Prevention of in vivo excitotoxicity by a family of trialkylglycines, a novel class of neuroprotectants

Excitotoxicity has been implicated in the etiology of ischemic stroke and chronic neurodegenerative disorders. Hence, the development of novel neuroprotectant molecules that ameliorate excitotoxic brain damage is vigorously pursued. We used a neuroprotection-based cellular assay to screen a synthetic combinatorial library of N-alkylglycine trimers. Two compounds (6-1-2 and 6-1-10) that efficiently prevented excitotoxic neurodegeneration in vitro and in vivo were identified. Both molecules protected primary cultures of cerebellar neurons against glutamate-induced neuronal death with an efficiency equivalent to N-methyl-D-aspartate (NMDA) receptor antagonists. These trialkylglycines did not block appreciably the NMDA receptor channel, or attenuated glutamate-induced increase of Ca(2+), or affect the glutamate-nitric oxide-cGMP pathway. Intraperitoneal injection of both peptoids in mice attenuated > or = 80% ammonia-induced, NMDA receptor-mediated animal death. Furthermore, these two molecules reduced by > or = 50% the neurodegeneration in striatum in a rat model of cerebral ischemia. Neuroprotection against ischemia was associated with decreased activation of caspase-3, reflecting prevention of apoptotic neuronal death. Collectively, the results reported indicate that these trialkylglycines are new neuroprotectant leads with important in vivo activity against excitotoxicity, and that they act on a novel, yet-unrecognized cellular target. These lead compounds may become tolerated drugs for the treatment of acute and chronic neurodegenerative diseases with fewer side effects than NMDA receptor antagonists.     

Biting midges (Diptera: Ceratopogonidae) in tree hole habitats in Slovakia

The water-filled tree hole fauna of biting midges (Diptera: Ceratopogonidae) in Slovakia is documented for the first time. Three Culicoides Latreille and two Dasyhelea Kieffer species were reared from these habitats. Epidemiological significance of C. obsoletus (Meigen, 1818) is briefly discussed.     

Sphincter-preserving R0 total mesorectal excision with resection of internal genitalia combined with pre-or postoperative chemoradiation for T4 rectal cancer in females

AIM: To evaluate the impact of chemoradiation admi- nistered pre- or postoperatively on prognosis in females following R0 extended resection with sphincter- preserving total mesorectal excision (TME) for locally advanced rectal cancer and to assess the association between chemoradiation and intra- and postoperative variables. METHODS: Twenty-one females were treated for locally advanced but preoperatively assessed as primarily resectable rectal cancer involving reproductive organs. Anterior resection with TME and excision of internal genitalia was combined with neo- or adjuvant chemoradiation. Two-year disease-free survival analysis was performed with the Kaplan-Meier method and log- rank test. The association between chemoradiation and other variables was evaluated with the Fisher’s exact test and Mann-Whitney test. RESULTS: Survival rate decreased in anaemic females (51.5% vs 57.4%), in patients older than 60 years (41.8% vs 66.7%) with poorly differentiated cancers (50.0% vs 55.6%) and tumors located ≤ 7 cm from the anal verge (42.9% vs 68.1%) but with the lack of importance. Patients with negative lymph nodes and women chemoradiated preoperatively had significantly favourable prognosis (85.7% vs 35.7%; P= 0.03 and 80.0% vs 27.3%; P = 0.01, respectively). Preoperative chemoradiation compared to adjuvant radiochemotherapy was not significantly associated with the duration of surgery, incidence of intraoperative bowel perforation and blood loss ≥ 1 L, rate of postoperative bladder and anorectal dysfunction, and minimal distal resection margin. It significantly influenced minimal radial margin (mean 4.2 mm vs 1.1 mm; P < 0.01). CONCLUSION: Despite involving internal genitalia, long-term disease-free survival and sphincter preservation may be achieved with combined-modality therapy for females with T4 locally advanced rectal carcinoma. Neoadjuvant chemoradiation does not compromise functional results and may significantly improve oncological outcomes probably due to enhanced radial clearance.     

