Mitochondria-targeted hydrogen sulfide donor reduces fatty liver and obesity in mice fed a high fat diet by inhibiting de novo lipogenesis and inflammation via mTOR/SREBP-1 and NF-κB signaling pathways.

Metabolic diseases that include obesity and metabolic-associated fatty liver disease (MAFLD) are a rapidly growing worldwide public health problem. The pathogenesis of MAFLD includes abnormally increased lipogenesis, chronic inflammation, and mitochondrial dysfunction. Mounting evidence suggests that hydrogen sulfide (H2S) is an important player in the liver, regulating lipid metabolism and mitochondrial function. However, direct delivery of H2S to mitochondria has not been investigated as a therapeutic strategy in obesity-related metabolic disorders. Therefore, our aim was to comprehensively evaluate the influence of prolonged treatment with a mitochondria sulfide delivery molecule (AP39) on the development of fatty liver and obesity in a high fat diet (HFD) fed mice. Our results demonstrated that AP39 reduced hepatic steatosis in HFD-fed mice, which was corresponded with decreased triglyceride content. Furthermore, treatment with AP39 downregulated pathways related to biosynthesis of unsaturated fatty acids, lipoprotein assembly and PPAR signaling. It also led to a decrease in hepatic de novo lipogenesis by downregulating mTOR/SREBP-1/SCD1 pathway. Moreover, AP39 administration alleviated obesity in HFD-fed mice, which was reflected by reduced weight of mice and adipose tissue, decreased leptin levels in the plasma and upregulated expression of adipose triglyceride lipase in epididymal white adipose tissue (eWAT). Finally, AP39 reduced inflammation in the liver and eWAT measured as the expression of proinflammatory markers (Il1b, Il6, Tnf, Mcp1), which was due to downregulated mTOR/NF-κB pathway. Taken together, mitochondria-targeted sulfide delivery molecules could potentially provide a novel therapeutic approach to the treatment/prevention of obesity-related metabolic disorders.

Is triggering receptor expressed on myeloid cell 1 (TREM-1) protein a new marker of serious infectious complications in colorectal surgery?: case-matched pilot study.

PURPOSE: The purpose of the study was to evaluate the usefulness of the triggering receptor expressed on myeloid cell 1 (TREM-1) protein as a marker for serious infectious complications during laparoscopic colorectal surgery. METHODS: Sixty-four patients with colon or rectal cancer, who underwent an elective laparoscopic colorectal cancer surgery from November 2018 to February 2020, were included in the analysis. Blood samples of the TREM-1 protein testing were collected four times from each patient: before and on three following postoperative days (PODs). Patients were divided into two groups according to the presence of infectious complications. Subsequently, patients with infectious complications (group 1) were matched 1:1 with patients without complications (group 2). The case-matched analysis was done by selecting patients from the control group by age, ASA scale, cancer stage, and type of surgery. RESULTS: There was no significant difference in demographic and operative characteristics between the two groups. The median length of hospital stay was longer in group 1 than in group 2 (11 days vs. 5 days, p < 0.001). Preoperative measurements of TREM-1 protein did not differ between the two groups. There were no significant differences in the measurements on the first and third postoperative days. However, the median TREM-1 measurement was higher in group 1 on the second postoperative day (542 pg/ml vs. 399 pg/ml; p = 0.040). The difference was more apparent when only severe postoperative complications were considered. When compared to the group without any complications, the median TREM-1 level was significantly higher in the group with severe infection complications in POD 1, POD 2, and POD 3 (p < 0.05). The receiver operating characteristic (ROC) curve demonstrated that TREM-1 readings in POD 2 had a sensitivity of 83% and a specificity of 84% for the presence of severe infection complications at a value of 579.3 pg/ml (AUC 0.8, 95%CI 0.65-0.96). CONCLUSION: TREM-1 measurements might become a helpful predictive marker in the early diagnosis of serious infectious complications in patients following laparoscopic colorectal surgery.

Analysis of biochemical parameters in an experimental model of chronic pancreatitis in rats.

