Cathepsin C role in inflammatory gastroenterological, renal, rheumatic, and pulmonary disorders

Cathepsin C (CatC, syn. Dipeptidyl peptidase I) is a lysosomal cysteine proteinase expressed in several tissues including inflammatory cells. This enzyme is important for maintaining multiple cellular functions and for processing immune cell-derived proteases. While mutations in the CatC gene were reported in Papillon-Lefèvre syndrome, a rare autosomal recessive disorder featuring hyperkeratosis and periodontitis, evidence from clinical and preclinical studies points toward pro-inflammatory effects of CatC in various disease processes that are mainly mediated by the activation of neutrophil serine proteinases. Moreover, tumor-promoting effects were ascribed to CatC. The aim of this review is to highlight current knowledge of the CatC as a potential therapeutic target in inflammatory disorders

Animal models for investigating chronic pancreatitis

Chronic pancreatitis is defined as a continuous or recurrent inflammatory disease of the pancreas characterized by progressive and irreversible morphological changes. It typically causes pain and permanent impairment of pancreatic function. In chronic pancreatitis areas of focal necrosis are followed by perilobular and intralobular fibrosis of the parenchyma, by stone formation in the pancreatic duct, calcifications in the parenchyma as well as the formation of pseudocysts. Late in the course of the disease a progressive loss of endocrine and exocrine function occurs. Despite advances in understanding the pathogenesis no causal treatment for chronic pancreatitis is presently available. Thus, there is a need for well characterized animal models for further investigations that allow translation to the human situation. This review summarizes existing experimental models and distinguishes them according to the type of pathological stimulus used for induction of pancreatitis. There is a special focus on pancreatic duct ligation, repetitive overstimulation with caerulein and chronic alcohol feeding. Secondly, attention is drawn to genetic models that have recently been generated and which mimic features of chronic pancreatitis in man. Each technique will be supplemented with data on the pathophysiological background of the model and their limitations will be discussed

Nutrition in Pancreatic Cancer: A Review

Background: Pancreatic cancer is the fourth leading cause of cancer-related mortality in both genders. More than 80% of patients suffer from significant weight loss at diagnosis and over time develop severe cachexia. Early nutritional support is therefore essential. Summary: This review evaluates the different nutritional therapies, such as enteral nutrition, parenteral nutrition and special nutritional supplements, on nutritional status, quality of life and survival. Key Message: Due to the high prevalence of malnutrition and the rapid development of anorexia-cachexia-syndrome, early nutritional intervention is crucial and supported by clinical data. Practical Implications: Enteral nutrition should be preferred over parenteral nutrition. Omega-3 fatty acids and L-carnitine are promising substances for the prevention of severe cachexia, but further randomized controlled trials are needed to establish generally accepted guidelines on nutrition in pancreatic cancer

Targeting cathepsin C ameliorates murine acetaminophen-induced liver injury

Acetaminophen (APAP) overdosing is a major cause of acute liver failure worldwide and an established model for drug-induced acute liver injury (ALI). While studying gene expression during murine APAP-induced ALI by 3\u27mRNA sequencing (massive analysis of cDNA ends, MACE), we observed splenic mRNA accumulation encoding for the neutrophil serine proteases cathepsin G, neutrophil elastase, and proteinase-3 - all are hierarchically activated by cathepsin C (CtsC). This, along with increased serum levels of these proteases in diseased mice, concurs with the established phenomenon of myeloid cell mobilization during APAP intoxication

Prophylactic Glycine Administration Attenuates Pancreatic Damage and Inflammation in Experimental Acute Pancreatitis

