Simultaneous transplantation of fetal mesencephalic cells to the striatum and globus pallidus of rats with lesions induced by 6-hydroxydopamine

INTRODUCTION: Studies of neural transplants in experimental models of Parkinson's disease have concentrated their attention on ectopic transplants of foetal mesencephalic cells to denervated striatum. However, the external globus pallidus has recently been shown to play an important part in the physiopathology of this disease. OBJECTIVE: Bearing in mind the importance of loss of extra-striatal dopamine in the genesis of the clinical signs found in parkinsonism, the objective of this study was to evaluate the effect of foetal mesencephalic transplantation to the globus pallidus of hemiparkinsonian rats. MATERIAL AND METHODS: Following conventional transplantation methodolgy, suspensions of cells from the ventral mesencephalum of rat embryos (E-14) were implanted. The tissue was grafted into the striatum, pallidum-striatum and pallidum areas of rats with unilateral lesions of the striatonigral bundle. One, two, three and six months after transplantation, the rotatory activity induced by D-amphetamine was evaluated. The rotatory behaviour induced by apomorphine was evaluated at three months. Motor ability of the front legs was evaluated in all experimental groups three months after transplantation using the 'ladder test'. RESULTS: In the experimental groups in which a transplant was made to the globus pallidus there was a significant reduction (p < 0.01) in rotatory activity induced by D-amphetamine and by apomorphine as compared with the non-transplanted groups. CONCLUSIONS: Transplants of foetal dopaminergic cells survive in the globus pallidus of hemiparkinsonian rats and can improve the rotational activity induced by dopaminergic agonists.     

Screening for child abuse: problems and possibilities

A historical review of the literature concerning replantation and transplantation of reproductive organs has included studies from this laboratory, using rats, over the past 25 years. From the basic observation of ischemic and traumatic injury due to the transplantation, syngeneic testicle transplants, resulting in a partner's impregnation and histological restoration of the testicles, led to human testicular transplantation. As to the ovarian transplants, granulosa-theca cell tumors may transform into malignancies if followed for a prolonged period as intrasplenic ovaries, and high doses (15 to 20 mg/kg b.w.) of azathioprine can produce such malignant tumors in a shorter period. By caval-portal shunt, ovarian hormones enter directly into the portal blood stream and no typical granulosa-theca cell tumors were produced, owing to the fact that the liver cannot degrade all the hormones secreted by both ovaries. While en-bloc vagino-utero-ovarian transplantation in the rat is possible, no impregnation has been yet achieved. Finally, it is hypothesized that those who have acquired microsurgical techniques and have a full understanding of the anatomy of the reproductive system will not only be able to perform replantation of the penis, but also will be capable of allogeneic transplantation of genital organs, whether ethically approved or not, and sooner than one may think. In such cases a penile part may be obtained at a sex-change surgery or from a cadaveric donor, similar to other vital organ transplantation practices.     

Reduction of advanced glycation end-product (AGE) levels in nervous tissue proteins of diabetic Lewis rats following islet transplants is related to different durations of poor metabolic control

Advanced glycation end-products (AGEs) are irreversible compounds which, by abnormally accumulating over proteins as a consequence of diabetic hyperglycaemia, can damage tissues and thus contribute to the pathogenesis of diabetic complications. This study was performed to evaluate whether restoration of euglycaemia by islet transplantation modifies AGE accumulation in central and peripheral nervous tissue proteins and, as a comparison, in proteins from a non-nervous tissue. Two groups of streptozotocin diabetic inbred Lewis rats with 4 (T1) or 8 (T2) months disease duration were grafted into the liver via the portal vein with 1200-1500 islets freshly isolated from normal Lewis rats. Transplanted rats, age-matched control and diabetic rats studied in parallel, were followed for a further 4-month period. At study conclusion, glycaemia, glycated haemoglobin and body weight were measured in all animals, and an oral glucose tolerance test (OGTT) performed in transplanted rats. AGE levels in cerebral cortex, spinal cord, sciatic nerve proteins and tail tendon collagen were measured by enzyme-linked immunosorbent assay (ELISA). Transplanted animal OGTTs were within normal limits, as were glycaemia and glycated haemoglobin. Diabetic animal AGEs were significantly higher than those of control animals. Protein AGE values were reduced in many transplanted animals compared to diabetic animals, reaching statistical significance in spinal cord (P < 0.05), sciatic nerve (P < 0.02) and tail tendon collagen (P < 0.05) of T1 animals. Thus, return to euglycaemia following islet transplantation after 4 months of diabetes with poor metabolic control reduces AGE accumulation rate in the protein fractions of the mixed and purely peripheral nervous tissues (spinal cord and sciatic nerve, respectively). However, after a double duration of bad metabolic control, a statistically significant AGE reduction has not been achieved in any of the tissues, suggesting the importance of an early therapeutic intervention to prevent the possibly pathological accumulation of AGEs in nervous and other proteins.     

