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The UDP-glucose ceramide glycosyltransferase (UGCG) is a key enzyme in the sphingolipid metabolism by generating glucosylceramide (GlcCer), the precursor for all glycosphingolipids (GSL), which are essential for proper cell function. Interestingly, the UGCG is also overexpressed in several cancer types and correlates with multidrug resistance protein 1 (MDR1) gene expression. This membrane protein is responsible for efflux of toxic substances and protects cancer cells from cell damage through chemotherapeutic agents. Studies showed a connection between UGCG and MDR1 overexpression and multidrug resistance development, but the precise underlying mechanisms are unknown. Here, we give an overview about the UGCG and its connection to MDR1 in multidrug resistant cells. Furthermore, we focus on UGCG transcriptional regulation, the impact of UGCG on cellular signaling pathways and the effect of UGCG and MDR1 on the lipid composition of membranes and how this could influence multidrug resistance development. To our knowledge, this is the first review presenting an overview about UGCG with focus on the relationship to MDR1 in the process of multidrug resistance development.
Objectives: The SAVI-TF (Symetis ACURATE neo Valve Implantation Using Transfemoral Access) registry was initiated to study the ACURATE neo transcatheter heart valve in a large patient population treated under real-world conditions.
Background: The self-expanding, supra-annular ACURATE neo prosthesis is a transcatheter heart valve that gained the Conformité Européene mark in 2014, but only limited clinical data are available so far.
Methods: This prospective, multicenter registry enrolled 1,000 patients at 25 European centers who were followed for 1 year post-procedure.
Results: Mean patient age was 81.1 ± 5.2 years; mean logistic European System for Cardiac Operative Risk Evaluation I score, European System for Cardiac Operative Risk Evaluation II score, and Society of Thoracic Surgeons score were 18.1 ± 12.5%, 6.6 ± 7.5%, and 6.0 ± 5.6%, respectively. At 1 year, 8.0% (95% confidence interval [CI]: 6.3% to 9.7%) of patients had died, 2.3% (95% CI: 1.3% to 3.2%) had disabling strokes, and 9.9% (95% CI: 8.1% to 11.8%) had permanent pacemaker implantations. Through 1 year, 5 reinterventions (0.5%; 95% CI: 0.1% to 1.0%) were performed: 3 valve-in-valve and 2 surgical aortic valve replacements. Mean effective orifice area was 1.84 ± 0.43 cm2, mean gradient was 7.3 ± 3.7 mm Hg, and greater than mild paravalvular leakage was observed in 3.6% of patients.
Conclusions: Transfemoral implantation of the ACURATE neo prosthesis resulted in favorable 1-year clinical and echocardiographic outcomes with very low mortality and new pacemaker rates.
Background & aims: Recent studies indicate that vitamin D deficiency is associated with increased morbidity and mortality in critically ill patients. Knowledge about the functional role and clinical relevance of vitamin D for patients undergoing cardiac surgery is sparse. Therefore, we investigated the clinical significance of vitamin D levels on outcome of cardiac surgery patients.
Methods: 92 patients undergoing elective cardiac surgery with cardiopulmonary arrest were included in this prospective observational pilot study. 25-hydroxyvitamin D (25OHD) and 1,25-dihydroxyvitamin D (1,25(OH)2D) levels were measured prior to surgery, immediately postoperatively as well as 6, 12 and 24 h after surgery. We assessed postoperative organ dysfunctions, infections and death until hospital discharge.
Results: The serum concentration of 1,25(OH)2D significantly decreased intraoperatively by 29.3% (p < 0.001) and was significantly lower at any postoperative time point compared to baseline values, whereas 25OHD levels did not show significant changes during the observation period. Coronary artery bypass graft (CABG) patients had significant higher baseline 1,25(OH)2D values than patients with valve surgery (39.7 ± 13.9 ng/l vs. 30.1 ± 14.1 ng/l, p = 0.010) or CABG + valve surgery (39.7 ± 13.9 ng/l vs. 32.6 ± 11.8 ng/l, p = 0.044).
Our data showed a significant odds ratio to develop postoperative organ dysfunction (OR 0.95; p = 0.009) and PCT levels ≥5 μg/l (OR 0.94; p = 0.046) for every ng/l increment in 1,25(OH)2D, when performing multivariable analysis and after adjusting for preoperative illness and demographics. In addition, multivariable-adjusted statistical analyses revealed that patients stayed significantly shorter on ICU (−0.21 h; p = 0.001) and in hospital (−2.6 days; p = 0.009) for every ng/l increment in 1,25(OH)2D.
Conclusion: Our data highlight important evidence about the clinical significance of 1,25(OH)2D levels in cardiac surgery patients. Higher levels were associated with significantly less postoperative organ dysfunctions, elevated PCT levels, death and prolonged hospital stay. 1,25(OH)2D levels decreased significantly intra- and postoperatively, while serum levels of 25OHD did not.
Trial registration: clinicaltrials.gov (NCT 02488876), registered May 1, 2015.
Bone metabolism appears to influence insulin secretion and sensitivity, and insulin promotes bone formation in animals, but similar evidence in humans is limited. The objectives of this study are to explore if bone turnover markers were associated with insulin secretion and sensitivity and to determine if bone turnover markers predict changes in insulin secretion and sensitivity. The study population encompassed 576 non-diabetic adult men with normal glucose tolerance (NGT; n = 503) or impaired glucose regulation (IGR; n = 73). Baseline markers of bone resorption (CTX) and formation (P1NP) were determined in the fasting state and after a 2-h hyperinsulinaemic, euglycaemic clamp. An intravenous glucose tolerance test (IVGTT) and a 2-h oral glucose tolerance test (OGTT) were performed at baseline, and the OGTT was repeated after 3 years. There were no differences in bone turnover marker levels between NGT and IGR. CTX and P1NP levels decreased by 8.0% (p < 0.001) and 1.9% (p < 0.01) between baseline and steady-state during the clamp. Fasting plasma glucose was inversely associated with CTX and P1NP both before and after adjustment for recruitment centre, age, BMI, smoking and physical activity. However, baseline bone turnover markers were neither associated with insulin sensitivity (assessed using hyperinsulinaemic euglycaemic clamp and OGTT) nor with insulin secretion capacity (based on IVGTT and OGTT) at baseline or at follow-up. Although inverse associations between fasting glucose and markers of bone turnover were identified, this study cannot support an association between insulin secretion and sensitivity in healthy, non-diabetic men.
Tubulogenesis is essential for the formation and function of internal organs. One such organ is the trachea, which allows gas exchange between the external environment and the lungs. However, the cellular and molecular mechanisms underlying tracheal tube development remain poorly understood. Here, we show that the potassium channel KCNJ13 is a critical modulator of tracheal tubulogenesis. We identify Kcnj13 in an ethylnitrosourea forward genetic screen for regulators of mouse respiratory organ development. Kcnj13 mutants exhibit a shorter trachea as well as defective smooth muscle (SM) cell alignment and polarity. KCNJ13 is essential to maintain ion homeostasis in tracheal SM cells, which is required for actin polymerization. This process appears to be mediated, at least in part, through activation of the actin regulator AKT, as pharmacological increase of AKT phosphorylation ameliorates the Kcnj13-mutant trachea phenotypes. These results provide insight into the role of ion homeostasis in cytoskeletal organization during tubulogenesis.
Damage control resuscitation may lead to postoperative intra-abdominal hypertension or abdominal compartment syndrome. These conditions may result in a vicious, self-perpetuating cycle leading to severe physiologic derangements and multiorgan failure unless interrupted by abdominal (surgical or other) decompression. Further, in some clinical situations, the abdomen cannot be closed due to the visceral edema, the inability to control the compelling source of infection or the necessity to re-explore (as a “planned second-look” laparotomy) or complete previously initiated damage control procedures or in cases of abdominal wall disruption. The open abdomen in trauma and non-trauma patients has been proposed to be effective in preventing or treating deranged physiology in patients with severe injuries or critical illness when no other perceived options exist. Its use, however, remains controversial as it is resource consuming and represents a non-anatomic situation with the potential for severe adverse effects. Its use, therefore, should only be considered in patients who would most benefit from it. Abdominal fascia-to-fascia closure should be done as soon as the patient can physiologically tolerate it. All precautions to minimize complications should be implemented.
