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.     

Bone marrow mesenchymal stem cells undergo nemosis and induce keratinocyte wound healing utilizing the HGF/c-Met/PI3K pathway

We previously showed cell–cell contacts of human dermal fibroblasts to induce expression of the hepatocyte growth factor/scatter factor (HGF) in a process designated as nemosis. Now we report on nemosis initiation in bone marrow mesenchymal stem cells (BMSCs). Because BMSCs are being used increasingly in cell transplantation therapy we aimed to demonstrate a functional effect and benefit of BMSC nemosis for wound healing. Nemotic and monolayer cells were used to stimulate HaCaT keratinocyte migration in a scratch-wound healing assay. Both indicators of nemosis, HGF production and cyclooxygenase-2 expression, were induced in BMSC spheroids. When compared with a similar amount of cells as monolayer, nemotic cells induced keratinocyte in vitro scratch-wound healing in a concentration-dependent manner. The HGF receptor, c-Met, was rapidly phosphorylated in the nemosis-stimulated keratinocytes. Nemosis-induced in vitro scratch-wound healing was inhibited by an HGF-neutralizing antibody as well as the small molecule c-Met inhibitor, SU11274. HGF-induced in vitro scratch-wound healing was inhibited by PI3K inhibitors, wortmannin and LY294002, while LY303511, an inactive structural analogue of LY294002, had no effect. Inhibitors of the mitogen-activated protein kinases MEK/ERK1/2 (PD98059 and U0126), and p38 (SB203580) attenuated HGF-induced keratinocyte in vitro scratch-wound healing. We conclude that nemosis of BMSCs can induce keratinocyte in vitro scratch-wound healing, and that in this effect signaling via HGF/c-Met is involved.     

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.     

Mutations in mammalian target of rapamycin regulator DEPDC5 cause focal epilepsy with brain malformations

We recently identified DEPDC5 as the gene for familial focal epilepsy with variable foci and found mutations in >10% of small families with nonlesional focal epilepsy. Here we show that DEPDC5 mutations are associated with both lesional and nonlesional epilepsies, even within the same family. DEPDC5‐associated malformations include bottom‐of‐the‐sulcus dysplasia (3 members from 2 families), and focal band heterotopia (1 individual). DEPDC5 negatively regulates the mammalian target of rapamycin (mTOR) pathway, which plays a key role in cell growth. The clinicoradiological phenotypes associated with DEPDC5 mutations share features with the archetypal mTORopathy, tuberous sclerosis, raising the possibility of therapies targeted to this pathway. Ann Neurol 2014;75:782–787     

Efficient total synthesis of (+)-dihydropinidine, (-)-epidihydropinidine, and (-)-pinidinone

The 2,6-disubstituted piperidine alkaloids (+)-dihydropinidine (1), (-)-epidihydropinidine (2) (as HCl salts), and (-)-pinidinone (3) were efficiently synthesized from (S)-epichlorohydrin (7) as common substrate using regioselective Wacker-Tsuji oxidation of alkenylazides 10 and 14 as well as a highly diastereoselective reduction of cyclic imine 11 as key steps. The protecting group free total syntheses represent the up to date shortest routes with highest overall yields for all three naturally occurring alkaloids (1-3). The first single-crystal X-ray analysis of (-)-epidihydropinidine hydrochloride (2·HCl) confirmed its proposed absolute configuration to be (2S,6S), corresponding to that of the isolated natural product.