Klinik und Poliklinik für Allgemein-, Viszeral-, Gefäß- und Kinderchirurgie (Chirurgische Klinik I)
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- Lehrstuhl für Tissue Engineering und Regenerative Medizin der Universität Würzburg (1)
Background
Simulator training is an effective way of acquiring laparoscopic skills but there remains a need to optimize teaching methods to accelerate learning. We evaluated the effect of the mental exercise ‘deconstruction into key steps’ (DIKS) on the time required to acquire laparoscopic skills.
Methods
A randomized controlled trial with undergraduate medical students was implemented into a structured curricular laparoscopic training course. The intervention group (IG) was trained using the DIKS approach, while the control group (CG) underwent the standard course. Laparoscopic performance of all participants was video-recorded at baseline (t0), after the first session (t1) and after the second session (t2) nine days later. Two double-blinded raters assessed the videos. The Impact of potential covariates on performance (gender, age, prior laparoscopic experience, self-assessed motivation and self-assessed dexterity) was evaluated with a self-report questionnaire.
Results
Both the IG (n = 58) and the CG (n = 68) improved their performance after each training session (p < 0.001) but with notable differences between sessions. Whereas the CG significantly improved their performance from t0 –t1 (p < 0.05), DIKS shortened practical exercise time by 58% so that the IG outperformed the CG from t1 -t2, (p < 0.05). High self-assessed motivation and dexterity associated with significantly better performance (p < 0.05). Male participants demonstrated significantly higher overall performance (p < 0.05).
Conclusion
Mental exercises like DIKS can improve laparoscopic performance and shorten practice times. Given the limited exposure of surgical residents to simulator training, implementation of mental exercises like DIKS is highly recommended. Gender, self-assessed dexterity, and motivation all appreciably influence performance in laparoscopic training.
The treatment of inguinal hernias with open and minimally invasive procedures has reached a high standard in terms of outcome over the past 30 years. However, there is still need for further improvement, mainly in terms of reduction of postoperative seroma, chronic pain, and recurrence. This video article presents the endoscopic anatomy of the groin with regard to robotic transabdominal preperitoneal patch plasty (r‑TAPP) and illustrates the surgical steps of r‑TAPP with respective video sequences. The results of a cohort study of 302 consecutive hernias operated by r‑TAPP are presented and discussed in light of the added value of the robotic technique, including advantages for surgical training. r‑TAPP is the natural evolution of conventional TAPP and has the potential to become a new standard as equipment availability increases and material costs decrease. Future studies will also have to refine the multifaceted added value of r‑TAPP with new parameters.
Purpose
A successful focused surgical approach in primary hyperparathyroidism (pHPT) relies on accurate preoperative localization of the parathyroid adenoma (PA). Most often, ultrasound is followed by [\(^{99m}\)Tc]-sestamibi scintigraphy, but the value of this approach is disputed. Here, we evaluated the diagnostic approach in patients with surgically treated pHPT in our center with the aim to further refine preoperative diagnostic procedures.
Methods
A single-center retrospective analysis of patients with pHPT from 01/2005 to 08/2021 was carried out followed by evaluation of the preoperative imaging modalities to localize PA. The localization of the PA had to be confirmed intraoperatively by the fresh frozen section and significant dropping of the intraoperative parathyroid hormone (PTH) levels.
Results
From 658 patients diagnosed with pHPT, 30 patients were excluded from the analysis because of surgery for recurrent or persistent disease. Median age of patients was 58.0 (13–93) years and 71% were female. Neck ultrasound was carried out in 91.7% and localized a PA in 76.6%. In 23.4% (135/576) of the patients, preoperative neck ultrasound did not detect a PA. In this group, [\(^{99m}\)Tc]-sestamibi correctly identified PA in only 25.4% of patients. In contrast, in the same cohort, the use of [\(^{11}\)C]-methionine or [\(^{11}\)C]-choline PET resulted in the correct identification of PA in 79.4% of patients (OR 13.23; 95% CI 5.24–33.56).
Conclusion
[\(^{11}\)C]-Methionine or [\(^{11}\)C]-choline PET/CT are superior second-line imaging methods to select patients for a focused surgical approach when previous ultrasound failed to identify PA.
Background
An intragastric balloon is used to cause weight loss in super-obese patients (BMI > 60 kg/m\(^2\)) prior to bariatric surgery. Whether weight loss from intragastric balloon influences that from bariatric surgery is poorly studied.
