Diagnostic accuracy of FeNO [fractional exhaled nitric oxide] and asthma symptoms increased when evaluated with a superior reference standard

Objectives: The objective of the study is to determine the impact of changing reference standards (RS), namely spirometry vs. whole-body plethysmography (WBP), on estimation of the diagnostic accuracy of fractional exhaled nitric oxide (FeNO) and clinical signs and symptoms (CSS) as index tests regarding asthma diagnosis. Study Design and Setting: This was a diagnostic study conducted in 393 patients attending a private practice of pneumologists with complaints suspicious of asthma. First, the index tests were compared with the diagnostic results of spirometry in terms of forced expiratory volume in the first second (FEV1) responsiveness. Second, the index tests were compared with the results of WBP in terms of specific airway resistance and FEV1 responsiveness. Areas under the curve (AUC) were compared with a generalized estimating equation approach based on binary logistic regression. Results: FeNO values and CSS ‘wheezing’ and ‘allergic rhinitis’ showed higher specificities (P < 0.001) and sensitivities (not significant) when evaluated with WBP; also, Youden indices increased in these CSS (P < 0.05). AUC of FeNO in combination with ‘wheezing’ and ‘allergic rhinitis’ when WBP was used as RS (AUC = 0.724; 95% confidence interval 0.672 to 0.776) was higher compared with spirometry as RS (AUC = 0.654; 95% confidence interval 0.585 to 0.722) (P < 0.001). Conclusion: In case of asthma, superior RS led to more favorable assessment of index tests. FeNO measurement might have been underestimated in some previous studies

Association of pregnancies with risk of multiple sclerosis

Background: Pregnancies have an impact on the disease course of multiple sclerosis (MS), but their relationship with MS risk is yet unclear. Objective: To determine the relationships of pregnancies and gynecological diagnoses with MS risk. Methods: In this retrospective case-control study, we assessed differences in gynecological International Classification of Diseases, 10th Revision (ICD-10) code recording rates between women with MS (n = 5720), Crohn's disease (n = 6280), or psoriasis (n = 40,555) and women without these autoimmune diseases (n = 26,729) in the 5 years before diagnosis. Results: Twenty-eight ICD-10 codes were recorded less frequently for women with MS as compared to women without autoimmune disease, 18 of which are pregnancy-related. After adjustment for pregnancies, all codes unrelated to pregnancies were still negatively associated with MS. In a sensitivity analysis excluding women with evidence for possible demyelinating events before diagnosis, all associations were more pronounced. In comparison to women with psoriasis, most associations could be confirmed;that was not true in comparison to women with Crohn's disease. Conclusion: Our findings provide evidence for a possible protective effect of pregnancies on MS risk likely independent of or in addition to a previously suggested reversed causality. The negative associations of gynecological disorders with disease risk need further investigation. The associations might be shared by different autoimmune diseases

A comparative analysis using flowmeter, laser-Doppler spectrophotometry, and indocyanine green-videoangiography for detection of vascular tenosis in free flaps

The effects of gradual vascular occlusion on the blood supply of perfused areas are poorly described. Information relating to the comparison of flap monitoring techniques is lacking. Varying stenotic conditions (0%, 25%, 50%, 75% and 100%) were generated on purpose at the A. and V. femoralis in the rat model. Analyses included flowmeter, simultaneous laser-Doppler flowmetry and tissue spectrophotometry (O2C) and indocyanine green- (ICG-) videoangiography with integrated FLOW 800 tool. A Random Forests prediction model was used to analyse the importance of each method to diagnose the stenotic conditions. The ability to discriminate and to accurately estimate the probability of stenosis was assessed by Receiver Operating Characteristic (ROC) curves and calibration plots. Blood flow changes for all modalities were described in detail. Flowmeter displayed earliest a linear decrease as a result of increasing stenosis. A stenosis of 50% degrees was most difficult to detect correctly. The combination of flowmeter and ICG-videoangiography showed high diagnostic power for each stenotic situation (area under the ROC > 0.79). Flowmeter and ICG-videoangiography showed to be most relevant in detection of varying stenotic conditions and may change the clinical outcome. The O2C showed less effect on varying stenotic situations as the only surface monitoring device

Carcinoid tumours of the lung and the ’PEPPS’ approach: evaluation of preoperative bronchoscopic tumour debulking as preparation for subsequent parenchyma-sparing surgery

