Endothelial Lipase: a key player in HDL metabolism modulates inflammation and atherosclerotic risk

Endothelial Lipase (EL) is a newly identified member of the triacylglycerol lipase family. Recent studies suggested that EL may be an important determinant of HDL-metabolism and inflammation acting at the level of the vessel wall. The aim of this review is to summarize important facts derived from experimental approaches and from epidemiologic human studies to provide a comprehensive view on the role of EL in inflammation and atherogenesis as well as target for potential pharmaceutical interventions.     

Synthesis and biological evaluation of NO-donor-tacrine hybrids as hepatoprotective anti-Alzheimer drug candidates

In search of safer anti-Alzheimer drugs, 14 NO-donor-tacrine hybrids (1- 14) were synthesized and evaluated for their ability to inhibit cholinesterases and for vasorelaxation effects. Compounds 1- 13 showed good cholinesterases inhibitory activities in vitro, while 14, particularly, was highly selective, preferring butyrylcholinesterase rather than acetylcholinesterase. Four selected compounds (1, 9, 11, and 14) moderately relaxed the porcine pulmonary arteries in organ bath. In the hepatotoxicity study, significant hepatotoxicity was caused by tacrine but not by 9.     

Mutations in genes encoding PI3K‐AKT and MAPK signaling define anogenital papillary hidradenoma

Papillary hidradenoma (a.k.a. hidradenoma papilliferum) is a benign tumor of the anogenital region that almost exclusively arises in middle‐aged Caucasian women. These tumors may recur and rare cases of malignant development have been reported. The genetic basis of papillary hidradenoma is currently unknown. Hence, we employed targeted high‐coverage next generation sequencing interrogating 50 cancer‐related genes and conventional Sanger sequencing to investigate the mutational landscape in a cohort of 15 cases. Additionally, we analyzed the HPV status of these tumors. Thirteen cases (87%) harbored mutations in cancer‐related genes. Recurrent mutations in PIK3CA and AKT1 were present in 10 of the cases (67%). One PIK3CA mutated case had a concomitant STK11 mutation. Three cases harbored mutually exclusive mutations in BRAF, APC and ERBB4. The remaining two cases showed no mutations. None of the cases harbored DNA of human papilloma virus. Our results also provide evidence that –just as BRAF V600E mutations in hyperplastic polyps and benign nevi‐ a mutated driver gene does not imply malignant behavior per se but may set the basis for malignant transformation. The latter point may explain why rare cases of papillary hidradenoma have been reported to take a malignant course. Lastly, our genetic data may suggest treatment avenues beyond conventional surgery for some of these tumors. © 2015 Wiley Periodicals, Inc.     

Tspan8 is expressed in breast cancer and regulates E-cadherin/catenin signalling and metastasis accompanied by increased circulating extracellular vesicles

Tspan8 exhibits a functional role in many cancer types including pancreatic, colorectal, oesophagus carcinoma, and melanoma. We present a first study on the expression and function of Tspan8 in breast cancer. Tspan8 protein was present in the majority of human primary breast cancer lesions and metastases in the brain, bone, lung, and liver. In a syngeneic rat breast cancer model, Tspan8⁺ tumours formed multiple liver and spleen metastases, while Tspan8⁻ tumours exhibited a significantly diminished ability to metastasise, indicating a role of Tspan8 in metastases. Addressing the underlying molecular mechanisms, we discovered that Tspan8 can mediate up-regulation of E-cadherin and down-regulation of Twist, p120-catenin, and β-catenin target genes accompanied by the change of cell phenotype, resembling the mesenchymal–epithelial transition. Furthermore, Tspan8⁺ cells exhibited enhanced cell–cell adhesion, diminished motility, and decreased sensitivity to irradiation. As a regulator of the content and function of extracellular vesicles (EVs), Tspan8 mediated a several-fold increase in EV number in cell culture and the circulation of tumour-bearing animals. We observed increased protein levels of E-cadherin and p120-catenin in these EVs; furthermore, Tspan8 and p120-catenin were co-immunoprecipitated, indicating that they may interact with each other. Altogether, our findings show the presence of Tspan8 in breast cancer primary lesion and metastases and indicate its role as a regulator of cell behaviour and EV release in breast cancer. © 2019 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.     

4-Chloro-m-cresol is a Trigger of Malignant Hyperthermia in Susceptible Swine

Background: 4-Chloro-m-cresol (4-CmC) induces marked contractures in skeletal muscle specimens from individuals susceptible to malignant hyperthermia (MHS). In contrast, 4-CmC induces only small contractures in specimens from normal (MHN) patients. 4-CmC is a preservative within a large number of commercially available drug-preparations (e.g., insulin, heparin, succinylcholine), and it has been suggested that 4-CmC might trigger malignant hyperthermia. This study was designed to investigate the effects of 4-CmC in vivo and in vitro in the same animals.

Methods: After approval of the animal care committee, six Pietrain MHS and six control (MHN) swine were anesthetized with azaperone 4 mg/kg intramuscularly and metomidate 10 mg/kg intraperitoneally. After endotracheal intubation, lungs were mechanically ventilated (inspired oxygen fraction 0.3) and anesthesia was maintained with etomidate 2.5 mg [middle dot] kg-1 [middle dot] h-1 and fentanyl 50 [micro sign]g [middle dot] kg-1 [middle dot] h-1. Animals were surgically prepared with arterial and central venous catheters for measurement of hemodynamic parameters and to obtain blood samples. Before exposure to 4-CmC in vivo, muscle specimens were excised for in vitro contracture tests with 4-CmC in concentrations of 75 and 200 [micro sign]M. Subsequently, pigs were exposed to cumulative administration of 3, 6, 12, 24, and 48 mg/kg 4-CmC intravenously. If an unequivocal episode of malignant hyperthermia occurred, as indicated by venous carbon dioxide concentration >or= to 70 mmHg, pH or= to 2 [degree sign]C, the animals were treated with dantrolene, 3.5 mg/kg.