Methods
In this retrospective, single-center study, the effects of intragastric balloon in 26 patients (BMI 69.26 ± 6.81) on weight loss after bariatric surgery (primary endpoint), postoperative complications within 30 days, hospital readmission, operation time, and MTL30 (secondary endpoints) were evaluated. Fifty-two matched-pair patients without intragastric balloon prior to bariatric surgery were used as controls.
Results
Intragastric balloon resulted in a weight loss of 17.3 ± 14.1 kg (BMI 5.75 ± 4.66 kg/m\(^2\)) with a nadir after 5 months. Surgical and postoperative outcomes including complications were comparable between both groups. Total weight loss was similar in both groups (29.0% vs. 32.2%, p = 0.362). Direct postoperative weight loss was more pronounced in the control group compared to the gastric balloon group (29.16 ± 7.53% vs 23.78 ± 9.89% after 1 year, p < 0.05 and 32.13 ± 10.5% vs 22.21 ± 10.9% after 2 years, p < 0.05), who experienced an earlier nadir and started to regain weight during the follow-up.
Conclusion
A multi-stage therapeutic approach with gastric balloon prior to bariatric surgery in super-obese patients may be effective to facilitate safe surgery. However, with the gastric balloon, pre-treated patients experienced an attenuated postoperative weight loss with an earlier nadir and earlier body weight regain. This should be considered when choosing the appropriate therapeutic regime and managing patients’ expectations.
The principle of targeted separation or weakening of individual components of the abdominal wall to relieve tension in the median line during major abdominal reconstruction has been known for over 30 years as anterior component separation (aCS) and is an established procedure. In search of alternatives with lower complication rates, posterior component separation (pCS) was developed; transversus abdominis release (TAR) is a nerve-sparing modification of pCS. With the ergonomic resources of robotics (e.g., angled instruments), TAR can be performed in a minimally invasive manner (r-TAR): hernia gaps of up to 14 cm can be closed and a large extraperitoneal mesh implanted. In this video article, the treatment of large incisional hernias using the r‑TAR technique is presented. Exemplary results of a cohort study in 13 consecutive patients are presented. The procedure is challenging, but our own results—as well as reports from the literature—are encouraging. The r‑TAR is becoming the pinnacle procedure for abdominal wall reconstruction.
Background
Endoscopic vacuum therapy (EVT) is an effective treatment option for leakage of the upper gastrointestinal (UGI) tract. The aim of this study was to evaluate the clinical impact of quality improvements in EVT management on patients’ outcome.
Methods
All patients treated by EVT at our center during 2012–2021 were divided into two consecutive and equal-sized cohorts (period 1 vs. period 2). Over time several quality improvement strategies were implemented including the earlier diagnosis and EVT treatment and technical optimization of endoscopy. The primary endpoint was defined as the composite score MTL30 (mortality, transfer, length-of-stay > 30 days). Secondary endpoints included EVT efficacy, complications, in-hospital mortality, length-of-stay (LOS) and nutrition status at discharge.
Results
A total of 156 patients were analyzed. During the latter period the primary endpoint MTL30 decreased from 60.8 to 39.0% (P = .006). EVT efficacy increased from 80 to 91% (P = .049). Further, the need for additional procedures for leakage management decreased from 49.9 to 29.9% (P = .013) and reoperations became less frequent (38.0% vs.15.6%; P = .001). The duration of leakage therapy and LOS were shortened from 25 to 14 days (P = .003) and 38 days to 25 days (P = .006), respectively. Morbidity (as determined by the comprehensive complication index) decreased from 54.6 to 46.5 (P = .034). More patients could be discharged on oral nutrition (70.9% vs. 84.4%, P = .043).
Conclusions
Our experience confirms the efficacy of EVT for the successful management of UGI leakage. Our quality improvement analysis demonstrates significant changes in EVT management resulting in accelerated recovery, fewer complications and improved functional outcome.
Purpose
In selected cases of severe Cushing’s syndrome due to uncontrolled ACTH secretion, bilateral adrenalectomy appears unavoidable. Compared with unilateral adrenalectomy (for adrenal Cushing’s syndrome), bilateral adrenalectomy has a perceived higher perioperative morbidity. The aim of the current study was to compare both interventions in endogenous Cushing’s syndrome regarding postoperative outcomes.
Methods
We report a single-center, retrospective cohort study comparing patients with hypercortisolism undergoing bilateral vs. unilateral adrenalectomy during 2008–2021. Patients with adrenal Cushing’s syndrome due to adenoma were compared with patients with ACTH-dependent Cushing’s syndrome (Cushing’s disease and ectopic ACTH production) focusing on postoperative morbidity and mortality as well as long-term survival.
