Background: Lymph node staging of ductal adenocarcinoma of the pancreatic head (PDAC) by cross-sectional imaging is limited. The aim of this study was to determine the diagnostic accuracy of expanded criteria in nodal staging in PDAC patients.

Methods: Sixty-six patients with histologically confirmed PDAC that underwent primary surgery were included in this retrospective IRB-approved study. Cross-sectional imaging studies (CT and/or MRI) were evaluated by a radiologist blinded to histopathology. Number and size of lymph nodes were measured (short-axis diameter) and characterized in terms of expanded morphological criteria of border contour (spiculated, lobulated, and indistinct) and texture (homogeneous or inhomogeneous). Sensitivities and specificities were calculated with histopathology as a reference standard.

Results: Forty-eight of 66 patients (80%) had histologically confirmed lymph node metastases (pN+). Sensitivity, specificity, and Youden’s Index for the criterion “size” were 44.2%, 82.4%, and 0.27; for “inhomogeneous signal intensity” 25.6%, 94.1%, and 0.20; and for “border contour” 62.7%, 52.9%, and 0.16, respectively. There was a significant association between the number of visible lymph nodes on preoperative CT and lymph node involvement (pN+, p = 0.031).

Conclusion: Lymph node staging in PDAC is mainly limited due to low sensitivity for detection of metastatic disease. Using expanded morphological criteria instead of size did not improve regional nodal staging due to sensitivity remaining low. Combining specific criteria yields improved sensitivity with specificity and PPV remaining high.

Background: Arterial hypertension is a major risk factor for cardiovascular disease and leads to target organ damage including stroke, heart failure, and kidney disease. About 1.5 billion people worldwide have hypertension, and it is estimated that it causes about 8 million deaths each year. Although there are several drugs available to lower blood pressure (BP), a great proportion of treated patients does not reach recommended treatment targets. Typical antihypertensive drugs target the vessels, the kidneys, and the heart. However, our gut microbiota also influences cardiovascular health, and gut dysbiosis is associated with hypertension. In this study protocol, we investigate the potential BP-lowering effect of a probiotic in patients with grade 1 hypertension.

Methods: This study is an exploratory, randomized, double-blind, placebo-controlled, parallel-group study. One hundred ten patients with grade 1 hypertension (treated or untreated) will be randomized to either the probiotic Vivomixx® or placebo. The primary endpoint is the nocturnal systolic BP measured by ambulatory blood pressure monitoring after 8 weeks adjusted for the baseline value. The secondary endpoints are changes from baseline in nocturnal diastolic BP, antihypertensive medication, fecal microbiome composition, fecal and serum metabolome, immune cell phenotypes, glucose variability after three standardized breakfasts, and health-related quality of life (PROMIS-29). We also assess the safety profile of the intervention.

Discussion: We postulate that various administrated bacteria (Lactobacilli, Bifidobacteria, and Streptococcus thermophilus) convert dietary components into active metabolites that positively affect immune cell function. A reduction of pro-inflammatory immune cell function could promote a BP-lowering effect.

Trial registration: ClinicalTrials.gov NCT03906578. Registered on 08 April 2019

Early life stress is an important factor in later psychopathology, including symptoms of posttraumatic stress disorder (PTSD), depression, and anxiety. The purpose of the present study was to investigate the effect of early life stress on psychiatric symptoms within a sample of Syrian refugees. In this model, the use of cognitive emotion regulation strategies was assessed as a potential mediator of the relationship between early life stress and current symptoms of PTSD, depression, and anxiety. Bootstrap analyses were generated to test the indirect effect of emotion regulation (Cognitive Emotion Regulation Questionnaire) on the relationship between early life stress (Childhood Trauma Questionnaire), PTSD (Harvard Trauma Questionnaire), depressive (PHQ-9) and anxiety (GAD-7) symptoms in eighty-nine Syrian refugees resided in Germany (n = 49) and Jordan (n = 40). The indirect effect of maladaptive strategies was significant between early life stress and psychopathology, whereas the mediation effect of adaptive strategies was not significant. The findings provide an evidence that emotional dysregulation is an underlying factor affecting psychological symptoms in refugees with adverse childhood experiences. These results suggest targeting cognitive emotion regulation in prospective prevention and treatment strategies.

