Mean stress and plasticity effect prediction on notch fatigue and crack growth threshold,combining the theory of critical distances and multiaxial fatigue criteria

In the present work, we propose a robust calibration of some bi‐parametric multiaxial fatigue criteria applied in conjunction with the theory of critical distances (TCD). This is based on least‐square fitting fatigue data generated using plain and sharp‐notched specimens tested at two different load ratios and allows for the estimation of the critical distance according to the point and line method formulation of TCD. It is shown that this combination permits to incorporate the mean stress effect into the fatigue strength calculation, which is not accounted for in the classical formulation of TCD based on the range of the maximum principal stress. It is also shown that for those materials exhibiting a low fatigue‐strength‐to‐yield‐stress ratio σ_fl,R = ?1/σ_YS, such as 7075‐T6 (σ_fl,R = ?1/σ_YS = 0.30), satisfactorily accurate predictions are obtained assuming a linear‐elastic stress distribution, even at the tip of sharp notches and cracks. Conversely, for any materials characterized by higher values of this ratio, as quenched and tempered 42CrMo4 (σ_fl,R = ?1/σ_YS = 0.54), it is recommended to consider the stabilized elastic‐plastic stress/strain distribution, also for plain and blunt‐notched samples and even in the high cycle fatigue regime still with the application of the TCD.     

Guide Cells Support Muscle Regeneration and Affect Neuro-Muscular Junction Organization

Muscular regeneration is a complex biological process that occurs during acute injury and chronic degeneration, implicating several cell types. One of the earliest events of muscle regeneration is the inflammatory response, followed by the activation and differentiation of muscle progenitor cells. However, the process of novel neuromuscular junction formation during muscle regeneration is still largely unexplored. Here, we identify by single-cell RNA sequencing and isolate a subset of vessel-associated cells able to improve myogenic differentiation. We termed them ‘guide’ cells because of their remarkable ability to improve myogenesis without fusing with the newly formed fibers. In vitro, these cells showed a marked mobility and ability to contact the forming myotubes. We found that these cells are characterized by CD44 and CD34 surface markers and the expression of Ng2 and Ncam2. In addition, in a murine model of acute muscle injury and regeneration, injection of guide cells correlated with increased numbers of newly formed neuromuscular junctions. Thus, we propose that guide cells modulate de novo generation of neuromuscular junctions in regenerating myofibers. Further studies are necessary to investigate the origin of those cells and the extent to which they are required for terminal specification of regenerating myofibers.     

Clinical and pathological correlations in Charcot-Marie-Tooth neuropathy type 1A with the 17p11.2p12 duplication: a cross-sectional morphometric and immunohistochemical study in twenty cases

In a cross-sectional, clinical, and morphometric analysis we assessed the correlation between the clinical and pathological evolution of disease in 20 unrelated patients of various ages affected by Charcot-Marie-Tooth neuropathy type 1A (CMT1A) with the 17p11.2p12 (peripheral myelin protein 22, PMP22) duplication. The severity of neurologic deficits and slowing of motor conduction velocity at the median nerve did not vary significantly with the patients' age. The amount of demyelination was significantly higher below 15 years than in older age groups; in contrast, myelinated fiber and onion bulb densities were similar at all ages. The results indicate that in duplicated CMT1A, the pathological process develops early in life and progresses little during the course of the disease. Younger patients had lower g-ratio values, suggesting that the trigger of demyelination in early years could be a hypermyelination, resulting from PMP22 overexpression. Yet none of the 20 patients examined had immunohistochemical evidence of altered PMP22 expression. The early onset and development of the disorder make it difficult to detect PMP22 overdosage in nerve biopsies.     

Electrochemical reduction of benzamide and their o- and p-halo-derivatives in non-aqueous solvents

The analysis of the polarographic, voltammetric and coulometric results shows that the overall reduction mechanism of benzamide occurs with the cleavage of the C---N bond. However, the first step of the electrochemical process leads to the formation of a radical anion which undergoes protonation by another benzamide molecule in DMF and DMSO or by the solvent in CH₃CN and C₂H₅OH. Theoretical calculations have been performed to clarify the mechanism. Halobenzamide reduction involves the C---halogen bond breaking as the first reduction step to give benzamide.     