Long-term normalization of GLUT 4 protein content in skeletal muscle of streptozotocin-diabetic Lewis rats after islet transplantation

Islet transplantation under the kidney capsule of STZ-diabetic Lewis rats was able to maintain near-normoglycemia over a period of 6 months. Fasting insulin in these animals was higher compared to controls but did not increase after feeding. Plasma glucose following an OGTT at 2 months was only slightly impaired, and after 6 months was more severely impaired in the Tx rats. An IVGTT 6 months after Tx confirmed impaired glucose tolerance and showed a loss of first phase insulin release. GLUT 4 protein content in skeletal muscle was completely restored in Tx animals. In conclusion, long-term near-normoglycemia after syngeneic islet transplantation under the kidney capsule of STZ-diabetic Lewis rats is associated with complete normalization of skeletal muscle GLUT 4 protein content, even in the presence of abnormal glucose tolerance and impaired insulin secretion.     

Endotoxin impairs the engraftment of rat islets transplanted beneath the kidney capsule of C57BL/6-mice

The primary objective of this investigation was to determine the effect of endotoxin on islet xenograft survival within the first three days after transplantation. Pancreatic islets from Lewis rats were prepared under endotoxin-free conditions with Liberase (Boehringer) and purified by centrifugation on endotoxin-free Ficoll/Histopaque. After overnight incubation, with or without 10 microg/ml endotoxin, the islets were transplanted beneath the kidney capsule of normoglycemic C57Bl/6-mice. Three days later, kidneys were removed and their insulin content were measured. We could demonstrate significant differences (P<0.01) in insulin recovery between lipopolysaccharide-free and lipopolysaccharide-containing grafts. In case of endotoxin contaminated islets, we found only 13+/-2% (n=9) of the original insulin content, in contrast to 53+/-7% (n=9) when endotoxin-free islets where grafted. In experiments with islets isolated by use of conventional (lipopolysaccharide-containing) collagenase, and then cultured in endotoxin-free medium, insulin recovery three days after transplantation was 36+/-1% (n=13).     

Effect of pancreas transplantation on the prevention of nephropathy in alloxan-induced diabetic rats

We studied the effects of pancreas transplantation on kidney lesions of rats with alloxan-induced diabetes. Ninety inbred male Lewis rats were randomly assigned to 3 experimental groups: group NC included 30 non-diabetic control rats, group DC included 30 alloxan-induced diabetic control rats, and group PT included 30 alloxan-induced diabetic rats that received pancreas transplants from normal donor Lewis rats. Each group was further divided into 3 subgroups of 10 rats which were sacrificed at 1, 3, and 6 months of follow-up, respectively. Clinical and laboratory parameters during these periods were documented. The kidneys of 5 rats in each subgroup were studied and 50 glomeruli and tubules from each kidney were analyzed by light microscopy by two different investigators in a double-blind study. There was progressive glomerular basement membrane thickening (GBMT), mesangial enlargement (ME), and Bowman's capsule thickening (BCT) in kidneys of rats in the 3 experimental groups during follow-up. These alterations were significantly higher in DC rats (GBMT: 1.99 +/- 0.31; ME: 2.00 +/- 0.33; BCT: 1.88 +/- 0.27) when compared to NC (GBMT: 1.54 +/- 0.30; ME: 1.56 +/- 0.47; BCT: 1.36 +/- 0.35) and PT rats (GBMT: 1.49 +/- 0.29; ME: 1.57 +/- 0.36; BCT: 1.35 +/- 0.28) at 6 months (P < 0.01). The extent of GBMT, ME, and BCT observed in DC rats at 1 and 3 months was not significantly different from NC and PT rats. The amount of kidney lesions in PT rats was similar to that of NC rats and lower than those of DC rats at 6 months (P < 0.01). In addition, Armanni-Ebstein lesions of the tubules (AE) and tubular lumen protein (PRO) observed in DC rats were not present in NC or PT rats. We conclude that pancreas transplantation in alloxan-induced diabetic rats prevents the development of kidney lesions beginning at 6 months after transplantation.     

