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Purpose: Subcutaneous allergen-specific immunotherapy (SCIT) is a well-established and clinically effective method to treat allergic diseases, such as rhinitis and asthma. It remains unclear how soon after initiation of an ultra-short course of grass pollen immunotherapy adjuvanted with monophosphoryl lipid A (MPL)-specific bronchial tolerance can be induced.
Methods: In a prospective study of 69 children double-sensitized to birch and grass pollens (51 males, average age 11.1 years), development of bronchial tolerance after 1 cycle of SCIT for grass was evaluated. In all the patients, the bronchial allergen provocation test (BAP) was performed before and after treatment. According to the results of the first BAP, the patients were divided into 2 groups: those showing a negative BAP with a decrease in FEV1 of <20% (seasonal allergic rhinitis [SAR] group, n=47); and those showing a positive BAP with a decrease in FEV1 of ≥20% (SAR with allergic asthma [SAR and Asthma] group, n=22). All the patients received MPL-adjuvanted, ultra-short course immunotherapy for birch, but only those with a positive BAP to grass received MPL-SCIT for grass.
Results: After the pollen season, the BAP in the SAR group remained unchanged, while it was improved in the SAR and Asthma group (decrease in FEV1 of 28.8% vs 12.5%, P<0.01). The IgG4 levels increased after SCIT (median before SCIT 0.34 to 11.4 after SCIT), whereas the total and specific IgE levels remained unchanged.
Conclusions: After 1 cycle of MPL-SCIT, specific bronchial tolerance may be significantly induced, whereas in patients without SCIT, bronchial hyperactivity may remain unchanged.
Ubiquitination plays a critical role in the activation of host immune responses to infection and serves as a signal for pathogen delivery to phagophores along the xenophagy pathway. We recently performed systematic ubiquitination site profiling of epithelial cells infected with Salmonella Typhimurium. Our findings specifically highlight components of the NFKB, membrane trafficking pathways and RHO GTPase systems as ubiquitination hubs during infection. In addition, a broad spectrum of bacterial effectors and several outer membrane proteins are ubiquitinated in infected cells. This comprehensive resource of ubiquitinome dynamics during Salmonella infection enables further understanding of the complex host-pathogen interplay and may reveal novel targets for the inhibition of Salmonella invasion and inflammation.
Background and Aims. Biliary complications are the most frequent complications after common liver surgeries. In this study, accuracy of hepatobiliary scintigraphy (HBS) and impact of hyperbilirubinemia were evaluated. Methods. Between November 2007 and February 2016, 131 patients underwent hepatobiliary scintigraphy after having liver surgery. 39 patients with 42 scans after LTX (n=13) or hepatic resection (n=26) were evaluated in the study; 27 were male, with mean age 60 years. The subjects underwent hepatobiliary scintigraphy with Tc-99m labeled Mebrofenin. The results were compared to ERCP as gold standard performed within one month after HBS. We calculated sensitivity, specificity, PPV, and NPV. We compared LTX patients to patients with other liver surgeries. Furthermore the influence of hyperbilirubinemia on HBS scans was evaluated. Results. HBS always provided the correct diagnosis in cases of bile leak in the liver-resected group (14/14). Overall diagnostic accuracy was 76% (19/25) in this group and 54% (7/13) in the LTX group. False negative (FN) diagnoses occurred more often among LTX patients (p=0.011). Hyperbilirubinemia (>5 mg/dL) significantly influenced the excretion function of the liver, prolonging HBS’s time-activity-curve (p=0.001). Conclusions. Hepatobiliary scintigraphy is a reliable tool to detect biliary complications, but reduced accuracy must be considered after LTX.
Mantle cell lymphoma (MCL) is a unique type of B-cell non-Hodgkin's lymphoma, which very rarely exhibits skin involvement. We herein describe the case of a 55-year-old woman, who initially presented with a nodular mass of the right infraorbital region. On histological analysis of the subcutaneous tissue, a diffuse neoplastic cell infiltration was identified, composed of medium‑sized lymphoid cells with irregular nuclei, which was diagnosed as MCL. The tumor cells were positive for CD5, CD20, CD79a, cyclin D1 and sex‑determining region Y-box 11, but negative for CD10 and CD23. Our patient received six cycles of R‑CHOP chemotherapy and intrathecal methotrexate as central nervous system prophylaxis. However, the patient relapsed 1 year later and was treated with two cycles of R‑DHAP and one cycle of intrathecal methotrexate. After achieving partial remission, the patient was consolidated with peripheral blood stem cell transplantation using the BEAM conditioning regime. While prior case studies suggest that skin invasion by MCL is associated with a poor prognosis, our patient remains alive almost 4 years after the initial presentation. Skin involvement as a first sign of systemic MCL is very rare and must be considered.
