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Einleitung: Die chronische Hepatitis C gehört zu den häufigen Ursachen einer Leberzirrhose. Durch die Entwicklung von direkt antiviralen Medikamenten (direct acting antiviral agent, DAA) können Heilungsraten von über 90% bei chronischer Hepatitis C erreicht werden. Der Einfluss des Therapieerfolgs auf Fibroseregression und portale Hypertension ist insbesondere für Patienten mit Leberzirrhose bisher nicht ausreichend geklärt. Elastographische Messungen von Leber und Milz können als Surrogatmarker zur nicht-invasiven Evaluation von Fibroseregression und Rückgang von portaler Hypertension dienen. Ziel der vorliegenden Arbeit war die Evaluation der Dynamik von Leberfibrose und portaler Hypertension mittels transienter Elastographie der Leber (L-TE) und Acoustic Radiation Force Impulse Elastographie von Leber (L-ARFI) und Milz (M-ARFI) bei Patienten mit DAA-induziertem anhaltendem virologischen Ansprechen (sustained virological response, SVR) und Hepatitis C Virus (HCV) assoziierter Leberzirrhose.
Patienten und Methoden: In dieser prospektiven, monozentrischen Studie wurden Daten von 56 Patienten mit chronischer Hepatitis C und assoziierter Leberzirrhose analysiert, die eine SVR nach 12-24 Wochen antiviraler Hepatitis C Therapie mit DAA's erreichten. Dabei wurden zu vier Zeitpunkten (Therapiebeginn [BL], Therapieende [EOT], 24 Wochen nach Therapieende [FU24] und 48 Wochen nach Therapieende [FU48]) Messungen vorgenommen. Zusätzlich wurden Leberzirrhose assoziierte Scores und Komplikationen sowie Laborparameter erhoben.
Ergebnisse: Die elastographischen Messungen der Leber zeigten signifikante Verbesserungen im Studienverlauf, am stärksten während der antiviralen Therapie. Im L-TE zeigten sich Verbesserungen zwischen BL [Median(Min-Max), 32,45(9,1-75)kPa] und FU48[Median (Min-Max), 17,1 (3,7-59,3) kPa] (p<0,0001) und im L-ARFI zwischen BL [Median (Min-Max), 2,7 (1,2-4,1) m/s] und FU24 [Median (Min-Max), 2,5 (1,2-3,9)m/s (p=0,011), wobei signifikante Verbesserungen (≥30%) bei 35/49 (71%) Patienten im L-TE und bei 6/55 (11%) im L-ARFI auftraten. Die M-ARFI Messungen als Korrelat der portalen Hypertension, zeigten kaum Veränderungen. Die medianen Werte blieben zwischen BL [Median (Min-Max), 3,4 (1,9-4,3) m/s] und FU48 [Median (Min-Max), 3,4(2-4,4) m/s] konstant (p=0,9). Nur 2/54 (4%) der Patentien zeigten signifikante Verbesserungen. In der univariaten Analyse zeigten sich 65 als positive Einflussfaktoren der L-TE- und L-ARFI-Verbesserung ein MELD Score bis 10 sowie ein BMI bis 30 kg/m².
Diskussion und Schlussfolgerung: In Zusammenschau der Ergebnisse kann bei einem Teil der Patienten von einer Fibroseregression und dem Rückgang der portalen Hypertension nach DAA-basierter, interferon-freier antiviraler Therapie ausgegangen werden. Die mittels L-ARFI und L-TE gemessene Verbesserung der Lebersteifigkeit unter antiviraler Therapie scheint auf einer Verbesserung von Nekroinflammation und Leberfibrose zu basieren. Bei Nichtbeachtung des Einflusses der Nekroinflammation auf nicht-invasive Messungen der Lebersteifigkeit kann es zur Überschätzung der Fibroseregression nach SVR kommen. Da es sich bei der Zirrhose- bzw. Fibroseregression anscheinend um einen langsamen Prozess handelt, sind ausreichend lange Nachbeobachtungszeiten in entsprechenden Studien zu fordern. Für die mit einer Leberzirrhose assoziierte portale Hypertension gelten ähnliche Überlegungen.
We analyse statistical and information-theoretical properties of EEG microstate sequences, as seen through the lens of five different clustering algorithms. Microstate sequences are computed for n = 20 resting state EEG recordings during wakeful rest. The input for all clustering algorithms is the set of EEG topographic maps obtained at local maxima of the spatial variance. This data set is processed by two classical microstate clustering algorithms (1) atomize and agglomerate hierarchical clustering (AAHC) and (2) a modified K-means algorithm, as well as by (3) K-medoids, (4) principal component analysis (PCA) and (5) fast independent component analysis (Fast-ICA). Using this technique, EEG topographies can be substituted with microstate labels by competitive fitting based on spatial correlation, resulting in a symbolic, non-metric time series, the microstate sequence. Microstate topographies and symbolic time series are further analyzed statistically, including static and dynamic properties. Static properties, which do not contain information about temporal dependencies of the microstate sequence include the maximum similarity of microstate maps within and between the tested clustering algorithms, the global explained variance and the Shannon entropy of the microstate sequences. Dynamic properties are sensitive to temporal correlations between the symbols and include the mixing time of the microstate transition matrix, the entropy rate of the microstate sequences and the location of the first local maximum of the autoinformation function. We also test the Markov property of microstate sequences, the time stationarity of the transition matrix and detect periodicities by means of time-lagged mutual information. Finally, possible long-range correlations of microstate sequences are assessed via Hurst exponent estimation. We find that while static properties partially reflect properties of the clustering algorithms, information-theoretical quantities are largely invariant with respect to the clustering method used. As each clustering algorithm has its own profile of computational speed, ease of implementation, determinism vs. stochasticity and theoretical underpinnings, our results convey a positive message concerning the free choice of method and the comparability of results obtained from different algorithms. The invariance of these quantities implies that the tested properties are algorithm-independent, inherent features of resting state EEG derived microstate sequences.
AMP-activated protein kinase (AMPK) is frequently reported to phosphorylate Ser1177 of the endothelial nitric-oxide synthase (eNOS), and therefore, is linked with a relaxing effect. However, previous studies failed to consistently demonstrate a major role for AMPK on eNOS-dependent relaxation. As AMPK also phosphorylates eNOS on the inhibitory Thr495 site, this study aimed to determine the role of AMPKα1 and α2 subunits in the regulation of NO-mediated vascular relaxation. Vascular reactivity to phenylephrine and acetylcholine was assessed in aortic and carotid artery segments from mice with global (AMPKα−/−) or endothelial-specific deletion (AMPKαΔEC) of the AMPKα subunits. In control and AMPKα1-depleted human umbilical vein endothelial cells, eNOS phosphorylation on Ser1177 and Thr495 was assessed after AMPK activation with thiopental or ionomycin. Global deletion of the AMPKα1 or α2 subunit in mice did not affect vascular reactivity. The endothelial-specific deletion of the AMPKα1 subunit attenuated phenylephrine-mediated contraction in an eNOS- and endothelium-dependent manner. In in vitro studies, activation of AMPK did not alter the phosphorylation of eNOS on Ser1177, but increased its phosphorylation on Thr495. Depletion of AMPKα1 in cultured human endothelial cells decreased Thr495 phosphorylation without affecting Ser1177 phosphorylation. The results of this study indicate that AMPKα1 targets the inhibitory phosphorylation Thr495 site in the calmodulin-binding domain of eNOS to attenuate basal NO production and phenylephrine-induced vasoconstriction.
Platelets participate in the development of liver fibrosis in animal models, but little is known about the benefit of antiplatelet agents in preventing liver fibrosis in humans. We therefore explored the relationship between the use of antiplatelet agents and liver fibrosis in a prospective cohort study of patients at high risk of liver fibrosis and cardiovascular events. Consecutive patients undergoing elective coronary angiography at the University Hospital Frankfurt were prospectively included in the present study. Associations between use of antiplatelet agents (acetyl salicylic acid, P2Y12 receptor antagonists) and liver fibrosis were assessed in regression models, and the relationship between platelet‐derived growth factor beta (PDGF‐β) serum concentration, platelets, liver fibrosis, and use of antiplatelet agents was characterized. Out of 505 included patients, 337 (67%) received antiplatelet agents and 134 (27%) had liver fibrosis defined as a FibroScan transient elastography (TE) value ≥7.9 kPa. Use of antiplatelet agents was inversely associated with the presence of liver fibrosis in univariate and multivariate analyses (multivariate odds ratio [OR], 0.67; 95% confidence interval [CI], 0.51‐0.89; P = 0.006). Use of antiplatelet agents was also inversely associated with FibroTest values (beta, –0.38; SD beta, 0.15; P = 0.02). Furthermore, there was a significant correlation between platelet counts and PDGF‐β serum concentration (rho, 0.33; P < 0.0001), but PDGF‐β serum levels were not affected by antiplatelet agents. Conclusion: There is a protective association between the use of antiplatelet agents and occurrence of liver fibrosis. A randomized controlled trial is needed to explore causality and the potential of antiplatelet agents as antifibrotic therapy in patients at risk for liver fibrosis progression.
