Stromal development in the ventral prostate, anterior prostate and seminal vesicle of the rat

The prostate and seminal vesicle (SV) are androgen-dependent secretory glands of the male genital tract. They produce the bulk of the seminal secretions. The object of the present study was to examine and document the ontogeny of stromal maturation in the rat anterior and ventral prostate and SV. These organs have a loosely organized cellular mesenchyme during fetal development. During prostatic development the mesenchyme condensed to form smooth muscle sheaths immediately surrounding the epithelium, with looser connective tissue between individual ducts. In the SV, a loose connective tissue layer called the lamina propria lies between the epithelium and developing muscle. Smooth muscle alpha-actin, myosin, desmin, laminin, vinculin, vimentin and androgen receptor (AR) expression were examined by immunocytochemical methods during the pre- and postnatal developmental periods. The first marker to be detected was vimentin, which was initially found throughout the mesenchyme. During development vimentin became mostly restricted to the interductal tissue of the prostate and the lamina propria of the SV. Smooth muscle markers were expressed in an orderly sequence in a proximal to distal manner along prostatic ducts, from the urethra towards the tips. Expression of alpha-actin was followed by vinculin, myosin, desmin, and laminin. These markers became localized to the developing smooth muscle sheaths and were not expressed in the interductal tissue of the prostate or the lamina propria of the SV. Organ culture experiments demonstrated that androgens were required for the differentiation of smooth muscle sheaths. Castration of adult rats demonstrated that androgens were required to maintain smooth muscle differentiation. In castrates, the stroma was relatively thicker but less dense than in intact animals. Following castration, expression of the smooth muscle markers was lost sequentially in the reverse order of their expression during development. In long-term castrates alpha-actin, vimentin and a small amount of vinculin were detected. AR were first detected in the urogenital sinus mesenchyme immediately surrounding the epithelium at 16 days of gestation. As development progressed expression of AR became more widespread, and postnatally was found throughout the mesenchyme. As maturation of smooth muscle occurred, stromal expression of AR became localized to the muscular sheath immediately surrounding the epithelium. In the prostate the interductal connective tissue displayed very low levels of AR expression. In the SV, AR were also observed in the lamina propria. In summary, stromal differentiation and dedifferentiation in the rat prostate and SV were found to be androgen-dependent processes with ordered sequential ontogenic expression of specific markers.     

Malacoplakia of the prostate and seminal vesicle. Ultrastructural study and review of the literature

OBJECTIVES: The present study describes a case of malacoplakia of the genitourinary tract arising in the seminal vesicle and prostate and reviews similar cases previously reported in the literature. METHOD: A 67-year-old male consulted for hemospermia and voiding symptoms. Prostatic neoplasm was suspected on the basis of the clinical and radiological findings. RESULTS: The diagnosis was made only after biopsy and histological analysis. Electron microscopy is a very useful tool. Long-term antibiotic therapy may achieve optimal results. Treatment with fluoroquinolones was successful. CONCLUSION: To avoid unwarranted radical approaches, we underscore the possibility that prostatic pseudotumors may be misinterpreted as neoplasia. Malacoplakia is diagnosed only by histology and requires medical treatment.     

Multiple transrectal ultrasound-guided biopsies for the detection of prostate cancer and determination of tumor volume, grade, and seminal vesicle invasion

Of 60 cases of neurotoxicity related to occupational exposures of workers at plants producing acrylamide monomers, cases involving neurotoxicity related to jobs using polymers with acrylamide monomer contamination have not been widely reported. In 1992, two patients were referred to the Division of Occupational and Environmental Health, Department of Family and Community Health, Marshall University School of Medicine, in Huntington, West Virginia for evaluation. The patients had worked in different coal preparation plants in southern West Virginia for over 10 years and had exposure to an acrylamide polymer flocculent contaminated with acrylamide monomer. Both patients had no instruction on proper use of, or the dangers of, acrylamide and were not given adequate safety equipment. Patient A developed Parkinsonism and Patient B peripheral neuropathies with a neurogenic bladder. These two case reports highlight the need to reemphasize the basic tenets of occupational health and safety. Many chemicals are being introduced into mining operations and awareness of potential toxic exposures and new diseases not previously reported in the mining industry must become part of the surveillance system by mine management and labor safety committees. Further studies on the extent of acrylamide neurotoxicity in the mining industry is encouraged.     

