Further characterization of a model system for the study of human epididymal physiology and its relation to sperm maturation.

Some preliminary speculations about the possible participation of epididymal antigens in sperm function may be supported by the above data. On the one hand, the reduction in the amount of antigens and their abnormal localization on spermatozoa from infertile patients may be coincident with our view about participation of epididymal antigens in the development of zona pellucida binding ability and fertilizing capacity by spermatozoa during maturation. This hypothesis is derived from experiments showing that immature hamster spermatozoa gain their ability to recognize and bind to zona pellucida and to penetrate homologous oocytes when exposed to preparations enriched in androgen-dependent epididymal secretory proteins or preincubated in conditions that favor their interaction with these proteins. Supporting our viewpoint for such a role in humans is evidence showing the progressive development of the ability to interact with hamster denuded oocytes as human spermatozoa pass along the epididymis. On the other hand, the apparent correlation between the loss of epididymal antigens during capacitation and the increased fertilization of human oocytes in vitro may be reminiscent of the removal of a decapacitation or acrosome stabilizing factor known to occur in many species and that must be removed prior to fertilization. Pending further understanding of their physiological role, the androgen-dependent epididymal proteins may become a useful marker of epididymal function and/or of sperm capacitation in humans. Within this context, we wish to stress the potential value of the model system that we have developed for the study of human epididymal physiology.

Induced hypoprolactinemia and testicular steroidogenesis in man.

The effects of short-term hypoprolactinemia on the pituitary-gonadal axis were evaluated in a group of patients with untreated prostatic carcinoma. Each patient was studied prior to and during 7-day oral administrations of bromocriptine (2.5 mg q.i.d.). Serum LH, prolactin (PRL), androst-4-ene-3,17 dione (androstenedione), testosterone, and 5 alpha-androstane-3 alpha, 17 beta-diol (5 alpha-Diol) levels, as well as intra-testicular testosterone, dihydrotestosterone (DHT), 5 alpha-Diol and zinc (Zn) concentrations, were determined. Daily administration of bromocriptine caused a marked suppression of serum PRL (mean +/- SEM, 23.8 +/- 2.5 vs. 6.4 +/- 1.0 ng/ml) without concomitant changes in serum LH levels (mean +/- SEM, 8.3 +/- 1.6 vs. 8.9 +/- 2.1 ng/ml). Hypoprolactinemia induced a significant decrease (P less than 0.05) in the mean peripheral testosterone levels; but 5 alpha-Diol and androstenedione remained unchanged. However, in testicular tissues, bromocriptine treatment resulted in significant increases in mean concentrations of total androgens (P less than 0.001), testosterone (P less than 0.001) and DHT (P less than 0.02). Testicular levels of 5 alpha-Diol were not significantly altered. There was no change in Zn levels in basal conditions and during bromocriptine administration. These results indicate that short-term suppression of serum PRL levels in man affects basal testicular function without altering serum LH. However, a direct action of bromocriptine on the human gonad cannot be excluded.

L-dopa malabsorption in a parkinsonian patient with Strongyloides stercoralis duodenitis.

We report a parkinsonian patient initially responding to L-dopa who developed a severe loss of drug efficacy due to Strongyloides stercoralis duodenitis. The patient was put on mebendazole and metronidazole, and the parasitosis abated, allowing L-dopa reduction by 33%. Our patient illustrates the advisability of searching for Strongyloides stercoralis when L-dopa malabsorption is suspected in Parkinson's disease.

Prostanoid production in endothelial and Kupffer liver cells from monocrotaline intoxicated rats.

