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As the prognosis of invasive aspergillosis remains unacceptably poor in patients undergoing hematopoietic stem cell transplantation (HSCT), there is a growing interest in the adoptive transfer of antifungal effector cells, such as Natural Killer (NK) cells. Because immunosuppressive agents are required in most HSCT recipients, knowledge of the impact of these compounds on the antifungal activity of NK cells is a prerequisite for clinical trials. We, therefore, assessed the effect of methylprednisolone (mPRED), cyclosporin A (CsA) and mycophenolic acid (MPA) at different concentrations on proliferation, apoptosis/necrosis, and the direct and indirect anti-Aspergillus activity of human NK cells. Methylprednisolone decreased proliferation and increased apoptosis of NK cells in a significant manner. After seven days, a reduction of viable NK cells was seen for all three immunosuppressants, which was significant for MPA only. Cyclosporin A significantly inhibited the direct hyphal damage by NK cells in a dose-dependent manner. None of the immunosuppressive compounds had a major impact on the measured levels of interferon-γ, granulocyte-macrophage colony-stimulating factor and RANTES (regulated on activation, normal T cell expressed and secreted; CCL5). Our data demonstrate that commonly used immunosuppressive compounds have distinct effects on proliferation, viability and antifungal activity of human NK cells, which should be considered in designing studies on the use of NK cells for adoptive antifungal immunotherapy.
Objective: Many cancer patients complain about cognitive dysfunction. While cognitive deficits have been attributed to the side effects of chemotherapy, there is evidence for impairment at disease onset, prior to cancer-directed therapy. Further debated issues concern the relationship between self-reported complaints and objective test performance and the role of psychological distress.
Method: We assessed performance on neuropsychological tests of attention and memory and obtained estimates of subjective distress and quality of life in 27 breast cancer patients and 20 healthy controls. Testing in patients took place shortly after the initial diagnosis, but prior to subsequent therapy.
Results: While patients showed elevated distress, cognitive performance differed on a few subtests only. Patients showed slower processing speed and poorer verbal memory than controls. Objective and self-reported cognitive function were unrelated, and psychological distress correlated more strongly with subjective complaints than with neuropsychological test performance.
Conclusion: This study provides further evidence of limited cognitive deficits in cancer patients prior to the onset of adjuvant therapy. Self-reported cognitive deficits seem more closely related to psychological distress than to objective test performance.
Ein Zell-Atlas des kranken Herzens : Einzelzelltechniken ermöglichen neue Einsichten auf Zellebene
(2019)
Herz und Gefäße bilden ein hochkomplexes Organsystem, in dem unterschiedlichste Zellen korrekt zusammenarbeiten müssen, um alle Organe mit Blut zu versorgen. In den vergangenen Jahrzehnten hat die Herzbiologie ganze Gewebe oder Zellisolate in den Blick genommen. Doch jetzt erlauben neue Technologien, die Vielfalt der Zelltypen und ihre individuelle Antwort auf Signale bis auf die Ebene von Proteinen und Genen zu verfolgen. Forscher hoffen, kranken Herzen dadurch besser bei der Regeneration helfen zu können.
Mutationen in Blutstammzellen müssen nicht unbedingt zu Blutkrebs führen. Erst vor Kurzem hat man entdeckt, dass Klone mutierter Blutzellen bei vielen gesunden Menschen im Alter nachweisbar sind. Dennoch stufen Forscher die klonale Hämatopoese inzwischen als Risikofaktor für Herz-Kreislauf-Erkrankungen ein – mit einer ähnlichen Bedeutung wie Rauchen, Übergewicht oder Bluthochdruck.
"Medizin bringt einem den Menschen nahe", sagt Dietmar Schranz. Schon als junger Arzt bereiste er die Welt. Er behandelte Leprakranke in Pakistan und war mit "Cap Anamur – Deutsche Not-Ärzte" in Asien. Dass er schließlich Kinderkardiologe wurde, verdankt er vier geistigen Vätern. Heute ist er selbst für viele Kardiologen weltweit zu einer prägenden Figur geworden.
In einem Wurm wurden sie 1993 zuerst entdeckt: kleine Ribonukleinsäuren (microRNAs), die nicht für ein Protein kodieren, sondern gezielt mit Boten-RNA (mRNA) paaren. Damit stoppen sie die Übersetzung der mRNA in Protein (Translation) oder lösen den Abbau der Ziel-mRNA aus. In den folgenden Jahren wurde deutlich, dass microRNAs auch beim Menschen eine wichtige Rolle spielen. Möglicherweise ist jedes dritte oder vierte Gen durch microRNA reguliert. Nur zwei bis drei Prozent des humanen Genoms kodiert Proteine; die Mehrzahl der gebildeten RNAs (über 80 Prozent) haben unbekannte oder regulatorische Funktionen. ...
Über epigenetische Prozesse können Umweltfaktoren und Lebensstil unsere Entwicklung und Gesundheit beeinflussen – auch über Generationen hinweg –, ohne die Sequenz der DNA zu verändern. Erst in jüngster Zeit ist es möglich, die Mechanismen auf der molekularen Ebene zu entschlüsseln. Für Herz-Kreislauf-Erkrankungen sind erste Ansätze für epigenetische Therapien in Sicht.
Heute weiß fast jeder, dass ein hoher Blutcholesterinspiegel ein Risikofaktor für Herz-Kreislauf-Erkrankungen ist. Inzwischen gibt es wirksame Therapien, die den Cholesterinstoffwechsel wieder in Gang setzen. Doch die Herzgesundheit hängt von so viel mehr ab als von Cholesterin. Zu den bekannten Mediatoren für Herz-Kreislauf-Erkrankungen sind neue hinzugekommen. Alle können durch Ernährung beeinflusst werden.
Transforming growth factor-β (TGF-β) suppresses innate and adaptive immune responses via multiple mechanisms. TGF-β also importantly contributes to the formation of an immunosuppressive tumor microenvironment thereby promoting tumor growth. Amongst others, TGF-β impairs tumor recognition by cytotoxic lymphocytes via NKG2D. NKG2D is a homodimeric C-type lectin-like receptor expressed on virtually all human NK cells and cytotoxic T cells, and stimulates their effector functions upon engagement by NKG2D ligands (NKG2DL). While NKG2DL are mostly absent from healthy cells, their expression is induced by cellular stress and malignant transformation, and, accordingly, frequently detected on various tumor cells. Hence, the NKG2D axis is thought to play a decisive role in cancer immunosurveillance and, obviously, often is compromised in clinically apparent tumors. There is mounting evidence that TGF-β, produced by tumor cells and immune cells in the tumor microenvironment, plays a key role in blunting the NKG2D-mediated tumor surveillance. Here, we review the current knowledge on the impairment of NKG2D-mediated cancer immunity through TGF-β and discuss therapeutic approaches aiming at counteracting this major immune escape pathway. By reducing tumor-associated expression of NKG2DL and blinding cytotoxic lymphocytes through down-regulation of NKG2D, TGF-β is acting upon both sides of the NKG2D axis severely compromising NKG2D-mediated tumor rejection. Consequently, novel therapies targeting the TGF-β pathway are expected to reinvigorate NKG2D-mediated tumor elimination and thereby to improve the survival of cancer patients.
Introduction and Objectives: Surgical techniques such as preservation of the full functional-length of the urethral sphincter (FFLU) have a positive impact on postoperative continence rates. Thereby, data on very early continence rates after radical prostatectomy (RP) are scarce. The aim of the present study was to analyze very early continence rates in patients undergoing FFLU during RP.
Materials and Methods: Very early-continence was assessed by using the PAD-test within 24 h after removal of the transurethral catheter. The PAD-test is a validated test that measures the amount of involuntary urine loss while performing predefined physical activities within 1 h (e.g., coughing, walking, climbing stairs). Full continence was defined as a urine loss below 1 g. Mild, moderate, and severe incontinence was defined as urine loss of 1–10 g, 11–50 g, and >50 g, respectively.
Results: 90 patients were prospectively analyzed. Removal of the catheter was performed on the 6th postoperative day. Proportions for no, mild, moderate and severe incontinence were 18.9, 45.5, 20.0, and 15.6%, respectively. In logistic regression younger age was associated with significant better continence (HR 2.52, p = 0.04), while bilateral nerve-sparing (HR 2.56, p = 0.057) and organ-confined tumor (HR 2.22, p = 0.078) showed lower urine loss, although the effect was statistically not significant. In MVA, similar results were recorded.
Conclusion: Overall, 64.4% of patients were continent or suffered only from mild incontinence at 24 h after catheter removal. In general, reduced urine loss was recorded in younger patients, patients with organ-confined tumor and in patients with bilateral nerve sparing. Severe incontinence rates were remarkably low with 15.6%.
Autophagy has important functions in maintaining energy metabolism under conditions of starvation and to alleviate stress by removal of damaged and potentially harmful cellular components. Therefore, autophagy represents a pro-survival stress response in the majority of cases. However, the role of autophagy in cell survival and cell death decisions is highly dependent on its extent, duration, and on the respective cellular context. An alternative pro-death function of autophagy has been consistently observed in different settings, in particular, in developmental cell death of lower organisms and in drug-induced cancer cell death. This cell death is referred to as autophagic cell death (ACD) or autophagy-dependent cell death (ADCD), a type of cellular demise that may act as a backup cell death program in apoptosis-deficient tumors. This pro-death function of autophagy may be exerted either via non-selective bulk autophagy or excessive (lethal) removal of mitochondria via selective mitophagy, opening new avenues for the therapeutic exploitation of autophagy/mitophagy in cancer treatment.
Health-related preferences of older patients with multimorbidity: the protocol for an evidence map
(2019)
Introduction: Interaction of conditions and treatments, complicated care needs and substantial treatment burden make patient–physician encounters involving multimorbid older patients highly complex. To optimally integrate patients’ preferences, define and prioritise realistic treatment goals and individualise care, a patient-centred approach is recommended. However, the preferences of older patients, who are especially vulnerable and frequently multimorbid, have not been systematically investigated with regard to their health status. The purpose of this evidence map is to explore current research addressing health-related preferences of older patients with multimorbidity, and to identify the knowledge clusters and research gaps.
Methods and analysis: To identify relevant research, we will conduct searches in the electronic databases MEDLINE, EMBASE, PsycINFO, PSYNDEX, CINAHL, Social Science Citation Index, Social Science Citation Index Expanded and the Cochrane library from their inception. We will check reference lists of relevant articles and carry out cited reference research (forward citation tracking). Two independent reviewers will screen titles and abstracts, check full texts for eligibility and extract the data. Any disagreement will be resolved and consensus reached with the help of a third reviewer. We will include both qualitative and quantitative studies, and address preferences from the patients’ perspectives in a multimorbid population of 60 years or older. There will be no restrictions on the publication language. Data extraction tables will present study and patient characteristics, aim of study, methods used to identify preferences and outcomes (ie, type of preferences). We will summarise the data using tables and figures (ie, bubble plot) to present the research landscape and to describe clusters and gaps.
Ethics and dissemination: Due to the nature of the proposed evidence map, ethics approval will not be required. Results from our research will be disseminated by means of specifically prepared materials for patients, at relevant (inter)national conferences and via publication in peer-reviewed journals.
Background: Cannabis proofed to be effective in pain relief, but one major side effect is its influence on memory in humans. Therefore, the role of memory on central processing of nociceptive information was investigated in healthy volunteers.
Methods: In a placebo-controlled cross-over study including 22 healthy subjects, the effect of 20 mg oral Δ9-tetrahydrocannabinol (THC) on memory involving nociceptive sensations was studied, using a delayed stimulus discrimination task (DSDT). To control for nociceptive specificity, a similar DSDT-based study was performed in a subgroup of thirteen subjects, using visual stimuli.
Results: For each nociceptive stimulus pair, the second stimulus was associated with stronger and more extended brain activations than the first stimulus. These differences disappeared after THC administration. The THC effects were mainly located in two clusters comprising the insula and inferior frontal cortex in the right hemisphere, and the caudate nucleus and putamen bilaterally. These cerebral effects were accompanied in the DSDT by a significant reduction of correct ratings from 41.61% to 37.05% after THC administration (rm-ANOVA interaction "drug" by "measurement": F (1,21) = 4.685, p = 0.042). Rating performance was also reduced for the visual DSDT (69.87% to 54.35%; rm-ANOVA interaction of "drug" by "measurement": F (1,12) = 13.478, p = 0.003) and reflected in a reduction of stimulus-related brain deactivations in the bilateral angular gyrus.
Conclusions: Results suggest that part of the effect of THC on pain may be related to memory effects. THC reduced the performance in DSDT of nociceptive and visual stimuli, which was accompanied by significant effects on brain activations. However, a pain specificity of these effects cannot be deduced from the data presented.
Objectives: The present randomized clinical trial assesses the six-month outcomes following surgical regenerative therapy of periimplantitis lesions using either an electrolytic method (EC) to remove biofilms or a combination of powder spray and electrolytic method (PEC).
Materials and Methods: 24 patients with 24 implants suffering from peri-implantitis with any type of bone defect were randomly treated by EC or PEC. Bone defects were augmented with a mixture of natural bone mineral and autogenous bone and left for submerged healing. The distance from implant shoulder to bone was assessed at six defined points at baseline (T0) and after six months at uncovering surgery (T1) by periodontal probe and standardized x-rays.
Results: One implant had to be removed at T1 because of reinfection and other obstacles. None of the other implants showed signs of inflammation. Bone gain was 2.71 ± 1.70 mm for EC and 2.81 ± 2.15 mm for PEC. No statistically significant difference between EC and PEC was detected. Significant clinical bone fill was observed for all 24 implants. Complete regeneration of bone was achieved in 12 implants. Defect morphology impacted the amount of regeneration.
Conclusion: EC needs no further mechanical cleaning by powder spray. Complete re-osseointegration in peri-implantitis cases is possible.
Background: Critical incident reporting systems (CIRS) can be an important tool for the identification of organisational safety needs and thus to improve patient safety. In German primary care, CIRS use is obligatory but remains rare. Studies on CIRS implementation in primary care are lacking, but those from secondary care recommend involving management personnel.
Objective: This project aimed to increase CIRS use in 69 practices belonging to a local practice network.
Methods: The intervention consisted of the provision of a web-based CIRS, accompanying measures to train practice teams in error management and CIRS, and the involvement of the network’s management. Three measurements were used: (1) number of incident reports and user access rates to the web-based CIRS were recorded, (2) staff were given a questionnaire addressing incident reporting, error management and safety climate and (3) qualitative reflection conferences were held with network management.
Results: Over 20 months, 17 critical incidents were reported to the web-based CIRS. The number of staff intending to report the next incident online decreased from 42% to 20% of participants. In contrast, the number of practices using an offline CIRS (eg, incident book) increased from 23% to 49% of practices. Practices also began proactively approaching network management for help with incidents. After project completion, participants scored higher in the patient safety climate factor ‘perception of causes of errors’. For many practices, the project provided the first contact with structured error management.
Conclusion: Specific measures to improve the use of CIRS in primary care should focus on network management and practice owners. Practices need basic training on safety culture and error management. Continuing, practices should implement an offline CIRS, before they can profit from the exchange of reports via web-based CIRS. It is crucial that practices receive feedback on incidents, and trained network management personnel can provide such support.
Classical Hodgkin lymphoma (cHL) is one of the most common malignant lymphomas in Western Europe. The nodular sclerosing subtype of cHL (NS cHL) is characterized by a proliferation of fibroblasts in the tumor microenvironment, leading to fibrotic bands surrounding the lymphoma infiltrate. Several studies have described a crosstalk between the tumour cells of cHL, the Hodgkin- and Reed-Sternberg (HRS) cells, and cancer-associated fibroblasts. However, to date a deep molecular characterization of these fibroblasts is lacking. Thus, the aim of the present study is a comprehensive characterization of these fibroblasts. Gene expression profiling and methylation profiles of fibroblasts isolated from primary lymph node suspensions revealed persistent differences between fibroblasts obtained from NS cHL and lymphadenitis. NS cHL derived fibroblasts exhibit a myofibroblastic phenotype characterized by myocardin (MYOCD) expression. Moreover, TIMP3, an inhibitor of matrix metalloproteinases, was strongly upregulated in NS cHL fibroblasts, likely contributing to the accumulation of collagen in sclerotic bands of NS cHL. As previously shown for other types of cancer-associated fibroblasts, treatment by luteolin could reverse this fibroblast phenotype and decrease TIMP3 secretion. NS cHL fibroblasts showed enhanced proliferation when they were exposed to soluble factors released from HRS cells. For HRS cells, soluble factors from fibroblasts were not sufficient to protect them from Brentuximab-Vedotin induced cell death. However, HRS cells adherent to fibroblasts were protected from Brentuximab-Vedotin induced injury. In summary, we confirm the importance of fibroblasts for HRS cell survival and identify TIMP3 which probably contributes as a major factor to the typical fibrosis observed in NS cHL.
