Similarities and differences of human and experimental mouse lymphangiomas.

Lymphangioma is a disfiguring malformation of early childhood. A mouse lymphangioma model has been established by injecting Freund's incomplete adjuvant (FIA) intraperitoneally, but has not been compared with the human disease. We show that, in accordance with studies from the 1960s, the mouse model represents an oil-granuloma, made up of CD45-positive leukocytes and invaded by blood and lymph vessels. Several markers of lymphatic endothelial cells are expressed in both mouse and human, like CD31, Prox1, podoplanin, and Lyve-1. However, the human disease affects all parts of the lymphovascular tree. We observed convolutes of lymphatic capillaries, irregularly formed collectors with signs of disintegration, and large lymph cysts. We observed VEGFR-2 and -3 expression in both blood vessels and lymphatics of the patients, whereas in mouse VEGFR-2 was confined to activated blood vessels. The experimental mouse FIA model represents a vascularized oil-granuloma rather than a lymphangioma and reflects the complexity of human lymphangioma only partially.     

Gastrocnemius mitochondrial respiration: are there any differences between men and women?

Introduction

Work on human and mouse skeletal muscle by our group and others has demonstrated that aging and age-related degenerative diseases are associated with mitochondrial dysfunction, which may be more prevalent in males. There have been, however, no studies that specifically examine the influence of male or female sex on human skeletal muscle mitochondrial respiration. The purpose of this study was to compare mitochondrial respiration in the gastrocnemius of adult men and women.

Methods

Gastrocnemius muscle was obtained from male (n = 19) and female (n = 11) human subjects with healthy lower-extremity musculoskeletal and arterial systems and normal ambulatory function. All patients were undergoing operations for the treatment of varicose veins in their legs. Mitochondrial respiration was determined with a Clark electrode in an oxygraph cell containing saponin-skinned muscle bundles. Complex I-, II-, III-, and IV-dependent respiration was measured individually and normalized to muscle weight, total protein content, and citrate synthase (CS, index of mitochondrial content).

Results

Male and female patients had no evidence of musculoskeletal or arterial disease and did not differ with regard to age, race, body mass index, or other clinical characteristics. Complex I-, II-, III-, and IV-dependent respiration normalized to muscle weight, total protein content, and CS did not statistically differ for males compared with females.

Conclusions

Our study evaluates, for the first time, gastrocnemius mitochondrial respiration of adult men and women who have healthy musculoskeletal and arterial systems and normal ambulatory function. Our data demonstrate there are no differences in the respiration of gastrocnemius mitochondria between men and women.     

Investigation of correlation among safety biomarkers in serum, histopathological examination, and toxicogenomics

This article addresses the issue of miscorrelation between hepatic injury biomarkers and histopathological findings in the drug development context. Our studies indicate that the use of toxicogenomics can aid in the drug development decision-making process associated with such miscorrelated data. BLZ945 was developed as a Colony-Stimulating Factor 1 Receptor (CSF-1R) inhibitor. Treatment of BLZ945 in rats and monkeys increased serum alanine aminotransferase (ALT) and aspartate transaminase (AST). However, liver hypertrophy was the only histopathological liver finding in rats, and there was no change in the livers of monkeys. Longer treatment of BLZ945 in rats for 6 weeks caused up to 6-fold elevation of ALT, yet hepatocyte necrosis was not detected microscopically. Toxicogenomic profiling of liver samples demonstrated that the genes associated with early response to liver injury, apoptosis/necrosis, inflammation, oxidative stress, and metabolic enzymes were upregulated. Studies are ongoing to evaluate the mechanisms underlying BL945-induced ALT and AST elevations.     

The lymphatic vascular system: secondary or primary?

It has generally been accepted that the blood vascular system is primary and the lymphatic vascular system secondary. Diseases of the blood vascular system are the leading cause for mortality and morbidity in developed nations. In contrast, lymphedema is seldom life-threatening and can generally be well-managed by combined physiotherapy. During ontogeny, the blood vessels and the heart develop much earlier than the lymphatic vessels. However, there is growing evidence that the first vascular system occurring during ontogeny and phylogeny has lymphatic functions. Defense mechanisms are crucial for all organisms irrespective of their size. Macrophages precede the emergence of erythrocytes during ontogeny, and their circulation in the hemolymphatic (more accurately, lymphohematic) system of insects, which do not possess erythrocytes, shows that the lymphatic function is primary whereas the nutritive function is secondary, needed only in larger organisms. In molluscs and arthropods, which have an open vascular system, hemocyanin has both oxygen transporting and defense functions. In vertebrates, the early blood vessels have structural characteristics of lymphatics and express the lymphendothelial receptor flt-4 (Vascular Endothelial Growth Factor Receptor-3). Later, flt-4 becomes restricted to the definitive lymphatics, which are either formed from the primary vessels or from mesodermal lymphangioblasts. The primary lymphatic function has become overruled by the nutritive function in blood vessels of larger animals. The circular movement of cells is driven by a blood heart, which, however, is not an unique organ. Lymph hearts are present in lower vertebrates, still develop transiently in birds, and are vestigial in the contractile lymphangion which "circulates" immune cells. We conclude that the definitive lymphatics are perhaps secondary in mammals, but the blood vascular system seems to develop on the basis of an ancestral lymphatic system with lymph hearts.     

