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Acute lymphoblastic leukemia (ALL) is the most common cancer in children. Pediatric patients with disease refractory to last chemotherapy, relapse after allogeneic hematopoietic stem-cell transplantation (alloHSCT), or second or further relapse have a particularly poor prognosis. Intensive chemotherapy followed by alloHSCT after achieving remission can result in cure for some patients. However, survival is still low with this approach. Thus, additional treatment modalities with acceptable toxicity are needed to improve long-term survival. ...
Background: To study the expression pattern, localisation and potential clinical significance of aquaporin water channels (AQP) both in prostate cancer (PC) cell lines and in benign and malignant human prostate tissue.
Methods: The AQP transcript and protein expression of HPrEC, LNCaP, DU-145 and PC3 cell lines was investigated using reverse transcriptase polymerase chain reaction (RT-PCR) and immunofluorescence (IF) microscopy labelling. Immunohistochemistry (IHC) was performed to assess AQP protein expression in surgical specimens of benign prostatic hyperplasia as well as in PC. Tissue mRNA expression of AQPs was quantified by single-step reverse transcriptase quantitative polymerase chain reaction (qPCR). Relative gene expression was determined using the 40-ΔCT method and correlated to clinicopathological parameters.
Results: Transcripts of AQP 1, 3, 4, 7, 8, 10 and 11 were expressed in all four cell lines, while AQP 9 transcripts were not detected in malignant cell lines. IF microscopy confirmed AQP 3, 4, 5, 7 and 9 protein expression. IHC revealed highly heterogeneous AQP 3 protein expression in PC specimens, with a marked decrease in expression in tumours of increasing malignancy. Loss of AQP 9 was shown in PC specimens. mRNA expression of AQP3 was found to be negatively correlated to PSA levels (ρ = − 0.354; p = 0.013), D’Amico risk stratification (ρ = − 0.336; p = 0.012), ISUP grade (ρ = − 0.321; p = 0.017) and Gleason score (ρ = − 0.342; p = 0.011).
Conclusions: This is the first study to systematically characterize human prostate cell lines, benign prostatic hyperplasia and PC in relation to all 13 members of the AQP family. Our results indicate the differential expression of several AQPs in benign and malignant prostate tissue. A significant correlation was observed between AQP 3 expression and tumour grade, with progressive loss in more malignant tumours. Taken together, AQPs may play a role in the progression of PC and AQP expression patterns may serve as a prognostic marker.
Background: With the aging population and a rising incidence of squamous cell carcinoma of the head and neck (SCCHN), there is an emerging need for developing strategies to treat elderly patients.
Patients and Methods: We retrospectively analyzed 158 patients treated with definitive, concurrent chemoradiotherapy (CRT) for SCCHN. Clinicopathological characteristics, acute toxicities, and oncological outcomes were compared between patients younger and older than (or of age equal to) 65, 70, and 75 years.
Results: RT dose, chemotherapy regimen, and total chemotherapy dose were balanced between the groups. After a median follow-up of 29 months, overall survival (OS), progression-free survival (PFS), local control rate, and distant metastasis-free survival stratified by age of ≥65, ≥70, or ≥75 years revealed no differences. The rate of acute toxicities was also not higher for older patients. Worse ECOG performance score (ECOG 2-3) was associated with impaired OS () and PFS ().
Conclusion: Definitive treatment with CRT for SCCHN is feasible and effective; even in advanced age treatment decisions should be made according to general condition and comorbidity, rather than calendar age alone.
This review provides an overview on components of the sphingolipid superfamily, on their localization and metabolism. Information about the sphingolipid biological activity in cell physiopathology is given. Recent studies highlight the role of sphingolipids in inflammatory process. We summarize the emerging data that support the different roles of the sphingolipid members in specific phases of inflammation: (1) migration of immune cells, (2) recognition of exogenous agents, and (3) activation/differentiation of immune cells.
Das Hodgkin Lymphom besteht aus zwei verschiedenen Typen, dem klassischen Hodgkin Lymphom (cHL) mit einem Anteil von 95% und dem nodulären lymphozytenprädominanten Hodgkin Lymphom (NLPHL). Letzteres kann sehr unterschiedliche histopathologische Wachstumsmuster zeigen, die nach Fan et al. grob in ein typisches knotiges (Muster A) und in atypische diffuse Wachstumsmuster (Muster C und E) unterteilt werden können. Patienten mit einem NLPHL, das zum diffus wachsenden Subtyp zählt, präsentieren sich häufiger in klinisch fortgeschrittenen Stadien als jene Patienten mit einem NLPHL, das ein knotiges Wachstumsmuster zeigt. Im Gegensatz dazu präsentiert sich das T-Zell/Histiozytenreiche großzellige B-Zell Lymphom (THRLBCL) in einem fortgeschrittenen Stadium mit einer oftmals schlechten Prognose. NLPHL vom diffusen Typ weisen starke Ähnlichkeiten mit dem THRLBCL sowohl in Bezug auf Histomorphologie als auch klinische Eigenschaften auf und sind dadurch manchmal nur schwer voneinander zu unterscheiden.
Das Wachstumsmuster eines Tumors hängt unter anderem von der Verteilung der Blutgefäße im Tumorgewebe ab. Viele aktuelle Studien weisen darauf hin, dass die Gefäßneubildung (Angiogenese) eine wichtige Rolle in der Entwicklung von hämatologischen Tumoren spielt. Durch diesen Prozess kann der Tumor zu ausreichend Sauerstoff und Nährstoffen gelangen, um invasiv zu wachsen und zu metastasieren. Die Gefäßdichte ist ein anerkannter Marker für die Auswertung von Gefäßneubildung in verschiedenen Tumoren.
Ein Ziel der Arbeit bestand darin, Parameter der Angiogenese, u.a. die Gefäßdichte und den queren Gefäßdurchmesser, in verschiedenen Subtypen des NLPHL und in THRLBCL im Hinblick auf eine mögliche Unterscheidbarkeit des diffusen NLPHL und des THRLBCL zu untersuchen sowie sie mit anderen Typen von malignen Lymphomen und reaktiven Lymphadenitiden (LA) zu vergleichen.
Von T-Lymphozyten ist bekannt, dass sie mit den Tumorzellen in Lymphomen in engem Kontakt stehen und einen nicht unerheblichen Anteil des Tumormikromilieus bilden. Die CD4+ Lymphozyten treten gewöhnlich über Gefäße, den hochendothelialen Venolen (HEVs), in den Lymphknoten ein.
Ein weiteres Ziel der Arbeit war es, eine mögliche Korrelation zwischen dem TLymphozyten-Zustrom und der Tumormorphologie in den betroffenen Lymphknoten zu untersuchen, um herauszufinden, ob dies die unterschiedliche Zusammensetzung im Mikromilieu der Lymphome erklären kann. Als Maß für den Zustrom wurde die Anzahl der intravaskulären T-Lymphozyten herangezogen. Zum Vergleich wurden weitere maligne Lymphome, die ein prominentes Tumormikromilieu besitzen, untersucht.
Im diffusen NLPHL und THRLBCL fanden wir eine niedrigere Gefäßdichte mit einer diffusen Blutgefäßverteilung. Im Gegensatz dazu zeigte das NLPHL mit einem typischen Wachstumsmuster, das cHL vom gemischtzelligen Typ (cHL MC) und das Angioimmunoblastische Lymphom (AITL) in den interfollikulären Arealen eine verstärkte Gefäßbildung. Es zeigte sich in allen Subtypen des NLPHL eine signifikant geringere Gefäßdichte, verglichen mit dem AITL oder den LA Fällen. LA wiesen insgesamt die höchste interfollikuläre Gefäßdichte auf. Das THRLBCL zeigte die niedrigste Gefäßdichte von allen malignen Lymphomen, die untersucht wurden, allerdings war der Vergleich von THRLBCL und den verschiedenen Subtypen des NLPHL nicht signifikant. Wir konnten zeigen, dass die diffusen Subtypen des NLPHL und das THRLBCL ein ähnliches Wachstumsmuster der Blutgefäße mit einer verminderten Gefäßdichte und nicht mehr identifizierbaren follikulären Bereichen vorweisen, im Gegensatz zu den beibehaltenen follikulären Mustern, die wir im typischen NLPHL fanden. Die Anzahl der intravaskulären T-Zellen war am höchsten im cHL MC sowie im typischen NLPHL. Signifikant geringer fielen die intravaskulären TLymphozyten-Werte im THRLBCL im Vergleich mit dem typischen NLPHL Muster A, C und dem cHL MC aus.
Da die LA Fälle eine hohe interfollikuläre Gefäßdichte und kleine Gefäßdurchmesser zeigten, kann man davon ausgehen, dass die Gefäße durch die schnell anschwellenden Keimzentren komprimiert wurden. In den atypischen NLPHL und THRLBCL Fällen lassen die geringe Gefäßdichte und relativ große Gefäßdurchmesser eine langsame Dehnung des Gefäßgerüstes des Lymphknotens annehmen. Die Resultate der T-Zell Quantifizierung legen den Schluss nahe, dass die relativ geringe Anzahl von intravaskulären T-Lymphozyten im THRLBCL zusammen mit einer geringen Gefäßdichte möglicherweise verantwortlich ist für die gewöhnlich relativ geringe Anzahl an T-Lymphozyten pro Fläche und hierdurch die hohe Anzahl an Makrophagen im Mikromilieu im THRLBCL hervorgerufen wird. Dies könnte im Zusammenhang stehen mit einer absolut verminderten T-Lymphozytenzahl im Blut oder einem reduzierten Eintritt der T-Lymphozyten in den Lymphknoten.
Purpose: The aim of the study was to compare three different elastography methods, namely Strain Elastography (SE), Point Shear-Wave Elastography (pSWE) using Acoustic Radiation Force Impulse (ARFI)-Imaging and 2D-Shear Wave Elastography (2D-SWE), in the same study population for the differentiation of thyroid nodules.
Materials and methods: All patients received a conventional ultrasound scan, SE and 2D-SWE, and all patients except for two received ARFI-Imaging. Cytology/histology of thyroid nodules was used as a reference method. SE measures the relative stiffness within the region of interest (ROI) using the surrounding tissue as reference tissue. ARFI mechanically excites the tissue at the ROI using acoustic pulses to generate localized tissue displacements. 2D-SWE measures tissue elasticity using the velocity of many shear waves as they propagate through the tissue.
Results: 84 nodules (73 benign and 11 malignant) in 62 patients were analyzed. Sensitivity, specificity and NPV of SE were 73%, 70% and 94%, respectively. Sensitivity, specificity and NPV of ARFI and 2D-SWE were 90%, 79%, 98% and 73%, 67%, 94% respectively, using a cut-off value of 1.98m/s for ARFI and 2.65m/s (21.07kPa) for 2D-SWE. The AUROC (Area under the Receiver Operating Characteristic) of SE, ARFI and 2D-SWE for the diagnosis of malignant thyroid nodules were 52%, 86% and 71%, respectively. A significant difference in AUROC was found between SE and ARFI (p = 0.008), while no significant difference was found between ARFI and SWE (86% vs. 71%, p = 0.31), or SWE and SE (71% vs. 52%, p = 0.26).
Conclusion: pSWE using ARFI and 2D-SWE showed comparable results for the differentiation of thyroid nodules. ARFI was superior to elastography using SE.
Zielsetzung: Beteiligung von Medizinstudierenden im Rahmen der konzeptionellen Entwicklung eines zielgruppenspezifischen und attraktiven allgemeinmedizinischen Lehrangebots im ländlichen Raum.
Methodik: Es wurde ein Fragebogen entwickelt, der die Bewertung der Studierenden hinsichtlich des aktuellen Ablaufs ihres Studiums, den späteren Berufswunsch sowie die Anforderungen an ein zu entwickelndes allgemeinmedizinisches Schwerpunktprogramm im ländlichen Raum erfasst. Mittels einer Online-Befragung wurden im Sommer 2015 alle Medizinstudierende ab dem vierten vorklinischen Semester (n=2.150) der Goethe-Universität Frankfurt einmalig befragt. Die statistische Auswertung erfolgte primär deskriptiv. Die persönliche Einstellung hinsichtlich der Bereitschaft, als Hausarzt tätig zu werden, wurde auf statistische Signifikanz überprüft. Zudem wurde erhoben, ob ein messbarer Zusammenhang zwischen der eigenen Herkunft und dem späteren Wunscharbeitsort besteht.
Ergebnisse: Von insgesamt 2.150 kontaktierten Studierenden nahmen 617 an der Befragung teil (Rücklaufquote=28,7%). Die Ergebnisse repräsentieren eine große Bandbreite an Ideen und Anregungen, die sowohl die Meinung von Befürwortern als auch eher kritisch gegenüber der Lehre in der Allgemeinmedizin eingestellten Medizinstudierenden widerspiegeln. Von dem geplanten Schwerpunktprogramm erwarten die Studierenden einen starken Praxisbezug ebenso wie das Kennenlernen administrativer sowie wirtschaftlicher Hintergründe zum Führen einer Praxis.
Schlussfolgerungen: Durch die Einbeziehung der Zielgruppe am Entwicklungsprozess bestand die Möglichkeit, das zu entwickelnde Schwerpunktprogramm auf die späteren Teilnehmer passgenauer zuzuschneiden. Zudem ist zu erwarten, dass die Beteiligung der Studierenden zu einer höheren Akzeptanz des Programms führt. Die gewonnenen Ergebnisse zur Gestaltung eines Lehrangebots können als Orientierung für die mögliche Entwicklung ähnlicher Schwerpunktprogramme an anderen medizinischen Fakultäten dienen.
Aim: Participation of medical students in the conceptual development of targeted and attractive teaching content for rural areas.
Method: A questionnaire was developed to gather information on students' views of their current medical studies, career interests, and what requirements should be met by an optional rural health program in general practice. By means of an online survey in summer 2015, all medical students from the fourth preclinical semester onwards (n=2,150) at Goethe University Frankfurt were surveyed on one occasion. Statistical analysis was mainly descriptive. Personal attitudes towards a career as a family practitioner were examined for statistical significance. Further information was gathered on whether a measurable correlation exists between personal background and desired work location.
Results: Of the 2,150 students that were contacted, 617 participated in the survey (response rate=28.7%). The results covered a wide range of ideas and recommendations and were representative both of medical students with a positive attitude toward general practice, as well as those that were rather critical of teaching in general practice. The students expected the planned health program to be of strong practical relevance and to acquaint them with the administrative and economic aspects of running a practice.
Conclusions: By including the target group in the development process, it was possible to tailor the health program to meet the needs of future participants more precisely. Student participation can also be expected to result in greater acceptance of the program. The results on teaching content may also provide other medical faculties with orientation when developing comparable programs.
Patients after orthopic liver transplantation (OLT) are at risk of developing graft dysfunction. Sphingolipids (SL’s) have been identified to play a pivotal role in the regulation of hepatocellular apoptosis, inflammation and immunity. We aimed to investigate the serum SL profile in a prospective real-world cohort of post-OLT patients. From October 2015 until July 2016, 149 well-characterized post-OLT patients were analyzed. SL’s were assessed in serum probes via Liquid Chromatography/Tandem Mass Spectrometry. Twenty-nine (20%) patients had a biopsy proven graft rejection with decreased C20-ceramide (Cer) (p = 0.042), C18-dihydroceramide (DHC) (p = 0.022) and C24DHC (p = 0.060) levels. Furthermore, C18DHC (p = 0.044) and C24DHC (p = 0.011) were significantly down-regulated in patients with ischemic type biliary lesions (ITBL; n = 15; 10%). One-hundred and thirty-three patients (89%) have so far received tacrolimus as the main immunosuppressive agent with observed elevations of C14Cer (p = 0.052), C18Cer (p = 0.049) and C18:1Cer (p = 0.024). Hepatocellular carcinoma (HCC) pre-OLT was associated with increases in C24:1Cer (p = 0.024) and C24:1DHC (p = 0.024). In this large prospective cross-sectional study of patients, post-OLT serum levels of (very-)long chain (dihydro-)ceramides associate with graft rejection, ITBL, tacrolimus intake and HCC pre-OLT. Hence, serum SL’s may be indicative of graft complications. Further research is necessary to identify their diverse mechanistic role in regulating immunity and inflammation in patients post-OLT.
Purpose: Collaborative care is effective in improving symptoms of patients with depression. The aims of this study were to characterize symptom trajectories in patients with major depression during one year of collaborative care and to explore associations between baseline characteristics and symptom trajectories.
Methods: We conducted a cluster-randomized controlled trial in primary care. The collaborative care intervention comprised case management and behavioral activation. We used the Patient Health Questionnaire-9 (PHQ-9) to assess symptom severity as the primary outcome. Statistical analyses comprised latent growth mixture modeling and a hierarchical binary logistic regression model.
Results: We included 74 practices and 626 patients (310 intervention and 316 control recipients) at baseline. Based on a minimum of 12 measurement points for each intervention recipient, we identified two latent trajectories, which we labeled "fast improvers" (60.5%) and "slow improvers" (39.5%). At all measurements after baseline, "fast improvers" presented higher PHQ mean values than "slow improvers". At baseline, "fast improvers" presented fewer physical conditions, higher health-related quality of life, and had made fewer suicide attempts in their history.
Conclusions: A notable proportion of 39.5% of patients improved only "slowly" and probably needed more intense treatment. The third follow-up in month two could well be a sensible time to adjust treatment to support "slow improvers".
Introduction: Migrants are overrepresented in the European HIV epidemic. We aimed to understand the barriers and facilitators to HIV testing and current treatment and healthcare needs of migrants living with HIV in Europe.
Methods: A cross‐sectional study was conducted in 57 HIV clinics in nine countries (Belgium, Germany, Greece, Italy, The Netherlands, Portugal, Spain, Switzerland and United Kingdom), July 2013 to July 2015. HIV‐positive patients were eligible for inclusion if they were as follows: 18 years or older; foreign‐born residents and diagnosed within five years of recruitment. Questionnaires were completed electronically in one of 15 languages and linked to clinical records. Primary outcomes were access to primary care and previous negative HIV test. Data were analysed using random effects logistic regression. Outcomes of interest are presented for women, heterosexual men and gay/bisexual men.