Introduction: Pediatric pneumococcal pneumonia complicated by parapneumonic pleural effusion/empyema (PPE/PE) remains a major concern despite general immunization with pneumococcal conjugate vaccines (PCVs).
Methods: In a nationwide pediatric hospital surveillance study in Germany we identified 584 children <18 years of age with bacteriologically confirmed PPE/PE from October 2010 to June 2018. Streptococcus pneumoniae was identified by culture and/or PCR of blood samples and/or pleural fluid and serotyped.
Results: S. pneumoniae was identified in 256 of 584 (43.8%) children by culture (n = 122) and/or PCR (n = 207). The following pneumococcal serotypes were detected in 114 children: serotype 3 (42.1%), 1 (25.4%), 7F (12.3%), 19A (7.9%), other PCV13 serotypes (4.4%) and non-PCV13 serotypes (7.9%). Between October 2010 and June 2014 serotype 1 (38.1%) and serotype 3 (25.4%) were most prevalent, whereas between July 2014 and June 2018 serotype 3 (62.7%) and non-PCV13 serotypes (15.7%) were dominant. Compared to children with other pneumococcal serotypes, children with serotype 3 associated PPE/PE were younger (median 3.2 years [IQR 2.1–4.3 years] vs. median 5.6 years [IQR 3.8–8.2 years]; p < 0.001) and more frequently admitted to intensive care (43 [89.6%] vs. 48 [73.8%]; p = 0.04). Seventy-six of 114 (66.7%) children with pneumococcal PPE/PE had been vaccinated with pneumococcal vaccines. Thirty-nine of 76 (51.3%) had received a vaccine covering the serotype detected. Thirty of these 39 breakthrough cases were age-appropriately vaccinated with PCV13 and considered vaccine failures, including 26 children with serotype 3, three children with serotype 19A and one child with serotype 1.
Conclusion: Following the introduction of PCV13 in general childhood vaccination we observed a strong emergence of serotype 3 associated PPE/PE in the German pediatric population, including a considerable number of younger children with serotype 3 vaccine breakthrough cases and failures. Future PCVs should not only cover newly emerging serotypes, but also include a more effective component against serotype 3.
Recent studies have proven that Dimethylfumarate (DMF) has a marked anti-proliferative impact on diverse cancer entities e.g., on malignant melanoma. To explore its anti-tumorigenic potential, we examined the effects of DMF on human colon carcinoma cell lines and the underlying mechanisms of action. Human colon cancer cell line HT-29 and human colorectal carcinoma cell line T84 were treated with or without DMF. Effects of DMF on proliferation, cell cycle progression, and apoptosis were analyzed mainly by Bromodeoxyuridine (BrdU)- and Lactatdehydrogenase (LDH)-assays, caspase activation, flowcytometry, immunofluorescence, and immunoblotting. In addition, combinational treatments with radiation and chemotherapy were performed. DMF inhibits cell proliferation in both cell lines. It was shown that DMF induces a cell cycle arrest in G0/G1 phase, which is accompanied by upregulation of p21 and downregulation of cyclin D1 and Cyclin dependent kinase (CDK)4. Furthermore, upregulation of autophagy associated proteins suggests that autophagy is involved. In addition, the activation of apoptotic markers provides evidence that apoptosis is involved. Our results show that DMF supports the action of oxaliplatin in a synergetic manner and failed synergy with radiation. We demonstrated that DMF has distinct anti-tumorigenic, cell dependent effects on colon cancer cells by arresting cell cycle in G0/G1 phase as well as activating both the autophagic and apoptotic pathways and synergizes with chemotherapy.
Adipose-derived mesenchymal stem cells (ASCs) are considered to be a useful tool for regenerative medicine, owing to their capabilities in differentiation, self-renewal, and immunomodulation. These cells have become a focus in the clinical setting due to their abundance and easy isolation. However, ASCs from different depots are not well characterized. Here, we analyzed the functional similarities and differences of subcutaneous and visceral ASCs. Subcutaneous ASCs have an extraordinarily directed mode of motility and a highly dynamic focal adhesion turnover, even though they share similar surface markers, whereas visceral ASCs move in an undirected random pattern with more stable focal adhesions. Visceral ASCs have a higher potential to differentiate into adipogenic and osteogenic cells when compared to subcutaneous ASCs. In line with these observations, visceral ASCs demonstrate a more active sonic hedgehog pathway that is linked to a high expression of cilia/differentiation related genes. Moreover, visceral ASCs secrete higher levels of inflammatory cytokines interleukin-6, interleukin-8, and tumor necrosis factor α relative to subcutaneous ASCs. These findings highlight, that both ASC subpopulations share multiple cellular features, but significantly differ in their functions. The functional diversity of ASCs depends on their origin, cellular context and surrounding microenvironment within adipose tissues. The data provide important insight into the biology of ASCs, which might be useful in choosing the adequate ASC subpopulation for regenerative therapies.
IL-27 regulates inflammatory diseases by exerting a pleiotropic impact on immune cells. In cancer, IL-27 restricts tumor growth by acting on tumor cells directly, while its role in the tumor microenvironment is still controversially discussed. To explore IL-27 signaling in the tumor stroma, we used a mammary carcinoma syngraft approach in IL27Rα-deficient mice. Tumor growth in animals lacking IL27Rα was markedly reduced. We noticed a decrease in immune cell infiltrates, enhanced tumor cell death, and fibroblast accumulation. However, most striking changes pertain the tumor vasculature. Tumors in IL27Rα-deficient mice were unable to form functional vessels. Blocking IL-27-STAT1 signaling in endothelial cells in vitro provoked an overshooting migration/sprouting of endothelial cells. Apparently, the lack of the IL-27 receptor caused endothelial cell hyper-activation via STAT1 that limited vessel maturation. Our data reveal a so far unappreciated role of IL-27 in endothelial cells with importance in pathological vessel formation.
Chemotherapy, nerve injuries, or diseases like multiple sclerosis can cause pathophysiological processes of persistent and neuropathic pain. Thereby, the activation threshold of ion channels is reduced in peripheral sensory neurons to normally noxious stimuli like heat, cold, acid, or mechanical due to sensitization processes. This leads to enhanced neuronal activity, which can result in mechanical allodynia, cold allodynia, thermal hyperalgesia, spontaneous pain, and may initiate persistent and neuropathic pain. The treatment options for persistent and neuropathic pain patients are limited; for about 50% of them, current medication is not efficient due to severe side effects or low response to the treatment. Therefore, it is of special interest to find additional treatment strategies. One approach is the control of neuronal sensitization processes. Herein, signaling lipids are crucial mediators and play an important role during the onset and maintenance of pain. As preclinical studies demonstrate, lipids may act as endogenous ligands or may sensitize transient receptor potential (TRP)-channels. Likewise, they can cause enhanced activity of sensory neurons by mechanisms involving G-protein coupled receptors and activation of intracellular protein kinases. In this regard, oxidized metabolites of the essential fatty acid linoleic acid, 9- and 13-hydroxyoctadecadienoic acid (HODE), their dihydroxy-metabolites (DiHOMEs), as well as epoxides of linoleic acid (EpOMEs) and of arachidonic acid (EETs), as well as lysophospholipids, sphingolipids, and specialized pro-resolving mediators (SPMs) have been reported to play distinct roles in pain transmission or inhibition. Here, we discuss the underlying molecular mechanisms of the oxidized linoleic acid metabolites and eicosanoids. Furthermore, we critically evaluate their role as potential targets for the development of novel analgesics and for the treatment of persistent or neuropathic pain.
Introduction: MRI-targeted biopsy (TB) increases overall prostate-cancer (PCa) detection-rates and decreases the risk of insignificant PCa detection. However, the impact of these findings on the definite pathology after radical prostatectomy (RP) is under debate.
Materials and Methods: Between 01/2014 and 12/2018, 366 patients undergoing prostate biopsy and RP were retrospectively analyzed. The correlation between biopsy Gleason-score (highest Gleason-score in a core) and the RP Gleason-score in patients undergoing systematic biopsy (SB-group) (n = 221) or TB+SB (TB-group, n = 145) was tested using the ISUP Gleason-group grading (GGG, scale 1–5). Sub analyses focused on biopsy GGG 1 and GGG ≥ 2.
Results: Proportions of biopsy GGG 1–5 in the SB-group and TB-group were 24.4, 37.6, 19, 10.9, 8.1% and 13.8, 43.4, 24.2, 13.8, 4.8%, respectively (p = 0.07). Biopsy and pathologic GGG were concordant in 108 of 221 (48.9%) in SB- and 74 of 145 (51.1%) in TB-group (p = 0.8). Gleason upgrading was recorded in 33.5 and 31.7% in SB- vs. TB-group (p = 0.8). Patients with biopsy GGG 1 undergoing RP showed an upgrading in 68.5%(37/54) in SB- and 75%(15/20) in TB-group (p = 0.8). In patients with biopsy GGG ≥ 2 concordance increased for both biopsy approaches (54.5 vs. 55.2% for SB- vs. TB-group, p = 0.9).
Discussion: Irrespective of differences in PCa detection-rates between TB- and SB-groups, no significant differences in GGG concordance and upgrading between patients of both groups undergoing biopsy, followed by RP, were recorded. Concordance rates increased in men with biopsy GGG ≥ 2. TB seems to detect more patients with PCa without a difference in concordance with final pathology.
Fibrogenesis is a progressive scarring event resulting from disrupted regular wound healing due to repeated tissue injury and can end in organ failure, like in liver cirrhosis. The protagonists in this process, either liver-resident cells or patrolling leukocytes attracted to the site of tissue damage, interact with each other by soluble factors but also by direct cell-cell contact mediated by cell adhesion molecules. Since cell adhesion molecules also support binding to the extracellular matrix, they represent excellent biosensors, which allow cells to modulate their behavior based on changes in the surrounding microenvironment. In this review, we focus on selectins, cadherins, integrins and members of the immunoglobulin superfamily of adhesion molecules as well as some non-classical cell adhesion molecules in the context of hepatic fibrosis. We describe their liver-specific contributions to leukocyte recruitment, cell differentiation and survival, matrix remodeling or angiogenesis and touch on their suitability as targets in antifibrotic therapies.
Background: Recent research has shown an increased risk of accidents and injuries in ADHD patients, which could potentially be reduced by stimulant treatment. Therefore, the first aim of our study was to evaluate the prevalence of adult ADHD in a trauma surgery population. The second aim was to investigate accident mechanisms and circumstances which could be specific to ADHD patients, in comparison to the general population.
Methods: We screened 905 accident victims for ADHD using the ASRS 18-item self-report questionnaire. The basic demographic data and circumstances of the accidents were also assessed.
Results: Prevalence of adult ADHD was found to be 6.18% in our trauma surgery patient sample. ADHD accident victims reported significantly higher rates of distraction, stress and overconfidence in comparison to non-ADHD accident victims. Overconfidence and being in thoughts as causal mechanisms for the accidents remained significantly higher in ADHD patients after correction for multiple comparison. ADHD patients additionally reported a history of multiple accidents.
Conclusion: The majority of ADHD patients in our sample had not previously been diagnosed and were therefore not receiving treatment. The results subsequently suggest that general ADHD screening in trauma surgery patients may be useful in preventing further accidents in ADHD patients. Furthermore, psychoeducation regarding specific causal accident mechanisms could be implemented in ADHD therapy to decrease accident incidence rate.
Cerebral radiation necrosis is a common complication of the radiotherapy of brain tumours that can cause significant mortality. Corticosteroids are the standard of care, but their efficacy is limited and the consequences of long-term steroid therapy are problematic, including the risk of adrenal insufficiency (AI). Off-label treatment with the vascular endothelial growth factor A antibody bevacizumab is highly effective in steroid-resistant radiation necrosis. Both the preservation of neural tissue integrity and the cessation of steroid therapy are key goals of bevacizumab treatment. However, the withdrawal of steroids may be impossible in patients who develop AI. In order to elucidate the frequency of AI in patients with cerebral radiation necrosis after treatment with corticosteroids and bevacizumab, we performed a retrospective study at our institution’s brain tumour centre. We obtained data on the tumour histology, age, duration and maximum dose of dexamethasone, radiologic response to bevacizumab, serum cortisol, and the need for hydrocortisone substitution for AI. We identified 17 patients with cerebral radiation necrosis who had received treatment with bevacizumab and had at least one available cortisol analysis. Fifteen patients (88%) had a radiologic response to bevacizumab. Five of the 17 patients (29%) fulfilled criteria for AI and required hormone substitution. Age, duration of dexamethasone treatment, and time since radiation were not statistically associated with the development of AI. In summary, despite the highly effective treatment of cerebral radiation necrosis with bevacizumab, steroids could yet not be discontinued due to the development of AI in roughly one-third of patients. Vigilance to spot the clinical and laboratory signs of AI and appropriate testing and management are, therefore, mandated.
Attractiveness ratings for musicians and non-musicians: An evolutionary-psychology perspective
(2019)
From an evolutionary perspective, musical behavior such as playing an instrument can be considered as part of an individual’s courting behavior. Playing a musical instrument or singing might fulfill a function similar to that of a bird’s colored feathers: attracting attention. Therefore, musicians may be rated as more attractive than non-musicians. In an online survey, 137 volunteers (95 female) with ages ranging from 16 to 39 years rated the attractiveness of fictitious persons of the opposite sex described in short verbal profiles. These profiles differed with respect to whether the described person made music or not. Additionally, the musicians’ profiles varied with regard to whether the described person played music or sang in public or in private only. Results show that musicians’ profiles were not generally rated as more attractive than non-musicians’, but attractiveness did vary according to setting: private musicians were rated as most attractive, followed by non-musicians and public musicians. Furthermore, results indicate that participants who played a musical instrument or sang themselves gave higher ratings to profiles of musicians. But for participants who do not make music themselves, higher attractiveness ratings for musicians playing instruments or sing in private settings were found. These results indicate that the impression of sharing a common interest (making music) and furthermore making music in private instrumental settings seems to make people attractive to other people. No additional support for the sexual selection hypotheses for the evolution of music was provided by the current results. The musical status of the rater affected his or her judgements, with musicians rating other people as more attractive if they share the common interest in making music. Not the display of being a musician seems to be critical for attractiveness ratings but the perceived or imagined similarity by the rater created by information on musicality, fostering the theoretical significance of the communication aspect of music.
Neurobiological systems rely on hierarchical and modular architectures to carry out intricate computations using minimal resources. A prerequisite for such systems to operate adequately is the capability to reliably and efficiently transfer information across multiple modules. Here, we study the features enabling a robust transfer of stimulus representations in modular networks of spiking neurons, tuned to operate in a balanced regime. To capitalize on the complex, transient dynamics that such networks exhibit during active processing, we apply reservoir computing principles and probe the systems' computational efficacy with specific tasks. Focusing on the comparison of random feed-forward connectivity and biologically inspired topographic maps, we find that, in a sequential set-up, structured projections between the modules are strictly necessary for information to propagate accurately to deeper modules. Such mappings not only improve computational performance and efficiency, they also reduce response variability, increase robustness against interference effects, and boost memory capacity. We further investigate how information from two separate input streams is integrated and demonstrate that it is more advantageous to perform non-linear computations on the input locally, within a given module, and subsequently transfer the result downstream, rather than transferring intermediate information and performing the computation downstream. Depending on how information is integrated early on in the system, the networks achieve similar task-performance using different strategies, indicating that the dimensionality of the neural responses does not necessarily correlate with nonlinear integration, as predicted by previous studies. These findings highlight a key role of topographic maps in supporting fast, robust, and accurate neural communication over longer distances. Given the prevalence of such structural feature, particularly in the sensory systems, elucidating their functional purpose remains an important challenge toward which this work provides relevant, new insights. At the same time, these results shed new light on important requirements for designing functional hierarchical spiking networks.
Detection of antihypertensive drugs in biological samples is an important tool to assess the adherence of hypertensive patients. Urine and serum/plasma screenings based on qualitative results may lead to misinterpretations regarding drugs with a prolonged detectability. The aim of the present study was to develop a method that can be used for therapeutic drug monitoring (TDM) of antihypertensive drugs with focus on adherence assessment. Therefore, a method for quantification of four diuretics and four β-blockers using high-performance liquid chromatography-mass spectrometric analysis (LC-MS/MS) of combined acidic and basic serum extracts was developed and validated. The method was applied to 40 serum samples from 20 patients in a supervised medication setting (trough and peak serum samples). Literature data on therapeutic concentration ranges, as well as dose-related drug concentrations (calculated from data of pharmacokinetic studies) were used to evaluate adherence assessment criteria. Concentrations were measured for bisoprolol (n = 9 patients), metoprolol (n = 7), nebivolol (n = 1), canrenone (n = 2, metabolite of spironolactone), hydrochlorothiazide (n = 10) and torasemide (n = 8). The measured concentrations were within the therapeutic reference ranges, except for 24% of the samples (mainly β-blockers). In contrast, all measured concentrations were above the lower dose-related concentration (DRC), which appears superior in evaluating adherence. In conclusion, the quantitative analysis of antihypertensive drugs in serum samples and its evaluation on the basis of the individually calculated lower DRC is a promising tool to differentially assess adherence. This method could possibly detect a lack of adherence or other causes of insufficient therapy more reliably than qualitative methods.
