Browsing by Author "Johnson, MD"

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    Cytokine gene polymorphisms and the outcome of invasive candidiasis: a prospective cohort study.
    (Clinical infectious diseases : an official publication of the Infectious Diseases Society of America, 2012-02) Johnson, MD; Plantinga, TS; van de Vosse, E; Velez Edwards, DR; Smith, PB; Alexander, BD; Yang, JC; Kremer, D; Laird, GM; Oosting, M; Joosten, LA; van der Meer, JW; van Dissel, JT; Walsh, TJ; Perfect, JR; Kullberg, BJ; Scott, WK; Netea, MG
    BACKGROUND:  Candida bloodstream infections cause significant morbidity and mortality among hospitalized patients. Although clinical and microbiological factors affecting prognosis have been identified, the impact of genetic variation in the innate immune responses mediated by cytokines on outcomes of infection remains to be studied. METHODS:  A cohort of 338 candidemia patients and 351 noninfected controls were genotyped for single-nucleotide polymorphisms (SNPs) in 6 cytokine genes (IFNG, IL10, IL12B, IL18, IL1β, IL8) and 1 cytokine receptor gene (IL12RB1). The association of SNPs with both candidemia susceptibility and outcome were assessed. Concentrations of pro- and antiinflammatory cytokines were measured in in vitro peripheral blood mononuclear cell stimulation assays and in serum from infected patients. RESULTS:  None of the cytokine SNPs studied were associated with susceptibility to candidemia. Persistent fungemia occurred in 13% of cases. In the multivariable model, persistent candidemia was significantly associated with (odds ratio [95% confidence interval]): total parenteral nutrition (2.79 [1.26-6.17]), dialysis dependence (3.76 [1.46-8.64]), and the SNPs IL10 rs1800896 (3.45 [1.33-8.93]) and IL12B rs41292470 (5.36 [1.51-19.0]). In vitro production capacity of interleukin-10 and interferon-γ was influenced by these polymorphisms, and significantly lower proinflammatory cytokine concentrations were measured in serum from patients with persistent fungemia. CONCLUSIONS:  Polymorphisms in IL10 and IL12B that result in low production of proinflammatory cytokines are associated with persistent fungemia in candidemia patients. This provides insights for future targeted management strategies for patients with Candida bloodstream infections.
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    Dark Energy Survey Year 1 Results: Cosmological Constraints from Cluster Abundances and Weak Lensing
    Abbott, TMC; Aguena, M; Alarcon, A; Allam, S; Allen, S; Annis, J; Avila, S; Bacon, D; Bechtol, K; Bermeo, A; Bernstein, GM; Bertin, E; Bhargava, S; Bocquet, S; Brooks, D; Brout, D; Buckley-Geer, E; Burke, DL; Carnero Rosell, A; Carrasco Kind, M; Carretero, J; Castander, FJ; Cawthon, R; Chang, C; Chen, X; Choi, A; Costanzi, M; Crocce, M; da Costa, LN; Davis, TM; De Vicente, J; DeRose, J; Desai, S; Diehl, HT; Dietrich, JP; Dodelson, S; Doel, P; Drlica-Wagner, A; Eckert, K; Eifler, TF; Elvin-Poole, J; Estrada, J; Everett, S; Evrard, AE; Farahi, A; Ferrero, I; Flaugher, B; Fosalba, P; Frieman, J; García-Bellido, J; Gatti, M; Gaztanaga, E; Gerdes, DW; Giannantonio, T; Giles, P; Grandis, S; Gruen, D; Gruendl, RA; Gschwend, J; Gutierrez, G; Hartley, WG; Hinton, SR; Hollowood, DL; Honscheid, K; Hoyle, B; Huterer, D; James, DJ; Jarvis, M; Jeltema, T; Johnson, MWG; Johnson, MD; Kent, S; Krause, E; Kron, R; Kuehn, K; Kuropatkin, N; Lahav, O; Li, TS; Lidman, C; Lima, M; Lin, H; MacCrann, N; Maia, MAG; Mantz, A; Marshall, JL; Martini, P; Mayers, J; Melchior, P; Mena-Fernández, J; Menanteau, F; Miquel, R; Mohr, JJ; Nichol, RC; Nord, B; Ogando, RLC; Palmese, A; Paz-Chinchón, F; Plazas, AA; Prat, J; Rau, MM; Romer, AK; Roodman, A; Rooney, P; Rozo, E; Rykoff, ES; Sako, M; Samuroff, S; Sánchez, C; Sanchez, E; Saro, A; Scarpine, V; Schubnell, M; Scolnic, D; Serrano, S; Sevilla-Noarbe, I; Sheldon, E; Smith, J Allyn; Smith, M; Suchyta, E; Swanson, MEC; Tarle, G; Thomas, D; To, C; Troxel, MA; Tucker, DL; Varga, TN; von der Linden, A; Walker, AR; Wechsler, RH; Weller, J; Wilkinson, RD; Wu, H; Yanny, B; Zhang, Y; Zhang, Z; Zuntz, J; Collaboration, DES