This review provides an overview on components of the sphingolipid superfamily, on their localization and metabolism. Information about the sphingolipid biological activity in cell physiopathology is given. Recent studies highlight the role of sphingolipids in inflammatory process. We summarize the emerging data that support the different roles of the sphingolipid members in specific phases of inflammation: (1) migration of immune cells, (2) recognition of exogenous agents, and (3) activation/differentiation of immune cells.
The lncRNA GATA6-AS epigenetically regulates endothelial gene expression via interaction with LOXL2
(2018)
Impaired or excessive growth of endothelial cells contributes to several diseases. However, the functional involvement of regulatory long non-coding RNAs in these processes is not well defined. Here, we show that the long non-coding antisense transcript of GATA6 (GATA6-AS) interacts with the epigenetic regulator LOXL2 to regulate endothelial gene expression via changes in histone methylation. Using RNA deep sequencing, we find that GATA6-AS is upregulated in endothelial cells during hypoxia. Silencing of GATA6-AS diminishes TGF-β2-induced endothelial–mesenchymal transition in vitro and promotes formation of blood vessels in mice. We identify LOXL2, known to remove activating H3K4me3 chromatin marks, as a GATA6-AS-associated protein, and reveal a set of angiogenesis-related genes that are inversely regulated by LOXL2 and GATA6-AS silencing. As GATA6-AS silencing reduces H3K4me3 methylation of two of these genes, periostin and cyclooxygenase-2, we conclude that GATA6-AS acts as negative regulator of nuclear LOXL2 function.
Macrophages are highly versatile cells, which acquire, depending on their microenvironment, pro- (M1-like), or antiinflammatory (M2-like) phenotypes. Here, we studied the role of the G-protein coupled receptor G2A (GPR132), in chemotactic migration and polarization of macrophages, using the zymosan-model of acute inflammation. G2A-deficient mice showed a reduced zymosan-induced thermal hyperalgesia, which was reversed after macrophage depletion. Fittingly, the number of M1-like macrophages was reduced in the inflamed tissue in G2A-deficient mice. However, G2A activation was not sufficient to promote M1-polarization in bone marrow-derived macrophages. While the number of monocyte-derived macrophages in the inflamed paw was not altered, G2A-deficient mice had less macrophages in the direct vicinity of the origin of inflammation, an area marked by the presence of zymosan, neutrophil accumulation and proinflammatory cytokines. Fittingly neutrophil efferocytosis was decreased in G2A-deficient mice and several lipids, which are released by neutrophils and promote G2A-mediated chemotaxis, were increased in the inflamed tissue. Taken together, G2A is necessary to position macrophages in the proinflammatory microenvironment surrounding the center of inflammation. In absence of G2A the macrophages are localized in an antiinflammatory microenvironment and macrophage polarization is shifted toward M2-like macrophages.
The FIRE AND ICE Trial (ClinicalTrials.gov, identifier NCT01490814) was initiated in 2012 as a multicenter, randomized, head‐to‐head comparison of radiofrequency current (RFC) and cryoballoon catheter ablation for the treatment of patients with drug‐refractory symptomatic paroxysmal atrial fibrillation (AF). Six years on, it remains the largest, randomized comparison of safety and efficacy between 2 catheter ablation modalities used in the treatment of patients with AF. This landmark trial not only established noninferiority between cryoballoon and RFC ablation for pulmonary vein isolation (PVI) with regard to the study's efficacy and safety primary end points,1 but also, it evaluated secondary end points that were critical for a representative study interpretation. ...
Early and adequate restoration of endothelial and tubular renal function is a substantial step during regeneration after ischemia reperfusion (IR) injury, occurring, e.g., in kidney transplantation, renal surgery, and sepsis. While tubular epithelial cell injury has long been of central importance, recent perception includes the renal vascular endothelium. In this regard, the fibrin cleavage product fibrinopeptide Bβ15-42 mitigate IR injury by stabilizing interendothelial junctions through its affinity to VE-cadherin. Therefore, this study focused on the effect of Bβ15-42 on post-acute physiological renal regeneration. For this, adult male C57BL/6 mice were exposed to a 30 min bilateral renal ischemia and reperfusion for 24 h or 48 h. Animals were randomized in a non-operative control group, two operative groups each treated with i.v. administration of either saline or Bβ15-42 (2.4 mg/kg) immediately prior to reperfusion. Endothelial activation and inflammatory response was attenuated in renal tissue homogenates by single application of Bβ15-42. Meanwhile, Bβ15-42 did not affect acute kidney injury markers. Regarding the angiogenetic players VEGF-A, Angiopoietin-1, Angiopoietin-2, however, we observed significant higher expressions at mRNA and trend to higher protein level in Bβ15-42 treated mice, compared to saline treated mice after 48 h of IR, thus pointing toward an increased angiogenetic activity. Similar dynamics were observed for the intermediate filament vimentin, the cytoprotective protein klotho, stathmin and the proliferation cellular nuclear antigen, which were significantly up-regulated at the same points in time. These results suggest a beneficial effect of anatomical contiguously located endothelial cells on tubular regeneration through stabilization of endothelial integrity. Therefore, it seems that Bβ15-42 represents a novel pharmacological approach in the targeted therapy of acute renal failure in everyday clinical practice.
Background: Since 2009, IPF patients across Europe are recruited into the eurIPFreg, providing epidemiological data and biomaterials for translational research.
Methods: The registry data are based on patient and physician baseline and follow-up questionnaires, comprising 1700 parameters. The mid- to long-term objectives of the registry are to provide clues for a better understanding of IPF phenotype sub-clusters, triggering factors and aggravating conditions, regional and environmental characteristics, and of disease behavior and management.
Results: This paper describes baseline data of 525 IPF subjects recruited from 11/2009 until 10/2016. IPF patients had a mean age of 68.1 years, and seeked medical advice due to insidious dyspnea (90.1%), fatigue (69.2%), and dry coughing (53.2%). A surgical lung biopsy was performed in 32% in 2009, but in only 8% of the cases in 2016, possibly due to increased numbers of cryobiopsy. At the time of inclusion in the eurIPFreg, FVC was 68.4% ± 22.6% of predicted value, DLco ranged at 42.1% ± 17.8% of predicted value (mean value ± SD). Signs of pulmonary hypertension were found in 16.8%. Steroids, immunosuppressants and N-Acetylcysteine declined since 2009, and were replaced by antifibrotics, under which patients showed improved survival (p = 0.001).
Conclusions: Our data provide important insights into baseline characteristics, diagnostic and management changes as well as outcome data in European IPF patients over time.
Trial registration: The eurIPFreg and eurIPFbank are listed in ClinicalTrials.gov(NCT02951416).
Purpose: There are little or no published data comparing the outcomes of ILUVIEN® (0.19 mg fluocinolone acetonide [FAc]) and OZURDEX® (0.7 mg dexamethasone [DEX]) implants in patients with diabetic macular edema (DME), and this case sought to compare their outcomes.
Methods: This case was extracted from a monocentric audit involving a pool of 25 patients (33 eyes) with DME and treated with a single FAc implant between October 2013 and December 2016. This case, a 61-year-old male with a pseudophakic lens, is from a patient that had received 4 intravitreal injections of a DEX implant prior to FAc implant and then was monitored for 3 years until re-treatment with a second FAc implant. Parameters measured included visual acuity (VA), central retinal thickness (CRT), and intraocular pressure (IOP).
Results: After the DEX implants, CRT transiently improved. In March 2014, the decision was taken to administer an FAc implant, and this led to a reduction in CRT below 300 µm (from a baseline of 748 µm), and this was sustained for 30 months. VA remained above 65 Early Treatment Diabetic Retinopathy Study letters to month 36, after which time a second FAc implant (in April 2017) was administered due to recurrence of edema and CRT decreased to below 300 µm and VA improved to 70 letters. Side effects included elevated IOP, which was effectively managed with IOP-lowering drops.
Conclusion: A single injection of FAc implant led to sustained improvements in CRT and VA that lasted for between 30 and 36 months, which is in contrast to the DEX implant where re-treatment was generally required within 6–7 months. After 36 months, re-treatment with the FAc implant again led to improved VA and CRT, and responses that were similar to those achieved with the first FAc implant.
Background: Histological evidence suggests that autism spectrum disorder (ASD) is accompanied by a reduced integrity of the grey-white matter boundary. This has also recently been confirmed by a structural neuroimaging study in vivo reporting significantly reduced grey-white matter tissue contrast (GWC) in adult individuals (18–42 years of age) with ASD relative to typically developing (TD) controls. However, it remains unknown whether the neuroanatomical differences in ASD at the grey-white matter boundary are stable across development or are age-dependent.