Telomerase is activated in the prostate and seminal vesicles of the castrated rat

Telomeres, the repetitive non-coding DNA sequences found at the ends of all eukaryotic chromosomes, shorten with each cell division. It has been proposed that telomere shortening may be the counting element of a mitotic clock that keeps track of cell divisions; with shortening to a critical length acting as a senescence signal underlying cellular aging. The enzyme telomerase functions to maintain telomere length, thus allowing unlimited cell division, and has been associated with cellular immortalization and cancer. Stem cells have large, perhaps unlimited, replicative capacities. Since these cells are potentially immortal, we reasoned that they might posses active telomerase. We therefore assayed for telomerase activity in the stem cell enriched pools of the androgen-depleted sex accessory tissues in the castrated male rat. Following castration, the ventral prostate and seminal vesicles of the rat involute, losing approximately 90% of their cells by 21 days. These residual glands persist, and are enriched for stem cells, being capable of fully regenerating these glands if testosterone is re-introduced into the animal. We assayed telomerase activity in extracts from normal, involuted, and regenerating ventral prostate and seminal vesicles. Normal glands were found to be telomerase negative, whereas telomerase activity appeared as these glands involuted following castration. Conversely, telomerase activity disappeared during testosterone-induced regeneration of these residual glands. These results provide strong evidence for the ability of androgen to negatively-regulate telomerase activity in stem cell populations of the rat ventral prostate and seminal vesicles. and represent the first in vivo model system for the modulation of telomerase activity.     

A model to study c-myc and v-H-ras induced prostate cancer progression in the Copenhagen rat

Normal rat prostate epithelial cells (EPYP-1) were isolated and immortalized with the Simian Virus-40 (SV40) large T-antigen, and transfected with the v-H-ras (EPYP-1-ras) and the c-myc oncogenes (EPYP-1-myc; EPYP-1-ras-myc) to serially create a step-wise model of tumor development in the rat prostate. Pronounced morphological differences were observed between EPYP-1 and the transfected sublines. The immortal epithelial cells (EPYP-1) maintained a cuboidal shape with orderly, contact mediated inhibition of growth. Oncogene transfected clones displayed a spindle shaped structure with multiple overlapping pseudopodia. Transfected cells also exhibited a greater degree of dysplasia, loss of contact inhibition growth and the upregulation of an epithelial tumor marker, cytokeratin-18. All cells exhibited anchorage independent and androgen independent growth. In vivo, EPYP-1 cells and EPYP-1-myc and formed slowly growing non-metastatic, benign tumors in immune compromised mice, while EPYP-1-ras and EPYP-1-ras-myc transfected cells produced rapidly growing, malignant tumors in similar animals. This model augments the hypothesis that tumor initiation and progression can be caused by as few as two discrete genetic events. In addition, the "normal" rat prostate epithelium and transfected daughter cell lines represent a tumor model system with distinct, well understood genetic alterations: activation of ras and myc. This model will be a valuable addition to the current cell lines used in the investigation of prostate cancer carcinogenesis.     