    We perform a joint analysis of the counts and weak lensing signal of redMaPPer clusters selected from the Dark Energy Survey (DES) Year 1 dataset. Our analysis uses the same shear and source photometric redshifts estimates as were used in the DES combined probes analysis. Our analysis results in surprisingly low values for $S_8 =\sigma_8(\Omega_{\rm m}/0.3)^{0.5}= 0.65\pm 0.04$, driven by a low matter density parameter, $\Omega_{\rm m}=0.179^{+0.031}_{-0.038}$, with $\sigma_8-\Omega_{\rm m}$ posteriors in $2.4\sigma$ tension with the DES Y1 3x2pt results, and in $5.6\sigma$ with the Planck CMB analysis. These results include the impact of post-unblinding changes to the analysis, which did not improve the level of consistency with other data sets compared to the results obtained at the unblinding. The fact that multiple cosmological probes (supernovae, baryon acoustic oscillations, cosmic shear, galaxy clustering and CMB anisotropies), and other galaxy cluster analyses all favor significantly higher matter densities suggests the presence of systematic errors in the data or an incomplete modeling of the relevant physics. Cross checks with X-ray and microwave data, as well as independent constraints on the observable--mass relation from SZ selected clusters, suggest that the discrepancy resides in our modeling of the weak lensing signal rather than the cluster abundance. Repeating our analysis using a higher richness threshold ($\lambda \ge 30$) significantly reduces the tension with other probes, and points to one or more richness-dependent effects not captured by our model.
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    Evaluation of a digital microfluidic real-time PCR platform to detect DNA of Candida albicans in blood.
    (Eur J Clin Microbiol Infect Dis, 2012-09) Schell, WA; Benton, JL; Smith, PB; Poore, M; Rouse, JL; Boles, DJ; Johnson, MD; Alexander, BD; Pamula, VK; Eckhardt, AE; Pollack, MG; Benjamin, DK; Perfect, JR; Mitchell, TG
    Species of Candida frequently cause life-threatening infections in neonates, transplant and intensive care unit (ICU) patients, and others with compromised host defenses. The successful management of systemic candidiasis depends upon early, rapid diagnosis. Blood cultures are the standard diagnostic method, but identification requires days and less than half of the patients are positive. These limitations may be eliminated by using real-time polymerase chain reaction (PCR) to detect Candida DNA in the blood specimens of patients at risk. Here, we optimized a PCR protocol to detect 5-10 yeasts in low volumes of simulated and clinical specimens. We also used a mouse model of systemic candidiasis and determined that candidemia is optimally detectable during the first few days after infection. However, PCR tests are often costly, labor-intensive, and inconvenient for routine use. To address these obstacles, we evaluated the innovative microfluidic real-time PCR platform (Advanced Liquid Logic, Inc.), which has the potential for full automation and rapid turnaround. Eleven and nine of 16 specimens from individual patients with culture-proven candidemia tested positive for C. albicans DNA by conventional and microfluidic real-time PCR, respectively, for a combined sensitivity of 94%. The microfluidic platform offers a significant technical advance in the detection of microbial DNA in clinical specimens.
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    The impact of caspase-12 on susceptibility to candidemia.
    (European journal of clinical microbiology & infectious diseases : official publication of the European Society of Clinical Microbiology, 2012-03) Rosentul, DC; Plantinga, TS; Scott, WK; Alexander, BD; van de Geer, NMD; Perfect, JR; Kullberg, BJ; Johnson, MD; Netea, MG
    Candida is one of the leading causes of sepsis, and an effective host immune response to Candida critically depends on the cytokines IL-1β and IL-18, which need caspase-1 cleavage to become bioactive. Caspase-12 has been suggested to inhibit caspase-1 activation and has been implicated as a susceptibility factor for bacterial sepsis. In populations of African descent, CASPASE-12 is either functional or non-functional. Here, we have assessed the frequencies of both CASPASE-12 alleles in an African-American Candida sepsis patients cohort compared to uninfected patients with similar predisposing factors. African-American Candida sepsis patients (n = 93) and non-infected African-American patients (n = 88) were genotyped for the CASPASE-12 genotype. Serum cytokine concentrations of IL-6, IL-8, and IFNγ were measured in the serum of infected patients. Statistical comparisons were performed in order to assess the effect of the CASPASE-12 genotype on susceptibility to candidemia and on serum cytokine concentrations. Our findings demonstrate that CASPASE-12 does not influence the susceptibility to Candida sepsis, nor has any effect on the serum cytokine concentrations in Candida sepsis patients during the course of infection. Although the functional CASPASE-12 allele has been suggested to increase susceptibility to bacterial sepsis, this could not be confirmed in our larger cohort of fungal sepsis patients.