Results: A total of 2093 respondents (658 women, 446 heterosexual men and 989 gay/bisexual men) were included. The prevalence of a previous negative HIV test was 46.7%, 43.4% and 82.0% for women, heterosexual and gay/bisexual men respectively. In multivariable analysis previous testing was positively associated with: receipt of post‐migration antenatal care among women, permanent residency among heterosexual men and identifying as gay rather than bisexual among gay/bisexual men. Access to primary care was found to be high (>83%) in all groups and was strongly associated with country of residence. Late diagnosis was common for women and heterosexual men (60.8% and 67.1%, respectively) despite utilization of health services prior to diagnosis. Across all groups almost three‐quarters of people on antiretrovirals had an HIV viral load <50 copies/mL.
Conclusions: Migrants access healthcare in Europe and while many migrants had previously tested for HIV, that they went on to test positive at a later date suggests that opportunities for HIV prevention are being missed. Expansion of testing beyond sexual health and antenatal settings is still required and testing opportunities should be linked with combination prevention measures such as access to PrEP and treatment as prevention.
Microangiopathy with subsequent organ damage represents a major complication in several diseases. The mechanisms leading to microvascular occlusion include von Willebrand factor (VWF), notably the formation of ultra-large von Willebrand factor fibers (ULVWFs) and platelet aggregation. To date, the contribution of erythrocytes to vascular occlusion is incompletely clarified. We investigated the platelet-independent interaction between stressed erythrocytes and ULVWFs and its consequences for microcirculation and organ function under dynamic conditions. In response to shear stress, erythrocytes interacted strongly with VWF to initiate the formation of ULVWF/erythrocyte aggregates via the binding of Annexin V to the VWF A1 domain. VWF-erythrocyte adhesion was attenuated by heparin and the VWF-specific protease ADAMTS13. In an in vivo model of renal ischemia/reperfusion injury, erythrocytes adhered to capillaries of wild-type but not VWF-deficient mice and later resulted in less renal damage. In vivo imaging in mice confirmed the adhesion of stressed erythrocytes to the vessel wall. Moreover, enhanced eryptosis rates and increased VWF binding were detected in blood samples from patients with chronic renal failure. Our study demonstrates that stressed erythrocytes have a pronounced binding affinity to ULVWFs. The discovered mechanisms suggest that erythrocytes are essential for the pathogenesis of microangiopathies and renal damage by actively binding to ULVWFs.
The dopamine (DA) system plays a major role in cognitive functions through its interactions with several brain regions including the prefrontal cortex (PFC). Conversely, disturbances in the DA system contribute to cognitive deficits in psychiatric diseases, yet exactly how they do so remains poorly understood. Here we show, using mice with disease-relevant alterations in DA signaling (D2R-OE mice), that deficits in working memory (WM) are associated with impairments in the WM-dependent firing patterns of DA neurons in the ventral tegmental area (VTA). The WM-dependent phase-locking of DA neurons to 4 Hz VTA-PFC oscillations is absent in D2R-OE mice and VTA-PFC synchrony deficits scale with their WM impairments. We also find reduced 4 Hz synchrony between VTA DA neurons and selective impairments in their representation of WM demand. These results identify how altered DA neuron activity—at the level of long-range network activity and task-related firing patterns—may underlie cognitive impairments.
Based on the concept of oxidative stress, reactive oxygen species (ROS) have been incriminated as the drivers behind almost every cardiovascular pathology. Redox alterations are, however, omnipresent bystanders to changes in cellular activity state. Even when ROS levels are altered, their contribution to pathology is not necessarily causal. Researchers should hesitate to engage in global ROS measurements and rather aim on identifying individual molecular targets of redox regulation.
Objectives: The SAVI-TF (Symetis ACURATE neo Valve Implantation Using Transfemoral Access) registry was initiated to study the ACURATE neo transcatheter heart valve in a large patient population treated under real-world conditions.
Background: The self-expanding, supra-annular ACURATE neo prosthesis is a transcatheter heart valve that gained the Conformité Européene mark in 2014, but only limited clinical data are available so far.
Methods: This prospective, multicenter registry enrolled 1,000 patients at 25 European centers who were followed for 1 year post-procedure.
Results: Mean patient age was 81.1 ± 5.2 years; mean logistic European System for Cardiac Operative Risk Evaluation I score, European System for Cardiac Operative Risk Evaluation II score, and Society of Thoracic Surgeons score were 18.1 ± 12.5%, 6.6 ± 7.5%, and 6.0 ± 5.6%, respectively. At 1 year, 8.0% (95% confidence interval [CI]: 6.3% to 9.7%) of patients had died, 2.3% (95% CI: 1.3% to 3.2%) had disabling strokes, and 9.9% (95% CI: 8.1% to 11.8%) had permanent pacemaker implantations. Through 1 year, 5 reinterventions (0.5%; 95% CI: 0.1% to 1.0%) were performed: 3 valve-in-valve and 2 surgical aortic valve replacements. Mean effective orifice area was 1.84 ± 0.43 cm2, mean gradient was 7.3 ± 3.7 mm Hg, and greater than mild paravalvular leakage was observed in 3.6% of patients.
Conclusions: Transfemoral implantation of the ACURATE neo prosthesis resulted in favorable 1-year clinical and echocardiographic outcomes with very low mortality and new pacemaker rates.
Background: Mitochondrial acyl-CoA dehydrogenase family member 9 (ACAD9) is essential for the assembly of mitochondrial respiratory chain complex I. Disease causing biallelic variants in ACAD9 have been reported in individuals presenting with lactic acidosis and cardiomyopathy.
Results: We describe the genetic, clinical and biochemical findings in a cohort of 70 patients, of whom 29 previously unpublished. We found 34 known and 18 previously unreported variants in ACAD9. No patients harbored biallelic loss of function mutations, indicating that this combination is unlikely to be compatible with life. Causal pathogenic variants were distributed throughout the entire gene, and there was no obvious genotype-phenotype correlation.
Most of the patients presented in the first year of life. For this subgroup the survival was poor (50% not surviving the first 2 years) comparing to patients with a later presentation (more than 90% surviving 10 years). The most common clinical findings were cardiomyopathy (85%), muscular weakness (75%) and exercise intolerance (72%). Interestingly, severe intellectual deficits were only reported in one patient and severe developmental delays in four patients. More than 70% of the patients were able to perform the same activities of daily living when compared to peers.
Conclusions: Our data show that riboflavin treatment improves complex I activity in the majority of patient-derived fibroblasts tested. This effect was also reported for most of the treated patients and is mirrored in the survival data. In the patient group with disease-onset below 1 year of age, we observed a statistically-significant better survival for patients treated with riboflavin.
Atopic dermatitis (AD) is a chronic inflammatory disease affecting children and adolescence. The traditional therapeutic options for AD, including emollients topically and immune modulatory agents systemically focusing on reducing skin inflammation and restoring the function of the epidermal barrier, are proven ineffective in many cases. Several studies have linked vitamin D supplementation with either a decreased risk to develop AD or a clinical improvement of the symptoms of AD patients. In this report, we present a girl with severe AD who under adequate supplementation with cholecalciferol was treated with calcitriol and subsequently with paricalcitol. She had significant improvement—almost healing of her skin lesions within 2 months, a result sustained for more than 3 years now. Because of hypercalciuria as a side effect from calcitriol therapy, treatment was continued with paricalcitol, a vitamin D analogue used in secondary hyperparathyroidism in chronic kidney disease. Calcitriol therapy may be considered as a safe and efficacious treatment option for patients with severe AD, particularly for those with refractory AD, under monitoring for possible side effects. Treatment with paricalcitol resolves hypercalciuria, is safe, and should be further investigated as an alternative treatment of atopic dermatitis and possibly other diseases of autoimmune origin.
Objectives: In the AURA3 trial, individuals received osimertinib 80 mg once daily or chemotherapy for advanced non-small cell lung cancer. Here, we explore patient-reported symptoms possibly related to treatment.
Materials and methods: AURA3 was an open-label, randomized phase III trial involving 419 patients. As part of the trial’s exploratory objectives, individuals were asked to complete the Patient-Reported Outcomes version of the Common Terminology Criteria for Adverse Events (PRO-CTCAE) electronically, first weekly for 18 weeks and then every 3 weeks for up to 57 weeks, subject to the availability of validated local-language versions (English, German, Japanese and Spanish versions were available).
Results: In total, 161 patients (38%; 102 receiving osimertinib, 59 receiving chemotherapy) provided data for PRO-CTCAE analyses (mean age: 64 years; 63% women). Diarrhea was reported more commonly with osimertinib than with chemotherapy, and was mostly graded as occurring rarely or occasionally. Decreased appetite was reported less commonly with osimertinib than with chemotherapy. The proportion of patients reporting nausea changed little from baseline with osimertinib and increased with chemotherapy. Few patients reported vomiting. Both nausea and vomiting were generally graded as mild in severity. Fatigue was reported less commonly with osimertinib than with chemotherapy, and was mostly graded as mild or moderate. Of patients reporting fatigue, the proportion grading it as interfering at least ‘somewhat’ with their usual or daily activities was lower with osimertinib than with chemotherapy.
Conclusion: Symptoms were generally mild and not frequent, with some differences in symptom patterns between the two treatment groups. The results support and complement the AURA3 trial data and give insight into patients’ experience with treatment.
kurz und kn@pp news : Nr. 43
(2018)
Systemic treatment is necessary for one third of patients with renal cell carcinoma. No valid biomarker is currently available to tailor personalized therapy. In this study we established a representative panel of patient derived xenograft (PDX) mouse models from patients with renal cell carcinomas and determined serum levels of high mobility group B1 (HMGB1) protein under treatment with sunitinib, pazopanib, sorafenib, axitinib, temsirolimus and bevacizumab. Serum HMGB1 levels were significantly higher in a subset of the PDX collection, which exhibited slower tumor growth during subsequent passages than tumors with low HMGB1 serum levels. Pre-treatment PDX serum HMGB1 levels also correlated with response to systemic treatment: PDX models with high HMGB1 levels predicted response to bevacizumab. Taken together, we provide for the first time evidence that the damage associated molecular pattern biomarker HMGB1 can predict response to systemic treatment with bevacizumab. Our data support the future evaluation of HMGB1 as a predictive biomarker for bevacizumab sensitivity in patients with renal cell carcinoma.
Predicting the requirement for renal replacement therapy in intensive care patients with sepsis
(2018)
Sepsis is one of the most frequent causes of acute kidney injury (AKI) in critically ill patients, with initial organ impairment often followed by dysfunction in other systems. Renal dysfunction may therefore represent one facet in the evolution towards multiple organ dysfunction syndrome (MODS) or, alternatively, may be indicative of system-wide endothelial damage caused by hyperinflammation and a positive fluid balance. Whilst numerous biomarkers have been investigated to predict renal replacement therapy (RRT) requirement, including NGAL, TIMP-2 and IGFBP-7, mid-regional proadrenomedullin (MR-proADM) may also be of interest due to its involvement in capillary leakage, endothelial dysfunction and the initial stages of multiple organ failure development. ...
Background: Stem cell therapy is considered as a promising alternative to treat intervertebral disc degeneration (IDD). Extensive work had been done on identifying and comparing different types of candidate stem cells, both in vivo and in vitro. However, few studies have shed light on degenerative nucleus pulposus cells (NPCs), especially their biological behavior under the influence of exogenous stem cells, specifically the gene expression and regulation pattern. In the present study, we aimed to determine messenger RNAs (mRNAs) and long non-coding RNAs (lncRNAs), which are differentially expressed during the co-culturing process with adipose-derived mesenchymal stem cells (ASCs) and to explore the involved signaling pathways and the regulatory networks.
Methods: We compared degenerative NPCs co-cultured with ASCs with those cultured solely using lncRNA-mRNA microarray analysis. Based on these data, we investigated the significantly regulated signaling pathways based on the Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway database. Moreover, 23 micro RNAs (miRNAs), which were demonstrated to be involved in IDD were chosen; we investigated their theoretic regulatory importance associated with our microarray data.
Results: We found 632 lncRNAs and 1682 mRNAs were differentially expressed out of a total of 40,716 probes. We then confirmed the microarray data by real-time PCR. Furthermore, we demonstrated 197 upregulated, and 373 downregulated Gene Ontology terms and 176 significantly enriched pathways, such as the mitogen-activated protein kinase (MAPK) pathway. Also, a signal-net was constructed to reveal the interplay among differentially expressed genes. Meanwhile, a mRNA-lncRNA co-expression network was constructed for the significantly changed mRNAs and lncRNAs. Also, the competing endogenous RNA (ceRNA) network was built.
Conclusion: Our results present the first comprehensive identification of differentially expressed lncRNAs and mRNAs of degenerative NPCs, altered by co-culturing with ASCs, and outline the gene expression regulation pattern. These may provide valuable information for better understanding of stem cell therapy and potential candidate biomarkers for IDD treatment.
Background: The rate of caesarean sections increased in the last decades to about 30% of births in western populations. Many caesarean sections are electively planned without an urgent medical reason for mother or child. Especially in women with a foregoing caesarean section, the procedure is planned early. An early caesarean section though may harm the newborn. Our aim is to evaluate the gestational time point after the 37th gestational week (after prematurity = term) of performing an elective caesarean section with the lowest morbidity for mother and child.
Methods: This is an update of a systematic review previously carried out on behalf of the German Federal Ministry of Health. We will perform a systematic literature search in MEDLINE, EMBASE, CENTRAL and CINAHL. Our primary outcome is the rate of admissions to the neonatal intensive care unit in early versus late term neonates. We will include (quasi) randomized controlled trials and cohort studies. The studies should include pregnant women who have an elective caesarean section at term. We will screen titles and abstracts and the identified full texts of studies for eligibility. Risk of bias will be assessed with the Cochrane Risk of Bias Tool for Randomized Trials or with the Risk of Bias Tool for Non-Randomized Studies of Interventions (ROBINS-I). These tasks will be performed independently by two reviewers. Data will be extracted in beforehand piloted extraction tables. A dose-response meta-analysis will be performed.
Discussion: Our aim is to reach a higher validity in the assessment of the time point of elective caesarean sections by performing a meta-analysis to support recommendations for clinical practice. We assume to identify less randomized controlled trials but a large number of cohort studies analyzing the given question. We will discuss similarities and differences in included studies as well as methodological strengths and weaknesses.
Systematic review registration: PROSPERO CRD42017078231
Ventriculoperitoneal shunts equipped with a reservoir and a valve to manually switch off the shunt function can be used for intraventricular injections of therapeutics in patients suffering from a communicating hydrocephalus caused by leptomeningeal metastases. These shunt devices avoid the risk of injecting therapeutics through the distal leg of the shunt system into the intraperitoneal space, which may cause toxicity. Furthermore, regular intraventricular injections of chemotherapeutics help to maintain sufficient concentrations in the ventricular space. Therefore, ventriculoperitoneal shunts equipped with an on-off valve are a useful tool to reliably inject chemotherapeutics into the ventricles. In order to systematically assess feasibility, safety, and efficacy of this procedure, we performed a retrospective analysis of all patients with leptomeningeal metastases who had received a shunt system at our institution. In total, six adult patients had a ventriculoperitoneal shunt equipped with an on-off valve implanted. Out of these six patients, two patients subsequently received intraventricular injections of chemotherapeutics. The configuration of the valve setting and the intraventricular injections were easily feasible in the setting of a neuro-oncology department. The complication of a shunt leakage occurred in one patient following the first intraventricular injection. No extra-central nervous system (CNS) toxicities were observed. In summary, ventriculoperitoneal shunts with on-off valves are useful tools for reliable intraventricular administration of therapeutics.
Background/Aims: Sphingosine 1-phosphate (S1P) is considered as a key molecule regulating various cell functions including cell growth and death. It is produced by two sphingosine kinases (SK) denoted as SK-1 and SK-2. Whereas SK-1 has been extensively studied and has been appointed a role in promoting cell growth, the function of SK-2 is controversial, and both pro-proliferative and pro-apoptotic functions have been suggested. In this study we investigated whether renal mesangial cells isolated from transgenic mice overexpressing the human Sphk2 gene (hSK2-tg) showed an altered cell response towards growth-inducing and apoptotic stimuli.
Methods: hSK2-tg mice were generated by using a Quick KnockinR strategy. Renal mesangial cells were isolated by a differential sieving method and further cultivated in vitro. Lipids were quantified by mass spectrometry. Protein expression was determined by Western blot analysis, cell proliferation was determined by 3H-thymidine incorporation, and apoptosis was determined by a DNA fragmentation ELISA.
Results: We show here that kidneys and mesangial cells from hSK2-tg mice express the hSK2 as well as the endogenous mouse mSK2. hSK2 and mSK2 predominantly resided in the cytosol of quiescent transgenic cells. However, S1P accumulated strongly in the nucleus and only minimally in the cytosol of transgenic cells. Functionally, hSK2-tg cells proliferated less than control cells under normal growth conditions and were also more sensitive towards stress-induced apoptosis. On the molecular level, this was reflected by reduced ERK and Akt/PKB activation, and upon staurosporine treatment, by a sensitized mitochondrial pathway as manifested by reduced anti-apoptotic Bcl-XL expression and increased cleavage of caspase-9, downstream caspase-3 and PARP-1.
Conclusion: Altogether, these data demonstrate that SK-2 exerts an antiproliferative and apoptosis-sensitizing effect in renal mesangial cells which suggests that selective inhibitors of SK-2 may promote proliferation and reduce apoptosis and this may have impact on the outcome of proliferation-associated diseases such as mesangioproliferative glomerulonephritis.
