Biomedical subjects
Publications and source records attributed to C Ho.
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The spin label technique has been used to study human hemoglobins A, F, Zürich, and Chesapeake as a function of carbon monoxide saturation. The experimental results suggest that the changes in the electron paramagnetic resonance spectra of hemoglobin labeled with N-(1-oxyl-2,2,6,6-tetramethyl-4-piperidinyl)iodoacetamide depend on the state of ligation of more than one heme group. For those hemoglobins with full or large cooperative ligand binding (such as A, F, and Zürich), there is a lack of isosbestic points in the spectra as a function of CO saturation. However, for those hemoglobins with little or no cooperative ligand binding (such as Chesapeake and methemoglobins), there is a sharp set of isosbestic points. These findings confirm and extend the early work of McConnell and co-workers. The absence of a set of isosbestic points in those hemoglobins with full cooperative ligand binding is consistent with the sequential model of Koshland, Némethy, and Filmer for cooperative oxygen binding to hemoglobin. The present results, with hemoglobin variants having known amino acid substitutions, also focus on the importance of the interactions among the amino acid residues located at alpha(1)-beta(2) or alpha(2)-beta(1) subunit contacts for the functioning of hemoglobin as an oxygen carrier. In addition, the resonance spectra of the spin label are very sensitive to small structural variations around the heme groups in the beta- or gamma-chains where the labels are attached. The results of the spin label experiment are discussed in relation to recent findings on the mechanism of oxygenation of hemoglobin from the nuclear magnetic resonance studies of this laboratory and the x-ray crystallographic analysis of Perutz and co-workers.
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Nuclear magnetic resonance spectroscopy (100-MHz proton) was used to study the low-spin (S = 1/2) azide derivatives of human adult (alpha(2)beta(2)), human fetal (alpha(2)gamma(2)), Zürich (alpha(2)beta(2) (63 His --> Arg)), and horse (alpha(2)'beta(2)') methemoglobins, as well as whale metmyoglobin in 0.1 M deuterated phosphate at pD 7 and at 31 degrees C. The experimental results indicate that the azide-bound heme groups of the alpha- and beta-chains in human adult methemoglobin and of the alpha- and gamma-chains in fetal methemoglobin are not equivalent. The affinity of the beta- or gamma-chain for azide ion appears larger than that of the alpha-chain. The nuclar magnetic resonance spectrum of hemoglobin Zürich shows that the environment of the azide-heme complex in the abnormal beta-chain is altered by the substitution of arginine for histidine in the beta-63 position, while the alpha-heme environment remains unaffected.
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One approach to gene therapy for the treatment of hemoglobinopathies has been focused on increasing normal globin gene expression. However, because of the high concentration of hemoglobin in the red blood cell (32-34 g/dl), merely introducing the normal globin gene may not be enough to counteract the effect of an abnormal globin. We propose that in addition to strategies to add normal beta- or gamma-globin production to sickle erythrocytes, a decrease in overall hemoglobin concentration would further decrease the polymerization potential and should be considered with other gene therapy approaches. Ribozymes offer the potential to target a selected gene product. A model system has been set up using the human alpha-globin gene for specific gene suppression by ribozymes by cleaving alpha-globin mRNA transcripts. Ribozymes, specifically targeted to five different sites in the 5' portion of human alpha-globin mRNA, have been designed and tested in vitro. Cleavage of 32P-labeled alpha-globin mRNA by these ribozymes has been observed in vitro and the highest level of activity has been found for a multi-ribozyme combining all five ribozymes. The multi-ribozyme gene along with promoters with varying activities in erythroid cells was transfected into human erythroleukemia K562 cells. The multi-ribozyme gene, under the control of human alpha-2-globin promoter alone and combined with the locus control region enhancer, caused a decrease in the level of alpha-globin mRNA of 50-75% compared to the control, determined by RNase protection and by real-time quantitative PCR. The decrease in alpha-globin transcripts has been found to be correlated with expression of the multi-ribozyme in a dose-dependent manner and does not appear to be mediated by an antisense effect. These results suggest that the multi-ribozyme may be useful in gene therapy as an effective suppressor of a specific globin gene.
We performed a blind prospective analysis of the shoulders of 20 asymptomatic volunteers, aged 25 to 55 years, to determine the frequency of magnetic resonance (MR) findings considered abnormal in symptomatic patients. Twenty symptomatic patients were used as controls. With regard to the asymptomatic shoulders, all 20 had intact rotator cuff tendons, although six (30%) of the tendons had abnormal internal signal, and one (5%) had abnormal morphology. Subdeltoid and subacromial fat planes were intact in 20 (100%) and 19 (95%) shoulders respectively. Subdeltoid or subacromial fluid was not present in any shoulder. Acromioclavicular osteophytes and supraspinatus depression were seen in seven (35%) and six (30%) respectively. The glenoid labrum was intact in all volunteers, although it had abnormal internal signal in 10 (50%). MR findings of abnormal signal in the glenoid labrum, and of abnormal signal and morphology of the rotator cuff tendons, supraspinatus depression, and acromioclavicular osteophytes have been reported as signs of instability, tendinitis, and impingement. Similar findings were seen in asymptomatic volunteers, indicating that these findings may not be a sign of clinically significant pathology.
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Drs. Mitchell et al. have provided a valuable radiologic perspective of trauma to the ankle and foot. Previous articles in this series consisted of analyzing ankle fractures, ligamentous injuries, trauma to the talus, calcaneus, and midfoot. Plain x-ray films and sophisticated studies will assist in recognizing conditions described in this series of papers. The following represents the final part of this discussion.
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