Studies on the mechanisms of action of MR33317.

MR33317 was synthesized as an acetylcholinesterase-inhibitor and an agonist at brain 5-HT4-receptors. MR33317 might be used to treat Morbus Alzheimer. This therapeutic action of MR33317 might be based on MR33317´s dual synergistic activity. We tested the hypothesis that MR33317 also stimulates 5-HT4-receptors in the heart. MR33317 (starting at 10 nM) increased force of contraction and beating rate in isolated atrial preparations from mice with cardiac confined overexpression of the human 5-HT4-serotonin receptor (5-HT4-TG) but was inactive in wild type mouse hearts (WT). Only in the presence of the phosphodiesterase III-inhibitor cilostamide, MR33317 raised force of contraction under isometric conditions in isolated paced (1 Hz) human right atrial preparations (HAP). This increase in force of contraction in human atrium by MR33317 was attenuated by 10 µM tropisetron or GR125487. These data suggest that MR33317 is an agonist at human 5-HT4-serotonin receptors in the human atrium. Clinically, one would predict that MR33317 may lead to atrial fibrillation.

On the normativity of evidence - Lessons from philosophy of science and the "VALIDATE" project.

"Evidence" is a key term in medicine and health services research, including Health Technology Assessment (HTA). Randomized clinical trials (RCTs) have undoubtedly dominated the scene of generating evidence for a long period of time, becoming the hallmark of evidence-based medicine (EBM). However, due to a number of misunderstandings, the lay audience and some researchers have sometimes placed too much trust in RCTs compared to other methods of investigation. One of the principal misunderstandings is to consider RCTs findings as isolated and self-apparent pieces of information. In other words, what has been essentially lacking was the awareness of the value-context of the evidence and, in particular, the value- and theory-ladenness (normativity) of scientific knowledge. This paper aims to emphasize the normativity that exists in the production of scientific knowledge, and in particular in the conduct of RCTs as well as in the performance of HTA. The work is based on some lessons learned from Philosophy of Science and the European project "VALIDATE" (VALues In Doing Assessments of healthcare TEchnologies"). VALIDATE was a three-year EU Erasmus+ strategic partnerships project (2018-2021), in which training in the field of HTA was further optimized by using insights from political science and ethics (in accordance with the recent definition of HTA). Our analysis may reveal useful insights for addressing some challenges that HTA is going to face in the future.

Image rejects in digital skeletal radiography in two public hospitals in Norway.

INTRODUCTION: The proportion of diagnostic images not applied for diagnostic purposes is an indicator of image quality, safety, and efficiency in radiography. Despite increased awareness, image reject is still a substantial problem and needs continued observation and targeted measures. Accordingly, the objective of this study is to estimate the extent, variation, and characteristics of image rejects, in order to improve the quality, safety, and efficiency in radiography. METHODS: All skeletal images at two digital X-ray rooms at two public hospitals in Norway were reviewed for four weeks in 2020. The number of exposed images, type of examination, and number of deleted images were registered. For each deleted image the deduced reasons for deleting the image were recorded. RESULTS: 2183 and 1467 X-ray images were taken at Hospital 1 and 2 respectively. The corresponding reject rates were 14.2% and 9.1%. The reject rate varied greatly from day to day (from 0% to 22%), and the examinations with the highest reject rate were X-ray of extremities (knee, elbow, ankle, wrist) (12-25%) and of the spine (14-19%). The two clearly dominating reasons for image rejects were positioning and centering errors. CONCLUSION: The reject rate is high and reduces quality, safety, and efficiency of imaging services. The reasons for image rejects are typical professionally reducible errors indicating great potential for improvement. IMPLICATIONS FOR PRACTICE: Monitoring and assessing image rejects are of great importance to management, training, education, patient safety, and for quality improvement of imaging services.

Cerebral perfusion changes in acute subdural hematoma.