Gezielte Früherkennung am Beispiel des Deutschen Konsortiums Familiärer Brust- und Eierstockkrebs / Rita Schmutzler
Modelle für eine erfolgreiche, risikoadaptierte Therapie –
am Beispiel der akuten lymphatischen Leukämie / Nicola Gökbuget
Modelle für eine erfolgreiche, risikoadaptierte Therapie –
am Beispiel des Hodgkin-Lymphoms / Andreas Engert
Modelle für eine erfolgreiche, risikoadaptierte Therapie –
am Beispiel der Keimzelltumoren des Mannes / Carsten Bokemeyer
Juvenile myoclonic epilepsy (JME) is a common epilepsy syndrome characterized by bilateral myoclonic and tonic-clonic seizures typically starting in adolescence and responding well to medication. Misdiagnosis of a more severe progressive myoclonus epilepsy (PME) as JME has been suggested as a cause of drug-resistance. Medical records of the Epilepsy Center Hessen-Marburg between 2005 and 2014 were automatically selected using keywords and manually reviewed regarding the presence of a JME diagnosis at any timepoint. The identified patients were evaluated regarding seizure outcome and drug resistance according to ILAE criteria. 87/168 identified JME patients were seizure-free at last follow-up including 61 drug-responsive patients (group NDR). Seventy-eight patients were not seizure-free including 26 drug-resistant patients (group DR). Valproate was the most efficacious AED. The JME diagnosis was revised in 7 patients of group DR including 6 in whom the diagnosis had already been questioned or revised during clinical follow-up. One of these was finally diagnosed with PME (genetically confirmed Lafora disease) based on genetic testing. She was initially reviewed at age 29 yrs and considered to be inconsistent with PME. Intellectual disability (p = 0.025), cognitive impairment (p < 0.001), febrile seizures in first-degree relatives (p = 0.023) and prominent dialeptic seizures (p = 0.009) where significantly more frequent in group DR. Individuals with PME are rarely found among drug-resistant alleged JME patients in a tertiary epilepsy center. Even a very detailed review by experienced epileptologists may not identify the presence of PME before the typical features evolve underpinning the need for early genetic testing in drug-resistant JME patients.
Physiologie des Menschen
(2019)
Wir haben mit diesem Lehrbuch eine Brücke zwischen den "dicken Wälzern", die viele Dozenten empfehlen, und den Kurzlehrbüchern, die bei Studenten so beliebt sind, geschlagen. Physiologie ist ein Fach, das man verstehen muss. Denn gerade in mündlichen Prüfungen und im Physikum werden Transferleistungen eingefordert, die sich durch reines Auswendiglernen nicht ohne Weiteres lösen lassen. Im Gegensatz zu Kurzlehrbüchern findest du bei uns mehr Erklärungen, die dir beim Verständnis der Zusammenhänge helfen. Damit unser Buch nicht zu dick und unübersichtlich wird, haben wir all den Ballast, den du in den "dicken Wälzern" findest, weggelassen. Das hilft dir, dich auf die wichtigen Dinge zu konzentrieren. Diese wichtigen Dinge erklären wir dafür ausführlicher. Unser Buch ist daher der ideale Begleiter für die vorklinischen Semester, weil alle relevanten Themenkomplexe einfach und verständlich erklärt werden. Je nach Universität kann es natürlich vorkommen, dass speziellere Themen gelehrt werden, die nicht unbedingt dem Lernzielkatalog entsprechen. Diese Themen sind in unserem Buch unter Umständen nicht oder nur knapp erwähnt. Wir empfehlen dir deshalb, die Vorlesungen deiner Universität zu besuchen, damit du genau weißt, worauf deine Dozenten wert legen. ...
Malaria is an environmental disease, influenced not only by physical and biological environmental factors but also by socio-cultural ones. These factors affect each other, and, in turn, cause the disease in endemic areas. Some factors that cause the high morbidity rate associated with the disease include climate change, physical environment that varies geographically, socio-economic circumstances, and human behaviour in the affected areas. Other risk factors include housing conditions and poor sanitation, lack of hygiene practices, and inadequate health services in endemic areas. Efforts to eliminate malaria have been a topic at various public health meetings for decades. However, in Indonesia, malaria continues to be one of the leading causes of morbidity and mortality. The research aimed to analyse and model the critical variables associated with malaria in endemic areas of Indonesia. So, this included relationships between malaria and both socio-demographic variables and physical environments. The research is in three parts, adding value to a model that determines malaria in Indonesia.
This dissertation follows a cross-sectional design survey. The research data in this PhD dissertation is drawn from four sources: routine reporting of malaria from provincial health departments in South Sumatra; the national basic health research data (IDN acronym: Riskesdas); climate data from the Meteorology, Climatology, and Geophysics Climatological Agency (IDN acronym: BMKG); spatial data from Geospatial Information Agency (IDN acronym: BIG). This study takes a holistic approach, integrating the following univariate, bivariate, and multivariable logistic regressions, to establish a modelling determinant of malaria. Additionally, the researchers compared the performance of both Geographically Weighted Regression (GWR) and Ordinary Least Square (OLS). It also used some statistical analysis software tools for data processing, analysis, visualisation, and the development of the model as follows: Statistical Package for the Social Sciences (SPSS), Stata, Aeronautical Reconnaissance Coverage Geographic Information System (ArcGIS) 10.3, and GWR 4.0 version 4.0.90 for Windows.
The prevalence of malaria varied according to the local area, which, in turn, was related to the local physical environment that varied geographically. The determinants for malaria cases varied locally and regionally as well. Rural areas with a high percentage of households keeping livestock/pets showed a higher proportion of malaria prevalence than the national average. Other socio-demographic risk factors included gender, age, occupation, knowledge about healthcare, protection against mosquito bites, and condition of dwellings. This study reveals that the independent variables - "rainfall", "altitude", and "distance from mosquito resting sites in the forest," in global OLS analysis- are significantly associated with malaria cases in South Sumatra, Indonesia.
On the other hand, in the GWR analysis, the determinants of malaria cases at the village level vary geographically. Therefore, it is essential for the decision maker, the government, to acquire a more in-depth understanding of region-specific, ecological factors that influence confirmed malaria cases. The findings lead to the recommendation for developing sustainable regional malaria control programs and incentivising malaria elimination efforts, particularly at the village level. In another setting, the research led to the conclusion that the presence of mid-sized livestock comprised a significant risk factor for contracting malaria in rural Indonesia. The recommendation, especially for the study area, is to employ integrated vector management (IVM), for example, the simultaneous implementation of insecticide-treated bed nets (ITNs) and insecticide-treated livestock (ITL). Other factors such as socio-demographic and use of health care facilities were also crucial as they related to malaria prevalence. Further, the research leads to the recommendation for increased education and increased promotion and utilisation of the health care framework to promote knowledge and awareness of villagers on how to protect themselves from Anopheles bites. Finally, improving information concerning the availability of health care services and access to various health facilities in endemic areas is essential.
Multimodal quantitative mri reveals no evidence for tissue pathology in idiopathic cervical dystonia
(2019)
Background: While in symptomatic forms of dystonia cerebral pathology is by definition present, it is unclear so far whether disease is associated with microstructural cerebral changes in idiopathic dystonia. Previous quantitative MRI (qMRI) studies assessing cerebral tissue composition in idiopathic dystonia revealed conflicting results.
Objective: Using multimodal qMRI, the presented study aimed to investigate alterations in different cerebral microstructural compartments associated with idiopathic cervical dystonia in vivo.
Methods: Mapping of T1, T2, T∗2, and proton density (PD) was performed in 17 patients with idiopathic cervical dystonia and 29 matched healthy control subjects. Statistical comparisons of the parametric maps between groups were conducted for various regions of interest (ROI), including major basal ganglia nuclei, the thalamus, white matter, and the cerebellum, and voxel-wise for the whole brain.
Results: Neither whole brain voxel-wise statistics nor ROI-based analyses revealed significant group differences for any qMRI parameter under investigation.
Conclusions: The negative findings of this qMRI study argue against the presence of overt microstructural tissue change in patients with idiopathic cervical dystonia. The results seem to support a common view that idiopathic cervical dystonia might primarily resemble a functional network disease.
In cells the interorganelle communication comprises vesicular and non-vesicular mechanisms. Non-vesicular material transfer predominantly takes place at regions of close organelle apposition termed membrane contact sites and is facilitated by a growing number of specialized proteins. Contacts of the endoplasmic reticulum (ER) and mitochondria are now recognized to be essential for diverse biological processes such as calcium homeostasis, phospholipid biosynthesis, apoptosis, and autophagy. In addition to these universal roles, ER-mitochondria communication serves also cell type-specific functions. In this review, we summarize the current knowledge on ER-mitochondria contacts in cells of the innate immune system, especially in macrophages. We discuss ER- mitochondria communication in the context of macrophage fatty acid metabolism linked to inflammatory and ER stress responses, its roles in apoptotic cell engulfment, activation of the inflammasome, and antiviral defense.
Glioblastomas (GBs) frequently display activation of the epidermal growth factor receptor (EGFR) and mammalian target of rapamycin (mTOR). mTOR exists as part of two multiprotein complexes, mTOR complex 1 (mTORC1) and 2 (mTORC2). In GBs, mTORC1 inhibitors such as rapamycin have performed poorly in clinical trials, and in vitro protect GB cells from nutrient and oxygen deprivation. Next generation ATP-competitive mTOR inhibitors with affinity for both mTOR complexes have been developed, but data exploring their effects on GB metabolism are scarce. In this study, we compared the ATP-competitive mTORC1/2 inhibitors torin2, INK-128 and NVP-Bez235 to the allosteric mTORC1 inhibitor rapamycin under conditions that mimic the glioma microenvironment. In addition to inhibiting mTORC2 signaling, INK-128 and NVP-Bez235 more effectively blocked mTORC1 signaling and prompted a stronger cell growth inhibition, partly by inducing cell cycle arrest. However, under hypoxic and nutrient-poor conditions mTORC1/2 inhibitors displayed even stronger cytoprotective effects than rapamycin by reducing oxygen and glucose consumption. Thus, therapies that arrest proliferation and inhibit anabolic metabolism must be expected to improve energy homeostasis of tumor cells. These results mandate caution when treating physiologically or therapeutically induced hypoxic GBs with mTOR inhibitors.
Cancer-associated fibroblasts (CAFs) in the tumor microenvironment contribute to all stages of tumorigenesis and are usually considered to be tumor-promoting cells. CAFs show a remarkable degree of heterogeneity, which is attributed to developmental origin or to local environmental niches, resulting in distinct CAF subsets within individual tumors. While CAF heterogeneity is frequently investigated in late-stage tumors, data on longitudinal CAF development in tumors are lacking. To this end, we used the transgenic polyoma middle T oncogene-induced mouse mammary carcinoma model and performed whole transcriptome analysis in FACS-sorted fibroblasts from early- and late-stage tumors. We observed a shift in fibroblast populations over time towards a subset previously shown to negatively correlate with patient survival, which was confirmed by multispectral immunofluorescence analysis. Moreover, we identified a transcriptomic signature distinguishing CAFs from early- and late-stage tumors. Importantly, the signature of early-stage CAFs correlated well with tumor stage and survival in human mammary carcinoma patients. A random forest analysis suggested predictive value of the complete set of differentially expressed genes between early- and late-stage CAFs on bulk tumor patient samples, supporting the clinical relevance of our findings. In conclusion, our data show transcriptome alterations in CAFs during tumorigenesis in the mammary gland, which suggest that CAFs are educated by the tumor over time to promote tumor development. Moreover, we show that murine CAF gene signatures can harbor predictive value for human cancer.
Allogeneic hematopoietic stem cell transplantation for congenital immune dysregulatory disorders
(2019)
Primary immunodeficiency disorders that predominantly affect immune regulation and mechanisms of self-tolerance have come into the limelight, because at least for a subgroup of monogenetic disorders, a targeted therapy has become available. Nevertheless, their management often involves the treatment of severely compromising, refractory, multi-organ autoimmunity, leading to further increased susceptibility to infections and complications of long-term immune suppressive treatment, including the risk of malignancy. While evidence for allogeneic hematopoietic stem cell transplantation (alloHSCT) as a curative treatment option for severely affected patients by this disease category accumulates, clear indications, and guidelines for alloHSCT are lacking. Predictive and stratification-relevant tools such as disease activity scores are largely missing and often there is not a consistent genotype-phenotype correlation within the same family to facilitate the decision whether to transplant or not. In this review, we provide a literature-based update on indications and outcomes of alloHSCT for congenital immune dysregulative inborn errors of immunity according to the IUIS classification 2017.
Collateral sprouting of surviving axons contributes to the synaptic reorganization after brain injury. To study this clinically relevant phenomenon, we used complex organotypic tissue cultures of mouse entorhinal cortex (EC) and hippocampus (H). Single EC-H cultures were generated to analyze associational sprouting, and double EC-H cultures were used to evaluate commissural sprouting of mossy cells in the dentate gyrus (DG) following entorhinal denervation. Entorhinal denervation (transection of the perforant path) was performed at 14 days in vitro (DIV) and associational/commissural sprouting was assessed at 28 DIV. First, associational sprouting was studied in genetically hybrid EC-H cultures of beta-actin-GFPtg and wild-type mice. Using calretinin as a marker, associational axons were found to re-innervate almost the entire entorhinal target zone. Denervation experiments performed with EC-H cultures of Thy1-YFPtg mice, in which mossy cells are YFP-positive, confirmed that the overwhelming majority of sprouting associational calretinin-positive axons are mossy cell axons. Second, we analyzed associational/commissural sprouting by combining wild-type EC-H cultures with calretinin-deficient EC-H cultures. In these cultures, only wild-type mossy cells contain calretinin, and associational and commissural mossy cell collaterals can be distinguished using calretinin as a marker. Nearly the entire DG entorhinal target zone was re-innervated by sprouting of associational and commissural mossy cell axons. Finally, viral labeling of newly formed associational/commissural axons revealed a rapid post-lesional sprouting response. These findings demonstrate extensive and rapid re-innervation of the denervated DG outer molecular layer by associational and commissural mossy cell axons, similar to what has been reported to occur in juvenile rodent DG in vivo.
Background: Malaria is an increasing concern in Indonesia. Socio-demographic factors were found to strongly influence malaria prevalence. This research aimed to explore the associations between socio-demographic factors and malaria prevalence in Indonesia.
Methods: The study used a cross-sectional design and analysed relationships among the explanatory variables of malaria prevalence in five endemic provinces using multivariable logistic regression.
Results: The analysis of baseline socio-demographic data revealed the following independent risk variables related to malaria prevalence: gender, age, occupation, knowledge of the availability of healthcare services, measures taken to protect from mosquito bites, and housing condition of study participants. Multivariable analysis showed that participants who were unaware of the availability of health facilities were 4.2 times more likely to have malaria than those who were aware of the health facilities (adjusted odds ratio = 4.18; 95% CI 1.52–11.45; P = 0.005).
Conclusions: Factors that can be managed and would favour malaria elimination include a range of prevention behaviours at the individual level and using the networks at the community level of primary healthcare centres. This study suggests that improving the availability of a variety of health facilities in endemic areas, information about their services, and access to these is essential.
Pharmakokinetik von JWH-018 und seinen Metaboliten in menschlichen Serum-, Urin- und Speichelproben
(2019)
Synthetische Cannabinoide sind seit Anfang der 2000er Jahre als Alternative zum Cannabiskonsum bekannt. Als erstes synthetisches Cannabinoid konnte JWH-018 in dem Produkt „Spice“ identifiziert werden. Aufgrund von teils behandlungspflichtigen, erheblichen Nebenwirkungen sowie von Todesfällen wurden bislang keine Probandenstudien durchgeführt.
Als erste kontrollierte Untersuchung wurde eine Pilotstudie mit sechs Probanden und sehr niedrigen Dosierungen (2 und 3 mg im Vergleich mit Placebo) mit der am besten erforschten Substanz, JWH-018, abgeschlossen. Mit der Entnahme von 14 Serum- und Speichel- sowie 5 Urinproben über einen Zeitraum von 12 Stunden nach Inhalation sollten Daten zur Pharmakokinetik und zum Metabolismus erhoben werden.
Blut, Urin und Speichel wurden nach flüssig-flüssig Extraktion mittels Flüssigchromatographie-Tandemmassenspektrometrie analysiert. Die Methoden wurden nach aktuellen Richtlinien vollständig validiert.
