Synthesis of substituted N-[3-(3-methoxyphenyl)propyl] amides as highly potent MT2-selective melatonin ligands

A series of substituted N-[3-(3-methoxyphenyl)propyl] amides were synthesized and their binding affinities towards human melatonin MT₁ and MT₂ receptors were evaluated. It was discovered that a benzyloxyl substituent incorporated at C6 position of the 3-methoxyphenyl ring dramatically enhanced the MT₂ binding affinity and at the same time decreased MT₁ binding affinity.     

Strain and micromotion in intact and resurfaced composite femurs: Experimental and numerical investigations

Understanding the load transfer within a resurfaced femur is necessary to determine the influence of mechanical factors on potential failure mechanisms such as early femoral neck fractures and stress shielding. In this study, an attempt has been made to measure the stem-bone micromotion and implant cup-bone relative displacements (along medial-lateral and anterior-posterior direction), in addition to surface strains at different locations and orientations on the proximal femur and to compare these measurements with those predicted by equivalent FE models. The loading and the support conditions of the experiment were closely replicated in the FE models. A new experimental set-up has been developed, with specially designed fixtures and load application mechanism, which can effectively impose bending and deflection of the tested femurs, almost in any direction. High correlation coefficient (0.92–0.95), low standard error of the estimate (170–379 με) and low percentage error in regression slope (12.8–17.5%), suggested good agreement between the numerical and measured strains. The effect of strain shielding was observed in two (out of eight) strain gauges located on the posterior side. A pronounced strain increase occurred in strain gauges located on the anterior head and neck regions after implantation. Experimentally measured stem-bone micromotion and implant cup-bone relative displacements (0–13.7 μm) were small and similar in trends predicted by the FE models (0–25 μm). Despite quantitative deviations in the measured and numerical results, it appears that the FE model can be used as a valid predictor of the actual strain and stem-bone micromotion.     

Polymerisation stress modelling in acrylic bone cement

Fatigue failure of the cement mantle has been proposed as one of the failure processes contributing to aseptic loosening of cemented joint replacements. It has also been suggested that fatigue failure is dramatically accelerated by residual stress generated during the cement polymerisation process. Previous computational models of the polymerisation process have investigated only the latter part of polymerisation by assuming both instantaneous hardening of the material (a stress locking point) and that all residual stress results from thermal shrinkage after this stress locking point. In this study, finite element models which use the local degree of polymerisation to calculate material properties and shrinkage have been used to predict residual stresses in two models of total hip replacement cement mantles. Results indicate that the final value of cement mantle stress may not be the highest stresses that the cement is subjected to during the polymerisation process. Two models are presented, a 2-dimensional model, which was adapted from a similar model in the literature (Lennon and Prendergast, 2002) and a 3-dimensional concentric-cylinders model. In both cases a chemical kinetics model was used to predict the progress of the polymerisation reaction and a second linear model used to predict cement mechanical properties and density, and so stress generation and volume change, over time. There was good agreement of the results of the 2D model with its counterpart in the literature. For the 3D model, the final residual stress magnitudes and patterns showed good agreement with similar physical and computational models in the literature.     

Cerebral artery responses to pressure and flow in uremic hypertensive and spontaneously hypertensive rats

Impaired cerebral blood flow autoregulation is seen in uremic hypertension, whereas in nonuremic hypertension autoregulation is shifted toward higher perfusion pressure. The cerebral artery constricts in response to a rise in either lumen pressure or flow; we examined these responses in isolated middle cerebral artery segments from uremic Wistar-Kyoto rats (WKYU), normotensive control rats (WKYC), and spontaneously hypertensive rats (SHR). Pressure-induced (myogenic) constriction developed at 100 mmHg; lumen flow was then increased in steps from 0 to 98 microl/min. Some vessels were studied after endothelium ablation. Myogenic constriction was significantly lower in WKYU (28 +/- 2.9%) compared with both WKYC (39 +/- 2.5%, P = 0.035) and SHR (40 +/- 3.1%, P = 0.018). Flow caused constriction of arteries from all groups in an endothelium-independent manner. The response to flow was similar in WKYU and WKYC, whereas SHR displayed increased constriction compared with WKYU (P < 0.001) and WKYC (P < 0.001). We conclude that cerebral myogenic constriction is decreased in WKYU, whereas flow-induced constriction is enhanced in SHR.     

Urinary homovanillic acid (HVA) and vanillymandelic acid (VMA) in workers exposed to manganese dust

The neurotoxicity of manganese (Mn) is well known, however, the neurochemical effect caused by this metal is less well investigated. In this study, urinary homovanillic acid (HVA) and vanillymandelic acid (VMA), two end products of catecholamine metabolism, were measured in 39 workers chronically exposed to Mn in a manganese smelting plant. The average duration of Mn exposure was 17.4 yr. Nineteen nonexposed workers were also studied. Concentrations of Mn in serum (MnS) and in urine (MnU) were measured by Zeeman graphite furnace atomic absorption spectrophotometry (ZAAS), and HVA and VMA determined by high performance liquid chromatography (HPLC). For Mn-exposed workers, the concentration of MnS was nearly 2.8 times (1.61 ± 0.16 mg/L vs 0.56 ± 0.16 mg/L) and MnU about 4.5 times higher (7.62 ± 0.17 mg/L vs 1.69 ± 0.16 mg/L) than the nonexposed. Although the geometric mean concentration of HVA in exposed workers was similar to that of the nonexposed (3.09 ± 1.39 mg/g ere. vs 2.99 ± 1.40 mg/g cre.), the VMA concentration was significantly higher (3.02 ± 1.43 mg/g cre. vs 2.49 ± 1.58 mg/g cre.,p = 0.033). Multiple regression analysis showed that although there were no correlations between any of these parameters with the duration of exposure to Mn, both HVA and VMA showed significant correlations with increase in MnS and MnU. These data provide evidence that exposure to Mn was associated with measurable increase in catecholamine metabolites. This finding is compatible with recent observations in laboratory animals that Mn interferes with neurochemical metabolism.     

DAX1 mutations map to putative structural domains in a deduced three-dimensional model.

The DAX1 protein is an orphan nuclear hormone receptor based on sequence similarity in the putative ligand-binding domain (LBD). DAX1 mutations result in X-linked adrenal hypoplasia congenita (AHC). Our objective was to identify DAX1 mutations in a series of families, to determine the types of mutations resulting in AHC and to locate single-amino-acid changes in a DAX1 structural model. The 14 new mutations identified among our 17 families with AHC brought the total number of families with AHC to 48 and the number of reported mutations to 42; 1 family showed gonadal mosaicism. These mutations included 23 frameshift, 12 nonsense, and six missense mutations and one single-codon deletion. We mapped the seven single-amino-acid changes to a homology model constructed by use of the three-dimensional crystal structures of the thyroid-hormone receptor and retinoid X receptor alpha. All single-amino-acid changes mapped to the C-terminal half of the DAX1 protein, in the conserved hydrophobic core of the putative LBD, and none affected residues expected to interact directly with a ligand. We conclude that most genetic alterations in DAX1 are frameshift or nonsense mutations and speculate that the codon deletion and missense mutations give insight into the structure and function of DAX1.