Effects of high-intensity interval training on trajectories of gas-exchange measures and blood lactate concentrations during cardiopulmonary exercise tests in cardiac rehabilitation-A randomized controlled trial.

BACKGROUND: The optimal allocation of training time to different intensities in cardiac rehabilitation is still under debate. The objective of this study was to explore whether in a 12-week cardiac rehabilitation program, replacement of two of four usual continuous endurance training (CET) sessions per week with energy expenditure-matched high-intensity interval training (HIIT) affects the trajectories of cardiopulmonary exercise test (CPET) variables such as ventilatory equivalents for O2 (EqO2 ) and CO2 (EqCO2 ), and blood lactate (BLa) during CPET. METHODS: Eighty-two male patients undergoing outpatient cardiac rehabilitation after an acute coronary syndrome were randomized to CET (age [mean ± SD] 61.7 ± 9.8 years, body mass index [BMI] 28.1 ± 3.4) or HIIT+CET (60.0 ± 9.4 years, BMI 28.5 ± 3.5). CPET was performed at baseline, after 6 and after 12 weeks. HIIT consisted of ten 60-s bouts of cycling at an intensity of 100% of the maximal power output (Pmax ) achieved in an incremental test to exhaustion, interspersed with 60 s at 20% Pmax . CET was performed at 60% Pmax with equal duration. Training intensities were adjusted after 6 weeks to account for the training-induced improvement in cardiorespiratory fitness. The entire functions defining the relationship between EqO2 , EqCO2 , and BLa, with power output were modeled using linear mixed models to assess how these trajectories are affected by HIIT. RESULTS: After 6 and 12 weeks, Pmax increased to 112.9% and 117.5% of baseline after CET, and to 113.9% and 124.7% after HIIT+CET (means). Twelve weeks of HIIT+CET elicited greater reductions of EqO2 and EqCO2 than CET alone (p < 0.0001 each) in a range above 100% baseline Pmax . Specifically, at 100% of baseline Pmax , least squares arithmetic mean EqO2 values of CET and HIIT+CET patients were 36.2 versus 33.5. At 115% and 130% of baseline Pmax , EqO2 values were 41.2 versus 37.1 and 47.2 versus 41.7. Similarly, corresponding EqCO2 values of CET and HIIT+CET patients were 32.4 versus 31.0, 34.3 versus 32.2, and 37.0 versus 34.0. Conversely, mean BLa levels (mM) were not differently affected (p = 0.64). At 100%, 115%, and 130% of baseline Pmax after 12 weeks, BLa levels did not differ to a relevant extent (least squares geometric means, 3.56 vs. 3.63, 5.59 vs. 5.61, 9.27 vs. 9.10). CONCLUSIONS: While HIIT+CET reduced ventilatory equivalents more effectively than CET alone, specifically when patients were approaching their maximal performance during CPET, both training strategies were equally effective in reducing BLa levels.

TRPA1 as Target in Myocardial Infarction.

Transient receptor potential cation channel subfamily A member 1 (TRPA1), an ion channel primarily expressed on sensory neurons, can be activated by substances occurring during myocardial infarction. Aims were to investigate whether activation, inhibition, or absence of TRPA1 affects infarcts and to explore underlying mechanisms. In the context of myocardial infarction, rats received a TRPA1 agonist, an antagonist, or vehicle at different time points, and infarct size was assessed. Wild type and TRPA1 knockout mice were also compared in this regard. In vitro, sensory neurons were co-cultured with cardiomyocytes and subjected to a model of ischemia-reperfusion. Although there was a difference between TRPA1 activation or inhibition in vivo, no experimental group was different to control animals in infarct size, which also applies to animals lacking TRPA1. In vitro, survival probability of cardiomyocytes challenged by ischemia-reperfusion increased from 32.8% in absence to 45.1% in presence of sensory neurons, which depends, at least partly, on TRPA1. This study raises doubts about whether TRPA1 is a promising target to reduce myocardial damage within a 24 h period. The results are incompatible with relevant enlargements of infarcts by TRPA1 activation or inhibition, which argues against adverse effects when TRPA1 is targeted for other indications.