BACKGROUND: Despite advanced research and great progress in understanding the chronic pancreatitis (CP) pathogenesis, no current causal treatment for the condition is available. For preclinical studies, the existence of a well-characterized CP animal model is essential. The aim of the study was to assess the impact of chronic pancreatitis on the antioxidant enzymes activity in rat blood serum and on the level of glutathione (intracellular antioxidant) in rat pancreas. METHODS: The experiments were carried out on the Wistar Kyoto rats in two groups: control and study group (CP), in which chemical induction of pancreatitis with dibutyl dichloride was performed. Serum enzyme activities of amylase, lipase, catalase and superoxide dismutase were analyzed. The levels of the following biochemical parameters were also investigated: total protein, albumin, calcium, magnesium, and triglycerides. Levels of low-molecular-weight thiols: reduced (GSH) and oxidized (GSSG) glutathione, were determined in pancreatic homogenates. RESULTS: Histopathological imaging of rat pancreatic parenchyma with induced inflammation confirmed focal lymphocytic interstitial chronic pancreatitis with fibrosis features and mild parenchymal atrophy, as well as pancreatic islets degeneration. In the CP group, we observed a statistically significant decrease in serum amylase and lipase activities and in total protein/albumin levels. Also, the elevated catalase activity was registered. In CP rats' tissues, we observed a 15-fold reduction in GSH levels. The other examined parameters remained unchanged. Clinically relevant are hypoalbuminemia and a moderate decrease in lipase activity. The described changes are most probably indicative of the impaired exocrine pancreas function, however without organ failure features.

Expanded insights into the neural component of the activity-based anorexia animal model - morphological changes in the enteric nervous system and altered pain perception.

Anorexia nervosa (AN) is an eating disorder characterized by distinct etiopathogenetic concepts that are gradually being linked together to unravel the dominant pathophysiological pathways underlying the disease. Excessive food restrictions, often accompanied by over-exercise and undertaken to lose weight, lead to the development of numerous complications. The biological concept of neurohormonal dysfunction in AN seems incomplete without demonstrating or excluding the role of the enteric nervous system (ENS). Using an animal model of activity-based anorexia (ABA), we conducted the preliminary assessment of the ENS structure. Here we show, in preparations stained by immunohistochemistry with anti- ChAT, anti-NOS, anti-PGP 9.5, anti-c-fos, and anti-TH antibodies, a lower density of cholinergic and nitrergic nerve fibers as well as reduced neuronal activity in myenteric plexus. Such structural and functional damage to the ENS may be responsible for a number of gastrointestinal symptoms that worsen the course of the disease. In addition, we expanded the study to address the unresolved issue of mechanical and thermal pain sensitivity in AN. The Von Frey and hot plate tests revealed, that in ABA animals, the pain threshold for mechanical stimulus decreases while for thermal increases. In this way, we have significantly supplemented the background of AN with potentially observable nervous system changes which may influence the evolution of the therapeutic approach in the future.

Pretreatment with Warfarin Attenuates the Development of Ischemia/Reperfusion-Induced Acute Pancreatitis in Rats.

In acute pancreatitis (AP), pancreatic damage leads to local vascular injury, manifesting as endothelial damage and activation, increased vascular permeability, leukocyte rolling, sticking and transmigration to pancreatic tissue as well as activation of coagulation. Previous studies have shown that pretreatment with heparin or acenocoumarol inhibits the development of AP. The aim of the present study was to check the impact of pretreatment with warfarin, an oral vitamin K antagonist, on the development of ischemia/reperfusion-induced AP in rats. AP was induced by pancreatic ischemia followed by reperfusion of the gland. Warfarin (90, 180 or 270 µg/kg/dose) or vehicle were administered intragastrically once a day for 7 days before induction of AP. The effect of warfarin on the severity of AP was assessed 6 h after pancreatic reperfusion. The assessment included histological, functional, and biochemical analyses. Pretreatment with warfarin given at a dose of 90 or 180 µg/kg/dose increased the international normalized ratio and reduced morphological signs of pancreatic damage such as pancreatic edema, vacuolization of acinar cells, necrosis and the number of hemorrhages. These effects were accompanied by an improvement of pancreatic blood flow and a decrease in serum level amylase, lipase, pro-inflammatory interleukin-1ß and plasma level of D-dimer. In contrast, pretreatment with warfarin given at a dose of 270 µg/kg/dose led to an increase in severity of pancreatic damage and biochemical indicators of AP. In addition, this dose of warfarin resulted in deaths in some animals. Pretreatment with low doses of warfarin inhibits the development of AP induced by pancreatic ischemia followed by reperfusion.

