FK 506 salvage of renal allografts with ongoing rejection failing cyclosporine immunosuppression.
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Biomedical subjects
Publications and source records attributed to G Carrieri.
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Kidney transplants from infant donors are associated in the literature with poor results as regards both functionality and the survival of the transplant. Hence the increasing frequency, for kidneys obtained from donors under 5 years of age, of a surgical technique defined as "en bloc", involving the transplant of both kidneys into a single receiver and using the donor aorta and vena cava for vascular anastomosis. This technique seems to provide results comparable with those obtained using adult organs. Ultrasound and Doppler investigations are routinely performed in patients undergoing such a transplant. This study presents ultrasound and Doppler images of "en bloc" transplants, with particular reference to one case of pseudoaneurysm of the donor aorta and one of stenosis of the renal artery, revealed by Echo-Color-Doppler. The importance of ultrasound in this kind of transplant is emphasized, as it enables post-operative monitoring of the physiological growth in volume of the two transplanted infant kidneys.
104 patients with acute bacterial prostatitis were randomized to an antibiotic therapy group (group I) and an antibiotic plus laser therapy group (group II). Laser therapy was applied ever other day through a trans-rectally inserted fiberoptic probe. Resolution of the symptoms occurred in 87% of the patients in group I and 92% in group II (p < 0.001). Transrectal ultrasound resulted in resolution of the peri-prostatic venous plexus congestion in 43.7% of the patients in group I and 89.7% in group II. In conclusion, the combination of laser therapy and antibiotics in bacterial prostatitis provides both a better resolution of the symptoms and a reduction or disappearance of the peri-prostatic venous congestion.
Sixty-two beagle dogs were given three doses of acetaminophen over a period of 24 hr in a fulminant liver failure model that is 70% lethal in 72 hr. Treatment of the animals with hepatic stimulatory substance alone or in a mixture with insulin, transforming growth factor-alpha and insulin-like growth factor II had no effect on mortality. Evidence of maximum regeneration with a mitotic index 20 to 25 times resting was the same in treated and untreated animals. Similarly, the biochemical and hematological indexes of liver injury were unaffected by therapy. These studies illustrate the futility of treating fulminant liver failure with exogenous growth factors that apparently are already present in large amounts in the natural response to liver injury. The results suggest that on-going liver injury by mechanisms other than lack of growth factors is the central problem of fulminant liver failure. If so, provision of regeneration-stimulating substance is an inappropriate therapeutic strategy.
Rapamycin, a potent immunosuppressive drug that disrupts normal signal-transduction processes, inhibited hepatocyte proliferation without evidence of inherent cytotoxicity in rat hepatocytes cultured in conventional medium or in a medium enriched with epidermal growth factor. The antiproliferative effect was dose dependent, uninfluenced by the concentration of epidermal growth factor in the medium and long lasting after a brief exposure. The effect of rapamycin was unaltered by the concomitant presence of FK 506 in the medium, suggesting that different binding affinities of these two drugs or even a separate rapamycin binding site may exist. Hepatocytes harvested 12 and 24 hr after partial hepatectomy were progressively less responsive to the antiproliferative effect of rapamycin. The gene expression of transforming growth factor-beta was reduced under in vivo rapamycin treatment, but at the same time the gene expression of albumin and glyceraldehyde-3-phosphate dehydrogenase was unchanged or increased. The experiments confirm that rapamycin has inherent growth-control qualities, and they strengthen the hypothesis that the recently defined immunophilin network is central to many aspects of cellular growth control.
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Transforming growth factor-beta canceled the hepatocyte proliferation caused by transforming growth factor-alpha when the two substances were mixed and administered through a disconnected central portal vein branch after creation of an Eck fistula. In contrast, transforming growth factor-beta had no antidotal action on the stimulatory effects of insulin or full test doses of insulinlike factor-2, hepatocyte growth factor, epidermal growth factor or triiodothymanine. A minor antidotal effect on hepatic stimulatory substance activity could be detected, but only with hepatic stimulatory substance was given in doses smaller than those known to cause maximum stimulatory response. These results suggest a highly specific pharmacological and physiological interaction between transforming growth factor-alpha and transforming growth factor-beta in the modulation of liver growth control.
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Completely diverting portacaval shunt (Eck's fistula) in dogs causes hepatocyte atrophy, disruption of hepatocyte organelles, fatty infiltration and low-grade hyperplasia. The effect of hepatic growth regulatory substances on these changes was assessed by constantly infusing test substances for four postoperative days after Eck's fistula into the detached left protal vein above the shunt. The directly infused left lobes were compared histopathologically with the untreated right lobes. In what has been called an hepatotrophic effect, stimulatory substances prevented the atrophy and increased hepatocyte mitoses. Of the hormones tested, only insulin was strongly hepatotrophic; T3 had a minor effect, and glucagon, prolactin, angiotensin II, vasopressin, norepinephrine and estradiol were inert. Insulin-like growth factor, hepatic stimulatory substance, transforming growth factor-alpha and hepatocyte growth factor (also known as hematopoietin A) were powerfully hepatotrophic, but epidermal growth factor had a barely discernible effect. Transforming growth factor-beta was inhibitory, but tamoxifen, interleukin-1 and interleukin-2 had no effect. The hepatotrophic action of insulin was not altered when the insulin infusate was mixed with transforming growth factor-beta or tamoxifen. These experiments show the importance of in vivo in addition to in vitro testing of putative growth control factors. They illustrate how Eck's fistula model can be used to screen for such substances and possibly to help delineate their mechanisms of action.
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The possibility that four loci (REN, THO, PARP, SOD2) are associated with longevity was explored by comparing the genotypic pools of subjects older than 100 years with those of younger subjects matched for sex and geographic area (northern and southern Italy). The markers (all located within the respective gene) were HUMREN4; HUMTHO1; HUMPARP (gt)845nt; SOD2(C/T)401nt. In order to reduce the number of genotypes, multiallelic polymorphisms were recoded as diallelic according to allele size and frequency patterns (small: S, and large: L, alleles). A significant loss of LL homozygous genotypes was found at the THO locus in male but not in female centenarians with respect to matched controls. On the other hand no significant difference was found between case/control genotypic frequencies at REN, PARP, SOD2 loci. The latter loci therefore do not affect inter-individual variability in life expectancy (at least in terms of qualitative variants associated with the tested markers). However, the data is consistent with an association between the THO locus and longevity.
Chronic drainage of the thoracic duct to the esophagus was developed in dogs, and its efficacy in immunomodulation was tested using kidney transplantation. Compared to 9.7 days in the control, the mean animal survival was prolonged to 9.9 days, 17.8 days, and 18.5 days when TDD was applied preoperatively for 3 weeks, 6 weeks, and 9 weeks, respectively. Prolongation was significant after 6 weeks. Patency of the fistula was 93.5, 80.4, and 76.1% at respective weeks. Number of peripheral T-lymphocytes determined by a new monoclonal antibody diminished after 3 weeks. All animals were in normal health, requiring no special care for fluid, electrolyte, or protein replacement.