Akt and mTORC1 signaling as predictive biomarkers for the EGFR antibody nimotuzumab in glioblastoma
(2018)
Glioblastoma (GB) is the most frequent primary brain tumor in adults with a dismal prognosis despite aggressive treatment including surgical resection, radiotherapy and chemotherapy with the alkylating agent temozolomide. Thus far, the successful implementation of the concept of targeted therapy where a drug targets a selective alteration in cancer cells was mainly limited to model diseases with identified genetic drivers. One of the most commonly altered oncogenic drivers of GB and therefore plausible therapeutic target is the epidermal growth factor receptor (EGFR). Trials targeting this signaling cascade, however, have been negative, including the phase III OSAG 101-BSA-05 trial. This highlights the need for further patient selection to identify subgroups of GB with true EGFR-dependency. In this retrospective analysis of treatment-naïve samples of the OSAG 101-BSA-05 trial cohort, we identify the EGFR signaling activity markers phosphorylated PRAS40 and phosphorylated ribosomal protein S6 as predictive markers for treatment efficacy of the EGFR-blocking antibody nimotuzumab in MGMT promoter unmethylated GBs. Considering the total trial population irrespective of MGMT status, a clear trend towards a survival benefit from nimotuzumab was already detectable when tumors had above median levels of phosphorylated ribosomal protein S6. These results could constitute a basis for further investigations of nimotuzumab or other EGFR- and downstream signaling inhibitors in selected patient cohorts using the reported criteria as candidate predictive biomarkers.
Despite being an essential consideration when deciding rule changes, injury prevention strategies, and athlete development models, there is little epidemiological data of U18 field hockey player injuries–something explicitly referred to in the 2015 International Olympic Committee’s Consensus Statement on Youth Athlete Development. The aim of this study was to quantify incidence and characteristics of injuries in elite youth field hockey players during a major international tournament. Standardized reporting forms detailing time, location on pitch, mechanism and anatomical location of injury were completed for new musculoskeletal conditions resulting in a time stoppage by the umpire and where a player was noticeably affected by an injury for up to 20 s regardless of time stoppage. Injury incidence was 1.35 and 2.20 injuries/match or 53 and 86 injuries per 1000 player match hours for boys (B) and girls (G) respectively; girls were over three times more likely to have a minor injury. Most injuries were contusions due to being hit by the ball or stick (B: 12, G: 27), with high numbers of injuries to the torso (B: 8) and head/face (G: 7). Injuries during the penalty corner (B: 3, G: 4) were to the lower limb and hand, and boys were less likely to wear facial protection (B: 65.9%, G: 86.4%). Results form an essential initial dataset of injuries in U18 field hockey players. Current reporting protocols under-report injuries and must be addressed by the international governing body. The high number of head/face injuries, particularly in females, requires further investigation.
Introduction: The clinical management of breech presentations at term is still a controversially discussed issue among clinicians. Clear predictive criteria for planned vaginal breech deliveries are desperately needed to prevent adverse fetal and maternal outcomes and to reduce elective cesarean section rates. The green-top guideline considers an estimated birth weight of 3.8 kg or more an indication to plan a cesarean section despite the lack of respective evidence.
Objective: To compare maternal and neonatal outcome of vaginal intended breech deliveries of births with children with a birth weight of 2.5 kg– 3.79 kg and children with a birth weight of 3.8 kg and more.
Design: Prospective cohort study.
Sample: All vaginal intended deliveries out of a breech position of newborns weighing between 2.5 kg and 4.5 kg at the Obstetrics department at Goethe University Hospital Frankfurt from January 2004 until December 2016
Methods: Neonatal and maternal outcome of a light weight group (LWG) (< 3.8 kg) was compared to and a high weight group (HWG) (≥ 3.8 kg) using Pearson’s Chi Square test and Fishers exact test. A logistic regression analysis was performed to detect an association between cesarean section rates, fetal outcome and the birth weight.
Results: No difference in neonatal morbidity was detected between the HWG (1.8%, n = 166) and the LWG (2.6%, n = 888). Cesarean section rate was significantly higher in the HWG with 45.2% in comparison to 28.8% in the LWG with an odds ratio of 1.57 (95% CI 1.29–1.91, p<0.0001). In vaginal deliveries, a high birth weight was not associated with an increased risk of maternal birth injuries (LWG in vaginal deliveries: 74.3%, HWG in vaginal deliveries: 73.6%; p = 0.887; OR = 1.9 (95% CI 0.9–1.1))
Conclusion: A fetal weight above 3.79 kg does not predict increased maternal or infant morbidity after delivery from breech presentation at term. Neither the literature nor our analyses document evidence for threshold of estimated birth weight that is associated with maternal and/or infant morbidity. However, patients should be informed about an increased likelihood of cesarean sections during labor when attempting vaginal birth from breech position at term in order to reach an informed shared decision concerning the birth strategy. Further investigations in multi center settings are needed to advance international guidelines on vaginal breech deliveries in the context of estimated birth weight and its impact on perinatal outcome.
Cancer metabolism is characterized by extensive glucose consumption through aerobic glycolysis. No effective therapy exploiting this cancer trait has emerged so far, in part, due to the substantial side effects of the investigated drugs. In this study, we examined the side effects of a combination of isocaloric ketogenic diet (KD) with the glycolysis inhibitor 2-deoxyglucose (2-DG). Two groups of eight athymic nude mice were either fed a standard diet (SD) or a caloric unrestricted KD with a ratio of 4 g fat to 1 g protein/carbohydrate. 2-DG was investigated in commonly employed doses of 0.5 to 4 g/kg and up to 8 g/kg. Ketosis was achieved under KD (ketone bodies: SD 0.5 ± 0.14 mmol/L, KD 1.38 ± 0.28 mmol/L, p < 0.01). The intraperitoneal application of 4 g/kg of 2-DG caused a significant increase in blood glucose, which was not prevented by KD. Sedation after the 2-DG treatment was observed and a behavioral test of spontaneous motion showed that KD reduced the sedation by 2-DG (p < 0.001). A 2-DG dose escalation to 8 g/kg was lethal for 50% of the mice in the SD and for 0% of the mice in the KD group (p < 0.01). A long-term combination of KD and an oral 1 or 2 g 2-DG/kg was well-tolerated. In conclusion, KD reduces the sedative effects of 2-DG and dramatically increases the maximum tolerated dose of 2-DG. A continued combination of KD and anti-glycolytic therapy is feasible. This is, to our knowledge, the first demonstration of increased tolerance to glycolysis inhibition by KD.
Background: Ever since it was discovered that zoophilic vectors can transmit malaria, zooprophylaxis has been used to prevent the disease. However, zoopotentiation has also been observed. Thus, the presence of livestock has been widely accepted as an important variable for the prevalence and risk of malaria, but the effectiveness of zooprophylaxis remained subject to debate. This study aims to critically analyse the effects of the presence of livestock on malaria prevalence using a large dataset from Indonesia.
Methods: This study is based on data from the Indonesia Basic Health Research ("Riskesdas") cross-sectional survey of 2007 organized by the National Institute of Health Research and Development of Indonesia’s Ministry of Health. The subset of data used in the present study included 259,885 research participants who reside in the rural areas of 176 regencies throughout the 15 provinces of Indonesia where the prevalence of malaria is higher than the national average. The variable "existence of livestock" and other independent demographic, social and behavioural variables were tested as potential determinants for malaria prevalence by multivariate logistic regressions.
Results: Raising medium-sized animals in the house was a significant predictor of malaria prevalence (OR = 2.980; 95% CI 2.348–3.782, P < 0.001) when compared to keeping such animals outside of the house (OR = 1.713; 95% CI 1.515–1.937, P < 0.001). After adjusting for gender, age, access to community health facility, sewage canal condition, use of mosquito nets and insecticide-treated bed nets, the participants who raised medium-sized animals inside their homes were 2.8 times more likely to contract malaria than respondents who did not (adjusted odds ratio = 2.809; 95% CI 2.207–3.575; P < 0.001).
Conclusions: The results of this study highlight the importance of livestock for malaria transmission, suggesting that keeping livestock in the house contributes to malaria risk rather than prophylaxis in Indonesia. Livestock-based interventions should therefore play a significant role in the implementation of malaria control programmes, and focus on households with a high proportion of medium-sized animals in rural areas. The implementation of a "One Health" strategy to eliminate malaria in Indonesia by 2030 is strongly recommended.
Objective: Amyloid β (Aβ) depositions in plaques and cerebral amyloid angiopathy (CAA) represent common features of Alzheimer's disease (AD). Sequential deposition of post‐translationally modified Aβ in plaques characterizes distinct biochemical stages of Aβ maturation. However, the molecular composition of vascular Aβ deposits in CAA and its relation to plaques remain enigmatic.
Methods: Vascular and parenchymal deposits were immunohistochemically analyzed for pyroglutaminated and phosphorylated Aβ in the medial temporal and occipital lobe of 24 controls, 27 pathologically‐defined preclinical AD, and 20 symptomatic AD cases.
Results: Sequential deposition of Aβ in CAA resembled Aβ maturation in plaques and enabled the distinction of three biochemical stages of CAA. B‐CAA stage 1 was characterized by deposition of Aβ in the absence of pyroglutaminated AβN3pE and phosphorylated AβpS8. B‐CAA stage 2 showed additional AβN3pE and B‐CAA stage 3 additional AβpS8. Based on the Aβ maturation staging in CAA and plaques, three case groups for Aβ pathology could be distinguished: group 1 with advanced Aβ maturation in CAA; group 2 with equal Aβ maturation in CAA and plaques; group 3 with advanced Aβ maturation in plaques. All symptomatic AD cases presented with end‐stage plaque maturation, whereas CAA could exhibit immature Aβ deposits. Notably, Aβ pathology group 1 was associated with arterial hypertension, and group 2 with the development of dementia.
Interpretation: Balance of Aβ maturation in CAA and plaques defines distinct pathological subgroups of β‐amyloidosis. The association of CAA‐related Aβ maturation with cognitive decline, the individual contribution of CAA and plaque pathology to the development of dementia within the defined Aβ pathology subgroups, and the subgroup‐related association with arterial hypertension should be considered for differential diagnosis and therapeutic intervention.
Background: Sputum induction is an important noninvasive method for analyzing bronchial inflammation in patients with asthma and other respiratory diseases. Most frequently, ultrasonic nebulizers are used for sputum induction, but breath-controlled nebulizers may target the small airways more efficiently. This treatment may produce a cell distribution similar to bronchoalveolar lavage (less neutrophils and more macrophages) and provide deeper insights into the underlying lung pathology. The goal of the study was to compare both types of nebulizer devices and their efficacy in inducing sputum to measure bronchial inflammation, i.e., cell composition and cytokines, in patients with mild allergic asthma and healthy controls.
Methods: The population of this study consisted of 20 healthy control subjects with a median age of 17 years, range: 8–25 years, and 20 patients with a median age of 12 years, range: 8–24 years, presenting with mild, controlled allergic asthma who were not administered an inhaled steroid treatment. We induced sputum in every individual using both devices on two separate days. The sputum weight, the cell composition and cytokine levels were analyzed using a cytometric bead assay (CBA) and by real-time quantitative PCR (qRT-PCR).
Results: We did not observe significant differences in the weight, cell distribution or cytokine levels in the sputum samples induced by both devices. In addition, the Bland-Altman correlation revealed good concordance of the cell distribution. As expected, eosinophils and IL-5 levels were significantly elevated in patients with asthma.
Conclusions: The hypothesis that sputum induction with a breath-controlled "smart" nebulizer is more efficient and different from an ultrasonic nebulizer was not confirmed. The Bland-Altman correlations showed good concordance when comparing the two devices.
Trial registration: NCT01543516 Retrospective registration date: March 5, 2012.
Background: In intensive care units (ICU) octogenarians become a routine patients group with aggravated therapeutic and diagnostic decision-making. Due to increased mortality and a reduced quality of life in this high-risk population, medical decision-making a fortiori requires an optimum of risk stratification. Recently, the VIP-1 trial prospectively observed that the clinical frailty scale (CFS) performed well in ICU patients in overall-survival and short-term outcome prediction. However, it is known that healthcare systems differ in the 21 countries contributing to the VIP-1 trial. Hence, our main focus was to investigate whether the CFS is usable for risk stratification in octogenarians admitted to diversified and high tech German ICUs.
Methods: This multicentre prospective cohort study analyses very old patients admitted to 20 German ICUs as a sub-analysis of the VIP-1 trial. Three hundred and eight patients of 80 years of age or older admitted consecutively to participating ICUs. CFS, cause of admission, APACHE II, SAPS II and SOFA scores, use of ICU resources and ICU- and 30-day mortality were recorded. Multivariate logistic regression analysis was used to identify factors associated with 30-day mortality.
Results: Patients had a median age of 84 [IQR 82–87] years and a mean CFS of 4.75 (± 1.6 standard-deviation) points. More than half of the patients (53.6%) were classified as frail (CFS ≥ 5). ICU-mortality was 17.3% and 30-day mortality was 31.2%. The cause of admission (planned vs. unplanned), (OR 5.74) and the CFS (OR 1.44 per point increase) were independent predictors of 30-day survival.
Conclusions: The CFS is an easy determinable valuable tool for prediction of 30-day ICU survival in octogenarians, thus, it may facilitate decision-making for intensive care givers in Germany.
Trial registration: The VIP-1 study was retrospectively registered on ClinicalTrials.gov (ID: NCT03134807) on May 1, 2017.
Hypofunction of the N-methyl-D-aspartate receptor (NMDAR) has been implicated as a possible mechanism underlying cognitive deficits and aberrant neuronal dynamics in schizophrenia. To test this hypothesis, we first administered a sub-anaesthetic dose of S-ketamine (0.006 mg/kg/min) or saline in a single-blind crossover design in 14 participants while magnetoencephalographic data were recorded during a visual task. In addition, magnetoencephalographic data were obtained in a sample of unmedicated first-episode psychosis patients (n = 10) and in patients with chronic schizophrenia (n = 16) to allow for comparisons of neuronal dynamics in clinical populations versus NMDAR hypofunctioning. Magnetoencephalographic data were analysed at source-level in the 1–90 Hz frequency range in occipital and thalamic regions of interest. In addition, directed functional connectivity analysis was performed using Granger causality and feedback and feedforward activity was investigated using a directed asymmetry index. Psychopathology was assessed with the Positive and Negative Syndrome Scale. Acute ketamine administration in healthy volunteers led to similar effects on cognition and psychopathology as observed in first-episode and chronic schizophrenia patients. However, the effects of ketamine on high-frequency oscillations and their connectivity profile were not consistent with these observations. Ketamine increased amplitude and frequency of gamma-power (63–80 Hz) in occipital regions and upregulated low frequency (5–28 Hz) activity. Moreover, ketamine disrupted feedforward and feedback signalling at high and low frequencies leading to hypo- and hyper-connectivity in thalamo-cortical networks. In contrast, first-episode and chronic schizophrenia patients showed a different pattern of magnetoencephalographic activity, characterized by decreased task-induced high-gamma band oscillations and predominantly increased feedforward/feedback-mediated Granger causality connectivity. Accordingly, the current data have implications for theories of cognitive dysfunctions and circuit impairments in the disorder, suggesting that acute NMDAR hypofunction does not recreate alterations in neural oscillations during visual processing observed in schizophrenia.
Soluble Triggering Receptor Expressed on Myeloid Cells 1 (sTREM-1) can be found in the sera of patients with infectious, autoimmune and malignant diseases. The primary objective of this study was to investigate the prognostic significance of sTREM-1 in lung cancer patients. We analyzed the sera of 164 patients with lung cancer of all histologies and all stages at the time of diagnosis. We employed an ELISA using the anti-TREM-1 clone 6B1.1G12 mAb and recombinant human TREM-1. Patient data was collected retrospectively by chart review. In ROC-analysis, a sTREM-1 serum level of 163.1 pg/ml showed the highest Youden-Index. At this cut-off value sTREM-1 was a marker of short survival in patients with NSCLC (median survival 8.5 vs. 13.3 months, p = 0.04). A Cox regression model showed stage (p < 0.001) and sTREM-1 (p = 0.011) to indicate short survival. There were no differences in sTREM-1 serum values among patients with or without infection, pleural effusion or COPD. sTREM-1 was not associated with metastasis at the time of diagnosis and was not a predictor of subsequent metastasis. In SCLC patients sTREM-1 levels were lower than in NSCLC patients (p = 0.001) and did not predict survival. sTREM-1 did not correlate with CRP or the number of neutrophils. In non-small cell lung cancer patients, sTREM-1 in serum has prognostic significance.
Growing evidence suggests that distributed spatial attention may invoke theta (3–9 Hz) rhythmic sampling processes. The neuronal basis of such attentional sampling is, however, not fully understood. Here we show using array recordings in visual cortical area V4 of two awake macaques that presenting separate visual stimuli to the excitatory center and suppressive surround of neuronal receptive fields (RFs) elicits rhythmic multi-unit activity (MUA) at 3–6 Hz. This neuronal rhythm did not depend on small fixational eye movements. In the context of a distributed spatial attention task, during which the monkeys detected a spatially and temporally uncertain target, reaction times (RTs) exhibited similar rhythmic fluctuations. RTs were fast or slow depending on the target occurrence during high or low MUA, resulting in rhythmic MUA-RT cross-correlations at theta frequencies. These findings show that theta rhythmic neuronal activity can arise from competitive RF interactions and that this rhythm may result in rhythmic RTs potentially subserving attentional sampling.