The mirror as a fixation aid for the fundus camera (author''s transl)

Self-emasculation is the end result of an unusual psychiatric disorder, which initially requires surgical treatment. Only 51 cases have been reported in the English literature since 1900. No previous attempt to preserve testicular androgen function by reimplantation or grafting has been reported. We describe an unsuccessful attempt to graft the testicles in subcutaneous thigh pockets. Microscopically, the biopsied autografts showed no viable interstitial or germinal testicular tissue. The objectives of the treatment of self-emasculation injury are restoration of anatomical and functional continuity of the urethra as a urinary channel, preservation of the capacity for sustained penile erection, preservation of testicular androgen activity, prompt psychiatric evaluation and treatment of the underlying illness, and restoration of the normal appearance of the scrotum.     

Chromosome structure and composition

Previous studies in rodents showed a severe deterioration of pineal physiology with aging. The present study investigated the age-related changes in the content of monoamines and metabolites in rat and Syrian hamster pineal gland. In addition to melatonin, the levels of 5-hydroxytryptophan (5HTP), serotonin (5HT), 5-hydroxyindoleacetic acid (5HIAA), N-acetylserotonin (N-Ac-SHT), dopamine (DA), 3,4-dihydroxyphenylacetic acid (DOPAC), and noradrenaline (NA) were measured by HPLC. Pronounced reductions were found in 5HT and 5HIAA contents during daytime in rats of 24 months, which had not been observed in animals of 12 months. In addition, nighttime pineal 5HIAA, N-Ac-5HT, and melatonin contents were decreased in the old rats, although a significant day:night variation persisted. Also a diurnal fluctuation in NA, DA, and DOPAC contents was present in young and middle-aged rats but not for NA and DOPAC in the oldest rats due to a decrease in the nighttime levels. Pineal DA levels were also reduced in 24-month-old rats during the night, although a marked day:night change was still found. In the Syrian hamster pineal, significant reductions in daytime 5HT and 5HIAA were found respectively at 12 and 18 months, while nighttime levels of these compounds were decreased from 18 months. The nocturnal content of N-Ac-5HT dropped gradually from 12 months, and melatonin was reduced by 74% and 86% in hamsters of 18 and 24 months, respectively. In all these compounds, a significant day:night variation was observed irrespective of age. However, neither a day:night variation nor an effect of aging was found in terms of pineal NA content. In contrast, pineal DA and DOPAC levels displayed a diurnal variation in hamsters of 1.5 and 6 months, but not in animals of 12 and 18 months due a reduced nighttime content. These data suggest that the decline of pineal melatonin with age is a consequence of a deficit in the pathway of serotonin utilization. This probably is explained by a reduced N-acetyltransferase activity, which may be linked to impaired pineal catecholaminergic neurotransmission.     