Radiological Response and Neutrophil-to-Lymphocyte Ratio as Predictive Factors for Progression-Free and Overall Survival in Metastatic Renal Cell Carcinoma Patients Treated with Sunitinib.

Renal cell carcinoma (RCC) represents 2-3% of all malignancies. Most RCC-related deaths are caused by metastases of the disease. Studies suggest that inflammation-related parameters are of prognostic significance in metastatic renal cell carcinoma (mRCC) patients. Neutrophilia and thrombocytosis are markers of systemic inflammation that accompanies cancer, while lymphopenia is related to dysfunctions of the immune system. Neutrophil-to-lymphocyte ratio (NLR) and platelet-to-lymphocyte ratio (PLR) thus seem particularly interesting from a clinical perspective. The goal of this study was to determine if the response to therapy, consisting of reductions in radiologically assessed tumor burden and in inflammation-related parameters after 12 weeks of treatment with sunitinib, has a predictive value for outcome. One hundred thirty-one mRCC patients treated with the first-line sunitinib were evaluated. Inflammation-related parameters and radiologic response were correlated with treatment outcomes, progression-free, and overall survival. We found that the longest median progression-free survival of 37 months (Q1; Q3-15; not reached) and overall survival of 40 months (Q1; Q3-26; not reached) were achieved by patients who had either partial or complete response according to RECIST 1.1 and NLR lower than 1.64. In conclusion, the study confirmed that both objective response and lower grade of inflammation during treatment are predictive of better outcomes in mRCC patients treated with sunitinib.

Hand-Foot Syndrome and Progression-Free Survival in Patients Treated with Sunitinib for Metastatic Clear Cell Renal Cell Carcinoma.

Patients with metastatic clear cell renal cell carcinoma (mRCC) typically receive systemic treatment with tyrosine kinase inhibitors (TKI). Side effects include the hand-foot syndrome (HFS), tiredness, nausea, decreased appetite, diarrhea, myelosuppression, and hypertension. This study seeks to define the relationship between the incidence of HFS after the first cycle of treatment with sunitinib as the first-line treatment for mRCC (50 mg/day, 6-week schedule: 4 weeks on and 2 weeks off) and progression-free survival. We found that patients, treated with sunitinib for mRCC, who did not experience HFS had the median progression-free survival of 9.8 months. HFS symptoms appeared in 20% of patients after the first treatment cycle. The appearance of HFS was a predictor of a longer progression-free survival. In fact, progression-free survival was elongated in the HFS group over and beyond the observation period of 60 months, which rendered the median progression-free survival calculation impossible. These findings reaffirm the importance of monitoring skin toxicity during treatment with TKI. We conclude that the appearance of adverse skin symptoms presages better outcomes in patients treated with sunitinib for mRCC.

Potential Prognostic Markers of Acute Kidney Injury in the Early Phase of Acute Pancreatitis.

Acute kidney injury (AKI) is a serious complication of acute pancreatitis (AP), which occurs in up to 70% of patients with severe AP and significantly increases the risk of mortality. At present, AKI is diagnosed based on dynamic increase in serum creatinine and decreased urine output; however, there is a need for earlier and more accurate biomarkers. The aim of the study was to review current evidence on the laboratory tests that were studied as the potential biomarkers of AKI in AP. We also briefly summarized the knowledge coming from the studies including sepsis or ICU patients since severe acute pancreatitis is associated with systemic inflammation and organ failure. Serum cystatin C and serum or urine NGAL have been shown to predict or diagnose AKI in AP; however, this evidence come from the single center studies of low number of patients. Other markers, such as urinary kidney injury molecule-1, cell cycle arrest biomarkers (tissue inhibitor metalloproteinase-2 and urine insulin-like growth factor-binding protein 7), interleukin-18, liver-type fatty acid-binding protein, or calprotectin have been studied in other populations suffering from systemic inflammatory states. In AP, the potential markers of AKI may be significantly influenced by either dehydration or inflammation, and the impact of these factors may be difficult to distinguish from kidney injury. The subject of AKI complicating AP is understudied. More studies are needed, for both exploratory (to choose the best markers) and clinical (to evaluate the diagnostic accuracy of the chosen markers in real clinical settings).

