Endothelin-1 in human prostatic carcinoma treated with androgen withdrawal: an immunohistochemical study.

BACKGROUND: Various reports suggest a role for endothelin-1 in prostatic carcinoma. The objective of the current study was to evaluate the changes of the immunodetectable endothelin-1 in prostatic carcinomas characterized by different grades of regression due to total androgen withdrawal. METHODS: An immunohistochemical study was made on eleven prostatic carcinomas treated with neoadjuvant hormonal therapy for 3 months, followed by radical prostatectomy. Another ten specimens of untreated carcinomas were studied for comparison. An appraisal of androgen receptors was associated. A highly specific polyclonal antibody against endothelin-1 and a commercial monoclonal mouse antibody for androgenic receptors were used. RESULTS: In all cases, a prevalent quantity of androgenic receptor-positive tumor cells were present. Neoplastic cells of untreated carcinomas showed a strong and heterogeneous staining for endothelin -1. In unregressed areas of treated cases, the features of endothelin-1 and androgen-receptor staining were the same as those of untreated cases. In areas characterized by moderate histologic regression, the endothelin-1 staining became more heterogeneous. In areas of strong histologic regression, a diffuse membrane staining was often noted. Only in completely regressed cancer cells was a definite loss of immunodetectable endothelin-1 and androgenic receptors observed. CONCLUSIONS: Endothelin-1 is one of the proteins intrinsic to prostatic epithelial cells, both benign and malignant. In cases treated with androgen withdrawal, histologic regression is not uniform. In unmodified areas, immunodetectable endothelin-1 and androgenic receptors also are unmodified, thus suggesting some mechanism that substitutes for the action of androgen. Only neoplastic cells with complete histologic regression also lose androgenic receptors and endothelin-1, whereas the preserved immunostaining in deeply modified prostatic neoplastic cells seems to indicate that these cells still are potentially active.

Analysis of the BCL-6 gene configuration in diffuse B-cell non-Hodgkin's lymphomas and Hodgkin's disease.

BCL-6 is a novel proto-oncogene that codes for a zinc-finger protein sharing homologies with many transcription factors. It has recently been shown that BCL-6 is involved in chromosome band 3q27 aberrations in non-Hodgkin's lymphomas (NHLs) and BCL-6 rearrangements have been detected in 34-45 per cent of diffuse large cell lymphomas with B immunophenotype. We have studied the BCL-6 gene configuration by Southern blot analysis in 60 cases of B-cell NHL and in 17 cases of Hodgkin's disease (HD). BCL-6 was rearranged in 15/46 (32.6 per cent) diffuse B-large cell lymphomas, mainly with centroblastic morphology, and in 2/11 (18.2 per cent) follicular (centroblastic-centrocytic) lymphomas. Conversely, all cases of HD, including four cases of lymphocyte predominant, nodular type (nodular paragranuloma), had a germline configuration. These findings confirm that BCL-6 is rearranged in a significant percentage of diffuse B-large cell lymphomas, suggesting that this proto-oncogene might have a pathogenetic role in this subset of NHLs, but our preliminary analysis suggests that BCL-6 lesions are not involved in the pathogenesis of HD. However, further investigations using more sensitive techniques are required to confirm these findings.

Effects of subcutaneous recombinant human erythropoietin in patients on continuous ambulatory peritoneal dialysis.

The use of recombinant human erythropoietin (rHuEPO) has revolutionized the treatment of renal anemia, but the dose regimens, the optimal frequency, and the effects on other target organs like the central nervous systems (CNS) are still under discussion. We designed a prospective, ongoing study with 10 stable continuous ambulatory peritoneal dialysis (CAPD) patients (6 males, 4 females; mean age 64.4 +/- 7.8 years), with a pretreatment hemoglobin (Hb) < 7.0 g% and requiring regular blood transfusions. Seven patients were treated with 4000 U rHuEPO once weekly (Eritrogen, Boehringer Mannheim), 2 patients received 4000 U every 5 and 8 days, and the last one 4000 U every 10 days. The target hematocrit was 33% and Hb 10.0 g%. The CNS activity was recorded as visual (VEP), brainstem (BAER), and somatosensory (SEP)-evoked potentials. The mean Hb concentration increased from 6.9 +/- 1.2 g% to 10.3 +/- 1.6 g% (p < 0.001) over 8 weeks. There were no significant changes in urea, creatinine, and potassium levels, and urine output. rHuEPO induced a decrease in latency of P100 VEP, in the four main components of BAER, and in the P27-N35 intertime of SEP. Parallel to the improvement of red cell indices, patients experienced a dramatic improvement in well-being. The subcutaneous administration of a single vial of rHuEPO is safe, convenient, and inexpensive in CAPD. The role of rHuEPO treatment in improving the electrophysiological brain function in uremic and anemic patients remains to be studied and may not necessarily be based on improved cerebral oxygenation.

