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1.
Am J Hum Genet ; 105(3): 549-561, 2019 Sep 05.
Artigo em Inglês | MEDLINE | ID: mdl-31447097

RESUMO

FOXN1 is the master regulatory gene of thymic epithelium development. FOXN1 deficiency leads to thymic aplasia, alopecia, and nail dystrophy, accounting for the nude/severe combined immunodeficiency (nu/SCID) phenotype in humans and mice. We identified several newborns with low levels of T cell receptor excision circles (TRECs) and T cell lymphopenia at birth, who carried heterozygous loss-of-function FOXN1 variants. Longitudinal analysis showed persistent T cell lymphopenia during infancy, often associated with nail dystrophy. Adult individuals with heterozygous FOXN1 variants had in most cases normal CD4+ but lower than normal CD8+ cell counts. We hypothesized a FOXN1 gene dosage effect on the function of thymic epithelial cells (TECs) and thymopoiesis and postulated that these effects would be more prominent early in life. To test this hypothesis, we analyzed TEC subset frequency and phenotype, early thymic progenitor (ETP) cell count, and expression of FOXN1 target genes (Ccl25, Cxcl12, Dll4, Scf, Psmb11, Prss16, and Cd83) in Foxn1nu/+ (nu/+) mice and age-matched wild-type (+/+) littermate controls. Both the frequency and the absolute count of ETP were significantly reduced in nu/+ mice up to 3 weeks of age. Analysis of the TEC compartment showed reduced expression of FOXN1 target genes and delayed maturation of the medullary TEC compartment in nu/+ mice. These observations establish a FOXN1 gene dosage effect on thymic function and identify FOXN1 haploinsufficiency as an important genetic determinant of T cell lymphopenia at birth.

2.
Front Immunol ; 10: 77, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30891027

RESUMO

Phosphoinositide 3-kinase (PI3K) plays an integral role in lymphocyte function. Mutations in PIK3CD and PIK3R1, encoding the PI3K p110δ and p85α subunits, respectively, cause increased PI3K activity and result in immunodeficiency with immune dysregulation. We describe here the first cases of disseminated and congenital toxoplasmosis in a mother and child who share a pathogenic mutation in PIK3R1 and review the mechanisms underlying susceptibility to severe Toxoplasma gondii infection in activated PI3Kδ syndrome (APDS) and in other forms of primary immunodeficiency.

3.
R I Med J (2013) ; 101(1): 21-25, 2018 Feb 02.
Artigo em Inglês | MEDLINE | ID: mdl-29393306

RESUMO

The Advance-Clinical and Translational Research (CTR) program was established in Rhode Island in May of 2016 with an IDeA Program Infrastructure award to collaborating institutions: Brown University, the University of Rhode Island, with the Lifespan, Care New England and Providence VA Medical Center healthcare institutions and the Rhode Island Quality Institute. To support programmatic planning, the Tracking and Evaluation Key Component Activity (KCA) of Advance-CTR developed and implemented a needs assessment survey to identify the obstacles to clinical and translational research at the participating institutions. We describe the methods used and the responses, which identified needs for study design and data analysis support. Support for project development, pilot funding and grants administration showed significant variation, depending on the affiliation of the respondent. The results of the survey are discussed in the context of Rhode Island's significant opportunities to support and develop the capabilities of scientists who engage in translational research. [Full article available at http://rimed.org/rimedicaljournal-2018-02.asp].


Assuntos
Ensaios Clínicos como Assunto/organização & administração , Determinação de Necessidades de Cuidados de Saúde , Pesquisa Médica Translacional/organização & administração , Atitude do Pessoal de Saúde , Feminino , Pesquisas sobre Serviços de Saúde , Humanos , Satisfação no Emprego , Masculino , Pesquisa Qualitativa , Apoio à Pesquisa como Assunto , Rhode Island
6.
Front Immunol ; 8: 798, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28769923

RESUMO

Mutations of the recombinase-activating genes 1 and 2 (RAG1 and RAG2) in humans are associated with a broad range of phenotypes. For patients with severe clinical presentation, hematopoietic stem cell transplantation (HSCT) represents the only curative treatment; however, high rates of graft failure and incomplete immune reconstitution have been observed, especially after unconditioned haploidentical transplantation. Studies in mice have shown that Rag-/- natural killer (NK) cells have a mature phenotype, reduced fitness, and increased cytotoxicity. We aimed to analyze NK cell phenotype and function in patients with mutations in RAG and in non-homologous end joining (NHEJ) genes. Here, we provide evidence that NK cells from these patients have an immature phenotype, with significant expansion of CD56bright CD16-/int CD57- cells, yet increased degranulation and high perforin content. Correlation was observed between in vitro recombinase activity of the mutant proteins, NK cell abnormalities, and in vivo clinical phenotype. Addition of serotherapy in the conditioning regimen, with the aim of depleting the autologous NK cell compartment, may be important to facilitate engraftment and immune reconstitution in patients with RAG and NHEJ defects treated by HSCT.