Stem cell-based therapies require cells with a maximum regenerative capacity in order to support regeneration after tissue injury and organ failure. Optimization of this regenerative potential of mesenchymal stromal/stem cells (MSC) or their conditioned medium by in vitro preconditioning regimens are considered to be a promising strategy to improve the release of regenerative factors. In the present study, MSC were isolated from inguinal adipose tissue (mASC) from C57BL/6 mice, cultured, and characterized. Then, mASC were either preconditioned by incubation in a hypoxic environment (0.5% O2), or in normoxia in the presence of murine epidermal growth factor (EGF) or tumor necrosis factor α (TNFα) for 48 h. Protein expression was measured by a commercially available array. Selected factors were verified by PCR analysis. The expression of 83 out of 308 proteins (26.9%) assayed was found to be increased after preconditioning with TNFα, whereas the expression of 61 (19.8%) and 70 (22.7%) proteins was increased after incubation with EGF or in hypoxia, respectively. Furthermore, we showed the proliferation-promoting effects of the preconditioned culture supernatants on injured epithelial cells in vitro. Our findings indicate that each preconditioning regimen tested induced an individual expression profile with a wide variety of factors, including several growth factors and cytokines, and therefore may enhance the regenerative potential of mASC for cell-based therapies.
Introduction: This study was designed to evaluate risk factors and incidence of epilepsy-related injuries and accidents (ERIA) at an outpatient clinic of a German epilepsy center providing healthcare to a mixed urban and rural population of over one million inhabitants.
Methods: Data acquisition was performed between 10/2013 and 09/2014 using a validated patient questionnaire on socioeconomic status, course of epilepsy, quality of life (QoL), depression, injuries and accidents associated with seizures or inadequate periictal patterns of behavior concerning a period of 3 months. Univariate analysis, multiple testing and regression analysis were performed to identify possible variables associated with ERIA.
Results: A total of 292 patients (mean age 40.8 years, range 18–86; 55% female) were enrolled and analyzed. Focal epilepsy was diagnosed in 75% of the patients. The majority was on an antiepileptic drug (AEDs) polytherapy (mean number of AEDs: 1.65). Overall, 41 patients (14.0%) suffered from epilepsy-related injuries and accidents in a 3-month period. Besides lacerations (n = 18, 6.2%), abrasions and bruises (n = 9, 3.1%), fractures (n = 6, 2.2%) and burns (n = 3, 1.0%), 17 mild injuries (5.8%) were reported. In 20 (6.8% of the total cohort) cases, urgent medical treatment with hospitalization was necessary. Epilepsy-related injuries and accidents were related to active epilepsy, occurrence of generalized tonic-clonic seizures (GTCS) and drug-refractory course as well as reported ictal falls, ictal loss of consciousness and abnormal peri-ictal behavior in the medical history. In addition, patients with ERIA had significantly higher depression rates and lower QoL.
Conclusion: ERIA and their consequences should be given more attention and standardized assessment for ERIA should be performed in every outpatient visit.
Background: Severely injured patients experience substantial immunological stress in the aftermath of traumatic insult, which often results in systemic immune dysregulation. Regulatory T cells (Treg) play a key role in the suppression of the immune response and in the maintenance of immunological homeostasis. Little is known about their presence and dynamics in blood after trauma, and nothing is known about Treg in the porcine polytrauma model. Here, we assessed different subsets of Treg in trauma patients (TP) and compared those to either healthy volunteers (HV) or data from porcine polytrauma.
Methods: Peripheral blood was withdrawn from 20 TP with injury severity score (ISS) ≥16 at the admittance to the emergency department (ED), and subsequently on day 1 and at day 3. Ten HV were included as controls (ctrl). The porcine polytrauma model consisted of a femur fracture, liver laceration, lung contusion, and hemorrhagic shock resulting in an ISS of 27. After polytrauma, the animals underwent resuscitation and surgical fracture fixation. Blood samples were withdrawn before and immediately after trauma, 24 and 72 h later. Different subsets of Treg, CD4+CD25+, CD4+CD25+FoxP3+, CD4+CD25+CD127−, and CD4+CD25+CD127−FoxP3+ were characterized by flow cytometry.
Results: Absolute cell counts of leukocytes were significantly increasing after trauma, and again decreasing in the follow-up in human and porcine samples. The proportion of human Treg in the peripheral blood of TP admitted to the ED was lower when compared to HV. Their numbers did not recover until 72 h after trauma. Comparable data were found for all subsets. The situation in the porcine trauma model was comparable with the clinical data. In porcine peripheral blood before trauma, we could identify Treg with the typical immunophenotype (CD4+CD25+CD127−), which were virtually absent immediately after trauma. Similar to the human situation, most of these cells expressed FoxP3, as assessed by intracellular FACS stain.
Conclusion: Despite minor percental differences in the recovery of Treg populations after trauma, our findings show a comparable decrease of Treg early after polytrauma, and strengthen the immunological significance of the porcine polytrauma model. Furthermore, the Treg subpopulation CD4+CD25+CD127− was characterized in porcine samples.
Widespread persistent inactivity makes continued efforts in physical activity promotion a persistent challenge. The precise content of physical activity recommendations is not broadly known, and there are concerns that the general messaging of the guidelines, including the recommendations to perform at least 150 min of at least moderate intensity physical activity per week might seem unattainable for and even actually discourage currently inactive people. Here we show that there are a myriad of ways of being physically active, and provide (in part) out-of-the-box examples of evidence based, pragmatic, easily accessible physical activity regimes below 150 min and/or with lower than moderate intensity that yield meaningful health benefits for currently inactive people.
HuR plays an important role in tumor cell survival mainly through posttranscriptional upregulation of prominent anti-apoptotic genes. In addition, HuR can inhibit the translation of pro-apoptotic factors as we could previously report for caspase-2. Here, we investigated the mechanisms of caspase-2 suppression by HuR and its contribution to chemotherapeutic drug resistance of colon carcinoma cells. In accordance with the significant drug-induced increase in cytoplasmic HuR abundance, doxorubicin and paclitaxel increased the interaction of cytoplasmic HuR with the 5ʹuntranslated region (5ʹUTR) of caspase-2 as shown by RNA pull down assay. Experiments with bicistronic reporter genes furthermore indicate the presence of an internal ribosome entry site (IRES) within the caspase-2-5ʹUTR. Luciferase activity was suppressed either by chemotherapeutic drugs or ectopic expression of HuR. IRES-driven luciferase activity was significantly increased upon siRNA-mediated knockdown of HuR implicating an inhibitory effect of HuR on caspase-2 translation which is further reinforced by chemotherapeutic drugs. Comparison of RNA-binding affinities of recombinant HuR to two fragments of the caspase-2-5ʹUTR by EMSA revealed a critical HuR-binding site residing between nucleotides 111 and 241 of caspase-2-5ʹUTR. Mapping of critical RNA binding domains within HuR revealed that a fusion of RNA recognition motif 2 (RRM2) plus the hinge region confers a full caspase-2-5ʹUTR-binding. Functionally, knockdown of HuR significantly increased the sensitivity of colon cancer cells to drug-induced apoptosis. Importantly, the apoptosis sensitizing effects by HuR knockdown were rescued after silencing of caspase-2. The negative caspase-2 regulation by HuR offers a novel therapeutic target for sensitizing colon carcinoma cells to drug-induced apoptosis.
Background: The aim of this study was to investigate the acceptance and assessment of work shadowing carried out by students and dentists in dental practices. Furthermore, the extent to which students perceive an improvement in their specialised, communication and social competencies, was to be examined.
Methods: 61 dental students in their clinical semesters at a German university participated in work shadowing placements at 27 different general dental practices. Before beginning, they received checklists of various competencies that they self-assessed using school grades (from 1 = "very good", to 6 = "failed"), which they also repeated after completion. The dentists supplemented this with their external assessments. In addition, the students were requested to fill out a 54-item questionnaire and compose a freely-structured report after the work shadowing; the dentists filled out a questionnaire containing 16 items. The statistical analysis was carried out by means of the Friedman Test, including a post-hoc test (Bonferroni-Holm correction).
Results: The analysis showed a significant overall improvement in the students’ self-assessed competencies by 0.71* ± 0.43 grades. With an average of 0.33* ± 0.36, the dentists’ external assessment proved significantly higher than the self-assessment. The greatest improvements were perceived by the students in the areas of accounting (1.17* ± 0.77), practice organisation (1.05* ± 0.61) and dentist’s discussions (0.94* ±0.80) [*p < 0.05]. The students confirmed experiencing an expansion of knowledge, an improvement in their communication skills and indicated a high degree of satisfaction in regard to the dentists (school grade 1.58 ± 0.93). A maximum amount of satisfaction towards the work shadow students was demonstrated by the dentists, and this form of teaching was assessed with a school grade of 1.69 ± 0.89.
Conclusion: Both students and dental practitioners demonstrated a high level of satisfaction in regard to the work shadowing. The students felt their knowledge had increased, viewed the dentists as motivating role models and acknowledged a significant improvement in their specialised, communication and social competencies. Work shadowing in dental teaching practices presents a sensible addition to academic teaching at a university.
Immune-modulating therapy is a promising therapy for patients with cholangiocarcinoma (CCA). Microsatellite instability (MSI) might be a favorable predictor for treatment response, but comprehensive data on the prevalence of MSI in CCA are missing. The aim of the current study was to determine the prevalence of MSI in a German tertiary care hospital. Formalin-fixed paraffin-embedded tissue samples, obtained in the study period from 2007 to 2015 from patients with CCA undergoing surgical resection with curative intention at Johann Wolfgang Goethe University hospital, were examined. All samples were investigated immunohistochemically for the presence of MSI (expression of MLH1, PMS2, MSH2, and MSH6) as well as by pentaplex polymerase chain reaction for five quasimonomorphic mononucleotide repeats (BAT-25, BAT-26, NR-21, NR-22, and NR-24). In total, 102 patients were included, presenting intrahepatic (n = 35, 34.3%), perihilar (n = 42, 41.2%), and distal CCA (n = 25, 24.5%). In the immunohistochemical analysis, no loss of expression of DNA repair enzymes was observed. In the PCR-based analysis, one out of 102 patients was found to be MSI-high and one out of 102 was found to be MSI-low. Thus, MSI seems to appear rarely in CCA in Germany. This should be considered when planning immune-modulating therapy trials for patients with CCA.
Dysregulation of blood sphingolipids is an emerging topic in clinical science. The objective of this study was to determine preanalytical biases that typically occur in clinical and translational studies and that influence measured blood sphingolipid levels. Therefore, we collected blood samples from four healthy male volunteers to investigate the effect of storage conditions (time, temperature, long-term storage, freeze–thaw cycles), blood drawing (venous or arterial sampling, prolonged venous compression), and sample preparation (centrifugation, freezing) on sphingolipid levels measured by LC-MS/MS. Our data show that sphingosine 1-phosphate (S1P) and sphinganine 1-phosphate (SA1P) were upregulated in whole blood samples in a time- and temperature-dependent manner. Increased centrifugation at higher speeds led to lower amounts of S1P and SA1P. All other preanalytical biases did not significantly alter the amounts of S1P and SA1P. Further, in almost all settings, we did not detect differences in (dihydro)ceramide levels. In summary, besides time-, temperature-, and centrifugation-dependent changes in S1P and SA1P levels, sphingolipids in blood remained stable under practically relevant preanalytical conditions.
Acute graft-versus-host disease (GvHD) is still a major cause of treatment-related mortality after allogeneic stem cell transplantation. Allo-antigen recognition of donor T cells after transplantation account for the onset and persistence of this disease. MicroRNAs (miRNAs) are molecular regulators involved in numerous processes during T-cell development, homeostasis, and activation. Thus, miRNAs also contribute to pathological T-cell function during GvHD. Given their capacity of fine-tuning T-cell function, miRNAs have emerged as promising therapeutic targets to curtail acute GvHD, but simultaneously maintain T-cell-mediated graft-versus-tumor effects. Here, we review the role of key miRNAs contributing to the pathophysiology of GvHD. We focus on those miRNAs acting in T cells and for which a role in GvHD has been established in preclinical models. Finally, we provide an outlook for clinical application of this new therapeutic target for GvHD prevention and treatment.
Background: Bradykinin-mediated angioedema (Bk-AE) can be life-threatening and requires specific targeted therapies. Knowledge of its epidemiology may help optimize its management.
Methods: We systematically searched the medical literature to identify abstracts of interest indexed between 1948 and March, 2016. We used published national survey data on the proportion of the population treated with angiotensin-converting enzyme inhibitors (ACEI) to derive estimates of the population prevalence of ACEI-AE in the USA, Germany and France. For hereditary angioedema (C1-INH-HAE) and C1-inhibitor related acquired angioedema (C1-INH-AAE), publications had to contain original epidemiologic data collection within a defined geographical area. Hereditary angioedema with normal C1-INH was not included in the analysis due to lack of clearly defined criteria.
Results: We identified 4 relevant publications on the prevalence of ACEI-AE, 6 on the prevalence of C1-INH-HAE, and 1 on the prevalence of C1-INH-AAE. The 1st year cumulative incidence of ACEI-AE was estimated to vary between 0.12 (population-based analyses) and 0.30 (meta-analyses of clinical trials) per 100 patient-years. The population prevalence of ACEI-AE was modeled to vary between 7 and 26 in 100,000. The prevalence of C1-INH-HAE was estimated to vary between 1.1 and 1.6 per 100,000. The prevalence of C1-INH-AAE was estimated to be 0.15 per 100,000 in one epidemiological investigation of AAE in Denmark.
Conclusions: Epidemiological evidence on Bk-AE is limited to North America and Europe. ACEI-AE is more common than C1-INH-HAE (~ 10:1), which is more common than C1-INH-AAE (~ 10:1). More studies are needed to comprehensively assess the epidemiological burden of Bk-AE.
Single nucleotide polymorphism (SNP) rs738409 C>G in the patatin‐like phospholipase domain containing 3 (PNPLA3) gene results in an amino acid exchange from isoleucin to methionine at position I148M of PNPLA3. The expression of this loss‐of‐function mutation leads to impaired hepatocellular triglyceride hydrolysis and is associated with the development of liver steatosis, fibrosis, and hepatocellular carcinoma. In contrast to these well‐established associations, the relationship of the PNPLA3 rs738409 variant with other metabolic traits is incompletely understood. We therefore assessed the association of the PNPLA3 rs738409 genotype with relevant metabolic traits in a prospective study of patients at high risk for cardiovascular events, i.e., patients undergoing coronary angiography. In a total of 270 patients, known associations of the PNPLA3 rs738409 GG genotype with nonalcoholic steatohepatitis and liver fibrosis were confirmed. In addition, we found an association of the PNPLA3 rs738409 G allele with the presence of diabetes (22% versus 28% versus 58% for CC versus CG versus GG genotype, respectively; P = 0.02). In contrast to its association with nonalcoholic fatty liver disease, liver fibrosis, and diabetes, the minor G allele of PNPLA3 rs738409 was inversely associated with total serum cholesterol and low‐density lipoprotein serum levels (P = 0.003 and P = 0.02, respectively). Finally, there was a trend toward an inverse association between the presence of the PNPLA3 rs738409 G allele and significant coronary heart disease. Comparable trends were observed for the transmembrane 6 superfamily member 2 (TM6SF2) 167 K variant, but the sample size was too small to evaluate this rarer variant. Conclusion: The PNPLA3 rs738409 G allele is associated with liver disease but also with a relatively benign cardiovascular risk profile.
Background: Immigration has a strong impact on the development of health systems, medicine and science worldwide. Therefore, this article provides a descriptive study on the overall research output.
Methods: Utilizing the scientific database Web of Science, data research was performed. The gathered bibliometric data was analyzed using the established platform NewQIS, a benchmarking system to visualize research quantity and quality indices.
Findings: Between 1900 and 2016 a total of 6763 articles on immigration were retrieved and analyzed. 86 different countries participated in the publications. Quantitatively the United States followed by Canada and Spain were prominent regarding the article numbers. On comparing by additionally taking the population size into account, Israel followed by Sweden and Norway showed the highest performance. The main releasing journals are the Public Health Reports, the Journal of Immigrant and Minority Health and Social Science & Medicine. Over the decades, an increasing number of Public, Environmental & Occupational Health articles can be recognized which finally forms the mainly used subject area.
Conclusion: Considerably increasing scientific work on immigration cannot only be explained by the general increase of scientific work but is also owed to the latest development with increased mobility, worldwide crises and the need of flight and migration. Especially countries with a good economic situation are highly affected by immigrants and prominent in their publication output on immigration, since the countries’ publication effort is connected with the appointed expenditures for research and development. Remarkable numbers of immigrants throughout Europe compel medical professionals to consider neglected diseases, requires the public health system to restructure itself and finally promotes science.
The HCV NS5A protein plays multiple roles during viral replication, including viral genome replication and virus particle assembly. The crystal structures of the NS5A N-terminal domain indicated the potential existence of the NS5A dimers formed via at least two or more distinct dimeric interfaces. However, it is unknown whether these different forms of NS5A dimers are involved in its numerous functions. To address this question, we mutated the residues lining the two different NS5A dimer interfaces and determined their effects on NS5A self-interaction, NS5A-cyclophilin A (CypA) interaction, HCV RNA replication and infectious virus production. We found that the mutations targeting either of two dimeric interfaces disrupted the NS5A self-interaction in cells. The NS5A dimer-interrupting mutations also inhibited both viral RNA replication and infectious virus production with some genotypic differences. We also determined that reduced NS5A self-interaction was associated with altered NS5A-CypA interaction, NS5A hyperphosphorylation and NS5A subcellular localization, providing the mechanistic bases for the role of NS5A self-interaction in multiple steps of HCV replication. The NS5A oligomers formed via different interfaces are likely its functional form, since the residues at two different dimeric interfaces played similar roles in different aspects of NS5A functions and, consequently, HCV replication. In conclusion, this study provides novel insight into the functional significance of NS5A self-interaction in different steps of the HCV replication, potentially, in the form of oligomers formed via multiple dimeric interfaces.