UNLABELLED: A single dose of monocrotaline, a pyrrolizidine alkaloid, was injected into rats in order to produce 25 (Group I) and 45 (Group II) days later a progressive and so called delayed liver injury. The present study investigated the prostanoid production of Kupffer cells and endothelial cells separated from Monocrotaline and saline (Group III) injected rat livers. Kupffer cells: formation of 6 keto Prostaglandin F1 alpha, the major prostacycline metabolite, gradually decreased in Groups I vs II (P < 0.01) and in both Groups I and II vs Controls (P < 0.01). In addition Prostaglandin F2 alpha showed a significant increase in Groups I and II when compared to Group III, (P < 0.001), and Thromboxane B2 was present in both Groups of Monocrotaline treated animals, while it was not detectable in the control Group III. Endothelial cells: 6 keto Prostaglandin F1 alpha decreased in Groups 1 vs II. This differences was significant when compared, and compared to controls (Group III, P < 0.001). Prostaglandin E2 was detected only in Groups I and II. Prostaglandin F2 alpha and Thromboxane B2 could not be detected in any Group. Ultramicroscopy showed morphological cell damage in nonparenchymal cells in Monocrotaline intoxication in Group II, rats sacrificed 45 days after the injection, while it shows normal features in those treated animals sacrificed 25 days after the injection, as well as in control group. CONCLUSION: A single Monocrotaline injection produces, 25 and 45 days later, severe and progressive alterations in the prostanoid production in Kupffer and Endothelial cells, while ultramicroscopic alterations was only observed 45 days after the injection of Monocrotaline. A decreased production of vasodilators and the presence of vasoconstrictor prostanoids that can participate in the production of the circulatory derangements enhancing liver injury and portal hypertension were also observed.

[Functional alterations in central nervous system of prehepatic portal hypertensive rats]. / Cambios funcionales en el sistema nervioso central de ratas hipertensas portales prehepaticas.

Prehepatic Portal Hypertension (PH) leads to morphologic changes in the rat Central Nervous System, including alterations of the blood brain barrier (BBB), and astrogliosis and angiogenesis in CA1 and CA4 hyppocampal fields. The present study investigates functional changes in portal hypertensive rats. Wistar Kyoto rats were used (240 g/bw) and allotted in two groups: GI (n = 8) portal hypertensive rats obtained through a regulated stenosis of the portal vein (Groszmann), and GII (n = 6), sham-operated rats. We have analyzed: BBB integrity with the Trypan Blue diffusion method (TB, Reynolds), protein concentration (PC) in Cerebrospinal Fluid (CSF) and plasma (Bradford method), electroencephalographic activity (EEG), cerebral edema expressed as brain water content (gravidimetric test), and behavior: Animex, righting reflex, pain reflex and Rotarod. TB was positive in GI in peripheral vascular areas in hippocampus, PC in CSF (ug/ml)(mean +/- SED) was GI: 40.6 +/- 6.8 and GII: 16.5 +/- 4.2 (p < 0.005), and the plasma levels were (mg/ml): GI: 108.8 +/- 7.6 and GII: 87.4 +/- 2 (NS). The EEG showed a higher power of the delta band in hypertensive rats (GI: 0.551 +/- 0.033 and GII: 0.342 +/- 0.031, p < 0.008), but water content was not different between GI and GII (water%/per/g/tissue) (GI: 79.21 +/- 0.2, GII: 78.95 +/- 0.18). These results, showing functional changes in the BBB and brain activity without behavioral alterations, suggest the development of a subclinic form of hepatic encephalopathy in our model of PH rats.

[Does TNF-alpha contribute to liver disease physiopathology?]. / Contribuye el TNF-alpha a la fisiopatología de las hepatopatías?

The aim of the present paper is to establish the possible role of serum TNF in the pathophysiology of three experimental models of liver injury: paracetamol intoxication, cholestasis followed by paracetamol intoxication and cholestasis. We concluded that under our experimental conditions the serum TNF-alpha levels were not responsible for the inflammatory phenomena described in our previous paper as apoptosis.

[Benzodiazepines metabolism in various models of experimental liver diseases]. / Metabolismo de benzodiacepinas en distintos modelos de hepatopatías experimentales.

The aim of the present paper is to establish possible disturbances in benzodiazepines glucuronidation in two experimental models of liver injury: paracetamol acute intoxication and cholestasis followed by paracetamol acute intoxication. We concluded that, despite the alterations observed in liver microsomal lipid profile, glucuronidation remained similar to controls in paracetamol intoxicated rats. On the contrary, cholestatic animals followed by paracetamol intoxication showed an increment in the glucuronidation of the utilized substrated.