International trends in the incidence of cervical cancer: I. Adenocarcinoma and adenosquamous cell carcinomas

The integrin alpha9beta1 is one of the recently identified integrins whose expression is restricted to specialized tissues. Its exact function is still unknown. In the present study, we have analyzed the expression of the alpha9 subunit in human fetal and adult small intestinal and colonic epithelia as well as in intestinal cell lines by indirect immunofluorescence, immunoprecipitation, Western blot, and Northern blot. In intact tissues, the antigen was restricted to the basolateral domain of epithelial cells in intestinal crypts at the fetal stage and was absent in the adult. The alpha9beta1 integrin was also detected in the intestinal cell lines HIEC-6 and Caco-2/15. The presence of alpha9beta1 in HIEC-6 was found to be consistent with their proliferative crypt-like status. In Caco-2/15 cells, the integrin was present at high levels in proliferating cells but was downregulated when cells cease to grow and undertake their differentiation. EGF treatment, which is known to maintain Caco-2/15 cells in a proliferative state, resulted in higher levels of alpha9 as compared to control cells. Taken together, these observations suggest a relation between integrin alpha9beta1 expression and proliferation in human intestinal cells.     

Effect of some synandrogens and antiandrogens on the conversion of testosterone to dihydrotestosterone in the cultured rat ventral prostate

Whereas defective interfering particles of Sindbis virus are readily produced in BHK-21 cells or chicken embryo fibroblasts by the techniques of serial undiluted passage, similar methods failed to generate such particles in Aedes albopictus cell cultures. In addition, Sindbis virus stocks produced in BHK-21 cells or chicken embryo fibroblasts and which contained defective interfering particles, when tested in A. albopictus cells, failed (i) to interfere with the replication of standard Sindbis virus and (ii) to change the pattern of intracellular viral RNA synthesis from that produced by infection with standard Sindbis virus alone. We conclude that defective interfering particles of Sindbis virus generated in chicken or hamster cells are silent or inert in mosquito cells.     

Determination of lung cancer incidence in the elderly using Medicare claims data

The Surveillance, Epidemiology, and End Results (SEER) program of the National Cancer Institute provides data for making national estimates of lung cancer incidence and for monitoring secular trends. The authors compared the number of cases of lung cancer and the incidence rates among elderly residents of the five states included in the SEER program in 1986-1987 with the number of incident cases identified and the rates calculated using hospitalization and enrollment data on elderly Medicare beneficiaries maintained by the Health Care Financing Administration (HCFA) for the same years. The SEER program state registries identified 5.9% more cases than did HCFA (p < 0.01). However, the overall rates were similar (274.2/100,000 population for SEER and 264.7/100,000 population for HCFA), as were the majority of the rates for the different demographic subgroups examined. Age-adjusted lung cancer incidence rates for 1986 through 1990 among elderly Medicare beneficiaries residing outside of all nine SEER areas were 8-13 percent higher than the rates calculated for SEER-area residents. This observation is supported by the existence of similar differences in the age-adjusted lung cancer mortality rates for 1979 through 1988 in the same populations. Because the SEER areas may not be representative of the entire nation for lung cancer incidence and HCFA data cover the entire country, the authors recommend using HCFA information to complement the SEER data system.     

Comparison between the binding of 19-nortestosterone, 5alpha-dihydrotestosterone and testosterone in rat prostate and bulbocavernosus/levator ani muscle

The metabolism of hydroxyproline was investigated in six healthy subjects and four patients with chronic renal insufficiency (creatinine clearances respectively 40, 10, 7, 2 1/2 ml/min). For this purpose hydroxy-DL-proline-2-(14)C was administered intravenously and the excretion patterns of radio-activity in plasma, urine and expired air (14CO2) were determined. A separation procedure (using thin layer chromatography followed by oxidation with D-amino acid oxidase) made it possible to determine the concentration of hydroxy-L-proline-2-(14)C in the presence of the D-isomer and the degradation products of both. Although the use of a racemic mixture as tracer made conclusions more difficult, it could be shown that in uremic patients the concentration of hydroxy-DL-proline -2-(14)C remained high in the blood for a longer period, the metabolites appeared in the urine later, and the peak respiratory 14CO2 excretion was reached later and was lower than in the healthy subjects. On this basis it was concluded that the metabolism of hydroxyproline is diminished in patients with renal insufficiency.     