Methods: Here, we examined differences in the neurodevelopmental trajectories of GWC in a cross-sectional sample of 77 male ASD individuals and 76 typically developing (TD) controls across childhood and early adulthood (from 7 to 25 years).
Results: Using nested model comparisons, we first established that the developmental trajectory of GWC is complex in many regions across the cortex and includes linear and non-linear effects of age. Second, while ASD individuals have significantly reduced GWC overall, these differences are age-dependent and are most prominent during childhood (< 15 years).
Conclusions: Taken together, our findings suggest that differences in GWC in ASD are unlikely to reflect atypical grey matter cytoarchitecture alone, but may also represent other aspects of the cortical architecture such as age-dependent variability in myelin integrity.
Background: Prostate cancer is the most common cancer in men in the UK. NICE guidelines on recognition and referral of suspected cancer, recommend performing digital rectal examination (DRE) on patients with urinary symptoms and urgently referring if the prostate feels malignant. However, this is based on the results of one case control study, so it is not known if DRE performed in primary care is an accurate method of detecting prostate cancer.
Methods: The aim of this review is to ascertain the sensitivity, specificity, positive and negative predictive value of DRE for the detection of prostate cancer in symptomatic patients in primary care.
CENTRAL, MEDLINE, EMBASE and CINAHL databases were searched in august 2015 for studies in which a DRE was performed in primary care on symptomatic patients and compared against a reference diagnostic procedure.
Results: Four studies were included with a total of 3225 patients. The sensitivity and specificity for DRE as a predictor of prostate cancer in symptomatic patients was 28.6 and 90.7%, respectively. The positive and negative predictive values were 42.3 and 84.2%, respectively.
Conclusion: This review found that DRE performed in general practice is accurate, and supports the UK NICE guidelines that patients with a malignant prostate on examination are referred urgently for suspected prostate cancer. Abnormal DRE carried a 42.3% chance of malignancy, above the 3% risk threshold which NICE guidance suggests warrants an urgent referral. However this review questions the benefit of performing a DRE in primary care in the first instance, suggesting that a patient’s risk of prostate cancer based on symptoms alone would warrant urgent referral even if the DRE feels normal.
Background: The Catechol-O-methyltransferase (COMT) represents the key enzyme in catecholamine degradation. Recent studies suggest that the COMT rs4680 polymorphism is associated with the response to endogenous and exogenous catecholamines. There are, however, conflicting data regarding the COMT Met/Met phenotype being associated with an increased risk of acute kidney injury (AKI) after cardiac surgery. The aim of the current study is to prospectively investigate the impact of the COMT rs4680 polymorphism on the incidence of AKI in patients undergoing cardiac surgery.
Methods: In this prospective single center cohort study consecutive patients hospitalized for elective cardiac surgery including cardiopulmonary-bypass (CPB) were screened for participation. Demographic clinical data, blood, urine and tissue samples were collected at predefined time points throughout the clinical stay. AKI was defined according to recent recommendations of the Kidney Disease Improving Global Outcome (KDIGO) group. Genetic analysis was performed after patient enrolment was completed.
Results: Between April and December 2014, 150 patients were recruited. The COMT genotypes were distributed as follows: Val/Met 48.7%, Met/Met 29.3%, Val/Val 21.3%. No significant differences were found for demography, comorbidities, or operative strategy according to the underlying COMT genotype. AKI occurred in 35 patients (23.5%) of the total cohort, and no differences were evident between the COMT genotypes (20.5% Met/Met, 24.7% Val/Met, 25.0% Val/Val, p = 0.66). There were also no differences in the post-operative period, including ICU or in-hospital stay.
Conclusions: We did not find statistically significant variations in the risk for postoperative AKI, length of ICU or in-hospital stay according to the underlying COMT genotype.
The emerging relapsing fever spirochete Borrelia (B.) miyamotoi is transmitted by ixodid ticks and causes the so-called hard tick-borne relapsing fever or B. miyamotoi disease (BMD). More recently, we identified a surface-exposed molecule, CbiA exhibiting complement binding and inhibitory capacity and rendering spirochetes resistant to complement-mediated lysis. To gain deeper insight into the molecular principles of B. miyamotoi-host interaction, we examined CbiA as a plasmin(ogen) receptor that enables B. miyamotoi to interact with the serine protease plasmin(ogen). Recombinant CbiA was able to bind plasminogen in a dose-dependent fashion. Moreover, lysine residues appear to play a crucial role in the protein-protein interaction as binding of plasminogen was inhibited by the lysine analog tranexamic acid as well as increasing ionic strength. Of relevance, plasminogen bound to CbiA can be converted by urokinase-type plasminogen activator (uPa) to active plasmin which cleaved both, the chromogenic substrate S-2251 and its physiologic substrate fibrinogen. Concerning the involvement of specific amino acids in the interaction with plasminogen, lysine residues located at the C-terminus are frequently involved in the binding as reported for various other plasminogen-interacting proteins of Lyme disease spirochetes. Lysine residues located within the C-terminal domain were substituted with alanine to generate single, double, triple, and quadruple point mutants. However, binding of plasminogen to the mutated CbiA proteins was not affected, suggesting that lysine residues distant from the C-terminus might be involved in the interaction.
Objective: The correlation of depleted blood through midline shift in acute subdural hematoma remains the most reliable clinical predictor to date. On the other hand, patient’s ABO blood type has a profound impact on coagulation and hemostasis. We conducted this study to evaluate the role of patient’s blood type in terms of incidence, clinical course and outcome after acute subdural hematoma bleeding.
Methods: 100 patients with acute subdural hematoma treated between 2010 and 2015 at the author’s institution were included. Baseline characteristics and clinical findings including Glasgow coma scale, Glasgow outcome scale, hematoma volume, rebleeding, midline shift, postoperative seizures and the presence of anticoagulation were analyzed for their association with ABO blood type.
Results: Patient’s with blood type O were found to have a lower midline shift (p<0.01) and significantly less seizures (OR: 0.43; p<0.05) compared to non-O patients. Furthermore, patients with blood type A had the a significantly higher midline shift (p<0.05) and a significantly increased risk for postoperative seizures (OR: 4.01; p<0.001). There was no difference in ABO blood type distribution between acute subdural hematoma patients and the average population.
Conclusion: The ABO blood type has significant influence on acute subdural hematoma sequelae. Patient’s with blood type O benefit in their clinical course after acute subdural hematoma whereas blood type A patients are at highest risk for increased midline shift and postoperative seizures. Further studies elucidating the biological mechanisms of blood type depended hemostaseology and its role in acute subdural hematoma are required for the development of an appropriate intervention.
The new edition of the 2016 World Health Organization (WHO) classification system for tumors of the hematopoietic and lymphoid tissues was published in September 2017. Under the category of myeloproliferative neoplasms (MPNs), the revised document includes seven subcategories: chronic myeloid leukemia, chronic neutrophilic leukemia, polycythemia vera (PV), primary myelofibrosis (PMF), essential thrombocythemia (ET), chronic eosinophilic leukemia-not otherwise specified and MPN, unclassifiable (MPN-U); of note, mastocytosis is no longer classified under the MPN category. In the current review, we focus on the diagnostic criteria for JAK2/CALR/MPL mutation-related MPNs: PV, ET, and PMF. In this regard, the 2016 changes were aimed at facilitating the distinction between masked PV and JAK2-mutated ET and between prefibrotic/early and overtly fibrotic PMF. In the current communication, we (i) provide practically useful resource tables and graphs on the new diagnostic criteria including outcome, (ii) elaborate on the rationale for the 2016 changes, (iii) discuss the complementary role of mutation screening, (iv) address ongoing controversies and propose solutions, (v) attend to the challenges of applying WHO criteria in routine clinical practice, and (vi) outline future directions from the perspectives of the clinical pathologist.
Background: Previous experimental research on testosterone (T) and psychological traits is inconclusive. Thus, we performed the first large-scale observational study of the association between T and dispositional optimism / pessimism.
Methods: We used prospective data from 6,493 primary-care patients (3,840 women) of the DETECT study (Diabetes Cardiovascular Risk-Evaluation: Targets and Essential Data for Commitment of Treatment), including repeated immunoassay-based measurement of serum T and optimism / pessimism assessed by the revised Life-Orientation Test (LOT-R). Cross-sectional and longitudinal associations of baseline T and one-year change in T with optimism and pessimism were investigated using age- and multivariable-adjusted regression models.
