Orally bioavailable factor Xa inhibitors containing alpha-substituted gem-dimethyl P4 moieties

In an effort to identify a potential back-up to apixaban (Eliquis®), we explored a series of diversified P4 moieties. Several analogs with substituted gem-dimethyl moieties replacing the terminal lactam of apixaban were identified which demonstrated potent FXa binding affinity (FXa K_i), good human plasma anticoagulant activity (PT EC_2x), cell permeability, and oral bioavailability.     

Normal contractile algorithm of swallowing related muscles revealed by needle EMG and its comparison to videofluoroscopic swallowing study and high resolution manometry studies: A preliminary study

The purpose of this study was to investigate the function and importance of infrahyoid muscles with the suprahyoid muscles during swallowing, and to investigate swallowing sequences using kinematic analysis, high-resolution manometry (HRM) and electromyography (EMG). As a preliminary study, ten healthy subjects were prospectively enrolled. A needle EMG evaluated the onset latency, peak latency and duration of the suprahyoid and infrahyoid muscles. HRM measured the time intervals among the velopharynx, tongue base, and upper esophageal sphincter. We also evaluated hyoid motion using an automated kinematic analysis software® (AKAS). All of these parameters were synchronized with a tilting motion of the epiglottis. In the EMG analysis, the activations of the suprahyoid muscles developed about 300 ms earlier than that of the infrahyoid muscles. There was a significant relationship between the differences of suprahyoid and infrahyoid muscles’ latency and total duration of the hyoid motion (p < 0.05). The interval time of anterior hyoid motion has a significant correlation in the upper esophageal sphincter (UES) opening time. In conclusions, the functions of the infrahyoid muscles are also as important as that of the suprahyoid muscles for prolonged laryngeal elevation and UES opening. Moreover, kinematic analysis of videofluoroscopic swallowing study (VFSS) and HRM studies could reflect results of needle EMG study and replace EMG study.     

How to deal with oxygen radicals stemming from mitochondrial fatty acid oxidation

Oxygen radical formation in mitochondria is an incompletely understood attribute of eukaryotic cells. Recently, a kinetic model was proposed, in which the ratio between electrons entering the respiratory chain via FADH₂ or NADH determines radical formation. During glucose breakdown, the ratio is low; during fatty acid breakdown, the ratio is high (the ratio increasing—asymptotically—with fatty acid length to 0.5, when compared with 0.2 for glucose). Thus, fatty acid oxidation would generate higher levels of radical formation. As a result, breakdown of fatty acids, performed without generation of extra FADH₂ in mitochondria, could be beneficial for the cell, especially in the case of long and very long chained ones. This possibly has been a major factor in the evolution of peroxisomes. Increased radical formation, as proposed by the model, can also shed light on the lack of neuronal fatty acid oxidation and tells us about hurdles during early eukaryotic evolution. We specifically focus on extending and discussing the model in light of recent publications and findings.     

Les synoviorthèses radio-isotopiques : synthèse des indications et des différents résultats rapportés dans la littérature

Radiosynoviorthesis is used for the local treatment of recurrent joint effusions and leads to synovial pannus necrosis after radionuclide administration. This procedure provides the opportunity to full recovery of normal synovium function after local corticosteroids and systemic modifying drugs failure.     

Mitochondrial Function Dependent Proliferation Assay for the Diagnosis of Mitochondrial Disorders in Human Fibroblasts

A media has been developed which enables the assessment of mitochondrial function in fibroblasts by measuring proliferation as an end point.     

Therapie mit Stammzellen

Therapeutic use of stem cells Here the hematopoetic system of blood‐ and immune cell renewal is reviewed. Curing of chronic leucemias and malignant lymphomas is the most successful stem cell based therapy up to date. However, mismatches of histocompatibility‐complexes (HLA‐types) between receiver and donor set narrow limits to such therapies. Whether other diseases such as Parkinson could be cured by infusion of stem cells is still in question.     

Studies of gonadal sex differentiation

Gonadal differentiation has a determinative influence on sex development in human embryos. Disorders of sexual development (DSD) have been associated with persistent embryonal differentiation stages. Between 1998 and 2015, 139 female patients with various (DSD) underwent operations at the Scientific Center of Obstetrics, Gynaecology and Perynatology in Moscow, Russia. Clinical investigations included karyotyping, ultrasound imaging, hormonal measurement and investigations of gonadal morphology. The male characteristics in the embryo are imposed by testicular hormones. When these are absent or inactive, the fetus may be arrested at between developmental stages, or stay on indifferent stage and become phenotypically female. A systematic analysis of gonadal morphology in DSD patients and a literature review revealed some controversies and led us to formulate a new hypothesis about sex differentiation. Proliferation of the mesonephric system (tubules and corpuscles) in the gonads stimulates the masculinization of gonads to testis. Sustentacular Sertoli cells of the testes are derived from mesonephric excretory tubules, while interstitial Leydig cells are derived from the original mesenchyme of the mesonephros. According of the new hypothesis, the original mesonephric cells (tubules and corpuscles) potentially persist in the ovarian parenchyma. In female gonads, some mesonephric excretory tubules regress and lose the tubular structure, but form ovarian theca interna and externa, becoming analogous to the sustentacular Sertoli cells in the testis. The ovarian interstitial Leydig cells are derived from intertubal mesenchyme of the mesonephros, similar to what occurs in male gonads (testis). Surprisingly, the leading determinative factor in sexual differentiation of the gonads is the mesonephros, represented by the embryonic urinary system.