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Limbic encephalitis, a term coined in 1960 as a clinical/ anatomic description (1), is a rare regional inflammation of the brain involving mainly the limbic system but also other anatomic [...]

In patients with COPD, it has not been comprehensively assessed whether the predictive value of comorbidities for mortality differs between men and women. We therefore aimed to examine sex differences of COPD comorbidities in regard with prognosis by classifying comorbidities into a comorbidome related to extrapulmonary disorders and a pulmorbidome, referring to pulmonary disorders. The study population comprised 1044 women and 1531 men with the diagnosis of COPD from COSYCONET, among them 2175 of GOLD grades 1–4 and 400 at risk. Associations of comorbidities with mortality were studied using Cox regression analysis for men and women separately. During the follow-up (median 3.7 years) 59 women and 159 men died. In men, obesity, hypertension, coronary artery disease, liver cirrhosis, osteoporosis, kidney disease, anaemia and increased heart rate (HR) predict mortality, in women heart failure, hyperuricemia, mental disorders, kidney disease and increased HR (p < 0.05 each). Regarding the pulmorbidome, significant predictors in men were impairment in diffusion capacity and hyperinflation, in women asthma and hyperinflation. Similar results were obtained when repeating the analyses in GOLD 1–4 patients only. Gender differences should be considered in COPD risk assessment for a tailored approach towards the treatment of COPD. Clinical Trial Registration: ClinicalTrials.gov NCT01245933. [ABSTRACT FROM AUTHOR]

We studied whether in patients with COPD the use of metformin for diabetes treatment was linked to a pattern of lung function decline consistent with the hypothesis of anti-aging effects of metformin. Patients of GOLD grades 1–4 of the COSYCONET cohort with follow-up data of up to 4.5 y were included. The annual decline in lung function (FEV1, FVC) and CO diffusing capacity (KCO, TLCO) in %predicted at baseline was evaluated for associations with age, sex, BMI, pack-years, smoking status, baseline lung function, exacerbation risk, respiratory symptoms, cardiac disease, as well as metformin-containing therapy compared to patients without diabetes and metformin. Among 2741 patients, 1541 (mean age 64.4 y, 601 female) fulfilled the inclusion criteria. In the group with metformin treatment vs. non-diabetes the mean annual decline in KCO and TLCO was significantly lower (0.2 vs 2.3, 0.8 vs. 2.8%predicted, respectively; p < 0.05 each), but not the decline of FEV1 and FVC. These results were confirmed using multiple regression and propensity score analyses. Our findings demonstrate an association between the annual decline of lung diffusing capacity and the intake of metformin in patients with COPD consistent with the hypothesis of anti-aging effects of metformin as reflected in a surrogate marker of emphysema. [ABSTRACT FROM AUTHOR]

The involvement of the IL-23/IL23R pathway is well known in the disease pathogenesis of sarcoidosis and other inflammatory diseases. To date, the pathogenic mechanism of IL-23 is most notably described on CD4+ Th17 lymphocytes. However, the function of the IL23R on myeloid cells in sarcoidosis is poorly understood. Thus, the aim of the study is to investigate the role of the IL23R on myeloid cell in pulmonary granuloma formation. Methods: We generated IL23RLysMCre mice lacking the IL23R gene in myeloid cells. The importance of IL23R in myeloid cells for the development of sarcoidosis was studied in a mouse model of inflammatory lung granuloma formation through embolization of PPD from Mycobacterium bovis-coated Sepharose beads into previously PPD-immunized mice. In addition the function of IL23R on myeloid cells was studied in LPS or IFNγ stimulated BMDMs and BMDCs. The mRNA and protein expression levels of relevant cytokines were analyzed by RT-PCR (TaqMan) and ELISA. The composition of immune cells in BALF was quantified by flow cytometry and alteration in granuloma sizes were observed by H&E stained lung sections. Results: Mycobacterium Ag-elicted pulmonary granulomas tend to be smaller in IL23RLysMCre mice and NF-κB dependent Th1 cytokines in the murine lungs are reduced compared to wildtype mice. In line, we observed that IL23R-deficient bone marrow-derived macrophages show a reduced production of Th1 cytokines after LPS stimulation. Conclusion: We here for the first time demonstrate a role for IL23R on myeloid cells in pulmonary inflammation and granuloma formation. Our findings provide essential insights in the pathogenesis of inflammatory lung diseases like sarcoidosis, which might be useful for the development of novel therapeutics targeting distinct immunological pathways like IL-23/IL23R. [ABSTRACT FROM AUTHOR]