Adult neurogenesis is regulated by stem cell niche-derived extrinsic factors and cell-intrinsic regulators, yet the mechanisms by which niche signals impinge on the activity of intrinsic neurogenic transcription factors remain poorly defined. Here, we report that MEIS2, an essential regulator of adult SVZ neurogenesis, is subject to posttranslational regulation in the SVZ olfactory bulb neurogenic system. Nuclear accumulation of MEIS2 in adult SVZ-derived progenitor cells follows downregulation of EGFR signaling and is modulated by methylation of MEIS2 on a conserved arginine, which lies in close proximity to nested binding sites for the nuclear export receptor CRM1 and the MEIS dimerization partner PBX1. Methylation impairs interaction with CRM1 without affecting PBX1 dimerization and thereby allows MEIS2 nuclear accumulation, a prerequisite for neuronal differentiation. Our results describe a form of posttranscriptional modulation of adult SVZ neurogenesis whereby an extrinsic signal fine-tunes neurogenesis through posttranslational modification of a transcriptional regulator of cell fate.
Vismodegib, an inhibitor of the Hedgehog signaling pathway, is an approved drug for monotherapy in locally advanced or metastatic basal cell carcinoma (BCC). Data on combined modality treatment by vismodegib and radiation therapy, however, are rare. In the present study, we examined the radiation sensitizing effects of vismodegib by analyzing viability, cell cycle distribution, cell death, DNA damage repair and clonogenic survival in three-dimensional cultures of a BCC and a head and neck squamous cell carcinoma (HNSCC) cell line. We found that vismodegib decreases expression of the Hedgehog target genes glioma-associated oncogene homologue (GLI1) and the inhibitor of apoptosis protein (IAP) Survivin in a cell line- and irradiation-dependent manner, most pronounced in squamous cell carcinoma (SCC) cells. Furthermore, vismodegib significantly reduced proliferation in both cell lines, while additional irradiation only slightly further impacted on viability. Analyses of cell cycle distribution and cell death induction indicated a G1 arrest in BCC and a G2 arrest in HNSCC cells and an increased fraction of cells in SubG1 phase following combined treatment. Moreover, a significant rise in the number of phosphorylated histone-2AX/p53-binding protein 1 (γH2AX/53BP1) foci in vismodegib- and radiation-treated cells was associated with a significant radiosensitization of both cell lines. In summary, these findings indicate that inhibition of the Hedgehog signaling pathway may increase cellular radiation response in BCC and HNSCC cells.
Comparative proteomics reveals a diagnostic signature for pulmonary head‐and‐neck cancer metastasis
(2018)
Patients with head‐and‐neck cancer can develop both lung metastasis and primary lung cancer during the course of their disease. Despite the clinical importance of discrimination, reliable diagnostic biomarkers are still lacking. Here, we have characterised a cohort of squamous cell lung (SQCLC) and head‐and‐neck (HNSCC) carcinomas by quantitative proteomics. In a training cohort, we quantified 4,957 proteins in 44 SQCLC and 30 HNSCC tumours. A total of 518 proteins were found to be differentially expressed between SQCLC and HNSCC, and some of these were identified as genetic dependencies in either of the two tumour types. Using supervised machine learning, we inferred a proteomic signature for the classification of squamous cell carcinomas as either SQCLC or HNSCC, with diagnostic accuracies of 90.5% and 86.8% in cross‐ and independent validations, respectively. Furthermore, application of this signature to a cohort of pulmonary squamous cell carcinomas of unknown origin leads to a significant prognostic separation. This study not only provides a diagnostic proteomic signature for classification of secondary lung tumours in HNSCC patients, but also represents a proteomic resource for HNSCC and SQCLC.
Atherosclerosis and its sequelae, such as myocardial infarction and stroke, are the leading cause of death worldwide. Vascular endothelial cells (EC) play a critical role in vascular homeostasis and disease. Atherosclerosis as well as its independent risk factors including diabetes, obesity, and aging, are hallmarked by endothelial activation and dysfunction. Metabolic pathways have emerged as key regulators of many EC functions, including angiogenesis, inflammation, and barrier function, processes which are deregulated during atherogenesis. In this review, we highlight the role of glucose, fatty acid, and amino acid metabolism in EC functions during physiological and pathological states, specifically atherosclerosis, diabetes, obesity and aging.
The present study evaluated the tissue response toward a resorbable collagen membrane derived from bovine achilles tendon (test group) in comparison to physiological wound healing (control group). After subcutaneous implantation in Wistar rats over 30 days, histochemical and immunohistochemical methods elucidated the cellular inflammatory response, vascularization pattern, membrane protein and cell absorbance capacity. After 30 days, the test-group induced two different inflammatory patterns. On the membrane surface, multinucleated giant cells (MNGCs) were formed after the accumulation of CD-68-positive cells (macrophages), whereas only mononuclear cells (MNCs) were found within the membrane central region. Peri-implant vascularization was significantly enhanced after the formation of MNGCs. No vessels were found within the central region of the membrane. Physiological wound healing revealed no MNGCs at any time point. These dynamic changes in the cellular reaction and vascularization within the test-group are related typical indications of a foreign body reaction. Due to the membrane-specific porosity, mononuclear cells migrated into the central region, and the membrane maintained its integrity over 30 days by showing no breakdown or disintegration. The ex vivo investigation analyzed the interaction between the membrane and a blood concentrate system, liquid platelet-rich fibrin (liquid PRF), derived from human peripheral blood and consisting of platelets, leukocytes and fibrin. PRF penetrated the membrane after just 15 min. The data question the role of biomaterial-induced MNGCs as a pathological reaction and whether this is acceptable to trigger vascularization or should be considered as an adverse reaction. Therefore, further pre-clinical and clinical studies are needed to identify the types of MNGCs that are induced by clinically approved biomaterials.
Background: Treatment complexity rises in line with the number of drugs, single doses, and administration methods, thereby threatening patient adherence. Patients with multimorbidity often need flexible, individualised treatment regimens, but alterations during the course of treatment may further increase complexity. The objective of our study was to explore medication changes in older patients with multimorbidity and polypharmacy in general practice.
Methods: We retrospectively analysed data from the cluster-randomised PRIMUM trial (PRIoritisation of MUltimedication in Multimorbidity) conducted in 72 general practices. We developed an algorithm for active pharmaceutical ingredients (API), strength, dosage, and administration method to assess changes in physician-reported medication data during two intervals (baseline to six-months: ∆1; six- to nine-months: ∆2), analysed them descriptively at prescription and patient levels, and checked for intervention effects.
Results: Of 502 patients (median age 72 years, 52% female), 464 completed the study. Changes occurred in 98.6% of patients (changes were 19% more likely in the intervention group): API changes during ∆1 and ∆2 occurred in 414 (82.5%) and 338 (67.3%) of patients, dosage alterations in 372 (74.1%) and 296 (59.2%), and changes in API strength in 158 (31.5%) and 138 (27.5%) respectively. Administration method changed in 79 (16%) of patients in both ∆1 and ∆2. Simvastatin, metformin and aspirin were most frequently subject to alterations.
Conclusion: Medication regimens in older patients with multimorbidity and polypharmacy changed frequently. These are mostly due to discontinuations and dosage alterations, followed by additions and restarts. These findings cast doubt on the effectiveness of cross-sectional assessments of medication and support longitudinal assessments where possible.
Trial registration: 1. Prospective registration: Trial registration number: NCT01171339; Name of registry: ClinicalTrials.gov; Date of registration: July 27, 2010; Date of enrolment of the first participant to the trial: August 12, 2010.
2. Peer reviewed trial registration: Trial registration number: ISRCTN99526053; Name of registry: Controlled Trials; Date of registration: August 31, 2010; Date of enrolment of the first participant to the trial: August 12, 2010.
Objective: Classifications of posture deviations are only possible compared with standard values. However, standard values have been published for healthy male adults but not for female adults.
Design: Observational study.
Setting: Institute of Occupational Medicine, Social Medicine and Environmental Medicine, Goethe-University Frankfurt/Main.
Participants: 106 healthy female volunteers (21–30 years old; 25.1±2.7 years) were included. Their body weight ranged from 46 to 106 kg (60.3±7.9 kg), the heights from 1.53 to 1.82 m (1.69±0.06 m) and the body mass index from 16.9 kg/m² to 37.6 kg/m² (21.1±2.6 kg/m²).