In several tumor entities, transketolase-like protein 1 (TKTL1) has been suggested to promote the nonoxidative part of the pentose phosphate pathway (PPP) and thereby to contribute to a malignant phenotype. However, its role in glioma biology has only been sparsely documented. In the present in vitro study using LNT-229 glioma cells, we analyzed the impact of TKTL1 gene suppression on basic metabolic parameters and on survival following oxygen restriction and ionizing radiation. TKTL1 was induced by hypoxia and by hypoxia-inducible factor-1α (HIF-1α). Knockdown of TKTL1 via shRNA increased the cells’ demand for glucose, decreased flux through the PPP and promoted cell death under hypoxic conditions. Following irradiation, suppression of TKTL1 expression resulted in elevated levels of reactive oxygen species (ROS) and reduced clonogenic survival. In summary, our results indicate a role of TKTL1 in the adaptation of tumor cells to oxygen deprivation and in the acquisition of radioresistance. Further studies are necessary to examine whether strategies that antagonize TKTL1 function will be able to restore the sensitivity of glioma cells towards irradiation and antiangiogenic therapies in the more complex in vivo environment.
Cardiac sarcoidosis is a rare immunologic disease causing heart involvement in 5% of patients. Cardiac sarcoidosis may manifest clinically as a cardiomyopathy with impaired left ventricular (LV) function or as tachyarrhythmias or bradyarrhythmias. On autopsy, cardiac granulomas can be found in approximately 25% of patients. The most common location for granulomas and scars is the LV free wall, followed by the intraventricular septum, often with involvement of the conduction system. ...
Tubulogenesis is essential for the formation and function of internal organs. One such organ is the trachea, which allows gas exchange between the external environment and the lungs. However, the cellular and molecular mechanisms underlying tracheal tube development remain poorly understood. Here, we show that the potassium channel KCNJ13 is a critical modulator of tracheal tubulogenesis. We identify Kcnj13 in an ethylnitrosourea forward genetic screen for regulators of mouse respiratory organ development. Kcnj13 mutants exhibit a shorter trachea as well as defective smooth muscle (SM) cell alignment and polarity. KCNJ13 is essential to maintain ion homeostasis in tracheal SM cells, which is required for actin polymerization. This process appears to be mediated, at least in part, through activation of the actin regulator AKT, as pharmacological increase of AKT phosphorylation ameliorates the Kcnj13-mutant trachea phenotypes. These results provide insight into the role of ion homeostasis in cytoskeletal organization during tubulogenesis.
Background: Most smokers start smoking during their early adolescence, often with the idea that smoking is glamorous. Interventions that harness the broad availability of mobile phones as well as adolescents' interest in their appearance may be a novel way to improve school-based prevention. A recent study conducted in Germany showed promising results. However, the transfer to other cultural contexts, effects on different genders, and implementability remains unknown.
Objective: In this observational study, we aimed to test the perception and implementability of facial-aging apps to prevent smoking in secondary schools in Brazil in accordance with the theory of planned behavior and with respect to different genders.
Methods: We used a free facial-aging mobile phone app ("Smokerface") in three Brazilian secondary schools via a novel method called mirroring. The students’ altered three-dimensional selfies on mobile phones or tablets and images were "mirrored" via a projector in front of their whole grade. Using an anonymous questionnaire, we then measured on a 5-point Likert scale the perceptions of the intervention among 306 Brazilian secondary school students of both genders in the seventh grade (average age 12.97 years). A second questionnaire captured perceptions of medical students who conducted the intervention and its conduction per protocol.
Results: The majority of students perceived the intervention as fun (304/306, 99.3%), claimed the intervention motivated them not to smoke (289/306, 94.4%), and stated that they learned new benefits of not smoking (300/306, 98.0%). Only a minority of students disagreed or fully disagreed that they learned new benefits of nonsmoking (4/306, 1.3%) or that they themselves were motivated not to smoke (5/306, 1.6%). All of the protocol was delivered by volunteer medical students.
Conclusions: Our data indicate the potential for facial-aging interventions to reduce smoking prevalence in Brazilian secondary schools in accordance with the theory of planned behavior. Volunteer medical students enjoyed the intervention and are capable of complete implementation per protocol.
Allogeneic hematopoietic stem cell transplantation (allo-HSCT) offers potential cure to acute myeloid leukemia (AML) patients. However, infections with commensal bacteria are an important cause for non-relapse mortality (NRM). We have previously described the impact of multidrug-resistant organism (MDRO) colonization on the survival of allo-HSCT patients. In the aforementioned publication, according to consensus, we there did not consider the opportunistic gram-negative bacterium Stenotrophomonas maltophilia (S. maltophilia) to be an MDRO. Since rate of S. maltophilia colonization is increasing, and it is not known whether this poses a risk for allo-HSCT patients, we here analyzed here its effect on the previously described and now extended patient cohort. We report on 291 AML patients undergoing allo-HSCT. Twenty of 291 patients (6.9%) were colonized with S. maltophilia. Colonized patients did not differ from non-colonized patients with respect to their age, remission status before allo-HSCT, donor type and HSCT-comorbidity index. S. maltophilia colonized patients had a worse overall survival (OS) from 6 months up to 60 months (85% vs. 88.1% and 24.7% vs. 59.7%; p = 0.007) due to a higher NRM after allo-HSCT (6 months: 15% vs. 4.8% and 60 months: 40.1% vs. 16.2% p = 0.003). The main cause of mortality in colonized patients was infection (46.2% of all deaths) and in non-colonized patients relapse (58.8% of all deaths). 5/20 colonized patients developed an invasive infection with S. maltophilia. The worse OS after allo-HSCT due to higher infection related mortality might implicate the screening of allo-HSCT patients for S. maltophilia and a closer observation of colonized patients as outpatients.
While interleukin (IL)-1β is a potent pro-inflammatory cytokine involved in host defense, high levels can cause life-threatening sterile inflammation including systemic inflammatory response syndrome. Hence, the control of IL-1β secretion is of outstanding biomedical importance. In response to a first inflammatory stimulus such as lipopolysaccharide, pro-IL-1β is synthesized as a cytoplasmic inactive pro-form. Extracellular ATP originating from injured cells is a prototypical second signal for inflammasome-dependent maturation and release of IL-1β. The human anti-protease alpha-1 antitrypsin (AAT) and IL-1β regulate each other via mechanisms that are only partially understood. Here, we demonstrate that physiological concentrations of AAT efficiently inhibit ATP-induced release of IL-1β from primary human blood mononuclear cells, monocytic U937 cells, and rat lung tissue, whereas ATP-independent IL-1β release is not impaired. Both, native and oxidized AAT are active, suggesting that the inhibition of IL-1β release is independent of the anti-elastase activity of AAT. Signaling of AAT in monocytic cells involves the lipid scavenger receptor CD36, calcium-independent phospholipase A2β, and the release of a small soluble mediator. This mediator leads to the activation of nicotinic acetylcholine receptors, which efficiently inhibit ATP-induced P2X7 receptor activation and inflammasome assembly. We suggest that AAT controls ATP-induced IL-1β release from human mononuclear blood cells by a novel triple-membrane-passing signaling pathway. This pathway may have clinical implications for the prevention of sterile pulmonary and systemic inflammation.
Effect of progesterone on Smad signaling and TGF-β/Smad-regulated genes in lung epithelial cells
(2018)
The effect of endogenous progesterone and/or exogenous pre- or postnatal progesterone application on lung function of preterm infants is poorly defined. While prenatal progesterone substitution may prevent preterm birth, in vitro and in vivo data suggest a benefit of postnatal progesterone replacement on the incidence and severity of bronchopulmonary dysplasia (BPD). However, the molecular mechanisms responsible for progesterone’s effects are undefined. Numerous factors are involved in lung development, airway inflammation, and airway remodeling: the transforming growth factor beta (TGF-β)/mothers against decapentaplegic homolog (Smad) signaling pathway and TGF-β-regulated genes, such as connective tissue growth factor (CTGF), transgelin (TAGLN), and plasminogen activator inhibitor-1 (PAI-1). These processes contribute to the development of BPD. The aim of the present study was to clarify whether progesterone could affect TGF-β1-activated Smad signaling and CTGF/transgelin/PAI-1 expression in lung epithelial cells. The pharmacological effect of progesterone on Smad signaling was investigated using a TGF-β1-inducible luciferase reporter and western blotting analysis of phosphorylated Smad2/3 in A549 lung epithelial cells. The regulation of CTGF, transgelin, and PAI-1 expression by progesterone was studied using a promoter-based luciferase reporter, quantitative real-time PCR, and western blotting in the same cell line. While progesterone alone had no direct effect on Smad signaling in lung epithelial cells, it dose-dependently inhibited TGF-β1-induced Smad3 phosphorylation, as shown by luciferase assays and western blotting analysis. Progesterone also antagonized the TGF-β1/Smad-induced upregulation of CTGF, transgelin, and PAI-1 at the promoter, mRNA, and/or protein levels. The present study highlights possible new molecular mechanisms involving progesterone, including inhibition of TGF-β1-activated Smad signaling and TGF-β1-regulated genes involved in BPD pathogenesis, which are likely to attenuate the development of BPD by inhibiting TGF-β1-mediated airway remodeling. Understanding these mechanisms might help to explain the effects of pre- or postnatal application of progesterone on lung diseases of preterm infants.
This study was designed to characterize morphologic stages during neuroma development post amputation with an eye toward developing better treatment strategies that intervene before neuromas are fully formed. Right forelimbs of 30 Sprague Dawley rats were amputated and limb stumps were collected at 3, 7, 28, 60 and 90 Days Post Amputation (DPA). Morphology of newly formed nerves and neuromas were assessed via general histology and neurofilament protein antibody staining. Analysis revealed six morphological characteristics during nerve and neuroma development; 1) normal nerve, 2) degenerating axons, 3) axonal sprouts, 4) unorganized bundles of axons, 5) unorganized axon growth into muscles, and 6) unorganized axon growth into fibrotic tissue (neuroma). At early stages (3 & 7 DPA) after amputation, normal nerves could be identified throughout the limb stump and small areas of axonal sprouts were present near the site of injury. Signs of degenerating axons were evident from 7 to 90 DPA. From day 28 on, variability of nerve characteristics with signs of unorganized axon growth into muscle and fibrotic tissue and neuroma formation became visible in multiple areas of stump tissue. These pathological features became more evident on days 60 and 90. At 90 DPA frank neuroma formation was present in all stump tissue. By following nerve regrowth and neuroma formation after amputation we were able to identify 6 separate histological stages of nerve regrowth and neuroma development. Axonal regrowth was observed as early as 3 DPA and signs of unorganized axonal growth and neuroma formation were evident by 28 DPA. Based on these observations we speculate that neuroma treatment and or prevention strategies might be more successful if targeted at the initial stages of development and not after 28 DPA.
Background and aims: Expression of carbonic anhydrase IX (CA9), an enzyme expressed in response to hypoxia, acidosis and oncogenic alterations, is reported to be a prognostic factor in HCC patients. Here we evaluated serum CA9 levels in HCC and cirrhosis patients.
Methods: HCC and cirrhosis patients were prospectively recruited and CA9 levels were determined. CA9 levels were compared to stages of cirrhosis and HCC stages. The association of the CA9 levels and overall survival (OS) was assessed. Furthermore, immunohistochemical CA9 expression in HCC and cirrhosis was evaluated.
Results: 215 patients with HCC were included. The median serum CA9 concentration in patients with HCC was 370 pg/ml and significantly higher than in a healthy cohort. Patients with advanced cancer stages (BCLC and ALBI score) had hid significant higher levels of CA9 in the serum. HCC patients with high serum CA9 concentrations (>400 pg/ml) had an increased mortality risk (hazard ratio (HR) 1.690, 95% confidence interval (CI) 1.017–2.809, P = 0.043). Serum CA9 concentration in cirrhotic patients did not differ significantly from HCC patients. Higher CA9 levels in cirrhotic patients correlated with portal hypertension and esophageal varices. Patients with ethanol induced cirrhosis had the highest CA9 levels in both cohorts. Levels of CA9 did not correlate with immunohistochemical expression.
Conclusions: We conclude that a high CA9 level is a possible prognostic indicator for a poor outcome in HCC patients. The high CA9 levels are probably mainly associated with portal hypertension. Ductular reactions might be a possible source of serum CA9.
Evoked potentials (EPs) are well established in clinical practice for diagnosis and prognosis in multiple sclerosis (MS). However, their value is limited to the assessment of their respective functional systems. Here, we used transcranial magnetic stimulation (TMS) coupled with electroencephalography (TMS-EEG) to investigate cortical excitability and spatiotemporal dynamics of TMS-evoked neural activity in MS patients. Thirteen patients with early relapsing–remitting MS (RRMS) with a median Expanded Disability Status Scale (EDSS) of 1.0 (range 0–2.5) and 16 age- and gender-matched healthy controls received single-pulse TMS of left and right primary motor cortex (L-M1 and R-M1), respectively. Resting motor threshold for L-M1 and R-M1 was increased in MS patients. Latencies and amplitudes of N45, P70, N100, P180, and N280 TMS-evoked EEG potentials (TEPs) were not different between groups, except a significantly increased amplitude of the N280 TEP in the MS group, both for L-M1 and R-M1 stimulation. Interhemispheric signal propagation (ISP), estimated from the area under the curve of TEPs in the non-stimulated vs. stimulated M1, also did not differ between groups. In summary, findings show that ISP and TEPs were preserved in early-stage RRMS, except for an exaggerated N280 amplitude. Our findings indicate that TMS-EEG is feasible in testing excitability and connectivity in cortical neural networks in MS patients, complementary to conventional EPs. However, relevance and pathophysiological correlates of the enhanced N280 will need further study.
Background: The recurrence rate in lumbar disc herniations (LDH) has been reported between 5 and 25%. There are only few data about this phenomenon that occurs within days of the initial operation. We analyse early recurrent LDH by analysis of data from the German Spine register.
Methods: Data from patients undergoing disc herniation surgery in the lumbar region were extracted from the German Spine Registry between 1st January 2012 and 31st December 2016. Patients with early recurrent LDH within days of initial surgery were separately analysed.
Results: A total of 9310 surgeries for LDH were documented in the German Spine Register. From these patients 115 (1.2%) presented an early recurrent disc surgeries within days of the initial surgery. The mean age was 70 ± 2.50 years. Most affected segment was L4/5 (47 cases, 41%), followed by L3/4 (45 cases, 39%). The most of our patients showed a normal or overweight Body Mass Index. Surgery for early recurrent LDH was associated with a high rate of incidental durotomies (20 cases, 17.6%). In 3 cases (2.6%) therapy with a lumbar drain was necessary.
Conclusions: The rate of early recurrent LDH within days of surgery is 1.2%. Age seems to be an important factor in early recurrent LDH while obesity does not. The data of the German Spine Register seems to have a reliable data collection system that can perform multicentre data analysis. The databases from this Register could be used in the future for various purposes, such as the evaluation of multicentre surgical techniques, results in patients with various surgical procedures and basic research in spine surgery.
Background: Juvenile dermatomyositis (JDM) is the most common inflammatory myopathy in childhood and a major cause of morbidity among children with pediatric rheumatic diseases. The management of JDM is very heterogeneous. The JDM working group of the Society for Pediatric Rheumatology (GKJR) aims to define consensus- and practice-based strategies in order to harmonize diagnosis, treatment and monitoring of JDM.
Methods: The JDM working group was established in 2015 consisting of 23 pediatric rheumatologists, pediatric neurologists and dermatologists with expertise in the management of JDM. Current practice patterns of management in JDM had previously been identified via an online survey among pediatric rheumatologists and neurologists. Using a consensus process consisting of online surveys and a face-to-face consensus conference statements were defined regarding the diagnosis, treatment and monitoring of JDM. During the conference consensus was achieved via nominal group technique. Voting took place using an electronic audience response system, and at least 80% consensus was required for individual statements.
Results: Overall 10 individual statements were developed, finally reaching a consensus of 92 to 100% regarding (1) establishing a diagnosis, (2) case definitions for the application of the strategies (moderate and severe JDM), (3) initial diagnostic testing, (4) monitoring and documentation, (5) treatment targets within the context of a treat-to-target strategy, (6) supportive therapies, (7) explicit definition of a treat-to-target strategy, (8) various glucocorticoid regimens, including intermittent intravenous methylprednisolone pulse and high-dose oral glucocorticoid therapies with tapering, (9) initial glucocorticoid-sparing therapy and (10) management of refractory disease.
Conclusion: Using a consensus process among JDM experts, statements regarding the management of JDM were defined. These statements and the strategies aid in the management of patients with moderate and severe JDM.
Testicular germ cell cancer in a metastatic state is curable with a cisplatin‑based first line chemotherapy. However, 10‑15% of these patients are resistant to first line chemotherapy and are thus left with only palliative options. Immunotherapies and inhibition of angiogenesis used in multiple types of cancer; however, the molecular context of angiogenesis and immune checkpoints in the development and progression of testicular cancers is still unknown. Therefore, the present study performed tissue micro array based analysis of 84 patients with immunohistochemistry of programmed cell death protein 1 (PD‑1), programmed cell death ligand 1 (PD‑L1) and vascular endothelial growth factor receptor 2 (VEGFR2) of testicular cancer and corresponding normal appearing testis tissue, matching the results with clinical data. The results demonstrated that PD‑L1 was significantly upregulated in testicular tumors and that PD‑1 positive cells significantly infiltrated the testicular tumor when compared with normal testicular tissue. VEGFR2 was significantly upregulated in testicular cancer. It was indicated that PD‑1 expressing cytotoxic cells may require pathologic tumor vessels to pass the blood‑testis‑barrier in order to migrate into the tumor. Notably, when matching the clinical data for PD‑1, PD‑L1 and VEGFR2 there were no differences in expression in the different International Germ Cell Cancer Collaborative Group stages of non‑seminoma. These data suggested that the anti‑PD‑1/PD‑L1 immunotherapy and the anti‑angiogenic therapy, sequentially or in combination, may be a promising option in the treatment of testicular cancer.