Background/objectives: A few preliminary studies have documented the safety and feasibility of repeated short-term fasting in patients undergoing chemotherapy. However, there is a lack of data from larger randomized trials on the effects of short-term fasting on quality of life, reduction of side effects during chemotherapy, and a possible reduction of tumor progression. Moreover, no data is available on the effectiveness of fasting approaches compared to so-called healthy diets. We aim to investigate whether the potentially beneficial effects of short-term fasting can be confirmed in a larger randomized trial and can compare favorably to a plant-based wholefood diet.

Methods: This is a multicenter, randomized, controlled, two-armed interventional study with a parallel group assignment. One hundred fifty patients, including 120 breast cancer patients and 30 patients with ovarian cancer, are to be randomized to one of two nutritional interventions accompanying chemotherapy: (1) repeated short-term fasting with a maximum energy supply of 350–400 kcal on fasting days or (2) repeated short-term normocaloric plant-based diet with restriction of refined carbohydrates. The primary outcome is disease-related quality of life, as assessed by the functional assessment of the chronic illness therapy measurement system. Secondary outcomes include changes in the Hospital Anxiety and Depression Score and as well as frequency and severity of chemotherapy-induced side effects based on the Common Terminology Criteria of Adverse Events. Explorative analysis in a subpopulation will compare histological complete remissions in patients with neoadjuvant treatments.

Discussion/planned outcomes: Preclinical data and a small number of clinical studies suggest that repeated short-term fasting may reduce the side effects of chemotherapy, enhance quality of life, and eventually slow down tumor progression. Experimental research suggests that the effects of fasting may partly be caused by the restriction of animal protein and refined carbohydrates. This study is the first confirmatory, randomized controlled, clinical study, comparing the effects of short-term fasting to a short-term, plant-based, low-sugar diet during chemotherapy on quality of life and histological tumor remission.

Trial registration. ClinicalTrials.gov NCT03162289. Registered on 22 May 2017

Stress-induced disturbances of brain homeostasis and neuroinflammation have been implicated in the pathophysiology of mood disorders. In major depressive disorder (MDD), elevated levels of proinflammatory cytokines and chemokines can be found in peripheral blood, but very little is known about the changes that occur directly in the brain. Microglia are the primary immune effector cells of the central nervous system and exquisitely sensitive to changes in the brain microenvironment. Here, we performed the first single-cell analysis of microglia from four different post-mortem brain regions (frontal lobe, temporal lobe, thalamus, and subventricular zone) of medicated individuals with MDD compared to controls. We found no evidence for the induction of inflammation-associated molecules, such as CD11b, CD45, CCL2, IL-1β, IL-6, TNF, MIP-1β (CCL4), IL-10, and even decreased expression of HLA-DR and CD68 in microglia from MDD cases. In contrast, we detected increased levels of the homeostatic proteins P2Y12 receptor, TMEM119 and CCR5 (CD195) in microglia from all brain regions of individuals with MDD. We also identified enrichment of non-inflammatory CD206hi macrophages in the brains of MDD cases. In sum, our results suggest enhanced homeostatic functions of microglia in MDD.

Theory predicts that self-sustained oscillations require robust delays and nonlinearities (ultrasensitivity). Delayed negative feedback loops with switch-like inhibition of transcription constitute the core of eukaryotic circadian clocks. The kinetics of core clock proteins such as PER2 in mammals and FRQ in Neurospora crassa is governed by multiple phosphorylations. We investigate how multiple, slow and random phosphorylations control delay and molecular switches. We model phosphorylations of intrinsically disordered clock proteins (IDPs) using conceptual models of sequential and distributive phosphorylations. Our models help to understand the underlying mechanisms leading to delays and ultrasensitivity. The model shows temporal and steady state switches for the free kinase and the phosphoprotein. We show that random phosphorylations and sequestration mechanisms allow high Hill coefficients required for self-sustained oscillations.