Distribution and immunohistochemical characteristics of neurons in the porcine caudal mesenteric ganglion projecting to the vas deferens and seminal vesicle

The subperiosteal browlift and midface lift combination is a total mobilization of the composite full-thickness soft tissues from the bony skeleton with superior suspension. The object is to correct midfacial ptosis and the "tired" look of the lateral eyelids. It is done in conjunction with a browlift so that a composite correction of the upper and midface is achieved. When indicated, a modified lower cheeklift and the usual procedures for correcting neck deformities are utilized in combination. We believe the procedure is safe and the results reported are natural and long-lasting. This review of 130 cases also stresses technical aspects and the safety of the procedure.     

Development of esophageal metaplasia and adenocarcinoma in a rat surgical model without the use of a carcinogen

In order to establish an animal model for studying the cause and prevention of esophageal adenocarcinoma (EAC) and its frequent precursor, Barrett's esophagus (BE), factors affecting the pathogenic processes were investigated in an esophagoduodenal anastomosis model with rats. Experiments by us and others have shown that surgical treatment produced reflux esophagitis with cell hyperproliferation, but not EAC. Additional treatment with a carcinogen has been shown to be necessary for the development of EAC, squamous cell carcinomas (SCC) or EAC/SCC mixtures. We found that the surgically treated animals developed anemia due possibly to reduced iron absorption. When the operated animals were supplemented with iron, EAC occurred at a high rate (73%) after 30 weeks, and treatment with N'-nitrosonornicotine did not enhance the rate of tumorigenesis. Treatment with carcinogen, however, induced SCC in the group of rats killed after 22 weeks. The results suggest that iron overload, which is known to cause oxidative damage, is an enhancing factor for adenocarcinogenesis. The pathogenesis of EAC in the iron-supplemented, non-carcinogen treated group resembles human esophageal adenocarcinogenesis in many features. All the BE was the specialized type with goblet cells (containing sialomucin or sulfomucin) and columnar cells (containing acid or neutral mucin) as well as an incompletely developed brush border. Almost all of the BE was located at the bottom of the esophagus and was continuous with the duodenal mucosa; dysplasia became more frequent at later time points. All of the cancers were well-differentiated mucinous EAC, and most of the EAC had an adjacent area of BE with dysplasia. The results are consistent with the proposed human sequence for pathogenic events of BE progression to 'BE with dysplasia' and then to EAC. Esophagoduodenal anastomosis and iron treatment in rats produces a high rate of BE and EAC which are morphologically similar to human BE and EAC; this may be a useful animal model to study the development and prevention of EAC in humans.     

Analysis of PTEN and the 10q23 region in primary prostate carcinomas

Deletions involving chromosome 10q23 occur frequently in prostatic carcinomas. Recently, a novel tumour suppressor gene, PTEN, mapping to this interval, has been identified. Mutation or deletion of PTEN has been observed in a proportion of prostate cancer cell lines; however, primary prostate carcinomas have not been studied. We have investigated the involvement of PTEN in primary prostatic adenocarcinomas using a panel of 51 matched normal and prostate tumour DNAs. We first determined the proportion of tumours with allele loss at loci in 10q23 which span the region containing the PTEN gene. Our results show that LOH involving 10q23 is common in primary prostate carcinomas. Twenty-five of 51 (49%) tumours showed loss of heterozygosity (LOH) over the region spanning the PTEN locus. We next directly analysed the PTEN gene for mutations of the coding region using single strand conformation polymorphism (SSCP) and sequence analyses. Of those tumours with LOH, only a single tumour was found to carry a missense mutation in PTEN. No mutations in PTEN were identified in tumours without LOH. Our results suggest either that mutation of PTEN is a late event in prostate tumorigenesis, or that another tumour suppressor gene important in prostate cancer may lie close to PTEN in 10q23.     