Short-term modulation of the androgen milieu alters pulsatile, but not exercise- or growth hormone (GH)-releasing hormone-stimulated GH secretion in healthy men: impact of gonadal steroid and GH secretory changes on metabolic outcomes

Gonadal steroids are known to alter GH secretion as well as tissue metabolism. The present study was designed to examine the effects of short term (2- to 3-week) alterations in gonadal steroids on basal pulsatile (nonstimulated) and exercise- and GH-releasing hormone-stimulated GH secretion, urinary nitrogen excretion, and basal and exercise-stimulated oxygen consumption. Two protocols were conducted, which reflect a total of 18 separate studies. In the first paradigm, 5 healthy young men were each studied in a double blind, randomized manner during 3 different gonadal hormone manipulations, in which serum testosterone was varied from hypogonadal (induced by leuprolide) to eugonadal (saline injections) to high levels (testosterone enanthate, 3 mg/kg.week, i.m.). There was a washout period of 8 weeks between treatments. In the second protocol, 3 of the original subjects were studied after 2 weeks of treatment with stanozolol (0.1 mg/kg.day). Two to 3 weeks after the desired changes in serum testosterone, each subject was admitted to the General Clinical Research Center for study. The hypogonadal state (serum testosterone, 33 ng/dL) increased urinary nitrogen loss (by 34%; P < 0.005) and decreased basal metabolic rate (by 12%; P < 0.02) compared with the eugonadal state (testosterone, 796 ng/dL). High dose testosterone (1609 ng/dL) further decreased urinary nitrogen loss over the eugonadal state (by 16%; P < 0.05). Stanozolol yielded the lowest urinary nitrogen excretion of all (P < 0.03). Like urinary nitrogen, the basal metabolic rate showed the greatest change between the hypogonadal and eugonadal states (12%; P < 0.02), with a lesser change during high dose testosterone treatment (4%). Analogously, end-exercise oxygen consumption rose by 11% between the hypogonadal and eugonadal states (P < 0.05). Between the hypogonadal and eugonadal states, no significant changes in pulsatile (nonstimulated), exercise-stimulated, or GRF-stimulated GH secretion or serum insulin-like growth factor I concentrations were observed. Raising testosterone to supraphysiological levels increased pulsatile GH secretion by 62% over that with leuprolide and by 22% over that with saline (P < 0.05). High dose testosterone treatment also increased serum insulin-like growth factor I concentrations by 21% and 34% over those during the eugonadal and hypogonadal states, respectively (P < 0.01). Testosterone did not affect either exercise- or GRF-stimulated GH secretion. In protocol 2, stanozolol did not affect any parameter of GH secretion. To examine the interaction between GH secretion and testosterone on urinary nitrogen excretion and basal metabolic rate, a one-way analysis of covariance was undertaken. Statistical examination of GH production as the covariate and testosterone (by tertile) as the interactive factor demonstrated significant relationships between serum testosterone levels and either urinary nitrogen (P < 0.02) or basal metabolic rate (P < 0.01), but not GH secretion (P = NS). In summary, these results demonstrate that short term modulation of the androgen milieu affects metabolic outcome without necessitating changes in GH secretion. These results have significance for both normal physiology and for the treatment of hypogonadal GH-deficient patients.     

Can clamping of splenic vessels prevent abrupt increase of portal vein pressure and migration of transplanted hepatocytes to the liver after intrasplenic hepatocyte transplantation?

BACKGROUND/AIMS: It is well known that hepatocyte transplantation can retain some proper functions, significantly improve the survival rate of rats with different models of acute fulminant hepatic failure, correct some congenital genetic disorders, and improve liver function in cirrhosis. Portal hypertension and hepatic embolization have been described following intrasplenic hepatocyte transplantation. We evaluated the effect of temporary occlusion of splenic vessels on changes in portal vein pressure and on distribution of transplanted hepatocytes after hepatocyte transplantation into the spleen in normal rats. METHODOLOGY: Liver cirrhosis has been induced in rats by 1% dimethylnitrosamine (Sigma, St. Louis, Mo) dissolved in normal saline at the dose of 10 ml of DMN/Kg, i.p., 3 consecutive days a week for 4 weeks. Donor hepatocytes were harvested by in situ ethylenediaminetetraacetic acid (EDTA) perfusion. Changes in portal vein pressures were monitored by a pressure monitor and distribution of transplanted hepatocytes was assayed by measurement of radioactivity of 51Cr-labeled transplanted hepatocytes according to clamping or non-clamping during intrasplenic hepatocyte transplantation. RESULTS: The changes in portal pressure remained significantly high 10 min after hepatocyte transplantation in the nonocclusion groups compared to the occlusion groups. However, the changes in portal vein pressures in cirrhotic rats returned to normal faster than in normal rats after cell transplantation in the nonocclusion groups. The distribution of 51Cr-labeled transplanted hepatocytes into the spleen significantly diminished radioactivity of the liver at 10 min, 2 hours, and 24 hours in the occlusion groups compared to the nonocclusion groups. Also, duration of clamping time of splenic vessels did not influence the initial distribution of transplanted hepatocytes at the time of intrasplenic hepatocyte injection. CONCLUSIONS: These results suggested that temporary occlusion of splenic vessels should be routinely used during intrasplenic hepatocyte transplantation.     