According to embodied cognition accounts, viewing others’ facial emotion can elicit the respective emotion representation in observers which entails simulations of sensory, motor, and contextual experiences. In line with that, published research found viewing others’ facial emotion to elicit automatic matched facial muscle activation, which was further found to facilitate emotion recognition. Perhaps making congruent facial muscle activity explicit produces an even greater recognition advantage. If there is conflicting sensory information, i.e., incongruent facial muscle activity, this might impede recognition. The effects of actively manipulating facial muscle activity on facial emotion recognition from videos were investigated across three experimental conditions: (a) explicit imitation of viewed facial emotional expressions (stimulus-congruent condition), (b) pen-holding with the lips (stimulus-incongruent condition), and (c) passive viewing (control condition). It was hypothesised that (1) experimental condition (a) and (b) result in greater facial muscle activity than (c), (2) experimental condition (a) increases emotion recognition accuracy from others’ faces compared to (c), (3) experimental condition (b) lowers recognition accuracy for expressions with a salient facial feature in the lower, but not the upper face area, compared to (c). Participants (42 males, 42 females) underwent a facial emotion recognition experiment (ADFES-BIV) while electromyography (EMG) was recorded from five facial muscle sites. The experimental conditions’ order was counter-balanced. Pen-holding caused stimulus-incongruent facial muscle activity for expressions with facial feature saliency in the lower face region, which reduced recognition of lower face region emotions. Explicit imitation caused stimulus-congruent facial muscle activity without modulating recognition. Methodological implications are discussed.
Cervical spine injuries are frequent and often caused by a blunt trauma mechanism. They can have severe consequences, with a high mortality rate and a high rate of neurological lesions.Diagnosis is a three-step process: 1) risk assessment according to the history and clinical features, guided by a clinical decision rule such as the Canadian C-Spine rule; 2) imaging if needed; 3) classification of the injury according to different classification systems in the different regions of the cervical spine.The urgency of treatment is dependent on the presence of a neurological lesion and/or instability. The treatment strategy depends on the morphological criteria as defined by the classification.
Background: Conversion from calcineurin inhibitor (CNI) therapy to everolimus within 6 months after kidney transplantation improves long-term graft function but can increase the risk of mild biopsy-proven acute cellular rejection (BPAR). We performed a post-hoc analysis of histological data from a randomized trial in order to further analyze histologic information obtained from indication and protocol biopsies up to 5 years after transplantation.
Methods: Biopsy samples obtained up to 5 years post-transplant were analyzed from the randomized ZEUS study, in which kidney transplant patients were randomized at month 4.5 to switch to everolimus (n = 154) or remain on cyclosporine (CsA)-based immunosuppression (n = 146). All patients received mycophenolate and steroids.
Results: At least one investigator-initiated biopsy was undertaken in 53 patients in each group between randomization and year 5, with a mean (SD) of 2.6 (1.7) and 2.2 (1.4) biopsies per patient in the everolimus and CsA groups, respectively. In the everolimus and CsA groups, investigator-initiated biopsies showed (i) BPAR in 12.3 and 7.5% (p = 0.182) of patients, respectively, with episodes graded mild in 22/24 and 18/20 cases (ii) CsA toxicity lesions in 4.5 and 10.3% of patients (p = 0.076) (iii) antibody-mediated rejection in 0.6 and 2.7% of patients (p = 0.204), respectively.
Conclusions: This analysis of histological findings in the ZEUS study to 5 years after kidney transplantation shows no increase in antibody-mediated rejection under everolimus-based therapy with a lower rate of CNI-related toxicity compared to a conventional CsA-based regimen, and confirms the preponderance of mild BPAR seen in the main study after the early switch to CsA-free everolimus therapy.
Trial registration: ClinicalTrials.gov NCT00154310. Date of registration: September 12, 2005.
Background: Subdural hematoma (SDH) is a common disease associated with high morbidity, which is becoming more prominent due to the increasing incidence. Decision for a surgical evacuation is made depending on the clinical appearance and the volume of SDH, wherefore it is important to have a simple ‘bedside’ method to measure and compare the volume of SDH.
Objective: The aim of the study was to verify the accuracy of the simplified ABC/2 volumetric formula to determine a valuable tool for the clinical practice.
Methods: Preoperative CT-scans of 83 patients with SDHs were used for the computer-assisted volumetric measurement via BrainLab® as well as the ABC/2 volumetric measurement. A = largest length (anterior to posterior) of the SDH; B = maximum width (lateral to midline) 90° to A; C = maximum height (coronal plane or multiplication of slices) of the hematoma. These measurements were performed by two independent clinicians in a blinded fashion. Both volumes were compared by linear regression analysis of Pearson and Bland-Altman regression analysis.
Results: Among 100 SDHs, 53% were under an 47% were over 100cm3 showing a well distribution of the hematoma sizes. There was an excellent correlation between computer-assisted volumetric measurement and ABC/2 (R2 = 0.947, p<0.0001) and no undesirable deviation and trend were detected (p = 0.101; p = 0.777). A 95% tolerance region of the ratios of both methods was [0.805–1.201].
Conclusion: The ABC/2 method is a simple and fast bedside formula for the measurement of SDH volume in a timely manner without limited access through simple adaption, which may replace the computer-assisted volumetric measurement in the clinical and research area. Reason for the good accuracy seems to be the spherical form of SDH, which has a similarity to a half ellipsoid.
The taxanes are effective microtubule-stabilizing chemotherapy drugs that inhibit mitosis, induce apoptosis, and produce regression in a fraction of cancers that arise at many sites including the ovary. Novel therapeutic targets that augment taxane effects are needed to improve clinical chemotherapy response in CCNE1-amplified high grade serous ovarian cancer (HGSOC) cells. In this study, we conducted an siRNA-based kinome screen to identify modulators of mitotic progression in CCNE1-amplified HGSOC cells that may influence clinical paclitaxel response. PLK1 is overexpressed in many types of cancer, which correlates with poor prognosis. Here, we identified a novel synthetic lethal interaction of the clinical PLK1 inhibitor BI6727 and the microtubule-targeting drug paclitaxel in HGSOC cell lines with CCNE1-amplification and elucidated the underlying molecular mechanisms of this synergism. BI6727 synergistically induces apoptosis together with paclitaxel in different cell lines including a patient-derived primary ovarian cancer culture. Moreover, the inhibition of PLK1 reduced the paclitaxel-induced neurotoxicity in a neurite outgrowth assay. Mechanistically, the combinatorial treatment with BI6727/paclitaxel triggers mitotic arrest, which initiates mitochondrial apoptosis by inactivation of anti-apoptotic BCL-2 family proteins, followed by significant loss of the mitochondrial membrane potential and activation of caspase-dependent effector pathways. This conclusion is supported by data showing that BI6727/paclitaxel-co-treatment stabilizes FBW7, a component of SCF-type ubiquitin ligases that bind and regulate key modulators of cell division and growth including MCL-1 and Cyclin E. This identification of a novel synthetic lethality of PLK1 inhibitors and a microtubule-stabilizing drug has important implications for developing PLK1 inhibitor-based combination treatments in CCNE1-amplified HGSOC cells.
Background: Prolonged immunosuppression or delayed T-cell recovery may favor Epstein-Barr virus (EBV) infection or reactivation after allogeneic hematopoietic stem cell transplantation (HSCT), which can lead to post-transplant lymphoproliferative disease (PTLD) and high-grade malignant B-cell lymphoma. Cytokine-induced killer (CIK) cells with dual specific anti-tumor and virus-specific cellular immunity may be applied in this context.
Methods: CIK cells with EBV-specificity were generated from peripheral blood mononuclear cells (PBMCs), expanded in the presence of interferon-γ, anti-CD3, interleukin (IL)-2 and IL-15 and were pulsed twice with EBV consensus peptide pool. CIK cells with EBV-specificity and conventional CIK cells were phenotypically and functionally analyzed. Additionally, CIK cells with EBV-specificity were applied to a patient with EBV-related PTLD rapidly progressing to highly aggressive B-cell lymphoma on a compassionate use basis after approval and agreement by the regulatory authorities.
Results: Pre-clinical analysis showed that generation of CIK cells with EBV-specificity was feasible. In vitro cytotoxicity analyses showed increased lysis of EBV-positive target cells, enhanced proliferative capacity and increased secretion of cytolytic and proinflammatory cytokines in the presence of EBV peptide-displaying target cells. In addition, 1 week after infusion of CIK cells with EBV-specificity, the patient's highly aggressive B-cell lymphoma persistently disappeared. CIK cells with EBV-specificity remained detectable for up to 32 days after infusion and infusion did not result in acute toxicity.
Discussion: The transfer of both anti-cancer potential and T-cell memory against EBV infection provided by EBV peptide-induced CIK cells might be considered a therapy for EBV-related PTLD.
Background: Electrical stimulation (ES) has a long history of successful use in the clinical treatment of refractory, non-healing bone fractures and has recently been proposed as an adjunct to bone tissue-engineering treatments to optimize their therapeutic potential. This idea emerged from ES’s demonstrated positive effects on stem cell migration, proliferation, differentiation and adherence to scaffolds, all cell behaviors recognized to be advantageous in Bone Tissue Engineering (BTE). In previous in vitro experiments we demonstrated that direct current ES, administered daily, accelerates Mesenchymal Stem Cell (MSC) osteogenic differentiation. In the present study, we sought to define the optimal ES regimen for maximizing this pro-osteogenic effect.
Methods: Rat bone marrow-derived MSC were exposed to 100 mV/mm, 1 hr/day for three, seven, and 14 days, then osteogenic differentiation was assessed at Day 14 of culture by measuring collagen production, calcium deposition, alkaline phosphatase activity and osteogenic marker gene expression.
Results: We found that exposing MSC to ES for three days had minimal effect, while seven and 14 days resulted in increased osteogenic differentiation, as indicated by significant increases in collagen and calcium deposits, and expression of osteogenic marker genes Col1a1, Osteopontin, Osterix and Calmodulin. We also found that cells treated with ES for seven days, maintained this pro-osteogenic activity long (for at least seven days) after discontinuing ES exposure.
Discussion: This study showed that while three days of ES is insufficient to solicit pro-osteogenic effects, seven and 14 days significantly increases osteogenic differentiation. Importantly, we found that cells treated with ES for only seven days, maintained this pro-osteogenic activity long after discontinuing ES exposure. This sustained positive osteogenic effect is likely due to the enhanced expression of RunX2 and Calmodulin we observed. This prolonged positive osteogenic effect, long after discontinuing ES treatment, if incorporated into BTE treatment protocols, could potentially improve outcomes and in doing so help BTE achieve its full therapeutic potential.
Intestinal graft-versus-host disease (GvHD) is a life-threatening, inflammatory donor T cell-mediated complication of allogeneic hematopoietic stem cell transplantation (allo-HSCT). In the light of the reported efficacy of interleukin-23 (IL-23)-blockade to mitigate syngeneic intestinal inflammation in inflammatory bowel disease patients, targeting IL-23 and thereby interleukin-17a (IL-17a) producing T helper (Th17) cells as the T cell subset assumed to be mostly regulated by IL-23, has emerged as a putatively general concept to harness immune-mediated mucosal inflammation irrespective of the underlying trigger. However, the role of Th17 cells during allo-response driven colitis remains ambiguous due to a series of studies with inconclusive results. Interestingly, we recently identified granulocyte-macrophage colony-stimulating factor (GM-CSF+) T cells to be promoted by interleukin-7 (IL-7) signaling and controlled by the activating protein-1 transcription factor family member basic leucine zipper transcription factor ATF-like (BATF) as critical mediators of intestinal GvHD in mice. Given the dual role of BATF, the contribution of IL-23-mediated signaling within donor T cells and bona fide Th17 cells remains to be delineated from the regulation of GM-CSF+ T cells in the absence of BATF. Here, we found in a complete MHC class I-mismatched model that genetic inactivation of the IL-23 receptor (IL-23R) or the transcription factor retinoic acid-related orphan receptor gamma t (RORγt) within donor T cells similarly ablated Th17 cell formation in vivo but preserved the T cells’ ability to induce intestinal GvHD in a compared to wild-type controls indistinguishable manner. Importantly, RORγt-independent manifestation of intestinal GvHD was completely dependent on BATF-regulated GM-CSF+ T cells as BATF/RORγt double-deficient T cells failed to induce colitis and the antibody-mediated blockage of IL-7/IL-7R interaction and GM-CSF significantly diminished signs of intestinal GvHD elicited by RORγt-deficient donor T cells. Finally, in analogy to our murine studies, colonic RORC expression levels inversely correlated with the presence of GvHD in allo-HSCT patients. Together, this study provides a crucial example of a BATF-dependent, however, IL-23R signaling- and RORγt-, i.e., Th17 fate-independent regulation of a colitogenic T cell population critically impacting the current understanding of intestinal GvHD.
We present an open-source Python package to compute information-theoretical quantities for electroencephalographic data. Electroencephalography (EEG) measures the electrical potential generated by the cerebral cortex and the set of spatial patterns projected by the brain's electrical potential on the scalp surface can be clustered into a set of representative maps called EEG microstates. Microstate time series are obtained by competitively fitting the microstate maps back into the EEG data set, i.e., by substituting the EEG data at a given time with the label of the microstate that has the highest similarity with the actual EEG topography. As microstate sequences consist of non-metric random variables, e.g., the letters A–D, we recently introduced information-theoretical measures to quantify these time series. In wakeful resting state EEG recordings, we found new characteristics of microstate sequences such as periodicities related to EEG frequency bands. The algorithms used are here provided as an open-source package and their use is explained in a tutorial style. The package is self-contained and the programming style is procedural, focusing on code intelligibility and easy portability. Using a sample EEG file, we demonstrate how to perform EEG microstate segmentation using the modified K-means approach, and how to compute and visualize the recently introduced information-theoretical tests and quantities. The time-lagged mutual information function is derived as a discrete symbolic alternative to the autocorrelation function for metric time series and confidence intervals are computed from Markov chain surrogate data. The software package provides an open-source extension to the existing implementations of the microstate transform and is specifically designed to analyze resting state EEG recordings.
Continuous blood glucose monitoring reveals enormous circadian variations in pregnant diabetic rats
(2018)
Aim: Diabetes in pregnancy is a major burden with acute and long-term consequences. Its treatment requires adequate diagnosis and monitoring of therapy. Many experimental research on diabetes during pregnancy has been performed in rats. Recently, continuous blood glucose monitoring of non-pregnant diabetic rats revealed an increased circadian variability of blood glucose that made a single blood glucose measurement per day inappropriate to reflect glycemic status. Continuous blood glucose measurement has never been performed in pregnant rats. We wanted to perform continuous blood glucose monitoring in pregnant rats to decipher the influence of pregnancy on blood glucose in diabetic and normoglycemic status.
Methods: We used the transgenic Tet29 diabetes rat model with an inducible knock down of the insulin receptor via RNA interference upon application of doxycycline (DOX) leading to insulin resistant type II diabetes. All Tet29 rats received a HD-XG telemetry implant (Data Sciences International, USA) that measured blood glucose and activity continuously. Rats were divided into four groups and blood glucose was monitored until end of pregnancy or the corresponding period: Tet29 + DOX (diabetic) non-pregnant, Tet29 + DOX (diabetic) pregnant, Tet29 (normoglycemic) non-pregnant, Tet29 (normoglycemic) pregnant.
Results: All analyzed rats displayed a circadian variation in blood glucose concentration. Circadian variability was much more pronounced in pregnant diabetic rats than in normoglycemic pregnant rats. Pregnancy ameliorated variation in blood glucose in diabetic situation. Pregnancy continuously decreased blood glucose during normoglycemic pregnancy. Diabetic rats were less active than normoglycemic rats. We performed a calculation showing that application of continuous blood glucose measurement reduces animal numbers needed to detect a given effect in experimental setting by decreasing variability and SD.
Interpretation: Continuous blood glucose monitoring via a telemetry device in pregnant rats provides a more informative picture of the glycemic situation in comparison to single measurements. This could improve diagnosis and therapy of diabetes, decrease animal numbers within experimental settings, and add another physiological parameter (activity) to the analysis that could be helpful in testing therapeutic concepts targeting blood glucose levels and peripheral muscle function. We propose continuous glucose monitoring as a new tool for the evaluation of pregnant diabetic rats.
Oxidized phospholipids (oxPAPC) induce endothelial dysfunction and atherosclerosis. Here we show that oxPAPC induce a gene network regulating serine-glycine metabolism with the mitochondrial methylenetetrahydrofolate dehydrogenase/cyclohydrolase (MTHFD2) as a causal regulator using integrative network modeling and Bayesian network analysis in human aortic endothelial cells. The cluster is activated in human plaque material and by atherogenic lipoproteins isolated from plasma of patients with coronary artery disease (CAD). Single nucleotide polymorphisms (SNPs) within the MTHFD2-controlled cluster associate with CAD. The MTHFD2-controlled cluster redirects metabolism to glycine synthesis to replenish purine nucleotides. Since endothelial cells secrete purines in response to oxPAPC, the MTHFD2-controlled response maintains endothelial ATP. Accordingly, MTHFD2-dependent glycine synthesis is a prerequisite for angiogenesis. Thus, we propose that endothelial cells undergo MTHFD2-mediated reprogramming toward serine-glycine and mitochondrial one-carbon metabolism to compensate for the loss of ATP in response to oxPAPC during atherosclerosis.
Objective: We present the statistical analysis plan of a prespecified Tranexamic Acid for Hyperacute Primary Intracerebral Haemorrhage (TICH)-2 sub-study aiming to investigate, if tranexamic acid has a different effect in intracerebral haemorrhage patients with the spot sign on admission compared to spot sign negative patients. The TICH-2 trial recruited above 2000 participants with intracerebral haemorrhage arriving in hospital within 8 h after symptom onset. They were included irrespective of radiological signs of on-going haematoma expansion. Participants were randomised to tranexamic acid versus matching placebo. In this subgroup analysis, we will include all participants in TICH-2 with a computed tomography angiography on admission allowing adjudication of the participants’ spot sign status.