Serumkonzentrationen wurden zur Korrelation mit beobachteten Wirkungen bestimmt. Die maximale Serumkonzentration von JWH-018 erreichte bereits 5 min nach Inhalation 2,9-9,9 ng/ml und nahm innerhalb der nächsten 1,5 h deutlich ab, gefolgt von einem multiexponentiellen Abfall (t½ im Median 1,3 h und 5,7 h). Bei zwei Probanden lagen noch bis zu 4 Wochen nach der Applikation Spuren von JWH-018 vor. Die Konzentration des Pentansäuremetaboliten war etwas höher als die der 3-, 4- und 5-Hydroxypentylmetaboliten und des 6-Hydroxyindolmetaboliten. Bei der JWH-018 Pentansäure zeigte sich jedoch im Vergleich ein späteres Erreichen der Maximalkonzentration sowie eine deutliche Plateauphase, was sich durch enterohepatisches Cycling erklären lassen könnte.
Speicheltests dienen im forensischen wie klinischen Umfeld häufig als Schnelltest und als Indikator für anhaltende Wirkungen. Die Speichelasservierung und -lagerung erfolgte mit dem Quantisal-System. Maximale Konzentrationen von JWH-018 waren 2,2-2036 (Median 25,7) ng/ml direkt nach Inhalation und sanken in der nächsten Stunde auf nur 0,08-8,42 (Median 0,89) ng/ml, Metabolite wurden nicht nachgewiesen. Innerhalb der Eliminationsphase (mittlere Halbwertszeit 1,69 h) konnte JWH-018 während 6-12 (Median 8) h nachgewiesen werden (0,024 ng/ml Quantifizierungs-grenze). Das Konzentrationsverhältnis von Speichel zu Serum variierte intra- und interindividuell stark in einem Bereich von 0,05-555 (Median 1,38) ng/ml, was eine Extrapolation der Speichelkonzentrationen auf Serum/Plasma ausschließt.
Urin wurde zu mindestens 5 Zeitpunkten entnommen und sowohl mit, als auch ohne β Glukuronidasebehandlung analysiert. Die Muttersubstanz war nicht nachweisbar, dafür 13 ihrer Metaboliten, die alle hochgradig konjugiert vorlagen. Die Konzentrationen des vorherrschenden Metaboliten, JWH-018 Pentansäure, lagen unter 5 ng/ml, wurden aber bei zwei Probanden noch bis zu 4 Wochen nach der Einnahme nachgewiesen. Die JWH-073 Butansäure wurde in die Urinanalyse miteinbezogen, da es Hinweise auf eine metabolische Bildung gab. Die Untersuchungsergebnisse können klar belegen, dass die Butansäure als Metabolit nach Konsum von JWH-018 entsteht. Wie im Serum wurden die Metabolite 3-, 4- und 5-Hydroxypentyl- sowie 6-Hydroxyindol-JWH-018 nachgewiesen. Zusätzlich zeigten sich aber auch geringe Signale von 4-, 5- und 7 Hydroxyindol- sowie von 2-Hydroxypentyl-JWH-018 und ein Signal neben dem 3 Hydroxypentylmetaboliten, welches ein weiteres hydroxyliertes Isomer repräsentieren dürfte. Weiterhin zeigten sich wie bereits im Serum auch in allen Urinproben bis zu zwei Messsignale mit den gleichen Fragmenten wie die JWH-018 Pentansäure. In Anlehnung an eine in-vitro Metabolismusstudie ist davon auszugehen, dass es sich um dihydroxylierte und dehydrierte Isomere von JWH-018 handelt, die als Hydroxy-Keto-Metabolite postuliert wurden. Im Allgemeinen lagen hydroxylierte Metaboliten bereits 10 h nach der Inhalation in Konzentrationen von weniger als 1 ng/ml vor. Die unterschiedliche Ausscheidung von Carbonsäuren und hydroxylierten Metaboliten kann bei der Einordnung des Konsumzeitpunkts helfen. Alle Konzentrationen lagen deutlich niedriger als für Urinproben von authentischen JWH-018 Konsumenten beschrieben.
Bei der Auswertung der Messdaten in Bezug auf die 2 mg und die 3 mg Dosis ließen sich keine signifikanten Unterschiede nachweisen, was sich nach Untersuchung der nicht inhalierten Restmengen durch erhebliche Schwankungen in der Applikation erklären lässt.
Die Daten sprechen für eine ausgeprägte Mehrkompartimentkinetik und eine langsame terminale Eliminierung von JWH-018 und allen Metaboliten, was zu einer Akkumulation bei chronischen Konsumenten führen kann. Dies ähnelt den Erfahrungen mit dem Cannabiswirkstoff Tetrahydrocannabinol (THC) und legt langanhaltende Effekte und eine Toleranzentwicklung nahe.
Invasive mold disease (IMD) of the central nervous system (CNS) is a severe infectious complication in immunocompromised patients, but early microbiological diagnosis is difficult. As data on the value of biomarkers in the CNS are scarce, in particular in children, we retrospectively analyzed the performance of galactomannan (GM) and PCR assays in CNS samples of 15 children with proven and probable CNS IMD and of 32 immunocompromised children without fungal infection. Galactomannan in the cerebrospinal fluid (CSF) was assessed in nine of the 15 pediatric patients and was positive in five of them. Polymerase chain reaction (PCR) was performed in eight of the 15 patients and detected nucleic acids from molds in six patients. Galactomannan and PCR in CNS samples were the only positive microbiologic parameter in the CNS in three and two patients, respectively. In four patients, PCR specified the pathogen detected in microscopy. Galactomannan and PCR results remained negative in the CSF of all immunocompromised children without evidence for CNS IMD. Our data suggest that GM and PCR in CNS specimens are valuable additional tools in diagnosing CNS IMD and should be included in the work up of all pediatric patients with suspected mold disease of the CNS.
Background. Tracheal intubation still represents the "gold standard" in securing the airway of unconscious patients in the prehospital setting. Especially in cases of restricted access to the patient, video laryngoscopy became more and more relevant.
Objectives. The aim of the study was to evaluate the performance and intubation success of four different video laryngoscopes, one optical laryngoscope, and a Macintosh blade while intubating from two different positions in a mannequin trial with difficult access to the patient.
Methods. A mannequin with a cervical collar was placed on the driver’s seat. Intubation was performed with six different laryngoscopes either through the driver’s window or from the backseat. Success, C/L score, time to best view (TTBV), time to intubation (TTI), and number of attempts were measured. All participants were asked to rate their favored device.
Results. Forty-two physicians participated. 100% of all intubations performed from the backseat were successful. Intubation success through the driver’s window was less successful. Only with the Airtraq® optical laryngoscope, 100% success was achieved. Best visualization (window C/L 2a; backseat C/L 2a) and shortest TTBV (window 4.7 s; backseat 4.1 s) were obtained when using the D-Blade video laryngoscope, but this was not associated with a higher success through the driver’s window. Fastest TTI was achieved through the window (14.2 s) when using the C-MAC video laryngoscope and from the backseat (7.3 s) when using a Macintosh blade.
Conclusions. Video laryngoscopy revealed better results in visualization but was not associated with a higher success. Success depended on the approach and familiarity with the device. We believe that video laryngoscopy is suitable for securing airways in trapped accident victims. The decision for an optimal device is complicated and should be based upon experience and regular training with the device.
Systematic reviews represent the core and backbone of evidence-based medicine (EBM) strategies in all fields of medicine. In order to depict a first global sketch of the international efforts in the Cochrane database systematic reviews (CDSR), we analyzed the systematic reviews of the Cochrane database. Our global maps of systematic reviewing offer intriguing structural insights into the world of EBM strategies. They demonstrate that for the CDSR, the UK and Commonwealth countries take the lead position. Since patients, care providers and health systems all over the world benefit from systematic reviewing, institutions in other countries should increase their commitment.
Background: Definitive chemoradiotherapy (CRT) is the primary treatment for non-metastatic anal squamous cell carcinoma (ASCC). Despite favorable treatment outcomes in general, failure rates up to 40% occur in locally advanced disease. For treatment escalation or de-escalation strategies easily assessable and valid biomarkers are needed.
Methods: We identified 125 patients with ASCC treated with standard CRT at our department. C-reactive protein (CRP) to albumin ratio (CAR) was calculated dividing baseline CRP by baseline albumin levels. We used maximally selected rank statistics to dichotomize patients to high and low risk groups. Associations of CAR with clinicopathologic parameters were evaluated and the prognostic impact was tested using univariate and multivariate cox regression analysis. In a subset of 78 patients, pretreatment tumor tissue was available and CD8+ tumor infiltrating lymphocytes (TILs) and p16INK4a status were scored by immunohistochemistry and correlated with CAR.
Results: Advanced T-stage and male gender were significantly associated with higher baseline CAR. Using the calculated cutoff of 0.117, a high baseline CAR was also associated with worse locoregional control (p = 0.002), distant metastasis-free survival (p = 0.01), disease-free survival (DFS, p = 0.002) and overall survival (OS, p < 0.001). A combined risk score incorporating N-stage and CAR, termed N-CAR score, was associated with worse outcome across all endpoints and in multivariate analysis independent of T-stage and Gender (HR 4.27, p = 0.003). In the subset of 78 patients, a strong infiltration with intratumoral CD8+ TIL was associated with a significantly lower CAR (p = 0.007). CAR is an easily accessible biomarker that is associated with DFS. Our study revealed a possible link between chronic systemic inflammation and an impaired intratumoral immune response.
Ataxia telangiectasia (A-T) is a devastating multi-system disorder characterized by progressive cerebellar ataxia, immunodeficiency, genetic instability, premature aging and growth retardation. Due to better care the patients get older than in the past and new disease entities like disturbed glucose tolerance and liver disease emerge. The objective of the present investigation is to determine the evolution of liver disease and its relation to age and neurological deterioration. The study included 67 patients aged 1 to 38 years with classical A-T. At least two measurements of liver enzymes were performed within a minimum interval of 6 months in 56 patients. The median follow-up period was 4 years (1–16 years). A total of 316 liver enzyme measurements were performed. For analysis, patients were divided into two age groups (Group 1: <12 years; group 2: ≥12 years). In addition, ultrasound of the liver and Klockgether Ataxia Score (KAS) were analyzed. We found significantly higher levels of alpha-fetoprotein (AFP) (226,8 ± 20.87 ng/ml vs. 565,1 ± 24.3 ng/ml, p < 0.0001), and liver enzymes like ALT (23.52 ± 0.77 IU/L vs. 87.83 ± 5.31 IU/L, p < 0.0001) in patients in group 2. In addition, we could show a significant correlation between age and AFP, GGT, and KAS. Ultrasound revealed hepatic steatosis in 11/19 (57.9%) patients in group 2. One female patient aged 37 years died due to a hepato-cellular carcinoma (HCC). Liver disease is present in the majority of older A-T patients. Structural changes, non-alcoholic fatty liver disease and fibrosis are frequent findings. Progress of liver disease is concomitant to neurological deterioration.
kurz und kn@pp news : Nr. 47
(2019)
Introduction: Vaginal delivery out of a breech presentation in pregnancies at term are being re-implemented into clinical practice. Still, recommendations regarding exclusion criteria leading to caesarean sections are based on expert opinions, not on evidence-based guidelines. The difference in perinatal outcome and course of delivery in births with babies in frank breech position and babies in incomplete or complete breech presentation never has been investigated in a large patient cohort.
Objective: To compare perinatal outcome of vaginally intended breech deliveries between births out of frank breech position and incomplete/complete breech presentation.
Design: Prospective cohort study.
Sample: 884 women at term with a singleton in frank breech presentation (FB) and 284 women with incomplete or complete breech presentation (CB) intending vaginal birth between January 2004 and December 2018.
Methods: Maternal and fetal outcome was compared between groups using Pearson’s Chi Square test. Birth duration parameters were analysed using logistic regression.
Results: There were no differences in cesarean section rates (FB: 25.1%, CB 22.2%, p = 0.317). Short-term fetal morbidity did not differ between groups (FB: 2.5%, CB: 2.8%, p = 0.761). In vaginal deliveries the necessity to perform manual assistance was significantly more frequent in deliveries of infants in CB (FB: 39.9%, CB: 51.6%, p = 0.0013). Cord loops (FB: 10.1%, CB: 18.0%, p = 0.0004) and cesarean sections necessary because of cord prolapses (FB: 1.4%, CB 8.1%, p = 0.005) were significantly more often in deliveries with babies in CB.
Conclusion: This study provides evidence, that perinatal morbidity is not associated with the fetal leg posture in vaginally intended breech deliveries. The higher risk for the need of manual assistance during vaginal birth in deliveries of babies out of complete or incomplete breech presentation suggests that obstetrical departments re-implementing the vaginal breech in their repertoire might start with births of babies out of frank breech presentation.
Attention-deficit/hyperactivity disorder (ADHD) is a common and highly heritable neurodevelopmental disorder. In recent years, genetic studies have revealed several risk gene variants associated with ADHD; however, these variants could only be partly replicated and are responsible for only a fraction of the whole heritability of ADHD estimated from family and twin studies. One factor that could potentially explain the ‘missing heritability’ of ADHD is that childhood and adult or persistent ADHD could be genetically distinct subtypes, which therefore need to be analyzed separately. Another approach to identify this missing heritability could be combining the investigation of both common and rare gene risk variants as well as polygenic risk scores. Finally, environmental factors are also thought to play an important role in the etiology of ADHD, acting either independently of the genetic background or more likely in gene–environment interactions. Environmental factors might additionally convey their influence by epigenetic mechanisms, which are relatively underexplored in ADHD. The aforementioned mechanisms might also influence the response of patients with ADHD to stimulant and other ADHD medication. We conducted a selective review with a focus on risk genes of childhood and adult ADHD, gene–environment interactions, and pharmacogenetics studies on medication response in childhood and adult ADHD.
Introduction: The neurobiological mechanisms behind panic disorder with agoraphobia (PD/AG) are not completely explored. The functional A/T single nucleotide polymorphism (SNP) rs324981 in the neuropeptide S receptor gene (NPSR1) has repeatedly been associated with panic disorder and might partly drive function respectively dysfunction of the neural “fear network”. We aimed to investigate whether the NPSR1 T risk allele was associated with malfunctioning in a fronto-limbic network during the anticipation and perception of agoraphobia-specific stimuli.
Method: 121 patients with PD/AG and 77 healthy controls (HC) underwent functional magnetic resonance imaging (fMRI) using the disorder specific “Westphal-Paradigm”. It consists of neutral and agoraphobia-specific pictures, half of the pictures were cued to induce anticipatory anxiety.
Results: Risk allele carriers showed significantly higher amygdala activation during the perception of agoraphobia-specific stimuli than A/A homozygotes. A linear group x genotype interaction during the perception of agoraphobia-specific stimuli showed a strong trend towards significance. Patients with the one or two T alleles displayed the highest and HC with the A/A genotype the lowest activation in the inferior orbitofrontal cortex (iOFC).
Discussion: The study demonstrates an association of the NPSR1rs324981 genotype and the perception of agoraphobia-specific stimuli. These results support the assumption of a fronto-limbic dysfunction as an intermediate phenotype of PD/AG.
This position paper describes clinically important, practical aspects of cervical pessary treatment. Transvaginal ultrasound is standard for the assessment of cervical length and selection of patients who may benefit from pessary treatment. Similar to other treatment modalities, the clinical use and placement of pessaries requires regular training. This training is essential for proper pessary placement in patients in emergency situations to prevent preterm delivery and optimize neonatal outcomes. Consequently, pessaries should only be applied by healthcare professionals who are not only familiar with the clinical implications of preterm birth as a syndrome but are also trained in the practical application of the devices. The following statements on the clinical use of pessary application and its removal serve as an addendum to the recently published German S2-consensus guideline on the prevention and treatment of preterm birth.
Previous studies in patients with single-sided deafness (SSD) have reported results of pitch comparisons between electric stimulation of their cochlear implant (CI) and acoustic stimulation presented to their near-normal hearing contralateral ear. These comparisons typically used sinusoids, although the percept elicited by electric stimulation may be closer to a wideband stimulus. Furthermore, it has been shown that pitch comparisons between sounds with different timbres is a difficult task and subjected to various types of range biases. The present study aims to introduce a method to minimize non-sensory biases, and to investigate the effect of different acoustic stimulus types on the frequency and variability of the electric-acoustic pitch matches. Pitch matches were collected from 13 CI users with SSD using the binary search procedure. Electric stimulation was presented at either an apical or a middle electrode position, at a rate of 800 pps. Acoustic stimulus types were sinusoids (SINE), 1/3-octave wide narrow bands of Gaussian noises (NBN), or 1/3-octave wide pulse spreading harmonic complexes (PSHC). On the one hand, NBN and PSHC are presumed to better mimic the spread of excitation produced by a single-electrode stimulation than SINE. On the other hand, SINE and PSHC contain less inherent fluctuations than NBN and may therefore provide a temporal pattern closer to that produced by a constant-amplitude electric pulse train. Analysis of mean pitch match variance showed no differences between stimulus types. However, mean pitch matches showed effects of electrode position and stimulus type, with the middle electrode always matched to a higher frequency than the apical one (p < 0.001), and significantly higher across-subject pitch matches for PSHC compared with SINE (p = 0.017). Mean pitch matches for all stimulus types were better predicted by place-dependent characteristic frequencies (CFs) based on an organ of Corti map compared with a spiral ganglion map. CF predictions were closest to pitch matches with SINE for the apical electrode position, and conversely with NBN or PSHC for the middle electrode position. These results provide evidence that the choice of acoustic stimulus type can have a significant effect on electric-acoustic pitch matching.