Long-duration Antarctic expeditions are characterized by isolation, confinement, and extreme environments. Here we describe the time course of cardiac autonomic modulation assessed by heart rate variability (HRV) during 14-month expeditions at the German Neumayer III station in Antarctica. Heart rate recordings were acquired in supine position in the morning at rest once before the expedition (baseline) and monthly during the expedition from February to October. The total set comprised twenty-five healthy crewmembers (n = 15 men, 38 ± 6 yrs, n = 10 women, 32 ± 6 yrs, mean ± SD). High frequency (HF) power and the ratio of low to high frequency power (LF/HF) were used as indices of vagal modulation and sympathovagal balance. HF power adjusted for baseline differences decreased significantly during the expedition, indicating a gradual reduction in vagal tone. LF/HF powers ratio progressively shifted toward a sympathetic predominance reaching statistical significance in the final trimester (August to October) relative to the first trimester (February to April). This effect was particularly pronounced in women. The depression of cardio-vagal tone and the shift toward a sympathetic predominance observed throughout the overwintering suggest a long-term cardiac autonomic modulation in response to isolation and confinement during Antartic overwintering.

Kambô, the secretion of the Amazonian Giant Leaf Frog (Phyllomedusa bicolor) contains a plethora of bioactive peptides and was originally used by indigenous communities from the Amazon basin as medicine for improving hunting capacities. In the last 20 years, Kambô has spread to Western urban healing circles. To date it is still controversial whether the acute effects of Kambô include alterations of consciousness similar to known psychoactive substance like serotonergic psychedelics. Here we retrospectively assessed psychological effects of Kambô in a sample of anonymous users (n = 22, mean age: 39 years, ± 8.5; 45.5% female), administering standardized questionnaires for the assessment of altered states of consciousness (ASC), including the Altered States of Consciousness Rating Scale, the Phenomenology of Consciousness Inventory (PCI), the Mystical Experience Questionnaire (MEQ), the Challenging Experience Questionnaire (CEQ) for acute effects and the Persisting Effects Questionnaire (PEQ) and a scale assessing connectedness for subacute effects. The intensity of retrospectively reported acute psychological effects remained on a mild to moderate level, with no psychedelic-type distortions of perception or thinking. Conversely, persisting effects were predominantly described as positive and pleasant, revealing high scores on measures of personal and spiritual significance.

In the search for anti-renal autoreactivity in human lupus nephritis, we stimulated blood-derived CD4+ T cells from patients with systemic lupus erythematosus with various kidney lysates. Although only minor responses were detectable, these experiments led to the development of a search algorithm that combined autoantibody association with human lupus nephritis and target gene expression in inflamed kidneys. Applying this algorithm, five potential T cell antigens were identified. Blood-derived CD4+ T cells were then stimulated with these antigens. The cells were magnetically enriched prior to measurement with flow cytometry to facilitate the detection of very rare autoantigen-specific cells. The detected responses were dominated by IFN-γ-producing CD4+ T cells. Additionally, IL-10-producing CD4+ T cells were found. In a next step, T cell reactivity to each single antigen was independently evaluated with T cell libraries and [3H]-thymidine incorporation assays. Here, Vimentin and Annexin A2 were identified as the main T cell targets. Finally, Vimentin reactive T cells were also found in the urine of three patients with active disease. Overall, our experiments show that antigen-specific CD4+ T cells targeting renally expressed antigens arise in human lupus nephritis and correlate with disease activity and are mainly of the Th1 subset.

