Myoblast-mediated gene transfer to the joint

Several genetic and acquired pathologic conditions of the musculoskeletal system, such as arthritis and damage to ligament, cartilage, and meniscus, may be amenable to gene therapy. Even though ex vivo gene transfer with synovial cells has been shown to deliver genes encoding for anti-arthritic proteins into the rabbit knee joint, its success has been limited by a transient transgene expression. In this study, data were investigated regarding the use of muscle cells as an alternative gene-delivery vehicle to the joint in newborn rabbit and adult severe combined immunodeficiency mice. We demonstrated that myoblasts were transduced more efficiently than synovial cells with use of the same adenoviral preparation in vitro. After intra-articular injection, the engineered muscle cells adhered to several structures in the joint, including the ligament, capsule, and synovium. In addition, myoblasts fused to form many post-mitotic myotubes and myofibers at different locations of the joint of the newborn rabbit 5 days after the injection. In the knee of the adult mouse, myoblasts fused and expressed the reporter gene for at least 35 days after the injection. The presence of post-mitotic myofibers in the knee joint raises the possibility of long-term expression of the secreted protein. Currently, numerous tissues in the joint (ligament, meniscus, and cartilage) have poor intrinsic healing capacity and frequently need surgical corrections. A stable gene-delivery vehicle to the joint producing proteins that ameliorate these different musculoskeletal conditions may change the clinical implications of these pathologies.     

Antiproteinuric effect predicts renal protection by angiotensin-converting enzyme inhibition in rats with established adriamycin nephrosis

1. The mechanism of renal protection by angiotensin-converting enzyme inhibition is still the subject of debate. Inhibition of proteinuria might play a role. If so, a good antiproteinuric response to angiotensin-converting enzyme inhibition should predict subsequent protection against renal structural damage. This hypothesis has not been tested in models where treatment is started after the renal disease is well established, i.e. models that mimic the clinical situation. 2. We therefore investigated this hypothesis in 96 male Wistar rats with established adriamycin nephrosis. Reduction of proteinuria was achieved by lisinopril (0, 2, 5 and 10 mg day-1 kg-1) on two different sodium diets (0.3% and 0.05% NaCl). Therapy started 6 weeks after adriamycin (at stable proteinuria) and was continued for 6 weeks. 3. Lisinopril reduced blood pressure by 32 +/- 4% and proteinuria by an average of 72 +/- 7%, with stabilization after 2 weeks. Considerable interindividual differences in antiproteinuric response was found. Glomerulosclerosis score was reduced by 15 +/- 5%. All the effects of angiotensin-converting enzyme inhibitors were enhanced by sodium depletion, but sodium depletion in itself did not affect blood pressure (124 +/- 4 mmHg), proteinuria (664 +/- 68 mg/day) or glomerulosclerosis score (30 +/- 5%). Interestingly, the more proteinuria was reduced initially in an individual rat, the less sclerosis was found in the long term in that rat. 4. In conclusion, angiotensin-converting enzyme inhibition lowers proteinuria and prevents glomerulosclerosis in established adriamycin nephrosis. These effects are enhanced by sodium depletion. The individual short-term antiproteinuric effect predicts the protection against ultimate glomerular damage. This is consistent with the hypothesis that reduction of proteinuria is a mechanism by which angiotensin-converting enzyme inhibitors exert renoprotection.     

Effect of profound hearing loss on a central auditory nucleus

The present study was designed to investigate the type and extent of degeneration occurring in the human central auditory system subsequent to profound hearing loss. The authors have examined the size of one population of neurons in the ventral cochlear nucleus in seven subjects with profound hearing loss (audiometric responses poorer than 90-100 dB HL). Six normal subjects, ages 35-78, were used as controls. Cell size in the hearing-impaired subjects ranged from normal to reduced by more than 50 percent. Two factors appear to contribute to the variability in cell size reduction. The correlation coefficient (Spearman rs) of cell size with duration of profound deafness was -0.48, indicating a moderate tendency for neurons to become smaller with longer periods of deafness. The correlation coefficient of cell size with number of surviving cochlear ganglion cells was 0.73, indicating a stronger tendency for neurons to be larger with greater eighth nerve innervation of the cochlear nucleus. Two cases of Scheibe degeneration showed the most severe degenerative change in the central auditory system.     