A model for the effect of cigarette smoking on lung cancer incidence in Connecticut

Population based data on smoking history derived from NCHS surveys were used to develop a model for lung cancer incidence in Connecticut. Trends in smoking prevalence suggest that, while the prevalence in men increased earlier than women, more male smokers have quit than their female counterparts. These trends in smoking prevalence suggest striking gender differences in a period effect for the smoking prevalence. Estimates of the proportion of current smokers, ex-smokers, and the mean duration of smoking were used in a model for the lung cancer incidence rates. The form for the relationship between smoking history and the incidence rate for these subgroups was based on information from cohort studies. The models represented a mixture of the smoking subgroups where the effect of smoking was considered to be either a multiplicative effect on the underlying age distribution, or a separate effect in which the level of exposure was the sole contribution to risk among smokers. The multiplicative model explained more than 80 per cent of the deviance for the period and cohort effects, while the non-multiplicative model could only account for trends in females. Hence, these results suggest that a sizeable portion of the period and cohort contributions to the lung cancer incidence trends in Connecticut can be attributed to the multiplicative model that utilizes this smoking information, although the lack of more detailed information is a limiting factor in developing the model.     

Influence of N-methyl-N-nitrosourea, testosterone, and N-(4-hydroxyphenyl)-all-trans-retinamide on prostate cancer induction in Wistar-Unilever rats

The influence of chemical carcinogen, hormonal stimulation, and chronic dietary administration of the synthetic retinoid, N-(4-hydroxyphenyl)-all-trans-retinamide (4-HPR), on the induction of prostate cancer in male Wistar-Unilever rats was determined. Three different tumor induction regimens were used: (a) a single i.v. dose of 50 mg of N-methyl-N-nitrosourea (MNU) per kg body weight, followed by chronic androgen stimulation via s.c. implantation of two silastic capsules containing 40 mg testosterone each; (b) a single i.v. dose of 50 mg of MNU per kg body weight (no testosterone treatment); and (c) chronic androgen stimulation with implanted testosterone capsules (no MNU treatment). In a fourth series of animals, the incidence of spontaneous prostate tumors was determined in groups of rats receiving neither carcinogen nor hormone stimulation. Within each series, parallel groups of animals were fed a control (vehicle-supplemented) diet or control diet supplemented with 4-HPR beginning 1 day after carcinogen administration; retinoid administration was continuous until termination of the study at 450 days. The incidence of accessory sex gland cancer in rats treated sequentially with MNU + testosterone was >60%, in comparison with cancer incidences of <20% in rats receiving MNU only and <5% in rats treated with testosterone only. No spontaneous accessory sex gland tumors were observed in rats receiving no carcinogen and no testosterone. Tumor induction in the accessory sex glands by MNU + testosterone was relatively specific for the prostate: the incidence of carcinoma of the dorsolateral/anterior prostate was more than 5-fold greater than the incidence of cancer present only in the seminal vesicle. 4-HPR conferred no protection against cancer induction in the prostate by any regimen of MNU and/or testosterone. These results demonstrate the importance of both carcinogen exposure and hormone stimulation on the induction of neoplasia in the prostate of Wistar-Unilever rats.     

Detection of circulating tumor cells in patients with prostate cancer using prostate specific membrane-derived primers in the polymerase chain reaction

Angiotensin-converting enzyme (ACE) is known to play an important role in the pathobiology of human essential hypertension. Similarly, cis-unsaturated fatty acids, prostaglandins, and free radicals are believed to play a role in the control of blood pressure. It was observed that all the cis-unsaturated fatty acids tested can inhibit ACE activity to a significant degree. On the other hand, prostaglandins and free radicals, superoxide anion, hydrogen peroxide, and hydroxyl radical did not show significant inhibitory effects on ACE activity in vitro. But, the nitric oxide donor sodium nitroprusside showed a potent inhibitory action on ACE activity, suggesting that one of the possible mechanism(s) by which nitric oxide can bring about its anti-hypertensive action might be by modulating ACE activity in addition to its direct vasodilator action. These results indicate that there is a close interaction among ACE activity, cis-unsaturated fatty acids, and nitric oxide, which may have relevance to the pathobiology of human essential hypertension.     

