Search

ApoE abnormality represents a well-known risk factor for cardiovascular diseases. Beyond its role in lipid metabolism, novel studies demonstrate a complex involvement of apoE in membrane homeostasis and signaling as well as in nuclear transcription. Due to the large spread of apoE isoforms in the human population, there is a need to understand the apoE’s role in pathological processes. Our study aims to dissect the involvement of apoE in heart failure. We showed that apoE-deficient rats present multiple organ damages (kidney, liver, lung and spleen) besides the known predisposition for obesity and affected lipid metabolism (two-fold increase in tissular damages in liver and one-fold increase in kidney, lung and spleen). Heart tissue also showed significant morphological changes in apoE−/− rats, mostly after a high-fat diet. Interestingly, the right ventricle of apoE−/− rats fed a high-fat diet showed more damage and affected collagen content (~60% less total collagen content and double increase in collagen1/collagen3 ratio) compared with the left ventricle (no significant differences in total collagen content or collagen1/collagen3 ratio). In patients, we were able to find a correlation between the presence of ε4 allele and cardiomyopathy (χ2 = 10.244, p = 0.001), but also with right ventricle dysfunction with decreased TAPSE (15.3 ± 2.63 mm in ε4-allele-presenting patients vs. 19.8 ± 3.58 mm if the ε4 allele is absent, p &lt, 0.0001*) and increased in systolic pulmonary artery pressure (50.44 ± 16.47 mmHg in ε4-allele-presenting patients vs. 40.68 ± 15.94 mmHg if the ε4 allele is absent, p = 0.0019). Our results confirm that the presence of the ε4 allele is a lipid-metabolism-independent risk factor for heart failure. Moreover, we show for the first time that the presence of the ε4 allele is associated with right ventricle dysfunction, implying different regulatory mechanisms of fibroblasts and the extracellular matrix in both ventricles. This is essential to be considered and thoroughly investigated before the design of therapeutical strategies for patients with heart failure.

The Pringle maneuver (PM) has been widely used to control blood loss during liver resection. However, hepatic inflow occlusion can also result in hepatic ischemia&ndash, reperfusion injury (IRI), especially in patients with a cholestatic, fibrotic, or cirrhotic liver. Here we investigate a nitric oxide synthase (NOS) inhibitor N-Nitroarginine methyl ester (L-NAME) on IRI after the PM and partial hepatectomy of cholestatic livers induced by bile duct ligation (BDL) in rats. Control group (non-BDL/no treatment), BDL + T group (BDL/L-NAME treatment) and BDL group (BDL/no treatment) were analyzed. Cholestasis was induced by BDL in the L-NAME and BDL group and a 50% partial hepatectomy with PM was performed. L-NAME was injected before PM in the BDL + T group. Hepatocellular damage, portal venous flow, microcirculation, endothelial lining, and eNOS, iNOS, interleukin (IL)-6, and transforming growth factor-&beta, (TGF-&beta, ) were evaluated. Microcirculation of the liver in the BDL + T group tended to be higher. Liver damage and apoptotic index were significantly lower and Ki-67 labeling index was higher in the BDL + T group while iNOS and TGF-&beta, expression was decreased. This was corroborated by a better preserved endothelial lining. L-NAME attenuated IRI following PM and improved proliferation/regeneration of cholestatic livers. These positive effects were considered as the result of improved hepatic microcirculation, prevention of iNOS formation, and TGF-&beta, mRNA upregulation.