Traditional palaeontological techniques of disease characterisation are limited to the analysis of osseous fossils, requiring several lines of evidence to support diagnoses. This study presents a novel stepwise concept for comprehensive diagnosis of pathologies in fossils by computed tomography imaging for morphological assessment combined with likelihood estimation based on systematic phylogenetic disease bracketing. This approach was applied to characterise pathologies of the left fibula and fused caudal vertebrae of the non-avian dinosaur Tyrannosaurus rex. Initial morphological assessment narrowed the differential diagnosis to neoplasia or infection. Subsequent data review from phylogenetically closely related species at the clade level revealed neoplasia rates as low as 3.1% and 1.8%, while infectious-disease rates were 32.0% and 53.9% in extant dinosaurs (birds) and non-avian reptiles, respectively. Furthermore, the survey of literature revealed that within the phylogenetic disease bracket the oldest case of bone infection (osteomyelitis) was identified in the mandible of a 275-million-year-old captorhinid eureptile Labidosaurus. These findings demonstrate low probability of a neoplastic aetiology of the examined pathologies in the Tyrannosaurus rex and in turn, suggest that they correspond to multiple foci of osteomyelitis.

Radiographs are the clinical first line imaging modality for evaluating hip morphology and pathology. MRI offers additional information and is the method of choice to evaluate soft tissue, bone marrow and preradiographic signs of osteoarthritis. Radiographs are used to measure the most morphometric parameters. The aim of this study was to compare susceptibility weighted MRI (SWMR) with radiographs to evaluate hip morphology. 40 Patients were examined with standard MR-sequences, coronal SWMR and radiographs in anteroposterior pelvic view. Coronal maximum intensity projection (MIP) images of both hips were automatically reconstructed on SWMR and T1weighted images. Sharp´s angle, Tönnis angle, lateral center–edge angle of Wiberg and caput-collum-diaphyseal angle were measured on coronal SWMR MIP-images, T1weighted MIP-images and radiographs. Measurements were compared by linear regression analysis and Bland-Altmann Plots, using radiographs as reference standard. Additionally, a ratio between the signal intensity of muscles and bone on SWMR and T1weighted MIP-images was calculated and compared between these two sequences. SWMR enables the reliable assessment of Sharp´s angle (SWMR: R2 = 0.80; T1weighted: R2 = 0.37), Tönnis angle (SWMR: R2 = 0.86; T1weighted: not measurable), lateral center–edge angle of Wiberg (SWMR: R2 = 0.88; T1weighted: R2 = 0.40) and caput-collum-diaphyseal angle (SWMR: R2 = 0.38; T1weighted: R2 = 0.18) compared to radiographs with a higher accuracy than conventional MR imaging. The ratio between the intensity of muscles and bone was significant higher on SWMR (2.00 and 2.02) than on T1weighted MIP-images (1.6 and 1.42; p < 0.001).

Background: Although considered complex and challenging, esophagectomy remains the best potentially curable treatment option for resectable esophageal and esophagogastric junction (AEG) carcinomas. The optimal surgical approach and technique as well as the extent of lymphadenectomy, particularly regarding quality of life and short- and long-term outcomes, are still a matter of debate. To lower perioperative morbidity, we combined the advantages of a one-cavity approach with extended lymph node dissection (usually achieved by only a two-cavity approach) and developed a modified single-cavity transhiatal approach for esophagectomy.

Methods: The aim of this study was to evaluate the outcome of an extended transhiatal esophageal resection with radical bilateral mediastinal en bloc lymphadenectomy (eTHE). A prospective database of 166 patients with resectable cancers of the esophagus (including adenocarcinomas of the AEG types I and II) were analyzed. Patients were treated between 2001 and 2017 with eTHE at a tertiary care university center. Relevant patient characteristics and outcome parameters were collected and analyzed. The primary endpoint was 5-year overall survival. Secondary outcomes included short-term morbidity, mortality, radicalness of en bloc resection and oncologic efficacy.

Results: The overall survival rates at 1, 3 and 5 years were 84, 70, and 61.0%, respectively. The in-hospital mortality rate after eTHE was 1.2%. Complications with a Clavien-Dindo score of III/IV occurred in 31 cases (18.6%). A total of 25 patients (15.1%) had a major pulmonary complication. The median hospital stay was 17 days (interquartile range (IQR) 12). Most patients (n = 144; 86.7%) received neoadjuvant treatment. The median number of lymph nodes resected was 25 (IQR 17). The R0 resection rate was 97%.