Analgesic Action of Acetaminophen via Kv7 Channels.

The mechanism of acetaminophen (APAP) analgesia is at least partially unknown. Previously, we showed that the APAP metabolite N-acetyl-p-benzoquinone imine (NAPQI) activated Kv7 channels in neurons in vitro, and this activation of Kv7 channels dampened neuronal firing. Here, the effect of the Kv7 channel blocker XE991 on APAP-induced analgesia was investigated in vivo. APAP had no effect on naive animals. Induction of inflammation with λ-carrageenan lowered mechanical and thermal thresholds. Systemic treatment with APAP reduced mechanical hyperalgesia, and co-application of XE991 reduced APAP's analgesic effect on mechanical pain. In a second experiment, the analgesic effect of systemic APAP was not antagonized by intrathecal XE991 application. Analysis of liver samples revealed APAP and glutathione-coupled APAP indicative of metabolization. However, there were no relevant levels of these metabolites in cerebrospinal fluid, suggesting no relevant APAP metabolite formation in the CNS. In summary, the results support an analgesic action of APAP by activating Kv7 channels at a peripheral site through formation of the metabolite NAPQI.

Cubital tunnel perfusion in different postures-An anatomical investigation.

INTRODUCTION/AIMS: For cubital tunnel syndrome, the avoidance of predisposing arm positions and the use of elbow splints are common conservative treatment options. The rationale is to prevent excessive stretching and compression of the nerve in the cubital tunnel, as this mechanical stress impedes intraneural perfusion. Data regarding those upper extremity postures to avoid, or whether elbow flexion alone is detrimental, are inconsistent. This study aimed to assess perfusion and size changes of the cubital tunnel during different postures in an experimental cadaver setup. METHODS: Axillary arteries in 30 upper extremities of fresh cadavers were injected with ultrasound contrast agent. High-resolution ultrasound of the cubital tunnel was performed during five different arm postures that gradually increased tension on the ulnar nerve and caused cubital tunnel narrowing. Contrast enhancement within the tunnel was measured to quantify perfusion. Cubital tunnel cross-sectional area was measured to detect compression. RESULTS: Increasing tension significantly reduced perfusion. When isolated, neither shoulder elevation, elbow flexion, pronation, nor extension of wrist and fingers impaired perfusion. However, combining two or more of these postures led to significant decreases. Significant narrowing of the cubital tunnel was seen in full elbow flexion and shoulder elevation. DISCUSSION: Combinations of some upper extremity joint positions reduce nerve perfusion, but isolated elbow flexion does not have a significant impact. We hypothesize that elbow splints alone may not influence cubital tunnel perfusion but may only prevent direct compression of the ulnar nerve. Advising patients about upper extremity postures that should be avoided may be more effective.

A Human TRPA1-Specific Pain Model.

