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Non-tuberculous mycobacterial (NTM) lymphadenitis typically presents as a unilateral, non-tender, slowly enlarging cervical, submandibular, or pre-auricular lymph node in children. Disseminated NTM infection is most often seen in immunocompromised children. Here, we present an unusual case of extensive bilateral cervical and retropharyngeal lymphadenitis caused by Mycobacterium Avium Complex (MAC) in an ostensibly immunocompetent pediatric patient.
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Linfadenitis , Infecciones por Mycobacterium no Tuberculosas , Niño , Humanos , Micobacterias no Tuberculosas , Infecciones por Mycobacterium no Tuberculosas/diagnóstico , Infecciones por Mycobacterium no Tuberculosas/tratamiento farmacológico , Infecciones por Mycobacterium no Tuberculosas/complicaciones , Linfadenitis/etiología , Linfadenitis/microbiología , Complejo Mycobacterium avium , Huésped InmunocomprometidoRESUMEN
Central B cell tolerance is believed to be regulated by B cell receptor signaling induced by the recognition of self-antigens in immature B cells. Using humanized mice with defective MyD88, TLR7, or TLR9 expression, we demonstrate that TLR9/MYD88 are required for central B cell tolerance and the removal of developing autoreactive clones. We also show that CXCL4, a chemokine involved in systemic sclerosis (SSc), abrogates TLR9 function in B cells by sequestering TLR9 ligands away from the endosomal compartments where this receptor resides. The in vivo production of CXCL4 thereby impedes both TLR9 responses in B cells and the establishment of central B cell tolerance. We conclude that TLR9 plays an essential early tolerogenic function required for the establishment of central B cell tolerance and that correcting defective TLR9 function in B cells from SSc patients may represent a novel therapeutic strategy to restore B cell tolerance.
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Factor Plaquetario 4 , Esclerodermia Sistémica , Receptor Toll-Like 9 , Animales , Humanos , Ratones , Linfocitos B , Ligandos , Factor 88 de Diferenciación Mieloide/metabolismo , Factor Plaquetario 4/metabolismo , Esclerodermia Sistémica/metabolismo , Receptor Toll-Like 7 , Receptor Toll-Like 9/metabolismoRESUMEN
The Tracking and Evaluation Core of Rhode Island Advance-CTR conducted an online needs assessment survey at the program's inception in 2016 and again in 2021. Now dealing with well-established support systems provided by the grant, we were particularly interested in how the perceived needs of the research community in Rhode Island might have changed over five years. Specifically, what barriers have been reduced or eliminated and which have persisted or increased? How do those barriers vary by demographic status and what implications do those differences have for the CTR? An online survey was completed by 199 researchers, who reported the extent to which they perceived the lack of access to a range of research supports as a barrier to conducting research at their institution. Overall, researchers indicated statistically significant changes from 2016 to 2021 such that a lack of pilot project funding and proposal development support had decreased as barriers, while space for research, and advice on commercial development, had increased. Statistically significant differences in the salience of particular barriers by some demographic variables were also noted and the results of this study suggest Centers for Clinical and Translational Research can have salutary effects on the research paradigm within their partnering institutions in a relatively short time.
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Investigadores , Investigación Biomédica Traslacional , Humanos , Proyectos Piloto , Rhode Island , Encuestas y CuestionariosRESUMEN
In evaluation research, "programs" are often conceptualized as clearly bounded, narrow in scope, focused on specific outcomes, using a well-defined linear causal model, and hence, suitable for standard evaluation methods. The evaluation work reported here was carried out in a more challenging context, where large, complex, interwoven systems were targets for change as a means to influence a diffuse array of outcomes. Our evaluation of an NIH-funded program to improve statewide infrastructure for clinical and translational health research ("Advance-CTR") used qualitative data provided by investigators who used the program's services, were funded awardees, or were members of an internal advisory committee (leadership representatives from partnering institutions). We examined perceived barriers to systemic changes to enhance research, as well as how systems have changed due to the Rhode Island Advance-CTR program's efforts, to what degree, and with what effects. Using the causal logic of our program to connect these more distal systemic outcomes to the services and components of Advance-CTR, we discuss the effects this program has had on researchers and their environments, contributing to the development of sustainable programs of research that ultimately improve the health and well-being of our state's residents.