OXA-48 is the most common carbapenemase in Enterobacterales in Germany and one of the most frequent carbapenemases worldwide. Several reports have associated blaOXA–48 with a virulent host phenotype. To challenge this hypothesis, 35 OXA-48-producing clinical isolates of Escherichia coli (n = 15) and Klebsiella pneumoniae (n = 20) were studied in vitro, in vivo employing the Galleria mellonella infection model and by whole-genome sequencing. Clinical isolates belonged to 7 different sequence types (STs) in E. coli and 12 different STs in K. pneumoniae. In 26/35 isolates blaOXA–48 was located on a 63 kb IncL plasmid. Horizontal gene transfer (HGT) to E. coli J53 was high in isolates with the 63 kb IncL plasmid (transconjugation frequency: ∼103/donor) but low in isolates with non-IncL plasmids (<10–6/donor). Several clinical isolates were both highly cytotoxic against human cells and virulent in vivo. However, 63 kb IncL transconjugants generated from these highly virulent isolates were not more cytotoxic or virulent when compared to the recipient strain. Additionally, no genes associated with virulence were detected by in silico analysis of OXA-48 plasmids. The 63 kb plasmid was highly stable and did not impair growth or fitness in E. coli J53. In conclusion, OXA-48 clinical isolates in Germany are diverse but typically harbor the same 63 kb IncL plasmid which has been reported worldwide. We demonstrate that this 63 kb IncL plasmid has a low fitness burden, high plasmid stability and can be transferred by highly efficient HGT which is likely the cause of the rapid dissemination of OXA-48 rather than the expansion of a single clone or gain of virulence.
Cystathionine γ lyase (CSE) is the major source of hydrogen sulfide-derived species (H2Sn) in endothelial cells and plays an important role in protecting against atherosclerosis. Here we investigated the molecular mechanisms underlying the regulation of CSE expression in endothelial cells by fluid shear stress/flow. Fluid shear stress decreased CSE expression in human and murine endothelial cells and was negatively correlated with the transcription factor Krüppel-like factor (KLF) 2. CSE was identified as a direct target of the KLF2-regulated microRNA, miR-27b and high expression of CSE in native human plaque-derived endothelial cells, was also inversely correlated with KLF2 and miR-27b levels. One consequence of decreased CSE expression was the loss of Prx6 sulfhydration (on Cys47), which resulted in Prx6 hyperoxidation, decamerization and inhibition, as well as a concomitant increase in endothelial cell reactive oxygen species and lipid membrane peroxidation. H2Sn supplementation in vitro was able to reverse the redox state of Prx6. Statin therapy, which is known to activate KLF2, also decreased CSE expression but increased CSE activity by preventing its phosphorylation on Ser377. As a result, the sulfhydration of Prx6 was partially restored in samples from plaque containing arteries from statin-treated donors. Taken together, the regulation of CSE expression by shear stress/disturbed flow is dependent on KLF2 and miR-27b. Moreover, in murine and human arteries CSE acts to maintain endothelial redox balance at least partly by targeting Prx6 to prevent its decamerization and inhibition of its peroxidase activity.
Background and Aims: Fecal biomarkers are important non-invasive markers monitoring disease activity in inflammatory bowel disease (IBD). We compared the significance of fecal eosinophil cationic protein (fECP) and fecal calprotectin (fCal).
Methods: fECP and fCal were measured in patients with Crohn's disease (CD, n = 97), ulcerative colitis (UC, n = 53), Clostridioides difficile infection (CDI, n = 9), primary food allergy (PFA, n = 11), pollen-associated food allergy (n = 25) and non-inflammatory controls (n = 78). Results were correlated with clinical and endoscopic IBD activity scores.
Results: fECP was significantly elevated in CD, UC, CDI and PFA compared to controls. fCal was significantly increased in CD, UC and CDI. fECP had lower diagnostic accuracy than fCal (area under the curve (AUC) = 0.88) in differentiating between endoscopically active and inactive patients with IBD (AUC = 0.77, ROC analysis). In contrast to fCal, fECP correlated negatively with age and levels were also elevated in clinically and endoscopically inactive patients with IBD <45 years (endoscopically inactive IBD vs controls; AUC for fECP = 0.86; AUC for fCal = 0.62). However, in those patients with low inflammatory activity (fCal <250 mg/kg), high fECP indicated the need for treatment modification or surgery (fECP <200 µg/kg = 22%; 200–600 µg/kg = 44%; >600 µg/kg = 82%) at month 48 of follow-up.
Conclusions: fECP is a diagnostic and prognostic marker in young patients with IBD in remission.
In-line filtration of intravenous infusion may reduce organ dysfunction of adult critical patients
(2019)
Background: The potential harmful effects of particle-contaminated infusions for critically ill adult patients are yet unclear. So far, only significant improved outcome in critically ill children and new-borns was demonstrated when using in-line filters, but for adult patients, evidence is still missing.
Methods: This single-centre, retrospective controlled cohort study assessed the effect of in-line filtration of intravenous fluids with finer 0.2 or 1.2 μm vs 5.0 μm filters in critically ill adult patients. From a total of n = 3215 adult patients, n = 3012 patients were selected by propensity score matching (adjusting for sex, age, and surgery group) and assigned to either a fine filter cohort (with 0.2/1.2 μm filters, n = 1506, time period from February 2013 to January 2014) or a control filter cohort (with 5.0 μm filters, n = 1506, time period from April 2014 to March 2015). The cohorts were compared regarding the occurrence of severe vasoplegia, organ dysfunctions (lung, kidney, and brain), inflammation, in-hospital complications (myocardial infarction, ischemic stroke, pneumonia, and sepsis), in-hospital mortality, and length of ICU and hospital stay.
Results: Comparing fine filter vs control filter cohort, respiratory dysfunction (Horowitz index 206 (119–290) vs 191 (104.75–280); P = 0.04), pneumonia (11.4% vs 14.4%; P = 0.02), sepsis (9.6% vs 12.2%; P = 0.03), interleukin-6 (471.5 (258.8–1062.8) ng/l vs 540.5 (284.5–1147.5) ng/l; P = 0.01), and length of ICU (1.2 (0.6–4.9) vs 1.7 (0.8–6.9) days; P < 0.01) and hospital stay (14.0 (9.2–22.2) vs 14.8 (10.0–26.8) days; P = 0.01) were reduced. Rate of severe vasoplegia (21.0% vs 19.6%; P > 0.20) and acute kidney injury (11.8% vs 13.7%; P = 0.11) was not significantly different between the cohorts.
Conclusions: In-line filtration with finer 0.2 and 1.2 μm filters may be associated with less organ dysfunction and less inflammation in critically ill adult patients.
Trial registration: The study was registered at ClinicalTrials.gov (number: NCT02281604).
Sepsis is a serious clinical condition which can cause life-threatening organ dysfunction, and has limited therapeutic options. The paradigm of limiting excessive inflammation and promoting anti-inflammatory responses is a simplified concept. Yet, the absence of intrinsic anti-inflammatory signaling at the early stage of an infection can lead to an exaggerated activation of immune cells, including monocytes and macrophages. There is emerging evidence that endogenous molecules control those mechanisms. Here we aimed to identify and describe the dynamic changes in monocyte and macrophage subsets and lung damage in CL57BL/6N mice undergoing blunt chest trauma with subsequent cecal ligation and puncture. We showed that early an increase in systemic and activated Ly6C+CD11b+CD45+Ly6G− monocytes was paralleled by their increased emigration into lungs. The ratio of pro-inflammatory Ly6ChighCD11b+CD45+Ly6G− to patrolling Ly6ClowCD11b+CD45+Ly6G− monocytes significantly increased in blood, lungs and bronchoalveolar lavage fluid (BALF) suggesting an early transition to inflammatory phenotypes during early sepsis development. Similar to monocytes, the level of pro-inflammatory Ly6ChighCD45+F4/80+ macrophages increased in lungs and BALF, while tissue repairing Ly6ClowCD45+F4/80+ macrophages declined in BALF. Levels of inflammatory mediators TNF-α and MCP-1 in blood and RAGE in lungs and BALF were elevated, and besides their boosting of inflammation via the recruitment of cells, they may promote monocyte and macrophage polarization, respectively, toward the pro-inflammatory phenotype. Neutralization of uteroglobin increased pro-inflammatory cytokine levels, activation of inflammatory phenotypes and their recruitment to lungs; concurrent with increased pulmonary damage in septic mice. In in vitro experiments, the influence of uteroglobin on monocyte functions including migratory behavior, TGF-β1 expression, cytotoxicity and viability were proven. These results highlight an important role of endogenous uteroglobin as intrinsic anti-inflammatory signal upon sepsis-induced early lung injury, which modules the early monocyte/macrophages driven inflammation.
Aims: Patients with aortic stenosis (AS) may have concomitant heart failure (HF) that determines prognosis despite successful transcatheter aortic valve implantation (TAVI). We compared outcomes of TAVI patients with low stroke volume index (SVI) ≤35 ml/m2 body surface area in different HF classes.
Methods and results: Patients treated by transfemoral TAVI at our center (n = 1822) were classified as 1) ‘HF with preserved ejection fraction (EF)’ (HFpEF, EF ≥50%), 2) ‘HF with mid-range EF’ (HFmrEF, EF 40–49%), or 3) ‘HF with reduced EF’ (HFrEF, EF <40%). Patients with SVI >35 ml/m2 served as controls. The prevalence of cardiovascular disease and symptoms increased stepwise from controls (n = 968) to patients with HFpEF (n = 591), HFmrEF (n = 97), and HFrEF (n = 166). Mortality tended to be highest in HFrEF patients 30 days post-procedure, and it became significant after one year: 10.2% (controls), 13.5% (HFpEF), 13.4% (HFmrEF), and 23.5% (HFrEF). However, symptomatic improvement in survivors of all groups was achieved in the majority of patients without differences among groups.
Conclusions: Patients with AS and HF benefit from TAVI with respect to symptom alleviation. TAVI in patients with HFpEF and HFmrEF led to an identical, favorable post-procedural prognosis that was significantly better than that of patients with HFrEF, which remains a high-risk population.
Objective: Studies using diffusion tensor imaging (DTI) to investigate white matter (WM) microstructure in youths with conduct disorder (CD) have reported disparate findings. We investigated WM alterations in a large sample of youths with CD, and examined the influence of sex and callous-unemotional (CU) traits.
Method: DTI data were acquired from 124 youths with CD (59 female) and 174 typically developing (TD) youths (103 female) 9 to 18 years of age. Tract-based spatial statistics tested for effects of diagnosis and sex-by-diagnosis interactions. Associations with CD symptoms, CU traits, a task measuring impulsivity, and the impact of comorbidity, and age- and puberty-related effects were examined.
Results: Youths with CD exhibited higher axial diffusivity in the corpus callosum and lower radial diffusivity and mean diffusivity in the anterior thalamic radiation relative to TD youths. Female and male youths with CD exhibited opposite changes within the internal capsule, fornix, posterior thalamic radiation, and uncinate fasciculus. Within the CD group, CD symptoms and callous traits exerted opposing influences on corpus callosum axial diffusivity, with callous traits identified as the unique clinical feature predicting higher axial diffusivity and lower radial diffusivity within the corpus callosum and anterior thalamic radiation, respectively. In an exploratory analysis, corpus callosum axial diffusivity partially mediated the association between callous traits and impulsive responses to emotional faces. Results were not influenced by symptoms of comorbid disorders, and no age- or puberty-related interactions were observed.
Conclusion: WM alterations within the corpus callosum represent a reliable neuroimaging marker of CD. Sex and callous traits are important factors to consider when examining WM in CD.
Utility of the new cobas HCV test for viral load monitoring during direct-acting antiviral therapy
(2019)
Background: The COBAS AmpliPrep/COBAS TaqMan assay HCV (CAP/CTM) is widely used in clinical routine for HCV testing. Recently, the new cobas HCV test was established for high throughput testing with minimal operator intervention. As different assays may yield different quantitative/qualitative results that possibly impact treatment decisions, the aim of this study was to externally evaluate the cobas HCV test performance in comparison to CAP/CTM in a clinically relevant setting.
Methods: Serum samples were obtained from 270 patients who received direct acting antiviral therapy with different treatment regimens at two study sites (Hannover and Frankfurt) in 2016. Overall, 1545 samples (baseline, on-treatment and follow-up) were tested in parallel by both assays.
Results: The mean difference between cobas HCV and CAP/CTM for the quantification of HCV RNA was 0.008 log10 IU/ml HCV RNA (95% limits of agreement: -0.02–0.036) showing excellent agreement of both assays. With respect to clinical cut offs (HCV RNA detectable vs. target not detected and HCV RNA above the lower limit of quantification (LLOQ) vs. <LLOQ), discordant results were obtained in 9.5% and 4.6%, respectively; the greatest differences were observed during early stages of antiviral therapy (week 1, week 2 and week 4), but none were statistically significant. Overall percent agreement for SVR between cobas HCV and CAP/CTM at the 15 IU/ml cutoff was 99.2% (95%CI 92.7%-100%).
Conclusion: The performance of the new cobas HCV test was comparable to CAP/CTM in a clinical setting representing a large patient population with HCV GT 1 and 3 treated with DAAs.
Objectives: To compare efficacy and safety of ixekizumab (IXE) to adalimumab (ADA) in biological disease-modifying antirheumatic drug-naïve patients with both active psoriatic arthritis (PsA) and skin disease and inadequate response to conventional synthetic disease-modifying antirheumatic drug (csDMARDs).
Methods: Patients with active PsA were randomised (1:1) to approved dosing of IXE or ADA in an open-label, head-to-head, blinded assessor clinical trial. The primary objective was to evaluate whether IXE was superior to ADA at week 24 for simultaneous achievement of a ≥50% improvement from baseline in the American College of Rheumatology criteria (ACR50) and a 100% improvement from baseline in the Psoriasis Area and Severity Index (PASI100). Major secondary objectives, also at week 24, were to evaluate whether IXE was: (1) non-inferior to ADA for achievement of ACR50 and (2) superior to ADA for PASI100 response. Additional PsA, skin, treat-to-target and quality-of-life outcome measures were assessed at week 24.
Results: The primary efficacy endpoint was met (IXE: 36%, ADA: 28%; p=0.036). IXE was non-inferior for ACR50 response (IXE: 51%, ADA: 47%; treatment difference: 3.9%) and superior for PASI100 response (IXE: 60%, ADA: 47%; p=0.001). IXE had greater response versus ADA in additional PsA, skin, nail, treat-to-target and quality-of-life outcomes. Serious adverse events were reported in 8.5% (ADA) and 3.5% (IXE) of patients.
Conclusions: IXE was superior to ADA in achievement of simultaneous improvement of joint and skin disease (ACR50 and PASI100) in patients with PsA and inadequate response to csDMARDs. Safety and tolerability for both biologicals were aligned with established safety profiles.
Malignant germ cell tumors (GCT) are the most common malignant tumors in young men between 18 and 40 years. The correct identification of histological subtypes, in difficult cases supported by immunohistochemistry, is essential for therapeutic management. Furthermore, biomarkers may help to understand pathophysiological processes in these tumor types. Two GCT cell lines, TCam-2 with seminoma-like characteristics, and NTERA-2, an embryonal carcinoma-like cell line, were compared by a quantitative proteomic approach using high-resolution mass spectrometry (MS) in combination with stable isotope labelling by amino acid in cell culture (SILAC). We were able to identify 4856 proteins and quantify the expression of 3936. 347 were significantly differentially expressed between the two cell lines. For further validation, CD81, CBX-3, PHF6, and ENSA were analyzed by western blot analysis. The results confirmed the MS results. Immunohistochemical analysis on 59 formalin-fixed and paraffin-embedded (FFPE) normal and GCT tissue samples (normal testis, GCNIS, seminomas, and embryonal carcinomas) of these proteins demonstrated the ability to distinguish different GCT subtypes, especially seminomas and embryonal carcinomas. In addition, siRNA-mediated knockdown of these proteins resulted in an antiproliferative effect in TCam-2, NTERA-2, and an additional embryonal carcinoma-like cell line, NCCIT. In summary, this study represents a proteomic resource for the discrimination of malignant germ cell tumor subtypes and the observed antiproliferative effect after knockdown of selected proteins paves the way for the identification of new potential drug targets.