Results: Primary outcome will be the ability of tranexamic acid to limit absolute haematoma volume on computed tomography at 24 h (± 12 h) after randomisation among spot sign positive and spot sign negative participants, respectively. Within all outcome measures, the effect of tranexamic acid in spot sign positive/negative participants will be compared using tests of interaction. This sub-study will investigate the important clinical hypothesis that spot sign positive patients might benefit more from administration of tranexamic acid compared to spot sign negative patients.
Trial registration: ISRCTN93732214 (http://www.isrctn.com)
The mechanistic target of the rapamycin (mTOR) inhibitor, temsirolimus, has significantly improved the outcome of patients with renal cell carcinoma (RCC). However, development of temsirolimus-resistance limits its effect and metastatic progression subsequently recurs. Since integrin α7 (ITGA7) is speculated to promote metastasis, this investigation was designed to investigate whether temsirolimus-resistance is associated with altered ITGA7 expression in RCC cell lines and modified tumor cell adhesion and invasion. Caki-1, KTCTL-26, and A498 RCC cell lines were driven to temsirolimus-resistance by exposing them to temsirolimus over a period of 12 months. Subsequently, adhesion to human umbilical vein endothelial cells, to immobilized fibronectin, or collagen was investigated. Chemotaxis was evaluated with a modified Boyden chamber assay and ITGA7 expression by flow cytometry and western blotting. Chemotaxis significantly decreased in temsirolimus-sensitive cell lines upon exposure to low-dosed temsirolimus, but increased in temsirolimus-resistant tumor cells upon reexposure to the same temsirolimus dose. The increase in chemotaxis was accompanied by elevated ITGA7 at the cell surface membrane with simultaneous reduction of intracellular ITGA7. ITGA7 knock-down significantly diminished motility of temsirolimous-sensitive cells but elevated chemotactic activity of temsirolimus-resistant Caki-1 and KTCTL-26 cells. Therefore, ITGA7 appears closely linked to adhesion and migration regulation in RCC cells. It is postulated that temsirolimus-resistance is associated with translocation of ITGA7 from inside the cell to the outer surface. This switch forces RCC migration forward. Whether ITGA7 can serve as an important target in combatting RCC requires further investigation.
Natural Killer (NK) cells are involved in the host immune response against infections due to viral, bacterial and fungal pathogens, all of which are a significant cause of morbidity and mortality in immunocompromised patients. Since the recovery of the immune system has a major impact on the outcome of an infectious complication, there is major interest in strengthening the host response in immunocompromised patients, either by using cytokines or growth factors or by adoptive cellular therapies transfusing immune cells such as granulocytes or pathogen-specific T-cells. To date, relatively little is known about the potential of adoptively transferring NK cells in immunocompromised patients with infectious complications, although the anti-cancer property of NK cells is already being investigated in the clinical setting. This review will focus on the antimicrobial properties of NK cells and the current standing and future perspectives of generating and using NK cells as immunotherapy in patients with infectious complications, an approach which is promising and might have an important clinical impact in the future.
Early and adequate restoration of endothelial and tubular renal function is a substantial step during regeneration after ischemia reperfusion (IR) injury, occurring, e.g., in kidney transplantation, renal surgery, and sepsis. While tubular epithelial cell injury has long been of central importance, recent perception includes the renal vascular endothelium. In this regard, the fibrin cleavage product fibrinopeptide Bβ15-42 mitigate IR injury by stabilizing interendothelial junctions through its affinity to VE-cadherin. Therefore, this study focused on the effect of Bβ15-42 on post-acute physiological renal regeneration. For this, adult male C57BL/6 mice were exposed to a 30 min bilateral renal ischemia and reperfusion for 24 h or 48 h. Animals were randomized in a non-operative control group, two operative groups each treated with i.v. administration of either saline or Bβ15-42 (2.4 mg/kg) immediately prior to reperfusion. Endothelial activation and inflammatory response was attenuated in renal tissue homogenates by single application of Bβ15-42. Meanwhile, Bβ15-42 did not affect acute kidney injury markers. Regarding the angiogenetic players VEGF-A, Angiopoietin-1, Angiopoietin-2, however, we observed significant higher expressions at mRNA and trend to higher protein level in Bβ15-42 treated mice, compared to saline treated mice after 48 h of IR, thus pointing toward an increased angiogenetic activity. Similar dynamics were observed for the intermediate filament vimentin, the cytoprotective protein klotho, stathmin and the proliferation cellular nuclear antigen, which were significantly up-regulated at the same points in time. These results suggest a beneficial effect of anatomical contiguously located endothelial cells on tubular regeneration through stabilization of endothelial integrity. Therefore, it seems that Bβ15-42 represents a novel pharmacological approach in the targeted therapy of acute renal failure in everyday clinical practice.
The myocyte enhancer factor 2 (MEF2) regulates transcription in cardiac myocytes and adverse remodeling of adult hearts. Activators of G protein‐coupled receptors (GPCRs) have been reported to activate MEF2, but a comprehensive analysis of GPCR activators that regulate MEF2 has to our knowledge not been performed. Here, we tested several GPCR agonists regarding their ability to activate a MEF2 reporter in neonatal rat ventricular myocytes. The inflammatory mediator prostaglandin E2 (PGE2) strongly activated MEF2. Using pharmacological and protein‐based inhibitors, we demonstrated that PGE2 regulates MEF2 via the EP3 receptor, the βγ subunit of Gi/o protein and two concomitantly activated downstream pathways. The first consists of Tiam1, Rac1, and its effector p21‐activated kinase 2, the second of protein kinase D. Both pathways converge on and inactivate histone deacetylase 5 (HDAC5) and thereby de‐repress MEF2. In vivo, endotoxemia in MEF2‐reporter mice induced upregulation of PGE2 and MEF2 activation. Our findings provide an unexpected new link between inflammation and cardiac remodeling by de‐repression of MEF2 through HDAC5 inactivation, which has potential implications for new strategies to treat inflammatory cardiomyopathies.
Primary cilia are microtubule-based organelles that detect mechanical and chemical stimuli. Although cilia house a number of oncogenic molecules (including Smoothened, KRAS, EGFR, and PDGFR), their precise role in cancer remains unclear. We have interrogated the role of cilia in acquired and de novo resistance to a variety of kinase inhibitors, and found that, in several examples, resistant cells are distinctly characterized by an increase in the number and/or length of cilia with altered structural features. Changes in ciliation seem to be linked to differences in the molecular composition of cilia and result in enhanced Hedgehog pathway activation. Notably, manipulating cilia length via Kif7 knockdown is sufficient to confer drug resistance in drug-sensitive cells. Conversely, targeting of cilia length or integrity through genetic and pharmacological approaches overcomes kinase inhibitor resistance. Our work establishes a role for ciliogenesis and cilia length in promoting cancer drug resistance and has significant translational implications.
An early identification of sepsis patients likely to progress towards multiple organ failure is crucial in order to initiate targeted therapeutic strategies to decrease mortality. Our recent publication highlighted the greater accuracy of mid-regional proadrenomedullin (MR-proADM) compared with conventional biomarkers and clinical scores in predicting 28-day mortality in patients with initially low (≤7 points; N = 240) or moderate (8–13 points; N = 653) Sepsis-related Organ Failure Assessment (SOFA) scores, thus confirming results from smaller investigations. This additional post hoc analysis aimed to further describe the non-surviving patient population of both subgroups and identify those likely to progress towards sepsis-related multiple organ failure. ...
Einleitung: Die konventionelle Galaktografie stellte jahrzehntelang das einzige bildgebende Verfahren zur Darstellung von Milchgängen in der Brust dar. Heute verfügen wir in der Diagnostik über ein multimodales Konzept aus hochauflösendem Ultraschall, der Magnetresonanz-(MR-)Mammografie und der Duktoskopie/Galaktoskopie mit Sensitivitäten und Spezifitäten bis zu 95%. Ziel unserer Untersuchung war es, erstmalig die Tomosynthesetechnik in der Galaktografie einzusetzen und die daraus generierten synthetischen digitalen 2-D-Vollfeld-Mammografien mit der etablierten Methode der duktusorientierten Sonografie zu vergleichen. Es sollen mit beiden Methoden invasive Mammakarzinome und deren Vorstufen wie duktale Carcinoma in situ (DCIS) sowie benigne Befunde erkannt werden. Material und Methoden: Wir führten bei 5 Patientinnen mit pathologischer Mamillensekretion sowohl eine duktusorientierte Sonografie, eine kontrastmittelunterstützte Galaktografie mithilfe der Tomosynthese in 3-D sowie auch den daraus generierten synthetischen digitalen 2-D-Vollfeld-Mammografien durch. Die Auswertung der unterschiedlichen Untersuchungsmodalitäten erfolgte durch 3 in der komplementären Mammadiagnostik erfahrene Untersucher (1, 5 und 15 Jahre) und wurde mit der endgültigen Histologie korreliert. Ergebnisse: Alle 3 Untersucher beurteilten unabhängig voneinander die Bilder des duktusorientierten Ultraschalls und der kontrastmittelunterstützten Galaktografie in Tomosynthesetechnik in 3-D und den daraus generierten, synthetischen digitalen 2-D-Vollfeld-Mammografien. Die Ergebnisse wurden mit den histopathologischen Befunden der Operationspräparate korreliert, wobei sich bei den 5 Patientinnen 1 invasives Mammakarzinom, 2-mal ein duktales Carcinoma in situ (DCIS) und 2 benigne Befunde ergaben. Alle drei Untersucher lagen bei der Verdachtsdiagnose in der Standardbildgebung der duktusorientierten Sonografie seltener richtig als bei der erstmalig durchgeführten, kontrastmittelunterstützten Galaktografie in Tomosynthesetechnik und den daraus generierten, synthetischen digitalen 2-D-Vollfeld-Mammografien. Schlussfolgerung: Erstmalig wurde die Brusttomosynthese in der Galaktografie (Galaktomosynthese) eingesetzt und ermöglichte eine digitale, 3-dimensionale Darstellung von suspekten Befunden. Zusammen mit den daraus synthetisierten, digitalen 2-D-Vollfeld-Mammografien könnte dies in Zukunft eine sinnvolle Ergänzung der komplementären Mammadiagnostik sein – und eine Renaissance dieser Methode. Im Vergleich mit dem duktusorientierten Ultraschall in Hochauflösung erzielten die Untersucher mit der kontrastmittelunterstützten Galaktografie in Tomosynthesetechnik und den daraus generierten, synthetischen digitalen 2-D-Vollfeld-Mammografien bessere Ergebnisse in Korrelation mit den histopathologischen Befunden.
Introduction: For decades, conventional galactography was the only imaging technique capable of showing the mammary ducts. Today, diagnosis is based on a multimodal concept which combines high-resolution ultrasound with magnetic resonance (MR) mammography and ductoscopy/galactoscopy and has a sensitivity and specificity of up to 95%. This study used tomosynthesis in galactography for the first time and compared the synthetic digital 2D full-field mammograms generated with this technique with the images created using the established method of ductal sonography. Both methods should be able to detect invasive breast cancers and their precursors such as ductal carcinoma in situ (DCIS) as well as being able to identify benign findings.
Material and Methods: Five patients with pathological nipple discharge were examined using ductal sonography, contrast-enhanced 3D galactography with tomosynthesis and the synthetic digital 2D full-field mammograms generated with the latter method. Evaluation of the images created with the different imaging modalities was done by three investigators with varying levels of experience with complementary breast diagnostics (1, 5 and 15 years), and their evaluations were compared with the histological findings.
Results: All 3 investigators independently evaluated the images created with ductal sonography, contrast-enhanced 3D galactography with tomosynthesis, and generated synthetic digital 2D full-field mammograms. Their evaluations were compared with the histopathological assessment of the surgical specimens resected from the 5 patients. There was 1 case of invasive breast cancer, 2 cases with ductal carcinoma in situ and 2 cases with benign findings. All 3 investigators made more mistakes when they used the standard imaging technique of ductal sonography to diagnose suspicious lesions than when they used contrast-enhanced galactography with tomosynthesis and the generated synthetic digital 2D full-field mammograms.
Conclusion: This is the first time breast tomosynthesis was used in galactography (galactomosynthesis) to create digital 3-dimensional images of suspicious findings. When used together with the generated synthetic digital 2D full-field mammograms, it could be a useful complementary procedure for the diagnosis of breast anomalies and could herald a renaissance of this method. Compared with high-resolution ductal ultrasound, the investigators achieved better results with contrast-enhanced galactography using tomosynthesis and the generated synthetic digital 2D full-field mammograms, as confirmed by histopathological findings.
Background: Definite diagnosis and therapeutic management of cholangiocarcinoma (CCA) remains a challenge. The aim of the current study was to investigate feasibility and potential impact on clinical management of targeted sequencing of intraductal biopsies.
Methods: Intraductal biopsies with suspicious findings from 16 patients with CCA in later clinical course were analyzed with targeted sequencing including tumor and control benign tissue (n = 55 samples). A CCA-specific sequencing panel containing 41 genes was designed and a dual strand targeted enrichment was applied.
Results: Sequencing was successfully performed for all samples. In total, 79 mutations were identified and a mean of 1.7 mutations per tumor sample (range 0–4) as well as 2.3 per biopsy (0–6) were detected and potentially therapeutically relevant genes were identified in 6/16 cases. In 14/18 (78%) biopsies with dysplasia or inconclusive findings at least one mutation was detected. The majority of mutations were found in both surgical specimen and biopsy (68%), while 28% were only present in biopsies in contrast to 4% being only present in the surgical tumor specimen.
Conclusion: Targeted sequencing from intraductal biopsies is feasible and potentially improves the diagnostic yield. A profound genetic heterogeneity in biliary dysplasia needs to be considered in clinical management and warrants further investigation.
Translational impact: The current study is the first to demonstrate the feasibility of sequencing of intraductal biopsies which holds the potential to impact diagnostic and therapeutical management of patients with biliary dysplasia and neoplasia.
Purpose: Anastomotic leakage is a major surgical complication following esophagectomy and gastric pull-up. Specific risk factors such as celiac trunk (TC) stenosis and high calcification score of the aorta have been identified, but no data are available on their relative prognostic values. This retrospective study aimed to compare and evaluate calcification score versus stenosis quantification with regards to prognostic impact on anastomotic leakage.
Patients and methods: Preoperative contrast-enhanced computed tomography scans of 164 consecutive patients with primary esophageal cancer were evaluated by two radiologists to apply a calcification score (0–3 scale) assessing the aorta, the celiac axis and the right and left postceliac arteries. Concurrently, the presence and degree of stenosis of TC and superior mesenteric artery were recorded for stenosis quantification.
Results: Anastomotic leakage was noted in 14/164 patients and 12/14 showed stenosis of TC (n=11). The presence of TC stenosis was found to have a significant impact on anastomotic healing (p=0.004). The odds ratio for the prediction of anastomotic leakage by the degree of stenosis was 1.04 (95% CI, 1.02–1.07). Ten of 14 patients had aortic calcification scores of 1 or 2, but calcification scores of the aorta, the celiac axis and the right and left postceliac arteries did not correlate with the corresponding TC stenosis values and showed no influence on patient outcome as defined by the occurrence of anastomotic insufficiency (p=0.565, 0.855, 0.518 and 1.000, respectively). Inter-reader reliability of computed tomography analysis and absolute agreement on calcium scoring was mostly over 90%. No significant differences in preoperative comorbidities and patient characteristics were found between those with and without anastomotic leakage.
Conclusion: Measurement of TC stenosis in preoperative contrast-enhanced computed tomography scans proved to be more reliable than calcification scores in predicting anastomotic leakage and should, therefore, be used in the risk assessment of patients undergoing esophagectomy and gastric pull-up.
Purpose: All-ceramic restorations required extensive tooth preparation. The purpose of this in vitro study was to investigate a minimally invasive preparation and thickness of monolithic zirconia crowns, which would provide sufficient mechanical endurance and strength.
Materials and methods: Crowns with thickness of 0.2 mm (group 0.2, n=32) or of 0.5 mm (group 0.5, n=32) were milled from zirconia and fixed with resin-based adhesives (groups 0.2A, 0.5A) or zinc phosphate cements (groups 0.2C, 0.5C). Half of the samples in each subgroup (n=8) underwent thermal cycling and mechanical loading (TCML)(TC: 5℃ and 55℃, 2×3,000 cycles, 2 min/cycle; ML: 50 N, 1.2×106 cycles), while the other samples were stored in water (37℃/24 h). Survival rates were compared (Kaplan-Maier). The specimens surviving TCML were loaded to fracture and the maximal fracture force was determined (ANOVA; Bonferroni; α=.05). The fracture mode was analyzed.
Results: In both 0.5 groups, all crowns survived TCML, and the comparison of fracture strength among crowns with and without TCML showed no significant difference (P=.628). Four crowns in group 0.2A and all of the crowns in group 0.2C failed during TCML. The fracture strength after 24 hours of the cemented 0.2 mm-thick crowns was significantly lower than that of adhesive bonded crowns. All cemented crowns provided fracture in the crown, while about 80% of the adhesively bonded crowns fractured through crown and die.
Conclusion: 0.5 mm thick monolithic crowns possessed sufficient strength to endure physiologic performance, regardless of the type of cementation. Fracture strength of the 0.2 mm cemented crowns was too low for clinical application.
Mannan-induced Nos2 in macrophages enhances IL-17–driven psoriatic arthritis by innate lymphocytes
(2018)
Previous identification of the inducible nitric oxide synthase (NOS2) gene as a risk allele for psoriasis (Ps) and psoriatic arthritis (PsA) suggests a possible pathogenic role of nitric oxide (NO). Using a mouse model of mannan-induced Ps and PsA (MIP), where macrophages play a regulatory role by releasing reactive oxygen species (ROS), we found that NO was detectable before disease onset in mice, independent of a functional nicotinamide adenine dinucleotide phosphate oxidase 2 complex. MIP was suppressed by either deletion of Nos2 or inhibition of NO synthases with NG-nitro-L-arginine methyl ester, demonstrating that Nos2-derived NO is pathogenic. NOS2 expression was also up-regulated in lipopolysaccharide- and interferon-γ–stimulated monocyte subsets from patients with PsA compared to healthy controls. Nos2-dependent interleukin-1α (IL-1α) release from skin macrophages was essential for arthritis development by promoting IL-17 production of innate lymphoid cells. We conclude that Nos2-derived NO by tissue macrophages promotes MIP, in contrast to the protective effect by ROS.
