Misoprostol Partially Inhibits the Renal Scarring of Chronic Cyclosporine Nephrotoxicity

Chronic cyclosporine (CY) nephrotoxicity is a well-known complication of this immunosuppressive agent, which may, in part, be attributed to abnormalities in renal prostaglandin content. We utilized misoprostol (M), a prostaglandin E(1) analog, in a rat model of chronic CY toxicity at 7 and 28 days to determine effectiveness in prevention of the renal damage. After 7 days, there were no differences in weight change, creatinine clearance, or renal scarring in rats treated with vehicle (V), CY, or CY + M; however, renal procollagen alpha 1(I) mRNA levels were increased in CY versus V rats (p < 0.05). In contrast, after 28 days CY rats had significant reductions in weight gain, glomerular filtration rate, and renal blood flow with increases in renal scarring and procollagen alpha 1 (IV) mRNA levels (all p < 0.05 versus V). Addition of M resulted in partial but significant improvement in GFR, RBF, and procollagen alpha 1(IV) mRNA levels, with lessening of the renal scarring. Skin fibroblasts also were incubated with CY and M to assess impact on procollagen MRNA levels. CY augmented fibroblast procollagen mRNA levels which enhanced by a large dose of M, but inhibited with a moderate dose. These data suggest that M improves renal scarring induced by CY by hemodynamic and/or direct effects.     

Bioequivalence of Two Recombinant Human Growth Hormones in Healthy Male Volunteers after Subcutaneous Administration

The bioequivalence of recombinant human growth hormone (rhGH) (somatropin) and its N-methionyl variant (Met-hGH) [Protropin((R)) (somatrem for injection)] was determined in 42 healthy male volunteers (n = 21 per treatment) who were randomized to receive either protein by subcutaneous administration of 0.1 mg kg(minus sign1). Serum samples were collected over 24 h after the injection, and the concentration of human growth hormone (hGH) were determined by an immunoradiometric assay. Bioequivalence of the two proteins was assessed by determining whether the 90% confidence limits for the ratio of geometric means using logarithmically transformed AUC and C(max) parameters (log(10)AUC(0--24), log(10)AUC(0--infty infinity), and log(10)C(max)) were within the 80--125% range. The bioequivalence of the two treatments was also tested by calculating a bioequivalance index (xi(2)) that measured the difference between the two mean concentration-time profiles. The 90% confidence intervals for the ratios of the geometric means for AUC were within the prescribed 80--125% range for bioequivalence. The upper limit of the 90% confidence interval for the ratio of the geometric means for C(max) fell slightly outside the 125% criterion even though the geometric mean itself, 106.6%, was very close to the ideal of 100%. There was a larger standard error associated with C(max) than with the AUCs, and this marginally larger confidence limit for C(max) resulted more from the variance among the subject than to the difference in the means. In fact, the bioequivalence index, xi(2), was 0.075, indicating that the mean curves after rhGH and Met-hGH are essentially superimposable.     

Chromosome 11q13 markers and D-type cyclins in breast cancer

Summary One in six primary human breast cancers has DNA amplification centered on the cyclin D1 gene (CCND1) on chromosome 11q13. This genetic abnormality is preferentially associated with estrogen-receptor positive tumors and may define a sub-class of patients with an adverse prognosis. AlthoughCCND1 has the credentials of a cellular oncogene, being a target for chromosomal translocation and retroviral integration, the 11q13 amplicon encompasses several other markers andCCND1 is not the only candidate for the key gene on the amplified DNA. To assess their relative importance, we have constructed a physical map of the amplified DNA and compared the extent and frequency of amplification across the region. Since it is likely that the gene providing the selective force for amplification will be expressed at elevated levels, we have also examined expression of both RNA and protein. By these criteria, cyclin D1 remains the strongest candidate for the key oncogene on the amplicon and we are currently investigating the functional consequences of its over-expression.Presented by Gordon Peters at the 16th Annual San Antonio Breast Cancer Symposium, San Antonio TX, USA, November 4, 1993; Minisymposium on Molecular Genetics in Breast Cancer.     