Variation in the hepatotoxic effects of carbon disulphide between different strains of rat

The hepatotoxic effects of carbon disulphide have been investigated in an outbred (Porton) strain of rat and in 8 inbred strains. Carbon disulphide (1.38 mmoles/kg body weight) was administered intraperitoneally to rats which had been pretreated with phenobarbitone and starved. Livers were taken for analysis 24 h later. A considerable genetic variation in the response of rats to carbon disulphide was observed. The extent of centrilobular hydropic degeneration varied greatly between strains and was accompanied by a high incidence of focal coagulative necrosis in the most susceptible rats. Analysis of variance of the accompanying changes in liver weight and water content and in total liver cytochrome P450 content gave statistical confirmation of a strain effect in the response to carbon disulphide. Highly significant strain x treatment interactions for these parameters were attributable to changes after carbon disulphide treatment rather than variation between phenobarbitone pretreated starved controls. The experiments were repeated in two blocks, 3 months apart. Block effects and interactions were significant in some cases but were quantitatively small and did not obscure a ranking based on histological assessment. AGUS rats were least affected by carbon disulphide whereas PVG and LEW rats showed extensive liver damage. Other strains (WA, Porton, F344, BDIX, WAG) showed a gradation of response between these extremes.     

Isolation of the pig islets of Langerhans: evaluation of in vitro and in vivo function

Pig islets are considered the best alternative to human islets in the treatment of insulin-dependent diabetes. Pigs could represent a potential islet donor for xenotransplantation in humans because of the close similarity between human and porcine insulin and the theoretically unlimited availability of porcine pancreas. From November 1991 to January 1997 we performed 221 pig islet isolations from 3 pig sources: group 1: minipigs (age 9-18 months) and white pigs (3-8 months), group 2: large white pigs (5-8 months), group 3: large white pigs (12-24 months). Islets were isolated according to a semi-automated method using enzymatic digestion and purification through discontinuous Euro-Ficoll gradients. The pancreases were surgically removed in our laboratory for group 1, while pancreases from groups 2 and 3 were removed at the slaughterhouse with an average warm ischemia time of 15 minutes. In vitro islet function was assessed by static incubations and perifusions, and in vivo islet function by transplantation under the kidney capsule of nude diabetic mice. The results were as follows: [table: see text] Insulin secretion increased twofold after in vitro glucose stimulation. We obtained restoration of euglycemia in diabetic mice which survived > 3 months after the graft and returned to diabetes after nephrectomy. This study shows that our isolated pig islets are viable and functional in vitro and in vivo after transplantation.     

The effect of parenteral testosterone replacement on prostate specific antigen in hypogonadal men with erectile dysfunction