Selective BRAF inhibitors such as vemurafenib have become a treatment option in patients with Langerhans cell Histiocytosis (LCH). To date, only 14 patients receiving vemurafenib for LCH have been reported. Although vemurafenib can stabilize the clinical condition of these patients, it does not seem to cure the patients, and it is unknown, when and how to stop vemurafenib treatment. We present a girl with severe multisystem LCH who responded only to vemurafenib. After 8 months of treatment, vemurafenib was tapered and replaced by prednisone and vinblastine, a strategy which has not been described to date. Despite chemotherapy, early relapse occurred, but remission was achieved by re-institution of vemurafenib. Further investigation needs to address the optimal duration of vemurafenib therapy in LCH and whether and which chemotherapeutic regimen may prevent disease relapse after cessation of vemurafenib.
Human papilloma virus (HPV) infection is linked to cervical cancer, which represents the world's fourth most common cancer in women. So far, no detailed map of the worldwide HPV research architecture has been constructed. Hence, this study focuses on the chronological development and geographical distribution of the global HPV-specific publications and evaluates citation-based parameters as well as socioeconomic features of the publishing countries.
In total, 29,330 HPV-related publications were identified. The US was the leading country with 12,270 publications. Only high-income-countries were found in the ranking of the fifteen most active countries with Germany, France, and Japan among the top five. Analysis of HPV research activity in relation to the economic strength demonstrated a lead position of Finland and Sweden with an average of 2248.78 and 1924.67 HPV-related publications per GDP in 1000 bn US-$, respectively. The most active upper-middle-income country was Mexico (416.78 HPV-related publications per GDP in 1000 bn US-$). India as lower-middle-income country reached a value of 279.78 HPV-related publications per GDP in 1000 bn US-$. Collaboration analysis pointed to the US as the center of the 4517 international HPV collaborations.
The worldwide HPV-research landscape is dominated by North American and Western European countries. By contrast, a high prevalence of HPV-related cervical cancer is documented for low-income countries. Hence, HPV-related public health interventions and prevention research specifically tailored to these countries needs to be fostered by monetary support and international collaborations.
Background: Sphingolipids are versatile signaling molecules derived from membrane lipids of eukaryotic cells. Ceramides regulate cellular processes such as proliferation, differentiation and apoptosis and are involved in cellular stress responses. Experimental evidence suggests a pivotal role of sphingolipids in the pathogenesis of cardiovascular diseases, including ischemic stroke. A neuroprotective effect has been shown for beta-adrenergic antagonists in rodent stroke models and supported by observational clinical data. However, the exact underlying pathophysiological mechanisms are still under investigation. We aimed to examine the influence of propranolol on the ceramide metabolism in the stroke-affected brain.
Methods: Mice were subjected to 60 or 180 min transient middle cerebral artery occlusion (tMCAO) and infarct size, functional neurological deficits, glucose tolerance, and brain ceramide levels were assessed after 12, 24, and 72 h to evaluate whether the latter two processes occur in a similar time frame. Next, we assessed the effects of propranolol (10 mg/kg bw) at 0, 4 and 8 h after tMCAO and FTY720 (fingolimod; 1 mg/kg) on infarct size, functional outcome, immune cell counts and brain ceramide levels at 24 h after 60 min tMCAO.
Results: We found a temporal coincidence between stroke-associated impaired glucose tolerance and brain ceramide accumulation. Whereas propranolol reduced ischemic lesion size, improved functional outcome and reduced brain ceramide accumulation without an effect on circulating immune cells, FTY720 showed the known neuroprotective effect and strong reduction of circulating immune cells without affecting brain ceramide accumulation.
Conclusions: Propranolol ameliorates both stroke-associated impairment of glucose tolerance and brain ceramide accumulation which are temporally linked, strengthening the evidence for a role of the sympathetic nervous system in regulating post-stroke glucose metabolism and its metabolic consequences in the brain.
5-aminoimidazole-4-carboxamide-1-β-D-ribofuranoside (AICAR) is an established pharmacological activator of AMP-activated protein kinase (AMPK). Both, AICAR and AMPK were reported to attenuate inflammation. However, AICAR is known for many AMPK-independent effects, although the mechanisms remain incompletely understood. Here we report a potent suppression of lipopolysaccharide (LPS)-induced inflammatory gene expression by AICAR in primary human macrophages, which occurred independently of its conversion to AMPK-activating 5-aminoimidazole-4-carboxamide-1-β-D-ribofuranosyl monophosphate. Although AICAR did not interfere with activation of cytosolic signalling cascades and nuclear translocation of nuclear factor - κB (NFκB) by LPS, it prevented the recruitment of NFκB and RNA polymerase II to target gene promoters. AICAR also inhibited signal transducer and activator of transcription 3 (STAT3)-dependent induction of interleukin (IL) IL-6 and IL-10 targets, while leaving STAT6 and HIF1α-dependent gene expression in IL-4 and dimethyloxalylgylcine-treated macrophages intact. This points to a transcription factor-specific mode of action. Attenuated gene expression correlated with impaired NFκB and STAT3, but not HIF-binding in electrophoretic mobility shift assays in vitro. Conclusively, AICAR interferes with DNA binding of NFκB and STAT3 to modulate inflammatory responses.
Inducible gene expression is an important tool in molecular biology research to study protein function. Most frequently, the antibiotic doxycycline is used for regulation of so-called tetracycline (Tet)-inducible systems. In contrast to stable gene overexpression, these systems allow investigation of acute and reversible effects of cellular protein induction. Recent reports have already called for caution when using Tet-inducible systems as the employed antibiotics can disturb mitochondrial function and alter cellular metabolism by interfering with mitochondrial translation. Reprogramming of energy metabolism has lately been recognized as an important emerging hallmark of cancer and is a central focus of cancer research. Therefore, the scope of this study was to systematically analyze dose-dependent metabolic effects of doxycycline on a panel of glioma cell lines with concomitant monitoring of gene expression from Tet-inducible systems. We report that doxycycline doses commonly used with inducible expression systems (0.01–1 µg/mL) substantially alter cellular metabolism: Mitochondrial protein synthesis was inhibited accompanied by reduced oxygen and increased glucose consumption. Furthermore, doxycycline protected human glioma cells from hypoxia-induced cell death. An impairment of cell growth was only detectable with higher doxycycline doses (10 µg/mL). Our findings describe settings where doxycycline exerts effects on eukaryotic cellular metabolism, limiting the employment of Tet-inducible systems.
Sphingosine kinase (SK) catalyses the formation of sphingosine 1-phosphate (S1P), which acts as a key regulator of inflammatory and fibrotic reactions, mainly via S1P receptor activation. Here, we show that in the human renal proximal tubular epithelial cell line HK2, the profibrotic mediator transforming growth factor β (TGFβ) induces SK-1 mRNA and protein expression, and in parallel, it also upregulates the expression of the fibrotic markers connective tissue growth factor (CTGF) and fibronectin. Stable downregulation of SK-1 by RNAi resulted in the increased expression of CTGF, suggesting a suppressive effect of SK-1-derived intracellular S1P in the fibrotic process, which is lost when SK-1 is downregulated. In a further approach, the S1P transporter Spns2, which is known to export S1P and thereby reduces intracellular S1P levels, was stably downregulated in HK2 cells by RNAi. This treatment decreased TGFβ-induced CTGF and fibronectin expression, and it abolished the strong induction of the monocyte chemotactic protein 1 (MCP-1) by the pro-inflammatory cytokines tumor necrosis factor (TNF)α and interleukin (IL)-1β. Moreover, it enhanced the expression of aquaporin 1, which is an important water channel that is expressed in the proximal tubules, and reverted aquaporin 1 downregulation induced by IL-1β/TNFα. On the other hand, overexpression of a Spns2-GFP construct increased S1P secretion and it resulted in enhanced TGFβ-induced CTGF expression. In summary, our data demonstrate that in human renal proximal tubular epithelial cells, SK-1 downregulation accelerates an inflammatory and fibrotic reaction, whereas Spns2 downregulation has an opposite effect. We conclude that Spns2 represents a promising new target for the treatment of tubulointerstitial inflammation and fibrosis.
Borrelia burgdorferi sensu lato (Bbsl), the causative agent of Lyme disease, establishes an initial infection in the host’s skin following a tick bite, and then disseminates to distant organs, leading to multisystem manifestations. Tick-to-vertebrate host transmission requires that Bbsl survives during blood feeding. Complement is an important innate host defense in blood and interstitial fluid. Bbsl produces a polymorphic surface protein, CspA, that binds to a complement regulator, Factor H (FH) to block complement activation in vitro. However, the role that CspA plays in the Bbsl enzootic cycle remains unclear. In this study, we demonstrated that different CspA variants promote spirochete binding to FH to inactivate complement and promote serum resistance in a host-specific manner. Utilizing a tick-to-mouse transmission model, we observed that a cspA-knockout B. burgdorferi is eliminated from nymphal ticks in the first 24 hours of feeding and is unable to be transmitted to naïve mice. Conversely, ectopically producing CspA derived from B. burgdorferi or B. afzelii, but not B. garinii in a cspA-knockout strain restored spirochete survival in fed nymphs and tick-to-mouse transmission. Furthermore, a CspA point mutant, CspA-L246D that was defective in FH-binding, failed to survive in fed nymphs and at the inoculation site or bloodstream in mice. We also allowed those spirochete-infected nymphs to feed on C3-/- mice that lacked functional complement. The cspA-knockout B. burgdorferi or this mutant strain complemented with cspA variants or cspA-L246D was found at similar levels as wild type B. burgdorferi in the fed nymphs and mouse tissues. These novel findings suggest that the FH-binding activity of CspA protects spirochetes from complement-mediated killing in fed nymphal ticks, which ultimately allows Bbsl transmission to mammalian hosts.
Epithelial-to-mesenchymal transition (EMT) is supposed to be responsible for increased invasion and metastases in epithelial cancer cells. The activation of EMT genes has further been proposed to be important in the process of malignant transformation of primary CNS tumors. Since the cellular source and clinical impact of EMT factors in primary CNS tumors still remain unclear, we aimed at deciphering their distribution in vivo and clinico-pathological relevance in human gliomas.
We investigated 350 glioma patients for the expression of the key EMT factors SLUG and TWIST by immunohistochemistry and immunofluorescence related to morpho-genetic alterations such as EGFR-amplification, IDH-1 (R132H) mutation and 1p/19q LOH. Furthermore, transcriptional cluster and survival analyses were performed.
Our data illustrate that SLUG and TWIST are overexpressed in gliomas showing vascular proliferation such as pilocytic astrocytomas and glioblastomas. EMT factors are exclusively expressed by non-neoplastic pericytes/vessel-associated mural cells (VAMCs). They are not associated with patient survival but correlate with pericytic/VAMC genes in glioblastoma cluster analysis.
In summary, the upregulation of EMT genes in pilocytic astrocytomas and glioblastomas reflects the level of activation of pericytes/VAMCs in newly formed blood vessels. Our results underscore that the negative prognostic potential of the EMT signature in the group of diffuse gliomas of WHO grade II-IV does most likely not derive from glioma cells but rather reflects the degree of proliferating mural cells thereby constituting a potential target for future alternative treatment approaches.
The spindle assembly checkpoint (SAC) acts as a molecular safeguard in ensuring faithful chromosome transmission during mitosis, which is regulated by a complex interplay between phosphatases and kinases including PLK1. Adenomatous polyposis coli (APC) germline mutations cause aneuploidy and are responsible for familial adenomatous polyposis (FAP). Here we study the role of PLK1 in colon cancer cells with chromosomal instability promoted by APC truncation (APC-ΔC). The expression of APC-ΔC in colon cells reduces the accumulation of mitotic cells upon PLK1 inhibition, accelerates mitotic exit and increases the survival of cells with enhanced chromosomal abnormalities. The inhibition of PLK1 in mitotic, APC-∆C-expressing cells reduces the kinetochore levels of Aurora B and hampers the recruitment of SAC component suggesting a compromised mitotic checkpoint. Furthermore, Plk1 inhibition (RNAi, pharmacological compounds) promotes the development of adenomatous polyps in two independent ApcMin/+ mouse models. High PLK1 expression increases the survival of colon cancer patients expressing a truncated APC significantly.
Objectives: The aim of this multicenter retrospective study was to investigate safety and efficacy of direct acting antiviral (DAA) treatment in the rare subgroup of patients with HCV/HIV-coinfection and advanced liver cirrhosis on the liver transplant waiting list or after liver transplantation, respectively.
Methods: When contacting 54 German liver centers (including all 23 German liver transplant centers), 12 HCV/HIV-coinfected patients on antiretroviral combination therapy were reported having received additional DAA therapy while being on the waiting list for liver transplantation (patient characteristics: Child-Pugh A (n = 6), B (n = 5), C (n = 1); MELD range 7–21; HCC (n = 2); HCV genotype 1a (n = 8), 1b (n = 2), 4 (n = 2)). Furthermore, 2 HCV/HIV-coinfected patients were denoted having received DAA therapy after liver transplantation (characteristics: HCV genotype 1a (n = 1), 4 (n = 1)).
Results: Applied DAA regimens were SOF/DAC (n = 7), SOF/LDV/RBV (n = 3), SOF/RBV (n = 3), PTV/r/OBV/DSV (n = 1), or PTV/r/OBV/DSV/RBV (n = 1), respectively. All patients achieved SVR 12, in the end. In one patient, HCV relapse occurred after 24 weeks of SOF/DAC therapy; subsequent treatment with 12 weeks PTV/r/OBV/DSV achieved SVR 12. One patient underwent liver transplantation while on DAA treatment. Analysis of liver function revealed either stable parameters or even significant improvement during DAA therapy and in follow-up. MELD scores were found to improve in 9/13 therapies in patients on the waiting list for liver transplantation; in only 2 patients a moderate increase of MELD scores persisted at the end of follow-up.
Conclusion: DAA treatment was safe and highly effective in this nation-wide cohort of patients with HCV/HIV-coinfection awaiting liver transplantation or being transplanted.
Purpose: Stereotactic radiosurgery (SRS) is an established primary treatment for newly diagnosed brain metastases with high local control rates. However, data about local re-irradiation in case of local failure after SRS (re-SRS) are rare. We evaluated the feasibility, efficacy and patient selection characteristics in treating locally recurrent metastases with a second course of SRS.
Methods: We retrospectively evaluated patients with brain metastases treated with re-SRS for local tumor progression between 2011 and 2017. Patient and treatment characteristics as well as rates of tumor control, survival and toxicity were analyzed.
Results: Overall, 32 locally recurrent brain metastases in 31 patients were irradiated with re-SRS. Median age at re-SRS was 64.9 years. The primary histology was breast cancer and non-small-cellular lung cancer (NSCLC) in respectively 10 cases (31.3%), in 5 cases malignant melanoma (15.6%). In the first SRS-course 19 metastases (59.4%) and in the re-SRS-course 29 metastases (90.6%) were treated with CyberKnife® and the others with Gamma Knife. Median planning target volume (PTV) for re-SRS was 2.5 cm3 (range, 0.1–37.5 cm3) and median dose prescribed to the PTV was 19 Gy (range, 12–28 Gy) in 1–5 fractions to the median 69% isodose (range, 53–80%). The 1-year overall survival rate was 61.7% and the 1-year local control rate was 79.5%. The overall rate of radiological radio-necrosis was 16.1% and four patients (12.9%) experienced grade ≥ 3 toxicities.
Conclusions: A second course of SRS for locally recurrent brain metastases after prior local SRS appears to be feasible with acceptable toxicity and can be considered as salvage treatment option for selected patients with high performance status. Furthermore, this is the first study utilizing robotic radiosurgery for this indication, as an additional option for frameless fractionated treatment.
Indication for combined cardiac surgery and orthotopic liver transplantation is rare and patients are at high risks. Individual surgical strategy must be developed since a general standard of such procedure does not exist. We report the case of a 45-year-old woman who underwent simultaneously modified Bentall procedure and orthotopic liver transplantation. Underlying diseases were end-stage polycystic liver, aneurysm of the ascending aorta, and severe aortic regurgitation. To avoid prolonged bypass times, both teams worked simultaneously. During cardiac reperfusion, time inferior vena cava stayed ligated while the cyst liver was explanted.
Background. The placement of an implant in a previously infected site is an important etiologic factor contributing to implant failure. The aim of this case report is to present the management of retrograde peri-implantitis (RPI) in a first maxillary molar site, 2 years after the implant placement. The RPI was treated using an air-abrasive device, Er,Cr:YSGG laser, and guided bone regeneration (GBR).
Case Description. A 65-year-old Caucasian male presented with a draining fistula associated with an implant at tooth #3. Tooth #3 revealed periapical radiolucency two years before the implant placement. Tooth #3 was extracted, and a ridge preservation procedure was performed followed by implant rehabilitation. A periapical radiograph (PA) showed lack of bone density around the implant apex. The site was decontaminated with an air-abrasive device and Er,Cr:YSGG laser, and GBR was performed. The patient was seen every two weeks until suture removal, followed by monthly visits for 12 months. The periapical X-rays, from 6 to 13 months postoperatively, showed increased bone density around the implant apex, with no signs of residual clinical or radiographic pathology and probing depths ≤4 mm.
Conclusions. The etiology of RPI in this case was the placement of an implant in a previously infected site. The use of an air-abrasive device, Er,Cr:YSGG, and GBR was utilized to treat this case of RPI. The site was monitored for 13 months, and increased radiographic bone density was noted.