RESUMO
BACKGROUND: Reasons for the highly variable and often poor protection conferred by the Mycobacterium bovis bacille Calmette-Guérin (BCG) vaccine are multifaceted and poorly understood. OBJECTIVES: We aimed to determine whether early-life exposure to PCBs (polychlorinated biphenyls) and DDE [1,1-dichloro-2,2-bis(p-chlorophenyl)ethylene] reduces 6-month infant BCG vaccine response. METHODS: Data came from families participating in a prospective birth cohort in eastern Slovakia. At birth, maternal and cord blood were collected for chemical analyses, and infants were immunized with BCG. Blood was collected from infants for chemical analyses and to determine 6-month BCG-specific immunoglobulin (Ig) G and IgA levels. Multivariable linear regression models were fit to examine chemical-BCG associations among approximately 500 mother-infant pairs, with adjustment for confounders. RESULTS: The median 6-month infant concentration of the prevalent congener PCB-153 was 113 ng/g lipid [interquartile range (IQR): 37-248], and 388 ng/g lipid (IQR: 115-847) for DDE. Higher 6-month infant concentrations of PCB-153 and DDE were strongly associated with lower 6-month BCG-specific antibody levels. For instance, BCG-specific IgG levels were 37% lower for infants with PCB-153 concentrations at the 75th percentile compared to the 25th percentile (95% CI: -42, -32; p < 0.001). Results were similar in magnitude and precision for DDE. There was also evidence of PCB-DDE additivity, where exposure to both compounds reduced anti-BCG levels more than exposure to either compound alone. CONCLUSIONS: The associations observed in this study indicate that environmental exposures may be overlooked contributors to poorer responses to BCG vaccine. The overall association between these exposures and tuberculosis incidence is unknown. CITATION: Jusko TA, De Roos AJ, Lee SY, Thevenet-Morrison K, Schwartz SM, Verner MA, Palkovicova Murinova L, Drobná B, Kocan A, Fabisiková A, Conka K, Trnovec T, Hertz-Picciotto I, Lawrence BP. 2016. A birth cohort study of maternal and infant serum PCB-153 and DDE concentrations and responses to infant tuberculosis vaccination. Environ Health Perspect 124:813-821; http://dx.doi.org/10.1289/ehp.1510101.
Assuntos
Diclorodifenil Dicloroetileno/sangue , Exposição Ambiental/estatística & dados numéricos , Poluentes Ambientais/sangue , Bifenilos Policlorados/sangue , Vacinas contra a Tuberculose/uso terapêutico , Sangue Fetal/metabolismo , Humanos , Lactente , Modelos Lineares , Estudos Prospectivos , Tuberculose , VacinaçãoRESUMO
Innate lymphoid cells (ILCs) contribute to barrier immunity, tissue homeostasis, and immune regulation at various anatomical sites throughout the body. How ILCs maintain their presence in lymphoid and peripheral tissues thus far has been unclear. We found that in the lymphoid and nonlymphoid organs of adult mice, ILCs are tissue-resident cells that were maintained and expanded locally under physiologic conditions, upon systemic perturbation of immune homeostasis and during acute helminth infection. However, at later time points after infection, cells from hematogenous sources helped to partially replenish the pool of resident ILCs. Thus, ILCs are maintained by self-renewal in broadly different microenvironments and physiological settings. Such an extreme "sedentary" lifestyle is consistent with the proposed roles of ILCs as sentinels and local keepers of tissue function.
Assuntos
Imunidade Inata , Linfócitos/imunologia , Tecido Linfoide/imunologia , Animais , Feminino , Helmintíase/imunologia , Homeostase/imunologia , Intestino Delgado/citologia , Intestino Delgado/imunologia , Pulmão/citologia , Pulmão/imunologia , Tecido Linfoide/citologia , Camundongos , Camundongos Endogâmicos C57BL , Especificidade de Órgãos/imunologia , Parabiose , Glândulas Salivares/citologia , Glândulas Salivares/imunologiaRESUMO
Although cytotoxicity assays provide several advantages over mouse bioassays, sodium channel-blocking marine toxins, such as those associated with paralytic shellfish poison (PSP), require prolonged incubation periods of 24-48 h. This is in marked contrast to in vitro detection of sodium channel-enhancing marine toxins such as ciguatoxins or brevetoxins which can be accomplished in as few as 4-6 h. We developed a modified PSP cell bioassay that is as rapid as in vitro methods for sodium channel-enhancing toxins. The cell bioassay is based on a saxitoxin-dependent antagonism of the rapid in vitro effects of brevetoxin or ciguatoxin. Comparative analysis of naturally incurred PSP residues by both antagonism cell bioassay and the mouse bioassay demonstrated significant correlation. The simplicity, sensitivity, and enhanced kinetics of the new antagonism cell bioassay format provide the basis for development of a practical alternative to conventional mouse testing for PSP.