Scientific reports 9, 18153 (2019). doi:10.1038/s41598-019-54541-z, Published by Macmillan Publishers Limited, part of Springer Nature, [London]

Background In vascular surgery, novel synthetic prosthesis materials for patch-angioplasties, interpositions, bypasses and shunts are continuously under development and optimization. The characteristics of an ideal vascular prosthesis would display long-term patency, biocompatibility, durability, low porosity, lack of stich hole bleeding, ease of handling, kink resistance, infection resistance and reasonable costs. The aim of this study was to establish and report a reliable sheep model including potential pitfalls where those parameters could be analyzed. Before surgery, sheep were acclimatized for 4–8 weeks, during which parasite infections were treated and blood and serum parameters monitored. Twenty-four sheep underwent surgery, and carotid patch-angioplasties (n = 12), graft interpositions (n = 6) or arteriovenous prosthetic shunts (n = 6) were implanted. Half of the animals in each group were sacrificed after 2 weeks and the other half after 8 weeks. The implants were analyzed for patency, endothelialization, thrombogenicity and biocompatibility by clinical observation, blood flow measurement and pathological and histopathological (H&E, EvG) as well as immunohistochemical (Ki67, CD31) evaluations. Results Health monitoring of the sheep revealed a parasitic burden with endoparasites in all animals. Some animals showed thereby infestations in the bile duct causing fibrotic cholangitis with calcifications in the liver. In addition, sarcosporidia were detected in histopathological specimen of the heart in all animals. Parasitic burden correlated with blood counts and serum bilirubin levels. Both were significantly reduced by albendazole treatment within the acclimatization time. Patches, interposition grafts, and straight shunts were successfully implanted bilaterally in all animals. The total average operation time was 136 ± 21 min. Most animals (23/24) showed good patency rates and general condition after implantation. Pathological and histopathological/immunohistochemical analyses were suitable to determine thrombogenicity, endothelialization, cellular/fibroblastic proliferation, biocompatibility, inflammatory cell infiltration, and thickness of neointima in the prosthesis material. Conclusions We have developed a suitable experimental protocol with standardized and successful anesthesia- and surgical-procedures for patch-angioplasty, graft interposition, and arteriovenous prosthetic shunts. This sheep model allows testing of new prosthetic materials for biocompatibility, thrombogenicity, and endothelialization.

Due to the shortage of suitable organs, the demand for partial liver transplantation from living donors has increased worldwide. N-acetylcysteine (NAC) has shown protective effects as a free radical scavenger during hypothermic preservation and warm ischemia-reperfusion liver injury; however, no study has reported the effects in partial liver transplantation. The aim of this study was to analyze the impact of NAC on liver graft microcirculation and graft function after partial liver transplantation in rats.Orthotopic partial liver transplantations were performed in 40 rats following cold storage in histidine-tryptophan-ketoglutarate solution for 3 h with 20 mM NAC (NAC group, n = 20) or without (control group, n = 20). We assessed portal circulation, graft microcirculation, and biochemical analyses of plasma at 1, 3, 24, and 168 h after portal reperfusion.(Control versus NAC, median and range): Portal venous pressure was significantly lower with NAC (P = 0.03). Microcirculation measured by laser Doppler was significantly improved with NAC throughout the time course (P = 0.003). Alanine aminotransferase levels were significantly lower in the NAC group (P0.05). Total antioxidative capacity was significantly higher in the NAC group at 1 h after reperfusion (Trolox equivalents: median, 3 μM; range, 2.9-6.7 versus median, 16.45 μM; range, 10.4-18.8). Lipid peroxidation was significantly abrogated in the NAC group (median, 177.6 nmol/mL; range, 75.9-398.1 versus median, 71.5 nmol/mL; range, 58.5-79 at 3 h).This study showed that NAC treatment during cold storage resulted in improved microcirculation and preservation quality of partial liver graft likely because of enhanced antioxidant capacity and reduced lipid peroxidation.

This paper introduces an improved physiological animal model with diabetic Gottingen minipigs, which focuses on the application of human therapy devices and metabolic system analysis. Based on measurement data-sets collected by metabolic test procedures, a new mathematical minipig model is developed. The model consists of 16 differential equations and describes the diabetic porcine glucose metabolism according to the human model published by Sorensen. In the future, the mathematical model will be used as a basis for controller design and the physiological model for experimental control performance evaluation.