Results
Of 83 patients with adrenalectomy for hypercortisolism (65.1% female, median age 53 years), the indication for adrenalectomy was due to adrenal Cushing’s syndrome in 60 patients (72.2%; 59 unilateral and one bilateral), and due to hypercortisolism caused by Cushing’s disease (n = 16) or non-pituitary uncontrolled ACTH secretion of unknown origin (n = 7) (27.7% of all adrenalectomies). Compared with unilateral adrenalectomy (n = 59), patients with bilateral adrenalectomy (n = 24) had a higher rate of severe complications (0% vs. 33%; p < 0.001) and delayed recovery (median: 10.2% vs. 79.2%; p < 0.001). Using the MTL30 marker, patients with bilateral adrenalectomy fared worse than patients after unilateral surgery (MTL30 positive: 7.2% vs. 25.0% p < 0.001). Postoperative mortality was increased in patients with bilateral adrenalectomy (0% vs. 8.3%; p = 0.081).
Conclusion
While unilateral adrenalectomy for adrenal Cushing’s syndrome represents a safe and definitive therapeutic option, bilateral adrenalectomy to control ACTH-dependent extra-adrenal Cushing’s syndrome or Cushing’s disease is a more complicated intervention with a mortality of nearly 10%.
Introduction
Low-grade appendiceal mucinous neoplasms (LAMN) are semi-malignant tumors of the appendix which are incidentally found in up to 1% of appendectomy specimen. To this day, no valid descriptive analysis on LAMN is available for the German population.
Methods
Data of LAMN (ICD-10: D37.3) were collected from the population-based cancer registries in Germany, provided by the German Center for Cancer Registry Data (Zentrum für Krebsregisterdaten—ZfKD). Data was anonymized and included gender, age at diagnosis, tumor staging according to the TNM-classification, state of residence, information on the performed therapy, and survival data.
Results
A total of 612 cases were reported to the ZfKD between 2011 and 2018. A total of 63.07% were female and 36.93% were male. Great inhomogeneity in reporting cases was seen in the federal states of Germany including the fact that some federal states did not report any cases at all. Age distribution showed a mean age of 62.03 years (SD 16.15) at diagnosis. However, data on tumor stage was only available in 24.86% of cases (n = 152). A total of 49.34% of these patients presented with a T4-stage. Likewise, information regarding performed therapy was available in the minority of patients: 269 patients received surgery, 22 did not and for 312 cases no information was available. Twenty-four patients received chemotherapy, 188 did not, and for 400 cases, no information was available. Overall 5-year survival was estimated at 79.52%. Patients below the age of 55 years at time of diagnosis had a significantly higher 5-year survival rate compared to patients above the age of 55 years (85.77% vs. 73.27%).
Discussion
In this study, we observed an incidence of LAMN in 0.13% of all appendectomy specimen in 2018. It seems likely that not all cases were reported to the ZfKD; therefore, case numbers may be considered underestimated. Age and gender distribution goes in line with international studies with females being predominantly affected. Especially regarding tumor stage and therapy in depth information cannot be provided through the ZfKD-database. This data analysis emphasizes the need for further studies and the need for setting up a specialized registry for this unique tumor entity to develop guidelines for the appropriate treatment and follow-up.
Die chirurgische Behandlung parastomaler Hernien gilt als komplex und ist bekanntermaßen komplikationsträchtig. In der Vergangenheit wurden diese Hernien durch die Relokation des Stomas oder Nahtverfahren der Austrittstelle versorgt. In den letzten Jahren wurden verschiedene netzbasierte Techniken vorgeschlagen, die heute in der minimal-invasiven Chirurgie eingesetzt werden. Mit der Verbreitung der roboterassistierten Hernienchirurgie wurden die Netzverfahren weiterentwickelt und die Ergebnisse für die Patienten erheblich verbessert. In diesem Beitrag wird ein Überblick über die verfügbaren Techniken der roboterassistierten Versorgung parastomaler Hernien präsentiert. Es werden technische Überlegungen und erste Ergebnisse des roboterassistierten modifizierten Sugarbaker-Verfahrens, der roboterassistierten Pauli-Technik und der Verwendung des trichterförmigen Netzes IPST vorgestellt. Darüber hinaus werden die Herausforderungen bei der roboterassistierten Versorgung parastomaler Hernien am Ileum-Conduit diskutiert. Die Operationstechniken werden durch Foto- und Videomaterial veranschaulicht.