INTRODUCTION: Acute subdural hematoma (aSDH) is one of the main causes of high mortality and morbidity in traumatic brain injury. Prognosis is poor due to the rapid volume shift and mass effect. Cerebral perfusion is likely affected in this condition. This study quantifies perfusion changes in aSDH using early ER polytrauma CT with perfusion imaging (CTP). METHODS: Data of 54 patients with traumatic aSDH were retrospectively collected. Glasgow Coma scale (GCS), perfusion parameters, therapeutic decisions and imaging data including hematoma thickness, midline shift, and hematoma localization were analyzed. The cortical perfusion parameters of each hemisphere, the area anterior to the hematoma (AAH), area below the hematoma (ABH), area posterior to the hematoma (PAH), and corresponding mirrored contralateral regions were determined. RESULTS: We found a significant difference in Tmax in affected and unaffected whole-hemisphere data (mean 4.0 s vs. 3.3 s, p < 0.05) and a significantly different mean for Tmax in ABH and for the corresponding mirrored area (mABH) (mean 3.8 s vs. 3.1 s, p < 0.05). No significant perfusion changes in cerebral blood flow (CBF), cerebral blood volume (CBV), and mean transit time (MTT) were found. CONCLUSION: There was a significant elevation of time to maximum (Tmax) values in the underlying cortical area of aSDH. Possible pathophysiological explanations, the influence on immediate surgical decision-making and further therapeutic consequences have to be evaluated.

Cantharidin increases the force of contraction and protein phosphorylation in isolated human atria.

Cantharidin, an inhibitor of protein phosphatase 1 (PP1) and protein phosphatase 2A (PP2A), is known to increase the force of contraction and shorten the time to relaxation in human ventricular preparations. We hypothesized that cantharidin has similar positive inotropic effects in human right atrial appendage (RAA) preparations. RAA were obtained during bypass surgery performed on human patients. These trabeculae were mounted in organ baths and electrically stimulated at 1 Hz. For comparison, we studied isolated electrically stimulated left atrial (LA) preparations and isolated spontaneously beating right atrial (RA) preparations from wild-type mice. Cumulatively applied (starting at 10 to 30 µM), cantharidin exerted a positive concentration-dependent inotropic effect that plateaued at 300 µM in the RAA, LA, and RA preparations. This positive inotropic effect was accompanied by a shortening of the time to relaxation in human atrial preparations (HAPs). Notably, cantharidin did not alter the beating rate in the RA preparations. Furthermore, cantharidin (100 µM) increased the phosphorylation state of phospholamban and the inhibitory subunit of troponin I in RAA preparations, which may account for the faster relaxation observed. The generated data indicate that PP1 and/or PP2A play a functional role in human atrial contractility.

MTT Heterogeneity in Perfusion CT Imaging as a Predictor of Outcome after Aneurysmal SAH.

BACKGROUND AND PURPOSE: Impairment of tissue oxygenation caused by inhomogeneous microscopic blood flow distribution, the so-called capillary transit time heterogeneity, is thought to contribute to delayed cerebral ischemia after aneurysmal SAH but has so far not been systematically evaluated in patients. We hypothesized that heterogeneity of the MTT, derived from CTP parameters, would give insight into the clinical course of patients with aneurysmal SAH and may identify patients at risk of poor outcome. MATERIALS AND METHODS: We retrospectively analyzed the heterogeneity of the MTT using the coefficient of variation in CTP scans from 132 patients. A multivariable logistic regression model was used to model the dichotomized mRS outcome. Linear regression was used to eliminate variables with high linear dependence. T tests were used to compare the means of 2 groups. Furthermore, the time of the maximum coefficient of variation for MTT after bleeding was evaluated for correlation with the mRS after 6 months. RESULTS: On average, each patient underwent 5.3 CTP scans during his or her stay. Patients with high coefficient of variation for MTT presented more often with higher modified Fisher (P = .011) and World Federation of Neurosurgical Societies grades (P = .014). A high coefficient of variation for MTT at days 3-21 after aneurysmal SAH correlated significantly with a worse mRS score after 6 months (P = .016). We found no correlation between the time of the maximum coefficient of variation for MTT after bleeding and the patients' outcomes after 6 months (P = .203). CONCLUSIONS: Heterogeneity of MTT in CTP after aneurysmal SAH correlates with the patients' outcomes. Because the findings are in line with the pathophysiologic concept of the capillary transit time heterogeneity, future studies should seek to verify the coefficient of variation for MTT as a potential imaging biomarker for outcome.