A simple chest radiograph score to predict chronic lung disease in prematurely born infants

A simple scoring system has been evaluated with regard to its ability to characterize the pre-term infant's chest radiograph appearance at 28 days and predict oxygen dependency beyond 36 weeks post-conceptional age (PCA). Chest radiographs taken at approximately 1 month of age in 42 infants (median gestational age 28 weeks) were assessed by the scoring system for the presence of fibrosis/interstitial shadows, cystic elements and degree of hyperinflation (maximum score 8). The system's results were then compared with those obtained using two previously published scoring systems. Using all three systems, there were significant differences in the scores of infants who were and were not oxygen dependent at 28 days (p < 0.001) and 36 weeks PCA (p < 0.001). For the three systems, the positive predictive values of a score of 3 or more to predict oxygen dependency at 36 weeks (PCA) were between 67% and 80% and similar receiver operating characteristic curves were obtained. We conclude that scoring only three abnormalities of the 28 day chest radiograph appearance of pre-term infants gives useful predictive information.     

Gas movement in the nonventilated lung at the onset of single-lung ventilation for video-assisted thoracoscopy

To assess the potential for atmospheric nitrogen to enter the nonventilated lung following the initiation of single-lung ventilation, the nonventilated lung of 10 patients undergoing video-assisted thoracoscopy was connected to the air in a water-filled spirometer, and gas movement out of and back into the lung was measured. Airway pressure from both lungs and pleural pressure from the nonventilated side were also measured. With each breath of positive-pressure ventilation to the ventilated lung prior to the thoracic cavity being opened to the atmosphere, the pressure transmitted to the opposite hemithorax generated a mean (range) tidal movement of gas in the nonventilated lung of 134 (65-265) ml. In addition, ongoing gas exchange resulted in a progressive influx of gas from the spirometer over the 110-120 s measurement period of a mean (range) volume of 155 (70-320) ml. This easily preventable influx of atmospheric nitrogen could, in theory, predispose to arterial desaturation and to delayed lung collapse after the parietal pleura is opened.     

Risk factors in calcium stone disease of the urinary tract.

The concept that calcium stone formation may be explained on the basis of a number of risk factors is developed. The main risk factors involved are shown to be calcium, oxalate, pH, acid mucopolysaccharides and uric acid. A method is described for calculating and combining the individual risk factors into a measure of the "relative probability" of forming stones (PSF). PSF values are generally lower in normal subjects than in stone-formers. Amongst the normals, PSF values are lower in children and women than in men. Recurrent stone-formers have the highest PSF values and these correlate well with the severity of the diseases as defined by the stone episode rate of the patient. Single stone-formers have PSF values intermediate between those of normal men and those of recurrent stone-formers.     

Lower Limb Swelling Due to Femoral Aneurysms

A man of 53 presented with left lower limb swelling, which was found to be caused by compression of the femoral vein by a common femoral artery aneurysm. Seven years later a similar situation developed in the opposite limb. On each occasion the diagnosis was confirmed radiologically and the symptoms resolved rapidly following surgery.

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Enhanced cell killing in lewis lung carcinoma and a human pancreatic-carcinoma xenograft by the combination of cytotoxic drugs and misonidazole.

The "chemosensitizing" properties of the radiosensitizer misonidazole (MISO) were examined in 2 tumour systems, murine Lewis lung carcinoma and human pancreatic adenocarcinoma xenografted into immune-suppressed mice, using a soft-agar colony assay to measure tumour-cell survival. In mice bearing Lewis lung tumour, the administration of MISO simultaneously with melphalan, cyclophosphamide. CCNU, FU or vincristine gave substantial enhancement of cytotoxicity (DEFs from 1.5 to 3.5). However, no enhancement was seen with bleomycin, VP 16-213 or cis-Pt. The same level of enhancement of cyclophosphamide effect (DEF = 2.0) was seen with both cell survival and growth delay end-points effect (DEF = 2.0) was seen with both cell survival and growth delay end-points of tumour response. Enhancement was also seen in the human tumour xenograft with melphalan, cyclophosphamide and MeCCNU, using a cell survival assay, but cis-Pt was again not enhanced.