Men and women differ in their vulnerability to a variety of stress-related illnesses, but the underlying neurobiological mechanisms are not well understood. This is likely due to a comparative dearth of neurobiological studies that assess male and female rodents at the same time, while human neuroimaging studies often don’t model sex as a variable of interest. These sex differences are often attributed to the actions of sex hormones, i.e. estrogens, progestogens and androgens. In this review, we summarize the results on sex hormone actions in the hippocampus and seek to bridge the gap between animal models and findings in humans. However, while effects of sex hormones on the hippocampus are largely consistent in animals and humans, methodological differences challenge the comparability of animal and human studies on stress effects. We summarise our current understanding of the neurobiological mechanisms that underlie sex-related differences in behavior and discuss implications for stress-related illnesses.
The ‘European Alliance Against Depression’ community-based intervention approach simultaneously targets depression and suicidal behaviour by a multifaceted community based intervention and has been implemented in more than 115 regions worldwide. The two main aims of the European Union funded project “Optimizing Suicide Prevention Programmes and Their Implementation in Europe” were to optimise this approach and to evaluate its implementation and impact. This paper reports on the primary outcome of the intervention (the number of completed and attempted suicides combined as ‘suicidal acts’) and on results concerning process evaluation analysis. Interventions were implemented in four European cities in Germany, Hungary, Portugal and Ireland, with matched control sites. The intervention comprised activities with predefined minimal intensity at four levels: training of primary care providers, a public awareness campaign, training of community facilitators, support for patients and their relatives. Changes in frequency of suicidal acts with respect to a one-year baseline in the four intervention regions were compared to those in the four control regions (chi-square tests). The decrease in suicidal acts compared to baseline in the intervention regions (-58 cases, -3.26%) did not differ significantly (χ2 = 0.13; p = 0.72) from the decrease in the control regions (-18 cases, -1.40%). However, intervention effects differed between countries (χ2 = 8.59; p = 0.04), with significant effects on suicidal acts in Portugal (χ2 = 4.82; p = 0.03). The interviews and observations explored local circumstances in each site throughout the study. Hypothesised mechanisms of action for successful implementation were observed and drivers for ‘added-value’ were identified: local partnership working and ‘in-kind’ contributions; an approach which valued existing partnership strengths; and synergies operating across intervention levels. It can be assumed that significant events during the implementation phase had a certain impact on the observed outcomes. However, this impact was, of course, not proven.
Secukinumab is a fully human monoclonal antibody that selectively neutralizes interleukin 17A, a key cytokine involved in the development of psoriasis. Secukinumab has shown long-lasting efficacy and safety in the complete spectrum of psoriatic disease, including disease localized to nails, scalp, palms and soles, and joints (peripheral and axial arthritis). Given the chronic and relapsing nature of psoriasis, long-term data might help to fully characterize the efficacy and safety profile of secukinumab as well as its impact on quality of life.
Background: The prognostic factors and outcome of aneurysms appear to be dependent on its locations. Therefore, we compared left- and right- sided aneurysms in patients with aneurysmal subarachnoid hemorrhage (SAH) in terms of differences in outcome and prognostic factors.
Methods: Patients with SAH were entered into a prospectively collected database. A total of 509 patients with aneurysmal subarachnoid hemorrhage were retrospectively selected and stratified in two groups depending on side of ruptured aneurysm (right n = 284 vs. left n = 225). Midline aneurysms of the basilar and anterior communicating arteries were excluded from the analysis. Outcomes were assessed using the modified Rankin Scale (mRS; favorable (mRS 0–2) vs. unfavorable (mRS 3–6)) six months after SAH.
Results: We did not identify any differences in outcome depending on left- and right-sided ruptured aneurysms. In both groups, the significant negative predictive factors included clinical admission status (WFNS IV+V), Fisher 3- bleeding pattern in CT, the occurrence of delayed cerebral ischemia (DCI), early hydrocephalus and later shunt-dependence. The side of the ruptured aneurysm does not seem to influence patients´ outcome. Interestingly, the aneurysm side predicts the side of infarction, with a significant influence on patients´ outcome in case of left-sided infarctions. In addition, the in multivariate analysis side of aneurysm was an independent predictor for the side of cerebral infarctions.
Conclusion: The side of the ruptured aneurysms (right or left) did not influence patients’ outcome. However, the aneurysm-side predicts the side of delayed infarctions and outcome appear to be worse in patients with left-sided infarctions.
Autologous hematopoietic stem cell transplantation (auto-HSCT) provides a potentially curative treatment option for relapsed and refractory lymphomas. Obesity displays an emerging epidemic risk factor for global mortality and is associated with an increased mortality in cancer patients. To date, the impact of obesity on the outcome of lymphoma patients undergoing auto-HSCT is understudied. We conducted a retrospective single-center study assessing 119 lymphoma patients who underwent auto-HSCT. Overall survival (OS) served as the primary endpoint whereas progression free survival (PFS), cumulative incidence of non-relapse related mortality (NRM) and cumulative incidence of relapse were analyzed as secondary endpoints. Obese patients (Body mass index, BMI≥30) had significantly lower OS (45.3% vs. 77.9%; p = 0.005) and PFS (29.8% vs. 67.2%; p<0.001) compared to non-obese patients at 48 months post-transplantation. The cumulative incidence of NRM displayed no significant differences while the cumulative incidence of relapse was significantly increased in patients with BMI≥30 (66.2% vs. 21.5%; p<0.001). Patients with a BMI<25 and overweight patients (BMI 25–30; 76.1% vs. 80.9%; p = 0.585), showed no significant difference in OS, whereas patients with BMI≥30 exhibited significant lower OS when compared to either of both groups (76.1% vs. 45.3%; p = .0.021 and 80.9% vs. 45.3%; p = 0.010). Furthermore, in a multivariate analysis, obesity was identified as an independent risk factor for death (Hazard ratio 2.231; 95% CI 1.024 to 4.860; p = 0.043). Further studies are needed to evaluate the reasons for the higher relapse rate causing higher mortality in obese patients.
Background: Although mechanistic target of rapamycin (mTOR) inhibitors, such as temsirolimus, show promise in treating bladder cancer, acquired resistance often hampers efficacy. This study evaluates mechanisms leading to resistance. Methods: Cell growth, proliferation, cell cycle phases, and cell cycle regulating proteins were compared in temsirolimus resistant (res) and sensitive (parental—par) RT112 and UMUC3 bladder cancer cells. To evaluate invasive behavior, adhesion to vascular endothelium or to immobilized extracellular matrix proteins and chemotactic activity were examined. Integrin α and β subtypes were analyzed and blocking was done to evaluate physiologic integrin relevance. Results: Growth of RT112res could no longer be restrained by temsirolimus and was even enhanced in UMUC3res, accompanied by accumulation in the S- and G2/M-phase. Proteins of the cdk-cyclin and Akt-mTOR axis increased, whereas p19, p27, p53, and p73 decreased in resistant cells treated with low-dosed temsirolimus. Chemotactic activity of RT112res/UMUC3res was elevated following temsirolimus re-exposure, along with significant integrin α2, α3, and β1 alterations. Blocking revealed a functional switch of the integrins, driving the resistant cells from being adhesive to being highly motile. Conclusion: Temsirolimus resistance is associated with reactivation of bladder cancer growth and invasive behavior. The α2, α3, and β1 integrins could be attractive treatment targets to hinder temsirolimus resistance.
Introduction: Recent animal studies have shown that the alternate renin-angiotensin system (RAS) consisting of angiotensin-converting enzyme 2 (ACE2), angiotensin-(1–7) (Ang-(1–7)) and the Mas receptor is upregulated in cirrhosis and contributes to splanchnic vasodilatation and portal hypertension. To determine the potential relevance of these findings to human liver disease, we evaluated its expression and relationship to the patients’ clinical status in subjects with cirrhosis. Methods: Blood sampling from peripheral and central vascular beds was performed intra-operatively for cirrhotic patients at the time of liver transplantation (LT) or trans-jugular intra-hepatic portosystemic shunt (TIPS) procedures to measure angiotensin II (Ang II) and Ang-(1–7) peptide levels and ACE and ACE2 enzyme activity. Relevant clinical and hemodynamic data were recorded pre-operatively for all subjects and peripheral blood sampling was repeated 3 months or later post-operatively. Results: Ang-(1–-7) and ACE2 activity were up-regulated more than twofold in cirrhotic subjects both at the time of LT and TIPS and levels returned to comparable levels as control subjects post-transplantation. Ang-(1–7) levels correlated positively with the degree of liver disease severity, as measured by the model for an end-stage liver disease (MELD) and also with clinical parameters of pathological vasodilatation including cardiac output (CO). There were strong correlations found between the ACE2:ACE and the Ang-(1–7):Ang II ratio highlighting the inter-dependence of the alternate and classical arms of the RAS and thus their potential impact on vascular tone. Conclusions: In human cirrhosis, the alternate RAS is markedly upregulated and the activation of this system is associated strongly with features of the hyperdynamic circulation in advanced human cirrhosis.
Purpose: Bacterial biofilms are a major problem in the treatment of infected dental and orthopedic implants. The purpose of this study is to investigate the cleaning effect of an electrolytic approach (EC) compared to a powder-spray system (PSS) on titanium surfaces. Materials and Methods: The tested implants (different surfaces and alloys) were collated into six groups and treated ether with EC or PSS. After a mature biofilm was established, the implants were treated, immersed in a nutritional solution, and streaked on Columbia agar. Colony-forming units (CFUs) were counted after breeding and testing (EC), and control (PSS) groups were compared using a paired sample t-test. Results: No bacterial growth was observed in the EC groups. After thinning to 1:1,000,000, 258.1 ± 19.9 (group 2), 264.4 ± 36.5 (group 4), and 245.3 ± 40.7 (group 6) CFUs could be counted in the PSS groups. The difference between the electrolytic approach (test groups 1, 3, and 5) and PSS (control groups 2, 4, and 6) was statistically extremely significant (p-value < 2.2 × 10−16). Conclusion: Only EC inactivated the bacterial biofilm, and PSS left reproducible bacteria behind. Within the limits of this in vitro test, clinical relevance could be demonstrated.
Of the hepatic cell lines developed for in vitro studies of hepatic functions as alternatives to primary human hepatocytes, many have lost major liver-like functions, but not HepaRG cells. The increasing use of the latter worldwide raises the need for establishing the reference functional status of early biobanked HepaRG cells. Using deep proteome and secretome analyses, the levels of master regulators of the hepatic phenotype and of the structural elements ensuring biliary polarity were found to be close to those in primary hepatocytes. HepaRG cells proved to be highly differentiated, with functional mitochondria, hepatokine secretion abilities, and an adequate response to insulin. Among differences between primary human hepatocytes and HepaRG cells, the factors that possibly support HepaRG transdifferentiation properties are discussed. The HepaRG cell system thus appears as a robust surrogate for primary hepatocytes, which is versatile enough to study not only xenobiotic detoxification, but also the control of hepatic energy metabolism, secretory function and disease-related mechanisms.
Pathophysiological role of prostanoids in coagulation of the portal venous system in liver cirrhosis
(2019)
Background: Prostanoids are important regulators of platelet aggregation and thrombotic arterial diseases. Their involvement in the development of portal vein thrombosis, frequent in decompensated liver cirrhosis, is still not investigated.
Methods: Therefore, we used pro-thrombotic venous milieu generation by bare metal stent transjugular intrahepatic portosystemic shunt insertion, to study the role of prostanoids in decompensated liver cirrhosis. Here, 89 patients receiving transjugular intrahepatic portosystemic shunt insertion were included in the study, and baseline levels of thromboxane B2, prostaglandin D2 and prostaglandin E2 were measured in the portal and the hepatic vein.
Results: While the hepatic vein contained higher levels of thromboxane B2 than the portal vein, levels of prostaglandin E2 and D2 were higher in the portal vein (all P<0.0001). Baseline concentrations of thromboxane B2 in the portal vein were independently associated with an increase of portal hepatic venous pressure gradient during short term follow-up, as an indirect sign of thrombogenic potential (multivariable P = 0.004). Moreover, severity of liver disease was inversely correlated with portal as well as hepatic vein levels of prostaglandin D2 and E2 (all P<0.0001).
Conclusions: Elevated portal venous thromboxane B2 concentrations are possibly associated with the extent of thrombogenic potential in patients with decompensated liver cirrhosis.
Trial registration: ClinicalTrials.gov identifier: NCT03584204.
Aims: The examination of histological sections is still the gold standard in diagnostic pathology. Important histopathological diagnostic criteria are nuclear shapes and chromatin distribution as well as nucleus-cytoplasm relation and immunohistochemical properties of surface and intracellular proteins. The aim of this investigation was to evaluate the benefits and drawbacks of three-dimensional imaging of CD30+ cells in classical Hodgkin Lymphoma (cHL) in comparison to CD30+ lymphoid cells in reactive lymphoid tissues.
Materials and results: Using immunoflourescence confocal microscopy and computer-based analysis, we compared CD30+ neoplastic cells in Nodular Sclerosis cHL (NScCHL), Mixed Cellularity cHL (MCcHL), with reactive CD30+ cells in Adenoids (AD) and Lymphadenitis (LAD). We confirmed that the percentage of CD30+ cell volume can be calculated. The amount in lymphadenitis was approx. 1.5%, in adenoids around 2%, in MCcHL up to 4,5% whereas the values for NScHL rose to more than 8% of the total cell cytoplasm. In addition, CD30+ tumour cells (HRS-cells) in cHL had larger volumes, and more protrusions compared to CD30+ reactive cells. Furthermore, the formation of large cell networks turned out to be a typical characteristic of NScHL.
Conclusion: In contrast to 2D histology, 3D laser scanning offers a visualisation of complete cells, their network interaction and spatial distribution in the tissue. The possibility to differentiate cells in regards to volume, surface, shape, and cluster formation enables a new view on further diagnostic and biological questions. 3D includes an increased amount of information as a basis of bioinformatical calculations.
Cardiovascular diseases are the most prominent cause of death in Western society, especially in the elderly. With the increasing life expectancy, the number of patients with cardiovascular diseases will rise in the near future, leading to an increased healthcare burden. There is a need for new therapies to treat this growing number of patients. The discovery of long non-coding RNAs has led to a novel group of molecules that could be considered for their potential as therapeutic targets. This review presents an overview of long non-coding RNAs that are regulated in vascular disease and aging and which might therefore give insight into new pathways that could be targeted to diagnose, prevent, and/or treat vascular diseases.
Chaperone-assisted selective autophagy (CASA) initiated by the cochaperone Bcl2-associated athanogene 3 (BAG3) represents an important mechanism for the disposal of misfolded and damaged proteins in mammalian cells. Under mechanical stress, the cochaperone cooperates with the small heat shock protein HSPB8 and the cytoskeleton-associated protein SYNPO2 to degrade force-unfolded forms of the actin-crosslinking protein filamin. This is essential for muscle maintenance in flies, fish, mice and men. Here, we identify the serine/threonine protein kinase 38 (STK38), which is part of the Hippo signaling network, as a novel interactor of BAG3. STK38 was previously shown to facilitate cytoskeleton assembly and to promote mitophagy as well as starvation and detachment induced autophagy. Significantly, our study reveals that STK38 exerts an inhibitory activity on BAG3-mediated autophagy. Inhibition relies on a disruption of the functional interplay of BAG3 with HSPB8 and SYNPO2 upon binding of STK38 to the cochaperone. Of note, STK38 attenuates CASA independently of its kinase activity, whereas previously established regulatory functions of STK38 involve target phosphorylation. The ability to exert different modes of regulation on central protein homeostasis (proteostasis) machineries apparently allows STK38 to coordinate the execution of diverse macroautophagy pathways and to balance cytoskeleton assembly and degradation.
Post-transcriptional gene regulation through microRNA (miRNA) has emerged as a major control mechanism of multiple biological processes, including development and function of T cells. T cells are vital components of the immune system, with conventional T cells playing a central role in adaptive immunity and unconventional T cells having additional functions reminiscent of both innate and adaptive immunity, such as involvement in stress responses and tissue homeostasis. Unconventional T cells encompass cells expressing semi-invariant T cell receptors (TCRs), such as invariant Natural Killer T (iNKT) and Mucosal-Associated Invariant T (MAIT) cells. Additionally, some T cells with diverse TCR repertoires, including γδT cells, intraepithelial lymphocytes (IEL) and regulatory T (Treg) cells, share some functional and/or developmental features with their semi-invariant unconventional counterparts. Unconventional T cells are particularly sensitive to disruption of miRNA function, both globally and on the individual miRNA level. Here, we review the role of miRNA in the development and function of unconventional T cells from an iNKT-centric point of view. The function of single miRNAs can provide important insights into shared and individual pathways for the formation of different unconventional T cell subsets.