Background
Pancreatic adenocarcinoma (PDAC) patients with preoperative carbohydrate antigen 19-9 (CA19-9) serum levels higher than 500 U/ml are classified as biologically borderline resectable (BR-B). To date, the impact of cholestasis on preoperative CA19-9 serum levels in these patients has remained unquantified.
Methods
Data on 3079 oncologic pancreatic resections due to PDAC that were prospectively acquired by the German Study, Documentation and Quality (StuDoQ) registry were analyzed in relation to preoperative CA19-9 and bilirubin serum values. Preoperative CA19-9 values were adjusted according to the results of a multivariable linear regression analysis of pathologic parameters, bilirubin, and CA19-9 values.
Results
Of 1703 PDAC patients with tumor located in the pancreatic head, 420 (24.5 %) presented with a preoperative CA19-9 level higher than 500 U/ml. Although receiver operating characteristics (ROC) analysis failed to determine exact CA19-9 cut-off values for prognostic indicators (R and N status), the T, N, and G status; the UICC stage; and the number of simultaneous vein resections increased with the level of preoperative CA19-9, independently of concurrent cholestasis. After adjustment of preoperative CA19-9 values, 18.5 % of patients initially staged as BR-B showed CA19-9 values below 500 U/ml. However, the postoperative pathologic results for these patients did not change compared with the patients who had CA19-9 levels higher than 500 U/ml after bilirubin adjustment.
Conclusions
In this multicenter dataset of PDAC patients, elevation of preoperative CA19-9 correlated with well-defined prognostic pathologic parameters. Bilirubin adjustment of CA19-9 is feasible but does not affect the prognostic value of CA19-9 in jaundiced patients.
In der vorliegenden Dissertation wurde das Zusammenspiel von enterischen Gliazellen (EGC) und Darmepithelzellen (Caco-2) thematisiert, wobei der Fokus auf der Bedeu-tung des neurotrophen Faktors GDNF für die Interaktion zwischen den beiden genann-ten Zelltypen lag. Weiterhin wurde evaluiert, ob die Tyrosinkinase RET auch in Darme-pithelzellen für die GDNF-Signaltransduktion unter Ruhebedingungen und bei Entzün-dungen verantwortlich ist.
Als Grundlage diente ein Ko-Kultur-Modell mit Caco-2 und EGC. Durch Permeabili-täts- und Widerstandsmessungen wurden die Auswirkungen von GDNF auf Zell-Monolayer ermittelt. Effekte auf die Barrieredifferenzierung wurden anhand subkon-fluenter Zell-Monolayer charakterisiert, wohingegen die Auswirkungen auf Entzün-dungsstimuli an konfluenten Zellen untersucht wurden. Veränderungen von Junktions-proteinen wurden mit Immunfluoreszenzfärbungen und Western-Blot-Analysen aufge-zeigt. Abschließend erfolgte eine Analyse humaner Gewebeproben von Patienten mit und ohne chronisch-entzündlichen Darmerkrankungen (CED) in Bezug auf deren GDNF-Expression.
Die verwendeten intestinalen Epithelzellen exprimieren die GDNF-Rezeptoren GFRα1, GFRα2, GFRα3 und RET. Nach Etablierung des Kultursystems zeigten Permeabilitäts-messungen, Messungen des Epithelwiderstandes sowie Immunfluoreszenz-Färbungen, dass die Differenzierung der Darmepithelzellen in der Ko-Kultur mit EGC durch GDNF vermittelt wird. Zudem war eine GDNF-abhängige, barrierestabilisierende Wirkung in einem Inflammationsmodell zu beobachten. Weiterhin wurde nachgewiesen, dass GDNF-Effekte auf Enterozyten auch im Darmepithel über die RET-Tyrosinkinase mit nachfolgender Hemmung des p38-MAPK-Signalwegs bedingt werden. Eine Stimulation der EGC mit Zytokinen bestätigte eine Hochregulation der GDNF-Expression und Sek-retion. In humanen Proben war intestinales GDNF bei schwerer Entzündung reduziert.
Zusammenfassend wurde erstmalig der Nachweis erbracht, dass von EGC sezerniertes GDNF die Differenzierung der Barriere in Darmepithelzellen induziert und diese gegen einen Zytokin-vermittelten Zusammenbruch schützt. Dies wird über eine RET-abhängige Regulation der p38-MAPK vermittelt. Die Reduktion der GDNF-Konzentration in transmuralen Gewebeproben von Patienten mit CED trägt möglicher-weise zur Pathogenese der CED bei.