Radioimmunoassay for the testosterone 5 alpha-reductase inhibitor turosteride in biological fluids

An antiserum against turosteride (code name FCE 26073), a potent testosterone 5 alpha-reductase inhibitor, has been raised in rabbits by immunization with an immunogen produced by conjugation of a derivative of FCE 26073 (FCE 27424) to bovine serum albumin. The antiserum was able to distinguish FCE 26073 from its derivatives modified at the 17 beta position and from all the endogenous steroids tested. A radioimmunoassay for the determination of FCE 26073 in human plasma and urine was developed using this antiserum and tritium labeled turosteride. FCE 26073 was extracted from 50 microliters of plasma or 25 microliters of urine using ethyl-ether with a recovery greater than 90%. Using this procedure it was possible to achieve a final limit of quantitation of 142 pg/ml in plasma and 284 pg/ml in urine. The assay was validated in terms of reproducibility, accuracy and precision in the range 3.9-250 pg/50 microliters of plasma and 25 microliters of urine. The plasma concentration of FCE 26073 in a healthy male volunteer who received 0.2 mg of the drug was measured using the radioimmunoassay.     

Detection of the proto-oncogene eIF4E in surgical margins may predict recurrence in head and neck cancer

Head and neck squamous cell cancers (HNSCC) have a high local recurrence rate due to incomplete tumor resection. The use of molecular markers to establish surgical margins may decrease local recurrence. Surgical margins are determined by histopathologic analysis on frozen sections. We postulate that genetic and molecular changes precede gross histologic alterations. Tumor markers may improve the reliability of pathology examination, but those evaluated to date lack the sensitivity needed for routine clinical use. Western blot analysis showed elevated eIF4E in all 26 HNSCC in contrast to its low expression in benign lesions. Surgical margins were analysed for eIF4E in 23 patients. Twelve patients showed elevated eIF4E in histologically negative margins. Cancer has recurred in 5 of the 12 patients as opposed to none of the 11 patients with eIF4E negative margins (P= 0.02, Log rank test). This is the first report of eIF4E in HNSCC, as a sensitive and specific marker for HNSCC, with potential for defining clear resection margins. The correlation between elevated levels of eIF4E at the margins and recurrence highlights its ability to detect malignant cells prior to clear-cut alterations in morphology. The accuracy and simplicity of these assays underscore the usefulness of eIF4E in managing HNSCC.     

Both early and committed haemopoietic progenitors are more frequent in peripheral blood than in bone marrow during mobilization induced by high-dose chemotherapy + G-CSF

The effect of progesterone and six other C21-deoxysteroids on renal sodium retention by male adrenalectomized rats was compared with the effect exerted by the natural corticoids aldosterone, 11-deoxycorticosterone, and corticosterone. Steroids were active in the following order: aldosterone > 11,19-oxidoprogesterone > 5 alpha H-3,20-pregnanedione > or = 5 beta H-3,20-pregnanedione > progesterone = 11-ketoprogesterone > 6,19-oxidoprogesterone = 11-keto-6,19-oxidoprogesterone > or = corticosterone. All C21-deoxysteroids, except 11,19-oxidoprogesterone, exhibited parabolic log dose-response functions, indicating an effect that opposes renal sodium retention at high doses. 11,19-Oxidoprogesterone and the natural corticoids exhibited normal, exponential, log dose-response curves. Diverse geometric parameters related to molecular planarity were calculated and their correlation with biopharmacological properties was attempted. The best linear regression was obtained for correlation of the concavity of log dose-response parabolas (second-order coefficients) of C21-deoxysteroids with the C3 = O/ring D angle of these molecules. A good linear regression could also be obtained for correlation of the affinity of C21-deoxysteroids, except 11,19-oxidoprogesterone, for purified type I mineralocorticoid receptors with those angles. The latter correlation deteriorated upon incorporation of the affinity data for the three natural corticoids, due to similar affinities of these hormones for type I mineralocorticoid receptors, but could be restored when the binding data for the unpurified, corticosterone-binding globulin-containing stage of the receptors were considered. In vivo binding data followed the same trend as that for unpurified receptors.