Correction: Warzecha, Z. et al. Protective Effect of Pretreatment with Acenocoumarol in Cerulein-Induced Acute Pancreatitis. Int. J. Mol. Sci. 2016, 17, 1709.

We would like to submit the correction to our published paper [...].

Correction: Warzecha, Z., et al. Therapeutic Effect of Low Doses of Acenocoumarol in the Course of Ischemia/Reperfusion-Induced Acute Pancreatitis in Rats. Int. J. Mol. Sci. 2017, 18, 882.

We would like to submit this correction to our published paper [...].

Correction: Bonior, J., et al. Capsaicin-Sensitive Sensory Nerves Are Necessary for the Protective Effect of Ghrelin in Cerulein-Induced Acute Pancreatitis in Rats. Int. J. Mol. Sci. 2017, 18, 1402.

We would like to submit the correction to our published paper [...].

Retinopathy severity correlates with RANTES concentrations and CCR 5-positive microvesicles in diabetes.

INTRODUCTION: RANTES regulates leukocyte recruitment to areas affected by the inflammatory process. Microvesicles (MVs) belong to a subpopulation of extracellular vesicles and show proangiogenic potential by transferring bioactive molecules to target cells. OBJECTIVES: the aim of this study was to determine the relationship between circulating proangiogenic factors (MVs and RANTES) and diabetes complications in patients with different severities of diabetic retinopathy (DR). CCR5 (CD195) receptors transported by annexin V-labeled MVs were also investigated. PATIENTS AND METHODS: Diabetic patients (n = 61), among whom 35 had confirmed DR classified according to guidelines, and controls (n = 25) were included. MVs were isolated by centrifugation and analyzed using flow cytometry, RANTES was assessed by ELISA. RESULTS: the study group differed from the control group with respect to BMI, age, heart rate and systolic blood pressure. Additionally, glucose and creatinine concentrations were significantly increased: 5.30 [5.09-5.62] vs. 9.38 [7.48-11.55] (p <0.0001) mmol/l and 74.59 [64-84] vs. 89.00 [77.11-105.44] µmol/l (p = 0.0005), respectively. RANTES concentrations were significantly increased in diabetic patients compared to those of controls (15.5 (9.7-18.1) vs. 8.9 (0.9-14.6) µg/ml (p = 0.011)), and RANTES concentration significantly increased with respect to nonproliferative DR progression. Moreover, the number of CCR5-positive MVs was significantly increased in patients with heavy nonproliferative diabetic retinopathy (HNPDR) compared to those with so nonproliferative DR (SNPDR): 1178 [836-2254] vs. 394 [275-799] counts/µl. CONCLUSIONS: Correlation of RANTES concentrations with the stage of nonproliferative DR and the statistically significant dependence of CCR5-positive MVs with disease progression suggest that MVs and RANTES can be considered new biomarkers.

Changes in plasma albumin levels in early detection of infectious complications after laparoscopic colorectal cancer surgery with ERAS protocol.

BACKGROUND: Combination of laparoscopic approach with ERAS protocol in colorectal surgery allows for an early discharge. However there is a risk that some of the discharged patients are developing, asymptomatic at the time, infectious complications. This may lead to a delay in diagnostics and proper treatment introduction. We aimed to assess the usefulness of preoperative plasma albumin concentration and their changes as indicators of infectious complications in patients undergoing colorectal cancer surgery. METHODS: Prospective analysis included 105 consecutive patients who underwent laparoscopic colorectal cancer resection between August 2014 and September 2016. In all cases standardised 16-item perioperative care ERAS protocol was used (mean compliance > 85%). Patients with IBD, distant metastases, undergoing emergency or multivisceral resection were excluded. Blood samples were collected preoperatively and on POD 1, 2, 3. Plasma albumin concentration was measured. Patients were divided into two groups depending on the presence of infectious complications. We analysed the differences in the levels of albumin and the dynamics of changes. RESULTS: Group 1-82 not complicated patients, Group 2-23 patients with at least one infectious complication. Preoperatively, there were no significant differences in the levels of serum albumin between those groups (Group 1-38.7 ± 4.9 g/l; Group 2-37.7 ± 5.0 g/l). In postoperative period, decrease was observed in both (POD 1: Group 1-36.5 ± 4.2 g/l, Group 2-34.7 ± 4.2 g/l, p = 0.07; POD 2: Group 1-36.2 ± 4.1 g/l, Group 2-32.6 ± 5.6 g/l, p = 0.01; POD 3: Group 1-36.0 ± 4.4 g/l, Group 2-30.9 ± 3.5 g/l, p = 0.01). The decrease was significantly greater in Group 2 on POD 2 and 3. CONCLUSIONS: We showed that a regular measurement of albumin in the early postoperative days may be beneficial in the detection of postoperative infectious complications. Although changes in albumins are observed early after surgery, this parameter is relatively unspecific.