Developmentally regulated features of innate immunity are thought to place preterm and term infants at risk of infection and inflammation-related morbidity. Underlying mechanisms are incompletely understood. Differences in monocyte function including toll-like receptor (TLR) expression and signaling have been discussed. Some studies point to generally impaired TLR signaling, others to differences in individual pathways. In the present study, we assessed mRNA and protein expression of pro- and anti-inflammatory cytokines in preterm and term cord blood (CB) monocytes compared with adult controls stimulated ex vivo with Pam3CSK4, zymosan, polyinosinic:polycytidylic acid, lipopolysaccharide, flagellin, and CpG oligonucleotide, which activate the TLR1/2, TLR2/6, TLR3, TLR4, TLR5, and TLR9 pathways, respectively. In parallel, frequencies of monocyte subsets, stimulus-driven TLR expression, and phosphorylation of TLR-associated signaling molecules were analyzed. Independent of stimulus, pro-inflammatory responses of term CB monocytes equaled adult controls. The same held true for preterm CB monocytes—except for lower IL-1β levels. In contrast, CB monocytes released lower amounts of anti-inflammatory IL-10 and IL-1ra, resulting in higher ratios of pro-inflammatory to anti-inflammatory cytokines. Phosphorylation of p65, p38, and ERK1/2 correlated with adult controls. However, stimulated CB samples stood out with higher frequencies of intermediate monocytes (CD14\(^+\)CD16\(^+\)). Both pro-inflammatory net effect and expansion of the intermediate subset were most pronounced upon stimulation with Pam3CSK4 (TLR1/2), zymosan (TR2/6), and lipopolysaccharide (TLR4). Our data demonstrate robust pro-inflammatory and yet attenuated anti-inflammatory responses in preterm and term CB monocytes, along with imbalanced cytokine ratios. Intermediate monocytes, a subset ascribed pro-inflammatory features, might participate in this inflammatory state.
Ein Schlüsselereignis, welches dem prognosebestimmenden Organversagen bei systemi-schen Entzündungsprozessen und Sepsis vorangeht, ist die Entwicklung einer mikrovas-kulären endothelialen Schrankenstörung. Das vaskuläre endotheliale (VE-) Cadherin als mechanischer Stabilisator der Endothelbarriere spielt dabei eine wichtige Rolle. In der Inflammation werden Spaltprodukte von VE-Cadherin (sVE-Cadherin) gebildet. Ge-genstand der vorliegenden Arbeit war die Untersuchung der Hypothese ob diese Spalt-produkte selbst an der Störung der endothelialen Barrierefunktion beteiligt sind.
Es wurde hierfür humanes sVE-Cadherin bestehend aus den extrazellulären Domänen EC1-5 (sVE-CadherinEC1-5) generiert. In Messungen des transendothelialen elektrischen Widerstands (TER), mit Immunfluoreszenzfärbungen und Western Blot Analysen wird gezeigt, dass sVE-Cadherin dosisabhängig die Barriere Integrität in primären humanen dermalen Endothelzellen stört. Dies führt zu einer Reduktion von VE-Cadherin und den assoziierten Proteinen α-, γ- und δ-Catenin und ZO-1, die nach der Applikation von sVE-Cadherin an den Zellgrenzen reduziert sind. Die Interaktion zwischen VE-PTP und VE-Cadherin wird durch sVE-CadherinEC1-5 reduziert. Durch pharmakologische Hem-mung der Phosphataseaktivität von VE-PTP mittels AKB9778 wird der durch sVE-CadherinEC1-5-induzierte Verlust der Endothelbarriere aufgehoben. Dagegen zeigt die direkte Aktivierung von Tie-2 mittels Angiopoetin-1 keinen protektiven Effekt auf die durch sVE-CadherinEC1-5 gestörte Endothelbarriere. Weitere Analysen zeigen eine erhöh-te Expression von GEF-H1 durch sVE-CadherinEC1-5. Diese ist ebenfalls durch AKB9778 hemmbar.
Zusätzlich zu diesen Untersuchungen wurden die Konstrukte EC1-4 und EC3-5 in ver-schiedene Vektoren kloniert, um zu bestimmen, ob die extrazelluläre Domäne 5 von VE-Cadherin die dominante Rolle bei den sVE-Cadherin-vermittelten Effekten spielt.
Zusammenfassend zeigen diese Untersuchungen zum ersten Mal, dass sVE-CadherinEC1-5 unabhängig von proinflammatorischen Auslösern über die Aktivierung des VE-PTP/RhoA-Signalweges den Zusammenbruch der Endothelbarriere mitversursacht. Dies stellt einen neuen pathophysiologischer Mechanismus dar, der zum Gesamtverständnis der entzündungsinduzierten Barriereveränderungen des Endothels beiträgt.