PURPOSE: Parenteral testosterone supplementation is a common treatment for erectile dysfunction in hypogonadal men. Despite its frequent use, the effect of testosterone on prostate specific antigen (PSA) in these patients has not been documented previously. In this study we determined the effect of parenteral testosterone replacement on PSA and PSA velocity in a group of men being treated for erectile dysfunction. MATERIALS AND METHODS: A retrospective analysis of 48 patients (mean age 65.9) was performed and 2 study groups were identified. Group 1 consisted of 27 patients with a serum PSA level before and after initiating testosterone replacement therapy, and group 2 consisted of 27 men with a minimum of 3 PSA measurements (intervals of 6 months or greater) while on testosterone replacement. Each man had erectile dysfunction, a normal digital rectal examination and a low or low-normal total serum testosterone level before initiating therapy. Testosterone replacement was discontinued if no subjective improvement in erectile function was obtained, or if prostate adenocarcinoma was suggested by digital rectal examination or PSA. RESULTS: The mean increase in PSA after initiating testosterone replacement was 0.29 ng./ml. representing a mean change of 37% from baseline (mean interval 12.8 months). The mean PSA velocity was 0.05 ng./ml. per year. Pretreatment testosterone level, age and testosterone dose did not independently alter the PSA during testosterone replacement. Eleven men required prostate biopsies during treatment. Biopsies were indicated for abnormal digital rectal examination in 10 men and an elevated PSA in 1. All biopsies were benign. CONCLUSIONS: Parenteral testosterone replacement in hypogonadal men with normal pretreatment digital rectal examination and serum PSA levels does not alter PSA or PSA velocity beyond established nontreatment norms. Thus, any significant increase in PSA or PSA velocity should not be attributed to testosterone replacement therapy and should be evaluated.     

A new rat infection-heart transplant model: effect of infection on graft survival studies

Considerable progress has been made in survival rates of heart transplant recipients; however, infections continue to be a major cause of death after transplantation. Although infection itself appears to cause immunologic suppression in some nontransplantation studies, the lack of an infection-transplant animal model has limited further investigation of this observation. We evaluated the utility of a heterotopic rat infection heart-transplant model by studying the effect of infection and limited administration of two immunosuppressive agents, cyclosporine and FK506, on allograft rejection and survival. Lewis rats received ACI heart allografts, and intraperitoneal infection was induced by cecal ligation. Infection was confirmed by blood and ascitic fluid cultures. Results showed that graft survival was slightly, but significantly, higher (p < 0.05) in group II (transplantation with infection) when compared to the control group I (transplantation only). Histologic rejection scores were less (p < 0.05) in group II 6 days after transplantation. The second phase of the study compared the effect of infection after transplantation in rats given a 1-week course of cyclosporine or FK506, which were discontinued after the induction of infection. Although the cyclosporine group had prolonged survival when compared to the FK506 group (p < 0.05), the respective infection groups receiving immunosuppression revealed no significant difference in allograft survival or histologic rejection scores when compared to the control groups. In this preliminary study, infection without immunosuppression resulted in a slight, but statistically significant, increase in allograft survival and reduced acute cellular rejection. In those groups receiving immunosuppressive agents, no additive immunosuppressive effect was attributable to bacterial infection.(ABSTRACT TRUNCATED AT 250 WORDS)     

Treatment and outcome of patients with acute myocardial infarction and prior cerebrovascular events in the thrombolytic era: the Israeli Thrombolytic National Survey

Changes in sleep after fetal preoptic (POA) tissue transplantation were studied in rats which had been made insomniac by a medial preoptic area (mPOA) lesion. Two days after the N-methyl D-aspartic acid (NMDA) lesion of the mPOA, fetal POA tissues (obtained from 14- to 17-day-old fetuses) were transplanted into the lesioned mPOA. Insomnia was less marked in these animals, as compared to nontransplanted lesioned rats, even on the 4th day after transplantation. The quantum of sleep nearly attained the prelesion level by the 20th day. Body weight also showed recovery after transplantation. Rectal temperature, which was increased by the lesion of the mPOA, remained unaltered even after the transplantation. These results suggest that the recovery of sleep and rectal temperature may follow different time courses. Surviving transplanted neurons were seen at the site of lesion on postmortem examination. Humoral interaction between the host and the transplant may be responsible for the early recovery of sleep, though the establishment of neural connections between the host and transplant might have contributed to the later recovery. This is the first study to show the recovery of sleep function in insomniac animals after fetal preoptic tissue transplantation. However, the specificity of the POA fetal tissue, in comparison with other neural tissues to promote sleep recovery, remains to be established.     

