Complement factor H serum levels determine resistance to pneumococcal invasive disease

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Role of complement factor H in pneumococcal infections

Contains fulltext : 173260.pdf (publisher's version ) (Open Access)Radboud University, 7 juni 2017Promotores : Groot, R. de, Hermans, P.W.M. Co-promotores : Flier, M. van der, Langereis, J.D

Is the Metronome-Paced Tachypnea Test (MPT) Ready for Clinical Use? Accuracy of the MPT in a Prospective and Clinical Study

Contains fulltext : 207183.pdf (publisher's version ) (Open Access)BACKGROUND: A simple technique to measure dynamic hyperinflation (DH) in patients with chronic obstructive pulmonary disease (COPD) is the metronome-paced tachypnea test (MPT). Earlier studies show conflicting results about the accuracy of the MPT compared to cardiopulmonary exercise testing (CPET). OBJECTIVES: The focus was to investigate the diagnostic accuracy of MPT to detect DH in a prospective and clinical study. METHODS: COPD patients were included; all underwent spirometry, CPET, and MPT. DH (DeltaIC) was calculated as the difference in % between inspiratory capacity (IC) at the start and end of the test divided by IC at the start. A subject was identified as a hyperinflator, if DeltaIC (% of ICrest) was smaller than -10.2 and -11.1% in CPET and MPT, respectively. With these values, sensitivity and specificity were calculated. Bland-Altman plots were made of DeltaIC (% of ICrest). RESULTS: In the prospective and clinical study, 107 and 48 patients were included, respectively. Sensitivity of the MPT was 85% in both studies. The specificities were 33 and 27%, respectively. In the prospective study, B = +2.6%, L = 30.6, and -25.6%. In the clinical study, B = +0.8%, L = 31.0, and -29.1%. CONCLUSION: MPT seems to be a good replacement for CPET in group studies. The mean amount of DH was not different between CPET and MPT. On an individual level, MPT cannot be used to identify hyperinflators; it should be kept in mind that MPT overdiagnoses DH. The amount of DH should not be interchanged between CPET and MPT

The C-terminal domain of chikungunya virus nsP2 independently governs viral RNA replication, cytopathicity, and inhibition of interferon signaling

Alphavirus nonstructural protein 2 (nsP2) has pivotal roles in viral RNA replication, host cell shutoff, and inhibition of antiviral responses. Mutations that individually rendered other alphaviruses noncytopathic were introduced into chikungunya virus nsP2. Results show that (i) nsP2 mutation P718S only in combination with KR649AA or adaptive mutation D711G allowed noncytopathic replicon RNA replication, (ii) prohibiting nsP2 nuclear localization abrogates inhibition of antiviral interferon-induced JAK-STAT signaling, and (iii) nsP2 independently affects RNA replication, cytopathicity, and JAK-STAT signalin

The C-terminal domain of chikungunya virus nsP2 independently governs viral RNA replication, cytopathicity, and inhibition of interferon signaling

Alphavirus nonstructural protein 2 (nsP2) has pivotal roles in viral RNA replication, host cell shutoff, and inhibition of antiviral responses. Mutations that individually rendered other alphaviruses noncytopathic were introduced into chikungunya virus nsP2. Results show that (i) nsP2 mutation P718S only in combination with KR649AA or adaptive mutation D711G allowed noncytopathic replicon RNA replication, (ii) prohibiting nsP2 nuclear localization abrogates inhibition of antiviral interferon-induced JAK-STAT signaling, and (iii) nsP2 independently affects RNA replication, cytopathicity, and JAK-STAT signalin

A retrospective analysis of the combined use of PERC rule and Wells score to exclude pulmonary embolism in the Emergency Department

BACKGROUND: The pulmonary embolism rule-out criteria (PERC) rule is an eight-factor decision rule to support the decision not to order a diagnostic test when the gestalt-based clinical suspicion on pulmonary embolism (PE) is low. METHODS: In a retrospective cohort study, we determined the accuracy of a negative PERC (0) in patients with a low Wells score (<2) to rule-out PE, and compared this to the accuracy of the default algorithm used in our hospital (a low Wells score in combination with a negative D-dimer). RESULTS: During the study period, 377 patients with a Wells score <2 were included. CT pulmonary angiography (CTPA) was performed in 86 patients, and V/Q scintigraphy in one patient. PE was diagnosed in 18 patients. 78 patients (21%) had a negative PERC score. When further diagnostic studies would have been omitted in these patients, two (subsegmental) PEs would have been missed, resulting in a sensitivity of 89% (64%-98%) and a negative likelihood ratio (LR-) of 0.52 (0.14-1.97). The default algorithm missed one (subsegmental) PE, resulting in a sensitivity of 95% (71%-99%) and an LR- of 0.25 (0.04-1.73). CONCLUSIONS: The combination of a Wells score <2 and a PERC rule of 0 had a suboptimal sensitivity for excluding PE in our sample of patients presenting in the ED. Further studies are warranted to test this algorithm in larger populations

Alternative pathway regulation by factor H modulates Streptococcus pneumoniae induced proinflammatory cytokine responses by decreasing C5a receptor crosstalk

Bacterial pathogens not only stimulate innate immune receptors, but also activate the complement system. Crosstalk between complement C5a receptor (C5aR) and other innate immune receptors is known to enhance the proinflammatory cytokine response. An important determinant of the magnitude of complement activation is the activity of the alternative pathway, which serves as an amplification mechanism for complement activation. Both alternative pathway activity as well as plasma levels of factor H, a key inhibitor of the alternative pathway, show large variation within the human population. Here, we studied the effect of factor H-mediated regulation of the alternative pathway on bacterial-induced proinflammatory cytokine responses. We used the human pathogen Streptococcus pneumoniae as a model stimulus to induce proinflammatory cytokine responses in human peripheral blood mononuclear cells. Serum containing active complement enhanced pneumococcal induced proinflammatory cytokine production through C5a release and C5aR crosstalk. We found that inhibition of the alternative pathway by factor H, with a concentration equivalent to a high physiological level, strongly reduced C5a levels and decreased proinflammatory cytokine production in human peripheral blood mononuclear cells. This suggests that variation in alternative pathway activity due to variation in factor H plasma levels affects individual cytokine responses during infection