The spectrum of alcoholic liver disease (ALD) is broad and includes alcoholic fatty liver, alcoholic steatohepatitis, alcoholic hepatitis, alcoholic fibrosis, alcoholic cirrhosis, and alcoholic hepatocellular carcinoma, best explained as a five-hit sequelae of injurious steps. ALD is not primarily the result of malnutrition as assumed for many decades but due to the ingested alcohol and its metabolic consequences although malnutrition may marginally contribute to disease aggravation. Ethanol is metabolized in the liver to the heavily reactive acetaldehyde via the alcohol dehydrogenase (ADH) and the cytochrome P450 isoform 2E1 of the microsomal ethanol-oxidizing system (MEOS). The resulting disturbances modify not only the liver parenchymal cells but also non-parenchymal cells such as Kupffer cells (KCs), hepatic stellate cells (HSCs), and liver sinusoidal endothelial cells (LSECs). These are activated by acetaldehyde, reactive oxygen species (ROS), and endotoxins, which are produced from bacteria in the gut and reach the liver due to gut leakage. A variety of intrahepatic signaling pathways and innate or acquired immune reactions are under discussion contributing to the pathogenesis of ALD via the five injurious hits responsible for disease aggravation. As some of the mechanistic steps are based on studies with in vitro cell systems or animal models, respective proposals for humans may be considered as tentative. However, sufficient evidence is provided for clinical risk factors that include the amount of alcohol used daily for more than a decade, gender differences with higher susceptibility of women, genetic predisposition, and preexisting liver disease. In essence, efforts within the last years were devoted to shed more light in the pathogenesis of ALD, much has been achieved but issues remain to what extent results obtained from experimental studies can be transferred to humans.
Background and aims: Patients with gastric cancer often show signs of malnutrition. We sought to evaluate the influence of sarcopenia in patients with locally advanced, not metastasized, gastric or gastro-esophageal junction (GEJ) cancer undergoing curative treatment (perioperative chemotherapy and surgery) on morbidity and mortality in order to identify patients in need for nutritional intervention.
Patients and methods: Two-centre study, conducted in the Frankfurt University Clinic and Krankenhaus Nordwest (Frankfurt) as part of the University Cancer Center Frankfurt (UCT). 47/83 patients were treated in the FLOT trial (NCT01216644). Patients´ charts were reviewed for clinical data. Two consecutive CT scans were retrospectively analyzed to determine the degree of sarcopenia. Survival was calculated using the Kaplan-Meier method, multivariate analysis was performed using the Cox regression.
Results: 60 patients (72.3%) were male and 23 (27.7%) female. 45 patients (54.2%) had GEJ type 1–3 and 38 (45.8%) gastric tumors, respectively. Sarcopenic patients were significantly older than non-sarcopenic patients (mean age 65.1 years vs. 59.5 years, p = 0.042), terminated the chemotherapy significantly earlier (50% vs. 22.6%, p = 0.037) and showed higher Clavien-Dindo scores, indicating more severe perioperative complications (score ≥3 43.3 vs. 17.0%, p = 0.019). Sarcopenic patients had a significantly shorter survival than non-sarcopenic patients (139.6 ± 19.5 [95% CI, 101.3–177.9] vs. 206.7 ± 13.8 [95% CI, 179.5–233.8] weeks, p = 0.004). Multivariate Cox regression analysis showed that, besides UICC stage, sarcopenia significantly influenced survival.
Conclusion: Sarcopenia is present in a large proportion of patients with locally advanced gastric or GEJ cancer and significantly influences tolerability of chemotherapy, surgical complications and survival.
The molecular basis of vitamin D signaling implies that the metabolite 1α,25-dihydroxyvitamin D3 (1,25(OH)2D3) of the secosteroid vitamin D3 activates the transcription factor vitamin D receptor (VDR), which in turn modulates the expression of hundreds of primary vitamin D target genes. Since the evolutionary role of nuclear receptors, such as VDR, was the regulation of cellular metabolism, the control of calcium metabolism became the primary function of vitamin D and its receptor. Moreover, the nearly ubiquitous expression of VDR enabled vitamin D to acquire additional physiological functions, such as the support of the innate immune system in its defense against microbes. Monocytes and their differentiated phenotypes, macrophages and dendritic cells, are key cell types of the innate immune system. Vitamin D signaling was most comprehensively investigated in THP-1 cells, which are an established model of human monocytes. This includes the 1,25(OH)2D3-modulated cistromes of VDR, the pioneer transcription factors PU.1 and CEBPA and the chromatin modifier CTCF as well as of the histone markers of promoter and enhancer regions, H3K4me3 and H3K27ac, respectively. These epigenome-wide datasets led to the development of our chromatin model of vitamin D signaling. This review discusses the mechanistic basis of 189 primary vitamin D target genes identified by transcriptome-wide analysis of 1,25(OH)2D3-stimulated THP-1 cells and relates the epigenomic basis of four different regulatory scenarios to the physiological functions of the respective genes.
Kinesins play an important role in many physiological functions including intracellular vesicle transport and mitosis. The emerging role of kinesins in different cancers led us to investigate the expression and functional role of kinesins in meningioma. Therefore, we re-analyzed our previous microarray dataset of benign, atypical, and anaplastic meningiomas (n = 62) and got evidence for differential expression of five kinesins (KIFC1, KIF4A, KIF11, KIF14 and KIF20A). Further validation in an extended study sample (n = 208) revealed a significant upregulation of these genes in WHO°I to °III meningiomas (WHO°I n = 61, WHO°II n = 88, and WHO°III n = 59), which was most pronounced in clinically more aggressive tumors of the same WHO grade. Immunohistochemical staining confirmed a WHO grade-associated upregulated protein expression in meningioma tissues. Furthermore, high mRNA expression levels of KIFC1, KIF11, KIF14 and KIF20A were associated with shorter progression-free survival. On a functional level, knockdown of kinesins in Ben-Men-1 cells and in the newly established anaplastic meningioma cell line NCH93 resulted in a significantly inhibited tumor cell proliferation upon siRNA-mediated downregulation of KIF11 in both cell lines by up to 95% and 71%, respectively. Taken together, in this study we were able to identify the prognostic and functional role of several kinesin family members of which KIF11 exhibits the most promising properties as a novel prognostic marker and therapeutic target, which may offer new treatment options for aggressive meningiomas.
Introduction: Dravet syndrome (DS) is a rare developmental and epileptic encephalopathy. This study estimated cost, cost-driving factors and quality of life (QoL) in patients with Dravet syndrome and their caregivers in a prospective, multicenter study in Germany.
Methods: A validated 3–12-month retrospective questionnaire and a prospective 3-month diary assessing clinical characteristics, QoL, and direct, indirect and out-of-pocket (OOP) costs were administered to caregivers of patients with DS throughout Germany.
Results: Caregivers of 93 patients (mean age 10.1 years, ±7.1, range 15 months–33.7 years) submitted questionnaires and 77 prospective diaries. The majority of patients (95%) experienced at least one seizure during the previous 12 months and 77% a status epilepticus (SE) at least once in their lives. Over 70% of patients had behavioural problems and delayed speech development and over 80% attention deficit symptoms and disturbance of motor skills and movement coordination. Patient QoL was lower than in the general population and 45% of caregivers had some form of depressive symptoms. Direct health care costs per three months were a mean of €6,043 ± €5,825 (median €4054, CI €4935-€7350) per patient. Inpatient costs formed the single most important cost category (28%, €1,702 ± €4,315), followed by care grade benefits (19%, €1,130 ± €805), anti-epileptic drug (AED) costs (15%, €892 ± €1,017) and ancillary treatments (9%, €559 ± €503). Total indirect costs were €4,399 ±€ 4,989 (median €0, CI €3466-€5551) in mothers and €391 ± €1,352 (median €0, CI €195-€841) in fathers. In univariate analysis seizure frequency, experience of SE, nursing care level and severe additional symptoms were found to be associated with total direct healthcare costs. Severe additional symptoms was the single independently significant explanatory factor in a multivariate analysis.
Conclusions: This study over a period up to 15 months revealed substantial direct and indirect healthcare costs of DS in Germany and highlights the relatively low patient and caregiver QoL compared with the general population.
AMPA receptors and interacting proteins are importantly involved in mediating stress-dependent plasticity. Previously we reported that GluA1-containing AMPA receptors and their interaction with PDZ-proteins are required for the experience-dependent expression of behavioral despair in the forced swim test. However, it is unclear if the expression of GluA1-containing AMPA receptors is affected by this type of behavior. Here we investigated in wild type mice, whether hippocampal gene or protein levels of GluA1 or associated PDZ proteins is altered following forced swim stress. We show that expression of Dlg4 (the gene coding for PSD-95) was strongly reduced after two days of forced swimming. In contrast, levels of Dlg1, Gria1, and Gria2 (coding for SAP97, GluA1, and GluA2 respectively) were not affected after one or two days of forced swimming. The changes in gene expression largely did not translate to the protein level. These findings indicate a limited acute effect of forced swim stress on the expression of the investigated targets and suggest that the acute involvement of GluA1-containing AMPA receptors tor forced swim behavior is a result of non-genomic mechanisms.
Introduction: Acute stroke care delivered by interdisciplinary teams is time-sensitive. Simulation-based team training is a promising tool to improve team performance in medical operations. It has the potential to improve process times, team communication, patient safety, and staff satisfaction. We aim to assess whether a multi-level approach consisting of a stringent workflow revision based on peer-to-peer review and 2–3 one-day in situ simulation trainings can improve acute stroke care processing times in high volume neurocenters within a 6 months period.
Methods and Analysis: The trial is being carried out in a pre-test-post-test design at 7 tertiary care university hospital neurocenters in Germany. The intervention is directed at the interdisciplinary multiprofessional stroke teams. Before and after the intervention, process times of all direct-to-center stroke patients receiving IV thrombolysis (IVT) and/or endovascular therapy (EVT) will be recorded. The primary outcome measure will be the “door-to-needle” time of all consecutive stroke patients directly admitted to the neurocenters who receive IVT. Secondary outcome measures will be intervention-related process times of the fraction of patients undergoing EVT and effects on team communication, perceived patient safety, and staff satisfaction via a staff questionnaire.
Interventions: We are applying a multi-level intervention in cooperation with three “STREAM multipliers” from each center. First step is a central meeting of the multipliers at the sponsor's institution with the purposes of algorithm review in a peer-to-peer process that is recorded in a protocol and an introduction to the principles of simulation training and debriefing as well as crew resource management and team communication. Thereafter, the multipliers cooperate with the stroke team trainers from the sponsor's institution to plan and execute 2–3 one-day simulation courses in situ in the emergency department and CT room of the trial centers whereupon they receive teaching materials to perpetuate the trainings.
Clinical Trial Registration: STREAM is a registered trial at https://clinicaltrials.gov/ct2/show/NCT03228251.
Head and neck squamous cell carcinoma (HNSCC) is the sixth most common cancer worldwide and often has a poor prognosis. The present study investigated the role of the low affinity nerve growth factor receptor CD271 as a putative therapy target in HNSCC. Neurotrophins that bind to CD271 also have a high affinity for the tropomyosin receptor kinase family (Trk), consisting of TrkA, TrkB, and TrkC, which must also be considered in addition to CD271. A retrospective study and functional in vitro cell line tests (migration assay and cell sorting) were conducted in order to evaluate the relevance of CD271 expression alone and with regard to Trk expression. CD271 and Trks were heterogeneously expressed in human HNSCC. The vast majority of tumors exhibited CD271 and TrkA, whereas only half of the tumors expressed TrkB and TrkC. High expression of CD271-positive cells predicted a bad clinical outcome of patients with HNSCC and was associated with distant metastases. However, the human carcinomas that also expressed TrkC had a reduced correlation with distant metastases and better survival rates. In vitro, CD271 expression marked a subpopulation with higher proliferation rates, but proliferation was lower in tumor cells that co-expressed CD271 and TrkC. The CD271 inhibitor LM11A 31 suppressed cell motility in vitro. However, neither TrkA nor TrkB expression were linked to prognosis or cell proliferation. We conclude that CD271 is a promising candidate that provides prognostic information for HNSCC and could be a putative target for HNSCC treatment.
Background: Outcomes of catheter ablation of atrial fibrillation (AF) are variable and the predictors of success require further elucidation since the identification of correctable risk factors could help to optimize therapy. We aimed to assess the impact of body mass index (BMI) in the overall safety and efficacy of catheter ablation of AF, with emphasis on the use of cryoballoon ablation and novel oral anticoagulants.
Methods and Results: There were 2497 consecutive patients undergoing catheter ablation of AF in 7 European high volume centers were stratified according to BMI (normal weight <25 kg/m2, pre‐obese 25–30 kg/m2, obesity 30–35 kg/m2, and morbid obesity ≥35 kg/m2) and comparisons of procedural outcomes evaluated. Pre‐obese and obese patients presented more comorbidities (hypertension, diabetes mellitus, and sleep apnea), and had higher rates of non‐paroxysmal AF ablation procedures. The rate of atrial 12‐month arrhythmia relapse increased alongside with BMI (35.2%, 35.7%, 43.6%, and 48.0% P<0.001). During a median follow‐up of 18.8 months (interquartile range 11–28), after adjusting for all baseline differences, BMI was an independent predictor of relapse (hazard ratio=1.01 per kg/m2; 95% CI 1.01–1.02; P=0.002), adding incremental predictive value to obstructive sleep apnea. BMI was not a predictor for any of the reported complications. Using novel oral anticoagulants and cryoballoon ablation was safe and efficacy was comparable with vitamin‐K antagonists and radiofrequency ablation.
Conclusions: Obese patients present with a more adverse comorbidity profile, more advanced forms of AF, and have lower chances of being free from AF relapse after ablation. Use of novel oral anticoagulants and cryoballoon ablation may be an option in this patient group.
In vivo functional diversity of midbrain dopamine neurons within identified axonal projections
(2019)
Functional diversity of midbrain dopamine (DA) neurons ranges across multiple scales, from differences in intrinsic properties and connectivity to selective task engagement in behaving animals. Distinct in vitro biophysical features of DA neurons have been associated with different axonal projection targets. However, it is unknown how this translates to different firing patterns of projection-defined DA subpopulations in the intact brain. We combined retrograde tracing with single-unit recording and labelling in mouse brain to create an in vivo functional topography of the midbrain DA system. We identified differences in burst firing among DA neurons projecting to dorsolateral striatum. Bursting also differentiated DA neurons in the medial substantia nigra (SN) projecting either to dorsal or ventral striatum. We found differences in mean firing rates and pause durations among ventral tegmental area (VTA) DA neurons projecting to lateral or medial shell of nucleus accumbens. Our data establishes a high-resolution functional in vivo landscape of midbrain DA neurons.
Intact-cell maldi-tof mass spectrometry for the authentication of drug-adapted cancer cell lines
(2019)
The use of cell lines in research can be affected by cell line misidentification. Short tandem repeat (STR) analysis is an effective method, and the gold standard, for the identification of the genetic origin of a cell line, but methods that allow the discrimination between cell lines of the same genetic origin are lacking. Here, we use intact cell MALDI-ToF mass spectrometry analysis, routinely used for the identification of bacteria in clinical diagnostic procedures, for the authentication of a set of cell lines consisting of three parental neuroblastoma cell lines (IMR-5, IMR-32 and UKF-NB-3) and eleven drug-adapted sublines. Principal component analysis (PCA) of intact-cell MALDI-ToF mass spectrometry data revealed clear differences between most, but not all, of the investigated cell lines. Mass spectrometry whole-cell fingerprints enabled the separation of IMR-32 and its clonal subline IMR-5. Sublines that had been adapted to closely related drugs, for example, the cisplatin- and oxaliplatin-resistant UKF-NB-3 sublines and the vincristine- and vinblastine-adapted IMR-5 sublines, also displayed clearly distinctive patterns. In conclusion, intact whole-cell MALDI-ToF mass spectrometry has the potential to be further developed into an authentication method for mammalian cells of a common genetic origin.
Anaplastic large cell lymphoma (ALCL) and classical Hodgkin lymphoma (cHL) are lymphomas that contain CD30-expressing tumor cells and have numerous pathological similarities. Whereas ALCL is usually diagnosed at an advanced stage, cHL more frequently presents with localized disease. The aim of the present study was to elucidate the mechanisms underlying the different clinical presentation of ALCL and cHL. Chemokine and chemokine receptor expression were similar in primary ALCL and cHL cases apart from the known overexpression of the chemokines CCL17 and CCL22 in the Hodgkin and Reed-Sternberg (HRS) cells of cHL. Consistent with the overexpression of these chemokines, primary cHL cases encountered a significantly denser T cell microenvironment than ALCL. Additionally to differences in the interaction with their microenvironment, cHL cell lines presented a lower and less efficient intrinsic cell motility than ALCL cell lines, as assessed by time-lapse microscopy in a collagen gel and transwell migration assays. We thus propose that the combination of impaired basal cell motility and differences in the interaction with the microenvironment hamper the dissemination of HRS cells in cHL when compared with the tumor cells of ALCL.