Mycophenolic acid: a welcome adjunct immunosuppressant after organ transplants

Three major double-blind trials in kidney transplantation patients have shown that mycophenolic acid (mycophenolate mofetil), added to an immunosuppressive regimen consisting of cyclosporine and prednisone, reduces the incidence of acute rejection after kidney transplantation by 50%, during the first six months. This statistically significant reduction is achieved equally with daily doses of 2 or of 3 g. In view of the fact that the side effects (diarrhoea, abdominal cramps, leukopenia) are more frequently found in the patients treated with 3 g, it is advised to prescribe 2 g mycophenolic acid. As acute rejection is a risk factor for the development of chronic rejection and because a beneficial effect of mycophenolic acid on chronic rejection in animal models has been observed, there may also be an effect on late graft loss due to chronic rejection after kidney transplantation in man.     

The effect of felodipine on renal function and blood pressure in cyclosporin-treated renal transplant recipients during the first three months after transplantation

BACKGROUND: Due to their vasodilatory effect, calcium antagonist may have a renoprotective against cyclosporin (CsA)-induced nephrotoxicity and rise in blood pressure (BP) seen in renal transplantation. METHODS: In order to evaluate the effect of the calcium antagonist felodipine on renal function and BP during cyclosporin treatment, 79 CsA-treated renal transplant recipients were investigated during the first 3 months after transplantation in a randomized, double-blind, placebo-controlled study with two parallel groups. Felodipine (ER tablets, 10 mg) or placebo was given prior to transplantation and each day during the study period. The patients were assessed twice, i.e. at 4-6 weeks and at 10-12 weeks after transplantation. Renal plasma flow (RPF) and glomerular filtration rate (GFR) were measured by constant infusion technique. Tubular function was estimated from clearance of lithium. RESULTS: At 6 weeks after transplantation, felodipine caused a significantly higher RPF [felodipine: 219 +/- 70 ml/min; placebo: 182+/-56 ml/min (mean+/-1 SD); P=0.03]. No differences were found in GFR, filtration fraction (FF), tubular sodium handling, or sodium excretion. Felodipine lowered BP significantly. At 12 weeks after transplantation, felodipine caused a significantly higher GFR (felodipine: 49+/-18 ml/min; placebo: 40+/-16 ml/min; P=0.05) and RPF (felodipine: 225+/-77 ml/min; placebo: 175+/-48 ml/min; P<0.01). No difference was found in FF. Felodipine lowered BP significantly. No differences were found with regard to duration of primary anuria, hospitalization time, number of rejection episodes, plasma creatinine day 7 post-transplant, or treatment doses of CsA. CONCLUSIONS: It is concluded that in renal transplant recipients treated with CsA, felodipine significantly increased both GFR and RPF 3 months after transplantation when compared with placebo, despite a concomitant lowering of BP. A possible antagonizing affect of felodipine against CsA-induced nephrotoxicity in these patients is suggested.     

Effect of dietary lactose at levels comparable to human consumption on cholesterol and bile acid metabolism of conventional and germfree rats

In recent years, the use of milk products and the concomitant intake of lactose have been tentatively linked to the etiology of cardiovascular disease. An effect of lactose on the microbial modification of acid and neutral sterols has been suggested. In the present study lactose intake, ranging up to 30% of total diet increased beta-muricholic (beta-MC) but not cholic acid concentrations in conventional (CV) rat small intestine to the extent that at the 20% and 30% intake level, the intestinal cholic: beta-MC ratio approached that in germ-free (GF) rats. Total intestinal bile acid (BA) content increased by approximately 1/3, but remained at less than half the value found in GF rats. At lactose intake levels within a range corresponding to the consumption of dairy products often recommended for adult man (5% to 10%) only moderate changes in intestinal, and little change in fecal BA were found during and after the 3 months experimental period. Intestinal beta-MC was increased in the presence and in the absence of an intestinal microflora. Experiments with GF rats fed 10% lactose or 10% maltose indicated that this increase is evoked similarly by both carbohydrates. The slight increase in serum cholesterol levels seen with disaccharide feeding, which became evident only in the GF rats, was again not specific for lactose. No influence was found of lactose feeding on liver cholesterol values. Comparison of CV rats fed nonsterile and radiation-sterilized lactose-containing diets suggested that this mode of sterilization has only a minor influence on the resulting data. When GF experiments are to be incorporated, sterilazation of diet by irradiation with 3.5 to 4.0 X 10(6) Rad is preferable to autoclaving. The present data indicate that no major effect specifically related to a normal dietary intake of lactose on cholesterol and BA metabolism of the adult rat could be demonstrated for the duration of these experiments.     