The cation channel transient receptor potential ankyrin 1 (TRPA1) plays an important role in sensing potentially hazardous substances. However, TRPA1 species differences are substantial and limit translational research. TRPA1 agonists tested previously in humans also have other targets. Therefore, the sensation generated by isolated TRPA1 activation in humans is unknown. The availability of 2-chloro-N-(4-(4-methoxyphenyl)thiazol-2-yl)-N-(3-methoxypropyl)-acetamide (JT010), a potent and specific TRPA1 agonist, allowed us to explore this issue. To corroborate the specificity of JT010, it was investigated whether the TRPA1 antagonist (1E,3E)-1-(4-fluorophenyl)-2-methyl-1-penten-3-one oxime (A-967079) abolishes JT010-elicited pain. Sixteen healthy volunteers of both sexes rated pain due to intraepidermal injections of different concentrations and combinations of the substances. The study design was a double-blind crossover study. All subjects received all types of injections, including a placebo without substances. Injections of the TRPA1 agonist dose-dependently caused pain with a half-maximal effective concentration of 0.31 µm Coinjection of A-967079 dose-dependently reduced and at a high concentration abolished JT010-induced pain. Quantification of JT010 by HPLC showed that a substantial part is adsorbed when in contact with polypropylene surfaces, but that this was overcome by handling in glass vials and injection using glass syringes. Isolated TRPA1 activation in humans causes pain. Thus, intradermal JT010 injection can serve as a tool to validate new TRPA1 antagonists concerning target engagement. More importantly, TRPA1-specific tools allow quantification of the TRPA1-dependent component in physiology and pathophysiology.SIGNIFICANCE STATEMENT This study showed that activation of the ion channel transient receptor potential ankyrin 1 (TRPA1) alone indeed suffices to elicit pain in humans, independent of other receptors previously found to be involved in pain generation. The newly established TRPA1-specific pain model allows different applications. First, it can be tested whether diseases are associated with compromised or exaggerated TRPA1-dependent painful sensations in the skin. Second, it can be investigated whether a new, possibly systemically applied drug directed against TRPA1 engages its target in humans. Further, the general possibility of quantitative inhibition of TRPA1 allows identification of the TRPA1-dependent disease component, given that the substance reaches its target. This contributes to a better understanding of pathophysiology, can lay the basis for new therapeutic approaches, and can bridge the gap between preclinical research and clinical trials.

Periodontal treatment does not result in detectable platelet activation in vivo.

OBJECTIVES: Periodontitis is associated with systemic inflammation, elevated platelet activation and enhanced risk for cardiovascular diseases, while periodontal treatment reduces tissue inflammation and shows desirable effects on the oral biofilm and dental health. However, subgingival debridement during conservative treatment can lead to local trauma and transient bacteraemia, which might affect cardiovascular risk in these patients. Therefore, we investigated the effect of periodontal treatment on systemic platelet activation. MATERIALS AND METHODS: In a prospective therapeutic trial, 26 patients underwent periodontal treatment and patient blood was analysed immediately before and immediately after intervention for platelet activation markers (flow cytometric analysis of P-selectin, CD63 and CD40L surface expression, integrin αIIbß3 activation and fibrinogen binding, intra-platelet reactive oxygen species production, platelet-leukocyte aggregate formation and intra-platelet vasodilator-stimulated phosphoprotein phosphorylation) in response to adenosine diphosphate (ADP). RESULTS: The present study shows that basal platelet activation levels remain largely unaltered in response to periodontal treatment. We also did not observe significant changes in platelet reactivity in response to different concentrations of platelet agonist ADP. CONCLUSION: Subgingival debridement does not result in relevantly elevated platelet activation. Thus, augmented platelet activation seems unlikely to be a causative triggering factor that increases the short-term risk for platelet-mediated thrombotic events in response to subgingival debridement. CLINICAL RELEVANCE: Subgingival debridement is a safe procedure and does not increase the short-term risk for platelet-mediated thrombotic events.

Pre- and postoperative headache in patients with meningioma.