Results: Cross-sectional analyses showed no association of T with optimism or pessimism in both sexes. Longitudinal analyses also showed no association of baseline T with optimism or pessimism at four-year follow-up. Multivariable analyses of total LOT-R score yielded similarly non-significant results (β-coefficient per unit change in T for men: -0.01 (95% CI: -0.24–0.22), women: 0.08 (-0.03–0.20)). Furthermore, change in T was not related to optimism or pessimism at four-year follow-up.
Conclusions: The present observational study of a large-scale prospective sample showed no association of T with optimism or pessimism. Integrating further experimental and interventional evidence from alternative methodological approaches would strengthen this conclusion and establish stronger evidence about the potential hormonal basis of psychological traits.
Most studies in the life sciences and other disciplines involve generating and analyzing numerical data of some type as the foundation for scientific findings. Working with numerical data involves multiple challenges. These include reproducible data acquisition, appropriate data storage, computationally correct data analysis, appropriate reporting and presentation of the results, and suitable data interpretation.
Finding and correcting mistakes when analyzing and interpreting data can be frustrating and time-consuming. Presenting or publishing incorrect results is embarrassing but not uncommon. Particular sources of errors are inappropriate use of statistical methods and incorrect interpretation of data by software. To detect mistakes as early as possible, one should frequently check intermediate and final results for plausibility. Clearly documenting how quantities and results were obtained facilitates correcting mistakes. Properly understanding data is indispensable for reaching well-founded conclusions from experimental results. Units are needed to make sense of numbers, and uncertainty should be estimated to know how meaningful results are. Descriptive statistics and significance testing are useful tools for interpreting numerical results if applied correctly. However, blindly trusting in computed numbers can also be misleading, so it is worth thinking about how data should be summarized quantitatively to properly answer the question at hand. Finally, a suitable form of presentation is needed so that the data can properly support the interpretation and findings. By additionally sharing the relevant data, others can access, understand, and ultimately make use of the results.
These quick tips are intended to provide guidelines for correctly interpreting, efficiently analyzing, and presenting numerical data in a useful way.
Background: Rare diseases are, by definition, very serious and chronic diseases with a high negative impact on quality of life. Approximately 350 million people worldwide live with rare diseases. The resulting high disease burden triggers health information search, but helpful, high-quality, and up-to-date information is often hard to find. Therefore, the improvement of health information provision has been integrated in many national plans for rare diseases, discussing the telephone as one access option. In this context, this study examines the need for a telephone service offering information for people affected by rare diseases, their relatives, and physicians.
Methods: In total, 107 individuals participated in a qualitative interview study conducted in Germany. Sixty-eight individuals suffering from a rare disease or related to somebody with rare diseases and 39 health care professionals took part. Individual interviews were conducted using a standardized semi-structured questionnaire. Interviews were analysed using the qualitative content analysis, triangulating patients, relatives, and health care professionals. The fulfilment of qualitative data processing standards has been controlled for.
Results: Out of 68 patients and relatives and 39 physicians, 52 and 18, respectively, advocated for the establishment of a rare diseases telephone service. Interviewees expected a helpline to include expert staffing, personal contact, good availability, low technical barriers, medical and psychosocial topics of counselling, guidance in reducing information chaos, and referrals. Health care professionals highlighted the importance of medical topics of counselling—in particular, differential diagnostics—and referrals.
Conclusions: Therefore, the need for a national rare diseases helpline was confirmed in this study. Due to limited financial resources, existing offers should be adapted in a stepwise procedure in accordance with the identified attributes.
Intestinal graft-versus-host disease (GvHD) is a life-threatening, inflammatory donor T cell-mediated complication of allogeneic hematopoietic stem cell transplantation (allo-HSCT). In the light of the reported efficacy of interleukin-23 (IL-23)-blockade to mitigate syngeneic intestinal inflammation in inflammatory bowel disease patients, targeting IL-23 and thereby interleukin-17a (IL-17a) producing T helper (Th17) cells as the T cell subset assumed to be mostly regulated by IL-23, has emerged as a putatively general concept to harness immune-mediated mucosal inflammation irrespective of the underlying trigger. However, the role of Th17 cells during allo-response driven colitis remains ambiguous due to a series of studies with inconclusive results. Interestingly, we recently identified granulocyte-macrophage colony-stimulating factor (GM-CSF+) T cells to be promoted by interleukin-7 (IL-7) signaling and controlled by the activating protein-1 transcription factor family member basic leucine zipper transcription factor ATF-like (BATF) as critical mediators of intestinal GvHD in mice. Given the dual role of BATF, the contribution of IL-23-mediated signaling within donor T cells and bona fide Th17 cells remains to be delineated from the regulation of GM-CSF+ T cells in the absence of BATF. Here, we found in a complete MHC class I-mismatched model that genetic inactivation of the IL-23 receptor (IL-23R) or the transcription factor retinoic acid-related orphan receptor gamma t (RORγt) within donor T cells similarly ablated Th17 cell formation in vivo but preserved the T cells’ ability to induce intestinal GvHD in a compared to wild-type controls indistinguishable manner. Importantly, RORγt-independent manifestation of intestinal GvHD was completely dependent on BATF-regulated GM-CSF+ T cells as BATF/RORγt double-deficient T cells failed to induce colitis and the antibody-mediated blockage of IL-7/IL-7R interaction and GM-CSF significantly diminished signs of intestinal GvHD elicited by RORγt-deficient donor T cells. Finally, in analogy to our murine studies, colonic RORC expression levels inversely correlated with the presence of GvHD in allo-HSCT patients. Together, this study provides a crucial example of a BATF-dependent, however, IL-23R signaling- and RORγt-, i.e., Th17 fate-independent regulation of a colitogenic T cell population critically impacting the current understanding of intestinal GvHD.
Aberrant activation of hedgehog (Hh) signaling has been observed in a wide variety of tumors and accounts for more than 25% of human cancer deaths. Inhibitors targeting the Hh signal transducer Smoothened (SMO) are widely used and display a good initial efficacy in patients suffering from basal cell carcinoma (BCC); however, a large number of patients relapse. Though SMO mutations may explain acquired therapy resistance, a growing body of evidence suggests that the non-canonical, SMO-independent activation of the Hh pathway in BCC patients can also account for this adverse effect. In this review, we highlight the importance of glioma-associated oncogene (GLI) transcription factors (the main downstream effectors of the canonical and the non-canonical Hh cascade) and their putative role in the regulation of multiple oncogenic signaling pathways. Moreover, we discuss the contribution of the Hh signaling to malignant transformation and propose GLIs as central hubs in tumor signaling networks and thus attractive molecular targets in anti-cancer therapies.
Oncogenic rearrangements leading to targetable gene fusions are well-established cancer driver events in lung adenocarcinoma. Accurate and reliable detection of these gene fusions is crucial to select the appropriate targeted therapy for each patient. We compared the targeted next-generation-sequencing Oncomine Focus Assay (OFA; Thermo Fisher Scientific) with conventional ALK FISH and anti-Alk immunohistochemistry in a cohort of 52 lung adenocarcinomas (10 ALK rearranged, 18 non-ALK rearranged, and 24 untested cases). We found a sensitivity and specificity of 100% for detection of ALK rearrangements using the OFA panel. In addition, targeted next generation sequencing allowed us to analyze a set of 23 driver genes in a single assay. Besides EML4-ALK (11/52 cases), we detected EZR-ROS1 (1/52 cases), KIF5B-RET (1/52 cases) and MET-MET (4/52 cases) fusions. All EML4-ALK, EZR-ROS1 and KIF5B-RET fusions were confirmed by multiplexed targeted next generation sequencing assay (Oncomine Solid Tumor Fusion Transcript Kit, Thermo Fisher Scientific). All cases with EML4-ALK rearrangement were confirmed by Alk immunohistochemistry and all but one by ALK FISH. In our experience, targeted next-generation sequencing is a reliable and timesaving tool for multiplexed detection of targetable rearrangements. Therefore, targeted next-generation sequencing represents an efficient alternative to time-consuming single target assays currently used in molecular pathology.