BACKGROUND Steatotic livers are associated with poor graft function after transplantation. We investigated the effects of venous-systemic oxygen persufflation with nitric oxide gas (VSOP-NO) on steatotic partial livers after transplantation. METHODS Steatotic livers induced by fasting for 2 days and subsequent refeeding for 3 days with a fat-free, carbohydrate-rich diet were reduced in size by 50% and transplanted into Lewis rats after 3 hr of cold storage in histidine-tryptophan-ketoglutarate solution. Gaseous oxygen with nitric oxide (40 ppm) was insufflated into the grafts through the suprahepatic vena cava during cold storage (VSOP-NO group; n=20). Transplantation of cold-static stored steatotic and normal grafts served as controls (Steatotic-Control and Normal-Control, respectively; n=20 for each group). RESULTS The graft microcirculation and portal venous flow were increased by VSOP-NO compared with Steatotic-Control (P

The prognosis for recipients of small liver grafts is poor. The aim of this study was to determine the impact of venous systemic oxygen persufflation (VSOP) with nitric oxide (NO) gas for 30% partial liver preservation and transplantation in rats. After we determined optimal NO concentration as 40 ppm in vitro with the isolated perfused rat liver model, we assessed liver injury and regeneration in vivo at 1, 3, 24 and 168 h after transplantation in the following three groups after 3 h-cold storage (n = 20 per group): control group = static storage; VSOP group = oxygen persufflation and VSOP+NO group = oxygen with NO persufflation. The liver graft persufflation was achieved with medical gas via the suprahepatic vena cava; In comparison with control group after transplantation, VSOP+NO preservation (1) increased portal circulation, (2) reduced AST and ALT release, (3) upregulated hepatic endothelial NO synthase, (4) reduced hepatocyte and bileductule damage and (5) improved liver regeneration. These results suggest that gaseous oxygen with NO persufflation is a novel and safe preservation method for small partial liver grafts, not only alleviating graft injury but also improve liver regeneration after transplantation.

Background Due to the severe shortage of deceased donors, demand for living-donor liver transplantation (LDLT) has increased worldwide. Here, we compared POLYSOL, a recently developed low-viscosity preservation solution, and histidine-tryptophan-ketoglutarate (HTK) for cold storage of partial liver graft in this study. Methods Partial liver transplantations with 30% of the native liver were performed in Lewis rats. The graft livers were flushed with either HTK or POLYSOL (n = 25, respectively) and stored in the respective solution for 3 h at 5°C. Graft function was evaluated regarding ischemia-reperfusion injury and regeneration at 1, 3, 24, and 168 h after reperfusion. Results POLYSOL preservation resulted in improvement of portal venous flow (HTK versus POLYSOL; mean ± SEM: 16.8 ± 2.2 versus 21.6 ± 2.1 mL/min; P = 0.005), microcirculation (383 ± 63 versus 532 ± 64 Flux; P = 0.045), ALT (310.2 ± 56.1 versus 181.8 ± 17.0 IU/L; P = 0.0262), LDH (4052.4 ± 764.4 versus 2494.1 ± 410.0 IU/L; P = 0.0215), total bilirubin (21.6 ± 14.2 versus 4.0 ± 0.6 IU/L; P = 0.0236), malondialdehyde (100.0 ± 4.3 versus 69.2 ± 4.0 nmol/mL; P = 0.0015), as well histologic findings at 24 h. Liver regeneration was improved in POLYSOL with regards to liver weight (4.0 ± 0.2 versus 4.3 ± 0.3 g; P = 0.038) and Ki-67 labeling index (9.67 ± 2.17 versus 1.10 ± 0.14%; P

Hepatitis monthly 16(8), e36821 (2016). doi:10.5812/hepatmon.36821, Published by Tehran