Outcome measures: A three-dimensional back scan was performed to measure the upper back posture in habitual standing. The tolerance ranges and CI were calculated. Group differences were tested by the Wilcoxon Mann-Whitney U test.
Results: In normal posture, the spinal column was marginally twisted to the left, and the vertebrae were marginally rotated to the right. The kyphosis angle is larger than the lumbar angle. Consequently, a more kyphotic posture is observed in the sagittal plane. The habitual posture is slightly scoliotic with a rotational component (scapular depression right, right scapula marginally more dorsally, high state of pelvic right, iliac right further rotated anteriorly).
Conclusions: Healthy young women have an almost ideally balanced posture with minimal ventral body inclination and a marginal scoliotic deviation. Compared with young males, women show only marginal differences in the upper body posture. These values allow a comparison to other studies, both for control and patient data, and may serve as guideline in both clinical practice and scientific studies.
Objective: To evaluate the efficacy and tolerability of brivaracetam (BRV) in a severely drug refractory cohort of patients with epileptic encephalopathies (EE).
Method: A multicenter, retrospective cohort study recruiting all patients treated with EE who began treatment with BRV in an enrolling epilepsy center between 2016 and 2017.
Results: Forty-four patients (27 male [61%], mean age 29 years, range 6 to 62) were treated with BRV. The retention rate was 65% at 3 months, 52% at 6 months and 41% at 12 months. A mean retention time of 5 months resulted in a cumulative exposure to BRV of 310 months. Three patients were seizure free during the baseline. At 3 months, 20 (45%, 20/44 as per intention-to-treat analysis considering all patients that started BRV including three who were seizure free during baseline) were either seizure free (n = 4; 9%, three of them already seizure-free at baseline) or reported at least 25% (n = 4; 9%) or 50% (n = 12; 27%) reduction in seizures. An increase in seizure frequency was reported in two (5%) patients, while there was no change in the seizure frequency of the other patients. A 50% long-term responder rate was apparent in 19 patients (43%), with two (5%) free from seizures for more than six months and in nine patients (20%, with one [2 %] free from seizures) for more than 12 months. Treatment-emergent adverse events were predominantly of psychobehavioural nature and were observed in 16%.
Significance: In this retrospective analysis the rate of patients with a 50% seizure reduction under BRV proofed to be similar to those seen in regulatory trials for focal epilepsies. BRV appears to be safe and relatively well tolerated in EE and might be considered in patients with psychobehavioral adverse events while on levetiracetam.
Our ability to select relevant information from the environment is limited by the resolution of attention – i.e., the minimum size of the region that can be selected. Neural mechanisms that underlie this limit and its development are not yet understood. Functional magnetic resonance imaging (fMRI) was performed during an object tracking task in 7- and 11-year-old children, and in young adults. Object tracking activated canonical fronto-parietal attention systems and motion-sensitive area MT in children as young as 7 years. Object tracking performance improved with age, together with stronger recruitment of parietal attention areas and a shift from low-level to higher-level visual areas. Increasing the required resolution of spatial attention – which was implemented by varying the distance between target and distractors in the object tracking task – led to activation increases in fronto-insular cortex, medial frontal cortex including anterior cingulate cortex (ACC) and supplementary motor area, superior colliculi, and thalamus. This core circuitry for attentional precision was recruited by all age groups, but ACC showed an age-related activation reduction. Our results suggest that age-related improvements in selective visual attention and in the resolution of attention are characterized by an increased use of more functionally specialized brain regions during the course of development.
Parkinson’s disease (PD) is characterized by distinct motor and non-motor symptoms. Sleep disorders are the most frequent and challenging non-motor symptoms in PD patients, and there is growing evidence that they are a consequence of disruptions within the circadian system. PD is characterized by a progressive degeneration of the dorsal vagal nucleus and midbrain dopaminergic neurons together with an imbalance of many other neurotransmitters. Mutations in α-synuclein (SNCA), a protein modulating SNARE complex-dependent neurotransmission, trigger dominantly inherited PD variants and sporadic cases of PD. The A53T SNCA missense mutation is associated with an autosomal dominant early-onset familial PD. To test whether this missense mutation affects the circadian system, we analyzed the spontaneous locomotor behavior of non-transgenic wildtype mice and transgenic mice overexpressing mutant human A53T α-synuclein (A53T). The mice were subjected to entrained- and free-running conditions as well as to experimental jet lag. Furthermore, the vesicular glutamate transporter 2 (VGLUT2) in the suprachiasmatic nucleus (SCN) was analyzed by immunohistochemistry. Free-running circadian rhythm and, thus, circadian rhythm generation, were not affected in A53T mice. A53T mice entrained to the light–dark cycle, however, with an advanced phase angle of 2.65 ± 0.5 h before lights off. Moreover, re-entrainment after experimental jet lag was impaired in A53T mice. Finally, VGLUT2 immunoreaction was reduced in the SCN of A53T mice. These data suggest an impaired light entrainment of the circadian system in A53T mice.
Chronic kidney disease and diabetes mellitus are associated with extensive media calcification, which leads to increased cardiovascular morbidity and mortality. Here, we investigated the role of autophagy in the pathogenesis of uremic vascular media calcification. DBA/2 mice were fed with high-phosphate diet (HPD) in order to cause vascular calcification. DBA/2 mice on standard chow diet were used as control. In parallel, autophagy and its response to rapamycin, 3-methyladenine (3-MA), and bafilomycin were studied in an in vitro model using mouse vascular smooth muscle cells (MOVAS). DBA/2 mice on HPD developed severe vascular media calcification, which is mirrored in vitro by culturing MOVAS under calcifying conditions. Both, in vitro and in vivo, autophagy significantly increased in MOVAS under calcifying conditions and in aortas of HPD mice, respectively. Histologically, autophagy was located to the aortic Tunica media, but also vascular endothelial cells, and was found to continuously increase during HPD treatment. 3-MA as well as bafilomycin blocked autophagy in MOVAS and increased calcification. Vice versa, rapamycin treatment further increased autophagy and resulted in a significant decrease of vascular calcification in vitro and in vivo. Rapamycin reduced Runx2 transcription levels in aortas and MOVAS to control levels, whereas it increased α-smooth muscle actin and Sm22α transcription in MOVAS to control levels. Furthermore, rapamycin-treated HPD mice survived significantly longer compared to HPD controls. These findings indicate that autophagy is an endogenous response of vascular smooth muscle cells (VSMC) to protect from calcification in uremia. Induction of autophagy by rapamycin protects cells and mice from uremic media calcification possibly by inhibiting osteogenic transdifferentiation of VSMC.
Rapid immune reconstitution (IR) following stem cell transplantation (SCT) is essential for a favorable outcome. The optimization of graft composition should not only enable a sufficient IR but also improve graft vs. leukemia/tumor effects, overcome infectious complications and, finally, improve patient survival. Especially in haploidentical SCT, the optimization of graft composition is controversial. Therefore, we analyzed the influence of graft manipulation on IR in 40 patients with acute leukemia in remission. We examined the cell recovery post haploidentical SCT in patients receiving a CD34+-selected or CD3/CD19-depleted graft, considering the applied conditioning regimen. We used joint model analysis for overall survival (OS) and analyzed the dynamics of age-adjusted leukocytes; lymphocytes; monocytes; CD3+, CD3+CD4+, and CD3+CD8+ T cells; natural killer (NK) cells; and B cells over the course of time after SCT. Lymphocytes, NK cells, and B cells expanded more rapidly after SCT with CD34+-selected grafts (P = 0.036, P = 0.002, and P < 0.001, respectively). Contrarily, CD3+CD4+ helper T cells recovered delayer in the CD34 selected group (P = 0.026). Furthermore, reduced intensity conditioning facilitated faster immune recovery of lymphocytes and T cells and their subsets (P < 0.001). However, the immune recovery for NK cells and B cells was comparable for patients who received reduced-intensity or full preparative regimens. Dynamics of all cell types had a significant influence on OS, which did not differ between patients receiving CD34+-selected and those receiving CD3/CD19-depleted grafts. In conclusion, cell reconstitution dynamics showed complex diversity with regard to the graft manufacturing procedure and conditioning regimen.