Background/Aims: Acute pancreatitis (AP) is characterized by premature zymogen activation, systemic inflammatory response resulting in inflammatory infiltrates, sustained intracellular calcium, neurogenic inflammation and pain. The inhibitory neurotransmitter and cytoprotective amino acid glycine exerts a direct inhibitory effect on inflammatory cells, inhibits calcium influx and neuronal activation and therefore represents a putative therapeutic agent in AP. Methods: To explore the impact of glycine, mild AP was induced in rats by supramaximal cerulein stimulation (10 µg/kg BW/h) and severe AP by retrograde injection of sodium taurocholate solution (3%) into the common biliopancreatic duct. 100/300 mmol glycine was administered intravenously before induction of AP. To elucidate the effect of glycine on AP, we determined pathomorphology, pancreatic cytokines as well as proteases, serum lipase and amylase, pancreatic and lung MPO activity and pain sensation. Results: Glycine administration resulted in a noticeable improvement of pathomorphological alterations in AP, such as a reduction of necrosis, inflammatory infiltrates and cytoplasmic vacuoles in cerulein pancreatitis. In taurocholate pancreatitis, glycine additionally diminished pancreatic cytokines and MPO activity, as well as serum lipase and amylase levels. Conclusions: Glycine reduced the severity of mild and much more of severe AP by attenuating the intrapancreatic and systemic inflammatory response. Therefore, glycine seems to be a promising tool for prophylactic treatment of AP

A diuranium carbide cluster stabilized inside a C80 fullerene cage.

Unsupported non-bridged uranium-carbon double bonds have long been sought after in actinide chemistry as fundamental synthetic targets in the study of actinide-ligand multiple bonding. Here we report that, utilizing Ih(7)-C80 fullerenes as nanocontainers, a diuranium carbide cluster, U=C=U, has been encapsulated and stabilized in the form of UCU@Ih(7)-C80. This endohedral fullerene was prepared utilizing the Krätschmer-Huffman arc discharge method, and was then co-crystallized with nickel(II) octaethylporphyrin (NiII-OEP) to produce UCU@Ih(7)-C80·[NiII-OEP] as single crystals. X-ray diffraction analysis reveals a cage-stabilized, carbide-bridged, bent UCU cluster with unexpectedly short uranium-carbon distances (2.03 Å) indicative of covalent U=C double-bond character. The quantum-chemical results suggest that both U atoms in the UCU unit have formal oxidation state of +5. The structural features of UCU@Ih(7)-C80 and the covalent nature of the U(f1)=C double bonds were further affirmed through various spectroscopic and theoretical analyses

Absence of the neutrophil serine protease cathepsin G decreases neutrophil granulocyte infiltration but does not change the severity of acute pancreatitis

Acute pancreatitis is characterized by an early intracellular protease activation and invasion of leukocytes into the pancreas. Cathepsins constitute a large group of lysosomal enzymes, that have been shown to modulate trypsinogen activation and neutrophil infiltration. Cathepsin G (CTSG) is a neutrophil serine protease of the chymotrypsin C family known to degrade extracellular matrix components and to have regulatory functions in inflammatory disorders. The aim of this study was to investigate the role of CTSG in pancreatitis. Isolated acinar cells were exposed to recombinant CTSG and supramaximal cholezystokinin stimulation. In CTSG(-/-) mice and corresponding controls acute experimental pancreatitis was induced by serial caerulein injections. Severity was assessed by histology, serum enzyme levels and zymogen activation. Neutrophil infiltration was quantified by chloro-acetate ersterase staining and myeloperoxidase measurement. CTSG was expessed in inflammatory cells but not in pancreatic acinar cells. CTSG had no effect on intra-acinar-cell trypsinogen activation. In CTSG(-/-) mice a transient decrease of neutrophil infiltration into the pancreas and lungs was found during acute pancreatitis while the disease severity remained largely unchanged. CTSG is involved in pancreatic neutrophil infiltration during pancreatitis, albeit to a lesser degree than the related neutrophil (PMN) elastase. Its absence therefore leaves pancreatitis severity essentially unaffected

Korruption: ein ungerechtfertigter Eingriff in internationale Menschenrechte? Chancen und Grenzen einer opferbezogenen Korruptionsperspektive