Zielsetzung. Diese Pilotstudie untersucht den therapeutischen Effekt des RelaxBogens in Bezug auf Bruxismus und Symptome einer kraniomandibulären Dysfunktion (CMD).
Probanden und Methoden. Untersucht wurde eine Gruppe von 10 Probanden. Auswahlkriterien waren ein vorliegender Bruxismus und erste Symptome einer CMD. Dies wurde durch die Anwendung einer Brux-Checker®-Folie für 2 Nächte und eine Schmerzanamnese verifiziert. Eingangs wurden neben einer ausführlichen zahnärztlichen Anamnese folgende CMDParameter erhoben: SL-NRS-Fragebogen sowie Palpation von 42 Muskeln im Kopf-HalsNacken-Bereich und der 6 Austrittspunkte des N. trigeminus. Nach der Voruntersuchung wurde der RelaxBogen mindestens 10 Wochen getragen. Danach wurden die genannten Parameter erneut erhoben und miteinander verglichen.
Ergebnisse. Die Vor- und Nachuntersuchungen zeigten starke Tendenzen der Reduktion sowohl der allgemeinen Symptomatik als auch der Schmerzempfindung im Kieferbereich. Nach dem Tragen des RelaxBogens konnte eine eindeutige Reduktion des durch Palpation ausgelösten, muskulären Schmerzes beobachtet werden. Ebenfalls deutlich positive Tendenzen ließen sich bei der Verbesserung des allgemeinen Wohlbefindens finden. Die Ergebnisse legen nahe, dass bei einer größeren Stichprobe eine statistische Signifikanz zu erwarten ist.
Schlussfolgerung. Der RelaxBogen führt nach den Ergebnissen dieser Pilotstudie bei Patienten, die unter Bruxismus- und CMD-Symptomen leiden, zu einer deutlichen Reduktion der Schmerzwahrnehmung sowie einer eindeutigen Steigerung des Wohlbefindens. Neben der Verringerung des Schmerzempfindens und einem reduzierten Spannungsgefühl in den großen Kiefermuskeln konnten auch positive Tendenzen im Bereich der Hals-, Nacken- und Schultermuskulatur festgestellt werden.
Within the family of NADPH oxidases, NOX4 is unique as it is predominantly localized in the endoplasmic reticulum, has constitutive activity, and generates hydrogen peroxide (H2O2). We hypothesize that these features are consequences of a so far unidentified NOX4-interacting protein. Two-dimensional blue native (BN) electrophorese combined with SDS-PAGE yielded NOX4 to reside in macromolecular complexes. Interacting proteins were screened by quantitative SILAC (stable isotope labeling of amino acids in cell culture) co-immunoprecipitation (Co-IP) in HEK293 cells stably overexpressing NOX4. By this technique, several interacting proteins were identified with calnexin showing the most robust interaction. Calnexin also resided in NOX4-containing complexes as demonstrated by complexome profiling from BN-PAGE. The calnexin NOX4 interaction could be confirmed by reverse Co-IP and proximity ligation assay, whereas NOX1, NOX2, or NOX5 did not interact with calnexin. Calnexin deficiency as studied in mouse embryonic fibroblasts from calnexin(-/-)mice or in response to calnexin shRNA reduced cellular NOX4 protein expression and reactive oxygen species formation. Our results suggest that endogenous NOX4 forms macromolecular complexes with calnexin, which are needed for the proper maturation, processing, and function of NOX4 in the endoplasmic reticulum.
Hepatitis C virus (HCV) substantially affects lipid metabolism, and remodeling of sphingolipids appears to be essential for HCV persistence in vitro. The aim of the current study is the evaluation of serum sphingolipid variations during acute HCV infection. We enrolled prospectively 60 consecutive patients with acute HCV infection, most of them already infected with human immunodeficiency virus (HIV), and serum was collected at the time of diagnosis and longitudinally over a six-month period until initiation of antiviral therapy or confirmed spontaneous clearance. Quantification of serum sphingolipids was performed by liquid chromatography-tandem mass spectrometry (LC-MS/MS). Spontaneous clearance was observed in 11 out of 60 patients (18.3%), a sustained viral response (SVR) in 43 out of 45 patients (95.5%) receiving an antiviral treatment after follow-up, whereas persistence of HCV occurred in six out of 60 patients (10%). C24-ceramide (C24-Cer)-levels increased at follow-up in patients with spontaneous HCV eradication (p < 0.01), as compared to baseline. Sphingosine and sphinganine values were significantly upregulated in patients unable to clear HCV over time compared to patients with spontaneous clearance of HCV infection on follow-up (p = 0.013 and 0.006, respectively). In summary, the persistence of HCV after acute infection induces a downregulation of C24Cer and a simultaneous elevation of serum sphingosine and sphinganine concentrations.