Inflammatory activation of astroglia adds to the pathology of various neurological diseases. Astrocytes respond to microglia-derived cytokines such as interleukin-1α (IL-1α) with enhanced inflammatory signaling. This provokes pro-inflammatory gene expression of, among others, the eicosanoid-generating enzyme prostaglandin endoperoxide synthase 2 (Ptgs2). Whereas metabolic regulation of innate immune cell inflammatory responses is intensely studied, pathways related to how metabolism modulates inflammatory signaling in astrocytes are underexplored. Here, we examined how mitochondrial oxidative phosphorylation affects inflammatory responses towards IL-1α and tumor necrosis factor α in neonatal rat astrocytes. Blocking respiratory complex I and III or adenosine triphosphate (ATP) synthase did not affect activation of inflammatory signaling by IL-1α, but did elicit differential effects on inflammatory gene mRNA expression. Remarkably, mRNA and protein expression of Ptgs2 by IL-1α was consistently up-regulated when oxidative phosphorylation was inhibited. The increase of Ptgs2 resulted from mRNA stabilization. Mitochondrial inhibitors also increased IL-1α-triggered secretion of eicosanoids, such as prostaglandin E2, prostaglandin F2α, and 6-keto-prostaglandin F1α, as assessed by liquid chromatography/mass spectrometry. Mechanistically, attenuating oxidative phosphorylation elevated adenosine monophosphate (AMP) and activated AMP-activated protein kinase (AMPK). AMPK silencing prevented Ptgs2 up-regulation by mitochondrial inhibitors, while AMPK activators recapitulated Ptgs2 mRNA stability regulation. Our data indicate modulation of astrocyte inflammatory responses by oxidative metabolism, with relevance towards eicosanoid production.
Background: Receiving a cancer diagnosis can be a major life event which causes distress even years after primary treatment.
Aim: To examine the prevalence of distress in older patients with cancer (OPCs) up until 5 years post-diagnosis, and identify predictors present at time of diagnosis. Results are compared with reference groups of middle-aged patients with cancer (MPCs) and older patients without a cancer diagnosis (OPs).
Design & setting: OPCs, MPCs, and OPs participated in a longitudinal cohort study in Belgium and the Netherlands by filling in questionnaires at designated time points from 2010–2019.
Method: Data from 541 patients were analysed using multivariable logistic regression analyses.
Results: At baseline, 40% of OPCs, 37% of MPCs, and 17% of OPs reported distress. After 5 years, 35% of OPCs, 23% of MPCs, and 25% of OPs reported distress. No significant predictors for long-term distress in OPCs and OPs were found. For MPCs, it was found that baseline distress (odds ratio [OR] 2.94; 95% confidence intervals [CI] = 1.40 to 6.19) and baseline fatigue (OR 4.71; 95% CI = 1.81 to 12.31) predicted long-term distress.
Conclusion: Distress is an important problem for people with cancer, with peaks at different moments after diagnosis. Feelings of distress are present shortly after diagnosis but they decrease quickly for the majority of patients. In the long term, however, OPCs in particular appear to be most at risk for distress. This warrants extra attention from primary healthcare professionals, such as GPs who are often patients’ first medical contact point. More research into risk factors occurring later in an illness trajectory might shed more light on predictors for development of long-term distress.
Introduction: An overview of the requirements for the head of a surgical department in Germany should be given.
Materials and methods: A retrospective literature research on surgical professional policy publications of the last 10 years in Germany was conducted.
Results: Surveys show that commercial influences on medical decisions in German hospitals have today become an everyday, predominantly negative, actuality. Nevertheless, in one survey, 82.9% of surgical chief physicians reported being very satisfied with their profession, compared with 61.5% of senior physicians and only 43.4% of hospital specialists. Here, the chief physician is challenged. Only 70% of those surveyed stated that they could rely on their direct superiors when difficulties arose at work, and only 34.1% regarded feedback on the quality of their work as sufficient. The high distress rate in surgery (58.2% for all respondents) has led to a lack in desirability and is reflected in a shortage of qualified applicants for resident positions. In various position papers, surgical residents (only 35% describe their working conditions as good) demand improved working conditions. Chief physicians are being asked to facilitate a suitable work-life balance with regular working hours and a corporate culture with participative management and collegial cooperation. Appreciation of employee performance must also be expressed. An essential factor contributing to dissatisfaction is that residents fill a large part of their daily working hours with non-physician tasks. In surveys, 70% of respondents stated that they spend up to ≥3 h a day on documentation and secretarial work.
Discussion: The chief physician is expected to relieve his medical staff by employing non-physician assistants to take care of non-physician tasks. Transparent and clearly structured training to achieve specialist status is essential. It has been shown that a balanced work-life balance can be achieved for surgeons. Family and career can be reconciled in appropriately organized departments by making use of part-time and shift models that exclude 24-h shifts and making working hours more flexible.
Therapy of acute myeloid leukemia (AML) is unsatisfactory. Histone deacetylase inhibitors (HDACi) are active against leukemic cells in vitro and in vivo. Clinical data suggest further testing of such epigenetic drugs and to identify mechanisms and markers for their efficacy. Primary and permanent AML cells were screened for viability, replication stress/DNA damage, and regrowth capacities after single exposures to the clinically used pan-HDACi panobinostat (LBH589), the class I HDACi entinostat/romidepsin (MS-275/FK228), the HDAC3 inhibitor RGFP966, the HDAC6 inhibitor marbostat-100, the non-steroidal anti-inflammatory drug (NSAID) indomethacin, and the replication stress inducer hydroxyurea (HU). Immunoblotting was used to test if HDACi modulate the leukemia-associated transcription factors β-catenin, Wilms tumor (WT1), and myelocytomatosis oncogene (MYC). RNAi was used to delineate how these factors interact. We show that LBH589, MS-275, FK228, RGFP966, and HU induce apoptosis, replication stress/DNA damage, and apoptotic fragmentation of β-catenin. Indomethacin destabilizes β-catenin and potentiates anti-proliferative effects of HDACi. HDACi attenuate WT1 and MYC caspase-dependently and -independently. Genetic experiments reveal a cross-regulation between MYC and WT1 and a regulation of β-catenin by WT1. In conclusion, reduced levels of β-catenin, MYC, and WT1 are molecular markers for the efficacy of HDACi. HDAC3 inhibition induces apoptosis and disrupts tumor-associated protein expression.
Purpose: The aim of this study is to record material- and surface-dependent heat dissipation during the process of inserting implants into native animal bone. Materials and Methods: Implants made of titanium and zirconium that were identical in macrodesign were inserted under controlled conditions into a bovine rib tempered to 37 °C. The resulting surface temperature was measured on two bone windows by an infrared camera. The results of the six experimental groups, ceramic machined (1), sandblasted (2), and sandblasted and acid-etched surfaces (3) versus titanium implants with the corresponding surfaces (4, 5, and 6) were statistically tested. Results: The average temperature increase, 3 mm subcrestally at ceramic implants, differed with high statistical significance (p = 7.163 × 10−9, resulting from group-adjusted linear mixed-effects model) from titanium. The surface texture of ceramic implants shows a statistical difference between group 3 (15.44 ± 3.63 °C) and group 1 (19.94 ± 3.28 °C) or group 2 (19.39 ± 5.73 °C) surfaces. Within the titanium implants, the temperature changes were similar for all surfaces. Conclusion: Within the limits of an in vitro study, the high temperature rises at ceramic versus titanium implants should be limited by a very slow insertion velocity.
Age Related Macular Degeneration (AMD) is the first cause of social blindness in people aged over 65 leading to atrophy of retinal pigment epithelial cells (RPE), photoreceptors and choroids, eventually associated with choroidal neovascularization. Accumulation of undigested cellular debris within RPE cells or under the RPE (Drusen), oxidative stress and inflammatory mediators contribute to the RPE cell death. The major risk to develop AMD is the Y402H polymorphism of complement factor H (CFH). CFH interacting with oxidized phospholipids on the RPE membrane modulates the functions of these cells, but the exact role of CFH in RPE cell death and survival remain poorly understood. The aim of this study was to analyze the potential protective mechanism of CFH on RPE cells submitted to oxidative stress. Upon exposure to oxidized lipids 4-HNE (4-hydroxy-2-nonenal) derived from photoreceptors, both the human RPE cell line ARPE-19 and RPE cells derived from human induced pluripotent stem cells were protected from death only in the presence of the full length human recombinant CFH in the culture medium. This protective effect was independent from the membrane attack complex (MAC) formation. CFH maintained RPE cells tight junctions’ structure and regulated the caspase dependent apoptosis process. These results demonstrated the CFH anti-oxidative stress functions independently of its capacity to inhibit MAC formation.
Background and Aims: Vitamin D has an inhibitory role in the inflammatory signaling pathways and supports the integrity of the intestinal barrier. Due to its immunomodulatory effect, vitamin D plays a role in chronic inflammatory bowel disease (IBD) and a deficiency is associated with an increased risk for a flare. We aimed to investigate to what extent the 25-hydroxyvitamin D (25(OH)D3) level correlates with disease activity and whether a cut-off value can be defined that discriminates between active disease and remission. Methods: Patients with IBD, treated at the University Hospital Frankfurt were analyzed retrospectively. The 25(OH)D3 levels were correlated with clinical activity indices and laboratory chemical activity parameters. A deficiency was defined as 25(OH)D3 levels <30 ng/mL. Results: A total of 470 (257 female) patients with IBD were included, 272 (57.9%) with Crohn’s disease (CD), 198 (42.1%) with ulcerative colitis (UC). The median age of the patients was 41 (18–84). In 283 patients (60.2%), a vitamin D deficiency was detected. 245 (53.6%) patients received oral vitamin D supplementation, and supplemented patients had significantly higher vitamin D levels (p < 0.0001). Remission, vitamin D substitution, and male gender were independently associated with the 25(OH)D3 serum concentration in our cohort in regression analysis. A 25(OH)D3 serum concentration of 27.5 ng/mL was the optimal cut-off value. Conclusion: Vitamin D deficiency is common in IBD patients and appears to be associated with increased disease activity. In our study, vitamin D levels were inversely associated with disease activity. Thus, close monitoring should be established, and optimized supplementation should take place.
The multifaceted p21 (Cip1/Waf1/CDKN1A) in cell differentiation, migration and cancer therapy
(2019)
Loss of cell cycle control is characteristic of tumorigenesis. The protein p21 is the founding member of cyclin-dependent kinase inhibitors and an important versatile cell cycle protein. p21 is transcriptionally controlled by p53 and p53-independent pathways. Its expression is increased in response to various intra- and extracellular stimuli to arrest the cell cycle ensuring genomic stability. Apart from its roles in cell cycle regulation including mitosis, p21 is involved in differentiation, cell migration, cytoskeletal dynamics, apoptosis, transcription, DNA repair, reprogramming of induced pluripotent stem cells, autophagy and the onset of senescence. p21 acts either as a tumor suppressor or as an oncogene depending largely on the cellular context, its subcellular localization and posttranslational modifications. In the present review, we briefly mention the general functions of p21 and summarize its roles in differentiation, migration and invasion in detail. Finally, regarding its dual role as tumor suppressor and oncogene, we highlight the potential, difficulties and risks of using p21 as a biomarker as well as a therapeutic target.
Introduction: Definitive chemoradiation (CRT) followed by high-dose-rate (HDR) brachytherapy (BT) represents state-of-the-art treatment for locally-advanced cervical cancer. Despite use of this treatment paradigm, disease-related outcomes have stagnated in recent years, indicating the need for biomarker development and improved patient stratification. Here, we report the association of Polo-like kinase (PLK) 3 expression and Caspase 8 T273 phosphorylation levels with survival among patients with cervical squamous cell carcinoma (CSCC) treated with CRT plus BT.
Methods: We identified 74 patients with FIGO Stage Ib to IVb cervix squamous cell carcinoma. Baseline immunohistochemical scoring of PLK3 and pT273 Caspase 8 levels was performed on pre-treatment samples. Correlation was then assessed between marker expression and clinical endpoints, including cumulative incidences of local and distant failure, cancer-specific survival (CSS) and overall survival (OS). Data were then validated using The Cancer Genome Atlas (TCGA) dataset.
Results: PLK3 expression levels were associated with pT273 Caspase 8 levels (p = 0.009), as well as N stage (p = 0.046), M stage (p = 0.026), and FIGO stage (p = 0.001). By the same token, pT273 Caspase 8 levels were associated with T stage (p = 0.031). Increased PLK3 levels corresponded to a lower risk of distant relapse (p = 0.009), improved CSS (p = 0.001), and OS (p = 0.003). Phospho T273 Caspase 8 similarly corresponded to decreased risk of distant failure (p = 0.021), and increased CSS (p < 0.001) and OS (p < 0.001) and remained a significant predictor for OS on multivariate analysis. TCGA data confirmed the association of low PLK3 expression with resistance to radiotherapy and BT (p < 0.05), as well as increased propensity for metastasis (p = 0.019). Finally, a combined PLK3 and pT273 Caspase 8 score predicted for decreased distant relapse (p = 0.005), and both improved CSS (p < 0.001) and OS (p < 0.001); this combined score independently predicted distant failure (p = 0.041) and CSS (p = 0.003) on multivariate analyses.
Conclusion: Increased pre-treatment tumor levels of PLK3 and pT273 Caspase 8 correspond to improved disease-related outcomes among cervical cancer patients treated with CRT plus BT, representing a potential biomarker in this context.
Introduction: Our aim was to highlight the characteristics of pediatric Meckel's diverticulum with a special focus on its complications.
Methods: We report a group of seven patients with Meckel's diverticulum and its resection from the Department of Pediatric Surgery between 2012 and 2017. We reviewed all patient records, clinical presentation, and intraoperative findings. The diagnosis was confirmed by surgery and pathology. For a systematic literature review, we used PubMed, Medline and Google Scholar search engines to locate articles containing terms such as Meckel's diverticulum, children, pediatric, complications and symptomatic. We included article reporting on case series in English and German on pediatric patients only.
Results: All included patients (n = 7) were symptomatic. Some patients showed isolated symptoms, and others presented with a combination of symptoms that consisted of abdominal pain, bloody stool or vomiting. The median age of our seven cases was 3.5 years, including 4 male and 3 female patients. Intestinal obstruction was the most common complication; it was seen in 5 out of 7 patients (intussusception in 4 cases, volvulus in 1 case). Ectopic gastric tissue was identified in 3 cases, and inclusion of pancreatic tissue was observed in 1 case. The literature review identified 8 articles for a total of 641 patients aged between 1 day and 17 years and a male:female ratio of 2.6:1. From this group, 528 patients showed clinical symptoms related to Meckel's diverticulum. The most common symptom was abdominal pain and bloody stool. The most common surgical finding in symptomatic patients was intestinal obstruction (41%), followed by intestinal hemorrhage (34%). Complications such as perforation (10%) and diverticulitis (13%) were less frequently reported. Heterotopic tissue was confirmed on histopathology in 53% of all patients enclosing gastric, pancreatic, and both gastric and pancreatic mucosae. In one case, large intestine tissue could be found. Overall, one death was reported.
Conclusion: The presented case series and literature review found similar clinical presentations and complications of Meckel's diverticulum in children. Intestinal obstruction and bleeding are more frequent than inflammation in pediatric Meckel's diverticulum. Bowel obstruction is the leading cause for complicated Meckel's diverticulum in patients younger than 12 years.
Background: We aimed to investigate the potential effects of a 4-week motor–cognitive dual-task training on cognitive and motor function as well as exercise motivation in young, healthy, and active adults.
Methods: A total of 26 participants (age 25 ± 2 years; 10 women) were randomly allocated to either the intervention group or a control group. The intervention group performed a motor–cognitive training (3×/week), while the participants of the control group received no intervention. Before and after the intervention period of 4 weeks, all participants underwent cognitive (d2-test, Trail Making Test) and motor (lower-body choice reaction test and time to stabilization test) assessments. Following each of the 12 workouts, self-reported assessments (rating of perceived exertion, enjoyment and pleasant anticipation of the next training session) were done. Analyses of covariances and 95% confidence intervals plotting for between group and time effects were performed.
Results: Data from 24 participants were analysed. No pre- to post-intervention improvement nor a between-group difference regarding motor outcomes (choice-reaction: F = 0.5; time to stabilization test: F = 0.7; p > 0.05) occurred. No significant training-induced changes were found in the cognitive tests (D2: F = 0.02; Trail Making Test A: F = 0.24; Trail Making Test B: F = 0.002; p > 0.05). Both enjoyment and anticipation of the next workout were rated as high.
Discussion: The neuro-motor training appears to have no significant effects on motor and cognitive function in healthy, young and physically active adults. This might be explained in part by the participants’ very high motor and cognitive abilities, the comparably low training intensity or the programme duration. The high degree of exercise enjoyment, however, may qualify the training as a facilitator to initiate and maintain regular physical activity. The moderate to vigorous intensity levels further point towards potential health-enhancing cardiorespiratory effects.