New technologies and therapies designed to facilitate development of personalized treatments are rapidly emerging in the field of biomedicine. Strikingly, the goal of personalized medicine refined the concept of therapy by developing cell-based therapies, the so-called “living drugs”. Breakthrough advancements were achieved in this regard in the fields of gene therapy, cell therapy, tissue-engineered products and advanced therapeutic techniques. The Advanced Therapies in Healthcare symposium, organized by the Clinical Research Center Department of Sidra Medicine, in Doha, Qatar (October 2017), brought together world-renowned experts from the fields of oncology, hematology, immunology, inflammation, autoimmune disorders, and stem cells to offer a comprehensive picture of the status of worldwide advanced therapies in both pre-clinical and clinical development, providing insights to the research phase, clinical data and regulatory aspects of these therapies. Highlights of the meeting are provided in this meeting report.
The taxanes are effective microtubule-stabilizing chemotherapy drugs that inhibit mitosis, induce apoptosis, and produce regression in a fraction of cancers that arise at many sites including the ovary. Novel therapeutic targets that augment taxane effects are needed to improve clinical chemotherapy response in CCNE1-amplified high grade serous ovarian cancer (HGSOC) cells. In this study, we conducted an siRNA-based kinome screen to identify modulators of mitotic progression in CCNE1-amplified HGSOC cells that may influence clinical paclitaxel response. PLK1 is overexpressed in many types of cancer, which correlates with poor prognosis. Here, we identified a novel synthetic lethal interaction of the clinical PLK1 inhibitor BI6727 and the microtubule-targeting drug paclitaxel in HGSOC cell lines with CCNE1-amplification and elucidated the underlying molecular mechanisms of this synergism. BI6727 synergistically induces apoptosis together with paclitaxel in different cell lines including a patient-derived primary ovarian cancer culture. Moreover, the inhibition of PLK1 reduced the paclitaxel-induced neurotoxicity in a neurite outgrowth assay. Mechanistically, the combinatorial treatment with BI6727/paclitaxel triggers mitotic arrest, which initiates mitochondrial apoptosis by inactivation of anti-apoptotic BCL-2 family proteins, followed by significant loss of the mitochondrial membrane potential and activation of caspase-dependent effector pathways. This conclusion is supported by data showing that BI6727/paclitaxel-co-treatment stabilizes FBW7, a component of SCF-type ubiquitin ligases that bind and regulate key modulators of cell division and growth including MCL-1 and Cyclin E. This identification of a novel synthetic lethality of PLK1 inhibitors and a microtubule-stabilizing drug has important implications for developing PLK1 inhibitor-based combination treatments in CCNE1-amplified HGSOC cells.
Cardiac sarcoidosis is a rare immunologic disease causing heart involvement in 5% of patients. Cardiac sarcoidosis may manifest clinically as a cardiomyopathy with impaired left ventricular (LV) function or as tachyarrhythmias or bradyarrhythmias. On autopsy, cardiac granulomas can be found in approximately 25% of patients. The most common location for granulomas and scars is the LV free wall, followed by the intraventricular septum, often with involvement of the conduction system. ...
The hippocampal dentate gyrus plays a role in spatial learning and memory and is thought to encode differences between similar environments. The integrity of excitatory and inhibitory transmission and a fine balance between them is essential for efficient processing of information. Therefore, identification and functional characterization of crucial molecular players at excitatory and inhibitory inputs is critical for understanding the dentate gyrus function. In this minireview, we discuss recent studies unraveling molecular mechanisms of excitatory/inhibitory synaptic transmission, long-term synaptic plasticity, and dentate granule cell excitability in the hippocampus of live animals. We focus on the role of three major postsynaptic proteins localized at excitatory (neuroligin-1) and inhibitory synapses (neuroligin-2 and collybistin). In vivo recordings of field potentials have the advantage of characterizing the effects of the loss of these proteins on the input-output function of granule cells embedded in a network with intact connectivity. The lack of neuroligin-1 leads to deficient synaptic plasticity and reduced excitation but normal granule cell output, suggesting unaltered excitation-inhibition ratio. In contrast, the lack of neuroligin-2 and collybistin reduces inhibition resulting in a shift towards excitation of the dentate circuitry.
Lysophosphatidic acid (LPA) is a synaptic phospholipid, which regulates cortical excitation/inhibition (E/I) balance and controls sensory information processing in mice and man. Altered synaptic LPA signaling was shown to be associated with psychiatric disorders. Here, we show that the LPA-synthesizing enzyme autotaxin (ATX) is expressed in the astrocytic compartment of excitatory synapses and modulates glutamatergic transmission. In astrocytes, ATX is sorted toward fine astrocytic processes and transported to excitatory but not inhibitory synapses. This ATX sorting, as well as the enzymatic activity of astrocyte-derived ATX are dynamically regulated by neuronal activity via astrocytic glutamate receptors. Pharmacological and genetic ATX inhibition both rescued schizophrenia-related hyperexcitability syndromes caused by altered bioactive lipid signaling in two genetic mouse models for psychiatric disorders. Interestingly, ATX inhibition did not affect naive animals. However, as our data suggested that pharmacological ATX inhibition is a general method to reverse cortical excitability, we applied ATX inhibition in a ketamine model of schizophrenia and rescued thereby the electrophysiological and behavioral schizophrenia-like phenotype. Our data show that astrocytic ATX is a novel modulator of glutamatergic transmission and that targeting ATX might be a versatile strategy for a novel drug therapy to treat cortical hyperexcitability in psychiatric disorders.
Background: Does the dogma of nephron sparing surgery (NSS) still stand for large renal masses? Available studies dealing with that issue are considerably biased often mixing imperative with elective indications for NSS and also including less malignant variants or even benign renal tumors. Here, we analyzed the oncological long-term outcomes of patients undergoing elective NSS or radical tumor nephrectomy (RN) for non-endophytic, large (≥7cm) clear cell renal carcinoma (ccRCC).
Methods: Prospectively acquired, clinical databases from two academic high-volume centers were screened for patients from 1980 to 2010. The query was strictly limited to patients with elective indications. Surgical complications were retrospectively assessed and classified using the Clavien-Dindo-classification system (CDS). Overall survival (OS) and cancer specific survival (CSS) were analyzed using the Kaplan-Meier-method and the log-rank test.
Results: Out of in total 8664 patients in the databases, 123 patients were identified (elective NSS (n = 18) or elective RN (n = 105)) for ≥7cm ccRCC. The median follow-up over all was 102 months (range 3–367 months). Compared to the RN group, the NSS group had a significantly longer median OS (p = 0.014) and median CSS (p = 0.04).
Conclusions: In large renal masses, NSS can be performed safely with acceptable complication rates. In terms of long-term OS and CSS, NSS was at least not inferior to RN. Our findings suggest that NSS should also be performed in patients presenting with renal tumors ≥7cm whenever technically feasible. Limitations include its retrospective nature and the limited availability of data concerning long-term development of renal function in the two groups.
Acute lymphoblastic leukemia (ALL) is the most common cancer in children. Pediatric patients with disease refractory to last chemotherapy, relapse after allogeneic hematopoietic stem-cell transplantation (alloHSCT), or second or further relapse have a particularly poor prognosis. Intensive chemotherapy followed by alloHSCT after achieving remission can result in cure for some patients. However, survival is still low with this approach. Thus, additional treatment modalities with acceptable toxicity are needed to improve long-term survival. ...
An oroantral fistula (OAF) is a pathological abnormal communication between the oral cavity and the maxillary sinus which may arise as a result of failure of primary healing of an OAF, dental infections, osteomyelitis, radiation therapy, trauma, or iatrogenic complications. With the presence of a fistula, the maxillary sinus is permanently open. Microbial flora passes from the oral cavity into the maxillary sinus, and the inflammation of the sinus occurs with all potential consequences. In literature, various techniques have been proposed for closure of OAFs. Due to the heterogeneity of the data and techniques found, we opted for a narrative review to highlight the variety of techniques discussed in the literature. Techniques of particular interest include the bone sandwich with resorbable guided tissue regeneration (GTR) membrane and platelet-rich fibrin (PRF) used alone as both a clot and a membrane. The great advantage of these techniques is that no donor site surgery is necessary, making the outcome valuable in terms of time savings, cost and, more importantly, less discomfort to the patient. Additionally, both bony and soft tissue closure is performed for OAF, in contrast to flaps, which are typically used for procedures in the sinus area. The reconstructed bony tissue regenerated from these techniques will also be appropriate for endosseous dental implantation.
Aim: To evaluate protective immunosuppressive dose and time-dependent effects of ethanol in an in vitro model of acute inflammation in human Chang liver cells.
