Publications

Effects of Bile Duct Ligation and Ghrelin Treatment on the Colonic Barrier and Microbiome of Mice.

Abstract (Expand)

INTRODUCTION: Cholestatic liver disease (CLD) is associated with intestinal barrier dysfunction. The peptide hormone ghrelin may exert both hepatoprotective and barrier-strengthening effects. Here, we … have evaluated these effects under the conditions of experimental cholestasis. METHODS: C57BL/6J mice with bile duct ligation (BDL) or sham surgery were treated with ghrelin or solvent for 9 days. Liver injury was assessed by histological and laboratory analyses. Paracellular macromolecule permeability and transmural electrical resistance (TMER) of colonic tissues were measured using a Ussing chamber. Expression of tight junction (TJ) genes was quantified by real-time PCR. Amplicon metagenomic sequencing was employed to analyze bacterial 16S rRNA from colonic stool samples. RESULTS: Mice with BDL exhibited weight loss and signs of severe liver injury. These changes were unaffected by ghrelin treatment. FITC-4-kDa-dextran flux was increased and TMER decreased after BDL. Treatment with ghrelin tended to reduce these effects. Furthermore, application of ghrelin was associated with higher mRNA levels of claudin-4, occludin, and ZO-1 in colonic tissues of mice with BDL. Reduced alpha-diversity of the microbiome was observed in solvent-treated mice with BDL but not in ghrelin-treated animals. CONCLUSION: Ghrelin treatment did not improve weight loss and liver damage but increased gene expression of colonic TJ proteins and restored the alpha-diversity of the microbiome. Since protective effects of ghrelin might be masked by the severity of the model, we suggest follow-up studies in models of milder CLD.

Authors: L. Ehlers, L. A. W. Netz, J. Reiner, P. Berlin, K. Bannert, M. Bastian, D. Zechner, G. Lamprecht, R. Jaster

Date Published: 4th Nov 2022

Publication Type: Journal

K(v)7 and K(ir)6 Channels Shape the Slow AHP in Mouse Dentate Gyrus Granule Cells and Control Burst-like Firing Behavior.

Abstract (Expand)

The slow afterhyperpolarizing potential (sAHP) can silence a neuron for hundreds of milliseconds. Thereby, the sAHP determines the discharge behavior of many types of neurons. In dentate granule cells … (DGCs), serving as a filter into the hippocampal network, mostly tonic or adapting discharge properties have been described. As under standard whole-cell recording conditions the sAHP is inhibited, we reevaluated the intrinsic functional phenotype of DGCs and the conductances underlying the sAHP, using gramicidine-perforated patch-clamp technique. We found that in 97/113 (86%) of the DGCs, a burst of action potentials (APs) to excitation ended by a large sAHP, despite continued depolarization. This result suggests that burst-like firing is the default functional phenotype of DGCs and that sAHPs are important for it. Indeed, burst-like firing DGCs showed a significantly higher sAHP-current (I(sAHP)) amplitude compared to spike-frequency adapting cells (16/113 = 14%). The I(sAHP) was mediated by K(v)7 and K(ir)6 channels by pharmacological inhibition using XE991 and tolbutamide, although heterogeneously among DGCs. The percent inhibition of I(sAHP) by these compounds also correlated with the AP number and AP burst length. Application of 100 microM nickel after XE991 and tolbutamide detected a third conductance contributing to burst-like firing and the sAHP, most likely mediated by T-type calcium channels. Lastly, medial perforant path-dentate gyrus long-term potentiation was amplified by XE991 and tolbutamide. In conclusion, the sAHP shapes intrinsic burst-like firing which, under physiological circumstances, could be controlled via cholinergic afferents and ATP metabolism.

Authors: D. Laker, F. Tolle, M. Stegen, M. Heerdegen, R. Kohling, T. Kirschstein, J. Wolfart

Date Published: 15th Jul 2021

Publication Type: Journal

Persistent Kv7.2/7.3 downregulation in the rat pilocarpine model of mesial temporal lobe epilepsy.