Markers of Glomerular and Tubular Damage in the Early Stage of Kidney Disease in Type 2 Diabetic Patients.

Diabetic kidney disease develops in half of genetically predisposed patients with type 2 diabetes (T2DM). Early diagnosis of kidney damage and nephroprotective treatment are the ways of preventing the disease progression. Our aim was to evaluate selected laboratory markers of glomerular and tubular damage in T2DM patients with early stages of chronic kidney disease (G1/G2, A1/A2) for their associations with A2 albuminuria and early decline in the estimated glomerular filtration rate (eGFR). Among 80 T2DM patients with median eGFR of 92.4 ml/min/1.73 m2 and median urinary albumin to creatinine ratio (uACR) of 4.69 mg/g, 19 had uACR > 30 mg/g (A2). Higher serum cystatin C, serum and urine neutrophil gelatinase associated lipocalin (NGAL), urine kidney injury molecule 1 (KIM-1), detectable urine transferrin and IgG, and lower serum uromodulin significantly predicted A2 albuminuria, urine KIM-1/creatinine ratio, and IgG being the best predictors. Albuminuria, urine NGAL/creatinine, and IgG correlated with diabetes duration. Albuminuria, urine NGAL, transferrin, IgG, and uromodulin correlated with diabetes control. In a subgroup of 29 patients, retrospective data were available on changes in eGFR and uACR over one year. Decline in eGFR was observed in 17 patients and increase in uACR in 10 patients. Serum and urine NGAL correlated with eGFR changes. Higher urine NGAL, KIM-1/creatinine ratio, and detectable IgG were significantly associated with the increase in uACR. Widely available markers, serum cystatin C, urine IgG, transferrin, and NGAL, may help in early assessment of kidney disease in T2DM patients; however, large prospective studies are needed to confirm the conclusion.

Does the Automatic Measurement of Interleukin 6 Allow for Prediction of Complications during the First 48 h of Acute Pancreatitis?

Acute pancreatitis (AP) in most patients takes a course of self-limiting local inflammation. However, up to 20% of patients develop severe AP (SAP), associated with systemic inflammation and/or pancreatic necrosis. Early prediction of SAP allows for the appropriate intensive treatment of severe cases, which reduces mortality. Serum interleukin-6 (IL-6) has been proposed as a biomarker to assist early diagnosis of SAP, however, most data come from studies utilizing IL-6 measurements with ELISA. Our aim was to verify the diagnostic usefulness of IL-6 for the prediction of SAP, organ failure, and need for intensive care in the course of AP using a fully automated assay. The study included 95 adult patients with AP of various severity (29 mild, 58 moderately-severe, 8 severe) admitted to a hospital within 24 h from the onset of symptoms. Serum IL-6 was measured using electochemiluminescence immunoassay in samples collected on admission and on the next day of hospital stay. On both days, patients with SAP presented the highest IL-6 levels. IL-6 correlated positively with other inflammatory markers (white blood cell and neutrophil counts, C-reactive protein, procalcitonin), the markers of renal injury (kidney injury molecule-1 and neutrophil gelatinase-associated lipocalin), and the markers of endothelial dysfunction (angiopoietin-2, soluble fms-like tyrosine kinase-1). IL-6 on admission significantly predicted SAP, vital organ failure, and the need for intensive care or death, with areas under the receiver operating curve between 0.75 and 0.78, not significantly different from multi-variable prognostic scores. The fully automated assay allows for fast and repeatable measurements of serum IL-6, enabling wider clinical use of this valuable biomarker.

