Mitochondria play a central role in nonischemic cardiomyocyte necrosis: common to acute and chronic stressor states

The survival of cardiomyocytes must be ensured as the myocardium adjusts to a myriad of competing physiological and pathophysiological demands. A significant loss of these contractile cells, together with their replacement by stiff fibrillar collagen in the form of fibrous tissue accounts for a transition from a usually efficient muscular pump into one that is failing. Cellular and subcellular mechanisms involved in the pathogenic origins of cardiomyocyte cell death have long been of interest. This includes programmed molecular pathways to either necrosis or apoptosis, which are initiated from ischemic or nonischemic origins. Herein, we focus on the central role played by a mitochondriocentric signal-transducer-effector pathway to nonischemic cardiomyocyte necrosis, which is common to acute and chronic stressor states. We begin by building upon the hypothesis advanced by Albrecht Fleckenstein and coworkers some 40?years ago based on the importance of calcitropic hormone-mediated intracellular Ca²⁺ overloading, which predominantly involves subsarcolemmal mitochondria and is the signal to pathway activation. Other pathway components, which came to be recognized in subsequent years, include the induction of oxidative stress and opening of the mitochondrial inner membrane permeability transition pore. The ensuing loss of cardiomyocytes and consequent replacement fibrosis, or scarring, represents a disease of adaptation and a classic example of when homeostasis begets dyshomeostasis.     

Anastomotic leakage after low anterior resection for rectal cancer: comparison of stapled versus compression anastomosis

Purpose

Surgical technique and perioperative management in rectal cancer surgery have been substantially improved and standardized during the last decades. However, anastomotic leakage following low anterior resection still is a significant problem. Based on animal experimental data of improved healing of compression anastomosis, we hypothesized that a compression anastomotic device might improve healing rates of the highest-risk anastomoses.

Methods

All low anterior resections for rectal cancer performed or directly supervised by the senior author between January 2004 and June 2012 were analyzed. Only patients with a stapled or compression anastomosis located within 6 cm from the anal verge were included. Until December 2008, circular staplers were employed, while since January 2009, a novel compression anastomotic device was used for rectal reconstruction exclusively.

Results

Out of 197 patients operated for rectal cancer, a total of 96 (34 females, 35.4 %) fulfilled inclusion criteria. Fifty-eight (60.4 %) were reconstructed with circular staplers and 38 (39.6 %) using a compression anastomotic device. Significantly, more laparoscopic procedures were recorded in the compression anastomosis group, but distribution of gender, age, body mass index, American Society of Anaesthesiologists score, rate of preoperative radiotherapy, tumor staging, or stoma diversion rate were similar. Anastomotic leakage was observed in seven cases (7/58, 12.1 %) in the stapled and twice (2/38, 5.3 %) in the compression anastomosis group (p?=?0.26).

Conclusions

In this series, rectal reconstruction following low anterior resection using a novel compression anastomotic device was safe and (at least) equally effective compared to traditional circular staplers concerning leak rate.     

Protection from epistaxis blood aerosol contamination: a novel use of a surgical facemask

Epistaxis is one of the most common otorhinolaryngological emergencies. It is also one of the most common emergencies that places medical staff at risk of blood contamination. We report a simple yet extremely effective method in which a standard surgical facemask is worn by the patient, thereby reducing blood aerosol contamination without interfering with effective management.     

Feasibility and diagnostic agreement in teledermatopathology using a virtual slide system

We investigated the feasibility and diagnostic agreement of a virtual slide system (VSS) in teledermatopathology. Forty-six biopsy specimens from inflammatory skin diseases were selected and scanned with a VSS at the Research Unit of Teledermatology, Medical University of Graz, Graz, Austria. Images were stored on a virtual slide server on which a specific Web application suited for telepathology (http://telederm.org/research/dermatopath/) runs. Twelve teleconsultants from 6 different countries reviewed the 46 cases, working directly on the Web application. Telediagnoses agreed with gold standard and conventional diagnosis with an average of 73% and 74%, respectively. Complete concordance among all teleconsultants with gold standard and conventional diagnosis was found in 20% of the cases. In 10 cases in which complete clinical data were missing, the average agreement of telediagnosis with gold standard diagnosis and conventional diagnosis decreased to 65% and 66%, respectively. Only 3 of 4 cases of inflammatory skin diseases were correctly diagnosed remotely with VSS. The system that we have used, despite its usability, is not completely feasible for teledermatopathology of inflammatory skin disease. Moreover, the performance seems to have been influenced by the availability of complete clinical data and by the intrinsic difficulty of the pathology of inflammatory skin diseases.     

Pattern of varicocele vein blood gases in patients undergoing microsurgical Varicocelectomy

Background

Varicocele is known to be associated with infertility and sperm disorders. The exact cause of this ailment is not fully understood. There are limited numbers of studies where venous blood gases (VBGs) of varicocele veins were determined with conflicting results. Therefore, we have investigated the pattern of VBGs in both internal spermatic and external spermatic varicocele veins and correlation with semen quality parameters in infertile individuals who underwent left microsurgical varicocelectomy.