Abstract (Expand)

Mutations within the Kv7.2 and Kv7.3 genes are well described causes for genetic childhood epilepsies. Knowledge on these channels in acquired focal epilepsy, especially in mesial temporal lobe epilepsy … (mTLE), however, is scarce. Here, we used the rat pilocarpine model of drug-resistant mTLE to elucidate both expression and function by quantitative polymerase-chain reaction, immunohistochemistry, and electrophysiology, respectively. We found transcriptional downregulation of Kv7.2 and Kv7.3 as well as reduced Kv7.2 expression in epileptic CA1. Consequences were altered synaptic transmission, hyperexcitability which consisted of epileptiform afterpotentials, and increased susceptibility to acute GABAergic disinhibition. Importantly, blocking Kv7 channels with XE991 increased hyperexcitability in control tissue, but not in chronically epileptic tissue suggesting that the Kv7 deficit had precluded XE991 effects in this tissue. Conversely, XE991 resulted in comparable reduction of the paired-pulse ratio in both experimental groups implying preserved presynaptic Kv7.2 function of Schaffer collateral terminals. Consistent with Kv7.2/7.3 downregulation, the Kv7.3 channel opener beta-hydroxybutyrate failed to mitigate hyperexcitability. Our findings demonstrate that compromised Kv7 function is not only relevant in genetic epilepsy, but also in acquired focal epilepsy. Moreover, they help explain reduced anti-seizure efficacy of Kv7 channel openers in drug-resistant epilepsy.

Authors: S. Muller, M. Kartheus, E. Hendinger, D. C. Hubner, E. Schnell, S. Rackow, A. Bertsche, R. Kohling, T. Kirschstein

Date Published: 23rd Feb 2024

Publication Type: Journal

Oral administration of the casein kinase 2 inhibitor TBB leads to persistent K(Ca)2.2 channel up-regulation in the epileptic CA1 area and cortex, but lacks anti-seizure efficacy in the pilocarpine epilepsy model.

Abstract (Expand)

Temporal lobe epilepsy (TLE) is the most common epileptic syndrome in adults and often presents with seizures that prove intractable with currently available anticonvulsants. Thus, there is still a … need for new anti-seizure drugs in this condition. Recently, we found that the casein kinase 2 inhibitor 4,5,6,7-tetrabromotriazole (TBB) prevented the emergence of spontaneous epileptic discharges in an acute in vitro epilepsy model. This prompted us to study the anti-seizure effects of TBB in the pilocarpine model of chronic epilepsy in vivo. To this end, we performed long-term video-EEG monitoring lasting 78-167 days of nine chronically epileptic rats and obtained a baseline seizure rate of 3.3 +/- 1.3 per day (baseline of 27-80 days). We found a significant age effect with more pronounced seizure rates in older animals as compared to younger ones. However, the seizure rate increased to 6.3 +/- 2.2 per day during the oral TBB administration (treatment period of 21-50 days), and following discontinuation of TBB, this rate remained stable with 5.2 +/- 1.4 seizures per day (follow-up of 30-55 days). After completing the video-EEG during the follow-up the hippocampal tissue was prepared and studied for the expression of the Ca(2+)-activated K(+) channel K(Ca)2.2. We found a significant up-regulation of K(Ca)2.2 in the epileptic CA1 region and in the neocortex, but in no other hippocampal subfield. Hence, our findings indicate that oral administration of TBB leads to persistent up-regulation of K(Ca)2.2 in the epileptic CA1 subfield and in the neocortex, but lacks anti-seizure efficacy in the pilocarpine epilepsy model.

Authors: R. Bajorat, K. Porath, J. Kuhn, E. Gossla, D. Goerss, T. Sellmann, R. Kohling, T. Kirschstein

Date Published: 17th Sep 2018

Publication Type: Journal

Physical exercise recommendations for patients with chronic myeloid leukemia based on individual preferences identified in a large international patient survey study of the East German Study Group for Hematology and Oncology (OSHO #97).