Conclusion: In patients with esophageal cancer, eTHE without thoracotomy resulted in excellent long-term survival, an above average number of resected lymph nodes and an acceptable postoperative morbidity and mortality.

Objective: Critical illness polyneuropathy (CIP) is a common complication of severe systemic illness treated in intensive care medicine. Ischemic stroke leads to an acute critical injury of the brain with hemiparesis, immunosuppression and subsequent infections, all of which require extended medical treatment. Stroke-induced sarcopenia further contributes to poor rehabilitation and is characterized by muscle wasting and denervation in the paralytic, but also the unaffected limbs. Therefore, we asked whether stroke leads to an additional CIP-like neurodegeneration.

Results: Focal brain ischemia was induced in adult mice by 60-min middle cerebral artery occlusion (MCAo) following reperfusion and led to functional deficits and marked hemispheric brain atrophy. Nerve conduction function and muscle potentials were measured in the ipsilateral sciatic nerve and gastrocnemius and quadriceps muscle with electroneurography/-myography on days 10, 22, 44 after stroke. An additional crush-injury to the sciatic nerve was included in two sham mice as positive control (sham +). We found no differences in nerve conduction function nor spontaneous electromyographic activity between MCAo and sham animals. Sham + mice developed marked reduction of the motor action potential amplitudes and conduction velocities with pathologic spontaneous activity. In conclusion, we found no peripheral nerve dysfunction/degeneration as signs of a CIP-like phenotype after MCAo.

The use of contextual information is an important capability to facilitate language comprehension. This can be shown by studying behavioral and neurophysiological measures of accelerated word recognition when semantically or phonemically related information is provided in advance, resulting in accompanying attenuation of the respective event-related potential, i.e. the N400 effect. Against the background of age-dependent changes in a broad variety of lexical capacities, we aimed to study whether word priming is accomplished differently in elderly compared to young persons. 19 young (29.9 ± 5.6 years) and 15 older (69.0 ± 7.2 years) healthy adults participated in a primed lexical decision task that required the classification of target stimuli (words or pseudo-words) following related or unrelated prime words. We assessed reaction time, task accuracy and N400 responses. Acceleration of word recognition by semantic and phonemic priming was significant in both groups, but resulted in overall larger priming effects in the older participants. Compared with young adults, the older participants were slower and less accurate in responding to unrelated word-pairs. The expected N400 effect was smaller in older than young adults, particularly during phonemic word and pseudo-word priming, with a rather similar N400 amplitude reduction by semantic relatedness. The observed pattern of results is consistent with preserved or even enhanced lexical context sensitivity in older compared to young adults. This, however, appears to involve compensatory cognitive strategies with higher lexical processing costs during phonological processing in particular, suggested by a reduced N400 effect in the elderly.

To investigate the imaging performance of an elastin-specific molecular magnetic resonance imaging (MRI) probe with respect to the extracellular matrix (ECM) in an experimental hepatic cancer model. Twelve rabbits with hepatic VX2 tumors were examined using 3 T MRI 14, 21, and 28 days after tumor implantation for two subsequent days (gadobutrol, day 1; elastin-specific probe, day 2). The relative enhancement (RE) of segmented tumor regions (central and margin) and the peritumoral matrix was calculated using pre-contrast and delayed-phase T1w sequences. MRI measurements were correlated to histopathology and element-specific and spatially resolved mass spectrometry (MS). Mixed-model analysis was performed to assess the performance of the elastin-specific probe. In comparison to gadobutrol, the elastin probe showed significantly stronger RE, which was pronounced in the tumor margin (day 14–28: P ≤ 0.007). In addition, the elastin probe was superior in discriminating between tumor regions (χ2(4) = 65.87; P < 0.001). MRI-based measurements of the elastin probe significantly correlated with the ex vivo elastinstain (R = .84; P <0 .001) and absolute gadolinium concentrations (ICP-MS: R = .73, P <0 .01). LA-ICP-MS imaging confirmed the colocalization of the elastin-specific probe with elastic fibers. Elastin-specific molecular MRI is superior to non-specific gadolinium-based contrast agents in imaging the ECM of hepatic tumors and the peritumoral tissue.