BACKGROUND: Preoperative bronchoscopic tumour ablation has been suggested as a beneficial treatment for bronchopulmonary carcinoid tumours, although data regarding its effects and long-term outcome are lacking. METHODS: In our case-matched cohort study with 208 patients with bronchopulmonary carcinoid tumours we investigated the role of preoperative bronchoscopic interventions before subsequent surgery and analysed the safety of this Procedure of Endobronchial Preparation for Parenchyma-sparing Surgery (PEPPS) based on metastasis and recurrence rates as well as survival data from 1991 to 2010. The subsequent surgery was classified into parenchyma-sparing procedures and classical lobectomies, bilobectomies and pneumonectomies. Data were obtained from the tumour registry and medical reports. Outcomes were the frequency of parenchyma-sparing surgery after bronchoscopic treatment as well as rates of metastasis, recurrence and survival. RESULTS: 132 of 208 carcinoids were located centrally. Among them, 77 patients could be recanalised preoperatively. After bronchoscopic preparation, the rate of subsequent parenchyma-sparing surgery methods was higher (p=0.021). The effect was measured by the number of segments removed. The 10-year survival rate was 89% (typical carcinoids) and 68% (atypical carcinoids), respectively. After applying PEPPS, long-term survival was slightly higher (p=0.23). Metastasis and recurrence rates showed no relevant differences between the bronchoscopically treated or non-treated groups, or between the two types of surgery classes or between the PEPPS and non-PEPPS groups. CONCLUSIONS: After preoperative bronchoscopic treatment, parenchyma-sparing surgery techniques can be applied more frequently. Furthermore, we detected no negative effects after PEPPS based on metastasis, recurrence and survival rates

IL-17A/F-Signaling Does Not Contribute to the Initial Phase of Mucosal Inflammation Triggered by S. Typhimurium

Salmonella enterica subspecies 1 serovar Typhimurium (S. Typhimurium) causes diarrhea and acute inflammation of the intestinal mucosa. The pro-inflammatory cytokines IL-17A and IL-17F are strongly induced in the infected mucosa but their contribution in driving the tissue inflammation is not understood. We have used the streptomycin mouse model to analyze the role of IL-17A and IL-17F and their cognate receptor IL-17RA in S. Typhimurium enterocolitis. Neutralization of IL-17A and IL-17F did not affect mucosal inflammation triggered by infection or spread of S. Typhimurium to systemic sites by 48 h p.i. Similarly, Il17ra−/− mice did not display any reduction in infection or inflammation by 12 h p.i. The same results were obtained using S. Typhimurium variants infecting via the TTSS1 type III secretion system, the TTSS1 effector SipA or the TTSS1 effector SopE. Moreover, the expression pattern of 45 genes encoding chemokines/cytokines (including CXCL1, CXCL2, IL-17A, IL-17F, IL-1α, IL-1β, IFNγ, CXCL-10, CXCL-9, IL-6, CCL3, CCL4) and antibacterial molecules was not affected by Il17ra deficiency by 12 h p.i. Thus, in spite of the strong increase in Il17a/Il17f mRNA in the infected mucosa, IL-17RA signaling seems to be dispensable for eliciting the acute disease. Future work will have to address whether this is attributable to redundancy in the cytokine signaling network

Prediction of Flap Necrosis by Using Indocyanine Green Videoangiography in Cases of Venous Occlusion in the Epigastric Flap Model of the Rat

Background A compromised free flap perfusion attributable to vascular occlusion requires immediate operative correction. Indocyanine green (ICG) videoangiography may reduce the risk of partial skin flap necrosis in high-risk free flaps in patients undergoing head and neck reconstruction. The purpose of this study was to determine the role of ICG in cases of venous congestion in a rat model. Methods A standardized epigastric flap was raised and repositioned in 35 rats. Full venous occlusion of the draining superficial inferior epigastric vein was temporarily applied for 4, 5, 6, or 7 hours. Blood flow measurements including simultaneous laser-Doppler flowmetry and tissue spectrophotometry (oxygen-to-see [O2C]) and ICG videoangiography with the FLOW 800 tool were performed before flap raising, after temporary venous stasis, and after clinical monitoring for 1 week. The Youden index computed from the receiver operating characteristic curve was used to define an optimal cutoff value for necrosis prediction after 4 and 6 hours of stasis. Results The ICG videoangiography with the FLOW 800 tool was found to be superior to O2C in the prediction of flap necrosis. The accuracy of prediction was moderate after an interval of 4 hours of stasis (area under the curve [AUC] = 0.661; 95% confidence interval [CI]: 0.489–0.834) and good after 6 hours of stasis (AUC = 0.787; 95% CI: 0.65–0.915). Conclusions The O2C does not reliably predict tissue necrosis in cases of venous congestion. ICG videoangiography is a valuable tool that can predict clinical outcome and provide guidance on whether to salvage a congested flap

Microbe sampling by mucosal dendritic cells is a discrete, MyD88-independent stepin ΔinvG S. Typhimurium colitis