Serotonin (5-hydroxytryptamine, 5-HT) as well as noradrenaline (NA) are key modulators of various fundamental brain functions including the control of appetite. While manipulations that alter brain serotoninergic signaling clearly affect body weight, studies implicating 5-HT transporters and NA transporters (5-HTT and NAT, respectively) as a main drug treatment target for human obesity have not been conclusive. The aim of this positron emission tomography (PET) study was to investigate how these central transporters are associated with changes of body weight after 6 months of dietary intervention or Roux-en-Y gastric bypass (RYGB) surgery in order to assess whether 5-HTT as well as NAT availability can predict weight loss and consequently treatment success. The study population consisted of two study cohorts using either the 5-HTT-selective radiotracer [\(^{11}\)C]DASB to measure 5-HTT availability or the NAT-selective radiotracer [\(^{11}\)C]MRB to assess NAT availability. Each group included non-obesity healthy participants, patients with severe obesity (body mass index, BMI, >35 kg/m\(^2\)) following a conservative dietary program (diet) and patients undergoing RYGB surgery within a 6-month follow-up. Overall, changes in BMI were not associated with changes of both 5-HTT and NAT availability, while 5-HTT availability in the dorsal raphe nucleus (DRN) prior to intervention was associated with substantial BMI reduction after RYGB surgery and inversely related with modest BMI reduction after diet. Taken together, the data of our study indicate that 5-HTT and NAT are involved in the pathomechanism of obesity and have the potential to serve as predictors of treatment outcomes.
(1) Background: Metabolically healthy obesity (MHO) is a concept that applies to obese patients without any elements of metabolic syndrome (metS). In turn, metabolically unhealthy obesity (MUO) defines the presence of elements of metS in obese patients. The components of MUO can be divided into subgroups regarding the elements of inflammation, lipid and glucose metabolism and cardiovascular disease. MUO patients appear to be at greater risk of developing non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH) compared to MHO patients. The aim of this study was to evaluate the influence of different MUO components on NAFLD and NASH in patients with morbid obesity undergoing bariatric surgery. (2) Methods: 141 patients undergoing bariatric surgery from September 2015 and October 2021 at RWTH Aachen university hospital (Germany) were included. Patients were evaluated pre-operatively for characteristics of metS and MUO (HbA1c, HOMA, CRP, BMI, fasting glucose, LDL, TG, HDL and the presence of arterial hypertension). Intraoperatively, a liver biopsy was taken from the left liver lobe and evaluated for the presence of NAFLD or NASH. In ordinal regression analyses, different factors were evaluated for their influence on NAFLD and NASH. (3) Results: Mean BMI of the patients was 52.3 kg/m\(^2\) (36–74.8, SD 8.4). Together, the parameters HbA1c, HOMA, CRP, BMI, fasting glucose, LDL, TG, HDL and the presence of arterial hypertension accounted for a significant amount of variance in the outcome, with a likelihood ratio of χ\(^2\) (9) = 41.547, p < 0.001, for predicting the presence of NASH. Only HOMA was an independent predictor of NASH (B = 0.102, SE = 0.0373, p = 0.007). Evaluation of steatosis showed a similar trend (likelihood ratio χ\(^2\) (9) = 40.272, p < 0.001). Independent predictors of steatosis were HbA1c (B = 0.833, SE = 0.343, p = 0.015) and HOMA (B = 0.136, SE = 0.039, p < 0.001). (4) Conclusions: The above-mentioned model, including components of MUO, was significant for diagnosing NASH in patients with morbid obesity undergoing bariatric surgery. Out of the different subitems, HOMA independently predicted the presence of NASH and steatosis, while HbA1c independently predicted steatosis and fibrosis. Taken together, the parameter of glucose metabolism appears to be more accurate for the prediction of NASH than the parameters of lipid metabolism, inflammation or the presence of cardiovascular disease.