Effects of uremia and dialysis on brain electrophysiology after recombinant erythropoietin treatment.

Quantitative electrophysiologic assessments are sensitive and useful indices of clinical state, and they are valuable in evaluating brain electrical activity before and after recombinant human erythropoietin (r-HuEPO) treatment. To study the hypothesis that, theoretically, anemia might be a cause of brain dysfunction in uremia, the authors assessed 18 patients (10 men and 8 women) on hemodialysis (RDT, age range, 35-58 years) before treatment (T1), and after 12 weeks (T2) and 24 weeks (T3) of r-HuEPO treatment, utilizing the following electrophysiologic tests: visual evoked potentials (VEP), brainstem auditory evoked responses (BAER), and somatosensory evoked potentials (SEP). The r-HuEPO was injected subcutaneously two times a week after RDT to produce hematocrit (Hct) levels of 30-35%. This drug induced a decrement of latency in P100 VEP (134.2 +/- 7.9 msec in T1 versus 116.5 +/- 6.9 msec in T2, p < 0.001, and versus 107.6 +/- 5.7 msec in T3, p < 0.005) and in the four main components of BAER. The most significant SEP changes were P27-N35 from peroneal nerve (p < 0.01), as an augmentation of SEP amplitude. Correction of anemia with r-HuEPO leads to a significant improvement in brain function in patients on RDT. The increased Hct level leads to enhanced brain oxygen delivery, directly improving brain metabolism. When the Hct rises, cerebral blood flow falls from high levels to normal, decreasing delivery of uremic "toxins" to the brain. The decrease in cerebral blood flow may decrease intracranial pressure and, in this way, may exert its beneficial effects by a rheologic pathway.

Clinical effects of recombinant human erythropoietin in hemodialysis patients. Results of the "Abruzzo" Multicenter Trial.

Anemia in regular dialysis treatment (RDT) patients is primarily due to a deficiency in renal-derived recombinant human erythropoietin (EPO). The aim of this study was to evaluate the results of a multicenter trial in 81 end-stage renal disease (ESRD) patients on RDT. An "open" study was conducted over 2 years; starting dose of r-HuEPO was 50 IU/kg/three times weekly i.v. and eventually was increased in steps of 25 Ul/kg/dialysis until 300 Ul/kg/week. Mean weekly dose per patient was 15 Ul/kg, with mean Hb increase of 27.5%. Mean hematocrit (Hct) levels increased in these patients from 22.9 +/- 2.5 to 31.7 +/- 2.8 (p less than 0.001) after 2 years of therapy. Both spontaneous and evoked potentials improved. The response to r-HuEPO is dose dependent; hypertension and hyperkalemia are the most common side effects, but they are easily controlled. Central nervous system function before and after treatment is improved, and seems consistent with an enhancement of patients' quality of life.

Therapeutic effects of simvastatin on hyperlipidemia in CAPD patients.

A causal link between hypercholesterolemia due to elevated plasma concentrations of LDL and VLDL remnants of CAPD patients has been established. The effects of 24 weeks of treatment with Simvastatin, a new HMG coenzyme A-reductase inhibitor (at 20 and 40 mg/day) on serum lipid, lipoprotein, and apolipoprotein A-I and B concentrations, as well as safety parameters and subjective side effects, were evaluated in eight patients (mean duration CAPD 24.80 +/- 7.50 months, age 54.50 +/- 13.70 years). Maximal effects on plasma lipoprotein and apolipoprotein concentrations were achieved after 4 weeks, and remained stable thereafter during the study. Mean fasting plasma cholesterol concentrations decreased from 280.5 +/- 60.2 mg% to 190.2 +/- 40.4 mg/dl (p less than 0.005) (-47%); mean plasma LDL-cholesterol concentrations also decreased from 257.6 +/- 13.4 mg% to 190.5 +/- 15.4 mg/dl (p less than 0.001) (-35%). Apolipoprotein A and B concentrations decreased significantly from 1.78 +/- 0.19 to 1.40 +/- 0.22 g/L (p less than .005) and 1.81 +/- 0.26 to 1.38 +/- 0.20 g/L (p less than .005). These data substantiate the view that Simvastatin is well tolerated and that no serious clinical or adverse laboratory effects have been observed. It appears to be a promising drug for the effective control of hyperlipemia in a large proportion of hypercholesterolemic patients, reducing their cardiovascular morbidity while on CAPD.

Computerised non-invasive monitoring of cardiovascular stress in haemodialysis patients.

