End-organ protection in hypertension by the novel and selective Rho-kinase inhibitor,SAR407899

AIM: To compare the therapeutic efficacy of SAR407899 with the current standard treatment for hypertension [an angiotensin converting enzyme (ACE)-inhibitor and a calcium channel blocker] and compare the frequency and severity of the hypertension-related end-organ damage.METHODS: Long-term pharmacological characte-rization of SAR407899 has been performed in two animal models of hypertension, of which one is sensitive to ACE-inhibition (LNAME) and the other is insensitive [deoxycorticosterone acetate (DOCA)]. SAR407899 efficiently lowered high blood pressure and significantly reduced late-stage end organ damage as indicated by improved heart, kidney and endothelial function and reduced heart and kidney fibrosis in both models of chronic hypertension.RESULTS: Long term treatment with SAR407899 has been well tolerated and dose-dependently reduced elevated blood pressure in both models with no signs of tachyphylaxia. Blood pressure lowering effects and protective effects on hypertension related end organ damage of SAR407899 were superior to ramipril and amlodipine in the DOCA rat. Typical end-organ damage was significantly reduced in the SAR407899-treated animals. Chronic administration of SAR407899 significantly reduced albuminuria in both models. The beneficial effect of SAR407899 was associated with a reduction in leukocyte/macrophage tissue infiltration. The overall protective effect of SAR407899 was superior or comparable to that of ACE-inhibition or calcium channel blockade. Chronic application of SAR407899 protects against hypertension and hypertension-induced end organ damage, regardless of the pathophysiological mechanism of hypertension.CONCLUSION: Rho-kinases-inhibition by the SAR407899 represents a new therapeutic option for the treatment of hypertension and its complications.     

High glucose uptake unexpectedly is accompanied by high levels of the mitochondrial β-F1-ATPase subunit in head and neck squamous cell carcinoma

A hallmark of solid tumors is the consumption of large amounts of glucose and production of lactate, also known as Warburg-like metabolism. This metabolic phenotype is typical for aggressive tumor growth, and can be visualized by ¹⁸F-fluorodeoxyglucose (¹⁸F-FDG) uptake detected by positron emission tomography (PET). High ¹⁸F-FDG uptake inversely correlates with survival and goes along with reduced expression of the catalytic beta-subunit of the H⁺-ATP synthase (β-F1-ATPase) in several tumor entities analyzed so far.For this study we characterized a series of 15 head and neck squamous cell carcinoma (HNSCC) by (i) determining ¹⁸F-FDG-uptake; (ii) quantitative expression analysis of β-F1-ATPase (Complex V), NDUF-S1 (Complex I) and COX1 (Complex IV) of the mitochondrial electron transport chain (ETC), as well as Hsp60 (mitochondrial mass) and GAPDH (glycolysis) in tumor cells; (iii) sequencing of the mtDNA of representative tumor samples.Whereas high ¹⁸F-FDG-uptake also correlates with poor prognosis in HNSCC, it surprisingly is accompanied by high levels of β-F1-ATPase, but not by any of the other analyzed proteins.In conclusion, we here describe a completely new phenotype of metabolic adaptation possibly enabling those tumors with highest levels of β-F1-ATPase to rapidly proliferate even in hypoxic zones, which are typical for HNSCC.     

Chronic Achilles Rupture Reconstructed with Achilles Tendon Allograft: A Case Report

Chronic ruptures of the Achilles tendon are more difficult to treat than acute tendon rupture. It has been shown that surgical treatment of chronic Achilles tendon rupture provides better functional results than nonoperative treatment. We present a case of neglected Achilles tendon rupture with a 12-cm defect that was repaired using an Achilles tendon allograft with interferential screws to fix the graft in the calcaneus. The patient recovered his ankle function to normal activities after rehabilitation.     

Surface Integrity and Tool Wear Analysis on Turning of Copper-Nickel 70/30 ASTM B122 Alloy under Low Initial Lubrication

Traditional flood lubrication in machining processes is considered an unsustainable technique. In this paper, the low initial lubrication (LIL) technique is analysed during turning of cupronickel 70/30 alloy, in terms of surface roughness. A tribological analysis has been developed on a pin-on-disk tribometer comparing different lubrication systems, obtaining comparative results of friction and tool wear. It has been found that the tool wear is 73% lower in comparison to flood lubrication. LIL technique shows the ability to reduce the friction coefficient compared to dry machining and leads to improve tool wear in comparison with flood lubrication. The surface integrity evaluation of machined parts finds that the LIL technique can improve the surface roughness under specific machining conditions.