Role of Cardiac A2A Receptors Under Normal and Pathophysiological Conditions.

This review presents an overview of cardiac A2A-adenosine receptors The localization of A2A-AR in the various cell types that encompass the heart and the role they play in force regulation in various mammalian species are depicted. The putative signal transduction systems of A2A-AR in cells in the living heart, as well as the known interactions of A2A-AR with membrane-bound receptors, will be addressed. The possible role that the receptors play in some relevant cardiac pathologies, such as persistent or transient ischemia, hypoxia, sepsis, hypertension, cardiac hypertrophy, and arrhythmias, will be reviewed. Moreover, the cardiac utility of A2A-AR as therapeutic targets for agonistic and antagonistic drugs will be discussed. Gaps in our knowledge about the cardiac function of A2A-AR and future research needs will be identified and formulated.

On inotropic effects of UTP in the human heart.

Uridine 5'-triphosphate (UTP) exerts a positive inotropic effect (PIE) in isolated electrically driven isolated right atrial trabeculae carneae from patients undergoing heart surgery. This review discusses some aspects of the current knowledge on the putative receptor(s) involved and the potential biochemical transduction steps leading to the PIE.

Regularized differential evolution for a blind phase retrieval problem in ultrashort laser pulse characterization.

Obtaining the temporal shape of an ultrashort laser pulse using the method of dispersion scan entails solving a nonlinear inverse problem, a challenging prospect on its own, yet still aggravated when the pulse shape being measured is temporally varying from pulse to pulse. For this purpose, we use a Differential Evolution (DE) algorithm enhanced by three different regularization methods. The DE algorithm in its standard form is insufficient for reconstructing the pulse in the case of unstable pulse trains. By modifying it to retrieve two independent functions and with the help of regularization, we were able to show that it is possible to simultaneously infer the average length and the coherence length of the pulses. The latter is the shortest pulse the laser source can produce. We also discuss the three different approaches for regularization used in this paper, and from the numerical results we present, we can conclude that a spline-based regularization method is far superior compared to the two other methods under investigation.

Characterization of Biostable Atomic Layer Deposited (ALD) Multilayer Passivation Coatings for Active Implants.

The next generation of flexible, electrically active implants, such as brain implants or retina chips require a flexible, biostable as well as biocompatible passivation, ensuring a degradation-free usage for long time periods on the order of several years. Until today, these passivations are prepared mostly by polyimides or parylene, both of which are water vapor permeable to a certain degree. To remedy this deficiency, Atomic Layer Deposited (ALD) thin films are characterized regarding their electrical passivating features under conditions of accelerated aging, such as elevated temperatures in a liquid environment. The initial electrical passivation by various ALD deposited multilayers, combining alternating thin Al2O3 and TiO2 layers is the goal of this research as well as the stability of these layers under induced degradation. Such layers, in combination with a parylene passivation, would ensure a water vapor impermeable and biocompatible coating.

Single nucleotide polymorphisms in long noncoding RNA, ANRIL, are not associated with severe periodontitis but with adverse cardiovascular events among patients with cardiovascular disease.