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Investigadores , Investigación Biomédica Traslacional , Comités Consultivos , Humanos , Liderazgo , Evaluación de Programas y Proyectos de SaludRESUMEN
INTRODUCTION: Advance Clinical and Translational Research (Advance-CTR) serves as a central hub to support and educate clinical and translational researchers in Rhode Island. Understanding barriers to clinical research in the state is the key to setting project aims and priorities. METHODS: We implemented a Group Concept Mapping exercise to characterize the views of researchers and administrators regarding how to increase the quality and quantity of clinical and translational research in their settings. Participants generated ideas in response to this prompt and rated each unique idea in terms of how important it was and feasible it seemed to them. RESULTS: Participants generated 78 unique ideas, from which 9 key themes emerged (e.g., Building connections between researchers). Items rated highest in perceived importance and feasibility included providing seed grants for pilot projects, connecting researchers with common interests and networking opportunities. Implications of results are discussed. CONCLUSIONS: The Group Concept Mapping exercise enabled our project leadership to better understand stakeholder-perceived priorities and to act on ideas and aims most relevant to researchers in the state. This method is well suited to translational research enterprises beyond Rhode Island when a participatory evaluation stance is desired.
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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.
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Factores de Transcripción Forkhead/genética , Heterocigoto , Linfopenia/genética , Linfocitos T/metabolismo , Timo/citología , Adulto , Anciano , Animales , Preescolar , Femenino , Factores de Transcripción Forkhead/fisiología , Humanos , Lactante , Recién Nacido , Masculino , Ratones , Ratones SCID , Persona de Mediana Edad , Adulto JovenRESUMEN
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.
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Fosfatidilinositol 3-Quinasa Clase I/genética , Fosfatidilinositol 3-Quinasa Clase Ia/genética , Síndromes de Inmunodeficiencia/inmunología , Mutación/genética , Toxoplasma/fisiología , Toxoplasmosis Congénita/inmunología , Adulto , Anticuerpos Antiprotozoarios/sangre , Niño , Femenino , Humanos , Inmunidad Materno-Adquirida , Síndromes de Inmunodeficiencia/diagnóstico , Síndromes de Inmunodeficiencia/genética , Lactante , Linfadenopatía , Madres , Fenotipo , Toxoplasmosis Congénita/diagnóstico , Toxoplasmosis Congénita/genéticaRESUMEN
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].
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Ensayos Clínicos como Asunto/organización & administración , Evaluación de Necesidades , Investigación Biomédica Traslacional/organización & administración , Actitud del Personal de Salud , Femenino , Encuestas de Atención de la Salud , Humanos , Satisfacción en el Trabajo , Masculino , Investigación Cualitativa , Apoyo a la Investigación como Asunto , Rhode IslandRESUMEN
[This corrects the article on p. 798 in vol. 8, PMID: 28769923.].
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Proteínas de Unión al ADN/genética , Proteínas de Homeodominio/genética , Síndromes de Inmunodeficiencia/genética , Síndromes de Inmunodeficiencia/inmunología , Proteínas Nucleares/genética , Receptores de Antígenos de Linfocitos T/inmunología , Linfocitos T/inmunología , Autoinmunidad , Niño , Preescolar , Humanos , Lactante , Recién NacidoRESUMEN
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.
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Síndromes de Inmunodeficiencia/diagnóstico , Proteínas de Microfilamentos/deficiencia , Humanos , Inmunoglobulina G/sangre , Inmunoglobulina M/sangre , Síndromes de Inmunodeficiencia/sangre , Recién Nacido , Linfopenia/sangre , Linfopenia/diagnóstico , Masculino , Proteínas de Microfilamentos/genética , Tamizaje NeonatalRESUMEN
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.
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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.
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Vacuna contra la Varicela/inmunología , Varicela/inmunología , Herpesvirus Humano 3/inmunología , Adolescente , Adulto , Factores de Edad , Anciano , Anciano de 80 o más Años , Linfocitos T CD4-Positivos/inmunología , Niño , Preescolar , Infecciones por VIH/inmunología , Humanos , Inmunidad Celular/inmunología , Lactante , Modelos Logísticos , Estudios Longitudinales , Persona de Mediana EdadRESUMEN
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.
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Herpes Zóster/prevención & control , Herpesvirus Humano 3/inmunología , Vacunas Virales/inmunología , Anciano , Anticuerpos Antivirales/sangre , Método Doble Ciego , Femenino , Herpes Zóster/inmunología , Humanos , Inmunidad Celular , Masculino , Persona de Mediana Edad , Neuralgia Posherpética/prevención & control , Factores de TiempoRESUMEN
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.
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Investigación Biomédica , Selección de Profesión , Distinciones y Premios , Curriculum , Financiación Gubernamental , Investigación sobre Servicios de Salud , Humanos , National Institutes of Health (U.S.) , Apoyo a la Investigación como Asunto , Estados UnidosRESUMEN
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.