An aerosol foam formulation of a once-daily, fixed-dose combination of a synthetic vitamin D3 analog/synthetic corticosteroid (calcipotriol [Cal] 50 µg/g and betamethasone dipropionate [BD] 0.5 mg/g) has recently been introduced for the topical treatment of plaque psoriasis in adults. Data from several sources – randomized controlled trials, case reports (as highlighted in this review), and real-world evidence (RWE) – underscore the considerable and rapid clinical response, effectiveness, and favorable safety and tolerability of Cal/BD aerosol foam in mild-to-moderate psoriatic patients previously treated with class 3 or 4 topical corticosteroids, in patients unsatisfied with ongoing phototherapy in combination with topical therapy and in patients with moderate-to-severe psoriasis. In addition, our case series, considered together with other RWE, highlights that Cal/BD aerosol foam is more effective and with greater levels of patient preference and acceptability than comparator preparations. Thus, Cal/BD aerosol foam offers several treatment advantages, including relief of itch, and is an appropriate first-line topical therapy for consideration in patients with psoriasis of any severity.
Damaged mitochondria are selectively eliminated by mitophagy. Parkin and PINK1, gene products mutated in familial Parkinson’s disease, play essential roles in mitophagy through ubiquitination of mitochondria. Cargo ubiquitination by E3 ubiquitin ligase Parkin is important to trigger selective autophagy. Although autophagy receptors recruit LC3-labeled autophagic membranes onto damaged mitochondria, how other essential autophagy units such as ATG9A-integrated vesicles are recruited remains unclear. Here, using mammalian cultured cells, we demonstrate that RABGEF1, the upstream factor of the endosomal Rab GTPase cascade, is recruited to damaged mitochondria via ubiquitin binding downstream of Parkin. RABGEF1 directs the downstream Rab proteins, RAB5 and RAB7A, to damaged mitochondria, whose associations are further regulated by mitochondrial Rab-GAPs. Furthermore, depletion of RAB7A inhibited ATG9A vesicle assembly and subsequent encapsulation of the mitochondria by autophagic membranes. These results strongly suggest that endosomal Rab cycles on damaged mitochondria are a crucial regulator of mitophagy through assembling ATG9A vesicles.
Background: There is no international consensus up to which age women with a diagnosis of triple-negative breast cancer (TNBC) and no family history of breast or ovarian cancer should be offered genetic testing for germline BRCA1 and BRCA2 (gBRCA) mutations. Here, we explored the association of age at TNBC diagnosis with the prevalence of pathogenic gBRCA mutations in this patient group.
Methods: The study comprised 802 women (median age 40 years, range 19–76) with oestrogen receptor, progesterone receptor, and human epidermal growth factor receptor type 2 negative breast cancers, who had no relatives with breast or ovarian cancer. All women were tested for pathogenic gBRCA mutations. Logistic regression analysis was used to explore the association between age at TNBC diagnosis and the presence of a pathogenic gBRCA mutation.
Results: A total of 127 women with TNBC (15.8%) were gBRCA mutation carriers (BRCA1: n = 118, 14.7%; BRCA2: n = 9, 1.1%). The mutation prevalence was 32.9% in the age group 20–29 years compared to 6.9% in the age group 60–69 years. Logistic regression analysis revealed a significant increase of mutation frequency with decreasing age at diagnosis (odds ratio 1.87 per 10 year decrease, 95%CI 1.50–2.32, p < 0.001). gBRCA mutation risk was predicted to be > 10% for women diagnosed below approximately 50 years.
Conclusions: Based on the general understanding that a heterozygous mutation probability of 10% or greater justifies gBRCA mutation screening, women with TNBC diagnosed before the age of 50 years and no familial history of breast and ovarian cancer should be tested for gBRCA mutations. In Germany, this would concern approximately 880 women with newly diagnosed TNBC per year, of whom approximately 150 are expected to be identified as carriers of a pathogenic gBRCA mutation.
Background: The city of Wrocław in Poland represents one of Central Europeans oldest capitals of science with numerous Nobel laureates. Due to a long history of political suppressions with Nazi Germany and Communism from 1933 until 1989, its scientific community was suppressed for more than half a century.
Methods: The present study assessed scientific activities in the field of social and neighbouring sciences using density equalizing mapping. On the basis of the NewQIS (New Quality and Quantity Indices in Science) platform and the Social Sciences Citation Index (SSCI) of the Web of Science database, a total of 1787 articles originating from Wrocław were identified between 1966 and 2017.
Results: In total, 549 research collaborations of Wrocław with 96 different countries were present (30.7%). Among the 107 research areas the highest activity was found for the field of Business and Economics with n = 272 articles (average citation rate (AVR) of 12.54), followed by Psychology (n = 252 articles, AVR = 9.06), Psychiatry (n = 205 articles, AVR = 4.74) and Public, Environmental and Occupational Health (n = 145 articles, AVR = 7.96). The highest AVR was found for Operations Research (25.36 with n = 87 articles). Density equalizing mapping procedures revealed a global pattern of social sciences research collaborations with scientists from Germany, the UK and the US as the primary cooperating partner of Wrocław. The different countries had major differences in the area of research collaborations.
Conclusions: This is the first study that depicts the global network of Wrocław scientific activities in the field of social sciences. The exorbitant increase in research activity from 2006 onwards can lead to the assumption that Wrocław social sciences encounter a fruitful future.
Determining the cell fate and the distribution of mesenchymal stromal/stem cells (MSCs) after transplantation are essential parts of characterizing the mechanisms of action and biosafety profile of stem cell therapy. Many recent studies have shown that MSCs migrate into injured tissues, but are only detectable at extremely low frequencies. We investigated the cell fate of MSCs after transplantation in an acute kidney injury (AKI) mouse model using in vivo bioluminescence imaging (BLI) and subsequent verification of cell migration using quantitative real-time polymerase chain reaction (qRT-PCR). The AKI was induced by a single injection of cisplatin (8 or 12 mg/kg). One day later, adipose-derived mesenchymal stromal/stem cells isolated from luciferase transgenic mice (Luc+-mASCs, 5 × 105) were intravenously transplanted. Migration kinetics of the cells was monitored using BLI on day 1, 3, and 6, and finally via quantitative real-time PCR at the endpoint on day 6. Using BLI, infused Luc+-mASCs could only be detected in the lungs, but not in the kidneys. In contrast, PCR endpoint analysis revealed that Luc-specific mRNA could be detected in injured renal tissue; compared to the control group, the induction was 2.2-fold higher for the 8 mg/kg cisplatin group (p < 0.05), respectively 6.1-fold for the 12 mg/kg cisplatin group (p < 0.001). In conclusion, our study demonstrated that Luc-based real-time PCR rather than BLI is likely to be a better tool for cell tracking after transplantation in models such as cisplatin-induced AKI.
GD2-directed immunotherapies improve survival of high-risk neuroblastoma (NB) patients (pts). Treatment with chimeric anti-GD2 antibodies (Ab), such as ch14.18, can induce development of human anti-chimeric Ab (HACA). Here, we report HACA effects on ch14.18/CHO pharmacokinetics, pharmacodynamics and pain intensity in pts treated by long-term infusion (LTI) of ch14.18/CHO combined with IL-2. 124 pts received up to 5 cycles of ch14.18/CHO 10 days (d) infusion (10 mg/m2/d; d8–18) combined with s.c. IL-2 (6 × 106 IU/m2/d; d1–5, d8–12). HACA, treatment toxicity, ch14.18/CHO levels, Ab-dependent cellular- (ADCC) and complement-dependent cytotoxicity (CDC) were assessed using respective validated assays. HACA-negative pts showed a steadily decreased pain in cycle 1 (74% pts without morphine by d5 of LTI) with further decrease in subsequent cycles. Ch14.18/CHO peak concentrations of 11.26 ± 0.50 µg/mL found in cycle 1 were further elevated in subsequent cycles and resulted in robust GD2-specific CDC and ADCC. Development of HACA (21% of pts) resulted in strong reduction of ch14.18/CHO levels, abrogated CDC and ADCC. Surprisingly, no difference in pain toxicity between HACA-positive and -negative pts was found. In conclusion, ch14.18/CHO LTI combined with IL-2 results in strong activation of Ab effector functions. Importantly, HACA response abrogated CDC but did not affect pain intensity indicating CDC-independent pain induction.
Introduction: Hip fracture surgery is associated with high in-hospital and 30-day mortality rates and serious adverse patient outcomes. Evidence from randomised controlled trials regarding effectiveness of spinal versus general anaesthesia on patient-centred outcomes after hip fracture surgery is sparse.
Methods and analysis: The iHOPE study is a pragmatic national, multicentre, randomised controlled, open-label clinical trial with a two-arm parallel group design. In total, 1032 patients with hip fracture (>65 years) will be randomised in an intended 1:1 allocation ratio to receive spinal anaesthesia (n=516) or general anaesthesia (n=516). Outcome assessment will occur in a blinded manner after hospital discharge and inhospital. The primary endpoint will be assessed by telephone interview and comprises the time to the first occurring event of the binary composite outcome of all-cause mortality or new-onset serious cardiac and pulmonary complications within 30 postoperative days. In-hospital secondary endpoints, assessed via in-person interviews and medical record review, include mortality, perioperative adverse events, delirium, satisfaction, walking independently, length of hospital stay and discharge destination. Telephone interviews will be performed for long-term endpoints (all-cause mortality, independence in walking, chronic pain, ability to return home cognitive function and overall health and disability) at postoperative day 30±3, 180±45 and 365±60.