The new partnership of genomics and chemistry for accelerated drug development

The Grashey shoulder position is used to demonstrate damage to the glenohumeral joint caused by osteoarthritis, sclerosis, tumors, fractures, osteophytes and cystic changes. However, it can be difficult to assess loss of articular cartilage using the Grashey shoulder position because little axial load is applied to the glenohumeral joint. This article describes a method of creating a loading force across the glenohumeral joint by adding weighted arm abduction during the Grashey position to demonstrate loss of the articular cartilage. Case studies and radiographs are presented to discuss the advantages of using the Grashey position with weighted abduction.     

Intermodality, retrospective image registration in the thorax

The purpose of this study was to develop an accurate, retrospectively applicable procedure for registering thoracic studies from different modalities in a short amount of time and with minimal operator intervention. METHODS: CT and PET studies were acquired from six patients. The pleural surfaces in both image sets were determined by segmenting based on 50% of the maximum soft-tissue value in the study. These surfaces were converted into three-dimensional volumes and used to register the CT and PET studies in three dimensions using a sum of least squares fitting approach. The registered PET study was then displayed in a hot metal scale overlayed on top of the gray scale CT study. The accuracy of the fit was evaluated through a phantom study and preliminary clinical evaluation. RESULTS: A phantom study was performed to determine the limits of this technique. The accuracy was determined to be less than 2.3 mm in the x and y direction and 3 mm in the z direction. Preliminary clinical evaluation was also performed with encouraging results. CONCLUSION: This technique accurately registers PET and CT images of the thorax, retrospectively, without the need for external fiducial markers or other a priori action.     

Endoscopic surveillance of Barrett's esophagus: a cost-effectiveness comparison with mammographic surveillance for breast cancer

OBJECTIVE: Endoscopic surveillance of Barrett's esophagus is commonly practiced to detect malignancy in an early and curable stage. However, the cost-effectiveness of this practice has been questioned. To clarify this issue, we undertook a cost analysis of endoscopic surveillance to detect adenocarcinoma in Barrett's esophagus compared with mammography used to detect occult carcinoma of the breast, a widely accepted cancer surveillance technique. METHODS: The rate of esophageal adenocarcinoma detected by endoscopic surveillance was calculated for Duluth Clinic patients with Barrett's esophagus seen from 1980 to 1995 and compared with published rates. The rate of occult breast cancer detection was calculated for all women undergoing surveillance mammography at the Duluth Clinic for the year 1994 and compared with published rates. Costs for screening studies and therapy for cancer treatment for both cancers were calculated based on clinical results and assumptions regarding outcomes derived from published reports, and the costs were compared. RESULTS: Endoscopic surveillance of 149 patients with benign Barrett's esophagus was performed for a total of 510 patient-yr, during which time seven patients developed adenocarcinoma, an incidence of one case per 73 patient-yr of follow-up. Occult breast cancer was detected in 50 of 12,537 mammograms, a detection rate of 0.4%. The incidences in both cases were comparable to published figures. The costs of detecting a case of adenocarcinoma in Barrett's esophagus and occult breast cancer were $37,928 and $54,513, respectively, and those for treatment resulting in cure were $83,340 and $83,292. Cost per life-yr saved was $4,151 for adenocarcinoma in Barrett's esophagus and $57,926 for breast cancer. CONCLUSION: Endoscopic surveillance of patients with Barrett's esophagus compares favorably with the common practice of surveillance mammography to detect early breast cancer, and should therefore be considered to be as cost-effective as surveillance mammography.