Microanalysis of Worn Surfaces of Selected Rotating Parts of an Internal Combustion Engine

The present paper analyzes the damage of surfaces at spots of frictional contact, namely, the friction nodes on a camshaft and the connecting rod pins of a crankshaft. The resulting wear of the monitored friction nodes reduces the technical life of the machines, which can lead to the decommissioning of the machine. Wear was assessed by measuring roughness and microhardness and by observing the microstructures of the materials. The results of the experiments show that the rotating parts displayed visible wear on the cams, as well as on the connecting rod pins. The experiments revealed that wear was caused by the heating of the material to a high temperature during the operation of the machine and that there was a gradual cooling and tempering of the material, which led to a reduction in the microhardness of the monitored object. Lower microhardness values can be a cause of greater wear of the monitored objects. When comparing the microhardness of the used and the new camshaft, the hardened layer of the new camshaft from secondary production has a significantly smaller thickness compared to worn cams, which leads to the finding of a different material quality compared to the original parts from primary production. This fact indicates that the wear of a new camshaft as a spare part can contribute to the shortening of the technical life of friction nodes.     

Dietary cholesterol withdrawal reduces vascular inflammation and induces coronary plaque stabilization in miniature pigs

OBJECTIVE: To study the effect of dietary cholesterol withdrawal on size and composition of LDL-hypercholesterolemia-induced coronary plaques in miniature pigs. METHODS: Pigs were on normal chow (control group), on a cholesterol-rich diet for 37 weeks (hypercholesterolemic group) or on a cholesterol-rich diet followed by normal chow for 26 weeks (cholesterol withdrawal group). Endothelial function was assessed with quantitative angiography after intracoronary infusion of acetylcholine, plaque load with intra-coronary ultrasound and plaque composition with image analysis of cross-sections. The effect of porcine serum on coronary smooth muscle cell (SMC) function was studied in vitro. RESULTS: Cholesterol-rich diet caused LDL-hypercholesterolemia, increased plasma levels of oxidized LDL (ox-LDL) and C-reactive protein (CRP), and induced endothelial dysfunction and coronary atherosclerosis. Dietary cholesterol withdrawal lowered LDL, ox-LDL and CRP. It restored endothelial function, did not affect plaque size but decreased lipid, ox-LDL and macrophage content. Smooth muscle cells and collagen accumulated within the plaque. Increased smoothelin-to-alpha-smooth muscle actin ratio indicated a more differentiated SMC phenotype. Cholesterol lowering reduced proliferation and apoptosis. In vitro, hypercholesterolemic serum increased SMC apoptosis and decreased SMC migration compared to non-hypercholesterolemic serum. CONCLUSIONS: Cholesterol lowering induced coronary plaque stabilization as evidenced by a decrease in lipids, ox-LDL, macrophages, apoptosis and cell proliferation, and an increase in differentiated SMC and collagen. Increased migration and decreased apoptosis of SMC may contribute to the disappearance of the a-cellular core after lipid lowering.     

Effect of deriving periosteal and endosteal contours from microCT scans on computation of cross‐sectional properties in non‐adults: the femur

Derivation of periosteal and endosteal contours taken from transversal long bone cross‐sections limits the accuracy of calculated biomechanical properties. Although several techniques are available for deriving both contours, the effect of these techniques on accuracy of calculated cross‐sectional properties in non‐adults is unknown. We examine a sample of 86 non‐adult femora from birth to 12 years of age to estimate the effect of error in deriving periosteal and endosteal contours on cross‐sectional properties. Midshaft cross‐sections were taken from microCT scans and contours were derived using manual, fully automatic, spline, and ellipse techniques. Agreement between techniques was assessed against manually traced periosteal and endosteal contours using percent prediction error (%PE), reduced major axis analysis, and limits of agreement. The %PEs were highest in the medullary area and lowest in the total area. Mean %PEs were sufficiently below the 5% level of acceptable error, except for medullary areas, but individual values can greatly exceed this 5% boundary given the high standard deviation of %PE means and wide minimum–maximum range of %PEs. Automatic processing produces greater errors than does combination with manual, spline, and ellipse processing. Although periosteal contour is estimated with stronger agreement compared with endosteal contour, error in deriving periosteal contour has a substantially greater effect on calculated section moduli than does error in deriving endosteal contours. We observed no size effect on the resulting bias. Nevertheless, cross‐sectional properties in a younger age category may be estimated with greater error compared with in an older age category. We conclude that non‐adult midshaft cross‐sectional properties can be derived from microCT scans of femoral diaphyses with mean error of < 5% and that derivation of endosteal contour can be simplified by the ellipse technique because fully automatic derivation of endosteal contour may increase the resulting error, especially in small samples.