Ethics and dissemination: iHOPE has been approved by the leading Ethics Committee of the Medical Faculty of the RWTH Aachen University on 14 March 2018 (EK 022/18). Approval from all other involved local Ethical Committees was subsequently requested and obtained. Study started in April 2018 with a total recruitment period of 24 months. iHOPE will be disseminated via presentations at national and international scientific meetings or conferences and publication in peer-reviewed international scientific journals.
Trial registration number: DRKS00013644; Pre-results
Isolated complex I deficiency is a common biochemical phenotype observed in pediatric mitochondrial disease and often arises as a consequence of pathogenic variants affecting one of the ∼65 genes encoding the complex I structural subunits or assembly factors. Such genetic heterogeneity means that application of next-generation sequencing technologies to undiagnosed cohorts has been a catalyst for genetic diagnosis and gene-disease associations. We describe the clinical and molecular genetic investigations of four unrelated children who presented with neuroradiological findings and/or elevated lactate levels, highly suggestive of an underlying mitochondrial diagnosis. Next-generation sequencing identified bi-allelic variants in NDUFA6, encoding a 15 kDa LYR-motif-containing complex I subunit that forms part of the Q-module. Functional investigations using subjects’ fibroblast cell lines demonstrated complex I assembly defects, which were characterized in detail by mass-spectrometry-based complexome profiling. This confirmed a marked reduction in incorporated NDUFA6 and a concomitant reduction in other Q-module subunits, including NDUFAB1, NDUFA7, and NDUFA12. Lentiviral transduction of subjects’ fibroblasts showed normalization of complex I. These data also support supercomplex formation, whereby the ∼830 kDa complex I intermediate (consisting of the P- and Q-modules) is in complex with assembled complex III and IV holoenzymes despite lacking the N-module. Interestingly, RNA-sequencing data provided evidence that the consensus RefSeq accession number does not correspond to the predominant transcript in clinically relevant tissues, prompting revision of the NDUFA6 RefSeq transcript and highlighting not only the importance of thorough variant interpretation but also the assessment of appropriate transcripts for analysis.
Aims: The ILUVIEN Registry Safety Study is an ongoing, multicentre, open-label, observational study collecting real-world data on the safety and effectiveness of the 0.2 µg/day fluocinolone acetonide (FAc) implant in patients treated according to the European label requirements.
Methods: Patients included in this analysis were treated for the licensed indication of chronic diabetic macular oedema (cDMO; that is, DMO that persists or recurs despite treatment). Data presented in the current analysis were collected from patient records up to 6 March 2017. Visual acuity (VA) data, including mean change in VA over time and at last observation, intraocular pressure (IOP) over the course of the study, IOP events, use of IOP-lowering therapy and cup:disc ratio were analysed. Information on additional DMO treatments post-FAc implant was also captured.
Results: Five hundred and sixty-three patients (593 eyes) were enrolled on the study. Mean IOP for the overall population remained within the normal range throughout follow-up and 76.7% of patients did not require IOP-lowering therapy following treatment with the FAc implant. Sixty-nine per cent of eyes did not require additional DMO treatments. Mean VA in the overall population increased from 51.9 letters at baseline to 55.6 letters at month 12, with a significant increase of 2.9 letters at last observation. Patients with short-term cDMO experienced greater VA gains than those with long-term cDMO.
Conclusions: The results of this analysis are comparable with those of other studies, including the Fluocinolone Acetate for Macular Edema study. The study reinforces the good safety and effectiveness profile of FAc, and demonstrates the benefit of early FAc treatment.
Oral anticoagulant-associated intracerebral hemorrhage (OAC-ICH) accounts for nearly 20% of all ICH. The number of patients with an indication for oral anticoagulant therapy (OAT) increases with increasing age. OAT became less complicate with the introduction of non-vitamin K oral anticoagulants (NOAC) OAT because of easier handling, favorable risk-benefit profile, reduced rates of ICH compared to vitamin K antagonists and no need for routine coagulation testing. Consequently, despite a better safety profile of NOAC the number of patients with OAC-ICH will increase. The mortality and complication rates of OAC-ICH are high and therefore they are the most feared complication of OAT. Immediate normalization of coagulation is the main goal and therefore knowledge of pharmacodynamics and coagulation status is essential. Laboratory measurements of anticoagulant activity in NOAC patients is challenging as specific tests are not widely available. More accessible tests such as the prothrombin time and activated partial thromboplastin time have important limitations. In dabigatran-associated ICH 5 g Idarucizumab should be administered. In rivaroxaban and apixaban-associated ICHs administration of andexanet alpha should be considered. Prothrombin complex concentrate may be considered if andexanet alpha is not available or in case of an ICH associated with edoxaban.
The authors review the current status of percutaneous left atrial appendage (LAA) occlusion therapy in patients with atrial fibrillation with the goal to prevent ischemic stroke and systemic embolism and to reduce oral anticoagulation associated bleeding. While we cover the historical and also surgical background, and all tested devices, the main focus rests on the single currently U.S. Food and Drug Administration (FDA) approved LAA occluder, the WATCHMAN device, and its approval process. The authors also give a critical appraisal beyond the review of mere facts, trying to put the current data into perspective.
Background: Obesity is a global problem leading to reduced life expectancy, cardiovascular diseases, diabetes and many types of cancer. Even people willing to accept treatment only achieve a mean weight loss of about 5 kg using commercial weight loss programs. Surgical interventions, e.g. sleeve gastrectomy or gastric bypass are effective but accompanied by risk of serious complications and side effects. Less invasive endoscopic procedures mainly comprise the intragastric balloon (IB) and the duodenal-jejunal bypass liner (DJBL). To date, a randomized comparison between these devices has not been undertaken or shown to be superior to a sham procedure.
Methods: We designed a multi-center, randomized, patient and assessor-blinded, controlled trial comparing weight loss in endoscopically implanted IB vs. DJBL vs. a sham procedure. A total of 150 patients with a BMI > 35 kg/m2 or > 30 with obesity-related comorbidities and indication for proton pump inhibitors are randomized to receive either IB, DJBL or a sham gastroscopy (2:2:1 ratio). All participants undergo regular dietary consultation. The IB will be removed after 6 months, whereas the DJBL will be explanted after 12 months. All patients will receive gastroscopies at implantation and explantation of the devices or sedation without gastroscopy to maintain blinding. Main exclusion criteria are malignant diseases, peptic ulcer or previous bariatric intervention. Weight loss 12 months after explantation of the devices, changes in comorbidities, quality of life, complication rates and safety will be evaluated.
Discussion: This trial could help to identify the most effective and safest endoscopic device, thus determining the new standard procedure for endoscopic bariatric treatment.
Trial registration: 16th January 2017. DRKS00011036. Funded by the German Research Foundation (DFG).
Different response of Ptch mutant and Ptch wildtype Rhabdomyosarcoma toward SMO and PI3K inhibitors
(2018)
Rhabdomyosarcoma (RMS) is the most common pediatric soft tissue sarcoma with poor prognosis. RMS frequently show Hedgehog (HH) pathway activity, which is predominantly seen in the embryonal subtype (ERMS). They also show activation of Phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K) signaling. Here we compared the therapeutic effectiveness and the impact on HH target gene expression of Smoothened (SMO) antagonists with those of the PI3K inhibitor pictilisib in ERMS with and without mutations in the HH receptor Patched1 (PTCH). Our data demonstrate that growth of ERMS showing canonical Hh signaling activity due to Ptch germline mutations is efficiently reduced by SMO antagonists. This goes along with strong downregulation of the Hh target Gli1. Likewise Ptch mutant tumors are highly responsive toward the PI3K inhibitor pictilisib, which involves modulation of AKT and caspase activity. Pictilisib also modulates Hh target gene expression, which, however, is rather not correlated with its antitumoral effects. In contrast, sporadic ERMS, which usually express HH target genes without having PTCH mutation, apparently lack canonical HH signaling activity. Thus, stimulation by Sonic HE (SHH) or SAG (Smoothened agonist) or inhibition by SMO antagonists do not modulate HH target gene expression. In addition, SMO antagonists do not provoke efficient anticancer effects and rather exert off-target effects. In contrast, pictilisib and other PI3K/AKT/mTOR inhibitors potently inhibit cellular growth. They also efficiently inhibit HH target gene expression. However, of whether this is correlated with their antitumoral effects it is not clear. Together, these data suggest that PI3K inhibitors are a good and reliable therapeutic option for all ERMS, whereas SMO inhibitors might only be beneficial for ERMS driven by PTCH mutations.