Assuntos
Saxitoxina/análise , Bloqueadores dos Canais de Sódio/toxicidade , Animais , Bioensaio , Linhagem Celular , Humanos , Camundongos , Saxitoxina/toxicidadeRESUMO
Rational combinatorial therapeutic strategies have proven beneficial for the management of cancer. Recent success of checkpoint blockade in highly immunogenic tumors has renewed interest in immunotherapy. Regulatory T (T reg) cells densely populate solid tumors, which may promote progression through suppressing anti-tumor immune responses. We investigated the role of T reg cells in murine mammary carcinogenesis using an orthotopic, polyoma middle-T antigen-driven model in Foxp3(DTR) knockin mice. T reg cell ablation resulted in significant determent of primary and metastatic tumor progression. Importantly, short-term ablation of T reg cells in advanced spontaneous tumors led to extensive apoptotic tumor cell death. This anti-tumor activity was dependent on IFN-γ and CD4(+) T cells but not on NK or CD8(+) T cells. Combination of T reg cell ablation with CTLA-4 or PD-1/PD-L1 blockade did not affect tumor growth or improve the therapeutic effect attained by T reg cell ablation alone. However, T reg cell targeting jointly with tumor irradiation significantly reduced tumor burden and improved overall survival. Together, our results demonstrate a major tumor-promoting role of T reg cells in an autochthonous model of tumorigenesis, and they reveal the potential therapeutic value of combining transient T reg cell ablation with radiotherapy for the management of poorly immunogenic, aggressive malignancies.
Assuntos
Depleção Linfocítica , Neoplasias Mamárias Animais/imunologia , Neoplasias Mamárias Animais/radioterapia , Oncogenes/genética , Linfócitos T Reguladores/imunologia , Animais , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD4-Positivos/efeitos da radiação , Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/efeitos da radiação , Pontos de Checagem do Ciclo Celular/efeitos da radiação , Morte Celular/efeitos da radiação , Proliferação de Células/efeitos da radiação , Progressão da Doença , Feminino , Interferon gama/metabolismo , Células Matadoras Naturais/imunologia , Células Matadoras Naturais/efeitos da radiação , Neoplasias Pulmonares/patologia , Neoplasias Pulmonares/secundário , Neoplasias Mamárias Animais/patologia , Camundongos , Radiação Ionizante , Linfócitos T Reguladores/efeitos da radiação , Carga Tumoral/imunologia , Carga Tumoral/efeitos da radiação , Microambiente Tumoral/efeitos da radiaçãoRESUMO
Fractures of the coronoid process of the ulna generally occur in relatively high-energy injuries and are commonly associated with injuries to other structures around the elbow. Damage to the coronoid process in addition to other elbow structures may complicate treatment. Several approaches have been used in the management of coronoid process fractures. This paper reports a method of coronoid process fracture fixation using suture anchors.
RESUMO
Traditional management of unstable fourth and fifth carpal-metacarpal (CMC) fracture-dislocations (fx-dislocs) of the hand includes closed reduction and percutaneous pinning (CRPP) versus open reduction internal fixation (ORIF). Traditional trajectory of pin placement is toward the base of the hook of the hamate. Our case series of CMC fx-dislocs treated with this trajectory led to the development of ulnar deep motor branch symptoms (sxs). We attempt to propose an alternative trajectory that could lower the chance of iatrogenic injury. Five fresh frozen cadaveric specimens underwent percutaneous pinning of the fifth CMC joint using fluoroscopic guidance. Each cadaver was dissected, and the proximity of the deep motor branch of the ulnar nerve was measured in relation to a pin that penetrated the volar cortex. Our results confirm the close proximity of the deep motor branch of the ulnar nerve to the volar cortex of the hamate and demonstrate the potential for iatrogenic injury during CRPP of the fifth CMC fx-dislocs, especially with penetration of the volar cortex. By demonstrating the close proximity of the deep motor branch to the volar cortex of the hamate in cadavers, we highlight the potential for iatrogenic injury with CRPP of CMC fx-dislocs as seen in our case series. We recommend a more midaxial starting point on the proximal metacarpal with a trajectory aimed at the midbody of the hamate to prevent penetration of the hamate volar cortex and limit the chances of iatrogenic injury.