8.
Case Reports Immunol ; 2016: 5083274, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-27403355

RESUMO

Severe combined immunodeficiency (SCID), a primary immunodeficiency arising from variable defects in lymphocyte development and survival, is characterized by significant deficiency of thymus derived (T-) lymphocytes and variable defects in the B-lymphocyte population. Newborn screening for SCID is based on detection of low numbers of T-cell receptor excision circles (TRECs) by real time quantitative PCR (RT-qPCR). This screening allows for early identification of individuals with SCID and other disorders characterized by T-lymphopenia. Higher rates of abnormal screens are commonly seen in premature and critically ill neonates, often representing false positives. It is possible that many abnormal screens seen in these populations are result of conditions that are characterized by systemic inflammation or stress, possibly in the context of stress-induced thymic involution. We present a case of a male infant delivered at 27 weeks, 6 days of gestation, with severe intrauterine growth restriction who had an abnormal TREC screen and a massive perivillous fibrin deposition (MPFD) of the placenta. This association has not been reported previously. We are raising the awareness to the fact that conditions, such as MPFD, that can create adverse intrauterine environment are capable of causing severe stress-induced thymic involution of the fetus which can present with abnormal TREC results on newborn screening.

9.
J Infect Dis ; 201(7): 1024-30, 2010 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-20170376

RESUMO

BACKGROUND: Varicella-zoster virus (VZV)-specific cell-mediated immunity is important for protection against VZV disease. We studied the relationship between VZV cell-mediated immunity and age after varicella or VZV vaccination in healthy and human immunodeficiency virus (HIV)-infected individuals. METHODS: VZV responder cell frequency (RCF) determinations from 752 healthy and 200 HIV-infected subjects were used to identify group-specific regression curves on age. RESULTS: In healthy individuals with past varicella, VZV RCF peaked at 34 years of age. Similarly, VZV-RCF after varicella vaccine increased with age in subjects aged <1 to 43 years. In subjects aged 61-90 years, VZV RCF after zoster vaccine decreased with age. HIV-infected children had lower VZV RCF estimates than HIV-infected adults. In both groups, VZV RCF results were low and constant over age. Varicella vaccination of HIV-infected children with CD4 levels 20% generated VZV RCF values higher than wild-type infection and comparable to vaccine-induced responses of healthy children. CONCLUSIONS: In immunocompetent individuals with prior varicella, VZV RCF peaked in early adulthood. Administration of varicella vaccine to HIV-infected or uninfected individuals aged >5 years generated VZV RCF values similar to those of immunocompetent individuals with immunity induced by wild-type infection. A zoster vaccine increased the VZV RCF of elderly adults aged <75 years to values higher than peak values induced by wild-type infection.


Assuntos
Vacina contra Varicela/imunologia , Varicela/imunologia , Herpesvirus Humano 3/imunologia , Adolescente , Adulto , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Linfócitos T CD4-Positivos/imunologia , Criança , Pré-Escolar , Infecções por HIV/imunologia , Humanos , Imunidade Celular/imunologia , Lactente , Modelos Logísticos , Estudos Longitudinais , Pessoa de Meia-Idade
11.
J Infect Dis ; 200(7): 1068-77, 2009 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-19712037

RESUMO

BACKGROUND: The objectives of this study were to evaluate the association between varicella-zoster virus (VZV)-specific humoral and cell-mediated immunity (CMI) to herpes zoster (HZ) and protection against HZ morbidity and to compare immune responses to HZ and zoster vaccine. METHODS: In 981 elderly persons who developed HZ during a zoster vaccine efficacy trial (321 vaccinees and 660 placebo recipients) and 1362 without HZ (682 vaccinees and 680 placebo recipients), CMI was measured by VZV responder cell frequency and interferon-gamma enzyme-linked immunospot, and antibodies were measured by VZV enzyme-linked immunosorbent assay against affinity-purified VZV glycoproteins (gpELISA). RESULTS: Robust VZV CMI at HZ onset correlated with reduced HZ morbidity, whereas VZV gpELISA titers did not. Three weeks after HZ onset, gpELISA titers were highest in those with more severe HZ and were slightly increased in placebo recipients (compared with zoster vaccine recipients) and in older individuals. VZV CMI responses to HZ were similar in zoster vaccine and placebo recipients and were not affected by demographic characteristics or antiviral therapy, except for responder cell frequency at HZ onset, which decreased with age. When responses to zoster vaccine and HZ could be compared, VZV CMI values were similar, but antibody titers were lower. CONCLUSIONS: Higher VZV CMI at HZ onset was associated with reduced HZ severity and less postherpetic neuralgia. Higher antibody titers were associated with increased HZ severity and occurrence of postherpetic neuralgia. HZ and zoster vaccine generated comparable VZV CMI.


