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1.
Artigo em Inglês | MEDLINE | ID: mdl-31445098

RESUMO

BACKGROUND: Although chiefly a B-lymphocyte disorder, several research groups have identified common variable immunodeficiency (CVID) subjects with numerical and/or functional T helper cell alterations. The causes, interrelationships and consequences of CVID-associated CD4+ T-cell derangements to hypogammaglobulinemia and/or autoantibody production remain unclear. OBJECTIVE: To determine how circulating CD4+ T-cells are altered in CVID subjects with autoimmune cytopenias (CVID+AIC) and the causes of these derrangements. METHODS: Using hypothesis-generating, high-dimensional single-cell analyses, we created comprehensive phenotypic maps of circulating CD4+ T cells. Differences between subject groups were confirmed in a large, genetically diverse CVID subject cohort (n=69) using flow cytometry, transcriptional profiling, multiplex cytokine/chemokine detection and a suite of in vitro functional assays measuring naive T cell differentiation, B cell/T cell co-cultures and Treg suppression. RESULTS: Whereas CD4+ T helper cell profiles from healthy donors and CVID subjects without autoimmune cytopenias were virtually indistinguishable, CVID+AIC T cells exhibited follicular features as early as thymic egress. Follicular skewing correlated with IgA deficiency-associated endotoxemia and endotoxin-induced expression of activin A and ICOSL. The resulting enlarged CVID+AIC circulating Tfh (cTfh) cell population provided efficient help to receptive HD B cells but not unresponsive CVID B cells. Despite this, CVID+AIC cTfh exhibited aberrant transcriptional profiles and altered chemokine/cytokine receptor expression patterns that interfered with Treg suppression assays and were associated with autoantibody production. CONCLUSIONS: Endotoxemia is associated with early commitment to the follicular T cell lineage in IgA-deficient CVID subjects, particularly those with AICs.

4.
Clin Infect Dis ; 67(1): 27-33, 2018 Jun 18.
Artigo em Inglês | MEDLINE | ID: mdl-29346543

RESUMO

Background: Patients hospitalized with hematologic malignancy are particularly vulnerable to infection. The impact of reported beta-lactam (BL) allergy in this population remains unknown. Methods: This was a retrospective cohort study of adult inpatients with hematologic malignancy admitted at 2 tertiary care hospitals from 2010 through 2015. The primary outcome was hospital length of stay (LOS) after administration of the first antibiotic. Secondary outcomes included readmission, mortality, complications, hospital charges, and antibiotic usage. Our goal was to define the impact of BL-only allergy (BLOA) label on clinical outcomes compared to those with no BL allergy (NBLA) in hematologic malignancy inpatients who required systemic antibiotics. Results: In our cohort (n = 4671), 38.3% had leukemia, 4.9% had Hodgkin lymphoma, 36.1% had non-Hodgkin lymphoma, and 20.7% had multiple myeloma. Among patients, 35.1% reported antibiotic allergy, and 14.1% (n = 660) had BLOA (including 9.3% with penicillin-only allergy and 3.3% cephalosporin-only allergy). Patients with BLOA had longer median LOS compared to patients with NBLA (11.3 vs 7.6 days, P < .001), which remained significant after multivariable adjustment. Patients with BLOA also had significantly worse outcomes in terms of mortality rate at 30 days (7.6% vs 5.3%, P = .017) and 180 days (15.8% vs 12.2%, P = .013), 30-day readmission rate, Clostridium difficile rate, hospital charges ($223 046 vs $173 256, P < .001), antibiotic classes used, and antibiotic duration. Conclusions: In hospitalized patients with hematologic malignancy, patients with reported BL allergy had worse clinical outcomes and higher healthcare cost than those without BL allergy label.

5.
Clin Vaccine Immunol ; 21(12): 1613-9, 2014 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-25253666

RESUMO

Given the resurgence of pertussis despite high rates of vaccination with the diphtheria-tetanus-acellular pertussis (DTaP) vaccine, a better understanding of vaccine-induced immune responses to Bordetella pertussis is needed. We investigated the antibody, cell-mediated, and cytokine responses to B. pertussis antigens in children who received the primary vaccination series (at 2, 4, and 6 months) and first booster vaccination (at 15 to 18 months) with 5-component acellular pertussis (aP) vaccine. The majority of subjects demonstrated a 4-fold increase in antibody titer to all four pertussis antigens (pertussis toxin [PT], pertactin [PRN], filamentous hemagglutinin [FHA], and fimbriae [FIM]) following the primary series and booster vaccination. Following the primary vaccine series, the majority of subjects (52 to 67%) mounted a positive T cell proliferative response (stimulation index of ≥ 3) to the PT and PRN antigens, while few subjects (7 to 12%) mounted positive proliferative responses to FHA and FIM. One month after booster vaccination (age 16 to 19 months), our study revealed significant increase in gamma interferon (IFN-γ) production in response to the PT and FIM antigens, a significant increase in IL-2 production with the PT, FHA, and PRN antigens, and a lack of significant interleukin-4 (IL-4) secretion with any of the antigens. While previous reports documented a mixed Th1/Th2 or Th2-skewed response to DTaP vaccine in children, our data suggest that following the first DTaP booster, children aged 16 to 19 months have a cytokine profile consistent with a Th1 response, which is known to be essential for clearance of pertussis infection. To better define aP-induced immune responses following the booster vaccine, further studies are needed to assess cytokine responses pre- and postbooster in DTaP recipients.