BACKGROUND AND OBJECTIVE: Biological plausibility of an association between severe periodontitis and cardiovascular disease (CVD) has been proven. Genetic characteristics play an important role in both complex inflammatory diseases. Polymorphisms (single nucleotide polymorphisms [SNPs]) in the long noncoding RNA, antisense noncoding RNA in the INK4 locus (ANRIL), were shown to play a leading role in both diseases. The primary objectives of the study were to assess, among cardiovascular (CV angiographically proven ≥50% stenosis of a main coronary artery) patients, the impact of ANRIL SNPs rs133049 and rs3217992 on the severity of periodontitis and the previous history of coronary events, as well as on the occurrence of further adverse CV events. MATERIAL AND METHODS: The prevalence of severe periodontitis was analyzed in 1002 CV patients. ANRIL SNPs rs133049 and rs3217992 were genotyped. The prognostic value of both ANRIL SNPs for combined CV endpoint (stroke/transient ischemic attack [TIA], myocardial infarction, death from a CV-related event, death from stroke) was evaluated after a 3-year follow-up period. Hazard ratios (HRs) were adjusted for established CV risk factors applying Cox regression. RESULTS: ANRIL SNPs rs133049 and rs3217992 were not associated with severe periodontitis or history of CVD in CV patients. In the Kaplan-Meier survival curve including the log rank-test (P = .036) and Cox regression (hazard ratio = 1.684, P = .009) the AA genotype of rs3217992 was shown to be an independent predictor for adverse CV events after 3 years of follow-up. CONCLUSION: SNPs in ANRIL are not risk modulators for severe periodontitis and history of CVD in CV patients. The AA genotype of ANRIL SNPs rs3217992 possesses prognostic power for further CV events within 3 years of follow-up.

Variation in caries treatment proposals among dentists in Norway: the best interest of the child.

AIM: To explore variation in treatment-related-decisions for severe caries in children among dentists in the Public Dental Service (PDS) in Norway. It was also to evaluate the treatment choices in relation to the best interest of children and a child's rights to enjoy the highest standard of health care. METHODS: A pre-coded questionnaire was sent electronically to all general dental practitioners (GDPs) working in the PDS in eight counties in Norway (n = 611). The questionnaire included two case scenarios to reflect common dental conditions related to severe caries among 5-year-old children. Paediatric dentists and paediatric students were invited to validate the different treatment options. Frequency distributions and statistical analyses were carried out using Chi square statistics. RESULTS: The response rate was 65% (n = 391) among the GDPs. A majority of the GDPs preferred a new appointment with behaviour management techniques (BMT) to a child presenting pulpitis and pain. Dentists educated outside the Nordic region would use restraint more often as a treatment alternative when the child was in pain than Nordic-educated dentists (p\0.05). Dentists with less than 10 years of experience preferred BMT and sedation more often when the child was in pain than their older colleagues, who, however, preferred a waiting approach and no immediate treatment if the child was not in pain(p\0.05) [corrected]. CONCLUSIONS: Use of BMT and sedation is related to region of education and years of experience. Awareness of ethical principles with the child´s best interest in mind, should receive increased attention.

HRG/HER2/HER3 signaling promotes AhR-mediated Memo-1 expression and migration in colorectal cancer.

Colorectal cancer (CRC) is a complex disease with still unsatisfactory prognosis even in western societies, although substantial progress has been made in pre-screening programs, surgical techniques and targeted therapy options. Mediator of motility-1 (Memo-1) was previously recognized as an important effector of cell migration downstream of receptor tyrosine kinase signaling in breast cancer. This study identified Memo-1 as frequently overexpressed in CRC and established a close link between extracellular HER2 activation, AhR/ARNT transcriptional activity and Memo-1 expression. Dissection of the hMemo-1 gene promoter using reporter assays and chromatin IP techniques revealed recruitment of Aryl hydrocarbon receptor (AhR)/Aryl hydrocarbon receptor nuclear-translocator (ARNT) complex, which positively influenced Memo-1 expression in cancer cells. We found that Memo-1 depletion negatively influenced the cellular actin network and that its expression is required for HER2-mediated cell migration and invasion. Moreover, analyses of Memo-1 expression in primary CRC revealed correlation with clinical parameters that point to Memo-1 as a new prognostic factor of aggressive disease in CRC patients. Altogether, these observations demonstrate that Memo-1 is an important downstream regulator of HER2-driven CRC cell migration and invasion through connecting extracellular signals from membrane to the cytoskeletal actin network.

Why is it so difficult to integrate ethics in Health Technology Assessment (HTA)? The epistemological viewpoint.