Abstract (Expand)

BACKGROUND: Tyrosine kinase inhibitors (TKIs) have significantly lowered mortality of chronic myeloid leukemia (CML) patients adjusting life expectancy to that of the standard population. However, CML … and its treatment with TKIs causes a high disease burden. Physical exercise (PE) could be a non-pharmacological approach to reducing these and improving quality of life. PURPOSE: The aim of this study was to determine the individual disease burden as well as PE preferences of CML patients and to deduce thereof specific PE recommendations. METHODS: This multicenter survey was conducted in cooperation with the LeukaNET/Leukemia-patient network including CML patients aged >/=18 years (German Registry of Clinical Trials, DRKS00023698). The severity of selected symptoms was assessed using the adapted Myeloproliferative Neoplasms Symptom Assessment Form: 0 (absent), 1-30 (mild), 31-70 (moderate), or 71-100 (severe). Information about patients' PE needs and preferences depending on their motivation was recorded. RESULTS: A total of 212 questionnaires were analyzed (52% female, median age 54 years). The prevalence of moderate-to-severe symptoms was 49% for fatigue, 40% for musculoskeletal pain, and 37% for concentration problems. Other commonly reported symptoms included skin reactions (42%) and weight gain (24%). The proportion of overweight/obese patients was 52%. Half of all respondents requested more information regarding PE. Patients with CML preferred individual training (82%), located outdoors (71%), at home (47%), or in an indoor swimming pool (31%). Regarding the training frequency, sports-inactive patients preferred a frequency of 1-2 training sessions per week, whereas sports-active patients preferred 3-4 sessions per week (p <0.001). Sports-inactive patients preferred a training time of 15-45 minutes, while sports-active patients preferred 30-60 minutes (p = 0.002). Subsequently, PE recommendations were developed for patients with CML. Combined resistance and endurance training (moderate intensity twice per week for 30 minutes) was recommended for beginners. Obese patients should prioritize joint-relieving sports. To reduce the risk of skin reactions, direct sunlight and possibly water sports should be avoided, and UV protection should be used. CONCLUSION: Counseling and motivation of CML patients to be physically active should be part of the standard of care as well as support for implementation.

Authors: L. Hollenbach, J. Rogahn, P. le Coutre, S. Schulze, L. O. Muegge, J. Geissler, J. Gruen, C. Junghanss, S. Felser

Date Published: 7th Mar 2024

Publication Type: Journal

Physical exercise recommendations for patients with polycythemia vera based on preferences identified in a large international patient survey study of the East German Study Group for Hematology and Oncology (OSHO #97).

Abstract (Expand)

BACKGROUND: Exercise therapy during cancer treatment reduces symptom burden and improves quality of life (QoL). Polycythemia vera (PV) is a myeloproliferative neoplasia associated with good overall … survival (up to decades) but a significant symptom burden, including thromboembolic events and dysesthesias. There are no specific exercise recommendations for patients with PV. Thus, we aimed to determine the exercise preferences of patients with PV and to derive specific recommendations based on the most commonly reported symptoms. METHODS: This multicenter survey included patients with PV >/=18 years old. Demographic, clinical, and disease burden data were collected. The severity of selected symptoms was assessed using the adapted Myeloproliferative Neoplasms Symptom Assessment Form: 0 (absent), 1-30 (mild), 31-70 (moderate), or 71-100 (severe). The patients' information needs about physical activity (PA) and exercise preferences were recorded depending on their motivation and analyzed with regard to demographic aspects. RESULTS: The sample comprised 182 patients (68% female, 61 +/- 12 years). The prevalence of moderate-to-severe symptoms was 60% for fatigue, 44% for concentration problems, and 35% for bone/muscle pain. Other commonly reported symptoms included skin reactions (49%), splenomegaly (35%), and increased bleeding tendency (28%). Overall, 67% of respondents requested more information regarding PA. Patients with PV preferred individual training (79%) located outdoors (79%) or at home (56%). Regarding the amount of training, sports-inactive patients preferred a frequency of 1-2 times/week and session durations of 15-45 min, whereas sports-active patients preferred 3-4 times/week and 30-60 min (p < 0.001). Higher sport-inactiveness was observed in patients with lower educational level compared to patients with higher educational level (69% vs. 50%, p = 0.021). For beginners, combined resistance-endurance (circuit) training two times/week, which can be performed outdoors or at home, should be recommended. In the case of splenomegaly or bleeding symptoms, exercises with a low injury risk should be chosen. CONCLUSION: PA is important for patients with PV; therefore, counseling should be integrated into the treatment plan. Specifically, patients with low educational level should be addressed. Prospective studies are warranted to evaluate the effects of the novel exercise recommendations.