Assuntos
Anticorpos Antibacterianos/sangue , Antígenos de Bactérias/imunologia , Bordetella pertussis/imunologia , Vacinas contra Difteria, Tétano e Coqueluche Acelular/imunologia , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Masculino , Vacinação , Coqueluche/prevenção & controle
6.
Ann Pharmacother ; 47(7-8): e30, 2013 Jul-Aug.
Artigo em Inglês | MEDLINE | ID: mdl-23715068

RESUMO

OBJECTIVE: To describe a case in which a linezolid desensitization protocol was successfully used for a polymicrobial surgical wound infection in a patient with multiple drug hypersensitivity reactions. CASE SUMMARY: A 24-year-old woman with vocal cord dysfunction requiring tracheostomy was admitted for a surgical wound infection following a tracheostomy fistula closure procedure. The patient reported multiple antibiotic allergies including penicillins (rash), sulfonamides (rash), vancomycin (anaphylaxis), azithromycin (rash), cephalosporins (anaphylaxis), levofloxacin (unspecified), clindamycin (unspecified), and carbapenems (unspecified). Gram stain of the purulent wound drainage demonstrated mixed gram-negative and gram-positive flora, and bacterial cultures were overgrown with Proteus mirabilis, which precluded identification of other pathogens. Following failed test doses of linezolid, tigecycline, and daptomycin, all of which resulted in hypersensitivity reactions, a 16-step linezolid desensitization protocol was developed and successfully implemented without adverse reactions. The patient completed a 2-week course of antibiotic therapy that included linezolid upon finishing the desensitization protocol. DISCUSSION: Linezolid is useful in treating complicated and uncomplicated skin and soft tissue infections caused by gram-positive bacteria. With precautions, including premedication, a monitored nursing unit, and immediate availability of an emergency anaphylaxis kit, drug desensitization allows patients the ability to safely use medications to which they may have an immediate hypersensitivity reaction. Minimal data exist on linezolid desensitization protocols. CONCLUSIONS: Linezolid desensitization can be a viable option in patients requiring antimicrobial therapy for complicated gram-positive skin infections.


Assuntos
Acetamidas/administração & dosagem , Anti-Infecciosos/administração & dosagem , Dessensibilização Imunológica/métodos , Hipersensibilidade a Drogas/tratamento farmacológico , Oxazolidinonas/administração & dosagem , Infecções dos Tecidos Moles/tratamento farmacológico , Hipersensibilidade a Drogas/diagnóstico , Hipersensibilidade a Drogas/imunologia , Feminino , Humanos , Infusões Intravenosas , Linezolida , Infecções dos Tecidos Moles/diagnóstico , Infecções dos Tecidos Moles/imunologia , Adulto Jovem
8.
Biochemistry ; 46(45): 13031-40, 2007 Nov 13.
Artigo em Inglês | MEDLINE | ID: mdl-17944490

RESUMO

Both metal and flavin-dependent sulfhydryl oxidases catalyze the net generation of disulfide bonds with the reduction of oxygen to hydrogen peroxide. The first mammalian sulfhydryl oxidase to be described was an iron-dependent enzyme isolated from bovine milk whey (Janolino, V.G., and Swaisgood, H.E. (1975) J. Biol. Chem. 250, 2532-2537). This protein was reported to contain 0.5 atoms of iron per 89 kDa subunit and to be completely inhibited by ethylenediaminetetraacetate (EDTA). However the present work shows that a soluble 62 kDa FAD-linked and EDTA-insensitive sulfhydryl oxidase apparently constitutes the dominant disulfide bond-generating activity in skim milk. Unlike the metalloenzyme, the flavoprotein is not associated tightly with skim milk membranes. Sequencing of the purified bovine enzyme (>70% coverage) showed it to be a member of the Quiescin-sulfhydryl oxidase (QSOX) family. Consistent with its solubility, this bovine QSOX1 paralogue lacks the C-terminal transmembrane span of the long form of these proteins. Bovine milk QSOX1 is highly active toward reduced RNase and with the model substrate dithiothreitol. The significance of these new findings is discussed in relation to the earlier reports of metal-dependent sulfhydryl oxidases.


Assuntos
Leite/enzimologia , Oxirredutases/metabolismo , Sequência de Aminoácidos , Animais , Bovinos , Galinhas , Cromatografia em Gel , Clara de Ovo/análise , Feminino , Dados de Sequência Molecular , Oxirredutases/isolamento & purificação , Alinhamento de Sequência
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