Abstract Background Hematopoietic stem cell transplantation is increasingly performed for hematologic diseases. As a major side effect, acute graft versus host disease (GvHD) with serious gastrointestinal symptoms including diarrhea, gastrointestinal bleeding and high mortality can be observed. Because surveillance and biopsies of human gastrointestinal GvHD are difficult to perform, rare information of the alterations of the gastrointestinal barrier exists resulting in a need for systematic animal models. Methods To investigate the effects of GvHD on the intestinal barrier of the small intestine we utilized an established acute semi allogenic GvHD in C57BL/6 and B6D2F1 mice. Results By assessing the differential uptake of lactulose and mannitol in the jejunum, we observed an increased paracellular permeability as a likely mechanism for disturbed intestinal barrier function. Electron microscopy, immunohistochemistry and PCR analysis indicated profound changes of the tight-junction complex, characterized by downregulation of the tight junction protein occludin without any changes in ZO-1. Furthermore TNF-α expression was significantly upregulated. Conclusions This analysis in a murine model of GvHD of the small intestine demonstrates serious impairment of intestinal barrier function in the jejunum, with an increased permeability and morphological changes through downregulation and localization shift of the tight junction protein occludin.

Background: Forced expiratory volume in one second (FEV1) characterizes the pathophysiology of COPD and different trajectories of FEV1 decline have been observed in patients with COPD (e.g. gradual or episodic). There is limited information about the development of patient-reported health-related quality of life (HRQL) over the full range of the natural history of COPD. We examined the longitudinal association between change in FEV1 and change in disease-specific and generic HRQL.Methods: We analysed data of 1734 patients with COPD participating in the COSYCONET cohort with up to 3 years of follow-up. Patients completed the Saint George's Respiratory Questionnaire (SGRQ) and the EQ-5D Visual Analog Scale (EQ VAS). Change score models were used to investigate the relationship between HRQL and FEV1 and to calculate mean changes in HRQL per FEV1 change categories [decrease (≤ - 100 ml), no change, increase (≥ 100 ml)] after 3 years. Applying hierarchical linear models (HLM), we estimated the cross-sectional between-subject difference and the longitudinal within-subject change of HRQL as related to a FEV1 difference or change.Results: We observed a statistically significant deterioration in SGRQ (total score + 1.3 units) after 3 years, which was completely driven by the activity component (+ 4 units). No significant change was found for the generic EQ VAS. Over the same period, 58% of patients experienced a decrease in FEV1, 28% were recorded as no change in FEV1, and 13% experienced an increase. The relationship between HRQL and FEV1 was found to be approximately linear with decrease in FEV1 being statistically significantly associated with a deterioration in SGRQ (+ 3.20 units). Increase in FEV1 was associated with improvements in SGRQ (- 3.81 units). The associations between change in FEV1 and the EQ VAS were similar. Results of the HLMs were consistent and highly statistically significant, indicating cross-sectional and longitudinal associations. The largest estimates were found for the association between FEV1 and the SGRQ activity domain.Conclusions: Difference and change in FEV1 over time correlate with difference and change in disease-specific and generic HRQL. We conclude, that deterioration of HRQL should induce timely re-examination of physical status and lung function and possibly reassessment of therapeutic regimes.Trial Registration: NCT01245933. Date of registration: 18 November 2010. [ABSTRACT FROM AUTHOR]

Background: Chronic pulmonary infections by Pseudomonas aeruginosa require frequent intravenous antibiotic treatment in cystic fibrosis (CF) patients. Emergence of antimicrobial resistance is common in these patients, which to date has been investigated at long-term intervals only.Objectives: To investigate under close to real-time conditions the dynamics of the response by P. aeruginosa to a single course of antibiotic therapy and the potentially associated rapid spread of antimicrobial resistance, as well as the impact on the airway microbiome.Methods: We investigated a cohort of adult CF patients that were treated with a single course of antimicrobial combination therapy. Using daily sampling during treatment, we quantified the expression of resistance by P. aeruginosa (median of six isolates per daily sample, 347 isolates in total), measured bacterial load by P. aeruginosa-specific quantitative PCR and characterized the airway microbiome with a 16S rRNA-based approach. WGS was performed to reconstruct intrapatient strain phylogenies.Results: In two patients, we found rapid and large increases in resistance to meropenem and ceftazidime. Phylogenetic reconstruction of strain relationships revealed that resistance shifts are probably due to de novo evolution and/or the selection of resistant subpopulations. We observed high interindividual variation in the reduction of bacterial load, microbiome composition and antibiotic resistance.Conclusions: We show that CF-associated P. aeruginosa populations can quickly respond to antibiotic therapy and that responses are patient specific. Thus, resistance evolution can be a direct consequence of treatment, and drug efficacy can be lost much faster than usually assumed. The consideration of these patient-specific rapid resistance shifts can help to improve treatment of CF-associated infections, for example by deeper sampling of bacteria for diagnostics, repeated monitoring of pathogen susceptibility and switching between drugs. [ABSTRACT FROM AUTHOR]