BACKGROUND: Meningiomas are generally slowly growing intracranial tumors. They are often incidentally diagnosed, given that symptoms may be absent even in cases of an enormous tumor size. Headache is a frequent but not consistent symptom. Therefore, we examined the association between structural, biochemical and histochemical tumor parameters with preoperative as well as postoperative occurrence of headache. METHODS: In our study, we prospectively investigated 69 consecutive patients enrolled for meningioma neurosurgery. Anatomical, histological and biochemical parameters were acquired, and headache parameters were registered from the clinical report and from a questionnaire filled by the patients before neurosurgery. The headache was re-evaluated one year after neurosurgery. The study was designed to exploratively investigate whether there is an association of acquired clinical and biological parameters with the occurrence of preoperative and postoperative headache. RESULTS: Edema diameter and the proliferation marker MIB-1 were negatively associated with the incidence and intensity of preoperative headache, while the content of prostaglandin E2 in the tumor tissue was positively associated with preoperative headache intensity. Headache was more prevalent when the meningioma was located in the area supplied by the ophthalmic trigeminal branch. Compared to preoperative headache levels, an overall reduction was observed one year postoperative, and patients with a larger tumor had a higher headache remission. In parietal and occipital meningiomas and in those with a larger edema, the percentage of the headache remission rate was higher compared to other locations or smaller edema. Multivariable analyses showed an involvement of substance P and prostaglandin E2 in preoperative headache. CONCLUSIONS: The study demonstrates new associations between meningiomas and headache. The postoperative headache outcome in the presented patient sample is encouraging for the performed neurosurgical intervention. These results should be tested in a prospective study that incorporates all patients with meningiomas.

Exercise-based cardiac rehabilitation is associated with a normalization of the heart rate performance curve deflection.

The heart rate (HR) rises with increased power output, whereby in most healthy individuals, the slope of HR levels off with higher intensity. This corresponds to a downward deflection of the heart rate performance curve (HRPC). Conversely, in patients after myocardial infarction, an upward HRPC deflection is frequently observed that is especially pronounced in patients with compromised left ventricular ejection fraction. To investigate whether regular endurance training during cardiac rehabilitation might normalize HRPC, data of 128 male patients were analyzed. All patients performed three exercise tests: at baseline, after 6 weeks, and after 1 year. Ninety-six patients exercised regularly according to guidelines for 1 year (training group, TG), and 32 stopped after 6 weeks (control group, CG). Similarly, upward-deflected HRPCs were observed at baseline and after 6 weeks in both groups. After 1 year, TG patients had less upward-deflected HRPCs compared with CG ones, corresponding to a partial normalization. Greater changes in HRPC deflection were associated with larger improvements in cardiorespiratory fitness. Our results might indicate improved myocardial function due to long-term rehabilitation. Further, HRPC alterations over time should be considered when prescribing exercise intensities using a target HR, as deflection flattening might render the intensity of corresponding exercise insufficient.

Periodontal treatment limits platelet activation in patients with periodontitis-a controlled-randomized intervention trial.

AIM: Periodontitis results in platelet activation and enhanced risk for cardiovascular disease. As it is currently unknown whether periodontal treatment reverses platelet hyper-reactivity, we aimed to investigate the role of periodontal treatment on platelet activation. MATERIALS AND METHODS: In a prospective controlled therapeutic trial, 52 patients were enrolled and randomly selected for periodontal treatment or monitored without treatment for 3 months. Patient blood was analysed by flow cytometry for platelet activation markers and by light transmission aggregometry for platelet aggregation in response to pro-thrombotic stimuli. RESULTS: In this study, platelet activation in the control group aggravated over the observation period of 3 months, whereas patients that underwent periodontal treatment showed unchanged levels of platelet activation, measured by surface expression of CD62P, CD40L, generation of reactive oxygen production, activation of GPIIb/IIIa and fibrinogen binding. Moreover, platelet turnover, measured by platelet RNA content and platelet aggregation in response to collagen, differed significantly between patients that were treated and those who were untreated. CONCLUSIONS: Subgingival debridement reduces the risk of aggravated platelet activation and therefore might potentially diminish subsequent diseases such as cardiovascular disease in periodontal patients.

A reliable technique for ultrasound-guided perineural injection in ulnar neuropathy at the elbow.