Assuntos
Herpes Zoster/prevenção & controle , Herpesvirus Humano 3/imunologia , Vacinas Virais/imunologia , Idoso , Anticorpos Antivirais/sangue , Método Duplo-Cego , Feminino , Herpes Zoster/imunologia , Humanos , Imunidade Celular , Masculino , Pessoa de Meia-Idade , Neuralgia Pós-Herpética/prevenção & controle , Fatores de Tempo
12.
Acad Med ; 84(4): 409-10, 2009 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-19318765

RESUMO

This commentary relates to three articles in this issue of Academic Medicine, which address the vision of the National Institutes of Health (NIH) for clinical and translational research. Those articles encompass the first successful Clinical and Translational Science Award applicants' stated aims for their programs, the success of a Harvard training program, and the case for exposing medical students to research experiences. The positive recommendations each makes are timely and give the author an opportunity to draw attention to related NIH education and outreach programs. Meeting the NIH's mission "to extend healthy life and reduce the burdens of illness and disability" will need a coordinated approach to ensure that health care workers are aware of the importance of research-and that clinical researchers see a secure, research-related career structure in academic health centers.


Assuntos
Pesquisa Biomédica , Escolha da Profissão , Distinções e Prêmios , Currículo , Financiamento Governamental , Pesquisa sobre Serviços de Saúde , Humanos , National Institutes of Health (U.S.) , Apoio à Pesquisa como Assunto , Estados Unidos
13.
Health Estate ; 61(8): 78-9, 2007 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-17892062

RESUMO

The Pontypridd and Rhondda NHS Trust is a multi-disciplinary Trust in South Wales, with acute, community and mental health facilitates making up a property portfolio of 20 buildings and 90,000m2. The flagship of the Trust is the nucleus design 600-bed Royal Glamorgan Hospital which was commissioned in December 1999 and boasts state-of-the-art services in providing healthcare to the population Rhondda Cynon Taf.


Assuntos
Poluição do Ar/prevenção & controle , Dióxido de Carbono , Conservação de Recursos Energéticos , Serviços Comunitários de Saúde Mental , Sistemas Multi-Institucionais , Estudos de Casos Organizacionais , País de Gales
17.
J Infect Dis ; 188(9): 1336-44, 2003 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-14593591

RESUMO

The safety and immunogenecity of a booster dose of live attenuated varicella-zoster virus (VZV) vaccine was evaluated in 196 healthy subjects, >or=60 years old, who had already received a VZV vaccine >5 years before. This repeat booster dose was well tolerated. Cell-mediated immunity (CMI) to VZV was measured by an interferon-gamma (IFN-gamma) enzyme-linked immunosorbent spot-forming cell (ELISPOT) assay and a limiting dilution responder cell frequency (RCF) assay. Prevaccination responses decreased as a function of increasing age but were detectable in all subjects by use of the IFN-gamma ELISPOT assay. In most subjects, VZV-specific CMI was increased at 6 weeks postvaccination. The magnitude of the vaccine-induced IFN-gamma ELISPOT response was inversely related to prevaccination values. Although there was a significant correlation between the IFN-gamma ELISPOT and RCF assays, the ELISPOT assay had greater sensitivity and a wider dynamic range. A live attenuated VZV vaccine is safe and immunogenic in an elderly population, and the vaccine-induced immunity may be monitored by the IFN-gamma ELISPOT assay.


Assuntos
Herpesvirus Humano 3/imunologia , Vacinas Virais/imunologia , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Antígenos Virais/imunologia , Divisão Celular/imunologia , Feminino , Herpes Zoster/imunologia , Herpes Zoster/prevenção & controle , Humanos , Imunidade Celular/imunologia , Imunização Secundária , Técnicas Imunoenzimáticas , Interferon gama/imunologia , Interferon gama/metabolismo , Masculino , Pessoa de Meia-Idade , Fatores Sexuais , Células Th1/imunologia , Vacinas Atenuadas/imunologia
18.
J Neurovirol ; 9(3): 404-7, 2003 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-12775423