Glutathione-S-transferase (GST) polymorphisms are associated with relapse after radical prostatectomy.

BACKGROUND: Organ confined prostate cancer (PCa) can be cured by radical retropubic prostatectomy (RRP); however, some tumors will still recur. Current tools fail to identify patients at risk of recurrence. Glutathione-S-transferases (GSTs) are involved in the metabolism of carcinogens, hormones and drugs. Thus, genetic polymorphisms that modify the GST activities may modify the risk of PCa recurrence. METHODS: We retrospectively recruited Argentine PCa patients treated with RRP to study the association between GST polymorphisms and PCa biochemical relapse after RRP. We genotyped germline DNA in 105 patients for: GSTP1 c.313A>G (p.105 Ile>Val, rs1695) by PCR-RFLP; and GSTT1 null and GSTM1 null polymorphisms by multiplex PCR. Kaplan-Meier curves and Cox proportional hazard models were used to evaluate these associations. RESULTS: Patients with GSTP1 c.313GG genotype showed shorter biochemical relapse-free survival (BRFS) (P = 0.003) and higher risk for recurrence in unadjusted (Hazard ratio (HR) = 3.16, 95% confidence interval (95% CI) = 1.41-7.06, P = 0.005) and multivariate models (HR = 3.01, 95% CI = 1.13-8.02, P = 0.028). We did not find significant associations for GSTT1 and GSTM1 genotypes. In addition, we found shorter BRFS (P = 0.010) and increased risk for recurrence for patients having two or more risk alleles when we combined the genotypes of the three GSTs in multivariate models (HR = 3.06, 95% CI = 1.20-7.80, P = 0.019). CONCLUSIONS: Our results give support to the implementation of GSTs genotyping for personalized therapies as a novel alternative for PCa management for patients who undergo RRP. To the best of our knowledge, this is the first study that examined GST polymorphisms in PCa progression in Argentine men. Replication of our findings in larger cohort is warranted.

Sex hormone binding globulin in arterial, and in peripheral, hepatic, renal and spermatic venous blood of children and adults.

Human sex hormone binding globulin (SHBG) was measured in arterial serum and in serum obtained from different venous territories. In 6 children, SHBG ranged from 44.4 +/- 4.8 (mean +/- SD) in arterial blood to 55.3 +/- 5.3 in the hepatic vein (P less than 0.01), while it did not change significantly in renal or peripheral tissue venous blood. In 6 male adults, no significant arteriovenous differences were found either in the peripheral tissues or in the splanchnic circulation. In the spermatic vein of 8 subjects, SHGB was significantly lower (17.1 +/- 5.7) than in the arterial blood (22.8 +/- 7.5), P less than 0.025. The arterio-venous difference found in the splanchnic circulation of children supports the hepatic origin of SHBG, and also suggests extra-hepatic clearance of the binding globulin. Testicular uptake of SHBG might be necessary to regulate delivery of androgens to Sertoli cells in the seminiferous tubules.

[Correlation between prostate specific antigen and histopathologic findings in ileum-obturator node dissection]. / Correlación entre el antígeno prostático específico y los hallazgos histopatológicos de la linfadenectomía ilioobturatriz.

OBJECTIVE: To determine the correlation between PSA values and the histopathological findings of ileo-obturator node dissection in prostatic cancer. METHODS: We reviewed the data of 51 patients with clinically localized prostatic carcinoma, submitted to ileo-obturator node dissection before definitive treatment of the tumor. The patients were classified into 4 groups according to their previous PSA values: A < 10 ng/ml, B > 10 and < 20 ng/ml, C > 20 and < 50 ng/ml and D < 50 ng/ml. RESULTS: Overall 17.6% of the patients had positive lymph nodes; 9.9% of the patients in group A, 15.4% of the patients in group B, 11.1% of those in group C and 41.7% of those in group D had positive nodes. Using 50 ng/ml as the cut-off point, 10% of those with PSA < 50 ng/ml had positive nodes vs 42.3% of those with PSA > 50 ng/ml, which was statistically significant with the Fischer test. CONCLUSION: Preoperative PSA has a statistically significant correlation with positive nodes, considering 50 ng/ml as the cut-off point. PSA determination in patients that have received no treatment is essential in the diagnosis and evaluation of therapy in prostate cancer.