Method: The study was performed in 2016 and 2017 in the research laboratory of the Department of Trauma, Hand and Reconstructive Surgery, the University Hospital of the Goethe-University Frankfurt. Chang liver cells were stimu - lated with either interleukin (IL)-1β or IL-6 and subsequent - ly treated with low-dose ethanol (85 mmol/L) or high-dose ethanol (170 mmol/L) for one hour (acute exposure) or 72 hours (subacute exposure). IL-6 and IL-1β release were de - termined by enzyme-linked immunosorbent assay. Neu - trophil adhesion to Chang liver monolayers, production of reactive oxygen species, and apoptosis or necrosis were analyzed.
Results: Contrary to high-dose ethanol, acute low-dose ethanol exposure significantly reduced IL-1β-induced IL-6 and IL-6-induced IL-1β release ( P <0.05). Subacute etha - nol exposure did not change proinflammatory cytokine release. Acute low-dose ethanol exposure significantly decreased inflammation-induced formation of reactive oxygen species ( P <0.05) and significantly improved cell survival ( P <0.05). Neither acute nor subacute high-dose ethanol exposure significantly changed inflammationinduced changes in reactive oxygen species or survival. Acute and subacute ethanol exposure, independently of the dose, significantly decreased neutrophil adhesion to inflamed Chang liver cells ( P <0.05).
Conclusion: Acute treatment of inflamed Chang liver cells with ethanol showed its immunosuppressive potential. However, the observed effects were limited to low-dose setting, indicating the relevance of ethanol dose in the modulation of inflammatory cell response.
In the context of limited donor pool in cardiothoracic transplantation, utilization of organs from high risk donors, such as suicidal hanging donors, while ensuring safety, is under consideration. We sought to evaluate the outcomes of lung transplantations (LTx) that use organs from this group.
Between January 2011 and December 2015, 265 LTx were performed at our center. Twenty-two recipients received lungs from donors after suicidal hanging (group 1). The remaining 243 transplantations were used as a control (group 2). Analysis of recipient and donor characteristics as well as outcomes was performed.
No statistically significant difference was found in the donor characteristics between analyzed groups, except for higher incidence of cardiac arrest, younger age and smoking history of hanging donors (P < .001, P = .022 and P = .0042, respectively). Recipient preoperative and perioperative characteristics were comparable. Postoperatively in group 1 there was a higher incidence of extracorporeal life support (27.3 vs 9.1%, P = .019). There were no significant differences in chronic lung allograft dysfunction-free survival between group 1 and 2: 92.3 vs 94% at 1 year and 65.9 vs 75.5% at 3 years (P = .99). The estimated cumulative survival rate was also similar between groups: 68.2 vs 83.2% at 1 year and 68.2% versus 72% at 3 years (P = .3758).
Hanging as a donor cause of death is not associated with poor mid-term survival or chronic lung allograft dysfunction following transplantation. These results encourage assessment of lungs from hanging donors, and their consideration for transplantation.
Atopic dermatitis (AD) is a chronic inflammatory disease affecting children and adolescence. The traditional therapeutic options for AD, including emollients topically and immune modulatory agents systemically focusing on reducing skin inflammation and restoring the function of the epidermal barrier, are proven ineffective in many cases. Several studies have linked vitamin D supplementation with either a decreased risk to develop AD or a clinical improvement of the symptoms of AD patients. In this report, we present a girl with severe AD who under adequate supplementation with cholecalciferol was treated with calcitriol and subsequently with paricalcitol. She had significant improvement—almost healing of her skin lesions within 2 months, a result sustained for more than 3 years now. Because of hypercalciuria as a side effect from calcitriol therapy, treatment was continued with paricalcitol, a vitamin D analogue used in secondary hyperparathyroidism in chronic kidney disease. Calcitriol therapy may be considered as a safe and efficacious treatment option for patients with severe AD, particularly for those with refractory AD, under monitoring for possible side effects. Treatment with paricalcitol resolves hypercalciuria, is safe, and should be further investigated as an alternative treatment of atopic dermatitis and possibly other diseases of autoimmune origin.
Objectives: The aim of this multicenter retrospective study was to investigate safety and efficacy of direct acting antiviral (DAA) treatment in the rare subgroup of patients with HCV/HIV-coinfection and advanced liver cirrhosis on the liver transplant waiting list or after liver transplantation, respectively.
Methods: When contacting 54 German liver centers (including all 23 German liver transplant centers), 12 HCV/HIV-coinfected patients on antiretroviral combination therapy were reported having received additional DAA therapy while being on the waiting list for liver transplantation (patient characteristics: Child-Pugh A (n = 6), B (n = 5), C (n = 1); MELD range 7–21; HCC (n = 2); HCV genotype 1a (n = 8), 1b (n = 2), 4 (n = 2)). Furthermore, 2 HCV/HIV-coinfected patients were denoted having received DAA therapy after liver transplantation (characteristics: HCV genotype 1a (n = 1), 4 (n = 1)).
Results: Applied DAA regimens were SOF/DAC (n = 7), SOF/LDV/RBV (n = 3), SOF/RBV (n = 3), PTV/r/OBV/DSV (n = 1), or PTV/r/OBV/DSV/RBV (n = 1), respectively. All patients achieved SVR 12, in the end. In one patient, HCV relapse occurred after 24 weeks of SOF/DAC therapy; subsequent treatment with 12 weeks PTV/r/OBV/DSV achieved SVR 12. One patient underwent liver transplantation while on DAA treatment. Analysis of liver function revealed either stable parameters or even significant improvement during DAA therapy and in follow-up. MELD scores were found to improve in 9/13 therapies in patients on the waiting list for liver transplantation; in only 2 patients a moderate increase of MELD scores persisted at the end of follow-up.
Conclusion: DAA treatment was safe and highly effective in this nation-wide cohort of patients with HCV/HIV-coinfection awaiting liver transplantation or being transplanted.
Background: In Germany, patients suffering from life-limiting conditions are eligible for specialized outpatient palliative care (SOPC). Evaluation of the quality of this service lacks currently integration of patient-relevant outcomes. There is also no scientific consensus how to prove quality of care in the special context of SOPC adequately. Existing quality reports are primarily based on descriptive structural data which do not allow for estimation of process quality or result quality. The ELSAH study ("Evaluation of Specialized Outpatient Palliative Care in the German state of Hesse") aims to choose - or, if necessary, to adopt - to evaluate and to implement a suit of measures to assess, evaluate and monitor the quality of specialized, home-based palliative care.
Methods: All 22 SOPC teams providing their services in the state of Hesse, Germany, participate in the ELSAH study. The study is divided in two phases: a preparation phase and a main study phase. Based on the findings of the preparation phase we have chosen a preliminary set of instruments including the Integrated Palliative Outcome Scale, Views on Care, Zarit Burden Interview, Phase of Illness, Goal Attainment Scaling, Eastern Cooperative Oncology Group Performance Status, Consumer Quality Indices Palliative Care and Sense of Security in Care. During the main study phase, we will use a mixed-methods approach to evaluate the instruments’ psychometric properties (reliability, validity, feasibility and practicability), to identify barriers, facilitators and limitations of their routine use and to explore how their use affects the care within the SOPC setting.
Discussion: At the end of this study, an outcome- and patient-centered, validated measurement approach should be provided, adapted for standardized evaluations in SOPC across patient groups, palliative care services and regions nationwide. The standardized application of instruments should allow for making valid statements and comparisons of health care quality in SOPC based on process- and outcome-evaluation rather than relying on structural data only. Moreover, the instruments might directly influence the care of patients in palliative situations.
Trial registration: German Clinical Trials Register (DRKS-ID: DRKS00012421).
Background: In 2007, the European Association of Palliative Care (EAPC) provided a comprehensive set of recommendations and standards for the provision of adequate pediatric palliative care. A number of studies have shown deficits in pediatric palliative care compared to EAPC standards. In Germany, pediatric palliative care patients can be referred to specialized outpatient palliative care (SOPC) services, which are known to enhance quality of life, e.g. by avoiding hospitalization. However, current regulations for the provision of SOPC in Germany do not account for the different circumstances and needs of children and their families compared to adult palliative care patients. The "Evaluation of specialized outpatient palliative care (SOPC) in the German state of Hesse (ELSAH)" study aims to perform a needs assessment for pediatric patients (children, adolescents and young adults) receiving SOPC. This paper presents the study protocol for this assessment (work package II).