Ten dogs suffering from discospondylitis were treated by percutaneous discectomy and local and systemic antibiotic therapy. With fluoroscopic guidance, a cylinder 5 mm in diameter was removed from the centre of the intervertebral space, yielding a fenestration and decompressing the disc without producing any spinal instability. The causative bacteria were identified in nine of the 10 biopsy specimens, but in only three urine cultures and four blood cultures. In two cases, the antibiotics used initially had to be changed owing to the organisms' antibiotic resistance. The clinical signs of the dogs improved markedly after two to nine days (mean 4.2 days) and had resolved completely after five to 14 days (mean 9.1 days). In all the cases the disease could be classified histologically as either acute or chronic, and the disease was classified as chronic in one dog. No side effects were observed.

World journal of hepatology 9(24), 1030-1039(2017). doi:10.4254/wjh.v9.i24.1030, Published by Beijing Baishideng BioMed Scientific Co., Beijing

Energy-based technologies for tissue sealing and cutting are increasingly supplementing current standards used for haemostasis and dissection during laparoscopic surgery. For their safe and efficacious use in clinical practice, these instruments have to guarantee sufficient burst resistance and low thermal damage to adjacent tissue in combination with good cutting characteristics.The novel laparoscopic, bipolar electrosurgical sealing and cutting instrument BiCision® was compared to a commercially available laparoscopic device (EnSeal(™)) on visceral and peripheral arteries and veins in an animal model.For all parameters investigated (burst pressure, cut quality, tissue adhering to the instrument, time needed to seal and cut the vessel and thermal damage), BiCision® was at least as good as EnSeal(™). Regarding the burst pressure, BiCision® was superior over EnSeal(™) in arteries: 600 mmHg (±478) versus 241 (±269) mmHg, respectively (p0.0001*). In veins, almost equivalent burst pressures of 155 ± 134 mmHg (BiCision®) and 173 ± 139 mmHg (EnSeal(™)) were obtained.BiCision® appeared to be as good as or even superior to EnSeal(™). Since EnSeal(™) has already been shown to be safe and has been successfully used in clinical practice, BiCision® is assumed to be as efficient and reliable as EnSeal(™) under pre-clinical conditions.

Annals of intensive care 2, S17 (2012). doi:10.1186/2110-5820-2-S1-S17 special issue: "Diagnosis and management of intra-abdominal hypertension and abdominal compartment syndrome", Published by Springer, Heidelberg

In order to reduce the number of animal experiments, the use of non-heart-beating donors (NHBDs) from a commercial abattoir has been proposed. Since the use of slaughterhouse organs is legally not defined as animal experiment, this would fulfil international standards as an alternative to animal experiments. The development of intravascular thrombosis after cardiac arrest negatively impacts organ preservation and thus viability during ischaemic storage and reperfusion. A fibrinolytic preflush with streptokinase might overcome these limitations. Therefore, the functional and histomorphological integrity of kidneys preserved immediately with intact circulation (control group A) and kidneys preserved after cardiac arrest with a 30 min period of warm ischaemia (WI) (group B) was compared with kidneys preflushed with 12.5 kU/L (group C) or 50 kU/L streptokinase (group D) after 30 min WI prior to preservation. We could demonstrate that kidneys preflushed with 12.5 kU/L streptokinase (group C) performed better than those without streptokinase pretreatment after WI (group B). Parameters like oxygen consumption, perfusion pressure, laboratory values, lactate dehydrogenase level and lipidperoxidation were closer to that of the control (group A) than in groups B and D. The higher streptokinase concentration of 50 kU/L (group D) resulted histologically in a more pronounced tissue damage and an attenuated renal function, indicating toxic effects. On the basis of our results we believe streptokinase preflushed slaughterhouse kidneys to be an adequate alternative to organs from laboratory animals with the potential to further reduce the number of animal experiments.