Treatment with Obestatin-A Ghrelin Gene-Encoded Peptide-Reduces the Severity of Experimental Colitis Evoked by Trinitrobenzene Sulfonic Acid.

Obestatin is a 23-amino acid peptide derived from proghrelin, a common prohormone for ghrelin and obestatin. Previous studies showed that obestatin exhibited some protective and therapeutic effects in the gut. The aim of our presented study was to examine the effect of treatment with obestatin on trinitrobenzene sulfonic acid (TNBS)-induced colitis. In rats anesthetized with ketamine, colitis was induced through intrarectal administration of 25 mg of 2,4,6-trinitrobenzene sulfonic acid (TNBS). Obestatin was administered intraperitoneally at doses of 4, 8, or 16 nmol/kg, twice per day for four consecutive days. The first dose of obestatin was given one day before the induction of colitis, and the last one was given two days after administration of TNBS. Fourteen days after the induction of colitis, rats were anesthetized again with ketamine, and the severity of colitis was determined. The administration of obestatin had no effect on the parameters tested in rats without the induction of colitis. In rats with colitis, administration of obestatin at doses of 8 or 16 nmol/kg reduced the area of colonic damage, and improved mucosal blood flow in the colon. These effects were accompanied by a reduction in the colitis-evoked increase in the level of blood leukocytes, and mucosal concentration of pro-inflammatory interleukin-1ß. Moreover, obestatin administered at doses of 8 or 16 nmol/kg reduced histological signs of colonic damage. The administration of obestatin at a dose of 4 nmol/kg failed to significantly affect the parameters tested. Overall, treatment with obestatin reduced the severity of TNBS-induced colitis in rats. This effect was associated with an improvement in mucosal blood flow in the colon, and a decrease in local and systemic inflammatory processes.

Neutrophil to lymphocyte ratio at the early phase of acute pancreatitis correlates with serum urokinase-type plasminogen activator receptor and interleukin 6 and predicts organ failure.

BACKGROUND: In early phase of acute pancreatitis (AP), systemic inflammatory response syndrome may lead to organ failure. The severe form of AP is associated with high mortality that may be prevented by timely diagnosis and treatment of the predicted severe cases. Serum interleukin 6 (IL-6) and urokinase-type plasminogen activator receptor (uPAR) have been proposed as accurate early markers of severe AP. The aim of the study was to assess whether widely available blood count indexes: neutrophil to lymphocyte (NLR), lymphocyte to monocyte (LMR) and platelet to lymphocyte ratios correlate with IL-6 and uPAR and may be utilized to predict organ complications at the early phase of AP. METHODS: The study included 95 adult patients with AP treated at the Surgical Ward Complex of Health Care Centers in Wadowice, Poland. Organ failure was diagnosed according to modi ed Marshall scoring system, as recommended by 2012 Atlanta classification. Blood samples for laboratory tests were collected on days 1, 2 and 3 following the onset of AP symptoms. RESULTS: Patients with organ failure presented significantly lower LMR on day 1 and significantly higher NLR on days 2 and 3. Strong positive correlations between NLR and IL-6 and moderate correlations between NLR and uPAR were observed throughout the study. Day 2 and 3 NLR values significantly predicted organ failure at the early phase of AP. CONCLUSIONS: Taking into account the wide availability of NLR, it may be considered as a surrogate of more expensive tests to help the early assessment of organ failure complicating AP.

The Interplay between Inflammation, Coagulation and Endothelial Injury in the Early Phase of Acute Pancreatitis: Clinical Implications.