Haemodynamic instability is one of the most frequent problems occurring during dialysis treatment. Ten clinically stable patients (8 M and 2 F) undergoing chronic maintenance haemodialysis for at least 6 months were investigated. Two groups of five patients each, were selected on the basis of presence (IG) or absence (SG) of cardiovascular instability during dialysis. The cardiovascular function was assessed by computerised electrical bioimpedance performed during dialysis setting and by echocardiography immediately pre- and post-dialysis. In SG dialysis treatment did not change cardiac index (CI), stroke index (SI) and systemic vascular resistances index (SVRI). However CI, SI and SVRI, tended to decrease in IG patients; the reduction in CI was primarily due to a decrease in SI. Ejection velocity index increased significantly in SG but not in IG. Evaluation of cardiac function by Döppler echocardiography revealed a significant increment in fractional shortening, mean velocity of circumferential fiber shortening and Suga' index in SG with dialysis but not in IG. Stress index decreased significantly in both groups. Hormonal and biochemical parameters were not significantly different before and after dialysis in both groups. In IG the decrease in mean blood pressure, due to a reduction of SI, recognises in the inadequate response of myocardial contractility to volume subtraction, the genesis of its drop. Finally, impedance cardiography in uraemic patients helps to identify the factors that contribute to the impairment of cardiac performance and that should be studied before selecting new and advanced dialysis programmes.

Phosphatidylcholine does not affect peritoneal transport of intact rabbits.

Ultrafiltration and solute transport during 60-min peritoneal dialyses of normal rabbits with intraperitoneal administration of phosphatidylcholine were compared to control values. The ultrafiltration rate of 0.27 mL/Kg/min did not increase when phosphatidylcholine was added. This agent had no effect on the ultrafiltration coefficient, sodium mass transport or solute clearances. Previously reported beneficial results with this agent could be due to repletion of a deficiency or an effect of the organic solvent. More studies of safety and efficacy of phosphatidylcholine are warranted before widespread clinical use.

Prolonged intraperitoneal dwell decreases ultrafiltration coefficient in rabbits.

In rabbits undergoing peritoneal dialysis, hypertonic (6% dextrose) dialysis solution increased the net ultrafiltration rate (UF) from 233 to 462 microL/kg/min, which was not proportional to the increment in the osmotic gradient, so the ultrafiltration coefficient decreased. As intraperitoneal dwell of hypertonic dialysate was prolonged, the gross and net UFs and ultrafiltration coefficients decreased, and the UF per dextrose absorption declined. The decrement in UF was multifactorial, including a component of fluid and solute stagnation, increasing the distance over which osmotic forces must exert their effects. Excessively hypertonic dialysis fluid should be used only briefly to achieve ultrafiltration efficiently and to avoid the high dextrose loading.

Electrophysiological aspects of nervous conduction in uremia.

Some neurophysiological techniques have been employed in clinical nephrology to record abnormalities of nervous conduction in central and peripheral pathways. The electrical monitoring on the peripheral and central nervous systems has allowed the detection of uremic neural injury, the diagnosis of specific electrophysiological abnormalities, the evaluation of various treatments employed and the identification of those abnormalities that uremia can induce. A group of 156 subjects subdivided into four groups were examined: 100 healthy subjects (64 M, 36 F); 56 patients (21 glomerulonephritis, 14 pyelonephritis, 5 nephrolithiasis, 5 polycystic kidney, 4 nephroangiosclerosis, 7 undetermined) with chronic renal failure treated with a conventional low nitrogen diet (CLND, 0.6 g/kg b.w./d. of proteins), 8 of whom passed from CLND to a very low nitrogen diet supplemented with alpha-keto-analogues; a group of 22 of these 56 underwent a regular dialysis treatment for 12 to 15 hours/weekly for 40.5 +/- 10.2 months. Three patients of the CLND group and 13 patients underwent renal transplantation after a variable period of RDT. In the uremic patients we found different populations of motor unit potentials; a decreased MNCV was found in 35% of the CLND patients, RDT patients had slowed MNCV in 42%. The SNCV was compromised more frequently than the MNCV. An increased duration of evoked potentials was sometimes observed in CLND and RDT patients inducing us to consider this a hallmark of uremic syndrome. The alpha-keto-analogues and HD/HP treated patients showed an improvement in several features.(ABSTRACT TRUNCATED AT 250 WORDS)

The natural history of uremic neuropathy.

The results obtained by electrophysiological recording allow to discover the constant presence of alterations to the central and/or peripheral nervous system in the uremic syndrome. Thus, it becomes possible to demonstrate the existence of an actual 'uremic neuropathy'. Moreover, the results show the persistence and progression of uremic involvement in the course of dialytic treatment; only after kidney transplantation a return to normal takes place. Methodological and interpretative progress will allow us in the future to broaden our knowledge of uremia by providing a useful guide to therapeutic strategies.