[Correlation between specific prostatic antigen and findings with total body bone scintigraphy]. / Correlación entre el antígeno prostático específico (P.S.A.) y los hallazgos del centellograma óseo corporal total (COCT).

OBJECTIVES: To analyze the correlation between PSA values, bony symptoms and total body bone scintiscanning in order to determine the utility of the latter technique in patients with adenocarcinoma of the prostate. METHODS: We analyzed the correlation between the PSA values, bony symptoms and total body bone scintiscan findings of 191 patients with adenocarcinoma of the prostate; of these, 129 patients met the criteria for inclusion into the study. RESULTS: Of the 128 patients, 32 (25%) had PSA value < 20 ng/ml, 48 (37.5%) had values ranging from 20-50 ng/ml and 48 (37.5%) had values > 50 ng/ml. The bone scintiscan was positive in only one of the 32 patients with PSA < 20 ng/ml, 45.8% of those with PSA values between 20-50 ng/ml and 70.8% of those with PSA values > 50 ng/ml. All of the patients with PSA < 20 ng/ml and no bony symptoms had a negative bone scintiscan. All patients with PSA > 20 ng/ml and bony symptoms had a positive bone scintiscan. CONCLUSIONS: PSA is a biological marker that can effectively predict the scintiscan findings. The bone scintiscan was negative in 96.9% of the patients with PSA < 20 ng/ml. Total body bone scintiscanning can therefore be obviated in patients with PSA < 20 ng/ml and no bony symptoms, thereby reducing health costs without altering the benefits.

[Correlation between computed axial tomography and ileum obturating lymphadenectomy in localized adenocarcinoma of the prostate]. / Correlación entre tomografía axial computada y linfadenectomía ileoobturatriz en el adenocarcinoma de próstata localizado.

OBJECTIVE: To correlate the findings of CT and ileoobturator lymphadenectomy in patients with localized adenocarcinoma of the prostate. METHODS: 94 patients with adenocarcinoma of the prostate were evaluated. Ileoobturator lymphadenectomy and brachytherapy were performed in 61.1%, radical prostatectomy in 22.5% and lymphadenectomy with prostatic labeling for subsequent external radiation therapy in 5%. Lymph node CT and pathology findings were correlated. RESULTS: Of 92 patients with a normal CT scan, 18 had positive nodes and 19.1% were understaged. Two patients with a CT scan suggestive of metastatic adenopathy had negative pathology findings. Seventy-two of the 92 patients with normal CT scans had negative nodes, accounting for a specificity of 76.6%. CONCLUSION: Pelvic lymph node involvement changes the prognosis of prostate cancer. However, the ability of CT to detect lymph node metastasis is limited. It is therefore not a reliable method and raises the costs of staging unnecessarily.

Increased recovery of androgen receptors from human prostate through the use of mersalyl: evidence for androgen regulation of the binding sites in carcinomatous prostate.

With a technique adapted for needle biopsies from human prostate, androgen receptors have been quantitated in normal, hyperplastic, and carcinomatous samples. An important improvement in the yield of cytosol specific binding sites was obtained when samples were pre-incubated with the mercurial reagent mersalyl, which dissociates endogenously bound hormone receptor complexes, before the binding assay with 3H-methyltrienolone (3H-R1881). Androgen receptors in normal prostate tissue were found to be highest (7.81 +/- 1.12 pmoles/g tissue), and significantly different from hyperplastic prostate (2.02 +/- 0.55 pmoles/g tissue, p less than 0.025), but not from carcinomatous samples (4.47 +/- 0.79 pmoles/g tissue). Mean values for hyperplastic and carcinoma were not statistically distinguishable (p less than 0.1). The clinical response to hormone therapy in 85% of 13 patients with prostatic adenocarcinoma reflected the prostatic androgen receptor content. Orchidectomy followed by estrogen administration for several months leads to a dramatic fall (8-fold) in total androgen receptors in carcinomatous prostate, while estrogen alone did not seem to produce a significant effect. These preliminary data suggest that androgen could directly regulate its binding sites, as demonstrated earlier for other animal target organs.