INTRODUCTION: Ulnar neuropathy at the elbow (UNE) is a common peripheral compression neuropathy and, in most cases, occurs at 2 sites, the retroepicondylar groove or the cubital tunnel. With regard to a potential therapeutic approach with perineural corticosteroid injection, the aim of this study was to evaluate the distribution of injection fluid applied at a standard site. METHODS: We performed ultrasound-guided (US-guided) perineural injections to the ulnar nerve halfway between the olecranon and the medial epicondyle in 21 upper limbs from 11 non-embalmed cadavers. In anatomic dissection we investigated the spread of injected ink. RESULTS: Ink was successfully injected into the perineural sheath of the ulnar nerve in all 21 cases (cubital tunnel: 21 of 21; retroepicondylar groove: 19 of 21). CONCLUSION: US-guided injection between the olecranon and the medial epicondyle is a feasible and safe method to reach the most common sites of ulnar nerve entrapment. Muscle Nerve 56: 237-241, 2017.

Correlation of TRPA1 RNAscope and Agonist Responses.

The TRPA1 ion channel is a sensitive detector of reactive chemicals, found primarily on sensory neurons. The phenotype exhibited by mice lacking TRPA1 suggests its potential as a target for pharmacological intervention. Antibody-based detection for distribution analysis is a standard technique. In the case of TRPA1, however, there is no antibody with a plausible validation in knockout animals or functional studies, but many that have failed in this regard. To this end we employed the single molecule in situ hybridization technique RNAscope on sensory neurons immediately after detection of calcium responses to the TRPA1 agonist allyl isothiocyanate. There is a clearly positive correlation between TRPA1 calcium imaging and RNAscope detection (R = 0.43), although less than what might have been expected. Thus, the technique of choice should be carefully considered to suit the research question. The marginal correlation between TRPV1 RNAscope and the specific agonist capsaicin indicates that such validation is advisable for every RNAscope target. Given the recent description of a long-awaited TRPA1 reporter mouse, TRPA1 RNAscope detection might still have its use cases, for detection of RNA at particular sites, for example, defined structurally or by other molecular markers.

A successful intervention to improve conceptual knowledge of medical students who rely on memorization of disclosed items.

Background: The mere memorization of isolated facts without the claim of integrating them is detrimental to the desired learning outcomes in medical education. The current study was conducted within an environment where items from summative assessments are regularly disclosed by the university and consequently collected into an item bank that is shared between students. Within this environment, we aimed to quantify 1) to which extent students use disclosed items for their preparation for the summative exam, 2) a putative mismatch between (isolated factual) knowledge regarding distinct questions from the item bank and conceptual knowledge, and 3) to which extent this mismatch can be ameliorated by a project aiming to steer student learning away from the memorization of isolated facts toward the acquisition of conceptual knowledge. Methods: This steering project in the midst of the first semester consisted of the implementation of an oral exam based on selected learning objectives, preceded by two seminars. After their summative exam at the end of semester, 135 students performed a voluntary exam for study purposes. Here, authentic (i.e., presumably preknown) physiology questions taken from the item bank were used to assess students' ability to 1) recognize the correct answer in a multiple choice (MC) question, 2) recall the answer (short answer), or 3) display conceptual knowledge closely corresponding to the question presented in the other formats. Additionally, students received a questionnaire addressing their learning habits and attitudes. Results: The median reported percentage of learning time for the summative exam exclusively spent with this item bank was 80%. The results of the voluntary exam indicate that students frequently recognize and recall correct answers of included items without displaying knowledge of the underlying concept. Compared to recall of the correct answer, the probability of giving a correct answer regarding the corresponding basal physiologic concept was lower by 47 percentage points (p <0.001) for topics not included in the steering project. Regarding topics included in the steering project, this discrepancy was reduced to 25.5% (p <0.001). Conclusion: The results of this study demonstrate the influence of disclosed items on student learning and learning outcomes and suggest that a carefully implemented assessment is able to improve conceptual knowledge in physiology.

TRPA1-dependent and -independent activation by commonly used preservatives.

