Tibiofemoral joint contact force in deep knee flexion and its consideration in knee osteoarthritis and joint replacement

The aim of the study was to estimate the tibiofemoral joint force in deep flexion to consider how the mechanical load affects the knee. We hypothesize that the joint force should not become sufficiently large to damage the joint under normal contact area, but should become deleterious to the joint under the limited contact area. Sixteen healthy knees were analyzed using a motion capture system, a force plate, a surface electromyography, and a knee model, and then tibiofemoral joint contact forces were calculated. Also, a contact stress simulation using the contact areas from the literature was performed. The peak joint contact forces (M +/- SD) were 4566 +/- 1932 N at 140 degrees in rising from full squat and 4479 +/- 1478 N at 90 degrees in rising from kneeling. Under normal contact area, the tibiofemoral contact stresses in deep flexion were less than 5 MPa and did not exceed the stress to damage the cartilage. The contact stress simulation suggests that knee prosthesis having the contact area smaller than 200 mm2 may be problematic since the contact stress in deep flexion would become larger than 21 MPa, and it would lead damage or wear of the polyethylene.     

Development of a Melting Tablet Containing Promethazine HCl Against Motion Sickness

The purpose of this study was to design a 'Traveller Friendly Drug Delivery System' for PM-HCl. Conventional promethazine (PM-HCl) tablets are bitter, need to be taken 1 h before symptoms and water is also needed. Taste-masked granules were produced with Eudragit E100 by extrusion, and analyzed with FTIR, DSC, and XRD. Tablets formulated from granules by direct compression using Ac-Di-Sol, Polyplasdone-XL, Primojel and ion-exchanger Tulsion339 and evaluated for mass uniformity, friability, tensile strength, drug content uniformity, water absorption ratio, in-vitro and in-vivo disintegration time and in-vitro dissolution studies. The observed drug-polymer interactions and reduced crystallinity may be reasons for increased dissolution rates. The formulated tablets were disintegrated within 15 s. Tablets (25 mg PM-HCl) with Ac-Di-Sol (4%) showed complete release within 1 min, while marketed conventional tablets (Phenergan; Rhone-Poulec) release 25% during the same period. A preliminary stability studies for the prepared tablets carried at 30 +/- 2 degrees C/60 +/- 5% RH, and 40 +/- 2 degrees C/75 +/- 5%RH for 3 months showed no significant changes in the tablets quality at 30 +/- 2 degrees C/60 +/- 5% RH. However, at 40 +/- 2 degrees C/75 +/- 5%RH marked increase in in-vitro disintegration time, tensile strength and decrease in friability and water absorption ratio was found. The present studies indicate the abilities of Eudragit E 100 for taste masking and improving the dissolution profile of PM-HCl after complexation. In addition, by employing cost effective direct compression method, fast-dissolving tablets of 400 mg total weight with an acceptable quality could be prepared.     

Screening for mitochondrial DNA heteroplasmy in children at risk for mitochondrial disease

Temporal temperature gradient gel electrophoresis was used to screen 70% of the mtDNA, including all 22 tRNA genes, for heteroplasmy in 75 children with neuromuscular and/or multi-system dysfunction and elevated lactate levels, and in 95 controls. Standard PCR/ASO (allele specific oligonucleotide) and Southern analyses were also employed. Excluding common length variants, heteroplasmy was found in 22 patients and two controls (P < 0.001), with four patients demonstrating heteroplasmy in two locations each. Of the 23 heteroplasmic variants sequenced among the patients, 17 were novel point variants in the control region (CR) and only two involved tRNA genes. Heteroplasmy is highly associated with the disease group, and is predominately found in the CR, an area rarely studied in patient populations. These variants may be pathological mutations or disease markers.     

Reversible photocontrol of peptide helix content: adjusting thermal stability of the cis state

Cross-linking reagents based on an azobenzene core can be used to reversibly photoregulate secondary structure when introduced as intramolecular bridges in peptides and proteins. Photoisomerization of the azobenzene core in the trans to cis direction is triggered by photon absorption but isomerization from cis to trans occurs thermally as well as photochemically. The rate of the thermal process effectively determines the half-life of the cis form as well as the extent to which the trans form can be recovered. We designed and characterized a series of methanethiosulfonate (MTS)-bearing thiol-reactive azo-benzene-based cross-linkers. These cross-linkers are shown to permit photoregulation of helix content in a test peptide with half-lives for the cis conformation ranging from 11 s to 43 h at 25 degrees C. The cross-linkers described here thus broaden the range of reagents available for reversible photocontrol of peptide and protein conformation.     