Nanoindentation technology with high spatial resolution and force sensitivity is widely used to measure the mechanical properties of hard biomaterials and tissues. However, its reliability to analyze soft biomaterials and organs has not been tested. Here, we evaluated the utility of nanoindentation to measure the passive mechanical properties of soft biological specimen. Kidney, liver, spleen and uterus samples were harvested from C57BL/6 N mice. We assessed test–retest repeatability in biological specimen and hydrogel controls using Bland–Altman diagrams, intraclass correlation coefficients (ICCs) and the within-subject coefficients of variation (COVs). The results were calculated using Hertzian, JKR and Oliver & Pharr models. Similar to hydrogels, Bland–Altman plots of all biological specimen showed good reliability in stiffness test and retest examinations. In gels, ICCs were larger than 0.8 and COVs were smaller than 15% in all three models. In kidney, liver, spleen and uterus, ICCs were consistently larger than 0.8 only in the Hertzian model but not in the JKR and Oliver & Pharr models. Similarly, COVs were consistently smaller than 15% in kidney, liver, spleen and uterus only in the Hertzian model but not in the other models. We conclude that nanoindentation technology is feasible in detecting the stiffness of kidney, liver, spleen and uterus. The Hertzian model is the preferred method to provide reliable results on ex vivo organ stiffness of the biological specimen under study.

In patients with aortic coarctation it would be desirable to assess pressure gradients as well as information about blood flow profiles at rest and during exercise. We aimed to assess the hemodynamic responses to physical exercise by combining MRI-ergometry with computational fluid dynamics (CFD). MRI was performed on 20 patients with aortic coarctation (13 men, 7 women, mean age 21.5 ± 13.7 years) at rest and during ergometry. Peak systolic pressure gradients, wall shear stress (WSS), secondary flow degree (SFD) and normalized flow displacement (NFD) were calculated using CFD. Stroke volume was determined based on MRI. On average, the pressure gradient was 18.0 ± 16.6 mmHg at rest and increased to 28.5 ± 22.6 mmHg (p < 0.001) during exercise. A significant increase in cardiac index was observed (p < 0.001), which was mainly driven by an increase in heart rate (p < 0.001). WSS significantly increased during exercise (p = 0.006), whereas SFD and NFD remained unchanged. The combination of MRI-ergometry with CFD allows assessing pressure gradients as well as flow profiles during physical exercise. This concept has the potential to serve as an alternative to cardiac catheterization with pharmacological stress testing and provides hemodynamic information valuable for studying the pathophysiology of aortic coarctation.

Glucose hypometabolism potentially contributes to Alzheimer’s disease (AD) and might even represent an underlying mechanism. Here, we investigate the relationship of diet-induced metabolic stress and AD as well as the therapeutic potential of chia seeds as a modulator of glucose metabolism in the APP23 mouse model. 4–6 (pre-plaque stage, PRE) and 28–32 (advanced-plaque stage, ADV) weeks old APP23 and wild type mice received pretreatment for 12 weeks with either sucrose-rich (SRD) or control diet, followed by 8 weeks of chia seed supplementation. Although ADV APP23 mice generally showed functioning glucose homeostasis, they were more prone to SRD-induced glucose intolerance. This was accompanied by elevated corticosterone levels and mild insulin insensitivity. Chia seeds improved spatial learning deficits but not impaired cognitive flexibility, potentially mediated by amelioration of glucose tolerance, attenuation of corticosterone levels and reversal of SRD-induced elevation of pro-inflammatory cytokine levels. Since cognitive symptoms and plaque load were not aggravated by SRD-induced metabolic stress, despite enhanced neuroinflammation in the PRE group, we conclude that impairments of glucose metabolism do not represent an underlying mechanism of AD in this mouse model. Nevertheless, chia seeds might provide therapeutic potential in AD as shown by the amelioration of cognitive symptoms.