Mutation of the androgen receptor at amino acid 708 (Gly-->Ala) abolishes partial agonist activity of steroidal antiandrogens

Mutation of a single amino acid in the ligand-binding domain (LBD) of the human androgen receptor (hAR) can induce functional abnormalities in androgen binding, stabilization of active conformation, or interaction with coactivators. The Gly708Ala and Gly708Val substitutions are associated with partial and complete androgen insensitivity syndromes, respectively. In this work, we introduced Ala, Val, and aromatic Phe mutations at position 708 on helix H3 of the hAR-LBD and tested the functional and structural consequences on hAR activity in the presence of steroidal or nonsteroidal agonists and antagonists. The residues involved in the specific recognition of these androgen ligands were identified and analyzed in the light of in vitro biological experiments and the 3D hAR-LBD structure. Our study demonstrated that the Gly708Ala mutation influenced the agonist versus antagonist activity of the ligands and confirmed the crucial role of this residue within the ligand-binding pocket (LBP) in the modulation of androgen agonists. The Gly708Ala mutation transformed the antiandrogen cyproterone acetate (CPA), a partial agonist, into a pure antiandrogen, and the pure nonsteroidal antiandrogen hydroxyflutamide in a partial agonist. From the docking studies, we suggest that CPA acts on AR through the novel mechanism called "passive antagonism".     

The kinematics of fixed- and mobile-bearing total knee arthroplasty

The success of any total knee arthroplasty (TKA) is influenced by a complex interaction between component geometry and the surrounding soft tissues. The objective of this study was to investigate posterior femoral translation and tibial rotation in a single design posterior-stabilized TKA offering fixed- and mobile-bearing tibial components. Specifically, we examined whether mobile-bearing TKA restores normal knee translation and rotation better than fixed-bearing TKA design. Eleven human knee specimens retrieved postmortem were tested using a robotic system. The translation and rotation of the intact and reconstructed knees were compared. The data indicate that for all knees, posterior femoral translation occurs along the passive path and under muscle loading conditions. Furthermore, increasing flexion angle corresponded with increased internal tibial rotation. Femoral translation and tibial rotation for fixed- and mobile-bearing posterior-stabilized TKAs were similar despite component design variations. However, both arthroplasties only partially restored intact knee translation and rotation. The data presented here may serve as an aid in the development of a rationale for additional improvement in surgical techniques and prosthesis design, so that normal knee function may be restored.     

Optimizing flexion after total knee arthroplasty: advances in prosthetic design

The clinical results with most modern total knee arthroplasty (TKA) designs are highly satisfactory regarding pain relief and improving walking ability. However, one problem that has not been addressed fully by most current designs is the ability to consistently achieve flexion greater than 120 degrees. Although the human knee is capable of flexion of more than 150 degrees, an analysis of the results of contemporary TKA reveals that on average, patients rarely flex beyond 120 degrees. Key factors influencing range of flexion after TKA include preoperative knee motion, surgical technique, prosthetic design, and rehabilitation. The success of any total knee system may in part be linked to its ability to optimally restore normal kinematic function. Some arthroplasty designs currently are available that incorporate modifications aimed at improving range of flexion, but limited data currently are available on their function and potential advantages. Currently, an in vitro experimental model incorporating robotics is being used to investigate the kinematics of the native knee and various TKA designs at flexion angles beyond 120 degrees. This robotic model in conjunction with clinical studies may provide an understanding of the limitations of contemporary knee designs regarding achieving higher degrees of knee flexion. This may lead to the refinement of existing designs and development of newer prostheses that may enhance the range of flexion that is achievable after TKA.     

Synthesis and in vitro calcium antagonist activity of 4-aryl-7,7-dimethyl/1,7,7-trimethyl-1,2,3,4,5,6,7,8-octahydroquinazoline-2,5-dione derivatives

In this study, a series of 4-aryl-7,7-dimethyl and 1,7,7-trimethyl-1,2,3,4,5,6,7,8-octahydroquinazoline-2,5-diones (1-25) were synthesized by condensing urea or N-methylurea with 5,5-dimethyl-1,3-cyclohexanedione and appropriate aromatic aldehydes according to the Biginelli reaction. The structures of the compounds were confirmed by spectral data and elementary analysis. The calcium antagonist activity of the compounds was tested in vitro on isolated rat ileum and lamb carotid artery. Compounds 16 and 19 were the most active derivatives on isolated rat ileum compared with the standard nicardipine. On isolated aortic strips of lamb the calcium antagonist activity of compound 16 (maximum relaxant effect: 38.83+/-5.84%) was found as high as that of nicardipine (maximum relaxant effect: 35.50+/-4.16%) used as a reference drug.     