Design, synthesis and evaluation of racemic 1-(4-hydroxyphenyl)-2-[3-(substituted phenoxy)-2-hydroxy-1-propyl]amino-1-propanol hydrochlorides as novel uterine relaxants

Novel 1-(4-hydroxyphenyl)-2-[3-(substituted phenoxy)-2-hydroxy-1-propyl]amino-1-propanol hydrochlorides were designed based on the pharmacophore for potent uterine relaxant activity and by utilizing the principles of structural hybridization. The designed molecules were synthesized as racemates by a novel route and were evaluated for uterine relaxant activity in vitro on isolated rat uterus and in vivo in pregnant rats. Their cAMP-releasing potential was studied using rat uterus tissue homogenates by the cAMP [(3)H] assay, and cardiac stimulant potential was evaluated on isolated guinea pig right atrium. All compounds exhibited potent uterine relaxant activity in vitro and produced a significant delay in the onset of labour in pregnant rats; their cAMP-releasing potential was slightly less, while their cardiac stimulant potential was insignificant as compared to isoxsuprine hydrochloride.     

Decreased renal preglomerular microvascular PGI2 and PGE2 biosynthesis in cholesterol-fed rabbits

Although atherosclerosis is a common disease afflicting the kidney, few studies have examined the biochemical disturbances associated with this process directly in the renal microvasculature. Using a technique developed in this laboratory to isolate renal preglomerular microvessels, we have examined whether these vascular segments have a reduced capacity to synthesize vasodilator prostanoids (i.e., PGI2 and PGE2), an observation which has been made in atherosclerotic blood vessels from other vascular beds. The synthesis of these two prostanoids was assessed by radioimmunoassay in a group of white New Zealand rabbits fed a 2% cholesterol diet for 30 days and the results compared to that obtained in a similar group of rabbits fed a normal diet. The results of these studies showed the development of hypercholesterolemia in the cholesterol-fed rabbits which was associated with a 35% decrease in the biosynthesis of PGI2 and a 51% decrease in PGE2 in freshly isolated renal preglomerular microvessels. These findings are similar to those observed in non-renal major blood vessels and suggest that common biochemical mechanisms may operate in the development of atherosclerosis in many organ systems.     

Specific absence of the alpha 1 subunit of the dihydropyridine receptor in mice with muscular dysgenesis

Muscular dysgenesis is a lethal mutation in mice that results in a complete absence of skeletal muscle contraction due to the failure of depolarization of the transverse tubular membrane to trigger calcium release from the sarcoplasmic reticulum. In order to determine whether the defect in muscular dysgenesis leads to a specific loss of one of the components of excitation-contraction coupling or to a generalized loss of all components of excitation-contraction coupling, we have analyzed skeletal muscle from control and dysgenic mice for the sarcoplasmic reticulum and transverse tubular proteins which are believe to function in excitation-contraction coupling. We report that the proteins involved in sarcoplasmic reticulum calcium transport, storage, and release [Ca2+ + Mg2+)-ATPase, calsequestrin, and calcium release channel) are present in dysgenic muscle. Also present in dysgenic muscle is the 175/150-kDa glycoprotein subunit (alpha 2) of the dihydropyridine receptor. However, the 170-kDa dihydropyridine binding subunit (alpha 1) of the dihydropyridine receptor is absent in dysgenic muscle. These results suggest that the specific absence of the alpha 1 subunit of the dihydropyridine receptor is responsible for the defects in muscular dysgenesis and that the alpha 1 subunit of the dihydropyridine receptor is essential for excitation-contraction coupling in skeletal muscle.     

Differentiation potential of individual olfactory c‐Kit+ progenitors determined via multicolor lineage tracing

Olfactory tissue undergoes lifelong renewal, due to the presence of basal neural stem cells. Multiple categories of globose basal stem cells have been identified, expressing markers such as Lgr5, Ascl1, GBC‐2, and c‐Kit. The differentiation potential of individual globose cells has remained unclear. Here, we utilized Cre/loxP lineage tracing with a multicolor reporter system to define c‐Kit+ cell contributions at clonal resolution. We determined that reporter expression permitted identification of c‐Kit derived progeny with fine cellular detail, and that clones were found to be comprised by neurons only, microvillar cells only, microvillar cells and neurons, or gland/duct cells. Quantification of reporter‐labeled cells indicated that c‐Kit+ cells behave as transit amplifying or immediate precursors, although we also found evidence for longer‐term c‐Kit+ cell contributions. Our results from the application of multicolor fate mapping delineate the clonal contributions of c‐Kit+ cells to olfactory epithelial renewal, and provide novel insight into tissue maintenance of an adult neuroepithelium. © 2015 Wiley Periodicals, Inc. Develop Neurobiol 76: 241–251, 2016