Background and purpose: Addition of preservatives ensures microbial stability, especially in multidose containers of parenterally administered pharmaceuticals. These compounds can cause side effects, and particularly at the site of application, might elicit or facilitate pain. TRPA1 is a cation channel expressed in peripheral neurons which contributes to pain and inflammation and is sensitive to many irritants. The most commonly used preservatives, in particular with a focus on parenteral formulations, were investigated for their potential to activate TRPA1. Experimental approach: Sixteen preservatives were screened for mediating calcium influx in human TRPA1-transfected HEK293t cells. Untransfected cells served as control, results were further validated in mouse sensory neurons. In addition, proinflammatory mediators serotonin, histamine and prostaglandin E2 were co-administered to probe a potential sensitisation of preservative-induced TRPA1 activation. Key results: Butylparaben, propylparaben, ethylparaben, bronopol, methylparaben, phenylethyl alcohol and phenol induced a TRPA1-dependent calcium influx in transfected HEK293t cells at concentrations used for preservation. Other preservatives increased calcium within the used concentration ranges, but to a similar degree in untransfected controls. Serotonin, histamine, and prostaglandin enhanced TRPA1 activation of phenylethyl alcohol, bronopol, ethylparaben, propylparaben and butylparaben. Conclusion and implications: Systematic screening of common preservatives applied for parenterally administered drugs resulted in identifying several preservatives with substantial TRPA1 channel activation. This activation was enhanced by the addition of proinflammatory meditators. This allows selecting a preservative without TRPA1 activation, particularly in case of pharmaceuticals that could act proinflammatory.

Immunoglobulin G production in COVID-19 - associations with age, outcome, viral persistence, inflammation and pro-thrombotic markers.

Age represents the major risk factor for fatal disease outcome in coronavirus disease (COVID-19) due to age-related changes in immune responses. On the one hand lymphocyte counts continuously decline with advancing age, on the other hand somatic hyper-mutations of B-lymphocytes and levels of class-switched antibodies diminish, resulting in lower neutralizing antibody titers. To date the impact of age on immunoglobulin G (IgG) production in response to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is unknown. Therefore, we investigated the impact of age on the onset of IgG production and its association with outcome, viral persistence, inflammatory and thrombotic markers in consecutive, hospitalized COVID-19 patients admitted to the Clinic Favoriten (Vienna, Austria) between April and October 2020 that fulfilled predefined inclusion criteria. Three different IgGs against SARS-CoV-2 (spike protein S1, nucleocapsid (NC), and the spike protein receptor binding domain (RBD)) were monitored in plasma of 97 patients upon admission and three times within the first week followed by weekly assessment during their entire hospital stay. We analyzed the association of clinical parameters including C-reactive protein (CRP), D-dimer levels and platelet count as well as viral persistence with the onset and concentration of different anti-SARS-CoV-2 specific IgGs. Our data demonstrate that in older individuals anti-SARS-CoV-2 IgG production increases earlier after symptom onset and that deceased patients have the highest amount of antibodies against SARS-CoV-2 whereas intensive care unit (ICU) survivors have the lowest titers. In addition, anti-SARS-CoV-2 IgG concentrations are not associated with curtailed viral infectivity, inflammatory or thrombotic markers, suggesting that not only serological memory but also other adaptive immune responses are involved in successful viral killing and protection against a severe COVID-19 infection.

Medical 3D printing with polyjet technology: effect of material type and printing orientation on printability, surface structure and cytotoxicity.

Due to its high printing resolution and ability to print multiple materials simultaneously, inkjet technology has found wide application in medicine. However, the biological safety of 3D-printed objects is not always guaranteed due to residues of uncured resins or support materials and must therefore be verified. The aim of this study was to evaluate the quality of standard assessment methods for determining the quality and properties of polyjet-printed scaffolds in terms of their dimensional accuracy, surface topography, and cytotoxic potential.Standardized 3D-printed samples were produced in two printing orientations (horizontal or vertical). Printing accuracy and surface roughness was assessed by size measurements, VR-5200 3D optical profilometer dimensional analysis, and scanning electron microscopy. Cytotoxicity tests were performed with a representative cell line (L929) in a comparative laboratory study. Individual experiments were performed with primary cells from clinically relevant tissues and with a Toxdent cytotoxicity assay.Dimensional measurements of printed discs indicated high print accuracy and reproducibility. Print accuracy was highest when specimens were printed in horizontal direction. In all cytotoxicity tests, the estimated mean cell viability was well above 70% (p < 0.0001) regardless of material and printing direction, confirming the low cytotoxicity of the final 3D-printed objects.