Methods

Patients (n?=?27) undergoing left microsurgical varicocelectomy at a tertiary care hospital, were included in the study. Before surgery, semen parameters and scrotal color Doppler ultrasonography was performed. During surgery, blood sample was drawn from varicocele veins (internal spermatic and external spermatic veins) and a peripheral arm vein of the same patient as a control. The VBGs of all veins under study were estimated and compared with each other. The VBGs were also correlated with various semen quality parameters. Data, expressed as Mean?±?SD, regarding VBGs in three veins were analyzed using one-way ANOVA. The correlation between VBGs and semen quality parameters was determined using Pearson’s correlation. Differences were considered significant at p?<?0.05.

Results

The pH was found to be higher (p?<?0.01) in the internal spermatic vein compared with the external spermatic and the peripheral veins. Partial pressure of oxygen (pO₂) and oxygen saturation (sO₂) were higher (p?<?0.01) in the internal spermatic vein compared with the peripheral vein. However, concentration of bicarbonate (HCO₃₎ was lower (p?<?0.01) in both veins compared with the peripheral vein. Partial pressure of carbon dioxide (pCO₂) was also lower (p?<?0.01) in the varicocele veins compared with the control vein.

Conclusion

The internal spermatic veins had higher pH and oxygen tension, but lower HCO₃ and pCO₂ levels compared with the control peripheral veins. External spermatic veins had lower pCO₂ and HCO₃ but other VBGs were similar to the peripheral veins. The shift of VBGs of internal spermatic vein toward arterial blood pattern may be a missing link to understand the pathophysiology of varicocele.

     

Discovery and SAR of a novel selective and orally bioavailable nonpeptide classical competitive inhibitor class of protein-tyrosine phosphatase 1B

Reversible phosphorylation and dephosphorylation of key proteins on tyrosine residues are important parts of intracellular signaling triggered by hormones and other agents. Recent knock-out studies in mice have identified PTP1B as a potential target for the treatment of diabetes and obesity. As a consequence, a number of academic and industrial groups are aggressively pursuing the development of selective PTP1B inhibitors. In addition, other protein-tyrosine phosphatases (PTPs) appear to be critically involved in major diseases such as cancer and autoimmunity. Given the diversity of PTPs and their potential as drug targets in different diseases, we have taken a broad approach to develop active site-directed selective inhibitors of specific members of this family of enzymes. Using a high throughput screening, we have previously identified 2-(oxalylamino)benzoic acid 3a as a relatively weak but classical competitive inhibitor of several PTPs.(4) On the basis of our early studies, indicating that 3a might be used as a starting point for the synthesis of selective PTP inhibitors, we now present our efforts in expansion of this concept and provide here a number of new chemical scaffolds for the development of inhibitors of different members of the PTP family. Although the core structure of these inhibitors is charged, good oral bioavailability has been observed in rat for some compounds. Furthermore, we have observed enhancement of 2-deoxy-glucose accumulation in C2C12 cells with prodrug analogues.     

Mitochondria-targeted cardioprotection in aldosteronism

Chronic aldosterone/salt treatment (ALDOST) is accompanied by an adverse structural remodeling of myocardium that includes multiple foci of microscopic scarring representing morphologic footprints of cardiomyocyte necrosis. Our previous studies suggested that signal-transducer-effector pathway leading to necrotic cell death during ALDOST includes intramitochondrial Ca overloading, together with an induction of oxidative stress and opening of the mitochondrial permeability transition pore (mPTP). To further validate this concept, we hypothesized that mitochondria-targeted interventions will prove to be cardioprotective. Accordingly, 8-week-old male Sprague-Dawley rats receiving 4 weeks ALDOST were cotreated with either quercetin, a flavonoid with mitochondrial antioxidant properties, or cyclosporine A (CsA), an mPTP inhibitor, and compared with ALDOST alone or untreated, age/sex-matched controls. We monitored mitochondrial free Ca and biomarkers of oxidative stress, including 8-isoprostane and H2O2 production; mPTP opening; total Ca in cardiac tissue; and collagen volume fraction to quantify replacement fibrosis, a biomarker of cardiomyocyte necrosis, and employed terminal deoxynucleotidyl transferase dUTP nick end labeling assay to address apoptosis in coronal sections of ventricular myocardium. Compared with controls, at 4 weeks ALDOST we found a marked increase in mitochondrial H2O2 production and 8-isoprostane levels, an increased propensity for mPTP opening, and greater concentrations of mitochondrial free [Ca]m and total tissue Ca, coupled with a 5-fold rise in collagen volume fraction without any terminal deoxynucleotidyl transferase dUTP nick end labeling-based evidence of cardiomyocyte apoptosis. Each of these pathophysiologic responses to ALDOST was prevented by quercetin or cyclosporine A cotreatment. Thus, mitochondria play a central role in initiating the cellular-subcellular mechanisms that lead to necrotic cell death and myocardial scarring. This destructive cycle can be interrupted and myocardium salvaged with its structure preserved by mitochondria-targeted cardioprotective strategies.