Intra-abdominal hypertension (IAH) and abdominal compartment syndrome are increasingly observed in patients with severe acute pancreatitis (SAP). The aim of this study was to investigate the effects of IAH on pancreatic histology and ultrastructure in a porcine model. We examined 16 intubated and anesthetized domestic pigs with a mean body weight of 50.6 (SD, 3.8) kg. Using a CO2 pneumoperitoneum, the intra-abdominal pressure was increased to 30 mmHg for an investigation period of 6 or 12 h (each study group n = 6). In the control group, the intra-abdominal pressure remained 3.9 (SD, 5.4) mmHg for 12 h. Additional Ringer's solution was infused to maintain cardiac output at the level of controls. After the observation period, specimens were taken for histological and ultrastructural analysis, and animals were killed. Cardiac output did not change when compared with control. Histologically, mild- to moderate-grade necrosis was observed after 12 h of IAH. In the ultrastructural analysis, leukocyte infiltration and swelling of endothelial cells were found. In the acinar cells of the exocrine pancreas, endoplasmic reticulum was dilated, and necrosis was noticed. Mitochondrial damage manifested as cisternal destruction with formation of large vacuoles. In this porcine model, 6 and 12 h of IAH resulted in light-microscopical and ultrastructural changes comparable to pancreatitis in humans. As SAP is often accompanied by IAH, the finding of the underlying study suggests a vicious cycle in which IAH may worsen pancreatitis. Ultimately, these findings are in favor of a decompression in patients with SAP and IAH.

Objectives: To determine retrospectively the prognosis and outcome for dogs diagnosed with thoracolumbar intervertebral disc disease treated with partial percutaneous discectomy (PPD). Methods: Three hundred and thirty-one dogs presenting with symptoms of thoracolumbar intervertebral disc disease from 1998 to 2003 were treated with PPD. Diagnosis and location of intervertebral disc disease was confirmed by clinical examination, radiography, myelography and magnetic resonance imaging. PPD was performed via fluoroscopy-guided removal of a 5 mm bore cylinder out of the central intervertebral space. Results: Clinical success after surgery was achieved in 159 (88·8 per cent) grade II to IV patients and 58 (38·2 per cent) grade V patients. The mean (sd) time from percutaneous discectomy to first improvement was 8·3 (13·2) days. Clinical Significance: The PPD approach to the thoracolumbar spine involves minor trauma (yielding rapid recovery) and less pain, and produces results comparable with open fenestration. Consequently, this simple minimal invasive technique can be recommended as an alternative to the technique of fenestration and can be easily performed in addition to open surgical decompression techniques or prophylactically. However, it is not a replacement for surgical treatment in dogs with thoracolumbar disc disease that require removal of disc fragments causing spinal cord or nerve root compression.

Laparoscopic techniques are increasingly applied for the treatment of diverse gastrointestinal diseases. With regard to reports of a pronounced decrease of intra-abdominal blood flow with increasing intra-abdominal pressure, the present study investigates the impact of pressure and gas type on ischemia in small bowel anastomoses in the rat model. Laparotomy and ileoileal anastomosis were performed in 39 male Sprague-Dawley rats. A CO2 or helium pneumoperitoneum of 3 mm Hg or of 6 mm Hg was maintained before and after anastomoses. Rats in the control group received no pneumoperitoneum. Animals were sacrificed after 5 d, and the anastomotic region was explanted for subsequent histopathological examinations. In hematoxylin and eosin (HE)-stained sections, the Chiu score, villi configuration, and number of goblet cells were analyzed. Proliferation (Ki67) and expression of a matrix metalloproteinase (MMP-8) were examined by immunohistochemistry. Mucosal damage according to the scoring system by Chiu, the number of goblet cells, the villus length, the proliferation (Ki67), and the submucosal expression of MMP-8 was similar in all groups. Our results suggest that within a certain range of pressures and time, laparoscopic assisted surgery using CO2 pneumoperitoneum can be performed safely. Helium gas offers no advantages over CO2.