Acute pancreatitis (AP) is an inflammatory disease with varied severity, ranging from mild local inflammation to severe systemic involvement resulting in substantial mortality. Early pathologic events in AP, both local and systemic, are associated with vascular derangements, including endothelial activation and injury, dysregulation of vasomotor tone, increased vascular permeability, increased leukocyte migration to tissues, and activation of coagulation. The purpose of the review was to summarize current evidence regarding the interplay between inflammation, coagulation and endothelial dysfunction in the early phase of AP. Practical aspects were emphasized: (1) we summarized available data on diagnostic usefulness of the markers of endothelial dysfunction and activated coagulation in early prediction of severe AP; (2) we reviewed in detail the results of experimental studies and clinical trials targeting coagulation-inflammation interactions in severe AP. Among laboratory tests, d-dimer and angiopoietin-2 measurements seem the most useful in early prediction of severe AP. Although most clinical trials evaluating anticoagulants in treatment of severe AP did not show benefits, they also did not show significantly increased bleeding risk. Promising results of human trials were published for low molecular weight heparin treatment. Several anticoagulants that proved beneficial in animal experiments are thus worth testing in patients.

Serum Concentrations of Angiopoietin-2 and Soluble fms-Like Tyrosine Kinase 1 (sFlt-1) Are Associated with Coagulopathy among Patients with Acute Pancreatitis.

In severe acute pancreatitis (SAP), systemic inflammation leads to endothelial dysfunction and activation of coagulation. Thrombotic disorders in acute pancreatitis (AP) include disseminated intravascular coagulation (DIC). Recently, angiopoietin-2 and soluble fms-like tyrosine kinase 1 (sFlt-1) were proposed as markers of endothelial dysfunction in acute states. Our aim was to assess the frequency of coagulation abnormalities in the early phase of AP and evaluate the relationships between serum angiopoietin-2 and sFlt-1 and severity of coagulopathy. Sixty-nine adult patients with AP were recruited: five with SAP, 15 with moderately severe AP (MSAP) and 49 with mild AP. Six patients were diagnosed with DIC according to International Society on Thrombosis and Haemostasis (ISTH) score. All patients had at least one abnormal result of routine tests of hemostasis (low platelet count, prolonged clotting times, decreased fibrinogen, and increased D-dimer). The severity of coagulopathy correlated with AP severity according to 2012 Atlanta criteria, bedside index of severity in AP and duration of hospital stay. D-dimers correlated independently with C-reactive protein and studied markers of endothelial dysfunction. Angiopoietin-2, D-dimer, and ISTH score were best predictors of SAP, while sFlt-1 was good predictor of MSAP plus SAP. In clinical practice, routine tests of hemostasis may assist prognosis of AP.

Essential Role of Growth Hormone and IGF-1 in Therapeutic Effect of Ghrelin in the Course of Acetic Acid-Induced Colitis.

Previous studies have shown that ghrelin exhibits a protective and therapeutic effect in the gut. The aim of the present study was to examine whether administration of ghrelin affects the course of acetic acid-induced colitis and to determine what is the role of growth hormone (GH) and insulin-like growth factor-1 (IGF-1) in this effect. In sham-operated or hypophysectomized male Wistar rats, colitis was induced by enema with 1 mL of 3% solution of acetic acid. Saline or ghrelin (given at the dose of 8 nmol/kg/dose) was administered intraperitoneally twice a day. Seven days after colitis induction, rats were anesthetized and the severity of the colitis was assessed. Treatment with ghrelin reduced the area of colonic mucosa damage in pituitary-intact rat. This effect was associated with increase in serum levels of GH and IGF-1. Moreover, administration of ghrelin improved blood flow in colonic mucosa and mucosal cell proliferation, as well as reduced mucosal concentration of proinflammatory interleukin-1ß (IL-1ß) and activity of myeloperoxidase. Hypophysectomy reduced serum levels of GH and IGF-1 and increased the area of colonic damage in rats with colitis. These effects were associated with additional reduction in mucosal blood follow and DNA synthesis when compared to pituitary-intact rats. Mucosal concentration of IL-1ß and mucosal activity of myeloperoxidase were maximally increased. Moreover, in hypophysectomized rats, administration of ghrelin failed to affect serum levels of GH or IGF-1, as well as the healing rate of colitis, mucosal cell proliferation, and mucosal concentration of IL-1ß, or activity of myeloperoxidase. We conclude that administration of ghrelin accelerates the healing of the acetic acid-induced colitis. Therapeutic effect of ghrelin in experimental colitis is mainly mediated by the release of endogenous growth hormone and IGF-1.