Results: All MHS swine developed malignant hyperthermia after administration of 4-CmC in doses of 12 or 24 mg/kg. Venous carbon dioxide concentration significantly increased and pH significantly decreased. Temperature increased in all MHS animals more than 2 [degree sign]C. Blood lactate concentrations and creatine kinase levels were significantly elevated. All MHS swine were treated successfully with dantrolene. In contrast, no MHN swine developed signs of malignant hyperthermia. After receiving 4-CmC in a concentration of 48 mg/kg, however, all MHN animals died by ventricular fibrillation. The in vitro experiments showed that both concentrations of 4-CmC produced significantly greater contractures in MHS than in MHN specimens.     

Klinische Erfahrungen mit dem implantierbaren atrialen Defibrillator (Atrioverter) bei Patienten mit Vorhofflimmern

Due to the limited efficacy of drug therapy in atrial fibrillation and the high rate of recurrence, strong efforts were made to find non-pharmacological strategies. For three years now, the implantable atrial defibrillator Metrix from InControl has been available as an alternative therapy. From October 1995 to the present the atrial defibrillator was implanted in 179 patients worldwide. The sensitivity of the system and its algorithms to detect atrial fibrillation is 90%; the specificity to detect sinus rhythm is 100%. In 121 of 179 patients, 748 episodes of spontaneous atrial fibrillation were treated with 2.4 shocks per episode. No proarrhythmic event or stroke was seen. A cardioversion to sinus rhythm could be achieved in 95% of patients; the overall clinical success rate was 88%. In 7% of all patients, early recurrence of atrial fibrillation (ERAF) occurred that could not be converted into stable sinus rhythm after further cardioversions and antiarrhythmic therapy. In 4.1% there were lead-related complications, in 4 patients the device had to be explanted because of ineffective therapy, and in 3 patients the device had to be changed because of loss of telemetry or early depletion of battery. In 8 patients, postoperative complications were seen (infections, pneumothorax and thrombosis of the subclavian vein). Overall, the implantable atrial defibrillator Metrix is an effective and safe alternative in treating atrial fibrillation.     

Attenuation of cochlear damage from noise trauma by an iron chelator, a free radical scavenger and glial cell line-derived neurotrophic factor in vivo

Tissue injury by reactive oxygen species (ROS) may play a role in noise-induced hearing loss (NIHL). Since iron is involved in ROS generation, we studied if an iron chelator, deferoxamine mesylate (DFO), alone or in combination with mannitol, a hydroxyl scavenger and weak iron chelator, attenuates NIHL. Further, we investigated if glial cell line-derived neurotrophic factor (GDNF) provides additive or synergistic protection of the cochlea from acoustic trauma when given together with DFO and mannitol. Pigmented female guinea pigs were exposed to noise (4 kHz octave band, 115 dB SPL, 5 h). One hour before, immediately after, and 5 h after noise exposure, subjects received an injection of 5 ml saline/kg (control, group I), 100 mg DFO/kg (group II), 15 mg mannitol/kg (group III), or both DFO and mannitol (group IV and V). Animals in group V underwent implantation of an osmotic pump filled with GDNF (100 ng/ml) in the left ear 4 days before noise. Each treatment afforded some protection from noise damage. Group I showed significantly greater outer hair cell loss and threshold shifts at two or more frequencies compared to groups II through V. GDNF provided an additive functional, but not morphological, protection with DFO and mannitol. These findings indicate that iron chelators can attenuate NIHL, as do ROS scavengers, supporting the notion that ROS generation plays a role in NIHL. Additional functional protection provided with GDNF suggests that GDNF may attenuate noise-induced cochlear damage through a mechanism that is additive with antioxidants.     

Tourniquet-induced Changes of Energy Metabolism in Human Skeletal Muscle Monitored by Microdialysis

Background: Tourniquets are often used as part of orthopedic surgery but may cause local and remote organ injury. The authors hypothesized that the procedures used to induce ischemia (circulatory occlusion or exsanguination) may have differential effects on the metabolic state of the muscle that should be reflected in the interstitial levels of metabolites.

Methods: Microdialysis probes were implanted in both quadriceps femoris muscles of 18 patients. Interstitial fluid was obtained during tourniquet-induced ischemia and reperfusion and was analyzed for glucose, lactate, choline, and purines by high-performance liquid chromatography.

Results: At a flow rate of 2 [mu]l/min, the average baseline concentrations in the dialysate were 2.5 mm for glucose, 1.7 mm for lactate, 5.2 [mu]m for choline, and 14.3 [mu]m for hypoxanthine. Circulatory occlusion by tourniquet caused a 40% decrease of the extracellular glucose concentration within 30 min. Concomitantly, the interstitial levels of lactate and hypoxanthine increased in a linear fashion to 206% (lactate) and 241% (hypoxanthine) of basal values. The extracellular concentration of choline was also significantly elevated. After exsanguination, the glucose levels were significantly more reduced (by 65%), and the levels of lactate (to 268%) and hypoxanthine (to 286%) were more increased than after circulatory occlusion alone.