conditions; however, individual rhythms in Tb continued to show clear sine wave-like waxing and waning. AGS displayed spontaneous torpor only during troughs in euthermic Tb. To assess sensitivity to A1AR activation, AGS were administered the A1AR agonist N(6)-cyclohexyladenosine (CHA, 0.1 mg/kg, ip), and subcutaneous Tb was monitored. AGS administered CHA during a seasonal minimum in euthermic Tb showed a greater drug-induced decrease in Tb (1.6 ± 0.3 °C) than did AGS administered CHA during a peak in euthermic Tb (0.4 ± 0.3 °C). These results provide evidence for a circannual rhythm in Tb that is associated with increased sensitivity to A1AR signaling and correlates with the onset of torpor.


Assuntos
Agonistas do Receptor A1 de Adenosina/farmacologia , Regulação da Temperatura Corporal/fisiologia , Hibernação/fisiologia , Sciuridae/fisiologia , Estações do Ano , Adenosina/análogos & derivados , Adenosina/farmacologia , Animais , Regiões Árticas , Temperatura Corporal/efeitos dos fármacos , Temperatura Corporal/fisiologia , Regulação da Temperatura Corporal/efeitos dos fármacos , Peso Corporal/efeitos dos fármacos , Peso Corporal/fisiologia , Interpretação Estatística de Dados , Ingestão de Alimentos/efeitos dos fármacos , Ingestão de Alimentos/fisiologia , Feminino , Hibernação/efeitos dos fármacos , Masculino , Temperatura Ambiente
7.
Psychopharmacology (Berl) ; 198(3): 413-20, 2008 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-18446322

RESUMO

RATIONALE: Schizophrenia patients and certain inbred mouse strains (i.e., DBA/2) show deficient sensory inhibition which has been linked to reduced numbers of hippocampal alpha7 nicotinic receptors and to underlying polymorphisms in the promoter region for the alpha7 gene. Increasing maternal dietary choline, a selective alpha7 agonist, during gestation has been shown to produce long-term changes in adult offspring behavior (i.e., improved learning and memory in rats). OBJECTIVES: The objective of this study is to improve sensory inhibition in DBA/2 mice through maternal choline supplementation. MATERIALS AND METHODS: DBA/2 dams were placed on normal (1.1 g/kg) or supplemented (5 g/kg) choline diet throughout gestation and lactation. Offspring were placed on normal diet at weaning and were assessed for sensory inhibition parameters at adulthood. Evoked EEG responses to identical paired auditory stimuli were compared. At the end of the study, the brains were collected for autoradiographic assessment of hippocampal levels of alpha-bungarotoxin binding to visualize alpha7 nicotinic receptors. RESULTS: Offspring mice which were choline supplemented during gestation showed significantly improved sensory inhibition compared to mice gestated on the normal choline diet. The improvement was produced by a significant reduction in the response to the second stimulus, demonstrating improved inhibition to that stimulus. There was a concurrent increase in alpha7 receptor numbers in both the CA1 and dentate gyrus regions of the hippocampus suggesting that this increase may be responsible for the improved inhibition. CONCLUSIONS: These data show that gestational choline supplementation produces permanent improvement in a deficit associated with schizophrenia and may have implications for human prenatal nutrition.


Assuntos
Colina/farmacologia , Inibição (Psicologia) , Nootrópicos/farmacologia , Estimulação Acústica , Animais , Autorradiografia , Bungarotoxinas/metabolismo , Colina/administração & dosagem , Dieta , Eletroencefalografia/efeitos dos fármacos , Potenciais Evocados Auditivos/efeitos dos fármacos , Feminino , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos DBA , Nootrópicos/administração & dosagem , Gravidez , Efeitos Tardios da Exposição Pré-Natal , Receptores Nicotínicos/metabolismo , Receptor Nicotínico de Acetilcolina alfa7
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