Methods/Design: The study uses a sequential mixed-methods study design with a focus on qualitative research. Data collection from professional and family caregivers and, as far as possible, pediatric patients, will involve both a written questionnaire based on European recommendations for pediatric palliative care, and semi-structured interviews. Additionally, professional caregivers will take part in focus group discussions and participatory observations. Interviews and focus groups will be tape- or video-recorded, transcribed verbatim and analyzed in accordance with the principles of grounded theory (interviews) and content analysis (focus groups). A structured field note template will be used to record notes taken during the participatory observations. Statistical Package for Social Sciences (SPSS, version 22 or higher) will be used for descriptive statistical analyses. The qualitative data analyses will be software-assisted by MAXQDA (version 12 or higher).
Discussion: This study will provide important information on what matters most to family caregivers and pediatric patients receiving SOPC. The results will add valuable knowledge to the criteria that distinguish SOPC for pediatric from SOPC for adult patients, and will provide an indication of how the German SOPC rule of procedure can be optimized to satisfy the special needs of pediatric patients.
Trial registration: Internet Portal of the German Clinical Trials Register (www.germanctr.de, DRKS-ID: DRKS00012431).
Objective: The influence of the jaw position on postural control, body posture, walking and running pattern has been reported in the literature. All these movements have in common that a relatively small, but well controlled muscle activation is required. The induced effects on motor output through changed jaw positions have been small. Therefore, it has been questioned if it could still be observed in maximal muscle activation.
Method: Twenty-three healthy, mid age recreational runners (mean age = 34.0 ± 10.3 years) participated in this study. Three different jump tests (squat jump, counter movement jump, and drop jumps from four different heights) and three maximal strength tests (trunk flexion and extension, leg press of the right and left leg) were conducted. Four different dental occlusion conditions and an additional familiarization condition were tested. Subjects performed the tests on different days for which the four occlusion conditions were randomly changed.
Results: No familiarization effect was found. Occlusion conditions with a relaxation position and with a myocentric condylar position showed significantly higher values for several tests compared to the neutral condition and the maximal occlusion position. Significance was found in the squat jump, countermovement jump, the drop jump from 32cm and 40cm, trunk extension, leg press force and rate of force development. The effect due to the splint conditions is an improvement between 3% and 12% (min and max). No influence of the jaw position on symmetry or balance between extension and flexion muscle was found.
Conclusion: An influence of occlusion splints on rate of force development (RFD) and maximal strength tests could be confirmed. A small, but consistent increase in the performance parameters could be measured. The influence of the occlusion condition is most likely small compared to other influences as for example training status, age, gender and circadian rhythm.
Allogeneic hematopoietic stem cell transplantation (allo-HSCT) offers potential cure to acute myeloid leukemia (AML) patients. However, infections with commensal bacteria are an important cause for non-relapse mortality (NRM). We have previously described the impact of multidrug-resistant organism (MDRO) colonization on the survival of allo-HSCT patients. In the aforementioned publication, according to consensus, we there did not consider the opportunistic gram-negative bacterium Stenotrophomonas maltophilia (S. maltophilia) to be an MDRO. Since rate of S. maltophilia colonization is increasing, and it is not known whether this poses a risk for allo-HSCT patients, we here analyzed here its effect on the previously described and now extended patient cohort. We report on 291 AML patients undergoing allo-HSCT. Twenty of 291 patients (6.9%) were colonized with S. maltophilia. Colonized patients did not differ from non-colonized patients with respect to their age, remission status before allo-HSCT, donor type and HSCT-comorbidity index. S. maltophilia colonized patients had a worse overall survival (OS) from 6 months up to 60 months (85% vs. 88.1% and 24.7% vs. 59.7%; p = 0.007) due to a higher NRM after allo-HSCT (6 months: 15% vs. 4.8% and 60 months: 40.1% vs. 16.2% p = 0.003). The main cause of mortality in colonized patients was infection (46.2% of all deaths) and in non-colonized patients relapse (58.8% of all deaths). 5/20 colonized patients developed an invasive infection with S. maltophilia. The worse OS after allo-HSCT due to higher infection related mortality might implicate the screening of allo-HSCT patients for S. maltophilia and a closer observation of colonized patients as outpatients.
Objective: Classifications of posture deviations are only possible compared with standard values. However, standard values have been published for healthy male adults but not for female adults.
Design: Observational study.
Setting: Institute of Occupational Medicine, Social Medicine and Environmental Medicine, Goethe-University Frankfurt/Main.
Participants: 106 healthy female volunteers (21–30 years old; 25.1±2.7 years) were included. Their body weight ranged from 46 to 106 kg (60.3±7.9 kg), the heights from 1.53 to 1.82 m (1.69±0.06 m) and the body mass index from 16.9 kg/m² to 37.6 kg/m² (21.1±2.6 kg/m²).
Outcome measures: A three-dimensional back scan was performed to measure the upper back posture in habitual standing. The tolerance ranges and CI were calculated. Group differences were tested by the Wilcoxon Mann-Whitney U test.
Results: In normal posture, the spinal column was marginally twisted to the left, and the vertebrae were marginally rotated to the right. The kyphosis angle is larger than the lumbar angle. Consequently, a more kyphotic posture is observed in the sagittal plane. The habitual posture is slightly scoliotic with a rotational component (scapular depression right, right scapula marginally more dorsally, high state of pelvic right, iliac right further rotated anteriorly).
Conclusions: Healthy young women have an almost ideally balanced posture with minimal ventral body inclination and a marginal scoliotic deviation. Compared with young males, women show only marginal differences in the upper body posture. These values allow a comparison to other studies, both for control and patient data, and may serve as guideline in both clinical practice and scientific studies.
The endoplasmic reticulum (ER) forms a complex endomembrane network that reaches into the cellular compartments of a neuron, including dendritic spines. Recent work discloses that the spine ER is a dynamic structure that enters and leaves spines. While evidence exists that ER Ca2+ release is involved in synaptic plasticity, the role of spine ER morphology remains unknown. Combining a new 3D spine generator with 3D Ca2+ modeling, we addressed the relevance of ER positioning on spine-to-dendrite Ca2+ signaling. Our simulations, which account for Ca2+ exchange on the plasma membrane and ER, show that spine ER needs to be present in distinct morphological conformations in order to overcome a barrier between the spine and dendritic shaft. We demonstrate that RyR-carrying spine ER promotes spine-to-dendrite Ca2+ signals in a position-dependent manner. Our simulations indicate that RyR-carrying ER can initiate time-delayed Ca2+ reverberation, depending on the precise position of the spine ER. Upon spine growth, structural reorganization of the ER restores spine-to-dendrite Ca2+ communication, while maintaining aspects of Ca2+ homeostasis in the spine head. Our work emphasizes the relevance of precise positioning of RyR-containing spine ER in regulating the strength and timing of spine Ca2+ signaling, which could play an important role in tuning spine-to-dendrite Ca2+ communication and homeostasis.
Background: The focus of this study is to identify particular microRNA (miRNA) signatures in exosomes derived from plasma of 435 human epidermal growth factor receptor 2 (HER2)-positive and triple-negative (TN) subtypes of breast cancer (BC).
Methods: First, miRNA expression profiles were determined in exosomes derived from the plasma of 15 TNBC patients before neoadjuvant therapy using a quantitative TaqMan real-time PCR-based microRNA array card containing 384 different miRNAs. Forty-five miRNAs associated with different clinical parameters were then selected and mounted on microRNA array cards that served for the quantification of exosomal miRNAs in 435 BC patients before therapy and 20 healthy women. Confocal microscopy, Western blot, and ELISA were used for exosome characterization.
Results: Quantification of 45 exosomal miRNAs showed that compared with healthy women, 10 miRNAs in the entire cohort of BC patients, 13 in the subgroup of 211 HER2-positive BC, and 17 in the subgroup of 224 TNBC were significantly deregulated. Plasma levels of 18 exosomal miRNAs differed between HER2-positive and TNBC subtypes, and 9 miRNAs of them also differed from healthy women. Exosomal miRNAs were significantly associated with the clinicopathological and risk factors. In uni- and multivariate models, miR-155 (p = 0.002, p = 0.003, respectively) and miR-301 (p = 0.002, p = 0.001, respectively) best predicted pathological complete response (pCR).
Conclusion: Our findings show a network of deregulated exosomal miRNAs with specific expression patterns in exosomes of HER2-positive and TNBC patients that are also associated with clinicopathological parameters and pCR within each BC subtype.