Danger signals in trauma
(2018)
This review summarizes a short list of currently discussed trauma-induced danger-associated molecular patterns (DAMP). Due to the bivalent character and often pleiotropic effects of a DAMP, it is difficult to describe its “friend or foe” role in post-traumatic inflammation and regeneration, both systemically as well locally in tissues. DAMP can be used as biomarkers to indicate or monitor disease or injury severity, but also may serve as clinically applicable parameters for better indication and timing of surgery. Due to the inflammatory processes at the local tissue level or the systemic level, the precise role of DAMP is not always clear to define. While in vitro and experimental studies allow for the detection of these biomarkers at the different levels of an organism—cellular, tissue, circulation—this is not always easily transferable to the human setting. Increased knowledge exploring the dual role of DAMP after trauma, and concentrating on their nuclear functions, transcriptional targets, release mechanisms, cellular sources, multiple functions, their interactions and potential therapeutic targeting is warranted.
Oncogenic rearrangements leading to targetable gene fusions are well-established cancer driver events in lung adenocarcinoma. Accurate and reliable detection of these gene fusions is crucial to select the appropriate targeted therapy for each patient. We compared the targeted next-generation-sequencing Oncomine Focus Assay (OFA; Thermo Fisher Scientific) with conventional ALK FISH and anti-Alk immunohistochemistry in a cohort of 52 lung adenocarcinomas (10 ALK rearranged, 18 non-ALK rearranged, and 24 untested cases). We found a sensitivity and specificity of 100% for detection of ALK rearrangements using the OFA panel. In addition, targeted next generation sequencing allowed us to analyze a set of 23 driver genes in a single assay. Besides EML4-ALK (11/52 cases), we detected EZR-ROS1 (1/52 cases), KIF5B-RET (1/52 cases) and MET-MET (4/52 cases) fusions. All EML4-ALK, EZR-ROS1 and KIF5B-RET fusions were confirmed by multiplexed targeted next generation sequencing assay (Oncomine Solid Tumor Fusion Transcript Kit, Thermo Fisher Scientific). All cases with EML4-ALK rearrangement were confirmed by Alk immunohistochemistry and all but one by ALK FISH. In our experience, targeted next-generation sequencing is a reliable and timesaving tool for multiplexed detection of targetable rearrangements. Therefore, targeted next-generation sequencing represents an efficient alternative to time-consuming single target assays currently used in molecular pathology.
Objective. Traumatic injury or severe surgery leads to a profound immune response with a diminished functionality of monocytes and subsequently their IL-1β release. IL-1β plays an important role in host immunity and protection against infections. Its biological activation via IL-1β-precursor processing requires the transcription of inflammasome components and their activation. Deregulated activity of NOD-like receptor inflammasomes (NLR) like NLRP3 that leads to the maturation of IL-1β has been described in various diseases. While the role of other inflammasomes has been studied in monocytes, nothing is known about NLRP3 inflammasome after a traumatic injury. Here, the role of the NLRP3 inflammasome in impaired monocyte functionality after a traumatic injury was analyzed.
Measurements and Main Results. Ex vivo-in vitro stimulation of isolated CD14+ monocytes with lipopolysaccharide (LPS) showed a significantly higher IL-1β secretion in healthy volunteers (HV) compared to trauma patients (TP) after admission. Reduced IL-1β secretion was paralleled by significantly lowered gene expression of NLRP3 in monocytes from TP compared to those of HV. Transfection of monocytes with NLRP3-encoding plasmid recovered the functionality of monocytes from TP regarding the IL-1β secretion.
Conclusions. This study demonstrates that CD14+ monocytes from TP are significantly diminished in their function and that the presence of NLRP3 components is necessary in recovering the ability of monocytes to produce active IL-1β. This recovery of the NLRP3 inflammasome in monocytes may imply a new target for treatment and therapy of immune suppression after severe injury.
New technologies and therapies designed to facilitate development of personalized treatments are rapidly emerging in the field of biomedicine. Strikingly, the goal of personalized medicine refined the concept of therapy by developing cell-based therapies, the so-called “living drugs”. Breakthrough advancements were achieved in this regard in the fields of gene therapy, cell therapy, tissue-engineered products and advanced therapeutic techniques. The Advanced Therapies in Healthcare symposium, organized by the Clinical Research Center Department of Sidra Medicine, in Doha, Qatar (October 2017), brought together world-renowned experts from the fields of oncology, hematology, immunology, inflammation, autoimmune disorders, and stem cells to offer a comprehensive picture of the status of worldwide advanced therapies in both pre-clinical and clinical development, providing insights to the research phase, clinical data and regulatory aspects of these therapies. Highlights of the meeting are provided in this meeting report.
Background: Histological evidence suggests that autism spectrum disorder (ASD) is accompanied by a reduced integrity of the grey-white matter boundary. This has also recently been confirmed by a structural neuroimaging study in vivo reporting significantly reduced grey-white matter tissue contrast (GWC) in adult individuals (18–42 years of age) with ASD relative to typically developing (TD) controls. However, it remains unknown whether the neuroanatomical differences in ASD at the grey-white matter boundary are stable across development or are age-dependent.
Methods: Here, we examined differences in the neurodevelopmental trajectories of GWC in a cross-sectional sample of 77 male ASD individuals and 76 typically developing (TD) controls across childhood and early adulthood (from 7 to 25 years).
Results: Using nested model comparisons, we first established that the developmental trajectory of GWC is complex in many regions across the cortex and includes linear and non-linear effects of age. Second, while ASD individuals have significantly reduced GWC overall, these differences are age-dependent and are most prominent during childhood (< 15 years).
Conclusions: Taken together, our findings suggest that differences in GWC in ASD are unlikely to reflect atypical grey matter cytoarchitecture alone, but may also represent other aspects of the cortical architecture such as age-dependent variability in myelin integrity.
Background: The focus of this study is to identify particular microRNA (miRNA) signatures in exosomes derived from plasma of 435 human epidermal growth factor receptor 2 (HER2)-positive and triple-negative (TN) subtypes of breast cancer (BC).
Methods: First, miRNA expression profiles were determined in exosomes derived from the plasma of 15 TNBC patients before neoadjuvant therapy using a quantitative TaqMan real-time PCR-based microRNA array card containing 384 different miRNAs. Forty-five miRNAs associated with different clinical parameters were then selected and mounted on microRNA array cards that served for the quantification of exosomal miRNAs in 435 BC patients before therapy and 20 healthy women. Confocal microscopy, Western blot, and ELISA were used for exosome characterization.
Results: Quantification of 45 exosomal miRNAs showed that compared with healthy women, 10 miRNAs in the entire cohort of BC patients, 13 in the subgroup of 211 HER2-positive BC, and 17 in the subgroup of 224 TNBC were significantly deregulated. Plasma levels of 18 exosomal miRNAs differed between HER2-positive and TNBC subtypes, and 9 miRNAs of them also differed from healthy women. Exosomal miRNAs were significantly associated with the clinicopathological and risk factors. In uni- and multivariate models, miR-155 (p = 0.002, p = 0.003, respectively) and miR-301 (p = 0.002, p = 0.001, respectively) best predicted pathological complete response (pCR).
Conclusion: Our findings show a network of deregulated exosomal miRNAs with specific expression patterns in exosomes of HER2-positive and TNBC patients that are also associated with clinicopathological parameters and pCR within each BC subtype.
We examined alterations in E/I-balance in schizophrenia (ScZ) through measurements of resting-state gamma-band activity in participants meeting clinical high-risk (CHR) criteria (n = 88), 21 first episode (FEP) patients and 34 chronic ScZ-patients. Furthermore, MRS-data were obtained in CHR-participants and matched controls. Magnetoencephalographic (MEG) resting-state activity was examined at source level and MEG-data were correlated with neuropsychological scores and clinical symptoms. CHR-participants were characterized by increased 64–90 Hz power. In contrast, FEP- and ScZ-patients showed aberrant spectral power at both low- and high gamma-band frequencies. MRS-data showed a shift in E/I-balance toward increased excitation in CHR-participants, which correlated with increased occipital gamma-band power. Finally, neuropsychological deficits and clinical symptoms in FEP and ScZ-patients were correlated with reduced gamma band-activity, while elevated psychotic symptoms in the CHR group showed the opposite relationship. The current study suggests that resting-state gamma-band power and altered Glx/GABA ratio indicate changes in E/I-balance parameters across illness stages in ScZ.