The role of prostate-specific antigen (PSA) testing patterns in the recent prostate cancer incidence decline in the United States

OBJECTIVES: Trends in first-time and later PSA procedure rates are ascertained using longitudinal data from a population-based cohort. These trends are compared to trends in prostate cancer incidence to determine the role of PSA in the recent decline in prostate cancer incidence. METHODS: Medicare data were linked with tumor registry data from the National Cancer Institute's Surveillance, Epidemiology, and End Results (SEER) Program. A 5 percent random sample (n = 39985) of Medicare beneficiaries from the SEER areas without a previous diagnosis of prostate cancer as of January 1, 1988 was followed through 1994. Trends in first-time PSA use were distinguished from those of second or later for men without diagnosed prostate cancer. RESULTS: Trends in the rate of first-time PSA procedures track closely with trends in prostate cancer incidence rates, increasing until 1992 and decreasing thereafter. Similar patterns were observed by race and age group. Geographic variability in the dissemination of PSA screening was observed, yet the association between testing and incidence remained. Men in the cohort had a 4.7 percent chance of being diagnosed within three months of an initial PSA test, with the percentage falling for subsequent tests. CONCLUSIONS: It is informative to distinguish first from later tests when assessing the effect of the diffusion of a test in a population. Taking this approach was useful in illuminating the role of PSA testing in a reversal of a long-term increase in prostate cancer incidence rates.     

Some ultrastructural effects of testosterone and insulin on the ventral prostate of rats in organ culture

The fine structure of the secretory epithelial cells of rat's ventral prostate has been studied following organ culture. Culturing with either testosterone or insulin alone, and with the two hormones combined, were carried out to investigate how insulin modifies the action of testosterone on the maintenance of cellular integrity. After 4 days in hormone-free culture, the secretory epithelial cells showed signs of cellular atrophy and regression, involving loss of the apical microvilli, absence of the apical secretory vacuoles, atrophy of the Golgi apparatus, decrease in rough endoplasmic reticulum and the appearance of autophagic vacuoles. The presence in the medium of either testosterone or insulin alone, or combined, prevented cellular atrophy and regression. The best maintenance of cellular integrity was obtained in a culture containing both hormones. The effects of insulin was approximately equivalent to those of testosterone in the maintenance of cellular integrity.     

Usefulness of ultrasound-guided prostate biopsy in the diagnosis and treatment of localized prostate cancer

OBJECTIVE: To evaluate the safety and efficacy of stapled anastomosis in left sided colorectal reconstructions. DESIGN: Prospective study. SETTING: District hospital, UK. SUBJECTS: 218 Consecutive patients who underwent elective colorectal reconstructions with stapled anastomoses between July 1980 and July 1994. INTERVENTIONS: 154 Anterior resections of the rectum using single or double stapled anastomoses, 37 rejoining after Hartmann's operations, and 28 restorative proctocolectomies with formation of J pouch ileoanal anastomoses. MAIN OUTCOME MEASURES: Morbidity and mortality. RESULTS: There were 5/154 clinical anastomotic leaks after anterior resection of the rectum and 1/28 after stapled J pouch ileoanal anastomoses. There were no leaks after rejoining of Hartmann's. The overall clinical leak rate was therefore 3%. 11/154 tumours recurred locally after anterior resection of the rectum (7%) during a mean follow up of 18 months, and 8 (73%) developed within 2 years of operation. All but one recurrence developed after single stapled anastomosis. Dukes' staging remains the most reliable prognostic indicator of the local recurrence of the tumour. There were five postoperative deaths after anterior resection but none after Hartmann's procedure or J pouch ileoanal anastomosis, giving an overall postoperative mortality of 2.3%. CONCLUSION: The use of stapling instruments in left sided colorectal anastomosis is safe and technically easy, with a low clinical anastomotic leak rate and an acceptable rate of local recurrence after anterior resection of the rectum.