Androgen metabolism in the human epididymis. Effect of in vivo estrogen administration.

Androgen metabolism in human epididymis was studied by incubating tissue fragments with isotopically labeled testosterone (T) and androstenedione (A) under batch and superfusion conditions. Epididymides were obtained from 16 patients with prostatic cancer, 5 of them treated with diethylstilbestrol (2.5 mg/d) for several months prior to castration. Results from batch incubations with [3H]T (100 nM) for 2 h at 25 degrees C indicated a markedly lower 5 alpha-reductase activity in tissues from estrogen-treated patients, as evaluated by measuring the amounts of radioactive 5 alpha-dihydrotestosterone, 5 alpha-androstanediols and 5 alpha-androstanedione present in tissue and medium at the end of the incubation period. Superfusion experiments confirmed this estrogen effect and also showed a shift of the interconversion between A and T towards the reductive direction and a diminished tissue retention of DHT after estrogen treatment. These effects may contribute to the marked regression of the epididymal epithelium that was noted in the estrogen-treated patients, which is thought to be mainly the result of the inhibition of androgen biosynthesis caused by chemical hypophysectomy.

[Intratubular neoplasm adjacent to germ cell tumor of the testis]. / Neoplasia intratubular adyacente a tumor germinal de testículo.

Because intratubular germ cell neoplasia (IGCN) is considered to be a precursor of testicular cancer, precise identification of this tumor type is important. The present study was undertaken to determine the cytological features of IGCN, its histological classification, and its incidence relative to other invasive germ cell tumors. We studied the biopsy specimens from a similar number of patients. The biopsy material was fixed in formol and embedded in paraffin. Sections were processed and analyzed with the hematoxylin-eosin and PAS stainings methods with and without diastase. IGCN classification was performed following the criteria recommended at the International Symposium on Testicular Cancer (Minneapolis, 1980). IGCN was recognized in 22 (26%) of the 85 biopsies and presented the following characteristic features; large cells with hyperchromatic nuclei, one or more nucleoli and abundant cytoplasm. Glycogen was present in most of the lesions but not in controls. In 12 patients (54.5%), the cytological anomaly was observed in the periphery of the tubules without the characteristic features of germ cell tumors. This lesion type was termed "unclassified". In 5 cases (22.7%), the tubule lumen was filled with atypical cells with round nucleus, scant chromatin, prominent nucleolus and scant cytoplasm. This variety was termed "intratubular seminoma". In 2 cases (9%) the intratubular lesion revealed large cells with pleomorphic nucleus and central necrosis. This variety was called "intratubular embryonal carcinoma".(ABSTRACT TRUNCATED AT 250 WORDS)

The effect of in vitro androgen stimulation upon androgen metabolism and trophic parameters in cultured human epididymis.

Previous results obtained with a model system of human epididymal tubules maintained in organ culture suggested that androgenic stimulation of this tissue resulted in responses similar to those obtained in epididymides of experimental animals under physiological conditions, as well as in other human androgen-dependent tissues. In this instance we have explored the possible influence of androgens on the activity of the androgen-converting enzymes 5 alpha-reductase and 17 beta-dehydrogenase. Activity of the former enzyme increases significantly during the culture period but no differences were found among the cultured groups, regardless of the addition of androgen. On the other hand, the activity of 17 beta-dehydrogenase was unchanged in all the experimental conditions tested. The co-culture of the tissue with explants of human testis was without effect. More than 85% of the activity of both enzymes was found localized in a fraction enriched in epithelial cells. Histological observation of the cultured tissues showed a marked disorganization of the pseudostratified epithelium in the absence of androgen while the inclusion of DHT in the media partially prevented these changes. We conclude that, under the conditions employed in these experiments, the activity of the enzymes studied is not influenced by androgens.