Authors: S. Felser, J. Rogahn, L. Hollenbach, J. Gruen, P. le Coutre, H. K. Al-Ali, S. Schulze, L. O. Muegge, V. Kraze-Kliebhahn, C. Junghanss

Date Published: 4th Oct 2023

Publication Type: Journal

Anxieties, age and motivation influence physical activity in patients with myeloproliferative neoplasms - a multicenter survey from the East German study group for hematology and oncology (OSHO #97).

Abstract (Expand)

BACKGROUND: Physical activity (PA) is a non-pharmacological approach to alleviate symptom burden and improve health-related quality of life (HrQoL) in cancer patients (pts). Whether pts with … myeloproliferative neoplasms (MPN) PA behavior changes due to symptom burden and/or knowledge of the putative beneficial effects of PA has not yet been investigated. METHODS: We performed a large questionnaire study in MPN pts. Self-reported PA behavior and potential influencing factors of 634 MPN pts were analyzed. Questionnaires were used to assess demographics, anxiety, severity of symptoms, HrQoL, current level of everyday and sports activities, and the level of information regarding the importance/possibilities of PA. According to their PA, the pts were assigned to the three groups: "inactive", "non-targeted active", and "sporty active" and compared with each other. RESULTS: Key findings are that in 73% of the pts, the disease had an impact on PA, with 30% of pts reducing their PA. The prevalence of anxieties (e.g., occurrence of thrombosis and bleeding) regarding PA was 45%. Sporty active pts had a lower symptom burden and better HrQoL (p </= 0.001) compared to the other groups. Inactive pts were significantly older and had a higher body mass index than sporty active pts. Inactive and non-targeted active pts felt less informed about the importance/possibilities of PA (p = 0.002). CONCLUSION: Our results suggest that especially older and non-sporty MPN pts could benefit from motivational as well as disease-specific PA information. This study was registered at the German Registry of Clinical Trials, DRKS00023698.

Authors: S. Felser, J. Rogahn, P. le Coutre, H. K. Al-Ali, S. Schulze, L. O. Muegge, J. Gruen, J. Geissler, V. Kraze-Kliebhahn, C. Junghanss

Date Published: 23rd Jan 2023

Publication Type: Journal

Association Between Cancer-Related Fatigue and Falls in Patients With Myeloproliferative Neoplasms: Results of a Multicenter Cross-Sectional Survey From the East German Study Group for Hematology and Oncology (OSHO #97).

Abstract (Expand)

OBJECTIVE: This study retrospectively examined the association between cancer-related fatigue (CrF) and the number of falls during the last 12 months in patients with myeloproliferative neoplasms (MPNs). … METHODS: A multicenter, 1-time anonymous survey was conducted using analog and digital questionnaires. Sex-stratified multinomial logistic regression analysis was applied to investigate the association between CrF and number of falls. All analyses were adjusted for age, school education, body mass index, MPN subtype, and quality of life. RESULTS: The final sample comprised 688 patients (mean age 57.4 +/- 13.8, 62.4% women). The fall rate was 16.2% in women and 12.2% in men (P = .153). There were no differences between women and men in terms of CrF between individuals with more than 1 fall, whereas women with 1 fall had a higher CrF compared to those without a fall (RRR = 1.019; 95% CI [1.002-1.039]), respectively. CONCLUSION: CrF increases the risk of falls in women with MPN. Physicians should evaluate and manage CrF symptoms and implement fall prevention strategies for those who are at increased risk. Further research is needed to better understand the effects of CrF on gait performance and associated fall risk.

Authors: S. Felser, M. Gube, J. Gruen, P. I. Coutre, S. Schulze, L. O. Muegge, C. Junghanss, S. Ulbricht

Date Published: 21st Dec 2022

Publication Type: Journal

Quantification of Video Sequences of the Microcirculation: A Comparison Between Automated Analysis Using Analysis Manager and Manual Analysis Using Capillary Mapper.