Association of Plasma Methylglyoxal Increase after Myocardial Infarction and the Left Ventricular Ejection Fraction.

Background: Preclinical studies suggest that methylglyoxal (MG) increases within the myocardium upon acute myocardial infarction (AMI) and thereafter contributes to adverse postinfarct remodeling. The aims of this study were to test whether MG increases in plasma of humans after AMI and whether this increase is related to the left ventricular ejection fraction (LVEF). Methods: The plasma samples of 37 patients with ST elevation AMI undergoing primary percutaneous coronary intervention (pPCI) acquired in a previously conducted randomized controlled trial testing remote ischemic conditioning (RIC) were analyzed by means of high-performance liquid chromatography. Time courses of the variables were analyzed by means of mixed linear models. Multiple regression analyses served to explore the relationship between MG levels and the LVEF. Results: Compared to the MG levels upon admission due to AMI, the levels were increased 2.4-fold (95% CI, 1.6−3.6) 0.5 h after reperfusion facilitated by pPCI, 2.6-fold (1.7−4.0) after 24 h and largely returned to the baseline after 30 d (1.1-fold, 0.8−1.5). The magnitude of the MG increase was largely independent of that of cardiac necrosis markers. Overall, the highest MG values within 24 h after AMI were associated with the lowest LVEF after 4 d. While markers of myocardial necrosis and stretch quantified within the first 24 h explained 52% of the variance of the LVEF, MG explained additional 23% of the variance (p < 0.001). Conclusions: Considering these observational data, it is plausible that the preclinical finding of MG generation after AMI negatively affecting the LVEF also applies to humans. Inhibition of MG generation or MG scavenging might provide a novel therapeutic strategy to target post-AMI myocardial remodeling and dysfunction.

Tumor cell budding in preoperative biopsies of esophageal and gastroesophageal junction carcinoma independently predicts survival in a grade-dependent manner.

BACKGROUND: Tumor budding is a prognostic factor in biopsies of different tumor entities. Recent evidence suggests that this also applies to esophageal squamous cell carcinomas. Since esophageal cancer is diagnosed by biopsy, the aim of this study was to investigate whether tumor budding in pretherapeutic biopsies of a mixed tumor population of the esophagus and gastroesophageal junction might predict survival. METHODS: In this retrospective analysis, samples of 78 patients were analyzed (55 adenocarcinomas, 17 squamous cell carcinomas, 5 adenosquamous carcinomas, 1 carcinosarcoma). In addition to preoperative biopsies, budding foci in corresponding resection specimens were assessed and related to overall and relapse-free survival. RESULTS: The main finding was that the number of budding foci in preoperative biopsies predicted overall survival independent of the patient's age and disease stage in a grade-specific (P = .009) manner. In patients with grade 2 tumors, each additional budding focus was associated with an increased chance of death by a factor of 1.28 (hazard ratio 95% confidence interval 1.06-1.55, P = .011). There was no significant association between survival and the number of budding foci in patients with grade 3 tumors, and no budding was observed in grade 1 tumors. Budding foci in resection specimens also showed a certain association with survival, but to a lesser degree. CONCLUSION: Budding foci in preoperative biopsies might serve to improve prognostic accuracy in esophageal carcinomas.

Interpretable brain disease classification and relevance-guided deep learning.

