Tamás Csonka

Red Cells, Hemoglobin, Heme, Iron, and Atherogenesis

Objective—We investigated whether red cell infiltration of atheromatous lesions promotes the later stages of atherosclerosis. Methods and Results—We find that oxidation of ferro (FeII) hemoglobin in ruptured advanced lesions occurs generating ferri (FeIII) hemoglobin and via more extensive oxidation ferrylhemoglobin (FeIII/FeIV=O). The protein oxidation marker dityrosine accumulates in complicated lesions, accompanied by the formation of cross-linked hemoglobin, a hallmark of ferrylhemoglobin. Exposure of normal red cells to lipids derived from atheromatous lesions causes hemolysis and oxidation of liberated hemoglobin. In the interactions between hemoglobin and atheroma lipids, hemoglobin and heme promote further lipid oxidation and subsequently endothelial reactions such as upregulation of heme oxygenase-1 and cytotoxicity to endothelium. Oxidative scission of heme leads to release of iron and a feed-forward process of iron-driven plaque lipid oxidation. The inhibition of heme release from globin by haptoglobin and sequestration of heme by hemopexin suppress hemoglobin-mediated oxidation of lipids of atheromatous lesions and attenuate endothelial cytotoxicity. Conclusion—The interior of advanced atheromatous lesions is a prooxidant environment in which erythrocytes lyse, hemoglobin is oxidized to ferri- and ferrylhemoglobin, and released heme and iron promote further oxidation of lipids. These events amplify the endothelial cell cytotoxicity of plaque components.

The age and genomic integrity of neurons after cortical stroke in humans

It has been unclear whether ischemic stroke induces neurogenesis or neuronal DNA rearrangements in the human neocortex. Using immunohistochemistry; transcriptome, genome and ploidy analyses; and determination of nuclear bomb test–derived 14C concentration in neuronal DNA, we found neither to be the case. A large proportion of cortical neurons displayed DNA fragmentation and DNA repair a short time after stroke, whereas neurons at chronic stages after stroke showed DNA integrity, demonstrating the relevance of an intact genome for survival.

Primary angiosarcoma of the pancreas mimicking severe acute pancreatitis – Case report

Primary angiosarcoma of the pancreas is an extremely rare neoplasm that often mimicks severe acute pancreatitis. A 58-year-old man was admitted with clinical and laboratory signs of severe acute pancreatitis. Contrast enhanced CT scan demonstrated haemorrhagic necrotizing inflammation of the pancreas involving the pancreatic tail, splenic hilum and small bowels with multiple peripancreatic and free abdominal fluid collection. Percutaneous drainage was performed. After 13 days, laparotomy was indicated because of persistent intra-abdominal bleeding, fever and a palpable, rapidly growing mass in the left upper quadrant of the abdomen. During the operation a necrotic, haemorrhagic mass was found in the pancreatic tail; a frozen section showed malignancy, although the tumour was unresectable. Despite all conservative and surgical therapeutic attempts, the patient died within four weeks after diagnosis. Final histology justified primary angiosarcoma of the pancreas. If a patient with signs of severe acute pancreatitis has fever without elevated PCT, the presence of a malignant tumour of the pancreas should be considered.

Lithocholic acid, a bacterial metabolite reduces breast cancer cell proliferation and aggressiveness

Our study aimed at finding a mechanistic relationship between the gut microbiome and breast cancer. Breast cancer cells are not in direct contact with these microbes, but disease could be influenced by bacterial metabolites including secondary bile acids that are exclusively synthesized by the microbiome and known to enter the human circulation. In murine and bench experiments, a secondary bile acid, lithocholic acid (LCA) in concentrations corresponding to its tissue reference concentrations (< 1 μM), reduced cancer cell proliferation (by 10-20%) and VEGF production (by 37%), aggressiveness and metastatic potential of primary tumors through inducing mesenchymal-to-epithelial transition, increased antitumor immune response, OXPHOS and the TCA cycle. Part of these effects was due to activation of TGR5 by LCA. Early stage breast cancer patients, versus control women, had reduced serum LCA levels, reduced chenodeoxycholic acid to LCA ratio, and reduced abundance of the baiH (7α/β-hydroxysteroid dehydroxylase, the key enzyme in LCA generation) gene in fecal DNA, all suggesting reduced microbial generation of LCA in early breast cancer.

Inclusion body myositis — a case based clinicopathological update

Inclusion body myositis is a slowly progressive myopathy affecting predominantly the middle-aged and older patient population. It is a major form of the idiopathic inflammatory myopathies which are chronic systemic autoimmune diseases characterized by symmetrical proximal muscle weakness. Unfortunately, there is no effective therapy yet; however, the early diagnosis is essential to provide treatment options which may significantly slow the progression of the disease. In our case-based clinicopathological study the importance of the close collaboration between the clinician and the neuropathologist is emphasised.

Inclusion body myositis – pathomechanism and lessons from genetics

Abstract Inclusion body myositis is a rare, late-onset myopathy. Both inflammatory and myodegenerative features play an important role in their pathogenesis. Overlapping clinicopathological entities are the familial inclusion body myopathies with or without dementia. These myopathies share several clinical and pathological features with the sporadic inflammatory disease. Therefore, better understanding of the genetic basis and pathomechanism of these rare familial cases may advance our knowledge and enable more effective treatment options in sporadic IBM, which is currently considered a relentlessly progressive incurable disease.