Background: This study assessed the impact of medical students’ emotion recognition ability and extraversion on their empathic communication, as perceived by simulated patients in a training context.
Methods: This study used a crossed-effect data structure and examined 245 students in their fourth year of medical school. The students’ personality traits were assessed based on a self-assessment questionnaire of the short form of the Big Five Inventory; their emotion recognition ability was measured using a performance test (Diagnostic Analysis of Nonverbal Accuracy-2, Adult Facial Expressions). Simulated patients evaluated the medical students’ empathic communication.
Results: Students with a combination of high emotion recognition ability and extraversion received more positive ratings from simulated patients than their fellow students with a combination of emotion recognition ability and low extraversion. The main effects of emotion recognition or extraversion were not sufficient to yield similar effects. There were no other effects related to the remaining Big Five variables.
Conclusions: The results support the hypothesis that to build rapport with patients, medical staff need to combine emotional capabilities with a dispositional interest in interpersonal encounters.
Most studies in the life sciences and other disciplines involve generating and analyzing numerical data of some type as the foundation for scientific findings. Working with numerical data involves multiple challenges. These include reproducible data acquisition, appropriate data storage, computationally correct data analysis, appropriate reporting and presentation of the results, and suitable data interpretation.
Finding and correcting mistakes when analyzing and interpreting data can be frustrating and time-consuming. Presenting or publishing incorrect results is embarrassing but not uncommon. Particular sources of errors are inappropriate use of statistical methods and incorrect interpretation of data by software. To detect mistakes as early as possible, one should frequently check intermediate and final results for plausibility. Clearly documenting how quantities and results were obtained facilitates correcting mistakes. Properly understanding data is indispensable for reaching well-founded conclusions from experimental results. Units are needed to make sense of numbers, and uncertainty should be estimated to know how meaningful results are. Descriptive statistics and significance testing are useful tools for interpreting numerical results if applied correctly. However, blindly trusting in computed numbers can also be misleading, so it is worth thinking about how data should be summarized quantitatively to properly answer the question at hand. Finally, a suitable form of presentation is needed so that the data can properly support the interpretation and findings. By additionally sharing the relevant data, others can access, understand, and ultimately make use of the results.
These quick tips are intended to provide guidelines for correctly interpreting, efficiently analyzing, and presenting numerical data in a useful way.
Perception of irony has been observed to be impaired in adults with autism spectrum disorder. In typically developed adults, the mismatch of verbal and nonverbal emotional cues can be perceived as an expression of irony even in the absence of any further contextual information. In this study, we evaluate to what extent high functioning autists perceive this incongruence as expressing irony. Our results show that incongruent verbal and nonverbal signals create an impression of irony significantly less often in participants with high-functioning autism than in typically developed control subjects. The extent of overall autistic symptomatology as measured with the autism-spectrum questionnaire (AQ), however, does not correlate with the reduced tendency to attribute incongruent stimuli as expressing irony. Therefore, the attenuation in irony attribution might rather be related to specific subdomains of autistic traits, such as a reduced tendency to interpret communicative signals in terms of complex intentional mental states. The observed differences in irony attribution support the assumption that a less pronounced tendency to engage in higher order mentalization processes might underlie the impairment of pragmatic language understanding in high functioning autism.
Fibroblasts were isolated from skin biopsies from two patients with bipolar I disorder. One patient was a 26 year old female carrying a risk haplotype in the DGKH (diacylglycerol kinase eta) gene and the other was a non-carrier 27 year old male. Patient fibroblasts were reprogrammed into human induced pluripotent stem cells (hiPSCs) by using a Sendai virus vector. DGKH-risk haplotype and non-risk haplotype hiPSCs showed expression of pluripotency markers and were able to differentiate into cells of the three germ layers. These cell models are useful to investigate the role of risk gene variants in bipolar disorder.
Radiographic outcomes following lateral alveolar ridge augmentation using autogenous tooth roots
(2018)
Background: To assess and compare the radiographic outcomes following lateral alveolar ridge augmentation using autogenous tooth roots (TR) and autogenous bone (AB) blocks.
Methods: In a total of 30 patients, lateral ridge augmentation was conducted in parallel groups using either (1) healthy autogenous tooth roots (e.g., retained wisdom or impacted teeth) (n = 15) or (2) cortical autogenous bone blocks harvested from the retromolar area. Cone-beam computed tomographic (CBCT) scans taken at 26 weeks of submerged healing were analyzed for the basal graft integration (i.e., contact between the graft and the host bone in %) (BI26) and the cross-sectional grafted area (mm2) (SA26).
Results: Both groups revealed a comparable clinical width of the alveolar ridge at baseline (CWb). Mean BI26 and SA26 values amounted to 69.26 ± 26.01% (median 72.44) and 22.07 ± 12.98 mm2 (median 18.83) in the TR group and 79.67 ± 15.66% (median 78.85) and 12.42 ± 10.11 mm2 (median 11.36) in the AB group, respectively. Between-group differences in mean SA26 values were statistically significant (p = 0.031). Linear regression analysis failed to reveal any significant correlations between BI26 and CWb/SA26 values in either group.
Conclusions: TR grafts may be associated with improved SA26 values following lateral alveolar ridge augmentation.
Trial registration: DRKS00009586. Registered 10 February 2016.
Background: In Germany, patients suffering from life-limiting conditions are eligible for specialized outpatient palliative care (SOPC). Evaluation of the quality of this service lacks currently integration of patient-relevant outcomes. There is also no scientific consensus how to prove quality of care in the special context of SOPC adequately. Existing quality reports are primarily based on descriptive structural data which do not allow for estimation of process quality or result quality. The ELSAH study ("Evaluation of Specialized Outpatient Palliative Care in the German state of Hesse") aims to choose - or, if necessary, to adopt - to evaluate and to implement a suit of measures to assess, evaluate and monitor the quality of specialized, home-based palliative care.
Methods: All 22 SOPC teams providing their services in the state of Hesse, Germany, participate in the ELSAH study. The study is divided in two phases: a preparation phase and a main study phase. Based on the findings of the preparation phase we have chosen a preliminary set of instruments including the Integrated Palliative Outcome Scale, Views on Care, Zarit Burden Interview, Phase of Illness, Goal Attainment Scaling, Eastern Cooperative Oncology Group Performance Status, Consumer Quality Indices Palliative Care and Sense of Security in Care. During the main study phase, we will use a mixed-methods approach to evaluate the instruments’ psychometric properties (reliability, validity, feasibility and practicability), to identify barriers, facilitators and limitations of their routine use and to explore how their use affects the care within the SOPC setting.
Discussion: At the end of this study, an outcome- and patient-centered, validated measurement approach should be provided, adapted for standardized evaluations in SOPC across patient groups, palliative care services and regions nationwide. The standardized application of instruments should allow for making valid statements and comparisons of health care quality in SOPC based on process- and outcome-evaluation rather than relying on structural data only. Moreover, the instruments might directly influence the care of patients in palliative situations.
Trial registration: German Clinical Trials Register (DRKS-ID: DRKS00012421).
Background: Many gene variants modulate the individual perception of pain and possibly also its persistence. The limited selection of single functional variants is increasingly being replaced by analyses of the full coding and regulatory sequences of pain-relevant genes accessible by means of next generation sequencing (NGS).
Methods: An NGS panel was created for a set of 77 human genes selected following different lines of evidence supporting their role in persisting pain. To address the role of these candidate genes, we established a sequencing assay based on a custom AmpliSeqTM panel to assess the exomic sequences in 72 subjects of Caucasian ethnicity. To identify the systems biology of the genes, the biological functions associated with these genes were assessed by means of a computational over-representation analysis.
Results: Sequencing generated a median of 2.85 ⋅ 106 reads per run with a mean depth close to 200 reads, mean read length of 205 called bases and an average chip loading of 71%. A total of 3,185 genetic variants were called. A computational functional genomics analysis indicated that the proposed NGS gene panel covers biological processes identified previously as characterizing the functional genomics of persisting pain.
Conclusion: Results of the NGS assay suggested that the produced nucleotide sequences are comparable to those earned with the classical Sanger sequencing technique. The assay is applicable for small to large-scale experimental setups to target the accessing of information about any nucleotide within the addressed genes in a study cohort.
Background: Ataxia telangiectasia (A-T) is a devastating multi-system disorder characterized by progressive cerebellar ataxia, growth retardation, immunodeficiency, chronic pulmonary disease and chromosomal instability. Cutaneous granulomas are a known phenomenon in A-T but extra-dermal manifestation of granulomas at bone and synovia has not been reported so far. The clinical presentation, immunological findings, the long-term course and treatment options of eight patients with severe granulomas will be reported.