Deep neural networks are increasingly used for neurological disease classification by MRI, but the networks' decisions are not easily interpretable by humans. Heat mapping by deep Taylor decomposition revealed that (potentially misleading) image features even outside of the brain tissue are crucial for the classifier's decision. We propose a regularization technique to train convolutional neural network (CNN) classifiers utilizing relevance-guided heat maps calculated online during training. The method was applied using T1-weighted MR images from 128 subjects with Alzheimer's disease (mean age = 71.9 ± 8.5 years) and 290 control subjects (mean age = 71.3 ± 6.4 years). The developed relevance-guided framework achieves higher classification accuracies than conventional CNNs but more importantly, it relies on less but more relevant and physiological plausible voxels within brain tissue. Additionally, preprocessing effects from skull stripping and registration are mitigated. With the interpretability of the decision mechanisms underlying CNNs, these results challenge the notion that unprocessed T1-weighted brain MR images in standard CNNs yield higher classification accuracy in Alzheimer's disease than solely atrophy.

Normothermic blood polarizing versus depolarizing cardioplegia in a porcine model of cardiopulmonary bypass.

OBJECTIVES: We have previously demonstrated beneficial cardiac protection with hypothermic polarizing cardioplegia compared to a hyperkalemic depolarizing cardioplegia. In this study, a porcine model of cardiopulmonary bypass was used to compare the protective effects of normothermic blood-based polarizing and depolarizing cardioplegia during cardiac arrest. METHODS: Thirteen pigs were randomized to receive either normothermic polarizing (n = 8) or depolarizing (n = 5) blood-based cardioplegia. After initiation of cardiopulmonary bypass, normothermic arrest (34°C, 60 min) was followed by 60 min of on-pump and 90 min of off-pump reperfusion. Primary outcome was myocardial injury measured as arterial myocardial creatine kinase concentration. Secondary outcome was haemodynamic function and the energy state of the hearts. RESULTS: During reperfusion, release of myocardial creatine kinase was comparable between groups (P = 0.36). In addition, most haemodynamic parameters showed comparable results between groups, but stroke volume (P = 0.03) was significantly lower in the polarizing group. Adenosine triphosphate levels were significantly (18.41 ± 3.86 vs 22.97 ± 2.73 nmol/mg; P = 0.03) lower in polarizing hearts, and the requirement for noradrenaline administration (P = 0.002) and temporary pacing (6 vs 0; P = 0.02) during reperfusion were significantly higher in polarizing hearts. CONCLUSIONS: Under normothermic conditions, polarizing blood cardioplegia was associated with similar myocardial injury to depolarizing blood cardioplegia. Reduced haemodynamic and metabolic outcome and a higher need for temporary pacing with polarized arrest may be associated with the blood-based dilution of this solution.

Platelet p110ß mediates platelet-leukocyte interaction and curtails bacterial dissemination in pneumococcal pneumonia.

Phosphatidylinositol 3-kinase catalytic subunit p110ß is involved in tumorigenesis and hemostasis. However, it remains unclear if p110ß also regulates platelet-mediated immune responses, which could have important consequences for immune modulation during anti-cancer treatment with p110ß inhibitors. Thus, we investigate how platelet p110ß affects inflammation and infection. Using a mouse model of Streptococcus pneumoniae-induced pneumonia, we find that both platelet-specific p110ß deficiency and pharmacologic inhibition of p110ß with TGX-221 exacerbate disease pathogenesis by preventing platelet-monocyte and neutrophil interactions, diminishing their infiltration and enhancing bacterial dissemination. Platelet p110ß mediates neutrophil phagocytosis of S. pneumoniae in vitro and curtails bacteremia in vivo. Genetic deficiency or inhibition of platelet p110ß also impairs macrophage recruitment in an independent model of sterile peritonitis. Our results demonstrate that platelet p110ß dysfunction exacerbates pulmonary infection by impeding leukocyte functions. Thereby, our findings provide important insights into the immunomodulatory potential of PI3K inhibitors in bacterial infection.