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Aim: To assess the parenting experience of mothers with cystic fibrosis (CF) and to compare with normative data.Methods: Cross-sectional study with a validated generic parental stress questionnaire (PSQ). This PSQ differentiates four components of parental stress: main factor “parental stress”, compounding factor “role restrictions”, protective factors “support from spouse”, and “social support”. Cut-off scores categorise results as “normal”, “borderline” or “concerning”. Sample: Seventy-three women were informed by their local CF centre. Of these, 36 enrolled and had a first-born child aged 1–12 years (consistent with reference values of the PSQ). Of these, 31 (86%) returned the PSQ. Mean age of mothers was 32.6 years ± 6.9 years, mean age of first-born child was 5.2 years ± 3.4 years. Most of the mothers had one biological child, five women had two children and one had three children.Results: Parental stress scores were normally distributed, the same applies for contributing factors and for the two protective factors. Favourable scores were twice as frequent as concerning scores. Mothers of younger children scored slightly better than mothers of school-aged children.Conclusion: In line with the only comparable study, mothers with CF seem to be a remarkably resilient group who mostly cope well with parental stress even in the face of a progressive, chronic disease requiring time-consuming treatment.Implications for RehabilitationToday, motherhood is increasingly becoming an option in fertile women with cystic fibrosis.The additional burden of parenting seems to be rewarded by fulfilling essential personal goals.CF clinics should routinely address a possible wish for a child and to discuss it, openly. [ABSTRACT FROM AUTHOR]

(1) Background: Acute kidney injury (AKI) is a common but under-investigated complication in patients receiving extracorporeal membrane oxygenation (ECMO). We aimed to define the incidence and clinical course, as well as the predictors of AKI in adults receiving ECMO support. (2) Materials and Methods: This is a retrospective analysis of all patients undergoing veno-venous ECMO treatment in a tertiary care center between December 2008 and December 2017. The primary endpoint was the new occurrence of an AKI of stage 2 or 3 according to the Kidney Disease: Improving Global Outcomes (KDIGO) classification after ECMO implantation. (3) Results: During the observation period, 103 patients underwent veno-venous ECMO implantation. In total, 59 patients (57.3%) met the primary endpoint with an AKI of stage 2 or 3 and 55 patients (53.4%) required renal replacement therapy. Patients with an AKI of 2 or 3 suffered from more bleeding and infectious complications. Whereas weaning failure from ECMO (30/59 (50.8%) vs. 15/44 (34.1%), p = 0.08) and 30-day mortality (35/59 (59.3%) vs. 17/44 (38.6%), p = 0.06) only tended to be higher in the group with an AKI of stage 2 or 3, long-term survival of up to five years was significantly lower in the group with an AKI of stage 2 or 3 (p = 0.015). High lactate, serum creatinine, and ECMO pump-speed levels, and low platelets, a low base excess, and a low hematocrit level before ECMO were independent predictors of moderate to severe AKI. Primary hypercapnic acidosis was more common in AKI non-survivors (12 (32.4%) vs. 0 (0.0%), p < 0.01). Accordingly, pCO2-levels prior to ECMO implantation tended to be higher in AKI non-survivors (76.12 ± 27.90 mmHg vs. 64.44 ± 44.31 mmHg, p = 0.08). In addition, the duration of mechanical ventilation prior to ECMO-implantation tended to be longer (91.14 ± 108.16 h vs. 75.90 ± 86.81 h, p = 0.078), while serum creatinine (180.92 ± 115.72 mmol/L vs. 124.95 ± 77.77 mmol/L, p = 0.03) and bicarbonate levels were significantly higher in non-survivors (28.22 ± 8.44 mmol/L vs. 23.36 ± 4.19 mmol/L, p = 0.04). (4) Conclusion: Two-thirds of adult patients receiving ECMO suffered from moderate to severe AKI, with a significantly increased morbidity and long-term mortality. [ABSTRACT FROM AUTHOR]

Summary: Background: N-terminal pro-brain natriuretic peptide (NT-ProBNP) has emerged as an important marker of cardiac stress and may reflect the severity of underlying cardiac dysfunction, which is thought to be associated with obstructive sleep apnoea syndrome (OSAS). Methods: This study evaluated the plasma concentration of NT-ProBNP in 60 consecutive patients (median age 55.7 years, median body mass index (BMI) 31.8) who were referred to a sleep laboratory with a suspicion of OSAS. Each subject underwent measurement of morning NT-ProBNP plasma levels, polysomnography and echocardiography. Patients were treated with nasal continuous or bilevel positive airway pressure ventilation (nCPAP/BIPAP) or without mechanical respiratory support, depending on clinical symptoms and results of polysomnography. Three months after treatment of OSAS 28 of the patients were reassessed for re-evaluation of NT-ProBNP and polysomnography. Results: Low or high levels of NT-proBNP were not associated with AHI and other sleep related indices (p>0.3). There was no correlation between NT-proBNP and AHI or other sleep related indices. In multiple regression analysis, NT-proBNP was significantly correlated with left ventricular ejection fraction, creatinine clearance and the presence of systemic arterial hypertension but not with AHI. Conclusions: Our results show by a robust multiple regression analysis, that NT-pro BNP is not associated with OSAS and NT-pro BNP cannot be used as a sensitive marker for underlying cardiovascular abnormalities in patients with OSAS. [Copyright &y& Elsevier]