Methods: From our cohort of 44 classical A-T patients, eight patients aged 2–11 years (18.2%) presented with granulomas. Immunological features of patients with and without granulomas were compared. Five patients suffered from cutaneous manifestation, in two patients we detected a bone and in one a joint involvement. Patients with significant extra-dermal involvement as well as one patient with massive skin manifestation were treated with TNF inhibitors. The patient with granulomas at his finger joint and elbow was treated with hematopoietic stem cell transplantation (HSCT).
Results: Interestingly, seven of eight patients with granulomas were total IgA deficient, but there were no differences in IgG and IgM levels. All lymphocytes subsets were equally distributed except patients with granuloma had significantly lower naïve CD8 cells. In patients without treatment, four of eight showed a slow but significant enlargement of the granuloma. Treatment success with TNF inhibitors was variable. In one patient, treatment with TNF inhibitors led to a total remission for 3 years up to now. In two patients, treatment with TNF inhibitors led to a partial regression of granulomas. Treatment interruptions caused deterioration again.
Conclusions: Granulomas in A-T progress slowly over years and can lead to significant morbidity.Treatment with TNF inhibitors was safe and in part successful in our patients. Interestingly HSCT leads to complete remission, and indicates that aberrant immune function is responsible for granulomas in A-T patients.
At a glance commentary:
Scientific knowledge on the subject: Little is known about the clinical presentation, course and treatment of granulomas in ataxia telangiectasia (A-T). In addition, this is the first report of extra-dermal manifestation of granulomas at bone and synovia in patients with A-T.
What This Study Adds to the Field: Granulomas in A-T progress slowly over years and can lead to significant morbidity. Treatment with TNF inhibitors was safe and in part successful in our patients.
Background and purpose: The astroglial protein GFAP is a blood biomarker indicative of intracerebral hemorrhage in patients with acute stroke. Due to its brain specificity and the necessity of brain damage for its detectability in blood, we hypothesized that GFAP could be an interesting marker in cases with primary cerebral cause of death, e.g., traumatic brain injury.
Methods: All corpses scheduled for an autopsy in the Frankfurt Department of Forensic medicine within a 15-month period were included in the study. Cases with a known history of brain disease in the 3 months before death were excluded. During autopsy, blood was collected and GFAP serum levels were determined using a commercially available ELISA. The autopsy protocols were reviewed for the presence of a primary cerebral or a primary non-cerebral cause of death. Agony time was also determined.
Results: A total of 129 autopsy cases were included. GFAP concentrations did not differ between cerebral (median 0.96 μg/l, IQR 5.03) and non-cerebral causes of death (1.21 μg/l, 3.58). GFAP levels were found to be unaffected by hemolysis or post-mortem interval. GFAP levels were found to be increased in cases with prolonged agony times (median 1.76 μg/l [IQR 4.70]) compared to short (0.58 μg/l [0.58]; p<0.001) and ultra-short agony times (0.21 μg/l [0.12]; p = 0.002).
Conclusion: Post-mortem GFAP serum concentrations correlate with agony time and might therefore be useful for the evaluation of the severity of brain damage in prolonged death. Elevated GFAP serum levels do not indicate a primary cerebral cause of death.
Background: Transient elastography (TE) has been validated as an effective noninvasive tool for the assessment of liver fibrosis. The XL probe is a new probe that was initially designed for use in patients with obesity. A meta-analysis was performed to assess the feasibility and efficacy of TE using the XL probe.
Methods: In September 2016, we systematically searched the PubMed and Science Direct search engines. The feasibility of TE was evaluated based on the failure rate and the results of the unreliable liver stiffness measurement (LSM). The efficacy of TE was measured using sensitivity, specificity, and summary receiver-operating characteristic as measures/indices assessed in different stages of fibrosis. Heterogeneity was measured using the chi-squared test and the Q-statistic. We used the 95% confidence interval (95% CI) as an effect measure.
Results: We included 8 studies in the meta-analysis. When the XL was compared to the M probe, the former showed a lower risk of failure rate [relative risk (RR) 0.24, 95% CI 0.14–0.38]. In patients with a body mass index ≥30 kg/m2, the XL probe showed a statistically significantly lower risk of failure rate (RR 0.16, 95% CI 0.08–0.32) but no significant improvement (RR 0.76, 95% CI 0.50–1.16) in the unreliable LSM result. In patients showing liver fibrosis stage ≥F2, the XL probe showed a sensitivity of 0.56 (95% CI 0.39–0.72), specificity of 0.71 (95% CI 0.61–0.79), and an area under the curve (AUC) of 0.71. The results observed in patients with liver fibrosis stage F4 were more promising with a sensitivity of 0.84 (95% CI 0.76–0.90), specificity of 0.78 (95% CI 0.70–0.84), and an AUC of 0.88.
Conclusion: TE using the XL probe demonstrates significant diagnostic utility in patients with liver fibrosis and is likely to be more reliable than the M probe in patients with obesity. Large prospective multicenter studies are, however, necessary to establish the new cut-off values to be used for the XL probe in patients with obesity.
Based on increasing evidence suggesting that MS pathology involves alterations in bioactive lipid metabolism, the present analysis was aimed at generating a complex serum lipid-biomarker. Using unsupervised machine-learning, implemented as emergent self-organizing maps of neuronal networks, swarm intelligence and Minimum Curvilinear Embedding, a cluster structure was found in the input data space comprising serum concentrations of d = 43 different lipid-markers of various classes. The structure coincided largely with the clinical diagnosis, indicating that the data provide a basis for the creation of a biomarker (classifier). This was subsequently assessed using supervised machine-learning, implemented as random forests and computed ABC analysis-based feature selection. Bayesian statistics-based biomarker creation was used to map the diagnostic classes of either MS patients (n = 102) or healthy subjects (n = 301). Eight lipid-markers passed the feature selection and comprised GluCerC16, LPA20:4, HETE15S, LacCerC24:1, C16Sphinganine, biopterin and the endocannabinoids PEA and OEA. A complex classifier or biomarker was developed that predicted MS at a sensitivity, specificity and accuracy of approximately 95% in training and test data sets, respectively. The present successful application of serum lipid marker concentrations to MS data is encouraging for further efforts to establish an MS biomarker based on serum lipidomics.
A point mutation in the Ncr1 signal peptide impairs the development of innate lymphoid cell subsets
(2018)
NKp46 (CD335) is a surface receptor shared by both human and mouse natural killer (NK) cells and innate lymphoid cells (ILCs) that transduces activating signals necessary to eliminate virus-infected cells and tumors. Here, we describe a spontaneous point mutation of cysteine to arginine (C14R) in the signal peptide of the NKp46 protein in congenic Ly5.1 mice and the newly generated NCRB6C14R strain. Ly5.1C14R NK cells expressed similar levels of Ncr1 mRNA as C57BL/6, but showed impaired surface NKp46 and reduced ability to control melanoma tumors in vivo. Expression of the mutant NKp46C14R in 293T cells showed that NKp46 protein trafficking to the cell surface was compromised. Although Ly5.1C14R mice had normal number of NK cells, they showed an increased number of early maturation stage NK cells. CD49a+ILC1s were also increased but these cells lacked the expression of TRAIL. ILC3s that expressed NKp46 were not detectable and were not apparent when examined by T-bet expression. Thus, the C14R mutation reveals that NKp46 is important for NK cell and ILC differentiation, maturation and function.
Objective: The correlation of depleted blood through midline shift in acute subdural hematoma remains the most reliable clinical predictor to date. On the other hand, patient’s ABO blood type has a profound impact on coagulation and hemostasis. We conducted this study to evaluate the role of patient’s blood type in terms of incidence, clinical course and outcome after acute subdural hematoma bleeding.
Methods: 100 patients with acute subdural hematoma treated between 2010 and 2015 at the author’s institution were included. Baseline characteristics and clinical findings including Glasgow coma scale, Glasgow outcome scale, hematoma volume, rebleeding, midline shift, postoperative seizures and the presence of anticoagulation were analyzed for their association with ABO blood type.
Results: Patient’s with blood type O were found to have a lower midline shift (p<0.01) and significantly less seizures (OR: 0.43; p<0.05) compared to non-O patients. Furthermore, patients with blood type A had the a significantly higher midline shift (p<0.05) and a significantly increased risk for postoperative seizures (OR: 4.01; p<0.001). There was no difference in ABO blood type distribution between acute subdural hematoma patients and the average population.
Conclusion: The ABO blood type has significant influence on acute subdural hematoma sequelae. Patient’s with blood type O benefit in their clinical course after acute subdural hematoma whereas blood type A patients are at highest risk for increased midline shift and postoperative seizures. Further studies elucidating the biological mechanisms of blood type depended hemostaseology and its role in acute subdural hematoma are required for the development of an appropriate intervention.