Perianal fistulizing Crohn’s Disease (CD) with abscess formation represents an aggressive phenotype in Inflammatory Bowel Disease (IBD) with increased morbidity. Treatment is multidisciplinary and includes antibiotics, but knowledge about the microbial spectrum is rare often resulting in inadequate antimicrobial therapy. In this single center retrospective study, all patients who were operated due to perianal abscess formation were retrospectively analyzed and the microbial spectrum evaluated. Patients were divided into a CD and non-CD group with further subgroup analysis. 138 patients were finally included in the analysis with 62 patients suffering from CD. Relevant differences were detected for the microbial spectrum with anaerobic bacteria being significantly more often isolated from non-CD patients. In a subgroup-analysis of CD patients only, medical therapy had a relevant effect on the microbial spectrum since Streptococcus groups and Enterobacterales were significantly more often isolated in patients treated with steroids compared to those being treated by antibodies. In conclusion, the microbial spectrum of patients suffering from CD varies significantly from non-CD patients and immunosuppressive medication has a relevant effect on isolated pathogens. Based on that, adaption of antibiotic treatment might be discussed in the future.
Die Kombination aus zytoreduktiver Chirurgie und einer anschließenden hyperthermen intraperitonealen Chemoperfusion (HIPEC) stellt sich als vielversprechende Therapiestrategie bei ausgesuchten Patienten mit Peritonealkarzinose, z. B. des kolorektalen Karzinoms, dar. Die intraperitoneale Chemoperfusion kombiniert eine lokale Hochdosis-Chemotherapie mit einer Hyperthermie. Hitzeschockproteinen (HSP) kommt dabei eine bedeutende Rolle zu, da sie infolge von zellulären Stressfaktoren wie Hitze oder Zytostatika-bedingter Chemotoxizität induziert werden. HSPs setzen Reparatur- und Zellschutzmechanismen in Gang und vermindern so in einzelnen überlebenden Tumorzellen möglicherweise den gewünschten Therapieerfolg der HIPEC. Ziel der Arbeit war es, mithilfe eines bereits etablierten in vitro HIPEC-Modells die Auswirkungen der äußeren Stressoren Hyperthermie und Zytostatika auf die Expression von Hitzeschockproteinen (HSP27, HSP70 und HSP90) in drei humanen Kolonkarzinomzelllinien zu untersuchen. Dazu wurden die Zelllinien HT29, SW480 und SW620 jeweils mit und ohne Zytostatika (Mitomycin C, MMC und Oxaliplatin, OXA) für eine Stunde drei verschiedenen Temperaturstufen von 37°C als Normothermie, 41°C und 43°C als Hyperthermie ausgesetzt und nach einer Regenerationszeit von 30 min, 24 h, 48 h und 72 h mit Hilfe von RT-qPCR-Analysen und Western Blots untersucht. Zudem wurden nach gleichem Ablauf Effekte der HIPEC auf die Tumorzellproliferation und Apoptose mittels Proliferationsmarkern Ki-67, PCNA und MTS-Tests sowie dem antiapoptotischen Protein Bcl-xL in in vitro Tumorzellansätzen sowie in ex vivo Patientenproben vor und nach HIPEC analysiert. Sowohl die einstündige Chemotherapie mit Mitomycin C oder Oxaliplatin unter hyperthermen Bedingungen als auch die isolierte Hyperthermiebehandlung führte im Vergleich zu normothermen Kontrollbedingungen bei 37°C zu einer signifikanten Überexpression der untersuchten HSPs in RTq-PCR-Analysenaller drei Kolonkarzinomzelllinien. Interessanterweise wurden vermehrte HSP Genexpressionsmuster noch drei Tage nach Behandlung beobachtet. Eine verstärkte Proteinexpression zeigte sich bestätigend insbesondere für HSP27 und HSP70 unter zytostatischer Behandlung mit MMC oder OXA und führte zu einer bis zu 3-fachen Expressionssteigerung wenn die Zellen hyperthermen Bedingungen ausgesetzt waren. Tumorzellen, die zuvor der hyperthermen Chemotherapie unterzogen wurden, zeigten interessanterweise zudem proliferative anstelle von anti-proliferativen Effekten. In durchgeführten MTS-Tests führte sowohl die Hyperthermie allein als auch die zusätzliche Zytostatikagabe zu einer deutlich erhöhten Zellviabilität im Vergleich zu normothermer Chemotherapie im Modellansatz. Übereinstimmend mit den Ergebnissen der MTS-Tests konnte eine Induktion der Proliferationsmarker PCNA und Ki-67 durch Hyperthermie und Chemotherapie auf Gen- und Proteinebene beobachtet werden. Im Falle von PCNA ließ sich eine verstärkte Proteinexpression in ex vivo Proben von Patienten nach klinisch durchgeführter HIPEC bestätigen. Zusätzliche Untersuchungen des anti-apoptotisch wirkenden Regulatorproteins Bcl-xL in in vitro Tumorzellansätzen sowie in ex vivo Proben von Patienten nach hyperthermer Chemotherapie, zeigten zudem eine deutlich gesteigerte Proteinexpression unter alleiniger Hyperthermie sowie insbesondere in Kombination mit Zytostatika. Durch die Induktion von HSP27, HSP70 und HSP90 infolge von hyperthermem und zytotoxischem Stress werden in überlebenden Zellen nach hyperthermer Chemotherapie, unerwünschte antiapopotische sowie proliferative Effekte im Sinne von Reparatur- und Zellschutzmechanismen induziert und nehmen negativen Einfluss auf den Therapieerfolg der HIPEC. Schlussfolgernd wäre der Einsatz von HSP-Inhibitoren um die beschriebenen, unerwünschten Zellmechanismen zu verhindern, zu überprüfen. Diese bieten eine interessante Möglichkeit die Effizienz der im klinischen Einsatz gängigen Zytostatika zu steigern und somit einen positiven Einfluss auf den Erfolg der Therapie und die Überlebenszeit von Patienten mit Peritonealkarzinose zu nehmen. Weiterführende Studien der eigenen Arbeitsgruppe mit kombinierten HSP70/HSP90-Inhibitoren zeigten bereits eine signifikant reduzierte Zellviabilität in Kolonkarzinomzellen, die zuvor der hyperthermen Chemotherapie unterzogen wurden.