Intestinal dendritic cells (DCs) are believed to sample and present commensal bacteria to the gut-associated immune system to maintain immune homeostasis. How antigen sampling pathways handle intestinal pathogens remains elusive. We present a murine colitogenic Salmonella infection model that is highly dependent on DCs. Conditional DC depletion experiments revealed that intestinal virulence of S. Typhimurium SL1344 ΔinvG mutant lacking a functional type 3 secretion system-1 (ΔinvG)critically required DCs for invasion across the epithelium. The DC-dependency was limited to the early phase of infection when bacteria colocalized with CD11c+CX3CR1+ mucosal DCs. At later stages, the bacteria became associated with other (CD11c−CX3CR1−) lamina propria cells, DC depletion no longer attenuated the pathology, and a MyD88-dependent mucosal inflammation was initiated. Using bone marrow chimeric mice, we showed that the MyD88 signaling within hematopoietic cells, which are distinct from DCs, was required and sufficient for induction of the colitis. Moreover, MyD88-deficient DCs supported transepithelial uptake of the bacteria and the induction of MyD88-dependent colitis. These results establish that pathogen sampling by DCs is a discrete, and MyD88-independent, step during the initiation of a mucosal innate immune response to bacterial infection in vivo

Salmonella Transiently Reside in Luminal Neutrophils in the Inflamed Gut

Enteric pathogens need to grow efficiently in the gut lumen in order to cause disease and ensure transmission. The interior of the gut forms a complex environment comprising the mucosal surface area and the inner gut lumen with epithelial cell debris and food particles. Recruitment of neutrophils to the intestinal lumen is a hallmark of non-typhoidal Salmonella enterica infections in humans. Here, we analyzed the interaction of gut luminal neutrophils with S. enterica serovar Typhimurium (S. Tm) in a mouse colitis model.Upon S. Tm(wt) infection, neutrophils transmigrate across the mucosa into the intestinal lumen. We detected a majority of pathogens associated with luminal neutrophils 20 hours after infection. Neutrophils are viable and actively engulf S. Tm, as demonstrated by live microscopy. Using S. Tm mutant strains defective in tissue invasion we show that pathogens are mostly taken up in the gut lumen at the epithelial barrier by luminal neutrophils. In these luminal neutrophils, S. Tm induces expression of genes typically required for its intracellular lifestyle such as siderophore production iroBCDE and the Salmonella pathogenicity island 2 encoded type three secretion system (TTSS-2). This shows that S. Tm at least transiently survives and responds to engulfment by gut luminal neutrophils. Gentamicin protection experiments suggest that the life-span of luminal neutrophils is limited and that S. Tm is subsequently released into the gut lumen. This "fast cycling" through the intracellular compartment of gut luminal neutrophils would explain the high fraction of TTSS-2 and iroBCDE expressing intra- and extracellular bacteria in the lumen of the infected gut. In conclusion, live neutrophils recruited during acute S. Tm colitis engulf pathogens in the gut lumen and may thus actively engage in shaping the environment of pathogens and commensals in the inflamed gut

Postextrasystolic Blood Pressure Potentiation Predicts Poor Outcome of Cardiac Patients

Background Postextrasystolic blood pressure potentiation (PESP), the pulse wave augmentation after an extrasystolic beat, is typically enhanced in heart failure (HF) patients. This study prospectively tested the association of PESP and mortality in cardiac patients. Methods and Results Consecutive patients (n=941; mean age, 61 years; 19% female) presenting with acute myocardial infarction were enrolled between May 2000 and March 2005 and followed up until August 2010. The main study outcome was 5-year all-cause mortality. Patients underwent noninvasive 30-minute recordings of ECG and continuous blood pressure. PESP presence was based on the ratio between the first postectopic pulse wave amplitude and the mean of the subsequent 9 pulse wave amplitudes. A ratio above 1 was prospectively defined as PESP present. Ventricular premature complexes (VPCs) suitable for PESP quantification were present in recordings of 220 patients. PESP was present in 62 of these patients. Patients without suitable VPCs were classified as PESP absent. During the follow-up, 72 patients died. Among the 220 patients in whom PESP was measurable, 27 died. Under univariable analysis, PESP was a significant predictor of death (P<0.001) as were GRACE score (P<0.001), left ventricular ejection fraction (LVEF) (P<0.001), and the number of recorded VPCs (P<0.001). Under multivariable analysis, PESP (P<0.001), GRACE score (P<0.001), and LVEF (P=0.001) were independently associated with outcome. The combination of PESP presence and LVEF ≤35% identified a subgroup of patients with a particularly high mortality of 46.7%. Separate validation reproduced the finding in an unrelated population of 146 HF patients. Conclusions PESP, which likely reflects abnormalities of myocardial calcium cycling, predicts the mortality risk in postinfarction patients