Do androgens regulate growth hormone-binding protein in adult man?

To determine whether adult serum GH-binding protein (GHBP) is regulated by androgen, serum GHBP concentrations were compared between 20 normal and 18 hypogonadal men matched for age and body mass index, and the effect of im testosterone treatment (250 mg testosterone enanthate) on GHBP levels in the 18 hypogonadal men was studied. Nine of the hypogonadal subjects had coexistent GH deficiency. Serum GHBP concentration was measured by a ligand immunofunctional assay. The mean serum GHBP level in untreated hypogonadal men was not significantly different from that of normal men (0.98 +/- 0.15 vs. 1.17 +/- 0.16 nmol/L). The mean serum insulin-like growth factor I (IGF-I) level was significantly lower in the hypogonadal men (132 +/- 22 vs. 206 +/- 17 ng/mL; P < 0.01). Basal testosterone (3.7 +/- 0.7 nmol/L) in hypogonadal men increased during treatment to a mean level of 29.1 +/- 2.8 nmol/L, which was not significantly higher than that in normal men (22.6 +/- 1.9 nmol/L). The mean serum GHBP level in hypogonadal men fell significantly during treatment to 0.60 +/- 0.11 nmol/L (P = 0.0003), whereas the serum IGF-I level rose significantly to 151 +/- 26 ng/mL (P < 0.04). The decrease in GHBP level was significant in both the GH-sufficient and GH-deficient subjects (P < 0.02 in both instances), whereas the increase in IGF-I level was significant in the GH-sufficient group (199 +/- 22 to 235 +/- 29 ng/mL; P < 0.04) but not in the GH-deficient group (53 +/- 7 to 55 +/- 5 ng/mL; P > 0.8). Thus, serum GHBP is normal in hypogonadal men but is reduced by testosterone treatment irrespective of endogenous GH-secretory status. It was concluded that the effect of testosterone on GHBP is pharmacological and occurs independent of GH mediation.     

Renal hemodynamics after lung transplantation. A prospective study

Renal function impairment is common after solid organ transplantation, due to the nephrotoxicity of cyclosporine. Moreover, in patients with severe respiratory failure, renal function is often impaired. This renal function impairment may predispose patients to further renal function impairment after lung transplantation. Therefore, renal hemodynamics were measured in 44 patients before lung transplantation and 1, 6, 12, 18, 24, and 30 months after transplantation. After transplantation, a decline in renal function occurred, with a progressive fall in glomerular filtration rate (GFR) of 33 +/- 4% at 12 months and 42 +/- 9% at 30 months. Effective renal blood flow fell by 22 +/- 5% at 12 months and remained stable thereafter. Changes in effective renal plasma flow (ERPF) were less pronounced than those of effective renal blood flow, due to a fall in hematocrit after transplantation. Blood pressure and renal vascular resistance increased significantly, consistent with the effects of cyclosporine. Prior to transplantation, renal function impairment with intense renal vasoconstriction had been found in a subset of the patients. Remarkably, the decrease in renal function after transplantation was less pronounced in patients with renal function impairment prior to transplantation, as indicated by significant negative correlations between pretransplantation GFR and the percentage change in GFR after transplantation, and pretransplantation ERPF and the percentage change in ERPF after transplantation. This suggests that the net course of renal hemodynamics after lung transplantation is the result of the opposed effects of cyclosporine nephrotoxicity and the favorable effects of the normalization of respiratory status. In conclusion, after lung transplantation a decline in renal function occurs that is less pronounced in patients with renal function impairment and intense renal vasoconstriction prior to transplantation. Such a renal function impairment, therefore, should not be considered a contraindication to lung transplantation.