Background Trauma, vascular lesions or peritonitis can cause an increase of the intra-abdominal pressure (IAP) or an abdominal compartment syndrome (ACS). Maintaining the cardiac output (CO) cannot prevent impairment of organ function. However, it is unknown, whether an IAP of 30 mmHg can lead to oragn damage within 6 an 12 h despite unchanged CO. Methods We examined 16 male pigs (50 kg, SD 1,8). Animals were ventilated volume controlled and analogue-sedated using ketamine and pentobarbital. Via CO2-pneumoperitoneum, IAD was increased to 30 mmHg for 6 and 12 h (each n = 6). In the control (n = 4) the IAP remained unchanged. Heartrate (HR), mean arterial pressure (MAP), central venous pressure (CVP), CO and peak inspiratory pressure (PIP) were continuously recorded. Additional to basic fluid replacement (2 ml/kg/h) crystalloid volume was given whenever continuously monitored CO was below control values. In the end, animals were given an overdose of pentobarbital and specimen were taken from lung, heart, kidney, liver stomach as well as small and large bowel. Damage of bowel specimen was classified according to Park whereas damage to other organs was classified as none, low, intermediate and high. Statistic analysis was performed using ANOVA and post-hoc analysis together with paired tests. A p Results A significant increase of CVP and PIP was found whereas the other haemodynamic data was not changed. Compared to control, an increased morphologic damage was found in lung, stomach (12 h), liver, bowel and kidney. The myocardium was statistically unchanged. Conclusion Even a short-termed increase of the IAP for 6 h results in morphologic organ impairment despite an unchanged CO. In the clinical regard, these results imply an immediate decompression in the presence of a critically increased IAP.

To investigate the effect of meloxicam on the gut-liver axis after cirrhotic liver resection.Forty-four male Wistar rats were assigned to three groups: (1) control group (CG); (2) bile duct ligation with meloxicam treatment (BDL + M); and (3) bile duct ligation without meloxicam treatment (BDL). Secondary biliary liver cirrhosis was induced via ligature of the bile duct in the BDL + M and BDL groups. After 2 wk, the animals underwent a 50% hepatectomy. In the BDL + M group 15 min prior to the hepatectomy, one single dose of meloxicam was administered. Parameters measured included: microcirculation of the liver and small bowel; portal venous flow (PVF); gastrointestinal (GI) transit; alanine aminotransferase (ALT); malondialdehyde; interleukin 6 (IL-6), transforming growth factor beta 1 (TGF-β1) and hypoxia-inducible factor 1 alpha (HIF-1α) levels; mRNA expression of cyclooxigenase-2 (COX-2), IL-6 and TGF-β1; liver and small bowel histology; immunohistochemical evaluation of hepatocyte and enterocyte proliferation with Ki-67 and COX-2 liver expression.Proliferative activity of hepatocytes after liver resection, liver flow and PVF were significantly higher in CG vs BDL + M and CG vs BDL group (P0.05), whereas one single dose of meloxicam ameliorated liver flow and proliferative activity of hepatocytes in BDL + M vs BDL group. COX-2 liver expression at 24 h observation time (OT), IL-6 concentration and mRNA IL-6 expression in the liver especially at 3 h OT, were significantly higher in BDL group when compared with the BDL + M and CG groups (P0.01, P0.001, P0.01, respectively). Liver and small bowel histology, according to a semi quantitative scoring system, showed better integrity in BDL + M and CG as compared to BDL group. ALT release and HIF-1α levels at 1 h OT were significantly higher in BDL + M compared to CG and BDL group (P0.001 and P0.01, respectively). Moreover, ALT release levels at 3 and 24 h OT were significantly higher in BDL group compared to CG, P0.01. GI transit, enterocyte proliferative activity and number of goblet cells were in favor of meloxicam treatment vs BDL group (P0.05, P0.001, P0.01, respectively). Additionally, villus length were higher in BDL + M as compared to BDL group.One single dose of meloxicam administered after cirrhotic liver resection was able to cause better function and integrity of the remaining liver and small bowel.