<p><b>Daily carbohydrate (A) and sugar (B) intake by groups and subgroups.</b> Carbohydrate (A) and sugar intake (B) as illustrated in percent. The boxes cover the first quartile on the bottom and the third quartile on the top. Whiskers reach from the minimum to the maximum value excluding outliers (illustrated by dots). Shift-working group and shift-working nursing-staff subgroup cover identical cohorts. NG, non-shift-working group; SG, shift-working group; SN, shift-working nursing-staff subgroup; NO, non-shift-working office-staff subgroup; NN, non-shift-working nursing-staff subgroup *p<0.05.</p

Peritonitis secondary to traumatic duodenal laceration in the presence of a large pancreatic pseudocyst: a case report

<p>Abstract</p> <p>Introduction</p> <p>A pancreatic pseudocyst is a common sequela of severe acute pancreatitis. Commonly, it presents with abdominal pain and a mass in the epigastrium several weeks after the acute episode and can be managed conservatively, endoscopically or surgically. We report a patient with a pancreatic pseudocyst awaiting endoscopic therapy who developed a life-threatening complication following a rather innocuous trauma to the abdomen.</p> <p>Case presentation</p> <p>A 23-year-old Asian male student presented as an emergency with an acute abdomen a week after a minor trauma to his upper abdomen. The injury occurred when he was innocently punched in the abdomen by a friend. He experienced only moderate discomfort briefly at the time. His past medical history included coeliac disease and an admission four months previously with severe acute pancreatitis. He was hospitalized for 15 days; his pancreatitis was thought to be due to alcohol binge drinking on weekends. Ultrasound scanning showed no evidence of gallstone disease. Five days after the trauma, he became anorexic, lethargic and feverish and started vomiting bilious content. Seven days post-trauma, he presented to our emergency department with severe abdominal pain. An emergency laparotomy was performed where a transverse linear duodenal laceration was found at the junction of the first and second part of his duodenum, with generalized peritonitis. His stomach and duodenum were stretched over a large pancreatic pseudocyst posterior to his stomach. It was postulated that an incomplete duodenal injury (possibly a serosal tear) occurred following the initial minor trauma, which was followed by local tissue necrosis at the injury site resulting in a delayed presentation of generalized peritonitis.</p> <p>Conclusion</p> <p>This is the first reported case of a traumatic duodenal laceration following minor blunt trauma in the presence of a large pancreatic pseudocyst. Minor blunt abdominal trauma in a normal healthy adult would not be expected to result in a significant duodenal injury. In the presence of a large pseudocyst, however, the stretching of the duodenum over the pseudocyst had probably predisposed the duodenum to this injury. Patients awaiting therapeutic interventions for their pancreatic pseudocysts should be warned about this unusual but life-threatening risk following minor blunt abdominal trauma.</p

Antimicrobial use in European acute care hospitals: results from the second point prevalence survey (PPS) of healthcare-associated infections and antimicrobial use, 2016 to 2017

Antimicrobial agents used to treat infections are life-saving. Overuse may result in more frequent adverse effects and emergence of multidrug-resistant microorganisms. In 2016-17, we performed the second point-prevalence survey (PPS) of healthcare-associated infections (HAIs) and antimicrobial use in European acute care hospitals. We included 1,209 hospitals and 310,755 patients in 28 of 31 European Union/European Economic Area (EU/EEA) countries. The weighted prevalence of antimicrobial use in the EU/EEA was 30.5% (95% CI: 29.2-31.9%). The most common indication for prescribing antimicrobials was treatment of a community-acquired infection, followed by treatment of HAI and surgical prophylaxis. Over half (54.2%) of antimicrobials for surgical prophylaxis were prescribed for more than 1 day. The most common infections treated by antimicrobials were respiratory tract infections and the most commonly prescribed antimicrobial agents were penicillins with beta-lactamase inhibitors. There was wide variation of patients on antimicrobials, in the selection of antimicrobial agents and in antimicrobial stewardship resources and activities across the participating countries. The results of the PPS provide detailed information on antimicrobial use in European acute care hospitals, enable comparisons between countries and hospitals, and highlight key areas for national and European action that will support efforts towards prudent use of antimicrobials