Early treatment with glucocorticoids could help reduce both cytotoxic and vasogenic edema, leading to improved clinical outcome after stroke. In our previous study, isosteviol sodium (STVNA) demonstrated neuroprotective effects in an in vitro stroke model, which utilizes oxygen-glucose deprivation (OGD). Herein, we tested the hypothesis that STVNA can activate glucocorticoid receptor (GR) transcriptional activity in brain microvascular endothelial cells (BMECs) as previously published for T cells. STVNA exhibited no effects on transcriptional activation of the glucocorticoid receptor, contrary to previous reports in Jurkat cells. However, similar to dexamethasone, STVNA inhibited inflammatory marker IL-6 as well as granulocyte-macrophage colony-stimulating factor (GM-CSF) secretion. Based on these results, STVNA proves to be beneficial as a possible prevention and treatment modality for brain ischemia-reperfusion injury-induced blood–brain barrier (BBB) dysfunction.
The pleiotropic function of 3′,5′-cyclic adenosine monophosphate (cAMP)-dependent pathways in health and disease led to the development of pharmacological phosphodiesterase inhibitors (PDE-I) to attenuate cAMP degradation. While there are many isotypes of PDE, a predominant role of PDE4 is to regulate fundamental functions, including endothelial and epithelial barrier stability, modulation of inflammatory responses and cognitive and/or mood functions. This makes the use of PDE4-I an interesting tool for various therapeutic approaches. However, due to the presence of PDE4 in many tissues, there is a significant danger for serious side effects. Based on this, the aim of this review is to provide a comprehensive overview of the approaches and effects of PDE4-I for different therapeutic applications. In summary, despite many obstacles to use of PDE4-I for different therapeutic approaches, the current data warrant future research to utilize the therapeutic potential of phosphodiesterase 4 inhibition.
Background: The hypothalamus is an important brain region for the regulation of energy balance. Roux-en-Y gastric bypass (RYGB) surgery and gut hormone-based treatments are known to reduce body weight, but their effects on hypothalamic gene expression and signaling pathways are poorly studied. Methods: Diet-induced obese male Wistar rats were randomized into the following groups: RYGB, sham operation, sham + body weight-matched (BWM) to the RYGB group, osmotic minipump delivering PYY3-36 (0.1 mg/kg/day), liraglutide s.c. (0.4 mg/kg/day), PYY3-36 + liraglutide, and saline. All groups (except BWM) were kept on a free choice of high- and low-fat diets. Four weeks after interventions, hypothalami were collected for RNA sequencing. Results: While rats in the RYGB, BWM, and PYY3-36 + liraglutide groups had comparable reductions in body weight, only RYGB and BWM treatment had a major impact on hypothalamic gene expression. In these groups, hypothalamic leptin receptor expression as well as the JAK–STAT, PI3K-Akt, and AMPK signaling pathways were upregulated. No significant changes could be detected in PYY3-36 + liraglutide-, liraglutide-, and PYY-treated groups. Conclusions: Despite causing similar body weight changes compared to RYGB and BWM, PYY3-36 + liraglutide treatment does not impact hypothalamic gene expression. Whether this striking difference is favorable or unfavorable to metabolic health in the long term requires further investigation.