Alterations of cognitive functions have been described in COPD. Our study aimed to disentangle the relationship between the degree of cognitive function and COPD characteristics including quality of life (QoL).Data from 1969 COPD patients of the COSYCONET cohort (GOLD grades 1-4; 1216 male/ 753 female; mean (SD) age 64.9 ± 8.4 years) were analysed using regression and path analysis. The DemTect screening tool was used to measure cognitive function, and the St. George's respiratory questionnaire (SGRQ) to assess disease-specific QoL.DemTect scores were < 9 points in 1.6% of patients and < 13 points in 12% when using the original evaluation algorithm distinguishing between < 60 or > =60 years of age. For statistical reasons, we used the average of both algorithms independent of age in all subsequent analyses. The DemTect scores were associated with oxygen content, 6-min-walking distance (6-MWD), C-reactive protein (CRP), modified Medical Research Council dyspnoea scale (mMRC) and the SGRQ impact score. Conversely, the SGRQ impact score was independently associated with 6-MWD, FVC, mMRC and DemTect. These results were combined into a path analysis model to account for direct and indirect effects. The DemTect score had a small, but independent impact on QoL, irrespective of the inclusion of COPD-specific influencing factors or a diagnosis of cognitive impairment.We conclude that in patients with stable COPD lower oxygen content of blood as a measure of peripheral oxygen supply, lower exercise capacity in terms of 6-MWD, and higher CRP levels were associated with reduced cognitive capacity. Furthermore, a reduction in cognitive capacity was associated with reduced disease-specific quality of life. As a potential clinical implication of this work, we suggest to screen especially patients with low oxygen content and low 6-MWD for cognitive impairment. [ABSTRACT FROM AUTHOR]

Background: Hematopoietic stem cell transplantation is increasingly performed for hematologic diseases. As a major side effect, acute graft versus host disease (GvHD) with serious gastrointestinal symptoms including diarrhea, gastrointestinal bleeding and high mortality can be observed. Because surveillance and biopsies of human gastrointestinal GvHD are difficult to perform, rare information of the alterations of the gastrointestinal barrier exists resulting in a need for systematic animal models.Methods: To investigate the effects of GvHD on the intestinal barrier of the small intestine we utilized an established acute semi allogenic GvHD in C57BL/6 and B6D2F1 mice.Results: By assessing the differential uptake of lactulose and mannitol in the jejunum, we observed an increased paracellular permeability as a likely mechanism for disturbed intestinal barrier function. Electron microscopy, immunohistochemistry and PCR analysis indicated profound changes of the tight-junction complex, characterized by downregulation of the tight junction protein occludin without any changes in ZO-1. Furthermore TNF-α expression was significantly upregulated.Conclusions: This analysis in a murine model of GvHD of the small intestine demonstrates serious impairment of intestinal barrier function in the jejunum, with an increased permeability and morphological changes through downregulation and localization shift of the tight junction protein occludin. [ABSTRACT FROM AUTHOR]

Objectives: To evaluate clinical and laboratory effects of the administration of recombinant human activated protein C (rhAPC) in the treatment of a 25-year-old patient with septic shock and multiple organ failure secondary to perinephritic abscesses. Interventions: Intravenous administration of rhAPC—or drotrecogin alfa (activated)—(24 mcg/kg/h) for a total of 80 h as an adjunct to antimicrobial therapy, mechanical ventilation, hemodynamic support, hemodiafiltration and surgical intervention. Measurements and Main Results: The administration of rhAPC was associated with a rapid recovery of the patient''s clinical condition reflected by decreasing Sepsis-related Organ Failure Assessment (SOFA) scores. Laboratory parameters monitoring inflammation and coagulopathy improved during the treatment. No drug-related adverse events were noted. Conclusions: RhAPC has been observed to have anticoagulant, anti-inflammatory and profibrinolytic properties in vitro and in vivo. This report describes the effects of rhAPC administration on standard laboratory parameters indicating that no single laboratory parameter exists that is capable of monitoring the effects of rhAPC on the coagulation cascade and the clinical course of sepsis. This description of a patient suffering from sepsis-induced multiple organ failure may illustrate a possible beneficial effect of rhAPC on the course of coagulopathy and systemic inflammatory response and provides evidence for rhAPC complementing standard intensive care therapy in severe sepsis. [Copyright &y& Elsevier]