Impact of stomatherapy on quality of life in patients with permanent colostomies or ileostomies

BACKGROUND AND AIMS: The impact of a stoma on a patient's life is little discussed and is often underestimated, as well as the contribution of stomatherapy to health-related quality of life (QOL). This present study examined the problems faced by patients with ileostomies or colostomies and the possible contribution of stomatherapy to QOL. PATIENTS AND METHODS: Forty-three selected and well-documented stoma patients who had properly constructed, well functioning end colostomies or ileostomies were analyzed. Further analyses were carried out for the subgroups of patients with irrigating colostomies ( n=16), nonirrigating colostomies ( n=15), and ileostomies ( n=12). The digestive disease QOL questionnaire 15 (DDQ-15) was used to analyze QOL before and 3 months after stomatherapy. A second questionnaire consisting of 11 questions with yes/no answers was also used before and 3 months after stomatherapy to define more specifically the stoma-related problems of each patient as well as the frequency of each issue in a patient group at a given time. RESULTS: Cumulatively the mean QOL score was significantly higher after stomatherapy than before. Before stomatherapy the irrigating colostomy patients had the highest QOL score and the ileostomy group the lowest. QOL scores 3 months after stomatherapy were significantly higher in all groups than before. Again, the irrigating colostomy patients had a significantly higher score than the nonirrigating colostomy and ileostomy patients. Cumulatively all of the items improved significantly after stomatherapy, such as getting dressed, bathing, and participating in sports. CONCLUSION: These findings confirm that colostomy or ileostomy has a profoundly negative impact on QOL. Specialized counseling of these patients by a dedicated team improves QOL significantly.     

Health hazards of welding fumes

Even in the twenty-first century, welding is still a common and a highly skilled occupation. The hazardous agents associated with welding processes are acetylene, carbon monoxide, oxides of nitrogen, ozone, phosgene, tungsten, arsenic, beryllium, cadmium, chromium, cobalt, copper, iron, lead, manganese, nickel, silver, tin, and zinc. All welding processes involve the potential hazards for inhalation exposures that may lead to acute or chronic respiratory diseases. According to literature described earlier it has been suggested that welding fumes cause the lung function impairment, obstructive and restrictive lung disease, cough, dyspnea, rhinitis, asthma, pneumonitis, pneumoconiosis, carcinoma of the lungs. In addition, welding workers suffer from eye irritation, photokeratitis, cataract, skin irritation, erythema, pterygium, non-melanocytic skin cancer, malignant melanoma, reduced sperm count, motility and infertility. Most of the studies have been attempted previously to evaluate the effects of welding fumes. However, no collectively effort illuminating the general effects of welding fumes on different organs or systems or both in human has not been published. Therefore, the aim of this review is to gather the potential toxic effects of welding fumes documented by individual efforts and provide informations to community on hazards of welding.     

Biomonitoring of genotoxic risks and haematological changes in workers in rubber industry

Several substances used in rubber processing are known to be of genotoxins and haematotoxins. Such as benzene, phenols, amines amides, naphthalene and benzo(a)pyrene. Twenty-five exposed workers from a rubber factory were compared with twenty-five controls working as administrative staff in the same factory. An elevated level of urinary thioether (mercapturic acid derivatives) a significant elevation in the level of DNA SSB was found among exposed workers in comparison with control group (p < 0.01). A significant increase in the absolute numbers of peripheral leukocytes and in erthrocyte mean cell volume was observed among exposed workers in comparison with controls (p < 0.01), while a significant decrease in the percentage of lymphocytes and eosinophils was found among exposed workers in comparison with controls. However, the percentage of monocytes was not altered. The reported results have justified the use of genotoxic biomarkers in assessing levels of genotoxic exposure in human population groups and as a screening biomarkers in periodic medical examination as a protective measure.