Spatial modelling of malaria cases associated with environmental factors in South Sumatra, Indonesia
(2018)
Background: Malaria, a parasitic infection, is a life-threatening disease in South Sumatra Province, Indonesia. This study aimed to investigate the spatial association between malaria occurrence and environmental risk factors.
Methods: The number of confirmed malaria cases was analysed for the year 2013 from the routine reporting of the Provincial Health Office of South Sumatra. The cases were spread over 436 out of 1613 villages. Six potential ecological predictors of malaria cases were analysed in the different regions using ordinary least square (OLS) and geographically weighted regression (GWR). The global pattern and spatial variability of associations between malaria cases and the selected potential ecological predictors was explored.
Results: The importance of different environmental and geographic parameters for malaria was shown at global and village-level in South Sumatra, Indonesia. The independent variables altitude, distance from forest, and rainfall in global OLS were significantly associated with malaria cases. However, as shown by GWR model and in line with recent reviews, the relationship between malaria and environmental factors in South Sumatra strongly varied spatially in different regions.
Conclusions: A more in-depth understanding of local ecological factors influencing malaria disease as shown in present study may not only be useful for developing sustainable regional malaria control programmes, but can also benefit malaria elimination efforts at village level.
Soluble Triggering Receptor Expressed on Myeloid Cells 1 (sTREM-1) can be found in the sera of patients with infectious, autoimmune and malignant diseases. The primary objective of this study was to investigate the prognostic significance of sTREM-1 in lung cancer patients. We analyzed the sera of 164 patients with lung cancer of all histologies and all stages at the time of diagnosis. We employed an ELISA using the anti-TREM-1 clone 6B1.1G12 mAb and recombinant human TREM-1. Patient data was collected retrospectively by chart review. In ROC-analysis, a sTREM-1 serum level of 163.1 pg/ml showed the highest Youden-Index. At this cut-off value sTREM-1 was a marker of short survival in patients with NSCLC (median survival 8.5 vs. 13.3 months, p = 0.04). A Cox regression model showed stage (p < 0.001) and sTREM-1 (p = 0.011) to indicate short survival. There were no differences in sTREM-1 serum values among patients with or without infection, pleural effusion or COPD. sTREM-1 was not associated with metastasis at the time of diagnosis and was not a predictor of subsequent metastasis. In SCLC patients sTREM-1 levels were lower than in NSCLC patients (p = 0.001) and did not predict survival. sTREM-1 did not correlate with CRP or the number of neutrophils. In non-small cell lung cancer patients, sTREM-1 in serum has prognostic significance.
Cardiovascular disease remains a leading cause of morbidity and mortality globally. Changing natural history of the disease due to improved care of acute conditions and ageing population necessitates new strategies to tackle conditions which have more chronic and indolent course. These include an increased deployment of safe screening methods, life-long surveillance, and monitoring of both disease activity and tailored-treatment, by way of increasingly personalized medical care. Cardiovascular magnetic resonance (CMR) is a non-invasive, ionising radiation-free method, which can support a significant number of clinically relevant measurements and offers new opportunities to advance the state of art of diagnosis, prognosis and treatment. The objective of the SCMR Clinical Trial Taskforce was to summarizes the evidence to emphasize where currently CMR-guided clinical care can indeed translate into meaningful use and efficient deployment of resources results in meaningful and efficient use. The objective of the present initiative was to provide an appraisal of evidence on analytical validation, including the accuracy and precision, and clinical qualification of parameters in disease context, clarifying the strengths and weaknesses of the state of art, as well as the gaps in the current evidence This paper is complementary to the existing position papers on standardized acquisition and post-processing ensuring robustness and transferability for widespread use. Themed imaging-endpoint guidance on trial design to support drug-discovery or change in clinical practice (part II), will be presented in a follow-up paper in due course. As CMR continues to undergo rapid development, regular updates of the present recommendations are foreseen.
Background: The city of Wrocław in Poland represents one of Central Europeans oldest capitals of science with numerous Nobel laureates. Due to a long history of political suppressions with Nazi Germany and Communism from 1933 until 1989, its scientific community was suppressed for more than half a century.
Methods: The present study assessed scientific activities in the field of social and neighbouring sciences using density equalizing mapping. On the basis of the NewQIS (New Quality and Quantity Indices in Science) platform and the Social Sciences Citation Index (SSCI) of the Web of Science database, a total of 1787 articles originating from Wrocław were identified between 1966 and 2017.
Results: In total, 549 research collaborations of Wrocław with 96 different countries were present (30.7%). Among the 107 research areas the highest activity was found for the field of Business and Economics with n = 272 articles (average citation rate (AVR) of 12.54), followed by Psychology (n = 252 articles, AVR = 9.06), Psychiatry (n = 205 articles, AVR = 4.74) and Public, Environmental and Occupational Health (n = 145 articles, AVR = 7.96). The highest AVR was found for Operations Research (25.36 with n = 87 articles). Density equalizing mapping procedures revealed a global pattern of social sciences research collaborations with scientists from Germany, the UK and the US as the primary cooperating partner of Wrocław. The different countries had major differences in the area of research collaborations.
Conclusions: This is the first study that depicts the global network of Wrocław scientific activities in the field of social sciences. The exorbitant increase in research activity from 2006 onwards can lead to the assumption that Wrocław social sciences encounter a fruitful future.
Protein aggregates and cytoplasmic vacuolization are major hallmarks of multisystem proteinopathies (MSPs) that lead to muscle weakness. Here, we identify METTL21C as a skeletal muscle-specific lysine methyltransferase. Insertion of a β-galactosidase cassette into the Mettl21c mouse locus revealed that METTL21C is specifically expressed in MYH7-positive skeletal muscle fibers. Ablation of the Mettl21c gene reduced endurance capacity and led to age-dependent accumulation of autophagic vacuoles in skeletal muscle. Denervation-induced muscle atrophy highlighted further impairments of autophagy-related proteins, including LC3, p62, and cathepsins, in Mettl21c−/− muscles. In addition, we demonstrate that METTL21C interacts with the ATPase p97 (VCP), which is mutated in various human MSP conditions. We reveal that METTL21C trimethylates p97 on the Lys315 residue and found that loss of this modification reduced p97 hexamer formation and ATPase activity in vivo. We conclude that the methyltransferase METTL21C is an important modulator of protein degradation in skeletal muscle under both normal and enhanced protein breakdown conditions.
Objectives: The CRYO4PERSISTENT AF (Cryoballoon Ablation for Early Persistent Atrial Fibrillation) trial aims to report long-term outcomes after a single pulmonary vein isolation (PVI)–only ablation procedure using the second-generation cryoballoon in persistent atrial fibrillation (PerAF) patients.
Background: Pulmonary vein isolation is recognized as the cornerstone of atrial fibrillation (AF) ablation, including ablation of PerAF.
Methods: The CRYO4PERSISTENT AF trial (NCT02213731) is a prospective, multicenter, single-arm trial designed to assess single-procedure outcomes of PVI using the cryoballoon. The primary endpoint was freedom from AF, atrial flutter, or atrial tachycardia ≥30 s after a 90-day blanking period. After enrollment, but before ablation, patients without 100% AF burden (18-h Holter monitoring or 3 consecutive electrocardiograms in a time frame ≥14 days) were excluded. Patients were followed at 3, 6, and 12 months, with 48-h Holter monitoring at 6 and 12 months. Quality of life and symptoms were evaluated at baseline and 12 months. Arrhythmia recurrence and adverse events were adjudicated by an independent committee.
Results: A total of 101 patients (62 ± 11 years of age, 74% men, left ventricular ejection fraction 56 ± 8%, left atrial diameter 43 ± 5 mm) meeting criteria, undergoing cryoballoon-based PVI, with follow-up data, were included. Kaplan-Meier estimate of freedom from AF, atrial flutter, or atrial tachycardia recurrence was 60.7% at 12 months. Compared with baseline, there were significantly fewer patients with arrhythmia-related symptoms at 12 months (16% vs. 92%; p < 0.0001). The symptom reduction was supported by significant improvement in 36-Item Short Form Health Survey composite scores and European Heart Rhythm Association score at 12 months. The only device related event was transient phrenic nerve injury in 2 (2%) patients, with resolution pre-discharge.
Conclusions: Cryoballoon ablation for treatment of PerAF demonstrated 61% single-procedure success at 12 months post-ablation in addition to significant reduction in arrhythmia-related symptoms and improved quality of life. (Cryoballoon Ablation for Early Persistent Atrial Fibrillation [Cryo4 Persistent AF]; NCT02213731)