Abstract (Expand)

OBJECTIVE: Microcirculatory disturbances can contribute to organ dysfunction in patients undergoing major surgeries and critical illness. Incident dark field imaging (CytoCam, Braedius Medical BV, … Huizen, Netherlands) provides direct visualization of the microcirculation. To utilize this method in daily clinical practice, automated image analysis is essential. This study aims to compare the automated analysis of recorded microcirculation video sequences using CytoCamTools V2 Analysis Manager (Braedius Medical BV) with established manual analysis using Capillary Mapper (Version 1.4.5, University Hospital Munster, Germany) as reference method. METHODS: Sublingual microcirculation video sequences were recorded in patients undergoing laparotomy at four time points (before surgery, 2 and 6 h after surgery, and on the first postoperative day) using incident dark field imaging. Agreement between automated and manual analysis of total vessel density (TVD), perfused vessel density (PVD), and proportion of perfused vessels (PPV) was compared using intraclass correlation (ICC) and Bland-Altman method. RESULTS: A total of 336 videos from 30 patients were analyzed. The ICC between the two measurement methods was 0.13 for TVD, 0.14 for PVD, and 0.16 for PPV. Bland-Altman analysis showed mean differences (95% limits of agreement) of 10.46 mm/mm(2) (-1.73-22.65 mm/mm(2)) for TVD, 8.25 mm/mm(2) (-9.88-26.39 mm/mm(2)) for PVD, and - 3.96% (-59.58%-51.65%) for PPV. DISCUSSION: Automated microcirculatory analysis using the Analysis Manager did not show clinically acceptable agreement with manual analysis using Capillary Mapper. Consequently, automated video analysis using the Analysis Manager does not appear to be a suitable approach. TRIAL REGISTRATION: ClinicalTrials.gov identifier: DRKS00020264.

Authors: F. Muller-Graf, D. Wrede, L. Bork, G. Klinkmann, M. Flick, D. A. Reuter, A. R. Zitzmann, S. H. Bohm, S. Reuter

Date Published: 13th Nov 2024

Publication Type: Journal

Feasibility of individualized home exercise programs for patients with head and neck cancer-study protocol and first results of a multicentre single-arm intervention trial (OSHO #94).

Abstract (Expand)

INTRODUCTION: Patients with head and neck cancer (PwHNC) benefit from targeted exercise interventions: symptom relief, compensation for dysfunction, improvement in quality of life (QoL). Data on … acceptance physical interventions in PwHNC are rare. The 'OSHO #94' trial investigates the short- and medium-term effects of individualized home exercise in PwHNC on QoL, physical activity and functionality. The study includes a feasibility phase (proof of concept) in order to evaluate the acceptance. Here we present the study protocol as well as the feasibility results. METHODS AND ANALYSIS: This prospective, multicentre, single-arm intervention study includes PwHNC >/=18 years of age in aftercare or palliative care with stable remission under immunotherapy. The study opened in January 01, 2021, with estimated completion by December 31, 2024. The PwHNC receive an individualized home exercise program consisting of mobilization, coordination, strengthening and stretching exercises. This should be carried out at least three times a week over 12 weeks for 15 to 30 minutes, supplemented by aerobic training two to three times a week for 30 minutes (intervention). Once weekly telephone calls with a physiotherapist are performed. Subsequently, there is a 12-week follow-up (FU) without exercise specifications/contact. Outcomes are measured before and after the intervention and following the FU. Primary outcome of the feasibility phase (n = 25) was the determination of the dropout rate during the intervention with a termination cut off if more than 30% PwHNC withdrew premature. The primary outcome of the OSHO #94' trial (N = 53) is the change in global QoL score from pre- to post-intervention (EORTC QLQ-C30). Secondary outcomes include clinical and patient-reported measures, training details as well as functional diagnostic data (e.g. level of physical activity, training frequency, flexibility, fall risk and aerobic performance). RESULTS: 25 PwHNC were enrolled onto the feasibility cohort. Only16% (4/25 patients) did not complete the study. Therefore, recruitment of PwHNC was continued. The dropout rate was adjusted from 30% (N = 60) to 20% (N = 53, calculated sample size n = 42 PwHNC and 20% (n = 11) to dropout). CONCLUSIONS: Individualized home exercise programs in PwHNC in aftercare seem feasible. Consequently, the aim is now to evaluate the short and medium-term effects of individualized home exercise.

Authors: S. Felser, J. Rogahn, A. Glass, L. A. Bonke, D. F. Struder, J. Stolle, S. Schulze, M. Blaurock, U. Kriesen, C. Junghanss, C. Grosse-Thie

Date Published: 22nd Aug 2024

Publication Type: Journal

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