Ethics has been identified as a key element in Health Technology Assessment (HTA) since its conception. However, ethical issues are still not frequently addressed explicitly in HTA. Several valuable reasons have been identified. The basis of the article is the claim that ethics is often not part of HTA for "epistemological reasons". Hence, the main aim of the contribution is to explore in more details and emphasize them by using the fact/value dichotomy. Our conclusion is that current HTA configuration is predominantly based on the comparison among objective and empirically testable "facts", whilst ethics is not empirically testable. In this sense, there is a sort of "epistemological gap", which can explain why it is so difficult to integrate ethics in HTA. We suggest that the epistemological differences among the various domains of HTA are addressed more explicitly.

Relationship between cardiac tissue glycation and skin autofluorescence in patients with coronary artery disease.

AIM: During ageing, advanced glycation end-products (AGEs) accumulate in extracellular matrix proteins like collagen and contribute to a decline in organ function. As skin autofluorescence (sAF) can assess subcutaneous accumulation of fluorescent AGEs, this study aimed to investigate the relationship between AGE-modified cardiac tissue collagen and AGE-related sAF in coronary artery bypass graft (CABG) surgery patients. METHODS: Between January 2011 and January 2012, data from 72 consecutive male patients undergoing isolated CABG were prospectively recorded. Collagen fractions were isolated from the right atrial appendages of these patients by proteolysis and collagenase digestion. Collagen was quantified by hydroxyproline assay, and AGEs by AGE-related intrinsic fluorescence; sAF was measured using an autofluorescence reader. RESULTS: Biochemical analysis showed that the insoluble cardiac collagen fraction contained the highest amounts of accumulated AGEs; the AGE-related intrinsic fluorescence of this fraction increased with age (P=0.0001), blood glucose (P=0.002), HbA1c (P=0.01) and sAF (P=0.008). CONCLUSION: This study demonstrated for the first time a relationship between cardiac tissue glycation and AGE-related sAF. In addition, cardiac tissue glycation was associated with age, blood glucose and long-term glucose values in patients with coronary artery disease.

Use of floss/interdental brushes is associated with lower risk for new cardiovascular events among patients with coronary heart disease.

BACKGROUND AND OBJECTIVE: Periodontitis has been found to be associated with coronary heart disease (CHD) and stroke. However, only little is known about whether periodontitis and associated confounders are associated with new cardiovascular events among patients with CHD. MATERIAL AND METHODS: A total of 942 inpatients with CHD were examined regarding periodontitis, oral care habits, bacteria in the subgingival biofilm and the expression of interleukin-(IL)-6 c. (coding DNA)-174 genotypes (rs 1800793) to determine whether these confounders are associated with new cardiovascular events within a 1-year follow-up period. Adjusted hazard ratios (HR) with respect of age, gender, smoking, body mass index, use of aids for interdental hygiene, plaque index, occurrence of severe periodontitis and further internal diseases such as diabetes, hypertension, dyslipoproteinemia, number of missing teeth, serological parameters and IL-6 genotypes were generated with Cox regression. RESULTS: In all, 941 cardiovascular patients completed the 1-year follow up and 7.3% of the patients achieved the primary endpoint (myocardial infarction: 2.1%, stroke/transient ischemic attack: 1.8%, cardiovascular deaths: 3.4%). Patients who reported practicing interdental cleaning were younger, less likely to be male or to have severe periodontitis, had a reduced tobacco exposure, had fewer missing teeth, less indices for plaque and bleeding on probing and a significant decreased adjusted risk for new cardiovascular events (HR = 0.2, CI 0.06-0.6, p = 0.01) than those patients with CHD who did not report practicing interdental cleaning. We did not obtain significant increased HR for patients with severe periodontitis (HR = 1.2, CI 0.7-2.1, p = 0.53), carriers of the IL-6 genotypes GC or CC (HR = 1.4, CI 0.8-2.5, p = 0.24) and did not find a significant association between the number of detected various oral species and the incidence of the combined endpoint (HR = 0.9, CI 0.8-1.01, p = 0.07). CONCLUSIONS: These findings suggest that flossing and brushing of interdental spaces might reduce the risk for new cardiovascular events among patients with CHD. The hypothesis that interdental cleaning per se reduces the risk of new cardiovascular events should be examined in an interventional study.