Influence of antibiotic-regimens on intensive-care unit-mortality and liver-cirrhosis as risk factor
(2016)
AIM: To assess the rate of infection, appropriateness of antimicrobial-therapy and mortality on intensive care unit (ICU). Special focus was drawn on patients with liver cirrhosis.
METHODS: The study was approved by the local ethical committee. All patients admitted to the Internal Medicine-ICU between April 1, 2007 and December 31, 2009 were included. Data were extracted retrospectively from all patients using patient charts and electronic documentations on infection, microbiological laboratory reports, diagnosis and therapy. Due to the large hepatology department and liver transplantation center, special interest was on the subgroup of patients with liver cirrhosis. The primary statistical-endpoint was the evaluation of the influence of appropriate versus inappropriate antimicrobial-therapy on in-hospital-mortality.
RESULTS: Charts of 1979 patients were available. The overall infection-rate was 53%. Multiresistant-bacteria were present in 23% of patients with infection and were associated with increased mortality (P < 0.000001). Patients with infection had significantly increased in-hospital-mortality (34% vs 17%, P < 0.000001). Only 9% of patients with infection received inappropriate initial antimicrobial-therapy, no influence on mortality was observed. Independent risk-factors for in-hospital-mortality were the presence of septic-shock, prior chemotherapy for malignoma and infection with Pseudomonas spp. Infection and mortality-rate among 175 patients with liver-cirrhosis was significantly higher than in patients without liver-cirrhosis. Infection increased mortality 2.24-fold in patients with cirrhosis. Patients with liver cirrhosis were at an increased risk to receive inappropriate initial antimicrobial therapy.
CONCLUSION: The results of the present study report the successful implementation of early-goal-directed therapy. Liver cirrhosis patients are at increased risk of infection, mortality and to receive inappropriate therapy. Increasing burden are multiresistant-bacteria.
Background and aims: Despite the clinical importance of atherosclerosis, the origin of cells within atherosclerotic plaques is not fully understood. Due to the lack of a definitive lineage-tracing strategy, previous studies have provided controversial results about the origin of cells expressing smooth muscle and macrophage markers in atherosclerosis. We here aim to identify the origin of vascular smooth muscle (SM) cells and macrophages within atherosclerosis lesions.
Methods: We combined a genetic fate mapping approach with single cell expression analysis in a murine model of atherosclerosis.
Results: We found that 16% of CD68-positive plaque macrophage-like cells were derived from mature SM cells and not from myeloid sources, whereas 31% of αSMA-positive smooth muscle-like cells in plaques were not SM-derived. Further analysis at the single cell level showed that SM-derived CD68+ cells expressed higher levels of inflammatory markers such as cyclooxygenase 2 (Ptgs2, p = 0.02), and vascular cell adhesion molecule (Vcam1, p = 0.05), as well as increased mRNA levels of genes related to matrix synthesis such as Col1a2 (p = 0.01) and Fn1 (p = 0.04), than non SM-derived CD68+ cells.
Conclusions: These results demonstrate that smooth muscle cells within atherosclerotic lesions can switch to a macrophage-like phenotype characterized by higher expression of inflammatory and synthetic markers genes that may further contribute to plaque progression.
Elevated tumor interstitial fluid pressure (TIFP) is a prominent feature of solid tumors and hampers the transmigration of therapeutic macromolecules, for example, large monoclonal antibodies, from tumor-supplying vessels into the tumor interstitium. TIFP values of up to 40 mm Hg have been measured in experimental solid tumors using two conventional invasive techniques: the wick-in-needle and the micropuncture technique. We propose a novel noninvasive method of determining TIFP via ultrasonic investigation with scanning acoustic microscopy at 30-MHz frequency. In our experimental setup, we observed for the impedance fluctuations in the outer tumor hull of A431-vulva carcinoma–derived tumor xenograft mice. The gain dependence of signal strength was quantified, and the relaxation of tissue was calibrated with simultaneous hydrostatic pressure measurements. Signal patterns from the acoustical images were translated into TIFP curves, and a putative saturation effect was found for tumor pressures larger than 3 mm Hg. This is the first noninvasive approach to determine TIFP values in tumors. This technique can provide a potentially promising noninvasive assessment of TIFP and, therefore, can be used to determine the TIFP before treatment approach as well to measure therapeutic efficacy highlighted by lowered TFP values.