RESUMO

Postherpetic neuralgia (PHN) is dermatomal distribution pain that persists for months to years after the resolution of herpes zoster rash. The cause of PHN is unknown. Herein, we report clinical, molecular virological, and immunological findings over an 11-year period in an immunocompetent elderly woman with PHN. Initially, blood mononuclear cells (MNCs) contained varicella-zoster virus (VZV) DNA on two consecutive occasions. Random testing after treatment with famciclovir to relieve pain did not detect VZV DNA. However, the patient was reluctant to continue famciclovir indefinitely and voluntarily stopped drug treatment five times. Pain always recurred within 1 week, and blood MNCs contained many, but not all, regions of the VZV genome on all five occasions. Immunological analysis revealed increased cell-mediated immunity to VZV. Chronic VZV ganglionitis-induced PHN best explains the recurrence of VZV DNA in MNCs whenever famciclovir was discontinued; the detection of only some regions of the viral genome in MNCs, compared to the detection of all regions of the VZV genome in latently infected ganglia; the increased cell-mediated immunity to VZV; and a gratifying clinical response to famciclovir. The presence of fragments of VZV DNA in MNCs likely represents partial degradation of viral DNA in MNCs that trafficked through ganglia during productive infection.


Assuntos
2-Aminopurina/análogos & derivados , Neuralgia Facial/etiologia , Herpes Zoster da Orelha Externa/complicações , Herpesvirus Humano 3/patogenicidade , 2-Aminopurina/uso terapêutico , Aciclovir/uso terapêutico , Amitriptilina/uso terapêutico , Analgésicos não Entorpecentes/uso terapêutico , Anticorpos Antivirais/sangue , Antivirais/uso terapêutico , Doença Crônica , DNA Viral/sangue , DNA Viral/isolamento & purificação , Disgeusia/etiologia , Exantema/etiologia , Neuralgia Facial/tratamento farmacológico , Neuralgia Facial/virologia , Paralisia Facial/etiologia , Famciclovir , Feminino , Seguimentos , Herpes Zoster da Orelha Externa/tratamento farmacológico , Herpesvirus Humano 3/imunologia , Herpesvirus Humano 3/isolamento & purificação , Humanos , Hiperacusia/etiologia , Imunoglobulina G/sangue , Imunoglobulina G/imunologia , Leucócitos Mononucleares/virologia , Pessoa de Meia-Idade , Couro Cabeludo
19.
J Infect Dis ; 187(8): 1257-63, 2003 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-12696005

RESUMO

Bonnet monkeys develop an enhanced disease after immunization with the formalin-inactivated (FI) respiratory syncytial virus (RSV) vaccine that is characterized by increased viral replication in perivascular sites of the lung. These sites contain many mononuclear cells, which are known to be permissive for RSV replication. To test the hypothesis that FI-RSV vaccine stimulates the production of enhancing antibodies that serve to increase the replication of RSV in macrophages, in vitro studies were done. Antibody-dependent enhancement was observed in animals immunized with FI-RSV but not in control animals with primary and tertiary infections or those immunized with FI-Vero cell culture. In the presence of serum samples from animals immunized with FI-RSV, an increased number of U937 cells was infected. The enhancement index correlated positively with the pathologic scores of the FI-RSV-vaccinated monkeys.


Assuntos
Anticorpos Antivirais/imunologia , Modelos Animais de Doenças , Macaca radiata/imunologia , Infecções por Vírus Respiratório Sincicial/imunologia , Infecções por Vírus Respiratório Sincicial/fisiopatologia , Vacinas contra Vírus Sincicial Respiratório/imunologia , Vírus Sinciciais Respiratórios/imunologia , Animais , Humanos , Células U937 , Vacinas de Produtos Inativados/imunologia , Replicação Viral
20.
J Med Virol ; 70 Suppl 1: S38-41, 2003.
Artigo em Inglês | MEDLINE | ID: mdl-12627485

RESUMO

An interferon-gamma ELISPOT assay has been developed for assessment of cellular immune responses to Varicella-Zoster Virus (VZV) in large, multi-center clinical vaccine trials. We show that the assay performed best when testing peripheral blood mononuclear cells (PBMCs) that had been isolated and then frozen on the same day as blood was drawn, and that freezing PBMCs from blood that was stored overnight before processing resulted in dramatically reduced responses. This assay was used to monitor cell-mediated immunity (CMI) in response to a booster immunization with an investigational live, attenuated VZV vaccine in an elderly population that had been vaccinated 8-10 years previously. The booster vaccine elicited a 1.6- to 1.7-fold rise in the VZV-specific cellular immune response as measured by the ELISPOT assay. The increase from pre to post booster vaccination response was more pronounced (approximately 2.2-fold rise) in a subset of subjects who had received two prior immunizations with a live, attenuated vaccine.


Assuntos
Vacina contra Varicela/administração & dosagem , Ensaio de Imunoadsorção Enzimática/métodos , Herpesvirus Humano 3/imunologia , Imunidade Celular , Interferon gama/análise , Idoso , Humanos , Imunização Secundária , Técnicas In Vitro , Interferon gama/biossíntese , Linfócitos T/imunologia
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