Inter-hospital transfer of ECMO-assisted patients with a portable miniaturized ECMO device: 4 years of experience.

OBJECTIVES: Extracorporeal membrane oxygenation (ECMO) in patients with severe pulmonary failure is able to keep patients alive until organ regeneration, until shunting out for further diagnostic and therapeutic options or until transportation to specialized centers. Nonetheless, extracorporeal techniques require a high degree of expertise, so that a confinement to specialized centers is meaningful. Following from this requirement, the need for inter-hospital transfer of patients with severely compromised pulmonary function is rising. METHODS: We report about our experience with a portable ECMO system during inter-hospital air or ground transfer of patients with cardiopulmonary failure. RESULTS: The portable ECMO system was used for transportation to the center and in-hospital treatment in 36 patients with an average age of 53 years suffering from respiratory failure. Accordingly, the ECMO system was implanted as a veno-venous extracorporeal system. Pre-ECMO ventilation time was 5.2 (2-9) days. Twelve patients were transported to our institution by ground and 24 patients by air ambulance over a median distance of 46 km. With the assistance of the ECMO device, prompt stabilization of cardiopulmonary function could be achieved in all patients without any technical complications. Post-ECMO ventilation was 9.8 days. Weaning from the ECMO system was successful in 61% of all patients after a median device working period of 12.7 days; median ICU stay was 34 days and a survival rate of 64% of patients was achieved. Technical (8%) and device-associated bleeding (11%)/thromboembolic (8%) complication rates showed very acceptable levels. CONCLUSION: Our experience demonstrates that miniaturized, portable ECMO therapy allows location-independent, out-of-center stabilization of pulmonary compromised patients with consecutive inter-hospital transfer and further in-house treatment, so that sophisticated ECMO therapy can be offered to every patient, even in hospitals with primary healthcare.

[Sexually transmitted infections as a cause for solid rectal pseudo tumors]. / Sexuell übertragbare Infektionen als Ursache von solide imponierenden Pseudotumoren des Rektums.

Two cases of symptomatic proctitis with rectal tumors suspicious for malignancy are presented. A florid regenerative proctitis was shown in the histological examination. In both cases a sexually transmitted infection (STI) was causing the symptoms. In rare cases STIs present as pseudo tumors mimicking malignancy in clinical examination and endoscopic/radiological analysis. A close collaboration between gastroenterologist and pathologist is necessary for a correct diagnosis and to prevent unnecessary surgical treatment.

Pancreatic cancer.

UNLABELLED: In recent years, it has become clear that the current standard therapeutic options for pancreatic cancer are not adequate and still do not meet the criteria to cure patients suffering from this lethal disease. Although research over the past decade has shown very interesting and promising new therapeutic options for these patients, only minor clinical success was achieved. Therefore, there is still an urgent need for new approaches that deal with early detection and new therapeutic options in pancreatic cancer. To provide optimal care for patients with pancreatic cancer, we need to understand better its complex molecular biology and thus to identify new target molecules that promote the proliferation and resistance to chemotherapy of pancreatic cancer cells. In spite of significant progress in curing cancers with chemotherapy, pancreatic cancer remains one of the most resistant solid tumour cancers and many studies suggest that drug-resistant cancer cells are the most aggressive with the highest relapse and metastatic rates. In this context, activated Notch signalling is strongly linked with chemoresistance and therefore reflects a rational new target to circumvent resistance to chemotherapy in pancreatic cancer. Here, we have focused our discussion on the latest research, current therapy options and recently identified target molecules such as Notch-2 and the heparin-binding growth factor midkine, which exhibit a wide range of cancer-relevant functions and therefore provide attractive new therapeutic target molecules, in terms of pancreatic cancer and other cancers also. LINKED ARTICLES: This article is part of a themed section on Midkine. To view the other articles in this section visit http://dx.doi.org/10.1111/bph.2014.171.issue-4.