Phytochemicals as Therapeutic Interventions in Peripheral Artery Disease

Peripheral artery disease (PAD) affects over 200 million people worldwide, resulting in significant morbidity and mortality, yet treatment options remain limited. Among the manifestations of PAD is a severe functional disability and decline, which is thought to be the result of different pathophysiological mechanisms including oxidative stress, skeletal muscle pathology, and reduced nitric oxide bioavailability. Thus, compounds that target these mechanisms may have a therapeutic effect on walking performance in PAD patients. Phytochemicals produced by plants have been widely studied for their potential health effects and role in various diseases including cardiovascular disease and cancer. In this review, we focus on PAD and discuss the evidence related to the clinical utility of different phytochemicals. We discuss phytochemical research in preclinical models of PAD, and we highlight the results of the available clinical trials that have assessed the effects of these compounds on PAD patient functional outcomes.     

LINX■ reflux management system to bridge the “treatment gap” in gastroesophageal reflux disease: A systematic review of 35 studies

BACKGROUND Gastroesophageal reflux disease(GERD) occurs when the reflux of stomach contents causes troublesome symptoms and/or complications. When medical therapy is insufficient, surgical therapy is indicated and, until now, Laparoscopic fundoplication(LF) constitutes the gold-standard method. However, magnetic sphincter augmentation(MSA) using the LINX^® Reflux Management System has recently emerged and disputes the standard therapeutic approach.AIM To investigate the device’s safety and efficacy in resolving GERD symptoms.METHODS This is a systematic review conducted in accordance to the PRISMA guidelines.We searched MEDLINE, Clinicaltrials.gov, EMBASE, Cochrane Central Register of Controlled Trials CENTRAL databases from inception until September 2019.RESULTS Overall, 35 studies with a total number of 2511 MSA patients were included and analyzed. Post-operative proton-pump inhibitor(PPI) cessation rates reached 100%, with less bloating symptoms and a better ability to belch or vomit in comparison to LF. Special patient groups(e.g., bariatric or large hiatal-hernias)had promising results too. The most common postoperative complication was dysphagia ranging between 6% and 83%. Dilation due to dysphagia occurred in 8% of patients with typical inclusion criteria. Esophageal erosion may occur in up to 0.03% of patients. Furthermore, a recent trial indicated MSA as an efficient alternative to double-dose PPIs in moderate-to-severe GERD.CONCLUSION The findings of our review suggest that MSA has the potential to bridge the treatment gap between maxed-out medical treatment and LF. However, further studies with longer follow-up are needed for a better elucidation of these results.     

Successful management of adhesion related small bowel ischemia without intestinal resection: A case report and review of literature

BACKGROUND Intraabdominal adhesions develop spontaneously or after an inflammatory process or surgical procedure in the abdomen. They are the most common cause of small bowel obstruction(SBO). SBO occasionally leads to intestinal ischemia(In Is) which can be a life-threatening condition that requires management as soon as possible. We herein report a case of SBO with In Is presented in our institution and treated without intestinal resection.CASE SUMMARY A 34-year-old man presented at the emergency department after a 12-h-onset diffuse abdominal pain, bloating and nausea. He had a history of traumatic right hepatectomy 11 years ago as well as adhesiolysis and resection of a long part of small bowel 2 years ago. An abdominal computed tomography(CT) showed dilated loops that led to the diagnosis of SBO. Due to deteriorating lactic acidosis,the patient was operated. Torsion of the small bowel around an adhesion led to2.30 m of ischemic ileum. After the application of N/S 40 °C for 20 min, the intestine showed signs of improvement and it was decided to avoid resection and instead temporary close the abdomen with vacuum-pack technique. At the second-look laparotomy 48 h later, the intestine appeared normal. The patient was discharged on the 8 th post-op day in excellent condition.CONCLUSION In case of SBO caused by adhesions, extreme caution is needed if In Is is present,as the clinical signs are mild and you should rely for diagnosis in CT findings and lactate levels. Conservative surgical approach could reverse the effects of In Is, if performed quickly, so that intestinal resection is avoided and should be used even when minimum signs of viability are present.     

Ursolic acid,a naturally occurring triterpenoid,demonstrates anticancer activity on human prostate cancer cells

Purpose Glucocorticoids are widely used as adjuvant therapy in hormonal refractory prostate cancer; their therapeutic role, however, remains unclear. Ursolic acid, a natural triterpene, structurally similar to dexamethasone, exhibits antitumor effects in various cell types. Our main objective was to investigate the effects of ursolic acid on cell viability, apoptosis and bcl-2 protein, in human hormone refractory and androgen-sensitive prostate cancer cells. Methods The ursolic acid-induced changes in cell viability, apoptosis and bcl-2 protein were examined in human hormone refractory prostate cancer PC-3 cells and androgen-sensitive LNCaP cells, by MTT assay, flow cytometry and western blot analysis, respectively. Results Ursolic acid inhibited significantly the cell viability and induced apoptosis in PC-3 cells at 55 μM and in LNCaP cells at 45 μM associated with a downregulation of bcl-2 protein. Conclusions The antiproliferative and apoptotic effects of ursolic acid in PC-3 and LNCaP cells implicate its potential therapeutic use for the treatment of hormone refractory and androgen-sensitive prostate cancer. The downregulation of bcl-2 may be one of the molecular mechanisms via which it induces apoptosis in PC-3 and LNCaP cells. Financial support by a grant PAVE from the General Secretariat of Research and Technology in cooperation with the company ELPEN.